0	30849994	TFE3 fusions escape from controlling of mTOR signaling pathway and accumulate in the nucleus promoting genes expression in Xp11.2 translocation renal cell carcinomas Xp11.2 translocation renal cell carcinoma (tRCC) is mainly caused by translocation of the TFE3 gene located on chromosome Xp11.2 and is characterized by overexpression of the TFE3 fusion gene.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (187, 207))	('RCC', 'Disease', (210, 213))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 207))	('translocation renal cell carcinomas', 'Disease', 'MESH:C538614', (130, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('TFE3', 'Gene', (256, 260))	('mTOR', 'Gene', (40, 44))	('TFE3', 'Gene', (0, 4))	('translocation renal cell carcinomas', 'Disease', (130, 165))	('signaling pathway', 'biological_process', 'GO:0007165', ('45', '62'))	('TFE3', 'Gene', '7030', (256, 260))	('TFE3', 'Gene', (341, 345))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('TFE3', 'Gene', '7030', (0, 4))	('nucleus', 'cellular_component', 'GO:0005634', ('85', '92'))	('translocation renal cell carcinoma', 'Disease', (173, 207))	('TFE3', 'Gene', '7030', (341, 345))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 164))	('mTOR', 'Gene', '2475', (40, 44))	('Xp11.2', 'Var', (166, 172))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (144, 165))	('chromosome', 'cellular_component', 'GO:0005694', ('277', '287'))
3	30849994	The purpose of this study was to investigate the pathogenic mechanism of TFE3 fusions in tRCC based on its subcellular localization, nuclear translocation and transcriptional activity.	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('TFE3', 'Gene', '7030', (73, 77))	('fusions', 'Var', (78, 85))	('localization', 'biological_process', 'GO:0051179', ('119', '131'))	('TFE3', 'Gene', (73, 77))	('RCC', 'Disease', (90, 93))
6	30849994	The transcriptional activity of TFE3 fusions was measured using a luciferase reporter assay and ChIP analysis.	('TFE3', 'Gene', '7030', (32, 36))	('TFE3', 'Gene', (32, 36))	('transcriptional activity', 'MPA', (4, 28))	('fusions', 'Var', (37, 44))
7	30849994	In some experiments, TFE3 fusions were depleted by RNAi or gene knockdown.	('depleted', 'NegReg', (39, 47))	('TFE3', 'Gene', '7030', (21, 25))	('gene knockdown', 'Var', (59, 73))	('TFE3', 'Gene', (21, 25))	('RNAi', 'biological_process', 'GO:0016246', ('51', '55'))
9	30849994	Our results demonstrated that TFE3 fusions were overexpressed in tRCC with a strong nuclear retention irrespective of treatment with an mTORC1 inhibitor or not.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('mTORC1', 'Gene', '382056', (136, 142))	('overexpressed', 'PosReg', (48, 61))	('mTORC1', 'Gene', (136, 142))	('TFE3', 'Gene', (30, 34))	('retention', 'biological_process', 'GO:0051235', ('92', '101'))	('TFE3', 'Gene', '7030', (30, 34))	('mTORC1', 'cellular_component', 'GO:0031931', ('136', '142'))	('RCC', 'Disease', (66, 69))	('nuclear retention', 'CPA', (84, 101))	('fusions', 'Var', (35, 42))
10	30849994	TFE3 fusions lost its co-localization with lysosomal proteins and decreased its interaction with the chaperone 14-3-3 proteins in UOK109 and UOK120 cells.	('lysosomal proteins', 'Protein', (43, 61))	('TFE3', 'Gene', '7030', (0, 4))	('lost', 'NegReg', (13, 17))	('decreased', 'NegReg', (66, 75))	('UOK109', 'Chemical', '-', (130, 136))	('fusions', 'Var', (5, 12))	('interaction', 'Interaction', (80, 91))	('localization', 'biological_process', 'GO:0051179', ('25', '37'))	('TFE3', 'Gene', (0, 4))	('co-localization', 'MPA', (22, 37))
11	30849994	However, the fusion segments of TFE3 could not translocate to the nucleus and inhibition of Gsk3beta could increase the cytoplasmic retention of TFE3 fusions.	('TFE3', 'Gene', (145, 149))	('TFE3', 'Gene', (32, 36))	('cytoplasmic', 'MPA', (120, 131))	('inhibition of Gsk', 'biological_process', 'GO:1902948', ('78', '95'))	('increase', 'PosReg', (107, 115))	('Gsk3beta', 'Gene', '2932', (92, 100))	('nucleus', 'cellular_component', 'GO:0005634', ('66', '73'))	('inhibition', 'Var', (78, 88))	('Gsk3beta', 'Gene', (92, 100))	('TFE3', 'Gene', '7030', (145, 149))	('Gsk', 'molecular_function', 'GO:0050321', ('92', '95'))	('TFE3', 'Gene', '7030', (32, 36))	('retention', 'biological_process', 'GO:0051235', ('132', '141'))
12	30849994	Both the luciferase reporter assay and ChIP analysis demonstrated that TFE3 fusions could bind to the promoters of the target genes as a wild-type TFE3 protein.	('TFE3', 'Gene', '7030', (147, 151))	('bind', 'Interaction', (90, 94))	('fusions', 'Var', (76, 83))	('TFE3', 'Gene', (71, 75))	('protein', 'cellular_component', 'GO:0003675', ('152', '159'))	('TFE3', 'Gene', (147, 151))	('TFE3', 'Gene', '7030', (71, 75))
14	30849994	The ChIP-seq data further verified that, in addition to lysosomal genes, TFE3 fusions could regulate genes involved in cellular responses to hypoxic stress and transcription.	('hypoxic stress', 'Disease', 'MESH:D004194', (141, 155))	('TFE3', 'Gene', '7030', (73, 77))	('hypoxic stress', 'Disease', (141, 155))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('regulate', 'Reg', (92, 100))	('fusions', 'Var', (78, 85))	('TFE3', 'Gene', (73, 77))
15	30849994	Our results indicated that the overexpressed TFE3 fusions were capable of escaping from the control by the mTOR signaling pathway and were accumulated in the nucleus in UOK109 and UOK120 cells.	('UOK109', 'Chemical', '-', (169, 175))	('TFE3', 'Gene', '7030', (45, 49))	('mTOR', 'Gene', (107, 111))	('nucleus', 'cellular_component', 'GO:0005634', ('158', '165'))	('mTOR', 'Gene', '2475', (107, 111))	('overexpressed', 'PosReg', (31, 44))	('fusions', 'Var', (50, 57))	('accumulated', 'PosReg', (139, 150))	('signaling pathway', 'biological_process', 'GO:0007165', ('112', '129'))	('TFE3', 'Gene', (45, 49))
16	30849994	The nuclear retention of TFE3 fusions promoted the expression of lysosomal genes and other target genes, facilitating cancer cell resistance against an extreme environment.	('cancer', 'Disease', (118, 124))	('TFE3', 'Gene', '7030', (25, 29))	('facilitating', 'PosReg', (105, 117))	('nuclear retention', 'CPA', (4, 21))	('fusions', 'Var', (30, 37))	('retention', 'biological_process', 'GO:0051235', ('12', '21'))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lysosomal genes', 'Gene', (65, 80))	('expression', 'MPA', (51, 61))	('TFE3', 'Gene', (25, 29))	('promoted', 'PosReg', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
26	30849994	Conversely, when nutrients are scarce, inactivation of mTORC1, together with Ser321 dephosphorylation, prevents TFE3 proteins from binding to 14-3-3, resulting in the rapid accumulation of TFE3 in the nucleus.	('TFE3', 'Gene', '7030', (189, 193))	('dephosphorylation', 'biological_process', 'GO:0016311', ('84', '101'))	('nucleus', 'cellular_component', 'GO:0005634', ('201', '208'))	('mTORC1', 'cellular_component', 'GO:0031931', ('55', '61'))	('mTORC1', 'Gene', '382056', (55, 61))	('TFE3', 'Gene', (112, 116))	('Ser321', 'Chemical', '-', (77, 83))	('binding', 'Interaction', (131, 138))	('Ser', 'cellular_component', 'GO:0005790', ('77', '80'))	('TFE3', 'Gene', (189, 193))	('binding', 'molecular_function', 'GO:0005488', ('131', '138'))	('prevents', 'NegReg', (103, 111))	('accumulation', 'PosReg', (173, 185))	('inactivation', 'Var', (39, 51))	('TFE3', 'Gene', '7030', (112, 116))	('mTORC1', 'Gene', (55, 61))
34	30849994	We found that highly overexpressed TFE3 fusions showed strong nuclear accumulation in Xp11.2 tRCCs and were capable of escaping from the control by the mTOR signaling pathway.	('nuclear accumulation', 'MPA', (62, 82))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('mTOR', 'Gene', (152, 156))	('fusions', 'Var', (40, 47))	('mTOR', 'Gene', '2475', (152, 156))	('TFE3', 'Gene', '7030', (35, 39))	('signaling pathway', 'biological_process', 'GO:0007165', ('157', '174'))	('TFE3', 'Gene', (35, 39))
35	30849994	Furthermore, the nuclear retention of TFE3 fusions could regulate the expression of lysosomal biogenesis genes, thus promoting cancer cells resistance against an extreme environment.	('TFE3', 'Gene', '7030', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('promoting', 'PosReg', (117, 126))	('regulate', 'Reg', (57, 65))	('lysosomal biogenesis genes', 'Gene', (84, 110))	('resistance against an', 'CPA', (140, 161))	('fusions', 'Var', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('expression', 'MPA', (70, 80))	('cancer', 'Disease', (127, 133))	('TFE3', 'Gene', (38, 42))	('retention', 'biological_process', 'GO:0051235', ('25', '34'))
58	30849994	Cells were plated in 6-well plates and transfected with short hairpin RNA (shRNA) for human TFE3 (Obio, Y3619 and Y3620) and a non-target shRNA control (Obio, Y007) at a final concentration of 1 mug/well using Lipofectamine 2000 Transfection Regent (Invitrogen) followed by incubation for 48 h. Next, cells were passaged and analyzed for knockdown efficiency 72 h post-transfection.	('Y3620', 'Var', (114, 119))	('TFE3', 'Gene', (92, 96))	('human', 'Species', '9606', (86, 91))	('mug', 'molecular_function', 'GO:0043739', ('195', '198'))	('TFE3', 'Gene', '7030', (92, 96))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (210, 228))	('RNA', 'cellular_component', 'GO:0005562', ('70', '73'))
65	30849994	We found that TFE3 fusions accumulated in the nucleus in Xp11.2 RCC tumor samples (Fig.	('RCC tumor', 'Disease', 'MESH:C538614', (64, 73))	('TFE3', 'Gene', '7030', (14, 18))	('fusions', 'Var', (19, 26))	('nucleus', 'cellular_component', 'GO:0005634', ('46', '53'))	('TFE3', 'Gene', (14, 18))	('RCC tumor', 'Disease', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('accumulated', 'PosReg', (27, 38))
68	30849994	For UOK109 and UOK120 cells, we tested their fusion type, and found that UOK109 was NonO-TFE3 and UOK120 was PRCC-TFE3 (Additional file 2: Supplement S2), which was consistent with previous reports.	('UOK109', 'Var', (73, 79))	('TFE3', 'Gene', '7030', (89, 93))	('tested', 'Reg', (32, 38))	('TFE3', 'Gene', (114, 118))	('UOK109', 'Chemical', '-', (73, 79))	('UOK120', 'Var', (98, 104))	('TFE3', 'Gene', '7030', (114, 118))	('TFE3', 'Gene', (89, 93))	('PRCC', 'Gene', '5546', (109, 113))	('NonO', 'Gene', (84, 88))	('NonO', 'Gene', '4841', (84, 88))	('UOK109', 'Chemical', '-', (4, 10))	('PRCC', 'Gene', (109, 113))
69	30849994	Compared with none TFE3 fusion cells (786-0 and HK-2), the expression of fusion TFE3 genes increased significantly in UOK109 and UOK120 at both mRNA and protein levels (Fig.	('UOK109', 'Var', (118, 124))	('UOK109', 'Chemical', '-', (118, 124))	('HK-2', 'Gene', '3099', (48, 52))	('UOK120', 'Var', (129, 135))	('TFE3', 'Gene', (19, 23))	('HK-2', 'Gene', (48, 52))	('protein', 'cellular_component', 'GO:0003675', ('153', '160'))	('HK-2', 'molecular_function', 'GO:0008256', ('48', '52'))	('TFE3', 'Gene', '7030', (80, 84))	('expression', 'MPA', (59, 69))	('TFE3', 'Gene', '7030', (19, 23))	('increased', 'PosReg', (91, 100))	('TFE3', 'Gene', (80, 84))
71	30849994	To study the subcellular localization of the fusion TFE3 protein and its response to the mTORC1 signaling pathway, we introduced the mTOR inhibitor (PP242) into UOK109 and UOK120.	('mTOR', 'Gene', '2475', (89, 93))	('mTORC1', 'Gene', '382056', (89, 95))	('PP242', 'Var', (149, 154))	('TFE3', 'Gene', '7030', (52, 56))	('UOK109', 'Chemical', '-', (161, 167))	('PP242', 'Chemical', 'MESH:C572919', (149, 154))	('mTOR', 'Gene', '2475', (133, 137))	('mTORC1', 'cellular_component', 'GO:0031931', ('89', '95'))	('mTORC1', 'Gene', (89, 95))	('localization', 'biological_process', 'GO:0051179', ('25', '37'))	('mTOR', 'Gene', (133, 137))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('TFE3', 'Gene', (52, 56))	('signaling pathway', 'biological_process', 'GO:0007165', ('96', '113'))	('mTOR', 'Gene', (89, 93))
72	30849994	After incubation with PP242 for 24 h, TFE3 fusions showed no nuclear translocation whereas nuclear retention was observed in the control cells left untreated (Fig.	('TFE3', 'Gene', '7030', (38, 42))	('PP242', 'Var', (22, 27))	('retention', 'biological_process', 'GO:0051235', ('99', '108'))	('TFE3', 'Gene', (38, 42))	('PP242', 'Chemical', 'MESH:C572919', (22, 27))	('nuclear translocation', 'MPA', (61, 82))
73	30849994	In contrast, in 786-O and HK-2 cells, wild-type TFE3 proteins showed a rapid translocation from cytosol to the nucleus following by treatment with PP242 (Additional file 2: Supplement S2).	('PP242', 'Chemical', 'MESH:C572919', (147, 152))	('TFE3', 'Gene', '7030', (48, 52))	('HK-2', 'molecular_function', 'GO:0008256', ('26', '30'))	('translocation', 'MPA', (77, 90))	('HK-2', 'Gene', '3099', (26, 30))	('PP242', 'Var', (147, 152))	('proteins', 'Protein', (53, 61))	('nucleus', 'cellular_component', 'GO:0005634', ('111', '118'))	('TFE3', 'Gene', (48, 52))	('HK-2', 'Gene', (26, 30))	('cytosol', 'cellular_component', 'GO:0005829', ('96', '103'))
76	30849994	We found that wild-type TFE3 could co-localize with LAMP2, and incubation with a mTOR inhibitor (PP242 or Torin1) could separate LAMP2 from TFE3 in HK-2 (Fig.	('LAMP2', 'Gene', (52, 57))	('TFE3', 'Gene', '7030', (24, 28))	('PP242', 'Var', (97, 102))	('HK-2', 'Gene', '3099', (148, 152))	('LAMP2', 'Gene', '3920', (52, 57))	('LAMP2', 'Gene', (129, 134))	('PP242', 'Chemical', 'MESH:C572919', (97, 102))	('HK-2', 'molecular_function', 'GO:0008256', ('148', '152'))	('HK-2', 'Gene', (148, 152))	('LAMP2', 'Gene', '3920', (129, 134))	('TFE3', 'Gene', (140, 144))	('mTOR', 'Gene', (81, 85))	('TFE3', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (81, 85))	('TFE3', 'Gene', '7030', (140, 144))
77	30849994	However, TFE3 fusions showed rare co-localization with LAMP2 in UOK109 and UOK120 cells, in which TFE3 fusions were mostly located in the nucleus and LAMP2 stayed at cytoplasm (Fig.	('LAMP2', 'Gene', (55, 60))	('fusions', 'Var', (103, 110))	('TFE3', 'Gene', (9, 13))	('nucleus', 'cellular_component', 'GO:0005634', ('138', '145'))	('localization', 'biological_process', 'GO:0051179', ('37', '49'))	('LAMP2', 'Gene', '3920', (55, 60))	('cytoplasm', 'cellular_component', 'GO:0005737', ('166', '175'))	('TFE3', 'Gene', (98, 102))	('TFE3', 'Gene', '7030', (9, 13))	('UOK109', 'Chemical', '-', (64, 70))	('LAMP2', 'Gene', (150, 155))	('LAMP2', 'Gene', '3920', (150, 155))	('TFE3', 'Gene', '7030', (98, 102))
78	30849994	And TFE3 fusions remained its nuclear retention after treatment with mTOR inhibitor.	('mTOR', 'Gene', (69, 73))	('fusions', 'Var', (9, 16))	('retention', 'biological_process', 'GO:0051235', ('38', '47'))	('TFE3', 'Gene', (4, 8))	('nuclear', 'MPA', (30, 37))	('mTOR', 'Gene', '2475', (69, 73))	('TFE3', 'Gene', '7030', (4, 8))
79	30849994	These data indicated that the subcellular localization of TFE3 fusions was capable of escaping from the control of mTOR signaling pathway and could not be recruited to the lysosomal surface.	('TFE3', 'Gene', '7030', (58, 62))	('mTOR', 'Gene', '2475', (115, 119))	('signaling pathway', 'biological_process', 'GO:0007165', ('120', '137'))	('mTOR', 'Gene', (115, 119))	('localization', 'biological_process', 'GO:0051179', ('42', '54'))	('TFE3', 'Gene', (58, 62))	('fusions', 'Var', (63, 70))
86	30849994	The Co-IP data suggested that the binding between TFE3 fusions and 14-3-3gamma was reduced in UOK109 and UOK120 cells compared with in HK-2 cells (Fig.	('TFE3', 'Gene', (50, 54))	('UOK120', 'Var', (105, 111))	('binding', 'molecular_function', 'GO:0005488', ('34', '41'))	('UOK109', 'Chemical', '-', (94, 100))	('binding', 'Interaction', (34, 41))	('reduced', 'NegReg', (83, 90))	('HK-2', 'Gene', '3099', (135, 139))	('TFE3', 'Gene', '7030', (50, 54))	('HK-2', 'molecular_function', 'GO:0008256', ('135', '139'))	('HK-2', 'Gene', (135, 139))	('14-3-3gamma', 'Gene', (67, 78))	('14-3-3gamma', 'Gene', '7532', (67, 78))	('fusions', 'Var', (55, 62))
90	30849994	Based on these findings, we designed three types of expression plasmids containing TFE3 fused to EGFP including H8116 (TFE3 296-575aa), 40,770 (TFE3 179-575aa) or H11660 (full TFE3).	('TFE3', 'Gene', '7030', (144, 148))	('TFE3', 'Gene', (176, 180))	('TFE3', 'Gene', '7030', (83, 87))	('H11660', 'Var', (163, 169))	('TFE3', 'Gene', '7030', (176, 180))	('TFE3', 'Gene', (119, 123))	('fused', 'Reg', (88, 93))	('TFE3', 'Gene', (144, 148))	('EGFP', 'Gene', (97, 101))	('TFE3', 'Gene', (83, 87))	('TFE3', 'Gene', '7030', (119, 123))
92	30849994	Western blot revealed that the TFE3 was dramatically increased in H11660 infected group and its target protein 4EBP3 was increased at the same time (Fig.	('H11660 infected', 'Var', (66, 81))	('protein', 'cellular_component', 'GO:0003675', ('103', '110'))	('TFE3', 'Gene', '7030', (31, 35))	('increased', 'PosReg', (53, 62))	('4EBP3', 'Gene', '8637', (111, 116))	('TFE3', 'Gene', (31, 35))	('4EBP3', 'Gene', (111, 116))
93	30849994	However, in H8116 and 40,770 infected group, even TFE3 (296-575 aa) and TFE3 (179-575 aa) showed evidently increases.	('TFE3', 'Gene', (50, 54))	('TFE3', 'Gene', (72, 76))	('increases', 'PosReg', (107, 116))	('TFE3', 'Gene', '7030', (50, 54))	('TFE3', 'Gene', '7030', (72, 76))	('H8116', 'Var', (12, 17))
95	30849994	TFE3 (296-575 aa) and TFE3 (176-575 aa) were mainly increased in the nucleus.	('nucleus', 'cellular_component', 'GO:0005634', ('69', '76'))	('TFE3', 'Gene', '7030', (0, 4))	('TFE3', 'Gene', (22, 26))	('176-575', 'Var', (28, 35))	('TFE3', 'Gene', (0, 4))	('TFE3', 'Gene', '7030', (22, 26))
97	30849994	TFE3 (296-575 aa) and TFE3 (176-575 aa) were mainly localized in the cytoplasm together with EGFP in 293 T cells confirmed by immunofluorescence assays.	('TFE3', 'Gene', '7030', (22, 26))	('TFE3', 'Gene', '7030', (0, 4))	('cytoplasm', 'cellular_component', 'GO:0005737', ('69', '78'))	('176-575 aa', 'Var', (28, 38))	('TFE3', 'Gene', (22, 26))	('TFE3', 'Gene', (0, 4))	('293 T', 'CellLine', 'CVCL:0063', (101, 106))	('296-575 aa', 'Var', (6, 16))
101	30849994	Two residues (Ser134 and Ser138) in TFE3 are highly conserved in MiTF family, which could be phosphorylated by GSK3beta leading to their cytoplasmic retention.	('GSK', 'molecular_function', 'GO:0050321', ('111', '114'))	('Ser138', 'Chemical', '-', (25, 31))	('retention', 'biological_process', 'GO:0051235', ('149', '158'))	('TFE3', 'Gene', (36, 40))	('GSK3beta', 'Gene', '2932', (111, 119))	('Ser134', 'Var', (14, 20))	('Ser134', 'Chemical', '-', (14, 20))	('TFE3', 'Gene', '7030', (36, 40))	('cytoplasmic retention', 'MPA', (137, 158))	('Ser', 'cellular_component', 'GO:0005790', ('14', '17'))	('Ser', 'cellular_component', 'GO:0005790', ('25', '28'))	('MiTF', 'Gene', (65, 69))	('MiTF', 'Gene', '4286', (65, 69))	('Ser138', 'Var', (25, 31))	('GSK3beta', 'Gene', (111, 119))
102	30849994	In UOK109 and UOK120 cells, we found that only PRCC-TFE3 fusions retained the two residues by sequence alignment (Additional file 3: Supplement S3).	('PRCC', 'Gene', (47, 51))	('TFE3', 'Gene', '7030', (52, 56))	('fusions', 'Var', (57, 64))	('TFE3', 'Gene', (52, 56))	('PRCC', 'Gene', '5546', (47, 51))	('UOK109', 'Chemical', '-', (3, 9))
103	30849994	Our data showed that TFE3 fusions failed to be subject to the regulation by mTORC1 and accumulated in the nucleus in Xp11.2 tRCCs.	('TFE3', 'Gene', '7030', (21, 25))	('accumulated', 'PosReg', (87, 98))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('fusions', 'Var', (26, 33))	('RCC', 'Disease', (125, 128))	('nucleus', 'cellular_component', 'GO:0005634', ('106', '113'))	('TFE3', 'Gene', (21, 25))	('mTORC1', 'Gene', '382056', (76, 82))	('mTORC1', 'cellular_component', 'GO:0031931', ('76', '82'))	('mTORC1', 'Gene', (76, 82))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))
105	30849994	It was revealed that TFE3 fusions were evidently increased in the cytoplasm (Fig.	('TFE3', 'Gene', '7030', (21, 25))	('fusions', 'Var', (26, 33))	('increased', 'PosReg', (49, 58))	('TFE3', 'Gene', (21, 25))	('cytoplasm', 'cellular_component', 'GO:0005737', ('66', '75'))
107	30849994	Next, we inhibited the ubiquitination degradation pathway by MG132 in HK-2 cells.	('inhibited', 'NegReg', (9, 18))	('HK-2', 'Gene', '3099', (70, 74))	('HK-2', 'Gene', (70, 74))	('ubiquitination', 'Pathway', (23, 37))	('HK-2', 'molecular_function', 'GO:0008256', ('70', '74'))	('MG132', 'Var', (61, 66))	('MG132', 'Chemical', 'MESH:C072553', (61, 66))	('degradation', 'biological_process', 'GO:0009056', ('38', '49'))
108	30849994	The expression of TFE3 was increased and mTOR inhibition mediated reduction was recovered after treatment with MG132 (Fig.	('increased', 'PosReg', (27, 36))	('TFE3', 'Gene', '7030', (18, 22))	('MG132', 'Var', (111, 116))	('expression', 'MPA', (4, 14))	('MG132', 'Chemical', 'MESH:C072553', (111, 116))	('mTOR', 'Gene', '2475', (41, 45))	('mTOR', 'Gene', (41, 45))	('TFE3', 'Gene', (18, 22))
109	30849994	These data indicated that activating Gsk3beta could lead to retention of TFE3 fusions in the cytoplasm which was accompanied with a reduction in its nuclear retention.	('activating', 'PosReg', (26, 36))	('retention', 'biological_process', 'GO:0051235', ('157', '166'))	('retention', 'biological_process', 'GO:0051235', ('60', '69'))	('TFE3', 'Gene', '7030', (73, 77))	('cytoplasm', 'cellular_component', 'GO:0005737', ('93', '102'))	('Gsk', 'molecular_function', 'GO:0050321', ('37', '40'))	('nuclear retention', 'MPA', (149, 166))	('reduction', 'NegReg', (132, 141))	('Gsk3beta', 'Gene', '2932', (37, 45))	('fusions', 'Var', (78, 85))	('Gsk3beta', 'Gene', (37, 45))	('TFE3', 'Gene', (73, 77))
114	30849994	Components associated with localization, organic substance transport, lytic vacuole organization, lysosome organization, and transport as shown in Table 1 significantly interacted with TFE3 fusions in UOK109 cells.	('lysosome', 'cellular_component', 'GO:0005764', ('98', '106'))	('interacted', 'Reg', (169, 179))	('organic substance transport', 'biological_process', 'GO:0071702', ('41', '68'))	('TFE3', 'Gene', '7030', (185, 189))	('UOK109', 'Chemical', '-', (201, 207))	('fusions', 'Var', (190, 197))	('transport', 'biological_process', 'GO:0006810', ('125', '134'))	('lytic vacuole', 'cellular_component', 'GO:0000323', ('70', '83'))	('lytic vacuole organization', 'biological_process', 'GO:0080171', ('70', '96'))	('TFE3', 'Gene', (185, 189))	('localization', 'biological_process', 'GO:0051179', ('27', '39'))	('lysosome organization', 'biological_process', 'GO:0007040', ('98', '119'))
115	30849994	The analysis of lysosomes demonstrated significant increases of the number of genes involved in the lysosome organization, endosome to lysosome transport and phagolysosome assembly, which suggested that TFE3 fusions could bind to the CLEAR element and regulate lysosomal biosynthesis.	('TFE3', 'Gene', '7030', (203, 207))	('endosome to lysosome transport', 'biological_process', 'GO:0008333', ('123', '153'))	('regulate', 'Reg', (252, 260))	('biosynthesis', 'biological_process', 'GO:0009058', ('271', '283'))	('lysosomal biosynthesis', 'MPA', (261, 283))	('fusions', 'Var', (208, 215))	('TFE3', 'Gene', (203, 207))	('bind', 'Interaction', (222, 226))	('phagolysosome assembly', 'biological_process', 'GO:0001845', ('158', '180'))	('phagolysosome', 'cellular_component', 'GO:0032010', ('158', '171'))	('lysosome', 'cellular_component', 'GO:0005764', ('100', '108'))	('endosome', 'cellular_component', 'GO:0005768', ('123', '131'))	('lysosome', 'cellular_component', 'GO:0005764', ('135', '143'))	('lysosome organization', 'biological_process', 'GO:0007040', ('100', '121'))
116	30849994	The analysis of KEGG pathway revealed that lysosomes were correlated with TFE3 (Table 2) which further confirmed NonO-TFE3 fusions could still regulate lysosomal biogenesis genes as the wild-type TFE3.	('TFE3', 'Gene', (118, 122))	('TFE3', 'Gene', (74, 78))	('regulate', 'Reg', (143, 151))	('lysosomal biogenesis genes', 'Gene', (152, 178))	('TFE3', 'Gene', (196, 200))	('NonO', 'Gene', (113, 117))	('TFE3', 'Gene', '7030', (118, 122))	('TFE3', 'Gene', '7030', (74, 78))	('fusions', 'Var', (123, 130))	('NonO', 'Gene', '4841', (113, 117))	('TFE3', 'Gene', '7030', (196, 200))
120	30849994	Since TFE3 fusions were significantly overexpressed and accumulated in the nucleus in UOK109 and UOK120 cells, we found that TFE3 fusions might also influence the expression of lysosomal genes or other target genes.	('TFE3', 'Gene', (125, 129))	('influence', 'Reg', (149, 158))	('TFE3', 'Gene', '7030', (6, 10))	('TFE3', 'Gene', '7030', (125, 129))	('overexpressed', 'PosReg', (38, 51))	('fusions', 'Var', (130, 137))	('accumulated', 'PosReg', (56, 67))	('expression', 'MPA', (163, 173))	('TFE3', 'Gene', (6, 10))	('nucleus', 'cellular_component', 'GO:0005634', ('75', '82'))	('lysosomal genes', 'Gene', (177, 192))	('fusions', 'Var', (11, 18))	('UOK109', 'Chemical', '-', (86, 92))
122	30849994	The expression of 4EBP3 at the protein level showed a significant decrease after TFE3 knockdown with plasmids or viral infection (Fig.	('viral infection', 'biological_process', 'GO:0016032', ('113', '128'))	('knockdown', 'Var', (86, 95))	('viral infection', 'Disease', (113, 128))	('4EBP3', 'Gene', '8637', (18, 23))	('expression', 'MPA', (4, 14))	('TFE3', 'Gene', (81, 85))	('4EBP3', 'Gene', (18, 23))	('protein', 'cellular_component', 'GO:0003675', ('31', '38'))	('decrease', 'NegReg', (66, 74))	('viral infection', 'Disease', 'MESH:D001102', (113, 128))	('TFE3', 'Gene', '7030', (81, 85))
123	30849994	In addition, the expression of S6 and p-S6 which are downstream of mTORC1 also showed an evident decrease.	('p-S6', 'Var', (38, 42))	('mTORC1', 'Gene', (67, 73))	('mTORC1', 'cellular_component', 'GO:0031931', ('67', '73'))	('expression', 'MPA', (17, 27))	('mTORC1', 'Gene', '382056', (67, 73))	('decrease', 'NegReg', (97, 105))
124	30849994	In TFE3 knockdown cells, the expression of TFE3 fusions was reduced, while the subcellular localization of TFE3 fusions remained unchanged in UOK109 and UOK120 cells (Fig.	('fusions', 'Var', (48, 55))	('TFE3', 'Gene', '7030', (3, 7))	('UOK109', 'Chemical', '-', (142, 148))	('localization', 'biological_process', 'GO:0051179', ('91', '103'))	('knockdown', 'Var', (8, 17))	('TFE3', 'Gene', (43, 47))	('TFE3', 'Gene', '7030', (107, 111))	('reduced', 'NegReg', (60, 67))	('TFE3', 'Gene', (3, 7))	('TFE3', 'Gene', '7030', (43, 47))	('expression', 'MPA', (29, 39))	('TFE3', 'Gene', (107, 111))
125	30849994	These data suggested that TFE3 fusions could bind to the CLEAR element as the wild-type TFE3 and could regulate the expression of lysosomal biogenesis genes.	('expression', 'MPA', (116, 126))	('TFE3', 'Gene', (88, 92))	('TFE3', 'Gene', (26, 30))	('TFE3', 'Gene', '7030', (88, 92))	('regulate', 'Reg', (103, 111))	('lysosomal biogenesis genes', 'Gene', (130, 156))	('TFE3', 'Gene', '7030', (26, 30))	('fusions', 'Var', (31, 38))	('bind', 'Interaction', (45, 49))
126	30849994	Furthermore, we chose 4EBP3 as a target gene to test the transcriptional activity of TFE3 fusions.	('TFE3', 'Gene', '7030', (85, 89))	('4EBP3', 'Gene', (22, 27))	('TFE3', 'Gene', (85, 89))	('4EBP3', 'Gene', '8637', (22, 27))	('fusions', 'Var', (90, 97))
128	30849994	Luciferase assay data showed that TFE3 fusions could bind to the 4EBP3 promoter region and activate its transcription, which indicated that the TFE3 fusions remained its transcriptional activity (Fig.	('TFE3', 'Gene', '7030', (144, 148))	('TFE3', 'Gene', '7030', (34, 38))	('4EBP3', 'Gene', '8637', (65, 70))	('fusions', 'Var', (39, 46))	('bind', 'Interaction', (53, 57))	('transcription', 'biological_process', 'GO:0006351', ('104', '117'))	('TFE3', 'Gene', (144, 148))	('transcription', 'MPA', (104, 117))	('4EBP3', 'Gene', (65, 70))	('TFE3', 'Gene', (34, 38))	('transcriptional activity', 'MPA', (170, 194))	('activate', 'PosReg', (91, 99))
129	30849994	In addition, we performed a chromatin immunoprecipitation assay to determine whether TFE3 fusions directly binds to the 4EBP3 promoter at the E-box.	('TFE3', 'Gene', '7030', (85, 89))	('4EBP3', 'Gene', '8637', (120, 125))	('binds', 'Interaction', (107, 112))	('chromatin', 'cellular_component', 'GO:0000785', ('28', '37'))	('4EBP3', 'Gene', (120, 125))	('TFE3', 'Gene', (85, 89))	('fusions', 'Var', (90, 97))
130	30849994	The chromatin immunoprecipitation data showed that TFE3 fusions bind to the DNA segment containing the E-box (- 129 to + 27) of the 4EBP3 promoter, but not the sites from - 522 to - 352 or from + 449 to + 639 (Fig.	('4EBP3', 'Gene', (132, 137))	('fusions', 'Var', (56, 63))	('- 129 to + 27', 'Var', (110, 123))	('TFE3', 'Gene', '7030', (51, 55))	('chromatin', 'cellular_component', 'GO:0000785', ('4', '13'))	('bind', 'Interaction', (64, 68))	('TFE3', 'Gene', (51, 55))	('DNA', 'cellular_component', 'GO:0005574', ('76', '79'))	('4EBP3', 'Gene', '8637', (132, 137))
131	30849994	Taken together, these results demonstrated that TFE3 fusions could mediate the transcriptional initiation of target genes just like the wild-type TFE3.	('TFE3', 'Gene', '7030', (48, 52))	('fusions', 'Var', (53, 60))	('TFE3', 'Gene', '7030', (146, 150))	('transcriptional initiation', 'MPA', (79, 105))	('mediate', 'Reg', (67, 74))	('TFE3', 'Gene', (48, 52))	('TFE3', 'Gene', (146, 150))
133	30849994	To study the function of 4EBP3, we examined the effect of mTOR inhibitors (PP242 and Torin1) on the expression of 4EBP3 in 786-0, HK-2, UOK109 and UOK120 cell lines.	('mTOR', 'Gene', (58, 62))	('PP242', 'Var', (75, 80))	('PP242', 'Chemical', 'MESH:C572919', (75, 80))	('4EBP3', 'Gene', '8637', (25, 30))	('UOK109', 'Chemical', '-', (136, 142))	('HK-2', 'molecular_function', 'GO:0008256', ('130', '134'))	('4EBP3', 'Gene', '8637', (114, 119))	('4EBP3', 'Gene', (25, 30))	('HK-2', 'Gene', '3099', (130, 134))	('4EBP3', 'Gene', (114, 119))	('mTOR', 'Gene', '2475', (58, 62))	('HK-2', 'Gene', (130, 134))
135	30849994	Furthermore, we found that fold-change of 4EBP3 in UOK109 and UOK120 were significantly reduced compared with HK-2 and 786-O cells (Fig.	('UOK109', 'Var', (51, 57))	('UOK109', 'Chemical', '-', (51, 57))	('fold-change', 'MPA', (27, 38))	('4EBP3', 'Gene', '8637', (42, 47))	('HK-2', 'Gene', (110, 114))	('4EBP3', 'Gene', (42, 47))	('UOK120', 'Var', (62, 68))	('reduced', 'NegReg', (88, 95))	('HK-2', 'molecular_function', 'GO:0008256', ('110', '114'))	('HK-2', 'Gene', '3099', (110, 114))
136	30849994	These findings suggested that TFE3 fusions promote the expression of 4EBP3 after mTOR inhibition, while the effect of mTOR inhibitor on TFE3 fusions was diminished in UOK109 and UOK120.	('promote', 'PosReg', (43, 50))	('TFE3', 'Gene', (136, 140))	('mTOR', 'Gene', (118, 122))	('UOK109', 'Chemical', '-', (167, 173))	('expression', 'MPA', (55, 65))	('mTOR', 'Gene', '2475', (118, 122))	('4EBP3', 'Gene', '8637', (69, 74))	('inhibition', 'Var', (86, 96))	('TFE3', 'Gene', (30, 34))	('4EBP3', 'Gene', (69, 74))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('TFE3', 'Gene', '7030', (30, 34))	('TFE3', 'Gene', '7030', (136, 140))
137	30849994	Since the discovery of TFE3 gene fusions, the mechanism underlying the oncogenic effects of these mutations in kidney largely remains unknown.	('TFE3', 'Gene', '7030', (23, 27))	('TFE3', 'Gene', (23, 27))	('fusions', 'Var', (33, 40))
138	30849994	As with other fusion proteins involving transcription factors, promoter substitution appears to be the key molecular event with TFE3 fusions, causing abnormal TFE3 protein activity.	('TFE3', 'Gene', (159, 163))	('activity', 'MPA', (172, 180))	('TFE3', 'Gene', '7030', (128, 132))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('causing', 'Reg', (142, 149))	('TFE3', 'Gene', '7030', (159, 163))	('fusions', 'Var', (133, 140))	('transcription', 'biological_process', 'GO:0006351', ('40', '53'))	('promoter substitution', 'Var', (63, 84))	('TFE3', 'Gene', (128, 132))
140	30849994	In this study, we found that the expression of NonO-TFE3 and PRCC-TFE3 fusions were definitely increased in UOK109 and UOK120 cells compared with the HK-2.	('HK-2', 'Gene', (150, 154))	('TFE3', 'Gene', (66, 70))	('PRCC', 'Gene', (61, 65))	('UOK109', 'Chemical', '-', (108, 114))	('TFE3', 'Gene', '7030', (52, 56))	('TFE3', 'Gene', '7030', (66, 70))	('fusions', 'Var', (71, 78))	('HK-2', 'molecular_function', 'GO:0008256', ('150', '154'))	('NonO', 'Gene', (47, 51))	('expression', 'MPA', (33, 43))	('TFE3', 'Gene', (52, 56))	('PRCC', 'Gene', '5546', (61, 65))	('increased', 'PosReg', (95, 104))	('HK-2', 'Gene', '3099', (150, 154))	('NonO', 'Gene', '4841', (47, 51))
147	30849994	In contrast to previous studies, we found that TFE3 fusions were capable of escaping from the regulation of mTORC1.	('escaping', 'NegReg', (76, 84))	('regulation', 'biological_process', 'GO:0065007', ('94', '104'))	('regulation', 'MPA', (94, 104))	('fusions', 'Var', (52, 59))	('TFE3', 'Gene', (47, 51))	('mTORC1', 'cellular_component', 'GO:0031931', ('108', '114'))	('TFE3', 'Gene', '7030', (47, 51))	('mTORC1', 'Gene', '382056', (108, 114))	('mTORC1', 'Gene', (108, 114))
148	30849994	Our results revealed that TFE3 fusions had lost its cytosol retention and were mainly accumulated in the nucleus in UOK109 and UOK120 cells.	('cytosol retention', 'MPA', (52, 69))	('retention', 'biological_process', 'GO:0051235', ('60', '69'))	('accumulated', 'PosReg', (86, 97))	('cytosol', 'cellular_component', 'GO:0005829', ('52', '59'))	('nucleus', 'cellular_component', 'GO:0005634', ('105', '112'))	('TFE3', 'Gene', (26, 30))	('UOK109', 'Chemical', '-', (116, 122))	('TFE3', 'Gene', '7030', (26, 30))	('fusions', 'Var', (31, 38))	('lost', 'NegReg', (43, 47))
149	30849994	In the cytoplasm, the interaction between TFE3 fusions and 14-3-3 proteins rarely occurred in UOK109 and UOK120 cells.	('TFE3', 'Gene', '7030', (42, 46))	('UOK109', 'Chemical', '-', (94, 100))	('cytoplasm', 'cellular_component', 'GO:0005737', ('7', '16'))	('fusions', 'Var', (47, 54))	('interaction', 'Interaction', (22, 33))	('TFE3', 'Gene', (42, 46))
150	30849994	We further demonstrated that TFE3 fusions failed to be localized on the lysosomal surface and were mainly localized in the nucleus.	('TFE3', 'Gene', (29, 33))	('nucleus', 'cellular_component', 'GO:0005634', ('123', '130'))	('TFE3', 'Gene', '7030', (29, 33))	('localized', 'Reg', (106, 115))	('fusions', 'Var', (34, 41))
160	30849994	Although the TFE3 fusions in UOK109 and UOK120 retained the phosphorylation site at Ser321, they lost the first 30 residues making them unavailable for the lysosome recruitment under mTORC1 inhibition.	('phosphorylation site at Ser321', 'MPA', (60, 90))	('UOK109', 'Var', (29, 35))	('UOK109', 'Chemical', '-', (29, 35))	('mTORC1', 'Gene', (183, 189))	('UOK120', 'Var', (40, 46))	('first 30 residues', 'MPA', (106, 123))	('Ser321', 'Chemical', '-', (84, 90))	('mTORC1', 'cellular_component', 'GO:0031931', ('183', '189'))	('TFE3', 'Gene', (13, 17))	('phosphorylation', 'biological_process', 'GO:0016310', ('60', '75'))	('lysosome', 'cellular_component', 'GO:0005764', ('156', '164'))	('mTORC1', 'Gene', '382056', (183, 189))	('lost', 'NegReg', (97, 101))	('TFE3', 'Gene', '7030', (13, 17))	('Ser', 'cellular_component', 'GO:0005790', ('84', '87'))
162	30849994	The nuclear retention of TFE3 fusions may be attributed to the retained NLS at the C-terminal of the fusion peptide.	('TFE3', 'Gene', '7030', (25, 29))	('nuclear retention', 'CPA', (4, 21))	('fusions', 'Var', (30, 37))	('retention', 'biological_process', 'GO:0051235', ('12', '21'))	('TFE3', 'Gene', (25, 29))	('NLS', 'MPA', (72, 75))
167	30849994	Previous studies indicated that TFEB can be phosphorylated by GSK3beta at residues Ser134 and Ser138, which are highly conversed between TFE3 and TFEB, leading to cytoplasmic retention.	('Ser138', 'Var', (94, 100))	('TFEB', 'Gene', (32, 36))	('leading to', 'Reg', (152, 162))	('cytoplasmic retention', 'MPA', (163, 184))	('GSK3beta', 'Gene', '2932', (62, 70))	('Ser138', 'Chemical', '-', (94, 100))	('GSK', 'molecular_function', 'GO:0050321', ('62', '65'))	('Ser', 'cellular_component', 'GO:0005790', ('94', '97'))	('Ser134', 'Var', (83, 89))	('Ser134', 'Chemical', '-', (83, 89))	('Ser', 'cellular_component', 'GO:0005790', ('83', '86'))	('retention', 'biological_process', 'GO:0051235', ('175', '184'))	('TFE3', 'Gene', (137, 141))	('TFE3', 'Gene', '7030', (137, 141))	('TFEB', 'Gene', '7942', (146, 150))	('GSK3beta', 'Gene', (62, 70))	('TFEB', 'Gene', (146, 150))	('TFEB', 'Gene', '7942', (32, 36))
170	30849994	In the HK-2 cells, inhibition of ubiquitination degradation increased TFE3 expression in the cytoplasm.	('TFE3', 'Gene', (70, 74))	('degradation', 'biological_process', 'GO:0009056', ('48', '59'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('93', '102'))	('inhibition', 'Var', (19, 29))	('TFE3', 'Gene', '7030', (70, 74))	('HK-2', 'Gene', (7, 11))	('HK-2', 'molecular_function', 'GO:0008256', ('7', '11'))	('increased', 'PosReg', (60, 69))	('ubiquitination degradation', 'MPA', (33, 59))	('expression', 'MPA', (75, 85))	('HK-2', 'Gene', '3099', (7, 11))
171	30849994	Taken together, phosphorylation of TFE3 fusions by GSK3beta promotes its cytoplasmic retention and dissociated TFE3 fusions in the cytoplasm can be degraded through the ubiquitination pathway.	('TFE3', 'Gene', (111, 115))	('promotes', 'PosReg', (60, 68))	('GSK3beta', 'Gene', '2932', (51, 59))	('TFE3', 'Gene', '7030', (111, 115))	('retention', 'biological_process', 'GO:0051235', ('85', '94'))	('phosphorylation', 'Var', (16, 31))	('TFE3', 'Gene', '7030', (35, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('16', '31'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('131', '140'))	('cytoplasmic retention', 'CPA', (73, 94))	('GSK3beta', 'Gene', (51, 59))	('GSK', 'molecular_function', 'GO:0050321', ('51', '54'))	('TFE3', 'Gene', (35, 39))
174	30849994	In this study, we demonstrated that the overexpressed TFE3 fusions could promote the expression of lysosomal biogenesis genes.	('expression', 'MPA', (85, 95))	('TFE3', 'Gene', (54, 58))	('TFE3', 'Gene', '7030', (54, 58))	('promote', 'PosReg', (73, 80))	('fusions', 'Var', (59, 66))	('lysosomal biogenesis genes', 'Gene', (99, 125))
175	30849994	Furthermore, the ChIP-seq analysis indicated that TFE3 fusions still maintained their regulation of lysosomal biogenesis in the UOK109 cells.	('regulation', 'MPA', (86, 96))	('TFE3', 'Gene', (50, 54))	('UOK109', 'Chemical', '-', (128, 134))	('regulation', 'biological_process', 'GO:0065007', ('86', '96'))	('TFE3', 'Gene', '7030', (50, 54))	('lysosomal biogenesis', 'MPA', (100, 120))	('fusions', 'Var', (55, 62))
176	30849994	In addition, the ChIP-seq also revealed that TFE3 fusions could regulate cellular responses to hypoxia stress, which could improve cancer cell resistance to hypoxia and thus promote cancer growth.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('regulate', 'Reg', (64, 72))	('TFE3', 'Gene', '7030', (45, 49))	('hypoxia', 'Disease', (95, 102))	('promote', 'PosReg', (174, 181))	('improve', 'PosReg', (123, 130))	('hypoxia', 'Disease', 'MESH:D000860', (95, 102))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('fusions', 'Var', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('hypoxia', 'Disease', (157, 164))	('hypoxia stress', 'Disease', 'MESH:D004194', (95, 109))	('hypoxia stress', 'Disease', (95, 109))	('cancer', 'Disease', (182, 188))	('TFE3', 'Gene', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
177	30849994	Therefore, these pathogenic mechanisms of TFE3 fusions may be potentially be exploited for the development of therapeutic targets.	('fusions', 'Var', (47, 54))	('TFE3', 'Gene', (42, 46))	('TFE3', 'Gene', '7030', (42, 46))
178	30849994	In summary, we observed that overexpressed TFE3 fusions in Xp11.2 tRCC were capable of escaping from the control of the mTOR signaling pathway and showed evident nuclear retention.	('fusions', 'Var', (48, 55))	('signaling pathway', 'biological_process', 'GO:0007165', ('125', '142'))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('TFE3', 'Gene', (43, 47))	('RCC', 'Disease', (67, 70))	('retention', 'biological_process', 'GO:0051235', ('170', '179'))	('nuclear retention', 'CPA', (162, 179))	('mTOR', 'Gene', (120, 124))	('TFE3', 'Gene', '7030', (43, 47))	('mTOR', 'Gene', '2475', (120, 124))
179	30849994	Inhibition of Gsk3beta could increase cytoplasm retention of TFE3 fusions.	('cytoplasm retention', 'CPA', (38, 57))	('cytoplasm', 'cellular_component', 'GO:0005737', ('38', '47'))	('TFE3', 'Gene', (61, 65))	('increase', 'PosReg', (29, 37))	('retention', 'biological_process', 'GO:0051235', ('48', '57'))	('Gsk3beta', 'Gene', '2932', (14, 22))	('Inhibition', 'Var', (0, 10))	('Inhibition of Gsk', 'biological_process', 'GO:1902948', ('0', '17'))	('TFE3', 'Gene', '7030', (61, 65))	('Gsk3beta', 'Gene', (14, 22))	('Gsk', 'molecular_function', 'GO:0050321', ('14', '17'))
180	30849994	In addition, TFE3 fusions could bind to target gene promoters as wild-type TFE3, promoting the expression of genes including lysosomal genes and hypoxia stress related genes, which could improve cell resistance against an extreme environment.	('fusions', 'Var', (18, 25))	('hypoxia stress', 'Disease', 'MESH:D004194', (145, 159))	('TFE3', 'Gene', (13, 17))	('TFE3', 'Gene', (75, 79))	('cell resistance', 'CPA', (195, 210))	('lysosomal genes', 'Gene', (125, 140))	('promoting', 'PosReg', (81, 90))	('TFE3', 'Gene', '7030', (13, 17))	('TFE3', 'Gene', '7030', (75, 79))	('improve', 'PosReg', (187, 194))	('expression', 'MPA', (95, 105))	('hypoxia stress', 'Disease', (145, 159))
181	30849994	Unveiling of these pathogenic mechanisms of TFE3 fusions may benefit the development of new cancer.	('benefit', 'PosReg', (61, 68))	('cancer', 'Disease', (92, 98))	('TFE3', 'Gene', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TFE3', 'Gene', '7030', (44, 48))	('development', 'CPA', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('fusions', 'Var', (49, 56))
251	28757600	The 44 ccRCCs were categorized into three groups according to the RTC value, which included groups of RTC <=0.6, 0.6< RTC <1, and RTC >=1.	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('0.6<', 'Var', (113, 117))	('RTC >=1', 'Gene', '8634', (130, 137))	('RTC <1', 'Gene', (118, 124))	('RTC <1', 'Gene', '8634', (118, 124))	('RTC <=0.6', 'Var', (102, 111))	('RTC >=1', 'Gene', (130, 137))
253	28757600	Significant difference was noted in MVD1 in the group of RTC <=0.6 with the other groups (F=7.98, p<0.01), while MVD1 did not differ significantly from the groups of 0.6< RTC <1 and RTC >=1.	('RTC >=1', 'Gene', '8634', (182, 189))	('RTC <1', 'Gene', (171, 177))	('RTC <1', 'Gene', '8634', (171, 177))	('RTC >=1', 'Gene', (182, 189))	('MVD1', 'Gene', '4597', (36, 40))	('MVD1', 'Gene', '4597', (113, 117))	('MVD1', 'Gene', (36, 40))	('RTC <=0.6', 'Var', (57, 66))	('MVD1', 'Gene', (113, 117))
291	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))
293	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))
294	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', (286, 292))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('PGs', 'Gene', (255, 258))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('cancers', 'Disease', (394, 401))	('cancer', 'Disease', (394, 400))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('Oncomine', 'Chemical', '-', (54, 62))	('signal transduction', 'biological_process', 'GO:0007165', ('301', '320'))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
299	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('signal transduction pathways', 'Pathway', (81, 109))	('PGC', 'Gene', (120, 123))	('signal transduction', 'biological_process', 'GO:0007165', ('81', '100'))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('inhibition', 'NegReg', (62, 72))	('PGC', 'Gene', '5225', (120, 123))	('PGs', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
305	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))
306	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))
310	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))
312	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('signal transduction', 'biological_process', 'GO:0007165', ('283', '302'))	('CCLE', 'Chemical', '-', (57, 61))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('cancers', 'Disease', (375, 382))	('copy number variation', 'Var', (212, 233))	('PGs', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (268, 274))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (375, 381))
332	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))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('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))
333	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))
338	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))
351	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))
363	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))
374	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))
398	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))
401	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('PGA5', 'Gene', '5222', (16, 20))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
402	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))
403	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))
404	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))
407	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))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('CCLE', 'Chemical', '-', (66, 70))	('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))
408	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('associated', 'Reg', (211, 221))	('affect', 'Reg', (338, 344))	('immune cell infiltration', 'CPA', (273, 297))	('activation', 'PosReg', (231, 241))	('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))	('PGC', 'Gene', (328, 331))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
427	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('protein', 'cellular_component', 'GO:0003675', ('122', '129'))	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('protein synthesis', 'biological_process', 'GO:0006412', ('122', '139'))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
429	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('synthesis', 'biological_process', 'GO:0009058', ('154', '163'))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
450	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))
451	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))
452	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))
453	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))
455	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))
456	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))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('PGC', 'Gene', '5225', (175, 178))
458	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('regulation', 'biological_process', 'GO:0065007', ('248', '258'))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
473	30466410	In metastatic pRCC with a MET amplification, crizotinib maybe a potential met-inhibitory therapeutic option.	('MET amplification', 'Var', (26, 43))	('pRCC', 'Gene', '5546', (14, 18))	('pRCC', 'Phenotype', 'HP:0006766', (14, 18))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('pRCC', 'Gene', (14, 18))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))
480	30466410	Here we present the case of a patient with a MET-amplified mpRCC successfully treated during 19 months with the MET-inhibitor crizotinib within the French AcSe- crizotinib program.	('patient', 'Species', '9606', (30, 37))	('pRCC', 'Gene', (60, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (126, 136))	('pRCC', 'Phenotype', 'HP:0006766', (60, 64))	('pRCC', 'Gene', '5546', (60, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (161, 171))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('MET-amplified', 'Var', (45, 58))
482	30466410	Histopathological examination revealed a tubulo-papillary renal cell carcinoma, type 1, grade 2 of Fuhrman, 20% of necrosis, without vascular embolus or peri-renal infiltration, R0, pT1bNx, vimentin +, CD 10+.	('necrosis', 'biological_process', 'GO:0008219', ('115', '123'))	('vimentin', 'cellular_component', 'GO:0045099', ('190', '198'))	('pT1bNx', 'Var', (182, 188))	('papillary renal cell carcinoma', 'Disease', (48, 78))	('CD 10', 'molecular_function', 'GO:0004245', ('202', '207'))	('necrosis', 'biological_process', 'GO:0008220', ('115', '123'))	('man', 'Species', '9606', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('necrosis', 'biological_process', 'GO:0070265', ('115', '123'))	('vimentin', 'Gene', '7431', (190, 198))	('necrosis', 'biological_process', 'GO:0019835', ('115', '123'))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (48, 78))	('necrosis', 'biological_process', 'GO:0001906', ('115', '123'))	('vimentin', 'cellular_component', 'GO:0045098', ('190', '198'))	('vimentin', 'Gene', (190, 198))	('necrosis', 'Disease', 'MESH:D009336', (115, 123))	('vascular embolus', 'Disease', (133, 149))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 78))	('necrosis', 'Disease', (115, 123))	('vascular embolus', 'Disease', 'MESH:D004617', (133, 149))
484	30466410	1) confirmed the morphology of papillary renal cell carcinoma, with papillary and foamy macrophages (A, B, C) and a positivity of CK7 (D), Racemase/P504S (E) with immunohistochemistry (IHC).	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Racemase/P504S', 'Var', (139, 153))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (31, 61))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (31, 61))	('foamy macrophages', 'Phenotype', 'HP:0003651', (82, 99))	('CK7', 'Gene', (130, 133))	('P504S', 'Mutation', 'p.P504S', (148, 153))	('CK7', 'Gene', '3855', (130, 133))	('papillary renal cell carcinoma', 'Disease', (31, 61))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))
514	30466410	described a pRCC patient with an activating MET gene mutation, pretreated by sunitinib and everolimus, with a long response to a tyrosine kinase inhibitor (TKI: PF-04217903).	('mutation', 'Var', (53, 61))	('tyrosine kinase', 'Gene', (129, 144))	('patient', 'Species', '9606', (17, 24))	('everolimus', 'Chemical', 'MESH:D000068338', (91, 101))	('pRCC', 'Phenotype', 'HP:0006766', (12, 16))	('pRCC', 'Gene', '5546', (12, 16))	('MET gene', 'Gene', (44, 52))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('activating', 'PosReg', (33, 43))	('sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('138', '154'))	('tyrosine kinase', 'Gene', '7294', (129, 144))	('pRCC', 'Gene', (12, 16))
516	30466410	Biologically, the proof of MET implication in pRCC was made in 1997 with the discovery that hereditary pRCC patients had a germline missense mutation in the MET proto-oncogene (7q3 locus), leading to constitutive activation of the MET protein.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('pRCC', 'Phenotype', 'HP:0006766', (103, 107))	('pRCC', 'Gene', '5546', (103, 107))	('protein', 'cellular_component', 'GO:0003675', ('235', '242'))	('pRCC', 'Phenotype', 'HP:0006766', (46, 50))	('pRCC', 'Gene', '5546', (46, 50))	('missense mutation', 'Var', (132, 149))	('constitutive activation', 'MPA', (200, 223))	('pRCC', 'Gene', (103, 107))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('patients', 'Species', '9606', (108, 116))	('MET protein', 'Protein', (231, 242))	('pRCC', 'Gene', (46, 50))
518	30466410	Another large series of pRCC (n = 164) described MET mutations in 17 tumors, mainly in type 1 pRCC and in the tyrosine kinase domain (14/17), and discovered an alternate MET RNA transcript leading to a constitutive activation of MET in a ligand-independent manner.	('tyrosine kinase', 'Gene', '7294', (110, 125))	('MET', 'Gene', (49, 52))	('pRCC', 'Gene', '5546', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MET', 'MPA', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))	('pRCC', 'Gene', '5546', (94, 98))	('activation', 'PosReg', (215, 225))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('pRCC', 'Gene', (24, 28))	('mutations', 'Var', (53, 62))	('tumors', 'Disease', (69, 75))	('ligand', 'molecular_function', 'GO:0005488', ('238', '244'))	('RNA', 'cellular_component', 'GO:0005562', ('174', '177'))	('man', 'Species', '9606', (257, 260))	('pRCC', 'Phenotype', 'HP:0006766', (94, 98))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('pRCC', 'Gene', (94, 98))	('tyrosine kinase', 'Gene', (110, 125))
520	30466410	First, foretinib (MET/VEGFR2 inhibitor) was examined in a phase II including 74 patients with mpRCC: the median PFS was 9.3 months and patients with a germline mutation were significantly more likely to respond.	('foretinib', 'Chemical', 'MESH:C544831', (7, 16))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (80, 88))	('pRCC', 'Gene', (95, 99))	('respond', 'MPA', (203, 210))	('VEGFR2', 'Gene', '3791', (22, 28))	('germline mutation', 'Var', (151, 168))	('pRCC', 'Gene', '5546', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('pRCC', 'Phenotype', 'HP:0006766', (95, 99))	('VEGFR2', 'Gene', (22, 28))
524	30466410	Interestingly, if the response rate was 0% in MET-independent pRCC, it was of 18% in patients with a MET-driven pRCC (chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations).	('copy gain', 'Var', (131, 140))	('pRCC', 'Phenotype', 'HP:0006766', (62, 66))	('pRCC', 'Gene', '5546', (62, 66))	('HGF', 'Gene', '3082', (155, 158))	('pRCC', 'Gene', (112, 116))	('MET kinase domain mutations', 'Var', (182, 209))	('chromosome', 'cellular_component', 'GO:0005694', ('118', '128'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('patients', 'Species', '9606', (85, 93))	('HGF', 'Gene', (155, 158))	('pRCC', 'Phenotype', 'HP:0006766', (112, 116))	('pRCC', 'Gene', (62, 66))	('pRCC', 'Gene', '5546', (112, 116))	('MET', 'Gene', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))
529	30466410	Only a previous case report described a MET-mutated pRCC patient pre-treated with sunitinib and tivantinib; however this mutation (missense base substitution MET H1094L) is rare compared to MET amplification, and the patient only remained on crizotinib therapy for 5 months (versus 19 months in our patient).	('H1094L', 'Mutation', 'p.H1094L', (162, 168))	('pRCC', 'Phenotype', 'HP:0006766', (52, 56))	('patient', 'Species', '9606', (57, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (242, 252))	('pRCC', 'Gene', '5546', (52, 56))	('patient', 'Species', '9606', (217, 224))	('MET H1094L', 'Var', (158, 168))	('tivantinib', 'Chemical', 'MESH:C551661', (96, 106))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pre', 'molecular_function', 'GO:0003904', ('65', '68'))	('patient', 'Species', '9606', (299, 306))	('pRCC', 'Gene', (52, 56))	('sunitinib', 'Chemical', 'MESH:D000077210', (82, 91))
531	30466410	Interestingly, in November 2017 were published the results of pRCC1 patients included in the CREATE trial (EORTC 90101), a multicentric prospective phase II clinical trial including patients with tumors harboring specific alterations leading to ALK and/or MET activation and treated with crizotinib.	('pRCC', 'Phenotype', 'HP:0006766', (62, 66))	('pRCC', 'Gene', '5546', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors', 'Disease', (196, 202))	('crizotinib', 'Chemical', 'MESH:D000077547', (288, 298))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('leading to', 'Reg', (234, 244))	('patients', 'Species', '9606', (68, 76))	('ALK', 'Gene', '238', (245, 248))	('patients', 'Species', '9606', (182, 190))	('pRCC', 'Gene', (62, 66))	('alterations', 'Var', (222, 233))	('MET activation', 'MPA', (256, 270))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('ALK', 'Gene', (245, 248))
533	30466410	This study demonstrated that crizotinib is active in pRCC, achieving long-lasting disease control in patients with MET mutations or amplification.	('pRCC', 'Gene', (53, 57))	('patients', 'Species', '9606', (101, 109))	('crizotinib', 'Chemical', 'MESH:D000077547', (29, 39))	('amplification', 'Var', (132, 145))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('MET mutations', 'Var', (115, 128))	('pRCC', 'Phenotype', 'HP:0006766', (53, 57))	('pRCC', 'Gene', '5546', (53, 57))
535	30466410	This precision treatment (crizotinib) was possible thanks to an original biology-driven national French program (AcSe crizotinib NCT02034981), giving access to crizotinib for patients with identified activating genomic alterations in the crizotinib target genes, with a safe monitoring.	('crizotinib', 'Chemical', 'MESH:D000077547', (238, 248))	('crizotinib', 'Chemical', 'MESH:D000077547', (118, 128))	('crizotinib', 'Chemical', 'MESH:D000077547', (26, 36))	('crizotinib', 'Chemical', 'MESH:D000077547', (160, 170))	('patients', 'Species', '9606', (175, 183))	('genomic alterations', 'Var', (211, 230))	('activating', 'PosReg', (200, 210))
551	32111252	Compared to molecular subtypes reported by TCGA or other similar approaches, the subtypes generated by DeClust had higher correlations with cancer-intrinsic genomic alterations (e.g., somatic mutations and copy number variations) and lower correlations with tumor purity.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor purity', 'Disease', (258, 270))	('correlations', 'Interaction', (122, 134))	('higher', 'PosReg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('copy number variations', 'Var', (206, 228))	('tumor purity', 'Disease', 'MESH:D009369', (258, 270))
552	32111252	While DeClust-identified subtypes were not more significantly associated with survival in general, DeClust identified a poor prognosis subtype of clear cell renal cancer, papillary renal cancer, and lung adenocarcinoma, all of which were characterized by CDKN2A deletions.	('renal cancer', 'Phenotype', 'HP:0009726', (157, 169))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (146, 169))	('renal cancer', 'Phenotype', 'HP:0009726', (181, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (199, 218))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (199, 218))	('deletions', 'Var', (262, 271))	('papillary renal cancer', 'Disease', 'MESH:D007680', (171, 193))	('CDKN2A', 'Gene', (255, 261))	('clear cell renal cancer', 'Disease', (146, 169))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('papillary renal cancer', 'Disease', (171, 193))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (171, 193))	('lung adenocarcinoma', 'Disease', (199, 218))	('CDKN2A', 'Gene', '1029', (255, 261))	('clear cell renal cancer', 'Disease', 'MESH:D002292', (146, 169))
594	32111252	In brief, cells were stained with fixable viability dye blue to ascertain viability (ThermoFisher) and BV510-labeled anti-CD45 (BioLegend).	('BV510-labeled', 'Var', (103, 116))	('CD45', 'Gene', '5788', (122, 126))	('CD45', 'Gene', (122, 126))
619	32111252	As a result, the expression profiles of SW780, BFTC950, and KU1919 cell lines in CCLE were chosen as the reference cancer cell profile for luminal, basal, and neuronal subtype, respectively.	('CCLE', 'Chemical', '-', (81, 85))	('cancer', 'Disease', (115, 121))	('SW780', 'CellLine', 'CVCL:1728', (40, 45))	('BFTC950', 'Var', (47, 54))	('KU1919', 'CellLine', 'CVCL:1344', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SW780', 'Var', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
637	32111252	For the pan-cancer dataset, we again focused on the accuracy of the primary outputs, but because ground truth in the pan-cancer dataset is not known, we examined how DeClust outputs compared to other approaches with regard to patient survival, known drive mutations, tumor purity, and cell compartment-specific gene expression (see Additional file 1: Figure S2 for an overview of our study workflow).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor purity', 'Disease', (267, 279))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patient', 'Species', '9606', (226, 233))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('gene expression', 'biological_process', 'GO:0010467', ('311', '326'))	('tumor purity', 'Disease', 'MESH:D009369', (267, 279))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (256, 265))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
649	32111252	We subsequently confirmed the associations between DeClust estimates of stromal proportion and survival in independent datasets: GSE3538 for KIRC and GSE32894 for BLCA, respectively (Additional file 1: Figure S6, see the "Methods" section for details).	('GSE3538', 'Var', (129, 136))	('GSE3538', 'Chemical', '-', (129, 136))	('GSE32894', 'Var', (150, 158))	('GSE', 'Chemical', '-', (129, 132))	('BLCA', 'Chemical', '-', (163, 167))	('GSE', 'Chemical', '-', (150, 153))
661	32111252	Cancer molecular subtypes driven by cancer cell-intrinsic properties as opposed to variations in non-cancer cell compartments are likely to be characterized by subtype-specific genomic alterations (somatic mutations or copy number alterations).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (101, 107))	('copy number alterations', 'Var', (219, 242))	('cancer', 'Disease', (36, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
663	32111252	For example, FGFR3 mutations, one of the best characterized features of luminal-papillary bladder cancer, were present in 37% of the luminal-papillary subtype based on DeClust, versus 31% by TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR', 'molecular_function', 'GO:0005007', ('13', '17'))	('mutations', 'Var', (19, 28))	('luminal-papillary bladder cancer', 'Disease', (72, 104))	('luminal-papillary', 'Disease', (133, 150))	('FGFR3', 'Gene', (13, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('luminal-papillary bladder cancer', 'Disease', 'MESH:D001749', (72, 104))	('FGFR3', 'Gene', '2261', (13, 18))
664	32111252	Methylation is another common type of genomic alteration in cancer cells.	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
666	32111252	A stronger subtype-specific association with genomic alterations is only an indirect indication that the subtypes are likely to be driven by cancer cell-intrinsic genomic alterations.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('alterations', 'Var', (53, 64))
675	32111252	In summary, compared to TCGA subtypes, DeClust subtypes were more likely driven by cancer cell-intrinsic genetic alterations as opposed to non-cancer cell variations, in addition to having a stronger association with survival outcomes in certain tumor types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('genetic alterations', 'Var', (105, 124))	('driven by', 'Reg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', (246, 251))	('cancer', 'Disease', (83, 89))
683	32111252	Interestingly, all were enriched for CDKN2A deletions (Fig.	('deletions', 'Var', (44, 53))	('CDKN2A', 'Gene', '1029', (37, 43))	('CDKN2A', 'Gene', (37, 43))
684	32111252	This is consistent with the previous discovery that samples with the same tumor suppressor gene inactivation in different cancer types tended to cluster together.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inactivation', 'Var', (96, 108))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
685	32111252	The associations of the worse survival and the outlier DeClust subtypes of KIRP, KIRC, and LUAD were replicated in independent datasets GSE2748, GSE3538, and GSE31210, respectively (Additional file 1: Figure S11).	('GSE', 'Chemical', '-', (136, 139))	('GSE', 'Chemical', '-', (145, 148))	('worse', 'NegReg', (24, 29))	('GSE3538', 'Var', (145, 152))	('GSE31210', 'Var', (158, 166))	('GSE2748', 'Var', (136, 143))	('GSE2748', 'Chemical', '-', (136, 143))	('GSE', 'Chemical', '-', (158, 161))	('GSE3538', 'Chemical', '-', (145, 152))
722	32111252	Since identifying subtype-specific genetic alterations is an important strategy for identification of potential driver genes and associated therapeutic targets, DeClust could be a useful tool for such purposes, and helping to uncover genetic associations that are otherwise obscured by the non-cancer cell compartments.	('genetic alterations', 'Var', (35, 54))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', (294, 300))	('alterations', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
724	32111252	DeClust identified poor prognosis subtypes in KIRC, KIRP, and LUAD, which were enriched for CDKN2A deletions, highlighting that for these cancer types, cancer cell-intrinsic molecular programs are key drivers of prognosis.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (152, 158))	('CDKN2A', 'Gene', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('deletions', 'Var', (99, 108))	('CDKN2A', 'Gene', '1029', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
751	32111252	The non-TCGA tumor expression datasets used in the study are available in GEO database: GSE2748, GSE3538, and GSE31210, GSE37614, GSE3538, GSE32894.	('tumor', 'Disease', (13, 18))	('GSE2748', 'Chemical', '-', (88, 95))	('GSE32894', 'Var', (139, 147))	('GSE3538', 'Chemical', '-', (97, 104))	('GSE', 'Chemical', '-', (110, 113))	('GSE', 'Chemical', '-', (97, 100))	('GSE', 'Chemical', '-', (139, 142))	('GSE3538', 'Chemical', '-', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('GSE37614', 'Var', (120, 128))	('GSE', 'Chemical', '-', (88, 91))	('GSE31210', 'Var', (110, 118))	('GSE', 'Chemical', '-', (120, 123))	('GSE3538', 'Var', (97, 104))	('GSE2748', 'Var', (88, 95))	('GSE', 'Chemical', '-', (130, 133))	('GSE3538', 'Var', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
775	31905821	Thus, the most frequent genetic alteration in CCRCC involves chromosome 3p deletion, VHL mutation and/or VHL promoter methylation, leading to VHL inactivation, an early and crucial event in sporadic CCRCC and in the familial cancer syndrome von Hippel-Lindau disease.	('VHL', 'Gene', (85, 88))	('inactivation', 'NegReg', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('familial cancer syndrome von Hippel-Lindau disease', 'Disease', (216, 266))	('VHL', 'Gene', '7428', (142, 145))	('methylation', 'biological_process', 'GO:0032259', ('118', '129'))	('CCRCC', 'Disease', 'MESH:D002292', (199, 204))	('VHL', 'Gene', '7428', (85, 88))	('CCRCC', 'Disease', (199, 204))	('CCRCC', 'Disease', 'MESH:D002292', (46, 51))	('VHL', 'Gene', (105, 108))	('familial cancer syndrome von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (216, 266))	('mutation', 'Var', (89, 97))	('CCRCC', 'Disease', (46, 51))	('CCRCC', 'Phenotype', 'HP:0006770', (199, 204))	('VHL', 'Gene', '7428', (105, 108))	('CCRCC', 'Phenotype', 'HP:0006770', (46, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('61', '71'))	('VHL', 'Gene', (142, 145))
777	31905821	Application in routine practice: The presence of VHL mutation, chromosome 3p deletion or VHL promoter methylation is considered useful for the confirmation of CCRCC diagnosis in difficult cases (see following sections).	('methylation', 'biological_process', 'GO:0032259', ('102', '113'))	('mutation', 'Var', (53, 61))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('VHL', 'Gene', (89, 92))	('CCRCC', 'Disease', (159, 164))	('VHL', 'Gene', '7428', (89, 92))	('CCRCC', 'Phenotype', 'HP:0006770', (159, 164))	('VHL', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (49, 52))	('CCRCC', 'Disease', 'MESH:D002292', (159, 164))
781	31905821	The most frequent genetic alterations in MCRCNLMP are identical to chromosome 3p deletion in 74% (14/19) of cases and VHL mutation in 25% (3/12) of cases.	('VHL', 'Gene', (118, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('67', '77'))	('VHL', 'Gene', '7428', (118, 121))	('mutation', 'Var', (122, 130))	('MCRCNLMP', 'Gene', (41, 49))
784	31905821	Application in routine practice: Similar to CCRCC, chromosome 3p deletion and VHL mutation might be found in MCRCNLMP, but no specific genetic alterations have so far been identified.	('CCRCC', 'Phenotype', 'HP:0006770', (44, 49))	('mutation', 'Var', (82, 90))	('VHL', 'Gene', (78, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('51', '61'))	('CCRCC', 'Disease', 'MESH:D002292', (44, 49))	('chromosome 3p deletion', 'Var', (51, 73))	('VHL', 'Gene', '7428', (78, 81))	('found', 'Reg', (100, 105))	('MCRCNLMP', 'Disease', (109, 117))	('CCRCC', 'Disease', (44, 49))
792	31905821	While mutations of MET are rarely referred for sporadic type 1 PRCC, it is commonly associated with hereditary papillary RCC syndrome.	('PRCC', 'Gene', '5546', (63, 67))	('papillary RCC', 'Gene', '5546', (111, 124))	('PRCC', 'Gene', (63, 67))	('associated', 'Reg', (84, 94))	('PRCC', 'Phenotype', 'HP:0006766', (63, 67))	('papillary RCC', 'Gene', (111, 124))	('mutations', 'Var', (6, 15))	('MET', 'Gene', (19, 22))
795	31905821	Although gains of chromosomes 7 and 17 were reported to be the most frequently listed CNV changes for this subtype, the recent literature show that trisomy/polysomy 7/17 is not commonly associated with type 2 PRCC.	('PRCC', 'Gene', '5546', (209, 213))	('PRCC', 'Gene', (209, 213))	('trisomy/polysomy 7/17', 'Var', (148, 169))	('associated', 'Reg', (186, 196))	('PRCC', 'Phenotype', 'HP:0006766', (209, 213))
798	31905821	Such tumors showed CDKN2A silencing, SETD2 mutations, and increased expression of the NRF2 antioxidant response element pathway.	('SETD2', 'Gene', '29072', (37, 42))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('NRF2', 'Gene', '4780', (86, 90))	('increased', 'PosReg', (58, 67))	('SETD2', 'Gene', (37, 42))	('expression', 'MPA', (68, 78))	('CDKN2A', 'Gene', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('NRF2', 'Gene', (86, 90))	('CDKN2A', 'Gene', '1029', (19, 25))	('silencing', 'NegReg', (26, 35))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
802	31905821	Some these tumors have shown to have a copy number pattern identical to renal oncocytoma: disomic status of chromosomes 7 and 17, some with deletion of chromosome 14, deletion of 1p (locus 1p36).	('renal oncocytoma', 'Disease', 'MESH:C537750', (72, 88))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('152', '162'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('renal oncocytoma', 'Disease', (72, 88))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('deletion of', 'Var', (167, 178))
805	31905821	Interestingly, this tumor is characterized by frequent KRAS mutations.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '3845', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (20, 25))
807	31905821	It should be noted that all of these variants are defined mostly using morphologic features and that their molecular-genetic features are widely varied, as generally observed in papillary RCCs.	('observed', 'Reg', (166, 174))	('papillary RCC', 'Gene', '5546', (178, 191))	('RCCs', 'Disease', (188, 192))	('RCCs', 'Disease', 'MESH:D002292', (188, 192))	('papillary RCC', 'Gene', (178, 191))	('RCCs', 'Phenotype', 'HP:0005584', (188, 192))	('variants', 'Var', (37, 45))
819	31905821	Testing germline mutations in the novel tumor suppressor gene FLCN (folliculin) can be used to support the diagnosis of Birt-Hogg-Dube syndrome, which predisposes to the so-called "hybrid" oncocytic/chromophobe tumors.	('germline mutations', 'Var', (8, 26))	('folliculin', 'Gene', '201163', (68, 78))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('40', '56'))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('FLCN', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('folliculin', 'Gene', (68, 78))	('Birt-Hogg-Dube syndrome', 'Disease', (120, 143))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (120, 143))	('FLCN', 'Gene', '201163', (62, 66))	('tumor', 'Disease', (211, 216))	('chromophobe tumors', 'Disease', (199, 217))	('chromophobe tumors', 'Disease', 'MESH:D000238', (199, 217))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor suppressor', 'biological_process', 'GO:0051726', ('40', '56'))
824	31905821	There are 3 basic genetic patterns in ROs: (1) loss of chromosome 1 (in whole or in part) and loss of chromosome Y, (2) rearrangements of 11q13 (mostly translocation t(5;11)(q35;q13)), chromosome 14 deletion, and (3) a normal karyotype.	('rearrangements', 'Var', (120, 134))	('ROs', 'Chemical', '-', (38, 41))	('ROs', 'Gene', (38, 41))	('t(5;11)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (166, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('185', '195'))	('translocation t(5;11)(q35;q13', 'Var', (152, 181))	('loss', 'NegReg', (94, 98))	('loss', 'NegReg', (47, 51))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('11q13', 'Gene', (138, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('RO', 'Phenotype', 'HP:0011798', (38, 40))
836	31905821	In fact, analysis of 3p25 loss and VHL gene alterations (mutations and methylation status) together with morphology and immunohistochemical profile would allow us to correctly diagnose almost all such cases.	('diagnose', 'Reg', (176, 184))	('methylation', 'biological_process', 'GO:0032259', ('71', '82'))	('alterations', 'Var', (44, 55))	('loss', 'NegReg', (26, 30))	('VHL', 'Gene', (35, 38))	('3p25', 'Protein', (21, 25))	('VHL', 'Gene', '7428', (35, 38))
840	31905821	In challenging cases where the morphology and/or immunohistochemical profile are not typical of CCPRCC, genetic testing for VHL mutation/methylation and/or chromosome 3p loss are essential for rendering an accurate diagnosis of CCPRCC.	('chromosome', 'cellular_component', 'GO:0005694', ('156', '166'))	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('VHL', 'Gene', '7428', (124, 127))	('CCPRCC', 'Disease', (96, 102))	('loss', 'NegReg', (170, 174))	('mutation/methylation', 'Var', (128, 148))	('PRCC', 'Phenotype', 'HP:0006766', (98, 102))	('CCPRCC', 'Disease', 'MESH:D002292', (96, 102))	('CCPRCC', 'Disease', (228, 234))	('PRCC', 'Phenotype', 'HP:0006766', (230, 234))	('CCPRCC', 'Disease', 'MESH:D002292', (228, 234))	('VHL', 'Gene', (124, 127))
841	31905821	Renal tumors with TFE3, TFEB, and MiTF rearrangements are "classic" translocation-associated RCCs, being diagnosed based on a combination of morphologic, immunohistochemical, and molecular genetic analyses.	('RCCs', 'Disease', (93, 97))	('RCCs', 'Disease', 'MESH:D002292', (93, 97))	('Renal tumors', 'Disease', (0, 12))	('TFE3', 'Gene', '7030', (18, 22))	('RCCs', 'Phenotype', 'HP:0005584', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('MiTF', 'Gene', (34, 38))	('TFEB', 'Gene', '7942', (24, 28))	('TFEB', 'Gene', (24, 28))	('rearrangements', 'Var', (39, 53))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MiTF', 'Gene', '4286', (34, 38))	('Renal tumors', 'Disease', 'MESH:D007680', (0, 12))	('TFE3', 'Gene', (18, 22))
842	31905821	RCC with TFE3 rearrangements (Xp11.2) is the most common of all translocation-associated RCCs.	('RCCs', 'Phenotype', 'HP:0005584', (89, 93))	('TFE3', 'Gene', (9, 13))	('translocation-associated', 'Disease', (64, 88))	('rearrangements', 'Var', (14, 28))	('common', 'Reg', (50, 56))	('RCC', 'Disease', (89, 92))	('TFE3', 'Gene', '7030', (9, 13))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('RCCs', 'Disease', (89, 93))	('RCCs', 'Disease', 'MESH:D002292', (89, 93))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('RCC', 'Disease', (0, 3))
847	31905821	Immunohistochemical analysis may not be sufficient to confirm the diagnosis of TFE3 translocation RCC, and that in some cases further molecular genetic testing maybe indicated.	('TFE3', 'Gene', '7030', (79, 83))	('RCC', 'Disease', (98, 101))	('translocation', 'Var', (84, 97))	('TFE3', 'Gene', (79, 83))	('RCC', 'Disease', 'MESH:D002292', (98, 101))
853	31905821	However, even in the group of TFEB or t(6;11) translocation RCC, there is morphologic variability and that not all cases follow a "classic" morphologic pattern with biphasic morphology (Figure 1).	('TFEB', 'Gene', '7942', (30, 34))	('TFEB', 'Gene', (30, 34))	('RCC', 'Disease', (60, 63))	('translocation', 'Var', (46, 59))	('RCC', 'Disease', 'MESH:D002292', (60, 63))
854	31905821	Recent studies have shown that amplification of the TFEB gene in TFEB or t(6;11) translocation RCCs can uncommonly occur and is associated with more aggressive clinical behavior with distant metastases (see RCC with TFEB amplification).	('RCCs', 'Disease', 'MESH:D002292', (95, 99))	('associated with', 'Reg', (128, 143))	('TFEB', 'Gene', (52, 56))	('metastases', 'Disease', 'MESH:D009362', (191, 201))	('RCCs', 'Phenotype', 'HP:0005584', (95, 99))	('t(6;11', 'Gene', (73, 79))	('metastases', 'Disease', (191, 201))	('RCC', 'Disease', (207, 210))	('TFEB', 'Gene', (216, 220))	('RCC', 'Disease', (95, 98))	('TFEB', 'Gene', '7942', (52, 56))	('TFEB', 'Gene', (65, 69))	('RCC', 'Disease', 'MESH:D002292', (207, 210))	('TFEB', 'Gene', '7942', (216, 220))	('RCC', 'Disease', 'MESH:D002292', (95, 98))	('TFEB', 'Gene', '7942', (65, 69))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (149, 177))	('RCCs', 'Disease', (95, 99))	('amplification', 'Var', (31, 44))
859	31905821	In other words, when the morphology and/or immunohistochemical profile is suggestive of TFE3 translocation RCC, NGS analysis is recommended for confirmation.	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('RCC', 'Disease', (107, 110))	('translocation', 'Var', (93, 106))	('TFE3', 'Gene', (88, 92))	('TFE3', 'Gene', '7030', (88, 92))
860	31905821	Amplification of TFEB gene seems to be a strong adverse prognostic indicator in TFEB translocation RCCs, however such cases are rare and less frequently encountered comparing with TFEB amplified RCCs (without TFEB break) its occurrence is rather rare.	('Amplification', 'Var', (0, 13))	('TFEB', 'Gene', '7942', (209, 213))	('TFEB', 'Gene', '7942', (17, 21))	('TFEB', 'Gene', (209, 213))	('TFEB', 'Gene', (17, 21))	('RCCs', 'Disease', (99, 103))	('RCCs', 'Disease', (195, 199))	('RCCs', 'Phenotype', 'HP:0005584', (99, 103))	('RCCs', 'Disease', 'MESH:D002292', (99, 103))	('RCCs', 'Phenotype', 'HP:0005584', (195, 199))	('TFEB', 'Gene', '7942', (180, 184))	('TFEB', 'Gene', '7942', (80, 84))	('RCCs', 'Disease', 'MESH:D002292', (195, 199))	('translocation', 'Var', (85, 98))	('TFEB', 'Gene', (180, 184))	('TFEB', 'Gene', (80, 84))
872	31905821	In fact, loss of chromosome 9 has been suggested as a characteristic feature of TC-RCC.	('loss', 'Var', (9, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('TC-RCC', 'Disease', 'MESH:D002292', (80, 86))	('TC-RCC', 'Disease', (80, 86))
878	31905821	RCCs with "Tubulocystic" features and high grade abrupt areas should raise the possibility of FH-deficient RCC and be further genetically tested for FH gene mutation/LOH.	('RCCs', 'Phenotype', 'HP:0005584', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('RCC', 'Disease', (107, 110))	('FH', 'Gene', '2271', (149, 151))	('FH', 'Gene', '2271', (94, 96))	('mutation/LOH', 'Var', (157, 169))	('RCCs', 'Disease', (0, 4))	('RCCs', 'Disease', 'MESH:D002292', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('RCC', 'Disease', (0, 3))
884	31905821	In rare cases where alterations of SMARCB1 gene or abnormal negative staining for the protein is documented in the absence of sickle trait, the term "RCC unclassified with medullary phenotype" has been proposed.	('negative', 'NegReg', (60, 68))	('alterations', 'Var', (20, 31))	('RCC', 'Disease', 'MESH:D002292', (150, 153))	('RCC', 'Disease', (150, 153))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))	('SMARCB1', 'Gene', '6598', (35, 42))	('SMARCB1', 'Gene', (35, 42))
900	31905821	SDH deficiency is almost always associated with germline SDH subunit mutation.	('SDH', 'Gene', (57, 60))	('SDH', 'Gene', (0, 3))	('deficiency', 'Var', (4, 14))	('associated', 'Reg', (32, 42))	('SDH', 'Gene', '6390', (57, 60))	('SDH', 'Gene', '6390', (0, 3))
903	31905821	The vast majority of SDH-deficient RCCs are associated with germline mutation of the SDHB subunit.	('associated', 'Reg', (44, 54))	('RCCs', 'Disease', (35, 39))	('SDH', 'Gene', (85, 88))	('germline mutation', 'Var', (60, 77))	('RCCs', 'Phenotype', 'HP:0005584', (35, 39))	('RCCs', 'Disease', 'MESH:D002292', (35, 39))	('SDH', 'Gene', (21, 24))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('SDH', 'Gene', '6390', (85, 88))	('SDH', 'Gene', '6390', (21, 24))
904	31905821	Genetic testing of SDH subunit mutation is not necessary, however in cases where the result of immunohistochemical examination is inconclusive, it is highly recommended.	('SDH', 'Gene', (19, 22))	('mutation', 'Var', (31, 39))	('SDH', 'Gene', '6390', (19, 22))
912	31905821	For screening, immunohistochemical staining with FH is useful, however cases where staining interpretation is not convincing or in suspected clinical settings it would be better to test for FH mutation/LOH.	('FH', 'Gene', '2271', (190, 192))	('FH', 'Gene', '2271', (49, 51))	('test', 'Reg', (181, 185))	('mutation/LOH', 'Var', (193, 205))
916	31905821	It is questionable whether all these variants will be regarded as established entities within future classifications or whether they will be reclassified as variants of some "traditional" renal tumors.	('renal tumors', 'Disease', 'MESH:D007680', (188, 200))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('renal tumors', 'Disease', (188, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('variants', 'Var', (37, 45))	('renal tumors', 'Phenotype', 'HP:0009726', (188, 200))	('renal tumor', 'Phenotype', 'HP:0009726', (188, 199))
923	31905821	Both familiar and sporadic tumors have molecular alterations of TSC1 or TSC2.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('TSC1', 'Gene', '7248', (64, 68))	('molecular alterations', 'Var', (39, 60))	('TSC2', 'Gene', '7249', (72, 76))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('TSC2', 'Gene', (72, 76))	('TSC1', 'Gene', (64, 68))	('sporadic tumors', 'Disease', 'MESH:D020821', (18, 33))	('sporadic tumors', 'Disease', (18, 33))
924	31905821	The molecular genetic revolution in the field of oncopathology has resulted in identifying more entities including a recently described subset of tumors harboring mutations of TSC1, TSC2, or MTOR, being recognized in sporadic patients as well as patients with tuberous sclerosis complex.	('tumors', 'Disease', (146, 152))	('TSC2', 'Gene', '7249', (182, 186))	('MTOR', 'Gene', (191, 195))	('TSC1', 'Gene', (176, 180))	('mutations', 'Var', (163, 172))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (260, 278))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TSC2', 'Gene', (182, 186))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('MTOR', 'Gene', '2475', (191, 195))	('patients', 'Species', '9606', (226, 234))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('260', '286'))	('tuberous sclerosis', 'Disease', (260, 278))	('TSC1', 'Gene', '7248', (176, 180))
927	31905821	They are distinct from both CCRCC and CCPRCC, harboring mutations of TCEB1 but with no VHL gene abnormalities.	('VHL', 'Gene', '7428', (87, 90))	('PRCC', 'Phenotype', 'HP:0006766', (40, 44))	('mutations', 'Var', (56, 65))	('CCPRCC', 'Disease', (38, 44))	('CCRCC', 'Disease', (28, 33))	('CCPRCC', 'Disease', 'MESH:D002292', (38, 44))	('CCRCC', 'Phenotype', 'HP:0006770', (28, 33))	('TCEB1', 'Gene', '6921', (69, 74))	('TCEB1', 'Gene', (69, 74))	('CCRCC', 'Disease', 'MESH:D002292', (28, 33))	('VHL', 'Gene', (87, 90))
934	31905821	Molecular genetics usually disclose amplification of TFEB/6p21/VEGFA, while rearrangement of TFEB is usually not present.	('VEGFA', 'Gene', (63, 68))	('TFEB', 'Gene', '7942', (53, 57))	('TFEB', 'Gene', (53, 57))	('amplification', 'Var', (36, 49))	('VEGFA', 'Gene', '7422', (63, 68))	('TFEB', 'Gene', '7942', (93, 97))	('disclose', 'Reg', (27, 35))	('TFEB', 'Gene', (93, 97))
935	31905821	However, in one of the first cases authors pointed out that amplification of TFEB gene might be a marker of aggressive behavior showed both rearrangement and amplification (Figure 4).	('rearrangement', 'Var', (140, 153))	('amplification', 'Var', (60, 73))	('TFEB', 'Gene', '7942', (77, 81))	('TFEB', 'Gene', (77, 81))	('amplification', 'Var', (158, 171))	('aggressive behavior', 'Disease', (108, 127))	('aggressive behavior', 'Phenotype', 'HP:0000718', (108, 127))	('aggressive behavior', 'biological_process', 'GO:0002118', ('108', '127'))	('aggressive behavior', 'Disease', 'MESH:D001523', (108, 127))
937	31905821	Rearrangement of ALK has been described in various tumors, mostly in lymphomas, lung carcinomas, and thyroid carcinomas.	('lymphomas', 'Disease', 'MESH:D008223', (69, 78))	('lymphomas', 'Phenotype', 'HP:0002665', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('lung carcinomas', 'Disease', 'MESH:D008175', (80, 95))	('described', 'Reg', (30, 39))	('lung carcinomas', 'Disease', (80, 95))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (101, 119))	('Rearrangement', 'Var', (0, 13))	('lymphomas', 'Disease', (69, 78))	('ALK', 'Gene', '238', (17, 20))	('thyroid carcinomas', 'Disease', (101, 119))	('ALK', 'Gene', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (101, 119))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))
964	30822312	The mutation of MET oncogene is a crucial step into the pathogenesis of hereditary pRCC forms, resulting in constitutive activation of the tyrosine kinase domain, which leads to increasing unregulated proliferation, invasion and metastases.	('pRCC', 'Phenotype', 'HP:0006766', (83, 87))	('pRCC', 'Gene', '5546', (83, 87))	('increasing', 'PosReg', (178, 188))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('unregulated', 'MPA', (189, 200))	('mutation', 'Var', (4, 12))	('metastases', 'Disease', (229, 239))	('tyrosine kinase domain', 'MPA', (139, 161))	('invasion', 'CPA', (216, 224))	('pRCC', 'Gene', (83, 87))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))	('metastases', 'Disease', 'MESH:D009362', (229, 239))	('activation', 'PosReg', (121, 131))
997	30822312	A risk score formula based on the expression level and coefficient of 5 mRNAs was created as follows: Risk score = (-0.560 * expression level of BUB1) + (0.337 * expression level of CCNB2) + (0.424 * expression level of IGF2BP3) + (0.516 * expression level of KIF18A) + (0.310 x expression level of PTTG1).	('KIF18A', 'Gene', '81930', (260, 266))	('0.337 *', 'Var', (154, 161))	('BUB1', 'Gene', '699', (145, 149))	('CCNB2', 'Gene', (182, 187))	('BUB1', 'Gene', (145, 149))	('IGF2BP3', 'Gene', (220, 227))	('IGF2BP3', 'Gene', '10643', (220, 227))	('expression', 'MPA', (240, 250))	('PTTG1', 'Gene', (299, 304))	('KIF18A', 'Gene', (260, 266))	('expression', 'MPA', (200, 210))	('PTTG1', 'Gene', '9232', (299, 304))	('CCNB2', 'Gene', '9133', (182, 187))	('-0.560', 'Var', (116, 122))
1011	30822312	The KEGG pathway enrichment analysis result showed that the DEGs were associated with calcium,cAMP,phosphollipase D, and hippo signaling pathway.	('hippo signaling pathway', 'biological_process', 'GO:0035329', ('121', '144'))	('cAMP', 'Chemical', '-', (94, 98))	('DEGs', 'Var', (60, 64))	('cAMP', 'Pathway', (94, 98))	('calcium', 'Disease', (86, 93))	('phosphollipase D', 'Pathway', (99, 115))	('associated', 'Reg', (70, 80))	('men', 'Species', '9606', (23, 26))	('calcium', 'Chemical', 'MESH:D002118', (86, 93))	('hippo signaling pathway', 'Pathway', (121, 144))
1016	30822312	There is increasing evidence that the Hippo pathway is dysregulated in many human cancers, and dysregulation of the Hippo pathway exerts a significant impact on cancer development, including liver, breast, lung, colon, ovary, and others.	('liver', 'Disease', (191, 196))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung', 'Disease', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('men', 'Species', '9606', (175, 178))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('colon', 'Disease', 'MESH:D015179', (212, 217))	('impact', 'Reg', (151, 157))	('Hippo', 'Gene', (116, 121))	('ovary', 'Disease', (219, 224))	('dysregulation', 'Var', (95, 108))	('colon', 'Disease', (212, 217))	('breast', 'Disease', (198, 204))	('human', 'Species', '9606', (76, 81))	('Hippo pathway', 'Pathway', (38, 51))
1017	30822312	Aberrant phospholipase D (PLD) expression has been identified in multiple facets of complex pathological states, including cancer and inflammatory diseases.	('PLD', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inflammatory diseases', 'Disease', 'MESH:D007249', (134, 155))	('Aberrant', 'Var', (0, 8))	('identified', 'Reg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('inflammatory diseases', 'Disease', (134, 155))	('cancer', 'Disease', (123, 129))	('phospholipase D', 'Gene', '2822', (9, 24))	('PLD', 'Gene', '2822', (26, 29))	('phospholipase D', 'Gene', (9, 24))
1034	30822312	In ovarian cancer, high expression of IGF2BP3 was associated with poor survival, and women diagnosed at advanced stages with elevated IGF2BP3 was at higher risk of developing chemoresistance.	('elevated', 'PosReg', (125, 133))	('IGF2BP3', 'Gene', '10643', (134, 141))	('IGF2BP3', 'Gene', (134, 141))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('IGF2BP3', 'Gene', '10643', (38, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('IGF2BP3', 'Gene', (38, 45))	('women', 'Species', '9606', (85, 90))	('ovarian cancer', 'Disease', (3, 17))	('chemoresistance', 'CPA', (175, 190))	('survival', 'MPA', (71, 79))	('poor', 'NegReg', (66, 70))
1035	30822312	revealed that normal colorectal epithelium was negative for IGF2BP3 in patients of normal mucosa adjacent to carcinoma, and IGF2BP3 was associated with poor differentiation, stage III-IV disease, BRAF mutation, and LINE-1 hypomethylation.	('carcinoma', 'Disease', (109, 118))	('negative', 'NegReg', (47, 55))	('poor differentiation', 'CPA', (152, 172))	('patients', 'Species', '9606', (71, 79))	('BRAF', 'Gene', '673', (196, 200))	('associated with', 'Reg', (136, 151))	('IGF2BP3', 'Gene', '10643', (124, 131))	('IGF2BP3', 'Gene', (124, 131))	('stage III-IV disease', 'Disease', (174, 194))	('BRAF', 'Gene', (196, 200))	('carcinoma', 'Disease', 'MESH:D002277', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('LINE-1 hypomethylation', 'Var', (215, 237))	('IGF2BP3', 'Gene', '10643', (60, 67))	('IGF2BP3', 'Gene', (60, 67))
1037	30822312	In the present study, it was demonstrated that the pRCC patients with IGF2BP3 alterations exhibited a poorer survival rate compared with those without the genetic alterations.	('patients', 'Species', '9606', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('poorer', 'NegReg', (102, 108))	('IGF2BP3', 'Gene', '10643', (70, 77))	('IGF2BP3', 'Gene', (70, 77))	('pRCC', 'Gene', (51, 55))	('alterations', 'Var', (78, 89))	('survival rate', 'CPA', (109, 122))	('pRCC', 'Phenotype', 'HP:0006766', (51, 55))	('pRCC', 'Gene', '5546', (51, 55))
1038	30822312	This result suggested that the mutation in IGF2BP3 reduces the survival rate of patients with pRCC.	('IGF2BP3', 'Gene', '10643', (43, 50))	('IGF2BP3', 'Gene', (43, 50))	('survival rate', 'CPA', (63, 76))	('patients', 'Species', '9606', (80, 88))	('pRCC', 'Gene', '5546', (94, 98))	('reduces', 'NegReg', (51, 58))	('mutation', 'Var', (31, 39))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('pRCC', 'Phenotype', 'HP:0006766', (94, 98))	('pRCC', 'Gene', (94, 98))
1044	30822312	The high level of PTTG1 is commonly associated with an enhanced proliferative capacity, increased tumour grade and high invasive potential.	('invasive potential', 'CPA', (120, 138))	('high level', 'Var', (4, 14))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('enhanced', 'PosReg', (55, 63))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('proliferative capacity', 'CPA', (64, 86))	('tumour', 'Disease', (98, 104))	('increased', 'PosReg', (88, 97))	('PTTG1', 'Gene', '9232', (18, 23))	('PTTG1', 'Gene', (18, 23))
1046	30822312	Mutations in BUB1, some of which are functional, occur in some cancers, including those that originate in the lung, colon, and are reported to be associated with chromosomal instability and lymph node metastasis, suggesting that silencing of this kinase may mediate aggressive clinical behavior.	('colon', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('occur', 'Reg', (49, 54))	('mediate', 'Reg', (258, 265))	('colon', 'Disease', 'MESH:D015179', (116, 121))	('Mutations', 'Var', (0, 9))	('BUB1', 'Gene', '699', (13, 17))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (266, 294))	('chromosomal instability', 'Phenotype', 'HP:0040012', (162, 185))	('BUB1', 'Gene', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('associated', 'Reg', (146, 156))
1112	28972818	The following antibodies were used in this study: CgA (M0869, Dako, Glostrup, Denmark, 1:200), synaptophysin (M7315, Dako, 1:200), NSE (BBS/NC/VI-H14, Dako, 1:200), CD56 (123C3, Dako, 1:50), and secretagogin (MAb 4878, R&D Systems, Minneapolis, MN, 1:200).	('M0869', 'Var', (55, 60))	('M7315', 'Var', (110, 115))	('MN', 'CellLine', 'CVCL:U508', (245, 247))
1227	28972818	Interestingly, the carcinomas of the stomach with focal NSE expression also expressed one or more other NE markers in the same areas, thus supporting the finding of NE differentiation in these tumors.	('NSE', 'Gene', (56, 59))	('carcinomas of the stomach', 'Disease', 'MESH:D013274', (19, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('tumors', 'Disease', (193, 199))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('focal', 'Var', (50, 55))	('carcinomas of the stomach', 'Disease', (19, 44))	('carcinomas of the stomach', 'Phenotype', 'HP:0006753', (19, 44))
1262	28662726	A two-gene methylation panel comprising OXR1 and MST1R identified malignancy with 98% sensitivity and 100% specificity, and clear cell renal cell carcinoma with 90% sensitivity and 98% specificity.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('clear cell renal cell carcinoma', 'Disease', (124, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('MST1R', 'Gene', (49, 54))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (124, 155))	('malignancy', 'Disease', (66, 76))	('methylation', 'Var', (11, 22))	('OXR1', 'Gene', (40, 44))	('MST1R', 'Gene', '4486', (49, 54))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('OXR1', 'Gene', '55074', (40, 44))
1264	28662726	Significantly higher OXR1 promoter methylation levels (p = 0.005) were associated with high nuclear grade in ccRCC.	('OXR1', 'Gene', (21, 25))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('OXR1', 'Gene', '55074', (21, 25))	('high nuclear', 'Var', (87, 99))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('higher', 'PosReg', (14, 20))
1267	28662726	Epigenetic deregulation is a frequent finding in renal cell tumors (RCT).	('Epigenetic deregulation', 'Var', (0, 23))	('renal cell tumors', 'Disease', (49, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('renal cell tumors', 'Disease', 'MESH:C538614', (49, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
1274	28662726	Among epigenetic alterations, aberrant promoter methylation, which generally entails gene silencing, has emerged as a promising class of biomarkers in urologic neoplasms, including RCTs.	('RCTs', 'Disease', (181, 185))	('neoplasms', 'Phenotype', 'HP:0002664', (160, 169))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('gene silencing', 'biological_process', 'GO:0016458', ('85', '99'))	('urologic neoplasms', 'Disease', (151, 169))	('urologic neoplasms', 'Disease', 'MESH:D014571', (151, 169))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('aberrant promoter methylation', 'Var', (30, 59))
1277	28662726	Recently, we showed that MST1R was also frequently methylated in RCC, and promoter methylation levels discriminated ccRCC from the remaining RCT subtypes with high specificity.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('MST1R', 'Gene', (25, 30))	('RCC', 'Disease', (118, 121))	('methylated', 'Var', (51, 61))	('MST1R', 'Gene', '4486', (25, 30))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('promoter methylation levels', 'MPA', (74, 101))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
1278	28662726	Nevertheless, over the last years, several high-throughput studies on RCC promoter methylation using an array-based approach, identified several other hypermethylated genes in RCC, which might be useful as diagnostic biomarkers.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', (70, 73))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('methylation', 'biological_process', 'GO:0032259', ('83', '94'))	('hypermethylated', 'Var', (151, 166))
1289	28662726	MST1R, the gene with the highest percent of hypermethylated DNA (representing the fraction of input DNA containing at least two methylated CpG sites in the targeted region) was selected for further analysis, and proved to be a specific ccRCC biomarker.	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('MST1R', 'Gene', '4486', (0, 5))	('RCC', 'Disease', (238, 241))	('hypermethylated', 'Var', (44, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (236, 241))	('DNA', 'cellular_component', 'GO:0005574', ('100', '103'))	('DNA', 'cellular_component', 'GO:0005574', ('60', '63'))	('MST1R', 'Gene', (0, 5))
1301	28662726	Tumor samples were categorized as HOXA9 or OXR1 methylated using the respective highest methylation ratio value observed in normal/control samples as cutoff (14.11 for HOXA9 and 1577.45 for OXR1).	('HOXA9', 'Gene', '3205', (34, 39))	('HOXA9', 'Gene', '3205', (168, 173))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('OXR1', 'Gene', '55074', (43, 47))	('1577.45', 'Var', (178, 185))	('HOXA9', 'Gene', (34, 39))	('HOXA9', 'Gene', (168, 173))	('OXR1', 'Gene', (190, 194))	('methylation', 'biological_process', 'GO:0032259', ('88', '99'))	('OXR1', 'Gene', (43, 47))	('OXR1', 'Gene', '55074', (190, 194))
1330	28662726	Using robust methylation-specific primers for each gene promoter and performing quantitative methylation-specific PCR, we found that OXR1 and MST1R promoter methylation discriminated between normal renal tissue and renal cell tumours with high specificity.	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('MST1R', 'Gene', (142, 147))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('OXR1', 'Gene', '55074', (133, 137))	('renal cell tumours', 'Disease', (215, 233))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('discriminated', 'Reg', (169, 182))	('methylation', 'Var', (157, 168))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('MST1R', 'Gene', '4486', (142, 147))	('renal cell tumours', 'Disease', 'MESH:C538614', (215, 233))	('OXR1', 'Gene', (133, 137))
1335	28662726	PCDH17 and TCF21 promoter methylation identified renal cell tumours with 67% sensitivity and 100% specificity, but OXR1 and MST1R were equally specific (100%) but more sensitive (98%) in the distinction between RCT and normal renal tissue.	('methylation', 'Var', (26, 37))	('PCDH17', 'Gene', '27253', (0, 6))	('MST1R', 'Gene', (124, 129))	('TCF21', 'Gene', (11, 16))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('PCDH17', 'Gene', (0, 6))	('renal cell tumours', 'Disease', 'MESH:C538614', (49, 67))	('MST1R', 'Gene', '4486', (124, 129))	('OXR1', 'Gene', (115, 119))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('renal cell tumours', 'Disease', (49, 67))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('RCT', 'Disease', (211, 214))	('TCF21', 'Gene', '6943', (11, 16))	('OXR1', 'Gene', '55074', (115, 119))
1337	28662726	Moreover, RASSF1A hypermethylation was shown to discriminate pRCC from normal renal tissue with 87.5% sensitivity and 73.3% specificity, although comparison with other RCT subtypes was not undertaken.	('discriminate', 'Reg', (48, 60))	('hypermethylation', 'Var', (18, 34))	('pRCC', 'Gene', (61, 65))	('RASSF1A', 'Gene', (10, 17))	('pRCC', 'Gene', '5546', (61, 65))	('RASSF1A', 'Gene', '11186', (10, 17))	('pRCC', 'Phenotype', 'HP:0006766', (61, 65))
1354	27092491	Current Insights into Long Non-Coding RNAs in Renal Cell Carcinoma Renal cell carcinoma (RCC) represents a deadly disease with rising mortality despite intensive therapeutic efforts.	('Renal Cell Carcinoma', 'Disease', (46, 66))	('Carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Renal cell carcinoma', 'Disease', (67, 87))	('RCC', 'Disease', (89, 92))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (46, 66))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 87))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('Long Non-Coding RNAs', 'Var', (22, 42))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (46, 66))
1365	27092491	It is frequently associated with loss of chromosome 3p and modifications of the von-Hippel-Lindau (VHL) gene complex, which stabilises the hypoxic-inducible factor (HIF) and thus controls oxygen sensing.	('modifications', 'Var', (59, 72))	('von-Hippel-Lindau', 'Gene', (80, 97))	('controls', 'Reg', (179, 187))	('associated', 'Reg', (17, 27))	('VHL', 'Gene', (99, 102))	('loss', 'NegReg', (33, 37))	('oxygen', 'Chemical', 'MESH:D010100', (188, 194))	('von-Hippel-Lindau', 'Gene', '7428', (80, 97))	('VHL', 'Gene', '7428', (99, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))	('oxygen sensing', 'MPA', (188, 202))
1372	27092491	Type I is associated with MET alterations, whereas Type II tumours are characterized by cyclin-dependent kinase Inhibitor 2A (CDKN2A) silencing, SETD2 mutations, transcription factor E3 (TFE3) fusions and increased expression of the nuclear factor-like 2 (NRF2)-antioxidant response element pathway.	('cyclin-dependent kinase Inhibitor 2A', 'Gene', '1029', (88, 124))	('increased', 'PosReg', (205, 214))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('kinase Inhibitor', 'biological_process', 'GO:0033673', ('105', '121'))	('SETD2', 'Gene', (145, 150))	('cyclin-dependent kinase Inhibitor', 'molecular_function', 'GO:0004861', ('88', '121'))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('transcription', 'biological_process', 'GO:0006351', ('162', '175'))	('NRF2', 'Gene', '4780', (256, 260))	('SETD2', 'Gene', '29072', (145, 150))	('transcription factor E3', 'Gene', '7030', (162, 185))	('mutations', 'Var', (151, 160))	('expression', 'MPA', (215, 225))	('fusions', 'Var', (193, 200))	('CDKN2A', 'Gene', (126, 132))	('nuclear factor-like 2', 'Gene', '4780', (233, 254))	('Type II tumours', 'Disease', 'MESH:D009369', (51, 66))	('transcription factor E3', 'Gene', (162, 185))	('NRF2', 'Gene', (256, 260))	('TFE3', 'Gene', (187, 191))	('cyclin-dependent kinase Inhibitor 2A', 'Gene', (88, 124))	('nuclear factor-like 2', 'Gene', (233, 254))	('TFE3', 'Gene', '7030', (187, 191))	('silencing', 'NegReg', (134, 143))	('CDKN2A', 'Gene', '1029', (126, 132))	('transcription factor', 'molecular_function', 'GO:0000981', ('162', '182'))	('Type II tumours', 'Disease', (51, 66))
1375	27092491	This subtype is linked to the Birt-Hogg-Dube-Syndrome, which is caused by mutations in the folliculin gene, whereas sporadic forms exhibit multiple copy number alterations in chromosomes 1, 2, 6, 10, 13 and 17.	('folliculin', 'Gene', (91, 101))	('mutations', 'Var', (74, 83))	('caused by', 'Reg', (64, 73))	('Birt-Hogg-Dube-Syndrome', 'Disease', (30, 53))	('linked', 'Reg', (16, 22))	('folliculin', 'Gene', '201163', (91, 101))
1377	27092491	Nowadays, systemic therapeutic options mainly in ccRCC include targeted therapies, monclonal antibodies against vascular endothelial growth factor (VEGF) and inhibitors for mammalian target of rapamycin (mTOR).	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('mammalian target of rapamycin', 'Gene', '2475', (173, 202))	('mammalian target of rapamycin', 'Gene', (173, 202))	('VEGF', 'Gene', (148, 152))	('vascular endothelial growth factor', 'Gene', '7422', (112, 146))	('inhibitors', 'Var', (158, 168))	('mTOR', 'Gene', (204, 208))	('mTOR', 'Gene', '2475', (204, 208))	('VEGF', 'Gene', '7422', (148, 152))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('112', '146'))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('vascular endothelial growth factor', 'Gene', (112, 146))	('RCC', 'Disease', (51, 54))
1384	27092491	Amongst other reasons, a large portion of the human genome is considered to be potentially non-coding due to missing sequence homologies to known proteins, the absence of open reading frames, and frequent codon substitutions.	('absence', 'NegReg', (160, 167))	('sequence', 'MPA', (117, 125))	('open reading frames', 'MPA', (171, 190))	('codon substitutions', 'Var', (205, 224))	('human', 'Species', '9606', (46, 51))	('missing', 'NegReg', (109, 116))
1411	27092491	A knock-down of MALAT1 in RCC cell lines inhibits cell proliferation, migration and invasion; moreover, it increases apoptosis rates.	('inhibits', 'NegReg', (41, 49))	('apoptosis rates', 'CPA', (117, 132))	('increases', 'PosReg', (107, 116))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('apoptosis', 'biological_process', 'GO:0097194', ('117', '126'))	('apoptosis', 'biological_process', 'GO:0006915', ('117', '126'))	('cell proliferation', 'CPA', (50, 68))	('MALAT1', 'Gene', (16, 22))	('knock-down', 'Var', (2, 12))
1412	27092491	2015 were able to show a direct activation of MALAT1 by c-fos, a transcription factor activated in conjunction with c-jun in the downstream pathway of VHL tumour suppressor gene inactivation in ccRCC.	('inactivation', 'Var', (178, 190))	('c-fos', 'Gene', '2353', (56, 61))	('c-jun', 'Gene', '3725', (116, 121))	('RCC', 'Disease', (196, 199))	('activation', 'PosReg', (32, 42))	('VHL tumour', 'Disease', (151, 161))	('c-jun', 'Gene', (116, 121))	('VHL tumour', 'Disease', 'MESH:D006623', (151, 161))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('transcription factor', 'molecular_function', 'GO:0000981', ('65', '85'))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('c-fos', 'Gene', (56, 61))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('MALAT1', 'Gene', (46, 52))
1413	27092491	Other lncRNAs, such as H19 and HOTAIR, are known to bind to PRC2 to induce gene silencing via H3K27 trimethylation.	('bind', 'Interaction', (52, 56))	('trimethylation', 'Var', (100, 114))	('H3K27', 'Protein', (94, 99))	('gene silencing', 'biological_process', 'GO:0016458', ('75', '89'))	('PRC2', 'Gene', (60, 64))	('H19', 'Gene', (23, 26))	('H19', 'Gene', '283120', (23, 26))	('gene silencing', 'MPA', (75, 89))
1416	27092491	After inactivation of MALAT1, decreased expression of EZH2, beta-catenin, H3K27me3 and c-myc in contrast to increased levels of E-cadherin could be demonstrated.	('EZH2', 'Gene', (54, 58))	('E-cadherin', 'Gene', (128, 138))	('expression', 'MPA', (40, 50))	('E-cadherin', 'Gene', '999', (128, 138))	('cadherin', 'molecular_function', 'GO:0008014', ('130', '138'))	('inactivation', 'Var', (6, 18))	('c-myc', 'Gene', '4609', (87, 92))	('c-myc', 'Gene', (87, 92))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('MALAT1', 'Gene', (22, 28))	('EZH2', 'Gene', '2146', (54, 58))	('H3K27me3', 'Protein', (74, 82))	('decreased', 'NegReg', (30, 39))
1423	27092491	Interestingly, a fusion of the Alpha Gene/MALAT1 with the basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor EB (TFEB) based on chromosomal translocation of t(6; 11)(p21; q13) was observed in pRCC as well as in paediatric RCC.	('TFEB', 'Gene', (131, 135))	('Gene/MALAT1', 'Gene', (37, 48))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (211, 214))	('p21', 'Gene', '644914', (184, 187))	('observed', 'Reg', (198, 206))	('fusion', 'Var', (17, 23))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('transcription factor', 'molecular_function', 'GO:0000981', ('106', '126'))	('p21', 'Gene', (184, 187))	('pRCC', 'Gene', (210, 214))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('TFEB', 'Gene', '7942', (131, 135))	('RCC', 'Disease', (240, 243))	('pRCC', 'Gene', '5546', (210, 214))
1424	27092491	In addition to the mentioned molecular insights, high levels of MALAT1 are significantly correlated with tumour size, pathologic T-stage, as well as lymph node metastases.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('high levels', 'Var', (49, 60))	('MALAT1', 'Protein', (64, 70))	('metastases', 'Disease', (160, 170))	('tumour', 'Disease', (105, 111))	('correlated', 'Reg', (89, 99))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('metastases', 'Disease', 'MESH:D009362', (160, 170))
1425	27092491	In a multivariate analysis, high MALAT1 expression represented an independent prognostic factor for shorter OS.	('expression', 'MPA', (40, 50))	('MALAT1', 'Protein', (33, 39))	('OS', 'Chemical', '-', (108, 110))	('high', 'Var', (28, 32))	('shorter OS', 'Disease', (100, 110))
1427	27092491	This has already been demonstrated in lung cancer, where antisense oligonucleotide blocking of MALAT1 prevented the spread of metastasis after tumour implantation in a mouse xenograft.	('MALAT1', 'Gene', (95, 101))	('lung cancer', 'Disease', (38, 49))	('antisense oligonucleotide blocking', 'Var', (57, 91))	('prevented', 'NegReg', (102, 111))	('mouse', 'Species', '10090', (168, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour implantation', 'Disease', (143, 162))	('tumour implantation', 'Disease', 'MESH:D057873', (143, 162))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('oligonucleotide', 'Chemical', 'MESH:D009841', (67, 82))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('spread of metastasis', 'CPA', (116, 136))
1431	27092491	When combined with mutation of p53, HIF1A promotes angiogenesis, tumourigenesis, multidrug resistance and the ability of cells to metastasise and survive.	('ability of cells to metastasise', 'CPA', (110, 141))	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('mutation', 'Var', (19, 27))	('HIF1A', 'Gene', (36, 41))	('HIF1A', 'Gene', '3091', (36, 41))	('multidrug resistance', 'CPA', (81, 101))	('angiogenesis', 'biological_process', 'GO:0001525', ('51', '63'))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('promotes', 'PosReg', (42, 50))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('angiogenesis', 'CPA', (51, 63))	('tumour', 'Disease', (65, 71))
1438	27092491	Knock-down of H19 results in decreased growth, migration, invasion, and in reduced wound healing capacity.	('H19', 'Gene', '283120', (14, 17))	('wound healing capacity', 'CPA', (83, 105))	('wound healing', 'biological_process', 'GO:0042060', ('83', '96'))	('H19', 'Gene', (14, 17))	('Knock-down', 'Var', (0, 10))	('reduced', 'NegReg', (75, 82))	('decreased growth', 'Phenotype', 'HP:0001510', (29, 45))	('invasion', 'CPA', (58, 66))	('decreased', 'NegReg', (29, 38))	('growth', 'CPA', (39, 45))	('reduced wound healing', 'Phenotype', 'HP:0001058', (75, 96))
1466	27092491	It is up-regulated in several types of cancer and knock-down of its expression leads to cell growth arrest, inhibition of invasion and elevated rates of apoptosis.	('knock-down', 'Var', (50, 60))	('growth arrest', 'Phenotype', 'HP:0001510', (93, 106))	('inhibition', 'NegReg', (108, 118))	('elevated', 'PosReg', (135, 143))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cell growth', 'biological_process', 'GO:0016049', ('88', '99'))	('invasion', 'CPA', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('apoptosis', 'biological_process', 'GO:0097194', ('153', '162'))	('growth arrest', 'Disease', (93, 106))	('growth arrest', 'Disease', 'MESH:D006323', (93, 106))	('up-regulated', 'PosReg', (6, 18))	('apoptosis', 'biological_process', 'GO:0006915', ('153', '162'))
1468	27092491	In RCC, SPRY4-IT1 is found in higher levels in ccRCC tissue and in RCC cell lines.	('RCC', 'Disease', (49, 52))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('SPRY4-IT1', 'Var', (8, 17))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
1470	27092491	Given that there is only one single publication regarding SPRY4-IT1 in RCC, the potential role of this non-coding RNA remains difficult to define.	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RNA', 'cellular_component', 'GO:0005562', ('114', '117'))	('SPRY4-IT1', 'Var', (58, 67))
1486	27092491	Knock-down of NBAT by siRNAs results in increased cell proliferation, migration and invasion in vitro.	('migration', 'CPA', (70, 79))	('Knock-down', 'Var', (0, 10))	('cell proliferation', 'biological_process', 'GO:0008283', ('50', '68'))	('increased', 'PosReg', (40, 49))	('invasion in vitro', 'CPA', (84, 101))	('NBAT', 'Gene', '6519', (14, 18))	('NBAT', 'Gene', (14, 18))	('cell proliferation', 'CPA', (50, 68))
1492	27092491	On the other hand, knockout of MALAT1 does not result in obvious alterations of pre- and post-natal development in mice.	('mice', 'Species', '10090', (115, 119))	('pre', 'molecular_function', 'GO:0003904', ('80', '83'))	('MALAT1', 'Gene', (31, 37))	('knockout', 'Var', (19, 27))
1493	27092491	Knockout of HOTAIR results in viable mice but with transformation of the spinal vertebrae and metacarpal bones, while knockout of Fendrr (Foxf1 adjacent non-coding developmental regulatory RNA) results in embryonic lethality.	('Fendrr', 'Gene', '68790', (130, 136))	('RNA', 'cellular_component', 'GO:0005562', ('189', '192'))	('Fendrr', 'Gene', (130, 136))	('embryonic lethality', 'Disease', 'MESH:D020964', (205, 224))	('embryonic lethality', 'Disease', (205, 224))	('knockout', 'Var', (118, 126))	('mice', 'Species', '10090', (37, 41))
1497	27092491	These approaches include e.g., small interfering RNAs, ribozymes, aptamers, antisense oligonucleotides, natural antisense transcripts and small molecules.	('oligonucleotides', 'Chemical', 'MESH:D009841', (86, 102))	('ribozymes', 'Var', (55, 64))	('antisense', 'Var', (76, 85))
1612	28759013	Tissue samples were cut into smaller pieces with surgical blades and digested overnight in full DMEM medium containing Collagenase Type I (300 U/ml, Thermo Fischer Scientific, Waltham, MA, USA) and DNase I, Type II (200 U/ml, Sigma Aldrich, St Louis, MO, USA).	('DNase I', 'molecular_function', 'GO:0004530', ('198', '205'))	('300 U/ml', 'Var', (139, 147))	('DMEM medium', 'Chemical', '-', (96, 107))	('200 U/ml', 'Var', (216, 224))
1634	28759013	Antibodies used were: CD14-FITC (555397, 1:10), CD206-APC (550889, 1:20), and CD1a-PE (555807, 1:10), all from BD Biosciences.	('CD14', 'Gene', (22, 26))	('CD14', 'Gene', '929', (22, 26))	('CD1a', 'Gene', (78, 82))	('CD206-APC', 'Disease', 'MESH:D011125', (48, 57))	('CD1a', 'Gene', '909', (78, 82))	('APC', 'cellular_component', 'GO:0005680', ('54', '57'))	('CD206-APC', 'Disease', (48, 57))	('550889', 'Var', (59, 65))
1687	28759013	On the contrary, in another study the presence of TAMs was reported to be associated with lower tumor grade and absence of vascular invasion in pRCC.	('pRCC', 'Phenotype', 'HP:0006766', (144, 148))	('presence', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('pRCC', 'Gene', (144, 148))	('lower', 'NegReg', (90, 95))	('TAMs', 'Chemical', '-', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('pRCC', 'Gene', '5546', (144, 148))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
1779	31361072	Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) in particular are identified as markers for differentiating between localized and advanced-stage type 2 PRCC.	('PRCC', 'Gene', (167, 171))	('cg00489401', 'Var', (11, 21))	('PRCC', 'Phenotype', 'HP:0006766', (167, 171))	('cg27649239', 'Chemical', '-', (23, 33))	('cg20555674', 'Chemical', '-', (35, 45))	('cg07196505', 'Var', (51, 61))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('cg27649239', 'Var', (23, 33))	('PRCC', 'Gene', '5546', (167, 171))	('cg20555674', 'Var', (35, 45))	('localized', 'Disease', (131, 140))
1780	31361072	Copy number analysis reveals that copy gain of PTK7 mostly occurs in advanced-stage type 2 PRCC.	('PTK7', 'Gene', (47, 51))	('PTK7', 'Gene', '5754', (47, 51))	('PRCC', 'Gene', (91, 95))	('PRCC', 'Phenotype', 'HP:0006766', (91, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('occurs', 'Reg', (59, 65))	('copy gain', 'Var', (34, 43))	('PRCC', 'Gene', '5546', (91, 95))
1781	31361072	Both the four CpG methylation changes and PTK7 copy number gain are associated with patient survival.	('associated', 'Reg', (68, 78))	('copy number', 'Var', (47, 58))	('PTK7', 'Gene', (42, 46))	('PTK7', 'Gene', '5754', (42, 46))	('methylation changes', 'Var', (18, 37))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))	('patient survival', 'CPA', (84, 100))	('patient', 'Species', '9606', (84, 91))	('gain', 'PosReg', (59, 63))
1782	31361072	RNA-seq analysis demonstrates that PTK7 copy gain leads to higher PTK7 expression relative to tumors without copy number gain.	('copy', 'Var', (40, 44))	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PTK7', 'Gene', (66, 70))	('PTK7', 'Gene', '5754', (66, 70))	('PTK7', 'Gene', (35, 39))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('PTK7', 'Gene', '5754', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('higher', 'PosReg', (59, 65))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
1784	31361072	In conclusion, DNA methylation markers that differentiate between localized and advanced-stage type 2 PRCC may serve as useful markers for disease staging or outcome, while PTK7 copy gain represents a potential treatment target for advanced-stage type 2 PRCC.	('PRCC', 'Gene', '5546', (254, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('PRCC', 'Gene', (102, 106))	('PRCC', 'Gene', (254, 258))	('DNA', 'cellular_component', 'GO:0005574', ('15', '18'))	('copy', 'Var', (178, 182))	('PRCC', 'Phenotype', 'HP:0006766', (102, 106))	('PRCC', 'Phenotype', 'HP:0006766', (254, 258))	('DNA methylation', 'biological_process', 'GO:0006306', ('15', '30'))	('PTK7', 'Gene', (173, 177))	('PRCC', 'Gene', '5546', (102, 106))	('PTK7', 'Gene', '5754', (173, 177))
1785	31361072	Stepwise methylation changes and copy number gain also associate with disease stage in PRCC patients.	('PRCC', 'Gene', '5546', (87, 91))	('copy number gain', 'Var', (33, 49))	('associate', 'Reg', (55, 64))	('patients', 'Species', '9606', (92, 100))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('PRCC', 'Gene', (87, 91))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('methylation changes', 'Var', (9, 28))	('PRCC', 'Phenotype', 'HP:0006766', (87, 91))	('disease', 'Disease', (70, 77))
1794	31361072	To address this issue, we examine 450k data from TCGA's KIRP dataset with a specific focus on identifying DNA methylation alterations and copy number variations (CNVs) that can be linked specifically to advanced-stage PRCC.	('PRCC', 'Gene', (218, 222))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))	('PRCC', 'Phenotype', 'HP:0006766', (218, 222))	('linked', 'Reg', (180, 186))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('PRCC', 'Gene', '5546', (218, 222))	('copy number variations', 'Var', (138, 160))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('methylation alterations', 'Var', (110, 133))
1797	31361072	To that end, we identify a subset of CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) and a CNV (PTK7 amplification) that differentiate localized from advanced-stage type 2 PRCC, demonstrating that both genetic and epigenetic features likely contribute to disease progression.	('PTK7', 'Gene', (106, 110))	('PRCC', 'Gene', '5546', (182, 186))	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('cg20555674', 'Var', (67, 77))	('PTK7', 'Gene', '5754', (106, 110))	('cg27649239', 'Chemical', '-', (55, 65))	('PRCC', 'Gene', (182, 186))	('cg07196505', 'Var', (83, 93))	('cg00489401', 'Var', (43, 53))	('cg20555674', 'Chemical', '-', (67, 77))	('PRCC', 'Phenotype', 'HP:0006766', (182, 186))	('localized', 'Disease', (145, 154))	('cg27649239', 'Var', (55, 65))
1798	31361072	Ten patients were reclassified based on review by a group of expert pathologists, as described in the TCGA-KIRP publication.1 We utilize the reclassified type 1 and type 2 data in this analysis: eight patients (TCGA-AL-7173, TCGA-B1-A47M, TCGA-B9-7268, TCGA-BQ-7060, TCGA-BQ-7062, TCGA-EV-5901, TCGA-HE-A5NI, and TCGA-PJ-A5Z8) are reclassified as type 1 while two patients (TCGA-A4-8098 and TCGA-J7-8537) are reclassified as type 2.	('patients', 'Species', '9606', (201, 209))	('TCGA-BQ-7060', 'Var', (253, 265))	('TCGA-BQ-7062', 'CellLine', 'CVCL:6383', (267, 279))	('A47M', 'Mutation', 'p.A47M', (233, 237))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (364, 372))	('TCGA-AL-7173', 'Var', (211, 223))
1801	31361072	RNA-seq raw gene counts for TCGA-KIRP are downloaded from GEO accession number GSM1536837 (tumor) and GSM1697009 (adjacent-normal).	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('GSM1697009', 'Var', (102, 112))	('tumor', 'Disease', (91, 96))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))
1807	31361072	Diseases and disorders analysis shows that the majority of genes with progressive promoter hyper- or hypomethylation are related to cancer.	('related', 'Reg', (121, 128))	('cancer', 'Disease', (132, 138))	('progressive', 'PosReg', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hypomethylation', 'Var', (101, 116))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
1808	31361072	Altogether, this analysis suggests that DNA methylation alterations have a functional impact on key pathways related to initiation and progression of PRCC.	('alterations', 'Var', (56, 67))	('PRCC', 'Gene', (150, 154))	('methylation alterations', 'Var', (44, 67))	('PRCC', 'Phenotype', 'HP:0006766', (150, 154))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('DNA methylation', 'biological_process', 'GO:0006306', ('40', '55'))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('key pathways', 'Pathway', (96, 108))	('impact', 'Reg', (86, 92))	('PRCC', 'Gene', '5546', (150, 154))
1811	31361072	Finally, three hypermethylated CpGs (cg00489401, cg27649239, cg20555674) and one hypomethylated CpG (cg07196505) were selected for further analysis.	('cg20555674', 'Var', (61, 71))	('cg00489401', 'Var', (37, 47))	('cg27649239', 'Chemical', '-', (49, 59))	('cg20555674', 'Chemical', '-', (61, 71))	('cg27649239', 'Var', (49, 59))
1812	31361072	Hierarchical clustering demonstrated that 29 of 35 advanced-stage type 2 PRCC clustered together and 48 of 51 localized-stage type 2 PRCC clustered together (P < 0.0001) based on methylation at these four sites (Figure 3A).	('PRCC', 'Gene', (133, 137))	('PRCC', 'Gene', '5546', (73, 77))	('PRCC', 'Phenotype', 'HP:0006766', (133, 137))	('methylation', 'Var', (179, 190))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('PRCC', 'Gene', (73, 77))	('PRCC', 'Gene', '5546', (133, 137))	('PRCC', 'Phenotype', 'HP:0006766', (73, 77))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))
1821	31361072	Genes associated with the four previously identified differentially methylated CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) are FLT4, LBXCOR1, ARL5C, and A2BP1, respectively.	('cg00489401', 'Var', (85, 95))	('LBXCOR1', 'Gene', '390598', (147, 154))	('ARL5C', 'Gene', '390790', (156, 161))	('LBXCOR1', 'Gene', (147, 154))	('cg20555674', 'Var', (109, 119))	('cg07196505', 'Var', (125, 135))	('ARL5C', 'Gene', (156, 161))	('cg27649239', 'Var', (97, 107))	('cg27649239', 'Chemical', '-', (97, 107))	('FLT4', 'Gene', (141, 145))	('FLT4', 'Gene', '2324', (141, 145))	('cg20555674', 'Chemical', '-', (109, 119))	('A2BP1', 'Gene', '54715', (167, 172))	('A2BP1', 'Gene', (167, 172))
1829	31361072	Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) differentiate between stages.	('cg00489401', 'Var', (11, 21))	('cg27649239', 'Chemical', '-', (23, 33))	('cg20555674', 'Chemical', '-', (35, 45))	('cg07196505', 'Var', (51, 61))	('cg27649239', 'Var', (23, 33))	('cg20555674', 'Var', (35, 45))
1835	31361072	Our present study also demonstrates that genes targeted for progressive hypermethylation in the transition to advanced-stage from localized PRCC are associated with adrenergic signaling, G protein signaling, and GABA receptor signaling.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('PRCC', 'Gene', '5546', (140, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('adrenergic signaling', 'MPA', (165, 185))	('signaling', 'biological_process', 'GO:0023052', ('226', '235'))	('PRCC', 'Gene', (140, 144))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('signaling', 'biological_process', 'GO:0023052', ('197', '206'))	('hypermethylation', 'Var', (72, 88))	('associated', 'Reg', (149, 159))	('PRCC', 'Phenotype', 'HP:0006766', (140, 144))	('G protein signaling', 'MPA', (187, 206))	('GABA receptor', 'Gene', (212, 225))	('GABA receptor', 'Gene', '11337', (212, 225))
1837	31361072	In the RCC cell line Caki-2, GABA stimulation promotes cancer cell invasion via ERK1/2-dependent upregulation of MMPs; an effect mediated mainly through the GABA-B receptor.19 Thus, while DNA methylation changes may serve as prognostic markers in pRCC, they may also functionally influence the underlying biology of the disease.	('upregulation', 'PosReg', (97, 109))	('DNA methylation', 'biological_process', 'GO:0006306', ('188', '203'))	('MMPs', 'CPA', (113, 117))	('ERK1', 'molecular_function', 'GO:0004707', ('80', '84'))	('Caki-2', 'CellLine', 'CVCL:0235', (21, 27))	('changes', 'Var', (204, 211))	('pRCC', 'Gene', (247, 251))	('ERK1/2', 'Gene', (80, 86))	('ERK1/2', 'Gene', '5595;5594', (80, 86))	('cancer', 'Disease', (55, 61))	('RCC', 'Phenotype', 'HP:0005584', (248, 251))	('RCC', 'Disease', (248, 251))	('DNA', 'cellular_component', 'GO:0005574', ('188', '191'))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('influence', 'Reg', (280, 289))	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('GABA', 'Chemical', 'MESH:D005680', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('promotes', 'PosReg', (46, 54))	('pRCC', 'Gene', '5546', (247, 251))	('GABA', 'Chemical', 'MESH:D005680', (29, 33))
1845	31361072	PF-06647020, an antibody-drug conjugate targeting PTK7, induces sustained tumor regression in patients with triple-negative breast cancer, ovarian cancer, and nonsmall cell lung cancer.33 Whether PF-06647020 has a similar effect in advanced-stage type 2 PRCC remains to be investigated.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (159, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('tumor', 'Disease', (74, 79))	('PF-06647020', 'Var', (196, 207))	('PRCC', 'Gene', '5546', (254, 258))	('antibody', 'molecular_function', 'GO:0003823', ('16', '24'))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ovarian cancer', 'Disease', (139, 153))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('antibody', 'cellular_component', 'GO:0042571', ('16', '24'))	('ovarian cancer', 'Phenotype', 'HP:0100615', (139, 153))	('breast cancer', 'Disease', (124, 137))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('nonsmall cell lung cancer', 'Disease', (159, 184))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('antibody', 'cellular_component', 'GO:0019814', ('16', '24'))	('PTK7', 'Gene', (50, 54))	('antibody', 'cellular_component', 'GO:0019815', ('16', '24'))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('PRCC', 'Gene', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PRCC', 'Phenotype', 'HP:0006766', (254, 258))	('PTK7', 'Gene', '5754', (50, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (139, 153))
1847	31361072	CNV analysis reveals that copy number gain in PTK7 is associated with poor survival and higher expression from localized-stage to advanced-stage type 2 PRCC, suggesting that PTK7 represents a promising treatment target for advanced-stage type 2 PRCC.	('higher', 'PosReg', (88, 94))	('poor', 'NegReg', (70, 74))	('PTK7', 'Gene', (174, 178))	('survival', 'CPA', (75, 83))	('PRCC', 'Phenotype', 'HP:0006766', (245, 249))	('RCC', 'Phenotype', 'HP:0005584', (246, 249))	('PTK7', 'Gene', '5754', (174, 178))	('PRCC', 'Phenotype', 'HP:0006766', (152, 156))	('copy number gain', 'Var', (26, 42))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('PRCC', 'Gene', '5546', (152, 156))	('PRCC', 'Gene', '5546', (245, 249))	('PTK7', 'Gene', (46, 50))	('PRCC', 'Gene', (152, 156))	('PTK7', 'Gene', '5754', (46, 50))	('PRCC', 'Gene', (245, 249))	('expression', 'MPA', (95, 105))
1864	30987368	These tumours are driven by inactivation of the von Hippel Lindau (VHL) tumour suppressor gene.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('von Hippel Lindau (VHL) tumour', 'Disease', 'MESH:D006623', (48, 78))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('inactivation', 'Var', (28, 40))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
1872	30987368	Recently, other common molecular drivers have been identified with mutations commonly involving chromatin-remodelling genes (PBRM1, KDM5C, SETD2, and BAP1).	('chromatin-remodelling', 'biological_process', 'GO:0006338', ('96', '117'))	('BAP1', 'Gene', (150, 154))	('SETD2', 'Gene', (139, 144))	('KDM5C', 'Gene', (132, 137))	('KDM5C', 'Gene', '8242', (132, 137))	('mutations', 'Var', (67, 76))	('chromatin', 'cellular_component', 'GO:0000785', ('96', '105'))	('PBRM1', 'Gene', (125, 130))	('BAP1', 'Gene', '8314', (150, 154))	('PBRM1', 'Gene', '55193', (125, 130))	('SETD2', 'Gene', '29072', (139, 144))
1875	30987368	Type 1 papillary renal cell carcinomas are enriched in MET alterations, mainly mutations and gains in chromosome 7 involving the MET locus.	('gains', 'PosReg', (93, 98))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (7, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (17, 37))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (17, 38))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (7, 38))	('Type 1 papillary renal cell carcinomas', 'Phenotype', 'HP:0011797', (0, 38))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('papillary renal cell carcinomas', 'Disease', (7, 38))	('mutations', 'Var', (79, 88))
1876	30987368	However, MET copy number gain is also found in up to 50% of type 2 pRCC.	('pRCC', 'Gene', (67, 71))	('copy number gain', 'Var', (13, 29))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('pRCC', 'Phenotype', 'HP:0006766', (67, 71))	('pRCC', 'Gene', '5546', (67, 71))
1877	30987368	Recurrent alterations of SETD2, EGFR, CDKN2A, NF2, TERT, and FH were also described and occurred more frequently in type 2 pRCC, suggesting deregulation of chromatin remodelling and activation of the cell cycle and MAP kinases pathway.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('pRCC', 'Gene', (123, 127))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('156', '177'))	('NF2', 'Gene', '4771', (46, 49))	('TERT', 'Gene', (51, 55))	('occurred', 'Reg', (88, 96))	('MAP', 'molecular_function', 'GO:0004239', ('215', '218'))	('NF2', 'Gene', (46, 49))	('TERT', 'Gene', '7015', (51, 55))	('EGFR', 'Gene', (32, 36))	('EGFR', 'molecular_function', 'GO:0005006', ('32', '36'))	('SETD2', 'Gene', (25, 30))	('alterations', 'Var', (10, 21))	('deregulation', 'Reg', (140, 152))	('chromatin', 'cellular_component', 'GO:0000785', ('156', '165'))	('cell cycle', 'biological_process', 'GO:0007049', ('200', '210'))	('CDKN2A', 'Gene', (38, 44))	('pRCC', 'Gene', '5546', (123, 127))	('SETD2', 'Gene', '29072', (25, 30))	('EGFR', 'Gene', '1956', (32, 36))	('pRCC', 'Phenotype', 'HP:0006766', (123, 127))	('FH', 'Disease', 'MESH:D006938', (61, 63))	('CDKN2A', 'Gene', '1029', (38, 44))
1878	30987368	Chromophobe renal cell carcinoma (cRCC) is an eosinophilic tumour (Figure 1C) derived from the distal nephron, characterized by mitochondrial alterations with increased mitochondria count, expression of genes involved the in citric acid cycle, and mutations in mitochondrial DNA copies.	('mutations', 'Var', (248, 257))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (12, 32))	('Chromophobe renal cell carcinoma', 'Disease', (0, 32))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('261', '278'))	('eosinophilic tumour', 'Disease', (46, 65))	('citric acid cycle', 'biological_process', 'GO:0006099', ('225', '242'))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (128, 153))	('RCC', 'Disease', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('mitochondria', 'cellular_component', 'GO:0005739', ('169', '181'))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('Chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 32))	('mitochondrial', 'Gene', (261, 274))	('citric acid', 'Chemical', 'MESH:D019343', (225, 236))	('increased', 'PosReg', (159, 168))	('eosinophilic tumour', 'Disease', 'MESH:D004802', (46, 65))	('increased mitochondria', 'Phenotype', 'HP:0041045', (159, 181))	('mitochondria count', 'MPA', (169, 187))
1889	30987368	Mutations of NF2, SETD2, and SMARCB1 were also reported.	('NF2', 'Gene', '4771', (13, 16))	('SMARCB1', 'Gene', '6598', (29, 36))	('SETD2', 'Gene', '29072', (18, 23))	('SMARCB1', 'Gene', (29, 36))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (18, 23))	('NF2', 'Gene', (13, 16))
1892	30987368	Sarcomatoid features can occur in each histologic subtype (Figure 1F) and in the sarcomatoid component, demonstrate an increased mutational burden along with a higher frequency of TP53, CDKN2A, and NF2 mutations and chromatin remodelling genes, BAP1 and ARID1A.	('chromatin', 'cellular_component', 'GO:0000785', ('216', '225'))	('Sarcomatoid', 'Disease', 'MESH:C538614', (0, 11))	('BAP1', 'Gene', '8314', (245, 249))	('TP53', 'Gene', (180, 184))	('NF2', 'Gene', '4771', (198, 201))	('CDKN2A', 'Gene', '1029', (186, 192))	('ARID1A', 'Gene', (254, 260))	('NF2', 'Gene', (198, 201))	('BAP1', 'Gene', (245, 249))	('ARID1A', 'Gene', '8289', (254, 260))	('Sarcomatoid', 'Disease', (0, 11))	('mutational burden', 'MPA', (129, 146))	('TP53', 'Gene', '7157', (180, 184))	('sarcomatoid component', 'Disease', (81, 102))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('216', '237'))	('sarcomatoid component', 'Disease', 'MESH:C538614', (81, 102))	('CDKN2A', 'Gene', (186, 192))	('increased', 'PosReg', (119, 128))	('mutations', 'Var', (202, 211))
1905	30987368	Biological rationale encouraged the synergy of CTLA-4 inhibition, which favours the development of an active immune response at the level of T-cell proliferation, with PD-1 inhibition, which modulates the immune response at the level of the tumour micro-environment.	('inhibition', 'Var', (54, 64))	('CTLA-4', 'Gene', '1493', (47, 53))	('CTLA-4', 'Gene', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('T-cell proliferation', 'biological_process', 'GO:0042098', ('141', '161'))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('favours', 'PosReg', (72, 79))	('immune response', 'biological_process', 'GO:0006955', ('205', '220'))	('immune response', 'biological_process', 'GO:0006955', ('109', '124'))	('tumour', 'Disease', (241, 247))	('active immune', 'MPA', (102, 115))
1906	30987368	In ccRCC, the inactivation of VHL results in an increase of growth factors, such as VEGF, that favour the proliferation and migration of endothelial cells.	('VHL', 'Gene', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('inactivation', 'Var', (14, 26))	('favour', 'PosReg', (95, 101))	('RCC', 'Disease', (5, 8))	('VEGF', 'Gene', (84, 88))	('VHL', 'Gene', '7428', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('migration of endothelial cells', 'CPA', (124, 154))	('growth factors', 'MPA', (60, 74))	('proliferation', 'CPA', (106, 119))	('VEGF', 'Gene', '7422', (84, 88))	('increase', 'PosReg', (48, 56))
1911	30987368	Interestingly, VEGF inhibitors are able to reverse these effects by improving dendritic cell function and antigen presentation, vasculature normalization with greater trafficking of immune cells, increased cytotoxic T cell infiltration, and decreased MDSC and T-regulatory cells that could potentially reduce the immunosuppressive effect in the tumour micro-environment.	('tumour', 'Disease', (345, 351))	('increased', 'PosReg', (196, 205))	('trafficking', 'CPA', (167, 178))	('cytotoxic T cell infiltration', 'CPA', (206, 235))	('antigen presentation', 'biological_process', 'GO:0019882', ('106', '126'))	('decreased', 'NegReg', (241, 250))	('VEGF', 'Gene', (15, 19))	('antigen presentation', 'MPA', (106, 126))	('vasculature', 'CPA', (128, 139))	('inhibitors', 'Var', (20, 30))	('greater', 'PosReg', (159, 166))	('tumour', 'Phenotype', 'HP:0002664', (345, 351))	('improving', 'PosReg', (68, 77))	('tumour', 'Disease', 'MESH:D009369', (345, 351))	('VEGF', 'Gene', '7422', (15, 19))	('dendritic cell function', 'CPA', (78, 101))
1936	30987368	Pembrolizumab and atezolizumab are currently being evaluated in the phase III trials, IMmotion010 (NCT03024996) and Keynote 564 (NCT03142334), respectively.	('NCT03024996', 'Var', (99, 110))	('Pembrolizumab', 'Chemical', 'MESH:C582435', (0, 13))	('atezolizumab', 'Chemical', 'MESH:C000594389', (18, 30))	('NCT03142334', 'Var', (129, 140))
1942	30987368	The coprimary endpoints were PFS in PD-L1+ patients and OS in intention-to-treat (ITT) patients.	('patients', 'Species', '9606', (43, 51))	('PD-L1+', 'Var', (36, 42))	('PFS', 'Disease', (29, 32))	('patients', 'Species', '9606', (87, 95))
1974	30987368	In concordance with the results on ccRCC, the expression of PD-L1 on tumour cells was associated with worse outcomes in nccRCC.	('tumour', 'Disease', (69, 75))	('expression', 'Var', (46, 56))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('PD-L1', 'Gene', (60, 65))	('associated', 'Reg', (86, 96))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (37, 40))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
1982	30987368	Among mutations, insertions/deletions, a rich source of immunogenic neoantigens, are more frequently observed in RCC.	('insertions/deletions', 'Var', (17, 37))	('observed', 'Reg', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))
1983	30987368	One hypothesis is that RCC with the worst clinical prognosis better responds to ICI due to a higher mutational load.	('better', 'PosReg', (61, 67))	('clinical', 'Species', '191496', (42, 50))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('ICI', 'Chemical', '-', (80, 83))	('RCC', 'Disease', (23, 26))	('responds to ICI', 'MPA', (68, 83))	('mutational', 'Var', (100, 110))
1998	30987368	The clinical utility of mutational burden has not yet been demonstrated in RCC studies and is still under evaluation and the proportion of insertions and deletions could be more relevant in RCC.	('clinical', 'Species', '191496', (4, 12))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('deletions', 'Var', (154, 163))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))
2001	25676555	TCEB1-mutated Renal Cell Carcinoma: A Distinct Genomic and Morphologic Subtype Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia inducible factor).	('clear cell renal cell carcinoma', 'Disease', (145, 176))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (156, 176))	('renal cell carcinomas', 'Disease', (156, 177))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (145, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('hypoxia', 'Disease', 'MESH:D000860', (282, 289))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (156, 177))	('VHL', 'Gene', '7428', (254, 257))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (145, 176))	('TCEB1', 'Gene', (216, 221))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('Renal Cell Carcinoma', 'Disease', (14, 34))	('TCEB1', 'Gene', (0, 5))	('TCEB1', 'Gene', '6921', (216, 221))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (14, 34))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('VHL complex', 'cellular_component', 'GO:0030891', ('254', '265'))	('tumors', 'Disease', (132, 138))	('mutations', 'Var', (203, 212))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 176))	('TCEB1', 'Gene', '6921', (0, 5))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('hotspot', 'PosReg', (195, 202))	('Carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('VHL', 'Gene', (254, 257))	('hypoxia', 'Disease', (282, 289))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (156, 177))
2002	25676555	We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (215, 245))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('clear cell papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 245))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (225, 245))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (168, 199))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (179, 199))	('mutations', 'Var', (59, 68))	('clear cell renal cell carcinoma', 'Disease', (168, 199))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (168, 199))	('TCEB1', 'Gene', (53, 58))	('clear cell papillary renal cell carcinoma', 'Disease', (204, 245))	('clear cell papillary renal cell carcinoma', 'Phenotype', 'HP:0006770', (204, 245))	('TCEB1', 'Gene', '6921', (53, 58))	('tumors', 'Disease', (15, 21))
2003	25676555	All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P.	('A100P', 'Var', (74, 79))	('TCEB1', 'Gene', (54, 59))	('Y79C', 'SUBSTITUTION', 'None', (60, 64))	('Y79C', 'Var', (60, 64))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('A100P', 'Mutation', 'p.A100P', (74, 79))	('TCEB1', 'Gene', '6921', (54, 59))
2006	25676555	All TCEB1 mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11).	('mutated', 'Var', (10, 17))	('TCEB1', 'Gene', '6921', (4, 9))	('TCEB1', 'Gene', (4, 9))	('TCEB1', 'Gene', '6921', (164, 169))	('VHL', 'Gene', (30, 33))	('TCEB1', 'Gene', (164, 169))	('PBRM1', 'Gene', (38, 43))	('VHL', 'Gene', '7428', (30, 33))	('tumors', 'Disease', (18, 24))	('PBRM1', 'Gene', '55193', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
2008	25676555	None of the clear cell papillary tumor harbored TCEB1 mutations.	('papillary tumor', 'Disease', (23, 38))	('mutations', 'Var', (54, 63))	('TCEB1', 'Gene', '6921', (48, 53))	('TCEB1', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('papillary tumor', 'Disease', 'MESH:D002291', (23, 38))
2012	25676555	In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation and characteristic morphologic features.	('renal cell carcinoma', 'Disease', (22, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (22, 42))	('activation', 'PosReg', (140, 150))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (22, 42))	('copy number alterations', 'Var', (107, 130))	('TCEB1', 'Gene', '6921', (8, 13))	('mutations', 'Var', (87, 96))	('TCEB1', 'Gene', (8, 13))
2020	25676555	Exome and copy number analysis has shown loss of 3p and VHL mutations to be fundamental events in carcinogenesis of clear cell renal cell carcinoma.	('VHL', 'Gene', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('VHL', 'Gene', '7428', (56, 59))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (116, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))	('mutations', 'Var', (60, 69))	('carcinogenesis of clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 147))	('loss', 'NegReg', (41, 45))	('carcinogenesis of clear cell renal cell carcinoma', 'Disease', (98, 147))
2023	25676555	Sato and colleagues recently identified a group of tumors within clear cell renal cell carcinoma that lacked the characteristic 3p loss and VHL mutations.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('3p loss', 'Protein', (128, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('tumors within clear cell renal cell carcinoma', 'Disease', 'MESH:D001929', (51, 96))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (65, 96))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors within clear cell renal cell carcinoma', 'Disease', (51, 96))	('VHL', 'Gene', (140, 143))	('mutations', 'Var', (144, 153))	('VHL', 'Gene', '7428', (140, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
2024	25676555	These tumors were defined by loss of heterozygosity on chromosome 8q along with characteristic transcription elongation factor B (TCEB1) hotspot mutations, affecting the binding site of VHL and thus the ability to ubiquitinate the hypoxia inducible factor (HIF) complex.	('hypoxia', 'Disease', 'MESH:D000860', (231, 238))	('TCEB1', 'Gene', '6921', (130, 135))	('TCEB1', 'Gene', (130, 135))	('VHL', 'Gene', (186, 189))	('hypoxia', 'Disease', (231, 238))	('mutations', 'Var', (145, 154))	('VHL', 'Gene', '7428', (186, 189))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('transcription', 'biological_process', 'GO:0006351', ('95', '108'))	('binding', 'molecular_function', 'GO:0005488', ('170', '177'))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('ability', 'MPA', (203, 210))	('affecting', 'Reg', (156, 165))	('binding', 'Interaction', (170, 177))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('ubiquitinate', 'MPA', (214, 226))
2027	25676555	The Sato et al cohort consisted of 8, mostly low-grade tumors with TCEB1 mutation.	('TCEB1', 'Gene', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('mutation', 'Var', (73, 81))	('TCEB1', 'Gene', '6921', (67, 72))
2034	25676555	To compare TCEB1 mutant and wild-type tumor genomic profiles, we combined TCEB1 mutant tumor samples from Sato et al and TCGA (n=11) and compared these to low grade TCGA tumors with complete genomic data (n=193).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutant', 'Var', (80, 86))	('TCEB1', 'Gene', '6921', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('TCEB1', 'Gene', (11, 16))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('TCEB1', 'Gene', '6921', (74, 79))	('tumors', 'Disease', (170, 176))	('TCEB1', 'Gene', (74, 79))
2035	25676555	We computed genome-wide estimates of DNA copy number gain or loss frequencies in the two tumor sets using the Integrated Genomics Viewer (gain: log2(CN/2) > 0.1; loss: log2(CN/2) <-0.1).	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('copy number', 'Var', (41, 52))	('loss', 'NegReg', (61, 65))	('gain', 'PosReg', (53, 57))	('tumor', 'Disease', (89, 94))
2037	25676555	Gene expression profiles of TCEB1 mutant tumors from the Sato et al (Agilent 4x44k microarrays) and TCGA (RNA-seq) cohorts, was performed by computing gene expression changes between TCEB1-mutated (Sato: n=5, TCGA: n=3) and wild-type (Sato: n=67, TCGA: n=180) tumors separately for each of the two distinct cohorts.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('gene expression', 'biological_process', 'GO:0010467', ('151', '166'))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('TCEB1', 'Gene', '6921', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('TCEB1', 'Gene', (28, 33))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TCEB1', 'Gene', '6921', (183, 188))	('RNA', 'cellular_component', 'GO:0005562', ('106', '109'))	('TCEB1', 'Gene', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('Gene expression', 'biological_process', 'GO:0010467', ('0', '15'))	('mutant', 'Var', (34, 40))	('tumors', 'Disease', (260, 266))
2040	25676555	We analyzed gene expression profiles of n=5 mutated vs 67 low-grade clear cell renal cell carcinoma tumors from the Sato et al cohort.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('clear cell renal cell carcinoma tumors', 'Disease', 'MESH:C538614', (68, 106))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutated', 'Var', (44, 51))	('clear cell renal cell carcinoma tumors', 'Disease', (68, 106))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (68, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
2041	25676555	Genes were sorted by mRNA expression change in TCEB1 mutant versus wild-type tumors, and GSEA was used to evaluate the null hypothesis that genes in particular gene sets or pathways were not differentially expressed in mutant versus wild-type samples.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('type tumors', 'Disease', (72, 83))	('type tumors', 'Disease', 'MESH:D009369', (72, 83))	('GSEA', 'Chemical', '-', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mRNA expression', 'MPA', (21, 36))	('mutant', 'Var', (53, 59))	('TCEB1', 'Gene', '6921', (47, 52))	('change', 'Reg', (37, 43))	('TCEB1', 'Gene', (47, 52))
2051	25676555	All TCGA TCEB1 mutations exclusively involved VHL-binding site residues Tyr79.	('VHL', 'Gene', (46, 49))	('VHL', 'Gene', '7428', (46, 49))	('mutations', 'Var', (15, 24))	('TCEB1', 'Gene', '6921', (9, 14))	('Tyr79', 'Var', (72, 77))	('TCEB1', 'Gene', (9, 14))	('binding', 'molecular_function', 'GO:0005488', ('50', '57'))	('Tyr79', 'Chemical', '-', (72, 77))	('involved', 'Reg', (37, 45))
2052	25676555	The TCEB1 mutant tumors, as assessed from either Sato et al or TCGA cohorts, had completely different mutation patterns compared to clear cell renal cell carcinoma which show frequently mutated 3p genes including VHL, PBRM1 or SETD2 (Supplemental Fig 2).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PBRM1', 'Gene', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('PBRM1', 'Gene', '55193', (218, 223))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (132, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (143, 163))	('mutant', 'Var', (10, 16))	('TCEB1', 'Gene', '6921', (4, 9))	('TCEB1', 'Gene', (4, 9))	('tumors', 'Disease', (17, 23))	('clear cell renal cell carcinoma', 'Disease', (132, 163))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('VHL', 'Gene', (213, 216))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (132, 163))	('SETD2', 'Gene', '29072', (227, 232))	('VHL', 'Gene', '7428', (213, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('SETD2', 'Gene', (227, 232))
2053	25676555	One tumor in the Sato et al cohort contained a mutation in BAP1, however this was a missense mutation predicted to have low functional impact, and was not accompanied by 3p loss.	('tumor', 'Disease', (4, 9))	('BAP1', 'Gene', (59, 63))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('BAP1', 'Gene', '8314', (59, 63))
2055	25676555	Further interrogation of both cohorts identified only two recurrent clear cell renal cell carcinoma-associated mutations in the TCEB1-mutated samples, a PIK3CA mutation (ccrcc-48) and a MUC4 mutation (ccrcc-35) (Figure 1B).	('PIK3CA', 'Gene', '5290', (153, 159))	('mutations', 'Var', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('MUC4', 'Gene', '4585', (186, 190))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (68, 99))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 99))	('MUC4', 'Gene', (186, 190))	('TCEB1', 'Gene', '6921', (128, 133))	('clear cell renal cell carcinoma', 'Disease', (68, 99))	('TCEB1', 'Gene', (128, 133))	('PIK3CA', 'Gene', (153, 159))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
2058	25676555	First, we compared the whole transcriptome expression profiles of TCEB1 mutant tumors from the Sato et al and TCGA cohorts (n=5 and 3, respectively).	('mutant', 'Var', (72, 78))	('TCEB1', 'Gene', '6921', (66, 71))	('TCEB1', 'Gene', (66, 71))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
2059	25676555	This result was concordant with our hypothesis that TCEB1 mutant tumors had unique expression signatures.	('mutant', 'Var', (58, 64))	('TCEB1', 'Gene', '6921', (52, 57))	('TCEB1', 'Gene', (52, 57))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
2060	25676555	Combined dataset pathway-based analysis revealed statistically significant gene expression changes associated with TCEB1 mutations.	('mutations', 'Var', (121, 130))	('TCEB1', 'Gene', '6921', (115, 120))	('gene expression changes', 'MPA', (75, 98))	('TCEB1', 'Gene', (115, 120))	('gene expression', 'biological_process', 'GO:0010467', ('75', '90'))
2064	25676555	On the other hand, while 25 low-grade clear cell renal cell carcinoma tumors showed 8-loss of heterozygosity, none had a TCEB1 mutation.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (38, 69))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (49, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('clear cell renal cell carcinoma tumors', 'Disease', 'MESH:C538614', (38, 76))	('mutation', 'Var', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('TCEB1', 'Gene', '6921', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('TCEB1', 'Gene', (121, 126))	('clear cell renal cell carcinoma tumors', 'Disease', (38, 76))
2067	25676555	However, other Pol II elongation pathway genes such as POLR2C, CDK7, POLR2E and TCEB2 were only significantly down-regulated in the presence of TCEB1 mutations (Figure 3B).	('CDK7', 'Gene', '1022', (63, 67))	('TCEB1', 'Gene', '6921', (144, 149))	('POLR2C', 'Gene', (55, 61))	('TCEB1', 'Gene', (144, 149))	('POLR2C', 'Gene', '5432', (55, 61))	('TCEB2', 'Gene', '6923', (80, 85))	('POLR2E', 'Gene', (69, 75))	('down-regulated', 'NegReg', (110, 124))	('mutations', 'Var', (150, 159))	('POLR2E', 'Gene', '5434', (69, 75))	('TCEB2', 'Gene', (80, 85))	('CDK', 'molecular_function', 'GO:0004693', ('63', '66'))	('CDK7', 'Gene', (63, 67))	('Pol II elongation pathway genes', 'Gene', (15, 46))
2068	25676555	In summary, these data suggest that TCEB1 mutations may affect RNA Pol II elongation efficiency by causing a concomitant reduction in expression of other elongation pathway members through mechanisms unknown at present.	('affect', 'Reg', (56, 62))	('elongation efficiency', 'CPA', (74, 95))	('TCEB1', 'Gene', '6921', (36, 41))	('expression', 'MPA', (134, 144))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('RNA Pol II', 'Gene', (63, 73))	('mutations', 'Var', (42, 51))	('reduction', 'NegReg', (121, 130))	('TCEB1', 'Gene', (36, 41))
2070	25676555	This signal was also evident in the TCGA cohort, although without statistical significance likely related to the smaller cohort (3 mutated tumors vs 180 low grade clear cell renal cell carcinomas).	('renal cell carcinomas', 'Disease', (174, 195))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (163, 194))	('clear cell renal cell carcinoma', 'Disease', (163, 194))	('mutated', 'Var', (131, 138))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (174, 195))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (163, 194))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (163, 195))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (174, 195))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (174, 194))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
2079	25676555	Except for the 3 tumors with TCEB1 mutations, none of the other 300 consecutive tumors with digital slides in the TCGA portal that were reviewed, showed morphological features similar to the TCEB1-mutated tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('TCEB1', 'Gene', '6921', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (205, 211))	('TCEB1', 'Gene', '6921', (191, 196))	('TCEB1', 'Gene', (29, 34))	('TCEB1', 'Gene', (191, 196))	('mutations', 'Var', (35, 44))
2091	25676555	Further distinguishing these tumors from clear cell renal cell carcinoma, they lack secondary alterations in tumors suppressors such as PBRM1, and mutations in genes such as SETD2, KDM5C and BAP1, which predict for aggressive forms of clear cell renal cell carcinoma (one tumor with a BAP1 missense mutation had no loss of 3p and had retained BAP1 protein expression on immunohistochemistry).	('BAP1', 'Gene', (343, 347))	('BAP1', 'Gene', '8314', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('PBRM1', 'Gene', '55193', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('KDM5C', 'Gene', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('BAP1', 'Gene', (191, 195))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (235, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('clear cell renal cell carcinoma', 'Disease', (41, 72))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('PBRM1', 'Gene', (136, 141))	('tumor', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('BAP1', 'Gene', (285, 289))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (29, 35))	('protein', 'cellular_component', 'GO:0003675', ('348', '355'))	('tumors', 'Disease', (109, 115))	('expression', 'MPA', (356, 366))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (41, 72))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (246, 266))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (235, 266))	('SETD2', 'Gene', (174, 179))	('BAP1', 'Gene', '8314', (343, 347))	('KDM5C', 'Gene', '8242', (181, 186))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('BAP1', 'Gene', '8314', (191, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('SETD2', 'Gene', '29072', (174, 179))	('clear cell renal cell carcinoma', 'Disease', (235, 266))	('missense mutation', 'Var', (290, 307))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (109, 114))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (41, 72))
2092	25676555	TCEB1-mutated tumors also did not possess any additional recurrent copy number events such as 5q amplifications or 14q or 9p losses that are common in clear cell renal cell carcinoma.	('5q amplifications', 'Var', (94, 111))	('TCEB1', 'Gene', '6921', (0, 5))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (151, 182))	('TCEB1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 182))	('clear cell renal cell carcinoma', 'Disease', (151, 182))
2094	25676555	Intriguingly, TCEB1 mutational patterns do not follow the classic tumor suppressor profile; the mutations almost always occur at a single hotspot amino acid residue (Tyr 79), which would follow more of an oncogene paradigm - although data from Sato et al suggests that the region interferes with VHL binding.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('binding', 'molecular_function', 'GO:0005488', ('300', '307'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('tumor', 'Disease', (66, 71))	('TCEB1', 'Gene', '6921', (14, 19))	('binding', 'Interaction', (300, 307))	('Tyr', 'Chemical', 'MESH:D014443', (166, 169))	('TCEB1', 'Gene', (14, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('VHL', 'Gene', (296, 299))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('VHL', 'Gene', '7428', (296, 299))	('mutations', 'Var', (96, 105))
2101	25676555	In our analysis, tumors with TCEB1 mutations have down regulation of multiple genes within this complex including POLR2E, POLR2C, CDK7, TCEA1 and TCEB2, in addition to TCEB1 (Figure 3).	('CDK7', 'Gene', '1022', (130, 134))	('tumors', 'Disease', (17, 23))	('TCEA1', 'Gene', '6917', (136, 141))	('regulation', 'biological_process', 'GO:0065007', ('55', '65'))	('TCEB1', 'Gene', '6921', (29, 34))	('CDK', 'molecular_function', 'GO:0004693', ('130', '133'))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('down regulation', 'NegReg', (50, 65))	('POLR2E', 'Gene', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TCEB1', 'Gene', (168, 173))	('TCEA1', 'Gene', (136, 141))	('POLR2C', 'Gene', '5432', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('TCEB1', 'Gene', '6921', (168, 173))	('TCEB2', 'Gene', '6923', (146, 151))	('TCEB2', 'Gene', (146, 151))	('CDK7', 'Gene', (130, 134))	('POLR2C', 'Gene', (122, 128))	('TCEB1', 'Gene', (29, 34))	('POLR2E', 'Gene', '5434', (114, 120))	('mutations', 'Var', (35, 44))
2102	25676555	This polygenic phenomenon suggests that mutated TCEB1, which is also associated with lower TCEB1 mRNA expression levels, may also impact a regulatory feedback loop for other genes in the POL II elongation complex.	('TCEB1', 'Gene', '6921', (91, 96))	('TCEB1', 'Gene', (91, 96))	('impact', 'NegReg', (130, 136))	('lower', 'NegReg', (85, 90))	('regulatory feedback loop', 'MPA', (139, 163))	('TCEB1', 'Gene', '6921', (48, 53))	('TCEB1', 'Gene', (48, 53))	('mutated', 'Var', (40, 47))	('mRNA expression levels', 'MPA', (97, 119))
2110	25676555	Because of some morphological and immunohistochemical overlap, and an understanding of the molecular profile [2, 16] of clear cell papillary renal cell carcinoma, we also performed targeted sequencing of 10 clear cell papillary renal cell carcinoma tumors for TCEB1 and VHL mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('TCEB1', 'Gene', (260, 265))	('clear cell papillary renal cell carcinoma tumors', 'Disease', 'MESH:C538614', (207, 255))	('clear cell papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 248))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (141, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (228, 248))	('VHL', 'Gene', '7428', (270, 273))	('clear cell papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 161))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (131, 161))	('TCEB1', 'Gene', '6921', (260, 265))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (218, 248))	('clear cell papillary renal cell carcinoma tumors', 'Phenotype', 'HP:0006770', (207, 255))	('clear cell papillary renal cell carcinoma', 'Phenotype', 'HP:0006770', (207, 248))	('clear cell papillary renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 161))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('VHL', 'Gene', (270, 273))	('clear cell papillary renal cell carcinoma', 'Disease', (120, 161))	('clear cell papillary renal cell carcinoma tumors', 'Disease', (207, 255))	('mutations', 'Var', (274, 283))
2118	25676555	The lack of 3p loss and associated mutations potentially explains the indolent nature of these tumors and offers insights into the metastatic underpinnings of clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (159, 190))	('clear cell renal cell carcinoma', 'Disease', (159, 190))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (159, 190))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (170, 190))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('loss', 'NegReg', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('tumors', 'Disease', (95, 101))	('mutations', 'Var', (35, 44))
2188	33505430	High TICRR expression in PRCC was associated with female sex, younger age, and worse clinical stages.	('PRCC', 'Gene', '5546', (25, 29))	('associated', 'Reg', (34, 44))	('High', 'Var', (0, 4))	('PRCC', 'Gene', (25, 29))	('TICRR', 'Gene', (5, 10))	('TICRR', 'Gene', '90381', (5, 10))
2198	33505430	Several mutated genes were proved to be associated with PRCC diagnosis and treatment, including MET, NF2, SETD2, and Nrf2 pathway genes.	('MET', 'Gene', '79811', (96, 99))	('NF2', 'Gene', '4771', (101, 104))	('mutated genes', 'Var', (8, 21))	('SETD2', 'Gene', '29072', (106, 111))	('PRCC', 'Gene', '5546', (56, 60))	('Nrf2', 'Gene', (117, 121))	('MET', 'Gene', (96, 99))	('men', 'Species', '9606', (80, 83))	('NF2', 'Gene', (101, 104))	('SETD2', 'Gene', (106, 111))	('Nrf2', 'Gene', '4780', (117, 121))	('PRCC', 'Gene', (56, 60))	('associated', 'Reg', (40, 50))
2231	33505430	As presented in Figures 2A-C and Supplementary Table 1, we found that several PRCC-related pathways were enriched, including epithelial cell differentiation (GO: 0030855, P < 0.001, enrichment factor = 2.654, FDR = 0.037), urogenital system development (GO: 0001655, P < 0.001, enrichment factor = 3.448, FDR = 0.141), and negative regulation of cell division (GO: 0051782, P = 0.001, enrichment factor = 15.802, FDR = 0.266).	('PRCC', 'Gene', (78, 82))	('men', 'Species', '9606', (248, 251))	('epithelial cell differentiation', 'biological_process', 'GO:0030855', ('125', '156'))	('GO: 0001655', 'Var', (254, 265))	('negative regulation of cell division', 'biological_process', 'GO:0051782', ('323', '359'))	('urogenital system development', 'biological_process', 'GO:0001655', ('223', '252'))	('epithelial cell differentiation', 'CPA', (125, 156))	('men', 'Species', '9606', (284, 287))	('PRCC', 'Gene', '5546', (78, 82))	('urogenital system development', 'CPA', (223, 252))	('negative', 'NegReg', (323, 331))	('men', 'Species', '9606', (39, 42))	('men', 'Species', '9606', (391, 394))	('men', 'Species', '9606', (188, 191))
2233	33505430	TICRR-associated DEGs were also enriched in cancer pathways (Figure 2L), especially the cell cycle-related Hedgehog signaling pathway (Figure 2M).	('Hedgehog signaling pathway', 'biological_process', 'GO:0007224', ('107', '133'))	('cell cycle-related Hedgehog signaling pathway', 'Pathway', (88, 133))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('DEGs', 'Var', (17, 21))	('TICRR', 'Gene', (0, 5))	('cell cycle', 'biological_process', 'GO:0007049', ('88', '98'))	('TICRR', 'Gene', '90381', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
2244	33505430	TICRR expression was significantly elevated in patients of female sex (Figure 4A), age below 60 years (Figure 4B), abnormal hemoglobin level (Figure 4C), clinical stages III and IV (Figure 4D), T stages T3 and T4 (Figure 4E), and N stages N1 and N2 (Figure 4F).	('abnormal hemoglobin', 'Gene', (115, 134))	('abnormal hemoglobin', 'Gene', '3048', (115, 134))	('expression', 'MPA', (6, 16))	('patients', 'Species', '9606', (47, 55))	('abnormal hemoglobin', 'Phenotype', 'HP:0011902', (115, 134))	('T stages T3', 'Var', (194, 205))	('abnormal hemoglobin level', 'Phenotype', 'HP:0020061', (115, 140))	('elevated', 'PosReg', (35, 43))	('TICRR', 'Gene', (0, 5))	('TICRR', 'Gene', '90381', (0, 5))
2253	33505430	As shown in Table 3, TICRR expression was an independent risk factor for overall survival (HR: 3.862, P = 0.036) and disease-specific survival (HR: 4.705, P = 0.039) in multivariate Cox regression, although it did not provide any significant predictive ability for progression-free interval.	('TICRR', 'Gene', '90381', (21, 26))	('overall survival', 'CPA', (73, 89))	('disease-specific survival', 'CPA', (117, 142))	('expression', 'Var', (27, 37))	('TICRR', 'Gene', (21, 26))
2278	33505430	In a different study focusing on breast cancer, TICRR showed a similar effect on tumorigenesis, as silencing of TICRR significantly inhibited DNA replication, arrested cell cycle progression, and activated DNA damage.	('DNA', 'cellular_component', 'GO:0005574', ('142', '145'))	('cell cycle', 'biological_process', 'GO:0007049', ('168', '178'))	('arrested cell cycle progression', 'CPA', (159, 190))	('DNA replication', 'CPA', (142, 157))	('activated', 'PosReg', (196, 205))	('TICRR', 'Gene', '90381', (112, 117))	('DNA replication', 'biological_process', 'GO:0006260', ('142', '157'))	('inhibited', 'NegReg', (132, 141))	('TICRR', 'Gene', '90381', (48, 53))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('TICRR', 'Gene', (112, 117))	('silencing', 'Var', (99, 108))	('DNA damage', 'MPA', (206, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('TICRR', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('DNA', 'cellular_component', 'GO:0005574', ('206', '209'))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
2286	33505430	Moreover, neutrophils proved to be associated with better prognosis in different cancers.	('neutrophils', 'Var', (10, 21))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
2287	33505430	Therefore, overexpressed TICRR seemed to dampen tumor immunity, help cancer cells escape from elimination, and finally accelerate tumorigenesis.	('accelerate', 'PosReg', (119, 129))	('TICRR', 'Gene', (25, 30))	('escape', 'CPA', (82, 88))	('overexpressed', 'Var', (11, 24))	('tumor', 'Disease', (48, 53))	('TICRR', 'Gene', '90381', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('help', 'PosReg', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (130, 135))	('dampen', 'NegReg', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (69, 75))
2325	31357507	Moderate ROS levels are widely recognized to trigger cancer initiation and progression by inducing mutations and promoting genome instability, eventually activating oncogenic signaling pathways that promote cell survival, proliferation, and stress resistance.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('promote', 'PosReg', (199, 206))	('cell survival', 'CPA', (207, 220))	('inducing', 'Reg', (90, 98))	('mutations', 'Var', (99, 108))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('proliferation', 'CPA', (222, 235))	('stress resistance', 'CPA', (241, 258))	('activating', 'Reg', (154, 164))	('promoting', 'PosReg', (113, 122))	('genome instability', 'MPA', (123, 141))	('oncogenic signaling pathways', 'Pathway', (165, 193))
2326	31357507	On the contrary, massive ROS accumulations can also limit cancer growth by causing severe oxidative damage of biomolecules, which finally can lead to cell death.	('cell death', 'CPA', (150, 160))	('oxidative damage of biomolecules', 'MPA', (90, 122))	('ROS', 'Chemical', 'MESH:D017382', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ROS', 'Protein', (25, 28))	('limit', 'NegReg', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('accumulations', 'Var', (29, 42))	('causing', 'Reg', (75, 82))	('cell death', 'biological_process', 'GO:0008219', ('150', '160'))	('cancer', 'Disease', (58, 64))	('lead to', 'Reg', (142, 149))
2341	31357507	About 90% of all ccRCCs carry mutations in the von Hippel-Lindau (VHL) tumor suppressor gene, which was originally identified in a hereditary disease called VHL syndrome.	('VHL syndrome', 'Disease', 'MESH:D006623', (157, 169))	('tumor suppressor', 'biological_process', 'GO:0051726', ('71', '87'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('71', '87'))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('hereditary disease', 'Disease', (131, 149))	('VHL syndrome', 'Disease', (157, 169))	('RCC', 'Disease', (19, 22))	('hereditary disease', 'Disease', 'MESH:D030342', (131, 149))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (30, 39))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (47, 76))
2361	31357507	The frequently activating mutations and amplification of MET in type I pRCC enable the activation of MET/HGF signaling and its above-mentioned downstream pathways to promote cancer cell proliferation, angiogenesis, and malignant transformation.	('angiogenesis', 'CPA', (201, 213))	('signaling', 'biological_process', 'GO:0023052', ('109', '118'))	('HGF', 'Gene', '3082', (105, 108))	('mutations', 'Var', (26, 35))	('angiogenesis', 'biological_process', 'GO:0001525', ('201', '213'))	('activating', 'PosReg', (15, 25))	('HGF', 'Gene', (105, 108))	('MET', 'Gene', (57, 60))	('MET', 'Gene', '4233', (57, 60))	('malignant transformation', 'CPA', (219, 243))	('cancer', 'Disease', (174, 180))	('pRCC', 'Gene', '5546', (71, 75))	('cell proliferation', 'biological_process', 'GO:0008283', ('181', '199'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('promote', 'PosReg', (166, 173))	('MET', 'Gene', '4233', (101, 104))	('MET', 'Gene', (101, 104))	('activation', 'PosReg', (87, 97))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('pRCC', 'Gene', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('amplification', 'Var', (40, 53))
2362	31357507	Frequent mutations in type II pRCC include CDKN2A silencing, SETD2 mutations, and TFE3 fusions.	('fusions', 'Var', (87, 94))	('CDKN2A', 'Gene', (43, 49))	('silencing', 'NegReg', (50, 59))	('TFE3', 'Gene', (82, 86))	('SETD2', 'Gene', (61, 66))	('pRCC', 'Gene', (30, 34))	('mutations', 'Var', (67, 76))	('CDKN2A', 'Gene', '1029', (43, 49))	('TFE3', 'Gene', '7030', (82, 86))	('pRCC', 'Gene', '5546', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
2365	31357507	Furthermore, fumarate hydratase (FH) mutations are also frequently found in type II pRCC.	('pRCC', 'Gene', (84, 88))	('fumarate hydratase', 'Gene', '2271', (13, 31))	('FH', 'Gene', '2271', (33, 35))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('found', 'Reg', (67, 72))	('fumarate hydratase', 'Gene', (13, 31))	('mutations', 'Var', (37, 46))	('pRCC', 'Gene', '5546', (84, 88))
2366	31357507	The FH gene encodes a TCA cycle enzyme that catalyzes the hydration of fumarate to malate, and its deficiency causes fumarate and succinate accumulation.	('FH', 'Gene', '2271', (4, 6))	('deficiency', 'Var', (99, 109))	('fumarate', 'Chemical', 'MESH:D005650', (71, 79))	('TCA cycle', 'biological_process', 'GO:0006099', ('22', '31'))	('succinate', 'Chemical', 'MESH:D019802', (130, 139))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('causes', 'Reg', (110, 116))	('malate', 'Chemical', 'MESH:C030298', (83, 89))	('TCA', 'Chemical', 'MESH:D014238', (22, 25))
2367	31357507	Accumulated fumarate and succinate are believed to be able to suppress the hydroxylation of the proline residues in the ODD domain of HIFalpha, and thus FH mutations in type II pRCC also cause the stabilization of HIFalpha, similarly to ccRCC.	('pRCC', 'Gene', '5546', (177, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('HIF', 'Gene', (214, 217))	('succinate', 'Chemical', 'MESH:D019802', (25, 34))	('HIF', 'Gene', (134, 137))	('hydroxylation of', 'MPA', (75, 91))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('fumarate', 'Chemical', 'MESH:D005650', (12, 20))	('pRCC', 'Gene', (177, 181))	('HIF', 'Gene', '405', (214, 217))	('HIF', 'Gene', '405', (134, 137))	('mutations', 'Var', (156, 165))	('stabilization', 'MPA', (197, 210))	('proline', 'Chemical', 'MESH:D011392', (96, 103))	('FH', 'Gene', '2271', (153, 155))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('cause', 'Reg', (187, 192))	('suppress', 'NegReg', (62, 70))	('RCC', 'Disease', 'MESH:C538614', (239, 242))
2369	31357507	Mutations of the above-mentioned genes and activation of the oncopathways are the main driver mutations in the progression of pRCC.	('Mutations', 'Var', (0, 9))	('pRCC', 'Gene', (126, 130))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('pRCC', 'Gene', '5546', (126, 130))
2370	31357507	How do these genetic alterations in pRCC translate to the protein and metabolite level?	('pRCC', 'Gene', (36, 40))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Gene', '5546', (36, 40))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))	('genetic alterations', 'Var', (13, 32))
2380	31357507	One of the most characteristic genetic features of chRCC is the monosomy of chromosomes 1, 2, 6, 10, 13, 17, and often 21.	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('monosomy', 'Var', (64, 72))
2381	31357507	The most commonly mutated genes in chRCC are TP53 (32%), PTEN (20%), and gene fusions involving the TERT promoter.	('TP53', 'Gene', (45, 49))	('gene fusions', 'Var', (73, 85))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('TERT', 'Gene', (100, 104))	('PTEN', 'Gene', (57, 61))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('PTEN', 'Gene', '5728', (57, 61))	('TERT', 'Gene', '7015', (100, 104))	('TP53', 'Gene', '7157', (45, 49))
2382	31357507	Mutations in these tumor suppressors combined with the deletion of one of their chromosomes leads to a complete loss of function.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (112, 116))	('tumor', 'Disease', (19, 24))	('deletion', 'Var', (55, 63))
2398	31357507	Validation by siRNA-mediated silencing of GCLC led to a strong cell number reduction of ccRCC cell lines, which was accompanied by significantly decreased GSH levels.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('GSH levels', 'MPA', (155, 165))	('GSH', 'Chemical', '-', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('silencing', 'Var', (29, 38))	('cell number', 'CPA', (63, 74))	('decreased', 'NegReg', (145, 154))	('reduction', 'NegReg', (75, 84))	('GCLC', 'Gene', (42, 46))	('GCLC', 'Gene', '2729', (42, 46))	('RCC', 'Disease', (90, 93))
2436	31357507	However, in response to a diverse array of stimuli, such as oxidative stress, the cysteine residues within KEAP1, Cys151, Cys273, and Cys288 can be modified, which results in a conformational change along with the dissociation of NRF2 to avoid KEAP1-mediated degradation.	('Cys273', 'Chemical', '-', (122, 128))	('Cys288', 'Var', (134, 140))	('Cys288', 'Chemical', '-', (134, 140))	('degradation', 'MPA', (259, 270))	('Cys273', 'Var', (122, 128))	('NRF2', 'Gene', '4780', (230, 234))	('Cys151', 'Chemical', '-', (114, 120))	('KEAP1', 'Gene', '9817', (244, 249))	('oxidative stress', 'Phenotype', 'HP:0025464', (60, 76))	('Cys151', 'Var', (114, 120))	('KEAP1', 'Gene', (244, 249))	('NRF2', 'Gene', (230, 234))	('KEAP1', 'Gene', '9817', (107, 112))	('dissociation', 'MPA', (214, 226))	('KEAP1', 'Gene', (107, 112))	('degradation', 'biological_process', 'GO:0009056', ('259', '270'))	('cysteine', 'Chemical', 'MESH:D003545', (82, 90))	('results in', 'Reg', (164, 174))	('conformational change', 'MPA', (177, 198))
2441	31357507	Apart from mutations in FH, NRF2, CUL3, or KEAP1 in type II pRCC, several other mechanisms can also lead to increased NRF2 activity in other cancers, including epigenetic silencing, modifications of cysteine residues, metabolic alterations, and oncogene-dependent signaling.	('mutations', 'Var', (11, 20))	('KEAP1', 'Gene', (43, 48))	('FH', 'Gene', '2271', (24, 26))	('pRCC', 'Gene', (60, 64))	('NRF2', 'Gene', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('metabolic alterations', 'CPA', (218, 239))	('cysteine', 'Chemical', 'MESH:D003545', (199, 207))	('epigenetic silencing', 'Var', (160, 180))	('NRF2', 'Gene', (28, 32))	('increased', 'PosReg', (108, 117))	('CUL3', 'Gene', (34, 38))	('signaling', 'biological_process', 'GO:0023052', ('264', '273'))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('oncogene-dependent', 'CPA', (245, 263))	('cancers', 'Disease', (141, 148))	('modifications', 'Var', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pRCC', 'Gene', '5546', (60, 64))	('activity', 'MPA', (123, 131))	('NRF2', 'Gene', '4780', (118, 122))	('CUL3', 'Gene', '8452', (34, 38))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('KEAP1', 'Gene', '9817', (43, 48))	('NRF2', 'Gene', '4780', (28, 32))
2458	31357507	Pharmacological inhibition of xCT decreases cystine uptake and induces ferroptosis in cancer cells, which makes xCT inhibitors potential treatment agents for cancer.	('xCT', 'Gene', '23657', (30, 33))	('induces', 'Reg', (63, 70))	('xCT', 'Gene', (112, 115))	('cancer', 'Disease', (158, 164))	('ferroptosis in cancer', 'Disease', 'MESH:D009369', (71, 92))	('cystine', 'Chemical', 'MESH:D003553', (44, 51))	('xCT', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('inhibition', 'Var', (16, 26))	('ferroptosis', 'biological_process', 'GO:0097707', ('71', '82'))	('cancer', 'Disease', (86, 92))	('decreases', 'NegReg', (34, 43))	('ferroptosis in cancer', 'Disease', (71, 92))	('cystine uptake', 'MPA', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('uptake', 'biological_process', 'GO:0098657', ('52', '58'))	('decreases cystine', 'Phenotype', 'HP:0500152', (34, 51))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('xCT', 'Gene', '23657', (112, 115))	('uptake', 'biological_process', 'GO:0098739', ('52', '58'))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
2459	31357507	Sorafenib, an FDA-approved kinase inhibitor drug used for almost 15 years for the treatment of RCC, has multiple kinase inhibition activities, including cell surface tyrosine kinases (e.g., vascular endothelial growth factor receptor, VEGFR; platelet-derived growth factor receptor, PDGFR; tyrosine-protein kinase kit, KIT; Fms-like tyrosine kinase 3, FLT3; RET proto-oncogene, RET) and downstream intracellular serine/threonine kinases (e.g., both wild-type and mutant BRAF and CRAF).	('vascular endothelial growth factor', 'Gene', '7422', (190, 224))	('intracellular', 'cellular_component', 'GO:0005622', ('398', '411'))	('Fms-like tyrosine kinase 3', 'Gene', '2322', (324, 350))	('KIT', 'molecular_function', 'GO:0005020', ('319', '322'))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('242', '272'))	('VEGFR', 'Gene', '3791', (235, 240))	('vascular endothelial growth factor', 'Gene', (190, 224))	('VEGFR', 'Gene', (235, 240))	('CRAF', 'Gene', (479, 483))	('cell surface', 'cellular_component', 'GO:0009986', ('153', '165'))	('Fms-like tyrosine kinase 3', 'Gene', (324, 350))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('190', '224'))	('PDGFR', 'Gene', (283, 288))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('PDGFR', 'Gene', '5159', (283, 288))	('RCC', 'Disease', (95, 98))	('FLT3', 'Gene', (352, 356))	('CRAF', 'Gene', '5894', (479, 483))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('Fms', 'molecular_function', 'GO:0005011', ('324', '327'))	('CRAF', 'molecular_function', 'GO:0004709', ('479', '483'))	('FLT3', 'Gene', '2322', (352, 356))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('27', '43'))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('BRAF', 'Gene', '673', (470, 474))	('protein', 'cellular_component', 'GO:0003675', ('299', '306'))	('BRAF', 'Gene', (470, 474))	('mutant', 'Var', (463, 469))
2463	31357507	Erastin is a small molecule that inhibits xCT activity through the mitochondrial voltage-dependent anion channel 2 and 3 (VDAC2 and VDAC3), causing abolition of the antioxidant defenses of the cell, and it furthermore has selectively lethal activity toward oncogenic RAS mutant cell lines.	('VDAC3', 'Gene', (132, 137))	('mutant', 'Var', (271, 277))	('antioxidant defenses', 'MPA', (165, 185))	('xCT', 'Gene', (42, 45))	('lethal activity', 'CPA', (234, 249))	('Erastin', 'Chemical', 'MESH:C477224', (0, 7))	('inhibits', 'NegReg', (33, 41))	('xCT', 'Gene', '23657', (42, 45))	('abolition', 'NegReg', (148, 157))	('VDAC3', 'Gene', '7419', (132, 137))
2464	31357507	A cystine addiction of VHL-deficient RCC cells was identified, and the deprivation thereof or treatment with erastin or sulfasalazine in RCC cells induced cell death.	('VHL-deficient RCC', 'Disease', 'MESH:C538614', (23, 40))	('VHL-deficient RCC', 'Disease', (23, 40))	('cell death', 'biological_process', 'GO:0008219', ('155', '165'))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('cystine', 'Chemical', 'MESH:D003553', (2, 9))	('erastin', 'Chemical', 'MESH:C477224', (109, 116))	('RCC', 'Disease', (37, 40))	('sulfasalazine', 'Chemical', 'MESH:D012460', (120, 133))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('cell death', 'CPA', (155, 165))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('deprivation thereof', 'Var', (71, 90))
2475	31357507	found that the abundance of pyruvate carboxylase (PC), which catalyzes the conversion of pyruvate to oxaloacetate to fuel the TCA cycle, strongly correlated with resistance, and knockdown of PC reduced TCA cycle activity and sensitized cells to CB-839 treatment, suggesting that PC expression may be a biomarker of resistance to CB-839.	('CB-839', 'Chemical', 'MESH:C000593334', (329, 335))	('correlated', 'Reg', (146, 156))	('pyruvate carboxylase', 'Gene', '397630', (28, 48))	('CB-839', 'Chemical', 'MESH:C000593334', (245, 251))	('oxaloacetate', 'Chemical', 'MESH:D062907', (101, 113))	('TCA', 'Enzyme', (202, 205))	('pyruvate', 'Chemical', 'MESH:D019289', (89, 97))	('TCA', 'Chemical', 'MESH:D014238', (126, 129))	('TCA', 'Chemical', 'MESH:D014238', (202, 205))	('pyruvate', 'Chemical', 'MESH:D019289', (28, 36))	('TCA cycle', 'biological_process', 'GO:0006099', ('126', '135'))	('pyruvate carboxylase', 'Gene', (28, 48))	('reduced', 'NegReg', (194, 201))	('knockdown', 'Var', (178, 187))	('TCA cycle', 'biological_process', 'GO:0006099', ('202', '211'))	('sensitized', 'Reg', (225, 235))	('resistance', 'MPA', (162, 172))
2477	31357507	In addition, decreases in mTOR signaling were also observed in RCC cell lines that were sensitive to CB-839, indicating that CB-839-induced glutamate deprivation has a direct influence on the mTOR pathway.	('decreases', 'NegReg', (13, 22))	('RCC', 'Disease', (63, 66))	('signaling', 'biological_process', 'GO:0023052', ('31', '40'))	('deprivation', 'NegReg', (150, 161))	('glutamate', 'Chemical', 'MESH:D018698', (140, 149))	('CB-839', 'Chemical', 'MESH:C000593334', (125, 131))	('influence', 'Reg', (175, 184))	('CB-839-induced', 'Var', (125, 139))	('CB-839', 'Chemical', 'MESH:C000593334', (101, 107))	('glutamate', 'MPA', (140, 149))	('mTOR', 'Gene', (26, 30))	('mTOR', 'Gene', '2475', (26, 30))	('mTOR', 'Gene', (192, 196))	('mTOR', 'Gene', '2475', (192, 196))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
2478	31357507	These observations suggest that receptor tyrosine kinase (RTK) signaling or mTOR inhibitors would have synergistic effects with CB-839 to increase cytotoxicity in RCC cell lines.	('increase', 'PosReg', (138, 146))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('signaling', 'biological_process', 'GO:0023052', ('63', '72'))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('mTOR', 'Gene', (76, 80))	('RCC', 'Disease', (163, 166))	('inhibitors', 'Var', (81, 91))	('mTOR', 'Gene', '2475', (76, 80))	('RTK', 'Gene', '5979', (58, 61))	('cytotoxicity', 'Disease', (147, 159))	('receptor tyrosine kinase', 'Gene', (32, 56))	('receptor tyrosine kinase', 'Gene', '5979', (32, 56))	('CB-839', 'Chemical', 'MESH:C000593334', (128, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (147, 159))	('RTK', 'Gene', (58, 61))
2494	31357507	In a pilot study and a phase I clinical trial, BSO in combination with melphalan was well tolerated and had therapeutic activity toward recurrent and refractory high-risk neuroblastoma (NCT00002730, NCT00005835).	('melphalan', 'Chemical', 'MESH:D008558', (71, 80))	('neuroblastoma', 'Disease', 'MESH:D009447', (171, 184))	('BSO', 'Chemical', 'MESH:D019328', (47, 50))	('neuroblastoma', 'Disease', (171, 184))	('NCT00002730', 'Var', (186, 197))	('neuroblastoma', 'Phenotype', 'HP:0003006', (171, 184))
2501	31357507	Individual DUB inhibitors, such as MI-2, PR-619, and EERI, were not effective in inducing cell death alone but led to an induction of proteotoxic stress and cell death in combination with BSO in many different cancer cell lines.	('PR-619', 'Var', (41, 47))	('MI-2', 'Var', (35, 39))	('led to', 'Reg', (111, 117))	('cell death', 'biological_process', 'GO:0008219', ('90', '100'))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('induction', 'Reg', (121, 130))	('BSO', 'Chemical', 'MESH:D019328', (188, 191))	('cell death', 'CPA', (157, 167))	('proteotoxic stress', 'MPA', (134, 152))	('cell death', 'biological_process', 'GO:0008219', ('157', '167'))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
2502	31357507	The significant decrease in the global ubiquitination pattern in rho0 cells can be explained by the lack of main ROS generators localized within the oxidative phosphorylation system, namely complex I and III, which reduce the oxidative damage of proteins to a minimal level.	('oxidative damage of proteins', 'MPA', (226, 254))	('decrease', 'NegReg', (16, 24))	('global ubiquitination pattern', 'MPA', (32, 61))	('complex I', 'cellular_component', 'GO:0030964', ('190', '199'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('149', '174'))	('rho0', 'Var', (65, 69))	('ROS', 'Chemical', 'MESH:D017382', (113, 116))
2515	31357507	As glutamine addiction is one of the main features of RCC, glutamine may be a limiting nutrient factor in the tumor microenvironment, and thus a lack of glutamine can induce immunosuppression.	('glutamine', 'Disease', (3, 12))	('glutamine', 'Protein', (153, 162))	('glutamine', 'Chemical', 'MESH:D005973', (153, 162))	('iron', 'Chemical', 'MESH:D007501', (124, 128))	('RCC', 'Disease', (54, 57))	('tumor', 'Disease', (110, 115))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('glutamine', 'Chemical', 'MESH:D005973', (59, 68))	('induce', 'Reg', (167, 173))	('glutamine', 'Chemical', 'MESH:D005973', (3, 12))	('lack', 'Var', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
2517	31357507	Reduced GSH levels in antigen-presenting cells have been shown to influence antigen processing and presentation as well as T-cell differentiation into T-helper 1 or 2 phenotypes.	('GSH levels', 'MPA', (8, 18))	('GSH', 'Chemical', '-', (8, 11))	('T-cell differentiation', 'CPA', (123, 145))	('T-cell differentiation', 'biological_process', 'GO:0030217', ('123', '145'))	('influence', 'Reg', (66, 75))	('Reduced', 'Var', (0, 7))	('antigen processing', 'MPA', (76, 94))	('antigen processing and presentation', 'biological_process', 'GO:0019882', ('76', '111'))	('presentation', 'MPA', (99, 111))
2522	31357507	The dysregulated respiratory chain is the main source of electron leakage, resulting in excessive ROS.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('dysregulated', 'Var', (4, 16))	('ROS', 'MPA', (98, 101))	('respiratory chain', 'cellular_component', 'GO:0070469', ('17', '34'))
2536	29468160	As currently no effective therapies exist to restore kidney function after CKD- as well as cancer-induced renal damage, it is important to elucidate new regulators of kidney development and disease as new therapeutic targets.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('renal damage', 'Disease', (106, 118))	('renal damage', 'Disease', 'MESH:D007674', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney development', 'biological_process', 'GO:0001822', ('167', '185'))	('CKD-', 'Var', (75, 79))	('CKD', 'Phenotype', 'HP:0012622', (75, 78))
2542	29468160	Our data indicate that most aGPCRs are expressed in different spatio-temporal patterns during kidney development and that altered aGPCR expression is associated with a variety of kidney diseases including CKD, diabetic nephropathy, lupus nephritis as well as renal cell carcinoma.	('nephropathy', 'Phenotype', 'HP:0000112', (219, 230))	('renal cell carcinoma', 'Disease', (259, 279))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (259, 279))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (210, 230))	('diabetic nephropathy', 'Disease', (210, 230))	('associated', 'Reg', (150, 160))	('expression', 'MPA', (136, 146))	('kidney disease', 'Phenotype', 'HP:0000112', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('kidney diseases', 'Disease', (179, 194))	('lupus nephritis', 'Disease', (232, 247))	('kidney diseases', 'Disease', 'MESH:D007674', (179, 194))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (259, 279))	('CKD', 'Disease', (205, 208))	('CKD', 'Phenotype', 'HP:0012622', (205, 208))	('altered', 'Var', (122, 129))	('nephritis', 'Phenotype', 'HP:0000123', (238, 247))	('aGPCR', 'Gene', (130, 135))	('lupus nephritis', 'Disease', 'MESH:D008181', (232, 247))	('kidney development', 'biological_process', 'GO:0001822', ('94', '112'))	('kidney diseases', 'Phenotype', 'HP:0000112', (179, 194))
2571	29468160	These are all processes that also play important roles in kidney development and disturbance of these processes are known to contribute to kidney disease (Sariola,; Schordan et al.,; Cabral and Garvin,; Xia et al.,; Gao et al.,; Kunimoto et al.,).	('kidney disease', 'Disease', (139, 153))	('kidney development', 'biological_process', 'GO:0001822', ('58', '76'))	('kidney disease', 'Phenotype', 'HP:0000112', (139, 153))	('contribute', 'Reg', (125, 135))	('kidney disease', 'Disease', 'MESH:D007674', (139, 153))	('disturbance', 'Var', (81, 92))
2576	29468160	Mutations in the corresponding genes, Pkd1 and Pkd2, have been associated with autosomal dominant polycystic kidney disease (ADPKD) (Ferreira et al.,).	('Pkd2', 'Gene', '18764', (47, 51))	('polycystic kidney', 'Phenotype', 'HP:0000113', (98, 115))	('autosomal dominant polycystic kidney disease', 'Disease', (79, 123))	('kidney disease', 'Phenotype', 'HP:0000112', (109, 123))	('associated', 'Reg', (63, 73))	('ADPKD', 'Disease', 'MESH:D007690', (125, 130))	('Mutations', 'Var', (0, 9))	('Pkd1', 'Gene', '18763', (38, 42))	('Pkd1', 'Gene', (38, 42))	('ADPKD', 'Disease', (125, 130))	('Pkd2', 'Gene', (47, 51))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (79, 123))
2601	29468160	Mice carrying mutations in Adgrc1 (Celsr1Crsh/Crsh and Celsr1Crsh/+) or Vangl2 (Vangl2Lp/+) exhibited branching defects in the ureteric tree at E13.5, which were more severe in Celsr1Crsh/+:Vangl2Lp/+ mice.	('Adgrc1', 'Gene', '12614', (27, 33))	('Mice', 'Species', '10090', (0, 4))	('Crsh', 'Gene', (46, 50))	('Crsh', 'Gene', '12614', (46, 50))	('Vangl2Lp/+', 'Gene', '93840', (80, 90))	('Vangl2Lp/+', 'Gene', '93840', (190, 200))	('mice', 'Species', '10090', (201, 205))	('Adgrc1', 'Gene', (27, 33))	('Vangl2Lp/+', 'Gene', (80, 90))	('Vangl2Lp/+', 'Gene', (190, 200))	('mutations', 'Var', (14, 23))	('Vangl2', 'Gene', (72, 78))	('Crsh', 'Gene', (61, 65))	('Crsh', 'Gene', '12614', (61, 65))	('Crsh', 'Gene', (41, 45))	('Crsh', 'Gene', (183, 187))	('Crsh', 'Gene', '12614', (41, 45))	('branching defects', 'CPA', (102, 119))	('Crsh', 'Gene', '12614', (183, 187))
2602	29468160	At E17.5 kidneys exhibited overall growth retardation (Celsr1Crsh/+:Vangl2Lp/+ > Celsr1Crsh/Crsh > Celsr1Crsh/+) and histological analysis revealed mitotic spindle misorientation (along the longitudinal axis of the kidney tubules), dilation of cortical tubules in Celsr1Crsh/Crsh mutants and an up-regulation of Gdnf and Ret mRNA levels in the Celsr1Crsh/+:Vangl2Lp/+ mutants.	('Crsh', 'Gene', '12614', (270, 274))	('Vangl2Lp/+', 'Gene', (68, 78))	('growth retardation', 'Phenotype', 'HP:0001510', (35, 53))	('Crsh', 'Gene', (350, 354))	('Crsh', 'Gene', (87, 91))	('Crsh', 'Gene', '12614', (350, 354))	('up-regulation', 'PosReg', (295, 308))	('Crsh', 'Gene', '12614', (87, 91))	('Crsh', 'Gene', (275, 279))	('mutants', 'Var', (280, 287))	('dilation', 'CPA', (232, 240))	('Crsh', 'Gene', '12614', (275, 279))	('growth retardation', 'Disease', 'MESH:D006130', (35, 53))	('growth retardation', 'Disease', (35, 53))	('Vangl2Lp/+', 'Gene', '93840', (357, 367))	('Crsh', 'Gene', (92, 96))	('Crsh', 'Gene', (61, 65))	('Crsh', 'Gene', '12614', (92, 96))	('Vangl2Lp/+', 'Gene', (357, 367))	('Crsh', 'Gene', '12614', (61, 65))	('mitotic spindle misorientation', 'CPA', (148, 178))	('Ret', 'Gene', (321, 324))	('Crsh', 'Gene', (105, 109))	('Ret', 'Gene', '19713', (321, 324))	('Gdnf', 'Gene', (312, 316))	('Crsh', 'Gene', '12614', (105, 109))	('mitotic spindle', 'cellular_component', 'GO:0072686', ('148', '163'))	('Gdnf', 'Gene', '14573', (312, 316))	('Vangl2Lp/+', 'Gene', '93840', (68, 78))	('Crsh', 'Gene', (270, 274))	('regulation', 'biological_process', 'GO:0065007', ('298', '308'))
2616	29468160	Moreover, no kidney phenotype has so far been described in Adgrg6 knockout mice, neither in the lines that are embryonic lethal at E11.5 (Patra et al.,) nor in Taconic knockouts of which some are born alive (Monk et al.,).	('Adgrg6', 'Gene', (59, 65))	('E11.5', 'Var', (131, 136))	('mice', 'Species', '10090', (75, 79))
2625	29468160	Previously, it has been demonstrated that it has a well-established role in lung surfactant homeostasis and that its deletion results in glucose intolerance and insulin resistance as well as a subtle vascular phenotype (Nie et al.,; Bridges et al.,; Fukuzawa et al.,; Yang et al.,; Niaudet et al.,).	('insulin resistance', 'CPA', (161, 179))	('lung surfactant homeostasis', 'MPA', (76, 103))	('glucose intolerance', 'Phenotype', 'HP:0001952', (137, 156))	('surfactant homeostasis', 'biological_process', 'GO:0043129', ('81', '103'))	('glucose intolerance', 'Disease', 'MESH:D018149', (137, 156))	('glucose intolerance', 'Disease', (137, 156))	('insulin', 'molecular_function', 'GO:0016088', ('161', '168'))	('results in', 'Reg', (126, 136))	('insulin resistance', 'Phenotype', 'HP:0000855', (161, 179))	('rat', 'Species', '10116', (31, 34))	('deletion', 'Var', (117, 125))
2635	29468160	Moreover, endothelial-specific deletion of Adgrf5/Adgrl4 utilizing VE-Cad-Cre mice, which are known to induce recombination in the endothelium of arteries and capillaries of the glomerulus of adult kidneys (Alva et al.,), resulted in no renal phenotype.	('induce', 'Reg', (103, 109))	('mice', 'Species', '10090', (78, 82))	('Adgrl4', 'Gene', '170757', (50, 56))	('deletion', 'Var', (31, 39))	('Adgrl4', 'Gene', (50, 56))	('renal', 'MPA', (237, 242))	('VE-Cad', 'Gene', '12562', (67, 73))	('VE-Cad', 'Gene', (67, 73))
2668	29468160	CKDs represent an important risk factor for cardiovascular or cerebrovascular diseases and progress toward end-stage renal disease (ESRD) (Eckardt et al.,; Balogun et al.,), which can only be treated by renal replacement therapies (RRT) like hemodialysis, peritoneal dialysis, or transplantation (Eckardt et al.,).	('cardiovascular or cerebrovascular diseases', 'Disease', (44, 86))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (107, 130))	('cardiovascular or cerebrovascular diseases', 'Disease', 'MESH:D002318', (44, 86))	('CKD', 'Phenotype', 'HP:0012622', (0, 3))	('ESRD', 'Disease', (132, 136))	('ESRD', 'Phenotype', 'HP:0003774', (132, 136))	('end-stage renal disease', 'Disease', (107, 130))	('CKDs', 'Var', (0, 4))	('end-stage renal disease', 'Disease', 'MESH:D007676', (107, 130))	('renal disease', 'Phenotype', 'HP:0000112', (117, 130))	('ESRD', 'Disease', 'MESH:D007676', (132, 136))
2683	29468160	Possible causes of ccRCC are mutations in the VHL gene (90%) as well as genetic aberrations of mTOR pathway proteins (Low et al.,; Inamura,; Shingarev and Jaimes,).	('VHL', 'Gene', (46, 49))	('VHL', 'Gene', '22346', (46, 49))	('Inamura', 'Disease', (131, 138))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('rat', 'Species', '10116', (84, 87))	('mutations', 'Var', (29, 38))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('mTOR', 'Gene', (95, 99))	('RCC', 'Disease', (21, 24))	('causes', 'Reg', (9, 15))	('mTOR', 'Gene', '56717', (95, 99))
2684	29468160	Type 1 pRCC is characterized by MET proto-oncogene-activating mutations and type 2 with activation of the NRF2/antioxidant response element pathway due to the increased oxidative stress.	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('oxidative stress', 'MPA', (169, 185))	('activation', 'PosReg', (88, 98))	('pRCC', 'Gene', '94315', (7, 11))	('mutations', 'Var', (62, 71))	('increased', 'PosReg', (159, 168))	('pRCC', 'Gene', (7, 11))	('NRF2', 'Gene', '18024', (106, 110))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (159, 185))	('NRF2', 'Gene', (106, 110))
2701	29468160	ADGRG1 knockdown resulted in melanoma growth inhibition and regression (Ke et al.,), while knockdown of the other 2 aGPCRs reduced lung (ADGRF5) (Tang et al.,) and/or bone metastasis (ADGRE5, ADGRF5) (Ward et al.,; Tang et al.,).	('melanoma growth inhibition', 'Disease', 'MESH:D008545', (29, 55))	('lung', 'CPA', (131, 135))	('melanoma', 'Phenotype', 'HP:0002861', (29, 37))	('melanoma growth inhibition', 'Disease', (29, 55))	('ADGRG1', 'Gene', (0, 6))	('bone metastasis', 'CPA', (167, 182))	('knockdown', 'Var', (91, 100))	('regression', 'CPA', (60, 70))	('knockdown', 'Var', (7, 16))	('reduced', 'NegReg', (123, 130))
2721	29468160	Richter and coworkers demonstrated that inhibition of Adgrg2 expression impaired colony formation in vitro (A673, SB-KMS-KS1 and TC-71) and suppressed local tumor growth and metastasis in an immunodeficient mouse xenograft model of human cancer [SB-KMS-KS1/Rag2(-/-)gammaC(-/-)].	('immunodeficient', 'Disease', (191, 206))	('formation', 'biological_process', 'GO:0009058', ('88', '97'))	('TC-71', 'Chemical', '-', (129, 134))	('human', 'Species', '9606', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mouse', 'Species', '10090', (207, 212))	('cancer', 'Disease', (238, 244))	('Adgrg2', 'Gene', '237175', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('inhibition', 'Var', (40, 50))	('suppressed', 'NegReg', (140, 150))	('rat', 'Species', '10116', (29, 32))	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('impaired', 'NegReg', (72, 80))	('Rag2', 'Gene', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('colony formation', 'CPA', (81, 97))	('Adgrg2', 'Gene', (54, 60))	('Rag2', 'Gene', '5897', (257, 261))	('immunodeficient', 'Disease', 'MESH:D007153', (191, 206))
2726	29468160	In addition, it has been demonstrated that, despite the large number of MMPs known to be expressed in the healthy kidney (Catania et al.,), changes in a single MMP can cause kidney disease (Cheng et al.,).	('MMP', 'molecular_function', 'GO:0004235', ('160', '163'))	('kidney disease', 'Disease', 'MESH:D007674', (174, 188))	('rat', 'Species', '10116', (32, 35))	('kidney disease', 'Phenotype', 'HP:0000112', (174, 188))	('cause', 'Reg', (168, 173))	('changes', 'Var', (140, 147))	('MMP', 'Gene', (72, 75))	('MMP', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (72, 75))	('MMP', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (160, 163))	('MMPs', 'Gene', '4312;17386;4313;17390;4314;4318;17386', (72, 76))	('kidney disease', 'Disease', (174, 188))	('MMP', 'Gene', (160, 163))	('MMPs', 'Gene', (72, 76))
2730	29468160	Around half of the double-deficient mice died perinatally, while the other half showed growth impairment and all died within 3 weeks to 3 months postnatally.	('growth impairment', 'Disease', 'MESH:D006130', (87, 104))	('growth impairment', 'Phenotype', 'HP:0001510', (87, 104))	('growth impairment', 'Disease', (87, 104))	('mice', 'Species', '10090', (36, 40))	('double-deficient', 'Var', (19, 35))
2733	29468160	Notably, even though Adgrl4 and Adgrf5 are highly expressed in endothelial cells, endothelial-specific deletion of Adgrf5/Adgrl4 utilizing VE-Cad-Cre mice resulted in no renal phenotype.	('renal phenotype', 'CPA', (170, 185))	('mice', 'Species', '10090', (150, 154))	('Adgrl4', 'Gene', '170757', (21, 27))	('Adgrl4', 'Gene', (21, 27))	('VE-Cad', 'Gene', '12562', (139, 145))	('VE-Cad', 'Gene', (139, 145))	('Adgrl4', 'Gene', '170757', (122, 128))	('Adgrl4', 'Gene', (122, 128))	('deletion', 'Var', (103, 111))
2739	29468160	It should be noted that ADGRL4 is downregulated (0.179-fold) and mutated (11%) in chRCC (Table 2), which might be explained, similarly as for ADGRB1, by the different types of vessels (fragile vs. thick-walled; Low et al.,; Inamura,; Shingarev and Jaimes,).	('downregulated', 'NegReg', (34, 47))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('ADGRL4', 'Gene', (24, 30))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('ADGRB1', 'Gene', '107831', (142, 148))	('ADGRB1', 'Gene', (142, 148))	('mutated', 'Var', (65, 72))
2750	29468160	Notably, Shi and coworkers reported recently that more (2-fold) macrophages invaded the kidney of Adgrg3 knockout mice on high-fat diet (HFD) compared to HFD wildtype mice (Shi et al.,).	('knockout', 'Var', (105, 113))	('Adgrg3', 'Gene', (98, 104))	('mice', 'Species', '10090', (114, 118))	('Adgrg3', 'Gene', '54672', (98, 104))	('mice', 'Species', '10090', (167, 171))	('more', 'PosReg', (50, 54))
2752	29468160	Yet, major metabolic phenotyping showed no difference between Adgrg3 knockout and wildtype mice on HFD.	('Adgrg3', 'Gene', '54672', (62, 68))	('mice', 'Species', '10090', (91, 95))	('knockout', 'Var', (69, 77))	('Adgrg3', 'Gene', (62, 68))
2844	33475752	Most patients received VEGF targeted therapy in the first line (88%; 8895 patients).	('targeted therapy', 'Var', (28, 44))	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (74, 82))	('VEGF', 'Gene', (23, 27))	('VEGF', 'Gene', '7422', (23, 27))
2898	33475752	This finding may in part be explained by the previously demonstrated tendency of localized nonclear cell histologic variants to have a lower risk of recurrence and/or death following surgical resection, resulting in skewed proportions in our cohort consisting exclusively of patients with metastatic disease.	('variants', 'Var', (116, 124))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (275, 283))
2929	27490806	Clear cell RCC is characteristically associated with the loss of function of the VHL (von Hippel-Landau) gene, in the majority of tumours, whether by somatic mutation, chromosomal loss or epigenetic silencing.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('von Hippel-Landau', 'Gene', (86, 103))	('loss of function', 'NegReg', (57, 73))	('VHL', 'Gene', (81, 84))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('VHL', 'Gene', '7428', (81, 84))	('tumours', 'Disease', (130, 137))	('chromosomal loss', 'Var', (168, 184))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('von Hippel-Landau', 'Gene', '7428', (86, 103))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('RCC', 'Disease', (11, 14))	('epigenetic silencing', 'Var', (188, 208))
2930	27490806	The VHL gene is on chromosome 3p25 and is an established two-hit tumour suppressor gene; one allele typically inactivated by mutation or promoter methylation, and the other lost due to a large deletion.	('deletion', 'Var', (193, 201))	('lost', 'NegReg', (173, 177))	('inactivated', 'NegReg', (110, 121))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('VHL', 'Gene', (4, 7))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('promoter methylation', 'Var', (137, 157))	('VHL', 'Gene', '7428', (4, 7))	('tumour', 'Disease', (65, 71))	('mutation', 'Var', (125, 133))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
2967	27490806	With a high frequency of VHL gene mutation in ccRCC, this gene has made an attractive candidate for a possible biomarker for patient outcome.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('mutation', 'Var', (34, 42))	('VHL', 'Gene', (25, 28))	('patient', 'Species', '9606', (125, 132))	('VHL', 'Gene', '7428', (25, 28))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
2968	27490806	Despite extensive evaluation there is currently no evidence that the absence or presence of a VHL mutation or the type of mutation has any predictive or prognostic value in sporadic ccRCC.	('VHL', 'Gene', '7428', (94, 97))	('mutation', 'Var', (98, 106))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('VHL', 'Gene', (94, 97))
2969	27490806	VHL inactivation alone is insufficient for the formation of RCC.	('inactivation', 'Var', (4, 16))	('formation', 'biological_process', 'GO:0009058', ('47', '56'))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', '7428', (0, 3))
2970	27490806	The genetics of RCC is distinctive in that in addition to mutations in VHL, these tumours have infrequent somatic mutations in known common cancer genes, such as p53 and RAS.	('mutations', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('p53', 'Gene', (162, 165))	('RCC', 'Disease', (16, 19))	('VHL', 'Gene', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RAS', 'Disease', (170, 173))	('cancer', 'Disease', (140, 146))	('p53', 'Gene', '7157', (162, 165))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumours', 'Disease', (82, 89))	('VHL', 'Gene', '7428', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
2972	27490806	The loss of 3p, which is present in >90% of ccRCC would knock out one allele of all the three of these tumour suppressor genes.	('RCC', 'Disease', (46, 49))	('tumour', 'Disease', (103, 109))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('knock out', 'NegReg', (56, 65))	('loss of 3p', 'Var', (4, 14))
2975	27490806	SETD2 knockout is embryonically lethal in mice due to the disruption of embryonic vascular development.	('mice', 'Species', '10090', (42, 46))	('embryonic vascular', 'Disease', (72, 90))	('SETD2', 'Gene', (0, 5))	('embryonic vascular', 'Disease', 'MESH:D000783', (72, 90))	('knockout', 'Var', (6, 14))	('disruption', 'NegReg', (58, 68))	('men', 'Species', '9606', (98, 101))
2977	27490806	Case series have unanimously found that tumours with BAP1 mutations are associated with more aggressive pathological features and a worse cancer-specific survival.	('aggressive pathological features', 'CPA', (93, 125))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (138, 144))	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('BAP1', 'Gene', '8314', (53, 57))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('BAP1', 'Gene', (53, 57))
2978	27490806	In another retrospective case series, BAP1 mutations were associated with the presence of metastatic disease at presentation and advanced clinical stage, when compared with tumours with PBRM1 mutations.	('PBRM1', 'Gene', '55193', (186, 191))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('associated', 'Reg', (58, 68))	('BAP1', 'Gene', (38, 42))	('metastatic', 'CPA', (90, 100))	('mutations', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('PBRM1', 'Gene', (186, 191))	('BAP1', 'Gene', '8314', (38, 42))
2979	27490806	In one cohort of 145 patients with ccRCC between 1998 and 2011, median OS was 4.6 years for patients whose tumours harboured BAP1 mutations vs 10.6 years for patients whose tumours harboured PBRM1 mutations.	('tumours', 'Disease', (107, 114))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (21, 29))	('RCC', 'Disease', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('patients', 'Species', '9606', (158, 166))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('PBRM1', 'Gene', '55193', (191, 196))	('BAP1', 'Gene', '8314', (125, 129))	('patients', 'Species', '9606', (92, 100))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('PBRM1', 'Gene', (191, 196))	('tumours', 'Disease', (173, 180))	('BAP1', 'Gene', (125, 129))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (130, 139))
2980	27490806	Data regarding the impact of PBRM1 mutations have been inconsistent, with another case series showing that small tumours (<4 cm) with PBRM1 mutations were six times more likely to attain pathological stage pT3a than pT1a.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('small tumours', 'Disease', 'MESH:D055752', (107, 120))	('PBRM1', 'Gene', '55193', (29, 34))	('PBRM1', 'Gene', (134, 139))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('PBRM1', 'Gene', '55193', (134, 139))	('small tumours', 'Disease', (107, 120))	('mutations', 'Var', (140, 149))	('PBRM1', 'Gene', (29, 34))
2982	27490806	BAP1 and PBRM1 mutations are almost always mutually exclusive, occurring together at much lower frequencies than would be expected statistically, but in case series, results for the minority of patients with both mutations have been inconsistent.	('patients', 'Species', '9606', (194, 202))	('BAP1', 'Gene', (0, 4))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', '8314', (0, 4))	('PBRM1', 'Gene', (9, 14))	('PBRM1', 'Gene', '55193', (9, 14))
2984	27490806	In a large retrospective cohort of 1400 patients could be divided into four distinct groups clinically based on their BAP1 and PBRM1 mutational status.	('patients', 'Species', '9606', (40, 48))	('PBRM1', 'Gene', (127, 132))	('BAP1', 'Gene', '8314', (118, 122))	('PBRM1', 'Gene', '55193', (127, 132))	('mutational status', 'Var', (133, 150))	('BAP1', 'Gene', (118, 122))
2987	27490806	The mechanism by which these genes responsible for chromatin remodelling may affect the biology of tumours is not understood, but it is interesting to note that in an assessment of tumour heterogeneity in ccRCC by found three different mutations in SETD2 in different metastatic loci, suggesting a role for these mutations as secondary events in the development of an invasive and metastatic phenotype.	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('chromatin', 'cellular_component', 'GO:0000785', ('51', '60'))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('SETD2', 'Gene', (249, 254))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumour', 'Disease', (99, 105))	('RCC', 'Disease', (207, 210))	('men', 'Species', '9606', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('tumours', 'Disease', (99, 106))	('mutations', 'Var', (236, 245))	('tumour', 'Disease', (181, 187))	('men', 'Species', '9606', (357, 360))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('51', '72'))
3010	27490806	Pazopanib is associated with higher rates of grade 3 or 4 LFT derangement (17% vs 4%) and is therefore inadvisable in patients with pre-existing bulky liver disease or baseline LFT derangement.	('liver disease', 'Disease', (151, 164))	('men', 'Species', '9606', (69, 72))	('pre', 'molecular_function', 'GO:0003904', ('132', '135'))	('grade 3', 'Disease', (45, 52))	('LFT', 'Gene', '167410', (58, 61))	('liver disease', 'Disease', 'MESH:D008107', (151, 164))	('Pazopanib', 'Chemical', 'MESH:C516667', (0, 9))	('LFT', 'Gene', (177, 180))	('bulky liver', 'Phenotype', 'HP:0002240', (145, 156))	('liver disease', 'Phenotype', 'HP:0001392', (151, 164))	('men', 'Species', '9606', (188, 191))	('LFT', 'Gene', '167410', (177, 180))	('LFT', 'Gene', (58, 61))	('patients', 'Species', '9606', (118, 126))	('Pazopanib', 'Var', (0, 9))
3041	27490806	Targeting mTOR is of particular relevance in RCC, because in the majority of cases, the loss of pVHL leads to constitutive activation of the HIFs, resulting in the upregulation of many HIF targets associated with angiogenesis, metabolic adaption and metastasis, including VEGF.	('VEGF', 'Gene', (272, 276))	('mTOR', 'Gene', (10, 14))	('pVHL', 'Gene', '7428', (96, 100))	('pVHL', 'Gene', (96, 100))	('constitutive', 'MPA', (110, 122))	('angiogenesis', 'biological_process', 'GO:0001525', ('213', '225'))	('VEGF', 'Gene', '7422', (272, 276))	('loss', 'Var', (88, 92))	('mTOR', 'Gene', '2475', (10, 14))	('activation', 'PosReg', (123, 133))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('upregulation', 'PosReg', (164, 176))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
3042	27490806	Mammalian target of rapamycin has been found to increase HIF at the translational level, therefore inhibition of mTOR can be seen to be particularly useful in RCC.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('inhibition', 'Var', (99, 109))	('Mammalian target of rapamycin', 'Gene', '2475', (0, 29))	('mTOR', 'Gene', (113, 117))	('mTOR', 'Gene', '2475', (113, 117))	('HIF at the translational', 'MPA', (57, 81))	('Mammalian target of rapamycin', 'Gene', (0, 29))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('increase', 'PosReg', (48, 56))
3057	27490806	The anti-FGFR and anti-VEGF TKI dovitinib showed no advantage in the third line over sorafenib in patients previously treated with both a TKI and mTOR inhibitor.	('anti-FGFR', 'Var', (4, 13))	('mTOR', 'Gene', '2475', (146, 150))	('mTOR', 'Gene', (146, 150))	('dovitinib', 'Chemical', 'MESH:C500007', (32, 41))	('patients', 'Species', '9606', (98, 106))	('FGFR', 'molecular_function', 'GO:0005007', ('9', '13'))	('VEGF', 'Gene', (23, 27))	('TKI', 'Var', (28, 31))	('sorafenib', 'Chemical', 'MESH:D000077157', (85, 94))	('VEGF', 'Gene', '7422', (23, 27))
3080	27490806	Hereditary type 1 pRCC is caused by a germline mutation in the c-MET proto-oncogene, and MET mutation or overexpression is commonly found in sporadic pRCC also.	('pRCC', 'Gene', '5546', (18, 22))	('c-MET', 'Gene', '4233', (63, 68))	('caused by', 'Reg', (26, 35))	('pRCC', 'Gene', (150, 154))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('pRCC', 'Gene', (18, 22))	('germline mutation', 'Var', (38, 55))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('pRCC', 'Gene', '5546', (150, 154))	('c-MET', 'Gene', (63, 68))
3082	27490806	Ongoing phase 2 trials are assessing the role of the MET inhibitors savolitinib, cabozantinib and crizotinib in pRCC (NCT02761057 and NCT02127710).	('NCT02761057', 'Var', (118, 129))	('pRCC', 'Gene', (112, 116))	('crizotinib', 'Chemical', 'MESH:D000077547', (98, 108))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('savolitinib', 'Chemical', 'MESH:C000593259', (68, 79))	('pRCC', 'Gene', '5546', (112, 116))	('cabozantinib', 'Chemical', 'MESH:C558660', (81, 93))	('NCT02127710', 'Var', (134, 145))
3092	27490806	Rates of grade 3 or 4 toxicity were similar in the lenvatinib-containing arms and higher than in the everolimus arms (45% for the combination, 44% for lenvatinib and 38% in the everolimus group).	('toxicity', 'Disease', 'MESH:D064420', (22, 30))	('toxicity', 'Disease', (22, 30))	('everolimus', 'Chemical', 'MESH:D000068338', (101, 111))	('everolimus', 'Chemical', 'MESH:D000068338', (177, 187))	('lenvatinib', 'Chemical', 'MESH:C531958', (151, 161))	('lenvatinib', 'Chemical', 'MESH:C531958', (51, 61))	('lenvatinib-containing', 'Var', (51, 72))
3143	27490806	Other early phase studies combining TKIs with TCCI are ongoing including pembrolizumab-pazopanib (NCT02014636), pembrolizumab-axitinib (NCT02133742) and pembrolizumab-lenvatinib (NCT02501096).	('pembrolizumab', 'Chemical', 'MESH:C582435', (73, 86))	('lenvatinib', 'Chemical', 'MESH:C531958', (167, 177))	('pembrolizumab', 'Chemical', 'MESH:C582435', (153, 166))	('NCT02133742', 'Var', (136, 147))	('pazopanib', 'Chemical', 'MESH:C516667', (87, 96))	('NCT02014636', 'Var', (98, 109))	('pembrolizumab-axitinib', 'Disease', 'None', (112, 134))	('pembrolizumab', 'Chemical', 'MESH:C582435', (112, 125))	('pembrolizumab-axitinib', 'Disease', (112, 134))	('TCCI', 'Chemical', '-', (46, 50))
3150	27490806	It has been postulated that high expression levels of programmed cell death 1 ligand (PD-L1) on tumour cell surfaces may be correlated with an enhanced response to nivolumab, as blockade of this pathway restores anti-tumour immunity.	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('response to nivolumab', 'MPA', (152, 173))	('PD-L1', 'Gene', '29126', (86, 91))	('enhanced', 'PosReg', (143, 151))	('tumour', 'Disease', 'MESH:D009369', (217, 223))	('blockade', 'Var', (178, 186))	('tumour immunity', 'Disease', (217, 232))	('ligand', 'molecular_function', 'GO:0005488', ('78', '84'))	('programmed cell death', 'biological_process', 'GO:0012501', ('54', '75'))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('nivolumab', 'Chemical', 'MESH:D000077594', (164, 173))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (217, 223))	('expression levels', 'MPA', (33, 50))	('restores', 'PosReg', (203, 211))	('tumour immunity', 'Disease', 'MESH:D009369', (217, 232))	('PD-L1', 'Gene', (86, 91))	('tumour', 'Disease', (96, 102))
3201	24129247	Expression levels of the five selected miRNAs (hsa-miR-21: Tm000397; hsa-miR-141: Tm000483; hsa-miR-155: Tm002626; hsa-miR-183: Tm002269; and hsa-miR-200b: Tm002251) were assessed in triplicate for each sample and two water blanks were added to each plate as negative controls.	('miR', 'Gene', (39, 42))	('miR-155', 'Gene', '406947', (96, 103))	('water', 'Chemical', 'MESH:D014867', (218, 223))	('miR', 'Gene', '220972', (51, 54))	('miR-200b', 'Gene', '406984', (146, 154))	('miR', 'Gene', '220972', (146, 149))	('miR-141', 'Gene', '406933', (73, 80))	('miR-183', 'Gene', '406959', (119, 126))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (51, 54))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (146, 149))	('miR-141', 'Gene', (73, 80))	('miR', 'Gene', '220972', (119, 122))	('miR-183', 'Gene', (119, 126))	('miR', 'Gene', (96, 99))	('Tm000483', 'Var', (82, 90))	('miR', 'Gene', (73, 76))	('miR-200b', 'Gene', (146, 154))	('Tm000397', 'Var', (59, 67))	('miR', 'Gene', '220972', (39, 42))	('hsa-miR-21', 'Gene', (47, 57))	('miR', 'Gene', (119, 122))	('miR-155', 'Gene', (96, 103))	('hsa-miR-21', 'Gene', '406991', (47, 57))
3273	24129247	Renal cell tumour subtypes display characteristic chromosomal aberrations, including whole or partial deletions and duplications.	('Renal cell tumour', 'Phenotype', 'HP:0005584', (0, 17))	('tumour subtype', 'Disease', (11, 25))	('duplications', 'Var', (116, 128))	('whole', 'Var', (85, 90))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumour subtype', 'Disease', 'MESH:C535673', (11, 25))	('Renal cell tumour', 'Disease', 'MESH:C538614', (0, 17))	('Renal cell tumour', 'Disease', (0, 17))	('partial deletions', 'Var', (94, 111))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (50, 73))
3303	30082842	Moreover, coexpression of OCT4 and NANOG is a strong independent predictor of unfavorable outcome and tumor recurrence in HCC patients and is associated with enhanced lung cancer malignancy and pancreatic carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('pancreatic carcinogenesis', 'Disease', (194, 219))	('lung cancer malignancy', 'Disease', (167, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('enhanced', 'PosReg', (158, 166))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('OCT4', 'Gene', '5460', (26, 30))	('coexpression', 'Var', (10, 22))	('NANOG', 'Gene', '79923', (35, 40))	('lung cancer malignancy', 'Disease', 'MESH:D008175', (167, 189))	('patients', 'Species', '9606', (126, 134))	('NANOG', 'Gene', (35, 40))	('OCT4', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (194, 219))
3361	30082842	The 5-year DSS and PFS survival rates were 82.0% and 49.0% in low nuclear OCT4 expression, and 84.0% and 30.0% in high nuclear OCT4 expression.	('DSS', 'Chemical', '-', (11, 14))	('OCT4', 'Gene', '5460', (127, 131))	('OCT4', 'Gene', '5460', (74, 78))	('OCT4', 'Gene', (74, 78))	('OCT4', 'Gene', (127, 131))	('PFS survival', 'CPA', (19, 31))	('high nuclear', 'Var', (114, 126))	('DSS', 'CPA', (11, 14))	('low nuclear', 'Var', (62, 73))
3390	30082842	Most ccRCCs cases have deletions in the short arm of Chromosome 3, which are highly specific for ccRCC, and are not observed in any other RCC subtypes.	('RCC', 'Disease', (138, 141))	('deletions', 'Var', (23, 32))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('Chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('short arm', 'Phenotype', 'HP:0009824', (40, 49))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('ccRCC', 'Phenotype', 'HP:0006770', (5, 10))
3401	30082842	Interestingly, cytoplasmic NANOG expression was an independent prognostic factor for poor PFS in RCC patients, which was a novel finding of our study, raising the possibility of its utility as a prognostic biomarker for RCC.	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('PFS', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('cytoplasmic', 'Var', (15, 26))	('NANOG', 'Gene', '79923', (27, 32))	('NANOG', 'Gene', (27, 32))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
3407	30082842	Similar to our observations, coexpression of OCT4 and NANOG was found to be significantly associated with tumor aggressiveness and poor prognosis of several malignances including breast and lung cancers and glioma.	('tumor aggressiveness', 'Disease', (106, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (190, 202))	('coexpression', 'Var', (29, 41))	('breast and lung cancers', 'Disease', 'MESH:D001943', (179, 202))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('NANOG', 'Gene', (54, 59))	('glioma', 'Disease', (207, 213))	('associated with', 'Reg', (90, 105))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (106, 126))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('OCT4', 'Gene', '5460', (45, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('OCT4', 'Gene', (45, 49))	('NANOG', 'Gene', '79923', (54, 59))
3412	30082842	demonstrated that knockdown of both OCT4 and NANOG expressions inhibit spontaneous changes in the expression of EMT-related genes and the migration of breast CSC in vitro.	('knockdown', 'Var', (18, 27))	('OCT4', 'Gene', '5460', (36, 40))	('migration of breast CSC', 'CPA', (138, 161))	('OCT4', 'Gene', (36, 40))	('NANOG', 'Gene', '79923', (45, 50))	('NANOG', 'Gene', (45, 50))	('EMT-related genes', 'Gene', (112, 129))	('inhibit', 'NegReg', (63, 70))	('EMT', 'biological_process', 'GO:0001837', ('112', '115'))	('expression', 'MPA', (98, 108))
3430	28593993	MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC.	('kidney tumours', 'Disease', (155, 169))	('pRCC tumours', 'Disease', 'MESH:D009369', (43, 55))	('pRCC tumours', 'Disease', (43, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('kidney tumours', 'Disease', 'MESH:D007680', (155, 169))	('RCC', 'Disease', (44, 47))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('human', 'Species', '9606', (187, 192))	('produce', 'Reg', (147, 154))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('RCC', 'Disease', (195, 198))	('deletion', 'Var', (131, 139))
3435	28593993	Here, the authors generate two mouse models of the most common RCC subtypes: the human papillary RCC through MYC activation and clear cell RCC through MYC activation combined with Vhl and Cdkn2a deletion.	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', (97, 100))	('MYC', 'Gene', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('mouse', 'Species', '10090', (31, 36))	('MYC', 'MPA', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('activation', 'PosReg', (113, 123))	('deletion', 'Var', (195, 203))	('Cdkn2a', 'Gene', (188, 194))	('human', 'Species', '9606', (81, 86))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
3438	28593993	Inherited RCC can be caused by germline mutations in multiple genes that are linked to specific histologic subtypes.	('RCC', 'Disease', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('caused by', 'Reg', (21, 30))	('germline mutations', 'Var', (31, 49))
3442	28593993	The von Hippel-Lindau tumour suppressor protein (pVHL) is broadly inactivated (~80%) in sporadic ccRCC by either mutation or promoter hypermethylation and its tumour suppressor activity is dependent on its downregulation of the alpha subunits of the hypoxia-inducible factor (HIFalpha) family of transcription factors and in particular HIF2alpha (refs).	('HIF2alpha', 'Gene', '13819', (336, 345))	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('inactivated', 'NegReg', (66, 77))	('tumour', 'Disease', (22, 28))	('downregulation', 'NegReg', (206, 220))	('RCC', 'Disease', (99, 102))	('mutation', 'Var', (113, 121))	('protein', 'cellular_component', 'GO:0003675', ('40', '47'))	('HIF2alpha', 'Gene', (336, 345))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('von Hippel-Lindau tumour', 'Disease', (4, 28))	('promoter hypermethylation', 'Var', (125, 150))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('transcription', 'biological_process', 'GO:0006351', ('296', '309'))	('HIFalpha', 'Gene', (276, 284))	('tumour', 'Disease', (159, 165))	('hypoxia', 'Disease', (250, 257))	('pVHL', 'Gene', (49, 53))	('HIFalpha', 'Gene', '15251;13819', (276, 284))	('pVHL', 'Gene', '22346', (49, 53))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (4, 28))	('hypoxia', 'Disease', 'MESH:D000860', (250, 257))
3444	28593993	ccRCC has a relatively low mutation burden relative to other solid tumours but does have characteristic large deletions and gains of chromosomes 3p, 14q and 5q, respectively, as well as more focal gains and losses of 8q24 (harbouring MYC) and 9p21 (harbouring CDKN2A), respectively.	('8q24', 'Gene', (217, 221))	('gains', 'PosReg', (124, 129))	('RCC', 'Disease', (2, 5))	('losses', 'NegReg', (207, 213))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('solid tumours', 'Disease', 'MESH:D009369', (61, 74))	('gains', 'PosReg', (197, 202))	('9p21', 'Gene', (243, 247))	('solid tumours', 'Disease', (61, 74))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('deletions', 'Var', (110, 119))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
3446	28593993	Gain of 8q, as assessed by classic cytogenetics, is associated with a high risk of lymph node and distant metastases and is an independent prognostic factor.	('metastases', 'Disease', 'MESH:D009362', (106, 116))	('metastases', 'Disease', (106, 116))	('Gain', 'Var', (0, 4))
3458	28593993	MYC mice had a significantly shortened survival relative to controls (Fig.	('MYC', 'Var', (0, 3))	('survival', 'CPA', (39, 47))	('shortened', 'NegReg', (29, 38))	('mice', 'Species', '10090', (4, 8))
3482	28593993	To model the interplay of genomic events observed in human RCC, we next examined the phenotypes of kidney specific Vhl inactivation in combination with MYC overexpression or combined MYC overexpression and Ink/Arf deletion.	('deletion', 'Var', (214, 222))	('kidney specific', 'MPA', (99, 114))	('human', 'Species', '9606', (53, 58))	('inactivation', 'NegReg', (119, 131))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
3494	28593993	Therefore, while Vhl loss combined with MYC activation is sufficient to induce modest clear cell changes, Vhl loss combined with MYC activation and Ink/Arf deletion induces bona fide clear cell RCC (Table 1).	('Ink/Arf', 'Gene', (148, 155))	('loss', 'NegReg', (110, 114))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('induces', 'Reg', (165, 172))	('RCC', 'Disease', (194, 197))	('Vhl', 'Gene', (106, 109))	('deletion', 'Var', (156, 164))
3495	28593993	We next examined whether human ccRCC tumours with similar genomic characteristics (VHL inactivation; VHL inactivation and MYC activation; and VHL inactivation, CDKN2A loss and MYC activation) have similar outcomes as those seen in our mouse models.	('VHL', 'Gene', (101, 104))	('ccRCC tumours', 'Disease', 'MESH:D009369', (31, 44))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('CDKN2A', 'Gene', (160, 166))	('MYC', 'CPA', (122, 125))	('inactivation', 'NegReg', (87, 99))	('human', 'Species', '9606', (25, 30))	('inactivation', 'Var', (146, 158))	('loss', 'NegReg', (167, 171))	('inactivation', 'NegReg', (105, 117))	('mouse', 'Species', '10090', (235, 240))	('ccRCC tumours', 'Disease', (31, 44))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('VHL', 'Gene', (142, 145))
3496	28593993	Of TCGA KIRC tumours (n=525), 87, 13 and 31% had VHL inactivation, MYC activation and CDKN2A deletion, respectively (Fig.	('VHL', 'MPA', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('MYC', 'MPA', (67, 70))	('activation', 'PosReg', (71, 81))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('inactivation', 'NegReg', (53, 65))	('deletion', 'Var', (93, 101))	('CDKN2A', 'Gene', (86, 92))
3497	28593993	We further classified these patients as V (n=286, 54%), VM (n=26, 5%) and VIM (n=32, 6.1%) and noted that VM and VIM patients had a significantly decreased survival relative to V patients (P=0.005 and P=5.086 x 10-9, respectively (Fig.	('survival', 'MPA', (156, 164))	('decreased', 'NegReg', (146, 155))	('VIM', 'Var', (113, 116))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (28, 36))
3512	28593993	There were a large number of genes that were differentially regulated (increased or decreased greater than two-fold; t-test FDR<0.05) by MYC activation (Dox) in both VM-3055 (799 up and 2491 down) and VIM-3039 (1017 up and 2159 down) cells (Fig.	('1017', 'Var', (211, 215))	('MYC', 'Protein', (137, 140))	('VIM-3039', 'CellLine', 'CVCL:X276', (201, 209))	('799', 'Var', (175, 178))	('Dox', 'Chemical', '-', (153, 156))	('decreased', 'NegReg', (84, 93))	('activation', 'PosReg', (141, 151))
3534	28593993	As predicted, VIM-3039 cells had significantly increased matrigel invasion (Fig.	('matrigel invasion', 'CPA', (57, 74))	('VIM-3039', 'CellLine', 'CVCL:X276', (14, 22))	('increased', 'PosReg', (47, 56))	('VIM-3039', 'Var', (14, 22))
3535	28593993	Therefore, Ink4a/Arf inactivation appears to facilitate EMT, invasion and metastases and the metastatic phenotype seen in vivo is recapitulated in vitro.	('inactivation', 'Var', (21, 33))	('EMT', 'CPA', (56, 59))	('facilitate', 'PosReg', (45, 55))	('EMT', 'biological_process', 'GO:0001837', ('56', '59'))	('metastases', 'Disease', (74, 84))	('Ink4a/Arf', 'Gene', (11, 20))	('metastases', 'Disease', 'MESH:D009362', (74, 84))
3543	28593993	Our own studies highlight the role of MYC in renal tumorigenesis and demonstrate that MYC activation is sufficient to generate papillary RCC and that when combined with Vhl and Ink4a/Arf inactivation results in bona fide clear cell renal cell carcinoma.	('results in', 'Reg', (200, 210))	('MYC', 'Gene', (86, 89))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 252))	('clear cell renal cell carcinoma', 'Disease', (221, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('inactivation', 'Var', (187, 199))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (221, 252))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (232, 252))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))
3546	28593993	Combined inactivation of Vhl with Trp53 does appear to induce renal tumours, which have clear cell changes but not bona fide clear cell RCC histology.	('Trp53', 'Gene', (34, 39))	('renal tumours', 'Disease', (62, 75))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('renal tumour', 'Phenotype', 'HP:0009726', (62, 74))	('induce', 'Reg', (55, 61))	('Trp53', 'Gene', '7157', (34, 39))	('inactivation', 'Var', (9, 21))	('Vhl', 'Gene', (25, 28))	('renal tumours', 'Disease', 'MESH:D007680', (62, 75))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
3547	28593993	A recent report demonstrated that combined inactivation of Vhl with Bap1 results in renal tumours with clear cell histology.	('Bap1', 'Gene', (68, 72))	('renal tumours', 'Disease', 'MESH:D007680', (84, 97))	('combined', 'Interaction', (34, 42))	('results in', 'Reg', (73, 83))	('renal tumour', 'Phenotype', 'HP:0009726', (84, 96))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('renal tumours', 'Disease', (84, 97))	('Vhl', 'Gene', (59, 62))	('Bap1', 'Gene', '104416', (68, 72))	('inactivation', 'Var', (43, 55))
3548	28593993	However, while inactivation of other tumour suppressor genes such as Flcn, Tsc1 or Fh results in renal carcinomas, they are rarely of the clear cell histologic subtype and they exhibit long latency, impacting their utility for routine investigation.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('renal carcinomas', 'Disease', (97, 113))	('tumour', 'Disease', (37, 43))	('Tsc1', 'Gene', (75, 79))	('Flcn', 'Gene', (69, 73))	('renal carcinomas', 'Phenotype', 'HP:0005584', (97, 113))	('Flcn', 'Gene', '216805', (69, 73))	('Tsc1', 'Gene', '64930', (75, 79))	('renal carcinomas', 'Disease', 'MESH:C538614', (97, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('results in', 'Reg', (86, 96))	('inactivation', 'Var', (15, 27))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
3559	28593993	VHL inactivation results in the stabilization of the alpha subunits of the hypoxia-inducible factor alpha (HIF) family of transcription factors of which HIF2alpha is thought to be a key oncogenic driver of ccRCC tumorigenesis, while emerging evidence suggests that HIF1alpha may be a tumour suppressor gene.	('hypoxia', 'Disease', (75, 82))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('inactivation', 'Var', (4, 16))	('transcription', 'biological_process', 'GO:0006351', ('122', '135'))	('HIF2alpha', 'Gene', (153, 162))	('stabilization', 'MPA', (32, 45))	('HIF1alpha', 'Gene', '15251', (265, 274))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('tumour', 'Disease', (284, 290))	('HIF1alpha', 'Gene', (265, 274))	('RCC', 'Disease', (208, 211))	('VHL', 'Gene', (0, 3))	('HIF2alpha', 'Gene', '13819', (153, 162))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
3562	28593993	Our studies demonstrate that Ink4a/Arf inactivation promotes liver metastases in an autochthonous ccRCC GEM model and that Ink4a/Arf loss is associated with gene expression patterns of EMT.	('gene expression', 'biological_process', 'GO:0010467', ('157', '172'))	('EMT', 'biological_process', 'GO:0001837', ('185', '188'))	('metastases', 'Disease', (67, 77))	('Ink4a/Arf', 'Gene', (123, 132))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('loss', 'NegReg', (133, 137))	('promotes', 'PosReg', (52, 60))	('metastases', 'Disease', 'MESH:D009362', (67, 77))	('inactivation', 'Var', (39, 51))	('RCC', 'Disease', (100, 103))	('Ink4a/Arf', 'Gene', (29, 38))
3607	25970683	The aim of our project was to investigate specific renal immunohistochemical biomarkers involved in the hypoxia-inducible factor pathway and mutations in the VHL gene to clarify the relationship between ccpRCC and RAT.	('mutations', 'Var', (141, 150))	('pRCC', 'Phenotype', 'HP:0006766', (205, 209))	('VHL', 'Gene', (158, 161))	('ccpRCC', 'Chemical', '-', (203, 209))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('hypoxia', 'Disease', (104, 111))	('ccpRCC', 'Phenotype', 'HP:0006770', (203, 209))	('RAT', 'Species', '10116', (214, 217))	('VHL', 'Gene', '24874', (158, 161))
3615	25970683	Genetic analysis revealed VHL mutations in 2/27 (7%) and 1/7 (14%) ccpRCC and RAT samples, respectively.	('pRCC', 'Phenotype', 'HP:0006766', (69, 73))	('VHL', 'Gene', (26, 29))	('revealed', 'Reg', (17, 25))	('ccpRCC', 'Phenotype', 'HP:0006770', (67, 73))	('mutations', 'Var', (30, 39))	('VHL', 'Gene', '24874', (26, 29))	('RAT', 'Species', '10116', (78, 81))	('ccpRCC', 'Chemical', '-', (67, 73))
3624	25970683	Despite significant morphologic, immunohistochemical and genetic similarities to clear cell renal cell carcinoma (ccRCC) and papillary renal cell carcinoma (pRCC), characteristic genetic differences include VHL gene mutations and 3p losses, found in ccRCC.	('3p losses', 'Var', (230, 239))	('ccRCC', 'Phenotype', 'HP:0006770', (250, 255))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (125, 155))	('clear cell renal cell carcinoma', 'Disease', (81, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('RCC', 'Disease', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('VHL', 'Gene', '24874', (207, 210))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (81, 112))	('papillary renal cell carcinoma', 'Disease', (125, 155))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (158, 161))	('pRCC', 'Phenotype', 'HP:0006766', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('VHL', 'Gene', (207, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('pRCC', 'Gene', '310687', (157, 161))	('pRCC', 'Gene', (157, 161))	('RCC', 'Disease', (252, 255))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 112))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (125, 155))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('mutations', 'Var', (216, 225))
3637	25970683	A total of 25 antibodies were selected as (i) they are involved in the VHL signaling pathway, (ii) they are known to be prognostic biomarkers of ccRCC and (iii) they have been reported as markers of ccpRCCs and RATs in a small group of ccpRCCs described in recent USCAP meetings (2011-2014).	('pRCC', 'Phenotype', 'HP:0006766', (201, 205))	('ccpRCC', 'Phenotype', 'HP:0006770', (236, 242))	('RCC', 'Disease', (147, 150))	('RATs', 'Species', '10116', (211, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (145, 150))	('RCC', 'Disease', (202, 205))	('involved', 'Reg', (55, 63))	('ccpRCC', 'Chemical', '-', (199, 205))	('VHL', 'Gene', '24874', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Disease', (239, 242))	('pRCC', 'Phenotype', 'HP:0006766', (238, 242))	('signaling pathway', 'biological_process', 'GO:0007165', ('75', '92'))	('ccpRCC', 'Phenotype', 'HP:0006770', (199, 205))	('ccpRCC', 'Chemical', '-', (236, 242))	('VHL', 'Gene', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('antibodies', 'Var', (14, 24))
3648	25970683	All VHL point mutations obtained were validated by a second separate PCR and sequencing analysis.	('mutations', 'Var', (14, 23))	('VHL', 'Gene', (4, 7))	('VHL', 'Gene', '24874', (4, 7))
3670	25970683	In contrast, the RAT tumors and the ccpRCC-like tumor with the VHL mutation showed a circumferential membranous staining pattern.	('RAT tumors', 'Disease', 'MESH:D009369', (17, 27))	('ccpRCC', 'Chemical', '-', (36, 42))	('tumor', 'Disease', (48, 53))	('mutation', 'Var', (67, 75))	('tumor', 'Disease', (21, 26))	('VHL', 'Gene', '24874', (63, 66))	('RAT tumors', 'Disease', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('ccpRCC', 'Phenotype', 'HP:0006770', (36, 42))	('VHL', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('pRCC', 'Phenotype', 'HP:0006766', (38, 42))
3674	25970683	In 9 of the cases FISH was not performed as there was not sufficient tissue after VHL mutation analysis and immunohistochemistry.	('VHL', 'Gene', '24874', (82, 85))	('VHL', 'Gene', (82, 85))	('mutation', 'Var', (86, 94))
3677	25970683	Three VHL mutations were detected in the ccpRCC group (3/27, 11%) in exon 2 (c.351G>C/p.Trp117Cys, c.461C>T/p.Pro154Leu, c.388G>C/p.Val130Leu) and one in the RAT group (1/7, 14%) in exon 1 (c.174_177delGCCG /p.Pro59GlyfsX7).	('ccpRCC', 'Phenotype', 'HP:0006770', (41, 47))	('c.461C>T', 'Mutation', 'c.461C>T', (99, 107))	('VHL', 'Gene', '24874', (6, 9))	('p.Trp117Cys', 'Var', (86, 97))	('c.461C>T/p.Pro154Leu', 'Var', (99, 119))	('c.351G>C', 'Mutation', 'c.351G>C', (77, 85))	('p.Trp117Cys', 'SUBSTITUTION', 'None', (86, 97))	('c.388G>C', 'Mutation', 'rs104893830', (121, 129))	('p.Pro154Leu', 'Mutation', 'p.P154L', (108, 119))	('VHL', 'Gene', (6, 9))	('c.174_177delGCCG', 'Mutation', 'c.174_177delGCCG', (190, 206))	('p.Pro59GlyfsX7', 'Mutation', 'p.P59GfsX7', (208, 222))	('ccpRCC', 'Chemical', '-', (41, 47))	('RAT', 'Species', '10116', (158, 161))	('p.Val130Leu', 'Mutation', 'rs104893830', (130, 141))	('c.388G>', 'Var', (121, 128))	('pRCC', 'Phenotype', 'HP:0006766', (43, 47))
3678	25970683	We identified two cases, harboring both a VHL mutation and 3p loss.	('VHL', 'Gene', (42, 45))	('VHL', 'Gene', '24874', (42, 45))	('mutation', 'Var', (46, 54))
3681	25970683	We found a VHL mutation rate of 11% in ccpRCC and 14% in RAT.	('pRCC', 'Phenotype', 'HP:0006766', (41, 45))	('mutation', 'Var', (15, 23))	('VHL', 'Gene', '24874', (11, 14))	('ccpRCC', 'Chemical', '-', (39, 45))	('ccpRCC', 'Disease', (39, 45))	('ccpRCC', 'Phenotype', 'HP:0006770', (39, 45))	('VHL', 'Gene', (11, 14))	('RAT', 'Species', '10116', (57, 60))
3689	25970683	The most relevant differential diagnoses include ccRCC that exhibit papillary features, pRCC exhibiting clear cell characteristics and Xp11 translocation carcinoma.	('carcinoma', 'Disease', (154, 163))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', (51, 54))	('RCC', 'Disease', (89, 92))	('carcinoma', 'Disease', 'MESH:D002277', (154, 163))	('pRCC', 'Phenotype', 'HP:0006766', (88, 92))	('papillary features', 'Phenotype', 'HP:0007482', (68, 86))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('Xp11 translocation', 'Var', (135, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('pRCC', 'Gene', '310687', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('pRCC', 'Gene', (88, 92))
3692	25970683	It is controversial whether TFE3 positivity is sufficient to diagnose TFE3 translocation carcinoma, but, from these 2 cases, we concluded that TFE3 translocation cancer falls within the differential diagnostic spectrum of ccpRCC/RAT.	('ccpRCC', 'Chemical', '-', (222, 228))	('RAT', 'Species', '10116', (229, 232))	('TFE3 translocation', 'Var', (143, 161))	('cancer falls', 'Disease', 'MESH:D009369', (162, 174))	('cancer falls', 'Disease', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('ccpRCC', 'Phenotype', 'HP:0006770', (222, 228))	('carcinoma', 'Disease', 'MESH:D002277', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('falls', 'Phenotype', 'HP:0002527', (169, 174))	('pRCC', 'Phenotype', 'HP:0006766', (224, 228))	('carcinoma', 'Disease', (89, 98))
3697	25970683	This case also revealed a mutation in the VHL gene and a 3p loss in the FISH analysis.	('revealed', 'Reg', (15, 23))	('mutation', 'Var', (26, 34))	('VHL', 'Gene', '24874', (42, 45))	('loss', 'NegReg', (60, 64))	('VHL', 'Gene', (42, 45))
3699	25970683	VHL gene mutations are the genetic hallmark of ccRCC.	('RCC', 'Disease', (49, 52))	('VHL', 'Gene', '24874', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('mutations', 'Var', (9, 18))	('VHL', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
3701	25970683	However, three groups have recently identified VHL mutations in ccpRCC at frequencies varying from 15% to 27%.	('ccpRCC', 'Phenotype', 'HP:0006770', (64, 70))	('mutations', 'Var', (51, 60))	('pRCC', 'Phenotype', 'HP:0006766', (66, 70))	('ccpRCC', 'Chemical', '-', (64, 70))	('VHL', 'Gene', (47, 50))	('ccpRCC', 'Disease', (64, 70))	('VHL', 'Gene', '24874', (47, 50))
3702	25970683	In concordance with these studies, we also identified VHL gene alterations in ccpRCC, but the prevalence of VHL gene mutations is significantly lower than in ccRCC.	('alterations', 'Var', (63, 74))	('VHL', 'Gene', (54, 57))	('VHL', 'Gene', '24874', (108, 111))	('ccpRCC', 'Chemical', '-', (78, 84))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('pRCC', 'Phenotype', 'HP:0006766', (80, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (158, 163))	('RCC', 'Disease', (81, 84))	('VHL', 'Gene', '24874', (54, 57))	('ccpRCC', 'Phenotype', 'HP:0006770', (78, 84))	('VHL', 'Gene', (108, 111))
3703	25970683	The discrepancy between the number of mutations found in our ccpRCC cases and that reported may be explained by the different detection methods employed, including single nucleotide polymorphism (SNPs) genotyping array, Sanger sequencing, and by the limited number of cases in previous studies.	('ccpRCC', 'Chemical', '-', (61, 67))	('ccpRCC', 'Disease', (61, 67))	('ccpRCC', 'Phenotype', 'HP:0006770', (61, 67))	('mutations', 'Var', (38, 47))	('pRCC', 'Phenotype', 'HP:0006766', (63, 67))
3704	25970683	Alternatively, cases with VHL mutations could represent ccRCCs with morphology and immunoprofile which closely mimics that of clear ccpRCC and RAT tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('VHL', 'Gene', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('ccpRCC', 'Phenotype', 'HP:0006770', (132, 138))	('RCC', 'Disease', (135, 138))	('RAT tumor', 'Disease', 'MESH:D009369', (143, 152))	('mutations', 'Var', (30, 39))	('RAT tumor', 'Disease', (143, 152))	('RCC', 'Disease', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('VHL', 'Gene', '24874', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('pRCC', 'Phenotype', 'HP:0006766', (134, 138))	('ccpRCC', 'Chemical', '-', (132, 138))
3709	25970683	VHL inactivation leads to a HIF-dependent CA-IX and GLUT-1 up-regulation.	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('inactivation', 'Var', (4, 16))	('VHL', 'Gene', '24874', (0, 3))	('VHL', 'Gene', (0, 3))	('GLUT-1', 'Gene', '24778', (52, 58))	('CA-IX', 'MPA', (42, 47))	('up-regulation', 'PosReg', (59, 72))	('GLUT-1', 'Gene', (52, 58))
3710	25970683	We only found few VHL mutations, but in combination with CA-IX and GLUT-1 immunoreactivity in both ccpRCC and RAT.	('GLUT-1', 'Gene', '24778', (67, 73))	('VHL', 'Gene', '24874', (18, 21))	('ccpRCC', 'Chemical', '-', (99, 105))	('RAT', 'Species', '10116', (110, 113))	('pRCC', 'Phenotype', 'HP:0006766', (101, 105))	('GLUT-1', 'Gene', (67, 73))	('mutations', 'Var', (22, 31))	('ccpRCC', 'Phenotype', 'HP:0006770', (99, 105))	('VHL', 'Gene', (18, 21))
3711	25970683	This clearly sets the ccpRCC and RAT apart from ccRCC, which shows VHL mutations in up to 80% of the cases.	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))	('ccpRCC', 'Chemical', '-', (22, 28))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('VHL', 'Gene', '24874', (67, 70))	('mutations', 'Var', (71, 80))	('RAT', 'Species', '10116', (33, 36))	('ccpRCC', 'Phenotype', 'HP:0006770', (22, 28))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))	('VHL', 'Gene', (67, 70))
3713	25970683	found various mutations in ccpRCC by using Next Generation Sequencing (NGS), including a non-synonymous T992I mutation in the MET proto-oncogene.	('ccpRCC', 'Gene', (27, 33))	('ccpRCC', 'Phenotype', 'HP:0006770', (27, 33))	('T992I', 'Var', (104, 109))	('pRCC', 'Phenotype', 'HP:0006766', (29, 33))	('T992I', 'Mutation', 'rs56391007', (104, 109))	('ccpRCC', 'Chemical', '-', (27, 33))	('mutations', 'Var', (14, 23))
3714	25970683	This gene was originally described as causing hereditary pRCC.	('pRCC', 'Gene', '310687', (57, 61))	('pRCC', 'Gene', (57, 61))	('causing', 'Reg', (38, 45))	('gene', 'Var', (5, 9))	('pRCC', 'Phenotype', 'HP:0006766', (57, 61))
3715	25970683	detected no VHL mutation, but found overexpression in all five members of the miR-200 family.	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '24874', (12, 15))	('mutation', 'Var', (16, 24))	('overexpression', 'PosReg', (36, 50))
3722	25970683	In our FISH analysis, we identified three chromosome 3p deletions in 20 ccpRCC and in 7 RAT samples.	('ccpRCC', 'Phenotype', 'HP:0006770', (72, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('deletions', 'Var', (56, 65))	('pRCC', 'Phenotype', 'HP:0006766', (74, 78))	('ccpRCC', 'Chemical', '-', (72, 78))	('RAT', 'Species', '10116', (88, 91))	('ccpRCC', 'Disease', (72, 78))
3723	25970683	All 3p deletions occurred in ccpRCC with a frequency of 14.3 %, but none was detected in RAT.	('ccpRCC', 'Disease', (29, 35))	('pRCC', 'Phenotype', 'HP:0006766', (31, 35))	('ccpRCC', 'Phenotype', 'HP:0006770', (29, 35))	('deletions', 'Var', (7, 16))	('occurred', 'Reg', (17, 25))	('ccpRCC', 'Chemical', '-', (29, 35))	('RAT', 'Species', '10116', (89, 92))
3725	25970683	concurrently harbored a VHL mutation like two of our three cases with a 3p loss.	('harbored', 'Reg', (13, 21))	('VHL', 'Gene', '24874', (24, 27))	('VHL', 'Gene', (24, 27))	('mutation', 'Var', (28, 36))
3726	25970683	also used FISH and observed monosomy of chromosome 3 in three cases in a series of 11 ccpRCC all lacking mutations in the VHL gene.	('VHL', 'Gene', '24874', (122, 125))	('ccpRCC', 'Phenotype', 'HP:0006770', (86, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('VHL', 'Gene', (122, 125))	('pRCC', 'Phenotype', 'HP:0006766', (88, 92))	('monosomy', 'Var', (28, 36))	('ccpRCC', 'Chemical', '-', (86, 92))
3730	25970683	However, some of the cases of ccRCC with smooth muscle stroma, particularly those that showed 3p loss, might represent ccRCCs with exuberant, infiltrative smooth muscle, whereas the others might in fact be RAT tumors, particularly the ones that do not show 3p loss.	('3p loss', 'Var', (94, 101))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('RAT tumors', 'Disease', 'MESH:D009369', (206, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('muscle stroma', 'Disease', (48, 61))	('RCC', 'Disease', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('RAT tumors', 'Disease', (206, 216))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('muscle stroma', 'Disease', 'MESH:D009133', (48, 61))
3731	25970683	Additionally, recent data shows that some tumors with RAT morphology and immunophenotype share a common mutation in the TCEB1 gene which inactivated the VHL pathway and upregulated proteins along the hypoxia-inducible pathway.	('hypoxia', 'Disease', 'MESH:D000860', (200, 207))	('inactivated', 'NegReg', (137, 148))	('VHL', 'Gene', (153, 156))	('TCEB1', 'Gene', (120, 125))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (104, 112))	('TCEB1', 'Gene', '64525', (120, 125))	('VHL', 'Gene', '24874', (153, 156))	('RAT', 'Species', '10116', (54, 57))	('upregulated', 'PosReg', (169, 180))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('proteins', 'Protein', (181, 189))	('hypoxia', 'Disease', (200, 207))
3756	25970683	Our group has reported that the expression of p27, CA-IX, CK7 and CK19 is associated with a better prognosis in sporadic RCC.	('p27', 'Gene', '83571', (46, 49))	('CK19', 'Gene', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('CK19', 'Gene', '360626', (66, 70))	('CK7', 'Gene', (58, 61))	('CK7', 'Gene', '300242', (58, 61))	('p27', 'Gene', (46, 49))	('CA-IX', 'Var', (51, 56))
3762	25970683	Taking into account the controversial relevance of the VHL mutation analysis in this differential diagnosis, direct VHL sequencing is not helpful in separation of ccRCC with prominent smooth muscle stroma from RAT.	('VHL', 'Gene', '24874', (116, 119))	('RAT', 'Species', '10116', (210, 213))	('VHL', 'Gene', '24874', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (163, 168))	('muscle stroma', 'Disease', 'MESH:D009133', (191, 204))	('VHL', 'Gene', (116, 119))	('mutation', 'Var', (59, 67))	('muscle stroma', 'Disease', (191, 204))	('VHL', 'Gene', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
3764	25970683	In some difficult cases VHL mutation testing and TFE3 FISH analysis are helpful tools to distinguish ccRCC and TFE3 translocation carcinoma from ccpRCC/RAT (Figure 5).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Disease', (148, 151))	('VHL', 'Gene', '24874', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('RAT', 'Species', '10116', (152, 155))	('ccpRCC', 'Phenotype', 'HP:0006770', (145, 151))	('carcinoma', 'Disease', 'MESH:D002277', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('VHL', 'Gene', (24, 27))	('ccpRCC', 'Chemical', '-', (145, 151))	('TFE3 translocation', 'Var', (111, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('carcinoma', 'Disease', (130, 139))	('pRCC', 'Phenotype', 'HP:0006766', (147, 151))
3798	32716909	Based on COX Regression model, we then identified 5 IR-lncRs which were associated with prognosis (sIRlncRs), such as AP001267.3, SNHG16, AC021054.1, AC026471.3 and ADAMTS9-AS1.	('AS1', 'Gene', (173, 176))	('AC021054.1', 'Var', (138, 148))	('AS1', 'Gene', '5729', (173, 176))	('prognosis', 'Disease', (88, 97))	('ADAMTS9', 'Gene', '56999', (165, 172))	('IR', 'Gene', '3643', (52, 54))	('IR', 'Gene', '3643', (100, 102))	('ADAMTS9', 'Gene', (165, 172))	('SNHG16', 'Gene', (130, 136))	('SNHG16', 'Gene', '100507246', (130, 136))
3801	32716909	And with the increase of risk score, the expression levels of AC026471.3 and SNHG16 were elevated, while AP001267.3 and ADAMTS9-AS1 expressed decreasingly (Figure 2C).	('AS1', 'Gene', (128, 131))	('expression levels', 'MPA', (41, 58))	('AC026471.3', 'Var', (62, 72))	('ADAMTS9', 'Gene', '56999', (120, 127))	('elevated', 'PosReg', (89, 97))	('ADAMTS9', 'Gene', (120, 127))	('SNHG16', 'Gene', (77, 83))	('SNHG16', 'Gene', '100507246', (77, 83))	('AS1', 'Gene', '5729', (128, 131))
3806	32716909	The expression levels of SNHG16 and AC026471.3 were higher in female patients (Figure 5A-5B).	('expression levels', 'MPA', (4, 21))	('SNHG16', 'Gene', (25, 31))	('SNHG16', 'Gene', '100507246', (25, 31))	('higher', 'PosReg', (52, 58))	('patients', 'Species', '9606', (69, 77))	('AC026471.3', 'Var', (36, 46))
3808	32716909	We further found the expression levels of AP001267.3 and ADAMTS9-AS1 were gradually decreased in the more advanced stage, T-stage, M-stage and N-stage, while the expression levels of AC026471.3 and SNHG16 were enhanced (Figure 6A-6D).	('expression levels', 'MPA', (21, 38))	('enhanced', 'PosReg', (210, 218))	('expression levels', 'MPA', (162, 179))	('ADAMTS9', 'Gene', '56999', (57, 64))	('ADAMTS9', 'Gene', (57, 64))	('AP001267.3', 'Var', (42, 52))	('SNHG16', 'Gene', '100507246', (198, 204))	('SNHG16', 'Gene', (198, 204))	('decreased', 'NegReg', (84, 93))	('AS1', 'Gene', '5729', (65, 68))	('AS1', 'Gene', (65, 68))
3825	32716909	In the present study, 322 pRCC patients were enrolled in a genome-wide analysis for lncRNAs, combining with 311 IRGs screened in Molecular Signatures Database v4.0 (Immune system process M13664, Immune response M19817), and 17 IR-lncRs were identified eventually.	('IR', 'Gene', '3643', (112, 114))	('pRCC', 'Gene', (26, 30))	('Immune system process', 'biological_process', 'GO:0002376', ('165', '186'))	('Immune response', 'biological_process', 'GO:0006955', ('195', '210'))	('IR', 'Gene', '3643', (227, 229))	('patients', 'Species', '9606', (31, 39))	('pRCC', 'Phenotype', 'HP:0006766', (26, 30))	('pRCC', 'Gene', '5546', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('M13664', 'Var', (187, 193))
3861	32716909	The formula was as followed, [Expression level of AP001267.3 * (-1.213353)] + [Expression level of SNHG16 * (0.581303)] + [Expression level of AC026471.3* (0.779272)] + [Expression level of ADAMTS9-AS1* (-0.233562)].	('SNHG16', 'Gene', (99, 105))	('ADAMTS9', 'Gene', '56999', (190, 197))	('ADAMTS9', 'Gene', (190, 197))	('AS1', 'Gene', '5729', (198, 201))	('AS1', 'Gene', (198, 201))	('SNHG16', 'Gene', '100507246', (99, 105))	('AP001267.3 *', 'Var', (50, 62))
3879	30816681	We found a significant difference in overall survival (OS) between groups, with high syntaxin 6 expression correlating with decreased survival.	('expression', 'MPA', (96, 106))	('decreased', 'NegReg', (124, 133))	('overall survival', 'MPA', (37, 53))	('syntaxin 6', 'Gene', (85, 95))	('survival', 'MPA', (134, 142))	('high', 'Var', (80, 84))	('syntaxin 6', 'Gene', '10228', (85, 95))
3885	30816681	Silencing of syntaxin 6 in ACHN cells significantly decreased the cell viability (p < 0.001).	('cell viability', 'CPA', (66, 80))	('decreased', 'NegReg', (52, 61))	('ACHN', 'Gene', '55323', (27, 31))	('syntaxin 6', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('ACHN', 'Gene', (27, 31))	('syntaxin 6', 'Gene', '10228', (13, 23))
3886	30816681	Overall, syntaxin 6 could be a prognostic biomarker for patients with papillary RCC and syntaxin 6 inhibitors hold promise as a novel therapy against RCC.	('patients', 'Species', '9606', (56, 64))	('syntaxin 6', 'Gene', (88, 98))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('inhibitors', 'Var', (99, 109))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('syntaxin 6', 'Gene', '10228', (9, 19))	('syntaxin 6', 'Gene', '10228', (88, 98))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('syntaxin 6', 'Gene', (9, 19))
3892	30816681	Classically, mutations in the von Hippel-Lindau (VHL) gene prevents ubiquitination and degradation of hypoxia-inducible factors (HIF) such as HIF-1alpha.	('ubiquitination', 'MPA', (68, 82))	('degradation', 'MPA', (87, 98))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('HIF-1alpha', 'Gene', (142, 152))	('VHL', 'Disease', 'MESH:D006623', (49, 52))	('von Hippel-Lindau', 'Gene', '7428', (30, 47))	('degradation', 'biological_process', 'GO:0009056', ('87', '98'))	('VHL', 'Disease', (49, 52))	('prevents', 'NegReg', (59, 67))	('hypoxia', 'Disease', (102, 109))	('mutations', 'Var', (13, 22))	('HIF-1alpha', 'Gene', '3091', (142, 152))	('von Hippel-Lindau', 'Gene', (30, 47))
3914	30816681	Those patients with high syntaxin 6 expression had a median overall survival of 5.844 years.	('syntaxin 6', 'Gene', '10228', (25, 35))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('syntaxin 6', 'Gene', (25, 35))	('expression', 'MPA', (36, 46))
3917	30816681	Median overall survival for ccRCC tumors with high syntaxin 6 expression was 6.140 years.	('high', 'Var', (46, 50))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('syntaxin 6', 'Gene', '10228', (51, 61))	('expression', 'MPA', (62, 72))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('syntaxin 6', 'Gene', (51, 61))
3919	30816681	Similarly, median overall survival for pRCC tumors with high syntaxin 6 expression (5.844 years) was significantly lower than survival for those tumors with low/medium syntaxin 6 expression (p < 0.0001) (Fig.	('tumors', 'Disease', (44, 50))	('pRCC', 'Gene', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('syntaxin 6', 'Gene', '10228', (168, 178))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('syntaxin 6', 'Gene', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('lower', 'NegReg', (115, 120))	('syntaxin 6', 'Gene', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('pRCC', 'Gene', '5546', (39, 43))	('syntaxin 6', 'Gene', '10228', (61, 71))	('high', 'Var', (56, 60))
3949	30816681	Interestingly, high co-expression of syntaxin 6 with VEGFR2, PDGF-beta, TP53 and VEGF all predicted significantly worse survival in those patients with pRCC (Fig.	('pRCC', 'Gene', '5546', (152, 156))	('VEGF', 'Gene', (53, 57))	('syntaxin 6', 'Gene', '10228', (37, 47))	('high', 'Var', (15, 19))	('syntaxin 6', 'Gene', (37, 47))	('TP53', 'Gene', '7157', (72, 76))	('pRCC', 'Gene', (152, 156))	('survival', 'MPA', (120, 128))	('patients', 'Species', '9606', (138, 146))	('PDGF-beta', 'Gene', '5155', (61, 70))	('VEGF', 'Gene', '7422', (81, 85))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('worse', 'NegReg', (114, 119))	('VEGF', 'Gene', (81, 85))	('VEGFR2', 'Gene', (53, 59))	('PDGF-beta', 'Gene', (61, 70))	('TP53', 'Gene', (72, 76))	('VEGFR2', 'Gene', '3791', (53, 59))	('VEGF', 'Gene', '7422', (53, 57))	('PDGF', 'molecular_function', 'GO:0005161', ('61', '65'))
3954	30816681	Syntaxin 6 knock-down was confirmed by real time-PCR (Fig.	('Syntaxin 6', 'Gene', (0, 10))	('Syntaxin 6', 'Gene', '10228', (0, 10))	('knock-down', 'Var', (11, 21))
3961	30816681	With c-met mutations known to be common in pRCC, MET inhibitors such as capozantanib and foretinib have been developed and are in clinical trials.	('mutations', 'Var', (11, 20))	('pRCC', 'Gene', (43, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('pRCC', 'Gene', '5546', (43, 47))	('c-met', 'Gene', (5, 10))	('foretinib', 'Chemical', 'MESH:C544831', (89, 98))	('capozantanib', 'Chemical', '-', (72, 84))	('c-met', 'Gene', '4233', (5, 10))
3962	30816681	Nevertheless, c-met mutations are specific to Type 1 pRCC, not the more aggressive Type 2 tumors.	('c-met', 'Gene', (14, 19))	('pRCC', 'Gene', (53, 57))	('c-met', 'Gene', '4233', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('aggressive Type 2 tumors', 'Disease', 'MESH:D001523', (72, 96))	('pRCC', 'Gene', '5546', (53, 57))	('mutations', 'Var', (20, 29))	('aggressive Type 2 tumors', 'Disease', (72, 96))
3968	30816681	The relationship between high syntaxin 6 expression and aggressive disease appears to be more strongly associated with type 2 pRCC tumors.	('aggressive disease', 'Disease', (56, 74))	('associated', 'Reg', (103, 113))	('expression', 'MPA', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('pRCC', 'Gene', (126, 130))	('syntaxin 6', 'Gene', (30, 40))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('high', 'Var', (25, 29))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('aggressive disease', 'Disease', 'MESH:D001523', (56, 74))	('syntaxin 6', 'Gene', '10228', (30, 40))	('pRCC', 'Gene', '5546', (126, 130))
3975	30816681	The exact mechanism through which high syntaxin 6 is promoting survival in pRCC cell lines is unclear.	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('syntaxin 6', 'Gene', (39, 49))	('survival', 'CPA', (63, 71))	('high', 'Var', (34, 38))	('promoting', 'PosReg', (53, 62))	('syntaxin 6', 'Gene', '10228', (39, 49))	('pRCC', 'Gene', '5546', (75, 79))
3978	30816681	They found that inhibition of syntaxin 6 function led to targeting of Golgi-localized VEGFR2 for degradation in lysosomes.	('Golgi', 'cellular_component', 'GO:0005794', ('70', '75'))	('VEGFR2', 'Gene', '3791', (86, 92))	('syntaxin 6', 'Gene', (30, 40))	('VEGFR2', 'Gene', (86, 92))	('degradation', 'biological_process', 'GO:0009056', ('97', '108'))	('degradation in lysosomes', 'MPA', (97, 121))	('syntaxin 6', 'Gene', '10228', (30, 40))	('targeting', 'MPA', (57, 66))	('inhibition', 'Var', (16, 26))
3984	30816681	Although these proangiogenic growth factors are known to play critical roles in the development of vascular ccRCC through VHL mutations, it is surprising to note their relatively high expression in pRCC, where VHL mutations rarely occur.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('pRCC', 'Gene', (198, 202))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('VHL', 'Disease', 'MESH:D006623', (122, 125))	('VHL', 'Disease', 'MESH:D006623', (210, 213))	('VHL', 'Disease', (122, 125))	('VHL', 'Disease', (210, 213))	('pRCC', 'Gene', '5546', (198, 202))	('mutations', 'Var', (126, 135))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
4016	30816681	ACHN cells (2 x 103 cells/well) were plated in 96 well plates and transfected with syntaxin 6 siRNA as described above.	('syntaxin 6', 'Gene', (83, 93))	('transfected', 'Var', (66, 77))	('syntaxin 6', 'Gene', '10228', (83, 93))	('ACHN', 'Gene', '55323', (0, 4))	('ACHN', 'Gene', (0, 4))
4034	23361235	For example, ccRCC often has 3p deletion, the majority of pRCC tumors harbor trisomy 7 and 17, chRCC contains multiple monosomies, and the majority of oncocytomas show a normal chromosomal profile.	('pRCC', 'Gene', '5546', (58, 62))	('pRCC', 'Phenotype', 'HP:0006766', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('oncocytomas', 'Disease', (151, 162))	('oncocytomas', 'Disease', 'MESH:D018249', (151, 162))	('ccRCC', 'Disease', (13, 18))	('tumors', 'Disease', (63, 69))	('pRCC', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('trisomy', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
4036	23361235	Studies of this syndrome identified a link to HRPT2, and a germ line mutation in this gene was shown to be responsible for HPT-JT syndrome.	('responsible', 'Reg', (107, 118))	('mutation', 'Var', (69, 77))	('HRPT2', 'Gene', (46, 51))	('HPT-JT syndrome', 'Disease', (123, 138))	('link', 'Reg', (38, 42))	('HRPT2', 'Gene', '79577', (46, 51))	('HPT-JT syndrome', 'Disease', 'MESH:C563273', (123, 138))
4096	23361235	It has been shown that there are frequent allelic imbalances and novel mutations of the HRPT2 gene in sporadic human renal tumors.	('HRPT2', 'Gene', (88, 93))	('renal tumors', 'Disease', (117, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('renal tumors', 'Phenotype', 'HP:0009726', (117, 129))	('human', 'Species', '9606', (111, 116))	('mutations', 'Var', (71, 80))	('renal tumors', 'Disease', 'MESH:D007674', (117, 129))	('HRPT2', 'Gene', '79577', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('imbalances', 'Phenotype', 'HP:0002172', (50, 60))	('allelic imbalances', 'Var', (42, 60))
4176	33632314	The SUVmax of high-grade (G3 and G4) papillary RCCs were significantly higher than that of low-grade (G1 and G2) tumors (9.44 +- 6.18 vs 4.83 +- 3.19, P = 0.008).	('higher', 'PosReg', (71, 77))	('papillary RCC', 'Disease', (37, 50))	('SUVmax', 'MPA', (4, 10))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('G4', 'Var', (33, 35))	('papillary RCC', 'Disease', 'MESH:C538614', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
4214	33632314	As several studies characterizing the FDG uptake of RCC reported, low-grade clear cell RCC had significantly lower FDG activity than high-grade clear cell RCC, which was mainly responsible for the low sensitivity for RCC detection.	('FDG', 'Gene', '23583', (115, 118))	('RCC', 'Disease', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (217, 220))	('lower', 'NegReg', (109, 114))	('FDG', 'Gene', (115, 118))	('RCC', 'Disease', (87, 90))	('low-grade', 'Var', (66, 75))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('uptake', 'biological_process', 'GO:0098657', ('42', '48'))	('uptake', 'biological_process', 'GO:0098739', ('42', '48'))	('FDG', 'Gene', '23583', (38, 41))	('FDG', 'Gene', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
4254	32359397	We found that RMC was characterized by high replication stress and an abundance of focal copy number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway.	('RMC', 'Disease', (14, 17))	('alterations', 'Var', (101, 112))	('cGAS-STING', 'Gene', (207, 217))	('RMC', 'Chemical', '-', (14, 17))	('activation', 'PosReg', (129, 139))
4257	32359397	These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors.	('high MYC expression', 'MPA', (49, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('RMC', 'Chemical', '-', (107, 110))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('leading to', 'Reg', (38, 48))	('SMARCB1', 'Gene', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (28, 37))
4266	32359397	Inactivation of SMARCB1 deregulates the activity of SWI/SNF, resulting in aggressive tumors.	('resulting in', 'Reg', (61, 73))	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('deregulates', 'Reg', (24, 35))	('SMARCB1', 'Gene', (16, 23))	('aggressive tumors', 'Disease', (74, 91))	('activity', 'MPA', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Inactivation', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
4267	32359397	In addition to RMC, inactivation of SMARCB1 occurs in the majority of malignant rhabdoid tumors (MRT), atypical teratoid/rhabdoid tumors (ATRT), and epithelioid sarcomas (ES).	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('occurs', 'Reg', (44, 50))	('inactivation', 'Var', (20, 32))	('sarcomas', 'Disease', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('malignant rhabdoid tumors', 'Disease', (70, 95))	('SMARCB1', 'Gene', (36, 43))	('rhabdoid tumors', 'Disease', (121, 136))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RMC', 'Chemical', '-', (15, 18))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (80, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (70, 95))
4272	32359397	Overall, rates of single nucleotide variants (SNVs) and insertion and deletion mutations (inDels) were very low for RMC.	('deletion mutations', 'Var', (70, 88))	('RMC', 'Chemical', '-', (116, 119))	('insertion', 'Var', (56, 65))	('RMC', 'Disease', (116, 119))	('single nucleotide variants', 'Var', (18, 44))
4274	32359397	A total of 1332 SNVs and inDels in 1165 genes were identified by WES, with a median of 24 per patient (Figure 1 and Supplementary Table 1).	('inDels', 'Var', (25, 31))	('SNVs', 'Var', (16, 20))	('men', 'Species', '9606', (122, 125))	('patient', 'Species', '9606', (94, 101))
4275	32359397	Clinical targeted next-generation sequencing of 5/31 untreated primary tumor samples (Figure 1) did not detect additional SNVs and inDels.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('inDels', 'Var', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SNVs', 'Var', (122, 126))	('tumor', 'Disease', (71, 76))
4278	32359397	Of the 1165 genes mutated in untreated primary RMC tumors from a total of 31 patients, only 22 were known tumor suppressors or oncogenes listed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Figure S1B and Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (51, 56))	('men', 'Species', '9606', (232, 235))	('RMC tumors', 'Disease', 'MESH:D009369', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (185, 191))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (106, 111))	('RMC tumors', 'Disease', (47, 57))
4282	32359397	SETD2 was mutated in 2/31 (6.5%) of RMC tumors and was the only established gene driver of other renal cell carcinomas to be altered in RMC (Figure 1 and Supplementary Table 1).	('mutated', 'Var', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('RMC', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('renal cell carcinomas', 'Disease', (97, 118))	('SETD2', 'Gene', '29072', (0, 5))	('RMC tumors', 'Disease', 'MESH:D009369', (36, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('SETD2', 'Gene', (0, 5))	('men', 'Species', '9606', (160, 163))	('RMC', 'Chemical', '-', (36, 39))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (97, 118))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RMC tumors', 'Disease', (36, 46))
4284	32359397	Whereas other SMARCB1-deficient malignancies, such as the rhabdoid tumors MRT and ATRT, harbor a simple genome with very few CNAs other than 22q11.23 loss (Figure S1E), RMC had recurrent focal chromosomal amplifications and deletions in addition to 22q11.23 loss (Figures 2C, 2D, and S2).	('loss', 'NegReg', (258, 262))	('rhabdoid tumors MRT', 'Disease', (58, 77))	('deletions', 'Var', (224, 233))	('deficient malignancies', 'Disease', 'MESH:D009369', (22, 44))	('RMC', 'Chemical', '-', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('rhabdoid tumors MRT', 'Disease', 'MESH:D018335', (58, 77))	('deficient malignancies', 'Disease', (22, 44))
4292	32359397	The most common focal deletion in both RMC and rhabdoid tumors was in the SMARCB1 locus 22q11.23 found in 9/15 (60%) RMC tumors and in 28/35 (80%) rhabdoid tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('deletion', 'Var', (22, 30))	('RMC tumors', 'Disease', (117, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('rhabdoid tumors', 'Disease', (147, 162))	('rhabdoid tumors', 'Disease', (47, 62))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SMARCB1', 'Gene', (74, 81))	('RMC', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (147, 162))	('RMC tumors', 'Disease', 'MESH:D009369', (117, 127))	('RMC', 'Chemical', '-', (39, 42))
4295	32359397	Furthermore, we found amplification of NOTCH2 in 6/15 (40%) RMC tumors, with 4/15 (26.7%) demonstrating concurrent deletion of NOTCH1 and NOTCH3 and amplification of NOTCH2, a distinct pattern also found in the basal subtype of bladder urothelial carcinoma (BLCA) and associated with increased cell-cycle progression and epithelial-mesenchymal transition (EMT).	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('RMC tumors', 'Disease', (60, 70))	('amplification', 'Var', (149, 162))	('NOTCH2', 'Gene', (166, 172))	('amplification', 'Var', (22, 35))	('NOTCH1', 'Gene', (127, 133))	('EMT', 'biological_process', 'GO:0001837', ('356', '359'))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cell-cycle', 'biological_process', 'GO:0007049', ('294', '304'))	('RMC tumors', 'Disease', 'MESH:D009369', (60, 70))	('bladder urothelial carcinoma', 'Disease', (228, 256))	('NOTCH1', 'Gene', '4851', (127, 133))	('NOTCH3', 'Gene', '4854', (138, 144))	('NOTCH2', 'Gene', '4853', (39, 45))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (228, 256))	('NOTCH3', 'Gene', (138, 144))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('321', '354'))	('deletion', 'Var', (115, 123))	('NOTCH2', 'Gene', '4853', (166, 172))	('cell-cycle progression', 'CPA', (294, 316))	('NOTCH2', 'Gene', (39, 45))	('increased', 'PosReg', (284, 293))	('epithelial-mesenchymal transition', 'CPA', (321, 354))
4297	32359397	By integrating our genomic and RNA-seq data we identified 341 genes (Supplementary Table 2) in areas of recurrent focal copy number gain or loss that were significantly (FDR < 0.1) upregulated or downregulated, respectively, in RMC tumors compared with adjacent normal kidney.	('focal copy number', 'Var', (114, 131))	('RMC tumors', 'Disease', 'MESH:D009369', (228, 238))	('RNA', 'cellular_component', 'GO:0005562', ('31', '34'))	('downregulated', 'NegReg', (196, 209))	('gain', 'PosReg', (132, 136))	('upregulated', 'PosReg', (181, 192))	('men', 'Species', '9606', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('RMC tumors', 'Disease', (228, 238))	('loss', 'NegReg', (140, 144))
4298	32359397	The reliability of our CNA analyses of WES data was confirmed in sample MED1T by array CGH (Figure 3A), which detected the presence of the focal amplification on chromosome 2p, large amplification of chromosome 8, monosomy of chromosomes 4 and 22, large deletions of chromosomes 15 and 16, and a focal deletion of chromosome 17p13.1 (TP53 gene region), which were also found by WES (Figure S2).	('chromosome', 'cellular_component', 'GO:0005694', ('314', '324'))	('MED1', 'Gene', (72, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('162', '172'))	('monosomy', 'Var', (214, 222))	('chromosome', 'cellular_component', 'GO:0005694', ('200', '210'))	('MED1', 'Gene', '5469', (72, 76))
4301	32359397	Less frequent were deletion of both SMARCB1 alleles (6/38 patients; 15.8%), deletion of one SMARCB1 allele and inDel of the second SMARCB1 allele (5/38 patients; 13.2%), and deletion of one SMARCB1 allele and truncating nonsense mutation of the second SMARCB1 allele (1/38 patients; 2.6%).	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (273, 281))	('SMARCB1', 'Gene', (190, 197))	('SMARCB1', 'Gene', (252, 259))	('deletion', 'Var', (19, 27))	('truncating nonsense mutation', 'Var', (209, 237))	('SMARCB1', 'Gene', (36, 43))	('deletion', 'Var', (174, 182))	('SMARCB1', 'Gene', (92, 99))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (152, 160))
4303	32359397	In addition, we determined that this pattern for SMARCB1 inactivation (inactivating translocation combined with hemizygous deletion) occurred not only in primary tumors but also in lymph node and liver mestastases of patients RMC38 and RMC32, respectively.	('inactivation', 'NegReg', (57, 69))	('liver mestastases', 'Disease', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RMC', 'Chemical', '-', (226, 229))	('patients', 'Species', '9606', (217, 225))	('RMC', 'Chemical', '-', (236, 239))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('RMC38', 'Var', (226, 231))	('liver mestastases', 'Disease', 'MESH:D017093', (196, 213))	('SMARCB1', 'Gene', (49, 56))
4304	32359397	Sanger sequencing confirmed that both the primary kidney tumor and the liver metastasis of patient RMC32 harbored the same translocation between the SMARCB1 and MYOM1 genes (Figures 3E and 3F).	('translocation', 'Var', (123, 136))	('kidney tumor', 'Disease', 'MESH:D007680', (50, 62))	('SMARCB1', 'Gene', (149, 156))	('kidney tumor', 'Phenotype', 'HP:0009726', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('kidney tumor', 'Disease', (50, 62))	('MYOM1', 'Gene', (161, 166))	('patient', 'Species', '9606', (91, 98))	('RMC', 'Chemical', '-', (99, 102))	('MYOM1', 'Gene', '8736', (161, 166))
4307	32359397	RNA-seq (see below) of 5 samples (RMC32T, RMC36T1, MED1T, MED2T, MED5T) that harbored inactivating translocations identified SMARCB1 fusion transcripts in 2/5 cases (RMC32T and MED1T) as shown in Figure 3E.	('RMC36T1', 'CellLine', 'CVCL:5354', (42, 49))	('MED1', 'Gene', '5469', (177, 181))	('SMARCB1', 'Gene', (125, 132))	('MED1', 'Gene', (177, 181))	('RMC', 'Chemical', '-', (34, 37))	('RMC', 'Chemical', '-', (42, 45))	('MED1', 'Gene', '5469', (51, 55))	('RMC32T', 'Var', (166, 172))	('MED5T', 'CellLine', 'CVCL:M137', (65, 70))	('RMC', 'Chemical', '-', (166, 169))	('MED1', 'Gene', (51, 55))	('RNA', 'cellular_component', 'GO:0005562', ('0', '3'))	('inactivating translocations', 'Var', (86, 113))
4311	32359397	The RMC36T1 sample that clustered within the CDC samples in our unsupervised analysis of protein-coding gene expression (Figure 4A) was confirmed to be RMC as the patient had sickle cell trait by hemoglobin electrophoresis (Figure 1) and the tumor was negative for SMARCB1 by immunohistochemistry (Figure S1A).	('sickle cell trait', 'Disease', (175, 192))	('RMC36T1', 'CellLine', 'CVCL:5354', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('RMC', 'Chemical', '-', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('gene expression', 'biological_process', 'GO:0010467', ('104', '119'))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (242, 247))	('RMC', 'Chemical', '-', (152, 155))	('RMC36T1', 'Var', (4, 11))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
4314	32359397	The distinct gene expression profiles of RMC compared with kidney MRT, despite their common renal origin and shared etiology of SMARCB1 inactivation, led us to explore the nephron site of origin of these malignancies.	('malignancies', 'Disease', (204, 216))	('inactivation', 'Var', (136, 148))	('SMARCB1', 'Gene', (128, 135))	('gene expression', 'biological_process', 'GO:0010467', ('13', '28'))	('RMC', 'Chemical', '-', (41, 44))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('RMC', 'Disease', (41, 44))
4348	32359397	In the mutational landscape of RMC we noted that the most common substitutions in most RMC tumors were C > T transitions (Figure 1), which are linked to the process of cytosine deamination often associated with age or DNA replication stress.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('RMC tumors', 'Disease', 'MESH:D009369', (87, 97))	('DNA replication', 'biological_process', 'GO:0006260', ('218', '233'))	('C > T transitions', 'Var', (103, 120))	('DNA', 'cellular_component', 'GO:0005574', ('218', '221'))	('RMC', 'Chemical', '-', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RMC tumors', 'Disease', (87, 97))	('RMC', 'Chemical', '-', (87, 90))	('cytosine', 'Chemical', 'MESH:D003596', (168, 176))
4349	32359397	However, patient age did not strongly correlate with the number of C > T mutations (Spearman rank correlation = 0.395, p = 0.145), suggesting that they are instead caused by replication stress in the setting of high cell turnover.	('patient', 'Species', '9606', (9, 16))	('caused by', 'Reg', (164, 173))	('C > T mutations', 'Var', (67, 82))
4350	32359397	Furthermore, the predominant mutational signature pattern in RMC tumors was Signature 1 (Figure S1C), which consists mainly of C > T transitions at CpG dinucleotide motifs and is known to be associated with age and/or high number of mitoses.	('RMC tumors', 'Disease', 'MESH:D009369', (61, 71))	('C > T transitions', 'Var', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('dinucleotide', 'Chemical', 'MESH:D015226', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RMC tumors', 'Disease', (61, 71))
4357	32359397	We additionally used a previously established established RMC cell line (RMC219), which is also negative for inactivating SMARCB1 translocations and harbors centromeric deletions of both SMARCB1 alleles (Supplementary Table 3 and Figure S6H).	('men', 'Species', '9606', (210, 213))	('RMC', 'Chemical', '-', (58, 61))	('SMARCB1', 'Gene', (187, 194))	('RMC219', 'Chemical', '-', (73, 79))	('RMC', 'Chemical', '-', (73, 76))	('translocations', 'Var', (130, 144))	('SMARCB1', 'Gene', (122, 129))
4361	32359397	As shown using our two RMC cell lines and two other SMARCB1-negative cell lines (MRT line G401 and epitheliod sarcoma line VA-ES-BJ) in Figure 6D, high c-MYC levels correlated with expression of the DNA damage marker gammaH2AX, expression of DNA damage repair enzymes Poly-(ADP-ribose) polymerase (PARP) and ataxia-telangiectasia and Rad3-related (ATR), ATR activation via phosphorylation at serine 428, upregulation and phosphorylation at serines 4 and 8 of the RPA32 subunit of human replication protein A (a marker of DNA damage response), upregulation of FANCD2 (which protects cells from replication stress), phosphorylation of CDK1 at tyrosine 15 (which regulates the G2-M checkpoint), as well as phosphorylation of TP53 at serine 15, a marker specific to DNA damage response and not to other stimuli such as hyper-proliferation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('ataxia', 'Phenotype', 'HP:0001251', (308, 314))	('CDK1', 'Gene', (633, 637))	('sarcoma', 'Disease', (110, 117))	('DNA', 'cellular_component', 'GO:0005574', ('199', '202'))	('phosphorylation', 'Var', (614, 629))	('DNA damage response', 'biological_process', 'GO:0006974', ('521', '540'))	('DNA damage response', 'biological_process', 'GO:0006974', ('762', '781'))	('ataxia-telangiectasia and Rad3-related', 'Gene', '685055', (308, 346))	('FANCD2', 'Gene', (559, 565))	('Poly-(ADP-ribose) polymerase', 'Gene', '25591', (268, 296))	('replication protein A', 'cellular_component', 'GO:0005662', ('486', '507'))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('serine', 'Chemical', 'MESH:D012694', (440, 446))	('CDK', 'molecular_function', 'GO:0004693', ('633', '636'))	('serine', 'Chemical', 'MESH:D012694', (392, 398))	('G2-M checkpoint', 'biological_process', 'GO:0000075', ('674', '689'))	('RPA32', 'Gene', '108689', (463, 468))	('RMC', 'Chemical', '-', (23, 26))	('phosphorylation', 'biological_process', 'GO:0016310', ('373', '388'))	('gammaH2AX', 'Gene', (217, 226))	('DNA', 'cellular_component', 'GO:0005574', ('762', '765'))	('DNA', 'cellular_component', 'GO:0005574', ('242', '245'))	('Rad', 'biological_process', 'GO:1990116', ('334', '337'))	('RPA32', 'Gene', (463, 468))	('BJ', 'CellLine', 'CVCL:6573', (129, 131))	('Poly-(ADP-ribose) polymerase', 'Gene', (268, 296))	('phosphorylation', 'biological_process', 'GO:0016310', ('703', '718'))	('telangiectasia', 'Phenotype', 'HP:0001009', (315, 329))	('upregulation', 'PosReg', (543, 555))	('serine', 'Chemical', 'MESH:D012694', (730, 736))	('RPA', 'cellular_component', 'GO:0005662', ('463', '466'))	('phosphorylation', 'MPA', (703, 718))	('phosphorylation', 'biological_process', 'GO:0016310', ('614', '629'))	('DNA', 'cellular_component', 'GO:0005574', ('521', '524'))	('TP53', 'Gene', (722, 726))	('gammaH2AX', 'Gene', '15270', (217, 226))	('phosphorylation', 'biological_process', 'GO:0016310', ('421', '436'))	('human', 'Species', '9606', (480, 485))
4362	32359397	Conversely, SMARCB1 knockout by CRISPR/Cas9 in human embryonic kidney (HEK-293FT) cells increased c-MYC and the resulting replication stress (Figures S7B and S7C).	('S7C', 'Mutation', 'p.S7C', (158, 161))	('embryonic kidney', 'Disease', 'MESH:D007674', (53, 69))	('Cas', 'cellular_component', 'GO:0005650', ('39', '42'))	('SMARCB1', 'Gene', (12, 19))	('replication', 'MPA', (122, 133))	('increased', 'PosReg', (88, 97))	('HEK-293FT', 'CellLine', 'CVCL:6911', (71, 80))	('knockout', 'Var', (20, 28))	('human', 'Species', '9606', (47, 52))	('embryonic kidney', 'Disease', (53, 69))	('c-MYC', 'MPA', (98, 103))
4371	32359397	We also found that SMARCB1-negative cell lines are sensitive to the ATR inhibitors VX970 and AZD6738 and to the WEE1 inhibitor adavosertib (Figure 7B).	('AZD6738', 'Var', (93, 100))	('ATR', 'Gene', (68, 71))	('sensitive', 'Reg', (51, 60))	('AZD6738', 'Chemical', 'MESH:C000611951', (93, 100))	('VX970', 'Var', (83, 88))	('WEE1', 'Gene', (112, 116))	('WEE1', 'Gene', '7465', (112, 116))	('adavosertib', 'Chemical', 'MESH:C549567', (127, 138))
4377	32359397	Mice harboring RMC2X tumors (n = 5 per group; average tumor volume of 158 mm3 at treatment initiation) were randomly assigned to receive niraparib, AZD6738, the combination of niraparib with AZD6738, or vehicle control for a total of 25 days.	('men', 'Species', '9606', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('AZD6738', 'Chemical', 'MESH:C000611951', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (21, 27))	('AZD6738', 'Chemical', 'MESH:C000611951', (191, 198))	('AZD6738', 'Var', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('niraparib', 'Chemical', 'MESH:C545685', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (54, 59))	('RMC', 'Chemical', '-', (15, 18))	('niraparib', 'Chemical', 'MESH:C545685', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
4380	32359397	Conversely, treatment with AZD6738 did not significantly reduce tumor volume compared with vehicle control (p = 0.54), and its combination with niraparib did not produce a stronger antitumor effect compared with niraparib alone (p = 0.868).	('tumor', 'Disease', (185, 190))	('AZD6738', 'Chemical', 'MESH:C000611951', (27, 34))	('tumor', 'Disease', (64, 69))	('AZD6738', 'Var', (27, 34))	('combination', 'Interaction', (127, 138))	('niraparib', 'Chemical', 'MESH:C545685', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('niraparib', 'Chemical', 'MESH:C545685', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('men', 'Species', '9606', (17, 20))
4390	32359397	CNAs in chromosomal fragile sites such as those noted in RMC can be both a source and a consequence of DNA replication stress in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RMC', 'Chemical', '-', (57, 60))	('DNA replication', 'biological_process', 'GO:0006260', ('103', '118'))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (8, 33))	('DNA', 'cellular_component', 'GO:0005574', ('103', '106'))	('CNAs', 'Var', (0, 4))
4441	32359397	Thus, although our WES had high sensitivity to detect dominant clonal or subclonal RMC tumor mutations, it would be less likely to detect more rare subclonal alterations.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RMC tumor', 'Disease', (83, 92))	('RMC tumor', 'Disease', 'MESH:D009369', (83, 92))	('mutations', 'Var', (93, 102))
4448	32359397	The somatic status of a specific SNV/inDel was reported once the matched germline had wild allele-based homozygous genotype and the tumor had heterozygous or mutant allele-based homozygous genotype with a certain cutoff of genotype likelihood/p value of 0.99.	('mutant', 'Var', (158, 164))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))
4463	32359397	DNA was labeled by random priming with CY5-dCTPs (tumor DNA) and CY3-dCTPs (control DNA), and was hybridized to 4x180K whole-genome Agilent arrays (G4448A).	('CY3-dCTPs', 'Var', (65, 74))	('CY3-dCTPs', 'Chemical', '-', (65, 74))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('DNA', 'cellular_component', 'GO:0005574', ('56', '59'))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CY5-dCTPs', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('G4448A', 'Mutation', 'rs1249266779', (148, 154))	('CY5-dCTPs', 'Chemical', 'MESH:C544355', (39, 48))	('tumor', 'Disease', (50, 55))
4489	32359397	Samples with break-apart in >= 15% of tumor nuclei were considered positive for SMARCB1 translocation.	('positive', 'Reg', (67, 75))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('SMARCB1', 'Gene', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('translocation', 'Var', (88, 101))
4490	32359397	Partial SMARCB1 deletion was defined as loss of either green or orange probes in >= 15% of tumor nuclei.	('SMARCB1', 'Gene', (8, 15))	('orange probes', 'MPA', (64, 77))	('deletion', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('green', 'MPA', (55, 60))	('Partial', 'Var', (0, 7))
4626	31737127	Numerous immunochemical markers have been reported, including CK7, CD117 (KIT), parvalbumin, DOG1 cyclin D1, vimentin, EMA, S1001A, kidney-specific cadherin (Ksp-cad), Claudin-7, and Claudin-8.	('vimentin', 'cellular_component', 'GO:0045098', ('109', '117'))	('KIT', 'molecular_function', 'GO:0005020', ('74', '77'))	('S1001A', 'Var', (124, 130))	('cadherin', 'molecular_function', 'GO:0008014', ('148', '156'))	('EMA', 'Chemical', 'MESH:C519317', (119, 122))	('CD117', 'Protein', (67, 72))	('S1001A', 'Mutation', 'p.S1001A', (124, 130))	('vimentin', 'cellular_component', 'GO:0045099', ('109', '117'))	('CK7', 'Var', (62, 65))	('cyclin', 'molecular_function', 'GO:0016538', ('98', '104'))
4628	31737127	Panels of immunostaining markers have been proposed to make a differential diagnosis: DOG1/cyclin D1/CK7/CD117/vimentin, CK7/CD117/PAX2, CK7/parvalbumin, CK7/vimentin/S100A1/CD117, S1001A/CD117, HNF1beta/S100A1, etc.. We have 10 years of experience with the combined immunohistochemistry for the "three 7" markers, that is, CK7, CD117, and Claudin-7, to diagnose chromophobe renal cell carcinoma and exclude the mimics.	('vimentin', 'cellular_component', 'GO:0045098', ('111', '119'))	('S1001A', 'SUBSTITUTION', 'None', (181, 187))	('cyclin', 'molecular_function', 'GO:0016538', ('91', '97'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (375, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('chromophobe renal cell carcinoma', 'Disease', (363, 395))	('vimentin', 'cellular_component', 'GO:0045099', ('158', '166'))	('vimentin', 'cellular_component', 'GO:0045099', ('111', '119'))	('S1001A', 'Var', (181, 187))	('vimentin', 'cellular_component', 'GO:0045098', ('158', '166'))
4630	31737127	Four-micrometer thick sections were obtained from 10% formalin-fixed and paraffin-embedded tissue blocks, followed by immunohistochemical staining using the following commercially available antibodies: anti-CK7 (EP16, 1 : 200; ZSGB-BIO, Beijing, China), anti-CD117 (YR145, prediluted; MXB Biotech, Fuzhou, Fujian, China), and anti-Claudin-7 (polyclonal, 1 : 500; Cambridge, MA, US).	('formalin', 'Chemical', 'MESH:D005557', (54, 62))	('ZSGB-BIO', 'Chemical', 'MESH:C483321', (227, 235))	('anti-CD117', 'Var', (254, 264))	('paraffin', 'Chemical', 'MESH:D010232', (73, 81))	('anti-CK7', 'Var', (202, 210))
4651	24877109	One of the most frequent nonrandom chromosomal CNAs confirmed in ccRCC is 9p deletion.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('9p deletion', 'Var', (74, 85))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))
4653	24877109	Two overlapping studies, from the same institution, suggested that integration of 9p status into prognostic models could improve the predictive accuracy of ccRCC specific survival to 89%.	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('improve', 'PosReg', (121, 128))	('9p status', 'Var', (82, 91))
4656	24877109	Evaluate the impact of chromosome 9p deletion on disease free survival (DFS) and cancer specific survival (CSS) in RCC.	('CSS', 'Chemical', '-', (107, 110))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('deletion', 'Var', (37, 45))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('RCC', 'Disease', (115, 118))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
4691	24877109	assessed CDKN2A sequence alterations in 113 ccRCC as an adjunct technique to microsatellite analysis.	('alterations', 'Var', (25, 36))	('CDKN2A', 'Gene', '1029', (9, 15))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('CDKN2A', 'Gene', (9, 15))
4692	24877109	They detected 24 bp deletion within exon 1 of CDKN2A in 12% of the tumours which did not correlate with pathological parameters or cancer specific survival.	('cancer', 'Disease', (131, 137))	('CDKN2A', 'Gene', (46, 52))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CDKN2A', 'Gene', '1029', (46, 52))	('deletion', 'Var', (20, 28))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
4693	24877109	They reported a homozygous G to C trans-version in Exon 3 of CDKN2A in 78.7% of cases, which correlated with higher tumour grade.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('CDKN2A', 'Gene', (61, 67))	('tumour', 'Disease', (116, 122))	('CDKN2A', 'Gene', '1029', (61, 67))	('G to C trans-version', 'Var', (27, 47))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
4696	24877109	Six studies assessed the relationship between chromosome 9p loss, grade, and stage of tumour specimens (Table 4).	('chromosome', 'Var', (46, 56))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('loss', 'NegReg', (60, 64))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('assessed', 'Reg', (12, 20))	('tumour', 'Disease', (86, 92))
4699	24877109	Sanjmyatav and colleagues also showed that loss of the region 9p21.3p24.1 on array CGH and I-FISH was significantly associated with the presence of metastasis.	('loss', 'Var', (43, 47))	('I-FISH', 'Species', '215395', (91, 97))	('metastasis', 'CPA', (148, 158))	('associated', 'Reg', (116, 126))
4702	24877109	In 7 ccRCC studies, 9p deletion was associated with worse outcomes, including being an independent prognostic factor in 3 studies on multivariate analysis.	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('9p deletion', 'Var', (20, 31))
4704	24877109	Two studies showed that localized ccRCC with 9p deletion carried a significantly higher risk of recurrence and cancer related deaths compared to nondeleted tumours.	('9p deletion', 'Var', (45, 56))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('RCC', 'Disease', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('recurrence', 'CPA', (96, 106))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('deaths', 'Disease', (126, 132))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('deaths', 'Disease', 'MESH:D003643', (126, 132))
4705	24877109	The 5-year DFS for 9p deleted tumours ranged between 26% and 50% compared to 71% and 98% in tumours without 9p deletion.	('9p deleted', 'Var', (19, 29))	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (30, 37))	('tumours', 'Disease', (92, 99))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
4706	24877109	Also, 5-year CSS ranged between 28% and 67% for 9p deleted compared to 87%-98% for nondeleted 9p tumours (Table 2).	('CSS', 'CPA', (13, 16))	('tumours', 'Disease', (97, 104))	('9p deleted', 'Var', (48, 58))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('CSS', 'Chemical', '-', (13, 16))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
4707	24877109	On multivariate analysis models, 9p loss was an independent prognostic factor for both DFS and CSS in localized ccRCC in one study (P = 0.15) and D9SS168 alterations (LOH or instability) on 9p was an independent prognostic factor for CSS in another study (P = 0.009).	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('CSS', 'Disease', (95, 98))	('loss', 'NegReg', (36, 40))	('CSS', 'Chemical', '-', (95, 98))	('D9SS168 alterations', 'Var', (146, 165))	('DFS', 'Disease', (87, 90))	('CSS', 'Chemical', '-', (234, 237))
4708	24877109	Two studies concluded that 9p loss in pT3N0 M0 ccRCC tumours was associated with worse DFS and CSS only on univariate analysis.	('RCC', 'Disease', (49, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('CSS', 'Chemical', '-', (95, 98))	('CSS', 'CPA', (95, 98))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('pT3N0 M0', 'Var', (38, 46))	('DFS', 'MPA', (87, 90))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
4709	24877109	Controversially, Presti et al., in a larger cohort of patients with pT3N0 M0 ccRCC tumours, noticed a trend towards worse DFS in patients with 9p deleted tumours but this did not reach statistical significance.	('worse', 'NegReg', (116, 121))	('tumours', 'Disease', (83, 90))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('9p deleted', 'Var', (143, 153))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (54, 62))	('DFS', 'MPA', (122, 125))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumours', 'Disease', (154, 161))	('tumours', 'Disease', 'MESH:D009369', (83, 90))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
4711	24877109	9p deleted tumours were associated significantly with lymph node and distant metastasis (P = 0.03).	('9p deleted', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))
4712	24877109	The 5-year CSS and DFS were 56% and 68%, respectively, for 9p deleted tumours compared to 90% and 97% for the nondeleted ones (P = 0.01).	('9p deleted', 'Var', (59, 69))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('CSS', 'MPA', (11, 14))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('CSS', 'Chemical', '-', (11, 14))	('tumours', 'Disease', (70, 77))
4714	24877109	Loss of 9p21.3p24.1 was the most prominent of these aberrations with the highest odds ratio for metastatic risk and was linked to shorter CSS only on univariate analysis.	('shorter', 'NegReg', (130, 137))	('Loss', 'Var', (0, 4))	('CSS', 'Chemical', '-', (138, 141))	('metastatic', 'Disease', (96, 106))
4716	24877109	In pRCC, 5-year overall survival was 40% for patients with LOH of D9S171 on 9p compared to 81% for patients without deletion (P = 0.008).	('pRCC', 'Gene', '5546', (3, 7))	('pRCC', 'Gene', (3, 7))	('LOH', 'Var', (59, 62))	('patients', 'Species', '9606', (99, 107))	('D9S171', 'Var', (66, 72))	('patients', 'Species', '9606', (45, 53))	('RCC', 'Phenotype', 'HP:0005584', (4, 7))
4721	24877109	Our systematic appraisal of the literature summarizes the evidence for 9p status and its clinical applicability in RCC.	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('9p status', 'Var', (71, 80))	('RCC', 'Disease', (115, 118))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))
4736	24877109	reported that D9S168 microsatellite alterations, located at 9p23-24 gene region, which encodes for protein tyrosine phosphate receptor delta (PTPRD), could contribute to worse prognosis.	('protein tyrosine phosphate receptor delta', 'Gene', '5789', (99, 140))	('contribute', 'Reg', (156, 166))	('protein tyrosine phosphate receptor delta', 'Gene', (99, 140))	('PTPRD', 'Gene', '5789', (142, 147))	('PTPRD', 'Gene', (142, 147))	('D9S168', 'Var', (14, 20))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))
4738	24877109	Results from genome sequence analysis helped to closely study and identify new mutations within genes implicated in RCC progression such as PBRM1, SETD2, and BAP1.	('PBRM1', 'Gene', (140, 145))	('BAP1', 'Gene', (158, 162))	('SETD2', 'Gene', '29072', (147, 152))	('PBRM1', 'Gene', '55193', (140, 145))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('SETD2', 'Gene', (147, 152))	('BAP1', 'Gene', '8314', (158, 162))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))	('mutations', 'Var', (79, 88))
4742	24877109	The evidence for chromosome 9p status in RCC is emerging mainly focusing on its value in predicting clinical outcomes; however, a number of concerns regarding methodology of research, quality of reporting, and its applicability in clinical practice exist.	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('chromosome 9p status', 'Var', (17, 37))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
4762	33634028	RING1 overexpression leads to cellular transformation via enhancing the expression of the proto-oncogenes, c-jun, and c-fos.	('c-fos', 'Gene', (118, 123))	('overexpression', 'Var', (6, 20))	('RING1', 'Gene', (0, 5))	('cellular transformation', 'CPA', (30, 53))	('expression', 'MPA', (72, 82))	('enhancing', 'PosReg', (58, 67))	('c-jun', 'Gene', '3725', (107, 112))	('c-jun', 'Gene', (107, 112))	('c-fos', 'Gene', '2353', (118, 123))	('RING1', 'Gene', '6015', (0, 5))
4767	33634028	In this study, the dysregulation of RING1 was observed in multiple types of cancers and was associated with poor outcomes.	('dysregulation', 'Var', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('observed', 'Reg', (46, 54))	('cancers', 'Disease', (76, 83))	('RING1', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('RING1', 'Gene', '6015', (36, 41))	('associated', 'Reg', (92, 102))
4775	33634028	In this study, Kaplan-Meier plotter in breast cancer or Pan-cancer was used to detect the OS, RFS, and DMFS of RING1 to explore its prognostic value in human cancers.	('RFS', 'Gene', '65211', (94, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('RING1', 'Gene', '6015', (111, 116))	('DMFS', 'Var', (103, 107))	('Pan-cancer', 'Disease', (56, 66))	('RFS', 'Gene', (94, 97))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Pan-cancer', 'Disease', 'MESH:D009369', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('RING1', 'Gene', (111, 116))	('breast cancer', 'Disease', (39, 52))
4793	33634028	The Kaplan-Meier curve and log-rank test results revealed that patients with high RING1 mRNA expression level have higher OS (overall survival) compared to the low expression group ( Figure 1C ).	('high', 'Var', (77, 81))	('RING1', 'Gene', (82, 87))	('patients', 'Species', '9606', (63, 71))	('RING1', 'Gene', '6015', (82, 87))	('higher', 'PosReg', (115, 121))
4812	33634028	The univariate analysis showed that ER (P = 0.008), P53 (P = 0.013), and RING1 (P = 0.015) were protective factors in breast cancer prognosis, while Her-2 was a risk factor.	('RING1', 'Gene', (73, 78))	('Her-2', 'Gene', '2064', (149, 154))	('ER', 'Gene', '2069', (36, 38))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Her-2', 'Gene', (149, 154))	('P53', 'Var', (52, 55))	('RING1', 'Gene', '6015', (73, 78))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
4834	33634028	Cancer is considered a genetic disease, in which abnormal gene expression causes tumor cells to lose normal characteristics.	('genetic disease', 'Disease', 'MESH:D030342', (23, 38))	('genetic disease', 'Disease', (23, 38))	('abnormal gene expression', 'Var', (49, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('gene expression', 'biological_process', 'GO:0010467', ('58', '73'))	('lose', 'NegReg', (96, 100))	('tumor', 'Disease', (81, 86))
4845	33634028	For cancer, recent studies have shown that the abnormal gene expression of RING1 leads to the development of a variety of cancers.	('leads to', 'Reg', (81, 89))	('RING1', 'Gene', (75, 80))	('abnormal gene expression', 'Var', (47, 71))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('RING1', 'Gene', '6015', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('cancer', 'Disease', (4, 10))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))
4862	33634028	found that RING1 overexpression promotes colony formation, cell multiplication and invasion of hepatic progenitor cells (HPCs), and that it also drives their malignant transformation by activating the Wnt/beta-catenin signal pathway.	('RING1', 'Gene', '6015', (11, 16))	('overexpression', 'Var', (17, 31))	('formation', 'biological_process', 'GO:0009058', ('48', '57'))	('cell multiplication', 'CPA', (59, 78))	('beta-catenin', 'Gene', (205, 217))	('malignant transformation', 'CPA', (158, 182))	('beta-catenin', 'Gene', '1499', (205, 217))	('invasion', 'CPA', (83, 91))	('drives', 'PosReg', (145, 151))	('activating', 'PosReg', (186, 196))	('colony formation', 'CPA', (41, 57))	('RING1', 'Gene', (11, 16))	('promotes', 'PosReg', (32, 40))
4871	28358873	Whole-genome analysis of papillary kidney cancer finds significant noncoding alterations To date, studies on papillary renal-cell carcinoma (pRCC) have largely focused on coding alterations in traditional drivers, particularly the tyrosine-kinase, Met.	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('pRCC', 'Phenotype', 'HP:0006766', (141, 145))	('pRCC', 'Gene', '5546', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('pRCC', 'Gene', (141, 145))	('papillary kidney cancer', 'Disease', (25, 48))	('kidney cancer', 'Phenotype', 'HP:0009726', (35, 48))	('papillary renal-cell carcinoma', 'Disease', 'MESH:C538614', (109, 139))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (25, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (25, 48))	('alterations', 'Var', (178, 189))	('papillary renal-cell carcinoma', 'Phenotype', 'HP:0006766', (109, 139))	('papillary renal-cell carcinoma', 'Disease', (109, 139))
4874	28358873	Elaborating on previous results on MET, we find a germline SNP (rs11762213) in this gene predicting prognosis.	('predicting', 'Reg', (89, 99))	('rs11762213', 'Mutation', 'rs11762213', (64, 74))	('rs11762213', 'Var', (64, 74))
4875	28358873	We also notice an elevation of mutations in the long noncoding RNA NEAT1, and these mutations are associated with increased expression and unfavorable outcome.	('NEAT1', 'Gene', (67, 72))	('mutations', 'Var', (31, 40))	('RNA', 'cellular_component', 'GO:0005562', ('63', '66'))	('increased', 'PosReg', (114, 123))	('expression', 'MPA', (124, 134))	('elevation', 'PosReg', (18, 27))	('NEAT1', 'Gene', '283131', (67, 72))
4877	28358873	First, we investigate genome-wide mutational patterns, finding they are governed mostly by methylation-associated C-to-T transitions.	('methylation-associated', 'Var', (91, 113))	('C-to-T transitions', 'Disease', (114, 132))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))
4878	28358873	We also observe significantly more mutations in open chromatin and early-replicating regions in tumors with chromatin-modifier alterations.	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('more', 'PosReg', (30, 34))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('53', '62'))	('alterations', 'Var', (127, 138))	('open', 'Protein', (48, 52))	('early-replicating regions', 'CPA', (67, 92))	('mutations', 'Var', (35, 44))
4893	28358873	An amino acid substitution that leads to constitutive activation and/or overexpression are two mechanisms of dysfunction of MET in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('activation', 'PosReg', (54, 64))	('tumor', 'Disease', (131, 136))	('amino acid substitution', 'Var', (3, 26))	('overexpression', 'MPA', (72, 86))
4906	28358873	We found rs11762213, a germline exonic single nucleotide polymorphism (SNP) inside MET, predicted cancer-specific survival (CSS) in type II pRCC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('pRCC', 'Phenotype', 'HP:0006766', (140, 144))	('C', 'Chemical', 'MESH:D002244', (143, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('pRCC', 'Gene', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('rs11762213', 'Mutation', 'rs11762213', (9, 19))	('predicted', 'Reg', (88, 97))	('rs11762213', 'Var', (9, 19))	('pRCC', 'Gene', '5546', (140, 144))	('C', 'Chemical', 'MESH:D002244', (142, 143))
4909	28358873	Methylation status drove the inter-sample mutation variation by promoting more C-to-T mutations in the CpG context.	('C', 'Chemical', 'MESH:D002244', (103, 104))	('Methylation', 'Var', (0, 11))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('C-to-T', 'MPA', (79, 85))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('promoting', 'PosReg', (64, 73))
4913	28358873	V1110I and M1268T were two recurrent mutations in this extra set.	('V1110I', 'Var', (0, 6))	('M1268T', 'Var', (11, 17))	('V1110I', 'Mutation', 'p.V1110I', (0, 6))	('M1268T', 'Mutation', 'p.M1268T', (11, 17))
4915	28358873	Additionally, we found two samples carrying H112Y and Y1248C respectively.	('H112Y', 'Mutation', 'p.H112Y', (44, 49))	('Y1248C', 'Var', (54, 60))	('H112Y', 'Var', (44, 49))	('Y1248C', 'Mutation', 'rs771116500', (54, 60))
4916	28358873	H1112Y has been observed in two patients in the original TCGA study cohort and H1118R is a long-known germline mutation associated with hereditary papillary renal carcinoma (HPRC).	('associated', 'Reg', (120, 130))	('patients', 'Species', '9606', (32, 40))	('H1118R', 'Mutation', 'p.H1118R', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('H1112Y', 'Mutation', 'p.H1112Y', (0, 6))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (147, 172))	('C', 'Chemical', 'MESH:D002244', (177, 178))	('renal carcinoma', 'Phenotype', 'HP:0005584', (157, 172))	('H1112Y', 'Var', (0, 6))	('H1118R', 'Var', (79, 85))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (136, 172))	('hereditary papillary renal carcinoma', 'Disease', (136, 172))	('C', 'Chemical', 'MESH:D002244', (58, 59))
4917	28358873	Y1248C has been observed in type I pRCC before and the TCGA cohort has a case carrying Y1248H.	('Y1248C', 'Mutation', 'rs771116500', (0, 6))	('Y1248H', 'Var', (87, 93))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('Y1248H', 'Mutation', 'p.Y1248H', (87, 93))	('pRCC', 'Phenotype', 'HP:0006766', (35, 39))	('pRCC', 'Gene', '5546', (35, 39))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('Y1248C', 'Var', (0, 6))	('pRCC', 'Gene', (35, 39))	('C', 'Chemical', 'MESH:D002244', (38, 39))
4919	28358873	Although many MET somatic mutations are believed to play a central role in pRCC, some germline MET mutations have also been associated with the disease.	('MET', 'Gene', (95, 98))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('associated', 'Reg', (124, 134))	('mutations', 'Var', (99, 108))	('pRCC', 'Gene', '5546', (75, 79))	('pRCC', 'Phenotype', 'HP:0006766', (75, 79))
4920	28358873	In particular, a germline SNP, rs11762213 (Fig 1A), has been discovered to predict recurrence and survival in a mixed RCC cohort.	('survival', 'CPA', (98, 106))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('rs11762213', 'Mutation', 'rs11762213', (31, 41))	('predict', 'Reg', (75, 82))	('rs11762213', 'Var', (31, 41))	('recurrence', 'CPA', (83, 93))
4926	28358873	Cancer-speccific survival was significantly worse in type II patients carrying the risk allele of rs11762213 (p = 0.034, Fig 1B).	('worse', 'NegReg', (44, 49))	('rs11762213', 'Var', (98, 108))	('patients', 'Species', '9606', (61, 69))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('rs11762213', 'Mutation', 'rs11762213', (98, 108))	('Cancer-speccific survival', 'CPA', (0, 25))
4928	28358873	We did not observe statistically significant correlation of rs11762213 with MET RNA expression in either tumor samples or normal controls (p > 0.1, two-sided rank-sum test).	('rs11762213', 'Mutation', 'rs11762213', (60, 70))	('rs11762213', 'Var', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('MET', 'Protein', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('RNA', 'cellular_component', 'GO:0005562', ('80', '83'))
4935	28358873	We further expanded our scope and ran FunSeq to identify potentially high-impact, noncoding variants in pRCC.	('pRCC', 'Phenotype', 'HP:0006766', (104, 108))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('pRCC', 'Gene', (104, 108))	('variants', 'Var', (92, 100))	('pRCC', 'Gene', '5546', (104, 108))
4942	28358873	Mutations we found all fell into a putative promoter and its flanking region of NEAT1.	('NEAT1', 'Gene', '283131', (80, 85))	('NEAT1', 'Gene', (80, 85))	('Mutations', 'Var', (0, 9))	('fell', 'Reg', (23, 27))
4943	28358873	We noticed NEAT1 mutations were associated with higher NEAT1 expression (Fig 2C, S2A Fig, p < 0.032, two-sided rank sum test).	('NEAT1', 'Gene', '283131', (11, 16))	('higher', 'PosReg', (48, 54))	('NEAT1', 'Gene', '283131', (55, 60))	('NEAT1', 'Gene', (11, 16))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('NEAT1', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('expression', 'MPA', (61, 71))
4944	28358873	We also found NEAT1 mutations were associated with worse prognosis (Fig 2D, p < 0.041, log-rank test).	('mutations', 'Var', (20, 29))	('NEAT1', 'Gene', (14, 19))	('NEAT1', 'Gene', '283131', (14, 19))
4948	28358873	The Catalogue of Somatic Mutations in Cancer (COSMIC) annotates MALAT1 as a cancer consensus gene, associating it with pediatric RCC and lung cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('MALAT1', 'Gene', (64, 70))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('MALAT1', 'Gene', '378938', (64, 70))	('Mutations', 'Var', (25, 34))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (76, 82))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('lung cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('pediatric RCC', 'Disease', (119, 132))	('C', 'Chemical', 'MESH:D002244', (4, 5))
4957	28358873	We found two cases with deletions in SDHB.	('SDHB', 'Gene', '6390', (37, 41))	('SDHB', 'Gene', (37, 41))	('deletions', 'Var', (24, 33))
4959	28358873	We validated the deletions affecting SDHB with another SV caller, Lumpy-SV.	('Lumpy-SV', 'Disease', 'MESH:D008166', (66, 74))	('SDHB', 'Gene', '6390', (37, 41))	('deletions', 'Var', (17, 26))	('SDHB', 'Gene', (37, 41))	('Lumpy-SV', 'Disease', (66, 74))
4960	28358873	Besides, we confirmed three cases carrying deletions affecting CDKN2A called by the TCGA array-based method but not the other two cases.	('deletions', 'Var', (43, 52))	('CDKN2A', 'Gene', '1029', (63, 69))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('CDKN2A', 'Gene', (63, 69))	('C', 'Chemical', 'MESH:D002244', (63, 64))
4963	28358873	Lastly, we observed several high-impact sporadic events, including duplications in EGFR and HIF1A, and deletions in DNMT3A and STAG2 (S2C Fig).	('EGFR', 'Gene', '1956', (83, 87))	('STAG2', 'Gene', '10735', (127, 132))	('DNMT3A', 'Gene', (116, 122))	('duplications', 'Var', (67, 79))	('DNMT3A', 'Gene', '1788', (116, 122))	('EGFR', 'Gene', (83, 87))	('deletions', 'Var', (103, 112))	('HIF1A', 'Gene', '3091', (92, 97))	('EGFR', 'molecular_function', 'GO:0005006', ('83', '87'))	('C', 'Chemical', 'MESH:D002244', (136, 137))	('HIF1A', 'Gene', (92, 97))	('STAG2', 'Gene', (127, 132))
4965	28358873	C-to-T in CpGs showed the highest mutation rates, which were roughly three to six-fold higher than mutation rates of other nucleotide contexts.	('CpGs', 'Gene', (10, 14))	('mutation', 'MPA', (34, 42))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CpGs', 'Chemical', 'MESH:C015772', (10, 14))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('C-to-T', 'Var', (0, 6))
4968	28358873	C-to-T in CpGs is highly associated with methylation.	('methylation', 'MPA', (41, 52))	('associated', 'Reg', (25, 35))	('methylation', 'biological_process', 'GO:0032259', ('41', '52'))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CpGs', 'Chemical', 'MESH:C015772', (10, 14))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('C-to-T', 'Var', (0, 6))
4972	28358873	We confirmed this association by showing samples from methylation cluster 1 had higher PC1 scores as well as higher C-to-T mutation counts and mutation percentages in CpGs (Fig 3C).	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('PC1', 'Gene', (87, 90))	('methylation', 'Var', (54, 65))	('higher', 'PosReg', (109, 115))	('mutation', 'Var', (143, 151))	('CpGs', 'Chemical', 'MESH:C015772', (167, 171))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('C-to-T mutation counts', 'CPA', (116, 138))	('CpGs', 'Disease', (167, 171))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('PC1', 'Gene', '3868', (87, 90))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('higher', 'PosReg', (80, 86))	('C', 'Chemical', 'MESH:D002244', (178, 179))
4975	28358873	C-to-T mutations in CpGs we observed in pRCCs were more likely to be in the coding region (OR = 1.54, 95%CI: 1.27-1.85, p<0.0001) and nonsynonymous (OR = 1.47, 95%CI: 1.17-1.84, p<0.001), which indicated they tended to be high-impact mutations.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('CpGs', 'Gene', (20, 24))	('nonsynonymous', 'Var', (134, 147))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('pRCC', 'Gene', '5546', (40, 44))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('pRCC', 'Phenotype', 'HP:0006766', (40, 44))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('CpGs', 'Chemical', 'MESH:C015772', (20, 24))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('C-to-T mutations', 'Var', (0, 16))	('pRCC', 'Gene', (40, 44))	('mutations', 'Var', (7, 16))
4976	28358873	However, C-to-T mutations in CpGs did not show functional bias between the two methylation clusters in noncoding regions (based on FunSeq score distribution).	('CpGs', 'Chemical', 'MESH:C015772', (29, 33))	('C', 'Chemical', 'MESH:D002244', (9, 10))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('C-to-T mutations', 'Var', (9, 25))	('CpGs', 'Gene', (29, 33))	('methylation', 'biological_process', 'GO:0032259', ('79', '90'))
4978	28358873	Interestingly, we found one type II pRCC case out of 155 somatic WXS sequenced samples exhibited APOBEC-associated mutation signatures 2 and 13.	('APOBEC', 'cellular_component', 'GO:0030895', ('97', '103'))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Phenotype', 'HP:0006766', (36, 40))	('pRCC', 'Gene', '5546', (36, 40))	('mutation signatures', 'Var', (115, 134))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('APOBEC-associated', 'Gene', (97, 114))	('pRCC', 'Gene', (36, 40))	('C', 'Chemical', 'MESH:D002244', (38, 39))
4980	28358873	This sample was statistically enriched of APOBEC-induced mutations (adjusted p-value < 0.0003).	('C', 'Chemical', 'MESH:D002244', (47, 48))	('mutations', 'Var', (57, 66))	('APOBEC', 'cellular_component', 'GO:0030895', ('42', '48'))	('APOBEC-induced', 'Gene', (42, 56))
4982	28358873	UC often carries APOBEC associated mutation signatures and our result is consistent with the TCGA bladder urothelial cancer study.	('bladder urothelial cancer', 'Disease', (98, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('APOBEC associated', 'Gene', (17, 34))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (98, 123))	('APOBEC', 'cellular_component', 'GO:0030895', ('17', '23'))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('mutation', 'Var', (35, 43))
4991	28358873	Chromatin remodeling genes are frequently mutated in pRCC and many other cancers, including ccRCC.	('pRCC', 'Gene', (53, 57))	('Chromatin', 'cellular_component', 'GO:0000785', ('0', '9'))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Chromatin remodeling genes', 'Gene', (0, 26))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('Chromatin remodeling', 'biological_process', 'GO:0006338', ('0', '20'))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('ccRCC', 'Disease', (92, 97))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('pRCC', 'Gene', '5546', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('mutated', 'Var', (42, 49))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('pRCC', 'Phenotype', 'HP:0006766', (53, 57))
4992	28358873	To test this, we tallied the number of mutations inside DNase I hypersensitive sites (DHS) inferred from 11 normal fetal kidney cortex samples (The NIH Roadmap Epigenomics Mapping Consortium), which represent normal tissues under physiological conditions.	('C', 'Chemical', 'MESH:D002244', (180, 181))	('DNase I', 'molecular_function', 'GO:0004530', ('56', '63'))	('mutations', 'Var', (39, 48))	('hypersensitive', 'Disease', 'MESH:D004342', (64, 78))	('DNase', 'Gene', (56, 61))	('hypersensitive', 'Disease', (64, 78))	('DHS', 'Chemical', '-', (86, 89))
4993	28358873	9/35 samples with disruptive mutations in ten chromatin remodeling genes, cancer-associated genes showed higher genome-wide mutation counts (p < 0.021, one-sided rank-sum test;), partially driven by higher mutation counts in the DHS regions (p < 0.0023, one-sided rank-sum test).	('genome-wide mutation counts', 'MPA', (112, 139))	('DHS', 'Chemical', '-', (229, 232))	('higher', 'PosReg', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutations', 'Var', (29, 38))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('46', '66'))	('higher', 'PosReg', (199, 205))	('cancer', 'Disease', (74, 80))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
4994	28358873	The median number of mutations in DHS regions considerably increased by 60% (67.5 versus 108) in samples carrying chromatin remodeling defects.	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('DHS', 'Chemical', '-', (34, 37))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('114', '134'))	('increased', 'PosReg', (59, 68))	('DHS regions', 'Gene', (34, 45))	('mutations', 'Var', (21, 30))
5004	28358873	Beyond traditionally driver events, we suggested several novel noncoding alterations potentially drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('noncoding alterations', 'Var', (63, 84))	('drive', 'Reg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
5007	28358873	Then we found an exonic SNP in MET, rs11762213, to be a prognostic germline variance in type II pRCC.	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('pRCC', 'Gene', '5546', (96, 100))	('rs11762213', 'Var', (36, 46))	('pRCC', 'Gene', (96, 100))	('pRCC', 'Phenotype', 'HP:0006766', (96, 100))	('rs11762213', 'Mutation', 'rs11762213', (36, 46))
5008	28358873	Previously, rs11762213 was found to predict outcome in a mixed RCC samples, predominated by ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('rs11762213', 'Var', (12, 22))	('ccRCC', 'Disease', (92, 97))	('predict', 'Reg', (36, 43))	('rs11762213', 'Mutation', 'rs11762213', (12, 22))
5010	28358873	However, it was never clear whether rs11762213 only predicts the outcome in ccRCC or other histological types as well.	('rs11762213', 'Var', (36, 46))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('ccRCC', 'Disease', (76, 81))	('rs11762213', 'Mutation', 'rs11762213', (36, 46))
5011	28358873	In this study, we concluded that the minor alternative allele of rs11762213 also forecasts unfavorable outcome in type II pRCC patients.	('pRCC', 'Gene', (122, 126))	('rs11762213', 'Mutation', 'rs11762213', (65, 75))	('patients', 'Species', '9606', (127, 135))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('rs11762213', 'Var', (65, 75))	('pRCC', 'Phenotype', 'HP:0006766', (122, 126))	('pRCC', 'Gene', '5546', (122, 126))
5013	28358873	Given the significant role of MET in pRCC, we think rs11762213 is affecting survival through MET, although the mechanism unknown.	('pRCC', 'Gene', (37, 41))	('rs11762213', 'Mutation', 'rs11762213', (52, 62))	('pRCC', 'Gene', '5546', (37, 41))	('rs11762213', 'Var', (52, 62))	('MET', 'Disease', (93, 96))	('affecting', 'Reg', (66, 75))	('pRCC', 'Phenotype', 'HP:0006766', (37, 41))	('survival', 'CPA', (76, 84))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))
5016	28358873	Our finding on rs11762213 is potentially meaningful in the clinical management of patients with the more aggressive type II pRCC.	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('patients', 'Species', '9606', (82, 90))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('pRCC', 'Gene', (124, 128))	('rs11762213', 'Mutation', 'rs11762213', (15, 25))	('rs11762213', 'Var', (15, 25))
5021	28358873	This implies a possible effect of rs11762213 on pRCC incidence among African Americans that is worth further investigation.	('pRCC', 'Phenotype', 'HP:0006766', (48, 52))	('pRCC', 'Gene', '5546', (48, 52))	('rs11762213', 'Mutation', 'rs11762213', (34, 44))	('rs11762213', 'Var', (34, 44))	('pRCC', 'Gene', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
5023	28358873	Methylation is a major source of silencing retrotransposon activities in the human genome.	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('Methylation', 'Var', (0, 11))	('silencing', 'MPA', (33, 42))	('human', 'Species', '9606', (77, 82))
5028	28358873	These mutations potentially disrupt regulatory elements of ERRFI1 and thus play a role in tumorigenesis.	('regulatory elements', 'MPA', (36, 55))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('play', 'Reg', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('ERRFI1', 'Gene', '54206', (59, 65))	('role', 'Reg', (82, 86))	('ERRFI1', 'Gene', (59, 65))	('mutations', 'Var', (6, 15))	('disrupt', 'Reg', (28, 35))
5031	28358873	Patients carrying mutations in NEAT1 had significantly higher NEAT1 expression and worse prognosis.	('expression', 'MPA', (68, 78))	('NEAT1', 'Gene', '283131', (31, 36))	('NEAT1', 'Gene', '283131', (62, 67))	('Patients', 'Species', '9606', (0, 8))	('NEAT1', 'Gene', (31, 36))	('NEAT1', 'Gene', (62, 67))	('higher', 'PosReg', (55, 61))	('mutations', 'Var', (18, 27))
5032	28358873	High expression of NEAT1 predicted significantly worse survival in ccRCC as well.	('NEAT1', 'Gene', (19, 24))	('High expression', 'Var', (0, 15))	('ccRCC', 'Disease', (67, 72))	('worse', 'NegReg', (49, 54))	('NEAT1', 'Gene', '283131', (19, 24))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
5033	28358873	NEAT1 has been shown to be hypermutated in other cancers and some studies also linked high NEAT1 association with unfavorable prognosis.	('NEAT1', 'Gene', (91, 96))	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('high', 'Var', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('NEAT1', 'Gene', '283131', (91, 96))
5037	28358873	In fact, we confirmed the well-known deletion of CDKN2A and found that we predicted its down-regulate expression better than the copy number variation analysis in TCGA study.	('CDKN2A', 'Gene', '1029', (49, 55))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('deletion', 'Var', (37, 45))	('down-regulate expression', 'MPA', (88, 112))	('CDKN2A', 'Gene', (49, 55))	('C', 'Chemical', 'MESH:D002244', (164, 165))
5040	28358873	Our SV study also discovered recurrent cases of SDHB deletion and expression data supported our finding.	('SDHB', 'Gene', '6390', (48, 52))	('deletion', 'Var', (53, 61))	('SDHB', 'Gene', (48, 52))
5047	28358873	We identified mutation rate dispersion of C-to-T transitions in CpGs motifs contributed the most to the inter-sample mutation spectra variation.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('C-to-T transitions', 'Var', (42, 60))	('CpGs', 'Chemical', 'MESH:C015772', (64, 68))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('CpGs', 'Gene', (64, 68))
5048	28358873	We further pinned down the cause of dispersion by showing the hypermethylated cluster, identified in the previous TCGA study, had a higher C-to-T rate in CpGs.	('higher', 'PosReg', (132, 138))	('C-to-T rate', 'CPA', (139, 150))	('hypermethylated', 'Var', (62, 77))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('CpGs', 'Disease', (154, 158))	('CpGs', 'Chemical', 'MESH:C015772', (154, 158))	('C', 'Chemical', 'MESH:D002244', (154, 155))
5049	28358873	Although increased C-to-T in CpGs is likely the result of hypermethylation, we cannot rule out the possibility the change of mutation landscape plays a role in cancer development.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('CpGs', 'Chemical', 'MESH:C015772', (29, 33))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('cancer', 'Disease', (160, 166))	('C-to-T', 'Var', (19, 25))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
5050	28358873	For example, C-to-T in methylated CpGs causes loss of methylation, which could have effects on local chromatin environment, trans-elements recruitment and gene expression regulation.	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('loss', 'NegReg', (46, 50))	('gene expression', 'biological_process', 'GO:0010467', ('155', '170'))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))	('CpGs', 'Chemical', 'MESH:C015772', (34, 38))	('effects', 'Reg', (84, 91))	('methylation', 'MPA', (54, 65))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('C', 'Chemical', 'MESH:D002244', (13, 14))	('regulation', 'biological_process', 'GO:0065007', ('171', '181'))	('C-to-T', 'Var', (13, 19))
5051	28358873	In our study, we observed C-to-Ts in CpGs were enriched in coding regions, which suggested they might have a higher functional impact in the cancer genome.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CpGs', 'Chemical', 'MESH:C015772', (37, 41))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('CpGs', 'Gene', (37, 41))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('C-to-Ts', 'Var', (26, 33))	('cancer', 'Disease', (141, 147))
5056	28358873	APOBEC mutation signature was also found in a small percentage of chromophobe renal cell carcinoma, although they are believed to have a different cellular origin.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('APOBEC', 'Gene', (0, 6))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('chromophobe renal cell carcinoma', 'Disease', (66, 98))	('mutation', 'Var', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('APOBEC', 'cellular_component', 'GO:0030895', ('0', '6'))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 98))	('found', 'Reg', (35, 40))
5062	28358873	We demonstrated pRCCs with defects in chromatin remodeling genes showed higher mutation rate in general, driven by an even stronger mutation rate increase in putative open chromatin regions in normal kidney tissues.	('defects', 'Var', (27, 34))	('increase', 'PosReg', (146, 154))	('pRCC', 'Gene', (16, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('38', '47'))	('chromatin remodeling genes', 'Gene', (38, 64))	('pRCC', 'Phenotype', 'HP:0006766', (16, 20))	('pRCC', 'Gene', '5546', (16, 20))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('higher', 'PosReg', (72, 78))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('38', '58'))	('mutation rate', 'MPA', (79, 92))
5064	28358873	Yet, high mutation burden in functional important open chromatin regions also raises the chance that tumor antigens activate the host immune system.	('activate', 'PosReg', (116, 124))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('mutation burden', 'Var', (10, 25))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
5066	28358873	These tumors also accumulate more mutations in early replicating regions.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('accumulate', 'Reg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (34, 43))
5071	28358873	In this first whole genome study of pRCC, we found several novel noncoding alterations that might drive tumor development and we explored the mutational landscape and evolutionary trees to better understand tumor heterogeneity.	('drive', 'Reg', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('noncoding alterations', 'Var', (65, 86))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('pRCC', 'Gene', '5546', (36, 40))	('pRCC', 'Phenotype', 'HP:0006766', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('pRCC', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
5105	28358873	However, adding BAP1 into the list did not change the significance of our key tests (p<0.0115 for mutation counts in DHS and p<0.020 for mutation percentage in DHS).	('mutation', 'Var', (98, 106))	('DHS', 'Chemical', '-', (160, 163))	('BAP1', 'Gene', '8314', (16, 20))	('DHS', 'Disease', (117, 120))	('BAP1', 'Gene', (16, 20))	('DHS', 'Chemical', '-', (117, 120))
5118	23063455	Collectively, these changes promote a glycolytic metabolic phenotype in renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('renal cancer', 'Disease', (72, 84))	('promote', 'PosReg', (28, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (72, 84))	('changes', 'Var', (20, 27))	('glycolytic metabolic phenotype', 'MPA', (38, 68))	('renal cancer', 'Disease', 'MESH:D007680', (72, 84))
5130	23063455	This review will focus on the metabolic alterations in the more common variants of RCC and the clinical relevance of these alterations.	('variants', 'Var', (71, 79))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('metabolic', 'MPA', (30, 39))
5145	23063455	The finding that the loss of several tumor suppressor genes may promote the Warburg effect suggests the latter.	('loss', 'Var', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('promote', 'PosReg', (64, 71))	('Warburg effect', 'CPA', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))
5151	23063455	Subsequent studies led to the finding that VHL alterations are common genetic events in sporadic ccRCC, indicating that, from the standpoint of tumor-initiating events, ccRCCs are a relatively homogenous population relative to other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('alterations', 'Var', (47, 58))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (233, 238))	('VHL', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('VHL', 'Gene', '7428', (43, 46))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('RCC', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
5152	23063455	It is estimated that 70% to 90% of ccRCCs demonstrate alterations of the VHL gene either via mutation or gene silencing (ie, hypermethylation).	('VHL', 'Gene', (73, 76))	('gene silencing', 'biological_process', 'GO:0016458', ('105', '119'))	('VHL', 'Gene', '7428', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('mutation', 'Var', (93, 101))	('alterations', 'Reg', (54, 65))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('gene', 'Var', (105, 109))
5175	23063455	Phosphorylation of PDH by PDK1 inactivates PDH, thereby blocking the conversion of pyruvate to acetyl CoA.	('pyruvate', 'Chemical', 'MESH:D019289', (83, 91))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('PDH', 'molecular_function', 'GO:0004246', ('19', '22'))	('PDH', 'molecular_function', 'GO:0033718', ('19', '22'))	('PDK1', 'Gene', '5163', (26, 30))	('Phosphorylation', 'Var', (0, 15))	('PDH', 'Gene', '54704', (19, 22))	('PDH', 'Gene', '54704', (43, 46))	('PDH', 'molecular_function', 'GO:0004739', ('19', '22'))	('blocking', 'NegReg', (56, 64))	('PDH', 'molecular_function', 'GO:0004246', ('43', '46'))	('acetyl CoA', 'Chemical', 'MESH:D000105', (95, 105))	('PDH', 'molecular_function', 'GO:0033718', ('43', '46'))	('PDH', 'Gene', (43, 46))	('conversion of pyruvate to acetyl CoA', 'MPA', (69, 105))	('PDH', 'Gene', (19, 22))	('PDK1', 'Gene', (26, 30))	('PDK1', 'molecular_function', 'GO:0004740', ('26', '30'))	('PDH', 'molecular_function', 'GO:0004739', ('43', '46'))	('inactivates', 'NegReg', (31, 42))
5184	23063455	In agreement with these findings, ICSU1/ISCU2 expression is decreased in ccRCC as well as in animal models with genetic disruption of VHL.	('decreased', 'NegReg', (60, 69))	('men', 'Species', '9606', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('genetic disruption', 'Var', (112, 130))	('VHL', 'Gene', (134, 137))	('ICSU1/ISCU2', 'Gene', (34, 45))	('VHL', 'Gene', '7428', (134, 137))	('expression', 'MPA', (46, 56))
5189	23063455	Interestingly, gene-expression profiling of ccRCCs with PBRM1 mutations falls into a hypoxic gene profiling.	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('PBRM1', 'Gene', '55193', (56, 61))	('falls', 'Phenotype', 'HP:0002527', (72, 77))	('gene-expression', 'biological_process', 'GO:0010467', ('15', '30'))	('PBRM1', 'Gene', (56, 61))	('hypoxic', 'Disease', (85, 92))	('hypoxic', 'Disease', 'MESH:D000860', (85, 92))	('mutations', 'Var', (62, 71))
5191	23063455	In addition, several other genes, such as SET domain containing 2 (SETD2), that regulate histone modifications are mutated in a subset of ccRCC.	('SETD2', 'Gene', '29072', (67, 72))	('mutated', 'Var', (115, 122))	('SETD2', 'Gene', (67, 72))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))
5196	23063455	Additionally, PI3K regulates signaling by mechanistic target of rapamycin (mTOR).	('regulates', 'Reg', (19, 28))	('signaling', 'biological_process', 'GO:0023052', ('29', '38'))	('mTOR', 'Gene', '2475', (75, 79))	('PI3K', 'Var', (14, 18))	('mechanistic target of rapamycin', 'Gene', (42, 73))	('mechanistic target of rapamycin', 'Gene', '2475', (42, 73))	('mTOR', 'Gene', (75, 79))	('signaling', 'MPA', (29, 38))	('PI3K', 'molecular_function', 'GO:0016303', ('14', '18'))
5197	23063455	MTOR's relevance to RCC has received much attention lately due to the emergence of mTOR inhibitors as US Food and Drug Administration-approved agents for the treatment of advanced renal cancer.	('mTOR', 'Gene', (83, 87))	('men', 'Species', '9606', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('advanced renal cancer', 'Disease', 'MESH:D007680', (171, 192))	('advanced renal cancer', 'Disease', (171, 192))	('renal cancer', 'Phenotype', 'HP:0009726', (180, 192))	('mTOR', 'Gene', '2475', (83, 87))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('MTOR', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('inhibitors', 'Var', (88, 98))	('RCC', 'Disease', (20, 23))	('MTOR', 'Gene', '2475', (0, 4))
5201	23063455	Hence, loss or mutation of these genes may lead to aberrant mTOR activation.	('mutation', 'Var', (15, 23))	('loss', 'NegReg', (7, 11))	('lead to', 'Reg', (43, 50))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (60, 64))
5206	23063455	As such, loss of either TSC1 or TSC2 leads to mTOR activation.	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (46, 50))	('TSC2', 'Gene', '7249', (32, 36))	('loss', 'Var', (9, 13))	('TSC2', 'Gene', (32, 36))	('TSC1', 'Gene', '7248', (24, 28))	('TSC1', 'Gene', (24, 28))
5208	23063455	Of note are recent reports demonstrating mTOR and TSC1 mutations in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('mutations', 'Var', (55, 64))	('TSC1', 'Gene', (50, 54))	('TSC1', 'Gene', '7248', (50, 54))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
5216	23063455	Patients with HPRC harbor activating mutations of the met proto-oncogene (hepatocyte growth factor receptor) (c-MET) in the germline.	('activating', 'PosReg', (26, 36))	('c-MET', 'Gene', (110, 115))	('met proto-oncogene (hepatocyte growth factor receptor', 'Gene', (54, 107))	('met proto-oncogene (hepatocyte growth factor receptor)', 'Gene', '4233', (54, 108))	('mutations', 'Var', (37, 46))	('Patients', 'Species', '9606', (0, 8))	('c-MET', 'Gene', '4233', (110, 115))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('74', '98'))
5220	23063455	c-MET appears to have a role in sporadic cancer as well as mutations, and amplifications of this gene have been identified in a subset of tumors from patients with sporadic type 1 pRCC.	('amplifications', 'Var', (74, 88))	('c-MET', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('c-MET', 'Gene', '4233', (0, 5))	('pRCC', 'Gene', '5546', (180, 184))	('tumors', 'Disease', (138, 144))	('patients', 'Species', '9606', (150, 158))	('identified', 'Reg', (112, 122))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('pRCC', 'Gene', (180, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
5223	23063455	However, the report of genetic predisposition to type 2 pRCC of patients with germline mutations of the fumarate hydratase (FH) gene led to further understanding of the metabolic aspect of this disease.	('patients', 'Species', '9606', (64, 72))	('pRCC', 'Gene', '5546', (56, 60))	('FH', 'Gene', '2271', (124, 126))	('fumarate hydratase', 'Gene', '2271', (104, 122))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('pRCC', 'Gene', (56, 60))	('fumarate hydratase', 'Gene', (104, 122))	('mutations', 'Var', (87, 96))
5249	23063455	With an improved understanding of genetic alterations in RCC, particularly ccRCC, investigators are now in a position to exploit the ensuing metabolic alterations for clinical applications.	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('genetic alterations', 'Var', (34, 53))
5250	23063455	Underlying gene defects such as VHL loss have profound impacts on the gene expression of many enzymes involved in key metabolic processes.	('defects', 'Var', (16, 23))	('gene expression', 'MPA', (70, 85))	('VHL loss', 'Disease', 'MESH:D006623', (32, 40))	('gene expression', 'biological_process', 'GO:0010467', ('70', '85'))	('VHL loss', 'Disease', (32, 40))	('impacts', 'Reg', (55, 62))
5309	33004995	In conclusion, the present study demonstrates the effectiveness and reliability of the NONO-TFE3 dual-fusion FISH probe for diagnosing NONO-TFE3 RCC.	('NONO-TFE3', 'Var', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
5319	33004995	Xp11.2 translocation RCC is typically characterized by strong nuclear immunoreactivity with TFE3 antibody and a larger split signal in the TFE3 break-apart FISH assay, respectively.	('antibody', 'cellular_component', 'GO:0019814', ('97', '105'))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('Xp11.2', 'Var', (0, 6))	('antibody', 'molecular_function', 'GO:0003823', ('97', '105'))	('split signal', 'MPA', (119, 131))	('antibody', 'cellular_component', 'GO:0042571', ('97', '105'))	('nuclear immunoreactivity', 'MPA', (62, 86))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('antibody', 'cellular_component', 'GO:0019815', ('97', '105'))
5321	33004995	However, the adjacent location of NONO and TFE3 genes result in an equivocal split signal distance of TFE3, which leads to the misdiagnosis of NONO-TFE3 RCC as non-Xp11.2 translocation RCC.	('RCC', 'Disease', (185, 188))	('split signal distance', 'MPA', (77, 98))	('TFE3', 'Gene', (43, 47))	('TFE3', 'Gene', (102, 106))	('NONO-TFE3', 'Var', (143, 152))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('leads to', 'Reg', (114, 122))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
5326	33004995	Moreover, 1G1R2F and 2G2R signal patterns were observed in 3% and 4.71-67.3% of female tumor cells.	('1G1R2F', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('2G2R', 'Var', (21, 25))	('observed', 'Reg', (47, 55))	('male tumor', 'Disease', (82, 92))	('male tumor', 'Disease', 'MESH:D018567', (82, 92))
5338	33004995	7f), RCC, CD10, P504S, and Ki-67; but negative for Vim, CA-IX (7 g), and CK7 (Fig.	('CD10', 'molecular_function', 'GO:0004245', ('10', '14'))	('P504S', 'Var', (16, 21))	('CK7', 'Gene', '3855', (73, 76))	('CA-IX', 'Gene', '768', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('Vim', 'Gene', '7431', (51, 54))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('P504S', 'Mutation', 'p.P504S', (16, 21))	('CA-IX', 'Gene', (56, 61))	('CK7', 'Gene', (73, 76))	('Vim', 'Gene', (51, 54))
5340	33004995	Xp11.2 translocation RCC is a rare tumor which mainly occurs in children and young adults.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('Xp11.2 translocation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('children', 'Species', '9606', (64, 72))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))
5341	33004995	Xp11.2 translocation RCC has been reported to have an incidence of 30, 15, and 1.5% in pediatrics, young adults (younger than 45 years), and adults, respectively.	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('translocation', 'Var', (7, 20))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('RCC', 'Disease', (21, 24))
5353	33004995	For example, the fusion of the ASPSCR1 and TFE3 genes could occur not only in ASPSCR1-TFE3 RCC, but also in alveolar soft part sarcoma (ASPS), a stromal tumor involving an unbalanced der (17) t(X; 17) (p11; q25) translocation.	('soft part sarcoma', 'Phenotype', 'HP:0030448', (117, 134))	('TFE3', 'Gene', (43, 47))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('ASPS', 'Gene', (78, 82))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (108, 134))	('ASPSCR1', 'Gene', '79058', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (127, 134))	('ASPS', 'Gene', '79058', (136, 140))	('ASPS', 'Gene', (31, 35))	('der (17) t(', 'Var', (183, 194))	('ASPSCR1', 'Gene', (31, 38))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('ASPS', 'Phenotype', 'HP:0012218', (136, 140))	('tumor', 'Disease', (153, 158))	('ASPS', 'Gene', '79058', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('ASPSCR1', 'Gene', (78, 85))	('ASPS', 'Phenotype', 'HP:0012218', (78, 82))	('fusion', 'Var', (17, 23))	('ASPS', 'Gene', '79058', (31, 35))	('ASPS', 'Phenotype', 'HP:0012218', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('sarcoma', 'Disease', 'MESH:D012509', (127, 134))	('ASPS', 'Gene', (136, 140))	('sarcoma', 'Disease', (127, 134))	('ASPSCR1', 'Gene', '79058', (31, 38))	('occur', 'Reg', (60, 65))
5363	33004995	In general, Xp11.2 translocation RCC tends to occur in patients aged between 20 to 50 years, and Xp11.2 translocation RCC is believed to be 2 to 3 times more prevalent in females compared to males.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('Xp11.2', 'Var', (97, 103))	('patients', 'Species', '9606', (55, 63))
5365	33004995	Compared with ASPSCR1-TFE3 RCC and PRCC-TFE3 RCC (Supplementary Table 2), patients of NONO-TFE3 RCC were younger and had smaller tumor sizes.	('RCC', 'Disease', (36, 39))	('PRCC', 'Gene', '5546', (35, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('tumor', 'Disease', (129, 134))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('ASPSCR1', 'Gene', '79058', (14, 21))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('patients', 'Species', '9606', (74, 82))	('ASPSCR1', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ASPS', 'Phenotype', 'HP:0012218', (14, 18))	('NONO-TFE3', 'Var', (86, 95))	('PRCC', 'Gene', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
5370	33004995	The physiological characteristics of NONO-TFE3 RCC need further investigation with a larger population and long-term follow-up.	('RCC', 'Disease', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('NONO-TFE3', 'Var', (37, 46))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
5371	33004995	In summary, we reported a newly designed NONO-TFE3 dual-fusion FISH assay and confirmed the accuracy of this novel probe for detecting NONO-TFE3 RCC.	('NONO-TFE3', 'Var', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
5402	23907150	Intracystic papillary carcinoma showed the highest proportions of genome copy number aberration, followed by ductal carcinoma in situ then by invasive ductal carcinoma (p=0.06).	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (109, 133))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (109, 125))	('invasive ductal carcinoma', 'Disease', (142, 167))	('ductal carcinoma in situ', 'Disease', (109, 133))	('Intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (0, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (109, 133))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (151, 167))	('Intracystic papillary carcinoma', 'Disease', (0, 31))	('genome copy number aberration', 'Var', (66, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (142, 167))
5404	23907150	Comparing intracystic papillary carcinoma with ductal carcinoma in situ vs. without ductal carcinoma in situ, the former had gain in 5q35.3 (p=0.041), 8q24.3 (p=0.041), and 21q13.2 to 21q13.31 (p=0.011).	('5q35.3', 'Var', (133, 139))	('ductal carcinoma in situ', 'Disease', (84, 108))	('8q24.3', 'Var', (151, 157))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (84, 108))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (84, 100))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (47, 71))	('ductal carcinoma in situ', 'Disease', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (47, 63))	('21q13.2', 'Var', (173, 180))	('gain', 'PosReg', (125, 129))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (84, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (10, 41))	('intracystic papillary carcinoma', 'Disease', (10, 41))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (47, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
5415	23907150	Genetic alterations in the form of interstitial deletions, loss of heterozygosity, at 16q and 1p numerical and structural alterations at chromosomes 16q and 1p with fusion of chromosome 16 and 1 [der(1;16)] have been described in intracystic papillary carcinoma.	('intracystic papillary carcinoma', 'Disease', (230, 261))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (230, 261))	('loss of heterozygosity', 'Var', (59, 81))
5436	23907150	Instead of using a fixed cut-off value, copy number gain/loss was called by CGHcall with 75% assumed tumor purity.	('gain/loss', 'PosReg', (52, 61))	('copy number', 'Var', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
5461	23907150	Intracystic papillary carcinoma showed 16p gain, 16q loss and 1q gain.	('gain', 'PosReg', (65, 69))	('Intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (0, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('loss', 'NegReg', (53, 57))	('Intracystic papillary carcinoma', 'Disease', (0, 31))	('16q', 'Var', (49, 52))	('gain', 'PosReg', (43, 47))
5462	23907150	The genomic variation between intracystic papillary carcinoma with ductal carcinoma in situ (n=6) vs. without ductal carcinoma in situ (n=8) showed that intracystic papillary carcinoma without ductal carcinoma in situ had 5q35.3, 176474585 to 180175485 gain in 3 of 4 cases vs. 1 of 10 intracystic papillary carcinoma with ductal carcinoma in situ (p=0.041).	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (30, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (110, 126))	('intracystic papillary carcinoma', 'Disease', (30, 61))	('ductal carcinoma in situ', 'Disease', (193, 217))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (323, 347))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (67, 91))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (110, 134))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (153, 184))	('ductal carcinoma in situ', 'Disease', (323, 347))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (323, 339))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (193, 217))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (67, 83))	('176474585 to 180175485', 'Var', (230, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (286, 317))	('intracystic papillary carcinoma', 'Disease', (153, 184))	('5q35.3', 'Var', (222, 228))	('gain', 'PosReg', (253, 257))	('ductal carcinoma in situ', 'Disease', (110, 134))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (323, 347))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (67, 91))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (193, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('intracystic papillary carcinoma', 'Disease', (286, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ductal carcinoma in situ', 'Disease', (67, 91))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (193, 217))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (110, 134))
5463	23907150	Intracystic papillary carcinoma without ductal carcinoma in situ had 8q24.3, 142015488 to 145957473 gain in 3 of 4 cases vs. 1 of 10 intracystic papillary carcinoma with ductal carcinoma in situ (p=0.041).	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (170, 194))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (133, 164))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (40, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('ductal carcinoma in situ', 'Disease', (170, 194))	('intracystic papillary carcinoma', 'Disease', (133, 164))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (40, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('Intracystic papillary carcinoma', 'Disease', (0, 31))	('142015488 to 145957473', 'Var', (77, 99))	('8q24.3', 'Gene', (69, 75))	('ductal carcinoma in situ', 'Disease', (40, 64))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (170, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('gain', 'PosReg', (100, 104))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (170, 186))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (40, 64))	('Intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (0, 31))
5464	23907150	Finally, intracystic papillary carcinoma without ductal carcinoma in situ had 21q13.2 to 21q13.31, 42127232 to 44695209 gain in 3 of 4 cases vs. 0 of 10 intracystic papillary carcinoma with ductal carcinoma in situ (p=0.011) (figure 3).	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (190, 214))	('ductal carcinoma in situ', 'Disease', (190, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (49, 73))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (190, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('intracystic papillary carcinoma', 'Disease', (153, 184))	('ductal carcinoma in situ', 'Disease', (49, 73))	('intracystic papillary carcinoma', 'Disease', (9, 40))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (9, 40))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (49, 73))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (49, 65))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (153, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('42127232 to 44695209', 'Var', (99, 119))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (190, 206))	('gain', 'PosReg', (120, 124))
5465	23907150	The genomic variation between intracystic papillary carcinoma with invasive ductal carcinoma (n=6) vs. without invasive ductal carcinoma (n=8) showed that the latter had 11q22.1 to 11q23.3 loss in 6 of 8 cases vs. 0 of 6 in the former (p=0.031).	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (111, 136))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (30, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('11q22.1 to 11q23.3', 'Var', (170, 188))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (120, 136))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (67, 92))	('invasive ductal carcinoma', 'Disease', (111, 136))	('invasive ductal carcinoma', 'Disease', (67, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('intracystic papillary carcinoma', 'Disease', (30, 61))	('loss', 'NegReg', (189, 193))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (76, 92))
5473	23907150	The major discordant copy number variations for intracystic papillary carcinoma were on chr7.	('copy number variations', 'Var', (21, 43))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (48, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('intracystic papillary carcinoma', 'Disease', (48, 79))
5475	23907150	The mean probability of copy number changes for ductal carcinoma in situ was similar to intracystic papillary carcinoma with the following additional focal changes that seen in ductal carcinoma in situ compared to intracystic papillary carcinoma: 8q22.2 to 8q22.3 gain (from 100114836 to 102268083, in 3 of 6 cases), 8q24.3 gain (from 142202743 to 145957473, in 3 of 6 cases), 11q25 loss, from 131565893 to 133557293, in 3 of 6 cases), and 12q24.31-12q24.33 loss (from 124302840 to 129818768, in 2 of 6 cases).	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (177, 193))	('loss', 'NegReg', (458, 462))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (48, 64))	('8q22.2', 'Var', (247, 253))	('ductal carcinoma in situ', 'Disease', (177, 201))	('145957473', 'Var', (348, 357))	('gain', 'PosReg', (264, 268))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (48, 72))	('from 124302840', 'Var', (464, 478))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (88, 119))	('from 100114836 to 102268083', 'Var', (270, 297))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (177, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('loss', 'NegReg', (383, 387))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('ductal carcinoma in situ', 'Disease', (48, 72))	('intracystic papillary carcinoma', 'Disease', (88, 119))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (214, 245))	('129818768', 'Var', (482, 491))	('from 142202743', 'Var', (330, 344))	('gain', 'PosReg', (324, 328))	('intracystic papillary carcinoma', 'Disease', (214, 245))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (48, 72))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (177, 201))
5476	23907150	There was one strong focal change within 1q gain: 1q21.3-1q23.1 (8 of 14 cases) (from 153183579 to 155186038) in intracystic papillary carcinoma.	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (113, 144))	('intracystic papillary carcinoma', 'Disease', (113, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('from 153183579', 'Var', (81, 95))	('155186038', 'Var', (99, 108))
5505	23907150	Then they acquire mutations and evolve into different tumors independently and in parallel.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (18, 27))
5507	23907150	Then, this tumor acquires another set of mutations producing a completely different tumor type.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
5512	23907150	When we compared intracystic papillary carcinoma with ductal carcinoma in situ vs. without ductal carcinoma in situ, we found that the latter had gain in small loci 5q35.3, 8q24.3 and 21q13.2.	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (54, 78))	('5q35.3', 'Var', (165, 171))	('ductal carcinoma in situ', 'Disease', (54, 78))	('intracystic papillary carcinoma', 'Disease', (17, 48))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (54, 70))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (91, 107))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (91, 115))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (54, 78))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (17, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('8q24.3', 'Var', (173, 179))	('gain', 'PosReg', (146, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (91, 115))	('ductal carcinoma in situ', 'Disease', (91, 115))
5513	23907150	Similarly, when we compared intracystic papillary carcinoma with invasive ductal carcinoma vs. without invasive ductal carcinoma, we found that the latter had two changes, 11q22.1 to 11q23.3 loss and chr5 gain.	('invasive ductal carcinoma', 'Disease', (65, 90))	('intracystic papillary carcinoma', 'Disease', (28, 59))	('invasive ductal carcinoma', 'Disease', (103, 128))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (74, 90))	('loss', 'NegReg', (191, 195))	('chr5', 'CPA', (200, 204))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (28, 59))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (112, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('gain', 'PosReg', (205, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('11q22.1 to 11q23.3', 'Var', (172, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (65, 90))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (103, 128))
5515	23907150	Therefore, we believe that when intracystic papillary carcinoma develops through acquired gains/losses of major chromosomes, it may start with a set of major changes (16p gain, 16q loss, 1q gain and 7q loss) than later acquires another major change (chr5 gain) when progresses into intracystic papillary carcinoma with invasive ductal carcinoma.	('gain', 'PosReg', (171, 175))	('gains/losses', 'PosReg', (90, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (282, 313))	('intracystic papillary carcinoma', 'Disease', (282, 313))	('intracystic papillary carcinoma', 'Disease', (32, 63))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (328, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('gain', 'PosReg', (190, 194))	('16p', 'Var', (167, 170))	('invasive ductal carcinoma', 'Disease', 'MESH:D018270', (319, 344))	('loss', 'NegReg', (181, 185))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (32, 63))	('gains/losses', 'NegReg', (90, 102))	('loss', 'NegReg', (202, 206))	('invasive ductal carcinoma', 'Disease', (319, 344))
5522	23907150	For the pathogenesis of pure intracystic papillary carcinoma vs. intracystic papillary carcinoma with ductal carcinoma in situ, we believe that they both start with major chromosomal changes (16p gain, 16q loss, 1q gain and 7q loss).	('gain', 'PosReg', (196, 200))	('pathogenesis', 'biological_process', 'GO:0009405', ('8', '20'))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (102, 126))	('ductal carcinoma in situ', 'Disease', (102, 126))	('intracystic papillary carcinoma', 'Disease', (65, 96))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (102, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (102, 126))	('gain', 'PosReg', (215, 219))	('intracystic papillary carcinoma', 'Disease', (29, 60))	('16p', 'Var', (192, 195))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (65, 96))	('pure', 'molecular_function', 'GO:0034023', ('24', '28'))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (29, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
5523	23907150	When intracystic papillary carcinoma was compared with concurrent ductal carcinoma in situ, we found that the former had 1q21.3-1q23 gain.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (5, 36))	('1q21.3-1q23', 'Var', (121, 132))	('intracystic papillary carcinoma', 'Disease', (5, 36))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (66, 90))	('ductal carcinoma in situ', 'Disease', (66, 90))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (66, 82))	('gain', 'PosReg', (133, 137))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
5525	23907150	Chromosomal rearrangements involving the NTRK1 gene are found in approximately 10% of thyroid papillary carcinoma.	('thyroid papillary carcinoma', 'Disease', 'MESH:D000077273', (86, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('NTRK1', 'Gene', (41, 46))	('thyroid papillary carcinoma', 'Phenotype', 'HP:0002895', (86, 113))	('NTRK1', 'Gene', '4914', (41, 46))	('thyroid papillary carcinoma', 'Disease', (86, 113))	('found', 'Reg', (56, 61))	('Chromosomal rearrangements', 'Var', (0, 26))
5527	23907150	PRCC is one of several genes that are involved in the renal cell carcinoma type that is associated with Xp11.2 translocations / TFE3 gene fusions.	('PRCC', 'Gene', '5546', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('translocations', 'Var', (111, 125))	('PRCC', 'Gene', (0, 4))	('TFE3', 'Gene', '7030', (128, 132))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (54, 74))	('renal cell carcinoma type', 'Disease', (54, 79))	('associated', 'Reg', (88, 98))	('Xp11.2', 'Gene', (104, 110))	('TFE3', 'Gene', (128, 132))	('renal cell carcinoma type', 'Disease', 'MESH:C538614', (54, 79))
5532	23907150	They suggested that this determination could be related to other changes including genetic aberrations other than gene copy number aberrations (ie copy number silent loss of heterozygosity events, somatic mutations or fusion genes), epigenetic changes or distinctive tumor-microenvironment interactions.	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('epigenetic changes', 'Var', (233, 251))	('loss of heterozygosity', 'NegReg', (166, 188))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('copy number silent', 'Var', (147, 165))	('fusion genes', 'Var', (218, 230))
5535	23907150	When compared ductal carcinoma in situ with concurrent intracystic papillary carcinoma, we found that the former had a set of copy number changes including 8q22.2 to 8q22.3 gain, 8q24.3 gain, 11q25 loss, and 12q24.31 to 12q24.33 loss.	('8q24.3', 'Var', (179, 185))	('12q24.31 to 12q24.33', 'Var', (208, 228))	('8q22.2 to 8q22.3', 'Var', (156, 172))	('loss', 'NegReg', (198, 202))	('loss', 'NegReg', (229, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (55, 86))	('intracystic papillary carcinoma', 'Disease', (55, 86))	('gain', 'PosReg', (186, 190))	('11q25', 'Var', (192, 197))	('ductal carcinoma in situ', 'Disease', 'MESH:D002285', (14, 38))	('ductal carcinoma in situ', 'Disease', (14, 38))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (14, 30))	('gain', 'PosReg', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (14, 38))
5539	23907150	Intracystic papillary carcinoma shares major copy number variation with minimal but significant genetic variation that may play a critical role in the pathogenesis and biology of this tumor.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('copy number variation', 'Var', (45, 66))	('play', 'Reg', (123, 127))	('Intracystic papillary carcinoma', 'Disease', 'MESH:D002291', (0, 31))	('tumor', 'Disease', (184, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Intracystic papillary carcinoma', 'Disease', (0, 31))	('pathogenesis', 'biological_process', 'GO:0009405', ('151', '163'))
5576	32495158	The CAL-54 cell line conforms with copy number amplifications (CNAs) in several key kidney cancer genes.	('kidney cancer', 'Disease', (84, 97))	('kidney cancer', 'Disease', 'MESH:D007680', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('copy number amplifications', 'Var', (35, 61))	('CAL-54', 'CellLine', 'CVCL:1111', (4, 10))
5609	32495158	The more comprehensive gene set (gs-ifng-m14004) had the highest enrichment score (ES) in SKCM tissues (ES = 0.825, FDR, q value 0.0; FWER p value 0.0) (Fig.	('SKCM', 'Disease', (90, 94))	('ES', 'Chemical', '-', (104, 106))	('ES', 'Chemical', '-', (83, 85))	('gs-ifng-m14004', 'Var', (33, 47))
5622	32495158	In SKCM with low PD-L1-mRNA tissue levels, patient survival was significantly shorter than in those with high-level PD-L1-mRNA levels (OS: HR 1.984; p < 0.0001 and DFS: HR 1.436; p = 0.0046).	('patient', 'Species', '9606', (43, 50))	('low', 'Var', (13, 16))	('PD-L1-mRNA', 'MPA', (17, 27))	('shorter', 'NegReg', (78, 85))	('patient survival', 'CPA', (43, 59))
5635	32495158	In IFN-gamma-responsive tumors such as melanoma and ccRCC, patients with high PD-L1-mRNA tissue levels had longer OS and DFS than those with low PD-L1-mRNA levels.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('DFS', 'CPA', (121, 124))	('melanoma', 'Disease', (39, 47))	('PD-L1-mRNA', 'MPA', (78, 88))	('RCC', 'Disease', (54, 57))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('longer', 'PosReg', (107, 113))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))
5647	32495158	Conversely, tandem amplification of PD-L1/PD-L2 and JAK2, causing enhanced IFN-gamma signaling, was associated with high responsiveness towards immune checkpoint blockade in Hodgkin's lymphoma.	('responsiveness', 'MPA', (121, 135))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (174, 192))	("Hodgkin's lymphoma", 'Disease', (174, 192))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (174, 192))	('enhanced', 'PosReg', (66, 74))	('PD-L2', 'Gene', (42, 47))	('PD-L2', 'Gene', '80380', (42, 47))	('IFN-gamma signaling', 'MPA', (75, 94))	('tandem amplification', 'Var', (12, 32))	('JAK', 'molecular_function', 'GO:0004713', ('52', '55'))	('JAK2', 'Gene', (52, 56))
5650	32495158	In melanoma, a high PD-L1 protein score was associated with shorter survival.	('high', 'Var', (15, 19))	('PD-L1 protein', 'Protein', (20, 33))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('survival', 'MPA', (68, 76))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('shorter', 'NegReg', (60, 67))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
5651	32495158	In particular, a high PD-L1 score, considering PD-L1 in cancer cells or macrophages, predicted both worse outcome and, in a mouse model, the knockout of PD-L1 or of IFN-gamma signaling by STAT1-knockdown in tumor cells prolonged survival.	('PD-L1', 'Gene', (153, 158))	('prolonged', 'PosReg', (219, 228))	('signaling', 'biological_process', 'GO:0023052', ('175', '184'))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mouse', 'Species', '10090', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('survival', 'CPA', (229, 237))	('knockout', 'Var', (141, 149))
5652	32495158	Furthermore, in RCC, a high PD-L1 protein score was predictive of poor outcome in patients who received anti-angiogenic TKI treatment with sunitinib or pazopanib (COMPARZ trial).	('PD-L1', 'Protein', (28, 33))	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('high', 'Var', (23, 27))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('patients', 'Species', '9606', (82, 90))	('pazopanib', 'Chemical', 'MESH:C516667', (152, 161))	('sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))
5674	31867475	Type 2 PRCC tends to have mutations in CDKN2A, SETD2, BAP1, PBRM1, TERT, NF2, FH, and NRF2-ARE pathway genes.	('TERT', 'Gene', (67, 71))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('CDKN2A', 'Gene', (39, 45))	('Type 2 PRCC', 'Disease', (0, 11))	('SETD2', 'Gene', '29072', (47, 52))	('NRF2', 'Gene', '4780', (86, 90))	('TERT', 'Gene', '7015', (67, 71))	('PBRM1', 'Gene', (60, 65))	('SETD2', 'Gene', (47, 52))	('NF2', 'Gene', (73, 76))	('CDKN2A', 'Gene', '1029', (39, 45))	('PBRM1', 'Gene', '55193', (60, 65))	('NRF2', 'Gene', (86, 90))	('BAP1', 'Gene', '8314', (54, 58))	('mutations', 'Var', (26, 35))	('PRCC', 'Phenotype', 'HP:0006766', (7, 11))	('NF2', 'Gene', '4771', (73, 76))	('BAP1', 'Gene', (54, 58))
5676	31867475	MET mutations are also found in other malignancies, such as hepatocellular carcinomas (HCC), lung cancer, breast cancer, colorectal cancer (CRC), head and neck squamous cell cancers (HNSCC), gastric carcinomas (GC), and cancers of unknown primary origin.	('CRC', 'Disease', (140, 143))	('colorectal cancer', 'Disease', (121, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HCC', 'Phenotype', 'HP:0001402', (87, 90))	('MET mutations', 'Var', (0, 13))	('neck squamous cell cancers', 'Disease', 'MESH:D002294', (155, 181))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('gastric carcinomas', 'Disease', 'MESH:D013274', (191, 209))	('gastric carcinomas', 'Disease', (191, 209))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('lung cancer', 'Disease', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('neck squamous cell cancers', 'Disease', (155, 181))	('CRC', 'Disease', 'MESH:D015179', (140, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('found', 'Reg', (23, 28))	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('malignancies', 'Disease', (38, 50))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', (220, 227))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (60, 85))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('neck', 'cellular_component', 'GO:0044326', ('155', '159'))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (160, 181))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (60, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('hepatocellular carcinomas', 'Disease', (60, 85))
5680	31867475	This interaction is further evidenced in non-small cell lung carcinomas (NSCLC) with acquired resistance to EGFR inhibitors due to amplifications in MET.	('EGFR', 'molecular_function', 'GO:0005006', ('108', '112'))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (41, 71))	('MET', 'Var', (149, 152))	('SCLC', 'Disease', 'MESH:D018288', (74, 78))	('SCLC', 'Disease', (74, 78))	('lung carcinomas', 'Disease', (56, 71))	('NSCLC', 'Disease', (73, 78))	('amplifications', 'Var', (131, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('SCLC', 'Phenotype', 'HP:0030357', (74, 78))	('lung carcinomas', 'Disease', 'MESH:D008175', (56, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (45, 71))
5688	31867475	For ccRCC, nivolumab improves OS with patients surviving 25 months with nivolumab versus 19.6 months with everolimus.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('nivolumab', 'Var', (72, 81))	('ccRCC', 'Disease', (4, 9))	('nivolumab', 'Chemical', 'MESH:D000077594', (72, 81))	('nivolumab', 'Chemical', 'MESH:D000077594', (11, 20))
5695	31867475	The phase 3 trial, METEOR, found significant improvement in OS for advanced ccRCC patients who received cabozantinib compared to everolimus (OS 21.4 months vs 17.1 months).	('cabozantinib', 'Chemical', 'MESH:C558660', (104, 116))	('improvement', 'PosReg', (45, 56))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('cabozantinib', 'Var', (104, 116))
5709	31867475	LY3164530 is an anti-EGFR/MET bispecific antibody created by fusing a cetuximab variable fragment to an emibetuzumab heavy chain.	('LY3164530', 'Var', (0, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (70, 79))	('cetuximab', 'Gene', (70, 79))	('LY3164530', 'Chemical', '-', (0, 9))	('antibody', 'cellular_component', 'GO:0042571', ('41', '49'))	('emibetuzumab', 'Chemical', 'MESH:C000599789', (104, 116))	('antibody', 'cellular_component', 'GO:0019814', ('41', '49'))	('antibody', 'cellular_component', 'GO:0019815', ('41', '49'))	('EGFR', 'molecular_function', 'GO:0005006', ('21', '25'))	('antibody', 'molecular_function', 'GO:0003823', ('41', '49'))
5728	25906110	In the training stage, the expression levels of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival, whereas mir-200c, mir-127, mir-34a, and mir-181c were identified by multivariate Cox regression analyses as potential independent prognostic factors in pRCC.	('mir-127', 'Gene', (248, 255))	('mir-200c', 'Gene', '406985', (238, 246))	('mir-127', 'Gene', '406914', (248, 255))	('pRCC', 'Gene', '5546', (382, 386))	('mir-141', 'Gene', (115, 122))	('mir-200c', 'Gene', (105, 113))	('expression', 'MPA', (27, 37))	('patient', 'Disease', (212, 219))	('mir-1468', 'Var', (134, 142))	('mir-200c', 'Gene', (238, 246))	('mir-181c', 'Gene', (270, 278))	('mir-379', 'Gene', '494328', (68, 75))	('pRCC', 'Phenotype', 'HP:0006766', (382, 386))	('mir-127', 'Gene', (77, 84))	('mir-127', 'Gene', '406914', (77, 84))	('mir-181c', 'Gene', (144, 152))	('mir-181c', 'Gene', '406957', (270, 278))	('Cox', 'Gene', '1351', (311, 314))	('pRCC', 'Gene', (382, 386))	('mir-34a', 'Gene', (257, 264))	('mir-1180', 'Var', (154, 162))	('mir-181c', 'Gene', '406957', (144, 152))	('mir-452', 'Gene', (86, 93))	('mir-3074', 'Var', (124, 132))	('mir-34a', 'Gene', '407040', (257, 264))	('patient', 'Species', '9606', (212, 219))	('RCC', 'Phenotype', 'HP:0005584', (383, 386))	('mir-199a', 'Var', (95, 103))	('mir-34a', 'Gene', (168, 175))	('mir-134', 'Gene', '406924', (59, 66))	('Cox', 'Gene', (311, 314))	('mir-141', 'Gene', '406933', (115, 122))	('mir-34a', 'Gene', '407040', (168, 175))	('associated with', 'Reg', (196, 211))	('mir-379', 'Gene', (68, 75))	('mir-200c', 'Gene', '406985', (105, 113))	('mir-452', 'Gene', '574412', (86, 93))	('mir-134', 'Gene', (59, 66))
5757	25906110	As indicated in the univariate Cox regression analyses (Table 2), a total of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were significantly associated with patient survival in pRCC, which were further confirmed by Kaplan-Meier survival analyses (Figures 2 and 3).	('mir-452', 'Gene', (115, 122))	('mir-34a', 'Gene', (197, 204))	('Cox', 'Gene', (31, 34))	('mir-3074', 'Var', (153, 161))	('mir-134', 'Gene', '406924', (88, 95))	('mir-34a', 'Gene', '407040', (197, 204))	('associated with', 'Reg', (225, 240))	('mir-141', 'Gene', '406933', (144, 151))	('mir-379', 'Gene', (97, 104))	('mir-134', 'Gene', (88, 95))	('mir-200c', 'Gene', '406985', (134, 142))	('mir-452', 'Gene', '574412', (115, 122))	('mir-141', 'Gene', (144, 151))	('mir-1180', 'Var', (183, 191))	('pRCC', 'Gene', '5546', (261, 265))	('mir-1468', 'Var', (163, 171))	('mir-200c', 'Gene', (134, 142))	('RCC', 'Phenotype', 'HP:0005584', (262, 265))	('mir-379', 'Gene', '494328', (97, 104))	('pRCC', 'Phenotype', 'HP:0006766', (261, 265))	('mir-181c', 'Gene', (173, 181))	('Cox', 'Gene', '1351', (31, 34))	('patient', 'Species', '9606', (241, 248))	('pRCC', 'Gene', (261, 265))	('mir-127', 'Gene', (106, 113))	('mir-181c', 'Gene', '406957', (173, 181))	('mir-127', 'Gene', '406914', (106, 113))	('mir-199a', 'Var', (124, 132))
5767	25906110	As an endogenous class of small, noncoding RNAs, miRNAs have been documented to be involved in a wide range of pathophysiological processes including carcinogenesis and metastasis.	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('metastasis', 'CPA', (169, 179))	('carcinogenesis', 'Disease', (150, 164))	('involved', 'Reg', (83, 91))	('miRNAs', 'Var', (49, 55))
5772	25906110	In the training stage of survival analysis, a summary of 12 miRNAs (mir-134, mir-379, mir-127, mir-452, mir-199a, mir-200c, mir-141, mir-3074, mir-1468, mir-181c, mir-1180, and mir-34a) were demonstrated to be significantly associated with prognosis by univariate Cox regression and Kaplan-Meier survival analyses.	('mir-200c', 'Gene', (114, 122))	('mir-379', 'Gene', '494328', (77, 84))	('associated', 'Reg', (224, 234))	('mir-127', 'Gene', (86, 93))	('mir-127', 'Gene', '406914', (86, 93))	('mir-181c', 'Gene', (153, 161))	('mir-1180', 'Var', (163, 171))	('mir-181c', 'Gene', '406957', (153, 161))	('mir-452', 'Gene', (95, 102))	('mir-3074', 'Var', (133, 141))	('mir-199a', 'Var', (104, 112))	('mir-141', 'Gene', '406933', (124, 131))	('mir-379', 'Gene', (77, 84))	('mir-34a', 'Gene', (177, 184))	('Cox', 'Gene', '1351', (264, 267))	('mir-34a', 'Gene', '407040', (177, 184))	('mir-134', 'Gene', '406924', (68, 75))	('mir-200c', 'Gene', '406985', (114, 122))	('mir-141', 'Gene', (124, 131))	('mir-452', 'Gene', '574412', (95, 102))	('mir-134', 'Gene', (68, 75))	('Cox', 'Gene', (264, 267))	('mir-1468', 'Var', (143, 151))
5777	25906110	However, the high expression of mir-200c was proved to be associated with a poor prognosis in pRCC, which were in consistent with the reports in other malignancies such as breast cancer, colorectal cancer, and ovarian cancer.	('colorectal cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mir-200c', 'Gene', '406985', (32, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('mir-200c', 'Gene', (32, 40))	('high', 'Var', (13, 17))	('malignancies', 'Disease', 'MESH:D009369', (151, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('malignancies', 'Disease', (151, 163))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('ovarian cancer', 'Disease', (210, 224))	('pRCC', 'Gene', '5546', (94, 98))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('breast cancer', 'Disease', (172, 185))	('associated', 'Reg', (58, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (187, 204))	('pRCC', 'Phenotype', 'HP:0006766', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('pRCC', 'Gene', (94, 98))
5915	21304509	Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle.	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (142, 160))	('TCA) cycle', 'biological_process', 'GO:0006099', ('162', '172'))	('germline mutation', 'Var', (61, 78))	('fumarate hydratase', 'Gene', '2271', (100, 118))	('FH', 'Gene', '2271', (120, 122))	('TCA', 'Chemical', 'MESH:D014233', (162, 165))	('fumarate hydratase', 'Gene', (100, 118))	('patient', 'Species', '9606', (23, 30))
5918	21304509	pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy.	('arising in', 'Reg', (7, 17))	('mTORC1', 'Gene', '382056', (157, 163))	('mutation', 'Var', (53, 61))	('renal cell cancer', 'Phenotype', 'HP:0005584', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('pRCC', 'Gene', (0, 4))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (74, 121))	('mTORC1', 'cellular_component', 'GO:0031931', ('157', '163'))	('patient', 'Species', '9606', (20, 27))	('FH', 'Gene', '2271', (50, 52))	('mTORC1', 'Gene', (157, 163))	('pRCC', 'Gene', '5546', (0, 4))
5940	21304509	HLRCC is a syndrome with an autosomal dominant pattern of inheritance caused by germline loss-of-function mutations in the gene encoding fumarate hydratase (FH).	('loss-of-function', 'NegReg', (89, 105))	('fumarate hydratase', 'Gene', '2271', (137, 155))	('HLRCC', 'Disease', (0, 5))	('fumarate hydratase', 'Gene', (137, 155))	('mutations', 'Var', (106, 115))	('FH', 'Gene', '2271', (157, 159))
5946	21304509	The mutation resulted in a nonconservative substitution of an evolutionarily conserved residue (Asp341Asn).	('Asp341Asn', 'Var', (96, 105))	('resulted in', 'Reg', (13, 24))	('Asp341Asn', 'SUBSTITUTION', 'None', (96, 105))
5949	21304509	FH functions as a tetramer, and studies of the previously reported crystal structure and reconstitution experiments suggested that the patient's mutation interfered with oligomerization and that mutant FH did not form stable tetramers (Box 1, Figure 4).	('FH', 'Gene', '2271', (0, 2))	('patient', 'Species', '9606', (135, 142))	('oligomerization', 'MPA', (170, 185))	('FH', 'Gene', '2271', (202, 204))	('interfered', 'NegReg', (154, 164))	('mutant', 'Var', (195, 201))	('mutation', 'Var', (145, 153))
5957	21304509	Germline FH mutations are uncommon, and there is no established treatment for metastatic pRCC-2 in HLRCC patients.	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (12, 21))	('pRCC', 'Gene', (89, 93))	('FH', 'Gene', '2271', (9, 11))	('pRCC', 'Gene', '5546', (89, 93))
5967	21304509	Thus, 2DG-6-phosphate acts as a competitive inhibitor of glucose-6-phosphate isomerase, which catalyzes the next step in glycolysis, as well as of glucose-6-phosphate dehydrogenase, which is involved in the pentose phosphate pathway.	('2DG-6-phosphate', 'Chemical', 'MESH:C015785', (6, 21))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (147, 180))	('pentose phosphate', 'Chemical', 'MESH:D010428', (207, 224))	('glucose-6-phosphate isomerase', 'Gene', (57, 86))	('glucose-6-phosphate isomerase', 'Gene', '2821', (57, 86))	('pentose phosphate pathway', 'biological_process', 'GO:0006098', ('207', '232'))	('glycolysis', 'biological_process', 'GO:0006096', ('121', '131'))	('2DG-6-phosphate', 'Var', (6, 21))	('glucose-6-phosphate dehydrogenase', 'Gene', (147, 180))
5973	21304509	Furthermore, there have been reports of mutations in patients that not only result in loss-of-function, but that are also dominant-negative and interfere with the function of the wild-type protein encoded by the remaining wild-type allele.	('protein', 'cellular_component', 'GO:0003675', ('189', '196'))	('patients', 'Species', '9606', (53, 61))	('loss-of-function', 'NegReg', (86, 102))	('mutations', 'Var', (40, 49))	('interfere', 'NegReg', (144, 153))	('function', 'MPA', (163, 171))
5974	21304509	While our studies suggested that Asp341Asn interfered with tetramerization, suggesting that it may not act in a dominant-negative fashion, further studies would be required to exclude this possibility.	('Asp341Asn', 'Var', (33, 42))	('interfered', 'NegReg', (43, 53))	('Asp341Asn', 'SUBSTITUTION', 'None', (33, 42))	('tetramerization', 'MPA', (59, 74))
5994	21304509	Despite the fact that the FH mutation seen in the patient was not previously associated with HLRCC, the diagnosis of HLRCC was supported by other evidence.	('mutation', 'Var', (29, 37))	('HLRCC', 'Disease', (93, 98))	('FH', 'Gene', '2271', (26, 28))	('patient', 'Species', '9606', (50, 57))	('associated', 'Reg', (77, 87))
5997	21304509	These data suggest that pRCC-2 probably developed as a result of a pre-disposition conferred by a germline loss-of-function mutation in the FH tumor suppressor gene.	('pRCC', 'Gene', '5546', (24, 28))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('143', '159'))	('FH tumor', 'Disease', 'MESH:D006938', (140, 148))	('pRCC', 'Gene', (24, 28))	('pre', 'molecular_function', 'GO:0003904', ('67', '70'))	('mutation', 'Var', (124, 132))	('FH tumor', 'Disease', (140, 148))	('loss-of-function', 'NegReg', (107, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('143', '159'))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
5999	21304509	The BRCA1/2 proteins are required for DNA repair by homologous recombination, and inactivation of this pathway renders cells dependent on nonhomologous DNA repair mechanisms, which, when inhibited, cause selective tumor cell death.	('DNA repair', 'biological_process', 'GO:0006281', ('152', '162'))	('BRCA1/2', 'Gene', '672;675', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('homologous recombination', 'biological_process', 'GO:0035825', ('52', '76'))	('DNA repair', 'biological_process', 'GO:0006281', ('38', '48'))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cell death', 'biological_process', 'GO:0008219', ('220', '230'))	('DNA', 'cellular_component', 'GO:0005574', ('152', '155'))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('tumor', 'Disease', (214, 219))	('death', 'Disease', 'MESH:D003643', (225, 230))	('death', 'Disease', (225, 230))	('inactivation', 'Var', (82, 94))	('BRCA1/2', 'Gene', (4, 11))
6003	21304509	Given the indispensable nature of ATP for basic cellular processes, such as the generation and maintenance of a membrane potential and protein translation, disruption of glycolysis and ATP production in tumor cells would be expected to result in their demise.	('disruption', 'Var', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('glycolysis', 'MPA', (170, 180))	('ATP', 'Chemical', 'MESH:D000255', (34, 37))	('result in', 'Reg', (236, 245))	('ATP', 'Chemical', 'MESH:D000255', (185, 188))	('protein translation', 'biological_process', 'GO:0006412', ('135', '154'))	('protein', 'cellular_component', 'GO:0003675', ('135', '142'))	('membrane', 'cellular_component', 'GO:0016020', ('112', '120'))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('glycolysis', 'biological_process', 'GO:0006096', ('170', '180'))	('protein translation', 'MPA', (135, 154))
6005	21304509	Our results showed that, at pharmacologically relevant concentrations, 2DG activates AMP-activated protein kinase (AMPK) in FH-deficient cells, leading to AMPK-mediated inhibition of mTORC1.	('2DG', 'Chemical', 'MESH:D003847', (71, 74))	('AMPK', 'molecular_function', 'GO:0050405', ('115', '119'))	('AMPK', 'molecular_function', 'GO:0004691', ('155', '159'))	('AMPK', 'Gene', (155, 159))	('FH-deficient', 'Disease', (124, 136))	('AMPK', 'Gene', (115, 119))	('AMPK', 'molecular_function', 'GO:0004691', ('115', '119'))	('FH-deficient', 'Disease', 'MESH:D006938', (124, 136))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('AMP-activated protein kinase', 'Gene', '5562', (85, 113))	('AMPK', 'molecular_function', 'GO:0047322', ('155', '159'))	('mTORC1', 'Gene', (183, 189))	('AMPK', 'molecular_function', 'GO:0047322', ('115', '119'))	('activates', 'PosReg', (75, 84))	('mTORC1', 'Gene', '382056', (183, 189))	('AMPK', 'Gene', '5562', (155, 159))	('AMPK', 'Gene', '5562', (115, 119))	('mTORC1', 'cellular_component', 'GO:0031931', ('183', '189'))	('2DG', 'Var', (71, 74))	('AMPK', 'molecular_function', 'GO:0050405', ('155', '159'))	('AMP-activated protein kinase', 'Gene', (85, 113))
6011	21304509	While DNA testing of the patient's parents was not performed, the absence of HLRCC symptoms in the parents suggests that the mutation occurred de novo.	('HLRCC', 'Disease', (77, 82))	('DNA', 'cellular_component', 'GO:0005574', ('6', '9'))	('patient', 'Species', '9606', (25, 32))	('mutation', 'Var', (125, 133))
6012	21304509	The type of mutation (nonconservative missense mutation of a universally conserved residue), combined with the results of structural studies, reconstitution experiments and functional studies in the tumor, strongly suggested that this was a loss-of-function mutation.	('tumor', 'Disease', (199, 204))	('loss-of-function', 'NegReg', (241, 257))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutation', 'Var', (12, 20))
6017	21304509	This dependency on glycolysis would be expected to be further exacerbated by mutations disrupting the TCA cycle.	('glycolysis', 'biological_process', 'GO:0006096', ('19', '29'))	('TCA', 'Pathway', (102, 105))	('TCA', 'Chemical', 'MESH:D014233', (102, 105))	('glycolysis', 'MPA', (19, 29))	('TCA cycle', 'biological_process', 'GO:0006099', ('102', '111'))	('mutations', 'Var', (77, 86))	('disrupting', 'NegReg', (87, 97))	('exacerbated', 'PosReg', (62, 73))
6024	21304509	Our data show that, at pharmacologically achievable concentrations, 2DG activated AMPK, resulting in AMPK-dependent inhibition of mTORC1 in FH-deficient cells.	('AMPK', 'molecular_function', 'GO:0050405', ('101', '105'))	('AMPK', 'molecular_function', 'GO:0047322', ('82', '86'))	('FH-deficient', 'Disease', 'MESH:D006938', (140, 152))	('AMPK', 'molecular_function', 'GO:0004691', ('82', '86'))	('AMPK', 'molecular_function', 'GO:0004691', ('101', '105'))	('mTORC1', 'Gene', (130, 136))	('AMPK', 'Gene', '5562', (82, 86))	('AMPK', 'molecular_function', 'GO:0047322', ('101', '105'))	('AMPK', 'Gene', (82, 86))	('2DG', 'Chemical', 'MESH:D003847', (68, 71))	('inhibition', 'NegReg', (116, 126))	('2DG', 'Var', (68, 71))	('mTORC1', 'cellular_component', 'GO:0031931', ('130', '136'))	('AMPK', 'molecular_function', 'GO:0050405', ('82', '86'))	('mTORC1', 'Gene', '382056', (130, 136))	('FH-deficient', 'Disease', (140, 152))	('AMPK', 'Gene', '5562', (101, 105))	('AMPK', 'Gene', (101, 105))
6031	21304509	We found that Asp341, an acidic, negatively charged amino acid, was involved in an intramolecular interaction with Lys337, a basic, positively charged residue, and that this interaction was buried deep within the intermolecular interface (Figure 4a).	('interaction', 'Interaction', (98, 109))	('Asp341', 'Chemical', '-', (14, 20))	('Asp341', 'Var', (14, 20))	('involved in', 'Reg', (68, 79))	('Lys337', 'Var', (115, 121))	('Lys337', 'Chemical', '-', (115, 121))
6032	21304509	A substitution of Asp341 for Asn, an uncharged amino acid, would leave Lys337 unpaired, resulting in an energetically unfavorable net positive charge in the hydrophobic intermolecular interface, which would be expected to destabilize the tetramer.	('Asp341 for Asn', 'Mutation', 'rs11545655', (18, 32))	('tetramer', 'Interaction', (238, 246))	('leave', 'Reg', (65, 70))	('substitution', 'Var', (2, 14))	('destabilize', 'NegReg', (222, 233))	('Asp341', 'Var', (18, 24))	('Lys337', 'Var', (71, 77))	('Lys337', 'Chemical', '-', (71, 77))
6033	21304509	To determine experimentally whether FHAsp341Asn would form stable tetrameric complexes, the mutation was engineered by site-directed mutagenesis and introduced into FH-deficient UOK262 cells (Figure 4b).	('FHAsp341Asn', 'Var', (36, 47))	('UOK262', 'CellLine', 'CVCL:1D72', (178, 184))	('FH-deficient', 'Disease', 'MESH:D006938', (165, 177))	('mutagenesis', 'biological_process', 'GO:0006280', ('133', '144'))	('FH-deficient', 'Disease', (165, 177))
6048	21304509	Indeed, at pharmacologically relevant concentrations, 2DG led to the activation of AMPK in FH-deficient cells (Figure 7).	('2DG', 'Chemical', 'MESH:D003847', (54, 57))	('2DG', 'Var', (54, 57))	('FH-deficient', 'Disease', (91, 103))	('AMPK', 'Gene', '5562', (83, 87))	('AMPK', 'molecular_function', 'GO:0004691', ('83', '87'))	('AMPK', 'molecular_function', 'GO:0050405', ('83', '87'))	('FH-deficient', 'Disease', 'MESH:D006938', (91, 103))	('AMPK', 'Gene', (83, 87))	('AMPK', 'molecular_function', 'GO:0047322', ('83', '87'))	('activation', 'PosReg', (69, 79))
6052	21304509	These data suggest that, at pharmacologically relevant concentrations, 2DG activates AMPK in FH-deficient cells and leads to inhibition of mTORC1 in an AMPK-dependent manner.	('2DG', 'Chemical', 'MESH:D003847', (71, 74))	('mTORC1', 'Gene', (139, 145))	('AMPK', 'Gene', (85, 89))	('mTORC1', 'Gene', '382056', (139, 145))	('AMPK', 'molecular_function', 'GO:0047322', ('152', '156'))	('inhibition', 'NegReg', (125, 135))	('AMPK', 'molecular_function', 'GO:0050405', ('85', '89'))	('FH-deficient', 'Disease', (93, 105))	('FH-deficient', 'Disease', 'MESH:D006938', (93, 105))	('AMPK', 'Gene', (152, 156))	('AMPK', 'molecular_function', 'GO:0004691', ('85', '89'))	('AMPK', 'Gene', '5562', (85, 89))	('AMPK', 'molecular_function', 'GO:0050405', ('152', '156'))	('activates', 'PosReg', (75, 84))	('2DG', 'Var', (71, 74))	('AMPK', 'molecular_function', 'GO:0047322', ('85', '89'))	('mTORC1', 'cellular_component', 'GO:0031931', ('139', '145'))	('AMPK', 'molecular_function', 'GO:0004691', ('152', '156'))	('AMPK', 'Gene', '5562', (152, 156))
6163	30031457	A recent study by the authors confirmed segmental inversion enhancement as an independent predictor of oncocytoma.	('men', 'Species', '9606', (67, 70))	('segmental inversion', 'Var', (40, 59))	('men', 'Species', '9606', (43, 46))	('oncocytoma', 'Disease', (103, 113))	('oncocytoma', 'Disease', 'MESH:D018249', (103, 113))
6205	28489074	Clustering copy number alterations shows that most cell lines resemble ccRCC, a few (including some often used as models of ccRCC) resemble pRCC, and none resemble chRCC.	('RCC', 'Disease', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))	('copy', 'Var', (11, 15))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
6207	28489074	We stratify mutations and copy number alterations for important kidney cancer genes by the consistency between databases, and classify cell lines into established gene expression-based indolent and aggressive subtypes.	('mutations', 'Var', (12, 21))	('gene expression', 'biological_process', 'GO:0010467', ('163', '178'))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('kidney cancer', 'Phenotype', 'HP:0009726', (64, 77))	('kidney cancer', 'Disease', 'MESH:D007680', (64, 77))	('kidney cancer', 'Disease', (64, 77))
6223	28489074	Recurrent copy number alterations (CNAs) of chromosomes 5, 8 and 14 have been identified as additional pathogenic mechanisms of ccRCC.	('CNA', 'Gene', (35, 38))	('CNA', 'Gene', '19055', (35, 38))	('copy number alterations', 'Var', (10, 33))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))
6234	28489074	This is in agreement with recent work reporting discrepancies in the detection of missense mutations in cell lines common to CCLE and CCLP (57% conformity).	('CCLE', 'Chemical', '-', (125, 129))	('CCLE', 'Disease', (125, 129))	('missense mutations', 'Var', (82, 100))
6249	28489074	These tumours also display a higher extent of copy number aberrations (mean fraction genome altered: 19% versus 12%), and more frequent mutations in genes such as BAP1 (12.3% versus 5.4%), SETD2 (12.7% versus 8.1%) and MTOR (6% versus 4.7%), which are associated with more aggressive disease (though only BAP1 has a statistically significant difference:P value 0.025, Fisher's exact test).	('BAP1', 'Gene', (305, 309))	('MTOR', 'Gene', '2475', (219, 223))	('aggressive disease', 'Disease', 'MESH:D001523', (273, 291))	('BAP1', 'Gene', '8314', (305, 309))	('BAP1', 'Gene', '8314', (163, 167))	('SETD2', 'Gene', '29072', (189, 194))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('aggressive disease', 'Disease', (273, 291))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('copy', 'MPA', (46, 50))	('mutations', 'Var', (136, 145))	('BAP1', 'Gene', (163, 167))	('MTOR', 'Gene', (219, 223))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('SETD2', 'Gene', (189, 194))	('tumours', 'Disease', (6, 13))
6254	28489074	In the set of 1,508 overlapping genes profiled for mutations by CCLE, CCLP and TCGA, the median number of mutated genes is 40 in CCLE kidney cell lines (minimum: 22, maximum: 92) and 26 in CCLP kidney cell lines (min 5, max 72) compared to 6 (min 0, max 27) in TCGA ccRCC tumours.	('mutations', 'Var', (51, 60))	('ccRCC tumours', 'Disease', (266, 279))	('tumour', 'Phenotype', 'HP:0002664', (272, 278))	('ccRCC tumours', 'Disease', 'MESH:D009369', (266, 279))	('tumours', 'Phenotype', 'HP:0002664', (272, 279))	('CCLE', 'Chemical', '-', (64, 68))	('CCLE', 'Chemical', '-', (129, 133))
6260	28489074	In the 16 important kidney cancer genes covered by CCLE, the CCLE kidney cell lines had a range of 0-3 mutations and a median of 1 mutation, with ACHN, KMRC1, KMRC3, SNU349, SNU1272, RCC10RGB and TUHR4TKB showing no mutations in these key genes.	('CCLE', 'Chemical', '-', (61, 65))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('kidney cancer', 'Phenotype', 'HP:0009726', (20, 33))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('CCLE', 'Chemical', '-', (51, 55))	('kidney cancer', 'Disease', (20, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (20, 33))
6261	28489074	None of the CCLP cell lines had a mutation in any of the genes FLCN, ARID1A, MICALCL, SLC1A3, STAG2 or TCEB1; while none of the CCLE cell lines had a mutation in FLCN, ARID1A, FLCN, NF2 or TSC1.	('SLC1A3', 'Gene', '6507', (86, 92))	('FLCN', 'Gene', (63, 67))	('NF2', 'Gene', '4771', (182, 185))	('ARID1A', 'Gene', '8289', (69, 75))	('CCLE', 'Chemical', '-', (128, 132))	('TSC1', 'Gene', '7248', (189, 193))	('NF2', 'Gene', (182, 185))	('STAG2', 'Gene', '10735', (94, 99))	('ARID1A', 'Gene', (168, 174))	('FLCN', 'Gene', '201163', (162, 166))	('MICALCL', 'Gene', '84953', (77, 84))	('STAG2', 'Gene', (94, 99))	('FLCN', 'Gene', (162, 166))	('ARID1A', 'Gene', '8289', (168, 174))	('TCEB1', 'Gene', (103, 108))	('MICALCL', 'Gene', (77, 84))	('SLC1A3', 'Gene', (86, 92))	('FLCN', 'Gene', '201163', (176, 180))	('mutation', 'Var', (150, 158))	('FLCN', 'Gene', '201163', (63, 67))	('TCEB1', 'Gene', '6921', (103, 108))	('FLCN', 'Gene', (176, 180))	('ARID1A', 'Gene', (69, 75))	('TSC1', 'Gene', (189, 193))
6263	28489074	Given that VHL is a notoriously challenging gene to sequence, we additionally culled the existing literature for evidence of VHL mutations in the various RCC cell lines (Supplementary Table 1).	('VHL', 'Gene', (125, 128))	('mutations', 'Var', (129, 138))	('VHL', 'Gene', '7428', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', (154, 157))	('VHL', 'Gene', (11, 14))	('VHL', 'Gene', '7428', (11, 14))
6264	28489074	Interestingly, several cell lines that cluster with ccRCC and demonstrate the classical copy number characteristics do not harbour VHL mutations.	('VHL', 'Gene', (131, 134))	('mutations', 'Var', (135, 144))	('VHL', 'Gene', '7428', (131, 134))	('RCC', 'Disease', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
6265	28489074	Furthermore, mutations of mTOR pathway genes including MTOR, TSC1, TSC2, PTEN and PIK3CA are detected in nine (41%) of CCLE and 14 (42%) of the CCLP RCC cell lines.	('RCC', 'Disease', (149, 152))	('CCLE', 'Chemical', '-', (119, 123))	('PTEN', 'Gene', (73, 77))	('MTOR', 'Gene', '2475', (55, 59))	('PIK3CA', 'Gene', (82, 88))	('PTEN', 'Gene', '5728', (73, 77))	('detected', 'Reg', (93, 101))	('mutations', 'Var', (13, 22))	('TSC1', 'Gene', '7248', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('TSC1', 'Gene', (61, 65))	('PIK3CA', 'Gene', '5290', (82, 88))	('mTOR', 'Gene', (26, 30))	('TSC2', 'Gene', '7249', (67, 71))	('mTOR', 'Gene', '2475', (26, 30))	('CCLE', 'Disease', (119, 123))	('TSC2', 'Gene', (67, 71))	('MTOR', 'Gene', (55, 59))
6276	28489074	Taken together, our analysis reveals CAL54 as the only cell line with perfect agreement on mutation and CNAs in key kidney cancer genes, with 769-P and a few other cell lines also showing a high degree of concordance.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (91, 99))	('CNA', 'Gene', '19055', (104, 107))	('kidney cancer', 'Phenotype', 'HP:0009726', (116, 129))	('CNA', 'Gene', (104, 107))	('key kidney cancer', 'Disease', (112, 129))	('key kidney cancer', 'Disease', 'MESH:D007680', (112, 129))
6278	28489074	To quantify 3p loss, we computed the fraction of chromosome 3p where the CNA data supported at least low-level copy number loss (using a log2 ratio).	('CNA', 'Gene', (73, 76))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('copy number loss', 'Var', (111, 127))	('CNA', 'Gene', '19055', (73, 76))
6279	28489074	While this characteristic ccRCC genomic feature is observed in the majority of ccRCC cell lines, 3p loss is absent or significantly diminished in several of them, namely VMRCRCW, SLR20, SLR21, and BFTC909 (as well as the immortalized epithelial cell lines HK2 and HEKTE) in CCLE; and U031, KMRC-1, 786-0, VMRC-RCW, SN12C and BFTC-909 in CCLP (Supplementary Table 2).	('loss', 'NegReg', (100, 104))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('BFTC', 'Chemical', '-', (325, 329))	('absent', 'NegReg', (108, 114))	('BFTC909', 'Var', (197, 204))	('SLR21', 'Var', (186, 191))	('HK2', 'CellLine', 'CVCL:0302', (256, 259))	('RCC', 'Disease', (81, 84))	('CCLE', 'Chemical', '-', (274, 278))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('SLR20', 'Var', (179, 184))	('HK2', 'molecular_function', 'GO:0008256', ('256', '259'))	('CCLE', 'Disease', (274, 278))	('KMRC-1', 'CellLine', 'CVCL:2983', (290, 296))	('BFTC', 'Chemical', '-', (197, 201))	('RCC', 'Disease', (28, 31))	('diminished', 'NegReg', (132, 142))
6280	28489074	Of the cell lines lacking 3p loss, SLR21 and SLR20 in CCLE and SN12C and U031 in CCLP also lack other characteristic features of ccRCC such as chromosomal gains in five and eight or losses in chromosome 14, though SLR21 and U031 do show some gain in 8q.	('U031', 'Var', (73, 77))	('lack', 'NegReg', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('loss', 'NegReg', (29, 33))	('lacking', 'NegReg', (18, 25))	('gain', 'PosReg', (242, 246))	('losses', 'NegReg', (182, 188))	('SN12C', 'Var', (63, 68))	('chromosome', 'cellular_component', 'GO:0005694', ('192', '202'))	('SLR21', 'Var', (35, 40))	('CCLE', 'Chemical', '-', (54, 58))
6288	28489074	In our cluster analysis, ACHN co-segregates with tumours displaying amplifications in chromosomes 7 and 17, furthering the notion that this appears to derive from papillary origins.	('tumours', 'Disease', (49, 56))	('amplifications in', 'Var', (68, 85))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('ACHN', 'Gene', (25, 29))	('tumours', 'Disease', 'MESH:D009369', (49, 56))
6291	28489074	Our results indicate that 786-0 harbours more alterations than A-498 even though both cluster with ccRCC on a copy number level and harbour VHL mutations (Fig.	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('VHL', 'Gene', (140, 143))	('mutations', 'Var', (144, 153))	('VHL', 'Gene', '7428', (140, 143))	('cluster', 'Reg', (86, 93))
6304	28489074	By comparing tumours which cluster with the cell lines based on CNAs with tumours that cluster away from the cell lines, we found that the tumours likely to be best represented by the cell lines carry hallmarks of aggressive disease, such as higher stage, higher grade, greater extent of CNAs, and more frequent mutations in genes such as SETD2, BAP1 and MTOR, which have been associated with more aggressive disease and poorer outcomes.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Disease', (139, 146))	('SETD2', 'Gene', '29072', (339, 344))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Disease', (74, 81))	('CNA', 'Gene', (288, 291))	('tumours', 'Phenotype', 'HP:0002664', (139, 146))	('tumours', 'Disease', 'MESH:D009369', (139, 146))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('CNA', 'Gene', '19055', (288, 291))	('BAP1', 'Gene', '8314', (346, 350))	('hallmarks of aggressive disease', 'Disease', (201, 232))	('aggressive disease', 'Disease', (398, 416))	('CNA', 'Gene', (64, 67))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('aggressive disease', 'Disease', 'MESH:D001523', (398, 416))	('tumours', 'Disease', (13, 20))	('CNA', 'Gene', '19055', (64, 67))	('aggressive disease', 'Disease', 'MESH:D001523', (214, 232))	('BAP1', 'Gene', (346, 350))	('MTOR', 'Gene', (355, 359))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('MTOR', 'Gene', '2475', (355, 359))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('mutations', 'Var', (312, 321))	('SETD2', 'Gene', (339, 344))	('hallmarks of aggressive disease', 'Disease', 'MESH:D001523', (201, 232))
6312	28489074	More specifically, we show that despite clustering with ccRCC, several of these cell lines lack VHL mutations.	('mutations', 'Var', (100, 109))	('lack', 'NegReg', (91, 95))	('VHL', 'Gene', (96, 99))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('VHL', 'Gene', '7428', (96, 99))
6316	28489074	Previous work from our group demonstrated that mTOR pathway activating mutations sensitize patients to rapalogs, hence this new information may now be applied to in vitro work as well.	('activating', 'PosReg', (60, 70))	('patients', 'Species', '9606', (91, 99))	('sensitize', 'Reg', (81, 90))	('mutations', 'Var', (71, 80))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (47, 51))
6317	28489074	We address the discrepancy in genomic data from CCLE and CCLP via a detailed comparison of mutations in 15 key kidney cancer genes, and of CNAs in 18 key kidney cancer genes (Fig.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('kidney cancer', 'Phenotype', 'HP:0009726', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('key kidney cancer', 'Disease', 'MESH:D007680', (107, 124))	('CCLE', 'Chemical', '-', (48, 52))	('key kidney cancer', 'Disease', (150, 167))	('mutations', 'Var', (91, 100))	('CNA', 'Gene', (139, 142))	('CNA', 'Gene', '19055', (139, 142))	('kidney cancer', 'Phenotype', 'HP:0009726', (154, 167))	('key kidney cancer', 'Disease', (107, 124))	('key kidney cancer', 'Disease', 'MESH:D007680', (150, 167))
6319	28489074	Thus, CAL-54 has the most reliable mutation and CNA data for key kidney cancer genes in terms of validation via two independent sources, while 769-P is a close second.	('CNA', 'Gene', '19055', (48, 51))	('kidney cancer', 'Phenotype', 'HP:0009726', (65, 78))	('CNA', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('key kidney cancer', 'Disease', (61, 78))	('mutation', 'Var', (35, 43))	('key kidney cancer', 'Disease', 'MESH:D007680', (61, 78))
6347	28489074	For the analysis of mutation in key kidney cancer genes, we chose not to further filter the CCLE data due to the risk of inadvertently removing mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('key kidney cancer', 'Disease', (32, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (144, 153))	('CCLE', 'Chemical', '-', (92, 96))	('key kidney cancer', 'Disease', 'MESH:D007680', (32, 49))	('kidney cancer', 'Phenotype', 'HP:0009726', (36, 49))
6352	28489074	A log2 (sample intensity/reference intensity) threshold of 0.2 (for amplification, -0.2 for deletion) was used for both the TCGA tumour samples as well as the CCLE cell lines.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('deletion', 'Var', (92, 100))	('tumour', 'Disease', (129, 135))	('CCLE', 'Chemical', '-', (159, 163))
6358	28489074	Tier 1 consists of cases with identical mutations in both CCLE and CCLP.	('mutations', 'Var', (40, 49))	('CCLE', 'Gene', (58, 62))	('CCLP', 'Gene', (67, 71))	('CCLE', 'Chemical', '-', (58, 62))
6359	28489074	Similarly, for CNAs, we defined three tiers using GISTIC scores (+2:high-level amplification, +1:gain, 0:no alteration, -1: shallow loss, -2: deep deletion) for a given gene and CNA.	('deep deletion', 'Var', (142, 155))	('loss', 'NegReg', (132, 136))	('CNA', 'Gene', (15, 18))	('gain', 'PosReg', (97, 101))	('CNA', 'Gene', '19055', (15, 18))	('CNA', 'Gene', (178, 181))	('CNA', 'Gene', '19055', (178, 181))
6392	23942078	It is also found that RSK4 is frequently hypermethylated in endometrial cancer cell lines and in primary endometrial cancers compared with normal endometrial tissue.	('endometrial cancers', 'Disease', (105, 124))	('endometrial cancer', 'Disease', 'MESH:D016889', (105, 123))	('endometrial cancer', 'Disease', 'MESH:D016889', (60, 78))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('endometrial cancer', 'Phenotype', 'HP:0012114', (60, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hypermethylated', 'Var', (41, 56))	('RSK4', 'Gene', (22, 26))	('endometrial cancer', 'Disease', (60, 78))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('endometrial cancer', 'Phenotype', 'HP:0012114', (105, 123))	('endometrial cancers', 'Disease', 'MESH:D016889', (105, 124))
6394	23942078	However, further study shows that RSK4 expression could limit the oncogenic, invasive, and metastatic potential of breast cancer cells.	('oncogenic', 'CPA', (66, 75))	('expression', 'Var', (39, 49))	('limit', 'NegReg', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('RSK4', 'Gene', (34, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
6395	23942078	Nevertheless,) have found that RSK4 overexpression is associated with sunitinib resistance in RCC cell lines, indicating that RSK4 may regulate treatment resistance and could promote tumour progression.	('regulate', 'Reg', (135, 143))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('tumour', 'Disease', (183, 189))	('overexpression', 'PosReg', (36, 50))	('RSK4', 'Gene', (31, 35))	('sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('promote', 'PosReg', (175, 182))	('treatment resistance', 'MPA', (144, 164))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('RSK4', 'Var', (126, 130))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('associated', 'Reg', (54, 64))
6400	23942078	Multiple human normal and tumour organ tissue arrays were purchased from US Biomax Inc. (FDA807-1 and FDA807-2, Rockville, MD, USA).	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('human', 'Species', '9606', (9, 14))	('FDA807-2', 'Var', (102, 110))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))
6420	23942078	After 48 h, cells were trypsinised and replated onto 10-cm culture dishes in the presence of 300 mug ml-1 G418 (Gibco).	('G418', 'Chemical', 'MESH:C010680', (106, 110))	('G418', 'Var', (106, 110))	('mug', 'molecular_function', 'GO:0043739', ('97', '100'))	('ml-1', 'Gene', (101, 105))	('ml-1', 'Gene', '112744', (101, 105))
6438	23942078	The cells were incubated in serum-free medium for 12 h, exposed to 10 muM U0126 or 10 muM BI-D1870 for 60 min, and then incubated in 10% FBS for 10 min.	('U0126', 'Var', (74, 79))	('FBS', 'Disease', 'MESH:D005198', (137, 140))	('U0126', 'Chemical', 'MESH:C113580', (74, 79))	('BI-D1870', 'Chemical', 'MESH:C516541', (90, 98))	('FBS', 'Disease', (137, 140))	('BI-D1870', 'Var', (90, 98))
6463	23942078	However, there was an increase in the percentage of G0-G1 cells in the shRSK4-GRC-1 cell line (75.39+-0.25 vs 59.68+-0.21, P<0.05, Supplementary Figure 2) and a decrease of cells in the S and G2-M phase (19.85+-0.87 vs 27.92+-0.87; 4.76+-0.14 vs 12.40+-0.27, P<0.05, Supplementary Figure 2), indicating that inhibition of RSK4 could cause cell cycle arrest.	('inhibition', 'Var', (308, 318))	('M phase', 'biological_process', 'GO:0000279', ('195', '202'))	('RSK4', 'Gene', (322, 326))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (339, 356))	('arrest', 'Disease', 'MESH:D006323', (350, 356))	('cell cycle arrest', 'biological_process', 'GO:0007050', ('339', '356'))	('arrest', 'Disease', (350, 356))
6471	23942078	Silencing of RSK4 expression in GRC-1 cells decreased expression of CD44 and MMP-9 proteins (Figure 5B).	('expression', 'MPA', (54, 64))	('CD44', 'Gene', '960', (68, 72))	('CD44', 'Gene', (68, 72))	('MMP-9', 'molecular_function', 'GO:0004229', ('77', '82'))	('MMP-9', 'Gene', '4318', (77, 82))	('RSK4', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))	('MMP-9', 'Gene', (77, 82))	('decreased', 'NegReg', (44, 53))
6473	23942078	We exposed GRC-1 cells to U0126 to block the ERK pathway or to BI-D1870 to inhibit RSK activity directly.	('ERK', 'Gene', (45, 48))	('ERK', 'molecular_function', 'GO:0004707', ('45', '48'))	('activity', 'MPA', (87, 95))	('inhibit', 'NegReg', (75, 82))	('BI-D1870', 'Chemical', 'MESH:C516541', (63, 71))	('RSK', 'Gene', '6195', (83, 86))	('RSK', 'Gene', (83, 86))	('BI-D1870', 'Var', (63, 71))	('U0126', 'Chemical', 'MESH:C113580', (26, 31))	('ERK', 'Gene', '5594', (45, 48))
6474	23942078	Prior treatment of cells with U0126 abolished the activation of ERK1/2 and RSK4.	('U0126', 'Var', (30, 35))	('ERK1/2', 'Protein', (64, 70))	('RSK4', 'Protein', (75, 79))	('U0126', 'Chemical', 'MESH:C113580', (30, 35))	('ERK1', 'molecular_function', 'GO:0004707', ('64', '68'))
6475	23942078	Treatment with the RSK inhibitor BI-D1870 almost completely suppressed RSK4 expression without affecting the activation of ERK1/2.	('suppressed', 'NegReg', (60, 70))	('BI-D1870', 'Var', (33, 41))	('RSK', 'Gene', '6195', (71, 74))	('expression', 'MPA', (76, 86))	('RSK', 'Gene', (71, 74))	('ERK1', 'molecular_function', 'GO:0004707', ('123', '127'))	('RSK', 'Gene', '6195', (19, 22))	('RSK', 'Gene', (19, 22))	('BI-D1870', 'Chemical', 'MESH:C516541', (33, 41))
6509	23942078	Thus, we used the specific inhibitors U0126 and BI-D1870 to block ERK and RSK4 activity, respectively.	('activity', 'MPA', (79, 87))	('ERK', 'molecular_function', 'GO:0004707', ('66', '69'))	('RSK4', 'Protein', (74, 78))	('BI-D1870', 'Chemical', 'MESH:C516541', (48, 56))	('U0126', 'Var', (38, 43))	('U0126', 'Chemical', 'MESH:C113580', (38, 43))	('ERK', 'Gene', '5594', (66, 69))	('BI-D1870', 'Var', (48, 56))	('ERK', 'Gene', (66, 69))
6519	23942078	In particular, RSK4 positivity was much higher (71.4%) in type 2 PRCC than that (14.3%) in type 1 PRCC (P=0.001, Figure 3B).	('PRCC', 'Gene', '5546', (65, 69))	('PRCC', 'Gene', (98, 102))	('positivity', 'Var', (20, 30))	('higher', 'PosReg', (40, 46))	('RSK4', 'Protein', (15, 19))	('PRCC', 'Gene', (65, 69))	('PRCC', 'Gene', '5546', (98, 102))
6567	32092671	Recently, the first syngeneic mouse model of metastatic RCC deficient in the von Hippel-Lindau (VHL) gene was established by CRISPR-mediated knockout of VHL with the use of lentiviral transduction.	('VHL', 'Disease', (153, 156))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('metastatic RCC deficient in the von Hippel-Lindau', 'Disease', 'MESH:D006623', (45, 94))	('transduction', 'biological_process', 'GO:0009293', ('184', '196'))	('VHL', 'Disease', 'MESH:D006623', (96, 99))	('metastatic RCC deficient in the von Hippel-Lindau', 'Disease', (45, 94))	('VHL', 'Disease', (96, 99))	('VHL', 'Disease', 'MESH:D006623', (153, 156))	('knockout', 'Var', (141, 149))
6570	32092671	Renal tumors appear in heterozygotes and in accordance with the Knudson "two-hit" hypothesis, a tumor occurs when a wild type allele is inactivated by loss of heterozygosity or somatic mutation.	('Renal tumor', 'Disease', 'MESH:D007680', (0, 11))	('Renal tumor', 'Phenotype', 'HP:0009726', (0, 11))	('Renal tumors', 'Disease', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss of heterozygosity', 'Var', (151, 173))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('Renal tumors', 'Disease', 'MESH:D007680', (0, 12))
6576	32092671	Although the frequency of mutations in p53 is not fully determined, many studies in human renal cancer derived tissues indicate that mutations in p53 occur rarely, as in Eker rats.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('p53', 'Gene', '7157', (39, 42))	('p53', 'Gene', (39, 42))	('mutations', 'Var', (133, 142))	('renal cancer', 'Phenotype', 'HP:0009726', (90, 102))
6577	32092671	In humans, alterations in TSC genes (humans possess two TSC1 or TSC2 genes) are connected with tuberous sclerosis.	('alterations', 'Var', (11, 22))	('TSC', 'Gene', (26, 29))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (95, 113))	('TSC1', 'Gene', (56, 60))	('TSC', 'Gene', (64, 67))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (56, 59))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (26, 29))	('TSC', 'Gene', '7248;7249;479883;22084;24855', (64, 67))	('TSC2', 'Gene', '7249', (64, 68))	('tuberous sclerosis', 'Disease', (95, 113))	('TSC1', 'Gene', '7248', (56, 60))	('TSC', 'Gene', (56, 59))	('TSC2', 'Gene', (64, 68))	('connected', 'Reg', (80, 89))
6586	32092671	Genetically engineered mouse (GEM) models are developed by the introduction of constitutively or conditionally expressed genetic alterations, associated with a particular disease/cancer.	('genetic alterations', 'Var', (121, 140))	('particular disease', 'Disease', 'MESH:D030342', (160, 178))	('particular disease', 'Disease', (160, 178))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))
6593	32092671	For example, kidney epithelium specific co-deletion of Vhl and Pten  or Kif3a (Kinesin Family Member 3A) in mice led to formation of simple, atypical cystic lesions that mimic precursor lesions observed in some ccRCC, however, no cancer cells were found.	('cystic lesions', 'Disease', 'MESH:D052177', (150, 164))	('Kif3a', 'Gene', (72, 77))	('ccRCC', 'Disease', (211, 216))	('Pten', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Kinesin', 'molecular_function', 'GO:0003777', ('79', '86'))	('Kinesin Family Member 3A', 'Gene', '16568', (79, 103))	('Kinesin Family Member 3A', 'Gene', (79, 103))	('co-deletion', 'Var', (40, 51))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('formation', 'biological_process', 'GO:0009058', ('120', '129'))	('Kif3a', 'Gene', '16568', (72, 77))	('cystic lesions', 'Disease', (150, 164))	('Vhl', 'Gene', (55, 58))	('Pten', 'Gene', '19211', (63, 67))
6594	32092671	More promising are models with genetic modifications in Vhl, Trp53 and Rb1 , Vhl and Pbrm1 , Vhl and Bap1 , Hif1alpha , Myc , Tfeb , Bhd  or NICD1  that are described below in more detail.	('Hif1alpha', 'Gene', (108, 117))	('Vhl', 'Gene', (77, 80))	('Rb1', 'Gene', (71, 74))	('Pbrm1', 'Gene', (85, 90))	('Bap1', 'Gene', (101, 105))	('genetic modifications', 'Var', (31, 52))	('Trp53', 'Gene', (61, 66))	('Vhl', 'Gene', (56, 59))	('Hif1alpha', 'Gene', '3091', (108, 117))	('Vhl', 'Gene', (93, 96))
6598	32092671	All of VhlDelta/DeltaPbrm1Delta/Delta mice by 20 months of age exhibited a spectrum of premalignant cysts and developed multifocal renal tumors arising within macroscopically normal parenchyma and they were confirmed to originate from proximal renal tubules.	('multifocal renal tumors', 'Disease', (120, 143))	('exhibited', 'Reg', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('developed', 'PosReg', (110, 119))	('renal tumors', 'Phenotype', 'HP:0009726', (131, 143))	('renal tumor', 'Phenotype', 'HP:0009726', (131, 142))	('multifocal renal tumors', 'Disease', 'None', (120, 143))	('VhlDelta/DeltaPbrm1Delta/Delta', 'Var', (7, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
6602	32092671	An additional knock-out of one copy of the mTORC1 negative regulator, Tsc1 gene, in the kidneys along with Vhl and Pbrm1 led to development of tumors with similar appearance to those observed in kidneys with intact Tsc1, but of higher grade and with increased mTORC1 activation.	('Tsc1', 'Gene', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mTORC1', 'Gene', (43, 49))	('mTORC1', 'Gene', (260, 266))	('mTORC1', 'cellular_component', 'GO:0031931', ('43', '49'))	('mTORC1', 'cellular_component', 'GO:0031931', ('260', '266'))	('Tsc1', 'Gene', '7248', (70, 74))	('tumors', 'CPA', (143, 149))	('Tsc1', 'Gene', (70, 74))	('mTORC1', 'Gene', '382056', (43, 49))	('knock-out', 'Var', (14, 23))	('Tsc1', 'Gene', '7248', (215, 219))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('mTORC1', 'Gene', '382056', (260, 266))
6607	32092671	described the role of Vhl and Brca1 associated protein-1 (Bap1) deletion in mice.	('Brca1 associated protein-1', 'Gene', '104416', (30, 56))	('deletion', 'Var', (64, 72))	('Bap1', 'Gene', (58, 62))	('protein', 'cellular_component', 'GO:0003675', ('47', '54'))	('Brca1 associated protein-1', 'Gene', (30, 56))
6608	32092671	Homozygous deletion of Vhl and Bap1 in the mouse (Six2-Cre; VhlDelta/DeltaBap1Delta/Delta) kidney resulted in early mortality before 1 month.	('Six2', 'Gene', '20472', (50, 54))	('Vhl', 'Gene', (23, 26))	('resulted in', 'Reg', (98, 109))	('Bap1', 'Gene', (31, 35))	('Six2', 'Gene', (50, 54))	('deletion', 'Var', (11, 19))
6612	32092671	Importantly, mutations in Pbrm1, Bap1 and Setd2 were not found in the examined animal tumors, providing evidence that this model may reflect approximately 50% of human ccRCC that do not harbor mutations in those tumor-suppressor genes.	('Setd2', 'Gene', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Pbrm1', 'Gene', (26, 31))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('212', '228'))	('ccRCC', 'Disease', (168, 173))	('Setd2', 'Gene', '29072', (42, 47))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('212', '228'))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('mutations', 'Var', (13, 22))	('Bap1', 'Gene', (33, 37))
6615	32092671	developed a conditional mouse model based on the ectopic expression of a constitutively active intracellular domain of Notch 1 (NICD1) and the disruption of the Vhl gene in renal proximal tubular epithelial cells.	('Notch', 'Gene', (119, 124))	('Notch 1', 'Gene', '18128', (119, 126))	('Notch', 'Gene', '31293', (119, 124))	('disruption', 'Var', (143, 153))	('Notch 1', 'Gene', (119, 126))	('intracellular', 'cellular_component', 'GO:0005622', ('95', '108'))	('NICD1', 'Gene', (128, 133))	('Vhl gene', 'Gene', (161, 169))
6620	32092671	FLCN homozygous deletion usually results in embryonic lethality.	('FLCN', 'Gene', (0, 4))	('embryonic lethality', 'Disease', (44, 63))	('results in', 'Reg', (33, 43))	('deletion', 'Var', (16, 24))	('embryonic lethality', 'Disease', 'MESH:D020964', (44, 63))
6634	32092671	They created a triple mutant (P402A, P564A, N803A) human HIF-1alpha construct using the kidney proximal tubule specific type 1 gamma-glutamyl transpeptidase (GGT) promoter to drive its expression in the proximal tubule cells.	('N803A', 'Var', (44, 49))	('P564A', 'Mutation', 'p.P564A', (37, 42))	('P402A', 'Var', (30, 35))	('P564A', 'Var', (37, 42))	('N803A', 'Mutation', 'p.N803A', (44, 49))	('P402A', 'Mutation', 'p.P402A', (30, 35))
6635	32092671	Transgenic mice developed normally and passed the transgene to offspring following a Mendelian inheritance pattern.	('developed', 'CPA', (16, 25))	('transgene', 'Var', (50, 59))	('Transgenic mice', 'Species', '10090', (0, 15))
6651	32092671	The model (Cdh16Cre::Tfebfs) was obtained by crossing the Tfeb conditional overexpressing mouse line carrying Tfeb-3xFlagfs/fs under the control of the chicken beta-actin promoter with the Cdh16Cre mouse strain, in which Cre recombinase is specifically expressed in renal tubular epithelial cells starting from the embryonic stage.	('Tfeb-3xFlagfs/fs', 'Var', (110, 126))	('Cdh16', 'Gene', (189, 194))	('chicken', 'Species', '9031', (152, 159))	('Cdh16', 'Gene', '12556', (189, 194))	('Cdh16Cre', 'Chemical', '-', (189, 197))	('Cdh16', 'Gene', '12556', (11, 16))	('Cdh16', 'Gene', (11, 16))	('Cdh16Cre', 'Chemical', '-', (11, 19))
6654	32092671	Additionally, the WNT inhibitor PKF118-310 was tested in vivo in this model, resulting in reduction of kidney mass, and the number of cystic and neoplastic lesions.	('PKF118-310', 'Var', (32, 42))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (145, 163))	('reduction of kidney mass', 'Disease', 'MESH:C536030', (90, 114))	('reduction of kidney mass', 'Disease', (90, 114))
6658	32092671	20% of tumors harbor inactivating mutations of the WT1 gene.	('inactivating mutations', 'Var', (21, 43))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('WT1', 'Gene', '7490', (51, 54))	('WT1', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
6663	32092671	Moreover, Wt1 ablation and Igf2 upregulation in tumors results in up-regulation of glucose utilization during initial stages of tumor development, followed by a gradual decrease in tumor glycolytic activity, consistent with the development of large areas of hemorrhagic necrosis.	('upregulation', 'PosReg', (32, 44))	('up-regulation', 'PosReg', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('necrosis', 'biological_process', 'GO:0070265', ('270', '278'))	('necrosis', 'biological_process', 'GO:0019835', ('270', '278'))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('necrosis', 'biological_process', 'GO:0001906', ('270', '278'))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('glucose utilization', 'MPA', (83, 102))	('hemorrhagic necrosis', 'Disease', 'MESH:D006470', (258, 278))	('tumor glycolytic activity', 'MPA', (181, 206))	('hemorrhagic necrosis', 'Disease', (258, 278))	('necrosis', 'biological_process', 'GO:0008219', ('270', '278'))	('decrease', 'NegReg', (169, 177))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Igf2', 'Gene', (27, 31))	('Igf2', 'Gene', '3481', (27, 31))	('hemorrhagic necrosis', 'Phenotype', 'HP:0010885', (258, 278))	('necrosis', 'biological_process', 'GO:0008220', ('270', '278'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('ablation', 'Var', (14, 22))
6664	32092671	The same authors have tried to develop this model further by additional stabilizing Ctnnb1 mutation under both the Cited1-Cre and the Six2-Cre recombinase that target nephron progenitors.	('mutation', 'Var', (91, 99))	('Cited1', 'Gene', '4435', (115, 121))	('Ctnnb1', 'Gene', (84, 90))	('Ctnnb1', 'Gene', '1499', (84, 90))	('Cited1', 'Gene', (115, 121))
6687	32092671	Moreover, CyA impairs the production of interleukin-2 and thus suppresses the generation of T-cells, what can promote tumor growth by silencing the immune response of the host animal.	('interleukin-2', 'Gene', (40, 53))	('immune response', 'biological_process', 'GO:0006955', ('148', '163'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('impairs', 'NegReg', (14, 21))	('interleukin-2', 'Gene', '3558', (40, 53))	('promote', 'PosReg', (110, 117))	('CyA', 'Var', (10, 13))	('tumor growth', 'CPA', (118, 130))	('suppresses', 'NegReg', (63, 73))	('generation of T-cells', 'MPA', (78, 99))
6691	32092671	2-Acetylaminofluorene (2-AAF) has been proposed as another carcinogen useful in establishing a chemically-induced RCC model, however, only 108 of 25916 (0.42 %) Balb/c female mice treated with several dose levels of 2-AAF developed renal tumors, with 27% of them diagnosed as carcinomas and 63% as adenomas.	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('2-AAF', 'Var', (216, 221))	('renal tumor', 'Phenotype', 'HP:0009726', (232, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('2-AAF', 'Chemical', 'MESH:D015073', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('2-AAF', 'Chemical', 'MESH:D015073', (216, 221))	('developed', 'PosReg', (222, 231))	('renal', 'Disease', (232, 237))	('renal tumors', 'Phenotype', 'HP:0009726', (232, 244))	('2-Acetylaminofluorene', 'Chemical', 'MESH:D015073', (0, 21))
6716	32092671	Fe-NTA is an iron chelate that was found to cause oxidative modification in the kidney, including DNA base modifications such as 8-oxoguanine, thymine-tyrosine cross-links, thiobarbituric acid-reactive substances, saturated and unsaturated mutagenic aldehydes such as 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA), and HNE- or MDA-modified proteins.	('cause', 'Reg', (44, 49))	('aldehydes', 'Chemical', 'MESH:D000447', (250, 259))	('DNA base', 'MPA', (98, 106))	('oxidative modification', 'MPA', (50, 72))	('malondialdehyde', 'Chemical', 'MESH:D008315', (298, 313))	('thymine', 'Chemical', 'MESH:D013941', (143, 150))	('4-hydroxy-2-nonenal', 'MPA', (268, 287))	('DNA', 'cellular_component', 'GO:0005574', ('98', '101'))	('Fe-NTA', 'Var', (0, 6))	('4-hydroxy-2-nonenal', 'Chemical', 'MESH:C027576', (268, 287))	('thiobarbituric acid', 'Chemical', 'MESH:C029684', (173, 192))	('proteins', 'Protein', (346, 354))	('tyrosine', 'Chemical', 'MESH:D014443', (151, 159))	('malondialdehyde', 'MPA', (298, 313))	('thymine-tyrosine', 'MPA', (143, 159))	('thiobarbituric acid-reactive substances', 'MPA', (173, 212))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (129, 141))
6723	32092671	This observation was confirmed by aCGH where deletions in the Cdkn2a/2b locus, containing p15, p16 and p19 genes, were frequently observed.	('p19', 'Gene', (103, 106))	('p19', 'Gene', '1029', (103, 106))	('deletions', 'Var', (45, 54))	('observed', 'Reg', (130, 138))	('Cdkn2a/2b', 'Gene', (62, 71))	('p19', 'cellular_component', 'GO:0070743', ('103', '106'))
6724	32092671	In this renal carcinogenesis model, preferred alterations were Cdkn2A/2B deletion and Met amplification.	('deletion', 'Var', (73, 81))	('Cdkn2A', 'Gene', (63, 69))	('Met amplification', 'Var', (86, 103))	('Cdkn2A', 'Gene', '1029', (63, 69))
6727	32092671	Despite the well-known potential to induce experimental sarcomas by 20-methylcholanthrene, it has not been successful in creation of renal sarcoma models, mostly due to lack of specificity and possible development of renal carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (223, 233))	('20-methylcholanthrene', 'Var', (68, 89))	('renal carcinomas', 'Phenotype', 'HP:0005584', (217, 233))	('creation of renal sarcoma', 'Disease', 'MESH:D007674', (121, 146))	('creation of renal sarcoma', 'Disease', (121, 146))	('sarcomas', 'Phenotype', 'HP:0100242', (56, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (56, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (217, 232))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('renal sarcoma', 'Phenotype', 'HP:0008663', (133, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
6731	32092671	Athymic nude mice are hairless, which is an effect of a Forkhead box protein N1 mutation (Foxn1nu).	('Foxn1nu', 'Gene', (90, 97))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('Foxn1nu', 'Gene', '15218', (90, 97))	('mutation', 'Var', (80, 88))
6732	32092671	SCID mice have a single nucleotide polymorphism in the DNA-dependent protein kinase of catalytic polypeptide Prkdc gene (Prkdcscid).	('single nucleotide polymorphism', 'Var', (17, 47))	('scid', 'Gene', (126, 130))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))	('DNA', 'cellular_component', 'GO:0005574', ('55', '58'))	('scid', 'Gene', '19090', (126, 130))
6748	32092671	Because stem cells were c-MET positive, c-MET inhibitor JNJ-38877605 was tested with this model resulting in a complete blockade of bone metastasis development.	('c-MET', 'Gene', '4233', (40, 45))	('blockade', 'NegReg', (120, 128))	('c-MET', 'Gene', '4233', (24, 29))	('c-MET', 'Gene', (40, 45))	('JNJ-38877605', 'Var', (56, 68))	('bone metastasis development', 'CPA', (132, 159))	('c-MET', 'Gene', (24, 29))	('JNJ-38877605', 'Chemical', 'MESH:C000599304', (56, 68))
6776	32092671	Human RCC patients with tumor PD-L1 also show significant increase in tumor progression and high mortality suggesting that PD-L1 is associated with poor prognosis in patients with tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Human', 'Species', '9606', (0, 5))	('increase', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor progression', 'CPA', (70, 87))	('PD-L1', 'Var', (30, 35))	('tumor PD-L1', 'Var', (24, 35))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))
6779	32092671	Mutations in the Flcn gene in humans are connected with the BHD syndrome, which predisposes to a wide spectrum of renal tumors (hybrid oncocytic tumors, chromophobe and clear cell carcinomas, renal oncocytosis).	('renal oncocytosis', 'Disease', (192, 209))	('renal oncocytosis', 'Disease', 'MESH:D007674', (192, 209))	('renal tumors', 'Disease', (114, 126))	('oncocytic tumors', 'Disease', (135, 151))	('clear cell carcinomas', 'Disease', (169, 190))	('BHD syndrome', 'Disease', (60, 72))	('oncocytic tumors', 'Disease', 'MESH:C535584', (135, 151))	('Mutations', 'Var', (0, 9))	('BHD syndrome', 'Disease', 'MESH:D058249', (60, 72))	('clear cell carcinomas', 'Disease', 'MESH:D002292', (169, 190))	('Flcn', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('renal tumors', 'Phenotype', 'HP:0009726', (114, 126))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('connected', 'Reg', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('renal tumor', 'Phenotype', 'HP:0009726', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
6786	32092671	Choline (also referred to as total choline, tCho, peak at 3.20 ppm) is in fact a sum of signals from trimethylamine groups in glycerylphosphocholine (GPC), phosphocholine (PC) and free choline (Cho).	('glycerylphosphocholine', 'MPA', (126, 148))	('GPC', 'Chemical', 'MESH:D005997', (150, 153))	('trimethylamine', 'Chemical', 'MESH:C023336', (101, 115))	('choline', 'Chemical', 'MESH:D002794', (185, 192))	('choline', 'Chemical', 'MESH:D002794', (35, 42))	('choline', 'Chemical', 'MESH:D002794', (163, 170))	('choline', 'Chemical', 'MESH:D002794', (141, 148))	('phosphocholine', 'Chemical', 'MESH:D010767', (134, 148))	('phosphocholine', 'Chemical', 'MESH:D010767', (156, 170))	('Choline', 'Chemical', 'MESH:D002794', (0, 7))	('Cho', 'molecular_function', 'GO:0043848', ('194', '197'))	('tCho', 'Chemical', '-', (44, 48))	('glycerylphosphocholine', 'Chemical', 'MESH:D005997', (126, 148))	('trimethylamine', 'Var', (101, 115))
6812	32092671	Moreover, discovery of dysregulation of the mammalian target of rapamycin (mTOR) signaling pathway and development of mTOR inhibitors was another step towards effective treatment of RCC.	('mammalian target of rapamycin', 'Gene', (44, 73))	('signaling pathway', 'biological_process', 'GO:0007165', ('81', '98'))	('dysregulation', 'Var', (23, 36))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', (182, 185))	('mammalian target of rapamycin', 'Gene', '2475', (44, 73))
6918	32694939	Three sDEmiRs with the most significant prognostic values (miR-34a-5p, miR-410-3p and miR-6720-3p) were employed to establish the RSM which was certified as an independent prognosis factor and closely correlated with OS.	('miR-6720-3p', 'Var', (86, 97))	('correlated', 'Reg', (201, 211))	('sDEmiRs', 'Chemical', '-', (6, 13))	('miR-410-3p', 'Chemical', '-', (71, 81))	('miR-34a-5p', 'Var', (59, 69))	('miR-6720-3p', 'Chemical', '-', (86, 97))	('miR-410-3p', 'Var', (71, 81))	('miR-34a-5p', 'Chemical', '-', (59, 69))
6919	32694939	In the verification of clinical samples, the overexpression of miR-410-3p and miR-6720-3p were detected to be associated with the advanced T-stages, while miR-34a-5p showed the reversed results.	('miR-34a-5p', 'Chemical', '-', (155, 165))	('miR-410-3p', 'Chemical', '-', (63, 73))	('miR-6720-3p', 'Chemical', '-', (78, 89))	('associated', 'Reg', (110, 120))	('miR-410-3p', 'Var', (63, 73))	('advanced T-stages', 'CPA', (130, 147))	('overexpression', 'PosReg', (45, 59))	('miR-6720-3p', 'Var', (78, 89))
6955	32694939	Based on COX Regression model, we screened 18 DEmiRs which were closely associated with the prognosis of patients with pRCC (sDEmiRs), such as miR-323a-3p, miR-409-5p, miR-34a-5p, miR-539-5p, miR-376c-3p, miR-379-5p, miR-337-3p, miR-410-3p, miR-216a-5p, miR-495-3p, miR-381-3p, miR-382-5p, miR-493-3p, miR-411-3p, miR-519a-5p, miR-6720-3p, miR-105-5p and miR-224-5p.	('miR-411-3p', 'Var', (302, 312))	('miR-381-3p', 'Var', (266, 276))	('miR-216a-5p', 'Var', (241, 252))	('miR-382', 'Gene', '494331', (278, 285))	('associated', 'Reg', (72, 82))	('pRCC', 'Gene', '5546', (119, 123))	('miR-382', 'Gene', (278, 285))	('miR-539', 'Gene', (180, 187))	('miR-539', 'Gene', '664612', (180, 187))	('miR-323a-3p', 'Var', (143, 154))	('miR-224', 'Gene', (355, 362))	('miR-493-3p', 'Var', (290, 300))	('miR-224', 'Gene', '407009', (355, 362))	('miR-337', 'Gene', '442905', (217, 224))	('miR-337', 'Gene', (217, 224))	('miR-379', 'Gene', '494328', (205, 212))	('miR-519a-5p', 'Var', (314, 325))	('miR-410-3p', 'Chemical', '-', (229, 239))	('pRCC', 'Phenotype', 'HP:0006766', (119, 123))	('miR-379', 'Gene', (205, 212))	('sDEmiRs', 'Chemical', '-', (125, 132))	('miR-495-3p', 'Var', (254, 264))	('patients', 'Species', '9606', (105, 113))	('pRCC', 'Gene', (119, 123))	('miR-376c-3p', 'Var', (192, 203))	('miR-105-5p', 'Var', (340, 350))	('miR-34a-5p', 'Var', (168, 178))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('miR-410-3p', 'Var', (229, 239))	('miR-6720-3p', 'Chemical', '-', (327, 338))	('miR-409', 'Gene', (156, 163))	('miR-6720-3p', 'Var', (327, 338))	('miR-409', 'Gene', '574413', (156, 163))	('miR-34a-5p', 'Chemical', '-', (168, 178))
6956	32694939	And the relationships between these sDEmiRs and prognosis were illustrated in the forest map, in which miR-34a-5p showed a reverse trend to that of other miRNAs, with the negative correlation with the poor clinical outcomes (Fig.	('miR-34a-5p', 'Chemical', '-', (103, 113))	('poor clinical outcomes', 'CPA', (201, 223))	('sDEmiRs', 'Chemical', '-', (36, 43))	('miR-34a-5p', 'Var', (103, 113))
6957	32694939	In order to establish the risk score model later, three sDEmiRs (miR-34a-5p, miR-410-3p and miR-6720-3p) with significant statistical difference were identified through the multivariate COX analysis (Additional file 1: Table S1).	('miR-6720-3p', 'Chemical', '-', (92, 103))	('miR-410-3p', 'Chemical', '-', (77, 87))	('miR-410-3p', 'Var', (77, 87))	('miR-34a-5p', 'Var', (65, 75))	('sDEmiRs', 'Chemical', '-', (56, 63))	('miR-6720-3p', 'Var', (92, 103))	('miR-34a-5p', 'Chemical', '-', (65, 75))
6958	32694939	Then, the survival curve of the three sDEmiRs showed that the higher expression level of miR-34a-5p was related with the longer OS, but the miR-410-3p and miR-6720-3p showed negative correlations with OS (Fig.	('longer OS', 'Disease', (121, 130))	('miR-34a-5p', 'Gene', (89, 99))	('expression level', 'MPA', (69, 85))	('miR-410-3p', 'Var', (140, 150))	('higher', 'PosReg', (62, 68))	('sDEmiRs', 'Chemical', '-', (38, 45))	('miR-34a-5p', 'Chemical', '-', (89, 99))	('miR-410-3p', 'Chemical', '-', (140, 150))	('miR-6720-3p', 'Chemical', '-', (155, 166))
6961	32694939	With the rise of the risk score, the expression levels of miR-6720-3p and miR-410-3p were enhanced, while there was no remarkable difference in the expression level of miR-34a-5p (Fig.	('miR-6720-3p', 'Var', (58, 69))	('miR-410-3p', 'Var', (74, 84))	('miR-410-3p', 'Chemical', '-', (74, 84))	('expression levels', 'MPA', (37, 54))	('miR-6720-3p', 'Chemical', '-', (58, 69))	('enhanced', 'PosReg', (90, 98))	('miR-34a-5p', 'Chemical', '-', (168, 178))
6966	32694939	As shown in Additional file 2: Figure S1, only did miR-34a-5p showed the significant correlation with the demographic characteristics and the older patients obtained the higher expression level of miR-34a-5p.	('patients', 'Species', '9606', (148, 156))	('higher', 'PosReg', (170, 176))	('miR-34a-5p', 'Var', (197, 207))	('miR-34a-5p', 'Chemical', '-', (197, 207))	('expression level', 'MPA', (177, 193))	('miR-34a-5p', 'Chemical', '-', (51, 61))
6968	32694939	7, We found the expression levels of miR-34a-5p was gradually decreased in patients with the more advanced stages, T-stages, N-stages and M-stages.	('N-stages', 'Disease', (125, 133))	('miR-34a-5p', 'Var', (37, 47))	('decreased', 'NegReg', (62, 71))	('patients', 'Species', '9606', (75, 83))	('M-stages', 'Var', (138, 146))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('expression levels', 'MPA', (16, 33))	('T-stages', 'Disease', (115, 123))
6969	32694939	However, the miR-410-3p showed the reversed variations, with the enhancement in patients with the more advanced stages, T-stages and N-stages.	('enhancement', 'PosReg', (65, 76))	('miR-410-3p', 'Var', (13, 23))	('patients', 'Species', '9606', (80, 88))	('T-stages', 'Disease', (120, 128))	('miR-410-3p', 'Chemical', '-', (13, 23))
6975	32694939	To further validate the predicting effects of sDEmiRs on clinical prognosis of pRCC and the correlations between sDEmiRs and the clinicopathological parameters, we examined the expression levels of miR-410-3p, miR-6720-3p and miR-34a-5p in tumor and adjacent tissues of pRCC patients with different T-stages.	('pRCC', 'Gene', '5546', (270, 274))	('miR-410-3p', 'Chemical', '-', (198, 208))	('patients', 'Species', '9606', (275, 283))	('pRCC', 'Gene', '5546', (79, 83))	('sDEmiRs', 'Chemical', '-', (46, 53))	('tumor', 'Disease', (240, 245))	('pRCC', 'Phenotype', 'HP:0006766', (270, 274))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('miR-6720-3p', 'Chemical', '-', (210, 221))	('miR-34a-5p', 'Var', (226, 236))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('pRCC', 'Gene', (270, 274))	('miR-410-3p', 'Var', (198, 208))	('pRCC', 'Phenotype', 'HP:0006766', (79, 83))	('miR-6720-3p', 'Var', (210, 221))	('pRCC', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('miR-34a-5p', 'Chemical', '-', (226, 236))	('sDEmiRs', 'Chemical', '-', (113, 120))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))
6978	32694939	10b) showed significantly higher expression levels in tumor tissues than those in adjacent tissues, however miR-34a-5p (Fig.	('miR-34a-5p', 'Chemical', '-', (108, 118))	('higher', 'PosReg', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('expression levels', 'MPA', (33, 50))	('tumor', 'Disease', (54, 59))	('miR-34a-5p', 'Var', (108, 118))
6979	32694939	Besides, compared with pRCC patients of T1 and T2 stages, the obviously less miR-34a-5p (Fig.	('pRCC', 'Gene', (23, 27))	('miR-34a-5p', 'Var', (77, 87))	('miR-34a-5p', 'Chemical', '-', (77, 87))	('pRCC', 'Gene', '5546', (23, 27))	('pRCC', 'Phenotype', 'HP:0006766', (23, 27))	('patients', 'Species', '9606', (28, 36))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('less', 'NegReg', (72, 76))
6980	32694939	10d) and the remarkably higher expression levels of miR-410-3p (Fig.	('miR-410-3p', 'Chemical', '-', (52, 62))	('expression levels', 'MPA', (31, 48))	('higher', 'PosReg', (24, 30))	('miR-410-3p', 'Var', (52, 62))
6989	32694939	ascertained the miR-200c and miR14 in exosomes were the early biomarkers for metastasis of breast cancer.	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (77, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('metastasis of breast cancer', 'Disease', (77, 104))	('miR-200c', 'Gene', (16, 24))	('miR-200c', 'Gene', '406985', (16, 24))	('miR14 in', 'Var', (29, 37))
6990	32694939	Accumulating evidence highlighted numerous miRNAs were involved in the oncogenic survival pathways and closely associated with the progression and prognosis of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('miRNAs', 'Var', (43, 49))	('associated', 'Reg', (111, 121))	('involved', 'Reg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('oncogenic survival pathways', 'Pathway', (71, 98))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
6996	32694939	Furthermore, certain specific sDEmiRs (miR-410-3p, miR-6720-3p and miR-34a-5p) with obvious clinical significances have also been validated to be implicated in the prognosis of pRCC and potentially serving as the molecular bioindicators for forecast and assessment of OS.	('miR-34a-5p', 'Var', (67, 77))	('sDEmiRs', 'Chemical', '-', (30, 37))	('implicated', 'Reg', (146, 156))	('miR-34a-5p', 'Chemical', '-', (67, 77))	('miR-6720-3p', 'Var', (51, 62))	('miR-410-3p', 'Chemical', '-', (39, 49))	('pRCC', 'Phenotype', 'HP:0006766', (177, 181))	('pRCC', 'Gene', '5546', (177, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('miR-410-3p', 'Var', (39, 49))	('miR-6720-3p', 'Chemical', '-', (51, 62))	('pRCC', 'Gene', (177, 181))
6998	32694939	Although the potency of sDEmiRs for predicting prognosis has been ascertained, and we also validated the expression levels of miR-410-3p, miR-6720-3p and miR-34a-5p in tumor tissues with different T-stages, some defects are still needed to be pointed out and further discussed.	('miR-410-3p', 'Var', (126, 136))	('tumor', 'Disease', (168, 173))	('miR-34a-5p', 'Var', (154, 164))	('miR-6720-3p', 'Var', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('miR-34a-5p', 'Chemical', '-', (154, 164))	('sDEmiRs', 'Chemical', '-', (24, 31))	('miR-410-3p', 'Chemical', '-', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('miR-6720-3p', 'Chemical', '-', (138, 149))
7000	32694939	Thirdly, except for miR-410-3p, miR-6720-3p and miR-34a-5p, other potential sDEmiRs and their target genes as well as the correlated underlying mechanisms remain to be further explored.	('sDEmiRs', 'Chemical', '-', (76, 83))	('miR-6720-3p', 'Chemical', '-', (32, 43))	('miR-410-3p', 'Var', (20, 30))	('miR-34a-5p', 'Var', (48, 58))	('miR-6720-3p', 'Var', (32, 43))	('miR-410-3p', 'Chemical', '-', (20, 30))	('miR-34a-5p', 'Chemical', '-', (48, 58))
7006	26602888	Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features Sarcomatoid differentiation in renal cell carcinoma (sRCC) is associated with a very poor prognosis.	('Sarcomatoid', 'Disease', (82, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Sarcomatoid', 'Disease', 'MESH:C538614', (82, 93))	('Genomic Copy Number Alterations', 'Var', (0, 31))	('Carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (35, 55))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (35, 55))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('RCC', 'Disease', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('Sarcomatoid', 'Disease', (61, 72))	('Renal Cell Carcinoma', 'Disease', (35, 55))	('Sarcomatoid', 'Disease', 'MESH:C538614', (61, 72))	('Sarcomatoid differentiation in renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 133))
7007	26602888	In this study, we aimed to pinpoint unique copy number alterations (CNAs) in sRCC when compared to classical RCC subtypes.	('copy number alterations', 'Var', (43, 66))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (78, 81))
7010	26602888	Copy number losses of chromosome arms 9q, 15q, 18p/q, and 22q and gains of gains of 1q and 8q occurred in a significantly higher proportion of sRCC tumors compared to the other 3 histologies.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('gains', 'PosReg', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('losses', 'NegReg', (12, 18))	('gains', 'PosReg', (75, 80))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('Copy number', 'Var', (0, 11))	('RCC', 'Disease', (144, 147))
7012	26602888	Patients with 9 or more CNAs also demonstrated significantly worse overall survival compared to those with fewer than 9 CNAs (p=0.004).	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (67, 83))	('worse', 'NegReg', (61, 66))	('CNAs', 'Var', (24, 28))
7013	26602888	Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal imbalances with losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurring at significantly higher frequencies in comparison to non-sRCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('losses', 'NegReg', (97, 103))	('Sarcomatoid', 'Disease', (0, 11))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('Sarcomatoid', 'Disease', 'MESH:C538614', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('gains', 'Var', (135, 140))	('RCC', 'Disease', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('imbalances', 'Phenotype', 'HP:0002172', (81, 91))
7021	26602888	A total of 89 patients undergoing renal mass excision for RCC between November 2010 and July 2014 at our institution underwent single-nucleotide polymorphism (SNP) array analysis on portions their tumors.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('tumors', 'Disease', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('RCC', 'Disease', (58, 61))	('single-nucleotide polymorphism', 'Var', (127, 157))	('patients', 'Species', '9606', (14, 22))
7036	26602888	Copy number losses that occurred in a significantly higher proportion of sRCC tumors when compared to all non-sRCC tumors combined, as well as to each non-sRCC histology group independently, are summarized in Table 2.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', (156, 159))	('RCC', 'Disease', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('Copy number losses', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
7047	26602888	Of the identified distinctive sRCC CNAs, only loss of 15q was more highly prevalent in sRCC patients experiencing disease-specific mortality compared to those alive at final follow up (86% vs 30%, p=0.02).	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('patients', 'Species', '9606', (92, 100))	('loss of 15q', 'Var', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
7048	26602888	Loss of 9q, 18p/q, 22q and gain of 1q and 8q were equivalently prevalent between those dying and not dying of sRCC.	('18p/q', 'Var', (12, 17))	('gain', 'PosReg', (27, 31))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('Loss', 'Var', (0, 4))
7052	26602888	This phenotypic difference suggests that sarcomatoid differentiation develops due to genetic alterations independent of those fundamental to original RCC tumor formation.	('original RCC tumor', 'Disease', 'MESH:C538614', (141, 159))	('sarcomatoid', 'Disease', (41, 52))	('alterations', 'Var', (93, 104))	('formation', 'biological_process', 'GO:0009058', ('160', '169'))	('sarcomatoid', 'Disease', 'MESH:C538614', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('original RCC tumor', 'Disease', (141, 159))
7054	26602888	previously reported karyotypic alterations in four sRCC cases, of which two had complex karyotypes, and one demonstrated a deletion of 22q12 as its sole abnormality.	('RCC', 'Disease', (52, 55))	('deletion of', 'Var', (123, 134))	('RCC', 'Disease', 'MESH:C538614', (52, 55))
7056	26602888	used metaphase-based comparative genomic hybridization and reported that loss of 13q (75%) and 4q (50%) were the most common CNAs found among the 12 sRCC tumors examined.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CNAs', 'Disease', (125, 129))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('metaphase', 'biological_process', 'GO:0051323', ('5', '14'))	('13q', 'Chemical', '-', (81, 84))	('loss of 13q', 'Var', (73, 84))
7057	26602888	In our series, 13q loss was seen in 53% of sRCC tumors, however it was also found in 50% of chromophobe tumors as well as in one tumor each for ccRCC and pRCC.	('RCC', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (48, 54))	('chromophobe tumors', 'Disease', 'MESH:D000238', (92, 110))	('RCC', 'Disease', (44, 47))	('tumors', 'Disease', (104, 110))	('tumor', 'Disease', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (155, 158))	('RCC', 'Disease', (146, 149))	('pRCC', 'Gene', (154, 158))	('loss', 'NegReg', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('13q', 'Chemical', '-', (15, 18))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('13q', 'Var', (15, 18))	('chromophobe tumors', 'Disease', (92, 110))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('pRCC', 'Gene', '5546', (154, 158))
7064	26602888	reported that loss of chromosome 9 and gain of chromosome 20 were independent predictors of the presence of a sarcomatoid component in ccRCC, based on karyotype analysis of 7 ccRCC specimens with sarcomatoid differentiation.	('loss', 'Var', (14, 18))	('chromosome', 'cellular_component', 'GO:0005694', ('22', '32'))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('sarcomatoid', 'Disease', (110, 121))	('sarcomatoid', 'Disease', 'MESH:C538614', (196, 207))	('chromosome', 'cellular_component', 'GO:0005694', ('47', '57'))	('sarcomatoid component', 'Disease', (110, 131))	('sarcomatoid', 'Disease', 'MESH:C538614', (110, 121))	('sarcomatoid', 'Disease', (196, 207))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('gain', 'PosReg', (39, 43))	('RCC', 'Disease', (137, 140))	('sarcomatoid component', 'Disease', 'MESH:C538614', (110, 131))
7071	26602888	CNAs found to be more prevalent in sRCC tumors when compared to non-sRCC tumors included losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('RCC', 'Disease', (69, 72))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('RCC', 'Disease', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('prevalent', 'Reg', (22, 31))	('losses', 'NegReg', (89, 95))	('18p/q', 'Var', (108, 113))	('tumors', 'Disease', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('gains', 'PosReg', (127, 132))	('tumors', 'Disease', (40, 46))	('15q', 'Var', (103, 106))
7073	26602888	Loss of chromosome arm 9q has been associated with higher grade and stage disease in ccRCC, as well as worse overall and recurrence-free survival.	('higher grade', 'CPA', (51, 63))	('stage disease', 'CPA', (68, 81))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('associated', 'Reg', (35, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('8', '18'))	('Loss', 'Var', (0, 4))
7076	26602888	Loss of fructose-1,6-bisphosphatase (FBP1) on chromosome arm 9q has been shown to be necessary for hypoxia inducible factor (HIF)-mediated tumorigenesis in ccRCC, as FBP1 normally inhibits HIF function within the nucleus.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('FBP1', 'Gene', (37, 41))	('hypoxia', 'Disease', (99, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('FBP1', 'Gene', '2203', (166, 170))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('nucleus', 'cellular_component', 'GO:0005634', ('213', '220'))	('RCC', 'Disease', (158, 161))	('FBP1', 'Gene', '2203', (37, 41))	('Loss', 'Var', (0, 4))	('FBP1', 'Gene', (166, 170))
7080	26602888	Stabilization of PML by small C-terminal domain phosphatases (SCPs) has been shown to result in suppression of malignant features in ccRCC including tumor proliferation, migration and invasion, and to increase ccRCC response to mTOR inhibitors.	('suppression', 'NegReg', (96, 107))	('invasion', 'CPA', (184, 192))	('increase', 'PosReg', (201, 209))	('migration', 'CPA', (170, 179))	('malignant features', 'CPA', (111, 129))	('PML', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('PML', 'Gene', '5371', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('RCC', 'Disease', (135, 138))	('mTOR', 'Gene', (228, 232))	('mTOR', 'Gene', '2475', (228, 232))	('Stabilization', 'Var', (0, 13))	('tumor', 'Disease', (149, 154))	('RCC', 'Disease', (212, 215))	('RCC', 'Disease', 'MESH:C538614', (212, 215))
7082	26602888	SMARCB1 inactivating mutations are found in rhabdoid tumors, which are aggressive pediatric soft tissue sarcomas that often arise in the kidney.	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('rhabdoid tumors', 'Disease', (44, 59))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (44, 59))	('inactivating mutations', 'Var', (8, 30))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sarcomas', 'Disease', (104, 112))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (92, 112))	('SMARCB1', 'Gene', '6598', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('SMARCB1', 'Gene', (0, 7))
7098	26602888	CNAs more prevalent in sRCC include losses of chromosome arms 9q, 15q, 18p/q, and 22q as well as gains of 1q and 8q.	('18p/q', 'Var', (71, 76))	('RCC', 'Disease', (24, 27))	('chromosome arms 9q', 'Var', (46, 64))	('gains', 'PosReg', (97, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('46', '56'))	('losses', 'NegReg', (36, 42))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
7119	33227984	All examinations were performed by one experienced consultant radiologist (European Federation of Societies for Ultrasound in Medicine and Biology Level 3) using high-end ultrasound systems with CEUS-specific protocols (GE Healthcare LOGIQ E9, Chicago, IL, USA, Philips EPIQ7, Seattle, Washington, USA, Siemens Ultrasound Sequoia S20000, S3000, ACUSON Sequoia, Mountain View, CA, USA).	('men', 'Species', '9606', (306, 309))	('ACUSON Sequoia', 'Disease', (345, 359))	('S3000', 'Var', (338, 343))
7201	29416756	For instance, the eosinophilic variants of chRCC and ccRCC can exhibit similar cytological features.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('eosinophilic', 'Var', (18, 30))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('eosin', 'Chemical', 'MESH:D004801', (18, 23))
7289	29416756	RCC subtypes exhibit characteristic chromosomal aberrations, such as whole or partial chromosomal duplications and deletions.	('partial chromosomal duplications', 'Var', (78, 110))	('whole', 'Var', (69, 74))	('deletions', 'Var', (115, 124))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (36, 59))
7296	29416756	Interestingly, loss of chromosome 9p and 9q have also been reported in ccRCC, however this occurs at a later stage of disease progression.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('reported', 'Reg', (59, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('23', '33'))	('loss', 'Var', (15, 19))
7307	29416756	Frequent copy number gains in chromosome 12 have been reported in chRCC.	('copy number gains', 'Var', (9, 26))	('RCC', 'Disease', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('30', '40'))
7358	31578141	Further, the prognostic models or modifications thereof were used to define inclusion criteria and to risk-stratify PRCC patients for adjuvant trials such as SORCE (NCT00492258) or ASSURE (NCT00326898, E2805) without previous validation, and others such as the 2018 Leibovich prognostic system were single centre, not externally validated and not assessed for calibration or clinical net benefit.	('NCT00492258', 'Var', (165, 176))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('PRCC', 'Gene', (116, 120))	('NCT00326898', 'Var', (189, 200))	('PRCC', 'Gene', '5546', (116, 120))	('patients', 'Species', '9606', (121, 129))
7463	28427189	Many biomarkers for renal clear cell carcinoma have been discovered, including VHL, VEGF, CAIX and HIF1a/2a mutations, some of which could predict therapeutic effect and clinical prognosis.	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (20, 46))	('renal clear cell carcinoma', 'Disease', (20, 46))	('mutations', 'Var', (108, 117))	('VHL', 'Disease', 'MESH:D006623', (79, 82))	('clinical', 'Species', '191496', (170, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('predict', 'Reg', (139, 146))	('VHL', 'Disease', (79, 82))	('VEGF', 'Gene', (84, 88))	('HIF1a/2a', 'Gene', (99, 107))	('CAIX', 'Gene', (90, 94))
7482	28427189	Clinical features of the PRCC patients in GSE2748 were shown in Supplementary Table 2.	('PRCC', 'Gene', '5546', (25, 29))	('GSE2748', 'Var', (42, 49))	('GSE2748', 'Chemical', '-', (42, 49))	('Clinical', 'Species', '191496', (0, 8))	('PRCC', 'Gene', (25, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('patients', 'Species', '9606', (30, 38))	('PRCC', 'Phenotype', 'HP:0006766', (25, 29))
7521	28427189	For example, data on four different cancers, ovarian, breast, lung and skin, was processed with WGCNA to compare patterns of co-expressed genes in tumors grouped according to their TP53 missense or null mutation status.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TP53', 'Gene', (181, 185))	('ovarian', 'Disease', (45, 52))	('tumors', 'Disease', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('ovarian', 'Disease', 'MESH:D010051', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('null mutation status', 'Var', (198, 218))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('missense', 'Var', (186, 194))	('breast', 'Disease', (54, 60))
7535	28427189	Overexpression of BUB1 was linked with poor outcomes in breast cancer patients.	('patients', 'Species', '9606', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BUB1', 'Gene', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('BUB1', 'Gene', '699', (18, 22))
7536	28427189	Aberrant expression of TPX2 may be essential in both malignant transformation of respiratory epithelium and progression of squamous cell lung cancer.	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (123, 148))	('Aberrant', 'Var', (0, 8))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (123, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TPX2', 'Gene', (23, 27))	('TPX2', 'Gene', '22974', (23, 27))	('essential', 'Reg', (35, 44))	('squamous cell lung cancer', 'Disease', (123, 148))
7559	28427189	Clinical information of PRCC patients in GSE2748 were extracted from a published literature.	('GSE2748', 'Var', (41, 48))	('GSE2748', 'Chemical', '-', (41, 48))	('patients', 'Species', '9606', (29, 37))	('PRCC', 'Gene', '5546', (24, 28))	('Clinical', 'Species', '191496', (0, 8))	('PRCC', 'Gene', (24, 28))	('PRCC', 'Phenotype', 'HP:0006766', (24, 28))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))
7569	28427189	In order to explore the potential mechanism of how module genes impact correlative clinical feature, all genes of module of interest were mapped into the DAVID database and subjected to GO functional and KEGG pathway enrichment analysis.	('genes', 'Var', (58, 63))	('clinical', 'Species', '191496', (83, 91))	('impact', 'Reg', (64, 70))
7661	32209138	Silencing RSK4 expression decreased their expression (Fig.	('expression', 'MPA', (42, 52))	('RSK4', 'Gene', '27330', (10, 14))	('Silencing', 'Var', (0, 9))	('decreased', 'NegReg', (26, 35))	('RSK4', 'Gene', (10, 14))
7678	32209138	The variant protein of CD44 could alter the biological behaviour of cells and promote cell invasion and metastasis by affecting the skeletal and signal transmission systems in cells.	('affecting', 'Reg', (118, 127))	('CD44', 'Gene', '960', (23, 27))	('protein', 'cellular_component', 'GO:0003675', ('12', '19'))	('promote', 'PosReg', (78, 85))	('metastasis', 'CPA', (104, 114))	('CD44', 'Gene', (23, 27))	('signal transmission', 'biological_process', 'GO:0023060', ('145', '164'))	('biological behaviour of cells', 'CPA', (44, 73))	('behaviour', 'biological_process', 'GO:0007610', ('55', '64'))	('protein', 'Protein', (12, 19))	('alter', 'Reg', (34, 39))	('cell invasion', 'CPA', (86, 99))	('variant', 'Var', (4, 11))
7726	27993170	As with primary RCC tumors, the mutation status of cancer including VLH, cMET and TP53 and a general marker immunohistochemistry profile may serve to define the histotype of RCC cell lines (Table 1).	('cMET', 'Gene', '4233', (73, 77))	('TP53', 'Gene', (82, 86))	('primary RCC tumors', 'Disease', (8, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('cMET', 'Gene', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (32, 40))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', '7157', (82, 86))	('primary RCC tumors', 'Disease', 'MESH:C538614', (8, 26))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
7741	27993170	Germline met proto-oncogene (MET) and fumarate hydratase (FH) alterations are the hallmark of these cancer syndromes, but are infrequent in sporadic cases.	('MET', 'Gene', (29, 32))	('fumarate hydratase', 'Gene', '2271', (38, 56))	('cancer syndromes', 'Disease', 'MESH:D009369', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer syndromes', 'Disease', (100, 116))	('fumarate hydratase', 'Gene', (38, 56))	('alterations', 'Var', (62, 73))	('FH', 'Gene', '2271', (58, 60))
7749	27993170	The von Hippel-Lindau (VHL) gene is known to be most often mutated in renal cell carcinoma of clear cell type (ccRCC) in up to 90% of sporadic ccRCC cases and multiple surprising and contradictory reports on the VHL gene status in common RCC cell lines have been published (Additional file 1: Table S1).	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('renal cell carcinoma', 'Disease', (70, 90))	('von Hippel-Lindau', 'Gene', (4, 21))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('RCC', 'Disease', (238, 241))	('VHL', 'Gene', (23, 26))	('renal cell carcinoma of clear cell type', 'Phenotype', 'HP:0006770', (70, 109))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('von Hippel-Lindau', 'Gene', '7428', (4, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('mutated', 'Var', (59, 66))
7754	27993170	Mutations in BAP1 and PBRM1 in ccRCC tend to be mutually exclusive.	('BAP1', 'Gene', (13, 17))	('PBRM1', 'Gene', '55193', (22, 27))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', '8314', (13, 17))	('PBRM1', 'Gene', (22, 27))
7768	27993170	Moreover, this cell line harbors a c-met polymorphism that is specific for papillary RCC.	('polymorphism', 'Var', (41, 53))	('c-met', 'Gene', (35, 40))	('papillary RCC', 'Gene', (75, 88))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('c-met', 'Gene', '4233', (35, 40))	('papillary RCC', 'Gene', '5546', (75, 88))
7771	27993170	No mutations in VHL and HIF-1alpha mRNA in ACHN cell line, could confirm non-clear cell histology.	('VHL', 'Gene', (16, 19))	('ACHN', 'Gene', '55323', (43, 47))	('HIF-1alpha', 'Gene', '3091', (24, 34))	('ACHN', 'Gene', (43, 47))	('mutations', 'Var', (3, 12))	('HIF-1alpha', 'Gene', (24, 34))
7776	27993170	The 786-O RCC line is defective in VHL expression, as it harbors mutated VHL with altered HIF and VEGF (Vascular endothelial growth factor) pathways and gives rise to clear cell tumors in nude mice.	('VHL', 'Gene', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('Vascular endothelial growth factor', 'Gene', (104, 138))	('Vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('104', '138'))	('Vascular endothelial growth factor', 'Gene', '22339', (104, 138))	('clear cell tumors', 'Disease', 'MESH:D008649', (167, 184))	('nude mice', 'Species', '10090', (188, 197))	('clear cell tumors', 'Disease', (167, 184))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('gives rise to', 'Reg', (153, 166))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('altered', 'Reg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('mutated', 'Var', (65, 72))
7777	27993170	In this RCC model the vast majority (122/160) of genes induced by hypoxia in wt-VHL transfected 786-O (VHL +) cells are not significantly up-regulated in VHL mutated 786-O cells, confirming that the loss of VHL is not equivalent to hypoxic exposure and that in RCC, the VHL tumor suppressor has a distinct role from its activity in the hypoxia-inducible pathway.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('RCC', 'Disease', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('274', '290'))	('loss', 'Var', (199, 203))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('VHL tumor', 'Disease', (270, 279))	('tumor suppressor', 'biological_process', 'GO:0051726', ('274', '290'))	('hypoxia', 'Disease', 'MESH:D000860', (336, 343))	('hypoxia', 'Disease', (66, 73))	('hypoxic', 'Disease', (232, 239))	('hypoxia', 'Disease', (336, 343))	('hypoxic', 'Disease', 'MESH:D000860', (232, 239))	('VHL tumor', 'Disease', 'MESH:D006623', (270, 279))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('RCC', 'Disease', (261, 264))	('RCC', 'Phenotype', 'HP:0005584', (261, 264))
7795	27993170	The 769-P cell line, established along with 786-O by, harbors mutated vhl and secretes high levels of VEGF, suggesting a ccRCC phenotype (Additional file 1: Table S1 for ref).	('suggesting', 'Reg', (108, 118))	('secretes', 'MPA', (78, 86))	('harbors', 'Reg', (54, 61))	('RCC', 'Disease', (123, 126))	('vhl', 'Gene', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('mutated', 'Var', (62, 69))
7798	27993170	Another interesting cell line is RCC4, a vhl mutant derived from a primary tumor widely used as a model for VHL-dependant mechanisms, witha commercially available counterpart cell line with restored wild-type gene.	('mutant', 'Var', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
7802	27993170	Vhl is mutated in cell lines SMKT-R2 and SMKT-R3, and in SMKT-R2 and SMKT-R3 HIF-alpha proteins are expressed.	('mutated', 'Var', (7, 14))	('Vhl', 'Gene', '7428', (0, 3))	('Vhl', 'Gene', (0, 3))
7808	27993170	The MSKCC panel covers cell lines obtained from tumors that developed in the most common RCC metastases loci, including the adrenal glands (SK-RC-45), lymph nodes (SK-RC-18, SK-RC-26b), lungs (SK-RC-26a SK-RC-31, SK-RC-38 SK-RC-54), bones (SK-RC-42, SK-RC-46), soft tissue (SK-RC-17, SK-RC-39), and the brain (SK-RC-9, SK-RC-13).	('SK-RC-46', 'CellLine', 'CVCL:6193', (250, 258))	('SK-RC-38 SK-RC-54', 'CellLine', 'CVCL:6200', (213, 230))	('RCC metastases', 'Disease', (89, 103))	('SK-RC-42', 'CellLine', 'CVCL:6192', (240, 248))	('SK-RC-26', 'CellLine', 'CVCL:6183', (193, 201))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('SK-RC-13', 'CellLine', 'CVCL:6178', (319, 327))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('RCC metastases', 'Disease', 'MESH:D009362', (89, 103))	('SK-RC-39', 'CellLine', 'CVCL:4021', (284, 292))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('SK-RC-26', 'CellLine', 'CVCL:6183', (174, 182))	('SK-RC-9', 'CellLine', 'CVCL:6174', (310, 317))	('SK-RC-42', 'Var', (240, 248))	('SK-RC-17', 'Var', (274, 282))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('SK-RC-26a SK-RC-31', 'CellLine', 'CVCL:6183', (193, 211))
7816	27993170	In particular, five cell lines were derived from clear cell RCC (SNU-228, -267, -328, -349, and -1272), one from granular RCC (SNU-482), and one from mixed clear and granular RCC (SNU-333).	('SNU-228', 'Var', (65, 72))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('RCC', 'Disease', (122, 125))
7840	27993170	The former was transduced with human papilloma virus (HPV 16) E6/E7 genes while the latter ectopically expresses the catalytic subunit of telomerase (TERT).	('TERT', 'Gene', (150, 154))	('HPV 16', 'Species', '333760', (54, 60))	('papilloma', 'Phenotype', 'HP:0012740', (37, 46))	('TERT', 'Gene', '7015', (150, 154))	('E6/E7 genes', 'Var', (62, 73))	('human papilloma virus', 'Species', '10566', (31, 52))
7841	27993170	These modifications enable the cells to be cultured continuously constituting a convenient control for RCC cell lines.	('modifications', 'Var', (6, 19))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('RCC', 'Disease', 'MESH:C538614', (103, 106))
7853	27993170	SK-RC-42 and SK-RC-46 also represent bone metastasis-derived cell lines, as well as the CRBM-1990 cell line, while ACHN and 786-O cells transplanted into the left ventricle establish bone metastases.	('CRBM-1990', 'CellLine', 'CVCL:6893', (88, 97))	('ACHN', 'Gene', (115, 119))	('SK-RC-46', 'Var', (13, 21))	('SK-RC-46', 'CellLine', 'CVCL:6193', (13, 21))	('ACHN', 'Gene', '55323', (115, 119))	('metastases', 'Disease', (188, 198))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('SK-RC-42', 'CellLine', 'CVCL:6192', (0, 8))
7866	27993170	Apart from gene mutation, vhl promoter region methylation often occurs in ccRCC samples which effects in no protein expression.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('methylation', 'Var', (46, 57))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('occurs', 'Reg', (64, 70))	('protein expression', 'MPA', (108, 126))	('vhl', 'Gene', (26, 29))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))
7869	27993170	The ACHN cell line expresses the protein, but harbors a heterozygous nonsense mutation, while 786-O, 769-P, Caki-1, and A-498 express wild-type PBRM1.	('769-P', 'Var', (101, 106))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('PBRM1', 'Gene', (144, 149))	('ACHN', 'Gene', '55323', (4, 8))	('PBRM1', 'Gene', '55193', (144, 149))	('ACHN', 'Gene', (4, 8))	('786-O', 'Var', (94, 99))
7870	27993170	The PBRM1 mutation is also reported in Caki-2 and A-704 lines; loss-of-function gene mutations in A-704 and the deletion in exon 17 of the PBRM1 gene in Caki-2 results in no protein expression.	('PBRM1', 'Gene', '55193', (139, 144))	('protein expression', 'MPA', (174, 192))	('deletion in', 'Var', (112, 123))	('PBRM1', 'Gene', (4, 9))	('loss-of-function', 'NegReg', (63, 79))	('PBRM1', 'Gene', '55193', (4, 9))	('mutations', 'Var', (85, 94))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('PBRM1', 'Gene', (139, 144))
7873	27993170	The knockdown of PBRM1 in cells with wild-type gene increased the proliferation, migration and colony formation abilities, supporting this gene's important role in RCC progression, as the loss of PBRM1 was correlated with a worse disease outcome in patients.	('increased', 'PosReg', (52, 61))	('patients', 'Species', '9606', (249, 257))	('proliferation', 'CPA', (66, 79))	('PBRM1', 'Gene', (17, 22))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('PBRM1', 'Gene', (196, 201))	('formation', 'biological_process', 'GO:0009058', ('102', '111'))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('PBRM1', 'Gene', '55193', (17, 22))	('RCC', 'Disease', (164, 167))	('PBRM1', 'Gene', '55193', (196, 201))	('loss', 'Var', (188, 192))	('knockdown', 'Var', (4, 13))	('colony formation abilities', 'CPA', (95, 121))
7874	27993170	BAP1 mutants are available as UM-RC-6, 769-P, and SN12C cell lines; however, 769-P cells still produce the protein.	('BAP1', 'Gene', (0, 4))	('769-P', 'Var', (77, 82))	('SN12C', 'CellLine', 'CVCL:1705', (50, 55))	('BAP1', 'Gene', '8314', (0, 4))	('protein', 'cellular_component', 'GO:0003675', ('107', '114'))
7875	27993170	The reintroduction of the wild-type gene reduced cell proliferation and sensitized cells to treatment, and it was proposed that BAP1 is a tumor suppressor, as gene loss is associated with patients with higher-grade RCC.	('tumor', 'Disease', (138, 143))	('BAP1', 'Gene', '8314', (128, 132))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('cell proliferation', 'biological_process', 'GO:0008283', ('49', '67'))	('RCC', 'Disease', (215, 218))	('RCC', 'Phenotype', 'HP:0005584', (215, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('138', '154'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('138', '154'))	('cell proliferation', 'CPA', (49, 67))	('gene loss', 'Var', (159, 168))	('BAP1', 'Gene', (128, 132))	('higher-grade', 'Disease', (202, 214))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
7876	27993170	SETD2 mutations have also been detected in A-498, A-704, Caki-1, and RCC-ER, PTEN mutations in 786-O, and OS-RC-2, while no mutated RCC cell lines could be found for KDM5C.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('KDM5C', 'Gene', '8242', (166, 171))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('SETD2', 'Gene', '29072', (0, 5))	('PTEN', 'Gene', (77, 81))	('SETD2', 'Gene', (0, 5))	('mutations', 'Var', (82, 91))	('PTEN', 'Gene', '5728', (77, 81))	('OS-RC-2', 'CellLine', 'CVCL:1626', (106, 113))	('KDM5C', 'Gene', (166, 171))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('mutations', 'Var', (6, 15))
7877	27993170	An mTOR mutation was found for SNU349 and RCC-ER cell lines only (see Additional file 1: Table S1 for ref).	('mTOR', 'Gene', '2475', (3, 7))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('mutation', 'Var', (8, 16))	('RCC', 'Disease', (42, 45))	('mTOR', 'Gene', (3, 7))
7878	27993170	Studies on SETD2-defective RCC cells proved that the mutation of this gene affects DNA repair and may correlate with in vivo disease progression.	('affects', 'Reg', (75, 82))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('mutation', 'Var', (53, 61))	('DNA repair', 'biological_process', 'GO:0006281', ('83', '93'))	('DNA', 'cellular_component', 'GO:0005574', ('83', '86'))	('SETD2', 'Gene', '29072', (11, 16))	('SETD2', 'Gene', (11, 16))	('DNA repair', 'MPA', (83, 93))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('correlate with', 'Reg', (102, 116))
7885	27993170	This cell line was also shown to contain an NF2 mutation, together with SN12C, while Caki-1, A-704, 769-P, TK10, 786-O, A-498, and OS-RC-2 were confirmed to be wild-type for NF2.	('NF2', 'Gene', '4771', (44, 47))	('SN12C', 'CellLine', 'CVCL:1705', (72, 77))	('OS-RC-2', 'CellLine', 'CVCL:1626', (131, 138))	('NF2', 'Gene', '4771', (174, 177))	('A-704', 'Var', (93, 98))	('mutation', 'Var', (48, 56))	('NF2', 'Gene', (44, 47))	('NF2', 'Gene', (174, 177))
7887	27993170	A FAT1 mutation was found in Caki-1, OS-RC-2, SN12C, RCC-FG2, and TK10 (COSMIC database) but no functional analysis of this gene in in vitro RCC was reported.	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('FAT1', 'Gene', '2195', (2, 6))	('SN12C', 'CellLine', 'CVCL:1705', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('FAT1', 'Gene', (2, 6))	('mutation', 'Var', (7, 15))	('OS-RC-2', 'CellLine', 'CVCL:1626', (37, 44))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
7888	27993170	Chromosome aberrations present in pRCC include chromosomes 7 and 17 gains and 9p loss.	('chromosomes', 'Var', (47, 58))	('pRCC', 'Gene', (34, 38))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('loss', 'NegReg', (81, 85))	('gains', 'PosReg', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('pRCC', 'Gene', '5546', (34, 38))
7890	27993170	TP53 tumor-suppressor mutations, present in 50% of tumor cases in general, are less frequent in RCC (around 20% cases), but confirmed in 786-O, A-498 (COSMIC and CCLE databases),,SN12C, TK10 and reported as wild-type in ACHN, Caki-1, and Caki-2.	('RCC', 'Disease', (96, 99))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('tumor', 'Disease', (51, 56))	('ACHN', 'Gene', '55323', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', (5, 10))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('SN12C', 'CellLine', 'CVCL:1705', (179, 184))	('ACHN', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
7897	27993170	Athymic nude mice are hairless, an effect of the Foxn1nu (Forkhead box protein N1) mutation, but more importantly they lack a thymus and are T-cell deficient but produce functional B-cells.	('protein', 'cellular_component', 'GO:0003675', ('71', '78'))	('Foxn1', 'Gene', (49, 54))	('nude mice', 'Species', '10090', (8, 17))	('Foxn1', 'Gene', '15218', (49, 54))	('mutation', 'Var', (83, 91))	('lack', 'NegReg', (119, 123))
7910	27993170	Ectopic xenograft models of athymic nude mice with various genetic backgrounds have been extensively used for studying established RCC lines, including 769-P, 786-O, Caki-1, SK-RC-38, SK-RC-42, SK-RC-44, SK-RC-45, SK-RC-46, and others.	('SK-RC-44', 'CellLine', 'CVCL:4022', (194, 202))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('SK-RC-42', 'Var', (184, 192))	('nude mice', 'Species', '10090', (36, 45))	('SK-RC-38', 'Var', (174, 182))	('SK-RC-42', 'CellLine', 'CVCL:6192', (184, 192))	('SK-RC-44', 'Var', (194, 202))	('SK-RC-38', 'CellLine', 'CVCL:6189', (174, 182))	('SK-RC-46', 'CellLine', 'CVCL:6193', (214, 222))
8030	22381246	We evaluated prevalence of RCC within a prospectively-accrued series of 219 patients found to have pathogenic germline PTEN mutations.	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (124, 133))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
8037	22381246	IHC demonstrated complete loss of PTEN protein in all PTEN mutation positive patients' pRCCs and patchy positivity in one chRCC.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('pRCC', 'Gene', '5546', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('pRCC', 'Gene', (87, 91))	('PTEN', 'Gene', (54, 58))	('patients', 'Species', '9606', (77, 85))	('mutation', 'Var', (59, 67))	('loss', 'NegReg', (26, 30))	('PTEN', 'Gene', '5728', (54, 58))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
8043	22381246	It is assumed that individuals with BRRS or another clinical diagnosis who have germline PTEN mutation, i.e.	('mutation', 'Var', (94, 102))	('BRRS', 'Disease', (36, 40))	('BRRS', 'Disease', 'None', (36, 40))	('PTEN', 'Gene', (89, 93))	('PTEN', 'Gene', '5728', (89, 93))
8047	22381246	It seems reasonable that patients with PHTS, who have one mutated PTEN gene in all bodily tissues, would be at increased risk for RCC.	('PHTS', 'Gene', (39, 43))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('PHTS', 'Gene', '116372', (39, 43))	('patients', 'Species', '9606', (25, 33))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('mutated', 'Var', (58, 65))
8052	22381246	Mutation analysis for all subjects included promoter sequencing and mutation scanning of all exons and flanking intronic regions by denaturing gel gradient electrophoresis (DGGE) or LightScanner technology; variants detected by DGGE or LightScanner were confirmed with single exon Sanger sequencing as per routine of the Eng lab as previously described.	('Eng', 'Gene', '2022', (321, 324))	('variants', 'Var', (207, 215))	('Eng', 'Gene', (321, 324))
8062	22381246	Of the 3,333 eligible research participants, 219 were found to have pathogenic germline PTEN mutations.	('mutations', 'Var', (93, 102))	('participants', 'Species', '9606', (31, 43))	('PTEN', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (88, 92))	('pathogenic', 'Reg', (68, 78))
8064	22381246	Nine of the 219 PTEN mutation positive patients were identified with a prevalent or incident history of RCC (Table 1).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('patients', 'Species', '9606', (39, 47))	('mutation', 'Var', (21, 29))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', '5728', (16, 20))	('RCC', 'Disease', (104, 107))
8065	22381246	Thus, the age-adjusted SIR for RCC in this PTEN mutation positive group is 31.7 (95% CI 15.4-58.1, p<0.001).	('PTEN', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))	('PTEN', 'Gene', '5728', (43, 47))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
8067	22381246	Family history was absent for RCC in the relatives of our 9 patients with germline PTEN mutation and RCC.	('mutation', 'Var', (88, 96))	('PTEN', 'Gene', '5728', (83, 87))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('patients', 'Species', '9606', (60, 68))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('PTEN', 'Gene', (83, 87))
8084	22381246	However, reduced Pten dose has been associated with risk of tumorigenesis in murine models, implicating that this patient's PTEN mutation may still have contributed to this cancer risk.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('PTEN', 'Gene', (124, 128))	('cancer', 'Disease', (173, 179))	('mutation', 'Var', (129, 137))	('PTEN', 'Gene', '5728', (124, 128))	('murine', 'Species', '10090', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('Pten', 'Gene', (17, 21))	('reduced', 'NegReg', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Pten', 'Gene', '19211', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('patient', 'Species', '9606', (114, 121))	('tumor', 'Disease', (60, 65))
8088	22381246	Eight of the nine patients in this series have germline PTEN mutations which are predicted to lead to protein truncation, the most common type of mutation observed in PHTS.	('PTEN', 'Gene', (56, 60))	('PHTS', 'Gene', (167, 171))	('PTEN', 'Gene', '5728', (56, 60))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('mutations', 'Var', (61, 70))	('PHTS', 'Gene', '116372', (167, 171))	('protein truncation', 'MPA', (102, 120))	('lead to', 'Reg', (94, 101))	('patients', 'Species', '9606', (18, 26))
8089	22381246	Four patients possessed the mutations Arg130Ter and Arg335Ter which are well-studied "hot-spot" mutations.	('Arg130Ter', 'Var', (38, 47))	('Ter', 'cellular_component', 'GO:0097047', ('58', '61'))	('patients', 'Species', '9606', (5, 13))	('Arg130Ter', 'Chemical', '-', (38, 47))	('Ter', 'cellular_component', 'GO:0097047', ('44', '47'))	('Arg335Ter', 'Var', (52, 61))	('Arg335Ter', 'SUBSTITUTION', 'None', (52, 61))
8090	22381246	Arg130Ter is within PTEN's phosphatase core motif; mutations in this area destroy PTEN's ability to dephosphorylate protein and lipid substrates, thereby causing loss of its tumor suppression functions.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (51, 60))	('protein', 'cellular_component', 'GO:0003675', ('116', '123'))	('loss', 'NegReg', (162, 166))	('ability', 'MPA', (89, 96))	('Arg130Ter', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('core', 'cellular_component', 'GO:0019013', ('39', '43'))	('destroy', 'NegReg', (74, 81))	('PTEN', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('lipid', 'Chemical', 'MESH:D008055', (128, 133))	('PTEN', 'Gene', '5728', (82, 86))	('PTEN', 'Gene', (20, 24))	('Ter', 'cellular_component', 'GO:0097047', ('6', '9'))	('PTEN', 'Gene', '5728', (20, 24))	('phosphatase', 'molecular_function', 'GO:0016791', ('27', '38'))
8091	22381246	This type of mutation has been shown to prevent PTEN from exiting the nucleus, limiting its ability to promote apoptosis through the AKT pathway.	('PTEN', 'Gene', (48, 52))	('limiting', 'NegReg', (79, 87))	('PTEN', 'Gene', '5728', (48, 52))	('apoptosis', 'biological_process', 'GO:0097194', ('111', '120'))	('apoptosis', 'biological_process', 'GO:0006915', ('111', '120'))	('AKT', 'Gene', (133, 136))	('mutation', 'Var', (13, 21))	('AKT', 'Gene', '207', (133, 136))	('nucleus', 'cellular_component', 'GO:0005634', ('70', '77'))	('promote', 'PosReg', (103, 110))	('apoptosis', 'CPA', (111, 120))
8092	22381246	This evidence may show that RCC tends to occur in those patients with a PTEN mutation predicted to cause a more severe phenotypic outcome.	('patients', 'Species', '9606', (56, 64))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('PTEN', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('PTEN', 'Gene', '5728', (72, 76))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
8098	22381246	A study by the Centers for Disease Control and Prevention estimated cost-effectiveness ratios of $45,000-$75,000 per year-life saved when mutation analysis is performed on colorectal cases with abnormal IHC results, implicating a risk for germline mutation in one of the four mismatch repair genes.	('mismatch repair', 'biological_process', 'GO:0006298', ('272', '287'))	('germline mutation', 'Var', (239, 256))	('colorectal', 'Disease', (172, 182))	('colorectal', 'Disease', 'MESH:D015179', (172, 182))
8099	22381246	Cost-effectiveness is increased further when family members of a mutation positive individual are able to discover their mutation status and pursue earlier and more frequent colonoscopy screening to remove adenomatous polyps and identify tumors at the earliest, most treatable stage.	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('adenomatous polyps', 'Disease', (206, 224))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('mutation', 'Var', (65, 73))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (206, 224))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Disease', (238, 244))	('adenomatous polyps', 'Disease', 'MESH:D018256', (206, 224))
8104	22381246	If a gene mutation can be identified, predictive testing can be offered to at-risk relatives to help them learn their genetic status, and if mutation positive, seek preventive screening and surgical measures to reduce their cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('mutation', 'Var', (10, 18))
8115	22381246	Our group has previously identified variants in the SDHB and SDHD genes and germline hypermethylation of KILLIN as being involved in PTEN mutation negative Cowden and Cowden-like syndromes.	('SDHB', 'Gene', (52, 56))	('SDHD', 'Gene', '6392', (61, 65))	('involved', 'Reg', (121, 129))	('PTEN', 'Gene', (133, 137))	('SDHD', 'Gene', (61, 65))	('Cowden', 'Disease', (156, 162))	('variants', 'Var', (36, 44))	('SDHB', 'Gene', '6390', (52, 56))	('PTEN', 'Gene', '5728', (133, 137))	('Cowden-like syndromes', 'Disease', (167, 188))	('KILLIN', 'Gene', (105, 111))	('KILLIN', 'Gene', '100144748', (105, 111))
8116	22381246	This preliminary work and other reports have shown that variation in SDHB/D and germline KILLIN hypermethylation are associated with increased risks of RCC over those with germline PTEN mutations.	('SDHB', 'Gene', (69, 73))	('KILLIN', 'Gene', (89, 95))	('KILLIN', 'Gene', '100144748', (89, 95))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('associated', 'Reg', (117, 127))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('variation', 'Var', (56, 65))	('SDHB', 'Gene', '6390', (69, 73))	('PTEN', 'Gene', (181, 185))	('PTEN', 'Gene', '5728', (181, 185))	('hypermethylation', 'Var', (96, 112))
8121	25097537	Expression of Von Hippel - Lindau (VHL) gene mutation in diagnosed cases of renal cell carcinoma Objective: To evaluate the expression of Von Hippel Lindau (VHL) gene in diagnosed cases of renal cell carcinoma.	('renal cell carcinoma.', 'Phenotype', 'HP:0005584', (189, 210))	('Von Hippel - Lindau', 'Disease', (14, 33))	('renal cell carcinoma', 'Disease', (76, 96))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('Von Hippel Lindau', 'Disease', (138, 155))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('VHL', 'Gene', (157, 160))	('Von Hippel - Lindau', 'Disease', 'MESH:D006623', (14, 33))	('mutation', 'Var', (45, 53))	('VHL', 'Gene', '7428', (157, 160))	('VHL', 'Gene', (35, 38))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('renal cell carcinoma', 'Disease', (189, 209))	('Von Hippel Lindau', 'Disease', 'MESH:D006623', (138, 155))	('VHL', 'Gene', '7428', (35, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
8123	25097537	A mutation in both copies of VHL gene within the same cell increases the risk of certain neoplasm.	('neoplasm', 'Disease', (89, 97))	('neoplasm', 'Disease', 'MESH:D009369', (89, 97))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('VHL', 'Gene', (29, 32))	('mutation in', 'Var', (2, 13))	('increases', 'PosReg', (59, 68))
8124	25097537	VHL carriers have a greatly increased risk of developing tumors compared to the general population.	('VHL', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('carriers', 'Var', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
8127	25097537	Therefore 75% to 80% of renal cell carcinomas are sporadic and show biallelic VHL gene defect.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('renal cell carcinomas', 'Disease', (24, 45))	('defect', 'Var', (87, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('VHL', 'Gene', (78, 81))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (24, 45))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (24, 45))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (24, 44))
8128	25097537	Trisomies of 3, 7, 12, 16, 17, 20, loss of Y chromosome for hereditary papillary renal cell carcinoma and c-Met mutations are responsible for sporadic papillary renal cell carcinoma.,- The present study is based on assessment of presence or absence of VHL mutations using Polymerase Chain Reaction in cases of renal cell carcinoma in our population.	('VHL', 'Gene', (252, 255))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 181))	('mutations', 'Var', (256, 265))	('sporadic papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (142, 181))	('hereditary papillary renal cell carcinoma', 'Disease', (60, 101))	('sporadic papillary renal cell carcinoma', 'Disease', (142, 181))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (161, 181))	('c-Met', 'Gene', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (81, 101))	('renal cell carcinoma.', 'Phenotype', 'HP:0005584', (161, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (71, 101))	('Y chromosome', 'cellular_component', 'GO:0000806', ('43', '55'))	('renal cell carcinoma', 'Disease', (310, 330))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (60, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (310, 330))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (151, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('papillary renal cell carcinoma.', 'Phenotype', 'HP:0006766', (151, 182))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 101))	('c-Met', 'Gene', '4233', (106, 111))
8147	25097537	Both the cases of papillary RCC were positive for mutations.	('mutations', 'Var', (50, 59))	('positive', 'Reg', (37, 45))	('papillary RCC', 'Disease', 'MESH:C538614', (18, 31))	('papillary RCC', 'Disease', (18, 31))
8149	25097537	Majority of clear cell carcinoma that is 95.23% (except one case), both the cases (100%) of papillary renal cell carcinoma and 75% hybrid tumors showed VHL mutations.	('VHL', 'Gene', (152, 155))	('papillary renal cell carcinoma', 'Disease', (92, 122))	('mutations', 'Var', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (12, 32))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (92, 122))	('clear cell carcinoma', 'Disease', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
8150	25097537	proposed that mutations in exon 2 leads to the VHL disease phenotype.	('leads to', 'Reg', (34, 42))	('VHL disease', 'Disease', (47, 58))	('mutations', 'Var', (14, 23))	('VHL disease', 'Disease', 'MESH:D006623', (47, 58))
8151	25097537	Single case of CCRCC that was negative for mutations in our study could be due to possibility of other gene mutations involved such as FH, SDH, PBRM 1, and BAP 1 as expressed by Gomey and Silva and Pawloski et al.	('SDH', 'Gene', (139, 142))	('BAP 1', 'Gene', (156, 161))	('mutations', 'Var', (108, 117))	('BAP 1', 'Gene', '8314', (156, 161))	('FH', 'Disease', 'MESH:D006938', (135, 137))	('SDH', 'Gene', '10993', (139, 142))	('CCRCC', 'Disease', (15, 20))	('PBRM 1', 'Gene', '55193', (144, 150))	('PBRM 1', 'Gene', (144, 150))
8152	25097537	An interesting finding in this study was that the 03 Hybrid tumors with foci of clear cells admixed with papillary and oncocytic pattern also showed the VHL mutations .Single case of hybrid tumor with large areas of chromophobe pattern was negative for mutations as in these cases other genes like BHD or FLCN mutations has been implicated as expressed in studies by Gatalcia et al and Adley et al.	('mutations', 'Var', (310, 319))	('FLCN', 'Gene', '201163', (305, 309))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('BHD', 'Gene', '50947', (298, 301))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('FLCN', 'Gene', (305, 309))	('BHD', 'Gene', (298, 301))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
8154	25097537	In the present study a single case of chronic pyelonephritis with end stage kidney from nephrectomy specimen of a 41 year old male patient which was processed as negative control for VHL surprisingly showed exon 3 VHL mutation.	('pyelonephritis', 'Phenotype', 'HP:0012330', (46, 60))	('VHL', 'Gene', (214, 217))	('exon 3', 'Var', (207, 213))	('pyelonephritis', 'Disease', 'MESH:D011704', (46, 60))	('pyelonephritis', 'Disease', (46, 60))
8155	25097537	As cited by Alpeers, some individuals with inherited germiline VHL mutations never develop cancer as second mutation never occurs.	('germiline', 'Var', (53, 62))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (67, 76))	('VHL', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
8157	25097537	Hemminki reports welding fumes as a risk factor and lay stress on consumption of vegetables, citrus fruits and selenium as protective factors against multiple mutations of VHL in RCC.	('VHL', 'Gene', (172, 175))	('mutations', 'Var', (159, 168))	('RCC', 'Gene', (179, 182))	('selenium', 'Chemical', 'MESH:D012643', (111, 119))
8160	25097537	Large scale study is recommended for detection of coexistence of other genes like c-Met pathway, BHD gene mutations or PBRM1 with VHL gene for the detection of causative genes for each morphological type of RCC.	('PBRM1', 'Gene', (119, 124))	('PBRM1', 'Gene', '55193', (119, 124))	('c-Met pathway', 'Pathway', (82, 95))	('BHD gene', 'Gene', (97, 105))	('mutations', 'Var', (106, 115))
8211	20679884	In clear cell RCC, inactivation of the vHL gene allows HIF 1-alpha to escape degradation, which leads to activation of downstream targets such as vascular endothelial growth factor (VEGF), GLUT-1, and CA IX.	('RCC', 'Disease', (14, 17))	('vHL', 'Gene', '7428', (39, 42))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('146', '180'))	('CA IX', 'Gene', '768', (201, 206))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('activation', 'PosReg', (105, 115))	('inactivation', 'Var', (19, 31))	('vascular endothelial growth factor', 'Gene', '7422', (146, 180))	('degradation', 'biological_process', 'GO:0009056', ('77', '88'))	('VEGF', 'Gene', (182, 186))	('vHL', 'Gene', (39, 42))	('HIF 1-alpha', 'Gene', (55, 66))	('vascular endothelial growth factor', 'Gene', (146, 180))	('GLUT-1', 'Gene', '6513', (189, 195))	('GLUT-1', 'Gene', (189, 195))	('HIF 1-alpha', 'Gene', '3091', (55, 66))	('CA IX', 'Gene', (201, 206))	('VEGF', 'Gene', '7422', (182, 186))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
8239	20679884	Immunoreactivity for phosphorylated S6 represents a measure of activation of the mammalian target of rapamycin (mTOR) pathway that promotes cell growth, is highly active in many RCC, and can be targeted for therapy.	('mammalian target of rapamycin', 'Gene', '2475', (81, 110))	('mammalian target of rapamycin', 'Gene', (81, 110))	('phosphorylated', 'Var', (21, 35))	('cell growth', 'biological_process', 'GO:0016049', ('140', '151'))	('active', 'MPA', (163, 169))	('cell growth', 'CPA', (140, 151))	('mTOR', 'Gene', '2475', (112, 116))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('mTOR', 'Gene', (112, 116))	('promotes', 'PosReg', (131, 139))	('activation', 'PosReg', (63, 73))
8274	20679884	Contrary to what in vitro studies might suggest, WT-1 and Bcl2 were infrequently expressed in Xp11 translocation RCC, despite the fact that the related transcription factor MiTF is known to induce BcL2 expression in osteoclasts and melanoma cells whereas over expression TFE3 or TFEB in NIH 3T3 cells are known to activate WT-1.	('Xp11', 'Gene', (94, 98))	('Bcl2', 'molecular_function', 'GO:0015283', ('58', '62'))	('BcL2', 'molecular_function', 'GO:0015283', ('197', '201'))	('melanoma', 'Phenotype', 'HP:0002861', (232, 240))	('melanoma', 'Disease', (232, 240))	('expression', 'MPA', (202, 212))	('NIH 3T3', 'CellLine', 'CVCL:0594', (287, 294))	('BcL2', 'Gene', '12043', (197, 201))	('Xp11', 'Gene', '111712', (94, 98))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('melanoma', 'Disease', 'MESH:D008545', (232, 240))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('transcription factor', 'molecular_function', 'GO:0000981', ('152', '172'))	('induce', 'PosReg', (190, 196))	('MiTF', 'Var', (173, 177))	('BcL2', 'Gene', (197, 201))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))
8278	27713405	Here we perform a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, single-nucleotide polymorphism array, fluorescence in situ hybridization, immunohistochemistry and cell-based assays.	('uRCC', 'Gene', (62, 66))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('uRCC', 'Gene', '54894', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('single-nucleotide', 'Var', (131, 148))
8280	27713405	Integrated analysis reveals a subset of 26% uRCC characterized by NF2 loss, dysregulated Hippo-YAP pathway and worse survival, whereas 21% uRCC with mutations of MTOR, TSC1, TSC2 or PTEN and hyperactive mTORC1 signalling are associated with better clinical outcome.	('MTOR', 'Gene', (162, 166))	('mTORC1', 'Gene', '382056', (203, 209))	('loss', 'NegReg', (70, 74))	('MTOR', 'Gene', '2475', (162, 166))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('PTEN', 'Gene', '5728', (182, 186))	('TSC2', 'Gene', (174, 178))	('mTORC1', 'cellular_component', 'GO:0031931', ('203', '209'))	('mutations', 'Var', (149, 158))	('uRCC', 'Gene', '54894', (44, 48))	('TSC1', 'Gene', (168, 172))	('hyperactive', 'Disease', 'MESH:D006948', (191, 202))	('uRCC', 'Gene', (44, 48))	('hyperactive', 'Disease', (191, 202))	('signalling', 'biological_process', 'GO:0023052', ('210', '220'))	('uRCC', 'Gene', '54894', (139, 143))	('NF2', 'Gene', (66, 69))	('dysregulated', 'Reg', (76, 88))	('PTEN', 'Gene', (182, 186))	('TSC1', 'Gene', '7248', (168, 172))	('mTORC1', 'Gene', (203, 209))	('uRCC', 'Gene', (139, 143))	('Hippo-YAP pathway', 'Pathway', (89, 106))	('TSC2', 'Gene', '7249', (174, 178))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
8293	27713405	We find recurrent somatic mutations in 29 genes, and identify distinct molecular subsets that are characterized by NF2 loss, hyperactive mTORC1 signalling, FH deficiency, chromatin/DNA damage regulator mutations or ALK translocation and associated with varying clinical outcomes.	('ALK', 'Gene', (215, 218))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('mTORC1', 'Gene', '382056', (137, 143))	('FH deficiency', 'Disease', (156, 169))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('ALK', 'Gene', '238', (215, 218))	('signalling', 'biological_process', 'GO:0023052', ('144', '154'))	('mutations', 'Var', (26, 35))	('NF2', 'Gene', (115, 118))	('mTORC1', 'Gene', (137, 143))	('FH deficiency', 'Disease', 'MESH:D006938', (156, 169))	('hyperactive', 'Disease', (125, 136))	('loss', 'NegReg', (119, 123))	('hyperactive', 'Disease', 'MESH:D006948', (125, 136))	('chromatin', 'cellular_component', 'GO:0000785', ('171', '180'))	('mutations', 'Var', (202, 211))
8298	27713405	We identified 29 recurrently mutated genes with an average of 2.6 (0-8) protein-coding somatic mutations per patient tumour (Fig.	('patient', 'Species', '9606', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('protein', 'cellular_component', 'GO:0003675', ('72', '79'))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (95, 104))	('tumour', 'Disease', (117, 123))
8300	27713405	The incidence of NF2 mutations in our cohort is markedly higher than what is reported in ccRCC (0-1%), pRCC (0-6%) and chRCC (0%).	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('mutations', 'Var', (21, 30))	('pRCC', 'Gene', '5546', (103, 107))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('RCC', 'Disease', (121, 124))	('higher', 'PosReg', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('pRCC', 'Gene', (103, 107))	('NF2', 'Gene', (17, 20))	('RCC', 'Disease', (104, 107))
8301	27713405	In ccRCC, VHL mutations occur at ~75%, and SETD2 and BAP1 at 10-20% frequencies, whereas in our uRCC cohort, only a single VHL mutation was detected in one case (T08).	('VHL', 'Gene', '7428', (10, 13))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('uRCC', 'Gene', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('SETD2', 'Gene', '29072', (43, 48))	('VHL', 'Gene', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('SETD2', 'Gene', (43, 48))	('RCC', 'Disease', (5, 8))	('uRCC', 'Gene', '54894', (96, 100))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('VHL', 'Gene', '7428', (123, 126))	('BAP1', 'Gene', '8314', (53, 57))	('VHL', 'Gene', (10, 13))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', (53, 57))
8303	27713405	The enrichment of cases with NF2 mutations (11 of 62) discovered in our uRCC cohort suggests that NF2 loss could potentially define a molecular subset of uRCC.	('uRCC', 'Gene', (154, 158))	('uRCC', 'Gene', (72, 76))	('mutations', 'Var', (33, 42))	('uRCC', 'Gene', '54894', (72, 76))	('uRCC', 'Gene', '54894', (154, 158))	('loss', 'NegReg', (102, 106))	('NF2', 'Gene', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('NF2', 'Gene', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
8304	27713405	To assess the NF2 status in uRCC beyond mutations, we next assessed the status of chromosome 22q12 where NF2 resides.	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('uRCC', 'Gene', (28, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('mutations', 'Var', (40, 49))	('uRCC', 'Gene', '54894', (28, 32))
8305	27713405	High-resolution, genome-wide SNP array analysis was performed for 15 of the 16 uRCC cases carrying NF2 mutations and/or exhibiting 22q12 copy-number loss (referred to as the 'NF2 loss' subset from here onwards; Fig.	('mutations', 'Var', (103, 112))	('uRCC', 'Gene', (79, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('uRCC', 'Gene', '54894', (79, 83))	('NF2', 'Gene', (99, 102))
8306	27713405	Thirteen cases were confirmed to exhibit hemizygous loss of 22q and the remaining two tumours (T22 and T64), known to carry NF2 somatic mutations, showed copy-neutral loss of heterozygosity (LOH) of 22q (Supplementary Fig.	('hemizygous loss', 'Disease', 'MESH:C564097', (41, 56))	('NF2', 'Gene', (124, 127))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('hemizygous loss', 'Disease', (41, 56))	('mutations', 'Var', (136, 145))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('loss of', 'NegReg', (167, 174))
8310	27713405	Germline mutation of NF2 is the principal genetic event underlying the human neurofibromatosis type 2 cancer predisposition syndrome.	('NF2', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('neurofibromatosis type 2 cancer', 'Disease', (77, 108))	('neurofibromatosis type 2 cancer', 'Disease', 'MESH:D009369', (77, 108))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (77, 94))	('Germline mutation', 'Var', (0, 17))	('human', 'Species', '9606', (71, 76))
8311	27713405	The role of NF2 as a tumour suppressor gene is further demonstrated by mouse models in which genetic loss of Nf2 results in various cancers.	('cancers', 'Disease', (132, 139))	('Nf2', 'Gene', (109, 112))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('Nf2', 'Gene', '18016', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('results in', 'Reg', (113, 123))	('tumour', 'Disease', (21, 27))	('mouse', 'Species', '10090', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('genetic loss', 'Var', (93, 105))
8312	27713405	We first focused on the NF2-Hippo tumour suppressor network, which was highlighted by a series of reports showing that NF2 enforces the Hippo tumour suppression signalling pathway by phosphorylating, sequestering, degrading and suppressing YAP/TAZ nuclear translocation, thereby disrupting oncogenic transcription.	('tumour', 'Disease', (142, 148))	('signalling pathway', 'biological_process', 'GO:0007165', ('161', '179'))	('transcription', 'biological_process', 'GO:0006351', ('300', '313'))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('degrading', 'NegReg', (214, 223))	('sequestering', 'MPA', (200, 212))	('NF2', 'Var', (119, 122))	('phosphorylating', 'MPA', (183, 198))	('enforces', 'PosReg', (123, 131))	('YAP/TAZ', 'MPA', (240, 247))	('disrupting', 'NegReg', (279, 289))	('tumour', 'Disease', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('oncogenic transcription', 'CPA', (290, 313))	('sequestering', 'biological_process', 'GO:0051235', ('200', '212'))	('suppressing', 'NegReg', (228, 239))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
8323	27713405	Furthermore, the occurrence of SETD2 (3p21) mutation was significantly higher in the NF2 loss than in the remaining uRCC tumours (44% versus 9%, Fisher's exact test, P=0.004).	('SETD2', 'Gene', (31, 36))	('higher', 'PosReg', (71, 77))	('uRCC tumours', 'Disease', 'MESH:D009369', (116, 128))	('mutation', 'Var', (44, 52))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('uRCC tumours', 'Disease', (116, 128))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('SETD2', 'Gene', '29072', (31, 36))	('NF2', 'Gene', (85, 88))	('loss', 'NegReg', (89, 93))
8327	27713405	Recurrent mutations of the other chromatin modulating genes including BAP1 did not show significant enrichment in the NF2 loss subset.	('chromatin', 'cellular_component', 'GO:0000785', ('33', '42'))	('BAP1', 'Gene', '8314', (70, 74))	('NF2', 'Gene', (118, 121))	('BAP1', 'Gene', (70, 74))	('loss', 'NegReg', (122, 126))	('mutations', 'Var', (10, 19))
8330	27713405	Nevertheless, as small number of RCC with NF2 mutations have been recently reported in pRCC and collecting duct RCC, it remains to be determined whether these tumours were distinct from or overlapped with our NF2 loss uRCC.	('NF2', 'Gene', (42, 45))	('loss uRCC', 'Disease', (213, 222))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('reported', 'Reg', (75, 83))	('tumours', 'Disease', (159, 166))	('pRCC', 'Gene', '5546', (87, 91))	('mutations', 'Var', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('loss uRCC', 'Disease', 'MESH:D014786', (213, 222))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('RCC', 'Disease', (33, 36))	('pRCC', 'Gene', (87, 91))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
8331	27713405	Somatic mutation analysis of our uRCC cohort demonstrated that potentially mTORC1 pathway activating mutations comprising MTOR (5), TSC1 (4), TSC2 (3) and PTEN (4) occurred mutually exclusively in 16 (26%) cases, which might indicate another distinct subset (Fig.	('mutations', 'Var', (101, 110))	('PTEN', 'Gene', (155, 159))	('TSC2', 'Gene', '7249', (142, 146))	('PTEN', 'Gene', '5728', (155, 159))	('uRCC', 'Gene', '54894', (33, 37))	('mTORC1', 'cellular_component', 'GO:0031931', ('75', '81'))	('mTORC1', 'Gene', (75, 81))	('TSC2', 'Gene', (142, 146))	('MTOR', 'Gene', (122, 126))	('uRCC', 'Gene', (33, 37))	('activating', 'PosReg', (90, 100))	('TSC1', 'Gene', '7248', (132, 136))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('mTORC1', 'Gene', '382056', (75, 81))	('MTOR', 'Gene', '2475', (122, 126))	('TSC1', 'Gene', (132, 136))
8332	27713405	Mutations of these genes have been described in ccRCC (12%), pRCC (8%) and chRCC (9%).	('described', 'Reg', (35, 44))	('pRCC', 'Gene', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('Mutations', 'Var', (0, 9))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))
8333	27713405	Of the MTOR mutations seen in this cohort (Fig.	('mutations', 'Var', (12, 21))	('MTOR', 'Gene', (7, 11))	('MTOR', 'Gene', '2475', (7, 11))
8334	27713405	3b), I1973F has been described and shown to be hyperactive in cell-based assays, whereas L2427R (recurred three times in our uRCC cohort) and V2475M mutations have not yet been reported.	('V2475M', 'SUBSTITUTION', 'None', (142, 148))	('hyperactive', 'Disease', (47, 58))	('hyperactive', 'Disease', 'MESH:D006948', (47, 58))	('uRCC', 'Gene', (125, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('L2427R', 'Var', (89, 95))	('L2427R', 'SUBSTITUTION', 'None', (89, 95))	('I1973F', 'Var', (5, 11))	('I1973F', 'SUBSTITUTION', 'None', (5, 11))	('uRCC', 'Gene', '54894', (125, 129))	('V2475M', 'Var', (142, 148))
8335	27713405	To interrogate the functional impact of individual MTOR mutations, we generated MTOR L2427R and V2475M mutants, and assessed the mTORC1 activity by phosphorylation of S6K and 4EBP1, two key mTORC1 downstream substrates.	('mTORC1', 'Gene', (190, 196))	('MTOR', 'Gene', '2475', (51, 55))	('V2475M', 'SUBSTITUTION', 'None', (96, 102))	('MTOR', 'Gene', (80, 84))	('mTORC1', 'cellular_component', 'GO:0031931', ('129', '135'))	('mTORC1', 'Gene', (129, 135))	('L2427R', 'Var', (85, 91))	('L2427R', 'SUBSTITUTION', 'None', (85, 91))	('MTOR', 'Gene', '2475', (80, 84))	('mTORC1', 'Gene', '382056', (190, 196))	('mTORC1', 'Gene', '382056', (129, 135))	('S6K and 4EBP1', 'Gene', '6198', (167, 180))	('phosphorylation', 'biological_process', 'GO:0016310', ('148', '163'))	('mTORC1', 'cellular_component', 'GO:0031931', ('190', '196'))	('MTOR', 'Gene', (51, 55))	('V2475M', 'Var', (96, 102))	('activity', 'MPA', (136, 144))
8336	27713405	When the MTOR mutant was co-expressed with HA-S6K in 293T human embryonic kidney cells, L2427R exhibited higher activity, whereas V2475M showed baseline mTORC1 kinase activity comparable to the wild-type MTOR (Fig.	('L2427R', 'Var', (88, 94))	('embryonic kidney', 'Disease', 'MESH:D007674', (64, 80))	('mTORC1', 'Gene', (153, 159))	('MTOR', 'Gene', (204, 208))	('MTOR', 'Gene', (9, 13))	('higher', 'PosReg', (105, 111))	('V2475M', 'Var', (130, 136))	('L2427R', 'SUBSTITUTION', 'None', (88, 94))	('human', 'Species', '9606', (58, 63))	('V2475M', 'SUBSTITUTION', 'None', (130, 136))	('MTOR', 'Gene', '2475', (9, 13))	('MTOR', 'Gene', '2475', (204, 208))	('293T', 'CellLine', 'CVCL:0063', (53, 57))	('mTORC1', 'Gene', '382056', (153, 159))	('activity', 'MPA', (112, 120))	('embryonic kidney', 'Disease', (64, 80))	('mTORC1', 'cellular_component', 'GO:0031931', ('153', '159'))	('kinase activity', 'molecular_function', 'GO:0016301', ('160', '175'))
8337	27713405	Consistent with cell-based assays, immunohistochemistry of the uRCC with L2427R mutation displayed strong p-4EBP1 and p-S6 staining, whereas that of V2475M did not (Fig.	('4EBP1', 'Gene', '1978', (108, 113))	('V2475M', 'Var', (149, 155))	('uRCC', 'Gene', (63, 67))	('L2427R', 'SUBSTITUTION', 'None', (73, 79))	('4EBP1', 'Gene', (108, 113))	('uRCC', 'Gene', '54894', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('V2475M', 'SUBSTITUTION', 'None', (149, 155))	('L2427R', 'Var', (73, 79))
8338	27713405	These findings suggest that the recurrent I1973F and L2427R MTOR mutations are likely pathogenic, whereas V2475M could be a passenger mutation.	('I1973F', 'Var', (42, 48))	('L2427R', 'Var', (53, 59))	('MTOR', 'Gene', (60, 64))	('L2427R', 'SUBSTITUTION', 'None', (53, 59))	('V2475M', 'Var', (106, 112))	('V2475M', 'SUBSTITUTION', 'None', (106, 112))	('MTOR', 'Gene', '2475', (60, 64))	('I1973F', 'SUBSTITUTION', 'None', (42, 48))
8339	27713405	Notably, all seven tumours with TSC1 or TSC2 mutations had high level of p-4EBP1 (H score=300), whereas only two of four tumours with PTEN mutations exhibited such staining (Fig.	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('mutations', 'Var', (45, 54))	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('TSC1', 'Gene', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('TSC2', 'Gene', '7249', (40, 44))	('4EBP1', 'Gene', '1978', (75, 80))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('4EBP1', 'Gene', (75, 80))	('TSC2', 'Gene', (40, 44))	('PTEN', 'Gene', (134, 138))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('PTEN', 'Gene', '5728', (134, 138))	('TSC1', 'Gene', '7248', (32, 36))
8340	27713405	Altogether, our integrated analysis demonstrated that 13 of the 16 uRCC tumours with MTOR, TSC1, TSC2 or PTEN mutations exhibited hyperactive mTORC1 signals (Fig.	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('hyperactive', 'Disease', (130, 141))	('hyperactive', 'Disease', 'MESH:D006948', (130, 141))	('uRCC tumours', 'Disease', (67, 79))	('PTEN', 'Gene', (105, 109))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('TSC1', 'Gene', (91, 95))	('uRCC tumours', 'Disease', 'MESH:D009369', (67, 79))	('mutations', 'Var', (110, 119))	('TSC1', 'Gene', '7248', (91, 95))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('TSC2', 'Gene', '7249', (97, 101))	('PTEN', 'Gene', '5728', (105, 109))	('mTORC1', 'Gene', (142, 148))	('TSC2', 'Gene', (97, 101))	('mTORC1', 'Gene', '382056', (142, 148))	('mTORC1', 'cellular_component', 'GO:0031931', ('142', '148'))	('MTOR', 'Gene', (85, 89))	('MTOR', 'Gene', '2475', (85, 89))
8343	27713405	As germline and somatic mutations of FH have been described in hereditary leiomyomatosis RCC (HLRCC) and a small number of sporadic type II pRCC, we performed 2SC (2-succino-cystein) and FH immunohistochemistry to investigate the recurrent FH somatic mutations observed in three of our uRCC cases (Fig.	('pRCC', 'Gene', (140, 144))	('hereditary leiomyomatosis RCC', 'Disease', 'MESH:C538614', (63, 92))	('uRCC', 'Gene', '54894', (286, 290))	('mutations', 'Var', (24, 33))	('uRCC', 'Gene', (286, 290))	('RCC', 'Disease', (89, 92))	('described', 'Reg', (50, 59))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (287, 290))	('2-succino-cystein', 'Chemical', '-', (164, 181))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', (287, 290))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('pRCC', 'Gene', '5546', (140, 144))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('hereditary leiomyomatosis RCC', 'Disease', (63, 92))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
8347	27713405	The remaining FH-negative/2SC-positive tumour (T41) harboured somatic homozygous deletion of the FH gene, revealing a somatic mechanism that can lead to FH functional loss (Supplementary Fig.	('tumour', 'Disease', (39, 45))	('deletion', 'Var', (81, 89))	('FH functional loss', 'Disease', (153, 171))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('FH functional loss', 'Disease', 'MESH:D006938', (153, 171))
8348	27713405	On the other hand, one tumour (T71) with FH G401V somatic mutation was found to be FH positive/2SC negative, and lacked histologic features of HLRCC or FH-deficient RCC, suggesting that FH G401V might be better categorized as a passenger mutation (Fig.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('FH-deficient RCC', 'Disease', 'MESH:C538614', (152, 168))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('tumour', 'Disease', (23, 29))	('G401V', 'SUBSTITUTION', 'None', (44, 49))	('G401V', 'Var', (44, 49))	('G401V', 'SUBSTITUTION', 'None', (189, 194))	('G401V', 'Var', (189, 194))	('FH-deficient RCC', 'Disease', (152, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (165, 168))
8353	27713405	Of the remaining 28 (45%) uRCC, 8 cases carried mutations of genes involved in chromatin modulation (SETD2, BAP1, KMT2A/C/D and PBRM1); 5 in DNA damage response (TP53, CHEK2 and BRCA2); and 15 without recurrent molecular features based on our analyses (Fig.	('uRCC', 'Gene', '54894', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('uRCC', 'Gene', (26, 30))	('mutations', 'Var', (48, 57))	('BRCA2', 'Gene', '675', (178, 183))	('PBRM1', 'Gene', '55193', (128, 133))	('DNA', 'cellular_component', 'GO:0005574', ('141', '144'))	('BAP1', 'Gene', '8314', (108, 112))	('TP53', 'Gene', (162, 166))	('PBRM1', 'Gene', (128, 133))	('chromatin', 'cellular_component', 'GO:0000785', ('79', '88'))	('DNA damage response', 'biological_process', 'GO:0006974', ('141', '160'))	('CHEK2', 'Gene', (168, 173))	('KMT2A/C/D', 'Gene', '4297', (114, 123))	('KMT2A/C/D', 'Gene', (114, 123))	('BAP1', 'Gene', (108, 112))	('SETD2', 'Gene', (101, 106))	('CHEK2', 'Gene', '11200', (168, 173))	('TP53', 'Gene', '7157', (162, 166))	('BRCA2', 'Gene', (178, 183))	('SETD2', 'Gene', '29072', (101, 106))
8354	27713405	The possibility of these tumours representing other RCC subtypes (for example, TFE3/TFEB translocation or SDHB deficiency) was also excluded by established diagnostic assays.	('translocation', 'Var', (89, 102))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('TFEB', 'Gene', '7942', (84, 88))	('TFE3', 'Gene', '7030', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('TFEB', 'Gene', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('SDHB deficiency', 'Disease', (106, 121))	('TFE3', 'Gene', (79, 83))	('SDHB deficiency', 'Disease', 'MESH:D007153', (106, 121))	('tumours', 'Disease', (25, 32))
8355	27713405	Commonly mutated in VHL-deficient ccRCC, chromatin modulators PBRM1, SETD2 and BAP1 were recurrently mutated in uRCC that lacked VHL mutations.	('BAP1', 'Gene', '8314', (79, 83))	('VHL-deficient ccRCC', 'Disease', (20, 39))	('uRCC', 'Gene', '54894', (112, 116))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('uRCC', 'Gene', (112, 116))	('chromatin', 'cellular_component', 'GO:0000785', ('41', '50'))	('mutated', 'Var', (101, 108))	('BAP1', 'Gene', (79, 83))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('VHL', 'Gene', (20, 23))	('PBRM1', 'Gene', '55193', (62, 67))	('VHL', 'Gene', (129, 132))	('VHL-deficient ccRCC', 'Disease', 'MESH:D006623', (20, 39))	('PBRM1', 'Gene', (62, 67))	('SETD2', 'Gene', (69, 74))	('VHL', 'Gene', '7428', (20, 23))	('mutated', 'Var', (9, 16))	('SETD2', 'Gene', '29072', (69, 74))	('VHL', 'Gene', '7428', (129, 132))
8356	27713405	Our finding that these mutations also recur in nccRCC is in line with the recently reported mutations of SWI/SNF and chromatin modifier pathways in type 1 and type 2 pRCC.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('chromatin modifier pathways', 'Pathway', (117, 144))	('pRCC', 'Gene', '5546', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('mutations', 'Var', (92, 101))	('RCC', 'Disease', (50, 53))	('mutations', 'Var', (23, 32))	('chromatin', 'cellular_component', 'GO:0000785', ('117', '126'))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('pRCC', 'Gene', (166, 170))	('SWI/SNF', 'Gene', (105, 112))
8357	27713405	Given the presence of mutations of chromatin modulation or DNA damage response genes in a wide variety of cancers and their known implications in tumorigenesis, we tentatively grouped together the uRCC cases with mutations in these pathways and lacking other apparent driver alterations.	('uRCC', 'Gene', '54894', (197, 201))	('DNA damage response genes', 'Gene', (59, 84))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('chromatin modulation', 'Gene', (35, 55))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('cancers', 'Disease', (106, 113))	('DNA damage response', 'biological_process', 'GO:0006974', ('59', '78'))	('mutations', 'Var', (22, 31))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('mutations', 'Var', (213, 222))	('uRCC', 'Gene', (197, 201))	('chromatin', 'cellular_component', 'GO:0000785', ('35', '44'))	('DNA', 'cellular_component', 'GO:0005574', ('59', '62'))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
8358	27713405	Among the 15 cases lacking recurrent features ('other' group), T62 and T69 had non-recurrent MET (H1094Y) or BRAF (Y472C) pathogenic mutations, respectively (Supplementary Data 2).	('H1094Y', 'Var', (98, 104))	('Y472C', 'Var', (115, 120))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('MET', 'Gene', '79811', (93, 96))	('MET', 'Gene', (93, 96))	('H1094Y', 'SUBSTITUTION', 'None', (98, 104))	('Y472C', 'SUBSTITUTION', 'None', (115, 120))
8359	27713405	Together, there were seven cases in which no mutation or other significant molecular alteration was detected by our panel of analyses, but the clinicopathologic features of these cases (for example, high-grade nuclear features, necrosis and so on) excluded the possibility of them being reclassified as renal oncocytomas.	('necrosis', 'Disease', 'MESH:D009336', (228, 236))	('renal oncocytomas', 'Disease', (303, 320))	('necrosis', 'biological_process', 'GO:0001906', ('228', '236'))	('renal oncocytomas', 'Disease', 'MESH:C537750', (303, 320))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (303, 320))	('necrosis', 'biological_process', 'GO:0070265', ('228', '236'))	('necrosis', 'biological_process', 'GO:0008219', ('228', '236'))	('necrosis', 'Disease', (228, 236))	('necrosis', 'biological_process', 'GO:0019835', ('228', '236'))	('high-grade', 'Var', (199, 209))	('necrosis', 'biological_process', 'GO:0008220', ('228', '236'))
8360	27713405	In addition, three uRCC tumours with somatic SMARCB1 mutations (T23, T38 and T41) retained the INI1 protein expression (encoded by SMARCB1), and were histologically distinct from renal medullary carcinoma that exhibits characteristic INI1 loss and occurs in individuals with sickle cell trait or other hemoglobinopathies (Supplementary Fig.	('T38', 'Var', (69, 72))	('carcinoma', 'Disease', 'MESH:D009369', (195, 204))	('T23', 'Var', (64, 67))	('INI1', 'Gene', (234, 238))	('INI1', 'Gene', '6598', (234, 238))	('protein', 'cellular_component', 'GO:0003675', ('100', '107'))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('SMARCB1', 'Gene', '6598', (131, 138))	('sickle cell trait', 'Disease', (275, 292))	('SMARCB1', 'Gene', (131, 138))	('uRCC tumours', 'Disease', (19, 31))	('uRCC tumours', 'Disease', 'MESH:D009369', (19, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('loss', 'NegReg', (239, 243))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('hemoglobinopathies', 'Disease', 'MESH:D006453', (302, 320))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinoma', 'Disease', (195, 204))	('INI1', 'Gene', (95, 99))	('INI1', 'Gene', '6598', (95, 99))	('T41', 'Var', (77, 80))	('hemoglobinopathies', 'Disease', (302, 320))	('SMARCB1', 'Gene', '6598', (45, 52))	('SMARCB1', 'Gene', (45, 52))
8368	27713405	Although some of these mutations are present in certain established subtypes of RCC, the overall mutation profiles, the frequencies of mutations in specific genes and a lack of characteristic molecular features of established RCC subtypes support the notion that these uRCC tumours are largely distinct from the established RCC subtypes and harbour their unique oncogenic pathways.	('RCC', 'Phenotype', 'HP:0005584', (324, 327))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('RCC', 'Disease', 'MESH:C538614', (324, 327))	('tumours', 'Phenotype', 'HP:0002664', (274, 281))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (270, 273))	('RCC', 'Disease', (270, 273))	('mutations', 'Var', (23, 32))	('uRCC tumours', 'Disease', 'MESH:D009369', (269, 281))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('RCC', 'Disease', (226, 229))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))	('uRCC tumours', 'Disease', (269, 281))	('RCC', 'Disease', (324, 327))
8369	27713405	This study identifies a subset of uRCC that is characterized by NF2 loss, dysregulated Hippo-YAP signalling and aggressive clinical behaviour (Figs 2 and 4).	('uRCC', 'Gene', (34, 38))	('behaviour', 'biological_process', 'GO:0007610', ('132', '141'))	('uRCC', 'Gene', '54894', (34, 38))	('signalling', 'biological_process', 'GO:0023052', ('97', '107'))	('Hippo-YAP signalling', 'MPA', (87, 107))	('loss', 'NegReg', (68, 72))	('dysregulated', 'Var', (74, 86))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('NF2', 'Gene', (64, 67))	('aggressive clinical behaviour', 'Phenotype', 'HP:0000718', (112, 141))
8370	27713405	The majority (69%) of this subset demonstrates biallelic inactivation of NF2 with concurrent NF2 mutation and LOH, a molecular feature that has not been reported in RCC.	('LOH', 'MPA', (110, 113))	('NF2', 'Gene', (73, 76))	('NF2', 'Gene', (93, 96))	('mutation', 'Var', (97, 105))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('biallelic inactivation', 'Var', (47, 69))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
8372	27713405	As the regulation of Hippo signalling could differ based on organ or cellular contexts, the YAP activation we observed predominantly in the NF2 loss subset of uRCC suggests that NF2 inactivation is an essential mechanism dysregulating Hippo signalling in RCC.	('inactivation', 'Var', (182, 194))	('Hippo signalling', 'MPA', (235, 251))	('activation', 'PosReg', (96, 106))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('uRCC', 'Gene', (159, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('signalling', 'biological_process', 'GO:0023052', ('27', '37'))	('signalling', 'biological_process', 'GO:0023052', ('241', '251'))	('uRCC', 'Gene', '54894', (159, 163))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('loss', 'NegReg', (144, 148))	('NF2', 'Gene', (140, 143))	('regulation', 'biological_process', 'GO:0065007', ('7', '17'))
8374	27713405	Other molecular features found in this subset of tumours include the enrichment of SETD2 mutations, frequent 1p and 3p losses and aberrant histone methylation (absence of H3K36me3) in cases with concurrent 3p loss and SETD2 mutation.	('tumours', 'Disease', (49, 56))	('SETD2', 'Gene', '29072', (218, 223))	('aberrant', 'Var', (130, 138))	('SETD2', 'Gene', (218, 223))	('H3K36me3', 'Protein', (171, 179))	('mutation', 'Var', (224, 232))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('SETD2', 'Gene', '29072', (83, 88))	('losses', 'NegReg', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('mutations', 'Var', (89, 98))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('SETD2', 'Gene', (83, 88))	('loss', 'NegReg', (209, 213))	('histone methylation', 'biological_process', 'GO:0016571', ('139', '158'))	('histone methylation', 'MPA', (139, 158))
8384	27713405	Similar to what have been described in ccRCC and pRCC, mutations in chromatin modulation genes are relatively frequent in uRCC, although none of which (for example, SETD2 and BAP1) was found to be significantly associated with clinical outcomes in this cohort.	('uRCC', 'Gene', (122, 126))	('pRCC', 'Gene', '5546', (49, 53))	('chromatin', 'cellular_component', 'GO:0000785', ('68', '77'))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('chromatin modulation genes', 'Gene', (68, 94))	('BAP1', 'Gene', (175, 179))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', (50, 53))	('pRCC', 'Gene', (49, 53))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('frequent', 'Reg', (110, 118))	('RCC', 'Disease', (41, 44))	('mutations', 'Var', (55, 64))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('SETD2', 'Gene', (165, 170))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('associated', 'Reg', (211, 221))	('uRCC', 'Gene', '54894', (122, 126))	('SETD2', 'Gene', '29072', (165, 170))	('BAP1', 'Gene', '8314', (175, 179))
8385	27713405	We did not observe specific patterns of distribution for these mutations, except for the enrichment of SETD2 mutations in the NF2 loss subset.	('SETD2', 'Gene', '29072', (103, 108))	('loss', 'NegReg', (130, 134))	('mutations', 'Var', (109, 118))	('SETD2', 'Gene', (103, 108))	('NF2', 'Gene', (126, 129))
8386	27713405	Further validation studies are needed to clarify the roles of these mutations in the oncogenesis of various types of RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('mutations', 'Var', (68, 77))
8387	27713405	MET mutations have been predominantly, but not exclusively detected in pRCC based on the recent genomic studies of RCC.	('MET', 'Gene', '79811', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('pRCC', 'Gene', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('MET', 'Gene', (0, 3))	('pRCC', 'Gene', '5546', (71, 75))	('mutations', 'Var', (4, 13))
8388	27713405	While the discovery of MET H1094Y mutation in one uRCC may suggest it represents a pRCC with atypical histologic features, more importantly it provides a potential therapeutic option for this patient.	('uRCC', 'Gene', '54894', (50, 54))	('MET', 'Gene', (23, 26))	('pRCC', 'Gene', '5546', (83, 87))	('patient', 'Species', '9606', (192, 199))	('H1094Y', 'SUBSTITUTION', 'None', (27, 33))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('H1094Y', 'Var', (27, 33))	('uRCC', 'Gene', (50, 54))	('pRCC', 'Gene', (83, 87))	('MET', 'Gene', '79811', (23, 26))
8401	27713405	Copy number was computed using tumour:normal ratios of normalized coverage data to determine amplifications and deletions except for data on chromosome X.	('deletions', 'Var', (112, 121))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('chromosome', 'cellular_component', 'GO:0005694', ('141', '151'))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))
8410	27713405	of South Carolina), FH (1:1,000, Clone J-13, Santa Cruz Biotechnology), INI1 (1:100, BAF47, BD Bioscience) and H3K36me3 (1:200, MABI-0333, Active Motif).	('H3K36me3', 'Var', (111, 119))	('INI1', 'Gene', '6598', (72, 76))	('INI1', 'Gene', (72, 76))
8420	27713405	Signals for ALK gene rearrangement are either 'broken apart' signal or 'single orange' signal (deleted green signal for 5'ALK).	('ALK', 'Gene', (12, 15))	('ALK', 'Gene', '238', (12, 15))	('rearrangement', 'Var', (21, 34))	('ALK', 'Gene', (122, 125))	("'broken apart", 'Phenotype', 'HP:0001061', (46, 59))	('ALK', 'Gene', '238', (122, 125))
8424	27713405	The mTOR single mutations were generated by introducing corresponding nucleotide changes into pcDNA3-Flag-mTOR using QuikChange II XL site-directed mutagenesis kit (Agilent).	('mutagenesis', 'biological_process', 'GO:0006280', ('148', '159'))	('mTOR', 'Gene', '2475', (106, 110))	('nucleotide changes', 'Var', (70, 88))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('introducing', 'Reg', (44, 55))
8425	27713405	The primers for site-directed mutagenesis are as follows: mTOR L2427R, 5'-CATCAGCCTCCAGTTCCGCAAGGGGTCATAGAC-3'; mTOR V2475M, 5'-AATAGATTCTGGCATTGTGGTCCCCGTTTTCTTATGGG-3'.	('mTOR', 'Gene', (58, 62))	('L2427R', 'SUBSTITUTION', 'None', (63, 69))	('mTOR', 'Gene', '2475', (112, 116))	('mTOR', 'Gene', (112, 116))	('V2475M', 'Var', (117, 123))	('mutagenesis', 'biological_process', 'GO:0006280', ('30', '41'))	('L2427R', 'Var', (63, 69))	('V2475M', 'SUBSTITUTION', 'None', (117, 123))	('mTOR', 'Gene', '2475', (58, 62))
8437	27713405	For mTORC1 signalling experiments, 293T cells were seeded in 6-well plates (1.8 x 106 cells per well) 24 h before transfection by 1.5 mug of vectors expressing wild type or mutant mTOR and 50 ng of vector expressing S6K using Lipofectamine 2000 (Invitrogen).	('mTORC1', 'cellular_component', 'GO:0031931', ('4', '10'))	('mTOR', 'Gene', (180, 184))	('mTOR', 'Gene', '2475', (180, 184))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (226, 244))	('mTORC1', 'Gene', '382056', (4, 10))	('293T', 'CellLine', 'CVCL:0063', (35, 39))	('mug', 'molecular_function', 'GO:0043739', ('134', '137'))	('mutant', 'Var', (173, 179))	('signalling', 'biological_process', 'GO:0023052', ('11', '21'))	('mTOR', 'Gene', '2475', (4, 8))	('mTOR', 'Gene', (4, 8))	('mTORC1', 'Gene', (4, 10))
8440	27713405	Antibodies used for immunoblot analysis are as follows: anti-NF2 (ab88957, Abcam), anti-YAP1 (no.	('anti-NF2', 'Var', (56, 64))	('YAP1', 'Gene', (88, 92))	('YAP1', 'Gene', '10413', (88, 92))
8441	27713405	12395, Cell Signaling Technology), anti-pSer-127 YAP1 (no.	('anti-pSer-127', 'Var', (35, 48))	('YAP1', 'Gene', (49, 53))	('Signaling', 'biological_process', 'GO:0023052', ('12', '21'))	('YAP1', 'Gene', '10413', (49, 53))
8444	27713405	2217, Cell Signaling Technology), anti-Flag (F1804, Sigma), anti-RAPTOR (no.	('Signaling', 'biological_process', 'GO:0023052', ('11', '20'))	('RAPTOR', 'Gene', (65, 71))	('F1804', 'Var', (45, 50))	('RAPTOR', 'Gene', '57521', (65, 71))
8464	32339157	ACE2 mainly splits angiotensin II (ANG II) into angiotensin-(1-7) and acts as a vasodilator in the renin-angiotension system.	('renin-angiotension', 'Phenotype', 'HP:0000841', (99, 117))	('ACE2', 'Var', (0, 4))	('angiotensin II', 'Gene', (19, 33))	('angiotension', 'Chemical', '-', (105, 117))	('renin', 'Gene', '5972', (99, 104))	('ANG II', 'Gene', (35, 41))	('ANG II', 'Gene', '183', (35, 41))	('renin', 'Gene', (99, 104))	('angiotensin II', 'Gene', '183', (19, 33))
8488	32339157	However, the high expression of ACE2 in renal cell carcinoma had a favorable prognosis (Supplementary Table 2).	('high', 'Var', (13, 17))	('renal cell carcinoma', 'Disease', (40, 60))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (40, 60))	('ACE2', 'Gene', (32, 36))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (40, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
8530	32339157	The Kaplan Meier plotter was used to investigate the effect of ACE2 on tumor prognosis, the results showed that high ACE2 had a favorable prognosis in UCEC and KIRP (Figure 2A, 2B).	('KIRP', 'Disease', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('high ACE2', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('UCEC', 'Disease', (151, 155))	('tumor', 'Disease', (71, 76))
8544	32339157	While ACE2 not only affects the progress of cardiovascular diseases, but also plays a new role in tumor pathology.	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (44, 67))	('tumor', 'Disease', (98, 103))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (44, 67))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ACE2', 'Var', (6, 10))	('plays', 'Reg', (78, 83))	('affects', 'Reg', (20, 27))	('cardiovascular diseases', 'Disease', (44, 67))
8584	28934212	Accordingly, RCC histopathology classification has been confirmed by (cyto)genetic analyses, with pRCC showing trisomy of chromosomes 7 and 17 and loss of chromosome Y, whereas clear cell RCC (ccRCC) frequently displays deletion of chromosome 3p and mutation of VHL gene.	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('VHL', 'Disease', 'MESH:D006623', (262, 265))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (99, 102))	('loss', 'NegReg', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('chromosome', 'Gene', (155, 165))	('RCC', 'Disease', (195, 198))	('mutation', 'Var', (250, 258))	('pRCC', 'Gene', (98, 102))	('trisomy', 'Var', (111, 118))	('deletion', 'Var', (220, 228))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('VHL', 'Disease', (262, 265))	('chromosome', 'cellular_component', 'GO:0005694', ('155', '165'))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('pRCC', 'Gene', '5546', (98, 102))
8605	28934212	Approval of the study was obtained from the ethics committee of the State Medical Board Brandenburg, Germany, the ethics committee of the University Hospital Frankfurt, Goethe-University, Germany (#4/09), the local ethics committee of the Faculty Hospital Plzen and Faculty of Medicine Plzen, Charles University, Prague, Czech Republic, the Medical Ethics Committee II of the Faculty of Medicine Mannheim, University of Heidelberg, Germany (#2014-811R-MA), the ethics committee of the State Medical Board Westfalen-Lippe and the Faculty of Medicine University of Muenster, Germany (#2015-506-f-S), San Raffaele Ethics Committee, University Vita-Salute San Raffaele, Milan, Italy (#2007/29082007/V3), the ethical committee of the University of Heidelberg, Germany (#206/2005), the local human research ethics committee of the Medical Faculty of the University of Wuerzburg, Germany, the institutional review board of Weill Cornell Medical College, New York, NY, USA (#1007011131), UT Southwestern Institutional Review Board, Dallas, TX, USA, the Washington University in St. Louis Institutional Review Board, St. Louis, MO, USA (#201102423), the ethics committee of the Technical University of Dresden, Germany (EK 269072014), the ethics committee of the Medical University of Vienna and Vienna General Hospital, Austria, and the ethics committee of the Medical University of Graz, Austria.	('#201102423', 'Var', (1128, 1138))	('human', 'Species', '9606', (786, 791))	('EK 269072014', 'Var', (1211, 1223))
8667	28934212	Given mutations of the mesenchymal-epithelial transition (MET) oncogene in pRCC type 1 and of fumarate hydratase (FH) in pRCC type 2, targeted agents assigning MET (e.g.	('pRCC', 'Gene', '5546', (121, 125))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('pRCC', 'Gene', (75, 79))	('MET', 'Gene', (58, 61))	('FH', 'Gene', '2271', (114, 116))	('mesenchymal-epithelial transition', 'biological_process', 'GO:0060231', ('23', '56'))	('pRCC', 'Gene', '5546', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('pRCC', 'Gene', (121, 125))	('fumarate hydratase', 'Gene', '2271', (94, 112))	('fumarate hydratase', 'Gene', (94, 112))	('mutations', 'Var', (6, 15))
8682	22666228	Epigenetic alterations are a hallmark of cancer cells and their role in renal tumorigenesis is starting to emerge.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal tumor', 'Disease', 'MESH:D007674', (72, 83))	('renal tumor', 'Phenotype', 'HP:0009726', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('renal tumor', 'Disease', (72, 83))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
8690	22666228	In this regard, cancer-related genetic and/or epigenetic alterations might be used as biomarkers enabling the detection of cancerous cells in clinical samples, thus increasing the ability to identify tumors at their earliest stages (Esteller,).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('clinical samples', 'Species', '191496', (142, 158))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', (16, 22))	('epigenetic alterations', 'Var', (46, 68))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (200, 206))	('cancer', 'Disease', (123, 129))	('increasing', 'PosReg', (165, 175))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancerous', 'Disease', (123, 132))
8693	22666228	On the contrary, epigenetic alterations carry an enormous potential as specific cancer biomarkers (Mulero-Navarro and Esteller,).	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epigenetic alterations', 'Var', (17, 39))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Esteller', 'Disease', (118, 126))	('cancer', 'Disease', (80, 86))
8694	22666228	Furthermore, owing to the reversible nature of epigenetic alterations, these might constitute attractive therapeutic targets, as demonstrated for some hemato-lymphoid neoplasms (Rodriguez-Paredes and Esteller,).	('neoplasms', 'Phenotype', 'HP:0002664', (167, 176))	('hemato-lymphoid neoplasms', 'Disease', 'MESH:D008223', (151, 176))	('epigenetic alterations', 'Var', (47, 69))	('lymphoid neoplasms', 'Phenotype', 'HP:0002665', (158, 176))	('hemato-lymphoid neoplasms', 'Disease', (151, 176))	('Rodriguez-Paredes', 'Disease', (178, 195))	('neoplasm', 'Phenotype', 'HP:0002664', (167, 175))	('Esteller', 'Disease', (200, 208))
8695	22666228	Thus, in this review, we address not only the role of epigenetic alterations in renal carcinogenesis, but also their clinical potential in RCT management.	('renal carcinogenesis', 'Disease', 'MESH:D007674', (80, 100))	('epigenetic alterations', 'Var', (54, 76))	('renal carcinogenesis', 'Disease', (80, 100))	('clinical', 'Species', '191496', (117, 125))
8699	22666228	Gene silencing associated with methylation of promoter regions containing CpG islands may be due to an obstruction of the access of transcription factors or through the promotion of binding of methylcytosine-binding proteins (MBD), which cooperate with DNMTs and histone deacetylases (HDACs; Fraga et al.,; Sharma et al.,).	('transcription', 'biological_process', 'GO:0006351', ('132', '145'))	('DAC', 'Gene', (286, 289))	('access', 'Interaction', (122, 128))	('MBD', 'Disease', 'MESH:D012080', (226, 229))	('binding', 'Interaction', (182, 189))	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('promotion', 'PosReg', (169, 178))	('methylation', 'biological_process', 'GO:0032259', ('31', '42'))	('methylation', 'Var', (31, 42))	('binding', 'molecular_function', 'GO:0005488', ('182', '189'))	('MBD', 'Disease', (226, 229))	('DAC', 'Gene', '6468', (286, 289))	('obstruction', 'NegReg', (103, 114))	('Gene silencing', 'NegReg', (0, 14))	('binding', 'molecular_function', 'GO:0005488', ('208', '215'))
8702	22666228	Aberrant DNA methylation is probably the best characterized cancer-related epigenetic alteration and it is considered by some as one of the earliest events in the process of tumorigenesis (Feinberg et al.,).	('tumor', 'Disease', (174, 179))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
8703	22666228	Whereas promoter hypomethylation may cause activation of proto-oncogenes, hypermethylation induces silencing of cancer-related genes with tumor suppressive properties (Feinberg et al.,; Sharma et al.,).	('silencing', 'MPA', (99, 108))	('proto-oncogenes', 'Gene', (57, 72))	('tumor', 'Disease', (138, 143))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('proto-oncogenes', 'MPA', (57, 72))	('activation', 'PosReg', (43, 53))	('promoter hypomethylation', 'Var', (8, 32))	('hypermethylation', 'Var', (74, 90))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
8704	22666228	It was also demonstrated that aberrant methylation may affect large extensions of DNA in cancer cells, resulting in extensive epigenetic reprogramming of entire chromosomal regions (Frigola et al.,).	('affect', 'Reg', (55, 61))	('epigenetic', 'MPA', (126, 136))	('aberrant methylation', 'Var', (30, 50))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('methylation', 'biological_process', 'GO:0032259', ('39', '50'))	('DNA', 'cellular_component', 'GO:0005574', ('82', '85'))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
8706	22666228	This set of histone modifications - the so-called "histone code" - determines the configuration of chromatin, adjusting the accessibility to effector proteins (Kouzarides,).	('modifications', 'Var', (20, 33))	('adjusting', 'Reg', (110, 119))	('accessibility', 'MPA', (124, 137))	('Kouzarides', 'Chemical', '-', (160, 170))
8707	22666228	For instance, whereas lysine acetylation is associated with active transcription, lysine methylation may lead to transcription activation or repression depending on the residue affected and the degree of modification (Kouzarides,).	('transcription', 'MPA', (113, 126))	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('Kouzarides', 'Chemical', '-', (218, 228))	('lead to', 'Reg', (105, 112))	('lysine', 'Chemical', 'MESH:D008239', (22, 28))	('lysine methylation', 'Var', (82, 100))	('lysine', 'Chemical', 'MESH:D008239', (82, 88))	('transcription', 'biological_process', 'GO:0006351', ('67', '80'))	('activation', 'PosReg', (127, 137))	('repression', 'NegReg', (141, 151))	('transcription', 'biological_process', 'GO:0006351', ('113', '126'))	('lysine', 'Var', (22, 28))
8708	22666228	For example, trimethylation of lysine 4 on histone H3 (H3K4me3) is associated with active transcription, whilst H3K27me3 and H3K9me3 are the two chief repressive marks (Kouzarides,).	('Kouzarides', 'Chemical', '-', (169, 179))	('active transcription', 'MPA', (83, 103))	('H3K27me3', 'Var', (112, 120))	('associated', 'Reg', (67, 77))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))	('trimethylation', 'Var', (13, 27))	('H3K9me3', 'Var', (125, 132))	('lysine', 'Chemical', 'MESH:D008239', (31, 37))
8710	22666228	Besides their important role in regulation of gene expression in somatic cells, covalent histone modifications are also critical for embryonic stem cell (ESC) development and differentiation (Kouzarides,; Shi,).	('covalent', 'Var', (80, 88))	('embryonic stem cell', 'CPA', (133, 152))	('Kouzarides', 'Chemical', '-', (192, 202))	('regulation of gene expression', 'biological_process', 'GO:0010468', ('32', '61'))
8714	22666228	Thus, it seems paradoxical that, in cancer development, the presence of H4K20me3 is also associated with local silencing of genes (Fullgrabe et al.,).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('presence', 'Var', (60, 68))	('local silencing of genes', 'MPA', (105, 129))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('H4K20me3', 'Var', (72, 80))
8717	22666228	In this regard, HDMs, like LSD1 which targets methylated H3K4 and H3K9, seem also to play an important role in some cancer models (Metzger et al.,; Schulte et al.,).	('LSD1', 'Gene', (27, 31))	('H3K4', 'Protein', (57, 61))	('LSD1', 'Gene', '23028', (27, 31))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('HDMs', 'Disease', (16, 20))	('play', 'Reg', (85, 89))	('HDMs', 'Disease', 'None', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('H3K9', 'Protein', (66, 70))	('methylated', 'Var', (46, 56))
8725	22666228	The mechanisms that lead to altered miRNA expression are similar to those of regular genes and include amplification, deletion, mutation, and promoter hypermethylation (Guil and Esteller,; Dudziec et al.,).	('altered', 'Reg', (28, 35))	('mutation', 'Var', (128, 136))	('miR', 'Gene', '220972', (36, 39))	('deletion', 'Var', (118, 126))	('miR', 'Gene', (36, 39))
8727	22666228	These characteristics not only endow epigenetic alterations a critical role in tumorigenesis, but they also set the basis for their use as cancer biomarkers for early detection, diagnosis, assessment of prognosis, patient monitoring, and prediction of response to therapy, as previously stated (Sharma et al.,; Berdasco and Esteller,).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patient', 'Species', '9606', (214, 221))	('tumor', 'Disease', (79, 84))	('epigenetic alterations', 'Var', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', (139, 145))
8728	22666228	In the next sections, the role of each epigenetic mechanism in renal cell tumorigenesis, as well as its potential use as biomarker and therapeutic target, will be discussed.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('epigenetic', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('renal cell', 'Disease', (63, 73))
8731	22666228	Moreover, because the frequency of point mutations affecting genes involved in familial RCC is relatively low in the sporadic cases, except for VHL, the relevance of aberrant promoter methylation in RCC carcinogenesis has been highlighted (McRonald et al.,).	('RCC carcinogenesis', 'Disease', (199, 217))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (199, 217))	('familial RCC', 'Disease', 'MESH:C538614', (79, 91))	('methylation', 'biological_process', 'GO:0032259', ('184', '195'))	('aberrant', 'Var', (166, 174))	('familial RCC', 'Disease', (79, 91))	('VHL', 'Gene', (144, 147))	('VHL', 'Gene', '7428', (144, 147))
8732	22666228	Indeed, several genes, like RASSF1A, SFRP1, DAPK1, and SPINT2, were consistently found to be silenced by promoter hypermethylation but rarely mutated in sporadic RCC (Morris et al.,).	('DAPK1', 'Gene', '1612', (44, 49))	('RCC', 'Disease', (162, 165))	('silenced', 'NegReg', (93, 101))	('promoter hypermethylation', 'Var', (105, 130))	('RASSF1A', 'Gene', (28, 35))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('DAPK1', 'Gene', (44, 49))	('SFRP1', 'Gene', '6422', (37, 42))	('RASSF1A', 'Gene', '11186', (28, 35))	('SFRP1', 'Gene', (37, 42))	('SPINT2', 'Gene', '10653', (55, 61))	('SPINT2', 'Gene', (55, 61))
8733	22666228	In this setting, functional epigenomic approaches emerged as efficient strategies to identify genes whose expression was silenced by promoter methylation in RCC, through the identification of genes re-expressed after treatment with demethylating drugs in RCC cell lines and further validated in primary tumor samples.	('silenced', 'NegReg', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('expression', 'MPA', (106, 116))	('re-expressed', 'PosReg', (198, 210))	('tumor', 'Disease', (303, 308))	('promoter methylation', 'Var', (133, 153))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', (157, 160))	('RCC', 'Disease', (255, 258))
8744	22666228	Promoter hypermethylation of some genes has been associated with clinical and pathological features of tumor aggressiveness and also to have prognostic relevance.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('associated', 'Reg', (49, 59))	('tumor aggressiveness', 'Disease', (103, 123))	('aggressiveness', 'Phenotype', 'HP:0000718', (109, 123))	('Promoter hypermethylation', 'Var', (0, 25))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (103, 123))	('clinical', 'Species', '191496', (65, 73))
8745	22666228	Thus, aberrant promoter methylation of APAF1 and DAPK1 (Christoph et al.,), as well as of GREM1 (van Vlodrop et al.,) was has been associated with aggressive forms of RCC.	('DAPK1', 'Gene', (49, 54))	('aberrant', 'Var', (6, 14))	('APAF1', 'Gene', (39, 44))	('associated', 'Reg', (131, 141))	('van Vlodrop', 'Disease', (97, 108))	('promoter methylation', 'MPA', (15, 35))	('GREM1', 'Gene', '26585', (90, 95))	('DAPK1', 'Gene', '1612', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('aggressive forms', 'Disease', (147, 163))	('APAF1', 'Gene', '317', (39, 44))	('GREM1', 'Gene', (90, 95))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('van Vlodrop', 'Disease', 'MESH:C536530', (97, 108))
8756	22666228	Lack of pVHL leads to increased levels of HIFs and increased expression of genes involved in cellular response to hypoxia, promoting angiogenesis, invasion and metastasis, evasion of cell death, and cellular metabolism (Rathmell and Chen,; Linehan et al.,).	('promoting', 'PosReg', (123, 132))	('expression of', 'MPA', (61, 74))	('increased', 'PosReg', (51, 60))	('HIFs', 'MPA', (42, 46))	('cellular metabolism', 'biological_process', 'GO:0044237', ('199', '218'))	('Lack', 'Var', (0, 4))	('angiogenesis', 'biological_process', 'GO:0001525', ('133', '145'))	('cell death', 'biological_process', 'GO:0008219', ('183', '193'))	('angiogenesis', 'CPA', (133, 145))	('levels', 'MPA', (32, 38))	('increased', 'PosReg', (22, 31))	('cellular metabolism', 'CPA', (199, 218))	('evasion of cell death', 'MPA', (172, 193))	('pVHL', 'Gene', '7428', (8, 12))	('pVHL', 'Gene', (8, 12))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('93', '121'))
8758	22666228	Indeed, hypoxia was reported to be associated with widespread repression of total RNA and mRNA synthesis and to induce global histone modifications typically associated with transcriptional repression (loss of H3K9ac, increase in H3K9me2, H3K27me2, H3K9me3, H3K27me3, H3K4me1), but also unpredictably with gene activation (increase in H3K14ac, H4R3me2 which may facilitate acetylation of histones associated with activation of transcription, H3K4me2, H3K4me3, and H3K7me2; Chen et al.,; Johnson et al.,).	('RNA', 'cellular_component', 'GO:0005562', ('82', '85'))	('acetylation', 'MPA', (373, 384))	('facilitate', 'PosReg', (362, 372))	('H3K27me2', 'Var', (239, 247))	('loss', 'NegReg', (202, 206))	('hypoxia', 'Disease', (8, 15))	('H3K4me3', 'Var', (451, 458))	('H3K9me3', 'Var', (249, 256))	('hypoxia', 'Disease', 'MESH:D000860', (8, 15))	('H4R3me2', 'Var', (344, 351))	('H3K14ac', 'Var', (335, 342))	('increase', 'PosReg', (218, 226))	('H3K9ac', 'Var', (210, 216))	('H3K27me3', 'Var', (258, 266))	('H3K7me2', 'Var', (464, 471))	('mRNA synthesis', 'biological_process', 'GO:0009299', ('90', '104'))	('transcription', 'biological_process', 'GO:0006351', ('427', '440'))	('H3K9me2', 'Var', (230, 237))	('histones', 'Protein', (388, 396))
8759	22666228	Gene-specific histone modifications included a decrease in H3K9ac and an increase in H3K9/27me2 at hypoxia-repressed genes, an increase in H3K9ac and a decrease in H3K9/27me2 at hypoxia-induced genes, and an increase in H3K4me3 and a decrease in H3K27me3 in all hypoxia-responsive genes (activated and repressed), suggesting that repressed chromatin H3K4me3 enriched and H3K27me3 deprived might be rapidly activated when hypoxia is reversed (Chen et al.,; Johnson et al.,).	('hypoxia', 'Disease', (421, 428))	('hypoxia', 'Disease', 'MESH:D000860', (262, 269))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('increase', 'PosReg', (73, 81))	('chromatin', 'cellular_component', 'GO:0000785', ('340', '349'))	('H3K9ac', 'MPA', (59, 65))	('decrease', 'NegReg', (47, 55))	('hypoxia', 'Disease', (99, 106))	('hypoxia', 'Disease', (178, 185))	('increase', 'PosReg', (208, 216))	('H3K9ac', 'MPA', (139, 145))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('modifications', 'Var', (22, 35))	('hypoxia', 'Disease', 'MESH:D000860', (421, 428))	('hypoxia', 'Disease', (262, 269))	('decrease', 'NegReg', (152, 160))	('H3K9/27me2', 'MPA', (85, 95))
8763	22666228	Since HIF upregulation is a feature of ccRCC, the regulation of histone methylation status, and thus of genetic expression, by JmjC histone demethylases might be another mechanism leading to epigenetic changes in RCC carcinogenesis.	('HIF', 'MPA', (6, 9))	('upregulation', 'PosReg', (10, 22))	('RCC carcinogenesis', 'Disease', (213, 231))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (213, 231))	('regulation of histone methylation', 'biological_process', 'GO:0031060', ('50', '83'))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('epigenetic changes', 'Var', (191, 209))
8765	22666228	In addition, genes encoding for histone-modifying enzymes have been also reported to be mutated in ccRCC (van Haaften et al.,; Dalgliesh et al.,; Table 2).	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('mutated', 'Var', (88, 95))	('RCC', 'Disease', (101, 104))
8766	22666228	Specifically, inactivating mutations were described for SETD2 (H3K36 methyltransferase), JARID1C/KDM5C (H3K4 demethylase), UTX/KMD6A (H3K27 demethylase), and MLL2 (an H3K4 methyltransferase; van Haaften et al.,; Dalgliesh et al.,).	('SETD2', 'Gene', (56, 61))	('JARID1C', 'Gene', (89, 96))	('KDM5C', 'Gene', '8242', (97, 102))	('inactivating mutations', 'Var', (14, 36))	('JARID1C', 'Gene', '8242', (89, 96))	('MLL2', 'Gene', '9757', (158, 162))	('SETD2', 'Gene', '29072', (56, 61))	('UTX', 'Gene', (123, 126))	('MLL2', 'Gene', (158, 162))	('UTX', 'Gene', '7403', (123, 126))	('KDM5C', 'Gene', (97, 102))
8767	22666228	More recently, mutations in the SWI/SNF chromatin remodeling complex gene PBRM1 has been identified in 41% of ccRCCs (Varela et al.,).	('chromatin remodeling', 'biological_process', 'GO:0006338', ('40', '60'))	('PBRM1', 'Gene', '55193', (74, 79))	('mutations', 'Var', (15, 24))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('40', '68'))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('identified', 'Reg', (89, 99))	('PBRM1', 'Gene', (74, 79))
8771	22666228	Several histone marks have been associated with poor prognosis in RCC, including low H3K4me2, H3K18ac, and H3K9me2 (Seligson et al.,).	('H3K4me2', 'Protein', (85, 92))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('low', 'NegReg', (81, 84))	('H3K18ac', 'Var', (94, 101))	('H3K9me2', 'Var', (107, 114))	('RCC', 'Disease', (66, 69))
8772	22666228	H3K4me1-3 levels were also found to be inversely correlated with Fuhrman grade, pT stage, lymph node involvement and distant metastases, and an H3K4me score (combining staining levels of H3K4me) was an independent factor for RCC progression-free survival (Ellinger et al.,).	('metastases', 'Disease', (125, 135))	('H3K4me1-3', 'MPA', (0, 9))	('RCC', 'Disease', (225, 228))	('Fuhrman', 'Disease', (65, 72))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('pT stage', 'Disease', (80, 88))	('H3K4me score', 'Var', (144, 156))
8773	22666228	Similar observations were made for global H3Ac and H4Ac levels, as well as for H3K9Ac levels in RCCs treated with partial nephrectomy (Minardi et al.,), whereas H3K18Ac levels were an independent predictor of RCC progression after surgery (Mosashvilli et al.,).	('RCC', 'Disease', (96, 99))	('H3Ac', 'Chemical', '-', (42, 46))	('H3K9Ac levels', 'MPA', (79, 92))	('H4Ac', 'Chemical', '-', (51, 55))	('H3K18Ac', 'Var', (161, 168))	('H4Ac levels', 'MPA', (51, 62))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('RCC', 'Disease', (209, 212))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
8775	22666228	Histone onco-modifications might also carry therapeutic implications, as patients with marks of poor prognosis including low levels of H3K4me2, H3K18ac, and H3K9me2 could benefit from innovative treatments with histone deacetylase inhibitors (HDACi) Histone onco-modifications might also carry therapeutic implications, as patients with marks of poor prognosis including low levels of H3K4me2, H3K18ac, and H3K9me2 could benefit from innovative treatments with histone deacetylase inhibitors (HDACi; Seligson et al.,).	('patients', 'Species', '9606', (323, 331))	('DAC', 'Gene', '6468', (494, 497))	('H3K18ac', 'Var', (394, 401))	('DAC', 'Gene', (244, 247))	('DAC', 'Gene', '6468', (244, 247))	('DAC', 'Gene', (494, 497))	('patients', 'Species', '9606', (73, 81))	('H3K9me2', 'Var', (407, 414))
8780	22666228	The combination of HDACi and retinoids might also provide an alternative therapeutic strategy because RARbeta2 expression is reduced in RCC, in part owing to gene-specific histone hypoacetylation, and its re-expression is associated with anti-neoplastic effects through the abrogation of retinoid-resistance (Touma et al.,; Wang et al.,).	('retinoid', 'Chemical', 'MESH:D012176', (29, 37))	('re-expression', 'PosReg', (205, 218))	('RARbeta2', 'Gene', (102, 110))	('anti-neoplastic effects', 'CPA', (238, 261))	('DAC', 'Gene', '6468', (20, 23))	('abrogation', 'Var', (274, 284))	('reduced', 'NegReg', (125, 132))	('expression', 'MPA', (111, 121))	('retinoid', 'Chemical', 'MESH:D012176', (288, 296))	('histone hypoacetylation', 'MPA', (172, 195))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('DAC', 'Gene', (20, 23))	('RCC', 'Disease', (136, 139))	('retinoids', 'Chemical', 'MESH:D012176', (29, 38))
8782	22666228	Deregulation of miRNA expression seems to be pivotal for RCC development and progression (Valera et al.,).	('Deregulation', 'Var', (0, 12))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))
8792	22666228	Bioinformatics, anti-correlation analysis of miRNA/mRNA levels and functional studies in paired tumorous and normal tissues are also revealing interesting data on cell function alterations due to deregulated miRNA in RCTs.	('miR', 'Gene', (208, 211))	('tumorous', 'Disease', 'MESH:D009369', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('deregulated', 'Var', (196, 207))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('tumorous', 'Disease', (96, 104))	('miR', 'Gene', '220972', (208, 211))
8793	22666228	Those have showed that deregulated microRNAs target genes are commonly involved in metabolic (71 target genes of 13 deregulated microRNAs), focal adhesion, cell adhesion molecules and ECM receptor interactions (30 target genes of 25 deregulated microRNAs), cell cycle regulation (24 target genes of 22 deregulated microRNAs), and apoptosis (14 target genes of 11 deregulated microRNAs) pathways in ccRCC (Zhou et al.,; Table 3).	('deregulated', 'Var', (23, 34))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('257', '278'))	('RCC', 'Disease', 'MESH:C538614', (400, 403))	('cell adhesion', 'biological_process', 'GO:0007155', ('156', '169'))	('RCC', 'Disease', (400, 403))	('apoptosis', 'biological_process', 'GO:0097194', ('330', '339'))	('apoptosis', 'biological_process', 'GO:0006915', ('330', '339'))	('focal adhesion', 'cellular_component', 'GO:0005925', ('140', '154'))	('apoptosis', 'Pathway', (330, 339))
8809	22666228	In ccRCC 23 miRNA are differentially expressed (let-7e, let-7f, let-7g, miR10b, miR-124, miR-126, miR-138, miR-140-5p, miR-142-5p, miR-144, miR-184, miR-200c, miR-203, miR-206, miR-210, miR-218, miR-27a, miR-27b, miR-335, miR-373, miR-378, miR-92a, miR-98; Valera et al.,).	('miR-378', 'Gene', '494327', (231, 238))	('miR', 'Gene', '220972', (249, 252))	('miR-126', 'Gene', (89, 96))	('miR', 'Gene', '220972', (98, 101))	('miR-1', 'Gene', '83856', (107, 112))	('miR-144', 'Gene', (131, 138))	('miR', 'Gene', (177, 180))	('miR', 'Gene', (131, 134))	('miR-203', 'Gene', (159, 166))	('miR', 'Gene', (186, 189))	('miR', 'Gene', '220972', (231, 234))	('miR-1', 'Gene', (131, 136))	('miR', 'Gene', (89, 92))	('miR', 'Gene', (240, 243))	('miR', 'Gene', (159, 162))	('miR-184', 'Gene', '406960', (140, 147))	('miR-126', 'Gene', '406913', (89, 96))	('miR', 'Gene', (213, 216))	('miR', 'Gene', '220972', (222, 225))	('miR', 'Gene', (119, 122))	('miR-206', 'Gene', '406989', (168, 175))	('miR-144', 'Gene', '406936', (131, 138))	('miR-1', 'Gene', (80, 85))	('miR', 'Gene', '220972', (107, 110))	('miR-184', 'Gene', (140, 147))	('miR', 'Gene', (12, 15))	('miR-210', 'Gene', '406992', (177, 184))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (140, 143))	('miR-335', 'Gene', '442904', (213, 220))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('miR-1', 'Gene', '83856', (131, 136))	('let-7f', 'Var', (56, 62))	('miR', 'Gene', (195, 198))	('miR-21', 'Gene', (186, 192))	('miR-373', 'Gene', (222, 229))	('let-7g', 'Gene', '406890', (64, 70))	('miR-1', 'Gene', (140, 145))	('let-7e', 'Gene', '406887', (48, 54))	('miR-210', 'Gene', (177, 184))	('miR-1', 'Gene', (98, 103))	('miR', 'Gene', '220972', (149, 152))	('miR-21', 'Gene', (177, 183))	('miR10b', 'Gene', '406903', (72, 78))	('miR-1', 'Gene', '83856', (80, 85))	('miR10b', 'Gene', (72, 78))	('miR', 'Gene', (72, 75))	('miR', 'Gene', (80, 83))	('miR-378', 'Gene', (231, 238))	('miR', 'Gene', '220972', (177, 180))	('miR-1', 'Gene', '83856', (140, 145))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (204, 207))	('miR', 'Gene', '220972', (186, 189))	('let-7e', 'Gene', (48, 54))	('miR-27b', 'Gene', (204, 211))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', '220972', (240, 243))	('miR-1', 'Gene', '83856', (98, 103))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', '220972', (213, 216))	('miR', 'Gene', (249, 252))	('let-7g', 'Gene', (64, 70))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (98, 101))	('miR-98', 'Gene', (249, 255))	('miR-335', 'Gene', (213, 220))	('miR', 'Gene', (231, 234))	('miR-206', 'Gene', (168, 175))	('miR-1', 'Gene', (89, 94))	('miR', 'Gene', '220972', (12, 15))	('miR-21', 'Gene', '406991', (186, 192))	('miR-27a', 'Gene', '407018', (195, 202))	('miR-200c', 'Gene', '406985', (149, 157))	('miR', 'Gene', (222, 225))	('miR', 'Gene', '220972', (140, 143))	('miR-98', 'Gene', '407054', (249, 255))	('miR', 'Gene', '220972', (195, 198))	('RCC', 'Disease', (5, 8))	('miR-1', 'Gene', (119, 124))	('miR-200c', 'Gene', (149, 157))	('miR-21', 'Gene', '406991', (177, 183))	('miR-27a', 'Gene', (195, 202))	('miR', 'Gene', (107, 110))	('miR-27b', 'Gene', '407019', (204, 211))	('miR-1', 'Gene', (107, 112))	('miR', 'Gene', (168, 171))	('miR-373', 'Gene', '442918', (222, 229))	('miR', 'Gene', '220972', (72, 75))	('miR-203', 'Gene', '406986', (159, 166))	('miR-1', 'Gene', '83856', (89, 94))	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (149, 152))	('miR', 'Gene', '220972', (204, 207))	('miR-1', 'Gene', '83856', (119, 124))
8810	22666228	However, some miRNAs are characteristic of sporadic ccRCC (let-7c, let-7d, miR-1, miR-100, miR-10a, miR-148b, miR-191, miR-199a-3p, miR-19a, miR-215, miR-29b, miR-30c, miR-363, miR-9) and others of hereditary (Von Hippel-Lindau syndrome-related) RCC (let-7a, miR-125a-5p, miR-125b, miR-143, miR-146b-5p, miR-15b, miR-17, miR-193a-5p, miR-193b, miR-196a, miR-20b, miR-214, miR-23b, miR-32, miR-372; Valera et al.,).	('miR', 'Gene', '220972', (259, 262))	('miR-1', 'Gene', (334, 339))	('miR', 'Gene', '220972', (291, 294))	('miR-19a', 'Gene', (132, 139))	('miR-214', 'Gene', (363, 370))	('miR', 'Gene', '220972', (344, 347))	('let-7a', 'Var', (251, 257))	('miR', 'Gene', (91, 94))	('miR-1', 'Gene', '83856', (100, 105))	('miR-1', 'Gene', '83856', (313, 318))	('miR-215', 'Gene', (141, 148))	('miR-30c', 'Gene', (159, 166))	('miR', 'Gene', '220972', (272, 275))	('miR', 'Gene', (282, 285))	('miR', 'Gene', (177, 180))	('miR-10a', 'Gene', (91, 98))	('miR-199a-3p', 'Gene', (119, 130))	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (304, 307))	('let-7c', 'Gene', (59, 65))	('miR', 'Gene', (82, 85))	('miR-1', 'Gene', (282, 287))	('miR-1', 'Gene', (132, 137))	('miR-199a-3p', 'Gene', '406977', (119, 130))	('miR-1', 'Gene', (82, 87))	('miR', 'Gene', (159, 162))	('miR-214', 'Gene', '406996', (363, 370))	('miR', 'Gene', '220972', (363, 366))	('miR', 'Gene', (119, 122))	('miR-1', 'Gene', (344, 349))	('miR-1', 'Gene', '83856', (334, 339))	('miR', 'Gene', (381, 384))	('miR-372', 'Gene', (389, 396))	('miR', 'Gene', '220972', (75, 78))	('Von Hippel-Lindau syndrome', 'Disease', (210, 236))	('miR-10a', 'Gene', '406902', (91, 98))	('miR', 'Gene', (100, 103))	('miR-143', 'Gene', '406935', (282, 289))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (313, 316))	('miR-193b', 'Gene', '574455', (334, 342))	('miR-372', 'Gene', '442917', (389, 396))	('miR-17', 'Gene', (313, 319))	('miR', 'Gene', (291, 294))	('miR-1', 'Gene', '83856', (282, 287))	('miR', 'Gene', '220972', (168, 171))	('miR-1', 'Gene', '83856', (132, 137))	('miR-1', 'Gene', (291, 296))	('miR', 'Gene', '220972', (389, 392))	('miR-1', 'Gene', '83856', (82, 87))	('miR-363', 'Gene', (168, 175))	('miR-148b', 'Gene', (100, 108))	('let-7d', 'Gene', '406886', (67, 73))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (210, 236))	('miR-363', 'Gene', '574031', (168, 175))	('miR-100', 'Gene', '406892', (82, 89))	('miR-1', 'Gene', (321, 326))	('miR-1', 'Gene', (304, 309))	('miR-1', 'Gene', '83856', (344, 349))	('miR-15b', 'Gene', (304, 311))	('miR-1', 'Gene', (75, 80))	('miR', 'Gene', (334, 337))	('miR', 'Gene', '220972', (110, 113))	('miR-20b', 'Gene', '574032', (354, 361))	('let-7d', 'Gene', (67, 73))	('miR-191', 'Gene', '406966', (110, 117))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('miR-191', 'Gene', (110, 117))	('miR', 'Gene', (141, 144))	('miR', 'Gene', (372, 375))	('miR-30c', 'Gene', '407031', (159, 166))	('miR', 'Gene', '220972', (91, 94))	('miR', 'Gene', '220972', (321, 324))	('miR-23b', 'Gene', '407011', (372, 379))	('miR-1', 'Gene', '83856', (291, 296))	('miR', 'Gene', (354, 357))	('miR', 'Gene', '220972', (282, 285))	('miR', 'Gene', (132, 135))	('miR', 'Gene', '220972', (177, 180))	('miR', 'Gene', '220972', (304, 307))	('miR', 'Gene', (259, 262))	('miR', 'Gene', '220972', (82, 85))	('miR-1', 'Gene', (110, 115))	('miR-1', 'Gene', (259, 264))	('miR-1', 'Gene', '83856', (304, 309))	('miR', 'Gene', '220972', (159, 162))	('miR-1', 'Gene', '83856', (75, 80))	('miR', 'Gene', (344, 347))	('miR-1', 'Gene', (313, 318))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', '220972', (381, 384))	('miR-1', 'Gene', (91, 96))	('miR', 'Gene', (272, 275))	('miR-1', 'Gene', (272, 277))	('miR', 'Gene', (150, 153))	('miR-193b', 'Gene', (334, 342))	('miR-17', 'Gene', '406952', (313, 319))	('miR', 'Gene', '220972', (100, 103))	('miR-32', 'Gene', (381, 387))	('miR', 'Gene', '220972', (14, 17))	('miR-29b', 'Gene', '407024', (150, 157))	('miR', 'Gene', (363, 366))	('miR-1', 'Gene', '83856', (110, 115))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('miR-1', 'Gene', '83856', (259, 264))	('miR-100', 'Gene', (82, 89))	('miR-1', 'Gene', (119, 124))	('miR', 'Gene', (321, 324))	('miR-143', 'Gene', (282, 289))	('miR-19a', 'Gene', '406979', (132, 139))	('miR-215', 'Gene', '406997', (141, 148))	('miR', 'Gene', (75, 78))	('miR-20b', 'Gene', (354, 361))	('miR-29b', 'Gene', (150, 157))	('miR', 'Gene', '220972', (334, 337))	('miR-1', 'Gene', '83856', (91, 96))	('miR-23b', 'Gene', (372, 379))	('miR', 'Gene', (313, 316))	('miR-1', 'Gene', '83856', (321, 326))	('miR-148b', 'Gene', '442892', (100, 108))	('miR-1', 'Gene', (100, 105))	('miR-15b', 'Gene', '406949', (304, 311))	('miR-1', 'Gene', '83856', (272, 277))	('RCC', 'Disease', (246, 249))	('miR', 'Gene', (168, 171))	('miR-32', 'Gene', '407036', (381, 387))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (389, 392))	('miR', 'Gene', '220972', (372, 375))	('let-7c', 'Gene', '406885', (59, 65))	('RCC', 'Disease', (54, 57))	('miR', 'Gene', '220972', (354, 357))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (110, 113))	('miR-1', 'Gene', '83856', (119, 124))
8820	22666228	The ubiquity of epigenetic alterations in RCT supports their fundamental role in renal carcinogenesis.	('renal carcinogenesis', 'Disease', (81, 101))	('epigenetic alterations', 'Var', (16, 38))	('renal carcinogenesis', 'Disease', 'MESH:D007674', (81, 101))	('RCT', 'Gene', (42, 45))
8821	22666228	Finally, owing to the reversible and plastic nature of epigenetic alterations, these constitute an attractive target for novel therapeutic approaches that might tackle one of the most chemoresistant types of human cancer.	('epigenetic alterations', 'Var', (55, 77))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('human', 'Species', '9606', (208, 213))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
8845	33322163	These drugs work particularly well for cancers with increased mutational load and highly expressed neo-antigens.	('increased', 'PosReg', (52, 61))	('mutational load', 'Var', (62, 77))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('neo-antigens', 'Protein', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
8943	33322163	It is associated with TFE3, TFEB, or MITF gene fusions, with various associated targetable signaling pathways.	('gene fusions', 'Var', (42, 54))	('associated', 'Reg', (6, 16))	('MITF', 'Gene', '4286', (37, 41))	('MITF', 'Gene', (37, 41))	('TFE3', 'Gene', (22, 26))	('TFEB', 'Gene', '7942', (28, 32))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('TFEB', 'Gene', (28, 32))	('TFE3', 'Gene', '7030', (22, 26))
8944	33322163	An example is the presence of an SFPQ-TFE fusion [t(X;1) (p11.2; p34)] resulting in "Xp11.2 translocation carcinoma", in which TFE3 chromatin immunoprecipitation followed by deep sequencing analysis indicated a strong enrichment for the PI3K/AKT/mTOR pathway.	('carcinoma', 'Disease', (106, 115))	('p11', 'Gene', '6281', (86, 89))	('p34', 'Gene', (65, 68))	('SFPQ-TFE', 'Var', (33, 41))	('p11', 'Gene', (86, 89))	('p11', 'Gene', (58, 61))	('TFE3', 'Gene', (127, 131))	('carcinoma', 'Disease', 'MESH:D009369', (106, 115))	('PI3K/AKT/mTOR pathway', 'Pathway', (237, 258))	('p34', 'Gene', '2967', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('p11', 'Gene', '6281', (58, 61))	('TFE3', 'Gene', '7030', (127, 131))
8945	33322163	The novel inhibitor SN202, a dual inhibitor of PI3K and mTOR pathways, has been studied in vitro and in mice, with a decrease in the phosphorylation of PI3K downstream signaling molecules AKT and S6K in renal cancer cells seen.	('phosphorylation', 'MPA', (133, 148))	('renal cancer', 'Disease', (203, 215))	('SN202', 'Var', (20, 25))	('mice', 'Species', '10090', (104, 108))	('AKT', 'Pathway', (188, 191))	('renal cancer', 'Phenotype', 'HP:0009726', (203, 215))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('S6K', 'Pathway', (196, 199))	('renal cancer', 'Disease', 'MESH:D007680', (203, 215))	('phosphorylation', 'biological_process', 'GO:0016310', ('133', '148'))	('PI3K downstream signaling', 'Pathway', (152, 177))	('decrease', 'NegReg', (117, 125))	('signaling', 'biological_process', 'GO:0023052', ('168', '177'))	('SN202', 'Chemical', '-', (20, 25))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
9025	33322163	ccRCC is characterized by the inactivation of Von Hippel-Lindau (VHL) tumor suppressor protein and subsequent VHL mutation in essentially all cases, which results in the accumulation of hypoxia-inducible factor (HIF) and subsequent downstream activation of pathways involved in cell metabolism, proliferation and angiogenesis.	('VHL', 'Gene', '7428', (65, 68))	('activation', 'PosReg', (243, 253))	('mutation', 'Var', (114, 122))	('accumulation', 'PosReg', (170, 182))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))	('VHL', 'Gene', '7428', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inactivation', 'Var', (30, 42))	('RCC', 'Disease', (2, 5))	('angiogenesis', 'biological_process', 'GO:0001525', ('313', '325'))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('pathways', 'Pathway', (257, 265))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('Von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (46, 75))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('70', '86'))	('met', 'Gene', '79811', (283, 286))	('VHL', 'Gene', (65, 68))	('met', 'Gene', (283, 286))	('tumor suppressor', 'biological_process', 'GO:0051726', ('70', '86'))	('metabolism', 'biological_process', 'GO:0008152', ('283', '293'))	('VHL', 'Gene', (110, 113))	('hypoxia', 'Disease', (186, 193))
9029	33322163	In patients with ccRCC, PBRM1 is the second most commonly altered gene, with up to 40% of these cancers having somatic loss-of-function mutations.	('loss-of-function', 'NegReg', (119, 135))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('PBRM1', 'Gene', (24, 29))	('PBRM1', 'Gene', '55193', (24, 29))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (136, 145))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('altered', 'Reg', (58, 65))
9030	33322163	In the localized disease setting, loss of PBRM1 is associated with unfavorable clinical outcomes, with these patients more likely to have stage III disease at presentation, as well as more aggressive pathology, and a higher likelihood of developing stage IV disease in the future.	('loss', 'Var', (34, 38))	('stage IV disease', 'Disease', 'MESH:D058625', (249, 265))	('patients', 'Species', '9606', (109, 117))	('stage III disease', 'Disease', 'MESH:D058625', (138, 155))	('PBRM1', 'Gene', (42, 47))	('PBRM1', 'Gene', '55193', (42, 47))	('stage IV disease', 'Disease', (249, 265))	('stage III disease', 'Disease', (138, 155))
9032	33322163	In the metastatic setting, however, loss of PBRM1 is associated with both improved PFS and OS, and may be explained by tumors harboring PBRM1 mutations being strongly angiogenic, resulting in the upregulation of targets of VEGF-directed therapies (e.g., HIF).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('PFS', 'Disease', (83, 86))	('mutations', 'Var', (142, 151))	('PBRM1', 'Gene', (44, 49))	('PBRM1', 'Gene', (136, 141))	('tumors', 'Disease', (119, 125))	('met', 'Gene', (7, 10))	('VEGF', 'Gene', '7422', (223, 227))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('PBRM1', 'Gene', '55193', (44, 49))	('PBRM1', 'Gene', '55193', (136, 141))	('loss', 'Var', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('improved', 'PosReg', (74, 82))	('upregulation', 'PosReg', (196, 208))	('met', 'Gene', '79811', (7, 10))	('VEGF', 'Gene', (223, 227))
9033	33322163	The favorable outcome associated with loss of PBRM1 is also found in the RECORD-3 and ImMotion150 trials, irrespective of treatment choice in each trial.	('loss', 'Var', (38, 42))	('PBRM1', 'Gene', (46, 51))	('PBRM1', 'Gene', '55193', (46, 51))
9035	33322163	Type 1 PRCC has been associated with both alterations in the MET gene and a gain in chromosome 7 (where the MET gene is located).	('PRCC', 'Gene', '5546', (7, 11))	('MET', 'Gene', (61, 64))	('alterations', 'Var', (42, 53))	('PRCC', 'Gene', (7, 11))	('gain', 'PosReg', (76, 80))	('MET', 'Gene', '79811', (108, 111))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('MET', 'Gene', (108, 111))	('MET', 'Gene', '79811', (61, 64))
9042	33322163	Foretinib had a 50.0% response rate among patients with a germline MET mutation, and Savolitinib had a 18.0% ORR in MET-driven tumors (compared to 0% ORR in non-MET driven tumors) with a median PFS of 6.2 months against 1.4 months in the respective arms (HR 0.33, 95% CI 0.20-0.52).	('MET', 'Gene', '79811', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (127, 133))	('tumors', 'Disease', (172, 178))	('mutation', 'Var', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (116, 119))	('MET', 'Gene', (161, 164))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('MET', 'Gene', '79811', (67, 70))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('Savolitinib', 'Chemical', 'MESH:C000593259', (85, 96))	('MET', 'Gene', (67, 70))	('patients', 'Species', '9606', (42, 50))	('MET', 'Gene', '79811', (116, 119))
9048	33322163	Type 2 PRCC has been linked to mutations in CDKN2A, SETD2, BAP1, PBRM1, TERT, NF2, FH, and NRF2-ARE pathway genes (among others), as well as a CpG island methylator phenotype.	('CDKN2A', 'Gene', (44, 50))	('PRCC', 'Gene', (7, 11))	('PBRM1', 'Gene', (65, 70))	('NRF2', 'Gene', '4780', (91, 95))	('SETD2', 'Gene', '29072', (52, 57))	('NF2', 'Gene', '4771', (78, 81))	('CDKN2A', 'Gene', '1029', (44, 50))	('SETD2', 'Gene', (52, 57))	('NRF2', 'Gene', (91, 95))	('BAP1', 'Gene', '8314', (59, 63))	('NF2', 'Gene', (78, 81))	('mutations', 'Var', (31, 40))	('PRCC', 'Gene', '5546', (7, 11))	('met', 'Gene', '79811', (154, 157))	('met', 'Gene', (154, 157))	('linked', 'Reg', (21, 27))	('BAP1', 'Gene', (59, 63))	('PBRM1', 'Gene', '55193', (65, 70))	('TERT', 'Gene', (72, 76))	('TERT', 'Gene', '7015', (72, 76))
9049	33322163	Various mutations in CDK2NA have also been seen frequently in CDCs although it is unclear whether and how this knowledge may be harnessed in future therapy selection.	('CDK2NA', 'Gene', '1017', (21, 27))	('CDCs', 'Disease', (62, 66))	('mutations', 'Var', (8, 17))	('CDK', 'molecular_function', 'GO:0004693', ('21', '24'))	('seen', 'Reg', (43, 47))	('CDK2NA', 'Gene', (21, 27))
9053	33322163	As an example, given the known association, the presence of FH may lead to the use of treatment regimens efficacious in patients with hereditary leiomyomata and renal cell cancer (HLRCC) or PRCC.	('lead to', 'Reg', (67, 74))	('presence', 'Var', (48, 56))	('renal cell cancer', 'Phenotype', 'HP:0005584', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('hereditary leiomyomata and renal cell cancer', 'Disease', 'MESH:C538614', (134, 178))	('PRCC', 'Gene', '5546', (190, 194))	('patients', 'Species', '9606', (120, 128))	('HLRCC', 'Disease', (180, 185))	('PRCC', 'Gene', (190, 194))	('HLRCC', 'Disease', 'MESH:C535516', (180, 185))
9054	33322163	An association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome with Everolimus was tested, but not confirmed.	('Everolimus', 'Chemical', 'MESH:D000068338', (87, 97))	('TSC1', 'Gene', '7248', (43, 47))	('TSC2', 'Gene', '7249', (48, 52))	('TSC2', 'Gene', (48, 52))	('TSC1', 'Gene', (43, 47))	('mutation status', 'Var', (23, 38))	('tested', 'Reg', (102, 108))
9060	33322163	Though treatment efficacy is greater in PD-L1 positive patients, it has been repeatedly demonstrated that ICI also provide clinical benefit to PD-L1 negative patients.	('PD-L1', 'Gene', (40, 45))	('PD-L1', 'Gene', (143, 148))	('PD-L1', 'Gene', '29126', (40, 45))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (158, 166))	('positive', 'Var', (46, 54))	('PD-L1', 'Gene', '29126', (143, 148))
9063	33322163	Interestingly however, an association with high PD-L1 and poor outcome when treated with VEGFr inhibitors has been shown.	('VEGFr', 'Gene', (89, 94))	('PD-L1', 'Gene', '29126', (48, 53))	('high', 'Var', (43, 47))	('VEGFr', 'Gene', '3791', (89, 94))	('PD-L1', 'Gene', (48, 53))
9065	33322163	However, the mutational load in RCC is usually very low and as yet, it is not in routine clinical use as a predictive biomarker in any setting.	('mutational load', 'Var', (13, 28))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))
9066	33322163	The generation of tumor neoantigens may come from higher frequencies of frameshift insertion and deletion mutations, and the ongoing TRACERx Renal study has shown secondary mutations and chromosomal changes involved in tumor evolution, outlining their clinical relevance.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (219, 224))	('deletion mutations', 'Var', (97, 115))	('frameshift insertion', 'Var', (72, 92))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
9070	33322163	As mentioned previously, tumors harboring PBRM1 mutations tend to be strongly angiogenic while BAP1 mutation is associated with poorly angiogenic tumors.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('BAP1', 'Gene', (95, 99))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PBRM1', 'Gene', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('BAP1', 'Gene', '8314', (95, 99))	('PBRM1', 'Gene', '55193', (42, 47))	('tumors', 'Disease', (146, 152))	('mutations', 'Var', (48, 57))
9091	33322163	It demonstrated a statistically significant improvement in ORR, PFS, and OS with Nivolumab, compared to Everolimus.	('PFS', 'MPA', (64, 67))	('Everolimus', 'Chemical', 'MESH:D000068338', (104, 114))	('Nivolumab', 'Chemical', 'MESH:D000077594', (81, 90))	('ORR', 'MPA', (59, 62))	('improvement', 'PosReg', (44, 55))	('Nivolumab', 'Var', (81, 90))
9116	30924768	For example, loss of fumarate hydratase (FH), succinate dehydrogenase (SDH), or isocitrate dehydrogenase (IDH) induces pathological accumulation of metabolites which potently inhibit alpha-ketoglutarate-dependent enzymes, inducing hypermethylation of the genome and a fundamental reprogramming of cellular identity.	('SDH', 'Gene', '6390', (71, 74))	('fumarate hydratase', 'Gene', (21, 39))	('inhibit', 'NegReg', (175, 182))	('induces', 'Reg', (111, 118))	('succinate dehydrogenase', 'Gene', '6390', (46, 69))	('loss', 'Var', (13, 17))	('isocitrate dehydrogenase', 'Gene', (80, 104))	('IDH', 'Gene', '3417', (106, 109))	('metabolites', 'MPA', (148, 159))	('hypermethylation', 'CPA', (231, 247))	('accumulation', 'MPA', (132, 144))	('inducing', 'Reg', (222, 230))	('SDH', 'Gene', (71, 74))	('fumarate hydratase', 'Gene', '2271', (21, 39))	('succinate dehydrogenase', 'Gene', (46, 69))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (183, 202))	('FH', 'Gene', '2271', (41, 43))	('isocitrate dehydrogenase', 'Gene', '3417', (80, 104))	('IDH', 'Gene', (106, 109))	('alpha-ketoglutarate-dependent enzymes', 'Enzyme', (183, 220))
9119	30924768	Data from tumor genomics, imaging and metabolomics have now demonstrated that not all tumors exhibit signatures of aerobic glycolysis, and that alterations both intrinsic to mitochondria (e.g.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aerobic glycolysis', 'MPA', (115, 133))	('mitochondria', 'cellular_component', 'GO:0005739', ('174', '186'))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (86, 91))	('glycolysis', 'biological_process', 'GO:0006096', ('123', '133'))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('alterations', 'Var', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
9121	30924768	While disruption of mitochondrial respiration is generally not viewed as a driver of oncogenesis, a handful of individual cancer types are peculiarly enriched for mitochondrial dysfunction.	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (163, 188))	('oncogenesis', 'biological_process', 'GO:0007048', ('85', '96'))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (163, 188))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('disruption', 'Var', (6, 16))	('mitochondrial dysfunction', 'Disease', (163, 188))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
9125	30924768	Similarly, chRCCs and renal oncocytomas are characterized by loss-of-function mutations in the mitochondrial genome resulting in accumulation of respiration-defective mitochondria.	('mitochondria', 'cellular_component', 'GO:0005739', ('167', '179'))	('mutations', 'Var', (78, 87))	('mitochondrial genome', 'Gene', (95, 115))	('renal oncocytomas', 'Disease', (22, 39))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('respiration', 'biological_process', 'GO:0007585', ('145', '156'))	('RCC', 'Disease', (13, 16))	('respiration', 'biological_process', 'GO:0045333', ('145', '156'))	('respiration-defective mitochondria', 'MPA', (145, 179))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('95', '115'))	('accumulation', 'PosReg', (129, 141))	('renal oncocytomas', 'Disease', 'MESH:C537750', (22, 39))	('loss-of-function', 'NegReg', (61, 77))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (22, 39))
9132	30924768	A handful of molecular studies have reported that cytogenetically, CCPAP tumors show neither deletion of chromosome 3p nor mutation of VHL, the characteristic molecular features of ccRCC.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('VHL', 'Gene', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('CCPAP', 'Chemical', '-', (67, 72))	('CCPAP', 'Disease', (67, 72))	('RCC', 'Disease', (183, 186))	('VHL', 'Gene', '7428', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('105', '115'))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('deletion', 'Var', (93, 101))
9148	30924768	We observed that high-sorbitol ccRCC tumors clustered with other ccRCC tumors and not with CCPAP samples.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high-sorbitol', 'Var', (17, 30))	('ccRCC tumors', 'Disease', 'MESH:D009369', (31, 43))	('ccRCC tumors', 'Disease', 'MESH:D009369', (65, 77))	('CCPAP', 'Chemical', '-', (91, 96))	('ccRCC tumors', 'Disease', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('sorbitol', 'Chemical', 'MESH:D013012', (22, 30))	('ccRCC tumors', 'Disease', (31, 43))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
9183	30924768	Five suspected cases of CCPAP (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177) were identified during re-review by the TCGA panel pathologists, including two at our institution as part of the TCGA effort and excluded from the final TCGA manuscript (Figure 3:figure supplement 1).	('BP-4795', 'Var', (49, 56))	('BP-4784', 'Var', (40, 47))	('BP-4177', 'Var', (67, 74))	('CCPAP', 'Chemical', '-', (24, 29))	('DV-5567', 'Var', (58, 65))	('CCPAP', 'Disease', (24, 29))	('BP-4760', 'Var', (31, 38))
9184	30924768	Importantly, prior to exclusion, each of these tumors was to some extent molecularly profiled, including by RNA-sequencing, whole-exome sequencing, methylation profiling, and miRNA sequencing.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RNA', 'cellular_component', 'GO:0005562', ('108', '111'))	('methylation', 'Var', (148, 159))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
9193	30924768	In prior work, our group estimated mtDNA copy number across ~322 ccRCC samples profiled by the TCGA, including 2 CCPAP samples misclassified as ccRCC.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('CCPAP', 'Chemical', '-', (113, 118))	('RCC', 'Disease', (67, 70))	('copy', 'Var', (41, 45))	('mtDNA', 'cellular_component', 'GO:0000262', ('35', '40'))
9195	30924768	Depletion of mtDNA copy number in a tumor cell may lead to a drop in mtRNA, and a consequent drop in the capacity of the cell to conduct oxygen-dependent mitochondrial respiration.	('respiration', 'biological_process', 'GO:0045333', ('168', '179'))	('oxygen', 'Chemical', 'MESH:D010100', (137, 143))	('drop', 'NegReg', (93, 97))	('Depletion', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mtDNA', 'cellular_component', 'GO:0000262', ('13', '18'))	('conduct oxygen-dependent mitochondrial respiration', 'MPA', (129, 179))	('capacity', 'MPA', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mtDNA', 'Gene', (13, 18))	('respiration', 'biological_process', 'GO:0007585', ('168', '179'))	('mtRNA', 'MPA', (69, 74))	('tumor', 'Disease', (36, 41))	('drop', 'NegReg', (61, 65))
9202	30924768	Given the distinct landscape of metabolic and transcriptomic alterations characterizing CCPAP, we sought to determine if CCPAP tumors were driven by genetic alterations similar to those driving more common kidney cancer types, for example ccRCC or pRCC.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('CCPAP', 'Chemical', '-', (88, 93))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('kidney cancer', 'Phenotype', 'HP:0009726', (206, 219))	('CCPAP', 'Chemical', '-', (121, 126))	('kidney cancer', 'Disease', 'MESH:D007680', (206, 219))	('alterations', 'Var', (157, 168))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('kidney cancer', 'Disease', (206, 219))	('RCC', 'Disease', (249, 252))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('RCC', 'Disease', (241, 244))	('driven by', 'Reg', (139, 148))
9204	30924768	Identified somatic variants were pooled with 3 CCPAP tumors profiled by exome sequencing in the TCGA.	('CCPAP', 'Chemical', '-', (47, 52))	('CCPAP', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('variants', 'Var', (19, 27))	('tumors', 'Disease', (53, 59))
9206	30924768	Notably, several of the non-synonymous mutations in CCPAP tumors were in genes previously associated with oncogenesis (e.g.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('oncogenesis', 'biological_process', 'GO:0007048', ('106', '117'))	('non-synonymous mutations', 'Var', (24, 48))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('associated', 'Reg', (90, 100))	('CCPAP', 'Chemical', '-', (52, 57))	('oncogenesis', 'Disease', (106, 117))	('CCPAP', 'Gene', (52, 57))
9207	30924768	GNAQ), but these mutations were not enriched in genes of any particular pathway or gene set.	('GNAQ', 'Gene', (0, 4))	('mutations', 'Var', (17, 26))	('GNAQ', 'Gene', '2776', (0, 4))
9216	30924768	by truncating or otherwise loss-of-function mutations) in CCPAP tumors.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('loss-of-function', 'NegReg', (27, 43))	('truncating', 'Var', (3, 13))	('CCPAP', 'Chemical', '-', (58, 63))	('CCPAP', 'Disease', (58, 63))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
9221	30924768	As shown in Figure 4E, we observed a handful of non-synonymous mtDNA mutations, with a frequency of <1 non-synonymous somatic mutation per sequenced tumor.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mtDNA', 'cellular_component', 'GO:0000262', ('63', '68'))	('tumor', 'Disease', (149, 154))	('mtDNA', 'Gene', (63, 68))
9222	30924768	Finally, to evaluate if DNA methylation changes may underlie CCPAP pathogenesis, we examined TCGA data on DNA methylation from 4 CCPAP cases (BP-4784, BP-4795, DV-5567, BP-4177, see Materials and methods, Figure 5:figure supplement 1B).	('BP-4795', 'Var', (151, 158))	('BP-4784', 'Var', (142, 149))	('CCPAP', 'Disease', (129, 134))	('CCPAP', 'Chemical', '-', (129, 134))	('BP-4177', 'Var', (169, 176))	('CCPAP', 'Chemical', '-', (61, 66))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DV-5567', 'Var', (160, 167))	('DNA', 'cellular_component', 'GO:0005574', ('106', '109'))	('DNA methylation', 'biological_process', 'GO:0006306', ('24', '39'))	('pathogenesis', 'biological_process', 'GO:0009405', ('67', '79'))	('DNA methylation', 'biological_process', 'GO:0006306', ('106', '121'))
9226	30924768	Our failure to identify recurrent mutations or copy number alterations is not atypical in the context of our institution's clinical sequencing experience; in fact,~8% of all tumors prospectively deep sequenced for alterations in 341 cancer-associated genes fail to show a single mutation.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('alterations', 'Var', (214, 225))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
9228	30924768	We sought to validate that CCPAP-specific depletion of respiratory genes is not an artifact of TCGA profiling, and to confirm that the depletion of the mitochondrial genome is specific to CCPAP tumor cells, as opposed to other cells in the tumor microenvironment.	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('depletion', 'MPA', (135, 144))	('CCPAP', 'Chemical', '-', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CCPAP', 'Chemical', '-', (188, 193))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('152', '172'))	('tumor', 'Disease', (194, 199))	('mitochondrial genome', 'MPA', (152, 172))	('CCPAP', 'Var', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
9238	30924768	A more comprehensive quantification using tissue array samples comprised of different subtypes of renal cell carcinoma also showed CCPAP has the highest 8-oxo-dG H-score (Figure 5D, Figure 5:source data 1).	('CCPAP', 'Var', (131, 136))	('8-oxo-dG', 'Chemical', 'MESH:C067134', (153, 161))	('8-oxo-dG H-score', 'MPA', (153, 169))	('renal cell carcinoma', 'Disease', (98, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('CCPAP', 'Chemical', '-', (131, 136))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 118))
9242	30924768	Specifically, oxidation of guanine bases is associated with a high prevalence of C:G > A:T transversions, typically associated with Signature 18 in the COSMIC database of mutation signatures.	('C:G > A:T transversions', 'Var', (81, 104))	('guanine', 'Chemical', 'MESH:D006147', (27, 34))	('oxidation', 'Var', (14, 23))
9259	30924768	While genetic/epigenetic alterations are certainly the drivers of all (or nearly all) cancers, our data reinforces the notion that such driver alterations need not be the distinguishing molecular feature of the tumor itself.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('genetic/epigenetic alterations', 'Var', (6, 36))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
9263	30924768	As described earlier, each of the common types of RCC are characterized in part by mitochondrial dysfunction: HIF activation and suppression of mitochondrial biogenesis in clear cell RCC, FH mutations in HLRCC, and mtDNA mutations in chromophobe RCC.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (83, 108))	('mitochondrial dysfunction', 'Disease', (83, 108))	('chromophobe RCC', 'Disease', (234, 249))	('FH', 'Gene', '2271', (188, 190))	('activation', 'PosReg', (114, 124))	('mutations', 'Var', (221, 230))	('mutations', 'Var', (191, 200))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', (183, 186))	('mtDNA', 'cellular_component', 'GO:0000262', ('215', '220'))	('RCC', 'Disease', (246, 249))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (206, 209))	('chromophobe RCC', 'Disease', 'MESH:C538614', (234, 249))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (83, 108))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', 'MESH:C538614', (246, 249))	('mitochondrial biogenesis', 'MPA', (144, 168))	('RCC', 'Disease', 'MESH:C538614', (206, 209))	('suppression', 'NegReg', (129, 140))
9264	30924768	Rare subtypes of RCC further support the recurring theme of mitochondrial dysfunction: mitochondrial Complex II dysfunction in SDH-mutant RCC, and loss-of-function mtDNA mutations in renal oncocytomas.	('loss-of-function', 'NegReg', (147, 163))	('Complex II dysfunction', 'Disease', 'MESH:C565375', (101, 123))	('SDH', 'Gene', '6390', (127, 130))	('RCC', 'Disease', (138, 141))	('mtDNA', 'cellular_component', 'GO:0000262', ('164', '169'))	('renal oncocytomas', 'Disease', 'MESH:C537750', (183, 200))	('RCC', 'Disease', (17, 20))	('mtDNA', 'Gene', (164, 169))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('SDH', 'Gene', (127, 130))	('Complex II dysfunction', 'Disease', (101, 123))	('mitochondrial dysfunction', 'Disease', (60, 85))	('renal oncocytomas', 'Disease', (183, 200))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (60, 85))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('Complex II dysfunction', 'Phenotype', 'HP:0008314', (101, 123))	('mutations', 'Var', (170, 179))	('Complex II', 'molecular_function', 'GO:0008177', ('101', '111'))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (60, 85))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (183, 200))
9306	30924768	Without application of the Battenberg algorithm, the resolution of subclonal copy number states is not possible, so copy number segments are called as single integer values (corresponding to the copy number state of the dominant cancer clone) on chromosome X. Mutational signature analysis of the substitutions was performed using the R package DeconstructSigs.	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('chromosome', 'cellular_component', 'GO:0005694', ('246', '256'))	('substitutions', 'Var', (297, 310))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
9332	30924768	Controlled access for TCGA sequencing data (RNA-sequencing and whole exome sequencing of CCPAP tumors) are available via GDC commons data portal (https://gdc.cancer.gov/) by querying the 5 CCPAP sample IDs (BP-4760, BP-4784, BP-4795, DV-5567, BP-4177).	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('CCPAP', 'Chemical', '-', (89, 94))	('CCPAP', 'Disease', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('RNA', 'cellular_component', 'GO:0005562', ('44', '47'))	('BP-4795', 'Var', (225, 232))	('cancer', 'Disease', (158, 164))	('CCPAP', 'Chemical', '-', (189, 194))	('DV-5567', 'Var', (234, 241))	('BP-4177', 'Var', (243, 250))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BP-4784', 'Var', (216, 223))	('tumors', 'Disease', (95, 101))	('BP-4760', 'Var', (207, 214))
9338	30924768	In some forms of kidney cancer, these alterations result from recurrent driver mutations such as the loss of VHL, fumarate hydratase, or components of the succinate dehydrogenase complex.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('result from', 'Reg', (50, 61))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045282', ('155', '186'))	('succinate dehydrogenase complex', 'cellular_component', 'GO:0045281', ('155', '186'))	('loss', 'Var', (101, 105))	('succinate dehydrogenase', 'Gene', (155, 178))	('kidney cancer', 'Disease', (17, 30))	('VHL', 'Gene', (109, 112))	('succinate dehydrogenase', 'Gene', '6390', (155, 178))	('VHL', 'Gene', '7428', (109, 112))	('fumarate hydratase', 'Gene', '2271', (114, 132))	('fumarate hydratase', 'Gene', (114, 132))
9367	30924768	a) Using a distinct metabolomic platform (RC15, see Materials and methods) we ran a standard curve with sorbitol to determine the absolute concentration of sorbitol in several CCPAP tumor samples, including both high- and low sorbitol CCPAP tumors (Figure 2:figure supplement 1B).	('high-', 'Var', (212, 217))	('CCPAP', 'Chemical', '-', (235, 240))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', (241, 246))	('sorbitol', 'Chemical', 'MESH:D013012', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('sorbitol', 'Chemical', 'MESH:D013012', (156, 164))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('low sorbitol', 'Var', (222, 234))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('CCPAP', 'Chemical', '-', (176, 181))	('sorbitol', 'Chemical', 'MESH:D013012', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
9387	30924768	We performed experiments by using more cells (from 10 cm dishes instead of 6 well dish), labeling with either U13C-fructose or U13C-glucose, and harvesting at 5 additional time points (0h, 2h, 4h, 8h, 24h).	('2h', 'Chemical', 'MESH:D003903', (189, 191))	('4h', 'Chemical', '-', (202, 204))	('4h', 'Chemical', '-', (193, 195))	('U13C-glucose', 'Var', (127, 139))	('U13C-fructose', 'Chemical', '-', (110, 123))	('U13C-fructose', 'Var', (110, 123))	('0h', 'Chemical', '-', (185, 187))	('24h', 'Chemical', '-', (201, 204))	('8h', 'Chemical', '-', (197, 199))	('U13C-glucose', 'Chemical', '-', (127, 139))
9401	30924768	the preference for C>A mutations at TpCpT trinucleotides in POLE-mutated tumors.	('trinucleotides', 'Chemical', '-', (42, 56))	('C>A mutations', 'Var', (19, 32))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TpCpT', 'Gene', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
9403	30924768	We observed that the majority of mutations were C>T, which is not consistent with the expected bias towards C>A mutations in conditions of high oxidative stress (subsection "Immunohistochemical Validation of the Molecular Phenotype of CCPAP", third paragraph, Figure 5:figure supplement 2).	('CCPAP', 'Chemical', '-', (235, 240))	('C>T', 'Var', (48, 51))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('mutations', 'Var', (33, 42))
9424	28809959	Imbalance in components of RAS has been associated with several chronic pathologies, including cancer.	('Imbalance', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Imbalance', 'Phenotype', 'HP:0002172', (0, 9))	('associated', 'Reg', (40, 50))
9461	28809959	Substrate specificity was checked by inhibition assays with captopril for ACE and DX600 for ACE2.	('ACE2', 'Gene', (92, 96))	('DX600', 'Var', (82, 87))	('ACE', 'Gene', '1636', (74, 77))	('ACE', 'Gene', '1636', (92, 95))	('DX600', 'Chemical', '-', (82, 87))	('ACE', 'Gene', (74, 77))	('ACE2', 'Gene', '59272', (92, 96))	('ACE', 'Gene', (92, 95))	('captopril', 'Chemical', 'MESH:D002216', (60, 69))
9465	28809959	Mann-Whitney U test (Mann-U) was used to detect differences in serum enzyme activity from RCC patients and their controls, and from patients with CCRCCs with different tumor size (more or less than 7cm), grade [G1/2 (low) vs. G3/4 (high)] and stage [pT1/2 (organ confined) vs. pT3/4 (non-organ confined)].	('RCC', 'Disease', (148, 151))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('pT3/4', 'Gene', (277, 282))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('pT3/4', 'Gene', '7694', (277, 282))	('G3/4', 'Var', (226, 230))	('pT1/2', 'Gene', '58492', (250, 255))	('enzyme activity', 'molecular_function', 'GO:0003824', ('69', '84'))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('pT1/2', 'Gene', (250, 255))	('patients', 'Species', '9606', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('RCC', 'Disease', (90, 93))
9511	28809959	Thus, lower ACE activity was observed in serum from patients with high grades (G1/G2 717.38 +- 187.94 vs G3/G4 634,5 +- 192,592; Mann-U p = 0.029) and metastatic CCRCC (local disease 706,1 +- 192,81 vs metastatic disease 565.18 +- 147.05; Mann-U p = 0.009).	('ACE', 'Gene', (12, 15))	('lower', 'NegReg', (6, 11))	('ACE activity', 'molecular_function', 'GO:0004246', ('12', '24'))	('G1/G2', 'Var', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('ACE', 'Gene', '1636', (12, 15))	('patients', 'Species', '9606', (52, 60))
9516	28809959	Thus, when serum NEP/CD10 activity was lower than 7350 UP/L, the overall survival was significantly worse according to Kaplan-Meier curves (Fig 6A) (log-rank, p = 0,007).	('7350 UP/L', 'Var', (50, 59))	('CD10', 'molecular_function', 'GO:0004245', ('21', '25'))	('overall survival', 'CPA', (65, 81))	('NEP', 'Gene', '4311', (17, 20))	('NEP', 'Gene', (17, 20))	('serum', 'MPA', (11, 16))	('worse', 'NegReg', (100, 105))	('CD10', 'Gene', (21, 25))	('lower', 'NegReg', (39, 44))	('CD10', 'Gene', '4311', (21, 25))
9523	28809959	Increasing evidence demonstrates that imbalances in RAS favoring the ACE-Ang II-AT1 receptor axis play a critical role in vascular endothelial growth factor (VEGF)-dependent angiogenesis.	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('122', '156'))	('vascular endothelial growth factor', 'Gene', (122, 156))	('VEGF', 'Gene', '7422', (158, 162))	('AT1', 'Gene', '185', (80, 83))	('imbalances', 'Phenotype', 'HP:0002172', (38, 48))	('AT1', 'Gene', (80, 83))	('ACE', 'Gene', (69, 72))	('vascular endothelial growth factor', 'Gene', '7422', (122, 156))	('Ang II', 'Gene', '183', (73, 79))	('angiogenesis', 'biological_process', 'GO:0001525', ('174', '186'))	('ACE', 'Gene', '1636', (69, 72))	('Ang II', 'Gene', (73, 79))	('imbalances', 'Var', (38, 48))	('VEGF', 'Gene', (158, 162))	('imbalance', 'Phenotype', 'HP:0002172', (38, 47))
9525	28809959	Recent studies in xenograft models of human RCC have showed that the blockade of this axis with ACEi and ARB decreases tumor diameter, vascularization and metastatic capacity, and enhances the antiangiogenic effect of sunitinib.	('enhances', 'PosReg', (180, 188))	('human', 'Species', '9606', (38, 43))	('ARB decreases tumor', 'Disease', 'MESH:C567518', (105, 124))	('ARB decreases tumor', 'Disease', (105, 124))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('metastatic capacity', 'CPA', (155, 174))	('RCC', 'Disease', (44, 47))	('vascularization', 'CPA', (135, 150))	('ACE', 'Gene', '1636', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('sunitinib', 'Chemical', 'MESH:D000077210', (218, 227))	('blockade', 'Var', (69, 77))	('ACE', 'Gene', (96, 99))	('antiangiogenic effect', 'CPA', (193, 214))
9556	28809959	On the other, NEP/CD10 activity was lower in serum of CCRCC patients with high UISS and SSIGN scores.	('lower', 'NegReg', (36, 41))	('CD10', 'Gene', '4311', (18, 22))	('RCC', 'Disease', (56, 59))	('CD10', 'Gene', (18, 22))	('high', 'Var', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('patients', 'Species', '9606', (60, 68))	('NEP', 'Gene', '4311', (14, 17))	('NEP', 'Gene', (14, 17))	('CD10', 'molecular_function', 'GO:0004245', ('18', '22'))
9566	28809959	In conclusion, the present study shows that ACE in tumor vessels and APA, ACE2 and NEP/CD10 in tumor cells are differentially expressed in different renal tumor subtypes, and that the presence/abscense of these enzymes is significantly associated with tumor aggressiveness and poor outcome of patients with CCRCC.	('presence/abscense', 'Var', (184, 201))	('RCC', 'Disease', 'MESH:C538614', (309, 312))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', (155, 160))	('CD10', 'molecular_function', 'GO:0004245', ('87', '91'))	('NEP', 'Gene', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (252, 272))	('ACE2', 'Gene', '59272', (74, 78))	('tumor', 'Disease', (51, 56))	('renal tumor', 'Phenotype', 'HP:0009726', (149, 160))	('APA', 'Gene', (69, 72))	('renal tumor', 'Disease', 'MESH:D007674', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('renal tumor', 'Disease', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ACE2', 'Gene', (74, 78))	('CD10', 'Gene', '4311', (87, 91))	('ACE', 'Gene', '1636', (44, 47))	('ACE', 'Gene', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NEP', 'Gene', '4311', (83, 86))	('associated with', 'Reg', (236, 251))	('RCC', 'Disease', (309, 312))	('tumor', 'Disease', (95, 100))	('CD10', 'Gene', (87, 91))	('ACE', 'Gene', '1636', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ACE', 'Gene', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('APA', 'Gene', '2028', (69, 72))	('aggressiveness', 'Phenotype', 'HP:0000718', (258, 272))	('tumor aggressiveness', 'Disease', (252, 272))	('tumor', 'Disease', (252, 257))	('patients', 'Species', '9606', (293, 301))
9584	29878354	Prior studies, based on smaller case series and individual reports have identified specific genetic mutations in patients diagnosed with both RCC and GIST within a lifetime [ - ].	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('patients', 'Species', '9606', (113, 121))	('genetic mutations', 'Var', (92, 109))
9612	29878354	Some studies have shown synchronous GIST and RCC occurrence due to germline mutations in SDHA, SDHC or a translocation of Xp11 [ - ].	('SDHC', 'Gene', (95, 99))	('mutations', 'Var', (76, 85))	('SDHA', 'Gene', (89, 93))	('SDHC', 'Gene', '6391', (95, 99))	('due', 'Reg', (60, 63))	('synchronous', 'Disease', 'MESH:D009378', (24, 35))	('translocation', 'Var', (105, 118))	('synchronous', 'Disease', (24, 35))	('SDHA', 'Gene', '6389', (89, 93))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
9617	29878354	Specific to RCC, the majority of cases is dependent on mutations of the VHL gene.	('VHL', 'Gene', '7428', (72, 75))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('mutations', 'Var', (55, 64))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('dependent', 'Reg', (42, 51))	('VHL', 'Gene', (72, 75))
9619	29878354	However when VHL is mutated, HIF-1alpha becomes perpetually active and binds to a variety of cofactors that ultimately promotes uninhibited transcription of products including VEGFR, which leads to angiogenesis, and EGFR and PDGFR, which leads to cell growth.	('HIF-1alpha', 'Gene', (29, 39))	('VHL', 'Gene', (13, 16))	('angiogenesis', 'biological_process', 'GO:0001525', ('198', '210'))	('cell growth', 'CPA', (247, 258))	('EGFR', 'molecular_function', 'GO:0005006', ('216', '220'))	('EGFR', 'Gene', (216, 220))	('VHL', 'Gene', '7428', (13, 16))	('EGFR', 'Gene', (177, 181))	('mutated', 'Var', (20, 27))	('leads to', 'Reg', (189, 197))	('angiogenesis', 'CPA', (198, 210))	('VEGFR', 'Gene', '3791', (176, 181))	('EGFR', 'Gene', '1956', (216, 220))	('HIF-1alpha', 'Gene', '3091', (29, 39))	('VEGFR', 'Gene', (176, 181))	('promotes', 'PosReg', (119, 127))	('PDGFR', 'Gene', (225, 230))	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('PDGFR', 'Gene', '5159', (225, 230))	('EGFR', 'Gene', '1956', (177, 181))	('uninhibited transcription', 'MPA', (128, 153))	('cell growth', 'biological_process', 'GO:0016049', ('247', '258'))
9621	29878354	Ultimately, mutations in VHL result in a downstream effect of increase in tyrosine kinase mediated proteins that promote RCC tumorigenesis.	('VHL', 'Gene', '7428', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('promote', 'PosReg', (113, 120))	('mutations', 'Var', (12, 21))	('tyrosine kinase', 'Gene', (74, 89))	('RCC tumor', 'Disease', 'MESH:C538614', (121, 130))	('VHL', 'Gene', (25, 28))	('tyrosine kinase', 'Gene', '7294', (74, 89))	('increase', 'PosReg', (62, 70))	('RCC tumor', 'Disease', (121, 130))
9623	29878354	Prior studies have shown that a majority of GIST cases (approximately 85%) carry KIT mutations and 5 - 7% of KIT-negative GISTs have activating mutations of PDGFR- alpha.	('GISTs', 'Phenotype', 'HP:0100723', (122, 127))	('activating', 'MPA', (133, 143))	('KIT', 'molecular_function', 'GO:0005020', ('109', '112'))	('PDGFR- alpha', 'Gene', '5156', (157, 169))	('KIT', 'molecular_function', 'GO:0005020', ('81', '84'))	('mutations', 'Var', (85, 94))	('PDGFR- alpha', 'Gene', (157, 169))
9624	29878354	Activating KIT and PDGFR- alpha mutations are dependent on tyrosine-kinase mediated pathways that are essential for GIST development.	('tyrosine-kinase mediated pathways', 'Pathway', (59, 92))	('PDGFR- alpha', 'Gene', (19, 31))	('PDGFR- alpha', 'Gene', '5156', (19, 31))	('mutations', 'Var', (32, 41))	('KIT', 'molecular_function', 'GO:0005020', ('11', '14'))	('KIT', 'Gene', (11, 14))	('dependent', 'Reg', (46, 55))
9625	29878354	Genetic mutations in tyrosine kinase pathways are essential for tumorigenesis of RCC and GIST, and the common origins for these tumors provide support for their clinical association.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (64, 69))	('tyrosine kinase', 'Gene', '7294', (21, 36))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('RCC', 'Disease', (81, 84))	('tyrosine kinase', 'Gene', (21, 36))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', (128, 133))	('Genetic mutations', 'Var', (0, 17))	('association', 'Interaction', (170, 181))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
9635	29878354	pRCC can occur as a recurrent familial tumor involving mutations in the receptor tyrosine kinase molecule c-MET.	('c-MET', 'Gene', '4233', (106, 111))	('mutations', 'Var', (55, 64))	('receptor tyrosine kinase', 'Gene', (72, 96))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('receptor tyrosine kinase', 'Gene', '5979', (72, 96))	('pRCC', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('c-MET', 'Gene', (106, 111))	('familial tumor', 'Disease', 'MESH:D009386', (30, 44))	('pRCC', 'Gene', '5546', (0, 4))	('familial tumor', 'Disease', (30, 44))
9648	27144525	Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation The genetic landscape and molecular features of collecting duct carcinoma (CDC) of the kidney remain largely unknown.	('carcinoma of the kidney', 'Phenotype', 'HP:0005584', (16, 39))	('carcinoma of the kidney', 'Disease', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('CDKN2A', 'Gene', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('duct carcinoma', 'Disease', (168, 182))	('duct carcinoma', 'Disease', 'MESH:D021441', (168, 182))	('up-regulation', 'PosReg', (95, 108))	('duct carcinoma', 'Disease', (11, 25))	('duct carcinoma', 'Disease', 'MESH:D021441', (11, 25))	('carcinoma of the kidney', 'Disease', 'MESH:C538614', (16, 39))	('SLC family gene', 'Gene', (79, 94))	('deletion', 'Var', (66, 74))	('regulation', 'biological_process', 'GO:0065007', ('98', '108'))	('CDKN2A', 'Gene', '1029', (59, 65))
9650	27144525	No recurrent somatic SNVs were observed except for MLL, which was found to be mutated (p.V297I and p.F407C) in 2 samples.	('p.V297I', 'Mutation', 'rs2305948', (87, 94))	('p.V297I', 'Var', (87, 94))	('p.F407C', 'Mutation', 'p.F407C', (99, 106))	('MLL', 'Gene', '4297', (51, 54))	('p.F407C', 'Var', (99, 106))	('MLL', 'Gene', (51, 54))
9652	27144525	SNP array data identified a CDKN2A homozygous deletion in 3 samples and SNV analysis showed a non-sense mutation of the CDKN2A gene with unknown somatic status.	('deletion', 'Var', (46, 54))	('CDKN2A', 'Gene', (120, 126))	('CDKN2A', 'Gene', (28, 34))	('CDKN2A', 'Gene', '1029', (120, 126))	('CDKN2A', 'Gene', '1029', (28, 34))
9663	27144525	To determine the genetic alterations associated with chemo sensitivity, a preclinical study with human cell lines established from CDC patients revealed topoisomerase I (TOPI) expression to be associated with high in vitro sensitivity to TOPI and TOPII inhibitors, such as topotecan, doxorubicin, and epirubicin, suggesting TOP1 as a potential molecular target for CDC.	('patients', 'Species', '9606', (135, 143))	('TOPI', 'Gene', (170, 174))	('doxorubicin', 'Chemical', 'MESH:D004317', (284, 295))	('human', 'Species', '9606', (97, 102))	('TOPI', 'Species', '9929', (170, 174))	('topoisomerase', 'molecular_function', 'GO:0003917', ('153', '166'))	('TOPI', 'Species', '9929', (238, 242))	('epirubicin', 'Chemical', 'MESH:D015251', (301, 311))	('associated with', 'Reg', (193, 208))	('topoisomerase', 'molecular_function', 'GO:0003918', ('153', '166'))	('topotecan', 'Chemical', 'MESH:D019772', (273, 282))	('TOPI', 'Species', '9929', (247, 251))	('expression', 'Var', (176, 186))
9669	27144525	In our study, the overall somatic changes, including SNVs, INDELs, and CNVs, of 4 samples with matched non-tumor are shown in Figure 1.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('non-tumor', 'Disease', (103, 112))	('non-tumor', 'Disease', 'MESH:D009369', (103, 112))	('INDELs', 'Var', (59, 65))
9670	27144525	Whole exome sequencing (WES) of all 4 tumor samples identified 368 putative somatic SNVs and INDELs, including 325 missense mutations, 24 non-sense mutations, 17 frameshift indels, and 2 protein deletions.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('non-sense mutations', 'Var', (138, 157))	('frameshift indels', 'Var', (162, 179))	('protein', 'Protein', (187, 194))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('missense mutations', 'Var', (115, 133))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))
9677	27144525	SNP array data revealed 4 samples (CDC1, CDC2, CDC4, and CDC5) as having large copy number changes and most of those were copy number gains, except for a chr15 q12 to q21.3 loss found in sample CDC5.	('CDC2', 'Gene', '983', (41, 45))	('CDC2', 'Gene', (41, 45))	('CDC4', 'Gene', (47, 51))	('CDC5', 'Gene', '988', (194, 198))	('CDC5', 'Gene', '988', (57, 61))	('copy number', 'Var', (122, 133))	('CDC5', 'Gene', (194, 198))	('CDC5', 'Gene', (57, 61))	('copy number changes', 'Var', (79, 98))	('CDC4', 'Gene', '55294', (47, 51))
9678	27144525	In addition, large scale LOH was more prevalent than copy number changes (Figure 1a) and all samples, except CDC7, had LOH in multiple whole chromosomes.	('CDC7', 'Gene', (109, 113))	('LOH', 'Disease', (25, 28))	('CDC7', 'Gene', '8317', (109, 113))	('LOH', 'Var', (119, 122))
9679	27144525	Focal homozygous deletions of chr 9 p-arm in all 3 samples (CDC1, CDC2, and CDC4) included CDKN2A.	('CDKN2A', 'Gene', (91, 97))	('included', 'Reg', (82, 90))	('CDC2', 'Gene', '983', (66, 70))	('deletions', 'Var', (17, 26))	('CDC2', 'Gene', (66, 70))	('CDKN2A', 'Gene', '1029', (91, 97))	('CDC4', 'Gene', '55294', (76, 80))	('chr 9 p-arm', 'Gene', (30, 41))	('CDC4', 'Gene', (76, 80))
9682	27144525	Combined with 9 FFPE samples, we found 7 samples with biallelic loss and 2 samples with single copy loss of CDKN2A.	('biallelic loss', 'Var', (54, 68))	('CDKN2A', 'Gene', '1029', (108, 114))	('CDKN2A', 'Gene', (108, 114))
9683	27144525	In CDC5, a sample without matched non-tumor, SNV analysis identified a cytosine-to-adenine transversion (c.360C > A), encoding a p.E120* non-sense mutation for CDKN2A gene with unknown somatic status.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('c.360C > A', 'Var', (105, 115))	('CDC5', 'Gene', (3, 7))	('p.E120*', 'Mutation', 'p.E120*', (129, 136))	('adenine', 'Chemical', 'MESH:D000225', (83, 90))	('CDKN2A', 'Gene', (160, 166))	('non-tumor', 'Disease', 'MESH:D009369', (34, 43))	('c.360C > A', 'Mutation', 'c.360C>A', (105, 115))	('CDKN2A', 'Gene', '1029', (160, 166))	('cytosine', 'Chemical', 'MESH:D003596', (71, 79))	('p.E120*', 'Var', (129, 136))	('CDC5', 'Gene', '988', (3, 7))	('non-tumor', 'Disease', (34, 43))
9689	27144525	Selective inhibitors for CDK4/CDK6 are currently in clinical development and, based on our findings, may represent a rational therapeutic strategy for CDC.	('CDK', 'molecular_function', 'GO:0004693', ('30', '33'))	('CDK6', 'Gene', (30, 34))	('CDK6', 'Gene', '1021', (30, 34))	('CDK4', 'Gene', (25, 29))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))	('inhibitors', 'Var', (10, 20))	('CDC', 'Disease', (151, 154))	('CDK4', 'Gene', '1019', (25, 29))
9695	27144525	A review of TCGA data showed HMGA2 to be overexpressed in ccRCC, but not in pRCC (Figure 7) and survival analysis showed significant poor outcome for the high HGMA2 expression group in both ccRCC and pRCC (log-rank test, p-value < 0.001 and 0.004, and adjusted p-value of < 0.001 and 0.026 for ccRCC and pRCC, respectively).	('pRCC', 'Gene', '5546', (200, 204))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (305, 308))	('RCC', 'Disease', (60, 63))	('pRCC', 'Gene', (76, 80))	('RCC', 'Disease', (296, 299))	('pRCC', 'Gene', (304, 308))	('overexpressed', 'PosReg', (41, 54))	('RCC', 'Disease', (201, 204))	('HMGA2', 'Gene', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (305, 308))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('RCC', 'Disease', (192, 195))	('pRCC', 'Gene', (200, 204))	('RCC', 'Disease', 'MESH:C538614', (296, 299))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('HMGA2', 'Gene', '8091', (29, 34))	('pRCC', 'Gene', '5546', (76, 80))	('high', 'Var', (154, 158))	('RCC', 'Disease', (77, 80))	('pRCC', 'Gene', '5546', (304, 308))
9696	27144525	Similarly, CTHRC1 was found to be significantly up-regulated in pRCC, but not in ccRCC, and the survival analysis showed significant poor overall survival for the high CTHRC1 expression group (log-rank test, p-value = 0.013 and 0.001, and adjusted p-value 0.053 and < 0.001 for ccRCC and pRCC, respectively).	('up-regulated', 'PosReg', (48, 60))	('pRCC', 'Gene', '5546', (64, 68))	('CTHRC1', 'Gene', '115908', (168, 174))	('CTHRC1', 'Gene', (11, 17))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', (289, 292))	('pRCC', 'Gene', (288, 292))	('expression', 'MPA', (175, 185))	('RCC', 'Disease', (280, 283))	('CTHRC1', 'Gene', (168, 174))	('RCC', 'Disease', (65, 68))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('pRCC', 'Gene', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('high', 'Var', (163, 167))	('poor', 'NegReg', (133, 137))	('pRCC', 'Gene', '5546', (288, 292))	('CTHRC1', 'Gene', '115908', (11, 17))
9697	27144525	To support the significance of CDKN2A loss in renal cancer, we further analyzed the available TCGA data and found worst survival for ccRCC and pRCC patients with CDKN2A alteration, as compared to wild type (Figure 8).	('loss in renal cancer', 'Disease', (38, 58))	('patients', 'Species', '9606', (148, 156))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('CDKN2A', 'Gene', '1029', (31, 37))	('pRCC', 'Gene', (143, 147))	('CDKN2A', 'Gene', (162, 168))	('pRCC', 'Gene', '5546', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('CDKN2A', 'Gene', '1029', (162, 168))	('RCC', 'Disease', (135, 138))	('worst', 'NegReg', (114, 119))	('renal cancer', 'Phenotype', 'HP:0009726', (46, 58))	('CDKN2A', 'Gene', (31, 37))	('loss in renal cancer', 'Disease', 'MESH:D007680', (38, 58))	('RCC', 'Disease', (144, 147))	('alteration', 'Var', (169, 179))
9705	27144525	Recently, the proline transporter, PROT, was reported to have a significant role in the tumor microenvironment and limiting of intracellular proline inhibits proliferation of renal cancer cells.	('renal cancer', 'Disease', (175, 187))	('limiting', 'Var', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('renal cancer', 'Phenotype', 'HP:0009726', (175, 187))	('intracellular', 'cellular_component', 'GO:0005622', ('127', '140'))	('proline', 'Chemical', 'MESH:D011392', (14, 21))	('renal cancer', 'Disease', 'MESH:D007680', (175, 187))	('inhibits', 'NegReg', (149, 157))	('proline', 'Chemical', 'MESH:D011392', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('proliferation', 'CPA', (158, 171))
9717	27144525	A recent genomic profiling study has suggested a potential therapeutic role for mTOR inhibitors in CDC with NF2 alterations.	('NF2', 'Gene', (108, 111))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('NF2', 'Gene', '4771', (108, 111))	('CDC', 'Disease', (99, 102))	('alterations', 'Var', (112, 123))
9720	27144525	Our RNASeq analysis confirmed the overexpression of CDK4, TP53, and MYC in the tumor samples, suggesting that indeed p16 deletion may play a critical role in the biology of CDC tumors by the overexpression of oncogenic signaling pathways.	('p16', 'Gene', '1029', (117, 120))	('TP53', 'Gene', '7157', (58, 62))	('oncogenic signaling pathways', 'Pathway', (209, 237))	('CDK4', 'Gene', (52, 56))	('CDC tumors', 'Disease', 'MESH:D009369', (173, 183))	('MYC', 'Gene', '4609', (68, 71))	('tumor', 'Disease', (177, 182))	('signaling', 'biological_process', 'GO:0023052', ('219', '228'))	('CDK4', 'Gene', '1019', (52, 56))	('tumor', 'Disease', (79, 84))	('TP53', 'Gene', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('overexpression', 'PosReg', (191, 205))	('CDC tumors', 'Disease', (173, 183))	('CDK', 'molecular_function', 'GO:0004693', ('52', '55'))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('p16', 'Gene', (117, 120))	('deletion', 'Var', (121, 129))	('MYC', 'Gene', (68, 71))
9728	27144525	Overexpression of CTHRC1 that encodes for a secretary protein involved in vascular remodeling through limiting collagen matrix deposition, has been associated with pancreatic cancer cells migration and metastasis, and melanoma invasiveness.	('collagen', 'molecular_function', 'GO:0005202', ('111', '119'))	('pancreatic cancer', 'Disease', (164, 181))	('CTHRC1', 'Gene', '115908', (18, 24))	('pancreatic cancer', 'Disease', 'MESH:D010190', (164, 181))	('melanoma invasiveness', 'Disease', (218, 239))	('protein', 'cellular_component', 'GO:0003675', ('54', '61'))	('CTHRC1', 'Gene', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('collagen matrix deposition', 'MPA', (111, 137))	('melanoma invasiveness', 'Disease', 'MESH:D008545', (218, 239))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (148, 158))	('limiting', 'NegReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
9735	27144525	For putative indels, the filter process re-aligns all reads in both tumor and paired normal at the indel site with a template sequence generated by replacing reference allele with mutant one.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutant', 'Var', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
9742	27144525	Triplicates tumor sections of each CDC tumor cores (1.0mm), de-identified numbers (CDC2, 458, 033, CDC1, 459 and 460) in TMA were utilized.	('TMA', 'Disease', 'MESH:D000783', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CDC2', 'Gene', '983', (83, 87))	('CDC2', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TMA', 'Disease', (121, 124))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (12, 17))	('CDC1', 'Var', (99, 103))
9765	31719751	IL20RB can also form a heterodimer with IL22RA1.	('IL20', 'molecular_function', 'GO:0045517', ('0', '4'))	('IL22RA1', 'Gene', '58985', (40, 47))	('IL20RB', 'Var', (0, 6))	('heterodimer', 'Interaction', (23, 34))	('IL22', 'molecular_function', 'GO:0045518', ('40', '44'))	('IL22RA1', 'Gene', (40, 47))	('form', 'Reg', (16, 20))
9781	31719751	4A and 4B, P<0.01), indicating that their invasion ability was obviously inhibited after infection with si-IL20RB.	('infection', 'Disease', (89, 98))	('infection', 'Disease', 'MESH:D007239', (89, 98))	('si-IL20RB', 'Var', (104, 113))	('invasion ability', 'CPA', (42, 58))	('inhibited', 'NegReg', (73, 82))	('IL20', 'molecular_function', 'GO:0045517', ('107', '111'))
9788	31719751	Furthermore, abnormal expression of Snail was related to poor survival in breast, hepatocellular, and ovarian cancers.	('hepatocellular', 'Disease', (82, 96))	('Snail', 'Gene', (36, 41))	('ovarian cancers', 'Phenotype', 'HP:0100615', (102, 117))	('ovarian cancers', 'Disease', (102, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancers', 'Disease', 'MESH:D010051', (102, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('breast', 'Disease', (74, 80))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))
9802	28415646	Therapies targeting vascular endothelial growth factor receptor and mammalian target of rapamycin may benefit patients with Xp11 translocation RCC; the MET signaling pathway is another possible target, since it is activated by ASPL-TFE3 fusion.	('MET signaling pathway', 'biological_process', 'GO:0048012', ('152', '173'))	('MET signaling pathway', 'Pathway', (152, 173))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('TFE3', 'Gene', (232, 236))	('mammalian target of rapamycin', 'Gene', '2475', (68, 97))	('mammalian target of rapamycin', 'Gene', (68, 97))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('20', '54'))	('ASPL', 'Gene', '79058', (227, 231))	('Xp11 translocation', 'Var', (124, 142))	('TFE3', 'Gene', '7030', (232, 236))	('RCC', 'Disease', (143, 146))	('ASPL', 'Gene', (227, 231))	('patients', 'Species', '9606', (110, 118))
9804	28415646	Therefore, differentiating Xp11 translocation RCC from other subtypes is of clinical importance and more than of academic interest.	('Xp11 translocation', 'Var', (27, 45))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))
9808	28415646	To compare three methods for diagnosing Xp11 translocation RCC, the present study examined the results of TFE3 immunohistochemistry, FISH, and RT-PCR using FFPE tissue.	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('TFE3', 'Gene', (106, 110))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('TFE3', 'Gene', '7030', (106, 110))	('RCC', 'Disease', (59, 62))	('Xp11 translocation', 'Var', (40, 58))
9823	28415646	ASPL- and PRCC-TFE3 translocations were detected in 13/14 (Figure 3D, 3E) and 1/14 (Figure 3F, 3G) TFE3-positive cases, respectively, of which two were excluded.	('TFE3', 'Gene', '7030', (99, 103))	('TFE3', 'Gene', (15, 19))	('PRCC', 'Gene', '5546', (10, 14))	('ASPL', 'Gene', '79058', (0, 4))	('PRCC', 'Gene', (10, 14))	('detected', 'Reg', (40, 48))	('TFE3', 'Gene', (99, 103))	('ASPL', 'Gene', (0, 4))	('TFE3', 'Gene', '7030', (15, 19))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('translocations', 'Var', (20, 34))
9827	28415646	All 14 cases showing moderate-to-strong TFE3 expression harbored TFE3 translocations by RT-PCR, with two cases negative by FISH.	('TFE3', 'Gene', (40, 44))	('TFE3', 'Gene', '7030', (65, 69))	('translocations', 'Var', (70, 84))	('harbored', 'Reg', (56, 64))	('TFE3', 'Gene', '7030', (40, 44))	('TFE3', 'Gene', (65, 69))
9833	28415646	All 13 TFE3-negative/cathepsin K-positive cases were negative by FISH; however, four showed translocations by RT-PCR (ASPL- and PRCC-TFE3, n = 2 each).	('cathepsin K', 'Gene', (21, 32))	('TFE3', 'Gene', '7030', (7, 11))	('PRCC', 'Gene', '5546', (128, 132))	('ASPL', 'Gene', (118, 122))	('translocations', 'Var', (92, 106))	('TFE3', 'Gene', (133, 137))	('cathepsin K', 'Gene', '1513', (21, 32))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('PRCC', 'Gene', (128, 132))	('TFE3', 'Gene', (7, 11))	('TFE3', 'Gene', '7030', (133, 137))	('ASPL', 'Gene', '79058', (118, 122))
9855	28415646	The incidence of Xp11 translocation RCC has been variably reported.	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('Xp11 translocation', 'Var', (17, 35))
9860	28415646	In conclusion, we suggest that moderate-to-strong TFE3 staining can be suspicious evidence of Xp11 translocation RCC and the high concordance rate of immunohistochemical and molecular studies is proved.	('TFE3', 'Gene', (50, 54))	('moderate-to-strong', 'Var', (31, 49))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('TFE3', 'Gene', '7030', (50, 54))	('Xp11 translocation', 'Var', (94, 112))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))
9884	24703100	CCRCC is characterized by cells with clear cytoplasm, expression of carbonic anhydrase IX (CAIX) and CD10, alteration of the VHL gene, and other recurrent copy number alterations including 5q gains and 9p loss.	('CCRCC', 'Disease', (0, 5))	('VHL', 'Gene', (125, 128))	('CCRCC', 'Phenotype', 'HP:0006770', (0, 5))	('CD10', 'Gene', '4311', (101, 105))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('CD10', 'Gene', (101, 105))	('CAIX', 'Gene', '768', (91, 95))	('VHL', 'Gene', '7428', (125, 128))	('CAIX', 'Gene', (91, 95))	('carbonic anhydrase IX', 'Gene', '768', (68, 89))	('9p loss', 'Var', (202, 209))	('cytoplasm', 'cellular_component', 'GO:0005737', ('43', '52'))	('5q gains', 'Var', (189, 197))	('CD10', 'molecular_function', 'GO:0004245', ('101', '105'))	('alteration', 'Var', (107, 117))	('carbonic anhydrase IX', 'Gene', (68, 89))
9898	24703100	To identify consensus of differentially regulated miRNA between renal carcinoma histologic types, we additionally determined differential miRNA expression using 2 publically available microarray data sets from the NCBI Gene Expression Omnibus database (GSE41282 and GSE3798).	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('renal carcinoma', 'Disease', (64, 79))	('Gene Expression', 'biological_process', 'GO:0010467', ('219', '234'))	('renal carcinoma', 'Phenotype', 'HP:0005584', (64, 79))	('GSE3798', 'Var', (266, 273))	('renal carcinoma', 'Disease', 'MESH:C538614', (64, 79))	('GSE41282', 'Var', (253, 261))
9904	24703100	Using CCRCC cell lines, Yamamura et al demonstrated that miR-34a suppresses c-MYC and its complexes and inhibits cell invasion, thus suggesting a role as a tumor suppressor in renal cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cell invasion', 'CPA', (113, 126))	('complexes', 'MPA', (90, 99))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('renal cancers', 'Disease', 'MESH:D007680', (176, 189))	('CCRCC', 'Phenotype', 'HP:0006770', (6, 11))	('inhibits', 'NegReg', (104, 112))	('c-MYC', 'Gene', (76, 81))	('tumor suppressor', 'biological_process', 'GO:0051726', ('156', '172'))	('renal cancers', 'Disease', (176, 189))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('156', '172'))	('renal cancer', 'Phenotype', 'HP:0009726', (176, 188))	('suppresses', 'NegReg', (65, 75))	('miR-34a', 'Var', (57, 64))	('c-MYC', 'Gene', '4609', (76, 81))
9910	24703100	Mikhaylova et al recently showed that miR-204 is a VHL-regulated tumor suppressor acting by inhibiting macroautophagy, with LC3B as a direct and functional target in CCRCC specimens.	('LC3B', 'Gene', (124, 128))	('macroautophagy', 'MPA', (103, 117))	('tumor suppressor', 'biological_process', 'GO:0051726', ('65', '81'))	('macroautophagy', 'biological_process', 'GO:0016236', ('103', '117'))	('CCRCC', 'Disease', (166, 171))	('miR-204', 'Var', (38, 45))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('CCRCC', 'Phenotype', 'HP:0006770', (166, 171))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('65', '81'))	('LC3B', 'Gene', '81631', (124, 128))	('inhibiting', 'NegReg', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
9918	30622286	Recurrent mutations in chromatin modifying genes KMT2C and KDM5C were detected in 2 of 9 tumors.	('KMT2C', 'Gene', '58508', (49, 54))	('KMT2C', 'Gene', (49, 54))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('detected', 'Reg', (70, 78))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('23', '32'))	('KDM5C', 'Gene', (59, 64))	('KDM5C', 'Gene', '8242', (59, 64))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
9952	30622286	Paired tumor and normal DNA samples of 5 other cases from MSKCC were analyzed using the targeted capture-based next-generation sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, MSK-IMPACT ) to identify somatic mutations and copy number alterations as described previously.	('Cancer', 'Disease', 'MESH:D009369', (208, 214))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('copy number alterations', 'Var', (271, 294))	('Paired tumor', 'Disease', (0, 12))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Cancer', 'Disease', (208, 214))	('Paired tumor', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
9972	30622286	Recurrent mutations in two chromatin modifying genes lysine N-methyltransferase (KMT2C), a histone methyltransferase, and lysine-specific demethylase 5C (KDM5C), a histone demethylase, were each identified in 2 of 9 (22%) cases.	('identified', 'Reg', (195, 205))	('lysine-specific demethylase 5C', 'Gene', '8242', (122, 152))	('lysine-specific demethylase 5C', 'Gene', (122, 152))	('KMT2C', 'Gene', (81, 86))	('KDM5C', 'Gene', (154, 159))	('KMT2C', 'Gene', '58508', (81, 86))	('histone methyltransferase', 'Gene', '56979', (91, 116))	('KDM5C', 'Gene', '8242', (154, 159))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('histone methyltransferase', 'Gene', (91, 116))	('mutations', 'Var', (10, 19))
9973	30622286	Other known or likely oncogenic mutations in PMS2, RAD21, TP53, FBXW7, and KEAP1 were also detected.	('KEAP1', 'Gene', (75, 80))	('FBXW7', 'Gene', '55294', (64, 69))	('PMS2', 'Gene', (45, 49))	('RAD21', 'Gene', '5885', (51, 56))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('PMS2', 'Gene', '5395', (45, 49))	('FBXW7', 'Gene', (64, 69))	('mutations', 'Var', (32, 41))	('KEAP1', 'Gene', '9817', (75, 80))	('RAD', 'biological_process', 'GO:1990116', ('51', '54'))	('oncogenic', 'CPA', (22, 31))	('RAD21', 'Gene', (51, 56))
9974	30622286	Case TC2 also showed amplification of MDM2 and CDK4 genes.	('CDK', 'molecular_function', 'GO:0004693', ('47', '50'))	('TC2', 'Gene', '6948', (5, 8))	('CDK4', 'Gene', (47, 51))	('MDM2', 'Gene', '4193', (38, 42))	('MDM2', 'Gene', (38, 42))	('CDK4', 'Gene', '1019', (47, 51))	('amplification', 'Var', (21, 34))	('TC2', 'Gene', (5, 8))
10006	30622286	3) Gains of chromosome 7, an almost universal feature in type 1 papillary renal cell carcinoma, are not seen in tubulocystic carcinoma.	('tubulocystic carcinoma', 'Disease', 'MESH:D009369', (112, 134))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (64, 94))	('Gains', 'Var', (3, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (64, 94))	('papillary renal cell carcinoma', 'Disease', (64, 94))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (74, 94))	('tubulocystic carcinoma', 'Disease', (112, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
10008	30622286	Shared chromosomal losses/gains, based on 1 or 2 chromosomes alone, cannot be justifiable as a proof of relatedness of different tumors.	('tumors', 'Disease', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('chromosomal losses/gains', 'Var', (7, 31))
10009	30622286	For example, loss of chromosome Y is not uncommon in a large number of non-renal tumors, as well as in many renal cell tumors, including clear cell and chromophobe renal cell carcinoma, and renal oncocytoma.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('non-renal tumors', 'Disease', (71, 87))	('non-renal tumors', 'Disease', 'MESH:D007674', (71, 87))	('chromosome', 'Gene', (21, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('loss', 'Var', (13, 17))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))	('renal oncocytoma', 'Disease', 'MESH:C537750', (190, 206))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (190, 206))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (152, 184))	('renal cell tumors', 'Disease', (108, 125))	('renal cell tumor', 'Phenotype', 'HP:0005584', (108, 124))	('clear cell', 'Disease', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('renal cell tumors', 'Disease', 'MESH:C538614', (108, 125))	('renal tumors', 'Phenotype', 'HP:0009726', (75, 87))	('chromophobe renal cell carcinoma', 'Disease', (152, 184))	('renal oncocytoma', 'Disease', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))
10016	30622286	However, 24 of these 29 cases (83%) had immunohistochemical staining patterns suggestive of FH-deficiency (FH-/2SC+ n=16; FH+-/2SC+ n=8); and 8 of 11 cases with FH-deficiency (72%) on sequencing showed FH gene mutations.	('FH', 'Gene', '2271', (202, 204))	('mutations', 'Var', (210, 219))	('2SC', 'Chemical', 'MESH:C511650', (127, 130))	('FH', 'Gene', '2271', (107, 109))	('FH-deficiency', 'Disease', 'MESH:D006938', (92, 105))	('FH-deficiency', 'Disease', (92, 105))	('FH-deficiency', 'Disease', 'MESH:D006938', (161, 174))	('FH-deficiency', 'Disease', (161, 174))	('FH', 'Gene', '2271', (122, 124))	('FH', 'Gene', '2271', (92, 94))	('2SC', 'Chemical', 'MESH:C511650', (111, 114))	('FH', 'Gene', '2271', (161, 163))
10020	30622286	A recent study on tubulocystic renal cell carcinoma by Lawrie et al reported recurrent mutations in ABL1 and PDFGRA genes.	('ABL1', 'Gene', (100, 104))	('tubulocystic renal cell carcinoma', 'Disease', 'MESH:C538614', (18, 51))	('tubulocystic renal cell', 'Phenotype', 'HP:0100611', (18, 41))	('tubulocystic renal cell carcinoma', 'Disease', (18, 51))	('PDFGRA', 'Gene', (109, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (31, 51))	('ABL1', 'Gene', '25', (100, 104))	('mutations', 'Var', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
10023	30622286	Our study identified recurrent oncogenic mutations in chromatin modifying genes KMT2C and KDM5C, as well as other oncogenic mutations such as those in involving DNA repair and DNA damage response genes such as PMS2, RAD21, and TP53.	('KDM5C', 'Gene', (90, 95))	('mutations', 'Var', (41, 50))	('KMT2C', 'Gene', (80, 85))	('KMT2C', 'Gene', '58508', (80, 85))	('DNA', 'cellular_component', 'GO:0005574', ('176', '179'))	('TP53', 'Gene', '7157', (227, 231))	('PMS2', 'Gene', (210, 214))	('KDM5C', 'Gene', '8242', (90, 95))	('DNA damage response', 'biological_process', 'GO:0006974', ('176', '195'))	('PMS2', 'Gene', '5395', (210, 214))	('TP53', 'Gene', (227, 231))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('RAD21', 'Gene', (216, 221))	('chromatin', 'cellular_component', 'GO:0000785', ('54', '63'))	('DNA repair', 'biological_process', 'GO:0006281', ('161', '171'))	('RAD', 'biological_process', 'GO:1990116', ('216', '219'))	('RAD21', 'Gene', '5885', (216, 221))
10030	30588036	RASSF1A promoter methylation correlated with RCC in tissue, blood, and urine samples.	('RASSF1A', 'Gene', (0, 7))	('correlated', 'Reg', (29, 39))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
10031	30588036	On multivariate analysis, RASSF1A promoter methylation was associated with tumor grade (grade 3-4 vs 1-2: OR=3.59), clinical stage (stage 3-4 vs 1-2: OR=2.15), T classification (pT2-4 vs pT1: OR=2.66), histologic subtypes (papillary vs clear cell: OR=2.91), and cancer-specific survival (HR=1.78), but it was not linked to age, gender, lymph node status, distant metastasis, or overall survival.	('cancer', 'Disease', (262, 268))	('pT1', 'Gene', '58492', (187, 190))	('RASSF1A', 'Gene', '11186', (26, 33))	('methylation', 'Var', (43, 54))	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('T classification', 'CPA', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('associated', 'Reg', (59, 69))	('pT1', 'Gene', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('RASSF1A', 'Gene', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Disease', (75, 80))
10032	30588036	The Cancer Genome Atlas data also showed that RASSF1A methylation was significantly more likely to be seen in papillary vs clear-cell RCC (OR=23.19).	('RASSF1A', 'Gene', '11186', (46, 53))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('methylation', 'Var', (54, 65))	('papillary', 'Disease', (110, 119))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('RASSF1A', 'Gene', (46, 53))	('seen', 'Reg', (102, 106))
10033	30588036	RASSF1A promoter methylation may be associated with the development and progression of RCC, as well as poor cancer-specific survival.	('RASSF1A', 'Gene', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('associated with', 'Reg', (36, 51))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
10034	30588036	Methylation was more frequent in papillary vs clear-cell RCC.	('Methylation', 'Var', (0, 11))	('papillary', 'Disease', (33, 42))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('frequent', 'Reg', (21, 29))
10041	30588036	DNA methylation within the promoter regions is an important mechanism underlying epigenetic modifications, which may cause inactivation of gene expression and play a crucial role in the carcinogenesis, progression, and prognosis of various human cancers.	('gene expression', 'MPA', (139, 154))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('cancers', 'Disease', (246, 253))	('human', 'Species', '9606', (240, 245))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('inactivation', 'MPA', (123, 135))	('gene expression', 'biological_process', 'GO:0010467', ('139', '154'))	('epigenetic modifications', 'Var', (81, 105))	('carcinogenesis', 'Disease', (186, 200))
10045	30588036	RASSF1A promoter methylation has been reported in tissue, blood, and urine samples from patients with RCC.	('RASSF1A', 'Gene', (0, 7))	('patients', 'Species', '9606', (88, 96))	('methylation', 'Var', (17, 28))	('RASSF1A', 'Gene', '11186', (0, 7))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))
10048	30588036	In contrast, RASSF1A promoter methylation was more frequent in RCC than in adjacent normal tissue samples in a study by Loginov et al.	('RASSF1A', 'Gene', (13, 20))	('RCC', 'Disease', (63, 66))	('promoter', 'MPA', (21, 29))	('methylation', 'Var', (30, 41))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('RASSF1A', 'Gene', '11186', (13, 20))	('frequent', 'Reg', (51, 59))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
10051	30588036	The following keywords and scientific search terms were used: (kidney OR renal) AND (cancer OR tumor OR neoplasm OR carcinoma) AND (methylation OR methylated OR hypermethylation OR epigene*) AND (RAS association domain family protein 1A OR RASSF1A OR RASSF1 OR RAS association domain family protein 1).	('protein', 'cellular_component', 'GO:0003675', ('226', '233'))	('neoplasm OR carcinoma', 'Disease', 'MESH:D009369', (104, 125))	('RASSF1', 'Gene', (251, 257))	('tumor', 'Disease', (95, 100))	('RASSF1A', 'Gene', (240, 247))	('kidney OR renal) AND (cancer', 'Disease', 'MESH:D007680', (63, 91))	('protein', 'cellular_component', 'GO:0003675', ('291', '298'))	('RASSF1', 'Gene', '11186', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('RASSF1A', 'Gene', '11186', (240, 247))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('RASSF1', 'Gene', '11186', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('epigene*', 'Var', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('neoplasm OR carcinoma', 'Disease', (104, 125))	('RASSF1', 'Gene', (240, 246))
10073	30588036	In four studies that included the comparison of 237 patients with RCC with 142 nonmalignant blood samples, RASSF1A promoter methylation was significantly more likely in RCC than in nonmalignant blood samples (OR=11.70, 95% CI=4.82-28.39, P<0.001; Figure 2).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('OR=11.70', 'Gene', '255725', (209, 217))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('likely', 'Reg', (159, 165))	('RASSF1A', 'Gene', (107, 114))	('OR=11.70', 'Gene', (209, 217))	('RASSF1A', 'Gene', '11186', (107, 114))	('RCC', 'Disease', (66, 69))	('methylation', 'Var', (124, 135))	('patients', 'Species', '9606', (52, 60))
10078	30588036	Four studies that included 257 patients with RCC showed that there was no correlation between RASSF1A promoter methylation and distant metastasis (OR=1.66, 95% CI=0.75-3.69, P=0.21; Figure 4).	('methylation', 'Var', (111, 122))	('RASSF1A', 'Gene', (94, 101))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('patients', 'Species', '9606', (31, 39))	('RASSF1A', 'Gene', '11186', (94, 101))	('distant metastasis', 'CPA', (127, 145))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
10079	30588036	In 13 studies that included 686 patients with RCC, a significant relationship was observed between RASSF1A promoter methylation and tumor grade (OR=3.59, 95% CI=1.85-6.95, P<0.001; Figure 5).	('patients', 'Species', '9606', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RCC', 'Disease', (46, 49))	('RASSF1A', 'Gene', '11186', (99, 106))	('methylation', 'Var', (116, 127))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('methylation', 'biological_process', 'GO:0032259', ('116', '127'))	('RASSF1A', 'Gene', (99, 106))
10080	30588036	RASSF1A promoter methylation was also linked to clinical stage in eight studies that included 463 patients with RCC (OR=2.15, 95% CI=1.34-3.45, P=0.001; Figure 5).	('RASSF1A', 'Gene', (0, 7))	('linked', 'Reg', (38, 44))	('methylation', 'Var', (17, 28))	('patients', 'Species', '9606', (98, 106))	('RCC', 'Disease', (112, 115))	('RASSF1A', 'Gene', '11186', (0, 7))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (112, 115))
10081	30588036	In seven studies that included 306 patients with RCC, a significant correlation was found between RASSF1A promoter methylation and T classification (OR=2.66, 95% CI=1.11-6.39, P=0.029; Figure 6).	('RCC', 'Disease', (49, 52))	('methylation', 'Var', (115, 126))	('RASSF1A', 'Gene', '11186', (98, 105))	('T classification', 'Disease', (131, 147))	('methylation', 'biological_process', 'GO:0032259', ('115', '126'))	('patients', 'Species', '9606', (35, 43))	('RASSF1A', 'Gene', (98, 105))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
10090	30588036	After adjusting for tumor stage (stage 3-4 vs stage 1-2) and tumor histology (pRCC vs ccRCC), RASSF1A promoter methylation was not associated with overall survival using multivariate analysis (HR=0.921, P=0.687) in 567 RCCs.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('RCC', 'Disease', (219, 222))	('methylation', 'Var', (111, 122))	('pRCC', 'Gene', '5546', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', (88, 91))	('associated', 'Reg', (131, 141))	('methylation', 'biological_process', 'GO:0032259', ('111', '122'))	('RASSF1A', 'Gene', '11186', (94, 101))	('RCC', 'Disease', (79, 82))	('tumor', 'Disease', (61, 66))	('pRCC', 'Gene', (78, 82))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RASSF1A', 'Gene', (94, 101))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('tumor', 'Disease', (20, 25))
10092	30588036	Tumor suppressor genes are commonly inactivated via promoter methylation within the CpG islands, which may affect several biological processes, including cell proliferation, cell death, cell migration, and cell invasion, and contribute to the initiation and progression of human cancers.	('cell proliferation', 'CPA', (154, 172))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor suppressor genes', 'Gene', (0, 22))	('cell migration', 'CPA', (186, 200))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('cell migration', 'biological_process', 'GO:0016477', ('186', '200'))	('cancers', 'Disease', (279, 286))	('affect', 'Reg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('promoter methylation', 'Var', (52, 72))	('contribute', 'Reg', (225, 235))	('biological processes', 'CPA', (122, 142))	('cell death', 'CPA', (174, 184))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))	('cell death', 'biological_process', 'GO:0008219', ('174', '184'))	('cell invasion', 'CPA', (206, 219))	('cell proliferation', 'biological_process', 'GO:0008283', ('154', '172'))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('inactivated', 'NegReg', (36, 47))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('0', '16'))	('human', 'Species', '9606', (273, 278))
10093	30588036	Studies have indicated that methylation of the promoter of the tumor suppressor gene RASSF1A reduces its expression, which may play an important role in RCC carcinogenesis.	('RASSF1A', 'Gene', (85, 92))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('63', '79'))	('RASSF1A', 'Gene', '11186', (85, 92))	('methylation', 'biological_process', 'GO:0032259', ('28', '39'))	('reduces', 'NegReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('RCC carcinogenesis', 'Disease', (153, 171))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (153, 171))	('methylation', 'Var', (28, 39))	('tumor suppressor', 'biological_process', 'GO:0051726', ('63', '79'))	('expression', 'MPA', (105, 115))	('promoter', 'MPA', (47, 55))
10097	30588036	Also, nine other studies showed that RASSF1A promoter methylation correlated positively with RCC.	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('methylation', 'biological_process', 'GO:0032259', ('54', '65'))	('RASSF1A', 'Gene', '11186', (37, 44))	('RCC', 'Disease', (93, 96))	('methylation', 'Var', (54, 65))	('RASSF1A', 'Gene', (37, 44))
10099	30588036	This suggests that RASSF1A promoter methylation is significantly associated with RCC carcinogenesis.	('RASSF1A', 'Gene', '11186', (19, 26))	('RCC carcinogenesis', 'Disease', (81, 99))	('RCC carcinogenesis', 'Disease', 'MESH:C538614', (81, 99))	('associated', 'Reg', (65, 75))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('RASSF1A', 'Gene', (19, 26))	('methylation', 'Var', (36, 47))
10109	30588036	These analyses suggest that RASSF1A promoter methylation may be closely associated with RCC progression.	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('RASSF1A', 'Gene', (28, 35))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('associated', 'Reg', (72, 82))	('methylation', 'Var', (45, 56))	('RASSF1A', 'Gene', '11186', (28, 35))
10117	30588036	In addition, Yu et al did not report whether RASSF1A promoter methylation was linked to clinical features (eg, gender, tumor grade, clinical stage, T classification, histologic subtypes, lymph node metastasis, and distant metastasis) and did not include an analysis of overall survival.	('tumor', 'Disease', (119, 124))	('methylation', 'biological_process', 'GO:0032259', ('62', '73'))	('RASSF1A', 'Gene', (45, 52))	('methylation', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RASSF1A', 'Gene', '11186', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lymph node metastasis', 'Disease', 'MESH:D009362', (187, 208))	('linked', 'Reg', (78, 84))	('lymph node metastasis', 'Disease', (187, 208))
10122	30588036	The present findings show that RASSF1A promoter methylation correlates with RCC in tissue, blood, and urine samples.	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RASSF1A', 'Gene', (31, 38))	('RASSF1A', 'Gene', '11186', (31, 38))	('methylation', 'Var', (48, 59))
10192	21763971	Despite the fact that VHL inactivation and the subsequent overexpression of hypoxia-inducible genes such as VEGF are hallmarks of CCRCC, patients with papillary, chromophobe and medullary histology can still demonstrate high expression of VEGF, VEGFR-1 and VEGFR-2 (especially in more advanced stages) that is correlated with worse survival, making VEGF-targeted therapy an attractive therapeutic option .	('VEGF', 'Gene', (108, 112))	('hypoxia', 'Disease', (76, 83))	('VHL', 'Gene', (22, 25))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('VEGFR-1', 'Gene', '2321', (245, 252))	('rat', 'Species', '10116', (215, 218))	('VEGF', 'Gene', '7422', (257, 261))	('VEGF', 'Gene', (257, 261))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('VEGFR-2', 'Gene', '3791', (257, 264))	('VHL', 'Gene', '7428', (22, 25))	('overexpression', 'PosReg', (58, 72))	('VEGF', 'Gene', '7422', (349, 353))	('VEGF', 'Gene', '7422', (239, 243))	('VEGF', 'Gene', (239, 243))	('patients', 'Species', '9606', (137, 145))	('VEGF', 'Gene', (349, 353))	('VEGFR-2', 'Gene', (257, 264))	('VEGF', 'Gene', '7422', (245, 249))	('VEGFR-1', 'Gene', (245, 252))	('inactivation', 'Var', (26, 38))	('VEGF', 'Gene', (245, 249))	('VEGF', 'Gene', '7422', (108, 112))
10207	21763971	Although only about 10% of sporadic type I PRCC have been reported to show somatic mutations in the c-MET gene, a genetic abnormality commonly seen as a germline mutation in hereditary cases , the c-Met pathway can be activated in many sporadic PRCC in the absence of c-Met mutation .	('PRCC', 'Phenotype', 'HP:0006766', (245, 249))	('c-Met', 'Gene', (268, 273))	('sporadic', 'Disease', (236, 244))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('c-Met', 'Gene', (197, 202))	('genetic abnormality', 'Disease', 'MESH:D030342', (114, 133))	('activated', 'PosReg', (218, 227))	('PRCC', 'Gene', '5546', (245, 249))	('genetic abnormality', 'Disease', (114, 133))	('PRCC', 'Gene', (43, 47))	('RCC', 'Phenotype', 'HP:0005584', (246, 249))	('PRCC', 'Phenotype', 'HP:0006766', (43, 47))	('c-Met', 'Gene', '4233', (268, 273))	('c-MET', 'Gene', '4233', (100, 105))	('c-Met', 'Gene', '4233', (197, 202))	('c-MET', 'Gene', (100, 105))	('mutations', 'Var', (83, 92))	('PRCC', 'Gene', '5546', (43, 47))	('PRCC', 'Gene', (245, 249))
10208	21763971	The group from the National Institutes of Health described the genetic abnormality associated with the hereditary form of the type 2 papillary RCC, consisting of mutations in the fumarate hydratase (FH) gene .	('mutations', 'Var', (162, 171))	('fumarate hydratase', 'Gene', '2271', (179, 197))	('fumarate hydratase', 'Gene', (179, 197))	('genetic abnormality', 'Disease', (63, 82))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('genetic abnormality', 'Disease', 'MESH:D030342', (63, 82))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('FH', 'Gene', '2271', (199, 201))
10213	21763971	Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumours, respectively.	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('G2-M checkpoint genes', 'Gene', (26, 47))	('Dysregulation', 'Var', (0, 13))	('G2-M checkpoint', 'biological_process', 'GO:0000075', ('26', '41'))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('G1-S', 'Gene', (17, 21))	('class 1', 'Disease', (62, 69))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
10237	21763971	Nevertheless, there are still several ongoing phase II trials investigating sunitinib therapy for PRCC, and their results will be useful in clarifying the role of sunitinib in NCCRCC (NCT00465179, NCT01034878 and NCT01219751).	('PRCC', 'Gene', (98, 102))	('NCT00465179', 'Var', (184, 195))	('NCT01219751', 'Var', (213, 224))	('PRCC', 'Phenotype', 'HP:0006766', (98, 102))	('sunitinib', 'Chemical', 'MESH:D000077210', (76, 85))	('sunitinib', 'Chemical', 'MESH:D000077210', (163, 172))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('NCT01034878', 'Var', (197, 208))	('PRCC', 'Gene', '5546', (98, 102))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
10277	21763971	It was observed that the mean EQ-5D score was higher in the temsirolimus arm compared to the IFN-alpha arm in NCCRCC patients.	('IFN-alpha', 'Gene', (93, 102))	('higher', 'PosReg', (46, 52))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('EQ-5D score', 'MPA', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('temsirolimus', 'Chemical', 'MESH:C401859', (60, 72))	('patients', 'Species', '9606', (117, 125))	('temsirolimus', 'Var', (60, 72))	('IFN-alpha', 'Gene', '3439', (93, 102))
10288	21763971	Although the RECIST response rate of 11% did not exceed pre-specified estimates (>= 20% response rate) for further study, single-agent erlotinib yielded encouraging DCR and OS results.	('DCR', 'MPA', (165, 168))	('rat', 'Species', '10116', (97, 100))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('erlotinib', 'Chemical', 'MESH:D000069347', (135, 144))	('rat', 'Species', '10116', (29, 32))	('erlotinib', 'Gene', (135, 144))	('single-agent', 'Var', (122, 134))
10290	21763971	(NCT 01130519, NCT 00060307) Foretinib (GSK1363089) is a novel inhibitor of receptor tyrosine kinases targeting MET and VEGFR.	('GSK1363089', 'Chemical', 'MESH:C544831', (40, 50))	('Foretinib', 'Chemical', 'MESH:C544831', (29, 38))	('VEGFR', 'Gene', '3791', (120, 125))	('GSK', 'molecular_function', 'GO:0050321', ('40', '43'))	('tyrosine kinase', 'Gene', (85, 100))	('VEGFR', 'Gene', (120, 125))	('GSK1363089', 'Var', (40, 50))	('tyrosine kinase', 'Gene', '7294', (85, 100))
10293	21763971	After enrollment, patients were stratified into two strata based on the presence or absence of a genetic aberration in c-MET (A: evidence of c-MET pathway activation; B: without evidence of activation).	('c-MET', 'Gene', (141, 146))	('c-MET', 'Gene', '4233', (119, 124))	('genetic aberration', 'Var', (97, 115))	('rat', 'Species', '10116', (54, 57))	('rat', 'Species', '10116', (109, 112))	('c-MET', 'Gene', '4233', (141, 146))	('patients', 'Species', '9606', (18, 26))	('c-MET', 'Gene', (119, 124))	('rat', 'Species', '10116', (34, 37))	('activation', 'PosReg', (155, 165))
10315	21763971	This autosomal dominant condition involves mutations in the BHD gene, resulting in benign cutaneous tumours, RCCs (especially with chromophobe histology) and spontaneous pneumothoraces.	('benign cutaneous tumours', 'Disease', 'MESH:D009369', (83, 107))	('spontaneous pneumothoraces', 'Phenotype', 'HP:0002108', (158, 184))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('resulting in', 'Reg', (70, 82))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('mutations', 'Var', (43, 52))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('BHD', 'Disease', 'MESH:D058249', (60, 63))	('benign cutaneous tumours', 'Disease', (83, 107))	('BHD', 'Disease', (60, 63))
10316	21763971	BHD encodes folliculin, a tumour suppressor, and it has been reported that BHD is also mutated in sporadic ChRCC .	('mutated', 'Var', (87, 94))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('BHD', 'Disease', (0, 3))	('BHD', 'Disease', 'MESH:D058249', (0, 3))	('tumour', 'Disease', (26, 32))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('BHD', 'Disease', (75, 78))	('BHD', 'Disease', 'MESH:D058249', (75, 78))
10317	21763971	Deranged expression of the receptor tyrosine kinase KIT is also understood to be important in ChRCC.	('RCC', 'Disease', (96, 99))	('tyrosine kinase', 'Gene', (36, 51))	('Deranged', 'Var', (0, 8))	('KIT', 'molecular_function', 'GO:0005020', ('52', '55'))	('tyrosine kinase', 'Gene', '7294', (36, 51))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
10340	21763971	(NCT 01182142) Renal medullary carcinoma (RMC) is a newly recognized aggressive form of kidney cancer, which was first described in a case series by Davis in 1995 .	('Renal medullary carcinoma', 'Disease', (15, 40))	('Renal medullary carcinoma', 'Disease', 'MESH:D007681', (15, 40))	('kidney cancer', 'Phenotype', 'HP:0009726', (88, 101))	('kidney cancer', 'Disease', 'MESH:D007680', (88, 101))	('NCT 01182142', 'Var', (1, 13))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('kidney cancer', 'Disease', (88, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
10353	21763971	Genetically, the loss of INI1, a factor in the ATP-dependent chromatin-modifying complex, is seen in some renal medullary carcinoma as well as renal rhabdoid tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('renal rhabdoid tumors', 'Disease', (143, 164))	('carcinoma', 'Disease', 'MESH:D002277', (122, 131))	('renal rhabdoid tumors', 'Disease', 'MESH:D018335', (143, 164))	('INI1', 'Gene', (25, 29))	('INI1', 'Gene', '6598', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('chromatin', 'cellular_component', 'GO:0000785', ('61', '70'))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('loss', 'Var', (17, 21))	('carcinoma', 'Disease', (122, 131))
10354	21763971	The absence of INI1 expression does not appear to be predictive of rhabdoid histopathology, but is associated with aggressive behavior in renal medullary carcinoma .	('INI1', 'Gene', '6598', (15, 19))	('associated with', 'Reg', (99, 114))	('INI1', 'Gene', (15, 19))	('aggressive behavior in renal medullary carcinoma', 'Disease', 'MESH:D010554', (115, 163))	('aggressive behavior', 'Phenotype', 'HP:0000718', (115, 134))	('aggressive behavior', 'biological_process', 'GO:0002118', ('115', '134'))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('absence', 'Var', (4, 11))	('aggressive behavior in renal medullary carcinoma', 'Disease', (115, 163))
10355	21763971	Rearrangement of the ALK receptor tyrosine kinase has been reported in renal medullary carcinoma, as well.	('Rearrangement', 'Var', (0, 13))	('reported', 'Reg', (59, 67))	('carcinoma', 'Disease', (87, 96))	('tyrosine kinase', 'Gene', (34, 49))	('ALK', 'Gene', (21, 24))	('tyrosine kinase', 'Gene', '7294', (34, 49))	('ALK', 'Gene', '238', (21, 24))	('carcinoma', 'Disease', 'MESH:D002277', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
10356	21763971	Marino-Enriquez et al identified a novel ALK oncoprotein in which the cytoskeletal protein vinculin (VCL) was fused to the ALK kinase domain in a case of RMC harboring a t(2;10)(p23; q22) translocation.	('vinculin', 'Gene', (91, 99))	('ALK', 'Gene', (123, 126))	('fused', 'Var', (110, 115))	('VCL', 'Gene', (101, 104))	('ALK', 'Gene', (41, 44))	('VCL', 'Gene', '7414', (101, 104))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('vinculin', 'Gene', '7414', (91, 99))	('ALK', 'Gene', '238', (123, 126))	('ALK', 'Gene', '238', (41, 44))
10489	32481542	Five out of the eight all-relevant features were significantly associated with the von Hippel-Lindau gene mutation.	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (83, 100))	('associated', 'Reg', (63, 73))	('mutation', 'Var', (106, 114))	('von Hippel-Lindau', 'Disease', (83, 100))
10509	32481542	BRCA1-associated protein (BAP1) gene mutations are found in ~15% of ccRCC and are associated with high-grade tumors and poor prognosis as reported in genome-wide association studies.	('BAP1', 'Gene', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('associated with', 'Reg', (82, 97))	('RCC', 'Disease', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('mutations', 'Var', (37, 46))	('BAP1', 'Gene', '8314', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BRCA1-associated protein', 'Gene', (0, 24))	('tumors', 'Disease', (109, 115))	('BRCA1-associated protein', 'Gene', '8315', (0, 24))
10510	32481542	tested radiomics to predict BAP1 mutation status on ccRCC and found an AUC of 0.71 for features retrieved from the NP phase of CECT scans.	('BAP1', 'Gene', '8314', (28, 32))	('mutation', 'Var', (33, 41))	('BAP1', 'Gene', (28, 32))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))
10511	32481542	aimed to predict the presence of gene PBRM1 mutations by creating an ANN algorithm and ML-based TA from CMP images; they found that the former outperformed the latter, upholding 95% accuracy and 0.987 AUC for PBRM1 mutation status.	('TA', 'Chemical', '-', (96, 98))	('PBRM1', 'Gene', (209, 214))	('PBRM1', 'Gene', '55193', (209, 214))	('PBRM1', 'Gene', (38, 43))	('PBRM1', 'Gene', '55193', (38, 43))	('mutations', 'Var', (44, 53))	('upholding', 'PosReg', (168, 177))
10512	32481542	This tumor suppressor gene's mutation was associated with advanced-stage and higher grade ccRCC, and it was also suggested to influence response rates to immune checkpoint inhibitors.	('mutation', 'Var', (29, 37))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('response', 'MPA', (136, 144))	('influence', 'Reg', (126, 135))	('tumor suppressor', 'biological_process', 'GO:0051726', ('5', '21'))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumor', 'Disease', (5, 10))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('5', '21'))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))
10556	19558708	Subsequently, WHO classified renal cell tumors into clear cell RCC, multilocular clear cell RCC, papillary RCC, chromophobe RCC, carcinoma of the collecting ducts of Bellini, renal medullary carcinoma, Xp11 translocation carcinoma, carcinoma associated with neuroblastoma, mucinous tubular and spindle cell carcinoma, renal cell carcinoma-unclassified, papillary adenoma and oncocytoma.	('carcinoma', 'Disease', (329, 338))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('spindle', 'cellular_component', 'GO:0005819', ('294', '301'))	('renal cell tumors', 'Disease', (29, 46))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (318, 338))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('carcinoma', 'Disease', (232, 241))	('papillary RCC, chromophobe RCC, carcinoma', 'Disease', 'MESH:C538614', (97, 138))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('oncocytoma', 'Disease', 'MESH:D018249', (375, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('Xp11 translocation', 'Var', (202, 220))	('carcinoma', 'Disease', 'MESH:D002277', (129, 138))	('carcinoma', 'Disease', (221, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Disease', 'MESH:D002277', (329, 338))	('carcinoma', 'Disease', (191, 200))	('papillary adenoma', 'Disease', 'MESH:D000236', (353, 370))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('papillary adenoma', 'Disease', (353, 370))	('renal cell tumors', 'Disease', 'MESH:C538614', (29, 46))	('renal cell carcinoma', 'Disease', (318, 338))	('carcinoma', 'Disease', 'MESH:D002277', (232, 241))	('carcinoma', 'Disease', (307, 316))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (318, 338))	('associated', 'Reg', (242, 252))	('neuroblastoma', 'Disease', (258, 271))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('oncocytoma', 'Disease', (375, 385))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('neuroblastoma', 'Phenotype', 'HP:0003006', (258, 271))	('carcinoma', 'Disease', 'MESH:D002277', (221, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('carcinoma', 'Disease', (129, 138))	('neuroblastoma', 'Disease', 'MESH:D009447', (258, 271))	('carcinoma', 'Disease', 'MESH:D002277', (307, 316))
10607	19558708	Third group of discordance was between eosinophilic variant of chromophobe RCC and oncocytoma.	('chromophobe RCC', 'Disease', 'MESH:C538614', (63, 78))	('oncocytoma', 'Disease', 'MESH:D018249', (83, 93))	('eosinophilic variant', 'Var', (39, 59))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('eosin', 'Chemical', 'MESH:D004801', (39, 44))	('chromophobe RCC', 'Disease', (63, 78))	('oncocytoma', 'Disease', (83, 93))
10648	19558708	This result is comparable to the studies by Mathers et al and Leroy et al who showed positivity of CK7 in 100% cases of chromophobe renal cell carcinoma, and one case of clear cell renal cell carcinoma.	('positivity', 'Var', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (132, 152))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (170, 201))	('CK7', 'Gene', (99, 102))	('chromophobe renal cell carcinoma', 'Disease', (120, 152))	('clear cell renal cell carcinoma', 'Disease', (170, 201))	('CK7', 'Gene', '3855', (99, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (170, 201))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
10649	19558708	Study by Yang et al showed 87-100% positivity of CK7 in papillary renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('CK7', 'Gene', '3855', (49, 52))	('positivity', 'Var', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 86))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (56, 86))	('CK7', 'Gene', (49, 52))	('papillary renal cell carcinoma', 'Disease', (56, 86))
10661	31690016	Here, we review the roles of Notch signaling identified from rodent kidney development and injury studies, while discussing human kidney diseases associated with aberrant Notch signaling.	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('kidney disease', 'Phenotype', 'HP:0000112', (130, 144))	('kidney diseases', 'Disease', (130, 145))	('kidney development', 'biological_process', 'GO:0001822', ('68', '86'))	('signaling', 'biological_process', 'GO:0023052', ('35', '44'))	('kidney diseases', 'Disease', 'MESH:D007674', (130, 145))	('human', 'Species', '9606', (124, 129))	('kidney diseases', 'Phenotype', 'HP:0000112', (130, 145))	('aberrant', 'Var', (162, 170))
10671	31690016	Interestingly, Ret signaling, which activates Etv4 and Etv5 in the UB tips, is required for cells to remain in the UB tip as Ret or Etv4 and Etv5 mutant cells tend to be excluded from the UB tips.	('Etv4', 'Gene', (132, 136))	('Etv4', 'Gene', (46, 50))	('Ret', 'Gene', '19713', (125, 128))	('Ret', 'Gene', '19713', (15, 18))	('Etv5', 'Gene', (55, 59))	('signaling', 'biological_process', 'GO:0023052', ('19', '28'))	('Etv5', 'Gene', '104156', (141, 145))	('Etv5', 'Gene', (141, 145))	('mutant', 'Var', (146, 152))	('Etv4', 'Gene', '18612', (132, 136))	('Etv4', 'Gene', '18612', (46, 50))	('UB', 'Chemical', '-', (67, 69))	('UB', 'Chemical', '-', (115, 117))	('Etv5', 'Gene', '104156', (55, 59))	('Ret', 'Gene', (125, 128))	('Ret', 'Gene', (15, 18))	('UB', 'Chemical', '-', (188, 190))
10674	31690016	Six2 expression is essential for maintenance of the NPC state, and cessation of Six2 expression marks the end of new nephron formation.	('Six2', 'Gene', '20472', (80, 84))	('Six2', 'Gene', (0, 4))	('formation', 'biological_process', 'GO:0009058', ('125', '134'))	('cessation', 'Var', (67, 76))	('Six2', 'Gene', (80, 84))	('Six2', 'Gene', '20472', (0, 4))	('NPC', 'cellular_component', 'GO:0005643', ('52', '55'))
10686	31690016	Inactivation of Notch components (RBPJ, or Notch1 and Notch2) sustain Six2 expression within the developing mouse kidney much after its expression should have been downregulated (Table 1).	('RBPJ', 'Gene', (34, 38))	('RBPJ', 'Gene', '19664', (34, 38))	('Six2', 'Gene', (70, 74))	('mouse', 'Species', '10090', (108, 113))	('Inactivation', 'Var', (0, 12))	('Six2', 'Gene', '20472', (70, 74))	('expression', 'MPA', (75, 85))
10687	31690016	Consistent with Notch signaling regulating the NPC self-renewal versus differentiation, forced expression of ectopic NICD1 (activated Notch1) or NICD2 within the Six2-expressing cells causes precocious differentiation of the NPCs.	('ectopic', 'Var', (109, 116))	('Six2', 'Gene', '20472', (162, 166))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('NPC', 'cellular_component', 'GO:0005643', ('47', '50'))	('Six2', 'Gene', (162, 166))	('NICD2', 'Gene', (145, 150))	('causes', 'Reg', (184, 190))	('precocious differentiation', 'CPA', (191, 217))
10690	31690016	Utilizing different Cre drivers to inactivate Notch1 and/or Notch2 within the nephrogenic lineage of the developing kidney reveals morphological defects in the conversion of RV into SSBs.	('SSBs', 'Chemical', 'MESH:C016118', (182, 186))	('Notch2', 'Gene', (60, 66))	('conversion', 'MPA', (160, 170))	('inactivate', 'Var', (35, 45))	('Notch1', 'Gene', (46, 52))	('defects', 'NegReg', (145, 152))
10691	31690016	Early experiments involving inactivation of Notch2 using Cre driven by Pax3 promoter indicated a role for Notch2 signaling in the acquisition of proximal nephron cell fates including that of proximal tubule and podocytes, similar to what was observed with pharmacologic inhibition of Notch signaling in explant mouse developing kidney cultures using Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) to inhibit Notch signaling (Table 1).	('signaling', 'biological_process', 'GO:0023052', ('434', '443'))	('signaling', 'biological_process', 'GO:0023052', ('113', '122'))	('Notch2', 'Gene', (44, 50))	('inhibit', 'NegReg', (420, 427))	('signaling', 'biological_process', 'GO:0023052', ('290', '299'))	('DAPT', 'Chemical', '-', (411, 415))	('Pax3', 'Gene', (71, 75))	('Notch signaling', 'MPA', (428, 443))	('inactivation', 'Var', (28, 40))	('Pax3', 'Gene', '18505', (71, 75))	('mouse', 'Species', '10090', (311, 316))	('Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester', 'Chemical', '-', (350, 409))
10692	31690016	The Pax3-Cre system targets the metanephric mesenchyme even prior to the formation of cap condensates and hence using this system to genetically inactivate Notch2 reveals the most severe renal defects caused by the loss of Notch2.	('formation', 'biological_process', 'GO:0009058', ('73', '82'))	('Notch2', 'Gene', (223, 229))	('loss', 'Var', (215, 219))	('renal defects', 'Disease', (187, 200))	('Pax3', 'Gene', '18505', (4, 8))	('Notch2', 'Gene', (156, 162))	('Pax3', 'Gene', (4, 8))	('renal defects', 'Disease', 'MESH:D007674', (187, 200))
10694	31690016	Polarized expression of Lhx1 in the top (distal) compartment of the RV closer to the UB occurs in Pax3-Cre;Notch2f/f kidneys just like in wild-type kidneys.	('Lhx1', 'Gene', '16869', (24, 28))	('Lhx1', 'Gene', (24, 28))	('Pax3', 'Gene', (98, 102))	('Pax3', 'Gene', '18505', (98, 102))	('Notch2f/f', 'Var', (107, 116))	('UB', 'Chemical', '-', (85, 87))
10697	31690016	The RVs of Six2-Cre;Notch1f/f;Notch2f/f do not have Lhx1 expression restricted to the distal compartment, indicating a failure of the nephron segmentation process.	('Notch1f/f;Notch2f/f', 'Var', (20, 39))	('Lhx1', 'Gene', '16869', (52, 56))	('Six2', 'Gene', (11, 15))	('Notch2f/f', 'Var', (30, 39))	('Lhx1', 'Gene', (52, 56))	('segmentation', 'biological_process', 'GO:0035282', ('142', '154'))	('Six2', 'Gene', '20472', (11, 15))
10698	31690016	The early Pax2-cre mediated inactivation of Notch1 does not alter nephron formation in kidney explant cultures, while inactivation of RBPJ does inhibit proximal tubule and podocyte development.	('formation', 'biological_process', 'GO:0009058', ('74', '83'))	('Pax2', 'Gene', '18504', (10, 14))	('inactivation', 'Var', (28, 40))	('RBPJ', 'Gene', (134, 138))	('inactivation', 'Var', (118, 130))	('RBPJ', 'Gene', '19664', (134, 138))	('inhibit', 'NegReg', (144, 151))	('Pax2', 'Gene', (10, 14))	('Notch1', 'Gene', (44, 50))	('podocyte development', 'biological_process', 'GO:0072015', ('172', '192'))
10699	31690016	A role for Notch1 in nephrogenesis is revealed when it is inactivated in a sensitized Notch signaling background created by inactivation of Notch2 using Six2-Cre line.	('Six2', 'Gene', '20472', (153, 157))	('nephrogenesis', 'Disease', (21, 34))	('nephrogenesis', 'Disease', 'None', (21, 34))	('Notch2', 'Gene', (140, 146))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('inactivation', 'Var', (124, 136))	('nephrogenesis', 'biological_process', 'GO:0001822', ('21', '34'))	('Six2', 'Gene', (153, 157))	('nephrogenesis', 'biological_process', 'GO:0072006', ('21', '34'))
10700	31690016	While most Six2-Cre;Notch2f/f mice develop normal sized kidneys with numerous proximal tubules, the additional inactivation of one allele of Notch1 in Six2-Cre;Notch2f/f;Notch1f/+ mice causes most of these to develop small kidneys with reduced number of nephrons, due to defective nephron segmentation during the conversion of RV into S-shaped bodies (Table 1).	('mice', 'Species', '10090', (30, 34))	('small kidneys', 'Phenotype', 'HP:0000089', (217, 230))	('Six2', 'Gene', (151, 155))	('Notch1', 'Gene', (141, 147))	('reduced number of nephrons', 'Phenotype', 'HP:0005563', (236, 262))	('segmentation', 'biological_process', 'GO:0035282', ('289', '301'))	('small kidneys', 'MPA', (217, 230))	('Six2', 'Gene', (11, 15))	('Six2', 'Gene', '20472', (151, 155))	('Six2', 'Gene', '20472', (11, 15))	('inactivation', 'Var', (111, 123))	('mice', 'Species', '10090', (180, 184))	('numerous proximal tubules', 'Phenotype', 'HP:0000114', (69, 94))	('Notch1f/+', 'Var', (170, 179))	('develop', 'PosReg', (209, 216))	('S-shaped bodies', 'Phenotype', 'HP:0007835', (335, 350))
10702	31690016	The different phenotypes observed in the Six2-Cre;Notch2f/f versus Pax3-Cre;Notch2 f/f mouse kidneys is likely due to the presence of sufficient wild-type Notch2 protein during the RV to S-Shaped body conversion in the Six2-Cre;Notch2f/f but not in the Pax3-Cre;Notch2 f/f kidneys.	('protein', 'cellular_component', 'GO:0003675', ('162', '169'))	('Six2', 'Gene', (219, 223))	('Six2', 'Gene', (41, 45))	('mouse', 'Species', '10090', (87, 92))	('Notch2', 'Var', (155, 161))	('Pax3', 'Gene', '18505', (253, 257))	('Pax3', 'Gene', '18505', (67, 71))	('Pax3', 'Gene', (253, 257))	('Pax3', 'Gene', (67, 71))	('Six2', 'Gene', '20472', (41, 45))	('Six2', 'Gene', '20472', (219, 223))	('S-Shaped body', 'Phenotype', 'HP:0007835', (187, 200))
10704	31690016	Interestingly, delaying Cre expression to the pre-tubular aggregate stage just prior to RV formation, using the Wnt4-Cre to inactivate both Notch1 and Notch2 along with a Rosa+/EYFP Cre reporter also results in defective nephrogenesis.	('nephrogenesis', 'biological_process', 'GO:0072006', ('221', '234'))	('Wnt4', 'Gene', (112, 116))	('defective', 'NegReg', (211, 220))	('nephrogenesis', 'biological_process', 'GO:0001822', ('221', '234'))	('nephrogenesis', 'Disease', (221, 234))	('Notch2', 'Gene', (151, 157))	('nephrogenesis', 'Disease', 'None', (221, 234))	('formation', 'biological_process', 'GO:0009058', ('91', '100'))	('inactivate', 'Var', (124, 134))	('Wnt4', 'Gene', '22417', (112, 116))	('pre', 'molecular_function', 'GO:0003904', ('46', '49'))	('Notch1', 'Gene', (140, 146))
10705	31690016	Mutant kidneys with Notch1 and Notch2 inactivation showed a deficiency in the expression of mature markers (Wt1, LTL, Slc12a1, or Slc12a3) of all nephron segments.	('Wt1', 'Gene', '22431', (108, 111))	('expression', 'MPA', (78, 88))	('inactivation', 'Var', (38, 50))	('Slc12a1', 'Gene', '20495', (118, 125))	('Slc12a1', 'Gene', (118, 125))	('Notch2', 'Gene', (31, 37))	('Slc12a3', 'Gene', '20497', (130, 137))	('Wt1', 'Gene', (108, 111))	('deficiency', 'Disease', 'MESH:D007153', (60, 70))	('deficiency', 'Disease', (60, 70))	('Mutant', 'Var', (0, 6))	('Slc12a3', 'Gene', (130, 137))	('Notch1', 'Gene', (20, 26))
10706	31690016	The delayed inactivation of Notch1 and Notch2 using the Wnt4-Cre allowed for the initial segmentation of the RV along proximodistal axis but reduced the expression of these early stage nephron segment specific markers Lhx1 at later stages resulting in the failure to form normal SSBs and nephrons.	('Notch2', 'Gene', (39, 45))	('Notch1', 'Gene', (28, 34))	('SSBs', 'Chemical', 'MESH:C016118', (279, 283))	('reduced', 'NegReg', (141, 148))	('Wnt4', 'Gene', (56, 60))	('Wnt4', 'Gene', '22417', (56, 60))	('Lhx1', 'Gene', '16869', (218, 222))	('inactivation', 'Var', (12, 24))	('expression', 'MPA', (153, 163))	('segmentation', 'biological_process', 'GO:0035282', ('89', '101'))	('Lhx1', 'Gene', (218, 222))
10709	31690016	The failure to form SSBs in the Wnt4-Cre;Notch1f/f;Notch2f/f kidneys clearly implicates a critical requirement for Notch signaling subsequent to suppressing Six2 expression and allowing NPCs to exit the progenitor state.	('Notch1f/f;Notch2f/f', 'Var', (41, 60))	('signaling', 'biological_process', 'GO:0023052', ('121', '130'))	('Six2', 'Gene', (157, 161))	('allowing', 'Reg', (177, 185))	('Wnt4', 'Gene', '22417', (32, 36))	('Six2', 'Gene', '20472', (157, 161))	('expression', 'MPA', (162, 172))	('Wnt4', 'Gene', (32, 36))	('suppressing', 'NegReg', (145, 156))	('SSBs', 'Chemical', 'MESH:C016118', (20, 24))
10713	31690016	The inactivation of Notch1 alone or Notch2 alone within Six2 expressing cells allows for normal nephron formation but results in proximal tubular cysts (Table 1).	('Notch2', 'Gene', (36, 42))	('inactivation', 'Var', (4, 16))	('Six2', 'Gene', '20472', (56, 60))	('results in', 'Reg', (118, 128))	('nephron formation', 'CPA', (96, 113))	('Six2', 'Gene', (56, 60))	('proximal tubular cysts', 'Disease', (129, 151))	('Notch1', 'Gene', (20, 26))	('formation', 'biological_process', 'GO:0009058', ('104', '113'))
10715	31690016	In this system, Pax8-> rtTA is used to turn on TRE-> dnMaml in a doxycycline dependent manner within the SSB and developing collecting ducts and results in collecting duct cysts in addition to proximal tubular cysts.	('doxycycline', 'Chemical', 'MESH:D004318', (65, 76))	('Pax8', 'Gene', (16, 20))	('TRE->', 'Var', (47, 52))	('Pax8', 'Gene', '18510', (16, 20))	('dnMaml', 'Chemical', '-', (53, 59))	('results in', 'Reg', (145, 155))	('collecting', 'Disease', (156, 166))
10718	31690016	Aged out Six2-Cre; Notch2f/f mice develop microadenomas within the cysts that resemble precursors to papillary renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('Six2', 'Gene', '20472', (9, 13))	('Notch2f/f', 'Var', (19, 28))	('microadenomas', 'Disease', (42, 55))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (101, 131))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (101, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Six2', 'Gene', (9, 13))	('mice', 'Species', '10090', (29, 33))	('papillary renal cell carcinoma', 'Disease', (101, 131))
10725	31690016	The earliest genes activated by ectopic expression of activated Notch1 within the developing mouse collecting ducts include Hes1 and Elf5.	('activated', 'PosReg', (19, 28))	('mouse', 'Species', '10090', (93, 98))	('ectopic expression', 'Var', (32, 50))	('Hes1', 'Gene', (124, 128))	('Elf5', 'Gene', (133, 137))	('Elf5', 'Gene', '13711', (133, 137))	('Notch1', 'Gene', (64, 70))
10731	31690016	Interestingly, inactivation of Tfcp2l1 results in reduced Jag1 expression and failure of duct cells to select the intercalated cell fate.	('expression', 'MPA', (63, 73))	('reduced', 'NegReg', (50, 57))	('Tfcp2l1', 'Gene', (31, 38))	('Tfcp2l1', 'Gene', '81879', (31, 38))	('Jag1', 'Protein', (58, 62))	('inactivation', 'Var', (15, 27))
10737	31690016	At postnatal day (P) 14, mice with overexpressed NICD1 started to demonstrate proteinuria, and histological indications of glomerulosclerosis started appearing at P21.	('proteinuria', 'Disease', 'MESH:D011507', (78, 89))	('glomerulosclerosis', 'Disease', (123, 141))	('mice', 'Species', '10090', (25, 29))	('P21', 'Gene', '237052', (163, 166))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (123, 141))	('P21', 'Gene', (163, 166))	('NICD1', 'Var', (49, 54))	('glomerulosclerosis', 'Disease', 'MESH:D005921', (123, 141))	('proteinuria', 'Disease', (78, 89))	('proteinuria', 'Phenotype', 'HP:0000093', (78, 89))	('rat', 'Species', '10116', (73, 76))
10739	31690016	The deleterious effects of Notch activation were rescued by podocyte specific inactivation of RBPj after the capillary loop stage.	('RBPj', 'Gene', (94, 98))	('inactivation', 'Var', (78, 90))	('RBPj', 'Gene', '19664', (94, 98))
10745	31690016	Activation of Notch in mature podocytes induced apoptosis possibly by the activation of p53, and the effect of Notch activation was blocked by a podocyte-specific genetic deletion of RBPj, a downstream mediator of Notch signaling.	('p53', 'Gene', '22060', (88, 91))	('RBPj', 'Gene', '19664', (183, 187))	('apoptosis', 'biological_process', 'GO:0006915', ('48', '57'))	('p53', 'Gene', (88, 91))	('RBPj', 'Gene', (183, 187))	('activation', 'PosReg', (74, 84))	('signaling', 'biological_process', 'GO:0023052', ('220', '229'))	('apoptosis', 'CPA', (48, 57))	('Notch', 'Var', (14, 19))	('apoptosis', 'biological_process', 'GO:0097194', ('48', '57'))
10750	31690016	Further evidence of the involvement or requirement of Notch signaling came from reduction of TIF in tubular epithelial cell-specific knockout of RBPj, and from induction of ICN1 by a doxycycline inducible model that led to TIF.	('reduction', 'NegReg', (80, 89))	('doxycycline', 'Chemical', 'MESH:D004318', (183, 194))	('knockout', 'Var', (133, 141))	('RBPj', 'Gene', '19664', (145, 149))	('RBPj', 'Gene', (145, 149))	('TIF', 'MPA', (93, 96))	('signaling', 'biological_process', 'GO:0023052', ('60', '69'))
10762	31690016	Tubule-specific knockout of Tfam led to altered mitochondrial structure and increased expression of profibrotic factors.	('Tfam', 'Gene', (28, 32))	('increased', 'PosReg', (76, 85))	('knockout', 'Var', (16, 24))	('mitochondrial structure', 'MPA', (48, 71))	('expression of', 'MPA', (86, 99))	('altered', 'Reg', (40, 47))	('Tfam', 'Gene', '21780', (28, 32))
10764	31690016	Taken together, the findings of these two studies indicate a role of Notch in perturbing metabolic pathways associated with cellular energy production to promote fibrosis.	('Notch', 'Var', (69, 74))	('promote', 'PosReg', (154, 161))	('perturbing', 'Reg', (78, 88))	('fibrosis', 'Disease', 'MESH:D005355', (162, 170))	('fibrosis', 'Disease', (162, 170))	('metabolic pathways', 'Pathway', (89, 107))
10801	31690016	Other studies point to a role for increased Notch signaling activity in the epithelial cells of the distal nephron segments to remodel the cell types in response to inactivation of the sodium chloride cotransporter (NCC).	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('sodium chloride cotransporter', 'MPA', (185, 214))	('inactivation', 'Var', (165, 177))	('sodium chloride', 'Chemical', 'MESH:D012965', (185, 200))	('NCC', 'Gene', '20497', (216, 219))	('activity', 'MPA', (60, 68))	('NCC', 'Gene', (216, 219))
10810	31690016	The Wilms' tumor suppressor gene WT1 is essential for podocyte development, maintenance and function, and mutations in WT1 are associated with FSGS.	('WT1', 'Gene', (33, 36))	('WT1', 'Gene', '22431', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FSGS', 'Disease', (143, 147))	('associated', 'Reg', (127, 137))	('WT1', 'Gene', (119, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	("Wilms' tumor", 'Disease', (4, 16))	("Wilms' tumor", 'Disease', 'MESH:D009396', (4, 16))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (4, 16))	('mutations', 'Var', (106, 115))	('podocyte development', 'biological_process', 'GO:0072015', ('54', '74'))	('WT1', 'Gene', '22431', (33, 36))	('FSGS', 'Disease', 'None', (143, 147))
10811	31690016	WT1 continues to be expressed in the mature podocytes, and deletion of WT1 in mature podocytes by a tamoxifen-inducible system led to podocyte loss, increased Notch signaling and glomerulosclerosis.	('WT1', 'Gene', (71, 74))	('glomerulosclerosis', 'Disease', (179, 197))	('increased', 'PosReg', (149, 158))	('WT1', 'Gene', '22431', (0, 3))	('glomerulosclerosis', 'Disease', 'MESH:D005921', (179, 197))	('WT1', 'Gene', (0, 3))	('signaling', 'biological_process', 'GO:0023052', ('165', '174'))	('podocyte', 'CPA', (134, 142))	('loss', 'NegReg', (143, 147))	('tamoxifen', 'Chemical', 'MESH:D013629', (100, 109))	('deletion', 'Var', (59, 67))	('WT1', 'Gene', '22431', (71, 74))	('Notch signaling', 'MPA', (159, 174))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (179, 197))
10812	31690016	Based on this study, disease onset begins at four days following initiation of WT1 deletion, and by day six extensive glomerulosclerosis occurs.	('glomerulosclerosis', 'Disease', 'MESH:D005921', (118, 136))	('WT1', 'Gene', '22431', (79, 82))	('WT1', 'Gene', (79, 82))	('glomerulosclerosis', 'Phenotype', 'HP:0000096', (118, 136))	('deletion', 'Var', (83, 91))	('glomerulosclerosis', 'Disease', (118, 136))
10814	31690016	Consistent with roles for Notch signaling in kidney development and maintenance, genetic mutations either inherited or acquired de novo in genes coding for Notch signaling pathway components are associated with renal diseases (Table 2 and Table 3), including Alagille syndrome (ALGS), Hajdu-Cheney syndrome (HCS), and congenital anomalies of the kidney and urinary tract (CAKUT).	('renal diseases', 'Disease', (211, 225))	('associated', 'Reg', (195, 205))	('renal disease', 'Phenotype', 'HP:0000112', (211, 224))	('congenital anomalies of the kidney', 'Disease', (318, 352))	('ALGS', 'Disease', 'MESH:D016738', (278, 282))	('renal diseases', 'Disease', 'MESH:D007674', (211, 225))	('Hajdu-Cheney syndrome', 'Disease', 'MESH:D030981', (285, 306))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('ALGS', 'Disease', (278, 282))	('congenital anomalies of the kidney', 'Disease', 'MESH:D007674', (318, 352))	('Hajdu-Cheney syndrome', 'Disease', (285, 306))	('mutations', 'Var', (89, 98))	('Alagille syndrome', 'Disease', (259, 276))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('156', '179'))	('HCS', 'molecular_function', 'GO:0004077', ('308', '311'))	('kidney development', 'biological_process', 'GO:0001822', ('45', '63'))	('anomalies of the kidney', 'Phenotype', 'HP:0000077', (329, 352))	('Alagille syndrome', 'Disease', 'MESH:D016738', (259, 276))
10818	31690016	Analysis of missense mutations in cell-based assays and mouse models indicate that the disease occurs due to loss-of-function.	('missense mutations', 'Var', (12, 30))	('loss-of-function', 'NegReg', (109, 125))	('mouse', 'Species', '10090', (56, 61))
10820	31690016	To date 694 pathogenic variants for JAG1 and 19 patients with pathogenic variants in NOTCH2 have been described.	('variants', 'Var', (73, 81))	('patients', 'Species', '9606', (48, 56))	('variants', 'Var', (23, 31))	('JAG1', 'Gene', (36, 40))	('NOTCH2', 'Gene', (85, 91))
10821	31690016	The majority of the patients (94.3%) have mutations in JAG1 and another 2.5% of patients have mutations in NOTCH2 gene.	('patients', 'Species', '9606', (80, 88))	('NOTCH2', 'Gene', (107, 113))	('mutations', 'Var', (94, 103))	('JAG1', 'Gene', (55, 59))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (42, 51))
10822	31690016	The remaining 3.2% of patients confirmed with ALGS-associated symptoms do not have mutations in JAG1 or NOTCH2 genes.	('mutations', 'Var', (83, 92))	('NOTCH2', 'Gene', (104, 110))	('JAG1', 'Gene', (96, 100))	('patients', 'Species', '9606', (22, 30))	('ALGS', 'Disease', 'MESH:D016738', (46, 50))	('ALGS', 'Disease', (46, 50))
10824	31690016	Renal anomalies are found in around 40% of the ALGS patients with mutations in JAG1.	('mutations', 'Var', (66, 75))	('ALGS', 'Disease', (47, 51))	('Renal anomalies', 'Phenotype', 'HP:0000077', (0, 15))	('JAG1', 'Gene', (79, 83))	('Renal anomalies', 'Disease', 'MESH:D007674', (0, 15))	('found', 'Reg', (20, 25))	('ALGS', 'Disease', 'MESH:D016738', (47, 51))	('Renal anomalies', 'Disease', (0, 15))	('patients', 'Species', '9606', (52, 60))
10828	31690016	HCS is caused by mutations in exon 34 of NOTCH2 gene, that results in the truncation of NOTCH2 protein and the absence of the c-terminal pest domain, which contains sequences necessary for the ubiquitinylation and degradation of NOTCH2 following association of the intracellular domain with RBPJ and Mastermind.	('NOTCH2', 'Gene', (41, 47))	('association', 'Interaction', (246, 257))	('ubiquitinylation', 'MPA', (193, 209))	('truncation', 'MPA', (74, 84))	('RBPJ', 'Gene', '19664', (291, 295))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('NOTCH2', 'Gene', (88, 94))	('HCS', 'molecular_function', 'GO:0004077', ('0', '3'))	('degradation', 'MPA', (214, 225))	('intracellular', 'cellular_component', 'GO:0005622', ('265', '278'))	('degradation', 'biological_process', 'GO:0009056', ('214', '225'))	('RBPJ', 'Gene', (291, 295))	('mutations in', 'Var', (17, 29))	('caused by', 'Reg', (7, 16))	('HCS', 'Disease', (0, 3))	('protein', 'Protein', (95, 102))	('absence', 'NegReg', (111, 118))
10829	31690016	So far there are less than 100 HSC cases reported in the medical literature, and HSC disease frequency is likely to be low due to the fact that only mutations that occur in exon 34 of NOTCH2 are correlated with HSC.	('mutations', 'Var', (149, 158))	('HSC disease', 'Disease', 'MESH:D003141', (81, 92))	('correlated with', 'Reg', (195, 210))	('HSC', 'Disease', (211, 214))	('NOTCH2', 'Gene', (184, 190))	('HSC', 'cellular_component', 'GO:0035301', ('211', '214'))	('HSC disease', 'Disease', (81, 92))	('HSC', 'cellular_component', 'GO:0035301', ('81', '84'))	('rat', 'Species', '10116', (69, 72))	('HSC', 'cellular_component', 'GO:0035301', ('31', '34'))
10836	31690016	Mutations in NOTCH2 exon 34 have also been linked to a disease termed Serpentine fibula polycystic kidney syndrome (SFPKS, MIM600330), and is likely to be part of the spectrum of phenotypic variability seen in HCS.	('HCS', 'molecular_function', 'GO:0004077', ('210', '213'))	('polycystic kidney', 'Phenotype', 'HP:0000113', (88, 105))	('fibula polycystic kidney syndrome', 'Disease', (81, 114))	('fibula polycystic kidney syndrome', 'Disease', 'MESH:C537586', (81, 114))	('Serpentine fibula', 'Phenotype', 'HP:0030045', (70, 87))	('cystic kidney', 'Phenotype', 'HP:0000107', (92, 105))	('kidney syndrome', 'Phenotype', 'HP:0000112', (99, 114))	('Mutations', 'Var', (0, 9))	('linked to', 'Reg', (43, 52))	('NOTCH2', 'Gene', (13, 19))
10839	31690016	Thus far, mutations in 185 genes are linked to CAKUT in mice, 179 genes are linked with syndromic CAKUT in humans and mutations in 40 monogenic genes for isolated CAKUT are known.	('syndromic CAKUT', 'Disease', 'MESH:C566906', (88, 103))	('CAKUT', 'Disease', (47, 52))	('mice', 'Species', '10090', (56, 60))	('linked', 'Reg', (37, 43))	('syndromic CAKUT', 'Disease', (88, 103))	('mutations', 'Var', (10, 19))	('humans', 'Species', '9606', (107, 113))
10844	31690016	Increased renal Notch signaling is detected in the patients with diabetic nephropathy, as evidenced by increased expression of cleaved Notch1.	('expression', 'MPA', (113, 123))	('nephropathy', 'Phenotype', 'HP:0000112', (74, 85))	('increased', 'PosReg', (103, 112))	('diabetic nephropathy', 'Disease', (65, 85))	('renal Notch signaling', 'MPA', (10, 31))	('Notch1', 'Gene', (135, 141))	('signaling', 'biological_process', 'GO:0023052', ('22', '31'))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (65, 85))	('Increased', 'PosReg', (0, 9))	('patients', 'Species', '9606', (51, 59))	('cleaved', 'Var', (127, 134))
10862	31690016	Taken together with the observation that conditional Notch2 inactivation in the mouse kidney results in renal tubular cysts with microadenomas that could be a precursor to papillary renal cell carcinoma, Notch signaling may play a tumor suppressor role in the kidney.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('results in', 'Reg', (93, 103))	('tumor suppressor', 'biological_process', 'GO:0051726', ('231', '247'))	('signaling', 'biological_process', 'GO:0023052', ('210', '219'))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (172, 202))	('renal tubular cysts with microadenomas', 'Disease', (104, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (172, 202))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('231', '247'))	('tumor', 'Disease', (231, 236))	('mouse', 'Species', '10090', (80, 85))	('renal tubular cysts with microadenomas', 'Disease', 'MESH:D005198', (104, 142))	('papillary renal cell carcinoma', 'Disease', (172, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('Notch2', 'Gene', (53, 59))	('inactivation', 'Var', (60, 72))
10864	31690016	Animal models of Notch dependent kidney cancers will be necessary to prove the ability of altered levels of Notch signaling to cause renal carcinoma.	('renal carcinoma', 'Disease', 'MESH:C538614', (133, 148))	('Notch dependent kidney cancers', 'Disease', 'MESH:D007680', (17, 47))	('signaling', 'biological_process', 'GO:0023052', ('114', '123'))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('altered', 'Var', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cause', 'Reg', (127, 132))	('renal carcinoma', 'Disease', (133, 148))	('renal carcinoma', 'Phenotype', 'HP:0005584', (133, 148))	('kidney cancers', 'Phenotype', 'HP:0009726', (33, 47))	('Notch dependent kidney cancers', 'Disease', (17, 47))	('dependent kidney', 'Phenotype', 'HP:0000083', (23, 39))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
10867	31690016	ALGS patients with the same NOTCH2 mutation may have no renal defects, or congenital cystic kidney disease or late adult onset kidney disease.	('congenital cystic kidney disease', 'Disease', 'MESH:D052177', (74, 106))	('NOTCH2', 'Gene', (28, 34))	('congenital cystic kidney disease', 'Disease', (74, 106))	('patients', 'Species', '9606', (5, 13))	('ALGS', 'Disease', 'MESH:D016738', (0, 4))	('ALGS', 'Disease', (0, 4))	('kidney disease', 'Phenotype', 'HP:0000112', (127, 141))	('renal defects', 'Disease', (56, 69))	('cystic kidney', 'Phenotype', 'HP:0000107', (85, 98))	('late adult onset kidney disease', 'Disease', 'MESH:D016891', (110, 141))	('mutation', 'Var', (35, 43))	('late adult onset kidney disease', 'Disease', (110, 141))	('renal defects', 'Disease', 'MESH:D007674', (56, 69))	('kidney disease', 'Phenotype', 'HP:0000112', (92, 106))
10870	31690016	For example, normally a null mutation in one allele of Notch1 does not cause kidney disease in mice, however when we combine this sensitized level of Notch signaling with the conditional inactivation of Notch2 in the developing kidney nephron progenitors this results in development of multicystic hypoplastic kidneys.	('mutation', 'Var', (29, 37))	('kidney disease', 'Phenotype', 'HP:0000112', (77, 91))	('mice', 'Species', '10090', (95, 99))	('multicystic hypoplastic kidneys', 'Disease', (286, 317))	('multicystic hypoplastic kidneys', 'Phenotype', 'HP:0000003', (286, 317))	('results in', 'Reg', (260, 270))	('Notch2', 'Gene', (203, 209))	('Notch1', 'Gene', (55, 61))	('kidney disease', 'Disease', (77, 91))	('hypoplastic kidneys', 'Phenotype', 'HP:0000089', (298, 317))	('signaling', 'biological_process', 'GO:0023052', ('156', '165'))	('multicystic hypoplastic kidneys', 'Disease', 'MESH:D021782', (286, 317))	('kidney disease', 'Disease', 'MESH:D007674', (77, 91))
10871	31690016	These mouse studies suggest that additional variations in the Notch signaling pathway genes could be present in some ALGS patients with severe kidney disease in addition to a mutation in JAG1 or NOTCH2.	('variations', 'Var', (44, 54))	('Notch signaling pathway', 'biological_process', 'GO:0007219', ('62', '85'))	('Notch signaling pathway genes', 'Gene', (62, 91))	('kidney disease', 'Disease', 'MESH:D007674', (143, 157))	('mutation', 'Var', (175, 183))	('ALGS', 'Disease', 'MESH:D016738', (117, 121))	('kidney disease', 'Phenotype', 'HP:0000112', (143, 157))	('ALGS', 'Disease', (117, 121))	('patients', 'Species', '9606', (122, 130))	('JAG1', 'Gene', (187, 191))	('NOTCH2', 'Gene', (195, 201))	('kidney disease', 'Disease', (143, 157))	('mouse', 'Species', '10090', (6, 11))
10906	25768256	A rabbit monoclonal antibody (Ab) SP183 against CDH17 from Cell Marque (Rocklin, CA) was used at a 1:100 dilution as the primary Ab.	('antibody', 'cellular_component', 'GO:0019815', ('20', '28'))	('CDH17', 'Gene', (48, 53))	('antibody', 'cellular_component', 'GO:0019814', ('20', '28'))	('rabbit', 'Species', '9986', (2, 8))	('antibody', 'molecular_function', 'GO:0003823', ('20', '28'))	('SP183', 'Var', (34, 39))	('antibody', 'cellular_component', 'GO:0042571', ('20', '28'))
10931	25768256	Similar to our findings, CD57 positivity was reported in 12.5% of WT, in mature appearing tubules of WT, and in 70% of s-PRCC.	('positivity', 'Var', (30, 40))	('CD57', 'Gene', (25, 29))	('PRCC', 'Gene', '5546', (121, 125))	('CD57', 'Gene', '27087', (25, 29))	('PRCC', 'Gene', (121, 125))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))
10945	25768256	In zebrafish, cdh17 is expressed specifically in the posterior portion of pronephric ducts during embryonic development and knockdown of cdh17 disrupts the normal formation of the posterior portion of the pronephric ducts.	('knockdown', 'Var', (124, 133))	('formation', 'biological_process', 'GO:0009058', ('163', '172'))	('zebrafish', 'Species', '7955', (3, 12))	('disrupts', 'NegReg', (143, 151))	('cdh17', 'Gene', (137, 142))
10967	30900418	Through mouse xenograft analysis, we confirmed that PRCC silencing significantly repressed a xenograft tumor mass in vivo (p<0.001).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('mouse', 'Species', '10090', (8, 13))	('silencing', 'Var', (57, 66))	('PRCC', 'Gene', (52, 56))	('repressed', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PRCC', 'Phenotype', 'HP:0006766', (52, 56))
10970	30900418	Recent identification of druggable mutations and development of inhibitors targeting the alterations has improved the treatment outcomes of lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('men', 'Species', '9606', (56, 59))	('lung cancers', 'Disease', 'MESH:D008175', (140, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancers', 'Phenotype', 'HP:0100526', (140, 152))	('improved', 'PosReg', (105, 113))	('men', 'Species', '9606', (123, 126))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('lung cancers', 'Disease', (140, 152))	('mutations', 'Var', (35, 44))
11039	30900418	We next explored the effect of PRCC silencing on the capability of migration and invasiveness of the lung cancer cells.	('invasiveness of the lung cancer', 'Disease', 'MESH:D008175', (81, 112))	('invasiveness of the lung cancer', 'Disease', (81, 112))	('PRCC', 'Gene', (31, 35))	('migration', 'CPA', (67, 76))	('silencing', 'Var', (36, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('PRCC', 'Phenotype', 'HP:0006766', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
11040	30900418	The number of migrating cells after PRCC knockdown was significantly lower than that in the siNEG-treated cells (NCI-H358: median 480.5, IQR 488.3-473.5 in siPRCC vs. median 1597.5, IQR 1618.8-1573.3 in siNEG, p=3.020x10-15; A549: median 298.5, IQR 308.0-292.8 in siPRCC vs. median 1171.5, IQR 1186.3-1162.8 in siNEG, p=4.152x10-16) (Fig.	('NCI-H358', 'CellLine', 'CVCL:1559', (113, 121))	('siPRCC', 'Chemical', '-', (264, 270))	('PRCC', 'Phenotype', 'HP:0006766', (266, 270))	('PRCC', 'Phenotype', 'HP:0006766', (36, 40))	('migrating cells', 'CPA', (14, 29))	('siPRCC', 'Chemical', '-', (156, 162))	('siNEG', 'Chemical', '-', (92, 97))	('lower', 'NegReg', (69, 74))	('siNEG', 'Chemical', '-', (311, 316))	('PRCC', 'Phenotype', 'HP:0006766', (158, 162))	('A549', 'CellLine', 'CVCL:0023', (225, 229))	('knockdown', 'Var', (41, 50))	('siNEG', 'Chemical', '-', (203, 208))
11041	30900418	The number of invading cells was also significantly lower in PRCC knockdown than in the siNEG (NCI-H358: median 295.0, IQR 305.0-291.0 in siPRCC vs. median 641.0, IQR 645.5-626.0 in siNEG, p=4.532x10-13; A549: median 174.0, IQR 182.5-164.8 in siPRCC vs. median 457.0, IQR 464.8-445.5 in siNEG, p=1.633x10-11) (Fig.	('siPRCC', 'Chemical', '-', (138, 144))	('PRCC', 'Gene', (61, 65))	('PRCC', 'Phenotype', 'HP:0006766', (245, 249))	('siNEG', 'Chemical', '-', (287, 292))	('PRCC', 'Phenotype', 'HP:0006766', (61, 65))	('lower', 'NegReg', (52, 57))	('siNEG', 'Chemical', '-', (88, 93))	('siPRCC', 'Chemical', '-', (243, 249))	('A549', 'CellLine', 'CVCL:0023', (204, 208))	('PRCC', 'Phenotype', 'HP:0006766', (140, 144))	('siNEG', 'Chemical', '-', (182, 187))	('knockdown', 'Var', (66, 75))	('NCI-H358', 'CellLine', 'CVCL:1559', (95, 103))
11047	30900418	Decreased expression of vimentin was observed in NCI-H358.	('vimentin', 'cellular_component', 'GO:0045098', ('24', '32'))	('vimentin', 'Gene', (24, 32))	('Decreased', 'NegReg', (0, 9))	('NCI-H358', 'CellLine', 'CVCL:1559', (49, 57))	('expression', 'MPA', (10, 20))	('vimentin', 'cellular_component', 'GO:0045099', ('24', '32'))	('NCI-H358', 'Var', (49, 57))	('vimentin', 'Gene', '7431', (24, 32))
11053	30900418	At 4 weeks after the injection, the fluorescence signals from the siPRCC-injected tumors became significantly lower than those from siNEG-injected tumors (p=3.837x10-5 at 6 weeks, n=6).	('fluorescence signals', 'MPA', (36, 56))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (82, 88))	('siPRCC-injected', 'Var', (66, 81))	('tumors', 'Disease', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('siNEG', 'Chemical', '-', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('PRCC', 'Phenotype', 'HP:0006766', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('lower', 'NegReg', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('siPRCC', 'Chemical', '-', (66, 72))
11055	30900418	Copy number alteration is a common genetic event in solid tumors including lung cancer, and they are known to contribute to tumorigenesis by affecting the activities of cancer-related genes in the altered chromosomal regions.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Disease', (169, 175))	('activities', 'MPA', (155, 165))	('tumor', 'Disease', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('affecting', 'Reg', (141, 150))	('cancer', 'Disease', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Disease', (58, 63))	('Copy number alteration', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('solid tumors', 'Disease', (52, 64))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('lung cancer', 'Disease', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('solid tumors', 'Disease', 'MESH:D009369', (52, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('contribute', 'Reg', (110, 120))
11056	30900418	Amplification of chromosome 1q has been reported to be recurrently occurred in NSCLCs.	('Amplification', 'Var', (0, 13))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('occurred', 'Reg', (67, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('NSCLC', 'Disease', (79, 84))
11064	30900418	Second, we aimed to elucidate the role of PRCC overexpression in lung tumorigenesis by knocking down overexpressed PRCC in two lung cancer cell lines that showed PRCC overexpression.	('PRCC', 'Phenotype', 'HP:0006766', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('lung cancer', 'Disease', (127, 138))	('PRCC', 'Phenotype', 'HP:0006766', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('knocking', 'Var', (87, 95))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('PRCC', 'Gene', (115, 119))	('PRCC', 'Phenotype', 'HP:0006766', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
11073	30900418	After silencing the PRCC in two PRCC overexpressed lung cancer cell lines, cell growth rate, colony formation, anchorage independent growth, and invasiveness were repressed in both cells.	('colony formation', 'CPA', (93, 109))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('PRCC', 'Phenotype', 'HP:0006766', (32, 36))	('invasiveness', 'CPA', (145, 157))	('PRCC', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('PRCC', 'Phenotype', 'HP:0006766', (20, 24))	('formation', 'biological_process', 'GO:0009058', ('100', '109'))	('cell growth rate', 'CPA', (75, 91))	('cell growth', 'biological_process', 'GO:0016049', ('75', '86'))	('anchorage independent growth', 'CPA', (111, 139))	('silencing', 'Var', (6, 15))
11076	30900418	As expected, key molecules known to be involved in cell proliferation and cell cycle, such as Ki67, cyclin D1, AKT-1, pAKT, and NF-kB p65, were decreased in siPRCC-transfected cells, compared with siNEG-transfected cells, suggesting that overexpression of PRCC is involved in uncontrolled cell proliferation, which may contribute to lung tumorigenesis.	('tumor', 'Disease', (338, 343))	('AKT', 'Gene', (111, 114))	('cell proliferation', 'CPA', (51, 69))	('p65', 'Gene', '5970', (134, 137))	('cell cycle', 'CPA', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('decreased', 'NegReg', (144, 153))	('AKT-1', 'Gene', (111, 116))	('AKT', 'Gene', '207', (119, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('289', '307'))	('cyclin', 'molecular_function', 'GO:0016538', ('100', '106'))	('cell cycle', 'biological_process', 'GO:0007049', ('74', '84'))	('AKT', 'Gene', '207', (111, 114))	('Ki67', 'Gene', (94, 98))	('siPRCC-transfected', 'Var', (157, 175))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('siNEG', 'Chemical', '-', (197, 202))	('contribute', 'Reg', (319, 329))	('siPRCC', 'Chemical', '-', (157, 163))	('AKT-1', 'Gene', '207', (111, 116))	('cyclin D1', 'Gene', (100, 109))	('cell proliferation', 'biological_process', 'GO:0008283', ('51', '69'))	('PRCC', 'Phenotype', 'HP:0006766', (256, 260))	('p65', 'Gene', (134, 137))	('AKT', 'Gene', (119, 122))	('cyclin D1', 'Gene', '595', (100, 109))	('PRCC', 'Phenotype', 'HP:0006766', (159, 163))
11087	30900418	First, although we observed recurrent PRCC overexpression in the primary NSCLCs and growth/migration inhibition after silencing overexpression in vitro, we could not observe significant clinical associations other than squamous cell carcinoma dominance in our primary NSCLCs.	('squamous cell carcinoma', 'Disease', (219, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (268, 273))	('growth/migration inhibition', 'CPA', (84, 111))	('NSCLC', 'Disease', (268, 273))	('overexpression', 'PosReg', (43, 57))	('PRCC', 'Gene', (38, 42))	('silencing', 'Var', (118, 127))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (268, 273))	('PRCC', 'Phenotype', 'HP:0006766', (38, 42))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 242))
11098	32468053	The analysis of the enriched pathway results suggested that SALL4 may act via translation initiation, and that the related genes promoted the progression of RCC.	('SALL4', 'Gene', '57167', (60, 65))	('promoted', 'PosReg', (129, 137))	('SALL4', 'Gene', (60, 65))	('translation initiation', 'biological_process', 'GO:0006413', ('78', '100'))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('genes', 'Var', (123, 128))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('progression', 'CPA', (142, 153))
11102	32468053	Furthermore, targeting of SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC or pRCC.	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('pRCC', 'Phenotype', 'HP:0006766', (107, 111))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('survival', 'CPA', (72, 80))	('prolong', 'NegReg', (60, 67))	('pRCC', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('improve', 'PosReg', (36, 43))	('SALL4', 'Gene', '57167', (26, 31))	('pRCC', 'Gene', '5546', (107, 111))	('SALL4', 'Gene', (26, 31))	('targeting', 'Var', (13, 22))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
11168	32468053	Therefore, the present results suggested that patients with pRCC and low SALL4 mRNA expression have a longer survival time compared with patients with high SALL4 expression.	('SALL4', 'Gene', '57167', (156, 161))	('survival time', 'CPA', (109, 122))	('patients', 'Species', '9606', (46, 54))	('SALL4', 'Gene', (73, 78))	('pRCC', 'Gene', (60, 64))	('longer', 'PosReg', (102, 108))	('SALL4', 'Gene', (156, 161))	('patients', 'Species', '9606', (137, 145))	('pRCC', 'Phenotype', 'HP:0006766', (60, 64))	('pRCC', 'Gene', '5546', (60, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('low', 'Var', (69, 72))	('SALL4', 'Gene', '57167', (73, 78))
11210	32468053	An invasion assay was performed in OSRC-2 cells, and the results indicated that knockdown of SALL4 decreased cell invasion compared with pLKO (3.32+-0.08 vs. 1.05+-0.11; P<0.01; Fig.	('knockdown', 'Var', (80, 89))	('decreased', 'NegReg', (99, 108))	('OSRC-2', 'CellLine', 'CVCL:1901', (35, 41))	('SALL4', 'Gene', '57167', (93, 98))	('SALL4', 'Gene', (93, 98))	('cell invasion', 'CPA', (109, 122))
11212	32468053	It was demonstrated that SALL4 knockdown decreased cell viability compared with the pLKO group (P=0.003 in OSRC-2 and P=0.001 in SW839 at day 3; Fig.	('decreased', 'NegReg', (41, 50))	('cell viability', 'CPA', (51, 65))	('SALL4', 'Gene', '57167', (25, 30))	('SW839', 'CellLine', 'CVCL:3604', (129, 134))	('OSRC-2', 'CellLine', 'CVCL:1901', (107, 113))	('SALL4', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
11228	32468053	Other studies have also confirmed a critical role of SALL4 in cell survival and tumorigenicity by knocking down SALL4.	('SALL4', 'Gene', '57167', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SALL4', 'Gene', (53, 58))	('SALL4', 'Gene', '57167', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SALL4', 'Gene', (112, 117))	('tumor', 'Disease', (80, 85))	('knocking', 'Var', (98, 106))
11241	32468053	Additionally, the copy number of SALL4 was positively associated with the survival curve.	('SALL4', 'Gene', '57167', (33, 38))	('SALL4', 'Gene', (33, 38))	('survival curve', 'CPA', (74, 88))	('copy number', 'Var', (18, 29))	('associated', 'Reg', (54, 64))
11254	32468053	Thus, targeting SALL4 may improve RCC therapy and prolong the survival of patients with ccRCC and pRCC.	('SALL4', 'Gene', (16, 21))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', (99, 102))	('pRCC', 'Phenotype', 'HP:0006766', (98, 102))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('pRCC', 'Gene', (98, 102))	('survival', 'CPA', (62, 70))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('prolong', 'NegReg', (50, 57))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('patients', 'Species', '9606', (74, 82))	('targeting', 'Var', (6, 15))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('improve', 'PosReg', (26, 33))	('SALL4', 'Gene', '57167', (16, 21))	('pRCC', 'Gene', '5546', (98, 102))
11262	32219034	The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression.	('expression', 'MPA', (182, 192))	('NFI family', 'Gene', (34, 44))	('hypermethylation', 'Var', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mRNA expression levels', 'MPA', (4, 26))	('downregulate', 'NegReg', (154, 166))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('127', '147'))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('NFI', 'Protein', (171, 174))	('DNA', 'cellular_component', 'GO:0005574', ('127', '130'))	('downregulated', 'NegReg', (64, 77))
11265	32219034	Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers.	('head and neck cancer', 'Phenotype', 'HP:0012288', (189, 209))	('head and neck cancers', 'Phenotype', 'HP:0012288', (189, 210))	('head and neck cancers', 'Disease', 'MESH:D006258', (189, 210))	('neck', 'cellular_component', 'GO:0044326', ('198', '202'))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('dysregulations', 'Var', (83, 97))	('breast', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('lung', 'Disease', (179, 183))	('NFI genes', 'Gene', (105, 114))	('correlated with', 'Reg', (134, 149))
11313	32219034	Breast invasive carcinoma patients with a NFIX gene alteration showed significantly poor overall survival (OS) and disease-free survival (DFS) compared with breast invasive carcinoma patients without NFIX gene alteration.	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (157, 182))	('OS', 'Chemical', '-', (107, 109))	('poor', 'NegReg', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast invasive carcinoma', 'Disease', (0, 25))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (0, 25))	('alteration', 'Var', (52, 62))	('disease-free survival', 'CPA', (115, 136))	('NFIX', 'Gene', (42, 46))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (0, 25))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (157, 182))	('overall survival', 'CPA', (89, 105))	('breast invasive carcinoma', 'Disease', (157, 182))
11318	32219034	Decreased NFIA expression showed better RFS, OS and DMFS in the HER2-enriched subtype.	('OS', 'Chemical', '-', (45, 47))	('NFIA', 'Protein', (10, 14))	('Decreased', 'NegReg', (0, 9))	('DMFS', 'Var', (52, 56))	('RFS', 'MPA', (40, 43))	('expression', 'MPA', (15, 25))	('better', 'PosReg', (33, 39))
11332	32219034	The NFI genes in lung cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low, and multiple alterations (Figs.	('amplification', 'Var', (93, 106))	('deep deletion', 'Var', (108, 121))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('NFI', 'Gene', (4, 7))
11333	32219034	Lung adenocarcinoma patients with NFIB gene alteration showed better DFS compared with lung adenocarcinoma patients without NFIB gene alteration (Fig.	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('better', 'PosReg', (62, 68))	('DFS', 'MPA', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('NFIB', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('gene alteration', 'Var', (39, 54))
11334	32219034	Lung squamous cell carcinoma patients with NFIA gene alteration showed worse OS compared with lung squamous cell carcinoma patients without NFIA gene alterations (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('gene alteration', 'Var', (48, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('OS', 'Chemical', '-', (77, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))
11351	32219034	Bladder urothelial carcinoma patients with NFIB gene alteration showed significantly better OS compared with bladder urothelial patients without NFIB gene alteration.	('better', 'PosReg', (85, 91))	('urothelial carcinoma', 'Disease', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('gene alteration', 'Var', (48, 63))	('NFIB', 'Gene', (43, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('OS', 'Chemical', '-', (92, 94))	('bladder urothelial', 'Disease', 'MESH:D001745', (109, 127))	('bladder urothelial', 'Disease', (109, 127))
11366	32219034	Head and neck cancer patients with NFIA gene alteration showed better OS compared with head and neck cancer patients without NFIA gene alteration.	('OS', 'Chemical', '-', (70, 72))	('neck', 'cellular_component', 'GO:0044326', ('9', '13'))	('neck cancer', 'Disease', 'MESH:D006258', (96, 107))	('NFIA', 'Gene', (35, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('neck cancer', 'Disease', 'MESH:D006258', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('neck cancer', 'Disease', (9, 20))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('better', 'PosReg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('neck', 'cellular_component', 'GO:0044326', ('96', '100'))	('gene alteration', 'Var', (40, 55))	('neck cancer', 'Disease', (96, 107))
11395	32219034	The NFI genes in kidney cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low and multiple alterations (Figs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('deep deletion', 'Var', (110, 123))	('kidney cancer', 'Disease', (17, 30))	('amplification', 'Var', (95, 108))	('NFI', 'Gene', (4, 7))
11397	32219034	Kidney renal papillary cell carcinoma patients with NFIX gene alteration showed worse OS compared with kidney renal papillary cell carcinoma patients without NFIX gene alteration (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('kidney renal papillary cell carcinoma', 'Disease', (103, 140))	('OS', 'Chemical', '-', (86, 88))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (103, 140))	('Kidney renal papillary cell carcinoma', 'Disease', (0, 37))	('gene alteration', 'Var', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (0, 37))	('NFIX', 'Gene', (52, 56))
11434	32219034	In the KM plotter database, high NFIA and NFIX expression predicted better OS and disease-specific survival (DSS) in liver cancer patients.	('DSS', 'Chemical', '-', (109, 112))	('NFIX', 'Protein', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disease-specific survival', 'CPA', (82, 107))	('better', 'PosReg', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('OS', 'Chemical', '-', (75, 77))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('liver cancer', 'Disease', (117, 129))	('NFIA', 'Protein', (33, 37))	('high', 'Var', (28, 32))
11452	32219034	Survival analysis indicated that almost none of the NFI genes with gene alterations were associated with OS or DFS.	('associated', 'Reg', (89, 99))	('gene alterations', 'Var', (67, 83))	('NFI genes', 'Gene', (52, 61))	('OS', 'Chemical', '-', (105, 107))	('DFS', 'Disease', (111, 114))
11453	32219034	These findings indicate that NFI gene alterations might not independently influence its transcription in various tumors.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('transcription', 'biological_process', 'GO:0006351', ('88', '101'))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('alterations', 'Var', (38, 49))	('NFI gene', 'Gene', (29, 37))	('transcription', 'MPA', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
11457	32219034	Glioblastoma multiforme (GBM) patients with higher NFIB expression survived significantly longer than patients with lower NFIB expression.	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('NFIB', 'Protein', (51, 55))	('Glioblastoma multiforme', 'Disease', (0, 23))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('expression', 'Var', (56, 66))
11458	32219034	In another study, NFIX DNA hypermethylation was reportedly associated with significantly decreased NFIX expression and was related to shorter OS and RFS in patients with lung adenocarcinoma.	('hypermethylation', 'Var', (27, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('RFS', 'MPA', (149, 152))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('23', '43'))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('OS', 'Chemical', '-', (142, 144))	('DNA', 'cellular_component', 'GO:0005574', ('23', '26'))	('lung adenocarcinoma', 'Disease', (170, 189))	('shorter OS', 'Disease', (134, 144))	('expression', 'MPA', (104, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('NFIX', 'Protein', (99, 103))	('NFIX', 'Gene', (18, 22))	('decreased', 'NegReg', (89, 98))
11460	32219034	In a previous study, high NFIA expression was shown an independent predictor of poor prognosis in esophageal squamous carcinoma, and high NFIB expression was a negative prognostic value in esophagogastric junction adenocarcinoma.	('high', 'Var', (133, 137))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('high', 'Var', (21, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('esophagogastric junction adenocarcinoma', 'Disease', (189, 228))	('esophagogastric junction adenocarcinoma', 'Disease', 'MESH:C537006', (189, 228))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (98, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (98, 127))	('esophageal squamous carcinoma', 'Disease', (98, 127))
11462	32219034	In the present study, high expression of NFIA, NFIB and NFIX was significantly associated with improved prognosis in breast cancer.	('high expression', 'Var', (22, 37))	('NFIX', 'Gene', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('NFIB', 'Gene', (47, 51))	('improved', 'PosReg', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('NFIA', 'Gene', (41, 45))
11468	32219034	In gastric cancer, high NFIX expression was significantly correlated with better overall prognosis in gastric cancer and HER2+ gastric cancer, and marginally correlated with PPS in HER2-gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2-gastric cancer', 'Disease', 'MESH:D013274', (181, 200))	('gastric cancer', 'Disease', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastric cancer', 'Disease', (127, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('better', 'PosReg', (74, 80))	('HER2-gastric cancer', 'Disease', (181, 200))	('PPS', 'Chemical', '-', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NFIX expression', 'MPA', (24, 39))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('high', 'Var', (19, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
11474	32219034	The breast cancer cell line, MCF7, treated with NFIC siRNA, enhanced EMT, motility, migration and invasion.	('EMT', 'biological_process', 'GO:0001837', ('69', '72'))	('EMT', 'CPA', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('NFIC', 'Var', (48, 52))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MCF7', 'CellLine', 'CVCL:0031;0.06756287128990074', (29, 33))	('invasion', 'CPA', (98, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('motility', 'CPA', (74, 82))	('enhanced', 'PosReg', (60, 68))
11477	32219034	Genomic analysis showed the alterations in each NFI family gene were less frequent in various tumors and had little influence on survival outcomes.	('NFI family gene', 'Gene', (48, 63))	('alterations', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('less', 'NegReg', (69, 73))
11479	32219034	A certain negative correlation was observed, indicating that epigenetic alteration is an important mechanism of dysregulated NFI expression in human cancers.	('cancers', 'Disease', (149, 156))	('NFI', 'Gene', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('epigenetic alteration', 'Var', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
11490	28352227	The expression of Abeta42 led to its accumulation in the brain and a moderate impairment of negative geotaxis at 18 days post-eclosion (d.p.e) as compared with genetic or parental controls.	('negative geotaxis', 'CPA', (92, 109))	('Abeta42', 'Gene', (18, 25))	('geotaxis', 'biological_process', 'GO:0042332', ('101', '109'))	('expression', 'Var', (4, 14))	('accumulation', 'PosReg', (37, 49))	('eclosion', 'biological_process', 'GO:0007562', ('126', '134'))	('impairment', 'NegReg', (78, 88))	('rat', 'Species', '10116', (73, 76))
11492	28352227	Six lines, including the deletion of 52 Drosophila genes with human orthologs, significantly modified Abeta42 neurotoxicity in 18-day-old flies.	('Abeta42 neurotoxicity', 'Disease', (102, 123))	('Drosophila', 'Species', '7227', (40, 50))	('modified', 'Reg', (93, 101))	('Abeta42 neurotoxicity', 'Disease', 'MESH:D020258', (102, 123))	('human', 'Species', '9606', (62, 67))	('deletion', 'Var', (25, 33))
11493	28352227	So far, we have validated CG11796 and identified CG17249 as a strong candidate (whose human orthologs are HPD and PRCC, respectively) by using RNAi or mutant hemizygous lines.	('CG17249', 'Gene', (49, 56))	('mutant', 'Var', (151, 157))	('HPD', 'Disease', 'MESH:D004421', (106, 109))	('RNAi', 'biological_process', 'GO:0016246', ('143', '147'))	('human', 'Species', '9606', (86, 91))	('CG17249', 'Gene', '38201', (49, 56))	('PRCC', 'Gene', '5546', (114, 118))	('HPD', 'Disease', (106, 109))	('PRCC', 'Gene', (114, 118))	('CG11796', 'Gene', (26, 33))	('CG11796', 'Gene', '40263', (26, 33))
11496	28352227	Interestingly, lines with a partial Df of HPD ortholog showed increased intraneuronal accumulation of Abeta42 that coincided with geotaxis impairment.	('increased', 'PosReg', (62, 71))	('coincided', 'Reg', (115, 124))	('Abeta42', 'Protein', (102, 109))	('HPD', 'Disease', 'MESH:D004421', (42, 45))	('geotaxis', 'biological_process', 'GO:0042332', ('130', '138'))	('geotaxis impairment', 'Disease', 'MESH:D009422', (130, 149))	('geotaxis impairment', 'Disease', (130, 149))	('partial Df', 'Var', (28, 38))	('intraneuronal accumulation', 'MPA', (72, 98))	('HPD', 'Disease', (42, 45))
11499	28352227	More than 95% of AD cases are sporadic, with age and the epsilon 4 allele of the apolipoprotein E gene as the major risk factors.	('apolipoprotein', 'molecular_function', 'GO:0005320', ('81', '95'))	('apolipoprotein', 'molecular_function', 'GO:0005319', ('81', '95'))	('epsilon 4 allele', 'Var', (57, 73))	('AD', 'Phenotype', 'HP:0002511', (17, 19))	('AD', 'Disease', 'MESH:D000544', (17, 19))	('apolipoprotein E', 'Gene', '11816', (81, 97))	('AD', 'Disease', (17, 19))	('apolipoprotein E', 'Gene', (81, 97))
11500	28352227	Rare familial forms are associated with mutations in the amyloid precursor protein and presenilin 1-2 genes (Campion et al.,; Newman et al.,; Kandimalla et al.,; De Strooper and Karran,).	('associated', 'Reg', (24, 34))	('presenilin 1', 'Gene', (87, 99))	('presenilin 1', 'Gene', '40260', (87, 99))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('mutations', 'Var', (40, 49))	('familial forms', 'Disease', (5, 19))
11502	28352227	Oligomeric species of Abeta42 have been proposed as early pathogenic molecules by inducing mitochondrial and endoplasmic reticulum stress, an increase in reactive oxygen species formation and action potential abnormalities (Karran et al.,; De Strooper and Karran,).	('reactive oxygen species formation', 'MPA', (154, 187))	('action potential abnormalities', 'MPA', (192, 222))	('increase', 'PosReg', (142, 150))	('Oligomeric species', 'Var', (0, 18))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (154, 177))	('Abeta42', 'Gene', (22, 29))	('inducing', 'PosReg', (82, 90))	('action potential', 'biological_process', 'GO:0001508', ('192', '208'))	('endoplasmic reticulum', 'cellular_component', 'GO:0005783', ('109', '130'))	('reactive oxygen species formation', 'biological_process', 'GO:1903409', ('154', '187'))
11512	28352227	By screening a collection of chromosomal deletions, the same group found that the toll-NFkappaB pathway enhanced both Abeta-induced rough eye and a negative effect upon life span (Tan et al.,).	('life span', 'CPA', (169, 178))	('Abeta-induced rough eye', 'Disease', (118, 141))	('enhanced', 'PosReg', (104, 112))	('deletions', 'Var', (41, 50))	('Abeta-induced rough eye', 'Disease', 'MESH:D005124', (118, 141))	('toll-NFkappaB pathway', 'Pathway', (82, 103))
11517	28352227	developed an automatic device for the Rapid Iterative Negative Geotaxis (RING) assay and screened a collection of chromosomal deletions to find modifiers of AbetaE22G neurotoxicity upon the giant fiber system neurons (Gargano et al.,; Liu et al.,).	('AbetaE22G neurotoxicity', 'Disease', 'MESH:D020258', (157, 180))	('Geotaxis', 'biological_process', 'GO:0042332', ('63', '71'))	('deletions', 'Var', (126, 135))	('rat', 'Species', '10116', (47, 50))	('AbetaE22G neurotoxicity', 'Disease', (157, 180))
11539	28352227	Brain samples from a transgenic mouse carrying the "Swedish" mutation of amyloid precursor protein (Tg2576) were used as positive controls.	('Tg2576', 'Gene', (100, 106))	('mutation', 'Var', (61, 69))	('mouse', 'Species', '10090', (32, 37))	('transgenic', 'Species', '10090', (21, 31))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
11545	28352227	Genetic controls included G4>+ and +>Abeta42.	('+>Abeta42', 'Var', (35, 44))	('G4', 'Chemical', '-', (26, 28))	('G4>+', 'Var', (26, 30))
11560	28352227	In 18-day-old flies, a significant decrease in climbing ability (~50%) was apparent only in Abeta42-expressing animals as compared to genetic controls, G4>+ and +>Abeta42 (Figure 2C).	('climbing ability', 'CPA', (47, 63))	('decrease', 'NegReg', (35, 43))	('G4', 'Chemical', '-', (152, 154))	('G4>+', 'Var', (152, 156))	('Abeta42-expressing', 'Gene', (92, 110))
11567	28352227	Df lines 24392, 27369, 27372, 27404 and 27917 worsened negative geotaxis while line 7681 reduced Abeta42 toxicity to a full rescue of the phenotype (Figure 4).	('27917', 'Var', (40, 45))	('worsened', 'NegReg', (46, 54))	('27369', 'Var', (16, 21))	('line 7681', 'Var', (79, 88))	('geotaxis', 'biological_process', 'GO:0042332', ('64', '72'))	('Abeta42 toxicity', 'Disease', (97, 113))	('27372', 'Var', (23, 28))	('Abeta42 toxicity', 'Disease', 'MESH:D064420', (97, 113))	('reduced', 'NegReg', (89, 96))	('27404', 'Var', (30, 35))	('negative geotaxis', 'MPA', (55, 72))
11570	28352227	The enhancer Df line 27372 included the deletion of CG17249 whose human ortholog is PRCC.	('CG17249', 'Gene', '38201', (52, 59))	('CG17249', 'Gene', (52, 59))	('deletion', 'Var', (40, 48))	('human', 'Species', '9606', (66, 71))	('PRCC', 'Gene', '5546', (84, 88))	('PRCC', 'Gene', (84, 88))
11572	28352227	A significant enhancement in Abeta42 neurotoxicity was observed in mutant hemizygous flies (Figure 5A).	('Abeta42 neurotoxicity', 'Disease', 'MESH:D020258', (29, 50))	('enhancement', 'PosReg', (14, 25))	('mutant', 'Var', (67, 73))	('Abeta42 neurotoxicity', 'Disease', (29, 50))
11574	28352227	Df lines 27917 and 27369 also worsened negative geotaxis in the presence of Abeta42 and the overlapping chromosomal segment included CG11796 whose human ortholog is HPD encoding HPPD, a key enzyme involved in tyrosine catabolism.	('27369', 'Var', (19, 24))	('tyrosine catabolism', 'biological_process', 'GO:0006572', ('209', '228'))	('negative geotaxis', 'MPA', (39, 56))	('HPD', 'Disease', 'MESH:D004421', (165, 168))	('HPPD', 'Disease', (178, 182))	('CG11796', 'Gene', '40263', (133, 140))	('human', 'Species', '9606', (147, 152))	('geotaxis', 'biological_process', 'GO:0042332', ('48', '56'))	('worsened', 'NegReg', (30, 38))	('HPD', 'Disease', (165, 168))	('Abeta42', 'Protein', (76, 83))	('tyrosine', 'Chemical', 'MESH:D014443', (209, 217))	('HPPD', 'Disease', 'OMIM:614187', (178, 182))	('CG11796', 'Gene', (133, 140))
11577	28352227	Yet, in the presence of pan-neuronal Abeta42 expression, CG11796 downregulation in both the RNAi and mutant lines induced a significant enhancement of Abeta42 toxicity, similar to the overall effect of the chromosomal deletions detected at stages I-II of the screen (Figures 5B,C).	('Abeta42 toxicity', 'Disease', 'MESH:D064420', (151, 167))	('Abeta42 toxicity', 'Disease', (151, 167))	('CG11796', 'Gene', '40263', (57, 64))	('RNAi', 'biological_process', 'GO:0016246', ('92', '96'))	('enhancement', 'PosReg', (136, 147))	('mutant', 'Var', (101, 107))	('downregulation', 'NegReg', (65, 79))	('CG11796', 'Gene', (57, 64))
11579	28352227	Abeta42 levels were analyzed in the brains of flies with partial Df of CG11796 at 18 days of age, when the toxic phenotype was detected.	('partial Df', 'Var', (57, 67))	('CG11796', 'Gene', '40263', (71, 78))	('CG11796', 'Gene', (71, 78))
11581	28352227	Western blots of head homogenates showed a 70%-80% increase in the Abeta monomer band in CG11796 mutant and RNAi lines, consistent with the immunofluorescence results (Figure 7).	('increase', 'PosReg', (51, 59))	('Abeta monomer band', 'MPA', (67, 85))	('CG11796', 'Gene', '40263', (89, 96))	('CG11796', 'Gene', (89, 96))	('RNAi', 'biological_process', 'GO:0016246', ('108', '112'))	('mutant', 'Var', (97, 103))
11586	28352227	Together, these results strongly suggest that a partial Df of the HPD ortholog promotes the accumulation of toxic Abeta42 oligomers in the CNS leading to cellular dysfunction without histologically detectable neuronal loss.	('accumulation', 'MPA', (92, 104))	('Abeta42 oligomers', 'Protein', (114, 131))	('neuronal loss', 'Disease', 'MESH:D009410', (209, 222))	('HPD', 'Disease', 'MESH:D004421', (66, 69))	('neuronal loss', 'Phenotype', 'HP:0002529', (209, 222))	('partial Df', 'Var', (48, 58))	('neuronal loss', 'Disease', (209, 222))	('HPD', 'Disease', (66, 69))	('cellular dysfunction', 'MPA', (154, 174))
11591	28352227	Previous modifier screens in the fly have yielded interesting candidates that modulate wild-type Abeta toxicity in the eye, upon life span, or negative geotaxis induced by an aggressive Abeta mutant (Cao et al.,; Tan et al.,; Rival et al.,; Liu et al.,).	('geotaxis', 'biological_process', 'GO:0042332', ('152', '160'))	('mutant', 'Var', (192, 198))	('negative geotaxis', 'CPA', (143, 160))	('modulate', 'Reg', (78, 86))	('Abeta toxicity', 'Disease', (97, 111))	('aggressive Abeta', 'Disease', (175, 191))	('aggressive Abeta', 'Disease', 'MESH:D001523', (175, 191))	('Abeta toxicity', 'Disease', 'MESH:D064420', (97, 111))
11594	28352227	Noteworthy, in both studies Df line 7681 was a strong suppressor, suggesting that one or more genes in homozygosity within this deletion are necessary for Abeta to impair geotaxis behavior, independent of Abeta species and type of neurons involved.	('Abeta to impair geotaxis behavior', 'Disease', (155, 188))	('Abeta to impair geotaxis behavior', 'Disease', 'MESH:D001523', (155, 188))	('geotaxis', 'biological_process', 'GO:0042332', ('171', '179'))	('deletion', 'Var', (128, 136))
11602	28352227	Mutations in HPD cause the rare diseases Tyrosinemia type 3 and Hawkinsiuria.	('Hawkinsiuria', 'Disease', 'None', (64, 76))	('HPD', 'Disease', (13, 16))	('cause', 'Reg', (17, 22))	('Hawkinsiuria', 'Disease', (64, 76))	('Mutations', 'Var', (0, 9))	('diseases Tyrosinemia', 'Disease', (32, 52))	('Tyrosinemia', 'Phenotype', 'HP:0003231', (41, 52))	('diseases Tyrosinemia', 'Disease', 'MESH:D020176', (32, 52))	('HPD', 'Disease', 'MESH:D004421', (13, 16))
11604	28352227	Hawkinsinuria is autosomal dominant and characterized by metabolic acidosis and urinary excretion of "hawkinsin", a cyclic amino acid derived from quinolacetic acid produced by mutant HPPD (Brownlee et al.,).	('acidosis', 'Disease', 'MESH:D000138', (67, 75))	('HPPD', 'Disease', 'OMIM:614187', (184, 188))	('metabolic acidosis', 'Phenotype', 'HP:0001942', (57, 75))	('quinolacetic acid', 'Chemical', 'MESH:C038893', (147, 164))	('acidosis', 'Disease', (67, 75))	('Hawkinsinuria', 'Disease', (0, 13))	('acidosis', 'Phenotype', 'HP:0001941', (67, 75))	('mutant', 'Var', (177, 183))	('urinary', 'MPA', (80, 87))	('HPPD', 'Disease', (184, 188))	('cyclic amino acid', 'Chemical', 'MESH:D000598', (116, 133))	('hawkinsin"', 'Chemical', 'MESH:C014578', (102, 112))	('Hawkinsinuria', 'Disease', 'MESH:C535845', (0, 13))	('excretion', 'biological_process', 'GO:0007588', ('88', '97'))
11606	28352227	In addition, high tyrosine levels may reduce the activity of thiol-dependent creatine kinases (CK) leading to misbalance of a key ATP buffering and shuttling system (Wallimann et al.,; de Andrade et al.,).	('tyrosine', 'Chemical', 'MESH:D014443', (18, 26))	('activity', 'MPA', (49, 57))	('high tyrosine levels', 'Phenotype', 'HP:0003231', (13, 33))	('high', 'Var', (13, 17))	('ATP', 'Chemical', 'MESH:D000255', (130, 133))	('leading to', 'Reg', (99, 109))	('thiol-dependent creatine kinases', 'Enzyme', (61, 93))	('reduce', 'NegReg', (38, 44))	('creatine', 'Chemical', 'MESH:D003401', (77, 85))	('tyrosine levels', 'MPA', (18, 33))
11608	28352227	Consistent with these findings, creatine accumulates in old transgenic mice expressing a mutant APP and in the hippocampus of AD patients (Gallant et al.,).	('APP', 'Gene', (96, 99))	('creatine', 'Chemical', 'MESH:D003401', (32, 40))	('AD', 'Disease', 'MESH:D000544', (126, 128))	('patients', 'Species', '9606', (129, 137))	('transgenic mice', 'Species', '10090', (60, 75))	('AD', 'Phenotype', 'HP:0002511', (126, 128))	('AD', 'Disease', (126, 128))	('mutant', 'Var', (89, 95))	('creatine accumulates', 'MPA', (32, 52))
11609	28352227	Our finding that the partial Df of HPD ortholog promoted the accumulation of oligomeric Abeta42 provides a likely explanation for the worsening of age-dependent geotaxis performance.	('Abeta42', 'Protein', (88, 95))	('HPD', 'Disease', 'MESH:D004421', (35, 38))	('oligomeric Abeta42', 'Protein', (77, 95))	('geotaxis', 'biological_process', 'GO:0042332', ('161', '169'))	('partial Df', 'Var', (21, 31))	('promoted', 'PosReg', (48, 56))	('HPD', 'Disease', (35, 38))	('accumulation', 'PosReg', (61, 73))
11610	28352227	With regard to possible mechanisms for Abeta accretion in the context of lower HPPD expression, the reduction in CK activity as a consequence of high tyrosine levels may accelerate Abeta aggregation or impair its clearance due to lower ATP availability and oxidative stress (Meyer et al.,).	('accelerate', 'PosReg', (170, 180))	('rat', 'Species', '10116', (176, 179))	('HPPD', 'Disease', (79, 83))	('tyrosine', 'Chemical', 'MESH:D014443', (150, 158))	('reduction', 'NegReg', (100, 109))	('Abeta aggregation', 'Disease', 'MESH:D020914', (181, 198))	('oxidative', 'MPA', (257, 266))	('Abeta aggregation', 'Disease', (181, 198))	('high tyrosine levels', 'Phenotype', 'HP:0003231', (145, 165))	('ATP availability', 'MPA', (236, 252))	('tyrosine levels', 'MPA', (150, 165))	('Abeta accretion', 'Disease', (39, 54))	('impair', 'NegReg', (202, 208))	('oxidative stress', 'Phenotype', 'HP:0025464', (257, 273))	('activity', 'MPA', (116, 124))	('HPPD', 'Disease', 'OMIM:614187', (79, 83))	('clearance', 'MPA', (213, 222))	('Abeta accretion', 'Disease', 'None', (39, 54))	('ATP', 'Chemical', 'MESH:D000255', (236, 239))	('high', 'Var', (145, 149))
11611	28352227	Alternatively, the possibility that a partial Df of HPPD is more directly involved in Abeta accumulation deserves further investigation.	('HPPD', 'Disease', 'OMIM:614187', (52, 56))	('Abeta', 'MPA', (86, 91))	('HPPD', 'Disease', (52, 56))	('partial Df', 'Var', (38, 48))	('involved', 'Reg', (74, 82))
11618	28352227	This work was supported by grants from the Alzheimer's Association (IIRG 11-205127 to EMC), Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) PICT2013-0318 (to EMC), PICT2013-1382 (to MFC) and CONICET-PIP0378 (to LM).	('PICT2013-0318', 'Var', (156, 169))	("Alzheimer's Association", 'Disease', 'MESH:D000544', (43, 66))	("Alzheimer's Association", 'Disease', (43, 66))	('EMC', 'cellular_component', 'GO:0072546', ('174', '177'))	('EMC', 'cellular_component', 'GO:0072546', ('86', '89'))	('PICT2013-1382', 'Var', (180, 193))
11648	32998233	In the precise case of ccRCC (clear cell renal cell carcinoma), up to 95% of the tumor genomes are constitutionally VHL gene muted or deleted, thus leading to constitutive activation of HIF1 and CAIX upregulation, even in normoxic conditions.	('upregulation', 'PosReg', (200, 212))	('muted', 'Gene', '63915', (125, 130))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (30, 61))	('VHL', 'Gene', (116, 119))	('deleted', 'Var', (134, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (41, 61))	('RCC', 'Disease', (25, 28))	('tumor', 'Disease', (81, 86))	('CAIX', 'Gene', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('HIF1', 'Gene', '3091', (186, 190))	('clear cell renal cell carcinoma', 'Disease', (30, 61))	('VHL', 'Gene', '7428', (116, 119))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('HIF1', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('muted', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('activation', 'PosReg', (172, 182))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (30, 61))
11649	32998233	The comparison of cDNA sequences between cancer and normal cells does not reveal any mutations or alternative splicing, and therefore the pathological mutations appear upstream in the signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('signaling pathway', 'Pathway', (184, 201))	('splicing', 'biological_process', 'GO:0045292', ('110', '118'))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (151, 160))	('signaling pathway', 'biological_process', 'GO:0007165', ('184', '201'))
11655	32998233	proposed a two-step strategy for the use of immunostaining in renal cell carcinoma subtype diagnosis: first with the triple panel described above (CK7, AMACR and CAIX) and then, if necessary, with others markers like c-kit, CD10 or cathepsin-K. Another team proposed to enlarge the panel adding the detection of TFE3 (transcription factor binding to IGHM enhancer 3) in IHC, permitting to detect the Xp11 translocation associated RCC.	('TFE3', 'Gene', (312, 316))	('Xp11 translocation', 'Var', (400, 418))	('CD10', 'molecular_function', 'GO:0004245', ('224', '228'))	('CK7', 'Gene', '3855', (147, 150))	('TFE3', 'Gene', '7030', (312, 316))	('cathepsin-K', 'Gene', (232, 243))	('CD10', 'Gene', '4311', (224, 228))	('c-kit', 'Gene', (217, 222))	('AMACR', 'Gene', (152, 157))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('318', '346'))	('cathepsin-K', 'Gene', '1513', (232, 243))	('RCC', 'Disease', (430, 433))	('CD10', 'Gene', (224, 228))	('IGHM', 'Gene', '3507', (350, 354))	('AMACR', 'Gene', '23600', (152, 157))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 82))	('RCC', 'Disease', 'MESH:C538614', (430, 433))	('transcription', 'biological_process', 'GO:0006351', ('318', '331'))	('c-kit', 'Gene', '3815', (217, 222))	('CK7', 'Gene', (147, 150))	('IGHM', 'Gene', (350, 354))	('renal cell carcinoma', 'Disease', (62, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
11665	32998233	Moreover, the principal rational is that High CAIX expression could witness the VHL-associated tumorigenesis, and ccRCC presenting an abnormally low CAIX rate could reflect the tumor de-differentiation and aggressiveness.	('tumor', 'Disease', (177, 182))	('VHL', 'Gene', (80, 83))	('aggressiveness', 'Disease', 'MESH:D001523', (206, 220))	('VHL', 'Gene', '7428', (80, 83))	('High', 'Var', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('CAIX', 'Protein', (46, 50))	('expression', 'MPA', (51, 61))	('aggressiveness', 'Disease', (206, 220))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('aggressiveness', 'Phenotype', 'HP:0000718', (206, 220))	('RCC', 'Disease', (116, 119))	('tumor', 'Disease', (95, 100))
11666	32998233	realized a retrospective study on 143 extirpated local ccRCC, and tested 6 markers in IHC on the tumor's samples: CAIX, c-MYC, Ki67, p53, vimentin and PTEN.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Ki67', 'Var', (127, 131))	('c-MYC', 'Gene', '4609', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('vimentin', 'cellular_component', 'GO:0045099', ('138', '146'))	('vimentin', 'Gene', (138, 146))	('p53', 'Gene', '7157', (133, 136))	('vimentin', 'cellular_component', 'GO:0045098', ('138', '146'))	('tumor', 'Disease', (97, 102))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('p53', 'Gene', (133, 136))	('tested', 'Reg', (66, 72))	('c-MYC', 'Gene', (120, 125))	('PTEN', 'Gene', (151, 155))	('vimentin', 'Gene', '7431', (138, 146))	('PTEN', 'Gene', '5728', (151, 155))
11667	32998233	The results showed that low CAIX expression (under 30%) and vimentin over-expression (over 50%) were associated with the worst outcomes (overall survival, progression-free survival and disease-free survival).	('under', 'Var', (45, 50))	('CAIX', 'Protein', (28, 32))	('over-expression', 'PosReg', (69, 84))	('vimentin', 'cellular_component', 'GO:0045099', ('60', '68'))	('progression-free survival', 'CPA', (155, 180))	('vimentin', 'Gene', '7431', (60, 68))	('low', 'NegReg', (24, 27))	('vimentin', 'cellular_component', 'GO:0045098', ('60', '68'))	('expression', 'MPA', (33, 43))	('vimentin', 'Gene', (60, 68))
11678	32998233	In other terms, high CAIX expression in ccRCC seemed to be associated with better prognosis, while high CAIX expression in pRCC seemed to be unfavorable.	('RCC', 'Disease', (124, 127))	('expression', 'MPA', (26, 36))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('high', 'Var', (16, 20))	('pRCC', 'Gene', (123, 127))	('pRCC', 'Gene', '5546', (123, 127))	('RCC', 'Disease', (42, 45))	('CAIX', 'Protein', (21, 25))
11679	32998233	High CAIX expression seemed to be associated with lower tumor stage (pT1T2 vs. pT3T4), lower tumor grade (G1G2 vs. G3G4), absence of nodal involvement (N0 vs. N+) and favorable ECOG score (0 vs. >=1).	('lower', 'NegReg', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('High', 'Var', (0, 4))	('lower', 'NegReg', (87, 92))	('tumor', 'Disease', (56, 61))	('nodal', 'Gene', (133, 138))	('expression', 'MPA', (10, 20))	('tumor', 'Disease', (93, 98))	('CAIX', 'Protein', (5, 9))	('nodal', 'Gene', '4838', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
11681	32998233	A high CAIX score (>200) was associated with prolonged DFS and OS.	('CAIX', 'Gene', (7, 11))	('DFS', 'Disease', (55, 58))	('>200', 'Var', (19, 23))	('DFS', 'Disease', 'None', (55, 58))
11683	32998233	analyzed the correlation between CAIX high expression in RCC metastatic patients and increased tumor sensitivity to interleukin-2 (IL-2).	('CAIX', 'Gene', (33, 37))	('IL-2', 'molecular_function', 'GO:0005134', ('131', '135'))	('high', 'Var', (38, 42))	('interleukin-2', 'Gene', '3558', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('IL-2', 'Gene', '3558', (131, 135))	('RCC', 'Disease', (57, 60))	('increased', 'PosReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IL-2', 'Gene', (131, 135))	('interleukin-2', 'Gene', (116, 129))	('tumor', 'Disease', (95, 100))	('patients', 'Species', '9606', (72, 80))
11764	32998233	Introduction of a pharmacological CAIX inhibitor, or transfection with shRNA-mediated knockdown of CAIX, in xenografted nude mice with ccRCC (786-O cells) resulted in a better response (in vitro) to irradiation (6Gy), compared with mice receiving either irradiation or pharmacological alone.	('response', 'MPA', (176, 184))	('transfection', 'Var', (53, 65))	('knockdown', 'Var', (86, 95))	('mice', 'Species', '10090', (125, 129))	('nude mice', 'Species', '10090', (120, 129))	('CAIX', 'Gene', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('better', 'PosReg', (169, 175))	('mice', 'Species', '10090', (232, 236))
11836	30510921	Unclassified renal cell carcinoma: diagnostic difficulties and treatment modalities Over the past few decades, the classification system of renal cell carcinoma (RCC) variants has witnessed tremendous and ongoing refinement driven by genomic profiling and morphological correlation that have provided valuable insights into tumor biology and characterization of this heterogeneous subset of tumors.	('tumors', 'Disease', (391, 397))	('renal cell carcinoma', 'Disease', (140, 160))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (140, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('tumor', 'Disease', (391, 396))	('RCC', 'Disease', (162, 165))	('tumors', 'Disease', 'MESH:D009369', (391, 397))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('variants', 'Var', (167, 175))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (140, 160))	('tumors', 'Phenotype', 'HP:0002664', (391, 397))	('tumor', 'Disease', (324, 329))	('renal cell carcinoma', 'Disease', (13, 33))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (13, 33))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
11879	30510921	Although there is extensive morphologic overlap among these entities, the underlying genetic alterations are different, with tumors with RAT morphology sharing a frequent mutation in TCEB1 gene.	('TCEB1', 'Gene', '64525', (183, 188))	('mutation', 'Var', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('TCEB1', 'Gene', (183, 188))	('RAT', 'Species', '10116', (137, 140))
11884	30510921	While gains of chromosomes 7 and 17 as well as MET alterations are seen in type 1 tumors, type 2 is increasingly recognized to represent a very distinct (from conventional pRCC) but quite heterogeneous group containing at least three distinct molecular clusters.	('MET alterations', 'Var', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('type 1 tumors', 'Disease', 'MESH:D009369', (75, 88))	('gains', 'PosReg', (6, 11))	('type 1 tumors', 'Disease', (75, 88))
11885	30510921	These include tumors with molecular alterations involving the NRF2-ARE pathway, chromatin-modifying genes, TFE3 fusions, CDKN2A silencing, and CpG island methylator phenotype.	('NRF2', 'Gene', '4780', (62, 66))	('CDKN2A', 'Gene', '1029', (121, 127))	('chromatin-modifying genes', 'Gene', (80, 105))	('silencing', 'NegReg', (128, 137))	('chromatin', 'cellular_component', 'GO:0000785', ('80', '89'))	('NRF2', 'Gene', (62, 66))	('TFE3', 'Gene', '7030', (107, 111))	('fusions', 'Var', (112, 119))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('CDKN2A', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('TFE3', 'Gene', (107, 111))
11889	30510921	MiTF-RCCs are a group of tumors characterized by recurrent rearrangements of TFE3 (at the Xp11 locus) or TFEB (at the 6p21 locus) genes, both of which are members of the MiT family of transcription factors.	('TFEB', 'Gene', '7942', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TFEB', 'Gene', (105, 109))	('transcription', 'biological_process', 'GO:0006351', ('184', '197'))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TFE3', 'Gene', (77, 81))	('rearrangements', 'Var', (59, 73))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('MiTF-RCC', 'Disease', (0, 8))	('TFE3', 'Gene', '7030', (77, 81))	('MiTF-RCC', 'Disease', 'MESH:C538614', (0, 8))
11894	30510921	On the other hand, tumors with PRCC-TFE3 rearrangement tend to have more of a nested, papillary, or compact architecture, with less abundant cytoplasm and lower grade nuclei.	('tumors', 'Disease', (19, 25))	('rearrangement', 'Var', (41, 54))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('cytoplasm', 'cellular_component', 'GO:0005737', ('141', '150'))	('TFE3', 'Gene', (36, 40))	('PRCC', 'Gene', '5546', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('TFE3', 'Gene', '7030', (36, 40))	('PRCC', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('papillary', 'CPA', (86, 95))	('nested', 'CPA', (78, 84))	('compact architecture', 'CPA', (100, 120))
11895	30510921	TFEB or t(6;11) translocation RCCs are more indolent tumors characterized by TFEB gene fusion with Alpha gene.	('t(6;11', 'Gene', (8, 14))	('TFEB', 'Gene', '7942', (77, 81))	('TFEB', 'Gene', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('TFEB', 'Gene', '7942', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TFEB', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('translocation', 'Var', (16, 29))	('tumors', 'Disease', (53, 59))
11898	30510921	This overall pattern is seen irrespective of whether carcinomas show TFE3 or TFEB rearrangements, though often TFEB-rearranged carcinomas show quite strong expression of melanocytic markers.	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('rearrangements', 'Var', (82, 96))	('carcinomas', 'Disease', (127, 137))	('TFEB', 'Gene', '7942', (77, 81))	('TFE3', 'Gene', (69, 73))	('TFE3', 'Gene', '7030', (69, 73))	('TFEB', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('TFEB', 'Gene', '7942', (111, 115))	('carcinomas', 'Disease', (53, 63))	('carcinomas', 'Disease', 'MESH:D002277', (53, 63))	('expression', 'MPA', (156, 166))	('TFEB', 'Gene', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))
11901	30510921	Dual-color break-apart fluorescence in situ hybridization assays for TFE3 and TFEB rearrangements are very sensitive and specific for confirming the diagnosis.	('TFEB', 'Gene', '7942', (78, 82))	('rearrangements', 'Var', (83, 97))	('TFEB', 'Gene', (78, 82))	('TFE3', 'Gene', '7030', (69, 73))	('TFE3', 'Gene', (69, 73))
11920	30510921	More recently described entities in this differential include SDH-deficient RCCs, such as that arise in the hereditary paraganglioma/pheochromocytoma syndromes (PGL1-4) or Carney Stratakis syndrome (with GISTs), in patients harboring germline mutation of SDH subunit genes.	('SDH', 'Gene', '6390', (62, 65))	('patients', 'Species', '9606', (215, 223))	('Carney Stratakis syndrome', 'Disease', (172, 197))	('SDH-deficient RCCs', 'Disease', 'MESH:D007153', (62, 80))	('Carney Stratakis syndrome', 'Disease', 'MESH:C564650', (172, 197))	('PGL1-4', 'Gene', (161, 167))	('paraganglioma', 'Phenotype', 'HP:0002668', (119, 132))	('SDH', 'Gene', (62, 65))	('PGL1-4', 'Gene', '54949;6391;6390', (161, 167))	('SDH', 'Gene', (255, 258))	('PGL', 'molecular_function', 'GO:0004598', ('161', '164'))	('germline mutation', 'Var', (234, 251))	('SDH-deficient RCCs', 'Disease', (62, 80))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (133, 149))	('SDH', 'Gene', '6390', (255, 258))	('hereditary paraganglioma/pheochromocytoma syndromes', 'Disease', 'MESH:D010673', (108, 159))
11925	30510921	In clinical practice, screening for SDH deficiency is done by SDHB immunohistochemical stain which also identifies deficiencies in other subunits of the enzyme (SDHA, SDHC, SDHD, SDHAF2) that result in destabilization of the SDH complex.	('SDHA', 'Gene', (161, 165))	('SDHAF2', 'Gene', '54949', (179, 185))	('SDHAF2', 'Gene', (179, 185))	('SDH', 'Gene', (179, 182))	('SDHA', 'Gene', '6389', (161, 165))	('SDH', 'Gene', '6390', (167, 170))	('SDH', 'Gene', (225, 228))	('SDHB', 'Gene', '6390', (62, 66))	('SDH', 'Gene', '6390', (62, 65))	('SDH deficiency', 'Disease', (36, 50))	('SDH', 'Gene', (161, 164))	('SDHC', 'Gene', '6391', (167, 171))	('SDH', 'Gene', '6390', (173, 176))	('SDH deficiency', 'Disease', 'MESH:D007153', (36, 50))	('SDHB', 'Gene', (62, 66))	('SDHD', 'Gene', '6392', (173, 177))	('SDH', 'Gene', (167, 170))	('SDH', 'Gene', (62, 65))	('SDH', 'Gene', '6390', (36, 39))	('deficiencies', 'Var', (115, 127))	('SDH', 'Gene', (173, 176))	('destabilization', 'MPA', (202, 217))	('SDH', 'Gene', '6390', (179, 182))	('SDHA', 'Gene', (179, 183))	('SDHC', 'Gene', (167, 171))	('SDHD', 'Gene', (173, 177))	('SDH', 'Gene', '6390', (225, 228))	('SDHA', 'Gene', '6389', (179, 183))	('SDH', 'Gene', (36, 39))	('SDH', 'Gene', '6390', (161, 164))
11943	30510921	The latter tumors generally arise in the syndrome of HLRCC, with cutaneous and uterine leiomyomatosis and germline mutations in the FH gene.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('HLRCC', 'Disease', 'MESH:C535516', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('leiomyomatosis', 'Disease', 'MESH:D018231', (87, 101))	('germline mutations', 'Var', (106, 124))	('arise in', 'Reg', (28, 36))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('FH', 'Gene', '2271', (132, 134))	('cutaneous and uterine leiomyomatosis', 'Phenotype', 'HP:0007620', (65, 101))	('leiomyomatosis', 'Disease', (87, 101))	('uterine leiomyomatosis', 'Phenotype', 'HP:0000131', (79, 101))	('HLRCC', 'Disease', (53, 58))
11946	30510921	Most cases with FH mutation demonstrate loss of expression of FH itself by immunohistochemistry, as well as aberrant expression of 2 succinyl-cysteine (2SC) on cytoplasmic and nuclear proteins, useful in confirming the diagnosis.	('FH', 'Gene', '2271', (62, 64))	('mutation', 'Var', (19, 27))	('expression', 'MPA', (117, 127))	('expression', 'MPA', (48, 58))	('aberrant', 'Var', (108, 116))	('loss', 'NegReg', (40, 44))	('FH', 'Gene', '2271', (16, 18))	('2SC', 'Chemical', 'MESH:C511650', (152, 155))	('2 succinyl-cysteine', 'Chemical', 'MESH:C511650', (131, 150))
11956	30510921	Further confirmation of the diagnosis may be supported by biallelic inactivation of SMARCB1 (INI-1) through deletion and/or genomic rearrangements, with overexpression of POU5F1 (Oct3/4) with widely available immunohistochemical assays.	('overexpression', 'PosReg', (153, 167))	('Oct3/4', 'Gene', '5460', (179, 185))	('Oct3/4', 'Gene', (179, 185))	('SMARCB1', 'Gene', '6598', (84, 91))	('INI-1', 'Gene', '6598', (93, 98))	('INI-1', 'Gene', (93, 98))	('SMARCB1', 'Gene', (84, 91))	('POU5F1', 'Gene', '5460', (171, 177))	('POU5F1', 'Gene', (171, 177))	('biallelic', 'Var', (58, 67))	('genomic rearrangements', 'Var', (124, 146))	('deletion', 'Var', (108, 116))
11961	30510921	p63, GATA3, and uroplakin 2 positivity, on the other hand, favors a primary UC.	('uroplakin 2', 'Gene', (16, 27))	('uroplakin 2', 'Gene', '7379', (16, 27))	('primary UC', 'Disease', (68, 78))	('p63', 'Gene', (0, 3))	('GATA3', 'Gene', (5, 10))	('positivity', 'Var', (28, 38))	('p63', 'Gene', '8626', (0, 3))	('GATA3', 'Gene', '2625', (5, 10))
11974	30510921	Molecular characterization of unclassified RCCs demonstrates many shared underlying genomic alterations compared with ccRCCs such as TP53 alterations, MTOR mutations, and NF2 mutations, while there are distinct differences such as lack of VHL alterations with unclassified RCC compared to ccRCC.	('VHL', 'Disease', (239, 242))	('VHL', 'Disease', 'MESH:D006623', (239, 242))	('MTOR', 'Gene', '2475', (151, 155))	('mutations', 'Var', (156, 165))	('NF2', 'Gene', '4771', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('RCC', 'Disease', (273, 276))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('mutations', 'Var', (175, 184))	('RCC', 'Disease', (291, 294))	('MTOR', 'Gene', (151, 155))	('RCC', 'Disease', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('NF2', 'Gene', (171, 174))
12039	30510921	These include CHECK2 alterations or PBRM1 alterations (potentially respond to checkpoint inhibitors), ALK translocations (ALK-targeted therapies), and ATM/BRCA2 alterations (PARP inhibitors), as examples.	('ATM', 'Gene', '472', (151, 154))	('PARP', 'Gene', '1302', (174, 178))	('PBRM1', 'Gene', (36, 41))	('alterations', 'Var', (42, 53))	('PBRM1', 'Gene', '55193', (36, 41))	('ALK', 'Gene', (102, 105))	('BRCA2', 'Gene', '675', (155, 160))	('CHECK2', 'Gene', (14, 20))	('PARP', 'Gene', (174, 178))	('ALK', 'Gene', (122, 125))	('ATM', 'Gene', (151, 154))	('ALK', 'Gene', '238', (102, 105))	('BRCA2', 'Gene', (155, 160))	('alterations', 'Var', (21, 32))	('ALK', 'Gene', '238', (122, 125))	('alterations', 'Var', (161, 172))
12115	24204800	A key epigenetic alteration involved in the initiation and progression of cancer is aberrant methylation in the promoter region of a gene.	('aberrant methylation', 'Var', (84, 104))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('methylation', 'Var', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
12116	24204800	The hypermethylation is associated with transcriptional repression and is an important mechanism of inactivation of tumor suppressor genes in neoplastic cells.	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor suppressor', 'biological_process', 'GO:0051726', ('116', '132'))	('transcriptional', 'MPA', (40, 55))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('116', '132'))	('tumor', 'Disease', (116, 121))	('hypermethylation', 'Var', (4, 20))
12119	24204800	Pairwise comparisons revealed genes aberrantly hypermethylated in a tumor type but unmethylated in normal, and often unmethylated in the other renal tumor types.	('tumor', 'Disease', (68, 73))	('renal tumor', 'Disease', 'MESH:D007674', (143, 154))	('renal tumor', 'Phenotype', 'HP:0009726', (143, 154))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('renal tumor', 'Disease', (143, 154))	('aberrantly', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
12131	24204800	Present knowledge of the molecular basis of cancer indicates that epigenetic alterations, e.g.	('epigenetic alterations', 'Var', (66, 88))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
12132	24204800	aberrant promoter methylation, make an important contribution to the biological behavior of a tumor.	('promoter', 'Protein', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('aberrant', 'Var', (0, 8))	('tumor', 'Disease', (94, 99))	('contribution', 'Reg', (49, 61))	('methylation', 'biological_process', 'GO:0032259', ('18', '29'))
12133	24204800	Epigenetic inactivation by aberrant methylation of promoter CpG islands in the classical tumor suppressor genes VHL and CDKN2A or other genes such as RASSF1A, GSTP1, MGMT and SFRP1 have been identified in RCC generally by a candidate approach.	('SFRP1', 'Gene', (175, 180))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('VHL', 'Gene', '7428', (112, 115))	('CDKN2A', 'Gene', (120, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('89', '105'))	('MGMT', 'Gene', '4255', (166, 170))	('methylation', 'biological_process', 'GO:0032259', ('36', '47'))	('SFRP1', 'Gene', '6422', (175, 180))	('Epigenetic', 'MPA', (0, 10))	('tumor', 'Disease', (89, 94))	('GSTP1', 'Gene', '2950', (159, 164))	('RASSF1A', 'Gene', '11186', (150, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('89', '105'))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('GSTP1', 'Gene', (159, 164))	('CDKN2A', 'Gene', '1029', (120, 126))	('RASSF1A', 'Gene', (150, 157))	('MGMT', 'molecular_function', 'GO:0003908', ('166', '170'))	('RCC', 'Disease', (205, 208))	('MGMT', 'Gene', (166, 170))	('VHL', 'Gene', (112, 115))	('aberrant methylation', 'Var', (27, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
12159	24204800	An internal control, a C not in a CG dinucleotide, for the efficiency of modification was included in the assay for the ATP2A3 gene promoter.	('ATP2A3', 'Gene', (120, 126))	('ATP2A3', 'Gene', '489', (120, 126))	('CG dinucleotide', 'Chemical', 'MESH:C015772', (34, 49))	('modification', 'Var', (73, 85))
12180	24204800	Three main groups were evident on the heatmap (Figure S2), one with frequent methylation, one with infrequent methylation, and an intermediate group, similar to analysis of CIMP with HM27 in studies of colorectal, brain, and breast cancer.	('methylation', 'biological_process', 'GO:0032259', ('110', '121'))	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('methylation', 'Var', (77, 88))	('brain', 'Disease', (214, 219))	('HM27', 'CellLine', 'CVCL:8807', (183, 187))	('CIMP', 'Chemical', '-', (173, 177))	('colorectal', 'Disease', 'MESH:D015179', (202, 212))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('colorectal', 'Disease', (202, 212))	('breast cancer', 'Disease', (225, 238))
12182	24204800	This may provide preliminary evidence for association of CIMP with clinicopathological parameters or might reflect the accumulation of aberrant methylation with a more advanced grade or stage of malignancy as noted by TCGA.	('malignancy', 'Disease', (195, 205))	('association', 'Interaction', (42, 53))	('CIMP', 'Chemical', '-', (57, 61))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))	('aberrant', 'Var', (135, 143))	('methylation', 'MPA', (144, 155))	('accumulation', 'PosReg', (119, 131))	('CIMP', 'Disease', (57, 61))
12184	24204800	The definition of CIMP in colorectal cancer was greatly aided by clear association with point mutation of BRAF .	('CIMP', 'Chemical', '-', (18, 22))	('colorectal cancer', 'Disease', (26, 43))	('BRAF', 'Gene', '673', (106, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (26, 43))	('BRAF', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('association', 'Interaction', (71, 82))	('point mutation', 'Var', (88, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (26, 43))
12187	24204800	This tumor had been noted by the pathologist to have an atypical karyotype (35, -X, -1, -4, -6, -8, -9, -13, -14, -15, -18, -22) i.e.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('35', 'Var', (76, 78))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
12188	24204800	monosomy of several chromosomes more similar to chrRCC than to pRCC.	('pRCC', 'Gene', '5546', (63, 67))	('monosomy', 'Var', (0, 8))	('pRCC', 'Gene', (63, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
12189	24204800	We first examined probes with the most differential methylation between NRP cells from age-matched individuals with no history or evidence of RCC or oncocytoma and the three subtypes of RCC grouped together by the Wilcoxon Rank sum test in a two group comparison with p<0.05 considered significant.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('oncocytoma', 'Disease', 'MESH:D018249', (149, 159))	('RCC', 'Disease', (142, 145))	('NRP', 'biological_process', 'GO:0085015', ('72', '75'))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))	('oncocytoma', 'Disease', (149, 159))
12191	24204800	First because Illumina reported that a Deltass detection sensitivity of 0.2 could be detected with 95% confidence across more than 90% of probes in HM27 and also that the Deltass sensitivity was higher (0.15) at the unmethylated state.	('probes', 'Var', (138, 144))	('HM27', 'CellLine', 'CVCL:8807', (148, 152))	('HM27', 'Gene', (148, 152))
12193	24204800	If 1 of 2 alleles of VHL were hypermethylated and the other allele inactivated by point mutation (and unmethylated) in a primary ccRCC specimen with typical 30% normal cell contamination then the maximum percentage of methylated alleles would be 35%.	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('hypermethylated', 'Var', (30, 45))	('VHL', 'Gene', (21, 24))	('VHL', 'Gene', '7428', (21, 24))	('point mutation', 'Var', (82, 96))
12194	24204800	The Wilcoxon test with these cut-offs generated a list of 335 probes hypermethylated in all RCC but unmethylated in NRP (p<0.05).	('RCC', 'Disease', (92, 95))	('hypermethylated', 'Var', (69, 84))	('NRP', 'biological_process', 'GO:0085015', ('116', '119'))	('RCC', 'Disease', 'MESH:C538614', (92, 95))
12199	24204800	Approximately 1.7% (in ccRCC) to 0.4% (in chrRCC) of genes analyzed after filtering were hypermethylated.	('hypermethylated', 'Var', (89, 104))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (25, 28))	('RCC', 'Disease', (45, 48))
12204	24204800	Importantly, for each tumor type the majority of aberrantly hypermethylated genes were unique to that type (Figure 2).	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('aberrantly hypermethylated genes', 'Var', (49, 81))	('tumor', 'Disease', (22, 27))
12206	24204800	Among the most frequently hypermethylated genes was ZNF177, which may be involved in regulation of transcription, hypermethylated in 20/49 (41%) RCC (Figure 3).	('regulation', 'biological_process', 'GO:0065007', ('85', '95'))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('99', '112'))	('ZNF177', 'Gene', '7730', (52, 58))	('hypermethylated', 'Var', (114, 129))	('ZNF177', 'Gene', (52, 58))
12207	24204800	The GRIK1 gene was hypermethylated in 14/25 (56%) ccRCC.	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('GRIK1', 'Gene', (4, 9))	('hypermethylated', 'Var', (19, 34))	('GRIK1', 'Gene', '2897', (4, 9))
12211	24204800	However, another ionotrophic glutamate receptor GRIN2A was recently found to have frequent point mutation in melanoma though its function in this disease is unknown.	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('melanoma', 'Disease', (109, 117))	('glutamate', 'Chemical', 'MESH:D018698', (29, 38))	('GRIN2A', 'Gene', (48, 54))	('point mutation', 'Var', (91, 105))	('GRIN2A', 'Gene', '2903', (48, 54))
12212	24204800	Another frequently hypermethylated gene was CHODL the transmembrane protein chondrolectin hypermethylated in 14/25 (56%) ccRCC (Figure 3).	('CHODL', 'Gene', (44, 49))	('transmembrane', 'cellular_component', 'GO:0044214', ('54', '67'))	('CHODL', 'Gene', '140578', (44, 49))	('transmembrane', 'cellular_component', 'GO:0016021', ('54', '67'))	('RCC', 'Disease', (123, 126))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('hypermethylated', 'Var', (90, 105))
12213	24204800	The Brevican (BCAN) gene was hypermethylated in 13 of 14 (93%) pRCC.	('pRCC', 'Gene', '5546', (63, 67))	('hypermethylated', 'Var', (29, 44))	('Brevican', 'Gene', '63827', (4, 12))	('BCAN', 'Gene', '63827', (14, 18))	('pRCC', 'Gene', (63, 67))	('BCAN', 'Gene', (14, 18))	('Brevican', 'Gene', (4, 12))
12215	24204800	The secretagogin protein (SCGN) was hypermethylated in 3/10 (30%) chrRCC.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('secretagogin', 'Gene', (4, 16))	('hypermethylated', 'Var', (36, 51))	('SCGN', 'Gene', '10590', (26, 30))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('SCGN', 'Gene', (26, 30))	('secretagogin', 'Gene', '10590', (4, 16))
12222	24204800	Several genes with significant hypermethylation were previously reported to be aberrantly methylated in cancers other than RCC e.g.	('hypermethylation', 'Var', (31, 47))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
12226	24204800	In our study, although VHL was hypermethylated as expected in 2/25 (8%) ccRCC it was not statistically significant (p = 0.094).	('VHL', 'Gene', (23, 26))	('RCC', 'Disease', (74, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('VHL', 'Gene', '7428', (23, 26))	('hypermethylated', 'Var', (31, 46))
12227	24204800	Two of the novel genes reported to have point mutation in ccRCC by TCGA showed aberrant hypermethylation in our study.	('TCGA', 'Gene', (67, 71))	('hypermethylation', 'MPA', (88, 104))	('RCC', 'Disease', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('point mutation', 'Var', (40, 54))
12231	24204800	The other study identified 205 genes as hypermethylated in 38 RCC, described as clear cell or papillary without information on size, grade or stage.	('RCC', 'Disease', (62, 65))	('hypermethylated', 'Var', (40, 55))	('RCC', 'Disease', 'MESH:C538614', (62, 65))
12241	24204800	Gene Ontology (GO) biological processes highlighted by DAVID as enriched (p<0.05) in the analysis of genes hypermethylated in all RCC included regulation of transcription, cell motility and migration, negative regulation of metabolic and biosynthetic processes, and angiogenesis or blood vessel development.	('transcription', 'MPA', (157, 170))	('blood vessel development', 'biological_process', 'GO:0001568', ('282', '306'))	('transcription', 'biological_process', 'GO:0006351', ('157', '170'))	('angiogenesis', 'CPA', (266, 278))	('regulation', 'biological_process', 'GO:0065007', ('143', '153'))	('regulation', 'biological_process', 'GO:0065007', ('210', '220'))	('cell motility', 'biological_process', 'GO:0048870', ('172', '185'))	('cell motility', 'CPA', (172, 185))	('angiogenesis', 'biological_process', 'GO:0001525', ('266', '278'))	('Gene Ontology', 'biological_process', 'GO:0003673', ('0', '13'))	('RCC', 'Disease', (130, 133))	('negative regulation', 'NegReg', (201, 220))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('blood vessel development', 'CPA', (282, 306))	('regulation', 'MPA', (143, 153))	('hypermethylated', 'Var', (107, 122))
12242	24204800	It has been reported by several groups that stem cell polycomb group (PcG) target genes are over-represented in the set of genes that show aberrant hypermethylation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('hypermethylation', 'Var', (148, 164))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
12243	24204800	Most studies have used the list of genes with the polycomb occupancy marks of the PRC2 subunits SUZ12 and EED associated with H3K27 methylation in human ES cells from Lee et al 2006 where ~4% (654 of 16,710) genes had all of the 3 marks examined (SUZ12, EED, H3K27) and 9.5% (1591 of 16,710) genes had 1 or more marks.	('SUZ12', 'Gene', '23512', (96, 101))	('H3K27', 'Var', (259, 264))	('human', 'Species', '9606', (147, 152))	('SUZ12', 'Gene', '23512', (247, 252))	('EED', 'Gene', '8726', (106, 109))	('SUZ12', 'Gene', (247, 252))	('EED', 'Gene', '8726', (254, 257))	('SUZ12', 'Gene', (96, 101))	('EED', 'Gene', (106, 109))	('methylation', 'biological_process', 'GO:0032259', ('132', '143'))	('EED', 'Gene', (254, 257))
12245	24204800	A recent study of the module of stem or progenitor cell genes with aberrant hypermethylation and downregulation in cancer noted the prominence of genes involved in neuronal development.	('cancer', 'Disease', (115, 121))	('aberrant hypermethylation', 'Var', (67, 92))	('hypermethylation', 'Var', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('downregulation', 'NegReg', (97, 111))
12247	24204800	De Carvalho et al examined the remaining DNA methylation in DKO cells compared to the parental HCT116 cells as an indicator of the minimum gene methylation, and therefore potential driver epigenetic alterations, necessary for tumor cell survival.	('HCT116', 'CellLine', 'CVCL:0291', (95, 101))	('DNA methylation', 'biological_process', 'GO:0006306', ('41', '56'))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('DNA', 'cellular_component', 'GO:0005574', ('41', '44'))	('methylation', 'Var', (45, 56))	('methylation', 'biological_process', 'GO:0032259', ('144', '155'))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))
12249	24204800	De Carvalho et al noted that many driver genes hypermethylated in the colorectal tumor cells were GPCRs and, while this family of genes is large, it was also significantly overrepresented in our analysis of genes hypermethylated in RCC.	('colorectal tumor', 'Disease', (70, 86))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('RCC', 'Disease', (232, 235))	('hypermethylated', 'Var', (47, 62))	('colorectal tumor', 'Disease', 'MESH:D015179', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
12251	24204800	We performed pairwise comparison between the tumor groups using the beta<0.15 cut-off for genes unmethylated in every tumor of one group but hypermethylated in at least one tumor from the other group.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (118, 123))	('hypermethylated', 'Var', (141, 156))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
12252	24204800	The Wilcoxon test was significant for 538 probes from 497 genes hypermethylated in RCC and unmethylated in oncocytoma (Table S4).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('oncocytoma', 'Disease', 'MESH:D018249', (107, 117))	('hypermethylated', 'Var', (64, 79))	('oncocytoma', 'Disease', (107, 117))
12253	24204800	The oxidation resistance protein 1 (OXR1) gene was hypermethylated in 24/39 (62%) ccRCC and pRCC but unmethylated in chrRCC or oncocytoma (Figure 5).	('pRCC', 'Gene', (92, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('oxidation resistance protein 1', 'Gene', '55074', (4, 34))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('pRCC', 'Gene', '5546', (92, 96))	('RCC', 'Disease', (84, 87))	('OXR1', 'Gene', (36, 40))	('oxidation resistance protein 1', 'Gene', (4, 34))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('oncocytoma', 'Disease', (127, 137))	('protein', 'cellular_component', 'GO:0003675', ('25', '32'))	('OXR1', 'Gene', '55074', (36, 40))	('oncocytoma', 'Disease', 'MESH:D018249', (127, 137))	('hypermethylated', 'Var', (51, 66))
12256	24204800	One top-ranked gene was GRIK1 hypermethylated in 14/25 (56%) ccRCC and unmethylated in oncocytoma (Figure 5).	('RCC', 'Disease', (63, 66))	('oncocytoma', 'Disease', (87, 97))	('oncocytoma', 'Disease', 'MESH:D018249', (87, 97))	('hypermethylated', 'Var', (30, 45))	('GRIK1', 'Gene', (24, 29))	('GRIK1', 'Gene', '2897', (24, 29))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
12259	24204800	The UCHL1 gene previously reported as methylated in RCC was hypermethylated in 4/25 (16%) ccRCC and unmethylated in oncocytoma.	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('hypermethylated', 'Var', (60, 75))	('UCHL1', 'Gene', '7345', (4, 9))	('RCC', 'Disease', (92, 95))	('oncocytoma', 'Disease', 'MESH:D018249', (116, 126))	('oncocytoma', 'Disease', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('UCHL1', 'Gene', (4, 9))
12260	24204800	Sixty genes were hypermethylated in oncocytoma but unmethylated in RCC (Table S6).	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('oncocytoma', 'Disease', (36, 46))	('oncocytoma', 'Disease', 'MESH:D018249', (36, 46))	('hypermethylated', 'Var', (17, 32))
12265	24204800	A further 80 genes were hypermethylated in oncocytoma and unmethylated in 10 chrRCC (Table S6) including RAC2 hypermethylated in 6/25 (24%) of oncocytoma (Figure 6).	('RCC', 'Disease', (80, 83))	('oncocytoma', 'Disease', (43, 53))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('oncocytoma', 'Disease', 'MESH:D018249', (43, 53))	('RAC2', 'Gene', '5880', (105, 109))	('oncocytoma', 'Disease', (143, 153))	('oncocytoma', 'Disease', 'MESH:D018249', (143, 153))	('RAC2', 'Gene', (105, 109))	('hypermethylated', 'Var', (110, 125))
12272	24204800	Top-ranked genes included the FBLIM1 gene, located at chromosome 1p36.21, hypermethylated in 68% (17/25) ccRCC but unmethylated in 10 chrRCC.	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('54', '64'))	('RCC', 'Disease', (107, 110))	('FBLIM1', 'Gene', (30, 36))	('hypermethylated', 'Var', (74, 89))	('FBLIM1', 'Gene', '54751', (30, 36))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))
12275	24204800	The tripartite motif containing 58 (TRIM58) gene was hypermethylated in 13/25 (52%) ccRCC and unmethylated in pRCC (Figure 6).	('hypermethylated', 'Var', (53, 68))	('tripartite motif containing 58', 'Gene', '25893', (4, 34))	('tripartite motif containing 58', 'Gene', (4, 34))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('TRIM58', 'Gene', '25893', (36, 42))	('pRCC', 'Gene', (110, 114))	('TRIM58', 'Gene', (36, 42))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('pRCC', 'Gene', '5546', (110, 114))
12279	24204800	The OXR1 gene was hypermethylated in 12/14 (86%) of pRCC and unmethylated in 10 chrRCC.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('OXR1', 'Gene', (4, 8))	('pRCC', 'Gene', '5546', (52, 56))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('pRCC', 'Gene', (52, 56))	('OXR1', 'Gene', '55074', (4, 8))	('hypermethylated', 'Var', (18, 33))
12280	24204800	The ABCA3 gene was hypermethylated in 8/10 (80%) chrRCC and unmethylated in all 14 pRCC (Figure 6) (Table S7).	('pRCC', 'Gene', '5546', (83, 87))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('hypermethylated', 'Var', (19, 34))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('ABCA3', 'Gene', (4, 9))	('RCC', 'Disease', (84, 87))	('pRCC', 'Gene', (83, 87))	('ABCA3', 'Gene', '21', (4, 9))
12292	24204800	In all RCC, 48 probes were hypomethylated compared with NRP, 18 of which were located within a CpG island and 11 of these within 1 kb of the TSS (Table S10).	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('RCC', 'Disease', (7, 10))	('NRP', 'biological_process', 'GO:0085015', ('56', '59'))	('hypomethylated', 'Var', (27, 41))
12296	24204800	CXCR5 was hypomethylated in 6/25 (24%) ccRCC and 6/14 (43%) pRCC.	('CXCR5', 'Gene', '643', (0, 5))	('pRCC', 'Gene', (60, 64))	('CXCR5', 'Gene', (0, 5))	('pRCC', 'Gene', '5546', (60, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('hypomethylated', 'Var', (10, 24))
12298	24204800	None appeared frequently methylated in RCC compared to NRP.	('RCC', 'Disease', (39, 42))	('NRP', 'biological_process', 'GO:0085015', ('55', '58'))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('methylated', 'Var', (25, 35))
12299	24204800	The most hypermethylated miRNA was miR-564 hypermethylated (ss = 0.63) in 1 ccRCC and unmethylated in NRP (ss = 0.05-0.07).	('NRP', 'biological_process', 'GO:0085015', ('102', '105'))	('miR-564', 'Gene', '693149', (35, 42))	('hypermethylated', 'Var', (43, 58))	('miR-564', 'Gene', (35, 42))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('hypermethylated', 'PosReg', (9, 24))
12309	24204800	Because cancer is generally believed to progress through the sequential accumulation of mutations, more advanced, i.e high grade and high stage RCC, might be expected to show higher frequencies of aberrant promoter methylation and/or may have additional genes methylated.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (88, 97))	('methylation', 'biological_process', 'GO:0032259', ('215', '226'))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('aberrant', 'Var', (197, 205))	('RCC', 'Disease', (144, 147))	('promoter methylation', 'MPA', (206, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
12315	24204800	Between 0.4-1.7% of genes were aberrantly hypermethylated in the renal tumor types, a proportion in line with the number of genes with exonic point mutation in ccRCC and other types of epithelial cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('epithelial cancer', 'Disease', 'MESH:D000077216', (185, 202))	('RCC', 'Disease', (162, 165))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('renal tumor', 'Phenotype', 'HP:0009726', (65, 76))	('aberrantly hypermethylated', 'Var', (31, 57))	('renal tumor', 'Disease', 'MESH:D007674', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('renal tumor', 'Disease', (65, 76))	('epithelial cancer', 'Phenotype', 'HP:0031492', (185, 202))	('epithelial cancer', 'Disease', (185, 202))
12316	24204800	Fewer genes still were commonly methylated (>=5% of tumors).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('methylated', 'Var', (32, 42))
12317	24204800	Furthermore, it seems likely that a proportion of the gene hypermethylation will be passenger rather than driver events in the renal tumor cell.	('renal tumor', 'Disease', 'MESH:D007674', (127, 138))	('hypermethylation', 'Var', (59, 75))	('renal tumor', 'Disease', (127, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('renal tumor', 'Phenotype', 'HP:0009726', (127, 138))
12318	24204800	The majority of genes identified as hypermethylated are novel with several examples of involvement in pathways known to be important in RCC.	('involvement', 'Reg', (87, 98))	('hypermethylated', 'Var', (36, 51))	('pathways', 'Pathway', (102, 110))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
12319	24204800	Novel pathways of metabolism, signal transduction and GPCRs, tissue response to injury, stem cell development and EMT are implicated by aberrant gene methylation.	('aberrant gene methylation', 'Var', (136, 161))	('stem cell development', 'CPA', (88, 109))	('EMT', 'CPA', (114, 117))	('signal transduction', 'biological_process', 'GO:0007165', ('30', '49'))	('injury', 'Disease', (80, 86))	('stem cell development', 'biological_process', 'GO:0048864', ('88', '109'))	('metabolism', 'biological_process', 'GO:0008152', ('18', '28'))	('injury', 'Disease', 'MESH:D058186', (80, 86))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))	('EMT', 'biological_process', 'GO:0001837', ('114', '117'))
12320	24204800	Functional validation of hypermethylated genes will first require evidence of association of hypermethylation with down-regulation of transcription in tumor cells and further analysis by standard growth and invasion assays will be necessary to provide support for a role in the biology of RCC.	('RCC', 'Disease', (289, 292))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('transcription', 'MPA', (134, 147))	('RCC', 'Disease', 'MESH:C538614', (289, 292))	('down-regulation', 'NegReg', (115, 130))	('hypermethylation', 'Var', (93, 109))	('tumor', 'Disease', (151, 156))	('transcription', 'biological_process', 'GO:0006351', ('134', '147'))	('regulation', 'biological_process', 'GO:0065007', ('120', '130'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
12326	24204800	Because there is no defined precursor of RCC, aberrantly hypermethylated genes in small T1a tumors likely represent early events in the development of RCC.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('RCC', 'Disease', (151, 154))	('aberrantly hypermethylated genes', 'Var', (46, 78))	('RCC', 'Disease', (41, 44))	('tumors', 'Disease', (92, 98))
12327	24204800	Because RCC is generally only curable if detected before metastasis, we and others have previously demonstrated sensitive and specific detection of aberrant gene hypermethylation in urine and blood from patients with RCC as a strategy for early detection.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (8, 11))	('RCC', 'Disease', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('aberrant gene hypermethylation', 'Var', (148, 178))	('patients', 'Species', '9606', (203, 211))
12335	24204800	CIMP-positive RCC, may indicate subsets of patients as candidates for epigenetic therapy.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('patients', 'Species', '9606', (43, 51))	('CIMP-positive', 'Var', (0, 13))	('CIMP', 'Chemical', '-', (0, 4))
12460	30740580	Although being T2 hypointense may mimic a pRCC, the specificity and accuracy for discriminating angiomyolipoma from RCC using T2 hypointensity combined with the enhancement pattern has been described as 99% and 96%, respectively.	('pRCC', 'Gene', '5546', (42, 46))	('T2 hypointensity', 'Var', (126, 142))	('angiomyolipoma', 'Disease', (96, 110))	('angiomyolipoma', 'Disease', 'MESH:D018207', (96, 110))	('angiomyolipoma', 'Phenotype', 'HP:0006772', (96, 110))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('pRCC', 'Gene', (42, 46))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
12501	21057600	The most common subtypes seen preferentially in children are the translocation-associated tumors, papillary renal cell carcinoma, renal medullary carcinoma, and oncocytic renal cell carcinoma following neuroblastoma.	('translocation-associated', 'Var', (65, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('neuroblastoma', 'Phenotype', 'HP:0003006', (202, 215))	('renal medullary carcinoma', 'Disease', 'MESH:D007681', (130, 155))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (171, 191))	('renal medullary carcinoma', 'Disease', (130, 155))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (98, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (98, 128))	('children', 'Species', '9606', (48, 56))	('oncocytic renal cell carcinoma', 'Phenotype', 'HP:0006770', (161, 191))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('oncocytic renal cell carcinoma following neuroblastoma', 'Disease', 'MESH:C538614', (161, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('papillary renal cell carcinoma', 'Disease', (98, 128))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))
12521	21057600	Furthermore, the histologic spectrum that may be seen in all the translocation variants is quite broad, even within individual tumors (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('translocation', 'Var', (65, 78))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
12535	21057600	Translocation-RCCs may also have a histologic appearance that is remarkably similar to epithelioid angiomyolipomas.	('Translocation-RCCs', 'Var', (0, 18))	('epithelioid angiomyolipomas', 'Disease', 'MESH:D018207', (87, 114))	('epithelioid angiomyolipomas', 'Phenotype', 'HP:0006772', (87, 114))	('epithelioid angiomyolipomas', 'Disease', (87, 114))
12543	21057600	However, some TFE3/PRCC translocation-associated RCC contain relatively little cytoplasm and demonstrate a more consolidated, homogeneous histology that may overlap with that of type 2 PRCC.	('RCC', 'Disease', (49, 52))	('PRCC', 'Gene', '5546', (185, 189))	('TFE3', 'Gene', '7030', (14, 18))	('cytoplasm', 'cellular_component', 'GO:0005737', ('79', '88'))	('PRCC', 'Gene', (185, 189))	('PRCC', 'Gene', (19, 23))	('PRCC', 'Gene', '5546', (19, 23))	('TFE3', 'Gene', (14, 18))	('translocation-associated', 'Var', (24, 48))
12574	21057600	Seventy-five per cent (24/32) presented with disease limited to the kidney, and 22 of the 24 were free of disease; death from disease occurred in one T2N0MX tumor and the other died from other causes.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('T2N0MX', 'Var', (150, 156))	('death', 'Disease', 'MESH:D003643', (115, 120))	('death', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
12575	21057600	Of the remaining eight patients with higher stage disease, three (T4N0MX, T3N1M0, T2,N2,M0) died of their disease.	('T3N1M0', 'Var', (74, 80))	('patients', 'Species', '9606', (23, 31))	('T4N0MX', 'Var', (66, 72))
12584	21057600	Translocation-associated renal cell carcinoma   Tubular, papillary, or tubulopapillary architecture positivity for EMA, RCC antigen, AMACR, CD10 negativity for TFE3 Type 1: Low-grade nuclear cytology, scant cytoplasm; diffuse positivity for cytokeratin 7.	('EMA', 'Gene', '4582', (115, 118))	('TFE3', 'Gene', (160, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 45))	('AMACR', 'Gene', (133, 138))	('Translocation-associated', 'Var', (0, 24))	('cytoplasm', 'cellular_component', 'GO:0005737', ('207', '216'))	('cytokeratin 7', 'Gene', '3855', (241, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('EMA', 'Gene', (115, 118))	('renal cell carcinoma', 'Disease', (25, 45))	('TFE3', 'Gene', '7030', (160, 164))	('AMACR', 'Gene', '23600', (133, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('CD10', 'molecular_function', 'GO:0004245', ('140', '144'))	('CD10', 'Gene', '4311', (140, 144))	('cytokeratin 7', 'Gene', (241, 254))	('CD10', 'Gene', (140, 144))
12588	33977078	Papillary Renal Cell Carcinoma in Lynch/Muir-Torre Syndrome with Germline Pathogenic Variant in MSH6 and Molecular Analysis: Report of a Case and Review of the Literature Lynch syndrome (LS) is an autosomal dominant inherited disorder due to pathogenic variations in the mismatch repair genes, which predisposes to malignancies, most commonly colon and endometrial carcinoma.	('Lynch syndrome', 'Disease', (171, 185))	('Variant', 'Var', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('endometrial carcinoma', 'Disease', (353, 374))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (10, 30))	('Carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('Papillary Renal Cell Carcinoma', 'Disease', (0, 30))	('Lynch syndrome', 'Disease', 'MESH:D003123', (171, 185))	('autosomal dominant inherited disorder', 'Disease', 'MESH:D030342', (197, 234))	('colon', 'Disease', (343, 348))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (353, 374))	('Papillary Renal Cell Carcinoma', 'Phenotype', 'HP:0006766', (0, 30))	('autosomal dominant inherited disorder', 'Disease', (197, 234))	('MSH6', 'Gene', (96, 100))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (353, 374))	('variations', 'Var', (253, 263))	('malignancies', 'Disease', 'MESH:D009369', (315, 327))	('mismatch repair', 'biological_process', 'GO:0006298', ('271', '286'))	('mismatch repair genes', 'Gene', (271, 292))	('malignancies', 'Disease', (315, 327))	('Papillary Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (0, 30))	('MSH6', 'Gene', '2956', (96, 100))
12593	33977078	The LS was diagnosed when he presented with multiple sebaceous adenomas and genetic testing showed a pathogenic variant in MSH6 mismatch repair gene.	('MSH6', 'Gene', '2956', (123, 127))	('pathogenic', 'Reg', (101, 111))	('sebaceous adenoma', 'Phenotype', 'HP:0009720', (53, 70))	('sebaceous adenomas', 'Phenotype', 'HP:0009720', (53, 71))	('variant', 'Var', (112, 119))	('MSH6', 'Gene', (123, 127))	('adenomas', 'Disease', 'MESH:D000236', (63, 71))	('mismatch repair', 'biological_process', 'GO:0006298', ('128', '143'))	('adenomas', 'Disease', (63, 71))
12601	33977078	These tumors showed MLH1 mutation most commonly, unlike the urothelial malignancies in LS which involve MSH2.	('urothelial malignancies', 'Disease', (60, 83))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (25, 33))	('tumors', 'Disease', (6, 12))	('MLH1', 'Gene', (20, 24))	('MSH2', 'Gene', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('MSH2', 'Gene', '4436', (104, 108))	('urothelial malignancies', 'Disease', 'MESH:D009369', (60, 83))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
12602	33977078	Among the 4 cases of RCC with MSH6 mutation, three were in females, indicating some gender differences.	('MSH6', 'Gene', '2956', (30, 34))	('mutation', 'Var', (35, 43))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('MSH6', 'Gene', (30, 34))
12604	33977078	It is associated with germline pathogenic variants in the DNA mismatch repair (MMR) genes including MLH1 (mutL homolog 1), MSH2/MSH6 (mutS homolog 2 or 6), and PMS2 (PMS1 homologue 2).	('PMS1 homologue 2', 'Gene', (166, 182))	('MSH2', 'Gene', (123, 127))	('DNA', 'Gene', (58, 61))	('MSH2', 'Gene', '4436', (123, 127))	('associated', 'Reg', (6, 16))	('MSH6', 'Gene', (128, 132))	('variants', 'Var', (42, 50))	('mismatch repair', 'biological_process', 'GO:0006298', ('62', '77'))	('DNA', 'cellular_component', 'GO:0005574', ('58', '61'))	('mutL homolog 1', 'Gene', '4292', (106, 120))	('MMR', 'biological_process', 'GO:0006298', ('79', '82'))	('MSH6', 'Gene', '2956', (128, 132))	('PMS2', 'Gene', (160, 164))	('mutL homolog 1', 'Gene', (106, 120))	('PMS2', 'Gene', '5395', (160, 164))	('MLH1', 'Gene', (100, 104))	('PMS1 homologue 2', 'Gene', '5395;5378', (166, 182))	('MMR', 'Gene', (79, 82))
12605	33977078	Rarely, it can also be caused by a deletion in the EPCAM (epithelial cell adhesion molecule) gene, which leads to epigenetic silencing of MSH2.	('epigenetic silencing', 'MPA', (114, 134))	('cell adhesion', 'biological_process', 'GO:0007155', ('69', '82'))	('EPCAM', 'Gene', '4072', (51, 56))	('epithelial cell adhesion molecule', 'Gene', (58, 91))	('caused by', 'Reg', (23, 32))	('epithelial cell adhesion molecule', 'Gene', '4072', (58, 91))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('69', '91'))	('MSH2', 'Gene', (138, 142))	('MSH2', 'Gene', '4436', (138, 142))	('EPCAM', 'Gene', (51, 56))	('deletion', 'Var', (35, 43))
12608	33977078	The routine screening for genetic colorectal adenocarcinoma by immunohistochemistry (IHC) and/or Microsatellite instability (MSI) testing has led to better detection and an increased understanding of LS.	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('Microsatellite', 'Var', (97, 111))	('colorectal adenocarcinoma', 'Disease', (34, 59))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (34, 59))
12610	33977078	Most commonly, the germline defect involves pathogenic variants in MLH1 or MSH2 genes.	('MLH1', 'Gene', (67, 71))	('MSH2', 'Gene', (75, 79))	('variants', 'Var', (55, 63))	('MSH2', 'Gene', '4436', (75, 79))	('pathogenic', 'Reg', (44, 54))	('germline defect', 'Disease', (19, 34))
12612	33977078	Although LS and MTS share a defect in one of the 4 MMR genes, a few studies have shown that the frequency of the MMR defect in patients with MTS mostly involves MSH2.	('defect', 'Var', (117, 123))	('MSH2', 'Gene', (161, 165))	('MSH2', 'Gene', '4436', (161, 165))	('patients', 'Species', '9606', (127, 135))	('MMR', 'biological_process', 'GO:0006298', ('113', '116'))	('MMR', 'biological_process', 'GO:0006298', ('51', '54'))
12614	33977078	Recent studies have shown increased frequency of pathogenic variants in MSH2 in urological malignancies.	('malignancies', 'Disease', (91, 103))	('MSH2', 'Gene', (72, 76))	('MSH2', 'Gene', '4436', (72, 76))	('malignancies', 'Disease', 'MESH:D009369', (91, 103))	('variants', 'Var', (60, 68))
12617	33977078	Here, we encountered a case of papillary RCC (PRCC) in a LS/MTS patient with germline MSH6 pathogenic variant.	('patient', 'Species', '9606', (64, 71))	('MSH6', 'Gene', (86, 90))	('papillary RCC', 'Disease', 'MESH:C538614', (31, 44))	('PRCC', 'Gene', '5546', (46, 50))	('papillary RCC', 'Disease', (31, 44))	('variant', 'Var', (102, 109))	('MSH6', 'Gene', '2956', (86, 90))	('PRCC', 'Gene', (46, 50))
12622	33977078	Genetic testing showed a pathogenic variant in MSH6 Exon 9 (c.3980_3983, dupATCA (p.L1330Vfs'12)).	('p.L1330V', 'SUBSTITUTION', 'None', (82, 90))	('dupATCA', 'Disease', (73, 80))	('p.L1330V', 'Var', (82, 90))	('MSH6', 'Gene', '2956', (47, 51))	('c.3980_3983', 'Var', (60, 71))	('MSH6', 'Gene', (47, 51))	('c.3980_3983, dupATCA', 'Mutation', 'rs267608121', (60, 80))	('pathogenic', 'Reg', (25, 35))
12623	33977078	In addition a heterozygous novel variant of uncertain significance (c.8419A>G(p.T2807A) in the APC gene was also detected.	('c.8419A>G', 'Mutation', 'rs147287751', (68, 77))	('APC', 'Disease', (95, 98))	('APC', 'cellular_component', 'GO:0005680', ('95', '98'))	('p.T2807A', 'Mutation', 'rs894164638', (78, 86))	('c.8419A>G', 'Var', (68, 77))	('APC', 'Disease', 'MESH:D011125', (95, 98))
12624	33977078	Since he did not have the typical presentation of polyposis and lack of certainty regarding pathogenicity of the APC variant as well as presence of pathogenic variant in the MSH6 gene, a diagnosis of LS was made.	('APC', 'Disease', 'MESH:D011125', (113, 116))	('APC', 'cellular_component', 'GO:0005680', ('113', '116'))	('MSH6', 'Gene', '2956', (174, 178))	('APC', 'Disease', (113, 116))	('variant', 'Var', (117, 124))	('variant', 'Var', (159, 166))	('MSH6', 'Gene', (174, 178))
12626	33977078	The subsequent subtotal colectomy showed a T3N0 mucin-producing adenocarcinoma in the cecum.	('adenocarcinoma', 'Disease', (64, 78))	('T3N0', 'Var', (43, 47))	('mucin', 'Gene', (48, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('mucin', 'Gene', '100508689', (48, 53))
12650	33977078	The genomic abnormalities included ARID1A S90fs*11, MSH6 L1330fs*12, SETD2 N1725fs*3, and STAG2 E143fs*3.	('S90fs', 'Mutation', 'p.S90fsX', (42, 47))	('S90fs*11', 'Var', (42, 50))	('E143fs', 'Mutation', 'p.E143fsX', (96, 102))	('MSH6', 'Gene', (52, 56))	('STAG2', 'Gene', (90, 95))	('STAG2', 'Gene', '10735', (90, 95))	('MSH6', 'Gene', '2956', (52, 56))	('SETD2', 'Gene', '29072', (69, 74))	('ARID1A', 'Gene', '8289', (35, 41))	('ARID1A', 'Gene', (35, 41))	('SETD2', 'Gene', (69, 74))	('N1725fs*3', 'Var', (75, 84))	('L1330fs*12', 'Var', (57, 67))	('E143fs*3', 'Var', (96, 104))
12651	33977078	In addition, variants of unknown significance (VUS) were detected in the tumor.	('variants', 'Var', (13, 21))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
12654	33977078	There has been an increasing understanding of LS attributed to pathogenic variants in one of the four mismatch repair (MMR) genes, namely, MLH1, MSH2, MSH6, and PMS2.	('PMS2', 'Gene', (161, 165))	('MLH1', 'Gene', (139, 143))	('PMS2', 'Gene', '5395', (161, 165))	('MSH6', 'Gene', '2956', (151, 155))	('MMR', 'Gene', (119, 122))	('mismatch repair', 'biological_process', 'GO:0006298', ('102', '117'))	('variants', 'Var', (74, 82))	('MMR', 'biological_process', 'GO:0006298', ('119', '122'))	('MSH2', 'Gene', (145, 149))	('MSH6', 'Gene', (151, 155))	('MSH2', 'Gene', '4436', (145, 149))
12656	33977078	These include three dinucleotide repeats (D2S123, D5S346, and D17S250) and two mononucleotide repeats (BAT25, BAT26).	('dinucleotide', 'Chemical', 'MESH:D015226', (20, 32))	('D5S346', 'Var', (50, 56))	('mononucleotide', 'Chemical', '-', (79, 93))	('D17S250', 'Var', (62, 69))	('D2S123', 'Var', (42, 48))
12671	33977078	Unlike the upper tract urothelial carcinoma, which are more commonly associated with MSH2 variants, RCC was associated with MLH1 variants, which was seen in 16 cases (57.1%).	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('MSH2', 'Gene', (85, 89))	('MSH2', 'Gene', '4436', (85, 89))	('urothelial carcinoma', 'Disease', (23, 43))	('associated', 'Reg', (69, 79))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('variants', 'Var', (90, 98))	('associated', 'Reg', (108, 118))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (23, 43))	('MLH1', 'Gene', (124, 128))	('RCC', 'Disease', (100, 103))	('variants', 'Var', (129, 137))
12672	33977078	Variants in MSH2 were seen in 7 cases (25%) and in MSH6 in 4 cases (14.8%).	('MSH2', 'Gene', '4436', (12, 16))	('Variants', 'Var', (0, 8))	('MSH6', 'Gene', '2956', (51, 55))	('seen', 'Reg', (22, 26))	('MSH2', 'Gene', (12, 16))	('MSH6', 'Gene', (51, 55))
12673	33977078	Interestingly, three out of four patients with the MSH6 variants were females.	('variants', 'Var', (56, 64))	('patients', 'Species', '9606', (33, 41))	('MSH6', 'Gene', (51, 55))	('MSH6', 'Gene', '2956', (51, 55))
12676	33977078	Abnormalities in the MSH6 gene were first discovered in studies involving hereditary nonpolyposis colorectal cancers, from 5 Japanese families who did not fulfill the Amsterdam criteria and had no pathogenic variants in MLH1 and MSH2 but had a family history of endometrial and ovarian cancers.	('MSH2', 'Gene', '4436', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancers', 'Phenotype', 'HP:0100615', (278, 293))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('MSH6', 'Gene', '2956', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('MLH1', 'Gene', (220, 224))	('variants', 'Var', (208, 216))	('hereditary nonpolyposis colorectal cancers', 'Disease', (74, 116))	('MSH6', 'Gene', (21, 25))	('hereditary nonpolyposis colorectal cancers', 'Disease', 'MESH:D003123', (74, 116))	('endometrial and ovarian cancers', 'Disease', 'MESH:D004714', (262, 293))	('MSH2', 'Gene', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))
12679	33977078	When a pathogenic variant in the MSH6 gene is suspected, a panel of five mononucleotides (NR21, BAT25, BAT26, NR24, and NR22) is recommended to assess the MSI status.	('MSH6', 'Gene', (33, 37))	('men', 'Species', '9606', (134, 137))	('mononucleotides', 'Chemical', '-', (73, 88))	('pathogenic', 'Reg', (7, 17))	('MSH6', 'Gene', '2956', (33, 37))	('variant', 'Var', (18, 25))
12680	33977078	There have been relatively few publications of isolated MSH6 variants.	('MSH6', 'Gene', (56, 60))	('MSH6', 'Gene', '2956', (56, 60))	('variants', 'Var', (61, 69))
12681	33977078	A large study of 113 families with MSH6 variant carriers from multiple countries has shown some differences in presentations and in malignancies associated with MSH6.	('variant', 'Var', (40, 47))	('MSH6', 'Gene', '2956', (161, 165))	('MSH6', 'Gene', (35, 39))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('presentations', 'MPA', (111, 124))	('MSH6', 'Gene', '2956', (35, 39))	('MSH6', 'Gene', (161, 165))	('malignancies', 'Disease', (132, 144))
12683	33977078	These studies suggest long-term screening requirement for patients with the MSH6 pathogenic variant.	('men', 'Species', '9606', (49, 52))	('MSH6', 'Gene', (76, 80))	('variant', 'Var', (92, 99))	('MSH6', 'Gene', '2956', (76, 80))	('patients', 'Species', '9606', (58, 66))
12684	33977078	Endometrial carcinoma is the most common presentation among women with pathogenic variants in this gene, and the women have a sixfold increased incidence of other cancers associated with LS including ovary, stomach, kidney, ureter, or brain.	('variants', 'Var', (82, 90))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('brain', 'Disease', (235, 240))	('Endometrial carcinoma', 'Disease', 'MESH:D016889', (0, 21))	('women', 'Species', '9606', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('stomach', 'Disease', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('kidney', 'Disease', (216, 222))	('ureter', 'Disease', (224, 230))	('women', 'Species', '9606', (113, 118))	('Endometrial carcinoma', 'Phenotype', 'HP:0012114', (0, 21))	('ovary', 'Disease', (200, 205))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('Endometrial carcinoma', 'Disease', (0, 21))
12686	33977078	The reported studies also show occurrence of other malignancies such as lymphoma, leukemia, Langerhan's cell histiocytosis, and testicular germ cell tumors with MSH6 variants.	("Langerhan's cell histiocytosis", 'Disease', (92, 122))	('leukemia', 'Disease', (82, 90))	('lymphoma', 'Phenotype', 'HP:0002665', (72, 80))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('lymphoma', 'Disease', 'MESH:D008223', (72, 80))	('MSH6', 'Gene', '2956', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('lymphoma', 'Disease', (72, 80))	('variants', 'Var', (166, 174))	('malignancies', 'Disease', (51, 63))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('histiocytosis', 'Phenotype', 'HP:0100727', (109, 122))	('germ cell tumors', 'Phenotype', 'HP:0100728', (139, 155))	('MSH6', 'Gene', (161, 165))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('leukemia', 'Disease', 'MESH:D007938', (82, 90))
12687	33977078	These studies suggest a different set of malignancies must be considered in the screening of patients with MSH6 pathogenic variant.	('malignancies', 'Disease', 'MESH:D009369', (41, 53))	('MSH6', 'Gene', (107, 111))	('variant', 'Var', (123, 130))	('malignancies', 'Disease', (41, 53))	('MSH6', 'Gene', '2956', (107, 111))	('patients', 'Species', '9606', (93, 101))
12688	33977078	There were six cases of kidney tumors in the study of pure MSH6 variants by Baglietto et al., but the type of tumor, whether urothelial carcinoma or RCC, was not specified.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('kidney tumors', 'Disease', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('not specified', 'Species', '32644', (158, 171))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (125, 145))	('pure', 'molecular_function', 'GO:0034023', ('54', '58'))	('variants', 'Var', (64, 72))	('MSH6', 'Gene', (59, 63))	('urothelial carcinoma', 'Disease', (125, 145))	('MSH6', 'Gene', '2956', (59, 63))	('kidney tumors', 'Disease', 'MESH:D007680', (24, 37))	('RCC', 'Disease', (149, 152))	('tumor', 'Disease', (31, 36))	('kidney tumors', 'Phenotype', 'HP:0009726', (24, 37))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
12691	33977078	Similarly, in our review, there were four RCCs associated with MSH6 variants including the current case.	('MSH6', 'Gene', (63, 67))	('variants', 'Var', (68, 76))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('MSH6', 'Gene', '2956', (63, 67))	('RCC', 'Disease', (42, 45))
12693	33977078	This current report is the only case of PRCC in a male with MTS and a pathogenic variant in MSH6.	('PRCC', 'Gene', '5546', (40, 44))	('variant', 'Var', (81, 88))	('MSH6', 'Gene', (92, 96))	('PRCC', 'Gene', (40, 44))	('MSH6', 'Gene', '2956', (92, 96))
12696	33977078	However, the loss of expression of the MSH6 protein by IHC and the MSH6 variant in this papillary tumor as confirmed by the tumor NGS analysis, confirms this to be definitively associated with MSH6.	('tumor', 'Disease', (124, 129))	('MSH6', 'Gene', (39, 43))	('tumor', 'Disease', (98, 103))	('variant', 'Var', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('MSH6', 'Gene', '2956', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('papillary tumor', 'Disease', 'MESH:D002291', (88, 103))	('papillary tumor', 'Disease', (88, 103))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MSH6', 'Gene', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('MSH6', 'Gene', '2956', (193, 197))	('MSH6', 'Gene', (67, 71))	('protein', 'Protein', (44, 51))	('MSH6', 'Gene', '2956', (67, 71))	('expression', 'MPA', (21, 31))	('loss', 'NegReg', (13, 17))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
12699	33977078	In one case with LS due to the MSH2 variant, loss of the MSH2 expression and MSI were present in the colon, ureter, and cervical adenocarcinoma, but the PRCC of the kidney was microsatellite stable and did not show any loss of the MMR proteins.	('adenocarcinoma', 'Disease', (129, 143))	('variant', 'Var', (36, 43))	('MSH2', 'Gene', '4436', (57, 61))	('MSH2', 'Gene', '4436', (31, 35))	('expression', 'MPA', (62, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('PRCC', 'Gene', '5546', (153, 157))	('MSH2', 'Gene', (31, 35))	('MSI', 'MPA', (77, 80))	('loss', 'NegReg', (45, 49))	('MMR', 'biological_process', 'GO:0006298', ('231', '234'))	('PRCC', 'Gene', (153, 157))	('MSH2', 'Gene', (57, 61))
12704	33977078	Our case is the first report of PRCC associated with pathogenic variants in MSH6 in LS/MTS.	('MSH6', 'Gene', (76, 80))	('PRCC', 'Gene', '5546', (32, 36))	('MSH6', 'Gene', '2956', (76, 80))	('associated', 'Reg', (37, 47))	('PRCC', 'Gene', (32, 36))	('variants', 'Var', (64, 72))
12705	33977078	The MSH6 abnormality (L1330fs*12) was also seen in the papillary carcinoma.	('L1330fs*12', 'Var', (22, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('papillary carcinoma', 'Disease', (55, 74))	('MSH6', 'Gene', '2956', (4, 8))	('papillary carcinoma', 'Disease', 'MESH:D002291', (55, 74))	('MSH6', 'Gene', (4, 8))
12706	33977078	Other abnormalities included ARID1A S90fs*11, SETD2 N1725fs*3, and STAG2 E143fs*3.	('SETD2', 'Gene', (46, 51))	('S90fs*11', 'Var', (36, 44))	('N1725fs*3', 'Var', (52, 61))	('E143fs', 'Mutation', 'p.E143fsX', (73, 79))	('E143fs*3', 'Var', (73, 81))	('SETD2', 'Gene', '29072', (46, 51))	('S90fs', 'Mutation', 'p.S90fsX', (36, 41))	('ARID1A', 'Gene', '8289', (29, 35))	('STAG2', 'Gene', (67, 72))	('STAG2', 'Gene', '10735', (67, 72))	('ARID1A', 'Gene', (29, 35))
12720	33977078	The MiT family translocation carcinomas include tumors with gene fusions involving the TFE3 or TFEB locus.	('TFE3', 'Gene', '7030', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('carcinomas', 'Disease', 'MESH:D009369', (29, 39))	('TFEB', 'Gene', '7942', (95, 99))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TFEB', 'Gene', (95, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('carcinomas', 'Disease', (29, 39))	('gene fusions', 'Var', (60, 72))	('TFE3', 'Gene', (87, 91))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
12731	33977078	The next-generation sequencing of 10 of these tumors performed by the same group showed KRAS missense variants in eight tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('KRAS', 'Gene', (88, 92))	('KRAS', 'Gene', '3845', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (46, 52))	('missense variants', 'Var', (93, 110))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
12733	33977078	One case of GATA3-positive papillary renal neoplasm with reverse polarity with KRAS and PIK3CA mutation is also described by Lee et al..	('PIK3CA', 'Gene', '5290', (88, 94))	('KRAS', 'Gene', '3845', (79, 83))	('GATA3', 'Gene', (12, 17))	('papillary renal neoplasm', 'Disease', (27, 51))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (27, 51))	('renal neoplasm', 'Phenotype', 'HP:0009726', (37, 51))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (27, 51))	('GATA3', 'Gene', '2625', (12, 17))	('PIK3CA', 'Gene', (88, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('KRAS', 'Gene', (79, 83))	('mutation', 'Var', (95, 103))
12734	33977078	Similarly, KRAS mutations were also observed by Kim and Tong et al.	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))
12735	33977078	who have described KRAS mutations in papillary renal neoplasm with reverse polarity, but GATA3 immunohistochemical stain was not performed in these two studies.	('GATA3', 'Gene', '2625', (89, 94))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (37, 61))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (37, 61))	('KRAS', 'Gene', (19, 23))	('renal neoplasm', 'Phenotype', 'HP:0009726', (47, 61))	('KRAS', 'Gene', '3845', (19, 23))	('GATA3', 'Gene', (89, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (53, 61))	('mutations', 'Var', (24, 33))	('papillary renal neoplasm', 'Disease', (37, 61))
12738	33977078	These studies indicate that the KRAS mutation is seen in oncocytic papillary neoplasms.	('seen', 'Reg', (49, 53))	('mutation', 'Var', (37, 45))	('neoplasms', 'Phenotype', 'HP:0002664', (77, 86))	('KRAS', 'Gene', (32, 36))	('oncocytic papillary neoplasms', 'Disease', (57, 86))	('oncocytic papillary neoplasms', 'Disease', 'MESH:C535584', (57, 86))	('KRAS', 'Gene', '3845', (32, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (77, 85))
12741	33977078	Interestingly, a KRAS variant was detected in this tumor as in papillary tumors with reverse polarity.	('papillary tumors', 'Disease', (63, 79))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('variant', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (51, 56))	('papillary tumors', 'Phenotype', 'HP:0007482', (63, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (73, 78))	('KRAS', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('KRAS', 'Gene', '3845', (17, 21))	('papillary tumors', 'Disease', 'MESH:D002291', (63, 79))
12745	33977078	The presence of KRAS mutation in this tumor suggests that this mutation may not be restricted to the papillary renal neoplasm with reverse polarity and this entity should be better defined with the study of large number of cases.	('renal neoplasm', 'Phenotype', 'HP:0009726', (111, 125))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('papillary renal neoplasm', 'Disease', 'MESH:D007681', (101, 125))	('neoplasm', 'Phenotype', 'HP:0002664', (117, 125))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('KRAS', 'Gene', (16, 20))	('papillary renal neoplasm', 'Disease', (101, 125))	('KRAS', 'Gene', '3845', (16, 20))	('papillary renal neoplasm', 'Phenotype', 'HP:0006766', (101, 125))
12757	33977078	We describe the first case of PRCC in a patient with Lynch/MTS with the MSH6 pathogenic variant.	('patient', 'Species', '9606', (40, 47))	('PRCC', 'Gene', (30, 34))	('MSH6', 'Gene', (72, 76))	('variant', 'Var', (88, 95))	('MSH6', 'Gene', '2956', (72, 76))	('PRCC', 'Gene', '5546', (30, 34))
12759	33977078	There was also KRAS mutation, but the tumor was microsatellite stable.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('KRAS', 'Gene', (15, 19))	('mutation', 'Var', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('KRAS', 'Gene', '3845', (15, 19))
12940	25357116	Germline mutation in the fumarate hydratase gene is the underlying genetic alteration of hereditary leiomyomatosis and RCC.	('hereditary leiomyomatosis', 'Disease', (89, 114))	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (89, 114))	('fumarate hydratase', 'Gene', '2271', (25, 43))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('fumarate hydratase', 'Gene', (25, 43))	('Germline mutation', 'Var', (0, 17))
12950	25357116	A number of translocations involving TFE3 resulting in fusion with other genes have been reported.	('TFE3', 'Gene', '7030', (37, 41))	('TFE3', 'Gene', (37, 41))	('fusion', 'Interaction', (55, 61))	('translocations', 'Var', (12, 26))
12960	25357116	In a study by Martignoni et al,  cathepsin K immunoreactivity was demonstrated in 60% of Xp11.2 and 100% of t(6;11) carcinomas, and not seen in other types of RCC.	('carcinomas', 'Disease', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('Xp11.2', 'Var', (89, 95))	('cathepsin K', 'Gene', '1513', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('cathepsin K', 'Gene', (33, 44))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
12964	25357116	Molecularly, t(6;11) carcinoma is less heterogeneous than Xp11.2, and the underlying abnormality is alpha-TFEB gene fusion.	('alpha-TFEB', 'Gene', '7942', (100, 110))	('carcinoma', 'Disease', (21, 30))	('gene fusion', 'Var', (111, 122))	('carcinoma', 'Disease', 'MESH:D002277', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('alpha-TFEB', 'Gene', (100, 110))
12990	17645803	Epigenetic alterations and gene promoter hypermethylation in particular, provide an emerging class of cancer biomarkers, holding the promise of sensitive and accurate disease detection even at the earliest stages.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))
12991	17645803	The power of epigenetic markers for molecular detection of the most common urological malignancy (i.e., prostate cancer) has been demonstrated in previous studies from our research team and others.	('malignancy', 'Disease', 'MESH:D009369', (86, 96))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('epigenetic markers', 'Var', (13, 31))	('malignancy', 'Disease', (86, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
12993	17645803	Thus, it might be stated that the discovery of methylation markers in RCC provides an attractive and still largely unexplored field for biomedical research.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('methylation', 'Var', (47, 58))	('RCC', 'Disease', (70, 73))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))
13024	17645803	However, RASSF1A methylation stands as the most distinctive feature of pRCC in this epigenetic profile.	('pRCC', 'Gene', (71, 75))	('methylation', 'Var', (17, 28))	('pRCC', 'Gene', '5546', (71, 75))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RASSF1A', 'Gene', (9, 16))	('RASSF1A', 'Gene', '11186', (9, 16))
13039	17645803	Whereas we confirmed the high RASSF1A promoter methylation levels in pRCC previously reported by Gonzalgo and co-workers, we additionally found that PTGS2 promoter methylation as a likely candidate marker for ccRCC, something that might permit a more accurate detection of this tumor type in limited tissue or needle-aspirate samples.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('RCC', 'Disease', (70, 73))	('RCC', 'Disease', (211, 214))	('PTGS2', 'Gene', '5743', (149, 154))	('PTGS', 'biological_process', 'GO:0016441', ('149', '153'))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('methylation', 'biological_process', 'GO:0032259', ('164', '175'))	('methylation', 'Var', (164, 175))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('pRCC', 'Gene', '5546', (69, 73))	('promoter methylation levels', 'MPA', (38, 65))	('marker', 'Reg', (198, 204))	('tumor', 'Disease', (278, 283))	('PTGS2', 'Gene', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('RASSF1A', 'Gene', '11186', (30, 37))	('pRCC', 'Gene', (69, 73))	('methylation', 'biological_process', 'GO:0032259', ('47', '58'))	('RASSF1A', 'Gene', (30, 37))
13050	17645803	Based on these findings, we are tempted to speculate that, at least in some cases, morphologically normal renal tissue might acquire aberrant methylation (eventually age-related) at some gene promoters owing to a "field-effect" phenomenon, with additional epigenetic or cytogenetic alterations then fostering tumor development.	('tumor', 'Disease', (309, 314))	('fostering', 'PosReg', (299, 308))	('methylation', 'biological_process', 'GO:0032259', ('142', '153'))	('methylation', 'MPA', (142, 153))	('epigenetic', 'Var', (256, 266))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('men', 'Species', '9606', (322, 325))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('men', 'Species', '9606', (233, 236))
13089	32340156	Thus, we sought to uncover the effect of lactate in epigenetic modulation of RCC aggressiveness, as well as the ability to epigenetically modulate adjacent normal cells.	('RCC aggressiveness', 'Disease', (77, 95))	('RCC aggressiveness', 'Disease', 'MESH:C538614', (77, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (81, 95))	('lactate', 'Chemical', 'MESH:D019344', (41, 48))	('epigenetic', 'Var', (52, 62))
13165	32340156	In addition, NAM promoted a decrease on global sirtuin activity in RCC, except for Caki2 cell line and normal kidney cells (Figure S2C).	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('decrease', 'NegReg', (28, 36))	('NAM', 'Var', (13, 16))	('NAM', 'Chemical', 'MESH:D009536', (13, 16))	('global sirtuin activity', 'MPA', (40, 63))
13203	32340156	In fact, it has been demonstrated that high lactate levels are associated with higher incidence of distant metastasis in different cancer types, although the mechanism is not completely understood.	('cancer', 'Disease', (131, 137))	('high', 'Var', (39, 43))	('lactate', 'Chemical', 'MESH:D019344', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lactate levels', 'MPA', (44, 58))	('distant metastasis', 'CPA', (99, 117))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
13227	32340156	Conversely, SIRT1 loss of expression promoted SMAD4 hyperacetylation; increased MMP7 levels; and, consequently, caused reduction of E-cadherin expression, and SIRT1 knockdown (KD) prevented beta-catenin degradation by promoting its translocation to the nucleus (a mesenchymal feature).	('increased', 'PosReg', (70, 79))	('cadherin', 'molecular_function', 'GO:0008014', ('134', '142'))	('translocation to the nucleus', 'MPA', (232, 260))	('E-cadherin', 'Gene', (132, 142))	('SIRT1', 'Gene', (12, 17))	('E-cadherin', 'Gene', '999', (132, 142))	('hyperacetylation', 'MPA', (52, 68))	('loss of expression', 'NegReg', (18, 36))	('SMAD4', 'Gene', '4089', (46, 51))	('beta-catenin', 'Gene', (190, 202))	('promoting', 'PosReg', (218, 227))	('MMP7', 'Gene', (80, 84))	('beta-catenin', 'Gene', '1499', (190, 202))	('prevented', 'NegReg', (180, 189))	('MMP7', 'molecular_function', 'GO:0004235', ('80', '84'))	('expression', 'MPA', (143, 153))	('promoted', 'PosReg', (37, 45))	('degradation', 'biological_process', 'GO:0009056', ('203', '214'))	('SIRT1', 'Gene', (159, 164))	('nucleus', 'cellular_component', 'GO:0005634', ('253', '260'))	('KD', 'Disease', 'MESH:C537017', (176, 178))	('knockdown', 'Var', (165, 174))	('reduction', 'NegReg', (119, 128))	('SMAD4', 'Gene', (46, 51))	('MMP7', 'Gene', '4316', (80, 84))
13234	32340156	Because CHC also inhibits lactate efflux with consequent reduction of glycolytic metabolism, NAD+ availability is augmented allowing for SIRT1 reactivation.	('inhibits', 'NegReg', (17, 25))	('NAD+', 'Chemical', 'MESH:D009243', (93, 97))	('lactate', 'Chemical', 'MESH:D019344', (26, 33))	('lactate efflux', 'MPA', (26, 40))	('NAD+', 'MPA', (93, 97))	('metabolism', 'biological_process', 'GO:0008152', ('81', '91'))	('efflux', 'biological_process', 'GO:0140115', ('34', '40'))	('CHC', 'Var', (8, 11))	('efflux', 'biological_process', 'GO:0140352', ('34', '40'))	('reduction of glycolytic metabolism', 'Disease', 'MESH:D007022', (57, 91))	('reduction of glycolytic metabolism', 'Disease', (57, 91))
13277	29462091	DNA samples extracted from macro- or microdissected tumor areas were analyzed for genome-wide copy number alterations using an SNP-array platform suitable for clinical archival material.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('copy number alterations', 'Var', (94, 117))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
13279	29462091	In contrast, cases with overlapping morphologic features of MTSCC and PRCC predominantly showed multiple chromosomal gains, most frequently involving chromosomes 7, 16, 17, and 20, similar to the chromosomal alteration pattern that was seen in the solid variant of type 1 PRCC cases.	('PRCC', 'Phenotype', 'HP:0006766', (70, 74))	('PRCC', 'Gene', '5546', (272, 276))	('MTSCC', 'Disease', (60, 65))	('MTSCC', 'Chemical', '-', (60, 65))	('chromosomal', 'Var', (105, 116))	('PRCC', 'Gene', (272, 276))	('PRCC', 'Gene', '5546', (70, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (273, 276))	('multiple chromosomal gains', 'Phenotype', 'HP:0040012', (96, 122))	('PRCC', 'Phenotype', 'HP:0006766', (272, 276))	('PRCC', 'Gene', (70, 74))	('gains', 'PosReg', (117, 122))
13281	29462091	Characteristic patterns of genome-wide copy number alterations strongly support MTSCC and PRCC as distinct entities despite their immunohistochemical and certain morphologic overlap, and help define histologic features useful for the classification of questionable cases.	('MTSCC', 'Chemical', '-', (80, 85))	('PRCC', 'Phenotype', 'HP:0006766', (90, 94))	('PRCC', 'Gene', '5546', (90, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('copy number alterations', 'Var', (39, 62))	('PRCC', 'Gene', (90, 94))	('MTSCC', 'Disease', (80, 85))
13288	29462091	have reported a unique pattern of losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, and 22 in all six MTSCC tumors analyzed by comparative genome hybridization (CGH) and loss of heterozygosity (LOH) analyses.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('losses', 'NegReg', (34, 40))	('loss of heterozygosity', 'Var', (169, 191))	('MTSCC', 'Disease', (101, 106))	('MTSCC', 'Chemical', '-', (101, 106))
13290	29462091	On the other hand, studies of the solid variant of PRCC and PRCC with low-grade spindle cell foci examined trisomies 7 and 17 by FISH analysis, with most identifying the presence of trisomy 7 and/or trisomy 17.	('PRCC', 'Gene', (60, 64))	('PRCC', 'Gene', '5546', (51, 55))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('trisomy 7', 'Var', (182, 191))	('PRCC', 'Phenotype', 'HP:0006766', (60, 64))	('PRCC', 'Gene', (51, 55))	('trisomy 17', 'Var', (199, 209))	('PRCC', 'Phenotype', 'HP:0006766', (51, 55))	('PRCC', 'Gene', '5546', (60, 64))	('trisomies', 'Var', (107, 116))	('spindle', 'cellular_component', 'GO:0005819', ('80', '87'))
13291	29462091	Using whole-exome sequencing, a very recent study of MTSCC with classic morphology revealed monosomy of chromosomes 1, 6, 9, 14, 15, and 22 in 100% of 22 cases, and frequent loss of chromosomes 4, 8, and 13 in 80-90% of cases.	('MTSCC', 'Chemical', '-', (53, 58))	('loss', 'NegReg', (174, 178))	('monosomy', 'Var', (92, 100))
13331	29462091	On the other hand, the 7 samples from 6 PRCC cases exhibited a consistently distinct pattern that predominantly included chromosomal gains of 7 (100%), 16 (71%), 17 (100%), and 20 (71%).	('PRCC', 'Phenotype', 'HP:0006766', (40, 44))	('PRCC', 'Gene', (40, 44))	('PRCC', 'Gene', '5546', (40, 44))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('chromosomal', 'Var', (121, 132))
13334	29462091	Interestingly, all 14 samples from 9 cases in the IND group with overlapping histologic features showed multiple chromosomal gains that most frequently involved 7 (79%), 16 (57%), 17 (100%), and 20 (93%), a pattern similar to the PRCC group (Fig.	('IND', 'Chemical', '-', (50, 53))	('gains', 'PosReg', (125, 130))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('chromosomal', 'Var', (113, 124))	('PRCC', 'Gene', (230, 234))	('PRCC', 'Phenotype', 'HP:0006766', (230, 234))	('multiple chromosomal gains', 'Phenotype', 'HP:0040012', (104, 130))	('PRCC', 'Gene', '5546', (230, 234))
13338	29462091	Overall, despite the morphologic ambiguity, the copy number alterations detected in these IND cases strongly support their classification as PRCC.	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('copy number alterations', 'Var', (48, 71))	('PRCC', 'Gene', '5546', (141, 145))	('IND', 'Chemical', '-', (90, 93))	('PRCC', 'Gene', (141, 145))	('PRCC', 'Phenotype', 'HP:0006766', (141, 145))
13359	29462091	In this study, we investigated genome-wide copy number alterations in MTSCC, solid variant of type 1 PRCC, and indeterminate cases with overlapping histologic features to elucidate molecular attributes that can be used in this differential diagnosis.	('copy number alterations', 'Var', (43, 66))	('PRCC', 'Phenotype', 'HP:0006766', (101, 105))	('MTSCC', 'Gene', (70, 75))	('PRCC', 'Gene', '5546', (101, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('PRCC', 'Gene', (101, 105))	('MTSCC', 'Chemical', '-', (70, 75))
13363	29462091	One unique feature of our study is that we examined intratumoral morphologic heterogeneity and showed that the overall patterns of chromosomal copy number alteration are identical or very similar among morphologically distinct areas within a given tumor.	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('chromosomal copy number alteration', 'Var', (131, 165))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
13367	29462091	One recent study included 6 such cases and found one case showing MTSCC-type multiple chromosomal losses, 2 with PRCC-type multiple gains, and 1 case without any abnormality, although details on morphologic and molecular correlation were not provided.	('PRCC', 'Gene', (113, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('MTSCC-type', 'Var', (66, 76))	('PRCC', 'Phenotype', 'HP:0006766', (113, 117))	('PRCC', 'Gene', '5546', (113, 117))	('MTSCC', 'Chemical', '-', (66, 71))
13368	29462091	In this study, we found that all cases from our IND group harbored copy number alterations characteristic of PRCC.	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('PRCC', 'Phenotype', 'HP:0006766', (109, 113))	('IND', 'Chemical', '-', (48, 51))	('harbored', 'Reg', (58, 66))	('PRCC', 'Gene', '5546', (109, 113))	('copy number alterations', 'Var', (67, 90))	('PRCC', 'Gene', (109, 113))
13375	29462091	Hippo pathway dysregulation has recently been suggested as a common molecular basis for MTSCC, with up to 90% cases exhibiting increased nuclear YAP1 protein expression in one study.	('MTSCC', 'Disease', (88, 93))	('MTSCC', 'Chemical', '-', (88, 93))	('YAP', 'Gene', (145, 148))	('dysregulation', 'Var', (14, 27))	('YAP', 'Gene', '363014', (145, 148))	('Hippo pathway', 'Pathway', (0, 13))	('protein', 'cellular_component', 'GO:0003675', ('150', '157'))	('increased', 'PosReg', (127, 136))
13384	29462091	However, in cases with more complex high-grade features or sarcomatoid change, chromosomal gains or additional LOH may be detected, although data in this regard are very limited.	('sarcomatoid change', 'Phenotype', 'HP:0100242', (59, 77))	('sarcomatoid change', 'Disease', 'MESH:C538614', (59, 77))	('sarcomatoid change', 'Disease', (59, 77))	('chromosomal', 'Var', (79, 90))
13394	32638386	Overall, BMI was associated positively with ccRCC risk, but inversely with pRCC risk.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('pRCC', 'Gene', (75, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('pRCC', 'Gene', '5546', (75, 79))	('BMI', 'Var', (9, 12))	('pRCC', 'Phenotype', 'HP:0006766', (75, 79))
13408	32638386	3 ,  4 ,  5 ,  6 ,  7 ,  8  Furthermore, alcohol consumption has been associated with a decreased RCC risk in multiple prospective epidemiological studies.	('RCC', 'Disease', (98, 101))	('alcohol', 'Chemical', 'MESH:D000438', (41, 48))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('decreased', 'NegReg', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('alcohol consumption', 'Var', (41, 60))
13456	32638386	BMI change per 1 kg/m2 increment since age 20 was associated with a nonstatistically significantly increased RCC risk.	('men', 'Species', '9606', (28, 31))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('change', 'Var', (4, 10))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))
13464	32638386	Furthermore, an increase in change in BMI since age 20 was associated with an increase in risk for ccRCC, and a decrease in pRCC risk.	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('decrease', 'NegReg', (112, 120))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('BMI', 'Gene', (38, 41))	('RCC', 'Disease', (101, 104))	('change', 'Var', (28, 34))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (99, 104))	('pRCC', 'Gene', (124, 128))
13465	32638386	Trouser size in men was associated with a statistically significantly increased ccRCC risk per size increase, while no association was found with pRCC risk.	('pRCC', 'Phenotype', 'HP:0006766', (146, 150))	('pRCC', 'Gene', '5546', (146, 150))	('increased', 'PosReg', (70, 79))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('men', 'Species', '9606', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('Trouser', 'Var', (0, 7))	('pRCC', 'Gene', (146, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))
13512	32638386	35  Therefore, the inactivation of VHL in ccRCC and the obesity-related increase in IGF-I may amplify the process of tumorigenesis.	('obesity', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('IGF-I', 'Gene', (84, 89))	('increase', 'PosReg', (72, 80))	('tumor', 'Disease', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (42, 47))	('RCC', 'Disease', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('amplify', 'PosReg', (94, 101))	('obesity', 'Phenotype', 'HP:0001513', (56, 63))	('VHL', 'Gene', (35, 38))	('inactivation', 'Var', (19, 31))	('obesity', 'Disease', 'MESH:D009765', (56, 63))	('IGF-I', 'Gene', '3479', (84, 89))	('VHL', 'Gene', '7428', (35, 38))
13553	29843367	The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes.	('high', 'Var', (44, 48))	('RNASEH2A', 'Gene', (49, 57))	('proliferation', 'CPA', (90, 103))	('kidney cancer', 'Disease', (112, 125))	('low', 'NegReg', (19, 22))	('CD151', 'Gene', (23, 28))	('RNASEH2A', 'Gene', '10535', (49, 57))	('impaired', 'NegReg', (81, 89))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('kidney cancer', 'Phenotype', 'HP:0009726', (112, 125))	('kidney cancer', 'Disease', 'MESH:D007680', (112, 125))	('expression', 'MPA', (29, 39))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
13557	29843367	Genomic instability facilitates tumor initiation and progression.	('progression', 'CPA', (53, 64))	('facilitates', 'PosReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Genomic instability', 'Var', (0, 19))	('tumor', 'Disease', (32, 37))
13559	29843367	Loss-of-function mutations in the nucleotide degrading enzymes sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1), Three prime repair exonuclease 1 (TREX1), and ribonuclease H2 subunits A, B, and C (RNASEH2A, RNASEH2B, RNASEH2C) in human germline mainly result in a hyper-inflammatory Aicardi-Goutieres syndrome (AGS), and in the development of malignancy in AGS patient is rare.	('HD', 'Disease', 'MESH:D006816', (100, 102))	('AGS', 'Disease', (339, 342))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (292, 337))	('SAMHD1', 'Gene', '25939', (132, 138))	('patient', 'Species', '9606', (389, 396))	('RNASEH2A', 'Gene', '10535', (225, 233))	('SAMHD1', 'Gene', (132, 138))	('mutations', 'Var', (17, 26))	('malignancy', 'Disease', 'MESH:D009369', (371, 381))	('result in', 'Reg', (280, 289))	('RNASEH2C', 'Gene', (245, 253))	('RNASEH2B', 'Gene', '79621', (235, 243))	('AGS', 'Disease', (385, 388))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', (292, 337))	('AGS', 'Disease', 'MESH:C535607', (339, 342))	('TREX1', 'Gene', '11277', (175, 180))	('RNASEH2C', 'Gene', '84153', (245, 253))	('RNASEH2B', 'Gene', (235, 243))	('Three prime repair exonuclease 1', 'Gene', (141, 173))	('malignancy', 'Disease', (371, 381))	('HD', 'Disease', 'MESH:D006816', (135, 137))	('RNASEH2A', 'Gene', (225, 233))	('TREX1', 'Gene', (175, 180))	('AGS', 'Disease', 'MESH:C535607', (385, 388))	('Three prime repair exonuclease 1', 'Gene', '11277', (141, 173))	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (258, 263))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
13569	29843367	It has been reported that certain genes have synthetic dosage lethality (SDL) interactions with genes that are frequently overexpressed in tumors and that inhibition of the SDL partners can decrease cancer proliferation.	('decrease', 'NegReg', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (139, 145))	('cancer', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('inhibition', 'Var', (155, 165))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('interactions', 'Interaction', (78, 90))
13578	29843367	In search of an alternative pathway that promotes tumor proliferation, we performed gene correlation studies in five kidney cancer patient samples with high RNASEH2A expression, low CDK1 expression, and bad clinical outcomes (death).	('death', 'Disease', 'MESH:D003643', (226, 231))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('RNASEH2A', 'Gene', (157, 165))	('tumor', 'Disease', (50, 55))	('death', 'Disease', (226, 231))	('kidney cancer', 'Disease', 'MESH:D007680', (117, 130))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('expression', 'MPA', (166, 176))	('RNASEH2A', 'Gene', '10535', (157, 165))	('low', 'NegReg', (178, 181))	('kidney cancer', 'Phenotype', 'HP:0009726', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('kidney cancer', 'Disease', (117, 130))	('CDK1', 'Gene', '983', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (131, 138))	('expression', 'MPA', (187, 197))	('CDK1', 'Gene', (182, 186))	('CDK', 'molecular_function', 'GO:0004693', ('182', '185'))	('high', 'Var', (152, 156))
13582	29843367	To study the interactions among RNASEH2A, CDK1, and CD151 and their impact on tumor proliferation, we performed si-RNA knockdown studies on three ccRCC cell lines (786O, A704, KMRC3, all with VHL mutation) and one kidney urothelial carcinoma cell line (BFTC909, without VHL mutation).	('RCC', 'Disease', (148, 151))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('VHL', 'Disease', (192, 195))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('CDK1', 'Gene', '983', (42, 46))	('RNASEH2A', 'Gene', '10535', (32, 40))	('CDK1', 'Gene', (42, 46))	('BFTC909', 'CellLine', 'CVCL:1084', (253, 260))	('VHL', 'Disease', (270, 273))	('kidney urothelial carcinoma', 'Disease', 'MESH:D007674', (214, 241))	('kidney urothelial carcinoma', 'Phenotype', 'HP:0030409', (214, 241))	('kidney urothelial carcinoma', 'Disease', (214, 241))	('tumor', 'Disease', (78, 83))	('RNA', 'cellular_component', 'GO:0005562', ('115', '118'))	('VHL', 'Disease', 'MESH:D006623', (192, 195))	('CDK', 'molecular_function', 'GO:0004693', ('42', '45'))	('mutation', 'Var', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RNASEH2A', 'Gene', (32, 40))	('one kidney', 'Phenotype', 'HP:0000122', (210, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('VHL', 'Disease', 'MESH:D006623', (270, 273))
13583	29843367	As shown in Figure 3A, CDK1 knockdown resulted in the upregulation of RNASEH2A and CD151 in all cell lines, however it did not significantly impair tumor proliferation (except for a mild effect on A704).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CDK1', 'Gene', (23, 27))	('CDK1', 'Gene', '983', (23, 27))	('RNASEH2A', 'Gene', (70, 78))	('tumor', 'Disease', (148, 153))	('upregulation', 'PosReg', (54, 66))	('RNASEH2A', 'Gene', '10535', (70, 78))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('knockdown', 'Var', (28, 37))	('CDK', 'molecular_function', 'GO:0004693', ('23', '26'))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CD151', 'Gene', (83, 88))
13584	29843367	Interestingly, in BFTC909, CDK1 could not be knocked down after a 96-hour si-CDK1 transfection, and the tumor survival rate even increased.	('CDK', 'molecular_function', 'GO:0004693', ('77', '80'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('transfection', 'Var', (82, 94))	('CDK1', 'Gene', (77, 81))	('CDK1', 'Gene', '983', (77, 81))	('tumor', 'Disease', (104, 109))	('increased', 'PosReg', (129, 138))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('CDK1', 'Gene', '983', (27, 31))	('CDK1', 'Gene', (27, 31))	('BFTC909', 'CellLine', 'CVCL:1084', (18, 25))	('CDK', 'molecular_function', 'GO:0004693', ('27', '30'))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
13585	29843367	Furthermore, RNASEH2A knockdown resulted in CD151 upregulation and decreased proliferation in all ccRCC cell lines.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('RNASEH2A', 'Gene', '10535', (13, 21))	('upregulation', 'PosReg', (50, 62))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('knockdown', 'Var', (22, 31))	('CD151', 'Gene', (44, 49))	('decreased', 'NegReg', (67, 76))	('RNASEH2A', 'Gene', (13, 21))	('RCC', 'Disease', (100, 103))	('proliferation', 'CPA', (77, 90))
13588	29843367	Cell viability assays were performed in ccRCC cell line 786O after transfection with si-CDK1, si-RNASEH2A, and si-CD151, which showed comparable results to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays (Figure 4).	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('CDK1', 'Gene', '983', (88, 92))	('MTT', 'Chemical', 'MESH:C070243', (222, 225))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('CDK1', 'Gene', (88, 92))	('RNASEH2A', 'Gene', (97, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('CDK', 'molecular_function', 'GO:0004693', ('88', '91'))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (160, 220))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('RNASEH2A', 'Gene', '10535', (97, 105))	('si-CD151', 'Var', (111, 119))	('RCC', 'Disease', (42, 45))	('si', 'Chemical', 'MESH:D012825', (94, 96))
13593	29843367	In KIRC, patients with scores lower than the cutoff (-1.925) had a significantly worse overall survival rate compared to those with scores above the cutoff value (mean survival of 955.3 days versus 2242.2 days, hazard ratio (HR) = 4.53 (3.05-6.73), p = 2.2 x 10-16, Figure 6A).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (9, 17))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('overall survival', 'CPA', (87, 103))	('scores', 'Var', (23, 29))	('worse', 'NegReg', (81, 86))
13595	29843367	In another ccRCC cohort, namely, the E-GEOD-22541 expression array data (n = 44), patients with scores lower than -1.596 also showed lower disease-free survival when compared to those with higher scores (mean survival of 390.0 days versus 1889.2 days, HR = 2.99 (1.07-8.35), p = 7.1 x 10-4, Figure 6C).	('lower', 'NegReg', (133, 138))	('patients', 'Species', '9606', (82, 90))	('scores lower than -1.596', 'Var', (96, 120))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('RCC', 'Disease', (13, 16))	('disease-free survival', 'CPA', (139, 160))	('si', 'Chemical', 'MESH:D012825', (56, 58))
13603	29843367	Similarly, in our study, CDK1 knockdown in RCC cell lines did not have a pronounced effect on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('CDK1', 'Gene', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('CDK1', 'Gene', '983', (25, 29))	('knockdown', 'Var', (30, 39))	('CDK', 'molecular_function', 'GO:0004693', ('25', '28'))
13606	29843367	In contrast to CDK1 knockdown, transfection of RCC cell lines with either si-RNASEH2A or si-CD151 resulted in impaired tumor proliferation.	('CDK1', 'Gene', '983', (15, 19))	('RNASEH2A', 'Gene', '10535', (77, 85))	('CDK1', 'Gene', (15, 19))	('impaired tumor', 'Disease', (110, 124))	('si-CD151', 'Var', (89, 97))	('CDK', 'molecular_function', 'GO:0004693', ('15', '18'))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RNASEH2A', 'Gene', (77, 85))	('impaired tumor', 'Disease', 'MESH:D015417', (110, 124))
13607	29843367	Upregulation of CD151 and RNASEH2A was noted 48 h after si-RNASEH2A and si-CD151 knockdown, respectively, in all kidney cancer cell lines.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('kidney cancer', 'Phenotype', 'HP:0009726', (113, 126))	('RNASEH2A', 'Gene', (59, 67))	('RNASEH2A', 'Gene', '10535', (26, 34))	('kidney cancer', 'Disease', (113, 126))	('RNASEH2A', 'Gene', '10535', (59, 67))	('CD151', 'Gene', (16, 21))	('si-CD151', 'Var', (72, 80))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('kidney cancer', 'Disease', 'MESH:D007680', (113, 126))	('RNASEH2A', 'Gene', (26, 34))
13615	29843367	Furthermore, according to the potential SDL relationships between CD151 and RNASEH2A identified by this study, CD151-high RCCs could be treated with RNASEH2A inhibitors.	('RNASEH2A', 'Gene', (76, 84))	('RNASEH2A', 'Gene', (149, 157))	('CD151-high', 'Var', (111, 121))	('RNASEH2A', 'Gene', '10535', (76, 84))	('RNASEH2A', 'Gene', '10535', (149, 157))	('RCCs', 'Phenotype', 'HP:0005584', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
13669	28252459	Inactivation of VHL either by mutation or epigenetic silencing occurs in over 90% cases of sporadic ccRCC.	('VHL', 'Gene', (16, 19))	('epigenetic silencing', 'Var', (42, 62))	('mutation', 'Var', (30, 38))	('VHL', 'Gene', '7428', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('Inactivation', 'NegReg', (0, 12))
13670	28252459	Additionally, TCGA analysis has demonstrated recurrent mutations in several chromatin remodeling genes, including PBRM1 (32.9%), SETD2 (11.5%), and BAP1 (10.1%).	('SETD2', 'Gene', '29072', (129, 134))	('PBRM1', 'Gene', '55193', (114, 119))	('chromatin', 'cellular_component', 'GO:0000785', ('76', '85'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('76', '96'))	('SETD2', 'Gene', (129, 134))	('BAP1', 'Gene', '8314', (148, 152))	('mutations', 'Var', (55, 64))	('BAP1', 'Gene', (148, 152))	('PBRM1', 'Gene', (114, 119))
13674	28252459	The study affirmed differences in type 1 and type 2 pRCC, and found 4 distinct molecular subgroups with progressively worse survival (C1, C2a, C2b, and C2c).	('C2a', 'Var', (138, 141))	('pRCC', 'Gene', '5546', (52, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pRCC', 'Gene', (52, 56))	('C2b', 'Var', (143, 146))	('worse', 'NegReg', (118, 123))
13675	28252459	C1 consisted of mostly type 1 pRCC tumors, characterized by gain of chromosome 7 and 17, as well as alterations in MET.	('MET', 'MPA', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('68', '78'))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('pRCC', 'Gene', (30, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('gain', 'PosReg', (60, 64))	('pRCC', 'Gene', '5546', (30, 34))	('alterations', 'Var', (100, 111))
13676	28252459	In contrast to the hereditary form of pRCC, Hereditary Papillary Renal Cancer (HPRC) which is characterized by germline MET mutations, somatic alterations of MET in non-hereditary pRCC was less common, occurring in ~15% of cases.	('pRCC', 'Gene', '5546', (38, 42))	('MET', 'Gene', (158, 161))	('pRCC', 'Gene', (38, 42))	('pRCC', 'Gene', '5546', (180, 184))	('Renal Cancer', 'Phenotype', 'HP:0009726', (65, 77))	('Hereditary Papillary Renal Cancer', 'Disease', 'MESH:D007681', (44, 77))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('Hereditary Papillary Renal Cancer', 'Disease', (44, 77))	('Papillary Renal Cancer', 'Phenotype', 'HP:0006766', (55, 77))	('pRCC', 'Gene', (180, 184))	('alterations', 'Var', (143, 154))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
13678	28252459	C2a consisted of early stage tumors, while C2b consisted of later stage tumors and was characterized by mutations in SETD2.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (104, 113))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('SETD2', 'Gene', '29072', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('SETD2', 'Gene', (117, 122))	('C2a', 'Disease', (0, 3))
13679	28252459	Other alterations in type 2 pRCC included loss of CDKN2a, activation of the NRF2 oxidative stress pathway, mutations of FH, gene fusions involving the MiTF gene family members TFE3 and TFEB, and mutations in chromatin remodeling genes.	('NRF2', 'Gene', '4780', (76, 80))	('oxidative stress', 'Phenotype', 'HP:0025464', (81, 97))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('pRCC', 'Gene', (28, 32))	('activation', 'PosReg', (58, 68))	('TFE3', 'Gene', (176, 180))	('gene fusions', 'Var', (124, 136))	('MiTF gene', 'Gene', (151, 160))	('NRF2', 'Gene', (76, 80))	('TFE3', 'Gene', '7030', (176, 180))	('CDKN2a', 'Gene', (50, 56))	('loss', 'NegReg', (42, 46))	('mutations', 'Var', (195, 204))	('TFEB', 'Gene', (185, 189))	('chromatin', 'cellular_component', 'GO:0000785', ('208', '217'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('208', '228'))	('pRCC', 'Gene', '5546', (28, 32))	('mutations', 'Var', (107, 116))	('CDKN2a', 'Gene', '1029', (50, 56))	('TFEB', 'Gene', '7942', (185, 189))
13682	28252459	The analysis from TCGA demonstrated that chRCC exhibit alterations in mitochondrial DNA and that 10% of cases had rearrangement in the TERT promoter.	('TERT', 'Gene', '7015', (135, 139))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('70', '87'))	('mitochondrial DNA', 'MPA', (70, 87))	('alterations', 'Reg', (55, 66))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('rearrangement', 'Var', (114, 127))	('TERT', 'Gene', (135, 139))
13683	28252459	Furthermore, TP53 was mutated in 32% of cases, and mTOR pathway changes occurred in 23% of cases.	('mTOR', 'Gene', (51, 55))	('TP53', 'Gene', (13, 17))	('changes', 'Reg', (64, 71))	('mutated', 'Var', (22, 29))	('TP53', 'Gene', '7157', (13, 17))	('mTOR', 'Gene', '2475', (51, 55))
13691	28252459	AXL is activated by HIF-1 and HIF-2, and inactivation of AXL decreases lung metastases in mice xenograft models of RCC.	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('inactivation', 'Var', (41, 53))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (20, 35))	('AXL decreases lung metastases', 'Disease', 'MESH:D009362', (57, 86))	('mice', 'Species', '10090', (90, 94))	('AXL decreases lung metastases', 'Disease', (57, 86))
13699	28252459	In a randomized phase II trial comparing cabozantinib and sunitinib in the first-line setting (CABOSUN) in 157 patients with intermediate or poor-risk mRCC, cabozantinib was associated with increased median PFS (8.2 v 5.6 months; HR 0.66; 95% CI, 0.46-0.95; one-sided p= .012), OS (30.3 vs 21.8 months; HR 0.8; 95% CI 0.5-1.26) and ORR (46%; 95% CI, 34-57 versus 18%; 95% CI, 10-28) with a similar incidence of grade 3-4 AEs (67% for cabozantinib and 68% for sunitinib).	('PFS', 'CPA', (207, 210))	('sunitinib', 'Chemical', 'MESH:D000077210', (58, 67))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('cabozantinib', 'Chemical', 'MESH:C558660', (41, 53))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('ORR', 'Disease', (332, 335))	('sunitinib', 'Chemical', 'MESH:D000077210', (459, 468))	('cabozantinib', 'Chemical', 'MESH:C558660', (434, 446))	('cabozantinib', 'Var', (157, 169))	('cabozantinib', 'Chemical', 'MESH:C558660', (157, 169))	('patients', 'Species', '9606', (111, 119))
13707	28252459	Cho and colleagues showed that PT2300 inhibits growth of VHL-deficient ccRCC cell lines in vitro and in mouse xenografts.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('VHL-deficient', 'Disease', 'MESH:D006623', (57, 70))	('inhibits', 'NegReg', (38, 46))	('growth', 'MPA', (47, 53))	('VHL-deficient', 'Disease', (57, 70))	('mouse', 'Species', '10090', (104, 109))	('PT2300', 'Var', (31, 37))	('Cho', 'molecular_function', 'GO:0043848', ('0', '3'))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
13727	28252459	There is significant interest in combining PD1/PDL-1 inhibitors with other agents, including other checkpoint inhibitors, VEGF inhibitors, HDAC inhibitors, and vaccines (Table 3).	('inhibitors', 'Var', (53, 63))	('VEGF', 'Gene', '7422', (122, 126))	('PDL-1', 'Gene', (47, 52))	('PD1', 'Gene', '5133', (43, 46))	('VEGF', 'Gene', (122, 126))	('PD1', 'Gene', (43, 46))	('PDL-1', 'Gene', '29126', (47, 52))
13736	28252459	Indeed, VEGF-pathway inhibitors seem to have an immunomodulatory effect.	('inhibitors', 'Var', (21, 31))	('VEGF-', 'Gene', '7422', (8, 13))	('VEGF-', 'Gene', (8, 13))
13761	28252459	A second randomized phase 2 study, ASPEN (Phase II Study of Afinitor Vs. Sutent in Patients with Metastatic Non-Clear Cell Renal Cell Carcinoma), in 108 patients with treatment-naive metastatic pRCC, chRCC or unclassified non-ccRCC subtypes demonstrated that Sunitnib was associated with an improved PFS (8.3 vs 5.6 mo; HR 1.4; p=0.16) compared to everolimus.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('Carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', (97, 143))	('PFS', 'MPA', (300, 303))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('Sunitnib', 'Chemical', '-', (259, 267))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('RCC', 'Disease', (195, 198))	('pRCC', 'Gene', (194, 198))	('Metastatic Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538445', (97, 143))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (111, 143))	('Sutent', 'Chemical', 'MESH:D000077210', (73, 79))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('Sunitnib', 'Var', (259, 267))	('improved', 'PosReg', (291, 299))	('patients', 'Species', '9606', (153, 161))	('RCC', 'Disease', (228, 231))	('everolimus', 'Chemical', 'MESH:D000068338', (348, 358))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('pRCC', 'Gene', '5546', (194, 198))	('Patients', 'Species', '9606', (83, 91))
13765	28252459	Other ongoing trials in pRCC include phase 2 studies of selective Met inhibitors, including INC280 and AZD6094, and the combination of the EGFR inhibitor erlotinib with bevacizumab, as summarized in Table 4.	('pRCC', 'Gene', '5546', (24, 28))	('bevacizumab', 'Chemical', 'MESH:D000068258', (169, 180))	('AZD6094', 'Var', (103, 110))	('INC280', 'Chemical', 'MESH:C000613976', (92, 98))	('EGFR', 'molecular_function', 'GO:0005006', ('139', '143'))	('pRCC', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (139, 143))	('AZD6094', 'Chemical', 'MESH:C000593259', (103, 110))	('erlotinib', 'Chemical', 'MESH:D000069347', (154, 163))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('EGFR', 'Gene', (139, 143))
13769	28252459	This phase III trial of 1943 patients with high-grade T1b or higher non-metastatic RCC randomized to receive 54 weeks of sunitinib, sorafenib or placebo demonstrated no improvement in outcome with adjuvant VEGFR TKIs (median PFS 5.8 years; HR 1.02; p=0.8 for sunitinib vs 6.1 years; HR 0.97; p=0.7 for sorafenib vs 6.6 years for placebo).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('patients', 'Species', '9606', (29, 37))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('T1b', 'Gene', (54, 57))	('sorafenib', 'Chemical', 'MESH:D000077157', (302, 311))	('sorafenib', 'Chemical', 'MESH:D000077157', (132, 141))	('high-grade', 'Var', (43, 53))	('VEGFR', 'Gene', '3791', (206, 211))	('sunitinib', 'Chemical', 'MESH:D000077210', (259, 268))	('VEGFR', 'Gene', (206, 211))
13771	28252459	In contrast, results from S-TRAC (Sunitinib as Adjuvant treatment for patients at high risk of recurrence of renal cell carcinoma following nephrectomy), a phase III trial that randomized 615 patients with T3 or greater RCC to sunitinib vs placebo for 1 year suggest that sunitinib was associated with improved DFS compared to placebo (6.8 vs 5.8 years, p = 0.03).	('patients', 'Species', '9606', (70, 78))	('sunitinib', 'Chemical', 'MESH:D000077210', (272, 281))	('DFS', 'MPA', (311, 314))	('renal cell carcinoma', 'Disease', (109, 129))	('sunitinib', 'Var', (272, 281))	('sunitinib', 'Chemical', 'MESH:D000077210', (227, 236))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('patients', 'Species', '9606', (192, 200))	('improved', 'PosReg', (302, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('TRAC', 'Gene', '28755', (28, 32))	('Sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('TRAC', 'Gene', (28, 32))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 129))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
13783	28252459	In 104 patients who received pazopanib, 61% went on to undergo nephrectomy.	('pazopanib', 'Var', (29, 38))	('pazopanib', 'Chemical', 'MESH:C516667', (29, 38))	('patients', 'Species', '9606', (7, 15))	('nephrectomy', 'Disease', (63, 74))
13788	28252459	While VEGFR inhibitors remain the standard first-line treatment for the majority of patients, this paradigm is being challenged by ongoing studies.	('patients', 'Species', '9606', (84, 92))	('inhibitors', 'Var', (12, 22))	('VEGFR', 'Gene', (6, 11))	('VEGFR', 'Gene', '3791', (6, 11))
13802	26233890	The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is activated by gene mutations and copy number alterations (CNAs) in more pathway components and in more tumor types than any other signaling pathways involved in cancer.	('copy number alterations', 'Var', (88, 111))	('tumor', 'Disease', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('signaling', 'biological_process', 'GO:0023052', ('185', '194'))	('AKT', 'Gene', '207', (41, 44))	('phosphatidylinositol 3 kinase', 'Gene', '5293', (4, 33))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cancer', 'Disease', (216, 222))	('phosphatidylinositol 3 kinase', 'Gene', (4, 33))	('activated', 'PosReg', (56, 65))	('AKT', 'Gene', (41, 44))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
13804	26233890	More importantly, genetic mutations result in activation of the PI3K/AKT pathway, which is composed of multiple bifurcating and converging kinase cascades, representing a "target-rich" environment for cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('PI3K', 'molecular_function', 'GO:0016303', ('64', '68'))	('AKT', 'Gene', (69, 72))	('cancer', 'Disease', (201, 207))	('activation', 'PosReg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('AKT', 'Gene', '207', (69, 72))	('genetic mutations', 'Var', (18, 35))
13815	26233890	Class I PI3Ks are heterodimers of a 110-kDa catalytic subunit (p110) and a regulatory subunit (i.e., p85).	('PI3Ks', 'Var', (8, 13))	('p110', 'Gene', (63, 67))	('p85', 'Gene', '5296', (101, 104))	('p110', 'Gene', '9733', (63, 67))	('p85', 'Gene', (101, 104))
13820	26233890	In addition to RTKs, G protein coupled receptors are another large group of classic upstream regulators that activate PI3K, most commonly p110beta.	('p110beta', 'Gene', (138, 146))	('protein', 'cellular_component', 'GO:0003675', ('23', '30'))	('p110beta', 'Gene', '5291', (138, 146))	('G protein coupled receptors', 'Protein', (21, 48))	('activate', 'PosReg', (109, 117))	('PI3K', 'Var', (118, 122))	('PI3K', 'molecular_function', 'GO:0016303', ('118', '122'))
13825	26233890	A key mediator responding to the PtdIns(3,4,5)P3 signal generated by PI3K is the serine/threonine kinase AKT.	('serine', 'Chemical', 'MESH:D012694', (81, 87))	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('AKT', 'Gene', '207', (105, 108))	('PtdIns(3,4,5)P3', 'Chemical', '-', (33, 48))	('PI3K', 'Var', (69, 73))	('AKT', 'Gene', (105, 108))	('threonine', 'Chemical', 'MESH:D013912', (88, 97))
13828	26233890	In the canonical PI3K/AKT activation model, AKT and its upstream kinase, 3-phosphoinositide-dependent protein kinase-1 (PDK1), are recruited to the inner cell membrane via interactions of their PH domains with PtdIns(3,4,5)P3 generated by PI3K, which initiates AKT phosphorylation at Thr308 (based on AKT1 amino acid sequence unless designated otherwise) in the activation T-loop by PDK1.	('Thr308', 'Chemical', '-', (284, 290))	('AKT', 'Gene', (261, 264))	('PDK1', 'molecular_function', 'GO:0004740', ('383', '387'))	('PtdIns(3,4,5)P3', 'Chemical', '-', (210, 225))	('interactions', 'Interaction', (172, 184))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', '5170', (73, 118))	('AKT', 'Gene', (22, 25))	('AKT1', 'Gene', (301, 305))	('recruited', 'PosReg', (131, 140))	('AKT', 'Gene', '207', (301, 304))	('AKT', 'Gene', '207', (261, 264))	('AKT', 'Gene', (44, 47))	('cell membrane', 'cellular_component', 'GO:0005886', ('154', '167'))	('phosphorylation', 'biological_process', 'GO:0016310', ('265', '280'))	('AKT', 'Gene', '207', (22, 25))	('Thr308', 'Var', (284, 290))	('protein', 'cellular_component', 'GO:0003675', ('102', '109'))	('PI3K', 'molecular_function', 'GO:0016303', ('17', '21'))	('PDK1', 'Gene', '5170', (383, 387))	('PDK1', 'Gene', (383, 387))	('PI3K', 'molecular_function', 'GO:0016303', ('239', '243'))	('PDK1', 'Gene', '5170', (120, 124))	('PDK1', 'Gene', (120, 124))	('PDK1', 'molecular_function', 'GO:0004740', ('120', '124'))	('AKT', 'Gene', '207', (44, 47))	('3-phosphoinositide-dependent protein kinase-1', 'Gene', (73, 118))	('AKT', 'Gene', (301, 304))	('AKT1', 'Gene', '207', (301, 305))
13829	26233890	mTOR complex 2 (mTORC2) and other potential kinases phosphorylate AKT at Ser473 in the regulatory hydrophobic domain, resulting in optimal activation .	('Ser473', 'Var', (73, 79))	('AKT', 'Gene', (66, 69))	('mTORC2', 'Gene', (16, 22))	('activation', 'PosReg', (139, 149))	('Ser473', 'Chemical', '-', (73, 79))	('mTORC2', 'Gene', '74343', (16, 22))	('mTOR', 'Gene', '2475', (0, 4))	('mTORC2', 'cellular_component', 'GO:0031932', ('16', '22'))	('mTOR complex', 'cellular_component', 'GO:0038201', ('0', '12'))	('Ser', 'cellular_component', 'GO:0005790', ('73', '76'))	('mTOR', 'Gene', '2475', (16, 20))	('mTOR', 'Gene', (16, 20))	('AKT', 'Gene', '207', (66, 69))	('mTOR', 'Gene', (0, 4))
13836	26233890	Phosphorylation at Thr305, Thr312, and Tyr474 has been shown to contribute to optimal AKT activation.	('activation', 'PosReg', (90, 100))	('AKT', 'Gene', (86, 89))	('Tyr474', 'Chemical', '-', (39, 45))	('Thr312', 'Chemical', '-', (27, 33))	('Thr312', 'Var', (27, 33))	('Phosphorylation', 'biological_process', 'GO:0016310', ('0', '15'))	('Thr305', 'Chemical', '-', (19, 25))	('AKT', 'Gene', '207', (86, 89))	('Tyr474', 'Var', (39, 45))
13837	26233890	Thr72 and Ser246 have been proposed to be trans-autophosphorylated, whereas Thr34, Thr450, and Tyr176 phosphorylation is likely mediated by upstream kinases, including atypical protein kinase C, c-Jun N-terminal kinases, and Ack1.	('Ser246', 'Var', (10, 16))	('Ack1', 'Gene', (225, 229))	('Thr450', 'Var', (83, 89))	('Tyr176', 'Chemical', '-', (95, 101))	('Ser', 'cellular_component', 'GO:0005790', ('10', '13'))	('Tyr176', 'Var', (95, 101))	('Thr450', 'Chemical', '-', (83, 89))	('Ack1', 'Gene', '10188', (225, 229))	('Thr34', 'Chemical', '-', (76, 81))	('protein', 'cellular_component', 'GO:0003675', ('177', '184'))	('phosphorylation', 'biological_process', 'GO:0016310', ('102', '117'))	('Ser246', 'Chemical', '-', (10, 16))	('Thr72', 'Chemical', '-', (0, 5))	('Thr34', 'Var', (76, 81))
13839	26233890	For example, AKT1 Ser129, but not the equivalent AKT2 Ser131, is phosphorylated by the casein kinase 2, contributing to AKT1-specific substrate recognition and potentially to differential functions of AKT1 and AKT2.	('AKT1', 'Gene', '207', (13, 17))	('AKT1', 'Gene', (13, 17))	('AKT2', 'Gene', '208', (210, 214))	('AKT1', 'Gene', (120, 124))	('contributing', 'Reg', (104, 116))	('Ser', 'cellular_component', 'GO:0005790', ('18', '21'))	('AKT1', 'Gene', '207', (201, 205))	('Ser131', 'Chemical', '-', (54, 60))	('Ser', 'cellular_component', 'GO:0005790', ('54', '57'))	('AKT1', 'Gene', (201, 205))	('Ser129', 'Chemical', '-', (18, 24))	('AKT1', 'Gene', '207', (120, 124))	('Ser129', 'Var', (18, 24))	('functions', 'MPA', (188, 197))	('AKT2', 'Gene', (210, 214))	('AKT2', 'Gene', (49, 53))	('AKT2', 'Gene', '208', (49, 53))
13842	26233890	Following insulin stimulation, a large percentage of AKT1 is phosphorylated at Thr308 and Ser473.	('AKT1', 'Gene', (53, 57))	('Thr308', 'Var', (79, 85))	('Ser473', 'Chemical', '-', (90, 96))	('insulin', 'molecular_function', 'GO:0016088', ('10', '17'))	('Thr308', 'Chemical', '-', (79, 85))	('AKT1', 'Gene', '207', (53, 57))	('insulin', 'Gene', (10, 17))	('Ser', 'cellular_component', 'GO:0005790', ('90', '93'))	('Ser473', 'Var', (90, 96))	('insulin', 'Gene', '3630', (10, 17))
13846	26233890	AKT phosphorylates and inhibits tuberous sclerosis (TSC) complex 1/2, a GTPase-activating protein for the Ras-related small G protein RHEB; therefore, AKT phosphorylation activates RHEB, which in turn activates mTORC1 (Fig.	('AKT', 'Gene', (0, 3))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (32, 50))	('activates', 'PosReg', (201, 210))	('AKT', 'Gene', (151, 154))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('phosphorylation', 'biological_process', 'GO:0016310', ('155', '170'))	('protein', 'cellular_component', 'GO:0003675', ('90', '97'))	('mTORC1', 'Gene', (211, 217))	('mTORC1', 'cellular_component', 'GO:0031931', ('211', '217'))	('RHEB', 'Protein', (181, 185))	('TSC', 'Gene', '7248;7249', (52, 55))	('tuberous sclerosis', 'Disease', (32, 50))	('AKT', 'Gene', '207', (0, 3))	('TSC', 'Gene', (52, 55))	('activates', 'PosReg', (171, 180))	('AKT', 'Gene', '207', (151, 154))	('mTORC1', 'Gene', '382056', (211, 217))	('phosphorylation', 'Var', (155, 170))
13856	26233890	Genetic alterations of the panel components were identified in every cancer lineage.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (69, 75))
13857	26233890	The mutation and CNA rates ranged from 6% in thyroid carcinoma to a striking 95% in endometrioid carcinoma (Fig.	('endometrioid carcinoma', 'Disease', (84, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutation', 'Var', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (45, 62))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (84, 106))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (84, 106))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (45, 62))	('thyroid carcinoma', 'Disease', (45, 62))
13858	26233890	The average genetic alteration rate was about 50% across all cancer types.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('genetic alteration', 'Var', (12, 30))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
13859	26233890	Genetic alterations were identified in every layer of the PI3K/AKT signaling cascade.	('PI3K', 'molecular_function', 'GO:0016303', ('58', '62'))	('Genetic alterations', 'Var', (0, 19))	('AKT', 'Gene', (63, 66))	('AKT signaling cascade', 'biological_process', 'GO:0043491', ('63', '84'))	('AKT', 'Gene', '207', (63, 66))
13860	26233890	For example, at the layer of PI3K, PIK3CA gene coding for the catalytic subunit p110alpha has been found to be frequently mutated in cancer, underscoring the importance of this isoform.	('p110alpha', 'Gene', '5290', (80, 89))	('PI3K', 'molecular_function', 'GO:0016303', ('29', '33'))	('p110alpha', 'Gene', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (35, 41))	('mutated', 'Var', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
13863	26233890	Strikingly, most of the mutations were observed in two small, highly conserved clusters in the helical and kinase domains of p110alpha, displaying a pattern of activation mutations.	('p110alpha', 'Gene', (125, 134))	('mutations', 'Var', (24, 33))	('p110alpha', 'Gene', '5290', (125, 134))
13864	26233890	Many additional studies revealed PIK3CA mutations in almost all cancer types, including ovarian, head and neck, cervical, endometrial, and kidney cancers.	('cancer', 'Disease', (146, 152))	('PIK3CA', 'Gene', '5290', (33, 39))	('kidney cancer', 'Phenotype', 'HP:0009726', (139, 152))	('neck', 'cellular_component', 'GO:0044326', ('106', '110'))	('kidney cancers', 'Phenotype', 'HP:0009726', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('endometrial', 'Disease', (122, 133))	('cancer', 'Disease', (64, 70))	('mutations', 'Var', (40, 49))	('revealed', 'Reg', (24, 32))	('PIK3CA', 'Gene', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cervical', 'Disease', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ovarian', 'Disease', (88, 95))	('ovarian', 'Disease', 'MESH:D010051', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('kidney cancers', 'Disease', (139, 153))	('kidney cancers', 'Disease', 'MESH:D007680', (139, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
13865	26233890	The recurrent mutations of PIK3CA were demonstrated to be oncogenic.	('PIK3CA', 'Gene', '5290', (27, 33))	('mutations', 'Var', (14, 23))	('PIK3CA', 'Gene', (27, 33))
13866	26233890	Intriguingly, PIK3CA mutations are generally mutually exclusive with mutations in other members of the pathway with the exception of endometrial cancer and a subset of bowel cancers where mutations in multiple pathway members are common.	('bowel cancers', 'Disease', 'MESH:D009369', (168, 181))	('bowel cancers', 'Disease', (168, 181))	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('endometrial cancer', 'Disease', 'MESH:D016889', (133, 151))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PIK3CA', 'Gene', (14, 20))	('endometrial cancer', 'Disease', (133, 151))	('PIK3CA', 'Gene', '5290', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (21, 30))
13868	26233890	However, the latest TCGA data indicate that PIK3CA is actually the most altered oncogene targeted by mutations and amplifications across all cancers, and PIK3CA mutation is particularly prevalent in endometrial cancer (57%), lung squamous cell carcinoma (48%), cervical cancer (42%), invasive breast cancer (39%), head and neck cancer (35%), colon cancer (30%), and ovarian cancer (30%; www.cbioportal.org).	('endometrial cancer', 'Disease', 'MESH:D016889', (199, 217))	('cervical cancer', 'Disease', 'MESH:D002583', (261, 276))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('cervical cancer', 'Disease', (261, 276))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('invasive breast cancer', 'Disease', (284, 306))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('lung squamous cell carcinoma', 'Disease', (225, 253))	('PIK3CA', 'Gene', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('ovarian cancer', 'Disease', 'MESH:D010051', (366, 380))	('PIK3CA', 'Gene', (154, 160))	('neck cancer', 'Disease', 'MESH:D006258', (323, 334))	('colon cancer', 'Phenotype', 'HP:0003003', (342, 354))	('neck cancer', 'Disease', (323, 334))	('mutation', 'Var', (161, 169))	('neck', 'cellular_component', 'GO:0044326', ('323', '327'))	('invasive breast cancer', 'Disease', 'MESH:D001943', (284, 306))	('head and neck cancer', 'Phenotype', 'HP:0012288', (314, 334))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('cancers', 'Disease', (141, 148))	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('colon cancer', 'Disease', 'MESH:D015179', (342, 354))	('ovarian cancer', 'Disease', (366, 380))	('ovarian cancer', 'Phenotype', 'HP:0100615', (366, 380))	('endometrial cancer', 'Phenotype', 'HP:0012114', (199, 217))	('prevalent', 'Reg', (186, 195))	('PIK3CA', 'Gene', '5290', (44, 50))	('PIK3CA', 'Gene', '5290', (154, 160))	('colon cancer', 'Disease', (342, 354))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('endometrial cancer', 'Disease', (199, 217))
13869	26233890	Likewise, frequent mutations of PIK3R1 gene coding for the p85 regulatory subunit, have also been identified in TCGA, particularly in endometrial cancer (34%), glioblastoma (11%), uterine carcinosarcoma (11%), and bladder urothelial carcinoma (7.8%; www.cbioportal.org).	('endometrial cancer', 'Phenotype', 'HP:0012114', (134, 152))	('p85', 'Gene', '5296', (59, 62))	('carcinosarcoma', 'Disease', (188, 202))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PIK3R1', 'Gene', '5295', (32, 38))	('endometrial cancer', 'Disease', (134, 152))	('carcinosarcoma', 'Disease', 'MESH:D002296', (188, 202))	('endometrial cancer', 'Disease', 'MESH:D016889', (134, 152))	('p85', 'Gene', (59, 62))	('bladder urothelial carcinoma', 'Disease', (214, 242))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (180, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (160, 172))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (214, 242))	('PIK3R1', 'Gene', (32, 38))	('glioblastoma', 'Disease', (160, 172))	('TCGA', 'Disease', (112, 116))	('glioblastoma', 'Phenotype', 'HP:0012174', (160, 172))	('mutations', 'Var', (19, 28))	('identified', 'Reg', (98, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
13870	26233890	Oncogenic mutations of p85alpha may target PI3K/AKT pathway activation by activating p110 or inhibiting PTEN.	('activating', 'PosReg', (74, 84))	('p85alpha', 'Gene', (23, 31))	('AKT', 'Gene', (48, 51))	('PI3K', 'molecular_function', 'GO:0016303', ('43', '47'))	('p85alpha', 'Gene', '5295', (23, 31))	('p110', 'Gene', '9733', (85, 89))	('activation', 'PosReg', (60, 70))	('mutations', 'Var', (10, 19))	('AKT', 'Gene', '207', (48, 51))	('inhibiting', 'NegReg', (93, 103))	('PTEN', 'Gene', (104, 108))	('p110', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (104, 108))
13871	26233890	Recently, neomorphic truncation mutations of p85alpha have been discovered to promote the mitogen-activated protein kinase pathway in cancer, revealing a new category of oncogenic functions for p85alpha mutations.	('p85alpha', 'Gene', (194, 202))	('promote', 'PosReg', (78, 85))	('p85alpha', 'Gene', '5295', (194, 202))	('mitogen-activated protein kinase pathway', 'Pathway', (90, 130))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('p85alpha', 'Gene', (45, 53))	('protein', 'cellular_component', 'GO:0003675', ('108', '115'))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('p85alpha', 'Gene', '5295', (45, 53))	('neomorphic', 'Var', (10, 20))
13873	26233890	Frequent mutations and deletions of PTEN have been found in various cancers, including endometrial cancer (67%), glioblastoma (42%), and prostate cancer (22%).	('endometrial cancer', 'Disease', (87, 105))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (9, 18))	('PTEN', 'Gene', (36, 40))	('endometrial cancer', 'Disease', 'MESH:D016889', (87, 105))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('found', 'Reg', (51, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('PTEN', 'Gene', '5728', (36, 40))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('prostate cancer', 'Disease', (137, 152))	('glioblastoma', 'Disease', (113, 125))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('deletions', 'Var', (23, 32))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('endometrial cancer', 'Phenotype', 'HP:0012114', (87, 105))	('cancers', 'Disease', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
13874	26233890	In addition to these genetic alterations, PTEN is also targeted by promoter methylation, transcriptional inhibition, microRNA, and posttranslational modifications, resulting in downregulation of PTEN functions and subsequently upregulation of PI3K/AKT pathway signaling in cancer.	('PTEN', 'Gene', (42, 46))	('downregulation', 'NegReg', (177, 191))	('upregulation', 'PosReg', (227, 239))	('PTEN', 'Gene', '5728', (42, 46))	('signaling', 'biological_process', 'GO:0023052', ('260', '269'))	('cancer', 'Disease', (273, 279))	('AKT', 'Gene', (248, 251))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('promoter methylation', 'Var', (67, 87))	('functions', 'MPA', (200, 209))	('PI3K', 'molecular_function', 'GO:0016303', ('243', '247'))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('PTEN', 'Gene', (195, 199))	('AKT', 'Gene', '207', (248, 251))	('PTEN', 'Gene', '5728', (195, 199))
13876	26233890	At the layer of AKT, the core component of the PI3K/AKT pathway, amplification and mutations of AKT isoforms have been identified in multiple cancer types, although not at high levels.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (83, 92))	('AKT', 'Gene', (96, 99))	('AKT', 'Gene', '207', (96, 99))	('AKT', 'Gene', '207', (16, 19))	('AKT', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('AKT', 'Gene', (16, 19))	('core', 'cellular_component', 'GO:0019013', ('25', '29'))	('AKT', 'Gene', '207', (52, 55))	('amplification', 'Var', (65, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('47', '51'))	('identified', 'Reg', (119, 129))	('cancer', 'Disease', (142, 148))
13877	26233890	Amplification of AKT2 was first identified in ovarian cancer and then in multiple other cancers, including pancreatic, gastric, liver, and lung cancers.	('liver', 'Disease', (128, 133))	('lung cancers', 'Disease', 'MESH:D008175', (139, 151))	('ovarian cancer', 'Disease', (46, 60))	('lung cancers', 'Disease', (139, 151))	('AKT2', 'Gene', '208', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pancreatic', 'Disease', (107, 117))	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('AKT2', 'Gene', (17, 21))	('identified', 'Reg', (32, 42))	('cancers', 'Disease', (144, 151))	('gastric', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Amplification', 'Var', (0, 13))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('pancreatic', 'Disease', 'MESH:D010195', (107, 117))	('cancers', 'Disease', 'MESH:D009369', (144, 151))
13878	26233890	The latest TCGA data show that AKT amplifications are prevalent in ovarian (21%), uterine (20%), invasive breast (18%), liver (15%), and bladder (12%) cancers.	('invasive breast', 'Disease', (97, 112))	('AKT', 'Gene', '207', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('AKT', 'Gene', (31, 34))	('prevalent', 'Reg', (54, 63))	('liver', 'Disease', (120, 125))	('uterine', 'Disease', (82, 89))	('amplifications', 'Var', (35, 49))	('bladder', 'Disease', (137, 144))	('ovarian', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('ovarian', 'Disease', 'MESH:D010051', (67, 74))
13881	26233890	E17K mutation was first identified in AKT1 in breast, colorectal, and ovarian cancers as an oncogenic mutation, and was then identified in more cancer types and in the AKT3 isoform.	('AKT3', 'Gene', (168, 172))	('colorectal', 'Disease', 'MESH:D015179', (54, 64))	('AKT1', 'Gene', '207', (38, 42))	('E17K mutation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('cancer', 'Disease', (144, 150))	('breast', 'Disease', (46, 52))	('ovarian cancers', 'Disease', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ovarian cancers', 'Disease', 'MESH:D010051', (70, 85))	('E17K', 'Mutation', 'rs121434592', (0, 4))	('AKT1', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (78, 84))	('colorectal', 'Disease', (54, 64))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('ovarian cancers', 'Phenotype', 'HP:0100615', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('AKT3', 'Gene', '10000', (168, 172))
13882	26233890	This mutation enhances the association of AKT with the cell membrane, promoting AKT activation.	('AKT', 'Gene', '207', (80, 83))	('AKT', 'Gene', (42, 45))	('activation', 'PosReg', (84, 94))	('association', 'Interaction', (27, 38))	('promoting', 'PosReg', (70, 79))	('AKT', 'Gene', (80, 83))	('enhances', 'PosReg', (14, 22))	('cell membrane', 'cellular_component', 'GO:0005886', ('55', '68'))	('AKT', 'Gene', '207', (42, 45))	('mutation', 'Var', (5, 13))
13883	26233890	At the layer downstream of AKT, mutations in TSC1/TSC2 have been identified but are relatively rare.	('AKT', 'Gene', (27, 30))	('TSC2', 'Gene', '7249', (50, 54))	('TSC1', 'Gene', '7248', (45, 49))	('mutations', 'Var', (32, 41))	('AKT', 'Gene', '207', (27, 30))	('TSC2', 'Gene', (50, 54))	('TSC1', 'Gene', (45, 49))
13886	26233890	More recently, a recurring activation mutation (Y35N) was identified in endometrial cancer and ccRCC, validating the oncogenic role of RHEB in the PI3K/AKT pathway.	('Y35N', 'Mutation', 'rs1057519949', (48, 52))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('AKT', 'Gene', '207', (152, 155))	('endometrial cancer', 'Disease', (72, 90))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('AKT', 'Gene', (152, 155))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('147', '151'))	('activation', 'PosReg', (27, 37))	('Y35N', 'Var', (48, 52))
13887	26233890	In summary, most components of the PI3K/AKT pathway harbor genetic alterations that activate the pathway across cancer lineages.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('AKT', 'Gene', '207', (40, 43))	('AKT', 'Gene', (40, 43))	('activate', 'PosReg', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('genetic alterations', 'Var', (59, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
13888	26233890	Next, we summarize the genetic alterations of the PI3K/AKT pathway specifically in the three major types of RCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('AKT', 'Gene', (55, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('genetic alterations', 'Var', (23, 42))	('AKT', 'Gene', '207', (55, 58))
13900	26233890	However, loss of VHL function alone is not sufficient for ccRCC initiation.	('VHL', 'Disease', (17, 20))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('loss', 'Var', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (60, 63))
13903	26233890	In the TCGA ccRCC dataset, the overall genetic alteration rate of the 20 representative PI3K/AKT pathway panel components in our analysis was 27.7% (Fig.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('genetic alteration', 'Var', (39, 57))	('RCC', 'Disease', (14, 17))	('AKT', 'Gene', (93, 96))	('PI3K', 'molecular_function', 'GO:0016303', ('88', '92'))	('AKT', 'Gene', '207', (93, 96))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
13904	26233890	Most of the components were identified with genetic alterations, including GNB2L1 amplification (6%), PIK3CA amplifications or mutations (5%), PTEN deletions or mutations (5%), or MTOR mutations (6%), in a largely mutually exclusive manner (Fig.	('amplification', 'PosReg', (82, 95))	('amplifications', 'PosReg', (109, 123))	('MTOR', 'Gene', (180, 184))	('GNB2L1', 'Gene', '10399', (75, 81))	('PIK3CA', 'Gene', (102, 108))	('GNB2L1', 'Gene', (75, 81))	('PTEN', 'Gene', '5728', (143, 147))	('MTOR', 'Gene', '2475', (180, 184))	('PIK3CA', 'Gene', '5290', (102, 108))	('deletions', 'Var', (148, 157))	('mutations', 'Var', (161, 170))	('PTEN', 'Gene', (143, 147))	('mutations', 'Var', (185, 194))	('mutations', 'Var', (127, 136))
13905	26233890	MTOR mutations are highly clustered in small regions in ccRCC, conferring mTOR hyperactivation.	('hyperactivation', 'PosReg', (79, 94))	('mutations', 'Var', (5, 14))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('MTOR', 'Gene', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('MTOR', 'Gene', '2475', (0, 4))
13906	26233890	Seven AKT mutations (~2%) were identified, including a known E40K activation mutation in AKT1 and an E17K activation mutation in AKT3.	('AKT', 'Gene', (6, 9))	('AKT1', 'Gene', '207', (89, 93))	('E40K', 'Var', (61, 65))	('E17K', 'Mutation', 'rs121434592', (101, 105))	('AKT', 'Gene', '207', (129, 132))	('E40K', 'Mutation', 'p.E40K', (61, 65))	('AKT1', 'Gene', (89, 93))	('AKT', 'Gene', '207', (89, 92))	('E17K', 'Var', (101, 105))	('AKT3', 'Gene', (129, 133))	('AKT', 'Gene', '207', (6, 9))	('AKT3', 'Gene', '10000', (129, 133))	('AKT', 'Gene', (89, 92))	('AKT', 'Gene', (129, 132))	('activation', 'PosReg', (66, 76))
13907	26233890	Three recurrent Y35N mutations in RHEB were identified, consistent with activation of the PI3K/AKT pathway.	('activation', 'PosReg', (72, 82))	('RHEB', 'Gene', (34, 38))	('AKT', 'Gene', '207', (95, 98))	('Y35N', 'Var', (16, 20))	('Y35N', 'Mutation', 'rs1057519949', (16, 20))	('AKT', 'Gene', (95, 98))	('PI3K', 'molecular_function', 'GO:0016303', ('90', '94'))
13910	26233890	Furthermore, considering the dysregulation of the PI3K/AKT pathway at epigenetic, posttranscriptional, and posttranslational levels, the aberrant pathway activation is likely more prevalent in ccRCC.	('AKT', 'Gene', (55, 58))	('PI3K', 'molecular_function', 'GO:0016303', ('50', '54'))	('activation', 'PosReg', (154, 164))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('AKT', 'Gene', '207', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('aberrant', 'Var', (137, 145))	('RCC', 'Disease', (195, 198))
13921	26233890	In addition to alterations in the VHL/HIF and PI3K/AKT pathways, high frequencies of gene mutations or deletions of PBRM1 (36%), SETD2 (15%), BAP1 (13%), and KDM5C (7%) have also been identified in the ccRCC TCGA dataset and other studies (Varela et al., 2011).	('SETD2', 'Gene', '29072', (129, 134))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('PBRM1', 'Gene', (116, 121))	('SETD2', 'Gene', (129, 134))	('BAP1', 'Gene', '8314', (142, 146))	('AKT', 'Gene', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', (204, 207))	('PBRM1', 'Gene', '55193', (116, 121))	('VHL', 'Disease', 'MESH:D006623', (34, 37))	('VHL', 'Disease', (34, 37))	('KDM5C', 'Gene', (158, 163))	('alterations', 'Reg', (15, 26))	('deletions', 'Var', (103, 112))	('BAP1', 'Gene', (142, 146))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('KDM5C', 'Gene', '8242', (158, 163))	('AKT', 'Gene', '207', (51, 54))
13922	26233890	Notably, all of these genes play important roles in chromatin remodeling, indicating that dysregulation of chromatin remodeling is a generalizable event in ccRCC.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('52', '72'))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('dysregulation', 'Var', (90, 103))	('chromatin', 'cellular_component', 'GO:0000785', ('107', '116'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('107', '127'))
13925	26233890	In the TCGA pRCC dataset, the overall genetic alteration rate of the PI3K/AKT pathway panel components was 28% (Fig.	('PI3K', 'molecular_function', 'GO:0016303', ('69', '73'))	('AKT', 'Gene', '207', (74, 77))	('genetic alteration', 'Var', (38, 56))	('pRCC', 'Gene', '5546', (12, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('AKT', 'Gene', (74, 77))	('pRCC', 'Gene', (12, 16))
13926	26233890	2), including amplifications of GNB2L1, PDK1, and RPTOR and mutations of PTEN and the PI3K subunits, many of which are known to activate the signaling pathway.	('PTEN', 'Gene', (73, 77))	('PDK1', 'Gene', (40, 44))	('RPTOR', 'Gene', '57521', (50, 55))	('GNB2L1', 'Gene', (32, 38))	('PTEN', 'Gene', '5728', (73, 77))	('signaling pathway', 'Pathway', (141, 158))	('GNB2L1', 'Gene', '10399', (32, 38))	('amplifications', 'Var', (14, 28))	('activate', 'PosReg', (128, 136))	('PDK1', 'Gene', '5170', (40, 44))	('signaling pathway', 'biological_process', 'GO:0007165', ('141', '158'))	('mutations', 'Var', (60, 69))	('PDK1', 'molecular_function', 'GO:0004740', ('40', '44'))	('PI3K', 'molecular_function', 'GO:0016303', ('86', '90'))	('RPTOR', 'Gene', (50, 55))
13928	26233890	Studies of hereditary pRCC revealed that type 1 pRCC is associated with mutations of the mesenchymal epithelial transition (MET) gene.	('mutations', 'Var', (72, 81))	('mesenchymal epithelial transition', 'biological_process', 'GO:0060231', ('89', '122'))	('pRCC', 'Gene', '5546', (48, 52))	('pRCC', 'Gene', (22, 26))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('MET', 'Gene', (124, 127))	('associated', 'Reg', (56, 66))	('pRCC', 'Gene', '5546', (22, 26))	('pRCC', 'Gene', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))
13930	26233890	Activation mutations of MET found in type 1 pRCC lead to increased proliferation, invasion, and metastases, owing at least in part to activation of the PI3K/AKT pathway.	('pRCC', 'Gene', (44, 48))	('mutations', 'Var', (11, 20))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('invasion', 'CPA', (82, 90))	('PI3K', 'molecular_function', 'GO:0016303', ('152', '156'))	('activation', 'PosReg', (134, 144))	('MET', 'Gene', (24, 27))	('AKT', 'Gene', '207', (157, 160))	('proliferation', 'CPA', (67, 80))	('pRCC', 'Gene', '5546', (44, 48))	('increased', 'PosReg', (57, 66))	('AKT', 'Gene', (157, 160))	('metastases', 'Disease', (96, 106))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
13931	26233890	Kinases activated by gene fusions are found in most cancer types, including pRCC.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('pRCC', 'Gene', '5546', (76, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('pRCC', 'Gene', (76, 80))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene fusions', 'Var', (21, 33))
13933	26233890	Type 2 pRCC was found to be associated with mutations in fumarate hydratase (FH).	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('fumarate hydratase', 'Gene', (57, 75))	('associated', 'Reg', (28, 38))	('FH', 'Gene', '2271', (77, 79))	('pRCC', 'Gene', (7, 11))	('mutations', 'Var', (44, 53))	('fumarate hydratase', 'Gene', '2271', (57, 75))	('pRCC', 'Gene', '5546', (7, 11))
13935	26233890	Loss of FH function owing to mutations results in accumulation of fumarate, leading to upregulation of HIF1alpha, which mimics the loss of VHL in ccRCC.	('VHL', 'Disease', (139, 142))	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('mutations', 'Var', (29, 38))	('FH', 'Gene', '2271', (8, 10))	('HIF1alpha', 'Gene', (103, 112))	('Loss', 'NegReg', (0, 4))	('fumarate', 'Chemical', 'MESH:D005650', (66, 74))	('accumulation', 'PosReg', (50, 62))	('HIF1alpha', 'Gene', '3091', (103, 112))	('VHL', 'Disease', 'MESH:D006623', (139, 142))	('fumarate', 'MPA', (66, 74))	('upregulation', 'PosReg', (87, 99))
13940	26233890	Mutations and CNAs have also been identified in multiple other components, including PDK1, AKT1, TSC1/TSC2, and mTOR.	('TSC2', 'Gene', (102, 106))	('AKT1', 'Gene', '207', (91, 95))	('TSC1', 'Gene', (97, 101))	('AKT1', 'Gene', (91, 95))	('PDK1', 'Gene', '5170', (85, 89))	('PDK1', 'Gene', (85, 89))	('PDK1', 'molecular_function', 'GO:0004740', ('85', '89'))	('Mutations', 'Var', (0, 9))	('mTOR', 'Gene', '2475', (112, 116))	('TSC2', 'Gene', '7249', (102, 106))	('mTOR', 'Gene', (112, 116))	('identified', 'Reg', (34, 44))	('TSC1', 'Gene', '7248', (97, 101))
13948	26233890	AKT is selectively phosphorylated on Thr308 through enhanced protein complex formation with PDK1 and 78-kDa glucose-regulated protein under glucose-deprivation conditions, which likely represents a novel AKT activation mechanism in RCC, as well as in other cancers when metabolic stress is present.	('AKT', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('78-kDa glucose-regulated protein', 'Gene', '3309', (101, 133))	('protein complex formation', 'biological_process', 'GO:0065003', ('61', '86'))	('PDK1', 'Gene', '5170', (92, 96))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('PDK1', 'Gene', (92, 96))	('glucose-deprivation conditions', 'Disease', 'MESH:D012892', (140, 170))	('RCC', 'Disease', (232, 235))	('78-kDa glucose-regulated protein', 'Gene', (101, 133))	('AKT', 'Gene', '207', (0, 3))	('AKT', 'Gene', (204, 207))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('glucose-deprivation conditions', 'Disease', (140, 170))	('protein', 'cellular_component', 'GO:0003675', ('126', '133'))	('protein complex', 'cellular_component', 'GO:0032991', ('61', '76'))	('Thr308', 'Var', (37, 43))	('RCC', 'Disease', 'MESH:C538614', (232, 235))	('PDK1', 'molecular_function', 'GO:0004740', ('92', '96'))	('protein', 'Protein', (61, 68))	('AKT', 'Gene', '207', (204, 207))	('enhanced', 'PosReg', (52, 60))	('Thr308', 'Chemical', '-', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancers', 'Disease', (257, 264))
13969	26233890	A new class of mTOR inhibitors that directly target mTOR kinase activity, including AZD8055, MLN0128, and OSI-027, are in clinical development and clinical trials for the treatment of ccRCC.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('MLN0128', 'Var', (93, 100))	('AZD8055', 'Chemical', 'MESH:C546624', (84, 91))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('mTOR', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('RCC', 'Disease', (186, 189))	('mTOR', 'Gene', '2475', (15, 19))	('MLN0128', 'Chemical', 'MESH:C572449', (93, 100))	('kinase activity', 'molecular_function', 'GO:0016301', ('57', '72'))	('AZD8055', 'Var', (84, 91))	('OSI-027', 'Chemical', 'MESH:C568605', (106, 113))
13972	26233890	Numerous pan or isoform specific PI3K inhibitors are in clinical development or clinical trials in RCC including GDC0941, XL147, BKM120, NVP-BYL719 (p110alpha specific), SAR260301 (p110beta specific), and TGR-1202 (p110beta specific).	('p110beta', 'Gene', '5291', (215, 223))	('p110alpha', 'Gene', (149, 158))	('p110alpha', 'Gene', '5290', (149, 158))	('p110beta', 'Gene', (215, 223))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('p110beta', 'Gene', '5291', (181, 189))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('SAR260301', 'Var', (170, 179))	('GDC0941', 'Var', (113, 120))	('p110beta', 'Gene', (181, 189))	('PI3K', 'molecular_function', 'GO:0016303', ('33', '37'))
13975	26233890	Allosteric AKT inhibitors (such as MK2206) and kinase inhibitors (such as GDC0068 and AZD5663) are being tested in ccRCC clinical trials.	('AKT', 'Gene', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('AZD5663', 'Chemical', '-', (86, 93))	('MK2206', 'Chemical', 'MESH:C548887', (35, 41))	('GDC0068', 'Chemical', 'MESH:C583616', (74, 81))	('AKT', 'Gene', '207', (11, 14))	('MK2206', 'Var', (35, 41))
13983	26233890	Considering that one-third of all VHL mutations in ccRCC are missense point mutations, generating a full-length unstable protein with residual functionality, we proposed that destabilized VHL could be refunctionalized by modulating the proteostasis of missense point mutated VHL, and we provided evidence that the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q, the most common hereditary mutation, and increase its ability to downregulate HIF2alpha.	('proteasome', 'molecular_function', 'GO:0004299', ('314', '324'))	('bortezomib', 'Chemical', 'MESH:D000069286', (336, 346))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('carfilzomib', 'Chemical', 'MESH:C524865', (351, 362))	('HIF2alpha', 'Gene', '2034', (500, 509))	('VHL', 'Disease', 'MESH:D006623', (188, 191))	('proteasome', 'cellular_component', 'GO:0000502', ('314', '324'))	('VHL', 'Disease', 'MESH:D006623', (411, 414))	('VHL', 'Disease', 'MESH:D006623', (275, 278))	('VHL', 'Disease', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('mutations', 'Var', (38, 47))	('downregulate', 'NegReg', (487, 499))	('R167Q', 'Mutation', 'rs5030821', (415, 420))	('VHL', 'Disease', (188, 191))	('VHL', 'Disease', 'MESH:D006623', (34, 37))	('VHL', 'Disease', (411, 414))	('VHL', 'Disease', (275, 278))	('HIF2alpha', 'Gene', (500, 509))	('stabilize', 'PosReg', (401, 410))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))
14016	25568749	Chromosomal and cytogenetic analyses have revealed gain of chromosomes 7 and 17, loss of Y chromosome, and additional gains (chromosome 3q,8p,12q,16q, and 20q) in type I pRCC, but the chromosomal aberrations of type II pRCC seems to be more heterogeneous.	('pRCC', 'Gene', '5546', (219, 223))	('chromosome', 'cellular_component', 'GO:0005694', ('125', '135'))	('gain', 'PosReg', (51, 55))	('pRCC', 'Phenotype', 'HP:0006766', (219, 223))	('pRCC', 'Gene', '5546', (170, 174))	('Y chromosome', 'cellular_component', 'GO:0000806', ('89', '101'))	('gains', 'PosReg', (118, 123))	('pRCC', 'Phenotype', 'HP:0006766', (170, 174))	('pRCC', 'Gene', (219, 223))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (184, 207))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('loss', 'NegReg', (81, 85))	('pRCC', 'Gene', (170, 174))	('chromosome 3q,8p,12q,16q', 'Var', (125, 149))
14092	24675233	Large-scale genetic sequencing of ccRCC tumors has identified a high frequency of mutations in several genes that are involved in the chromatin remodeling process.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('134', '154'))	('RCC', 'Disease', (36, 39))	('chromatin', 'cellular_component', 'GO:0000785', ('134', '143'))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
14095	24675233	In a second study, mutations in the genes encoding the SET domain containing 2 (SETD2) and BRCA-1 associated protein-1 (BAP1) were found in 4% and 8%, respectively, of 98 ccRCC tumors evaluated.	('found', 'Reg', (131, 136))	('RCC', 'Disease', (173, 176))	('SETD2', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('BRCA-1 associated protein-1', 'Gene', (91, 118))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('BAP1', 'Gene', '8314', (120, 124))	('tumors', 'Disease', (177, 183))	('BRCA-1 associated protein-1', 'Gene', '8314', (91, 118))	('SETD2', 'Gene', '29072', (80, 85))	('BAP1', 'Gene', (120, 124))
14097	24675233	In one study, targeted sequencing on 185 ccRCC and matched normal tissue confirmed that PBRM1, BAP1, and SETD2 were mutated in 29%, 6%, and 8% of the cases, respectively.	('SETD2', 'Gene', '29072', (105, 110))	('PBRM1', 'Gene', (88, 93))	('PBRM1', 'Gene', '55193', (88, 93))	('BAP1', 'Gene', (95, 99))	('SETD2', 'Gene', (105, 110))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('BAP1', 'Gene', '8314', (95, 99))	('mutated', 'Var', (116, 123))
14099	24675233	Tumors with mutations in any one of these genes were more likely to present with stage III disease or higher (P=0.01 and P=0.001, respectively).	('mutations', 'Var', (12, 21))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('stage III disease', 'Disease', (81, 98))
14100	24675233	BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (P=0.052) and are associated with worse cancer specific survival.	('associated', 'Reg', (78, 88))	('BAP1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('III-IV tumors', 'Disease', 'MESH:D009369', (46, 59))	('III-IV tumors', 'Disease', (46, 59))	('worse', 'NegReg', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('occur', 'Reg', (23, 28))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('BAP1', 'Gene', '8314', (0, 4))
14101	24675233	Another study evaluating PBRM1 and BAP1 mutations in 145 patients with ccRCC reported that median overall survival (OS) was significantly shorter for patients with BAP1 mutation than for patients with PBRM1 mutation (4.6 vs. 10.6 years, HR 2.7, 95%CI 0.99-7.6, P=0.044); These findings were validated in an independent cohort from The Cancer Genome Atlas (TCGA) study (Median OS 1.9 vs. 5.4 years, for BAP 1 and PBRM1 respectively, HR 2.8, 95%CI 1.4-5.9; P=0.004).	('PBRM1', 'Gene', '55193', (201, 206))	('Cancer Genome Atlas', 'Disease', (335, 354))	('patients', 'Species', '9606', (150, 158))	('BAP1', 'Gene', (35, 39))	('BAP 1', 'Gene', '8314', (402, 407))	('PBRM1', 'Gene', '55193', (25, 30))	('PBRM1', 'Gene', (201, 206))	('patients', 'Species', '9606', (187, 195))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('shorter', 'NegReg', (138, 145))	('mutations', 'Var', (40, 49))	('PBRM1', 'Gene', (25, 30))	('BAP 1', 'Gene', (402, 407))	('PBRM1', 'Gene', '55193', (412, 417))	('BAP1', 'Gene', '8314', (164, 168))	('mutation', 'Var', (169, 177))	('RCC', 'Disease', (73, 76))	('PBRM1', 'Gene', (412, 417))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('patients', 'Species', '9606', (57, 65))	('BAP1', 'Gene', (164, 168))	('BAP1', 'Gene', '8314', (35, 39))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (335, 354))	('overall survival', 'MPA', (98, 114))
14102	24675233	Patients with mutations in both PBRM1 and BAP1 had the worst OS in both cohorts (median 2.1 years, 95%CI 0.3-3.8 for study cohort, and 0.2 years, 95%CI 0-1.2 for the TCGA cohort).	('BAP1', 'Gene', '8314', (42, 46))	('PBRM1', 'Gene', (32, 37))	('PBRM1', 'Gene', '55193', (32, 37))	('BAP1', 'Gene', (42, 46))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (14, 23))
14104	24675233	In an analysis of primary ccRCC tumors obtained from over 400 nephrectomy specimens, this study confirmed the presence of previously described mutations in VHL and in genes encoding chromatin remodeling proteins.	('men', 'Species', '9606', (79, 82))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('VHL', 'Gene', (156, 159))	('VHL', 'Gene', '7428', (156, 159))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('182', '202'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('chromatin', 'cellular_component', 'GO:0000785', ('182', '191'))	('tumors', 'Disease', (32, 38))	('RCC', 'Disease', (28, 31))	('mutations', 'Var', (143, 152))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
14107	24675233	While identification of genetic and epigenetic alterations beyond those affecting VHL activity is a step forward in furthering our understanding of the complex molecular changes underlying ccRCC, it must be emphasized that the precise role of these aberrations remain unclear.	('RCC', 'Disease', (191, 194))	('RCC', 'Disease', 'MESH:C538614', (191, 194))	('epigenetic alterations', 'Var', (36, 58))	('VHL', 'Gene', (82, 85))	('VHL', 'Gene', '7428', (82, 85))
14115	24675233	In contrast, there was a higher discontinuation rate in the pazopanib group (24%) compared to the sunitinib group (20%), which was primarily due to a significantly higher rate of liver function abnormalities.	('pazopanib', 'Chemical', 'MESH:C516667', (60, 69))	('discontinuation', 'MPA', (32, 47))	('liver function abnormalities', 'Disease', (179, 207))	('higher', 'PosReg', (164, 170))	('pazopanib', 'Var', (60, 69))	('liver function abnormalities', 'Disease', 'MESH:D056486', (179, 207))	('sunitinib', 'Chemical', 'MESH:D000077210', (98, 107))	('higher rate of liver function abnormalities', 'Phenotype', 'HP:0002910', (164, 207))
14132	24675233	791 patients with previously untreated metastatic ccRCC were randomized to one of the aforementioned groups; the primary endpoint was PFS.	('PFS', 'Var', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('men', 'Species', '9606', (91, 94))	('patients', 'Species', '9606', (4, 12))
14164	24675233	A phase I dose escalating trial with BMS-936559, a PD-L1 specific monoclonal antibody, was conducted in patients with advanced solid tumors.	('BMS-936559', 'Var', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('solid tumors', 'Disease', (127, 139))	('antibody', 'molecular_function', 'GO:0003823', ('77', '85'))	('antibody', 'cellular_component', 'GO:0042571', ('77', '85'))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('solid tumors', 'Disease', 'MESH:D009369', (127, 139))	('antibody', 'cellular_component', 'GO:0019815', ('77', '85'))	('antibody', 'cellular_component', 'GO:0019814', ('77', '85'))	('patients', 'Species', '9606', (104, 112))
14174	24675233	The role of this pathway in sporadic forms of pRCC remains under investigation, but somatic mutations of MET, as well as duplication of the chromosome bearing both MET and its ligand HGF(chromosome 7), have been seen in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('pRCC', 'Gene', '5546', (46, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('187', '197'))	('mutations', 'Var', (92, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('HGF', 'Gene', (183, 186))	('duplication', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('seen', 'Reg', (212, 216))	('HGF', 'Gene', '3082', (183, 186))	('ligand', 'molecular_function', 'GO:0005488', ('176', '182'))	('MET', 'Gene', (105, 108))	('pRCC', 'Gene', (46, 50))
14175	24675233	A second form of hereditary pRCC is associated with alterations in the fumarate hydratase gene (FH), which encodes a TCA cycle enzyme that catalyzes the conversion of fumarate to malate.	('malate', 'Chemical', 'MESH:C030298', (179, 185))	('fumarate hydratase', 'Gene', (71, 89))	('pRCC', 'Gene', '5546', (28, 32))	('alterations', 'Var', (52, 63))	('fumarate', 'Chemical', 'MESH:D005650', (71, 79))	('fumarate', 'Chemical', 'MESH:D005650', (167, 175))	('FH', 'Gene', (96, 98))	('pRCC', 'Gene', (28, 32))	('TCA cycle', 'biological_process', 'GO:0006099', ('117', '126'))	('TCA', 'Chemical', 'MESH:D014238', (117, 120))	('associated', 'Reg', (36, 46))	('fumarate hydratase', 'Gene', '2271', (71, 89))
14176	24675233	Germline FH mutations are seen in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC), a condition associated with a highly aggressive variant of type II pRCC.	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (48, 95))	('pRCC', 'Gene', '5546', (172, 176))	('renal cell cancer', 'Phenotype', 'HP:0005584', (78, 95))	('RCC', 'Disease', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('mutations', 'Var', (12, 21))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('pRCC', 'Gene', (172, 176))	('RCC', 'Disease', (99, 102))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
14177	24675233	Loss of FH activity promotes a metabolic shift in these tumors, characterized by disruption of the Krebs cycle and a consequent reliance on aerobic glycolysis to satisfy cellular bioenergetic requirements.	('Krebs', 'Pathway', (99, 104))	('men', 'Species', '9606', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('metabolic', 'MPA', (31, 40))	('glycolysis', 'biological_process', 'GO:0006096', ('148', '158'))	('Krebs', 'Chemical', '-', (99, 104))	('FH activity', 'Gene', (8, 19))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('Krebs cycle', 'biological_process', 'GO:0006099', ('99', '110'))	('Loss', 'Var', (0, 4))
14178	24675233	It has long been recognized that accumulation of fumarate, resulting from FH inactivation, leads to a VHL-independent upregulation of intracellular HIF, and transcriptional activation of downstream proangiogenic and growth factors.	('upregulation', 'PosReg', (118, 130))	('intracellular HIF', 'MPA', (134, 151))	('activation', 'PosReg', (173, 183))	('intracellular', 'cellular_component', 'GO:0005622', ('134', '147'))	('VHL', 'Gene', (102, 105))	('fumarate', 'Chemical', 'MESH:D005650', (49, 57))	('VHL', 'Gene', '7428', (102, 105))	('accumulation', 'PosReg', (33, 45))	('transcriptional', 'MPA', (157, 172))	('inactivation', 'Var', (77, 89))
14202	24675233	Selective VEGFR inhibitors might be better tolerated compared to first generation agents such as sunitinib, without significant differences in clinical activity.	('VEGFR', 'Gene', '3791', (10, 15))	('sunitinib', 'Chemical', 'MESH:D000077210', (97, 106))	('inhibitors', 'Var', (16, 26))	('VEGFR', 'Gene', (10, 15))
14229	33819300	Both betaglycan and endoglin knockouts (KOs) are lethal during embryonic development due to heart and liver defects and defective vascular development, respectively, highlighting the shared physiological importance of these coreceptors.	('betaglycan', 'molecular_function', 'GO:0070123', ('5', '15'))	('endoglin', 'molecular_function', 'GO:0070123', ('20', '28'))	('endoglin', 'Gene', '2022', (20, 28))	('knockouts', 'Var', (29, 38))	('defective', 'NegReg', (120, 129))	('liver defects', 'Disease', (102, 115))	('liver defects', 'Phenotype', 'HP:0001392', (102, 115))	('betaglycan', 'Gene', (5, 15))	('endoglin', 'Gene', (20, 28))	('embryonic', 'Disease', 'MESH:D020964', (63, 72))	('betaglycan', 'Gene', '7049', (5, 15))	('liver defects', 'Disease', 'MESH:D056486', (102, 115))	('embryonic', 'Disease', (63, 72))
14235	33819300	Evidence in ovarian cancer also suggests that endoglin expression may impact metastasis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('endoglin', 'Gene', (46, 54))	('endoglin', 'molecular_function', 'GO:0070123', ('46', '54'))	('ovarian cancer', 'Disease', (12, 26))	('metastasis', 'CPA', (77, 87))	('endoglin', 'Gene', '2022', (46, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (12, 26))	('impact', 'Reg', (70, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (12, 26))	('expression', 'Var', (55, 65))
14243	33819300	Similarly a peptide domain of betaglycan called p144 and soluble betaglycan have been tested in multiple cancer types as an anti-TGF-beta treatment strategy that decreases tumor growth, angiogenesis, metastasis, and augments immunotherapy.	('immunotherapy', 'CPA', (225, 238))	('angiogenesis', 'CPA', (186, 198))	('angiogenesis', 'biological_process', 'GO:0001525', ('186', '198'))	('decreases tumor', 'Disease', (162, 177))	('cancer', 'Disease', (105, 111))	('augments', 'NegReg', (216, 224))	('p144', 'Var', (48, 52))	('rat', 'Species', '10116', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('betaglycan', 'Gene', (65, 75))	('TGF-beta', 'Gene', '7039', (129, 137))	('decreases tumor', 'Disease', 'MESH:D002303', (162, 177))	('betaglycan', 'Gene', '7049', (65, 75))	('betaglycan', 'molecular_function', 'GO:0070123', ('30', '40'))	('TGF-beta', 'Gene', (129, 137))	('soluble', 'cellular_component', 'GO:0005625', ('57', '64'))	('betaglycan', 'molecular_function', 'GO:0070123', ('65', '75'))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('betaglycan', 'Gene', (30, 40))	('betaglycan', 'Gene', '7049', (30, 40))	('metastasis', 'CPA', (200, 210))
14253	33819300	The Affymetrix Probe IDs used in gene chip analysis in KM Plotter were: INHA (210141_s_at), INHBA (204926_at), INHBB (205258_at), TGFBR3 (204731_at), and ENG (201808_s_at).	('210141_s_at', 'Var', (78, 89))	('204926_at', 'Var', (99, 108))	('INHBA', 'Gene', (92, 97))	('INHBB', 'Gene', (111, 116))	('INHBB', 'Gene', '3625', (111, 116))	('205258_at', 'Var', (118, 127))	('204731_at', 'Var', (138, 147))	('INHBA', 'Gene', '3624', (92, 97))
14275	33819300	To begin to evaluate the impact of this relationship more broadly in cancers we analyzed gene alterations including mutations, amplifications, and deletions for the genes encoding inhibin/activin subunits (Fig 1a) INHA, INHBA, INHBB, and the key coreceptors:TGFBR3, and ENG in all public datasets available in cBioPortal (Fig 1b, S1 Table).	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('INHBB', 'Gene', (227, 232))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('TGFBR3', 'Gene', (258, 264))	('activin', 'molecular_function', 'GO:0005160', ('188', '195'))	('activin', 'molecular_function', 'GO:0016915', ('188', '195'))	('inhibin', 'molecular_function', 'GO:0016916', ('180', '187'))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('inhibin', 'molecular_function', 'GO:0005160', ('180', '187'))	('activin', 'Gene', (188, 195))	('deletions', 'Var', (147, 156))	('INHBA', 'Gene', '3624', (220, 225))	('rat', 'Species', '10116', (98, 101))	('INHBB', 'Gene', '3625', (227, 232))	('activin', 'Gene', '83729', (188, 195))	('INHBA', 'Gene', (220, 225))	('cancers', 'Disease', (69, 76))
14288	33819300	For these analyses, we used the DepMap project (www.depmap.org) which is a comprehensive library of human genes that have been either knocked down or knocked out through CRISPR technology in 1,776 human cell lines representing multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('knocked', 'Var', (134, 141))	('cancer', 'Disease', (236, 242))	('human', 'Species', '9606', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('human', 'Species', '9606', (197, 202))	('knocked out', 'NegReg', (150, 161))
14294	33819300	In an attempt to identify genes most impacted by alteration to each of the individual genes, we examined how RNAi and CRISPR interventions would affect their correlation to specific genes.	('RNAi', 'biological_process', 'GO:0016246', ('109', '113'))	('affect', 'Reg', (145, 151))	('rat', 'Species', '10116', (53, 56))	('alteration', 'Var', (49, 59))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('correlation', 'MPA', (158, 169))
14298	33819300	Since alterations in expression of inhibin, activin, TGFBR3 and ENG exist in human cancers and prior studies have implicated each of these in patient outcomes; we conducted a comprehensive analysis of each of these genes on overall survival (OS), progression-free survival (PFS), or relapse free survival (RFS) in a broad panel of cancers.	('alterations', 'Var', (6, 17))	('activin', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ENG', 'Gene', (64, 67))	('cancers', 'Disease', 'MESH:D009369', (331, 338))	('relapse', 'Disease', (283, 290))	('TGFBR3', 'Gene', (53, 59))	('activin', 'Gene', '83729', (44, 51))	('activin', 'molecular_function', 'GO:0005160', ('44', '51'))	('patient', 'Species', '9606', (142, 149))	('overall', 'Disease', (224, 231))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('inhibin', 'molecular_function', 'GO:0016916', ('35', '42'))	('activin', 'molecular_function', 'GO:0016915', ('44', '51'))	('human', 'Species', '9606', (77, 82))	('cancers', 'Phenotype', 'HP:0002664', (331, 338))	('cancers', 'Disease', (331, 338))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('rat', 'Species', '10116', (10, 13))	('inhibin', 'molecular_function', 'GO:0005160', ('35', '42'))	('cancers', 'Disease', (83, 90))
14301	33819300	Patients in KM plotter with p53 mutation status known showed 83% were mutated, cBioportal data sets showed 82.5% frequency of p53 mutation, and it has been reported that over 90% of ovarian cancers present p53 mutations.	('p53', 'Gene', (28, 31))	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('p53', 'Gene', '7157', (126, 129))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('mutations', 'Var', (210, 219))	('p53', 'Gene', '7157', (28, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('mutation', 'Var', (130, 138))	('ovarian cancers', 'Phenotype', 'HP:0100615', (182, 197))	('Patients', 'Species', '9606', (0, 8))	('ovarian cancers', 'Disease', (182, 197))	('ovarian cancers', 'Disease', 'MESH:D010051', (182, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('p53', 'Gene', (126, 129))
14304	33819300	However, in p53 mutated cancers, INHA was a strong negative predictor of survival for both breast and ovarian cancers (HR = 1.99, p = 0.0056 and HR = 1.55, p = 0.0039, respectively), along with ENG in ovarian cancer (HR = 1.36, p = 0.0098, Figs 2 and 3).	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('negative', 'NegReg', (51, 59))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (91, 117))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (110, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('ovarian cancer', 'Disease', (201, 215))	('p53', 'Gene', '7157', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('ovarian cancers', 'Phenotype', 'HP:0100615', (102, 117))	('mutated', 'Var', (16, 23))	('p53', 'Gene', (12, 15))	('ovarian cancer', 'Disease', (102, 116))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
14318	33819300	In this analysis, we find that that when separating patients into high or low expressing TGFBR3 or ENG groups (Table 1) in p53 mutated breast cancers, where INHA is a negative predictor of survival in all patients (Fig 2), INHA was only a predictor of poor survival in patients with low TGFBR3 (HR = 2.29, p = 0.015) or low ENG (HR = 2.24, p = 0.035).	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))	('patients', 'Species', '9606', (205, 213))	('low', 'Var', (283, 286))	('mutated', 'Var', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('rat', 'Species', '10116', (45, 48))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('p53', 'Gene', (123, 126))	('breast cancers', 'Disease', (135, 149))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('p53', 'Gene', '7157', (123, 126))	('patients', 'Species', '9606', (269, 277))	('patients', 'Species', '9606', (52, 60))
14320	33819300	In contrast to breast and renal clear cell cancers where TGFBR3 and ENG both impacted the effect of INHA on survival, TGFBR3 levels did not change INHA's impact on p53 mutated serous ovarian cancers (Table 1).	('mutated', 'Var', (168, 175))	('impacted', 'Reg', (77, 85))	('p53', 'Gene', '7157', (164, 167))	('ovarian cancers', 'Phenotype', 'HP:0100615', (183, 198))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('serous ovarian cancers', 'Disease', (176, 198))	('breast and renal clear cell cancers', 'Disease', 'MESH:D001943', (15, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('ovarian cancer', 'Phenotype', 'HP:0100615', (183, 197))	('p53', 'Gene', (164, 167))	('serous ovarian cancers', 'Disease', 'MESH:D018284', (176, 198))	('effect', 'MPA', (90, 96))
14321	33819300	In ENG high p53 mutated serous ovarian cancer patients, INHA had a more significant negative prediction outcome (HR = 2.12, p = 1.8E-6) compared to ENG low (HR = 0.8, p = 0.18, Table 1).	('patients', 'Species', '9606', (46, 54))	('ENG', 'Gene', (3, 6))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (24, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('mutated', 'Var', (16, 23))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('high', 'Var', (7, 11))	('negative', 'NegReg', (84, 92))	('serous ovarian cancer', 'Disease', (24, 45))
14323	33819300	However, INHA remained a robust negative predictor of survival in lung adenocarcinomas patients expressing low ENG (HR = 2.12, p = 0.00041) but was not significant in ENG high expressing patients (HR = 1.25, p = 0.14) (Table 1).	('patients', 'Species', '9606', (187, 195))	('lung adenocarcinomas', 'Disease', (66, 86))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (66, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('low ENG', 'Var', (107, 114))	('negative', 'NegReg', (32, 40))	('patients', 'Species', '9606', (87, 95))
14324	33819300	Together, these findings suggest that INHA expression as a predictive tool for survival is influenced by the coreceptors ENG and TGFBR3 in renal clear cell, lung, and p53 mutated breast and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (190, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('ENG', 'Gene', (121, 124))	('influenced', 'Reg', (91, 101))	('mutated', 'Var', (171, 178))	('p53', 'Gene', '7157', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('p53', 'Gene', (167, 170))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (179, 205))	('TGFBR3', 'Gene', (129, 135))	('renal clear cell', 'Disease', (139, 155))	('lung', 'Disease', (157, 161))
14369	33819300	In both breast and ovarian cancers, INHA was a negative predictor of survival in patients that had p53 mutations indicating a potential dependency of INHA functions on the p53 status.	('mutations', 'Var', (103, 112))	('negative', 'NegReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ovarian cancers', 'Phenotype', 'HP:0100615', (19, 34))	('p53', 'Gene', '7157', (172, 175))	('patients', 'Species', '9606', (81, 89))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (8, 34))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (19, 33))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('p53', 'Gene', (172, 175))
14370	33819300	INHA expression alterations have been observed in p53 mutated adrenocortical tumors and INHA was suggested to be a contributing factor to tumorigenesis in these cancers.	('expression', 'MPA', (5, 15))	('tumor', 'Disease', (138, 143))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutated', 'Var', (54, 61))	('p53', 'Gene', (50, 53))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adrenocortical tumors', 'Disease', (62, 83))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('rat', 'Species', '10116', (20, 23))	('INHA', 'Gene', (0, 4))	('alterations', 'Reg', (16, 27))	('p53', 'Gene', '7157', (50, 53))	('tumor', 'Disease', (77, 82))
14371	33819300	One of the most characterized transcriptional activators of INHA is GATA4, which can also regulate p53 in cancer and could contribute to the different survival outcomes observed for INHA in p53 mutated cancers versus wild-type p53 cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('p53', 'Gene', (227, 230))	('cancer', 'Disease', (106, 112))	('GATA4', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancer', 'Disease', (231, 237))	('cancers', 'Disease', (231, 238))	('p53', 'Gene', '7157', (190, 193))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('p53', 'Gene', (190, 193))	('GATA4', 'Gene', '2626', (68, 73))	('mutated', 'Var', (194, 201))	('p53', 'Gene', '7157', (99, 102))	('regulate', 'Reg', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('p53', 'Gene', '7157', (227, 230))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('p53', 'Gene', (99, 102))	('cancer', 'Disease', (202, 208))
14372	33819300	INHA's link to functional outcomes in the background on p53 mutations remains to be fully elucidated.	('mutations', 'Var', (60, 69))	('p53', 'Gene', '7157', (56, 59))	('p53', 'Gene', (56, 59))
14374	33819300	In p53 mutated cancers, ENG remained a negative predictor.	('p53', 'Gene', '7157', (3, 6))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('p53', 'Gene', (3, 6))	('cancers', 'Disease', (15, 22))	('mutated', 'Var', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
14376	33819300	However, a previous study showed that positive ENG expression was associated with increased survival in breast cancer patients who had undergone anthracycline treatment.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('anthracycline', 'Chemical', 'MESH:D018943', (145, 158))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('positive', 'Var', (38, 46))	('breast cancer', 'Disease', (104, 117))	('survival', 'MPA', (92, 100))	('ENG', 'Protein', (47, 50))	('increased', 'PosReg', (82, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (118, 126))
14388	33819300	Expression of ENG and TGFBR3 was not significantly different between wild-type and p53 mutated cancers indicating p53 likely does not impact expression itself.	('p53', 'Gene', (83, 86))	('p53', 'Gene', (114, 117))	('mutated', 'Var', (87, 94))	('p53', 'Gene', '7157', (83, 86))	('p53', 'Gene', '7157', (114, 117))	('ENG', 'Gene', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TGFBR3', 'Gene', (22, 28))
14389	33819300	Whether protein secretion of these coreceptors is altered in these cancers is currently unknown, and cannot be ruled out, as previous studies have shown increased endoglin folding and maturation in p53 mutation settings.	('endoglin', 'Gene', (163, 171))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('maturation', 'MPA', (184, 194))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('increased', 'PosReg', (153, 162))	('endoglin', 'molecular_function', 'GO:0070123', ('163', '171'))	('mutation', 'Var', (202, 210))	('protein secretion', 'biological_process', 'GO:0009306', ('8', '25'))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('altered', 'Reg', (50, 57))	('p53', 'Gene', (198, 201))	('rat', 'Species', '10116', (188, 191))	('endoglin', 'Gene', '2022', (163, 171))	('p53', 'Gene', '7157', (198, 201))
14391	33819300	Alterations in protein maturation could explain the differential patient outcomes observed between wild-type and p53 mutated cancers, when assessing for ENG and TGFBR3, despite changes in expression not being observed.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('mutated', 'Var', (117, 124))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('protein', 'cellular_component', 'GO:0003675', ('15', '22'))	('protein maturation', 'MPA', (15, 33))	('p53', 'Gene', '7157', (113, 116))	('patient', 'Species', '9606', (65, 72))	('rat', 'Species', '10116', (27, 30))	('p53', 'Gene', (113, 116))	('protein maturation', 'biological_process', 'GO:0051604', ('15', '33'))	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Reg', (0, 11))
14395	33819300	We found INHA to only be a negative predictor of survival in patients expressing low ENG indicating INHA might act independent of either coreceptor in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('low', 'Var', (81, 84))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('ENG', 'Gene', (85, 88))
14492	28561705	These metabolic changes can result from genetic aberrations in metabolic enzymes themselves, but can also be a downstream consequence of activating mutations in numerous growth factors and oncogenes, loss of tumor suppressor signaling, or epigenetic alterations, all of which we will discuss in more detail in later sections of this manuscript.	('mutations', 'Var', (148, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('208', '224'))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('signaling', 'biological_process', 'GO:0023052', ('225', '234'))	('loss', 'NegReg', (200, 204))	('genetic aberrations', 'Disease', (40, 59))	('result', 'Reg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('208', '224'))	('epigenetic alterations', 'Var', (239, 261))	('tumor', 'Disease', (208, 213))	('genetic aberrations', 'Disease', 'MESH:D030342', (40, 59))	('metabolic', 'MPA', (6, 15))
14496	28561705	Interestingly, although the overall mutational burden is relatively low in RCC in comparison to many other tumor types, the vast majority of mutations identified in these tumors are in some way involved in the cell's ability to sense or respond to nutrients, oxygen, iron, or energy, suggesting that metabolic pathway alterations are key drivers of proliferation in all subsets of RCC.	('involved', 'Reg', (194, 202))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutations', 'Var', (141, 150))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('oxygen', 'Chemical', 'MESH:D010100', (259, 265))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (171, 176))	('RCC', 'Disease', 'MESH:C538614', (381, 384))	('RCC', 'Disease', (381, 384))	('tumors', 'Disease', (171, 177))	('iron', 'Chemical', 'MESH:D007501', (267, 271))
14497	28561705	Mutations resulting in dysregulation of specific steps of glycolysis, the TCA cycle, and the ETC pathways have all been found in subtypes of RCC, illustrating the diversity of metabolic alterations that may contribute to tumorigenesis (Fig.	('ETC pathways', 'Pathway', (93, 105))	('RCC', 'Disease', (141, 144))	('dysregulation', 'Var', (23, 36))	('TCA', 'Chemical', 'MESH:D014238', (74, 77))	('contribute', 'Reg', (207, 217))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('found', 'Reg', (120, 125))	('glycolysis', 'biological_process', 'GO:0006096', ('58', '68'))	('Mutations', 'Var', (0, 9))	('glycolysis', 'MPA', (58, 68))	('TCA cycle', 'biological_process', 'GO:0006099', ('74', '83'))	('TCA cycle', 'MPA', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
14498	28561705	Here, we discuss three examples of mutations that alter different metabolic pathways in RCC.	('alter', 'Reg', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('mutations', 'Var', (35, 44))	('metabolic pathways', 'Pathway', (66, 84))
14499	28561705	Mutations in the von-Hippel-Lindau gene (VHL) are associated with a hereditary form of RCC found in patients with germline VHL Disease, but are also observed in nearly 90% of patients with sporadic clear cell kidney cancer (ccRCC).	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('VHL Disease', 'Disease', 'MESH:D006623', (123, 134))	('patients', 'Species', '9606', (100, 108))	('RCC', 'Disease', (226, 229))	('von-Hippel-Lindau', 'Disease', 'MESH:D006623', (17, 34))	('kidney cancer', 'Phenotype', 'HP:0009726', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('sporadic clear cell kidney cancer', 'Disease', 'MESH:D008649', (189, 222))	('VHL', 'Gene', (123, 126))	('Mutations', 'Var', (0, 9))	('RCC', 'Disease', 'MESH:C538614', (226, 229))	('von-Hippel-Lindau', 'Disease', (17, 34))	('VHL Disease', 'Disease', (123, 134))	('VHL', 'Gene', '7428', (123, 126))	('VHL', 'Gene', (41, 44))	('RCC', 'Disease', (87, 90))	('patients', 'Species', '9606', (175, 183))	('sporadic clear cell kidney cancer', 'Disease', (189, 222))	('associated', 'Reg', (50, 60))	('VHL', 'Gene', '7428', (41, 44))
14501	28561705	In the majority of cases of ccRCC, inactivating mutations in VHL inhibit its ability to interact with the HIF proteins, and consequently the HIF proteins are stabilized, even during normoxic conditions.	('HIF proteins', 'Disease', 'MESH:D011488', (141, 153))	('inactivating mutations', 'Var', (35, 57))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('HIF proteins', 'Disease', (141, 153))	('RCC', 'Disease', (30, 33))	('VHL', 'Gene', (61, 64))	('interact', 'Interaction', (88, 96))	('VHL', 'Gene', '7428', (61, 64))	('inhibit', 'NegReg', (65, 72))	('HIF proteins', 'Disease', 'MESH:D011488', (106, 118))	('HIF proteins', 'Disease', (106, 118))	('ability', 'MPA', (77, 84))
14503	28561705	The aberrant activation of these proteins and growth factors is believed to contribute to tumor growth and proliferation downstream of inactivating mutations in VHL.	('proliferation', 'CPA', (107, 120))	('aberrant', 'Var', (4, 12))	('tumor growth', 'Disease', (90, 102))	('inactivating mutations', 'Var', (135, 157))	('tumor growth', 'Disease', 'MESH:D006130', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('VHL', 'Gene', (161, 164))	('activation', 'PosReg', (13, 23))	('VHL', 'Gene', '7428', (161, 164))	('contribute', 'Reg', (76, 86))
14516	28561705	Mutations in several TCA cycle enzymes have been observed in papillary renal cell carcinoma (pRCC).	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (61, 91))	('pRCC', 'Gene', '5546', (93, 97))	('papillary renal cell carcinoma', 'Disease', (61, 91))	('pRCC', 'Phenotype', 'HP:0006766', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('TCA', 'Chemical', 'MESH:D014238', (21, 24))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (61, 91))	('Mutations', 'Var', (0, 9))	('TCA cycle', 'biological_process', 'GO:0006099', ('21', '30'))	('pRCC', 'Gene', (93, 97))	('observed', 'Reg', (49, 57))	('TCA cycle', 'Gene', (21, 30))
14519	28561705	Likewise, germline mutations in fumarate hydratase (FH), the enzyme that catalyzes the conversion of fumarate to malate in the TCA cycle, have been found in patients with Herditary Leiomyomatosis Renal Cell Carcinoma (HLRCC) and very rarely, in sporadic cases of pRCC Since both SDH and FH mutations block normal TCA Cycle and ETC activity, cells from these tumors take up almost no oxygen, and rely primarily on glycolysis to supply energy and macromolecules needed for replication and growth.	('Carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('glycolysis', 'MPA', (413, 423))	('block', 'NegReg', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('patients', 'Species', '9606', (157, 165))	('tumors', 'Disease', (358, 364))	('pRCC', 'Gene', '5546', (263, 267))	('ETC activity', 'MPA', (327, 339))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('fumarate hydratase', 'Gene', '2271', (32, 50))	('TCA Cycle', 'biological_process', 'GO:0006099', ('313', '322'))	('TCA Cycle', 'MPA', (313, 322))	('FH', 'Gene', '2271', (52, 54))	('SDH', 'Gene', (279, 282))	('tumors', 'Disease', 'MESH:D009369', (358, 364))	('pRCC', 'Phenotype', 'HP:0006766', (263, 267))	('TCA', 'Chemical', 'MESH:D014238', (313, 316))	('fumarate', 'Chemical', 'MESH:D005650', (101, 109))	('RCC', 'Disease', (264, 267))	('TCA cycle', 'biological_process', 'GO:0006099', ('127', '136'))	('pRCC', 'Gene', (263, 267))	('malate', 'Chemical', 'MESH:C030298', (113, 119))	('FH', 'Gene', '2271', (287, 289))	('oxygen', 'Chemical', 'MESH:D010100', (383, 389))	('Herditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (171, 216))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('fumarate hydratase', 'Gene', (32, 50))	('TCA', 'Chemical', 'MESH:D014238', (127, 130))	('mutations', 'Var', (19, 28))	('Herditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', (171, 216))	('tumors', 'Phenotype', 'HP:0002664', (358, 364))	('mutations', 'Var', (290, 299))	('glycolysis', 'biological_process', 'GO:0006096', ('413', '423'))	('fumarate', 'Chemical', 'MESH:D005650', (32, 40))	('RCC', 'Disease', (220, 223))	('SDH', 'Gene', '6390', (279, 282))
14527	28561705	FH mutations similarly result in the accumulation of both succinate and fumarate due to the malfunction of the FH enzyme in the TCA cycle.	('FH', 'Gene', '2271', (0, 2))	('malfunction', 'MPA', (92, 103))	('FH', 'Gene', '2271', (111, 113))	('fumarate', 'Chemical', 'MESH:D005650', (72, 80))	('succinate', 'MPA', (58, 67))	('TCA', 'Chemical', 'MESH:D014238', (128, 131))	('accumulation', 'PosReg', (37, 49))	('TCA cycle', 'biological_process', 'GO:0006099', ('128', '137'))	('mutations', 'Var', (3, 12))	('fumarate', 'MPA', (72, 80))	('succinate', 'Chemical', 'MESH:D019802', (58, 67))
14529	28561705	Similarly to SDH-mutant tumors, pRCC tumors with FH mutations have upregulated expression of the HIF target genes involved in proliferation, glycolysis, and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('upregulated', 'PosReg', (67, 78))	('glycolysis', 'biological_process', 'GO:0006096', ('141', '151'))	('pRCC tumors', 'Disease', 'MESH:D009369', (32, 43))	('expression', 'MPA', (79, 89))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('pRCC', 'Phenotype', 'HP:0006766', (32, 36))	('angiogenesis', 'biological_process', 'GO:0001525', ('157', '169'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SDH', 'Gene', '6390', (13, 16))	('tumors', 'Disease', (37, 43))	('pRCC tumors', 'Disease', (32, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('SDH', 'Gene', (13, 16))	('FH', 'Gene', '2271', (49, 51))
14532	28561705	The malfunctions of mitochondrial respiration and upregulation of glycolysis in these cells appear to be key factors in their proliferation, and thus investigation of these pathways may be important for improving outcome for patients with FH mutations.	('patients', 'Species', '9606', (225, 233))	('mitochondrial respiration', 'MPA', (20, 45))	('upregulation', 'PosReg', (50, 62))	('respiration', 'biological_process', 'GO:0045333', ('34', '45'))	('FH', 'Gene', '2271', (239, 241))	('malfunctions', 'Var', (4, 16))	('glycolysis', 'MPA', (66, 76))	('upregulation of glycolysis', 'biological_process', 'GO:0045821', ('50', '76'))	('respiration', 'biological_process', 'GO:0007585', ('34', '45'))
14538	28561705	Mitochondrial DNA sequencing has revealed that many chRCC tumors have mutations in genes involved in the ETC complex I, particularly in MT-ND5, and that these mitochondrial gene mutations also correlate with samples exhibiting an eosinophilic histological phenotype.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (70, 79))	('MT-ND5', 'Gene', (136, 142))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('complex I', 'cellular_component', 'GO:0030964', ('109', '118'))	('RCC', 'Disease', (54, 57))	('Mitochondrial DNA', 'cellular_component', 'GO:0000262', ('0', '17'))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('MT-ND5', 'Gene', '4540', (136, 142))	('mutations', 'Var', (178, 187))
14543	28561705	A number of different kinds of genetic mutations have been associated with the dysregulation of metabolic pathways in various tumor types.	('genetic mutations', 'Var', (31, 48))	('metabolic pathways', 'Pathway', (96, 114))	('associated', 'Reg', (59, 69))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('dysregulation', 'MPA', (79, 92))	('tumor', 'Disease', (126, 131))
14548	28561705	While mutations in the MTOR gene itself can occur, it is more commonly activated downstream of gain-of-function mutations in the PI3K-AKT pathway or growth factors, or through inactivation of tumor suppressors such as PTEN.	('gain-of-function', 'PosReg', (95, 111))	('AKT', 'Gene', (134, 137))	('tumor', 'Disease', (192, 197))	('activated', 'PosReg', (71, 80))	('MTOR', 'Gene', (23, 27))	('PTEN', 'Gene', (218, 222))	('mutations', 'Var', (112, 121))	('PI3K', 'molecular_function', 'GO:0016303', ('129', '133'))	('PTEN', 'Gene', '5728', (218, 222))	('MTOR', 'Gene', '2475', (23, 27))	('inactivation', 'Var', (176, 188))	('AKT', 'Gene', '207', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
14557	28561705	However, resistance to these inhibitors appears to develop over time, possibly due to the accumulation of additional mutations in the mTOR pathway or through negative feedback of the pathway itself, as inhibiting mTOR signaling can also upregulate AKT signaling through insulin-like growth factor receptor 1 (IGF-1R).	('mTOR', 'Gene', (213, 217))	('mutations', 'Var', (117, 126))	('IGF-1R', 'Gene', (309, 315))	('AKT signaling', 'biological_process', 'GO:0043491', ('248', '261'))	('AKT', 'Gene', (248, 251))	('inhibiting', 'Var', (202, 212))	('IGF-1R', 'Gene', '3480', (309, 315))	('signaling', 'biological_process', 'GO:0023052', ('218', '227'))	('upregulate', 'PosReg', (237, 247))	('insulin-like growth factor', 'molecular_function', 'GO:0005159', ('270', '296'))	('mTOR', 'Gene', (134, 138))	('mTOR', 'Gene', '2475', (134, 138))	('AKT', 'Gene', '207', (248, 251))	('mTOR', 'Gene', '2475', (213, 217))
14578	28561705	Therefore, mutations in IDH1 and 2 are believed to both alter cellular metabolism and potentially increase rates of DNA damage due to altered NADPH protection.	('mutations', 'Var', (11, 20))	('rates', 'MPA', (107, 112))	('IDH1 and 2', 'Gene', '3417;3418', (24, 34))	('cellular metabolism', 'MPA', (62, 81))	('DNA', 'cellular_component', 'GO:0005574', ('116', '119'))	('NADPH', 'Chemical', 'MESH:D009249', (142, 147))	('increase', 'PosReg', (98, 106))	('altered', 'Reg', (134, 141))	('alter', 'Reg', (56, 61))	('cellular metabolism', 'biological_process', 'GO:0044237', ('62', '81'))
14579	28561705	Mutations in IDH1 and 2 have been observed in several types of tumors, including leukemias, lymphomas, and gliomas.	('leukemias', 'Disease', 'MESH:D007938', (81, 90))	('gliomas', 'Disease', 'MESH:D005910', (107, 114))	('IDH1 and 2', 'Gene', '3417;3418', (13, 23))	('gliomas', 'Disease', (107, 114))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('lymphomas', 'Disease', (92, 101))	('lymphomas', 'Disease', 'MESH:D008223', (92, 101))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('leukemias', 'Phenotype', 'HP:0001909', (81, 90))	('leukemias', 'Disease', (81, 90))	('observed', 'Reg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lymphomas', 'Phenotype', 'HP:0002665', (92, 101))
14580	28561705	The mutations identified in IDH1 and 2 in cancers appear to be gain-of-function point mutations that occur at specific arginine residues that presumably alter the structure of these proteins.	('proteins', 'Protein', (182, 190))	('cancers', 'Disease', (42, 49))	('arginine', 'Chemical', 'MESH:D001120', (119, 127))	('alter', 'Reg', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('IDH1 and 2', 'Gene', '3417;3418', (28, 38))	('gain-of-function', 'PosReg', (63, 79))	('structure', 'MPA', (163, 172))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
14582	28561705	High levels of D-2HG have been associated with increases in histone and DNA methylation, contributing to tumor progression.	('DNA', 'cellular_component', 'GO:0005574', ('72', '75'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('DNA methylation', 'biological_process', 'GO:0006306', ('72', '87'))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('DNA methylation', 'MPA', (72, 87))	('increases', 'PosReg', (47, 56))	('histone', 'MPA', (60, 67))	('tumor', 'Disease', (105, 110))	('D-2HG', 'Var', (15, 20))
14583	28561705	It has also been shown that mutant IDH1 heterodimerizes with wild-type IDH1, inhibiting the activity of the wild-type enzyme and reducing levels of alpha-KG, which may play a role in the degradation of HIF proteins.	('HIF proteins', 'Disease', (202, 214))	('IDH1', 'Gene', (35, 39))	('mutant', 'Var', (28, 34))	('inhibiting', 'NegReg', (77, 87))	('HIF proteins', 'Disease', 'MESH:D011488', (202, 214))	('alpha-KG', 'Chemical', 'MESH:D007656', (148, 156))	('degradation', 'MPA', (187, 198))	('levels of alpha-KG', 'MPA', (138, 156))	('degradation', 'biological_process', 'GO:0009056', ('187', '198'))	('activity', 'MPA', (92, 100))	('reducing', 'NegReg', (129, 137))
14584	28561705	Thus, mutant IDH1 may also play a role in the stabilization of HIFs and increased activation of their transcription factors involved in tumorigenesis and angiogenesis.	('transcription', 'biological_process', 'GO:0006351', ('102', '115'))	('transcription', 'MPA', (102, 115))	('mutant', 'Var', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('IDH1', 'Gene', (13, 17))	('activation', 'PosReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('angiogenesis', 'biological_process', 'GO:0001525', ('154', '166'))
14585	28561705	Several targeted chemical inhibitors of the activity of specific IDH1 and IDH2 point mutants have been designed and have been shown to reduce D-2HG and growth in cells and mouse models .	('point mutants', 'Var', (79, 92))	('IDH2', 'Gene', (74, 78))	('mouse', 'Species', '10090', (172, 177))	('growth', 'CPA', (152, 158))	('D-2HG', 'MPA', (142, 147))	('IDH1', 'Gene', (65, 69))	('reduce', 'NegReg', (135, 141))
14595	28561705	Currently, several chemical inhibitors, as well as genetic ablation of FASN by RNAi, are being tested for effectiveness in reducing tumor cell growth and proliferation.	('FASN', 'Gene', (71, 75))	('reducing', 'NegReg', (123, 131))	('FASN', 'Gene', '2194', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cell growth', 'biological_process', 'GO:0016049', ('138', '149'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('genetic ablation', 'Var', (51, 67))	('RNAi', 'biological_process', 'GO:0016246', ('79', '83'))	('tumor', 'Disease', (132, 137))
14600	28561705	Thus, epigenetic changes downstream of metabolic alterations can influence the expression levels of many genes in cancer cells, possibly giving them a survival and growth advantage.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('expression levels', 'MPA', (79, 96))	('giving', 'Reg', (137, 143))	('survival', 'CPA', (151, 159))	('epigenetic changes', 'Var', (6, 24))	('influence', 'Reg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('growth advantage', 'CPA', (164, 180))	('cancer', 'Disease', (114, 120))
14603	28561705	Dysregulation of carbon metabolism pathways in cancer can alter the levels of SAM and methyl donors available, thus influencing the epigenetic modifications and expression of genes in these cells .	('carbon', 'Chemical', 'MESH:D002244', (17, 23))	('SAM', 'Chemical', 'MESH:D012436', (78, 81))	('influencing', 'Reg', (116, 127))	('expression of genes', 'MPA', (161, 180))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (47, 53))	('carbon', 'Enzyme', (17, 23))	('metabolism', 'biological_process', 'GO:0008152', ('24', '34'))	('alter', 'Reg', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('epigenetic modifications', 'MPA', (132, 156))	('donor', 'Species', '9606', (93, 98))
14604	28561705	Another mechanism by which metabolic pathways can effect epigenetics is through the TCA cycle metabolites.	('effect', 'Reg', (50, 56))	('TCA', 'Chemical', 'MESH:D014238', (84, 87))	('TCA cycle', 'biological_process', 'GO:0006099', ('84', '93'))	('epigenetics', 'Var', (57, 68))
14606	28561705	Likewise, D-2HG, the protein made from alpha-KG by cancer cells with IDH1/2 mutations (discussed above), inhibits the activity of alpha-KG-dependent demethylases.	('alpha-KG-dependent demethylases', 'Enzyme', (130, 161))	('mutations', 'Var', (76, 85))	('activity', 'MPA', (118, 126))	('alpha-KG', 'Chemical', 'MESH:D007656', (39, 47))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('alpha-KG', 'Chemical', 'MESH:D007656', (130, 138))	('inhibits', 'NegReg', (105, 113))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('IDH1/2', 'Gene', (69, 75))
14607	28561705	SDH and FH mutations which result in accumulation of succinate and fumarate in cancer cells can also act as competitive antagonists for inhibiting these alpha-KG-dependent demethylases.	('inhibiting', 'NegReg', (136, 146))	('mutations', 'Var', (11, 20))	('fumarate', 'Chemical', 'MESH:D005650', (67, 75))	('succinate', 'MPA', (53, 62))	('fumarate', 'MPA', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('alpha-KG', 'Chemical', 'MESH:D007656', (153, 161))	('SDH', 'Gene', (0, 3))	('FH', 'Gene', '2271', (8, 10))	('succinate', 'Chemical', 'MESH:D019802', (53, 62))	('alpha-KG-dependent demethylases', 'Enzyme', (153, 184))	('accumulation', 'PosReg', (37, 49))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('SDH', 'Gene', '6390', (0, 3))
14615	28561705	The mechanisms behind the metabolic reprogramming that takes place in most tumor cells are diverse, and include oncogenic activation, the repression of tumor suppressor signaling, epigenetic modifications, and mutations in metabolic enzymes themselves.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (210, 219))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('epigenetic modifications', 'Var', (180, 204))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
14641	29053609	One copy of VHL is either mutated or silenced in 90% of sporadic CCRCCs, whereas another copy is typically lost through 3p deletions, according to the comprehensive molecular profiling of CCRCCs by The Cancer Genome Atlas (TCGA).	('VHL', 'Gene', (12, 15))	('VHL', 'Gene', '7428', (12, 15))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', (190, 193))	('silenced', 'NegReg', (37, 45))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('RCCs', 'Phenotype', 'HP:0005584', (190, 194))	('Cancer Genome Atlas', 'Disease', (202, 221))	('mutated', 'Var', (26, 33))	('RCCs', 'Phenotype', 'HP:0005584', (67, 71))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (202, 221))
14643	29053609	According to the TCGA, CCRCCs are characterized by recurrent mutations in the PI3K/AKT/MTOR pathway (a potential therapeutic target), mutations in SETD2 (associated with widespread DNA hypomethylation), and mutations involving the SWI/SNF chromatin remodeling complex (PBRM1, ARID1A, and SMARCA4).	('AKT', 'Gene', '207', (83, 86))	('RCCs', 'Phenotype', 'HP:0005584', (25, 29))	('SETD2', 'Gene', (147, 152))	('PI3K', 'molecular_function', 'GO:0016303', ('78', '82'))	('DNA', 'cellular_component', 'GO:0005574', ('181', '184'))	('SETD2', 'Gene', '29072', (147, 152))	('mutations', 'Var', (207, 216))	('mutations', 'Var', (134, 143))	('MTOR', 'Gene', (87, 91))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('239', '259'))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('181', '200'))	('RCC', 'Disease', (25, 28))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('239', '267'))	('PBRM1', 'Gene', '55193', (269, 274))	('SMARCA4', 'Gene', '6597', (288, 295))	('MTOR', 'Gene', '2475', (87, 91))	('AKT', 'Gene', (83, 86))	('mutations', 'Var', (61, 70))	('PBRM1', 'Gene', (269, 274))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('ARID1A', 'Gene', (276, 282))	('ARID1A', 'Gene', '8289', (276, 282))	('SMARCA4', 'Gene', (288, 295))
14649	29053609	Hereditary PRCC syndrome with germline mutations in MET is associated with type 1 PRCCs.	('RCCs', 'Phenotype', 'HP:0005584', (83, 87))	('PRCC', 'Gene', (82, 86))	('PRCC', 'Gene', '5546', (11, 15))	('Hereditary PRCC syndrome', 'Disease', 'MESH:D009386', (0, 24))	('germline mutations', 'Var', (30, 48))	('PRCC', 'Gene', (11, 15))	('associated', 'Reg', (59, 69))	('Hereditary PRCC syndrome', 'Disease', (0, 24))	('MET', 'Gene', (52, 55))	('PRCC', 'Gene', '5546', (82, 86))
14656	29053609	Of note, CK7 positivity is more prominent in type 1 PRCCs and is often decreased in type 2 PRCCs.	('positivity', 'Var', (13, 23))	('CK7', 'Gene', (9, 12))	('PRCC', 'Gene', '5546', (52, 56))	('PRCC', 'Gene', (91, 95))	('CK7', 'Gene', '3855', (9, 12))	('RCCs', 'Phenotype', 'HP:0005584', (53, 57))	('PRCC', 'Gene', (52, 56))	('RCCs', 'Phenotype', 'HP:0005584', (92, 96))	('decreased', 'NegReg', (71, 80))	('PRCC', 'Gene', '5546', (91, 95))
14659	29053609	According to the comprehensive molecular profiling of PRCCs by TCGA, type 1 PRCCs are characterized by MET alterations, whereas type 2 PRCCs are characterized by CDKN2A silencing, SETD2 mutations, and increased expression of the NRF2-antioxidant response element pathway.	('RCCs', 'Phenotype', 'HP:0005584', (136, 140))	('CDKN2A', 'Gene', (162, 168))	('RCCs', 'Phenotype', 'HP:0005584', (55, 59))	('increased', 'PosReg', (201, 210))	('PRCC', 'Gene', '5546', (135, 139))	('PRCC', 'Gene', '5546', (54, 58))	('PRCC', 'Gene', (76, 80))	('NRF2', 'Gene', '4780', (229, 233))	('silencing', 'NegReg', (169, 178))	('CDKN2A', 'Gene', '1029', (162, 168))	('RCCs', 'Phenotype', 'HP:0005584', (77, 81))	('SETD2', 'Gene', (180, 185))	('mutations', 'Var', (186, 195))	('PRCC', 'Gene', '5546', (76, 80))	('NRF2', 'Gene', (229, 233))	('SETD2', 'Gene', '29072', (180, 185))	('PRCC', 'Gene', (135, 139))	('expression', 'MPA', (211, 221))	('PRCC', 'Gene', (54, 58))
14663	29053609	C2b PRCCs are associated with later stages of tumor development and SETD2 mutations.	('PRCC', 'Gene', '5546', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PRCC', 'Gene', (4, 8))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (46, 51))	('associated', 'Reg', (14, 24))	('SETD2', 'Gene', '29072', (68, 73))	('C2b', 'Gene', (0, 3))	('RCCs', 'Phenotype', 'HP:0005584', (5, 9))	('SETD2', 'Gene', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
14665	29053609	Birt-Hogg-Dube syndrome with FLCN mutations is associated with a higher incidence of ChRCCs.	('FLCN', 'Gene', '201163', (29, 33))	('RCCs', 'Phenotype', 'HP:0005584', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('FLCN', 'Gene', (29, 33))	('Birt-Hogg-Dube syndrome', 'Disease', (0, 23))	('mutations', 'Var', (34, 43))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (0, 23))
14672	29053609	Recurrent DNA rearrangement breakpoints within the TERT promoter region in 10% of examined cases of ChRCCs, which are associated with high TERT expression and manifestation of kataegis, represent a mechanism for increased TERT expression in these tumors, differing from the point mutations of TERT observed in various malignancies.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (247, 253))	('TERT', 'Gene', (222, 226))	('TERT', 'Gene', '7015', (222, 226))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('malignancies', 'Disease', 'MESH:D009369', (318, 330))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('malignancies', 'Disease', (318, 330))	('TERT', 'Gene', (51, 55))	('DNA', 'Gene', (10, 13))	('TERT', 'Gene', '7015', (51, 55))	('RCCs', 'Phenotype', 'HP:0005584', (102, 106))	('TERT', 'Gene', (139, 143))	('rearrangement breakpoints', 'Var', (14, 39))	('TERT', 'Gene', '7015', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('RCC', 'Disease', (102, 105))	('TERT', 'Gene', (293, 297))	('TERT', 'Gene', '7015', (293, 297))	('increased', 'PosReg', (212, 221))
14673	29053609	A recent study has demonstrated that metastatic ChRCCs were characterized by TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (ICD) (25%), suggesting these genomic changes are involved in metastatic evolution for ChRCCs.	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('mutations', 'Var', (104, 113))	('RCC', 'Disease', (248, 251))	('ICD', 'Disease', 'OMIM:252500', (160, 163))	('RCCs', 'Phenotype', 'HP:0005584', (248, 252))	('RCCs', 'Phenotype', 'HP:0005584', (50, 54))	('ICD', 'Disease', (160, 163))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('imbalanced chromosome duplication', 'Var', (125, 158))	('mutations', 'Var', (82, 91))	('chromosome', 'cellular_component', 'GO:0005694', ('136', '146'))	('PTEN', 'Gene', (99, 103))	('TP53', 'Gene', '7157', (77, 81))	('PTEN', 'Gene', '5728', (99, 103))	('TP53', 'Gene', (77, 81))
14678	29053609	Similar to CCRCC, chromosome 3p deletions and VHL mutations were found in 74% and 25% of these tumors, respectively.	('VHL', 'Gene', (46, 49))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (50, 59))	('VHL', 'Gene', '7428', (46, 49))	('chromosome', 'cellular_component', 'GO:0005694', ('18', '28'))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('found', 'Reg', (65, 70))	('tumors', 'Disease', (95, 101))
14679	29053609	Xp11 TRCC was established as an RCC subtype in the 2004 WHO classification.	('Xp11', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
14681	29053609	Both Xp11 translocation and t(6;11) RCC are characterized by the rearrangement of the MiT transcription factors, TFE3 and TFEB.	('TFE3', 'Gene', (113, 117))	('TFEB', 'Gene', '7942', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('TFEB', 'Gene', (122, 126))	('TFE3', 'Gene', '7030', (113, 117))	('transcription', 'biological_process', 'GO:0006351', ('90', '103'))	('Xp11 translocation', 'Var', (5, 23))
14682	29053609	Xp11 TRCC comprises 20-40% of pediatric RCCs and 1-4% of adult RCCs, with an average age of onset of 50 years.	('RCC', 'Disease', (63, 66))	('RCCs', 'Phenotype', 'HP:0005584', (63, 67))	('Xp11', 'Var', (0, 4))	('RCC', 'Disease', (40, 43))	('RCCs', 'Phenotype', 'HP:0005584', (40, 44))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
14685	29053609	Morphologically, Xp11 TRCC is typically composed of cells with clear/eosinophilic cytoplasm with papillary and nested structures and psammoma bodies.	('Xp11', 'Var', (17, 21))	('psammoma bodies', 'Disease', 'MESH:D001835', (133, 148))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('psammoma bodies', 'Disease', (133, 148))	('cytoplasm', 'cellular_component', 'GO:0005737', ('82', '91'))
14689	29053609	Specifically, Xp11 TRCC and t(6;11) RCC display positive nuclear immunostaining for TFE3 and TFEB, respectively.	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('TFE3', 'Gene', (84, 88))	('RCC', 'Disease', (36, 39))	('Xp11', 'Var', (14, 18))	('TFE3', 'Gene', '7030', (84, 88))	('TFEB', 'Gene', '7942', (93, 97))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('TFEB', 'Gene', (93, 97))	('RCC', 'Disease', (20, 23))
14690	29053609	Xp11/TFEB TRCC is diagnosed by the utilization of TFE3/TFEB immunohistochemistry or break-apart TFE3/TFEB fluorescence in in situ hybridization in formalin-fixed paraffin-embedded (FFPE) specimens.	('TFE3', 'Gene', (50, 54))	('TFEB', 'Gene', '7942', (5, 9))	('TFEB', 'Gene', (5, 9))	('TFE3', 'Gene', '7030', (96, 100))	('paraffin', 'Chemical', 'MESH:D010232', (162, 170))	('TFE3', 'Gene', '7030', (50, 54))	('formalin', 'Chemical', 'MESH:D005557', (147, 155))	('TFE3', 'Gene', (96, 100))	('TFEB', 'Gene', '7942', (55, 59))	('TFEB', 'Gene', '7942', (101, 105))	('break-apart', 'Var', (84, 95))	('TFEB', 'Gene', (55, 59))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('TFEB', 'Gene', (101, 105))	('RCC', 'Disease', (11, 14))
14692	29053609	Another recent study demonstrated that TFEB-amplified RCCs with or without TFEB translocation were characterized by aggressive clinical behavior, variable morphology, aberrant melanocytic marker expression, and high frequency of immunohistochemical positivity for TFEB.	('aberrant', 'Var', (167, 175))	('TFEB', 'Gene', '7942', (39, 43))	('expression', 'MPA', (195, 205))	('aggressive clinical behavior', 'Phenotype', 'HP:0000718', (116, 144))	('TFEB', 'Gene', (39, 43))	('TFEB', 'Gene', '7942', (75, 79))	('RCC', 'Disease', (54, 57))	('TFEB', 'Gene', (75, 79))	('RCCs', 'Phenotype', 'HP:0005584', (54, 58))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('translocation', 'Var', (80, 93))	('TFEB', 'Gene', '7942', (264, 268))	('TFEB', 'Gene', (264, 268))
14725	29053609	Genetically, the defining molecular abnormality in SDH-deficient RCC is the double-hit inactivation of one of the SDH genes, most commonly SDHB.	('SDH', 'Gene', '6390', (51, 54))	('SDH-deficient RCC', 'Disease', (51, 68))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', '6390', (114, 117))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (51, 68))	('SDHB', 'Gene', '6390', (139, 143))	('SDHB', 'Gene', (139, 143))	('inactivation', 'Var', (87, 99))	('SDH', 'Gene', '6390', (139, 142))	('SDH', 'Gene', (51, 54))	('SDH', 'Gene', (114, 117))
14730	29053609	A diagnosis of HLRCC-associated RCC is confirmed by the presence of germline FH mutations.	('mutations', 'Var', (80, 89))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))
14747	29053609	Genetically, a subgroup of this tumor demonstrates a TFE3/TFEB rearrangement.	('TFE3', 'Gene', (53, 57))	('rearrangement', 'Var', (63, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TFEB', 'Gene', '7942', (58, 62))	('TFE3', 'Gene', '7030', (53, 57))	('TFEB', 'Gene', (58, 62))	('tumor', 'Disease', (32, 37))
14755	29053609	ALK rearrangement-associated RCC occurs in children and adults, with or without sickle cell trait, comprising approximately 0.4% of all adult RCCs.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCCs', 'Phenotype', 'HP:0005584', (142, 146))	('RCC', 'Disease', (29, 32))	('children', 'Species', '9606', (43, 51))	('rearrangement-associated', 'Var', (4, 28))	('ALK', 'Gene', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('ALK', 'Gene', '238', (0, 3))
14766	29053609	Immunohistochemically, the epithelial component is typically positive for CAIX, CD10, CK7, 34betaE12, and PAX8, and negative for AMACR and HMB45.	('CK7', 'Gene', '3855', (86, 89))	('PAX8', 'Gene', (106, 110))	('CAIX', 'Gene', (74, 78))	('CD10', 'Gene', (80, 84))	('positive', 'Reg', (61, 69))	('CD10', 'Gene', '4311', (80, 84))	('34betaE12', 'Var', (91, 100))	('CAIX', 'Gene', '768', (74, 78))	('AMACR', 'Gene', (129, 134))	('AMACR', 'Gene', '23600', (129, 134))	('CD10', 'molecular_function', 'GO:0004245', ('80', '84'))	('PAX8', 'Gene', '7849', (106, 110))	('CK7', 'Gene', (86, 89))
14769	29053609	Recent evidence suggests an association of this tumor with TCEB1 mutations.	('TCEB1', 'Gene', '6921', (59, 64))	('tumor', 'Disease', (48, 53))	('TCEB1', 'Gene', (59, 64))	('association', 'Interaction', (28, 39))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (65, 74))
14822	26301110	In this syndrome patients also develop multiple cutaneous leiomyomas in almost all cases and definitive diagnosis is only made by the presence of a germline mutation in the fumarate hydratase gene.	('develop', 'PosReg', (31, 38))	('cutaneous leiomyomas', 'Disease', (48, 68))	('cutaneous leiomyomas', 'Disease', 'MESH:C535516', (48, 68))	('multiple cutaneous leiomyomas', 'Phenotype', 'HP:0007437', (39, 68))	('patients', 'Species', '9606', (17, 25))	('cutaneous leiomyomas', 'Phenotype', 'HP:0007620', (48, 68))	('fumarate hydratase', 'Gene', '2271', (173, 191))	('germline mutation', 'Var', (148, 165))	('fumarate hydratase', 'Gene', (173, 191))
14937	32206160	VHL syndrome is an autosomal dominant disease caused by germline mutations in the VHL gene.	('VHL syndrome', 'Disease', 'MESH:D006623', (0, 12))	('caused by', 'Reg', (46, 55))	('autosomal dominant disease', 'Disease', (19, 45))	('VHL', 'Gene', (82, 85))	('VHL syndrome', 'Disease', (0, 12))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (19, 45))	('germline mutations', 'Var', (56, 74))
14939	32206160	Latif and colleagues were the first to identify the VHL gene, and the following year VHL was also shown to be mutated in sporadic ccRCC.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('mutated', 'Var', (110, 117))	('VHL', 'Gene', (85, 88))	('VHL', 'Gene', (52, 55))
14940	32206160	Nearly two decades later, Nickerson and colleagues evaluated a cohort of 205 ccRCC samples, the largest cohort at that time, for aberrations in the VHL gene through targeted sequencing.	('VHL', 'Gene', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('aberrations', 'Var', (129, 140))	('RCC', 'Disease', (79, 82))
14941	32206160	They identified non-silent somatic mutations with a prevalence of 82% and VHL promoter hypermethylation in an additional 8.3% of tumors, for a total of 90% of tumors.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('VHL', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promoter hypermethylation', 'Var', (78, 103))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
14942	32206160	In sporadic ccRCC, the initiating event is thought to be loss of 3p through a chromothripsis event.	('chromothripsis', 'Disease', 'MESH:D000072837', (78, 92))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('loss of 3p', 'Var', (57, 67))	('chromothripsis', 'Disease', (78, 92))
14943	32206160	While VHL loss is nearly universal in ccRCC, VHL inactivation has also been shown in preneoplastic cysts, and mice with VHL disruption in the kidneys do not develop ccRCC.	('VHL loss', 'Disease', 'MESH:D006623', (6, 14))	('VHL loss', 'Disease', (6, 14))	('RCC', 'Disease', (40, 43))	('mice', 'Species', '10090', (110, 114))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('RCC', 'Disease', (167, 170))	('disruption', 'Var', (124, 134))
14947	32206160	Interestingly, mutations in TCEB1 (encoding Elongin C) have been reported in up to 5% of ccRCC cases and are associated with loss of heterozygosity of chromosome 8, which contains TCEB1.	('associated', 'Reg', (109, 119))	('reported', 'Reg', (65, 73))	('Elongin C', 'Gene', (44, 53))	('TCEB1', 'Gene', '6921', (28, 33))	('mutations', 'Var', (15, 24))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('TCEB1', 'Gene', (28, 33))	('RCC', 'Disease', (91, 94))	('TCEB1', 'Gene', '6921', (180, 185))	('TCEB1', 'Gene', (180, 185))	('chromosome', 'cellular_component', 'GO:0005694', ('151', '161'))	('Elongin C', 'Gene', '6921', (44, 53))
14948	32206160	In addition, mutations in CUL2 were found in up to 1% of ccRCCs.	('CUL2', 'Gene', (26, 30))	('found', 'Reg', (36, 41))	('CUL2', 'Gene', '8453', (26, 30))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
14949	32206160	Mutations in TCEB1 and CUL2 tend to be mutually exclusive with VHL mutations and likely represent other mechanisms to disrupt VHL function.	('TCEB1', 'Gene', '6921', (13, 18))	('TCEB1', 'Gene', (13, 18))	('CUL2', 'Gene', (23, 27))	('mutations', 'Var', (67, 76))	('Mutations', 'Var', (0, 9))	('CUL2', 'Gene', '8453', (23, 27))	('VHL', 'Gene', (63, 66))
14950	32206160	The first large scale sequencing reports in ccRCC came out in 2009, and demonstrated frequent mutations in the chromatin remodeling genes SETD2, KDM6A (also known as UTX), KDM5C (also known as JARID1C), and MLL2.	('JARID1C', 'Gene', '8242', (193, 200))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('111', '131'))	('RCC', 'Disease', (46, 49))	('mutations', 'Var', (94, 103))	('MLL2', 'Gene', (207, 211))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('JARID1C', 'Gene', (193, 200))	('KDM6A', 'Gene', (145, 150))	('UTX', 'Gene', (166, 169))	('SETD2', 'Gene', '29072', (138, 143))	('UTX', 'Gene', '7403', (166, 169))	('KDM5C', 'Gene', '8242', (172, 177))	('KDM5C', 'Gene', (172, 177))	('MLL2', 'Gene', '8085', (207, 211))	('KDM6A', 'Gene', '7403', (145, 150))	('SETD2', 'Gene', (138, 143))	('chromatin', 'cellular_component', 'GO:0000785', ('111', '120'))
14951	32206160	These reports were limited to sequencing a panel of ~3,500 genes, a small subset of the entire human exome, and the genes identified were mutated in up to 15% of tumors.	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutated', 'Var', (138, 145))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', (162, 168))
14953	32206160	Varela and colleagues performed WES of seven ccRCC and matching normal samples and identified truncating mutations in PBRM1 in four tumors.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('tumors', 'Disease', (132, 138))	('truncating mutations', 'Var', (94, 114))	('PBRM1', 'Gene', (118, 123))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
14956	32206160	By incorporating tumorgrafts, our studies allowed for accurate calls of mutant allele frequencies (MAF) thereby confidently nominating putative two-hit tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutant', 'Var', (72, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('tumor', 'Disease', (152, 157))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
14958	32206160	Subsequent BAP1 targeted sequencing studies identified mutations in 24 out of 176 (14%) largely primary ccRCC samples.	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('mutations', 'Var', (55, 64))	('RCC', 'Disease', (106, 109))
14960	32206160	The BAP1 protein is a nuclear-localized deubiquitinase which acts to deubiquitylate H2AK119ub1 to reverse polycomb-mediated gene repression.	('polycomb-mediated gene', 'Gene', (106, 128))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('40', '54'))	('BAP1', 'Gene', (4, 8))	('protein', 'cellular_component', 'GO:0003675', ('9', '16'))	('reverse', 'PosReg', (98, 105))	('H2AK119ub1', 'Chemical', '-', (84, 94))	('H2AK119ub1', 'Var', (84, 94))
14963	32206160	Notably, BAP1 and PBRM1 mutations were found to anticorrelate in ccRCC and the prevalence of combined BAP1/PBRM1 deficient ccRCC is ~1-2%, less than the ~5% rate expected given the rates of PBRM1 (~45%) and BAP1 (~12%) mutations in ccRCC.	('deficient', 'NegReg', (113, 122))	('BAP1', 'Gene', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('BAP1/PBRM1', 'Gene', (102, 112))	('PBRM1', 'Gene', (18, 23))	('BAP1', 'Gene', (207, 211))	('mutations', 'Var', (24, 33))	('PBRM1', 'Gene', (190, 195))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('RCC', 'Disease', (234, 237))
14964	32206160	Furthermore, BAP1 mutant tumors exhibited higher nucleolar grade, more aggressive histology, and demonstrated worsened RCCspecific survival.	('nucleolar grade', 'MPA', (49, 64))	('BAP1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('mutant', 'Var', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('higher', 'PosReg', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('more', 'PosReg', (66, 70))	('aggressive', 'CPA', (71, 81))	('worsened', 'NegReg', (110, 118))
14965	32206160	This finding was subsequently confirmed in metastatic RCC, as BAP1 mutations were independently associated with worsened overall survival.	('overall survival', 'MPA', (121, 137))	('RCC', 'Disease', (54, 57))	('BAP1', 'Gene', (62, 66))	('worsened', 'NegReg', (112, 120))	('mutations', 'Var', (67, 76))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
14966	32206160	Together these findings led us to propose a model where following inactivation of VHL and 3p loss, inactivation of the remaining copy of BAP1 caused aggressive ccRCC and inactivation of PBRM1, less aggressive ccRCC.	('BAP1', 'Gene', (137, 141))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (149, 165))	('aggressive ccRCC', 'Disease', 'MESH:D001523', (198, 214))	('caused', 'Reg', (142, 148))	('VHL', 'Gene', (82, 85))	('aggressive ccRCC', 'Disease', (149, 165))	('inactivation', 'Var', (66, 78))	('aggressive ccRCC', 'Disease', (198, 214))	('inactivation', 'Var', (170, 182))	('PBRM1', 'Gene', (186, 191))	('inactivation', 'Var', (99, 111))
14967	32206160	Using methods we developed, this model was subsequently revised by the TRACERx consortium to show that the first event in sporadic tumors is likely the loss of 3p.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('sporadic tumors', 'Disease', 'MESH:D009369', (122, 137))	('loss of 3p', 'Var', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('sporadic tumors', 'Disease', (122, 137))
14970	32206160	We showed that ccRCC development required not only Vhl inactivation, but also the inactivation of Bap1 (or Pbrm1).	('inactivation', 'Var', (55, 67))	('Vhl', 'MPA', (51, 54))	('Pbrm1', 'Gene', (107, 112))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('inactivation', 'Var', (82, 94))
14972	32206160	However, the simultaneous inactivation of Vhl and Pbrm1 caused ccRCC.	('inactivation', 'Var', (26, 38))	('Pbrm1', 'Gene', (50, 55))	('caused', 'Reg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('Vhl', 'Gene', (42, 45))	('RCC', 'Disease', (65, 68))
14976	32206160	These discoveries explain why germline VHL mutations cause kidney cancer in humans, but not in mice.	('cause', 'Reg', (53, 58))	('germline', 'Var', (30, 38))	('mice', 'Species', '10090', (95, 99))	('kidney cancer', 'Disease', 'MESH:D007680', (59, 72))	('kidney cancer', 'Phenotype', 'HP:0009726', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('VHL', 'Gene', (39, 42))	('kidney cancer', 'Disease', (59, 72))	('mutations', 'Var', (43, 52))	('humans', 'Species', '9606', (76, 82))
14977	32206160	As it turns out, we found that in mice the Bap1 and Pbrm1 genes are on a different chromosome than Vhl and as such, loss of the chromosome arm containing the Vhl gene in the mouse would have no effect on Bap1 or Pbrm1 genes.	('Bap1', 'Gene', (43, 47))	('mouse', 'Species', '10090', (174, 179))	('mice', 'Species', '10090', (34, 38))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('Pbrm1', 'Gene', (212, 217))	('Vhl', 'Gene', (158, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('83', '93'))	('Pbrm1', 'Gene', (52, 57))	('Bap1', 'Gene', (204, 208))	('loss', 'Var', (116, 120))
14983	32206160	Or how do mutations in TCEB1 and CUL2, which are located on chromosome 8 and 10 respectively, lead to ccRCC formation, and what are the specific cooperating events?	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('CUL2', 'Gene', (33, 37))	('formation', 'biological_process', 'GO:0009058', ('108', '117'))	('CUL2', 'Gene', '8453', (33, 37))	('lead to', 'Reg', (94, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))	('TCEB1', 'Gene', '6921', (23, 28))	('mutations', 'Var', (10, 19))	('TCEB1', 'Gene', (23, 28))	('RCC', 'Disease', (104, 107))
14988	32206160	Other findings of significance included loss of one CDKN2A allele in 16.2% of ccRCCs (mostly through deletion of 9p21.3), and mutation of TP53 in 2.6% of cases.	('deletion', 'Var', (101, 109))	('TP53', 'Gene', '7157', (138, 142))	('RCC', 'Disease', (80, 83))	('mutation', 'Var', (126, 134))	('loss', 'NegReg', (40, 44))	('TP53', 'Gene', (138, 142))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', '1029', (52, 58))
14989	32206160	In a similar analysis of non-ccRCC, we found distinct mutated genes and SCNA alterations highlighting the diverse molecular landscape of RCC.	('mutated genes', 'Var', (54, 67))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))
14991	32206160	Activating MET mutations were identified in 15% (10/65) of pRCC analyzed, including 4 previously unreported mutations.	('MET', 'Gene', '79811', (11, 14))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (15, 24))	('MET', 'Gene', (11, 14))	('pRCC', 'Gene', (59, 63))	('pRCC', 'Gene', '5546', (59, 63))
14993	32206160	These findings were confirmed in a subsequent analysis of the pRCC TCGA cohort, where activating MET mutations were identified in 17% (14/75) of type I pRCC samples, which exhibited near universal gain of chromosomes 7 and 17.	('mutations', 'Var', (101, 110))	('pRCC', 'Gene', '5546', (62, 66))	('pRCC', 'Gene', '5546', (152, 156))	('MET', 'Gene', '79811', (97, 100))	('activating', 'PosReg', (86, 96))	('gain', 'PosReg', (197, 201))	('pRCC', 'Gene', (62, 66))	('MET', 'Gene', (97, 100))	('pRCC', 'Gene', (152, 156))
14996	32206160	CIMP tumors were characterized by universal hypermethylation of CDKN2A, frequent fumarate hydratase (FH) mutations (including somatic mutations; 57%), and worse survival relative to non-CIMP pRCC.	('fumarate hydratase', 'Gene', '2271', (81, 99))	('pRCC', 'Gene', '5546', (191, 195))	('survival', 'CPA', (161, 169))	('CDKN2A', 'Gene', (64, 70))	('worse', 'NegReg', (155, 160))	('fumarate hydratase', 'Gene', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('FH', 'Gene', '2271', (101, 103))	('CIMP tumors', 'Disease', 'MESH:D009369', (0, 11))	('CDKN2A', 'Gene', '1029', (64, 70))	('mutations', 'Var', (105, 114))	('hypermethylation', 'Var', (44, 60))	('pRCC', 'Gene', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('CIMP tumors', 'Disease', (0, 11))
15007	32206160	Studies from TCGA and our own group found that TP53 mutations were significantly enriched (P = 2.3E-5) in the classic chRCC subtype.	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (47, 51))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('TP53', 'Gene', (47, 51))
15008	32206160	The two most frequently mutated genes across chRCC variants are TP53 (31.1%) and PTEN (9%).	('variants', 'Var', (51, 59))	('PTEN', 'Gene', (81, 85))	('TP53', 'Gene', '7157', (64, 68))	('RCC', 'Disease', (47, 50))	('PTEN', 'Gene', '5728', (81, 85))	('TP53', 'Gene', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (47, 50))
15009	32206160	Mutually exclusive mutations in genes of the PI3K/AKT/mTOR pathway were observed in 23% of cases.	('observed', 'Reg', (72, 80))	('AKT', 'Gene', '207', (50, 53))	('PI3K', 'molecular_function', 'GO:0016303', ('45', '49'))	('mutations', 'Var', (19, 28))	('mTOR', 'Gene', '2475', (54, 58))	('AKT', 'Gene', (50, 53))	('mTOR', 'Gene', (54, 58))
15010	32206160	Interestingly, analysis of mitochondrial DNA in chRCC revealed recurring mutations in genes encoding components of complex 1 of the electron transport chain (ETC), although these mutations were not associated with changes in the expression of genes implicated in oxidative phosphorylation.	('electron transport chain', 'biological_process', 'GO:0022900', ('132', '156'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('263', '288'))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('27', '44'))	('mutations', 'Var', (73, 82))
15011	32206160	chRCC are particularly enriched in mutations involving metabolic genes, including deleterious mutations in PDHB (which encodes a critical component of the pyruvate dehydrogenase complex) and PRKAG2 (encoding one of three subunits of AMP-Kinase (AMPK)).	('AMPK', 'Gene', '5562', (245, 249))	('AMPK', 'Gene', (245, 249))	('mutations', 'Var', (94, 103))	('RCC', 'Disease', (2, 5))	('AMP-Kinase', 'Gene', '5562', (233, 243))	('PDHB', 'Gene', (107, 111))	('AMPK', 'molecular_function', 'GO:0050405', ('245', '249'))	('PRKAG2', 'Gene', '51422', (191, 197))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('155', '185'))	('AMPK', 'molecular_function', 'GO:0004691', ('245', '249'))	('PRKAG2', 'Gene', (191, 197))	('PDHB', 'Gene', '5162', (107, 111))	('AMPK', 'molecular_function', 'GO:0047322', ('245', '249'))	('AMP-Kinase', 'Gene', (233, 243))	('mutations', 'Var', (35, 44))
15026	32206160	We previously demonstrated that BAP1 and PBRM1 expression by immunohistochemistry (IHC) are highly correlated with mutation status (P = 3E-58 and 4E-23 respectively and that BAP1/PBRM1 expression by IHC are independent predictors of both disease-free survival and overall survival in the localized disease setting.	('localized disease', 'Disease', 'MESH:D012594', (288, 305))	('mutation status', 'Var', (115, 130))	('disease-free', 'Disease', (238, 250))	('correlated', 'Reg', (99, 109))	('BAP1', 'Gene', (32, 36))	('PBRM1', 'Gene', (41, 46))	('localized disease', 'Disease', (288, 305))
15032	32206160	Many of the key driver mutations in RCC have been shown to have negative (BAP1, SETD2, PTEN, and TP53) and positive (PBRM1) prognostic significance, although it is important to interpret the prognostic implications of these mutations in the context of histology.	('PTEN', 'Gene', (87, 91))	('SETD2', 'Gene', (80, 85))	('PTEN', 'Gene', '5728', (87, 91))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('TP53', 'Gene', '7157', (97, 101))	('RCC', 'Disease', (36, 39))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (23, 32))	('negative', 'NegReg', (64, 72))	('SETD2', 'Gene', '29072', (80, 85))
15033	32206160	For example, PBRM1 mutations which tend to associate with favorable prognosis in ccRCC were strongly associated with reduced survival in type I pRCC (p<0.0001).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('survival', 'MPA', (125, 133))	('PBRM1', 'Gene', (13, 18))	('reduced', 'NegReg', (117, 124))	('pRCC', 'Gene', (144, 148))	('mutations', 'Var', (19, 28))	('pRCC', 'Gene', '5546', (144, 148))
15041	32206160	Tumors in the e.3 cluster tended to have frequent loss of the CDKN2A gene, frequent BAP1 mutations, and overexpression of cell cycle and hypoxia-related genes.	('hypoxia', 'Disease', 'MESH:D000860', (137, 144))	('loss', 'NegReg', (50, 54))	('CDKN2A', 'Gene', '1029', (62, 68))	('cell cycle', 'biological_process', 'GO:0007049', ('122', '132'))	('hypoxia', 'Disease', (137, 144))	('Tumors', 'Disease', (0, 6))	('CDKN2A', 'Gene', (62, 68))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (89, 98))	('BAP1', 'Gene', (84, 88))	('overexpression', 'PosReg', (104, 118))
15042	32206160	Additionally, e.3 was enriched in inflammatory gene expression relative to e.2, and expression of PDCD1 (encoding for PD1) and CTLA4 were independent predictors of poor prognosis across the ccRCC subtype.	('PDCD1', 'Gene', (98, 103))	('expression', 'Var', (84, 94))	('CTLA4', 'Gene', '1493', (127, 132))	('PD1', 'Gene', '5133', (118, 121))	('CTLA4', 'Gene', (127, 132))	('gene expression', 'biological_process', 'GO:0010467', ('47', '62'))	('PD1', 'Gene', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (192, 195))	('PDCD1', 'Gene', '5133', (98, 103))
15048	32206160	They found that patients with the AngioHigh gene signature had an improved progression-free survival (PFS) compared to those with AngioLow with the angiogenesis inhibitor, sunitinib.	('angiogenesis', 'biological_process', 'GO:0001525', ('148', '160'))	('sunitinib', 'Chemical', 'MESH:D000077210', (172, 181))	('improved', 'PosReg', (66, 74))	('patients', 'Species', '9606', (16, 24))	('AngioHigh gene signature', 'Var', (34, 58))	('progression-free survival', 'CPA', (75, 100))
15049	32206160	In line with these findings, a similar analysis of the COMPARZ trial evaluating two anti-angiogenic agents, sunitinib and pazopanib, found that high expression of angiogenesis genes was associated with improved response rates.	('pazopanib', 'Chemical', 'MESH:C516667', (122, 131))	('improved', 'PosReg', (202, 210))	('response', 'MPA', (211, 219))	('sunitinib', 'Chemical', 'MESH:D000077210', (108, 117))	('high', 'Var', (144, 148))	('angiogenesis genes', 'Gene', (163, 181))	('angiogenesis', 'biological_process', 'GO:0001525', ('163', '175'))
15050	32206160	Furthermore, tumors with PBRM1 mutations demonstrated significantly higher angiogenesis gene expression scores than those with BAP1 mutations.	('mutations', 'Var', (31, 40))	('gene expression', 'biological_process', 'GO:0010467', ('88', '103'))	('angiogenesis gene expression scores', 'MPA', (75, 110))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('angiogenesis', 'biological_process', 'GO:0001525', ('75', '87'))	('higher', 'PosReg', (68, 74))	('PBRM1', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
15051	32206160	In the IMmotion150 trial, patients with the TeffHigh gene signature had improved PFS with atezo+bev compared to the sunitinib and the atezo arms.	('bev', 'Chemical', '-', (96, 99))	('atezo', 'Chemical', 'MESH:C000594389', (134, 139))	('improved', 'PosReg', (72, 80))	('patients', 'Species', '9606', (26, 34))	('atezo+bev', 'Var', (90, 99))	('PFS', 'Disease', (81, 84))	('atezo', 'Chemical', 'MESH:C000594389', (90, 95))	('TeffHigh gene', 'Var', (44, 57))	('sunitinib', 'Chemical', 'MESH:D000077210', (116, 125))
15063	32206160	Notably, the presence of such variables is associated with intermediate/poor risk disease, which suggests that inflammatory tumors are particularly aggressive in patients.	('patients', 'Species', '9606', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('intermediate/poor', 'Disease', (59, 76))	('inflammatory', 'Disease', (111, 123))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('presence', 'Var', (13, 21))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
15066	32206160	In one of the earliest attempts to measure ITH in ccRCC, Gerlinger and colleagues performed multiregional WES of two primary tumors and demonstrated that only 31% of the somatic mutations were ubiquitous amongst all sampled regions.	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (178, 187))
15071	32206160	Interestingly, while BAP1 and PBRM1 mutations could be identified in the same tumor, they were typically located in spatially distinct regions, consistent with previous reports that these mutations anticorrelate with one another and are found in different areas of the same tumors.	('PBRM1', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('BAP1', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumors', 'Disease', (274, 280))
15087	32206160	NGS has allowed the identification of activating mutations in oncogenes, and these have been very effective targets in cancers such as melanoma and non-small cell lung carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('oncogenes', 'Protein', (62, 71))	('lung carcinoma', 'Disease', (163, 177))	('lung carcinoma', 'Disease', 'MESH:D008175', (163, 177))	('mutations', 'Var', (49, 58))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('activating', 'PosReg', (38, 48))	('melanoma', 'Disease', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (148, 177))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (152, 177))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
15092	32206160	In a phase III trial comparing second line cabozantinib to everolimus in ccRCC, cabozantinib was found to result in an improved OS rate (HR 0.66 [95% CI: 0.53 - 0.83]; p= 2.6E-4), as well as improved PFS (HR 0.51 [95% CI: 0.41 - 0.62]; p< 1E-4).	('PFS', 'MPA', (200, 203))	('cabozantinib', 'Var', (80, 92))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('improved', 'PosReg', (191, 199))	('cabozantinib', 'Chemical', 'MESH:C558660', (80, 92))	('improved', 'PosReg', (119, 127))	('OS rate', 'MPA', (128, 135))	('cabozantinib', 'Chemical', 'MESH:C558660', (43, 55))	('everolimus', 'Chemical', 'MESH:D000068338', (59, 69))
15095	32206160	For the small subset of patients with genomic data, 40% (4/10) of pRCC patients with MET mutations demonstrated partial responses.	('MET', 'Gene', (85, 88))	('pRCC', 'Gene', '5546', (66, 70))	('patients', 'Species', '9606', (71, 79))	('pRCC', 'Gene', (66, 70))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (24, 32))	('MET', 'Gene', '79811', (85, 88))
15097	32206160	While targeting driver mutations may provide benefit to a subset of RCC patients, techniques leveraging tumor suppressor genes therapeutically are needed to benefit the larger population.	('tumor suppressor', 'biological_process', 'GO:0051726', ('104', '120'))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('104', '120'))	('tumor', 'Disease', (104, 109))	('mutations', 'Var', (23, 32))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('patients', 'Species', '9606', (72, 80))
15098	32206160	One strategy to tackle loss-of-function mutations in tumor suppressor proteins has been to inhibit downstream effector pathways.	('loss-of-function', 'NegReg', (23, 39))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('53', '69'))	('inhibit', 'NegReg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('downstream effector pathways', 'Pathway', (99, 127))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (53, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('53', '69'))
15101	32206160	This led to the development of PT2385 and PT2399, which were shown to be potent and highly selective inhibitors leading to the dissociation of HIF-2 complexes Preclinical testing of PT2399 in our laboratory demonstrated decreased tumor growth across ~50% of ccRCC tumorgrafts analyzed (P<0.0001), including in sunitinib resistant tumors.	('tumor', 'Disease', (330, 335))	('sunitinib', 'Chemical', 'MESH:D000077210', (310, 319))	('ccRCC tumorgrafts', 'Disease', (258, 275))	('PT2399', 'Chemical', 'MESH:C000614278', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('tumor', 'Disease', (264, 269))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('PT2399', 'Var', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('decreased', 'NegReg', (220, 229))	('tumors', 'Disease', (330, 336))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('ccRCC tumorgrafts', 'Disease', 'None', (258, 275))	('PT2399', 'Chemical', 'MESH:C000614278', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('PT2385', 'Chemical', 'MESH:C000614279', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
15102	32206160	However, prolonged therapy with PT2399 led to the development of acquired resistance in tumorgraft models.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('PT2399', 'Var', (32, 38))	('PT2399', 'Chemical', 'MESH:C000614278', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('acquired resistance', 'MPA', (65, 84))
15103	32206160	Sequencing of tumorgrafts with acquired resistance to PT2399 led to the identification of point mutations which restored dimerization in the presence of inhibitors, one of which was subsequently identified in patient tumors that developed resistance to HIF-2 inhibition.	('dimerization', 'MPA', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (14, 19))	('patient', 'Species', '9606', (209, 216))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PT2399', 'Chemical', 'MESH:C000614278', (54, 60))	('PT2399', 'Gene', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('restored', 'PosReg', (112, 120))	('mutations', 'Var', (96, 105))
15110	32206160	An alternative approach to targeting tumor suppressor genes leverages "synthetic lethality," where loss of two genes results in cell death whereas loss of either gene does not.	('death', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor suppressor', 'biological_process', 'GO:0051726', ('37', '53'))	('loss', 'Var', (99, 103))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('37', '53'))	('death', 'Disease', 'MESH:D003643', (133, 138))
15112	32206160	In one of the first such studies, Turcotte and colleagues screened a panel of ~64,000 small molecules in parallel on VHL deficient RCC4 cells and RCC4 cells with re-introduced VHL.	('RCC4', 'CellLine', 'CVCL:0498', (131, 135))	('RCC4', 'CellLine', 'CVCL:0498', (146, 150))	('deficient', 'Var', (121, 130))	('VHL', 'Gene', (117, 120))
15113	32206160	They found that STF-62247 was able to selectively induce apoptosis in VHL deficient cells, likely through inhibition of protein trafficking.	('protein', 'Protein', (120, 127))	('STF-62247', 'Var', (16, 25))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('apoptosis', 'CPA', (57, 66))	('apoptosis', 'biological_process', 'GO:0006915', ('57', '66'))	('STF-62247', 'Chemical', 'MESH:C530878', (16, 25))	('inhibition', 'NegReg', (106, 116))	('induce', 'PosReg', (50, 56))	('apoptosis', 'biological_process', 'GO:0097194', ('57', '66'))
15114	32206160	Utilizing the same screen, STF-31 which acts through inhibition of GLUT1, was also found to have preferential toxicity among VHL deficient cells.	('GLUT1', 'Gene', '6513', (67, 72))	('inhibition', 'NegReg', (53, 63))	('toxicity', 'Disease', 'MESH:D064420', (110, 118))	('STF-31', 'Var', (27, 33))	('preferential', 'PosReg', (97, 109))	('toxicity', 'Disease', (110, 118))	('GLUT1', 'Gene', (67, 72))
15118	32206160	More recently, an expanded shRNA library targeting ~1000 genes identified EZH1 depletion to be synthetically lethal with VHL loss.	('EZH1', 'Gene', '2145', (74, 78))	('VHL loss', 'Disease', 'MESH:D006623', (121, 129))	('VHL loss', 'Disease', (121, 129))	('depletion', 'Var', (79, 88))	('EZH1', 'Gene', (74, 78))
15122	32206160	Whereas EZH2 was not identified as exhibiting synthetic lethality in the aforementioned screen, there is preclinical evidence that EZH2 inhibitors may be effective in the setting of BAP1 deficiency.	('inhibitors', 'Var', (136, 146))	('BAP1', 'Gene', (182, 186))	('EZH2', 'Gene', '2146', (8, 12))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))	('deficiency', 'Var', (187, 197))	('EZH2', 'Gene', (8, 12))
15123	32206160	Mice with isolated BAP1 deficiency in hematopoietic precursors develop myelodysplastic syndrome.	('deficiency', 'Var', (24, 34))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (71, 95))	('develop', 'Reg', (63, 70))	('Mice', 'Species', '10090', (0, 4))	('BAP1', 'Gene', (19, 23))	('myelodysplastic syndrome', 'Disease', (71, 95))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (71, 95))
15124	32206160	In these models, BAP1 deficiency results in increased EZH2 expression and methylation of H3K27.	('EZH2', 'Gene', (54, 58))	('expression', 'MPA', (59, 69))	('H3K27', 'Protein', (89, 94))	('BAP1', 'Gene', (17, 21))	('increased', 'PosReg', (44, 53))	('methylation', 'MPA', (74, 85))	('EZH2', 'Gene', '2146', (54, 58))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))	('deficiency', 'Var', (22, 32))
15127	32206160	In addition, RCC-derived cell lines deficient in BAP1 overexpress EZH2, and are sensitive to EZH2 inhibitors in vitro.	('overexpress', 'PosReg', (54, 65))	('deficient', 'Var', (36, 45))	('BAP1', 'Gene', (49, 53))	('EZH2', 'Gene', '2146', (93, 97))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('EZH2', 'Gene', (93, 97))	('RCC', 'Disease', (13, 16))	('sensitive', 'Reg', (80, 89))
15128	32206160	Furthermore, in a sunitinib-resistant xenograft model of RCC, the EZH2 inhibitor EPZ011929 demonstrated rescue of sunitinib sensitivity through epigenetic reprograming (BAP1 status was not reported in this study).	('EPZ011929', 'Chemical', '-', (81, 90))	('rescue', 'PosReg', (104, 110))	('sunitinib', 'Chemical', 'MESH:D000077210', (18, 27))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('sunitinib sensitivity', 'MPA', (114, 135))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (114, 123))	('EPZ011929', 'Var', (81, 90))	('epigenetic', 'Var', (144, 154))
15143	32206160	Activating mutations in ccRCC are less frequent than type II pRCC, however, emerging evidence suggests epigenetic silencing of KEAP1 may contribute to NRF2/ARE deregulation in ccRCC.	('KEAP1', 'Gene', '9817', (127, 132))	('deregulation', 'MPA', (160, 172))	('pRCC', 'Gene', (61, 65))	('KEAP1', 'Gene', (127, 132))	('RCC', 'Disease', (26, 29))	('epigenetic silencing', 'Var', (103, 123))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('contribute', 'Reg', (137, 147))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', (178, 181))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('NRF2', 'Gene', '4780', (151, 155))	('NRF2', 'Gene', (151, 155))
15144	32206160	Consistent with a potential role of NRF2/ARE in ccRCC, NRF2 depletion via shRNA was recently shown to decrease proliferation and increase sensitivity to sunitinib in the 786-O ccRCC cell line.	('NRF2', 'Gene', (55, 59))	('decrease', 'NegReg', (102, 110))	('NRF2', 'Gene', '4780', (36, 40))	('proliferation', 'CPA', (111, 124))	('depletion', 'Var', (60, 69))	('NRF2', 'Gene', (36, 40))	('RCC', 'Disease', (50, 53))	('sensitivity to sunitinib', 'MPA', (138, 162))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('increase', 'PosReg', (129, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (153, 162))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('NRF2', 'Gene', '4780', (55, 59))
15166	31143076	The mutations present in polycystic kidney disease (PKD1 and PKD2) are causative genes for ADPKD, while 20% of ADPLD is caused by mutations in the protein kinase C substrate 80K-H (PRKCSH) or SEC63, leaving the other 80% with unknown etiologies.	('PRKCSH', 'Gene', '5589', (181, 187))	('PKD2', 'Gene', (61, 65))	('PRKCSH', 'Gene', (181, 187))	('protein kinase C substrate 80K-H', 'Gene', (147, 179))	('ADPKD', 'Disease', 'MESH:D007690', (91, 96))	('polycystic kidney disease', 'Disease', (25, 50))	('PKD2', 'Gene', '5311', (61, 65))	('PKD1', 'Gene', '5310', (52, 56))	('protein kinase C substrate 80K-H', 'Gene', '5589', (147, 179))	('caused by', 'Reg', (120, 129))	('polycystic kidney', 'Phenotype', 'HP:0000113', (25, 42))	('ADPKD', 'Disease', (91, 96))	('kidney disease', 'Phenotype', 'HP:0000112', (36, 50))	('SEC63', 'Gene', (192, 197))	('polycystic kidney disease', 'Disease', 'MESH:D007690', (25, 50))	('mutations', 'Var', (4, 13))	('protein', 'cellular_component', 'GO:0003675', ('147', '154'))	('SEC63', 'Gene', '11231', (192, 197))	('ADPLD', 'Disease', (111, 116))	('PKD1', 'Gene', (52, 56))	('mutations', 'Var', (130, 139))
15279	23198258	showed that only 1 out of 10 tumors had low copy number gains of chromosomes 7 and 17.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('low copy number gains', 'Var', (40, 61))
15291	23198258	Genetically, while CCRCC shows a deletion of chromosome 3p and mutation in VHL gene in majority of sporadic cases, CCPRCC does not have such changes.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('VHL', 'Gene', (75, 78))	('RCC', 'Disease', (118, 121))	('PRCC', 'Gene', '5546', (117, 121))	('deletion', 'Var', (33, 41))	('VHL', 'Gene', '7428', (75, 78))	('CCPRCC', 'Phenotype', 'HP:0006770', (115, 121))	('mutation', 'Var', (63, 71))	('PRCC', 'Phenotype', 'HP:0006766', (117, 121))	('PRCC', 'Gene', (117, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('CCRCC', 'Phenotype', 'HP:0006770', (19, 24))
15310	33922974	Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC.	('regulate', 'Reg', (149, 157))	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('ccRCC', 'Phenotype', 'HP:0006770', (177, 182))	('epigenetically', 'Var', (134, 148))	('ncRNA', 'Gene', (112, 117))	('gene expression', 'MPA', (158, 173))	('histone modification', 'biological_process', 'GO:0016570', ('86', '106'))	('ncRNA', 'Gene', '220202', (112, 117))	('DNA methylation', 'biological_process', 'GO:0006306', ('69', '84'))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('gene expression', 'biological_process', 'GO:0010467', ('158', '173'))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
15311	33922974	Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('epigenetic modifiers genes', 'Var', (14, 40))	('RCC', 'Disease', (90, 93))
15312	33922974	We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications.	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('ccRCC initiation', 'Disease', (115, 131))	('ccRCC initiation', 'Disease', 'MESH:D007319', (115, 131))	('epigenetic changes', 'Var', (55, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('determine', 'Reg', (74, 83))
15314	33922974	Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('epigenetic treatments', 'Var', (31, 52))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
15340	33922974	Blockade of the PD1-PDL1 axis promotes T cell activation and immune killing of cancer cells.	('PDL1', 'Gene', '29126', (20, 24))	('promotes', 'PosReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Blockade', 'Var', (0, 8))	('T cell activation', 'biological_process', 'GO:0042110', ('39', '56'))	('PDL1', 'Gene', (20, 24))	('T cell activation', 'CPA', (39, 56))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
15346	33922974	Response rates are better in PDL1 positive tumors, but PDL1 negative ones also respond.	('PDL1', 'Gene', (29, 33))	('better', 'PosReg', (19, 25))	('Response', 'MPA', (0, 8))	('PDL1', 'Gene', '29126', (55, 59))	('positive', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PDL1', 'Gene', '29126', (29, 33))	('PDL1', 'Gene', (55, 59))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
15351	33922974	Abnormal epigenetic patterns will give new opportunities to develop novel therapies in RCC.	('epigenetic patterns', 'Var', (9, 28))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
15353	33922974	Maybe closer is the practical utility of epigenetic therapies to solve or delay therapy resistance in ccRCC, and also to identify the populations in which prolonged response to a certain therapy could be expected.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('delay', 'NegReg', (74, 79))	('epigenetic therapies', 'Var', (41, 61))	('solve', 'Reg', (65, 70))	('therapy resistance', 'MPA', (80, 98))	('RCC', 'Disease', (104, 107))
15355	33922974	As such, cancer epigenetics deals with the inheritable but reversible changes associated with gene expression dysregulation that manifest in a pre-malignant phenotype with the genomic sequence unaltered.	('cancer', 'Disease', (9, 15))	('pre', 'molecular_function', 'GO:0003904', ('143', '146'))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('dysregulation', 'Var', (110, 123))
15356	33922974	Interest in epigenetic alterations associated with ccRCC provides an optimal scenario in the search for new tumor markers in this malignancy, and also to develop new treatment strategies facilitated by the reversibility of epigenetic modifications.	('malignancy', 'Disease', (130, 140))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('epigenetic alterations', 'Var', (12, 34))	('associated', 'Reg', (35, 45))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('tumor', 'Disease', (108, 113))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))
15357	33922974	The main epigenetic mechanisms are DNA methylation, chromatin remodeling, post-translational histone modifications, short-noncoding RNAs, also known as microRNAs (miRNA), and long-noncoding RNAs (lncRNA).	('chromatin remodeling', 'CPA', (52, 72))	('ncRNA', 'Gene', (197, 202))	('methylation', 'Var', (39, 50))	('DNA methylation', 'biological_process', 'GO:0006306', ('35', '50'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('52', '72'))	('ncRNA', 'Gene', '220202', (197, 202))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('short-noncoding RNAs', 'Var', (116, 136))	('DNA', 'Var', (35, 38))	('long-noncoding RNAs', 'Var', (175, 194))
15358	33922974	These changes can be due to genetic alterations, linking genetics, and epigenetics in carcinogenesis.	('carcinogenesis', 'Disease', (86, 100))	('genetic alterations', 'Var', (28, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('due', 'Reg', (21, 24))	('epigenetics', 'Var', (71, 82))
15359	33922974	Among the many epigenetic changes and signatures identified in RCC, aberrant promoter methylation of more than 200 genes have been reported and more than 120 miRNAs are deregulated.	('RCC', 'Disease', (63, 66))	('deregulated', 'Reg', (169, 180))	('methylation', 'biological_process', 'GO:0032259', ('86', '97'))	('reported', 'Reg', (131, 139))	('promoter methylation', 'MPA', (77, 97))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('aberrant', 'Var', (68, 76))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
15360	33922974	In addition, the selection of normal tissue for comparison with neoplasia can be problematic because aberrant promoter methylation is an early event in carcinogenesis allowing its detection in normal appearing tissue surrounding the tumor.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('carcinogenesis', 'Disease', (152, 166))	('tumor', 'Disease', (233, 238))	('neoplasia', 'Phenotype', 'HP:0002664', (64, 73))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))	('neoplasia', 'Disease', (64, 73))	('aberrant', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))	('neoplasia', 'Disease', 'MESH:D009369', (64, 73))
15362	33922974	Firstly, epigenetic deregulation can lead precursor cells to proliferate and block their differentiation as seems to occur in germ cell malignancies.	('epigenetic deregulation', 'Var', (9, 32))	('lead', 'Reg', (37, 41))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('malignancies', 'Disease', (136, 148))	('germ cell malignancies', 'Phenotype', 'HP:0100728', (126, 148))	('proliferate', 'CPA', (61, 72))	('block', 'NegReg', (77, 82))	('differentiation', 'CPA', (89, 104))
15364	33922974	Probably the most interesting epigenetic mechanism in ccRCC stands in common mutations in chromatin regulator genes that complement the inactivation of Von Hippel Lindau (VHL) tumor suppressor gene (TSG), and Hypoxia-inducible factors (HIF) pathway that allow tumor cell survival in a characteristic status of pseudo-hypoxia.	('Hypoxia', 'Disease', (209, 216))	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('176', '192'))	('low tumor', 'Disease', 'MESH:D009800', (256, 265))	('tumor suppressor', 'biological_process', 'GO:0051726', ('176', '192'))	('tumor suppressor', 'Gene', '7248', (176, 192))	('VHL', 'Gene', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('low tumor', 'Disease', (256, 265))	('hypoxia', 'Disease', (317, 324))	('mutations', 'Var', (77, 86))	('VHL', 'Gene', '7428', (171, 174))	('hypoxia', 'Disease', 'MESH:D000860', (317, 324))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('Hypoxia', 'Disease', 'MESH:D000860', (209, 216))	('tumor suppressor', 'Gene', (176, 192))
15365	33922974	VHL gene is frequently inactivated in sporadic ccRCC by mutation, loss of heterozygosity, or promoter hypermethylation.	('RCC', 'Disease', (49, 52))	('promoter hypermethylation', 'Var', (93, 118))	('ccRCC', 'Phenotype', 'HP:0006770', (47, 52))	('loss of heterozygosity', 'Var', (66, 88))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('mutation', 'Var', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('inactivated', 'NegReg', (23, 34))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
15370	33922974	Recent genome-wide sequencing studies have revealed a number of mutations of genes coding for epigenome modifiers and chromatin remodelers, like PBRM1 (40%), SETD2 (10%), KDM5C (10%), KDM6A (1%), and BAP1 (10-15%).	('BAP1', 'Gene', '8314', (200, 204))	('KDM5C', 'Gene', (171, 176))	('chromatin', 'cellular_component', 'GO:0000785', ('118', '127'))	('SETD2', 'Gene', '29072', (158, 163))	('KDM6A', 'Gene', (184, 189))	('KDM5C', 'Gene', '8242', (171, 176))	('mutations', 'Var', (64, 73))	('BAP1', 'Gene', (200, 204))	('PBRM1', 'Gene', (145, 150))	('KDM6A', 'Gene', '7403', (184, 189))	('SETD2', 'Gene', (158, 163))
15371	33922974	Most of the mutations of histone modifier genes described in ccRCC are truncating and inactivating mutations producing loss of functions.	('inactivating', 'Var', (86, 98))	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('mutations', 'Var', (12, 21))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
15372	33922974	Apart from VHL mutations these are among the most common somatic genetic abnormalities encountered in renal tumors.	('renal tumors', 'Phenotype', 'HP:0009726', (102, 114))	('genetic abnormalities encountered in renal tumors', 'Disease', 'MESH:D030342', (65, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('genetic abnormalities encountered in renal tumors', 'Disease', (65, 114))	('mutations', 'Var', (15, 24))	('VHL', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('VHL', 'Gene', '7428', (11, 14))
15378	33922974	Liquid biopsy from direct washing of fresh biopsies can be an optimal method as well, to evaluate epigenetic changes that would facilitate accurate detection, tumor subtype determination, and evaluation of prognosis as well.	('tumor', 'Disease', (159, 164))	('epigenetic changes', 'Var', (98, 116))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
15381	33922974	The growing field of knowledge to determine the real impact of altered epigenetic patterns and their role in the diagnosis, monitoring, classification, prognosis, and treatment of kidney cancer is the main objective of this review.	('epigenetic patterns', 'Var', (71, 90))	('kidney cancer', 'Phenotype', 'HP:0009726', (180, 193))	('kidney cancer', 'Disease', 'MESH:D007680', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('kidney cancer', 'Disease', (180, 193))
15382	33922974	DNA methylation is the most widely studied epigenetic modification so far, and consists of the addition of a methyl group to the Cytosine within the CpG dinucleotide.	('DNA methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (149, 165))	('Cytosine', 'Chemical', 'MESH:D003596', (129, 137))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('methylation', 'Var', (4, 15))	('DNA', 'Disease', (0, 3))	('methyl group', 'MPA', (109, 121))
15388	33922974	Two major changes occur in cancer affecting DNA methylation: global DNA hypomethylation of the genome and aberrant hypermethylation of the promoter region of TSGs.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('aberrant', 'Var', (106, 114))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('68', '87'))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('DNA', 'cellular_component', 'GO:0005574', ('44', '47'))	('DNA methylation', 'biological_process', 'GO:0006306', ('44', '59'))
15390	33922974	In addition, the hypomethylation of CpG sites has been associated with the over-expression of oncogenes within cancer cells and with deregulation of proteins involved in the complex balance between methylation and the maintenance of the chromatin structure.	('oncogenes', 'Gene', (94, 103))	('hypomethylation', 'Var', (17, 32))	('CpG', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (55, 65))	('proteins', 'Protein', (149, 157))	('methylation', 'biological_process', 'GO:0032259', ('198', '209'))	('chromatin', 'cellular_component', 'GO:0000785', ('237', '246'))	('deregulation', 'Var', (133, 145))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('over-expression', 'PosReg', (75, 90))
15391	33922974	Hypermethylation of CpG islands located in the promoter regions of some TSGs prevents gene expression and, therefore, its protective role in the development of tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('gene expression', 'biological_process', 'GO:0010467', ('86', '101'))	('Hypermethylation', 'Var', (0, 16))	('prevents', 'NegReg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('gene expression', 'MPA', (86, 101))	('TSGs', 'Gene', (72, 76))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
15392	33922974	Gene silencing by promoter hypermethylation in cancer has been studied in depth and affects important functions for cell cycle, DNA repair, cell adhesion and invasion, apoptosis, miRNA expression, metabolism of carcinogens, and response to hormones.	('DNA repair', 'biological_process', 'GO:0006281', ('128', '138'))	('Gene silencing', 'biological_process', 'GO:0016458', ('0', '14'))	('apoptosis', 'biological_process', 'GO:0097194', ('168', '177'))	('apoptosis', 'biological_process', 'GO:0006915', ('168', '177'))	('miRNA expression', 'MPA', (179, 195))	('affects', 'Reg', (84, 91))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('DNA repair', 'MPA', (128, 138))	('cell adhesion', 'CPA', (140, 153))	('cell adhesion', 'biological_process', 'GO:0007155', ('140', '153'))	('cell cycle', 'biological_process', 'GO:0007049', ('116', '126'))	('functions', 'MPA', (102, 111))	('cell cycle', 'CPA', (116, 126))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('DNA', 'cellular_component', 'GO:0005574', ('128', '131'))	('metabolism', 'biological_process', 'GO:0008152', ('197', '207'))	('metabolism', 'MPA', (197, 207))	('apoptosis', 'CPA', (168, 177))	('invasion', 'CPA', (158, 166))	('promoter hypermethylation', 'Var', (18, 43))
15396	33922974	Thirdly, methylation-specific PCR (MSP) derived methods enable a fast, simple method to detect methylated alleles of a certain gene in samples with low tumor content and even in biological fluids.	('low tumor', 'Disease', 'MESH:D009800', (148, 157))	('methylated', 'Var', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('low tumor', 'Disease', (148, 157))	('detect', 'Reg', (88, 94))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))
15397	33922974	However, among the limitations to generalize application of epigenetic markers in RCC is also cell type specificity and the aforementioned heterogeneity of this malignancy.	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('malignancy', 'Disease', (161, 171))	('epigenetic markers', 'Var', (60, 78))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))
15398	33922974	Aberrant DNA methylation is an early event in carcinogenesis, thus DNA methylation biomarkers has been implemented for the diagnosis of a wide range of malignancies including prostate, colorectal, and pulmonary neoplasia.	('pulmonary neoplasia', 'Disease', 'MESH:D009369', (201, 220))	('DNA methylation', 'biological_process', 'GO:0006306', ('67', '82'))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('Aberrant', 'Var', (0, 8))	('pulmonary neoplasia', 'Disease', (201, 220))	('carcinogenesis', 'Disease', (46, 60))	('pulmonary neoplasia', 'Phenotype', 'HP:0100526', (201, 220))	('DNA', 'cellular_component', 'GO:0005574', ('9', '12'))	('prostate', 'Disease', (175, 183))	('malignancies', 'Disease', 'MESH:D009369', (152, 164))	('colorectal', 'Disease', (185, 195))	('DNA methylation', 'biological_process', 'GO:0006306', ('9', '24'))	('neoplasia', 'Phenotype', 'HP:0002664', (211, 220))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('malignancies', 'Disease', (152, 164))
15405	33922974	RASSF1A and SPINT2 are more frequently methylated in pRCC while COL1A1 and IGFBP1 hypermethylation is more common in ccRCC.	('pRCC', 'Gene', (53, 57))	('SPINT2', 'Gene', (12, 18))	('COL1A1', 'Gene', (64, 70))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('methylated', 'Var', (39, 49))	('IGFBP1', 'Gene', (75, 81))	('common', 'Reg', (107, 113))	('SPINT2', 'Gene', '10653', (12, 18))	('IGFBP1', 'Gene', '3484', (75, 81))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RASSF1A', 'Gene', '11186', (0, 7))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('pRCC', 'Gene', '5546', (53, 57))	('RASSF1A', 'Gene', (0, 7))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('COL1A1', 'Gene', '1277', (64, 70))
15407	33922974	In fact, data from The Cancer Genome Atlas (TCGA) revealed that of all RCC subtypes, oncocytoma and chRCC are the most similar but, what is even more interesting, a signature of 30 hypermethylated genes distinguishes oncocytoma from chRCC involved, among others, in Wnt, MAPK, and TGFbeta signaling.	('Cancer', 'Disease', (23, 29))	('signaling', 'biological_process', 'GO:0023052', ('289', '298'))	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (235, 238))	('distinguishes', 'Reg', (203, 216))	('oncocytoma', 'Disease', 'MESH:D018249', (217, 227))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('oncocytoma', 'Disease', (85, 95))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('MAPK', 'molecular_function', 'GO:0004707', ('271', '275'))	('RCC', 'Disease', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('oncocytoma', 'Disease', (217, 227))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('TGFbeta', 'Gene', (281, 288))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('RCC', 'Disease', (102, 105))	('hypermethylated genes', 'Var', (181, 202))	('oncocytoma', 'Disease', 'MESH:D018249', (85, 95))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('TGFbeta', 'Gene', '7039', (281, 288))
15419	33922974	Very recently some methylated genes with prognostic value in pRCC have also been described.	('methylated', 'Var', (19, 29))	('pRCC', 'Gene', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('pRCC', 'Gene', '5546', (61, 65))
15422	33922974	Each of them, with the exception of MBD3, is capable of binding specifically to methylated DNA.	('MBD3', 'Gene', (36, 40))	('DNA', 'cellular_component', 'GO:0005574', ('91', '94'))	('DNA', 'Protein', (91, 94))	('methylated', 'Var', (80, 90))	('binding', 'Interaction', (56, 63))	('binding', 'molecular_function', 'GO:0005488', ('56', '63'))	('MBD3', 'Gene', '53615', (36, 40))
15431	33922974	Similarly, it has been suggested that H3K9Ac and H3K18Ac levels could monitor patients with RCC after surgery, but as far as we know these likely markers have not been confirmed in prospective validations.	('patients', 'Species', '9606', (78, 86))	('H3K9Ac', 'MPA', (38, 44))	('RCC', 'Disease', (92, 95))	('H3K18Ac', 'Var', (49, 56))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (92, 95))
15433	33922974	Additionally, H3K27me1/-me2/-me3 staining is significantly more intense in pRCC than in ccRCC, and H3K27me3 levels are higher in oncocytoma than in RCC.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (148, 151))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('ccRCC', 'Phenotype', 'HP:0006770', (88, 93))	('pRCC', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('H3K27me3 levels', 'MPA', (99, 114))	('higher', 'PosReg', (119, 125))	('oncocytoma', 'Disease', (129, 139))	('H3K27me1/-me2/-me3', 'Var', (14, 32))	('oncocytoma', 'Disease', 'MESH:D018249', (129, 139))	('pRCC', 'Gene', '5546', (75, 79))	('intense', 'PosReg', (64, 71))	('RCC', 'Disease', (90, 93))
15438	33922974	One of the mechanisms involved in the epigenetic-altered landscape in RCC related to hypoxic effect is the regulation of Jumonji domain containing histone demethylases by the mediator of hypoxic response HIFalpha.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('regulation', 'biological_process', 'GO:0065007', ('107', '117'))	('epigenetic-altered', 'Var', (38, 56))	('hypoxic', 'Disease', (187, 194))	('hypoxic', 'Disease', 'MESH:D000860', (187, 194))	('hypoxic', 'Disease', (85, 92))	('hypoxic', 'Disease', 'MESH:D000860', (85, 92))
15439	33922974	A number of genes that encode histone-modifying enzymes are mutated in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('RCC', 'Disease', (73, 76))	('mutated', 'Var', (60, 67))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
15440	33922974	Inactivating mutations described for SETD2 (H3K36 methyltransferase), KDM5C (H3K4 demethylase), KMD6A (H3K27 demethylase), MLL2 (H3K4 methyltransferase), Polybromo 1 (PBRM1), BRCA1 Associated Protein-1 (BAP1) remain among the most interesting epigenetic mechanisms for ccRCC progression.	('BAP1', 'Gene', '8314', (203, 207))	('SETD2', 'Gene', '29072', (37, 42))	('MLL2', 'Gene', '8085', (123, 127))	('Polybromo 1', 'Gene', '55193', (154, 165))	('ccRCC', 'Phenotype', 'HP:0006770', (269, 274))	('PBRM1', 'Gene', (167, 172))	('Polybromo 1', 'Gene', (154, 165))	('SETD2', 'Gene', (37, 42))	('BAP1', 'Gene', (203, 207))	('Inactivating mutations', 'Var', (0, 22))	('RCC', 'Disease', (271, 274))	('BRCA1 Associated Protein-1', 'Gene', '8314', (175, 201))	('MLL2', 'Gene', (123, 127))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('KDM5C', 'Gene', (70, 75))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('BRCA1 Associated Protein-1', 'Gene', (175, 201))	('KDM5C', 'Gene', '8242', (70, 75))
15442	33922974	This gene is involved in genome stability as trimethylation of H3K36 by SETD2 is required for DNA repairing system through both homologous recombination repair and mismatch repair.	('DNA', 'cellular_component', 'GO:0005574', ('94', '97'))	('mismatch', 'Var', (164, 172))	('mismatch repair', 'biological_process', 'GO:0006298', ('164', '179'))	('homologous recombination', 'biological_process', 'GO:0035825', ('128', '152'))	('H3K36', 'Protein', (63, 68))	('SETD2', 'Gene', '29072', (72, 77))	('SETD2', 'Gene', (72, 77))
15443	33922974	DNMT3B-mediated de novo DNA methylation occurs at the intron of genes marked with H3K36me3 but not those lacking H3K36me3.	('H3K36me3', 'Var', (82, 90))	('de novo DNA methylation', 'biological_process', 'GO:0043046', ('16', '39'))	('DNA', 'cellular_component', 'GO:0005574', ('24', '27'))	('DNMT3B', 'Gene', '1789', (0, 6))	('DNMT3B', 'Gene', (0, 6))	('de novo DNA methylation', 'biological_process', 'GO:0043045', ('16', '39'))
15444	33922974	Mutations in the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex gene PBRM1 are identified in approximately 40% of ccRCC.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('69', '89'))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('69', '97'))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', (103, 108))	('ccRCC', 'Phenotype', 'HP:0006770', (148, 153))	('identified', 'Reg', (113, 123))	('sucrose', 'Chemical', 'MESH:D013395', (37, 44))
15446	33922974	Thus, inactivation of the PBRM1 TSG amplifies the HIF-response of VHL negative ccRCC.	('PBRM1', 'Gene', (26, 31))	('inactivation', 'Var', (6, 18))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('VHL', 'Gene', (66, 69))	('HIF-response', 'MPA', (50, 62))	('VHL', 'Gene', '7428', (66, 69))	('amplifies', 'PosReg', (36, 45))
15452	33922974	KDM6A codifies a protein that demethylases lysine 27 in histone 3 (H3K27) and is mutated in only 1% of ccRCCs, while KDM5C encodes H3K4 demethylase and its mutation is present in approximately 10% of ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('lysine', 'Chemical', 'MESH:D008239', (43, 49))	('KDM6A', 'Gene', '7403', (0, 5))	('mutated', 'Var', (81, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (200, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (103, 108))	('protein', 'cellular_component', 'GO:0003675', ('17', '24'))	('KDM5C', 'Gene', (117, 122))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('KDM5C', 'Gene', '8242', (117, 122))	('KDM6A', 'Gene', (0, 5))
15454	33922974	Inhibition of EZH2 has been suggested as an effective therapeutic approach to KDM6A-mutated tumors.	('KDM6A', 'Gene', '7403', (78, 83))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Inhibition', 'Var', (0, 10))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('KDM6A', 'Gene', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
15455	33922974	KDM5C acts as TSG and its deficiency results in genomic instability and aggressive forms of ccRCC.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('genomic instability', 'CPA', (48, 67))	('deficiency', 'Var', (26, 36))	('RCC', 'Disease', (94, 97))	('results in', 'Reg', (37, 47))	('ccRCC', 'Phenotype', 'HP:0006770', (92, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('KDM5C', 'Gene', (0, 5))	('KDM5C', 'Gene', '8242', (0, 5))	('aggressive forms', 'CPA', (72, 88))
15456	33922974	Interestingly both KMD6A and KDM5C are considered escape from X-inactivation tumor suppressor or EXIT genes.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('77', '93'))	('KDM5C', 'Gene', (29, 34))	('tumor suppressor', 'Gene', (77, 93))	('KDM5C', 'Gene', '8242', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KMD6A', 'Var', (19, 24))	('tumor suppressor', 'Gene', '7248', (77, 93))	('tumor suppressor', 'biological_process', 'GO:0051726', ('77', '93'))
15459	33922974	Lysine-specific histone Demethylase 1A (LSD1 or KDM1A) can demethylate both lysine 4 and lysine 9 of histone H3 (H3K4me and H3K9me), thereby acting as a co-activator or a co-repressor, depending on the context.	('KDM1A', 'Gene', (48, 53))	('Lysine-specific histone Demethylase 1A', 'Gene', (0, 38))	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('Lysine-specific histone Demethylase 1A', 'Gene', '23028', (0, 38))	('demethylate', 'Var', (59, 70))	('LSD1', 'Gene', '23028', (40, 44))	('LSD1', 'Gene', (40, 44))	('KDM1A', 'Gene', '23028', (48, 53))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('H3K9me', 'Var', (124, 130))
15465	33922974	However, more recent evidence has confirmed high EZH2 expression correlates with poor overall survival in RCC, especially in advanced disease by promoting VEGF expression and cell proliferation while inhibiting apoptosis.	('EZH2', 'Gene', '2146', (49, 53))	('expression', 'Var', (54, 64))	('EZH2', 'Gene', (49, 53))	('VEGF', 'Gene', '7422', (155, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('175', '193'))	('overall survival', 'MPA', (86, 102))	('cell proliferation', 'CPA', (175, 193))	('VEGF', 'Gene', (155, 159))	('inhibiting', 'NegReg', (200, 210))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('expression', 'MPA', (160, 170))	('apoptosis', 'CPA', (211, 220))	('high', 'Var', (44, 48))	('promoting', 'PosReg', (145, 154))	('poor', 'NegReg', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('apoptosis', 'biological_process', 'GO:0097194', ('211', '220'))	('apoptosis', 'biological_process', 'GO:0006915', ('211', '220'))
15467	33922974	Mutations in SETD2 and KDM5C are mutually exclusive, as are mutations of PBRM1 and BAP1.	('KDM5C', 'Gene', (23, 28))	('BAP1', 'Gene', (83, 87))	('KDM5C', 'Gene', '8242', (23, 28))	('SETD2', 'Gene', '29072', (13, 18))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', (13, 18))	('mutations', 'Var', (60, 69))	('PBRM1', 'Gene', (73, 78))	('BAP1', 'Gene', '8314', (83, 87))
15468	33922974	BAP1 or KDM5C mutations in ccRCC associate with aggressive disease, high Fuhrman grade, and metastatic at presentation (Figure 1), that imply worse prognosis and instantaneous activation of mTOR signaling.	('KDM5C', 'Gene', (8, 13))	('BAP1', 'Gene', (0, 4))	('mTOR', 'Gene', '2475', (190, 194))	('KDM5C', 'Gene', '8242', (8, 13))	('mTOR', 'Gene', (190, 194))	('associate', 'Reg', (33, 42))	('RCC', 'Disease', (29, 32))	('BAP1', 'Gene', '8314', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('aggressive disease', 'Disease', 'MESH:D001523', (48, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (27, 32))	('signaling', 'biological_process', 'GO:0023052', ('195', '204'))	('high', 'Disease', (68, 72))	('aggressive disease', 'Disease', (48, 66))	('mutations', 'Var', (14, 23))	('metastatic at', 'CPA', (92, 105))
15469	33922974	However, mTOR activation in PBRM1 mutated tumors occurs after long latency periods.	('activation', 'PosReg', (14, 24))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mTOR', 'Gene', (9, 13))	('PBRM1', 'Gene', (28, 33))	('mTOR', 'Gene', '2475', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutated', 'Var', (34, 41))
15470	33922974	Additionally, the clinical significance of SETD2 and PBRM1 mutations is not well known.	('SETD2', 'Gene', '29072', (43, 48))	('PBRM1', 'Gene', (53, 58))	('mutations', 'Var', (59, 68))	('SETD2', 'Gene', (43, 48))
15471	33922974	miRNAs regulate a wide spectrum of cellular processes acting as oncogene or as tumor suppressors of the genes they regulate.	('cellular', 'CPA', (35, 43))	('tumor suppressor', 'Gene', '7248', (79, 95))	('regulate', 'Reg', (7, 15))	('tumor suppressor', 'Gene', (79, 95))	('miRNAs', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15489	33922974	MiR-454 inhibition and MECP2 overexpression could both decrease the proliferative, migrative, and invasive abilities of RCC cells and also serve as an independent prognostic factor in RCC.	('MiR-454', 'Gene', (0, 7))	('overexpression', 'PosReg', (29, 43))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('invasive abilities', 'CPA', (98, 116))	('MECP2', 'Gene', (23, 28))	('RCC', 'Disease', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('decrease', 'NegReg', (55, 63))	('migrative', 'CPA', (83, 92))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('MiR-454', 'Gene', '768216', (0, 7))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('inhibition', 'Var', (8, 18))	('proliferative', 'CPA', (68, 81))	('MECP2', 'Gene', '4204', (23, 28))
15500	33922974	The cooperation between DMDRMR and IGF2BP3 regulates target genes in an m6A-dependent manner and may represent a potential diagnostic, prognostic, and likely therapeutic target in ccRCC.	('DMDRMR', 'Gene', (24, 30))	('regulates', 'Reg', (43, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('cooperation', 'Var', (4, 15))	('IGF2BP3', 'Gene', '10643', (35, 42))	('IGF2BP3', 'Gene', (35, 42))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))
15504	33922974	The N6-methyladenosine (m6A) RNA methylation is the most frequent, abundant, and conserved form of RNA methylation reported both in messenger RNAs and lncRNAs.	('ncRNA', 'Gene', '220202', (152, 157))	('RNA', 'cellular_component', 'GO:0005562', ('99', '102'))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (4, 22))	('RNA methylation', 'biological_process', 'GO:0001510', ('29', '44'))	('N6-methyladenosine', 'Var', (4, 22))	('RNA methylation', 'biological_process', 'GO:0001510', ('99', '114'))	('RNA', 'cellular_component', 'GO:0005562', ('29', '32'))	('ncRNA', 'Gene', (152, 157))
15505	33922974	Other well-characterized RNA modifications are 5-methylcytosine (m5C), N7-methylguanosine (m7G), and pseudo-uridine.	('N7-methylguanosine', 'Var', (71, 89))	('pseudo-uridine', 'Chemical', 'MESH:D011560', (101, 115))	('N7-methylguanosine', 'Chemical', 'MESH:C016578', (71, 89))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('5-methylcytosine', 'MPA', (47, 63))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (47, 63))	('pseudo-uridine', 'Var', (101, 115))
15513	33922974	This group of proteins include the bromodomain-containing family of proteins that recognize acetylated lysine residues, the chromodomain-containing proteins that bind to methylated histones, and MBDs, mentioned previously, that bind to methylated DNA.	('bind', 'Interaction', (162, 166))	('MBDs', 'Disease', (195, 199))	('MBDs', 'Disease', 'None', (195, 199))	('bind', 'Interaction', (228, 232))	('DNA', 'cellular_component', 'GO:0005574', ('247', '250'))	('histones', 'Protein', (181, 189))	('methylated', 'Var', (236, 246))	('lysine', 'Chemical', 'MESH:D008239', (103, 109))
15522	33922974	So, DNMTi produce passive DNA demethylation and induce the expression of genes that have been silenced by promoter DNA methylation, thus reactivating silenced TSGs in cancer.	('DNA methylation', 'biological_process', 'GO:0006306', ('115', '130'))	('silenced TSGs', 'Disease', 'None', (150, 163))	('silenced TSGs', 'Disease', (150, 163))	('passive DNA demethylation', 'MPA', (18, 43))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('DNA demethylation', 'biological_process', 'GO:0080111', ('26', '43'))	('expression of', 'MPA', (59, 72))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('induce', 'PosReg', (48, 54))	('cancer', 'Disease', (167, 173))	('DNMTi', 'Var', (4, 9))	('DNA', 'cellular_component', 'GO:0005574', ('115', '118'))	('reactivating', 'PosReg', (137, 149))	('DNMTi', 'Chemical', '-', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
15523	33922974	The exposure of different tumor cells to low doses of DNMTi cause apoptosis, reduced cell cycle activity, and decreased stem cell function.	('apoptosis', 'biological_process', 'GO:0006915', ('66', '75'))	('stem cell function', 'CPA', (120, 138))	('DNMTi', 'Var', (54, 59))	('cell cycle activity', 'CPA', (85, 104))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cell cycle', 'biological_process', 'GO:0007049', ('85', '95'))	('decreased', 'NegReg', (110, 119))	('DNMTi', 'Chemical', '-', (54, 59))	('reduced', 'NegReg', (77, 84))	('apoptosis', 'CPA', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('apoptosis', 'biological_process', 'GO:0097194', ('66', '75'))
15528	33922974	Epigenetic therapy is a promising potential therapy for solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Epigenetic therapy', 'Var', (0, 18))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))
15529	33922974	Integrative expression and methylation data analysis of 63 cancer cell lines (breast, colorectal, and ovarian) after treatment with the DNMTi azacytidine demonstrated significant enrichment for immunomodulatory pathways.	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('ovarian', 'Disease', 'MESH:D010049', (102, 109))	('immunomodulatory', 'Pathway', (194, 210))	('DNMTi', 'Var', (136, 141))	('azacytidine', 'Chemical', 'MESH:D001374', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('DNMTi', 'Chemical', '-', (136, 141))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('colorectal', 'Disease', (86, 96))	('ovarian', 'Disease', (102, 109))
15531	33922974	On the other hand, suppressed cell proliferation (>50% reduction in colony formation assay) with azacytidine therapy was detected, both in cell lines with VHL promoter methylation and also in some RCC cell lines without VHL TSG methylation, thus suggesting that multiple methylated TSGs might determine the response to demethylating therapies.	('VHL', 'Gene', '7428', (155, 158))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('cell proliferation', 'CPA', (30, 48))	('reduction', 'NegReg', (55, 64))	('suppressed', 'NegReg', (19, 29))	('RCC', 'Phenotype', 'HP:0005584', (197, 200))	('formation', 'biological_process', 'GO:0009058', ('75', '84'))	('azacytidine', 'Chemical', 'MESH:D001374', (97, 108))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('methylation', 'Var', (168, 179))	('RCC', 'Disease', (197, 200))	('VHL', 'Gene', (220, 223))	('VHL', 'Gene', '7428', (220, 223))	('methylation', 'biological_process', 'GO:0032259', ('228', '239'))	('determine', 'Reg', (293, 302))	('VHL', 'Gene', (155, 158))	('cell proliferation', 'biological_process', 'GO:0008283', ('30', '48'))
15540	33922974	Preclinical evidence with the DNMTi decitabine is abundant in renal cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('DNMTi', 'Var', (30, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('DNMTi', 'Chemical', '-', (30, 35))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('decitabine', 'Chemical', 'MESH:D000077209', (36, 46))
15551	33922974	Resistance of RCC to the apoptosis-inducing effects of IFNs was postulated to result from epigenetic silencing of genes by DNA methylation.	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('DNA', 'cellular_component', 'GO:0005574', ('123', '126'))	('epigenetic silencing', 'Var', (90, 110))	('apoptosis', 'biological_process', 'GO:0097194', ('25', '34'))	('apoptosis', 'biological_process', 'GO:0006915', ('25', '34'))	('DNA methylation', 'biological_process', 'GO:0006306', ('123', '138'))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
15553	33922974	The proapoptotic tumor suppressor RASSF1A was reactivated by DNMT1 inhibitors in the cell lines investigated and this was associated with demethylation of its promoter region.	('associated', 'Reg', (122, 132))	('inhibitors', 'Var', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('demethylation', 'biological_process', 'GO:0070988', ('138', '151'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('17', '33'))	('RASSF1A', 'Gene', (34, 41))	('DNMT1', 'Gene', (61, 66))	('reactivated', 'PosReg', (46, 57))	('tumor suppressor', 'Gene', (17, 33))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('17', '33'))	('RASSF1A', 'Gene', '11186', (34, 41))	('DNMT1', 'Gene', '1786', (61, 66))	('demethylation', 'MPA', (138, 151))	('tumor suppressor', 'Gene', '7248', (17, 33))
15554	33922974	The combination of anticancer agents and epigenetic drugs sustains a novel therapeutic strategy.	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('epigenetic drugs', 'Var', (41, 57))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
15558	33922974	Another inhibitor of DNMT, the antisense oligodeoxynucleotide MG98 was intravenously administered at a dose of 360 mg/m2 twice weekly for three consecutive weeks out of four in 17 patients with advanced RCC receiving a median of two cycles with no objective responses.	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('MG98', 'Chemical', '-', (62, 66))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (41, 61))	('DNMT', 'Gene', '1786', (21, 25))	('MG98', 'Var', (62, 66))	('DNMT', 'Gene', (21, 25))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('patients', 'Species', '9606', (180, 188))
15561	33922974	Another phase-II trial explored two schedules of MG98 with IFNalpha2b and described frequent disease stabilization and partial response in one case.	('MG98', 'Chemical', '-', (49, 53))	('IFNalpha2b', 'Gene', (59, 69))	('IFNalpha2b', 'Gene', '3440', (59, 69))	('MG98', 'Var', (49, 53))	('disease stabilization', 'CPA', (93, 114))
15623	33922974	The strategies investigated include silence miRNAs that are overexpressed, such as, for example anti-mRNA oligonucleotides, miRNA-mask antisense oligonucleotides, and miRNA sponges to restore the expression of miRNAs that are downregulated.	('oligonucleotides', 'Chemical', 'MESH:D009841', (145, 161))	('expression', 'MPA', (196, 206))	('antisense', 'Var', (135, 144))	('oligonucleotides', 'Chemical', 'MESH:D009841', (106, 122))
15626	33922974	Oblimersen (G3139) is a phosphorothioate antisense oligonucleotide used for chronic lymphocytic leukemia and for advanced melanoma.	('G3139', 'Var', (12, 17))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('oligonucleotide', 'Chemical', 'MESH:D009841', (51, 66))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (76, 104))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (84, 104))	('lymphocytic leukemia', 'Disease', (84, 104))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('phosphorothioate', 'Chemical', '-', (24, 40))
15636	33922974	Many deregulated lncRNA interact with EZH2 to silence TSGs and to induce EMT.	('TSGs', 'Gene', (54, 58))	('ncRNA', 'Gene', '220202', (18, 23))	('deregulated', 'Var', (5, 16))	('EMT', 'CPA', (73, 76))	('EZH2', 'Gene', '2146', (38, 42))	('EZH2', 'Gene', (38, 42))	('induce', 'PosReg', (66, 72))	('ncRNA', 'Gene', (18, 23))	('silence', 'NegReg', (46, 53))	('EMT', 'biological_process', 'GO:0001837', ('73', '76'))
15637	33922974	As a result, inhibitors of EZH2 and consequently H3K27 methylation remain a very interesting opportunity to develop future RCC therapies.	('H3K27', 'Protein', (49, 54))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('inhibitors', 'Var', (13, 23))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))
15638	33922974	For example, loss of SETD2 becomes synthetically lethal with loss of mitotic inhibitor protein kinase Wee1, loss of BAP1 is synthetically lethal with simultaneous inhibition of EZH2 or PRC2, and a third mechanism is loss of PBRM1, ARID1A, and some components of the SWI/SNF complex, together with inhibition of EZH2.	('SETD2', 'Gene', '29072', (21, 26))	('loss', 'NegReg', (61, 65))	('loss', 'Var', (13, 17))	('EZH2', 'Gene', '2146', (177, 181))	('EZH2', 'Gene', (177, 181))	('EZH2', 'Gene', '2146', (311, 315))	('EZH2', 'Gene', (311, 315))	('loss', 'Var', (108, 112))	('PBRM1', 'Gene', (224, 229))	('loss', 'NegReg', (216, 220))	('BAP1', 'Gene', '8314', (116, 120))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('ARID1A', 'Gene', (231, 237))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('266', '281'))	('ARID1A', 'Gene', '8289', (231, 237))	('Wee1', 'Gene', (102, 106))	('BAP1', 'Gene', (116, 120))	('SETD2', 'Gene', (21, 26))	('Wee1', 'Gene', '7465', (102, 106))
15641	33922974	Targeting the epigenome appears an attractive treatment option for RCC because the epigenetic dysregulation of this neoplasia is very extensive and affects many different signaling pathways and tumor hallmarks.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('RCC', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('neoplasia', 'Disease', (116, 125))	('tumor hallmarks', 'Disease', 'MESH:D009369', (194, 209))	('tumor hallmarks', 'Disease', (194, 209))	('epigenetic dysregulation', 'Var', (83, 107))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('neoplasia', 'Disease', 'MESH:D009369', (116, 125))	('affects', 'Reg', (148, 155))
15642	33922974	The most important limitation is the lack of selectivity because epigenetic events are ubiquitously distributed across normal and cancer cells.	('cancer', 'Disease', (130, 136))	('epigenetic events', 'Var', (65, 82))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
15646	33922974	In fact, results of epigenetic therapy in hematologic malignancies are impressive, but not in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('hematologic malignancies', 'Disease', (42, 66))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic therapy', 'Var', (20, 38))	('hematologic malignancies', 'Disease', 'MESH:D019337', (42, 66))
15649	33922974	Multi-regional sequencing has confirmed that renal tumors often harbor different sub-clones that can differ in their spectra of mutations in different epigenetic regulatory tumor suppressor genes.	('tumor suppressor', 'Gene', (173, 189))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('renal tumors', 'Phenotype', 'HP:0009726', (45, 57))	('mutations', 'Var', (128, 137))	('tumor suppressor', 'biological_process', 'GO:0051726', ('173', '189'))	('tumor suppressor', 'Gene', '7248', (173, 189))	('renal tumors', 'Disease', 'MESH:D007674', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('173', '189'))	('renal tumors', 'Disease', (45, 57))
15650	33922974	These findings suggest that new therapeutic strategies targeting gene dosage and epigenetic modification should be considered for improved personalized cancer medicine.	('epigenetic modification', 'Var', (81, 104))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
15654	33922974	It would be desirable that epigenetics-based treatments could re-sensitize the host immune response to immunotherapies and restore immunogenicity enforcing the expression of tumor associated antigens, checkpoint ligands in tumor cells, and antigen-processing machinery components.	('tumor', 'Disease', (174, 179))	('expression', 'MPA', (160, 170))	('immune response', 'biological_process', 'GO:0006955', ('84', '99'))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('restore', 'PosReg', (123, 130))	('antigen-processing', 'biological_process', 'GO:0019882', ('240', '258'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('epigenetics-based', 'Var', (27, 44))	('immunogenicity', 'MPA', (131, 145))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
15656	33922974	PBRM1 deficient RenCa subcutaneous tumors in mice are more resistant to ICI, and a retrospective analysis of the IMmotion150 trial also suggests that PBRM1 mutation reduces benefit from immune checkpoint blockade.	('immune checkpoint blockade', 'MPA', (186, 212))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (22, 41))	('PBRM1', 'Gene', (150, 155))	('reduces', 'NegReg', (165, 172))	('mice', 'Species', '10090', (45, 49))	('deficient RenCa subcutaneous tumors', 'Disease', 'MESH:D013352', (6, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('PBRM1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('deficient RenCa subcutaneous tumors', 'Disease', (6, 41))	('mutation', 'Var', (156, 164))
15657	33922974	Nevertheless, the role of PBRM1 mutations in ccRCC in relation to the immune microenvironment is not totally clear.	('PBRM1', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
15659	33922974	Recent studies show truncating mutations in PBRM1 increase the clinical benefit of ICI therapy in patients with metastatic ccRCC.	('PBRM1', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('truncating mutations', 'Var', (20, 40))	('patients', 'Species', '9606', (98, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('increase', 'PosReg', (50, 58))	('clinical benefit', 'MPA', (63, 79))
15660	33922974	PBRM1 alterations have also been clinically validated as marker of ICI responsiveness in RCC but the effect on response and survival is modest and has been mainly observed in the subset of patients who received prior antiangiogenic therapy.	('alterations', 'Var', (6, 17))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('patients', 'Species', '9606', (189, 197))
15662	33922974	So, epigenetic treatments, via several signaling mechanisms involving both tumor cells and host immune cells, might enhance the efficacy of immune checkpoint therapy in RCC.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('enhance', 'PosReg', (116, 123))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('epigenetic treatments', 'Var', (4, 25))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('signaling', 'biological_process', 'GO:0023052', ('39', '48'))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('efficacy', 'MPA', (128, 136))	('tumor', 'Disease', (75, 80))
15663	33922974	Additionally, genetic alterations in histone modifier genes in RCC could not only be responsible for the pathogenesis of the disease but also represent potential biomarkers of response to immunotherapies.	('RCC', 'Disease', (63, 66))	('genetic alterations', 'Var', (14, 33))	('responsible', 'Reg', (85, 96))	('pathogenesis', 'biological_process', 'GO:0009405', ('105', '117'))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
15664	33922974	In this sense, despite the initial failure of epigenetic treatments to reach the clinic, epigenetic therapy is currently a promising strategy for anticancer treatment and for development of new ccRCC tumor markers.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('new ccRCC tumor', 'Disease', 'MESH:C000657245', (190, 205))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('new ccRCC tumor', 'Disease', (190, 205))	('epigenetic therapy', 'Var', (89, 107))	('RCC', 'Phenotype', 'HP:0005584', (196, 199))	('ccRCC', 'Phenotype', 'HP:0006770', (194, 199))
15665	33922974	Epigenetic studies have provided a large body of evidence regarding hypermethylated genes, histone-modifying enzymes or miRNAs and new challenges at bench side of patients with RCC.	('patients', 'Species', '9606', (163, 171))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('hypermethylated genes', 'Var', (68, 89))
15667	33922974	Additionally, early clinical trials have been conducted to evaluate epigenetic therapies for RCC, either alone or in combination with other therapies including IFN-alpha2b, IL-2, anti-VEGF, TKIs, and mTOR inhibitors.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('IFN-alpha2b', 'Gene', (160, 171))	('VEGF', 'Gene', (184, 188))	('mTOR', 'Gene', (200, 204))	('mTOR', 'Gene', '2475', (200, 204))	('IL-2', 'molecular_function', 'GO:0005134', ('173', '177'))	('VEGF', 'Gene', '7422', (184, 188))	('IL-2', 'Gene', (173, 177))	('IL-2', 'Gene', '3558', (173, 177))	('epigenetic therapies', 'Var', (68, 88))	('IFN-alpha2b', 'Gene', '3440', (160, 171))
15672	30428628	Among all modifications occurring in RNA molecules, N6-methyladenosine (m6A) is the most frequent, especially among mRNAs.	('m6A', 'Gene', (72, 75))	('m6A', 'Gene', '56339', (72, 75))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (52, 70))	('RNA', 'cellular_component', 'GO:0005562', ('37', '40'))	('N6-methyladenosine', 'Var', (52, 70))
15682	30428628	Importantly, contrarily to DNA modifications that primarily regulate gene transcription, RNA modifications regulate the many aspects of RNAs fate, including localization, splicing, nuclear export, targeting for destruction, stability, secondary structure and efficiency of translation, ultimately allowing the formation of a functional RNA molecule.	('splicing', 'MPA', (171, 179))	('targeting for', 'MPA', (197, 210))	('translation', 'biological_process', 'GO:0006412', ('273', '284'))	('localization', 'MPA', (157, 169))	('stability', 'MPA', (224, 233))	('translation', 'MPA', (273, 284))	('transcription', 'biological_process', 'GO:0006351', ('74', '87'))	('localization', 'biological_process', 'GO:0051179', ('157', '169'))	('formation', 'MPA', (310, 319))	('regulate', 'Reg', (107, 115))	('secondary structure', 'MPA', (235, 254))	('DNA', 'cellular_component', 'GO:0005574', ('27', '30'))	('D', 'Chemical', 'MESH:D003903', (27, 28))	('modifications', 'Var', (93, 106))	('allowing', 'Reg', (297, 305))	('RNA', 'cellular_component', 'GO:0005562', ('336', '339'))	('nuclear export', 'MPA', (181, 195))	('RNAs', 'Protein', (136, 140))	('nuclear export', 'biological_process', 'GO:0051168', ('181', '195'))	('RNA', 'cellular_component', 'GO:0005562', ('89', '92'))	('RNA', 'Gene', (89, 92))	('splicing', 'biological_process', 'GO:0045292', ('171', '179'))	('formation', 'biological_process', 'GO:0009058', ('310', '319'))
15689	30428628	The epitranscriptome of cancer cells has been demonstrated to be disrupted, and associations with dysregulation of expression of m6A-related proteins (i.e., their writer, readers and erasers) have been increasingly found in many neoplasms.	('dysregulation', 'Var', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('neoplasms', 'Phenotype', 'HP:0002664', (229, 238))	('found', 'Reg', (215, 220))	('associations', 'Interaction', (80, 92))	('cancer', 'Disease', (24, 30))	('m6A', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('expression', 'MPA', (115, 125))	('neoplasms', 'Disease', 'MESH:D009369', (229, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('epitranscriptome', 'MPA', (4, 20))	('neoplasms', 'Disease', (229, 238))	('m6A', 'Gene', '56339', (129, 132))
15692	30428628	Modifications in m6A levels and/or m6A-related proteins expression have been found in a broad spectrum of cancer types.	('m6A', 'Gene', (35, 38))	('m6A', 'Gene', '56339', (35, 38))	('found', 'Reg', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('expression', 'MPA', (56, 66))	('cancer', 'Disease', (106, 112))	('m6A', 'Gene', (17, 20))	('Modifications', 'Var', (0, 13))	('m6A', 'Gene', '56339', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
15695	30428628	Polymorphisms in intron 1 of FTO have been associated with a higher risk for development of many neoplasms; however, a metanalysis concluded that, except for pancreatic cancer, the risk was mainly due to body mass index (BMI).	('pancreatic cancer', 'Disease', (158, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('FTO', 'Gene', (29, 32))	('Polymorphisms', 'Var', (0, 13))	('neoplasms', 'Disease', 'MESH:D009369', (97, 106))	('neoplasms', 'Disease', (97, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('men', 'Species', '9606', (84, 87))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('FTO', 'Gene', '79068', (29, 32))	('associated', 'Reg', (43, 53))	('neoplasms', 'Phenotype', 'HP:0002664', (97, 106))
15696	30428628	However, a single-nucleotide polymorphism (SNP) in FTO intron 8 was found to be associated with a higher risk for melanoma, and, as for breast cancer (BCa), another SNP in FTO intron 1 was identified as a susceptibility locus for estrogen-negative BCa, both not explained by BMI.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('single-nucleotide polymorphism', 'Var', (11, 41))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('FTO', 'Gene', '79068', (172, 175))	('FTO', 'Gene', '79068', (51, 54))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('associated', 'Reg', (80, 90))	('FTO', 'Gene', (172, 175))	('BCa', 'Phenotype', 'HP:0003002', (151, 154))	('FTO', 'Gene', (51, 54))	('estrogen-negative BCa', 'Disease', (230, 251))	('BCa', 'Phenotype', 'HP:0003002', (248, 251))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
15698	30428628	Also in BCa, a link between hypoxia, tumor invasiveness/metastasis and m6A has been proposed, with hypoxia-inducible factors (HIFs) leading to increased mRNA expression of the pluripotency factor homeobox transcription factor Nanog (NANOG) (and subsequent BCa stem cells specification) by means of m6A demethylation by the eraser ALKBH5.	('increased', 'PosReg', (143, 152))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('m6A', 'Gene', (71, 74))	('BCa', 'Phenotype', 'HP:0003002', (256, 259))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('demethylation', 'Var', (302, 315))	('mRNA expression', 'MPA', (153, 168))	('demethylation', 'biological_process', 'GO:0070988', ('302', '315'))	('BCa', 'Phenotype', 'HP:0003002', (8, 11))	('transcription', 'biological_process', 'GO:0006351', ('205', '218'))	('NANOG', 'Gene', '79923', (233, 238))	('NANOG', 'Gene', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor invasiveness/metastasis', 'Disease', 'MESH:D009362', (37, 66))	('transcription factor', 'molecular_function', 'GO:0000981', ('205', '225'))	('m6A', 'Gene', '56339', (298, 301))	('BCa', 'Disease', (8, 11))	('m6A', 'Gene', (298, 301))	('homeobox transcription factor Nanog', 'Gene', '79923', (196, 231))	('ALKBH5', 'Gene', (330, 336))	('hypoxia', 'Disease', (99, 106))	('homeobox transcription factor Nanog', 'Gene', (196, 231))	('hypoxia', 'Disease', (28, 35))	('tumor invasiveness/metastasis', 'Disease', (37, 66))	('m6A', 'Gene', '56339', (71, 74))	('ALKBH5', 'Gene', '54890', (330, 336))
15701	30428628	In this tumor model, METTL3-mediated m6A modification targets suppressor of cytokine signaling 2 (SOCS2), promoting its degradation, in a process dependent of YTHDF2 reader.	('degradation', 'biological_process', 'GO:0009056', ('120', '131'))	('SOCS2', 'Gene', '8835', (98, 103))	('METTL3', 'Gene', '56339', (21, 27))	('signaling', 'biological_process', 'GO:0023052', ('85', '94'))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('METTL3', 'Gene', (21, 27))	('suppressor of cytokine signaling 2', 'Gene', (62, 96))	('suppressor of cytokine signaling 2', 'Gene', '8835', (62, 96))	('m6A', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('YTHDF2', 'Gene', '51441', (159, 165))	('modification', 'Var', (41, 53))	('SOCS2', 'Gene', (98, 103))	('tumor', 'Disease', (8, 13))	('promoting', 'PosReg', (106, 115))	('degradation', 'MPA', (120, 131))	('YTHDF2', 'Gene', (159, 165))	('m6A', 'Gene', '56339', (37, 40))
15703	30428628	In addition, m6A and related proteins are implicated in treatment resistance, as shown in pancreatic cancer cells, in which knockdown of the writer METTL3 improved sensitivity to both chemo- and radiation therapy, clearly demonstrating the rationale for using treatments targeting m6A modulators.	('knockdown', 'Var', (124, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('men', 'Species', '9606', (265, 268))	('improved', 'PosReg', (155, 163))	('pancreatic cancer', 'Disease', (90, 107))	('METTL3', 'Gene', '56339', (148, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('m6A', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('m6A', 'Gene', (281, 284))	('men', 'Species', '9606', (61, 64))	('METTL3', 'Gene', (148, 154))	('implicated', 'Reg', (42, 52))	('sensitivity to', 'MPA', (164, 178))	('m6A', 'Gene', '56339', (13, 16))	('m6A', 'Gene', '56339', (281, 284))
15706	30428628	Again, the knockdown of YTHDF3 sensitized cancer cells to chemotherapy and, additionally, oncogene c-Myc was found to drive YTHDF1 expression.	('YTHDF3', 'Gene', (24, 30))	('YTHDF1', 'Gene', (124, 130))	('drive', 'PosReg', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('sensitized', 'Reg', (31, 41))	('expression', 'MPA', (131, 141))	('YTHDF3', 'Gene', '253943', (24, 30))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('c-Myc', 'Gene', '4609', (99, 104))	('c-Myc', 'Gene', (99, 104))	('knockdown', 'Var', (11, 20))	('YTHDF1', 'Gene', '54915', (124, 130))
15710	30428628	More recently, it was demonstrated that the eraser FTO is also upregulated in cervical cancer and leads to chemo- and radiation therapy resistance by demethylating the mRNA transcripts of its target, beta-catenin.	('mRNA transcripts', 'MPA', (168, 184))	('FTO', 'Gene', '79068', (51, 54))	('demethylating', 'Var', (150, 163))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('beta-catenin', 'Gene', (200, 212))	('cervical cancer', 'Disease', (78, 93))	('upregulated', 'PosReg', (63, 74))	('beta-catenin', 'Gene', '1499', (200, 212))	('FTO', 'Gene', (51, 54))	('chemo- and', 'MPA', (107, 117))	('leads to', 'Reg', (98, 106))
15711	30428628	In addition, a recent study in endometrial cancer has elegantly shown that decreased m6A caused by a mutation in METTL14 or downregulation of METTL3 ultimately leads to increased proliferation by activating the AKT signaling pathway.	('signaling pathway', 'biological_process', 'GO:0007165', ('215', '232'))	('endometrial cancer', 'Phenotype', 'HP:0012114', (31, 49))	('METTL3', 'Gene', (142, 148))	('m6A', 'Gene', '56339', (85, 88))	('METTL14', 'Gene', (113, 120))	('endometrial cancer', 'Disease', (31, 49))	('METTL3', 'Gene', '56339', (142, 148))	('AKT', 'Gene', (211, 214))	('m6A', 'Gene', (85, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (31, 49))	('downregulation', 'NegReg', (124, 138))	('proliferation', 'CPA', (179, 192))	('AKT signaling', 'biological_process', 'GO:0043491', ('211', '224'))	('increased', 'PosReg', (169, 178))	('activating', 'PosReg', (196, 206))	('AKT', 'Gene', '207', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('mutation', 'Var', (101, 109))	('METTL14', 'Gene', '57721', (113, 120))	('decreased', 'NegReg', (75, 84))
15713	30428628	In addition, high levels of the eraser ALKBH5 associated with poor prognostic features and METTL3 associated with radiation therapy resistance.	('associated with', 'Reg', (98, 113))	('METTL3', 'Gene', (91, 97))	('high', 'Var', (13, 17))	('ALKBH5', 'Gene', '54890', (39, 45))	('ALKBH5', 'Gene', (39, 45))	('radiation therapy resistance', 'CPA', (114, 142))	('associated', 'Reg', (46, 56))	('METTL3', 'Gene', '56339', (91, 97))	('poor prognostic features', 'CPA', (62, 86))
15717	30428628	It was shown that mutations in m6A-related proteins confer poor prognosis in acute myeloid leukemia (AML).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (77, 99))	('AML', 'Disease', 'MESH:D015470', (101, 104))	('m6A', 'Gene', '56339', (31, 34))	('AML', 'Phenotype', 'HP:0004808', (101, 104))	('acute myeloid leukemia', 'Disease', (77, 99))	('AML', 'Disease', (101, 104))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (83, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (77, 99))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('m6A', 'Gene', (31, 34))	('mutations', 'Var', (18, 27))
15718	30428628	Mutations in writers (METTL3, METTL14, WTAP, RBM15) promote and maintain leukemogenesis in AML, whereas overexpression of the eraser FTO in AML cell lines also promoted proliferation and decreased apoptosis.	('WTAP', 'Gene', (39, 43))	('promoted', 'PosReg', (160, 168))	('RBM15', 'Gene', '64783', (45, 50))	('METTL3', 'Gene', (22, 28))	('apoptosis', 'biological_process', 'GO:0097194', ('197', '206'))	('apoptosis', 'CPA', (197, 206))	('apoptosis', 'biological_process', 'GO:0006915', ('197', '206'))	('leukemogenesis', 'Disease', (73, 87))	('AML', 'Phenotype', 'HP:0004808', (140, 143))	('Mutations', 'Var', (0, 9))	('METTL3', 'Gene', '56339', (22, 28))	('METTL14', 'Gene', '57721', (30, 37))	('WTAP', 'Gene', '9589', (39, 43))	('METTL14', 'Gene', (30, 37))	('RBM15', 'Gene', (45, 50))	('FTO', 'Gene', '79068', (133, 136))	('AML', 'Disease', 'MESH:D015470', (91, 94))	('FTO', 'Gene', (133, 136))	('AML', 'Disease', (91, 94))	('AML', 'Disease', 'MESH:D015470', (140, 143))	('AML', 'Phenotype', 'HP:0004808', (91, 94))	('AML', 'Disease', (140, 143))	('decreased', 'NegReg', (187, 196))	('promote', 'PosReg', (52, 59))
15719	30428628	Moreover, FTO plays a role in response to all-trans-retinoic acid (ATRA) and, interestingly, D-2-hydroxyglutarate (D2-HG) (the metabolite accumulated in isocitrate dehydrogenase 1 and 2 (IDH1/2)-mutant leukemias (20% of AMLs)) functions as an inhibitor of FTO demethylase, meaning that FTO expression is context-dependent and has to be interpreted according to IDH mutational status.	('ATRA', 'Chemical', 'MESH:D014212', (67, 71))	('D', 'Chemical', 'MESH:D003903', (93, 94))	('IDH', 'Gene', '3417', (361, 364))	('FTO', 'Gene', '79068', (256, 259))	('D', 'Chemical', 'MESH:D003903', (188, 189))	('FTO', 'Gene', '79068', (10, 13))	('FTO', 'Gene', (256, 259))	('D', 'Chemical', 'MESH:D003903', (115, 116))	('IDH1/2', 'Gene', '3417;3418', (187, 193))	('D', 'Chemical', 'MESH:D003903', (362, 363))	('FTO', 'Gene', (10, 13))	('all-trans-retinoic acid', 'Chemical', 'MESH:D014212', (42, 65))	('IDH1/2', 'Gene', (187, 193))	('-mutant', 'Var', (194, 201))	('IDH', 'Gene', (187, 190))	('leukemias', 'Disease', 'MESH:D007938', (202, 211))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('FTO', 'Gene', '79068', (286, 289))	('AML', 'Disease', 'MESH:D015470', (220, 223))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (95, 113))	('AML', 'Phenotype', 'HP:0004808', (220, 223))	('leukemias', 'Phenotype', 'HP:0001909', (202, 211))	('AML', 'Disease', (220, 223))	('FTO', 'Gene', (286, 289))	('IDH', 'Gene', (361, 364))	('IDH', 'Gene', '3417', (187, 190))	('leukemias', 'Disease', (202, 211))
15721	30428628	One of our main research goals is to uncover and characterize new epigenetic modifiers in urological malignancies, to be applied in diagnosis, prognosis and disease monitoring.	('malignancies', 'Disease', (101, 113))	('epigenetic', 'Var', (66, 76))	('malignancies', 'Disease', 'MESH:D009369', (101, 113))
15737	30428628	In addition, no mutations are described for YTHDF3 and YTHDC2 that may explain the deregulation, and only three samples disclosed a missense mutation in VIRMA.	('YTHDF3', 'Gene', '253943', (44, 50))	('YTHDC2', 'Gene', '64848', (55, 61))	('missense mutation', 'Var', (132, 149))	('YTHDC2', 'Gene', (55, 61))	('YTHDF3', 'Gene', (44, 50))
15743	30428628	Although still largely unexplored, there is already a study (using both cell lines and human tissues from 35 patients) reporting m6A alterations in PCa.	('patients', 'Species', '9606', (109, 117))	('human', 'Species', '9606', (87, 92))	('m6A', 'Gene', (129, 132))	('alterations', 'Var', (133, 144))	('PCa', 'Disease', (148, 151))	('m6A', 'Gene', '56339', (129, 132))
15752	30428628	In addition, the manipulation of these Epi-markers might provide ways of uncovering therapies with improved antitumor activity, less toxicity and that may overcome cisplatin resistance.	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('improved', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cisplatin resistance', 'MPA', (164, 184))	('overcome', 'NegReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('manipulation', 'Var', (17, 29))	('tumor', 'Disease', (112, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
15757	30428628	Paralleling our analysis on PCa, deregulation of VIRMA and the reader YTHDF3 is particularly interesting in TGCTs as well, being the two most commonly altered genes in the pathway (52% and 48% of samples, respectively).	('YTHDF3', 'Gene', '253943', (70, 76))	('altered', 'Reg', (151, 158))	('YTHDF3', 'Gene', (70, 76))	('deregulation', 'Var', (33, 45))
15771	30428628	Regarding survival analysis, the only genes with impact on survival were METTL4 (cases with alterations showing worse DFS, p = 0.0249), WTAP (cases with alterations showing worse DFS, p = 0.0402) and YTHDF1 (cases with alterations showing worse OS, p = 0.0440).	('D', 'Chemical', 'MESH:D003903', (203, 204))	('WTAP', 'Gene', '9589', (136, 140))	('YTHDF1', 'Gene', (200, 206))	('D', 'Chemical', 'MESH:D003903', (179, 180))	('METTL4', 'Gene', '64863', (73, 79))	('D', 'Chemical', 'MESH:D003903', (118, 119))	('alterations', 'Var', (92, 103))	('YTHDF1', 'Gene', '54915', (200, 206))	('METTL4', 'Gene', (73, 79))	('WTAP', 'Gene', (136, 140))
15802	30428628	The rate of somatic mutations in these genes was only 0.5%, 0.5% and 0.7% for YTHDF1, METTL4, and YTHDF3, respectively; VIRMA and RBM15 mutations were found in 9 (2.2%) and 12 (2.9%) cases.	('RBM15', 'Gene', '64783', (130, 135))	('YTHDF3', 'Gene', (98, 104))	('METTL4', 'Gene', '64863', (86, 92))	('YTHDF3', 'Gene', '253943', (98, 104))	('RBM15', 'Gene', (130, 135))	('YTHDF1', 'Gene', '54915', (78, 84))	('YTHDF1', 'Gene', (78, 84))	('mutations', 'Var', (136, 145))	('METTL4', 'Gene', (86, 92))	('found', 'Reg', (151, 156))
15829	30428628	Nevertheless, it emphasizes the relevance of epitranscriptomics, and of m6A alteration in particular, in the genesis and progression of urological cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('m6A', 'Gene', (72, 75))	('urological cancers', 'Disease', 'MESH:D014571', (136, 154))	('m6A', 'Gene', '56339', (72, 75))	('urological cancers', 'Disease', (136, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('alteration', 'Var', (76, 86))
15843	26448938	Cancer is often described as a genetic disease, caused by genetic alterations which regulate cell growth.	('caused', 'Reg', (48, 54))	('cell growth', 'biological_process', 'GO:0016049', ('93', '104'))	('genetic disease', 'Disease', 'MESH:D030342', (31, 46))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genetic disease', 'Disease', (31, 46))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic alterations', 'Var', (58, 77))
15844	26448938	Hence, distinctive genetic aberrations in each RCC subtype affect the clinical course and prognosis of the tumour.	('prognosis', 'CPA', (90, 99))	('affect', 'Reg', (59, 65))	('clinical course', 'CPA', (70, 85))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('genetic aberrations', 'Var', (19, 38))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('tumour', 'Disease', (107, 113))
15847	26448938	Genetic alterations such as duplication, deletion, translocation, hypermethylation, or mutations result in the activation or inactivation of genes and the over- or underexpression of the corresponding proteins in RCCs.	('activation', 'PosReg', (111, 121))	('underexpression', 'NegReg', (164, 179))	('hypermethylation', 'Var', (66, 82))	('proteins', 'Protein', (201, 209))	('inactivation', 'NegReg', (125, 137))	('translocation', 'Var', (51, 64))	('deletion', 'Var', (41, 49))	('RCC', 'Disease', 'MESH:C538614', (213, 216))	('RCC', 'Disease', (213, 216))	('RCC', 'Phenotype', 'HP:0005584', (213, 216))	('duplication', 'Var', (28, 39))	('genes', 'Gene', (141, 146))	('mutations', 'Var', (87, 96))	('over-', 'PosReg', (155, 160))
15854	26448938	The most common and characteristic genetic changes in ccRCCs are aberrations such as LOH, hypermethylation, or mutation in 3p chromosome region, which are found in up to 91% of the tumours.	('RCC', 'Disease', (56, 59))	('mutation in', 'Var', (111, 122))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('LOH', 'Disease', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('chromosome region', 'cellular_component', 'GO:0098687', ('126', '143'))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('hypermethylation', 'Disease', (90, 106))	('tumours', 'Disease', 'MESH:D009369', (181, 188))	('tumours', 'Disease', (181, 188))	('3p chromosome region', 'Gene', (123, 143))
15863	26448938	Inactivation of VHL, which occurs through mutation, deletion, or methylation, causes the accumulation of HIFalpha under normal oxygen conditions and encourages tumour growth.	('encourages', 'PosReg', (149, 159))	('VHL', 'Gene', (16, 19))	('accumulation', 'PosReg', (89, 101))	('VHL', 'Gene', '7428', (16, 19))	('oxygen', 'Chemical', 'MESH:D010100', (127, 133))	('mutation', 'Var', (42, 50))	('methylation', 'Var', (65, 76))	('HIFalpha', 'MPA', (105, 113))	('methylation', 'biological_process', 'GO:0032259', ('65', '76'))	('tumour growth', 'Disease', (160, 173))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('Inactivation', 'Var', (0, 12))	('deletion', 'Var', (52, 60))	('tumour growth', 'Disease', 'MESH:D006130', (160, 173))
15867	26448938	VHL genetic changes are believed to be exclusively associated with ccRCC but van Houwelingen and colleagues have detected VHL mutations in 15% of non-ccRCCs from a cohort of sporadic RCC patients in Netherlands.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('patients', 'Species', '9606', (187, 195))	('RCC', 'Disease', (69, 72))	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (152, 155))	('RCC', 'Disease', (183, 186))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('VHL', 'Gene', (122, 125))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (122, 125))	('detected', 'Reg', (113, 121))	('mutations', 'Var', (126, 135))	('VHL', 'Gene', '7428', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
15868	26448938	They noted that the percentage of patients with VHL mutation was significantly higher for ccRCC compared to RCCs of other histological types.	('VHL', 'Gene', '7428', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('higher', 'Reg', (79, 85))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('patients', 'Species', '9606', (34, 42))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('mutation', 'Var', (52, 60))	('VHL', 'Gene', (48, 51))
15869	26448938	Other studies however found no VHL mutation in other subtypes.	('VHL', 'Gene', '7428', (31, 34))	('VHL', 'Gene', (31, 34))	('mutation', 'Var', (35, 43))
15870	26448938	Inactivation of VHL may play an important role in the pathogenesis of ccRCC, but the association of VHL status with clinicopathological parameters and disease progression is still unclear and contradictory.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('VHL', 'Gene', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('VHL', 'Gene', '7428', (16, 19))	('pathogenesis', 'biological_process', 'GO:0009405', ('54', '66'))	('VHL', 'Gene', (100, 103))	('Inactivation', 'Var', (0, 12))	('VHL', 'Gene', '7428', (100, 103))
15872	26448938	It has also been shown that there is no correlation between VHL mutation or methylation status with angiogenesis and proliferation of ccRCC.	('mutation', 'Var', (64, 72))	('proliferation', 'CPA', (117, 130))	('angiogenesis', 'biological_process', 'GO:0001525', ('100', '112'))	('VHL', 'Gene', (60, 63))	('VHL', 'Gene', '7428', (60, 63))	('angiogenesis', 'CPA', (100, 112))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('methylation', 'biological_process', 'GO:0032259', ('76', '87'))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
15874	26448938	In contrast, several other studies revealed favourable prognosis for tumours with VHL inactivation or alteration.	('tumours', 'Disease', (69, 76))	('alteration', 'Var', (102, 112))	('VHL', 'Gene', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('inactivation', 'Var', (86, 98))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('VHL', 'Gene', '7428', (82, 85))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
15881	26448938	Targeted therapy has improved treatment outcome as the overall and cancer specific survival of metastatic RCC patients has improved in the targeted therapy era compared to the immunotherapy era.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('targeted therapy', 'Var', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('improved', 'PosReg', (123, 131))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('patients', 'Species', '9606', (110, 118))
15882	26448938	A number of studies have reported hereditary ccRCC associated with translocation of chromosome 3, thus supporting the role of chromosome 3 in the pathogenesis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('associated', 'Reg', (51, 61))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Disease', (47, 50))	('chromosome', 'cellular_component', 'GO:0005694', ('126', '136'))	('translocation', 'Var', (67, 80))	('pathogenesis', 'biological_process', 'GO:0009405', ('146', '158'))
15884	26448938	These translocations such as t(1;3)(q32;q13), t(2;3)(q33;q21), t(2;3)(q35;q21), t(3;6)(q12;q15), and t(3;8)(p13;q24) were found in familial ccRCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('t(2;3)(q35;q21', 'Var', (63, 77))	('t(2;3)(q33;q21', 'Var', (46, 60))	('t(3;6)(q12;q15)', 'STRUCTURAL_ABNORMALITY', 'None', (80, 95))	('t(1;3)(q32;q13', 'Var', (29, 43))	('t(2;3)(q33;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (46, 61))	('t(1;3)(q32;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (29, 44))	('t(3;8)(p13;q24', 'Var', (101, 115))	('t(3;6)(q12;q15', 'Var', (80, 94))	('t(2;3)(q35;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 78))	('t(3;8)(p13;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (101, 116))
15885	26448938	In some familial chromosome 3 translocations identified, t(3;4)(p13;p16), t(3;4)(q21;q13), t(3;6)(p13;q25), and t(3;15)(p11;q21), only one family member developed ccRCC.	('t(3;6)(p13;q25', 'Var', (91, 105))	('t(3;4)(p13;p16', 'Var', (57, 71))	('t(3;4)(q21;q13', 'Var', (74, 88))	('t(3;6)(p13;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (91, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('t(3;15)(p11;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 128))	('t(3;15)(p11;q21', 'Var', (112, 127))	('t(3;4)(p13;p16)', 'STRUCTURAL_ABNORMALITY', 'None', (57, 72))	('t(3;4)(q21;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (74, 89))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', (165, 168))
15886	26448938	The involvement of several TSG genes has been suggested, for example, t(1;3)(q32;q13) (NORE1 and LSAMP), t(2;3)(q33;q21) (DIRC1), t(2;3)(q35;q21) (DIRC2 and DIRC3), and t(3;8)(p14.2;q24) (FHIT and TRC8).	('TSG', 'Gene', '57045', (27, 30))	('DIRC2', 'Gene', (147, 152))	('involvement', 'Reg', (4, 15))	('TSG', 'Gene', (27, 30))	('LSAMP', 'Gene', (97, 102))	('t(3', 'Var', (169, 172))	('NORE1', 'Gene', (87, 92))	('t(2;3)(q35;q21', 'Var', (130, 144))	('DIRC2', 'Gene', '84925', (147, 152))	('DIRC3', 'Gene', (157, 162))	('t(1;3)(q32;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 85))	('LSAMP', 'Gene', '4045', (97, 102))	('DIRC1', 'Gene', '116093', (122, 127))	('t(3;8)(p14.2;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (169, 186))	('DIRC3', 'Gene', '729582', (157, 162))	('t(2;3)(q33;q21', 'Var', (105, 119))	('t(2;3)(q35;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (130, 145))	('TRC8', 'Gene', (197, 201))	('TRC8', 'Gene', '11236', (197, 201))	('NORE1', 'Gene', '83593', (87, 92))	('DIRC1', 'Gene', (122, 127))	('t(2;3)(q33;q21)', 'STRUCTURAL_ABNORMALITY', 'None', (105, 120))
15890	26448938	In ccRCC with 3p deletion with and without VHL alterations, inactivation of TSGs at 3p12-p21 appears to play a role in tumourigenesis.	('VHL alterations', 'Disease', 'MESH:D006623', (43, 58))	('role', 'Reg', (111, 115))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('TSG', 'Gene', (76, 79))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('p21', 'Gene', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('VHL alterations', 'Disease', (43, 58))	('tumour', 'Disease', (119, 125))	('p21', 'Gene', '1026', (89, 92))	('TSG', 'Gene', '57045', (76, 79))	('play', 'Reg', (104, 108))	('inactivation', 'Var', (60, 72))
15896	26448938	As a result of inactivation, FHIT protein expression is low or absent in most ccRCC tumours.	('protein', 'cellular_component', 'GO:0003675', ('34', '41'))	('ccRCC tumours', 'Disease', (78, 91))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('absent', 'NegReg', (63, 69))	('expression', 'MPA', (42, 52))	('ccRCC tumours', 'Disease', 'MESH:D009369', (78, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('low', 'NegReg', (56, 59))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('inactivation', 'Var', (15, 27))	('FHIT protein', 'Protein', (29, 41))
15898	26448938	For example, there was an increase in formation of spontaneous tumours and susceptibility to carcinogen-induced tumours in FHIT knockout mice compared to mice with functional FHIT.	('tumours', 'Disease', (63, 70))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('mice', 'Species', '10090', (154, 158))	('FHIT', 'Gene', (123, 127))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Disease', (112, 119))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('spontaneous', 'CPA', (51, 62))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('increase', 'PosReg', (26, 34))	('knockout', 'Var', (128, 136))	('mice', 'Species', '10090', (137, 141))	('tumours', 'Disease', 'MESH:D009369', (63, 70))	('susceptibility', 'Reg', (75, 89))
15899	26448938	There is a significant correlation between low or absence of FHIT protein expression and low grade and early stage ccRCC tumours indicating that LOH of FHIT may play a role in early tumour development.	('expression', 'MPA', (74, 84))	('absence', 'NegReg', (50, 57))	('tumour', 'Disease', (182, 188))	('low', 'NegReg', (43, 46))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('FHIT protein', 'Protein', (61, 73))	('ccRCC tumours', 'Disease', 'MESH:D009369', (115, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('LOH', 'Var', (145, 148))	('low', 'Disease', (89, 92))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('ccRCC tumours', 'Disease', (115, 128))	('protein', 'cellular_component', 'GO:0003675', ('66', '73'))
15902	26448938	suggested that reversible epigenetic inactivation such as gene hypermethylation or posttranslational events may reactivate FHIT as the tumour progresses.	('gene hypermethylation', 'Var', (58, 79))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('FHIT', 'Disease', (123, 127))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))
15905	26448938	RASS1A is inactivated by hypermethylation in the promoter region and this is frequently seen in ovarian, breast, and lung tumours, including ccRCC.	('ovarian', 'Disease', (96, 103))	('hypermethylation', 'Var', (25, 41))	('RASS1A', 'Gene', (0, 6))	('lung tumours', 'Disease', 'MESH:D008175', (117, 129))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('lung tumours', 'Disease', (117, 129))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('seen', 'Reg', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('breast', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
15907	26448938	The normal tissue was obtained from histologically benign region of the tumour bearing kidney, suggesting that hypermethylation of RASSF1A is involved in early tumour formation of RCC.	('tumour', 'Disease', (160, 166))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('hypermethylation', 'Var', (111, 127))	('tumour bearing kidney', 'Disease', 'MESH:D007680', (72, 93))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('involved', 'Reg', (142, 150))	('RASSF1A', 'Gene', (131, 138))	('tumour bearing kidney', 'Disease', (72, 93))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('formation', 'biological_process', 'GO:0009058', ('167', '176'))	('tumour', 'Disease', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('RASSF1A', 'Gene', '11186', (131, 138))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
15908	26448938	In ccRCC patients, hypermethylation of the RASSF1A promoter was significantly associated with advanced stage, higher grade, and unfavorable patient survival.	('associated', 'Reg', (78, 88))	('higher grade', 'CPA', (110, 122))	('patients', 'Species', '9606', (9, 17))	('advanced stage', 'CPA', (94, 108))	('RASSF1A', 'Gene', '11186', (43, 50))	('patient', 'Species', '9606', (140, 147))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('hypermethylation', 'Var', (19, 35))	('patient', 'Species', '9606', (9, 16))	('RASSF1A', 'Gene', (43, 50))
15912	26448938	Although less frequently reported, RASSF1A inactivation is also found in approximately 44% of papillary RCC.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('RASSF1A', 'Gene', (35, 42))	('RASSF1A', 'Gene', '11186', (35, 42))	('inactivation', 'Var', (43, 55))	('RCC', 'Disease', (104, 107))
15913	26448938	Recently, NGS or exome sequencing studies have discovered several novel genes involved in chromatin modification which are mutated in ccRCC.	('chromatin modification', 'biological_process', 'GO:0006325', ('90', '112'))	('chromatin', 'cellular_component', 'GO:0000785', ('90', '99'))	('chromatin modification', 'biological_process', 'GO:0016569', ('90', '112'))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('mutated', 'Var', (123, 130))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
15915	26448938	PBRM1 mutations are found in up to 41% of ccRCC, making it the second most mutated gene after VHL.	('VHL', 'Gene', '7428', (94, 97))	('PBRM1', 'Gene', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('PBRM1', 'Gene', '55193', (0, 5))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('mutations', 'Var', (6, 15))	('VHL', 'Gene', (94, 97))
15917	26448938	As loss or deletion of 3p chromosome region is common in ccRCC, inactivation of these genes is achieved by further mutations in the remaining allele.	('loss', 'NegReg', (3, 7))	('deletion', 'Var', (11, 19))	('chromosome region', 'cellular_component', 'GO:0098687', ('26', '43'))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
15919	26448938	This provides an insight into the various mutations that may take part in tumour initiation or progression and possibly aid in fine tuning targeted therapy in the future.	('tumour initiation', 'Disease', 'MESH:D009369', (74, 91))	('tumour initiation', 'Disease', (74, 91))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (42, 51))	('aid', 'Reg', (120, 123))
15922	26448938	A ubiquitous mutation is found in all regions of a tumour analysed, whereas subclonal mutations are only found in a subpopulation of tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('mutation', 'Var', (13, 21))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
15924	26448938	and Sankin et al.. BAP1, PBRM1, SETD2, and KDM5C mutations were found in different subclones in the same tumour, indicating that these were later mutations.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('SETD2', 'Gene', '29072', (32, 37))	('mutations', 'Var', (49, 58))	('KDM5C', 'Gene', (43, 48))	('SETD2', 'Gene', (32, 37))	('tumour', 'Disease', (105, 111))	('BAP1', 'Gene', '8314', (19, 23))	('PBRM1', 'Gene', (25, 30))	('KDM5C', 'Gene', '8242', (43, 48))	('BAP1', 'Gene', (19, 23))	('PBRM1', 'Gene', '55193', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
15926	26448938	reported an increased mutation frequency in intratumour multiregion analysis, compared to earlier large scale sequencing studies.	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('mutation', 'Var', (22, 30))	('tumour', 'Disease', (49, 55))
15928	26448938	Although most studies have focused on mutations of these genes in sporadic ccRCC, germline PBRM1 and BAP1 mutations have been detected in familial ccRCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('PBRM1', 'Gene', (91, 96))	('PBRM1', 'Gene', '55193', (91, 96))	('BAP1', 'Gene', '8314', (101, 105))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('BAP1', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))	('detected', 'Reg', (126, 134))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
15929	26448938	Germline BAP1 mutation also predisposes affected individuals to uveal melanoma, malignant pleural mesothelioma, and cutaneous melanoma.	('predisposes', 'Reg', (28, 39))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('BAP1', 'Gene', '8314', (9, 13))	('mutation', 'Var', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (90, 110))	('malignant pleural mesothelioma', 'Disease', (80, 110))	('cutaneous melanoma', 'Disease', (116, 134))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (80, 110))	('uveal melanoma', 'Disease', 'MESH:C536494', (64, 78))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('BAP1', 'Gene', (9, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (64, 78))	('uveal melanoma', 'Disease', (64, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))
15931	26448938	Alterations of the chromatin modification proteins could lead to disruptions of transcriptional regulation and tumour formation.	('Alterations', 'Var', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('lead to', 'Reg', (57, 64))	('disruptions', 'MPA', (65, 76))	('chromatin modification', 'biological_process', 'GO:0006325', ('19', '41'))	('regulation', 'biological_process', 'GO:0065007', ('96', '106'))	('formation', 'biological_process', 'GO:0009058', ('118', '127'))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))	('chromatin modification', 'biological_process', 'GO:0016569', ('19', '41'))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('transcriptional regulation', 'MPA', (80, 106))	('tumour', 'Disease', (111, 117))	('chromatin modification proteins', 'Protein', (19, 50))
15932	26448938	For example, silencing of PBRM1 in ccRCC cell lines increased proliferation and migration, supporting its role as a TSG.	('TSG', 'Gene', '57045', (116, 119))	('increased', 'PosReg', (52, 61))	('proliferation', 'CPA', (62, 75))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('migration', 'CPA', (80, 89))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('TSG', 'Gene', (116, 119))	('silencing', 'Var', (13, 22))
15933	26448938	In a RCC cell line with BAP1 mutation, 769-P, cell proliferation was inhibited by the introduction of wild type BAP1.	('BAP1', 'Gene', (112, 116))	('mutation', 'Var', (29, 37))	('BAP1', 'Gene', (24, 28))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('BAP1', 'Gene', '8314', (112, 116))	('inhibited', 'NegReg', (69, 78))	('cell proliferation', 'CPA', (46, 64))	('BAP1', 'Gene', '8314', (24, 28))	('cell proliferation', 'biological_process', 'GO:0008283', ('46', '64'))
15934	26448938	The roles of these chromatin modification genes and their proteins products are not fully understood yet, but various studies have shown that the mutational status of these genes may possess prognostic influence on ccRCC.	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('RCC', 'Disease', (217, 220))	('mutational', 'Var', (146, 156))	('chromatin modification', 'biological_process', 'GO:0006325', ('19', '41'))	('chromatin modification', 'biological_process', 'GO:0016569', ('19', '41'))	('chromatin', 'cellular_component', 'GO:0000785', ('19', '28'))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))
15936	26448938	found no relationship between disease-free or disease specific survival and PBRM1 mutational status.	('mutational status', 'Var', (82, 99))	('PBRM1', 'Gene', (76, 81))	('PBRM1', 'Gene', '55193', (76, 81))
15938	26448938	Compared to tumours exclusively mutated for PBRM1, tumours with BAP1 only mutation conferred adverse clinicopathological features and prognosis.	('mutation', 'Var', (74, 82))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('PBRM1', 'Gene', (44, 49))	('tumours', 'Disease', (12, 19))	('PBRM1', 'Gene', '55193', (44, 49))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('BAP1', 'Gene', '8314', (64, 68))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumours', 'Disease', (51, 58))	('BAP1', 'Gene', (64, 68))
15939	26448938	Based on these findings, BAP1 mutational status appears to be a strong prognostic indicator for ccRCC.	('BAP1', 'Gene', (25, 29))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('BAP1', 'Gene', '8314', (25, 29))	('mutational status', 'Var', (30, 47))
15940	26448938	Low ARID1A mRNA and BAF250a (protein product of ARID1A) levels also correlated with higher stage, grade, and worse prognosis while SETD2 mutation was associated with worse disease specific survival.	('mutation', 'Var', (137, 145))	('ARID1A', 'Gene', '8289', (48, 54))	('ARID1A', 'Gene', '8289', (4, 10))	('ARID1A', 'Gene', (48, 54))	('ARID1A', 'Gene', (4, 10))	('BAF250a', 'Gene', '8289', (20, 27))	('BAF250a', 'Gene', (20, 27))	('protein', 'cellular_component', 'GO:0003675', ('29', '36'))	('SETD2', 'Gene', '29072', (131, 136))	('stage', 'CPA', (91, 96))	('Low', 'NegReg', (0, 3))	('grade', 'CPA', (98, 103))	('higher', 'PosReg', (84, 90))	('SETD2', 'Gene', (131, 136))
15941	26448938	Other genetic aberrations of interest, such as changes at chromosome regions 5q, 8p, 9p, and 14, may affect the prognosis of ccRCC.	('affect', 'Reg', (101, 107))	('changes', 'Var', (47, 54))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('chromosome', 'cellular_component', 'GO:0005694', ('58', '68'))
15942	26448938	LOH in 8p, 9p, and 14q has been associated with higher grade, stage, unfavourable prognosis, and tumour recurrence.	('higher grade', 'CPA', (48, 60))	('tumour', 'Disease', (97, 103))	('stage', 'CPA', (62, 67))	('LOH in 8p', 'Var', (0, 9))	('associated', 'Reg', (32, 42))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))
15957	26448938	Clear cell tubulopapillary RCCs lack deletions of 3p typical of ccRCC or gains of chromosome 7 and loss of chromosome Y characteristic of pRCC.	('deletions', 'Var', (37, 46))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('gains', 'PosReg', (73, 78))	('pRCC', 'Gene', '5546', (138, 142))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('chromosome', 'Gene', (107, 117))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('pRCC', 'Gene', (138, 142))	('RCC', 'Disease', (27, 30))	('loss', 'NegReg', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
15958	26448938	In addition, clear cell tubulopapillary RCC lacks VHL mutation commonly found in the ccRCC subtype.	('mutation', 'Var', (54, 62))	('lacks', 'NegReg', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('VHL', 'Gene', (50, 53))	('RCC', 'Disease', (87, 90))	('clear cell', 'Disease', (13, 23))	('VHL', 'Gene', '7428', (50, 53))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
15967	26448938	Based on past studies, polysomy 7 is not a reliable predictor of survival, stage, grade, or proliferation rate of papillary renal tumours.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('papillary renal tumours', 'Disease', (114, 137))	('polysomy 7', 'Var', (23, 33))	('papillary renal tumours', 'Disease', 'MESH:D007681', (114, 137))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
15968	26448938	Polysomy 7 in ccRCC however was correlated with higher stage and grade.	('RCC', 'Disease', (16, 19))	('Polysomy 7', 'Var', (0, 10))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (16, 19))
15971	26448938	significantly correlated chromosome 17 polysomy with lower stage, less lymph node, and distant metastases, as well as a favourable survival.	('lower stage', 'CPA', (53, 64))	('less lymph node', 'CPA', (66, 81))	('chromosome', 'cellular_component', 'GO:0005694', ('25', '35'))	('metastases', 'Disease', (95, 105))	('polysomy', 'Var', (39, 47))	('chromosome 17', 'Gene', (25, 38))	('metastases', 'Disease', 'MESH:D009362', (95, 105))
15973	26448938	Hereditary pRCC (HPRC) associated with type 1 tumours is caused by the mutation of the MET protooncogene at 7q31.	('pRCC', 'Gene', '5546', (11, 15))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('mutation', 'Var', (71, 79))	('type 1 tumours', 'Disease', 'MESH:D009369', (39, 53))	('caused by', 'Reg', (57, 66))	('pRCC', 'Gene', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('type 1 tumours', 'Disease', (39, 53))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
15977	26448938	The role of c-met in pRCC has not been clearly elucidated but in hereditary pRCC it is suggested that germline mutations of the MET gene promote proliferation, tubulogenesis, and tumour initiation.	('mutations', 'Var', (111, 120))	('tubulogenesis', 'biological_process', 'GO:0048754', ('160', '173'))	('tumour initiation', 'Disease', (179, 196))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('pRCC', 'Gene', '5546', (76, 80))	('pRCC', 'Gene', (21, 25))	('promote', 'PosReg', (137, 144))	('proliferation', 'CPA', (145, 158))	('c-met', 'Gene', (12, 17))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('MET', 'Gene', (128, 131))	('pRCC', 'Gene', '5546', (21, 25))	('pRCC', 'Gene', (76, 80))	('c-met', 'Gene', '4233', (12, 17))	('tumour initiation', 'Disease', 'MESH:D009369', (179, 196))	('tubulogenesis', 'CPA', (160, 173))
15979	26448938	reported copy number gains of MET in 46% of type II pRCC and in 81% of type I pRCC.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('pRCC', 'Gene', (78, 82))	('pRCC', 'Gene', '5546', (52, 56))	('pRCC', 'Gene', '5546', (78, 82))	('copy number gains', 'Var', (9, 26))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('pRCC', 'Gene', (52, 56))	('MET', 'Var', (30, 33))
15980	26448938	The c-met protein is strongly expressed in 80-90% of pRCC, indicating a role of MET copy number gains in protein activation.	('pRCC', 'Gene', (53, 57))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('c-met', 'Gene', '4233', (4, 9))	('MET copy number gains', 'Var', (80, 101))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('pRCC', 'Gene', '5546', (53, 57))	('c-met', 'Gene', (4, 9))
15989	26448938	Besides MET mutation associated HPRC, another form of hereditary pRCC is found in the autosomal dominant syndrome, hereditary leiomyomatosis, and renal cell carcinoma (HLRCC).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (86, 113))	('renal cell carcinoma', 'Disease', (146, 166))	('autosomal dominant syndrome', 'Disease', (86, 113))	('pRCC', 'Gene', '5546', (65, 69))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 166))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('pRCC', 'Gene', (65, 69))	('hereditary leiomyomatosis', 'Disease', (115, 140))	('MET mutation', 'Var', (8, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('HPRC', 'Disease', (32, 36))	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (115, 140))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))
15995	26448938	As a consequence of missense, frameshift, insertion/deletion, nonsense, or complete deletions of the FH gene, enzymatic activity of FH is significantly decreased.	('missense', 'Var', (20, 28))	('FH', 'Gene', '2271', (101, 103))	('decreased', 'NegReg', (152, 161))	('enzymatic activity', 'MPA', (110, 128))	('insertion/deletion', 'Var', (42, 60))	('FH', 'Gene', '2271', (132, 134))	('frameshift', 'Var', (30, 40))	('nonsense', 'Var', (62, 70))
15999	26448938	Compared to VHL and MET, mutation of FH in sporadic RCC is very rare.	('VHL', 'Gene', (12, 15))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('VHL', 'Gene', '7428', (12, 15))	('RCC', 'Disease', (52, 55))	('mutation', 'Var', (25, 33))	('FH', 'Gene', '2271', (37, 39))
16000	26448938	For example, according to the COSMIC (Catalogue of Somatic Mutations in Cancer) database, FH mutations were found in 3 out of 1383 renal tumours analysed.	('found', 'Reg', (108, 113))	('renal tumours', 'Disease', 'MESH:D007680', (131, 144))	('mutations', 'Var', (93, 102))	('FH', 'Gene', '2271', (90, 92))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('renal tumours', 'Disease', (131, 144))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
16001	26448938	Deletions are often found in chromosomes X and Y of pRCC tumours.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('pRCC tumours', 'Disease', (52, 64))	('pRCC tumours', 'Disease', 'MESH:D009369', (52, 64))	('Deletions', 'Var', (0, 9))
16002	26448938	The effects of these chromosomal losses in pRCC are not well documented in literature and no TSG has been identified yet.	('TSG', 'Gene', (93, 96))	('pRCC', 'Gene', (43, 47))	('chromosomal losses', 'Var', (21, 39))	('TSG', 'Gene', '57045', (93, 96))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('pRCC', 'Gene', '5546', (43, 47))
16011	26448938	Allelic alteration of 3p, which is characteristic of ccRCC, is also found in pRCC, although the incidence is lower.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('pRCC', 'Gene', (77, 81))	('Allelic alteration', 'Var', (0, 18))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('pRCC', 'Gene', '5546', (77, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
16012	26448938	Loss of 3p in pRCC was associated with worse prognosis such as higher T stage and grade, lymph node involvement, distant metastasis, larger tumour size, and worse survival.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('pRCC', 'Gene', '5546', (14, 18))	('Loss of 3p', 'Var', (0, 10))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('pRCC', 'Gene', (14, 18))	('distant metastasis', 'CPA', (113, 131))	('tumour', 'Disease', (140, 146))	('T stage', 'CPA', (70, 77))	('lymph node involvement', 'CPA', (89, 111))	('higher', 'PosReg', (63, 69))	('grade', 'CPA', (82, 87))
16015	26448938	Some studies showed no difference in polysomies 7 and 17 frequency in types 1 and 2 tumours but others reported higher frequency of chromosomes 7 and 17 gains in type 1 compared to type 2.	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('gains', 'PosReg', (153, 158))	('chromosomes 7', 'Var', (132, 145))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
16017	26448938	For example, type 2 tumours have a higher frequency of chromosomes 3p, 8, and 18 losses and 1q, 2, and 8q gains.	('type 2 tumours', 'Disease', 'MESH:D009369', (13, 27))	('losses', 'NegReg', (81, 87))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('gains', 'PosReg', (106, 111))	('type 2 tumours', 'Disease', (13, 27))	('chromosomes', 'Var', (55, 66))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
16025	26448938	Other genetic aberrations in metanephric adenoma are gains of chromosome 19 and deletions in chromosome 2.	('metanephric adenoma', 'Disease', 'MESH:D000236', (29, 48))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('gains', 'PosReg', (53, 58))	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('deletions', 'Var', (80, 89))	('metanephric adenoma', 'Disease', (29, 48))
16026	26448938	Recently, an activating missense mutation in the BRAF gene was discovered, which could be specific to metanephric adenoma.	('missense mutation', 'Var', (24, 41))	('activating', 'PosReg', (13, 23))	('metanephric adenoma', 'Disease', (102, 121))	('metanephric adenoma', 'Disease', 'MESH:D000236', (102, 121))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', (49, 53))
16027	26448938	The substitution of valine for glutamic acid in the BRAF gene results in the V600E variant protein, which has increased activation potential compared to the wild type BRAF.	('glutamic acid', 'Chemical', 'MESH:D018698', (31, 44))	('increased', 'PosReg', (110, 119))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('activation potential', 'MPA', (120, 140))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('V600E', 'Var', (77, 82))	('valine', 'Chemical', 'MESH:D014633', (20, 26))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
16041	26448938	Xp11.2 translocation RCCs predominantly affect children and adolescents but are found in adults as well.	('translocation', 'Var', (7, 20))	('children', 'Species', '9606', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('p11', 'Gene', '8909', (1, 4))	('RCC', 'Disease', (21, 24))	('p11', 'Gene', (1, 4))
16045	26448938	The gene fusions lead to overexpression of TFE3 protein and immunoreactivity with TFE3 protein is a distinguishing feature of Xp11.2 translocation RCCs.	('protein', 'cellular_component', 'GO:0003675', ('48', '55'))	('fusions', 'Var', (9, 16))	('lead', 'Reg', (17, 21))	('p11', 'Gene', (127, 130))	('TFE3', 'Gene', (82, 86))	('TFE3', 'Gene', (43, 47))	('p11', 'Gene', '8909', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('TFE3', 'Gene', '7030', (82, 86))	('TFE3', 'Gene', '7030', (43, 47))	('overexpression', 'PosReg', (25, 39))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))
16055	26448938	LOH, frameshift, or missense mutations inactivate the BHD gene, decreasing BHD mRNA levels and folliculin protein expression.	('inactivate', 'NegReg', (39, 49))	('folliculin', 'Gene', (95, 105))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('BHD', 'Gene', '50947', (75, 78))	('missense mutations', 'Var', (20, 38))	('BHD', 'Gene', '50947', (54, 57))	('decreasing', 'NegReg', (64, 74))	('BHD', 'Gene', (54, 57))	('BHD', 'Gene', (75, 78))	('frameshift', 'Var', (5, 15))	('folliculin', 'Gene', '201163', (95, 105))
16059	26448938	reported BHD mutations in 10.9% of chRCC and 5.6% of oncocytomas from their case series of sporadic renal tumours.	('oncocytomas', 'Disease', 'MESH:D018249', (53, 64))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('sporadic renal tumours', 'Disease', (91, 113))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('BHD', 'Gene', '50947', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('BHD', 'Gene', (9, 12))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('sporadic renal tumours', 'Disease', 'MESH:D007680', (91, 113))	('RCC', 'Disease', (37, 40))	('mutations', 'Var', (13, 22))	('oncocytomas', 'Disease', (53, 64))
16060	26448938	Common genetic alterations found in sporadic chRCC are the LOH at chromosomes 1, 2, 6, 10, 13, 17, and 21.	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('LOH', 'Var', (59, 62))
16064	26448938	identified mutations of PTEN in chRCC but an earlier study by Sukosd et al.	('PTEN', 'Gene', '5728', (24, 28))	('mutations', 'Var', (11, 20))	('RCC', 'Disease', (34, 37))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('PTEN', 'Gene', (24, 28))
16065	26448938	found no PTEN mutation in chRCC.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('mutation', 'Var', (14, 22))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
16075	26448938	Other genetic alterations characteristic of ROs are losses at chromosomes 1, 14, and Y, as well as chromosome rearrangement at 11q13.	('chromosome', 'cellular_component', 'GO:0005694', ('99', '109'))	('chromosome', 'Var', (99, 109))	('ROs', 'Gene', (44, 47))	('ROs', 'Chemical', '-', (44, 47))	('losses', 'NegReg', (52, 58))	('RO', 'Phenotype', 'HP:0011798', (44, 46))
16076	26448938	Rearrangement of cyclin D1 (CCND1) gene has been linked to the translocation at 11q13.	('Rearrangement', 'Var', (0, 13))	('cyclin', 'molecular_function', 'GO:0016538', ('17', '23'))	('CCND1', 'Gene', '595', (28, 33))	('linked', 'Reg', (49, 55))	('cyclin D1', 'Gene', '595', (17, 26))	('CCND1', 'Gene', (28, 33))	('cyclin D1', 'Gene', (17, 26))
16077	26448938	ROs with rearrangement at 11q13 have been reported along with overexpression of cyclin D1, the protein product of CCDN1 gene.	('RO', 'Phenotype', 'HP:0011798', (0, 2))	('cyclin D1', 'Gene', (80, 89))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('cyclin', 'molecular_function', 'GO:0016538', ('80', '86'))	('cyclin D1', 'Gene', '595', (80, 89))	('rearrangement', 'Var', (9, 22))	('CCDN1', 'Gene', (114, 119))	('ROs', 'Chemical', '-', (0, 3))
16079	26448938	Dysregulation of cyclin D1 may contribute to the overproliferation of cells leading to RO formation.	('cyclin', 'molecular_function', 'GO:0016538', ('17', '23'))	('Dysregulation', 'Var', (0, 13))	('overproliferation', 'CPA', (49, 66))	('RO', 'Phenotype', 'HP:0011798', (87, 89))	('formation', 'biological_process', 'GO:0009058', ('90', '99'))	('cyclin D1', 'Gene', (17, 26))	('cyclin D1', 'Gene', '595', (17, 26))	('contribute', 'Reg', (31, 41))	('RO formation', 'Disease', (87, 99))
16089	26448938	A cytogenetics study found monosomies 1, 6, 14, 15, and 22 in three CDRCC tumours.	('CDRCC tumours', 'Disease', (68, 81))	('monosomies 1', 'Var', (27, 39))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('CDRCC tumours', 'Disease', 'MESH:D009369', (68, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
16092	26448938	Hence, loss of chromosome 1 might be more characteristic of renal tumours from the collecting duct whereas chromosome 3p loss is more typical of renal tumours from the proximal tubule.	('renal tumours', 'Disease', 'MESH:D007680', (145, 158))	('renal tumours', 'Disease', 'MESH:D007680', (60, 73))	('loss', 'Var', (7, 11))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('loss', 'NegReg', (121, 125))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('renal tumours', 'Disease', (145, 158))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('renal tumours', 'Disease', (60, 73))	('chromosome', 'cellular_component', 'GO:0005694', ('107', '117'))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('chromosome 1', 'Gene', (15, 27))
16093	26448938	detected a region of genetic loss at 1q32.1-32.2 in 69% of CDRCC but no TSG has been identified yet.	('TSG', 'Gene', (72, 75))	('genetic', 'Var', (21, 28))	('loss', 'NegReg', (29, 33))	('TSG', 'Gene', '57045', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
16095	26448938	A better understanding of the contribution of genetic alterations in CDRCC would be interesting because of the aggressive behaviour of the disease.	('behaviour', 'biological_process', 'GO:0007610', ('122', '131'))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('genetic alterations', 'Var', (46, 65))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (111, 131))
16117	26448938	These genetic changes may play an important role in tumourigenesis and affect the progression or prognosis of the tumour.	('tumour', 'Disease', (114, 120))	('genetic changes', 'Var', (6, 21))	('progression', 'CPA', (82, 93))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('affect', 'Reg', (71, 77))	('role', 'Reg', (44, 48))	('play', 'Reg', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('prognosis', 'CPA', (97, 106))
16120	26448938	Recent genetic studies have employed gene sequencing or gene expression profiling for discovery of novel gene mutations which could identify possible differentially expressed proteins in RCC subtypes.	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('mutations', 'Var', (110, 119))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('gene expression', 'biological_process', 'GO:0010467', ('56', '71'))
16129	31043488	Expression of the receptor tyrosine kinase Ret was elevated in the kidneys of the TFE3-RCC mice, and treatment with RET inhibitor vandetanib significantly suppressed RCC growth.	('mice', 'Species', '10090', (91, 95))	('RCC growth', 'CPA', (166, 176))	('Ret', 'Gene', (43, 46))	('vandetanib', 'Chemical', 'MESH:C452423', (130, 140))	('Ret', 'Gene', '19713', (43, 46))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('Expression', 'MPA', (0, 10))	('suppressed', 'NegReg', (155, 165))	('elevated', 'PosReg', (51, 59))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('TFE3-RCC', 'Var', (82, 90))	('men', 'Species', '9606', (106, 109))
16130	31043488	Moreover, we found that Gpnmb (Glycoprotein nonmetastatic B) expression was notably elevated in the TFE3-RCC mouse kidneys as seen in human TFE3-RCC tumors, and confirmed that GPNMB is the direct transcriptional target of TFE3 fusions.	('TFE3-RCC tumors', 'Disease', (140, 155))	('human', 'Species', '9606', (134, 139))	('TFE3-RCC', 'Var', (100, 108))	('Gpnmb', 'Gene', (24, 29))	('elevated', 'PosReg', (84, 92))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('TFE3-RCC tumors', 'Disease', 'MESH:C538614', (140, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Glycoprotein nonmetastatic B', 'Gene', '93695', (31, 59))	('Glycoprotein nonmetastatic B', 'Gene', (31, 59))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('expression', 'MPA', (61, 71))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('mouse', 'Species', '10090', (109, 114))
16134	31043488	TFE3 Xp11.2 translocation RCC (TFE3-RCC) was defined as an independent subtype of RCC by WHO in 2004 and is characterized by distinctive morphological features and Xp11.2 rearrangements that create TFE3 gene fusions with a variety of partner genes (PRCC, SFPQ, ASPSCR, CLTC, NONO, RBM10, PARP14, LUC7L3, KHSRP etc.)	('CLTC', 'Gene', (269, 273))	('PARP14', 'Gene', '547253', (288, 294))	('PARP14', 'Gene', (288, 294))	('Xp11', 'Gene', '111712', (164, 168))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('Xp11', 'Gene', (5, 9))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('Xp11', 'Gene', (164, 168))	('RBM10', 'Gene', (281, 286))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RBM10', 'Gene', '236732', (281, 286))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('CLTC', 'Gene', '67300', (269, 273))	('KHSRP', 'Gene', '16549', (304, 309))	('TFE3', 'Gene', (198, 202))	('LUC7L3', 'Gene', '67684', (296, 302))	('fusions', 'Var', (208, 215))	('LUC7L3', 'Gene', (296, 302))	('men', 'Species', '9606', (180, 183))	('Xp11', 'Gene', '111712', (5, 9))	('KHSRP', 'Gene', (304, 309))
16142	31043488	We determined that GPNMB (glycoprotein nonmetastatic B) is directly transcribed and upregulated by chimeric TFE3 and performed GPNMB immunohistochemical staining in human TFE3-RCCs to investigate its potential in the diagnosis of this form of RCC.	('upregulated', 'PosReg', (84, 95))	('human', 'Species', '9606', (165, 170))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('RCC', 'Disease', (243, 246))	('chimeric', 'Var', (99, 107))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('glycoprotein nonmetastatic B', 'Gene', '93695', (26, 54))	('TFE3', 'Gene', (108, 112))	('GPNMB', 'Gene', (19, 24))	('glycoprotein nonmetastatic B', 'Gene', (26, 54))
16165	31043488	UOK111, UOK115 and UOK140 are cell lines derived from ccRCC tumors with VHL gene mutations that were established in the UOB, NCI.	('VHL', 'Gene', '7428', (72, 75))	('ccRCC tumors', 'Disease', (54, 66))	('UOK115', 'CellLine', 'CVCL:B094', (8, 14))	('UOK111', 'CellLine', 'CVCL:B090', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (81, 90))	('ccRCC tumors', 'Disease', 'MESH:D009369', (54, 66))	('VHL', 'Gene', (72, 75))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
16173	31043488	The Cancer Genome Atlas (TCGA) dataset was used to validate candidate transcriptional target genes of chimeric TFE3, which were identified by RNAseq analysis.	('TFE3', 'Gene', (111, 115))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('chimeric', 'Var', (102, 110))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
16191	31043488	If a yellow signal was observed in 30% or more of 100 counted cells, the tumor was defined as harboring SFPQ-TFE3.	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SFPQ-TFE3', 'Var', (104, 113))
16240	31043488	We transfected reporter plasmids carrying wild type or mutant M-box motifs into doxycycline-inducible PRCC-TFE3 expressing HEK293 cells (Fig.3e).	('PRCC-TFE3', 'Gene', (102, 111))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('doxycycline', 'Chemical', 'MESH:D004318', (80, 91))	('HEK293', 'CellLine', 'CVCL:0045', (123, 129))	('M-box', 'Gene', (62, 67))	('mutant', 'Var', (55, 61))	('PRCC-TFE3', 'Gene', '94315;209446', (102, 111))
16242	31043488	Importantly, this PRCC-TFE3 dependent GPNMB promoter activity was attenuated in cells transfected with mutated M-box1 or M-box2 reporter plasmids.	('mutated', 'Var', (103, 110))	('GPNMB', 'Gene', (38, 43))	('PRCC-TFE3', 'Gene', '94315;209446', (18, 27))	('attenuated', 'NegReg', (66, 76))	('PRCC-TFE3', 'Gene', (18, 27))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))
16243	31043488	Furthermore, complete absence of PRCC-TFE3 dependent promoter activity was seen in cells transfected with a reporter plasmid in which both M-box1 and M-box2 were mutated (Fig.3f).	('absence', 'NegReg', (22, 29))	('mutated', 'Var', (162, 169))	('PRCC-TFE3', 'Gene', '94315;209446', (33, 42))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('PRCC-TFE3', 'Gene', (33, 42))
16253	31043488	4d, while GPNMB expression levels were statistically significantly higher (p<0.0001) in TFE3-RCC than in either papillary type 1 RCC, papillary type 2 RCC (p<0.0001) or total papillary RCC (p<0.0001), there were no statistically significant differences in Cathepsin K expression between TFE3-RCC and either papillary type 1 RCC, papillary type 2 RCC or total papillary RCC.	('papillary RCC', 'Disease', 'MESH:C538614', (175, 188))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('papillary RCC', 'Disease', (175, 188))	('higher', 'PosReg', (67, 73))	('expression', 'MPA', (268, 278))	('papillary RCC', 'Disease', 'MESH:C538614', (359, 372))	('Cathepsin K', 'Gene', (256, 267))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('GPNMB expression levels', 'MPA', (10, 33))	('TFE3-RCC', 'Var', (88, 96))	('papillary RCC', 'Disease', (359, 372))	('Cathepsin K', 'Gene', '13038', (256, 267))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Phenotype', 'HP:0005584', (292, 295))
16259	31043488	Interestingly, the 4 cases from a total of 76 clear cell and papillary RCC that were positive for GPNMB were also positive for nuclear TFE3 staining, which suggests that GPNMB positivity is the consequence of TFE3 activation by an unknown mechanism other than Xp11.2 translocation.	('Xp11', 'Gene', '111712', (260, 264))	('papillary RCC', 'Disease', (61, 74))	('activation', 'PosReg', (214, 224))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('positivity', 'Var', (176, 186))	('positive', 'Reg', (114, 122))	('TFE3', 'Gene', (209, 213))	('GPNMB', 'Gene', (170, 175))	('Xp11', 'Gene', (260, 264))	('papillary RCC', 'Disease', 'MESH:C538614', (61, 74))
16265	31043488	Results from the evaluation of our PRCC-TFE3-expressing mouse model have confirmed that chimeric PRCC-TFE3 is an oncogene which is responsible for RCC development in vivo.	('PRCC-TFE3', 'Gene', '94315;209446', (35, 44))	('PRCC-TFE3', 'Gene', '94315;209446', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('mouse', 'Species', '10090', (56, 61))	('chimeric', 'Var', (88, 96))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('PRCC-TFE3', 'Gene', (35, 44))	('RCC', 'Disease', (147, 150))	('PRCC-TFE3', 'Gene', (97, 106))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('men', 'Species', '9606', (158, 161))
16267	31043488	Indeed, overexpressed PRCC-TFE3 and SFPQ-TFE3 (data not shown) demonstrated predominant nuclear localization, while overexpressed wild-type TFE3 localized in the cytoplasm of HEK 293 cells.	('PRCC-TFE3', 'Gene', (22, 31))	('SFPQ-TFE3', 'Var', (36, 45))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('localization', 'biological_process', 'GO:0051179', ('96', '108'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('162', '171'))	('nuclear localization', 'MPA', (88, 108))	('PRCC-TFE3', 'Gene', '94315;209446', (22, 31))	('HEK 293', 'CellLine', 'CVCL:0045', (175, 182))
16275	31043488	It will be of great importance to clarify the details of the transcriptional network, including Nr4a1, perturbed by chimeric TFE3.	('TFE3', 'Gene', (125, 129))	('chimeric', 'Var', (116, 124))	('Nr4a1', 'Gene', (96, 101))	('Nr4a1', 'Gene', '15370', (96, 101))	('perturbed', 'Reg', (103, 112))
16289	31043488	Identification and characterization of additional TFE3-RCC driver gene mutations will contribute to a better understanding of the causes of TFE3-RCC heterogeneity and facilitate the development of effective targeted therapeutics.	('men', 'Species', '9606', (189, 192))	('mutations', 'Var', (71, 80))	('TFE3-RCC', 'Gene', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))
16290	31043488	This PRCC-TFE3 mouse model can be utilized in future studies to evaluate potential driver gene mutations by crossing with genetically engineered mice for selective gene deletion.	('PRCC-TFE3', 'Gene', '94315;209446', (5, 14))	('mouse', 'Species', '10090', (15, 20))	('mutations', 'Var', (95, 104))	('mice', 'Species', '10090', (145, 149))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('PRCC-TFE3', 'Gene', (5, 14))
16291	31043488	Since the chimeric TFE3 proteins responsible for TFE3-RCC development act as oncogenic transcription factors, transcriptionally upregulated direct targets of chimeric TFE3 could be promising candidates for TFE3-RCC diagnostic markers.	('TFE3', 'Gene', (19, 23))	('men', 'Species', '9606', (65, 68))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('chimeric', 'Var', (158, 166))	('upregulated', 'PosReg', (128, 139))	('transcription', 'biological_process', 'GO:0006351', ('87', '100'))
16334	30693127	Fluorescent in situ hybridization (FISH) analysis demonstrated no evidence of aneuploidy for chromosome 7 in either tumor area.	('chromosome', 'cellular_component', 'GO:0005694', ('93', '103'))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('aneuploidy', 'Var', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
16352	30693127	Genetic analysis of PRCC typically demonstrates chromosomal gain, most often of chromosomes 7 and 17, present in 68-75% and 67-80% of PRCCs, respectively.	('PRCC', 'Gene', '5546', (20, 24))	('PRCC', 'Gene', '5546', (134, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('PRCC', 'Gene', (20, 24))	('PRCC', 'Gene', (134, 138))	('PRCC', 'Phenotype', 'HP:0006766', (20, 24))	('PRCC', 'Phenotype', 'HP:0006766', (134, 138))	('gain', 'PosReg', (60, 64))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('chromosomal', 'Var', (48, 59))
16355	30693127	In contrast, non-random gain of chromosome 17 is uncommon in other forms of RCC (present in 2.6% of CCRCCs) and other human cancers and is quite specific for PRCC.	('PRCC', 'Gene', (158, 162))	('RCC', 'Gene', (102, 105))	('PRCC', 'Phenotype', 'HP:0006766', (158, 162))	('non-random', 'Var', (13, 23))	('RCC', 'Gene', '5891', (102, 105))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))	('PRCC', 'Gene', '5546', (158, 162))	('RCC', 'Gene', (76, 79))	('gain', 'PosReg', (24, 28))	('RCC', 'Gene', '5891', (76, 79))	('human', 'Species', '9606', (118, 123))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('RCC', 'Gene', (159, 162))	('cancers', 'Disease', (124, 131))	('chromosome', 'cellular_component', 'GO:0005694', ('32', '42'))	('RCC', 'Gene', '5891', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
16402	25524502	Fortunately, a DECT scanner was recently installed at an affiliate hospital of the Southern Illinois University School of Medicine (St John's Hospital - Springfield, IL), and the Radiology Department at St. John's Hospital had communicated to us the possible benefit of DECT in renal tumors with equivocal enhancement characteristics.	('renal tumors', 'Disease', (278, 290))	('DECT', 'Var', (270, 274))	('renal tumors', 'Phenotype', 'HP:0009726', (278, 290))	('renal tumor', 'Phenotype', 'HP:0009726', (278, 289))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('renal tumors', 'Disease', 'MESH:D007674', (278, 290))
16449	27893792	In conclusion, Xp11.2 tRCC is a rare subtype of renal cell carcinoma that mainly occurs in young females.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (48, 68))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('Xp11.2', 'Var', (15, 21))	('renal cell carcinoma', 'Disease', (48, 68))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (48, 68))
16452	27893792	Since being recognized as a distinct entity by the World Health Organization (WHO) in 2004, Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC) has attracted broad attention.	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('Xp11.2', 'Var', (92, 98))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (99, 133))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('translocation renal cell carcinoma', 'Disease', (99, 133))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))
16459	27893792	To date, TFE3 break-apart fluorescence in situ hybridization (FISH) is regarded as the best method to diagnose Xp11.2 tRCC due to its advantages of high sensitivity and specificity.	('TFE3', 'Gene', (9, 13))	('Xp11.2', 'Var', (111, 117))	('TFE3', 'Gene', '7030', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))
16464	27893792	Surgical treatment, especially radical nephrectomy (RN), remains the most common strategy to treat Xp11.2 tRCC.	('Xp11.2', 'Var', (99, 105))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('RCC', 'Disease', (107, 110))
16483	27893792	Females with Xp11.2 tRCC in the age range of 18-45 years accounted for 81% of the patient population (17/21).	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('Xp11.2', 'Var', (13, 19))	('RCC', 'Disease', (21, 24))	('patient', 'Species', '9606', (82, 89))
16508	27893792	Hirobe and Masumori suggested that the combination of TFE3-IHC and FISH is an effective method to diagnose Xp11.2 tRCCs, which can improve specificity and potentially eliminate false-positives resulting from overstaining.	('TFE3-IHC', 'Gene', (54, 62))	('false', 'biological_process', 'GO:0071878', ('177', '182'))	('TFE3-IHC', 'Gene', '7030', (54, 62))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('Xp11.2', 'Var', (107, 113))	('false', 'biological_process', 'GO:0071877', ('177', '182'))	('specificity', 'MPA', (139, 150))	('improve', 'PosReg', (131, 138))
16509	27893792	In the report by Argani on 28 cases of Xp11.2 tRCC, there was a strong female (22 cases, 79%) and a slight right (14/22, 64%) preference, of which 22 cases (79%) were younger than 45 years.	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('Xp11.2', 'Var', (39, 45))
16515	27893792	Urologists and patients usually puzzled with the management between a completion nephrectomy and close surveillance when a patient was incidentally diagnosed with Xp11.2 tRCC after a partial nephrectomy.	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (15, 23))	('patient', 'Species', '9606', (123, 130))	('Xp11.2', 'Var', (163, 169))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))
16519	27893792	Herein, the treatment of Xp11.2 RCC by LNSS obtained a satisfactory result with a mean follow-up of 20 months.	('NSS', 'Chemical', '-', (40, 43))	('Xp11.2', 'Var', (25, 31))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))
16524	27893792	Since chemotherapy and radiotherapy proved to be invalid for Xp11 tRCC, the optimal and reliable adjuvant treatment remains to be developed.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('Xp11', 'Var', (61, 65))
16537	27893792	Nevertheless, a meta-analysis showed that Xp11.2 tRCCs showed a poorer prognostic than non-Xp11.2 translocation carcinomas in children and young adults.	('translocation carcinomas', 'Disease', 'MESH:D014178', (98, 122))	('Xp11.2', 'Var', (42, 48))	('translocation carcinomas', 'Disease', (98, 122))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('children', 'Species', '9606', (126, 134))	('poorer', 'NegReg', (64, 70))
16538	27893792	Similar to conventional RCCs, advanced TNM stage and inferior vena cava tumor thrombosis are the most significant factors that predict poor prognosis in Xp11 tRCC, which was verified by univariate and multivariate analyses in our study.	('RCC', 'Disease', (24, 27))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('TNM', 'Gene', (39, 42))	('inferior vena cava tumor thrombosis', 'Disease', (53, 88))	('vena cava tumor thrombosis', 'Phenotype', 'HP:0031041', (62, 88))	('inferior vena cava tumor thrombosis', 'Disease', 'MESH:D013479', (53, 88))	('TNM', 'Gene', '10178', (39, 42))	('RCC', 'Disease', (159, 162))	('Xp11', 'Var', (153, 157))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
16546	27893792	As its low-frequency, the reported Xp11.2 tRCCs which were diagnosed by FISH or PCR less than 150 all over the world.	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('Xp11.2', 'Var', (35, 41))
16553	27893792	Xp11.2 tRCC is a rare subset of RCC that mainly occurs in children and young females with gross hematuria.	('hematuria', 'Phenotype', 'HP:0000790', (96, 105))	('RCC', 'Disease', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('Xp11.2', 'Var', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('hematuria', 'Disease', (96, 105))	('gross hematuria', 'Phenotype', 'HP:0012587', (90, 105))	('hematuria', 'Disease', 'MESH:D006417', (96, 105))	('children', 'Species', '9606', (58, 66))
16554	27893792	The combination of the TFE3-IHC assay and FISH analysis is an accurate and effective approach to screen and confirm, respectively, the diagnosis of Xp11.2 tRCC.	('TFE3-IHC', 'Gene', (23, 31))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('TFE3-IHC', 'Gene', '7030', (23, 31))	('Xp11.2', 'Var', (148, 154))
16619	24690616	Approximately 50% to 84% of cases of sporadic clear cell RCC exhibit inactivation of the Von Hippel-Lindau tumor suppressor gene on chromosome 3p, with consequent accumulation of hypoxia-inducible factor and promotion of angiogenesis via overexpression of vascular endothelial growth factor (VEGF) and platelet-dervived growth factor.	('VEGF', 'Gene', (292, 296))	('vascular endothelial growth factor', 'Gene', (256, 290))	('inactivation', 'Var', (69, 81))	('promotion', 'PosReg', (208, 217))	('hypoxia', 'Disease', 'MESH:D000860', (179, 186))	('tumor suppressor', 'biological_process', 'GO:0051726', ('107', '123'))	('angiogenesis', 'biological_process', 'GO:0001525', ('221', '233'))	('chromosome', 'cellular_component', 'GO:0005694', ('132', '142'))	('Von Hippel-Lindau tumor suppressor', 'Gene', '7428', (89, 123))	('Von Hippel-Lindau tumor suppressor', 'Gene', (89, 123))	('angiogenesis', 'CPA', (221, 233))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('overexpression', 'PosReg', (238, 252))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('256', '290'))	('vascular endothelial growth factor', 'Gene', '7422', (256, 290))	('VEGF', 'Gene', '7422', (292, 296))	('accumulation', 'PosReg', (163, 175))	('hypoxia', 'Disease', (179, 186))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('107', '123'))
16657	24690616	The MRI findings in less common tumor subtypes such as Xp11.2 translocation RCC and clear cell papillary type as well as other histopathologic differentiations of RCC (eg, rhabdoid) have not been widely described.	('rhabdoid', 'Disease', (172, 180))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('RCC', 'Disease', (163, 166))	('translocation', 'Var', (62, 75))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('papillary type', 'Phenotype', 'HP:0007482', (95, 109))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('rhabdoid', 'Disease', 'MESH:D018335', (172, 180))	('tumor', 'Disease', (32, 37))
16723	24690616	Finally, one study reported that a predominant cystic component had a specificity of up to 94% for the prediction of low nuclear grade for clear cell RCC.	('low', 'Var', (117, 120))	('to 9', 'Species', '1214577', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))
16945	33947142	Downregulating either member of the PVT1/Mcl-1 axis inhibits proliferation and colony formation and promotes apoptosis.	('PVT1', 'Gene', '5820', (36, 40))	('apoptosis', 'CPA', (109, 118))	('formation', 'biological_process', 'GO:0009058', ('86', '95'))	('promotes', 'PosReg', (100, 108))	('inhibits', 'NegReg', (52, 60))	('Downregulating', 'Var', (0, 14))	('apoptosis', 'biological_process', 'GO:0097194', ('109', '118'))	('apoptosis', 'biological_process', 'GO:0006915', ('109', '118'))	('PVT1', 'Gene', (36, 40))
16947	33947142	On a molecular level, the most frequent cause of either sporadic or hereditary RCC is the inactivation of the von Hippel-Lindau (VHL) gene.	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('cause', 'Reg', (40, 45))	('VHL', 'Gene', (129, 132))	('VHL', 'Gene', '7428', (129, 132))	('von Hippel-Lindau', 'Gene', (110, 127))	('inactivation', 'Var', (90, 102))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('von Hippel-Lindau', 'Gene', '7428', (110, 127))	('RCC', 'Disease', (79, 82))
16948	33947142	Mutations causing the loss of heterozygosity of the 3p chromosome or hypermethylation of the VHL promotor are common in RCC patients.	('hypermethylation', 'Var', (69, 85))	('VHL', 'Gene', '7428', (93, 96))	('loss of', 'NegReg', (22, 29))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('VHL', 'Gene', (93, 96))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))	('patients', 'Species', '9606', (124, 132))
16949	33947142	Defective protein VHL enables the stabilization of the hypoxia-induced factor (HIF) protein family, which would be otherwise degraded in a proteasome.	('VHL', 'Gene', '7428', (18, 21))	('proteasome', 'cellular_component', 'GO:0000502', ('139', '149'))	('proteasome', 'molecular_function', 'GO:0004299', ('139', '149'))	('protein', 'Protein', (10, 17))	('protein', 'cellular_component', 'GO:0003675', ('84', '91'))	('hypoxia', 'Disease', 'MESH:D000860', (55, 62))	('stabilization', 'MPA', (34, 47))	('protein', 'cellular_component', 'GO:0003675', ('10', '17'))	('Defective', 'Var', (0, 9))	('hypoxia', 'Disease', (55, 62))	('VHL', 'Gene', (18, 21))
16952	33947142	tie the involvement of PVT1 in MYC and VHL regulation together (Figure 1), as their team identified a unique polymorphism at 8q24.21 associated with renal cancer susceptibility.	('regulation', 'biological_process', 'GO:0065007', ('43', '53'))	('PVT1', 'Gene', (23, 27))	('associated with', 'Reg', (133, 148))	('MYC', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('VHL', 'Gene', (39, 42))	('PVT1', 'Gene', '5820', (23, 27))	('renal cancer', 'Disease', (149, 161))	('VHL', 'Gene', '7428', (39, 42))	('polymorphism at', 'Var', (109, 124))	('MYC', 'Gene', '4609', (31, 34))	('renal cancer', 'Phenotype', 'HP:0009726', (149, 161))	('renal cancer', 'Disease', 'MESH:D007680', (149, 161))
16953	33947142	The polymorphism influences the expression of MYC and PVT1, as it is localized in the HIF-binding enhancer, affecting both the cellular MYC (c-MYC) gene and PVT1 gene.	('MYC', 'Gene', (136, 139))	('influences', 'Reg', (17, 27))	('binding', 'molecular_function', 'GO:0005488', ('90', '97'))	('PVT1', 'Gene', '5820', (54, 58))	('c-MYC', 'Gene', (141, 146))	('PVT1', 'Gene', (157, 161))	('MYC', 'Gene', '4609', (136, 139))	('PVT1', 'Gene', (54, 58))	('MYC', 'Gene', (46, 49))	('MYC', 'Gene', '4609', (143, 146))	('affecting', 'Reg', (108, 117))	('PVT1', 'Gene', '5820', (157, 161))	('c-MYC', 'Gene', '4609', (141, 146))	('expression', 'MPA', (32, 42))	('MYC', 'Gene', (143, 146))	('polymorphism', 'Var', (4, 16))	('MYC', 'Gene', '4609', (46, 49))
16954	33947142	The polymorphism's effect is restricted to renal tubular cells, and the renal cancer susceptibility depends on the genotype of the respective polymorphism site in the enhancer, affecting its accessibility to HIF proteins.	('affecting', 'Reg', (177, 186))	('polymorphism', 'Var', (142, 154))	('renal cancer', 'Disease', (72, 84))	('renal cancer', 'Phenotype', 'HP:0009726', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('renal cancer', 'Disease', 'MESH:D007680', (72, 84))	('accessibility to HIF proteins', 'MPA', (191, 220))
16955	33947142	pVHL defects enhanced expression of c-MYC and PVT1, hence the notorious upregulation of PVT1 in RCC.	('RCC', 'Disease', (96, 99))	('pVHL', 'Gene', '7428', (0, 4))	('PVT1', 'Gene', '5820', (46, 50))	('enhanced', 'PosReg', (13, 21))	('upregulation', 'PosReg', (72, 84))	('pVHL', 'Gene', (0, 4))	('c-MYC', 'Gene', '4609', (36, 41))	('PVT1', 'Gene', '5820', (88, 92))	('defects', 'Var', (5, 12))	('PVT1', 'Gene', (46, 50))	('c-MYC', 'Gene', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('expression', 'MPA', (22, 32))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('PVT1', 'Gene', (88, 92))
16956	33947142	The polymorphisms in the HIF-responding regulatory elements could affect renal tumorigenesis.	('affect', 'Reg', (66, 72))	('tumor', 'Disease', (79, 84))	('polymorphisms', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
16966	33947142	The authors further identified a new splicing variant of PVT1, whose levels were even higher in the tumor tissue and tumor cell lines than the levels of the full-length original splicing variant and had an even higher effect on the cell proliferation.	('splicing variant', 'Var', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('levels', 'MPA', (69, 75))	('PVT1', 'Gene', (57, 61))	('splicing', 'biological_process', 'GO:0045292', ('178', '186'))	('cell proliferation', 'biological_process', 'GO:0008283', ('232', '250'))	('higher', 'PosReg', (211, 217))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PVT1', 'Gene', '5820', (57, 61))	('splicing', 'biological_process', 'GO:0045292', ('37', '45'))	('higher', 'PosReg', (86, 92))	('cell proliferation', 'CPA', (232, 250))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
16968	33947142	An in-silico target prediction showed that miR-16-5p is a target of PVT1.	('miR-16-5p', 'Chemical', '-', (43, 52))	('PVT1', 'Gene', (68, 72))	('PVT1', 'Gene', '5820', (68, 72))	('miR-16-5p', 'Var', (43, 52))
16970	33947142	Moreover, the strong negative regulatory connection of PVT1 and miR-16-5p has been observed in colorectal cancer.	('negative', 'NegReg', (21, 29))	('colorectal cancer', 'Disease', (95, 112))	('miR-16-5p', 'Chemical', '-', (64, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('PVT1', 'Gene', (55, 59))	('miR-16-5p', 'Var', (64, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('PVT1', 'Gene', '5820', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
16972	33947142	In their work, they found the interactions of miR-145 miR-211, miR-216a, mIR-133a, and miR-133b with PVT1.	('miR-216a', 'Gene', (63, 71))	('mIR-133a', 'Var', (73, 81))	('PVT1', 'Gene', '5820', (101, 105))	('miR-216a', 'Gene', '406998', (63, 71))	('interactions', 'Interaction', (30, 42))	('miR-145', 'Gene', (46, 53))	('miR-133b', 'Gene', '442890', (87, 95))	('miR-145', 'Gene', '406937', (46, 53))	('miR-133b', 'Gene', (87, 95))	('miR-211', 'Var', (54, 61))	('PVT1', 'Gene', (101, 105))
16976	33947142	In PVT1, though, SP1 has been identified as a potential target of PVT1, miR-145, miR-133a, and miR-133b.	('miR-145', 'Gene', '406937', (72, 79))	('PVT1', 'Gene', (3, 7))	('miR-133a', 'Var', (81, 89))	('PVT1', 'Gene', (66, 70))	('miR-133b', 'Gene', '442890', (95, 103))	('miR-145', 'Gene', (72, 79))	('PVT1', 'Gene', '5820', (3, 7))	('miR-133b', 'Gene', (95, 103))	('PVT1', 'Gene', '5820', (66, 70))
17010	33947142	Dysregulation of the PVT1 expression is easily detectable and correlates with a specific clinical behavior and RCC subtype.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('Dysregulation', 'Var', (0, 13))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('PVT1', 'Gene', (21, 25))	('PVT1', 'Gene', '5820', (21, 25))
17081	24885240	Mann-Whitney test was used to detect differences between non-tumour and tumour tissues, and between CCRCCs with different Fuhrman's grade [G1/2 (low) vs. G3/4 (high)] and stage [pT1/2 (organ confined) vs. pT3/4 (non-organ confined)].	('pT1/2', 'Gene', (178, 183))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('pT3/4', 'Gene', (205, 210))	('non-tumour', 'Disease', (57, 67))	('pT1/2', 'Gene', '58492', (178, 183))	('non-tumour', 'Disease', 'MESH:D009369', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('pT3/4', 'Gene', '7694', (205, 210))	('tumour', 'Disease', (61, 67))	('G3/4', 'Var', (154, 158))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('CCRCCs', 'Disease', (100, 106))
17088	24885240	Table 2 represents GAP activity in the different grades and stages of CCRCC group (Low grade: G1-G2, n = 24 vs. High grade: G3-G4, n = 26; Low stage: T1-T2, n = 34 vs. High stage: T3-T4, n = 16).	('GAP', 'Gene', '2028', (19, 22))	('GAP', 'Gene', (19, 22))	('T1-T2', 'Var', (150, 155))	('CCRCC', 'Disease', (70, 75))	('GAP activity', 'molecular_function', 'GO:0005096', ('19', '31'))
17129	24885240	Furthermore, intracellular angiotensin II has been reported to also induce cell proliferation in several tissues.	('induce', 'PosReg', (68, 74))	('cell proliferation in several tissues', 'CPA', (75, 112))	('intracellular', 'Var', (13, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('75', '93'))	('angiotensin II', 'Gene', '183', (27, 41))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))	('angiotensin II', 'Gene', (27, 41))
17152	33535553	We concentrated on potentially oncocytoma-specific miRNAs (miRNA-424-5p, miRNA-146b-5p, miRNA-183-5p, miRNA-218-5p), pRCC-specific (miRNA-127-3p, miRNA-139-5p) and ccRCC-specific miRNAs (miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p and miRNA-204-5p, 21-5p, miRNA-224-5p, miRNA-155-5p, miRNA-210-3p) and validated their expression in an independent sample set.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('miRNA-204', 'Gene', (233, 242))	('miRNA-146b', 'Gene', '574447', (73, 83))	('oncocytoma', 'Disease', (31, 41))	('miRNA-155', 'Gene', (268, 277))	('miRNA-21', 'Gene', '406991', (102, 110))	('miRNA-363-3p', 'Var', (216, 228))	('miRNA-204', 'Gene', '406987', (233, 242))	('oncocytoma-', 'Phenotype', 'HP:0011798', (31, 42))	('miRNA-21', 'Gene', (102, 110))	('miRNA-200c-3p', 'Var', (187, 200))	('miRNA-146b', 'Gene', (73, 83))	('miRNA-224', 'Gene', '407009', (254, 263))	('pRCC', 'Gene', '5546', (117, 121))	('miRNA-127-3p', 'Var', (132, 144))	('21-5p', 'Var', (247, 252))	('miRNA-21', 'Gene', '406991', (282, 290))	('oncocytoma', 'Disease', 'MESH:D018249', (31, 41))	('miRNA-183', 'Gene', '406959', (88, 97))	('miRNA-424', 'Gene', (59, 68))	('RCC', 'Disease', (118, 121))	('RCC', 'Disease', (166, 169))	('miRNA-362-5p', 'Var', (202, 214))	('miRNA-183', 'Gene', (88, 97))	('miRNA-21', 'Gene', (282, 290))	('pRCC', 'Gene', (117, 121))	('miRNA-155', 'Gene', '406947', (268, 277))	('miRNA-224', 'Gene', (254, 263))	('miRNA-424', 'Gene', '494336', (59, 68))
17175	33535553	Mature miRNA can occur in isoforms (iso-miRNA) processed from the same pri-miRNA and different at 5' and 3' ends as a result of inaccurate cleavage by DROSHA and DICER1.	('cleavage', 'MPA', (139, 147))	('inaccurate', 'Var', (128, 138))	('DROSHA', 'Gene', '29102', (151, 157))	('DICER1', 'Gene', (162, 168))	('DICER1', 'Gene', '23405', (162, 168))	('DROSHA', 'Gene', (151, 157))
17176	33535553	Deregulations of miRNA expression have been previously correlated with changes in protein levels engaged in proliferation, motility or cell invasiveness and in consequence promotion of tumor development and growth.	('changes', 'Reg', (71, 78))	('tumor', 'Disease', (185, 190))	('promotion', 'PosReg', (172, 181))	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('Deregulations', 'Var', (0, 13))	('growth', 'CPA', (207, 213))	('proliferation', 'CPA', (108, 121))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('protein levels engaged', 'MPA', (82, 104))	('miRNA', 'Protein', (17, 22))	('cell invasiveness', 'CPA', (135, 152))	('motility', 'CPA', (123, 131))
17178	33535553	The most commonly identified as downregulated in ccRCC tumor samples were miR-141, miRNA-200c.	('downregulated', 'NegReg', (32, 45))	('ccRCC tumor', 'Disease', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ccRCC tumor', 'Disease', 'MESH:D009369', (49, 60))	('miR-141', 'Gene', (74, 81))	('miRNA-200c', 'Var', (83, 93))	('miR-141', 'Gene', '406933', (74, 81))
17202	33535553	Specific "iso-miRNA primers," which discriminate miRNA-363-3p or miRNA-224-5p shorter isoforms and amplify longer isoforms, were used in qPCR.	('miRNA-224', 'Gene', '407009', (65, 74))	('miRNA-224', 'Gene', (65, 74))	('miRNA-363-3p', 'Var', (49, 61))
17212	33535553	After comparison of all available data sets eight commonly deregulated miRNAs in ccRCC were selected (Figure 1c) and those included: miR-200c-3p, miR-362-5p, miR-363-3p and miR-204-5p as downregulated and miR-21-5p, miR-224-5p, miR-155-5p and miR-210-3p as upregulated (Figure 1d).	('downregulated', 'NegReg', (187, 200))	('miR-210-3p', 'Chemical', '-', (243, 253))	('miR-200c', 'Gene', (133, 141))	('miR-363-3p', 'Var', (158, 168))	('miR-362', 'Gene', (146, 153))	('miR-155', 'Gene', (228, 235))	('miR-210-3p', 'Var', (243, 253))	('RCC', 'Disease', (83, 86))	('miR-362', 'Gene', '574030', (146, 153))	('miR-155', 'Gene', '406947', (228, 235))	('miR-363-3p', 'Chemical', '-', (158, 168))	('miR-21-5p', 'Gene', (205, 214))	('upregulated', 'PosReg', (257, 268))	('miR-21-5p', 'Gene', '406997', (205, 214))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('miR-204-5p', 'Chemical', '-', (173, 183))	('miR-204-5p', 'Var', (173, 183))	('miR-224', 'Gene', '407009', (216, 223))	('miR-224', 'Gene', (216, 223))	('miR-200c', 'Gene', '406985', (133, 141))
17214	33535553	Additionally, this analysis suggests that deregulation of miR-21-5p, miR-155-5p and miR-210-3p could be ccRCC-specific.	('miR-21-5p', 'Gene', (58, 67))	('deregulation', 'Var', (42, 54))	('miR-21-5p', 'Gene', '406997', (58, 67))	('miR-155', 'Gene', '406947', (69, 76))	('miR-210-3p', 'Var', (84, 94))	('RCC', 'Disease', (106, 109))	('miR-155', 'Gene', (69, 76))	('miR-210-3p', 'Chemical', '-', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
17223	33535553	According to high-throughput data miRNA-127-3p and miRNA-139-5p should be downregulated in pRCC tumors.	('miRNA-139-5p', 'Var', (51, 63))	('pRCC tumors', 'Disease', 'MESH:D009369', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('miRNA-127-3p', 'Var', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pRCC tumors', 'Disease', (91, 102))	('downregulated', 'NegReg', (74, 87))
17224	33535553	Although, in contrast to previous reports, in our sample set miRNA-127-3p appears to be significantly upregulated in pRCC (29-fold change, p < 0.01).	('pRCC', 'Gene', '5546', (117, 121))	('upregulated', 'PosReg', (102, 113))	('miRNA-127-3p', 'Var', (61, 73))	('pRCC', 'Gene', (117, 121))
17225	33535553	Increase in expression of miRNA-139-5p does not significantly differ in pRCC and oncocytoma (Figure 2b), however miRNA-139-5p appears to be downregulated in ccRCC (0.2-fold change, p = 0.04).	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('downregulated', 'NegReg', (140, 153))	('pRCC', 'Gene', '5546', (72, 76))	('oncocytoma', 'Disease', (81, 91))	('oncocytoma', 'Disease', 'MESH:D018249', (81, 91))	('miRNA-139-5p', 'Var', (113, 125))	('pRCC', 'Gene', (72, 76))	('RCC', 'Disease', (159, 162))
17231	33535553	Only miR-204-5p, was significantly downregulated in all RCC tumor types as compared to controls (ccRCC, 0.09-fold change, p = 0.011; pRCC, 0.006-fold change, p < 0.01; oncocytoma, 0.03-fold change, p < 0.001).	('RCC', 'Disease', (56, 59))	('pRCC', 'Gene', (133, 137))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC tumor', 'Disease', 'MESH:C538614', (56, 65))	('miR-204-5p', 'Var', (5, 15))	('miR-204-5p', 'Chemical', '-', (5, 15))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('RCC', 'Disease', (99, 102))	('pRCC', 'Gene', '5546', (133, 137))	('oncocytoma', 'Disease', (168, 178))	('RCC', 'Disease', (134, 137))	('downregulated', 'NegReg', (35, 48))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('oncocytoma', 'Disease', 'MESH:D018249', (168, 178))	('RCC tumor', 'Disease', (56, 65))
17234	33535553	There was no significant change in the expression of miR-21-5p, miR-224-5p and miR-210-3p among the subtypes (Figure 2d).	('miR-210-3p', 'Chemical', '-', (79, 89))	('miR-224', 'Gene', (64, 71))	('miR-224', 'Gene', '407009', (64, 71))	('miR-21-5p', 'Gene', (53, 62))	('miR-21-5p', 'Gene', '406997', (53, 62))	('miR-210-3p', 'Var', (79, 89))
17237	33535553	Figure 2e shows no significant changes in different tumor grades in case of miRNA-200c-3p.	('tumor', 'Disease', (52, 57))	('miRNA-200c-3p', 'Var', (76, 89))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
17238	33535553	miRNA-200c-3p is one of most commonly identified as ccRCC downregulated miRNA.	('miRNA-200c-3p', 'Var', (0, 13))	('RCC', 'Disease', (54, 57))	('miRNA', 'MPA', (72, 77))	('downregulated', 'NegReg', (58, 71))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
17242	33535553	Consistent downregulation throughout all tumor grades were observed in case of miR-362-5p (G1, 0.09-fold change, p < 0.01; G3, 0.03-fold change, p < 0.001; G4, 0.09-fold change, p = 0.013), miR-363-3p (G1, 0.3-fold change, p = 0.019; G3, 0.08-fold change, p < 0.001; G4, 0.07-fold change, p < 0.01) and miR-204-5p (G1, 0.3-fold change, p = 0.042; G3, 0.01-fold change, p < 0.001; G4, 0.05-fold change, p = 0.02) (Figure 2e).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('miR-204-5p', 'Var', (303, 313))	('miR-204-5p', 'Chemical', '-', (303, 313))	('miR-362', 'Gene', '574030', (79, 86))	('tumor', 'Disease', (41, 46))	('miR-362', 'Gene', (79, 86))	('downregulation', 'NegReg', (11, 25))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miR-363-3p', 'Var', (190, 200))	('miR-363-3p', 'Chemical', '-', (190, 200))
17244	33535553	The following miRNAs displayed elevated expression in all samples: miR-210-3p (G1, 21-fold change, p < 0.001; G2, 7.4-fold change, p = 0.013; G3, 12-fold change, p < 0.01; G4, 11-fold change, p < 0.01) and miR-155-5p (G1, 22-fold change, p < 0.01; G2, 7.4-fold change, p = 0.02; G3, 8-fold change, p = 0.03; G4, 47-fold change, p < 0.001).	('expression', 'MPA', (40, 50))	('miR-155', 'Gene', '406947', (206, 213))	('miR-155', 'Gene', (206, 213))	('miR-210-3p', 'Var', (67, 77))	('elevated', 'PosReg', (31, 39))	('miR-210-3p', 'Chemical', '-', (67, 77))
17250	33535553	pRCC could be classified using miRNA-362-5p (AUC = 0.87, p < 0.001), miRNA-363-3p (AUC = 0.75, p = 0.03), miRNA-204-5p (AUC = 0.9, p < 0.001), miRNA-21-5p (AUC = 0.79, p = 0.02) and miRNA-210-3p (AUC = 0.86, p = 0.01) while oncocytoma with miRNA-204-5p (AUC = 0.9, p < 0.001) and miRNA-224-5p (AUC = 0.79, p < 0.01).	('oncocytoma', 'Disease', 'MESH:D018249', (224, 234))	('miRNA-21', 'Gene', (182, 190))	('miRNA-204', 'Gene', (106, 115))	('miRNA-224', 'Gene', (280, 289))	('miRNA-363-3p', 'Var', (69, 81))	('miRNA-204', 'Gene', '406987', (106, 115))	('pRCC', 'Gene', (0, 4))	('miRNA-204', 'Gene', (240, 249))	('miRNA-224', 'Gene', '407009', (280, 289))	('miRNA-204', 'Gene', '406987', (240, 249))	('miRNA-21', 'Gene', '406991', (143, 151))	('miRNA-21', 'Gene', '406991', (182, 190))	('pRCC', 'Gene', '5546', (0, 4))	('oncocytoma', 'Disease', (224, 234))	('miRNA-21', 'Gene', (143, 151))
17251	33535553	Furthermore, ccRCC could be significantly distinguished from pRCC with miRNA-362-5p (AUC = 0.76, p < 0.01) and miRNA-155-5p (AUC = 0.79, p < 0.01) or from oncocytoma with miRNA-155-5p (AUC = 0.81, p < 0.01).	('miRNA-362-5p', 'Var', (71, 83))	('oncocytoma', 'Disease', 'MESH:D018249', (155, 165))	('pRCC', 'Gene', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('miRNA-155', 'Gene', (111, 120))	('miRNA-155', 'Gene', '406947', (171, 180))	('miRNA-155', 'Gene', (171, 180))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('miRNA-155', 'Gene', '406947', (111, 120))	('oncocytoma', 'Disease', (155, 165))
17258	33535553	Mature miRNA could occur in isoforms that vary in length or presence of poly(A) or poly(U) tails on 3' end.	('poly(A)', 'Chemical', 'MESH:D011061', (72, 79))	('poly(A', 'Protein', (72, 78))	('poly(U)', 'Chemical', 'MESH:D011072', (83, 90))	('poly(U) tails', 'Var', (83, 96))
17262	33535553	As shown in Figure 4a (upper panel), among four downregulated miRNAs, two: miR-363-3p and miR-204-5p exhibit significantly different isoform expression pattern in ccRCC tumors.	('miR-204-5p', 'Chemical', '-', (90, 100))	('miR-363-3p', 'Chemical', '-', (75, 85))	('isoform expression', 'MPA', (133, 151))	('different', 'Reg', (123, 132))	('miR-204-5p', 'Var', (90, 100))	('miR-363-3p', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ccRCC tumors', 'Disease', 'MESH:D009369', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('ccRCC tumors', 'Disease', (163, 175))
17263	33535553	In case of miR-363-3p, shortening of 3' end is more frequent with simultaneous reduction of elongation, with 67% and 14% contribution as compared to control: 52% and 20%, respectively (p < 0.01 and p = 0.047, respectively).	("3' end", 'MPA', (37, 43))	('miR-363-3p', 'Var', (11, 21))	('shortening', 'Var', (23, 33))	('miR-363-3p', 'Chemical', '-', (11, 21))	('reduction', 'NegReg', (79, 88))	('elongation', 'CPA', (92, 102))
17264	33535553	Similarly, poly(U) addition is more common in non-ccRCC tissue (control 15%, ccRCC 7.3%; p < 0.01).	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('poly(U)', 'Chemical', 'MESH:D011072', (11, 18))	('poly(U) addition', 'Var', (11, 27))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
17266	33535553	In the group of potentially ccRCC-specific, upregulated miRNAs (Figure 4a lower panel) miRNAs miR-21-5p displayed slight, less frequent, though statistically significant modifications, with addition of poly(A) (control 4%, ccRCC 3%; p < 0.001) and poly(U) (control 0.3%, ccRCC 0.2%).	('poly(U)', 'Chemical', 'MESH:D011072', (248, 255))	('miRNAs', 'MPA', (56, 62))	('poly(U', 'Var', (248, 254))	('upregulated', 'PosReg', (44, 55))	('RCC', 'Disease', (225, 228))	('miR-21-5p', 'Gene', (94, 103))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('miR-21-5p', 'Gene', '406997', (94, 103))	('RCC', 'Disease', (30, 33))	('RCC', 'Disease', (273, 276))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (273, 276))	('poly(A', 'Var', (202, 208))	('poly(A)', 'Chemical', 'MESH:D011061', (202, 209))
17270	33535553	Specific primers used in qPCR ("iso-miRNA primer") (Figure 4b,e) discriminate miRNA-363-3p and miRNA-224-5p shorter isoforms and amplify longer isoforms.	('miRNA-363-3p', 'Var', (78, 90))	('miRNA-224', 'Gene', '407009', (95, 104))	('miRNA-224', 'Gene', (95, 104))	('amplify', 'MPA', (129, 136))
17294	33535553	Chromosomal rearrangements which are ccRCC drivers occur decades before diagnosis in childhood or adolescence which makes early detection of the diseases difficult.	('RCC', 'Disease', (39, 42))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('Chromosomal rearrangements', 'Var', (0, 26))
17300	33535553	Based on the meta-analysis ccRCC could be potentially classified by the comparison of expression levels of eight miRNAs: miRNA-200c-3p, miRNA-362-5p, miRNA-363-3p, miRNA-204-5p, miRNA-21-5p, miRNA-224-5p, miRNA-155-5p and miRNA-210-3p.	('miRNA-362-5p', 'Var', (136, 148))	('miRNA-155', 'Gene', '406947', (205, 214))	('miRNA-21', 'Gene', '406991', (222, 230))	('RCC', 'Disease', (29, 32))	('miRNA-21', 'Gene', '406991', (178, 186))	('miRNA-204', 'Gene', (164, 173))	('miRNA-363-3p', 'Var', (150, 162))	('miRNA-224', 'Gene', (191, 200))	('miRNA-200c-3p', 'Var', (121, 134))	('miRNA-155', 'Gene', (205, 214))	('miRNA-224', 'Gene', '407009', (191, 200))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('miRNA-204', 'Gene', '406987', (164, 173))	('miRNA-21', 'Gene', (222, 230))	('miRNA-21', 'Gene', (178, 186))
17311	33535553	Many miRNA-210-3p targets are engaged in angiogenesis, cell survival and differentiation miRNA-200c-3p is one of the most significantly downregulated miRNAs in ccRCC tumors.	('downregulated', 'NegReg', (136, 149))	('miRNA-21', 'Gene', '406991', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('miRNA-200c-3p', 'Var', (89, 102))	('angiogenesis', 'biological_process', 'GO:0001525', ('41', '53'))	('miRNA-21', 'Gene', (5, 13))	('ccRCC tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('ccRCC tumors', 'Disease', (160, 172))
17312	33535553	miRNA-200c is member of miRNA-200 family (miRNA-200a, miRNA-200b, miRNA-200c, miRNA-141 and miRNA-429), commonly deregulated in other cancer types.	('miRNA-200b', 'Var', (54, 64))	('miRNA-141', 'Var', (78, 87))	('cancer', 'Disease', (134, 140))	('deregulated', 'PosReg', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('miRNA-200c', 'Var', (66, 76))	('miRNA-429', 'Var', (92, 101))	('miRNA-200c', 'Gene', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
17314	33535553	miRNA-362-5p has been classified as oncogenic in solid tumors and could be a potential therapeutic target or prognostic factor for human cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('miRNA-362-5p', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (131, 136))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('cancers', 'Disease', (137, 144))
17316	33535553	Its downregulation was reported in cervical cancer promotes vascular invasion and metastasis miRNA-363-3p is well known as miRNA with an anti-tumor role in many human cancers such as hepatocellular carcinoma and lung cancer.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('hepatocellular carcinoma', 'Disease', (183, 207))	('cancer', 'Disease', (167, 173))	('vascular invasion', 'CPA', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lung cancer', 'Disease', (212, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('promotes', 'PosReg', (51, 59))	('cancers', 'Disease', (167, 174))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (183, 207))	('tumor', 'Disease', (142, 147))	('downregulation', 'NegReg', (4, 18))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Disease', (44, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (183, 207))	('cancer', 'Disease', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('metastasis', 'CPA', (82, 92))	('miRNA-363-3p', 'Var', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
17324	33535553	Other interesting examples are potential targets of miRNA-362-3p belong to homotypic fusion and vacuole protein sorting (HOPS) complex (Table 1, Table S3 and Figure S4a), controlling cell homeostasis, which dysfunctions are associated with various cancer types including renal cancers.	('cancer', 'Disease', (248, 254))	('renal cancers', 'Disease', (271, 284))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('renal cancer', 'Phenotype', 'HP:0009726', (271, 283))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('miRNA-362-3p', 'Var', (52, 64))	('HOPS) complex', 'cellular_component', 'GO:0030897', ('121', '134'))	('vacuole', 'cellular_component', 'GO:0005773', ('96', '103'))	('associated', 'Reg', (224, 234))	('protein', 'cellular_component', 'GO:0003675', ('104', '111'))	('homeostasis', 'biological_process', 'GO:0042592', ('188', '199'))	('renal cancers', 'Disease', 'MESH:D007680', (271, 284))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
17331	33535553	As a result of our meta-analysis, we would like to propose a miRNA panel that could potentially aid RCC classification, with miRNA-362-5p, miRNA-363-3p, miRNA-224-5p, miRNA-155-5p and miRNA-210-3p as classifiers of ccRCC, miRNA-362-5p, miRNA-363-3p, miRNA-21-5p, miRNA-204-5p as characteristic for pRCC and miRNA-204-5p and miRNA-224-5p for oncocytoma (Figure 1, Figure 2 and Figure 3).	('miRNA-21', 'Gene', '406991', (184, 192))	('miRNA-204', 'Gene', '406987', (307, 316))	('pRCC', 'Gene', (298, 302))	('miRNA-21', 'Gene', (184, 192))	('miRNA-363-3p', 'Var', (236, 248))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', 'MESH:C538614', (299, 302))	('miRNA-204', 'Gene', (263, 272))	('miRNA-224', 'Gene', (324, 333))	('miRNA-224', 'Gene', '407009', (153, 162))	('miRNA-362-5p', 'Var', (222, 234))	('oncocytoma', 'Disease', 'MESH:D018249', (341, 351))	('RCC', 'Disease', (217, 220))	('miRNA-204', 'Gene', '406987', (263, 272))	('miRNA-155', 'Gene', '406947', (167, 176))	('pRCC', 'Gene', '5546', (298, 302))	('miRNA-204', 'Gene', (307, 316))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('miRNA-224', 'Gene', '407009', (324, 333))	('miRNA-21', 'Gene', '406991', (250, 258))	('miRNA-224', 'Gene', (153, 162))	('miRNA-21', 'Gene', (250, 258))	('miRNA-155', 'Gene', (167, 176))	('RCC', 'Disease', (100, 103))	('oncocytoma', 'Disease', (341, 351))	('RCC', 'Disease', (299, 302))
17336	33535553	Regrettably, we did not validate the alteration of miRNA-200c-3p expression in ccRCC tumors likely due to low specificity of the qPCR primer.	('ccRCC tumors', 'Disease', 'MESH:D009369', (79, 91))	('ccRCC tumors', 'Disease', (79, 91))	('miRNA-200c-3p', 'Var', (51, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
17363	31852068	Here we describe the clinical case and radiological and nuclear medicine imaging investigations performed by our patient, highlighting that 18F-FDG PET/CT shows greater adequacy in assessing the response to therapy, avoiding premature drug discontinuation, and ensuring better management of a patient with advanced PRCC.	('PRCC', 'Disease', 'MESH:D002292', (315, 319))	('patient', 'Species', '9606', (113, 120))	('18F-FDG', 'Chemical', 'MESH:D019788', (140, 147))	('PRCC', 'Phenotype', 'HP:0006766', (315, 319))	('PRCC', 'Disease', (315, 319))	('patient', 'Species', '9606', (293, 300))	('premature drug discontinuation', 'Phenotype', 'HP:0020172', (225, 255))	('RCC', 'Phenotype', 'HP:0005584', (316, 319))	('18F-FDG', 'Var', (140, 147))
17387	31852068	At the same time there was a deterioration in performance status (from ECOG 0-1 to ECOG 2-3), anemia (HGB 9.3 g/dl) and liver function index (ALT 186 U/L, AST 75 U/L, ALP 1500 U/L).	('anemia', 'Disease', 'MESH:D000740', (94, 100))	('AST', 'Gene', (155, 158))	('liver function index', 'MPA', (120, 140))	('ALT', 'Var', (142, 145))	('anemia', 'Phenotype', 'HP:0001903', (94, 100))	('ALP', 'Gene', (167, 170))	('AST', 'Gene', '26503', (155, 158))	('performance status', 'MPA', (46, 64))	('ALT', 'molecular_function', 'GO:0004021', ('142', '145'))	('ALP', 'Gene', '250', (167, 170))	('anemia', 'Disease', (94, 100))
17404	31852068	The overall survival (OS) of PRCC patients treated with targeted therapy is significantly longer than the OS of those not treated with targeted therapy (median 22.5 vs 6.3 months).	('PRCC', 'Phenotype', 'HP:0006766', (29, 33))	('PRCC', 'Disease', (29, 33))	('targeted therapy', 'Var', (56, 72))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (34, 42))	('PRCC', 'Disease', 'MESH:D002292', (29, 33))	('overall survival', 'MPA', (4, 20))
17407	31852068	Regarding patients with PRCC, 3 randomized, phase 2 trials showed a longer progression-free survival in patients treated with sunitinib compared to everolimus.	('sunitinib', 'Var', (126, 135))	('PRCC', 'Disease', 'MESH:D002292', (24, 28))	('everolimus', 'Chemical', 'MESH:C107135', (148, 158))	('longer', 'PosReg', (68, 74))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('sunitinib', 'Chemical', 'MESH:C473478', (126, 135))	('PRCC', 'Phenotype', 'HP:0006766', (24, 28))	('patients', 'Species', '9606', (10, 18))	('PRCC', 'Disease', (24, 28))	('patients', 'Species', '9606', (104, 112))	('progression-free survival', 'CPA', (75, 100))
17443	31484429	The cytogenetic differences are a trisomy 7 and 17 in pRCC type I and the loss of 1p and 3p in pRCC type II tumors.	('pRCC type II tumors', 'Disease', 'MESH:D009369', (95, 114))	('trisomy 7', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pRCC', 'Gene', (95, 99))	('pRCC type II tumors', 'Disease', (95, 114))	('loss', 'NegReg', (74, 78))	('pRCC', 'Gene', '5546', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('pRCC', 'Gene', '5546', (95, 99))	('pRCC', 'Gene', (54, 58))
17444	31484429	Intra- and interchromosomal rearrangements are significantly increased in pRCC type II, leading frequently to a gene fusion involving the transcription factor TFE3, by which the promoter substitution appears to be the key molecular event, causing dysregulation of many signaling pathways already implicated in carcinogenesis.	('TFE3', 'Gene', (159, 163))	('signaling', 'biological_process', 'GO:0023052', ('269', '278'))	('transcription factor', 'molecular_function', 'GO:0000981', ('138', '158'))	('TFE3', 'Gene', '7030', (159, 163))	('increased', 'PosReg', (61, 70))	('pRCC', 'Gene', '5546', (74, 78))	('causing', 'Reg', (239, 246))	('carcinogenesis', 'Disease', 'MESH:D063646', (310, 324))	('signaling pathways', 'Pathway', (269, 287))	('transcription', 'biological_process', 'GO:0006351', ('138', '151'))	('dysregulation', 'MPA', (247, 260))	('carcinogenesis', 'Disease', (310, 324))	('substitution', 'Var', (187, 199))	('pRCC', 'Gene', (74, 78))
17445	31484429	Type I of this malignant tumor is characterized by frequent mutations in the MET oncogene, including alternative splice variants.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('malignant tumor', 'Disease', (15, 30))	('MET oncogene', 'Gene', (77, 89))	('malignant tumor', 'Disease', 'MESH:D009369', (15, 30))	('mutations', 'Var', (60, 69))
17447	31484429	Type II has more likely mutations such as SETD2, NF2, and the inactivation of CDKN2A by mutation, deletion, or CpG island hypermethylation.	('mutation', 'Var', (88, 96))	('NF2', 'Gene', (49, 52))	('CDKN2A', 'Gene', (78, 84))	('inactivation', 'NegReg', (62, 74))	('deletion', 'Var', (98, 106))	('CDKN2A', 'Gene', '1029', (78, 84))	('SETD2', 'Gene', '29072', (42, 47))	('NF2', 'Gene', '4771', (49, 52))	('SETD2', 'Gene', (42, 47))
17448	31484429	Structural variants were observed in sporadic events, including duplications in EGFR and HIF1A, and deletions in SDHB, DNMT3A, and STAG2.	('SDHB', 'Gene', '6390', (113, 117))	('HIF1A', 'Gene', (89, 94))	('HIF1A', 'Gene', '3091', (89, 94))	('duplications', 'Var', (64, 76))	('STAG2', 'Gene', (131, 136))	('STAG2', 'Gene', '10735', (131, 136))	('DNMT3A', 'Gene', (119, 125))	('SDHB', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (80, 84))	('DNMT3A', 'Gene', '1788', (119, 125))	('EGFR', 'Gene', (80, 84))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('deletions', 'Var', (100, 109))
17451	31484429	pRCC type II tumors are more likely to metastasize, and FH mutations and DNA hypermethylation were found to be correlate with inferior prognosis.	('N', 'Chemical', 'MESH:D009584', (74, 75))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('pRCC type II tumors', 'Disease', 'MESH:D009369', (0, 19))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('73', '93'))	('pRCC type II tumors', 'Disease', (0, 19))	('metastasize', 'CPA', (39, 50))	('FH', 'Disease', 'OMIM:143890', (56, 58))	('mutations', 'Var', (59, 68))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hypermethylation', 'Var', (77, 93))
17454	31484429	Nephrectomy or partial nephrectomy and in the presence of metastases, and treatment with vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors are currently considered the standard treatments.	('VEGF', 'Gene', (125, 129))	('partial', 'Var', (15, 22))	('vascular endothelial growth factor', 'Gene', (89, 123))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('vascular endothelial growth factor', 'Gene', '7422', (89, 123))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('89', '123'))	('VEGF', 'Gene', '7422', (125, 129))	('metastases', 'Disease', (58, 68))	('mammalian target of rapamycin', 'Gene', '2475', (135, 164))	('mammalian target of rapamycin', 'Gene', (135, 164))	('metastases', 'Disease', 'MESH:D009362', (58, 68))
17464	31484429	The assembly of mitochondrial whole-exome sequencing (WES) reads derived from 19 patients with pRCC and matched with adjacent healthy kidney tissues showed adequate coverage and quality for reliable mtDNA reconstruction and variant calling (Table S3).	('mtDNA', 'cellular_component', 'GO:0000262', ('199', '204'))	('pRCC', 'Gene', (95, 99))	('patients', 'Species', '9606', (81, 89))	('pRCC', 'Gene', '5546', (95, 99))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('variant', 'Var', (224, 231))
17466	31484429	A total of 260 somatic mtDNA mutations were detected in pRCC samples.	('N', 'Chemical', 'MESH:D009584', (26, 27))	('pRCC', 'Gene', '5546', (56, 60))	('mutations', 'Var', (29, 38))	('mtDNA', 'cellular_component', 'GO:0000262', ('23', '28'))	('mtDNA', 'Gene', (23, 28))	('detected', 'Reg', (44, 52))	('pRCC', 'Gene', (56, 60))
17469	31484429	An analysis of copy number variations (CNV) revealed a fragmented pattern of chromosomal gains and losses spread over all chromosomes in all pRCC types (Figure S2), but no clear chromosomal patterns were identified.	('pRCC', 'Gene', '5546', (141, 145))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('chromosomal', 'Var', (77, 88))	('losses', 'NegReg', (99, 105))	('gains', 'PosReg', (89, 94))	('pRCC', 'Gene', (141, 145))
17486	31484429	This was explained by several specific low-level heteroplasmic mtDNA mutations of the CI genes in renal oncocytomas.	('mutations', 'Var', (69, 78))	('renal oncocytomas', 'Phenotype', 'HP:0011798', (98, 115))	('mtDNA', 'cellular_component', 'GO:0000262', ('63', '68'))	('renal oncocytomas', 'Disease', (98, 115))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('renal oncocytomas', 'Disease', 'MESH:C537750', (98, 115))
17527	31484429	Tracing of 13C515N glutamic acid revealed a significant and (6.3-, 3.9-fold) increase of 13C515N proline after 12 h in the pRCC derived cell lines Caki-2 and ACHN versus HK-2 (Figure 6K).	('13C515N proline', 'Chemical', 'MESH:C513342', (89, 104))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('HK-2', 'Gene', '3099', (170, 174))	('pRCC', 'Gene', (123, 127))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('HK-2', 'molecular_function', 'GO:0008256', ('170', '174'))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('HK-2', 'Gene', (170, 174))	('increase', 'PosReg', (77, 85))	('pRCC', 'Gene', '5546', (123, 127))	('13C515N glutamic acid', 'Chemical', 'MESH:C513342', (11, 32))	('13C515N', 'Var', (89, 96))
17537	31484429	Blocking of mTOR activity was shown to augment shuttling of pyruvate into gluconeogenesis, which results in futile cycling of glucose that finally leads to a halt in cancer cell proliferation and ultimately to cell death.	('cancer', 'Disease', (166, 172))	('halt', 'NegReg', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('leads to', 'Reg', (147, 155))	('results in', 'Reg', (97, 107))	('Blocking', 'Var', (0, 8))	('cell death', 'biological_process', 'GO:0008219', ('210', '220'))	('cell proliferation', 'biological_process', 'GO:0008283', ('173', '191'))	('shuttling of pyruvate into gluconeogenesis', 'MPA', (47, 89))	('mTOR', 'Gene', '2475', (12, 16))	('mTOR', 'Gene', (12, 16))	('gluconeogenesis', 'biological_process', 'GO:0006094', ('74', '89'))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('glucose', 'Chemical', 'MESH:D005947', (126, 133))	('augment', 'PosReg', (39, 46))	('futile cycling of glucose', 'MPA', (108, 133))	('pyruvate', 'Chemical', 'MESH:D011773', (60, 68))
17551	31484429	Furthermore, silencing ALDOA expression in ccRCC cell lines decreased their proliferative, migratory, and invasive abilities, while ALDOA overexpression increased these abilities.	('proliferative', 'CPA', (76, 89))	('decreased', 'NegReg', (60, 69))	('ALDOA', 'Gene', (23, 28))	('ALDOA', 'Gene', (132, 137))	('invasive abilities', 'Disease', 'MESH:D009361', (106, 124))	('silencing', 'Var', (13, 22))	('migratory', 'CPA', (91, 100))	('invasive abilities', 'Disease', (106, 124))	('ALDOA', 'Gene', '226', (132, 137))	('ALDOA', 'Gene', '226', (23, 28))	('RCC', 'Disease', 'MESH:D002292', (45, 48))	('RCC', 'Disease', (45, 48))
17571	31484429	This is in agreement with another study, which found that glutamine dependence in ccRCC suppresses oxidative stress.	('suppresses', 'NegReg', (88, 98))	('oxidative stress', 'MPA', (99, 115))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('glutamine dependence', 'Var', (58, 78))	('glutamine', 'Chemical', 'MESH:C578860', (58, 67))	('oxidative stress', 'Phenotype', 'HP:0025464', (99, 115))
17590	31484429	The same pipeline allows haplogroup prediction of mtDNA sequences, detection of mismatches, insertions and deletions and the functional annotation of the identified variants.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('mismatches', 'Var', (80, 90))	('mtDNA', 'Gene', (50, 55))	('deletions', 'Var', (107, 116))	('mtDNA', 'cellular_component', 'GO:0000262', ('50', '55'))	('insertions', 'Var', (92, 102))
17613	31484429	As GSSG can be made of either one or two labeled GSH molecules, both versions were measured (13C6 glucose: M+3 and M+6; 13C515N-glutamic acid: M+5 and M+10).	('GSH', 'Chemical', 'MESH:D005978', (49, 52))	('M+10', 'Var', (151, 155))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('As GSSG', 'Chemical', 'MESH:D019803', (0, 7))	('M+6', 'Var', (115, 118))	('13C515N-glutamic acid', 'Chemical', 'MESH:C513342', (120, 141))
17708	30816528	The inhibition of HDACs may reverse resistance to angiogenesis inhibitors and enhance oncologic chemotherapy responses in advanced RCC.	('enhance', 'PosReg', (78, 85))	('HDAC', 'Gene', (18, 22))	('reverse', 'NegReg', (28, 35))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('HDAC', 'Gene', '9734', (18, 22))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('inhibition', 'Var', (4, 14))	('oncologic chemotherapy responses', 'CPA', (86, 118))	('angiogenesis', 'biological_process', 'GO:0001525', ('50', '62'))	('resistance to angiogenesis inhibitors', 'MPA', (36, 73))
17716	30816528	From the prediction of drug targets, it was observed that vorinostat is directly targeted to TP53, and there have been a number of published studies, that argue that the mutation of TP53 greatly contributes to the tumorigenesis and development of RCC.	('vorinostat', 'Chemical', 'MESH:D000077337', (58, 68))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('mutation', 'Var', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('TP53', 'Gene', '7157', (93, 97))	('contributes', 'Reg', (195, 206))	('TP53', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('RCC', 'Phenotype', 'HP:0005584', (247, 250))	('tumor', 'Disease', (214, 219))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('RCC', 'Disease', (247, 250))	('development', 'CPA', (232, 243))
17723	30816528	However, these 2 genes are considered as oncologic therapeutic targets in the PRCC treatment as their key roles of hub genes in the regulation network of DEGs, therefore, the suppression of these 2 genes may interfere with a series of interactions between the DEGs, thereby inhibiting the development and progression of PRCC and then help to treat patients with PRCC.	('patients', 'Species', '9606', (348, 356))	('PRCC', 'Gene', (78, 82))	('PRCC', 'Gene', '5546', (320, 324))	('RCC', 'Phenotype', 'HP:0005584', (321, 324))	('PRCC', 'Phenotype', 'HP:0006766', (78, 82))	('PRCC', 'Gene', (362, 366))	('PRCC', 'Phenotype', 'HP:0006766', (362, 366))	('inhibiting', 'NegReg', (274, 284))	('PRCC', 'Gene', '5546', (78, 82))	('help', 'Reg', (334, 338))	('PRCC', 'Gene', '5546', (362, 366))	('suppression', 'Var', (175, 186))	('PRCC', 'Gene', (320, 324))	('PRCC', 'Phenotype', 'HP:0006766', (320, 324))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('progression', 'CPA', (305, 316))	('interfere', 'NegReg', (208, 217))	('RCC', 'Phenotype', 'HP:0005584', (363, 366))	('regulation', 'biological_process', 'GO:0065007', ('132', '142'))	('development', 'CPA', (289, 300))	('interactions', 'Interaction', (235, 247))
17726	30816528	Surprisingly, the results as observed from docking tests demonstrate that vorinostat can recognize and interact with both C3 and ANXN1 proteins (docking tests >4), which suggests that vorinostat has a considerably prospective performance in PRCC treatment by suppressing the regulation network of DEGs through inhibiting C3 and ANXN1 proteins.	('DEGs', 'MPA', (297, 301))	('suppressing', 'NegReg', (259, 270))	('PRCC', 'Gene', '5546', (241, 245))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('vorinostat', 'Var', (184, 194))	('vorinostat', 'Chemical', 'MESH:D000077337', (74, 84))	('vorinostat', 'Chemical', 'MESH:D000077337', (184, 194))	('PRCC', 'Gene', (241, 245))	('regulation', 'biological_process', 'GO:0065007', ('275', '285'))	('inhibiting', 'NegReg', (310, 320))	('PRCC', 'Phenotype', 'HP:0006766', (241, 245))	('regulation network', 'MPA', (275, 293))
17786	28596583	The K trans of ccRCC and non-ccRCC (0.459 +- 0.190 min-1 and 0.251 +- 0.130 min-1, respectively) was statistically significantly different (p < 0.001).	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('min-1', 'Gene', '966', (51, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (15, 20))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))	('min-1', 'Gene', (51, 56))	('min-1', 'Gene', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('min-1', 'Gene', '966', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('0.251', 'Var', (61, 66))
17801	28596583	For ccRCC and non-ccRCC, K trans was statistically significantly different and K trans had a large area under the ROC curve for diagnosing ccRCC (0.819); however, the V e values were not significantly different.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', (141, 144))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('ccRCC', 'Phenotype', 'HP:0006770', (139, 144))	('K trans', 'Var', (79, 86))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('different', 'Reg', (65, 74))	('ccRCC', 'Phenotype', 'HP:0006770', (4, 9))	('ccRCC', 'Phenotype', 'HP:0006770', (18, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
17829	29905933	In contrast, RCC with translocations involving members of the microphthalmia transcription factor (MiT) family (TFE3 and TFEB) occur more frequently in younger patients.	('patients', 'Species', '9606', (160, 168))	('microphthalmia', 'Disease', 'MESH:D008850', (62, 76))	('microphthalmia', 'Disease', (62, 76))	('transcription factor', 'molecular_function', 'GO:0000981', ('77', '97'))	('TFE3', 'Gene', (112, 116))	('transcription', 'biological_process', 'GO:0006351', ('77', '90'))	('translocations', 'Var', (22, 36))	('RCC', 'Disease', (13, 16))	('TFE3', 'Gene', '7030', (112, 116))	('TFEB', 'Gene', '7942', (121, 125))	('microphthalmia', 'Phenotype', 'HP:0000568', (62, 76))	('TFEB', 'Gene', (121, 125))
17846	29905933	Further evidence of TFE3 gene rearrangement was present in 72/82, including all 5 cases in which TFE3 immunohistochemistry was not performed.	('TFE3', 'Gene', (97, 101))	('rearrangement', 'Var', (30, 43))	('TFE3', 'Gene', '7030', (20, 24))	('TFE3', 'Gene', '7030', (97, 101))	('TFE3', 'Gene', (20, 24))
17850	29905933	Most tumors (21/25) with ASPL-TFE3 fusion transcripts showed pattern 1 while pattern 2 predominated in PRCC-TFE3 tumors (19/24), similar to previous reports.	('pattern', 'MPA', (61, 68))	('tumors', 'Disease', (5, 11))	('PRCC-TFE3 tumors', 'Disease', (103, 119))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TFE3', 'Gene', '7030', (108, 112))	('ASPL', 'Gene', '79058', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('ASPL', 'Gene', (25, 29))	('TFE3', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('fusion transcripts', 'Var', (35, 53))	('PRCC-TFE3 tumors', 'Disease', 'MESH:D009369', (103, 119))	('TFE3', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('TFE3', 'Gene', '7030', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
17873	29905933	One additional tumor was shown to have a translocation involving chromosome 3p13 (VHL gene locus) (Table 2).	('VHL', 'Disease', (82, 85))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('translocation', 'Var', (41, 54))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('65', '75'))
17875	29905933	Mutations in the fumarate hydratase (FH) gene were identified by NGS in 3 tumors (Table 2) initially classified as RCC-NOS, and the morphological features were similar to those previously described.	('identified', 'Reg', (51, 61))	('fumarate hydratase', 'Gene', '2271', (17, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('fumarate hydratase', 'Gene', (17, 35))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('FH', 'Gene', '2271', (37, 39))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
17882	29905933	Nine cases had either a personal and/or familial history of tuberous sclerosis (TS, 5 cases) or were discovered during this study to have mutations in the TSC2 gene (4 cases) within tumor (Table 2) through NGS analysis (the mutations could therefore be either germline or somatic).	('tuberous sclerosis', 'Disease', 'MESH:D014402', (60, 78))	('tumor', 'Disease', (182, 187))	('TSC2', 'Gene', '7249', (155, 159))	('TSC2', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tuberous sclerosis', 'Disease', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('mutations', 'Var', (138, 147))
17901	29905933	Both cases were negative for TSC1/TSC2 mutations by NGS.	('TSC2', 'Gene', '7249', (34, 38))	('TSC2', 'Gene', (34, 38))	('TSC1', 'Gene', (29, 33))	('mutations', 'Var', (39, 48))	('TSC1', 'Gene', '7248', (29, 33))
17909	29905933	Among cases with confirmed TFE3 rearrangements, the ASPL and PRCC genes were the most common fusion partners, in keeping with the existing literature.	('TFE3', 'Gene', '7030', (27, 31))	('PRCC', 'Gene', (61, 65))	('common', 'Reg', (86, 92))	('ASPL', 'Gene', '79058', (52, 56))	('TFE3', 'Gene', (27, 31))	('rearrangements', 'Var', (32, 46))	('PRCC', 'Gene', '5546', (61, 65))	('ASPL', 'Gene', (52, 56))	('fusion', 'Interaction', (93, 99))
17914	29905933	The combination of characteristic morphological features, underexpression of epithelial markers and diffuse and strong nuclear TFE3 immunohistochemical expression reliably detected RCC with TFE3 rearrangements in our series, without the need for molecular studies.	('TFE3', 'Gene', (190, 194))	('detected', 'Reg', (172, 180))	('TFE3', 'Gene', (127, 131))	('TFE3', 'Gene', '7030', (190, 194))	('TFE3', 'Gene', '7030', (127, 131))	('RCC', 'Disease', (181, 184))	('rearrangements', 'Var', (195, 209))
17916	29905933	These observations may explain why 2/82 tumors classified as TFE3 MiT-RCC (2.4%) showed TFE3 positivity, characteristic histologic and immunophenotypic features, yet were negative for a TFE3 rearrangement by FISH.	('MiT-RCC', 'Disease', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('TFE3', 'Gene', (88, 92))	('TFE3', 'Gene', (61, 65))	('TFE3', 'Gene', '7030', (186, 190))	('MiT-RCC', 'Disease', 'MESH:C538614', (66, 73))	('positivity', 'Var', (93, 103))	('TFE3', 'Gene', '7030', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TFE3', 'Gene', '7030', (61, 65))	('tumors', 'Disease', (40, 46))	('TFE3', 'Gene', (186, 190))
17924	29905933	Of the 212 patients in this study, 9 had either a history of TS or a documented TSC2 mutation.	('patients', 'Species', '9606', (11, 19))	('TSC2', 'Gene', '7249', (80, 84))	('TSC2', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))
17925	29905933	Two additional cases demonstrated morphologically similar tumors (one of which was bilateral), suggesting the possibility of mutations in related genes, or undetected mutations in TSC1/TSC2.	('TSC1', 'Gene', (180, 184))	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TSC2', 'Gene', '7249', (185, 189))	('TSC2', 'Gene', (185, 189))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('TSC1', 'Gene', '7248', (180, 184))
18020	30563989	In general, pRCC is a heterogeneous RCC subtype consisting of two distinct subtypes characterised by genetic variations in the MET-gene for type 1 pRCC and in fumarate hydratase for type 2 pRCC.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('pRCC', 'Gene', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('pRCC', 'Gene', (12, 16))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('pRCC', 'Gene', '5546', (189, 193))	('MET-gene', 'Gene', (127, 135))	('pRCC', 'Gene', '5546', (147, 151))	('variations', 'Var', (109, 119))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('pRCC', 'Gene', (189, 193))	('pRCC', 'Gene', '5546', (12, 16))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))
18038	30563989	The presence of these solutes may affect cell metabolism, which could potentially result in the development of distinct renal cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('renal cancer', 'Disease', 'MESH:D007680', (120, 132))	('renal cancer', 'Phenotype', 'HP:0009726', (120, 132))	('cell metabolism', 'MPA', (41, 56))	('result in', 'Reg', (82, 91))	('men', 'Species', '9606', (103, 106))	('metabolism', 'biological_process', 'GO:0008152', ('46', '56'))	('presence', 'Var', (4, 12))	('affect', 'Reg', (34, 40))	('renal cancer', 'Disease', (120, 132))
18073	25472429	Clear cell renal cell carcinoma (ccRCC), the most clinically aggressive subtype, comprises 75% of cases and is characterized by inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, a regulator of oxygen sensing in the cell by controlling HIF1alpha protein levels.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('Clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))	('Clear cell renal cell carcinoma', 'Disease', (0, 31))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (148, 177))	('oxygen', 'Chemical', 'MESH:D010100', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('inactivation', 'Var', (128, 140))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))	('Clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (0, 31))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('172', '188'))	('HIF1alpha', 'Gene', '3091', (252, 261))	('clinical', 'Species', '191496', (50, 58))	('tumor suppressor', 'biological_process', 'GO:0051726', ('172', '188'))	('HIF1alpha', 'Gene', (252, 261))
18074	25472429	Papillary RCC (pRCC; 10% of cases) commonly has trisomy of chromosomes 7 and 17 and may be less clinically aggressive than ccRCC.	('clinical', 'Species', '191496', (96, 104))	('Papillary RCC', 'Gene', '5546', (0, 13))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (16, 19))	('RCC', 'Disease', (125, 128))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('Papillary RCC', 'Gene', (0, 13))	('pRCC', 'Gene', '5546', (15, 19))	('trisomy', 'Var', (48, 55))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (123, 128))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('pRCC', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (10, 13))
18080	25472429	Such previous studies indicated that DNA methylation changes are early events in carcinogenesis, but these experiments were not designed to identify cancer-specific diagnostic biomarkers.	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('cancer', 'Disease', (149, 155))	('changes', 'Var', (53, 60))	('DNA methylation', 'MPA', (37, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('carcinogenesis', 'Disease', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA methylation', 'biological_process', 'GO:0006306', ('37', '52'))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
18100	25472429	Diagnostic biomarker validation for ccRCC patients utilized HumanMethylation27 tumor and matched benign adjacent normal ccRCC TCGA data only.	('RCC', 'Disease', (38, 41))	('tumor', 'Disease', (79, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (120, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('HumanMethylation27', 'Var', (60, 78))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('patients', 'Species', '9606', (42, 50))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
18101	25472429	Diagnostic biomarker validation for the general RCC patients utilized both HumanMethylation27 and HumanMethylation450 tumor and matched benign adjacent normal ccRCC, pRCC, and ChRCC TCGA data.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('HumanMethylation450', 'Var', (98, 117))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('pRCC', 'Gene', '5546', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('patients', 'Species', '9606', (52, 60))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('pRCC', 'Gene', (166, 170))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('tumor', 'Disease', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('HumanMethylation27', 'Var', (75, 93))
18108	25472429	To identify CpGs carrying tumor-specific aberrant methylation, we performed linear mixed modeling with paired tumor/normal data at each CpG.	('methylation', 'biological_process', 'GO:0032259', ('50', '61'))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('aberrant methylation', 'Var', (41, 61))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('methylation', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
18119	25472429	However, we did not see significant DNA methylation changes for PBRM1, a gene previously shown to have truncating mutations in RCC at a level superseded only by VHL.	('mutations', 'Var', (114, 123))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('VHL', 'Gene', (161, 164))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('VHL', 'Gene', '7428', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))
18131	25472429	This 5 CpG model (comprised of cg13156411, cg14456683, cg18003231, cg12782180, and cg22719623) had a ROC area of 0.991 and a BH-adjusted highly significant P value of 8.10 x 10-31 for the null hypothesis that the ROC curve area is 0.5 (which would indicate that a model would not discriminate between tumor and benign adjacent tissue).	('cg12782180', 'Chemical', '-', (67, 77))	('cg13156411', 'Var', (31, 41))	('cg13156411', 'Chemical', '-', (31, 41))	('cg12782180', 'Var', (67, 77))	('cg18003231', 'Var', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('cg14456683', 'Chemical', '-', (43, 53))	('cg18003231', 'Chemical', '-', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('cg22719623', 'Var', (83, 93))	('cg14456683', 'Var', (43, 53))	('tumor', 'Disease', (301, 306))	('BH', 'Chemical', '-', (125, 127))	('cg22719623', 'Chemical', '-', (83, 93))
18140	25472429	When the ccRCC patients were analyzed separately, 4 CpGs (cg04511534, cg11098259, cg14391855, and cg26366091) produced a ROC AUC of 0.990 with a BH-adjusted P = 1.46 x 10-20 for the null hypothesis that the ROC AUC is 0.5.	('BH', 'Chemical', '-', (145, 147))	('patients', 'Species', '9606', (15, 23))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('cg04511534', 'Chemical', '-', (58, 68))	('cg04511534', 'Var', (58, 68))	('cg26366091', 'Chemical', '-', (98, 108))	('cg11098259', 'Var', (70, 80))	('cg26366091', 'Var', (98, 108))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('cg11098259', 'Chemical', '-', (70, 80))	('cg14391855', 'Chemical', '-', (82, 92))	('ROC', 'MPA', (121, 124))	('RCC', 'Disease', (11, 14))	('cg14391855', 'Var', (82, 92))
18144	25472429	For example, at cg04511534, we saw no statistical difference between our data and TCGA data (P = 0.25 and 0.18); however, the difference between tumor and normal was consistent between the two data sets (P <0.0001) (Figure 4, Panel B) (Additional file 2: Figure S1).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cg04511534', 'Chemical', '-', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('cg04511534', 'Var', (16, 26))
18146	25472429	For example, cg04511534, located in the first intron of the gene encoding gamma-glutamyltransferase 6 (GGT6), is hypermethylated in tumors compared to normal tissues.	('GGT6', 'Gene', (103, 107))	('GGT6', 'Gene', '124975', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('gamma-glutamyltransferase 6', 'Gene', (74, 101))	('cg04511534', 'Chemical', '-', (13, 23))	('gamma-glutamyltransferase 6', 'Gene', '124975', (74, 101))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('cg04511534', 'Var', (13, 23))
18148	25472429	The relationship between cg04511534 DNA methylation and GGT6 expression shows significant correlation, following the expected canonical model of increased DNA methylation in the tumors leading to decreased expression (linear regression, P <0.0001; R2 = 0.503; Figure 4, Panel D).	('DNA', 'cellular_component', 'GO:0005574', ('155', '158'))	('GGT6', 'Gene', (56, 60))	('decreased', 'NegReg', (196, 205))	('cg04511534 DNA', 'Var', (25, 39))	('expression', 'MPA', (206, 216))	('tumors', 'Disease', (178, 184))	('GGT6', 'Gene', '124975', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('correlation', 'Interaction', (90, 101))	('DNA methylation', 'biological_process', 'GO:0006306', ('36', '51'))	('DNA', 'cellular_component', 'GO:0005574', ('36', '39'))	('DNA methylation', 'biological_process', 'GO:0006306', ('155', '170'))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('expression', 'MPA', (61, 71))	('cg04511534', 'Chemical', '-', (25, 35))
18157	25472429	Some panel CpGs are in the promoters of genes previously implicated as biomarkers, or involved in carcinogenesis, cancer progression, or treatment response.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('CpGs', 'Var', (11, 15))	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('carcinogenesis', 'Disease', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
18158	25472429	For example, PENK promoter methylation was demonstrated in prostate cancer, breast cancer brain metastasis, and pulmonary adenocarcinoma, and as a potential methylation biomarker for colorectal, meningioma, and bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (112, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Disease', (59, 74))	('meningioma', 'Disease', 'MESH:D008577', (195, 205))	('methylation', 'biological_process', 'GO:0032259', ('27', '38'))	('breast cancer brain metastasis', 'Disease', 'MESH:D009362', (76, 106))	('colorectal', 'Disease', (183, 193))	('PENK', 'Gene', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('PENK', 'Gene', '5179', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('bladder cancer', 'Phenotype', 'HP:0009725', (211, 225))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('methylation', 'Var', (27, 38))	('colorectal', 'Disease', 'MESH:D015179', (183, 193))	('breast cancer brain metastasis', 'Disease', (76, 106))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('bladder cancer', 'Disease', 'MESH:D001749', (211, 225))	('bladder cancer', 'Disease', (211, 225))	('meningioma', 'Disease', (195, 205))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 136))	('meningioma', 'Phenotype', 'HP:0002858', (195, 205))	('pulmonary adenocarcinoma', 'Disease', (112, 136))
18159	25472429	KLK10 promoter methylation has been implicated in head and neck squamous cell carcinoma progression, as well as a potential prostate cancer and non-small cell lung cancer biomarker.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (148, 170))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (144, 170))	('implicated', 'Reg', (36, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('methylation', 'Var', (15, 26))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (50, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('non-small cell lung cancer', 'Disease', (144, 170))	('neck', 'cellular_component', 'GO:0044326', ('59', '63'))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('KLK10', 'Gene', (0, 5))	('neck squamous cell carcinoma', 'Disease', (59, 87))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (144, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (124, 139))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (59, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('prostate cancer', 'Disease', (124, 139))	('KLK10', 'Gene', '5655', (0, 5))
18160	25472429	ZIC1 was implicated as a tumor suppressor silenced via promoter methylation in malignant pleural mesothelioma and gastric cancer.	('promoter methylation', 'Var', (55, 75))	('gastric cancer', 'Disease', (114, 128))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('25', '41'))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('tumor', 'Disease', (25, 30))	('malignant pleural mesothelioma', 'Disease', (79, 109))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (79, 109))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (89, 109))	('ZIC1', 'Gene', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('methylation', 'biological_process', 'GO:0032259', ('64', '75'))	('ZIC1', 'Gene', '7545', (0, 4))	('tumor suppressor', 'biological_process', 'GO:0051726', ('25', '41'))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('silenced', 'NegReg', (42, 50))
18162	25472429	Additionally, C21ORF123 promoter methylation has been implicated in cisplatin resistance in non-small cell lung cancer and RIN1 is a tumor suppressor that is deregulated through aberrant promoter methylation in breast cancer.	('RIN1', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (92, 118))	('C21ORF123', 'Gene', (14, 23))	('RIN1', 'Gene', '9610', (123, 127))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('breast cancer', 'Disease', (211, 224))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (92, 118))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('133', '149'))	('methylation', 'biological_process', 'GO:0032259', ('196', '207'))	('tumor', 'Disease', (133, 138))	('aberrant', 'Var', (178, 186))	('cisplatin resistance', 'MPA', (68, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor suppressor', 'biological_process', 'GO:0051726', ('133', '149'))	('C21ORF123', 'Gene', '378832', (14, 23))	('non-small cell lung cancer', 'Disease', (92, 118))	('implicated', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
18170	25472429	For example, differential methylation of Sept9 in patient blood is used for diagnosis of colorectal cancer and detection of the non-coding RNA PCA3 in patient urine is used for risk assessment of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (196, 211))	('Sept9', 'Gene', '10801', (41, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (196, 211))	('differential', 'Var', (13, 25))	('Sept9', 'Gene', (41, 46))	('RNA', 'cellular_component', 'GO:0005562', ('139', '142'))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('prostate cancer', 'Disease', (196, 211))	('patient', 'Species', '9606', (151, 158))	('PCA3', 'Gene', '50652', (143, 147))	('methylation', 'biological_process', 'GO:0032259', ('26', '37'))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('PCA3', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('patient', 'Species', '9606', (50, 57))
18197	30099580	The high frequency of A:T-to-T:A transversions consistent with mutational damage as a result of aristolochic acid exposure was detected via sequencing of patients from Eastern Europe and has directly influenced primary prevention strategies.	('aristolochic acid', 'Chemical', 'MESH:C000228', (96, 113))	('influenced', 'Reg', (200, 210))	('transversions', 'Var', (33, 46))	('patients', 'Species', '9606', (154, 162))
18200	30099580	The two correlated variants on 2p21 map to EPAS1, a transcription factor previously implicated in RCC, whereas the variant on 11q13.3 contains no characterised genes.	('EPAS1', 'Gene', (43, 48))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('variants', 'Var', (19, 27))	('transcription factor', 'molecular_function', 'GO:0000981', ('52', '72'))	('EPAS1', 'Gene', '2034', (43, 48))
18201	30099580	An additional susceptibility locus on 12p11.23 was later discovered containing two variants in the ITPR2 gene, though direct functional evidence between ITPR2 and oncogenesis is lacking.	('variants', 'Var', (83, 91))	('ITPR2', 'Gene', (99, 104))	('ITPR2', 'Gene', '3709', (153, 158))	('oncogenesis', 'biological_process', 'GO:0007048', ('163', '174'))	('ITPR2', 'Gene', '3709', (99, 104))	('ITPR2', 'Gene', (153, 158))
18205	30099580	The second copy of VHL is lost, usually much later in life, by either non-synonymous mutation or epigenetic down-regulation.	('VHL', 'Gene', (19, 22))	('epigenetic down-regulation', 'Var', (97, 123))	('non-synonymous mutation', 'Var', (70, 93))	('VHL', 'Gene', '7428', (19, 22))	('regulation', 'biological_process', 'GO:0065007', ('113', '123'))
18206	30099580	VHL inactivation prevents the ubiquitination of hypoxia-inducible factor (HIF) for degradation.	('inactivation', 'Var', (4, 16))	('degradation', 'MPA', (83, 94))	('VHL', 'Gene', (0, 3))	('prevents', 'NegReg', (17, 25))	('degradation', 'biological_process', 'GO:0009056', ('83', '94'))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('VHL', 'Gene', '7428', (0, 3))	('hypoxia', 'Disease', (48, 55))	('ubiquitination', 'MPA', (30, 44))
18211	30099580	The first three of these genes are also co-located with VHL on chromosome 3p, meaning that after 3p loss, any further non-synonymous mutation will result in complete inactivation of these haploinsufficient genes.	('VHL', 'Gene', (56, 59))	('haploinsufficient', 'Disease', 'MESH:D058495', (188, 205))	('mutation', 'Var', (133, 141))	('VHL', 'Gene', '7428', (56, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('haploinsufficient', 'Disease', (188, 205))	('inactivation', 'NegReg', (166, 178))	('loss', 'NegReg', (100, 104))
18213	30099580	PBRM1's inactivation could lead to loss of DNA methylation via reduction of H3K36me3.	('DNA methylation', 'MPA', (43, 58))	('loss', 'NegReg', (35, 39))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('inactivation', 'Var', (8, 20))	('DNA', 'cellular_component', 'GO:0005574', ('43', '46'))	('DNA methylation', 'biological_process', 'GO:0006306', ('43', '58'))	('reduction', 'NegReg', (63, 72))	('H3K36me3', 'Protein', (76, 84))
18214	30099580	SETD2 is mutated in 10-30% of ccRCCs.	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('SETD2', 'Gene', '29072', (0, 5))	('mutated', 'Var', (9, 16))	('RCC', 'Disease', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCCs', 'Phenotype', 'HP:0005584', (32, 36))	('SETD2', 'Gene', (0, 5))
18215	30099580	SETD2's intracellular roles are numerous, including the regulation of transcription elongation, RNA processing, and double-stranded DNA break repair that may then activate the p53-mediated checkpoint in the absence of specific p53 mutations.	('p53', 'Gene', (227, 230))	('RNA', 'cellular_component', 'GO:0005562', ('96', '99'))	('p53', 'Gene', (176, 179))	('mutations', 'Var', (231, 240))	('regulation', 'biological_process', 'GO:0065007', ('56', '66'))	('p53', 'Gene', '7157', (227, 230))	('SETD2', 'Gene', '29072', (0, 5))	('RNA processing', 'biological_process', 'GO:0006396', ('96', '110'))	('DNA', 'cellular_component', 'GO:0005574', ('132', '135'))	('p53', 'Gene', '7157', (176, 179))	('SETD2', 'Gene', (0, 5))	('activate', 'PosReg', (163, 171))	('intracellular', 'cellular_component', 'GO:0005622', ('8', '21'))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))
18216	30099580	BAP1, a histone deubiquitinase, is mutated in up to 5-15% of ccRCCs.	('RCC', 'Disease', (63, 66))	('mutated', 'Var', (35, 42))	('RCCs', 'Phenotype', 'HP:0005584', (63, 67))	('BAP1', 'Gene', (0, 4))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('16', '30'))	('BAP1', 'Gene', '8314', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
18219	30099580	A retrospective, validated analysis found that tumours with BAP1 mutations conferred a worse prognosis, higher grade, and worse overall survival when compared to those with PBRM1 mutations or when compared to those without BAP1 mutations.	('PBRM1', 'Gene', (173, 178))	('BAP1', 'Gene', '8314', (223, 227))	('PBRM1', 'Gene', '55193', (173, 178))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('BAP1', 'Gene', (223, 227))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('BAP1', 'Gene', '8314', (60, 64))	('grade', 'CPA', (111, 116))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('higher', 'PosReg', (104, 110))	('BAP1', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
18220	30099580	The presence of BAP1 and PBRM1 mutants appeared anti-correlated, though when co-existing, their presence conferred the worst overall survival.	('mutants', 'Var', (31, 38))	('PBRM1', 'Gene', (25, 30))	('BAP1', 'Gene', '8314', (16, 20))	('worst', 'NegReg', (119, 124))	('PBRM1', 'Gene', '55193', (25, 30))	('BAP1', 'Gene', (16, 20))
18221	30099580	Similarly, the presence of SETD2 confers worse overall survival by a hazard ratio of 1.7.	('presence', 'Var', (15, 23))	('worse', 'NegReg', (41, 46))	('SETD2', 'Gene', '29072', (27, 32))	('overall survival', 'MPA', (47, 63))	('SETD2', 'Gene', (27, 32))
18222	30099580	Genomic profiling of tumours from patients with ccRCC is beginning to illustrate how the presence of mutations in chromatin-modifying genes may aid systemic treatment stratification.	('chromatin-modifying genes', 'Gene', (114, 139))	('mutations', 'Var', (101, 110))	('aid', 'Reg', (144, 147))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('tumours', 'Disease', 'MESH:D009369', (21, 28))	('chromatin', 'cellular_component', 'GO:0000785', ('114', '123'))	('patients', 'Species', '9606', (34, 42))	('tumours', 'Disease', (21, 28))	('systemic treatment stratification', 'CPA', (148, 181))
18224	30099580	Immuno-oncological agents are now showing increasing promise in metastatic ccRCC settings, where PBRM1 mutations appear to confer clinical benefit after treatment with these agents.	('mutations', 'Var', (103, 112))	('clinical', 'MPA', (130, 138))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('benefit', 'PosReg', (139, 146))	('PBRM1', 'Gene', (97, 102))	('PBRM1', 'Gene', '55193', (97, 102))
18225	30099580	Somatic mutations have been detected within the core promoter and 5'UTR of telomerase reverse transcriptase (TERT) in 6-14% of ccRCCs.	('core', 'cellular_component', 'GO:0019013', ('48', '52'))	('TERT', 'Gene', '7015', (109, 113))	('detected', 'Reg', (28, 36))	('mutations', 'Var', (8, 17))	('RCCs', 'Phenotype', 'HP:0005584', (129, 133))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('transcriptase', 'molecular_function', 'GO:0003899', ('94', '107'))	('RCC', 'Disease', (129, 132))	('telomerase reverse transcriptase', 'Gene', (75, 107))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('transcriptase', 'molecular_function', 'GO:0003968', ('94', '107'))	('telomerase reverse transcriptase', 'Gene', '7015', (75, 107))	('TERT', 'Gene', (109, 113))	('transcriptase', 'molecular_function', 'GO:0034062', ('94', '107'))
18226	30099580	Furthermore, the presence of TERT promoter mutations has been shown to decrease cancer-specific survival and increased disease stage.	('TERT', 'Gene', '7015', (29, 33))	('TERT', 'Gene', (29, 33))	('decrease', 'NegReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('disease stage', 'CPA', (119, 132))	('mutations', 'Var', (43, 52))	('presence', 'Var', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('increased', 'PosReg', (109, 118))	('cancer', 'Disease', (80, 86))
18227	30099580	The PTEN gene undergoes both recurrent point mutations (2-12% of samples) and focal deletions (approximately 7% of samples) in ccRCC.	('PTEN', 'Gene', '5728', (4, 8))	('point mutations', 'Var', (39, 54))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (129, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('PTEN', 'Gene', (4, 8))	('deletions', 'Var', (84, 93))
18229	30099580	An interrogation of the TCGA data set revealed that bi-allelic loss of PTEN was uncommon but conferred worse overall survival.	('worse', 'NegReg', (103, 108))	('PTEN', 'Gene', (71, 75))	('overall survival', 'MPA', (109, 125))	('PTEN', 'Gene', '5728', (71, 75))	('bi-allelic', 'Var', (52, 62))	('loss', 'NegReg', (63, 67))
18230	30099580	Tumours with mutant PTEN status showed a non-significant increase in rates of progression when compared to non-PTEN mutant tumours after either VEGFR or MTOR inhibition in metastatic patients in the RECORD-3 trial.	('mutant', 'Var', (13, 19))	('MTOR', 'Gene', (153, 157))	('PTEN', 'Gene', (111, 115))	('VEGFR', 'Gene', '3791', (144, 149))	('PTEN', 'Gene', '5728', (111, 115))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('MTOR', 'Gene', '2475', (153, 157))	('increase', 'PosReg', (57, 65))	('patients', 'Species', '9606', (183, 191))	('VEGFR', 'Gene', (144, 149))	('tumours', 'Disease', (123, 130))	('PTEN', 'Gene', (20, 24))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('PTEN', 'Gene', '5728', (20, 24))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
18231	30099580	The PI3K-AKT-mTOR signalling axis is directly augmented via MTOR mutations, observed in 4-9% of ccRCC neoplasms.	('AKT', 'Gene', '207', (9, 12))	('MTOR', 'Gene', (60, 64))	('PI3K', 'molecular_function', 'GO:0016303', ('4', '8'))	('mTOR', 'Gene', '2475', (13, 17))	('neoplasms', 'Phenotype', 'HP:0002664', (102, 111))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('AKT', 'Gene', (9, 12))	('mTOR', 'Gene', (13, 17))	('augmented', 'PosReg', (46, 55))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('MTOR', 'Gene', '2475', (60, 64))	('signalling', 'biological_process', 'GO:0023052', ('18', '28'))	('neoplasms', 'Disease', 'MESH:D009369', (102, 111))	('mutations', 'Var', (65, 74))	('neoplasms', 'Disease', (102, 111))
18237	30099580	There is some evidence that tumours with mutations in MTOR/TSC1/2 have a better response to rapalogs, although statistical significance has not been reached.	('mutations', 'Var', (41, 50))	('response', 'MPA', (80, 88))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('MTOR', 'Gene', (54, 58))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('MTOR', 'Gene', '2475', (54, 58))	('better', 'PosReg', (73, 79))	('TSC1/2', 'Gene', '7248;7249', (59, 65))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))	('TSC1/2', 'Gene', (59, 65))
18239	30099580	However, aberrations in genes involved in the P53 pathway are relatively common implying that the p53 pathway and cell-cycle checkpoint inhibition play significant roles in ccRCC.	('P53', 'Gene', '7157', (46, 49))	('aberrations', 'Var', (9, 20))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('cell-cycle checkpoint', 'biological_process', 'GO:0000075', ('114', '135'))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('P53', 'Gene', (46, 49))
18241	30099580	Aside from translocation renal cell carcinoma, gene fusions are uncommon in renal cell cancer.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 45))	('renal cell cancer', 'Disease', 'MESH:C538614', (76, 93))	('renal cell cancer', 'Disease', (76, 93))	('translocation', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('renal cell carcinoma', 'Disease', (25, 45))	('renal cell cancer', 'Phenotype', 'HP:0005584', (76, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))
18245	30099580	In bladder cancer amongst others, mutational burden as a surrogate for neoantigen levels has been associated with enhanced response to targeted immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('mutational burden', 'Var', (34, 51))	('response', 'MPA', (123, 131))	('enhanced', 'PosReg', (114, 122))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))
18252	30099580	Somatic mutations that are found in all sampled tumour regions present in the trunk of the phylogenetic tree, including VHL mutations and 3p loss.	('mutations', 'Var', (124, 133))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('VHL', 'Gene', (120, 123))	('trunk', 'cellular_component', 'GO:0043198', ('78', '83'))	('tumour', 'Disease', (48, 54))	('VHL', 'Gene', '7428', (120, 123))
18253	30099580	This finding supports the Knudson two-hit hypothesis, where two 'hits' (i.e., bi-allelic inactivation of VHL) are required for clonal expansion to yield a clone large enough to stochastically acquire independent branches.	('VHL', 'Gene', '7428', (105, 108))	('VHL', 'Gene', (105, 108))	('bi-allelic inactivation', 'Var', (78, 101))
18259	30099580	Papillary RCC (pRCC) represents approximately 20% of all kidney cancers and accumulates mutations at a similar rate to ccRCC, again with a predominance of a clock-like process.	('mutations', 'Var', (88, 97))	('Papillary RCC', 'Disease', (0, 13))	('kidney cancers', 'Disease', 'MESH:D007680', (57, 71))	('kidney cancers', 'Disease', (57, 71))	('pRCC', 'Gene', '5546', (15, 19))	('Papillary RCC', 'Disease', 'MESH:C538614', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('kidney cancer', 'Phenotype', 'HP:0009726', (57, 70))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('kidney cancers', 'Phenotype', 'HP:0009726', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', (121, 124))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('pRCC', 'Gene', (15, 19))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (16, 19))
18263	30099580	Some of the shared genomic features, such as gene fusions involving TFE3 or TFEB, are present in approximately 10% of samples and show no particular disposition to type I or type II cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('type II cancers', 'Disease', (174, 189))	('gene fusions', 'Var', (45, 57))	('TFE3', 'Gene', (68, 72))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('type I', 'Disease', (164, 170))	('TFEB', 'Gene', '7942', (76, 80))	('TFE3', 'Gene', '7030', (68, 72))	('TFEB', 'Gene', (76, 80))	('type II cancers', 'Disease', 'MESH:D009369', (174, 189))
18264	30099580	Hereditary papillary renal cancer (HPRC) predisposes to type I pRCC via autosomal dominant inheritance of a mutation in the MET proto-oncogene.	('pRCC', 'Gene', '5546', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (11, 33))	('renal cancer', 'Phenotype', 'HP:0009726', (21, 33))	('Hereditary papillary renal cancer', 'Disease', (0, 33))	('MET proto-oncogene', 'Gene', (124, 142))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('pRCC', 'Gene', (63, 67))	('mutation', 'Var', (108, 116))	('Hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (0, 33))
18270	30099580	Despite widening the net to discover other candidate driver mutations through known-cancer associated genes, one-third of tumours had no clearly discernible driver, other than trisomy of broad copy number alterations, most commonly chromosome 7.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('trisomy', 'Var', (176, 183))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('232', '242'))	('chromosome 7', 'Var', (232, 244))	('mutations', 'Var', (60, 69))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
18272	30099580	Sporadic FH mutations are rarely found; however, mutations of genes in the downstream NRF2-antioxidant response element (ARE) pathway such as NFE2L2 are recurrently detected.	('NRF2', 'Gene', '4780', (86, 90))	('mutations', 'Var', (49, 58))	('NRF2', 'Gene', (86, 90))	('NFE2L2', 'Gene', '4780', (142, 148))	('FH', 'Gene', '2271', (9, 11))	('NFE2L2', 'Gene', (142, 148))
18273	30099580	CDKN2A alterations are present in 25% of type II pRCC tumours when loss of heterogeneity, promoter hypermethylation, and somatic mutations are considered together.	('type II pRCC tumours', 'Disease', 'MESH:D009369', (41, 61))	('alterations', 'Var', (7, 18))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('type II pRCC tumours', 'Disease', (41, 61))	('CDKN2A', 'Gene', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('present', 'Reg', (23, 30))	('CDKN2A', 'Gene', '1029', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
18275	30099580	The presence of CDKN2A alterations was also adversely associated survival in univariate analysis of the whole cohort and when limited to the more aggressive type II phenotype.	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('alterations', 'Var', (23, 34))	('presence', 'Var', (4, 12))	('survival', 'MPA', (65, 73))	('associated', 'Reg', (54, 64))
18276	30099580	A small subset of type II pRCC; CpG island methylator phenotype (CIMP) had universal hypermethylation of the CDKN2A promoter and also a high prevalence of germline or somatic mutations in FH.	('pRCC', 'Gene', (26, 30))	('CDKN2A', 'Gene', (109, 115))	('hypermethylation', 'MPA', (85, 101))	('germline', 'Var', (155, 163))	('CDKN2A', 'Gene', '1029', (109, 115))	('pRCC', 'Gene', '5546', (26, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('FH', 'Gene', '2271', (188, 190))
18282	30099580	These tumours derived from the distal nephron accumulate mutations at a low rate (~ 0.4 per Mb).	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('mutations', 'Var', (57, 66))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
18284	30099580	Recurrent aberrations in the TERT gene were also detected with some harbouring the canonical 228T mutations, but mainly via structural variants that correlated strongly with increased TERT expression.	('TERT', 'Gene', '7015', (29, 33))	('detected', 'Reg', (49, 57))	('TERT', 'Gene', '7015', (184, 188))	('increased', 'PosReg', (174, 183))	('mutations', 'Var', (98, 107))	('variants', 'Var', (135, 143))	('228T', 'Gene', (93, 97))	('TERT', 'Gene', (184, 188))	('TERT', 'Gene', (29, 33))
18285	30099580	The eosinophilic subtype, describing an eosinophilic cytoplasm with densely packed mitochondria, harboured cases that were devoid of copy number aberrations and some that were enriched for the mitochondrial MT-ND5 gene mutations.	('mitochondria', 'cellular_component', 'GO:0005739', ('83', '95'))	('MT-ND5', 'Gene', '4540', (207, 213))	('cytoplasm', 'cellular_component', 'GO:0005737', ('53', '62'))	('mutations', 'Var', (219, 228))	('eosinophilic subtype', 'Disease', 'MESH:D004802', (4, 24))	('MT-ND5', 'Gene', (207, 213))	('eosinophilic subtype', 'Disease', (4, 24))
18288	30099580	TP53 mutations were found in 33% of tumours, while loss of HNF1B was seen in 88%.	('HNF1B', 'Gene', (59, 64))	('TP53', 'Gene', '7157', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('TP53', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mutations', 'Var', (5, 14))	('tumours', 'Disease', (36, 43))	('HNF1B', 'Gene', '6928', (59, 64))	('found', 'Reg', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('loss', 'NegReg', (51, 55))
18289	30099580	Prevalence of both TP53 mutations and loss of HNF1b increased with tumour stage and were linked with poor survival.	('HNF1b', 'Gene', '6928', (46, 51))	('increased', 'PosReg', (52, 61))	('tumour', 'Disease', (67, 73))	('TP53', 'Gene', '7157', (19, 23))	('HNF1b', 'Gene', (46, 51))	('TP53', 'Gene', (19, 23))	('tumour', 'Disease', 'MESH:D009369', (67, 73))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (24, 33))	('loss', 'NegReg', (38, 42))	('linked', 'Reg', (89, 95))
18291	30099580	TP53 mutations (58%), PTEN mutations (24%), and imbalanced chromosome duplication (duplication of >= 3 chromosomes, 25%) were enriched in patients with metastatic disease.	('mutations', 'Var', (27, 36))	('metastatic disease', 'Disease', (152, 170))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('imbalanced chromosome duplication', 'Var', (48, 81))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (22, 26))	('PTEN', 'Gene', '5728', (22, 26))	('patients', 'Species', '9606', (138, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))
18292	30099580	Oncocytomas are benign tumours that share many features with eosinophilic chRCCs, including derivation from the distal tubule and recurrent mutations in mitochondria-encoded proteins.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('RCC', 'Disease', (76, 79))	('benign tumours', 'Disease', (16, 30))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCCs', 'Phenotype', 'HP:0005584', (76, 80))	('mitochondria-encoded', 'Gene', (153, 173))	('benign tumours', 'Disease', 'MESH:D009369', (16, 30))	('Oncocytomas', 'Disease', 'MESH:D018249', (0, 11))	('mitochondria', 'cellular_component', 'GO:0005739', ('153', '165'))	('Oncocytomas', 'Disease', (0, 11))	('mutations', 'Var', (140, 149))
18294	30099580	The absence of PT53 mutations and activation of the p53 pathway in oncocytomas highlights p53 as a barrier to oncocytoma progression.	('p53', 'Gene', (90, 93))	('oncocytomas', 'Disease', 'MESH:D018249', (67, 78))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('activation', 'PosReg', (34, 44))	('PT53', 'Gene', (15, 19))	('oncocytomas', 'Disease', (67, 78))	('mutations', 'Var', (20, 29))
18300	27256309	DNA Methylation Signature Reveals Cell Ontogeny of Renal Cell Carcinomas DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition.	('methylation', 'Var', (77, 88))	('Renal Cell Carcinomas', 'Disease', (51, 72))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (51, 71))	('DNA methylation', 'biological_process', 'GO:0006306', ('73', '88'))	('Renal Cell Carcinomas', 'Phenotype', 'HP:0005584', (51, 72))	('Renal Cell Carcinomas', 'Disease', 'MESH:C538614', (51, 72))	('DNA Methylation', 'biological_process', 'GO:0006306', ('0', '15'))	('Carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('DNA', 'cellular_component', 'GO:0005574', ('73', '76'))	('Carcinomas', 'Phenotype', 'HP:0030731', (62, 72))
18304	27256309	Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.	('epigenetic', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('patients', 'Species', '9606', (97, 105))
18312	27256309	The importance of DNA methylation alterations in cancer has been extensively studied, with the discovery of both hypermethylation within promoter regions of certain tumor-suppressor genes and long-range hypomethylation which broadly contributes to cell transformation.	('contributes', 'Reg', (233, 244))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('hypomethylation', 'Var', (203, 218))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cell transformation', 'CPA', (248, 267))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('hypermethylation', 'Var', (113, 129))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('165', '181'))	('cancer', 'Disease', (49, 55))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('165', '181'))	('tumor', 'Disease', (165, 170))
18358	27256309	Using the following criteria, at least 2% methylation gain for unmethylated CG sites (<=1%) or demethylation below or equal to 1% for methylated CG sites (>=2%), we estimated the FDR of our method to be 0.01.	('methylation', 'MPA', (42, 53))	('demethylation', 'Var', (95, 108))	('demethylation', 'biological_process', 'GO:0070988', ('95', '108'))	('CG', 'Chemical', 'MESH:C028505', (145, 147))	('CG', 'Chemical', 'MESH:C028505', (76, 78))	('gain', 'PosReg', (54, 58))	('methylation', 'biological_process', 'GO:0032259', ('42', '53'))	('below', 'NegReg', (109, 114))
18380	27256309	As genes that gain DNA methylation in cancer have been shown to be Polycomb targets in embryonic stem cells and adult stem/progenitor cells, we thus analyzed our results using the chromatin marks of the embryonic stem (ES) cells and found that 487 (68.3%) of gene promoters gaining DNA methylation in our RCC samples were marked by H3K27me3 in ES cells.	('DNA methylation', 'biological_process', 'GO:0006306', ('282', '297'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('chromatin', 'cellular_component', 'GO:0000785', ('180', '189'))	('RCC', 'Disease', 'MESH:C538614', (305, 308))	('RCC', 'Disease', (305, 308))	('H3K27me3', 'Var', (332, 340))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('DNA methylation', 'biological_process', 'GO:0006306', ('19', '34'))	('cancer', 'Disease', (38, 44))	('DNA', 'cellular_component', 'GO:0005574', ('282', '285'))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
18387	27256309	Overall, 25 genes were identified as methylated and repressed in at least 2% of ccRCC samples, the majority of them never reported previously in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Disease', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('methylated', 'Var', (37, 47))
18402	27256309	When then asked whether epigenetic signature is capable of predicting outcome for patients with clear-cell RCC.	('patients', 'Species', '9606', (82, 90))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('epigenetic signature', 'Var', (24, 44))	('RCC', 'Disease', (107, 110))
18412	27256309	Recent studies that incorporate DNA methylation profiling have identified chromophobe RCC-specific methylation or differentially methylated regions between RCC tumors and adjacent uninvolved kidney.	('DNA methylation', 'biological_process', 'GO:0006306', ('32', '47'))	('methylation', 'Var', (99, 110))	('chromophobe RCC', 'Disease', (74, 89))	('RCC tumors', 'Disease', (156, 166))	('methylation', 'biological_process', 'GO:0032259', ('99', '110'))	('DNA', 'cellular_component', 'GO:0005574', ('32', '35'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('chromophobe RCC', 'Disease', 'MESH:C538614', (74, 89))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('differentially methylated regions', 'MPA', (114, 147))	('RCC tumors', 'Disease', 'MESH:C538614', (156, 166))
18420	27256309	We speculate that activation of the PRC2 in the proximal tubules cell of origin might explain the aggressiveness of derived tumor subtypes in C1 epi-cluster, in contrast to distal tubules cell of origin giving rise to oncocytoma and chromophobe which have usually good outcome.	('aggressiveness', 'Disease', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('C1 epi-cluster', 'Var', (142, 156))	('aggressiveness', 'Phenotype', 'HP:0000718', (98, 112))	('oncocytoma', 'Disease', (218, 228))	('tumor', 'Disease', (124, 129))	('oncocytoma', 'Disease', 'MESH:D018249', (218, 228))	('PRC2', 'Gene', (36, 40))	('aggressiveness', 'Disease', 'MESH:D001523', (98, 112))	('activation', 'PosReg', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
18421	27256309	We thus suggest that epigenetic therapies may have utility against a broad range of the most life-threatening kidney cancers, independent of genotype and morphological phenotype.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('kidney cancers', 'Disease', (110, 124))	('kidney cancers', 'Phenotype', 'HP:0009726', (110, 124))	('kidney cancers', 'Disease', 'MESH:D007680', (110, 124))	('kidney cancer', 'Phenotype', 'HP:0009726', (110, 123))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('epigenetic therapies', 'Var', (21, 41))
18424	27256309	Indeed, the mutation rates per exome for ccRCC (n=43) and pRCC (n=59) are by far higher than chromophobe (n=17) and oncocytoma (n=15) RCC.	('pRCC', 'Gene', '5546', (58, 62))	('higher', 'PosReg', (81, 87))	('oncocytoma', 'Disease', 'MESH:D018249', (116, 126))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('oncocytoma', 'Disease', (116, 126))	('RCC', 'Disease', (43, 46))	('pRCC', 'Gene', (58, 62))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('RCC', 'Disease', (134, 137))	('mutation', 'Var', (12, 20))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
18426	27256309	Our 56 genes epi-signature was also able to predict survival of patients with ccRCC.	('patients', 'Species', '9606', (64, 72))	('epi-signature', 'Var', (13, 26))	('RCC', 'Disease', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('predict', 'Reg', (44, 51))
18434	27256309	Finally, our epigenetic ontogeny signature was associated with worse outcomes of patients with clear-cell RCC.	('patients', 'Species', '9606', (81, 89))	('epigenetic', 'Var', (13, 23))	('RCC', 'Disease', (106, 109))	('associated', 'Reg', (47, 57))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
18437	24467611	Ex vivo fine needle aspiration biopsies of 122 resected renal cortical neoplasms were subjected to FISH using a series of seven-probe sets to assess gain or loss of 10 chromosomes and rearrangement of the 11q13 locus.	('neoplasms', 'Phenotype', 'HP:0002664', (71, 80))	('11q13', 'Gene', (205, 210))	('sp', 'Chemical', 'MESH:C000604007', (21, 23))	('10 chromosomes', 'CPA', (165, 179))	('renal cortical neoplasms', 'Disease', 'MESH:D007680', (56, 80))	('rearrangement', 'Var', (184, 197))	('renal cortical neoplasms', 'Disease', (56, 80))	('gain', 'PosReg', (149, 153))	('aspiration', 'Phenotype', 'HP:0002835', (20, 30))	('neoplasm', 'Phenotype', 'HP:0002664', (71, 79))	('loss', 'NegReg', (157, 161))
18456	24467611	Genetic alterations have been found to be associated with each of the main renal cortical neoplasm subtypes and sometimes with prognostic value.	('Genetic alterations', 'Var', (0, 19))	('renal cortical neoplasm subtypes', 'Disease', 'MESH:D007680', (75, 107))	('associated', 'Reg', (42, 52))	('renal cortical neoplasm subtypes', 'Disease', (75, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (90, 98))
18457	24467611	Because of its relative abundance, ccRCC has been studied most extensively, and inactivation of the Von Hippel-Lindau (VHL) gene at the 3p25 locus, mostly by deletion but also by mutation and methylation, is considered to have an aetiological role.	('Von Hippel-Lindau', 'Disease', (100, 117))	('VHL', 'Disease', 'MESH:D006623', (119, 122))	('VHL', 'Disease', (119, 122))	('methylation', 'Var', (192, 203))	('methylation', 'biological_process', 'GO:0032259', ('192', '203'))	('mutation', 'Var', (179, 187))	('inactivation', 'NegReg', (80, 92))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('deletion', 'Var', (158, 166))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (100, 117))
18461	24467611	Another subtype of renal cortical neoplasm exhibiting an Xp11 rearrangement occurs rarely, and mostly in a younger population; therefore, subtype-associated genetic alterations offer an additional means by which the main renal cortical neoplasm subtypes can be classified.	('renal cortical neoplasm', 'Disease', (19, 42))	('renal cortical neoplasm subtypes', 'Disease', 'MESH:D007680', (221, 253))	('neoplasm', 'Phenotype', 'HP:0002664', (34, 42))	('renal cortical neoplasm subtypes', 'Disease', (221, 253))	('renal cortical neoplasm', 'Disease', 'MESH:D007680', (221, 244))	('renal cortical neoplasm', 'Disease', 'MESH:D007680', (19, 42))	('genetic alterations', 'Var', (157, 176))	('alterations', 'Var', (165, 176))	('neoplasm', 'Phenotype', 'HP:0002664', (236, 244))
18474	24467611	The individual probes were labelled by nick translation (Abbott Molecular, Des Plaines, IL, USA) incorporating one of three fluorochromes: Red 580 dUTP, Green 496 dUTP, or Gold 525 dUTP (ENZO Life Sciences Inc., Farmingdale, NY, USA) and combined according to Table 1.	('dUTP', 'Chemical', 'MESH:C027078', (163, 167))	('Gold 525 dUTP', 'Var', (172, 185))	('dUTP', 'Chemical', 'MESH:C027078', (147, 151))	('Red 580 dUTP', 'Var', (139, 151))	('dUTP', 'Chemical', 'MESH:C027078', (181, 185))	('translation', 'biological_process', 'GO:0006412', ('44', '55'))	('Green 496 dUTP', 'Var', (153, 167))
18483	24467611	The score for loss of 3p, 3p21 or 3p25, was the sum of nuclei containing fewer than two signals of a probe and nuclei containing a fewer number of signals of the 3p probe with respect to the 3q11 probe.	('3p21', 'Var', (26, 30))	('3p25', 'Var', (34, 38))	('sp', 'Chemical', 'MESH:C000604007', (178, 180))	('loss', 'NegReg', (14, 18))
18490	24467611	Initially, FISH was also performed to detect the Xp11 rearrangement, but was not considered further because of sample availability limitations and the rarity of this RCC subtype, especially in the older target population in whom less invasive procedures would be mostly considered.	('sp', 'Chemical', 'MESH:C000604007', (180, 182))	('Xp11 rearrangement', 'Var', (49, 67))	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('RCC', 'Disease', (166, 169))
18501	24467611	Representative FISH images for specimen K-126 (sp-histology: ccRCC) which exhibited loss of 3p (3p25 and 3p21) are shown in Fig.	('RCC', 'Disease', (63, 66))	('sp', 'Chemical', 'MESH:C000604007', (47, 49))	('3p21', 'Var', (105, 109))	('loss', 'NegReg', (84, 88))	('sp', 'Chemical', 'MESH:C000604007', (31, 33))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
18503	24467611	When a specimen could not be classified based on these aberrations, then presence/absence calls were required from probe set 6 to detect rearrangement of the CCND1 locus at 11q13, observed in OC.	('CCND1', 'Gene', (158, 163))	('sp', 'Chemical', 'MESH:C000604007', (7, 9))	('rearrangement', 'Var', (137, 150))
18524	24467611	For the remaining two ccRCCs misclassified as pRCC, gains of 3p25, 3p21, and 3q11 were found, and it is possible in these cases that VHL was inactivated by other mechanisms such as mutation or methylation rather than deletion.	('VHL', 'Disease', 'MESH:D006623', (133, 136))	('RCC', 'Disease', (24, 27))	('methylation', 'Var', (193, 204))	('gains', 'PosReg', (52, 57))	('VHL', 'Disease', (133, 136))	('3p21', 'Gene', (67, 71))	('methylation', 'biological_process', 'GO:0032259', ('193', '204'))	('inactivated', 'NegReg', (141, 152))	('mutation', 'Var', (181, 189))	('3q11', 'Gene', (77, 81))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('3p25', 'Gene', (61, 65))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
18527	24467611	Another was from a patient with Birt-Hogg-Dube syndrome, wherein mutations in FLCN predispose carriers to chromophobe/oncocytic/hybrid renal tumours.	('patient', 'Species', '9606', (19, 26))	('chromophobe/oncocytic/hybrid renal tumours', 'Disease', (106, 148))	('sp', 'Chemical', 'MESH:C000604007', (88, 90))	('FLCN', 'Gene', '201163', (78, 82))	('renal tumour', 'Phenotype', 'HP:0009726', (135, 147))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('predispose', 'Reg', (83, 93))	('chromophobe/oncocytic/hybrid renal tumours', 'Disease', 'MESH:D007680', (106, 148))	('Birt-Hogg-Dube syndrome', 'Disease', (32, 55))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (32, 55))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('FLCN', 'Gene', (78, 82))	('mutations', 'Var', (65, 74))
18550	24467611	Interestingly, however, deletion at the 3p21 locus was found to be associated with OC and was observed in two of the 10 OC specimens as a classifying abnormality when observed without the gain of 5q that is commonly detected in ccRCC.	('3p21', 'Gene', (40, 44))	('sp', 'Chemical', 'MESH:C000604007', (123, 125))	('associated', 'Reg', (67, 77))	('deletion', 'Var', (24, 32))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))
18552	24467611	In ccRCC, mutational inactivation of the PBRM1 gene mapped to 3p21 has been implicated in tumorigenesis and also recently suggested to be associated with longer overall survival.	('longer', 'PosReg', (154, 160))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('associated', 'Reg', (138, 148))	('PBRM1', 'Gene', (41, 46))	('mutational inactivation', 'Var', (10, 33))	('implicated', 'Reg', (76, 86))	('tumorigenesis', 'CPA', (90, 103))
18556	24467611	This is exemplified in ccRCC, where VHL can also undergo inactivation by mutation and/or methylation.	('methylation', 'biological_process', 'GO:0032259', ('89', '100'))	('methylation', 'Var', (89, 100))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('VHL', 'Disease', (36, 39))	('mutation', 'Var', (73, 81))	('VHL', 'Disease', 'MESH:D006623', (36, 39))	('RCC', 'Disease', (25, 28))
18566	32532746	Targeting MET Dysregulation in Cancer Aberrant MET signaling can drive tumorigenesis in several cancer types through a variety of molecular mechanisms including MET gene amplification, mutation, rearrangement, and overexpression.	('MET', 'Gene', '79811', (47, 50))	('rearrangement', 'Var', (195, 208))	('MET', 'Gene', (10, 13))	('drive', 'Reg', (65, 70))	('MET', 'Gene', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('signaling', 'biological_process', 'GO:0023052', ('51', '60'))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (185, 193))	('Dysregulation', 'Var', (14, 27))	('MET', 'Gene', '79811', (161, 164))	('MET', 'Gene', (47, 50))	('MET', 'Gene', '79811', (10, 13))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (71, 76))	('overexpression', 'PosReg', (214, 228))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Cancer', 'Disease', (31, 37))
18570	32532746	In cancer, aberrant MET oncogenic signaling has been known to play a role in promoting tumor invasion, angiogenesis, and metastasis; however, the initial development of targeted therapies against MET in unselected patient populations and across different tumor types did not translate into improved clinical outcomes.	('MET', 'Gene', '79811', (196, 199))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('signaling', 'biological_process', 'GO:0023052', ('34', '43'))	('aberrant', 'Var', (11, 19))	('promoting', 'PosReg', (77, 86))	('MET', 'Gene', '79811', (20, 23))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('angiogenesis', 'CPA', (103, 115))	('patient', 'Species', '9606', (214, 221))	('tumor', 'Disease', (255, 260))	('MET', 'Gene', (196, 199))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('angiogenesis', 'biological_process', 'GO:0001525', ('103', '115'))	('metastasis', 'CPA', (121, 131))	('MET', 'Gene', (20, 23))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
18574	32532746	Upon ligand binding, MET homodimerization results in the phosphorylation of key intracellular tyrosine residues at positions Y1234/35 within the kinase domain and Y1349/56 in the docking site.	('intracellular', 'cellular_component', 'GO:0005622', ('80', '93'))	('MET', 'Gene', (21, 24))	('Y1349/56', 'Var', (163, 171))	('tyrosine', 'Chemical', 'MESH:D014443', (94, 102))	('ligand', 'molecular_function', 'GO:0005488', ('5', '11'))	('phosphorylation', 'biological_process', 'GO:0016310', ('57', '72'))	('results in', 'Reg', (42, 52))	('phosphorylation', 'MPA', (57, 72))	('MET', 'Gene', '79811', (21, 24))	('binding', 'molecular_function', 'GO:0005488', ('12', '19'))
18578	32532746	Exon 14 in MET is 141 nucleotides long, spanning from nucleotides c.2888 to c.3028, corresponding to amino acids p.D963 to p.D1010 (NM_000245.2, variant 2).	('MET', 'Gene', '79811', (11, 14))	('p.D1010', 'Var', (123, 130))	('D963', 'Chemical', '-', (115, 119))	('D1010', 'Chemical', '-', (125, 130))	('MET', 'Gene', (11, 14))	('c.3028', 'Var', (76, 82))	('p.D963', 'Var', (113, 119))
18579	32532746	Of note, in an alternative splice isoform of MET which is 54 nucleotides longer (NM_001127500.2 Variant 1), exon 14 spans from nucleotides c.2942 to c.3082, corresponding to amino acids p.D981 to p.D1028.	('p.D981', 'Var', (186, 192))	('D1028', 'Chemical', '-', (198, 203))	('MET', 'Gene', '79811', (45, 48))	('MET', 'Gene', (45, 48))	('p.D1028', 'Var', (196, 203))	('c.3082', 'Var', (149, 155))
18582	32532746	Since then, across diverse tumor types, multiple biological alterations in MET have been discovered including exon 14 skipping mutations, activating mutations in the kinase domain, gene amplification, and protein overexpression.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('protein', 'cellular_component', 'GO:0003675', ('205', '212'))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', (27, 32))	('exon', 'Var', (110, 114))	('overexpression', 'PosReg', (213, 227))	('skipping', 'Gene', (118, 126))	('activating', 'PosReg', (138, 148))	('MET', 'Gene', '79811', (75, 78))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('MET', 'Gene', (75, 78))
18584	32532746	Approximately 3% of advanced non-small cell lung cancers (NSCLC) harbor point mutations or deletions in MET exon 14 or its flanking introns which affect splicing sequences including 5'- and 3'-splice sites, the branch-point adenosine, or the polypyrimidine tract.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('lung cancers', 'Phenotype', 'HP:0100526', (44, 56))	("5'-", 'MPA', (182, 185))	('MET', 'Gene', (104, 107))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (29, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('adenosine', 'Chemical', 'MESH:D000241', (224, 233))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (33, 55))	('deletions', 'Var', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('polypyrimidine', 'Chemical', '-', (242, 256))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (33, 56))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('MET', 'Gene', '79811', (104, 107))	('splicing sequences', 'MPA', (153, 171))	('affect', 'Reg', (146, 152))	('point mutations', 'Var', (72, 87))	('branch-point adenosine', 'MPA', (211, 233))	('NSCLC', 'Disease', (58, 63))	('splicing', 'biological_process', 'GO:0045292', ('153', '161'))	('lung cancers', 'Disease', 'MESH:D008175', (44, 56))	('small cell lung cancer', 'Disease', 'MESH:D055752', (33, 55))	('lung cancers', 'Disease', (44, 56))	('small cell lung cancer', 'Disease', (33, 55))
18585	32532746	These alterations result in MET exon 14 skipping during pre-mRNA splicing, resulting in loss of the CBL-binding site and increased half-life of the MET receptor (Figure 1A).	('alterations', 'Var', (6, 17))	('pre', 'molecular_function', 'GO:0003904', ('56', '59'))	('CBL', 'Gene', (100, 103))	('increased', 'PosReg', (121, 130))	('MET', 'Gene', '79811', (28, 31))	('pre-mRNA splicing', 'biological_process', 'GO:0000398', ('56', '73'))	('skipping', 'NegReg', (40, 48))	('half-life', 'MPA', (131, 140))	('loss', 'NegReg', (88, 92))	('CBL', 'Gene', '867', (100, 103))	('MET', 'Gene', '79811', (148, 151))	('MET', 'Gene', (28, 31))	('binding', 'molecular_function', 'GO:0005488', ('104', '111'))	('MET', 'Gene', (148, 151))
18586	32532746	As has been described in some hereditary syndromes, point mutations in the last nucleotide of an exon often result in exon skipping, and point mutations in the last nucleotide of MET exon 14 (c.3028 = c.3082; D1010X = D1028X in the shorter and longer isoforms of MET, respectively) also tend to cause exon 14 skipping.	('D1010X', 'Mutation', 'p.D1010X', (209, 215))	('hereditary syndromes', 'Disease', (30, 50))	('MET', 'Gene', (263, 266))	('result in', 'Reg', (108, 117))	('MET', 'Gene', '79811', (179, 182))	('hereditary syndromes', 'Disease', 'MESH:D061325', (30, 50))	('cause', 'Reg', (295, 300))	('MET', 'Gene', (179, 182))	('c.3028 = c.3082; D1010X = D1028X', 'Var', (192, 224))	('exon skipping', 'MPA', (118, 131))	('exon 14 skipping', 'MPA', (301, 317))	('MET', 'Gene', '79811', (263, 266))	('point mutations', 'Var', (52, 67))	('D1028X', 'Mutation', 'p.D1028X', (218, 224))
18587	32532746	Additional point mutations causing amino acid substitution of the Y1003 residue (=Y1021), such as Y1003C or Y1003F, are predicted to cause a similar biologic effect through loss of the CBL binding site without causing exon 14 skipping.	('Y1003F', 'Var', (108, 114))	('Y1003', 'Var', (66, 71))	('binding', 'molecular_function', 'GO:0005488', ('189', '196'))	('Y1003F', 'Mutation', 'p.Y1003F', (108, 114))	('CBL', 'Gene', (185, 188))	('CBL', 'Gene', '867', (185, 188))	('Y1003C', 'Var', (98, 104))	('loss', 'NegReg', (173, 177))	('Y1003C', 'Mutation', 'p.Y1003C', (98, 104))	('cause', 'Reg', (133, 138))
18588	32532746	Splice site and Y1003X mutations differ from other mutations within exon 14, like T992I (=T1010I).	('T992I', 'Mutation', 'p.T992I', (82, 87))	('Y1003X', 'Var', (16, 22))	('Y1003X', 'Mutation', 'p.Y1003X', (16, 22))	('T1010I', 'Mutation', 'p.T1010I', (90, 96))	('T992I', 'Var', (82, 87))
18589	32532746	The oncogenic potential of this variant is controversial, as some preclinical studies suggest that it imparts greater tumor growth and invasion potential whereas others report a lack of transforming capacity; this variant does not cause MET exon 14 skipping or seem to affect the CBL binding site.	('CBL', 'Gene', '867', (280, 283))	('MET', 'Gene', '79811', (237, 240))	('affect', 'Reg', (269, 275))	('binding site', 'Interaction', (284, 296))	('transforming', 'MPA', (186, 198))	('MET', 'Gene', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('lack', 'NegReg', (178, 182))	('binding', 'molecular_function', 'GO:0005488', ('284', '291'))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('greater', 'PosReg', (110, 117))	('variant', 'Var', (214, 221))	('tumor', 'Disease', (118, 123))	('invasion potential', 'CPA', (135, 153))	('CBL', 'Gene', (280, 283))
18590	32532746	MET exon 14 mutant NSCLC tends to occur in older patients (median age ~72) with a history of tobacco use, but can also be found in never smokers.	('MET', 'Gene', '79811', (0, 3))	('occur', 'Reg', (34, 39))	('MET', 'Gene', (0, 3))	('mutant', 'Var', (12, 18))	('NSCLC', 'Disease', (19, 24))	('patients', 'Species', '9606', (49, 57))	('tobacco', 'Species', '4097', (93, 100))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))
18591	32532746	These alterations are most commonly detected in lung adenocarcinomas, but are also enriched in pulmonary sarcomatoid (pleomorphic) carcinomas and can be found in squamous and adenosquamous NSCLC, and also rarely in other cancer types like gliomas and unknown primary tumors.	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (48, 68))	('detected', 'Reg', (36, 44))	('gliomas', 'Phenotype', 'HP:0009733', (239, 246))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumors', 'Disease', (267, 273))	('lung adenocarcinomas', 'Disease', (48, 68))	('pulmonary sarcomatoid (pleomorphic) carcinomas', 'Disease', 'MESH:C538614', (95, 141))	('cancer', 'Disease', (221, 227))	('squamous and adenosquamous NSCLC', 'Disease', 'MESH:D018196', (162, 194))	('gliomas', 'Disease', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('gliomas', 'Disease', 'MESH:D005910', (239, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
18592	32532746	De novo MET exon 14 alterations are almost always mutually exclusive with other oncogenic driver mutations like KRAS, EGFR, ALK, ROS1, and RET, and commonly co-occurring genomic alterations include mutations in TP53, loss of CDKN2A/B, and amplifications of MET, MDM2, and CDK4/6.	('ALK', 'Gene', '238', (124, 127))	('CDK4/6', 'Gene', '1019;1021', (272, 278))	('ALK', 'Gene', (124, 127))	('TP53', 'Gene', (211, 215))	('MET', 'Gene', (8, 11))	('alterations', 'Var', (20, 31))	('amplifications', 'Var', (239, 253))	('RET', 'Gene', (139, 142))	('ROS1', 'Gene', '6098', (129, 133))	('MET', 'Gene', '79811', (257, 260))	('CDKN2A/B', 'Gene', '1029;1030', (225, 233))	('mutations', 'Var', (198, 207))	('EGFR', 'Gene', '1956', (118, 122))	('KRAS', 'Gene', '3845', (112, 116))	('loss', 'NegReg', (217, 221))	('CDK', 'molecular_function', 'GO:0004693', ('272', '275'))	('TP53', 'Gene', '7157', (211, 215))	('MET', 'Gene', '79811', (8, 11))	('MDM2', 'Gene', (262, 266))	('KRAS', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('118', '122'))	('CDK4/6', 'Gene', (272, 278))	('ROS1', 'Gene', (129, 133))	('MET', 'Gene', (257, 260))	('MDM2', 'Gene', '4193', (262, 266))	('EGFR', 'Gene', (118, 122))	('CDKN2A/B', 'Gene', (225, 233))	('RET', 'Gene', '5979', (139, 142))
18593	32532746	The large diversity of MET genomic alterations leading to exon 14 skipping can pose a challenge for the routine detection of these mutations and deletions in clinical practice.	('MET', 'Gene', (23, 26))	('exon', 'Var', (58, 62))	('leading to', 'Reg', (47, 57))	('MET', 'Gene', '79811', (23, 26))
18594	32532746	Current methods used to identify lung cancers harboring MET exon 14 mutations include DNA next generation sequencing (NGS) platforms, Sanger sequencing of exon 14 and its flanking introns, and the detection of MET exon 14 skipping using RNA-based assays like reverse transcription polymerase chain reaction (RT-qPCR) and RNA based NGS.	('RNA', 'cellular_component', 'GO:0005562', ('321', '324'))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('RNA', 'cellular_component', 'GO:0005562', ('237', '240'))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('MET', 'Gene', '79811', (210, 213))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('reverse transcription', 'biological_process', 'GO:0001171', ('259', '280'))	('skipping', 'NegReg', (222, 230))	('MET', 'Gene', (210, 213))	('MET', 'Gene', '79811', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('MET', 'Gene', (56, 59))	('lung cancers', 'Disease', (33, 45))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('mutations', 'Var', (68, 77))
18595	32532746	At present, there are no certified companion diagnostic tests for the detection of MET exon 14 skipping alterations that are recommended to identify patients for treatment with specific MET inhibitors; however NGS and RT-qPCR assays appear to demonstrate higher sensitivity compared to Sanger sequencing.	('patients', 'Species', '9606', (149, 157))	('MET', 'Gene', '79811', (83, 86))	('MET', 'Gene', (83, 86))	('MET', 'Gene', '79811', (186, 189))	('skipping', 'Var', (95, 103))	('MET', 'Gene', (186, 189))
18597	32532746	With mounting evidence that MET exon 14 mutant NSCLC can respond to MET tyrosine kinase inhibitors (see "Targeting MET alterations in cancer"), the inclusion of this promising biomarker in clinical sequencing assays among patients with advanced NSCLC should be strongly encouraged.	('MET', 'Gene', (68, 71))	('MET', 'Gene', '79811', (28, 31))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('NSCLC', 'Disease', (245, 250))	('MET', 'Gene', '79811', (115, 118))	('patients', 'Species', '9606', (222, 230))	('MET', 'Gene', (28, 31))	('NSCLC', 'Disease', (47, 52))	('NSCLC', 'Disease', 'MESH:D002289', (245, 250))	('mutant', 'Var', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MET', 'Gene', (115, 118))	('MET', 'Gene', '79811', (68, 71))
18598	32532746	Activating oncogenic mutations can also occur in other domains of MET, including in the tyrosine kinase domain (TKD), leading to ligand-independent receptor phosphorylation and signaling (Figure 1B).	('signaling', 'MPA', (177, 186))	('Activating', 'PosReg', (0, 10))	('signaling', 'biological_process', 'GO:0023052', ('177', '186'))	('phosphorylation', 'biological_process', 'GO:0016310', ('157', '172'))	('MET', 'Gene', '79811', (66, 69))	('MET', 'Gene', (66, 69))	('tyrosine', 'Chemical', 'MESH:D014443', (88, 96))	('ligand-independent receptor phosphorylation', 'MPA', (129, 172))	('ligand', 'molecular_function', 'GO:0005488', ('129', '135'))	('mutations', 'Var', (21, 30))
18599	32532746	Activating hereditary or sporadic point mutations in the MET TKD are found in about 13-20% of type 1 papillary renal cell carcinomas (pRCC) and result in constitutive MET receptor activation by affecting the inhibitory conformation of the activation loop, favoring kinase domain phosphorylation and prompting the downstream oncogenic signaling cascades.	('papillary renal cell carcinomas', 'Disease', (101, 132))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (101, 132))	('favoring', 'PosReg', (256, 264))	('MET', 'Gene', (57, 60))	('prompting', 'Reg', (299, 308))	('MET', 'Gene', (167, 170))	('point mutations', 'Var', (34, 49))	('type 1 papillary renal cell carcinomas', 'Phenotype', 'HP:0011797', (94, 132))	('signaling', 'biological_process', 'GO:0023052', ('334', '343'))	('affecting', 'Reg', (194, 203))	('pRCC', 'Gene', '5546', (134, 138))	('inhibitory conformation of the activation loop', 'MPA', (208, 254))	('phosphorylation', 'biological_process', 'GO:0016310', ('279', '294'))	('result in', 'Reg', (144, 153))	('kinase domain phosphorylation', 'MPA', (265, 294))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (101, 132))	('MET', 'Gene', '79811', (57, 60))	('activation', 'PosReg', (180, 190))	('MET', 'Gene', '79811', (167, 170))	('oncogenic', 'CPA', (324, 333))	('pRCC', 'Gene', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (111, 132))
18600	32532746	The variety of MET activating mutations found in pRCC include: V1092I (V1110), H1094Y/R/L (H1112), H1124D (H1142), L1195F/V (L1213), F1200I (F1218), V1188L (V1206), Y1220I (Y1238), D1228H/N (D1246), Y1230C/D/H (Y1248), M1131T (M1149), and M1250T (M1268).	('pRCC', 'Gene', '5546', (49, 53))	('Y1220I', 'Mutation', 'p.Y1220I', (165, 171))	('V1188L', 'Mutation', 'p.V1188L', (149, 155))	('H1094Y', 'SUBSTITUTION', 'None', (79, 85))	('M1250T', 'Mutation', 'p.M1250T', (239, 245))	('F1200I', 'Mutation', 'p.F1200I', (133, 139))	('D1228H', 'Var', (181, 187))	('L1195F', 'Var', (115, 121))	('M1131T', 'Mutation', 'p.M1131T', (219, 225))	('V1092I', 'Mutation', 'p.V1092I', (63, 69))	('V1206', 'Var', (157, 162))	('pRCC', 'Gene', (49, 53))	('H1124D', 'Mutation', 'p.H1124D', (99, 105))	('Y1220I (Y1238', 'Var', (165, 178))	('MET', 'Gene', (15, 18))	('V1188L (V1206', 'Var', (149, 162))	('Y1230C', 'Var', (199, 205))	('F1200I (F1218', 'Var', (133, 146))	('H1094Y', 'Var', (79, 85))	('M1250T', 'Var', (239, 245))	('Y1230C', 'SUBSTITUTION', 'None', (199, 205))	('V1092I', 'Var', (63, 69))	('L1195F', 'SUBSTITUTION', 'None', (115, 121))	('D1228H', 'SUBSTITUTION', 'None', (181, 187))	('MET', 'Gene', '79811', (15, 18))	('Y1248', 'Chemical', '-', (211, 216))
18601	32532746	Additionally, higher levels of MET expression are observed in pRCC due to allelic imbalances resulting from chromosome 7 polysomy, suggesting that additive oncogenic mechanisms are required to drive MET dependency in this tumor type.	('MET', 'Gene', '79811', (199, 202))	('pRCC', 'Gene', '5546', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('imbalances', 'Phenotype', 'HP:0002172', (82, 92))	('MET', 'Gene', '79811', (31, 34))	('polysomy', 'Var', (121, 129))	('MET', 'Gene', (31, 34))	('expression', 'MPA', (35, 45))	('MET', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('pRCC', 'Gene', (62, 66))	('chromosome 7 polysomy', 'Var', (108, 129))	('levels', 'MPA', (21, 27))	('higher', 'PosReg', (14, 20))
18603	32532746	Interestingly, several of these activating MET mutations can also cause resistance to MET TKIs.	('resistance', 'MPA', (72, 82))	('MET', 'Gene', (43, 46))	('MET', 'Gene', '79811', (86, 89))	('MET', 'Gene', (86, 89))	('mutations', 'Var', (47, 56))	('cause', 'Reg', (66, 71))	('MET', 'Gene', '79811', (43, 46))	('activating', 'PosReg', (32, 42))
18604	32532746	For example, the L1195V/F, D1228X and Y1230X mutations, which are activating MET mutations, also cause acquired resistance to MET TKIs in MET exon 14 mutant lung cancers (See "Resistance Mechanisms to MET TKI").	('MET', 'Gene', '79811', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('acquired resistance', 'MPA', (103, 122))	('MET', 'Gene', '79811', (138, 141))	('MET', 'Gene', '79811', (201, 204))	('D1228X', 'Var', (27, 33))	('Y1230X', 'Var', (38, 44))	('MET', 'Gene', (77, 80))	('MET', 'Gene', (126, 129))	('lung cancers', 'Disease', 'MESH:D008175', (157, 169))	('Y1230X', 'SUBSTITUTION', 'None', (38, 44))	('L1195V', 'Var', (17, 23))	('L1195V', 'SUBSTITUTION', 'None', (17, 23))	('lung cancers', 'Disease', (157, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('MET', 'Gene', '79811', (77, 80))	('MET', 'Gene', (138, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (157, 169))	('MET', 'Gene', (201, 204))	('D1228X', 'SUBSTITUTION', 'None', (27, 33))	('cause', 'Reg', (97, 102))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
18605	32532746	A similar phenomenon has been observed with activating mutations of ALK; for example, the ALK F1174L driver mutation in neuroblastoma is a known mechanism of acquired resistance in TKI-treated ALK-rearranged lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('F1174L', 'Var', (94, 100))	('ALK', 'Gene', (68, 71))	('ALK', 'Gene', '238', (90, 93))	('ALK', 'Gene', '238', (193, 196))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('neuroblastoma', 'Disease', 'MESH:D009447', (120, 133))	('F1174L', 'Mutation', 'rs863225281', (94, 100))	('ALK', 'Gene', (90, 93))	('ALK', 'Gene', '238', (68, 71))	('neuroblastoma', 'Disease', (120, 133))	('ALK', 'Gene', (193, 196))	('neuroblastoma', 'Phenotype', 'HP:0003006', (120, 133))	('lung cancer', 'Disease', (208, 219))
18606	32532746	This suggests that TKI-resistance mutations in MET may also result in increases in kinase activity.	('MET', 'Gene', '79811', (47, 50))	('MET', 'Gene', (47, 50))	('kinase activity', 'MPA', (83, 98))	('increases', 'PosReg', (70, 79))	('kinase activity', 'molecular_function', 'GO:0016301', ('83', '98'))	('mutations', 'Var', (34, 43))
18607	32532746	In addition to MET kinase domain mutations, mutations affecting the Sema domain in the extracellular compartment have been described in cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('Sema', 'Gene', (68, 72))	('Sema', 'Gene', '7869', (68, 72))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (44, 53))	('MET', 'Gene', '79811', (15, 18))	('extracellular', 'cellular_component', 'GO:0005576', ('87', '100'))	('MET', 'Gene', (15, 18))	('described', 'Reg', (123, 132))
18608	32532746	Sema mutations may affect ligand-binding, though the functional implications of these mutations in MET signaling and their therapeutic relevance is unknown.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('MET', 'Gene', (99, 102))	('ligand-binding', 'Interaction', (26, 40))	('ligand', 'molecular_function', 'GO:0005488', ('26', '32'))	('mutations', 'Var', (5, 14))	('affect', 'Reg', (19, 25))	('signaling', 'biological_process', 'GO:0023052', ('103', '112'))	('Sema', 'Gene', (0, 4))	('MET', 'Gene', '79811', (99, 102))	('Sema', 'Gene', '7869', (0, 4))
18622	32532746	In MET exon 14 mutant lung cancer, concomitant MET amplification is found in ~15% of cases, showing that MET dependency in lung cancer can be driven by synergistic genomic events.	('lung cancer', 'Disease', (22, 33))	('MET', 'Gene', '79811', (47, 50))	('MET', 'Gene', '79811', (3, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MET', 'Gene', (47, 50))	('MET', 'Gene', (3, 6))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('MET', 'Gene', '79811', (105, 108))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutant', 'Var', (15, 21))	('MET', 'Gene', (105, 108))
18625	32532746	MET amplification is a common determinant of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with lung cancers harboring EGFR sensitizing mutations.	('MET', 'Gene', '79811', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('EGFR', 'Gene', (147, 151))	('lung cancers', 'Disease', (124, 136))	('EGFR', 'molecular_function', 'GO:0005006', ('147', '151'))	('EGFR', 'Gene', (68, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (124, 136))	('MET', 'Gene', (0, 3))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'molecular_function', 'GO:0005006', ('68', '72'))	('lung cancers', 'Disease', 'MESH:D008175', (124, 136))	('EGFR', 'Gene', '1956', (147, 151))	('mutations', 'Var', (164, 173))	('patients', 'Species', '9606', (110, 118))	('acquired resistance', 'MPA', (45, 64))
18631	32532746	Rearrangements involving the kinase domain of ALK, ROS1, RET, and NTRK occur in lung cancer and other tumors and are predictive biomarkers of clinical benefit with selected tyrosine kinase inhibitors.	('Rearrangements', 'Var', (0, 14))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('ROS1', 'Gene', (51, 55))	('RET', 'Gene', (57, 60))	('ROS1', 'Gene', '6098', (51, 55))	('ALK', 'Gene', '238', (46, 49))	('lung cancer', 'Disease', (80, 91))	('tyrosine', 'Chemical', 'MESH:D014443', (173, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('RET', 'Gene', '5979', (57, 60))	('NTRK', 'Gene', (66, 70))	('ALK', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('occur', 'Reg', (71, 76))
18636	32532746	MET rearrangements have been identified in patients with NSCLC (~0.5%), pediatric (10%) and adult glioblastomas (3%), and as single case reports in patients with salivary secretory carcinoma and infantile spindle sarcomas.	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))	('patients', 'Species', '9606', (148, 156))	('glioblastomas', 'Phenotype', 'HP:0012174', (98, 111))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcomas', 'Disease', (213, 221))	('MET', 'Gene', (0, 3))	('spindle', 'cellular_component', 'GO:0005819', ('205', '212'))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('carcinoma', 'Disease', (181, 190))	('patients', 'Species', '9606', (43, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('identified', 'Reg', (29, 39))	('glioblastomas', 'Disease', (98, 111))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))	('MET', 'Gene', '79811', (0, 3))	('rearrangements', 'Var', (4, 18))	('glioblastomas', 'Disease', 'MESH:D005909', (98, 111))	('carcinoma', 'Disease', 'MESH:D009369', (181, 190))	('NSCLC', 'Disease', (57, 62))
18639	32532746	In secondary glioblastoma, PTPRZ1-MET fusions are detected in 14% of cases and are associated with detrimental survival outcomes.	('MET', 'Gene', '79811', (34, 37))	('PTPRZ1', 'Gene', (27, 33))	('glioblastoma', 'Disease', (13, 25))	('glioblastoma', 'Disease', 'MESH:D005909', (13, 25))	('MET', 'Gene', (34, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (13, 25))	('detected', 'Reg', (50, 58))	('associated', 'Reg', (83, 93))	('PTPRZ1', 'Gene', '5803', (27, 33))	('fusions', 'Var', (38, 45))
18653	32532746	Several type I MET TKIs are currently in clinical development, and are further subdivided according to their interaction with the solvent front residue G1163: type Ia inhibitors like crizotinib (Xalkori, Pfizer) interact with this residue, and type Ib inhibitors like tepotinib (MSC2156119J, Merck), capmatinib (INC280, Novartis), and savolitinib (AZD6094, AstraZeneca) and APL-101 (Apollomics) which are independent of G1163 interaction.	('crizotinib', 'Chemical', 'MESH:D000077547', (183, 193))	('G1163', 'Chemical', '-', (152, 157))	('AZD6094', 'Var', (348, 355))	('tepotinib', 'Chemical', 'MESH:C582858', (268, 277))	('APL', 'Disease', 'MESH:D015473', (374, 377))	('APL', 'Disease', (374, 377))	('G1163', 'Chemical', '-', (420, 425))	('capmatinib', 'Chemical', 'MESH:C000613976', (300, 310))	('AZD6094', 'Chemical', 'MESH:C000593259', (348, 355))	('MET', 'Gene', '79811', (15, 18))	('MET', 'Gene', (15, 18))	('savolitinib', 'Chemical', 'MESH:C000593259', (335, 346))
18654	32532746	In addition, type II MET inhibitors include cabozantinib (Cabometyx, Exelixis), foretinib (XL-880, GlaxoSmithKline), merestinib (LY2801653, Lilly), and glesatinib (MGCD265, Mirati Therapeutics).	('LY2801653', 'Var', (129, 138))	('Cabometyx', 'Chemical', 'MESH:C558660', (58, 67))	('LY2801653', 'Chemical', 'MESH:C586252', (129, 138))	('foretinib', 'Chemical', 'MESH:C544831', (80, 89))	('MET', 'Gene', (21, 24))	('merestinib', 'Chemical', 'MESH:C586252', (117, 127))	('cabozantinib', 'Chemical', 'MESH:C558660', (44, 56))	('glesatinib', 'Chemical', 'MESH:C000627807', (152, 162))	('MET', 'Gene', '79811', (21, 24))
18656	32532746	Several clinical trials are studying the efficacy of MET TKIs in the treatment of patients with MET exon 14 mutant NSCLC.	('MET', 'Gene', '79811', (96, 99))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (115, 120))	('mutant', 'Var', (108, 114))	('MET', 'Gene', (96, 99))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('MET', 'Gene', '79811', (53, 56))	('MET', 'Gene', (53, 56))
18657	32532746	Results presented in studies of crizotinib (NCT00585195), capmatinib (NCT02414139), tepotinib (NCT02864992), and savolitinib (NCT02897479) have shown a response rate to type I TKIs ranging from 32% to 68% (Table 1).	('NCT02414139', 'Var', (70, 81))	('type I TKIs', 'Disease', (169, 180))	('crizotinib', 'Chemical', 'MESH:D000077547', (32, 42))	('capmatinib', 'Chemical', 'MESH:C000613976', (58, 68))	('tepotinib', 'Chemical', 'MESH:C582858', (84, 93))	('NCT00585195', 'Var', (44, 55))	('NCT02864992', 'Var', (95, 106))	('savolitinib', 'Chemical', 'MESH:C000593259', (113, 124))	('NCT02897479', 'Var', (126, 137))
18658	32532746	In addition to type I MET inhibitors, clinical trials with type II TKIs like cabozantinib (NCT01639508) and merestinib (NCT02920996) are ongoing.	('NCT01639508', 'Var', (91, 102))	('merestinib', 'Chemical', 'MESH:C586252', (108, 118))	('MET', 'Gene', '79811', (22, 25))	('MET', 'Gene', (22, 25))	('cabozantinib', 'Chemical', 'MESH:C558660', (77, 89))
18664	32532746	This combination is being further explored prospectively in the SAVANNAH (NCT03778229) and ORCHARD studies (NCT03944772), which also aim to refine the optimal method and tool for defining MET amplification in a clinically-relevant setting.	('MET', 'Gene', (188, 191))	('NCT03944772', 'Var', (108, 119))	('ORCHARD', 'Disease', (91, 98))	('NCT03778229', 'Var', (74, 85))	('ORCHARD', 'Disease', 'None', (91, 98))	('MET', 'Gene', '79811', (188, 191))
18668	32532746	Furthermore, a phase II study of the dual MET/ VEGFR2 inhibitor foretinib (GSK1363089, GlaxoSmithKline) in patients with MET-altered pRCC (including germline mutations, somatic MET mutations, amplifications or chromosome 7 duplications) showed a 13.5% response rate and a median PFS of 9.3 months (95% CI: 6.9-12.9).	('GSK', 'molecular_function', 'GO:0050321', ('75', '78'))	('patients', 'Species', '9606', (107, 115))	('VEGFR2', 'Gene', (47, 53))	('pRCC', 'Gene', (133, 137))	('MET', 'Gene', '79811', (42, 45))	('amplifications', 'Var', (192, 206))	('MET', 'Gene', '79811', (121, 124))	('MET', 'Gene', (42, 45))	('MET', 'Gene', '79811', (177, 180))	('foretinib', 'Chemical', 'MESH:C544831', (64, 73))	('pRCC', 'Gene', '5546', (133, 137))	('mutations', 'Var', (181, 190))	('MET', 'Gene', (121, 124))	('MET', 'Gene', (177, 180))	('VEGFR2', 'Gene', '3791', (47, 53))	('chromosome', 'cellular_component', 'GO:0005694', ('210', '220'))	('chromosome', 'Var', (210, 220))	('GSK1363089', 'Chemical', 'MESH:C544831', (75, 85))
18669	32532746	Together, these early studies support the development of MET TKIs for the treatment of MET-driven papillary renal carcinomas; however, to identify which specific activating mutations are sensitive to MET TKIs, detailed genomic information among responders and non-responders should be made available from these studies.	('MET', 'Gene', (57, 60))	('papillary renal carcinomas', 'Phenotype', 'HP:0006766', (98, 124))	('MET', 'Gene', '79811', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('MET', 'Gene', '79811', (57, 60))	('renal carcinomas', 'Phenotype', 'HP:0005584', (108, 124))	('mutations', 'Var', (173, 182))	('MET', 'Gene', '79811', (200, 203))	('MET', 'Gene', (87, 90))	('papillary renal carcinomas', 'Disease', 'MESH:C538614', (98, 124))	('papillary renal carcinomas', 'Disease', (98, 124))	('MET', 'Gene', (200, 203))
18672	32532746	In the randomized phase III of the monoclonal antibody onartuzumab (MetMAb, Roche) in unselected patients with NSCLC, adding onartuzumab to erlotinib in patients previously treated with chemotherapy had a detrimental effect on overall survival; this therapy also showed no benefit in an exploratory analysis of patients with MET-amplified tumors by FISH (>5 copies).	('detrimental', 'NegReg', (205, 216))	('NSCLC', 'Disease', (111, 116))	('overall', 'MPA', (227, 234))	('antibody', 'molecular_function', 'GO:0003823', ('46', '54'))	('antibody', 'cellular_component', 'GO:0042571', ('46', '54'))	('onartuzumab', 'Var', (125, 136))	('MET', 'Gene', (325, 328))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('MetMAb', 'Chemical', 'MESH:C584058', (68, 74))	('tumors', 'Disease', (339, 345))	('antibody', 'cellular_component', 'GO:0019815', ('46', '54'))	('MET', 'Gene', '79811', (325, 328))	('onartuzumab', 'Chemical', 'MESH:C584058', (55, 66))	('patients', 'Species', '9606', (97, 105))	('patients', 'Species', '9606', (153, 161))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('antibody', 'cellular_component', 'GO:0019814', ('46', '54'))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('patients', 'Species', '9606', (311, 319))	('erlotinib', 'Chemical', 'MESH:D000069347', (140, 149))	('adding onartuzumab', 'Var', (118, 136))	('onartuzumab', 'Chemical', 'MESH:C584058', (125, 136))
18677	32532746	The etiology of the negative impact of combining MET inhibition with chemotherapy in unselected patients is unclear, but one hypothesis is that MET inhibitors may dysregulate immune-mediated cytotoxicity and factors in the tumor microenvironment.	('inhibitors', 'Var', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('MET', 'Gene', '79811', (49, 52))	('MET', 'Gene', '79811', (144, 147))	('MET', 'Gene', (144, 147))	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('dysregulate', 'Reg', (163, 174))	('MET', 'Gene', (49, 52))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cytotoxicity', 'Disease', (191, 203))
18681	32532746	Sym015 (Symphogen A/S, Denmark) is a mixture of two IgG1 humanized monoclonal antibodies (Hu9006 and Hu9338) directed against non-overlapping epitopes in the SEMA alpha-domain of MET.	('MET', 'Gene', '79811', (179, 182))	('Hu9006', 'Var', (90, 96))	('SEMA', 'Gene', (158, 162))	('SEMA', 'Gene', '7869', (158, 162))	('MET', 'Gene', (179, 182))	('Hu9006', 'CellLine', 'CVCL:8357', (90, 96))	('Hu9338', 'Var', (101, 107))	('Hu9338', 'CellLine', 'CVCL:8357', (101, 107))	('IgG1', 'cellular_component', 'GO:0071735', ('52', '56'))	('human', 'Species', '9606', (57, 62))
18682	32532746	This combination of antibodies confers potent in vitro and in vivo activity in MET-amplified and MET exon 14 mutant models and is currently in clinical development (NCT02648724).	('MET', 'Gene', '79811', (79, 82))	('MET', 'Gene', '79811', (97, 100))	('MET', 'Gene', (79, 82))	('activity', 'MPA', (67, 75))	('mutant', 'Var', (109, 115))	('MET', 'Gene', (97, 100))
18685	32532746	Preliminary reports of the phase I dose escalation cohort showed encouraging clinical activity for patients with EGFR mutations.	('mutations', 'Var', (118, 127))	('patients', 'Species', '9606', (99, 107))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('EGFR', 'molecular_function', 'GO:0005006', ('113', '117'))
18691	32532746	Established biological mechanisms of resistance to TKIs include: 1) acquisition of on-target kinase domain mutations affecting drug binding to the receptor or its ATP affinity, 2) bypass track activation of oncogenic signaling pathways, and 3) histological transformation such epithelial-mesenchymal transition or small cell lung cancer transformation, although in many cases, the molecular mechanisms of drug resistance are unknown.	('lung cancer', 'Phenotype', 'HP:0100526', (325, 336))	('drug resistance', 'Phenotype', 'HP:0020174', (405, 420))	('epithelial-mesenchymal transition', 'CPA', (277, 310))	('signaling', 'biological_process', 'GO:0023052', ('217', '226'))	('mutations', 'Var', (107, 116))	('small cell lung cancer', 'Disease', 'MESH:D055752', (314, 336))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (314, 336))	('drug binding', 'molecular_function', 'GO:0008144', ('127', '139'))	('oncogenic signaling pathways', 'Pathway', (207, 235))	('ATP', 'Chemical', 'MESH:D000255', (163, 166))	('small cell lung cancer', 'Disease', (314, 336))	('affecting', 'Reg', (117, 126))	('binding', 'Interaction', (132, 139))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('277', '310'))	('drug resistance', 'biological_process', 'GO:0009315', ('405', '420'))	('drug resistance', 'biological_process', 'GO:0042493', ('405', '420'))
18692	32532746	In the MET-amplified or MET exon 14-alterated NSCLC, secondary MET kinase domain mutations have been clinically documented and preclinically characterized to confer resistance to type I and type II MET TKIs.	('MET', 'Gene', (198, 201))	('MET', 'Gene', '79811', (7, 10))	('MET', 'Gene', '79811', (24, 27))	('MET', 'Gene', '79811', (63, 66))	('MET', 'Gene', (7, 10))	('NSCLC', 'Disease', (46, 51))	('MET', 'Gene', (63, 66))	('MET', 'Gene', (24, 27))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('domain mutations', 'Var', (74, 90))	('MET', 'Gene', '79811', (198, 201))	('resistance', 'MPA', (165, 175))
18694	32532746	The solvent front mutation G1163R, which is analogous to the ALK G1202R and ROS1 G2023R TKI resistance solvent front mutations, confers resistance to the type Ia MET inhibitor crizotinib but not to type Ib or II MET TKIs (Figure 2B).	('G2023R', 'Var', (81, 87))	('MET', 'Gene', '79811', (212, 215))	('crizotinib', 'Chemical', 'MESH:D000077547', (176, 186))	('MET', 'Gene', (162, 165))	('ALK', 'Gene', (61, 64))	('G1202R', 'Mutation', 'rs1057519783', (65, 71))	('resistance', 'MPA', (136, 146))	('MET', 'Gene', (212, 215))	('G2023R', 'Mutation', 'p.G2023R', (81, 87))	('MET', 'Gene', '79811', (162, 165))	('G1163R', 'Mutation', 'p.G1163R', (27, 33))	('ROS1', 'Gene', (76, 80))	('ALK', 'Gene', '238', (61, 64))	('G1202R', 'Var', (65, 71))	('ROS1', 'Gene', '6098', (76, 80))	('G1163R', 'Var', (27, 33))
18696	32532746	The efficacy of type II MET inhibitors in overcoming resistance to type I TKI-resistant tumors, particularly with acquiring mutations at residues D1228 and Y1230, is supported by preclinical rational and clinical reports.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('overcoming', 'PosReg', (42, 52))	('MET', 'Gene', '79811', (24, 27))	('MET', 'Gene', (24, 27))	('Y1230', 'Var', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Y1230', 'Chemical', '-', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('D1228', 'Chemical', '-', (146, 151))
18698	32532746	Other mutations, involving residues F1200 and L1195, affect the binding of type II inhibitors to the DFG-out conformation resulting in resistance to these compounds (Figure 2C).	('binding', 'Interaction', (64, 71))	('binding', 'molecular_function', 'GO:0005488', ('64', '71'))	('DFG', 'Chemical', '-', (101, 104))	('F1200', 'Var', (36, 41))	('affect', 'Reg', (53, 59))	('L1195', 'Var', (46, 51))	('type', 'Enzyme', (75, 79))	('resistance', 'MPA', (135, 145))
18699	32532746	In vitro assays suggest that F1200I also confers resistance to type I MET TKI with the exception of savolitinib.	('savolitinib', 'Chemical', 'MESH:C000593259', (100, 111))	('F1200I', 'Mutation', 'p.F1200I', (29, 35))	('MET', 'Gene', '79811', (70, 73))	('F1200I', 'Var', (29, 35))	('MET', 'Gene', (70, 73))	('resistance', 'MPA', (49, 59))
18701	32532746	Understanding the implication of these secondary kinase domain mutations in conferring sensitivity or resistance to the growing repertoire of available MET TKIs may help guide clinical strategies to sequence MET inhibitors at the time of resistance.	('mutations', 'Var', (63, 72))	('MET', 'Gene', '79811', (208, 211))	('MET', 'Gene', '79811', (152, 155))	('MET', 'Gene', (152, 155))	('MET', 'Gene', (208, 211))
18703	32532746	Activation of the MAPK pathway has been reported to drive acquired resistance to crizotinib through the development of wild-type KRAS amplification or KRAS mutations in patients with MET exon 14 altered tumors.	('KRAS', 'Gene', '3845', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('MAPK pathway', 'Pathway', (18, 30))	('patients', 'Species', '9606', (169, 177))	('tumors', 'Disease', (203, 209))	('mutations', 'Var', (156, 165))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('MET', 'Gene', '79811', (183, 186))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('KRAS', 'Gene', (129, 133))	('KRAS', 'Gene', '3845', (129, 133))	('acquired resistance', 'MPA', (58, 77))	('MET', 'Gene', (183, 186))	('KRAS', 'Gene', (151, 155))	('MAPK', 'molecular_function', 'GO:0004707', ('18', '22'))
18704	32532746	Furthermore, preclinical and preliminary clinical studies suggests that baseline KRAS/NF1/RASA1 mutations are associated with primary resistance to MET TKIs, and efforts to correlate absence of MET or KRAS expression with a lack of response to MET inhibitors are underway.	('KRAS', 'Gene', '3845', (81, 85))	('RASA1', 'Gene', '5921', (90, 95))	('MET', 'Gene', '79811', (244, 247))	('KRAS', 'Gene', (201, 205))	('RASA1', 'Gene', (90, 95))	('KRAS', 'Gene', '3845', (201, 205))	('NF1', 'Gene', '4763', (86, 89))	('MET', 'Gene', '79811', (148, 151))	('MET', 'Gene', (244, 247))	('associated', 'Reg', (110, 120))	('MET', 'Gene', '79811', (194, 197))	('NF1', 'Gene', (86, 89))	('KRAS', 'Gene', (81, 85))	('MET', 'Gene', (148, 151))	('MET', 'Gene', (194, 197))	('mutations', 'Var', (96, 105))
18705	32532746	In addition, PI3KCA mutations and EGFR activation has been reported to drive resistance to MET inhibitors in vitro.	('EGFR', 'Gene', (34, 38))	('activation', 'PosReg', (39, 49))	('EGFR', 'molecular_function', 'GO:0005006', ('34', '38'))	('EGFR', 'Gene', '1956', (34, 38))	('MET', 'Gene', '79811', (91, 94))	('PI3KCA mutations', 'Var', (13, 29))	('MET', 'Gene', (91, 94))	('drive', 'Reg', (71, 76))
18709	32532746	Biomarkers like MET exon 14 skipping mutations and high levels of focal MET amplification have been effective for identifying patients who would benefit from treatment with MET TKIs.	('skipping mutations', 'Var', (28, 46))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', '79811', (173, 176))	('MET', 'Gene', (173, 176))	('MET', 'Gene', '79811', (16, 19))	('patients', 'Species', '9606', (126, 134))	('MET', 'Gene', (16, 19))	('MET', 'Gene', (72, 75))
18748	31348324	The survival risk score was calculated as follows: survival risk score = (0.34745) x ERG + (0.76291) x RRM2 + (0.33446) x EGF.	('RRM2', 'Gene', (103, 107))	('RRM2', 'Gene', '6241', (103, 107))	('0.33446', 'Var', (111, 118))	('EGF', 'molecular_function', 'GO:0005154', ('122', '125'))	('EGF', 'Gene', (122, 125))	('EGF', 'Gene', '1950', (122, 125))	('ERG', 'Gene', '2078', (85, 88))	('ERG', 'Gene', (85, 88))
18754	31348324	5 of 11 DEmiRNAs were associated with OS, including hsa-mir-145, hsa-mir-211, hsa-mir-214, hsa-mir-216a, hsa-mir-217 (Fig.	('mir-145', 'Gene', '406937', (56, 63))	('mir-214', 'Gene', '406996', (82, 89))	('mir-217', 'Gene', (109, 116))	('mir-217', 'Gene', '406999', (109, 116))	('hsa-mir-216a', 'Var', (91, 103))	('mir-211', 'Gene', (69, 76))	('mir-211', 'Gene', '406993', (69, 76))	('mir-145', 'Gene', (56, 63))	('associated', 'Reg', (22, 32))	('mir-214', 'Gene', (82, 89))
18769	31348324	Due to the gene fusion with the promoter region of the androgen-induced TMPRRSS2 gene, ERG has become highly correlated with prostate cancer development.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('gene fusion', 'Var', (11, 22))	('prostate cancer', 'Disease', 'MESH:D011471', (125, 140))	('ERG', 'Gene', '2078', (87, 90))	('ERG', 'Gene', (87, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('prostate cancer', 'Disease', (125, 140))	('androgen', 'Chemical', 'MESH:D000728', (55, 63))	('TMPRRSS2', 'Gene', (72, 80))	('correlated with', 'Reg', (109, 124))
18771	31348324	Overexpression of RRM2 has been showed to be associated with aggressiveness and prognosis of bladder cancer, head and neck cancer, adrenocortical cancer, breast cancer, and pancreas adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('RRM2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('head and neck cancer', 'Disease', 'MESH:D006258', (109, 129))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('pancreas adenocarcinoma', 'Disease', 'MESH:D000230', (173, 196))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (131, 152))	('pancreas adenocarcinoma', 'Phenotype', 'HP:0006725', (173, 196))	('pancreas adenocarcinoma', 'Disease', (173, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('associated', 'Reg', (45, 55))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('adrenocortical cancer', 'Disease', (131, 152))	('aggressiveness', 'Disease', (61, 75))	('breast cancer', 'Disease', (154, 167))	('bladder cancer', 'Disease', (93, 107))	('RRM2', 'Gene', '6241', (18, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (61, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))	('head and neck cancer', 'Phenotype', 'HP:0012288', (109, 129))	('aggressiveness', 'Disease', 'MESH:D001523', (61, 75))	('neck', 'cellular_component', 'GO:0044326', ('118', '122'))
18773	31348324	Dysregulation of EGF has been recognized as an essential molecular event in carcinogenesis.	('Dysregulation', 'Var', (0, 13))	('EGF', 'Gene', (17, 20))	('EGF', 'molecular_function', 'GO:0005154', ('17', '20'))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('EGF', 'Gene', '1950', (17, 20))	('carcinogenesis', 'Disease', (76, 90))
18787	31348324	However, there are still a deficiency of reports on correlations between AP000525.1, GDNF-AS1, GPC5-AS1, LINC00327, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('AS1', 'Gene', '5729', (90, 93))	('GPC5', 'Gene', (95, 99))	('GDNF-AS1', 'Gene', '100861519', (85, 93))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('LINC00327', 'Gene', (105, 114))	('LINC00327', 'Gene', '100506697', (105, 114))	('AS1', 'Gene', '5729', (100, 103))	('AS1', 'Gene', (100, 103))	('AS1', 'Gene', (90, 93))	('AP000525.1', 'Var', (73, 83))	('GPC5', 'Gene', '2262', (95, 99))	('GDNF-AS1', 'Gene', (85, 93))
18805	31855296	Renal tumors were divided into 25 immune cell subsets (4 CD4+ T cells, 7 CD8+ T cells, 1 B cells, 8 macrophages, 1 dendritic cells, 2 natural killer (NK) cells, 1 granulocyte, and 1 other subset) and 7 stem-like cells subsets (based on positivity of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47).	('CD13', 'Gene', '290', (279, 283))	('vimentin', 'Gene', '7431', (250, 258))	('vimentin', 'Gene', (250, 258))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('CD34', 'Gene', '947', (267, 271))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('vimentin', 'cellular_component', 'GO:0045099', ('250', '258'))	('CD13', 'molecular_function', 'GO:0004179', ('279', '283'))	('CD90', 'Gene', (273, 277))	('CD44', 'Gene', '960', (285, 289))	('CD8', 'Gene', (73, 76))	('CD47', 'Gene', '961', (295, 299))	('CD44', 'Gene', (285, 289))	('Renal tumors', 'Disease', 'MESH:D007674', (0, 12))	('Renal tumors', 'Disease', (0, 12))	('CD90', 'Gene', '7070', (273, 277))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('CD326', 'Var', (260, 265))	('CD13', 'Gene', (279, 283))	('CD34', 'Gene', (267, 271))	('vimentin', 'cellular_component', 'GO:0045098', ('250', '258'))	('CD8', 'Gene', '925', (73, 76))	('CD47', 'Gene', (295, 299))
18848	31855296	A 20-well barcoding group was composed of unique combinations of six barcoding metals (102 Pd, 104 Pd, 105 Pd, 106 Pd, 108 Pd, and 110 Pd.	('A 20', 'Gene', (0, 4))	('102 Pd', 'Var', (87, 93))	('A 20', 'Gene', '28935', (0, 4))	('metal', 'Chemical', 'MESH:D008670', (79, 84))
18883	31855296	Renal tumors were divided into 7 stem-like cells subsets (based on positivity of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47), and some stem-like cells subsets have the characteristics of co-expression (Figure 3B).	('CD34', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('vimentin', 'cellular_component', 'GO:0045098', ('81', '89'))	('CD47', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CD13', 'Gene', '290', (110, 114))	('vimentin', 'Gene', '7431', (81, 89))	('vimentin', 'Gene', (81, 89))	('Renal tumors', 'Disease', 'MESH:D007674', (0, 12))	('CD90', 'Gene', (104, 108))	('Renal tumors', 'Disease', (0, 12))	('CD34', 'Gene', '947', (98, 102))	('CD13', 'molecular_function', 'GO:0004179', ('110', '114'))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('CD90', 'Gene', '7070', (104, 108))	('vimentin', 'cellular_component', 'GO:0045099', ('81', '89'))	('CD47', 'Gene', '961', (126, 130))	('CD44', 'Gene', '960', (116, 120))	('CD326', 'Var', (91, 96))	('CD44', 'Gene', (116, 120))	('CD13', 'Gene', (110, 114))
18908	31855296	We found 7 stem-like cells subsets in the renal tumors (based on the expression of vimentin, CD326, CD34, CD90, CD13, CD44, and CD47).	('vimentin', 'Gene', (83, 91))	('vimentin', 'cellular_component', 'GO:0045099', ('83', '91'))	('renal tumor', 'Phenotype', 'HP:0009726', (42, 53))	('CD34', 'Gene', '947', (100, 104))	('CD13', 'Gene', '290', (112, 116))	('CD47', 'Gene', '961', (128, 132))	('renal tumors', 'Disease', (42, 54))	('CD90', 'Gene', (106, 110))	('CD326', 'Var', (93, 98))	('vimentin', 'cellular_component', 'GO:0045098', ('83', '91'))	('CD34', 'Gene', (100, 104))	('CD90', 'Gene', '7070', (106, 110))	('renal tumors', 'Disease', 'MESH:D007674', (42, 54))	('CD13', 'molecular_function', 'GO:0004179', ('112', '116'))	('CD44', 'Gene', '960', (118, 122))	('CD44', 'Gene', (118, 122))	('renal tumors', 'Phenotype', 'HP:0009726', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('CD47', 'Gene', (128, 132))	('CD13', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('vimentin', 'Gene', '7431', (83, 91))
19088	32150988	These results are consistent with recently documented results showing 60% (6/10) positivity in TFE3 and 100% (7/7) in TFEB.	('TFE3', 'Gene', '7030', (95, 99))	('positivity', 'Var', (81, 91))	('TFE3', 'Gene', (95, 99))
19135	32150988	Therefore, both CK7 and CAIX positivity is unique in renal neoplasm of the low-malignant-potential group including multilocular cystic renal neoplasms and in CCPRCC.	('cystic renal neoplasm', 'Phenotype', 'HP:0000800', (128, 149))	('renal neoplasm', 'Phenotype', 'HP:0009726', (53, 67))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('CAIX', 'Gene', (24, 28))	('positivity', 'Var', (29, 39))	('CAIX', 'Gene', '768', (24, 28))	('CCPRCC', 'Disease', (158, 164))	('neoplasm', 'Phenotype', 'HP:0002664', (59, 67))	('CK7', 'Gene', (16, 19))	('cystic renal neoplasms', 'Disease', (128, 150))	('cystic renal neoplasms', 'Disease', 'MESH:D052177', (128, 150))	('cystic renal neoplasms', 'Phenotype', 'HP:0000800', (128, 150))	('renal neoplasm', 'Disease', (53, 67))	('renal neoplasms', 'Phenotype', 'HP:0009726', (135, 150))	('CK7', 'Gene', '3855', (16, 19))	('CCPRCC', 'Chemical', '-', (158, 164))	('renal neoplasm', 'Disease', 'MESH:D007674', (135, 149))	('renal neoplasm', 'Phenotype', 'HP:0009726', (135, 149))	('renal neoplasm', 'Disease', 'MESH:D007674', (53, 67))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))
19138	32150988	MiT RCC is a genetic fusion gene-associated malignant tumor caused by uncontrolled overexpression of MiT factors, followed by translocation with several partner genes, such as PRCC-TFE3 [t (X:1) (p11.2; q21.2)], ASPSCR1-TFE3, SFPQ-TFE3, and NONO-TFE3 fusion genes, and so on.	('translocation', 'Var', (126, 139))	('MiT RCC', 'Disease', (0, 7))	('p11', 'Gene', (196, 199))	('overexpression', 'PosReg', (83, 97))	('caused by', 'Reg', (60, 69))	('ASPSCR1', 'Gene', '79058', (212, 219))	('NONO', 'Gene', (241, 245))	('TFE3', 'Gene', (231, 235))	('PRCC-TFE3', 'Gene', '5546;7030', (176, 185))	('TFE3', 'Gene', '7030', (231, 235))	('PRCC-TFE3', 'Gene', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('malignant tumor', 'Disease', (44, 59))	('MiT RCC', 'Disease', 'MESH:C538614', (0, 7))	('TFE3', 'Gene', (246, 250))	('ASPSCR1', 'Gene', (212, 219))	('SFPQ', 'Gene', '6421', (226, 230))	('TFE3', 'Gene', (220, 224))	('TFE3', 'Gene', (181, 185))	('TFE3', 'Gene', '7030', (246, 250))	('SFPQ', 'Gene', (226, 230))	('malignant tumor', 'Disease', 'MESH:D009369', (44, 59))	('TFE3', 'Gene', '7030', (181, 185))	('NONO', 'Gene', '4841', (241, 245))	('TFE3', 'Gene', '7030', (220, 224))	('p11', 'Gene', '6281', (196, 199))
19150	32150988	When purely melanocytic differentiation occurs with MiT genetic translocation, melanotic MiT tumors may be same as PEComa.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MiT genetic translocation', 'Var', (52, 77))	('PEComa', 'Disease', 'MESH:D054973', (115, 121))	('melanotic MiT tumors', 'Disease', 'MESH:D017600', (79, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('melanotic MiT tumors', 'Disease', (79, 99))	('PEComa', 'Disease', (115, 121))
19163	32150988	Although aberrant cytoplasmic beta-catenin is associated with unfavorable RCC, unlike one prior study, beta-catenin proved to be the least supportive marker for subtyping of renal cell tumors in the present study.	('beta-catenin', 'Gene', '1499', (30, 42))	('renal cell tumors', 'Disease', (174, 191))	('beta-catenin', 'Gene', (103, 115))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('RCC', 'Disease', (74, 77))	('beta-catenin', 'Gene', '1499', (103, 115))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('renal cell tumors', 'Disease', 'MESH:C538614', (174, 191))	('aberrant', 'Var', (9, 17))	('associated', 'Reg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('beta-catenin', 'Gene', (30, 42))
19182	31086581	Bioinformatics analysis revealed that CD105 is overexpressed in ccRCC tumor tissue vs. normal renal tissue, and a higher CD105 copy number in ccRCC tissues was significantly associated with longer patient survival.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('RCC tumor', 'Disease', 'MESH:C538614', (66, 75))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('CD105', 'Gene', '13805', (38, 43))	('RCC', 'Disease', (144, 147))	('copy number', 'Var', (127, 138))	('CD105', 'Gene', (38, 43))	('CD105', 'Gene', (121, 126))	('CD105', 'Gene', '13805', (121, 126))	('longer', 'PosReg', (190, 196))	('RCC tumor', 'Disease', (66, 75))	('RCC', 'Disease', (66, 69))	('patient', 'Species', '9606', (197, 204))	('higher', 'PosReg', (114, 120))	('overexpressed', 'PosReg', (47, 60))
19188	31086581	The exact influence of CD105 mRNA expression and copy number in RCC tumors on patient survival and the underlying mechanisms require further elucidation.	('CD105', 'Gene', (23, 28))	('RCC tumors', 'Disease', 'MESH:C538614', (64, 74))	('patient', 'Species', '9606', (78, 85))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('copy number', 'Var', (49, 60))	('RCC tumors', 'Disease', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CD105', 'Gene', '13805', (23, 28))
19197	31086581	RCC exhibits a poor response to chemotherapy and radiotherapy due to the survival of CSCs, and it is important to identify molecular markers to isolate and characterize the CSCs among the tumor cells; of note, targeting of CSCs in RCC has provided a novel treatment strategy, particularly for metastatic RCC.	('tumor', 'Disease', (188, 193))	('men', 'Species', '9606', (261, 264))	('RCC', 'Disease', (231, 234))	('CSCs', 'Protein', (223, 227))	('RCC', 'Phenotype', 'HP:0005584', (231, 234))	('RCC', 'Phenotype', 'HP:0005584', (304, 307))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('RCC', 'Disease', (304, 307))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('targeting', 'Var', (210, 219))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
19220	31086581	Patients were stratified into two groups (high and low) based on the mean levels of CD105 mRNA expression or copy number.	('CD105', 'Gene', (84, 89))	('Patients', 'Species', '9606', (0, 8))	('CD105', 'Gene', '13805', (84, 89))	('copy number', 'Var', (109, 120))
19253	31086581	Time to death was plotted in a Kaplan-Meier curve for those cases with a CD105 copy number above the median (n=265) and equal to or below the median (n=267).	('CD105', 'Gene', '13805', (73, 78))	('CD105', 'Gene', (73, 78))	('copy number', 'Var', (79, 90))	('above', 'PosReg', (91, 96))
19256	31086581	However, in pRCC and chRCC, no significant impact of the CD105 copy number on survival was noted, but there was a trend, with those pRCC cases with a lower copy number of CD105 surviving for longer (Fig.	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('pRCC', 'Gene', (12, 16))	('CD105', 'Gene', '13805', (57, 62))	('CD105', 'Gene', (171, 176))	('pRCC', 'Gene', '5546', (132, 136))	('longer', 'PosReg', (191, 197))	('CD105', 'Gene', (57, 62))	('lower', 'NegReg', (150, 155))	('copy number', 'Var', (156, 167))	('CD105', 'Gene', '13805', (171, 176))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('pRCC', 'Gene', '5546', (12, 16))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', (13, 16))	('RCC', 'Disease', (133, 136))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('pRCC', 'Gene', (132, 136))
19290	31086581	Of note, the association of CD105 mRNA expression and copy number with various types of RCC, their association with patient survival and the underlying mechanisms require further study.	('association', 'Interaction', (13, 24))	('copy number', 'Var', (54, 65))	('patient', 'Species', '9606', (116, 123))	('CD105', 'Gene', (28, 33))	('mRNA expression', 'MPA', (34, 49))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('CD105', 'Gene', '13805', (28, 33))
19295	33233657	While many different genes have been found to be mutated and to drive the initiation and progression of these lethal cancers, a fine molecular understanding of the process is still lacking.	('mutated', 'Var', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('drive', 'PosReg', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
19298	33233657	In the kidney, its function is essential in appropriate cellular response to oxidative stress, however its aberrant activation supports progression, metastasis, and resistance to therapies in renal cell carcinoma, similarly to what happens in other nonrenal cancers.	('metastasis', 'CPA', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('renal cancer', 'Phenotype', 'HP:0009726', (252, 264))	('progression', 'CPA', (136, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('resistance', 'CPA', (165, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('renal cancers', 'Disease', 'MESH:D007680', (252, 265))	('aberrant', 'Var', (107, 115))	('activation', 'PosReg', (116, 126))	('renal cell carcinoma', 'Disease', (192, 212))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (192, 212))	('renal cancers', 'Disease', (252, 265))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cellular response to oxidative stress', 'biological_process', 'GO:0034599', ('56', '93'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (192, 212))
19316	33233657	Although activators of NRF2 are opening new perspectives in the treatment of different renal pathologies, underlying its protective role in kidney tissue, its aberrant hyperactivation is becoming a central driver of progression of different cancer types, such as renal cell carcinoma.	('renal cell carcinoma', 'Disease', (263, 283))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (263, 283))	('aberrant', 'Var', (159, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('NRF2', 'Gene', (23, 27))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (263, 283))
19332	33233657	Indeed, several pathways potentially involved in RCC subtypes progression were found to be altered by somatic mutations, genomic rearrangements, or epigenetic modifications targeting newly found or already known key genes.	('RCC', 'Disease', (49, 52))	('pathways', 'Pathway', (16, 24))	('altered', 'Reg', (91, 98))	('genomic rearrangements', 'Var', (121, 143))	('epigenetic modifications', 'Var', (148, 172))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
19333	33233657	ccRCC is mainly characterized by genomic alteration in the short arm of chromosome 3 that encodes for the Von Hippel Lindau tumor suppressor gene VHL, reported in almost 90% of the cases.	('VHL', 'Gene', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('124', '140'))	('RCC', 'Disease', (2, 5))	('VHL', 'Gene', '7428', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('124', '140'))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('alteration', 'Var', (41, 51))	('Von Hippel Lindau tumor suppressor', 'Gene', '7428', (106, 140))	('Von Hippel Lindau tumor suppressor', 'Gene', (106, 140))
19336	33233657	Loss of VHL stabilizes HIF1alpha and HIF2alpha in normal oxygen conditions, leading to a state of pseudohypoxia.	('VHL', 'Gene', '7428', (8, 11))	('HIF1alpha', 'Gene', '3091', (23, 32))	('pseudohypoxia', 'Disease', (98, 111))	('oxygen', 'Chemical', 'MESH:D010100', (57, 63))	('HIF2alpha', 'Gene', (37, 46))	('HIF2alpha', 'Gene', '2034', (37, 46))	('pseudohypoxia', 'Disease', 'None', (98, 111))	('Loss', 'Var', (0, 4))	('leading to', 'Reg', (76, 86))	('HIF1alpha', 'Gene', (23, 32))	('VHL', 'Gene', (8, 11))
19338	33233657	ccRCCs that are not mutated in VHL carry mutations mainly in the PI3K/AKT/mTOR pathway, with an upregulation of mTORC1 signaling observed in about 80% of the cases, in the chromatin remodeling and histone modifying pathways.	('mutations', 'Var', (41, 50))	('VHL', 'Gene', '7428', (31, 34))	('AKT', 'Gene', '207', (70, 73))	('VHL', 'Gene', (31, 34))	('mTORC1', 'Gene', (112, 118))	('RCC', 'Disease', (2, 5))	('PI3K', 'molecular_function', 'GO:0016303', ('65', '69'))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('histone modifying pathways', 'Pathway', (197, 223))	('AKT', 'Gene', (70, 73))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('172', '192'))	('chromatin', 'cellular_component', 'GO:0000785', ('172', '181'))	('mTORC1', 'cellular_component', 'GO:0031931', ('112', '118'))	('upregulation', 'PosReg', (96, 108))	('signaling', 'biological_process', 'GO:0023052', ('119', '128'))	('mTORC1', 'Gene', '382056', (112, 118))
19342	33233657	Among them, activating mutations or alterations in the MET signature have been reported in 81% of cases, with a prevalence of somatic or germline mutations in the MET gene (18.6%), which results in the upregulation of cell survival, proliferation, and migration pathways.	('proliferation', 'CPA', (233, 246))	('mutations', 'Var', (146, 155))	('MET', 'Gene', '79811', (55, 58))	('MET', 'Gene', '79811', (163, 166))	('alterations', 'Var', (36, 47))	('MET', 'Gene', (55, 58))	('mutations', 'Var', (23, 32))	('cell survival', 'CPA', (218, 231))	('MET', 'Gene', (163, 166))	('activating', 'PosReg', (12, 22))	('migration pathways', 'CPA', (252, 270))	('upregulation', 'PosReg', (202, 214))
19344	33233657	While sporadic type II pRCC mainly displays mutations in cyclin-dependent kinase inhibitor 2A (CDKN2A), histone lysine methyltransferase (SETD2), and transcription factor E3 (TFE3), hereditary type II pRCC is triggered by germ line mutations in the fumarate hydratase gene (FH), an enzyme of the tricarboxylic acid cycle (TCA), which causes an intracellular accumulation of the oncometabolite fumarate.	('transcription factor E3', 'Gene', (150, 173))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (57, 93))	('triggered by', 'Reg', (209, 221))	('pRCC', 'Phenotype', 'HP:0006766', (201, 205))	('SETD2', 'Gene', '29072', (138, 143))	('mutations', 'Var', (232, 241))	('transcription factor', 'molecular_function', 'GO:0000981', ('150', '170'))	('pRCC', 'Gene', (201, 205))	('TCA', 'Gene', (322, 325))	('fumarate hydratase', 'Gene', (249, 267))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (57, 93))	('intracellular', 'cellular_component', 'GO:0005622', ('344', '357'))	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('57', '90'))	('tricarboxylic acid cycle', 'biological_process', 'GO:0006099', ('296', '320'))	('pRCC', 'Gene', '5546', (23, 27))	('TFE3', 'Gene', (175, 179))	('FH', 'Gene', '2271', (274, 276))	('TFE3', 'Gene', '7030', (175, 179))	('hereditary type II pRCC', 'Disease', 'MESH:D020176', (182, 205))	('CDKN2A', 'Gene', (95, 101))	('fumarate hydratase', 'Gene', '2271', (249, 267))	('pRCC', 'Phenotype', 'HP:0006766', (23, 27))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('74', '90'))	('fumarate', 'Chemical', 'MESH:D005650', (393, 401))	('fumarate', 'Chemical', 'MESH:D005650', (249, 257))	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('pRCC', 'Gene', (23, 27))	('pRCC', 'Gene', '5546', (201, 205))	('hereditary type II pRCC', 'Disease', (182, 205))	('transcription factor E3', 'Gene', '7030', (150, 173))	('CDKN2A', 'Gene', '1029', (95, 101))	('mutations', 'Var', (44, 53))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (296, 314))	('SETD2', 'Gene', (138, 143))
19346	33233657	This group of tumors features both somatic and germline mutations in the FH gene, resulting in fumarate accumulation, as described for HLRCC patients.	('FH', 'Gene', '2271', (73, 75))	('germline mutations', 'Var', (47, 65))	('fumarate', 'Chemical', 'MESH:D005650', (95, 103))	('tumors', 'Disease', (14, 20))	('fumarate accumulation', 'MPA', (95, 116))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('patients', 'Species', '9606', (141, 149))
19351	33233657	Mutations involving the major players of the NRF2 pathway are generally mutually exclusive, even if they can co-occur in tumors with known association to exposure to carcinogenic factors.	('NRF2 pathway', 'Pathway', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('Mutations', 'Var', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('carcinogenic', 'Disease', 'MESH:D063646', (166, 178))	('carcinogenic', 'Disease', (166, 178))
19352	33233657	These mutations involve directly the NRF2 coding gene NFE2L2, but also genes encoding for the regulatory proteins KEAP1 and CUL3, and NRF2 transcriptional targets (Table 1).	('involve', 'Reg', (16, 23))	('NFE2L2', 'Gene', '4780', (54, 60))	('NFE2L2', 'Gene', (54, 60))	('KEAP1', 'Gene', '9817', (114, 119))	('CUL3', 'Gene', '8452', (124, 128))	('NRF2', 'Gene', (37, 41))	('KEAP1', 'Gene', (114, 119))	('CUL3', 'Gene', (124, 128))	('mutations', 'Var', (6, 15))
19358	33233657	Despite activating hotspots in NFE2L2 and inactivating mutations in its negative regulators, KEAP1, CUL3, and SIRT1 have been reported, they do not justify themselves the overexpression of NRF2 transcriptional signature in the different tumor types.	('SIRT1', 'Gene', (110, 115))	('tumor', 'Disease', (237, 242))	('inactivating mutations', 'Var', (42, 64))	('KEAP1', 'Gene', '9817', (93, 98))	('NFE2L2', 'Gene', '4780', (31, 37))	('KEAP1', 'Gene', (93, 98))	('activating', 'MPA', (8, 18))	('CUL3', 'Gene', '8452', (100, 104))	('CUL3', 'Gene', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('NFE2L2', 'Gene', (31, 37))	('SIRT1', 'Gene', '23411', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
19360	33233657	However, as described for ccRCC, hyperactivation of the NRF2 signature associates with tumor progression and decreased survival.	('decreased', 'NegReg', (109, 118))	('survival', 'CPA', (119, 127))	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NRF2', 'Gene', (56, 60))	('tumor', 'Disease', (87, 92))	('hyperactivation', 'Var', (33, 48))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RCC', 'Disease', (28, 31))
19374	33233657	Indeed, NRF2 activators were reported to reduce cisplatin cytotoxicity in kidney epithelial cells, thus allowing to think about a combinatory treatment to prevent chemotherapy side effects, even if their effect is still contradictory in in vivo experiments because of biodistribution and bioavailability.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('reduce', 'NegReg', (41, 47))	('cytotoxicity', 'Disease', (58, 70))	('activators', 'Var', (13, 23))	('NRF2', 'Gene', (8, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
19384	33233657	This occurs also in metastatic RCC, where the EMT process is activated by different mechanisms, such as chronic oxidative stress, loss of VHL, and stabilization of HIF-1 alpha and activation of Wilm's tumor transcription factor 1, that induces an epithelial-to-mesenchymal hybrid transition in which the cells retain both epithelial and mesenchymal features.	('activation', 'PosReg', (180, 190))	('VHL', 'Gene', '7428', (138, 141))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('EMT', 'biological_process', 'GO:0001837', ('46', '49'))	('VHL', 'Gene', (138, 141))	('HIF-1 alpha', 'Gene', '3091', (164, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	("Wilm's tumor", 'Phenotype', 'HP:0002667', (194, 206))	('HIF-1 alpha', 'Gene', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('transcription factor', 'molecular_function', 'GO:0000981', ('207', '227'))	('transcription', 'biological_process', 'GO:0006351', ('207', '220'))	("Wilm's tumor", 'Disease', 'MESH:D009396', (194, 206))	('loss', 'Var', (130, 134))	('epithelial-to-mesenchymal hybrid transition', 'CPA', (247, 290))	('induces', 'Reg', (236, 243))	('RCC', 'Disease', (31, 34))	("Wilm's tumor", 'Disease', (194, 206))
19388	33233657	Indeed, cancers harboring mutations in the NFE2L2 gene and featuring NRF2 constitutive activation show increased proliferation, anchorage-independent growth, and metastatic potential, dependent on mTORC1 activation.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('increased', 'PosReg', (103, 112))	('NFE2L2', 'Gene', (43, 49))	('NRF2', 'Gene', (69, 73))	('metastatic potential', 'CPA', (162, 182))	('mTORC1', 'Gene', (197, 203))	('mTORC1', 'cellular_component', 'GO:0031931', ('197', '203'))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('anchorage-independent growth', 'CPA', (128, 156))	('mTORC1', 'Gene', '382056', (197, 203))	('NFE2L2', 'Gene', '4780', (43, 49))
19389	33233657	Moreover, expression of mutant NRF2 gene in human embryonic kidney (HEK)-293 cells is sufficient to confer them an oncogenic and metastatic phenotype.	('mutant', 'Var', (24, 30))	('human', 'Species', '9606', (44, 49))	('NRF2', 'Gene', (31, 35))	('HEK)-293', 'CellLine', 'CVCL:0045', (68, 76))	('embryonic kidney', 'Disease', (50, 66))	('embryonic kidney', 'Disease', 'MESH:D007674', (50, 66))
19399	33233657	In order to understand how genetic alterations in the KEAP1-NRF2 axis can impact on cancer progression in the kidney, it is helpful to describe the major animal models that feature NRF2 hyperactivation with implications in this tissue.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('NRF2', 'Gene', (181, 185))	('KEAP1', 'Gene', (54, 59))	('cancer', 'Disease', (84, 90))	('impact', 'Reg', (74, 80))	('hyperactivation', 'PosReg', (186, 201))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('KEAP1', 'Gene', '9817', (54, 59))	('genetic alterations', 'Var', (27, 46))
19400	33233657	Keap1 knockout mice feature postnatal lethality, due to hyperkeratosis in the upper digestive tract, which is corrected by local deletion of the Nrf2 gene.	('hyperkeratosis', 'Disease', 'MESH:D017488', (56, 70))	('Nrf2', 'Gene', (145, 149))	('local deletion', 'Var', (123, 137))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (56, 70))	('mice', 'Species', '10090', (15, 19))	('hyperkeratosis', 'Disease', (56, 70))
19401	33233657	Interestingly, these mice show polyuria and kidney damage, probably due to downregulation of aquaporin 2 and reduced water resorption, as demonstrated in mice with Keap1 specific deletion in renal tubules.	('aquaporin 2', 'Gene', (93, 104))	('aquaporin', 'molecular_function', 'GO:0015250', ('93', '102'))	('downregulation', 'NegReg', (75, 89))	('mice', 'Species', '10090', (154, 158))	('reduced', 'NegReg', (109, 116))	('mice', 'Species', '10090', (21, 25))	('polyuria', 'Disease', 'MESH:D011141', (31, 39))	('downregulation of aquaporin', 'biological_process', 'GO:1902428', ('75', '102'))	('kidney damage', 'Disease', (44, 57))	('kidney damage', 'Phenotype', 'HP:0000112', (44, 57))	('aquaporin 2', 'Gene', '11827', (93, 104))	('polyuria', 'Phenotype', 'HP:0000103', (31, 39))	('deletion', 'Var', (179, 187))	('water', 'Chemical', 'MESH:D014867', (117, 122))	('water', 'MPA', (117, 122))	('kidney damage', 'Disease', 'MESH:D007674', (44, 57))	('polyuria', 'Disease', (31, 39))
19403	33233657	However, systemic or kidney-specific deletion of the Keap1 gene is not sufficient to cause an aggressive tumor formation, suggesting that NRF2 plays a role in supporting tumor growth and drug resistance, but not in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('deletion', 'Var', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cause', 'Reg', (85, 90))	('formation', 'biological_process', 'GO:0009058', ('111', '120'))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (170, 175))	('drug resistance', 'CPA', (187, 202))	('drug resistance', 'Phenotype', 'HP:0020174', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('drug resistance', 'biological_process', 'GO:0009315', ('187', '202'))	('drug resistance', 'biological_process', 'GO:0042493', ('187', '202'))	('tumor', 'Disease', (215, 220))	('Keap1', 'Gene', (53, 58))	('tumor', 'Disease', (105, 110))	('supporting', 'PosReg', (159, 169))
19404	33233657	This is further sustained by the observation that human germline loss of function mutations in the KEAP1 gene are not associated with cancer formation, even if it predisposes to multinodular goiters.	('multinodular goiters', 'Disease', (178, 198))	('KEAP1', 'Gene', (99, 104))	('multinodular goiters', 'Phenotype', 'HP:0005987', (178, 198))	('goiters', 'Phenotype', 'HP:0000853', (191, 198))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('cancer', 'Disease', (134, 140))	('loss of function', 'NegReg', (65, 81))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (82, 91))	('KEAP1', 'Gene', '9817', (99, 104))	('human', 'Species', '9606', (50, 55))	('multinodular goiters', 'Disease', 'MESH:C564546', (178, 198))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
19406	33233657	Several mutations involve directly the NFE2L2 gene and are highly conserved among different cancer types.	('involve', 'Reg', (18, 25))	('NFE2L2', 'Gene', (39, 45))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('NFE2L2', 'Gene', '4780', (39, 45))
19407	33233657	The analysis of TCGA catalogue has identified almost 2% of unique NRF2-mutant tumors among all cases reported, with the 63% of tumor type harboring NLE2L2 mutations.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('NRF2-mutant', 'Gene', (66, 77))	('NRF2-mutant', 'Var', (66, 77))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
19408	33233657	These mutations localize mainly in ETGE and DLG motives of the Neh2 domain, which determine KEAP1 ability to bind NRF2 and direct its CUL3-dependent degradation.	('KEAP1', 'Gene', (92, 97))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('Neh2', 'Gene', (63, 67))	('CUL3', 'Gene', '8452', (134, 138))	('CUL3', 'Gene', (134, 138))	('bind', 'Interaction', (109, 113))	('direct', 'Reg', (123, 129))	('Neh2', 'Gene', '252969', (63, 67))	('KEAP1', 'Gene', '9817', (92, 97))	('NRF2', 'Protein', (114, 118))	('mutations', 'Var', (6, 15))
19409	33233657	In RCCs, NFE2L2 is among the 20 aberrant genes, harboring mainly missense mutations in activating hotspots, prevalently reported in PRCC (Table 2).	('activating hotspots', 'MPA', (87, 106))	('PRCC', 'Gene', '5546', (132, 136))	('PRCC', 'Gene', (132, 136))	('missense mutations', 'Var', (65, 83))	('NFE2L2', 'Gene', '4780', (9, 15))	('RCC', 'Disease', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('NFE2L2', 'Gene', (9, 15))
19410	33233657	However, NRF2 signature harbors mutations also in 3.2% of ccRCCs, with 2% of mutations involving directly NFE2L2 and copy number alteration in position 2q31.2 (Table 1).	('NFE2L2', 'Gene', '4780', (106, 112))	('RCC', 'Disease', (60, 63))	('NFE2L2', 'Gene', (106, 112))	('NRF2', 'Gene', (9, 13))	('mutations', 'Var', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (60, 63))
19411	33233657	Indeed, rs6721961 single nucleotide polymorphism (SNP) in the promoter of NFE2L2 gene has been described to support carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('carcinogenesis', 'Disease', (116, 130))	('NFE2L2', 'Gene', (74, 80))	('rs6721961', 'Mutation', 'rs6721961', (8, 17))	('NFE2L2', 'Gene', '4780', (74, 80))	('rs6721961 single nucleotide polymorphism', 'Var', (8, 48))	('support', 'PosReg', (108, 115))
19412	33233657	However, NFE2L2 gene alterations in the primary tumor, both in homo- and in heterozygosity, impact not only on tumor progression, but also on the clinical outcome and in the response to therapy, with patients developing chronic kidney disease after partial nephrectomy and reduced response of metastasis to vascular endothelial growth factor-targeting therapy.	('alterations', 'Var', (21, 32))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('chronic kidney disease', 'Disease', 'MESH:D051436', (220, 242))	('vascular endothelial growth factor', 'Gene', '7422', (307, 341))	('kidney disease', 'Phenotype', 'HP:0000112', (228, 242))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (220, 242))	('vascular endothelial growth factor', 'Gene', (307, 341))	('NFE2L2', 'Gene', '4780', (9, 15))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (111, 116))	('chronic kidney disease', 'Disease', (220, 242))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('NFE2L2', 'Gene', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('patients', 'Species', '9606', (200, 208))	('impact', 'Reg', (92, 98))	('developing', 'Reg', (209, 219))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('307', '341'))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
19413	33233657	However, the described NFE2L2 alterations are not the only cause of the hyperactivation of NRF2-ARE signatures reported in RCCs.	('NFE2L2', 'Gene', '4780', (23, 29))	('NFE2L2', 'Gene', (23, 29))	('RCC', 'Disease', (123, 126))	('alterations', 'Var', (30, 41))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('NRF2-ARE', 'Gene', (91, 99))
19414	33233657	Indeed, a plethora of mutations involving genes encoding for the regulatory interactors of NRF2 have been reported in different types of RCC (Table 1).	('reported', 'Reg', (106, 114))	('mutations', 'Var', (22, 31))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('plethora', 'Phenotype', 'HP:0001050', (10, 18))	('RCC', 'Disease', (137, 140))	('NRF2', 'Gene', (91, 95))
19415	33233657	Mutations in KEAP1 and CUL3 genes are mutually exclusive with the one in the NFE2L2 gene present in 6.6% of ccRCCs; indeed 10.4% of the tumor analyzed presented a deletion in the CUL3 locus 2q36.	('RCC', 'Disease', (110, 113))	('CUL3', 'Gene', '8452', (23, 27))	('deletion', 'Var', (163, 171))	('KEAP1', 'Gene', '9817', (13, 18))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('NFE2L2', 'Gene', (77, 83))	('CUL3', 'Gene', (23, 27))	('KEAP1', 'Gene', (13, 18))	('CUL3', 'Gene', '8452', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('CUL3', 'Gene', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('NFE2L2', 'Gene', '4780', (77, 83))
19416	33233657	Inactivating mutations in the same genes are described also in PRCCs.	('PRCC', 'Gene', '5546', (63, 67))	('PRCC', 'Gene', (63, 67))	('Inactivating mutations', 'Var', (0, 22))
19417	33233657	In addition, a dominant negative mutation in the SIRT1 gene has been described in co-occurance with NFE2L2 mutation in one case of sporadic type II PRCC.	('SIRT1', 'Gene', (49, 54))	('PRCC', 'Gene', '5546', (148, 152))	('NFE2L2', 'Gene', '4780', (100, 106))	('negative', 'NegReg', (24, 32))	('SIRT1', 'Gene', '23411', (49, 54))	('NFE2L2', 'Gene', (100, 106))	('PRCC', 'Gene', (148, 152))	('mutation', 'Var', (107, 115))
19420	33233657	Mutations in the key genes of the NRF2 pathway are not always sufficient to justify its aberrantly increased transcriptional activity in different solid tumors, such as lung cancer and PRCC.	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('NRF2', 'Gene', (34, 38))	('solid tumors', 'Disease', (147, 159))	('PRCC', 'Gene', '5546', (185, 189))	('PRCC', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('increased', 'PosReg', (99, 108))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('transcriptional activity', 'MPA', (109, 133))
19421	33233657	The NRF2 axis is subjected to epigenetic regulation, which is the most frequent mechanism of downregulation of KEAP1 in solid tumors, caused by the methylation of CpGs located in the P1 region of the promoter, near the transcriptional starting site.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('KEAP1', 'Gene', '9817', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('regulation', 'biological_process', 'GO:0065007', ('41', '51'))	('CpGs', 'Gene', (163, 167))	('methylation', 'biological_process', 'GO:0032259', ('148', '159'))	('KEAP1', 'Gene', (111, 116))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('methylation', 'Var', (148, 159))	('downregulation', 'NegReg', (93, 107))
19422	33233657	This is relevant in RCC, since DNA methylation and epigenetic modifications have been extensively investigated in this set of tumors, resulting in the characterization of a new type II PRCC (CIMP-PRCC) associated with hypermethylation of CpG islands.	('CIMP-PRCC', 'Gene', '5546', (191, 200))	('PRCC', 'Gene', '5546', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('PRCC', 'Gene', (196, 200))	('RCC', 'Disease', 'MESH:C538614', (197, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('RCC', 'Disease', (20, 23))	('tumors', 'Disease', (126, 132))	('RCC', 'Disease', (186, 189))	('DNA methylation', 'biological_process', 'GO:0006306', ('31', '46'))	('DNA', 'cellular_component', 'GO:0005574', ('31', '34'))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('PRCC', 'Gene', '5546', (196, 200))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('PRCC', 'Gene', (185, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('associated', 'Reg', (202, 212))	('RCC', 'Disease', (197, 200))	('CIMP-PRCC', 'Gene', (191, 200))	('hypermethylation', 'Var', (218, 234))
19425	33233657	Indeed, it is known that also the NFE2L2 promoter is subjected to epigenetic modifications in some kinds of cancer.	('NFE2L2', 'Gene', '4780', (34, 40))	('subjected', 'Reg', (53, 62))	('NFE2L2', 'Gene', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('epigenetic', 'Var', (66, 76))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
19427	33233657	Colorectal cancer featuring hypomethylation of the NFE2L2 promoter and consequent hyperactivation of the NRF2 axis shows resistance to different chemotherapeutic drugs.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypomethylation', 'Var', (28, 43))	('NFE2L2', 'Gene', '4780', (51, 57))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('NRF2', 'Gene', (105, 109))	('Colorectal cancer', 'Disease', (0, 17))	('NFE2L2', 'Gene', (51, 57))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
19434	33233657	Indeed, miR-200c, through the downregulation of HMOX1, a target gene of NRF2, sensitizes ccRCC to chemotherapeutic agents, suggesting that miRNAs regulation of the NRF2-ARE signature can impact on different features of RCC.	('miR-200c', 'Gene', (8, 16))	('impact', 'Reg', (187, 193))	('miR-200c', 'Gene', '406985', (8, 16))	('miRNAs', 'Var', (139, 145))	('downregulation', 'NegReg', (30, 44))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('sensitizes', 'Reg', (78, 88))	('HMOX1', 'Gene', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('RCC', 'Disease', (219, 222))	('regulation', 'biological_process', 'GO:0065007', ('146', '156'))	('HMOX1', 'Gene', '3162', (48, 53))
19438	33233657	Curiously, miR-101 is downregulated in ccRCC and the consequent overexpression of its targets (e.g., DONSON) associates with resistance to Sunitinib treatment, while its restoration inhibits the invasive behavior of RCC cells.	('DONSON', 'Gene', '29980', (101, 107))	('miR-101', 'Chemical', '-', (11, 18))	('Sunitinib', 'Chemical', 'MESH:D000077210', (139, 148))	('inhibits', 'NegReg', (182, 190))	('overexpression', 'PosReg', (64, 78))	('restoration', 'Var', (170, 181))	('miR-101', 'Gene', (11, 18))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (216, 219))	('RCC', 'Disease', (41, 44))	('DONSON', 'Gene', (101, 107))	('resistance to Sunitinib treatment', 'MPA', (125, 158))	('downregulated', 'NegReg', (22, 35))
19440	33233657	Thus, even if a precise definition of which specific miRNAs impact on the NRF2-ARE signature in the different types of RCC is lacking, multiple lines of evidence suggest that they can play a crucial role in supporting NRF2 aberrant activation in cancer.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (246, 252))	('impact', 'Reg', (60, 66))	('aberrant', 'Var', (223, 231))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('RCC', 'Disease', (119, 122))	('NRF2', 'Gene', (218, 222))
19448	33233657	On the other hand, despite the fact that amplification of KRAS was described in RCC, as reported for c-MYC, mutations in RAS and BRAF are extremely rare in kidney tumors (almost 1%).	('KRAS', 'Gene', (58, 62))	('KRAS', 'Gene', '3845', (58, 62))	('BRAF', 'Gene', (129, 133))	('mutations', 'Var', (108, 117))	('c-MYC', 'Gene', (101, 106))	('RCC', 'Disease', (80, 83))	('BRAF', 'Gene', '673', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('RAS', 'Gene', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('described', 'Reg', (67, 76))	('kidney tumors', 'Disease', (156, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('kidney tumors', 'Disease', 'MESH:D007680', (156, 169))	('c-MYC', 'Gene', '4609', (101, 106))	('kidney tumors', 'Phenotype', 'HP:0009726', (156, 169))
19449	33233657	While some studies outlined a different incidence of mutations among the RAS isoforms in RCC samples, with 0-16% of KRAS mutation and very rare events in NRAS and HRAS, others did not detect any mutation of KRAS, such as BRAF, neither in primary nor in metastatic ccRCC or PRCC.	('RCC', 'Disease', (274, 277))	('RCC', 'Disease', (266, 269))	('KRAS', 'Gene', (116, 120))	('NRAS', 'Gene', (154, 158))	('BRAF', 'Gene', '673', (221, 225))	('BRAF', 'Gene', (221, 225))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('HRAS', 'Gene', '3265', (163, 167))	('KRAS', 'Gene', '3845', (207, 211))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (274, 277))	('HRAS', 'Gene', (163, 167))	('mutation', 'Var', (121, 129))	('PRCC', 'Gene', (273, 277))	('KRAS', 'Gene', (207, 211))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('NRAS', 'Gene', '4893', (154, 158))	('PRCC', 'Gene', '5546', (273, 277))	('KRAS', 'Gene', '3845', (116, 120))
19467	33233657	Curiously, co-occurrence between mutations in PI3K/AKT and NRF2 pathways have been reported in different kind of tumors, and activation of PI3K was described to induce NRF2 accumulation and metabolic rewiring with the aim to support cell proliferation and protection from oxidative stress, suggesting a direct interaction among the two pathways.	('support', 'PosReg', (225, 232))	('tumors', 'Disease', (113, 119))	('cell proliferation', 'CPA', (233, 251))	('mutations', 'Var', (33, 42))	('PI3K', 'Var', (139, 143))	('NRF2', 'Gene', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('induce', 'PosReg', (161, 167))	('NRF2', 'Protein', (168, 172))	('cell proliferation', 'biological_process', 'GO:0008283', ('233', '251'))	('PI3K', 'molecular_function', 'GO:0016303', ('46', '50'))	('accumulation', 'PosReg', (173, 185))	('AKT', 'Gene', (51, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('139', '143'))	('metabolic rewiring', 'CPA', (190, 208))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('oxidative stress', 'Phenotype', 'HP:0025464', (272, 288))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('AKT', 'Gene', '207', (51, 54))
19476	33233657	However, the role of NRF2 post-translational modification in promoting its nuclear accumulation and protumorigenic activity in RCC has been reported by different studies.	('NRF2', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('nuclear accumulation', 'CPA', (75, 95))	('tumor', 'Disease', (103, 108))	('post-translational modification', 'biological_process', 'GO:0043687', ('26', '57'))	('post-translational modification', 'Var', (26, 57))	('promoting', 'PosReg', (61, 70))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
19491	33233657	For example, it was demonstrated that the hyperactivation of mTORC1 and p62 triggers renal carcinogenesis in models of tuberous sclerosis characterized by inactivation of the tuberous sclerosis complex 2 (TSC2), but in this case it does not rely on the consequent hyperactivation of Nrf2.	('tuberous sclerosis complex 2', 'Gene', (175, 203))	('triggers', 'Reg', (76, 84))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (119, 137))	('renal carcinogenesis', 'Disease', (85, 105))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (175, 193))	('mTORC1', 'cellular_component', 'GO:0031931', ('61', '67'))	('TSC2', 'Gene', '7249', (205, 209))	('inactivation', 'Var', (155, 167))	('mTORC1', 'Gene', (61, 67))	('renal carcinogenesis', 'Disease', 'MESH:D063646', (85, 105))	('tuberous sclerosis complex 2', 'Gene', '7249', (175, 203))	('p62', 'Gene', '8878', (72, 75))	('TSC2', 'Gene', (205, 209))	('p62', 'Gene', (72, 75))	('tuberous sclerosis', 'Disease', (119, 137))	('mTORC1', 'Gene', '382056', (61, 67))	('hyperactivation', 'Var', (42, 57))	('tuberous sclerosis complex', 'cellular_component', 'GO:0033596', ('175', '201'))
19492	33233657	On the other hand, ccRCC features copy number gains on chromosome 5q, which contains the SQSTM1 gene, in 70% of the cases with consequent overexpression of p62.	('copy number gains', 'Var', (34, 51))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('SQSTM1', 'Gene', (89, 95))	('p62', 'Gene', '8878', (156, 159))	('p62', 'Gene', (156, 159))	('SQSTM1', 'Gene', '8878', (89, 95))	('RCC', 'Disease', (21, 24))	('chromosome', 'cellular_component', 'GO:0005694', ('55', '65'))
19506	33233657	Moreover, fumarate accumulation is involved in a process called succination, in which there is nucleophilic addition of fumarate on cysteine residues (Michael addition type reaction) forming adducts of S-2-succynil cysteine (2SC), that have been proposed as marker for HLRCC and PRCC type II featuring FH mutations that are not detected as changes in the protein levels.	('FH', 'Gene', '2271', (302, 304))	('S-2-succynil cysteine', 'Chemical', '-', (202, 223))	('cysteine', 'Chemical', 'MESH:D003545', (132, 140))	('PRCC', 'Gene', '5546', (279, 283))	('fumarate', 'Chemical', 'MESH:D005650', (120, 128))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('cysteine', 'Chemical', 'MESH:D003545', (215, 223))	('RCC', 'Disease', (280, 283))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('PRCC', 'Gene', (279, 283))	('mutations', 'Var', (305, 314))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Disease', (271, 274))	('protein', 'cellular_component', 'GO:0003675', ('355', '362'))
19507	33233657	Through this mechanism, fumarate interacts with Cys151 and Cys288 in KEAP1, inducing the release of NRF2, which can translocate into the nucleus and support target genes production.	('Cys151', 'Var', (48, 54))	('NRF2', 'Gene', (100, 104))	('translocate', 'MPA', (116, 127))	('KEAP1', 'Gene', '9817', (69, 74))	('release', 'MPA', (89, 96))	('Cys151', 'Chemical', '-', (48, 54))	('inducing', 'Reg', (76, 84))	('Cys288', 'Var', (59, 65))	('KEAP1', 'Gene', (69, 74))	('fumarate', 'Chemical', 'MESH:D005650', (24, 32))	('Cys288', 'Chemical', '-', (59, 65))	('nucleus', 'cellular_component', 'GO:0005634', ('137', '144'))
19510	33233657	Indeed, our group described a new murine model of PRCC type II, in which mice feature slowly progressive transformation of cystic epithelium into carcinomas, in consequence of inactivation of a single gene Tsc1, and mTORC1 hyperactivation.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('mTORC1', 'cellular_component', 'GO:0031931', ('216', '222'))	('hyperactivation', 'PosReg', (223, 238))	('carcinomas', 'Disease', 'MESH:D009369', (146, 156))	('mice', 'Species', '10090', (73, 77))	('mTORC1', 'Gene', '382056', (216, 222))	('murine', 'Species', '10090', (34, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('Tsc1', 'Gene', (206, 210))	('PRCC', 'Gene', '5546', (50, 54))	('inactivation', 'Var', (176, 188))	('mTORC1', 'Gene', (216, 222))	('Tsc1', 'Gene', '64930', (206, 210))	('PRCC', 'Gene', (50, 54))
19517	33233657	What is particularly interestingly is that modulation of the concentration of DMF can differentially regulate the activation of NRF2 signaling.	('NRF2 signaling', 'Pathway', (128, 142))	('DMF', 'Chemical', 'MESH:D000069462', (78, 81))	('signaling', 'biological_process', 'GO:0023052', ('133', '142'))	('DMF', 'Var', (78, 81))	('activation', 'MPA', (114, 124))	('regulate', 'Reg', (101, 109))
19518	33233657	have reported that low doses of DMF in cancer cells promote activation of NRF2 antioxidant pathway, impairing KEAP1 binding and resulting in cytoprotective effects and tumor progression.	('DMF', 'Var', (32, 35))	('binding', 'molecular_function', 'GO:0005488', ('116', '123'))	('cytoprotective effects', 'CPA', (141, 163))	('tumor', 'Disease', (168, 173))	('cancer', 'Disease', (39, 45))	('impairing', 'NegReg', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('KEAP1', 'Gene', '9817', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('activation', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('DMF', 'Chemical', 'MESH:D000069462', (32, 35))	('KEAP1', 'Gene', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('NRF2 antioxidant pathway', 'Pathway', (74, 98))
19519	33233657	On the other hand, high doses of DMF not only result in succination of KEAP1, but also DJ-1, an NRF2 binding protein encoded by the PARK7 gene and necessary for NRF2 nuclear translocation.	('PARK7', 'Gene', '11315', (132, 137))	('result', 'Reg', (46, 52))	('KEAP1', 'Gene', (71, 76))	('DMF', 'Var', (33, 36))	('protein', 'cellular_component', 'GO:0003675', ('109', '116'))	('succination', 'MPA', (56, 67))	('PARK7', 'Gene', (132, 137))	('KEAP1', 'Gene', '9817', (71, 76))	('DJ-1', 'Gene', (87, 91))	('DJ-1', 'Gene', '11315', (87, 91))	('binding', 'molecular_function', 'GO:0005488', ('101', '108'))	('DMF', 'Chemical', 'MESH:D000069462', (33, 36))
19520	33233657	This modification on Cys106 accounts for a reduction of nuclear NRF2 and consequent tumor cell sensitization to cell death.	('Cys106', 'Chemical', '-', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('nuclear NRF2', 'Protein', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('reduction', 'NegReg', (43, 52))	('tumor', 'Disease', (84, 89))	('death', 'Disease', 'MESH:D003643', (117, 122))	('sensitization', 'biological_process', 'GO:0046960', ('95', '108'))	('death', 'Disease', (117, 122))	('cell death', 'biological_process', 'GO:0008219', ('112', '122'))	('Cys106', 'Var', (21, 27))
19521	33233657	This effect is not evident in normal cells, where the expression of DJ-1 is very low, while it is further exacerbated in KRAS mutated cells, as some kind of RCC.	('expression', 'MPA', (54, 64))	('KRAS', 'Gene', (121, 125))	('low', 'NegReg', (81, 84))	('DJ-1', 'Gene', (68, 72))	('DJ-1', 'Gene', '11315', (68, 72))	('KRAS', 'Gene', '3845', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('exacerbated', 'PosReg', (106, 117))	('mutated', 'Var', (126, 133))
19528	33233657	In a first stage, the inability to produce fumarate near the nucleus impairs DNA damage repair and accounts for accumulation of mutations, then the proliferation of FH deficient cells leads to accumulation of fumarate that supports tumor progression.	('DNA', 'cellular_component', 'GO:0005574', ('77', '80'))	('DNA damage repair', 'MPA', (77, 94))	('nucleus', 'cellular_component', 'GO:0005634', ('61', '68'))	('fumarate', 'Chemical', 'MESH:D005650', (43, 51))	('mutations', 'Var', (128, 137))	('FH deficient', 'Disease', 'MESH:D006938', (165, 177))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('FH deficient', 'Disease', (165, 177))	('fumarate', 'Chemical', 'MESH:D005650', (209, 217))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('fumarate', 'MPA', (209, 217))	('supports', 'PosReg', (223, 231))	('accumulation', 'PosReg', (193, 205))	('impairs', 'NegReg', (69, 76))	('tumor', 'Disease', (232, 237))
19532	33233657	As previously reported, ccRCC features mutations mainly in VHL/HIF and PI3K/AKT/mTOR pathways, thus the currently approved therapeutical approaches involve VEGF or mTOR inhibitors (such as Tensirolimus or Everolimus), for advanced RCC.	('VHL', 'Gene', '7428', (59, 62))	('AKT', 'Gene', '207', (76, 79))	('VEGF', 'Gene', (156, 160))	('RCC', 'Disease', (231, 234))	('Tensirolimus', 'Chemical', '-', (189, 201))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('mutations', 'Var', (39, 48))	('AKT', 'Gene', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('Everolimus', 'Chemical', 'MESH:D000068338', (205, 215))	('VEGF', 'Gene', '7422', (156, 160))	('VHL', 'Gene', (59, 62))	('PI3K', 'molecular_function', 'GO:0016303', ('71', '75'))
19534	33233657	On the other hand, PRCC is mainly characterized by mutations in the MET gene or loss of the FH gene that characterize type I and type II, respectively.	('MET', 'Gene', (68, 71))	('mutations', 'Var', (51, 60))	('loss', 'NegReg', (80, 84))	('PRCC', 'Gene', '5546', (19, 23))	('FH', 'Gene', '2271', (92, 94))	('PRCC', 'Gene', (19, 23))	('MET', 'Gene', '79811', (68, 71))
19536	33233657	Alterations in NRF2 signature are one of the targets initially related to PRCC type II, but that is becoming a common feature among the principal RCC types.	('PRCC', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('Alterations', 'Var', (0, 11))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('NRF2', 'Gene', (15, 19))	('PRCC', 'Gene', '5546', (74, 78))
19541	33233657	Thus, understanding the different pathways and players that cooperate in sustaining the aberrant activation of NRF2 in cancers such as RCC represents a good opportunity to identify indirect targeted strategies.	('activation', 'PosReg', (97, 107))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('RCC', 'Disease', (135, 138))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('NRF2', 'Gene', (111, 115))	('cancers', 'Disease', (119, 126))	('aberrant', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
19552	33233657	Interestingly, dimethyl fumarate, which is approved by FDA as an NRF2 activator, displays some anticancer activities, and indeed at high concentrations it appears to behave as a NRF2 inhibitor.	('dimethyl', 'Var', (15, 23))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('dimethyl fumarate', 'Chemical', 'MESH:D000069462', (15, 32))
19557	33233657	This study supports the idea that a combinatory targeted therapy, modulating NRF2-ARE signature directly or indirectly, can be a promising opportunity for the treatment of RCCs featuring NRF2 hyperactivation.	('modulating', 'Var', (66, 76))	('NRF2', 'Gene', (187, 191))	('hyperactivation', 'Var', (192, 207))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('NRF2-ARE', 'Gene', (77, 85))
19566	24832166	Tumor cells from 17 of 24 TSC-associated PRCC showed strong, diffuse labeling for CA-IX (100%), CK7 (94%), vimentin (88%), CD10 (83%), and were uniformly negative for succinate dehydrogenase subunit B (SDHB), TFE3 and AMACR.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('vimentin', 'Gene', '7431', (107, 115))	('succinate dehydrogenase subunit B', 'Gene', (167, 200))	('vimentin', 'Gene', (107, 115))	('AMACR', 'Gene', (218, 223))	('vimentin', 'cellular_component', 'GO:0045098', ('107', '115'))	('TFE3', 'Gene', (209, 213))	('CD10', 'Var', (123, 127))	('CK7', 'Gene', (96, 99))	('TFE3', 'Gene', '7030', (209, 213))	('SDHB', 'Gene', '6390', (202, 206))	('AMACR', 'Gene', '23600', (218, 223))	('CK7', 'Gene', '3855', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('TSC', 'Gene', (26, 29))	('PRCC', 'Gene', (41, 45))	('CA-IX', 'Gene', (82, 87))	('vimentin', 'cellular_component', 'GO:0045099', ('107', '115'))	('CD10', 'molecular_function', 'GO:0004245', ('123', '127'))	('TSC', 'Gene', '7248;7249', (26, 29))	('SDHB', 'Gene', (202, 206))	('succinate dehydrogenase subunit B', 'Gene', '6390', (167, 200))	('CA-IX', 'Gene', '768', (82, 87))	('PRCC', 'Gene', '5546', (41, 45))
19572	24832166	A disease-causing mutation in either TSC1 (Chromosome 9q34), encoding the protein hamartin, or in TSC2 (chromosome 16p13), encoding the protein tuberin, can be identified in most patients with TSC.	('TSC1', 'Gene', (37, 41))	('TSC1', 'Gene', '7248', (37, 41))	('TSC', 'Gene', (37, 40))	('protein', 'cellular_component', 'GO:0003675', ('136', '143'))	('tuberin', 'Gene', '7249', (144, 151))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (179, 187))	('TSC', 'Gene', '7248;7249', (37, 40))	('Chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('TSC', 'Gene', (193, 196))	('TSC2', 'Gene', '7249', (98, 102))	('hamartin', 'Gene', '7248', (82, 90))	('tuberin', 'Gene', (144, 151))	('hamartin', 'Gene', (82, 90))	('TSC', 'Gene', (98, 101))	('TSC', 'Gene', '7248;7249', (193, 196))	('TSC2', 'Gene', (98, 102))	('TSC', 'Gene', '7248;7249', (98, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('104', '114'))	('disease-causing', 'Reg', (2, 17))	('protein', 'cellular_component', 'GO:0003675', ('74', '81'))
19582	24832166	Absence of von Hippel-Lindau (VHL) gene mutation and loss of heterozygosity (LOH) was reported in 6 clear cell TSC-associated RCCs, in contrast to cytogenetic findings in sporadic RCC of the general non-TSC population, suggesting that clear cell TSC-associated RCC develops independently of canonical pathways.	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('VHL', 'Gene', (30, 33))	('TSC', 'Gene', '7248;7249', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('von Hippel-Lindau', 'Disease', (11, 28))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('TSC', 'Gene', (203, 206))	('VHL', 'Gene', '7428', (30, 33))	('RCCs', 'Phenotype', 'HP:0005584', (126, 130))	('mutation', 'Var', (40, 48))	('TSC', 'Gene', '7248;7249', (203, 206))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (11, 28))	('TSC', 'Gene', (246, 249))	('RCC', 'Disease', (261, 264))	('RCC', 'Phenotype', 'HP:0005584', (261, 264))	('TSC', 'Gene', '7248;7249', (246, 249))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('Absence', 'NegReg', (0, 7))	('TSC', 'Gene', (111, 114))
19691	24832166	In general, the tumors were reactive for PAX8, CD117 and CD10, and negative for TFE3, HMB45, and CA-IX.	('CA-IX', 'Gene', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('TFE3', 'Gene', (80, 84))	('PAX8', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('TFE3', 'Gene', '7030', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('CA-IX', 'Gene', '768', (97, 102))	('CD10', 'Var', (57, 61))	('CD10', 'molecular_function', 'GO:0004245', ('57', '61'))	('CD117', 'Gene', '3815', (47, 52))	('tumors', 'Disease', (16, 22))	('PAX8', 'Gene', '7849', (41, 45))	('CD117', 'Gene', (47, 52))
19728	24832166	Each of the four known RCC subtypes--clear cell RCC, type 1 papillary RCC, Xp11 translocation RCC, clear cell (tubulo) papillary RCC--share some morphological and immunological features with the TSC-associated papillary RCC (Table 4).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('Xp11 translocation', 'Var', (75, 93))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('papillary RCC', 'Disease', 'MESH:C538614', (210, 223))	('RCC', 'Disease', (129, 132))	('TSC', 'Gene', (195, 198))	('papillary RCC', 'Disease', (210, 223))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('TSC', 'Gene', '7248;7249', (195, 198))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('RCC', 'Disease', (48, 51))	('papillary RCC', 'Disease', 'MESH:C538614', (119, 132))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('papillary RCC', 'Disease', (119, 132))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', (23, 26))	('papillary RCC', 'Disease', 'MESH:C538614', (60, 73))	('papillary RCC', 'Disease', (60, 73))	('RCC', 'Disease', (220, 223))
19732	24832166	similarly found neither VHL loss of heterozygosity nor other VHL gene mutation in any of their six clear cell RCC tumors from TSC patients.	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('loss', 'Var', (28, 32))	('VHL', 'Gene', '7428', (24, 27))	('RCC tumors', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('TSC', 'Gene', (126, 129))	('patients', 'Species', '9606', (130, 138))	('VHL', 'Gene', (61, 64))	('RCC tumors', 'Disease', 'MESH:C538614', (110, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('VHL', 'Gene', (24, 27))	('VHL', 'Gene', '7428', (61, 64))	('TSC', 'Gene', '7248;7249', (126, 129))
19734	24832166	Xp11 translocation RCC is another renal tumor in the differential diagnosis.	('renal tumor', 'Disease', 'MESH:D007674', (34, 45))	('renal tumor', 'Phenotype', 'HP:0009726', (34, 45))	('Xp11 translocation', 'Var', (0, 18))	('renal tumor', 'Disease', (34, 45))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))
19736	24832166	Nuclear labeling for TFE3 protein by immunohistochemistry is a characteristic feature of Xp11 translocation carcinoma and was not identified in any of the neoplasm in our series.	('TFE3', 'Gene', '7030', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('neoplasm', 'Disease', (155, 163))	('Xp11 translocation', 'Var', (89, 107))	('neoplasm', 'Phenotype', 'HP:0002664', (155, 163))	('neoplasm', 'Disease', 'MESH:D009369', (155, 163))	('TFE3', 'Gene', (21, 25))	('carcinoma', 'Disease', (108, 117))	('Nuclear labeling', 'MPA', (0, 16))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('protein', 'Protein', (26, 33))	('carcinoma', 'Disease', 'MESH:D009369', (108, 117))
19739	24832166	Psammoma bodies that are common in Xp11 translocation RCC were also not seen in any of these TSC-associated tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RCC', 'Disease', (54, 57))	('TSC', 'Gene', '7248;7249', (93, 96))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('Xp11 translocation', 'Var', (35, 53))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('TSC', 'Gene', (93, 96))	('Psammoma bodies', 'Disease', (0, 15))
19760	24832166	Together, less than 20 patients with any SDHx gene mutations have been reported thus far, and mostly with a personal and/or family history of PHEO/PGL.	('PHEO', 'Chemical', '-', (142, 146))	('mutations', 'Var', (51, 60))	('PGL', 'molecular_function', 'GO:0004598', ('147', '150'))	('patients', 'Species', '9606', (23, 31))	('SDH', 'Gene', (41, 44))	('SDH', 'Gene', '6390', (41, 44))
19762	24832166	Therefore, immunohistochemistry for SDHB is negative whenever there is mutation/inactivation of SDHA, SDHB, SDHC, SDHD, or SDHAF2.	('SDHAF2', 'Gene', '54949', (123, 129))	('SDHAF2', 'Gene', (123, 129))	('SDHD', 'Gene', (114, 118))	('SDHD', 'Gene', '6392', (114, 118))	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('SDHA', 'Gene', (96, 100))	('SDHB', 'Gene', '6390', (102, 106))	('SDHC', 'Gene', (108, 112))	('SDHA', 'Gene', '6389', (123, 127))	('SDHB', 'Gene', (102, 106))	('SDHC', 'Gene', '6391', (108, 112))	('SDHA', 'Gene', '6389', (96, 100))	('SDHA', 'Gene', (123, 127))	('mutation/inactivation', 'Var', (71, 92))
19763	24832166	Negative staining for SDHB has been quite reliable in identifying germline mutation of the SDH B, C and D subunits in PHEO/PGL.	('SDH B', 'Gene', (91, 96))	('PGL', 'molecular_function', 'GO:0004598', ('123', '126'))	('SDH B', 'Gene', '6390', (91, 96))	('PHEO', 'Chemical', '-', (118, 122))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('germline mutation', 'Var', (66, 83))
19766	24832166	The absence of a family history does not formally exclude the possibility of paraganglioma syndromes given the age related penetrance of SDHx gene mutation and phenotypic heterogeneity.	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('mutation', 'Var', (147, 155))	('SDH', 'Gene', (137, 140))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (77, 100))	('SDH', 'Gene', '6390', (137, 140))	('paraganglioma syndromes', 'Disease', (77, 100))
19768	24832166	Renal tumors associated with SDHx mutations from earlier reports were classified as clear cell, chromophobe, papillary, and unclassified RCC, or oncocytoma, without detailed description or illustration of morphologic features.	('oncocytoma', 'Disease', (145, 155))	('associated', 'Reg', (13, 23))	('Renal tumors', 'Disease', (0, 12))	('oncocytoma', 'Disease', 'MESH:D018249', (145, 155))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('SDH', 'Gene', (29, 32))	('Renal tumors', 'Disease', 'MESH:D007674', (0, 12))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('SDH', 'Gene', '6390', (29, 32))	('Renal tumors', 'Phenotype', 'HP:0009726', (0, 12))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('papillary', 'Disease', (109, 118))	('RCC', 'Disease', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (34, 43))	('clear cell', 'Disease', (84, 94))	('chromophobe', 'Disease', (96, 107))
19772	24832166	It is known that lack of SDH enzyme activity results in abnormal hypoxia signaling and may trigger tumor formation.	('trigger', 'Reg', (91, 98))	('tumor', 'Disease', (99, 104))	('SDH', 'Gene', (25, 28))	('lack', 'Var', (17, 21))	('activity', 'MPA', (36, 44))	('signaling', 'biological_process', 'GO:0023052', ('73', '82'))	('formation', 'biological_process', 'GO:0009058', ('105', '114'))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypoxia', 'Disease', (65, 72))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('results in', 'Reg', (45, 55))	('SDH', 'Gene', '6390', (25, 28))	('enzyme activity', 'molecular_function', 'GO:0003824', ('29', '44'))
19775	24832166	This effect may contribute to carcinogenesis in these tumors in the absence of VHL mutation or chromosome 3p loss, and explain the diffuse membranous IHC labeling for CA-IX we observed.	('VHL', 'Gene', '7428', (79, 82))	('contribute', 'Reg', (16, 26))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))	('chromosome', 'Gene', (95, 105))	('carcinogenesis', 'Disease', (30, 44))	('loss', 'NegReg', (109, 113))	('CA-IX', 'Gene', (167, 172))	('mutation', 'Var', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('VHL', 'Gene', (79, 82))	('CA-IX', 'Gene', '768', (167, 172))	('tumors', 'Disease', (54, 60))
19777	24832166	SDHx germline mutation seems quite unlikely since these patients had no features of SDH genetic syndromes, and the co-existence of TSC1 or TSC2 plus SDHx germline gene mutations would be an extremely rare event to recur in this clustered fashion by random chance.	('patients', 'Species', '9606', (56, 64))	('TSC1', 'Gene', (131, 135))	('SDH genetic syndromes', 'Disease', 'MESH:D030342', (84, 105))	('SDH', 'Gene', '6390', (149, 152))	('SDH', 'Gene', (0, 3))	('TSC2', 'Gene', '7249', (139, 143))	('SDH', 'Gene', '6390', (84, 87))	('SDH', 'Gene', (149, 152))	('SDH', 'Gene', '6390', (0, 3))	('TSC2', 'Gene', (139, 143))	('SDH genetic syndromes', 'Disease', (84, 105))	('TSC1', 'Gene', '7248', (131, 135))	('SDH', 'Gene', (84, 87))	('mutations', 'Var', (168, 177))
19778	24832166	One possible mechanism may be the acquisition of somatic mutations that inactivate one or more of the SDHx genes, hence contributing to tumorigenesis.	('contributing', 'Reg', (120, 132))	('SDH', 'Gene', '6390', (102, 105))	('SDH', 'Gene', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('inactivate', 'NegReg', (72, 82))	('tumor', 'Disease', (136, 141))
19781	24832166	If germline SDHx mutation is found in this group of tumors, it poses a possibility that two tumor suppressor genes (SDH and TSC) may together contribute to one oncogenic event.	('SDH', 'Gene', (116, 119))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TSC', 'Gene', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TSC', 'Gene', '7248;7249', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('92', '108'))	('tumors', 'Disease', (52, 58))	('SDH', 'Gene', '6390', (12, 15))	('SDH', 'Gene', '6390', (116, 119))	('tumor suppressor', 'biological_process', 'GO:0051726', ('92', '108'))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (92, 97))	('SDH', 'Gene', (12, 15))	('contribute', 'Reg', (142, 152))
19787	24832166	Interestingly, renal tumors with HOCT morphology are identified in both TSC and Birt-Hogg Dube syndromes in which mutations in the TSC and folliculin genes, respectively, result in downstream mTOR activation.	('mTOR', 'Gene', (192, 196))	('renal tumors', 'Disease', 'MESH:D007674', (15, 27))	('mutations', 'Var', (114, 123))	('Birt-Hogg Dube syndrome', 'Disease', 'MESH:D058249', (80, 103))	('renal tumors', 'Disease', (15, 27))	('activation', 'PosReg', (197, 207))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('TSC', 'Gene', '7248;7249', (72, 75))	('TSC', 'Gene', '7248;7249', (131, 134))	('renal tumor', 'Phenotype', 'HP:0009726', (15, 26))	('TSC', 'Gene', (72, 75))	('mTOR', 'Gene', '2475', (192, 196))	('Birt-Hogg Dube syndrome', 'Disease', (80, 103))	('renal tumors', 'Phenotype', 'HP:0009726', (15, 27))	('folliculin', 'Gene', (139, 149))	('TSC', 'Gene', (131, 134))
19790	24832166	Similar to other well-defined hereditary renal cancer syndromes in which distinct RCC morphologic features are associated with specific mutations, these neoplasms, in addition to angiomyolipomas may help to identify morphologic clues to renal neoplasms associated with TSC.	('neoplasms', 'Phenotype', 'HP:0002664', (243, 252))	('TSC', 'Gene', '7248;7249', (269, 272))	('mutations', 'Var', (136, 145))	('neoplasms', 'Disease', (153, 162))	('neoplasm', 'Phenotype', 'HP:0002664', (243, 251))	('renal neoplasms', 'Disease', 'MESH:D007674', (237, 252))	('hereditary renal cancer syndromes', 'Disease', 'MESH:D007680', (30, 63))	('angiomyolipoma', 'Phenotype', 'HP:0006772', (179, 193))	('renal neoplasms', 'Disease', (237, 252))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('renal neoplasms', 'Phenotype', 'HP:0009726', (237, 252))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('neoplasms', 'Disease', 'MESH:D009369', (243, 252))	('neoplasms', 'Phenotype', 'HP:0002664', (153, 162))	('angiomyolipomas', 'Disease', 'MESH:D018207', (179, 194))	('renal cancer', 'Phenotype', 'HP:0009726', (41, 53))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('neoplasms', 'Disease', (243, 252))	('neoplasm', 'Phenotype', 'HP:0002664', (153, 161))	('angiomyolipomas', 'Disease', (179, 194))	('hereditary renal cancer syndromes', 'Disease', (30, 63))	('neoplasms', 'Disease', 'MESH:D009369', (153, 162))	('TSC', 'Gene', (269, 272))	('renal neoplasm', 'Phenotype', 'HP:0009726', (237, 251))
19860	33993889	In our cohort, tumor seeding within the perinephric adipose tissue along the biopsy needle tract was observed in 6 % (6/98) of all RCC resection cases, but exclusively among patients with PRCC (6/28, 21 %).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('PRCC', 'Phenotype', 'HP:0006766', (188, 192))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('resection', 'Var', (135, 144))	('patients', 'Species', '9606', (174, 182))	('tumor', 'Disease', (15, 20))	('PRCC', 'Gene', '5546', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('PRCC', 'Gene', (188, 192))
19881	33993889	Localized pT1a or pT1b renal cell carcinomas are considered as low-risk disease, with recurrence risk of 1-8 %.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (23, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('renal cell carcinomas', 'Disease', (23, 44))	('Localized', 'Disease', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('pT1b', 'Var', (18, 22))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (23, 44))
19894	33993889	The follow-up data based on our series of PRCC seem to show a low risk of recurrence between patients with low grade pT1a disease with and without tumor seeding in the perinephric adipose tissue.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('PRCC', 'Gene', '5546', (42, 46))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('PRCC', 'Gene', (42, 46))	('low grade', 'Var', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('PRCC', 'Phenotype', 'HP:0006766', (42, 46))	('patients', 'Species', '9606', (93, 101))	('pT1a', 'Gene', (117, 121))
19925	33977237	Following these findings, a pathological diagnosis of pT1aNxMx, CCPRCC, G2, Fuhrman grade 2, INFa, v0, ly0 was made.	('CCPRCC', 'Gene', '5546', (64, 70))	('INFa', 'Gene', '3451', (93, 97))	('CCPRCC', 'Gene', (64, 70))	('pT1aNxMx', 'Var', (54, 62))	('INFa', 'Gene', (93, 97))
20000	31948514	In addition, we also found that the light cyan, light yellow, pink, gray, salmon, dark red, yellow, yellow-green, and light green modules were associated with new tumor events (p < 0.05) (Fig.	('associated', 'Reg', (143, 153))	('light green', 'Var', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('light cyan', 'Var', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('yellow-green', 'Var', (100, 112))	('tumor', 'Disease', (163, 168))	('light yellow', 'Var', (48, 60))	('dark red', 'Var', (82, 90))	('yellow', 'Var', (92, 98))
20028	31948514	In addition, the aberrant expression of genes involved in the regulation of transcriptional activator activity pathways could also influence tumorigenesis.	('expression', 'MPA', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('aberrant', 'Var', (17, 25))	('regulation', 'biological_process', 'GO:0065007', ('62', '72'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('genes', 'Gene', (40, 45))	('tumor', 'Disease', (141, 146))	('transcriptional activator activity', 'molecular_function', 'GO:0016563', ('76', '110'))	('influence', 'Reg', (131, 140))
20042	31382581	In the nineties, among Xp11 renal cell carcinoma, ASPL, PRCC, and SFPQ (PSF) were the first genes recognized as partners in TFE3 rearrangement.	('rearrangement', 'Var', (129, 142))	('SFPQ', 'Gene', '6421', (66, 70))	('SFPQ', 'Gene', (66, 70))	('ASPL', 'Gene', (50, 54))	('TFE3', 'Gene', '7030', (124, 128))	('PSF', 'Gene', (72, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 48))	('PRCC', 'Gene', '5546', (56, 60))	('p11', 'Gene', (24, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (28, 48))	('PRCC', 'Gene', (56, 60))	('renal cell carcinoma', 'Disease', (28, 48))	('PSF', 'Gene', '6421', (72, 75))	('p11', 'Gene', '6281', (24, 27))	('TFE3', 'Gene', (124, 128))	('ASPL', 'Gene', '79058', (50, 54))
20047	31382581	Recently, renal cell carcinomas with TFEB amplification have been described in connection with t(6;11) renal cell carcinoma.	('renal cell carcinoma', 'Disease', (103, 123))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (10, 30))	('renal cell carcinomas', 'Disease', (10, 31))	('TFEB', 'Gene', '7942', (37, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('TFEB', 'Gene', (37, 41))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (10, 31))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (10, 31))	('amplification', 'Var', (42, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (10, 30))
20053	31382581	However, the translocation is balanced in t(X;17) renal cell carcinoma and unbalanced in alveolar soft part sarcoma, which presumably explains the clinical and morphological differences.	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (89, 115))	('renal cell carcinoma', 'Disease', (50, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (98, 115))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (50, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (89, 115))	('t(X;17', 'Var', (42, 48))	('alveolar soft part sarcoma', 'Disease', (89, 115))
20070	31382581	For this reason, the identification of the TFE3 rearrangement by FISH assays on formalin-fixed and paraffin-embedded tissue sections is currently the gold standard to reach the correct diagnosis.	('paraffin', 'Chemical', 'MESH:D010232', (99, 107))	('formalin', 'Chemical', 'MESH:D005557', (80, 88))	('TFE3', 'Gene', (43, 47))	('rearrangement', 'Var', (48, 61))	('TFE3', 'Gene', '7030', (43, 47))
20072	31382581	It is important to keep in mind that the FISH assay is unable to detect subtle TFE3 gene inversions, such as those that result in the RBM10-TFE3 gene fusion.	('fusion', 'Var', (150, 156))	('RBM10', 'Gene', '8241', (134, 139))	('TFE3', 'Gene', '7030', (79, 83))	('TFE3', 'Gene', '7030', (140, 144))	('inv', 'Gene', (89, 92))	('result in', 'Reg', (120, 129))	('TFE3', 'Gene', (140, 144))	('TFE3', 'Gene', (79, 83))	('inv', 'Gene', '89782', (89, 92))	('RBM10', 'Gene', (134, 139))
20074	31382581	In our practice, the fraction of cells showing the translocation is commonly high, supporting the idea that it is the main driver event in tumorigenesis.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('translocation', 'Var', (51, 64))
20089	31382581	Among Xp11 translocation renal cell carcinoma, patients with ASPL-TFE3 fusion seem to have a worse prognosis and more frequently lymph node metastasis, but it is still unclear whether the fusion partner plays a prognostic role.	('more', 'PosReg', (113, 117))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (25, 45))	('ASPL', 'Gene', '79058', (61, 65))	('TFE3', 'Gene', '7030', (66, 70))	('p11', 'Gene', (7, 10))	('patients', 'Species', '9606', (47, 55))	('lymph node metastasis', 'CPA', (129, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('ASPL', 'Gene', (61, 65))	('renal cell carcinoma', 'Disease', (25, 45))	('p11', 'Gene', '6281', (7, 10))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('TFE3', 'Gene', (66, 70))	('fusion', 'Var', (71, 77))
20095	31382581	With regard to the treatment, the optimal therapy for MiT family translocation renal cell carcinoma remains to be determined.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (79, 99))	('MiT family translocation', 'Var', (54, 78))	('renal cell carcinoma', 'Disease', (79, 99))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (79, 99))
20101	31382581	t(6;11) renal cell carcinoma is an extremely rare variant and accounts for 0.02% of all renal carcinomas.	('renal carcinomas', 'Disease', 'MESH:C538614', (88, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('t(6;11', 'Var', (0, 6))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (8, 28))	('renal carcinomas', 'Disease', (88, 104))	('renal carcinomas', 'Phenotype', 'HP:0005584', (88, 104))	('renal cell carcinoma', 'Disease', (8, 28))
20117	31382581	As previously discussed for Xp11 translocation renal cell carcinomas, it is of paramount importance to define a proper cut-off to establish the occurrence of TFEB rearrangement, even in t(6;11) renal cell carcinoma, when the frequency of split signals is high (>38%).	('p11', 'Gene', (29, 32))	('occurrence', 'Reg', (144, 154))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (47, 68))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (47, 68))	('renal cell carcinoma', 'Disease', (194, 214))	('TFEB', 'Gene', '7942', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('p11', 'Gene', '6281', (29, 32))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('TFEB', 'Gene', (158, 162))	('rearrangement', 'Var', (163, 176))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('renal cell carcinomas', 'Disease', (47, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
20123	31382581	Most instances of t(6;11) renal cell carcinoma have an indolent clinical course.	('renal cell carcinoma', 'Disease', (26, 46))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (26, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('t(6;11', 'Var', (18, 24))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (26, 46))
20127	31382581	However, it is possible that an increase in the copy number of the TFEB gene region in t(6;11) renal cell carcinoma may predict an aggressive clinical course.	('TFEB', 'Gene', '7942', (67, 71))	('increase', 'PosReg', (32, 40))	('TFEB', 'Gene', (67, 71))	('renal cell carcinoma', 'Disease', (95, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (95, 115))	('copy number', 'Var', (48, 59))	('predict', 'Reg', (120, 127))
20130	31382581	More recently, renal cell carcinomas with TFEB amplification have been described and appear to be associated with a poor outcome.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (15, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('renal cell carcinomas', 'Disease', (15, 36))	('TFEB', 'Gene', '7942', (42, 46))	('amplification', 'Var', (47, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('TFEB', 'Gene', (42, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('associated', 'Reg', (98, 108))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (15, 36))
20131	31382581	TFEB amplification in renal cell carcinoma can occur independently of or in association with TFEB rearrangement.	('renal cell carcinoma', 'Disease', (22, 42))	('amplification', 'Var', (5, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (22, 42))	('TFEB', 'Gene', '7942', (0, 4))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (22, 42))	('TFEB', 'Gene', (0, 4))	('TFEB', 'Gene', '7942', (93, 97))	('TFEB', 'Gene', (93, 97))	('rearrangement', 'Var', (98, 111))
20132	31382581	TFEB gene rearrangement or amplification increases TFEB expression which causes the subsequent expression of immunohistochemical markers such as cathepsin K, Melan-A, and HMB45.	('rearrangement', 'Var', (10, 23))	('increases', 'PosReg', (41, 50))	('TFEB', 'Gene', '7942', (51, 55))	('cathepsin K', 'Gene', (145, 156))	('TFEB', 'Gene', '7942', (0, 4))	('causes', 'Reg', (73, 79))	('cathepsin K', 'Gene', '1513', (145, 156))	('expression', 'MPA', (56, 66))	('TFEB', 'Gene', (0, 4))	('Melan-A', 'Gene', (158, 165))	('TFEB', 'Gene', (51, 55))	('Melan-A', 'Gene', '2315', (158, 165))	('amplification', 'Var', (27, 40))	('expression', 'MPA', (95, 105))
20137	31382581	Fourth, TFEB amplified renal cell carcinomas typically have a poor outcome while t(6;11) renal cell carcinomas are usually indolent.	('amplified', 'Var', (13, 22))	('TFEB', 'Gene', '7942', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (23, 44))	('TFEB', 'Gene', (8, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (89, 110))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (89, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (23, 43))	('renal cell carcinomas', 'Disease', (23, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (89, 109))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (23, 44))	('renal cell carcinomas', 'Disease', (89, 110))
20138	31382581	Of note, it has been demonstrated that renal cell carcinomas showing TFEB amplification harbor concurrent vascular endothelial growth factor A (VEGFA) gene amplification.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (39, 60))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (39, 60))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('106', '140'))	('amplification', 'Var', (74, 87))	('vascular endothelial growth factor A', 'Gene', (106, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('renal cell carcinomas', 'Disease', (39, 60))	('VEGFA', 'Gene', '7422', (144, 149))	('TFEB', 'Gene', '7942', (69, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('vascular endothelial growth factor A', 'Gene', '7422', (106, 142))	('TFEB', 'Gene', (69, 73))	('VEGFA', 'Gene', (144, 149))
20144	31382581	Overall, this review emphasizes that MiT family translocation renal cell carcinoma is a distinctive entity and therefore stresses the importance of recognizing it as a specific category of renal cell carcinoma to properly identify these cases in future clinical trials looking for effective therapies.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (189, 209))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('MiT family translocation', 'Var', (37, 61))	('renal cell carcinoma', 'Disease', (189, 209))	('renal cell carcinoma', 'Disease', (62, 82))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
20154	28949976	Xp11.2 translocation renal cell carcinoma (tRCC), a rare subtype of renal cell carcinoma (RCC), result from gene fusions involving the TFE3 transcription factor gene, and it is included into the MiT family tRCCs in the recently published World Health Organization (WHO) classification of tumors of the urinary system.	('RCC', 'Disease', (44, 47))	('renal cell carcinoma', 'Disease', (68, 88))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('result from', 'Reg', (96, 107))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (7, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('gene fusions', 'Var', (108, 120))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (21, 41))	('translocation renal cell carcinoma', 'Disease', (7, 41))	('TFE3', 'Gene', (135, 139))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', (207, 210))	('TFE3', 'Gene', '7030', (135, 139))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 88))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('transcription', 'biological_process', 'GO:0006351', ('140', '153'))	('transcription factor', 'molecular_function', 'GO:0000981', ('140', '160'))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (21, 41))	('tumors', 'Disease', (288, 294))
20156	28949976	Most common gene fusions in Xp11.2 tRCC are TFE3 gene on Xp11.2 with PRCC at 1q21 and TFE3 with ASPL at 17q25, which arise from the translocations t(X; 1) (p11.2; q21) and t(X; 17) (p11.2; q25.3).	('TFE3', 'Gene', (86, 90))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('PRCC', 'Gene', '5546', (69, 73))	('TFE3', 'Gene', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('PRCC', 'Gene', (69, 73))	('TFE3', 'Gene', '7030', (86, 90))	('t(X; 1) (p11.2; q21', 'Var', (147, 166))	('TFE3', 'Gene', '7030', (44, 48))	('t(X; 17) (p11.2', 'Var', (172, 187))
20157	28949976	Other less recurrent reported TFE3 fusion partners include SFPQ (alias PSF), NonO, CLTC and RBM10, resulting from t(X; 1) (p11.2; p34), inv(X) (p11.2q12), t(X; 17) (p11.2; q23), and inv(X) (p11.2p11.23), respectively.	('t(X; 1) (p11.2; p34', 'Var', (114, 133))	('RBM10', 'Gene', (92, 97))	('TFE3', 'Gene', '7030', (30, 34))	('alias PSF', 'Disease', 'None', (65, 74))	('inv(X) (p11.2p11.23', 'Var', (182, 201))	('inv(X) (p11.2q12', 'Var', (136, 152))	('TFE3', 'Gene', (30, 34))	('t(X; 17) (p11.2; q23', 'Var', (155, 175))	('alias PSF', 'Disease', (65, 74))	('CLTC', 'Chemical', '-', (83, 87))
20160	28949976	However, in archival formalin-fixed paraffin-embedded (FFPE) tissues, morphological characteristics and immunohistochemistry (IHC) are the diagnostic bases of Xp11.2 tRCC.	('paraffin', 'Chemical', 'MESH:D010232', (36, 44))	('Xp11.2', 'Var', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('formalin', 'Chemical', 'MESH:D005557', (21, 29))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
20161	28949976	Morphologically, distinctive features of Xp11.2 tRCC are papillary architecture composed of clear or eosinophilic cells and psammoma bodies.	('RCC', 'Disease', (49, 52))	('psammoma bodies', 'Disease', (124, 139))	('Xp11.2', 'Var', (41, 47))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('psammoma bodies', 'Disease', 'MESH:D001835', (124, 139))
20162	28949976	However, Xp11.2 tRCCs often present with unusual morphology, which can mimic other types of RCC, and can also be mimicked by some other atypical tumors.	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('tumors', 'Disease', (145, 151))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('Xp11.2', 'Var', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (17, 20))
20173	28949976	The breakpoint of the translocation in PRCC-TFE3 RCC was cloned in 1996, and it was found that this translocation resulted in a fusion of the TFE3 gene on the Xp11.2 to a novel PRCC gene on 1q21.2.	('PRCC', 'Gene', (39, 43))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('PRCC', 'Gene', '5546', (177, 181))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('TFE3', 'Gene', (142, 146))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('PRCC', 'Gene', '5546', (39, 43))	('resulted in', 'Reg', (114, 125))	('RCC', 'Disease', (49, 52))	('TFE3', 'Gene', '7030', (142, 146))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('fusion', 'Var', (128, 134))	('RCC', 'Disease', 'MESH:C538614', (49, 52))	('PRCC', 'Gene', (177, 181))	('TFE3', 'Gene', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('TFE3', 'Gene', '7030', (44, 48))
20203	28949976	TFE3 and cathepsin K IHC were performed on the 23 Xp11.2 tRCCs and 40 non- Xp11.2 tRCCs.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('TFE3', 'Gene', '7030', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('TFE3', 'Gene', (0, 4))	('RCC', 'Disease', (58, 61))	('Xp11.2', 'Var', (50, 56))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
20233	28949976	Immunohistochemically, except for molecular genetic analysis, nuclear reactivity of TFE3 protein is the most sensitive and specific method for TFE3 rearrangement-associated neoplasm.	('neoplasm', 'Disease', 'MESH:D009369', (173, 181))	('TFE3', 'Gene', (84, 88))	('TFE3', 'Gene', (143, 147))	('neoplasm', 'Disease', (173, 181))	('TFE3', 'Gene', '7030', (84, 88))	('TFE3', 'Gene', '7030', (143, 147))	('rearrangement-associated', 'Var', (148, 172))	('neoplasm', 'Phenotype', 'HP:0002664', (173, 181))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
20234	28949976	But TFE3 IHC in diagnosing Xp11.2 tRCC may lead to false-positive or false-negative results.	('RCC', 'Disease', (35, 38))	('false', 'biological_process', 'GO:0071877', ('69', '74'))	('Xp11.2', 'Var', (27, 33))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('false', 'biological_process', 'GO:0071878', ('69', '74'))	('false', 'biological_process', 'GO:0071878', ('51', '56'))	('TFE3', 'Gene', (4, 8))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('false', 'biological_process', 'GO:0071877', ('51', '56'))	('TFE3', 'Gene', '7030', (4, 8))
20241	28949976	It was reported that Xp11.2 tRCC typically had a predominance of females and affects young adults less than 45 years of age.	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('Xp11.2', 'Var', (21, 27))
20303	23696129	Tumors with nccRCC histology included papillary RCC (n= 151, 59.9%), chromophobe RCC (n= 37, 14.7%), collecting duct (n= 7, 2.8%), unclassified (n= 34, 13.5%), and RCC with Xp11 translocation (n=4, 1.6%).	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('chromophobe RCC', 'Disease', 'MESH:C538614', (69, 84))	('papillary RCC', 'Disease', 'MESH:C538614', (38, 51))	('collecting duct', 'Disease', (101, 116))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('RCC', 'Disease', (15, 18))	('papillary RCC', 'Disease', (38, 51))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('Tumors', 'Disease', (0, 6))	('chromophobe RCC', 'Disease', (69, 84))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Xp11 translocation', 'Var', (173, 191))	('RCC', 'Disease', (48, 51))
20350	23696129	In chRCC preclinical studies have demonstrated that mTOR is activated by inactivation of its negative regulatory protein folliculin.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('protein', 'cellular_component', 'GO:0003675', ('113', '120'))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('inactivation', 'Var', (73, 85))	('activated', 'PosReg', (60, 69))	('RCC', 'Disease', (5, 8))
20353	23696129	Recently, a recent phase II trial with foretinib, a dual inhibition of VEGFR2 and MET, has demonstrated an overall response rate of 13.5% (all PR) and a PFS of 9.3 months with an intriguing 50% response in pRCC patients with a germline MET mutation.	('VEGFR2', 'Gene', (71, 77))	('MET', 'Gene', (82, 85))	('patients', 'Species', '9606', (211, 219))	('VEGFR2', 'Gene', '3791', (71, 77))	('pRCC', 'Gene', (206, 210))	('foretinib', 'Chemical', 'MESH:C544831', (39, 48))	('germline MET mutation', 'Var', (227, 248))	('PR', 'Chemical', 'MESH:D011221', (143, 145))	('pRCC', 'Gene', '5546', (206, 210))
20370	31159774	In the Oncomine database, FBXO11 mRNA levels were lower in normal tissues than in cancer tissues, including clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), hereditary ccRCC, non-hereditary ccRCC, VHL mutant ccRCC and VHL wild-type ccRCC.	('Oncomine', 'Chemical', '-', (7, 15))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('VHL', 'Gene', (228, 231))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (108, 139))	('cancer', 'Disease', (82, 88))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 179))	('mutant', 'Var', (232, 238))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('RCC', 'Disease', (265, 268))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('FBXO11', 'Gene', (26, 32))	('ccRCC', 'Phenotype', 'HP:0006770', (199, 204))	('VHL', 'Gene', '7428', (228, 231))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 139))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('cell renal cell carcinoma', 'Disease', (114, 139))	('papillary renal cell carcinoma', 'Disease', (149, 179))	('pRCC', 'Gene', '5546', (181, 185))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (159, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (221, 226))	('lower', 'NegReg', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('VHL', 'Gene', (249, 252))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (141, 146))	('RCC', 'Disease', (182, 185))	('RCC', 'Disease', (143, 146))	('pRCC', 'Phenotype', 'HP:0006766', (181, 185))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', (223, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('VHL', 'Gene', '7428', (249, 252))	('pRCC', 'Gene', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (149, 179))	('RCC', 'Disease', 'MESH:C538614', (182, 185))
20378	31159774	Although RCC-related mortality has decreased due to the advent of minimally invasive surgery, targeted therapy, etc., it is still a major health concern in Asia.	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('RCC', 'Disease', (9, 12))	('targeted therapy', 'Var', (94, 110))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))
20410	31159774	1c), as well as than that in VHL mutant and wild-type ccRCC (P < 0.001, F = 13.30, Fig.	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('VHL', 'Gene', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('ccRCC', 'Phenotype', 'HP:0006770', (54, 59))	('VHL', 'Gene', '7428', (29, 32))	('mutant', 'Var', (33, 39))
20424	31159774	Incorporation of FBXO11 increased the predictive value of these three models, namely, when assessing OS: 0.703 versus 0.674 for the UISS score cohort, and 0.676 versus 0.598 for the SSIGN score cohort (Table 3).	('predictive', 'MPA', (38, 48))	('Incorporation', 'Var', (0, 13))	('OS', 'Chemical', '-', (101, 103))	('FBXO11', 'Gene', (17, 23))	('increased', 'PosReg', (24, 33))
20430	31159774	Taken together, these data suggest that high FBXO11 expression is associated with the degree of malignancy and poor patient prognosis for ccRCC.	('high', 'Var', (40, 44))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('patient', 'Species', '9606', (116, 123))	('malignancy', 'Disease', (96, 106))	('expression', 'MPA', (52, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (138, 143))	('FBXO11', 'Gene', (45, 51))	('RCC', 'Disease', 'MESH:C538614', (140, 143))	('RCC', 'Disease', (140, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))
20440	31159774	FBXO11 gene silencing led to the development of diffuse large B-cell lymphoma (DLBCL) by targeting the degradation of Bcl-6, while FBXO11 inactivation resulted in abnormal germinal-centre formation.	('targeting', 'NegReg', (89, 98))	('gene silencing', 'biological_process', 'GO:0016458', ('7', '21'))	('B-cell lymphoma', 'Disease', (62, 77))	('gene', 'Var', (7, 11))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('Bcl-6', 'Gene', '604', (118, 123))	('inactivation', 'Var', (138, 150))	('formation', 'biological_process', 'GO:0009058', ('188', '197'))	('germinal-centre formation', 'CPA', (172, 197))	('Bcl-6', 'Gene', (118, 123))	('FBXO11', 'Gene', (0, 6))	('degradation', 'biological_process', 'GO:0009056', ('103', '114'))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (62, 77))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (62, 77))
20444	31159774	For example, the Jeff mouse model of chronic otitis media harbours a FBXO11 mutation, which interferes with TGF-betasignalling.	('otitis media', 'Phenotype', 'HP:0000388', (45, 57))	('otitis', 'Disease', 'MESH:D010031', (45, 51))	('chronic otitis', 'Phenotype', 'HP:0000389', (37, 51))	('otitis', 'Disease', (45, 51))	('mouse', 'Species', '10090', (22, 27))	('mutation', 'Var', (76, 84))	('FBXO11', 'Gene', (69, 75))
20456	30428910	Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis Metastasis is the primary cause of death in renal cell carcinoma (RCC).	('death in renal cell carcinoma', 'Disease', (180, 209))	('CLDN7', 'Gene', (18, 23))	('RCC', 'Disease', (211, 214))	('Downregulation', 'NegReg', (0, 14))	('RCC', 'Phenotype', 'HP:0005584', (211, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('RCC', 'Disease', 'MESH:C538614', (211, 214))	('CLDN7', 'Gene', '1366', (18, 23))	('death in renal cell carcinoma', 'Disease', 'MESH:C538614', (180, 209))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 113))	('human', 'Species', '9606', (76, 81))	('clear cell renal cell carcinoma', 'Disease', (82, 113))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (82, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (93, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (189, 209))	('associated', 'Reg', (60, 70))	('promoter hypermethylation', 'Var', (31, 56))
20465	30428910	Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('hypermethylation', 'Var', (65, 81))	('downregulated', 'NegReg', (47, 60))	('CLDN7', 'Gene', (27, 32))
20467	30428910	Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis.	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('related', 'Reg', (58, 65))	('hypermethylation', 'Var', (15, 31))	('CLDN7', 'Gene', (39, 44))
20470	30428910	We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('CLDN7', 'Gene', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('potentiates', 'PosReg', (113, 124))	('tumor', 'Disease', (133, 138))	('loss', 'Var', (99, 103))	('EMT', 'biological_process', 'GO:0001837', ('125', '128'))
20483	30428910	In this study, we confirmed that downregulation of CLDN7 due to hypermethylation may help predict aggressive tumor status and poor prognosis in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('aggressive tumor', 'Disease', (98, 114))	('CLDN7', 'Gene', (51, 56))	('patients', 'Species', '9606', (150, 158))	('hypermethylation', 'Var', (64, 80))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('aggressive tumor', 'Disease', 'MESH:D001523', (98, 114))	('downregulation', 'NegReg', (33, 47))
20496	30428910	Additionally, gene-set enrichment analysis (GSEA) was performed to compare differences in molecular pathways in cell processes between the low CLDN7 and high CLDN7 groups on the data from the ccRCC dataset of TCGA.	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('low CLDN7', 'Var', (139, 148))	('high CLDN7', 'Var', (153, 163))	('GSEA', 'Chemical', '-', (44, 48))	('molecular pathways', 'Pathway', (90, 108))
20510	30428910	GAPDH (TA309157) and Ki-67 (TA500265) were purchased from ZSGB-BIO, Beijing, China.	('TA309157', 'Var', (7, 15))	('GAPDH', 'Gene', '2597', (0, 5))	('TA500265', 'Var', (28, 36))	('GAPDH', 'Gene', (0, 5))
20536	30428910	Ten minutes after D-Luciferin, sodium salt (150 mg/kg) was injected intraperitoneally, and cancer cells were detected with an in vivo imaging system, Xenogen IVIS (PerkinElmer, MA, USA).	('D-Luciferin', 'Var', (18, 29))	('D-Luciferin', 'Chemical', 'MESH:C532924', (18, 29))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('sodium salt', 'Chemical', '-', (31, 42))
20561	30428910	Epigenetic alterations, such as promoter CpG methylation, could mediate the activation of oncogene and inactivate tumor suppressor genes, thus contributing to tumorigenesis.	('Epigenetic alterations', 'Var', (0, 22))	('oncogene', 'Gene', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('114', '130'))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('promoter CpG methylation', 'Var', (32, 56))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (159, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('114', '130'))	('inactivate', 'NegReg', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('activation', 'PosReg', (76, 86))	('contributing', 'Reg', (143, 155))
20563	30428910	In the TCGA ccRCC dataset, we generated a comparable heatmap in which we found that when some regions of the CLDN7 promoter were hypermethylated, CLDN7 expression was lower (Fig.	('lower', 'NegReg', (167, 172))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('hypermethylated', 'Var', (129, 144))	('CLDN7', 'Gene', (146, 151))	('expression', 'MPA', (152, 162))	('CLDN7', 'Gene', (109, 114))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
20564	30428910	Moreover, we observed that CLDN7 methylation status was negatively related to its mRNA and protein expression in the TCGA ccRCC dataset (Fig.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('methylation', 'biological_process', 'GO:0032259', ('33', '44'))	('methylation', 'Var', (33, 44))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('negatively', 'NegReg', (56, 66))	('CLDN7', 'Gene', (27, 32))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))
20568	30428910	Hypermethylated CLDN7 was significantly correlated with advanced age, pathologic T and histologic G, which agrees with our bioinformatic analysis of the TCGA ccRCC Methylation 450 K dataset (n = 319, Additional file 7: Table S4).	('Hypermethylated', 'Var', (0, 15))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('Methylation', 'biological_process', 'GO:0032259', ('164', '175'))	('correlated', 'Reg', (40, 50))	('CLDN7', 'Gene', (16, 21))	('pathologic T', 'Disease', (70, 82))
20569	30428910	Therefore, hypermethylation of CLDN7 promoter was associated with downregulation of CLDN7 and a poor prognosis in ccRCC patients.	('hypermethylation', 'Var', (11, 27))	('CLDN7', 'Gene', (31, 36))	('CLDN7', 'Gene', (84, 89))	('patients', 'Species', '9606', (120, 128))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('downregulation', 'NegReg', (66, 80))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('RCC', 'Disease', (116, 119))
20570	30428910	2, promoter hypermethylation was associated with low CLDN7 expression in ccRCC patients.	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('expression', 'MPA', (59, 69))	('low', 'NegReg', (49, 52))	('patients', 'Species', '9606', (79, 87))	('CLDN7', 'Gene', (53, 58))	('promoter hypermethylation', 'Var', (3, 28))
20574	30428910	CLDN7 hypermethylation was also found in 34/108 (31.5%) ccRCC tissues (Fig.	('hypermethylation', 'Var', (6, 22))	('found', 'Reg', (32, 37))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('CLDN7', 'Gene', (0, 5))
20582	30428910	Consistent with the weak proliferative ability and high apoptotic rate observed in the CLDN7 overexpressed Caki-1 and A498 cells, a xenograft experiment in mice found that CLDN7 overexpressed tumors grew slower than those in a control group (Fig.	('CLDN7', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('A498', 'CellLine', 'CVCL:1056', (118, 122))	('mice', 'Species', '10090', (156, 160))	('slower', 'NegReg', (204, 210))	('CLDN7', 'Var', (172, 177))	('grew', 'CPA', (199, 203))
20584	30428910	A transwell migratory and invasive assay also found that migratory and invasive cells were clearly attenuated in Caki-1 and A498 cells that overexpressed CLDN7, compared with control cells (Fig.	('overexpressed', 'Var', (140, 153))	('attenuated', 'NegReg', (99, 109))	('CLDN7', 'Gene', (154, 159))	('A498', 'CellLine', 'CVCL:1056', (124, 128))
20585	30428910	To understand the tumor suppressive role of CLDN7 in ccRCC, gene-set enrichment analysis on the data from the database of TCGA was used to compare the differences in cell processes between the low- and high- CLDN7 groups.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('tumor', 'Disease', (18, 23))	('high- CLDN7', 'Var', (202, 213))	('low-', 'Var', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
20586	30428910	Interestingly, the results suggest that several pathways relating to cancer and TGF-beta, WNT, Focal adhesion and NOTCH pathways relating to epithelial-mesenchymal transition (EMT) and tumor progression were all decreased in ccRCC with high CLDN7 mRNA expression (Additional file 9: Figure S5 and Additional file 10: Table S5).	('Focal adhesion', 'cellular_component', 'GO:0005925', ('95', '109'))	('WNT', 'Pathway', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('RCC', 'Disease', (227, 230))	('tumor', 'Disease', (185, 190))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('mRNA expression', 'MPA', (247, 262))	('epithelial-mesenchymal transition', 'biological_process', 'GO:0001837', ('141', '174'))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('Focal adhesion', 'CPA', (95, 109))	('decreased', 'NegReg', (212, 221))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('TGF-beta', 'Gene', '7040', (80, 88))	('high', 'Var', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (69, 75))	('NOTCH pathways', 'Pathway', (114, 128))	('EMT', 'biological_process', 'GO:0001837', ('176', '179'))	('CLDN7', 'Gene', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TGF-beta', 'Gene', (80, 88))	('epithelial-mesenchymal transition', 'CPA', (141, 174))
20591	30428910	Cell pro-apoptotic markers, such as cleaved-PARP1 and cleaved-Caspase3, were upregulated by CLDN7 in Caki-1 and A498 cells, and the anti-apoptotic marker BCL2 was downregulated (Fig.	('A498', 'CellLine', 'CVCL:1056', (112, 116))	('Caspase3', 'Gene', '836', (62, 70))	('BCL2', 'Gene', (154, 158))	('Caspase3', 'Gene', (62, 70))	('CLDN7', 'Var', (92, 97))	('upregulated', 'PosReg', (77, 88))	('BCL2', 'molecular_function', 'GO:0015283', ('154', '158'))	('PARP1', 'Gene', '142', (44, 49))	('BCL2', 'Gene', '596', (154, 158))	('PARP1', 'Gene', (44, 49))
20597	30428910	Bioinformatic Data Mining found that DNA hypermethylation in the promoter of CLDN7, and MSP and BGS results confirmed the CLDN7 promoter hypermethylation in ccRCC tissues.	('BGS', 'Disease', (96, 99))	('hypermethylation', 'Var', (41, 57))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('DNA', 'cellular_component', 'GO:0005574', ('37', '40'))	('BGS', 'Disease', 'MESH:C536788', (96, 99))	('hypermethylation', 'Var', (137, 153))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('37', '57'))	('CLDN7', 'Gene', (77, 82))	('CLDN7', 'Gene', (122, 127))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
20599	30428910	To explore the molecular mechanism of the tumor suppressive function of CLDN7 in ccRCC, GSEA was performed to evaluate the different gene expression profiles between low- and high-CLDN7 expression groups of ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('tumor', 'Disease', (42, 47))	('high-CLDN7', 'Gene', (175, 185))	('high-CLDN7', 'Var', (175, 185))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('GSEA', 'Chemical', '-', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('patients', 'Species', '9606', (213, 221))	('RCC', 'Disease', (209, 212))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('gene expression', 'biological_process', 'GO:0010467', ('133', '148'))
20600	30428910	We found that cancer pathways and EMT-related pathways both decreased in ccRCC patients with high CLDN7 expression.	('cancer', 'Disease', (14, 20))	('decreased', 'NegReg', (60, 69))	('EMT-related', 'CPA', (34, 45))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('EMT', 'biological_process', 'GO:0001837', ('34', '37'))	('patients', 'Species', '9606', (79, 87))	('CLDN7', 'Gene', (98, 103))	('high', 'Var', (93, 97))
20603	30428910	Previous study has shown that TGFB1 exposure decreased expression of CLDN7 and diminished epithelial barrier function, however, CLDN7 overexpression resulted in protection from TGFB1-mediated barrier dysfunction.	('overexpression', 'Var', (134, 148))	('TGFB1', 'Gene', (30, 35))	('CLDN7', 'Gene', (69, 74))	('decreased', 'NegReg', (45, 54))	('epithelial', 'MPA', (90, 100))	('expression', 'MPA', (55, 65))	('CLDN7', 'Gene', (128, 133))	('diminished', 'NegReg', (79, 89))	('TGFB1', 'Gene', '7040', (30, 35))	('TGFB1', 'Gene', '7040', (177, 182))	('TGFB1', 'Gene', (177, 182))
20612	30428910	And CLDN7 was revealed to increase chemosensitivity through the activation of caspase pathway in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('chemosensitivity', 'MPA', (35, 51))	('CLDN7', 'Var', (4, 9))	('activation', 'PosReg', (64, 74))	('caspase pathway', 'Pathway', (78, 93))	('lung cancer', 'Disease', (97, 108))	('increase', 'PosReg', (26, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
20674	27659687	Also, heterogeneity of RCCs at different stages of development may induce user error by choosing a cross-section that is not entirely representative of the entire mass.	('heterogeneity', 'Var', (6, 19))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('induce', 'Reg', (67, 73))
20705	25845370	As of June 2012, of 3250 patients enrolled on AREN03B2, 120 (3.7%) had unilateral RCC (median age 12.9 years, range 1.9-22.1; 52.5% female).	('AREN03B2', 'Var', (46, 54))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('patients', 'Species', '9606', (25, 33))
20735	25845370	As of June 2012, 3250 patients have enrolled on AREN03B2, and of these, 122 (3.75%) patients have central pathologic confirmation of RCC.	('patients', 'Species', '9606', (84, 92))	('AREN03B2', 'Var', (48, 56))	('patients', 'Species', '9606', (22, 30))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))
20738	25845370	Patients with renal medullary carcinoma (RMC) were all noted to have sickle cell trait, and the single patient with clear cell RCC had multiple endocrine neoplasia type I. Tumor histology is translocation morphology (tRCC: 56; 46.7%), RCC not otherwise specified (RCC NOS: 25; 20.8%), papillary (20; 16.7%), RMC (13; 10.8%), chromophobe (4; 3.3%), oncocytoma (1; 0.8%), and clear cell (1; 0.8%).	('RCC', 'Phenotype', 'HP:0005584', (235, 238))	('RCC', 'Disease', (235, 238))	('neoplasia', 'Phenotype', 'HP:0002664', (154, 163))	('oncocytoma', 'Disease', (348, 358))	('papillary', 'Disease', (285, 294))	('multiple endocrine neoplasia type I', 'Disease', 'MESH:D018761', (135, 170))	('Patients', 'Species', '9606', (0, 8))	('RCC', 'Disease', (218, 221))	('RCC', 'Disease', 'MESH:C538614', (235, 238))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (144, 163))	('patient', 'Species', '9606', (103, 110))	('RCC', 'Disease', (264, 267))	('RCC', 'Phenotype', 'HP:0005584', (264, 267))	('Tumor', 'Phenotype', 'HP:0002664', (172, 177))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RMC', 'Disease', (308, 311))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('RCC', 'Disease', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('renal medullary carcinoma', 'Disease', 'MESH:D007681', (14, 39))	('multiple endocrine neoplasia type I', 'Disease', (135, 170))	('renal medullary carcinoma', 'Disease', (14, 39))	('oncocytoma', 'Disease', 'MESH:D018249', (348, 358))	('chromophobe', 'Disease', (325, 336))	('translocation', 'Var', (191, 204))	('RCC', 'Disease', 'MESH:C538614', (127, 130))
20751	25845370	At initial surgery, patients undergoing NSS were less likely than those undergoing RN to have LNs sampled (6 of 18 (33.3%) vs. 65 of 88 (73.9%), p=0.002), as were patients with lower T-Stage (Table III, p=0.003).	('patients', 'Species', '9606', (163, 171))	('NSS', 'Var', (40, 43))	('patients', 'Species', '9606', (20, 28))	('NSS', 'Chemical', '-', (40, 43))	('LNs sampled', 'CPA', (94, 105))	('less', 'NegReg', (49, 53))	('T-Stage', 'CPA', (183, 190))
20758	25845370	There appears to be no gender predilection in pRCC overall, though there is a slight female predominance for translocation or TFE RCC (tRCC) specifically.	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Disease', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('translocation', 'Var', (109, 122))	('RCC', 'Disease', (136, 139))
20774	25845370	Predicated on the rationale that TFE RCC shares similar biology to other TFE-translocation associated cancers such as sarcomas and reported clinical benefit of chemotherapy for sarcomatoid RCC variants, conventional chemotherapies (typically gemcitabine-based) have been used with anecdotal response and disease stabilization.	('sarcomas', 'Disease', 'MESH:D012509', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('sarcomatoid RCC', 'Disease', 'MESH:C538614', (177, 192))	('sarcomas', 'Phenotype', 'HP:0100242', (118, 126))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('sarcomas', 'Disease', (118, 126))	('variants', 'Var', (193, 201))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('gemcitabine', 'Chemical', 'MESH:C056507', (242, 253))	('cancers', 'Disease', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('sarcomatoid RCC', 'Disease', (177, 192))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))
20816	26448948	These differences of tumor characteristics may partly explain why the patients with high NLR or neutrophilia in our cohort had more aggressive disease.	('aggressive disease', 'Disease', (132, 150))	('neutrophilia', 'Phenotype', 'HP:0011897', (96, 108))	('high NLR', 'Var', (84, 92))	('neutrophilia', 'Var', (96, 108))	('aggressive disease', 'Disease', 'MESH:D001523', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
20827	33207686	A high expression of FAP and low levels sFAP are significantly associated with high tumour diameter, high grade, and high pT stage, lymph node invasion, development of early metastases, and worse 5-year cancer specific survival of CCRCC patients.	('high grade', 'CPA', (101, 111))	('high pT stage', 'CPA', (117, 130))	('FAP', 'Gene', '2191', (21, 24))	('FAP', 'Gene', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('patients', 'Species', '9606', (237, 245))	('RCC', 'Disease', (233, 236))	('associated', 'Reg', (63, 73))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('low levels', 'Var', (29, 39))	('metastases', 'Disease', 'MESH:D009362', (174, 184))	('FAP', 'Gene', '2191', (41, 44))	('cancer', 'Disease', (203, 209))	('FAP', 'Gene', (21, 24))	('metastases', 'Disease', (174, 184))	('CCRCC', 'Phenotype', 'HP:0006770', (231, 236))	('high tumour', 'Disease', 'MESH:D009369', (79, 90))	('high tumour', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lymph node invasion', 'CPA', (132, 151))	('worse', 'NegReg', (190, 195))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))
20839	33207686	The identification of alterations that may influence this unpredictable tumour behaviour and clinical outcome both in primary tumour tissues and in liquid biopsies is needed to improve the management of these patients.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('influence', 'Reg', (43, 52))	('behaviour', 'biological_process', 'GO:0007610', ('79', '88'))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('alterations', 'Var', (22, 33))	('patients', 'Species', '9606', (209, 217))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
20845	33207686	Regarding renal cancer, in vitro studies have demonstrated that the crosstalk communication between CAFs and tumour cells induces pro-invasive properties in RCC cell lines.	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('renal cancer', 'Disease', (10, 22))	('induces', 'Reg', (122, 129))	('renal cancer', 'Phenotype', 'HP:0009726', (10, 22))	('tumour', 'Disease', (109, 115))	('pro-invasive properties', 'CPA', (130, 153))	('CAF', 'Gene', (100, 103))	('renal cancer', 'Disease', 'MESH:D007680', (10, 22))	('RCC', 'Phenotype', 'HP:0005584', (157, 160))	('crosstalk', 'Var', (68, 77))	('RCC', 'Disease', (157, 160))	('CAF', 'Gene', '8850', (100, 103))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
20922	33207686	We validated previous results in a new series of CCRCCs, and the association between FAP positivity and worse prognosis was confirmed, regardless of the area of the tumour in which the protein was expressed.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('positivity', 'Var', (89, 99))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('FAP', 'Gene', (85, 88))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('FAP', 'Gene', '2191', (85, 88))	('tumour', 'Disease', (165, 171))	('CCRCC', 'Phenotype', 'HP:0006770', (49, 54))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
20955	33207686	Some of these stromal targets are being evaluated in pancreatic cancer, either by depleting CAFs using CAF-related cell-surface markers, such as alpha-SMA or FAP, reprogramming CAFs into quiescent fibroblasts, or targeting interactions between CAFs and their surrounding microenvironment.	('CAF', 'Gene', '8850', (244, 247))	('CAF', 'Gene', '8850', (92, 95))	('CAF', 'Gene', (244, 247))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('CAF', 'Gene', (92, 95))	('CAF', 'Gene', '8850', (177, 180))	('FAP', 'Gene', (158, 161))	('depleting', 'NegReg', (82, 91))	('pancreatic cancer', 'Disease', (53, 70))	('CAF', 'Gene', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('alpha-SMA', 'Gene', (145, 154))	('interactions', 'Interaction', (223, 235))	('cell-surface', 'cellular_component', 'GO:0009986', ('115', '127'))	('alpha-SMA', 'Gene', '58', (145, 154))	('FAP', 'Gene', '2191', (158, 161))	('CAF', 'Gene', '8850', (103, 106))	('reprogramming', 'Var', (163, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('targeting', 'Reg', (213, 222))	('CAF', 'Gene', (103, 106))
20988	33207686	At the infiltrating front of these non-organ-confined tumours, FAP positive cases almost duplicated the expression of pT1 tumours, although it did not reach statistical significance, and pT2 tumours had higher FAP expression than pT1 ones.	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('FAP', 'Gene', '2191', (210, 213))	('tumours', 'Disease', (191, 198))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('higher', 'PosReg', (203, 209))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('tumours', 'Phenotype', 'HP:0002664', (191, 198))	('FAP', 'Gene', (63, 66))	('tumours', 'Disease', 'MESH:D009369', (191, 198))	('tumours', 'Disease', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))	('pT1', 'Gene', '58492', (230, 233))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('pT1', 'Gene', '58492', (118, 121))	('pT1', 'Gene', (230, 233))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('FAP', 'Gene', '2191', (63, 66))	('pT1', 'Gene', (118, 121))	('FAP', 'Gene', (210, 213))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('pT2', 'Var', (187, 190))
20999	30863498	The ccRCC type is often characterized by aberrations in the VHL gene on chromosome 3p, usually causing the loss of the VHL-mediated degradation of the hypoxia-inducible factor alpha (HIF-alpha) under normoxic conditions.	('chromosome', 'cellular_component', 'GO:0005694', ('72', '82'))	('loss', 'NegReg', (107, 111))	('VHL', 'Gene', (60, 63))	('VHL', 'Gene', (119, 122))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('VHL', 'Gene', '7428', (119, 122))	('VHL', 'Gene', '7428', (60, 63))	('degradation', 'biological_process', 'GO:0009056', ('132', '143'))	('hypoxia', 'Disease', (151, 158))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('aberrations', 'Var', (41, 52))
21022	30863498	To test whether exogenous TGF-beta1 treatment has an effect on survival and growth, five ccRCC cell lines (786-O, Caki-1, Caki-2, MZ1851RC, MZ2733RC) and one pRCC cell line (MZ2858RC) were left untreated or treated with 10 ng/mL TGF-beta for 48 to 96 hours, before their cell viability, proliferation and apoptosis was analyzed.	('apoptosis', 'biological_process', 'GO:0097194', ('305', '314'))	('MZ2733RC', 'Var', (140, 148))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('apoptosis', 'biological_process', 'GO:0006915', ('305', '314'))	('MZ1851RC', 'Var', (130, 138))	('TGF-beta', 'Gene', '7040', (229, 237))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('pRCC', 'Gene', (158, 162))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('TGF-beta', 'Gene', '7040', (26, 34))	('TGF-beta', 'Gene', (229, 237))	('MZ2733RC', 'Chemical', '-', (140, 148))	('pRCC', 'Gene', '5546', (158, 162))	('TGF-beta', 'Gene', (26, 34))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
21028	30863498	As shown in Figure 1, heterogeneous results were obtained for the 7 different cell lines, which could be classified into 3 groups according to their extent of morphological change: MCF-10, Caki-1, and Caki-2 showed drastic changes in morphology upon TGF-beta1 stimulation (+++); MZ1851RC, MZ2733RC, and MZ2858RC showed minor differences after TGF-beta1 stimulation (+) while for 786-O no obvious differences in shape were detected after TGF-beta1 treatment (-) (Figure 1).	('MZ2733RC', 'Chemical', '-', (289, 297))	('morphology', 'MPA', (234, 244))	('MZ1851RC', 'Var', (279, 287))	('MZ2733RC', 'Var', (289, 297))	('MCF-10', 'CellLine', 'CVCL:5555', (181, 187))	('changes', 'Reg', (223, 230))	('MZ2858RC', 'Var', (303, 311))
21031	30863498	After treatment with TGF-beta1, the mRNA level of TGFBR2 was down-regulated in all RCC cells, while TGFBR1 levels were rather increased or not regulated in these cells with the exception of MZ2733RC, in which a down-regulation of TGFBR1 mRNA levels was detected (Figure 2A).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('TGFBR1', 'Gene', (100, 106))	('TGF-beta1', 'Gene', (21, 30))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('MZ2733RC', 'Chemical', '-', (190, 198))	('down-regulated', 'NegReg', (61, 75))	('regulation', 'biological_process', 'GO:0065007', ('216', '226'))	('TGFBR2', 'Gene', (50, 56))	('MZ2733RC', 'Var', (190, 198))	('TGFBR1', 'Gene', (230, 236))	('increased', 'PosReg', (126, 135))	('mRNA level', 'MPA', (36, 46))	('TGFBR1', 'Gene', '7046', (230, 236))	('TGFBR1', 'Gene', '7046', (100, 106))
21047	30863498	In contrast, HLA-ABC, B7-H2, and B7-H3 were upregulated in the ccRCC MZ2733RC.	('B7-H3', 'Gene', '102657', (33, 38))	('B7-H3', 'Gene', (33, 38))	('B7-H2', 'Gene', '23308', (22, 27))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('upregulated', 'PosReg', (44, 55))	('ABC', 'Gene', '10058', (17, 20))	('MZ2733RC', 'Var', (69, 77))	('B7-H2', 'Gene', (22, 27))	('MZ2733RC', 'Chemical', '-', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('ABC', 'Gene', (17, 20))	('RCC', 'Disease', (65, 68))
21048	30863498	Comparable to MZ2858RC, the expression of the cell adhesion molecule ICAM-1 was reduced after TGF-beta1 treatment of MZ2733RC.	('MZ2733RC', 'Chemical', '-', (117, 125))	('ICAM-1', 'Gene', '3383', (69, 75))	('expression', 'MPA', (28, 38))	('MZ2733RC', 'Var', (117, 125))	('reduced', 'NegReg', (80, 87))	('ICAM-1', 'Gene', (69, 75))	('cell adhesion', 'biological_process', 'GO:0007155', ('46', '59'))	('cell adhesion molecule', 'molecular_function', 'GO:0098631', ('46', '68'))
21049	30863498	No surface expression of B7-H1 was observed for MZ2733RC.	('B7-H1', 'Gene', '29126', (25, 30))	('B7-H1', 'Gene', (25, 30))	('MZ2733RC', 'Chemical', '-', (48, 56))	('MZ2733RC', 'Var', (48, 56))
21050	30863498	Analysis of APM components on mRNA level demonstrated mostly a down-regulation of the four genes tested after TGF-beta1 treatment in both cell lines (Supplementary Figure 1) which is in accordance with MHC I surface expression in MZ2858RC, but not in MZ2733RC.	('APM', 'Gene', '290', (12, 15))	('MHC', 'Gene', '3107', (202, 205))	('regulation', 'biological_process', 'GO:0065007', ('68', '78'))	('APM', 'Gene', (12, 15))	('MZ2858RC', 'Var', (230, 238))	('MZ2733RC', 'Chemical', '-', (251, 259))	('MHC', 'Gene', (202, 205))	('down-regulation', 'NegReg', (63, 78))
21059	30863498	For the one representative ccRCC cell line MZ2733RC and the pRCC cell line MZ2858RC, the MMP2 mRNA levels directly correlate with endogenous TGFB1 mRNA levels.	('MMP2', 'Gene', (89, 93))	('mRNA levels', 'MPA', (94, 105))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('pRCC', 'Gene', (60, 64))	('TGFB1', 'Gene', '7040', (141, 146))	('MZ2733RC', 'Chemical', '-', (43, 51))	('RCC', 'Disease', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('pRCC', 'Gene', '5546', (60, 64))	('MMP2', 'Gene', '4313', (89, 93))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('TGFB1', 'Gene', (141, 146))	('MMP2', 'molecular_function', 'GO:0004228', ('89', '93'))	('MZ2733RC', 'Var', (43, 51))
21061	30863498	When the TGFB1 levels increased even in the absence of the exogenous stimulus, the MMP2 simultaneously increased as demonstrated for MZ2733RC.	('increased', 'PosReg', (103, 112))	('MMP2', 'Gene', (83, 87))	('TGFB1', 'Gene', '7040', (9, 14))	('MZ2733RC', 'Chemical', '-', (133, 141))	('levels', 'MPA', (15, 21))	('increased', 'PosReg', (22, 31))	('TGFB1', 'Gene', (9, 14))	('MMP2', 'molecular_function', 'GO:0004228', ('83', '87'))	('MMP2', 'Gene', '4313', (83, 87))	('MZ2733RC', 'Var', (133, 141))
21074	30863498	For MZ2858RC, the TGF-beta1 protein level reverted to the level of untreated cells after 96 h re-culturing in the presence of the inhibitor indicating that no TGF-beta1 protein was secreted anymore into the supernatant by the pRCC cells (Figure 9B).	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('TGF-beta1', 'MPA', (18, 27))	('pRCC', 'Gene', (226, 230))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('pRCC', 'Gene', '5546', (226, 230))	('MZ2858RC', 'Var', (4, 12))	('protein', 'cellular_component', 'GO:0003675', ('28', '35'))
21076	30863498	In RCC, EMT can be induced by a variety of factors, such as TNF-alpha, oxidative stress, loss of VHL or FOXO3A, and deregulation of miRNAs.	('FOXO3A', 'Gene', '2309', (104, 110))	('induced by', 'Reg', (19, 29))	('VHL', 'Gene', '7428', (97, 100))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('EMT', 'Gene', (8, 11))	('miRNAs', 'Enzyme', (132, 138))	('loss', 'NegReg', (89, 93))	('oxidative stress', 'MPA', (71, 87))	('EMT', 'Gene', '3702', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('RCC', 'Disease', 'MESH:C538614', (3, 6))	('RCC', 'Disease', (3, 6))	('TNF-alpha', 'Gene', '7124', (60, 69))	('FOXO3A', 'Gene', (104, 110))	('EMT', 'biological_process', 'GO:0001837', ('8', '11'))	('deregulation', 'Var', (116, 128))	('VHL', 'Gene', (97, 100))	('TNF-alpha', 'Gene', (60, 69))
21083	30863498	It was found that loss of one TGFBR2 allele is associated with tumor progression and metastasis.	('tumor', 'Disease', (63, 68))	('loss', 'Var', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('metastasis', 'CPA', (85, 95))	('associated', 'Reg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TGFBR2', 'Gene', (30, 36))
21084	30863498	Furthermore, a tumor-suppressive role for an intact TGFBR2 and signaling pathway was shown in mice.	('signaling pathway', 'biological_process', 'GO:0007165', ('63', '80'))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('TGFBR2', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mice', 'Species', '10090', (94, 98))	('intact', 'Var', (45, 51))	('signaling pathway', 'Pathway', (63, 80))
21085	30863498	These data were further underlined by the survival of RCC patients according to Kaplan-Meier curves, which showed a significantly lower overall survival in ccRCC patients with low levels of TGFBR2 in comparison to the ones with high expression of TGFBR2 (Supplementary Figure 4).	('lower', 'NegReg', (130, 135))	('patients', 'Species', '9606', (162, 170))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('TGFBR2', 'Gene', (190, 196))	('low levels', 'Var', (176, 186))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('overall survival', 'MPA', (136, 152))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('patients', 'Species', '9606', (58, 66))
21086	30863498	The levels of TGFBR2 were shown to regulate the downstream signaling pathway: high expression induces the Smad-dependent signaling pathway while a low expression triggers signaling via the non-Smad-dependent MAP/ERK pathway in colon cancer.	('ERK', 'molecular_function', 'GO:0004707', ('212', '215'))	('triggers', 'Reg', (162, 170))	('colon cancer', 'Disease', (227, 239))	('ERK', 'Gene', '2048', (212, 215))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('signaling pathway', 'biological_process', 'GO:0007165', ('59', '76'))	('high expression', 'Var', (78, 93))	('signaling', 'biological_process', 'GO:0023052', ('171', '180'))	('MAP', 'molecular_function', 'GO:0004239', ('208', '211'))	('TGFBR2', 'Gene', (14, 20))	('induces', 'Reg', (94, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))	('Smad-dependent signaling pathway', 'Pathway', (106, 138))	('signaling pathway', 'biological_process', 'GO:0007165', ('121', '138'))	('ERK', 'Gene', (212, 215))
21099	30863498	However, a correlation of high TGFB1 levels and worse overall survival was only determined for the clear cell but not for the papillary type of RCC (Supplementary Figure 5).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('high', 'Var', (26, 30))	('papillary type', 'Phenotype', 'HP:0007482', (126, 140))	('TGFB1', 'Gene', '7040', (31, 36))	('high TGFB1 levels', 'Phenotype', 'HP:0030269', (26, 43))	('TGFB1', 'Gene', (31, 36))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))
21103	30863498	Besides similarities in EMT induction, we detected differences in surface expression of immune modulatory molecules for the representative ccRCC cell line MZ2733RC and the pRCC cell line MZ2858RC.	('RCC', 'Disease', (141, 144))	('pRCC', 'Gene', '5546', (172, 176))	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('EMT', 'biological_process', 'GO:0001837', ('24', '27'))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('EMT', 'Gene', (24, 27))	('MZ2733RC', 'Var', (155, 163))	('RCC', 'Disease', 'MESH:C538614', (141, 144))	('EMT', 'Gene', '3702', (24, 27))	('differences', 'Reg', (51, 62))	('pRCC', 'Gene', (172, 176))	('MZ2733RC', 'Chemical', '-', (155, 163))	('surface expression', 'MPA', (66, 84))
21120	30863498	For MZ2733RC slightly higher TGF-beta1 protein levels relative to the untreated control were detected after 96 h inhibitor treatment.	('MZ2733RC', 'Var', (4, 12))	('protein', 'cellular_component', 'GO:0003675', ('39', '46'))	('higher', 'PosReg', (22, 28))	('MZ2733RC', 'Chemical', '-', (4, 12))	('TGF-beta1 protein levels', 'MPA', (29, 53))
21128	30863498	MZ1851RC, MZ2733RC, and MZ2858RC were generated from primary tumors of the clear cell or papillary subtype as previously described.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('MZ2733RC', 'Var', (10, 18))	('MZ2733RC', 'Chemical', '-', (10, 18))	('MZ1851RC', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MZ2858RC', 'Var', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
21136	30863498	In brief, the ccRCC cell type (MZ1851RC) and the pRCC cell type (MZ2858RC) were grown in 6-well plates +/- 10 ng/mL TGF-beta1 for 96 h to 100% confluence.	('pRCC', 'Gene', '5546', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('MZ1851RC', 'Var', (31, 39))	('RCC', 'Disease', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('pRCC', 'Gene', (49, 53))
21149	30863498	Datasets were obtained from "The Cancer Genome Atlas" (https://portal.gdc.cancer.gov) with 604 patients for TCGA-KIRC (ccRCC) and 320 patients for TCGA-KIRP (pRCC).	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('Cancer Genome Atlas', 'Disease', (33, 52))	('RCC', 'Disease', (121, 124))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (33, 52))	('pRCC', 'Gene', (158, 162))	('patients', 'Species', '9606', (134, 142))	('TCGA-KIRC', 'Var', (108, 117))	('cancer', 'Disease', (74, 80))	('pRCC', 'Gene', '5546', (158, 162))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
21169	27621699	However, loss of VHL function alone is not sufficient for ccRCC initiation, and a higher number of genetic or epigenetic events are required.	('RCC', 'Disease', (60, 63))	('loss', 'Var', (9, 13))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))
21201	27621699	A more recent study investigated genetic alterations of 20 representative PI3K/AKT pathway components in ccRCC, such as PIK3CA amplifications or mutations (5%), PTEN deletions or mutations (5%), or mTOR mutations (6%), reiterating the critical role of the PI3K/AKT pathway in this cancer.	('PI3K/AKT', 'Gene', '5290;207', (256, 264))	('mutations', 'Var', (145, 154))	('PIK3CA', 'Gene', '5290', (120, 126))	('RCC', 'Disease', (107, 110))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('PTEN', 'Gene', (161, 165))	('PIK3CA', 'Gene', (120, 126))	('PI3K/AKT', 'Gene', (74, 82))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('PI3K', 'molecular_function', 'GO:0016303', ('256', '260'))	('mTOR', 'Gene', (198, 202))	('mutations', 'Var', (179, 188))	('PI3K', 'molecular_function', 'GO:0016303', ('74', '78'))	('mutations', 'Var', (203, 212))	('PTEN', 'Gene', '5728', (161, 165))	('deletions', 'Var', (166, 175))	('PI3K/AKT', 'Gene', '5290;207', (74, 82))	('cancer', 'Disease', (281, 287))	('PI3K/AKT', 'Gene', (256, 264))	('mTOR', 'Gene', '2475', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
21204	27621699	Mutations in FH, associated with type 2 pRCC, result in the accumulation of fumarate, which leads to the upregulation of HIF-1alpha and activation of mTOR pathway through the mechanism described earlier.	('mTOR', 'Gene', '2475', (150, 154))	('fumarate', 'MPA', (76, 84))	('HIF-1alpha', 'Gene', (121, 131))	('upregulation', 'PosReg', (105, 117))	('pRCC', 'Gene', '5546', (40, 44))	('Mutations', 'Var', (0, 9))	('activation', 'PosReg', (136, 146))	('HIF-1alpha', 'Gene', '3091', (121, 131))	('fumarate', 'Chemical', 'MESH:D005650', (76, 84))	('accumulation', 'PosReg', (60, 72))	('mTOR', 'Gene', (150, 154))	('pRCC', 'Gene', (40, 44))
21213	27621699	The disruption of p-S6K1 and 4EBP1 function, the two main downstream effectors of mTORC1, interferes with mRNA translation of genes involved in cell cycle regulation and cellular response to hypoxia.	('cell cycle', 'CPA', (144, 154))	('p-S6K1', 'Gene', '6198', (18, 24))	('4EBP1', 'Gene', '1978', (29, 34))	('mTORC1', 'Gene', '382056', (82, 88))	('translation', 'biological_process', 'GO:0006412', ('111', '122'))	('interferes', 'NegReg', (90, 100))	('mTORC1', 'cellular_component', 'GO:0031931', ('82', '88'))	('mTORC1', 'Gene', (82, 88))	('4EBP1', 'Gene', (29, 34))	('hypoxia', 'Disease', 'MESH:D000860', (191, 198))	('cellular response to hypoxia', 'biological_process', 'GO:0071456', ('170', '198'))	('mRNA translation of genes', 'MPA', (106, 131))	('disruption', 'Var', (4, 14))	('p-S6K1', 'Gene', (18, 24))	('cell cycle regulation', 'biological_process', 'GO:0051726', ('144', '165'))	('hypoxia', 'Disease', (191, 198))
21276	27621699	The rationale of associating two different agents in the treatment of RCC results from the notion that blocking the VEGF pathway can lead to hypoxia, and inhibiting the mTOR response to hypoxia may block the cellular response to the hypoxic stress.	('VEGF', 'Gene', '7422', (116, 120))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('inhibiting', 'NegReg', (154, 164))	('hypoxia', 'Disease', 'MESH:D000860', (186, 193))	('response to hypoxia', 'biological_process', 'GO:0001666', ('174', '193'))	('lead to', 'Reg', (133, 140))	('mTOR', 'Gene', '2475', (169, 173))	('cellular response', 'CPA', (208, 225))	('mTOR', 'Gene', (169, 173))	('hypoxic stress', 'Disease', (233, 247))	('hypoxia', 'Disease', 'MESH:D000860', (141, 148))	('blocking', 'Var', (103, 111))	('VEGF', 'Gene', (116, 120))	('block', 'NegReg', (198, 203))	('hypoxic stress', 'Disease', 'MESH:D004194', (233, 247))	('hypoxia', 'Disease', (141, 148))	('hypoxia', 'Disease', (186, 193))
21285	27621699	One hundred and fifty-three enrolled patients progressive to first-line VEGFR-TKI were randomly assigned to receive lenvatinib plus everolimus, single-agent lenvatinib, or single-agent everolimus.	('patients', 'Species', '9606', (37, 45))	('lenvatinib', 'Var', (116, 126))	('lenvatinib', 'Chemical', 'MESH:C531958', (116, 126))	('VEGFR', 'Gene', '3791', (72, 77))	('everolimus', 'Chemical', 'MESH:D000068338', (132, 142))	('lenvatinib', 'Chemical', 'MESH:C531958', (157, 167))	('everolimus', 'Chemical', 'MESH:D000068338', (185, 195))	('VEGFR', 'Gene', (72, 77))
21298	27621699	In support to this hypothesis, a large Phase III trial explored the efficacy of temsirolimus, an mTOR inhibitor, in 626 patients with previously untreated poor-prognosis mRCC: in this study, temsirolimus showed a better outcome compared to IFN in patients with non-clear cell histotype (n=73).	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('temsirolimus', 'Chemical', 'MESH:C401859', (191, 203))	('temsirolimus', 'Chemical', 'MESH:C401859', (80, 92))	('patients', 'Species', '9606', (247, 255))	('IFN', 'Gene', '3439', (240, 243))	('patients', 'Species', '9606', (120, 128))	('temsirolimus', 'Var', (191, 203))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', (171, 174))	('IFN', 'Gene', (240, 243))
21304	27621699	Interestingly, patients with chromophobe histology tended to have longer PFS than those with other nccRCC subtypes (13.1 vs 3.4 months, P=0.084).	('patients', 'Species', '9606', (15, 23))	('chromophobe histology', 'Var', (29, 50))	('PFS', 'MPA', (73, 76))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('longer', 'PosReg', (66, 72))
21305	27621699	In a post hoc subgroup analysis of metastatic nccRCC patients (n=66) enrolled in the RECORD-3 trial, mPFS was shorter for patients treated with everolimus compared to those treated with sunitinib in first-line setting (5.1 vs 7.2 months; HR 1.5, 95% CI 0.9-2.8).	('RCC', 'Disease', (49, 52))	('patients', 'Species', '9606', (53, 61))	('everolimus', 'Var', (144, 154))	('shorter', 'NegReg', (110, 117))	('sunitinib', 'Chemical', 'MESH:D000077210', (186, 195))	('patients', 'Species', '9606', (122, 130))	('mPFS', 'MPA', (101, 105))	('everolimus', 'Chemical', 'MESH:D000068338', (144, 154))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
21324	27621699	After TKI failure in Chinese RCC patients, a Phase Ib trial of everolimus explored the expression of p-AKT, p-mTOR, p-4EBP1, and p-S6RP by immunohistochemistry in paraffin-embedded tumor tissue specimens derived from 18 RCC patients.	('mTOR', 'Gene', (110, 114))	('AKT', 'Gene', '207', (103, 106))	('mTOR', 'Gene', '2475', (110, 114))	('tumor', 'Disease', (181, 186))	('patients', 'Species', '9606', (33, 41))	('4EBP1', 'Gene', '1978', (118, 123))	('everolimus', 'Chemical', 'MESH:D000068338', (63, 73))	('p-S6RP', 'Var', (129, 135))	('RCC', 'Disease', (29, 32))	('AKT', 'Gene', (103, 106))	('paraffin', 'Chemical', 'MESH:D010232', (163, 171))	('4EBP1', 'Gene', (118, 123))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('patients', 'Species', '9606', (224, 232))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('RCC', 'Disease', (220, 223))
21325	27621699	In this study, patients with the expression of p-mTOR or p-S6RP on the primary tumor had longer mPFS compared to patients with no expression (11.3 vs 3.7 months for p-mTOR, P=0.001; 11.3 vs 3.7 months for p-S6RP, P=0.002); co-expression of these two targets with p-4EBP1 was also associated with a longer PFS.	('PFS', 'CPA', (305, 308))	('mTOR', 'Gene', (49, 53))	('patients', 'Species', '9606', (15, 23))	('mTOR', 'Gene', '2475', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('4EBP1', 'Gene', (265, 270))	('patients', 'Species', '9606', (113, 121))	('longer', 'PosReg', (89, 95))	('mTOR', 'Gene', '2475', (167, 171))	('4EBP1', 'Gene', '1978', (265, 270))	('mTOR', 'Gene', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p-S6RP', 'Var', (57, 63))
21326	27621699	Moreover, none of the patients without expression of p-mTOR or p-S6RP experienced benefits with everolimus.	('everolimus', 'Chemical', 'MESH:D000068338', (96, 106))	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('patients', 'Species', '9606', (22, 30))	('benefits', 'PosReg', (82, 90))	('p-S6RP', 'Var', (63, 69))
21327	27621699	According to the results of this study, it could be supposed that expression status of p-mTOR and p-S6RP (that could imply a hyperactivation of mTOR pathway) may be applied as a potential predictive biomarker for everolimus efficacy in patients with mRCC, and a potential indicator for selection of patients.	('mTOR', 'Gene', '2475', (89, 93))	('hyperactivation', 'PosReg', (125, 140))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('p-S6RP', 'Var', (98, 104))	('patients', 'Species', '9606', (236, 244))	('patients', 'Species', '9606', (299, 307))	('RCC', 'Disease', (251, 254))	('everolimus', 'Chemical', 'MESH:D000068338', (213, 223))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))	('mTOR', 'Gene', (89, 93))
21328	27621699	However, these data may have been confounded by a bias, since the detection of p-mTOR and p-S6RP has been assessed on tissue available after nephrectomy at baseline, before TKI treatment, and not just before everolimus therapy.	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('everolimus', 'Chemical', 'MESH:D000068338', (208, 218))	('p-S6RP', 'Var', (90, 96))
21329	27621699	A more recent study by Knoll et al explored the role of p-S6RP, the major mediator of antitumoral effects exerted by everolimus, in vitro and in a novel ex vivo tissue slice model using fresh vital human RCC tissue, and then incubating the tissue with everolimus.	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', (204, 207))	('tumor', 'Disease', (90, 95))	('everolimus', 'Chemical', 'MESH:D000068338', (252, 262))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('human', 'Species', '9606', (198, 203))	('p-S6RP', 'Var', (56, 62))	('everolimus', 'Chemical', 'MESH:D000068338', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
21333	27621699	Until now, there is no prospectively validated predictive biomarker to monitor everolimus response or to apply a useful selection of patient candidate to mTOR inhibition; S6RP, a main downstream effector of the cascade, and its phosphorylated form p-S6RP are promising for this role, but their clinical use should be further validated.	('patient', 'Species', '9606', (133, 140))	('S6RP', 'Var', (171, 175))	('mTOR', 'Gene', (154, 158))	('mTOR', 'Gene', '2475', (154, 158))	('everolimus', 'Chemical', 'MESH:D000068338', (79, 89))
21343	27621699	mTOR pathway has been implicated in insulin resistance: mTOR inhibitors are known to be associated with hyperglycemia because of their effects on inhibition of glucose uptake and insulin synthesis.	('insulin', 'Gene', (36, 43))	('insulin resistance', 'Phenotype', 'HP:0000855', (36, 54))	('hyperglycemia', 'Phenotype', 'HP:0003074', (104, 117))	('insulin', 'Gene', (179, 186))	('mTOR', 'Gene', (0, 4))	('mTOR', 'Gene', (56, 60))	('inhibitors', 'Var', (61, 71))	('glucose uptake', 'biological_process', 'GO:0046323', ('160', '174'))	('mTOR', 'Gene', '2475', (0, 4))	('hyperglycemia', 'Disease', (104, 117))	('mTOR', 'Gene', '2475', (56, 60))	('inhibition', 'NegReg', (146, 156))	('glucose uptake', 'MPA', (160, 174))	('insulin', 'Gene', '3630', (36, 43))	('glucose', 'Chemical', 'MESH:D005947', (160, 167))	('insulin synthesis', 'biological_process', 'GO:1901144', ('179', '196'))	('insulin', 'molecular_function', 'GO:0016088', ('179', '186'))	('hyperglycemia', 'Disease', 'MESH:D006943', (104, 117))	('associated', 'Reg', (88, 98))	('insulin', 'molecular_function', 'GO:0016088', ('36', '43'))	('insulin', 'Gene', '3630', (179, 186))
21344	27621699	Moreover, inhibition of mTOR interferes with cell metabolism, leading to dyslipidemia.	('dyslipidemia', 'Disease', (73, 85))	('cell metabolism', 'MPA', (45, 60))	('interferes', 'NegReg', (29, 39))	('dyslipidemia', 'Disease', 'MESH:D050171', (73, 85))	('metabolism', 'biological_process', 'GO:0008152', ('50', '60'))	('inhibition', 'Var', (10, 20))	('dyslipidemia', 'Phenotype', 'HP:0003119', (73, 85))	('mTOR', 'Gene', (24, 28))	('leading to', 'Reg', (62, 72))	('mTOR', 'Gene', '2475', (24, 28))
21377	33137568	While human cancer cell lines are easy to handle and helpful for the evaluation of the efficacy of cytotoxic drugs, they tend to accumulate additional mutations over time, lack heterogeneity and poorly reflect early-stage cancer development.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('human', 'Species', '9606', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mutations', 'Var', (151, 160))	('heterogeneity', 'MPA', (177, 190))
21387	33137568	hPSC-derived cells, containing cancer-associated mutations, can be used to capture the earliest molecular events in cancer initiation, to trace cancer origins and to recapitulate cancer progression.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer initiation', 'Disease', 'MESH:D009369', (116, 133))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer initiation', 'Disease', (116, 133))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
21389	33137568	iPSC lines have been derived from patients with Li-Fraumeni syndrome (LFS) (TP53 mutation), Fanconi anemia (FA) (FANCA and FANCC mutations), Familial platelet disorder with associated myeloid malignancy (FPD/AML) (RUNX1 mutation) and breast cancer predisposition (BRCA1 mutation).	('Familial platelet disorder', 'Disease', (141, 167))	('FA', 'Phenotype', 'HP:0001994', (123, 125))	('Familial platelet disorder', 'Disease', 'MESH:D001791', (141, 167))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('FANCA', 'Gene', '2175', (113, 118))	('Li-Fraumeni syndrome', 'Disease', (48, 68))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (48, 68))	('FA', 'Phenotype', 'HP:0001994', (113, 115))	('AML', 'Disease', 'MESH:D015470', (208, 211))	('BRCA1', 'Gene', '672', (264, 269))	('Fanconi anemia', 'Disease', (92, 106))	('AML', 'Phenotype', 'HP:0004808', (208, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('AML', 'Disease', (208, 211))	('BRCA1', 'Gene', (264, 269))	('Fanconi anemia', 'Disease', 'MESH:D005199', (92, 106))	('TP53', 'Gene', (76, 80))	('FANCA', 'Gene', (113, 118))	('FPD', 'Disease', (204, 207))	('myeloid malignancy', 'Disease', (184, 202))	('platelet disorder', 'Phenotype', 'HP:0001872', (150, 167))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('anemia', 'Phenotype', 'HP:0001903', (100, 106))	('breast cancer', 'Disease', (234, 247))	('mutation', 'Var', (81, 89))	('FANCC', 'Gene', '2176', (123, 128))	('FPD', 'Disease', 'MESH:C563324', (204, 207))	('myeloid malignancy', 'Disease', 'MESH:D009369', (184, 202))	('LFS', 'Disease', (70, 73))	('patients', 'Species', '9606', (34, 42))	('LFS', 'Disease', 'MESH:D016864', (70, 73))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (92, 106))	('FA', 'Phenotype', 'HP:0001994', (108, 110))	('RUNX1', 'Gene', (214, 219))	('RUNX1', 'Gene', '861', (214, 219))	('mutation', 'Var', (220, 228))	('FANCC', 'Gene', (123, 128))
21404	33137568	Cancer-associated genetic alterations can be introduced into either ASC- or hPSC-derived organoids by CRISPR/Cas9-mediated gene editing.	('genetic alterations', 'Var', (18, 37))	('ASC', 'Gene', '29108', (68, 71))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cas', 'cellular_component', 'GO:0005650', ('109', '112'))	('ASC', 'Gene', (68, 71))
21405	33137568	This method enables the generation of cancer-associated mutations under normal conditions, as well as in isogenic controls, facilitating the study of the dynamic events of cancer initiation and cancer evolution, but the application of stem cell-derived organoids requires widely accepted, standardized differentiation protocols for their generation.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (194, 200))	('cancer initiation', 'Disease', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer initiation', 'Disease', 'MESH:D009369', (172, 189))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
21411	33137568	ASCs, with their inherent self-renewal capacity, proliferative potential and multipotency, are deemed compelling candidates of oncogenesis as they continue to accumulate genetic mutations over their lifetime and respond to external stimuli such as inflammation.	('inflammation', 'Disease', (248, 260))	('ASC', 'Gene', (0, 3))	('oncogenesis', 'biological_process', 'GO:0007048', ('127', '138'))	('inflammation', 'biological_process', 'GO:0006954', ('248', '260'))	('genetic mutations', 'Var', (170, 187))	('ASC', 'Gene', '29108', (0, 3))	('accumulate', 'PosReg', (159, 169))	('inflammation', 'Disease', 'MESH:D007249', (248, 260))
21418	33137568	Deregulation of a number of growth-factor induced signaling cascades and developmental pathways are implicated in glioma and medulloblastoma formation, respectively.	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('Deregulation', 'Var', (0, 12))	('glioma', 'Disease', (114, 120))	('growth-factor induced signaling cascades', 'Pathway', (28, 68))	('formation', 'biological_process', 'GO:0009058', ('141', '150'))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('medulloblastoma', 'Disease', 'MESH:D008527', (125, 140))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('developmental pathways', 'Pathway', (73, 95))	('medulloblastoma', 'Phenotype', 'HP:0002885', (125, 140))	('medulloblastoma', 'Disease', (125, 140))	('implicated', 'Reg', (100, 110))
21421	33137568	Bi-allelic inactivation of the NF1 gene gives rise to optic pathway gliomas (OPGs) in about 15-20% children with NF1 and additionally, other brainstem gliomas.	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('brainstem gliomas', 'Phenotype', 'HP:0010796', (141, 158))	('optic pathway gliomas', 'Phenotype', 'HP:0009734', (54, 75))	('optic pathway gliomas', 'Disease', (54, 75))	('gliomas', 'Disease', (68, 75))	('NF1', 'Gene', (31, 34))	('OPGs', 'Phenotype', 'HP:0009734', (77, 81))	('children', 'Species', '9606', (99, 107))	('gliomas', 'Phenotype', 'HP:0009733', (151, 158))	('gliomas', 'Disease', 'MESH:D005910', (68, 75))	('gives rise', 'Reg', (40, 50))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('Bi-allelic inactivation', 'Var', (0, 23))	('NF1', 'Gene', '4763', (113, 116))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('gliomas', 'Disease', (151, 158))	('OPGs', 'Chemical', '-', (77, 81))	('NF1', 'Gene', (113, 116))	('optic pathway gliomas', 'Disease', 'MESH:D020339', (54, 75))	('NF1', 'Gene', '4763', (31, 34))	('gliomas', 'Disease', 'MESH:D005910', (151, 158))
21422	33137568	The prospects for the use of hPSCs in neuroblastoma modeling were expanded with the development of an iPSC model from Gorlin syndrome (GS) harboring heterozygous mutations in PTCH1 to investigate medulloblastoma occurrence in children, as well as SMARCB1-deficient iPSC models for atypical teratoid/rhabdoid tumor (AT/RT).	('mutations', 'Var', (162, 171))	('GS', 'Disease', 'MESH:D011125', (135, 137))	('neuroblastoma', 'Phenotype', 'HP:0003006', (38, 51))	('PTCH1', 'Gene', (175, 180))	('medulloblastoma', 'Disease', 'MESH:D008527', (196, 211))	('medulloblastoma', 'Phenotype', 'HP:0002885', (196, 211))	('children', 'Species', '9606', (226, 234))	('medulloblastoma', 'Disease', (196, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (38, 51))	('PTCH1', 'Gene', '5727', (175, 180))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (299, 313))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('neuroblastoma', 'Disease', (38, 51))	('rhabdoid tumor', 'Disease', (299, 313))
21423	33137568	Myeloid malignancies are postulated to be the result of oncogenic transformation induced by mutations and epigenetic changes within hematopoietic stem cells (HSCs) or their committed progenitors.	('malignancies', 'Disease', (8, 20))	('mutations', 'Var', (92, 101))	('malignancies', 'Disease', 'MESH:D009369', (8, 20))	('epigenetic changes', 'Var', (106, 124))
21426	33137568	MDS-iPSCs, AML-iPSCs, myelofibrosis-iPSCs, and 8p11 myeloproliferative syndrome (EMS)-iPSCs, harboring chromosomal aberrations, have been generated.	('myelofibrosis', 'Phenotype', 'HP:0011974', (22, 35))	('myeloproliferative syndrome', 'Phenotype', 'HP:0005547', (52, 79))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (103, 126))	('MDS-iPSCs, AML-iPSCs, myelofibrosis-iPSCs', 'Disease', 'MESH:D015470', (0, 41))	('myeloproliferative syndrome', 'Disease', (52, 79))	('AML', 'Phenotype', 'HP:0004808', (11, 14))	('myeloproliferative syndrome', 'Disease', 'MESH:D009196', (52, 79))	('8p11', 'Var', (47, 51))	('MDS', 'Phenotype', 'HP:0002863', (0, 3))
21431	33137568	For instance, the role of mutant TP53 in LFS, a cancer predisposition syndrome, has been explored using LFS-iPSCs.	('LFS', 'Disease', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('LFS-iPSCs', 'Disease', (104, 113))	('LFS', 'Disease', (104, 107))	('LFS-iPSCs', 'Disease', 'MESH:D016864', (104, 113))	('cancer', 'Disease', (48, 54))	('LFS', 'Disease', 'MESH:D016864', (41, 44))	('TP53', 'Gene', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutant', 'Var', (26, 32))	('LFS', 'Disease', 'MESH:D016864', (104, 107))
21434	33137568	Heterozygous mutations in BRCA1, a gene regulating DNA damage response, genetic stability and cell cycle progression, predisposes women - who typically have a familial history of cancer - to up to a 45% increase in lifetime risk of developing breast cancer.	('breast cancer', 'Disease', (243, 256))	('predisposes', 'Reg', (118, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('BRCA1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('DNA damage response', 'biological_process', 'GO:0006974', ('51', '70'))	('DNA', 'cellular_component', 'GO:0005574', ('51', '54'))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('women', 'Species', '9606', (130, 135))	('cell cycle', 'biological_process', 'GO:0007049', ('94', '104'))	('Heterozygous mutations', 'Var', (0, 22))	('BRCA1', 'Gene', '672', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('cancer', 'Disease', (179, 185))	('increase', 'PosReg', (203, 211))
21436	33137568	Although no differences were observed in the differentiation capacity of wild-type and BRCA1 mutants, an increase in protein kinase C-theta levels was observed in BRCA1-mutant iPSCs, as well as in cancer cell lines harboring BRCA1 mutations and hormone receptor negative breast cancers.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (231, 240))	('BRCA1', 'Gene', '672', (225, 230))	('mutants', 'Var', (93, 100))	('BRCA1', 'Gene', '672', (163, 168))	('BRCA1', 'Gene', (225, 230))	('cancer', 'Disease', (278, 284))	('BRCA1', 'Gene', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('hormone receptor', 'Gene', (245, 261))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('protein kinase C-theta', 'Gene', (117, 139))	('BRCA1', 'Gene', '672', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('cancer', 'Disease', (197, 203))	('breast cancers', 'Disease', 'MESH:D001943', (271, 285))	('breast cancers', 'Disease', (271, 285))	('increase', 'PosReg', (105, 113))	('BRCA1', 'Gene', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('protein kinase C-theta', 'Gene', '5588', (117, 139))	('breast cancers', 'Phenotype', 'HP:0003002', (271, 285))	('protein', 'cellular_component', 'GO:0003675', ('117', '124'))	('hormone receptor', 'Gene', '3164', (245, 261))
21437	33137568	Mutagenesis within crypt cells, subsequent cycles of niche succession, and clonal expansion promote colon cancer progression.	('Mutagenesis', 'biological_process', 'GO:0006280', ('0', '11'))	('promote', 'PosReg', (92, 99))	('Mutagenesis', 'Var', (0, 11))	('colon cancer', 'Phenotype', 'HP:0003003', (100, 112))	('colon cancer', 'Disease', 'MESH:D015179', (100, 112))	('colon cancer', 'Disease', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
21438	33137568	Traditionally, sequential progression of CRC occurs via a multi-step process involving heterozygous APC inactivation, KRAS oncogenic activation, loss of heterozygosity, and TP53 inactivation.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('APC', 'cellular_component', 'GO:0005680', ('100', '103'))	('CRC', 'Disease', 'MESH:D015179', (41, 44))	('KRAS', 'Gene', (118, 122))	('APC', 'Gene', (100, 103))	('APC', 'Gene', '324', (100, 103))	('loss of heterozygosity', 'Var', (145, 167))	('KRAS', 'Gene', '3845', (118, 122))	('CRC', 'Disease', (41, 44))
21439	33137568	iPSCs derived from patients diagnosed with hereditary familial adenomatous polyposis (FAP) have been differentiated toward colonic organoids to recapitulate the abnormal enhanced WNT activity caused by APC mutations, and have revealed aberrations in cell identity, cell polarity, defective anaphase mechanisms and centrosome numbers as well.	('APC', 'cellular_component', 'GO:0005680', ('202', '205'))	('cell polarity', 'CPA', (265, 278))	('cell polarity', 'biological_process', 'GO:0007163', ('265', '278'))	('FAP', 'Disease', (86, 89))	('hereditary familial adenomatous polyposis', 'Disease', (43, 84))	('FAP', 'Disease', 'MESH:C567782', (86, 89))	('APC', 'Gene', '324', (202, 205))	('cell identity', 'CPA', (250, 263))	('anaphase', 'biological_process', 'GO:0051322', ('290', '298'))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (63, 84))	('mutations', 'Var', (206, 215))	('patients', 'Species', '9606', (19, 27))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('centrosome numbers', 'CPA', (314, 332))	('APC', 'Gene', (202, 205))	('hereditary familial adenomatous polyposis', 'Disease', 'MESH:D011125', (43, 84))	('enhanced', 'PosReg', (170, 178))	('centrosome', 'cellular_component', 'GO:0005813', ('314', '324'))	('anaphase mechanisms', 'CPA', (290, 309))
21440	33137568	The cell-of-origin of cancer refers to normal cells that first acquire the mutations required for cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer initiation', 'Disease', 'MESH:D009369', (98, 115))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer initiation', 'Disease', (98, 115))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
21445	33137568	Likewise, different types of brain tumors are generated when mutations occur in NSCs, NPCs, oligodendrocyte progenitors (OPCs), or neuroepithelial stem cells.	('brain tumors', 'Disease', 'MESH:D001932', (29, 41))	('brain tumors', 'Phenotype', 'HP:0030692', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('brain tumors', 'Disease', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('brain tumor', 'Phenotype', 'HP:0030692', (29, 40))	('mutations', 'Var', (61, 70))	('neuroepithelial stem', 'Phenotype', 'HP:0000384', (131, 151))	('NS', 'Disease', 'MESH:D009404', (80, 82))
21446	33137568	Thus, mutations in either stem cells or progenitor cells give rise to distinct tumor types.	('give rise to', 'Reg', (57, 69))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mutations', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
21449	33137568	The majority of AT/RTs harbor genome alterations in SMARCB1 (also known as INI1; SNF5, or BAF47).	('SNF5', 'Gene', '6598', (81, 85))	('SMARCB1', 'Gene', (52, 59))	('INI1', 'Gene', (75, 79))	('INI1', 'Gene', '6598', (75, 79))	('BAF47', 'Gene', '6598', (90, 95))	('genome alterations', 'Var', (30, 48))	('BAF47', 'Gene', (90, 95))	('SNF5', 'Gene', (81, 85))
21450	33137568	Mouse models of SMARCB1 ablation suggested that AT/RT may arise from NSCs or NPCs.	('SMARCB1', 'Gene', (16, 23))	('arise from', 'Reg', (58, 68))	('NS', 'Disease', 'MESH:D009404', (69, 71))	('Mouse', 'Species', '10090', (0, 5))	('AT/RT', 'Disease', (48, 53))	('ablation', 'Var', (24, 32))	('NPCs', 'Disease', (77, 81))
21451	33137568	Recently, a group deconstructed the driving force of tumorigenesis by generating a human AT/RT model using SMARCB1- and TP53-deficient hiPSCs (hiPSCs SMARCB1-/-; TP53-/-) generated using the CRISPR/Cas9 system.	('Cas', 'cellular_component', 'GO:0005650', ('198', '201'))	('SMARCB1-', 'Var', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('human', 'Species', '9606', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53-deficient hiPSCs', 'Disease', 'MESH:D007153', (120, 141))	('tumor', 'Disease', (53, 58))	('TP53-deficient hiPSCs', 'Disease', (120, 141))
21455	33137568	DIPGs are highly aggressive pediatric brainstem tumors featuring the H3.3K27M mutation, which results in the global loss of H3K27me3 marks.	('H3.3K27M', 'Var', (69, 77))	('DIPGs', 'Disease', (0, 5))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('H3K27me3', 'Protein', (124, 132))	('loss', 'NegReg', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
21456	33137568	used a combination of lentiviruses, encoding H3.3 wt or H3.3K27M, PDGFRA, and sh-p53, to transform hESC-derived NPCs and found that the introduction of the H3.3K27M mutation in NPCs resulted in neoplastic transformation.	('PDGFRA', 'Gene', '5156', (66, 72))	('PDGFRA', 'Gene', (66, 72))	('resulted in', 'Reg', (182, 193))	('neoplastic transformation', 'CPA', (194, 219))	('NPCs', 'Gene', (177, 181))	('p53', 'Gene', (81, 84))	('H3.3K27M', 'Var', (156, 164))	('p53', 'Gene', '7157', (81, 84))
21458	33137568	However, GiPSC-derived neural progenitors remained malignant, although there was a widespread epigenetic resetting of common glioblastoma multiforme (GBM)-associated changes, including promoter regions of the TES, CDKN1C, and PRC2 target genes, which are normally hypermethylated.	('changes', 'Var', (166, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (125, 137))	('PRC2 target', 'Gene', (226, 237))	('CDKN1C', 'Gene', (214, 220))	('CDKN1C', 'Gene', '1028', (214, 220))	('TES', 'Gene', '26136', (209, 212))	('TES', 'Gene', (209, 212))	('glioblastoma multiforme', 'Disease', (125, 148))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (125, 148))
21468	33137568	The pluripotent derivatives were found to be distinct from the parental counterparts, displaying reduced tumorigenicity in vivo and in vitro, especially upon the use of episomal vectors for reprogramming.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('reduced', 'NegReg', (97, 104))	('pluripotent', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
21470	33137568	Point mutations, microsatellite instability (MIN), and chromosomal instability (CIN), initiate genomic instability, which leads to the development of cancer.	('microsatellite instability', 'MPA', (17, 43))	('CIN', 'Disease', 'MESH:D007674', (80, 83))	('initiate', 'PosReg', (86, 94))	('genomic instability', 'MPA', (95, 114))	('leads to', 'Reg', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('CIN', 'Phenotype', 'HP:0040012', (80, 83))	('cancer', 'Disease', (150, 156))	('chromosomal', 'MPA', (55, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (55, 78))	('MIN', 'Disease', 'None', (45, 48))	('MIN', 'Disease', (45, 48))	('Point mutations', 'Var', (0, 15))	('CIN', 'Disease', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
21472	33137568	Meanwhile, evasion from growth suppressors occurs via loss-of-function mutations in tumor suppressors, which results in the inhibition of critical cellular functions, including apoptosis, differentiation, maintenance of genomic integrity, DNA damage response, and intercellular interactions.	('DNA', 'cellular_component', 'GO:0005574', ('239', '242'))	('apoptosis', 'CPA', (177, 186))	('inhibition', 'NegReg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('apoptosis', 'biological_process', 'GO:0097194', ('177', '186'))	('DNA damage response', 'biological_process', 'GO:0006974', ('239', '258'))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('DNA damage', 'MPA', (239, 249))	('tumor', 'Disease', (84, 89))	('mutations', 'Var', (71, 80))	('apoptosis', 'biological_process', 'GO:0006915', ('177', '186'))	('intercellular', 'CPA', (264, 277))	('critical cellular functions', 'MPA', (138, 165))	('loss-of-function', 'NegReg', (54, 70))	('evasion', 'MPA', (11, 18))	('differentiation', 'CPA', (188, 203))	('genomic integrity', 'CPA', (220, 237))
21474	33137568	hPSC technologies have enabled investigations into proliferative pathways in cancer pathogenesis, especially in cancers with dysregulated RAS/MAPK and PI3K/AKT pathways.	('RAS/MAPK', 'Pathway', (138, 146))	('AKT', 'Gene', '207', (156, 159))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Disease', (77, 83))	('dysregulated', 'Var', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('AKT', 'Gene', (156, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('pathogenesis', 'biological_process', 'GO:0009405', ('84', '96'))	('MAPK', 'molecular_function', 'GO:0004707', ('142', '146'))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
21476	33137568	Gain of function mutations in PTPN11 modeled using iPSCs have been found to constitutively activate growth factor granulocyte macrophage colony-stimulating factor (GM-CSF) signaling and increase STAT5/ERK phosphorylation in JMML and Noonan syndrome (NS).	('Noonan syndrome', 'Disease', 'MESH:D009634', (233, 248))	('mutations', 'Var', (17, 26))	('activate', 'PosReg', (91, 99))	('granulocyte macrophage colony-stimulating factor', 'molecular_function', 'GO:0005129', ('114', '162'))	('PTPN11', 'Gene', (30, 36))	('ERK', 'Gene', (201, 204))	('GM-CSF', 'Gene', (164, 170))	('PTPN11', 'Gene', '5781', (30, 36))	('ERK', 'Gene', '2048', (201, 204))	('NS', 'Disease', 'MESH:D009404', (250, 252))	('signaling', 'biological_process', 'GO:0023052', ('172', '181'))	('increase', 'PosReg', (186, 194))	('JMML', 'Disease', (224, 228))	('GM-CSF', 'Gene', '1437', (164, 170))	('JMML', 'Phenotype', 'HP:0012209', (224, 228))	('STAT5', 'Gene', '6776', (195, 200))	('Gain of function', 'PosReg', (0, 16))	('STAT5', 'Gene', (195, 200))	('Noonan syndrome', 'Disease', (233, 248))	('ERK', 'molecular_function', 'GO:0004707', ('201', '204'))	('phosphorylation', 'biological_process', 'GO:0016310', ('205', '220'))
21478	33137568	iPSC-derived cancerous myeloid cells generated from patients harboring PTPN11 mutations have uncovered novel roles of miR-223 and miR-15a in activating the STAT5 pathway and inducing myeloid proliferation.	('inducing', 'Reg', (174, 182))	('miR-223', 'Gene', '407008', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('myeloid proliferation', 'CPA', (183, 204))	('activating', 'MPA', (141, 151))	('mutations', 'Var', (78, 87))	('miR-15a', 'Gene', (130, 137))	('cancerous myeloid', 'Disease', (13, 30))	('miR-223', 'Gene', (118, 125))	('miR-15a', 'Gene', '406948', (130, 137))	('PTPN11', 'Gene', '5781', (71, 77))	('STAT5', 'Gene', '6776', (156, 161))	('cancerous myeloid', 'Disease', 'MESH:D009369', (13, 30))	('STAT5', 'Gene', (156, 161))	('PTPN11', 'Gene', (71, 77))	('patients', 'Species', '9606', (52, 60))
21479	33137568	In addition, specific mutations in PTPN11, including DG1H and G503R, were revealed to particularly promote hypersensitivity to GM-CSF.	('hypersensitivity', 'Disease', 'MESH:D004342', (107, 123))	('promote', 'PosReg', (99, 106))	('DG1H', 'Var', (53, 57))	('GM-CSF', 'Gene', (127, 133))	('G503R', 'SUBSTITUTION', 'None', (62, 67))	('hypersensitivity', 'Disease', (107, 123))	('PTPN11', 'Gene', '5781', (35, 41))	('GM-CSF', 'Gene', '1437', (127, 133))	('PTPN11', 'Gene', (35, 41))	('hypersensitivity', 'biological_process', 'GO:0002524', ('107', '123'))	('G503R', 'Var', (62, 67))
21481	33137568	A previous study modeling JMML using PTPN11 E76K or CBL Y371H mutant iPSCs brought the role of CBL, an E3 ubiquitin ligase, to light.	('Y371H', 'Var', (56, 61))	('E76K', 'SUBSTITUTION', 'None', (44, 48))	('JMML', 'Phenotype', 'HP:0012209', (26, 30))	('Y371H', 'SUBSTITUTION', 'None', (56, 61))	('E76K', 'Var', (44, 48))	('CBL', 'Gene', (52, 55))	('PTPN11', 'Gene', '5781', (37, 43))	('CBL', 'Gene', '867', (52, 55))	('PTPN11', 'Gene', (37, 43))	('CBL', 'Gene', (95, 98))	('CBL', 'Gene', '867', (95, 98))	('ubiquitin', 'molecular_function', 'GO:0031386', ('106', '115'))
21482	33137568	iPSCs harboring PTPN11 mutations differentially activated RAS/MAPK signaling, while those that carried CBL mutations stimulated JAK/STAT signaling, indicating varied leukemogenic dependencies.	('STAT', 'Gene', (132, 136))	('CBL', 'Gene', '867', (103, 106))	('leukemogenic dependencies', 'Disease', (166, 191))	('JAK', 'Gene', '3717', (128, 131))	('STAT', 'Gene', '6774', (132, 136))	('CBL', 'Gene', (103, 106))	('MAPK', 'molecular_function', 'GO:0004707', ('62', '66'))	('mutations', 'Var', (23, 32))	('MAPK signaling', 'biological_process', 'GO:0000165', ('62', '76'))	('signaling', 'biological_process', 'GO:0023052', ('137', '146'))	('JAK', 'molecular_function', 'GO:0004713', ('128', '131'))	('PTPN11', 'Gene', '5781', (16, 22))	('RAS/MAPK signaling', 'MPA', (58, 76))	('activated', 'PosReg', (48, 57))	('stimulated', 'PosReg', (117, 127))	('leukemogenic dependencies', 'Disease', 'MESH:D019966', (166, 191))	('JAK', 'Gene', (128, 131))	('PTPN11', 'Gene', (16, 22))
21483	33137568	Sequencing studies on JMML iPSC clones have identified other single nucleotide variants including OSBP2 (c.389C > T), VPS13B (c.3379G > T), and SMC (c.2560A > G) and elucidated the co-occurrence of PTPN11 mutations with OSBP2 mutations.	('VPS13B', 'Gene', '157680', (118, 124))	('c.389C > T', 'Var', (105, 115))	('JMML', 'Phenotype', 'HP:0012209', (22, 26))	('mutations', 'Var', (205, 214))	('SMC', 'cellular_component', 'GO:0016029', ('144', '147'))	('c.2560A > G', 'Var', (149, 160))	('OSBP2', 'Gene', '23762', (220, 225))	('OSBP2', 'Gene', '23762', (98, 103))	('c.3379G > T', 'Var', (126, 137))	('OSBP2', 'Gene', (98, 103))	('PTPN11', 'Gene', '5781', (198, 204))	('VPS13B', 'Gene', (118, 124))	('PTPN11', 'Gene', (198, 204))	('OSBP2', 'Gene', (220, 225))
21484	33137568	Although the role of the specific mutations was not extensively explored, some of the mutations identified may contribute to Ras-induced tumorigenesis.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (137, 142))	('Ras-induced', 'Disease', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('contribute', 'Reg', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
21489	33137568	Mutant c-MET iPSC-derived embryoid bodies, representative of PRCC, were generated and found to display a remarkably similar gene expression profile to primary human c-MET mutated PRCC, with overexpression of genes, such as KDM4C and BHLHE40.	('PRCC', 'Gene', (61, 65))	('c-MET', 'Gene', '4233', (165, 170))	('PRCC', 'Gene', (179, 183))	('PRCC', 'Phenotype', 'HP:0006766', (61, 65))	('c-MET', 'Gene', '4233', (7, 12))	('human', 'Species', '9606', (159, 164))	('PRCC', 'Phenotype', 'HP:0006766', (179, 183))	('mutated', 'Var', (171, 178))	('c-MET', 'Gene', (165, 170))	('c-MET', 'Gene', (7, 12))	('BHLHE40', 'Gene', (233, 240))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('Mutant', 'Var', (0, 6))	('PRCC', 'Gene', '5546', (61, 65))	('PRCC', 'Gene', '5546', (179, 183))	('overexpression', 'PosReg', (190, 204))	('BHLHE40', 'Gene', '8553', (233, 240))	('KDM4C', 'Gene', (223, 228))	('KDM4C', 'Gene', '23081', (223, 228))
21493	33137568	Moreover, iPSC-derived leukemic cell lines were applied to evaluate the response of varied KRAS mutants to Ras small molecule inhibitors.	('leukemic', 'Disease', (23, 31))	('leukemic', 'Disease', 'MESH:D007938', (23, 31))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))	('mutants', 'Var', (96, 103))
21494	33137568	The role of STAT signaling in oncogenesis has been explored in iPSC-derived models harboring JAK2 V617F mutations in a range of myeloid malignancies, including secondary myelofibrosis, PV, CML and other myeloproliferative disorders.	('STAT', 'Gene', '6774', (12, 16))	('JAK', 'molecular_function', 'GO:0004713', ('93', '96'))	('STAT', 'Gene', (12, 16))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (203, 231))	('CML', 'Phenotype', 'HP:0005506', (189, 192))	('V617F', 'SUBSTITUTION', 'None', (98, 103))	('mutations', 'Var', (104, 113))	('oncogenesis', 'biological_process', 'GO:0007048', ('30', '41'))	('JAK2', 'Gene', '3717', (93, 97))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (203, 231))	('myelofibrosis', 'Disease', (170, 183))	('myelofibrosis', 'Disease', 'MESH:D055728', (170, 183))	('CML', 'Disease', 'MESH:D015464', (189, 192))	('myeloproliferative disorders', 'Disease', (203, 231))	('CML', 'Disease', (189, 192))	('JAK2', 'Gene', (93, 97))	('signaling', 'biological_process', 'GO:0023052', ('17', '26'))	('V617F', 'Var', (98, 103))	('myeloid malignancies', 'Disease', 'MESH:D009369', (128, 148))	('myeloid malignancies', 'Disease', (128, 148))	('myelofibrosis', 'Phenotype', 'HP:0011974', (170, 183))
21496	33137568	In an ESC-based model of Ewing sarcoma (EWS), knockdown of p53, in addition to the doxycycline inducible expression of the oncogenic EWS-FLI1 transcript, was critical for the generation of embryoid bodies exhibiting a transformed phenotype and a strong EWS gene expression signature.	('p53', 'Gene', (59, 62))	('EWS', 'Gene', '2130', (253, 256))	('EWS', 'Gene', '2130', (133, 136))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('doxycycline', 'Chemical', 'MESH:D004318', (83, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('EWS', 'Gene', (40, 43))	('EWS', 'Phenotype', 'HP:0012254', (40, 43))	('EWS', 'Gene', (253, 256))	('Ewing sarcoma', 'Disease', (25, 38))	('EWS', 'Gene', (133, 136))	('FLI1', 'Gene', (137, 141))	('p53', 'Gene', '7157', (59, 62))	('knockdown', 'Var', (46, 55))	('EWS', 'Gene', '2130', (40, 43))	('EWS', 'Phenotype', 'HP:0012254', (133, 136))	('EWS', 'Phenotype', 'HP:0012254', (253, 256))	('gene expression', 'biological_process', 'GO:0010467', ('257', '272'))	('FLI1', 'Gene', '2313', (137, 141))
21497	33137568	Likewise, aberrant p53 signaling and receptor tyrosine kinase signaling was found to be integral to the recapitulation of GTICs from NPCs.	('tyrosine kinase', 'Gene', (46, 61))	('aberrant', 'Var', (10, 18))	('signaling', 'biological_process', 'GO:0023052', ('62', '71'))	('tyrosine kinase', 'Gene', '7294', (46, 61))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('signaling', 'biological_process', 'GO:0023052', ('23', '32'))
21499	33137568	Typical loss of function mutations in other tumor suppressors and an enhancement of tumorigenic potential has been observed in multiple cancer types modeled using hPSCs.	('mutations', 'Var', (25, 34))	('enhancement', 'PosReg', (69, 80))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('loss of function', 'NegReg', (8, 24))	('tumor', 'Disease', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
21500	33137568	In one study, knockout of PTEN using TALEN in ESCs and subsequent differentiation to NSCs stimulated tumorigenesis and the formation of glioblastoma owing to an increase in PAX7 expression.	('PAX7', 'Gene', (173, 177))	('NS', 'Disease', 'MESH:D009404', (85, 87))	('glioblastoma', 'Disease', (136, 148))	('expression', 'MPA', (178, 188))	('glioblastoma', 'Disease', 'MESH:D005909', (136, 148))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (136, 148))	('PAX7', 'Gene', '5081', (173, 177))	('increase', 'PosReg', (161, 169))	('PTEN', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('knockout', 'Var', (14, 22))	('stimulated', 'PosReg', (90, 100))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
21517	33137568	PTPRZ1 has been proposed to reactivate mitotic somal translocation (MST) in outer radial glia-like cells derived from glioblastoma stem cells, thus promoting the invasive capacity of these cells.	('PTPRZ1', 'Gene', (0, 6))	('reactivate', 'Var', (28, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (118, 130))	('promoting', 'PosReg', (148, 157))	('invasive capacity', 'CPA', (162, 179))	('somal translocation', 'biological_process', 'GO:0021802', ('47', '66'))	('glioblastoma', 'Disease', (118, 130))	('glioblastoma', 'Disease', 'MESH:D005909', (118, 130))	('mitotic somal translocation', 'MPA', (39, 66))	('PTPRZ1', 'Gene', '5803', (0, 6))
21526	33137568	Cancer progression is marked by a continuum of disease progression with the accumulation of genetic mutations and acquisition of epigenetic changes within cellular populations.	('epigenetic changes', 'Var', (129, 147))	('genetic mutations', 'Var', (92, 109))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
21533	33137568	The simulation of each stage confirmed the role of GATA2 mutations, additional mutational events and chromosomal aberrations in driving MDS to AML progression.	('MDS', 'Phenotype', 'HP:0002863', (136, 139))	('GATA2', 'Gene', (51, 56))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('mutations', 'Var', (57, 66))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (101, 124))	('GATA2', 'Gene', '2624', (51, 56))	('AML', 'Disease', (143, 146))	('MDS', 'Disease', (136, 139))	('MDS', 'Disease', 'MESH:D009190', (136, 139))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
21540	33137568	By using transformed hiPSC/ESC-derived NPCs as well as NSCs to screen libraries of chemicals, several inhibitors of brain tumor growth have been identified, including MI-2, nelarabine, letrozole, capecitabine and MMC.	('capecitabine', 'Chemical', 'MESH:D000069287', (196, 208))	('brain tumor', 'Disease', (116, 127))	('MMC', 'Chemical', 'MESH:D016685', (213, 216))	('MI-2', 'Var', (167, 171))	('brain tumor', 'Disease', 'MESH:D001932', (116, 127))	('nelarabine', 'Chemical', 'MESH:C104457', (173, 183))	('NS', 'Disease', 'MESH:D009404', (55, 57))	('brain tumor', 'Phenotype', 'HP:0030692', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('letrozole', 'Chemical', 'MESH:D000077289', (185, 194))
21541	33137568	studied the impact of DOT1L inhibition on MLL-rearranged iPSCs and found that the DOT1L inhibitor, EPZ-5676, specifically inhibited the growth of hematopoietic cells differentiated from MLL-rearranged AML-iPSCs, while exhibiting a minimal growth inhibition of undifferentiated AML-iPSCs.	('DOT1L', 'Gene', (22, 27))	('undifferentiated AML-iPSCs', 'Disease', (260, 286))	('AML', 'Phenotype', 'HP:0004808', (201, 204))	('MLL', 'Gene', (42, 45))	('AML-iPSCs', 'Disease', (277, 286))	('undifferentiated AML-iPSCs', 'Disease', 'MESH:D015470', (260, 286))	('MLL', 'Gene', '4297', (42, 45))	('DOT1L', 'Gene', (82, 87))	('inhibited', 'NegReg', (122, 131))	('DOT1L', 'Gene', '84444', (22, 27))	('EPZ-5676', 'Chemical', 'MESH:C583893', (99, 107))	('AML-iPSCs', 'Disease', (201, 210))	('EPZ-5676', 'Var', (99, 107))	('AML-iPSCs', 'Disease', 'MESH:D015470', (277, 286))	('growth', 'MPA', (136, 142))	('DOT1L', 'Gene', '84444', (82, 87))	('AML', 'Phenotype', 'HP:0004808', (277, 280))	('AML-iPSCs', 'Disease', 'MESH:D015470', (201, 210))	('MLL', 'Gene', (186, 189))	('MLL', 'Gene', '4297', (186, 189))
21542	33137568	Hence, cytotoxicity induced by EPZ-5676 was dependent on the specific differentiation state of AML cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (7, 19))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('AML', 'Disease', (95, 98))	('EPZ-5676', 'Chemical', 'MESH:C583893', (31, 39))	('cytotoxicity', 'Disease', (7, 19))	('EPZ-5676', 'Var', (31, 39))
21547	33137568	Recently, colon organoids generated from FAP-iPSCs with mutations in APC were used as a platform for drug testing.	('APC', 'cellular_component', 'GO:0005680', ('69', '72'))	('mutations', 'Var', (56, 65))	('FA', 'Phenotype', 'HP:0001994', (41, 43))	('APC', 'Gene', (69, 72))	('FAP-iPSCs', 'Disease', (41, 50))	('FAP-iPSCs', 'Disease', 'MESH:C567782', (41, 50))	('APC', 'Gene', '324', (69, 72))
21548	33137568	The authors found that a ribosome-binding antibiotic, geneticin, could rescue APC expression, reduce WNT overactivation, and block colonic epithelial cell hyperproliferation specifically in APC mutant FAP colon organoids.	('APC', 'Gene', '324', (190, 193))	('APC', 'Gene', (78, 81))	('expression', 'MPA', (82, 92))	('WNT overactivation', 'MPA', (101, 119))	('APC', 'cellular_component', 'GO:0005680', ('78', '81'))	('block colonic epithelial', 'Disease', (125, 149))	('APC', 'Gene', '324', (78, 81))	('mutant', 'Var', (194, 200))	('FAP colon organoids', 'Disease', (201, 220))	('FAP colon organoids', 'Disease', 'MESH:D003110', (201, 220))	('rescue', 'PosReg', (71, 77))	('ribosome', 'cellular_component', 'GO:0005840', ('25', '33'))	('FA', 'Phenotype', 'HP:0001994', (201, 203))	('ribosome-binding', 'molecular_function', 'GO:0043022', ('25', '41'))	('reduce', 'NegReg', (94, 100))	('block colonic epithelial', 'Disease', 'MESH:D003110', (125, 149))	('APC', 'Gene', (190, 193))	('APC', 'cellular_component', 'GO:0005680', ('190', '193'))
21552	33137568	Further analysis of these 107 proteins revealed increased levels of THBS2 and CA19-9, which were considered potential markers of PDAC as well.	('increased', 'PosReg', (48, 57))	('HB', 'Phenotype', 'HP:0002884', (69, 71))	('THBS2', 'Gene', (68, 73))	('PDAC', 'Disease', (129, 133))	('PDAC', 'Phenotype', 'HP:0006725', (129, 133))	('CA19-9', 'Var', (78, 84))	('THBS2', 'Gene', '7058', (68, 73))	('PDAC', 'Chemical', '-', (129, 133))
21561	33137568	Xenograft transplantation of hiPSC-derived cancer cell lines with EZH2 or RAD21 deletion significantly extended the overall survival of mice.	('mice', 'Species', '10090', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('RAD21', 'Gene', (74, 79))	('deletion', 'Var', (80, 88))	('cancer', 'Disease', (43, 49))	('EZH2', 'Gene', (66, 70))	('RAD', 'biological_process', 'GO:1990116', ('74', '77'))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('overall survival', 'CPA', (116, 132))	('extended', 'PosReg', (103, 111))
21564	33137568	Intra-tumoral heterogeneity is a result of stochastic genetic variations and/or epigenetic alterations, the presence of a minor subpopulation of cancer stem cells (CSCs) residing in tumors, or the dynamic shift between CSCs and non-CSCs.	('cancer', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', (182, 187))	('epigenetic alterations', 'Var', (80, 102))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
21567	33137568	They identified two distinct AML-iPSC subclones (KRAS mutant or KRAS WT) from the same AML patient that shared all other leukemia-associated mutations, but exhibited differential cytokine (GM-CSF) dependence in vitro, differential leukemogenic properties in vivo, and differential sensitivity to MEK inhibitors.	('leukemia', 'Disease', (121, 129))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('KRAS', 'Gene', '3845', (49, 53))	('MEK', 'Gene', '5609', (296, 299))	('GM-CSF', 'Gene', (189, 195))	('KRAS', 'Gene', '3845', (64, 68))	('AML-iPSC', 'Disease', 'MESH:D015470', (29, 37))	('AML', 'Disease', 'MESH:D015470', (87, 90))	('KRAS', 'Gene', (49, 53))	('AML', 'Phenotype', 'HP:0004808', (87, 90))	('mutations', 'Var', (141, 150))	('AML', 'Disease', (87, 90))	('MEK', 'Gene', (296, 299))	('KRAS', 'Gene', (64, 68))	('GM-CSF', 'Gene', '1437', (189, 195))	('AML-iPSC', 'Disease', (29, 37))	('patient', 'Species', '9606', (91, 98))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('AML', 'Disease', (29, 32))
21572	33137568	By using this platform, they identified t(4;12) to be an earlier event in a case of MDS, followed by mutations in SF3B1, EZH2, and del(5q).	('SF3B1', 'Gene', '23451', (114, 119))	('mutations', 'Var', (101, 110))	('MDS', 'Disease', (84, 87))	('MDS', 'Disease', 'MESH:D009190', (84, 87))	('MDS', 'Phenotype', 'HP:0002863', (84, 87))	('EZH2', 'Gene', (121, 125))	('SF3B1', 'Gene', (114, 119))	('del(5q', 'Var', (131, 137))
21573	33137568	Notably, single-cell sequencing has impacted many areas of cancer research and provided a greater understanding of clonal evolution and intra-tumoral heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('single-cell', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('intra-tumoral', 'Disease', 'MESH:D009369', (136, 149))	('impacted', 'Reg', (36, 44))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('intra-tumoral', 'Disease', (136, 149))
21610	30412103	Immunohistochemistry showed positive reactivity for CK7, CK18, pax-8, EMA, vimentin, CK19, CAIX, P504S, ki67 (5%).	('CK7', 'Gene', (52, 55))	('P504S', 'Var', (97, 102))	('CK19', 'Gene', '3880', (85, 89))	('ki67', 'Var', (104, 108))	('pax-8', 'Gene', '7849', (63, 68))	('CK18', 'Gene', '3875', (57, 61))	('CK7', 'Gene', '3855', (52, 55))	('vimentin', 'cellular_component', 'GO:0045098', ('75', '83'))	('CAIX', 'Gene', (91, 95))	('pax-8', 'Gene', (63, 68))	('P504S', 'Mutation', 'p.P504S', (97, 102))	('reactivity', 'MPA', (37, 47))	('vimentin', 'Gene', '7431', (75, 83))	('CK19', 'Gene', (85, 89))	('CAIX', 'Gene', '768', (91, 95))	('vimentin', 'Gene', (75, 83))	('vimentin', 'cellular_component', 'GO:0045099', ('75', '83'))	('CK18', 'Gene', (57, 61))
21626	30412103	They summarized the CT features of MTSCC as follows: the center of the tumor is located in the medulla of the kidney; isodense on unenhanced CT, poorly defined margin, and less enhancement than the cortex and medulla on all phases (Table 1).	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('isodense', 'Var', (118, 126))	('tumor', 'Disease', (71, 76))	('enhancement', 'MPA', (177, 188))
21662	22903703	Infiltrative MRI appearance and renal vein thrombus identify a subset of pathological type 2 pRCC at a significantly increased risk of metastatic disease.	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('pRCC', 'Gene', '5546', (93, 97))	('pRCC', 'Phenotype', 'HP:0006766', (93, 97))	('vein thrombus', 'Phenotype', 'HP:0004936', (38, 51))	('renal vein thrombus', 'Disease', 'MESH:D013927', (32, 51))	('pRCC', 'Gene', (93, 97))	('pathological', 'Var', (73, 85))	('metastatic disease', 'Disease', (135, 153))	('renal vein thrombus', 'Disease', (32, 51))
21683	22903703	Each mass was also classified in terms of one of three appearances on MRI: (I) focal encapsulated solid hypoenhancing mass; (II) focal encapsulated cystic lesion containing T1-hyperintense (i.e.	('T1-hyperintense', 'Var', (173, 188))	('cystic lesion', 'Disease', (148, 161))	('cystic lesion', 'Disease', 'MESH:D052177', (148, 161))
21690	22903703	Tumours were divided into three pRCC categories: focal type 1 (MRI appearance I or II and pathological type 1), focal type 2 (MRI appearance I or II and pathological type 2) or infiltrative (MRI appearance III, either pathologicaltype).	('pRCC', 'Phenotype', 'HP:0006766', (32, 36))	('pRCC', 'Gene', '5546', (32, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('focal type 2', 'Var', (112, 124))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('pRCC', 'Gene', (32, 36))
21711	22903703	Features associated with metastatic disease at univariate analysis include higher stage, larger size, central location, poor encapsulation, irregular margin, perirenal invasion, retroperitoneal collaterals, renal vein thrombus, predominantly high nuclear grade, pathological type 2 and infiltrative MRI appearance (P values ranging from less than 0.001 to 0.027).	('high', 'Var', (242, 246))	('vein thrombus', 'Phenotype', 'HP:0004936', (213, 226))	('perirenal invasion', 'CPA', (158, 176))	('metastatic disease', 'Disease', (25, 43))	('renal vein thrombus', 'Disease', (207, 226))	('renal vein thrombus', 'Disease', 'MESH:D013927', (207, 226))
21716	22903703	While PFS was significantly worse among patients with pathological type 2 than pathological type 1 pRCC (0.043), there was no significant difference in PFS between focal type 1 pRCC and focal type 2 pRCC (0.633) or between MRI appearances I and II (P00.179).	('worse', 'NegReg', (28, 33))	('PFS', 'MPA', (6, 9))	('patients', 'Species', '9606', (40, 48))	('pRCC', 'Gene', (99, 103))	('pRCC', 'Gene', '5546', (199, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('pRCC', 'Gene', (199, 203))	('pRCC', 'Gene', '5546', (177, 181))	('pRCC', 'Phenotype', 'HP:0006766', (177, 181))	('pathological type', 'Var', (54, 71))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('pRCC', 'Phenotype', 'HP:0006766', (99, 103))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('pRCC', 'Phenotype', 'HP:0006766', (199, 203))	('pRCC', 'Gene', (177, 181))
21727	22903703	However, a small fraction of pathological type 2 pRCC exhibited an infiltrative morphology on MRI, an appearance that we identified to have a substantially worse prognosis among cases of type 2 pRCC.	('pRCC', 'Gene', (194, 198))	('pRCC', 'Gene', '5546', (49, 53))	('pRCC', 'Phenotype', 'HP:0006766', (49, 53))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('pRCC', 'Gene', '5546', (194, 198))	('pRCC', 'Gene', (49, 53))	('pRCC', 'Phenotype', 'HP:0006766', (194, 198))	('pathological type', 'Var', (29, 46))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))
21750	29896907	Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy Papillary renal cell carcinoma (PRCC) is the most common nonclear cell RCCs and is known to comprise two histological subtypes.	('Modulating', 'Var', (0, 10))	('papillary renal cell carcinoma type 2', 'Phenotype', 'HP:0006732', (48, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('papillary renal cell carcinoma type 2', 'Disease', (48, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('Papillary renal cell carcinoma', 'Disease', (138, 168))	('PRCC', 'Gene', '5546', (170, 174))	('papillary renal cell carcinoma type 2', 'Disease', 'MESH:C538614', (48, 85))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (48, 78))	('Papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (138, 168))	('PRCC', 'Gene', (170, 174))	('ATP binding', 'molecular_function', 'GO:0005524', ('11', '22'))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 168))
21758	29896907	ABCC2 blockage resulted in higher sunitinib uptake, both in vitro (P = 0.0016) and in vivo (P = 0.0031).	('sunitinib', 'Chemical', 'MESH:D000077210', (34, 43))	('ABCC2', 'Gene', (0, 5))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('sunitinib uptake', 'MPA', (34, 50))	('higher', 'PosReg', (27, 33))	('blockage', 'Var', (6, 14))
21760	29896907	Our results demonstrate that combined targeted therapy with sunitinib and ABCC2 blocker in PRCC2 has therapeutic potential.	('PRCC', 'Gene', (91, 95))	('blocker', 'Var', (80, 87))	('ABCC2', 'Gene', (74, 79))	('sunitinib', 'Chemical', 'MESH:D000077210', (60, 69))	('PRCC', 'Gene', '5546', (91, 95))
21786	29896907	Blockage of ABCC2 in addition to the standard first-line therapies of metastatic RCCs might be of added benefit to the tumor treatment.	('metastatic RCCs', 'Disease', (70, 85))	('ABCC2', 'Gene', (12, 17))	('Blockage', 'Var', (0, 8))	('tumor', 'Disease', (119, 124))	('benefit', 'PosReg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
21838	29896907	The group of cells treated with MK571 only also showed a considerable reduction in cell viability.	('cell viability', 'CPA', (83, 97))	('MK571', 'Var', (32, 37))	('reduction', 'NegReg', (70, 79))	('MK571', 'Chemical', 'MESH:C059141', (32, 37))
21845	29896907	MK571-treated cells showed considerable dye uptake (indicating dye retention), whereas untreated cells failed to stain indicating an active export of the Hoescht dye by ABCC2.	('dye uptake', 'MPA', (40, 50))	('export', 'MPA', (140, 146))	('uptake', 'biological_process', 'GO:0098657', ('44', '50'))	('uptake', 'biological_process', 'GO:0098739', ('44', '50'))	('MK571-treated', 'Var', (0, 13))	('MK571', 'Chemical', 'MESH:C059141', (0, 5))	('retention', 'biological_process', 'GO:0051235', ('67', '76'))
21848	29896907	The results show a near doubling of the uptake of sunitinib after the addition of MK571, from 28 044 median fluorescence intensity (MFI) to 54 421 MFI (Fig.	('uptake', 'MPA', (40, 46))	('MK571', 'Var', (82, 87))	('sunitinib', 'Chemical', 'MESH:D000077210', (50, 59))	('MK571', 'Chemical', 'MESH:C059141', (82, 87))	('uptake', 'biological_process', 'GO:0098657', ('40', '46'))	('uptake', 'biological_process', 'GO:0098739', ('40', '46'))
21856	29896907	Similar to what was observed in vitro, the best tumor response (final tumor size and tumor rate of growth) was observed in the group that was exposed to the sunitinib and MK571 treatment (Fig.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MK571', 'Var', (171, 176))	('MK571', 'Chemical', 'MESH:C059141', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('sunitinib', 'Chemical', 'MESH:D000077210', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
21861	29896907	The sunitinib + MK571 group showed the highest level of apoptosis (mean 43.125%), which was significantly higher (P = 0.0045) compared to other treatment groups (Fig.	('sunitinib', 'Chemical', 'MESH:D000077210', (4, 13))	('higher', 'PosReg', (106, 112))	('MK571', 'Var', (16, 21))	('MK571', 'Chemical', 'MESH:C059141', (16, 21))	('apoptosis', 'biological_process', 'GO:0097194', ('56', '65'))	('apoptosis', 'CPA', (56, 65))	('apoptosis', 'biological_process', 'GO:0006915', ('56', '65'))
21884	29896907	We hypothesized that blocking ABCC2 would enhance the cancer response to the current first-line therapy (VEGF TKI, e.g., sunitinib) (Tivnan et al., 2015).	('ABCC2', 'Gene', (30, 35))	('enhance', 'PosReg', (42, 49))	('blocking', 'Var', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('sunitinib', 'Chemical', 'MESH:D000077210', (121, 130))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
21896	29896907	Contrarily ABCC2-low RCC cell lines (CAL-54) did not show an increase in sunitinib uptake upon ABCC2 blockage.	('ABCC2', 'Gene', (95, 100))	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('blockage', 'Var', (101, 109))	('uptake', 'biological_process', 'GO:0098739', ('83', '89'))	('sunitinib uptake', 'MPA', (73, 89))	('uptake', 'biological_process', 'GO:0098657', ('83', '89'))
21897	29896907	The results ascertain what was shown in other studies regarding an increase in drug uptake upon ABC transporter blockage, especially in cancer with a high level of transporters (S. Shukla et al., 2011).	('ABC', 'Gene', (96, 99))	('ABC transporter', 'molecular_function', 'GO:0140359', ('96', '111'))	('drug uptake', 'MPA', (79, 90))	('ABC', 'Gene', '10058', (96, 99))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('increase', 'PosReg', (67, 75))	('cancer', 'Disease', (136, 142))	('blockage', 'Var', (112, 120))	('uptake', 'biological_process', 'GO:0098739', ('84', '90'))	('uptake', 'biological_process', 'GO:0098657', ('84', '90'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
21904	29896907	Interestingly, ABCC2 blockage alone by MK571 also affected the PRCC2 cell line growth both in vitro and in vivo, in keeping with emerging evidence suggesting that ABC transporters contribute to tumor growth in ways beyond drug efflux (Fletcher et al., 2010; Nozaki et al., 2010).	('PRCC', 'Gene', '5546', (63, 67))	('ABC', 'Gene', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('ABC', 'Gene', '10058', (15, 18))	('PRCC', 'Gene', (63, 67))	('MK571', 'Var', (39, 44))	('MK571', 'Chemical', 'MESH:C059141', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('efflux', 'biological_process', 'GO:0140115', ('227', '233'))	('ABC', 'Gene', (15, 18))	('blockage', 'NegReg', (21, 29))	('tumor', 'Disease', (194, 199))	('ABC', 'Gene', '10058', (163, 166))	('efflux', 'biological_process', 'GO:0140352', ('227', '233'))	('contribute', 'Reg', (180, 190))	('affected', 'Reg', (50, 58))
21916	29896907	in the SUPAP trial assessing the effect of sunitinib treatment only on the two PRCC subtypes found slightly superior benefit with type 1 versus the type 2 (better partial response, longer stable disease, and overall survival).	('PRCC', 'Gene', '5546', (79, 83))	('partial', 'NegReg', (163, 170))	('PRCC', 'Gene', (79, 83))	('sunitinib', 'Chemical', 'MESH:D000077210', (43, 52))	('type', 'Var', (130, 134))
22016	32063918	A Novel Prognostic Index Based on Alternative Splicing in Papillary Renal Cell Carcinoma Papillary renal cell carcinoma (pRCC) is a heterogeneous multifocal or isolated tumor with an invasive phenotype.	('pRCC', 'Phenotype', 'HP:0006766', (121, 125))	('Alternative Splicing', 'Var', (34, 54))	('Papillary renal cell carcinoma', 'Disease', (89, 119))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('Papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (89, 119))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('Carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Papillary Renal Cell Carcinoma', 'Phenotype', 'HP:0006766', (58, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('Papillary Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (58, 88))	('tumor', 'Disease', (169, 174))	('Papillary Renal Cell Carcinoma', 'Disease', (58, 88))	('Splicing', 'biological_process', 'GO:0045292', ('46', '54'))	('Papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (89, 119))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (68, 88))
22017	32063918	Previous studies presented that alternative splicing, as a crucial posttranscriptional regulator in gene expression, is associated with tumorigenesis.	('associated', 'Reg', (120, 130))	('alternative splicing', 'Var', (32, 52))	('gene expression', 'biological_process', 'GO:0010467', ('100', '115'))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('splicing', 'biological_process', 'GO:0045292', ('44', '52'))
22022	32063918	Our study provides new insights into the mechanism of alternative splicing events in tumorigenesis and their clinical potential for pRCC.	('tumor', 'Disease', (85, 90))	('pRCC', 'Phenotype', 'HP:0006766', (132, 136))	('alternative splicing events', 'Var', (54, 81))	('pRCC', 'Disease', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('splicing', 'biological_process', 'GO:0045292', ('66', '74'))
22032	32063918	Dysregulation of splicing factors (SFs) can distort mRNA splicing programs, which could result in cancer development and progression.	('mRNA splicing programs', 'MPA', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mRNA splicing', 'biological_process', 'GO:0000372', ('52', '65'))	('mRNA splicing', 'biological_process', 'GO:0000394', ('52', '65'))	('splicing', 'biological_process', 'GO:0045292', ('17', '25'))	('result in', 'Reg', (88, 97))	('Dysregulation', 'Var', (0, 13))	('mRNA splicing', 'biological_process', 'GO:0006371', ('52', '65'))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('progression', 'CPA', (121, 132))	('distort', 'Reg', (44, 51))	('mRNA splicing', 'biological_process', 'GO:0000374', ('52', '65'))	('cancer', 'Disease', (98, 104))	('mRNA splicing', 'biological_process', 'GO:0000373', ('52', '65'))	('mRNA splicing', 'biological_process', 'GO:0000398', ('52', '65'))
22033	32063918	Studies have also shown that aberrant AS events during transcription, which are tissue-specific and stage-specific, can evoke tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('evoke', 'Reg', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('aberrant', 'Var', (29, 37))	('transcription', 'biological_process', 'GO:0006351', ('55', '68'))	('tumor', 'Disease', (126, 131))
22051	32063918	AS events generating from these genes might influence the occurrence and development of pRCC through interfering with the above BPs and pathways.	('genes', 'Var', (32, 37))	('influence', 'Reg', (44, 53))	('BPs', 'Chemical', 'MESH:C039301', (128, 131))	('pRCC', 'Phenotype', 'HP:0006766', (88, 92))	('interfering', 'NegReg', (101, 112))	('development', 'CPA', (73, 84))	('pRCC', 'Disease', (88, 92))
22065	32063918	Abnormal AS is associated with tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('associated', 'Reg', (15, 25))	('Abnormal AS', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
22068	32063918	Targeted therapy against VEGF was a traditional medical treatment for renal cell carcinoma.	('renal cell carcinoma', 'Disease', (70, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (70, 90))	('VEGF', 'Gene', '7422', (25, 29))	('Targeted therapy', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('VEGF', 'Gene', (25, 29))
22081	32063918	It was reported that inactivation of CLDN11 could promote cell migration in nasopharyngeal carcinoma.	('cell migration', 'CPA', (58, 72))	('inactivation', 'Var', (21, 33))	('promote', 'PosReg', (50, 57))	('CLDN11', 'Gene', (37, 43))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (76, 100))	('cell migration', 'biological_process', 'GO:0016477', ('58', '72'))	('carcinoma', 'Disease', 'MESH:D002277', (91, 100))	('CLDN11', 'Gene', '5010', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Disease', (91, 100))
22093	32063918	These results indicated that these altered SFs, as independent molecules, can construct a regulatory network in the carcinogenesis and progression in pRCC.	('pRCC', 'Disease', (150, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('altered', 'Var', (35, 42))	('carcinogenesis', 'Disease', (116, 130))	('pRCC', 'Phenotype', 'HP:0006766', (150, 154))
22097	31097977	Importantly, the aberrant activation or accumulation of NRF2, a common event in many tumors, confers a selective advantage to cancer cells and is associated to malignant progression, therapy resistance, and poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('associated to', 'Reg', (146, 159))	('malignant progression', 'CPA', (160, 181))	('aberrant', 'Var', (17, 25))	('lignan', 'Chemical', 'MESH:D017705', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('advantage', 'PosReg', (113, 122))	('NRF2', 'Gene', (56, 60))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('activation', 'PosReg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('accumulation', 'PosReg', (40, 52))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
22102	31097977	In this regard, not only fluctuations in the nutrient/oxygen availability but also the presence of electrophiles or xenobiotics can induce alterations in the redox balance and promote cell death by damaging essential macromolecules such as lipids, proteins, and DNA, particularly susceptible to reactive oxygen species (ROS).	('essential macromolecules', 'MPA', (207, 231))	('oxygen', 'Chemical', 'MESH:D010100', (304, 310))	('induce alterations', 'Reg', (132, 150))	('oxygen', 'Chemical', 'MESH:D010100', (54, 60))	('presence', 'Var', (87, 95))	('proteins', 'Protein', (248, 256))	('cell death', 'biological_process', 'GO:0008219', ('184', '194'))	('lipids', 'Chemical', 'MESH:D008055', (240, 246))	('cell death', 'CPA', (184, 194))	('redox balance', 'MPA', (158, 171))	('damaging', 'Reg', (198, 206))	('ROS', 'Chemical', 'MESH:D017382', (320, 323))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (295, 318))	('lipids', 'MPA', (240, 246))	('DNA', 'cellular_component', 'GO:0005574', ('262', '265'))	('rat', 'Species', '10116', (143, 146))	('promote', 'PosReg', (176, 183))
22116	31097977	Among them, Cys151, located within the BTB domain, was found to facilitate NRF2 activation, while Cys273, 288, and 297, located in the IVR, were found to suppress NRF2 activity facilitating its interaction with KEAP1 (see Figure 1(b)).	('activity', 'MPA', (168, 176))	('NRF2', 'Enzyme', (75, 79))	('Cys273', 'Chemical', '-', (98, 104))	('Cys151', 'Var', (12, 18))	('BTB', 'Chemical', '-', (39, 42))	('Cys151', 'Chemical', '-', (12, 18))	('BTB domain', 'molecular_function', 'GO:0031208', ('39', '49'))	('interaction', 'Interaction', (194, 205))	('NRF2', 'Enzyme', (163, 167))	('suppress', 'NegReg', (154, 162))	('Cys273', 'Var', (98, 104))	('facilitate', 'PosReg', (64, 74))	('activation', 'PosReg', (80, 90))
22117	31097977	Similarly, seven highly conserved and redox-sensitive cysteines (Cys119, 235, 311, 316, 414, and 516) have been identified in NRF2 and their oxidative modification was found to prevent KEAP1 recognition and binding.	('cysteines', 'Chemical', 'MESH:D003545', (54, 63))	('Cys119', 'Chemical', '-', (65, 71))	('binding', 'molecular_function', 'GO:0005488', ('207', '214'))	('Cys119', 'Var', (65, 71))	('KEAP1', 'Protein', (185, 190))	('recognition', 'Interaction', (191, 202))	('binding', 'Interaction', (207, 214))	('oxidative modification', 'MPA', (141, 163))	('prevent', 'NegReg', (177, 184))	('NRF2', 'Gene', (126, 130))
22125	31097977	In the following sections, we will discuss the oncogenic alterations in the NRF2/KEAP1 pathway that confer a selective advantage to malignant cells and their relevance as therapeutic targets in the treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('rat', 'Species', '10116', (61, 64))	('alterations', 'Var', (57, 68))	('lignan', 'Chemical', 'MESH:D017705', (134, 140))	('NRF2/KEAP1', 'Gene', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
22126	31097977	The molecular events that lead to cancer initiation, promotion, and progression are characterized by genetic and epigenetic changes in oncogenes and tumor suppressors that control key biological events related to cell proliferation, survival, and metabolism.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cell proliferation', 'biological_process', 'GO:0008283', ('213', '231'))	('oncogenes', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('rat', 'Species', '10116', (225, 228))	('epigenetic changes', 'Var', (113, 131))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer initiation', 'Disease', 'MESH:D009369', (34, 51))	('tumor', 'Disease', (149, 154))	('metabolism', 'biological_process', 'GO:0008152', ('247', '257'))	('cancer initiation', 'Disease', (34, 51))	('changes', 'Var', (124, 131))
22129	31097977	In this regard, despite that initial studies recognized its chemopreventive function in carcinogenesis and its cytoprotective role in many human pathologies, growing evidence also indicates that aberrant activation of the NRF2/KEAP1 pathway is frequently found in many tumors, promoting cancer growth, survival, metastasis formation, and therapy resistance.	('activation', 'PosReg', (204, 214))	('carcinogenesis', 'Disease', (88, 102))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('aberrant', 'Var', (195, 203))	('metastasis formation', 'CPA', (312, 332))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('formation', 'biological_process', 'GO:0009058', ('323', '332'))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('therapy resistance', 'CPA', (338, 356))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumors', 'Disease', (269, 275))	('NRF2/KEAP1 pathway', 'Pathway', (222, 240))	('promoting', 'PosReg', (277, 286))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('human', 'Species', '9606', (139, 144))	('survival', 'CPA', (302, 310))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))
22130	31097977	The occurrence of genetic mutations in the NRF2, KEAP1, or CUL3 genes represents the most frequent and well-characterized mechanism of sustained NRF2 activation in cancer (see Figure 3(a)).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('activation', 'PosReg', (150, 160))	('CUL3', 'Gene', '8452', (59, 63))	('CUL3', 'Gene', (59, 63))	('NRF2', 'Gene', (145, 149))	('KEAP1', 'Gene', (49, 54))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NRF2', 'Gene', (43, 47))	('genetic mutations', 'Var', (18, 35))
22131	31097977	In this regard, loss-of-function (LOF) mutations in the KEAP1 gene, targeting the Kelch/DGR domain, normally required for NRF2 interaction and degradation, were initially identified in tissues or cell lines derived from lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('patients', 'Species', '9606', (232, 240))	('lung cancer', 'Disease', (220, 231))	('mutations', 'Var', (39, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('degradation', 'biological_process', 'GO:0009056', ('143', '154'))	('KEAP1', 'Gene', (56, 61))	('loss-of-function', 'NegReg', (16, 32))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
22132	31097977	These observations were confirmed in subsequent studies reporting that the biallelic inactivation of KEAP1 caused by somatic mutations in the Kelch domain or in the IVR region was a frequent event in non-small-cell lung carcinoma (NSCLC).	('mutations in', 'Var', (125, 137))	('small-cell lung carcinoma', 'Disease', (204, 229))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (204, 229))	('NSCLC', 'Phenotype', 'HP:0030358', (231, 236))	('biallelic', 'Var', (75, 84))	('NSCLC', 'Disease', (231, 236))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (204, 229))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('KEAP1', 'Gene', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (200, 229))
22133	31097977	Indeed, LOF mutations in KEAP1 gene were, respectively, found in 50% (6/12) or 19% (10/54) of the cancer cell lines or cancer samples analyzed, while loss of heterozygosity at 19p13.2, the genetic locus of KEAP1, occurred at frequencies of 61% and 41% in NSCLC-derived cell lines and tumor tissues, respectively.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Disease', (255, 260))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('cancer', 'Disease', (119, 125))	('KEAP1', 'Gene', (25, 30))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('tumor', 'Disease', (284, 289))	('LOF', 'NegReg', (8, 11))
22135	31097977	Additional research further expanded the list of KEAP1 mutations in several cohorts of patients with different subtypes of lung cancer, pointing out the existence of widely distributed alterations beyond the DGR and the IVR motifs of the KEAP1 protein.	('mutations', 'Var', (55, 64))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('protein', 'cellular_component', 'GO:0003675', ('244', '251'))	('KEAP1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('patients', 'Species', '9606', (87, 95))	('rat', 'Species', '10116', (189, 192))	('alterations', 'Reg', (185, 196))
22136	31097977	Consistently, all these alterations produced typical clinicopathological features associated with increased NRF2 activity, therapy resistance, and poor prognosis, suggesting that the genetic status of KEAP1 might be used to stratify NSCLC patients and select personalized therapeutic options.	('NSCLC', 'Disease', (233, 238))	('alterations', 'Var', (24, 35))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('patients', 'Species', '9606', (239, 247))	('NRF2', 'Protein', (108, 112))	('therapy resistance', 'CPA', (123, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (233, 238))	('increased', 'PosReg', (98, 107))	('activity', 'MPA', (113, 121))	('rat', 'Species', '10116', (226, 229))	('KEAP1', 'Gene', (201, 206))	('rat', 'Species', '10116', (28, 31))
22140	31097977	Notably, KEAP1 missense or nonsense mutations have also been reported in malignant melanoma and hepatocellular, papillary thyroid, and endometrial carcinomas as well as gall bladder, breast, cervical, and ovarian cancers.	('KEAP1', 'Gene', (9, 14))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (135, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('ovarian cancers', 'Disease', (205, 220))	('nonsense mutations', 'Var', (27, 45))	('ovarian cancers', 'Disease', 'MESH:D010051', (205, 220))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (135, 157))	('papillary thyroid', 'Disease', (112, 129))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('malignant melanoma', 'Phenotype', 'HP:0002861', (73, 91))	('malignant melanoma', 'Disease', 'MESH:D008545', (73, 91))	('cervical', 'Disease', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('gall bladder', 'Disease', 'MESH:D005705', (169, 181))	('hepatocellular', 'Disease', (96, 110))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('ovarian cancers', 'Phenotype', 'HP:0100615', (205, 220))	('endometrial carcinomas', 'Disease', (135, 157))	('breast', 'Disease', (183, 189))	('malignant melanoma', 'Disease', (73, 91))	('gall bladder', 'Disease', (169, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('reported', 'Reg', (61, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
22141	31097977	As concerning the NRF2 gene, mutations in the DLG/ETGE motifs of the Neh2 domain resulting in decreased KEAP1 binding were also initially identified in biopsies and cell lines from lung cancer.	('binding', 'molecular_function', 'GO:0005488', ('110', '117'))	('NRF2', 'Gene', (18, 22))	('Neh2', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (29, 38))	('lung cancer', 'Disease', (181, 192))	('KEAP1', 'MPA', (104, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('decreased', 'NegReg', (94, 103))	('Neh2', 'Gene', '252969', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
22142	31097977	A similar pattern of NRF2 mutations was also observed in head and neck carcinoma, hepatocellular carcinoma, and papillary renal cell carcinoma (PRCC) as well as esophageal and skin cancers, resulting in increased malignant potential and chemoresistance.	('NRF2', 'Gene', (21, 25))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('papillary renal cell carcinoma', 'Disease', (112, 142))	('mutations', 'Var', (26, 35))	('skin cancers', 'Disease', (176, 188))	('PRCC', 'Gene', '5546', (144, 148))	('increased', 'PosReg', (203, 212))	('skin cancers', 'Disease', 'MESH:D012878', (176, 188))	('neck', 'cellular_component', 'GO:0044326', ('66', '70'))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('observed', 'Reg', (45, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (112, 142))	('lignan', 'Chemical', 'MESH:D017705', (215, 221))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('neck carcinoma', 'Disease', (66, 80))	('neck carcinoma', 'Disease', 'MESH:D006258', (66, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (112, 142))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PRCC', 'Gene', (144, 148))	('malignant potential', 'CPA', (213, 232))	('esophageal', 'Disease', (161, 171))	('PRCC', 'Phenotype', 'HP:0006766', (144, 148))	('chemoresistance', 'CPA', (237, 252))	('skin cancers', 'Phenotype', 'HP:0008069', (176, 188))	('hepatocellular carcinoma', 'Disease', (82, 106))
22143	31097977	In a recent study, Kerins and Ooi provided a comprehensive dataset of NRF2 gain-of-function mutations in The Cancer Genome Atlas (TCGA), identifying 226 NRF2-mutant tumors from 10364 cases.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRF2-mutant', 'Gene', (153, 164))	('NRF2', 'Gene', (70, 74))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('gain-of-function', 'PosReg', (75, 91))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
22145	31097977	reported the first example of increased NRF2 signaling being not caused by somatic mutations, since the genetic deletion of NRF2 exon 2 (see Figure 3(b)) was found to promote elevated NRF2 activity and stability in head-neck squamous carcinoma (HNSC) and NSCLC, by removing the KEAP1-interacting domain in the absence of other genetic changes.	('NRF2', 'Enzyme', (184, 188))	('head-neck squamous carcinoma', 'Phenotype', 'HP:0012288', (215, 243))	('signaling', 'biological_process', 'GO:0023052', ('45', '54'))	('HNSC', 'Phenotype', 'HP:0012288', (245, 249))	('stability', 'MPA', (202, 211))	('promote elevated', 'PosReg', (167, 183))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (225, 243))	('NRF2', 'Gene', (124, 128))	('deletion', 'Var', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('KEAP1-interacting domain', 'MPA', (278, 302))	('neck', 'cellular_component', 'GO:0044326', ('220', '224'))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('head-neck squamous carcinoma (HNSC) and NSCLC', 'Disease', 'MESH:C535575', (215, 260))	('activity', 'MPA', (189, 197))
22146	31097977	Last but not least, inactivating mutations or copy number loss of the CUL3 or RBX1 genes that control NRF2 ubiquitylation/degradation has also been described in PRCC and papillary thyroid, esophageal, and serous ovarian cancers.	('described', 'Reg', (148, 157))	('RBX1', 'Gene', (78, 82))	('degradation', 'biological_process', 'GO:0009056', ('122', '133'))	('papillary thyroid', 'Disease', (170, 187))	('serous ovarian cancers', 'Disease', (205, 227))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (205, 227))	('ubiquitylation/degradation', 'MPA', (107, 133))	('esophageal', 'Disease', (189, 199))	('CUL3', 'Gene', '8452', (70, 74))	('copy number loss', 'Var', (46, 62))	('PRCC', 'Gene', (161, 165))	('PRCC', 'Phenotype', 'HP:0006766', (161, 165))	('RBX1', 'Gene', '9978', (78, 82))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('ovarian cancers', 'Phenotype', 'HP:0100615', (212, 227))	('NRF2', 'Gene', (102, 106))	('CUL3', 'Gene', (70, 74))	('inactivating mutations', 'Var', (20, 42))	('PRCC', 'Gene', '5546', (161, 165))
22147	31097977	In summary, genetic alterations in the NRF2/KEAP1 pathway are one of the leading causes of its prooncogenic activation.	('causes', 'Reg', (81, 87))	('genetic alterations', 'Var', (12, 31))	('NRF2/KEAP1 pathway', 'Pathway', (39, 57))	('prooncogenic activation', 'MPA', (95, 118))	('rat', 'Species', '10116', (24, 27))
22150	31097977	On the other hand, the mutation status of KEAP1 and NRF2 genes in NSCLC patients might have a clinical relevance and represent not only a valid predictive biomarker but also a molecular indication for the choice of a personalized therapy.	('NRF2', 'Gene', (52, 56))	('NSCLC', 'Disease', (66, 71))	('mutation', 'Var', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('KEAP1', 'Gene', (42, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
22151	31097977	Modifications of the epigenetic status in the NRF2 or KEAP1 genes have been shown to induce NRF2 stabilization and increased target gene expression in many tumors.	('induce', 'PosReg', (85, 91))	('KEAP1', 'Gene', (54, 59))	('epigenetic status', 'Var', (21, 38))	('expression', 'MPA', (137, 147))	('increased', 'PosReg', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NRF2', 'Gene', (46, 50))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('Modifications', 'Var', (0, 13))	('tumors', 'Disease', (156, 162))	('stabilization', 'MPA', (97, 110))	('gene expression', 'biological_process', 'GO:0010467', ('132', '147'))	('NRF2', 'Protein', (92, 96))
22152	31097977	For example, the hypermethylation of CpG islands within the KEAP1 promoter region (see Figure 3(c)) has been reported to induce chemoresistance in malignant glioma and breast, prostate, colorectal, thyroid renal, and lung cancers, due to a marked decrease in the KEAP1 mRNA levels and an augmented expression of NRF2 target genes.	('expression', 'MPA', (298, 308))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('induce', 'PosReg', (121, 127))	('CpG', 'Gene', (37, 40))	('lung cancers', 'Disease', 'MESH:D008175', (217, 229))	('thyroid renal', 'Disease', 'MESH:D013959', (198, 211))	('colorectal', 'Disease', 'MESH:D015179', (186, 196))	('augmented', 'PosReg', (288, 297))	('lung cancers', 'Disease', (217, 229))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('KEAP1 mRNA levels', 'MPA', (263, 280))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancers', 'Phenotype', 'HP:0100526', (217, 229))	('decrease', 'NegReg', (247, 255))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('malignant glioma', 'Disease', 'MESH:D005910', (147, 163))	('malignant glioma', 'Disease', (147, 163))	('colorectal', 'Disease', (186, 196))	('chemoresistance', 'CPA', (128, 143))	('breast', 'Disease', (168, 174))	('hypermethylation', 'Var', (17, 33))	('prostate', 'Disease', (176, 184))	('thyroid renal', 'Disease', (198, 211))
22156	31097977	While decreased NRF2 activity due to hypermethylation of the NRF2 promoter has been observed in prostate cancers, its hypomethylation was recently reported in colorectal cancer, an event associated to NRF2 overexpression and augmented chemoresistance.	('prostate cancers', 'Disease', 'MESH:D011471', (96, 112))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRF2', 'Gene', (61, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('hypermethylation', 'MPA', (37, 53))	('NRF2', 'Gene', (201, 205))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('prostate cancers', 'Phenotype', 'HP:0012125', (96, 112))	('prostate cancers', 'Disease', (96, 112))	('chemoresistance', 'CPA', (235, 250))	('colorectal cancer', 'Disease', (159, 176))	('activity', 'MPA', (21, 29))	('decreased', 'NegReg', (6, 15))	('NRF2', 'Enzyme', (16, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('hypomethylation', 'Var', (118, 133))	('overexpression', 'PosReg', (206, 220))
22162	31097977	Importantly, an emerging mechanism of NRF2/KEAP1 epigenetic deregulation in cancer is represented by microRNAs (miRNAs), small noncoding molecules that recognize the 3'-untranslated regions (UTRs) of specific mRNAs and negatively regulate their abundance by translation blocking or forced degradation (see Figure 3(e)).	('NRF2/KEAP1', 'Gene', (38, 48))	('abundance', 'MPA', (245, 254))	('regulate', 'Reg', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('degradation', 'biological_process', 'GO:0009056', ('289', '300'))	('translation', 'biological_process', 'GO:0006412', ('258', '269'))	('epigenetic deregulation', 'Var', (49, 72))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('negatively', 'NegReg', (219, 229))
22164	31097977	Similarly, miR-507, miR-634, miR-450a, and miR-129-5p were found to directly inhibit NRF2 expression while their low levels were associated with poor outcome in esophageal carcinoma.	('NRF2', 'Gene', (85, 89))	('miR-507', 'Gene', '574512', (11, 18))	('associated', 'Reg', (129, 139))	('miR-634', 'Gene', (20, 27))	('miR-450a', 'Var', (29, 37))	('inhibit', 'NegReg', (77, 84))	('miR-129-5p', 'Gene', '100302178', (43, 53))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (161, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (161, 181))	('miR-129-5p', 'Gene', (43, 53))	('miR-634', 'Gene', '693219', (20, 27))	('expression', 'MPA', (90, 100))	('miR-507', 'Gene', (11, 18))	('esophageal carcinoma', 'Disease', (161, 181))
22169	31097977	In the same cell line, miR-153, miR27a, and miR-142-5p were also found to repress NRF2-dependent transactivation of cytoprotective genes while the forced expression of each miRNA was sufficient to markedly decrease the levels of GCLC and GSR.	('NRF2-dependent', 'Gene', (82, 96))	('GCLC', 'Gene', (229, 233))	('GSR', 'MPA', (238, 241))	('GCLC', 'Gene', '2729', (229, 233))	('decrease', 'NegReg', (206, 214))	('miR-142-5p', 'Var', (44, 54))	('repress', 'NegReg', (74, 81))	('miR27a', 'Gene', (32, 38))	('miR-153', 'Var', (23, 30))	('transactivation', 'biological_process', 'GO:2000144', ('97', '112'))	('miR27a', 'Gene', '407018', (32, 38))	('cytoprotective genes', 'Gene', (116, 136))
22170	31097977	Recently, miR-155 inhibition was found to attenuate the malignancy and promote apoptosis in arsenic-transformed bronchial epithelial cells by repressing NRF2, suggesting that miR-155 might promote malignant transformation of lung cells exposed to arsenite.	('miR-155', 'Gene', '406947', (10, 17))	('miR-155', 'Gene', (175, 182))	('malignancy', 'Disease', (56, 66))	('lignan', 'Chemical', 'MESH:D017705', (58, 64))	('miR-155', 'Gene', '406947', (175, 182))	('promote', 'PosReg', (71, 78))	('arsenite', 'Chemical', 'MESH:C015001', (247, 255))	('lignan', 'Chemical', 'MESH:D017705', (199, 205))	('inhibition', 'Var', (18, 28))	('repressing', 'PosReg', (142, 152))	('attenuate', 'NegReg', (42, 51))	('NRF2', 'Gene', (153, 157))	('promote', 'PosReg', (189, 196))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('apoptosis', 'biological_process', 'GO:0097194', ('79', '88'))	('apoptosis', 'biological_process', 'GO:0006915', ('79', '88'))	('miR-155', 'Gene', (10, 17))	('malignant transformation', 'CPA', (197, 221))	('apoptosis', 'CPA', (79, 88))	('arsenic', 'Chemical', 'MESH:D001151', (92, 99))
22171	31097977	Similarly, miR-153 and miR-93a were also proposed to drive breast carcinogenesis, since their increased expression was paralleled by reduced NRF2 protein content in mammary tumors and breast cancer cell lines treated with 17beta-estradiol.	('miR-93a', 'Var', (23, 30))	('protein', 'cellular_component', 'GO:0003675', ('146', '153'))	('increased', 'PosReg', (94, 103))	('breast carcinogenesis', 'Disease', (59, 80))	('NRF2 protein', 'Protein', (141, 153))	('tumors and breast cancer', 'Disease', 'MESH:D001943', (173, 197))	('protein', 'Protein', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('expression', 'MPA', (104, 114))	('drive', 'Reg', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('17beta-estradiol', 'Chemical', 'MESH:D004958', (222, 238))	('reduced', 'NegReg', (133, 140))	('miR-153', 'Var', (11, 18))	('breast carcinogenesis', 'Disease', 'MESH:D061325', (59, 80))
22177	31097977	In another context, increased expression of miR-200a was shown to negatively modulate KEAP1 levels in response to methylseleninic acid (MSA), while the use of antagomir-200a attenuated the KEAP1 downregulation induced by MSA in ESCC cells.	('miR-200a', 'Gene', (44, 52))	('attenuated', 'NegReg', (174, 184))	('increased', 'PosReg', (20, 29))	('negatively', 'NegReg', (66, 76))	('response to methylseleninic acid', 'MPA', (102, 134))	('downregulation', 'NegReg', (195, 209))	('expression', 'Var', (30, 40))	('KEAP1', 'MPA', (86, 91))	('MSA', 'Chemical', 'MESH:C008493', (221, 224))	('modulate', 'Reg', (77, 85))	('methylseleninic acid', 'Chemical', 'MESH:C008493', (114, 134))	('MSA', 'Chemical', 'MESH:C008493', (136, 139))	('miR-200a', 'Gene', '406983', (44, 52))
22190	31097977	Indeed, an earlier study reported that high levels of p62 were significantly correlated with HER2 overexpression in human breast cancers, while a role for p62 in breast carcinogenesis was further evidenced in a recent study wherein p62 was shown to facilitate HER2-dependent mammary tumorigenesis in MMTV-Neu transgenic mice by the activation of multiple pathways, including the NRF2/KEAP1.	('MMTV', 'Species', '11757', (300, 304))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('breast carcinogenesis', 'Disease', 'MESH:D061325', (162, 183))	('HER2', 'Gene', (260, 264))	('transgenic mice', 'Species', '10090', (309, 324))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('overexpression', 'PosReg', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('facilitate', 'PosReg', (249, 259))	('HER2', 'Gene', '2064', (93, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast carcinogenesis', 'Disease', (162, 183))	('HER2', 'Gene', '2064', (260, 264))	('p62', 'Var', (232, 235))	('human', 'Species', '9606', (116, 121))	('tumor', 'Disease', (283, 288))	('HER2', 'Gene', (93, 97))
22191	31097977	Also, altered p62 expression was associated to increased NRF2 activation and enhanced chemoresistance in cancer stem cell- (CSC-) enriched mammospheres derived from MCF-7 breast cancer cells, compared to monolayer cultured cells.	('enhanced', 'PosReg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('increased', 'PosReg', (47, 56))	('cancer', 'Disease', (178, 184))	('expression', 'MPA', (18, 28))	('p62', 'Gene', (14, 17))	('MCF-7 breast cancer', 'Disease', (165, 184))	('activation', 'PosReg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('NRF2', 'Gene', (57, 61))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (165, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('chemoresistance', 'CPA', (86, 101))	('altered', 'Var', (6, 13))
22193	31097977	In another context, it has been proposed that p62 might serve as a prognostic marker in patients with glioma, being its content positively correlated to the NRF2 levels and a poor prognosis.	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('positively', 'PosReg', (128, 138))	('correlated', 'Reg', (139, 149))	('content', 'MPA', (120, 127))	('patients', 'Species', '9606', (88, 96))	('NRF2 levels', 'MPA', (157, 168))	('glioma', 'Disease', (102, 108))	('p62', 'Var', (46, 49))
22194	31097977	From a clinical perspective, p62 was also found to decrease arsenic sensitivity in human transformed lung bronchial epithelial BEAS-2B cells, by noncanonical stimulation of the NRF2/KEAP1 pathway, presumably due to its constitutive activation after carcinogenesis induction.	('p62', 'Var', (29, 32))	('carcinogenesis', 'Disease', (249, 263))	('stimulation', 'PosReg', (158, 169))	('BEAS-2B', 'CellLine', 'CVCL:0168', (127, 134))	('human', 'Species', '9606', (83, 88))	('NRF2/KEAP1 pathway', 'Pathway', (177, 195))	('arsenic sensitivity', 'MPA', (60, 79))	('decrease', 'NegReg', (51, 59))	('arsenic', 'Chemical', 'MESH:D001151', (60, 67))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))
22198	31097977	Also, since amplification of the p62 gene or aberrant accumulation of its phosphorylated form is frequently found in many cancers, either inhibitors of p62 phosphorylation or antagonists of p62/NRF2 interaction might restore the route of NRF2 proteasomal degradation in the context of a functional KEAP1 expression.	('degradation', 'biological_process', 'GO:0009056', ('255', '266'))	('restore', 'PosReg', (217, 224))	('p62', 'Gene', (33, 36))	('phosphorylation', 'biological_process', 'GO:0016310', ('156', '171'))	('amplification', 'Var', (12, 25))	('route', 'MPA', (229, 234))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('NRF2 proteasomal degradation', 'MPA', (238, 266))
22202	31097977	Collectively, these data suggest that the overexpression of different types of ETGE-containing proteins in cancer cells might sustain NRF2 activity even in the absence of activating mutations in the NRF2 or inactivating mutations in the KEAP1 genes.	('NRF2', 'Protein', (134, 138))	('NRF2', 'Gene', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('KEAP1', 'Gene', (237, 242))	('inactivating mutations', 'Var', (207, 229))	('activity', 'MPA', (139, 147))	('overexpression', 'PosReg', (42, 56))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
22203	31097977	With this respect, the lack of fumarate hydratase (FH), an enzyme that converts fumarate to malate in the TCA (tricarboxylic acid) cycle, was found to promote fumarate accumulation and lead to succinylation of KEAP1 cysteines, NRF2 stabilization, and subsequent transactivation of stress-related genes (see Figure 3(g)) in PRCC.	('malate', 'Chemical', 'MESH:C030298', (92, 98))	('stabilization', 'MPA', (232, 245))	('fumarate', 'Chemical', 'MESH:D005650', (31, 39))	('transactivation', 'biological_process', 'GO:2000144', ('262', '277'))	('stress-related genes', 'Gene', (281, 301))	('PRCC', 'Gene', (323, 327))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (111, 129))	('fumarate', 'Chemical', 'MESH:D005650', (80, 88))	('PRCC', 'Phenotype', 'HP:0006766', (323, 327))	('fumarate accumulation', 'MPA', (159, 180))	('lack', 'Var', (23, 27))	('TCA', 'Chemical', 'MESH:D014233', (106, 109))	('NRF2', 'Gene', (227, 231))	('fumarate hydratase', 'Gene', '2271', (31, 49))	('succinylation', 'MPA', (193, 206))	('promote', 'PosReg', (151, 158))	('tricarboxylic acid) cycle', 'biological_process', 'GO:0006099', ('111', '136'))	('lack of fumarate hydratase', 'Phenotype', 'HP:0003536', (23, 49))	('FH', 'Gene', '2271', (51, 53))	('PRCC', 'Gene', '5546', (323, 327))	('cysteines', 'Chemical', 'MESH:D003545', (216, 225))	('fumarate', 'Chemical', 'MESH:D005650', (159, 167))	('transactivation', 'PosReg', (262, 277))	('fumarate hydratase', 'Gene', (31, 49))
22204	31097977	Accumulating evidence suggests that other cancer-specific alterations, particularly those related to oncogenic signaling can strongly influence the activity of NRF2 without affecting its protein stability but rather increasing its mRNA levels (see Figure 3).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('influence', 'Reg', (134, 143))	('activity', 'MPA', (148, 156))	('signaling', 'biological_process', 'GO:0023052', ('111', '120'))	('rat', 'Species', '10116', (209, 212))	('mRNA levels', 'MPA', (231, 242))	('protein stability', 'MPA', (187, 204))	('cancer', 'Disease', (42, 48))	('NRF2', 'Gene', (160, 164))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('rat', 'Species', '10116', (62, 65))	('increasing', 'Reg', (216, 226))	('protein', 'cellular_component', 'GO:0003675', ('187', '194'))	('alterations', 'Var', (58, 69))
22210	31097977	Importantly, increased expression of the antioxidant genes NQO1 and HMOX1 was found to promote an aggressive phenotype associated to chemoresistance, while the genetic ablation of NRF2 by CRISPR/Cas9 was able to impair the malignant progression and restore the sensitivity to several anticancer drugs.	('impair', 'NegReg', (212, 218))	('lignan', 'Chemical', 'MESH:D017705', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('aggressive phenotype', 'MPA', (98, 118))	('NRF2', 'Gene', (180, 184))	('expression', 'MPA', (23, 33))	('cancer', 'Disease', (288, 294))	('NQO1', 'molecular_function', 'GO:0003955', ('59', '63'))	('HMOX1', 'Gene', (68, 73))	('malignant progression', 'CPA', (223, 244))	('NQO1', 'Gene', (59, 63))	('restore', 'PosReg', (249, 256))	('chemoresistance', 'Disease', (133, 148))	('Cas', 'cellular_component', 'GO:0005650', ('195', '198'))	('promote', 'PosReg', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('increased', 'PosReg', (13, 22))	('genetic ablation', 'Var', (160, 176))
22212	31097977	Importantly, strong evidence also indicates that aberrant activation of the PI3K/AKT pathway, a master regulator of cancer cell growth, survival, and metabolism can act upstream NRF2 signaling in different types of tumors (see Figure 3(h)).	('act', 'Reg', (165, 168))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('metabolism', 'biological_process', 'GO:0008152', ('150', '160'))	('AKT', 'Gene', '207', (81, 84))	('signaling', 'biological_process', 'GO:0023052', ('183', '192'))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('aberrant', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('AKT', 'Gene', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cell growth', 'biological_process', 'GO:0016049', ('123', '134'))	('activation', 'PosReg', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))	('PI3K', 'molecular_function', 'GO:0016303', ('76', '80'))
22213	31097977	Initial studies provided indirect evidence of a functional interaction between the PI3K/AKT and NRF2/KEAP1 pathways since the pharmacologic inhibition of the former was able to prevent NRF2 nuclear accumulation in renal adenocarcinoma cells and auditory cells.	('PI3K', 'molecular_function', 'GO:0016303', ('83', '87'))	('inhibition', 'Var', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('AKT', 'Gene', '207', (88, 91))	('nuclear accumulation', 'MPA', (190, 210))	('AKT', 'Gene', (88, 91))	('NRF2', 'Protein', (185, 189))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (214, 234))	('renal adenocarcinoma', 'Disease', 'MESH:D002292', (214, 234))	('renal adenocarcinoma', 'Disease', (214, 234))	('prevent', 'NegReg', (177, 184))
22214	31097977	Later studies conducted on lung cancer cell lines with KEAP1 (A549 and H2126) or NRF2 (EBC1 and LK2) mutations demonstrated that the sustained activation of the PI3K/AKT pathway was accompanied by increased NRF2 mRNA levels and NRF2 nuclear accumulation leading to metabolic reprogramming, enhanced cell proliferation, and apoptosis evasion.	('apoptosis evasion', 'CPA', (323, 340))	('H2126', 'CellLine', 'CVCL:1532', (71, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('AKT', 'Gene', (166, 169))	('increased', 'PosReg', (197, 206))	('NRF2', 'Protein', (207, 211))	('metabolic reprogramming', 'CPA', (265, 288))	('NRF2', 'Gene', (228, 232))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (101, 110))	('AKT', 'Gene', '207', (166, 169))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('lung cancer', 'Disease', (27, 38))	('nuclear accumulation', 'CPA', (233, 253))	('activation', 'PosReg', (143, 153))	('mRNA levels', 'MPA', (212, 223))	('enhanced', 'PosReg', (290, 298))	('NRF2', 'Gene', (81, 85))	('apoptosis', 'biological_process', 'GO:0097194', ('323', '332'))	('PI3K', 'molecular_function', 'GO:0016303', ('161', '165'))	('apoptosis', 'biological_process', 'GO:0006915', ('323', '332'))	('rat', 'Species', '10116', (311, 314))	('cell proliferation', 'CPA', (299, 317))	('cell proliferation', 'biological_process', 'GO:0008283', ('299', '317'))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
22230	31097977	Importantly, disruption of the PERK/NRF2 axis was able to reverse both the resistance to ER stress and to anticancer drugs.	('resistance to ER stress', 'MPA', (75, 98))	('cancer', 'Disease', (110, 116))	('PERK', 'Gene', (31, 35))	('disruption', 'Var', (13, 23))	('PERK', 'Gene', '9451', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('reverse', 'NegReg', (58, 65))
22236	31097977	Taken together, these data highlight the existence of a complex interrelation between the NRF2/KEAP1 pathway and stress-related responses commonly found in the microenvironment of malignant tumors, confirming that aberrant NRF2 activation can represent a common feature of cancer cells, even in the absence of alterations of the redox status or prooncogenic mutations in NRF2/KEAP1 genes.	('malignant tumors', 'Disease', 'MESH:D009369', (180, 196))	('NRF2', 'Gene', (223, 227))	('cancer', 'Disease', (273, 279))	('activation', 'PosReg', (228, 238))	('rat', 'Species', '10116', (314, 317))	('iron', 'Chemical', 'MESH:D007501', (168, 172))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('malignant tumors', 'Disease', (180, 196))	('aberrant', 'Var', (214, 222))
22242	31097977	For example, aberrant NRF2 activation has been shown to induce overexpression of the MDR1 (multidrug resistance protein 1), MRP1-5 (multi-drug resistance-associated protein 1-5), and BCRP (breast cancer resistance protein) genes or to increase the activity of their corresponding proteins, leading to widespread chemoresistance.	('MRP1', 'Gene', '4363', (124, 128))	('activity', 'MPA', (248, 256))	('MDR1', 'Gene', (85, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('protein', 'cellular_component', 'GO:0003675', ('112', '119'))	('breast cancer resistance protein', 'Gene', (189, 221))	('activation', 'PosReg', (27, 37))	('drug resistance', 'biological_process', 'GO:0009315', ('138', '153'))	('NRF2', 'Gene', (22, 26))	('drug resistance', 'biological_process', 'GO:0042493', ('138', '153'))	('protein', 'cellular_component', 'GO:0003675', ('165', '172'))	('widespread chemoresistance', 'CPA', (301, 327))	('drug resistance', 'Phenotype', 'HP:0020174', (138, 153))	('increase', 'PosReg', (235, 243))	('proteins', 'Protein', (280, 288))	('MRP1', 'Gene', (124, 128))	('multidrug resistance protein 1', 'Gene', '5243', (91, 121))	('MDR', 'molecular_function', 'GO:0004745', ('85', '88'))	('aberrant', 'Var', (13, 21))	('overexpression', 'MPA', (63, 77))	('multidrug resistance protein', 'molecular_function', 'GO:0008559', ('91', '119'))	('drug resistance', 'Phenotype', 'HP:0020174', (96, 111))	('multidrug resistance protein 1', 'Gene', (91, 121))	('MDR1', 'Gene', '5243', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('leading to', 'Reg', (290, 300))	('breast cancer resistance protein', 'Gene', '9429', (189, 221))	('BCRP', 'Gene', (183, 187))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('BCRP', 'Gene', '9429', (183, 187))
22246	31097977	For example, by using high-throughput screening to identify small molecule inhibitors of the NRF2 transcriptional activity at ARE sites, AEM1 was found to broadly impair the expression of NRF2 target genes, leading to growth inhibition and increased chemosensitivity of A549 NSCLC cells in vitro and in vivo (see Table 1).	('increased', 'PosReg', (240, 249))	('growth inhibition', 'CPA', (218, 235))	('expression', 'MPA', (174, 184))	('NSCLC', 'Disease', (275, 280))	('NRF2', 'Gene', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('AEM1', 'Var', (137, 141))	('A549', 'CellLine', 'CVCL:0023', (270, 274))	('impair', 'NegReg', (163, 169))	('chemosensitivity', 'CPA', (250, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (275, 280))
22247	31097977	Also, a quantitative high-throughput screening on ~400 000 small molecules made by Singh and coworkers led to the identification of ML385, a compound with high specificity and selectivity for NSCLC with constitutive NRF2 activation caused by inactivating mutations of KEAP1 (see Table 1).	('NRF2', 'Gene', (216, 220))	('NSCLC', 'Disease', (192, 197))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('activation', 'PosReg', (221, 231))	('KEAP1', 'Gene', (268, 273))	('ML385', 'Var', (132, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('inactivating mutations', 'Var', (242, 264))
22248	31097977	In preclinical models of NSCLC, the combined use of ML385 with Carboplatin was associated to significant antitumor activity, confirming that NRF2 targeting is a promising strategy for the treatment of advanced NSCLC.	('rat', 'Species', '10116', (173, 176))	('Carboplatin', 'Chemical', 'MESH:D016190', (63, 74))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', (210, 215))	('ML385', 'Var', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('tumor', 'Disease', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
22272	31097977	Later studies conducted on mouse Hepa-1c1c7 hepatoma cells and primary human hepatocytes consistently reported that Brusatol could transiently and rapidly deplete the NRF2 protein levels in a KEAP1-independent way through a posttranscriptional mechanism, strongly increasing the cell sensitivity to electrophilic stress inducers (see Table 1).	('Hepa-1c1c7 hepatoma', 'Disease', (33, 52))	('deplete', 'NegReg', (155, 162))	('Brusatol', 'Var', (116, 124))	('mouse', 'Species', '10090', (27, 32))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('NRF2 protein levels', 'MPA', (167, 186))	('increasing', 'PosReg', (264, 274))	('cell sensitivity to electrophilic stress inducers', 'MPA', (279, 328))	('Brusatol', 'Chemical', 'MESH:C020237', (116, 124))	('human', 'Species', '9606', (71, 76))	('Hepa-1c1c7 hepatoma', 'Disease', 'MESH:D006528', (33, 52))
22311	31097977	Mechanistically, Honokiol markedly activated the JNK pathway while in contrast, it strongly reduced both NF-kappaB activity and NRF2 protein levels, leading to increased ROS production and apoptosis, as further confirmed in BALB/C nude mice injected with Raji cells.	('Raji', 'CellLine', 'CVCL:0511', (255, 259))	('NRF2 protein levels', 'MPA', (128, 147))	('increased', 'PosReg', (160, 169))	('NF-kappaB activity', 'MPA', (105, 123))	('nude mice', 'Species', '10090', (231, 240))	('apoptosis', 'biological_process', 'GO:0097194', ('189', '198'))	('JNK pathway', 'Pathway', (49, 60))	('apoptosis', 'biological_process', 'GO:0006915', ('189', '198'))	('Honokiol', 'Var', (17, 25))	('apoptosis', 'CPA', (189, 198))	('Honokiol', 'Chemical', 'MESH:C005499', (17, 25))	('increased ROS production', 'Phenotype', 'HP:0025464', (160, 184))	('protein', 'cellular_component', 'GO:0003675', ('133', '140'))	('reduced', 'NegReg', (92, 99))	('ROS production', 'MPA', (170, 184))	('ROS', 'Chemical', 'MESH:D017382', (170, 173))	('JNK', 'molecular_function', 'GO:0004705', ('49', '52'))	('activated', 'PosReg', (35, 44))
22325	31097977	Known for its anti-inflammatory, antimicrobial, and antihelminthic effects, Berberine was recently found to exert also antineoplastic activity in breast cancer by inducing oxidative stress.	('Berberine', 'Chemical', 'MESH:D001599', (76, 85))	('inducing', 'PosReg', (163, 171))	('antineoplastic activity', 'CPA', (119, 142))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (172, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('oxidative stress', 'MPA', (172, 188))	('Berberine', 'Var', (76, 85))
22362	31097977	Importantly, when used as an adjuvant, PIK-75 was able to counteract the increase in NRF2 induced by Gemcitabine and to significantly potentiate its antitumor effects both in vitro and in vivo.	('NRF2', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('potentiate', 'PosReg', (134, 144))	('increase', 'PosReg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('Gemcitabine', 'Chemical', 'MESH:C056507', (101, 112))	('PIK-75', 'Var', (39, 45))
22364	31097977	In another study conducted on U251 human glioblastoma cells, the ERK and PI3K signaling cascades were found to regulate the expression and activation of NRF2, while the cotreatment with pharmacologic inhibitors (PD98059 for ERK and LY292004 for PI3K) was able to revert these changes and trigger cell death.	('cell death', 'biological_process', 'GO:0008219', ('296', '306'))	('human glioblastoma', 'Disease', (35, 53))	('PD98059', 'Var', (212, 219))	('PI3K signaling', 'biological_process', 'GO:0014065', ('73', '87'))	('cell death', 'CPA', (296, 306))	('PI3K', 'molecular_function', 'GO:0016303', ('245', '249'))	('PI3K', 'molecular_function', 'GO:0016303', ('73', '77'))	('LY292004', 'Chemical', '-', (232, 240))	('activation', 'MPA', (139, 149))	('trigger', 'Reg', (288, 295))	('NRF2', 'Gene', (153, 157))	('LY292004', 'Var', (232, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (41, 53))	('ERK', 'molecular_function', 'GO:0004707', ('65', '68'))	('PD98059', 'Chemical', 'MESH:C093973', (212, 219))	('expression', 'MPA', (124, 134))	('human glioblastoma', 'Disease', 'MESH:D005909', (35, 53))	('regulate', 'Reg', (111, 119))	('U251', 'CellLine', 'CVCL:0021', (30, 34))	('ERK', 'molecular_function', 'GO:0004707', ('224', '227'))
22365	31097977	Interestingly, LGB-321 and AZD1208, two inhibitors of PIM kinase, a protein frequently overexpressed in many tumors exposed to hypoxia, were found to impair tumor growth and selectively kill different types of hypoxic cancer cells in vitro and in vivo, preventing NRF2 nuclear accumulation and leading to the buildup of ROS, suggesting that this strategy might overcome the hypoxia-mediated therapy resistance frequently encountered in the treatment of many tumors.	('hypoxic cancer', 'Disease', 'MESH:D009369', (210, 224))	('impair', 'NegReg', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('hypoxic cancer', 'Disease', (210, 224))	('buildup', 'MPA', (309, 316))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('preventing', 'NegReg', (253, 263))	('NRF2', 'Protein', (264, 268))	('AZD1208', 'Chemical', 'MESH:C587575', (27, 34))	('LGB-321', 'Gene', (15, 22))	('tumors', 'Phenotype', 'HP:0002664', (458, 464))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (348, 351))	('hypoxia', 'Disease', (127, 134))	('leading to', 'Reg', (294, 304))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('hypoxia', 'Disease', (374, 381))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (458, 464))	('tumors', 'Disease', (109, 115))	('hypoxia', 'Disease', 'MESH:D000860', (127, 134))	('hypoxia', 'Disease', 'MESH:D000860', (374, 381))	('ROS', 'MPA', (320, 323))	('tumor', 'Disease', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (458, 464))	('nuclear accumulation', 'MPA', (269, 289))	('AZD1208', 'Var', (27, 34))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('ROS', 'Chemical', 'MESH:D017382', (320, 323))	('tumor', 'Disease', (458, 463))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('protein', 'cellular_component', 'GO:0003675', ('68', '75'))	('tumor', 'Disease', (109, 114))
22368	31097977	With this respect, by establishing Gefitinib-resistant (GR) NSCLC cells, it has been shown that the increased overexpression of several NRF2-dependent target genes was due to an acquired KEAP1 mutation, an event promoting a malignant phenotype and cross-resistance to the EGFR-TKIs Afatinib and Osimertinib both in vitro and in vivo.	('EGFR', 'Gene', '1956', (272, 276))	('Afatinib', 'Chemical', 'MESH:D000077716', (282, 290))	('EGFR', 'molecular_function', 'GO:0005006', ('272', '276'))	('Osimertinib', 'Chemical', 'MESH:C000603933', (295, 306))	('EGFR', 'Gene', (272, 276))	('increased overexpression', 'PosReg', (100, 124))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('malignant phenotype', 'CPA', (224, 243))	('lignan', 'Chemical', 'MESH:D017705', (226, 232))	('Gefitinib', 'Chemical', 'MESH:D000077156', (35, 44))	('promoting', 'PosReg', (212, 221))	('mutation', 'Var', (193, 201))	('KEAP1', 'Gene', (187, 192))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
22369	31097977	Here, the inhibition of NRF2, either by treatment with Brusatol or by restored expression of wild-type KEAP1, suppressed tumor cell proliferation and tumorigenicity in vitro and in vivo, confirming that deregulation of the NRF2/KEAP1 pathway can be responsible for the acquired resistance to EGFR-TKIs observed in many NSCLC patients, while its pharmacologic ablation might represent a valid option to overcome this phenomenon.	('NSCLC', 'Disease', (319, 324))	('inhibition', 'NegReg', (10, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (319, 324))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('EGFR', 'Gene', '1956', (292, 296))	('tumor', 'Disease', (121, 126))	('suppressed', 'NegReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('EGFR', 'molecular_function', 'GO:0005006', ('292', '296'))	('Brusatol', 'Chemical', 'MESH:C020237', (55, 63))	('deregulation', 'Var', (203, 215))	('tumor', 'Disease', (150, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('127', '145'))	('patients', 'Species', '9606', (325, 333))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (319, 324))	('NRF2', 'Gene', (24, 28))	('rat', 'Species', '10116', (139, 142))	('EGFR', 'Gene', (292, 296))	('tumor', 'Disease', 'MESH:D009369', (150, 155))
22371	31097977	Here, the authors demonstrated that Icotinib and Gefitinib triggered apoptosis in EGFR mutant HCC827 but not in EGFR wild-type A549 NSCLC cells without inducing protective autophagy.	('Icotinib', 'Chemical', 'MESH:C531470', (36, 44))	('EGFR', 'molecular_function', 'GO:0005006', ('112', '116'))	('autophagy', 'biological_process', 'GO:0016236', ('172', '181'))	('apoptosis', 'CPA', (69, 78))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('apoptosis', 'biological_process', 'GO:0097194', ('69', '78'))	('EGFR', 'Gene', (82, 86))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('apoptosis', 'biological_process', 'GO:0006915', ('69', '78'))	('autophagy', 'biological_process', 'GO:0006914', ('172', '181'))	('HCC827', 'Gene', (94, 100))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('Gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('EGFR', 'Gene', (112, 116))	('EGFR', 'molecular_function', 'GO:0005006', ('82', '86'))	('mutant', 'Var', (87, 93))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', '1956', (82, 86))	('triggered', 'Reg', (59, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('rat', 'Species', '10116', (25, 28))	('EGFR', 'Gene', '1956', (112, 116))
22372	31097977	Moreover, suppression of the NRF2 activity with the inhibitor Brusatol significantly reduced the cell survival of A549 cells, without further sensitizing them to EGFR TKI-induced cell death, suggesting that suppression of NRF2 can be used to induce autophagy-independent cell death in NSCLC tumors.	('activity', 'MPA', (34, 42))	('suppression', 'NegReg', (10, 21))	('EGFR', 'Gene', (162, 166))	('autophagy-independent cell', 'CPA', (249, 275))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('autophagy', 'biological_process', 'GO:0016236', ('249', '258'))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('cell death', 'biological_process', 'GO:0008219', ('271', '281'))	('cell survival', 'CPA', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('autophagy', 'biological_process', 'GO:0006914', ('249', '258'))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))	('suppression', 'Var', (207, 218))	('NSCLC tumors', 'Disease', (285, 297))	('induce', 'PosReg', (242, 248))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'molecular_function', 'GO:0005006', ('162', '166'))	('reduced', 'NegReg', (85, 92))	('NRF2', 'Protein', (29, 33))	('cell death', 'biological_process', 'GO:0008219', ('179', '189'))	('Brusatol', 'Chemical', 'MESH:C020237', (62, 70))	('NRF2', 'Gene', (222, 226))	('NSCLC tumors', 'Disease', 'MESH:D009369', (285, 297))
22376	31097977	Surprisingly, the synergistic combination of the drugs was found to decrease the transcriptional activity of NRF2, inducing oxidative stress-dependent cell death in MDA-MB-231 and MDA-MB-436 breast cancer cells by strongly depleting the intracellular levels of GSH and NADPH, observations further confirmed in human xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('GSH', 'Chemical', 'MESH:D005978', (261, 264))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (165, 175))	('intracellular', 'cellular_component', 'GO:0005622', ('237', '250'))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (180, 190))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('intracellular levels of GSH', 'MPA', (237, 264))	('decrease', 'NegReg', (68, 76))	('human', 'Species', '9606', (310, 315))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('transcriptional activity', 'MPA', (81, 105))	('drugs', 'Var', (49, 54))	('oxidative stress-dependent', 'MPA', (124, 150))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('xenograft tumors', 'Disease', (316, 332))	('NADPH', 'Chemical', 'MESH:D009249', (269, 274))	('depleting', 'NegReg', (223, 232))	('xenograft tumors', 'Disease', 'MESH:D009369', (316, 332))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('inducing', 'Reg', (115, 123))	('NRF2', 'Gene', (109, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
22379	31097977	Another recent study investigated the anticancer effects of CP-673451, a selective PDGFRbeta inhibitor, in models of NSCLC.	('NSCLC', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('PDGFRbeta', 'Gene', '5156', (83, 92))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('CP-673451', 'Chemical', '-', (60, 69))	('PDGFRbeta', 'Gene', (83, 92))	('CP-673451', 'Var', (60, 69))
22380	31097977	Here, CP-673451 was found to suppress NRF2 expression and promote a significant increase in cell apoptosis, accompanied by ROS accumulation in A549 and H358 NSCLC cell lines that was further exacerbated by the coadministration of Cisplatin.	('NRF2', 'Gene', (38, 42))	('increase', 'PosReg', (80, 88))	('NSCLC', 'Disease', (157, 162))	('A549', 'CellLine', 'CVCL:0023', (143, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('rat', 'Species', '10116', (220, 223))	('CP-673451', 'Var', (6, 15))	('accumulation', 'PosReg', (127, 139))	('ROS', 'MPA', (123, 126))	('H358', 'CellLine', 'CVCL:1559', (152, 156))	('CP-673451', 'Chemical', '-', (6, 15))	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('apoptosis', 'biological_process', 'GO:0097194', ('97', '106'))	('cell apoptosis', 'CPA', (92, 106))	('suppress', 'NegReg', (29, 37))	('apoptosis', 'biological_process', 'GO:0006915', ('97', '106'))	('Cisplatin', 'Chemical', 'MESH:D002945', (230, 239))	('expression', 'MPA', (43, 53))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
22389	31097977	Apart from the use of chemical compounds with inhibitory effects, genetic inactivation of NRF2 by RNA interference is also a promising strategy to selectively impair NRF2 activity and overcome chemoresistance.	('chemoresistance', 'CPA', (193, 208))	('RNA', 'cellular_component', 'GO:0005562', ('98', '101'))	('NRF2', 'Gene', (90, 94))	('overcome', 'PosReg', (184, 192))	('rat', 'Species', '10116', (137, 140))	('RNA interference', 'MPA', (98, 114))	('impair', 'NegReg', (159, 165))	('NRF2', 'Protein', (166, 170))	('genetic inactivation', 'Var', (66, 86))	('RNA interference', 'biological_process', 'GO:0016246', ('98', '114'))	('activity', 'MPA', (171, 179))
22393	31097977	In another study, MDA-MB-231 breast carcinoma cells with stable NRF2 knockdown displayed enhanced sensitivity to photodynamic therapy (PDT) due to increased ROS levels.	('sensitivity', 'MPA', (98, 109))	('ROS', 'Chemical', 'MESH:D017382', (157, 160))	('increased', 'PosReg', (147, 156))	('enhanced', 'PosReg', (89, 97))	('breast carcinoma', 'Phenotype', 'HP:0003002', (29, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('NRF2', 'Gene', (64, 68))	('increased ROS levels', 'Phenotype', 'HP:0025464', (147, 167))	('knockdown', 'Var', (69, 78))	('breast carcinoma', 'Disease', 'MESH:D001943', (29, 45))	('breast carcinoma', 'Disease', (29, 45))	('ROS levels', 'MPA', (157, 167))
22394	31097977	Importantly, these observations were also confirmed in breast MCF-7, colon HCT116, renal A498 carcinoma, and glioblastoma A172 cells, indicating that genetic ablation of NRF2 might potentially increase the efficacy of PDT in malignant tumors of different origin by altered redox homeostasis and cytotoxic ROS accumulation.	('genetic ablation', 'Var', (150, 166))	('malignant tumors', 'Disease', (225, 241))	('malignant tumors', 'Disease', 'MESH:D009369', (225, 241))	('glioblastoma', 'Disease', (109, 121))	('PDT', 'CPA', (218, 221))	('increase', 'PosReg', (193, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('altered', 'Reg', (265, 272))	('redox homeostasis', 'MPA', (273, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('homeostasis', 'biological_process', 'GO:0042592', ('279', '290'))	('NRF2', 'Gene', (170, 174))	('breast MCF-7, colon HCT116, renal A498 carcinoma', 'Disease', 'MESH:D001943', (55, 103))	('efficacy', 'MPA', (206, 214))	('ROS', 'Chemical', 'MESH:D017382', (305, 308))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
22396	31097977	Interestingly, knockdown of AATBCC by siRNAs was able to downregulate NRF2 protein levels and increase the sensitivity of UM-UC-3 and EJ bladder cancer cells to Cisplatin.	('AATBC', 'Gene', (28, 33))	('knockdown', 'Var', (15, 24))	('downregulate', 'NegReg', (57, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('increase', 'PosReg', (94, 102))	('protein levels', 'MPA', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EJ', 'CellLine', 'CVCL:7039', (134, 136))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('sensitivity', 'MPA', (107, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('NRF2', 'Protein', (70, 74))	('Cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('bladder cancer', 'Disease', (137, 151))	('AATBC', 'Gene', '284837', (28, 33))
22397	31097977	Also, it has been proposed that the use of NRF2 siRNAs might have a therapeutic relevance in the treatment of laryngeal squamous cancer, since Hep-2 cells refractory to Cisplatin due to high levels of the antioxidant enzyme HO-1 were found to be strongly sensitized by NRF2 knockdown and subsequent ROS elevation.	('HO-1', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('laryngeal squamous cancer', 'Phenotype', 'HP:0012118', (110, 135))	('HO-1', 'Gene', '3162', (224, 228))	('laryngeal squamous cancer', 'Disease', 'MESH:D007822', (110, 135))	('Cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('ROS', 'Chemical', 'MESH:D017382', (299, 302))	('NRF2', 'Gene', (269, 273))	('ROS', 'Gene', (299, 302))	('Hep-2', 'CellLine', 'CVCL:1906', (143, 148))	('knockdown', 'Var', (274, 283))	('squamous cancer', 'Phenotype', 'HP:0002860', (120, 135))	('elevation', 'PosReg', (303, 312))	('laryngeal squamous cancer', 'Disease', (110, 135))	('ROS elevation', 'Phenotype', 'HP:0025464', (299, 312))	('sensitized', 'PosReg', (255, 265))
22398	31097977	Lastly, siRNAs against NRF2 were found to enhance the cytotoxicity of Cisplatin in human cholangiocarcinoma KKU-100 cells, further elevating the production of ROS normally induced by the single administration of various anticancer drugs.	('ROS', 'MPA', (159, 162))	('ROS', 'Chemical', 'MESH:D017382', (159, 162))	('siRNAs', 'Var', (8, 14))	('cancer', 'Disease', (224, 230))	('Cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('elevating', 'PosReg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (89, 107))	('cholangiocarcinoma KKU-100', 'Disease', 'MESH:D018281', (89, 115))	('cytotoxicity', 'Disease', (54, 66))	('cholangiocarcinoma KKU-100', 'Disease', (89, 115))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('rat', 'Species', '10116', (202, 205))	('enhance', 'PosReg', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('human', 'Species', '9606', (83, 88))	('production', 'MPA', (145, 155))	('NRF2', 'Gene', (23, 27))
22401	31097977	In this regard, an earlier study reported that high levels of NRF2 were associated to Cisplatin and Paclitaxel resistance in endometrial serous carcinoma (ESC).	('Cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('endometrial serous carcinoma', 'Disease', (125, 153))	('endometrial serous carcinoma', 'Disease', 'MESH:D016889', (125, 153))	('NRF2', 'Gene', (62, 66))	('Paclitaxel', 'Chemical', 'MESH:D017239', (100, 110))	('associated', 'Reg', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('high levels', 'Var', (47, 58))
22405	31097977	identified K67, a small noncovalent inhibitor of phospho-p62/KEAP1 interaction, as a molecule capable of restoring the main route of NRF2 degradation in human HCC lines.	('K67', 'Var', (11, 14))	('degradation', 'biological_process', 'GO:0009056', ('138', '149'))	('K67', 'Chemical', '-', (11, 14))	('restoring', 'PosReg', (105, 114))	('human', 'Species', '9606', (153, 158))	('main route of NRF2 degradation', 'MPA', (119, 149))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
22406	31097977	Importantly, K67 exerted also antineoplastic effects in several HCC cell lines by decreasing proliferation and enhancing the cytotoxicity of either Sorafenib or Cisplatin, confirming that this inhibitor might be exploited to treat HCC cancers with p62-dependent NRF2 hyperactivation.	('Sorafenib', 'Chemical', 'MESH:D000077157', (148, 157))	('K67', 'Var', (13, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('HCC', 'Disease', (231, 234))	('K67', 'Chemical', '-', (13, 16))	('proliferation', 'CPA', (93, 106))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('cancers', 'Disease', (235, 242))	('decreasing', 'NegReg', (82, 92))	('enhancing', 'PosReg', (111, 120))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('Cisplatin', 'Chemical', 'MESH:D002945', (161, 170))	('cytotoxicity', 'Disease', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('rat', 'Species', '10116', (100, 103))
22407	31097977	However, due to K67 low solubility, the authors proposed that changes in its chemical structure would have been required before performing any clinical study.	('K67', 'Var', (16, 19))	('K67', 'Chemical', '-', (16, 19))	('solubility', 'MPA', (24, 34))
22410	31097977	Here, by using therapy-resistant HCC BEL-7402/5-FU cells, the authors showed that DMC promoted a significant increase in the KEAP1 protein levels, preventing NRF2 nuclear translocation and subsequent target gene transactivation.	('BEL-7402', 'CellLine', 'CVCL:5492', (37, 45))	('KEAP1 protein levels', 'MPA', (125, 145))	('NRF2', 'Protein', (158, 162))	('increase', 'PosReg', (109, 117))	('DMC', 'Chemical', 'MESH:C501649', (82, 85))	('nuclear translocation', 'MPA', (163, 184))	('protein', 'cellular_component', 'GO:0003675', ('131', '138'))	('HCC', 'Phenotype', 'HP:0001402', (33, 36))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('transactivation', 'MPA', (212, 227))	('transactivation', 'biological_process', 'GO:2000144', ('212', '227'))	('preventing', 'NegReg', (147, 157))	('DMC', 'Var', (82, 85))
22419	31097977	Other experimental work from the group of Furfaro focused on malignant neuroblastoma, wherein the activation of NRF2 has been proposed to promote resistance to proteasome inhibitors such as Bortezomib (BTZ).	('proteasome', 'molecular_function', 'GO:0004299', ('160', '170'))	('neuroblastoma', 'Disease', 'MESH:D009447', (71, 84))	('BTZ', 'Chemical', 'MESH:D000069286', (202, 205))	('resistance to', 'MPA', (146, 159))	('neuroblastoma', 'Disease', (71, 84))	('malignant neuroblastoma', 'Phenotype', 'HP:0100697', (61, 84))	('Furfaro', 'Chemical', '-', (42, 49))	('promote', 'PosReg', (138, 145))	('neuroblastoma', 'Phenotype', 'HP:0003006', (71, 84))	('proteasome', 'cellular_component', 'GO:0000502', ('160', '170'))	('Bortezomib', 'Chemical', 'MESH:D000069286', (190, 200))	('activation', 'Var', (98, 108))	('NRF2', 'Gene', (112, 116))	('lignan', 'Chemical', 'MESH:D017705', (63, 69))
22424	31097977	investigated the potential role of NRF2 signaling in CSC-like properties of ovarian CSCs exhibiting high enzymatic activity of aldehyde dehydrogenase1 (ALDH1) and high expression levels of p62, a hallmark associated also to aggressive behavior and drug resistance.	('drug resistance', 'biological_process', 'GO:0042493', ('248', '263'))	('aggressive behavior', 'biological_process', 'GO:0002118', ('224', '243'))	('expression levels', 'MPA', (168, 185))	('ALDH1', 'Gene', (152, 157))	('p62', 'Var', (189, 192))	('ALDH1', 'Gene', '216', (152, 157))	('drug resistance', 'Phenotype', 'HP:0020174', (248, 263))	('ovarian', 'Disease', (76, 83))	('ALDH', 'molecular_function', 'GO:0004030', ('152', '156'))	('signaling', 'biological_process', 'GO:0023052', ('40', '49'))	('ovarian', 'Disease', 'MESH:D010049', (76, 83))	('drug resistance', 'biological_process', 'GO:0009315', ('248', '263'))	('aggressive behavior', 'Phenotype', 'HP:0000718', (224, 243))
22426	31097977	Among these features, chemoresistance, colony/sphere formation, tumor growth, and the expression of CSC markers were strongly abrogated, an effect that was also produced by NRF2 silencing (see Table 2).	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('colony/sphere formation', 'CPA', (39, 62))	('tumor', 'Disease', (64, 69))	('chemoresistance', 'CPA', (22, 37))	('NRF2', 'Gene', (173, 177))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('abrogated', 'NegReg', (126, 135))	('silencing', 'Var', (178, 187))	('formation', 'biological_process', 'GO:0009058', ('53', '62'))	('CSC markers', 'Gene', (100, 111))
22429	31097977	In another context, by screening a collection of 5879 known bioactive compounds and FDA-approved drugs in HepG2, Liu and coworkers demonstrated that the CDC7/CDK9 inhibitor PHA-767491 was also a potent suppressor of NRF2 transcriptional activity.	('NRF2', 'Gene', (216, 220))	('rat', 'Species', '10116', (138, 141))	('PHA-767491', 'Var', (173, 183))	('CDC7', 'Gene', (153, 157))	('CDK', 'molecular_function', 'GO:0004693', ('158', '161'))	('suppressor', 'NegReg', (202, 212))	('HepG2', 'CellLine', 'CVCL:0027', (106, 111))	('CDC7', 'Gene', '8317', (153, 157))	('CDK9', 'Gene', (158, 162))	('transcriptional activity', 'MPA', (221, 245))	('CDK9', 'Gene', '1025', (158, 162))
22430	31097977	Validation assays performed in MM cells confirmed that PHA-767491 prevented NRF2 nuclear translocation, increased the mitochondrial superoxide generation, and suppressed cell growth (see Table 2).	('PHA-767491', 'Var', (55, 65))	('cell growth', 'CPA', (170, 181))	('increased', 'PosReg', (104, 113))	('superoxide', 'Chemical', 'MESH:D013481', (132, 142))	('NRF2', 'Gene', (76, 80))	('nuclear translocation', 'CPA', (81, 102))	('mitochondrial superoxide generation', 'MPA', (118, 153))	('prevented', 'NegReg', (66, 75))	('rat', 'Species', '10116', (147, 150))	('suppressed', 'NegReg', (159, 169))	('cell growth', 'biological_process', 'GO:0016049', ('170', '181'))
22435	31097977	However, this indicates that NRF2 inhibitors might effectively increase the efficacy of many chemotherapeutics in HCC patients (see Table 2).	('increase', 'PosReg', (63, 71))	('efficacy', 'MPA', (76, 84))	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('inhibitors', 'Var', (34, 44))	('NRF2', 'Gene', (29, 33))	('HCC', 'Disease', (114, 117))	('patients', 'Species', '9606', (118, 126))
22441	31097977	Mechanistically, CP was found to prevent NRF2 nuclear accumulation and promote its degradation through the beta-TrCP-dependent pathway, leading to ROS accumulation and marked suppression of anchorage-independent growth in several NSCLC cell lines with mutant KEAP1.	('NRF2', 'Gene', (41, 45))	('prevent', 'NegReg', (33, 40))	('promote', 'PosReg', (71, 78))	('degradation', 'MPA', (83, 94))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('accumulation', 'PosReg', (151, 163))	('nuclear accumulation', 'MPA', (46, 66))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('anchorage-independent growth', 'CPA', (190, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('beta-TrCP', 'Gene', (107, 116))	('beta-TrCP', 'Gene', '8945', (107, 116))	('mutant', 'Var', (252, 258))	('degradation', 'biological_process', 'GO:0009056', ('83', '94'))	('ROS', 'MPA', (147, 150))	('NSCLC', 'Disease', (230, 235))	('suppression', 'NegReg', (175, 186))
22442	31097977	Moreover, when used alone or in combination with Rapamycin in vitro or in vivo, CP impaired the growth of tumors harboring KEAP1 or both KEAP1/LKB1 mutations, a frequent event in lung cancer.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('mutations', 'Var', (148, 157))	('LKB1', 'Gene', '6794', (143, 147))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CP impaired the growth of tumors', 'Disease', (80, 112))	('CP impaired the growth of tumors', 'Disease', 'MESH:D006130', (80, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('LKB1', 'Gene', (143, 147))
22443	31097977	Therefore, CP could be a repurposed therapeutic agent for tumors with high NRF2 activity while the combined use of CP and Rapamycin might be a valid clinical approach in tumors with KEAP1 and LKB1 mutations (see Table 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('LKB1', 'Gene', (192, 196))	('Rapamycin', 'Chemical', 'MESH:D020123', (122, 131))	('tumors', 'Disease', (58, 64))	('LKB1', 'Gene', '6794', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('NRF2', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (197, 206))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('activity', 'MPA', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))
22455	31097977	In this regard, earlier studies reported that Metformin inhibited proliferation in several cancer cell lines by suppressing HO-1 expression through the inhibition of a RAF/ERK/NRF2 signaling and AMPK-independent pathways that promoted a marked decrease in the NRF2 protein content.	('inhibition', 'NegReg', (152, 162))	('decrease', 'NegReg', (244, 252))	('AMPK', 'Gene', (195, 199))	('NRF2 protein content', 'MPA', (260, 280))	('protein', 'cellular_component', 'GO:0003675', ('265', '272'))	('AMPK', 'molecular_function', 'GO:0004691', ('195', '199'))	('RAF', 'Gene', (168, 171))	('expression', 'MPA', (129, 139))	('Metformin', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Metformin', 'Chemical', 'MESH:D008687', (46, 55))	('ERK', 'molecular_function', 'GO:0004707', ('172', '175'))	('AMPK', 'molecular_function', 'GO:0047322', ('195', '199'))	('HO-1', 'Gene', '3162', (124, 128))	('AMPK', 'Gene', '5562', (195, 199))	('inhibited', 'NegReg', (56, 65))	('AMPK', 'molecular_function', 'GO:0050405', ('195', '199'))	('HO-1', 'Gene', (124, 128))	('cancer', 'Disease', (91, 97))	('proliferation', 'CPA', (66, 79))	('suppressing', 'NegReg', (112, 123))	('signaling', 'biological_process', 'GO:0023052', ('181', '190'))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('RAF', 'Gene', '22882', (168, 171))	('rat', 'Species', '10116', (73, 76))
22464	31097977	Here, Metformin was shown to exert antineoplastic effects by inhibiting cell proliferation and enhancing apoptotic cell death in HT29 CRC cell lines, as a consequence of the transcriptional inactivation produced on NRF2 and NF-kappaB (see Table 2).	('HT29 CRC', 'CellLine', 'CVCL:8478', (129, 137))	('apoptotic cell death', 'CPA', (105, 125))	('inhibiting', 'NegReg', (61, 71))	('CRC', 'Phenotype', 'HP:0003003', (134, 137))	('apoptotic cell death', 'biological_process', 'GO:0006915', ('105', '125'))	('enhancing', 'PosReg', (95, 104))	('cell proliferation', 'biological_process', 'GO:0008283', ('72', '90'))	('rat', 'Species', '10116', (84, 87))	('NRF2', 'Gene', (215, 219))	('cell proliferation', 'CPA', (72, 90))	('NF-kappaB', 'Protein', (224, 233))	('Metformin', 'Var', (6, 15))	('transcriptional', 'MPA', (174, 189))	('CRC', 'Phenotype', 'HP:0030731', (134, 137))	('Metformin', 'Chemical', 'MESH:D008687', (6, 15))
22465	31097977	Also, additional research from Yu and coworkers demonstrated that Metformin was able to sensitize A549 NSCLC cells but not normal lung epithelial BEAS-2B cells, to the natural compound EGCG by inducing ROS-dependent apoptosis.	('Metformin', 'Var', (66, 75))	('Metformin', 'Chemical', 'MESH:D008687', (66, 75))	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('inducing', 'PosReg', (193, 201))	('NSCLC', 'Disease', (103, 108))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('apoptosis', 'biological_process', 'GO:0097194', ('216', '225'))	('apoptosis', 'biological_process', 'GO:0006915', ('216', '225'))	('EGCG', 'Chemical', 'MESH:C045651', (185, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('BEAS-2B', 'CellLine', 'CVCL:0168', (146, 153))	('rat', 'Species', '10116', (55, 58))	('ROS-dependent apoptosis', 'CPA', (202, 225))
22470	31097977	Interestingly, the antitubercular agent Isoniazid (INH) known to induce hepatotoxicity in patients subdued to long-term treatment was found to induce ROS accumulation and apoptosis in HepG2 HCC and in transformed human liver THLE-2 cells, by preventing NRF2 nuclear translocation due to the inhibition of its importer Karyopherin beta1 (see Table 2).	('hepatotoxicity', 'Disease', (72, 86))	('THLE-2', 'CellLine', 'CVCL:3803', (225, 231))	('ROS', 'MPA', (150, 153))	('importer', 'MPA', (309, 317))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('nuclear translocation', 'MPA', (258, 279))	('accumulation', 'PosReg', (154, 166))	('preventing', 'NegReg', (242, 252))	('apoptosis', 'CPA', (171, 180))	('HCC', 'Phenotype', 'HP:0001402', (190, 193))	('inhibition', 'NegReg', (291, 301))	('Isoniazid', 'Var', (40, 49))	('hepatotoxicity', 'Disease', 'MESH:D056486', (72, 86))	('Isoniazid', 'Chemical', 'MESH:D007538', (40, 49))	('NRF2', 'Protein', (253, 257))	('human', 'Species', '9606', (213, 218))	('induce', 'PosReg', (143, 149))	('Karyopherin beta1', 'cellular_component', 'GO:0005648', ('318', '335'))	('patients', 'Species', '9606', (90, 98))	('apoptosis', 'biological_process', 'GO:0097194', ('171', '180'))	('apoptosis', 'biological_process', 'GO:0006915', ('171', '180'))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (184, 193))
22475	31097977	Of note, given the functional location of NRF2 at the crossroad of multiple pathways, pharmacologic manipulations of upstream regulators or downstream effectors of NRF2 signaling might also produce remarkable anticancer effects and synergize with already established drugs through mechanisms that almost invariantly converge on the disruption of the intracellular redox homeostasis.	('NRF2', 'Gene', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('NRF2', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('intracellular', 'cellular_component', 'GO:0005622', ('350', '363'))	('pharmacologic', 'Var', (86, 99))	('cancer', 'Disease', (213, 219))	('homeostasis', 'biological_process', 'GO:0042592', ('370', '381'))
22536	25465300	Loss of PBRM1 and BAP1 Expression Is Less Common in Non-Clear Cell Renal Cell Carcinoma Than in Clear Cell Renal Cell Carcinoma Recurrent mutations in polybromo-1 (PBRM1, ~40%) and BRCA1-associated protein-1 (BAP1, ~10%) occur in clear cell renal cell carcinoma (ccRCC), but their prevalence in non clear cell renal cell carcinoma (non-ccRCC) or renal oncocytoma (RO) is unknown.	('RCC', 'Phenotype', 'HP:0005584', (338, 341))	('BAP1', 'Gene', (209, 213))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (299, 330))	('ccRCC', 'Phenotype', 'HP:0006770', (336, 341))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (96, 127))	('BAP1', 'Gene', (18, 22))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (56, 87))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (230, 261))	('renal oncocytoma', 'Disease', (346, 362))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (241, 261))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('polybromo-1', 'Gene', '55193', (151, 162))	('RCC', 'Disease', (265, 268))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (52, 87))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))	('RCC', 'Disease', 'MESH:C538614', (338, 341))	('RO', 'Phenotype', 'HP:0011798', (364, 366))	('PBRM1', 'Gene', '55193', (8, 13))	('-Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (55, 87))	('clear cell renal cell carcinoma', 'Disease', (230, 261))	('BRCA1-associated protein-1', 'Gene', '8314', (181, 207))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('PBRM1', 'Gene', (8, 13))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (299, 330))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (96, 127))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (56, 87))	('polybromo-1', 'Gene', (151, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('renal oncocytoma', 'Disease', 'MESH:C537750', (346, 362))	('BRCA1-associated protein-1', 'Gene', (181, 207))	('PBRM1', 'Gene', '55193', (164, 169))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (346, 362))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('BAP1', 'Gene', '8314', (209, 213))	('mutations', 'Var', (138, 147))	('Non-Clear Cell Renal Cell Carcinoma', 'Disease', (52, 87))	('clear cell renal cell carcinoma', 'Disease', (299, 330))	('BAP1', 'Gene', '8314', (18, 22))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (230, 261))	('PBRM1', 'Gene', (164, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (310, 330))	('Clear Cell Renal Cell Carcinoma', 'Disease', (96, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('RCC', 'Disease', (338, 341))
22537	25465300	We evaluated loss of PBRM1 and BAP1 staining in ccRCC, papillary RCC (pRCC), chromophobe RCC (chRCC) and RO tumors using an immunohistochemistry (IHC) assay for which negative staining associates with loss-of-function mutations.	('loss-of-function', 'NegReg', (201, 217))	('BAP1', 'Gene', '8314', (31, 35))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', (89, 92))	('chromophobe RCC', 'Disease', 'MESH:C538614', (77, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', (65, 68))	('RCC', 'Disease', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('pRCC', 'Gene', '5546', (70, 74))	('RCC', 'Disease', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('PBRM1', 'Gene', '55193', (21, 26))	('BAP1', 'Gene', (31, 35))	('tumors', 'Disease', (108, 114))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RO', 'Phenotype', 'HP:0011798', (105, 107))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('chromophobe RCC', 'Disease', (77, 92))	('mutations', 'Var', (218, 227))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('PBRM1', 'Gene', (21, 26))	('papillary RCC', 'Disease', 'MESH:C538614', (55, 68))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('pRCC', 'Gene', (70, 74))	('papillary RCC', 'Disease', (55, 68))	('loss', 'NegReg', (13, 17))
22545	25465300	Our data suggest that biallelic inactivation of PBRM1 or BAP1 is less common in non-ccRCC when compared to ccRCC tumors.	('common', 'Reg', (70, 76))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('PBRM1', 'Gene', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('BAP1', 'Gene', '8314', (57, 61))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('biallelic inactivation', 'Var', (22, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('PBRM1', 'Gene', '55193', (48, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('BAP1', 'Gene', (57, 61))	('RCC', 'Disease', (86, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
22546	25465300	These findings suggest that loss of PBRM1 or BAP1 are key events in ccRCC, whereas other pathways may support tumorigenesis in non-ccRCC subtypes.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('loss', 'Var', (28, 32))	('RCC', 'Disease', (70, 73))	('PBRM1', 'Gene', (36, 41))	('BAP1', 'Gene', (45, 49))	('PBRM1', 'Gene', '55193', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('support', 'PosReg', (102, 109))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (131, 136))	('BAP1', 'Gene', '8314', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
22553	25465300	Specifically, several investigators have reported that loss-of-function mutations in chromatin-modifying enzymes, such as polybromo-1 (PBRM1 [~40%]), BRCA1-associated protein-1 (BAP1 [~10%]), and SET domain containing protein-2 (SETD2 [~12%]) are common events in ccRCC tumors.	('BAP1', 'Gene', (178, 182))	('RCC', 'Disease', (266, 269))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('ccRCC', 'Phenotype', 'HP:0006770', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('PBRM1', 'Gene', '55193', (135, 140))	('mutations', 'Var', (72, 81))	('tumors', 'Disease', (270, 276))	('polybromo-1', 'Gene', (122, 133))	('protein', 'cellular_component', 'GO:0003675', ('167', '174'))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('PBRM1', 'Gene', (135, 140))	('BRCA1-associated protein-1', 'Gene', '8314', (150, 176))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('SETD2', 'Gene', (229, 234))	('BRCA1-associated protein-1', 'Gene', (150, 176))	('loss-of-function', 'NegReg', (55, 71))	('BAP1', 'Gene', '8314', (178, 182))	('SETD2', 'Gene', '29072', (229, 234))	('protein', 'cellular_component', 'GO:0003675', ('218', '225'))	('chromatin', 'cellular_component', 'GO:0000785', ('85', '94'))	('polybromo-1', 'Gene', '55193', (122, 133))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
22559	25465300	We previously validated IHC assays to evaluate PBRM1 and BAP1 protein expression in which negative staining associates with PBRM1 and BAP1 mutant genotypes.	('PBRM1', 'Gene', (47, 52))	('BAP1', 'Gene', (134, 138))	('PBRM1', 'Gene', '55193', (47, 52))	('mutant', 'Var', (139, 145))	('BAP1', 'Gene', '8314', (57, 61))	('PBRM1', 'Gene', (124, 129))	('BAP1', 'Gene', '8314', (134, 138))	('BAP1', 'Gene', (57, 61))	('PBRM1', 'Gene', '55193', (124, 129))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
22560	25465300	Sanger sequencing confirmed mutations in 90% of PBRM1 IHC negative and 95% of BAP1 IHC negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('PBRM1', 'Gene', (48, 53))	('negative', 'NegReg', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('BAP1', 'Gene', '8314', (78, 82))	('PBRM1', 'Gene', '55193', (48, 53))	('mutations', 'Var', (28, 37))	('BAP1', 'Gene', (78, 82))
22570	25465300	We previously validated IHC assays with Sanger sequencing to evaluate PBRM1 and BAP1 protein expression in which negative nuclear staining associates with PBRM1 and BAP1 mutations.	('BAP1', 'Gene', (165, 169))	('mutations', 'Var', (170, 179))	('BAP1', 'Gene', '8314', (80, 84))	('PBRM1', 'Gene', (70, 75))	('PBRM1', 'Gene', (155, 160))	('BAP1', 'Gene', (80, 84))	('PBRM1', 'Gene', '55193', (155, 160))	('BAP1', 'Gene', '8314', (165, 169))	('PBRM1', 'Gene', '55193', (70, 75))	('protein', 'cellular_component', 'GO:0003675', ('85', '92'))
22582	25465300	Although recurrent mutations are observed in chromatin-modifying enzymes in ccRCC, there are no data regarding expression in pRCC, chRCC or RO.	('chromatin-modifying enzymes', 'Enzyme', (45, 72))	('pRCC', 'Gene', '5546', (125, 129))	('mutations', 'Var', (19, 28))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('pRCC', 'Gene', (125, 129))	('RCC', 'Disease', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('chromatin', 'cellular_component', 'GO:0000785', ('45', '54'))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('RO', 'Phenotype', 'HP:0011798', (140, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
22583	25465300	We evaluated loss of PBRM1 and BAP1 staining in ccRCC, pRCC, chRCC and RO tumors using an IHC assay for which negative staining associates with loss-of-function mutations.	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('pRCC', 'Gene', '5546', (55, 59))	('BAP1', 'Gene', '8314', (31, 35))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('tumors', 'Disease', (74, 80))	('RCC', 'Disease', (50, 53))	('loss-of-function', 'NegReg', (144, 160))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('PBRM1', 'Gene', '55193', (21, 26))	('BAP1', 'Gene', (31, 35))	('pRCC', 'Gene', (55, 59))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', (63, 66))	('RCC', 'Disease', (56, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('PBRM1', 'Gene', (21, 26))	('RO', 'Phenotype', 'HP:0011798', (71, 73))	('mutations', 'Var', (161, 170))	('loss', 'NegReg', (13, 17))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
22584	25465300	Our data are the first to suggest that biallelic inactivation of PBRM1 and BAP1 are less common in pRCC, chRCC and RO tumors than in ccRCC tumors.	('BAP1', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('PBRM1', 'Gene', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('RCC', 'Disease', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('pRCC', 'Gene', (99, 103))	('biallelic inactivation', 'Var', (39, 61))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (118, 124))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('RO', 'Phenotype', 'HP:0011798', (115, 117))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('BAP1', 'Gene', '8314', (75, 79))	('common', 'Reg', (89, 95))	('less', 'NegReg', (84, 88))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', (135, 138))	('PBRM1', 'Gene', '55193', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
22585	25465300	Phylogenetic trees generated by multiregion sequencing of ccRCC tumors identified intratumor heterogeneity for PBRM1 and BAP1 mutations.	('tumors', 'Disease', (64, 70))	('BAP1', 'Gene', '8314', (121, 125))	('tumor', 'Disease', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('RCC', 'Disease', (60, 63))	('BAP1', 'Gene', (121, 125))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (126, 135))	('PBRM1', 'Gene', (111, 116))	('PBRM1', 'Gene', '55193', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
22589	25465300	To date, we have not evaluated the association of weak positive PBRM1 staining with risk of cancer specific death in any RCC subtypes.	('weak positive', 'Var', (50, 63))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('PBRM1', 'Gene', (64, 69))	('PBRM1', 'Gene', '55193', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
22595	25465300	Similarly, our IHC data suggest that loss of BAP1 staining could potentially discriminate ccRCC tumors from pRCC or chRCC tumors.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('BAP1', 'Gene', '8314', (45, 49))	('discriminate', 'Reg', (77, 89))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('loss', 'Var', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('BAP1', 'Gene', (45, 49))	('pRCC', 'Gene', '5546', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (122, 128))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('pRCC', 'Gene', (108, 112))
22603	25465300	Similarly, BAP1 mutations have been detected in 10% of ccRCC tumors, whereas we did not observe loss of BAP1 staining in our pRCC, chRCC, or RO tumors.	('tumors', 'Disease', (144, 150))	('RO', 'Phenotype', 'HP:0011798', (141, 143))	('detected', 'Reg', (36, 44))	('BAP1', 'Gene', (104, 108))	('BAP1', 'Gene', (11, 15))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (61, 67))	('pRCC', 'Gene', '5546', (125, 129))	('RCC', 'Disease', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (57, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('BAP1', 'Gene', '8314', (104, 108))	('BAP1', 'Gene', '8314', (11, 15))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('pRCC', 'Gene', (125, 129))	('RCC', 'Disease', (133, 136))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
22604	25465300	The 4 most common mutations (VHL, PBRM1, SETD2, and BAP1) in ccRCC are located on a region of chromosome 3p that is deleted in more than 90% of ccRCCs, supporting a model that leads to biallelic inactivation (concurrent copy number loss and mutation) of these genes.	('PBRM1', 'Gene', (34, 39))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('chromosome', 'cellular_component', 'GO:0005694', ('94', '104'))	('mutation', 'Var', (241, 249))	('SETD2', 'Gene', (41, 46))	('VHL', 'Disease', 'MESH:D006623', (29, 32))	('mutations', 'Var', (18, 27))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('BAP1', 'Gene', '8314', (52, 56))	('SETD2', 'Gene', '29072', (41, 46))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', (63, 66))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('PBRM1', 'Gene', '55193', (34, 39))	('BAP1', 'Gene', (52, 56))	('VHL', 'Disease', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
22611	25465300	Although our IHC assay evaluates protein expression and may not detect monoallelic mutations or copy number loss at PBRM1 and BAP1 loci, the different patterns of chromosomal aberrations from ccRCC suggest that biallelic inactivation of BAP1 and PBRM1 is less common in pRCC, chRCC and RO tumors.	('RCC', 'Disease', 'MESH:C538614', (278, 281))	('protein', 'cellular_component', 'GO:0003675', ('33', '40'))	('pRCC', 'Gene', '5546', (270, 274))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('BAP1', 'Gene', '8314', (126, 130))	('BAP1', 'Gene', '8314', (237, 241))	('PBRM1', 'Gene', '55193', (246, 251))	('ccRCC', 'Phenotype', 'HP:0006770', (192, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('RCC', 'Disease', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('pRCC', 'Gene', (270, 274))	('PBRM1', 'Gene', (246, 251))	('different patterns of chromosomal aberrations', 'Phenotype', 'HP:0040012', (141, 186))	('BAP1', 'Gene', (126, 130))	('BAP1', 'Gene', (237, 241))	('PBRM1', 'Gene', '55193', (116, 121))	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (278, 281))	('RCC', 'Disease', (278, 281))	('PBRM1', 'Gene', (116, 121))	('RO', 'Phenotype', 'HP:0011798', (286, 288))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumors', 'Disease', (289, 295))	('biallelic inactivation', 'Var', (211, 233))
22614	25465300	Consistent with our findings, whole-exome sequencing of chRCC identified recurrent mutations in TP53 (32%) and PTEN (9%).	('mutations', 'Var', (83, 92))	('PTEN', 'Gene', (111, 115))	('TP53', 'Gene', (96, 100))	('PTEN', 'Gene', '5728', (111, 115))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('TP53', 'Gene', '7157', (96, 100))
22616	25465300	Prognostic algorithms that incorporate PBRM1 or BAP1 mutations and/or loss of expression may not be applicable to pRCC and chRCC.	('PBRM1', 'Gene', '55193', (39, 44))	('BAP1', 'Gene', '8314', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('loss of expression', 'NegReg', (70, 88))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('BAP1', 'Gene', (48, 52))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('mutations', 'Var', (53, 62))	('pRCC', 'Gene', '5546', (114, 118))	('pRCC', 'Gene', (114, 118))	('PBRM1', 'Gene', (39, 44))
22630	30372395	This review will explore the major sources of metabolic impact in kidney tumors, through the classical biochemistry of cellular metabolism: highlighting features associated with the pseudohypoxia associated with clear cell renal cell carcinoma (ccRCC), disturbances of glucose regulation and glycolysis, factors influencing the Kreb's cycle in papillary renal cell carcinoma (pRCC), factors that fuel reductive carboxylation, and mitochondrial defects resulting from mutations in electron transport genes occurring in chromophobe renal cell carcinoma (chRCC).	('RCC', 'Disease', 'MESH:C538614', (554, 557))	('papillary renal cell carcinoma', 'Disease', (344, 374))	('glucose', 'Chemical', 'MESH:D005947', (269, 276))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (354, 374))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (530, 550))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (212, 243))	('pRCC', 'Phenotype', 'HP:0006766', (376, 380))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('kidney tumors', 'Disease', (66, 79))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (518, 550))	('carcinoma', 'Phenotype', 'HP:0030731', (541, 550))	('RCC', 'Disease', (377, 380))	('RCC', 'Phenotype', 'HP:0005584', (377, 380))	('pRCC', 'Gene', (376, 380))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('cellular metabolism', 'biological_process', 'GO:0044237', ('119', '138'))	('regulation', 'biological_process', 'GO:0065007', ('277', '287'))	('kidney tumors', 'Disease', 'MESH:D007680', (66, 79))	('RCC', 'Phenotype', 'HP:0005584', (247, 250))	('RCC', 'Disease', 'MESH:C538614', (377, 380))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (344, 374))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (212, 243))	('RCC', 'Disease', (247, 250))	('mutations', 'Var', (467, 476))	('ccRCC', 'Phenotype', 'HP:0006770', (245, 250))	('electron transport genes', 'Gene', (480, 504))	('chromophobe renal cell carcinoma', 'Disease', (518, 550))	('hypoxia', 'Disease', (188, 195))	('mitochondrial defects', 'Disease', (430, 451))	('mitochondrial defects', 'Disease', 'MESH:D028361', (430, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (344, 374))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('kidney tumors', 'Phenotype', 'HP:0009726', (66, 79))	('clear cell renal cell carcinoma', 'Disease', (212, 243))	('electron transport', 'biological_process', 'GO:0006118', ('480', '498'))	('RCC', 'Disease', (554, 557))	('RCC', 'Phenotype', 'HP:0005584', (554, 557))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (223, 243))	('glycolysis', 'biological_process', 'GO:0006096', ('292', '302'))	('pRCC', 'Gene', '5546', (376, 380))	('hypoxia', 'Disease', 'MESH:D000860', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))
22644	30372395	It is impossible to consider metabolism without examining the quintessential phenotype of ccRCC; dysregulation of hypoxia signaling via mutations in the VHL gene.	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('VHL', 'Gene', (153, 156))	('signaling', 'biological_process', 'GO:0023052', ('122', '131'))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('metabolism', 'biological_process', 'GO:0008152', ('29', '39'))	('mutations', 'Var', (136, 145))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('hypoxia', 'Disease', (114, 121))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('dysregulation', 'MPA', (97, 110))
22645	30372395	VHL is a key mediator of oxygen sensing, and absence or alteration of this protein is associated with stabilization of hypoxia inducible factor (HIF) family members.	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))	('stabilization', 'MPA', (102, 115))	('hypoxia', 'Disease', (119, 126))	('oxygen', 'Chemical', 'MESH:D010100', (25, 31))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('VHL', 'Gene', (0, 3))	('alteration', 'Var', (56, 66))	('absence', 'Var', (45, 52))
22648	30372395	However, with mutation (or loss) of VHL, such as in ccRCC, VHL cannot target and degrade HIF, even in normoxia, and HIF accumulates.	('degrade', 'NegReg', (81, 88))	('VHL', 'Gene', (36, 39))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('mutation', 'Var', (14, 22))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('HIF', 'MPA', (89, 92))	('loss', 'NegReg', (27, 31))
22649	30372395	HIF accumulation then activates the expression of a broad repertoire of genes involved in the hypoxic response pathway, including notable regulators of glucose uptake and glycolytic metabolism.	('accumulation', 'Var', (4, 16))	('glucose', 'Chemical', 'MESH:D005947', (152, 159))	('glucose uptake', 'biological_process', 'GO:0046323', ('152', '166'))	('activates', 'PosReg', (22, 31))	('metabolism', 'biological_process', 'GO:0008152', ('182', '192'))	('expression', 'MPA', (36, 46))
22658	30372395	The growth of VHL mutated cancer cells is dependent on HIF upregulation.	('mutated', 'Var', (18, 25))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('growth', 'MPA', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('upregulation', 'PosReg', (59, 71))	('VHL', 'Gene', (14, 17))
22661	30372395	Multiple lines of evidence implied this was a high value target for RCC: upregulation of phosphor-AKT and phosphor-S6 in a subset of poor risk tumors, mTOR functioning as a regulator of HIF translation (and as a pathway activated as a result of HIF stabilization), and as a master regulator of glycolytic activity (Figure 3).	('translation', 'biological_process', 'GO:0006412', ('190', '201'))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('phosphor-S6', 'Var', (106, 117))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('AKT', 'Gene', '207', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('RCC', 'Disease', (68, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('AKT', 'Gene', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('upregulation', 'PosReg', (73, 85))
22664	30372395	Although the demonstrated benefit of these drugs was brief, certain patients have been observed to demonstrate prolonged response, and harbor mutations in components of the overall mTOR signaling pathway, including PTEN, PIK3CA, and activating mutations in mTOR itself.	('mTOR', 'Gene', (257, 261))	('mutations', 'Var', (142, 151))	('PIK3CA', 'Gene', '5290', (221, 227))	('activating', 'Reg', (233, 243))	('signaling pathway', 'biological_process', 'GO:0007165', ('186', '203'))	('PTEN', 'Gene', (215, 219))	('patients', 'Species', '9606', (68, 76))	('PTEN', 'Gene', '5728', (215, 219))	('PIK3CA', 'Gene', (221, 227))	('mTOR', 'Gene', '2475', (181, 185))	('mTOR', 'Gene', '2475', (257, 261))	('mTOR', 'Gene', (181, 185))
22678	30372395	Type II pRCC includes a subset of tumors found to have driver mutations in the gene for the Krebs cycle enzyme, fumarate hydratase (FH), and presents with highly aggressive disease, similar to the germline syndrome of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('fumarate hydratase', 'Gene', '2271', (112, 130))	('aggressive disease', 'Disease', 'MESH:D001523', (162, 180))	('pRCC', 'Gene', '5546', (8, 12))	('FH', 'Gene', '2271', (132, 134))	('RCC', 'Phenotype', 'HP:0005584', (272, 275))	('mutations', 'Var', (62, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (248, 268))	('RCC', 'Disease', (272, 275))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('fumarate hydratase', 'Gene', (112, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('RCC', 'Disease', (9, 12))	('RCC', 'Phenotype', 'HP:0005584', (9, 12))	('pRCC', 'Phenotype', 'HP:0006766', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (272, 275))	('pRCC', 'Gene', (8, 12))	('tumors', 'Disease', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (9, 12))	('aggressive disease', 'Disease', (162, 180))	('Krebs cycle', 'biological_process', 'GO:0006099', ('92', '103'))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 268))	('Krebs', 'Chemical', '-', (92, 97))
22701	30372395	One feature of chRCC, known as the eosinophilic variant, is recurrent mutations in genes involved in electron transport housed within the mitochondrial genome (Figure 4).	('mutations', 'Var', (70, 79))	('mitochondrial genome', 'cellular_component', 'GO:0000262', ('138', '158'))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('electron transport', 'biological_process', 'GO:0006118', ('101', '119'))
22702	30372395	The effect of these mutations is an accumulation of defective mitochondria, which may be a checkpoint limiting autophagy and inhibiting tumor progression.	('mitochondria', 'CPA', (62, 74))	('autophagy', 'CPA', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('autophagy', 'biological_process', 'GO:0016236', ('111', '120'))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mitochondria', 'cellular_component', 'GO:0005739', ('62', '74'))	('inhibiting', 'NegReg', (125, 135))	('limiting', 'NegReg', (102, 110))	('accumulation', 'PosReg', (36, 48))	('autophagy', 'biological_process', 'GO:0006914', ('111', '120'))	('tumor', 'Disease', (136, 141))	('mutations', 'Var', (20, 29))
22711	30372395	These changes impact the balance of available nutrients, discarded metabolites, and secreted waste products and other local features, such as pH, oxygen tension, and redox state, that may directly or indirectly impact stromal and immune cells.	('balance of available nutrients', 'MPA', (25, 55))	('impact', 'Reg', (211, 217))	('changes', 'Var', (6, 13))	('oxygen', 'Chemical', 'MESH:D010100', (146, 152))	('impact', 'Reg', (14, 20))
22713	30372395	The earliest stages of VHL inactivation in precancerous cells can mount an inflammatory response, which sets the stage for later tumor cell-immune cell.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('inactivation', 'Var', (27, 39))	('VHL', 'Gene', (23, 26))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('inflammatory response', 'CPA', (75, 96))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('inflammatory response', 'biological_process', 'GO:0006954', ('75', '96'))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mount', 'Reg', (66, 71))	('tumor', 'Disease', (129, 134))
22733	30555801	Clear cell renal cell carcinomas (ccRCC) harbor mutations in the VHL gene, whereas papillary RCC (pRCC) have a functional VHL.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('VHL', 'Gene', '7428', (65, 68))	('RCC', 'Disease', (93, 96))	('RCC', 'Disease', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (34, 39))	('RCC', 'Disease', (99, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('pRCC', 'Gene', '5546', (98, 102))	('mutations', 'Var', (48, 57))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('Clear cell renal cell carcinomas', 'Disease', (0, 32))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('pRCC', 'Gene', (98, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('papillary RCC', 'Gene', (83, 96))	('Clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (0, 32))	('papillary RCC', 'Gene', '5546', (83, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('VHL', 'Gene', (122, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (11, 32))	('VHL', 'Gene', (65, 68))	('Clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (0, 32))	('VHL', 'Gene', '7428', (122, 125))
22734	30555801	These natural occurring VHL variants in RCC enable the testing, in clinical samples, of the hypothesis that ascorbate modulates HIF-alpha levels through its role as a cofactor for the HIF hydroxylases.	('VHL', 'Gene', '7428', (24, 27))	('variants', 'Var', (28, 36))	('ascorbate', 'Chemical', 'MESH:D001205', (108, 117))	('RCC', 'Disease', (40, 43))	('clinical samples', 'Species', '191496', (67, 83))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('VHL', 'Gene', (24, 27))
22748	30555801	Hydroxylation of an asparagine in the C-terminal transactivation domain of HIF-alpha by the enzyme factor-inhibiting HIF (FIH) leads to repression of transcriptional activity by inhibiting interaction with the p300 coactivator.	('interaction', 'Interaction', (189, 200))	('transactivation', 'biological_process', 'GO:2000144', ('49', '64'))	('inhibiting', 'NegReg', (178, 188))	('repression', 'NegReg', (136, 146))	('Hydroxylation', 'Var', (0, 13))	('asparagine', 'Chemical', 'MESH:D001216', (20, 30))	('transcriptional activity', 'MPA', (150, 174))
22751	30555801	A number of studies have demonstrated that low intracellular ascorbate concentration exacerbates HIF-1 activation in cancer and normal cells.	('HIF-1', 'Gene', '3091', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('low', 'Var', (43, 46))	('intracellular', 'cellular_component', 'GO:0005622', ('47', '60'))	('activation', 'MPA', (103, 113))	('HIF-1', 'Gene', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('exacerbates', 'PosReg', (85, 96))	('ascorbate', 'Chemical', 'MESH:D001205', (61, 70))	('cancer', 'Disease', (117, 123))
22761	30555801	About 90% of ccRCC tumors harbor biallelic alterations in the VHL tumor suppressor gene, while pRCCs retain a functional VHL protein.	('VHL', 'Gene', '7428', (121, 124))	('ccRCC tumors', 'Disease', 'MESH:D009369', (13, 25))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('66', '82'))	('VHL', 'Gene', '7428', (62, 65))	('tumor suppressor', 'biological_process', 'GO:0051726', ('66', '82'))	('pRCC', 'Gene', '5546', (95, 99))	('VHL tumor', 'Disease', (62, 71))	('protein', 'cellular_component', 'GO:0003675', ('125', '132'))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('VHL tumor', 'Disease', 'MESH:D006623', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('VHL', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pRCC', 'Gene', (95, 99))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('biallelic alterations', 'Var', (33, 54))	('ccRCC tumors', 'Disease', (13, 25))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('VHL', 'Gene', (62, 65))
22763	30555801	The presence of natural occurring VHL variants in RCC allowed us to investigate the role of VHL in the response of HIFs to ascorbate.	('ascorbate', 'Chemical', 'MESH:D001205', (123, 132))	('variants', 'Var', (38, 46))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('VHL', 'Gene', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('VHL', 'Gene', '7428', (92, 95))	('investigate', 'Reg', (68, 79))	('VHL', 'Gene', (34, 37))	('VHL', 'Gene', '7428', (34, 37))
22834	30555801	In ccRCC patients with higher HIF-2 pathway scores, all-cause mortality and disease-free survival tended to be worse, although significance was not reached (p = 0.063 and p = 0.092, respectively; Table S3).	('patients', 'Species', '9606', (9, 17))	('scores', 'Var', (44, 50))	('higher', 'PosReg', (23, 29))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('worse', 'NegReg', (111, 116))	('all-cause', 'CPA', (52, 61))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('disease-free survival', 'CPA', (76, 97))	('HIF-2 pathway', 'Gene', (30, 43))
22850	30555801	The current investigation into the two renal cell carcinoma sub-types has allowed us to investigate the potential interaction between ascorbate and the HIF hydroxylases in tumors using ccRCC as an example of naturally occurring tumor mutations, resulting in a dysfunctional VHL protein.	('RCC', 'Disease', (187, 190))	('RCC', 'Phenotype', 'HP:0005584', (187, 190))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (172, 177))	('protein', 'cellular_component', 'GO:0003675', ('278', '285'))	('ccRCC', 'Phenotype', 'HP:0006770', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('dysfunctional VHL', 'Disease', 'MESH:D006623', (260, 277))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('ascorbate', 'Chemical', 'MESH:D001205', (134, 143))	('dysfunctional VHL', 'Disease', (260, 277))	('mutations', 'Var', (234, 243))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Disease', (39, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('tumor', 'Disease', (228, 233))
22851	30555801	This mutation prevents degradation of the hydroxylated HIF-alpha chains and increases subsequent transcriptional activity of the HIFs in ccRCC, and is therefore independent of the hypoxic status of the tumor, or the availability of other hydroxylase substrates or co-factors, including ascorbate (Figure 6).	('tumor', 'Disease', (202, 207))	('ascorbate', 'Chemical', 'MESH:D001205', (286, 295))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('increases', 'PosReg', (76, 85))	('HIF-alpha chains', 'Protein', (55, 71))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('degradation', 'biological_process', 'GO:0009056', ('23', '34'))	('degradation', 'MPA', (23, 34))	('transcriptional activity', 'MPA', (97, 121))	('prevents', 'NegReg', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('mutation', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
22854	30555801	It is also possible that HIF activation is regulated by variations in the PHD or FIH enzymes.	('PHD', 'Disease', (74, 77))	('HIF', 'CPA', (25, 28))	('variations', 'Var', (56, 66))	('PHD', 'molecular_function', 'GO:0050175', ('74', '77'))	('PHD', 'Disease', 'MESH:D011547', (74, 77))
22857	30555801	Modulation of the HIF pathways in RCC by any means is likely to impact on tumor growth and progression.	('Modulation', 'Var', (0, 10))	('progression', 'CPA', (91, 102))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('impact', 'Reg', (64, 70))	('tumor', 'Disease', (74, 79))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('HIF pathways', 'Pathway', (18, 30))	('RCC', 'Disease', (34, 37))
22859	30555801	This seems to be especially evident in VHL-defective ccRCC, where HIF-1 can have tumor suppressive effects, whereas HIF-2 appears to be the major player in tumorigenesis and is associated with higher grade, stage and poor patient outcome.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('VHL-defective', 'Disease', (39, 52))	('HIF-1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patient', 'Species', '9606', (222, 229))	('HIF-2', 'Var', (116, 121))	('tumor', 'Disease', (156, 161))	('VHL-defective', 'Disease', 'MESH:D006623', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('associated with', 'Reg', (177, 192))	('HIF-1', 'Gene', '3091', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('tumor', 'Disease', (81, 86))
22867	30555801	Our finding that VEGF tended to increase in higher-grade ccRCC supports evidence that high VEGF expression is a poor prognostic indicator for patients with ccRCC and is thus a preferential target for therapy.	('VEGF', 'Gene', '7422', (91, 95))	('VEGF', 'Gene', '7422', (17, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('expression', 'MPA', (96, 106))	('VEGF', 'Gene', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('VEGF', 'Gene', (17, 21))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('patients', 'Species', '9606', (142, 150))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('high', 'Var', (86, 90))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
22881	30555801	In contrast, we suggest that manipulating ascorbate levels in ccRCC would not affect the hypoxic response and thus would not change tumor aggression that is dependent on this pathway.	('tumor aggression', 'Disease', 'MESH:D001523', (132, 148))	('tumor aggression', 'Disease', (132, 148))	('manipulating', 'Var', (29, 41))	('ascorbate', 'Chemical', 'MESH:D001205', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('aggression', 'Phenotype', 'HP:0000718', (138, 148))	('hypoxic', 'MPA', (89, 96))	('aggression', 'biological_process', 'GO:0002118', ('138', '148'))
22903	27705936	While overexpression or activating mutations of MET proto-oncogene encoding for a hepatocyte growth factor receptor (HGFR) are common in PRCC1, PRCC2 has been associated with activation of the NRF2-ARE pathway and CDKN2A silencing.	('CDKN2A', 'Gene', (214, 220))	('PRCC', 'Gene', (137, 141))	('silencing', 'NegReg', (221, 230))	('PRCC', 'Gene', (144, 148))	('activating', 'PosReg', (24, 34))	('NRF2', 'Gene', '4780', (193, 197))	('CDKN2A', 'Gene', '1029', (214, 220))	('PRCC', 'Gene', '5546', (137, 141))	('activation', 'PosReg', (175, 185))	('NRF2', 'Gene', (193, 197))	('HGFR', 'Gene', '4233', (117, 121))	('overexpression', 'PosReg', (6, 20))	('hepatocyte growth factor receptor', 'Gene', '4233', (82, 115))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('82', '106'))	('HGFR', 'Gene', (117, 121))	('hepatocyte growth factor receptor', 'Gene', (82, 115))	('PRCC', 'Gene', '5546', (144, 148))	('mutations', 'Var', (35, 44))
22904	27705936	Interestingly, differential expression of components regulating cell-extracellular matrix (ECM) interactions has also been implicated in PRCC1.	('PRCC', 'Gene', (137, 141))	('expression', 'MPA', (28, 38))	('implicated', 'Reg', (123, 133))	('ECM', 'Gene', '22915', (91, 94))	('extracellular matrix', 'cellular_component', 'GO:0031012', ('69', '89'))	('PRCC', 'Gene', '5546', (137, 141))	('differential', 'Var', (15, 27))	('ECM', 'Gene', (91, 94))
22930	27705936	ITGA5 expression levels in unclassified PRCC patients in the GSE15641 dataset tended to be higher than in healthy controls but this difference was not statistically significant (Figure 5B).	('ITGA5', 'Gene', '3678', (0, 5))	('higher', 'PosReg', (91, 97))	('GSE15641', 'Var', (61, 69))	('PRCC', 'Gene', '5546', (40, 44))	('patients', 'Species', '9606', (45, 53))	('PRCC', 'Gene', (40, 44))	('ITGA5', 'Gene', (0, 5))	('expression levels', 'MPA', (6, 23))
22975	27705936	In GSE11024 and GSE2748 datasets, gender information was available for a total of 25 PRCC1 and 21 PRCC2 samples which were analyzed by expression profiling microarray using GPL6671 and GPL570 platforms, respectively.	('PRCC', 'Gene', (98, 102))	('PRCC', 'Gene', (85, 89))	('GSE2748', 'Chemical', '-', (16, 23))	('GSE11024', 'Var', (3, 11))	('GSE2748 datasets', 'Var', (16, 32))	('PRCC', 'Gene', '5546', (98, 102))	('PRCC', 'Gene', '5546', (85, 89))
22984	26975036	TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer.	('melanotic Xp11 translocation renal cancer', 'Disease', 'MESH:D007680', (261, 302))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('translocation renal cell carcinoma', 'Disease', 'MESH:C538614', (150, 184))	('cancers', 'Disease', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('epithelioid cell tumor', 'Disease', 'MESH:D054973', (224, 246))	('renal cancer', 'Phenotype', 'HP:0009726', (290, 302))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Cancers', 'Disease', (102, 109))	('Cancers', 'Phenotype', 'HP:0002664', (102, 109))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('RCC', 'Disease', (186, 189))	('melanotic Xp11 translocation renal cancer', 'Disease', (261, 302))	('TFE3', 'Gene', (0, 4))	('translocation renal cell carcinoma', 'Disease', (150, 184))	('TFE3', 'Gene', '7030', (0, 4))	('Xp11 translocation', 'Var', (192, 210))	('PEComa', 'Disease', 'MESH:D054973', (248, 254))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('epithelioid cell tumor', 'Phenotype', 'HP:0032060', (224, 246))	('PEComa', 'Disease', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('epithelioid cell tumor', 'Disease', (224, 246))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cancers', 'Disease', 'MESH:D009369', (102, 109))
22985	26975036	In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners, however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined.	('fusion', 'Var', (77, 83))	('Xp11 translocation', 'Gene', (3, 21))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancers', 'Disease', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('TFE3', 'Gene', (87, 91))	('cancers', 'Disease', (244, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
22987	26975036	The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('renal cancer', 'Phenotype', 'HP:0009726', (135, 147))	('PEComas', 'Disease', 'MESH:D054973', (91, 98))	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Xp11 translocation', 'Var', (7, 25))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('PEComas', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('melanotic Xp11 translocation renal cancers', 'Disease', 'MESH:D007680', (106, 148))	('melanotic Xp11 translocation renal cancers', 'Disease', (106, 148))	('Xp11 translocation', 'Var', (46, 64))	('cancers', 'Disease', (141, 148))	('RCC', 'Disease', (65, 68))
22992	26975036	Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3 and ASPL-TFE3 gene fusions, the RCC are almost always PAX8-positive, cathepsin K-negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8-negative, cathepsin K-positive.	('ASPL', 'Gene', (74, 78))	('PEComas', 'Disease', (242, 249))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (299, 325))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (318, 325))	('NONO', 'Gene', (49, 53))	('neoplasms', 'Phenotype', 'HP:0002664', (19, 28))	('melanotic Xp11 translocation renal cancers', 'Disease', (251, 293))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (299, 325))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('neoplasm', 'Phenotype', 'HP:0002664', (19, 27))	('renal cancer', 'Phenotype', 'HP:0009726', (280, 292))	('SFPQ', 'Gene', '6421', (38, 42))	('DVL2-TFE3', 'Var', (60, 69))	('SFPQ', 'Gene', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('ASPL', 'Gene', '79058', (74, 78))	('alveolar soft part sarcoma', 'Disease', (299, 325))	('neoplasms', 'Disease', 'MESH:D009369', (19, 28))	('NONO', 'Gene', '4841', (49, 53))	('melanotic Xp11 translocation renal cancers', 'Disease', 'MESH:D007680', (251, 293))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (308, 325))	('neoplasms', 'Disease', (19, 28))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('PEComas', 'Disease', 'MESH:D054973', (242, 249))
22999	26975036	Xp11 translocation RCC comprise the majority of pediatric RCC and approximately 1-4% adult RCC.	('Xp11 translocation', 'Var', (0, 18))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (91, 94))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
23016	26975036	Two other cases of Xp11 translocation PEComa in this study were included from the original description of this entity and one other case was reviewed by one author (PA) in consultation and subsequently reported by others.	('Xp11 translocation', 'Var', (19, 37))	('PEComa', 'Disease', 'MESH:D054973', (38, 44))	('PEComa', 'Disease', (38, 44))
23025	26975036	These included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComa (2 renal, 6 non-renal), and 5 melanotic Xp11 translocation renal cancers.	('PEComa', 'Disease', 'MESH:D054973', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('melanotic Xp11 translocation renal cancers', 'Disease', 'MESH:D007680', (100, 142))	('melanotic Xp11 translocation renal cancers', 'Disease', (100, 142))	('RCC', 'Phenotype', 'HP:0005584', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('PEComa', 'Disease', (63, 69))	('renal cancer', 'Phenotype', 'HP:0009726', (129, 141))	('Xp11 translocation', 'Var', (44, 62))
23063	26975036	Both cases with adequate RNA for RNA seq demonstrated an SFPQ-TFE3 gene fusion, fusing exon 9 of SFPQ with exon 6 of TFE3 (Table 2, cases 12 and 14).	('SFPQ', 'Gene', '6421', (97, 101))	('SFPQ', 'Gene', (97, 101))	('fusing', 'Var', (80, 86))	('SFPQ', 'Gene', '6421', (57, 61))	('RNA', 'cellular_component', 'GO:0005562', ('25', '28'))	('fusion', 'Var', (72, 78))	('SFPQ', 'Gene', (57, 61))	('RNA', 'cellular_component', 'GO:0005562', ('33', '36'))
23068	26975036	All 3 cases with adequate RNA for RNA seq demonstrated an SFPQ-TFE3 gene fusion, fusing exon 9 of SFPQ with exon 6 of TFE3 (Table 2, cases 16-18).	('SFPQ', 'Gene', (58, 62))	('RNA', 'cellular_component', 'GO:0005562', ('34', '37'))	('SFPQ', 'Gene', '6421', (98, 102))	('SFPQ', 'Gene', (98, 102))	('fusing', 'Var', (81, 87))	('fusion', 'Var', (73, 79))	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('SFPQ', 'Gene', '6421', (58, 62))
23086	26975036	In our study, similar to the NONO-TFE3 neoplasms, we found that the DVL2-TFE3 RCC was PAX8 positive and cathepsin K negative, whereas the DVL2-TFE3 PEComa was cathepsin K positive and PAX8 negative.	('DVL2-TFE3', 'Var', (68, 77))	('PEComa', 'Disease', 'MESH:D054973', (148, 154))	('neoplasms', 'Phenotype', 'HP:0002664', (39, 48))	('NONO', 'Gene', (29, 33))	('NONO', 'Gene', '4841', (29, 33))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('neoplasm', 'Phenotype', 'HP:0002664', (39, 47))	('PEComa', 'Disease', (148, 154))	('neoplasms', 'Disease', 'MESH:D009369', (39, 48))	('neoplasms', 'Disease', (39, 48))
23096	26975036	The frequent sub-nuclear vacuolization seen indicates that these Xp11 translocation RCC should also be considered in the differential diagnosis of clear cell papillary RCC.	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('Xp11 translocation', 'Var', (65, 83))	('RCC', 'Disease', (84, 87))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))
23113	26975036	We note that neither of the ASPCR1-TFE3 and PRCC-TFE3 gene fusions was or has previously been identified in an Xp11 translocation PEComa.	('ASPCR1', 'Gene', '79058', (28, 34))	('PRCC', 'Gene', (44, 48))	('PEComa', 'Disease', (130, 136))	('PEComa', 'Disease', 'MESH:D054973', (130, 136))	('PRCC', 'Gene', '5546', (44, 48))	('fusions', 'Var', (59, 66))	('ASPCR1', 'Gene', (28, 34))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
23115	26975036	Of note, the PRCC-TFE3 RCC is the one known subtype of Xp11 translocation RCC which does express cathepsin K frequently, whereas our study shows that other Xp11 translocation RCC are typically cathepsin k negative and have a mesenchymal counterpart with the identical gene fusion that is cathepsin k positive (Table 6).	('RCC', 'Disease', (14, 17))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('Xp11', 'Var', (156, 160))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('PRCC-TFE3 RCC', 'Gene', (13, 26))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('cathepsin k', 'Gene', '1513', (193, 204))	('cathepsin k', 'Gene', '1513', (288, 299))	('PRCC-TFE3 RCC', 'Gene', '5546', (13, 26))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('RCC', 'Disease', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', (23, 26))	('cathepsin k', 'Gene', (193, 204))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('cathepsin k', 'Gene', (288, 299))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
23117	26975036	Given the variable clinical presentation and morphologic appearances described in this and other manuscripts, one could be tempted to conclude that all RCCs be worked up by molecular techniques to exclude Xp11 translocation RCC.	('RCC', 'Disease', (224, 227))	('RCC', 'Phenotype', 'HP:0005584', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('Xp11 translocation', 'Var', (205, 223))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
23119	26975036	For cases which present with metastatic disease, the diagnosis of Xp11 translocation RCC would make a patient ineligible for some treatments designed to specifically target clear cell RCC and eligible for treatments that target cancers with TFE3 gene fusions.	('metastatic disease', 'Disease', (29, 47))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Disease', (228, 235))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('RCC', 'Disease', 'MESH:C538614', (184, 187))	('patient', 'Species', '9606', (102, 109))	('RCC', 'Disease', (184, 187))	('Xp11 translocation', 'Var', (66, 84))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))
23124	26975036	We also perform TFE3 FISH for many unclassified RCCs, given the morphologic variability demonstrated by Xp11 translocation RCC including its ability to have a non-descript high grade RCC appearance.	('RCC', 'Phenotype', 'HP:0005584', (183, 186))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (183, 186))	('RCC', 'Disease', (183, 186))	('Xp11 translocation', 'Var', (104, 122))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
23126	26975036	Clinical clues such as young age, morphologic clues such as the presence of psammoma bodies, and immunohistochemical clues such as minimal immunoreactivity for CA-IX should suggest the possibility of Xp11 translocation RCC.	('CA-IX', 'Gene', (160, 165))	('Xp11 translocation', 'Var', (200, 218))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('CA-IX', 'Gene', '768', (160, 165))	('psammoma bodies', 'Disease', (76, 91))	('psammoma bodies', 'Disease', 'MESH:D001835', (76, 91))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
23128	26975036	We also highlight the strong association of cathepsin K immunoreactivity in Xp11 translocation RCC with the presence of a PRCC-TFE3 gene fusion.	('presence', 'Var', (108, 116))	('PRCC', 'Gene', (122, 126))	('immunoreactivity', 'MPA', (56, 72))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('Xp11 translocation', 'Gene', (76, 94))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('cathepsin', 'Protein', (44, 53))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (95, 98))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('PRCC', 'Gene', '5546', (122, 126))	('association', 'Interaction', (29, 40))
23146	26167383	Prominent nucleoli number also increases with Gleason grading in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('increases', 'PosReg', (31, 40))	('Gleason grading', 'Var', (46, 61))	('prostate cancer', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
23196	26167383	A rectangular window wi    U x B can be defined by, wi = (uminr, umaxr, umintheta, umaxtheta, b) uminr, umaxr, umintheta, umaxtheta define a bounding box in  U and b   B specifies from which block the image gradient is calculated from.	('eta', 'Gene', (78, 81))	('uminr', 'Var', (97, 102))	('eta', 'Gene', '1909', (117, 120))	('eta', 'Gene', '1909', (128, 131))	('eta', 'Gene', (117, 120))	('eta', 'Gene', (128, 131))	('eta', 'Gene', '1909', (89, 92))	('eta', 'Gene', '1909', (78, 81))	('eta', 'Gene', (89, 92))
23233	23799849	Deregulated miRNAs might contribute to the high chemotherapy resistance of RCC.	('Deregulated', 'Var', (0, 11))	('chemotherapy resistance', 'MPA', (48, 71))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('miRNAs', 'MPA', (12, 18))	('RCC', 'Disease', (75, 78))
23241	23799849	In cases of familiar pRCC syndromes, mutations of the c-MET proto-oncogene are correlated with a pRCC1 morphology, whereas in cases of Hereditary leiomyomatosis and renal cell cancer there is a high incidence for mutations in the fumarate hydratase (FH) gene, leading to the occurrence of pRCC2.	('fumarate hydratase', 'Gene', '2271', (230, 248))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (135, 182))	('pRCC', 'Gene', '5546', (97, 101))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pRCC', 'Gene', (289, 293))	('pRCC1', 'Gene', (97, 102))	('pRCC1', 'Gene', '5546', (97, 102))	('FH', 'Gene', '2271', (250, 252))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('mutations', 'Var', (213, 222))	('pRCC', 'Gene', '5546', (21, 25))	('correlated', 'Reg', (79, 89))	('pRCC', 'Gene', (97, 101))	('c-MET', 'Gene', '4233', (54, 59))	('fumarate hydratase', 'Gene', (230, 248))	('renal cell cancer', 'Phenotype', 'HP:0005584', (165, 182))	('mutations', 'Var', (37, 46))	('c-MET', 'Gene', (54, 59))	('pRCC', 'Gene', '5546', (289, 293))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('pRCC', 'Gene', (21, 25))
23314	23799849	For the miRNAs miR-145, miR-200c miR-210 and miR-502-3p, which discriminated between tumour and normal samples, a total of 1629 potential target mRNAs were identified.	('miRNAs', 'Var', (8, 14))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('miR-210', 'Gene', (33, 40))	('miR-502', 'Gene', '574504', (45, 52))	('tumour', 'Disease', (85, 91))	('miR-145', 'Gene', (15, 22))	('miR-145', 'Gene', '406937', (15, 22))	('miR-210', 'Gene', '406992', (33, 40))	('miR-502', 'Gene', (45, 52))	('miR-200c', 'Gene', (24, 32))	('miR-200c', 'Gene', '406985', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
23367	23799849	This points towards the possibility that deregulated miRNAs contribute to RCC chemoresistance.	('contribute', 'Reg', (60, 70))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('deregulated', 'Var', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('miRNAs', 'Protein', (53, 59))
23374	23817689	The most common alteration was a 17q gain in 7 tumors (44%), followed by a 9p loss in 6 cases (37%).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('loss', 'NegReg', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('17q', 'Chemical', '-', (33, 36))	('gain', 'PosReg', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('17q', 'Var', (33, 36))
23375	23817689	Patients with 17q gain were older (P = 0.0006), displayed more genetic alterations (P < 0.003) and had a worse outcome (P = 0.002) than patients without it.	('gain', 'PosReg', (18, 22))	('17q', 'Var', (14, 17))	('17q', 'Chemical', '-', (14, 17))	('genetic alterations', 'CPA', (63, 82))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (136, 144))
23384	23817689	tRCC can also be related to translocations involving the TFEB gene.	('TFEB', 'Gene', '7942', (57, 61))	('TFEB', 'Gene', (57, 61))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('RCC', 'Disease', (1, 4))	('related', 'Reg', (17, 24))	('translocations', 'Var', (28, 42))
23391	23817689	Other renal tumors are characterized by specific chromosomal imbalances, such as 3p loss in clear-cell RCC (ccRCC) and trisomies 7 and 17 in papillary RCC (pRCC).	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('renal tumors', 'Disease', 'MESH:D007674', (6, 18))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('imbalances', 'Phenotype', 'HP:0002172', (61, 71))	('papillary RCC', 'Gene', (141, 154))	('renal tumors', 'Phenotype', 'HP:0009726', (6, 18))	('papillary RCC', 'Gene', '5546', (141, 154))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('pRCC', 'Gene', '5546', (156, 160))	('renal tumor', 'Phenotype', 'HP:0009726', (6, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('pRCC', 'Gene', (156, 160))	('RCC', 'Disease', (151, 154))	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', (103, 106))	('3p loss', 'Var', (81, 88))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (157, 160))	('renal tumors', 'Disease', (6, 18))	('trisomies 7', 'Var', (119, 130))
23392	23817689	The aims of our study were to investigate whether there are any additional genetic/epigenetic alterations beside TFE3/TFEB translocations, and assess whether there are associations between specific chromosomal imbalances and classical clinicopathologic factors and overall survival (OS).	('TFEB', 'Gene', (118, 122))	('associations', 'Interaction', (168, 180))	('TFE3', 'Gene', (113, 117))	('imbalances', 'Phenotype', 'HP:0002172', (210, 220))	('TFE3', 'Gene', '7030', (113, 117))	('translocations', 'Var', (123, 137))	('TFEB', 'Gene', '7942', (118, 122))
23393	23817689	Tissue specimens from 21 patients with a histopathologic diagnosis of tRCC supported by TFE3 positivity on immunohistochemistry were collected after approval of the institutional review board of each of the participating centers.	('TFE3', 'Gene', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('men', 'Species', '9606', (12, 15))	('RCC', 'Disease', (71, 74))	('positivity', 'Var', (93, 103))	('TFE3', 'Gene', '7030', (88, 92))	('patients', 'Species', '9606', (25, 33))
23401	23817689	DNA was available for studying LINE-1 methylation in 12 patients for whom SNP-array analysis was performed (all except the following 4 cases: LOY009, MRCC106, MRCC107, and MRCC117).	('patients', 'Species', '9606', (56, 64))	('RCC', 'Disease', (173, 176))	('DNA', 'cellular_component', 'GO:0005574', ('0', '3'))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('LOY009', 'Var', (142, 148))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
23403	23817689	Seven of those patients had confirmed translocation by karyotyping and/or RT-PCR, and the remaining had their diagnosis confirmed by TFE3 immunostaining, as previously described.	('TFE3', 'Gene', '7030', (133, 137))	('patients', 'Species', '9606', (15, 23))	('TFE3', 'Gene', (133, 137))	('translocation', 'Var', (38, 51))
23413	23817689	For 4 translocation Xp11 cases (T31, T32, T34, T1), RNA of good quality with RNA integrity number values between 8.0 and 10.0 was available.	('T34', 'Var', (42, 45))	('T32', 'Var', (37, 40))	('p11', 'Gene', (21, 24))	('RNA', 'cellular_component', 'GO:0005562', ('77', '80'))	('T31', 'Var', (32, 35))	('p11', 'Gene', '6281', (21, 24))	('T1', 'Var', (47, 49))	('RNA', 'cellular_component', 'GO:0005562', ('52', '55'))
23415	23817689	The average degree of change between the normalized RPKM values of 2 samples with partial 17q gain and 2 samples without was calculated, and genes were ranked by order of expression in the 2 samples with partial 17q gain.	('gain', 'PosReg', (94, 98))	('17q', 'Chemical', '-', (212, 215))	('partial 17q', 'Var', (82, 93))	('17q', 'Chemical', '-', (90, 93))
23418	23817689	VHL mutations were assessed using four primers pairs as previously described.	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))
23424	23817689	Translocation carcinomas showed significant heterogeneity in cytogenomic profiles (Figure 1/Table 1).	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('Translocation', 'Var', (0, 13))	('carcinomas', 'Disease', 'MESH:D002277', (14, 24))	('carcinomas', 'Disease', (14, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
23429	23817689	Overall, the 16 cases of tRCC with a confirmed translocation could be classified into 4 groups on the basis of their similarities to cytogenomic profiles of other renal epithelial tumors.	('translocation', 'Var', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('renal epithelial tumors', 'Disease', (163, 186))	('renal epithelial tumors', 'Disease', 'MESH:D007674', (163, 186))	('RCC', 'Disease', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('RCC', 'Disease', 'MESH:C538614', (26, 29))
23437	23817689	Of the 7 cases (44%) that had a gain of 17q, 2 tumors had a confirmed t(X;17)(p11;q25) translocation and 1 case had a TFEB translocation.	('tumors', 'Disease', (47, 53))	('TFEB', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('gain', 'Var', (32, 36))	('17q', 'Chemical', '-', (40, 43))	('t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('TFEB', 'Gene', '7942', (118, 122))
23438	23817689	Interestingly, in four of the seven cases with 17q gain, 17p loss has been demonstrated consistent with the generation of an isochromosome 17q, or i(17q).	('gain', 'PosReg', (51, 55))	('17q', 'Chemical', '-', (149, 152))	('17q', 'Chemical', '-', (139, 142))	('17p', 'MPA', (57, 60))	('loss', 'NegReg', (61, 65))	('isochromosome 17q', 'Var', (125, 142))	('17q', 'Chemical', '-', (47, 50))
23439	23817689	In contrast, none of 4 cases overexpressing TFE3 but negative by FISH had gain of 17q or loss of 17p, and 2 of them had 3p loss (Supplementary Table 2).	('17p', 'MPA', (97, 100))	('overexpressing', 'Var', (29, 43))	('TFE3', 'Gene', (44, 48))	('17q', 'MPA', (82, 85))	('men', 'Species', '9606', (135, 138))	('loss', 'NegReg', (123, 127))	('gain', 'PosReg', (74, 78))	('TFE3', 'Gene', '7030', (44, 48))	('17q', 'Chemical', '-', (82, 85))	('loss', 'NegReg', (89, 93))
23450	23817689	In addition, patients with 17q gain were older than those without: their median age was 40.2 years (range, 20.4-54.6) vs. 16.7 years (range, 9.1-33.1) (P = 0.0006).	('17q', 'Var', (27, 30))	('patients', 'Species', '9606', (13, 21))	('17q', 'Chemical', '-', (27, 30))	('gain', 'PosReg', (31, 35))
23454	23817689	Patients with 3p loss had a higher pT stage than did those without 3p loss (P = 0.03).	('higher', 'PosReg', (28, 34))	('pT stage', 'CPA', (35, 43))	('3p loss', 'Var', (14, 21))	('Patients', 'Species', '9606', (0, 8))
23456	23817689	Patients with 3p loss also had a shorter OS time than did those without 3p loss, with median 12.7 months vs. not reached (P = 0.001).	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (33, 40))	('OS time', 'MPA', (41, 48))	('3p loss', 'Var', (14, 21))
23457	23817689	To assess whether 3p loss was associated with VHL mutations, as is the case for ccRCC, somatic mutations of VHL were analyzed in 12 cases, but no mutations were identified.	('associated', 'Reg', (30, 40))	('VHL', 'Gene', (46, 49))	('VHL', 'Gene', '7428', (108, 111))	('mutations', 'Var', (50, 59))	('VHL', 'Gene', '7428', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('loss', 'NegReg', (21, 25))	('VHL', 'Gene', (108, 111))
23458	23817689	Patients with 9p loss had more genetic alterations than did patients without 9p loss: 15.0 +- 2.3 vs. 4.3 +- 1.9 (P = 0.003).	('Patients', 'Species', '9606', (0, 8))	('9p loss', 'Var', (14, 21))	('patients', 'Species', '9606', (60, 68))	('genetic alterations', 'Var', (31, 50))
23459	23817689	No statistically significant associations were found between 9p loss and age, gender, TNM stage classification, pT stage, lymph node involvement, or metastasis; patients with 9p loss had a shorter OS time than did those without 9p loss, with median OS of 26 months vs. 66 months.	('men', 'Species', '9606', (140, 143))	('shorter', 'NegReg', (189, 196))	('9p loss', 'Var', (175, 182))	('patients', 'Species', '9606', (161, 169))	('OS time', 'MPA', (197, 204))
23471	23817689	Because partial 17q gain was the most common abnormality after TFE3 translocations and because patients with 17q had a poorer outcome than did patients without 17q, we investigated the expression pattern on chromosome 17.	('gain', 'PosReg', (20, 24))	('TFE3', 'Gene', '7030', (63, 67))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (143, 151))	('17q', 'Chemical', '-', (16, 19))	('partial 17q', 'Var', (8, 19))	('translocations', 'Var', (68, 82))	('17q', 'Chemical', '-', (160, 163))	('TFE3', 'Gene', (63, 67))	('17q', 'Chemical', '-', (109, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('207', '217'))
23472	23817689	To identify chromosomal regions differentially expressed in cases with partial 17q gain and those without, we performed global gene expression analysis using RNA-seq in 4 Xp11 cases for which RNA was available.	('RNA', 'cellular_component', 'GO:0005562', ('158', '161'))	('17q', 'Chemical', '-', (79, 82))	('gene expression', 'biological_process', 'GO:0010467', ('127', '142'))	('gain', 'PosReg', (83, 87))	('p11', 'Gene', (172, 175))	('RNA', 'cellular_component', 'GO:0005562', ('192', '195'))	('partial 17q', 'Var', (71, 82))	('p11', 'Gene', '6281', (172, 175))
23473	23817689	Two cases with partial 17q gain, including patients T34 and T1, were compared with 2 cases with balanced virtual karyotypes, including patients T31 and T32.	('patients', 'Species', '9606', (135, 143))	('gain', 'PosReg', (27, 31))	('patients', 'Species', '9606', (43, 51))	('partial 17q', 'Var', (15, 26))	('17q', 'Chemical', '-', (23, 26))
23474	23817689	GSEA showed significant enrichment of genes located in the 17q arm as follows: 17q25 [false discovery rate (FDR) = 0.0001; P < 0.0001], 17q23 (FDR = 0.07; P < 0.001), 17q21 (FDR = 0.08; P < 0.001), 17q24 (FDR = 0.10; P < 0.001), and 17q22 (FDR = 0.10; P < 0.001) (Fig.	('false', 'biological_process', 'GO:0071878', ('86', '91'))	('17q', 'Chemical', '-', (233, 236))	('17q', 'Chemical', '-', (136, 139))	('17q25', 'Var', (79, 84))	('17q22', 'Var', (233, 238))	('17q', 'Chemical', '-', (59, 62))	('17q', 'Chemical', '-', (79, 82))	('17q24', 'Var', (198, 203))	('false', 'biological_process', 'GO:0071877', ('86', '91'))	('17q21', 'Var', (167, 172))	('men', 'Species', '9606', (30, 33))	('17q', 'Chemical', '-', (198, 201))	('17q23', 'Var', (136, 141))	('GSEA', 'Chemical', '-', (0, 4))	('17q', 'Chemical', '-', (167, 170))
23476	23817689	Interestingly, when genes were classified according to the C6 oncogenic signature in the Molecular Signatures Database, we found enrichment for genes down-regulated by TP53 in NCI-60 panel of cell lines with mutated TP53 as compared to those classified as normal (Fig.	('TP53', 'Gene', (216, 220))	('down-regulated', 'NegReg', (150, 164))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('men', 'Species', '9606', (135, 138))	('mutated', 'Var', (208, 215))	('TP53', 'Gene', '7157', (216, 220))
23477	23817689	As gain of 17q was frequently associated with loss of 17p, which contains the p53 tumor suppressor gene, and as p53 loss is commonly associated with a poor prognosis in various malignancies, we assessed for the presence of TP53 mutations.	('17q', 'Chemical', '-', (11, 14))	('loss', 'Var', (46, 50))	('loss', 'NegReg', (116, 120))	('tumor', 'Disease', (82, 87))	('p53', 'Gene', '7157', (112, 115))	('malignancies', 'Disease', 'MESH:D009369', (177, 189))	('TP53', 'Gene', '7157', (223, 227))	('gain', 'PosReg', (3, 7))	('malignancies', 'Disease', (177, 189))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('p53', 'Gene', (112, 115))	('p53', 'Gene', '7157', (78, 81))	('associated', 'Reg', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', (78, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('17p', 'Gene', (54, 57))	('TP53', 'Gene', (223, 227))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))
23479	23817689	Interestingly, Ingenuity Pathway Analysis identified TP53 inactivation as the top transcription regulator factor predicted to be inactivated in the two cases (RCC-T34 and RCC-T1) with concomitant partial 17q gain as compared to the two cases (RCC-T31 and RCC-T32) with balanced karyotype (Supplementary Table 3).	('partial 17q', 'Var', (196, 207))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('RCC-T31 and RCC-T32', 'Disease', 'MESH:C538614', (243, 262))	('inactivation', 'NegReg', (58, 70))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('RCC', 'Disease', (243, 246))	('17q', 'Chemical', '-', (204, 207))	('TP53', 'Gene', '7157', (53, 57))	('gain', 'PosReg', (208, 212))	('men', 'Species', '9606', (295, 298))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('RCC', 'Disease', (171, 174))	('RCC', 'Disease', (255, 258))	('transcription', 'biological_process', 'GO:0006351', ('82', '95'))	('RCC', 'Disease', (159, 162))	('TP53', 'Gene', (53, 57))
23481	23817689	Also consistent with TP53 inactivation, GSEA showed enrichment for multiple pathways related to mitosis as follows: the M phase of the mitotic cycle (FDR = 0.10; P < 0.001), mitosis (FDR = 0.10; P < 0.001), and the M phase (FDR = 0.10; P < 0.001), in keeping with the aggressive phenotype of cases with partial 17q gain (Supplementary Figure 3A).	('mitosis', 'biological_process', 'GO:0000278', ('174', '181'))	('TP53', 'Gene', (21, 25))	('inactivation', 'Var', (26, 38))	('M phase', 'biological_process', 'GO:0000279', ('215', '222'))	('M phase', 'CPA', (215, 222))	('mitosis', 'biological_process', 'GO:0000278', ('96', '103'))	('GSEA', 'Chemical', '-', (40, 44))	('men', 'Species', '9606', (327, 330))	('mitosis', 'Disease', (174, 181))	('mitosis', 'Disease', 'None', (96, 103))	('17q', 'Chemical', '-', (311, 314))	('mitosis', 'Disease', 'None', (174, 181))	('M phase', 'biological_process', 'GO:0000279', ('120', '127'))	('mitosis', 'Disease', (96, 103))	('men', 'Species', '9606', (58, 61))	('TP53', 'Gene', '7157', (21, 25))
23482	23817689	KEGG (Kyoto Encyclopedia of Genes and Genomes) and BioCarta (BioCarta LLC, San Diego, CA) pathways (C2 gene set) using GSEA and Ingenuity analysis (Ingenuity Systems, Inc., Redwood City, CA) showed consistent results with T-cell activation in the subgroup of patients with partial 17q gain.	('partial 17q gain', 'Var', (273, 289))	('T-cell', 'CPA', (222, 228))	('T-cell activation', 'biological_process', 'GO:0042110', ('222', '239'))	('patients', 'Species', '9606', (259, 267))	('Redwood', 'Species', '28980', (173, 180))	('LLC', 'cellular_component', 'GO:0038045', ('70', '73'))	('activation', 'PosReg', (229, 239))	('GSEA', 'Chemical', '-', (119, 123))	('17q', 'Chemical', '-', (281, 284))
23485	23817689	Of note, 17 of 95 genes (17.9%) related to the CTLA-4 pathway were upregulated in patients with 17q gain (Supplementary Figure 3B).	('CTLA-4', 'Gene', '1493', (47, 53))	('17q', 'Chemical', '-', (96, 99))	('patients', 'Species', '9606', (82, 90))	('17q gain', 'Var', (96, 104))	('CTLA-4', 'Gene', (47, 53))	('men', 'Species', '9606', (112, 115))	('upregulated', 'PosReg', (67, 78))
23486	23817689	Immunohistochemistry for CD3 and CD5 T-cell markers showed increase of T lymphocytes in the 2 cases with 17q gain (10-20%) as compared with less than 1-2% in the 2 cases without 17q gain (not shown).	('CD3', 'Gene', (25, 28))	('17q gain', 'Var', (105, 113))	('17q', 'Chemical', '-', (178, 181))	('T lymphocytes', 'CPA', (71, 84))	('17q', 'Chemical', '-', (105, 108))	('CD5', 'Gene', (33, 36))	('CD5', 'Gene', '921', (33, 36))	('increase', 'PosReg', (59, 67))
23488	23817689	LINE-1 methylation levels correlated inversely with the number of genetic abnormalities in cases with both SNP-array and LINE-1 methylation data (Spearman's [rho] = - 0.6; P = 0.04) (Fig.	('methylation', 'biological_process', 'GO:0032259', ('128', '139'))	('genetic abnormalities', 'Disease', 'MESH:D030342', (66, 87))	('methylation', 'Var', (128, 139))	('genetic abnormalities', 'Disease', (66, 87))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
23493	23817689	Moreover, our data show that a partial 17q gain is frequent in tumors from adult patients, particularly in men, and this genetic lesion is associated with poor outcome.	('partial 17q', 'Var', (31, 42))	('men', 'Species', '9606', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('17q', 'Chemical', '-', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('gain', 'PosReg', (43, 47))
23494	23817689	Although the identification of significant correlations between cytogenetic alterations and histopathological subtypes of RCC is well established for common renal cancer subtypes, such as ccRCC (e.g., 3p loss) and pRCC (e.g., trisomy 7 and/or 17), little is known about chromosome copy number alterations in tRCC.	('pRCC', 'Gene', (214, 218))	('RCC', 'Disease', 'MESH:C538614', (309, 312))	('RCC', 'Disease', (309, 312))	('renal cancer', 'Phenotype', 'HP:0009726', (157, 169))	('chromosome', 'cellular_component', 'GO:0005694', ('270', '280'))	('RCC', 'Disease', 'MESH:C538614', (215, 218))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (215, 218))	('RCC', 'Disease', (190, 193))	('renal cancer', 'Disease', 'MESH:D007680', (157, 169))	('renal cancer', 'Disease', (157, 169))	('pRCC', 'Gene', '5546', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('trisomy 7', 'Var', (226, 235))
23498	23817689	Historically, the translocation involving TFE3 (or TFEB) is considered as the defining feature for this disease.	('TFE3', 'Gene', '7030', (42, 46))	('translocation', 'Var', (18, 31))	('TFEB', 'Gene', '7942', (51, 55))	('TFEB', 'Gene', (51, 55))	('TFE3', 'Gene', (42, 46))
23499	23817689	Mechanistic studies have demonstrated the transforming effect of the TFE3 and TFEB translocations in cell lines.	('TFEB', 'Gene', '7942', (78, 82))	('TFEB', 'Gene', (78, 82))	('TFE3', 'Gene', '7030', (69, 73))	('TFE3', 'Gene', (69, 73))	('translocations', 'Var', (83, 97))
23500	23817689	performed knock-down of PSF-TFE3 in UOK-145 cell line and showed that it leads to impaired growth, proliferation, invasion potential and long-term survival.	('long-term survival', 'CPA', (137, 155))	('PSF', 'Gene', (24, 27))	('TFE3', 'Gene', '7030', (28, 32))	('impaired', 'NegReg', (82, 90))	('knock-down', 'Var', (10, 20))	('PSF', 'Gene', '6421', (24, 27))	('invasion potential', 'CPA', (114, 132))	('growth', 'CPA', (91, 97))	('UOK-145', 'CellLine', 'CVCL:B122', (36, 43))	('TFE3', 'Gene', (28, 32))	('proliferation', 'CPA', (99, 112))
23508	23817689	VHL mutations don't appear to play a role in tRCC, as VHL mutations were not identified in our cohort.	('RCC', 'Disease', (46, 49))	('VHL', 'Gene', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('VHL', 'Gene', '7428', (54, 57))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
23509	23817689	However, other tumor suppressor genes with roles in RCC biology have been recently identified in 3p (PBRM1, SETD2 and BAP1), and thus 3p loss in tRCC tumors might be associated with inactivation of one or more of these genes.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('SETD2', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SETD2', 'Gene', '29072', (108, 113))	('RCC', 'Disease', (146, 149))	('RCC', 'Disease', (52, 55))	('BAP1', 'Gene', '8314', (118, 122))	('loss', 'NegReg', (137, 141))	('tRCC tumors', 'Disease', 'MESH:D009369', (145, 156))	('PBRM1', 'Gene', '55193', (101, 106))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumor', 'Disease', (15, 20))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('15', '31'))	('BAP1', 'Gene', (118, 122))	('PBRM1', 'Gene', (101, 106))	('tumor', 'Disease', (150, 155))	('tRCC tumors', 'Disease', (145, 156))	('inactivation', 'Var', (182, 194))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor suppressor', 'biological_process', 'GO:0051726', ('15', '31'))
23510	23817689	Alternatively, tumor initiation by the TFE3/TFEB translocation might trigger chromosomal instability pathways that resemble those in ccRCC and pRCC subtypes.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('TFEB', 'Gene', '7942', (44, 48))	('pRCC', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('TFEB', 'Gene', (44, 48))	('TFE3', 'Gene', (39, 43))	('chromosomal instability pathways', 'Pathway', (77, 109))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('RCC', 'Disease', (135, 138))	('translocation', 'Var', (49, 62))	('tumor', 'Disease', (15, 20))	('TFE3', 'Gene', '7030', (39, 43))	('pRCC', 'Gene', '5546', (143, 147))	('RCC', 'Disease', (144, 147))	('trigger', 'Reg', (69, 76))	('chromosomal instability', 'Phenotype', 'HP:0040012', (77, 100))
23512	23817689	Interestingly, tRCC patients with 3p loss (ccRCC-like profile) had worse outcomes compared to those without 3p loss.	('3p loss', 'Var', (34, 41))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('patients', 'Species', '9606', (20, 28))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
23522	23817689	Patients with 17q gain were more frequently men, displayed more genetic alterations, and had worse outcomes.	('men', 'Species', '9606', (44, 47))	('gain', 'PosReg', (18, 22))	('17q', 'Var', (14, 17))	('17q', 'Chemical', '-', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('genetic alterations', 'Var', (64, 83))
23524	23817689	Of interest 17q gains are rare in ccRCC and pRCC, in contrast to trisomy 7 and 17, which are very frequent in pRCC.	('pRCC', 'Gene', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Disease', (36, 39))	('pRCC', 'Gene', (110, 114))	('17q gains', 'Var', (12, 21))	('17q', 'Chemical', '-', (12, 15))	('pRCC', 'Gene', '5546', (44, 48))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('pRCC', 'Gene', '5546', (110, 114))
23526	23817689	Together with G-banding and SNP results available for 3 cell lines (HCR-59, MDA-92, and UOK146), our data showed that 2 cases had multiple translocations involving 17q, leading to 17q gain concomitant with i(17q) formation in 1 case, and 1 case had only an i(17q) without other associated translocations.	('MDA-92', 'CellLine', 'CVCL:8607', (76, 82))	('UOK146', 'CellLine', 'CVCL:B123', (88, 94))	('translocations', 'Var', (139, 153))	('17q', 'Chemical', '-', (180, 183))	('gain', 'PosReg', (184, 188))	('17q', 'Chemical', '-', (208, 211))	('17q', 'Chemical', '-', (259, 262))	('17q', 'MPA', (180, 183))	('17q', 'Chemical', '-', (164, 167))	('formation', 'biological_process', 'GO:0009058', ('213', '222'))
23527	23817689	Two cases had breakpoints in 17p11.2 and were thus considered isodicentric chromosomes.	('breakpoints', 'Var', (14, 25))	('p11', 'Gene', '6281', (31, 34))	('p11', 'Gene', (31, 34))
23528	23817689	Of note, 17p11.2 has been reported to contain a cluster region characterized by large palindromic and low copy-repeat sequences in chronic myeloid leukemia (CML), medulloblastoma with idic(p11), and high hyperdiploid childhood acute lymphoblastic leukemia.	('p11', 'Gene', (189, 192))	('p11', 'Gene', '6281', (11, 14))	('chronic myeloid leukemia', 'Disease', (131, 155))	('p11', 'Gene', (11, 14))	('medulloblastoma', 'Disease', 'MESH:D008527', (163, 178))	('medulloblastoma', 'Phenotype', 'HP:0002885', (163, 178))	('high hyperdiploid childhood acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (199, 255))	('medulloblastoma', 'Disease', (163, 178))	('CML', 'Disease', 'MESH:D015464', (157, 160))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('low', 'NegReg', (102, 105))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (227, 255))	('CML', 'Disease', (157, 160))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (233, 255))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (131, 155))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (131, 155))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('leukemia', 'Phenotype', 'HP:0001909', (247, 255))	('palindromic', 'Var', (86, 97))	('p11', 'Gene', '6281', (189, 192))
23532	23817689	It is important to note that CML that bear an i(17q) have a poor prognosis, and medulloblastomas with an i(17q) or a 17q gain also have a poor outcome.	('17q', 'Chemical', '-', (48, 51))	('CML', 'Disease', (29, 32))	('17q', 'Chemical', '-', (117, 120))	('17q', 'Chemical', '-', (107, 110))	('i(17q', 'Var', (105, 110))	('medulloblastomas', 'Disease', 'MESH:D008527', (80, 96))	('medulloblastoma', 'Phenotype', 'HP:0002885', (80, 95))	('i(17q', 'Var', (46, 51))	('medulloblastomas', 'Disease', (80, 96))	('CML', 'Disease', 'MESH:D015464', (29, 32))
23533	23817689	In our study, GSEA analysis of a subset of Xp11 cases with and without partial 17q gain found enrichment of pathways involved in mitosis and the cell cycle in patients with 17q gain, suggesting a proliferative advantage in tumors harboring this chromosomal abnormality.	('cell cycle', 'biological_process', 'GO:0007049', ('145', '155'))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('17q', 'Gene', (79, 82))	('men', 'Species', '9606', (100, 103))	('17q gain', 'Var', (173, 181))	('17q', 'Chemical', '-', (79, 82))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('p11', 'Gene', '6281', (44, 47))	('17q', 'Chemical', '-', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('mitosis', 'Disease', (129, 136))	('mitosis', 'biological_process', 'GO:0000278', ('129', '136'))	('mitosis', 'Disease', 'None', (129, 136))	('patients', 'Species', '9606', (159, 167))	('GSEA', 'Chemical', '-', (14, 18))	('p11', 'Gene', (44, 47))
23536	23817689	Among our 14 previously reported cases, we found one case, that of a 2-year-old girl, who had a t(5;17)(q23;q25), in addition to a t(X;17)(p11.2,17q25) leading to the ASPSCR1-TFE3 fusion, consistent with multiple translocations occurring on the 17q arm.	('t(5;17)(q23;q25', 'Var', (96, 111))	('ASPSCR1', 'Gene', (167, 174))	('leading to', 'Reg', (152, 162))	('girl', 'Species', '9606', (80, 84))	('p11', 'Gene', '6281', (139, 142))	('17q', 'Chemical', '-', (145, 148))	('17q', 'Chemical', '-', (245, 248))	('TFE3', 'Gene', (175, 179))	('ASPSCR1', 'Gene', '79058', (167, 174))	('t(5;17)(q23;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 112))	('TFE3', 'Gene', '7030', (175, 179))	('p11', 'Gene', (139, 142))
23539	23817689	that described tRCC, they identified a complex nonreciprocal t(X;17)(p11.2;q25), involving not only the translocation of Xp11 to 17q25 but also of 17q25 to another chromosome.	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (61, 79))	('17q', 'Chemical', '-', (147, 150))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('RCC', 'Disease', (16, 19))	('p11', 'Gene', (122, 125))	('translocation', 'Var', (104, 117))	('p11', 'Gene', (69, 72))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))	('p11', 'Gene', '6281', (122, 125))	('17q', 'Chemical', '-', (129, 132))	('p11', 'Gene', '6281', (69, 72))
23543	23817689	In conclusion, our data show that tRCC is genetically heterogeneous and share cytogenomic profiles with other renal cell tumors, raising important questions about the role for TFE3/TFEB translocations in tumor initiation and/or progression.	('RCC', 'Disease', (35, 38))	('TFE3', 'Gene', (176, 180))	('renal cell tumors', 'Disease', 'MESH:C538614', (110, 127))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TFEB', 'Gene', '7942', (181, 185))	('translocations', 'Var', (186, 200))	('TFE3', 'Gene', '7030', (176, 180))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('TFEB', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('renal cell tumors', 'Disease', (110, 127))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', (204, 209))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
23575	26170866	At the cystic component, the tumor cells were focally positive for 34BE12 but not for CK-AE1 and CK19.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('CK19', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CK19', 'Gene', '3880', (97, 101))	('tumor', 'Disease', (29, 34))	('positive', 'Reg', (54, 62))	('34BE12', 'Var', (67, 73))
23651	33963171	In addition, high CCL18 and LAMA4 expression in kidney cancer facilitates tumor progression, while its effect can be reversed by miR-622, and C-C motif chemokine 18(CCL18) and laminin subunit alpha-4 (LAMA4) play key roles in tumor progression.	('LAMA4', 'Gene', (28, 33))	('expression', 'MPA', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('C-C motif chemokine 18', 'Gene', (142, 164))	('tumor', 'Disease', (74, 79))	('CCL18', 'Gene', (165, 170))	('LAMA4', 'Gene', '3910', (28, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (48, 61))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('high', 'Var', (13, 17))	('C-C motif chemokine 18', 'Gene', '6362', (142, 164))	('LAMA4', 'Gene', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('CCL18', 'Gene', '6362', (165, 170))	('laminin subunit alpha-4', 'Gene', (176, 199))	('kidney cancer', 'Phenotype', 'HP:0009726', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CCL', 'molecular_function', 'GO:0044101', ('165', '168'))	('kidney cancer', 'Disease', (48, 61))	('LAMA4', 'Gene', '3910', (201, 206))	('miR-622', 'Gene', (129, 136))	('CCL18', 'Gene', (18, 23))	('miR-622', 'Gene', '693207', (129, 136))	('facilitates', 'PosReg', (62, 73))	('CCL', 'molecular_function', 'GO:0044101', ('18', '21'))	('laminin subunit alpha-4', 'Gene', '3910', (176, 199))	('CCL18', 'Gene', '6362', (18, 23))	('tumor', 'Disease', (226, 231))
23657	33963171	The expression of PI3K and Akt can be downregulated by miR-338-3p, miR-15a, and miR-488 or upregulated by KIFC (Kinesin family member C1), eIF4E (eukaryotic initiation factor 4E), and HMGN5 (High-mobility group nucleosome binding domain 5) in RCC.	('Kinesin', 'molecular_function', 'GO:0003777', ('112', '119'))	('eukaryotic initiation factor 4E', 'Gene', '1977', (146, 177))	('expression', 'MPA', (4, 14))	('miR-15a', 'Gene', (67, 74))	('eIF4E', 'Gene', (139, 144))	('eukaryotic initiation factor 4E', 'Gene', (146, 177))	('RCC', 'Disease', (243, 246))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('miR-488', 'Gene', (80, 87))	('eIF4', 'cellular_component', 'GO:0008304', ('139', '143'))	('PI3K', 'Gene', (18, 22))	('upregulated', 'PosReg', (91, 102))	('eIF4E', 'Gene', '1977', (139, 144))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('Akt', 'Gene', (27, 30))	('High-mobility group nucleosome binding domain 5', 'Gene', '79366', (191, 238))	('miR-15a', 'Gene', '406948', (67, 74))	('downregulated', 'NegReg', (38, 51))	('Akt', 'Gene', '207', (27, 30))	('KIFC (Kinesin family member C1', 'Gene', '3833', (106, 136))	('miR-488', 'Gene', '574441', (80, 87))	('nucleosome', 'cellular_component', 'GO:0000786', ('211', '221'))	('miR-338-3p', 'Var', (55, 65))	('nucleosome binding', 'molecular_function', 'GO:0031491', ('211', '229'))	('HMGN5', 'Gene', '79366', (184, 189))	('High-mobility group nucleosome binding domain 5', 'Gene', (191, 238))	('PI3K', 'molecular_function', 'GO:0016303', ('18', '22'))	('HMGN5', 'Gene', (184, 189))
23658	33963171	In addition, overexpression of miR-338-3p, miR-15a, and miR-488 leads to repression of renal cancer progression induced by KIFC1, eIF4E, and HMGN5, respectively.	('HMGN5', 'Gene', '79366', (141, 146))	('eIF4', 'cellular_component', 'GO:0008304', ('130', '134'))	('renal cancer', 'Disease', (87, 99))	('miR-488', 'Gene', (56, 63))	('eIF4E', 'Gene', '1977', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('renal cancer', 'Phenotype', 'HP:0009726', (87, 99))	('HMGN5', 'Gene', (141, 146))	('eIF4E', 'Gene', (130, 135))	('miR-488', 'Gene', '574441', (56, 63))	('KIFC1', 'Gene', '3833', (123, 128))	('KIFC1', 'Gene', (123, 128))	('renal cancer', 'Disease', 'MESH:D007680', (87, 99))	('miR-15a', 'Gene', '406948', (43, 50))	('miR-338-3p', 'Var', (31, 41))	('miR-15a', 'Gene', (43, 50))	('repression', 'NegReg', (73, 83))
23659	33963171	KIFC1, eIF4E, and HMGN5 have been reported to act as oncogenes in various cancers Moreover, the expression of PTEN, which is a master regulator of the PI3K/Akt pathway, could be augmented by miR-520/372/373 and miR-203 or diminished by SPOP in RCC.	('PTEN', 'Gene', '5728', (110, 114))	('RCC', 'Disease', (244, 247))	('RCC', 'Phenotype', 'HP:0005584', (244, 247))	('augmented', 'PosReg', (178, 187))	('miR-203', 'Gene', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('KIFC1', 'Gene', '3833', (0, 5))	('SPOP', 'Gene', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('Akt', 'Gene', (156, 159))	('PI3K', 'molecular_function', 'GO:0016303', ('151', '155'))	('miR-203', 'Gene', '406986', (211, 218))	('expression', 'MPA', (96, 106))	('Akt', 'Gene', '207', (156, 159))	('diminished', 'NegReg', (222, 232))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('HMGN5', 'Gene', '79366', (18, 23))	('PTEN', 'Gene', (110, 114))	('eIF4E', 'Gene', (7, 12))	('miR-520/372/373', 'Var', (191, 206))	('HMGN5', 'Gene', (18, 23))	('KIFC1', 'Gene', (0, 5))	('eIF4E', 'Gene', '1977', (7, 12))	('eIF4', 'cellular_component', 'GO:0008304', ('7', '11'))	('SPOP', 'Gene', '8405', (236, 240))
23660	33963171	Overexpression of miR-520/372/373 results in attenuated renal tumor development by impairing SPOP, and speckle-type POZ protein (SPOP) has been reported to act as an oncogene in renal cancer (Table 1).	('attenuated renal tumor', 'Disease', (45, 67))	('speckle-type POZ protein', 'Gene', (103, 127))	('miR-520/372/373', 'Var', (18, 33))	('impairing', 'NegReg', (83, 92))	('renal cancer', 'Phenotype', 'HP:0009726', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('renal cancer', 'Disease', 'MESH:D007680', (178, 190))	('SPOP', 'Gene', '8405', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('120', '127'))	('SPOP', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('SPOP', 'Gene', '8405', (129, 133))	('renal tumor', 'Phenotype', 'HP:0009726', (56, 67))	('SPOP', 'Gene', (129, 133))	('attenuated renal tumor', 'Disease', 'MESH:C538265', (45, 67))	('renal cancer', 'Disease', (178, 190))	('speckle-type POZ protein', 'Gene', '8405', (103, 127))
23663	33963171	Additionally, the expression of P-Akt and P-ERK can be improved by splicing factor 2 (SF2) and reduced by miR-766-3p in RCC.	('P-ERK', 'Gene', (42, 47))	('improved', 'PosReg', (55, 63))	('SF2', 'Gene', '6426', (86, 89))	('splicing', 'biological_process', 'GO:0045292', ('67', '75'))	('ERK', 'molecular_function', 'GO:0004707', ('44', '47'))	('P-ERK', 'Gene', '9451', (42, 47))	('SF2', 'Gene', (86, 89))	('splicing factor 2', 'Gene', '6426', (67, 84))	('expression', 'MPA', (18, 28))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('reduced', 'NegReg', (95, 102))	('Akt', 'Gene', '207', (34, 37))	('miR-766-3p', 'Chemical', '-', (106, 116))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('Akt', 'Gene', (34, 37))	('miR-766-3p', 'Var', (106, 116))	('splicing factor 2', 'Gene', (67, 84))
23664	33963171	Overexpression of miR-766-3p leads to suppression of tumor growth by regulating SF2, and SF2 belongs to the splicing factor family and promotes carcinoma formation.	('carcinoma', 'Disease', (144, 153))	('SF2', 'Gene', (89, 92))	('miR-766-3p', 'Var', (18, 28))	('formation', 'biological_process', 'GO:0009058', ('154', '163'))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('miR-766-3p', 'Chemical', '-', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppression', 'NegReg', (38, 49))	('carcinoma', 'Disease', 'MESH:D009369', (144, 153))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))	('SF2', 'Gene', '6426', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', (53, 58))	('promotes', 'PosReg', (135, 143))	('SF2', 'Gene', '6426', (89, 92))	('SF2', 'Gene', (80, 83))
23672	33963171	Similarly, miR-218 not only decreases the expression of VEGFA and p-PI3K/p-Akt/p-mTOR and restrains the migration ability of HUVECs (human umbilical vein endothelial cells), but also diminishes tumor angiogenesis in RCC by downregulating GRB2-associated binding protein 2 (GAB2).	('expression', 'MPA', (42, 52))	('angiogenesis', 'biological_process', 'GO:0001525', ('200', '212'))	('tumor', 'Disease', (194, 199))	('decreases', 'NegReg', (28, 37))	('VEGFA', 'Gene', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('GAB2', 'Gene', '9846', (273, 277))	('Akt', 'Gene', (75, 78))	('GAB2', 'Gene', (273, 277))	('mTOR', 'Gene', (81, 85))	('human', 'Species', '9606', (133, 138))	('RCC', 'Disease', (216, 219))	('migration ability', 'CPA', (104, 121))	('GRB2-associated binding protein 2', 'Gene', (238, 271))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('Akt', 'Gene', '207', (75, 78))	('PI3K', 'molecular_function', 'GO:0016303', ('68', '72'))	('miR-218', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('binding', 'molecular_function', 'GO:0005488', ('254', '261'))	('VEGFA', 'Gene', '7422', (56, 61))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('miR-218', 'Chemical', '-', (11, 18))	('mTOR', 'Gene', '2475', (81, 85))	('protein', 'cellular_component', 'GO:0003675', ('262', '269'))	('downregulating', 'NegReg', (223, 237))	('restrains', 'NegReg', (90, 99))	('diminishes', 'NegReg', (183, 193))	('GRB2-associated binding protein 2', 'Gene', '9846', (238, 271))
23676	33963171	In addition miR-148b-3p impairs the expression of VEGF-A and platelet-derived growth factor-BB/D(PDGF-BB/D) in RCC, and PDGF-BB/D act as pro-angiogenic actors in multiple cancers (Table 1).	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('PDGF-BB/D', 'Gene', '80310', (97, 106))	('VEGF-A', 'Gene', (50, 56))	('PDGF', 'molecular_function', 'GO:0005161', ('97', '101'))	('multiple cancers', 'Disease', (162, 178))	('PDGF', 'molecular_function', 'GO:0005161', ('120', '124'))	('miR-148b-3p', 'Chemical', '-', (12, 23))	('PDGF-BB/D', 'Gene', (97, 106))	('PDGF-BB/D', 'Gene', '80310', (120, 129))	('PDGF-BB/D', 'Gene', (120, 129))	('VEGF-A', 'Gene', '7422', (50, 56))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('61', '91'))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('miR-148b-3p', 'Var', (12, 23))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('multiple cancers', 'Disease', 'MESH:D009369', (162, 178))	('impairs', 'NegReg', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('expression', 'MPA', (36, 46))
23688	33963171	Indeed, PDK1 high expression in ccRCC cells boosts ECAR (extracellular acidification rate) under hypoxic conditions, improves ATP production, and diminishes the oxygen consumption rate (OCR) of tumor cells, whereas these effects can be reversed by miR-409-3p.	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('tumor', 'Disease', (194, 199))	('improves', 'PosReg', (117, 125))	('extracellular', 'cellular_component', 'GO:0005576', ('57', '70'))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('miR-409', 'Gene', (248, 255))	('miR-409', 'Gene', '574413', (248, 255))	('RCC', 'Phenotype', 'HP:0005584', (34, 37))	('ATP production', 'MPA', (126, 140))	('PDK1', 'Gene', '5163', (8, 12))	('RCC', 'Disease', (34, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('oxygen consumption rate', 'MPA', (161, 184))	('acidification', 'biological_process', 'GO:0045851', ('71', '84'))	('diminishes', 'NegReg', (146, 156))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('boosts', 'PosReg', (44, 50))	('PDK1', 'molecular_function', 'GO:0004740', ('8', '12'))	('high expression', 'Var', (13, 28))	('oxygen', 'Chemical', 'MESH:D010100', (161, 167))	('hypoxic', 'Disease', 'MESH:D000860', (97, 104))	('hypoxic', 'Disease', (97, 104))	('PDK1', 'Gene', (8, 12))
23704	33963171	Indeed, IMPA2 underexpression in ccRCC diminishes the expression of N-cadherin and Slug, and sabotages tumor metastasis by downregulating miR-25-3p.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('IMPA2', 'Gene', (8, 13))	('Slug', 'Gene', '6591', (83, 87))	('miR', 'Gene', '220972', (138, 141))	('underexpression', 'Var', (14, 29))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))	('RCC', 'Disease', (35, 38))	('N-cadherin', 'Gene', (68, 78))	('sabotages', 'NegReg', (93, 102))	('N-cadherin', 'Gene', '1000', (68, 78))	('miR', 'Gene', (138, 141))	('downregulating', 'NegReg', (123, 137))	('RCC', 'Disease', 'MESH:C538614', (35, 38))	('tumor metastasis', 'Disease', 'MESH:D009362', (103, 119))	('IMPA2', 'Gene', '3613', (8, 13))	('Slug', 'Gene', (83, 87))	('expression', 'MPA', (54, 64))	('tumor metastasis', 'Disease', (103, 119))	('diminishes', 'NegReg', (39, 49))	('cadherin', 'molecular_function', 'GO:0008014', ('70', '78'))
23724	33963171	Likewise, miR-543 and miR-125b facilitate tumor growth through negatively regulating DKK1 and DKK3, respectively, in RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('miR-543', 'Gene', '100126335', (10, 17))	('miR-125b', 'Var', (22, 30))	('RCC', 'Disease', (117, 120))	('tumor', 'Disease', (42, 47))	('miR-543', 'Gene', (10, 17))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('DKK1', 'Gene', '22943', (85, 89))	('DKK1', 'Gene', (85, 89))	('facilitate', 'PosReg', (31, 41))	('DKK3', 'Gene', '27122', (94, 98))	('DKK3', 'Gene', (94, 98))	('miR-125b', 'Chemical', '-', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('negatively regulating', 'NegReg', (63, 84))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
23725	33963171	In addition, overexpression of miR-125b leads to decreasing sensitivity to doxorubicin and sunitinib in renal cancer cells (Figure 2).	('doxorubicin', 'Chemical', 'MESH:D004317', (75, 86))	('renal cancer', 'Disease', (104, 116))	('miR-125b', 'Var', (31, 39))	('sensitivity to doxorubicin', 'MPA', (60, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('overexpression', 'PosReg', (13, 27))	('decreasing', 'NegReg', (49, 59))	('miR-125b', 'Chemical', '-', (31, 39))	('sunitinib', 'Chemical', 'MESH:D000077210', (91, 100))
23732	33963171	In contrast, miR-381-3p inhibits TNF-induced apoptosis and necroptosis through downregulating caspase-8, caspase-3, and RIPK3 (receptor-interacting protein kinase 1) in renal cancer, whereas it has no effect on TNF-induced NF-kappaB activation, thus facilitating tumor progression and implying a poor outcome for papillary RCC patients; these findings suggest that the NF kappaB pathway has different functions in different cells.	('RIPK3', 'Gene', '11035', (120, 125))	('receptor-interacting protein kinase 1', 'Gene', '8737', (127, 164))	('RCC', 'Phenotype', 'HP:0005584', (323, 326))	('inhibits', 'NegReg', (24, 32))	('papillary RCC', 'Disease', 'MESH:C538614', (313, 326))	('caspase-3', 'Gene', '836', (105, 114))	('papillary RCC', 'Disease', (313, 326))	('caspase-3', 'Gene', (105, 114))	('necroptosis', 'biological_process', 'GO:0070266', ('59', '70'))	('NF-kappaB', 'Gene', (223, 232))	('TNF', 'Gene', '7124', (211, 214))	('NF-kappaB activation', 'biological_process', 'GO:0051092', ('223', '243'))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('necroptosis', 'biological_process', 'GO:0097528', ('59', '70'))	('miR-381-3p', 'Chemical', '-', (13, 23))	('necroptosis', 'CPA', (59, 70))	('receptor-interacting protein kinase 1', 'Gene', (127, 164))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('NF-kappaB', 'Gene', '4790', (223, 232))	('tumor', 'Disease', (263, 268))	('caspase-8', 'Gene', '841', (94, 103))	('TNF', 'Gene', (33, 36))	('apoptosis', 'CPA', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('renal cancer', 'Disease', (169, 181))	('NF kappaB', 'Gene', (369, 378))	('RIPK3', 'Gene', (120, 125))	('renal cancer', 'Phenotype', 'HP:0009726', (169, 181))	('patients', 'Species', '9606', (327, 335))	('TNF', 'Gene', '7124', (33, 36))	('downregulating', 'NegReg', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('miR-381-3p', 'Var', (13, 23))	('NF kappaB', 'Gene', '4790', (369, 378))	('caspase-8', 'Gene', (94, 103))	('TNF', 'Gene', (211, 214))	('apoptosis', 'biological_process', 'GO:0097194', ('45', '54'))	('apoptosis', 'biological_process', 'GO:0006915', ('45', '54'))	('renal cancer', 'Disease', 'MESH:D007680', (169, 181))
23734	33963171	The expression of KRAS can be attenuated by solute carrier family 4 (SLC4A4) and increased by miR-223-3p in ccRCC.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('KRAS', 'Gene', (18, 22))	('miR-223-3p', 'Var', (94, 104))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('SLC4A4', 'Gene', (69, 75))	('SLC4A4', 'Gene', '8671', (69, 75))	('expression', 'MPA', (4, 14))	('miR-223-3p', 'Chemical', '-', (94, 104))	('carrier', 'molecular_function', 'GO:0005215', ('51', '58'))	('ccRCC', 'Phenotype', 'HP:0006770', (108, 113))	('increased', 'PosReg', (81, 90))	('attenuated', 'NegReg', (30, 40))
23764	33963171	For instance, the expression of miR-10a-5p, miR-10b-5p, miR-106a-5p, and miR-142-5p is decreased in RCC nephrectomy specimens and has a sensitivity of 91.7% and specificity of 94% for distinguishing cancer from benign tissues.	('miR-106a', 'Gene', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-10b', 'Gene', (44, 51))	('decreased', 'NegReg', (87, 96))	('miR-142-5p', 'Chemical', '-', (73, 83))	('miR-10a', 'Gene', '406902', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('miR-142-5p', 'Var', (73, 83))	('expression', 'MPA', (18, 28))	('cancer', 'Disease', (199, 205))	('RCC nephrectomy', 'Disease', 'MESH:C538614', (100, 115))	('miR-10b', 'Gene', '406903', (44, 51))	('RCC nephrectomy', 'Disease', (100, 115))	('miR-106a', 'Gene', '406899', (56, 64))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('miR-10a', 'Gene', (32, 39))
23772	33963171	Furthermore, miR-99a-3p suppresses RCC development and facilitates TKI treatment by modifying RRM2 (ribonucleotide reductase regulatory subunit M2).	('miR-99a-3p', 'Chemical', '-', (13, 23))	('RCC', 'Disease', (35, 38))	('ribonucleotide reductase regulatory subunit M2', 'Gene', (100, 146))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('miR-99a-3p', 'Var', (13, 23))	('TKI', 'Disease', (67, 70))	('modifying', 'Reg', (84, 93))	('facilitates', 'PosReg', (55, 66))	('RRM2', 'Gene', '6241', (94, 98))	('RRM2', 'Gene', (94, 98))	('suppresses', 'NegReg', (24, 34))	('ribonucleotide reductase regulatory subunit M2', 'Gene', '6241', (100, 146))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
23782	33963171	In addition, RCC patients with high expression of miR-144-5p have better disease-free survival (DFS) than those with low expression of miR-144-5p.	('miR-144', 'Gene', '406936', (135, 142))	('better', 'PosReg', (66, 72))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('disease-free survival', 'CPA', (73, 94))	('RCC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('high expression', 'Var', (31, 46))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('miR-144', 'Gene', (135, 142))	('miR-144', 'Gene', (50, 57))	('miR-144', 'Gene', '406936', (50, 57))
23794	28056882	Within this study, we verify the existence of CD105+ and CD133+ populations in selected papillary subtype RCC (pRCC) cell lines.	('pRCC', 'Gene', '5546', (111, 115))	('papillary subtype RCC', 'Disease', 'MESH:C538614', (88, 109))	('papillary subtype RCC', 'Disease', (88, 109))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('CD105', 'Gene', (46, 51))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('CD105', 'Gene', '13805', (46, 51))	('pRCC', 'Gene', (111, 115))	('CD133+', 'Var', (57, 63))
23840	28056882	Cells were stained with (i) CD105-PE (BD Pharmingen, San Diego, CA, USA, clone 266) plus CD133/1-APC (Miltenyi Biotec, Bergisch Gladbach, Germany, clone AC133); or (ii) CD105-FITC (Biolegend, San Diego, CA, USA, clone 43A3) plus CD133/2-APC (Miltenyi Biotec, Bergisch Gladbach, Germany, clone 293C3) according to the manufacturers' protocols with the appropriate isotype controls.	('CD105', 'Gene', '13805', (169, 174))	('APC', 'cellular_component', 'GO:0005680', ('97', '100'))	('293C3', 'CellLine', 'CVCL:0045', (293, 298))	('CD133/1-APC', 'Var', (89, 100))	('CD105', 'Gene', (28, 33))	('APC', 'cellular_component', 'GO:0005680', ('237', '240'))	('CD105', 'Gene', '13805', (28, 33))	('CD105', 'Gene', (169, 174))
23896	28056882	However, oct4 and sox2 expression increased in low O2.	('sox2', 'Gene', '6657', (18, 22))	('sox2', 'Gene', (18, 22))	('O2', 'Chemical', 'MESH:D010100', (51, 53))	('low O2', 'Var', (47, 53))	('oct4', 'Gene', (9, 13))	('oct4', 'Gene', '5460', (9, 13))	('increased', 'PosReg', (34, 43))	('expression', 'MPA', (23, 33))
24072	23601445	With larger sample sizes, it may be possible to detect more subtle differences among low- and high-grade variants of RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('variants', 'Var', (105, 113))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))
24141	22771265	There were no significant differences in ORR, PFS, and OS between previously untreated and previously treated patients (Tables 3B/C).	('OS', 'Chemical', '-', (55, 57))	('patients', 'Species', '9606', (110, 118))	('ORR', 'MPA', (41, 44))	('3B/C', 'Var', (127, 131))	('3B/C', 'SUBSTITUTION', 'None', (127, 131))
24169	22771265	However, over-expression of MET in pRCC tumors is not limited to cases of mutation.	('MET', 'Var', (28, 31))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('pRCC', 'Gene', '5546', (35, 39))	('over-expression', 'PosReg', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('pRCC', 'Gene', (35, 39))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
24177	22771265	Two ongoing clinical trials are comparing everolimus, an oral mTOR inhibitor, to sunitinib (NCT01185366 and NCT01108445).	('mTOR', 'Gene', '2475', (62, 66))	('mTOR', 'Gene', (62, 66))	('NCT01185366', 'Var', (92, 103))	('NCT01108445', 'Var', (108, 119))	('sunitinib', 'Chemical', 'MESH:D000077210', (81, 90))	('everolimus', 'Chemical', 'MESH:D000068338', (42, 52))
24198	28701475	HIF Activation Causes Synthetic Lethality Between the VHL Tumor Suppressor and the EZH1 Histone Methyltransferase Inactivation of the von Hippel Lindau tumor suppressor protein (pVHL) is the signature lesion in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC).	('VHL Tumor', 'Disease', (54, 63))	('Inactivation', 'Var', (114, 126))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('152', '168'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (250, 281))	('von Hippel Lindau tumor', 'Disease', (134, 157))	('Synthetic Lethality', 'MPA', (22, 41))	('von Hippel Lindau tumor', 'Disease', 'MESH:D006623', (134, 157))	('tumor suppressor', 'biological_process', 'GO:0051726', ('152', '168'))	('protein', 'cellular_component', 'GO:0003675', ('169', '176'))	('Tumor Suppressor', 'molecular_function', 'GO:0008181', ('58', '74'))	('VHL Tumor', 'Disease', 'MESH:D006623', (54, 63))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (250, 281))	('EZH1', 'Gene', (83, 87))	('Tumor Suppressor', 'biological_process', 'GO:0051726', ('58', '74'))	('kidney cancer', 'Disease', (235, 248))	('kidney cancer', 'Disease', 'MESH:D007680', (235, 248))	('EZH1', 'Gene', '2145', (83, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (261, 281))	('ccRCC', 'Phenotype', 'HP:0006770', (283, 288))	('pVHL', 'Gene', (178, 182))	('pVHL', 'Gene', '7428', (178, 182))	('Tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('clear cell renal cell carcinoma', 'Disease', (250, 281))	('kidney cancer', 'Phenotype', 'HP:0009726', (235, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
24203	28701475	The most common form of kidney cancer is clear cell renal carcinoma (ccRCC), which is often linked to mutational inactivation or hypermethylation of the VHL tumor suppressor gene.	('kidney cancer', 'Phenotype', 'HP:0009726', (24, 37))	('kidney cancer', 'Disease', 'MESH:D007680', (24, 37))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (41, 67))	('renal carcinoma', 'Phenotype', 'HP:0005584', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('VHL tumor', 'Disease', 'MESH:D006623', (153, 162))	('kidney cancer', 'Disease', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor suppressor', 'biological_process', 'GO:0051726', ('157', '173'))	('linked', 'Reg', (92, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (69, 74))	('mutational inactivation', 'Var', (102, 125))	('clear cell renal carcinoma', 'Disease', (41, 67))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('157', '173'))	('hypermethylation', 'Var', (129, 145))	('VHL tumor', 'Disease', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (41, 67))
24208	28701475	Deregulation of HIFalpha, and particularly HIF2alpha, drives the development of pVHL-defective ccRCC.	('Deregulation', 'Var', (0, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('pVHL', 'Gene', '7428', (80, 84))	('pVHL', 'Gene', (80, 84))	('HIF2alpha', 'Gene', (43, 52))	('HIF2alpha', 'Gene', '2034', (43, 52))
24209	28701475	VHL inactivation is an early "gatekeeper" event in ccRCC, but is not sufficient to cause ccRCC.	('inactivation', 'Var', (4, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (89, 94))	('gatekeeper', 'Species', '111938', (30, 40))	('VHL', 'Gene', (0, 3))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('ccRCC', 'Disease', (51, 56))
24210	28701475	Additional genetic changes that cooperate with VHL loss to promote tumorigenesis include loss of chromosome 14q and gain of chromosome 5q, as well as intragenic mutations that frequently affect chromatin regulators such as BAF180, BAF250, BRG1, BAP1, KDM6A, KDM5C, SETD2, and MLL3.	('VHL loss', 'Disease', (47, 55))	('BAP1', 'Gene', '8314', (245, 249))	('tumor', 'Disease', (67, 72))	('chromatin', 'cellular_component', 'GO:0000785', ('194', '203'))	('MLL3', 'Gene', (276, 280))	('VHL loss', 'Disease', 'MESH:D006623', (47, 55))	('SETD2', 'Gene', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('BAF250', 'Gene', '8289', (231, 237))	('affect', 'Reg', (187, 193))	('BAF250', 'Gene', (231, 237))	('BRG1', 'Gene', '6597', (239, 243))	('KDM5C', 'Gene', (258, 263))	('KDM6A', 'Gene', '7403', (251, 256))	('BAP1', 'Gene', (245, 249))	('SETD2', 'Gene', '29072', (265, 270))	('chromosome', 'cellular_component', 'GO:0005694', ('124', '134'))	('BRG1', 'Gene', (239, 243))	('chromosome', 'cellular_component', 'GO:0005694', ('97', '107'))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('BAF180', 'Gene', '55193', (223, 229))	('loss', 'NegReg', (89, 93))	('KDM6A', 'Gene', (251, 256))	('MLL3', 'Gene', '58508', (276, 280))	('promote', 'PosReg', (59, 66))	('mutations', 'Var', (161, 170))	('BAF180', 'Gene', (223, 229))	('KDM5C', 'Gene', '8242', (258, 263))	('gain', 'PosReg', (116, 120))
24221	28701475	Some pRCCs have high HIF expression due to mutations affecting genes other than VHL.	('pRCC', 'Gene', (5, 9))	('VHL', 'Gene', (80, 83))	('pRCC', 'Gene', '5546', (5, 9))	('mutations', 'Var', (43, 52))	('pRCCs', 'Phenotype', 'HP:0006766', (5, 10))	('HIF expression', 'MPA', (21, 35))
24232	28701475	The two EZH1 shRNAs that most effectively downregulated EZH1 (10708 and 734) also selectively inhibited VHL-/- ccRCC cells, whereas the relatively ineffective EZH1 shRNAs had minimal effect (Fig.	('EZH1', 'Gene', '2145', (56, 60))	('10708', 'Var', (62, 67))	('EZH1', 'Gene', '2145', (8, 12))	('downregulated', 'NegReg', (42, 55))	('VHL-/- ccRCC', 'Disease', (104, 116))	('EZH1', 'Gene', (159, 163))	('EZH1', 'Gene', (56, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))	('EZH1', 'Gene', (8, 12))	('inhibited', 'NegReg', (94, 103))	('EZH1', 'Gene', '2145', (159, 163))
24240	28701475	We also showed that inactivating EZH1 using CRISPR/Cas9 with two different sgRNAs preferentially inhibited VHL-/- cells (Fig.	('EZH1', 'Gene', '2145', (33, 37))	('Cas', 'cellular_component', 'GO:0005650', ('51', '54'))	('inactivating', 'Var', (20, 32))	('inhibited', 'NegReg', (97, 106))	('EZH1', 'Gene', (33, 37))	('VHL-/- cells', 'CPA', (107, 119))
24246	28701475	3B) and is cytotoxic to EZH2 mutant lymphoma cells (fig.	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('EZH2', 'Gene', '2146', (24, 28))	('mutant', 'Var', (29, 35))	('EZH2', 'Gene', (24, 28))	('lymphoma', 'Disease', (36, 44))	('lymphoma', 'Disease', 'MESH:D008223', (36, 44))
24247	28701475	We confirmed that JQ-EZ-05 reversibly and specifically inhibited H3K27me3 in VHL-/- ccRCC cells, as determined by immunoblot analysis (Fig.	('JQ-EZ-05', 'Var', (18, 26))	('JQ-EZ-05', 'Chemical', '-', (18, 26))	('H3K27me3', 'Protein', (65, 73))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('inhibited', 'NegReg', (55, 64))
24248	28701475	Consistent with our genetic studies, JQ-EZ-05 preferentially inhibited the growth and viability of VHL-/- ccRCC cells compared to their pVHL-proficient counterparts in monolayer assays (Fig.	('inhibited', 'NegReg', (61, 70))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('JQ-EZ-05', 'Chemical', '-', (37, 45))	('preferentially', 'PosReg', (46, 60))	('JQ-EZ-05', 'Var', (37, 45))	('pVHL', 'Gene', '7428', (136, 140))	('pVHL', 'Gene', (136, 140))
24250	28701475	4A), which is consistent with the knowledge that the latter is controlled primarily by EZH2 and that the biochemical Ki of JQ-EZ-05 for EZH1 is 10 fold-higher than its Ki for EZH2 (Fig.	('EZH1', 'Gene', (136, 140))	('EZH2', 'Gene', '2146', (175, 179))	('EZH2', 'Gene', (175, 179))	('EZH2', 'Gene', '2146', (87, 91))	('EZH1', 'Gene', '2145', (136, 140))	('EZH2', 'Gene', (87, 91))	('fold-higher', 'PosReg', (147, 158))	('JQ-EZ-05', 'Chemical', '-', (123, 131))	('JQ-EZ-05', 'Var', (123, 131))
24251	28701475	Notably, differential suppression of VHL-/- ccRCC cells relative to pVHL-proficient ccRCC cells by JQ-EZ-05 and GSK-126 might be attenuated because, in addition to EZH1, they both inhibit EZH2 and perhaps other targets.	('EZH2', 'Gene', (188, 192))	('JQ-EZ-05', 'Chemical', '-', (99, 107))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('EZH1', 'Gene', (164, 168))	('inhibit', 'NegReg', (180, 187))	('EZH1', 'Gene', '2145', (164, 168))	('ccRCC', 'Phenotype', 'HP:0006770', (84, 89))	('pVHL', 'Gene', '7428', (68, 72))	('GSK', 'molecular_function', 'GO:0050321', ('112', '115'))	('EZH2', 'Gene', '2146', (188, 192))	('pVHL', 'Gene', (68, 72))	('GSK-126', 'Gene', (112, 119))	('JQ-EZ-05', 'Var', (99, 107))
24253	28701475	Finally, JQ-EZ-05 impeded VHL-/- ccRCC cells in orthotopic tumor assays in vivo (Fig.	('tumor', 'Disease', (59, 64))	('JQ-EZ-05', 'Chemical', '-', (9, 17))	('JQ-EZ-05', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('impeded', 'NegReg', (18, 25))	('VHL-/- ccRCC cells', 'CPA', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (33, 38))
24257	28701475	To more formally address whether the antiproliferative effects of JQ-EZ-05 on VHL-/- ccRCC cells were on-target, we asked whether they could be reversed by JQ-EZ-05-resistant EZH1 variants, identified using two different approaches.	('JQ-EZ-05', 'Chemical', '-', (66, 74))	('JQ-EZ-05', 'Chemical', '-', (156, 164))	('EZH1', 'Gene', (175, 179))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('EZH1', 'Gene', '2145', (175, 179))	('variants', 'Var', (180, 188))
24261	28701475	Introduction of this EZH1 variant (DeltaPSET) into VHL-/- ccRCC cells also blunted the antiproliferative effects of JQ-EZ-05 (Fig.	('blunted', 'NegReg', (75, 82))	('EZH1', 'Gene', (21, 25))	('variant', 'Var', (26, 33))	('antiproliferative effects', 'MPA', (87, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (58, 63))	('EZH1', 'Gene', '2145', (21, 25))	('JQ-EZ-05', 'Chemical', '-', (116, 124))
24262	28701475	We also randomly mutagenized a lentiviral EZH1 expression plasmid by propagating it in error-prone E. coli (XL1-Red).	('E. coli', 'Species', '562', (99, 106))	('mutagenized', 'Var', (17, 28))	('EZH1', 'Gene', '2145', (42, 46))	('EZH1', 'Gene', (42, 46))
24265	28701475	Moreover, JQ-EZ-05's effect on H3K27me3 after 3 weeks was slightly attenuated in the polyclonal cells that received the mutagenized EZH1 relative to newly infected cells that were infected to produce wild-type EZH1 or GFP (Fig.	('mutagenized', 'Var', (120, 131))	('EZH1', 'Gene', (210, 214))	('H3K27me3', 'Protein', (31, 39))	('EZH1', 'Gene', (132, 136))	('attenuated', 'NegReg', (67, 77))	('EZH1', 'Gene', '2145', (210, 214))	('EZH1', 'Gene', '2145', (132, 136))	('JQ-EZ-05', 'Chemical', '-', (10, 18))
24266	28701475	5E), suggesting that some of the EZH1 random variants could, like the DeltaPSET variant, assume EZH2-like properties.	('EZH1', 'Gene', '2145', (33, 37))	('EZH2', 'Gene', '2146', (96, 100))	('variants', 'Var', (45, 53))	('EZH2', 'Gene', (96, 100))	('EZH1', 'Gene', (33, 37))
24267	28701475	We pooled the resistant cells and used next-gen sequencing to identify the enriched EZH1 variants, which were then individually cloned and studied in secondary assays.	('variants', 'Var', (89, 97))	('EZH1', 'Gene', (84, 88))	('EZH1', 'Gene', '2145', (84, 88))
24268	28701475	We confirmed that two such variants, Y727F and D745N, conferred partial resistance to JQ-EZ-05 in cell viability assays (Fig.	('JQ-EZ-05', 'Chemical', '-', (86, 94))	('D745N', 'Mutation', 'rs138757221', (47, 52))	('Y727F', 'Mutation', 'p.Y727F', (37, 42))	('Y727F', 'Var', (37, 42))	('resistance', 'MPA', (72, 82))	('D745N', 'Var', (47, 52))
24269	28701475	In biochemical and cell-based assays, we confirmed decreased binding of JQ-EZ-05 to the D745N and DeltaPSET EZH1 variants (fig.	('variants', 'Var', (113, 121))	('D745N', 'Mutation', 'rs138757221', (88, 93))	('JQ-EZ-05', 'Chemical', '-', (72, 80))	('EZH1', 'Gene', (108, 112))	('decreased', 'NegReg', (51, 60))	('JQ-EZ-05', 'Gene', (72, 80))	('D745N', 'Var', (88, 93))	('binding', 'molecular_function', 'GO:0005488', ('61', '68'))	('EZH1', 'Gene', '2145', (108, 112))	('binding', 'Interaction', (61, 68))
24270	28701475	S9, E and F), which argues that these variants confer resistance by restoring EZH1 catalytic activity in the presence of JQ-EZ-05 rather than by drug sequestration.	('JQ-EZ-05', 'Chemical', '-', (121, 129))	('catalytic activity', 'molecular_function', 'GO:0003824', ('83', '101'))	('variants', 'Var', (38, 46))	('EZH1', 'Gene', '2145', (78, 82))	('catalytic activity', 'MPA', (83, 101))	('restoring', 'PosReg', (68, 77))	('EZH1', 'Gene', (78, 82))
24271	28701475	In contrast, despite the modeled proximity of Y727 to the putative JQ-EZ-05 binding site within EZH1 (Fig.	('Y727', 'Var', (46, 50))	('EZH1', 'Gene', (96, 100))	('binding', 'molecular_function', 'GO:0005488', ('76', '83'))	('JQ-EZ-05', 'Chemical', '-', (67, 75))	('EZH1', 'Gene', '2145', (96, 100))	('binding', 'Interaction', (76, 83))
24273	28701475	One possibility, among many, is that the Y727F mutation attenuates JQ-EZ-05's effect on EZH1 catalytic activity in vivo, perhaps by increasing EZH1's affinity for S-Adenosyl Methionine (SAM) or EZH1's kcat.	('kcat', 'MPA', (201, 205))	('increasing', 'PosReg', (132, 142))	('Y727F', 'Mutation', 'p.Y727F', (41, 46))	('EZH1', 'Gene', (143, 147))	('EZH1', 'Gene', '2145', (194, 198))	('Methionine', 'Chemical', 'MESH:D008715', (174, 184))	('JQ-EZ-05', 'Gene', (67, 75))	('EZH1', 'Gene', '2145', (88, 92))	('catalytic activity', 'molecular_function', 'GO:0003824', ('93', '111'))	('Y727F', 'Var', (41, 46))	('attenuates', 'NegReg', (56, 66))	('EZH1', 'Gene', '2145', (143, 147))	('affinity', 'Interaction', (150, 158))	('JQ-EZ-05', 'Chemical', '-', (67, 75))	('EZH1', 'Gene', (194, 198))	('catalytic activity', 'MPA', (93, 111))	('EZH1', 'Gene', (88, 92))
24274	28701475	The D745N and Y727F EZH1 variants, unlike the DeltaPSET EZH1 mutant, had little (D745N) or no (Y727F) discernable effect on the loss of bulk H3K27me3 caused by JQ-EZ-05 (Fig.	('EZH1', 'Gene', '2145', (56, 60))	('loss', 'NegReg', (128, 132))	('D745N', 'Var', (4, 9))	('Y727F', 'Var', (14, 19))	('EZH1', 'Gene', (20, 24))	('D745N', 'Mutation', 'rs138757221', (81, 86))	('JQ-EZ-05', 'Var', (160, 168))	('D745N', 'Mutation', 'rs138757221', (4, 9))	('JQ-EZ-05', 'Chemical', '-', (160, 168))	('EZH1', 'Gene', '2145', (20, 24))	('bulk', 'MPA', (136, 140))	('EZH1', 'Gene', (56, 60))	('H3K27me3', 'Protein', (141, 149))	('Y727F', 'Mutation', 'p.Y727F', (95, 100))	('Y727F', 'Mutation', 'p.Y727F', (14, 19))
24276	28701475	The fact that all three EZH1 variants, including the Y727F variant, rescued VHL-/- ccRCC cell viability in the face of a dual EZH1/2 inhibitor suggests that EZH1 has genomic locus-specific effects that are not reflected in bulk H3K27me3 measurements.	('EZH1', 'Gene', (157, 161))	('rescued', 'PosReg', (68, 75))	('EZH1', 'Gene', (126, 130))	('EZH1', 'Gene', (24, 28))	('EZH1', 'Gene', '2145', (157, 161))	('EZH1/2', 'Gene', (126, 132))	('variants', 'Var', (29, 37))	('Y727F', 'Mutation', 'p.Y727F', (53, 58))	('Y727F', 'Var', (53, 58))	('VHL-/- ccRCC', 'Disease', (76, 88))	('EZH1', 'Gene', '2145', (126, 130))	('EZH1', 'Gene', '2145', (24, 28))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('EZH1/2', 'Gene', '2145;2146', (126, 132))
24280	28701475	Similarly, downregulating ARNT using two highly effective shRNAs or with C RISPR/Cas9 conferred resistance to JQ-EZ-05 (Fig 6, E to H, and fig.	('Cas', 'cellular_component', 'GO:0005650', ('81', '84'))	('JQ-EZ-05', 'Chemical', '-', (110, 118))	('resistance', 'MPA', (96, 106))	('downregulating', 'NegReg', (11, 25))	('JQ-EZ-05', 'Var', (110, 118))	('ARNT', 'Gene', '405', (26, 30))	('ARNT', 'Gene', (26, 30))
24284	28701475	Moreover, we consistently noted that compared to their VHL-/- counterparts, the pharmacodynamic effects of JQ-EZ-05 on H3K27me3 were blunted in lentivirally-reconstituted (Fig 4A and fig.	('pharmacodynamic effects', 'MPA', (80, 103))	('JQ-EZ-05', 'Chemical', '-', (107, 115))	('H3K27me3', 'Protein', (119, 127))	('JQ-EZ-05', 'Var', (107, 115))	('blunted', 'NegReg', (133, 140))
24286	28701475	S11C), and restoration of pVHL function in VHL-deficient cells increased H3K27me3 (fig.	('increased', 'PosReg', (63, 72))	('VHL-deficient', 'Disease', 'MESH:D006623', (43, 56))	('S11C', 'SUBSTITUTION', 'None', (0, 4))	('VHL-deficient', 'Disease', (43, 56))	('H3K27me3', 'Protein', (73, 81))	('pVHL', 'Gene', '7428', (26, 30))	('pVHL', 'Gene', (26, 30))	('S11C', 'Var', (0, 4))
24287	28701475	S11D), suggesting that VHL-/- ccRCC cells either have increased H3K27 demethylase activity or decreased H3K27 methyltransferase activity.	('activity', 'MPA', (128, 136))	('ccRCC', 'Phenotype', 'HP:0006770', (30, 35))	('demethylase activity', 'molecular_function', 'GO:0032451', ('70', '90'))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('110', '136'))	('S11D', 'Var', (0, 4))	('increased', 'PosReg', (54, 63))	('S11D', 'SUBSTITUTION', 'None', (0, 4))	('decreased', 'NegReg', (94, 103))	('H3K27 methyltransferase', 'Enzyme', (104, 127))	('activity', 'MPA', (82, 90))	('H3K27', 'Protein', (64, 69))
24288	28701475	In support of the former, we observed that extracts from VHL-deficient cells demethylate H3K27, but not H3K9, on calf thymus core histones more rapidly than extracts from pVHL-proficient cells (Fig.	('pVHL', 'Gene', (171, 175))	('VHL-deficient', 'Disease', 'MESH:D006623', (57, 70))	('VHL-deficient', 'Disease', (57, 70))	('H3K27', 'Protein', (89, 94))	('core', 'cellular_component', 'GO:0019013', ('125', '129'))	('demethylate', 'Var', (77, 88))	('pVHL', 'Gene', '7428', (171, 175))	('calf', 'Species', '9913', (113, 117))
24293	28701475	Although KDM6B can be regulated by HIF1alpha, KDM6B levels were decreased by ARNT sh/sgRNAs in 786-O cells, which contain HIF2alpha and not HIF1alpha, suggesting that KDM6B can be regulated by HIF2alpha (fig S12B).	('HIF1alpha', 'Gene', (140, 149))	('KDM6B', 'Gene', (9, 14))	('HIF1alpha', 'Gene', '3091', (35, 44))	('KDM6B', 'Gene', (167, 172))	('KDM6B', 'Gene', '23135', (9, 14))	('HIF1alpha', 'Gene', (35, 44))	('HIF2alpha', 'Gene', (122, 131))	('ARNT', 'Gene', '405', (77, 81))	('KDM6B', 'Gene', '23135', (167, 172))	('KDM6B', 'Gene', (46, 51))	('S12B', 'SUBSTITUTION', 'None', (208, 212))	('decreased', 'NegReg', (64, 73))	('ARNT', 'Gene', (77, 81))	('KDM6B', 'Gene', '23135', (46, 51))	('HIF2alpha', 'Gene', (193, 202))	('HIF2alpha', 'Gene', '2034', (122, 131))	('HIF1alpha', 'Gene', '3091', (140, 149))	('S12B', 'Var', (208, 212))	('HIF2alpha', 'Gene', '2034', (193, 202))
24294	28701475	Consistent with this notion, eliminating HIF2alpha with CRISPR/Cas9 in UMRC-2 cells, which contain both HIF1alpha and HIF2alpha, downregulated KDM6B (Fig.	('downregulated', 'NegReg', (129, 142))	('eliminating', 'Var', (29, 40))	('HIF2alpha', 'Gene', (118, 127))	('Cas', 'cellular_component', 'GO:0005650', ('63', '66'))	('KDM6B', 'Gene', (143, 148))	('HIF2alpha', 'Gene', '2034', (41, 50))	('UMRC-2', 'CellLine', 'CVCL:2739', (71, 77))	('HIF1alpha', 'Gene', (104, 113))	('HIF1alpha', 'Gene', '3091', (104, 113))	('HIF2alpha', 'Gene', '2034', (118, 127))	('HIF2alpha', 'Gene', (41, 50))	('KDM6B', 'Gene', '23135', (143, 148))
24297	28701475	Therefore, deregulation of HIF-responsive demethylases, and particularly KDM6B, increases the dependence of VHL-/- ccRCCs on EZH1 activity.	('dependence', 'MPA', (94, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (115, 120))	('demethylases', 'Enzyme', (42, 54))	('deregulation', 'Var', (11, 23))	('KDM6B', 'Gene', '23135', (73, 78))	('increases', 'PosReg', (80, 89))	('EZH1', 'Gene', (125, 129))	('KDM6B', 'Gene', (73, 78))	('EZH1', 'Gene', '2145', (125, 129))
24300	28701475	S13A), suggesting a non-redundant role for these enzymes in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('ccRCC', 'Disease', (60, 65))	('S13A', 'Var', (0, 4))	('S13A', 'SUBSTITUTION', 'None', (0, 4))
24305	28701475	8B) inactivation of EZH1 and performed GSEA.	('EZH1', 'Gene', (20, 24))	('inactivation', 'Var', (4, 16))	('EZH1', 'Gene', '2145', (20, 24))	('GSEA', 'Chemical', '-', (39, 43))
24306	28701475	Because JQ-EZ-05 inhibits both EZH1 and EZH2, we treated cells expressing wild-type EZH1 and cells expressing the EZH1 Y727F JQ-EZ-05-resistant variant (Fig.	('inhibits', 'NegReg', (17, 25))	('Y727F', 'Mutation', 'p.Y727F', (119, 124))	('EZH1', 'Gene', '2145', (114, 118))	('JQ-EZ-05', 'Chemical', '-', (125, 133))	('JQ-EZ-05', 'Chemical', '-', (8, 16))	('EZH1', 'Gene', '2145', (84, 88))	('EZH1', 'Gene', (31, 35))	('EZH1', 'Gene', '2145', (31, 35))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('EZH1', 'Gene', (114, 118))	('EZH1', 'Gene', (84, 88))	('Y727F', 'Var', (119, 124))
24308	28701475	We focused specifically on gene sets that are induced upon EZH1 loss because H3K27me3 is usually a repressive mark.	('EZH1', 'Gene', (59, 63))	('loss', 'NegReg', (64, 68))	('H3K27me3', 'Var', (77, 85))	('EZH1', 'Gene', '2145', (59, 63))
24310	28701475	A potential link between EZH1 and sterol biosynthesis is noteworthy because dysregulated fatty acid metabolism is believed to cause the 'clear cell' phenotype of VHL-deficient ccRCC.	('VHL-deficient', 'Disease', 'MESH:D006623', (162, 175))	('VHL-deficient', 'Disease', (162, 175))	('EZH1', 'Gene', (25, 29))	('cause', 'Reg', (126, 131))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('89', '110'))	('sterol biosynthesis', 'biological_process', 'GO:0016126', ('34', '53'))	("'clear", 'PosReg', (136, 142))	('fatty acid metabolism', 'MPA', (89, 110))	('dysregulated', 'Var', (76, 88))	('sterol', 'Chemical', 'MESH:D013261', (34, 40))	('EZH1', 'Gene', '2145', (25, 29))	('ccRCC', 'Phenotype', 'HP:0006770', (176, 181))	('fatty acid', 'Chemical', 'MESH:D005227', (89, 99))	('ccRCC', 'Disease', (176, 181))
24311	28701475	We confirmed that multiple SREBP-responsive mRNAs, including the HMGCS1 and SQLE mRNAs, are far more highly induced after EZH1 inactivation in VHL-/- ccRCC cells than in their pVHL-proficient counterparts (Fig.	('EZH1', 'Gene', (122, 126))	('SQLE', 'Gene', (76, 80))	('HMGCS1', 'Gene', '3157', (65, 71))	('inactivation', 'Var', (127, 139))	('ccRCC', 'Phenotype', 'HP:0006770', (150, 155))	('HMGCS1', 'Gene', (65, 71))	('pVHL', 'Gene', '7428', (176, 180))	('EZH1', 'Gene', '2145', (122, 126))	('pVHL', 'Gene', (176, 180))	('SQLE', 'Gene', '6713', (76, 80))	('highly induced', 'PosReg', (101, 115))
24317	28701475	This still did not explain why only loss of KDM6B, but not KDM6A, reversed the dependence on EZH1.	('KDM6A', 'Gene', (59, 64))	('KDM6B', 'Gene', (44, 49))	('loss', 'Var', (36, 40))	('KDM6A', 'Gene', '7403', (59, 64))	('EZH1', 'Gene', (93, 97))	('dependence', 'MPA', (79, 89))	('KDM6B', 'Gene', '23135', (44, 49))	('EZH1', 'Gene', '2145', (93, 97))
24320	28701475	These analyses reveal that the VHL-/- ccRCC cell lines that are hypersensitive to loss of EZH1 H3K27 methyltransferase activity have a gene expression signature consistent with H3K27 hypomethylation and probably depend primarily on KDM6B for H3K27 homeostasis due to decreased KDM6A.	('EZH1', 'Gene', '2145', (90, 94))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('101', '127'))	('H3K27 methyltransferase', 'Enzyme', (95, 118))	('KDM6A', 'Gene', '7403', (277, 282))	('KDM6B', 'Gene', (232, 237))	('homeostasis', 'biological_process', 'GO:0042592', ('248', '259'))	('gene expression', 'biological_process', 'GO:0010467', ('135', '150'))	('EZH1', 'Gene', (90, 94))	('H3K27', 'Protein', (177, 182))	('KDM6B', 'Gene', '23135', (232, 237))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('loss', 'NegReg', (82, 86))	('hypersensitive', 'Disease', (64, 78))	('activity', 'MPA', (119, 127))	('hypomethylation', 'Var', (183, 198))	('hypersensitive', 'Disease', 'MESH:D004342', (64, 78))	('KDM6A', 'Gene', (277, 282))
24324	28701475	Specifically, the chromatin-associated mutations in ccRCC might arise to mitigate or amplify the effects of HIF-responsive chromatin modifiers that would otherwise suppress or enhance, respectively, tumor growth.	('tumor', 'Disease', (199, 204))	('ccRCC', 'Gene', (52, 57))	('ccRCC', 'Phenotype', 'HP:0006770', (52, 57))	('mutations', 'Var', (39, 48))	('enhance', 'PosReg', (176, 183))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('chromatin', 'cellular_component', 'GO:0000785', ('123', '132'))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('chromatin', 'cellular_component', 'GO:0000785', ('18', '27'))	('suppress', 'NegReg', (164, 172))
24330	28701475	We ensured that the antiproliferative effects of EZH1 shRNAs in VHL-/- ccRCC cells were rescued by restoring the expression of EZH1 with an shRNA-resistant mRNA, and we corroborated our shRNA results with two orthogonal approaches: elimination of EZH1 with CRISPR/Cas9 and pharmacological inhibition of EZH1 methyltransferase activity, again with controls to ensure that the effects we observed were on-target.	('ccRCC', 'Phenotype', 'HP:0006770', (71, 76))	('pharmacological', 'Var', (273, 288))	('EZH1', 'Gene', (49, 53))	('EZH1', 'Gene', (303, 307))	('EZH1', 'Gene', '2145', (127, 131))	('EZH1', 'Gene', '2145', (247, 251))	('methyltransferase activity', 'molecular_function', 'GO:0008168', ('308', '334'))	('EZH1', 'Gene', '2145', (49, 53))	('EZH1', 'Gene', '2145', (303, 307))	('EZH1', 'Gene', (127, 131))	('Cas', 'cellular_component', 'GO:0005650', ('264', '267'))	('EZH1', 'Gene', (247, 251))
24349	28701475	For example, the H3K36 demethylase KDM4A (JMJD2A), which can act as an oncogene, also scored as synthetic lethal with VHL in our screen.	('H3K36', 'Var', (17, 22))	('KDM4A', 'Gene', '9682', (35, 40))	('JMJD2A', 'Gene', '9682', (42, 48))	('JMJD2A', 'Gene', (42, 48))	('KDM4A', 'Gene', (35, 40))
24353	28701475	Moreover, the antitumor effects of JQ-EZ-05 for VHL-/- ccRCCs in vivo were markedly reduced in mice with high tumor burdens.	('JQ-EZ-05', 'Var', (35, 43))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('reduced', 'NegReg', (84, 91))	('high tumor', 'Disease', (105, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (55, 60))	('high tumor', 'Disease', 'MESH:D009369', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('JQ-EZ-05', 'Chemical', '-', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
24354	28701475	On the other hand, JQ-EZ-05 more potently inhibits EZH2 than EZH1 in biochemical assays in vitro, and has not been optimized for in vivo bioavailability.	('EZH1', 'Gene', (61, 65))	('inhibits', 'NegReg', (42, 50))	('EZH2', 'Gene', '2146', (51, 55))	('EZH2', 'Gene', (51, 55))	('JQ-EZ-05', 'Var', (19, 27))	('EZH1', 'Gene', '2145', (61, 65))	('JQ-EZ-05', 'Chemical', '-', (19, 27))
24374	31227023	Furthermore, compared with targeted sequencing, WES was more likely to generate false positives and false negatives due to insufficient base coverage.	('insufficient', 'Disease', (123, 135))	('insufficient', 'Disease', 'MESH:D000309', (123, 135))	('false', 'biological_process', 'GO:0071878', ('80', '85'))	('WES', 'Var', (48, 51))	('false', 'biological_process', 'GO:0071878', ('100', '105'))	('false', 'biological_process', 'GO:0071877', ('80', '85'))	('false', 'biological_process', 'GO:0071877', ('100', '105'))	('base coverage', 'MPA', (136, 149))
24376	31227023	Based on the current understanding, programmed death-1 (PD-1) can combine with programmed death-ligand 1 (PD-L1) to confine T cell activity in the tumor microenvironment, and inhibition of the PD-1/PD-L1 pathway can increase the anti-tumor immune response.	('tumor', 'Disease', (234, 239))	('PD-1', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('PD-1', 'Gene', '5133', (193, 197))	('tumor', 'Disease', (147, 152))	('programmed death-ligand 1', 'Gene', (79, 104))	('PD-L1', 'Gene', (198, 203))	('inhibition', 'Var', (175, 185))	('ligand', 'molecular_function', 'GO:0005488', ('96', '102'))	('programmed death-1', 'Gene', (36, 54))	('programmed death-1', 'Gene', '5133', (36, 54))	('PD-L1', 'Gene', '29126', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('programmed death-ligand 1', 'Gene', '29126', (79, 104))	('PD-1', 'Gene', (56, 60))	('PD-1', 'Gene', '5133', (56, 60))	('increase', 'PosReg', (216, 224))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('immune response', 'biological_process', 'GO:0006955', ('240', '255'))	('PD-L1', 'Gene', (106, 111))	('PD-L1', 'Gene', '29126', (106, 111))
24383	31227023	The functional significance of missense mutations was predicted via several algorithms, including SIFT, PolyPhen2 HDIV, PolyPhen2 HVAR, LRT, MutationTaster, MutationAssessor, and FATHMM.	('missense mutations', 'Var', (31, 49))	('PolyPhen2', 'Var', (120, 129))	('SIFT', 'Disease', 'None', (98, 102))	('SIFT', 'Disease', (98, 102))
24387	31227023	In the present study, VHL was somatically mutated in 10 ccRCC specimens, including five frameshift mutations, namely, p. K159fs, p. L135fs, p. P2fs, p. S183fs, and p. R58fs, all of which had not been reported previously and were deemed to be very strong evidence of pathogenicity.	('K159fs', 'Var', (121, 127))	('VHL', 'Disease', 'MESH:D006623', (22, 25))	('P2fs', 'Var', (143, 147))	('P2fs', 'FRAMESHIFT', 'None', (143, 147))	('K159fs', 'FRAMESHIFT', 'None', (121, 127))	('S183fs', 'Var', (152, 158))	('RCC', 'Disease', (58, 61))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (56, 61))	('L135fs', 'FRAMESHIFT', 'None', (132, 138))	('VHL', 'Disease', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('L135fs', 'Var', (132, 138))	('S183fs', 'FRAMESHIFT', 'None', (152, 158))	('R58fs', 'Var', (167, 172))	('R58fs', 'FRAMESHIFT', 'None', (167, 172))
24389	31227023	Most of the mutations in PBRM1 were frameshift mutations, which had not been reported previously and were predicted to be deleterious.	('PBRM1', 'Gene', (25, 30))	('PBRM1', 'Gene', '55193', (25, 30))	('mutations', 'Var', (12, 21))	('frameshift', 'Var', (36, 46))
24392	31227023	For instance, BAP1 was somatically mutated in 3 ccRCC specimens in the present study, namely a frameshift deletion (p. S432fs) and insertion (p. P462fs) in sample 9, a deletion-insertion mutation [p. E642_I643delins (39)] in sample 13, and a frameshift insertion (p. P339fs) and deletion-insertion mutation [p. I191_D192delins (18)] in sample 20.	('BAP1', 'Gene', '8314', (14, 18))	('S432fs', 'Var', (119, 125))	('D192delins', 'Mutation', 'p.192delinsD', (316, 326))	('P462fs', 'Var', (145, 151))	('P339fs', 'Var', (267, 273))	('S432fs', 'FRAMESHIFT', 'None', (119, 125))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('BAP1', 'Gene', (14, 18))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', (50, 53))	('p. E642_I643delins', 'Mutation', 'p.642,643delinsI', (197, 215))	('P462fs', 'FRAMESHIFT', 'None', (145, 151))	('P339fs', 'FRAMESHIFT', 'None', (267, 273))
24393	31227023	Mutated BAP1 or loss of BAP1 expression was reported to be associated with poor outcome in ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('ccRCC', 'Phenotype', 'HP:0006770', (91, 96))	('RCC', 'Disease', (93, 96))	('BAP1', 'Gene', (24, 28))	('BAP1', 'Gene', '8314', (8, 12))	('loss', 'NegReg', (16, 20))	('BAP1', 'Gene', (8, 12))	('expression', 'MPA', (29, 39))	('Mutated', 'Var', (0, 7))	('BAP1', 'Gene', '8314', (24, 28))
24397	31227023	Three somatic mutations in DEPDC4 were identified in ccRCC specimens, namely 2 frameshift deletions (p. F150fs and p. R21fs) and 1 deletion-insertion [p. E147_L148delins (8)], all of which were predicted to be deleterious.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('R21fs', 'FRAMESHIFT', 'None', (118, 123))	('[p. E147_L148delins', 'Var', (150, 169))	('frameshift deletions', 'Reg', (79, 99))	('DEPDC4', 'Gene', (27, 33))	('R21fs', 'Var', (118, 123))	('L148delins', 'Mutation', 'p.148delinsL', (159, 169))	('DEPDC4', 'Gene', '120863', (27, 33))	('F150fs', 'Var', (104, 110))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('F150fs', 'FRAMESHIFT', 'None', (104, 110))
24402	31227023	Among the 20 ccRCC specimens in the present study, DDX51 was somatically mutated in 5 specimens with six mutations, namely, a deletion-insertion mutation [p. K611_V612delins (35)] in 1 specimen, a missense mutation (p. S116N) in 2 specimens, two frameshift insertion mutations (p. G147fs and p. H28fs) in 1 specimen, and a frameshift deletion (p.A273fs) in 1 specimen.	('S116N', 'SUBSTITUTION', 'None', (219, 224))	('p.A273fs', 'Mutation', 'p.A273fsX', (344, 352))	('H28fs', 'FRAMESHIFT', 'None', (295, 300))	('H28fs', 'Var', (295, 300))	('RCC', 'Disease', 'MESH:C538614', (15, 18))	('DDX51', 'Gene', (51, 56))	('RCC', 'Disease', (15, 18))	('p.A273fs', 'Var', (344, 352))	('S116N', 'Var', (219, 224))	('G147fs', 'FRAMESHIFT', 'None', (281, 287))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('G147fs', 'Var', (281, 287))	('V612delins', 'Mutation', 'p.612delinsV', (163, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (13, 18))	('DDX51', 'Gene', '317781', (51, 56))	('frameshift deletion', 'Reg', (323, 342))
24403	31227023	Notably, the frameshift deletion (p. A273fs) was located in the DEAD protein domain of DDX51 (Fig.	('frameshift', 'Reg', (13, 23))	('DDX51', 'Gene', (87, 92))	('DDX51', 'Gene', '317781', (87, 92))	('A273fs', 'FRAMESHIFT', 'None', (37, 43))	('A273fs', 'Var', (37, 43))	('protein', 'cellular_component', 'GO:0003675', ('69', '76'))
24404	31227023	The missense mutation in DDX51 in both specimens was predicted to be benign or neutral, whereas the deletion-insertion mutation and three frameshift mutations were most likely to be deleterious according to the ACMG guidelines.	('DDX51', 'Gene', (25, 30))	('missense mutation', 'Var', (4, 21))	('deletion-insertion mutation', 'Var', (100, 127))	('DDX51', 'Gene', '317781', (25, 30))
24405	31227023	Furthermore, somatic mutations in DDX51 were also identified in two other RCC subtypes, including a frameshift deletion (p. R519fs) in PRCC predicted to be deleterious and a missense mutation (p. P123R) in ChRCC predicted to be benign or neutral.	('PRCC', 'Phenotype', 'HP:0006766', (135, 139))	('P123R', 'Var', (196, 201))	('identified', 'Reg', (50, 60))	('P123R', 'SUBSTITUTION', 'None', (196, 201))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('PRCC', 'Gene', '5546', (135, 139))	('DDX51', 'Gene', (34, 39))	('R519fs', 'Var', (124, 130))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('R519fs', 'FRAMESHIFT', 'None', (124, 130))	('RCC', 'Disease', (208, 211))	('DDX51', 'Gene', '317781', (34, 39))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('PRCC', 'Gene', (135, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))
24409	31227023	We identified 6 genes, VHL, INADL, MUC4, RAD21, CSPG4, and BAP1, that were somatically mutated in 3 of the 4 PD-L1-positive ccRCC specimens.	('mutated', 'Var', (87, 94))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('VHL', 'Disease', 'MESH:D006623', (23, 26))	('RAD21', 'Gene', (41, 46))	('INADL', 'Gene', '10207', (28, 33))	('INADL', 'Gene', (28, 33))	('BAP1', 'Gene', '8314', (59, 63))	('RAD21', 'Gene', '5885', (41, 46))	('MUC4', 'Gene', '4585', (35, 39))	('PD-L1', 'Gene', (109, 114))	('MUC4', 'Gene', (35, 39))	('PD-L1', 'Gene', '29126', (109, 114))	('CSPG4', 'Gene', (48, 53))	('CSPG4', 'Gene', '1464', (48, 53))	('VHL', 'Disease', (23, 26))	('BAP1', 'Gene', (59, 63))	('RAD', 'biological_process', 'GO:1990116', ('41', '44'))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
24410	31227023	Nevertheless, only mutated RAD21 and BAP1 were associated with PD-L1 expression in tumor cells.	('RAD21', 'Gene', '5885', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('RAD', 'biological_process', 'GO:1990116', ('27', '30'))	('mutated', 'Var', (19, 26))	('expression', 'MPA', (69, 79))	('BAP1', 'Gene', '8314', (37, 41))	('PD-L1', 'Gene', (63, 68))	('BAP1', 'Gene', (37, 41))	('RAD21', 'Gene', (27, 32))	('associated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PD-L1', 'Gene', '29126', (63, 68))
24412	31227023	The somatic mutations in BAP1 (p. P352fs, p. H193Q, p. S432fs, and p. P462fs) and RAD21 (p. F2 L, p. F304S, p. R402fs, and p. L515fs) detected in the 3 PD-L1-positive ccRCC samples were all predicted to be deleterious.	('BAP1', 'Gene', (25, 29))	('PD-L1', 'Gene', '29126', (152, 157))	('p. F2 L', 'Mutation', 'p.F2L', (89, 96))	('PD-L1', 'Gene', (152, 157))	('RAD21', 'Gene', '5885', (82, 87))	('P352fs', 'Var', (34, 40))	('S432fs', 'FRAMESHIFT', 'None', (55, 61))	('P462fs', 'Var', (70, 76))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('ccRCC', 'Phenotype', 'HP:0006770', (167, 172))	('RCC', 'Disease', (169, 172))	('S432fs', 'Var', (55, 61))	('F304S', 'Var', (101, 106))	('L515fs', 'FRAMESHIFT', 'None', (126, 132))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('P462fs', 'FRAMESHIFT', 'None', (70, 76))	('R402fs', 'Var', (111, 117))	('BAP1', 'Gene', '8314', (25, 29))	('H193Q', 'SUBSTITUTION', 'None', (45, 50))	('H193Q', 'Var', (45, 50))	('RAD', 'biological_process', 'GO:1990116', ('82', '85'))	('p. F2 L', 'Var', (89, 96))	('L515fs', 'Var', (126, 132))	('RAD21', 'Gene', (82, 87))	('F304S', 'SUBSTITUTION', 'None', (101, 106))	('R402fs', 'FRAMESHIFT', 'None', (111, 117))	('P352fs', 'FRAMESHIFT', 'None', (34, 40))
24420	30297534	Pathological Oxidation of PTPN12 Underlies ABL1 Phosphorylation in Hereditary Leiomyomatosis and Renal Cell Carcinoma Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited cancer syndrome associated with a highly aggressive form of type 2 papillary renal cell carcinoma (PRCC).	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (260, 290))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (148, 168))	('PTPN12', 'Gene', '5782', (26, 32))	('ABL1', 'Gene', '25', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('PRCC', 'Phenotype', 'HP:0006766', (292, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('Phosphorylation', 'biological_process', 'GO:0016310', ('48', '63'))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (260, 290))	('type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (253, 290))	('Pathological', 'Var', (0, 12))	('PTPN12', 'Gene', (26, 32))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (118, 168))	('inherited cancer syndrome', 'Disease', 'MESH:D009386', (183, 208))	('inherited cancer syndrome', 'Disease', (183, 208))	('Leiomyomatosis and Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (78, 117))	('PRCC', 'Disease', 'MESH:D002292', (292, 296))	('papillary renal cell carcinoma', 'Disease', (260, 290))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (270, 290))	('HLRCC', 'Disease', (170, 175))	('HLRCC', 'Disease', 'MESH:C535516', (170, 175))	('Phosphorylation', 'MPA', (48, 63))	('ABL1', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('PRCC', 'Disease', (292, 296))
24421	30297534	Germline inactivating alterations in fumarate hydratase (FH) cause HLRCC and result in elevated levels of reactive oxygen species (ROS).	('cause', 'Reg', (61, 66))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (87, 129))	('fumarate hydratase', 'Gene', (37, 55))	('HLRCC', 'Disease', 'MESH:C535516', (67, 72))	('levels of reactive oxygen species', 'MPA', (96, 129))	('fumarate hydratase', 'Gene', '2271', (37, 55))	('FH', 'Gene', '2271', (57, 59))	('alterations', 'Var', (22, 33))	('oxygen', 'Chemical', 'MESH:D010100', (115, 121))	('elevated', 'PosReg', (87, 95))	('HLRCC', 'Disease', (67, 72))
24429	30297534	Using substrate-trapping mutants, we mapped PTPs to their putative substrates and found that only PTPN12 could target ABL1.	('mutants', 'Var', (25, 32))	('ABL1', 'Gene', '25', (118, 122))	('PTPN12', 'Gene', '5782', (98, 104))	('ABL1', 'Gene', (118, 122))	('PTPN12', 'Gene', (98, 104))
24441	30297534	Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an inherited syndrome, caused by germline inactivating alterations in fumarate hydratase (FH), that places patients at risk of a highly aggressive, poor prognosis form of type 2 papillary renal cell carcinoma (PRCC).	('Hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (0, 50))	('inherited syndrome', 'Disease', 'MESH:D061325', (65, 83))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (250, 270))	('PRCC', 'Disease', 'MESH:D002292', (272, 276))	('fumarate hydratase', 'Gene', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (240, 270))	('PRCC', 'Disease', (272, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (240, 270))	('HLRCC', 'Disease', (52, 57))	('inherited syndrome', 'Disease', (65, 83))	('PRCC', 'Phenotype', 'HP:0006766', (272, 276))	('fumarate hydratase', 'Gene', '2271', (132, 150))	('HLRCC', 'Disease', 'MESH:C535516', (52, 57))	('inactivating alterations', 'Var', (104, 128))	('patients', 'Species', '9606', (169, 177))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('FH', 'Gene', '2271', (152, 154))	('papillary renal cell carcinoma', 'Disease', (240, 270))	('caused by', 'Reg', (85, 94))	('type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (233, 270))
24449	30297534	Using this approach, we found that several PTPs were highly oxidized in FH-deficient PRCC cell lines, and identified PTPN12 oxidation as the cause of increased ABL1 tyrosyl phosphorylation, establishing a novel mechanism of tumorigenesis.	('phosphorylation', 'biological_process', 'GO:0016310', ('173', '188'))	('PRCC', 'Disease', 'MESH:D002292', (85, 89))	('PTPN12', 'Gene', (117, 123))	('FH', 'Gene', '2271', (72, 74))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('ABL1', 'Gene', '25', (160, 164))	('tumor', 'Disease', (224, 229))	('PRCC', 'Phenotype', 'HP:0006766', (85, 89))	('ABL1', 'Gene', (160, 164))	('PRCC', 'Disease', (85, 89))	('oxidation', 'Var', (124, 133))	('PTPN12', 'Gene', '5782', (117, 123))	('increased', 'PosReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
24488	30297534	To test our refined protocol, we treated Rat1 and HeLa cells with 0.1-1 mM of H2O2, subjected cell lysates to q-oxPTPome, and resolved the treated lysates by SDS-PAGE, followed by immunoblotting with oxPTP antibody (Ab).	('H2O2', 'Chemical', 'MESH:D014867', (78, 82))	('antibody', 'cellular_component', 'GO:0019814', ('206', '214'))	('antibody', 'cellular_component', 'GO:0019815', ('206', '214'))	('HeLa', 'CellLine', 'CVCL:0030', (50, 54))	('PTP', 'Gene', '10076', (114, 117))	('antibody', 'molecular_function', 'GO:0003823', ('206', '214'))	('H2O2', 'Var', (78, 82))	('SDS', 'Chemical', 'MESH:C032259', (158, 161))	('PTP', 'Gene', '10076', (202, 205))	('PTP', 'Gene', (202, 205))	('antibody', 'cellular_component', 'GO:0042571', ('206', '214'))	('Rat1', 'CellLine', 'CVCL:0492', (41, 45))	('PTP', 'Gene', (114, 117))
24491	30297534	Indeed, PTP1B showed an H2O2 dose-dependent increase in oxidation, with levels as low as 50 nM evoking detectable signals (Fig.	('PTP1B', 'Gene', (8, 13))	('H2O2', 'Var', (24, 28))	('PTP1B', 'Gene', '5770', (8, 13))	('oxidation', 'MPA', (56, 65))	('increase', 'PosReg', (44, 52))	('H2O2', 'Chemical', 'MESH:D014867', (24, 28))	('evoking', 'Reg', (95, 102))
24527	30297534	PTP substrate-trapping mutants, including mutants of the catalytic cysteine to serine (CS) or the aspartate in the WPD motif to alanine (DA), are used widely for substrate identification; such mutants retain substrate binding capacity without catalyzing dephosphorylation.	('dephosphorylation', 'biological_process', 'GO:0016311', ('254', '271'))	('serine', 'Chemical', 'MESH:C047902', (79, 85))	('mutants', 'Var', (42, 49))	('cysteine', 'Chemical', 'MESH:D003545', (67, 75))	('substrate', 'MPA', (208, 217))	('mutants', 'Var', (193, 200))	('binding', 'molecular_function', 'GO:0005488', ('218', '225'))	('PTP', 'Gene', (0, 3))	('mutants', 'Var', (23, 30))	('PTP', 'Gene', '10076', (0, 3))	('aspartate', 'Chemical', 'None', (98, 107))
24543	30297534	To investigate the function of PEST-type PTPs in FH-deficient PRCC, we knocked down PTPN12 or PTPN18 in UOK262 FH-WT or FH-deficient lines.	('knocked down', 'Var', (71, 83))	('PTPN12', 'Gene', '5782', (84, 90))	('PRCC', 'Disease', 'MESH:D002292', (62, 66))	('PTPN18', 'Gene', '26469', (94, 100))	('UOK262', 'CellLine', 'CVCL:1D72', (104, 110))	('PTPN12', 'Gene', (84, 90))	('FH', 'Gene', '2271', (49, 51))	('FH', 'Gene', '2271', (111, 113))	('PTPN18', 'Gene', (94, 100))	('FH', 'Gene', '2271', (120, 122))	('PRCC', 'Phenotype', 'HP:0006766', (62, 66))	('PRCC', 'Disease', (62, 66))
24548	30297534	PSTPIP2 knockdown did not affect PTPN12 KD-induced ABL1 phosphorylation (Supplementary Fig.	('ABL1', 'Gene', (51, 55))	('PTPN12', 'Gene', '5782', (33, 39))	('phosphorylation', 'biological_process', 'GO:0016310', ('56', '71'))	('knockdown', 'Var', (8, 17))	('PTPN12', 'Gene', (33, 39))	('PSTPIP2', 'Gene', (0, 7))	('ABL1', 'Gene', '25', (51, 55))	('PSTPIP2', 'Gene', '9050', (0, 7))
24569	30297534	In TNBC, however, PTPN12 is mainly inactivated through deletion or loss-of-function mutations.	('PTPN12', 'Gene', (18, 24))	('TNBC', 'Gene', (3, 7))	('mutations', 'Var', (84, 93))	('deletion', 'Var', (55, 63))	('loss-of-function', 'NegReg', (67, 83))	('PTPN12', 'Gene', '5782', (18, 24))
24570	30297534	Our data demonstrate that oxidative stress-induced PTPN12 oxidation can inhibit PTPN12 without deletion/mutation, and suggest that activation of (a) PTK(s) via ROS-mediated inactivation of cognate PTPs is a novel mechanism for cancer pathogenesis.	('PTPN12', 'Gene', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('PTPN12', 'Gene', (80, 86))	('pathogenesis', 'biological_process', 'GO:0009405', ('234', '246'))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('oxidation', 'Var', (58, 67))	('inhibit', 'NegReg', (72, 79))	('cancer', 'Disease', (227, 233))	('PTPN12', 'Gene', '5782', (51, 57))	('inactivation', 'Var', (173, 185))	('PTPN12', 'Gene', '5782', (80, 86))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))
24571	30334014	Parallel (Randomized) Phase II Evaluation of Tivantinib (ARQ197) and Tivantinib in Combination with Erlotinib in Papillary Renal Cell Carcinoma: SWOG S1107 Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway.	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('MET', 'Gene', '4233', (247, 250))	('Carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('Papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (156, 186))	('MET', 'Gene', (247, 250))	('SWOG S1107', 'Var', (145, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('activation', 'PosReg', (233, 243))	('EGFR', 'Gene', '1956', (213, 217))	('Papillary Renal Cell Carcinoma', 'Disease', (113, 143))	('pRCC', 'Gene', '5546', (188, 192))	('Erlotinib', 'Chemical', 'MESH:D000069347', (100, 109))	('Papillary Renal Cell Carcinoma', 'Phenotype', 'HP:0006766', (113, 143))	('Papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (156, 186))	('Tivantinib', 'Chemical', 'MESH:C551661', (69, 79))	('Tivantinib', 'Chemical', 'MESH:C551661', (45, 55))	('EGFR', 'molecular_function', 'GO:0005006', ('213', '217'))	('pRCC', 'Gene', (188, 192))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (166, 186))	('EGFR', 'Gene', (213, 217))	('activation of MET signaling pathway', 'biological_process', 'GO:1902204', ('233', '268'))	('Papillary Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (113, 143))	('Papillary renal cell carcinoma', 'Disease', (156, 186))
24573	30334014	Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2).	('BID', 'Gene', (136, 139))	('pRCC', 'Gene', (23, 27))	('tivantinib', 'Var', (118, 128))	('tivantinib', 'Chemical', 'MESH:C551661', (85, 95))	('erlotinib', 'Chemical', 'MESH:D000069347', (145, 154))	('BID', 'Gene', (103, 106))	('BID', 'Gene', '637', (136, 139))	('pRCC', 'Gene', '5546', (23, 27))	('Patients', 'Species', '9606', (0, 8))	('Arm 2', 'Gene', '51155', (169, 174))	('Arm 1', 'Gene', (108, 113))	('Arm 1', 'Gene', '9622', (108, 113))	('tivantinib', 'Chemical', 'MESH:C551661', (118, 128))	('BID', 'Gene', '637', (103, 106))	('Arm 2', 'Gene', (169, 174))
24579	30334014	Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1 and NF2.	('pRCC', 'Gene', '5546', (49, 53))	('NF2', 'Gene', (116, 119))	('FAT1', 'Gene', '2195', (107, 111))	('FAT1', 'Gene', (107, 111))	('CDKN2A', 'Gene', (78, 84))	('KDM6A', 'Gene', (100, 105))	('NF2', 'Gene', '4771', (116, 119))	('PBRM1', 'Gene', (86, 91))	('CDKN2A', 'Gene', '1029', (78, 84))	('pRCC', 'Gene', (49, 53))	('KDM6A', 'Gene', '7403', (100, 105))	('SETD2', 'Gene', '29072', (93, 98))	('associated', 'Reg', (16, 26))	('PBRM1', 'Gene', '55193', (86, 91))	('SETD2', 'Gene', (93, 98))	('mutations', 'Var', (6, 15))
24581	30334014	The S1107 cohort had a low proportion of patients with MET alterations.	('patients', 'Species', '9606', (41, 49))	('MET', 'Gene', (55, 58))	('S1107', 'Var', (4, 9))	('MET', 'Gene', '4233', (55, 58))
24593	30334014	Activating germline mutations in the MET tyrosine kinase (TK) domain are present in the majority of patients with hereditary pRCC.	('MET', 'Gene', (37, 40))	('Activating', 'PosReg', (0, 10))	('pRCC', 'Gene', '5546', (125, 129))	('patients', 'Species', '9606', (100, 108))	('pRCC', 'Gene', (125, 129))	('TK', 'Gene', (58, 60))	('germline mutations', 'Var', (11, 29))	('MET', 'Gene', '4233', (37, 40))
24594	30334014	More common sporadic pRCCs exhibit activating MET mutation only in about 10-20% of cases but other mechanisms of MET activation including amplification of the MET gene locus resulting in MET overexpression are common.	('MET', 'Gene', (113, 116))	('overexpression', 'PosReg', (191, 205))	('MET', 'Gene', '4233', (113, 116))	('pRCC', 'Gene', (21, 25))	('MET', 'Gene', '4233', (159, 162))	('MET', 'Gene', (187, 190))	('MET', 'Gene', (159, 162))	('MET', 'Gene', '4233', (187, 190))	('MET', 'Gene', '4233', (46, 49))	('pRCC', 'Gene', '5546', (21, 25))	('amplification', 'Var', (138, 151))	('MET', 'Gene', (46, 49))	('mutation', 'Var', (50, 58))
24600	30334014	Multiple other measures of somatic MET pathway activation were noted, including gain of chromosome 7 (27%), somatic MET mutations (7%), and MET amplification (3%).	('MET', 'Gene', '4233', (116, 119))	('MET', 'Gene', (140, 143))	('MET', 'Gene', '4233', (140, 143))	('MET', 'Gene', (116, 119))	('MET', 'Gene', '4233', (35, 38))	('activation', 'PosReg', (47, 57))	('MET', 'Gene', (35, 38))	('gain', 'PosReg', (80, 84))	('chromosome', 'cellular_component', 'GO:0005694', ('88', '98'))	('mutations', 'Var', (120, 129))
24603	30334014	Preclinical RCC data had revealed that absence of von Hippel-Lindau (VHL) mutations (as typically observed in pRCC) is associated with greater activity of EGFR inhibitors against RCC.	('von Hippel-Lindau', 'Gene', '7428', (50, 67))	('pRCC', 'Gene', '5546', (110, 114))	('EGFR', 'molecular_function', 'GO:0005006', ('155', '159'))	('EGFR', 'Gene', '1956', (155, 159))	('mutations', 'Var', (74, 83))	('VHL', 'Disease', 'MESH:D006623', (69, 72))	('EGFR', 'Gene', (155, 159))	('VHL', 'Disease', (69, 72))	('pRCC', 'Gene', (110, 114))	('von Hippel-Lindau', 'Gene', (50, 67))	('greater', 'PosReg', (135, 142))	('activity', 'MPA', (143, 151))	('RCC', 'Disease', (179, 182))
24632	30334014	The variants are further filtered to retain the ones that are most likely relevant to tumor based on the following criteria: 1) variant frequency <2% or not present in esp6500 database; 2) variant frequency <2% or not present in 1000 genome project; 3) not present in dbSNP v138; 4) not present in EXAC database or frequency <2%.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('variant', 'Var', (128, 135))	('tumor', 'Disease', (86, 91))	('esp', 'Gene', '148713', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('esp', 'Gene', (168, 171))	('variant', 'Var', (189, 196))
24649	30334014	MUC2 and MUC4 mutations detected in our samples are also frequently mutated in TCGA cohort, and they have been shown to be associated with various types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('associated', 'Reg', (123, 133))	('MUC2', 'Gene', (0, 4))	('cancers', 'Disease', (156, 163))	('MUC2', 'Gene', '4583', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('MUC4', 'Gene', '4585', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('MUC4', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
24650	30334014	Only 1 of 16 samples harbored MET mutation located in tyrosine kinase domain (K1198I).	('MET', 'Gene', '4233', (30, 33))	('K1198I', 'Var', (78, 84))	('K1198I', 'Mutation', 'p.K1198I', (78, 84))	('MET', 'Gene', (30, 33))
24651	30334014	Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1, NF2 and CUL.	('pRCC', 'Gene', '5546', (49, 53))	('FAT1', 'Gene', '2195', (107, 111))	('NF2', 'Gene', '4771', (113, 116))	('FAT1', 'Gene', (107, 111))	('CDKN2A', 'Gene', (78, 84))	('KDM6A', 'Gene', (100, 105))	('PBRM1', 'Gene', (86, 91))	('CDKN2A', 'Gene', '1029', (78, 84))	('pRCC', 'Gene', (49, 53))	('KDM6A', 'Gene', '7403', (100, 105))	('PBRM1', 'Gene', '55193', (86, 91))	('SETD2', 'Gene', '29072', (93, 98))	('associated', 'Reg', (16, 26))	('NF2', 'Gene', (113, 116))	('SETD2', 'Gene', (93, 98))	('mutations', 'Var', (6, 15))
24657	30334014	The results showed MET amplification in 6 cases (37.5%), and 3 cases with EGFR amplification and one case with EGFR deletion.	('MET', 'Gene', '4233', (19, 22))	('EGFR', 'molecular_function', 'GO:0005006', ('111', '115'))	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'molecular_function', 'GO:0005006', ('74', '78'))	('EGFR', 'Gene', (111, 115))	('EGFR', 'Gene', '1956', (74, 78))	('amplification', 'Var', (79, 92))	('EGFR', 'Gene', (74, 78))	('MET', 'Gene', (19, 22))
24658	30334014	We also observed 6 cases with CDKN2A amplification, which is surprising as only CDKN2A deletions were found in TCGA pRCC cohort.	('CDKN2A', 'Gene', '1029', (80, 86))	('pRCC', 'Gene', (116, 120))	('CDKN2A', 'Gene', (30, 36))	('amplification', 'Var', (37, 50))	('CDKN2A', 'Gene', '1029', (30, 36))	('pRCC', 'Gene', '5546', (116, 120))	('CDKN2A', 'Gene', (80, 86))
24668	30334014	However, assessment of copy number pointed to the importance of MET particularly in type I pRCC; specifically, 81% of patients with type I pRCC had copy number alternations, as compared to 46% in type II pRCC.	('MET', 'Gene', '4233', (64, 67))	('pRCC', 'Gene', (91, 95))	('MET', 'Gene', (64, 67))	('pRCC', 'Gene', '5546', (139, 143))	('pRCC', 'Gene', '5546', (204, 208))	('copy number alternations', 'Var', (148, 172))	('pRCC', 'Gene', '5546', (91, 95))	('pRCC', 'Gene', (139, 143))	('patients', 'Species', '9606', (118, 126))	('pRCC', 'Gene', (204, 208))
24672	30334014	One of the few reported clinical trials in pRCC utilizing MET inhibitor (specifically dual VEGFR2 and MET inhibitor) foretinib demonstrated clinical activity essentially restricted to rare patients with hereditary pRCC harboring germline MET mutations and did not reveal significant activity in more common patients with sporadic pRCC associated with other mechanisms of MET activation including MET amplification, duplication of chromosome 7 (location of MET gene) or other copy number aberrations.	('VEGFR2', 'Gene', (91, 97))	('MET', 'Gene', '4233', (238, 241))	('MET', 'Gene', (238, 241))	('VEGFR2', 'Gene', '3791', (91, 97))	('patients', 'Species', '9606', (189, 197))	('patients', 'Species', '9606', (307, 315))	('pRCC', 'Gene', (43, 47))	('duplication of chromosome', 'Var', (415, 440))	('pRCC', 'Gene', '5546', (214, 218))	('MET', 'Gene', '4233', (396, 399))	('MET', 'Gene', (396, 399))	('pRCC', 'Gene', '5546', (330, 334))	('MET', 'Gene', '4233', (371, 374))	('MET', 'Gene', (102, 105))	('MET', 'Gene', '4233', (102, 105))	('MET', 'Gene', (371, 374))	('chromosome', 'cellular_component', 'GO:0005694', ('430', '440'))	('pRCC', 'Gene', (214, 218))	('foretinib', 'Chemical', 'MESH:C544831', (117, 126))	('MET', 'Gene', '4233', (58, 61))	('MET', 'Gene', (456, 459))	('MET', 'Gene', (58, 61))	('MET', 'Gene', '4233', (456, 459))	('mutations', 'Var', (242, 251))	('pRCC', 'Gene', (330, 334))	('pRCC', 'Gene', '5546', (43, 47))
24677	30334014	Recent emergence of PD1 inhibition as an effective approach for the treatment of ccRCC poses important question regarding its potential applicability for non-clear cell variants.	('ccRCC', 'Disease', (81, 86))	('PD1', 'Gene', (20, 23))	('inhibition', 'Var', (24, 34))	('PD1', 'Gene', '5133', (20, 23))
24681	30334014	It appears that S1107 patient cohort had a high proportion of patients with molecular subtypes not driven by MET alterations and would not be expected to respond well to MET inhibitor therapy.	('MET', 'Gene', (109, 112))	('MET', 'Gene', '4233', (170, 173))	('MET', 'Gene', '4233', (109, 112))	('S1107', 'Var', (16, 21))	('patient', 'Species', '9606', (62, 69))	('patients', 'Species', '9606', (62, 70))	('esp', 'Gene', '148713', (155, 158))	('MET', 'Gene', (170, 173))	('esp', 'Gene', (155, 158))	('patient', 'Species', '9606', (22, 29))
24686	30334014	The National Cancer Institute of the National Institutes of Health supported this research under grant awards CA180888; CA180819; CA180820, CA180818, CA189957, CA180835, CA189821, CA180835, CA189960, CA189954, CA189853, CA189829, CA180834, CA180801, CA180798, CA12644, CA22433, CA11083 and CA13612.	('CA189954', 'Var', (200, 208))	('Cancer', 'Disease', (13, 19))	('CA189853', 'Var', (210, 218))	('CA180835', 'Var', (160, 168))	('CA189957', 'Var', (150, 158))	('CA189829', 'Var', (220, 228))	('CA180888; CA180819; CA180820', 'Var', (110, 138))	('CA180818', 'Var', (140, 148))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('CA180834', 'Var', (230, 238))	('CA180835', 'Var', (180, 188))	('CA189821', 'Var', (170, 178))	('CA180801', 'Var', (240, 248))	('CA13612', 'Var', (290, 297))	('CA22433', 'Var', (269, 276))	('CA180798', 'Var', (250, 258))	('CA11083', 'Var', (278, 285))	('CA12644', 'Var', (260, 267))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('CA189960', 'Var', (190, 198))	('CA180820', 'Var', (130, 138))
24689	29535838	Alteration of the NF2 tumor suppressor gene, encoding a key regulator of the Hippo signaling pathway, is observed in 22.5% of PRCC.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('22', '38'))	('PRCC', 'Gene', '5546', (126, 130))	('NF2', 'Gene', (18, 21))	('observed', 'Reg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('Alteration', 'Var', (0, 10))	('PRCC', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('77', '100'))	('tumor', 'Disease', (22, 27))	('NF2', 'Gene', '4771', (18, 21))	('tumor suppressor', 'biological_process', 'GO:0051726', ('22', '38'))
24691	29535838	Loss of NF2 results in aberrant YAP1 activation.	('activation', 'PosReg', (37, 47))	('NF2', 'Gene', (8, 11))	('YAP1', 'Gene', '10413', (32, 36))	('YAP1', 'Gene', (32, 36))	('NF2', 'Gene', '4771', (8, 11))	('Loss', 'Var', (0, 4))
24694	29535838	NF2-deficency correlated with increased expression of YAP1 transcriptional targets and siRNA-based knockdown of YAP1 and Yes1 downregulated this pathway and dramatically reduced cell viability.	('expression', 'MPA', (40, 50))	('YAP1', 'Gene', '10413', (112, 116))	('NF2', 'Gene', (0, 3))	('cell viability', 'CPA', (178, 192))	('downregulated', 'NegReg', (126, 139))	('NF2', 'Gene', '4771', (0, 3))	('reduced', 'NegReg', (170, 177))	('knockdown', 'Var', (99, 108))	('YAP1', 'Gene', (54, 58))	('Yes1', 'Gene', '7525', (121, 125))	('increased', 'PosReg', (30, 39))	('Yes1', 'Gene', (121, 125))	('YAP1', 'Gene', (112, 116))	('YAP1', 'Gene', '10413', (54, 58))
24701	29535838	HPRC patients carry germline activating mutations within the tyrosine kinase domain of the MET oncogene and presents with bilateral, multifocal type 1 PRCC, while HLRCC patients inherit germline inactivating mutation of the FH tumor suppressor gene and can have an aggressive variant of type 2 PRCC.	('PRCC', 'Gene', '5546', (294, 298))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('PRCC', 'Gene', '5546', (151, 155))	('HPRC', 'Disease', (0, 4))	('patients', 'Species', '9606', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('RCC', 'Disease', (152, 155))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('227', '243'))	('RCC', 'Disease', (295, 298))	('MET', 'Gene', (91, 94))	('HPRC', 'Disease', 'None', (0, 4))	('PRCC', 'Gene', (294, 298))	('patients', 'Species', '9606', (169, 177))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('PRCC', 'Gene', (151, 155))	('tumor suppressor', 'biological_process', 'GO:0051726', ('227', '243'))	('FH tumor', 'Disease', 'MESH:D006938', (224, 232))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('germline', 'Var', (186, 194))	('FH tumor', 'Disease', (224, 232))	('RCC', 'Disease', (165, 168))
24703	29535838	This study highlighted that amplification of chromosome 7 and 17 and activating mutations of the MET gene, on chromosome 7, are associated with type 1 PRCC, while type 2 PRCC was more genetically diverse including tumors that had either germline or somatic FH mutation, chromosomal translocations producing TFE3-fusions, or NRF2 pathway mutations in NFE2L2 (NRF2) or CUL3.	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('NRF2', 'Gene', (324, 328))	('tumors', 'Disease', (214, 220))	('associated', 'Reg', (128, 138))	('MET', 'Gene', (97, 100))	('PRCC', 'Gene', '5546', (151, 155))	('NRF2', 'Gene', '4780', (358, 362))	('CUL3', 'Gene', (367, 371))	('mutations', 'Var', (80, 89))	('chromosomal translocations', 'Var', (270, 296))	('PRCC', 'Gene', (170, 174))	('chromosome', 'cellular_component', 'GO:0005694', ('45', '55'))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('NFE2L2', 'Gene', '4780', (350, 356))	('NRF2', 'Gene', (358, 362))	('TFE3', 'Gene', (307, 311))	('mutations', 'Var', (337, 346))	('CUL3', 'Gene', '8452', (367, 371))	('NRF2', 'Gene', '4780', (324, 328))	('PRCC', 'Gene', (151, 155))	('TFE3', 'Gene', '7030', (307, 311))	('PRCC', 'Gene', '5546', (170, 174))	('NFE2L2', 'Gene', (350, 356))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
24704	29535838	In addition, whole genome sequencing of all PRCC types identified five frequently mutated genes, MET, SETD2, NF2, KDM6A, and SMARCB1, suggesting that alterations to the MET signaling pathway, Hippo signaling pathway, and the chromatin modifier pathways may play an important role in PRCC carcinogenesis.	('SMARCB1', 'Gene', '6598', (125, 132))	('SMARCB1', 'Gene', (125, 132))	('KDM6A', 'Gene', (114, 119))	('PRCC', 'Gene', (283, 287))	('PRCC', 'Gene', (44, 48))	('NF2', 'Gene', '4771', (109, 112))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('192', '215'))	('MET signaling pathway', 'Pathway', (169, 190))	('NF2', 'Gene', (109, 112))	('chromatin', 'cellular_component', 'GO:0000785', ('225', '234'))	('chromatin modifier pathways', 'Pathway', (225, 252))	('MET signaling pathway', 'biological_process', 'GO:0048012', ('169', '190'))	('carcinogenesis', 'Disease', (288, 302))	('SETD2', 'Gene', (102, 107))	('alterations', 'Var', (150, 161))	('PRCC', 'Gene', '5546', (44, 48))	('play', 'Reg', (257, 261))	('PRCC', 'Gene', '5546', (283, 287))	('KDM6A', 'Gene', '7403', (114, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (288, 302))	('SETD2', 'Gene', '29072', (102, 107))	('Hippo signaling pathway', 'Pathway', (192, 215))
24707	29535838	Heterozygous germline inactivating mutations of NF2 are responsible for the hereditary tumor predisposition syndrome neurofibromatosis type 2, which is characterized by the development of multiple tumors in the nervous system.	('multiple tumors', 'Disease', (188, 203))	('neurofibromatosis type 2', 'Gene', '4771', (117, 141))	('multiple tumors', 'Disease', 'MESH:D009369', (188, 203))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors in the nervous system', 'Phenotype', 'HP:0004375', (197, 225))	('germline inactivating mutations', 'Var', (13, 44))	('NF2', 'Gene', (48, 51))	('neurofibromatosis type 2', 'Gene', (117, 141))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('hereditary tumor', 'Disease', (76, 92))	('NF2', 'Gene', '4771', (48, 51))	('hereditary tumor', 'Disease', 'MESH:D009386', (76, 92))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('responsible', 'Reg', (56, 67))
24712	29535838	Aberrant YAP1 transcriptional activity can also be driven in beta-catenin active tumors via the activation of the Src family tyrosine-protein kinase Yes.	('beta-catenin', 'Gene', '1499', (61, 73))	('tumors', 'Disease', (81, 87))	('driven', 'Reg', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('Aberrant', 'Var', (0, 8))	('Src family tyrosine-protein kinase Yes', 'Pathway', (114, 152))	('transcriptional activity', 'MPA', (14, 38))	('protein', 'cellular_component', 'GO:0003675', ('134', '141'))	('YAP1', 'Gene', (9, 13))	('beta-catenin', 'Gene', (61, 73))	('YAP1', 'Gene', '10413', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('activation', 'PosReg', (96, 106))
24716	29535838	We investigated three PRCC cell lines bearing NF2 mutations and assessed the effect of Yes inhibitors on their proliferation and survival in vitro and in vivo with the goal of developing a novel potential therapeutic approach for PRCC patients whose tumors are characterized by an NF2 deficiency.	('PRCC', 'Gene', (22, 26))	('NF2 deficiency', 'Disease', 'MESH:C537392', (281, 295))	('NF2 deficiency', 'Disease', (281, 295))	('NF2', 'Gene', '4771', (281, 284))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (235, 243))	('PRCC', 'Gene', (230, 234))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('NF2', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('PRCC', 'Gene', '5546', (22, 26))	('tumors', 'Disease', (250, 256))	('NF2', 'Gene', (281, 284))	('PRCC', 'Gene', '5546', (230, 234))	('NF2', 'Gene', '4771', (46, 49))
24718	29535838	Furthermore, copy number loss of the NF2 gene was observed in 21.8% of cases with most mutation positive cases also demonstrating copy number loss (Figure 1B).	('NF2', 'Gene', (37, 40))	('NF2', 'Gene', '4771', (37, 40))	('copy number loss', 'Var', (13, 29))	('copy', 'MPA', (130, 134))
24719	29535838	While the presence of a NF2 mutation did not correlate with survival, the 22.5% of PRCC cases that demonstrated either NF2 mutation or copy number loss demonstrated a strong correlation with poorer survival (p = 0.00189; Figure 1C).	('PRCC', 'Gene', '5546', (83, 87))	('mutation', 'Var', (123, 131))	('copy number loss', 'Var', (135, 151))	('NF2', 'Gene', (24, 27))	('NF2', 'Gene', '4771', (119, 122))	('PRCC', 'Gene', (83, 87))	('NF2', 'Gene', '4771', (24, 27))	('poorer', 'NegReg', (191, 197))	('NF2', 'Gene', (119, 122))
24720	29535838	These data suggest that dysregulation of the Hippo signaling pathway might be a critical driver for PRCC growth.	('PRCC', 'Gene', '5546', (100, 104))	('dysregulation', 'Var', (24, 37))	('PRCC', 'Gene', (100, 104))	('Hippo signaling pathway', 'Pathway', (45, 68))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('45', '68'))
24721	29535838	To provide a cell line model of Hippo signaling pathway loss, the patient-derived cell lines generated at the Urologic Oncology Branch from PRCC patient material were screened for complete mutational loss of the NF2 gene.	('PRCC', 'Gene', '5546', (140, 144))	('NF2', 'Gene', (212, 215))	('Oncology', 'Phenotype', 'HP:0002664', (119, 127))	('mutational loss', 'Var', (189, 204))	('PRCC', 'Gene', (140, 144))	('patient', 'Species', '9606', (66, 73))	('NF2', 'Gene', '4771', (212, 215))	('patient', 'Species', '9606', (145, 152))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('32', '55'))
24722	29535838	This identified one cell line derived from a patient with type 1 PRCC, UOK342, with a homozygous NF2 insertion/deletion alteration that resulted in frameshift mutation and the loss of a splice site (Figure 2A) and one cell line derived from a patient with type 2 PRCC, UOK275, with a homozygous NF2 single nucleotide insertion that resulted in frameshift mutation (Figure 2B).	('PRCC', 'Gene', '5546', (65, 69))	('UOK342', 'Chemical', '-', (71, 77))	('frameshift', 'MPA', (344, 354))	('loss', 'NegReg', (176, 180))	('patient', 'Species', '9606', (243, 250))	('NF2', 'Gene', '4771', (295, 298))	('frameshift', 'MPA', (148, 158))	('insertion/deletion alteration', 'Var', (101, 130))	('UOK275', 'CellLine', 'CVCL:D760', (269, 275))	('NF2', 'Gene', (97, 100))	('PRCC', 'Gene', (65, 69))	('patient', 'Species', '9606', (45, 52))	('splice site', 'MPA', (186, 197))	('PRCC', 'Gene', '5546', (263, 267))	('NF2', 'Gene', '4771', (97, 100))	('NF2', 'Gene', (295, 298))	('PRCC', 'Gene', (263, 267))
24723	29535838	These two newly identified NF2-deficient cell lines were combined with the existing ACHN cell line, known to have a homozygous NF2 stop codon mutation (https://cansar.icr.ac.uk/cansar/cell-lines/ACHN/mutations/) (Figure 2C), for further study.	('NF2', 'Gene', (127, 130))	('NF2', 'Gene', (27, 30))	('NF2-deficient', 'Disease', (27, 40))	('ACHN', 'Gene', '55323', (84, 88))	('ACHN', 'Gene', (84, 88))	('NF2', 'Gene', '4771', (27, 30))	('NF2', 'Gene', '4771', (127, 130))	('ACHN', 'Gene', '55323', (195, 199))	('ACHN', 'Gene', (195, 199))	('mutation', 'Var', (142, 150))	('NF2-deficient', 'Disease', 'MESH:C537392', (27, 40))
24724	29535838	NF2 alteration leads to the activation of the transcription factor YAP1 and the expression of multiple downstream targets promoting tumor cell survival and proliferation.	('transcription', 'biological_process', 'GO:0006351', ('46', '59'))	('NF2', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('transcription factor', 'molecular_function', 'GO:0000981', ('46', '66'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('proliferation', 'CPA', (156, 169))	('NF2', 'Gene', '4771', (0, 3))	('alteration', 'Var', (4, 14))	('tumor', 'Disease', (132, 137))	('activation', 'PosReg', (28, 38))	('expression', 'MPA', (80, 90))	('promoting', 'PosReg', (122, 131))	('YAP1', 'Gene', (67, 71))	('YAP1', 'Gene', '10413', (67, 71))
24725	29535838	Since homozygous mutation of NF2 was found in UOK275, UOK342 and ACHN, we investigated whether these alterations led to the expression of YAP1 downstream targets.	('UOK342', 'Chemical', '-', (54, 60))	('NF2', 'Gene', '4771', (29, 32))	('YAP1', 'Gene', (138, 142))	('UOK342', 'Gene', (54, 60))	('led', 'Reg', (113, 116))	('YAP1', 'Gene', '10413', (138, 142))	('ACHN', 'Gene', '55323', (65, 69))	('UOK275', 'CellLine', 'CVCL:D760', (46, 52))	('NF2', 'Gene', (29, 32))	('UOK275', 'Var', (46, 52))	('ACHN', 'Gene', (65, 69))
24729	29535838	Taken together, these data demonstrate that the Hippo pathway is activated in UOK275, UOK342 and ACHN.	('ACHN', 'Gene', (97, 101))	('UOK275', 'CellLine', 'CVCL:D760', (78, 84))	('UOK275', 'Var', (78, 84))	('UOK342', 'Var', (86, 92))	('UOK342', 'Chemical', '-', (86, 92))	('activated', 'PosReg', (65, 74))	('ACHN', 'Gene', '55323', (97, 101))	('Hippo pathway', 'Pathway', (48, 61))
24731	29535838	To assess whether loss of the Hippo signaling pathway due to NF2 mutation may provide a therapeutic target, either YAP1 or its regulator Yes were transiently silenced using small interference RNAs (Supplementary Figure 1B).	('loss', 'NegReg', (18, 22))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('30', '53'))	('Supplementary Figure 1B', 'Disease', (198, 221))	('NF2', 'Gene', '4771', (61, 64))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (198, 221))	('Hippo signaling pathway', 'Pathway', (30, 53))	('mutation', 'Var', (65, 73))	('YAP1', 'Gene', (115, 119))	('YAP1', 'Gene', '10413', (115, 119))	('NF2', 'Gene', (61, 64))
24733	29535838	This suggests that inhibition of the Hippo pathway in NF2-deficient PRCC may have a therapeutic value and may selectively target the tumor cells.	('inhibition', 'Var', (19, 29))	('Hippo pathway', 'Pathway', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('NF2-deficient', 'Disease', 'MESH:C537392', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('NF2-deficient', 'Disease', (54, 67))	('tumor', 'Disease', (133, 138))	('PRCC', 'Gene', '5546', (68, 72))	('PRCC', 'Gene', (68, 72))
24735	29535838	Despite the role of Yes in regulating the Hippo signaling pathway through phosphorylation of YAP and supporting tumor growth, there are currently only a small proportion of the clinically approved Src kinase family inhibitors that effectively target Yes, such as dasatinib and saracatinib.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('YAP', 'Gene', (93, 96))	('phosphorylation', 'Var', (74, 89))	('saracatinib', 'Chemical', 'MESH:C515233', (277, 288))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Hippo signaling pathway', 'Pathway', (42, 65))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('42', '65'))	('tumor', 'Disease', (112, 117))	('phosphorylation', 'biological_process', 'GO:0016310', ('74', '89'))	('dasatinib', 'Chemical', 'MESH:D000069439', (263, 272))	('YAP', 'Gene', '10413', (93, 96))
24738	29535838	Since silencing of YES1 was lethal to NF2-deficient PRCC tumor cells, their survival was assessed following dasatinib and saracatinib treatment.	('NF2-deficient PRCC tumor', 'Disease', (38, 62))	('YES1', 'Gene', (19, 23))	('dasatinib', 'Chemical', 'MESH:D000069439', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NF2-deficient PRCC tumor', 'Disease', 'MESH:C537392', (38, 62))	('saracatinib', 'Chemical', 'MESH:C515233', (122, 133))	('silencing', 'Var', (6, 15))	('YES1', 'Gene', '7525', (19, 23))
24743	29535838	The levels of Yes-dependent phosphorylation on YAP1 (Tyr357) were also assessed by immunoblotting.	('Tyr357', 'Chemical', '-', (53, 59))	('YAP1', 'Gene', (47, 51))	('Tyr357', 'Var', (53, 59))	('phosphorylation', 'biological_process', 'GO:0016310', ('28', '43'))	('YAP1', 'Gene', '10413', (47, 51))
24745	29535838	The Hippo signaling pathway is critical in mediating those signals, thus alteration of NF2 and YAP1 activation lead to aberrant cell proliferation and loss of contact inhibition.	('YAP1', 'Gene', (95, 99))	('YAP1', 'Gene', '10413', (95, 99))	('NF2', 'Gene', (87, 90))	('contact inhibition', 'biological_process', 'GO:0060242', ('159', '177'))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('4', '27'))	('cell proliferation', 'CPA', (128, 146))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (119, 146))	('NF2', 'Gene', '4771', (87, 90))	('activation', 'PosReg', (100, 110))	('loss', 'NegReg', (151, 155))	('alteration', 'Var', (73, 83))	('cell proliferation', 'biological_process', 'GO:0008283', ('128', '146'))	('contact inhibition', 'CPA', (159, 177))
24747	29535838	As shown in Figure 5A-5C, inhibition of YAP1 with dasatinib led to a G0/G1 arrest in NF2-deficient cell lines but did not affect the cell cycle of HEK293 (see also Supplementary Table 1).	('cell cycle', 'biological_process', 'GO:0007049', ('133', '143'))	('G0/G1 arrest', 'CPA', (69, 81))	('inhibition', 'Var', (26, 36))	('NF2-deficient', 'Disease', 'MESH:C537392', (85, 98))	('HEK293', 'CellLine', 'CVCL:0045', (147, 153))	('NF2-deficient', 'Disease', (85, 98))	('YAP1', 'Gene', (40, 44))	('YAP1', 'Gene', '10413', (40, 44))	('dasatinib', 'Chemical', 'MESH:D000069439', (50, 59))
24756	29535838	Mutation of NF2, a key regulator of the Hippo signaling pathway was observed in 3.6% of PRCC and, in combination with copy number loss, NF2 alterations were present in 22.5% PRCC, including both type 1 and type 2 PRCC histologies.	('PRCC', 'Gene', (88, 92))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('40', '63'))	('NF2', 'Gene', (136, 139))	('PRCC', 'Gene', '5546', (174, 178))	('PRCC', 'Gene', '5546', (213, 217))	('observed', 'Reg', (68, 76))	('PRCC', 'Gene', (174, 178))	('Mutation', 'Var', (0, 8))	('PRCC', 'Gene', (213, 217))	('NF2', 'Gene', '4771', (136, 139))	('NF2', 'Gene', (12, 15))	('alterations', 'Var', (140, 151))	('PRCC', 'Gene', '5546', (88, 92))	('NF2', 'Gene', '4771', (12, 15))
24757	29535838	We identified 2 PRCC cell lines bearing NF2 mutations; one derived from a patient with type 2 PRCC, UOK275, and one derived from a patient with type 1 PRCC, UOK342.	('PRCC', 'Gene', (16, 20))	('PRCC', 'Gene', '5546', (151, 155))	('patient', 'Species', '9606', (74, 81))	('NF2', 'Gene', '4771', (40, 43))	('UOK342', 'Chemical', '-', (157, 163))	('PRCC', 'Gene', (151, 155))	('PRCC', 'Gene', '5546', (94, 98))	('UOK275', 'CellLine', 'CVCL:D760', (100, 106))	('NF2', 'Gene', (40, 43))	('mutations', 'Var', (44, 53))	('PRCC', 'Gene', (94, 98))	('patient', 'Species', '9606', (131, 138))	('PRCC', 'Gene', '5546', (16, 20))
24758	29535838	In addition, a known, commonly used type 1 PRCC cell line, ACHN, had been reported to have a NF2 mutation and this was confirmed within this study.	('NF2', 'Gene', (93, 96))	('ACHN', 'Gene', '55323', (59, 63))	('ACHN', 'Gene', (59, 63))	('PRCC', 'Gene', '5546', (43, 47))	('mutation', 'Var', (97, 105))	('NF2', 'Gene', '4771', (93, 96))	('PRCC', 'Gene', (43, 47))
24764	29535838	Comparative analysis using these two different sets of src inhibitors demonstrated a specific effect viability and expression of YAP1 downstream targets from the Yes kinase inhibitors and no effect from the src inhibitors that lacked Yes kinase inhibition.	('inhibitors', 'Var', (173, 183))	('YAP1', 'Gene', (129, 133))	('YAP1', 'Gene', '10413', (129, 133))	('expression', 'MPA', (115, 125))
24766	29535838	These data were further complemented by showing that Yes kinase inhibitors induced a G0/G1 arrest in all 3 NF2-deficient PRCC cell lines, but had no effect on the HEK293 control cell lines, while the alternative src inhibitors had no effect on cell cycle in any cell line.	('NF2-deficient', 'Disease', (107, 120))	('induced', 'Reg', (75, 82))	('NF2-deficient', 'Disease', 'MESH:C537392', (107, 120))	('PRCC', 'Gene', '5546', (121, 125))	('inhibitors', 'Var', (64, 74))	('PRCC', 'Gene', (121, 125))	('HEK293', 'CellLine', 'CVCL:0045', (163, 169))	('cell cycle', 'biological_process', 'GO:0007049', ('244', '254'))	('G0/G1 arrest', 'CPA', (85, 97))
24768	29535838	In NF2-deficient PRCC, the disruption of the Hippo pathway and aberrant activation of YAP1 are likely to promote cell proliferation.	('activation', 'PosReg', (72, 82))	('PRCC', 'Gene', (17, 21))	('promote', 'PosReg', (105, 112))	('cell proliferation', 'CPA', (113, 131))	('aberrant', 'Var', (63, 71))	('NF2-deficient', 'Disease', 'MESH:C537392', (3, 16))	('YAP1', 'Gene', (86, 90))	('disruption', 'Var', (27, 37))	('YAP1', 'Gene', '10413', (86, 90))	('NF2-deficient', 'Disease', (3, 16))	('Hippo pathway', 'Pathway', (45, 58))	('PRCC', 'Gene', '5546', (17, 21))	('cell proliferation', 'biological_process', 'GO:0008283', ('113', '131'))
24775	29535838	The recent uncovering of a subgroup of PRCC patients with NF2 mutation has paved the way for the development of novel targeted therapies.	('NF2', 'Gene', (58, 61))	('PRCC', 'Gene', (39, 43))	('patients', 'Species', '9606', (44, 52))	('NF2', 'Gene', '4771', (58, 61))	('mutation', 'Var', (62, 70))	('PRCC', 'Gene', '5546', (39, 43))
24783	29535838	Mutations in NF2 were validated by PCR using a Qiagen Taq PCR Core Kit (Qiagen, MD, USA) per the manufacturer's specifications, followed by bidirectional sequencing using the BigDye Terminator v.1.1 Cycle Sequencing Kit (Applied Biosystems, CA, USA) per the manufacturer's specifications.	('NF2', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('NF2', 'Gene', '4771', (13, 16))
24791	29535838	Rabbit antibodies against survivin (#2808), YAP (#4912), and cyclin D1 (#2922), and mouse antibodies against beta-actin (#3700) and alpha-tubulin (#3873) were from Cell Signaling Technology, Inc (Danvers, MA, USA).	('#3873', 'Var', (147, 152))	('Signaling', 'biological_process', 'GO:0023052', ('169', '178'))	('#4912', 'Var', (49, 54))	('#2922', 'Var', (72, 77))	('cyclin D1', 'Gene', '595', (61, 70))	('YAP', 'Gene', '10413', (44, 47))	('#3700', 'Var', (121, 126))	('beta-actin', 'Gene', '728378', (109, 119))	('cyclin D1', 'Gene', (61, 70))	('beta-actin', 'Gene', (109, 119))	('mouse', 'Species', '10090', (84, 89))	('YAP', 'Gene', (44, 47))	('Rabbit', 'Species', '9986', (0, 6))	('cyclin', 'molecular_function', 'GO:0016538', ('61', '67'))	('#2808', 'Var', (36, 41))
24792	29535838	Rabbit antibody against CTGF (#ab5097) and phospho-YAP (Tyr357) (#ab62751) was from Abcam (Cambridge, MA, USA).	('CTGF', 'Gene', '1490', (24, 28))	('CTGF', 'Gene', (24, 28))	('antibody', 'cellular_component', 'GO:0019815', ('7', '15'))	('#ab5097', 'Var', (30, 37))	('YAP', 'Gene', (51, 54))	('antibody', 'cellular_component', 'GO:0019814', ('7', '15'))	('antibody', 'molecular_function', 'GO:0003823', ('7', '15'))	('#ab62751', 'Var', (65, 73))	('antibody', 'cellular_component', 'GO:0042571', ('7', '15'))	('Tyr357) (#ab62751', 'Var', (56, 73))	('YAP', 'Gene', '10413', (51, 54))	('Tyr357', 'Chemical', '-', (56, 62))	('Rabbit', 'Species', '9986', (0, 6))
24796	29535838	The following set probes were used: BIRC5 (Hs03043574_m1), CTGF (Hs01026927_g1), and CCND1 (Hs00765553_m1).	('CCND1', 'Gene', '595', (85, 90))	('Hs00765553_m1', 'Var', (92, 105))	('BIRC5', 'Gene', '332', (36, 41))	('BIRC5', 'Gene', (36, 41))	('Hs03043574_m1', 'Var', (43, 56))	('CCND1', 'Gene', (85, 90))	('CTGF', 'Gene', '1490', (59, 63))	('Hs01026927_g1', 'Var', (65, 78))	('CTGF', 'Gene', (59, 63))
24809	29535838	Forty female athymic nude mice (Taconic, Germantown, NY, USA) were injected on the right flank with 2 million of UOK342 or UOK275 cells diluted in matrigel (100%; BD Bioscience, San Jose, CA, USA); 20 mice per cell lines).	('UOK275', 'CellLine', 'CVCL:D760', (123, 129))	('UOK342', 'Chemical', '-', (113, 119))	('UOK275', 'Var', (123, 129))	('UOK342', 'Gene', (113, 119))	('mice', 'Species', '10090', (201, 205))	('nude mice', 'Species', '10090', (21, 30))	('mice', 'Species', '10090', (26, 30))
24811	29535838	Mice were randomized into four groups of ten mice bearing either UOK342 or UOK275.	('mice', 'Species', '10090', (45, 49))	('UOK275', 'Var', (75, 81))	('UOK342', 'Chemical', '-', (65, 71))	('UOK342', 'Var', (65, 71))	('Mice', 'Species', '10090', (0, 4))	('UOK275', 'CellLine', 'CVCL:D760', (75, 81))
24829	28029648	using both The Cancer Genome Atlas (TCGA) data set and a validation set, it was found that VHL mutations occurred at a lower frequency in black patients and also that vascular endothelial growth factors (VEGF) and hypoxia-inducible factor (HIF) pathways were up-regulated less in black patients.	('Cancer Genome Atlas', 'Disease', (15, 34))	('Cancer', 'Phenotype', 'HP:0002664', (15, 21))	('hypoxia', 'Disease', (214, 221))	('lower', 'NegReg', (119, 124))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (15, 34))	('hypoxia', 'Disease', 'MESH:D000860', (214, 221))	('VEGF', 'Gene', (204, 208))	('patients', 'Species', '9606', (286, 294))	('up-regulated', 'PosReg', (259, 271))	('patients', 'Species', '9606', (144, 152))	('mutations', 'Var', (95, 104))	('VEGF', 'Gene', '7422', (204, 208))	('VHL', 'Disease', 'MESH:D006623', (91, 94))	('VHL', 'Disease', (91, 94))
24834	28029648	pRCC vs. ccRCC is specifically characterized by MET mutations and gains of chromosomes 7,12,16 and 17 as possible drivers whereas losses of heterozygosity of chromosome 3p and inactivating mutations of the VHL gene characterize ccRCC.	('chromosome', 'cellular_component', 'GO:0005694', ('158', '168'))	('VHL', 'Disease', 'MESH:D006623', (206, 209))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('inactivating mutations', 'Var', (176, 198))	('losses', 'NegReg', (130, 136))	('VHL', 'Disease', (206, 209))	('RCC', 'Disease', (1, 4))	('pRCC', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('pRCC', 'Gene', '5546', (0, 4))	('RCC', 'Disease', (11, 14))
24867	28029648	However, pRCC is a genetically distinct form of RCC driven by MET mutations and gains of chromosomes 7,12,16 and 17 as possible drivers; and in the present study, enrichment of VEGF pathway conversely suggests increased responsiveness of VEGFR tartgeted therapies among black patients with pRCC.	('patients', 'Species', '9606', (276, 284))	('pRCC', 'Gene', (290, 294))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('VEGFR', 'Gene', (238, 243))	('pRCC', 'Gene', '5546', (9, 13))	('RCC', 'Disease', (291, 294))	('RCC', 'Phenotype', 'HP:0005584', (291, 294))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('RCC', 'Disease', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('pRCC', 'Gene', (9, 13))	('VEGF', 'Gene', '7422', (177, 181))	('responsiveness', 'MPA', (220, 234))	('increased', 'PosReg', (210, 219))	('VEGF', 'Gene', (177, 181))	('MET mutations', 'Var', (62, 75))	('pRCC', 'Gene', '5546', (290, 294))	('VEGF', 'Gene', '7422', (238, 242))	('RCC', 'Disease', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('VEGF', 'Gene', (238, 242))	('VEGFR', 'Gene', '3791', (238, 243))
24892	28029648	Specifically distinct subclones with distinct mutation and expression within the same tumor may have provided us with different outcomes depending on the sample of the tumor sequenced.	('provided', 'Reg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mutation', 'Var', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
24901	28029648	The present retrospective study relied on the University of California Santa Cruz Genome (UCSC) Browser to download publicly available gene-level non-silent somatic mutation data (nonsense, missense, frame-shift indels, splice site mutations, stop codon read-throught, change of start codon, inframe indels) relied on Firewbrowse to download RNASeq gene expression and clinical pRCC TCGA data.	('pRCC', 'Gene', '5546', (378, 382))	('RCC', 'Phenotype', 'HP:0005584', (379, 382))	('gene expression', 'biological_process', 'GO:0010467', ('349', '364'))	('California Santa Cruz Genome', 'Disease', 'MESH:D004670', (60, 88))	('pRCC', 'Gene', (378, 382))	('missense', 'Var', (190, 198))	('frame-shift', 'Var', (200, 211))	('California Santa Cruz Genome', 'Disease', (60, 88))
24907	28029648	In a subset of propensity matched pRCC patients with gene-level mutation and paired clinical data available (n=71), rates of non-silent somatic gene-level mutations were compared between 41 (57.7%) black and 30 (42.3%) white patients.	('patients', 'Species', '9606', (225, 233))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (39, 47))	('pRCC', 'Gene', (34, 38))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('pRCC', 'Gene', '5546', (34, 38))
24939	30957192	To investigate the regulatory mechanisms of ceRNA networks in PRCC, and aid improvements in the diagnosis and prognosis of PRCC, a comprehensive analysis of the genomic and epigenomic landscape of PRCC was conducted to identify statistically significant genetic alterations in tumors in the present study.	('PRCC', 'Gene', (197, 201))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('PRCC', 'Gene', (123, 127))	('PRCC', 'Gene', '5546', (62, 66))	('PRCC', 'Phenotype', 'HP:0006766', (197, 201))	('PRCC', 'Phenotype', 'HP:0006766', (123, 127))	('genetic', 'Var', (254, 261))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('PRCC', 'Gene', (62, 66))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('PRCC', 'Gene', '5546', (197, 201))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('PRCC', 'Phenotype', 'HP:0006766', (62, 66))	('PRCC', 'Gene', '5546', (123, 127))	('tumors', 'Disease', (277, 283))
24987	30957192	It has been established that calcium ions affect almost every aspect of cellular life, and that variations in cytosolic calcium concentrations induce important cellular events.	('affect', 'Reg', (42, 48))	('induce', 'Reg', (143, 149))	('calcium', 'Chemical', 'MESH:D002118', (29, 36))	('variations', 'Var', (96, 106))	('cellular events', 'CPA', (160, 175))	('calcium', 'Chemical', 'MESH:D002118', (120, 127))
25022	33026261	Herein, we report an adult case of Xp11.2 translocation RCC, and review the relevant literature to improve our understanding of the pathogenesis, epidemiology, clinical manifestations, diagnosis, differential diagnosis, treatment, and other aspects of the disease.	('RCC', 'Disease', (56, 59))	('p11', 'Gene', '6281', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('translocation', 'Var', (42, 55))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('pathogenesis', 'biological_process', 'GO:0009405', ('132', '144'))	('p11', 'Gene', (36, 39))
25025	33026261	The origin of the name of this disease reflects the fact that it is characterized by fusions involving the TFE3 gene, located on chromosome Xp11.2, which leads to overexpression of the TFE3 protein in the nucleus of cancer cells.	('TFE3', 'Gene', '7030', (185, 189))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TFE3', 'Gene', '7030', (107, 111))	('nucleus', 'cellular_component', 'GO:0005634', ('205', '212'))	('protein', 'cellular_component', 'GO:0003675', ('190', '197'))	('p11', 'Gene', (141, 144))	('fusions', 'Var', (85, 92))	('cancer', 'Disease', (216, 222))	('TFE3', 'Gene', (185, 189))	('protein', 'Protein', (190, 197))	('p11', 'Gene', '6281', (141, 144))	('TFE3', 'Gene', (107, 111))	('overexpression', 'PosReg', (163, 177))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))
25046	33026261	Immunohistochemical features are shown in Figure 3, with positive staining for TFE3, vimentin, CD10, P504S, PAX8, CK-pan (scattered) and negative staining for CK7 and carbonic anhydrase IX.	('CK-pan', 'Chemical', '-', (114, 120))	('PAX8', 'Gene', '7849', (108, 112))	('carbonic anhydrase IX', 'Gene', (167, 188))	('P504S', 'Mutation', 'p.P504S', (101, 106))	('CK7', 'Gene', (159, 162))	('P504S', 'Var', (101, 106))	('vimentin', 'cellular_component', 'GO:0045098', ('85', '93'))	('TFE3', 'Gene', (79, 83))	('CK7', 'Gene', '3855', (159, 162))	('TFE3', 'Gene', '7030', (79, 83))	('CD10', 'Gene', '4311', (95, 99))	('CD10', 'molecular_function', 'GO:0004245', ('95', '99'))	('vimentin', 'cellular_component', 'GO:0045099', ('85', '93'))	('PAX8', 'Gene', (108, 112))	('carbonic anhydrase IX', 'Gene', '768', (167, 188))	('CD10', 'Gene', (95, 99))	('vimentin', 'Gene', '7431', (85, 93))	('vimentin', 'Gene', (85, 93))	('CK-pan', 'Gene', (114, 120))
25050	33026261	This genetic disease is caused by increased TFE3 expression as a result of translocation of the TFE3 gene on chromosome Xp11.2, and it is associated with cytotoxic chemotherapy in pediatric patients.	('translocation', 'Var', (75, 88))	('genetic disease', 'Disease', (5, 20))	('p11', 'Gene', '6281', (121, 124))	('TFE3', 'Gene', (44, 48))	('TFE3', 'Gene', '7030', (96, 100))	('patients', 'Species', '9606', (190, 198))	('expression', 'MPA', (49, 59))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('p11', 'Gene', (121, 124))	('TFE3', 'Gene', '7030', (44, 48))	('TFE3', 'Gene', (96, 100))	('increased', 'PosReg', (34, 43))	('genetic disease', 'Disease', 'MESH:D030342', (5, 20))
25052	33026261	Clinically, the most common types of gene fusions are the first three: t(X;1)(p11.2;q21.2), with the PRCC gene; t(X;17)(p11.2;q25) with the ASPL gene (also called ASPSCR1); and t(X;1)(p11.2;p34) with the SFPQ gene (also called PSF).	('PSF', 'Gene', '6421', (227, 230))	('t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (112, 130))	('t(X;17)(p11.2;q25', 'Var', (112, 129))	('ASPSCR1', 'Gene', '79058', (163, 170))	('t(X;1)(p11.2;p34)', 'STRUCTURAL_ABNORMALITY', 'None', (177, 194))	('PSF', 'Gene', (227, 230))	('SFPQ', 'Gene', '6421', (204, 208))	('SFPQ', 'Gene', (204, 208))	('ASPL', 'Gene', '79058', (140, 144))	('PRCC', 'Gene', '5546', (101, 105))	('ASPSCR1', 'Gene', (163, 170))	('ASPL', 'Gene', (140, 144))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('t(X;1)(p11.2;q21.2', 'Var', (71, 89))	('PRCC', 'Gene', (101, 105))	('t(X;1)(p11.2;q21.2)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 90))
25068	33026261	Xp11.2/TFE3-related RCC usually has the following immunohistochemical characteristics: PAX8+, vimentin+, P504S+, CK7-, carbonic anhydrase IX-, and CD10+.	('CD10', 'molecular_function', 'GO:0004245', ('147', '151'))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('CD10', 'Gene', (147, 151))	('P504S+', 'Var', (105, 111))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('vimentin', 'cellular_component', 'GO:0045098', ('94', '102'))	('p11', 'Gene', '6281', (1, 4))	('PAX8', 'Gene', (87, 91))	('TFE3', 'Gene', (7, 11))	('p11', 'Gene', (1, 4))	('CK7-, carbonic anhydrase IX', 'Gene', '3855;768', (113, 140))	('P504S', 'Mutation', 'p.P504S', (105, 110))	('vimentin', 'Gene', '7431', (94, 102))	('TFE3', 'Gene', '7030', (7, 11))	('PAX8', 'Gene', '7849', (87, 91))	('vimentin', 'Gene', (94, 102))	('vimentin', 'cellular_component', 'GO:0045099', ('94', '102'))	('CD10', 'Gene', '4311', (147, 151))
25082	33026261	In addition, RCC associated with Xp11.2 translocation/TFE3 gene fusions can be differentiated from PRCC by alpha-methylacyl COA racemase (AMACR) and CK7.	('alpha-methylacyl COA racemase', 'Gene', '23600', (107, 136))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('AMACR', 'Gene', '23600', (138, 143))	('PRCC', 'Gene', '5546', (99, 103))	('p11', 'Gene', '6281', (34, 37))	('CK7', 'Gene', (149, 152))	('PRCC', 'Gene', (99, 103))	('TFE3', 'Gene', (54, 58))	('p11', 'Gene', (34, 37))	('TFE3', 'Gene', '7030', (54, 58))	('CK7', 'Gene', '3855', (149, 152))	('alpha-methylacyl COA racemase', 'Gene', (107, 136))	('fusions', 'Var', (64, 71))	('RCC', 'Disease', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('AMACR', 'Gene', (138, 143))
25085	33026261	All of these characteristics help differentiate RCC with TFE3 gene fusions from common types of RCC.	('RCC', 'Disease', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (48, 51))	('gene fusions', 'Var', (62, 74))	('TFE3', 'Gene', (57, 61))	('TFE3', 'Gene', '7030', (57, 61))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
25097	33026261	For patients with metastatic Xp11.2 translocation RCC, adjuvant therapies such as targeted therapy and immunotherapy are being tested.	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('p11', 'Gene', '6281', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('patients', 'Species', '9606', (4, 12))	('translocation', 'Var', (36, 49))	('p11', 'Gene', (30, 33))
25099	33026261	Overall, the incidence of Xp11.2 translocation RCC is relatively low, especially in adults, and the clinical features and underlying mechanisms of the disease have not been fully clarified.	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('p11', 'Gene', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('p11', 'Gene', '6281', (27, 30))	('translocation', 'Var', (33, 46))
25103	31627758	ALK-TPM3 rearrangement in adult renal cell carcinoma: a case report and literature review Translocation-associated renal cell carcinoma involving ALK (ALK-tRCC) is a rare subtype of adult renal cell carcinoma (RCC) reported in recent years.	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (115, 135))	('RCC', 'Disease', (156, 159))	('TPM3', 'Gene', (4, 8))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('renal cell carcinoma', 'Disease', (115, 135))	('adult renal cell carcinoma', 'Disease', 'MESH:D002292', (26, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (115, 135))	('adult renal cell carcinoma', 'Disease', (26, 52))	('ALK', 'Gene', '238', (146, 149))	('RCC', 'Disease', 'MESH:D002292', (156, 159))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (32, 52))	('rearrangement', 'Var', (9, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('ALK', 'Gene', (146, 149))	('RCC', 'Disease', 'MESH:D002292', (210, 213))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('adult renal cell carcinoma', 'Disease', 'MESH:D002292', (182, 208))	('adult renal cell carcinoma', 'Disease', (182, 208))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (188, 208))	('ALK', 'Gene', '238', (151, 154))	('ALK', 'Gene', '238', (0, 3))	('TPM3', 'Gene', '7170', (4, 8))	('ALK', 'Gene', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('ALK', 'Gene', (0, 3))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (188, 208))
25109	31627758	Fluorescent in situ hybridization (FISH) showed a rearrangement of ALK in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ALK', 'Gene', '238', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('rearrangement', 'Var', (50, 63))	('ALK', 'Gene', (67, 70))
25112	31627758	Anaplastic lymphoma kinase (ALK) translocation was first reported in a distinct subset of anaplastic large cell lymphoma, which is a rare subtype of T-cell lymphoma.	('ALK', 'Gene', '238', (28, 31))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (0, 19))	('cell lymphoma', 'Phenotype', 'HP:0012191', (151, 164))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (149, 164))	('cell lymphoma', 'Phenotype', 'HP:0012191', (107, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('Anaplastic lymphoma kinase', 'Gene', (0, 26))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (90, 120))	('ALK', 'Gene', (28, 31))	('cell lymphoma', 'Disease', 'MESH:D016399', (151, 164))	('cell lymphoma', 'Disease', 'MESH:D016399', (107, 120))	('Anaplastic lymphoma kinase', 'Gene', '238', (0, 26))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('translocation', 'Var', (33, 46))	('T-cell lymphoma', 'Disease', (149, 164))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (149, 164))	('cell lymphoma', 'Disease', (107, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))
25113	31627758	Subsequently, ALK rearrangements have been found in various types of neoplasm, such as inflammatory myofibroblastic tumor, the diffuse large B-cell lymphoma, plasmacytoma, non-small cell lung carcinoma, esophageal squamous cell carcinoma, breast carcinoma, colonic adenocarcinoma, thyroid carcinoma and, recently RCC.	('ALK', 'Gene', '238', (14, 17))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (141, 156))	('neoplasm', 'Phenotype', 'HP:0002664', (69, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('found', 'Reg', (43, 48))	('inflammatory myofibroblastic tumor', 'Disease', 'MESH:D009369', (87, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (214, 237))	('rearrangements', 'Var', (18, 32))	('ALK', 'Gene', (14, 17))	('colonic adenocarcinoma', 'Disease', 'MESH:D015179', (257, 279))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (176, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('RCC', 'Disease', (313, 316))	('RCC', 'Phenotype', 'HP:0005584', (313, 316))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (172, 201))	('breast carcinoma', 'Disease', 'MESH:D001943', (239, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (281, 298))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (203, 237))	('inflammatory myofibroblastic tumor', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('colonic adenocarcinoma', 'Disease', (257, 279))	('thyroid carcinoma', 'Disease', (281, 298))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (100, 121))	('RCC', 'Disease', 'MESH:D002292', (313, 316))	('neoplasm', 'Disease', 'MESH:D009369', (69, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('B-cell lymphoma, plasmacytoma, non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (141, 201))	('breast carcinoma', 'Phenotype', 'HP:0003002', (239, 255))	('plasmacytoma', 'Phenotype', 'HP:0011857', (158, 170))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (281, 298))	('cell lymphoma', 'Phenotype', 'HP:0012191', (143, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('breast carcinoma', 'Disease', (239, 255))	('neoplasm', 'Disease', (69, 77))	('esophageal squamous cell carcinoma', 'Disease', (203, 237))
25114	31627758	Several groups had continuously reported translocation-associated renal cell carcinomas (ALK-tRCCs).	('RCC', 'Disease', 'MESH:D002292', (94, 97))	('RCC', 'Disease', (94, 97))	('renal cell carcinomas', 'Disease', (66, 87))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('ALK', 'Gene', (89, 92))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('translocation-associated', 'Var', (41, 65))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (66, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('ALK', 'Gene', '238', (89, 92))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (66, 87))
25144	31627758	In addition, 4 genetic variants with uncertain significance were found, including BARD1 (c.773 T > C), MSH3 (c.178G > C), FANCA (c.1756G > A) and NF1 (c.4382 T > C) (Additional file 1: Table S1).	('c.1756G > A', 'Var', (129, 140))	('NF1', 'Gene', '4763', (146, 149))	('BARD1', 'Gene', '580', (82, 87))	('c.4382 T > C', 'Var', (151, 163))	('BARD1', 'Gene', (82, 87))	('c.178G > C', 'Var', (109, 119))	('c.178G > C', 'Mutation', 'c.178G>C', (109, 119))	('c.1756G > A', 'Mutation', 'c.1756G>A', (129, 140))	('FANCA', 'Gene', '2175', (122, 127))	('FANCA', 'Gene', (122, 127))	('c.773 T > C', 'Mutation', 'c.773T>C', (89, 100))	('c.4382 T > C', 'Mutation', 'c.4382T>C', (151, 163))	('MSH3', 'Gene', (103, 107))	('c.773 T > C', 'Var', (89, 100))	('MSH3', 'Gene', '4437', (103, 107))	('NF1', 'Gene', (146, 149))
25171	31627758	As everyone knows, the vast majority of TFE3-positive renal tumors are cases of Xp11.2 translocation carcinoma.	('TFE3', 'Gene', (40, 44))	('renal tumors', 'Disease', 'MESH:D007680', (54, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('renal tumors', 'Disease', (54, 66))	('TFE3', 'Gene', '7030', (40, 44))	('Xp11.2 translocation', 'Var', (80, 100))	('renal tumors', 'Phenotype', 'HP:0009726', (54, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
25180	31627758	FISH is the most widely used method to confirm ALK gene rupture and rearrangement.	('rearrangement', 'Var', (68, 81))	('rupture', 'Disease', (56, 63))	('ALK', 'Gene', (47, 50))	('rupture', 'Disease', 'MESH:D012421', (56, 63))	('ALK', 'Gene', '238', (47, 50))
25192	31627758	reported one special case demonstrating increased copy number of intact 2p23, the chromosomal region containing the ALK gene, rather than exhibiting a chromosomal translocation involving ALK .	('copy number', 'Var', (50, 61))	('chromosomal region', 'cellular_component', 'GO:0098687', ('82', '100'))	('ALK', 'Gene', '238', (187, 190))	('ALK', 'Gene', (116, 119))	('increased', 'PosReg', (40, 49))	('ALK', 'Gene', (187, 190))	('ALK', 'Gene', '238', (116, 119))
25196	31627758	Our case tested TFEB gene breakage too.	('gene breakage', 'Var', (21, 34))	('TFEB', 'Gene', '7942', (16, 20))	('TFEB', 'Gene', (16, 20))
25201	31627758	In our case, we detected the ALK-TPM3 translocation by NGS, in addition some genetic mutations with uncertain significance were found, including BARD1 (c.773 T > C), MSH3 (c.178G > C), FANCA (c.1756G > A) and NF1 (c.4382 T > C).	('BARD1', 'Gene', (145, 150))	('MSH3', 'Gene', '4437', (166, 170))	('ALK', 'Gene', '238', (29, 32))	('FANCA', 'Gene', (185, 190))	('TPM3', 'Gene', '7170', (33, 37))	('c.178G > C', 'Var', (172, 182))	('c.178G > C', 'Mutation', 'c.178G>C', (172, 182))	('ALK', 'Gene', (29, 32))	('c.773 T > C', 'Mutation', 'c.773T>C', (152, 163))	('c.1756G > A', 'Mutation', 'c.1756G>A', (192, 203))	('NF1', 'Gene', '4763', (209, 212))	('c.1756G > A', 'Var', (192, 203))	('TPM3', 'Gene', (33, 37))	('c.4382 T > C', 'Mutation', 'c.4382T>C', (214, 226))	('NF1', 'Gene', (209, 212))	('c.773 T > C', 'Var', (152, 163))	('FANCA', 'Gene', '2175', (185, 190))	('c.4382 T > C', 'Var', (214, 226))	('BARD1', 'Gene', '580', (145, 150))	('MSH3', 'Gene', (166, 170))
25202	31627758	The correlation between these genes' mutation and ALK-tRCC occurrence retains unknown.	('RCC', 'Disease', 'MESH:D002292', (55, 58))	('RCC', 'Disease', (55, 58))	('ALK', 'Gene', (50, 53))	('mutation', 'Var', (37, 45))	('ALK', 'Gene', '238', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
25294	30693167	Histologically, it had a papillary architecture mimicking ovarian serous carcinoma and was immunopositive for paired box gene 8 (PAX8), vimentin, P504S, P53, and CK20 (focal) and negative for CK7, WT-1, high molecular weight cytokeratin and p63, CK5/6, CD10, and estrogen receptors, supporting the diagnosis of RCCU.	('P53', 'Gene', (153, 156))	('CK20', 'Gene', '54474', (162, 166))	('CK7', 'Gene', (192, 195))	('estrogen receptor', 'Gene', '2099', (263, 280))	('WT-1', 'Gene', (197, 201))	('PAX8', 'Gene', (129, 133))	('CK5/6', 'Gene', '3852', (246, 251))	('paired box gene 8', 'Gene', (110, 127))	('P53', 'Gene', '7157', (153, 156))	('paired box gene 8', 'Gene', '7849', (110, 127))	('PAX8', 'Gene', '7849', (129, 133))	('ovarian serous carcinoma', 'Disease', (58, 82))	('P504S', 'Mutation', 'p.P504S', (146, 151))	('vimentin', 'Gene', '7431', (136, 144))	('vimentin', 'cellular_component', 'GO:0045098', ('136', '144'))	('CK7', 'Gene', '3855', (192, 195))	('P504S', 'Var', (146, 151))	('vimentin', 'Gene', (136, 144))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (58, 82))	('CD10', 'molecular_function', 'GO:0004245', ('253', '257'))	('CD10', 'Gene', '4311', (253, 257))	('estrogen receptor', 'Gene', (263, 280))	('CK5/6', 'Gene', (246, 251))	('p63', 'Gene', (241, 244))	('CK20', 'Gene', (162, 166))	('WT-1', 'Gene', '7490', (197, 201))	('vimentin', 'cellular_component', 'GO:0045099', ('136', '144'))	('p63', 'Gene', '8626', (241, 244))	('CD10', 'Gene', (253, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
25303	29390196	Segmental enhancement inversion was an independent predictor of oncocytomas (OR: 16.21 [1.0, 275.4], p=0.049), with moderate inter-reader agreement (kappa=0.49).	('oncocytomas', 'Disease', (64, 75))	('Segmental', 'Var', (0, 9))	('oncocytomas', 'Disease', 'MESH:D018249', (64, 75))	('men', 'Species', '9606', (3, 6))	('men', 'Species', '9606', (143, 146))	('men', 'Species', '9606', (17, 20))
25378	29390196	These authors also reported a sensitivity of 100% and specificity of 89% combining quantitative T2W and DCE-MRI, contrasting with our data, which did not show the degree of contrast enhancement or the enhancement characteristics on post-contrast multiphasic MRI to be significant predictors of mfAML histology.	('AML', 'Disease', (296, 299))	('men', 'Species', '9606', (189, 192))	('DCE-MRI', 'Var', (104, 111))	('DCE', 'Chemical', '-', (104, 107))	('men', 'Species', '9606', (208, 211))	('AML', 'Disease', 'MESH:D015470', (296, 299))
25394	29390196	Segmental enhancement inversion is an independent predictor of oncocytoma (OR: 16.21 [1.0, 275.4], p=0.049), although inter-reader agreement is only moderate (kappa=0.49).	('enhancement', 'PosReg', (10, 21))	('oncocytoma', 'Disease', 'MESH:D018249', (63, 73))	('Segmental', 'Var', (0, 9))	('men', 'Species', '9606', (3, 6))	('men', 'Species', '9606', (136, 139))	('oncocytoma', 'Disease', (63, 73))	('men', 'Species', '9606', (17, 20))
25400	24977159	Twenty-two genes showed methylation and/or deletion in 17-57% of tumors.	('deletion', 'Var', (43, 51))	('methylation', 'Var', (24, 35))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('methylation', 'biological_process', 'GO:0032259', ('24', '35'))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
25402	24977159	Bisulfite sequencing analysis confirmed methylation as a frequent event in ccRCC.	('methylation', 'Var', (40, 51))	('ccRCC', 'Phenotype', 'HP:0006770', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))
25420	24977159	Hypermethylation of promoter region of genes, primarily tumor suppressor genes (TSGs), and hypomethylation of other genome elements are common events in cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('men', 'Species', '9606', (126, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('56', '72'))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (153, 159))	('TSG', 'Gene', (80, 83))	('tumor', 'Disease', (56, 61))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TSG', 'Gene', '57045', (80, 83))	('hypomethylation', 'Var', (91, 106))	('tumor suppressor', 'biological_process', 'GO:0051726', ('56', '72'))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
25421	24977159	Hemizygous deletion of several regions of chromosome 3p (short arm of chromosome 3) and inactivation of TSG VHL are the most common genetic alteration in ccRCC.	('TSG', 'Gene', (104, 107))	('VHL', 'Gene', '7428', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('ccRCC', 'Phenotype', 'HP:0006770', (154, 159))	('RCC', 'Disease', (156, 159))	('short arm', 'Phenotype', 'HP:0009824', (57, 66))	('TSG', 'Gene', '57045', (104, 107))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('chromosome', 'cellular_component', 'GO:0005694', ('42', '52'))	('inactivation', 'Var', (88, 100))	('VHL', 'Gene', (108, 111))
25424	24977159	This technology was successfully used for analysis of methylations/deletions in lung, ovary, and cervical cancer.	('cervical cancer', 'Disease', (97, 112))	('lung', 'Disease', (80, 84))	('methylations/deletions', 'Var', (54, 76))	('ovary', 'Disease', (86, 91))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
25425	24977159	CpG-islands are located in promoter region of many genes associated with cancer and its hypermethylation has been observed as a frequent mechanism of TSGs inactivation, which contributes to malignant transformation.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('inactivation', 'NegReg', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('malignant transformation', 'CPA', (190, 214))	('TSG', 'Gene', (150, 153))	('hypermethylation', 'Var', (88, 104))	('TSG', 'Gene', '57045', (150, 153))
25429	24977159	The aim of our study was to identify epigenetic and genetic alterations of chromosome 3 genes in ccRCC.	('epigenetic', 'Var', (37, 47))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('chromosome 3 genes', 'Gene', (75, 93))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('ccRCC', 'Phenotype', 'HP:0006770', (97, 102))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))
25453	24977159	To confirm the results of NMA hybridizations, methylation status of promoter CpG-island of 5 genes with frequency of M/D 30-57% (according NMA) was analyzed: NKIRAS1 (sample number 22 from Figures 1 and 2), LRRN1 (numbers 5 and 17), LRRC3B (numbers 4 and 16), CTDSPL (numbers 8, 16, and 21), and VHL (numbers 1 and 5).	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('LRRN1', 'Gene', '57633', (207, 212))	('CTDSPL', 'Gene', '10217', (260, 266))	('LRRN1', 'Gene', (207, 212))	('CTDSPL', 'Gene', (260, 266))	('M/D 30', 'Var', (117, 123))	('LRRC3B', 'Gene', (233, 239))	('NKIRAS1', 'Gene', (158, 165))	('VHL', 'Gene', (296, 299))	('LRRC3B', 'Gene', '116135', (233, 239))	('NKIRAS1', 'Gene', '28512', (158, 165))	('VHL', 'Gene', '7428', (296, 299))	('M/D 30', 'SUBSTITUTION', 'None', (117, 123))
25454	24977159	Methylation was confirmed in all tested cases, except sample number 22 for NKIRAS1 gene and sample number 1 for VHL gene.	('NKIRAS1', 'Gene', (75, 82))	('Methylation', 'Var', (0, 11))	('NKIRAS1', 'Gene', '28512', (75, 82))	('VHL', 'Gene', (112, 115))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('VHL', 'Gene', '7428', (112, 115))
25455	24977159	According to our previous qPCR data, deletions are the main mechanism of NKIRAS1 gene inactivation in RCC, and deletion of VHL gene locus is a common genetic alteration in ccRCC.	('deletions', 'Var', (37, 46))	('NKIRAS1', 'Gene', '28512', (73, 80))	('NKIRAS1', 'Gene', (73, 80))	('VHL', 'Gene', (123, 126))	('inactivation', 'NegReg', (86, 98))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (174, 177))	('RCC', 'Disease', (102, 105))	('VHL', 'Gene', '7428', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('ccRCC', 'Phenotype', 'HP:0006770', (172, 177))	('deletion', 'Var', (111, 119))
25457	24977159	Thus, bisulfite sequencing data are in good concordance with NotI-microarrays results and suggest that methylation of 5' regulator regions of genes is a frequent event in ccRCC.	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('bisulfite', 'Chemical', 'MESH:C042345', (6, 15))	('methylation', 'Var', (103, 114))	('methylation', 'biological_process', 'GO:0032259', ('103', '114'))
25458	24977159	Quantitative expression estimation was performed for eight genes showing high methylation/deletion frequency in ccRCC (LRRN1, GORASP1, IQSEC1, FOXP1, GNAI2, FGD5, PLCL2, and ALDH1L1; Figure 4).	('ALDH1L1', 'Gene', '10840', (174, 181))	('FGD5', 'Gene', (157, 161))	('methylation', 'biological_process', 'GO:0032259', ('78', '89'))	('ccRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (114, 117))	('GORASP1', 'Gene', (126, 133))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('FOXP1', 'Gene', '27086', (143, 148))	('IQSEC1', 'Gene', '9922', (135, 141))	('PLCL2', 'Gene', '23228', (163, 168))	('IQSEC1', 'Gene', (135, 141))	('ALDH1L1', 'Gene', (174, 181))	('FGD5', 'Gene', '152273', (157, 161))	('ALDH', 'molecular_function', 'GO:0004030', ('174', '178'))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('methylation/deletion', 'Var', (78, 98))	('FOXP1', 'Gene', (143, 148))	('LRRN1', 'Gene', '57633', (119, 124))	('GNAI2', 'Gene', '2771', (150, 155))	('PLCL2', 'Gene', (163, 168))	('LRRN1', 'Gene', (119, 124))	('GORASP1', 'Gene', '64689', (126, 133))	('GNAI2', 'Gene', (150, 155))
25464	24977159	The comparison of our NotI-microarray and qPCR data (Tables 2 and 3) showed that, for LRRN1, GORASP1, FOXP1, and FGD5 genes M/D and downregulation, frequencies were close.	('downregulation', 'NegReg', (132, 146))	('LRRN1', 'Gene', (86, 91))	('FOXP1', 'Gene', '27086', (102, 107))	('GORASP1', 'Gene', '64689', (93, 100))	('FGD5', 'Gene', (113, 117))	('FOXP1', 'Gene', (102, 107))	('GORASP1', 'Gene', (93, 100))	('FGD5', 'Gene', '152273', (113, 117))	('M/D', 'Var', (124, 127))	('LRRN1', 'Gene', '57633', (86, 91))
25465	24977159	This allows us to assume that methylation and/or deletions were the main mechanisms of inactivation of these genes in ccRCC.	('methylation', 'Var', (30, 41))	('inactivation', 'NegReg', (87, 99))	('methylation', 'biological_process', 'GO:0032259', ('30', '41'))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('deletions', 'Var', (49, 58))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ccRCC', 'Phenotype', 'HP:0006770', (118, 123))
25474	24977159	In this study we revealed 22 genes from chromosome 3 with high frequency (17-57%) of methylation and/or deletion in ccRCC using sensitive method of DNA hybridization on NotI-microarrays.	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('methylation', 'Var', (85, 96))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('chromosome', 'cellular_component', 'GO:0005694', ('40', '50'))	('deletion', 'Var', (104, 112))
25479	24977159	These findings suggest that genetic and epigenetic destabilization of genes at chromosome 3 (especially 3p) are common mechanisms of epithelial tumors development.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('epithelial tumors', 'Disease', (133, 150))	('destabilization', 'NegReg', (51, 66))	('epigenetic', 'Var', (40, 50))	('epithelial tumors', 'Disease', 'MESH:D002277', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('men', 'Species', '9606', (158, 161))	('chromosome', 'cellular_component', 'GO:0005694', ('79', '89'))
25482	24977159	We have validated our NotI-microarray data for NKIRAS1, LRRN1, LRRC3B, CTDSPL, and VHL genes by bisulfite genomic sequencing and have revealed that DNA methylation of the tested genes took place in ccRCC.	('took place', 'Reg', (184, 194))	('NKIRAS1', 'Gene', (47, 54))	('NKIRAS1', 'Gene', '28512', (47, 54))	('VHL', 'Gene', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (198, 203))	('DNA', 'cellular_component', 'GO:0005574', ('148', '151'))	('CTDSPL', 'Gene', '10217', (71, 77))	('CTDSPL', 'Gene', (71, 77))	('DNA methylation', 'biological_process', 'GO:0006306', ('148', '163'))	('RCC', 'Disease', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('bisulfite', 'Chemical', 'MESH:C042345', (96, 105))	('LRRN1', 'Gene', '57633', (56, 61))	('LRRN1', 'Gene', (56, 61))	('LRRC3B', 'Gene', '116135', (63, 69))	('LRRC3B', 'Gene', (63, 69))	('VHL', 'Gene', '7428', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('methylation', 'Var', (152, 163))
25483	24977159	For example, frequent deletions of ABHD5 gene in ccRCC were firstly discovered in the recent work.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('deletions', 'Var', (22, 31))	('ABHD5', 'Gene', '51099', (35, 40))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('ABHD5', 'Gene', (35, 40))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
25484	24977159	We observed M/D of ABHD5 gene region in 22% of samples, and our result supports this finding.	('M/D', 'Var', (12, 15))	('ABHD5', 'Gene', (19, 24))	('ABHD5', 'Gene', '51099', (19, 24))
25489	24977159	If methylation and/or deletion were found in two or more of these markers, then samples would be recognized as ccRCC.	('deletion', 'Var', (22, 30))	('methylation', 'Var', (3, 14))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('methylation', 'biological_process', 'GO:0032259', ('3', '14'))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))
25490	24977159	Methylation alterations are one of the earliest events occurring during the tumor cell transformation process, and the gene methylation biomarkers are one of the most effective and advantageous for the early stage cancer screening.	('Methylation alterations', 'Var', (0, 23))	('cancer', 'Disease', (214, 220))	('methylation', 'biological_process', 'GO:0032259', ('124', '135'))	('alterations', 'Var', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
25491	24977159	QPCR revealed that methylation and/or deletions considerably contribute to inactivation of the majority of examined genes (LRRN1, GORASP1, IQSEC1, FOXP1, GNAI2, FGD5, PLCL2, and ALDH1L1) in ccRCC.	('FGD5', 'Gene', '152273', (161, 165))	('methylation', 'biological_process', 'GO:0032259', ('19', '30'))	('GORASP1', 'Gene', '64689', (130, 137))	('FOXP1', 'Gene', (147, 152))	('inactivation', 'NegReg', (75, 87))	('PLCL2', 'Gene', (167, 172))	('GNAI2', 'Gene', '2771', (154, 159))	('LRRN1', 'Gene', '57633', (123, 128))	('RCC', 'Disease', (192, 195))	('LRRN1', 'Gene', (123, 128))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('GORASP1', 'Gene', (130, 137))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('ALDH1L1', 'Gene', '10840', (178, 185))	('GNAI2', 'Gene', (154, 159))	('FGD5', 'Gene', (161, 165))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('PLCL2', 'Gene', '23228', (167, 172))	('methylation', 'Var', (19, 30))	('FOXP1', 'Gene', '27086', (147, 152))	('IQSEC1', 'Gene', '9922', (139, 145))	('deletions', 'Var', (38, 47))	('IQSEC1', 'Gene', (139, 145))	('ALDH', 'molecular_function', 'GO:0004030', ('178', '182'))	('ALDH1L1', 'Gene', (178, 185))
25499	24977159	Epigenetic silencing was shown in lung adenocarcinoma, spleen cancer, liver cancer, hemangioma, hepatocellular carcinoma, and cancer cell lines (A549, HepG2, HCT116).	('hepatocellular carcinoma', 'Disease', (96, 120))	('hemangioma', 'Disease', (84, 94))	('liver cancer', 'Phenotype', 'HP:0002896', (70, 82))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('liver cancer', 'Disease', (70, 82))	('lung adenocarcinoma', 'Disease', (34, 53))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (62, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (34, 53))	('HepG2', 'CellLine', 'CVCL:0027', (151, 156))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hemangioma', 'Phenotype', 'HP:0001028', (84, 94))	('HCT116', 'CellLine', 'CVCL:0291', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('hemangioma', 'Disease', 'MESH:D006391', (84, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (34, 53))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Disease', (76, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('liver cancer', 'Disease', 'MESH:D006528', (70, 82))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))
25505	24977159	It revealed several pairs of genes that could be coregulated by common microRNAs: NKIRAS1 and ABHD5 (miRs: 17, 106b, 20a, 93, 519c-3p), NKIRAS1 and FGD5 (miRs: 93, 519d, 20b), NKIRAS1 and IQSEC1 (miRs: 106b, 17, 519d), FGD5 and ABHD5 (miRs: 519d, 17, 106b, 20a, 93, 124, 506), and FGD5 and IQSEC1 (miRs: 106b, 93, 20b, 519d, 373, 520e, 520a-3p, 302c, 372, 520f, 4469, 212).	('IQSEC1', 'Gene', (290, 296))	('FGD5', 'Gene', (148, 152))	('FGD5', 'Gene', (219, 223))	('373', 'Var', (325, 328))	('FGD5', 'Gene', '152273', (148, 152))	('NKIRAS1', 'Gene', (136, 143))	('ABHD5', 'Gene', '51099', (94, 99))	('FGD5', 'Gene', (281, 285))	('NKIRAS1', 'Gene', (82, 89))	('NKIRAS1', 'Gene', '28512', (136, 143))	('NKIRAS1', 'Gene', '28512', (82, 89))	('ABHD5', 'Gene', '51099', (228, 233))	('ABHD5', 'Gene', (94, 99))	('IQSEC1', 'Gene', '9922', (188, 194))	('miRs: 106b', 'Var', (298, 308))	('NKIRAS1', 'Gene', (176, 183))	('ABHD5', 'Gene', (228, 233))	('FGD5', 'Gene', '152273', (219, 223))	('NKIRAS1', 'Gene', '28512', (176, 183))	('IQSEC1', 'Gene', (188, 194))	('IQSEC1', 'Gene', '9922', (290, 296))	('FGD5', 'Gene', '152273', (281, 285))
25510	24977159	NotI-microarray analysis revealed 22 genes with methylation and/or deletion frequency of more than 17% in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('methylation', 'biological_process', 'GO:0032259', ('48', '59'))	('ccRCC', 'Phenotype', 'HP:0006770', (106, 111))	('deletion', 'Var', (67, 75))	('methylation', 'Var', (48, 59))
25512	24977159	Bisulfite genomic sequencing data confirmed NotI-microarrays results and showed that methylation of chromosome 3 genes (especially short arm:3p) is a common event in ccRCC.	('methylation', 'Var', (85, 96))	('methylation', 'biological_process', 'GO:0032259', ('85', '96'))	('ccRCC', 'Phenotype', 'HP:0006770', (166, 171))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('chromosome', 'cellular_component', 'GO:0005694', ('100', '110'))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('short arm', 'Phenotype', 'HP:0009824', (131, 140))	('common event', 'Reg', (150, 162))
25513	24977159	QPCR analysis revealed frequent (20-92%) downregulation of 6 genes with high methylation/deletion frequency in ccRCC.	('methylation', 'biological_process', 'GO:0032259', ('77', '88'))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (113, 116))	('methylation/deletion', 'Var', (77, 97))	('downregulation', 'NegReg', (41, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (111, 116))
25567	32047554	The 20-muL PCR mix contained QX200  ddPCR  EvaGreen Supermix (Bio-Rad), 300 nM each primer and approximately 50 ng of cDNA template.	('Rad', 'Gene', (66, 69))	('mix', 'Gene', '83881', (15, 18))	('mix', 'Gene', (15, 18))	('Rad', 'biological_process', 'GO:1990116', ('66', '69'))	('mix', 'Gene', '83881', (57, 60))	('mix', 'Gene', (57, 60))	('QX200  ddPCR', 'Var', (29, 41))	('Rad', 'Gene', '6236', (66, 69))
25577	32047554	High CYP4A11 expression in the 139 RCCs was positively associated with PPARalpha expression, males, the non-ccRCC type, and high histologic grades (grade 1/2 versus grade 3/4) (p=0.001, p=0.018, p<0.001 and p<0.001).	('ccRCC', 'Disease', (108, 113))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (110, 113))	('ccRCC', 'Disease', 'MESH:D002292', (108, 113))	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('High', 'Var', (0, 4))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('expression', 'MPA', (13, 23))	('PPARalpha', 'Gene', (71, 80))	('CYP4A11', 'Gene', (5, 12))	('CYP4A11', 'Gene', '1579', (5, 12))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))
25579	32047554	Kaplan-Meier survival curves and log-rank tests showed a significant association between high CYP4A11 expression and short OS (log-rank=7.994, p=0.005), while no association with DFS was observed (log-rank=0.005, p=0.945) (Fig.	('CYP4A11', 'Gene', (94, 101))	('expression', 'MPA', (102, 112))	('CYP4A11', 'Gene', '1579', (94, 101))	('short OS', 'Disease', (117, 125))	('high', 'Var', (89, 93))
25599	32047554	In ccRCC, inactivation or loss of VHL leads to aberrant accumulation of HIF proteins, which in turn results in angiogenesis, glycolysis, apoptosis, and lipid deposition in ccRCC.	('angiogenesis', 'MPA', (111, 123))	('HIF proteins', 'Disease', 'MESH:D058495', (72, 84))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('glycolysis', 'MPA', (125, 135))	('apoptosis', 'biological_process', 'GO:0097194', ('137', '146'))	('apoptosis', 'biological_process', 'GO:0006915', ('137', '146'))	('HIF proteins', 'Disease', (72, 84))	('glycolysis', 'biological_process', 'GO:0006096', ('125', '135'))	('ccRCC', 'Disease', 'MESH:D002292', (172, 177))	('apoptosis', 'CPA', (137, 146))	('lipid deposition', 'MPA', (152, 168))	('inactivation', 'Var', (10, 22))	('angiogenesis', 'biological_process', 'GO:0001525', ('111', '123'))	('VHL', 'Gene', (34, 37))	('ccRCC', 'Disease', (172, 177))	('accumulation', 'PosReg', (56, 68))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('ccRCC', 'Disease', 'MESH:D002292', (3, 8))	('ccRCC', 'Disease', (3, 8))	('loss', 'Var', (26, 30))	('VHL', 'Gene', '7428', (34, 37))	('results in', 'Reg', (100, 110))
25645	28775935	Certain subtypes of RCC, such as those that are dependent on aerobic glycolysis due to dysfunction in one of their Krebs cycle enzymes [e.g., hereditary leiomyomatosis and renal cell cancer (HLRCC)-associated papillary type II RCC or succinate dehydrogenase (SDH)-associated RCC], may be especially well suited to imaging with PET/CT.	('SDH', 'Gene', (259, 262))	('Krebs cycle', 'biological_process', 'GO:0006099', ('115', '126'))	('succinate dehydrogenase', 'Gene', (234, 257))	('papillary type II RCC', 'Disease', (209, 230))	('Krebs', 'Chemical', '-', (115, 120))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', (227, 230))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (142, 189))	('succinate dehydrogenase', 'Gene', '6390', (234, 257))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('SDH', 'Gene', '6390', (259, 262))	('papillary type II RCC', 'Disease', 'MESH:C538614', (209, 230))	('papillary type', 'Phenotype', 'HP:0007482', (209, 223))	('dysfunction', 'Var', (87, 98))	('renal cell cancer', 'Phenotype', 'HP:0005584', (172, 189))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))	('glycolysis', 'biological_process', 'GO:0006096', ('69', '79'))
25650	28775935	This study was the first clinical validation of 124I-cG250 PET as a biomarker for RCC.	('cG250', 'Chemical', 'MESH:C106533', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('124I-cG250 PET', 'Var', (48, 62))
25651	28775935	The chief disadvantage of using the monoclonal antibody 124I-cG250 is that its half-life is several days, requiring prolonged waiting times after injection before tumor to background ratios are adequate.	('124I-cG250', 'Var', (56, 66))	('antibody', 'cellular_component', 'GO:0042571', ('47', '55'))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cG250', 'Chemical', 'MESH:C106533', (61, 66))	('antibody', 'cellular_component', 'GO:0019814', ('47', '55'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('antibody', 'cellular_component', 'GO:0019815', ('47', '55'))	('tumor', 'Disease', (163, 168))	('antibody', 'molecular_function', 'GO:0003823', ('47', '55'))
25678	28775935	of diffusion-weighted imaging (DWI) studies in the characterization of renal masses showed moderate accuracy for distinguishing between benign vs. malignant lesions (86% sensitivity and 78% specificity) and low-vs. high-grade ccRCC (AUC of 0.83).	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('ccRCC', 'Phenotype', 'HP:0006770', (226, 231))	('RCC', 'Disease', (228, 231))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('renal masses', 'Phenotype', 'HP:0009726', (71, 83))	('low-vs. high-grade', 'Var', (207, 225))
25710	28775935	In patients treated with pazopanib, low levels of IL-8, HGF, osteopontin and TIMP-1 were all associated with significantly longer PFS.	('IL-8', 'Gene', (50, 54))	('low levels', 'Var', (36, 46))	('longer', 'PosReg', (123, 129))	('osteopontin', 'Gene', '6696', (61, 72))	('IL-8', 'molecular_function', 'GO:0005153', ('50', '54'))	('TIMP-1', 'Gene', (77, 83))	('pazopanib', 'Chemical', 'MESH:C516667', (25, 34))	('patients', 'Species', '9606', (3, 11))	('TIMP-1', 'Gene', '7076', (77, 83))	('HGF', 'Gene', (56, 59))	('osteopontin', 'Gene', (61, 72))	('IL-8', 'Gene', '3576', (50, 54))	('HGF', 'Gene', '3082', (56, 59))
25718	28775935	High serum LDH is an established poor prognostic factor in RCC and is part of the MSKCC risk score.	('High', 'Var', (0, 4))	('LDH', 'Protein', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
25751	28775935	performed targeted gene sequencing on four tumor specimens from patients with locally advanced or mRCC to identify known RCC mutations.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('mutations', 'Var', (125, 134))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('RCC', 'Disease', (121, 124))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('RCC', 'Disease', (99, 102))	('tumor', 'Disease', (43, 48))
25783	28775935	Due to its role in MITF transcription, it also shows positivity in translocation RCCs, as translocation RCCs involves the TFE3 or TFEB genes, which are members of the MITF family.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('MITF', 'Gene', '4286', (19, 23))	('MITF', 'Gene', (167, 171))	('MITF', 'Gene', (19, 23))	('TFEB', 'Gene', '7942', (130, 134))	('TFEB', 'Gene', (130, 134))	('TFE3', 'Gene', (122, 126))	('MITF', 'Gene', '4286', (167, 171))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('positivity', 'Var', (53, 63))	('TFE3', 'Gene', '7030', (122, 126))	('transcription', 'biological_process', 'GO:0006351', ('24', '37'))	('RCC', 'Disease', (104, 107))
25797	28775935	CD10 is also positive for Xp11.2 translocation RCC but negative for all other RCC histologies.	('CD10', 'Gene', '4311', (0, 4))	('positive', 'Reg', (13, 21))	('RCC', 'Disease', (78, 81))	('Xp11.2 translocation', 'Var', (26, 46))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('CD10', 'Gene', (0, 4))	('CD10', 'molecular_function', 'GO:0004245', ('0', '4'))
25803	28775935	Other RCC associated mutations include PBRM1, SETD2, KDM5C, PTEN, BAP1, MTOR, and TP53.	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('TP53', 'Gene', (82, 86))	('SETD2', 'Gene', (46, 51))	('PBRM1', 'Gene', '55193', (39, 44))	('KDM5C', 'Gene', (53, 58))	('MTOR', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (66, 70))	('PBRM1', 'Gene', (39, 44))	('KDM5C', 'Gene', '8242', (53, 58))	('MTOR', 'Gene', '2475', (72, 76))	('BAP1', 'Gene', (66, 70))	('PTEN', 'Gene', (60, 64))	('PTEN', 'Gene', '5728', (60, 64))	('TP53', 'Gene', '7157', (82, 86))	('SETD2', 'Gene', '29072', (46, 51))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('mutations', 'Var', (21, 30))
25804	28775935	By cytogenetics, VHL tumors commonly show loss of heterozygosity (LOH) of chromosome 3p, and biallelic inactivation of VHLgene (3p25), as well as gain of 5q22, loss of 6q, 8p, 9p and 14q.	('VHL', 'Disease', 'MESH:D006623', (119, 122))	('VHL', 'Disease', (119, 122))	('VHL tumors', 'Disease', (17, 27))	('VHL', 'Disease', (17, 20))	('VHL tumors', 'Disease', 'MESH:D006623', (17, 27))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('biallelic inactivation', 'Var', (93, 115))	('loss', 'Var', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gain', 'PosReg', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('chromosome', 'cellular_component', 'GO:0005694', ('74', '84'))	('loss', 'NegReg', (42, 46))
25805	28775935	A more recent entity, multilocular cystic renal neoplasm of low malignant potential has also been found to be associated with 3p deletion and in some cases, VHL mutations.	('VHL', 'Disease', 'MESH:D006623', (157, 160))	('multilocular cystic renal neoplasm', 'Disease', 'MESH:D052177', (22, 56))	('cystic renal neoplasm', 'Phenotype', 'HP:0000800', (35, 56))	('VHL', 'Disease', (157, 160))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('associated', 'Reg', (110, 120))	('mutations', 'Var', (161, 170))	('renal neoplasm', 'Phenotype', 'HP:0009726', (42, 56))	('multilocular cystic renal neoplasm', 'Disease', (22, 56))
25807	28775935	Papillary type II is more heterogeneous and may be associated with silencing of CDKN2A, mutations in SETD2 and NRF2-ARE pathways, TFE3 fusions, as well as some CpG island methylator phenotypes.	('SETD2', 'Gene', (101, 106))	('CDKN2A', 'Gene', '1029', (80, 86))	('Papillary type II', 'Disease', (0, 17))	('NRF2', 'Gene', '4780', (111, 115))	('SETD2', 'Gene', '29072', (101, 106))	('silencing', 'NegReg', (67, 76))	('TFE3', 'Gene', (130, 134))	('mutations', 'Var', (88, 97))	('Papillary type II', 'Disease', 'MESH:D002291', (0, 17))	('NRF2', 'Gene', (111, 115))	('associated', 'Reg', (51, 61))	('TFE3', 'Gene', '7030', (130, 134))	('CDKN2A', 'Gene', (80, 86))	('Papillary type', 'Phenotype', 'HP:0007482', (0, 14))
25808	28775935	Patients with hereditary papillary renal cancer (HPRC) develop bilateral multifocal type I tumors, while those with HLRCC, which is caused by a germline mutation of the fumarate hydratase gene, develop papillary type II tumors that characteristically have eosinophilic cytoplasm and large inclusion-like nucleoli.	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('caused by', 'Reg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('papillary type II tumors', 'Disease', 'MESH:D002291', (202, 226))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('renal cancer', 'Phenotype', 'HP:0009726', (35, 47))	('Patients', 'Species', '9606', (0, 8))	('bilateral multifocal type I tumors', 'Disease', (63, 97))	('fumarate hydratase', 'Gene', (169, 187))	('mutation', 'Var', (153, 161))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('papillary type II tumors', 'Disease', (202, 226))	('hereditary papillary renal cancer', 'Disease', (14, 47))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (25, 47))	('RCC', 'Disease', (118, 121))	('bilateral multifocal type I tumors', 'Disease', 'MESH:D009369', (63, 97))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (14, 47))	('papillary type', 'Phenotype', 'HP:0007482', (202, 216))	('fumarate hydratase', 'Gene', '2271', (169, 187))	('develop', 'PosReg', (194, 201))	('cytoplasm', 'cellular_component', 'GO:0005737', ('269', '278'))
25811	28775935	TFE3 and TFEB of the MiT family transcriptions factors are associated with Xp11.2 and t(6;11)(p21;q12) translocation RCCs, respectively.	('Xp11.2', 'Disease', (75, 81))	('TFEB', 'Gene', (9, 13))	('RCC', 'Disease', (117, 120))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('t(6;11)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (86, 102))	('TFE3', 'Gene', '7030', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('t(6;11)(p21;q12', 'Var', (86, 101))	('associated', 'Reg', (59, 69))	('TFE3', 'Gene', (0, 4))	('TFEB', 'Gene', '7942', (9, 13))
25814	28775935	Significant mutations have been found in TP53 and PTEN.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (12, 21))	('PTEN', 'Gene', (50, 54))	('PTEN', 'Gene', '5728', (50, 54))
25816	28775935	Oncocytoma is frequently associated with CCND1 mutations, and most commonly shows complete or partial loss of chromosome 1.	('associated', 'Reg', (25, 35))	('CCND1', 'Gene', '595', (41, 46))	('mutations', 'Var', (47, 56))	('Oncocytoma', 'Disease', 'MESH:D018249', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('loss', 'NegReg', (102, 106))	('Oncocytoma', 'Disease', (0, 10))	('CCND1', 'Gene', (41, 46))
25818	28775935	Multiple chRCCs, oncocytomas, hybrid tumors and/or oncocytosis are seen in Birt-Hogg-Dube (BHD) syndrome, caused by a mutation in the folliculin gene.	('folliculin', 'Gene', '201163', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('Birt-Hogg-Dube (BHD) syndrome', 'Disease', 'MESH:D058249', (75, 104))	('folliculin', 'Gene', (134, 144))	('oncocytomas', 'Disease', (17, 28))	('oncocytosis', 'Disease', (51, 62))	('oncocytomas', 'Disease', 'MESH:D018249', (17, 28))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('caused by', 'Reg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (118, 126))	('tumors', 'Disease', (37, 43))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
25852	28991563	A recent meta-analysis also suggested that high cadmium exposure was associated with an increased risk for renal cancer as well .	('high cadmium', 'Var', (43, 55))	('renal cancer', 'Disease', (107, 119))	('cadmium', 'Chemical', 'MESH:D002104', (48, 55))	('renal cancer', 'Phenotype', 'HP:0009726', (107, 119))	('renal cancer', 'Disease', 'MESH:D007680', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
25855	28991563	Although a complete discussion of the various syndromes is beyond the scope of this review, the reader should be aware that each of these syndromes tend to be associated with specific histologic subtypes of RCC due to their underlying genetic alterations and that those neoplasms are associated to variable levels of aggressiveness.	('aggressiveness', 'Disease', 'MESH:D001523', (317, 331))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('neoplasms', 'Phenotype', 'HP:0002664', (270, 279))	('RCC', 'Disease', (207, 210))	('associated', 'Reg', (159, 169))	('aggressiveness', 'Disease', (317, 331))	('genetic alterations', 'Var', (235, 254))	('neoplasm', 'Phenotype', 'HP:0002664', (270, 278))	('neoplasms', 'Disease', 'MESH:D009369', (270, 279))	('aggressiveness', 'Phenotype', 'HP:0000718', (317, 331))	('neoplasms', 'Disease', (270, 279))
25932	28991563	Irregularity or interruption of the tumor pseudocapsule, a rim of normal renal parenchyma surrounding the tumor, suggests locally advanced disease and a high nuclear grade .	('advanced disease', 'Disease', (130, 146))	('advanced disease', 'Disease', 'MESH:D020178', (130, 146))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (36, 41))	('Irregularity', 'Var', (0, 12))
25950	28991563	For SRMs, partial and radical nephrectomies show similar risks for progression and renal cancer-related deaths, with the former's risks estimated to be 4.5% and 3%, respectively .	('renal cancer', 'Disease', (83, 95))	('progression', 'Disease', (67, 78))	('partial', 'Var', (10, 17))	('renal cancer', 'Disease', 'MESH:D007680', (83, 95))	('renal cancer', 'Phenotype', 'HP:0009726', (83, 95))	('death', 'Disease', 'MESH:D003643', (104, 109))	('death', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
26045	26422014	DCE images were acquired for a total of 5 minutes 45 sec at a 5 sec temporal resolution with the following parameters: TR/TE = 3/1.53 ms, FA = 10 , NSA = 1, slice thickness = 5mm, FOV = 180x408 mm2, matrix = 120x288, bandwidth = 1326 Hz/pixel.	('DCE', 'Gene', '1718', (0, 3))	('DCE', 'Gene', (0, 3))	('FOV', 'Var', (180, 183))
26225	23320739	One is represented by the hereditary papillary renal carcinoma (HPRC; MIM# 605074) usually consisting of papillary RCC type I with a better prognosis showing activating mutations in the met proto-oncogene (MET) on chromosome 7q32 are responsible for HPRC.	('hereditary papillary renal carcinoma', 'Disease', (26, 62))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('papillary RCC type I', 'Disease', 'MESH:C538614', (105, 125))	('MET', 'Gene', (206, 209))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (37, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('HPRC', 'Disease', 'None', (64, 68))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (26, 62))	('activating mutations', 'Var', (158, 178))	('HPRC', 'Disease', 'None', (250, 254))	('renal carcinoma', 'Phenotype', 'HP:0005584', (47, 62))	('chromosome', 'cellular_component', 'GO:0005694', ('214', '224'))	('HPRC', 'Disease', (250, 254))	('papillary RCC type I', 'Disease', (105, 125))	('HPRC', 'Disease', (64, 68))
26228	23320739	The intracellular hypoxia inducible factor (HIF) is stabilized due to an accumulation of FH based on the mutations in this gene region and is responsible for a pseudohypoxic state causing the release of different tumor promoting factors like VEGF, PDGF, and TGF-alpha.	('tumor', 'Disease', (213, 218))	('intracellular', 'cellular_component', 'GO:0005622', ('4', '17'))	('TGF-alpha', 'Gene', '7039', (258, 267))	('accumulation', 'PosReg', (73, 85))	('VEGF', 'Gene', (242, 246))	('PDGF', 'molecular_function', 'GO:0005161', ('248', '252'))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('mutations', 'Var', (105, 114))	('TGF-alpha', 'Gene', (258, 267))	('hypoxia', 'Disease', 'MESH:D000860', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('FH', 'Gene', '2271', (89, 91))	('VEGF', 'Gene', '7422', (242, 246))	('hypoxia', 'Disease', (18, 25))
26255	23320739	The subsequent analysis of the FH gene revealed a missense mutation (c.539A > G) leading to amino acid substitution H180R at the protein level (Figure 4).	('H180R', 'Var', (116, 121))	('FH', 'Gene', '2271', (31, 33))	('c.539A > G', 'Var', (69, 79))	('c.539A > G', 'Mutation', 'rs863224015', (69, 79))	('protein', 'cellular_component', 'GO:0003675', ('129', '136'))	('H180R', 'Mutation', 'rs863224015', (116, 121))
26256	23320739	Furthermore, this mutation could be shown to be associated with a reduced activity of FH by approximately 45%.	('reduced', 'NegReg', (66, 73))	('mutation', 'Var', (18, 26))	('FH', 'Gene', '2271', (86, 88))	('activity', 'MPA', (74, 82))
26259	23320739	One of these variants is the HLRCC syndrome associated with different mutations in the FH gene, which functions as a tumor suppressor gene.	('associated', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutations', 'Var', (70, 79))	('HLRCC syndrome', 'Disease', 'MESH:C535516', (29, 43))	('FH', 'Gene', '2271', (87, 89))	('tumor', 'Disease', (117, 122))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('HLRCC syndrome', 'Disease', (29, 43))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
26262	23320739	In addition FH mutations have also been described in case of uterine fibroids.	('uterine fibroids', 'Disease', (61, 77))	('mutations', 'Var', (15, 24))	('FH', 'Gene', '2271', (12, 14))	('uterine fibroids', 'Phenotype', 'HP:0000131', (61, 77))	('described', 'Reg', (40, 49))
26270	23320739	The genetic examination showed a mutation in the FH gene typical for HLRCC.	('FH', 'Gene', '2271', (49, 51))	('mutation', 'Var', (33, 41))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('HLRCC', 'Disease', (69, 74))
26286	33141518	But, for patients less than 45 years old and patients with metastatic RCC, the survival outcome of pRCC is worse contrarily.	('patients', 'Species', '9606', (9, 17))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('pRCC', 'Gene', (99, 103))	('metastatic', 'Var', (59, 69))	('patients', 'Species', '9606', (45, 53))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
26297	33141518	11  Patients with either ccRCC (International Classification of Disease for Oncology [ICD-O-3] code 8310/3) or pRCC (code 8260/3) from 2004 to 2017 were included in the present study.	('pRCC', 'Gene', '5546', (111, 115))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', (27, 30))	('Patients', 'Species', '9606', (4, 12))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('code 8260/3', 'Var', (117, 128))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('pRCC', 'Gene', (111, 115))	('Oncology', 'Phenotype', 'HP:0002664', (76, 84))
26370	31516581	KM survival analysis revealed the prognostic significance of two protective biomarkers, AC024022.1 and GAS6-AS1, and three adverse biomarkers, AC087379.2, AL352984.1, and AL499627.1.	('AC024022.1', 'Var', (88, 98))	('GAS', 'molecular_function', 'GO:0034005', ('103', '106'))	('AC087379.2', 'Var', (143, 153))	('AL352984.1', 'Var', (155, 165))	('GAS6-AS1', 'Gene', '650669;2621;5729', (103, 111))	('AL499627.1', 'Var', (171, 181))	('GAS6-AS1', 'Gene', (103, 111))	('AL352984', 'Chemical', '-', (155, 163))
26371	31516581	It was predicted that AC024022.1 and AC087379.2 may be located in the cytoplasm and GAS6-AS1 may be located in the cytosol.	('GAS6-AS1', 'Gene', '650669;2621;5729', (84, 92))	('GAS6-AS1', 'Gene', (84, 92))	('AC024022.1', 'Var', (22, 32))	('cytosol', 'cellular_component', 'GO:0005829', ('115', '122'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('70', '79'))	('AC087379.2', 'Var', (37, 47))	('GAS', 'molecular_function', 'GO:0034005', ('84', '87'))
26380	31516581	Specific lncRNA expression patterns, such as overexpression, depletion, or mutations of lncRNA genes are associated with numerous human diseases.	('overexpression', 'MPA', (45, 59))	('lncRNA genes', 'Gene', (88, 100))	('depletion', 'MPA', (61, 70))	('numerous human diseases', 'Disease', 'MESH:D015658', (121, 144))	('mutations', 'Var', (75, 84))	('associated', 'Reg', (105, 115))	('numerous human diseases', 'Disease', (121, 144))	('lncRNA expression', 'MPA', (9, 26))
26381	31516581	Altered expression of specific lncRNAs may promote tumor formation, progression and metastasis in many malignancies, including RCC.	('formation', 'biological_process', 'GO:0009058', ('57', '66'))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('promote', 'PosReg', (43, 50))	('progression', 'CPA', (68, 79))	('tumor', 'Disease', (51, 56))	('metastasis', 'CPA', (84, 94))	('Altered', 'Var', (0, 7))	('malignancies', 'Disease', 'MESH:D009369', (103, 115))	('lncRNAs', 'Protein', (31, 38))	('expression', 'MPA', (8, 18))	('malignancies', 'Disease', (103, 115))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
26405	31516581	Based on the results of the multivariate Cox regression, six lncRNAs, AC024022.1, AC087379.2, AL352984.1, AL499627.1, GAS6-AS1 and MEG3, were used for further KM survival analysis.	('MEG3', 'Gene', (131, 135))	('Cox', 'Gene', '1351', (41, 44))	('AL352984', 'Chemical', '-', (94, 102))	('AL352984.1', 'Var', (94, 104))	('Cox', 'Gene', (41, 44))	('MEG3', 'Gene', '55384', (131, 135))	('GAS', 'molecular_function', 'GO:0034005', ('118', '121'))	('GAS6-AS1', 'Gene', '650669;2621;5729', (118, 126))	('GAS6-AS1', 'Gene', (118, 126))	('AL499627.1', 'Var', (106, 116))
26406	31516581	AC024022.1 and GAS6-AS1 were identified as protective prognostic biomarkers, while AC087379.2, AL352984.1 and AL499627.1 were identified as adverse prognostic biomarkers (Fig.	('GAS6-AS1', 'Gene', (15, 23))	('GAS', 'molecular_function', 'GO:0034005', ('15', '18'))	('AL499627.1', 'Var', (110, 120))	('AL352984', 'Chemical', '-', (95, 103))	('AC024022.1', 'Var', (0, 10))	('AC087379.2', 'Var', (83, 93))	('GAS6-AS1', 'Gene', '650669;2621;5729', (15, 23))	('AL352984.1', 'Var', (95, 105))
26408	31516581	lncLocator predicted that AC024022.1 and AC087379.2 were located in the cytoplasm and GAS6-AS1 was located in the cytosol (Table I).	('cytosol', 'cellular_component', 'GO:0005829', ('114', '121'))	('GAS', 'molecular_function', 'GO:0034005', ('86', '89'))	('AC087379.2', 'Var', (41, 51))	('GAS6-AS1', 'Gene', '650669;2621;5729', (86, 94))	('AC024022.1', 'Var', (26, 36))	('cytoplasm', 'cellular_component', 'GO:0005737', ('72', '81'))	('GAS6-AS1', 'Gene', (86, 94))
26409	31516581	The subcellular localizations of AL352984.1 and AL499627.1 were not predicted as lncRNAMap website did not possess a record of their sequences.	('AL499627.1', 'Var', (48, 58))	('AL352984', 'Chemical', '-', (33, 41))	('AL352984.1', 'Var', (33, 43))
26412	31516581	At present, there is increasing evidence that aberrations within lncRNAs such as overexpression, deficiency or mutations drive important cancer phenotypes, including tumor formation, progression and metastasis in many types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('drive', 'Reg', (121, 126))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('progression', 'CPA', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (111, 120))	('aberrations', 'Var', (46, 57))	('deficiency', 'Disease', 'MESH:D007153', (97, 107))	('formation', 'biological_process', 'GO:0009058', ('172', '181'))	('tumor', 'Disease', (166, 171))	('overexpression', 'PosReg', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('deficiency', 'Disease', (97, 107))	('cancer', 'Disease', (227, 233))	('lncRNAs', 'Gene', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('metastasis', 'CPA', (199, 209))
26413	31516581	In addition, certain aberrant lncRNAs are additionally associated with increasing the malignant biological behaviors of cancer cells, clinicopathological features and poor prognosis of cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('increasing', 'PosReg', (71, 81))	('aberrant', 'Var', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancer', 'Disease', (185, 191))	('cancers', 'Disease', (185, 192))
26423	31516581	The prognostic values of five lncRNAs, AC024022.1, AC087379.2, AL352984.1, AL499627.1, and GAS6-AS1 (all P<0.05), were validated by KM survival analysis.	('GAS', 'molecular_function', 'GO:0034005', ('91', '94'))	('GAS6-AS1', 'Gene', (91, 99))	('AC024022.1', 'Var', (39, 49))	('AL352984.1', 'Var', (63, 73))	('AL499627.1', 'Var', (75, 85))	('AL352984', 'Chemical', '-', (63, 71))	('GAS6-AS1', 'Gene', '650669;2621;5729', (91, 99))
26431	31516581	It was predicted that AC024022.1 (ENSG00000250781) and AC087379.2 (ENSG00000254695) were likely located in the cytoplasm, and GAS6-AS1 (ENSG00000233695) were likely located in the cytosol.	('cytoplasm', 'cellular_component', 'GO:0005737', ('111', '120'))	('GAS6-AS1', 'Gene', '650669;2621;5729', (126, 134))	('ENSG00000250781', 'Var', (34, 49))	('GAS6-AS1', 'Gene', (126, 134))	('cytosol', 'cellular_component', 'GO:0005829', ('180', '187'))	('ENSG00000233695', 'Var', (136, 151))	('ENSG00000254695', 'Var', (67, 82))	('GAS', 'molecular_function', 'GO:0034005', ('126', '129'))
26432	31516581	The subcellular localization of AL352984.1 (ENSG00000258386) and AL499627.1 (ENSG00000260542) were not predicted because their sequence information was not present on lncRNAMap.	('AL352984.1', 'Var', (32, 42))	('AL352984', 'Chemical', '-', (32, 40))	('localization', 'biological_process', 'GO:0051179', ('16', '28'))	('AL499627.1', 'Var', (65, 75))
26433	31516581	Therefore, we hypothesized that lncRNAs AC024022.1 (ENSG00000250781), AC087379.2 (ENSG00000254695), and GAS6-AS1 (ENSG00000233695) acted as ceRNA, and served a role in regulating the stability or translation of mRNA.	('ENSG00000254695', 'Var', (82, 97))	('translation', 'biological_process', 'GO:0006412', ('196', '207'))	('mRNA', 'MPA', (211, 215))	('GAS', 'molecular_function', 'GO:0034005', ('104', '107'))	('ENSG00000233695', 'Var', (114, 129))	('GAS6-AS1', 'Gene', '650669;2621;5729', (104, 112))	('regulating', 'Reg', (168, 178))	('translation', 'MPA', (196, 207))	('stability', 'MPA', (183, 192))	('GAS6-AS1', 'Gene', (104, 112))	('ENSG00000250781', 'Var', (52, 67))
26434	31516581	In summary, a 17-lncRNA signature was constructed by mining the TCGA database, and identified two protective lncRNAs, AC024022.1 (ENSG00000250781) and GAS6-AS1 (ENSG00000233695), and three potentially tumorigenic lncRNAs, AC087379.2 (ENSG00000254695), AL352984.1 (ENSG00000258386) and AL499627.1 (ENSG00000260542).	('AL499627.1', 'Var', (285, 295))	('GAS6-AS1', 'Gene', '650669;2621;5729', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('AL352984', 'Chemical', '-', (252, 260))	('GAS6-AS1', 'Gene', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('GAS', 'molecular_function', 'GO:0034005', ('151', '154'))	('tumor', 'Disease', (201, 206))	('AL352984.1', 'Var', (252, 262))
26435	31516581	AC024022.1 (ENSG00000250781) and AC087379.2 (ENSG00000254695) might be located in the cytoplasm while GAS6-AS1 (ENSG00000233695) might be located in the cytosol.	('ENSG00000233695', 'Var', (112, 127))	('ENSG00000250781', 'Var', (12, 27))	('GAS6-AS1', 'Gene', '650669;2621;5729', (102, 110))	('cytosol', 'cellular_component', 'GO:0005829', ('153', '160'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('86', '95'))	('GAS6-AS1', 'Gene', (102, 110))	('GAS', 'molecular_function', 'GO:0034005', ('102', '105'))	('ENSG00000254695', 'Var', (45, 60))
26493	23320235	It is believed that ectopic kidneys carry similar risks of developing diseases compared to those of normally positioned kidneys, except for urinary calculus formation and hydronephrosis.	('urinary calculus', 'Phenotype', 'HP:0000787', (140, 156))	('developing', 'Disease', (59, 69))	('positioned kidneys', 'Phenotype', 'HP:0000086', (109, 127))	('ectopic kidneys', 'Phenotype', 'HP:0000086', (20, 35))	('hydronephrosis', 'Phenotype', 'HP:0000126', (171, 185))	('formation', 'biological_process', 'GO:0009058', ('157', '166'))	('ectopic kidney', 'Phenotype', 'HP:0000086', (20, 34))	('ectopic', 'Var', (20, 27))	('urinary calculus', 'Disease', 'MESH:D014545', (140, 156))	('hydronephrosis', 'Disease', 'MESH:D006869', (171, 185))	('urinary calculus', 'Disease', (140, 156))	('hydronephrosis', 'Disease', (171, 185))
26617	32397685	A recent sex-specific genome-wide association analysis on a dataset of 13,230 patients (8193 men, 5087 women) with RCC underlined a gender-related association for four single-nucleotide polymorphisms (SNPs) on genes DPF3, EPAS1, SAMD5, and BTBD11.	('EPAS1', 'Gene', (222, 227))	('SAMD5', 'Gene', (229, 234))	('BTBD11', 'Gene', '121551', (240, 246))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('SAMD5', 'Gene', '389432', (229, 234))	('men', 'Species', '9606', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('DPF3', 'Gene', (216, 220))	('patients', 'Species', '9606', (78, 86))	('men', 'Species', '9606', (105, 108))	('DPF3', 'Gene', '8110', (216, 220))	('single-nucleotide polymorphisms', 'Var', (168, 199))	('EPAS1', 'Gene', '2034', (222, 227))	('women', 'Species', '9606', (103, 108))	('BTBD11', 'Gene', (240, 246))
26622	32397685	performed an analysis of three large ccRCC mutation sequencing datasets, and found, in both sexes, mutations of KDM5C, histone demethylase, or BAP1, and the gene coding for a deubiquitinase (both being X-chromosome encoded genes).	('BAP1', 'Gene', (143, 147))	('X-chromosome', 'cellular_component', 'GO:0000805', ('202', '214'))	('KDM5C', 'Gene', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('mutations', 'Var', (99, 108))	('KDM5C', 'Gene', '8242', (112, 117))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('175', '189'))	('BAP1', 'Gene', '8314', (143, 147))
26623	32397685	Mutation of BAP1 was associated with a poorer overall survival (p = 0.0039) in all, and in females (p = 0.0021), but not in males.	('Mutation', 'Var', (0, 8))	('overall survival', 'MPA', (46, 62))	('BAP1', 'Gene', '8314', (12, 16))	('poorer', 'NegReg', (39, 45))	('BAP1', 'Gene', (12, 16))
26624	32397685	Mutation in KDM5C did not reduce patients' survival in total or by gender.	('reduce', 'NegReg', (26, 32))	('patients', 'Species', '9606', (33, 41))	('KDM5C', 'Gene', (12, 17))	('KDM5C', 'Gene', '8242', (12, 17))	('Mutation', 'Var', (0, 8))
26643	32397685	In this regard, there is no significant gender difference in recurrence rate in patients with N0M0 ccRCC after nephrectomy, even if the prognosis is more favorable in women, after recurrence.	('patients', 'Species', '9606', (80, 88))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('women', 'Species', '9606', (167, 172))	('N0M0', 'Var', (94, 98))
26651	32397685	The complexity of nephron-sparing surgery (NSS) for RCC could be predicted, in a presurgical setting, by nephrometry scores: the higher the score, the more complex the NSS.	('RCC', 'Disease', (52, 55))	('score', 'Var', (140, 145))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))
26653	32397685	on 111 RCCs cT1aN0M0 showed that males had a higher retroperitoneal fat tissue thickness (determined by computed tomography scan) than females, and that, as a consequence, the operative time during retroperitoneal laparoscopic NSS was significantly longer in male patients than in female patients (181.8 +- 34.9 min in males, 150.7 +- 24.7 min in females; p < 0.001).	('retroperitoneal fat tissue thickness', 'MPA', (52, 88))	('longer', 'PosReg', (249, 255))	('patients', 'Species', '9606', (288, 296))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('patients', 'Species', '9606', (264, 272))	('cT1aN0M0', 'Var', (12, 20))	('higher', 'PosReg', (45, 51))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))
26658	32397685	A recent study on the Surveillance Epidemiology and End Results (SEER) database reported that male gender predicted higher risk for nonsurgical treatment (OR: 1.23, CI 1.13-1.33; p < 0.001) in a population-based study on T1-2N0M0 RCC.	('nonsurgical treatment', 'Disease', (132, 153))	('T1-2N0M0', 'Var', (221, 229))	('men', 'Species', '9606', (149, 152))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('RCC', 'Disease', (230, 233))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))
26683	32397685	In a subgroup analysis of OS, males had a clear survival advantage with nivolumab (HR: 0.73; 95% CI: 0.58-0.92), while in females there was a survival advantage, but it was not as significant (HR: 0.84; 95% CI: 0.57-1.24).	('nivolumab', 'Chemical', 'MESH:D000077594', (72, 81))	('nivolumab', 'Var', (72, 81))	('advantage', 'PosReg', (57, 66))
26703	32397685	RCC renal cell carcinoma  BMI body mass index  OS overall survival  CSS cancer-specific survival  OR odds ratio  HR hazard ratio  CI confidence interval  NSS nephron sparing surgery  RN radical nephrectomy  ECOG scale Eastern Cooperative Oncology Group scale  AR androgen receptor  RFS recurrence-free survival  ERbeta oestrogen receptor-beta  RR relative risk  SNPs single-nucleotide polymorphisms  CSM cancer-specific mortality  VEGF vascular endothelial growth factor  TKI tyrosine kinase inhibitor  mTOR mammalian target of rapamycin  PD-1 programmed cell death protein-1  CTLA-4 cytotoxic T-lymphocyte-associated protein 4  PFS progression-free survival	('CTLA-4', 'Gene', (577, 583))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('ERbeta', 'Gene', '2099', (312, 318))	('mTOR', 'Gene', (503, 507))	('mortality', 'Disease', 'MESH:D003643', (420, 429))	('mammalian target of rapamycin', 'Gene', (508, 537))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (4, 24))	('programmed cell death', 'biological_process', 'GO:0012501', ('544', '565'))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('436', '470'))	('cancer', 'Disease', (72, 78))	('RCC renal cell carcinoma  BMI body', 'Disease', (0, 34))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (584, 627))	('RCC renal cell carcinoma  BMI body', 'Disease', 'MESH:C538614', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('mTOR', 'Gene', '2475', (503, 507))	('programmed cell death protein-1', 'Gene', '5133', (544, 575))	('VEGF', 'Gene', '7422', (431, 435))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (584, 627))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('485', '501'))	('protein', 'cellular_component', 'GO:0003675', ('566', '573'))	('cancer', 'Disease', (404, 410))	('VEGF', 'Gene', (431, 435))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('single-nucleotide polymorphisms', 'Var', (367, 398))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('PD-1', 'Gene', (539, 543))	('mortality', 'Disease', (420, 429))	('PD-1', 'Gene', '5133', (539, 543))	('androgen receptor', 'Gene', (263, 280))	('programmed cell death protein-1', 'Gene', (544, 575))	('AR', 'Gene', '367', (260, 262))	('NSS nephron', 'Disease', 'MESH:D007683', (154, 165))	('CTLA-4', 'Gene', '1493', (577, 583))	('NSS nephron', 'Disease', (154, 165))	('mammalian target of rapamycin', 'Gene', '2475', (508, 537))	('Oncology', 'Phenotype', 'HP:0002664', (238, 246))	('protein', 'cellular_component', 'GO:0003675', ('618', '625'))	('ERbeta', 'Gene', (312, 318))	('androgen receptor', 'Gene', '367', (263, 280))
26704	28061437	Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells.	('Keap1', 'Gene', (0, 5))	('kidney cancer', 'Disease', (22, 35))	('clear renal cell carcinoma', 'Phenotype', 'HP:0006770', (84, 110))	('clear renal cell carcinoma', 'Disease', (84, 110))	('Nrf2', 'Gene', '4780', (121, 125))	('drugs resistance', 'Phenotype', 'HP:0020174', (274, 290))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('methylation', 'Var', (46, 57))	('Keap1', 'Gene', '9817', (115, 120))	('Nrf2', 'Gene', (121, 125))	('Nrf2', 'Gene', '4780', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (84, 110))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Keap1', 'Gene', (115, 120))	('KEAP1', 'Gene', '9817', (61, 66))	('kidney cancer', 'Disease', 'MESH:D007680', (22, 35))	('Keap1', 'Gene', '9817', (0, 5))	('KEAP1', 'Gene', (61, 66))	('tumor', 'Disease', (294, 299))	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('Nrf2', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('kidney cancer', 'Phenotype', 'HP:0009726', (22, 35))
26709	28061437	Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('KEAP1', 'Gene', (78, 83))	('renal cell carcinoma', 'Disease', (302, 322))	('KEAP1', 'Gene', (136, 141))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (302, 322))	('expression', 'MPA', (142, 152))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (302, 322))	('modulation', 'Reg', (122, 132))	('KEAP1', 'Gene', '9817', (136, 141))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('Nrf2', 'Gene', '4780', (204, 208))	('RCC', 'Disease', (158, 161))	('KEAP1', 'Gene', '9817', (78, 83))	('deregulation', 'Var', (214, 226))	('epigenetic silencing', 'Var', (54, 74))	('Keap1', 'Gene', '9817', (198, 203))	('Keap1', 'Gene', (198, 203))	('Nrf2', 'Gene', (204, 208))
26711	28061437	Various histotypes of RCC have come to be defined on the basis of their histologic appearance, the presence of distinct driver mutations, varying clinical course, and different responses to therapy.	('RCC', 'Disease', (22, 25))	('mutations', 'Var', (127, 136))	('RCC', 'Disease', 'MESH:C538614', (22, 25))
26722	28061437	Genetic alterations of Keap1/Nrf2 axis were described with a variable incidence in RCC, more frequently in PRCC2.	('Nrf2', 'Gene', (29, 33))	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Disease', (83, 86))	('RCC', 'Disease', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PRCC', 'Gene', '5546', (107, 111))	('PRCC', 'Gene', (107, 111))	('Keap1', 'Gene', '9817', (23, 28))	('Keap1', 'Gene', (23, 28))	('Nrf2', 'Gene', '4780', (29, 33))
26723	28061437	Genetic alterations of the Keap1/Nrf2 pathway were reported in a very small fraction of ccRCC patients.	('Genetic alterations', 'Var', (0, 19))	('Nrf2', 'Gene', (33, 37))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('patients', 'Species', '9606', (94, 102))	('Keap1', 'Gene', '9817', (27, 32))	('Keap1', 'Gene', (27, 32))	('Nrf2', 'Gene', '4780', (33, 37))	('RCC', 'Disease', (90, 93))
26724	28061437	However, several studies demonstrated a general high impact of Nrf2 dysfunction in renal cell carcinoma, suggesting that the deregulation of the Keap1 may play a role in carcinogenesis process histotypes beside the presence of genomic alterations.	('Nrf2 dysfunction in renal cell carcinoma', 'Disease', (63, 103))	('carcinogenesis', 'Disease', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('role', 'Reg', (162, 166))	('Keap1', 'Gene', '9817', (145, 150))	('Keap1', 'Gene', (145, 150))	('Nrf2 dysfunction in renal cell carcinoma', 'Disease', 'MESH:C538614', (63, 103))	('deregulation', 'Var', (125, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('play', 'Reg', (155, 159))
26725	28061437	We have previously reported that epigenetic modification by promoter methylation is a main mechanism of regulation of KEAP1 gene expression in Non Small Cell Lung Cancer, malignant gliomas, breast cancer and that it was associated with worst progression free survival.	('Lung Cancer', 'Phenotype', 'HP:0100526', (158, 169))	('regulation', 'biological_process', 'GO:0065007', ('104', '114'))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('epigenetic modification', 'Var', (33, 56))	('Non Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (143, 169))	('promoter', 'MPA', (60, 68))	('gliomas', 'Phenotype', 'HP:0009733', (181, 188))	('malignant gliomas', 'Disease', 'MESH:D005910', (171, 188))	('KEAP1', 'Gene', '9817', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('gene expression', 'biological_process', 'GO:0010467', ('124', '139'))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (147, 169))	('malignant gliomas', 'Disease', (171, 188))	('KEAP1', 'Gene', (118, 123))	('Non Small Cell Lung Cancer', 'Disease', (143, 169))	('Non Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (143, 169))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
26726	28061437	Since the role of DNA methylation and genes epigenetically altered in RCC have been an active area of research over the past decade, the main purpose of this study is to investigate the contribution of epigenetic deregulation of the KEAP1 gene in different histotypes of renal cell carcinomas.	('KEAP1', 'Gene', '9817', (233, 238))	('renal cell carcinomas', 'Disease', (271, 292))	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (282, 292))	('KEAP1', 'Gene', (233, 238))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (271, 292))	('DNA methylation', 'biological_process', 'GO:0006306', ('18', '33'))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (271, 292))	('DNA', 'cellular_component', 'GO:0005574', ('18', '21'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (271, 291))	('epigenetic', 'Var', (202, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))
26731	28061437	Since the histologic appearance is considered the primary determinant in the classification of Renal Cancer, the discovery of specific variations in methylation profiles could further help to stratify the clear cell renal carcinoma subtype from others.	('clear cell renal carcinoma', 'Disease', (205, 231))	('methylation', 'biological_process', 'GO:0032259', ('149', '160'))	('Renal Cancer', 'Phenotype', 'HP:0009726', (95, 107))	('Renal Cancer', 'Disease', 'MESH:D007680', (95, 107))	('Renal Cancer', 'Disease', (95, 107))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (205, 231))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (205, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('variations', 'Var', (135, 145))	('renal carcinoma', 'Phenotype', 'HP:0005584', (216, 231))	('help', 'Reg', (184, 188))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
26732	28061437	Moreover, our findings of KEAP1 hypermethylation provide the first indication that this epigenetic mechanism is important also in the regulation of KEAP1 expression in an aggressive renal cancer histotype and could represents an additional and attractive diagnostic and prognostic biomarker.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('KEAP1', 'Gene', (26, 31))	('aggressive renal cancer', 'Disease', 'MESH:D007680', (171, 194))	('KEAP1', 'Gene', '9817', (148, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (182, 194))	('regulation', 'biological_process', 'GO:0065007', ('134', '144'))	('hypermethylation', 'Var', (32, 48))	('KEAP1', 'Gene', (148, 153))	('important', 'Reg', (112, 121))	('KEAP1', 'Gene', '9817', (26, 31))	('aggressive renal cancer', 'Disease', (171, 194))
26746	28061437	In ccRCC methylation was detected in 18 out of 37 cases (48.6%), (Supplementary Figure 4).	('methylation', 'Var', (9, 20))	('men', 'Species', '9606', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('RCC', 'Disease', (5, 8))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('detected', 'Reg', (25, 33))
26751	28061437	A highly significant inverse correlation of aberrant KEAP1 promoter methylation and KEAP1 mRNA expression was found in both ccRCC and PRCC samples showing a methylation value > 0,10 (Figure 2B).	('PRCC', 'Gene', '5546', (134, 138))	('methylation', 'biological_process', 'GO:0032259', ('157', '168'))	('PRCC', 'Gene', (134, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('KEAP1', 'Gene', '9817', (53, 58))	('inverse', 'NegReg', (21, 28))	('KEAP1', 'Gene', (53, 58))	('KEAP1', 'Gene', '9817', (84, 89))	('methylation', 'biological_process', 'GO:0032259', ('68', '79'))	('RCC', 'Disease', (126, 129))	('aberrant', 'Var', (44, 52))	('KEAP1', 'Gene', (84, 89))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
26752	28061437	However, a methylation value > 0,10 was observed only in 3% (7 out of 265) of PRCCs, thus confirming results obtained on our small cohort of an inconsistent contribution of the KEAP1 promoter epigenetic silencing in this histology, (Supplementary Figure 5).	('epigenetic silencing', 'Var', (192, 212))	('PRCC', 'Gene', (78, 82))	('methylation', 'biological_process', 'GO:0032259', ('11', '22'))	('KEAP1', 'Gene', '9817', (177, 182))	('PRCC', 'Gene', '5546', (78, 82))	('men', 'Species', '9606', (239, 242))	('KEAP1', 'Gene', (177, 182))
26755	28061437	Moreover, there was no significant association between KEAP1 methylation and disease free survival, local recurrence or overall survival.	('methylation', 'Var', (61, 72))	('KEAP1', 'Gene', '9817', (55, 60))	('local recurrence', 'CPA', (100, 116))	('methylation', 'biological_process', 'GO:0032259', ('61', '72'))	('KEAP1', 'Gene', (55, 60))	('disease free survival', 'CPA', (77, 98))
26758	28061437	Relevant results were summarized in Table 2: CpG methylation at exon 1 and intron 1 revealed significant association with Overall Survival (OS), grading, staging and tumor dimension.	('staging', 'CPA', (154, 161))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CpG methylation', 'Var', (45, 60))	('Overall Survival', 'MPA', (122, 138))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('grading', 'CPA', (145, 152))	('methylation', 'biological_process', 'GO:0032259', ('49', '60'))	('OS', 'Chemical', '-', (140, 142))	('men', 'Species', '9606', (174, 177))	('association', 'Interaction', (105, 116))
26773	28061437	A growing amount of evidence suggest that an increased activity of Nrf2 due to NFE2L2 or KEAP1 mutations may play a pivotal role in the pathogenesis of many solid tumors and recently emerged as one of the main pathways implicated in Renal Carcinoma.	('solid tumors', 'Disease', (157, 169))	('NFE2L2', 'Gene', (79, 85))	('Renal Carcinoma', 'Phenotype', 'HP:0005584', (233, 248))	('KEAP1', 'Gene', '9817', (89, 94))	('activity', 'MPA', (55, 63))	('Nrf2', 'Gene', (67, 71))	('KEAP1', 'Gene', (89, 94))	('play', 'Reg', (109, 113))	('increased', 'PosReg', (45, 54))	('solid tumors', 'Disease', 'MESH:D009369', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Renal Carcinoma', 'Disease', (233, 248))	('Carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('pathogenesis', 'biological_process', 'GO:0009405', ('136', '148'))	('NFE2L2', 'Gene', '4780', (79, 85))	('Renal Carcinoma', 'Disease', 'MESH:C538614', (233, 248))	('Nrf2', 'Gene', '4780', (67, 71))
26778	28061437	KEAP1 promoter epigenetic silencing as just reported in cancers as well as in the other diseases with a clear association with tumors having a low incidence of somatic mutations.	('cancers', 'Disease', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('tumors', 'Disease', (127, 133))	('KEAP1', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('epigenetic silencing', 'Var', (15, 35))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('KEAP1', 'Gene', '9817', (0, 5))
26780	28061437	As main result, an aberrant promoter KEAP1 methylation was identified in the ccRCC subset with a frequency of 49%.	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('KEAP1', 'Gene', '9817', (37, 42))	('aberrant', 'Var', (19, 27))	('KEAP1', 'Gene', (37, 42))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
26785	28061437	Moreover, ccRCCs are heterogeneous/multifocal tumours and intra-tumoral heterogeneity could involve epigenetic changes similar to genetic and genomic events.	('intra-tumoral', 'Disease', (58, 71))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('RCC', 'Disease', (12, 15))	('multifocal tumours', 'Disease', (35, 53))	('involve', 'Reg', (92, 99))	('multifocal tumours', 'Disease', 'None', (35, 53))	('epigenetic changes', 'Var', (100, 118))	('intra-tumoral', 'Disease', 'MESH:D009369', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
26786	28061437	QMSP is a highly sensitive methodology and methylation signals may be obtained even if cells that carry KEAP1 promoter methylation represent a small proportion among the majority of cells with unmethylated promoter.	('methylation', 'biological_process', 'GO:0032259', ('43', '54'))	('methylation', 'Var', (119, 130))	('KEAP1', 'Gene', '9817', (104, 109))	('KEAP1', 'Gene', (104, 109))	('methylation', 'biological_process', 'GO:0032259', ('119', '130'))
26791	28061437	In papillary RCCs, 8 out of 183 non-synonymous NFE2L2 mutations are described (4%),.	('NFE2L2', 'Gene', (47, 53))	('mutations', 'Var', (54, 63))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('NFE2L2', 'Gene', '4780', (47, 53))
26792	28061437	This result partially confirms the previous available published data that reported a low rate of inactivating mutations of CUL3 or activating mutations of NFE2L2 in sporadic PRCC2.	('PRCC', 'Gene', '5546', (174, 178))	('CUL3', 'Gene', '8452', (123, 127))	('CUL3', 'Gene', (123, 127))	('inactivating mutations', 'Var', (97, 119))	('PRCC', 'Gene', (174, 178))	('NFE2L2', 'Gene', '4780', (155, 161))	('activating', 'PosReg', (131, 141))	('NFE2L2', 'Gene', (155, 161))
26799	28061437	A clear association was observed between the hypermethylation of CpGs located in the KEAP1 promoter and an increased ccRCC tumor grading and staging, further supporting their biological relevance.	('CpGs', 'Protein', (65, 69))	('tumor', 'Disease', (123, 128))	('hypermethylation', 'Var', (45, 61))	('KEAP1', 'Gene', (85, 90))	('increased', 'PosReg', (107, 116))	('staging', 'CPA', (141, 148))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('KEAP1', 'Gene', '9817', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
26801	28061437	An increased methylation level of 5/7 CpGs was strongly associated with worse OS in ccRCCs.	('increased', 'PosReg', (3, 12))	('methylation', 'biological_process', 'GO:0032259', ('13', '24'))	('methylation level', 'MPA', (13, 30))	('worse OS', 'Disease', (72, 80))	('OS', 'Chemical', '-', (78, 80))	('CpGs', 'Var', (38, 42))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
26802	28061437	Our study reports for the first time the epigenetic modulation of KEAP1 by CpGs promoter hypermethylation as the leading mechanism of KEAP1 deregulation in ccRCC and together with recently published data on PRCC2, corroborate the hypothesis of a driver role of the Keap1/Nrf2 pathway in the ccRCCs subtypes with a specific epigenetic deregulation mechanism.	('Nrf2', 'Gene', '4780', (271, 275))	('RCC', 'Disease', 'MESH:C538614', (293, 296))	('RCC', 'Disease', (293, 296))	('KEAP1', 'Gene', '9817', (66, 71))	('KEAP1', 'Gene', (134, 139))	('Nrf2', 'Gene', (271, 275))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('Keap1', 'Gene', (265, 270))	('RCC', 'Disease', (208, 211))	('Keap1', 'Gene', '9817', (265, 270))	('PRCC', 'Gene', '5546', (207, 211))	('KEAP1', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('KEAP1', 'Gene', '9817', (134, 139))	('PRCC', 'Gene', (207, 211))	('epigenetic modulation', 'Var', (41, 62))
26803	28061437	In line with data from previous molecular studies, this epigenetic finding represents a new disease molecular marker for a specific subtype of RCC.	('RCC', 'Disease', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('epigenetic finding', 'Var', (56, 74))
26856	28061437	Proportional hazard Cox regression analysis was performed to assess the association between KEAP1 methylation and overall survival.	('KEAP1', 'Gene', (92, 97))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('association', 'Interaction', (72, 83))	('methylation', 'biological_process', 'GO:0032259', ('98', '109'))	('methylation', 'Var', (98, 109))	('KEAP1', 'Gene', '9817', (92, 97))
26878	33578778	Thus, imbalances in components of the intrarenal RAS, such as the up-regulation of AT1Rs in RCC cells and ACE in tumour vessels, have been associated with renal cancer development and progression.	('renal cancer', 'Disease', (155, 167))	('up-regulation', 'PosReg', (66, 79))	('renal cancer', 'Phenotype', 'HP:0009726', (155, 167))	('AT1R', 'Gene', '185', (83, 87))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('imbalances', 'Var', (6, 16))	('associated with', 'Reg', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('AT1R', 'Gene', (83, 87))	('regulation', 'biological_process', 'GO:0065007', ('69', '79'))	('imbalances', 'Phenotype', 'HP:0002172', (6, 16))	('renal cancer', 'Disease', 'MESH:D007680', (155, 167))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Disease', (113, 119))	('ACE', 'Gene', '1636', (106, 109))	('ACE', 'Gene', (106, 109))
26927	33578778	PRR expression at the centre and at the infiltration front of pT2 tumours was significantly higher than in pT1 ones.	('higher', 'PosReg', (92, 98))	('PRR', 'molecular_function', 'GO:0038187', ('0', '3'))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('expression', 'MPA', (4, 14))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('pT2', 'Var', (62, 65))	('pT1', 'Gene', (107, 110))	('PRR', 'Gene', '10159', (0, 3))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('PRR', 'Gene', (0, 3))	('tumours', 'Disease', (66, 73))	('pT1', 'Gene', '58492', (107, 110))
26998	26814892	The association of loss of AR with increasing cancer aggressiveness in these studies suggests a tumor suppressor role for AR in RCC, yet two recent studies found that increased expression of AR mRNA associated with poor prognosis.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (46, 67))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('96', '112'))	('aggressiveness', 'Phenotype', 'HP:0000718', (53, 67))	('tumor', 'Disease', (96, 101))	('increased', 'PosReg', (167, 176))	('loss', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer aggressiveness', 'Disease', (46, 67))	('expression', 'MPA', (177, 187))	('tumor suppressor', 'biological_process', 'GO:0051726', ('96', '112'))
27057	26814892	Our study found that AR expression in ccRCC was prognostic and that high expression predicted better overall survival in both males and females.	('overall survival', 'MPA', (101, 117))	('high', 'Var', (68, 72))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('better', 'PosReg', (94, 100))
27086	26814892	In addition, dysregulation of circadian rhythms is associated with the development of hypertension and accelerated progression of chronic kidney disease.	('chronic kidney disease', 'Disease', 'MESH:D051436', (130, 152))	('dysregulation', 'Var', (13, 26))	('chronic kidney disease', 'Disease', (130, 152))	('associated', 'Reg', (51, 61))	('hypertension', 'Disease', 'MESH:D006973', (86, 98))	('circadian rhythms', 'MPA', (30, 47))	('kidney disease', 'Phenotype', 'HP:0000112', (138, 152))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (130, 152))	('men', 'Species', '9606', (78, 81))	('hypertension', 'Disease', (86, 98))	('hypertension', 'Phenotype', 'HP:0000822', (86, 98))
27097	26636097	Xp11.2 RCC more frequently affected young (30.7 +- 8.7 years) women (16/25, 64%) with gross hematuria (12/25, 48%), while PRCC more frequently involved middle-aged (54.8 +- 11.1 years) men (28/39, 71.8%) asymptomatically.	('men', 'Species', '9606', (185, 188))	('hematuria', 'Disease', 'MESH:D006417', (92, 101))	('Xp11.2', 'Var', (0, 6))	('gross hematuria', 'Phenotype', 'HP:0012587', (86, 101))	('affected', 'Reg', (27, 35))	('hematuria', 'Phenotype', 'HP:0000790', (92, 101))	('men', 'Species', '9606', (64, 67))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('hematuria', 'Disease', (92, 101))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('women', 'Species', '9606', (62, 67))
27099	26636097	CT features including diameter, boundary, attenuation, nature, and circular calcification of the tumor, combined with demographic information and symptoms, may be useful to differentiate Xp11.2 RCC from different subtypes of PRCC.	('circular calcification of the tumor', 'Disease', (67, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Xp11.2 RCC', 'Var', (187, 197))	('circular calcification of the tumor', 'Disease', 'MESH:D002114', (67, 102))	('tumor', 'Disease', (97, 102))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))
27101	26636097	Microscopically, Xp11.2 RCC shows various features, including abundant clear or eosinophilic cytoplasm, irregular nuclei with vesicular chromatin, and prominent nucleoli with papillary, nested, alveolar, or tubular architectures.	('Xp11.2', 'Var', (17, 23))	('cytoplasm', 'cellular_component', 'GO:0005737', ('93', '102'))	('chromatin', 'cellular_component', 'GO:0000785', ('136', '145'))	('alveolar', 'Disease', (194, 202))	('nested', 'CPA', (186, 192))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('alveolar', 'Disease', 'MESH:D002282', (194, 202))
27103	26636097	Previous studies with computed tomography (CT) have shown that Xp11.2 RCC appears as a large, well-defined cystic-solid renal mass with intratumoral hemorrhage and circular calcification.	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hemorrhage', 'Disease', (149, 159))	('Xp11.2', 'Var', (63, 69))	('hemorrhage', 'Disease', 'MESH:D006470', (149, 159))
27115	26636097	Circular calcification was observed in Xp11.2 RCC (15/25, 60%) more often than PRCC (6/39, 15.4%).	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('Circular calcification', 'Disease', 'MESH:D002114', (0, 22))	('Xp11.2 RCC', 'Var', (39, 49))	('observed', 'Reg', (27, 35))	('Circular calcification', 'Disease', (0, 22))
27119	26636097	Many Xp11.2 RCCs contained cysts (22/25, 88%), while type 1 PRCCs were all solid lesions (12/12, 100%) without cystic degeneration or necrosis.	('necrosis', 'biological_process', 'GO:0001906', ('134', '142'))	('PRCCs', 'Phenotype', 'HP:0006766', (60, 65))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('cysts', 'Disease', (27, 32))	('necrosis', 'Disease', 'MESH:D009336', (134, 142))	('necrosis', 'biological_process', 'GO:0008219', ('134', '142'))	('RCCs', 'Phenotype', 'HP:0005584', (12, 16))	('contained', 'Reg', (17, 26))	('necrosis', 'biological_process', 'GO:0070265', ('134', '142'))	('cystic degeneration', 'Disease', 'MESH:C538364', (111, 130))	('cystic degeneration', 'Phenotype', 'HP:0007667', (111, 130))	('necrosis', 'biological_process', 'GO:0019835', ('134', '142'))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('cystic degeneration', 'Disease', (111, 130))	('RCCs', 'Phenotype', 'HP:0005584', (61, 65))	('necrosis', 'Disease', (134, 142))	('Xp11.2', 'Var', (5, 11))	('necrosis', 'biological_process', 'GO:0008220', ('134', '142'))
27132	22824167	SNP array analysis demonstrated differing frequencies of chromosomal copy number alterations among RCC subgroups.	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('chromosomal copy number alterations', 'Var', (57, 92))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))
27136	22824167	RCC can be pathologically subdivided into different histological subtypes  based on the microscopic phenotype and the presence or absence of von Hippel-Lindau (VHL) gene alterations.	('VHL', 'Gene', (160, 163))	('alterations', 'Var', (170, 181))	('von Hippel-Lindau', 'Gene', (141, 158))	('VHL', 'Gene', '7428', (160, 163))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))	('von Hippel-Lindau', 'Gene', '7428', (141, 158))
27139	22824167	In the search of critical genes, molecular studies identified several onco- and tumorsupressor gene candidates that are mutated and/or located within frequently gained and lost chromosomal regions of RCC .	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('RCC', 'Disease', (200, 203))	('RCC', 'Phenotype', 'HP:0005584', (200, 203))	('tumorsupressor', 'Disease', (80, 94))	('RCC', 'Disease', 'MESH:C538614', (200, 203))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumorsupressor', 'Disease', 'None', (80, 94))	('mutated', 'Var', (120, 127))
27140	22824167	Although multiple genes and signaling pathways have been implicated in renal cancer, VHL is the best characterized driver mutation, as it is mutated in the majority of sporadic ccRCC .	('mutated', 'Var', (141, 148))	('renal cancer', 'Disease', 'MESH:D007680', (71, 83))	('renal cancer', 'Phenotype', 'HP:0009726', (71, 83))	('VHL', 'Gene', (85, 88))	('signaling', 'biological_process', 'GO:0023052', ('28', '37'))	('VHL', 'Gene', '7428', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('renal cancer', 'Disease', (71, 83))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
27142	22824167	In addition to VHL, alterations of the genes MET, FH and BHD are thought to be responsible for the development of familial RCC .	('alterations', 'Var', (20, 31))	('VHL', 'Gene', (15, 18))	('MET', 'Gene', (45, 48))	('VHL', 'Gene', '7428', (15, 18))	('familial RCC', 'Disease', 'MESH:C538614', (114, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('BHD', 'Gene', '50947', (57, 60))	('BHD', 'Gene', (57, 60))	('familial RCC', 'Disease', (114, 126))
27185	22824167	Therefore at least one third of A was occupied with randomly selected ccRCC from B and C. 500 times label shuffling and classification trials resulted in zero times same or better classification accuracy (p < 0.002).	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('C. 500 times', 'Var', (87, 99))	('better', 'PosReg', (173, 179))
27190	22824167	By displaying all CNAs mapped to 811 cytogenetic bands (UCSC - hg18 cytogenetic mapping; chromosomes 1-22), all chromosomes were affected including the known RCC subtype-specific genomic alterations 3p-, 5q+(ccRCC) and 7+, 17+, 20+ (pRCC).	('pRCC', 'Gene', '5546', (233, 237))	('affected', 'Reg', (129, 137))	('RCC', 'Phenotype', 'HP:0005584', (234, 237))	('pRCC', 'Gene', (233, 237))	('3p-', 'Var', (199, 202))	('RCC', 'Disease', (158, 161))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('5q+', 'Var', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('RCC', 'Disease', (210, 213))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('RCC', 'Disease', 'MESH:C538614', (234, 237))	('RCC', 'Disease', (234, 237))	('RCC', 'Disease', 'MESH:C538614', (210, 213))
27239	22824167	The inactivation of pVHL leads to HIF-alpha stabilization and, hence, to the upregulation of a number of genes involved in RCC progression (i.e.	('pVHL', 'Gene', '7428', (20, 24))	('inactivation', 'Var', (4, 16))	('pVHL', 'Gene', (20, 24))	('stabilization', 'MPA', (44, 57))	('HIF-alpha', 'Protein', (34, 43))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('upregulation', 'PosReg', (77, 89))	('RCC', 'Disease', 'MESH:C538614', (123, 126))
27244	22824167	A recent study demonstrated that the thermodynamic stability and the functionality of pVHL is dependent on the location and the type of mutation .	('pVHL', 'Gene', (86, 90))	('mutation', 'Var', (136, 144))	('pVHL', 'Gene', '7428', (86, 90))
27245	22824167	As the frequencies and types of VHL mutations were similar in all three RCC groups, it was not surprising that there was no association with the gene expression patterns, neither with the VHL mutation status nor with any HIF-driven pathways (data not shown).	('VHL', 'Gene', (32, 35))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('VHL', 'Gene', '7428', (32, 35))	('RCC', 'Disease', (72, 75))	('gene expression', 'biological_process', 'GO:0010467', ('145', '160'))	('mutations', 'Var', (36, 45))	('VHL', 'Gene', (188, 191))	('VHL', 'Gene', '7428', (188, 191))	('gene expression patterns', 'MPA', (145, 169))
27253	22824167	mutations, methylations, transcriptional and translational modifications), which together support the regulation of molecular components to reach one of the three tumor groups.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('mutations', 'Var', (0, 9))	('methylations', 'Var', (11, 23))
27269	31063758	YAP/TAZ inhibition induces metabolic and signaling rewiring resulting in targetable vulnerabilities in NF2-deficient tumor cells Merlin/NF2 is a bona fide tumor suppressor whose mutations underlie inherited tumor syndrome Neurofibromatosis Type 2 (NF2) as well as various sporadic cancers including kidney cancer.	('YAP', 'Gene', (0, 3))	('NF2', 'Gene', (248, 251))	('NF2', 'Gene', '4771', (136, 139))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('deficient tumor', 'Disease', 'MESH:D009369', (107, 122))	('inherited tumor syndrome Neurofibromatosis Type', 'Disease', 'MESH:C537392', (197, 244))	('NF2', 'Gene', '4771', (103, 106))	('cancers', 'Phenotype', 'HP:0002664', (281, 288))	('cancers', 'Disease', (281, 288))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('NF2', 'Gene', (136, 139))	('inherited tumor syndrome Neurofibromatosis Type', 'Disease', (197, 244))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('NF2', 'Gene', (103, 106))	('Merlin', 'Gene', '4771', (129, 135))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (222, 246))	('YAP', 'Gene', '10413', (0, 3))	('underlie', 'Reg', (188, 196))	('deficient tumor', 'Disease', (107, 122))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('155', '171'))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (222, 239))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('kidney cancer', 'Disease', 'MESH:D007680', (299, 312))	('signaling', 'biological_process', 'GO:0023052', ('41', '50'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('155', '171'))	('cancers', 'Disease', 'MESH:D009369', (281, 288))	('tumor', 'Disease', (207, 212))	('kidney cancer', 'Phenotype', 'HP:0009726', (299, 312))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('Merlin', 'Gene', (129, 135))	('Neurofibromatosis Type 2', 'Disease', (222, 246))	('kidney cancer', 'Disease', (299, 312))	('NF2', 'Gene', '4771', (248, 251))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
27271	31063758	However, the molecular mechanisms underpinning the growth and survival of NF2 mutant tumors remain poorly understood.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('NF2', 'Gene', (74, 77))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutant', 'Var', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
27272	31063758	Using an inducible orthotopic kidney tumor model, we demonstrate that YAP/TAZ silencing is sufficient to induce regression of pre-established NF2-deficient tumors.	('pre', 'molecular_function', 'GO:0003904', ('126', '129'))	('kidney tumor', 'Phenotype', 'HP:0009726', (30, 42))	('kidney tumor', 'Disease', 'MESH:D007680', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('silencing', 'Var', (78, 87))	('deficient tumors', 'Disease', (146, 162))	('deficient tumors', 'Disease', 'MESH:D009369', (146, 162))	('regression', 'CPA', (112, 122))	('YAP/TAZ', 'Gene', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('kidney tumor', 'Disease', (30, 42))
27273	31063758	Mechanistically, YAP/TAZ depletion diminishes glycolysis-dependent growth and increases mitochondrial respiration and ROS buildup, resulting in oxidative stress-induced cell death when challenged by nutrient stress.	('glycolysis', 'biological_process', 'GO:0006096', ('46', '56'))	('cell death', 'biological_process', 'GO:0008219', ('169', '179'))	('respiration', 'biological_process', 'GO:0045333', ('102', '113'))	('ROS buildup', 'MPA', (118, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('respiration', 'biological_process', 'GO:0007585', ('102', '113'))	('diminishes', 'NegReg', (35, 45))	('oxidative stress-induced', 'MPA', (144, 168))	('depletion', 'Var', (25, 34))	('glycolysis-dependent growth', 'MPA', (46, 73))	('increases', 'PosReg', (78, 87))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('mitochondrial respiration', 'MPA', (88, 113))	('cell death', 'CPA', (169, 179))
27277	31063758	demonstrate YAP/TAZ are required for the maintenance of NF2 mutant tumors.	('NF2', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (60, 66))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
27281	31063758	Deletions or loss-of-function mutations of NF2 underlie Neurofibromatosis Type 2 (NF2), an inherited syndrome characterized by the development of bilateral vestibular schwannomas, schwannomas from cranial or peripheral nerves, meningiomas, and/or ependymomas.	('schwannomas', 'Disease', 'MESH:D009442', (167, 178))	('schwannomas', 'Phenotype', 'HP:0100008', (180, 191))	('bilateral vestibular schwannomas', 'Disease', (146, 178))	('meningiomas', 'Phenotype', 'HP:0002858', (227, 238))	('schwannomas', 'Disease', (167, 178))	('bilateral vestibular schwannomas', 'Disease', 'MESH:D009464', (146, 178))	('meningiomas', 'Disease', (227, 238))	('Neurofibromatosis Type 2', 'Disease', 'MESH:C537392', (56, 80))	('vestibular schwannomas', 'Phenotype', 'HP:0009588', (156, 178))	('inherited syndrome', 'Disease', (91, 109))	('schwannoma', 'Phenotype', 'HP:0100008', (167, 177))	('ependymomas', 'Disease', (247, 258))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (56, 73))	('schwannomas', 'Disease', 'MESH:D009442', (180, 191))	('schwannomas', 'Disease', (180, 191))	('schwannomas', 'Phenotype', 'HP:0100008', (167, 178))	('mutations', 'Var', (30, 39))	('inherited syndrome', 'Disease', 'MESH:D061325', (91, 109))	('schwannoma', 'Phenotype', 'HP:0100008', (180, 190))	('loss-of-function', 'NegReg', (13, 29))	('Neurofibromatosis Type 2', 'Disease', (56, 80))	('bilateral vestibular schwannomas', 'Phenotype', 'HP:0009589', (146, 178))	('meningioma', 'Phenotype', 'HP:0002858', (227, 237))	('NF2', 'Gene', (43, 46))	('meningiomas', 'Disease', 'MESH:D008577', (227, 238))	('ependymomas', 'Disease', 'MESH:D004806', (247, 258))	('Deletions', 'Var', (0, 9))
27282	31063758	Beyond NF2, somatic NF2 mutations are frequently detected in sporadic schwannomas, meningiomas, ependymomas and mesotheliomas, and to a lesser extent in thyroid cancer, colorectal cancer, melanoma, renal cell carcinomas (RCC) and a host of other solid tumors.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (198, 219))	('ependymomas', 'Disease', 'MESH:D004806', (96, 107))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('schwannomas', 'Disease', 'MESH:D009442', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (24, 33))	('colorectal cancer', 'Disease', (169, 186))	('schwannomas', 'Disease', (70, 81))	('mesotheliomas', 'Disease', (112, 125))	('meningiomas', 'Disease', 'MESH:D008577', (83, 94))	('meningioma', 'Phenotype', 'HP:0002858', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('thyroid cancer', 'Disease', (153, 167))	('ependymomas', 'Disease', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('meningiomas', 'Phenotype', 'HP:0002858', (83, 94))	('mesotheliomas', 'Disease', 'MESH:D008654', (112, 125))	('tumors', 'Disease', (252, 258))	('meningiomas', 'Disease', (83, 94))	('detected', 'Reg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('thyroid cancer', 'Disease', 'MESH:D013964', (153, 167))	('schwannomas', 'Phenotype', 'HP:0100008', (70, 81))	('schwannoma', 'Phenotype', 'HP:0100008', (70, 80))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('NF2', 'Gene', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('thyroid cancer', 'Phenotype', 'HP:0002890', (153, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (198, 218))	('RCC', 'Disease', (221, 224))	('melanoma, renal cell carcinomas', 'Disease', 'MESH:C538614', (188, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))
27284	31063758	Loss of Merlin/NF2 triggers deregulation of numerous signaling pathways including MST1/2-LATS1/2 (Hippo), RAC-PAK, RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, FAK-SRC, STAT3, and a number of receptor tyrosine kinases (RTKs).	('mTOR', 'Gene', '2475', (141, 145))	('Merlin', 'Gene', (8, 14))	('Hippo', 'Gene', '37247', (98, 103))	('FAK', 'Gene', (147, 150))	('AKT', 'Gene', '207', (137, 140))	('SRC', 'Gene', '6714', (151, 154))	('RAF', 'Gene', '22882', (119, 122))	('deregulation', 'MPA', (28, 40))	('FAK', 'molecular_function', 'GO:0004717', ('147', '150'))	('PI3K', 'molecular_function', 'GO:0016303', ('132', '136'))	('MEK', 'Gene', '5609', (123, 126))	('ERK', 'Gene', '5594', (127, 130))	('FAK', 'Gene', '5747', (147, 150))	('SRC', 'Gene', (151, 154))	('RAF', 'Gene', (119, 122))	('LATS1/2', 'Gene', '9113;26524', (89, 96))	('Merlin', 'Gene', '4771', (8, 14))	('signaling pathways', 'Pathway', (53, 71))	('MEK', 'Gene', (123, 126))	('MST1/2', 'Gene', '4485;6788', (82, 88))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('LATS1/2', 'Gene', (89, 96))	('MST1/2', 'Gene', (82, 88))	('STAT3', 'Gene', (156, 161))	('ERK', 'Gene', (127, 130))	('Loss', 'Var', (0, 4))	('AKT', 'Gene', (137, 140))	('mTOR', 'Gene', (141, 145))	('STAT3', 'Gene', '6774', (156, 161))	('ERK', 'molecular_function', 'GO:0004707', ('127', '130'))	('Hippo', 'Gene', (98, 103))
27285	31063758	Despite their prevalent activation in NF2-mutant tumors, clinical trials with drugs targeting mTOR, MEK, and several RTKs have yielded largely disappointing results in treating NF2, underscoring the need to fully explore the molecular mechanisms that govern the growth and survival of NF2-deficient tumors.	('NF2-mutant', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MEK', 'Gene', (100, 103))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('deficient tumors', 'Disease', (289, 305))	('tumors', 'Disease', (299, 305))	('deficient tumors', 'Disease', 'MESH:D009369', (289, 305))	('tumors', 'Disease', (49, 55))	('MEK', 'Gene', '5609', (100, 103))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('activation', 'PosReg', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('NF2-mutant', 'Gene', (38, 48))
27290	31063758	In NF2 mutant tumors, due to the inactivation of LATS1/2, unphosphorylated YAP and TAZ become stabilized and free to enter the nucleus where they bind to and partner with the TEAD family of transcription factors to regulate gene expression.	('transcription', 'biological_process', 'GO:0006351', ('190', '203'))	('nucleus', 'cellular_component', 'GO:0005634', ('127', '134'))	('bind', 'Interaction', (146, 150))	('mutant', 'Var', (7, 13))	('LATS1/2', 'Gene', '9113;26524', (49, 56))	('partner', 'Interaction', (158, 165))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('gene expression', 'biological_process', 'GO:0010467', ('224', '239'))	('LATS1/2', 'Gene', (49, 56))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('inactivation', 'Var', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('NF2', 'Gene', (3, 6))	('regulate', 'Reg', (215, 223))
27291	31063758	A number of studies have assessed the effects of YAP inhibition in NF2 mutant tumor cells in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NF2', 'Gene', (67, 70))	('mutant', 'Var', (71, 77))	('tumor', 'Disease', (78, 83))
27292	31063758	Liver-specific YAP deletion was shown to inhibit hyperproliferation of liver progenitor cells and prevent tumorigenesis induced by NF2 deficiency.	('prevent', 'NegReg', (98, 105))	('deficiency', 'Disease', (135, 145))	('deletion', 'Var', (19, 27))	('deficiency', 'Disease', 'MESH:D007153', (135, 145))	('NF2', 'Gene', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('YAP', 'Gene', (15, 18))	('hyperproliferation of liver progenitor cells', 'CPA', (49, 93))	('inhibit', 'NegReg', (41, 48))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
27293	31063758	Similarly, YAP knockdown inhibited the initiation of NF2-deficient schwannomas in vivo, and reduced the proliferation of NF2-deficient meningioma and mesothelioma cell lines in vitro.	('meningioma', 'Phenotype', 'HP:0002858', (135, 145))	('schwannomas', 'Phenotype', 'HP:0100008', (67, 78))	('schwannoma', 'Phenotype', 'HP:0100008', (67, 77))	('knockdown', 'Var', (15, 24))	('proliferation', 'CPA', (104, 117))	('deficient schwannomas', 'Disease', (57, 78))	('initiation', 'MPA', (39, 49))	('deficient schwannomas', 'Disease', 'MESH:D009442', (57, 78))	('deficient meningioma and mesothelioma', 'Disease', 'MESH:D008654', (125, 162))	('reduced', 'NegReg', (92, 99))	('inhibited', 'NegReg', (25, 34))
27294	31063758	However, the roles of YAP and TAZ in the maintenance of NF2 mutant tumors have not been established.	('NF2', 'Gene', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('mutant', 'Var', (60, 66))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
27295	31063758	Moreover, the molecular mechanisms by which YAP and/or TAZ govern the growth and survival of NF2 mutant tumors remain poorly defined.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('NF2', 'Gene', (93, 96))	('mutant', 'Var', (97, 103))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))
27297	31063758	In particular, biallelic inactivation of NF2 has been identified in significant fractions of the more aggressive RCC subtypes including clear cell RCC (ccRCC) with sarcomatoid dedifferentiation (19%), Type II papillary RCC (pRCC, 13%) and unclassified RCC (uRCC, 18%), for which there are no standard therapies.	('NF2', 'Gene', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('RCC', 'Disease', (154, 157))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('sarcomatoid', 'Disease', (164, 175))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('RCC', 'Disease', (258, 261))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (113, 116))	('dedifferentiation', 'biological_process', 'GO:0043696', ('176', '193'))	('biallelic inactivation', 'Var', (15, 37))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('pRCC', 'Gene', (224, 228))	('RCC', 'Disease', (113, 116))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('Type II papillary RCC', 'Disease', (201, 222))	('RCC', 'Disease', 'MESH:C538614', (258, 261))	('RCC', 'Disease', 'MESH:C538614', (219, 222))	('sarcomatoid', 'Disease', 'MESH:C538614', (164, 175))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('identified', 'Reg', (54, 64))	('RCC', 'Disease', (252, 255))	('Type II papillary RCC', 'Disease', 'MESH:C538614', (201, 222))	('pRCC', 'Gene', '5546', (224, 228))
27299	31063758	Here, by employing NF2 deficient RCC and schwannoma cells engineered to inducibly express shRNAs targeting YAP and TAZ, we have systematically examined the effects and mechanisms of YAP/TAZ depletion on the growth and survival of NF2 mutant tumor cells in vitro and in vivo.	('NF2', 'Gene', (230, 233))	('mutant', 'Var', (234, 240))	('survival', 'CPA', (218, 226))	('tumor', 'Disease', (241, 246))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('deficient RCC and schwannoma', 'Disease', 'MESH:C538614', (23, 51))	('schwannoma', 'Phenotype', 'HP:0100008', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
27300	31063758	Our work unravels a complex and intercalated metabolic and signaling circuitry centered around YAP/TAZ that governs the growth and survival of NF2 mutant tumor cells, laying the ground work for developing more comprehensive and better informed treatment strategies to eradicate NF2 tumors.	('mutant', 'Var', (147, 153))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('signaling', 'biological_process', 'GO:0023052', ('59', '68'))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumor', 'Disease', (282, 287))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('NF2', 'Gene', (143, 146))
27301	31063758	To investigate the roles of YAP and TAZ in the maintenance of NF2 deficient tumors, we stably expressed doxycycline (Dox) inducible shRNAs against YAP and TAZ (shY/T) or a vector control (Ctrl) in SN12C renal cell carcinoma cells which contain homozygous truncating NF2 mutations (Figure S1A).	('doxycycline', 'Chemical', 'MESH:D004318', (104, 115))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (203, 223))	('Dox', 'Chemical', 'MESH:D004318', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (270, 279))	('deficient tumors', 'Disease', (66, 82))	('SN12C', 'CellLine', 'CVCL:1705', (197, 202))	('deficient tumors', 'Disease', 'MESH:D009369', (66, 82))	('NF2', 'Gene', (266, 269))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('renal cell carcinoma', 'Disease', (203, 223))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (203, 223))
27304	31063758	Dox-induced YAP/TAZ depletion led to rapid reduction in BLI signals, which remained stagnant for additional 3 weeks before starting to increase again (Figures 1B-1C).	('reduction', 'NegReg', (43, 52))	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('BLI signals', 'MPA', (56, 67))	('depletion', 'Var', (20, 29))
27313	31063758	This apparent difference between in vitro and in vivo led us to hypothesize that in conjunction with YAP/TAZ loss, additional environmental or nutrient stress experienced by tumor cells in vivo but not under standard in vitro culture conditions might be necessary to trigger cell death in NF2 null tumor cells.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (298, 303))	('NF2', 'Gene', (289, 292))	('null', 'Var', (293, 297))	('cell death', 'biological_process', 'GO:0008219', ('275', '285'))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
27316	31063758	Unexpectedly, we found that lowering oxygen levels did not significantly affect the proliferation rates or survival of either shY/T or Ctrl SN12C cells, even though it did cause the anticipated increase in HIF1a protein levels in vitro (Figures S1H-S1I), thus excluding hypoxia as a major contributing factor to YAP/TAZ-depletion-induced regression of NF2 mutant tumors.	('hypoxia', 'Disease', 'MESH:D000860', (270, 277))	('tumors', 'Disease', (363, 369))	('tumors', 'Disease', 'MESH:D009369', (363, 369))	('tumors', 'Phenotype', 'HP:0002664', (363, 369))	('hypoxia', 'Disease', (270, 277))	('HIF1a', 'Gene', '3091', (206, 211))	('protein', 'cellular_component', 'GO:0003675', ('212', '219'))	('NF2', 'Gene', (352, 355))	('increase', 'PosReg', (194, 202))	('HIF1a', 'Gene', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('lowering oxygen levels', 'Phenotype', 'HP:0012418', (28, 50))	('SN12C', 'CellLine', 'CVCL:1705', (140, 145))	('protein levels', 'MPA', (212, 226))	('mutant', 'Var', (356, 362))	('oxygen', 'Chemical', 'MESH:D010100', (37, 43))
27321	31063758	Even though knockdown of TAZ had little effects on its own across all conditions, it enhanced the growth inhibition in nutrient replete conditions and cell death in glutamine-deprived conditions caused by YAP knockdown (Fig S2E), suggesting YAP and TAZ function redundantly in promoting the growth and survival of NF2 mutant cells.	('enhanced', 'PosReg', (85, 93))	('growth inhibition', 'CPA', (98, 115))	('cell death', 'biological_process', 'GO:0008219', ('151', '161'))	('mutant', 'Var', (318, 324))	('cell death', 'CPA', (151, 161))	('NF2', 'Gene', (314, 317))	('promoting', 'PosReg', (277, 286))	('glutamine', 'Chemical', 'MESH:D005973', (165, 174))
27327	31063758	Overexpression of a constitutively active mutant YAP was recently shown to promote aerobic glycolysis by increasing glucose uptake.	('increasing', 'PosReg', (105, 115))	('mutant', 'Var', (42, 48))	('promote', 'PosReg', (75, 82))	('glycolysis', 'biological_process', 'GO:0006096', ('91', '101'))	('YAP', 'Gene', (49, 52))	('glucose uptake', 'MPA', (116, 130))	('glucose uptake', 'biological_process', 'GO:0046323', ('116', '130'))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))	('aerobic glycolysis', 'MPA', (83, 101))
27328	31063758	Consistent with these reports, we found that YAP/TAZ depletion dramatically reduced glucose uptake in SN12C cells (Figure S2G).	('glucose uptake', 'MPA', (84, 98))	('depletion', 'Var', (53, 62))	('glucose', 'Chemical', 'MESH:D005947', (84, 91))	('glucose uptake', 'biological_process', 'GO:0046323', ('84', '98'))	('reduced', 'NegReg', (76, 83))	('SN12C', 'CellLine', 'CVCL:1705', (102, 107))
27329	31063758	Moreover, YAP/TAZ depletion caused a marked reduction in glycolysis rate as well as total glycolytic capacity in SN12C cells, as demonstrated by the changes in extracellular acidification rate (ECAR) following the addition of glucose and subsequently mitochondrial ATP synthase inhibitor oligomycin (oligo) (Figure 2C).	('acidification', 'biological_process', 'GO:0045851', ('174', '187'))	('glycolysis', 'biological_process', 'GO:0006096', ('57', '67'))	('glycolysis rate', 'MPA', (57, 72))	('extracellular', 'cellular_component', 'GO:0005576', ('160', '173'))	('ATP synthase', 'molecular_function', 'GO:0016468', ('265', '277'))	('oligo', 'Chemical', 'MESH:D009840', (300, 305))	('oligo', 'Chemical', 'MESH:D009840', (288, 293))	('oligomycin', 'Chemical', 'MESH:D009840', (288, 298))	('ATP synthase', 'molecular_function', 'GO:0016467', ('265', '277'))	('extracellular acidification rate', 'MPA', (160, 192))	('glycolytic capacity', 'MPA', (90, 109))	('reduction', 'NegReg', (44, 53))	('depletion', 'Var', (18, 27))	('ATP', 'Chemical', 'MESH:D000255', (265, 268))	('SN12C', 'CellLine', 'CVCL:1705', (113, 118))	('glucose', 'Chemical', 'MESH:D005947', (226, 233))	('changes', 'Reg', (149, 156))
27331	31063758	In further support of the roles of YAP/TAZ in promoting aerobic glycolysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolic profiling of Ctrl and shY/T SC4 cells showed that YAP/TAZ depletion downregulated a number of glycolytic metabolites including G6P, G3P, PEP and lactate (Figure S2J).	('G6P', 'MPA', (271, 274))	('downregulated', 'NegReg', (212, 225))	('lactate', 'MPA', (289, 296))	('G3P', 'Chemical', '-', (276, 279))	('G3P', 'MPA', (276, 279))	('glycolysis', 'biological_process', 'GO:0006096', ('64', '74'))	('YAP/TAZ', 'Gene', (194, 201))	('PEP', 'Gene', (281, 284))	('PEP', 'Gene', '5047', (281, 284))	('depletion', 'Var', (202, 211))	('glycolytic metabolites', 'MPA', (238, 260))	('G6P', 'Chemical', '-', (271, 274))	('lactate', 'Chemical', 'MESH:D019344', (289, 296))	('SC4', 'CellLine', 'CVCL:6F23', (172, 175))
27332	31063758	To directly assess how aerobic glycolysis contributes to the proliferation of NF2 mutant cells, we replaced glucose in the culture medium of SN12C cells with galactose (Gal), a glucose isomer that is processed through glycolysis but does not yield any net glycolytic-ATP.	('glycolysis', 'biological_process', 'GO:0006096', ('218', '228'))	('glucose', 'Chemical', 'MESH:D005947', (108, 115))	('SN12C', 'CellLine', 'CVCL:1705', (141, 146))	('ATP', 'Chemical', 'MESH:D000255', (267, 270))	('glucose', 'Chemical', 'MESH:D005947', (177, 184))	('galactose', 'Chemical', 'MESH:D005690', (158, 167))	('glycolysis', 'biological_process', 'GO:0006096', ('31', '41'))	('Gal', 'Chemical', 'MESH:D005690', (169, 172))	('NF2', 'Gene', (78, 81))	('mutant', 'Var', (82, 88))
27333	31063758	While galactose substitution had very little effect on shY/T cells with already compromised glycolysis, it completely blocked the proliferation of Ctrl cells (Figure S2K), underscoring the importance of high aerobic glycolysis in sustaining the proliferation of NF2 mutant tumor cells.	('blocked', 'NegReg', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('NF2', 'Gene', (262, 265))	('glycolysis', 'biological_process', 'GO:0006096', ('216', '226'))	('proliferation', 'CPA', (130, 143))	('galactose', 'Chemical', 'MESH:D005690', (6, 15))	('mutant', 'Var', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('glycolysis', 'biological_process', 'GO:0006096', ('92', '102'))
27334	31063758	YAP was recently shown to increase glucose uptake in part by transcribing GLUT3, HK2 and PFKFB3.	('glucose', 'Chemical', 'MESH:D005947', (35, 42))	('PFKFB3', 'Gene', (89, 95))	('HK2', 'Gene', (81, 84))	('transcribing', 'Var', (61, 73))	('HK2', 'Gene', '3099', (81, 84))	('PFKFB3', 'Gene', '5209', (89, 95))	('increase glucose', 'Phenotype', 'HP:0003074', (26, 42))	('glucose uptake', 'biological_process', 'GO:0046323', ('35', '49'))	('GLUT3', 'Gene', '6515', (74, 79))	('HK2', 'molecular_function', 'GO:0008256', ('81', '84'))	('GLUT3', 'Gene', (74, 79))	('increase', 'PosReg', (26, 34))	('glucose uptake', 'MPA', (35, 49))
27335	31063758	Consistent with these reports, we found that YAP/TAZ depletion specifically reduced the mRNA levels of GLUT3 and HK2 as well as other glycolytic enzymes including HK1, PFKFB4, PFKP, GAPDH, PGK1, PGAM1, LDHA, PDHA1 and PDHB (Figures 2D-2E).	('depletion', 'Var', (53, 62))	('HK1', 'molecular_function', 'GO:0004673', ('163', '166'))	('PFKP', 'Gene', '5214', (176, 180))	('GLUT3', 'Gene', '6515', (103, 108))	('HK2', 'Gene', (113, 116))	('HK2', 'Gene', '3099', (113, 116))	('reduced', 'NegReg', (76, 83))	('PFKFB4', 'Gene', (168, 174))	('PGAM1', 'Gene', (195, 200))	('LDHA', 'Gene', '3939', (202, 206))	('HK1', 'Gene', '3098', (163, 166))	('PGK1', 'Gene', '5230', (189, 193))	('PGAM1', 'Gene', '5223', (195, 200))	('GAPDH', 'Gene', '2597', (182, 187))	('PFKFB4', 'Gene', '5210', (168, 174))	('GLUT3', 'Gene', (103, 108))	('HK2', 'molecular_function', 'GO:0008256', ('113', '116'))	('PDHB', 'Gene', (218, 222))	('glycolytic', 'MPA', (134, 144))	('PGK1', 'Gene', (189, 193))	('LDHA', 'Gene', (202, 206))	('GAPDH', 'Gene', (182, 187))	('PDHA1', 'Gene', '5160', (208, 213))	('PFKP', 'Gene', (176, 180))	('PDHA1', 'Gene', (208, 213))	('HK1', 'Gene', (163, 166))	('PDHB', 'Gene', '5162', (218, 222))	('PGK', 'molecular_function', 'GO:0004618', ('189', '192'))
27337	31063758	Unexpectedly, ectopic expression of GLUT3 only minimally increased proliferation in nutrient replete conditions and did not rescue cell death under nutrient deprived conditions (Figures 2F and S2L), suggesting additional mechanisms may mediate the regulation of glycolysis by YAP/TAZ.	('GLUT3', 'Gene', (36, 41))	('regulation', 'biological_process', 'GO:0065007', ('248', '258'))	('glycolysis', 'biological_process', 'GO:0006096', ('262', '272'))	('proliferation', 'CPA', (67, 80))	('glycolysis', 'MPA', (262, 272))	('cell death', 'biological_process', 'GO:0008219', ('131', '141'))	('GLUT3', 'Gene', '6515', (36, 41))	('ectopic expression', 'Var', (14, 32))
27342	31063758	As shown in Figure 2H, YAP/TAZ silencing caused substantial decrease in AKT phosphorylation, which correlated with reduced pEGFR and increased PTEN levels, implying downregulation of RTK signaling as the likely cause of AKT inactivation.	('AKT', 'Gene', (220, 223))	('silencing', 'Var', (31, 40))	('AKT', 'Gene', '207', (72, 75))	('decrease', 'NegReg', (60, 68))	('EGF', 'Gene', '1950', (124, 127))	('phosphorylation', 'biological_process', 'GO:0016310', ('76', '91'))	('signaling', 'biological_process', 'GO:0023052', ('187', '196'))	('reduced', 'NegReg', (115, 122))	('AKT', 'Gene', (72, 75))	('AKT', 'Gene', '207', (220, 223))	('EGF', 'Gene', (124, 127))	('PTEN', 'Gene', (143, 147))	('increased', 'PosReg', (133, 142))	('PTEN', 'Gene', '5728', (143, 147))
27349	31063758	Together, these findings reconciled previous reported functions of YAP/TAZ in glycolysis and regulation of RTK-AKT signaling, establishing YAP/TAZ as master regulators that coordinate the expression of glycolytic enzymes and GFs and RTK-AKT signaling to promote glycolysis, thereby sustaining the proliferation of NF2 mutant tumor cells (Figure 2M).	('AKT', 'Gene', '207', (111, 114))	('AKT', 'Gene', (237, 240))	('regulation', 'biological_process', 'GO:0065007', ('93', '103'))	('AKT signaling', 'biological_process', 'GO:0043491', ('237', '250'))	('sustaining', 'PosReg', (282, 292))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('glycolysis', 'biological_process', 'GO:0006096', ('262', '272'))	('AKT signaling', 'biological_process', 'GO:0043491', ('111', '124'))	('mutant', 'Var', (318, 324))	('AKT', 'Gene', (111, 114))	('promote', 'PosReg', (254, 261))	('NF2', 'Gene', (314, 317))	('glycolysis', 'MPA', (262, 272))	('proliferation', 'CPA', (297, 310))	('AKT', 'Gene', '207', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('glycolysis', 'biological_process', 'GO:0006096', ('78', '88'))
27358	31063758	We hypothesized that the increase in mitochondrial respiration induced by YAP/TAZ depletion might lead to elevated ROS production, which when compounded by reduced anti-oxidant capacity caused by glucose or glutamine starvation, might cause oxidative-stress-induced cell death.	('elevated ROS production', 'Phenotype', 'HP:0025464', (106, 129))	('respiration', 'biological_process', 'GO:0007585', ('51', '62'))	('depletion', 'Var', (82, 91))	('cell death', 'biological_process', 'GO:0008219', ('266', '276'))	('YAP/TAZ', 'Gene', (74, 81))	('respiration', 'biological_process', 'GO:0045333', ('51', '62'))	('glutamine', 'Chemical', 'MESH:D005973', (207, 216))	('ROS production', 'MPA', (115, 129))	('oxidative-stress', 'Phenotype', 'HP:0025464', (241, 257))	('elevated', 'PosReg', (106, 114))	('ROS', 'Chemical', 'MESH:D017382', (115, 118))	('increase', 'PosReg', (25, 33))	('glucose', 'Chemical', 'MESH:D005947', (196, 203))	('mitochondrial respiration', 'MPA', (37, 62))	('cause', 'Reg', (235, 240))
27361	31063758	Similarly, YAP/TAZ depletion also increased ROS levels and mitochondrial mass in SC4 cells (Figure S3G).	('depletion', 'Var', (19, 28))	('mitochondrial mass', 'MPA', (59, 77))	('SC4', 'CellLine', 'CVCL:6F23', (81, 84))	('ROS levels', 'MPA', (44, 54))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('increased', 'PosReg', (34, 43))	('increased ROS levels', 'Phenotype', 'HP:0025464', (34, 54))
27372	31063758	Although expression of Myr-AKT largely rescued glycolysis and proliferation in shY/T cells, it did not reduce mitochondrial mass, only partially reversed the increase in intracellular ROS levels, and failed to prevent cell death caused by Gln withdrawal in shY/T cells (Figures 2J-2L and S3I-S3J).	('cell death', 'biological_process', 'GO:0008219', ('218', '228'))	('expression', 'Var', (9, 19))	('rescued', 'PosReg', (39, 46))	('AKT', 'Gene', (27, 30))	('proliferation', 'CPA', (62, 75))	('intracellular ROS levels', 'MPA', (170, 194))	('glycolysis', 'biological_process', 'GO:0006096', ('47', '57'))	('glycolysis', 'MPA', (47, 57))	('reduce mitochondrial mass', 'Phenotype', 'HP:0040013', (103, 128))	('intracellular', 'cellular_component', 'GO:0005622', ('170', '183'))	('mitochondrial mass', 'MPA', (110, 128))	('AKT', 'Gene', '207', (27, 30))	('Gln', 'Chemical', 'MESH:D005973', (239, 242))	('ROS', 'Chemical', 'MESH:D017382', (184, 187))	('increase', 'PosReg', (158, 166))	('increase in intracellular ROS levels', 'Phenotype', 'HP:0025464', (158, 194))
27373	31063758	Next, we used Pyr or Gln to directly stimulate TCA cycle and OXPHOS in Ctrl and shY/T cells, bypassing glycolysis.	('stimulate', 'PosReg', (37, 46))	('OXPHOS', 'biological_process', 'GO:0002082', ('61', '67'))	('TCA', 'Chemical', '-', (47, 50))	('Pyr', 'Var', (14, 17))	('Pyr', 'Chemical', 'MESH:D019289', (14, 17))	('TCA cycle', 'biological_process', 'GO:0006099', ('47', '56'))	('bypassing', 'NegReg', (93, 102))	('Gln', 'Var', (21, 24))	('glycolysis', 'biological_process', 'GO:0006096', ('103', '113'))	('OXPHOS', 'MPA', (61, 67))	('glycolysis', 'MPA', (103, 113))	('Gln', 'Chemical', 'MESH:D005973', (21, 24))	('TCA cycle', 'MPA', (47, 56))
27374	31063758	As shown in Figure S3K, both Pyr and Gln increased mitochondrial respiration to a significantly higher extent in YAP/TAZ-depleted cells, suggesting that YAP/TAZ suppress mitochondrial respiratory capacity and ROS production independent of their regulation of glycolysis.	('ROS', 'Chemical', 'MESH:D017382', (209, 212))	('glycolysis', 'biological_process', 'GO:0006096', ('259', '269'))	('ROS production', 'MPA', (209, 223))	('increased', 'PosReg', (41, 50))	('regulation', 'biological_process', 'GO:0065007', ('245', '255'))	('respiration', 'biological_process', 'GO:0007585', ('65', '76'))	('mitochondrial respiration', 'MPA', (51, 76))	('Gln', 'Var', (37, 40))	('Gln', 'Chemical', 'MESH:D005973', (37, 40))	('mitochondrial respiratory capacity', 'MPA', (170, 204))	('respiration', 'biological_process', 'GO:0045333', ('65', '76'))	('suppress', 'NegReg', (161, 169))	('Pyr', 'Var', (29, 32))	('Pyr', 'Chemical', 'MESH:D019289', (29, 32))
27375	31063758	Indicative of increased oxidative stress, H2AX was activated both in vitro and in vivo following YAP/TAZ knockdown (Figures 1E, 1G and S4A), which correlated with significant increase in the NAD+/NADH, NADP+/NADPH and GSSG/GSH ratios (Figure 3I).	('increased', 'PosReg', (14, 23))	('NADH', 'Chemical', 'MESH:D009243', (196, 200))	('GSH', 'Chemical', '-', (223, 226))	('oxidative stress', 'Phenotype', 'HP:0025464', (24, 40))	('NADP+', 'Chemical', 'MESH:D009249', (202, 207))	('NAD+', 'Chemical', 'MESH:D009243', (191, 195))	('H2AX', 'Gene', (42, 46))	('NAD+/NADH', 'MPA', (191, 200))	('NADPH', 'Gene', (208, 213))	('activated', 'PosReg', (51, 60))	('GSSG', 'Chemical', 'MESH:D019803', (218, 222))	('H2AX', 'Gene', '3014', (42, 46))	('NADPH', 'Gene', '1666', (208, 213))	('knockdown', 'Var', (105, 114))	('oxidative stress', 'MPA', (24, 40))	('YAP/TAZ', 'Gene', (97, 104))	('GSSG/GSH ratios', 'MPA', (218, 233))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (14, 40))	('increase', 'PosReg', (175, 183))
27377	31063758	As expected, withdrawal of glucose or glutamine raised ROS levels in both Ctrl and shY/T cells (Figure 3J).	('glutamine raised', 'Phenotype', 'HP:0003217', (38, 54))	('withdrawal', 'Var', (13, 23))	('ROS levels', 'MPA', (55, 65))	('ROS', 'Chemical', 'MESH:D017382', (55, 58))	('glutamine', 'Protein', (38, 47))	('glutamine', 'Chemical', 'MESH:D005973', (38, 47))	('raised ROS levels', 'Phenotype', 'HP:0025464', (48, 65))	('raised', 'PosReg', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (27, 34))
27381	31063758	Together, our findings expose a function for YAP/TAZ in limiting mitochondrial respiratory capacity and ROS production, which is necessary for maintaining redox balance and survival of NF2 mutant tumor cells under nutrient-deprived conditions.	('tumor', 'Disease', (196, 201))	('limiting', 'NegReg', (56, 64))	('mutant', 'Var', (189, 195))	('NF2', 'Gene', (185, 188))	('mitochondrial respiratory capacity', 'MPA', (65, 99))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('ROS production', 'MPA', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
27382	31063758	Our in vitro and in vivo data so far indicate that although NF2 mutant tumor cells require YAP/TAZ for proliferation, they are capable of surviving YAP/TAZ loss and the resulting rise in ROS levels and oxidative stress when both glucose and glutamine are readily available.	('rise', 'PosReg', (179, 183))	('loss', 'NegReg', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('oxidative stress', 'Phenotype', 'HP:0025464', (202, 218))	('rise in ROS levels', 'Phenotype', 'HP:0025464', (179, 197))	('ROS levels', 'MPA', (187, 197))	('glucose', 'Chemical', 'MESH:D005947', (229, 236))	('NF2', 'Gene', (60, 63))	('ROS', 'Chemical', 'MESH:D017382', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('oxidative stress', 'MPA', (202, 218))	('YAP/TAZ', 'MPA', (148, 155))	('tumor', 'Disease', (71, 76))	('mutant', 'Var', (64, 70))	('glutamine', 'Chemical', 'MESH:D005973', (241, 250))
27383	31063758	This led us to investigate whether NF2 mutant tumor cells could activate certain stress response pathways to counter the redox imbalance caused by YAP/TAZ loss.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('stress response pathways', 'Pathway', (81, 105))	('counter', 'MPA', (109, 116))	('NF2', 'Gene', (35, 38))	('redox imbalance', 'MPA', (121, 136))	('tumor', 'Disease', (46, 51))	('mutant', 'Var', (39, 45))	('imbalance', 'Phenotype', 'HP:0002172', (127, 136))	('redox imbalance', 'Phenotype', 'HP:0025463', (121, 136))	('activate', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
27384	31063758	Indeed, western blot analysis showed that multiple stress response pathways including ERK, AMPK and p38 were activated in response to YAP/TAZ knockdown (Figures S4A-S4B).	('p38', 'Gene', (100, 103))	('AMPK', 'Gene', '5563', (91, 95))	('AMPK', 'molecular_function', 'GO:0050405', ('91', '95'))	('ERK', 'molecular_function', 'GO:0004707', ('86', '89'))	('AMPK', 'molecular_function', 'GO:0004691', ('91', '95'))	('activated', 'PosReg', (109, 118))	('AMPK', 'Gene', (91, 95))	('p38', 'Gene', '5594', (100, 103))	('AMPK', 'molecular_function', 'GO:0047322', ('91', '95'))	('stress response pathways', 'Pathway', (51, 75))	('ERK', 'Gene', '5594', (86, 89))	('knockdown', 'Var', (142, 151))	('ERK', 'Gene', (86, 89))
27389	31063758	These results demonstrate that activation of the RAF-MEK-ERK pathway is necessary for the survival of YAP/TAZ-depleted NF2 mutant cells.	('MEK', 'Gene', (53, 56))	('RAF', 'Gene', '22882', (49, 52))	('ERK', 'molecular_function', 'GO:0004707', ('57', '60'))	('RAF', 'Gene', (49, 52))	('ERK', 'Gene', '5594', (57, 60))	('ERK', 'Gene', (57, 60))	('MEK', 'Gene', '5609', (53, 56))	('NF2', 'Gene', (119, 122))	('mutant', 'Var', (123, 129))
27392	31063758	In contrast, the MEK inhibitor Trametinib and pan-RAF inhibitors LY3009120 and Sorafenib inhibited pERK levels in shY/T cells, but did not reduce pAKT levels in Ctrl cells (Figures 4D and S4E).	('MEK', 'Gene', (17, 20))	('Trametinib', 'Chemical', 'MESH:C560077', (31, 41))	('pERK', 'Gene', '9451', (99, 103))	('pERK', 'Gene', (99, 103))	('LY3009120', 'Chemical', 'MESH:C000600963', (65, 74))	('inhibited', 'NegReg', (89, 98))	('MEK', 'Gene', '5609', (17, 20))	('LY3009120', 'Var', (65, 74))	('AKT', 'Gene', '207', (147, 150))	('RAF', 'Gene', '22882', (50, 53))	('RAF', 'Gene', (50, 53))	('Sorafenib', 'Chemical', 'MESH:D000077157', (79, 88))	('AKT', 'Gene', (147, 150))
27402	31063758	To determine which of these two mechanisms were responsible for activation of cAMP-PKA/EPAC signaling upon YAP/TAZ depletion, we treated shY/T cells with GPCR inhibitors (SCH 202676, GRA-1, or Sotalol) or a sAC inhibitor (KH7).	('cAMP', 'Gene', (78, 82))	('cAMP', 'Gene', '820', (78, 82))	('GPCR', 'Gene', '10663', (154, 158))	('SCH 202676', 'Var', (171, 181))	('EPAC', 'Gene', (87, 91))	('PKA', 'molecular_function', 'GO:0004691', ('83', '86'))	('signaling', 'biological_process', 'GO:0023052', ('92', '101'))	('sAC', 'biological_process', 'GO:0071173', ('207', '210'))	('Sotalol', 'Chemical', 'MESH:D013015', (193, 200))	('KH7', 'Chemical', '-', (222, 225))	('EPAC', 'Gene', '10411', (87, 91))	('PKA', 'cellular_component', 'GO:0005952', ('83', '86'))	('GPCR', 'Gene', (154, 158))	('activation', 'PosReg', (64, 74))	('sAC', 'cellular_component', 'GO:0035003', ('207', '210'))	('SCH 202676', 'Chemical', 'MESH:C418425', (171, 181))
27403	31063758	While none of the GPCR inhibitors reduced ERK phosphorylation, the sAC inhibitor KH7 drastically inhibited pERK levels in shY/T cells but not pAKT in Ctrl cells (Figures 4E and S4J).	('ERK', 'Gene', (42, 45))	('sAC', 'cellular_component', 'GO:0035003', ('67', '70'))	('phosphorylation', 'biological_process', 'GO:0016310', ('46', '61'))	('ERK', 'Gene', (108, 111))	('ERK', 'molecular_function', 'GO:0004707', ('42', '45'))	('GPCR', 'Gene', '10663', (18, 22))	('reduced ERK', 'Phenotype', 'HP:0000654', (34, 45))	('KH7', 'Chemical', '-', (81, 84))	('AKT', 'Gene', '207', (143, 146))	('pERK', 'Gene', '9451', (107, 111))	('pERK', 'Gene', (107, 111))	('sAC', 'biological_process', 'GO:0071173', ('67', '70'))	('inhibited', 'NegReg', (97, 106))	('ERK', 'Gene', '5594', (42, 45))	('GPCR', 'Gene', (18, 22))	('AKT', 'Gene', (143, 146))	('KH7', 'Var', (81, 84))	('ERK', 'Gene', '5594', (108, 111))
27405	31063758	In addition, intracellular calcium concentration was markedly increased in shY/T cells compared to Ctrl cells (Figure 4H).	('shY/T', 'Var', (75, 80))	('increased', 'PosReg', (62, 71))	('intracellular calcium concentration', 'MPA', (13, 48))	('calcium', 'Chemical', 'MESH:D002118', (27, 34))	('intracellular', 'cellular_component', 'GO:0005622', ('13', '26'))
27413	31063758	We therefore first investigated whether the dramatic increase in mitochondrial capacity and respiratory activity induced by YAP/TAZ silencing could be the cause of noncanonical ERK activation.	('ERK', 'Gene', '5594', (177, 180))	('ERK', 'molecular_function', 'GO:0004707', ('177', '180'))	('silencing', 'Var', (132, 141))	('ERK', 'Gene', (177, 180))	('mitochondrial', 'MPA', (65, 78))	('increase', 'PosReg', (53, 61))	('respiratory activity', 'MPA', (92, 112))	('YAP/TAZ', 'Gene', (124, 131))
27415	31063758	In line with this finding, staining of Ctrl and shY/T cells with a LAMP1 antibody or acridine orange (AO, marker of acidic vesicles) showed that YAP/TAZ knockdown caused markedly increase in the numbers of lysosomes, which was rescued by re-expression of YAP (Figures 5B and S5D-S5F).	('antibody', 'cellular_component', 'GO:0019814', ('73', '81'))	('antibody', 'molecular_function', 'GO:0003823', ('73', '81'))	('knockdown', 'Var', (153, 162))	('acridine orange', 'Chemical', 'MESH:D000165', (85, 100))	('LAMP1', 'Gene', '3916', (67, 72))	('LAMP1', 'Gene', (67, 72))	('antibody', 'cellular_component', 'GO:0042571', ('73', '81'))	('increase', 'PosReg', (179, 187))	('antibody', 'cellular_component', 'GO:0019815', ('73', '81'))	('YAP/TAZ', 'Gene', (145, 152))
27417	31063758	Treatment of Ctrl and shY/T cells with two different lysosome inhibitors (Bafilomycin and Chloroquine) under different nutrient conditions showed that YAP/TAZ depletion increased the sensitivity of NF2 mutant cells to lysosomal inhibition, especially under nutrient-deprived conditions (Figures S5G-S5H).	('Chloroquine', 'Chemical', 'MESH:D002738', (90, 101))	('Bafilomycin', 'Chemical', '-', (74, 85))	('increased', 'PosReg', (169, 178))	('sensitivity', 'MPA', (183, 194))	('NF2', 'Gene', (198, 201))	('lysosome', 'cellular_component', 'GO:0005764', ('53', '61'))	('mutant', 'Var', (202, 208))
27425	31063758	While either Yap/Taz-depletion or Trametinib treatment alone significantly delayed tumor growth compared to Ctrl tumors, simultaneous Yap/Taz knockdown and Mek inhibition halted tumor growth for several weeks (Figure 5H).	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('inhibition halted', 'NegReg', (160, 177))	('Mek', 'Gene', '5609', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('Trametinib', 'Chemical', 'MESH:C560077', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('delayed', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('knockdown', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Mek', 'Gene', (156, 159))
27426	31063758	Taken together, our data demonstrate that NF2 mutant tumor cells compensate for YAP/TAZ loss by expanding their lysosomal capacity, which raises the cytosolic pH and calcium concentration, leading to the activation of RAF-MEK-ERK signaling, which represents a vulnerability that could be combined with YAP/TAZ inhibition to achieve more durable control of NF2 mutant tumors (Figure 5I).	('MEK', 'Gene', '5609', (222, 225))	('NF2', 'Gene', (42, 45))	('tumors', 'Disease', (367, 373))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ERK', 'Gene', (226, 229))	('RAF', 'Gene', (218, 221))	('raises', 'PosReg', (138, 144))	('MEK', 'Gene', (222, 225))	('tumors', 'Disease', 'MESH:D009369', (367, 373))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('signaling', 'biological_process', 'GO:0023052', ('230', '239'))	('tumor', 'Disease', (367, 372))	('expanding', 'PosReg', (96, 105))	('mutant', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('lysosomal capacity', 'MPA', (112, 130))	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('ERK', 'molecular_function', 'GO:0004707', ('226', '229'))	('activation', 'PosReg', (204, 214))	('calcium', 'Chemical', 'MESH:D002118', (166, 173))	('ERK', 'Gene', '5594', (226, 229))	('RAF', 'Gene', '22882', (218, 221))	('tumor', 'Disease', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))
27428	31063758	To assess the clinical relevance of our findings, we first generated a high-confidence YAP/TAZ signature by filtering genes downregulated by YAP/TAZ knockdown from our microarray analysis of SN12C cells against a recently published gene list ranked based on gene expression pattern similarities across 1,037 cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) (Figure 6A).	('knockdown', 'Var', (149, 158))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('Cancer', 'Disease', 'MESH:D009369', (335, 341))	('Cancer', 'Disease', (335, 341))	('Cancer', 'Phenotype', 'HP:0002664', (335, 341))	('gene expression', 'biological_process', 'GO:0010467', ('258', '273'))	('downregulated', 'NegReg', (124, 137))	('cancer', 'Disease', (308, 314))	('SN12C', 'CellLine', 'CVCL:1705', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))
27430	31063758	Importantly, pRCC and ccRCC tumors with either NF2 mutations or copy number loss where enriched in Y/T-High groups compared to Y/T-Low groups, further validating our YAP/TAZ signature (Figure S6).	('mutations', 'Var', (51, 60))	('pRCC', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('ccRCC tumors', 'Disease', (22, 34))	('copy number loss', 'Var', (64, 80))	('pRCC', 'Gene', '5546', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('NF2', 'Gene', (47, 50))	('ccRCC tumors', 'Disease', 'MESH:D009369', (22, 34))
27431	31063758	In agreement with our findings in NF2 mutant cells, primary RCC tumors from the Y/T-High groups displayed elevated expression of glycolysis genes and correspondingly decreased expression of OXPHOS and lysosomal genes compared to the tumors from the Y/T-Low groups in both pRCC and VHL-WT ccRCC datasets (Figures 6B-6C, and Table S2).	('pRCC', 'Gene', '5546', (272, 276))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('RCC', 'Phenotype', 'HP:0005584', (290, 293))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('expression', 'MPA', (176, 186))	('OXPHOS', 'biological_process', 'GO:0002082', ('190', '196'))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('glycolysis', 'biological_process', 'GO:0006096', ('129', '139'))	('decreased', 'NegReg', (166, 175))	('RCC', 'Phenotype', 'HP:0005584', (273, 276))	('pRCC', 'Gene', (272, 276))	('elevated', 'PosReg', (106, 114))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('VHL-WT ccRCC', 'Disease', (281, 293))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('Y/T-High', 'Var', (80, 88))	('glycolysis', 'MPA', (129, 139))	('RCC tumors', 'Disease', (60, 70))	('expression', 'MPA', (115, 125))	('VHL-WT ccRCC', 'Disease', 'MESH:D006623', (281, 293))	('RCC tumors', 'Disease', 'MESH:C538614', (60, 70))
27433	31063758	Taken together, these results suggest YAP/TAZ activities may play important roles in determining the metabolic states of RCC tumors beyond NF2 mutations.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('RCC tumors', 'Disease', 'MESH:C538614', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('NF2', 'Gene', (139, 142))	('mutations', 'Var', (143, 152))	('RCC tumors', 'Disease', (121, 131))
27434	31063758	Inactivation of NF2/Merlin has been shown to elicit deregulation of a wide array of signaling pathways, but it is unknown how NF2 mutant tumor cells rewire their metabolic and signaling network to overcome nutrient stress.	('signaling', 'biological_process', 'GO:0023052', ('84', '93'))	('deregulation', 'MPA', (52, 64))	('tumor', 'Disease', (137, 142))	('Merlin', 'Gene', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('signaling', 'biological_process', 'GO:0023052', ('176', '185'))	('Merlin', 'Gene', '4771', (20, 26))	('elicit', 'Reg', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mutant', 'Var', (130, 136))	('signaling pathways', 'Pathway', (84, 102))	('Inactivation', 'Var', (0, 12))	('NF2', 'Gene', (126, 129))
27435	31063758	Here, we identify YAP/TAZ as master regulators of transcriptional, signaling, metabolic, and organelle responses to nutrient deprivation in NF2 mutant tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('NF2', 'Gene', (140, 143))	('organelle', 'cellular_component', 'GO:0043226', ('93', '102'))	('mutant', 'Var', (144, 150))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
27438	31063758	Despite these important functions, YAP/TAZ are not absolutely required for the survival of NF2 mutant tumor cells, especially under nutrient replete conditions.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NF2', 'Gene', (91, 94))	('mutant', 'Var', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
27439	31063758	We find that NF2 mutant tumor cells adapt to YAP/TAZ depletion by ramping up RAF-MEK-ERK signaling through a mechanism mediated by upregulation of lysosomes and GPCR-independent activation of cAMP signaling.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cAMP', 'Gene', '820', (192, 196))	('mutant', 'Var', (17, 23))	('signaling', 'biological_process', 'GO:0023052', ('89', '98'))	('RAF', 'Gene', '22882', (77, 80))	('ERK', 'molecular_function', 'GO:0004707', ('85', '88'))	('NF2', 'Gene', (13, 16))	('MEK', 'Gene', '5609', (81, 84))	('cAMP', 'Gene', (192, 196))	('tumor', 'Disease', (24, 29))	('ERK', 'Gene', '5594', (85, 88))	('GPCR', 'Gene', (161, 165))	('RAF', 'Gene', (77, 80))	('cAMP signaling', 'biological_process', 'GO:0019933', ('192', '206'))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MEK', 'Gene', (81, 84))	('upregulation', 'PosReg', (131, 143))	('ERK', 'Gene', (85, 88))	('lysosomes', 'MPA', (147, 156))	('ramping up', 'PosReg', (66, 76))	('GPCR', 'Gene', '10663', (161, 165))
27440	31063758	Previous work has implicated YAP as an oncogenic driver of NF2 mutant tumors, but the underlying molecular mechanisms have not been fully elucidated.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NF2', 'Gene', (59, 62))	('mutant', 'Var', (63, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('YAP', 'Disease', (29, 32))
27445	31063758	These findings not only serve to reconcile the long-standing controversy in the NF2 field regarding the relationship between RTK signaling and YAP/TAZ in NF2 tumorigenesis, but also shed light on the metabolic consequences of YAP/TAZ-RTK crosstalk, firmly establishing YAP/TAZ as the master regulators of a transcriptional, metabolic and signaling network necessary for sustaining the growth of NF2 mutant tumors.	('tumors', 'Disease', (406, 412))	('NF2', 'Gene', (395, 398))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (406, 411))	('tumors', 'Disease', 'MESH:D009369', (406, 412))	('long-standing', 'Phenotype', 'HP:0003698', (47, 60))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('tumor', 'Disease', (406, 411))	('signaling', 'biological_process', 'GO:0023052', ('129', '138'))	('mutant', 'Var', (399, 405))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (406, 412))	('signaling', 'biological_process', 'GO:0023052', ('338', '347'))
27451	31063758	We recently reported that in a liver-specific Nf2 knockout model, Nf2-loss-induced activation of Rac1 elevates cellular ROS levels, which activates p53-mediated DNA damage response, limiting the proliferation of Nf2 mutant liver epithelial cells.	('Nf2', 'Gene', (66, 69))	('p53-mediated DNA damage response', 'biological_process', 'GO:0030330', ('148', '180'))	('Nf2', 'Gene', '4771', (66, 69))	('Rac1', 'Gene', '5879', (97, 101))	('activation', 'PosReg', (83, 93))	('elevates cellular ROS levels', 'Phenotype', 'HP:0025464', (102, 130))	('mutant', 'Var', (216, 222))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('activates', 'PosReg', (138, 147))	('proliferation', 'CPA', (195, 208))	('limiting', 'NegReg', (182, 190))	('p53', 'Gene', '7157', (148, 151))	('DNA', 'cellular_component', 'GO:0005574', ('161', '164'))	('cellular ROS levels', 'MPA', (111, 130))	('elevates', 'PosReg', (102, 110))	('Nf2', 'Gene', '4771', (46, 49))	('Rac1', 'Gene', (97, 101))	('Nf2', 'Gene', (46, 49))	('p53', 'Gene', (148, 151))	('Nf2', 'Gene', '4771', (212, 215))	('Nf2', 'Gene', (212, 215))
27452	31063758	Our current study showed YAP/TAZ depletion increases mitochondrial respiration and further exacerbates oxidative stress, rendering NF2 mutant tumor cells even more susceptible to nutrient-stress-induced cell death.	('more', 'PosReg', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('respiration', 'biological_process', 'GO:0007585', ('67', '78'))	('tumor', 'Disease', (142, 147))	('mutant', 'Var', (135, 141))	('exacerbates', 'PosReg', (91, 102))	('NF2', 'Gene', (131, 134))	('respiration', 'biological_process', 'GO:0045333', ('67', '78'))	('cell death', 'biological_process', 'GO:0008219', ('203', '213'))	('increases', 'PosReg', (43, 52))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('mitochondrial respiration', 'MPA', (53, 78))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('oxidative stress', 'MPA', (103, 119))
27453	31063758	In contrast to the differential sensitivities to nutrient stress, we find that NF2 mutant cells respond similarly to hypoxia in the presence or absence of YAP/TAZ.	('hypoxia', 'Disease', (117, 124))	('NF2', 'Gene', (79, 82))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('mutant', 'Var', (83, 89))
27455	31063758	Given that NF2 loss leads to constitutive activation of YAP/TAZ, it would be interesting in future studies to determine whether matrix stiffness would influence how NF2 mutant tumor cells respond to YAP/TAZ inhibition.	('NF2', 'Gene', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('NF2', 'Gene', (165, 168))	('tumor', 'Disease', (176, 181))	('loss', 'NegReg', (15, 19))	('respond to YAP/TAZ inhibition', 'MPA', (188, 217))	('activation', 'PosReg', (42, 52))	('constitutive', 'MPA', (29, 41))	('mutant', 'Var', (169, 175))	('YAP/TAZ', 'MPA', (56, 63))	('influence', 'Reg', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
27456	31063758	Here we show that lysosomes also act as important signaling hubs, which by modulating the cytosolic calcium and pH levels, control the activity of a cAMP-PKA/EPACRAF-MEK-ERK signaling cascade that allows NF2 mutant cells to survive the loss of YAP/TAZ.	('calcium', 'Chemical', 'MESH:D002118', (100, 107))	('ERK', 'Gene', '5594', (170, 173))	('signaling', 'biological_process', 'GO:0023052', ('50', '59'))	('signaling cascade', 'biological_process', 'GO:0007165', ('174', '191'))	('cytosolic', 'MPA', (90, 99))	('ERK', 'molecular_function', 'GO:0004707', ('170', '173'))	('ERK', 'Gene', (170, 173))	('mutant', 'Var', (208, 214))	('activity', 'MPA', (135, 143))	('NF2', 'Gene', (204, 207))	('MEK', 'Gene', (166, 169))	('MEK', 'Gene', '5609', (166, 169))	('cAMP', 'Gene', '820', (149, 153))	('PKA', 'molecular_function', 'GO:0004691', ('154', '157'))	('PKA', 'cellular_component', 'GO:0005952', ('154', '157'))	('cAMP', 'Gene', (149, 153))
27464	31063758	YAP upregulation was previously reported to mediate resistance to RAF and MEK inhibitors in BRAF and KRAS mutant tumors.	('MEK', 'Gene', '5609', (74, 77))	('RAF', 'Gene', (66, 69))	('YAP', 'Gene', (0, 3))	('mutant', 'Var', (106, 112))	('tumors', 'Disease', (113, 119))	('BRAF', 'Gene', '673', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('KRAS', 'Gene', (101, 105))	('BRAF', 'Gene', (92, 96))	('RAF', 'Gene', '22882', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('RAF', 'Gene', (93, 96))	('KRAS', 'Gene', '3845', (101, 105))	('RAF', 'Gene', '22882', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('upregulation', 'PosReg', (4, 16))	('MEK', 'Gene', (74, 77))
27465	31063758	Here we show that a reciprocal lysosome-mediated noncanonical activation of RAF-MEK-ERK activation allows NF2 mutant tumor cells to survive YAP/TAZ inhibition, revealing that inhibition of YAP/TAZ and the RAF-MEK-ERK pathway also synergize in suppressing the growth of NF2 mutant tumor cells in vitro and in vivo.	('lysosome', 'cellular_component', 'GO:0005764', ('31', '39'))	('RAF', 'Gene', (76, 79))	('ERK', 'Gene', (84, 87))	('MEK', 'Gene', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('suppressing', 'NegReg', (243, 254))	('MEK', 'Gene', '5609', (209, 212))	('NF2', 'Gene', (269, 272))	('ERK', 'Gene', '5594', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('RAF', 'Gene', '22882', (205, 208))	('tumor', 'Disease', (280, 285))	('ERK', 'molecular_function', 'GO:0004707', ('84', '87'))	('MEK', 'Gene', (209, 212))	('ERK', 'molecular_function', 'GO:0004707', ('213', '216'))	('mutant', 'Var', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('RAF', 'Gene', (205, 208))	('ERK', 'Gene', (213, 216))	('ERK', 'Gene', '5594', (84, 87))	('RAF', 'Gene', '22882', (76, 79))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('mutant', 'Var', (273, 279))	('MEK', 'Gene', '5609', (80, 83))	('NF2', 'Gene', (106, 109))	('growth', 'MPA', (259, 265))
27466	31063758	This finding is highly significant, because it predicts that co-targeting of these two pathways could significantly improve the treatment outcomes of NF2 mutant tumors.	('treatment outcomes', 'CPA', (128, 146))	('improve', 'PosReg', (116, 123))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NF2', 'Gene', (150, 153))	('mutant', 'Var', (154, 160))
27468	31063758	Moreover, recent breakthroughs in exosome-mediated delivery of siRNA could potentially be utilized to silence YAP/TAZ in NF2 mutant tumors.	('exosome-mediated', 'biological_process', 'GO:0099156', ('34', '50'))	('exosome', 'cellular_component', 'GO:0070062', ('34', '41'))	('mutant', 'Var', (125, 131))	('silence', 'NegReg', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NF2', 'Gene', (121, 124))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('YAP/TAZ', 'MPA', (110, 117))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
27488	31063758	Successful YAP and TAZ knockdown in shY/T lines was confirmed via western blot and qRT-PCR analyses following 3-4 days of Dox treatment.	('Dox', 'Chemical', 'MESH:D004318', (122, 125))	('YAP', 'Gene', (11, 14))	('knockdown', 'Var', (23, 32))	('TAZ', 'Gene', (19, 22))
27489	31063758	To allow BLI imaging, Ctrl and shY/T SN12C cells were further infected with pHAGE-GFP-luciferase virus (Addgene plasmid #46793) produced in HEK293T as described above and sorted by flow cytometry to enrich for GFP+ cells.	('infected', 'Disease', 'MESH:D007239', (62, 70))	('SN12C', 'CellLine', 'CVCL:1705', (37, 42))	('HEK293T', 'CellLine', 'CVCL:0063', (140, 147))	('infected', 'Disease', (62, 70))	('HEK293T', 'Var', (140, 147))
27501	31063758	Unstained slides were deparaffinized, rehydrated, and heated in antigen retrieval buffer (IHC-Tek  Epitope Retrieval Solution, IHC World LLC, Woodstock, MD or TRIS solution (10mM Tris Base, 1mM EDTA Solution, 0.05% Tween 20, pH 9.0)) for 30 min at 95 C. Ki67 (1:200, #RM-9106, ThermoFisher Scientific), GLUT1 (1:5000, #07-1401, Millipore Sigma), PIMO (Hypoxyprobe, 1:500, #HP1, Hypoxyprobe, Inc.) and LAMP1 (1:200, #9091s, CST) stained tissues received IHC-Tek  antigen retrieval buffer and YAP (1: 25, #4912s, Cell signaling Technology, CST, Danvers, MA), TAZ (1:200, #4883s, CST), and pH2AX (1:100, #9718s, CST) received TRIS antigen retrieval solution.	('1:200', 'Var', (562, 567))	('Tek', 'Gene', (94, 97))	('HP1', 'Gene', (373, 376))	('GLUT1', 'Gene', '6513', (303, 308))	('CST', 'Gene', '106478911', (609, 612))	('H2AX', 'Gene', (588, 592))	('Tek', 'Gene', '7010', (94, 97))	('CST', 'Gene', (423, 426))	('LAMP1', 'Gene', (401, 406))	('CST', 'Gene', '106478911', (538, 541))	('CST', 'Gene', '106478911', (577, 580))	('signaling', 'biological_process', 'GO:0023052', ('516', '525'))	('H2AX', 'Gene', '3014', (588, 592))	('HP1', 'Gene', '23468', (373, 376))	('Tek', 'Gene', (457, 460))	('CST', 'Gene', (609, 612))	('GLUT1', 'Gene', (303, 308))	('LLC', 'cellular_component', 'GO:0038045', ('137', '140'))	('Tween 20', 'Chemical', 'MESH:D011136', (215, 223))	('CST', 'Gene', (538, 541))	('paraffin', 'Chemical', 'MESH:D010232', (24, 32))	('CST', 'Gene', (577, 580))	('Tek', 'Gene', '7010', (457, 460))	('LAMP1', 'Gene', '3916', (401, 406))	('CST', 'Gene', '106478911', (423, 426))
27562	31063758	YAP/TAZ promote glycolysis and NF2 tumor growth via transcription and PI3K AKT signaling YAP/TAZ suppress mitochondrial respiratory capacity and ROS buildup in NF2 mutant cells Lysosome biogenesis promotes compensatory MAPK activation in YAP/TAZ-depleted cells YAP/TAZ depletion with MEK inhibition results in a durable suppression of NF2 tumors	('mitochondrial respiratory capacity', 'MPA', (106, 140))	('tumor', 'Disease', (339, 344))	('MAPK', 'molecular_function', 'GO:0004707', ('219', '223'))	('glycolysis', 'biological_process', 'GO:0006096', ('16', '26'))	('MAPK', 'Gene', (219, 223))	('NF2', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('Lysosome', 'cellular_component', 'GO:0005764', ('177', '185'))	('AKT signaling', 'biological_process', 'GO:0043491', ('75', '88'))	('MEK', 'Gene', (284, 287))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('suppress', 'NegReg', (97, 105))	('tumor', 'Disease', (35, 40))	('Lysosome biogenesis', 'MPA', (177, 196))	('AKT', 'Gene', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumors', 'Disease', (339, 345))	('MAPK activation', 'biological_process', 'GO:0000187', ('219', '234'))	('ROS', 'MPA', (145, 148))	('mutant', 'Var', (164, 170))	('suppression', 'NegReg', (320, 331))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('AKT', 'Gene', '207', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ROS', 'Chemical', 'MESH:D017382', (145, 148))	('transcription', 'biological_process', 'GO:0006351', ('52', '65'))	('PI3K', 'molecular_function', 'GO:0016303', ('70', '74'))	('NF2', 'Gene', (335, 338))	('MEK', 'Gene', '5609', (284, 287))
27568	31959887	The quantitation of particular combinations of ATG1, ATG16L1, ATG5, LC3B and p62, all of which measure the basal level of autophagy, were able to discriminate among normal tissue, crRCC and ccRCC, suggesting that the basal level of autophagy would be a potentially useful parameter for RCC discrimination.	('RCC', 'Disease', 'MESH:D002292', (286, 289))	('LC3B', 'Gene', '81631', (68, 72))	('ATG16L1', 'Gene', '55054', (53, 60))	('ATG1', 'Gene', '8408', (53, 57))	('p62', 'Gene', '8878', (77, 80))	('ATG16L1', 'Gene', (53, 60))	('crRCC', 'Disease', 'MESH:D002292', (180, 185))	('autophagy', 'biological_process', 'GO:0016236', ('232', '241'))	('p62', 'Gene', (77, 80))	('discriminate', 'Reg', (146, 158))	('ATG1', 'Gene', (47, 51))	('RCC', 'Disease', (192, 195))	('autophagy', 'biological_process', 'GO:0006914', ('232', '241'))	('ATG5', 'Gene', '9474', (62, 66))	('ATG1', 'Gene', (53, 57))	('autophagy', 'biological_process', 'GO:0016236', ('122', '131'))	('RCC', 'Disease', 'MESH:D002292', (192, 195))	('RCC', 'Disease', (182, 185))	('crRCC', 'Disease', (180, 185))	('RCC', 'Disease', (286, 289))	('combinations', 'Var', (31, 43))	('ATG5', 'Gene', (62, 66))	('ATG1', 'Gene', '8408', (47, 51))	('autophagy', 'biological_process', 'GO:0006914', ('122', '131'))	('RCC', 'Disease', 'MESH:D002292', (182, 185))	('LC3B', 'Gene', (68, 72))
27580	31959887	In RCC with characteristic cytoplasmic inclusions composed of protein aggregates and peroxisomes, somatic mutations or high frequencies of genetic variations in ATG7, ATG5 and ATG10 were found to be associated with the formation of these inclusions, suggesting a possible defect in autophagy in these patients.	('ATG5', 'Gene', (167, 171))	('associated', 'Reg', (199, 209))	('ATG10', 'Gene', '83734', (176, 181))	('ATG7', 'Gene', '10533', (161, 165))	('patients', 'Species', '9606', (301, 309))	('RCC', 'Disease', (3, 6))	('genetic variations', 'Disease', 'MESH:D030342', (139, 157))	('ATG5', 'Gene', '9474', (167, 171))	('autophagy', 'biological_process', 'GO:0016236', ('282', '291'))	('autophagy', 'biological_process', 'GO:0006914', ('282', '291'))	('mutations', 'Var', (106, 115))	('ATG7', 'Gene', (161, 165))	('formation', 'biological_process', 'GO:0009058', ('219', '228'))	('genetic variations', 'Disease', (139, 157))	('RCC', 'Disease', 'MESH:D002292', (3, 6))	('ATG10', 'Gene', (176, 181))	('protein', 'cellular_component', 'GO:0003675', ('62', '69'))
27650	31561459	Obesity-related alterations in the amounts and/or spectrum of adipokine release have been linked to metabolic disorders such as hyperlipidemia and type 2 diabetes and are increasingly recognized as a key factor linking obesity with cancer.	('metabolic disorders', 'Disease', (100, 119))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('obesity', 'Phenotype', 'HP:0001513', (219, 226))	('Obesity', 'Disease', 'MESH:D009765', (0, 7))	('linked', 'Reg', (90, 96))	('hyperlipidemia and type 2 diabetes', 'Disease', 'MESH:D003924', (128, 162))	('cancer', 'Disease', (232, 238))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (128, 142))	('alterations', 'Var', (16, 27))	('Obesity', 'Disease', (0, 7))	('Obesity', 'Phenotype', 'HP:0001513', (0, 7))	('amounts', 'MPA', (35, 42))	('obesity', 'Disease', 'MESH:D009765', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('metabolic disorders', 'Disease', 'MESH:D008659', (100, 119))	('obesity', 'Disease', (219, 226))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (147, 162))	('rat', 'Species', '10116', (20, 23))
27683	31561459	These results were validated in an in vivo xenograft model, where BALB/c nu/nu mice injected S.C. with OE21 human esophageal carcinoma cells along with CAMs had more infiltrated MSCs than those mice injected with OE21 cells alone.	('infiltrated MSCs', 'CPA', (166, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('OE21', 'Var', (103, 107))	('more', 'PosReg', (161, 165))	('mice', 'Species', '10090', (79, 83))	('esophageal carcinoma', 'Disease', (114, 134))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (114, 134))	('human', 'Species', '9606', (108, 113))	('rat', 'Species', '10116', (172, 175))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (114, 134))	('MSCs', 'molecular_function', 'GO:0043854', ('178', '182'))	('mice', 'Species', '10090', (194, 198))
27691	31561459	Conditioned media from CAMs, more so than conditioned media from ATMs and NTMs, stimulated migration and Matrigel invasion of OE21 cells, which could be partially blocked by chemerin neutralization, siRNA knockdown of chemerin or chemerin1, or pharmacological antagonism of chemerin1 with CCX832.	('stimulated', 'PosReg', (80, 90))	('rat', 'Species', '10116', (94, 97))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('NTM', 'Gene', (74, 77))	('knockdown', 'Var', (205, 214))	('migration', 'CPA', (91, 100))	('NTM', 'Gene', '50863', (74, 77))
27695	31561459	In the metaplasia-dysplasia-carcinoma sequence of Barrett's esophagus (BE) to high-grade dysplasia BE and esophageal carcinoma, a significant increase in myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) density was observed that coincided with increased expression of their respective chemotactic factors, macrophage inflammatory protein-3 alpha (MIP3alpha), and chemerin in the same regions.	('macrophage inflammatory protein-3 alpha', 'Gene', '6364', (324, 363))	('increase', 'PosReg', (142, 150))	('expression', 'MPA', (272, 282))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('mDC', 'Gene', (178, 181))	('metaplasia', 'biological_process', 'GO:0036074', ('7', '17'))	('mDC', 'Gene', '20299', (178, 181))	('BE', 'Phenotype', 'HP:0100580', (99, 101))	('MIP3alpha', 'Gene', '6364', (365, 374))	('dysplasia', 'Disease', (18, 27))	("Barrett's esophagus", 'Disease', (50, 69))	('BE', 'Disease', 'MESH:D001471', (99, 101))	('dysplasia', 'Disease', (89, 98))	('protein', 'cellular_component', 'GO:0003675', ('348', '355'))	('high-grade', 'Var', (78, 88))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (50, 69))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('myeloid dendritic', 'Disease', 'MESH:D007635', (154, 171))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('BE', 'Phenotype', 'HP:0100580', (71, 73))	('myeloid dendritic', 'Disease', (154, 171))	('metaplasia-dysplasia-carcinoma', 'Disease', (7, 37))	('metaplasia-dysplasia-carcinoma', 'Disease', 'MESH:D008679', (7, 37))	('dysplasia', 'Disease', 'MESH:D015792', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('BE', 'Disease', 'MESH:D001471', (71, 73))	('increased', 'PosReg', (262, 271))	('esophageal carcinoma', 'Disease', (106, 126))	('dysplasia', 'Disease', 'MESH:D015792', (89, 98))	('MIP', 'molecular_function', 'GO:0004243', ('365', '368'))	('MIP3alpha', 'Gene', (365, 374))	('macrophage inflammatory protein-3 alpha', 'Gene', (324, 363))
27729	31561459	While CCRL2 expression was detectable in several colorectal cell lines (SW480, SW620, LS174T, Caco2), siRNA-mediated knockdown of CCRL2 mRNA reduced proliferation, colony formation and migration only in LS174T cells.	('rat', 'Species', '10116', (156, 159))	('formation', 'biological_process', 'GO:0009058', ('171', '180'))	('reduced', 'NegReg', (141, 148))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('proliferation', 'CPA', (149, 162))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('rat', 'Species', '10116', (188, 191))	('knockdown', 'Var', (117, 126))	('colony formation', 'CPA', (164, 180))	('migration', 'CPA', (185, 194))	('CCRL2', 'Gene', (130, 135))	('CCRL2', 'Gene', (6, 11))
27744	31561459	Localized chemerin expression in melanoma has been demonstrated to decrease the presence of pDCs in the tumor microenvironment, ultimately inhibiting immune escape mechanisms.	('presence', 'MPA', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('decrease', 'NegReg', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('expression', 'Var', (19, 29))	('tumor', 'Disease', (104, 109))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('rat', 'Species', '10116', (58, 61))	('immune escape mechanisms', 'CPA', (150, 174))	('pDCs', 'Protein', (92, 96))	('inhibiting', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
27752	31561459	Similarly, mice injected hepatically with PVTT-1-Che cells exhibited reduced liver tumor foci development, a 1.3-fold increase in survival (54 days versus 41 days) compared to mice injected with control PVTT-1 cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('survival', 'CPA', (130, 138))	('reduced', 'NegReg', (69, 76))	('increase', 'PosReg', (118, 126))	('liver tumor', 'Disease', 'MESH:D008113', (77, 88))	('PVTT-1-Che', 'Var', (42, 52))	('men', 'Species', '9606', (101, 104))	('liver tumor', 'Disease', (77, 88))	('mice', 'Species', '10090', (11, 15))	('mice', 'Species', '10090', (176, 180))	('liver tumor', 'Phenotype', 'HP:0002896', (77, 88))
27780	31561459	detected no significant difference in recurrence-free survival or disease-free survival between patients classified with having low (<= 130.5 ng/mL) and high (> 130.5 ng/mL) serum chemerin concentration.	('> 130.5 ng/mL', 'Var', (159, 172))	('<= 130.5 ng/mL', 'Var', (133, 147))	('patients', 'Species', '9606', (96, 104))	('rat', 'Species', '10116', (196, 199))	('serum chemerin concentration', 'MPA', (174, 202))
27796	31561459	Interestingly, mice transplanted with human chemerin-expressing H295R tumors had higher serum concentrations of human chemerin but proportionally lower mouse serum chemerin suggesting a type of negative regulatory feedback mechanism.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('rat', 'Species', '10116', (101, 104))	('human', 'Species', '9606', (38, 43))	('higher', 'PosReg', (81, 87))	('H295R', 'Var', (64, 69))	('mouse', 'Species', '10090', (152, 157))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('lower', 'NegReg', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mouse serum chemerin', 'MPA', (152, 172))	('mice', 'Species', '10090', (15, 19))	('human', 'Species', '9606', (112, 117))	('serum concentrations of human chemerin', 'MPA', (88, 126))
27806	31561459	In further support of a direct tumor suppressive (rather than immune-mediated) effect of chemerin, H295R cells with stable expression of human chemerin had decreased colony formation and invasion in in vitro assays and formed smaller tumors when xenografted into the flanks immunodeficient T-cell deficient athymic nude and T, B, and NK-cell deficient and macrophage and dendritic cell-impaired NOD Scid gamma mice.	('colony formation', 'CPA', (166, 182))	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('chemerin', 'Gene', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('mice', 'Species', '10090', (410, 414))	('human', 'Species', '9606', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('H295R', 'Var', (99, 104))	('flanks immunodeficient T-cell deficient athymic nude', 'Disease', 'MESH:D021501', (267, 319))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('smaller', 'NegReg', (226, 233))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('decreased', 'NegReg', (156, 165))	('formation', 'biological_process', 'GO:0009058', ('173', '182'))	('N', 'Chemical', 'MESH:D009584', (334, 335))	('rat', 'Species', '10116', (50, 53))	('tumor', 'Disease', (31, 36))	('N', 'Chemical', 'MESH:D009584', (395, 396))	('tumors', 'Disease', (234, 240))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
27818	31561459	In the study by Krawczyk et al., foamy macrophages were histologically identified in 82% of pRCC tumors and the macrophages expressed cell surface markers CD689 and CD163 that are characteristic of the M2 anti-inflammatory phenotype.	('CD163', 'Var', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('foamy macrophages', 'Phenotype', 'HP:0003651', (33, 50))	('pRCC', 'Disease', 'MESH:D002292', (92, 96))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('pRCC', 'Disease', (92, 96))	('CD689', 'Var', (155, 160))	('pRCC', 'Phenotype', 'HP:0006766', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('cell surface', 'cellular_component', 'GO:0009986', ('134', '146'))
27851	31561459	Depletion experiments indicated a critical role of NK cells and CD8+ T cells in the tumor suppression response to chemerin, while the depletion of CD4+ T regulatory cells enhanced tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('enhanced', 'PosReg', (171, 179))	('CD8', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('CD4', 'Gene', '920', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('depletion', 'Var', (134, 143))	('CD8', 'Gene', '925', (64, 67))	('tumor', 'Disease', (180, 185))	('men', 'Species', '9606', (16, 19))	('tumor', 'Disease', (84, 89))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('CD4', 'Gene', (147, 150))
27892	31561459	However, while serum chemerin concentrations increased with Gleason score, the opposite effect was observed for chemerin expression in prostate tumor tissue.	('prostate tumor', 'Phenotype', 'HP:0100787', (135, 149))	('increased', 'PosReg', (45, 54))	('rat', 'Species', '10116', (37, 40))	('prostate tumor', 'Disease', 'MESH:D011471', (135, 149))	('serum chemerin concentrations', 'MPA', (15, 44))	('Gleason', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('prostate tumor', 'Disease', (135, 149))
27985	30755832	Genetic alteration of histone lysine methyltransferases and their significance in renal cell carcinoma Histone lysine methyltransferases (HMTs), a category of enzymes, play essential roles in regulating transcription, cellular differentiation, and chromatin construction.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('HMT', 'Gene', (138, 141))	('transcription', 'biological_process', 'GO:0006351', ('203', '216'))	('Genetic alteration', 'Var', (0, 18))	('HMT', 'Gene', '3176', (138, 141))	('renal cell carcinoma', 'Disease', (82, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('248', '257'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 102))
27987	30755832	We conducted an integrative analysis of 50 HMTs in RCC and discovered the internal relations among copy number alterations (CNAs), expressive abundance, mutations, and clinical outcome.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('expressive', 'MPA', (131, 141))	('copy', 'Var', (99, 103))	('HMT', 'Gene', (43, 46))	('HMT', 'Gene', '3176', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
27988	30755832	We confirmed 12 HMTs with the highest frequency of genetic alterations, including seven HMTs with high-level amplification, two HMTs with somatic mutation, and three HMTs with putative homozygous deletion.	('HMT', 'Gene', (128, 131))	('HMT', 'Gene', (166, 169))	('HMT', 'Gene', (16, 19))	('amp', 'Chemical', 'MESH:D000249', (109, 112))	('HMT', 'Gene', '3176', (128, 131))	('HMT', 'Gene', (88, 91))	('HMT', 'Gene', '3176', (166, 169))	('HMT', 'Gene', '3176', (16, 19))	('HMT', 'Gene', '3176', (88, 91))	('genetic alterations', 'Var', (51, 70))
27991	30755832	Systematic analysis identified six HMTs (ASH1L, PRDM6, NSD1, EZH2, WHSC1L1, SETD2) which were dysregulated by genetic alterations as candidate therapeutic targets.	('SETD2', 'Gene', (76, 81))	('HMT', 'Gene', (35, 38))	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('WHSC1L1', 'Gene', '54904', (67, 74))	('NSD1', 'Gene', (55, 59))	('alterations', 'Var', (118, 129))	('HMT', 'Gene', '3176', (35, 38))	('ASH1L', 'Gene', '55870', (41, 46))	('WHSC1L1', 'Gene', (67, 74))	('ASH1L', 'Gene', (41, 46))	('NSD1', 'Gene', '64324', (55, 59))	('PRDM6', 'Gene', '93166', (48, 53))	('PRDM6', 'Gene', (48, 53))	('SETD2', 'Gene', '29072', (76, 81))
27992	30755832	In summary, our findings strongly evidenced that genetic alteration of HMTs may play an important role in generation and development of RCC, which lays a solid foundation for the mechanism for further research in the future.	('HMT', 'Gene', (71, 74))	('HMT', 'Gene', '3176', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('genetic alteration', 'Var', (49, 67))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))	('play', 'Reg', (80, 84))
27999	30755832	Recent researches have shown that HMT dysregulation leads to uncontrollable histone methylation pathways and contributes to the pathogenesis of many human cancers, including RCC.	('uncontrollable', 'MPA', (61, 75))	('contributes', 'Reg', (109, 120))	('HMT', 'Gene', '3176', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('histone methylation', 'biological_process', 'GO:0016571', ('76', '95'))	('human', 'Species', '9606', (149, 154))	('dysregulation', 'Var', (38, 51))	('leads to', 'Reg', (52, 60))	('RCC', 'Disease', (174, 177))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('histone', 'Pathway', (76, 83))	('pathogenesis', 'biological_process', 'GO:0009405', ('128', '140'))	('cancers', 'Disease', (155, 162))	('HMT', 'Gene', (34, 37))
28000	30755832	Several studies indicated that the methyltransferase gene SETD2 was frequently mutated during epigenetic progress in RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('epigenetic progress', 'Var', (94, 113))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('SETD2', 'Gene', '29072', (58, 63))	('SETD2', 'Gene', (58, 63))
28003	30755832	Increasing evidences showed that genetic alterations of several HMTs play crucial roles in oncogenesis.	('oncogenesis', 'CPA', (91, 102))	('roles', 'Reg', (82, 87))	('genetic alterations', 'Var', (33, 52))	('HMT', 'Gene', (64, 67))	('oncogenesis', 'biological_process', 'GO:0007048', ('91', '102'))	('HMT', 'Gene', '3176', (64, 67))
28005	30755832	Furthermore, the clinical relevance of genetic alterations in each HMT in RCC remains unclear.	('HMT', 'Gene', (67, 70))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('genetic alterations', 'Var', (39, 58))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('HMT', 'Gene', '3176', (67, 70))
28009	30755832	In addition, 78 samples of Tokyo university downloaded from cBioportal were added to persuasively compare the tumor stage and overall survival between 62 SET-domain mutated patients and 16 non-SET-domain mutated patients.	('overall survival', 'CPA', (126, 142))	('patients', 'Species', '9606', (173, 181))	('SET-domain mutated', 'Var', (154, 172))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('patients', 'Species', '9606', (212, 220))	('tumor', 'Disease', (110, 115))	('amp', 'Chemical', 'MESH:D000249', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
28026	30755832	The shRNA plasmids for SETD2 and EZH2 knockdown were constructed from pSicoR (#11579; Addgene, Watertown, MA, USA) with target sequences of shSETD2: TAGTACACCAAGACTCCAG, and shEZH2: CCAACACAAGTCATCCCATTA.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (23, 28))	('EZH2', 'Gene', '2146', (176, 180))	('EZH2', 'Gene', '2146', (33, 37))	('SETD2', 'Gene', '29072', (142, 147))	('EZH2', 'Gene', (176, 180))	('knockdown', 'Var', (38, 47))	('EZH2', 'Gene', (33, 37))	('SETD2', 'Gene', (142, 147))
28028	30755832	Copy number alteration and somatic mutations are crucial mechanisms for oncogenesis or inactivating tumor suppressor genes in the occurrence and development of cancer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('100', '116'))	('inactivating', 'Var', (87, 99))	('Copy number alteration', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', (100, 105))	('oncogenesis', 'biological_process', 'GO:0007048', ('72', '83'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('100', '116'))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
28029	30755832	We hypothesized that genetic alterations of HMTs play significant roles in the development and progression of RCC.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('HMT', 'Gene', (44, 47))	('HMT', 'Gene', '3176', (44, 47))	('roles', 'Reg', (66, 71))	('genetic alterations', 'Var', (21, 40))
28032	30755832	We found a different pattern of altered copy number and mutation of HMTs in RCC.	('HMT', 'Gene', '3176', (68, 71))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('copy number', 'MPA', (40, 51))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('altered', 'Reg', (32, 39))	('HMT', 'Gene', (68, 71))	('mutation', 'Var', (56, 64))
28034	30755832	Three HMT genes, SETD2, SETD5, and SETMAR, showed homozygous deletion in more than 10% ccRCC samples.	('HMT', 'Gene', '3176', (6, 9))	('SETD5', 'Gene', '55209', (24, 29))	('SETMAR', 'Gene', (35, 41))	('deletion', 'Var', (61, 69))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('SETD2', 'Gene', '29072', (17, 22))	('SETMAR', 'Gene', '6419', (35, 41))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (87, 92))	('SETD2', 'Gene', (17, 22))	('SETD5', 'Gene', (24, 29))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('HMT', 'Gene', (6, 9))
28037	30755832	Several studies revealed that SETD2 was frequently mutated in ccRCC and SETD2-mutated signal pathway played a vital role in the process of oncogenesis.	('SETD2', 'Gene', '29072', (30, 35))	('SETD2', 'Gene', (30, 35))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('SETD2', 'Gene', '29072', (72, 77))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('oncogenesis', 'biological_process', 'GO:0007048', ('139', '150'))	('SETD2', 'Gene', (72, 77))	('mutated', 'Var', (51, 58))
28039	30755832	Furthermore, HMTs showed different frequencies of CNA and mutation in different subtypes of RCC.	('RCC', 'Disease', (92, 95))	('mutation', 'Var', (58, 66))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('HMT', 'Gene', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('HMT', 'Gene', '3176', (13, 16))
28043	30755832	Additionally, in 213 ccRCC, 113 pRCC, and 65 chRCC, of the most commonly mutated HMTs, SETD2, and KMT2C were most frequently mutated in ccRCC and pRCC subtypes, whereas SETD2 was mutated in less than 1.54% of tumor samples and KMT2C did not exhibit mutation in chRCC (Fig.	('KMT2C', 'Gene', '58508', (98, 103))	('KMT2C', 'Gene', (98, 103))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('RCC', 'Disease', (138, 141))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('SETD2', 'Gene', (169, 174))	('tumor', 'Disease', (209, 214))	('ccRCC', 'Phenotype', 'HP:0006770', (136, 141))	('mutated', 'Var', (125, 132))	('amp', 'Chemical', 'MESH:D000249', (216, 219))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('SETD2', 'Gene', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('SETD2', 'Gene', '29072', (169, 174))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('RCC', 'Disease', (263, 266))	('RCC', 'Disease', (33, 36))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('SETD2', 'Gene', '29072', (87, 92))	('HMT', 'Gene', '3176', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (21, 26))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('RCC', 'Disease', (23, 26))	('HMT', 'Gene', (81, 84))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('KMT2C', 'Gene', '58508', (227, 232))	('KMT2C', 'Gene', (227, 232))
28044	30755832	The above data indicates that the subtype of ccRCC has a higher CNA and somatic mutation frequency in several HMTs, including amplification of NSD1 and PRDM6, homozygous deletion of SETD2, SETD5, and SETMAR, and mutation of KMT2C and SETD2.	('PRDM6', 'Gene', (152, 157))	('SETD2', 'Gene', '29072', (234, 239))	('NSD1', 'Gene', '64324', (143, 147))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('HMT', 'Gene', (110, 113))	('HMT', 'Gene', '3176', (110, 113))	('KMT2C', 'Gene', '58508', (224, 229))	('KMT2C', 'Gene', (224, 229))	('SETD5', 'Gene', (189, 194))	('SETMAR', 'Gene', '6419', (200, 206))	('SETD2', 'Gene', (182, 187))	('NSD1', 'Gene', (143, 147))	('SETD5', 'Gene', '55209', (189, 194))	('PRDM6', 'Gene', '93166', (152, 157))	('higher', 'PosReg', (57, 63))	('SETMAR', 'Gene', (200, 206))	('mutation', 'Var', (212, 220))	('amp', 'Chemical', 'MESH:D000249', (126, 129))	('amplification', 'Var', (126, 139))	('SETD2', 'Gene', (234, 239))	('SETD2', 'Gene', '29072', (182, 187))	('ccRCC', 'Phenotype', 'HP:0006770', (45, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))
28057	30755832	Results showed that a total of 78 SETD2 mutations were found whereas 14 mutations were excluded because their data were untested.	('mutations', 'Var', (40, 49))	('SETD2', 'Gene', (34, 39))	('SETD2', 'Gene', '29072', (34, 39))
28058	30755832	In addition, 24 KMT2C gene mutations were identified, including 10 missense mutations, five nonsense mutations, three frameshift deletions, two splice, and four other mutations (Fig.	('KMT2C', 'Gene', (16, 21))	('frameshift deletions', 'Var', (118, 138))	('missense mutations', 'Var', (67, 85))	('KMT2C', 'Gene', '58508', (16, 21))
28059	30755832	A mutation map was performed to display the distribution of SETD2 and KMT2C mutations (Fig.	('mutations', 'Var', (76, 85))	('SETD2', 'Gene', '29072', (60, 65))	('SETD2', 'Gene', (60, 65))	('KMT2C', 'Gene', '58508', (70, 75))	('KMT2C', 'Gene', (70, 75))
28060	30755832	By systematic analysis of the mutation distribution, we found that SETD2 mutations were more likely to occur at SET domain area.	('SETD2', 'Gene', '29072', (67, 72))	('SETD2', 'Gene', (67, 72))	('mutations', 'Var', (73, 82))	('occur', 'Reg', (103, 108))
28061	30755832	Taking account of the crucial function of SET domain in SETD2, we predicted that mutations at the SET domain might result in the loss of methyltransferases features of SETD2 and poor prognosis of ccRCC patients.	('SETD2', 'Gene', (56, 61))	('methyltransferases', 'Enzyme', (137, 155))	('loss', 'NegReg', (129, 133))	('SETD2', 'Gene', '29072', (168, 173))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('patients', 'Species', '9606', (202, 210))	('RCC', 'Disease', (198, 201))	('SETD2', 'Gene', '29072', (56, 61))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('SETD2', 'Gene', (168, 173))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('mutations', 'Var', (81, 90))
28065	30755832	First of all, samples were divided into the following three groups for each HMT: amp/gain (high-level amplification/low-level gain), diploid, and deletion.	('deletion', 'Var', (146, 154))	('amp', 'Chemical', 'MESH:D000249', (15, 18))	('HMT', 'Gene', (76, 79))	('amp', 'Chemical', 'MESH:D000249', (81, 84))	('amp', 'Chemical', 'MESH:D000249', (102, 105))	('HMT', 'Gene', '3176', (76, 79))	('diploid', 'Var', (133, 140))
28066	30755832	For six HMTs (EZH2, NSD1, PRDM6, SETD2, SETD5, and SETMAR), copy number amp/gain and deletion were significantly related to poorer survival in RCC patients (P < 0.05).	('survival', 'MPA', (131, 139))	('HMT', 'Gene', (8, 11))	('PRDM6', 'Gene', (26, 31))	('HMT', 'Gene', '3176', (8, 11))	('poorer', 'NegReg', (124, 130))	('NSD1', 'Gene', (20, 24))	('SETD2', 'Gene', (33, 38))	('patients', 'Species', '9606', (147, 155))	('SETD2', 'Gene', '29072', (33, 38))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('EZH2', 'Gene', (14, 18))	('SETD5', 'Gene', (40, 45))	('EZH2', 'Gene', '2146', (14, 18))	('SETMAR', 'Gene', '6419', (51, 57))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('deletion', 'Var', (85, 93))	('NSD1', 'Gene', '64324', (20, 24))	('RCC', 'Disease', (143, 146))	('SETD5', 'Gene', '55209', (40, 45))	('amp', 'Chemical', 'MESH:D000249', (72, 75))	('SETMAR', 'Gene', (51, 57))	('PRDM6', 'Gene', '93166', (26, 31))	('copy number amp/gain', 'Var', (60, 80))
28067	30755832	Deletions of KMT2C and PRDM6 were related to shorter survival, however, only amp/gain of EZH2 and PRDM14 was more likely related to poorer survival.	('EZH2', 'Gene', '2146', (89, 93))	('amp', 'Chemical', 'MESH:D000249', (77, 80))	('shorter', 'NegReg', (45, 52))	('EZH2', 'Gene', (89, 93))	('PRDM14', 'Gene', (98, 104))	('PRDM6', 'Gene', (23, 28))	('PRDM6', 'Gene', '93166', (23, 28))	('PRDM14', 'Gene', '63978', (98, 104))	('KMT2C', 'Gene', '58508', (13, 18))	('KMT2C', 'Gene', (13, 18))	('Deletions', 'Var', (0, 9))
28068	30755832	More importantly, deletion of NSD1 was significantly related to poorer survival; amp/gain of NSD1 was significantly related to longer survival, compared with diploid or deletion groups (Fig.	('NSD1', 'Gene', (30, 34))	('NSD1', 'Gene', '64324', (93, 97))	('amp', 'Chemical', 'MESH:D000249', (81, 84))	('NSD1', 'Gene', (93, 97))	('longer', 'PosReg', (127, 133))	('amp/gain', 'Var', (81, 89))	('NSD1', 'Gene', '64324', (30, 34))	('deletion', 'Var', (18, 26))
28072	30755832	Results indicated that amp/gain of ASH1L had a hazard radio (HR), a ratio of death probabilities, of 1.533 compared with non-amp/gain of ASH1L in RCC patients.	('ASH1L', 'Gene', (35, 40))	('ASH1L', 'Gene', '55870', (35, 40))	('amp', 'Chemical', 'MESH:D000249', (125, 128))	('amp/gain', 'Var', (23, 31))	('death', 'Disease', 'MESH:D003643', (77, 82))	('death', 'Disease', (77, 82))	('RCC', 'Disease', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('patients', 'Species', '9606', (150, 158))	('ASH1L', 'Gene', (137, 142))	('ASH1L', 'Gene', '55870', (137, 142))
28073	30755832	In addition, deletion of PRDM8 was significantly associated with shorter survival (HR = 1.516, P < 0.05) in RCC patients.	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('survival', 'MPA', (73, 81))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('shorter', 'NegReg', (65, 72))	('patients', 'Species', '9606', (112, 120))	('deletion', 'Var', (13, 21))	('PRDM8', 'Gene', '56978', (25, 30))	('PRDM8', 'Gene', (25, 30))
28076	30755832	Also, amp/gain of PRDM6 (HR = 0.703), PRDM9 (HR = 0.662), PRDM7 (HR = 0.640), SETD1A (HR = 0.638), NSD1 (HR = 0.598), and DOT1L (HR = 0.592) was negative correlated with shorter survival in RCC patients (P < 0.05).	('PRDM9', 'Gene', '56979', (38, 43))	('PRDM7', 'Gene', '11105', (58, 63))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('PRDM7', 'Gene', (58, 63))	('DOT1L', 'Gene', (122, 127))	('amp/gain', 'Var', (6, 14))	('shorter', 'NegReg', (170, 177))	('SETD1A', 'Gene', (78, 84))	('NSD1', 'Gene', (99, 103))	('patients', 'Species', '9606', (194, 202))	('negative', 'NegReg', (145, 153))	('DOT1L', 'Gene', '84444', (122, 127))	('PRDM6', 'Gene', '93166', (18, 23))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('NSD1', 'Gene', '64324', (99, 103))	('SETD1A', 'Gene', '9739', (78, 84))	('amp', 'Chemical', 'MESH:D000249', (6, 9))	('PRDM9', 'Gene', (38, 43))	('PRDM6', 'Gene', (18, 23))
28089	30755832	Assays showed a higher proliferative ability in 786-O cell line with SETD2 knockdown.	('higher', 'PosReg', (16, 22))	('proliferative ability in 786-O cell line', 'CPA', (23, 63))	('knockdown', 'Var', (75, 84))	('SETD2', 'Gene', '29072', (69, 74))	('SETD2', 'Gene', (69, 74))
28090	30755832	However, the migration and invasion ability showed no significant differences with or without SETD2 knockdown.	('knockdown', 'Var', (100, 109))	('SETD2', 'Gene', (94, 99))	('invasion ability', 'CPA', (27, 43))	('migration', 'CPA', (13, 22))	('SETD2', 'Gene', '29072', (94, 99))
28091	30755832	Meanwhile EZH2 knockdown reduced the ability of cell proliferation, migration, and invasion significantly.	('reduced', 'NegReg', (25, 32))	('knockdown', 'Var', (15, 24))	('EZH2', 'Gene', '2146', (10, 14))	('EZH2', 'Gene', (10, 14))	('invasion', 'CPA', (83, 91))	('migration', 'CPA', (68, 77))	('cell proliferation', 'biological_process', 'GO:0008283', ('48', '66'))
28095	30755832	Oncogenic alterations of HMTs, including amplification, homozygous deletion, and mutation, were associated with various human cancers, including RCC.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (120, 125))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RCC', 'Disease', (145, 148))	('HMT', 'Gene', '3176', (25, 28))	('associated', 'Reg', (96, 106))	('mutation', 'Var', (81, 89))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('amplification', 'Var', (41, 54))	('amp', 'Chemical', 'MESH:D000249', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('homozygous deletion', 'Var', (56, 75))	('HMT', 'Gene', (25, 28))
28096	30755832	EZH2 is overexpressed and mutated frequently in RCC and other types of tumors, contributing to tumorigenic potential of cancer.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('cancer', 'Disease', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('contributing', 'Reg', (79, 91))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutated', 'Var', (26, 33))	('tumor', 'Disease', (71, 76))	('RCC', 'Disease', (48, 51))	('tumor', 'Disease', (95, 100))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))
28099	30755832	Taking chromosome 3p as an illustration, ccRCC was characterized by a high frequency of allelic deletion or loss of heterozygosity on chromosome 3p, causing biallelic mutation or promoter hypermethylation of von Hippel-Lindau (VHL) gene.	('VHL', 'Gene', '7428', (227, 230))	('chromosome', 'cellular_component', 'GO:0005694', ('7', '17'))	('promoter hypermethylation', 'MPA', (179, 204))	('causing', 'Reg', (149, 156))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('von Hippel-Lindau', 'Gene', (208, 225))	('allelic deletion', 'Var', (88, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (41, 46))	('chromosome', 'cellular_component', 'GO:0005694', ('134', '144'))	('VHL', 'Gene', (227, 230))	('von Hippel-Lindau', 'Gene', '7428', (208, 225))	('biallelic', 'MPA', (157, 166))
28101	30755832	Several researches explored their relationship between methylation of VHL promoter, SETD2 mutation and CNA of other genes located at 3p, including SETD5 and BAP1.	('VHL', 'Gene', (70, 73))	('methylation', 'biological_process', 'GO:0032259', ('55', '66'))	('SETD2', 'Gene', (84, 89))	('SETD5', 'Gene', '55209', (147, 152))	('BAP1', 'Gene', (157, 161))	('VHL', 'Gene', '7428', (70, 73))	('BAP1', 'Gene', '8314', (157, 161))	('mutation', 'Var', (90, 98))	('SETD5', 'Gene', (147, 152))	('SETD2', 'Gene', '29072', (84, 89))
28104	30755832	SETD2 was most mutated in ccRCC with highest frequency rate of 11.51%.	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (26, 31))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('mutated', 'Var', (15, 22))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
28106	30755832	Clinical stage of patients with SETD2 mutations occurred in SET domain region were often higher than those of patients whose SETD2 mutations did not located in SET domain.	('SETD2', 'Gene', '29072', (32, 37))	('Clinical stage', 'CPA', (0, 14))	('SETD2', 'Gene', (32, 37))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (18, 26))	('SETD2', 'Gene', '29072', (125, 130))	('mutations', 'Var', (38, 47))	('patients', 'Species', '9606', (110, 118))	('SETD2', 'Gene', (125, 130))
28107	30755832	Taking our results of the GO enrichment analysis into account, among all the predefined Hallmarks gene sets, DNA repair, E2F targets, G2M checkpoint, and mitotic spindle were found to be significantly associated with SET domain mutation, suggesting that SET domain mutation may be involved in ccRCC development and progression through the above cancer-associated biological processes.	('mitotic spindle', 'cellular_component', 'GO:0072686', ('154', '169'))	('DNA', 'cellular_component', 'GO:0005574', ('109', '112'))	('involved', 'Reg', (281, 289))	('G2M checkpoint', 'biological_process', 'GO:0000075', ('134', '148'))	('SET domain mutation', 'Var', (254, 273))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('DNA repair', 'biological_process', 'GO:0006281', ('109', '119'))	('SET', 'Gene', (217, 220))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('associated', 'Reg', (201, 211))	('RCC', 'Disease', (295, 298))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('ccRCC', 'Phenotype', 'HP:0006770', (293, 298))	('cancer', 'Disease', (345, 351))
28108	30755832	The above potential pathway involved in DNA repair, cell circle, dual chromatin, and cytoskeletal remodeling might constitute the reason for poor prognosis in patients with SETD2 mutations.	('SETD2', 'Gene', (173, 178))	('DNA repair', 'biological_process', 'GO:0006281', ('40', '50'))	('chromatin', 'cellular_component', 'GO:0000785', ('70', '79'))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('mutations', 'Var', (179, 188))	('patients', 'Species', '9606', (159, 167))	('SETD2', 'Gene', '29072', (173, 178))
28123	26536169	MET alterations were associated with Type 1 tumors, whereas Type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-ARE pathway.	('TFE3', 'Gene', (131, 135))	('increased', 'PosReg', (149, 158))	('Type 2 tumors', 'Disease', 'MESH:D009369', (60, 73))	('TFE3', 'Gene', '7030', (131, 135))	('Type 1 tumors', 'Disease', 'MESH:D009369', (37, 50))	('mutations', 'Var', (120, 129))	('Type 1 tumors', 'Disease', (37, 50))	('alterations', 'Var', (4, 15))	('SETD2', 'Gene', (114, 119))	('Type 2 tumors', 'Disease', (60, 73))	('NRF2', 'Gene', '4780', (177, 181))	('expression', 'MPA', (159, 169))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('CDKN2A', 'Gene', (96, 102))	('SETD2', 'Gene', '29072', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('associated', 'Reg', (21, 31))	('fusions', 'Var', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('NRF2', 'Gene', (177, 181))	('silencing', 'NegReg', (103, 112))	('CDKN2A', 'Gene', '1029', (96, 102))
28124	26536169	A CpG island methylator phenotype (CIMP) was found in a distinct subset of Type 2 papillary renal cell carcinoma characterized by poor survival and mutation of the fumarate hydratase (FH) gene.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (82, 112))	('Type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (75, 112))	('CIMP', 'Chemical', '-', (35, 39))	('FH', 'Gene', '2271', (184, 186))	('Type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (75, 112))	('fumarate hydratase', 'Gene', '2271', (164, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('fumarate hydratase', 'Gene', (164, 182))	('mutation', 'Var', (148, 156))	('Type 2 papillary renal cell carcinoma', 'Disease', (75, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
28126	26536169	Alterations in the MET pathway are associated with Type 1 and activation of the NRF2-ARE pathway with Type 2; CDKN2A loss and CIMP in Type 2 convey a poor prognosis.	('CDKN2A', 'Gene', (110, 116))	('NRF2', 'Gene', '4780', (80, 84))	('loss', 'NegReg', (117, 121))	('CDKN2A', 'Gene', '1029', (110, 116))	('CIMP', 'Var', (126, 130))	('Alterations', 'Var', (0, 11))	('MET pathway', 'Pathway', (19, 30))	('NRF2', 'Gene', (80, 84))	('CIMP', 'Chemical', '-', (126, 130))	('Type 1', 'Disease', (51, 57))	('activation', 'PosReg', (62, 72))
28134	26536169	Hereditary papillary renal cell carcinoma, a rare disorder presenting with an increased risk of Type 1 disease, is characterized by activating germline mutations of the MET gene.	('rare disorder', 'Disease', 'MESH:D035583', (45, 58))	('Type 1 disease', 'Disease', (96, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (21, 41))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (11, 41))	('Hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (0, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('germline mutations', 'Var', (143, 161))	('MET', 'Gene', (169, 172))	('Type 1 disease', 'Disease', 'MESH:D005776', (96, 110))	('activating', 'PosReg', (132, 142))	('rare disorder', 'Disease', (45, 58))	('Hereditary papillary renal cell carcinoma', 'Disease', (0, 41))
28135	26536169	Somatic MET mutations are found in 13%-15% of non-hereditary papillary renal cell carcinomas.	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (61, 92))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (71, 92))	('mutations', 'Var', (12, 21))	('papillary renal cell carcinomas', 'Disease', (61, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (61, 92))	('MET mutations', 'Var', (8, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (61, 91))
28136	26536169	Hereditary leiomyomatosis and renal cell carcinoma, a hereditary cancer syndrome in which affected individuals are at risk of developing an aggressive form of Type 2 papillary renal cell carcinoma, is caused by germline mutation of the tricarboxylic acid (TCA) cycle enzyme gene, fumarate hydratase (FH).	('Hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (0, 50))	('FH', 'Gene', '2271', (300, 302))	('TCA', 'Chemical', 'MESH:D014233', (256, 259))	('hereditary cancer syndrome', 'Disease', (54, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('germline mutation', 'Var', (211, 228))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (176, 196))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (236, 254))	('fumarate hydratase', 'Gene', (280, 298))	('Type 2 papillary renal cell carcinoma', 'Disease', (159, 196))	('caused by', 'Reg', (201, 210))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (54, 80))	('TCA) cycle', 'biological_process', 'GO:0006099', ('256', '266'))	('Type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (159, 196))	('Type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (159, 196))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (166, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (30, 50))	('fumarate hydratase', 'Gene', '2271', (280, 298))
28138	26536169	Mutations in the genes that regulate the NRF2/ARE pathway, such as CUL3 and NFE2L2 (NRF2), have also been found in sporadic papillary renal cell carcinoma.	('NRF2', 'Gene', (41, 45))	('sporadic papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (115, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('CUL3', 'Gene', '8452', (67, 71))	('CUL3', 'Gene', (67, 71))	('sporadic papillary renal cell carcinoma', 'Disease', (115, 154))	('NRF2', 'Gene', '4780', (84, 88))	('NFE2L2', 'Gene', '4780', (76, 82))	('found', 'Reg', (106, 111))	('Mutations', 'Var', (0, 9))	('NRF2', 'Gene', '4780', (41, 45))	('NRF2', 'Gene', (84, 88))	('NFE2L2', 'Gene', (76, 82))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (124, 154))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))
28146	26536169	Single nucleotide polymorphism (SNP) array-based profiling of somatic copy number alterations revealed distinctive patterns across three main tumor subgroups.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Single', 'Var', (0, 6))
28149	26536169	While one subgroup had few copy number alterations, the other was characterized by a high degree of aneuploidy with multiple chromosomal losses, including frequent chromosome 9p loss, and associated with poorer survival (p<0.0001) (Fig.	('aneuploidy', 'Disease', (100, 110))	('survival', 'MPA', (211, 219))	('aneuploidy', 'Disease', 'MESH:D000782', (100, 110))	('poorer', 'NegReg', (204, 210))	('chromosome 9p loss', 'Var', (164, 182))	('chromosome', 'cellular_component', 'GO:0005694', ('164', '174'))
28150	26536169	Whole-exome sequencing identified 10,380 putative somatic mutations in 157 tumors with an average of 1.45 non-silent mutations per megabase (https://tcga-data.nci.nih.gov/tcgafiles/ftp_auth/distro_ftpusers/anonymous 8/tumor/kirp/gsc/hgsc.bcm.edu/illuminaga_dnaseq_curated/mutations/hgsc.bcm.edu_KIRP.IlluminaGA_DNASeq_curated.Level_2.1.0.0/).	('mutations', 'Var', (58, 67))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('gsc', 'cellular_component', 'GO:0032593', ('229', '232'))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (218, 223))	('tumors', 'Disease', (75, 81))	('tumor', 'Disease', (75, 80))
28152	26536169	Further analysis, performed restricting the multiple hypothesis testing to genes previously associated with cancer by the PanCan21, identified 6 additional significantly mutated genes (FAT1, BAP1, PBRM1, STAG2, NFE2L2 and TP53) with 36% of cases demonstrating mutation of at least one (Fig.	('FAT1', 'Gene', (185, 189))	('PBRM1', 'Gene', (197, 202))	('PBRM1', 'Gene', '55193', (197, 202))	('NFE2L2', 'Gene', (211, 217))	('STAG2', 'Gene', (204, 209))	('STAG2', 'Gene', '10735', (204, 209))	('BAP1', 'Gene', '8314', (191, 195))	('mutation', 'Var', (260, 268))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('NFE2L2', 'Gene', '4780', (211, 217))	('FAT1', 'Gene', '2195', (185, 189))	('BAP1', 'Gene', (191, 195))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', (222, 226))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
28154	26536169	Assessment of genes within these pathways (Table S4 in the Supplementary Appendix) demonstrated a high number of mutations in both Type 1 and Type 2 tumors involving SWI/SNF complex (19.7% and 26.7% respectively), chromatin modifier pathways (35.2% and 38.3% respectively) and Hippo signaling pathway (2.8% and 10.0% respectively) (Fig.	('Type 1', 'Disease', (131, 137))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('277', '300'))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('166', '181'))	('chromatin', 'cellular_component', 'GO:0000785', ('214', '223'))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SWI/SNF complex', 'Gene', (166, 181))	('Hippo signaling pathway', 'Pathway', (277, 300))	('mutations', 'Var', (113, 122))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Type 2 tumors', 'Disease', 'MESH:D009369', (142, 155))	('chromatin modifier pathways', 'Pathway', (214, 241))	('Type 2 tumors', 'Disease', (142, 155))
28155	26536169	Gene fusions involving TFE3/TFEB have previously been associated with papillary renal cell carcinoma (reviewed in Kaufman, et al.).	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('TFE3', 'Gene', (23, 27))	('Gene fusions', 'Var', (0, 12))	('TFEB', 'Gene', '7942', (28, 32))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 100))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (70, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('TFE3', 'Gene', '7030', (23, 27))	('papillary renal cell carcinoma', 'Disease', (70, 100))	('TFEB', 'Gene', (28, 32))	('associated', 'Reg', (54, 64))
28157	26536169	Four of the TFE3 fusions involved known fusion partners, PRCC and SFPQ, and 2 involved novel fusion partners, RBM10 and DVL2 (Fig.	('DVL2', 'Gene', '1856', (120, 124))	('SFPQ', 'Gene', '6421', (66, 70))	('SFPQ', 'Gene', (66, 70))	('RBM10', 'Gene', '8241', (110, 115))	('involved', 'Reg', (25, 33))	('TFE3', 'Gene', (12, 16))	('RBM10', 'Gene', (110, 115))	('TFE3', 'Gene', '7030', (12, 16))	('fusions', 'Var', (17, 24))	('PRCC', 'Gene', '5546', (57, 61))	('DVL2', 'Gene', (120, 124))	('PRCC', 'Gene', (57, 61))
28159	26536169	The two TFEB fusions both involved novel fusion partners, COL21A1 and CADM2, with the COL21A1-TFEB fusion resulting in a similar construct to the known MALAT1-TFEB fusions and the TFEB-CADM2 fusion resulting in a novel truncated version of TFEB that had lost several microRNA binding sites (Fig.	('TFEB', 'Gene', (159, 163))	('TFEB', 'Gene', (8, 12))	('CADM2', 'Gene', '253559', (185, 190))	('CADM2', 'Gene', (185, 190))	('COL21A1', 'Gene', '81578', (58, 65))	('MALAT1', 'Gene', (152, 158))	('COL21A1', 'Gene', (86, 93))	('TFEB', 'Gene', '7942', (159, 163))	('TFEB', 'Gene', (180, 184))	('TFEB', 'Gene', (94, 98))	('fusion', 'Var', (99, 105))	('TFEB', 'Gene', '7942', (8, 12))	('involved', 'Reg', (26, 34))	('microRNA binding', 'molecular_function', 'GO:0035198', ('267', '283'))	('MALAT1', 'Gene', '378938', (152, 158))	('TFEB', 'Gene', '7942', (180, 184))	('TFEB', 'Gene', '7942', (94, 98))	('CADM2', 'Gene', '253559', (70, 75))	('truncated', 'MPA', (219, 228))	('CADM2', 'Gene', (70, 75))	('COL21A1', 'Gene', (58, 65))	('TFEB', 'Gene', (240, 244))	('COL21A1', 'Gene', '81578', (86, 93))	('TFEB', 'Gene', '7942', (240, 244))	('microRNA binding sites', 'MPA', (267, 289))
28161	26536169	Seven of the TFE3/TFEB fusions were identified in the Type 2 tumors (7/60 - 11.7%).	('Type 2 tumors', 'Disease', (54, 67))	('Type 2 tumors', 'Disease', 'MESH:D009369', (54, 67))	('TFE3', 'Gene', (13, 17))	('fusions', 'Var', (23, 30))	('TFEB', 'Gene', '7942', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TFEB', 'Gene', (18, 22))	('TFE3', 'Gene', '7030', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
28162	26536169	We found mutation of MET in seventeen tumors, three of which were germline.	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('MET', 'Gene', (21, 24))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('found', 'Reg', (3, 8))
28163	26536169	Most mutations were in the tyrosine kinase domain (14/17) and were found primarily in Type 1 tumors (13/75, 18.6%) (Fig.	('Type 1 tumors', 'Disease', 'MESH:D009369', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (5, 14))	('found', 'Reg', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Type 1 tumors', 'Disease', (86, 99))
28169	26536169	GISTIC2.0 analysis identified loss of 1p36 in 18 (11.1%) papillary renal cell carcinomas involved candidate tumor suppressor ERRFI1, a negative regulator of EGFR (Fig.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (67, 87))	('tumor', 'Disease', (108, 113))	('EGFR', 'Gene', '1956', (157, 161))	('ERRFI1', 'Gene', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('papillary renal cell carcinomas', 'Disease', (57, 88))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (57, 88))	('loss', 'Var', (30, 34))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (57, 87))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (67, 88))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('108', '124'))	('EGFR', 'molecular_function', 'GO:0005006', ('157', '161'))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('1p36', 'Protein', (38, 42))	('EGFR', 'Gene', (157, 161))	('tumor suppressor', 'biological_process', 'GO:0051726', ('108', '124'))	('ERRFI1', 'Gene', '54206', (125, 131))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (57, 88))
28170	26536169	S6 in the Supplementary Appendix), which deletions significantly co-occurred (p=0.021, Fisher's exact) with chromosome 7 gain and EGFR amplification.	('gain', 'PosReg', (121, 125))	('EGFR', 'molecular_function', 'GO:0005006', ('130', '134'))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('deletions', 'Var', (41, 50))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
28172	26536169	We found mutation or promoter hypermethylation of CDKN2A in 11 tumors (Fig.	('promoter', 'MPA', (21, 29))	('mutation', 'Var', (9, 17))	('CDKN2A', 'Gene', (50, 56))	('CDKN2A', 'Gene', '1029', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
28174	26536169	CDKN2A alteration was strongly associated with Type 2 histology with 25.0% (15/60) of Type 2 tumors demonstrating alterations.	('Type 2 histology', 'Disease', (47, 63))	('Type 2 tumors', 'Disease', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Type 2 tumors', 'Disease', 'MESH:D009369', (86, 99))	('associated', 'Reg', (31, 41))	('alteration', 'Var', (7, 17))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
28179	26536169	Type 2 tumors were associated with mutations in the chromatin modifying genes, SETD2, BAP1 and PBRM1, which are frequently mutated in clear cell kidney tumors in combination with chromosome 3p loss.	('associated', 'Reg', (19, 29))	('chromosome', 'cellular_component', 'GO:0005694', ('179', '189'))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('BAP1', 'Gene', '8314', (86, 90))	('PBRM1', 'Gene', '55193', (95, 100))	('SETD2', 'Gene', (79, 84))	('clear cell kidney tumors', 'Disease', 'MESH:D008649', (134, 158))	('clear cell kidney tumors', 'Disease', (134, 158))	('PBRM1', 'Gene', (95, 100))	('SETD2', 'Gene', '29072', (79, 84))	('BAP1', 'Gene', (86, 90))	('Type 2 tumors', 'Disease', 'MESH:D009369', (0, 13))	('chromatin', 'cellular_component', 'GO:0000785', ('52', '61'))	('kidney tumors', 'Phenotype', 'HP:0009726', (145, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Type 2 tumors', 'Disease', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (35, 44))
28180	26536169	Mutations of BAP1 and PBRM1 were mutually exclusive but PBRM1 mutations were frequently concurrent with SETD2 mutations (Fig.	('SETD2', 'Gene', (104, 109))	('BAP1', 'Gene', (13, 17))	('mutations', 'Var', (110, 119))	('PBRM1', 'Gene', '55193', (22, 27))	('PBRM1', 'Gene', (56, 61))	('BAP1', 'Gene', '8314', (13, 17))	('SETD2', 'Gene', '29072', (104, 109))	('PBRM1', 'Gene', '55193', (56, 61))	('mutations', 'Var', (62, 71))	('PBRM1', 'Gene', (22, 27))
28181	26536169	Although loss of chromosome 3p was also associated with Type 2 papillary renal cell carcinoma, only 3 of 13 Type 2 papillary renal cell carcinomas with SETD2, BAP1 or PBRM1 mutation demonstrated loss and no promoter hypermethylation was observed (Fig.	('BAP1', 'Gene', '8314', (159, 163))	('PBRM1', 'Gene', '55193', (167, 172))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (115, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 145))	('loss', 'NegReg', (195, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('Type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (108, 145))	('SETD2', 'Gene', (152, 157))	('associated', 'Reg', (40, 50))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (125, 146))	('PBRM1', 'Gene', (167, 172))	('SETD2', 'Gene', '29072', (152, 157))	('BAP1', 'Gene', (159, 163))	('Type 2 papillary renal cell carcinomas', 'Disease', (108, 146))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (63, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (115, 146))	('chromosome', 'cellular_component', 'GO:0005694', ('17', '27'))	('Type 2 papillary renal cell carcinoma', 'Disease', (56, 93))	('Type 2 papillary renal cell carcinomas', 'Phenotype', 'HP:0006732', (108, 146))	('Type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 93))	('Type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (56, 93))	('Type 2 papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (108, 146))	('mutation', 'Var', (173, 181))
28183	26536169	This represents a novel kidney-associated CpG island methylator phenotype (CIMP) that included universal hypermethylation of the CDKN2A promoter (Fig.	('hypermethylation', 'Var', (105, 121))	('CDKN2A', 'Gene', '1029', (129, 135))	('CDKN2A', 'Gene', (129, 135))	('CIMP', 'Chemical', '-', (75, 79))
28185	26536169	In five tumors we found germline and/or somatic mutation of FH (55.6%).	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('germline', 'Var', (24, 32))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('FH', 'Gene', '2271', (60, 62))
28194	26536169	4a) Cluster C1 was predominantly Type 1 papillary renal cell carcinoma and strongly associated with gain of chromosome 7, MET mutation, mRNA cluster 1, and low tumor stage (Fig.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (40, 70))	('gain', 'PosReg', (100, 104))	('MET mutation', 'Var', (122, 134))	('low tumor', 'Disease', 'MESH:D009800', (156, 165))	('papillary renal cell carcinoma', 'Disease', (40, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('low tumor', 'Disease', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('chromosome', 'cellular_component', 'GO:0005694', ('108', '118'))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (40, 70))
28196	26536169	Cluster C2b consisted exclusively of Type 2 and unclassified papillary renal cell carcinomas and was associated with DNA methylation cluster 1, higher tumor stage (III/IV), and mutation of SETD2 (Fig.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (71, 92))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('C2b', 'Gene', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutation', 'Var', (177, 185))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (61, 92))	('DNA methylation', 'biological_process', 'GO:0006306', ('117', '132'))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('associated', 'Reg', (101, 111))	('SETD2', 'Gene', (189, 194))	('DNA', 'cellular_component', 'GO:0005574', ('117', '120'))	('SETD2', 'Gene', '29072', (189, 194))	('papillary renal cell carcinomas', 'Disease', (61, 92))	('tumor', 'Disease', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('C2b', 'Gene', '100130342', (8, 11))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (61, 92))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (61, 91))
28198	26536169	The best survival was associated with clusters C1 and C2a, while patients in cluster C2b tumors had a poorer survival.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cluster C2b tumors', 'Disease', (77, 95))	('clusters C1', 'Var', (38, 49))	('C2a', 'Var', (54, 57))	('patients', 'Species', '9606', (65, 73))	('cluster C2b tumors', 'Disease', 'MESH:D003027', (77, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
28203	26536169	S18a in the Supplementary Appendix) and increased NQO1 expression associated with decreased survival (p=0.001, Fig.	('NQO1', 'Gene', (50, 54))	('NQO1', 'Gene', '1728', (50, 54))	('NQO1', 'molecular_function', 'GO:0003955', ('50', '54'))	('expression', 'MPA', (55, 65))	('survival', 'MPA', (92, 100))	('increased', 'PosReg', (40, 49))	('S18a', 'Var', (0, 4))	('decreased', 'NegReg', (82, 91))
28204	26536169	These findings are consistent with recent studies demonstrating increased activation of the NRF2-ARE pathway in Type 2 tumors and mutations in NRF2-ARE pathway genes (NFE2L2, CUL3, KEAP1 and SIRT1).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('SIRT1', 'Gene', '23411', (191, 196))	('SIRT1', 'Gene', (191, 196))	('KEAP1', 'Gene', (181, 186))	('NFE2L2', 'Gene', (167, 173))	('Type 2 tumors', 'Disease', (112, 125))	('CUL3', 'Gene', '8452', (175, 179))	('NRF2', 'Gene', '4780', (92, 96))	('CUL3', 'Gene', (175, 179))	('Type 2 tumors', 'Disease', 'MESH:D009369', (112, 125))	('activation', 'PosReg', (74, 84))	('mutations', 'Var', (130, 139))	('NRF2', 'Gene', '4780', (143, 147))	('NRF2', 'Gene', (92, 96))	('NFE2L2', 'Gene', '4780', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('KEAP1', 'Gene', '9817', (181, 186))	('NRF2', 'Gene', (143, 147))
28205	26536169	Four NFE2L2 (NRF2) mutations in known activating hotspots were identified as well as mutations in both CUL3 (n=5) and KEAP1 (n=1).	('NFE2L2', 'Gene', (5, 11))	('mutations', 'Var', (19, 28))	('NRF2', 'Gene', '4780', (13, 17))	('CUL3', 'Gene', '8452', (103, 107))	('KEAP1', 'Gene', '9817', (118, 123))	('CUL3', 'Gene', (103, 107))	('NRF2', 'Gene', (13, 17))	('KEAP1', 'Gene', (118, 123))	('NFE2L2', 'Gene', '4780', (5, 11))
28206	26536169	These NFE2L2/CUL3/KEAP1 mutations correlated with high expression levels of NQO1 (p<1E-6, t-test), but did not solely account for the observed NQO1 expression differences among subtypes (Fig.	('NQO1', 'molecular_function', 'GO:0003955', ('76', '80'))	('NQO1', 'Gene', (76, 80))	('NQO1', 'Gene', '1728', (76, 80))	('CUL3', 'Gene', '8452', (13, 17))	('CUL3', 'Gene', (13, 17))	('NFE2L2', 'Gene', '4780', (6, 12))	('NQO1', 'molecular_function', 'GO:0003955', ('143', '147'))	('NQO1', 'Gene', (143, 147))	('expression levels', 'MPA', (55, 72))	('KEAP1', 'Gene', (18, 23))	('NQO1', 'Gene', '1728', (143, 147))	('NFE2L2', 'Gene', (6, 12))	('mutations', 'Var', (24, 33))	('KEAP1', 'Gene', '9817', (18, 23))
28208	26536169	Manual pathway analysis identified candidate driver mutations in an additional 27% of the cases affecting known cancer-associated genes, such as PTEN, NRAS, KRAS, TP53, TSC2 and those in the MLL and ARID families (Fig.	('mutations', 'Var', (52, 61))	('KRAS', 'Gene', '3845', (157, 161))	('ARID', 'Disease', (199, 203))	('PTEN', 'Gene', (145, 149))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PTEN', 'Gene', '5728', (145, 149))	('TP53', 'Gene', '7157', (163, 167))	('ARID', 'Disease', 'None', (199, 203))	('TSC2', 'Gene', '7249', (169, 173))	('TSC2', 'Gene', (169, 173))	('TP53', 'Gene', (163, 167))	('NRAS', 'Gene', (151, 155))	('MLL', 'Gene', '4297', (191, 194))	('MLL', 'Gene', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('KRAS', 'Gene', (157, 161))	('NRAS', 'Gene', '4893', (151, 155))
28211	26536169	Twenty-six (70%) of these thirty seven PRCCs were Type 1 (p=0.0013, Fisher's exact) and most (21/26, 81%) demonstrated gain of chromosome 7 which includes MET.	('PRCC', 'Gene', (39, 43))	('MET', 'Var', (155, 158))	('chromosome', 'cellular_component', 'GO:0005694', ('127', '137'))	('PRCC', 'Gene', '5546', (39, 43))	('gain', 'PosReg', (119, 123))
28217	26536169	The utility of CDKN2A alterations as an independent prognostic marker associated with Type 2 tumors requires validation.	('Type 2 tumors', 'Disease', (86, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('CDKN2A', 'Gene', (15, 21))	('CDKN2A', 'Gene', '1029', (15, 21))	('associated', 'Reg', (70, 80))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('alterations', 'Var', (22, 33))	('Type 2 tumors', 'Disease', 'MESH:D009369', (86, 99))
28218	26536169	This study shows that TFE3/TFEB fusions are underappreciated in adult Type 2 tumors and should be considered in any Type 2 patient.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('fusions', 'Var', (32, 39))	('patient', 'Species', '9606', (123, 130))	('adult Type 2 tumors', 'Disease', 'MESH:C538053', (64, 83))	('TFE3', 'Gene', (22, 26))	('TFEB', 'Gene', '7942', (27, 31))	('TFEB', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('adult Type 2 tumors', 'Disease', (64, 83))	('TFE3', 'Gene', '7030', (22, 26))
28219	26536169	Although TFE3 and TFEB papillary renal cell carcinomas are generally considered diseases of children and young adults, our mean age was 52, and we found TFEB fusions tumors in patients 64 and 71 years of age.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TFE3', 'Gene', (9, 13))	('TFE3', 'Gene', '7030', (9, 13))	('tumors', 'Disease', (166, 172))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (23, 54))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (33, 53))	('TFEB', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (23, 53))	('TFEB', 'Gene', (153, 157))	('patients', 'Species', '9606', (176, 184))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (33, 54))	('fusions', 'Var', (158, 165))	('TFEB', 'Gene', '7942', (18, 22))	('papillary renal cell carcinomas', 'Disease', (23, 54))	('children', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (23, 54))	('TFEB', 'Gene', '7942', (153, 157))
28223	26536169	Germline mutation of FH is found in the aggressive Type 2 tumor associated with hereditary leiomyomatosis and renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('associated', 'Reg', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (80, 130))	('aggressive Type 2 tumor', 'Disease', 'MESH:D001523', (40, 63))	('Germline mutation', 'Var', (0, 17))	('aggressive Type 2 tumor', 'Disease', (40, 63))	('FH', 'Gene', '2271', (21, 23))
28225	26536169	The subgrouping of the Type 2 tumors by molecular features and the presence of specific subsets of Type 2 tumors, such as those with TFE3 fusions or CIMP, suggests that sub-stratification of Type 2 papillary renal cell carcinoma by specific molecular markers may provide more accurate diagnosis that could lead to the development of mechanistic, disease-specific targeted therapies.	('Type 2 tumors', 'Disease', (23, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('CIMP', 'Chemical', '-', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Type 2 tumors', 'Disease', 'MESH:D009369', (99, 112))	('lead to', 'Reg', (306, 313))	('fusions', 'Var', (138, 145))	('TFE3', 'Gene', (133, 137))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (208, 228))	('Type 2 tumors', 'Disease', (99, 112))	('Type 2 papillary renal cell carcinoma', 'Disease', (191, 228))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (198, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('TFE3', 'Gene', '7030', (133, 137))	('Type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (191, 228))	('Type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (191, 228))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Type 2 tumors', 'Disease', 'MESH:D009369', (23, 36))
28227	26536169	Alteration of the MET gene or gain of chromosome 7 was found in a large percentage (81%) of Type 1 tumors.	('Type 1 tumors', 'Disease', (92, 105))	('MET gene', 'Gene', (18, 26))	('Alteration', 'Var', (0, 10))	('chromosome', 'cellular_component', 'GO:0005694', ('38', '48'))	('Type 1 tumors', 'Disease', 'MESH:D009369', (92, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('gain', 'PosReg', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
28228	26536169	Antitumor activity of an agent targeting the MET/VEGFR2 pathways has been demonstrated in a Phase II trial in patients with papillary renal cell carcinoma, with a particularly high response rate in tumors with MET mutations.	('tumor', 'Disease', (4, 9))	('papillary renal cell carcinoma', 'Disease', (124, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('VEGFR2', 'Gene', '3791', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('MET mutations', 'Var', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 154))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('VEGFR2', 'Gene', (49, 55))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', (198, 203))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (124, 154))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (110, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (134, 154))
28229	26536169	Mutation of the Hippo pathway tumor suppressor, NF2, was observed in a number of papillary renal cell carcinomas.	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (81, 111))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (81, 112))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (91, 112))	('NF2', 'Gene', (48, 51))	('papillary renal cell carcinomas', 'Disease', (81, 112))	('observed', 'Reg', (57, 65))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('NF2', 'Gene', '4771', (48, 51))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (81, 112))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor', 'Disease', (30, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
28230	26536169	This pathway has been targeted in other cancers with agents such as dasatinib, an inhibitor of the YES1 kinase that interacts with the YAP transcription factor that is upregulated with Hippo pathway dysregulation.	('YES1', 'Gene', '7525', (99, 103))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('transcription factor', 'molecular_function', 'GO:0000981', ('139', '159'))	('dasatinib', 'Chemical', 'MESH:D000069439', (68, 77))	('dysregulation', 'Var', (199, 212))	('upregulated', 'PosReg', (168, 179))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('cancers', 'Disease', (40, 47))	('YES1', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
28248	21710693	Indeed, primary tumors and corresponding grafts displayed identical VHL mutations.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('VHL', 'Gene', (68, 71))	('primary tumors', 'Disease', (8, 22))	('VHL', 'Gene', '7428', (68, 71))	('primary tumors', 'Disease', 'MESH:D009369', (8, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))
28282	21710693	Briefly, sections were deparaffinized and rehydrated in water, and antigen retrieval was done by heating slides in citrate buffer (pH 6.0) for CAIX, CD34 and CD45 or EDTA buffer (pH 8.0) for Ki67, CD10, and VEGF in a pressure cooker for 2 minutes.	('CD10', 'molecular_function', 'GO:0004245', ('197', '201'))	('paraffin', 'Chemical', 'MESH:D010232', (25, 33))	('VEGF', 'Gene', (207, 211))	('rat', 'Species', '10116', (118, 121))	('CD34', 'Var', (149, 153))	('citrate', 'Chemical', 'MESH:D019343', (115, 122))	('Ki67', 'Chemical', '-', (191, 195))	('CAIX', 'Gene', (143, 147))	('EDTA', 'Chemical', 'MESH:D004492', (166, 170))	('rat', 'Species', '10116', (47, 50))	('CD10', 'Gene', '4311', (197, 201))	('CD10', 'Gene', (197, 201))	('CAIX', 'Gene', '768', (143, 147))	('water', 'Chemical', 'MESH:D014867', (56, 61))	('VEGF', 'Gene', '7422', (207, 211))
28329	21710693	Since 60-80% of sporadic cRCCs harbor mutations in VHL, we performed VHL mutational analysis in a subset of 10 cases for which frozen tissue was available (9 cRCC and 1 pRCC).	('pRCC', 'Gene', (169, 173))	('VHL', 'Gene', '7428', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('RCC', 'Disease', (26, 29))	('pRCC', 'Gene', '5546', (169, 173))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('VHL', 'Gene', '7428', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('VHL', 'Gene', (69, 72))	('mutations', 'Var', (38, 47))	('VHL', 'Gene', (51, 54))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
28330	21710693	By direct sequencing, we detected VHL mutations of in 7/9 (78%) cRCC cases analyzed.	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('VHL', 'Gene', '7428', (34, 37))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (38, 47))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
28331	21710693	As expected, no VHL mutations were observed in the pRCC case.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('VHL', 'Gene', (16, 19))	('VHL', 'Gene', '7428', (16, 19))	('pRCC', 'Gene', (51, 55))	('mutations', 'Var', (20, 29))	('pRCC', 'Gene', '5546', (51, 55))
28332	21710693	Of note, for all cases, identical mutations were found in the original RCC tissues and the corresponding grafts (Table 2).	('RCC', 'Disease', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('mutations', 'Var', (34, 43))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))
28333	21710693	Since it has been suggested that VHL mutations might have prognostic value in patients with cRCC, we investigated the relation between VHL mutations and tumor growth.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('VHL', 'Gene', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('VHL', 'Gene', '7428', (135, 138))	('VHL', 'Gene', (33, 36))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', '7428', (33, 36))
28341	21710693	Such alteration consisted of chromosome 1q amplification in one case (#3) and amplification of portion of chromosome 5p in the other case (#19).	('rat', 'Species', '10116', (9, 12))	('chromosome', 'Gene', (29, 39))	('chromosome', 'cellular_component', 'GO:0005694', ('29', '39'))	('chromosome', 'cellular_component', 'GO:0005694', ('106', '116'))	('amplification', 'PosReg', (43, 56))	('amplification of', 'Var', (78, 94))
28353	21710693	Indeed, residual human vasculature was observed in 9 of 13 cases (69%) with tumor volume below 200 mm3, but in none of the six cases with tumor volume higher than 200 mm3 (Fisher's exact test; p = 0.01).	('tumor', 'Disease', (138, 143))	('human', 'Species', '9606', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('below 200 mm3', 'Var', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
28375	21710693	Remarkably, overlapping histopathologic features and identical VHL mutations were observed in the pre-implantation tumors and the corresponding xenografts at the first passage.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pre', 'molecular_function', 'GO:0003904', ('98', '101'))	('mutations', 'Var', (67, 76))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('pre-implantation tumors', 'Phenotype', 'HP:0032479', (98, 121))	('VHL', 'Gene', (63, 66))	('VHL', 'Gene', '7428', (63, 66))
28393	29180625	Using a multi-institutional cohort of 204 pRCC patients we assessed the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient's long-term survival.	('patient', 'Species', '9606', (47, 54))	('pRCC', 'Gene', '5546', (42, 46))	('patients', 'Species', '9606', (47, 55))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('Ki67', 'Chemical', '-', (141, 145))	('Ki67', 'Var', (141, 145))	('pRCC', 'Gene', (42, 46))	('MINA53', 'Gene', (129, 135))	('patient', 'Species', '9606', (160, 167))	('MINA53', 'Gene', '84864', (129, 135))
28412	29180625	To gain insight into the molecular consequences of deregulated miRNA expression, we performed a gene set enrichment analysis and found that 10 genes involved in the Jak-STAT pathway are potential targets of the deregulated miRNAs miR-210 and let-7c, including the v-myc myelocytomatosis viral oncogene homolog (MYC).	('deregulated', 'PosReg', (211, 222))	('let-7c', 'Gene', (242, 248))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', (264, 309))	('let-7c', 'Gene', '406885', (242, 248))	('miR-210', 'Gene', (230, 237))	('Jak', 'molecular_function', 'GO:0004713', ('165', '168'))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', '4609', (264, 309))	('miRNAs', 'Var', (223, 229))	('miR-210', 'Gene', '406992', (230, 237))
28415	29180625	In transgenic mouse models, ectopic MYC expression was sufficient to induce RCCs that, depending on the promoter driving ectopic MYC expression, resemble different RCC entities.	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('mouse', 'Species', '10090', (14, 19))	('RCC', 'Disease', (76, 79))	('ectopic MYC', 'Var', (28, 39))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('RCC', 'Disease', (164, 167))	('RCC', 'Phenotype', 'HP:0005584', (164, 167))
28420	29180625	The aim of the present study was to assess the additional value of the immunohistochemical markers MYC, MINA53, and Ki67 in predicting patient's long-term survival.	('patient', 'Species', '9606', (135, 142))	('Ki67', 'Var', (116, 120))	('Ki67', 'Chemical', '-', (116, 120))	('MINA53', 'Gene', (104, 110))	('MINA53', 'Gene', '84864', (104, 110))
28436	29180625	Regarding OS, patients with mixed-histology pRCCs had a mean survival of 85.5 months compared to patients with type 2 (93.1 months) or type 1 pRCCs (140.7 months; log-rank p < 0.001; Table 2 and Supplementary Fig.	('pRCC', 'Gene', (44, 48))	('pRCC', 'Gene', '5546', (142, 146))	('pRCCs', 'Phenotype', 'HP:0006766', (44, 49))	('OS', 'Chemical', '-', (10, 12))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('pRCCs', 'Phenotype', 'HP:0006766', (142, 147))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('mixed-histology', 'Var', (28, 43))	('pRCC', 'Gene', '5546', (44, 48))	('pRCC', 'Gene', (142, 146))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (97, 105))
28437	29180625	Among the three immunohistochemical markers (MYC, MINA53 and Ki67), only the Ki67 labeling index was associated with CSS (Table 2 and Supplementary Fig.	('Ki67', 'Var', (77, 81))	('CSS', 'Chemical', '-', (117, 120))	('Ki67', 'Chemical', '-', (61, 65))	('MINA53', 'Gene', (50, 56))	('MINA53', 'Gene', '84864', (50, 56))	('associated', 'Reg', (101, 111))	('CSS', 'Disease', (117, 120))	('Ki67', 'Chemical', '-', (77, 81))
28438	29180625	Regarding the CSS of pRCC patients stratified by their MYC staining patterns, we observed that patients with intermediate MYC staining in their tumors exhibited the worst prognosis, while patients with negative or strong MYC staining had a tendency towards a better long-term survival.	('tumors', 'Disease', (144, 150))	('CSS', 'Chemical', '-', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('intermediate MYC staining', 'Var', (109, 134))	('pRCC', 'Gene', (21, 25))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (188, 196))	('pRCC', 'Gene', '5546', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
28441	29180625	Moreover, when regarding the actual numbers of cancer-specific death events, we noted that only one of 22 patients (4.5%) with strong MYC staining suffered a cancer-related death, compared to 9 of 67 (13.4%) cases with absent MYC staining and 18 of 110 (16.4%) cases with intermediate MYC staining.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('death', 'Disease', 'MESH:D003643', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('death', 'Disease', (63, 68))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (158, 164))	('to 9', 'Species', '1214577', (189, 193))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MYC staining', 'Var', (134, 146))	('death', 'Disease', 'MESH:D003643', (173, 178))	('death', 'Disease', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
28450	29180625	Likewise, an elevated Ki67 labeling index of >=5% was associated with CSS, resulting in a 3.4-fold increased risk of cancer-specific death (p = 0.002; Table 3).	('death', 'Disease', (133, 138))	('Ki67', 'Chemical', '-', (22, 26))	('Ki67', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('CSS', 'Chemical', '-', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('CSS', 'Disease', (70, 73))	('death', 'Disease', 'MESH:D003643', (133, 138))
28452	29180625	In OS, pRCC type 1 tumors with intermediate MYC staining were associated with a 5.3-fold increased risk of death compared to pRCC type 1 tumors with negative/strong MYC staining (p = 0.028; Table 3).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('pRCC', 'Gene', '5546', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('death', 'Disease', 'MESH:D003643', (107, 112))	('pRCC', 'Gene', (7, 11))	('pRCC', 'Gene', (125, 129))	('death', 'Disease', (107, 112))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('OS', 'Chemical', '-', (3, 5))	('intermediate MYC staining', 'Var', (31, 56))	('pRCC', 'Gene', '5546', (7, 11))
28475	29180625	During our analysis, however, the Kaplan-Meier tables suggested a tendency for a survival advantage for the patients with negative or strong MYC staining over intermediate MYC staining.	('survival', 'CPA', (81, 89))	('MYC', 'Protein', (141, 144))	('patients', 'Species', '9606', (108, 116))	('advantage', 'PosReg', (90, 99))	('negative', 'Var', (122, 130))
28480	29180625	Ki67 has recently been recognized as independent biomarker for RCC recurrence.	('RCC', 'Disease', (63, 66))	('Ki67', 'Chemical', '-', (0, 4))	('Ki67', 'Var', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
28531	33993869	Immune and stromal scores were calculated by ESTIMATE packages of R. PRCC samples were split into high and low groups on the basis of median immune/stromal score, limma package of R was utilized to compare DEGs,  Log2FC  > 1 and FDR < 0.05 were deemed significant.	('PRCC', 'Gene', '5546', (69, 73))	('PRCC', 'Gene', (69, 73))	('Log2FC', 'Var', (213, 219))
28555	33993869	Study has shown changes in mesenchymal stromal cell differentiation promoted the progression of multiple tumors by altering the tumor microenvironment.	('tumors', 'Disease', (105, 111))	('changes', 'Var', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('cell differentiation', 'biological_process', 'GO:0030154', ('47', '67'))	('mesenchymal stromal cell differentiation', 'CPA', (27, 67))	('promoted', 'PosReg', (68, 76))	('progression', 'CPA', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('altering', 'Reg', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (105, 110))
28670	33672271	The criteria of the algorithm for obtaining significant dPPIs were set as q-value < 0.10 (significantly repressed in tumor phenotype), q-value > 0.90 (significantly activated in tumor phenotype), and a normalized observation frequency either in normal or tumor phenotype > 20%.	('q-value > 0.90', 'Var', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('tumor', 'Disease', (117, 122))	('activated', 'PosReg', (165, 174))	('dPPIs', 'Chemical', '-', (56, 61))	('q-value < 0.10', 'Var', (74, 88))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
28707	33672271	Dysregulations in various biochemical pathways play an important role in cancer formation and development.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('biochemical pathways', 'Pathway', (26, 46))	('Dysregulations', 'Var', (0, 14))	('development', 'CPA', (94, 105))	('formation', 'biological_process', 'GO:0009058', ('80', '89'))
28735	33672271	Furthermore, ZINC73196087, ZINC72318117, ZINC72318118, ZINC73163075, ZINC73165724, ZINC73196196, and ZINC72318119 have been shown to demonstrate effective anti-proliferative activity against a panel of c-Met-amplified gastric cancer cell lines.	('c-Met', 'Gene', '4233', (202, 207))	('ZINC72318119', 'Chemical', '-', (101, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (218, 232))	('ZINC73196196', 'Var', (83, 95))	('ZINC72318118', 'Var', (41, 53))	('ZINC73196087', 'Var', (13, 25))	('ZINC73196196', 'Chemical', '-', (83, 95))	('ZINC73163075', 'Chemical', '-', (55, 67))	('ZINC72318117', 'Var', (27, 39))	('ZINC73165724', 'Chemical', '-', (69, 81))	('ZINC72318117', 'Chemical', '-', (27, 39))	('c-Met', 'Gene', (202, 207))	('ZINC73165724', 'Var', (69, 81))	('gastric cancer', 'Disease', (218, 232))	('ZINC72318119', 'Var', (101, 113))	('ZINC72318118', 'Chemical', '-', (41, 53))	('ZINC73196087', 'Chemical', '-', (13, 25))	('anti-proliferative activity', 'CPA', (155, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (218, 232))	('ZINC73163075', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
28741	26636767	A highly significant correlation was observed between the percentage of tumor cells with MET gene copy number >=3 and CEP7 copy number >=3 (R2 = 0.90, p<0.001) across two subtypes of PRCC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CEP7', 'Gene', (118, 122))	('tumor', 'Disease', (72, 77))	('PRCC', 'Gene', '5546', (183, 187))	('RCC', 'Phenotype', 'HP:0005584', (184, 187))	('copy number >=3', 'Var', (123, 138))	('CEP', 'molecular_function', 'GO:0047849', ('118', '121'))	('PRCC', 'Gene', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('PRCC', 'Phenotype', 'HP:0006766', (183, 187))
28742	26636767	In addition, the percentage of tumor cells with MET gene copy number >=3 was found to increase along with increases in MET IHC score.	('increase', 'PosReg', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('MET gene copy number >=3', 'Var', (48, 72))	('MET IHC', 'Disease', (119, 126))	('increases', 'PosReg', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
28752	26636767	When bound to its only known ligand, hepatocyte growth factor (HGF), MET protein activates downstream signaling pathways which promote cell proliferation, migration, invasion, angiogenesis and prevent cells from apoptosing.	('hepatocyte growth factor', 'Gene', '3082', (37, 61))	('ligand', 'molecular_function', 'GO:0005488', ('29', '35'))	('signaling', 'biological_process', 'GO:0023052', ('102', '111'))	('protein', 'cellular_component', 'GO:0003675', ('73', '80'))	('hepatocyte growth factor', 'Gene', (37, 61))	('cells', 'CPA', (201, 206))	('angiogenesis', 'CPA', (176, 188))	('promote', 'PosReg', (127, 134))	('HGF', 'Gene', '3082', (63, 66))	('cell proliferation', 'CPA', (135, 153))	('angiogenesis', 'biological_process', 'GO:0001525', ('176', '188'))	('migration', 'CPA', (155, 164))	('HGF', 'Gene', (63, 66))	('prevent', 'NegReg', (193, 200))	('invasion', 'CPA', (166, 174))	('MET', 'Var', (69, 72))	('cell proliferation', 'biological_process', 'GO:0008283', ('135', '153'))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('37', '61'))	('activates', 'PosReg', (81, 90))
28753	26636767	It has been shown that germline mutations in MET lead to the development of hereditary Type 1 PRCC, sparking interest in the development of MET inhibitors to treat PRCC patients.	('hereditary Type', 'Disease', (76, 91))	('germline mutations', 'Var', (23, 41))	('hereditary Type', 'Disease', 'MESH:D030342', (76, 91))	('patients', 'Species', '9606', (169, 177))	('PRCC', 'Gene', (164, 168))	('PRCC', 'Gene', '5546', (94, 98))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('MET', 'Gene', (45, 48))	('PRCC', 'Phenotype', 'HP:0006766', (164, 168))	('PRCC', 'Gene', (94, 98))	('lead to', 'Reg', (49, 56))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('PRCC', 'Phenotype', 'HP:0006766', (94, 98))	('PRCC', 'Gene', '5546', (164, 168))
28755	26636767	In sporadic PRCC patients, MET gene mutation, gene copy number alteration and MET protein overexpression were also observed.	('protein', 'cellular_component', 'GO:0003675', ('82', '89'))	('PRCC', 'Phenotype', 'HP:0006766', (12, 16))	('MET', 'Gene', (27, 30))	('patients', 'Species', '9606', (17, 25))	('PRCC', 'Gene', '5546', (12, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('gene copy number alteration', 'Var', (46, 73))	('overexpression', 'PosReg', (90, 104))	('PRCC', 'Gene', (12, 16))
28758	26636767	Furthermore, tumors from PRCC patients carrying MET gene mutations commonly show trisomy 7 with non-random duplicated mutant MET genes and one wildtype MET gene.	('PRCC', 'Gene', '5546', (25, 29))	('trisomy', 'Disease', (81, 88))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('MET gene', 'Gene', (48, 56))	('PRCC', 'Gene', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (30, 38))	('PRCC', 'Phenotype', 'HP:0006766', (25, 29))	('show', 'Reg', (76, 80))	('MET', 'Gene', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
28789	26636767	Tumor cells with MET gene copy number >=3 were observed in 90.1% (82/91) patients, while tumor cells with CEP7 copy number >=3 were observed in 92.3% (84/91) patients.	('CEP', 'molecular_function', 'GO:0047849', ('106', '109'))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MET gene copy number >=3', 'Var', (17, 41))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
28790	26636767	The percentage of tumor cells with MET or CEP7 copy number >=3 was variable among patients.	('CEP', 'molecular_function', 'GO:0047849', ('42', '45'))	('MET', 'Var', (35, 38))	('tumor', 'Disease', (18, 23))	('patients', 'Species', '9606', (82, 90))	('copy number >=3', 'Var', (47, 62))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CEP7', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
28795	26636767	After evaluation of MET and CEP7 copy numbers in the tumor cells, a significant correlation was found between the percentage of tumor cells with MET gene copy number increase (>=3) (%MET) and the percentage of tumor cells with CEP7 gene copy number increase (>=3) (%CEP7) (R2 = 0.90, p<0.001, Spearman's correlation analysis, Fig 2).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CEP', 'molecular_function', 'GO:0047849', ('28', '31'))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('MET', 'Var', (145, 148))	('increase', 'PosReg', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('CEP', 'molecular_function', 'GO:0047849', ('266', '269'))	('tumor', 'Disease', (128, 133))	('CEP7', 'Gene', (227, 231))	('CEP', 'molecular_function', 'GO:0047849', ('227', '230'))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
28796	26636767	This indicates that copy number gains in Chromosome 7 are likely the cause of MET gene copy number increase in PRCC tumors.	('PRCC tumors', 'Disease', 'MESH:D009369', (111, 122))	('copy number gains', 'Var', (20, 37))	('PRCC tumors', 'Disease', (111, 122))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('increase', 'PosReg', (99, 107))	('PRCC', 'Phenotype', 'HP:0006766', (111, 115))	('Chromosome', 'cellular_component', 'GO:0005694', ('41', '51'))
28799	26636767	No significant relationship was found between %MET and clinical stage (p = 0.82), indicating that the increase in the percentage of tumor cells with MET gene copy number increase may not be directly related to the severity of the disease or tumor metastasis.	('MET gene copy number', 'Var', (149, 169))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (241, 246))	('increase', 'PosReg', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor metastasis', 'Disease', 'MESH:D009362', (241, 257))	('tumor', 'Disease', (132, 137))	('tumor metastasis', 'Disease', (241, 257))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
28800	26636767	After stratification of the tumor subtypes, no significant relationship was found between %MET and tumor grades (p = 0.89, Type 1; p = 0.73, Type 2) or clinical stages (p = 0.82, Type 1; p = 0.54, Type 2).	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (28, 33))	('%MET', 'Var', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
28802	26636767	Further studies using IF combined with FISH showed that MET protein overexpression (IF 3+) was colocalized in tumor tissues with average MET gene copy number >5 (PRCC-009, 052, 097; Fig 4).	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('MET gene copy number >5', 'Var', (137, 160))	('PRCC', 'Gene', '5546', (162, 166))	('protein', 'cellular_component', 'GO:0003675', ('60', '67'))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('PRCC', 'Gene', (162, 166))	('overexpression', 'PosReg', (68, 82))	('MET protein', 'Protein', (56, 67))	('PRCC', 'Phenotype', 'HP:0006766', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
28806	26636767	Hereditary Type 1 PRCC has been linked to a genetic mutation in the MET gene.	('MET', 'Gene', (68, 71))	('PRCC', 'Gene', '5546', (18, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('genetic mutation', 'Var', (44, 60))	('PRCC', 'Gene', (18, 22))	('linked', 'Reg', (32, 38))	('PRCC', 'Phenotype', 'HP:0006766', (18, 22))
28807	26636767	In addition, in a previous phase II clinical trial, Foretinib (targeting VEGF/MET) showed a high (50%) response rate in PRCC patients with germline MET mutations.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('PRCC', 'Gene', (120, 124))	('PRCC', 'Phenotype', 'HP:0006766', (120, 124))	('VEGF', 'Gene', '7422', (73, 77))	('MET mutations', 'Var', (148, 161))	('Foretinib', 'Chemical', 'MESH:C544831', (52, 61))	('PRCC', 'Gene', '5546', (120, 124))	('germline', 'Var', (139, 147))	('VEGF', 'Gene', (73, 77))	('patients', 'Species', '9606', (125, 133))
28815	26636767	These results suggest a role for Chromosome 7 trisomy or polysomy during the pathogenesis of sporadic PRCC.	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('PRCC', 'Gene', (102, 106))	('Chromosome', 'cellular_component', 'GO:0005694', ('33', '43'))	('PRCC', 'Phenotype', 'HP:0006766', (102, 106))	('pathogenesis', 'biological_process', 'GO:0009405', ('77', '89'))	('trisomy', 'Var', (46, 53))	('polysomy', 'Var', (57, 65))	('PRCC', 'Gene', '5546', (102, 106))
28816	26636767	Chromosome 7 gain (trisomy 7) has also been observed in hereditary PRCC, and causes duplication of a mutated MET gene.	('MET', 'Gene', (109, 112))	('PRCC', 'Gene', (67, 71))	('duplication', 'MPA', (84, 95))	('mutated', 'Var', (101, 108))	('PRCC', 'Phenotype', 'HP:0006766', (67, 71))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('PRCC', 'Gene', '5546', (67, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('gain', 'PosReg', (13, 17))
28818	26636767	Furthermore, we also found an increasing trend in the percentage of tumor cells with MET gene copy number >=3 together with higher MET IHC score, suggestive of a relationship between MET gene copy number increase and MET protein overexpression.	('tumor', 'Disease', (68, 73))	('protein', 'cellular_component', 'GO:0003675', ('221', '228'))	('MET gene copy number >=3', 'Var', (85, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
28819	26636767	Finally, our findings from the combined IF/FISH studies provide direct evidence that MET protein overexpression is observed in the same PRCC tumor cells with a high MET gene copy number increase (>5), but not in those tumor cells with normal MET gene copy number.	('overexpression', 'PosReg', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('PRCC', 'Gene', (136, 140))	('increase', 'PosReg', (186, 194))	('high MET gene copy number', 'Var', (160, 185))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (141, 146))	('PRCC', 'Phenotype', 'HP:0006766', (136, 140))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('PRCC', 'Gene', '5546', (136, 140))	('tumor', 'Disease', (218, 223))	('MET protein', 'Protein', (85, 96))	('protein', 'cellular_component', 'GO:0003675', ('89', '96'))
28821	26636767	Our results clearly demonstrate that MET gene copy number increases in PRCC tumors are highly associated with increases in the copy number of Chromosome 7, which differs from previous observations in lung and gastric cancer.	('increases', 'PosReg', (58, 67))	('PRCC tumors', 'Disease', 'MESH:D009369', (71, 82))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('PRCC', 'Phenotype', 'HP:0006766', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('copy number', 'MPA', (127, 138))	('increases', 'PosReg', (110, 119))	('gastric cancer', 'Disease', (209, 223))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MET', 'Var', (37, 40))	('PRCC tumors', 'Disease', (71, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (209, 223))	('gastric cancer', 'Phenotype', 'HP:0012126', (209, 223))	('Chromosome', 'cellular_component', 'GO:0005694', ('142', '152'))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
28904	32570266	RN was widely utilized for cT1b tumors, while it was also a recommended therapy for T2a (TNM classification) and other tumors with relatively large sizes.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', (119, 125))	('cT1b', 'Var', (27, 31))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('TNM', 'Gene', (89, 92))	('men', 'Species', '9606', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('T2a', 'Disease', (84, 87))	('tumors', 'Disease', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('TNM', 'Gene', '10178', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
28929	31006167	Notably, we also observed increased miR-204-5p levels in urinary exosomes in 20-week-old renal PRCC-TFE3 Tg mice prior to tRCC development, and those levels were equivalent to those in 40-week-old Tg mice, suggesting that miR-204-5p increases follow expression of constitutively active TFE3 fusion proteins in renal tubular epithelial cells prior to overt tRCC development.	('RCC', 'Disease', (96, 99))	('increases', 'PosReg', (233, 242))	('miR-204-5p', 'Var', (222, 232))	('mice', 'Species', '10090', (108, 112))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('mice', 'Species', '10090', (200, 204))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (357, 360))	('RCC', 'Disease', (357, 360))	('RCC', 'Phenotype', 'HP:0005584', (357, 360))	('RCC', 'Phenotype', 'HP:0005584', (96, 99))	('expression', 'MPA', (250, 260))	('TFE3 fusion proteins', 'Protein', (286, 306))	('RCC', 'Disease', 'MESH:C538614', (96, 99))
28931	31006167	These findings suggest that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.	('Xp11', 'Gene', (124, 128))	('Xp11', 'Gene', '111712', (124, 128))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('miR-204-5p', 'Var', (28, 38))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('patients', 'Species', '9606', (110, 118))
28934	31006167	Here, we overcome this hurdle by generating transgenic (Tg) mice overexpressing a human PRCC-TFE3 fusion gene in renal tubular epithelial cells as an Xp11 tRCC mouse model.	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('Xp11', 'Gene', '111712', (150, 154))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('RCC', 'Disease', (89, 92))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('transgenic', 'Species', '10090', (44, 54))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('fusion gene', 'Var', (98, 109))	('Xp11', 'Gene', (150, 154))	('mice', 'Species', '10090', (60, 64))	('mouse', 'Species', '10090', (160, 165))	('human', 'Species', '9606', (82, 87))
28937	31006167	Interestingly, we also observed increased miR-204-5p levels in urinary exosomes from renal PRCC-TFE3 Tg mice prior to tRCC development, suggesting that miR-204-5p increases as a consequence of constitutively active TFE3 chimeric proteins in renal tubular epithelial cells rather than as a consequence of tRCC development.	('miR-204-5p', 'Var', (152, 162))	('RCC', 'Disease', 'MESH:C538614', (305, 308))	('mice', 'Species', '10090', (104, 108))	('RCC', 'Disease', (305, 308))	('increases', 'PosReg', (163, 172))	('RCC', 'Phenotype', 'HP:0005584', (305, 308))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('increased', 'PosReg', (32, 41))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('TFE3 chimeric proteins', 'Protein', (215, 237))
28938	31006167	We conclude that miR-204-5p in urinary exosomes could be a useful biomarker for early diagnosis of patients with Xp11 tRCC.	('Xp11', 'Gene', '111712', (113, 117))	('Xp11', 'Gene', (113, 117))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('patients', 'Species', '9606', (99, 107))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('miR-204-5p', 'Var', (17, 27))
28946	31006167	Genotyping of tail DNA was carried out using the following the primers: Rosa26-S (5'-GTTTCCGACTTGAGTT-3') and Rosa26-AS (5'-AACCCCAGATGACTAC-3') to detect the WT allele; and mRosa26-S (5'-GGCGGACTGGCGGGACTA-3') and mRosa26-AS (5'-GGGACAGGATAAGTATGACATCATCAAGG-3') to detect the mutant allele.	('mutant', 'Var', (278, 284))	('Rosa26', 'Gene', (216, 222))	('Rosa26', 'Gene', (72, 78))	('Rosa26', 'Gene', (110, 116))	('Rosa26', 'Gene', '14910', (175, 181))	('Rosa26', 'Gene', '14910', (216, 222))	('Rosa26', 'Gene', (175, 181))	('Rosa26', 'Gene', '14910', (72, 78))	('Rosa26', 'Gene', '14910', (110, 116))	('DNA', 'cellular_component', 'GO:0005574', ('19', '22'))
28979	31006167	Moreover, we observed no significant difference in body weight between control and renal PRCC-TFE3 Tg mice at 20 weeks of age; in contrast, by 40 weeks, renal PRCC-TFE3 Tg mice showed significantly decreased body weight compared with control mice (Figure S2A).	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('mice', 'Species', '10090', (102, 106))	('decreased body weight', 'Phenotype', 'HP:0004325', (198, 219))	('renal PRCC-TFE3 Tg', 'Var', (153, 171))	('RCC', 'Phenotype', 'HP:0005584', (160, 163))	('mice', 'Species', '10090', (172, 176))	('decreased', 'NegReg', (198, 207))	('body weight', 'CPA', (208, 219))	('mice', 'Species', '10090', (242, 246))
28987	31006167	Of the remaining 2 candidates, levels of miR-204-5p significantly increased in Tg mice relative to controls at both 20 and 40 weeks of age.	('levels', 'MPA', (31, 37))	('miR-204-5p', 'Var', (41, 51))	('increased', 'PosReg', (66, 75))	('mice', 'Species', '10090', (82, 86))
28989	31006167	Moreover, levels of both miR-204-5p and miR-211-5p in urinary exosomes were comparable in 20- and 40-week-old Tg mice, suggesting that changes in their expression are detectable prior to overt tRCC development.	('RCC', 'Disease', 'MESH:C538614', (194, 197))	('RCC', 'Disease', (194, 197))	('RCC', 'Phenotype', 'HP:0005584', (194, 197))	('miR-211-5p', 'Gene', '100313840', (40, 50))	('miR-211-5p', 'Gene', (40, 50))	('mice', 'Species', '10090', (113, 117))	('miR-204-5p', 'Var', (25, 35))
28990	31006167	We next asked whether miR-204-5p and miR-211-5p are secreted from cancer cells in kidneys of renal PRCC-TFE3 Tg mice.	('cancer', 'Disease', (66, 72))	('miR-204-5p', 'Var', (22, 32))	('miR-211-5p', 'Gene', '100313840', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR-211-5p', 'Gene', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('mice', 'Species', '10090', (112, 116))
28998	31006167	Overall, these results suggest that exosomes containing miR-204-5p or miR-211-5p are secreted from some tRCC lines.	('miR-211-5p', 'Gene', (70, 80))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('miR-211-5p', 'Gene', '100313840', (70, 80))	('miR-204-5p', 'Var', (56, 66))
29001	31006167	In tRCC1 and tRCC2 lines, Trpm1 and Trpm3 expression levels were significantly increased relative to levels seen in M-1 cells, suggesting that expression of miR-211-5p and miR-204-5p as well as Trpm1 and Trpm3 is positively correlated with expression of PRCC-TFE3 fusion proteins in kidney cancer cells.	('Trpm1', 'Gene', (194, 199))	('kidney cancer', 'Disease', (283, 296))	('RCC', 'Disease', (14, 17))	('Trpm3', 'Gene', (36, 41))	('Trpm1', 'Gene', '4308', (194, 199))	('RCC', 'Disease', (4, 7))	('RCC', 'Phenotype', 'HP:0005584', (4, 7))	('miR-211-5p', 'Gene', (157, 167))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('Trpm1', 'Gene', (26, 31))	('Trpm1', 'Gene', '4308', (26, 31))	('RCC', 'Disease', (255, 258))	('RCC', 'Phenotype', 'HP:0005584', (255, 258))	('RCC', 'Disease', 'MESH:C538614', (4, 7))	('Trpm3', 'Gene', '80036', (204, 209))	('correlated', 'Reg', (224, 234))	('kidney cancer', 'Disease', 'MESH:D007680', (283, 296))	('miR-211-5p', 'Gene', '100313840', (157, 167))	('RCC', 'Disease', 'MESH:C538614', (255, 258))	('miR-204-5p', 'Var', (172, 182))	('increased', 'PosReg', (79, 88))	('Trpm3', 'Gene', (204, 209))	('expression levels', 'MPA', (42, 59))	('Trpm3', 'Gene', '80036', (36, 41))	('kidney cancer', 'Phenotype', 'HP:0009726', (283, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
29004	31006167	Expression levels of both miR-204-5p and miR-211-5p significantly increased in doxycycline-treated relative to untreated HEK293/PRCC-TFE3 cells (Figure 4C), as did TRPM1 and TRPM3 expression (Figure 4D).	('miR-211-5p', 'Gene', (41, 51))	('doxycycline', 'Chemical', 'MESH:D004318', (79, 90))	('increased', 'PosReg', (66, 75))	('Expression levels', 'MPA', (0, 17))	('expression', 'MPA', (180, 190))	('TRPM3', 'Gene', (174, 179))	('miR-204-5p', 'Var', (26, 36))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('TRPM1', 'Gene', (164, 169))	('HEK293', 'CellLine', 'CVCL:0045', (121, 127))	('miR-211-5p', 'Gene', '100313840', (41, 51))
29008	31006167	We next examined miR-211-5p and miR-204-5p expression in UOK120, UOK124, and HK-2 cells (Figure 5C).	('miR-211-5p', 'Gene', (17, 27))	('miR-204-5p', 'Var', (32, 42))	('HK-2', 'Gene', '3099', (77, 81))	('miR-211-5p', 'Gene', '100313840', (17, 27))	('HK-2', 'molecular_function', 'GO:0008256', ('77', '81'))	('UOK124', 'CellLine', 'CVCL:B105', (65, 71))	('HK-2', 'Gene', (77, 81))
29011	31006167	Accordingly, we observed no difference in TRPM1 expression among UOK120, UOK124, and HK-2 cells, whereas TRPM3 expression levels significantly increased in UOK120 and UOK124 relative to HK-2 cells (Figure 5E).	('increased', 'PosReg', (143, 152))	('UOK124', 'CellLine', 'CVCL:B105', (167, 173))	('expression', 'MPA', (48, 58))	('UOK124', 'Var', (167, 173))	('HK-2', 'Gene', '3099', (186, 190))	('HK-2', 'molecular_function', 'GO:0008256', ('85', '89'))	('HK-2', 'molecular_function', 'GO:0008256', ('186', '190'))	('HK-2', 'Gene', (186, 190))	('TRPM1', 'Gene', (42, 47))	('TRPM3 expression levels', 'MPA', (105, 128))	('HK-2', 'Gene', '3099', (85, 89))	('UOK124', 'CellLine', 'CVCL:B105', (73, 79))	('UOK120', 'Var', (156, 162))	('HK-2', 'Gene', (85, 89))
29012	31006167	These results show that expression of both miR-204-5p and TRPM3 is upregulated in human Xp11 tRCC cells and that human Xp11 tRCC cells secrete exosomes containing miR-204-5p.	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('miR-204-5p', 'Var', (163, 173))	('expression', 'MPA', (24, 34))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('secrete', 'MPA', (135, 142))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('Xp11', 'Gene', (88, 92))	('TRPM3', 'Gene', (58, 63))	('Xp11', 'Gene', (119, 123))	('human', 'Species', '9606', (113, 118))	('miR-204-5p', 'Gene', (43, 53))	('Xp11', 'Gene', '111712', (88, 92))	('upregulated', 'PosReg', (67, 78))	('human', 'Species', '9606', (82, 87))	('Xp11', 'Gene', '111712', (119, 123))
29014	31006167	Immunoblotting analysis revealed decreased levels of PRCC-TFE3 fusion proteins in siTFE3-1- or siTFE3-2-transfected Xp11 tRCC cells relative to control cells (Figure S4A).	('siTFE3-1-', 'Var', (82, 91))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('levels', 'MPA', (43, 49))	('Xp11', 'Gene', (116, 120))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('decreased', 'NegReg', (33, 42))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('Xp11', 'Gene', '111712', (116, 120))
29017	31006167	Levels of PRCC-TFE3 fusion proteins in doxycycline-treated HEK293/PRCC-TFE3 cells also markedly decreased following transfection with siTFE3-2 (Figure S5A).	('Levels', 'MPA', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('transfection', 'Var', (116, 128))	('decreased', 'NegReg', (96, 105))	('HEK293', 'CellLine', 'CVCL:0045', (59, 65))	('doxycycline', 'Chemical', 'MESH:D004318', (39, 50))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))
29018	31006167	Furthermore, PRCC-TFE3 knockdown significantly reduced expression levels of miR-204-5p and TRPM3 in doxycycline-treated HEK293/PRCC-TFE3 cells (Figure S5B,C).	('TRPM3', 'Gene', (91, 96))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('HEK293', 'CellLine', 'CVCL:0045', (120, 126))	('knockdown', 'Var', (23, 32))	('miR-204-5p', 'Gene', (76, 86))	('expression levels', 'MPA', (55, 72))	('reduced', 'NegReg', (47, 54))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))	('doxycycline', 'Chemical', 'MESH:D004318', (100, 111))
29019	31006167	Taken together, these results suggest that expression of both miR-204-5p and TRPM3 in noncancerous kidney cells is upregulated in a TFE3 fusion protein-dependent manner, whereas TFE3 fusion proteins are no longer required for their expression in Xp11 tRCC cells.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('RCC', 'Phenotype', 'HP:0005584', (252, 255))	('TRPM3', 'Gene', (77, 82))	('RCC', 'Disease', 'MESH:C538614', (252, 255))	('Xp11', 'Gene', (246, 250))	('RCC', 'Disease', (252, 255))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('expression', 'MPA', (43, 53))	('Xp11', 'Gene', '111712', (246, 250))	('upregulated', 'PosReg', (115, 126))	('miR-204-5p', 'Var', (62, 72))
29020	31006167	Here, we show that miR-204-5p levels in urinary exosomes from our established Xp11 tRCC mouse model significantly increase relative to those in control mice.	('increase', 'PosReg', (114, 122))	('Xp11', 'Gene', (78, 82))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('miR-204-5p', 'Var', (19, 29))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('mice', 'Species', '10090', (152, 156))	('mouse', 'Species', '10090', (88, 93))	('Xp11', 'Gene', '111712', (78, 82))
29023	31006167	Moreover, we found that tRCCs secrete exosomes containing miR-204-5p.	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('miR-204-5p', 'Var', (58, 68))	('RCC', 'Disease', (25, 28))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))
29024	31006167	These findings suggest that the presence of miR-204-5p in urinary exosomes could be a useful biomarker for early detection of Xp11 tRCC.	('Xp11', 'Gene', '111712', (126, 130))	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('miR-204-5p', 'Var', (44, 54))	('Xp11', 'Gene', (126, 130))
29030	31006167	These observations support the idea that miR-204-5p in urinary exosomes could serve as an early diagnostic biomarker of Xp11 tRCC progression at pretumorigenic disease stages.	('Xp11', 'Gene', '111712', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (148, 153))	('Xp11', 'Gene', (120, 124))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('miR-204-5p', 'Var', (41, 51))	('RCC', 'Disease', 'MESH:C538614', (126, 129))
29036	31006167	However, we did not detect miR-211-5p in human Xp11 tRCC lines that show abundant miR-204-5p expression.	('Xp11', 'Gene', '111712', (47, 51))	('miR-211-5p', 'Gene', (27, 37))	('human', 'Species', '9606', (41, 46))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('Xp11', 'Gene', (47, 51))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('miR-204-5p', 'Var', (82, 92))	('miR-211-5p', 'Gene', '100313840', (27, 37))
29039	31006167	It would be of interest to investigate whether either miR-204-5p or miR-211-5p contained in liquid biopsy samples predicts Xp11 tRCC occurrence in patients prior to overt tRCC development.	('miR-211-5p', 'Gene', (68, 78))	('predicts', 'Reg', (114, 122))	('Xp11', 'Gene', '111712', (123, 127))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('miR-211-5p', 'Gene', '100313840', (68, 78))	('RCC', 'Disease', (129, 132))	('Xp11', 'Gene', (123, 127))	('miR-204-5p', 'Var', (54, 64))	('patients', 'Species', '9606', (147, 155))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
29045	31006167	The MiT family proteins, including TFE3, activate transcription of targets through the E-box consensus motif CANNTG,9 as do TFE3 fusion proteins.2, 9 Numerous transcription factors reportedly bind E-boxes and some, such as myc and hypoxia-inducible factor, are activated in human RCC cells.34, 38 These factors might also contribute to expression of both miR-204-5p and TRPM3 in Xp11 tRCC cells.	('miR-204-5p', 'Var', (355, 365))	('hypoxia', 'Disease', 'MESH:D000860', (231, 238))	('contribute', 'Reg', (322, 332))	('Xp11', 'Gene', (379, 383))	('hypoxia', 'Disease', (231, 238))	('TRPM3', 'Gene', (370, 375))	('RCC', 'Disease', 'MESH:C538614', (280, 283))	('transcription', 'biological_process', 'GO:0006351', ('159', '172'))	('RCC', 'Disease', (280, 283))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('transcription', 'biological_process', 'GO:0006351', ('50', '63'))	('Xp11', 'Gene', '111712', (379, 383))	('RCC', 'Phenotype', 'HP:0005584', (385, 388))	('RCC', 'Disease', 'MESH:C538614', (385, 388))	('human', 'Species', '9606', (274, 279))	('RCC', 'Disease', (385, 388))
29047	31006167	In summary, we found that miR-204-5p levels in urinary exosomes are significantly increased in both pretumorigenic and tumor developing stages in renal PRCC-TFE3 Tg mice.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (103, 108))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('miR-204-5p', 'Var', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('increased', 'PosReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
29062	30458744	Xp11.2 translocation RCC results from gene fusions between the transcription factor E3 (TFE3) gene located on chromosome Xp11.2 and various fusion partners.	('gene fusions', 'Var', (38, 50))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))	('p11', 'Gene', '6281', (1, 4))	('TFE3', 'Gene', (88, 92))	('p11', 'Gene', (122, 125))	('transcription factor', 'molecular_function', 'GO:0000981', ('63', '83'))	('transcription factor E3', 'Gene', (63, 86))	('results from', 'Reg', (25, 37))	('TFE3', 'Gene', '7030', (88, 92))	('transcription', 'biological_process', 'GO:0006351', ('63', '76'))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('transcription factor E3', 'Gene', '7030', (63, 86))	('p11', 'Gene', '6281', (122, 125))	('p11', 'Gene', (1, 4))
29065	30458744	A common fusion partner gene is alveolar soft part sarcoma critical region 1 (ASPSCR1), der(17)t(X;17)(p11.2;q25).	('ASPSCR1', 'Gene', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('der(17)t(X;17)(p11.2;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (88, 113))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (32, 58))	('alveolar soft part sarcoma', 'Disease', (32, 58))	('ASPSCR1', 'Gene', '79058', (78, 85))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (32, 58))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (41, 58))	('der(17)t(X;17)(p11.2;q25', 'Var', (88, 112))
29070	30458744	In this report, we present an extremely rare case of bilateral Xp11.2 translocation RCC occurring metachronously, and discuss the uncommon features of this case as determined by histopathological, cytogenetic and molecular approaches.	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('p11', 'Gene', '6281', (64, 67))	('p11', 'Gene', (64, 67))	('translocation', 'Var', (70, 83))
29093	30458744	A fused or closely approximated green-red signal pattern was interpreted as a normal result, whereas a TFE3 fusion resulted in a split-signal pattern.	('TFE3', 'Gene', '7030', (103, 107))	('green-red signal pattern', 'MPA', (32, 56))	('fusion', 'Var', (108, 114))	('TFE3', 'Gene', (103, 107))	('split-signal', 'MPA', (129, 141))
29096	30458744	The TFE3 gene showed gene splitting in 71.55% of 130 neoplastic cells and in 76.82% of 233 neoplastic cells in the present and the previous tumor, respectively.	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('gene splitting', 'Var', (21, 35))	('TFE3', 'Gene', (4, 8))	('TFE3', 'Gene', '7030', (4, 8))
29107	30458744	There is variation in the histological features of Xp11.2 translocation RCC such as clear cell, papillary, alveolar, and nested.	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('p11', 'Gene', '6281', (52, 55))	('translocation', 'Var', (58, 71))	('alveolar', 'Disease', (107, 115))	('papillary', 'Disease', (96, 105))	('p11', 'Gene', (52, 55))	('clear', 'Disease', (84, 89))
29108	30458744	Seventy five percent of adult Xp11.2 translocation RCC is predominately the clear cell histological type, whereas most pediatric cases consist of papillary histological features.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('p11', 'Gene', '6281', (31, 34))	('p11', 'Gene', (31, 34))	('translocation', 'Var', (37, 50))
29115	30458744	Melanosome and Melanin A staining have not been reported in Xp11.2 translocation RCC with ASPL-TFE3 and PRCC-TFE3 fusion.	('p11', 'Gene', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('PRCC-TFE3', 'Gene', '5546;7030', (104, 113))	('Melanosome', 'cellular_component', 'GO:0042470', ('0', '10'))	('PRCC-TFE3', 'Gene', (104, 113))	('p11', 'Gene', '6281', (61, 64))	('ASPL-TFE3', 'Gene', '79058;7030', (90, 99))	('translocation', 'Var', (67, 80))	('ASPL-TFE3', 'Gene', (90, 99))	('Melanin', 'Chemical', 'MESH:D008543', (15, 22))
29122	30458744	Analysis of von Hippel Lindau tumor suppressor gene mutation by direct sequencing and multiplex ligation-dependent probe amplification methods also gave a negative result (data not shown).	('von Hippel Lindau tumor', 'Disease', (12, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('von Hippel Lindau tumor', 'Disease', 'MESH:D006623', (12, 35))	('mutation', 'Var', (52, 60))	('tumor suppressor', 'biological_process', 'GO:0051726', ('30', '46'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('30', '46'))
29124	30458744	In conclusion, we present a case that may be diagnosed as bilateral Xp11.2 translocation RCC metachronously occurring.	('translocation', 'Var', (75, 88))	('p11', 'Gene', (69, 72))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('p11', 'Gene', '6281', (69, 72))
29149	30093597	Furthermore, we studied the earliest precursor lesions of ccRCC: CA9+ proximal tubular cells residing in morphologically normal kidney, predisposed to ccRCC through pathogenic germline mutation of VHL.	('VHL', 'Disease', 'MESH:D006623', (197, 200))	('germline mutation', 'Var', (176, 193))	('ccRCC', 'Disease', (151, 156))	('VHL', 'Disease', (197, 200))
29157	30093597	S18A) exhibited lymphangiogenic VEGFC and FLT1.	('S18A', 'SUBSTITUTION', 'None', (0, 4))	('S18A', 'Var', (0, 4))	('VEGFC', 'Gene', (32, 37))	('VEGFC', 'Gene', '7424', (32, 37))
29196	28414866	To determine the utility of the International mRCC Database Consortium (IMDC) prognostic model in pRCC, patients were stratified into risk groups based on the IMDC prognostic factors: hemoglobin below the lower limit of normal (LLN), corrected calcium greater than the upper limit of normal (ULN), neutrophils above ULN, platelets above ULN, Karnofsky performance status (KPS) below 80%, and time from diagnosis to treatment of <1 year 12.	('below', 'NegReg', (195, 200))	('below', 'NegReg', (377, 382))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('hemoglobin', 'MPA', (184, 194))	('pRCC', 'Gene', (98, 102))	('Karnofsky performance status', 'CPA', (342, 370))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('platelets', 'CPA', (321, 330))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('pRCC', 'Gene', '5546', (98, 102))	('pRCC', 'Phenotype', 'HP:0006766', (98, 102))	('calcium', 'Chemical', 'MESH:D002118', (244, 251))	('corrected calcium', 'MPA', (234, 251))	('patients', 'Species', '9606', (104, 112))	('neutrophils', 'Var', (298, 309))
29224	28414866	Only two clinical trials, SUPAP (NCT00541008) and RAPTOR (NCT00688753), have enrolled pRCC patients by subtype, but each enrolled only 15 and 13 type I patients, respectively 19, 20.	('NCT00541008', 'Var', (33, 44))	('patients', 'Species', '9606', (91, 99))	('pRCC', 'Phenotype', 'HP:0006766', (86, 90))	('pRCC', 'Gene', '5546', (86, 90))	('RAPTOR', 'Gene', (50, 56))	('RAPTOR', 'Gene', '57521', (50, 56))	('NCT00688753', 'Var', (58, 69))	('pRCC', 'Gene', (86, 90))	('patients', 'Species', '9606', (152, 160))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
29236	28414866	ASPEN included 70 pRCC patients and found sunitinib to have a higher ORR (24% vs. 5%) and a longer median PFS (8.1 months vs. 5.5 months) than everolimus, but reported no difference in OS 27.	('sunitinib', 'Var', (42, 51))	('sunitinib', 'Chemical', 'MESH:D000077210', (42, 51))	('pRCC', 'Gene', '5546', (18, 22))	('patients', 'Species', '9606', (23, 31))	('pRCC', 'Phenotype', 'HP:0006766', (18, 22))	('PFS', 'MPA', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('ORR', 'MPA', (69, 72))	('pRCC', 'Gene', (18, 22))	('higher', 'PosReg', (62, 68))	('everolimus', 'Chemical', 'MESH:D000068338', (143, 153))
29248	28414866	MET pathway alterations were traditionally associated with type I pRCC, however recent studies have identified that type II pRCCs can also display high-MET expression 4, 5.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('pRCC', 'Gene', '5546', (124, 128))	('pRCC', 'Gene', '5546', (66, 70))	('alterations', 'Var', (12, 23))	('pRCC', 'Phenotype', 'HP:0006766', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('pRCC', 'Gene', (124, 128))	('pRCC', 'Gene', (66, 70))	('MET pathway', 'Pathway', (0, 11))	('high-MET expression', 'MPA', (147, 166))
29264	25790038	We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour.	('SETD2', 'Gene', '29072', (54, 59))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('SETD2', 'Gene', (54, 59))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (60, 69))	('tumour', 'Disease', (111, 117))
29265	25790038	By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution.	('pRCC', 'Phenotype', 'HP:0006766', (110, 114))	('large copy number gains', 'Var', (13, 36))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('pRCC', 'Gene', (110, 114))	('pRCC', 'Gene', '5546', (110, 114))
29266	25790038	The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.	('pRCC', 'Phenotype', 'HP:0006766', (72, 76))	('pRCC', 'Gene', '5546', (72, 76))	('large copy number variants', 'Var', (20, 46))	('pRCC', 'Gene', (72, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
29270	25790038	The most common type of RCC has a clear cell morphology (ccRCC) and usually arises owing to mutations in the VHL tumour suppressor gene.	('RCC', 'Disease', (24, 27))	('VHL tumour', 'Disease', 'MESH:D006623', (109, 119))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('arises owing to', 'Reg', (76, 91))	('mutations', 'Var', (92, 101))	('VHL tumour', 'Disease', (109, 119))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
29271	25790038	Several other ccRCC driver mutations have been identified.	('RCC', 'Disease', (16, 19))	('mutations', 'Var', (27, 36))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (16, 19))
29272	25790038	Papillary RCC (pRCC) is the second most common morphological type and germline MET, FH and, occasionally, FLCN mutations predispose to pRCCs.	('predispose', 'Reg', (121, 131))	('mutations', 'Var', (111, 120))	('Papillary RCC', 'Gene', '5546', (0, 13))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('Papillary RCC', 'Gene', (0, 13))	('pRCC', 'Gene', '5546', (15, 19))	('pRCC', 'Gene', '5546', (135, 139))	('FLCN', 'Gene', '201163', (106, 110))	('pRCC', 'Phenotype', 'HP:0006766', (135, 139))	('pRCC', 'Phenotype', 'HP:0006766', (15, 19))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Phenotype', 'HP:0005584', (10, 13))	('FLCN', 'Gene', (106, 110))	('pRCC', 'Gene', (15, 19))	('pRCC', 'Gene', (135, 139))
29273	25790038	These mutations respectively cause the Mendelian conditions of hereditary pRCC, hereditary leiomyomatosis and RCC, and Birt-Hogg-Dube syndrome.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('hereditary leiomyomatosis', 'Disease', (80, 105))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('mutations', 'Var', (6, 15))	('pRCC', 'Gene', '5546', (74, 78))	('pRCC', 'Phenotype', 'HP:0006766', (74, 78))	('Birt-Hogg-Dube syndrome', 'Disease', (119, 142))	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (80, 105))	('cause', 'Reg', (29, 34))	('Birt-Hogg-Dube syndrome', 'Disease', 'MESH:D058249', (119, 142))	('pRCC', 'Gene', (74, 78))
29274	25790038	Somatic MET mutations occur in a small proportion of sporadic pRCCs and a greater number show somatic copy number gains involving the MET locus on chromosome 7q.	('copy number gains', 'Var', (102, 119))	('pRCC', 'Phenotype', 'HP:0006766', (62, 66))	('pRCC', 'Gene', '5546', (62, 66))	('mutations', 'Var', (12, 21))	('pRCC', 'Gene', (62, 66))	('MET', 'Gene', (8, 11))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))
29276	25790038	The genetic basis of these less common lesions is complex, and includes germline FLCN mutations in some cases.	('mutations', 'Var', (86, 95))	('FLCN', 'Gene', '201163', (81, 85))	('FLCN', 'Gene', (81, 85))
29277	25790038	RCCs resulting from high-penetrance germline mutations are frequently multi-focal, but up to 20% of apparently sporadic RCCs also have several discrete nodules in one or both kidneys.	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('germline', 'Var', (36, 44))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
29280	25790038	Recent studies based on next-generation sequencing have largely resolved the issue of ccRCC clonality, showing a common initiating VHL mutation, followed by divergence as different subsequent driver mutations are acquired and selected.	('VHL', 'Gene', (131, 134))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('VHL', 'Gene', '7428', (131, 134))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('mutation', 'Var', (135, 143))
29287	25790038	In contrast to ccRCC, relatively little is known about the mutations that drive pRCC growth and the clonality of copy number events and single-nucleotide variants (SNVs), apart from the small minority of cancers with changes in MET and FH.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('pRCC', 'Gene', '5546', (80, 84))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('single-nucleotide variants', 'Var', (136, 162))	('pRCC', 'Phenotype', 'HP:0006766', (80, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('RCC', 'Disease', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('pRCC', 'Gene', (80, 84))
29289	25790038	We find driver mutations in BAP1, SETD2, ARID2 and Nrf2 pathway genes that frequently occur within sub-clones, and recurrent, large-scale copy number changes that are usually present in major clones.	('BAP1', 'Gene', '8314', (28, 32))	('ARID2', 'Gene', (41, 46))	('Nrf2', 'Gene', '4780', (51, 55))	('mutations', 'Var', (15, 24))	('BAP1', 'Gene', (28, 32))	('SETD2', 'Gene', '29072', (34, 39))	('Nrf2', 'Gene', (51, 55))	('SETD2', 'Gene', (34, 39))	('ARID2', 'Gene', '196528', (41, 46))
29294	25790038	Nineteen tumours (P01-07, P16-23, GK116_2, GK116_3, GK102 and RK133) underwent Agilent SureSelect or Illumina TruSeq exome capture, followed by sequencing on the Illumina HiSeq platform at median 110 x depth (cross-sample range 27-372 x ).	('P16', 'Gene', (26, 29))	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('tumours', 'Disease', (9, 16))	('P16', 'Gene', '1029', (26, 29))	('P01-07', 'Var', (18, 24))	('GK102', 'Var', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('GK116_2', 'Var', (34, 41))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('GK116_3', 'Var', (43, 50))
29295	25790038	A further four cancers (GK101, GK116_1, RK30 and RK36) underwent multi-region sampling, SureSelect exome capture and Illumina HiSeq sequencing, but the sequence data from the multiple regions of these tumours were combined for our initial analyses, resulting in median 173 x read depth (cross-sample range 131-240 x ).	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('tumours', 'Disease', (201, 208))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('GK116_1', 'Var', (31, 38))	('GK101', 'Var', (24, 29))
29298	25790038	C:G>T:A changes were the most common, followed by T:A>C:G, C:G>A:T and C:G>G:C changes.	('C:G>T:A changes', 'Var', (0, 15))	('changes', 'Var', (8, 15))	('C:G>A:T', 'Var', (59, 66))	('C:G>G', 'Var', (71, 76))	('T:A>C:G', 'Var', (50, 57))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (59, 60))
29301	25790038	Of the four most extreme cancers, two (GK102, P17) had a large proportion of C:G>T:A changes, one (P07) tended to acquire C:G>A:T changes and another (RK30) had mostly T:A>G:C changes.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('P17', 'Gene', '653820', (46, 49))	('changes', 'Var', (85, 92))	('C:G>T:A changes', 'Var', (77, 92))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('cancers', 'Disease', (25, 32))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('C', 'Chemical', 'MESH:D002244', (122, 123))	('P17', 'Gene', (46, 49))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('C', 'Chemical', 'MESH:D002244', (174, 175))
29304	25790038	Signature 5 is characterized by a small excess of C>T and T>C changes of uncertain aetiology with no clear trinucleotide context bias.	('T>C', 'Var', (58, 61))	('trinucleotide', 'Chemical', '-', (107, 120))	('C', 'Chemical', 'MESH:D002244', (50, 51))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C>T', 'Var', (50, 53))
29305	25790038	With the exception of the relatively hypermutant cancers highlighted above, most of our pRCCs' mutation spectra were consistent with signature 5 (Supplementary Data 1).	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('pRCC', 'Phenotype', 'HP:0006766', (88, 92))	('pRCC', 'Gene', '5546', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('pRCC', 'Gene', (88, 92))	('cancers', 'Disease', (49, 56))	('mutation', 'Var', (95, 103))
29306	25790038	Signature 2 is characterized by C>T and C>G changes, especially when the preceding base is T, but none of our cancers clearly had this signature.	('cancers', 'Disease', (110, 117))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('C>T', 'Var', (32, 35))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
29313	25790038	We initially investigated all 31 cancers and paired constitutional DNA for mutations in the Mendelian pRCC genes MET, FH and FLCN (Supplementary Table 2).	('investigated', 'Reg', (13, 25))	('MET', 'Gene', (113, 116))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('pRCC', 'Gene', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('FLCN', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (75, 84))	('DNA', 'cellular_component', 'GO:0005574', ('67', '70'))	('FLCN', 'Gene', '201163', (125, 129))	('pRCC', 'Phenotype', 'HP:0006766', (102, 106))	('pRCC', 'Gene', '5546', (102, 106))
29314	25790038	Patient P11 carried the germline FH variant c.1189G>A (p.Gly397Arg) and the tumour showed copy-neutral LOH around FH.	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('c.1189G>A', 'Mutation', 'c.1189G>A', (44, 53))	('p.Gly397Arg', 'Mutation', 'p.G397R', (55, 66))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('P11', 'Gene', (8, 11))	('tumour', 'Disease', (76, 82))	('c.1189G>A', 'Var', (44, 53))	('P11', 'Gene', '6281', (8, 11))	('Patient', 'Species', '9606', (0, 7))
29315	25790038	Tumour RK36 had acquired a somatic MET mutation, c.G799A (p.Glu267Lys; Table 2) that has strong predicted functional effects and lies next to a residue recurrently mutated in human cancer, but has not itself been reported as mutated (http://cancer.sanger.ac.uk/cosmic/gene/overview?ln=MET).	('human', 'Species', '9606', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('c.G799A', 'Mutation', 'rs186148199', (49, 56))	('c.G799A', 'Var', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('p.Glu267Lys', 'Mutation', 'rs1193289616', (58, 69))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (181, 187))
29316	25790038	No germline FLCN mutations were present, although the cancer of patient P15 carried a somatic, protein-truncating mutation (c.1568_1569insG, p.Lys523fs) in the last exon of FLCN (Table 2).	('FLCN', 'Gene', '201163', (12, 16))	('c.1568_1569insG', 'Var', (124, 139))	('patient', 'Species', '9606', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('P15', 'Gene', (72, 75))	('P15', 'Gene', '1030', (72, 75))	('protein', 'cellular_component', 'GO:0003675', ('95', '102'))	('cancer', 'Disease', (54, 60))	('FLCN', 'Gene', (12, 16))	('p.Lys523fs', 'Var', (141, 151))	('p.Lys523fs', 'Mutation', 'p.K523fsX', (141, 151))	('FLCN', 'Gene', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('c.1568_1569insG', 'Mutation', 'c.1568_1569insG', (124, 139))	('FLCN', 'Gene', '201163', (173, 177))
29317	25790038	For discovery of somatic pRCC driver mutations, we examined somatic mutation calls from the 31 cancers with exome- and genome-sequence data, and restricted our analysis to protein-coding regions.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('protein', 'cellular_component', 'GO:0003675', ('172', '179'))	('cancers', 'Disease', (95, 102))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('pRCC', 'Gene', (25, 29))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('pRCC', 'Phenotype', 'HP:0006766', (25, 29))	('pRCC', 'Gene', '5546', (25, 29))
29323	25790038	SETD2 and BAP1 both lie on the short arm of chromosome 3, undergo copy-neutral LOH or deletion (Fig.	('chromosome', 'cellular_component', 'GO:0005694', ('44', '54'))	('BAP1', 'Gene', (10, 14))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', (0, 5))	('LOH', 'NegReg', (79, 82))	('BAP1', 'Gene', '8314', (10, 14))	('short arm', 'Phenotype', 'HP:0009824', (31, 40))	('deletion', 'Var', (86, 94))
29327	25790038	Following independent confirmation of the SETD2, BAP1 and ARID2 mutations in our discovery phase samples using Sanger or Ion Torrent sequencing, we screened a replication set of 60 archival pRCCs for mutations in these genes (Supplementary Table 3), resulting in an additional five BAP1, three SETD2, and three ARID2 mutations.	('mutations', 'Var', (200, 209))	('BAP1', 'Gene', (49, 53))	('ARID2', 'Gene', '196528', (311, 316))	('SETD2', 'Gene', (42, 47))	('ARID2', 'Gene', (58, 63))	('mutations', 'Var', (317, 326))	('pRCC', 'Gene', '5546', (190, 194))	('SETD2', 'Gene', '29072', (42, 47))	('mutations', 'Var', (64, 73))	('ARID2', 'Gene', (311, 316))	('BAP1', 'Gene', '8314', (282, 286))	('RCC', 'Phenotype', 'HP:0005584', (191, 194))	('SETD2', 'Gene', (294, 299))	('pRCC', 'Phenotype', 'HP:0006766', (190, 194))	('pRCC', 'Gene', (190, 194))	('BAP1', 'Gene', '8314', (49, 53))	('SETD2', 'Gene', '29072', (294, 299))	('BAP1', 'Gene', (282, 286))	('ARID2', 'Gene', '196528', (58, 63))
29328	25790038	Most of these mutations had good evidence of being pathogenic, based on prediction programs, conservation, presence of deletion/LOH, mutation reports in other cancer types and previous functional studies.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('deletion/LOH', 'Var', (119, 131))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mutations', 'Var', (14, 23))
29329	25790038	Further details of the functional annotation of the BAP1, SETD2 and ARID2 mutations, together with additional information on our search for new driver mutations, are given in Supplementary Table 4.	('BAP1', 'Gene', '8314', (52, 56))	('mutations', 'Var', (74, 83))	('BAP1', 'Gene', (52, 56))	('SETD2', 'Gene', '29072', (58, 63))	('ARID2', 'Gene', '196528', (68, 73))	('SETD2', 'Gene', (58, 63))	('ARID2', 'Gene', (68, 73))
29330	25790038	Since there was pre-existing functional evidence for the importance of the stress response mediator Nrf2 in the pathogenesis of pRCCs and a small independent study (five pRCC exomes) had provided limited support for this notion, we performed a focussed examination of three members of the Nrf2 pathway for somatic mutations: NFE2L2, which encodes Nrf2; CUL3, an Nrf2 ubiquitin ligase; and KEAP1, the Nrf2-specific ubiquitin ligase adaptor.	('CUL3', 'Gene', (353, 357))	('NFE2L2', 'Gene', (325, 331))	('pRCC', 'Gene', '5546', (128, 132))	('pRCC', 'Phenotype', 'HP:0006766', (170, 174))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('Nrf2', 'Gene', (289, 293))	('Nrf2', 'Gene', (400, 404))	('pRCC', 'Gene', (170, 174))	('pre', 'molecular_function', 'GO:0003904', ('16', '19'))	('KEAP1', 'Gene', '9817', (389, 394))	('pRCC', 'Phenotype', 'HP:0006766', (128, 132))	('RCC', 'Phenotype', 'HP:0005584', (129, 132))	('pRCC', 'Gene', (128, 132))	('KEAP1', 'Gene', (389, 394))	('CUL3', 'Gene', '8452', (353, 357))	('Nrf2', 'Gene', '4780', (100, 104))	('Nrf2', 'Gene', '4780', (362, 366))	('Nrf2', 'Gene', '4780', (347, 351))	('NFE2L2', 'Gene', '4780', (325, 331))	('pathogenesis', 'biological_process', 'GO:0009405', ('112', '124'))	('mutations', 'Var', (314, 323))	('pRCC', 'Gene', '5546', (170, 174))	('Nrf2', 'Gene', '4780', (289, 293))	('ubiquitin', 'molecular_function', 'GO:0031386', ('367', '376'))	('Nrf2', 'Gene', '4780', (400, 404))	('Nrf2', 'Gene', (100, 104))	('Nrf2', 'Gene', (362, 366))	('ubiquitin', 'molecular_function', 'GO:0031386', ('414', '423'))	('Nrf2', 'Gene', (347, 351))
29331	25790038	We found KEAP1 mutations in two cancers (Table 2).	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('KEAP1', 'Gene', '9817', (9, 14))	('mutations', 'Var', (15, 24))	('KEAP1', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
29333	25790038	A protein-truncating CUL3 mutation was found in one cancer (P16).	('P16', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (26, 34))	('found', 'Reg', (39, 44))	('protein', 'cellular_component', 'GO:0003675', ('2', '9'))	('P16', 'Gene', '1029', (60, 63))	('protein-truncating', 'NegReg', (2, 20))	('CUL3', 'Gene', '8452', (21, 25))	('CUL3', 'Gene', (21, 25))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
29343	25790038	While deletions, and occasional copy-neutral LOH, of chromosome 3p usually involved all or most of the whole-chromosome arm, in a few cases, smaller changes occurred and these clearly targeted the region around the SETD2 and BAP1 loci (Fig.	('involved', 'Reg', (75, 83))	('SETD2', 'Gene', '29072', (215, 220))	('deletions', 'Var', (6, 15))	('SETD2', 'Gene', (215, 220))	('BAP1', 'Gene', '8314', (225, 229))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('targeted', 'Reg', (184, 192))	('BAP1', 'Gene', (225, 229))	('chromosome', 'cellular_component', 'GO:0005694', ('53', '63'))
29344	25790038	One cancer, P17, had acquired two small regions of deletion, one around SETD2 and the other around BAP1, although we did not detect pathogenic SNVs of either gene in this tumour (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('BAP1', 'Gene', (99, 103))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('P17', 'Gene', '653820', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', (171, 177))	('SETD2', 'Gene', '29072', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('BAP1', 'Gene', '8314', (99, 103))	('P17', 'Gene', (12, 15))	('deletion', 'Var', (51, 59))	('cancer', 'Disease', (4, 10))	('SETD2', 'Gene', (72, 77))
29346	25790038	However, one of the focal SCNAs involved a gene with strong a priori importance in cancer, this being a deletion of ~1 Mb around CDKN2A in tumour P02.	('tumour', 'Disease', (139, 145))	('deletion of', 'Var', (104, 115))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('P02', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDKN2A', 'Gene', (129, 135))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('CDKN2A', 'Gene', '1029', (129, 135))	('P02', 'Gene', '7178', (146, 149))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (83, 89))
29350	25790038	Although some known fragile site changes were detected (for example, WWOX and FHIT), no recurrent or clearly pathogenic fusion genes, intra-gene deletions or translocations were present (Supplementary Data 1).	('FHIT', 'Gene', (78, 82))	('FHIT', 'Gene', '2272', (78, 82))	('changes', 'Var', (33, 40))	('WWOX', 'Gene', '51741', (69, 73))	('WWOX', 'Gene', (69, 73))
29354	25790038	On chromosome 2, the sequence data showed the gross rearrangements almost all to be intrachromosomal, resulting in segmental disorder and multiple copy number changes.	('segmental disorder', 'Disease', (115, 133))	('resulting in', 'Reg', (102, 114))	('rearrangements', 'Var', (52, 66))	('chromosome', 'cellular_component', 'GO:0005694', ('3', '13'))	('segmental disorder', 'Disease', 'MESH:C537538', (115, 133))
29355	25790038	A further large-scale mutation of interest was identified from a split read in the Complete Genomics data between chr1:27,080,702 (intron 16 of ARID1A) and chr1: 109,834,252 (close to MYBPHL) in cancer P13.	('ARID1A', 'Gene', '8289', (144, 150))	('ARID1A', 'Gene', (144, 150))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('MYBPHL', 'Gene', (184, 190))	('MYBPHL', 'Gene', '343263', (184, 190))	('P13', 'Gene', (202, 205))	('P13', 'Gene', '440926', (202, 205))	('chr1', 'Var', (156, 160))	('C', 'Chemical', 'MESH:D002244', (83, 84))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
29356	25790038	This change was confirmed using the SNP array data to comprise a deletion from the short-arm telomere to a site within intron 4 of ARID1A (Supplementary Fig.	('deletion', 'Var', (65, 73))	('telomere', 'cellular_component', 'GO:0005696', ('93', '101'))	('ARID1A', 'Gene', '8289', (131, 137))	('ARID1A', 'Gene', (131, 137))	('telomere', 'cellular_component', 'GO:0000781', ('93', '101'))
29358	25790038	This change deletes the 5' end of ARID1A, and is thus predicted to inactivate protein function.	('inactivate', 'NegReg', (67, 77))	('ARID1A', 'Gene', '8289', (34, 40))	('protein function', 'MPA', (78, 94))	('ARID1A', 'Gene', (34, 40))	('protein', 'cellular_component', 'GO:0003675', ('78', '85'))	('deletes', 'NegReg', (12, 19))	("5' end", 'MPA', (24, 30))	('change', 'Var', (5, 11))
29360	25790038	BAP1 and ARID2 mutations mostly mapped to major clones, whereas SETD2 and Nrf2 pathway mutations were almost all predicted to be sub-clonal (Supplementary Table 8).	('ARID2', 'Gene', '196528', (9, 14))	('BAP1', 'Gene', (0, 4))	('ARID2', 'Gene', (9, 14))	('Nrf2', 'Gene', (74, 78))	('mutations', 'Var', (15, 24))	('SETD2', 'Gene', '29072', (64, 69))	('SETD2', 'Gene', (64, 69))	('Nrf2', 'Gene', '4780', (74, 78))	('BAP1', 'Gene', '8314', (0, 4))
29361	25790038	Papillary carcinomas of different stages were collected from four patients (RK30, RK36, GK101 and GK116; Table 1) and subjected to M-seq.	('RK36', 'Var', (82, 86))	('Papillary carcinomas', 'Disease', (0, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (10, 20))	('GK101', 'Var', (88, 93))	('GK116', 'Var', (98, 103))	('patients', 'Species', '9606', (66, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Papillary carcinomas', 'Disease', 'MESH:D002291', (0, 20))
29366	25790038	The three earlier-stage tumours (RK30, GK116_1 and GK101) displayed minimal regional mutational heterogeneity or evidence of branched tumour evolution (Fig.	('tumours', 'Disease', (24, 31))	('GK101', 'Var', (51, 56))	('branched tumour', 'Disease', (125, 140))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('branched tumour', 'Disease', 'MESH:D009369', (125, 140))	('GK116_1', 'Var', (39, 46))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('RK30', 'Var', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
29367	25790038	3), and the data were entirely consistent with the origins of GK116_1 and GK116_2 as separate cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('GK116_1', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
29370	25790038	9), with relative SCNA uniformity found in the three earlier-stage tumours (Table 1), while RK36 exhibited greater intra-tumour heterogeneity.	('RK36', 'Var', (92, 96))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('intra-tumour', 'Disease', 'MESH:D009369', (115, 127))	('tumours', 'Disease', (67, 74))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('intra-tumour', 'Disease', (115, 127))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
29375	25790038	This patient carried three spatially separated, truncating mutations in SETD2 (p.Glu2277X in R2, p.Val212fs in R8 and p.Glu1667X in LN), all accompanied by 3p deletions that were not all concordant with respect to haplotype (Supplementary Fig.	('patient', 'Species', '9606', (5, 12))	('p.Glu1667X', 'Mutation', 'p.E1667X', (118, 128))	('p.Glu1667X', 'Var', (118, 128))	('p.Val212fs', 'Var', (97, 107))	('p.Val212fs', 'Mutation', 'p.V212fsX', (97, 107))	('p.Glu2277X', 'Var', (79, 89))	('SETD2', 'Gene', '29072', (72, 77))	('p.Glu2277X', 'Mutation', 'p.E2277X', (79, 89))	('SETD2', 'Gene', (72, 77))
29377	25790038	Events such as this and the Nrf2 pathway mutations in the single-sample cancer RK133:converging on single genes in the same pathway:indicate remarkably strong selection for these mutations in particular tumours at certain stages of their growth.	('mutations', 'Var', (41, 50))	('particular tumours', 'Disease', 'MESH:D009369', (192, 210))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Nrf2', 'Gene', '4780', (28, 32))	('tumours', 'Phenotype', 'HP:0002664', (203, 210))	('mutations', 'Var', (179, 188))	('Nrf2', 'Gene', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('particular tumours', 'Disease', (192, 210))	('cancer', 'Disease', (72, 78))
29378	25790038	Genome and exome sequencing have shown that pRCC driver mutations overlap with those of other cancers, but there are also genetic features specific to pRCC.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('pRCC', 'Gene', (44, 48))	('mutations', 'Var', (56, 65))	('pRCC', 'Gene', '5546', (151, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('pRCC', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('pRCC', 'Phenotype', 'HP:0006766', (44, 48))	('pRCC', 'Gene', '5546', (44, 48))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('pRCC', 'Phenotype', 'HP:0006766', (151, 155))	('cancers', 'Disease', (94, 101))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
29379	25790038	We have identified probable pathogenic pRCC driver mutations in BAP1, SETD2, ARID2 and the Nrf2 pathway genes, and where investigation by M-seq was possible, these mutations were sub-clonal drivers.	('pRCC', 'Gene', (39, 43))	('mutations', 'Var', (51, 60))	('Nrf2', 'Gene', (91, 95))	('ARID2', 'Gene', '196528', (77, 82))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('SETD2', 'Gene', '29072', (70, 75))	('BAP1', 'Gene', '8314', (64, 68))	('pRCC', 'Phenotype', 'HP:0006766', (39, 43))	('pRCC', 'Gene', '5546', (39, 43))	('ARID2', 'Gene', (77, 82))	('SETD2', 'Gene', (70, 75))	('pathogenic', 'Reg', (28, 38))	('Nrf2', 'Gene', '4780', (91, 95))	('BAP1', 'Gene', (64, 68))
29380	25790038	This was evidenced most strikingly in the parallel evolution of tumour RK36 that acquired three distinct, truncating SETD2 mutations associated with deletions of different 3p haplotypes in three regions out of nine tested.	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('SETD2', 'Gene', '29072', (117, 122))	('SETD2', 'Gene', (117, 122))	('deletions', 'Var', (149, 158))	('mutations', 'Var', (123, 132))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('associated', 'Reg', (133, 143))
29381	25790038	The fact that 7 of 31 pRCCs had no detectable SNVs or small insertion-deletions (indels) of probable pathogenic effect in the top genes (Table 2; Fig.	('pRCC', 'Gene', (22, 26))	('insertion-deletions', 'Var', (60, 79))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('pRCC', 'Phenotype', 'HP:0006766', (22, 26))	('pRCC', 'Gene', '5546', (22, 26))
29383	25790038	This suggested that the major, truncal drivers for pRCC might be copy number changes.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('pRCC', 'Gene', (51, 55))	('copy number changes', 'Var', (65, 84))	('pRCC', 'Phenotype', 'HP:0006766', (51, 55))	('pRCC', 'Gene', '5546', (51, 55))
29384	25790038	In keeping with this hypothesis, we typically found that large-scale copy number gains on chromosomes 7, 16 and 17 are often clonal changes that are strong candidates for major pRCC drivers, even though the genes targeted by these changes have not unambiguously been identified.	('copy number gains', 'Var', (69, 86))	('pRCC', 'Phenotype', 'HP:0006766', (177, 181))	('pRCC', 'Gene', '5546', (177, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('pRCC', 'Gene', (177, 181))
29386	25790038	Pathogenic BAP1 and SETD2 mutations have now been found in several cancer types, especially in bladder tumours and ccRCC.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('cancer', 'Disease', (67, 73))	('BAP1', 'Gene', '8314', (11, 15))	('Pathogenic', 'Reg', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('SETD2', 'Gene', '29072', (20, 25))	('found', 'Reg', (50, 55))	('bladder tumours', 'Disease', (95, 110))	('mutations', 'Var', (26, 35))	('BAP1', 'Gene', (11, 15))	('SETD2', 'Gene', (20, 25))	('bladder tumours', 'Disease', 'MESH:D001749', (95, 110))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
29387	25790038	Our additional focus on ARID2 mutations as pRCC drivers was prompted by our initial finding that all three mutations in our discovery phase were protein truncating, and by the role that the ARID2 protein plays in chromatin remodelling.	('ARID2', 'Gene', '196528', (190, 195))	('pRCC', 'Gene', (43, 47))	('mutations', 'Var', (107, 116))	('chromatin remodelling', 'biological_process', 'GO:0006338', ('213', '234'))	('protein', 'Protein', (145, 152))	('protein', 'cellular_component', 'GO:0003675', ('145', '152'))	('ARID2', 'Gene', (190, 195))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('pRCC', 'Gene', '5546', (43, 47))	('chromatin', 'cellular_component', 'GO:0000785', ('213', '222'))	('mutations', 'Var', (30, 39))	('truncating', 'NegReg', (153, 163))	('pRCC', 'Phenotype', 'HP:0006766', (43, 47))	('ARID2', 'Gene', '196528', (24, 29))	('ARID2', 'Gene', (24, 29))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
29389	25790038	Our finding of somatic Nrf2 pathway (KEAP1, CUL3 and NFE2L2) mutations in pRCCs is in line with a small, previous study.	('NFE2L2', 'Gene', (53, 59))	('CUL3', 'Gene', '8452', (44, 48))	('Nrf2', 'Gene', (23, 27))	('CUL3', 'Gene', (44, 48))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('mutations', 'Var', (61, 70))	('KEAP1', 'Gene', '9817', (37, 42))	('pRCC', 'Phenotype', 'HP:0006766', (74, 78))	('pRCC', 'Gene', '5546', (74, 78))	('NFE2L2', 'Gene', '4780', (53, 59))	('Nrf2', 'Gene', '4780', (23, 27))	('KEAP1', 'Gene', (37, 42))	('pRCC', 'Gene', (74, 78))
29390	25790038	It is possible that targeting Nrf2 signalling will have limited clinical potential given that the mutations are often sub-clonal, but there remains hope for such treatments given that one cancer acquired Nrf2 activation by both KEAP1 and NFE2L2 mutations in what appeared to be different cancer sub-clones.	('KEAP1', 'Gene', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Nrf2', 'Gene', (204, 208))	('mutations', 'Var', (245, 254))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('Nrf2', 'Gene', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('Nrf2', 'Gene', '4780', (204, 208))	('activation', 'PosReg', (209, 219))	('KEAP1', 'Gene', '9817', (228, 233))	('cancer', 'Disease', (188, 194))	('NFE2L2', 'Gene', '4780', (238, 244))	('signalling', 'biological_process', 'GO:0023052', ('35', '45'))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('Nrf2', 'Gene', '4780', (30, 34))	('NFE2L2', 'Gene', (238, 244))
29392	25790038	It is established that pRCC differs markedly from ccRCC in the near-complete absence of VHL mutations in the former and their almost ubiquitous presence in the latter, and it appears from our study that pRCCs also have fewer PBRM1 mutations than ccRCCs.	('pRCC', 'Phenotype', 'HP:0006766', (203, 207))	('mutations', 'Var', (231, 240))	('RCC', 'Disease', (204, 207))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('pRCC', 'Gene', (203, 207))	('VHL', 'Gene', '7428', (88, 91))	('fewer', 'NegReg', (219, 224))	('absence', 'NegReg', (77, 84))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('pRCC', 'Gene', '5546', (23, 27))	('RCC', 'Phenotype', 'HP:0005584', (248, 251))	('RCC', 'Disease', (248, 251))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('mutations', 'Var', (92, 101))	('pRCC', 'Phenotype', 'HP:0006766', (23, 27))	('RCC', 'Phenotype', 'HP:0005584', (24, 27))	('PBRM1', 'Gene', '55193', (225, 230))	('RCC', 'Disease', (24, 27))	('pRCC', 'Gene', '5546', (203, 207))	('RCC', 'Disease', 'MESH:C538614', (248, 251))	('pRCC', 'Gene', (23, 27))	('VHL', 'Gene', (88, 91))	('PBRM1', 'Gene', (225, 230))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
29394	25790038	It has been proposed in ccRCC that, following a VHL mutation, one copy of 3p is deleted and that the other genes are 'opportunistic' in that they can act as tumour suppressors, while only requiring a single 'hit', because they have been rendered hemizygous by the VHL 'second hit' (summarized in ref.).	('VHL', 'Gene', '7428', (48, 51))	('VHL', 'Gene', '7428', (264, 267))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('mutation', 'Var', (52, 60))	('tumour', 'Disease', (157, 163))	('VHL', 'Gene', (48, 51))	('VHL', 'Gene', (264, 267))
29395	25790038	The pRCC data show that a model whereby the other 3p mutations depend on preceding VHL mutations is unlikely to be correct, and that loss of 3p is an important event in pRCC development in the absence of VHL changes.	('pRCC', 'Gene', (169, 173))	('VHL', 'Gene', '7428', (83, 86))	('VHL', 'Gene', (204, 207))	('pRCC', 'Phenotype', 'HP:0006766', (4, 8))	('pRCC', 'Gene', (4, 8))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('pRCC', 'Gene', '5546', (169, 173))	('VHL', 'Gene', '7428', (204, 207))	('pRCC', 'Phenotype', 'HP:0006766', (169, 173))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('loss', 'Var', (133, 137))	('mutations', 'Var', (87, 96))	('VHL', 'Gene', (83, 86))	('pRCC', 'Gene', '5546', (4, 8))
29396	25790038	However, it remains entirely possible that SETD2 mutation can be opportunistic in both ccRCC and pRCC, depending on a preceding BAP1 mutation and 3p deletion in the latter case.	('mutation', 'Var', (133, 141))	('BAP1', 'Gene', '8314', (128, 132))	('SETD2', 'Gene', '29072', (43, 48))	('pRCC', 'Gene', '5546', (97, 101))	('pRCC', 'Phenotype', 'HP:0006766', (97, 101))	('mutation', 'Var', (49, 57))	('RCC', 'Disease', (89, 92))	('RCC', 'Disease', (98, 101))	('SETD2', 'Gene', (43, 48))	('BAP1', 'Gene', (128, 132))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (89, 92))	('pRCC', 'Gene', (97, 101))
29397	25790038	pRCCs also have relatively few mutations in ccRCC drivers such as KDM5C, PTEN, MTOR and PIK3CA, while ccRCCs have few ARID2 mutations and gains of chromosomes 7, 16 and 17 are uncommon.	('PIK3CA', 'Gene', '5290', (88, 94))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('pRCC', 'Gene', '5546', (0, 4))	('KDM5C', 'Gene', '8242', (66, 71))	('PIK3CA', 'Gene', (88, 94))	('MTOR', 'Gene', (79, 83))	('pRCC', 'Phenotype', 'HP:0006766', (0, 4))	('RCC', 'Disease', (104, 107))	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('PTEN', 'Gene', (73, 77))	('mutations', 'Var', (31, 40))	('ARID2', 'Gene', '196528', (118, 123))	('MTOR', 'Gene', '2475', (79, 83))	('RCC', 'Disease', (1, 4))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('pRCC', 'Gene', (0, 4))	('KDM5C', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('PTEN', 'Gene', '5728', (73, 77))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('ARID2', 'Gene', (118, 123))
29398	25790038	Mutations in the Nrf2 pathway genes appear to be specific to pRCC, but re-analysis of TCGA ccRCC data (details not shown) using Intogen does shows that a small, but significant proportion (~2%) has mutations in NFE2L2 (ref.).	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', (93, 96))	('pRCC', 'Gene', (61, 65))	('NFE2L2', 'Gene', '4780', (211, 217))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('Nrf2', 'Gene', (17, 21))	('mutations', 'Var', (198, 207))	('C', 'Chemical', 'MESH:D002244', (63, 64))	('C', 'Chemical', 'MESH:D002244', (87, 88))	('NFE2L2', 'Gene', (211, 217))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('pRCC', 'Gene', '5546', (61, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('pRCC', 'Phenotype', 'HP:0006766', (61, 65))	('Nrf2', 'Gene', '4780', (17, 21))
29403	25790038	Finally, additional clonal reconstruction and M-seq analyses will be required to pick apart the evolutionary complexity of pRCCs and to confirm or refute our model that copy number gains typically drive the initial stages of pRCC pathogenesis, with many driver SNVs acting in sub-clones.	('drive', 'Reg', (197, 202))	('pRCC', 'Gene', (225, 229))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('pathogenesis', 'biological_process', 'GO:0009405', ('230', '242'))	('pRCC', 'Gene', (123, 127))	('pRCC', 'Phenotype', 'HP:0006766', (225, 229))	('pRCC', 'Gene', '5546', (225, 229))	('copy number gains', 'Var', (169, 186))	('pRCC', 'Phenotype', 'HP:0006766', (123, 127))	('pRCC', 'Gene', '5546', (123, 127))	('RCC', 'Phenotype', 'HP:0005584', (226, 229))
29405	25790038	Shared mutated genes include BAP1 and SETD2, but mutations in genes such as ARID2 and KEAP1 are specifically associated with pRCC.	('associated', 'Reg', (109, 119))	('ARID2', 'Gene', '196528', (76, 81))	('mutations', 'Var', (49, 58))	('pRCC', 'Phenotype', 'HP:0006766', (125, 129))	('KEAP1', 'Gene', '9817', (86, 91))	('ARID2', 'Gene', (76, 81))	('pRCC', 'Gene', '5546', (125, 129))	('SETD2', 'Gene', '29072', (38, 43))	('BAP1', 'Gene', '8314', (29, 33))	('KEAP1', 'Gene', (86, 91))	('pRCC', 'Gene', (125, 129))	('SETD2', 'Gene', (38, 43))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('BAP1', 'Gene', (29, 33))
29407	25790038	Although VHL and PBRM1 mutations are known to be frequent truncal drivers in ccRCCs, similar high-frequency, major pRCC driver mutations appear not to exist in pRCCs.	('pRCC', 'Phenotype', 'HP:0006766', (115, 119))	('pRCC', 'Gene', '5546', (160, 164))	('VHL', 'Gene', '7428', (9, 12))	('PBRM1', 'Gene', '55193', (17, 22))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', (116, 119))	('pRCC', 'Gene', (115, 119))	('pRCC', 'Phenotype', 'HP:0006766', (160, 164))	('PBRM1', 'Gene', (17, 22))	('mutations', 'Var', (23, 32))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('pRCC', 'Gene', (160, 164))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('RCC', 'Disease', (79, 82))	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('VHL', 'Gene', (9, 12))	('pRCC', 'Gene', '5546', (115, 119))	('RCC', 'Disease', 'MESH:C538614', (79, 82))
29423	25790038	Variants were annotated with ANNOVAR (RefSeq gene models) using: dbSNP (132); 1,000 genomes project allele frequencies (November 2011); University of California Santa Cruz (UCSC) segmental duplication scores; and UCSC 46 species conservation scores; and predictions of functional importance from SIFT and PolyPhen2.	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', (296, 300))	('C', 'Chemical', 'MESH:D002244', (216, 217))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('California Santa Cruz', 'Disease', (150, 171))	('C', 'Chemical', 'MESH:D002244', (214, 215))	('SIFT', 'Disease', 'None', (296, 300))	('California Santa Cruz', 'Disease', 'MESH:D004670', (150, 171))	('C', 'Chemical', 'MESH:D002244', (150, 151))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('C', 'Chemical', 'MESH:D002244', (174, 175))
29432	25790038	We had previously used Ion Torrent technology to show that the Illumina-Stampy-Playtpus pipeline produces >95% validated variants in comparable cancer samples.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('variants', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
29435	25790038	For analysis of mutation burden and spectra, we applied the following exclusion filters to somatic variants: (i) presence in a segmental duplication region or a region with mappability score <0.5; (ii) variant present in any read from the paired normal sample; (iii) fewer than 10 reads in total at the variant site in the normal sample; (iv) fewer than eight reads in total in the tumour; (v) fewer than three variant reads in the tumour; (vi) variant allele frequency <10% in the tumour; and (vi) presence of variant in public databases (Exome Variant Server, 1,000 genomes project, Complete Genomics 69 reference genomes) at a frequency of >1%.	('tumour', 'Disease', 'MESH:D009369', (482, 488))	('C', 'Chemical', 'MESH:D002244', (585, 586))	('variants', 'Var', (99, 107))	('tumour', 'Disease', (482, 488))	('tumour', 'Disease', (382, 388))	('tumour', 'Phenotype', 'HP:0002664', (432, 438))	('tumour', 'Disease', 'MESH:D009369', (432, 438))	('variant', 'Var', (511, 518))	('presence', 'Reg', (499, 507))	('tumour', 'Phenotype', 'HP:0002664', (382, 388))	('tumour', 'Phenotype', 'HP:0002664', (482, 488))	('variant', 'Var', (202, 209))	('tumour', 'Disease', (432, 438))	('tumour', 'Disease', 'MESH:D009369', (382, 388))
29436	25790038	Variants identified in constitutional DNA from any of the other local, non-cancer sequencing projects (for example, 29 million variants across 284 samples from the Oxford-Illumina WGS500 consortium) were discarded as being more likely due to systematic error in our pipeline than genuine somatic mutation.	('variants', 'Var', (127, 135))	('systematic error', 'Disease', (242, 258))	('Variants', 'Var', (0, 8))	('non-cancer', 'Disease', 'MESH:D009369', (71, 81))	('non-cancer', 'Disease', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('DNA', 'cellular_component', 'GO:0005574', ('38', '41'))	('systematic error', 'Disease', 'MESH:D012030', (242, 258))
29438	25790038	Validation in the original discovery set and replication in the set of 60 additional pRCCs were performed for mutations in BAP1, SETD2 and ARID2, and validation of FH, MET and KEAP1 using bidirectional Sanger sequencing of the coding regions of each gene (details available from authors).	('BAP1', 'Gene', (123, 127))	('SETD2', 'Gene', '29072', (129, 134))	('mutations', 'Var', (110, 119))	('SETD2', 'Gene', (129, 134))	('ARID2', 'Gene', '196528', (139, 144))	('KEAP1', 'Gene', '9817', (176, 181))	('pRCC', 'Gene', (85, 89))	('ARID2', 'Gene', (139, 144))	('KEAP1', 'Gene', (176, 181))	('BAP1', 'Gene', '8314', (123, 127))	('pRCC', 'Phenotype', 'HP:0006766', (85, 89))	('pRCC', 'Gene', '5546', (85, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
29440	25790038	Any variants found were replication-tested in a second, independent DNA sample from the same tumour.	('tumour', 'Disease', (93, 99))	('variants', 'Var', (4, 12))	('DNA', 'cellular_component', 'GO:0005574', ('68', '71'))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))
29450	25790038	Gene-based and pathway analyses to detect significantly over-represented mutant genes and pathways were performed by Intogen 23 and MutSigCV using the annotated, quality-filtered, somatic mutations from all cancers.	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('over-represented', 'PosReg', (56, 72))	('mutant', 'Var', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
29456	25790038	Single-nucleotide variant calling was performed using CAVEMAN and small insertions and deletions were identified using a modified version on Pindel in paired tumour-normal mode.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('Single-nucleotide', 'Var', (0, 17))	('tumour', 'Disease', (158, 164))	('C', 'Chemical', 'MESH:D002244', (54, 55))
29478	25790038	Mi.K., C.N., S.H., M.S., C.B., C.S.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('C', 'Chemical', 'MESH:D002244', (7, 8))	('M.S.', 'Var', (19, 23))	('Mi', 'Chemical', 'MESH:C011506', (0, 2))	('C.B.', 'Var', (25, 29))	('C', 'Chemical', 'MESH:D002244', (25, 26))
29480	25790038	Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.	('papillary renal cancer', 'Disease', 'MESH:D007681', (76, 98))	('papillary renal cancer', 'Disease', (76, 98))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (76, 98))	('renal cancer', 'Phenotype', 'HP:0009726', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('chromosomal gains', 'Var', (10, 27))
29488	30349421	For both ccRCC and PRCC, the most frequent substitution in somatic missense mutations was T:A > A:T, which was different from that recorded in the COSMIC database.	('PRCC', 'Phenotype', 'HP:0006766', (19, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (9, 14))	('T:A > A', 'Var', (90, 97))	('PRCC', 'Gene', '5546', (19, 23))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('PRCC', 'Gene', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (20, 23))
29490	30349421	All the mutations detected in those genes had not been reported in ccRCC before, except for alterations in VHL and PBRM1.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('VHL', 'Gene', '7428', (107, 110))	('RCC', 'Disease', (69, 72))	('ccRCC', 'Phenotype', 'HP:0006770', (67, 72))	('mutations', 'Var', (8, 17))	('PBRM1', 'Gene', (115, 120))	('VHL', 'Gene', (107, 110))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('PBRM1', 'Gene', '55193', (115, 120))
29491	30349421	Regarding the frequently mutated genes in PRCC in our study, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) were newly detected gene mutations predicted to be deleterious.	('p.F342L', 'Var', (104, 111))	('p.E293A', 'Mutation', 'p.E293A', (69, 76))	('PRCC', 'Gene', '5546', (42, 46))	('p.N401Y', 'Mutation', 'p.N401Y', (95, 102))	('p.H554Q', 'Mutation', 'rs891159195', (124, 131))	('PNLIP', 'Gene', (88, 93))	('p.E293A', 'Var', (69, 76))	('p.M1T', 'Mutation', 'rs1312268347', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('DEPDC4', 'Gene', '120863', (61, 67))	('p.M1T', 'Var', (133, 138))	('PNLIP', 'Gene', '5406', (88, 93))	('PRCC', 'Gene', (42, 46))	('p.N401Y', 'Var', (95, 102))	('p.F342L', 'Mutation', 'p.F342L', (104, 111))	('p.T279A', 'Var', (78, 85))	('p.H554Q', 'Var', (124, 131))	('PRCC', 'Phenotype', 'HP:0006766', (42, 46))	('p.T279A', 'Mutation', 'rs754882817', (78, 85))	('SARDH', 'Gene', '1757', (117, 122))	('SARDH', 'Gene', (117, 122))	('DEPDC4', 'Gene', (61, 67))
29496	30349421	Using WES, we identified somatic mutations in 26 Chinese patients with RCC, which enriched the racial diversity of the somatic mutation profiles of RCC subjects, and revealed a few discrepancies in molecular characterizations between our study and published datasets.	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('patients', 'Species', '9606', (57, 65))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('mutations', 'Var', (33, 42))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))
29497	30349421	We also identified numerous newly detected somatic mutations, which further supplements the somatic mutation landscape of RCC.	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))	('mutations', 'Var', (51, 60))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))
29507	30349421	Notably, somatic mutations in MET are mainly found in type 1 PRCC, whereas type 2 PRCC is primarily associated with somatic mutations in SETD2, BAP1 and PBRM1, all of which are also frequently mutated in human ccRCC.	('PBRM1', 'Gene', '55193', (153, 158))	('ccRCC', 'Phenotype', 'HP:0006770', (210, 215))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('mutations', 'Var', (17, 26))	('PBRM1', 'Gene', (153, 158))	('PRCC', 'Gene', (61, 65))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('BAP1', 'Gene', (144, 148))	('PRCC', 'Phenotype', 'HP:0006766', (61, 65))	('SETD2', 'Gene', (137, 142))	('MET', 'Gene', (30, 33))	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('PRCC', 'Gene', (82, 86))	('SETD2', 'Gene', '29072', (137, 142))	('associated', 'Reg', (100, 110))	('PRCC', 'Phenotype', 'HP:0006766', (82, 86))	('human', 'Species', '9606', (204, 209))	('RCC', 'Disease', (62, 65))	('PRCC', 'Gene', '5546', (61, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('mutations', 'Var', (124, 133))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('found', 'Reg', (45, 50))	('PRCC', 'Gene', '5546', (82, 86))	('BAP1', 'Gene', '8314', (144, 148))
29508	30349421	Furthermore, TFE3 and TFEB gene fusion and loss of CNKD2A have been shown to be dominant in type 2 PRCC.	('CNKD2A', 'Gene', (51, 57))	('TFEB', 'Gene', '7942', (22, 26))	('PRCC', 'Gene', (99, 103))	('gene fusion', 'Var', (27, 38))	('TFE3', 'Gene', (13, 17))	('TFEB', 'Gene', (22, 26))	('PRCC', 'Phenotype', 'HP:0006766', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('loss', 'NegReg', (43, 47))	('TFE3', 'Gene', '7030', (13, 17))	('PRCC', 'Gene', '5546', (99, 103))
29517	30349421	A recent study indicated that a longer progression-free survival was achieved with nivolumab plus ipilimumab than with sunitinib among advanced RCC patients with >= 1% PD-L1 expression but not among those with < 1% PD-L1 expression.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('longer', 'PosReg', (32, 38))	('patients', 'Species', '9606', (148, 156))	('PD-L1', 'Gene', '29126', (168, 173))	('PD-L1', 'Gene', (215, 220))	('expression', 'Var', (174, 184))	('nivolumab', 'Chemical', 'MESH:D000077594', (83, 92))	('PD-L1', 'Gene', (168, 173))	('PD-L1', 'Gene', '29126', (215, 220))	('ipilimumab', 'Chemical', 'MESH:D000074324', (98, 108))	('progression-free survival', 'CPA', (39, 64))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('sunitinib', 'Chemical', 'MESH:D000077210', (119, 128))
29529	30349421	The functional impacts of missense mutations were predicted by SIFT, PolyPhen2 HDIV, PolyPhen2 HVAR, LRT, MutationTaster, MutationAssessor, and FATHMM.	('missense mutations', 'Var', (26, 44))	('PolyPhen2', 'Var', (85, 94))	('SIFT', 'Disease', (63, 67))	('SIFT', 'Disease', 'None', (63, 67))
29542	30349421	In 15 ccRCC cases, we identified 1024 missense mutations, 81stop-gain mutations, 50 frameshift mutations, 48 splice mutations and 6 stop-loss mutations (Fig.	('RCC', 'Disease', (8, 11))	('mutations', 'Var', (70, 79))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('missense mutations', 'Var', (38, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('frameshift mutations', 'Var', (84, 104))	('81stop-gain', 'PosReg', (58, 69))
29543	30349421	The most frequent substitution in somatic missense mutations was exposed to be T:A > A:T, which was also the least common type in ChRCC cases (Fig.	('RCC', 'Disease', 'MESH:C538614', (132, 135))	('RCC', 'Disease', (132, 135))	('RCC', 'Phenotype', 'HP:0005584', (132, 135))	('missense mutations', 'Var', (42, 60))	('T:A > A', 'Var', (79, 86))
29545	30349421	These mutations contained five missense mutations (p.P86L, p.R120G, p.S80N, p.V130L, p.F136V), three frameshift deletions (p.G127fs, p.N141fs, p.N90fs) and two stop-gain mutations (p.E70X, p.Q145X).	('p.F136V', 'Mutation', 'p.F136V', (85, 92))	('p.N90fs', 'Mutation', 'rs869025623', (143, 150))	('p.P86L', 'Var', (51, 57))	('p.G127fs', 'Mutation', 'p.G127fsX', (123, 131))	('p.N90fs', 'Var', (143, 150))	('p.N141fs', 'Var', (133, 141))	('p.S80N', 'Mutation', 'rs5030805', (68, 74))	('p.Q145X', 'Mutation', 'rs749704215', (189, 196))	('p.P86L', 'Mutation', 'rs730882034', (51, 57))	('p.Q145X', 'Var', (189, 196))	('p.S80N', 'Var', (68, 74))	('p.E70X', 'Mutation', 'rs5030802', (181, 187))	('p.V130L', 'Var', (76, 83))	('p.F136V', 'Var', (85, 92))	('p.R120G', 'Var', (59, 66))	('p.N141fs', 'Mutation', 'p.N141fsX', (133, 141))	('p.G127fs', 'Var', (123, 131))	('p.V130L', 'Mutation', 'rs104893830', (76, 83))	('p.R120G', 'Mutation', 'rs5030818', (59, 66))	('p.E70X', 'Var', (181, 187))
29546	30349421	Those variants in VHL were located in the commonly known region of the VHL protein domain, all of which had been reported in the TCGA or COSMIC database (Fig.	('VHL', 'Gene', '7428', (18, 21))	('variants', 'Var', (6, 14))	('VHL', 'Gene', (71, 74))	('VHL', 'Gene', '7428', (71, 74))	('protein', 'cellular_component', 'GO:0003675', ('75', '82'))	('VHL', 'Gene', (18, 21))
29548	30349421	In the CDC42EP1 gene, the somatic missense mutation (S260P) was detected in three cases, which was not located in the protein domain for CDC42EP1 and was predicted to be benign.	('CDC42EP1', 'Gene', '11135', (137, 145))	('S260P', 'Mutation', 'rs62235034', (53, 58))	('CDC42EP1', 'Gene', (7, 15))	('S260P', 'Var', (53, 58))	('CDC42EP1', 'Gene', '11135', (7, 15))	('CDC42EP1', 'Gene', (137, 145))	('protein', 'cellular_component', 'GO:0003675', ('118', '125'))
29549	30349421	Regarding 5 PRCC cases, 537 missense mutations, 56 stop-gain mutations, 31 frameshift mutations, 34 splice mutations and 2 stop-loss mutations were detected (Fig.	('stop-gain', 'MPA', (51, 60))	('PRCC', 'Phenotype', 'HP:0006766', (12, 16))	('splice', 'MPA', (100, 106))	('missense mutations', 'Var', (28, 46))	('frameshift mutations', 'Var', (75, 95))	('PRCC', 'Gene', '5546', (12, 16))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('PRCC', 'Gene', (12, 16))
29550	30349421	Like in the ccRCC cases, the most common substitution in missense mutations was T:A > A:T (Fig.	('missense mutations', 'Var', (57, 75))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('ccRCC', 'Phenotype', 'HP:0006770', (12, 17))	('RCC', 'Disease', (14, 17))	('T:A > A', 'Var', (80, 87))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
29552	30349421	None of the variants detected in PER3 were located in its protein domain and they were all predicted to be neutral or benign.	('PER3', 'Gene', (33, 37))	('PER3', 'Gene', '8863', (33, 37))	('variants', 'Var', (12, 20))	('protein', 'cellular_component', 'GO:0003675', ('58', '65'))
29553	30349421	Among the remaining frequently mutated genes, DEPDC4 (p.E293A, p.T279A), PNLIP (p.N401Y, p.F342L) and SARDH (p.H554Q, p.M1T) had not been reported to correlate with PRCC before, and they were all predicted to be deleterious.	('p.E293A', 'Var', (54, 61))	('PRCC', 'Gene', (165, 169))	('PRCC', 'Phenotype', 'HP:0006766', (165, 169))	('PNLIP', 'Gene', (73, 78))	('p.N401Y', 'Mutation', 'p.N401Y', (80, 87))	('DEPDC4', 'Gene', '120863', (46, 52))	('PRCC', 'Gene', '5546', (165, 169))	('p.M1T', 'Mutation', 'rs1312268347', (118, 123))	('p.F342L', 'Mutation', 'p.F342L', (89, 96))	('p.H554Q', 'Var', (109, 116))	('p.T279A', 'Var', (63, 70))	('PNLIP', 'Gene', '5406', (73, 78))	('p.T279A', 'Mutation', 'rs754882817', (63, 70))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('p.N401Y', 'Var', (80, 87))	('SARDH', 'Gene', (102, 107))	('SARDH', 'Gene', '1757', (102, 107))	('p.E293A', 'Mutation', 'p.E293A', (54, 61))	('p.F342L', 'Var', (89, 96))	('DEPDC4', 'Gene', (46, 52))	('p.H554Q', 'Mutation', 'rs891159195', (109, 116))
29554	30349421	In the 6 ChRCC cases, 128 missense mutations, 2 stop-gain mutations, 3 frameshift mutations and 4 splice mutations were identified (Fig.	('missense mutations', 'Var', (26, 44))	('frameshift', 'Var', (71, 81))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
29555	30349421	The most recurrent substitution in missense mutations was G:C > A:T, which was distinct from that in ccRCC and PRCC cases (Fig.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('G:C > A:T', 'Var', (58, 67))	('PRCC', 'Gene', '5546', (111, 115))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('PRCC', 'Gene', (111, 115))	('missense mutations', 'Var', (35, 53))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('PRCC', 'Phenotype', 'HP:0006766', (111, 115))
29557	30349421	It's worth noting that the ZNF814 gene was also mutated in 4 ccRCC cases and 2 PRCC cases.	('RCC', 'Disease', (63, 66))	('PRCC', 'Gene', '5546', (79, 83))	('mutated', 'Var', (48, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (61, 66))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('PRCC', 'Gene', (79, 83))	('ZNF814', 'Gene', '730051', (27, 33))	('RCC', 'Phenotype', 'HP:0005584', (63, 66))	('ZNF814', 'Gene', (27, 33))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
29558	30349421	Among all these mutations in ZNF814 gene, p.P323H, p.R322K and p.G320E presented as a fixed combination occurring in three RCC types.	('p.G320E', 'Var', (63, 70))	('ZNF814', 'Gene', '730051', (29, 35))	('ZNF814', 'Gene', (29, 35))	('p.R322K', 'Mutation', 'rs113623532', (51, 58))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('p.P323H', 'Var', (42, 49))	('p.G320E', 'Mutation', 'rs760366488', (63, 70))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('p.P323H', 'Mutation', 'rs111727691', (42, 49))	('p.R322K', 'Var', (51, 58))
29559	30349421	Furthermore, p.P323H and p.G320E in ZNF814 were predicted to be deleterious, while p.R322K was predicted to be benign.	('ZNF814', 'Gene', '730051', (36, 42))	('p.R322K', 'Mutation', 'rs113623532', (83, 90))	('ZNF814', 'Gene', (36, 42))	('p.P323H', 'Mutation', 'rs111727691', (13, 20))	('p.P323H', 'Var', (13, 20))	('p.G320E', 'Mutation', 'rs760366488', (25, 32))	('p.G320E', 'Var', (25, 32))	('p.R322K', 'Var', (83, 90))
29561	30349421	Among the 4 missense mutations in KRTAP4-8, p.V71M and p.S68R were forecasted to be deleterious, while p.H91R and p.K76R were predicted to be benign.	('p.K76R', 'Mutation', 'rs1407887023', (114, 120))	('p.S68R', 'Mutation', 'rs200462175', (55, 61))	('p.H91R', 'Mutation', 'rs78132858', (103, 109))	('p.V71M', 'Var', (44, 50))	('KRTAP4-8', 'Gene', '728224', (34, 42))	('p.S68R', 'Var', (55, 61))	('KRTAP4-8', 'Gene', (34, 42))	('p.H91R', 'Var', (103, 109))	('p.V71M', 'Mutation', 'rs202107241', (44, 50))	('p.K76R', 'Var', (114, 120))
29562	30349421	In the COSMIC database, the most frequent substitution in missense mutations in ccRCC is G:C > A:T, which is different from what we found in this study (T:A > A:T).	('missense mutations', 'Var', (58, 76))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))	('G:C > A:T', 'Var', (89, 98))
29564	30349421	It's worth noting that the amino acid alterations p.P352fs and p.H193Q in BAP1, p.W1562C and p.S512X in SETD2, p.V343fs in PTEN and p.R882S in MTOR had not been reported previously in ccRCC, all of which were considered to be deleterious in this study.	('p.V343fs', 'Mutation', 'p.V343fsX', (111, 119))	('p.S512X', 'Mutation', 'p.S512X', (93, 100))	('p.H193Q', 'Var', (63, 70))	('PTEN', 'Gene', (123, 127))	('p.P352fs', 'Mutation', 'p.P352fsX', (50, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (184, 189))	('p.P352fs', 'Var', (50, 58))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('p.R882S', 'Mutation', 'p.R882S', (132, 139))	('MTOR', 'Gene', (143, 147))	('RCC', 'Disease', (186, 189))	('PTEN', 'Gene', '5728', (123, 127))	('MTOR', 'Gene', '2475', (143, 147))	('SETD2', 'Gene', (104, 109))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('p.V343fs', 'Var', (111, 119))	('BAP1', 'Gene', '8314', (74, 78))	('p.R882S', 'Var', (132, 139))	('p.H193Q', 'Mutation', 'p.H193Q', (63, 70))	('SETD2', 'Gene', '29072', (104, 109))	('p.W1562C', 'Var', (80, 88))	('p.W1562C', 'SUBSTITUTION', 'None', (80, 88))	('p.S512X', 'Var', (93, 100))	('BAP1', 'Gene', (74, 78))
29565	30349421	Figure 5 shows the distribution of somatic mutations identified in this study in functional domains for VHL, PBRM1, BAP1 and SETD2.	('VHL', 'Gene', '7428', (104, 107))	('BAP1', 'Gene', (116, 120))	('PBRM1', 'Gene', (109, 114))	('PBRM1', 'Gene', '55193', (109, 114))	('mutations', 'Var', (43, 52))	('SETD2', 'Gene', '29072', (125, 130))	('BAP1', 'Gene', '8314', (116, 120))	('VHL', 'Gene', (104, 107))	('SETD2', 'Gene', (125, 130))
29567	30349421	Notably, PBRM1 gene that was mutated in one ccRCC case was also altered in one PRCC case (type 2), which was reported to be mutated at a frequency of 2% in the COSMIC database and 3.9% in the TCGA database.	('PRCC', 'Gene', '5546', (79, 83))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('PRCC', 'Gene', (79, 83))	('mutated', 'Var', (29, 36))	('PBRM1', 'Gene', (9, 14))	('altered', 'Reg', (64, 71))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))	('PBRM1', 'Gene', '55193', (9, 14))
29568	30349421	Moreover, in accordance with ccRCC, the most common substitution in missense mutations in PRCC in the COSMIC database is G:C > A:T, which is distinct from what we found in this study (T:A > A:T).	('PRCC', 'Phenotype', 'HP:0006766', (90, 94))	('ccRCC', 'Phenotype', 'HP:0006770', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('G:C > A:T', 'Var', (121, 130))	('missense mutations', 'Var', (68, 86))	('RCC', 'Disease', (91, 94))	('PRCC', 'Gene', '5546', (90, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('PRCC', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('RCC', 'Disease', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (31, 34))
29570	30349421	Moreover, the amino acid alteration p.R81Q in TP53 had not been reported before and was predicted to be deleterious.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('p.R81Q', 'Var', (36, 42))	('p.R81Q', 'Mutation', 'rs587778720', (36, 42))
29571	30349421	In the COSMIC database, the most frequent substitution in missense mutations in ChRCC is G:C > A:T, which is consistent with our finding.	('missense mutations', 'Var', (58, 76))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('G:C > A:T', 'Var', (89, 98))
29575	30349421	In ChRCC, a few mutated genes were identified as components of the signaling pathways mentioned above, including the PI3K-Akt (3/6), MAPK (2/6) and HIF-1 (2/6) signaling pathway.	('MAPK', 'molecular_function', 'GO:0004707', ('133', '137'))	('signaling pathway', 'biological_process', 'GO:0007165', ('160', '177'))	('HIF-1', 'Gene', (148, 153))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('mutated', 'Var', (16, 23))	('RCC', 'Disease', (5, 8))	('Akt', 'Gene', '207', (122, 125))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('MAPK', 'Pathway', (133, 137))	('PI3K', 'molecular_function', 'GO:0016303', ('117', '121'))	('Akt', 'Gene', (122, 125))	('signaling', 'biological_process', 'GO:0023052', ('67', '76'))	('HIF-1', 'Gene', '3091', (148, 153))
29587	30349421	For instance, in a study focusing on racial differences in the sequencing results of hereditary malignancies, Caswell and colleagues reported that a higher proportion of whites than nonwhites carried deleterious CHEK2 mutations.	('hereditary malignancies', 'Disease', 'MESH:D009369', (85, 108))	('CHEK2', 'Gene', (212, 217))	('mutations', 'Var', (218, 227))	('CHEK2', 'Gene', '11200', (212, 217))	('hereditary malignancies', 'Disease', (85, 108))
29595	30349421	According to the TCGA database, the mutation frequency of VHL was 51.42%, which was much lower (20%) in the WES study performed on 10 Chinese patients with ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (156, 161))	('VHL', 'Gene', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('VHL', 'Gene', '7428', (58, 61))	('patients', 'Species', '9606', (142, 150))	('mutation', 'Var', (36, 44))
29596	30349421	In our study on 15 paired tumor-normal ccRCC samples from Chinese patients, the mutation frequency of VHL was 66.67%, which was much higher than that in the WES study performed on 10 Chinese with ccRCC previously.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('VHL', 'Gene', (102, 105))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('ccRCC', 'Phenotype', 'HP:0006770', (196, 201))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('VHL', 'Gene', '7428', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('RCC', 'Disease', (41, 44))	('mutation', 'Var', (80, 88))	('patients', 'Species', '9606', (66, 74))
29598	30349421	In this study, all of the somatic mutations in VHL were located in the known domain for VHL and determined to be deleterious to protein function.	('protein', 'cellular_component', 'GO:0003675', ('128', '135'))	('VHL', 'Gene', (88, 91))	('VHL', 'Gene', '7428', (88, 91))	('VHL', 'Gene', (47, 50))	('VHL', 'Gene', '7428', (47, 50))	('mutations', 'Var', (34, 43))
29603	30349421	Considering these published ideas together, we can speculate that the deleterious mutations in VHL identified in our study might play a leading role in the oncogenesis of ccRCC.	('oncogenesis', 'biological_process', 'GO:0007048', ('156', '167'))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('VHL', 'Gene', (95, 98))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('VHL', 'Gene', '7428', (95, 98))	('mutations', 'Var', (82, 91))	('role', 'Reg', (144, 148))
29604	30349421	However, loss of VHL activity is unable to induce ccRCC by itself, as there are some other ingredients cooperating with that towards the oncogenesis of ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('oncogenesis', 'biological_process', 'GO:0007048', ('137', '148'))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (50, 55))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('loss', 'Var', (9, 13))	('RCC', 'Disease', (154, 157))	('VHL', 'Gene', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (154, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (152, 157))	('VHL', 'Gene', '7428', (17, 20))	('activity', 'MPA', (21, 29))
29605	30349421	Amrita and colleagues demonstrated that the deficiencies of Vhl and Pbrm1 in the mouse kidney can lead to multifocal ccRCC with a tendency of metastasis.	('lead to', 'Reg', (98, 105))	('metastasis', 'CPA', (142, 152))	('Pbrm1', 'Gene', (68, 73))	('Vhl', 'Gene', (60, 63))	('Pbrm1', 'Gene', '66923', (68, 73))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))	('mouse', 'Species', '10090', (81, 86))	('Vhl', 'Gene', '22346', (60, 63))	('deficiencies', 'Var', (44, 56))
29606	30349421	Sabine and colleagues showed that the combined deletion of Vhl, Trp53 and Rb1 targeted in renal epithelial cells in mice caused ccRCC, which shared molecular markers and mRNA expression with human ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (128, 133))	('mice', 'Species', '10090', (116, 120))	('caused', 'Reg', (121, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (197, 202))	('Vhl', 'Gene', '22346', (59, 62))	('Rb1', 'Gene', (74, 77))	('Rb1', 'Gene', '19645', (74, 77))	('Trp53', 'Gene', '22059', (64, 69))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('deletion', 'Var', (47, 55))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('Vhl', 'Gene', (59, 62))	('human', 'Species', '9606', (191, 196))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('RCC', 'Disease', 'MESH:C538614', (199, 202))	('Trp53', 'Gene', (64, 69))
29608	30349421	In this study, only a stop-gain mutation (p.E981X) in PBRM1 was detected in one ccRCC case, which had been reported previously.	('PBRM1', 'Gene', (54, 59))	('PBRM1', 'Gene', '55193', (54, 59))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('p.E981X', 'Mutation', 'p.E981X', (42, 49))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('p.E981X', 'Var', (42, 49))	('ccRCC', 'Phenotype', 'HP:0006770', (80, 85))
29609	30349421	Compared with the data documented in the TCGA (30.6%) and COSMIC datasets (31%), the mutation frequency of PBRM1 in ccRCC in this study was relatively lower (6.7%).	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('mutation', 'Var', (85, 93))	('lower', 'NegReg', (151, 156))	('PBRM1', 'Gene', (107, 112))	('PBRM1', 'Gene', '55193', (107, 112))
29613	30349421	It had been demonstrated that loss of Vhl and Pbrm1 in mouse kidney could generate ccRCC.	('Pbrm1', 'Gene', (46, 51))	('generate', 'Reg', (74, 82))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('Vhl', 'Gene', '22346', (38, 41))	('mouse', 'Species', '10090', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))	('Vhl', 'Gene', (38, 41))	('loss', 'Var', (30, 34))	('Pbrm1', 'Gene', '66923', (46, 51))
29617	30349421	In addition, the PBRM1 mutation was also identified in one type 2 PRCC case in this study, which was consistent with the previous finding that mutated PBRM1 was mainly associated with type 2 PRCC.	('associated', 'Reg', (168, 178))	('identified', 'Reg', (41, 51))	('PRCC', 'Gene', '5546', (66, 70))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('PRCC', 'Phenotype', 'HP:0006766', (191, 195))	('PRCC', 'Gene', '5546', (191, 195))	('PBRM1', 'Gene', (17, 22))	('PRCC', 'Gene', (66, 70))	('PBRM1', 'Gene', (151, 156))	('PBRM1', 'Gene', '55193', (17, 22))	('PBRM1', 'Gene', '55193', (151, 156))	('mutated', 'Var', (143, 150))	('PRCC', 'Gene', (191, 195))	('PRCC', 'Phenotype', 'HP:0006766', (66, 70))
29618	30349421	Apart from VHL and PBRM1, there are some other genes significantly mutated in ccRCC based on the TCGA and COSMIC datasets, such as SETD2 and BAP1, which are both located at chromosome 3p21.	('PBRM1', 'Gene', '55193', (19, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('BAP1', 'Gene', '8314', (141, 145))	('chromosome', 'cellular_component', 'GO:0005694', ('173', '183'))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('SETD2', 'Gene', '29072', (131, 136))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('BAP1', 'Gene', (141, 145))	('mutated', 'Var', (67, 74))	('VHL', 'Gene', (11, 14))	('VHL', 'Gene', '7428', (11, 14))	('PBRM1', 'Gene', (19, 24))	('SETD2', 'Gene', (131, 136))
29619	30349421	For BAP1, a missense mutation (p.H193Q) and a frameshift-deletion (p.P352fs) were found in two different ccRCC cases in this study.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('p.P352fs', 'Var', (67, 75))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('ccRCC', 'Phenotype', 'HP:0006770', (105, 110))	('RCC', 'Disease', (107, 110))	('BAP1', 'Gene', (4, 8))	('found', 'Reg', (82, 87))	('p.H193Q', 'Var', (31, 38))	('p.H193Q', 'Mutation', 'p.H193Q', (31, 38))	('p.P352fs', 'Mutation', 'p.P352fsX', (67, 75))	('BAP1', 'Gene', '8314', (4, 8))
29620	30349421	Regarding SETD2, we also identified two somatic mutations in two distinct ccRCC cases consisting of a missense mutation (p.W1562C) and a stop-gain mutation (p.S512X).	('p.S512X', 'Mutation', 'p.S512X', (157, 164))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('SETD2', 'Gene', '29072', (10, 15))	('SETD2', 'Gene', (10, 15))	('p.W1562C', 'SUBSTITUTION', 'None', (121, 129))	('p.W1562C', 'Var', (121, 129))	('p.S512X', 'Var', (157, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (74, 79))
29621	30349421	All of those mutations in SETD2 and BAP1 had not been reported before and were predicted to be deleterious.	('SETD2', 'Gene', '29072', (26, 31))	('BAP1', 'Gene', '8314', (36, 40))	('SETD2', 'Gene', (26, 31))	('BAP1', 'Gene', (36, 40))	('mutations', 'Var', (13, 22))
29622	30349421	Serving as tumor suppressor genes in ccRCC, BAP1 and SETD2 mutations were related to worse cancer-specific survival.	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('worse', 'NegReg', (85, 90))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('BAP1', 'Gene', '8314', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('related', 'Reg', (74, 81))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('11', '27'))	('mutations', 'Var', (59, 68))	('BAP1', 'Gene', (44, 48))	('ccRCC', 'Phenotype', 'HP:0006770', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('SETD2', 'Gene', (53, 58))	('cancer', 'Disease', (91, 97))	('tumor suppressor', 'biological_process', 'GO:0051726', ('11', '27'))	('RCC', 'Disease', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SETD2', 'Gene', '29072', (53, 58))
29623	30349421	In the TCGA database, only mutations in BAP1 were reported to be associated with poor survival outcome.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (40, 44))	('associated', 'Reg', (65, 75))	('BAP1', 'Gene', '8314', (40, 44))
29625	30349421	Thus, ccRCC patients who were confirmed to have BAP1 and SETD2 mutations should be followed up regularly.	('mutations', 'Var', (63, 72))	('SETD2', 'Gene', '29072', (57, 62))	('RCC', 'Disease', (8, 11))	('BAP1', 'Gene', '8314', (48, 52))	('patients', 'Species', '9606', (12, 20))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('RCC', 'Disease', 'MESH:C538614', (8, 11))	('BAP1', 'Gene', (48, 52))	('ccRCC', 'Phenotype', 'HP:0006770', (6, 11))	('SETD2', 'Gene', (57, 62))
29628	30349421	While Casuscelli and partners unraveled that TP53 was mutated at a frequency of 58% in 38 metastatic ChRCC cases, which was much higher than that unmasked by the TCGA project and our study.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('TP53', 'Gene', (45, 49))	('mutated', 'Var', (54, 61))	('TP53', 'Gene', '7157', (45, 49))
29629	30349421	In addition, those researchers found that mutations in TP53 and PTEN and imbalanced chromosome duplication in primary ChRCC were associated with worse survival.	('associated', 'Reg', (129, 139))	('PTEN', 'Gene', '5728', (64, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('imbalanced chromosome duplication', 'Var', (73, 106))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('PTEN', 'Gene', (64, 68))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('mutations', 'Var', (42, 51))
29632	30349421	Thus, we hypothesised that somatically mutated TP53 might serve as an important factor contributing to the aggressiveness of ChRCC.	('somatically mutated', 'Var', (27, 46))	('contributing', 'Reg', (87, 99))	('aggressiveness', 'Disease', 'MESH:D001523', (107, 121))	('TP53', 'Gene', '7157', (47, 51))	('aggressiveness', 'Phenotype', 'HP:0000718', (107, 121))	('aggressiveness', 'Disease', (107, 121))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('TP53', 'Gene', (47, 51))
29641	30349421	None of those gene mutations were reported to correlate with PD-L1 expression in RCC tumor cells previously.	('RCC tumor', 'Disease', 'MESH:C538614', (81, 90))	('PD-L1', 'Gene', (61, 66))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('mutations', 'Var', (19, 28))	('RCC tumor', 'Disease', (81, 90))	('PD-L1', 'Gene', '29126', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
29645	30349421	Previous studies had revealed that PD-L1 expression had an association with poor overall survival in ccRCC, while the TCGA database indicated that only mutations in BAP1 were associated with poor survival in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('poor', 'NegReg', (76, 80))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (210, 213))	('PD-L1', 'Gene', '29126', (35, 40))	('mutations', 'Var', (152, 161))	('BAP1', 'Gene', (165, 169))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('ccRCC', 'Phenotype', 'HP:0006770', (101, 106))	('overall survival', 'MPA', (81, 97))	('RCC', 'Disease', (210, 213))	('PD-L1', 'Gene', (35, 40))	('BAP1', 'Gene', '8314', (165, 169))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (208, 213))
29651	30349421	We identified somatic mutations in RCC from 26 Chinese patients using WES, which enriched the racial diversity of the somatic mutation profiles of RCC subjects.	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (147, 150))	('mutations', 'Var', (22, 31))	('RCC', 'Phenotype', 'HP:0005584', (147, 150))	('patients', 'Species', '9606', (55, 63))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
29652	30349421	We also detected numerous novel somatic mutations in this study, which further supplements the somatic mutation profiles of RCC.	('RCC', 'Disease', (124, 127))	('mutations', 'Var', (40, 49))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))
29677	27921007	It was recently reported that the expression of programed cell death-ligand 1 (PD-L1) in the immune component increased with pazopanib therapy, while CD8 expression decreased.	('CD8', 'Gene', (150, 153))	('CD8', 'Gene', '925', (150, 153))	('expression', 'MPA', (34, 44))	('increased', 'PosReg', (110, 119))	('cell death', 'biological_process', 'GO:0008219', ('58', '68'))	('pazopanib', 'Chemical', 'MESH:C516667', (125, 134))	('PD-L1', 'Gene', (79, 84))	('pazopanib', 'Var', (125, 134))	('ligand', 'molecular_function', 'GO:0005488', ('69', '75'))	('expression', 'MPA', (154, 164))
29683	27921007	It is well known that the abnormal tumor vasculature can impede T effector cell infiltration into tumors and create a hypoxic and acidic tumor microenvironment that, among other actions, increases the accumulation of regulatory T (Treg) cells and myeloid-derived suppressor cells (MDSCs), decreases T cell priming, impairs T effector cells, and polarizes tumor-associated macrophages (TAMs) to the immune inhibitory M2-like phenotype.	('tumors', 'Disease', (98, 104))	('impairs', 'NegReg', (315, 322))	('abnormal tumor', 'Phenotype', 'HP:0002664', (26, 40))	('impede', 'NegReg', (57, 63))	('increases', 'PosReg', (187, 196))	('hypoxic', 'Disease', (118, 125))	('hypoxic', 'Disease', 'MESH:D000860', (118, 125))	('tumor', 'Disease', (98, 103))	('acidic tumor', 'Disease', 'MESH:D009369', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('acidic tumor', 'Disease', (130, 142))	('T effector cell infiltration', 'CPA', (64, 92))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('polarizes', 'Reg', (345, 354))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (137, 142))	('T effector cells', 'CPA', (323, 339))	('TAMs', 'Chemical', '-', (385, 389))	('T cell priming', 'CPA', (299, 313))	('decreases', 'NegReg', (289, 298))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('decreases T cell', 'Phenotype', 'HP:0005403', (289, 305))	('decreases T cell priming', 'Phenotype', 'HP:0005419', (289, 313))	('tumor', 'Disease', (355, 360))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('abnormal', 'Var', (26, 34))
29700	27921007	in animal models of autoimmune kidney disease, glomerular and tubular damage is greater in PD-L1 knockout mice compared to wild-type mice.	('autoimmune kidney disease', 'Disease', (20, 45))	('knockout', 'Var', (97, 105))	('mice', 'Species', '10090', (133, 137))	('mice', 'Species', '10090', (106, 110))	('PD-L1', 'Gene', (91, 96))	('glomerular and tubular damage', 'Disease', 'MESH:D007674', (47, 76))	('kidney disease', 'Phenotype', 'HP:0000112', (31, 45))	('greater', 'PosReg', (80, 87))	('autoimmune kidney disease', 'Disease', 'MESH:D007674', (20, 45))
29701	27921007	Taking this into account, we hypothesize that in humans the blockade of the PD-1/PD-L1 axis with nivolumab is responsible for the disinhibition of different immune cells related to renal damage, unbalancing the equilibrium toward a proinflammatory state, and, finally, facilitating the development of an acute renal impairment.	('blockade', 'Var', (60, 68))	('acute renal impairment', 'Disease', 'MESH:D058186', (304, 326))	('facilitating', 'Reg', (269, 281))	('acute renal impairment', 'Phenotype', 'HP:0001919', (304, 326))	('equilibrium', 'MPA', (211, 222))	('disinhibition', 'Phenotype', 'HP:0000734', (130, 143))	('disinhibition', 'NegReg', (130, 143))	('renal impairment', 'Phenotype', 'HP:0000083', (310, 326))	('renal damage', 'Disease', 'MESH:D007674', (181, 193))	('renal damage', 'Disease', (181, 193))	('PD-1', 'Gene', (76, 80))	('nivolumab', 'Chemical', 'MESH:D000077594', (97, 106))	('PD-1', 'Gene', '5133', (76, 80))	('acute renal impairment', 'Disease', (304, 326))	('humans', 'Species', '9606', (49, 55))	('unbalancing', 'Reg', (195, 206))
29727	33977240	He had undergone a right radical nephrectomy 3 years before and was diagnosed with PRCC type 2, pT3bN0M0 (Fig.	('PRCC', 'Gene', (83, 87))	('PRCC', 'Gene', '5546', (83, 87))	('pT3bN0M0', 'Var', (96, 104))
29768	33046021	KANK1-NTRK3 fusions define a subset of BRAF mutation negative renal metanephric adenomas Metanephric adenoma (MA) is a rare benign renal neoplasm.	('benign renal neoplasm', 'Disease', 'MESH:D007674', (124, 145))	('fusions', 'Var', (12, 19))	('NTRK3', 'Gene', (6, 11))	('mutation', 'Var', (44, 52))	('KANK1', 'Gene', (0, 5))	('BRAF', 'Gene', '673', (39, 43))	('KANK1', 'Gene', '23189', (0, 5))	('renal metanephric adenomas', 'Disease', 'MESH:D000236', (62, 88))	('renal metanephric adenomas', 'Disease', (62, 88))	('Metanephric adenoma', 'Disease', 'MESH:D000236', (89, 108))	('BRAF', 'Gene', (39, 43))	('NTRK3', 'Gene', '4916', (6, 11))	('negative', 'NegReg', (53, 61))	('renal neoplasm', 'Phenotype', 'HP:0009726', (131, 145))	('benign renal neoplasm', 'Disease', (124, 145))	('Metanephric adenoma', 'Disease', (89, 108))	('neoplasm', 'Phenotype', 'HP:0002664', (137, 145))
29777	33046021	Our data shows that BRAF mutation in MA may not be as frequent as suggested in the literature and KANK-NTRK3 fusions may account for a subset of BRAFWT cases in younger patients.	('account', 'Reg', (121, 128))	('patients', 'Species', '9606', (169, 177))	('BRAF', 'Gene', (145, 149))	('NTRK3', 'Gene', (103, 108))	('KANK', 'Gene', (98, 102))	('NTRK3', 'Gene', '4916', (103, 108))	('fusions', 'Var', (109, 116))	('KANK', 'Gene', '23189', (98, 102))	('BRAF', 'Gene', '673', (20, 24))	('BRAF', 'Gene', (20, 24))	('BRAF', 'Gene', '673', (145, 149))	('WT', 'Phenotype', 'HP:0002667', (149, 151))
29780	33046021	BRAF mutations have been identified in metanephric stromal tumor and metanephric adenofibroma in addition to metanephric adenoma, which justifies their grouping as family of metanephric tumors by the World Health Organization (WHO).	('metanephric stromal tumor', 'Disease', (39, 64))	('metanephric adenoma', 'Disease', (109, 128))	('metanephric adenofibroma', 'Disease', 'MESH:D000232', (69, 93))	('metanephric adenoma', 'Disease', 'MESH:D000236', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (5, 14))	('metanephric tumors', 'Disease', (174, 192))	('BRAF', 'Gene', '673', (0, 4))	('metanephric adenofibroma', 'Disease', (69, 93))	('metanephric stromal tumor', 'Disease', 'MESH:D036821', (39, 64))	('metanephric tumors', 'Disease', 'MESH:D009369', (174, 192))	('BRAF', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
29792	33046021	BRAFV600E gene mutations are frequently detected in a wide range of benign and malignant human tumors, however, BRAF mutations in renal tumors such as renal cell carcinoma (RCC), oncocytoma, and WT are essentially absent.	('tumors', 'Disease', (136, 142))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', '673', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BRAF', 'Gene', (0, 4))	('tumors', 'Disease', (95, 101))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 171))	('human', 'Species', '9606', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('WT', 'Phenotype', 'HP:0002667', (195, 197))	('renal tumors', 'Disease', (130, 142))	('oncocytoma', 'Disease', (179, 189))	('mutations', 'Var', (117, 126))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('renal tumors', 'Disease', 'MESH:D007674', (130, 142))	('renal cell carcinoma', 'Disease', (151, 171))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (151, 171))	('renal tumor', 'Phenotype', 'HP:0009726', (130, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('renal tumors', 'Phenotype', 'HP:0009726', (130, 142))	('RCC', 'Disease', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('oncocytoma', 'Disease', 'MESH:D018249', (179, 189))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
29793	33046021	This data coupled with Choueiri's data suggests that BRAF mutations are specific for MA amongst renal tumors.	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', '673', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('renal tumors', 'Phenotype', 'HP:0009726', (96, 108))	('BRAF', 'Gene', (53, 57))	('renal tumor', 'Phenotype', 'HP:0009726', (96, 107))	('renal tumors', 'Disease', 'MESH:D007674', (96, 108))	('renal tumors', 'Disease', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
29818	33046021	FFPE sections were evaluated for the BRAF mutation on a Roche LightCycler 2.0 instrument (Mannheim, Germany) utilizing the allelic discrimination by real time polymerase chain reaction (PCR), which was performed at the Clinical Laboratory Improvements Amendments (CLIA) certified ACL Laboratories (Rosemont, IL, USA).	('men', 'Species', '9606', (257, 260))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('men', 'Species', '9606', (246, 249))	('men', 'Species', '9606', (84, 87))	('mutation', 'Var', (42, 50))	('men', 'Species', '9606', (253, 256))
29834	33046021	Thus, concordance between FISH testing and chromosome analysis evaluation for the detection of the rearrangement and involvement of KANK1-NTRK3 genes was 100% (2/2 cases).	('rearrangement', 'Var', (99, 112))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (108, 111))	('NTRK3', 'Gene', (138, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('KANK1', 'Gene', (132, 137))	('KANK1', 'Gene', '23189', (132, 137))	('NTRK3', 'Gene', '4916', (138, 143))
29838	33046021	Of the 28 cases studied, the BRAF mutational analysis was informative in 24 cases (86%), Fig.	('BRAF', 'Gene', '673', (29, 33))	('mutational', 'Var', (34, 44))	('BRAF', 'Gene', (29, 33))
29846	33046021	There were no cases demonstrating both the translocation and BRAFV600E mutation, suggesting mutual exclusivity between BRAFV600E and KANK1-NTRK3 fusion, Fig.	('NTRK3', 'Gene', '4916', (139, 144))	('NTRK3', 'Gene', (139, 144))	('BRAFV600E', 'Mutation', 'rs113488022', (61, 70))	('BRAFV600E', 'Mutation', 'rs113488022', (119, 128))	('KANK1', 'Gene', '23189', (133, 138))	('BRAFV600E', 'Var', (119, 128))	('KANK1', 'Gene', (133, 138))
29848	33046021	and Rakheja et al., observed balanced translocation t(9;15)(p24;q24), while Lerut et al., reported the presence of the dual balanced translocation, t(1,22)(q22;q13), and t(15;16)(q21;p13).	('t(9;15)(p24;q24', 'Var', (52, 67))	('t(1,22)(q22;q13', 'Var', (148, 163))	('t(9;15)(p24;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (52, 68))	('t(15;16)(q21;p13)', 'STRUCTURAL_ABNORMALITY', 'None', (170, 187))	('t(15;16)(q21;p13', 'Var', (170, 186))
29851	33046021	The novel findings of our study are that the typical MAs which do not harbor BRAF mutations can demonstrate cytogenetic aberrations.	('BRAF', 'Gene', '673', (77, 81))	('mutations', 'Var', (82, 91))	('MAs', 'cellular_component', 'GO:0034992', ('53', '56'))	('BRAF', 'Gene', (77, 81))
29855	33046021	published the largest series of MA demonstrating that 90% of MAs harbor a BRAF V600E mutation.	('V600E', 'Var', (79, 84))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('MAs', 'cellular_component', 'GO:0034992', ('61', '64'))	('V600E', 'Mutation', 'rs113488022', (79, 84))
29857	33046021	Additionally, they tested 129 non-MA renal neoplasms and detected BRAF V600E mutation in only one PRCC.	('PRCC', 'Gene', (98, 102))	('tested', 'Reg', (19, 25))	('renal neoplasms', 'Disease', (37, 52))	('neoplasms', 'Phenotype', 'HP:0002664', (43, 52))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('renal neoplasms', 'Phenotype', 'HP:0009726', (37, 52))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('PRCC', 'Phenotype', 'HP:0006766', (98, 102))	('renal neoplasm', 'Phenotype', 'HP:0009726', (37, 51))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', '673', (66, 70))	('renal neoplasms', 'Disease', 'MESH:D007674', (37, 52))	('neoplasm', 'Phenotype', 'HP:0002664', (43, 51))	('PRCC', 'Gene', '5546', (98, 102))	('BRAF', 'Gene', (66, 70))
29858	33046021	Cytogenetic analysis of this PRCC case revealed the presence of trisomy of chromosomes 7 and 17.	('PRCC', 'Phenotype', 'HP:0006766', (29, 33))	('PRCC', 'Gene', '5546', (29, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('trisomy', 'Var', (64, 71))	('PRCC', 'Gene', (29, 33))
29859	33046021	suggest that molecular BRAFV600E mutation analysis is a valuable diagnostic tool in the differential diagnosis of this rare kidney tumor that may be diagnostically challenging.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('kidney tumor', 'Disease', (124, 136))	('BRAFV600E', 'Var', (23, 32))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('kidney tumor', 'Phenotype', 'HP:0009726', (124, 136))	('kidney tumor', 'Disease', 'MESH:D007680', (124, 136))
29860	33046021	studied pediatric MA cases for BRAFV600E mutations and found three out of four cases to be positive for BRAFV600E mutation; 10 cases of pediatric renal cell carcinoma and 10 cases of Wilms' tumor did not exhibit BRAFV600E mutation.	('mutations', 'Var', (41, 50))	('renal cell carcinoma', 'Disease', (146, 166))	('BRAFV600E', 'Mutation', 'rs113488022', (31, 40))	('BRAFV600E', 'Mutation', 'rs113488022', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	("Wilms' tumor", 'Disease', (183, 195))	('BRAFV600E', 'Mutation', 'rs113488022', (212, 221))	("Wilms' tumor", 'Disease', 'MESH:D009396', (183, 195))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (183, 195))
29861	33046021	To date, there are no cases reported in literature of Wilms' tumor exhibiting BRAF mutations.	('mutations', 'Var', (83, 92))	("Wilms' tumor", 'Disease', (54, 66))	('BRAF', 'Gene', '673', (78, 82))	("Wilms' tumor", 'Disease', 'MESH:D009396', (54, 66))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (54, 66))	('BRAF', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))
29864	33046021	Overall, 90% of all published MA cases evaluated for BRAF mutations harbor BRAF exon 15 mutations.	('mutations', 'Var', (58, 67))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', '673', (75, 79))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', (75, 79))
29865	33046021	examined the genetic profiles using next-generation sequencing on eleven conventional MAs and revelated all eleven cases harboring BRAF V600E mutations.	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('V600E', 'Mutation', 'rs113488022', (136, 141))	('V600E', 'Var', (136, 141))	('MAs', 'cellular_component', 'GO:0034992', ('86', '89'))
29867	33046021	Our results differ significantly from those in the literature in the overall lower frequency of BRAF mutations (62% vs. 90%).	('BRAF', 'Gene', (96, 100))	('BRAF', 'Gene', '673', (96, 100))	('mutations', 'Var', (101, 110))
29871	33046021	Lastly, we compared BRAFV600E mutation analysis results with FISH for KANK1-NTRK3 gene fusion.	('BRAFV600E', 'Mutation', 'rs113488022', (20, 29))	('NTRK3', 'Gene', '4916', (76, 81))	('NTRK3', 'Gene', (76, 81))	('KANK1', 'Gene', '23189', (70, 75))	('KANK1', 'Gene', (70, 75))	('BRAFV600E', 'Var', (20, 29))
29876	33046021	Overall, 13 of 20 (65%) cases lacking t (9;15) harbored BRAF mutations.	('BRAF', 'Gene', '673', (56, 60))	('harbored', 'Reg', (47, 55))	('mutations', 'Var', (61, 70))	('BRAF', 'Gene', (56, 60))
29881	33046021	This finding supports the initial suggestion that KANK1-NTRK3 is the pathogenetically significant fusion transcript in tumors carrying a t (9,15)(p24;q24) and lacking BRAFV600E mutation in younger patient cohort.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('KANK1', 'Gene', '23189', (50, 55))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('NTRK3', 'Gene', (56, 61))	('BRAFV600E', 'Var', (167, 176))	('BRAFV600E', 'Mutation', 'rs113488022', (167, 176))	('t (9,15)(p24;q24', 'Var', (137, 153))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('patient', 'Species', '9606', (197, 204))	('KANK1', 'Gene', (50, 55))	('NTRK3', 'Gene', '4916', (56, 61))
29885	33046021	For those case lacking BRAF mutations, alternative testing such as FISH analysis for KANK1-NTRK3 fusion and/or cytogenetic chromosome analysis to look for t(9;15)(p24;q24) may be warranted.	('BRAF', 'Gene', '673', (23, 27))	('KANK1', 'Gene', '23189', (85, 90))	('KANK1', 'Gene', (85, 90))	('BRAF', 'Gene', (23, 27))	('t(9;15)(p24;q24)', 'STRUCTURAL_ABNORMALITY', 'None', (155, 171))	('NTRK3', 'Gene', '4916', (91, 96))	('fusion', 'Var', (97, 103))	('chromosome', 'cellular_component', 'GO:0005694', ('123', '133'))	('NTRK3', 'Gene', (91, 96))
29890	30660076	Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma1 Bi-allelic inactivation of the VHL gene on chromosome 3p is the characteristic feature in most clear cell renal cell carcinomas (ccRCC).	('BAP1', 'Gene', (43, 47))	('PBRM1', 'Gene', (36, 41))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (238, 259))	('Renal Cell Carcinoma1', 'Phenotype', 'HP:0005584', (110, 131))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (227, 259))	('carcinomas', 'Phenotype', 'HP:0030731', (249, 259))	('SETD2', 'Gene', '29072', (52, 57))	('clear cell renal cell carcinomas', 'Disease', (227, 259))	('VHL', 'Gene', (163, 166))	('Clear Cell Renal Cell Carcinoma1', 'Phenotype', 'HP:0006770', (99, 131))	('Clear Cell Renal Cell Carcinoma1', 'Disease', (99, 131))	('RCC', 'Disease', (263, 266))	('BAP1', 'Gene', '8314', (43, 47))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (227, 259))	('Clear Cell Renal Cell Carcinoma1', 'Disease', 'MESH:C538614', (99, 131))	('PBRM1', 'Gene', '55193', (36, 41))	('chromosome', 'cellular_component', 'GO:0005694', ('175', '185'))	('Bi-allelic inactivation', 'Var', (132, 155))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('SETD2', 'Gene', (52, 57))
29891	30660076	Frequent gene alterations were also identified in SETD2, BAP1 and PBRM1, all of which are situated on chromosome 3p and encode histone/chromatin regulators.	('alterations', 'Var', (14, 25))	('SETD2', 'Gene', '29072', (50, 55))	('SETD2', 'Gene', (50, 55))	('PBRM1', 'Gene', (66, 71))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('chromatin', 'cellular_component', 'GO:0000785', ('135', '144'))	('BAP1', 'Gene', (57, 61))
29894	30660076	In ccRCC loss of nuclear PBRM1 (68%), BAP1 (40%) and H3K36me3 (47%) expression was significantly correlated with each other, advanced tumor stage, poor tumor differentiation (P < .0001 each), and necrosis (P < .005) Targeted next generation sequencing of 83 ccRCC samples demonstrated a significant association of genetic mutations in PBRM1, BAP1, and SETD2 with absence of PBRM1, BAP1, and HEK36me3 protein expression (P < .05, each).	('necrosis', 'biological_process', 'GO:0070265', ('196', '204'))	('RCC', 'Disease', (5, 8))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('necrosis', 'biological_process', 'GO:0019835', ('196', '204'))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('necrosis', 'biological_process', 'GO:0001906', ('196', '204'))	('genetic mutations', 'Var', (314, 331))	('BAP1', 'Gene', (342, 346))	('BAP1', 'Gene', (381, 385))	('necrosis', 'Disease', 'MESH:D009336', (196, 204))	('PBRM1', 'Gene', (335, 340))	('SETD2', 'Gene', (352, 357))	('absence', 'NegReg', (363, 370))	('tumor', 'Disease', (152, 157))	('PBRM1', 'Gene', (374, 379))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('HEK36', 'CellLine', 'CVCL:2658', (391, 396))	('protein', 'cellular_component', 'GO:0003675', ('400', '407'))	('necrosis', 'Disease', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('SETD2', 'Gene', '29072', (352, 357))	('loss', 'NegReg', (9, 13))	('necrosis', 'biological_process', 'GO:0008219', ('196', '204'))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('HEK36me3', 'MPA', (391, 399))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RCC', 'Disease', (260, 263))	('necrosis', 'biological_process', 'GO:0008220', ('196', '204'))
29896	30660076	Bi-allelic inactivation of the tumor suppressor gene von Hippel-Lindau (VHL) due to chromosome 3p deletion and gene mutation is a hallmark of clear cell RCC (ccRCC), the most common subtype of RCC.	('von Hippel-Lindau', 'Gene', '7428', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor suppressor', 'biological_process', 'GO:0051726', ('31', '47'))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('RCC', 'Disease', (193, 196))	('Bi-allelic inactivation', 'Var', (0, 23))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('tumor', 'Disease', (31, 36))	('RCC', 'Disease', 'MESH:C538614', (160, 163))	('deletion', 'Var', (98, 106))	('RCC', 'Disease', (160, 163))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('31', '47'))	('von Hippel-Lindau', 'Gene', (53, 70))	('gene mutation', 'Var', (111, 124))
29897	30660076	Despite its prominent role as multi-adaptor protein that interacts with more than 30 different binding partners involved in many oncogenic processes, functional inactivation of pVHL is not sufficient for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('inactivation', 'Var', (161, 173))	('interacts', 'Interaction', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('binding', 'molecular_function', 'GO:0005488', ('95', '102'))	('pVHL', 'Gene', (177, 181))	('protein', 'cellular_component', 'GO:0003675', ('44', '51'))
29898	30660076	Recent data suggest that additional genetic and epigenetic events in driver genes act cooperatively with a loss of pVHL function to promote ccRCC progression.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('pVHL', 'Gene', (115, 119))	('epigenetic', 'Var', (48, 58))	('promote', 'PosReg', (132, 139))
29902	30660076	Mutations in PBRM1 have been detected in 40% of ccRCC, whereas 12 and 19% have sequence alterations in BAP1 and SETD2, respectively.	('SETD2', 'Gene', '29072', (112, 117))	('PBRM1', 'Gene', (13, 18))	('BAP1', 'Gene', (103, 107))	('SETD2', 'Gene', (112, 117))	('detected', 'Reg', (29, 37))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('Mutations', 'Var', (0, 9))
29903	30660076	All three proteins are involved in cellular pathways related to tumorigenesis and the high frequency of mutations in their genes support their role as tumor suppressors in ccRCC.	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('RCC', 'Disease', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('involved', 'Reg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
29904	30660076	Inactivation of PBRM1 has been shown to promote ccRCC cancer cell proliferation and migration as well as to enhance the HIF-response.	('promote', 'PosReg', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('PBRM1', 'Gene', (16, 21))	('enhance', 'PosReg', (108, 115))	('migration', 'CPA', (84, 93))	('cancer', 'Disease', (54, 60))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('cell proliferation', 'biological_process', 'GO:0008283', ('61', '79'))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Inactivation', 'Var', (0, 12))	('HIF-response', 'CPA', (120, 132))
29906	30660076	Mice deficient for either VHL or VHL together with one allele of BAP1 developed multiple lesions spanning from benign cysts to cystic and solid ccRCC suggesting a tumor suppressive cooperation between BAP1 and pVHL.	('benign cysts', 'Disease', (111, 123))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cystic', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BAP1', 'Gene', (65, 69))	('developed', 'Reg', (70, 79))	('tumor', 'Disease', (163, 168))	('Mice', 'Species', '10090', (0, 4))	('deficient', 'Var', (5, 14))
29907	30660076	Notably, a cooperative function was also reported for BAP1 and PBRM1 by demonstrating that combined loss of BAP1 and PBRM1 drive ccRCC in mice.	('loss', 'Var', (100, 104))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('RCC', 'Disease', (131, 134))	('mice', 'Species', '10090', (138, 142))	('BAP1', 'Gene', (108, 112))	('PBRM1', 'Gene', (117, 122))
29909	30660076	Finally, SETD2 knockdown in renal primary tubular epithelial cells led to bypass the senescence barrier, facilitating a malignant transformation toward ccRCC.	('SETD2', 'Gene', (9, 14))	('facilitating', 'PosReg', (105, 117))	('knockdown', 'Var', (15, 24))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('senescence', 'biological_process', 'GO:0010149', ('85', '95'))	('RCC', 'Disease', (154, 157))	('SETD2', 'Gene', '29072', (9, 14))	('malignant transformation', 'CPA', (120, 144))
29913	30660076	To analyze the expression of PBRM1, BAP1 and H3K36me3 in RCC, two tissue microarrays (TMA) containing 721 RCC and 44 normal kidney tissue (one punch per sample) were constructed as described.	('H3K36me3', 'Var', (45, 53))	('TMA', 'Chemical', '-', (86, 89))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', (106, 109))	('BAP1', 'Gene', (36, 40))	('PBRM1', 'Gene', (29, 34))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
29932	30660076	Nuclear and cytoplasmic BAP1 positivity was seen in most of the RCC cell lines including 769-P known to be BAP1 mutated but still expresses the protein.	('protein', 'cellular_component', 'GO:0003675', ('144', '151'))	('BAP1', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('RCC', 'Disease', (64, 67))	('mutated', 'Var', (112, 119))
29933	30660076	Although SETD2 mutations have been reported for A-498, A-704, and Caki-1, all RCC cell lines were SETD2 positive.	('SETD2', 'Gene', (9, 14))	('SETD2', 'Gene', '29072', (98, 103))	('mutations', 'Var', (15, 24))	('SETD2', 'Gene', (98, 103))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('SETD2', 'Gene', '29072', (9, 14))
29935	30660076	H3K36me3 was absent in SETD2 mutated A-498 and A-704 but not in Caki-1 suggesting different effects of SETD2 mutations on SETD2 function in these cell lines.	('SETD2', 'Gene', '29072', (23, 28))	('SETD2', 'Gene', (23, 28))	('SETD2', 'Gene', '29072', (122, 127))	('H3K36me3', 'Protein', (0, 8))	('A-498', 'Var', (37, 42))	('SETD2', 'Gene', (122, 127))	('SETD2', 'Gene', '29072', (103, 108))	('mutated A-498', 'Var', (29, 42))	('SETD2', 'Gene', (103, 108))	('absent', 'NegReg', (13, 19))	('A-704', 'Var', (47, 52))
29937	30660076	Based on these results we decided to use H3K36me3-specific antibody as surrogate marker for SETD2 activity for TMA analysis.	('SETD2', 'Gene', '29072', (92, 97))	('antibody', 'cellular_component', 'GO:0019815', ('59', '67'))	('antibody', 'cellular_component', 'GO:0019814', ('59', '67'))	('SETD2', 'Gene', (92, 97))	('antibody', 'molecular_function', 'GO:0003823', ('59', '67'))	('H3K36me3-specific', 'Var', (41, 58))	('antibody', 'cellular_component', 'GO:0042571', ('59', '67'))	('TMA', 'Chemical', '-', (111, 114))
29940	30660076	Weak staining intensity may be caused by mutations and chromosomal loss of 3p, which may influence protein expression of PBRM1, BAP1, and H3K36me3, but also by the age of paraffin blocks, tissue fixation, and IHC detection protocols, making it difficult to distinguish between genomic driven and artificial reduction of protein expression.	('mutations', 'Var', (41, 50))	('protein', 'cellular_component', 'GO:0003675', ('320', '327'))	('caused', 'Reg', (31, 37))	('influence', 'Reg', (89, 98))	('BAP1', 'Gene', (128, 132))	('loss', 'NegReg', (67, 71))	('PBRM1', 'Gene', (121, 126))	('H3K36me3', 'Protein', (138, 146))	('protein', 'cellular_component', 'GO:0003675', ('99', '106'))	('protein expression', 'MPA', (99, 117))	('paraffin', 'Chemical', 'MESH:D010232', (171, 179))
29943	30660076	Expression frequencies of PBRM1, BAP1 and H3K36me3 in different RCC subtypes are listed in Table 1.	('PBRM1', 'Gene', (26, 31))	('RCC', 'Disease', (64, 67))	('H3K36me3', 'Var', (42, 50))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('BAP1', 'Gene', (33, 37))
29949	30660076	By linking our TMA IHC data to pathological parameters we found that loss of BAP1, H3K36me3 and PBRM1 was highly associated with late tumor stage as well as high nuclear differentiation grade (P < .0001, each; Table 2).	('TMA', 'Chemical', '-', (15, 18))	('late tumor', 'Disease', 'MESH:D009369', (129, 139))	('loss', 'Var', (69, 73))	('high nuclear differentiation grade', 'CPA', (157, 191))	('H3K36me3', 'Protein', (83, 91))	('PBRM1', 'Gene', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('late tumor', 'Disease', (129, 139))	('BAP1', 'Gene', (77, 81))	('associated', 'Reg', (113, 123))
29952	30660076	Also, loss of PBRM1, H3K36me3, and BAP1 expression was significantly associated with presence of necrosis and, excepting H3K36me3, a high density of tumor infiltrating lymphocytes (Table 3).	('loss', 'NegReg', (6, 10))	('expression', 'MPA', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('H3K36me3', 'Var', (21, 29))	('PBRM1', 'Gene', (14, 19))	('necrosis', 'Disease', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('necrosis', 'biological_process', 'GO:0008219', ('97', '105'))	('necrosis', 'biological_process', 'GO:0070265', ('97', '105'))	('necrosis', 'biological_process', 'GO:0019835', ('97', '105'))	('tumor', 'Disease', (149, 154))	('necrosis', 'Disease', 'MESH:D009336', (97, 105))	('BAP1', 'Gene', (35, 39))	('necrosis', 'biological_process', 'GO:0001906', ('97', '105'))	('necrosis', 'biological_process', 'GO:0008220', ('97', '105'))
29958	30660076	Seventeen of 83 (20%) ccRCC had PBRM1 mutations and 11 tumors had BAP1 and SETD2 mutations (13%, each).	('RCC', 'Disease', (24, 27))	('PBRM1', 'Gene', (32, 37))	('SETD2', 'Gene', '29072', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SETD2', 'Gene', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (38, 47))	('RCC', 'Disease', 'MESH:C538614', (24, 27))
29959	30660076	In 4 ccRCC (5%) both PBRM1 and BAP1 were affected, 2 tumors had mutations in PBRM1 and SETD2 (2%), and 1 tumor in BAP1 and SETD2 (1%).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SETD2', 'Gene', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('SETD2', 'Gene', '29072', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (64, 73))	('SETD2', 'Gene', (87, 92))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('SETD2', 'Gene', '29072', (87, 92))	('RCC', 'Disease', (7, 10))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('PBRM1', 'Gene', (77, 82))	('PBRM1', 'Gene', (21, 26))	('affected', 'Reg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (53, 58))	('RCC', 'Disease', 'MESH:C538614', (7, 10))
29961	30660076	Sequence alterations that highly likely lead to truncation of the proteins (frameshift, nonsense, splice site) were seen in 15 of 17 (88%; PBRM1), 6 of 11 (56%; BAP1), and 9 of 11 (82%; SETD2) mutated ccRCC.	('SETD2', 'Gene', (186, 191))	('lead to', 'Reg', (40, 47))	('proteins', 'Protein', (66, 74))	('mutated', 'Var', (193, 200))	('alterations', 'Var', (9, 20))	('truncation', 'MPA', (48, 58))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('RCC', 'Disease', (203, 206))	('SETD2', 'Gene', '29072', (186, 191))
29963	30660076	4, PBRM1, BAP1, and SETD2 mutations correlated with loss of PBRM1, BAP1 expression and H3K36me3 methylation.	('loss', 'NegReg', (52, 56))	('BAP1', 'Gene', (10, 14))	('PBRM1', 'Gene', (60, 65))	('PBRM1', 'Gene', (3, 8))	('SETD2', 'Gene', '29072', (20, 25))	('expression', 'MPA', (72, 82))	('mutations', 'Var', (26, 35))	('SETD2', 'Gene', (20, 25))	('methylation', 'biological_process', 'GO:0032259', ('96', '107'))	('H3K36me3', 'Protein', (87, 95))	('BAP1', 'Gene', (67, 71))
29974	30660076	Loss of expression of the three proteins was highest in ccRCC with about 70% for PBRM1, 40% for BAP1, and 50% for H3K36me3.	('PBRM1', 'Gene', (81, 86))	('BAP1', 'Gene', (96, 100))	('Loss', 'NegReg', (0, 4))	('H3K36me3', 'Var', (114, 122))	('expression', 'MPA', (8, 18))	('RCC', 'Disease', (58, 61))	('RCC', 'Disease', 'MESH:C538614', (58, 61))
29976	30660076	In pRCC, in which 5-10% of the tumors have also PBRM1, SETD2, and BAP1 mutations, approximately 40% were PBRM1 negative in both main subtypes type 1 and type 2.	('pRCC', 'Gene', '5546', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('PBRM1', 'Gene', (48, 53))	('pRCC', 'Gene', (3, 7))	('BAP1', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (71, 80))	('SETD2', 'Gene', '29072', (55, 60))	('SETD2', 'Gene', (55, 60))
29980	30660076	Mutations in PBRM1, BAP1 and SETD2 contribute to loss of protein expression.	('SETD2', 'Gene', '29072', (29, 34))	('loss', 'NegReg', (49, 53))	('BAP1', 'Gene', (20, 24))	('SETD2', 'Gene', (29, 34))	('PBRM1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('protein', 'cellular_component', 'GO:0003675', ('57', '64'))	('protein expression', 'MPA', (57, 75))
29982	30660076	By doubling the number of RCCs from 300 to 600 we could confirm the results from a previous study showing that loss of PBRM1 expression is strongly linked to a more aggressive tumor behavior.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('linked to', 'Reg', (148, 157))	('aggressive tumor', 'Disease', 'MESH:D001523', (165, 181))	('loss', 'Var', (111, 115))	('PBRM1', 'Gene', (119, 124))	('aggressive tumor', 'Disease', (165, 181))	('RCC', 'Disease', (26, 29))	('RCC', 'Disease', 'MESH:C538614', (26, 29))
29985	30660076	Following the classical two-hit hypothesis of tumor suppressor genes, gene inactivation by mechanisms such as truncating mutations occurs mainly in late stage and high grade tumors.	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor suppressor', 'biological_process', 'GO:0051726', ('46', '62'))	('gene', 'Var', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('truncating mutations', 'Var', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('46', '62'))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
29986	30660076	The fractions of non-expressing tumors in our tumor cohort was generally higher (40% BAP1, 50% H3K36me3, 70% PBRM1) compared to those described in several previous studies, which ranged between 10-50% for BAP1, 14-34% for SETD2, and 31-70% for PBRM1.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('BAP1', 'Var', (85, 89))	('SETD2', 'Gene', '29072', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SETD2', 'Gene', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumor', 'Disease', (32, 37))	('H3K36me3', 'Var', (95, 103))	('higher', 'PosReg', (73, 79))
29988	30660076	However, regardless of the diverse patient cohorts and strategies used to examine ccRCC, the consistent finding of these studies is that loss of expression of PBRM1, SETD2 and BAP1 is closely linked to tumor progression.	('tumor', 'Disease', (202, 207))	('patient', 'Species', '9606', (35, 42))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('RCC', 'Disease', (84, 87))	('BAP1', 'Gene', (176, 180))	('loss of', 'Var', (137, 144))	('SETD2', 'Gene', '29072', (166, 171))	('PBRM1', 'Gene', (159, 164))	('SETD2', 'Gene', (166, 171))	('linked', 'Reg', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
29989	30660076	Mutations of PBRM1, BAP1 and SETD2 determined in 83 ccRCC revealed their important negative influence on protein expression, but in a considerable fraction of tumors loss or reduction of expression seem to follow mechanisms other than mutations and chromosome 3p loss.	('SETD2', 'Gene', '29072', (29, 34))	('protein', 'cellular_component', 'GO:0003675', ('105', '112'))	('BAP1', 'Gene', (20, 24))	('SETD2', 'Gene', (29, 34))	('PBRM1', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('RCC', 'Disease', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('Mutations', 'Var', (0, 9))	('tumors loss', 'Disease', 'MESH:D009369', (159, 170))	('tumors loss', 'Disease', (159, 170))	('chromosome', 'cellular_component', 'GO:0005694', ('249', '259'))	('reduction', 'NegReg', (174, 183))	('expression', 'MPA', (187, 197))	('protein expression', 'MPA', (105, 123))
29991	30660076	Also, SETD2, BAP1 as well as PBRM1 mutations have been reported in pRCC, which has no chromosome 3p deletions.	('pRCC', 'Gene', (67, 71))	('BAP1', 'Gene', (13, 17))	('reported', 'Reg', (55, 63))	('SETD2', 'Gene', '29072', (6, 11))	('chromosome', 'cellular_component', 'GO:0005694', ('86', '96'))	('SETD2', 'Gene', (6, 11))	('pRCC', 'Gene', '5546', (67, 71))	('PBRM1', 'Gene', (29, 34))	('mutations', 'Var', (35, 44))
29994	30660076	Although gene mutations were significantly associated with loss of protein expression in our ccRCC cohort, BAP1 and H3K36me3 were expressed in a small subset of ccRCC despite BAP1 and SETD2 mutations.	('BAP1', 'Gene', (175, 179))	('RCC', 'Disease', 'MESH:C538614', (163, 166))	('loss', 'NegReg', (59, 63))	('H3K36me3', 'Protein', (116, 124))	('RCC', 'Disease', (163, 166))	('protein', 'cellular_component', 'GO:0003675', ('67', '74'))	('mutations', 'Var', (190, 199))	('BAP1', 'Gene', (107, 111))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('SETD2', 'Gene', '29072', (184, 189))	('protein expression', 'MPA', (67, 85))	('mutations', 'Var', (14, 23))	('SETD2', 'Gene', (184, 189))
29995	30660076	It is therefore conceivable that PBRM1, BAP1, and SETD2 mutations identified in ccRCC, as well as in other cancer types, may also exert diverse effects on protein expression and function.	('mutations', 'Var', (56, 65))	('function', 'MPA', (178, 186))	('SETD2', 'Gene', '29072', (50, 55))	('effects', 'Reg', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SETD2', 'Gene', (50, 55))	('protein', 'cellular_component', 'GO:0003675', ('155', '162'))	('protein expression', 'MPA', (155, 173))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('BAP1', 'Gene', (40, 44))	('cancer', 'Disease', (107, 113))	('PBRM1', 'Gene', (33, 38))
29996	30660076	Inactivation of tumor suppressor genes by genetic or epigenetic events is crucial for tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('epigenetic events', 'Var', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (86, 91))	('tumor suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('genetic', 'Var', (42, 49))	('tumor', 'Disease', (16, 21))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('Inactivation', 'Var', (0, 12))
29997	30660076	In this context, PBRM1, BAP1, and SETD2 mutation and loss of expression was described to be associated with advanced tumor stage, high grade and patient outcome.	('mutation', 'Var', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BAP1', 'Gene', (24, 28))	('tumor', 'Disease', (117, 122))	('PBRM1', 'Gene', (17, 22))	('high grade', 'CPA', (130, 140))	('loss of expression', 'NegReg', (53, 71))	('SETD2', 'Gene', '29072', (34, 39))	('patient', 'Species', '9606', (145, 152))	('SETD2', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
29999	30660076	Our study demonstrates a significant association between PBRM1 alterations and a high amount of TIL in ccRCC.	('PBRM1', 'Gene', (57, 62))	('alterations', 'Var', (63, 74))	('TIL', 'Gene', '7096', (96, 99))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('TIL', 'Gene', (96, 99))
30000	30660076	showing an increased clinical benefit of immune checkpoint therapy in ccRCC patients with inactivated PBRM1.	('patients', 'Species', '9606', (76, 84))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('PBRM1', 'Gene', (102, 107))	('inactivated', 'Var', (90, 101))	('benefit', 'PosReg', (30, 37))
30001	30660076	PBRM1 loss-of-function mutations may thus serve as unfavorable prognostic marker but also as favorable predictive marker regarding PD-(L)1 blockade therapy.	('PD-(L)1', 'Gene', '29126', (131, 138))	('PBRM1', 'Gene', (0, 5))	('loss-of-function', 'NegReg', (6, 22))	('mutations', 'Var', (23, 32))	('PD-(L)1', 'Gene', (131, 138))
30005	30660076	In this context, it was recently shown that deletion of VHL together with either BAP1 or PBRM1 drives tumor grade.	('VHL', 'Gene', (56, 59))	('deletion', 'Var', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('drives', 'Reg', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
30006	30660076	Notably, functional inactivation of the four tumor suppressors pVHL, PBRM1, BAP1 and SETD2 affects spindle orientation, spindle assembly, histone modification, nucleosome stabilization and chromatin remodeling, all of which strongly impair chromosomal stability.	('SETD2', 'Gene', '29072', (85, 90))	('pVHL', 'Gene', (63, 67))	('nucleosome', 'MPA', (160, 170))	('tumor', 'Disease', (45, 50))	('spindle', 'cellular_component', 'GO:0005819', ('120', '127'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('189', '209'))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('histone modification', 'biological_process', 'GO:0016570', ('138', '158'))	('affects', 'Reg', (91, 98))	('chromosomal stability', 'CPA', (240, 261))	('inactivation', 'Var', (20, 32))	('spindle orientation', 'CPA', (99, 118))	('histone modification', 'MPA', (138, 158))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('impair', 'NegReg', (233, 239))	('PBRM1', 'Gene', (69, 74))	('spindle assembly', 'CPA', (120, 136))	('nucleosome', 'cellular_component', 'GO:0000786', ('160', '170'))	('spindle orientation', 'biological_process', 'GO:0051294', ('99', '118'))	('chromatin remodeling', 'CPA', (189, 209))	('chromatin', 'cellular_component', 'GO:0000785', ('189', '198'))	('spindle', 'cellular_component', 'GO:0005819', ('99', '106'))	('SETD2', 'Gene', (85, 90))	('BAP1', 'Gene', (76, 80))	('spindle assembly', 'biological_process', 'GO:0051225', ('120', '136'))
30011	30660076	Notably, in five of these subtypes PBRM1, SETD2, and BAP1 mutations play a dominant role as driver genes.	('mutations', 'Var', (58, 67))	('SETD2', 'Gene', '29072', (42, 47))	('PBRM1', 'Gene', (35, 40))	('SETD2', 'Gene', (42, 47))	('BAP1', 'Gene', (53, 57))
30012	30660076	These subtypes were defined i) by mutations in PBRM1 followed by SETD2; ii) by PBRM1 mutations followed by alterations in the PI3K/AKT pathway; iii) by mutations in PBRM1 followed by a driver somatic copy number alteration event; iv) by BAP1 mutations as the single driver event with VHL, and v) by tumors in which at least two of the genes BAP1, SETD2, PBRM1 or PTEN where clonally mutated.	('AKT', 'Gene', '207', (131, 134))	('mutations', 'Var', (152, 161))	('SETD2', 'Gene', (65, 70))	('PI3K', 'molecular_function', 'GO:0016303', ('126', '130'))	('PTEN', 'Gene', '5728', (363, 367))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('SETD2', 'Gene', '29072', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('BAP1', 'Gene', (341, 345))	('BAP1', 'Gene', (237, 241))	('AKT', 'Gene', (131, 134))	('PBRM1', 'Gene', (165, 170))	('tumors', 'Disease', (299, 305))	('mutations', 'Var', (85, 94))	('SETD2', 'Gene', (347, 352))	('mutations', 'Var', (242, 251))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('SETD2', 'Gene', '29072', (347, 352))	('PTEN', 'Gene', (363, 367))	('PBRM1', 'Gene', (354, 359))	('mutations', 'Var', (34, 43))
30014	30660076	Given the subclonal diversity and its different impact on patient outcome in ccRCC, it becomes evident why the frequencies and clinical relevance of gene mutations and protein expression of BAP1, SETD2, and PBRM1, let alone their subtyping, differ from each other.	('PBRM1', 'Gene', (207, 212))	('protein', 'cellular_component', 'GO:0003675', ('168', '175'))	('patient', 'Species', '9606', (58, 65))	('BAP1', 'Gene', (190, 194))	('SETD2', 'Gene', '29072', (196, 201))	('mutations', 'Var', (154, 163))	('SETD2', 'Gene', (196, 201))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
30015	30660076	The different combinations of BAP1, PBRM1 or SETD2 expression changes obtained from our TMA immunostainings support the proposed genetic and clonal evolution features and suggest that the diverse clinical phenotypes of ccRCC may also be identified by protein expression data.	('SETD2', 'Gene', (45, 50))	('TMA', 'Chemical', '-', (88, 91))	('BAP1', 'Gene', (30, 34))	('PBRM1', 'Gene', (36, 41))	('RCC', 'Disease', 'MESH:C538614', (221, 224))	('RCC', 'Disease', (221, 224))	('changes', 'Var', (62, 69))	('SETD2', 'Gene', '29072', (45, 50))	('protein', 'cellular_component', 'GO:0003675', ('251', '258'))
30020	30660076	This is in line with the hypothesis that a strong niche-specific selection of SETD2 mutant subclones induce a limited clonal growth.	('mutant', 'Var', (84, 90))	('clonal growth', 'CPA', (118, 131))	('SETD2', 'Gene', (78, 83))	('SETD2', 'Gene', '29072', (78, 83))
30023	30660076	PBRM1 driven subtypes followed by SETD2, as well as copy number alterations and alterations in the PI3K/AKT pathway were assigned to 69 (16.1%) and 72 (16.8%) tumors, respectively.	('PI3K', 'molecular_function', 'GO:0016303', ('99', '103'))	('AKT', 'Gene', (104, 107))	('copy number alterations', 'Var', (52, 75))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PBRM1', 'Gene', (0, 5))	('SETD2', 'Gene', '29072', (34, 39))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('SETD2', 'Gene', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('AKT', 'Gene', '207', (104, 107))	('alterations', 'Reg', (80, 91))
30044	28086852	Anti-CTLA-4 antibodies, which are used to treat advanced melanoma patients, have been reported to have an excellent therapeutic effect.	('antibodies', 'Var', (12, 22))	('CTLA-4', 'Gene', '1493', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('CTLA-4', 'Gene', (5, 11))	('patients', 'Species', '9606', (66, 74))
30049	28086852	Although some studies have demonstrated that a high expression of PD-L1 was associated with poor clinical outcomes, few studies have investigated PD-L1 expression in pRCC.	('pRCC', 'Gene', (166, 170))	('PD-L1', 'Gene', '29126', (146, 151))	('PD-L1', 'Gene', '29126', (66, 71))	('high', 'Var', (47, 51))	('pRCC', 'Phenotype', 'HP:0006766', (166, 170))	('pRCC', 'Gene', '5546', (166, 170))	('expression', 'MPA', (52, 62))	('associated', 'Reg', (76, 86))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('PD-L1', 'Gene', (146, 151))	('PD-L1', 'Gene', (66, 71))
30091	28086852	Although PD-L1 expression appeared to be related to worse overall survival, there was no significant correlation between PD-L1 expression and clinical prognosis.	('PD-L1', 'Gene', (121, 126))	('overall survival', 'MPA', (58, 74))	('expression', 'Var', (15, 25))	('PD-L1', 'Gene', '29126', (121, 126))	('PD-L1', 'Gene', '29126', (9, 14))	('worse', 'NegReg', (52, 57))	('PD-L1', 'Gene', (9, 14))
30094	20815920	Epigenetics of renal cell carcinoma: the path towards new diagnostics and therapeutics Aberrant DNA methylation, in particular promoter hypermethylation and transcriptional silencing of tumor suppressor genes, has an important role in the development of many human cancers, including renal cell carcinoma (RCC).	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Disease', (186, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('promoter hypermethylation', 'Var', (127, 152))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('RCC', 'Disease', (306, 309))	('Aberrant', 'Var', (87, 95))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (15, 35))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (284, 304))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('186', '202'))	('RCC', 'Disease', 'MESH:C538614', (306, 309))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('DNA', 'cellular_component', 'GO:0005574', ('96', '99'))	('human', 'Species', '9606', (259, 264))	('tumor suppressor', 'biological_process', 'GO:0051726', ('186', '202'))	('DNA methylation', 'biological_process', 'GO:0006306', ('96', '111'))	('renal cell carcinoma', 'Disease', (15, 35))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('renal cell carcinoma', 'Disease', (284, 304))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (284, 304))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancers', 'Disease', (265, 272))
30095	20815920	Indeed, apart from mutations in the well studied von Hippel-Lindau gene (VHL), the mutation frequency rates of known tumor suppressor genes in RCC are generally low, but the number of genes found to show frequent inactivation by promoter methylation in RCC continues to grow.	('VHL', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('inactivation', 'NegReg', (213, 225))	('VHL', 'Gene', '7428', (73, 76))	('von Hippel-Lindau', 'Gene', (49, 66))	('tumor', 'Disease', (117, 122))	('promoter methylation', 'Var', (229, 249))	('methylation', 'biological_process', 'GO:0032259', ('238', '249'))	('RCC', 'Disease', 'MESH:C538614', (253, 256))	('tumor suppressor', 'biological_process', 'GO:0051726', ('117', '133'))	('RCC', 'Disease', (253, 256))	('RCC', 'Phenotype', 'HP:0005584', (253, 256))	('von Hippel-Lindau', 'Gene', '7428', (49, 66))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('RCC', 'Disease', (143, 146))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('117', '133'))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
30096	20815920	Here, we review the genes identified as epigenetically silenced in RCC and their relationship to pathways of tumor development.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('epigenetically silenced', 'Var', (40, 63))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
30101	20815920	The most common genetic event in the evolution of sporadic ccRCC is inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene (TSG).	('tumor suppressor', 'molecular_function', 'GO:0008181', ('112', '128'))	('TSG', 'Gene', (135, 138))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (88, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('TSG', 'Gene', '57045', (135, 138))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('112', '128'))	('inactivation', 'Var', (68, 80))
30102	20815920	VHL inactivation leads to stabilization of the hypoxia-inducible transcription factors HIF-1 and HIF-2 and activation of a wide repertoire of hypoxia response genes.	('inactivation', 'Var', (4, 16))	('stabilization', 'MPA', (26, 39))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('VHL', 'Gene', (0, 3))	('HIF-1 and HIF-2', 'Disease', 'MESH:D003924', (87, 102))	('transcription', 'biological_process', 'GO:0006351', ('65', '78'))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('VHL', 'Gene', '7428', (0, 3))	('hypoxia', 'Disease', (142, 149))	('activation', 'PosReg', (107, 117))
30103	20815920	The frequency of VHL mutations in sporadic ccRCC has been reported to be as high as 75% (although VHL mutations are rare in non-clear-cell forms of RCC).	('RCC', 'Disease', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('VHL', 'Gene', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (98, 101))	('VHL', 'Gene', '7428', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('mutations', 'Var', (21, 30))
30104	20815920	In addition to VHL mutations, VHL allele loss of 3p25, resulting in biallelic VHL inactivation, is the most frequent copy number abnormality in ccRCC (as predicted by a classical 'two hit' model of tumorigenesis, where loss of the second allele of a key tumour suppressor is required for tumour formation to occur).	('VHL', 'Gene', (15, 18))	('VHL', 'Gene', (30, 33))	('VHL', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inactivation', 'NegReg', (82, 94))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('VHL', 'Gene', '7428', (15, 18))	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', '7428', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('tumour', 'Disease', 'MESH:D009369', (288, 294))	('tumour', 'Disease', (288, 294))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('loss of 3p25', 'Var', (41, 53))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('formation', 'biological_process', 'GO:0009058', ('295', '304'))
30105	20815920	Although the VHL mutations in primary RCC were detected about 16 years ago, attempts to identify other frequently mutated RCC genes have been unsuccessful, with none of the thousands of genes tested so far mutated in over 15% of tumors.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('RCC', 'Disease', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('VHL', 'Gene', (13, 16))	('mutations', 'Var', (17, 26))	('VHL', 'Gene', '7428', (13, 16))	('RCC', 'Phenotype', 'HP:0005584', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', (122, 125))	('tumors', 'Disease', (229, 235))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
30106	20815920	TSG inactivation may result from genetic or epigenetic events, and it is well recognized that epigenetic silencing of TSGs has a significant role in the pathogenesis of many, if not all, human cancers.	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('TSG', 'Gene', '57045', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('TSG', 'Gene', (118, 121))	('cancers', 'Disease', (193, 200))	('pathogenesis', 'biological_process', 'GO:0009405', ('153', '165'))	('epigenetic silencing', 'Var', (94, 114))	('result', 'Reg', (21, 27))	('TSG', 'Gene', '57045', (118, 121))	('human', 'Species', '9606', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('TSG', 'Gene', (0, 3))	('inactivation', 'NegReg', (4, 16))
30107	20815920	Indeed, promoter methylation and epigenetic silencing of VHL in RCC was one of the first examples of this phenomenon and so far approximately 60 genes have been suggested to be epigenetically dysregulated in RCC (Table 1).	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('promoter methylation', 'Var', (8, 28))	('RCC', 'Disease', 'MESH:C538614', (208, 211))	('RCC', 'Disease', (208, 211))	('VHL', 'Gene', (57, 60))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('methylation', 'biological_process', 'GO:0032259', ('17', '28'))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('VHL', 'Gene', '7428', (57, 60))	('RCC', 'Disease', (64, 67))	('epigenetic silencing', 'Var', (33, 53))
30110	20815920	These regions (CpG islands, 0.4 to 4 kb long and found in over 50% of all genes) are generally unmethylated in normal cells but may be hypermethylated in tumors, where CpG island methylation is also associated with histone modification and chromatin remodeling resulting in transcriptional silencing.	('associated', 'Reg', (199, 209))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('CpG island methylation', 'Var', (168, 190))	('histone modification', 'biological_process', 'GO:0016570', ('215', '235'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('240', '260'))	('methylation', 'Var', (179, 190))	('transcriptional', 'MPA', (274, 289))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('histone', 'MPA', (215, 222))	('chromatin', 'cellular_component', 'GO:0000785', ('240', '249'))	('methylation', 'biological_process', 'GO:0032259', ('179', '190'))
30111	20815920	Thus, epigenetic silencing of 'gatekeeper' or 'caretaker' TSGs can occur frequently at the earliest stages of cancer initiation, resulting in the clonal evolution of a population of cells at risk of obtaining further genetic or epigenetic lesions.	('cancer initiation', 'Disease', 'MESH:D009369', (110, 127))	('epigenetic silencing', 'Var', (6, 26))	('clonal evolution', 'CPA', (146, 162))	('TSG', 'Gene', '57045', (58, 61))	('cancer initiation', 'Disease', (110, 127))	('epigenetic lesions', 'Var', (228, 246))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('TSG', 'Gene', (58, 61))	('resulting in', 'Reg', (129, 141))	('gatekeeper', 'Species', '111938', (31, 41))
30114	20815920	Of the 58 genes that were identified as being methylated in RCC (Table 1, Figure 1; see Table 1 for full gene names), 43 had a mean combined methylation/mutation rate of over 20% and the characteristics of these genes were analyzed in further detail (although 31 genes had been reported only by a single study).	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('methylation/mutation', 'MPA', (141, 161))	('methylation', 'biological_process', 'GO:0032259', ('141', '152'))	('methylated', 'Var', (46, 56))
30115	20815920	Deletions of 3p are frequent in many adult cancers and occur in 45 to 90% of sporadic RCCs.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('occur', 'Reg', (55, 60))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('Deletions', 'Var', (0, 9))
30116	20815920	Inactivation of the 3p25 TSG VHL is of critical importance to the pathogenesis of ccRCC and occurs in up to 86% of tumors.	('occurs', 'Reg', (92, 98))	('TSG', 'Gene', '57045', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('VHL', 'Gene', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('VHL', 'Gene', '7428', (29, 32))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('tumors', 'Disease', (115, 121))	('RCC', 'Disease', (84, 87))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('TSG', 'Gene', (25, 28))	('pathogenesis', 'biological_process', 'GO:0009405', ('66', '78'))	('Inactivation', 'Var', (0, 12))	('3p25', 'Protein', (20, 24))
30117	20815920	Although VHL mutations are rare in non-clear-cell RCC, VHL methylation has been reported in pRCC and ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('pRCC', 'Gene', (92, 96))	('RCC', 'Disease', (93, 96))	('VHL', 'Gene', '7428', (9, 12))	('VHL', 'Gene', '7428', (55, 58))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('pRCC', 'Gene', '5546', (92, 96))	('methylation', 'Var', (59, 70))	('reported', 'Reg', (80, 88))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('VHL', 'Gene', (9, 12))	('methylation', 'biological_process', 'GO:0032259', ('59', '70'))	('VHL', 'Gene', (55, 58))
30118	20815920	VHL methylation does not associate with tumor stage, consistent with the interpretation that it is an early event in tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('methylation', 'Var', (4, 15))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))	('formation', 'biological_process', 'GO:0009058', ('123', '132'))
30119	20815920	In addition to VHL, several other 3p candidate TSGs have been reported to be methylated in RCC (Figure 1).	('TSG', 'Gene', '57045', (47, 50))	('VHL', 'Gene', (15, 18))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('VHL', 'Gene', '7428', (15, 18))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('TSG', 'Gene', (47, 50))	('methylated', 'Var', (77, 87))
30121	20815920	Somatic RASSF1A mutations are infrequent in cancer, but RASSF1 is frequently methylated in sporadic RCC (and various other common cancers), either biallelically or as a second hit following 3p deletion.	('RASSF1', 'Gene', (8, 14))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('RASSF1', 'Gene', (56, 62))	('RASSF1A', 'Gene', '11186', (8, 15))	('methylated', 'Var', (77, 87))	('RASSF1A', 'Gene', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', (130, 136))	('RASSF1', 'Gene', '11186', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('RASSF1', 'Gene', '11186', (8, 14))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
30123	20815920	In a study by Costa et al., frequent RASSF1A methylation was detected in kidney tissue surrounding the excised tumor.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('RASSF1A', 'Gene', '11186', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('methylation', 'Var', (45, 56))	('detected', 'Reg', (61, 69))	('RASSF1A', 'Gene', (37, 44))
30124	20815920	Aberrant methylation in morphologically normal renal tissue adjacent to the tumor (but not in more distant normal tissue) has been interpreted as evidence that the TSG methylation is part of a 'field effect' at an early stage of tumorigenesis that produces a large number of cells with an initial epigenetic lesion that is then followed by additional genetic and/or epigenetic events that lead to tumor development.	('methylation', 'Var', (9, 20))	('methylation', 'biological_process', 'GO:0032259', ('168', '179'))	('TSG', 'Gene', '57045', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('methylation', 'Var', (168, 179))	('tumor', 'Disease', (229, 234))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Disease', (397, 402))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('TSG', 'Gene', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
30126	20815920	In one study of 61 tumors, TU3A was methylated in 42% of ccRCC and 25% of pRCC.	('tumors', 'Disease', (19, 25))	('methylated', 'Var', (36, 46))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('TU3A', 'Gene', (27, 31))	('RCC', 'Disease', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('pRCC', 'Gene', '5546', (74, 78))	('TU3A', 'Gene', '11170', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('pRCC', 'Gene', (74, 78))
30130	20815920	In vivo, re-expression of FHIT has tumor suppressing activity.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('re-expression', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('FHIT', 'Gene', (26, 30))	('tumor', 'Disease', (35, 40))	('FHIT', 'Gene', '2272', (26, 30))
30136	20815920	The SFRP1, SFRP2, SFRP4, SFRP5 and related WIF1 genes are all frequently methylated in RCC (47 to 73%), as are the Dickkopf genes DKK1, DKK2 and DKK3 (44 to 58%).	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('methylated', 'Var', (73, 83))	('SFRP5', 'Gene', '6425', (25, 30))	('SFRP2', 'Gene', '6423', (11, 16))	('SFRP5', 'Gene', (25, 30))	('WIF1', 'Gene', '11197', (43, 47))	('Dickkopf', 'Gene', '22943', (115, 123))	('SFRP4', 'Gene', '6424', (18, 23))	('DKK1', 'Gene', '22943', (130, 134))	('DKK1', 'Gene', (130, 134))	('SFRP1', 'Gene', (4, 9))	('Dickkopf', 'Gene', (115, 123))	('SFRP2', 'Gene', (11, 16))	('DKK3', 'Gene', (145, 149))	('WIF1', 'Gene', (43, 47))	('SFRP4', 'Gene', (18, 23))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))	('DKK2', 'Gene', (136, 140))	('RCC', 'Disease', (87, 90))	('DKK2', 'Gene', '27123', (136, 140))	('DKK3', 'Gene', '27122', (145, 149))	('SFRP1', 'Gene', '6422', (4, 9))
30138	20815920	As described above, germline VHL mutations cause inherited RCC and VHL inactivation is also critical to the development of most ccRCC.	('cause', 'Reg', (43, 48))	('VHL', 'Gene', '7428', (67, 70))	('VHL', 'Gene', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))	('mutations', 'Var', (33, 42))	('VHL', 'Gene', '7428', (29, 32))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('VHL', 'Gene', (67, 70))
30141	20815920	Nevertheless, SPINT2 (HAI2), which encodes a secreted inhibitor of MET activity (activating mutations in the MET proto-oncogene are associated with familial pRCC, although somatic mutations are infrequent in sporadic pRCC), was found to be methylated in 30% of ccRCC and 45% of pRCC.	('SPINT2', 'Gene', (14, 20))	('pRCC', 'Gene', '5546', (217, 221))	('methylated', 'Var', (240, 250))	('SPINT2', 'Gene', '10653', (14, 20))	('pRCC', 'Gene', '5546', (278, 282))	('pRCC', 'Gene', (217, 221))	('RCC', 'Disease', (218, 221))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('pRCC', 'Gene', '5546', (157, 161))	('RCC', 'Disease', (279, 282))	('RCC', 'Phenotype', 'HP:0005584', (279, 282))	('HAI2', 'Gene', '10653', (22, 26))	('RCC', 'Disease', (263, 266))	('RCC', 'Phenotype', 'HP:0005584', (263, 266))	('mutations', 'Var', (92, 101))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('HAI2', 'Gene', (22, 26))	('RCC', 'Disease', (158, 161))	('pRCC', 'Gene', (278, 282))	('associated', 'Reg', (132, 142))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('RCC', 'Disease', 'MESH:C538614', (279, 282))	('pRCC', 'Gene', (157, 161))	('RCC', 'Disease', 'MESH:C538614', (263, 266))	('RCC', 'Disease', 'MESH:C538614', (158, 161))
30142	20815920	This observation demonstrates how TSG methylation can target familial RCC gene pathways.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('TSG', 'Gene', '57045', (34, 37))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('methylation', 'Var', (38, 49))	('target', 'Reg', (54, 60))	('TSG', 'Gene', (34, 37))	('methylation', 'biological_process', 'GO:0032259', ('38', '49'))
30143	20815920	We note that several other epigenetically inactivated candidate TSGs, including members of the Wnt regulatory pathway, p16INK4a , CASP8 , GREM1 , RPRM , collagens, IGFBP1 , IGFBP3  and PTGS2 , can be related to VHL-regulated pathways.	('CASP8', 'Gene', (130, 135))	('RPRM', 'Gene', '56475', (146, 150))	('PTGS2', 'Gene', (185, 190))	('IGFBP1', 'Gene', (164, 170))	('p16INK4a', 'Gene', '1029', (119, 127))	('IGFBP1', 'Gene', '3484', (164, 170))	('RPRM', 'Gene', (146, 150))	('VHL', 'Gene', (211, 214))	('IGFBP3', 'Gene', (173, 179))	('Wnt', 'Pathway', (95, 98))	('TSG', 'Gene', '57045', (64, 67))	('PTGS', 'biological_process', 'GO:0016441', ('185', '189'))	('PTGS2', 'Gene', '5743', (185, 190))	('VHL', 'Gene', '7428', (211, 214))	('TSG', 'Gene', (64, 67))	('IGFBP3', 'Gene', '3486', (173, 179))	('related', 'Reg', (200, 207))	('CASP8', 'Gene', '841', (130, 135))	('p16INK4a', 'Gene', (119, 127))	('GREM1', 'Gene', '26585', (138, 143))	('epigenetically', 'Var', (27, 41))	('GREM1', 'Gene', (138, 143))
30144	20815920	However, genes involved in many other cellular processes have also been found to be epigenetically silenced in RCC (Table 1).	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('epigenetically silenced', 'Var', (84, 107))	('RCC', 'Disease', 'MESH:C538614', (111, 114))
30149	20815920	The functional epigenomics strategy uses 5-aza-2'-deoxycytidine treatment of cancer cell lines to identify genes whose expression is reactivated following demethylation.	('demethylation', 'Var', (155, 168))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (41, 63))	('expression', 'MPA', (119, 129))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('demethylation', 'biological_process', 'GO:0070988', ('155', '168'))
30150	20815920	Although this strategy can provide an unbiased approach to identifying candidate epigenetically inactivated TSGs, only a minority of the re-expressed genes are ultimately proven to be silenced in primary tumors.	('epigenetically inactivated', 'Var', (81, 107))	('TSG', 'Gene', (108, 111))	('primary tumors', 'Disease', (196, 210))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('TSG', 'Gene', '57045', (108, 111))	('primary tumors', 'Disease', 'MESH:D009369', (196, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
30153	20815920	For less well studied genes the evidence for pathogenicity is strengthened by reports of frequent tumor-specific methylation (or mutations) in other tumor types; this is the case for BNC1 , PDLIM4 , CST6 SLIT2 , IGFBP3  and SPINT2 .	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('PDLIM4', 'Gene', (190, 196))	('PDLIM4', 'Gene', '8572', (190, 196))	('tumor', 'Disease', (98, 103))	('CST6', 'Gene', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('BNC1', 'Gene', '646', (183, 187))	('SLIT2', 'Gene', (204, 209))	('SPINT2', 'Gene', (224, 230))	('CST6', 'Gene', '1474', (199, 203))	('IGFBP3', 'Gene', (212, 218))	('BNC1', 'Gene', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('SLIT2', 'Gene', '9353', (204, 209))	('SPINT2', 'Gene', '10653', (224, 230))	('methylation', 'biological_process', 'GO:0032259', ('113', '124'))	('mutations', 'Var', (129, 138))	('IGFBP3', 'Gene', '3486', (212, 218))	('tumor', 'Disease', (149, 154))
30155	20815920	Recent studies in colorectal cancer have indicated that methylation extends well beyond discrete islands.	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colorectal cancer', 'Disease', (18, 35))	('methylation', 'biological_process', 'GO:0032259', ('56', '67'))	('methylation', 'Var', (56, 67))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
30156	20815920	Further investigation of global genomic methylation patterns is necessary to elucidate the full role of epigenetic gene silencing (and oncogene activation) in RCC development.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('epigenetic gene silencing', 'Var', (104, 129))	('gene silencing', 'biological_process', 'GO:0016458', ('115', '129'))	('methylation', 'biological_process', 'GO:0032259', ('40', '51'))	('RCC', 'Disease', (159, 162))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
30159	20815920	The role of abnormal histone modification as an epigenetic factor in RCC development also remains to be investigated in depth.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('histone modification', 'biological_process', 'GO:0016570', ('21', '41'))	('histone', 'Protein', (21, 28))	('abnormal', 'Var', (12, 20))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
30160	20815920	However, recent large-scale sequencing screens of RCC revealed mutations in the histone-modifying genes ubiquitously transcribed tetratricopeptide repeat gene on x chromosome (UTX), set domain-containing protein 2 (SETD2) and lysine-specific demethylase 5C (KDM5C, JARID1C), and that loss of these genes correlated with transcriptional deregulation.	('JARID1C', 'Gene', (265, 272))	('transcriptional deregulation', 'MPA', (320, 348))	('protein', 'cellular_component', 'GO:0003675', ('204', '211'))	('mutations', 'Var', (63, 72))	('lysine-specific demethylase 5C', 'Gene', '8242', (226, 256))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('set domain-containing protein 2', 'Gene', '29072', (182, 213))	('RCC', 'Disease', (50, 53))	('KDM5C', 'Gene', (258, 263))	('x chromosome', 'cellular_component', 'GO:0000805', ('162', '174'))	('SETD2', 'Gene', (215, 220))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('JARID1C', 'Gene', '8242', (265, 272))	('set domain-containing protein 2', 'Gene', (182, 213))	('SETD2', 'Gene', '29072', (215, 220))	('UTX', 'Gene', (176, 179))	('lysine-specific demethylase 5C', 'Gene', (226, 256))	('UTX', 'Gene', '7403', (176, 179))	('loss', 'NegReg', (284, 288))	('KDM5C', 'Gene', '8242', (258, 263))
30161	20815920	The interplay between erroneous histone modification and aberrant DNA methylation in the evolution of RCC merits further investigation.	('DNA methylation', 'biological_process', 'GO:0006306', ('66', '81'))	('DNA', 'cellular_component', 'GO:0005574', ('66', '69'))	('histone modification', 'biological_process', 'GO:0016570', ('32', '52'))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('aberrant DNA methylation', 'Var', (57, 81))	('erroneous histone modification', 'Var', (22, 52))
30162	20815920	Methylated TSGs provide attractive options for biomarkers for the detection and prognosis prediction of cancers, including RCC.	('TSG', 'Gene', '57045', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('RCC', 'Disease', (123, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('Methylated', 'Var', (0, 10))	('TSG', 'Gene', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
30172	20815920	Using a panel of previously identified RCC-specific methylated genes, two of these studies have found a strong correlation between tumor methylation and methylated DNA obtained from patient urine.	('methylation', 'biological_process', 'GO:0032259', ('137', '148'))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patient', 'Species', '9606', (182, 189))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumor', 'Disease', (131, 136))	('RCC', 'Phenotype', 'HP:0005584', (39, 42))	('DNA', 'cellular_component', 'GO:0005574', ('164', '167'))	('methylated', 'Var', (153, 163))
30178	20815920	Methylation of COL14A1 and BNC1 was significantly associated with a poorer prognosis and this was a better prognostic indicator than tumor stage or grade.	('COL14A1', 'Gene', '7373', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Methylation', 'Var', (0, 11))	('BNC1', 'Gene', (27, 31))	('BNC1', 'Gene', '646', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Methylation', 'biological_process', 'GO:0032259', ('0', '11'))	('poorer', 'CPA', (68, 74))	('COL14A1', 'Gene', (15, 22))	('tumor', 'Disease', (133, 138))	('associated', 'Reg', (50, 60))
30179	20815920	JUP methylation was detected in a very high proportion of tumors tested (91%) and was reported to be an independent indicator of disease progression and patient survival.	('detected', 'Reg', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('JUP', 'Gene', (0, 3))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('methylation', 'Var', (4, 15))	('JUP', 'Gene', '3728', (0, 3))	('patient', 'Species', '9606', (153, 160))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
30180	20815920	Similarly, a significant correlation between methylation of the bone morphogenetic protein antagonist GREM1 and tumor grade and stage and poor prognosis was reported, and methylation of TU3A was significantly associated with advanced tumor stage (later than stage T2) and poor survival.	('associated with', 'Reg', (209, 224))	('TU3A', 'Gene', '11170', (186, 190))	('methylation', 'MPA', (45, 56))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('TU3A', 'Gene', (186, 190))	('methylation', 'biological_process', 'GO:0032259', ('45', '56'))	('protein', 'cellular_component', 'GO:0003675', ('83', '90'))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('GREM1', 'Gene', '26585', (102, 107))	('GREM1', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('bone morphogenetic protein', 'Gene', '649', (64, 90))	('methylation', 'Var', (171, 182))	('bone morphogenetic protein', 'Gene', (64, 90))	('poor survival', 'CPA', (272, 285))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('methylation', 'biological_process', 'GO:0032259', ('171', '182'))
30181	20815920	The methylation status of several TSGs has been correlated with tumor pathological characteristics but not prognosis.	('tumor', 'Disease', (64, 69))	('TSG', 'Gene', '57045', (34, 37))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('correlated', 'Reg', (48, 58))	('TSG', 'Gene', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('methylation', 'biological_process', 'GO:0032259', ('4', '15'))
30182	20815920	HOXB13 methylation, for example, was correlated with tumor grade, stage, size and microvessel invasion, whereas DKK1 methylation correlated with increased pathological grade and DKK2 methylation correlated with both increased stage and grade.	('methylation', 'biological_process', 'GO:0032259', ('183', '194'))	('DKK1', 'Gene', '22943', (112, 116))	('DKK1', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('correlated', 'Reg', (37, 47))	('increased', 'PosReg', (145, 154))	('DKK2', 'Gene', (178, 182))	('methylation', 'Var', (7, 18))	('DKK2', 'Gene', '27123', (178, 182))	('HOXB13', 'Gene', '10481', (0, 6))	('methylation', 'Var', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('microvessel invasion', 'CPA', (82, 102))	('HOXB13', 'Gene', (0, 6))	('methylation', 'biological_process', 'GO:0032259', ('117', '128'))	('methylation', 'biological_process', 'GO:0032259', ('7', '18'))
30183	20815920	However, most of these studies require replication and, although RASSF1 methylation was reported to correlate with stage and grade, the largest study so far found no correlation with grade.	('methylation', 'biological_process', 'GO:0032259', ('72', '83'))	('methylation', 'Var', (72, 83))	('RASSF1', 'Gene', '11186', (65, 71))	('correlate', 'Reg', (100, 109))	('RASSF1', 'Gene', (65, 71))
30185	20815920	As the number of potential methylated TSG biomarkers increases, it will be of great importance to assay these in a standardized manner in prospective studies to establish their clinical utility.	('TSG', 'Gene', (38, 41))	('TSG', 'Gene', '57045', (38, 41))	('methylated', 'Var', (27, 37))
30186	20815920	The identification of frequently methylated RCC TSGs highlights critical pathways that could potentially be targeted for novel therapeutic interventions in RCC and other cancer types.	('TSG', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('RCC', 'Phenotype', 'HP:0005584', (156, 159))	('cancer', 'Disease', (170, 176))	('frequently methylated', 'Var', (22, 43))	('RCC', 'Disease', 'MESH:C538614', (156, 159))	('RCC', 'Disease', (156, 159))	('TSG', 'Gene', '57045', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
30188	20815920	However, epigenetic therapy to alter cancer methylation or histone modification status is an area of increasing clinical trial activity.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('epigenetic therapy', 'Var', (9, 27))	('cancer', 'Disease', (37, 43))	('histone modification', 'MPA', (59, 79))	('histone modification', 'biological_process', 'GO:0016570', ('59', '79'))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('methylation', 'biological_process', 'GO:0032259', ('44', '55'))
30192	20815920	One advantage of these approaches over the older 'candidate gene epigenetic status approach' is that the simultaneous analysis of many genes allows a better comparison of TSG methylation frequencies for specific genes and is likely to facilitate comparison between different studies.	('TSG', 'Gene', '57045', (171, 174))	('methylation', 'Var', (175, 186))	('TSG', 'Gene', (171, 174))	('methylation', 'biological_process', 'GO:0032259', ('175', '186'))
30193	20815920	With increasing numbers of methylated TSGs in RCC identified, our knowledge of the molecular pathogenesis of RCC will increase and with it the potential for developing novel biomarkers and potential therapeutic interventions.	('pathogenesis', 'biological_process', 'GO:0009405', ('93', '105'))	('RCC', 'Disease', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('TSG', 'Gene', '57045', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('methylated', 'Var', (27, 37))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('TSG', 'Gene', (38, 41))
30197	31575031	We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carcinoma (PRCC).	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (99, 129))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (99, 129))	('patient', 'Species', '9606', (61, 68))	('papillary renal cell carcinoma', 'Disease', (99, 129))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (109, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('c-met-mutated', 'Var', (85, 98))
30201	31575031	This analysis, applied to primary cancers with and without c-met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated embryoid bodies transcriptome.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PRCC tumors', 'Disease', 'MESH:D009369', (148, 159))	('cancers', 'Disease', (34, 41))	('KDM4C', 'Gene', (116, 121))	('KDM4C', 'Gene', '23081', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BHLHE40', 'Gene', (104, 111))	('overexpression', 'PosReg', (82, 96))	('PRCC tumors', 'Disease', (148, 159))	('BHLHE40', 'Gene', '8553', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('c-met-mutated', 'Var', (134, 147))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
30203	31575031	Hereditary cancers are due to oncogenic mutations or deletions and represent a major challenge in terms of diagnosis, prognosis, and prevention.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('deletions', 'Var', (53, 62))	('Hereditary cancers', 'Disease', (0, 18))	('Hereditary cancers', 'Disease', 'MESH:D009386', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))
30205	31575031	It has been shown that this strategy can be used for modeling BRCA1-mutated breast cancer and Li-Fraumeni syndrome with TP53 deletions.	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (94, 114))	('BRCA1', 'Gene', '672', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Li-Fraumeni syndrome', 'Disease', (94, 114))	('BRCA1', 'Gene', (62, 67))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('deletions', 'Var', (125, 134))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
30206	31575031	The major problem regarding the modeling of cancer using iPSC is that the effects of oncogenic mutations may appear only in the tissue in which the cancer develops.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
30213	31575031	The propositus patient is a patient in whom the diagnosis of the c-met mutation was performed during a genetic study realized in her family, because of the occurrence of PRCC in her mother.	('patient', 'Species', '9606', (15, 22))	('PRCC', 'Disease', (170, 174))	('mutation', 'Var', (71, 79))	('patient', 'Species', '9606', (28, 35))	('c-met', 'Gene', (65, 70))
30214	31575031	This analysis showed the presence of a mutation in the c-met oncogene atc.3900 G > A, p.Val1238Ile.	('atc.3900 G > A', 'Var', (70, 84))	('c.3900 G > A', 'Mutation', 'c.3900G>A', (72, 84))	('c-met', 'Gene', (55, 60))	('p.Val1238Ile', 'Var', (86, 98))	('p.Val1238Ile', 'Mutation', 'p.V1238I', (86, 98))
30218	31575031	The mother of the patient (UPN5) had developed two recurrent, c-met-mutated PRCC (Tumor Sample UPN5) and presented as expected, the same mutation as the patient (c.3900 G > A, p.Val1238Ile).	('c.3900 G > A', 'Mutation', 'c.3900G>A', (162, 174))	('c.3900 G > A', 'Var', (162, 174))	('patient', 'Species', '9606', (18, 25))	('patient', 'Species', '9606', (153, 160))	('Tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p.Val1238Ile', 'Mutation', 'p.V1238I', (176, 188))	('PRCC', 'Disease', (76, 80))
30219	31575031	A second patient with c-met-mutated PRCC (Tumor Sample UPN4) presented the c-met mutation (c.A3523G, p.His1112Arg) as published previously.	('p.His1112Arg', 'Var', (101, 113))	('PRCC', 'Disease', (36, 40))	('Tumor', 'Phenotype', 'HP:0002664', (42, 47))	('c.A3523G', 'Var', (91, 99))	('c.A3523G', 'Mutation', 'c.3523A>G', (91, 99))	('p.His1112Arg', 'Mutation', 'p.H1112R', (101, 113))	('patient', 'Species', '9606', (9, 16))
30224	31575031	Flow cytometric analysis demonstrated that the majority of met-IPSC as well as control iPSC co-expressed SSEA4 and TRA-1-60 (91.3% and 89.8% respectively) markers (Figure S1B,C) as expected for human pluripotent stem cells.	('met-IPSC', 'Var', (59, 67))	('TRA-1', 'Gene', (115, 120))	('SSEA4', 'Gene', (105, 110))	('human', 'Species', '9606', (194, 199))	('TRA-1', 'Gene', '57088', (115, 120))
30226	31575031	First, met-IPSC-A were characterized using immunocytochemistry for expression of phospho-Met and Brachyury.	('Brachyury', 'Gene', (97, 106))	('phospho-Met', 'Var', (81, 92))	('phospho-Met', 'Chemical', 'MESH:C034758', (81, 92))
30228	31575031	Of note, the level of phospho-Met expression was higher in both control and met-IPSC-A culture as compared to the monolayer counterparts (Figure S2B).	('higher', 'PosReg', (49, 55))	('met-IPSC-A', 'Var', (76, 86))	('phospho-Met expression', 'MPA', (22, 44))	('phospho-Met', 'Chemical', 'MESH:C034758', (22, 33))
30231	31575031	These data demonstrate that aggregate formation strongly favors the emergence of double-positive SIX2 and PODXL expressing kidney progenitors from both control and met-IPSC.	('SIX2', 'Gene', '10736', (97, 101))	('PODXL', 'Gene', (106, 111))	('formation', 'biological_process', 'GO:0009058', ('38', '47'))	('double-positive', 'Var', (81, 96))	('SIX2', 'Gene', (97, 101))	('PODXL', 'Gene', '5420', (106, 111))
30246	31575031	As compared with control iPSC-derived kidney embryoid bodies, phospho-Met signal was strongly detected in met-IPSC-derived kidney embryoid bodies (Figure 4B,C).	('phospho-Met', 'Chemical', 'MESH:C034758', (62, 73))	('met-IPSC-derived', 'Var', (106, 122))	('phospho-Met signal', 'MPA', (62, 80))
30256	31575031	Meta-analysis between met-IPSC signature and PRCC signature revealed a significant enrichment of met-IPSC profile as predictive of c-met-mutated PRCC tumor status (Fold of enrichment: 5.68; p-value < 2.2 x 10-16, Figure 6B).	('c-met-mutated', 'Var', (131, 144))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('met-IPSC profile', 'MPA', (97, 113))
30258	31575031	Expression heat map performed on PRCC tumors samples with the 77 meta-analysis intersection genes (Figure 6D) revealed a distinct expression pattern of these genes in PRCC patients that carried c-met mutations as compared to others; also the proportion of up-regulated and down-regulated genes is even in this subgroup of patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('expression', 'MPA', (130, 140))	('PRCC tumors', 'Disease', 'MESH:D009369', (33, 44))	('mutations', 'Var', (200, 209))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (322, 330))	('c-met', 'Gene', (194, 199))	('PRCC', 'Disease', (167, 171))	('PRCC tumors', 'Disease', (33, 44))	('patients', 'Species', '9606', (172, 180))	('up-regulated', 'PosReg', (256, 268))	('down-regulated', 'NegReg', (273, 287))
30263	31575031	Fold-change concordance analysis between met-IPSC-A model and PRCC tumors revealed 11 up-regulated markers with c-met mutation status (Figure 6G).	('PRCC tumors', 'Disease', (62, 73))	('up-regulated', 'PosReg', (86, 98))	('markers', 'MPA', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('c-met mutation status', 'Var', (112, 133))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('PRCC tumors', 'Disease', 'MESH:D009369', (62, 73))
30270	31575031	For this purpose, we analyzed 5 primary PRCC, 2 from patients with c-met mutation (UPN4 and UPN5) and 3 from patients without c-met-mutation (UPN1, UPN2, and UPN3).	('mutation', 'Var', (73, 81))	('c-met', 'Gene', (67, 72))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (109, 117))
30273	31575031	To evaluate their level of expression, we performed immunohistochemistry in primary tumors derived from type 1 PRCC with and without and c-met mutation using specific antibodies.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('primary tumors', 'Disease', (76, 90))	('c-met mutation', 'Var', (137, 151))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('type 1 PRCC', 'Disease', (104, 115))	('primary tumors', 'Disease', 'MESH:D001932', (76, 90))
30274	31575031	As seen in Figure 7, KDM4C and BHLHE40 were markedly overexpressed in the c-met-mutated type 1 PRCC tumors (UPN4, UPN5, Figure 7D,E) as compared to type 1 PRCC tumors without c-met mutation (UPN1, UPN2, UPN3, Figure 7A-C).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('PRCC tumors', 'Disease', 'MESH:D009369', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PRCC tumors', 'Disease', (155, 166))	('PRCC tumors', 'Disease', 'MESH:D009369', (95, 106))	('overexpressed', 'PosReg', (53, 66))	('BHLHE40', 'Gene', '8553', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('BHLHE40', 'Gene', (31, 38))	('c-met-mutated', 'Var', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('KDM4C', 'Gene', '23081', (21, 26))	('KDM4C', 'Gene', (21, 26))	('PRCC tumors', 'Disease', (95, 106))
30280	31575031	Similarly, met-IPSC-derived kidney-like structures treated with cisplatin harbored KIM-1 up-regulation albeit to lesser degree than that observed in control iPSC-derived structures (Figure 8B-E).	('kidney-like structures', 'Phenotype', 'HP:0012210', (28, 50))	('regulation', 'biological_process', 'GO:0065007', ('92', '102'))	('KIM-1', 'Gene', '26762', (83, 88))	('cisplatin', 'Var', (64, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))	('up-regulation', 'PosReg', (89, 102))	('KIM-1', 'Gene', (83, 88))
30282	31575031	Germline mutations at the origin of family cancers represent a major challenge in oncology as there are no experimental models to study the future cancer development.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('oncology', 'Phenotype', 'HP:0002664', (82, 90))	('cancer', 'Disease', (43, 49))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (147, 153))
30283	31575031	c-met-mutated PRCC represents a major form of hereditary kidney cancer among kidney cancers which are the seventh most common malignancies in the United States.	('hereditary kidney cancer', 'Disease', (46, 70))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('kidney cancer', 'Phenotype', 'HP:0009726', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('malignancies', 'Disease', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('PRCC', 'Disease', (14, 18))	('kidney cancer', 'Phenotype', 'HP:0009726', (57, 70))	('c-met-mutated', 'Var', (0, 13))	('kidney cancers', 'Disease', 'MESH:D007680', (77, 91))	('hereditary kidney cancer', 'Disease', 'MESH:D009386', (46, 70))	('kidney cancers', 'Disease', (77, 91))	('kidney cancers', 'Phenotype', 'HP:0009726', (77, 91))
30290	31575031	As can be shown in Figure S2B-D, the comparison of monolayer cultures and aggregate cultures revealed the overexpression of phospho-Met in both met-IPSC and control iPSC.	('overexpression', 'PosReg', (106, 120))	('phospho-Met', 'Chemical', 'MESH:C034758', (124, 135))	('phospho-Met', 'Var', (124, 135))	('met-IPSC', 'Var', (144, 152))
30298	31575031	As can be seen in Figure 5, met-IPSC-derived cells induced larger tumors as compared to controls and expressed kidney cancer markers TFE3 (transcription factor for immunoglobulin heavy chain enhancer 3) and cytokeratin 7 demonstrating the generation in vivo cancer embryoid bodies from the met-IPSC.	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('immunoglobulin', 'molecular_function', 'GO:0003823', ('164', '178'))	('transcription factor', 'molecular_function', 'GO:0000981', ('139', '159'))	('kidney cancer', 'Disease', 'MESH:D007680', (111, 124))	('cytokeratin 7', 'Gene', '3855', (207, 220))	('cancer', 'Disease', (118, 124))	('cytokeratin 7', 'Gene', (207, 220))	('kidney cancer', 'Phenotype', 'HP:0009726', (111, 124))	('TFE3', 'Gene', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (258, 264))	('kidney cancer', 'Disease', (111, 124))	('transcription factor for immunoglobulin heavy chain enhancer 3', 'Gene', '7030', (139, 201))	('TFE3', 'Gene', '7030', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('transcription', 'biological_process', 'GO:0006351', ('139', '152'))	('tumors', 'Disease', (66, 72))	('met-IPSC-derived', 'Var', (28, 44))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
30299	31575031	Interestingly, 77 of these genes have also been found to be expressed specifically in c-met-mutated human kidney carcinoma (Figure 6B) which appeared to be different from the signature observed in PRCC without c-met mutation.	('kidney carcinoma', 'Disease', (106, 122))	('c-met-mutated', 'Var', (86, 99))	('human', 'Species', '9606', (100, 105))	('kidney carcinoma', 'Disease', 'MESH:D007680', (106, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('kidney carcinoma', 'Phenotype', 'HP:0005584', (106, 122))
30300	31575031	Most importantly, several of the 11 genes which have been identified as being overexpressed in our met-IPSC, have also been overexpressed in primary human c-met-mutated PRCC such as KDM4C and BHLHE40 (Figure 7).	('BHLHE40', 'Gene', '8553', (192, 199))	('BHLHE40', 'Gene', (192, 199))	('overexpressed', 'PosReg', (124, 137))	('c-met-mutated', 'Var', (155, 168))	('human', 'Species', '9606', (149, 154))	('KDM4C', 'Gene', (182, 187))	('KDM4C', 'Gene', '23081', (182, 187))
30302	31575031	Alteration of KDM4C gene has been shown to occur in renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (52, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('Alteration', 'Var', (0, 10))	('KDM4C', 'Gene', (14, 19))	('KDM4C', 'Gene', '23081', (14, 19))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (52, 72))	('renal cell carcinoma', 'Disease', (52, 72))	('occur', 'Reg', (43, 48))
30307	31575031	To this end, we have used primary kidney tumors from 2 patients with c-met-mutated PRCC and 3 PRCC patients without c-met mutation.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('kidney tumors', 'Disease', (34, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('kidney tumors', 'Disease', 'MESH:D007680', (34, 47))	('patients', 'Species', '9606', (99, 107))	('kidney tumors', 'Phenotype', 'HP:0009726', (34, 47))	('patients', 'Species', '9606', (55, 63))	('PRCC', 'Disease', (83, 87))	('c-met-mutated', 'Var', (69, 82))
30308	31575031	The factors KDM4C and BHLHE40 were found to be overexpressed only in the tumors with c-met mutation, validating the use of iPSC technology for the analysis of these hereditary cancers.	('BHLHE40', 'Gene', (22, 29))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('mutation', 'Var', (91, 99))	('BHLHE40', 'Gene', '8553', (22, 29))	('KDM4C', 'Gene', '23081', (12, 17))	('hereditary cancers', 'Disease', 'MESH:D009386', (165, 183))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('c-met', 'Gene', (85, 90))	('hereditary cancers', 'Disease', (165, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('overexpressed', 'PosReg', (47, 60))	('KDM4C', 'Gene', (12, 17))
30309	31575031	We confirmed that phospho-Met, KDM4C and BHLHE40 were overexpressed in the tumors of two patients with the c-met-mutated type 1 PRCC UPN4 and UPN5 (Figure 7D,E).	('UPN5', 'PosReg', (142, 146))	('c-met-mutated', 'Var', (107, 120))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('BHLHE40', 'Gene', (41, 48))	('BHLHE40', 'Gene', '8553', (41, 48))	('patients', 'Species', '9606', (89, 97))	('overexpressed', 'PosReg', (54, 67))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('KDM4C', 'Gene', (31, 36))	('phospho-Met', 'Chemical', 'MESH:C034758', (18, 29))	('tumors', 'Disease', (75, 81))	('KDM4C', 'Gene', '23081', (31, 36))
30316	31575031	In conclusion, we demonstrate in this work for the first time that c-met-mutated hereditary kidney cancer can be modeled in vitro using patient-derived iPSC.	('patient', 'Species', '9606', (136, 143))	('hereditary kidney cancer', 'Disease', (81, 105))	('c-met-mutated', 'Var', (67, 80))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hereditary kidney cancer', 'Disease', 'MESH:D009386', (81, 105))
30324	31575031	Finally, in the setting of healthy persons presenting a hereditary cancer-risk mutation, these results could pave the way for the future use of this technology to generate predictive strategies.	('hereditary cancer', 'Disease', 'MESH:D009386', (56, 73))	('hereditary cancer', 'Disease', (56, 73))	('persons', 'Species', '9606', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutation', 'Var', (79, 87))
30334	31575031	Primary antibodies were diluted in PBS 10% serum at the following concentrations: Brachyury (ab140661, 1:200, Abcam, Cambridge, UK), phospho-Met (3077S, 1:200, Ozyme, Saint-Cyr-l'Ecole, France), PODXL (ab178566, 1:200, Abcam, Cambridge, UK), SIX2 (11562-1-AP, 1:200, Euromedex, Souffelweyersheim, France), and then washed in PBS.	('SIX2', 'Gene', (242, 246))	('phospho-Met', 'Chemical', 'MESH:C034758', (133, 144))	('PODXL', 'Gene', (195, 200))	('SIX2', 'Gene', '10736', (242, 246))	('ab178566', 'Var', (202, 210))	('AP, 1', 'cellular_component', 'GO:0005907', ('256', '261'))	('PODXL', 'Gene', '5420', (195, 200))
30343	31575031	Primary antibodies were diluted in PBS 10% serum at the following concentrations: Nephrin (ab85379, 1:100, Abcam, Cambridge, UK), CD31 (ab24590, 1:50, Abcam, Cambridge, UK), PODXL (ab178566, 1:100, Abcam, Cambridge, UK), LTL (FL-132, 1:50, Clinisciences, Nanterre, France), VHL (SC-5575, 1:30, Bio-Techne, Minneapolis, USA), Phalloidin (A12381, 1:100, Invitrogen, Carlsbad, USA), cytokeratin 7 (ab9021, 1:100, Abcam, Cambridge, UK), TFE3 (ab179804, 1:100, Abcam, Cambridge, UK), Cubilin (ab191073, 1:50, Abcam, Cambridge, UK), phospho-Met (3077S, 1:100, Ozyme, Saint-Cyr-l'Ecole, France), KDM4C (LS-C114684-100, 1:50, LSBio, Seattle, USA), BHLHE40 (ab70723, 1:50, Abcam, Cambridge, UK) and then washed in PBS.	('Nephrin', 'Gene', (82, 89))	('VHL', 'Disease', (274, 277))	('TFE3', 'Gene', '7030', (433, 437))	('Cubilin', 'Gene', '8029', (479, 486))	('PODXL', 'Gene', (174, 179))	('CD31', 'Gene', (130, 134))	('phospho-Met', 'Chemical', 'MESH:C034758', (527, 538))	('LS-C114684-100', 'Var', (596, 610))	('Cubilin', 'Gene', (479, 486))	('VHL', 'Disease', 'MESH:D006623', (274, 277))	('BHLHE40', 'Gene', (640, 647))	('Phalloidin', 'Chemical', 'MESH:D010590', (325, 335))	('CD31', 'Gene', '5175', (130, 134))	('KDM4C', 'Gene', '23081', (589, 594))	('KDM4C', 'Gene', (589, 594))	('PODXL', 'Gene', '5420', (174, 179))	('cytokeratin 7', 'Gene', '3855', (380, 393))	('BHLHE40', 'Gene', '8553', (640, 647))	('C114684-100', 'Chemical', 'MESH:C031208', (599, 610))	('cytokeratin 7', 'Gene', (380, 393))	('TFE3', 'Gene', (433, 437))	('Nephrin', 'Gene', '4868', (82, 89))	('ab70723', 'Var', (649, 656))
30356	31575031	Primary antibodies were diluted in PBS 10% serum at the following concentrations: Nephrin (ab85379, 1:200, Abcam, Cambridge, UK), CD31 (ab24590, 1:200, Abcam, Cambridge, UK), TFE3 (ab179804, 1:200, Abcam, Cambridge, UK), cytokeratin 7 (ab9021, 1:200, Abcam, Cambridge, UK), then washed three times in PBS.	('Nephrin', 'Gene', (82, 89))	('ab179804', 'Var', (181, 189))	('ab24590', 'Var', (136, 143))	('cytokeratin 7', 'Gene', (221, 234))	('CD31', 'Gene', (130, 134))	('TFE3', 'Gene', (175, 179))	('ab9021', 'Var', (236, 242))	('CD31', 'Gene', '5175', (130, 134))	('cytokeratin 7', 'Gene', '3855', (221, 234))	('Nephrin', 'Gene', '4868', (82, 89))	('TFE3', 'Gene', '7030', (175, 179))
30358	31575031	This analyzed dataset comprised 291 samples of PRCC tumors quantified by RNA-seq at level V2 Z-scores:21 patients were found mutated for c-met in this cohort (Table S5).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutated', 'Var', (125, 132))	('RNA', 'cellular_component', 'GO:0005562', ('73', '76'))	('PRCC tumors', 'Disease', 'MESH:D009369', (47, 58))	('PRCC tumors', 'Disease', (47, 58))
30363	31575031	Two patients with c-met-mutated PRCC (Tumor Samples UPN4, UPN5) and primary PRCC tumors from three patients without c-met mutation (Tumor samples UPN1, UPN2 and UPN3) kidney tissue were embedded in paraffin.	('c-met-mutated', 'Var', (18, 31))	('PRCC', 'Disease', (32, 36))	('Tumor', 'Phenotype', 'HP:0002664', (38, 43))	('PRCC tumors', 'Disease', (76, 87))	('patients', 'Species', '9606', (99, 107))	('Tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('PRCC tumors', 'Disease', 'MESH:D009369', (76, 87))
30364	31575031	Primary antibodies were diluted in PBS 10% serum at the following concentrations: KDM4C (LS-C114684-100, 1:200, LSBio, Seattle, USA), BHLHE40 (ab70723, 1:200, Abcam, Cambridge, UK) and then washed three times in PBS.	('BHLHE40', 'Gene', (134, 141))	('LS-C114684-100', 'Var', (89, 103))	('KDM4C', 'Gene', '23081', (82, 87))	('KDM4C', 'Gene', (82, 87))	('ab70723', 'Var', (143, 150))	('C114684-100', 'Chemical', 'MESH:C031208', (92, 103))	('BHLHE40', 'Gene', '8553', (134, 141))
30372	23369289	Renal cancer pathologies occur sporadically or in heritable syndromes caused by germline mutations in tumor suppressor genes including VHL.	('VHL', 'Gene', (135, 138))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('caused', 'Reg', (70, 76))	('Renal cancer', 'Disease', 'MESH:D007680', (0, 12))	('tumor suppressor', 'biological_process', 'GO:0051726', ('102', '118'))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Renal cancer', 'Phenotype', 'HP:0009726', (0, 12))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('102', '118'))	('Renal cancer', 'Disease', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('germline mutations', 'Var', (80, 98))
30393	23369289	Tuberous sclerosis (TSC) is associated with germline mutations in the TSC1/Harmatin (MIM605284) and TSC2/Tuburin (MIM191092) genes.	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('TSC1', 'Gene', (70, 74))	('Tuberous sclerosis', 'Disease', (0, 18))	('TSC2', 'Gene', (100, 104))	('associated', 'Reg', (28, 38))	('TSC', 'Gene', '7248', (70, 73))	('TSC', 'Gene', (20, 23))	('germline mutations', 'Var', (44, 62))	('MIM191092', 'Var', (114, 123))	('TSC', 'Gene', (100, 103))	('TSC', 'Gene', '7248', (100, 103))	('TSC', 'Gene', '7248', (20, 23))	('TSC', 'Gene', (70, 73))	('MIM605284', 'Var', (85, 94))	('TSC1', 'Gene', '7248', (70, 74))	('TSC2', 'Gene', '7249', (100, 104))
30395	23369289	Birt-Hogg-Dube syndrome (BHD) is a monogenic disorder caused by mutations in FLCN/Folliculin (MIM607273).	('Folliculin', 'Gene', '201163', (82, 92))	('caused by', 'Reg', (54, 63))	('BHD', 'Disease', (25, 28))	('BHD', 'Disease', 'MESH:D058249', (25, 28))	('FLCN', 'Gene', '201163', (77, 81))	('disorder', 'Disease', 'MESH:D030342', (45, 53))	('disorder', 'Disease', (45, 53))	('mutations', 'Var', (64, 73))	('Birt-Hogg-Dube syndrome', 'Disease', (0, 23))	('MIM607273', 'Var', (94, 103))	('FLCN', 'Gene', (77, 81))	('Folliculin', 'Gene', (82, 92))
30447	23369289	VHL interacts with the essential cilia microtubule motor complex kinesin-2 and loss of cilia in mouse tissues is observed upon loss of Vhlh (the mouse ortholog of VHL) and either Pten or Gsk3beta.	('loss', 'NegReg', (79, 83))	('kinesin', 'molecular_function', 'GO:0003777', ('65', '72'))	('Vhlh', 'Gene', (135, 139))	('Gsk3beta', 'Gene', (187, 195))	('kinesin-2', 'Gene', (65, 74))	('Gsk3beta', 'Gene', '56637', (187, 195))	('mouse', 'Species', '10090', (96, 101))	('mouse', 'Species', '10090', (145, 150))	('Pten', 'Gene', (179, 183))	('cilia', 'CPA', (87, 92))	('Pten', 'Gene', '19211', (179, 183))	('Gsk', 'molecular_function', 'GO:0050321', ('187', '190'))	('microtubule', 'cellular_component', 'GO:0005874', ('39', '50'))	('kinesin-2', 'Gene', '16563', (65, 74))	('loss', 'Var', (127, 131))	('Vhlh', 'Gene', '22346', (135, 139))
30449	23369289	In contrast, loss of Tsc1 or Tsc2 enhances cilia length in mouse embryonic fibroblasts (MEFs), and intriguingly, clinically there is a relatively low frequency of renal cyst and RCC formation in TSC patients.	('Tsc2', 'Gene', (29, 33))	('MEFs', 'CellLine', 'CVCL:9115', (88, 92))	('mouse', 'Species', '10090', (59, 64))	('Tsc1', 'Gene', (21, 25))	('enhances', 'PosReg', (34, 42))	('TSC', 'Gene', (195, 198))	('TSC', 'Gene', '7248', (195, 198))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('Tsc1', 'Gene', '64930', (21, 25))	('RCC', 'Disease', (178, 181))	('patients', 'Species', '9606', (199, 207))	('renal cyst', 'Phenotype', 'HP:0000107', (163, 173))	('Tsc2', 'Gene', '22084', (29, 33))	('loss', 'Var', (13, 17))	('cilia length', 'CPA', (43, 55))	('formation', 'biological_process', 'GO:0009058', ('182', '191'))	('renal cyst', 'Disease', (163, 173))
30455	23369289	One possibility is that the loss of cilia promotes, or at least contributes to, an environment rendering these cells more susceptible to mitogenic cues that initiate proliferation.	('promotes', 'PosReg', (42, 50))	('loss', 'Var', (28, 32))	('iron', 'Chemical', 'MESH:D007501', (86, 90))	('cilia', 'Protein', (36, 41))
30462	23369289	Therapies aimed at restoring, stabilizing or molecularly circumventing cilia function might therefore be a suitable addition to current treatment strategies in an endeavor to prevent early events such as cyst formation and subsequent tumorigenic progression from this premalignant state.	('cyst', 'Disease', (204, 208))	('tumor', 'Disease', (234, 239))	('cilia', 'CPA', (71, 76))	('molecularly', 'Var', (45, 56))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('formation', 'biological_process', 'GO:0009058', ('209', '218'))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
30477	19493342	43 genes were methylated in >20% of primary RCC (range 20-45%) and most (37/43) of these had not been reported previously to be methylated in RCC.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('methylated', 'Var', (14, 24))
30479	19493342	Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC.	('methylation', 'Var', (74, 85))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('RCC', 'Disease', (14, 17))	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('RCC', 'Disease', (118, 121))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('VHL RCC', 'Disease', 'MESH:C538614', (135, 142))	('tumour', 'Disease', (54, 60))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('VHL RCC', 'Disease', (135, 142))	('RCC', 'Disease', (139, 142))	('papillary RCC', 'Disease', 'MESH:C538614', (108, 121))	('prevalent', 'Reg', (95, 104))	('papillary RCC', 'Disease', (108, 121))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('methylation', 'biological_process', 'GO:0032259', ('74', '85'))
30480	19493342	Many of the genes preferentially methylated in pRCC were linked to TGFbeta or ERK/Akt signalling.	('TGFbeta', 'Gene', (67, 74))	('Akt', 'Gene', '207', (82, 85))	('pRCC', 'Gene', (47, 51))	('preferentially', 'PosReg', (18, 32))	('ERK', 'Gene', '5594', (78, 81))	('ERK', 'molecular_function', 'GO:0004707', ('78', '81'))	('TGFbeta', 'Gene', '7040', (67, 74))	('ERK', 'Gene', (78, 81))	('linked', 'Reg', (57, 63))	('pRCC', 'Gene', '5546', (47, 51))	('signalling', 'biological_process', 'GO:0023052', ('86', '96'))	('Akt', 'Gene', (82, 85))	('methylated', 'Var', (33, 43))
30481	19493342	These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('methylation', 'biological_process', 'GO:0032259', ('176', '187'))	('CpG', 'Protein', (65, 68))	('RCC', 'Disease', (203, 206))	('VHL', 'Gene', (84, 87))	('RCC', 'Disease', (129, 132))	('methylation', 'Var', (69, 80))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('VHL', 'Gene', '7428', (84, 87))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('VHL', 'Gene', (96, 99))	('papillary RCC', 'Disease', 'MESH:C538614', (119, 132))	('tumour', 'Disease', (49, 55))	('papillary RCC', 'Disease', (119, 132))	('RCC', 'Disease', (111, 114))	('methylation', 'biological_process', 'GO:0032259', ('69', '80'))	('VHL', 'Gene', '7428', (96, 99))
30487	19493342	Epigenetic inactivation of TSGs by methylation of promoter region CpG dinucleotides has been frequently implicated in the pathogenesis of human cancers including RCC.	('CpG', 'Gene', (66, 69))	('implicated', 'Reg', (104, 114))	('RCC', 'Disease', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pathogenesis', 'biological_process', 'GO:0009405', ('122', '134'))	('TSG', 'Gene', '57045', (27, 30))	('TSG', 'Gene', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (162, 165))	('human', 'Species', '9606', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('methylation', 'Var', (35, 46))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('methylation', 'biological_process', 'GO:0032259', ('35', '46'))	('Epigenetic inactivation', 'Var', (0, 23))
30488	19493342	Thus epigenetic silencing of VHL may occur in up to 20% of sporadic cRCC.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('epigenetic silencing', 'Var', (5, 25))	('occur', 'Reg', (37, 42))
30489	19493342	Although VHL promoter methylation is not a feature of pRCC, methylation of some TSGs, e.g.	('VHL', 'Gene', (9, 12))	('methylation', 'Var', (60, 71))	('TSG', 'Gene', (80, 83))	('VHL', 'Gene', '7428', (9, 12))	('methylation', 'biological_process', 'GO:0032259', ('22', '33'))	('pRCC', 'Gene', '5546', (54, 58))	('methylation', 'biological_process', 'GO:0032259', ('60', '71'))	('TSG', 'Gene', '57045', (80, 83))	('pRCC', 'Gene', (54, 58))
30500	19493342	84 genes were methylated (Mt > 0.25 in all 6 NKT but unmethylated (MtI <= 0.25) in one or more primary tumours.	('primary tumours', 'Disease', (95, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('methylated', 'Var', (14, 24))	('primary tumours', 'Disease', 'MESH:D009369', (95, 110))
30501	19493342	To allow for normal variation, attention was focussed on 18 genes that were methylated in 100% of NKT but <72% (lower 95% CI) of primary renal tumours tested.	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('renal tumours', 'Disease', 'MESH:D007680', (137, 150))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('methylated', 'Var', (76, 86))	('renal tumours', 'Disease', (137, 150))	('NKT', 'Disease', (98, 101))
30508	19493342	260 genes were methylated in tumour but not in NKT, and Euclidean cluster analysis was performed on these genes (see later).	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('tumour', 'Disease', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('methylated', 'Var', (15, 25))
30512	19493342	43 of 260 candidate non-imprinted tumour suppressor genes were methylated in >= 20% (range 20-45%) of tumours (these were designated "frequently methylated" genes).	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumour', 'Disease', (34, 40))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumour', 'Disease', (102, 108))	('methylated', 'Var', (63, 73))	('tumours', 'Disease', (102, 109))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
30515	19493342	There was no consistent pattern in the frequency of methylation loss in the different subtypes of renal tumours (Figure 3).	('renal tumours', 'Disease', 'MESH:D007680', (98, 111))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('loss', 'NegReg', (64, 68))	('renal tumours', 'Disease', (98, 111))	('methylation', 'biological_process', 'GO:0032259', ('52', '63'))	('methylation', 'Var', (52, 63))
30517	19493342	Thus, papillary RCCs demonstrated a geometric mean of 62.5 tumour-specific methylated CpGs per tumour, sporadic cRCCs had a geometric mean of 25.5 and VHL-associated cRCCs 20.9 methylated CpGs per tumour (See Figure 1).	('tumour', 'Disease', 'MESH:D009369', (197, 203))	('tumour', 'Disease', (197, 203))	('VHL', 'Gene', '7428', (151, 154))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('RCC', 'Disease', (113, 116))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('RCC', 'Disease', (16, 19))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('RCC', 'Disease', (167, 170))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('methylated', 'Var', (75, 85))	('papillary RCC', 'Disease', 'MESH:C538614', (6, 19))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('papillary RCC', 'Disease', (6, 19))	('tumour', 'Disease', (95, 101))	('VHL', 'Gene', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))
30524	19493342	genes methylated in > 20% of at least one tumour type) were significantly (p < 0.025) more frequently methylated in wtVHL sporadic RCC than in VHL RCC (RASSF1, TWIST1 PITX2, CDH13, HS3ST2, TAL1, WT1, MMP2, DCC, ICA1 and TUSC3:(all p < 0.025; log-likelihood G-test; see Additional file 2).	('VHL', 'Gene', (118, 121))	('RASSF1', 'Gene', (152, 158))	('WT1', 'Gene', (195, 198))	('RCC', 'Disease', (147, 150))	('TWIST1', 'Gene', (160, 166))	('HS3ST2', 'Gene', (181, 187))	('PITX2', 'Gene', (167, 172))	('VHL', 'Gene', '7428', (143, 146))	('CDH13', 'Gene', '1012', (174, 179))	('TAL1', 'Gene', (189, 193))	('WT1', 'Gene', '7490', (195, 198))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('TUSC3', 'Gene', (220, 225))	('VHL', 'Gene', '7428', (118, 121))	('RCC', 'Disease', (131, 134))	('HS3ST2', 'Gene', '9956', (181, 187))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('MMP2', 'Gene', (200, 204))	('tumour', 'Disease', (42, 48))	('TWIST1', 'Gene', '7291', (160, 166))	('RCC', 'Disease', 'MESH:C538614', (147, 150))	('DCC', 'cellular_component', 'GO:0120206', ('206', '209'))	('methylated', 'Var', (102, 112))	('RCC', 'Disease', 'MESH:C538614', (131, 134))	('DCC', 'Gene', (206, 209))	('CDH13', 'Gene', (174, 179))	('PITX2', 'Gene', '5308', (167, 172))	('more', 'PosReg', (86, 90))	('DCC', 'Gene', '1630', (206, 209))	('MMP2', 'Gene', '4313', (200, 204))	('ICA1', 'Gene', (211, 215))	('ICA1', 'Gene', '3382', (211, 215))	('MMP2', 'molecular_function', 'GO:0004228', ('200', '204'))	('VHL', 'Gene', (143, 146))	('TAL1', 'Gene', '6886', (189, 193))	('TUSC3', 'Gene', '7991', (220, 225))	('VHL RCC', 'Disease', 'MESH:C538614', (143, 150))	('VHL RCC', 'Disease', (143, 150))	('RASSF1', 'Gene', '11186', (152, 158))
30525	19493342	One frequently methylated gene was significantly more frequently methylated in VHL-associated cRCC than in wtVHL sporadic cRCC: GABRB3 (48% vs 20%; log-likelihood G-test, p < 0.05; a less stringent p-value was used due to the lower overall frequency of methylation in the VHL subgroup).	('VHL', 'Gene', '7428', (79, 82))	('VHL', 'Gene', (109, 112))	('GABRB3', 'Gene', (128, 134))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('methylated', 'Var', (65, 75))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (95, 98))	('VHL', 'Gene', '7428', (109, 112))	('methylation', 'biological_process', 'GO:0032259', ('253', '264'))	('VHL', 'Gene', (272, 275))	('more', 'PosReg', (49, 53))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('VHL', 'Gene', (79, 82))	('VHL', 'Gene', '7428', (272, 275))	('GABRB3', 'Gene', '2562', (128, 134))
30526	19493342	For genes more methylated in wtVHL than VHL-RCC, RASSF1, PITX2, CDH13, HS3ST2, TAL1, TUSC3 and DCC were at least as frequently methylated in tumours < 5 cm as those >= 5 cm.	('RASSF1', 'Gene', (49, 55))	('TAL1', 'Gene', (79, 83))	('VHL', 'Gene', '7428', (40, 43))	('more', 'PosReg', (10, 14))	('RCC', 'Disease', (44, 47))	('methylated', 'Var', (15, 25))	('PITX2', 'Gene', (57, 62))	('CDH13', 'Gene', '1012', (64, 69))	('TUSC3', 'Gene', (85, 90))	('VHL', 'Gene', '7428', (31, 34))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('tumours', 'Disease', (141, 148))	('CDH13', 'Gene', (64, 69))	('DCC', 'Gene', '1630', (95, 98))	('PITX2', 'Gene', '5308', (57, 62))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('TAL1', 'Gene', '6886', (79, 83))	('HS3ST2', 'Gene', (71, 77))	('DCC', 'Gene', (95, 98))	('VHL', 'Gene', (40, 43))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('DCC', 'cellular_component', 'GO:0120206', ('95', '98'))	('TUSC3', 'Gene', '7991', (85, 90))	('RASSF1', 'Gene', '11186', (49, 55))	('VHL', 'Gene', (31, 34))	('HS3ST2', 'Gene', '9956', (71, 77))
30528	19493342	8/14 genes that were significantly more methylated in pRCC than cRCC were represented in a network with links to TGFbeta and ERK/Akt pathways (see Figure 4).	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('RCC', 'Disease', (55, 58))	('ERK', 'Gene', '5594', (125, 128))	('methylated', 'Var', (40, 50))	('pRCC', 'Gene', (54, 58))	('Akt', 'Gene', '207', (129, 132))	('TGFbeta', 'Gene', (113, 120))	('ERK', 'molecular_function', 'GO:0004707', ('125', '128'))	('ERK', 'Gene', (125, 128))	('TGFbeta', 'Gene', '7040', (113, 120))	('pRCC', 'Gene', '5546', (54, 58))	('Akt', 'Gene', (129, 132))	('more', 'PosReg', (35, 39))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('links', 'Reg', (104, 109))	('RCC', 'Disease', (65, 68))
30529	19493342	The link to these pathways was more pronounced (9/12) for those 12 genes that were more frequently methylated in pRCC than in wtVHL-cRCC (see Figure 5 (see figure 6 for key to nodal shape in figures 4 and 5).	('pRCC', 'Gene', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (114, 117))	('methylated', 'Var', (99, 109))	('VHL', 'Gene', '7428', (128, 131))	('pRCC', 'Gene', '5546', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('VHL', 'Gene', (128, 131))
30535	19493342	Detection of methylated CpGs in urine has been investigated as a potential screening tool for RCC and other urinary tract neoplasms (reviewed in ref 11).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('methylated', 'Var', (13, 23))	('urinary tract neoplasms', 'Phenotype', 'HP:0010786', (108, 131))	('neoplasms', 'Phenotype', 'HP:0002664', (122, 131))	('urinary tract neoplasms', 'Disease', (108, 131))	('urinary tract neoplasms', 'Disease', 'MESH:D014571', (108, 131))	('CpGs', 'Protein', (24, 28))
30544	19493342	However, using an unbiased approach to defining putative CIMP-related markers, Weisenberger et al (a) provided evidence for CIMP+ colorectal cancer and (b) demonstrated that CIMP+ sporadic colorectal cancers were associated with the presence of a BRAF mutation and microsatellite instability (from MLH1 promoter methylation) (12).	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('colorectal cancer', 'Disease', (130, 147))	('mutation', 'Var', (252, 260))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('colorectal cancers', 'Disease', (189, 207))	('CIMP+', 'Chemical', '-', (124, 129))	('CIMP', 'Chemical', '-', (174, 178))	('CIMP', 'Chemical', '-', (124, 128))	('associated', 'Reg', (213, 223))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('methylation', 'biological_process', 'GO:0032259', ('312', '323'))	('MLH1', 'Gene', (298, 302))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('microsatellite instability', 'Var', (265, 291))	('MLH1', 'Gene', '4292', (298, 302))	('colorectal cancers', 'Disease', 'MESH:D015179', (189, 207))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CIMP+', 'Chemical', '-', (174, 179))	('BRAF', 'Gene', '673', (247, 251))	('CIMP', 'Chemical', '-', (57, 61))	('BRAF', 'Gene', (247, 251))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))
30546	19493342	However, we note that Dulaimi et al reported that a subset of RCC (~3%) were methylated for at least five out of the ten genes studied.	('RCC', 'Disease', (62, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('methylated', 'Var', (77, 87))
30550	19493342	Several genes were significantly (p < 0.025) more frequently methylated in papillary than in cRCC (and similarly methylated in both cRCC subtypes).	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('methylated', 'Var', (61, 71))	('RCC', 'Disease', (94, 97))	('more', 'PosReg', (45, 49))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('papillary', 'Disease', (75, 84))
30554	19493342	It is noteworthy that both HOXA11 and HOXC6 were preferentially methylated in papillary RCC.	('preferentially', 'PosReg', (49, 63))	('HOXA11', 'Gene', (27, 33))	('HOXC6', 'Gene', (38, 43))	('methylated', 'Var', (64, 74))	('papillary RCC', 'Disease', 'MESH:C538614', (78, 91))	('HOXA11', 'Gene', '3207', (27, 33))	('papillary RCC', 'Disease', (78, 91))	('HOXC6', 'Gene', '3223', (38, 43))
30556	19493342	Three genes, CDH1, PTGS2 and TWIST1 were specifically methylated in cRCC (both p < 0.025 compared to papillary RCC).	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('CDH1', 'Gene', '999', (13, 17))	('RCC', 'Disease', (69, 72))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('PTGS2', 'Gene', '5743', (19, 24))	('TWIST1', 'Gene', (29, 35))	('papillary RCC', 'Disease', 'MESH:C538614', (101, 114))	('TWIST1', 'Gene', '7291', (29, 35))	('PTGS', 'biological_process', 'GO:0016441', ('19', '23'))	('PTGS2', 'Gene', (19, 24))	('papillary RCC', 'Disease', (101, 114))	('CDH1', 'Gene', (13, 17))	('methylated', 'Var', (54, 64))
30557	19493342	Germline mutations in CDH1 and TWIST1 may be associated with inherited cancer susceptibility.	('Germline mutations', 'Var', (0, 18))	('CDH1', 'Gene', '999', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TWIST1', 'Gene', (31, 37))	('TWIST1', 'Gene', '7291', (31, 37))	('cancer', 'Disease', (71, 77))	('associated', 'Reg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CDH1', 'Gene', (22, 26))
30558	19493342	Thus, CDH1 mutations cause familial diffuse type gastric cancer and the TWIST1 transcription factor is mutated in Saethre-Chotzen syndrome, which is characterised by developmental defects (craniosynostosis and digital anomalies) and is also reported to be associated with an increased risk of breast cancer.	('mutations', 'Var', (11, 20))	('familial diffuse type gastric cancer', 'Disease', 'MESH:D013274', (27, 63))	('CDH1', 'Gene', '999', (6, 10))	('TWIST1', 'Gene', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (293, 306))	('CDH1', 'Gene', (6, 10))	('familial diffuse type gastric cancer', 'Disease', (27, 63))	('craniosynostosis', 'Phenotype', 'HP:0001363', (189, 205))	('TWIST1', 'Gene', '7291', (72, 78))	('Saethre-Chotzen syndrome', 'Disease', (114, 138))	('developmental defects', 'Disease', 'MESH:D003147', (166, 187))	('breast cancer', 'Disease', (293, 306))	('breast cancer', 'Disease', 'MESH:D001943', (293, 306))	('craniosynostosis and digital anomalies', 'Disease', 'MESH:C565666', (189, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('transcription factor', 'molecular_function', 'GO:0000981', ('79', '99'))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('developmental defects', 'Disease', (166, 187))	('cause', 'Reg', (21, 26))	('transcription', 'biological_process', 'GO:0006351', ('79', '92'))	('digital anomalies', 'Phenotype', 'HP:0011297', (210, 227))	('associated', 'Reg', (256, 266))
30565	19493342	To our knowledge, this is the first investigation of epigenetic alterations in VHL-null and VHL-wt RCC.	('VHL', 'Gene', '7428', (79, 82))	('VHL-wt RCC', 'Disease', 'MESH:C538614', (92, 102))	('epigenetic alterations', 'Var', (53, 75))	('VHL', 'Gene', (92, 95))	('VHL-wt RCC', 'Disease', (92, 102))	('VHL', 'Gene', '7428', (92, 95))	('VHL', 'Gene', (79, 82))
30566	19493342	We found that a number of loci, including RASSF1, PITX2, CDH13, HS3ST2, TWIST1, TAL1, TUSC3 and DCC were significantly more frequently methylated in VHL-wt sporadic RCC than in VHL RCC.	('HS3ST2', 'Gene', '9956', (64, 70))	('TUSC3', 'Gene', (86, 91))	('TWIST1', 'Gene', (72, 78))	('TAL1', 'Gene', (80, 84))	('methylated', 'Var', (135, 145))	('PITX2', 'Gene', (50, 55))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('VHL', 'Gene', '7428', (149, 152))	('CDH13', 'Gene', (57, 62))	('TWIST1', 'Gene', '7291', (72, 78))	('DCC', 'cellular_component', 'GO:0120206', ('96', '99'))	('DCC', 'Gene', '1630', (96, 99))	('VHL', 'Gene', (177, 180))	('VHL RCC', 'Disease', 'MESH:C538614', (177, 184))	('RASSF1', 'Gene', '11186', (42, 48))	('VHL RCC', 'Disease', (177, 184))	('PITX2', 'Gene', '5308', (50, 55))	('TUSC3', 'Gene', '7991', (86, 91))	('DCC', 'Gene', (96, 99))	('TAL1', 'Gene', '6886', (80, 84))	('RASSF1', 'Gene', (42, 48))	('VHL', 'Gene', '7428', (177, 180))	('more frequently', 'PosReg', (119, 134))	('HS3ST2', 'Gene', (64, 70))	('CDH13', 'Gene', '1012', (57, 62))	('VHL', 'Gene', (149, 152))	('RCC', 'Disease', (181, 184))	('RCC', 'Disease', (165, 168))
30569	19493342	However, although CDH1 expression is downregulated by VHL inactivation, and DAPK1 by RASSF1A inactivation, CDH1 and DAPK1 methylation frequencies were similar in wtVHL sporadic RCC and VHL RCC.	('RASSF1A', 'Gene', (85, 92))	('VHL', 'Gene', (54, 57))	('inactivation', 'Var', (93, 105))	('VHL', 'Gene', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('methylation', 'biological_process', 'GO:0032259', ('122', '133'))	('RCC', 'Disease', (177, 180))	('VHL', 'Gene', '7428', (54, 57))	('CDH1', 'Gene', '999', (107, 111))	('DAPK1', 'Gene', (116, 121))	('VHL', 'Gene', '7428', (164, 167))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('DAPK1', 'Gene', (76, 81))	('CDH1', 'Gene', (107, 111))	('inactivation', 'Var', (58, 70))	('CDH1', 'Gene', '999', (18, 22))	('VHL', 'Gene', (185, 188))	('VHL RCC', 'Disease', 'MESH:C538614', (185, 192))	('expression', 'MPA', (23, 33))	('downregulated', 'NegReg', (37, 50))	('VHL RCC', 'Disease', (185, 192))	('DAPK1', 'Gene', '1612', (116, 121))	('CDH1', 'Gene', (18, 22))	('RASSF1A', 'Gene', '11186', (85, 92))	('DAPK1', 'Gene', '1612', (76, 81))	('VHL', 'Gene', '7428', (185, 188))	('RCC', 'Disease', (189, 192))
30573	19493342	VHL-inactivation may be associated with activation of the epidermal growth factor receptor/phosphatidylinositol-3-OH kinase/protein kinase B (AKT)/IkappaB-kinase alpha/NF-kappaB signalling cascade, and so RCC without VHL inactivation may be predisposed to dysregulate these key signalling pathways by preferential methylation of other regulators.	('protein kinase B', 'Gene', '2185', (124, 140))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('AKT', 'Gene', (142, 145))	('VHL', 'Gene', '7428', (0, 3))	('IkappaB-kinase alpha', 'Gene', (147, 167))	('protein kinase B', 'Gene', (124, 140))	('IkappaB-kinase alpha', 'Gene', '1147', (147, 167))	('AKT', 'Gene', '207', (142, 145))	('protein', 'cellular_component', 'GO:0003675', ('124', '131'))	('signalling cascade', 'biological_process', 'GO:0007165', ('178', '196'))	('epidermal growth factor', 'molecular_function', 'GO:0005154', ('58', '81'))	('activation', 'PosReg', (40, 50))	('preferential', 'PosReg', (301, 313))	('VHL', 'Gene', (217, 220))	('methylation', 'Var', (314, 325))	('RCC', 'Disease', (205, 208))	('methylation', 'biological_process', 'GO:0032259', ('314', '325'))	('signalling', 'biological_process', 'GO:0023052', ('278', '288'))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (217, 220))
30574	19493342	Although it might be predicted that the pathways of tumourigenesis in VHL mutated sporadic clear cell RCC will be similar to those in RCC from VHL patients, further studies (using the methods utilised in this study) are indicated to investigate this point.	('VHL', 'Gene', (70, 73))	('VHL', 'Gene', '7428', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (147, 155))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('RCC', 'Disease', (102, 105))	('VHL', 'Gene', (143, 146))	('mutated', 'Var', (74, 81))	('RCC', 'Disease', (134, 137))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('tumour', 'Disease', (52, 58))	('VHL', 'Gene', '7428', (143, 146))
30576	19493342	TSGs may be targeted by epigenetic silencing and/or inactivating mutations during tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('TSG', 'Gene', '57045', (0, 3))	('epigenetic silencing', 'Var', (24, 44))	('inactivating mutations', 'Var', (52, 74))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('TSG', 'Gene', (0, 3))
30577	19493342	However, whereas the repertoire of inactivating mutations in a typical tumour suppressor gene is extensive, patterns of CpG island methylation causing epigenetic silencing are much more restricted and hence are easier to detect.	('tumour', 'Disease', (71, 77))	('inactivating mutations', 'Var', (35, 57))	('methylation', 'biological_process', 'GO:0032259', ('131', '142'))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('epigenetic silencing', 'MPA', (151, 171))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
30578	19493342	The relative frequency of CpG island methylation and inactivation mutations for individual TSGs is variable.	('methylation', 'biological_process', 'GO:0032259', ('37', '48'))	('methylation', 'Var', (37, 48))	('TSG', 'Gene', (91, 94))	('inactivation', 'MPA', (53, 65))	('TSG', 'Gene', '57045', (91, 94))
30581	19493342	Thus, with the exception of VHL, epigenetic biomarkers are likely to provide a better approach for novel prognostic and diagnostic strategies than genetic markers.	('VHL', 'Gene', (28, 31))	('epigenetic biomarkers', 'Var', (33, 54))	('VHL', 'Gene', '7428', (28, 31))
30583	19493342	Further characterisation of the genes and pathways that are epigenetically altered in RCC of different subtypes may thus lead to the development of novel minimally-invasive diagnostic and prognostic tools for kidney cancer, and, in the longer term, may enable more focused treatments for individual tumours.	('kidney cancer', 'Phenotype', 'HP:0009726', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('kidney cancer', 'Disease', (209, 222))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('epigenetically altered', 'Var', (60, 82))	('tumours', 'Phenotype', 'HP:0002664', (299, 306))	('tumours', 'Disease', 'MESH:D009369', (299, 306))	('kidney cancer', 'Disease', 'MESH:D007680', (209, 222))	('lead to', 'Reg', (121, 128))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('tumours', 'Disease', (299, 306))
30603	32106629	Recently, the expression of TfR1 was associated with progression and mortality in clear cell RCC (ccRCC), identifying TfR1 as a novel RCC biomarker and potential therapeutic target.	('expression', 'Var', (14, 24))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('RCC', 'Disease', (93, 96))	('TfR1', 'Gene', (28, 32))	('TfR1', 'Gene', '7037', (28, 32))	('mortality', 'Disease', 'MESH:D003643', (69, 78))	('RCC', 'Disease', 'MESH:C538614', (134, 137))	('associated', 'Reg', (37, 47))	('RCC', 'Disease', (134, 137))	('TfR1', 'Gene', '7037', (118, 122))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('mortality', 'Disease', (69, 78))	('TfR1', 'Gene', (118, 122))
30619	32106629	Accordingly, TAMs were shown to positively associate with tumor progression and worse patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TAMs', 'Var', (13, 17))	('associate', 'Reg', (43, 52))	('TAMs', 'Chemical', 'MESH:D013629', (13, 17))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
30628	32106629	We next analyzed the mRNA expression of iron-dependent genes in relation to tumor grade (G1-G2 vs. G3-G4) and tumor pT-stage (pT1 pT2 vs. pT3-pT4).	('G1-G2', 'Var', (89, 94))	('pT1', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('pT3', 'Gene', '7694', (138, 141))	('pT3', 'Gene', (138, 141))	('iron', 'Chemical', 'MESH:D007501', (40, 44))	('pT1', 'Gene', '58492', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
30662	32106629	In particular, the tridentate chelating unit of EC1 includes a thiosemicarbazone moiety that is common to many anti-proliferative iron chelators; however, the incorporation of a negatively charged sulfonate group significantly limits the ability of EC1 to cross cellular membranes.	('thiosemicarbazone', 'Chemical', 'MESH:D013882', (63, 80))	('limits', 'NegReg', (227, 233))	('iron', 'Chemical', 'MESH:D007501', (130, 134))	('EC1', 'Gene', (48, 51))	('EC1', 'Gene', '4819', (48, 51))	('incorporation', 'Var', (159, 172))	('EC1', 'Gene', (249, 252))	('EC1', 'Gene', '4819', (249, 252))	('sulfonate', 'Chemical', 'MESH:D000476', (197, 206))	('ability', 'MPA', (238, 245))
30700	32106629	Nonetheless, modulating the iron-retaining tumor phenotype reduced growth and progression of both human and mouse carcinomas.	('reduced', 'NegReg', (59, 66))	('modulating', 'Var', (13, 23))	('carcinomas', 'Disease', 'MESH:D009369', (114, 124))	('iron', 'Chemical', 'MESH:D007501', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('carcinomas', 'Disease', (114, 124))	('mouse', 'Species', '10090', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('human', 'Species', '9606', (98, 103))
30778	32106629	HRMS-ESI (m/z): [M - Na]- calcd for [C14H12-N3O4S2]-, 350.02747; found, 350.02741; [M + H]+ calcd for [C14H13-N3NaO4S2]+, 374.02397; found, 374.02401.	('H12-N3', 'Species', '546801', (40, 46))	('4H', 'Chemical', '-', (105, 107))	('[C14H13-N3NaO4S2]+', 'Var', (102, 120))	('[C14H12-N3O4S2]-', 'Var', (36, 52))	('H13-N3', 'Species', '222773', (106, 112))	('4H', 'Chemical', '-', (39, 41))
30797	25048860	The recent publication of the TCGA Network's clear cell kidney cancer paper provides further evidence for the importance of gene fusions by identifying 5 tumors harboring SFPQ-TFE3 fusions that otherwise lacked the common clear cell RCC associated mutation.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('kidney cancer', 'Phenotype', 'HP:0009726', (56, 69))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (45, 69))	('kidney cancer', 'Disease', 'MESH:D007680', (56, 69))	('kidney cancer', 'Disease', (56, 69))	('RCC', 'Disease', 'MESH:C538614', (233, 236))	('RCC', 'Phenotype', 'HP:0005584', (233, 236))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('SFPQ-TFE3', 'Gene', (171, 180))	('fusions', 'Var', (181, 188))	('RCC', 'Disease', (233, 236))	('SFPQ-TFE3', 'Gene', '6421;7030', (171, 180))
30799	25048860	A total of 5 TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, CLTC-TFE3) and 1 TFEB gene fusion (MALAT1-TFEB) have been identified in RCC tumors and characterized at the mRNA transcript level, with considerable heterogeneity in exon structure across different tumors, even for the same fusion partners.	('ASPSCR1', 'Gene', (43, 50))	('MALAT1', 'Gene', '378938', (114, 120))	('ASPS', 'Phenotype', 'HP:0012218', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('SFPQ-TFE3', 'Gene', (57, 66))	('SFPQ-TFE3', 'Gene', '6421;7030', (57, 66))	('tumors', 'Disease', (277, 283))	('identified', 'Reg', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('NONO', 'Gene', '4841', (68, 72))	('CLTC', 'Gene', '1213', (79, 83))	('RCC tumors', 'Disease', (151, 161))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TFE3', 'Gene', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (33, 36))	('RCC tumors', 'Disease', 'MESH:C538614', (151, 161))	('tumors', 'Disease', (155, 161))	('TFEB', 'Gene', (96, 100))	('CLTC', 'Gene', (79, 83))	('ASPSCR1', 'Gene', '79058', (43, 50))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('TFEB', 'Gene', (121, 125))	('PRCC-TFE3', 'Var', (32, 41))	('TFEB', 'Gene', '7942', (96, 100))	('MALAT1', 'Gene', (114, 120))	('NONO', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('TFEB', 'Gene', '7942', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
30803	25048860	Chromosomal rearrangement resulting in the fusion of two different genes is the most common type of mutation in human cancer.	('fusion', 'MPA', (43, 49))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (112, 117))	('Chromosomal rearrangement', 'Var', (0, 25))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
30804	25048860	The role of these mutations in sarcomas and hematologic malignancies has been well established for several decades but has only recently become more apparent in common carcinomas due to advances in genetic analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('carcinomas', 'Disease', (168, 178))	('sarcomas and hematologic malignancies', 'Disease', 'MESH:D019337', (31, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('sarcomas', 'Phenotype', 'HP:0100242', (31, 39))	('carcinomas', 'Disease', 'MESH:D002277', (168, 178))	('mutations', 'Var', (18, 27))
30809	25048860	These have revealed the importance of mutations within chromatin remodeling genes, including PBRM1, SETD2, KDM6A (UTX), KDM5C (JARID1C), ARID1A and BAP1, as well as confirming the continued importance of VHL mutation and chromosome 3p loss.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('55', '75'))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('JARID1C', 'Gene', '8242', (127, 134))	('SETD2', 'Gene', '29072', (100, 105))	('ARID1A', 'Gene', (137, 143))	('BAP1', 'Gene', '8314', (148, 152))	('KDM5C', 'Gene', '8242', (120, 125))	('PBRM1', 'Gene', '55193', (93, 98))	('KDM6A', 'Gene', '7403', (107, 112))	('mutations', 'Var', (38, 47))	('JARID1C', 'Gene', (127, 134))	('VHL', 'Disease', 'MESH:D006623', (204, 207))	('ARID1A', 'Gene', '8289', (137, 143))	('UTX', 'Gene', (114, 117))	('UTX', 'Gene', '7403', (114, 117))	('BAP1', 'Gene', (148, 152))	('PBRM1', 'Gene', (93, 98))	('KDM6A', 'Gene', (107, 112))	('KDM5C', 'Gene', (120, 125))	('chromosome', 'cellular_component', 'GO:0005694', ('221', '231'))	('VHL', 'Disease', (204, 207))	('SETD2', 'Gene', (100, 105))
30810	25048860	Gene fusions of two genes from the micropthalmia transcription factor (MiT) gene family genetically define a histologically variable group of approximately 1-5% of sporadic RCC tumors.	('transcription factor', 'molecular_function', 'GO:0000981', ('49', '69'))	('RCC', 'Phenotype', 'HP:0005584', (173, 176))	('Gene fusions', 'Var', (0, 12))	('sporadic RCC tumors', 'Disease', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('transcription', 'biological_process', 'GO:0006351', ('49', '62'))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('MiT', 'Gene', (71, 74))	('sporadic RCC tumors', 'Disease', 'MESH:C538614', (164, 183))
30813	25048860	In contrast to the histologically defined RCC types, these gene fusion associated kidney cancers are more common among pediatric patients, with the prevalence peaking in early adulthood.	('kidney cancers', 'Disease', (82, 96))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('kidney cancers', 'Phenotype', 'HP:0009726', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('patients', 'Species', '9606', (129, 137))	('gene fusion', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('kidney cancer', 'Phenotype', 'HP:0009726', (82, 95))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('kidney cancers', 'Disease', 'MESH:D007680', (82, 96))
30815	25048860	Yet despite nearly two decades since the discovery of the MiT family gene fusions in RCC, the molecular biology underlying these cancers remains largely uncharacterized and effective targeted therapies are yet to be identified.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('gene fusions', 'Var', (69, 81))	('cancers', 'Disease', (129, 136))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('MiT family', 'Gene', (58, 68))
30817	25048860	Critical to developing effective therapeutics for RCC patients with TFE3 or TFEB gene fusions is identification of the key clinical pathways driving these particular cancers.	('patients', 'Species', '9606', (54, 62))	('TFE3', 'Gene', (68, 72))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Disease', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('TFEB', 'Gene', '7942', (76, 80))	('gene fusions', 'Var', (81, 93))	('particular cancers', 'Disease', (155, 173))	('TFEB', 'Gene', (76, 80))	('particular cancers', 'Disease', 'MESH:D009369', (155, 173))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
30818	25048860	Herein, we summarize the contemporary understanding of the molecular biology underlying these gene fusion associated (translocation) RCCs, which we subsequently refer to within as "TFE-fusion RCCs".	('gene fusion', 'Var', (94, 105))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('RCC', 'Disease', (133, 136))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))
30827	25048860	Characterization of the NONO-TFE3 fusion, resulting from inversion of the TFE3 and NONO loci on chromosome Xp, revealed that chromosomal rearrangements other than translocations could generate TFE3 gene fusions.	('NONO', 'Gene', (83, 87))	('TFE3', 'Gene', (193, 197))	('NONO', 'Gene', '4841', (83, 87))	('generate', 'Reg', (184, 192))	('TFE3', 'Gene', (74, 78))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('NONO', 'Gene', (24, 28))	('NONO', 'Gene', '4841', (24, 28))	('inversion', 'Var', (57, 66))
30833	25048860	The existence of additional TFE3-fusion partners is suggested by case reports of Xp11.2 rearrangements with other chromosomal loci in RCC tumors, including 3q23 and 19q13.1, however TFE3 fusions were not genetically confirmed in these studies.	('p11', 'Gene', (82, 85))	('RCC tumors', 'Disease', 'MESH:C538614', (134, 144))	('p11', 'Gene', '6281', (82, 85))	('RCC tumors', 'Disease', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('rearrangements', 'Var', (88, 102))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
30834	25048860	The recent publication of the TCGA Network's clear cell kidney cancer project (KIRC) paper provides further evidence for the importance of gene fusions in RCC and identified 5 tumors harboring SFPQ-TFE3 fusions by RNASeq analysis.	('RCC', 'Disease', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('kidney cancer', 'Phenotype', 'HP:0009726', (56, 69))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (45, 69))	('kidney cancer', 'Disease', 'MESH:D007680', (56, 69))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('gene fusions', 'Var', (139, 151))	('kidney cancer', 'Disease', (56, 69))	('SFPQ-TFE3', 'Gene', (193, 202))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('SFPQ-TFE3', 'Gene', '6421;7030', (193, 202))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
30836	25048860	Exome sequencing analysis demonstrated that only one of these tumors had a VHL mutation, normally very common in cell clear RCC, and no tumors demonstrated mutations in any of the commonly mutated genes in clear cell RCC (PBRM1, SETD2, BAP1, MTOR, PIK3CA, ARID1A, ATM, PTEN, KDM5C).	('RCC', 'Disease', (124, 127))	('VHL', 'Disease', (75, 78))	('tumors', 'Disease', (136, 142))	('KDM5C', 'Gene', '8242', (275, 280))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('PTEN', 'Gene', (269, 273))	('MTOR', 'Gene', (242, 246))	('MTOR', 'Gene', '2475', (242, 246))	('PIK3CA', 'Gene', '5290', (248, 254))	('ATM', 'Gene', (264, 267))	('ARID1A', 'Gene', (256, 262))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('PBRM1', 'Gene', '55193', (222, 227))	('tumors', 'Disease', (62, 68))	('PTEN', 'Gene', '5728', (269, 273))	('BAP1', 'Gene', '8314', (236, 240))	('VHL', 'Disease', 'MESH:D006623', (75, 78))	('KDM5C', 'Gene', (275, 280))	('ARID1A', 'Gene', '8289', (256, 262))	('RCC', 'Phenotype', 'HP:0005584', (217, 220))	('RCC', 'Disease', (217, 220))	('PBRM1', 'Gene', (222, 227))	('SETD2', 'Gene', (229, 234))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('mutation', 'Var', (79, 87))	('PIK3CA', 'Gene', (248, 254))	('BAP1', 'Gene', (236, 240))	('SETD2', 'Gene', '29072', (229, 234))	('RCC', 'Disease', 'MESH:C538614', (217, 220))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('ATM', 'Gene', '472', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
30838	25048860	Chromosomal rearrangements resulting in the fusion between the Transcription factor EB (TFEB) gene on chromosome 6p21.2 and the non-protein encoding Metastasis associated lung adenocarcinoma transcript 1 gene known as MALAT1 (previously referred to as Alpha) on chromosome 11q13 is the most recently described gene fusion in RCC.	('fusion', 'Interaction', (44, 50))	('Transcription factor EB', 'Gene', '7942', (63, 86))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('lung adenocarcinoma', 'Disease', (171, 190))	('chromosome', 'cellular_component', 'GO:0005694', ('262', '272'))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))	('Transcription factor EB', 'Gene', (63, 86))	('RCC', 'Disease', (325, 328))	('RCC', 'Phenotype', 'HP:0005584', (325, 328))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('rearrangements', 'Var', (12, 26))	('MALAT1', 'Gene', (218, 224))	('TFEB', 'Gene', (88, 92))	('p21', 'Gene', (114, 117))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('p21', 'Gene', '644914', (114, 117))	('MALAT1', 'Gene', '378938', (218, 224))	('chromosome', 'cellular_component', 'GO:0005694', ('102', '112'))	('TFEB', 'Gene', '7942', (88, 92))
30840	25048860	Less than two dozen cases are documented with genetic confirmation of the MALAT1-TFEB fusion or t(6;11)(p21.2;q13) mutation to date, and the incidence of this fusion is approximately 1:15-1:20 compared to that of TFE3 fusions.	('TFEB', 'Gene', '7942', (81, 85))	('TFEB', 'Gene', (81, 85))	('t(6;11)(p21.2', 'Gene', (96, 109))	('fusion', 'Var', (86, 92))	('MALAT1', 'Gene', '378938', (74, 80))	('t(6;11)(p21.2;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (96, 114))	('mutation', 'Var', (115, 123))	('MALAT1', 'Gene', (74, 80))
30843	25048860	Also in contrast to TFE3 fusions, the MALAT1-TFEB fusion may be associated with a favorable clinical prognosis.	('TFEB', 'Gene', '7942', (45, 49))	('MALAT1', 'Gene', (38, 44))	('TFEB', 'Gene', (45, 49))	('MALAT1', 'Gene', '378938', (38, 44))	('fusion', 'Var', (50, 56))
30847	25048860	Wild-type TFE3 mRNA is translated into a 575 amino-acid (AA) protein (61.5 kD) sharing highly conserved peptide domains with other MiT family members, including a 12-AA transcription activation domain (AD 260AA-271AA) spanning exons 4-5, a 54-AA basic region and helix-loop-helix domain (bHLH 346AA-399AA) within exons 7-9, and a 22-AA leucine-zipper domain (LZ 409AA-430AA) within exons 9-10.	('LZ 409AA-430AA', 'Var', (359, 373))	('AD', 'Disease', 'MESH:D000544', (202, 204))	('TFE3', 'Gene', (10, 14))	('AD', 'Disease', (202, 204))	('transcription', 'MPA', (169, 182))	('transcription', 'biological_process', 'GO:0006351', ('169', '182'))	('protein', 'cellular_component', 'GO:0003675', ('61', '68'))
30853	25048860	(Figures 2, Figure 4) MALAT1-TFEB fusion breakpoints generally occur before the start codon in TFEB exon 3, resulting in retention of the complete TFEB coding sequence.	('TFEB', 'Gene', (29, 33))	('TFEB', 'Gene', '7942', (147, 151))	('retention', 'biological_process', 'GO:0051235', ('121', '130'))	('TFEB', 'Gene', '7942', (95, 99))	('TFEB', 'Gene', (95, 99))	('MALAT1', 'Gene', '378938', (22, 28))	('breakpoints', 'Var', (41, 52))	('TFEB', 'Gene', (147, 151))	('MALAT1', 'Gene', (22, 28))	('TFEB', 'Gene', '7942', (29, 33))
30854	25048860	(Figure 4) Until recently, all MALAT1-TFEB fusions were believed to occur within a 289-bp breakpoint cluster region (BCR) upstream of TFEB exon 3, and within a 1,205-bp BCR of MALAT1.	('MALAT1', 'Gene', '378938', (176, 182))	('TFEB', 'Gene', '7942', (134, 138))	('TFEB', 'Gene', '7942', (38, 42))	('MALAT1', 'Gene', (176, 182))	('MALAT1', 'Gene', (31, 37))	('TFEB', 'Gene', (134, 138))	('fusions', 'Var', (43, 50))	('TFEB', 'Gene', (38, 42))	('MALAT1', 'Gene', '378938', (31, 37))
30860	25048860	Over a dozen rodent models with germline MiTF mutations in the bHLH-LZ regions are described with various pigmentation defects including albinism, ocular defects (micropthalmia), and deafness.	('ocular defects', 'Disease', 'MESH:D005128', (147, 161))	('albinism, ocular', 'Phenotype', 'HP:0001107', (137, 153))	('mutations', 'Var', (46, 55))	('deafness', 'Disease', 'MESH:D003638', (183, 191))	('albinism', 'Phenotype', 'HP:0001022', (137, 145))	('deafness', 'Phenotype', 'HP:0000365', (183, 191))	('MiTF', 'Gene', (41, 45))	('pigmentation defects', 'Disease', (106, 126))	('deafness', 'Disease', (183, 191))	('pigmentation', 'biological_process', 'GO:0043473', ('106', '118'))	('pigmentation defects', 'Phenotype', 'HP:0001000', (106, 126))	('ocular defects', 'Disease', (147, 161))	('pigmentation defects', 'Disease', 'MESH:D010859', (106, 126))	('bHLH-LZ', 'Gene', (63, 70))	('albinism', 'Disease', (137, 145))
30861	25048860	In humans, heterozygous MiTF mutations are responsible for Waardenburg Syndrome IIA, characterized by melanocyte deficiency and similar phenotypic manifestation.	('Waardenburg Syndrome IIA', 'Disease', (59, 83))	('melanocyte deficiency', 'Disease', 'MESH:D009508', (102, 123))	('mutations', 'Var', (29, 38))	('Waardenburg Syndrome IIA', 'Disease', 'MESH:C536464', (59, 83))	('responsible', 'Reg', (43, 54))	('MiTF', 'Gene', (24, 28))	('melanocyte deficiency', 'Disease', (102, 123))	('humans', 'Species', '9606', (3, 9))
30868	25048860	Hence, MiTF mutations in the basic domain lead to osteoporosis in mice despite wild-type TFE3, presumably due to TFE3 sequestration in transcriptionally inactive heterodimers with the mutant MiTF protein.	('osteoporosis', 'Phenotype', 'HP:0000939', (50, 62))	('mutations', 'Var', (12, 21))	('mice', 'Species', '10090', (66, 70))	('osteoporosis', 'Disease', 'MESH:D010024', (50, 62))	('MiTF', 'Gene', (7, 11))	('osteoporosis', 'Disease', (50, 62))	('lead to', 'Reg', (42, 49))	('protein', 'cellular_component', 'GO:0003675', ('196', '203'))
30870	25048860	For example, ectopic expression of the PRCC-TFE3 fusion confers tumorigenicity to fibroblast cells in nude mice and enables benign proximal renal tubule cells to overcome in vitro growth arrest.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('growth arrest', 'Phenotype', 'HP:0001510', (180, 193))	('nude mice', 'Species', '10090', (102, 111))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('growth arrest', 'Disease', 'MESH:D006323', (180, 193))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('ectopic expression', 'Var', (13, 31))	('PRCC-TFE3', 'Gene', (39, 48))	('growth arrest', 'Disease', (180, 193))
30872	25048860	The first model ("lost activity model") presumes a wild-type tumor-suppressive gene function which is disrupted by the gene fusion; however, a fusion protein is not generally translated in such cases.	('gene fusion', 'Var', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('function', 'MPA', (84, 92))
30873	25048860	Furthermore, the dysregulated activity model is known to be the mechanism for TFEB-fusion oncogenesis, with MALAT1-TFEB fusions generally upregulating a full-length wild-type TFEB protein as opposed to a chimeric protein.	('TFEB', 'Gene', '7942', (78, 82))	('TFEB', 'Gene', (115, 119))	('TFEB', 'Gene', (78, 82))	('TFEB', 'Gene', '7942', (175, 179))	('MALAT1', 'Gene', '378938', (108, 114))	('TFEB', 'Gene', (175, 179))	('protein', 'cellular_component', 'GO:0003675', ('213', '220'))	('upregulating', 'PosReg', (138, 150))	('MALAT1', 'Gene', (108, 114))	('fusions', 'Var', (120, 127))	('oncogenesis', 'biological_process', 'GO:0007048', ('90', '101'))	('protein', 'cellular_component', 'GO:0003675', ('180', '187'))	('TFEB', 'Gene', '7942', (115, 119))
30874	25048860	The dysregulated activity model is consistent with gene fusion mechanisms in other cancers, in which promoter substitution leads to upregulation of a transcription factor oncogene, such as TMPRSS2-ERG in prostate cancer.	('prostate cancer', 'Disease', (204, 219))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('transcription', 'biological_process', 'GO:0006351', ('150', '163'))	('upregulation', 'PosReg', (132, 144))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (204, 219))	('prostate cancer', 'Phenotype', 'HP:0012125', (204, 219))	('TMPRSS2', 'Gene', (189, 196))	('ERG', 'Gene', '2078', (197, 200))	('transcription factor', 'molecular_function', 'GO:0000981', ('150', '170'))	('ERG', 'Gene', (197, 200))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('promoter substitution', 'Var', (101, 122))	('cancers', 'Disease', (83, 90))	('TMPRSS2', 'Gene', '7113', (189, 196))
30879	25048860	For example, MiTF is amplified in 20% of metastatic melanomas, and a germline activating MiTF amino-acid substitution recently been identified in association with increased risk of RCC and/or melanoma.	('melanomas', 'Disease', 'MESH:D008545', (52, 61))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('amino-acid substitution', 'Var', (94, 117))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanomas', 'Disease', (52, 61))	('MiTF', 'Gene', (89, 93))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('RCC', 'Disease', 'MESH:C538614', (181, 184))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('RCC', 'Disease', (181, 184))	('RCC', 'Phenotype', 'HP:0005584', (181, 184))
30893	25048860	(Figure 5) In liver and muscle, TFE3 governs insulin signaling and glucose metabolism through upregulation of IRS-2 and the hexokinase enzymes, inhibiting lipogenesis and increasing glycogen synthesis.	('IRS-2', 'Gene', (110, 115))	('governs insulin', 'Disease', 'MESH:D007333', (37, 52))	('hexokinase', 'Gene', (124, 134))	('lipogenesis', 'biological_process', 'GO:0008610', ('155', '166'))	('IRS-2', 'Gene', '8660', (110, 115))	('increasing', 'PosReg', (171, 181))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('hexokinase', 'Gene', '3098', (124, 134))	('TFE3', 'Var', (32, 36))	('glycogen synthesis', 'biological_process', 'GO:0005978', ('182', '200'))	('insulin', 'molecular_function', 'GO:0016088', ('45', '52'))	('signaling', 'biological_process', 'GO:0023052', ('53', '62'))	('glycogen', 'Chemical', 'MESH:D006003', (182, 190))	('inhibiting', 'NegReg', (144, 154))	('upregulation', 'PosReg', (94, 106))	('lipogenesis', 'MPA', (155, 166))	('glucose metabolism', 'MPA', (67, 85))	('glucose metabolism', 'biological_process', 'GO:0006006', ('67', '85'))	('governs insulin', 'Disease', (37, 52))	('glycogen synthesis', 'MPA', (182, 200))
30909	25048860	Nearly two decades since the discovery of TFE3 gene fusions and one decade since the discovery of TFEB gene fusions, the mechanisms underlying the oncogenic effects of these mutations in kidneys remain largely unclear.	('TFEB', 'Gene', '7942', (98, 102))	('TFEB', 'Gene', (98, 102))	('gene fusions', 'Var', (47, 59))	('TFE3', 'Gene', (42, 46))	('fusions', 'Var', (108, 115))
30913	25048860	Whether dysreguation of these pathways contributes to TFE-fusion carcinogenesis warrants further investigation, with an ultimate goal of pinpointing the most promising molecular targets for novel therapeutics.	('contributes', 'Reg', (39, 50))	('dysreguation', 'Var', (8, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('carcinogenesis', 'Disease', (65, 79))
30915	30285995	VSTM2A Over-expression is a Sensitive and Specific Biomarker for Mucinous Tubular and Spindle Cell Carcinoma (MTSCC) of the Kidney Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('VSTM2A', 'Gene', '222008', (0, 6))	('Spindle Cell Carcinoma', 'Disease', (86, 108))	('Carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('spindle', 'cellular_component', 'GO:0005819', ('262', '269'))	('mucinous tubular and spindle cell carcinoma', 'Disease', 'MESH:D002277', (241, 284))	('mutations', 'Var', (198, 207))	('VSTM2A', 'Gene', (0, 6))	('Hippo pathway', 'Pathway', (224, 237))	('Spindle Cell Carcinoma', 'Disease', 'MESH:D002277', (86, 108))	('Spindle', 'cellular_component', 'GO:0005819', ('86', '93'))	('chromosomal losses', 'Var', (167, 185))
30928	30285995	Our previous multi-institutional cohort sequencing study found MTSCC to be molecularly distinct from other RCC subtypes and typified by characteristic chromosomal losses, recurrent somatic mutations in Hippo signaling pathway genes, and the absence of chromosome 7 or 17 gains; our major findings have been independently confirmed by other groups.	('RCC', 'Phenotype', 'HP:0005584', (107, 110))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('202', '225'))	('RCC', 'Disease', 'MESH:C538614', (107, 110))	('losses', 'NegReg', (163, 169))	('RCC', 'Disease', (107, 110))	('chromosome', 'cellular_component', 'GO:0005694', ('252', '262'))	('Hippo', 'Gene', (202, 207))	('MTSCC', 'Disease', (63, 68))	('mutations', 'Var', (189, 198))
30960	30285995	Trisomy of chromosomes 7 and/or 17 was considered as a characteristic genomic feature of PRCC.	('PRCC', 'Gene', '5546', (89, 93))	('PRCC', 'Gene', (89, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('Trisomy', 'Var', (0, 7))
31019	30285995	Our study of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and frequent biallelic alteration of Hippo pathway genes, resulting in increased YAP1 nuclear expression; however, YAP1 expression was not found to be of diagnostic use in differentiating MTSCC from PRCC in an independent study.	('RCC', 'Phenotype', 'HP:0005584', (286, 289))	('MTSCC', 'Disease', (274, 279))	('PRCC', 'Gene', '5546', (285, 289))	('Hippo pathway genes', 'Gene', (123, 142))	('YAP1', 'Gene', (201, 205))	('biallelic alteration', 'Var', (99, 119))	('rat', 'Species', '10116', (113, 116))	('YAP1', 'Gene', '10413', (201, 205))	('PRCC', 'Gene', (285, 289))	('YAP1', 'Gene', '10413', (167, 171))	('nuclear expression', 'MPA', (172, 190))	('increased', 'PosReg', (157, 166))	('chromosomal losses', 'Var', (67, 85))	('YAP1', 'Gene', (167, 171))
31036	30285995	Hence, our results indicate that for an individual tumor with morphologic features that can be observed in either MTSCC or PRCC, high VSTM2A expression above an ISH score cutoff of 200 will support an interpretation of MTSCC.	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('PRCC', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (129, 133))	('tumor', 'Disease', (51, 56))	('VSTM2A', 'Gene', (134, 140))	('MTSCC', 'Disease', (219, 224))	('support', 'Reg', (190, 197))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('PRCC', 'Gene', '5546', (123, 127))	('VSTM2A', 'Gene', '222008', (134, 140))	('MTSCC', 'Disease', (114, 119))
31077	30023184	However, two recently described but less-common RCCs, clear cell papillary renal cell carcinoma, CPRCC and Xp11 translocation RCC, characteristically feature both papillary architecture and cells with clear cytoplasm.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('Xp11 translocation', 'Var', (107, 125))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('RCCs', 'Phenotype', 'HP:0005584', (48, 52))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (65, 95))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PRCC', 'Gene', (98, 102))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (65, 95))	('clear cell papillary renal cell carcinoma', 'Phenotype', 'HP:0006770', (54, 95))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('papillary renal cell carcinoma', 'Disease', (65, 95))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('PRCC', 'Gene', '5546', (98, 102))	('cytoplasm', 'cellular_component', 'GO:0005737', ('207', '216'))
31082	30023184	Xp11 translocation RCC was initially described in children and young adults.	('Xp11 translocation', 'Var', (0, 18))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('children', 'Species', '9606', (50, 58))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))
31083	30023184	Recently, the term "MiTF/TFE family translocation-associated carcinoma" has been proposed for tumors that have translocations involving TFE3.	('translocations', 'Var', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MiTF', 'Gene', (20, 24))	('TFE3', 'Gene', (136, 140))	('carcinoma', 'Disease', 'MESH:D002277', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('carcinoma', 'Disease', (61, 70))	('MiTF', 'Gene', '4286', (20, 24))	('TFE3', 'Gene', '7030', (136, 140))
31121	30023184	Overall, of the 60 cases, 28 (47%) were CRCC, 15 (25%) PRCC, 8 (13%) CPRCC and 9 (15%) Xp11 translocation RCC were identified.	('RCC', 'Disease', (56, 59))	('PRCC', 'Gene', (70, 74))	('PRCC', 'Gene', '5546', (55, 59))	('RCC', 'Phenotype', 'HP:0005584', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('PRCC', 'Gene', (55, 59))	('Xp11 translocation', 'Var', (87, 105))	('PRCC', 'Gene', '5546', (70, 74))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('RCC', 'Phenotype', 'HP:0005584', (41, 44))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
31130	30023184	Renal carcinomas with Xp11.2 translocation have a characteristic morphology; they are composed of very large clear cells that form nests, alveoli, and papillae (Fig.	('carcinomas', 'Phenotype', 'HP:0030731', (6, 16))	('Xp11.2 translocation', 'Var', (22, 42))	('Renal carcinomas', 'Disease', 'MESH:C538614', (0, 16))	('Renal carcinomas', 'Phenotype', 'HP:0005584', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('Renal carcinomas', 'Disease', (0, 16))
31155	30023184	The present study included 60 cases consist of CRCC, PRCC, CPRCC and Xp11.2 translocation RCC.	('PRCC', 'Gene', (60, 64))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))	('PRCC', 'Gene', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('Xp11.2 translocation', 'Var', (69, 89))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('PRCC', 'Gene', '5546', (53, 57))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('PRCC', 'Gene', '5546', (60, 64))	('RCC', 'Disease', (48, 51))	('RCC', 'Disease', (90, 93))
31166	30023184	Xp11.2 translocation RCC has a distinctive pattern which is the presence of both clear cells and papillary architecture.	('Xp11.2 translocation', 'Var', (0, 20))	('translocation', 'Var', (7, 20))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('RCC', 'Disease', (21, 24))	('RCC', 'Phenotype', 'HP:0005584', (21, 24))
31175	30023184	In this study, it has been shown that this marker is usually positive in PRCC and Xp11 translocation RCC with a diffuse strong cytoplasmic staining pattern.	('Xp11 translocation', 'Var', (82, 100))	('positive', 'Reg', (61, 69))	('RCC', 'Phenotype', 'HP:0005584', (101, 104))	('PRCC', 'Gene', '5546', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('RCC', 'Disease', (101, 104))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('PRCC', 'Gene', (73, 77))	('RCC', 'Disease', 'MESH:C538614', (74, 77))
31220	25984679	Six BACs located on the 2 sides surrounding the TFE3 gene were chosen: CTD-2516D6, CTD-2522M13, and RP11-416B14 were located on the telomeric side of the TFE3 gene, and CTD-2312C1, CTD-2248C21, and RP11-959H17 were located on the centromeric side of the TFE3 gene.	('TFE3', 'Gene', '7030', (48, 52))	('TFE3', 'Gene', '7030', (254, 258))	('CTD-2312C1', 'Var', (169, 179))	('CTD-2516D6', 'Var', (71, 81))	('TFE3', 'Gene', (154, 158))	('CTD-2522M13', 'Var', (83, 94))	('CTD-2248C21', 'Var', (181, 192))	('TFE3', 'Gene', (254, 258))	('RP11-416B14', 'Var', (100, 111))	('RP11-959H17', 'Var', (198, 209))	('TFE3', 'Gene', (48, 52))	('TFE3', 'Gene', '7030', (154, 158))
31222	25984679	Dual-fusion dual-color probe design: After being selected from http://genome.ucsc.edu/, RP11-634L10, RP11-51H16, and RP11-475F12 were labeled with tetramethylrhodamine-5-dUTP as red fluorescein, were located on the long arm of chromosome 17 and covered the entire ASPL gene.	('RP11-51H16', 'Var', (101, 111))	('fluorescein', 'Chemical', 'MESH:D019793', (182, 193))	('chromosome', 'cellular_component', 'GO:0005694', ('227', '237'))	('H16', 'CellLine', 'CVCL:0H99', (108, 111))	('ASPL', 'Gene', '79058', (264, 268))	('RP11-634L10', 'Var', (88, 99))	('tetramethylrhodamine-5-dUTP', 'Chemical', '-', (147, 174))	('ASPL', 'Gene', (264, 268))	('RP11-475F12', 'Var', (117, 128))
31223	25984679	CTD-2311N12, RP11-416B14, CTD-2522M13, CTD-2516D6, CTD-2312C1, CTD-2248C21, and RP11-959H17 were located on the short arm of the X chromosome and covered the entire TFE3 gene.	('TFE3', 'Gene', '7030', (165, 169))	('X chromosome', 'cellular_component', 'GO:0000805', ('129', '141'))	('RP11-959H17', 'Var', (80, 91))	('CTD-2516D6', 'Var', (39, 49))	('short arm', 'Phenotype', 'HP:0009824', (112, 121))	('TFE3', 'Gene', (165, 169))	('RP11-416B14', 'Var', (13, 24))	('CTD-2248C21', 'Var', (63, 74))	('CTD-2522M13', 'Var', (26, 37))	('CTD-2312C1', 'Var', (51, 61))
31249	25984679	There were 22 cases that positively predicted the translocation of TFE3 gene among the 65 cases, whereas the other 43/65 cases and the control groups were negative.	('translocation', 'Var', (50, 63))	('TFE3', 'Gene', '7030', (67, 71))	('TFE3', 'Gene', (67, 71))
31269	25984679	In Malouf et al's study, 2 patients with ASPL-TFE3 fusion had more aggressive progression compared with those who had other fusion genes.	('TFE3', 'Gene', (46, 50))	('ASPL', 'Gene', '79058', (41, 45))	('patients', 'Species', '9606', (27, 35))	('fusion', 'Var', (51, 57))	('aggressive progression', 'CPA', (67, 89))	('TFE3', 'Gene', '7030', (46, 50))	('ASPL', 'Gene', (41, 45))
31271	25984679	Ellis's group found that regional lymph nodes were involved in 24 of the 32 ASPL-TFE3 RCC cases and that patients who had distant metastasis also displayed ASPL-TFE3 fusion genes.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('ASPL', 'Gene', (76, 80))	('patients', 'Species', '9606', (105, 113))	('ASPL', 'Gene', (156, 160))	('TFE3', 'Gene', (81, 85))	('fusion genes', 'Var', (166, 178))	('involved', 'Reg', (51, 59))	('ASPL', 'Gene', '79058', (76, 80))	('TFE3', 'Gene', (161, 165))	('ASPL', 'Gene', '79058', (156, 160))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('TFE3', 'Gene', '7030', (161, 165))	('RCC', 'Disease', (86, 89))	('TFE3', 'Gene', '7030', (81, 85))
31282	25984679	This novel dual-fusion probe can accurately distinguish the balanced and unbalanced translocation of the TFE3 gene, which is the superior to single fusion probe strategy.	('TFE3', 'Gene', '7030', (105, 109))	('TFE3', 'Gene', (105, 109))	('balanced', 'Var', (60, 68))	('unbalanced translocation', 'Var', (73, 97))
31283	25984679	Furthermore, our new TFE3 break-apart and ASPL-TFE3 dual-fusion probes can be applied diagnostically in other tumors that harbor translocation of the TFE3 gene and the ASPL-TFE3 fusion gene.	('TFE3', 'Gene', '7030', (21, 25))	('TFE3', 'Gene', '7030', (150, 154))	('TFE3', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('TFE3', 'Gene', (47, 51))	('ASPL', 'Gene', '79058', (168, 172))	('TFE3', 'Gene', (21, 25))	('tumors', 'Disease', (110, 116))	('TFE3', 'Gene', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('TFE3', 'Gene', '7030', (47, 51))	('ASPL', 'Gene', '79058', (42, 46))	('TFE3', 'Gene', '7030', (173, 177))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ASPL', 'Gene', (42, 46))	('ASPL', 'Gene', (168, 172))	('translocation', 'Var', (129, 142))
31284	25984679	PEComas have been found to have TFE3 gene rearrangement and to harbor a PSF-TFE3 gene fusion; thus, the TFE3 break-apart probe could be applied to detect the translocation of the TFE3 gene.	('PEComas', 'Disease', (0, 7))	('TFE3', 'Gene', (32, 36))	('TFE3', 'Gene', (76, 80))	('TFE3', 'Gene', '7030', (104, 108))	('PSF', 'Gene', (72, 75))	('rearrangement', 'Var', (42, 55))	('TFE3', 'Gene', '7030', (76, 80))	('TFE3', 'Gene', (179, 183))	('PEComas', 'Disease', 'MESH:D054973', (0, 7))	('TFE3', 'Gene', '7030', (32, 36))	('TFE3', 'Gene', (104, 108))	('PSF', 'Gene', '6421', (72, 75))	('TFE3', 'Gene', '7030', (179, 183))
31290	25984679	Furthermore, these FISH assays can be used as an adjunctive method to improve the accuracy of diagnosis for Xp11.2 tRCC, ASPS, PEComas, and other neoplasms that are characterized by a rearrangement of the TFE3 gene and the presence of the ASPL-TFE3 fusion gene.	('p11', 'Gene', (109, 112))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('neoplasms', 'Phenotype', 'HP:0002664', (146, 155))	('RCC', 'Disease', (116, 119))	('ASPS', 'Phenotype', 'HP:0012218', (121, 125))	('ASPS', 'Disease', 'MESH:D018234', (121, 125))	('ASPL', 'Gene', (239, 243))	('rearrangement', 'Var', (184, 197))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('ASPS', 'Disease', (121, 125))	('TFE3', 'Gene', (205, 209))	('neoplasms', 'Disease', 'MESH:D009369', (146, 155))	('TFE3', 'Gene', '7030', (205, 209))	('PEComas', 'Disease', 'MESH:D054973', (127, 134))	('TFE3', 'Gene', (244, 248))	('TFE3', 'Gene', '7030', (244, 248))	('PEComas', 'Disease', (127, 134))	('ASPL', 'Gene', '79058', (239, 243))	('neoplasms', 'Disease', (146, 155))	('p11', 'Gene', '8909', (109, 112))
31323	23402579	The tumour stage was determined to be pT1 cN3 cM1b S3 (TNM) and clinical stage IIIC poor prognosis group (Lugano classification).	('pT1 cN3 cM1b S3', 'Var', (38, 53))	('TNM', 'Gene', '10178', (55, 58))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('TNM', 'Gene', (55, 58))	('tumour', 'Disease', (4, 10))
31417	31249659	The specific tumor comprises of 9.3% of all renal tumors in young adults with an age range of 18-88 years (Wang Y, Ding Y, Wang J, Gu M, Wang Z, Qin C et al.	('tumor', 'Disease', (13, 18))	('Gu M', 'Var', (131, 135))	('renal tumors', 'Disease', 'MESH:D007674', (44, 56))	('Qin', 'Gene', (145, 148))	('renal tumors', 'Disease', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('Qin', 'Gene', '2290', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('renal tumors', 'Phenotype', 'HP:0009726', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('renal tumor', 'Phenotype', 'HP:0009726', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (50, 55))
31441	31249659	3) and p504s supporting the diagnosis of CCPRCC.	('CCPRCC', 'Phenotype', 'HP:0006770', (41, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('PRCC', 'Gene', '5546', (43, 47))	('p504s', 'Var', (7, 12))	('PRCC', 'Gene', (43, 47))
31453	31249659	On the contrary, PRCC is associated with trisomy of chromosome 7, 17 and loss of Y chromosome.	('loss', 'NegReg', (73, 77))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('52', '62'))	('PRCC', 'Gene', (17, 21))	('trisomy', 'Var', (41, 48))	('Y chromosome', 'cellular_component', 'GO:0000806', ('81', '93'))	('associated', 'Reg', (25, 35))	('PRCC', 'Gene', '5546', (17, 21))
31456	31249659	No mutation or methylation of VHL gene has been reported in cases of CCPRCC.	('methylation', 'Var', (15, 26))	('VHL', 'Disease', 'MESH:D006623', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('methylation', 'biological_process', 'GO:0032259', ('15', '26'))	('CCPRCC', 'Phenotype', 'HP:0006770', (69, 75))	('PRCC', 'Gene', '5546', (71, 75))	('VHL', 'Disease', (30, 33))	('PRCC', 'Gene', (71, 75))
31559	32047266	RASSF10 is frequently epigenetically inactivated in kidney cancer and its knockout promotes neoplasia in cancer prone mice Kidney cancer incidences are rising globally, thereby fueling the demand for targeted therapies and precision medicine.	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('knockout', 'Var', (74, 82))	('promotes', 'PosReg', (83, 91))	('neoplasia', 'Disease', 'MESH:D009369', (92, 101))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('RASSF10', 'Gene', '78748', (0, 7))	('RASSF10', 'Gene', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('neoplasia', 'Disease', (92, 101))	('Kidney cancer', 'Disease', 'MESH:D007680', (123, 136))	('Kidney cancer', 'Disease', (123, 136))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('cancer', 'Disease', (130, 136))	('Kidney cancer', 'Phenotype', 'HP:0009726', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('neoplasia', 'Phenotype', 'HP:0002664', (92, 101))	('cancer', 'Disease', (59, 65))
31564	32047266	Especially Rassf10-/- and p53-deficient mice exhibited threefold increased rates of kidney cysts compared with p53-/- controls.	('increased', 'PosReg', (65, 74))	('Rassf10-/-', 'Var', (11, 21))	('kidney cysts', 'CPA', (84, 96))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '22059', (111, 114))	('p53', 'Gene', (26, 29))	('increased rates of kidney', 'Phenotype', 'HP:0000105', (65, 90))	('kidney cysts', 'Phenotype', 'HP:0000107', (84, 96))	('p53', 'Gene', '22059', (26, 29))	('mice', 'Species', '10090', (40, 44))
31566	32047266	Primary tumors of renal clear cell and papillary cell carcinoma confirmed that RASSF10 methylation is associated with decreased expression in comparison to normal kidney tissue.	('Primary tumors of renal clear cell and papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('methylation', 'biological_process', 'GO:0032259', ('87', '98'))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('RASSF10', 'Gene', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('decreased', 'NegReg', (118, 127))	('expression', 'MPA', (128, 138))	('methylation', 'Var', (87, 98))
31567	32047266	In independent data sets, we could validate that RASSF10 inactivation clinically correlated with decreased survival and with progressed disease state of kidney cancer patients and polycystic kidney size.	('survival', 'MPA', (107, 115))	('disease state of kidney', 'Phenotype', 'HP:0000112', (136, 159))	('progressed', 'Disease', (125, 135))	('patients', 'Species', '9606', (167, 175))	('RASSF10', 'Gene', (49, 56))	('polycystic kidney', 'Disease', 'MESH:D007690', (180, 197))	('kidney cancer', 'Disease', 'MESH:D007680', (153, 166))	('decreased', 'NegReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('polycystic kidney', 'Phenotype', 'HP:0000113', (180, 197))	('progressed disease state of kidney', 'Phenotype', 'HP:0012622', (125, 159))	('polycystic kidney', 'Disease', (180, 197))	('kidney cancer', 'Phenotype', 'HP:0009726', (153, 166))	('inactivation', 'Var', (57, 69))	('kidney cancer', 'Disease', (153, 166))
31569	32047266	In combination with other markers, RASSF10 silencing can serve as diagnostic and prognostic cancer biomarker in kidney diseases.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('kidney diseases', 'Disease', (112, 127))	('RASSF10', 'Gene', (35, 42))	('silencing', 'Var', (43, 52))	('kidney diseases', 'Disease', 'MESH:D007674', (112, 127))	('kidney diseases', 'Phenotype', 'HP:0000112', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('kidney disease', 'Phenotype', 'HP:0000112', (112, 126))
31575	32047266	Our group focuses on epigenetically inactivated tumor suppressors as candidate biomarkers, which are predicted to play a prominent role in the near future.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('epigenetically inactivated', 'Var', (21, 47))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
31579	32047266	Epigenetic inactivation of RASSF10 by its promoter hypermethylation is a frequent event in pathogenesis of human cancers.	('promoter', 'MPA', (42, 50))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('RASSF10', 'Gene', (27, 34))	('cancers', 'Disease', (113, 120))	('pathogenesis', 'biological_process', 'GO:0009405', ('91', '103'))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Epigenetic inactivation', 'Var', (0, 23))
31580	32047266	In previous studies, we have shown that the RASSF10 promoter is methylated in patient tumors samples of the adrenal gland, head and neck, sarcoma, pancreas carcinoma, and Merkel cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patient', 'Species', '9606', (78, 85))	('sarcoma', 'Disease', (138, 145))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (171, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('methylated', 'Var', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Merkel cell carcinoma', 'Disease', (171, 192))	('adrenal gland', 'Disease', (108, 121))	('tumors', 'Disease', (86, 92))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (147, 165))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('pancreas carcinoma', 'Disease', (147, 165))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('RASSF10', 'Gene', (44, 51))	('neck', 'cellular_component', 'GO:0044326', ('132', '136'))
31581	32047266	We showed the epigenetic inactivation of RASSF10 in breast cancer, lung cancer, skin cancer, and thyroid cancer and showed that RASSF10 inhibited the growth of breast cancer, pancreas carcinoma, and sarcoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('epigenetic inactivation', 'Var', (14, 37))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (175, 193))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RASSF10', 'Gene', (41, 48))	('pancreas carcinoma', 'Disease', (175, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('RASSF10', 'Var', (128, 135))	('skin cancer', 'Disease', (80, 91))	('lung cancer', 'Disease', (67, 78))	('thyroid cancer', 'Disease', (97, 111))	('inhibited', 'NegReg', (136, 145))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Disease', (52, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('growth', 'MPA', (150, 156))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('skin cancer', 'Disease', 'MESH:D012878', (80, 91))	('breast cancer', 'Disease', (160, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('sarcoma', 'Disease', (199, 206))
31585	32047266	Moreover, we revealed that RASSF10 is frequently epigenetically inactivated in kidney cancer, and we show the clinical potential of RASSF10 as a biomarker in different kidney diseases.	('kidney cancer', 'Disease', 'MESH:D007680', (79, 92))	('kidney cancer', 'Phenotype', 'HP:0009726', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('epigenetically inactivated', 'Var', (49, 75))	('kidney diseases', 'Disease', (168, 183))	('kidney cancer', 'Disease', (79, 92))	('RASSF10', 'Gene', (27, 34))	('kidney disease', 'Phenotype', 'HP:0000112', (168, 182))	('RASSF10', 'Gene', (132, 139))	('kidney diseases', 'Disease', 'MESH:D007674', (168, 183))	('kidney diseases', 'Phenotype', 'HP:0000112', (168, 183))
31590	32047266	At 80 weeks animals showed no differences between wt (n = 27) and Rassf10-/- (n = 44), regarding the occurrence of various diseases/neoplasia (diseased wt 56% vs. Rassf10-/- 57%).	('Rassf10-/-', 'Var', (66, 76))	('neoplasia', 'Disease', (132, 141))	('Rassf10-/-', 'Var', (163, 173))	('neoplasia', 'Disease', 'MESH:D009369', (132, 141))	('neoplasia', 'Phenotype', 'HP:0002664', (132, 141))
31594	32047266	In the Rassf1A-/- tumor-suppressor background, the additional Rassf10 knockout reduced significantly the overall survival (p = 0.018; Fig.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('18', '34'))	('reduced', 'NegReg', (79, 86))	('overall survival', 'MPA', (105, 121))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('18', '34'))	('Rassf1A-/- tumor-suppressor', 'Gene', '56289', (7, 34))	('Rassf1A-/- tumor-suppressor', 'Gene', (7, 34))	('Rassf10', 'Gene', (62, 69))	('knockout', 'Var', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
31595	32047266	In detail Rassf10 knockout animals mostly suffered from lymphoma, and the mean size of measurable lymph nodes increased from 86 mg for Rassf10 wt to 285 mg Rassf10+/- to 401 mg for Rassf10-/- (Fig.	('suffered', 'Reg', (42, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('Rassf10-/-', 'Var', (181, 191))	('Rassf10', 'Var', (135, 142))	('increased', 'PosReg', (110, 119))	('knockout', 'Var', (18, 26))	('lymph nodes increased', 'Phenotype', 'HP:0002716', (98, 119))	('lymphoma', 'Disease', (56, 64))	('lymphoma', 'Disease', 'MESH:D008223', (56, 64))	('Rassf10', 'Gene', (10, 17))
31597	32047266	In addition, Rassf1A knockout animals not only developed megaesophagus (reported earlier), but also megaileum/megacolon at a total incidence 16%.	('Rassf1A', 'Gene', '56289', (13, 20))	('Rassf1A', 'Gene', (13, 20))	('megacolon', 'Phenotype', 'HP:0002251', (110, 119))	('knockout', 'Var', (21, 29))	('megaesophagus', 'CPA', (57, 70))	('developed', 'PosReg', (47, 56))
31598	32047266	In the p53-/- tumor-suppressor background, survival analysis by Kaplan-Meier revealed that Rassf10 knockout animals (n = 77; Rassf10+/-/Rassf10-/-) had a reduced survival rate vs. Rassf10+/+ animals (n = 24, Fig.	('tumor', 'Disease', (14, 19))	('Rassf10', 'Gene', (91, 98))	('p53', 'Gene', '22059', (7, 10))	('Rassf10+/-/Rassf10-/-', 'Var', (125, 146))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('14', '30'))	('survival rate', 'CPA', (162, 175))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('14', '30'))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('reduced', 'NegReg', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('p53', 'Gene', (7, 10))
31599	32047266	We observed diseased animals at the following rates (p53-/- background): wt 58% (14/24), Rassf10+/- 81% (30/37), and Rassf10-/- 70% (28/40).	('Rassf10-/-', 'Var', (117, 127))	('p53', 'Gene', '22059', (53, 56))	('p53', 'Gene', (53, 56))	('Rassf10+/-', 'Var', (89, 99))
31600	32047266	Interestingly, enlarged thymus and thymoma were found in 24% Rassf10-/- (8/33), in 46% Rassf10+/- (12/26) but only in 11% Rassf10-wt (2/18) animals, significant regarding Rassf10+/- vs. wt (Table 2; Fig.	('thymus and thymoma', 'Disease', 'MESH:D013945', (24, 42))	('Rassf10+/-', 'Var', (87, 97))	('thymoma', 'Phenotype', 'HP:0100522', (35, 42))	('Rassf10+/-', 'Var', (171, 181))	('Rassf10-/-', 'Var', (61, 71))	('enlarged', 'PosReg', (15, 23))	('enlarged thymus', 'Phenotype', 'HP:0010516', (15, 30))
31603	32047266	The mean thymus weight (all weighed thymus) increased by 87% heterozygous Rassf10 knockout animals (344.8 mg) compared with wildtyp (184.6 mg).	('thymus weight', 'Disease', (9, 22))	('knockout', 'Var', (82, 90))	('Rassf10', 'Gene', (74, 81))	('increased', 'PosReg', (44, 53))	('thymus weight', 'Disease', 'MESH:D015431', (9, 22))
31604	32047266	We also found a more than threefold increased occurrence of kidney cysts in Rassf10 knockout (p53-/-) animals 25% Rassf10-/-, 11% Rassf10+/- vs. 8% wt (Table 2 and Fig.	('Rassf10', 'Gene', (76, 83))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '22059', (94, 97))	('kidney cysts', 'Disease', (60, 72))	('Rassf10-/-', 'Var', (114, 124))	('increased', 'PosReg', (36, 45))	('kidney cysts', 'Phenotype', 'HP:0000107', (60, 72))	('Rassf10+/-', 'Var', (130, 140))
31607	32047266	Tumor-suppressor inactivation in cancer can occur by the loss of function mutation or promoter methylation.	('loss of function', 'NegReg', (57, 73))	('mutation', 'Var', (74, 82))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Tumor-suppressor', 'biological_process', 'GO:0051726', ('0', '16'))	('Tumor-suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Tumor-suppressor', 'CPA', (0, 16))	('methylation', 'biological_process', 'GO:0032259', ('95', '106'))	('promoter methylation', 'Var', (86, 106))
31612	32047266	We found that RASSF10 is epigenetically inactivated by promoter hypermethylation in 60% of kidney cancer cell lines (9/15, Fig.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('kidney cancer', 'Disease', (91, 104))	('RASSF10', 'Gene', (14, 21))	('epigenetically', 'Var', (25, 39))	('kidney cancer', 'Phenotype', 'HP:0009726', (91, 104))	('kidney cancer', 'Disease', 'MESH:D007680', (91, 104))	('promoter hypermethylation', 'Var', (55, 80))
31613	32047266	We could significantly reestablish the expression of RASSF10 by DNMT inhibition treatment with 5-Aza-2'deoxycytidine in MZ1257 and MZ1973 (Fig.	('MZ1257', 'Var', (120, 126))	('MZ1973', 'CellLine', 'CVCL:E046', (131, 137))	('DNMT', 'Gene', (64, 68))	('MZ1257', 'CellLine', 'CVCL:E044', (120, 126))	('DNMT', 'Gene', '13433', (64, 68))	('expression', 'MPA', (39, 49))	('MZ1973', 'Var', (131, 137))	('RASSF10', 'Gene', (53, 60))	('Aza', 'Chemical', 'MESH:D001379', (97, 100))
31614	32047266	Primary tumors of renal clear cell and renal papillary cell carcinoma confirmed that RASSF10 methylation correlated with decreased expression in comparison with normal kidney tissue (Fig.	('RASSF10', 'Gene', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('decreased', 'NegReg', (121, 130))	('methylation', 'biological_process', 'GO:0032259', ('93', '104'))	('expression', 'MPA', (131, 141))	('Primary tumors of renal clear cell and renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 69))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('methylation', 'Var', (93, 104))
31620	32047266	In renal carcinoma (papillary and clear cells) overall survival correlated with high RASSF10 expression (Fig.	('RASSF10', 'Gene', (85, 92))	('renal carcinoma', 'Disease', 'MESH:C538614', (3, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('renal carcinoma', 'Disease', (3, 18))	('renal carcinoma', 'Phenotype', 'HP:0005584', (3, 18))	('expression', 'MPA', (93, 103))	('high', 'Var', (80, 84))
31627	32047266	To gain insight in the molecular processes that are deregulated upon Rassf10 inactivation we utilized mouse embryonic fibroblasts (MEFs) isolated from Rassf10 knockout and wildtype mice.	('mice', 'Species', '10090', (181, 185))	('mouse', 'Species', '10090', (102, 107))	('MEFs', 'CellLine', 'CVCL:9115', (131, 135))	('Rassf10', 'Gene', (151, 158))	('Rassf10', 'Gene', (69, 76))	('knockout', 'Var', (159, 167))	('inactivation', 'Var', (77, 89))
31630	32047266	Other hallmarks that were significantly associated the Rassf1a knockout belong to allograft rejection, inflammatory response, complement, and interferon gamma response gene sets.	('interferon gamma', 'Gene', '15978', (142, 158))	('inflammatory response', 'CPA', (103, 124))	('Rassf1a', 'Gene', '56289', (55, 62))	('interferon gamma', 'Gene', (142, 158))	('allograft rejection', 'CPA', (82, 101))	('inflammatory response', 'biological_process', 'GO:0006954', ('103', '124'))	('Rassf1a', 'Gene', (55, 62))	('knockout', 'Var', (63, 71))	('interferon gamma', 'molecular_function', 'GO:0005133', ('142', '158'))
31631	32047266	These results suggest that upon Rassf10 depletion several oncogenic pathways including RAS signaling are activated.	('Rassf10', 'Gene', (32, 39))	('RA', 'Chemical', 'MESH:D011883', (87, 89))	('depletion', 'Var', (40, 49))	('activated', 'PosReg', (105, 114))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('oncogenic pathways', 'Pathway', (58, 76))	('RAS signaling', 'Pathway', (87, 100))
31636	32047266	In renal clear cell carcinoma, we also detected an inverse correlation between RASSF10 and MYC expression indicating that the loss of RASSF10 is associated with MYC induction (Fig.	('MYC induction', 'Disease', (161, 174))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (3, 29))	('renal clear cell carcinoma', 'Disease', (3, 29))	('associated', 'Reg', (145, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('RASSF10', 'Gene', (134, 141))	('loss', 'Var', (126, 130))
31638	32047266	Interestingly, we found that RASSF10 expression is positively associated with increased CDH1 levels in renal clear cell carcinoma (Fig.	('expression', 'Var', (37, 47))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (103, 129))	('renal clear cell carcinoma', 'Disease', (103, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('increased', 'PosReg', (78, 87))	('CDH1', 'Gene', (88, 92))	('CDH1', 'Gene', '12550', (88, 92))	('RASSF10', 'Gene', (29, 36))
31639	32047266	Our data suggest that MYC and VEGF are negatively regulated by RASSF10 and that combination of high RASSF10 and low MYC or VEGF expression is associated with a favorable prognosis for renal cancer patients.	('patients', 'Species', '9606', (197, 205))	('high', 'Var', (95, 99))	('RASSF10', 'Gene', (63, 70))	('renal cancer', 'Disease', (184, 196))	('RASSF10', 'Gene', (100, 107))	('negatively', 'NegReg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (128, 138))	('renal cancer', 'Disease', 'MESH:D007680', (184, 196))	('renal cancer', 'Phenotype', 'HP:0009726', (184, 196))
31641	32047266	Rassf10 knockout promotes increased numbers of thymoma (p53-/-), cystic kidneys (p53-/-), lymphoma (Rassf1A-/-, p53-/-), and splenomegaly (Rassf1A-/-, p53-/-).	('p53', 'Gene', '22059', (56, 59))	('p53', 'Gene', (81, 84))	('Rassf1A', 'Gene', '56289', (139, 146))	('Rassf1A', 'Gene', (139, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (90, 98))	('splenomegaly', 'Disease', (125, 137))	('p53', 'Gene', (112, 115))	('cystic kidneys', 'Disease', 'MESH:D052177', (65, 79))	('knockout', 'Var', (8, 16))	('p53', 'Gene', (151, 154))	('p53', 'Gene', '22059', (151, 154))	('thymoma', 'Disease', 'MESH:D013945', (47, 54))	('p53', 'Gene', (56, 59))	('splenomegaly', 'Disease', 'MESH:D013163', (125, 137))	('p53', 'Gene', '22059', (81, 84))	('lymphoma', 'Disease', (90, 98))	('increased', 'PosReg', (26, 35))	('cystic kidneys', 'Disease', (65, 79))	('lymphoma', 'Disease', 'MESH:D008223', (90, 98))	('splenomegaly', 'Phenotype', 'HP:0001744', (125, 137))	('Rassf1A', 'Gene', '56289', (100, 107))	('thymoma', 'Disease', (47, 54))	('Rassf1A', 'Gene', (100, 107))	('thymoma', 'Phenotype', 'HP:0100522', (47, 54))	('Rassf10', 'Gene', (0, 7))	('cystic kidneys', 'Phenotype', 'HP:0000107', (65, 79))	('p53', 'Gene', '22059', (112, 115))
31642	32047266	Rassf10 heterozygous animals already suffer from an overall increased disease incidence (Table 2), suggesting Rassf10 is a haploinsufficient tumor suppressor, and the loss of one allele is sufficient for its loss of function and contribution to carcinogenesis.	('tumor suppressor', 'biological_process', 'GO:0051726', ('141', '157'))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('carcinogenesis', 'Disease', (245, 259))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('141', '157'))	('disease incidence', 'CPA', (70, 87))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (123, 146))	('Rassf10', 'Gene', (0, 7))	('haploinsufficient tumor', 'Disease', (123, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (245, 259))	('loss', 'Var', (167, 171))	('increased', 'PosReg', (60, 69))	('Rassf10', 'Gene', (110, 117))	('loss of function', 'NegReg', (208, 224))
31648	32047266	We reported that knockdown of RASSF10 increased mitosis and increased cell proliferation and invasion, as well as RASSF10 reexpression halted proliferation.	('mitosis', 'Disease', (48, 55))	('mitosis', 'Disease', 'None', (48, 55))	('proliferation', 'CPA', (142, 155))	('cell proliferation', 'biological_process', 'GO:0008283', ('70', '88'))	('cell proliferation', 'CPA', (70, 88))	('increased', 'PosReg', (60, 69))	('mitosis', 'biological_process', 'GO:0000278', ('48', '55'))	('RASSF10', 'Gene', (114, 121))	('knockdown', 'Var', (17, 26))	('invasion', 'CPA', (93, 101))	('halted', 'NegReg', (135, 141))	('RASSF10', 'Gene', (30, 37))	('increased', 'PosReg', (38, 47))
31650	32047266	Interestingly, we found that the loss of Rassf10 in MEFs is associated with upregulation of KRAS and IL6/JAK/STAT3 signaling (Fig.	('IL6', 'Gene', '16193', (101, 104))	('upregulation', 'PosReg', (76, 88))	('Rassf10', 'Gene', (41, 48))	('IL6', 'molecular_function', 'GO:0005138', ('101', '104'))	('STAT3', 'Gene', '20848', (109, 114))	('loss', 'Var', (33, 37))	('signaling', 'biological_process', 'GO:0023052', ('115', '124'))	('MEFs', 'CellLine', 'CVCL:9115', (52, 56))	('KRAS', 'MPA', (92, 96))	('STAT3', 'Gene', (109, 114))	('IL6', 'Gene', (101, 104))	('JAK', 'molecular_function', 'GO:0004713', ('105', '108'))
31654	32047266	Across different renal cancer entities, we found a significant epigenetic inactivation of RASSF10 (Figs.	('renal cancer', 'Disease', 'MESH:D007680', (17, 29))	('renal cancer', 'Phenotype', 'HP:0009726', (17, 29))	('epigenetic inactivation', 'Var', (63, 86))	('RASSF10', 'Gene', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('renal cancer', 'Disease', (17, 29))
31655	32047266	In addition, we can exclude mutation events in the inactivation of RASSF10 in cancer (Table S1).	('inactivation', 'Var', (51, 63))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('RASSF10', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
31658	32047266	The successful pharmacological inhibition of DNA methylation restored RASSF10 expression, which we reported earlier in other cancer entities.	('restored', 'PosReg', (61, 69))	('expression', 'MPA', (78, 88))	('inhibition of DNA methylation', 'biological_process', 'GO:1905642', ('31', '60'))	('RASSF10', 'Gene', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('DNA', 'cellular_component', 'GO:0005574', ('45', '48'))	('inhibition', 'Var', (31, 41))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
31659	32047266	We suggest that for the inactivation of the haploinsufficient tumor-suppressor RASSF10 the methylation of one allele is sufficient and found that low methylation levels of RASSF10 already decreased its expression dramatically.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('62', '78'))	('decreased', 'NegReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('RASSF10', 'Gene', (172, 179))	('methylation levels', 'MPA', (150, 168))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (44, 67))	('inactivation', 'Var', (24, 36))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('62', '78'))	('haploinsufficient tumor', 'Disease', (44, 67))	('expression', 'MPA', (202, 212))	('RASSF10', 'Gene', (79, 86))	('methylation', 'biological_process', 'GO:0032259', ('91', '102'))	('methylation', 'MPA', (91, 102))	('methylation', 'biological_process', 'GO:0032259', ('150', '161'))
31661	32047266	Our clinical patient data revealed that the loss of RASSF10 is a common and general event in kidney carcinogenesis (Fig.	('patient', 'Species', '9606', (13, 20))	('kidney carcinogenesis', 'Disease', (93, 114))	('kidney carcinogenesis', 'Disease', 'MESH:D063646', (93, 114))	('RASSF10', 'Gene', (52, 59))	('loss', 'Var', (44, 48))
31664	32047266	Low RASSF10 and high MYC or high VEGF was significantly associated with poor prognosis of renal papillary cell cancer patients and the combination of two markers had a higher impact on impaired probability of survival compared with the low RASSF10 alone (Figs.	('renal papillary cell cancer', 'Disease', (90, 117))	('renal papillary cell cancer', 'Disease', 'MESH:C538614', (90, 117))	('Low RASSF10', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (118, 126))
31671	32047266	An epigenetic assay for RASSF1A methylation in prostate cancer, however, still biopsy based, is available.	('prostate cancer', 'Phenotype', 'HP:0012125', (47, 62))	('methylation', 'Var', (32, 43))	('RASSF1A', 'Gene', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('methylation', 'biological_process', 'GO:0032259', ('32', '43'))	('prostate cancer', 'Disease', (47, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (47, 62))
31672	32047266	We could show that epigenetic editing of RASSF10 is possible, and one could think of targeted therapies in the future using virally applied CRISPR-Cas9 Epigenetic Editors to patients for reactivation of e.g.	('epigenetic', 'Var', (19, 29))	('patients', 'Species', '9606', (174, 182))	('RASSF10', 'Gene', (41, 48))	('Cas', 'cellular_component', 'GO:0005650', ('147', '150'))
31673	32047266	hypermethylated RASSF10 specifically in cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('RASSF10', 'Gene', (16, 23))	('hypermethylated', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
31686	32047266	At first mouse Rassf10 was cloned into pCMVTag1, linearized by digestion with ApaL1, Rassf10 was transcribed by T7 polymerase, and thereby Rassf10-RNA labeled with the RNA Labeling DIG Kit (Roche), and followed by Rassf10-RNA probe purification.	('RNA', 'cellular_component', 'GO:0005562', ('168', '171'))	('RNA', 'cellular_component', 'GO:0005562', ('222', '225'))	('Rassf10-RNA', 'Var', (139, 150))	('Rassf10', 'Gene', (85, 92))	('mouse', 'Species', '10090', (9, 14))	('Kit', 'Gene', '16590', (185, 188))	('digestion', 'biological_process', 'GO:0007586', ('63', '72'))	('RNA', 'cellular_component', 'GO:0005562', ('147', '150'))	('Kit', 'Gene', (185, 188))
31696	32047266	Reagents/equipments were GeneChip  WT PLUS Reagent Kit, P/N: 902280; GeneChip  Hybridization, Wash, and Stain Kit P/N 900720, GeneChip Scanner, GeneChip Fluidics Station 450, GeneChip Hybridization Oven 640, Bioanalyzer 2100 (Agilent) and RNA600 NanoKit (Agilent).	('Kit', 'Gene', '16590', (250, 253))	('Kit', 'Gene', (51, 54))	('Kit', 'Gene', (110, 113))	('P/N', 'Var', (114, 117))	('Kit', 'Gene', (250, 253))	('RNA', 'cellular_component', 'GO:0005562', ('239', '242'))	('Kit', 'Gene', '16590', (51, 54))	('Kit', 'Gene', '16590', (110, 113))
31704	32047266	The following antibodies were used: a-GAPDH (FL335, sc-25778 from Santa Cruz), a-RASSF10 (AP12444c-ev2020, Abgent), and HRP-coupled secondary antibodies anti-rabbit (sc2004, sc2357, Santa Cruz).	('FL335', 'Var', (45, 50))	('AP12444c-ev2020', 'Var', (90, 105))	('GAPDH', 'Gene', (38, 43))	('sc2004', 'Var', (166, 172))	('GAPDH', 'Gene', '14433', (38, 43))
31717	31627266	Additionally, a growing body of evidence supports the role of long non-coding RNAs (lncRNAs) in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('progression', 'CPA', (119, 130))	('long non-coding RNAs', 'Var', (62, 82))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
31718	31627266	Most studies on non-coding RNAs in RCC focus on clear-cell histology, and there is a relatively limited number of studies on non-ccRCC subtypes.	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Disease', (35, 38))	('ccRCC', 'Phenotype', 'HP:0006770', (129, 134))	('ccRCC', 'Disease', (129, 134))	('non-coding RNAs', 'Var', (16, 31))	('RCC', 'Disease', 'MESH:D002292', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Phenotype', 'HP:0005584', (131, 134))	('ccRCC', 'Disease', 'MESH:D002292', (129, 134))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))
31719	31627266	The aim of this review is to give an overview of the current knowledge regarding the role of non-coding RNAs (including short and long non-coding RNAs) in non-ccRCC and to highlight possible implications as diagnostic, prognostic and predictive biomarkers.	('short and long non-coding RNAs', 'Var', (120, 150))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (159, 164))	('ccRCC', 'Disease', (159, 164))	('ccRCC', 'Disease', 'MESH:D002292', (159, 164))
31744	31627266	The present review aims to summarize the current literature of non-coding RNA research in five non-clear cell RCC histologies and to focus on their potential clinical implementations in diagnosis, prognosis and therapy.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('non-coding', 'Var', (63, 73))	('RCC', 'Disease', 'MESH:D002292', (110, 113))	('RNA', 'cellular_component', 'GO:0005562', ('74', '77'))
31746	31627266	Studies that investigated non-coding RNAs in at least one non-clear cell RCC subtype were included in this review.	('non-coding RNAs', 'Var', (26, 41))	('RCC', 'Disease', 'MESH:D002292', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
31749	31627266	In addition, MET mutations are common in type 1 tumors.	('common', 'Reg', (31, 37))	('MET mutations', 'Var', (13, 26))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
31750	31627266	In type 2, CDKN2A alterations, either by mutations or by hypermethylation, occur frequently.	('mutations', 'Var', (41, 50))	('alterations', 'Reg', (18, 29))	('CDKN2A', 'Gene', (11, 17))	('hypermethylation', 'Var', (57, 73))	('CDKN2A', 'Gene', '1029', (11, 17))
31757	31627266	In addition, in pRCC, increased miR-21 expression (gene locus 17q23.1) is linked to copy number changes of the genome, since pRCC cells feature a high frequency of trisomy 17 and, therefore, an increase of the related gene products.	('pRCC', 'Gene', (16, 20))	('pRCC', 'Gene', '5546', (125, 129))	('miR-21', 'Gene', '406991', (32, 38))	('increase', 'PosReg', (194, 202))	('increased', 'PosReg', (22, 31))	('trisomy 17', 'Var', (164, 174))	('pRCC', 'Gene', (125, 129))	('miR-21', 'Gene', (32, 38))	('pRCC', 'Gene', '5546', (16, 20))	('expression', 'MPA', (39, 49))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))
31758	31627266	As mentioned earlier, numerical chromosomal alterations are more frequently associated with type 1 pRCC.	('numerical chromosomal alterations', 'Var', (22, 55))	('pRCC', 'Gene', (99, 103))	('associated', 'Reg', (76, 86))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
31773	31627266	In the first step, the miRNAs used to distinguish between healthy and tumor tissue were miR-145, miR-200c, miR-210 and mi-R502-3p.	('miR-200c', 'Gene', (97, 105))	('miR', 'Gene', (88, 91))	('miR', 'Gene', '220972', (23, 26))	('miR-200c', 'Gene', '406985', (97, 105))	('miR-210', 'Gene', (107, 114))	('miR', 'Gene', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-210', 'Gene', '406992', (107, 114))	('tumor', 'Disease', (70, 75))	('miR-145', 'Gene', (88, 95))	('mi-R502-3p', 'Var', (119, 129))	('miR-145', 'Gene', '406937', (88, 95))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('miR', 'Gene', '220972', (88, 91))
31778	31627266	Nonetheless, higher HIF1alpha levels and, consequently, elevated miR-210 expression may also occur in non-hypoxic states due to mutations of the Von Hippel Lindau (VHL) gene, which leads to insufficient HIF1alpha-degradation.	('miR-210', 'Gene', '406992', (65, 72))	('elevated', 'PosReg', (56, 64))	('hypoxic', 'Disease', (106, 113))	('VHL', 'Disease', (164, 167))	('hypoxic', 'Disease', 'MESH:D000860', (106, 113))	('mutations', 'Var', (128, 137))	('Von Hippel Lindau', 'Gene', (145, 162))	('HIF1alpha', 'Gene', (20, 29))	('VHL', 'Disease', 'MESH:D006623', (164, 167))	('degradation', 'biological_process', 'GO:0009056', ('213', '224'))	('higher', 'PosReg', (13, 19))	('HIF1alpha', 'Gene', (203, 212))	('Von Hippel Lindau', 'Gene', '7428', (145, 162))	('expression', 'MPA', (73, 83))	('HIF1alpha', 'Gene', '3091', (203, 212))	('HIF1alpha', 'Gene', '3091', (20, 29))	('miR-210', 'Gene', (65, 72))
31873	31627266	Xp11 translocation RCC is the most common renal neoplasm in children.	('Xp11 translocation', 'Var', (0, 18))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('RCC', 'Disease', 'MESH:D002292', (19, 22))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('children', 'Species', '9606', (60, 68))	('renal neoplasm', 'Disease', (42, 56))	('renal neoplasm', 'Disease', 'MESH:D007680', (42, 56))	('renal neoplasm', 'Phenotype', 'HP:0009726', (42, 56))
31874	31627266	Xp11 RCCs show characteristic chromosomal translocations at a breaking point:the locus Xp11.2:resulting in a distinctive gene fusion including the TFE3 transcription factor gene.	('TFE3 transcription factor gene', 'Gene', (147, 177))	('RCC', 'Disease', 'MESH:D002292', (5, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('locus', 'Var', (81, 86))	('breaking point', 'Phenotype', 'HP:0001061', (62, 76))	('transcription', 'biological_process', 'GO:0006351', ('152', '165'))	('gene fusion', 'MPA', (121, 132))	('transcription factor', 'molecular_function', 'GO:0000981', ('152', '172'))
31879	31627266	Mutations of the putative promoter region of the lncRNA NEAT1 (nuclear-enriched abundant transcript 1) were found in 17% of pRCC.	('found', 'Reg', (108, 113))	('pRCC', 'Gene', '5546', (124, 128))	('nuclear-enriched abundant transcript 1', 'Gene', '283131', (63, 101))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('NEAT1', 'Gene', '283131', (56, 61))	('Mutations', 'Var', (0, 9))	('pRCC', 'Gene', (124, 128))	('NEAT1', 'Gene', (56, 61))	('nuclear-enriched abundant transcript 1', 'Gene', (63, 101))
31888	31627266	Furthermore, high levels of lncRNAs AC003092.1, RP6-191P20.4, RP11-401P9.4 and RP11-496D24.2 correlated with worse prognosis.	('RP11', 'Gene', (62, 66))	('AC003092.1', 'Var', (36, 46))	('RP6-191P20.4', 'Var', (48, 60))	('RP11', 'Gene', '26121', (62, 66))	('RP11', 'Gene', '26121', (79, 83))	('RP11', 'Gene', (79, 83))
31899	31627266	The lncRNAs included in the signature are AC003092.1, AC079160.1, COL18A1-AS1, LINC00520, LINC02154 and SLC7A11-AS1.	('AC079160.1', 'Var', (54, 64))	('COL18A1-AS1', 'Gene', '378832', (66, 77))	('COL18A1-AS1', 'Gene', (66, 77))	('SLC7A11-AS1', 'Gene', '641364', (104, 115))	('LINC02154', 'Var', (90, 99))	('AC003092.1', 'Var', (42, 52))	('LINC00520', 'Gene', '645687', (79, 88))	('LINC02154', 'Chemical', 'None', (90, 99))	('LINC00520', 'Gene', (79, 88))	('SLC7A11-AS1', 'Gene', (104, 115))
31914	27467134	The genomic characterization of renal cell carcinoma (RCC) has significantly evolved since clear cell renal cell carcinoma (ccRCC) was defined simply by alterations in the von Hippel-Lindau (VHL) tumor suppressor gene.	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (91, 122))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('alterations', 'Var', (153, 164))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('196', '212'))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('renal cell carcinoma', 'Disease', (32, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('tumor suppressor', 'biological_process', 'GO:0051726', ('196', '212'))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (172, 201))	('RCC', 'Disease', (54, 57))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('renal cell carcinoma', 'Disease', (102, 122))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('RCC', 'Disease', (126, 129))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (124, 129))
31927	27467134	Chromosomal 3p loss is another ubiquitous finding in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (55, 58))	('ccRCC', 'Phenotype', 'HP:0006770', (53, 58))	('RCC', 'Disease', (55, 58))	('Chromosomal 3p loss', 'Var', (0, 19))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))
31929	27467134	The stratification of patients with ccRCC on the basis of mutations in BAP1 and PBRM1 has been shown to correlate with clinical outcomes in localized disease.	('PBRM1', 'Gene', '55193', (80, 85))	('mutations', 'Var', (58, 67))	('RCC', 'Disease', (38, 41))	('localized disease', 'Disease', (140, 157))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('patients', 'Species', '9606', (22, 30))	('BAP1', 'Gene', '8314', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('PBRM1', 'Gene', (80, 85))	('correlate', 'Reg', (104, 113))	('BAP1', 'Gene', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
31932	27467134	For example, patients with metastatic disease and a mutation in mammalian target of rapamycin (MTOR) can show exceptional response to targeted agents such as everolimus.	('mammalian target of rapamycin', 'Gene', '2475', (64, 93))	('mammalian target of rapamycin', 'Gene', (64, 93))	('patients', 'Species', '9606', (13, 21))	('response', 'MPA', (122, 130))	('MTOR', 'Gene', (95, 99))	('metastatic disease', 'Disease', (27, 45))	('mutation', 'Var', (52, 60))	('everolimus', 'Chemical', 'MESH:D000068338', (158, 168))	('MTOR', 'Gene', '2475', (95, 99))
31934	27467134	Unfortunately, mutations in the mTOR signaling pathway are seen in only a minority of patients with RCC.	('signaling pathway', 'biological_process', 'GO:0007165', ('37', '54'))	('mTOR', 'Gene', '2475', (32, 36))	('mutations', 'Var', (15, 24))	('mTOR', 'Gene', (32, 36))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('patients', 'Species', '9606', (86, 94))
31935	27467134	A recently published report on the RECORD-3 study, and another on correlations between molecular subclassifications of ccRCC and targeted therapy response highlight several other possible mutations associated with treatment response in the metastatic setting, including BAP1, PBRM1, lysine (k)-specific demethylase 5C (KDM5C), tuberous sclerosis 1 (TSC1) and tuberous sclerosis 2 (TSC2) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA).	('TSC2', 'Gene', (381, 385))	('tuberous sclerosis 1', 'Gene', (327, 347))	('tuberous sclerosis 1', 'Gene', '7248', (327, 347))	('associated', 'Reg', (198, 208))	('BAP1', 'Gene', (270, 274))	('PBRM1', 'Gene', '55193', (276, 281))	('PIK3CA', 'Gene', (463, 469))	('KDM5C', 'Gene', '8242', (319, 324))	('tuberous sclerosis 2', 'Gene', (359, 379))	('PBRM1', 'Gene', (276, 281))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('TSC1', 'Gene', (349, 353))	('mutations', 'Var', (188, 197))	('tuberous sclerosis 2', 'Gene', '7249', (359, 379))	('TSC2', 'Gene', '7249', (381, 385))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('TSC1', 'Gene', '7248', (349, 353))	('BAP1', 'Gene', '8314', (270, 274))	('KDM5C', 'Gene', (319, 324))	('PIK3CA', 'Gene', '5290', (463, 469))	('lysine (k)-specific demethylase 5C', 'Gene', '8242', (283, 317))
31941	27467134	Alterations in several cancer-associated pathways were found across the spectrum of pRCC tumors, including alterations in the Hippo signaling pathway (mutations in the NF2 [neurofibromin 2] gene), in the SWI/SNF complex (PBRM1 and SMARCB1 [SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1]) and in several chromatin modifier pathways (SETD2, BAP1, and KDM6A [lysine (k)-specific demethylase 6A]).	('pRCC', 'Gene', (84, 88))	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('204', '219'))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('BAP1', 'Gene', '8314', (387, 391))	('chromatin', 'cellular_component', 'GO:0000785', ('303', '312'))	('PBRM1', 'Gene', '55193', (221, 226))	('NF2', 'Gene', (168, 171))	('chromatin modifier pathways', 'Pathway', (351, 378))	('KDM6A', 'Gene', (397, 402))	('Hippo signaling pathway', 'Pathway', (126, 149))	('PBRM1', 'Gene', (221, 226))	('Alterations', 'Reg', (0, 11))	('mutations', 'Var', (151, 160))	('BAP1', 'Gene', (387, 391))	('SMARCB1', 'Gene', '6598', (231, 238))	('alterations', 'Reg', (107, 118))	('SETD2', 'Gene', (380, 385))	('SMARCB1', 'Gene', (231, 238))	('cancer', 'Disease', (23, 29))	('pRCC', 'Gene', '5546', (84, 88))	('RCC tumors', 'Disease', (85, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('351', '360'))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1', 'Gene', '6598', (240, 333))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neurofibromin 2', 'Gene', '4771', (173, 188))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('neurofibromin 2', 'Gene', (173, 188))	('RCC tumors', 'Disease', 'MESH:C538614', (85, 95))	('SETD2', 'Gene', '29072', (380, 385))	('Hippo signaling pathway', 'biological_process', 'GO:0035329', ('126', '149'))	('NF2', 'Gene', '4771', (168, 171))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('pRCC', 'Phenotype', 'HP:0006766', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('KDM6A', 'Gene', '7403', (397, 402))
31944	27467134	At the molecular and metabolic level many of these tumors have germline or somatic mutations in fumarate hydratase (FH).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('germline', 'Var', (63, 71))	('tumors', 'Disease', (51, 57))	('fumarate hydratase', 'Gene', '2271', (96, 114))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('FH', 'Gene', '2271', (116, 118))	('fumarate hydratase', 'Gene', (96, 114))
31945	27467134	Patients with germline FH mutations can develop hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome.	('renal cell cancer', 'Phenotype', 'HP:0005584', (78, 95))	('FH', 'Gene', '2271', (23, 25))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('mutations', 'Var', (26, 35))	('Patients', 'Species', '9606', (0, 8))	('germline', 'Var', (14, 22))	('develop', 'Reg', (40, 47))	('hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome', 'Disease', 'MESH:C535516', (48, 112))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
31947	27467134	The TCGA study also noted poor outcomes for patients with alterations in cyclin-dependent kinase inhibitor 2A (CDKN2A).	('cyclin-dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('73', '106'))	('patients', 'Species', '9606', (44, 52))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (73, 109))	('CDKN2A', 'Gene', (111, 117))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('90', '106'))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (73, 109))	('CDKN2A', 'Gene', '1029', (111, 117))	('alterations', 'Var', (58, 69))
31948	27467134	A more surprising result from the TCGA study was the finding that a large number of their adult cohort of patients with pRCC type 2 were identified as having mutations or fusions in their transcription factor binding to IGHM enhancer 3 (TFE3) or transcription factor EB (TFEB) genes.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('transcription', 'biological_process', 'GO:0006351', ('246', '259'))	('transcription factor', 'molecular_function', 'GO:0000981', ('246', '266'))	('transcription factor', 'MPA', (188, 208))	('pRCC', 'Gene', (120, 124))	('TFE3', 'Gene', '7030', (237, 241))	('TFEB', 'Gene', '7942', (271, 275))	('TFEB', 'Gene', (271, 275))	('transcription', 'biological_process', 'GO:0006351', ('188', '201'))	('transcription factor EB', 'Gene', '7942', (246, 269))	('patients', 'Species', '9606', (106, 114))	('fusions', 'Var', (171, 178))	('pRCC', 'Gene', '5546', (120, 124))	('pRCC', 'Phenotype', 'HP:0006766', (120, 124))	('mutations', 'Var', (158, 167))	('TFE3', 'Gene', (237, 241))	('transcription factor EB', 'Gene', (246, 269))	('transcription factor binding', 'molecular_function', 'GO:0008134', ('188', '216'))
31950	27467134	While germline mutations in MET occur in patients with hereditary papillary renal cell carcinoma, the high number of somatic alterations in MET for patients with spontaneous pRCC tumors presents a possible therapeutic target in select cases.	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 96))	('patients', 'Species', '9606', (148, 156))	('RCC tumors', 'Disease', 'MESH:C538614', (175, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('pRCC', 'Gene', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('RCC tumors', 'Disease', (175, 185))	('germline mutations', 'Var', (6, 24))	('patients', 'Species', '9606', (41, 49))	('MET', 'Gene', (28, 31))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (66, 96))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('occur', 'Reg', (32, 37))	('hereditary papillary renal cell carcinoma', 'Disease', (55, 96))	('pRCC', 'Phenotype', 'HP:0006766', (174, 178))	('pRCC', 'Gene', '5546', (174, 178))
31952	27467134	Mutations or amplifications of this gene typically result in it's over activation in pRCC tumors.	('RCC tumors', 'Disease', (86, 96))	('over activation', 'PosReg', (66, 81))	('amplifications', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('pRCC', 'Gene', (85, 89))	('RCC tumors', 'Disease', 'MESH:C538614', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Mutations', 'Var', (0, 9))	('pRCC', 'Phenotype', 'HP:0006766', (85, 89))	('pRCC', 'Gene', '5546', (85, 89))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('result in', 'Reg', (51, 60))
31960	27467134	In a cohort of 37 patients with metastatic chRCC, enrichment for these mutations was seen with TP53 mutations rising to 61% and PTEN to 27%.	('mutations', 'Var', (100, 109))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('rising', 'PosReg', (110, 116))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('RCC', 'Disease', (45, 48))	('patients', 'Species', '9606', (18, 26))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
31962	27467134	These TERT promoter alterations, which many times lead to increased TERT expression, are being investigated in several other malignancies and may represent a unique or enhanced pathway for tumorigenesis.	('alterations', 'Var', (20, 31))	('tumor', 'Disease', (189, 194))	('increased', 'PosReg', (58, 67))	('TERT', 'Gene', (68, 72))	('TERT', 'Gene', '7015', (68, 72))	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (6, 10))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('malignancies', 'Disease', (125, 137))
31966	27467134	Several investigators have identified alterations in the tumor suppressor gene SMARCB1 to be frequently associated with RMC tumors, with sensitivity ranging from 30% to 100%.	('RMC tumors', 'Disease', (120, 130))	('SMARCB1', 'Gene', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('57', '73'))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (124, 129))	('RMC tumors', 'Disease', 'MESH:D009369', (120, 130))	('associated', 'Reg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('alterations', 'Var', (38, 49))	('tumor suppressor', 'biological_process', 'GO:0051726', ('57', '73'))	('tumor', 'Disease', (57, 62))	('SMARCB1', 'Gene', '6598', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
31967	27467134	Loss of SMARCB1 in RMC tumors has also been associated with increased levels of EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit), which may represent a possible actionable target.	('SMARCB1', 'Gene', '6598', (8, 15))	('SMARCB1', 'Gene', (8, 15))	('RMC tumors', 'Disease', 'MESH:D009369', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('EZH2', 'Gene', (80, 84))	('EZH2', 'Gene', '2146', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('Loss', 'Var', (0, 4))	('increased', 'PosReg', (60, 69))	('RMC tumors', 'Disease', (19, 29))
31970	27467134	Both studies reported an enrichment of TP53 mutations (42.3% in Malouf et al, 31.5% in Bi et al) within tumor regions with sarcomatoid differentiation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sarcomatoid', 'Disease', 'MESH:C538614', (123, 134))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('sarcomatoid', 'Disease', (123, 134))	('TP53', 'Gene', (39, 43))
31971	27467134	A third study reported no TP53 mutations in seven cases of ccRCC with sarcomatoid differentiation that underwent whole genome sequencing.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('sarcomatoid', 'Disease', (70, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('sarcomatoid', 'Disease', 'MESH:C538614', (70, 81))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('TP53', 'Gene', '7157', (26, 30))
31972	27467134	Enrichment of other somatic mutations in these tumors was also identified but will need to be reproduced in larger cohort studies before their significance can be fully evaluated.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (28, 37))
31991	33154194	Method: Gene expression matrix and clinical data were obtained from TCGA (The Cancer Genome Atlas), GSE26574, GSE2048, and GSE7023.	('GSE2048', 'Var', (110, 117))	('Cancer', 'Disease', (78, 84))	('GSE', 'Chemical', '-', (100, 103))	('GSE', 'Chemical', '-', (110, 113))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('GSE26574', 'Var', (100, 108))	('GSE7023', 'Var', (123, 130))	('GSE2048', 'Chemical', '-', (110, 117))	('TCGA', 'Gene', (68, 72))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Gene expression', 'biological_process', 'GO:0010467', ('8', '23'))	('GSE7023', 'Chemical', '-', (123, 130))	('GSE', 'Chemical', '-', (123, 126))
32045	33154194	The results of transwell assays showed that Knockdown of TPX2 inhibited cell migration (Figure 11G and 11H).	('Knockdown', 'Var', (44, 53))	('TPX2', 'Gene', (57, 61))	('cell migration', 'CPA', (72, 86))	('cell migration', 'biological_process', 'GO:0016477', ('72', '86'))	('TPX2', 'Gene', '22974', (57, 61))	('inhibited', 'NegReg', (62, 71))
32062	33154194	In the TPX2 co-expression module, the synergistic effect between CENPF and FOXM1 were found to activate prostate malignancies; experimental verification showed that the synergistic effect of FOXM1 and CENPF promoted tumor growth by activating key signaling pathways and acted as an important marker of tumor prognosis and survival.	('prostate malignancies', 'Disease', (104, 125))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('key signaling pathways', 'Pathway', (243, 265))	('tumor', 'Disease', (216, 221))	('prostate malignancies', 'Disease', 'MESH:D011471', (104, 125))	('FOXM1', 'Gene', '2305', (191, 196))	('FOXM1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('synergistic', 'Var', (169, 180))	('prostate malignancies', 'Phenotype', 'HP:0100787', (104, 125))	('CENPF', 'Gene', (65, 70))	('tumor', 'Disease', (302, 307))	('CENPF', 'Gene', '1063', (65, 70))	('TPX2', 'Gene', (7, 11))	('promoted', 'PosReg', (207, 215))	('activate', 'PosReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CENPF', 'Gene', (201, 206))	('TPX2', 'Gene', '22974', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('CENPF', 'Gene', '1063', (201, 206))	('FOXM1', 'Gene', '2305', (75, 80))	('FOXM1', 'Gene', (191, 196))	('activating', 'PosReg', (232, 242))
32067	33154194	suggested TXNRD2 polymorphisms acted as the protective factors of gastric cancer.	('TXNRD2', 'Gene', '10587', (10, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('polymorphisms', 'Var', (17, 30))	('TXNRD2', 'Gene', (10, 16))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
32076	33154194	It is currently believed that tumors with high mutation burden are more likely to be detected and killed by the immune system, and to generate a stronger immune response.	('high mutation burden', 'Var', (42, 62))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('immune response', 'CPA', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('stronger', 'PosReg', (145, 153))	('immune response', 'biological_process', 'GO:0006955', ('154', '169'))
32120	32022527	This test specifically genotyped single nucleotide polymorphisms (SNPs) that were relevant to: (a) pharmaceutical drug response (b) genetic diseases and (c) complex diseases.	('genetic diseases', 'Disease', (132, 148))	('single nucleotide polymorphisms', 'Var', (33, 64))	('genetic diseases', 'Disease', 'MESH:D030342', (132, 148))
32126	32022527	The other two (rs8065832 y rs2018781) are located near splicing sites, which makes them clinically relevant but still unknown.	('rs8065832', 'Mutation', 'rs8065832', (15, 24))	('rs2018781', 'Mutation', 'rs2018781', (27, 36))	('rs2018781', 'Var', (27, 36))	('splicing', 'biological_process', 'GO:0045292', ('55', '63'))	('rs8065832', 'Var', (15, 24))
32129	32022527	The in silico analyses (Table-3) predicted that the variant rs2018781 most likely has probably no impact on splicing.	('rs2018781', 'Var', (60, 69))	('splicing', 'MPA', (108, 116))	('rs2018781', 'Mutation', 'rs2018781', (60, 69))	('splicing', 'biological_process', 'GO:0045292', ('108', '116'))
32130	32022527	However, for the variant rs8065832, two of the algorithms predicted a higher score than the natural splicing site score (> 10%).	('splicing', 'biological_process', 'GO:0045292', ('100', '108'))	('rs8065832', 'Var', (25, 34))	('higher', 'PosReg', (70, 76))	('score', 'MPA', (77, 82))	('rs8065832', 'Mutation', 'rs8065832', (25, 34))
32135	32022527	The patient was classified as having right clear cell carcinoma (T1aN0M0) and left papillary-type renal carcinoma (T1aN0M0).	('left papillary-type renal carcinoma', 'Disease', (78, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('papillary-type renal carcinoma', 'Phenotype', 'HP:0006766', (83, 113))	('patient', 'Species', '9606', (4, 11))	('T1aN0M0', 'Var', (65, 72))	('right clear cell carcinoma', 'Disease', (37, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (98, 113))	('T1aN0M0', 'Var', (115, 122))	('left papillary-type renal carcinoma', 'Disease', 'MESH:C538614', (78, 113))	('right clear cell carcinoma', 'Disease', 'MESH:C538614', (37, 63))
32139	32022527	The only exception was a variant in the FLCN gene, c.1062+6C>T (rs8065832).	('c.1062+6C>T', 'Mutation', 'rs8065832', (51, 62))	('FLCN', 'Gene', '201163', (40, 44))	('c.1062+6C>T', 'Var', (51, 62))	('FLCN', 'Gene', (40, 44))	('rs8065832', 'Mutation', 'rs8065832', (64, 73))
32154	32022527	As previously mentioned, mutations in VHL, MET, FH, and FLCN genes have been associated with von Hippel-Lindau (VHL)-mediated ccRCC, hereditary type I pRCC, hereditary leiomyomatosis, type II pRCC and BHD.	('MET', 'Gene', (43, 46))	('FLCN', 'Gene', (56, 60))	('von Hippel-Lindau', 'Gene', (93, 110))	('VHL', 'Gene', '7428', (112, 115))	('VHL', 'Gene', (38, 41))	('mutations', 'Var', (25, 34))	('RCC', 'Disease', (193, 196))	('RCC', 'Phenotype', 'HP:0005584', (193, 196))	('hereditary type I pRCC, hereditary leiomyomatosis, type II pRCC', 'Disease', 'MESH:C535516', (133, 196))	('von Hippel-Lindau', 'Gene', '7428', (93, 110))	('VHL', 'Gene', '7428', (38, 41))	('associated', 'Reg', (77, 87))	('RCC', 'Disease', (128, 131))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('BHD', 'Disease', 'MESH:C564185', (201, 204))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('VHL', 'Gene', (112, 115))	('BHD', 'Disease', (201, 204))	('FLCN', 'Gene', '201163', (56, 60))
32155	32022527	The most common form of sporadic ccRCC showed that VHL is affected by loss of heterozygosity at chromosome 3p in 90% of cases.	('RCC', 'Disease', (35, 38))	('VHL', 'Gene', '7428', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (35, 38))	('loss of heterozygosity', 'Var', (70, 92))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('VHL', 'Gene', (51, 54))	('RCC', 'Disease', 'MESH:C538614', (35, 38))
32156	32022527	However, somatic mutations or epigenetic silencing have been reported in >80% of these tumors, which is not surprising considering that this gene is a major driver of ccRCC pathogenesis.	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('RCC', 'Disease', (169, 172))	('pathogenesis', 'biological_process', 'GO:0009405', ('173', '185'))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('epigenetic silencing', 'Var', (30, 50))	('reported', 'Reg', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
32159	32022527	In our patient, we have found an intronic variant (rs8065832) that potentially affects the splicing of the FLCN gene, which has been associated with BHD syndrome.	('rs8065832', 'Mutation', 'rs8065832', (51, 60))	('splicing', 'MPA', (91, 99))	('BHD syndrome', 'Disease', (149, 161))	('patient', 'Species', '9606', (7, 14))	('splicing', 'biological_process', 'GO:0045292', ('91', '99'))	('FLCN', 'Gene', (107, 111))	('rs8065832', 'Var', (51, 60))	('affects', 'Reg', (79, 86))	('FLCN', 'Gene', '201163', (107, 111))	('BHD syndrome', 'Disease', 'MESH:C564185', (149, 161))	('associated', 'Reg', (133, 143))
32162	32022527	They also found this variant had a higher frequency among CRC cases compared to control patients (p=0.055), which suggests that this variant is in linkage disequilibrium with other pathogenic variants.	('CRC', 'Phenotype', 'HP:0003003', (58, 61))	('CRC', 'Disease', 'MESH:D015179', (58, 61))	('patients', 'Species', '9606', (88, 96))	('variant', 'Var', (133, 140))	('CRC', 'Disease', (58, 61))
32163	32022527	In this patient, the FLCN gene variant was not associated with other clinical symptoms usually related with FLCN mutation and BHD syndrome.	('FLCN', 'Gene', (21, 25))	('BHD syndrome', 'Disease', 'MESH:C564185', (126, 138))	('FLCN', 'Gene', (108, 112))	('FLCN', 'Gene', '201163', (21, 25))	('BHD syndrome', 'Disease', (126, 138))	('patient', 'Species', '9606', (8, 15))	('FLCN', 'Gene', '201163', (108, 112))	('variant', 'Var', (31, 38))
32165	32022527	have investigated the mutation in the tumor suppressor gene FLCN that is associated with renal cancer, but additional functional and biochemical validation are required to guide further research regarding the role of FCLN in RCC development.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('renal cancer', 'Disease', (89, 101))	('FLCN', 'Gene', '201163', (60, 64))	('mutation', 'Var', (22, 30))	('FCLN', 'Chemical', '-', (217, 221))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('38', '54'))	('RCC', 'Disease', (225, 228))	('renal cancer', 'Phenotype', 'HP:0009726', (89, 101))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('renal cancer', 'Disease', 'MESH:D007680', (89, 101))	('associated', 'Reg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('FLCN', 'Gene', (60, 64))	('tumor suppressor', 'biological_process', 'GO:0051726', ('38', '54'))
32167	32022527	We found that variant rs6983267 and the G/G genotype found in the patient is associated with higher risk of not only colorectal cancer, but an increased risk of thyroid, prostate, lung and renal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('rs6983267', 'Mutation', 'rs6983267', (22, 31))	('thyroid', 'Disease', (161, 168))	('renal cancer', 'Disease', (189, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('lung', 'Disease', (180, 184))	('renal cancer', 'Phenotype', 'HP:0009726', (189, 201))	('patient', 'Species', '9606', (66, 73))	('colorectal cancer', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('renal cancer', 'Disease', 'MESH:D007680', (189, 201))	('variant rs6983267', 'Var', (14, 31))	('prostate', 'Disease', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
32170	32022527	Since variant has a high frequency in some populations, it is possible that this variant might be a low-penetrance cancer susceptibility allele.	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('variant', 'Var', (6, 13))
32171	32022527	The patient has the G/G genotype for rs6983267, which has been associated a higher risk for developing CRC and renal cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patient', 'Species', '9606', (4, 11))	('renal cancer', 'Disease', (111, 123))	('rs6983267', 'Var', (37, 46))	('CRC', 'Disease', 'MESH:D015179', (103, 106))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('renal cancer', 'Phenotype', 'HP:0009726', (111, 123))	('renal cancer', 'Disease', 'MESH:D007680', (111, 123))	('CRC', 'Disease', (103, 106))	('rs6983267', 'Mutation', 'rs6983267', (37, 46))
32172	32022527	To our knowledge, these polymorphisms (rs8065832 and rs6983267) have not been described previously in the context of ccRCC or pRCC.	('rs8065832', 'Var', (39, 48))	('rs6983267', 'Mutation', 'rs6983267', (53, 62))	('pRCC', 'Gene', (126, 130))	('rs8065832', 'Mutation', 'rs8065832', (39, 48))	('rs6983267', 'Var', (53, 62))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('RCC', 'Disease', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('pRCC', 'Gene', '5546', (126, 130))
32174	32022527	Although these results are promising, future research is necessary to establish the role of FLCN variants rs8065832, and rs6983267 in regard to increasing susceptibility to renal cancer.	('variants rs8065832', 'Var', (97, 115))	('renal cancer', 'Disease', 'MESH:D007680', (173, 185))	('rs6983267', 'Var', (121, 130))	('FLCN', 'Gene', '201163', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('rs8065832', 'Var', (106, 115))	('rs6983267', 'Mutation', 'rs6983267', (121, 130))	('rs8065832', 'Mutation', 'rs8065832', (106, 115))	('renal cancer', 'Disease', (173, 185))	('FLCN', 'Gene', (92, 96))	('renal cancer', 'Phenotype', 'HP:0009726', (173, 185))
32179	27330105	Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes.	('mutations', 'Var', (91, 100))	('metabolic dysregulation', 'Disease', 'MESH:D021081', (56, 79))	('chromatin modifier genes', 'Gene', (104, 128))	('chromatin', 'cellular_component', 'GO:0000785', ('104', '113'))	('metabolic dysregulation', 'Disease', (56, 79))
32200	27330105	This tumor type is well known to overlap significantly with the ccRCC occurring in the setting of von Hippel-Lindau (VHL) disease, and indeed, mutation of the VHL gene which causes VHL disease is observed in up to 90% of sporadic cases of this cancer.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('VHL disease', 'Disease', 'MESH:D006623', (181, 192))	('VHL', 'Gene', (181, 184))	('RCC', 'Disease', (66, 69))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('VHL', 'Gene', (117, 120))	('VHL disease', 'Disease', (181, 192))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (98, 129))	('causes', 'Reg', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('VHL', 'Gene', '7428', (181, 184))	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('VHL', 'Gene', '7428', (117, 120))	('mutation', 'Var', (143, 151))	('VHL', 'Gene', (159, 162))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', (5, 10))	('VHL', 'Gene', '7428', (159, 162))
32204	27330105	As a result, despite the lack of actionable tumor cell intrinsic targets, the field has sought to take advantage of the unique biology imparted on this cancer as a result of VHL mutation: namely, VEGF-promoted angiogenesis.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('VEGF', 'Gene', '7422', (196, 200))	('mutation', 'Var', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('VHL', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('VHL', 'Gene', '7428', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('VEGF', 'Gene', (196, 200))	('angiogenesis', 'CPA', (210, 222))	('angiogenesis', 'biological_process', 'GO:0001525', ('210', '222'))	('tumor', 'Disease', (44, 49))
32207	27330105	The benefit of these drugs as monotherapy in this setting, in contrast to many other tumors, is clearly tied to the central biological feature of enhanced vascularity driven by the deregulation of hypoxia inducible factors (HIFs) that is inherent in VHL-mutated ccRCC.	('RCC', 'Disease', 'MESH:C538614', (264, 267))	('RCC', 'Disease', (264, 267))	('VHL', 'Gene', (250, 253))	('deregulation', 'Var', (181, 193))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('hypoxia', 'Disease', (197, 204))	('hypoxia', 'Disease', 'MESH:D000860', (197, 204))	('VHL', 'Gene', '7428', (250, 253))	('enhanced', 'PosReg', (146, 154))	('vascularity', 'MPA', (155, 166))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
32210	27330105	The copy number analysis of ccRCC samples revealed a strong signature of 3p deletion and 5q gains, with other modifications largely scattered across the genome.	('gains', 'PosReg', (92, 97))	('3p deletion', 'Var', (73, 84))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))
32211	27330105	Some alterations of interest included frequent deletions of CDKN2A (p16/INK4A tumor suppressors) and RB loci, as well as MYC amplification.	('INK4A', 'Gene', (72, 77))	('deletions', 'Var', (47, 56))	('p16', 'Gene', (68, 71))	('tumor suppressor', 'Gene', (78, 94))	('MYC', 'Var', (121, 124))	('CDKN2A', 'Gene', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('CDKN2A', 'Gene', '1029', (60, 66))	('p16', 'Gene', '1029', (68, 71))	('tumor suppressor', 'Gene', '7248', (78, 94))	('INK4A', 'Gene', '1029', (72, 77))
32212	27330105	In general, the number of focal and arm level alterations was much smaller on a per-tumor basis than that commonly observed in other types of cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('alterations', 'Var', (46, 57))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (142, 148))
32213	27330105	WES revealed common VHL mutations, as expected, which when coupled with promoter hypermethylation, indicated VHL inactivation occurred in over 60% of cases.	('VHL', 'Gene', (109, 112))	('mutations', 'Var', (24, 33))	('VHL', 'Gene', '7428', (109, 112))	('VHL', 'Gene', (20, 23))	('VHL', 'Gene', '7428', (20, 23))
32218	27330105	Subsequent studies have suggested that mutations in BAP1 may identify a subgroup of tumors with a higher malignant potential.	('BAP1', 'Gene', '8314', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mutations', 'Var', (39, 48))	('BAP1', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
32220	27330105	Alterations in one or more components of this pathway were present in approximately 28% of TCGA ccRCC samples.	('RCC', 'Disease', (98, 101))	('Alterations', 'Var', (0, 11))	('TCGA', 'Gene', (91, 95))	('RCC', 'Disease', 'MESH:C538614', (98, 101))
32221	27330105	Recently, study of aggressive sarcomatoid renal cell carcinomas found an association between mTOR pathway activation and increased proliferation, and tumors with mutations in this pathway are, in some instances, more sensitive to mTOR inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mTOR', 'Gene', '2475', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumors', 'Disease', (150, 156))	('activation', 'PosReg', (106, 116))	('mTOR', 'Gene', (230, 234))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (42, 62))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('aggressive sarcomatoid renal cell carcinomas', 'Disease', 'MESH:C538614', (19, 63))	('increased', 'PosReg', (121, 130))	('more', 'PosReg', (212, 216))	('proliferation', 'CPA', (131, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (42, 63))	('mTOR', 'Gene', '2475', (230, 234))	('aggressive sarcomatoid renal cell carcinomas', 'Disease', (19, 63))	('mutations', 'Var', (162, 171))	('mTOR', 'Gene', (93, 97))	('sensitive', 'MPA', (217, 226))
32222	27330105	While sequencing analysis of ccRCC did not reveal distinct genetic subgroupings, gene expression and microRNA analyses did identify four unique subgroups (m1-m4 and mi1-mi4, respectively), including predicted mRNA targets for the miRNA subgroups.	('mi1-mi4', 'Var', (165, 172))	('RCC', 'Disease', 'MESH:C538614', (31, 34))	('gene expression', 'biological_process', 'GO:0010467', ('81', '96'))	('RCC', 'Disease', (31, 34))
32232	27330105	These findings suggest that there are either inherent metabolic differences that may influence the progression of ccRCC tumors, or that a metabolic switch occurs favoring HIF targeted glycolytic gene expression and higher rates of glycolysis during tumor progression, the latter of which has been suggested by studies showing fructose bisphosphatase 1 downregulation, and commensurate increase in glucose uptake in tumor samples displaying loss of this enzyme and patterns of poor risk gene expression.	('tumor', 'Disease', (249, 254))	('ccRCC tumors', 'Disease', (114, 126))	('differences', 'Var', (64, 75))	('loss', 'NegReg', (440, 444))	('tumor', 'Disease', (415, 420))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('glycolytic', 'MPA', (184, 194))	('ccRCC tumors', 'Disease', 'MESH:D009369', (114, 126))	('fructose bisphosphatase 1', 'Gene', (326, 351))	('gene expression', 'biological_process', 'GO:0010467', ('486', '501'))	('tumor', 'Disease', 'MESH:D009369', (415, 420))	('tumor', 'Disease', (120, 125))	('increase', 'PosReg', (385, 393))	('gene expression', 'biological_process', 'GO:0010467', ('195', '210'))	('glucose uptake', 'biological_process', 'GO:0046323', ('397', '411'))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('glycolysis', 'biological_process', 'GO:0006096', ('231', '241'))	('influence', 'Reg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('downregulation', 'NegReg', (352, 366))	('glucose uptake', 'MPA', (397, 411))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('glucose', 'Chemical', 'MESH:D005947', (397, 404))	('fructose bisphosphatase 1', 'Gene', '2203', (326, 351))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
32235	27330105	Overall, methylation patterns in ccRCC tumors in the TCGA favored hypermethylation when compared with normal kidney.	('methylation', 'Var', (9, 20))	('ccRCC tumors', 'Disease', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('methylation', 'biological_process', 'GO:0032259', ('9', '20'))	('ccRCC tumors', 'Disease', 'MESH:D009369', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('hypermethylation', 'MPA', (66, 82))
32236	27330105	In contrast, the SETD2 mutant tumors displayed a unique signature pattern of global DNA hypomethylation at non-promoter regions that distinguished them from other tumors.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('DNA', 'cellular_component', 'GO:0005574', ('84', '87'))	('global DNA hypomethylation at', 'MPA', (77, 106))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('SETD2', 'Gene', '29072', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('84', '103'))	('SETD2', 'Gene', (17, 22))	('mutant', 'Var', (23, 29))
32237	27330105	The implications of this remain uncertain, although recent studies have demonstrated that SETD2 mutations alter chromatin accessibility and that expanded methylation coordinated with changes in histone methylation across the genome.	('chromatin accessibility', 'MPA', (112, 135))	('SETD2', 'Gene', (90, 95))	('histone methylation', 'MPA', (194, 213))	('methylation', 'MPA', (154, 165))	('chromatin', 'cellular_component', 'GO:0000785', ('112', '121'))	('alter', 'Reg', (106, 111))	('expanded', 'PosReg', (145, 153))	('methylation', 'biological_process', 'GO:0032259', ('154', '165'))	('histone methylation', 'biological_process', 'GO:0016571', ('194', '213'))	('SETD2', 'Gene', '29072', (90, 95))	('changes', 'Reg', (183, 190))	('mutations', 'Var', (96, 105))
32238	27330105	As mutations in these chromatin-regulators were associated with altered expression patterns in a large number of other genes, chromatin remodeling appears to play a key role in the progression of clear cell RCC.	('chromatin', 'cellular_component', 'GO:0000785', ('126', '135'))	('associated', 'Reg', (48, 58))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('chromatin', 'cellular_component', 'GO:0000785', ('22', '31'))	('altered', 'Reg', (64, 71))	('mutations', 'Var', (3, 12))	('expression patterns', 'MPA', (72, 91))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('126', '146'))
32256	27330105	TFE3 and TFEB gene fusions were also found to occur frequently in pRCC, resulting in higher levels of expression of their transcriptional targets.	('TFEB', 'Gene', (9, 13))	('TFE3', 'Gene', '7030', (0, 4))	('higher', 'PosReg', (85, 91))	('pRCC', 'Gene', '5546', (66, 70))	('fusions', 'Var', (19, 26))	('pRCC', 'Gene', (66, 70))	('TFE3', 'Gene', (0, 4))	('transcriptional targets', 'MPA', (122, 145))	('levels of expression', 'MPA', (92, 112))	('TFEB', 'Gene', '7942', (9, 13))
32262	27330105	Consistent with prior observations, pRCC-I tumors were enriched for MET mutations: of the 14 observed somatic MET mutations, only one was in a pRCC-II tumor.	('pRCC-I tumors', 'Disease', (36, 49))	('pRCC-I tumors', 'Disease', 'MESH:D009369', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('pRCC-II', 'Gene', '5546', (143, 150))	('mutations', 'Var', (114, 123))	('pRCC-II', 'Gene', (143, 150))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MET mutations', 'Var', (110, 123))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
32263	27330105	In addition to somatic tumor mutations, several of the samples contained a previously described germline MET mutation reported in hereditary papillary renal cell carcinoma (HPRCC)).	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('hereditary papillary renal cell carcinoma', 'Disease', (130, 171))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (141, 171))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('RCC', 'Disease', (175, 178))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (151, 171))	('tumor', 'Disease', (23, 28))	('hereditary papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (130, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('mutation', 'Var', (109, 117))
32268	27330105	In addition to MET mutations, pRCC-I tumors were frequently observed to have chromosomal gains of the MET-encoding chromosome 7.	('pRCC-I tumors', 'Disease', (30, 43))	('pRCC-I tumors', 'Disease', 'MESH:D009369', (30, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('115', '125'))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('chromosomal gains', 'Var', (77, 94))
32269	27330105	Thus, trisomy 7 may also contribute to the overall increase in MET mRNA expression and HGF receptor activation observed in pRCC-I relative to pRCC-II tumors.	('increase', 'PosReg', (51, 59))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('pRCC-II tumors', 'Disease', 'MESH:D009369', (142, 156))	('MET mRNA expression', 'MPA', (63, 82))	('pRCC', 'Gene', '5546', (142, 146))	('trisomy', 'Var', (6, 13))	('pRCC-II tumors', 'Disease', (142, 156))	('pRCC', 'Gene', (123, 127))	('HGF receptor', 'Gene', (87, 99))	('HGF receptor', 'Gene', '4233', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('pRCC', 'Gene', (142, 146))	('pRCC', 'Gene', '5546', (123, 127))	('activation', 'PosReg', (100, 110))
32273	27330105	For example, alterations in CDKN2A, which encodes p16 (INK4A), were more common amongst pRCC-II samples, resulting in proliferation-associated increases in expression of phosphorylated Rb and cell cycle genes.	('increases', 'PosReg', (143, 152))	('INK4A', 'Gene', '1029', (55, 60))	('cell cycle', 'biological_process', 'GO:0007049', ('192', '202'))	('cell', 'CPA', (192, 196))	('pRCC-II', 'Gene', (88, 95))	('expression', 'MPA', (156, 166))	('INK4A', 'Gene', (55, 60))	('p16', 'Gene', '1029', (50, 53))	('phosphorylated', 'MPA', (170, 184))	('CDKN2A', 'Gene', (28, 34))	('pRCC-II', 'Gene', '5546', (88, 95))	('alterations', 'Var', (13, 24))	('CDKN2A', 'Gene', '1029', (28, 34))	('p16', 'Gene', (50, 53))
32274	27330105	In addition, as seen for ccRCC, mutations in the chromosome modifier genes SETD2, BAP1, and PBRM1 were also more commonly observed in pRCC-II tumors.	('BAP1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SETD2', 'Gene', '29072', (75, 80))	('PBRM1', 'Gene', '55193', (92, 97))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('SETD2', 'Gene', (75, 80))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('pRCC-II tumors', 'Disease', 'MESH:D009369', (134, 148))	('mutations', 'Var', (32, 41))	('observed', 'Reg', (122, 130))	('pRCC-II tumors', 'Disease', (134, 148))	('BAP1', 'Gene', '8314', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('PBRM1', 'Gene', (92, 97))
32276	27330105	This observation is consistent with reports that have documented mutations in NRF2/ARE pathway genes in pRCC-II tumors.	('pRCC-II tumors', 'Disease', (104, 118))	('pRCC-II tumors', 'Disease', 'MESH:D009369', (104, 118))	('NRF2', 'Gene', '4780', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NRF2', 'Gene', (78, 82))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (65, 74))
32279	27330105	Indeed, inactivating mutations in genes involved in NFE2L2 degradation, such as KEAP1 and CUL3, as well NFE2L2 mutations that render it resistant to degradation, have been observed in cancers and are associated with poor outcomes.	('mutations', 'Var', (111, 120))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('degradation', 'biological_process', 'GO:0009056', ('149', '160'))	('cancers', 'Disease', (184, 191))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('NFE2L2', 'Gene', '4780', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('KEAP1', 'Gene', '9817', (80, 85))	('inactivating mutations', 'Var', (8, 30))	('NFE2L2', 'Gene', '4780', (104, 110))	('associated', 'Reg', (200, 210))	('NFE2L2', 'Gene', (52, 58))	('degradation', 'biological_process', 'GO:0009056', ('59', '70'))	('NFE2L2', 'Gene', (104, 110))	('KEAP1', 'Gene', (80, 85))	('CUL3', 'Gene', '8452', (90, 94))	('observed', 'Reg', (172, 180))	('CUL3', 'Gene', (90, 94))
32285	27330105	In addition, the pRCC-IIb tumors harbored the majority of the SETD2 mutations identified among all the pRCC samples.	('pRCC', 'Gene', '5546', (103, 107))	('pRCC-II', 'Gene', (17, 24))	('pRCC', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('SETD2', 'Gene', '29072', (62, 67))	('pRCC', 'Gene', (103, 107))	('pRCC', 'Gene', '5546', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (68, 77))	('SETD2', 'Gene', (62, 67))	('tumors', 'Disease', (26, 32))	('pRCC-II', 'Gene', '5546', (17, 24))
32290	27330105	In addition, the CIMP tumors demonstrated marked metabolic dysregulation highlighted by the presence of either somatic or germline mutations in the gene fumarate hydratase (FH) in 6 of the 9 CIMP tumors and low FH expression in all CIMP tumors.	('metabolic dysregulation', 'Disease', (49, 72))	('CIMP tumors', 'Disease', 'MESH:D009369', (191, 202))	('CIMP tumors', 'Disease', (191, 202))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('FH', 'Gene', '2271', (173, 175))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('FH', 'Gene', '2271', (211, 213))	('expression', 'MPA', (214, 224))	('fumarate hydratase', 'Gene', (153, 171))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('CIMP tumors', 'Disease', 'MESH:D009369', (232, 243))	('mutations', 'Var', (131, 140))	('CIMP tumors', 'Disease', (232, 243))	('CIMP tumors', 'Disease', 'MESH:D009369', (17, 28))	('metabolic dysregulation', 'Disease', 'MESH:D021081', (49, 72))	('fumarate hydratase', 'Gene', '2271', (153, 171))	('CIMP tumors', 'Disease', (17, 28))
32298	27330105	Collectively, these tumors exhibit activated NRF2/ARE as well as inactivation of the tumor suppressor CDKN2A.	('tumors', 'Disease', (20, 26))	('NRF2', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor suppressor', 'biological_process', 'GO:0051726', ('85', '101'))	('inactivation', 'Var', (65, 77))	('CDKN2A', 'Gene', (102, 108))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('85', '101'))	('tumor suppressor', 'Gene', (85, 101))	('CDKN2A', 'Gene', '1029', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('NRF2', 'Gene', '4780', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('activated', 'PosReg', (35, 44))	('tumor suppressor', 'Gene', '7248', (85, 101))
32299	27330105	The CIMP tumors were identified as a group with especially poor prognosis and early onset, characterized by genome-wide hypermethylation, FH mutations or low expression, and a shift to a Warburg-like metabolism.	('low', 'NegReg', (154, 157))	('mutations', 'Var', (141, 150))	('expression', 'MPA', (158, 168))	('FH', 'Gene', '2271', (138, 140))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('metabolism', 'biological_process', 'GO:0008152', ('200', '210'))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('CIMP tumors', 'Disease', 'MESH:D009369', (4, 15))	('CIMP tumors', 'Disease', (4, 15))	('hypermethylation', 'Var', (120, 136))
32308	27330105	One of the most characteristic features of chRCC is monosomy of many chromosomes.	('monosomy', 'Var', (52, 60))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
32312	27330105	Tumor suppressor gene alterations are prominent in chRCC.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('alterations', 'Var', (22, 33))	('Tumor suppressor', 'Gene', '7248', (0, 16))	('Tumor suppressor', 'biological_process', 'GO:0051726', ('0', '16'))	('Tumor suppressor', 'Gene', (0, 16))	('Tumor suppressor', 'molecular_function', 'GO:0008181', ('0', '16'))
32314	27330105	As anticipated, TP53 mutations are largely inactivating and, combined with chromosome 17 deletion, results in loss of function of this important tumor suppressor.	('tumor suppressor', 'molecular_function', 'GO:0008181', ('145', '161'))	('tumor suppressor', 'Gene', (145, 161))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor suppressor', 'Gene', '7248', (145, 161))	('loss of function', 'NegReg', (110, 126))	('TP53', 'Gene', '7157', (16, 20))	('tumor suppressor', 'biological_process', 'GO:0051726', ('145', '161'))	('TP53', 'Gene', (16, 20))	('chromosome', 'cellular_component', 'GO:0005694', ('75', '85'))	('mutations', 'Var', (21, 30))
32318	27330105	Again, pairing these mutations with the near ubiquitous loss of chromosome 10 results in complete loss of function of this tumor suppressor, which acts as a brake on the PI3K signaling pathway.	('PI3K signaling', 'biological_process', 'GO:0014065', ('170', '184'))	('loss', 'NegReg', (56, 60))	('loss of function', 'NegReg', (98, 114))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('tumor suppressor', 'Gene', (123, 139))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('PI3K signaling pathway', 'Pathway', (170, 192))	('signaling pathway', 'biological_process', 'GO:0007165', ('175', '192'))	('tumor suppressor', 'biological_process', 'GO:0051726', ('123', '139'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('123', '139'))	('tumor suppressor', 'Gene', '7248', (123, 139))	('PI3K', 'molecular_function', 'GO:0016303', ('170', '174'))	('mutations', 'Var', (21, 30))
32319	27330105	The expected activation of mTOR signaling down-stream from PI3K has been previously observed in small studies, and provides additional validation for the expanded use of mTOR inhibitors in this disease.	('PI3K', 'Var', (59, 63))	('mTOR', 'Gene', (170, 174))	('mTOR', 'Gene', '2475', (170, 174))	('signaling', 'biological_process', 'GO:0023052', ('32', '41'))	('activation', 'PosReg', (13, 23))	('down-stream', 'NegReg', (42, 53))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))	('PI3K', 'molecular_function', 'GO:0016303', ('59', '63'))
32324	27330105	Mutations of the TERT promoter were also identified, as had been previously described in melanoma, though tumors harboring these mutations had less robust surges in TERT gene expression levels.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('gene expression', 'biological_process', 'GO:0010467', ('170', '185'))	('TERT', 'Gene', (17, 21))	('tumors', 'Disease', (106, 112))	('TERT', 'Gene', (165, 169))	('mutations', 'Var', (129, 138))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('TERT', 'Gene', '7015', (17, 21))	('TERT', 'Gene', '7015', (165, 169))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
32329	27330105	chRCCs and oncocytomas have previously been reported to harbor mitochondrial gene mutations, but the frequency of these events, or the association with other features of chRCC, were unknown due to the rarity of this cancer.	('mitochondrial gene', 'Gene', (63, 81))	('RCC', 'Disease', (2, 5))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('oncocytomas', 'Disease', (11, 22))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('mutations', 'Var', (82, 91))	('oncocytomas', 'Disease', 'MESH:D018249', (11, 22))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))
32330	27330105	In particular, mutations in MT-ND5, a key component of this large complex, dominated the mutation landscape.	('MT-ND5', 'Gene', '4540', (28, 34))	('mutations', 'Var', (15, 24))	('MT-ND5', 'Gene', (28, 34))
32337	27330105	The major findings in this cancer are 1) a highly stochastic copy number profile, indicative of a cellular genomic event that results in aneuploidy and massive elimination of chromosomal material; 2) a program of TP53 and PTEN mutations more aligned with breast and ovarian tumors than the classical tumors of the kidney cortex; 3) high frequency gene fusions involving the TERT promoter that are associated with increased gene expression, and presumably contribute to the self-renewing phenotype of these cells as well as kataegis, and an APOBEC-type mutational spectrum in a subset of tumors; and 4) a unique phenotype of mitochondrial perturbation resulting from inactivating mutations in key members of the electron transport chain.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('TP53', 'Gene', (213, 217))	('tumors', 'Phenotype', 'HP:0002664', (587, 593))	('aneuploidy', 'Disease', 'MESH:D000782', (137, 147))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('PTEN', 'Gene', '5728', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (587, 592))	('APOBEC', 'cellular_component', 'GO:0030895', ('540', '546'))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('gene expression', 'biological_process', 'GO:0010467', ('423', '438'))	('tumors', 'Disease', (587, 593))	('tumors', 'Disease', (300, 306))	('breast and ovarian tumors than the classical tumors of the kidney cortex', 'Disease', 'MESH:D001943', (255, 327))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('aneuploidy', 'Disease', (137, 147))	('TP53', 'Gene', '7157', (213, 217))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (587, 593))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('ovarian tumors', 'Phenotype', 'HP:0100615', (266, 280))	('electron transport chain', 'biological_process', 'GO:0022900', ('711', '735'))	('mitochondrial', 'MPA', (624, 637))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', (274, 280))	('mutations', 'Var', (227, 236))	('inactivating mutations', 'Var', (666, 688))	('TERT', 'Gene', (374, 378))	('perturbation', 'NegReg', (638, 650))	('PTEN', 'Gene', (222, 226))	('TERT', 'Gene', '7015', (374, 378))	('cancer', 'Disease', (27, 33))
32345	27330105	For example, WES in the pRCC dataset revealed an average of 1.45 non-silent mutations per megabase pair (MBP), comparable to the rate of 1.1 mutations/MBP observed in the ccRCC and significantly higher than the 0.4 mutations/MBP seen in most of the chRCC tumors (Fig.	('pRCC', 'Gene', '5546', (24, 28))	('RCC', 'Disease', (173, 176))	('mutations', 'Var', (76, 85))	('chRCC tumors', 'Disease', 'MESH:D009369', (249, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('pRCC', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('chRCC tumors', 'Disease', (249, 261))	('RCC', 'Disease', (251, 254))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('RCC', 'Disease', (25, 28))
32348	27330105	Among the significantly mutated genes identified in each RCC subtype were those anticipated from the genetic syndromes known to predispose individuals to RCC, including the enrichment of VHL mutations in ccRCC, MET mutations in pRCC-I, and FH mutations in pRCC-II.	('pRCC', 'Gene', (228, 232))	('RCC', 'Disease', 'MESH:C538614', (229, 232))	('RCC', 'Disease', (154, 157))	('pRCC', 'Gene', '5546', (256, 260))	('RCC', 'Disease', (257, 260))	('VHL', 'Gene', (187, 190))	('pRCC-II', 'Gene', (256, 263))	('mutations', 'Var', (191, 200))	('RCC', 'Disease', 'MESH:C538614', (154, 157))	('RCC', 'Disease', 'MESH:C538614', (257, 260))	('VHL', 'Gene', '7428', (187, 190))	('pRCC', 'Gene', (256, 260))	('pRCC', 'Gene', '5546', (228, 232))	('mutations', 'Var', (243, 252))	('RCC', 'Disease', (57, 60))	('MET mutations', 'Var', (211, 224))	('RCC', 'Disease', (206, 209))	('FH', 'Gene', '2271', (240, 242))	('RCC', 'Disease', (229, 232))	('pRCC-II', 'Gene', '5546', (256, 263))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
32349	27330105	However, mutations in genes previously not associated with specific subtypes of RCC also emerged.	('RCC', 'Disease', (80, 83))	('mutations', 'Var', (9, 18))	('RCC', 'Disease', 'MESH:C538614', (80, 83))
32350	27330105	While NFE2L2 mutations were observed in some ccRCC tumors, they did not reach statistical significance as they did in pRCC tumors.	('RCC tumors', 'Disease', 'MESH:C538614', (47, 57))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ccRCC tumors', 'Disease', 'MESH:D009369', (45, 57))	('RCC tumors', 'Disease', 'MESH:C538614', (119, 129))	('NFE2L2', 'Gene', (6, 12))	('pRCC', 'Gene', '5546', (118, 122))	('NFE2L2', 'Gene', '4780', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('RCC tumors', 'Disease', (119, 129))	('ccRCC tumors', 'Disease', (45, 57))	('mutations', 'Var', (13, 22))	('observed', 'Reg', (28, 36))	('pRCC', 'Gene', (118, 122))
32352	27330105	Thus, mutations in NRF2/ARE genes may be most important in pRCC, especially type II.	('NRF2', 'Gene', '4780', (19, 23))	('important', 'Reg', (46, 55))	('pRCC', 'Gene', (59, 63))	('pRCC', 'Gene', '5546', (59, 63))	('NRF2', 'Gene', (19, 23))	('type II', 'Disease', (76, 83))	('mutations', 'Var', (6, 15))
32353	27330105	Similarly, the relatively high rate of TP53 mutations in chRCC was not shared by ccRCC or pRCC tumors.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC tumors', 'Disease', 'MESH:C538614', (91, 101))	('RCC', 'Disease', (83, 86))	('TP53', 'Gene', (39, 43))	('pRCC', 'Gene', '5546', (90, 94))	('RCC tumors', 'Disease', (91, 101))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('pRCC', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
32354	27330105	For example, mutations in mTOR pathway genes, including those shown to correlate with robust mTOR-inhibitor response in RCC, were seen in all three subtypes (clear cell 14%, papillary 7%, and chromophobe 14%).	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('mTOR', 'Gene', (26, 30))	('mTOR', 'Gene', '2475', (26, 30))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('mutations', 'Var', (13, 22))
32355	27330105	ccRCC tumors had frequent mutations in the chromatin modifier pathway (35%) as did pRCC-I and -II (35% and 38%, respectively).	('pRCC', 'Gene', '5546', (83, 87))	('ccRCC tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('chromatin', 'cellular_component', 'GO:0000785', ('43', '52'))	('ccRCC tumors', 'Disease', (0, 12))	('mutations', 'Var', (26, 35))	('pRCC', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('chromatin modifier pathway', 'Pathway', (43, 69))
32357	27330105	Similarly, components of the chromatin-remodeling complex SWI/SNF were frequently mutated in both papillary subtypes (20% and 27%, respectively), a frequency intermediate between clear cell RCC (43%) and chromophobe RCC (3%).	('chromatin-remodeling', 'biological_process', 'GO:0006338', ('29', '49'))	('chromophobe RCC', 'Disease', 'MESH:C538614', (204, 219))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('clear cell', 'Disease', (179, 189))	('chromatin-remodeling complex', 'cellular_component', 'GO:0016585', ('29', '57'))	('mutated', 'Var', (82, 89))	('chromophobe RCC', 'Disease', (204, 219))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))
32359	27330105	How mutations in chromatin modifier mutations impact growth, metastasis, and drug sensitivity of these tumors remains an intense area of research.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('impact', 'Reg', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('drug sensitivity', 'Phenotype', 'HP:0020174', (77, 93))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('metastasis', 'CPA', (61, 71))	('growth', 'CPA', (53, 59))	('mutations', 'Var', (4, 13))
32360	27330105	The TCGA analysis also identified alterations in CDKN2A as an oncogenic pathway of importance across the RCC spectrum.	('CDKN2A', 'Gene', '1029', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('RCC', 'Disease', (105, 108))	('alterations', 'Var', (34, 45))	('CDKN2A', 'Gene', (49, 55))
32361	27330105	A variety of mechanisms were identified that could inactivate CDKN2A, including mutations in the gene, focal deletions in 9p21, and hypermethylation of the CDKN2A promoter.	('CDKN2A', 'Gene', (156, 162))	('deletions', 'Var', (109, 118))	('mutations', 'Var', (80, 89))	('CDKN2A', 'Gene', '1029', (156, 162))	('hypermethylation', 'Var', (132, 148))	('CDKN2A', 'Gene', (62, 68))	('9p21', 'Gene', (122, 126))	('CDKN2A', 'Gene', '1029', (62, 68))	('inactivate', 'NegReg', (51, 61))
32366	27330105	Thus, in both papillary and clear cell RCC, tumors with CDKN2A alterations correlate with aggressive subtypes.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('alterations', 'Var', (63, 74))	('papillary', 'Disease', (14, 23))	('RCC', 'Disease', 'MESH:C538614', (39, 42))	('RCC', 'Disease', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('CDKN2A', 'Gene', (56, 62))	('CDKN2A', 'Gene', '1029', (56, 62))
32367	27330105	While no mutations were observed, 4 of the chRCC tumors displayed epigenetic silencing of CDKN2A, therefore strategies to target CDKN2A biology may prove useful across the kidney cancer spectrum.	('CDKN2A', 'Gene', '1029', (90, 96))	('kidney cancer', 'Disease', 'MESH:D007680', (172, 185))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('kidney cancer', 'Phenotype', 'HP:0009726', (172, 185))	('chRCC tumors', 'Disease', 'MESH:D009369', (43, 55))	('CDKN2A', 'Gene', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('kidney cancer', 'Disease', (172, 185))	('CDKN2A', 'Gene', '1029', (129, 135))	('chRCC tumors', 'Disease', (43, 55))	('CDKN2A', 'Gene', (90, 96))	('epigenetic', 'Var', (66, 76))
32382	27330105	How TFE3 fusions promote oncogenesis in RCC is incompletely understood, though TFE3 is known to regulate several oncogenic pathways involved in cell growth and metabolism, including the mTOR and TGFbeta signaling pathways, MET, and AMPK.	('mTOR', 'Gene', (186, 190))	('AMPK', 'Gene', '5562', (232, 236))	('promote', 'PosReg', (17, 24))	('AMPK', 'molecular_function', 'GO:0004691', ('232', '236'))	('mTOR', 'Gene', '2475', (186, 190))	('TFE3', 'Gene', (79, 83))	('TFE3', 'Gene', '7030', (79, 83))	('AMPK', 'molecular_function', 'GO:0047322', ('232', '236'))	('cell growth', 'biological_process', 'GO:0016049', ('144', '155'))	('oncogenic pathways', 'Pathway', (113, 131))	('AMPK', 'Gene', (232, 236))	('oncogenesis', 'CPA', (25, 36))	('RCC', 'Disease', (40, 43))	('signaling', 'biological_process', 'GO:0023052', ('203', '212'))	('regulate', 'Reg', (96, 104))	('oncogenesis', 'biological_process', 'GO:0007048', ('25', '36'))	('fusions', 'Var', (9, 16))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('metabolism', 'biological_process', 'GO:0008152', ('160', '170'))	('TFE3', 'Gene', (4, 8))	('AMPK', 'molecular_function', 'GO:0050405', ('232', '236'))	('TFE3', 'Gene', '7030', (4, 8))
32386	27330105	Among the TCGA samples, in addition to seven TFE3/TFEB translocations identified in pRCC, five were observed in ccRCC cases.	('TFEB', 'Gene', (50, 54))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('pRCC', 'Gene', (84, 88))	('RCC', 'Disease', (114, 117))	('TFE3', 'Gene', '7030', (45, 49))	('translocations', 'Var', (55, 69))	('pRCC', 'Gene', '5546', (84, 88))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('TFE3', 'Gene', (45, 49))	('TFEB', 'Gene', '7942', (50, 54))
32387	27330105	Thus, translocation RCC may be histologically indistinguishable from other RCC types, and identifiable only at the genetic level.	('translocation', 'Var', (6, 19))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('RCC', 'Disease', (20, 23))
32393	26169172	Many aberrant STPs have been associated with various cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('aberrant STPs', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (29, 39))
32421	26169172	provide evidence to support a role for aberrant Rap1 activation in prostate cancer progression.	('prostate cancer', 'Disease', (67, 82))	('activation', 'PosReg', (53, 63))	('Rap1', 'Gene', '5906', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('Rap1', 'Gene', (48, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('aberrant', 'Var', (39, 47))
32432	26169172	Furthermore, there is research substantiating that the BRAF mutation is prominent in melanoma and colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('mutation', 'Var', (60, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('BRAF', 'Gene', '673', (55, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (55, 59))
32478	26169172	This result indicates that there might be a common region of aberrant signaling in these two cancers, which does not overlap with regions of aberrant signaling in other cancers.	('aberrant', 'Var', (61, 69))	('cancers', 'Disease', (93, 100))	('cancers', 'Disease', (169, 176))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('signaling', 'biological_process', 'GO:0023052', ('70', '79'))	('signaling', 'biological_process', 'GO:0023052', ('150', '159'))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
32542	28860812	Giulietti et al found that miR-302d-3p, miR-513c-5p, miR-3918, and miR-6076 could be candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by targeting CYC.	('miR-513c-5p', 'Var', (40, 51))	('miR-6076', 'Gene', '102464828', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('CYC', 'Gene', (162, 165))	('miR-302d-3p', 'Var', (27, 38))	('pancreatic ductal adenocarcinoma', 'Disease', (116, 148))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (116, 148))	('miR-3918', 'Gene', '100500851', (53, 61))	('miR-6076', 'Gene', (67, 75))	('targeting', 'Reg', (152, 161))	('CYC', 'Gene', '54205', (162, 165))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 148))	('miR-3918', 'Gene', (53, 61))
32543	28860812	Tang et al showed that five novel lncRNAs (CYP4F26P, RP11-108M12.3, RP11-38M8.1, RP11-54H7.4, and ZNF503-AS1), based on the prognostic signature, could be therapeutic targets for lung squamous cell carcinoma patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('H7.4', 'CellLine', 'CVCL:1934', (88, 92))	('RP11', 'Gene', '26121', (81, 85))	('patients', 'Species', '9606', (208, 216))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 207))	('ZNF503-AS1', 'Gene', (98, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('RP11', 'Gene', '26121', (68, 72))	('RP11', 'Gene', (53, 57))	('lung squamous cell carcinoma', 'Disease', (179, 207))	('RP11', 'Gene', (68, 72))	('CYP4F26P', 'Var', (43, 51))	('RP11', 'Gene', (81, 85))	('ZNF503-AS1', 'Gene', '253264', (98, 108))	('RP11', 'Gene', '26121', (53, 57))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (179, 207))
32584	28860812	We found that hsa-mir-217, hsa-mir-133b, hsa-mir-216a, hsa-mir-133a, hsa-mir-145, hsa-mir-211, and hsa-mir-1297 were also closely related with these target DEmRNAs.	('hsa-mir-1297', 'Gene', (99, 111))	('hsa-mir-217', 'Gene', '406999', (14, 25))	('related', 'Reg', (130, 137))	('hsa-mir-133b', 'Gene', '442890', (27, 39))	('hsa-mir-1297', 'Gene', '100302187', (99, 111))	('hsa-mir-133b', 'Gene', (27, 39))	('hsa-mir-145', 'Gene', (69, 80))	('hsa-mir-133a', 'Var', (55, 67))	('hsa-mir-145', 'Gene', '406937', (69, 80))	('mir-216a', 'Gene', (45, 53))	('hsa-mir-217', 'Gene', (14, 25))	('hsa-mir-211', 'Gene', '406993', (82, 93))	('mir-216a', 'Gene', '406998', (45, 53))	('hsa-mir-211', 'Gene', (82, 93))
32585	28860812	PVT1, as a key DElncRNA, had interactive associations with mir-145, mir-211, mir-216a, mir-133a, and mir-133b in this network.	('mir-211', 'Gene', '406993', (68, 75))	('mir-145', 'Gene', (59, 66))	('interactive', 'Interaction', (29, 40))	('mir-133a', 'Var', (87, 95))	('PVT1', 'Gene', (0, 4))	('mir-133b', 'Gene', (101, 109))	('mir-216a', 'Gene', '406998', (77, 85))	('mir-216a', 'Gene', (77, 85))	('PVT1', 'Gene', '5820', (0, 4))	('mir-133b', 'Gene', '442890', (101, 109))	('mir-145', 'Gene', '406937', (59, 66))	('mir-211', 'Gene', (68, 75))
32590	28860812	High expression of five DElncRNAs, including AC003092.1, PVT1, RP6-191P20.4, RP11-401P9.4, and RP11-496D24.2, was associated with poor prognosis (Figure 4B).	('RP6-191P20.4', 'Var', (63, 75))	('PVT1', 'Gene', (57, 61))	('PVT1', 'Gene', '5820', (57, 61))	('RP11', 'Gene', (77, 81))	('AC003092.1', 'Var', (45, 55))	('RP11', 'Gene', (95, 99))	('RP11', 'Gene', '26121', (77, 81))	('RP11', 'Gene', '26121', (95, 99))
32594	28860812	Most attention has been focused on the study of tumor progression mediated through dysregulated lncRNAs, and the influence that neoplastic metastasis has on prognosis.	('dysregulated', 'Var', (83, 95))	('tumor', 'Disease', (48, 53))	('neoplastic metastasis', 'Disease', (128, 149))	('neoplastic metastasis', 'Disease', 'MESH:D009362', (128, 149))	('lncRNAs', 'Protein', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
32597	28860812	In this study, 16 DElncRNAs were identified as hub lncR-NAs, and six of these (PVT1, PR11-401P9.4, PR11-496D24.2, PR11-476D10.1, PR11-557H15.3, and LINC00475), which were distinctly enriched in the ceRNA network, could be prognostic biomarkers for PRCC.	('PR11-557H15.3', 'Var', (129, 142))	('PR11-496D24.2', 'Var', (99, 112))	('hub', 'Gene', '1993', (47, 50))	('PRCC', 'Gene', '5546', (248, 252))	('PR11-476D10.1', 'Var', (114, 127))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('PRCC', 'Gene', (248, 252))	('LINC00475', 'Gene', (148, 157))	('hub', 'Gene', (47, 50))	('PVT1', 'Gene', (79, 83))	('LINC00475', 'Gene', '158314', (148, 157))	('PRCC', 'Phenotype', 'HP:0006766', (248, 252))	('PVT1', 'Gene', '5820', (79, 83))	('PR11-401P9.4', 'Var', (85, 97))
32600	28860812	Overexpression of PVT1 has been confirmed to be associated with many types of cancers, including breast and ovarian cancers, acute myeloid leuke-mia, and Hodgkin lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (162, 170))	('associated', 'Reg', (48, 58))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (154, 170))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('myeloid leuke', 'Phenotype', 'HP:0012324', (131, 144))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (97, 123))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (154, 170))	('acute myeloid leuke-mia', 'Disease', 'MESH:D015470', (125, 148))	('Overexpression', 'Var', (0, 14))	('acute myeloid leuke-mia', 'Disease', (125, 148))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('acute myeloid leuke', 'Phenotype', 'HP:0004808', (125, 144))	('Hodgkin lymphoma', 'Disease', (154, 170))	('PVT1', 'Gene', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))	('ovarian cancers', 'Phenotype', 'HP:0100615', (108, 123))	('PVT1', 'Gene', '5820', (18, 22))
32603	28860812	It can be suggested that PVT1 knockdown may prevent cell proliferation in PRCC, and prolong survival time of patients.	('PRCC', 'Gene', (74, 78))	('prevent', 'NegReg', (44, 51))	('survival time', 'CPA', (92, 105))	('patients', 'Species', '9606', (109, 117))	('PVT1', 'Gene', (25, 29))	('PRCC', 'Phenotype', 'HP:0006766', (74, 78))	('cell proliferation', 'CPA', (52, 70))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('cell proliferation', 'biological_process', 'GO:0008283', ('52', '70'))	('prolong', 'PosReg', (84, 91))	('knockdown', 'Var', (30, 39))	('PRCC', 'Gene', '5546', (74, 78))	('PVT1', 'Gene', '5820', (25, 29))
32607	28860812	Many dysregulated miRNAs in adenocarcinoma have been reported to play various roles in carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('adenocarcinoma', 'Disease', (28, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('dysregulated', 'Var', (5, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (28, 42))	('carcinogenesis', 'Disease', (87, 101))	('miRNAs', 'Protein', (18, 24))
32608	28860812	To our knowledge, we found that seven miRNAs, namely, mir-217, mir-133b, mir-216a, mir-133a, mir-145, mir-211, and mir-1297, involved in the ceRNA network, can be supportive to further investigation.	('mir-211', 'Gene', (102, 109))	('mir-216a', 'Gene', (73, 81))	('mir-211', 'Gene', '406993', (102, 109))	('mir-145', 'Gene', '406937', (93, 100))	('mir-133b', 'Gene', (63, 71))	('mir-216a', 'Gene', '406998', (73, 81))	('mir-1297', 'Gene', '100302187', (115, 123))	('mir-133a', 'Var', (83, 91))	('mir-217', 'Gene', (54, 61))	('mir-145', 'Gene', (93, 100))	('mir-133b', 'Gene', '442890', (63, 71))	('mir-1297', 'Gene', (115, 123))	('mir-217', 'Gene', '406999', (54, 61))
32614	28860812	In addition, survival analysis demonstrated that high mir-211 expression can prolong patient survival time.	('patient', 'Species', '9606', (85, 92))	('expression', 'MPA', (62, 72))	('patient survival time', 'CPA', (85, 106))	('prolong', 'PosReg', (77, 84))	('high', 'Var', (49, 53))	('mir-211', 'Gene', (54, 61))	('mir-211', 'Gene', '406993', (54, 61))
32617	28860812	In the construction of the ceRNA network, SP1 can be a direct target of three hub DEmiRNAs, including miR-133a, miR-133b, and miR-145.	('miR-133b', 'Gene', (112, 120))	('hub', 'Gene', '1993', (78, 81))	('miR-133a', 'Var', (102, 110))	('miR-145', 'Gene', (126, 133))	('hub', 'Gene', (78, 81))	('miR-133b', 'Gene', '442890', (112, 120))	('miR-145', 'Gene', '406937', (126, 133))
32622	23890189	Deregulation of PAX2 expression in renal cell tumours: mechanisms and potential use in differential diagnosis Expression of PAX2 (Paired-box 2) is suppressed through promoter methylation at the later stages of embryonic development, but eventually reactivated during carcinogenesis.	('PAX2', 'Gene', '5076', (16, 20))	('carcinogenesis', 'Disease', (267, 281))	('PAX2', 'Gene', (124, 128))	('promoter methylation', 'Var', (166, 186))	('methylation', 'biological_process', 'GO:0032259', ('175', '186'))	('Paired-box 2', 'Gene', (130, 142))	('suppressed', 'NegReg', (147, 157))	('Expression', 'MPA', (110, 120))	('carcinogenesis', 'Disease', 'MESH:D063646', (267, 281))	('PAX2', 'Gene', (16, 20))	('PAX2', 'Gene', '5076', (124, 128))	('renal cell tumours', 'Disease', 'MESH:C538614', (35, 53))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('renal cell tumour', 'Phenotype', 'HP:0005584', (35, 52))	('Paired-box 2', 'Gene', '5076', (130, 142))	('renal cell tumours', 'Disease', (35, 53))
32633	23890189	For instance, the eosinophilic variant of chrRCC may be difficult to discriminate from oncocytoma, yet this distinction is critical because the former is a malignant tumour and the latter is a benign one, thus entailing different clinical approaches.	('chrRCC', 'Gene', (42, 48))	('oncocytoma', 'Disease', (87, 97))	('eosinophilic', 'Var', (18, 30))	('oncocytoma', 'Disease', 'MESH:D018249', (87, 97))	('malignant tumour', 'Disease', 'MESH:D009369', (156, 172))	('malignant tumour', 'Disease', (156, 172))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('eosin', 'Chemical', 'MESH:D004801', (18, 23))
32636	23890189	Although the precise mechanism of Pax-2 expression downregulation is not fully understood, epigenetic silencing mediated by PAX2 promoter methylation has been reported in the normal adult kidney cells of rats.	('epigenetic', 'MPA', (91, 101))	('PAX2', 'Gene', (124, 128))	('Pax-2', 'Gene', (34, 39))	('methylation', 'biological_process', 'GO:0032259', ('138', '149'))	('promoter methylation', 'Var', (129, 149))	('downregulation', 'NegReg', (51, 65))	('rats', 'Species', '10116', (204, 208))
32649	23890189	Primers and probes for PAX2 (Hs01057413_m1) and HPRT1 (Hs 99999909_m1) (endogenous control) were purchased as pre-designed optimized real-time PCR assay reagents from Applied Biosystems.	('HPRT1', 'Gene', '3251', (48, 53))	('Hs01057413_m1', 'Var', (29, 42))	('Hs 99999909_m1', 'Var', (55, 69))	('HPRT', 'molecular_function', 'GO:0004422', ('48', '52'))	('PAX2', 'Gene', (23, 27))	('HPRT1', 'Gene', (48, 53))	('pre', 'molecular_function', 'GO:0003904', ('110', '113'))
32674	23890189	Bacterial Artificial Chromosome (BAC) clones targeting the PAX2 gene (RP11_1061B5) were selected using the UCSC Human Genome Browser platform and obtained from the BACPAC Resources Center (Oakland, USA).	('RP11_1061B5', 'Var', (70, 81))	('Chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('Human', 'Species', '9606', (112, 117))	('PAX2', 'Gene', (59, 63))
32728	31489193	And thus, Type II is in fact a group of tumors that are cause by the various hereditary cancer syndromes such as fumarate hydratase (FH) gene mutations that result in hereditary leiomyoma renal cell carcinoma (HLRCC).	('fumarate hydratase', 'Gene', '2271', (113, 131))	('hereditary leiomyoma renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 208))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('hereditary cancer', 'Disease', (77, 94))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('tumors', 'Disease', (40, 46))	('FH', 'Gene', '2271', (133, 135))	('mutations', 'Var', (142, 151))	('hereditary cancer', 'Disease', 'MESH:D009369', (77, 94))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('fumarate hydratase', 'Gene', (113, 131))	('hereditary leiomyoma renal cell carcinoma', 'Disease', (167, 208))	('result in', 'Reg', (157, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (188, 208))	('RCC', 'Disease', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
32732	31489193	The CCC tumors were found to have mutations in the von Hippel-Lindau (VHL) gene with a defective gene product, VHL protein.	('CCC tumors', 'Disease', (4, 14))	('CCC', 'cellular_component', 'GO:0030896', ('4', '7'))	('CCC tumors', 'Disease', 'MESH:C535313', (4, 14))	('von Hippel-Lindau', 'Gene', (51, 68))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('VHL', 'Disease', (70, 73))	('VHL', 'Disease', 'MESH:D006623', (111, 114))	('VHL', 'Disease', 'MESH:D006623', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('VHL', 'Disease', (111, 114))	('von Hippel-Lindau', 'Gene', '7428', (51, 68))	('mutations', 'Var', (34, 43))	('protein', 'cellular_component', 'GO:0003675', ('115', '122'))
32780	30061365	Upregulation of PI3/AKT/mTOR pathway in additional TFE3-tRCC models were confirmed by significantly higher expression of phospho-S6 (P<0.0001) and phospho-4EBP1 (P<0.0001) in established tRCC cell lines compared to clear cell RCC cells.	('phospho', 'Chemical', 'MESH:C033601', (121, 128))	('RCC', 'Disease', (226, 229))	('RCC', 'Disease', 'MESH:D002292', (188, 191))	('PI3', 'Gene', '5266', (16, 19))	('higher', 'PosReg', (100, 106))	('mTOR', 'Gene', (24, 28))	('phospho-S6', 'Var', (121, 131))	('RCC', 'Disease', 'MESH:D002292', (226, 229))	('AKT', 'Gene', (20, 23))	('PI3', 'Gene', (16, 19))	('phospho', 'Chemical', 'MESH:C033601', (147, 154))	('RCC', 'Disease', (57, 60))	('mTOR', 'Gene', '2475', (24, 28))	('Upregulation', 'PosReg', (0, 12))	('BP1', 'Gene', '474256', (157, 160))	('expression', 'MPA', (107, 117))	('RCC', 'Disease', 'MESH:D002292', (57, 60))	('RCC', 'Disease', (188, 191))	('BP1', 'Gene', (157, 160))	('AKT', 'Gene', '207', (20, 23))
32784	30061365	Micropthalmia transcription factor (MiT) family tRCC is a distinct subtype of kidney cancer characterized by gene fusions resulting from translocations involving TFE3 (Xp11.2 locus or TFEB (6p21 locus) with various partner gene.	('RCC', 'Disease', 'MESH:D002292', (49, 52))	('RCC', 'Disease', (49, 52))	('Micropthalmia transcription factor', 'Disease', (0, 34))	('TFEB', 'Gene', (184, 188))	('p11', 'Gene', '6281', (169, 172))	('transcription factor', 'molecular_function', 'GO:0000981', ('14', '34'))	('transcription', 'biological_process', 'GO:0006351', ('14', '27'))	('Micropthalmia transcription factor', 'Disease', 'OMIM:602482', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('kidney cancer', 'Phenotype', 'HP:0009726', (78, 91))	('p11', 'Gene', (169, 172))	('kidney cancer', 'Disease', 'MESH:D007680', (78, 91))	('translocations', 'Var', (137, 151))	('TFEB', 'Gene', '7942', (184, 188))	('kidney cancer', 'Disease', (78, 91))
32789	30061365	Genetically engineered cell lines, as well mouse models, have been generated to study the biology of various tumors harboring TFE3 fusions.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('fusions', 'Var', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('TFE3', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mouse', 'Species', '10090', (43, 48))	('tumors', 'Disease', (109, 115))
32801	30061365	Furthermore, dysregulated miRNAs have been frequently implicated in carcinogenesis.	('miRNAs', 'Protein', (26, 32))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('implicated', 'Reg', (54, 64))	('carcinogenesis', 'Disease', (68, 82))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('dysregulated', 'Var', (13, 25))
32854	30061365	Approximately six-week old NSG mice were implanted subcutaneously with ~ 3 mm3 pieces of RP-R07 tumor and allowed to grow until tumors reached 200 mm3 in volume prior to treatment with either vehicle, Rapamycin (EMD chemicals, USA), MLN0128 (kindly provided by Millenium Pharmaceuticals, USA) or BEZ-235 (kindly provided by Novartis Pharmaceuticals, USA).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (31, 35))	('tumors', 'Disease', (128, 134))	('Millenium', 'Chemical', 'None', (261, 270))	('EMD', 'Disease', (212, 215))	('N', 'Chemical', 'MESH:D009584', (235, 236))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('EMD', 'Disease', 'None', (212, 215))	('MLN0128', 'Var', (233, 240))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('BEZ-235', 'Chemical', 'MESH:C531198', (296, 303))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('MLN0128', 'Chemical', 'MESH:C572449', (233, 240))	('Rapamycin', 'Chemical', 'MESH:D020123', (201, 210))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('N', 'Chemical', 'MESH:D009584', (324, 325))
32882	30061365	We identified enhanced nuclear immunoreactivity of C-terminal TFE3 in three different tRCC models: RP-R07 (SFPQ-TFE3), UOK-109 (NONO-TFE3), and UOK-146 (PRCC-TFE3).	('RP-R07', 'Var', (99, 105))	('NONO-TFE3', 'Gene', (128, 137))	('RCC', 'Disease', 'MESH:D002292', (87, 90))	('RCC', 'Disease', (87, 90))	('SFPQ-TFE3', 'Gene', (107, 116))	('nuclear immunoreactivity', 'MPA', (23, 47))	('enhanced', 'PosReg', (14, 22))	('C-terminal', 'Protein', (51, 61))	('SFPQ-TFE3', 'Gene', '6421;7030', (107, 116))	('PRCC-TFE3', 'Gene', '5546;7030', (153, 162))	('UOK-146', 'CellLine', 'CVCL:B123', (144, 151))	('RCC', 'Disease', (154, 157))	('UOK-109', 'Var', (119, 126))	('RCC', 'Disease', 'MESH:D002292', (154, 157))	('PRCC-TFE3', 'Gene', (153, 162))	('UOK-146', 'Var', (144, 151))	('NONO-TFE3', 'Gene', '4841;7030', (128, 137))	('TFE3', 'Gene', (62, 66))
32896	30061365	Expression profile analysis of the whole microRNAome in tRCC (RP-R07t), ccRCC and pRCC PDX models (also established in our lab) was performed using TaqMan  low-density array human microRNA card set A+B.	('RCC', 'Disease', 'MESH:D002292', (83, 86))	('RCC', 'Disease', (83, 86))	('human', 'Species', '9606', (174, 179))	('pRCC', 'Gene', (82, 86))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('RP-R07t', 'Var', (62, 69))	('RCC', 'Disease', (74, 77))	('RCC', 'Disease', 'MESH:D002292', (57, 60))	('RCC', 'Disease', (57, 60))	('RCC', 'Disease', 'MESH:D002292', (74, 77))	('N', 'Chemical', 'MESH:D009584', (186, 187))	('pRCC', 'Gene', '5546', (82, 86))
32903	30061365	Hierarchical clustering heatmap revealed significantly targeted pathways by the miRNA signature in cluster 3 (Fig.	('N', 'Chemical', 'MESH:D009584', (83, 84))	('targeted', 'Reg', (55, 63))	('miRNA signature', 'Var', (80, 95))
32906	30061365	A complete list of the statistically enriched pathways targeted by differential expression of miRNA in cluster 3 is available in Supplementary Table S6.	('N', 'Chemical', 'MESH:D009584', (97, 98))	('miRNA', 'Gene', (94, 99))	('differential expression', 'Var', (67, 90))
32908	30061365	S5) shows that almost all predicted genes in this pathway are targeted by aberrantly expressed miRNA in cluster 3, including PI3KCA, AKT1, IRS1, RPS6, TSC1, eIF4BP1, and mTOR among others.	('eIF4BP1', 'Gene', (157, 164))	('RPS6', 'Gene', '6194', (145, 149))	('PI3', 'Gene', (125, 128))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('TSC1', 'Gene', '7248', (151, 155))	('mTOR', 'Gene', (170, 174))	('mTOR', 'Gene', '2475', (170, 174))	('IRS1', 'Gene', '3667', (139, 143))	('aberrantly', 'Var', (74, 84))	('IRS1', 'Gene', (139, 143))	('RPS6', 'Gene', (145, 149))	('eIF4BP1', 'Gene', '319118', (157, 164))	('PI3', 'Gene', '5266', (125, 128))	('TSC1', 'Gene', (151, 155))	('eIF4', 'cellular_component', 'GO:0008304', ('157', '161'))	('AKT1', 'Gene', '207', (133, 137))	('miRNA', 'Gene', (95, 100))	('AKT1', 'Gene', (133, 137))
32921	30061365	We designed three vertical inhibition schemas to target the PI3K/AKT/mTOR axis at different points within the pathway: 1) PI3K/AKT axis inhibition with the P13K inhibitor BKM-120, 2) m-TOR axis inhibition with the pan-mTOR inhibitor MLN0128, and 3) simultaneous inhibition of the PI3K/AKT and mTOR axis with the dual P13K/mTOR inhibitor BEZ-235.	('mTOR', 'Gene', '2475', (69, 73))	('TOR', 'Gene', (323, 326))	('TOR', 'Gene', (70, 73))	('AKT', 'Gene', (285, 288))	('PI3', 'Gene', '5266', (122, 125))	('PI3', 'Gene', (60, 63))	('P13K', 'Var', (156, 160))	('mTOR', 'Gene', '2475', (322, 326))	('mTOR', 'Gene', (218, 222))	('AKT', 'Gene', '207', (65, 68))	('TOR', 'Gene', '6097', (185, 188))	('TOR', 'Gene', '6097', (219, 222))	('TOR', 'Gene', (219, 222))	('P13K', 'Mutation', 'p.P13K', (156, 160))	('PI3', 'Gene', (280, 283))	('mTOR', 'Gene', '2475', (218, 222))	('BKM-120', 'Var', (171, 178))	('PI3', 'Gene', '5266', (280, 283))	('PI3K', 'molecular_function', 'GO:0016303', ('280', '284'))	('AKT', 'Gene', '207', (127, 130))	('TOR', 'Gene', '6097', (294, 297))	('PI3', 'Gene', (122, 125))	('AKT', 'Gene', '207', (285, 288))	('MLN0128', 'Var', (233, 240))	('TOR', 'Gene', (185, 188))	('inhibition', 'NegReg', (194, 204))	('mTOR', 'Gene', (293, 297))	('TOR', 'Gene', (294, 297))	('mTOR', 'Gene', (69, 73))	('BEZ-235', 'Chemical', 'MESH:C531198', (337, 344))	('PI3', 'Gene', '5266', (60, 63))	('TOR', 'Gene', '6097', (323, 326))	('TOR', 'Gene', '6097', (70, 73))	('mTOR', 'Gene', '2475', (293, 297))	('AKT', 'Gene', (65, 68))	('MLN0128', 'Chemical', 'MESH:C572449', (233, 240))	('PI3K', 'molecular_function', 'GO:0016303', ('60', '64'))	('mTOR', 'Gene', (322, 326))	('inhibition', 'NegReg', (136, 146))	('PI3K', 'molecular_function', 'GO:0016303', ('122', '126'))	('P13K', 'Mutation', 'p.P13K', (317, 321))	('AKT', 'Gene', (127, 130))
32926	30061365	An MTT assay was performed after cells were treated with different concentrations of BKM-120, MLN0128, rapamycin or BEZ-235 for 96 hours to assess the anti-tumor activity of these agents (Fig.	('MLN0128', 'Var', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('BKM-120', 'Var', (85, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('MLN0128', 'Chemical', 'MESH:C572449', (94, 101))	('BEZ-235', 'Chemical', 'MESH:C531198', (116, 123))	('tumor', 'Disease', (156, 161))	('rapamycin', 'Chemical', 'MESH:D020123', (103, 112))	('MTT', 'Chemical', 'MESH:C022616', (3, 6))
32927	30061365	BKM-120 treatment inhibited cellular proliferation in a concentration-dependent manner with IC50 values of 420, 373.6 and 714 nM for RP-R07, UOK-109, and UOK-146, respectively (Fig.	('RP-R07', 'Var', (133, 139))	('UOK-146', 'CellLine', 'CVCL:B123', (154, 161))	('UOK-146', 'Var', (154, 161))	('inhibited', 'NegReg', (18, 27))	('cellular proliferation', 'CPA', (28, 50))	('UOK-109', 'Var', (141, 148))
32928	30061365	The dual TORC1/TORC2 inhibitor MLN0128 demonstrated greater anti-proliferative effect than the PI3K inhibitor BKM-120 with 10-fold lower IC50 values (RP-R07: IC50=49.4 nM, UOK-109: IC50=24.3 nM, and UOK-146: IC50=8.18 nM).	('PI3', 'Gene', '5266', (95, 98))	('IC50 values', 'MPA', (137, 148))	('MLN0128', 'Var', (31, 38))	('anti-proliferative effect', 'CPA', (60, 85))	('TORC2', 'cellular_component', 'GO:0031932', ('15', '20'))	('TORC1', 'Gene', '23373', (9, 14))	('PI3K', 'molecular_function', 'GO:0016303', ('95', '99'))	('MLN0128', 'Chemical', 'MESH:C572449', (31, 38))	('TORC1', 'cellular_component', 'GO:0031931', ('9', '14'))	('PI3', 'Gene', (95, 98))	('TORC1', 'Gene', (9, 14))	('lower', 'NegReg', (131, 136))	('UOK-146', 'CellLine', 'CVCL:B123', (199, 206))	('TORC2', 'Gene', '200186', (15, 20))	('TORC2', 'Gene', (15, 20))
32931	30061365	To validate whether the anti-proliferative effect of BEZ-235 in RP-R07 cells was associated with biochemical attenuation of the PI3K/AKT/mTOR pathway, we assessed the phosphorylation and expression levels of selected key nodes by immunofluorescence.	('PI3', 'Gene', (128, 131))	('BEZ-235', 'Chemical', 'MESH:C531198', (53, 60))	('AKT', 'Gene', '207', (133, 136))	('PI3K', 'molecular_function', 'GO:0016303', ('128', '132'))	('mTOR', 'Gene', (137, 141))	('PI3', 'Gene', '5266', (128, 131))	('anti-proliferative effect', 'MPA', (24, 49))	('mTOR', 'Gene', '2475', (137, 141))	('phospho', 'Chemical', 'MESH:C033601', (167, 174))	('phosphorylation', 'biological_process', 'GO:0016310', ('167', '182'))	('AKT', 'Gene', (133, 136))	('BEZ-235', 'Var', (53, 60))
32937	30061365	First, we confirmed the efficacy of our siRNA treatment by assessing TFE3 endogenous mRNA transcript level and protein expression after cells treatment with TFE3-siRNA and negative control-siRNA, scramble RNA (Fig.	('endogenous mRNA transcript level', 'MPA', (74, 106))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('protein expression', 'MPA', (111, 129))	('N', 'Chemical', 'MESH:D009584', (165, 166))	('RNA', 'cellular_component', 'GO:0005562', ('205', '208'))	('N', 'Chemical', 'MESH:D009584', (192, 193))	('protein', 'cellular_component', 'GO:0003675', ('111', '118'))	('N', 'Chemical', 'MESH:D009584', (87, 88))	('TFE3-siRNA', 'Var', (157, 167))	('TFE3', 'Gene', (69, 73))	('N', 'Chemical', 'MESH:D009584', (206, 207))
32939	30061365	Next, we assessed whether inhibition of TFE3 provides regulatory feedback on PI3K/AKT/mTOR signaling axis.	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('TFE3', 'Gene', (40, 44))	('mTOR', 'Gene', '2475', (86, 90))	('PI3', 'Gene', '5266', (77, 80))	('inhibition', 'Var', (26, 36))	('mTOR', 'Gene', (86, 90))	('PI3', 'Gene', (77, 80))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('AKT', 'Gene', '207', (82, 85))	('signaling', 'biological_process', 'GO:0023052', ('91', '100'))	('AKT', 'Gene', (82, 85))
32947	30061365	SiRNA mediated silencing of TFE3 decreased endogenous expression of IRS-1 mRNA transcript compared to scramble RNA treatment (P<0.01) (Fig.	('RNA', 'cellular_component', 'GO:0005562', ('111', '114'))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('silencing', 'Var', (15, 24))	('IRS-1', 'Gene', '3667', (68, 73))	('TFE3', 'Gene', (28, 32))	('decreased', 'NegReg', (33, 42))	('endogenous expression of', 'MPA', (43, 67))	('IRS-1', 'Gene', (68, 73))	('N', 'Chemical', 'MESH:D009584', (76, 77))
32948	30061365	Next, the analysis of immunofluorescence images further demonstrated the decrease of IRS-1 protein expression following TFE3-siRNA treatment compared to scramble RNA treatment (P<0.001) (Fig.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('TFE3-siRNA', 'Var', (120, 130))	('protein', 'cellular_component', 'GO:0003675', ('91', '98'))	('decrease', 'NegReg', (73, 81))	('IRS-1', 'Gene', '3667', (85, 90))	('IRS-1', 'Gene', (85, 90))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('RNA', 'cellular_component', 'GO:0005562', ('162', '165'))
32949	30061365	Following TFE3-siRNA treatment at 96 hrs and 110 hrs, the cell number was significantly reduced (96 hrs P=0.04, 110 hrs P< 0.00001) in RP-R07 compared to the non-silencing control siRNA transfected cells and non-treated cells.	('cell number', 'CPA', (58, 69))	('TFE3-siRNA', 'Gene', (10, 20))	('RP-R07', 'Var', (135, 141))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('reduced', 'NegReg', (88, 95))	('N', 'Chemical', 'MESH:D009584', (183, 184))
32950	30061365	Next, we investigated the anti-proliferative effect of MLN0128 and BEZ-235 in vivo.	('N', 'Chemical', 'MESH:D009584', (57, 58))	('BEZ-235', 'Chemical', 'MESH:C531198', (67, 74))	('anti-proliferative effect', 'MPA', (26, 51))	('MLN0128', 'Var', (55, 62))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('MLN0128', 'Chemical', 'MESH:C572449', (55, 62))	('BEZ-235', 'Gene', (67, 74))
32953	30061365	Therefore, we postulated that MLN0128 and BEZ-235 could provide superior anti-tumor effects as compared to rapamycin given their ability to impact this resistance pathway.	('resistance pathway', 'Pathway', (152, 170))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('BEZ-235', 'Var', (42, 49))	('impact', 'Reg', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLN0128', 'Var', (30, 37))	('tumor', 'Disease', (78, 83))	('rapamycin', 'Chemical', 'MESH:D020123', (107, 116))	('MLN0128', 'Chemical', 'MESH:C572449', (30, 37))	('BEZ-235', 'Chemical', 'MESH:C531198', (42, 49))
32956	30061365	Treatment of RP-R07 xenografts with MLN0128, rapamycin, and BEZ-235 resulted in decreased tumor weight (Fig.	('decreased tumor weight', 'Disease', 'MESH:D015431', (80, 102))	('BEZ-235', 'Chemical', 'MESH:C531198', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MLN0128', 'Var', (36, 43))	('decreased tumor weight', 'Disease', (80, 102))	('rapamycin', 'Chemical', 'MESH:D020123', (45, 54))	('MLN0128', 'Chemical', 'MESH:C572449', (36, 43))
32957	30061365	However, only treatment with BEZ-235 resulted in a statistically significant lower tumor weight when compared to vehicle control (P<0.01).	('lower', 'NegReg', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('BEZ-235', 'Chemical', 'MESH:C531198', (29, 36))	('BEZ-235', 'Var', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
32965	30061365	Therapeutic strategies to effectively treat MiT family translocation renal cell carcinoma have yet to be established.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('MiT family translocation', 'Var', (44, 68))	('renal cell carcinoma', 'Disease', (69, 89))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (69, 89))
32976	30061365	Consistent with our ChiP-seq data, PI3K/AKT/mTOR was identified once again as a pathway with significant (P=4.91E-9) association with the miRNA signatures in RP-R07.	('PI3', 'Gene', (35, 38))	('RP-R07', 'Var', (158, 164))	('miRNA signatures', 'Var', (138, 154))	('AKT', 'Gene', '207', (40, 43))	('association', 'Interaction', (117, 128))	('mTOR', 'Gene', (44, 48))	('PI3', 'Gene', '5266', (35, 38))	('mTOR', 'Gene', '2475', (44, 48))	('AKT', 'Gene', (40, 43))	('N', 'Chemical', 'MESH:D009584', (141, 142))	('PI3K', 'molecular_function', 'GO:0016303', ('35', '39'))
32978	30061365	It is noteworthy that some pathways associated with differential miRNA expression identified in our study are the same miRNA associated pathways identified in previous work using larger panel of tRCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tRCC tumors', 'Disease', 'MESH:D009369', (195, 206))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('differential', 'Var', (52, 64))	('miRNA expression', 'MPA', (65, 81))	('tRCC tumors', 'Disease', (195, 206))
32986	30061365	Then, we enacted a variable, multi-nodal P13K/AKT/mTOR inhibition strategy using three treatment arms to examine the effects of blocking this pathway at different points in vitro and in vivo: 1) PI3K inhibition with BKM-120, 2) pan-mTOR inhibition with MLN0128, and 3) simultaneous vertical inhibition of PI3K and mTOR with BEZ-235.	('PI3K', 'molecular_function', 'GO:0016303', ('305', '309'))	('mTOR', 'Gene', (50, 54))	('PI3', 'Gene', (305, 308))	('mTOR', 'Gene', (314, 318))	('AKT', 'Gene', (46, 49))	('MLN0128', 'Var', (253, 260))	('inhibition', 'NegReg', (237, 247))	('PI3', 'Gene', (195, 198))	('BEZ-235', 'Chemical', 'MESH:C531198', (324, 331))	('mTOR', 'Gene', '2475', (314, 318))	('mTOR', 'Gene', '2475', (50, 54))	('PI3K', 'molecular_function', 'GO:0016303', ('195', '199'))	('mTOR', 'Gene', (232, 236))	('MLN0128', 'Chemical', 'MESH:C572449', (253, 260))	('AKT', 'Gene', '207', (46, 49))	('mTOR', 'Gene', '2475', (232, 236))	('P13K', 'Mutation', 'p.P13K', (41, 45))	('BKM-120', 'Var', (216, 223))	('PI3', 'Gene', '5266', (305, 308))	('inhibition', 'NegReg', (200, 210))	('PI3', 'Gene', '5266', (195, 198))
32987	30061365	While all three treatment arms had a greater anti-proliferative effect as compared to the MET inhibitor crizotinib, BKM-120 had a modest effect, which is possibly due to inadequate inhibition by targeting PI3K axis alone.	('PI3', 'Gene', (205, 208))	('PI3K', 'molecular_function', 'GO:0016303', ('205', '209'))	('BKM-120', 'Var', (116, 123))	('anti-proliferative effect', 'MPA', (45, 70))	('crizotinib', 'Chemical', 'MESH:C551994', (104, 114))	('PI3', 'Gene', '5266', (205, 208))
32988	30061365	In contrast, MLN0128 and BEZ-235 potently inhibited proliferation of all tRCC cells models tested in a concentration-dependent fashion, with BEZ-235 exerting the greatest effect.	('proliferation', 'CPA', (52, 65))	('MLN0128', 'Chemical', 'MESH:C572449', (13, 20))	('BEZ-235', 'Gene', (25, 32))	('RCC', 'Disease', (74, 77))	('inhibited', 'NegReg', (42, 51))	('RCC', 'Disease', 'MESH:D002292', (74, 77))	('BEZ-235', 'Chemical', 'MESH:C531198', (25, 32))	('BEZ-235', 'Chemical', 'MESH:C531198', (141, 148))	('MLN0128', 'Var', (13, 20))
32995	30061365	BEZ-235 was the only treatment that resulted in significant tumor reduction in vivo compared to the modest tumor growth inhibition by rapamycin or MLN0128 alone.	('BEZ-235', 'Var', (0, 7))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MLN0128', 'Chemical', 'MESH:C572449', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('BEZ-235', 'Chemical', 'MESH:C531198', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (60, 65))	('reduction', 'NegReg', (66, 75))
32996	30061365	Even though dual mTOR inhibition with MLN0128 conferred greater efficacy of tumor growth inhibition compared to partial mTOR inhibition, possibly due to attenuation of the mTORC2-AKT reactivation mechanism, our results suggest that neither form of mTOR blockade in isolation is sufficient to elicit significant tumor control in TFE3-tRCC.	('mTOR', 'Gene', (172, 176))	('tumor', 'Disease', (76, 81))	('mTOR', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('mTOR', 'Gene', '2475', (172, 176))	('MLN0128', 'Var', (38, 45))	('mTOR', 'Gene', (248, 252))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (17, 21))	('tumor', 'Disease', (311, 316))	('mTOR', 'Gene', '2475', (248, 252))	('AKT', 'Gene', (179, 182))	('RCC', 'Disease', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('MLN0128', 'Chemical', 'MESH:C572449', (38, 45))	('mTORC2', 'Gene', (172, 178))	('mTORC2', 'cellular_component', 'GO:0031932', ('172', '178'))	('mTOR', 'Gene', '2475', (120, 124))	('RCC', 'Disease', 'MESH:D002292', (334, 337))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('AKT', 'Gene', '207', (179, 182))	('mTORC2', 'Gene', '74343', (172, 178))
33001	30061365	By using siRNA mediated TFE3 silencing strategy, we showed that attenuated wild type TFE3 expression exerts inhibitory effect on RP-R07 cell proliferation.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('TFE3', 'Gene', (85, 89))	('attenuated', 'Var', (64, 74))	('inhibitory', 'NegReg', (108, 118))	('cell proliferation', 'biological_process', 'GO:0008283', ('136', '154'))	('RP-R07 cell proliferation', 'CPA', (129, 154))
33006	30061365	Furthermore, we showed that TFE3 silencing inhibits IRS-1 expression.	('IRS-1', 'Gene', '3667', (52, 57))	('expression', 'MPA', (58, 68))	('IRS-1', 'Gene', (52, 57))	('silencing', 'Var', (33, 42))	('TFE3', 'Gene', (28, 32))	('inhibits', 'NegReg', (43, 51))
33016	30061365	The abbreviations used are: tRCC translocation renal cell carcinoma ccRCC clear cell renal cell carcinoma pRCC papillary renal cell carcinoma PDX patient-derived xenograft PIK3CA phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ChIP-Seq chromatin immune precipitation sequencing miRNA microRNA MiT Micropthalmia transcription factor NGS next generation sequencing RT-qPCR quantitative reverse transcription polymerase chain reaction IRS-1 insulin receptor substrate 1 NSG NOD-SCID gamma Despite the significant progress achieved by targeted therapies in renal cell carcinoma, patients with translocation RCC continue do have a poor outcome.	('RCC', 'Disease', (70, 73))	('transcription', 'biological_process', 'GO:0006351', ('334', '347'))	('RCC', 'Disease', 'MESH:D002292', (626, 629))	('RCC', 'Disease', (29, 32))	('N', 'Chemical', 'MESH:D009584', (490, 491))	('PIK3CA', 'Gene', (172, 178))	('N', 'Chemical', 'MESH:D009584', (313, 314))	('renal cell carcinoma', 'Disease', (85, 105))	('renal cell carcinoma', 'Disease', (576, 596))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (85, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (576, 596))	('papillary renal cell carcinoma', 'Disease', (111, 141))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (121, 141))	('N', 'Chemical', 'MESH:D009584', (304, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('RCC', 'Disease', 'MESH:D002292', (70, 73))	('RCC', 'Disease', (107, 110))	('pRCC', 'Gene', (106, 110))	('IRS-1', 'Gene', (455, 460))	('Micropthalmia transcription factor', 'Disease', (320, 354))	('RCC', 'Disease', 'MESH:D002292', (29, 32))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (74, 105))	('Micropthalmia transcription factor', 'Disease', 'OMIM:602482', (320, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (587, 596))	('patients', 'Species', '9606', (598, 606))	('transcription factor', 'molecular_function', 'GO:0000981', ('334', '354'))	('RCC', 'Disease', 'MESH:D002292', (107, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('N', 'Chemical', 'MESH:D009584', (494, 495))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (47, 67))	('chromatin', 'cellular_component', 'GO:0000785', ('259', '268'))	('translocation', 'Var', (612, 625))	('PIK3CA', 'Gene', '5290', (172, 178))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (111, 141))	('reverse transcription', 'biological_process', 'GO:0001171', ('407', '428'))	('IRS-1', 'Gene', '3667', (455, 460))	('NGS', 'Disease', 'None', (355, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('RCC', 'Disease', (626, 629))	('insulin', 'molecular_function', 'GO:0016088', ('461', '468'))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (111, 141))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (576, 596))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:C106336', (179, 216))	('renal cell carcinoma', 'Disease', (47, 67))	('NGS', 'Disease', (355, 358))	('patient', 'Species', '9606', (598, 605))	('pRCC', 'Gene', '5546', (106, 110))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (85, 105))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('patient', 'Species', '9606', (146, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('N', 'Chemical', 'MESH:D009584', (355, 356))
33042	32349455	Scientific evidence has demonstrated that the alterations in the volatile part of exometabolome (VOCs and volatile carbonyl compounds (VCCs) profiles) reflect the genetic mutations, adaptations and modifications in biochemical pathways of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('volatile carbonyl compounds', 'MPA', (106, 133))	('alterations', 'Reg', (46, 57))	('volatile part of exometabolome', 'MPA', (65, 95))	('modifications', 'Reg', (198, 211))	('biochemical pathways', 'Pathway', (215, 235))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (239, 244))	('mutations', 'Var', (171, 180))
33065	32349455	2-Ethoxy-2-methylpropane, 2,4-dimethyl-1-heptene and 4-methylbenzaldehyde were consumed by all cell lines but at a lower extent in 769-P and 786-O compared with HK-2 (Table 1).	('HK-2', 'Gene', (161, 165))	('769-P', 'Var', (131, 136))	('HK-2', 'molecular_function', 'GO:0008256', ('161', '165'))	('2,4-dimethyl-1-heptene', 'Chemical', '-', (26, 48))	('lower', 'NegReg', (115, 120))	('2-Ethoxy-2-methylpropane', 'Chemical', 'MESH:C098546', (0, 24))	('4-methylbenzaldehyde', 'Chemical', 'MESH:C020627', (53, 73))	('HK-2', 'Gene', '3099', (161, 165))	('786-O', 'Var', (141, 146))
33104	32349455	Moreover, acetaldehyde can lead to activation of proto-oncogenes, inactivation of tumor suppressor genes in replicating cells and inhibition of many important enzymes of DNA synthesis pathways, playing an important role in carcinogenesis.	('DNA', 'cellular_component', 'GO:0005574', ('170', '173'))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (223, 237))	('inactivation', 'NegReg', (66, 78))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('inhibition', 'NegReg', (130, 140))	('acetaldehyde', 'Chemical', 'MESH:D000079', (10, 22))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('proto-oncogenes', 'Gene', (49, 64))	('carcinogenesis', 'Disease', (223, 237))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('acetaldehyde', 'Var', (10, 22))	('tumor', 'Disease', (82, 87))	('DNA synthesis', 'biological_process', 'GO:0071897', ('170', '183'))	('activation', 'PosReg', (35, 45))
33123	32349455	Nevertheless, our findings support the hypothesis that altered energy production in RCC cells enables them to survive under oxidative stress conditions and to migrate to other tissues and form metastases.	('energy production', 'MPA', (63, 80))	('migrate', 'CPA', (159, 166))	('metastases', 'Disease', (193, 203))	('altered', 'Var', (55, 62))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('RCC', 'Disease', 'MESH:C538614', (84, 87))	('RCC', 'Disease', (84, 87))	('oxidative stress', 'Phenotype', 'HP:0025464', (124, 140))	('metastases', 'Disease', 'MESH:D009362', (193, 203))
33131	32349455	Thus, 769-P and 786-O are recognized as primary ccRCC while Caki-1 is a metastatic ccRCC cell line.	('786-O', 'Var', (16, 21))	('RCC', 'Phenotype', 'HP:0005584', (50, 53))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('RCC', 'Disease', (50, 53))	('ccRCC', 'Phenotype', 'HP:0006770', (48, 53))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('ccRCC', 'Phenotype', 'HP:0006770', (83, 88))	('RCC', 'Disease', (85, 88))
33143	32349455	The results showed that alterations in the volatile profile are capable of discriminating RCC from non-tumorigenic renal cells.	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('alterations', 'Var', (24, 35))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('volatile profile', 'MPA', (43, 59))	('RCC', 'Disease', (90, 93))
33177	31409759	Exploration of functional pseudogenes associated with renal cell carcinoma and their corresponding ceRNA mechanism may provide novel insights for diagnosis, therapy and prognosis of renal cell carcinoma in the future.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('associated', 'Reg', (38, 48))	('renal cell carcinoma', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (54, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (54, 74))	('renal cell carcinoma', 'Disease', (182, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (182, 202))	('pseudogenes', 'Var', (26, 37))
33178	31409759	In this study, we first screened differentially expressed pseudogenes in RCC by analyzing dreamBase and GEPIA.	('pseudogenes', 'Var', (58, 69))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
33181	31409759	Therefore, differentially expressed pseudogenes in ccRCC was first obtained to explore the functional pseudogenes and excavate their potential mechanisms of action in RCC using human pseudogene database, namely dreamBase.	('pseudogenes', 'Var', (102, 113))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('RCC', 'Disease', (53, 56))	('RCC', 'Phenotype', 'HP:0005584', (53, 56))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('ccRCC', 'Phenotype', 'HP:0006770', (51, 56))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('human', 'Species', '9606', (177, 182))
33184	31409759	Next, we determined the prognostic values of 47 potential pseudogenes in human ccRCC based on TCGA data using GEPIA database.	('pseudogenes', 'Var', (58, 69))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('human', 'Species', '9606', (73, 78))	('RCC', 'Disease', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))
33186	31409759	Among the 47 potential pseudogenes, only high expression of three upregulated pseudogenes (AC007326.9, DUXAP8 and DUXAP9) and four downregulated pseudogenes (NUDT4P2, RP11-255H23.2, AF186192.5 and SLC2A3P1) indicated poorer and better OS and RFS in patients with ccRCC, respectively (Supplementary Table 3).	('NUDT4P2', 'Gene', (158, 165))	('RFS', 'Disease', 'MESH:D005198', (242, 245))	('NUDT4P2', 'Gene', '170688', (158, 165))	('RP11', 'Gene', '26121', (167, 171))	('SLC2A3P1', 'Gene', (197, 205))	('ccRCC', 'Phenotype', 'HP:0006770', (263, 268))	('RCC', 'Disease', (265, 268))	('RCC', 'Phenotype', 'HP:0005584', (265, 268))	('poorer', 'NegReg', (217, 223))	('SLC2A3P1', 'Gene', '100128062', (197, 205))	('upregulated', 'PosReg', (66, 77))	('RFS', 'Disease', (242, 245))	('RCC', 'Disease', 'MESH:C538614', (265, 268))	('AF186192.5', 'Var', (182, 192))	('DUXAP9', 'Gene', '503638', (114, 120))	('patients', 'Species', '9606', (249, 257))	('RP11', 'Gene', (167, 171))	('DUXAP8', 'Gene', (103, 109))	('DUXAP9', 'Gene', (114, 120))	('DUXAP8', 'Gene', '503637', (103, 109))	('better', 'PosReg', (228, 234))
33197	31409759	In the next step, we determined the expression and prognostic values of the three miRNAs (miR-29c-3p, miR-92b-3p and miR-500a-3p) in ccRCC.	('miR-500a-3p', 'Var', (117, 128))	('ccRCC', 'Phenotype', 'HP:0006770', (133, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('miR-92b-3p', 'Var', (102, 112))	('miR-29c', 'Gene', '407026', (90, 97))	('miR-29c', 'Gene', (90, 97))
33200	31409759	We also found that miR-500a-3p expression in cancer tissues was significantly lower than that in normal tissues (Figure 4C).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('miR-500a-3p', 'Var', (19, 30))	('expression', 'MPA', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('lower', 'NegReg', (78, 83))
33201	31409759	Survival analysis for the three miRNAs demonstrated that ccRCC patients with higher expression of miR-29c-3p and miR-92b-3p had better and worse prognosis as presented in Figure 4D and Figure 4E, respectively.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('higher', 'PosReg', (77, 83))	('miR-92b-3p', 'Var', (113, 123))	('miR-29c', 'Gene', '407026', (98, 105))	('miR-29c', 'Gene', (98, 105))	('patients', 'Species', '9606', (63, 71))	('expression', 'MPA', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
33215	31409759	As shown in Table 4, high expression of GAPDH, COL1A1 and COL1A2 indicated a poor prognosis in patients with ccRCC.	('COL1A2', 'Gene', (58, 64))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('patients', 'Species', '9606', (95, 103))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('high', 'Var', (21, 25))	('COL1A1', 'Gene', (47, 53))	('GAPDH', 'Gene', '2597', (40, 45))	('GAPDH', 'Gene', (40, 45))
33231	31409759	Subsequently, we employed siRNAs of DUXAP8/ DUXAP9 to knockdown DUXAP8/DUXAP9 and used mimic of miR-29c-3p to upregulate miR-29c-3p.	('miR-29c', 'Gene', '407026', (121, 128))	('DUXAP9', 'Gene', (44, 50))	('DUXAP8', 'Gene', '503637', (64, 70))	('knockdown', 'Var', (54, 63))	('miR-29c', 'Gene', (121, 128))	('DUXAP9', 'Gene', (71, 77))	('DUXAP9', 'Gene', '503638', (71, 77))	('DUXAP9', 'Gene', '503638', (44, 50))	('miR-29c', 'Gene', '407026', (96, 103))	('DUXAP8', 'Gene', (36, 42))	('miR-29c', 'Gene', (96, 103))	('DUXAP8', 'Gene', '503637', (36, 42))	('DUXAP8', 'Gene', (64, 70))	('upregulate', 'PosReg', (110, 120))
33233	31409759	As shown in Figure 7L, knockdown of DUXAP8 or DUXAP9 could significantly suppress cell growth and overexpression of miR-29c-3p also inhibited cell growth.	('cell growth', 'CPA', (142, 153))	('suppress', 'NegReg', (73, 81))	('inhibited', 'NegReg', (132, 141))	('DUXAP8', 'Gene', (36, 42))	('cell growth', 'biological_process', 'GO:0016049', ('82', '93'))	('knockdown', 'Var', (23, 32))	('DUXAP9', 'Gene', (46, 52))	('miR-29c', 'Gene', '407026', (116, 123))	('DUXAP9', 'Gene', '503638', (46, 52))	('miR-29c', 'Gene', (116, 123))	('cell growth', 'CPA', (82, 93))	('cell growth', 'biological_process', 'GO:0016049', ('142', '153'))	('DUXAP8', 'Gene', '503637', (36, 42))
33236	31409759	Taken together, amplification of pseudogenes DUXAP8 and DUXAP9 may lead to increase expression of COL1A1 and COL1A2 by competitively binding to miR-29c-3p, resulting in uncontrolled cell proliferation in renal cell carcinoma (Figure 8).	('DUXAP9', 'Gene', (56, 62))	('renal cell carcinoma', 'Disease', (204, 224))	('uncontrolled cell proliferation', 'CPA', (169, 200))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (204, 224))	('COL1A2', 'Gene', (109, 115))	('miR-29c', 'Gene', (144, 151))	('DUXAP8', 'Gene', (45, 51))	('DUXAP8', 'Gene', '503637', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (204, 224))	('binding', 'molecular_function', 'GO:0005488', ('133', '140'))	('increase', 'PosReg', (75, 83))	('expression', 'MPA', (84, 94))	('DUXAP9', 'Gene', '503638', (56, 62))	('cell proliferation', 'biological_process', 'GO:0008283', ('182', '200'))	('amplification', 'Var', (16, 29))	('COL1A1', 'Gene', (98, 104))	('miR-29c', 'Gene', '407026', (144, 151))	('pseudogenes', 'Var', (33, 44))	('binding', 'Interaction', (133, 140))
33240	31409759	In this study, we first screened several differentially expressed pseudogenes in ccRCC using the dreamBase database, after which expression levels of these pseudogenes were further validated using another database (GEPIA).	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('ccRCC', 'Phenotype', 'HP:0006770', (81, 86))	('pseudogenes', 'Var', (66, 77))
33245	31409759	All these reports together with the previous analytic results suggest that pseudogene DUXAP8 and DUXAP9 may serve as two promising therapeutic targets ad prognostic biomarkers for RCC.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('DUXAP8', 'Gene', '503637', (86, 92))	('DUXAP9', 'Gene', (97, 103))	('DUXAP8', 'Gene', (86, 92))	('DUXAP9', 'Gene', '503638', (97, 103))	('pseudogene', 'Var', (75, 85))
33261	31409759	The group of Li J also supposed that COL1A1 and COL1A2 might predict poor clinical outcomes in gastric cancer patients.	('COL1A2', 'Gene', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('COL1A1', 'Var', (37, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (95, 109))	('gastric cancer', 'Disease', (95, 109))	('clinical', 'Species', '191496', (74, 82))	('patients', 'Species', '9606', (110, 118))	('gastric cancer', 'Phenotype', 'HP:0012126', (95, 109))
33275	31409759	StarBase (version 3) (http://starbase.sysu.edu.cn/) was also utilized to perform correlation analysis between pseudogene and miRNA in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('pseudogene', 'Var', (110, 120))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('RCC', 'Disease', (136, 139))
33285	31409759	The cells were maintained in minimal essential medium (MEM) supplemented with 10% FBS, penicillin (100 U/ml) and streptomycin (100ug/ml).	('FBS', 'Disease', (82, 85))	('FBS', 'Disease', 'MESH:D005198', (82, 85))	('100ug/ml', 'Var', (127, 135))	('streptomycin', 'Chemical', 'MESH:D013307', (113, 125))	('penicillin', 'Chemical', 'MESH:D010406', (87, 97))	('essential medium', 'Chemical', '-', (37, 53))
33288	31409759	The expression level of DUXAP8, DUXAP9, miR- 29c-3p, COL1A1 and COL1A2 was analyzed by quantitative real-time PCR as we previously described.	('DUXAP8', 'Gene', (24, 30))	('DUXAP8', 'Gene', '503637', (24, 30))	('COL1A1', 'Gene', (53, 59))	('DUXAP9', 'Gene', (32, 38))	('DUXAP9', 'Gene', '503638', (32, 38))	('miR- 29c-3p', 'Var', (40, 51))	('COL1A2', 'Gene', (64, 70))
33294	31409759	To sum up, this study for the first time comprehensively and systematically explored the function and ceRNA regulatory mechanism of pseudogenes in renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 167))	('pseudogenes', 'Var', (132, 143))	('renal cell carcinoma', 'Disease', (147, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))
33424	26613881	The investigators indicated, however, a potential association between high baseline Ktrans and a prolonged time to progression or death.	('death', 'Disease', 'MESH:D003643', (130, 135))	('death', 'Disease', (130, 135))	('Ktrans', 'Protein', (84, 90))	('Ktrans', 'Chemical', '-', (84, 90))	('time to progression', 'CPA', (107, 126))	('high', 'Var', (70, 74))
33455	26613881	Hyperintense detrusor muscle signal underlying tumor on T2-weighted and/or DWIs suggests muscle invasion.	('muscle invasion', 'CPA', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Hyperintense', 'Var', (0, 12))	('tumor', 'Disease', (47, 52))
33486	25120953	As molecular abnormalities occur for various reasons, ranging from single nucleotide polymorphisms to large chromosomal defects, conducting whole-genome association studies using high-throughput techniques seems inevitable.	('molecular abnormalities', 'Disease', (3, 26))	('molecular abnormalities', 'Disease', 'MESH:C567116', (3, 26))	('single nucleotide polymorphisms', 'Var', (67, 98))
33488	25120953	Genetic alterations are mostly unique for each histological RCC subtype.	('Genetic alterations', 'Var', (0, 19))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('RCC', 'Disease', (60, 63))
33498	25120953	Around 40-60% of patients with mutated VHL suffer from clear cell renal cell carcinoma (ccRCC).	('clear cell renal cell carcinoma', 'Disease', (55, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('suffer from', 'Reg', (43, 54))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (55, 86))	('VHL', 'Gene', (39, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (55, 86))	('patients', 'Species', '9606', (17, 25))	('mutated', 'Var', (31, 38))	('RCC', 'Disease', (90, 93))
33500	25120953	They may also comprise recently recognized rare malignancies, such as (4) collecting ducts of Bellini renal cell carcinoma (cdRCC); (5) renal medullary carcinoma; (6) renal carcinoma associated with the translocation of locus 11.2 on the short arm of the X chromosome; and (7) mucinous tubular spindle cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('carcinoma', 'Disease', 'MESH:D002277', (173, 182))	('carcinoma', 'Disease', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('spindle', 'cellular_component', 'GO:0005819', ('294', '301'))	('carcinoma', 'Disease', (113, 122))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('translocation of locus', 'Var', (203, 225))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('malignancies', 'Disease', (48, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('carcinoma', 'Disease', 'MESH:D002277', (152, 161))	('X chromosome', 'cellular_component', 'GO:0000805', ('255', '267'))	('Bellini renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Disease', (307, 316))	('carcinoma', 'Disease', 'MESH:D002277', (113, 122))	('carcinoma', 'Disease', (173, 182))	('Bellini renal cell carcinoma', 'Disease', (94, 122))	('short arm', 'Phenotype', 'HP:0009824', (238, 247))	('renal carcinoma', 'Disease', 'MESH:C538614', (167, 182))	('renal carcinoma', 'Disease', (167, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('renal carcinoma', 'Phenotype', 'HP:0005584', (167, 182))	('RCC', 'Disease', (126, 129))	('carcinoma', 'Disease', 'MESH:D002277', (307, 316))
33505	25120953	VHL mutation was observed in renal cell carcinoma inter alia by Seizinger et al.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (29, 49))	('mutation', 'Var', (4, 12))	('observed', 'Reg', (17, 25))	('VHL', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('renal cell carcinoma inter alia', 'Disease', (29, 60))	('renal cell carcinoma inter alia', 'Disease', 'MESH:C538614', (29, 60))
33509	25120953	This complex study took almost 10 years to complete and it resulted in the fundamental identification of many mutations in 1998.	('men', 'Species', '9606', (80, 83))	('resulted in', 'Reg', (59, 70))	('mutations', 'Var', (110, 119))
33525	25120953	Furthermore, the authors will present evidence that those mutations are significant components of crucial signaling pathways leading to cancerogenesis and metastases.	('mutations', 'Var', (58, 67))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('signaling', 'biological_process', 'GO:0023052', ('106', '115'))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('metastases', 'Disease', (155, 165))
33529	25120953	This means that patients with RCC exhibit different sets of mutations depending on what histological subtype of RCC they suffer from.	('patients', 'Species', '9606', (16, 24))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Disease', (30, 33))	('RCC', 'Disease', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('mutations', 'Var', (60, 69))
33531	25120953	These include the previously mentioned loss of function of the VHL tumor suppressor gene, inactivation of the SET domain containing protein 2 (SETD2), KDM6A, KDM5C - both lysine (K)-specific demethylases - and polybromo1 (PBRM1).	('KDM5C', 'Gene', (158, 163))	('VHL tumor', 'Disease', (63, 72))	('lysine', 'Chemical', 'MESH:D008239', (171, 177))	('protein', 'cellular_component', 'GO:0003675', ('132', '139'))	('KDM6A', 'Gene', '7403', (151, 156))	('VHL tumor', 'Disease', 'MESH:D006623', (63, 72))	('polybromo1', 'Gene', (210, 220))	('PBRM1', 'Gene', '55193', (222, 227))	('PBRM1', 'Gene', (222, 227))	('KDM6A', 'Gene', (151, 156))	('polybromo1', 'Gene', '55193', (210, 220))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('67', '83'))	('SETD2', 'Gene', (143, 148))	('inactivation', 'Var', (90, 102))	('KDM5C', 'Gene', '8242', (158, 163))	('tumor suppressor', 'biological_process', 'GO:0051726', ('67', '83'))	('SETD2', 'Gene', '29072', (143, 148))	('loss', 'NegReg', (39, 43))	('men', 'Species', '9606', (29, 32))
33540	25120953	Apart from the significant percentage of mutations of the three genes mentioned above, KDM5C was also shown to be mutated in 8% of the cases.	('KDM5C', 'Gene', (87, 92))	('mutated', 'Var', (114, 121))	('men', 'Species', '9606', (70, 73))	('KDM5C', 'Gene', '8242', (87, 92))
33541	25120953	A study of 145 patients with developed ccRCC reported that in those harboring BAP1 and PBMR1 mutations, the overall survival (OS) rate was significantly shorter than in patients harboring only PBMR1 mutation.	('overall survival', 'MPA', (108, 124))	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (93, 102))	('shorter', 'NegReg', (153, 160))	('PBMR1', 'Gene', (87, 92))	('BAP1', 'Gene', '8314', (78, 82))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))	('BAP1', 'Gene', (78, 82))
33550	25120953	SNP-based arrays performed by this scientific group showed the deletion of 3p in 16 out of 20 tumors (80% cases).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('deletion', 'Var', (63, 71))
33554	25120953	Mutations of MET proto-oncogene have been noticed in its tyrosine kinase domain, which has classified HPRCC for targeted therapy against MET and vascular endothelial growth factor (VEGF) receptors.	('MET', 'Gene', (13, 16))	('PRCC', 'Gene', '5546', (103, 107))	('VEGF', 'Gene', '7422', (181, 185))	('PRCC', 'Gene', (103, 107))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('145', '179'))	('Mutations', 'Var', (0, 9))	('VEGF', 'Gene', (181, 185))	('vascular endothelial growth factor', 'Gene', (145, 179))	('vascular endothelial growth factor', 'Gene', '7422', (145, 179))	('tyrosine kinase domain', 'MPA', (57, 79))
33556	25120953	They also screened a large group of sporadic papillary renal carcinomas and many other solid tumors for various mutations in MET proto-oncogene.	('sporadic papillary renal carcinomas', 'Disease', 'MESH:C538614', (36, 71))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('renal carcinomas', 'Phenotype', 'HP:0005584', (55, 71))	('solid tumors', 'Disease', (87, 99))	('mutations', 'Var', (112, 121))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('papillary renal carcinomas', 'Phenotype', 'HP:0006766', (45, 71))	('sporadic papillary renal carcinomas', 'Disease', (36, 71))	('renal carcinoma', 'Phenotype', 'HP:0005584', (55, 70))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))
33557	25120953	Summarizing these and the previous results, they have presented such mutations in 17 out of 129 sporadic papillary renal carcinomas, but not in other solid tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutations', 'Var', (69, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('solid tumors', 'Disease', (150, 162))	('renal carcinoma', 'Phenotype', 'HP:0005584', (115, 130))	('papillary renal carcinomas', 'Phenotype', 'HP:0006766', (105, 131))	('sporadic papillary renal carcinomas', 'Disease', (96, 131))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('renal carcinomas', 'Phenotype', 'HP:0005584', (115, 131))	('sporadic papillary renal carcinomas', 'Disease', 'MESH:C538614', (96, 131))	('solid tumors', 'Disease', 'MESH:D009369', (150, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))
33560	25120953	If a specific mutation disables the FH gene, the Krebs cycle would be modified, favoring the excessive synthesis of fatty acids, which in turn promotes tumor growth (Warburg effect).	('synthesis of fatty acids', 'MPA', (103, 127))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('Krebs cycle', 'biological_process', 'GO:0006099', ('49', '60'))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('FH gene', 'Gene', (36, 43))	('promotes', 'PosReg', (143, 151))	('favoring', 'PosReg', (80, 88))	('tumor', 'Disease', (152, 157))	('disables', 'NegReg', (23, 31))	('mutation', 'Var', (14, 22))	('Krebs', 'Chemical', '-', (49, 54))	('fatty acids', 'Chemical', 'MESH:D005227', (116, 127))	('synthesis', 'biological_process', 'GO:0009058', ('103', '112'))
33567	25120953	BHD has turned out to be connected with the folliculin-coding gene (FLCN) mutation.	('BHD', 'Gene', (0, 3))	('mutation', 'Var', (74, 82))	('FLCN', 'Gene', '201163', (68, 72))	('folliculin-coding gene', 'Gene', '201163', (44, 66))	('folliculin-coding gene', 'Gene', (44, 66))	('BHD', 'Gene', '50947', (0, 3))	('connected', 'Reg', (25, 34))	('FLCN', 'Gene', (68, 72))
33568	25120953	Generally, it is perceived as a tumor suppressor as its several types of mutations lead to various tumor formations.	('tumor', 'Disease', (99, 104))	('tumor suppressor', 'biological_process', 'GO:0051726', ('32', '48'))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('32', '48'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('lead to', 'Reg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (32, 37))	('mutations', 'Var', (73, 82))
33569	25120953	have identified folliculin mutation in about 70% of patients in the research probe.	('mutation', 'Var', (27, 35))	('folliculin', 'Gene', (16, 26))	('patients', 'Species', '9606', (52, 60))
33576	25120953	For example, the gene most often up-regulated in hypoxia conditions and in the presence of VHL mutation is cyclin D1.	('cyclin D1', 'Gene', (107, 116))	('hypoxia conditions', 'Disease', (49, 67))	('cyclin', 'molecular_function', 'GO:0016538', ('107', '113'))	('VHL', 'Gene', (91, 94))	('hypoxia conditions', 'Disease', 'MESH:D000860', (49, 67))	('up-regulated', 'PosReg', (33, 45))	('cyclin D1', 'Gene', '595', (107, 116))	('mutation', 'Var', (95, 103))
33593	25120953	One of them states that "molecular pathways involved in tumor survival and progression are often enacted by genetic alterations".	('genetic alterations', 'Var', (108, 127))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('enacted', 'Reg', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
33596	25120953	However, a few large genome-wide associated studies have shown recently that some nucleotide polymorphisms (SNPs) exist and that they may increase the patients' risk of developing renal cell cancer.	('increase', 'PosReg', (138, 146))	('renal cell cancer', 'Disease', (180, 197))	('nucleotide polymorphisms', 'Var', (82, 106))	('renal cell cancer', 'Disease', 'MESH:C538614', (180, 197))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('renal cell cancer', 'Phenotype', 'HP:0005584', (180, 197))
33610	25120953	Many other mutations have been reported to be unique for ccRCC and such results have been obtained mostly via detailed genomic analyses or even large-scale sequencing.	('mutations', 'Var', (11, 20))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
33613	25120953	Mutations of MET proto-oncogene were shown to be present in its tyrosine kinase domain, which has classified HPRC for targeted therapy against MET and VEGF receptors.	('Mutations', 'Var', (0, 9))	('MET', 'Gene', (13, 16))	('VEGF', 'Gene', '7422', (151, 155))	('VEGF', 'Gene', (151, 155))
33614	25120953	Summarizing these along with previous results, they presented such mutations in 17 out of 129 sporadic papillary renal carcinomas, but not in other solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('sporadic papillary renal carcinomas', 'Disease', (94, 129))	('renal carcinoma', 'Phenotype', 'HP:0005584', (113, 128))	('mutations', 'Var', (67, 76))	('solid tumors', 'Disease', (148, 160))	('sporadic papillary renal carcinomas', 'Disease', 'MESH:C538614', (94, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('papillary renal carcinomas', 'Phenotype', 'HP:0006766', (103, 129))	('renal carcinomas', 'Phenotype', 'HP:0005584', (113, 129))
33615	25120953	What is striking is that even in 1999, molecular modeling studies suggested the importance of activating mutations and it was known that such phenomena tended to facilitate the transition to the active form kinases, which, in this case was MET kinase, leading to the formation of a different histological RCC subtype.	('facilitate', 'PosReg', (162, 172))	('RCC', 'Disease', 'MESH:C538614', (305, 308))	('RCC', 'Disease', (305, 308))	('mutations', 'Var', (105, 114))	('formation', 'biological_process', 'GO:0009058', ('267', '276'))	('transition', 'MPA', (177, 187))	('men', 'Species', '9606', (147, 150))
33647	25120953	Physiologically, the VHL gene is needed for HIF-1alpha degradation; therefore, in the case of VHL mutation (occurring in ccRCC), HIF-1alpha is not properly degraded and is subsequently overproduced.	('HIF-1alpha degradation', 'Disease', 'MESH:D055959', (44, 66))	('mutation', 'Var', (98, 106))	('overproduced', 'PosReg', (185, 197))	('HIF-1alpha', 'Gene', '3091', (44, 54))	('degradation', 'biological_process', 'GO:0009056', ('55', '66'))	('HIF-1alpha', 'Gene', '3091', (129, 139))	('HIF-1alpha degradation', 'Disease', (44, 66))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('HIF-1alpha', 'Gene', (44, 54))	('HIF-1alpha', 'Gene', (129, 139))	('VHL', 'Gene', (94, 97))
33648	25120953	Overproduction of this subunit leads to the increase in the binding of HIF-1alpha to the so-called hypoxia responsive elements, which in turn causes the over-expression of the VEGF.	('VEGF', 'Gene', (176, 180))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('binding', 'molecular_function', 'GO:0005488', ('60', '67'))	('HIF-1alpha', 'Gene', '3091', (71, 81))	('men', 'Species', '9606', (121, 124))	('hypoxia', 'Disease', (99, 106))	('increase', 'PosReg', (44, 52))	('over-expression', 'MPA', (153, 168))	('Overproduction', 'Var', (0, 14))	('HIF-1alpha', 'Gene', (71, 81))	('VEGF', 'Gene', '7422', (176, 180))	('causes', 'Reg', (142, 148))	('binding', 'Interaction', (60, 67))
33668	25120953	An interesting and highly probable hypothesis, which states that genetic mutations or other alterations that condition metastases formation occur earlier than the actual metastasis, has been proposed by Gerlinger et al.	('genetic mutations', 'Var', (65, 82))	('metastases', 'Disease', (119, 129))	('formation', 'biological_process', 'GO:0009058', ('130', '139'))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
33671	25120953	It has been brought to our attention by authors of several publications that most human cancers are caused by two to eight alterations occurring one after another and which tend to develop in the course of 20-30 years.	('caused by', 'Reg', (100, 109))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('alterations', 'Var', (123, 134))	('human', 'Species', '9606', (82, 87))
33679	25120953	It may be assumed that heterogeneity in RCC may significantly reduce the effectiveness of biomarker research.	('RCC', 'Disease', (40, 43))	('reduce', 'NegReg', (62, 68))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('effectiveness', 'MPA', (73, 86))	('heterogeneity', 'Var', (23, 36))
33778	25120953	Finding specific mutations which lead to adequate adverse effects in RCC patient is another obstacle and the reason for future research as well.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('patient', 'Species', '9606', (73, 80))	('mutations', 'Var', (17, 26))
33786	25120953	discovered RCC genetic variants in relation to its etiology.	('variants', 'Var', (23, 31))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))
33791	25120953	Studying such mutations in RCC may be possible in the future, especially if the multicenter networks of the patients' molecular characterization are established.	('patients', 'Species', '9606', (108, 116))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('mutations', 'Var', (14, 23))
33798	25120953	Finally, also Hakimi's research team has shown that the analysis of the Cancer Genome Atlas Project Association enables to gather a significant amount of information, in this case it were mutations in, previously mentioned in the article, chromatin modifiers, which positively correlated with poor survival in ccRCC.	('chromatin', 'cellular_component', 'GO:0000785', ('239', '248'))	('correlated', 'Reg', (277, 287))	('RCC', 'Disease', 'MESH:C538614', (312, 315))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RCC', 'Disease', (312, 315))	('mutations', 'Var', (188, 197))	('men', 'Species', '9606', (213, 216))
33814	33539630	In this study, we displayed that c-met is an appropriate therapeutic target for papillary renal cell carcinoma (PRCC) using clinical samples, developed an anti-human c-met CAR-T cells, and investigated the anti-tumor efficacy of the CAR-T cells using an orthotopic mouse model as pre-clinical research.	('c-met', 'Gene', (166, 171))	('tumor', 'Disease', (211, 216))	('CAR', 'cellular_component', 'GO:0005826', ('172', '175'))	('CAR-T', 'CellLine', 'CVCL:4140', (233, 238))	('c-met', 'Gene', '4233', (33, 38))	('papillary renal cell carcinoma', 'Disease', (80, 110))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (90, 110))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CAR', 'cellular_component', 'GO:0005826', ('233', '236'))	('pre', 'molecular_function', 'GO:0003904', ('280', '283'))	('c-met', 'Gene', '4233', (166, 171))	('human', 'Species', '9606', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (80, 110))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('c-met', 'Gene', (33, 38))	('mouse', 'Species', '10090', (265, 270))	('PRCC', 'Phenotype', 'HP:0006766', (112, 116))	('anti-human', 'Var', (155, 165))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (80, 110))	('CAR-T', 'CellLine', 'CVCL:4140', (172, 177))
33818	33539630	Administration of the anti-human c-met CAR-T cells induced unambiguous suppression of the tumor growth in an orthotopic model of papillary renal cell carcinoma.	('papillary renal cell carcinoma', 'Disease', (129, 159))	('CAR-T', 'CellLine', 'CVCL:4140', (39, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (139, 159))	('CAR', 'cellular_component', 'GO:0005826', ('39', '42'))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('c-met', 'Gene', (33, 38))	('tumor', 'Disease', (90, 95))	('human', 'Species', '9606', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('suppression', 'NegReg', (71, 82))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (129, 159))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (129, 159))	('anti-human', 'Var', (22, 32))	('c-met', 'Gene', '4233', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
33837	33539630	32 ,  33 ,  34 ,  35   In this study, we generated an anti-human c-met CAR-T cells with human T cells, and examined whether the CAR-T cells exhibited therapeutic efficacy against PRCC.	('human', 'Species', '9606', (59, 64))	('CAR-T', 'CellLine', 'CVCL:4140', (128, 133))	('CAR', 'cellular_component', 'GO:0005826', ('71', '74'))	('CAR-T', 'CellLine', 'CVCL:4140', (71, 76))	('c-met', 'Gene', '4233', (65, 70))	('CAR', 'cellular_component', 'GO:0005826', ('128', '131'))	('PRCC', 'Disease', (179, 183))	('PRCC', 'Phenotype', 'HP:0006766', (179, 183))	('human', 'Species', '9606', (88, 93))	('c-met', 'Gene', (65, 70))	('anti-human', 'Var', (54, 64))
33930	33539630	In addition, blockade of the interaction between vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) with antibodies or TKIs including axitinib has been reported to normalize tumor vasculature consisting of immunosuppressive endothelial cells and to enhance T cell-endothelial cell interaction, resulting in the enhancement of T cell infiltration in tumor tissues.	('VEGF', 'Gene', '7422', (85, 89))	('VEGFR', 'Gene', '3791', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('vascular endothelial growth factor', 'Gene', (49, 83))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('49', '83'))	('T cell-endothelial cell interaction', 'CPA', (274, 309))	('VEGF', 'Gene', (85, 89))	('men', 'Species', '9606', (335, 338))	('VEGFR', 'Gene', (110, 115))	('normalize', 'NegReg', (181, 190))	('interaction', 'Interaction', (29, 40))	('enhance', 'PosReg', (266, 273))	('tumor', 'Disease', (366, 371))	('VEGF receptor', 'Gene', (95, 108))	('VEGF', 'Gene', '7422', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Disease', (191, 196))	('VEGF receptor', 'Gene', '3791', (95, 108))	('enhance T cell', 'Phenotype', 'HP:0100828', (266, 280))	('VEGF', 'Gene', (110, 114))	('VEGF', 'Gene', '7422', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('blockade', 'Var', (13, 21))	('axitinib', 'Chemical', 'MESH:D000077784', (151, 159))	('enhancement', 'PosReg', (328, 339))	('VEGF', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('vascular endothelial growth factor', 'Gene', '7422', (49, 83))
34018	31428683	In order to explain the role of PYCR1 accurately, we knocked down PYCR1 using siRNA in Ketr-3 cells.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('knocked', 'Var', (53, 60))	('PYCR1', 'Gene', '5831', (32, 37))	('PYCR1', 'Gene', (66, 71))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('PYCR1', 'Gene', (32, 37))	('PYCR1', 'Gene', '5831', (66, 71))
34021	31428683	As shown in Fig.2D, knockdown of PYCR1 blocked cell growth remarkably 48 h and 72 h after transfection (P < 0.01).	('PYCR1', 'Gene', '5831', (33, 38))	('blocked', 'NegReg', (39, 46))	('cell growth', 'biological_process', 'GO:0016049', ('47', '58'))	('cell growth', 'CPA', (47, 58))	('knockdown', 'Var', (20, 29))	('PYCR1', 'Gene', (33, 38))
34023	31428683	This investigation indicated that low-expression of PYCR1 weakened cell colony formation and the clone numbers verified this result (Fig.2E and 2F, P < 0.01).	('cell colony formation', 'CPA', (67, 88))	('low-expression', 'Var', (34, 48))	('PYCR1', 'Gene', (52, 57))	('formation', 'biological_process', 'GO:0009058', ('79', '88'))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('weakened', 'NegReg', (58, 66))	('PYCR1', 'Gene', '5831', (52, 57))	('clone numbers', 'CPA', (97, 110))
34024	31428683	Next, transwell assays were implemented to explore cell migration and invasion in Ketr-3 cells after PYCR1 knockdown.	('knockdown', 'Var', (107, 116))	('PYCR1', 'Gene', '5831', (101, 106))	('cell migration', 'biological_process', 'GO:0016477', ('51', '65'))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('PYCR1', 'Gene', (101, 106))
34025	31428683	The experimental results demonstrated that deficiency of PYCR1 inhibited Ketr-3 cell activity in the aspect of invasion while there was no significant difference in the control group (Fig.3A).	('PYCR1', 'Gene', (57, 62))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('Ketr-3 cell activity', 'CPA', (73, 93))	('con', 'Chemical', '-', (169, 172))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('PYCR1', 'Gene', '5831', (57, 62))	('inhibited', 'NegReg', (63, 72))	('invasion', 'CPA', (111, 119))	('deficiency', 'Var', (43, 53))
34032	31428683	All the data pointed to PYCR1 manipulating the Akt/mTOR pathway to affect cell proliferation, migration and invasion in PRCC.	('mTOR', 'Gene', (51, 55))	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('PRCC', 'Gene', (120, 124))	('cell proliferation', 'CPA', (74, 92))	('mTOR', 'Gene', '2475', (51, 55))	('PYCR1', 'Gene', (24, 29))	('Akt', 'Gene', '207', (47, 50))	('migration', 'CPA', (94, 103))	('affect', 'Reg', (67, 73))	('PRCC', 'Phenotype', 'HP:0006766', (120, 124))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('manipulating', 'Var', (30, 42))	('PYCR1', 'Gene', '5831', (24, 29))	('Akt', 'Gene', (47, 50))	('PRCC', 'Gene', '5546', (120, 124))	('invasion', 'CPA', (108, 116))	('cell proliferation', 'biological_process', 'GO:0008283', ('74', '92'))
34037	31428683	Recent studies have shown that proline metabolism plays an important function in humans, especially in cancer, suggesting that disruption of proline metabolism may be an attractive strategy for tumor treatment.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('humans', 'Species', '9606', (81, 87))	('proline', 'Chemical', 'MESH:D011392', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('proline metabolism', 'biological_process', 'GO:0006560', ('31', '49'))	('proline', 'Chemical', 'MESH:D011392', (141, 148))	('disruption', 'Var', (127, 137))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('proline metabolism', 'biological_process', 'GO:0006560', ('141', '159'))
34044	31428683	Moreover, the homolog of PYCR1, PYCR2, induces mutations related to microcephaly and hypomyelination.	('microcephaly and hypomyelination', 'Disease', 'MESH:D008831', (68, 100))	('hypomyelination', 'Phenotype', 'HP:0003429', (85, 100))	('mutations', 'Var', (47, 56))	('PYCR1', 'Gene', (25, 30))	('PYCR2', 'Gene', '29920', (32, 37))	('PYCR1', 'Gene', '5831', (25, 30))	('microcephaly', 'Phenotype', 'HP:0000252', (68, 80))	('PYCR2', 'Gene', (32, 37))	('induces', 'Reg', (39, 46))	('related to microcephaly', 'Phenotype', 'HP:0005484', (57, 80))
34048	31428683	In order to determine how PYCR1 regulates the physiological processes of tumor cells, we first examined the effect of silencing PYCR1 on the Akt/mTOR pathway.	('PYCR1', 'Gene', (26, 31))	('amine', 'Chemical', 'MESH:D000588', (97, 102))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('PYCR1', 'Gene', '5831', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mTOR', 'Gene', (145, 149))	('PYCR1', 'Gene', '5831', (26, 31))	('mTOR', 'Gene', '2475', (145, 149))	('silencing', 'Var', (118, 127))	('tumor', 'Disease', (73, 78))	('Akt', 'Gene', '207', (141, 144))	('PYCR1', 'Gene', (128, 133))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('Akt', 'Gene', (141, 144))
34049	31428683	The results of western blotting showed p-Akt and p-mTOR were impaired owing to knockdown PYCR1.	('mTOR', 'Gene', (51, 55))	('knockdown', 'Var', (79, 88))	('PYCR1', 'Gene', (89, 94))	('Akt', 'Gene', '207', (41, 44))	('impaired', 'NegReg', (61, 69))	('PYCR1', 'Gene', '5831', (89, 94))	('Akt', 'Gene', (41, 44))	('mTOR', 'Gene', '2475', (51, 55))
34054	31428683	The vitality of colony formation was also inhibited because of silencing PYCR1.	('PYCR1', 'Gene', '5831', (73, 78))	('formation', 'biological_process', 'GO:0009058', ('23', '32'))	('vitality of colony formation', 'CPA', (4, 32))	('inhibited', 'NegReg', (42, 51))	('PYCR1', 'Gene', (73, 78))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('silencing', 'Var', (63, 72))
34059	27741505	We identified mutations in the VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1, TP53 genes.	('RB1', 'Gene', (86, 89))	('FGFR3', 'Gene', (73, 78))	('PTEN', 'Gene', (36, 40))	('FGFR3', 'Gene', '2261', (73, 78))	('EGFR', 'Gene', '1956', (80, 84))	('JAK3', 'Gene', '3718', (42, 46))	('VHL', 'Gene', '7428', (31, 34))	('RB1', 'Gene', '5925', (86, 89))	('PTEN', 'Gene', '5728', (36, 40))	('MET', 'Gene', (48, 51))	('ERBB4', 'Gene', '2066', (53, 58))	('CDKN2A', 'Gene', (65, 71))	('mutations', 'Var', (14, 23))	('ERBB4', 'Gene', (53, 58))	('APC', 'Disease', 'MESH:D011125', (60, 63))	('TP53', 'Gene', (91, 95))	('APC', 'Disease', (60, 63))	('FGFR', 'molecular_function', 'GO:0005007', ('73', '77'))	('EGFR', 'molecular_function', 'GO:0005006', ('80', '84'))	('EGFR', 'Gene', (80, 84))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('CDKN2A', 'Gene', '1029', (65, 71))	('APC', 'cellular_component', 'GO:0005680', ('60', '63'))	('TP53', 'Gene', '7157', (91, 95))	('VHL', 'Gene', (31, 34))	('JAK3', 'Gene', (42, 46))
34060	27741505	Most mutations hit VHL1 (31,8%) followed by PTEN (13,6%), JAK3, FGFR and TP53 (9% each).	('JAK3', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (73, 77))	('JAK3', 'Gene', '3718', (58, 62))	('VHL1', 'Gene', (19, 23))	('FGFR', 'molecular_function', 'GO:0005007', ('64', '68'))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (5, 14))	('PTEN', 'Gene', (44, 48))	('PTEN', 'Gene', '5728', (44, 48))	('JAK', 'molecular_function', 'GO:0004713', ('58', '61'))	('VHL1', 'Gene', '7428', (19, 23))	('hit', 'Reg', (15, 18))
34064	27741505	Among the 4 partial responders, 1 (25%) was wild-type and 3 (75%) harbored different VHL1 variants.	('variants', 'Var', (90, 98))	('VHL1', 'Gene', (85, 89))	('VHL1', 'Gene', '7428', (85, 89))	('harbored', 'Reg', (66, 74))
34065	27741505	Among the 7 patients with disease stabilization 2 (29%) were wild-type, 2 (29%) PTEN mutated, and single patients (14% each) displayed mutations in VHL1, JAK3 and APC/CDKN2A.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (105, 113))	('PTEN', 'Gene', (80, 84))	('JAK', 'molecular_function', 'GO:0004713', ('154', '157'))	('PTEN', 'Gene', '5728', (80, 84))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('mutations', 'Var', (135, 144))	('APC', 'Disease', (163, 166))	('VHL1', 'Gene', '7428', (148, 152))	('APC', 'Disease', 'MESH:D011125', (163, 166))	('JAK3', 'Gene', (154, 158))	('APC', 'cellular_component', 'GO:0005680', ('163', '166'))	('JAK3', 'Gene', '3718', (154, 158))	('VHL1', 'Gene', (148, 152))
34078	27741505	According to the Cancer Genome Atlas database the most frequent somatic mutations in ccRCC include mainly alterations of the VHL gene and its partners involved in neo-angiogenesis and response to hypoxia, followed by alterations of the PI(3)K/AKT/mTOR pathway.	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('mTOR', 'Gene', (247, 251))	('mutations', 'Var', (72, 81))	('VHL', 'Gene', (125, 128))	('angiogenesis', 'biological_process', 'GO:0001525', ('167', '179'))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mTOR', 'Gene', '2475', (247, 251))	('alterations', 'Reg', (217, 228))	('AKT', 'Gene', (243, 246))	('response to hypoxia', 'biological_process', 'GO:0001666', ('184', '203'))	('Cancer', 'Disease', (17, 23))	('VHL', 'Gene', '7428', (125, 128))	('hypoxia', 'Disease', (196, 203))	('alterations', 'Reg', (106, 117))	('RCC', 'Disease', (87, 90))	('AKT', 'Gene', '207', (243, 246))	('PI(3)K', 'molecular_function', 'GO:0016303', ('236', '242'))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('hypoxia', 'Disease', 'MESH:D000860', (196, 203))
34079	27741505	Conversely, the most frequent somatic genetic changes in non-ccRCC such as the papillary histotype (pRCC) involve mutations or copy number variations of the MET oncogene or loss of the tumor suppressor gene CDKN2A.	('RCC', 'Disease', (63, 66))	('loss of the tumor', 'Disease', (173, 190))	('pRCC', 'Gene', '5546', (100, 104))	('CDKN2A', 'Gene', (207, 213))	('CDKN2A', 'Gene', '1029', (207, 213))	('mutations', 'Var', (114, 123))	('tumor suppressor', 'biological_process', 'GO:0051726', ('185', '201'))	('RCC', 'Disease', 'MESH:C538614', (101, 104))	('papillary histotype', 'Phenotype', 'HP:0007482', (79, 98))	('RCC', 'Disease', (101, 104))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('185', '201'))	('pRCC', 'Gene', (100, 104))	('MET oncogene', 'Gene', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('copy number variations', 'Var', (127, 149))	('papillary histotype', 'Disease', (79, 98))	('loss of the tumor', 'Disease', 'MESH:D009369', (173, 190))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
34109	27741505	We identified mutations in the genes VHL, PTEN, JAK3, MET, ERBB4, APC, CDKN2A, FGFR3, EGFR, RB1 and TP53.	('FGFR3', 'Gene', '2261', (79, 84))	('TP53', 'Gene', (100, 104))	('EGFR', 'molecular_function', 'GO:0005006', ('86', '90'))	('JAK3', 'Gene', (48, 52))	('VHL', 'Gene', (37, 40))	('EGFR', 'Gene', '1956', (86, 90))	('APC', 'cellular_component', 'GO:0005680', ('66', '69'))	('RB1', 'Gene', (92, 95))	('JAK', 'molecular_function', 'GO:0004713', ('48', '51'))	('MET', 'Gene', (54, 57))	('mutations', 'Var', (14, 23))	('JAK3', 'Gene', '3718', (48, 52))	('PTEN', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (100, 104))	('ERBB4', 'Gene', '2066', (59, 64))	('FGFR', 'molecular_function', 'GO:0005007', ('79', '83'))	('CDKN2A', 'Gene', (71, 77))	('VHL', 'Gene', '7428', (37, 40))	('ERBB4', 'Gene', (59, 64))	('APC', 'Disease', 'MESH:D011125', (66, 69))	('APC', 'Disease', (66, 69))	('RB1', 'Gene', '5925', (92, 95))	('PTEN', 'Gene', '5728', (42, 46))	('FGFR3', 'Gene', (79, 84))	('CDKN2A', 'Gene', '1029', (71, 77))	('EGFR', 'Gene', (86, 90))
34111	27741505	In particular, the most frequent mutations (7/22 patients 31,8%) affected the VHL1 gene, all were in different loci and except for 3 cases were always associated with other mutations.	('associated', 'Reg', (151, 161))	('VHL1', 'Gene', (78, 82))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (65, 73))	('patients', 'Species', '9606', (49, 57))	('VHL1', 'Gene', '7428', (78, 82))
34112	27741505	VHL1 was mutated in 6 primary RCC, in 2 metastatic sites and in 1 sarcomatoid and 2 rhabdoid components of primary RCCs.	('VHL1', 'Gene', '7428', (0, 4))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('mutated', 'Var', (9, 16))	('RCC', 'Disease', (115, 118))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('sarcomatoid', 'Disease', 'MESH:C538614', (66, 77))	('RCC', 'Disease', (30, 33))	('VHL1', 'Gene', (0, 4))	('sarcomatoid', 'Disease', (66, 77))	('rhabdoid component', 'Disease', 'MESH:D018335', (84, 102))	('rhabdoid component', 'Disease', (84, 102))
34113	27741505	The VHL1 mutation variant was concordant between primary and the corresponding metastasis in 1 out of 2 cases.	('variant', 'Var', (18, 25))	('VHL1', 'Gene', (4, 8))	('VHL1', 'Gene', '7428', (4, 8))	('mutation variant', 'Var', (9, 25))
34114	27741505	PTEN was found mutated in 3/22 (13,6%) patients and only in 1 case was associated with mutations of VHL 1 and FGFR3.	('patients', 'Species', '9606', (39, 47))	('FGFR', 'molecular_function', 'GO:0005007', ('110', '114'))	('PTEN', 'Gene', '5728', (0, 4))	('FGFR3', 'Gene', '2261', (110, 115))	('VHL 1', 'Gene', '7428', (100, 105))	('VHL 1', 'Gene', (100, 105))	('PTEN', 'Gene', (0, 4))	('FGFR3', 'Gene', (110, 115))	('mutations', 'Var', (87, 96))
34115	27741505	Two cases harbored the same PTEN variant (L320S).	('PTEN', 'Gene', (28, 32))	('L320S', 'Mutation', 'p.L320S', (42, 47))	('L320S', 'Var', (42, 47))	('PTEN', 'Gene', '5728', (28, 32))
34116	27741505	Two patients (2/22) ( 9%) showed the same JAK3 mutation variant (V722I); it was associated with a VHL 1 mutation and was revealed both in the sarcomatoid and rhadboid component of the same patient, while in the other patient it was present as a single mutation in the primary RCC and the metastatic lesion.	('VHL 1', 'Gene', '7428', (98, 103))	('RCC', 'Disease', 'MESH:C538614', (276, 279))	('VHL 1', 'Gene', (98, 103))	('sarcomatoid', 'Disease', (142, 153))	('V722I);', 'Var', (65, 72))	('RCC', 'Disease', (276, 279))	('patient', 'Species', '9606', (217, 224))	('V722I', 'Mutation', 'rs3213409', (65, 70))	('patient', 'Species', '9606', (4, 11))	('patient', 'Species', '9606', (189, 196))	('associated', 'Reg', (80, 90))	('mutation', 'Var', (104, 112))	('sarcomatoid', 'Disease', 'MESH:C538614', (142, 153))	('patients', 'Species', '9606', (4, 12))	('JAK', 'molecular_function', 'GO:0004713', ('42', '45'))	('JAK3', 'Gene', (42, 46))	('JAK3', 'Gene', '3718', (42, 46))
34117	27741505	Two patients (9%) harboured a mutation of the FGFR3 gene (F386L); in both cases it was associated with a VHL1 mutation (1 cases also with a PTEN mutation) and each patient presented respectively the mutation both in the primary RCC and the corresponding metastasis and the clear cell and in the rhabdoid component.	('VHL1', 'Gene', (105, 109))	('rhabdoid component', 'Disease', (295, 313))	('RCC', 'Disease', (228, 231))	('RCC', 'Disease', 'MESH:C538614', (228, 231))	('patient', 'Species', '9606', (164, 171))	('FGFR', 'molecular_function', 'GO:0005007', ('46', '50'))	('patient', 'Species', '9606', (4, 11))	('associated', 'Reg', (87, 97))	('FGFR3', 'Gene', '2261', (46, 51))	('PTEN', 'Gene', '5728', (140, 144))	('rhabdoid component', 'Disease', 'MESH:D018335', (295, 313))	('mutation', 'Var', (110, 118))	('patients', 'Species', '9606', (4, 12))	('F386L);', 'Var', (58, 65))	('VHL1', 'Gene', '7428', (105, 109))	('FGFR3', 'Gene', (46, 51))	('PTEN', 'Gene', (140, 144))	('F386L', 'Mutation', 'rs17881656', (58, 63))
34119	27741505	Mutation in MET gene was found in 1/22 patients (4,5%) in the primary RCC and in association with VHL1 mutation.	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('VHL1', 'Gene', '7428', (98, 102))	('RCC', 'Disease', (70, 73))	('patients', 'Species', '9606', (39, 47))	('Mutation', 'Var', (0, 8))	('VHL1', 'Gene', (98, 102))	('MET', 'Gene', (12, 15))	('found', 'Reg', (25, 30))
34120	27741505	ERBB4 mutation were discovered in 1/22 (4,5%) patients in both primary and metastatic RCC sites, in association with VHL1 mutation.	('ERBB4', 'Gene', '2066', (0, 5))	('VHL1', 'Gene', (117, 121))	('patients', 'Species', '9606', (46, 54))	('mutation', 'Var', (6, 14))	('ERBB4', 'Gene', (0, 5))	('VHL1', 'Gene', '7428', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))
34121	27741505	Double mutations in the APC and DCKN2A genes was found in the same patient in the primary RCC.	('RCC', 'Disease', (90, 93))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('Double mutations', 'Var', (0, 16))	('APC', 'cellular_component', 'GO:0005680', ('24', '27'))	('DCKN2A', 'Gene', (32, 38))	('APC', 'Disease', 'MESH:D011125', (24, 27))	('APC', 'Disease', (24, 27))	('patient', 'Species', '9606', (67, 74))	('found', 'Reg', (49, 54))
34122	27741505	Mutations of EGFR and RB1genes were both detected in 1 patients in the rhabdoid component of the primary RCC.	('rhabdoid component of the primary RCC', 'Disease', 'MESH:C538614', (71, 108))	('RB1', 'Gene', (22, 25))	('rhabdoid component of the primary RCC', 'Disease', (71, 108))	('Mutations', 'Var', (0, 9))	('EGFR', 'molecular_function', 'GO:0005006', ('13', '17'))	('patients', 'Species', '9606', (55, 63))	('RB1', 'Gene', '5925', (22, 25))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('detected', 'Reg', (41, 49))
34125	27741505	In particular the four pRCC harbored mutations in the APC, DCKN2A, PTEN and TP53 genes but not in VHL1.	('APC', 'Disease', 'MESH:D011125', (54, 57))	('DCKN2A', 'Gene', (59, 65))	('APC', 'Disease', (54, 57))	('VHL1', 'Gene', '7428', (98, 102))	('pRCC', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (76, 80))	('VHL1', 'Gene', (98, 102))	('harbored', 'Reg', (28, 36))	('TP53', 'Gene', (76, 80))	('PTEN', 'Gene', (67, 71))	('mutations', 'Var', (37, 46))	('pRCC', 'Gene', '5546', (23, 27))	('PTEN', 'Gene', '5728', (67, 71))	('APC', 'cellular_component', 'GO:0005680', ('54', '57'))
34126	27741505	Eight (42%) out of the remaining 19 ccRCC tumors habored at least one VHL1 mutation although with different variants.	('RCC', 'Disease', (38, 41))	('VHL1', 'Gene', (70, 74))	('tumors habored', 'Disease', (42, 56))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (75, 83))	('tumors habored', 'Disease', 'MESH:D009369', (42, 56))	('VHL1', 'Gene', '7428', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
34127	27741505	As depicted in Table 3, the concordance between the primary RCC and its rhadboid/sarcomatoid component was seen in 2/3 cases: FGFR3 F386L and VHL1 V13fs*7 (rhabdoid and primary RCC) and VHL1 P97R and JAK3 (rhabdoid and sarcomatoid component of RCC).	('RCC', 'Disease', (244, 247))	('JAK', 'molecular_function', 'GO:0004713', ('200', '203'))	('JAK3', 'Gene', (200, 204))	('FGFR3', 'Gene', (126, 131))	('RCC', 'Disease', (60, 63))	('F386L', 'Mutation', 'rs17881656', (132, 137))	('FGFR3', 'Gene', '2261', (126, 131))	('VHL1', 'Gene', (142, 146))	('rhabdoid', 'Disease', (206, 214))	('RCC', 'Disease', 'MESH:C538614', (244, 247))	('RCC', 'Disease', (177, 180))	('JAK3', 'Gene', '3718', (200, 204))	('sarcomatoid component', 'Disease', (219, 240))	('VHL1', 'Gene', '7428', (142, 146))	('sarcomatoid component', 'Disease', 'MESH:C538614', (219, 240))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('rhabdoid', 'Disease', 'MESH:D018335', (206, 214))	('FGFR', 'molecular_function', 'GO:0005007', ('126', '130'))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('P97R', 'Mutation', 'rs587782886', (191, 195))	('rhabdoid', 'Disease', (156, 164))	('F386L', 'Var', (132, 137))	('rhabdoid', 'Disease', 'MESH:D018335', (156, 164))	('sarcomatoid component', 'Disease', (81, 102))	('sarcomatoid component', 'Disease', 'MESH:C538614', (81, 102))	('VHL1', 'Gene', (186, 190))	('VHL1', 'Gene', '7428', (186, 190))	('rhabdoid and sarcomatoid component of RCC', 'Disease', 'MESH:C538614', (206, 247))
34134	27741505	Among the 4 partial responders, 1 (25%) was wild-type for all genes and 3 (75%) harbored different VHL1 variants.	('VHL1', 'Gene', '7428', (99, 103))	('VHL1', 'Gene', (99, 103))	('variants', 'Var', (104, 112))	('harbored', 'Reg', (80, 88))
34138	27741505	Among the 11 non-responders 7 (64%) were wild-type for all genes, 2 (18%) were TP53 mutated (in different loci) and 2 (18%) were VHL1 mutated.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('VHL1', 'Gene', (129, 133))	('mutated', 'Var', (84, 91))	('VHL1', 'Gene', '7428', (129, 133))
34141	27741505	Two patients harbouring just the same PTEN L320S mutation survived for at least 27 or 30 months.	('PTEN', 'Gene', '5728', (38, 42))	('L320S', 'Mutation', 'p.L320S', (43, 48))	('L320S', 'Var', (43, 48))	('patients', 'Species', '9606', (4, 12))	('PTEN', 'Gene', (38, 42))
34143	27741505	The ccRCC is largely the most common histotype and it is tightly associated with alteration of the VHL1-HIF pathway, while non-clear cell tumors are characterized by alterations of the PI3K and MET pathways.	('VHL1', 'Gene', '7428', (99, 103))	('PI3K', 'molecular_function', 'GO:0016303', ('185', '189'))	('alteration', 'Var', (81, 91))	('cell tumors', 'Disease', 'MESH:D005935', (133, 144))	('alterations', 'Reg', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('VHL1', 'Gene', (99, 103))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))	('cell tumors', 'Disease', (133, 144))
34146	27741505	Although we did not find a significant association between histotype and mutation variants we found that approximately 40% of ccRCC harboured mutations of VHL1 gene compared to none in the pRCC group.	('VHL1', 'Gene', (155, 159))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('mutations', 'Var', (142, 151))	('RCC', 'Disease', (128, 131))	('pRCC', 'Gene', '5546', (189, 193))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', (190, 193))	('pRCC', 'Gene', (189, 193))	('VHL1', 'Gene', '7428', (155, 159))
34147	27741505	Mutations in some genes such as VHL1, PTEN, JAK3 and TP53 are well recognized.	('PTEN', 'Gene', '5728', (38, 42))	('JAK', 'molecular_function', 'GO:0004713', ('44', '47'))	('VHL1', 'Gene', (32, 36))	('JAK3', 'Gene', (44, 48))	('JAK3', 'Gene', '3718', (44, 48))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (53, 57))	('VHL1', 'Gene', '7428', (32, 36))	('TP53', 'Gene', (53, 57))
34148	27741505	By contrast, mutations in the genes APC, ERBB4, RB1, EGFR, FGFR3 have been rarely or never found in RCC but were encountered in our series.	('FGFR3', 'Gene', '2261', (59, 64))	('RB1', 'Gene', (48, 51))	('FGFR', 'molecular_function', 'GO:0005007', ('59', '63'))	('FGFR3', 'Gene', (59, 64))	('ERBB4', 'Gene', '2066', (41, 46))	('RB1', 'Gene', '5925', (48, 51))	('EGFR', 'Gene', (53, 57))	('EGFR', 'molecular_function', 'GO:0005006', ('53', '57'))	('APC', 'cellular_component', 'GO:0005680', ('36', '39'))	('EGFR', 'Gene', '1956', (53, 57))	('ERBB4', 'Gene', (41, 46))	('mutations', 'Var', (13, 22))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('APC', 'Disease', 'MESH:D011125', (36, 39))	('APC', 'Disease', (36, 39))
34150	27741505	Taken together all these data bring to the conclusion that more gene variants than expected are associated with mRCC, and are non-mutually exclusive.	('variants', 'Var', (69, 77))	('RCC', 'Disease', 'MESH:C538614', (113, 116))	('associated', 'Reg', (96, 106))	('RCC', 'Disease', (113, 116))
34151	27741505	Mutations of VHL1 are the most frequent but involve wide number of loci.	('frequent', 'Reg', (31, 39))	('Mutations', 'Var', (0, 9))	('VHL1', 'Gene', (13, 17))	('VHL1', 'Gene', '7428', (13, 17))
34153	27741505	In addition, our mutational analysis is based on a panel generating 207 amplicons covering approximately 2,800 COSMIC mutations from 50 of the most altered oncogenes and tumor suppressor genes in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('170', '186'))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('solid tumors', 'Disease', (196, 208))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', (170, 175))	('solid tumors', 'Disease', 'MESH:D009369', (196, 208))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('170', '186'))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
34158	27741505	In fact, we found that three of the four patients experiencing partial response after first-line therapy were treated with a TKI with anti-angiogenetic activity and actually harbored mutations of the pro-angiogenic gene VHL1, although in different loci.	('mutations', 'Var', (183, 192))	('harbored', 'Reg', (174, 182))	('VHL1', 'Gene', '7428', (220, 224))	('patients', 'Species', '9606', (41, 49))	('VHL1', 'Gene', (220, 224))
34159	27741505	By contrast, other three patients with tumors harboring VHL1 mutations experienced progressive disease with similar therapies.	('VHL1', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('experienced', 'Reg', (71, 82))	('mutations', 'Var', (61, 70))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('VHL1', 'Gene', '7428', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (25, 33))	('progressive', 'Disease', (83, 94))	('tumors', 'Disease', (39, 45))
34160	27741505	Although in few patients, this finding is in line with other studies reporting no association between VHL1 mutations and objective responses to anti-angiogenic TKIs.	('patients', 'Species', '9606', (16, 24))	('VHL1', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))	('VHL1', 'Gene', '7428', (102, 106))
34164	27741505	It is also noteworthy that our data do not seem to confirm the well known role of mutations within the mTOR patway components to predict long term benefit from mTOR inhibitors.	('mTOR', 'Gene', (103, 107))	('mTOR', 'Gene', '2475', (160, 164))	('mTOR', 'Gene', (160, 164))	('mutations', 'Var', (82, 91))	('mTOR', 'Gene', '2475', (103, 107))
34166	27741505	An interesting aspect of our work is the finding of rare potentially actionable mutations such as FGFR3 and JAK3 for which effective targeted agents are available and currently under investigation in other tumor types We can therefore conclude that in the absence of established molecular predictors of response to targeted therapies in mRCC an NGS approach may address single patients to basket trials enrolling according to molecular specific alterations regardless of the pathological features.	('JAK3', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('JAK3', 'Gene', '3718', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (338, 341))	('FGFR3', 'Gene', (98, 103))	('mutations', 'Var', (80, 89))	('tumor', 'Disease', (206, 211))	('JAK', 'molecular_function', 'GO:0004713', ('108', '111'))	('patients', 'Species', '9606', (377, 385))	('FGFR', 'molecular_function', 'GO:0005007', ('98', '102'))	('FGFR3', 'Gene', '2261', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('RCC', 'Disease', (338, 341))
34187	29090117	However, eosinophilic examples of chromophobe renal cell carcinoma may exhibit less extensive CK7 labeling, making selection of a positive staining threshold more challenging.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (46, 66))	('chromophobe renal cell carcinoma', 'Disease', (34, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('eosinophilic', 'Var', (9, 21))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 66))	('CK7', 'Protein', (94, 97))
34204	29090117	Based on karyotype data, oncocytomas have been generally found to exhibit either a diploid karyotype, loss of chromosome 1, loss of Y, or rearrangement of 11q13, including t(5;11)(q35;q13).	('loss', 'NegReg', (124, 128))	('t(5;11)(q35;q13', 'Var', (172, 187))	('oncocytomas', 'Disease', (25, 36))	('rearrangement', 'Var', (138, 151))	('chromosome', 'cellular_component', 'GO:0005694', ('110', '120'))	('t(5;11)(q35;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (172, 188))	('loss', 'NegReg', (102, 106))	('oncocytomas', 'Disease', 'MESH:D018249', (25, 36))	('11q13', 'Gene', (155, 160))
34205	29090117	As it is the locus of the CCND1 gene (cyclin D1), it has been subsequently found that many of these likely represent rearrangements involving CCND1, and emerging data suggest that oncocytomas harboring such rearrangements may represent a distinctive tumor subset.	('CCND1', 'Gene', (142, 147))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('cyclin', 'molecular_function', 'GO:0016538', ('38', '44'))	('rearrangements', 'Var', (207, 221))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('cyclin D1', 'Gene', '595', (38, 47))	('cyclin D1', 'Gene', (38, 47))	('oncocytomas', 'Disease', (180, 191))	('oncocytomas', 'Disease', 'MESH:D018249', (180, 191))
34206	29090117	found that more than half of oncocytomas with cyclin D1 immunohistochemical labeling had CCND1 rearrangement by FISH, compared to only a single tumor with rearrangement by FISH but without cyclin D1 staining.	('tumor', 'Disease', (144, 149))	('oncocytomas', 'Disease', (29, 40))	('cyclin D1', 'Gene', '595', (46, 55))	('oncocytomas', 'Disease', 'MESH:D018249', (29, 40))	('cyclin', 'molecular_function', 'GO:0016538', ('46', '52'))	('cyclin', 'molecular_function', 'GO:0016538', ('189', '195'))	('cyclin D1', 'Gene', (46, 55))	('cyclin D1', 'Gene', (189, 198))	('CCND1', 'Gene', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cyclin D1', 'Gene', '595', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('rearrangement', 'Var', (95, 108))
34210	29090117	Both oncocytoma and chromophobe renal cell carcinoma are noted to have mutations in mitochondrial genes.	('oncocytoma and chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (5, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (32, 52))	('mitochondrial genes', 'Gene', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('mutations', 'Var', (71, 80))
34219	29090117	In general, a diploid karyotype or loss of chromosome 1 in the appropriate morphologic and immunohistochemical context can be considered supportive of an oncocytoma diagnosis, whereas other losses or other alterations not typical of oncocytoma might be used to favor a borderline diagnosis or classification as chromophobe renal cell carcinoma.	('diploid', 'Var', (14, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (323, 343))	('chromophobe renal cell carcinoma', 'Disease', (311, 343))	('chromosome', 'cellular_component', 'GO:0005694', ('43', '53'))	('loss', 'Var', (35, 39))	('oncocytoma', 'Disease', (154, 164))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (311, 343))	('oncocytoma', 'Disease', 'MESH:D018249', (154, 164))	('oncocytoma', 'Disease', (233, 243))	('oncocytoma', 'Disease', 'MESH:D018249', (233, 243))
34246	29090117	These tumors are associated with an autosomal dominant mutation in subunits of the SDH complex genes, a component of the mitochondrial complex II.	('associated', 'Reg', (17, 27))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('SDH', 'Gene', '6390', (83, 86))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('SDH', 'Gene', (83, 86))	('complex II', 'molecular_function', 'GO:0008177', ('135', '145'))	('autosomal dominant mutation', 'Var', (36, 63))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
34252	29090117	Although rare renal tumors with mutations in other subunits of the SDH complex or negative SDHA staining have been reported, in general it appears that defects in any of the subunits destabilize the enzyme complex, resulting in abnormal negative SDHB staining regardless of which gene harbors the mutation, making SDHB a useful screening immunohistochemical marker.	('SDH', 'Gene', (91, 94))	('SDH', 'Gene', '6390', (246, 249))	('negative', 'NegReg', (237, 245))	('renal tumors', 'Disease', 'MESH:D007674', (14, 26))	('SDH', 'Gene', (314, 317))	('renal tumors', 'Disease', (14, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('defects', 'Var', (152, 159))	('renal tumors', 'Phenotype', 'HP:0009726', (14, 26))	('staining', 'MPA', (251, 259))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('SDH', 'Gene', (246, 249))	('renal tumor', 'Phenotype', 'HP:0009726', (14, 25))	('SDH', 'Gene', '6390', (67, 70))	('SDH', 'Gene', '6390', (91, 94))	('enzyme complex', 'cellular_component', 'GO:1902494', ('199', '213'))	('destabilize', 'NegReg', (183, 194))	('SDH', 'Gene', '6390', (314, 317))	('SDHA', 'Chemical', '-', (91, 95))	('SDH', 'Gene', (67, 70))
34256	29090117	Although positive CK7 is generally considered a feature of papillary renal cell carcinoma, this is less true in eosinophilic examples, and therefore limited CK7 staining may not be helpful in excluding the possibility of papillary renal cell carcinoma.	('CK7', 'Var', (18, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (59, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (231, 251))	('papillary renal cell carcinoma', 'Disease', (59, 89))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (221, 251))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (221, 251))	('papillary renal cell carcinoma', 'Disease', (221, 251))
34277	28454375	A comprehensive analysis of cancer-driving mutations and genes in kidney cancer An accumulation of driver mutations is important for cancer formation and progression, and leads to the disruption of genes and signaling pathways.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('disruption', 'NegReg', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('kidney cancer', 'Disease', 'MESH:D007680', (66, 79))	('signaling', 'biological_process', 'GO:0023052', ('208', '217'))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (66, 79))	('accumulation', 'PosReg', (83, 95))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutations', 'Var', (106, 115))	('kidney cancer', 'Disease', (66, 79))	('cancer', 'Disease', (28, 34))	('formation', 'biological_process', 'GO:0009058', ('140', '149'))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
34278	28454375	The present study was performed to identify cancer-driving mutations and genes in renal cell carcinoma (RCC), prioritizing noncoding variants with a high functional impact, in order to analyze the most informative features.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('renal cell carcinoma', 'Disease', (82, 102))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('mutations', 'Var', (59, 68))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (82, 102))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('RCC', 'Disease', (104, 107))
34280	28454375	A total of 1,327 coding mutations in clear cell RCC, 258 in chromophobe RCC and 1,186 in papillary RCC were predicted to be deleterious by all three of MutationAssessor, Polyphen2 and SIFT.	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('chromophobe RCC', 'Disease', (60, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('SIFT', 'Disease', (184, 188))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('RCC', 'Disease', (99, 102))	('chromophobe RCC', 'Disease', 'MESH:C538614', (60, 75))	('SIFT', 'Disease', 'None', (184, 188))	('mutations', 'Var', (24, 33))	('RCC', 'Disease', (48, 51))	('RCC', 'Phenotype', 'HP:0005584', (48, 51))
34282	28454375	In conclusion, the present study identified a list of cancer-driving genes and signaling pathways, features like regulatory elements, conserved regions, replication time, expression, GC content and recombination rate are major factors that affect the distribution of high-scoring non-coding mutations in kidney cancer.	('kidney cancer', 'Disease', (304, 317))	('non-coding mutations', 'Var', (280, 300))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', (54, 60))	('kidney cancer', 'Disease', 'MESH:D007680', (304, 317))	('signaling', 'biological_process', 'GO:0023052', ('79', '88'))	('rat', 'Species', '10116', (212, 215))	('kidney cancer', 'Phenotype', 'HP:0009726', (304, 317))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
34283	28454375	Rapid advancements in sequencing technology and its wide applications have identified hundreds of thousands of mutations in cancer genomes; a small fraction of these mutations, termed drivers, are critical for carcinogenesis and are able to confer a growth advantage to tumor cells by affecting driver genes.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (270, 275))	('mutations', 'Var', (166, 175))	('growth advantage', 'CPA', (250, 266))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('carcinogenesis', 'Disease', 'MESH:D063646', (210, 224))	('affecting', 'Reg', (285, 294))	('driver genes', 'Gene', (295, 307))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('carcinogenesis', 'Disease', (210, 224))
34285	28454375	Various computational approaches have been developed to prioritize deleterious cancer mutations, including the Sorting Intolerant From Tolerant (SIFT) algorithm, Polymorphism Phenotyping version 2 (PolyPhen2) tool and MutationAssessor.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SIFT', 'Disease', (145, 149))	('SIFT', 'Disease', 'None', (145, 149))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
34288	28454375	OncodriveFM detects genes with a bias towards the accumulation of variants with high functional impacts, as evaluated by SIFT, PolyPhen2 and MutationAssessor.	('accumulation', 'PosReg', (50, 62))	('SIFT', 'Disease', 'None', (121, 125))	('SIFT', 'Disease', (121, 125))	('variants', 'Var', (66, 74))
34289	28454375	Another program, OncodriveCLUST, identifies genes with a significant bias towards gain-of-function mutations that are clustered within the protein-coding sequence, based on the knowledge that the clustering of gain-of-function mutations in specific protein regions provides an adaptive advantage to cancer cells, and is consequently positively selected for during tumoral evolution.	('protein', 'cellular_component', 'GO:0003675', ('249', '256'))	('gain-of-function', 'PosReg', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('gain-of-function', 'PosReg', (210, 226))	('mutations', 'Var', (99, 108))	('adaptive advantage', 'CPA', (277, 295))	('tumoral', 'Disease', (364, 371))	('tumoral', 'Disease', 'MESH:D009369', (364, 371))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('protein', 'cellular_component', 'GO:0003675', ('139', '146'))	('mutations', 'Var', (227, 236))
34297	28454375	The current study was conducted to analyze the somatic mutations detected by whole-genome sequencing of 14 clear-cell renal cell carcinoma (ccRCC) tissue samples and exome sequencing of 106 ccRCC tissue specimens, 65 paired chromophobe renal cell carcinoma (chRCC) tissue samples and 100 paired papillary renal cell carcinoma (PRCC) tissue samples.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('PRCC', 'Gene', '5546', (327, 331))	('papillary renal cell carcinoma', 'Disease', (295, 325))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (305, 325))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (236, 256))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (107, 138))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (224, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('RCC', 'Phenotype', 'HP:0005584', (328, 331))	('RCC', 'Disease', (328, 331))	('RCC', 'Disease', (192, 195))	('RCC', 'Phenotype', 'HP:0005584', (192, 195))	('ccRCC', 'Phenotype', 'HP:0006770', (190, 195))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (295, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('mutations', 'Var', (55, 64))	('chromophobe renal cell carcinoma', 'Disease', (224, 256))	('PRCC', 'Gene', (327, 331))	('RCC', 'Disease', 'MESH:C538614', (328, 331))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (305, 325))	('RCC', 'Disease', 'MESH:C538614', (192, 195))	('PRCC', 'Phenotype', 'HP:0006766', (327, 331))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (236, 256))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (295, 325))	('renal cell carcinoma', 'Disease', (118, 138))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('RCC', 'Disease', (260, 263))
34299	28454375	The enrichment of high-scoring variants for a wide range of noncoding features was also examined to identify the features that most contribute to the functionalities of noncoding cancer mutations.	('variants', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (186, 195))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))
34301	28454375	Data for chRCC and PRCC mutations that had been identified using exome-sequencing of 65 and 100 paired chRCC and PRCC tissue samples by Lawrence et al were also obtained.	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Phenotype', 'HP:0005584', (20, 23))	('mutations', 'Var', (24, 33))	('RCC', 'Disease', (11, 14))	('RCC', 'Disease', (20, 23))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (105, 108))	('RCC', 'Disease', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('PRCC', 'Gene', (19, 23))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('PRCC', 'Gene', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('PRCC', 'Phenotype', 'HP:0006766', (19, 23))	('PRCC', 'Phenotype', 'HP:0006766', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (105, 108))	('PRCC', 'Gene', '5546', (19, 23))	('PRCC', 'Gene', '5546', (113, 117))
34302	28454375	The functional impacts of somatic mutations in the coding genome were predicted using SIFT, Polyphen2 and MutationAssessor version 3.	('SIFT', 'Disease', (86, 90))	('mutations', 'Var', (34, 43))	('SIFT', 'Disease', 'None', (86, 90))
34303	28454375	Variants were considered deleterious based on the following criteria: SIFT score <0.05; the presence of non-benign variants in the HumDiv and HumVar predictions of Polyphen2; and a MutationAssessor score >1.9.	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', (70, 74))	('variants', 'Var', (115, 123))	('SIFT', 'Disease', 'None', (70, 74))	('HumDiv', 'Gene', (131, 137))
34320	28454375	In total, 70,659 noncoding variants detected by whole-genome sequencing of 14 paired ccRCC tissue samples were scored for deleteriousness using CADD v1.0 , FunSeq2.1.2  and GWAVA v1.0 , and all parameters were set to default.	('variants', 'Var', (27, 35))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('ccRCC', 'Phenotype', 'HP:0006770', (85, 90))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
34324	28454375	In total, 76,595 somatic mutations were obtained from Sato et al, comprising 71,424 mutations generated by whole-genome sequencing of 14 ccRCC tissue samples and 5,171 mutations detected by whole-exome sequencing of 106 ccRCC specimens.	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (222, 225))	('RCC', 'Disease', (139, 142))	('mutations', 'Var', (84, 93))	('rat', 'Species', '10116', (98, 101))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('ccRCC', 'Phenotype', 'HP:0006770', (137, 142))	('RCC', 'Disease', (222, 225))	('ccRCC', 'Phenotype', 'HP:0006770', (220, 225))
34325	28454375	A total of 1,381 mutations detected by exome sequencing of 65 paired chRCC tissue samples included 1,287 SNVs and 94 indels; whereas 6,349 mutations were detected by exome sequencing of the 100 paired PRCC specimens, consisting of 5,489 SNVs, 677 indels and 180 dinitropyrenes.	('PRCC', 'Phenotype', 'HP:0006766', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('RCC', 'Disease', (71, 74))	('PRCC', 'Gene', '5546', (201, 205))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('PRCC', 'Gene', (201, 205))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('RCC', 'Disease', (202, 205))	('RCC', 'Phenotype', 'HP:0005584', (202, 205))	('mutations', 'Var', (17, 26))	('dinitropyrenes', 'Chemical', '-', (262, 276))
34326	28454375	The fraction of mutations that were predicted to be deleterious varied greatly across cancer subtypes and prediction tools.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', (86, 92))
34327	28454375	The percentages of predicted deleterious mutations were as follows: 44.52% (2673/6004; SIFT), 50.45% (2393/4743; Polyphen2) and 39.18% (1941/4954; MutationAssessor) in ccRCC; 41.04% (2464/6330; SIFT), 55.91% (2110/3774; Polyphen2) and 44.47% (390/877; MutationAssessor) in chRCC; and 37.58% (519/1381; SIFT), 57.26% (469/819; Polyphen2) and 44.33% (1752/3952; MutationAssessor) in PRCC.	('SIFT', 'Disease', 'None', (87, 91))	('SIFT', 'Disease', 'None', (302, 306))	('PRCC', 'Gene', '5546', (381, 385))	('mutations', 'Var', (41, 50))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Disease', (170, 173))	('RCC', 'Phenotype', 'HP:0005584', (170, 173))	('SIFT', 'Disease', (194, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (168, 173))	('RCC', 'Phenotype', 'HP:0005584', (382, 385))	('RCC', 'Disease', (382, 385))	('RCC', 'Disease', 'MESH:C538614', (170, 173))	('SIFT', 'Disease', 'None', (194, 198))	('SIFT', 'Disease', (87, 91))	('SIFT', 'Disease', (302, 306))	('PRCC', 'Gene', (381, 385))	('RCC', 'Disease', 'MESH:C538614', (382, 385))	('PRCC', 'Phenotype', 'HP:0006766', (381, 385))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
34330	28454375	T>C/A>G, C>T/G>A and C>A/G>T accounted for 24.96, 23.16 and 17.86% of the variants in ccRCC, 9.34, 57.13 and 12.53% of the variants in chRCC and 17.31, 28.29 and 12.24% of the variants in PRCC, respectively.	('C>A/G>T', 'Var', (21, 28))	('PRCC', 'Phenotype', 'HP:0006766', (188, 192))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('C>T/G>A', 'Var', (9, 16))	('T>C/A>G', 'Var', (0, 7))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (86, 91))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('PRCC', 'Gene', '5546', (188, 192))	('RCC', 'Disease', (137, 140))	('variants', 'Var', (74, 82))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))	('variants', 'Var', (123, 131))	('PRCC', 'Gene', (188, 192))
34331	28454375	T>C/A>G, C>T/G>A and C>A/G>T were therefore the three most common transitions identified in kidney cancer tissues (Fig.	('C>A/G>T', 'Var', (21, 28))	('kidney cancer', 'Disease', (92, 105))	('C>T/G>A', 'Var', (9, 16))	('T>C/A>G', 'Var', (0, 7))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('kidney cancer', 'Disease', 'MESH:D007680', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
34332	28454375	Predicted deleterious mutations were mapped onto established cancer genes that had been annotated in the COSMIC database, revealing that the coding regions of cancer genes had a significantly higher enrichment of deleterious mutations, in comparison with those of non-cancer genes in ccRCC (259.68 vs. 95.06 variants/Mb; P<2.2x10-16), chRCC (46.23 vs. 18.93 variants/Mb; P=4.15x10-6) and PRCC (195.78 vs. 87.69 variants/Mb; P<2.2x10-16; Fisher's exact test; Fig.	('RCC', 'Disease', 'MESH:C538614', (286, 289))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('PRCC', 'Gene', (388, 392))	('PRCC', 'Phenotype', 'HP:0006766', (388, 392))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', (159, 165))	('RCC', 'Disease', (337, 340))	('RCC', 'Phenotype', 'HP:0005584', (337, 340))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-cancer', 'Disease', 'MESH:D009369', (264, 274))	('RCC', 'Disease', (389, 392))	('RCC', 'Disease', 'MESH:C538614', (337, 340))	('PRCC', 'Gene', '5546', (388, 392))	('RCC', 'Phenotype', 'HP:0005584', (389, 392))	('cancer', 'Disease', (61, 67))	('non-cancer', 'Disease', (264, 274))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (389, 392))	('cancer', 'Disease', (268, 274))	('RCC', 'Phenotype', 'HP:0005584', (286, 289))	('ccRCC', 'Phenotype', 'HP:0006770', (284, 289))	('mutations', 'Var', (225, 234))	('RCC', 'Disease', (286, 289))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))
34347	28454375	2C shows that conserved regions and regulatory elements contained higher densities of high-scoring variants, as predicted by all scoring methods individually and in combination, including conserved regions, conserved TFBS, promoters, H3K27ac, H2BK5ac, H4K91ac, PolII, H3K18ac, H2BK120ac, H3K4me2 and H3K4me3.	('H4K91ac', 'Var', (252, 259))	('H3K27ac', 'Var', (234, 241))	('H2BK120ac', 'Var', (277, 286))	('H3K4me2', 'Var', (288, 295))	('H3K4me3', 'Var', (300, 307))	('H2BK5ac', 'Var', (243, 250))	('H3K18ac', 'Var', (268, 275))	('TFBS', 'Chemical', '-', (217, 221))
34350	28454375	Regions with a high average recombination rate possessed a higher density of high-scoring variants compared with regions with a low average recombination rate for common variants (P=1.357x10-5), CADD (P=2.583x10-3), FunSeq2 (P=2.063x10-3) and GWAVA (P=3.834x10-6; Fisher's exact test).	('variants', 'Var', (90, 98))	('high-scoring', 'PosReg', (77, 89))	('rat', 'Species', '10116', (154, 157))	('rat', 'Species', '10116', (42, 45))
34351	28454375	In addition, the expression levels, replication time, GC content and recombination rate exhibited positive correlations with the densities of high-scoring variants (Fig.	('rat', 'Species', '10116', (83, 86))	('expression', 'MPA', (17, 27))	('variants', 'Var', (155, 163))
34352	28454375	All these findings suggest that conserved regions, regulatory elements, high expression levels, early replication time, high GC content and high recombination rate are important features that affect the functionalities of noncoding variants in kidney cancer.	('noncoding variants', 'Var', (222, 240))	('functionalities', 'MPA', (203, 218))	('kidney cancer', 'Disease', 'MESH:D007680', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('kidney cancer', 'Phenotype', 'HP:0009726', (244, 257))	('kidney cancer', 'Disease', (244, 257))	('affect', 'Reg', (192, 198))	('rat', 'Species', '10116', (159, 162))
34353	28454375	The current study performed a full analysis of the somatic mutations generated by whole-genome and -exome sequencing of kidney cancer samples, revealing 1,327, 258 and 1,186 deleterious coding variants in ccRCC, chRCC and PRCC, respectively, predicted by SIFT, Polyphen2 and MutationAssessor.	('PRCC', 'Gene', (222, 226))	('RCC', 'Disease', 'MESH:C538614', (223, 226))	('PRCC', 'Phenotype', 'HP:0006766', (222, 226))	('variants', 'Var', (193, 201))	('RCC', 'Disease', 'MESH:C538614', (214, 217))	('kidney cancer', 'Disease', 'MESH:D007680', (120, 133))	('PRCC', 'Gene', '5546', (222, 226))	('SIFT', 'Disease', (255, 259))	('kidney cancer', 'Phenotype', 'HP:0009726', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('kidney cancer', 'Disease', (120, 133))	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', (207, 210))	('mutations', 'Var', (59, 68))	('RCC', 'Phenotype', 'HP:0005584', (223, 226))	('RCC', 'Disease', (223, 226))	('ccRCC', 'Phenotype', 'HP:0006770', (205, 210))	('SIFT', 'Disease', 'None', (255, 259))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (214, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('rat', 'Species', '10116', (73, 76))
34360	28454375	The oncogenic role of TCEBI has been reported in ccRCC tumors containing TCEB1 mutations, which exhibited increased expression levels of hypoxia-inducible factor (HIF)-1alpha, a gene that is implicated to be dysregulated in various cancer-associated processes, including vascularization, angiogenesis, energy metabolism, cell survival and tumor invasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (339, 344))	('cancer', 'Disease', (232, 238))	('angiogenesis', 'CPA', (288, 300))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cell survival', 'CPA', (321, 334))	('mutations', 'Var', (79, 88))	('RCC', 'Disease', (51, 54))	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('vascularization', 'CPA', (271, 286))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('metabolism', 'biological_process', 'GO:0008152', ('309', '319'))	('tumors', 'Disease', (55, 61))	('ccRCC', 'Phenotype', 'HP:0006770', (49, 54))	('increased', 'PosReg', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('TCEB1', 'Gene', (73, 78))	('angiogenesis', 'biological_process', 'GO:0001525', ('288', '300'))	('tumor', 'Disease', (55, 60))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (137, 174))	('TCEB1', 'Gene', '6921', (73, 78))
34365	28454375	Alterations in UMPP are associated with the overexpression of HIF-1alpha and HIF-2alpha, which are two crucial hypoxia regulatory factors in the HIF-1 signaling pathway; therefore, alterations in UMPP may contribute to the pathogenesis of ccRCC via the activation of the HIF-1 signaling pathway, which is important role in ccRCC tumorigenesis.	('alterations', 'Var', (181, 192))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (62, 87))	('contribute', 'Reg', (205, 215))	('HIF-1', 'Gene', '3091', (145, 150))	('UMPP', 'Chemical', '-', (15, 19))	('UMPP', 'Chemical', '-', (196, 200))	('HIF-1', 'Gene', (145, 150))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('tumor', 'Disease', (329, 334))	('HIF-1', 'Gene', '3091', (271, 276))	('ccRCC', 'Phenotype', 'HP:0006770', (239, 244))	('signaling pathway', 'biological_process', 'GO:0007165', ('151', '168'))	('HIF-1', 'Gene', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('HIF-1', 'Gene', '3091', (62, 67))	('hypoxia', 'Disease', (111, 118))	('HIF-1', 'Gene', (62, 67))	('RCC', 'Disease', (325, 328))	('RCC', 'Phenotype', 'HP:0005584', (325, 328))	('ccRCC', 'Phenotype', 'HP:0006770', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('rat', 'Species', '10116', (4, 7))	('activation', 'PosReg', (253, 263))	('RCC', 'Disease', 'MESH:C538614', (325, 328))	('signaling pathway', 'biological_process', 'GO:0007165', ('277', '294'))	('UMPP', 'Gene', (196, 200))	('pathogenesis', 'biological_process', 'GO:0009405', ('223', '235'))	('rat', 'Species', '10116', (185, 188))
34368	28454375	An advantage of OncodriveFM and OncodriveCluster is that these two tools identify those genes and signaling pathways that accumulate variants with a high functional impact independently of cancer mutation frequency, enabling the identification of potential cancer genes and signaling pathways that are not highly mutated in cancer.	('signaling', 'biological_process', 'GO:0023052', ('274', '283'))	('cancer', 'Disease', (324, 330))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('signaling', 'biological_process', 'GO:0023052', ('98', '107'))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('variants', 'Var', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('cancer', 'Disease', (189, 195))
34373	28454375	Recombination between homologous DNA sequences may lead to rearrangements, including a loss of heterozygosity, deletions, duplications, inversions and gene fusion; therefore, a higher recombination rate may be an important cause of the development of harmful mutations in the noncoding genome and predisposition to cancer.	('loss', 'NegReg', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA', 'cellular_component', 'GO:0005574', ('33', '36'))	('duplications', 'Var', (122, 134))	('cancer', 'Disease', (315, 321))	('rearrangements', 'MPA', (59, 73))	('lead', 'Reg', (51, 55))	('rat', 'Species', '10116', (198, 201))	('deletions', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('heterozygosity', 'MPA', (95, 109))
34374	28454375	This supports the hypothesis that high expression levels, early replication time, high GC content and high recombination rate characterize cancer-implicated regions within the noncoding genome, in which variants are more likely to be pathogenic.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('variants', 'Var', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rat', 'Species', '10116', (121, 124))	('expression levels', 'MPA', (39, 56))	('pathogenic', 'Reg', (234, 244))	('cancer', 'Disease', (139, 145))
34376	28454375	Features including conservation, regulatory elements, replication time, expression levels, GC content and recombination rate may be important for the functional impact of noncoding mutations in renal cell carcinoma.	('renal cell carcinoma', 'Disease', (194, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('rat', 'Species', '10116', (120, 123))	('noncoding mutations', 'Var', (171, 190))
34388	22343386	Subsequent work demonstrated loss of VHL in nearly 90% of sporadic ccRCC by either loss of heterozygosity (LOH), or epigenetic silencing.	('epigenetic silencing', 'Var', (116, 136))	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('VHL', 'Gene', (37, 40))	('VHL', 'Gene', '7428', (37, 40))	('loss', 'NegReg', (29, 33))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('loss', 'NegReg', (83, 87))
34389	22343386	More recently, mutations in a number of genes affecting chromatin remodeling have been identified in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('mutations', 'Var', (15, 24))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('56', '76'))	('identified', 'Reg', (87, 97))	('chromatin', 'cellular_component', 'GO:0000785', ('56', '65'))
34392	22343386	Elucidation of the molecular pathways that are dysregulated following VHL tumor suppressor inactivation has opened the doors to an era of targeted therapy in the treatment of kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('VHL tumor', 'Disease', 'MESH:D006623', (70, 79))	('kidney cancer', 'Disease', (175, 188))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor suppressor', 'biological_process', 'GO:0051726', ('74', '90'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('74', '90'))	('VHL tumor', 'Disease', (70, 79))	('inactivation', 'Var', (91, 103))	('kidney cancer', 'Phenotype', 'HP:0009726', (175, 188))	('kidney cancer', 'Disease', 'MESH:D007680', (175, 188))	('men', 'Species', '9606', (167, 170))
34413	22343386	Somatic MET mutations have also been detected in 5-13% of sporadic pRCC.	('pRCC', 'Gene', (67, 71))	('RCC', 'Phenotype', 'HP:0005584', (68, 71))	('detected', 'Reg', (37, 45))	('pRCC', 'Gene', '5546', (67, 71))	('MET mutations', 'Var', (8, 21))	('pRCC', 'Phenotype', 'HP:0006766', (67, 71))
34431	22343386	In the US, patients with advanced non-clear RCC histologies, including pRCC, can be enrolled in phase II trials comparing everolimus to sunitinib (NCT01185366 or NCT01108445).	('RCC', 'Phenotype', 'HP:0005584', (72, 75))	('pRCC', 'Gene', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('RCC', 'Disease', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('pRCC', 'Phenotype', 'HP:0006766', (71, 75))	('pRCC', 'Gene', '5546', (71, 75))	('NCT01108445', 'Var', (162, 173))	('everolimus', 'Chemical', 'MESH:D000068338', (122, 132))	('patients', 'Species', '9606', (11, 19))	('NCT01185366', 'Var', (147, 158))	('sunitinib', 'Chemical', 'MESH:D000077210', (136, 145))
34433	22343386	In a hereditary form of pRCC, patients have germline mutations of the gene encoding the Krebs cycle enzyme, fumarate hydratase (FH), which is located on chromosome 1.	('pRCC', 'Gene', '5546', (24, 28))	('Krebs cycle', 'biological_process', 'GO:0006099', ('88', '99'))	('chromosome', 'cellular_component', 'GO:0005694', ('153', '163'))	('pRCC', 'Gene', (24, 28))	('FH', 'Gene', '2271', (128, 130))	('germline mutations', 'Var', (44, 62))	('patients', 'Species', '9606', (30, 38))	('fumarate hydratase', 'Gene', '2271', (108, 126))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('Krebs', 'Chemical', '-', (88, 93))	('fumarate hydratase', 'Gene', (108, 126))	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))
34436	22343386	Isaacs and colleagues demonstrated that loss of FH leads to accumulation of fumarate, a competitive inhibitor of prolyl hydroxylase, which is a critical enzyme required for hydroxylation of HIF and its subsequent binding to VHL.	('fumarate', 'MPA', (76, 84))	('VHL', 'Gene', '7428', (224, 227))	('binding', 'Interaction', (213, 220))	('FH', 'Gene', '2271', (48, 50))	('binding', 'molecular_function', 'GO:0005488', ('213', '220'))	('loss', 'Var', (40, 44))	('fumarate', 'Chemical', 'MESH:D005650', (76, 84))	('accumulation', 'PosReg', (60, 72))	('VHL', 'Gene', (224, 227))
34437	22343386	Inhibition of prolyl hydroxylase interferes with VHL-dependent degradation of HIF and upregulation of hypoxia inducible genes.	('upregulation', 'PosReg', (86, 98))	('VHL-dependent degradation of HIF', 'Disease', 'MESH:C563918', (49, 81))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('interferes', 'NegReg', (33, 43))	('hypoxia', 'Disease', (102, 109))	('degradation', 'biological_process', 'GO:0009056', ('63', '74'))	('Inhibition', 'Var', (0, 10))	('VHL-dependent degradation of HIF', 'Disease', (49, 81))
34445	22343386	Xp11 translocation RCC is one of the newly identified RCC variants added to the WHO 2004 classification.	('Xp11', 'Var', (0, 4))	('RCC', 'Disease', (54, 57))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (54, 57))	('RCC', 'Disease', (19, 22))	('RCC', 'Phenotype', 'HP:0005584', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (54, 57))
34446	22343386	Translocation carcinoma is the result of gene fusions of the TFE3 transcription factor gene with one of a variety of other genes.	('gene fusions', 'Var', (41, 53))	('transcription', 'biological_process', 'GO:0006351', ('66', '79'))	('Translocation carcinoma', 'Disease', 'MESH:D014178', (0, 23))	('TFE3', 'Gene', (61, 65))	('transcription factor', 'molecular_function', 'GO:0000981', ('66', '86'))	('result', 'Reg', (31, 37))	('Translocation carcinoma', 'Disease', (0, 23))	('TFE3', 'Gene', '7030', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
34452	22343386	In addition, elevated expression of phosphorylated S6 has been described in translocation carcinomas, suggesting that the mTOR pathway may be a potential therapeutic target.	('phosphorylated', 'Var', (36, 50))	('translocation carcinoma', 'Disease', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('elevated', 'PosReg', (13, 21))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('carcinomas', 'Disease', (90, 100))	('translocation carcinoma', 'Disease', 'MESH:D014178', (76, 99))	('expression', 'MPA', (22, 32))
34462	22343386	In addition, pathway analyses suggest dysregulation of mTOR and c-erbB2 signaling in chRCC.	('c-erbB2', 'Gene', (64, 71))	('RCC', 'Disease', 'MESH:C538614', (87, 90))	('RCC', 'Disease', (87, 90))	('mTOR', 'MPA', (55, 59))	('dysregulation', 'Var', (38, 51))	('signaling', 'biological_process', 'GO:0023052', ('72', '81'))	('c-erbB2', 'Gene', '2064', (64, 71))	('RCC', 'Phenotype', 'HP:0005584', (87, 90))
34466	22343386	This is an autosomal dominant renal carcinoma syndrome caused by germline alterations in the folliculin (FLCN) gene, located on chromosome 17p11.2.	('caused by', 'Reg', (55, 64))	('autosomal dominant renal carcinoma syndrome', 'Disease', (11, 54))	('chromosome', 'cellular_component', 'GO:0005694', ('128', '138'))	('folliculin', 'Gene', '201163', (93, 103))	('renal carcinoma', 'Phenotype', 'HP:0005584', (30, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('FLCN', 'Gene', (105, 109))	('alterations', 'Var', (74, 85))	('autosomal dominant renal carcinoma syndrome', 'Disease', 'MESH:D007674', (11, 54))	('folliculin', 'Gene', (93, 103))
34472	22343386	Patients with metastatic chRCC are eligible for inclusion in phase II trials of everolimus versus sunitinib in non-clear cell RCC (NCT01185366, NCT01108445).	('NCT01185366', 'Var', (131, 142))	('everolimus', 'Chemical', 'MESH:D000068338', (80, 90))	('RCC', 'Phenotype', 'HP:0005584', (126, 129))	('Patients', 'Species', '9606', (0, 8))	('sunitinib', 'Chemical', 'MESH:D000077210', (98, 107))	('RCC', 'Disease', (126, 129))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('NCT01108445', 'Var', (144, 155))
34473	22343386	Germline mutations affecting succinate dehydrogenase subunit B (SDHB) have been associated with hereditary paraganglioma and pheochromocytoma.	('Germline mutations', 'Var', (0, 18))	('SDHB', 'Gene', '6390', (64, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (125, 141))	('paraganglioma', 'Phenotype', 'HP:0002668', (107, 120))	('SDHB', 'Gene', (64, 68))	('associated', 'Reg', (80, 90))	('succinate dehydrogenase subunit B', 'Gene', '6390', (29, 62))	('succinate dehydrogenase subunit B', 'Gene', (29, 62))	('hereditary paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (96, 141))
34496	22343386	The recent identification of mutations in genes involved in chromatin remodeling will likely lead to the investigation of components of this critical process as valid therapeutic targets in clear cell RCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('mutations', 'Var', (29, 38))	('chromatin', 'cellular_component', 'GO:0000785', ('60', '69'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('60', '80'))
34497	22343386	Similarly, efforts to decipher the molecular mechanisms underlying non-clear cell variants of RCC are beginning to engender novel therapeutic strategies directed against these rarer forms of kidney cancer.	('variants', 'Var', (82, 90))	('RCC', 'Disease', 'MESH:C538614', (94, 97))	('RCC', 'Disease', (94, 97))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('kidney cancer', 'Phenotype', 'HP:0009726', (191, 204))	('kidney cancer', 'Disease', 'MESH:D007680', (191, 204))	('kidney cancer', 'Disease', (191, 204))
34503	32411604	Analysis from The Human Protein Atlas dataset shows that high collagen 1 or 4A2, fibronectin, entactin, or syndecan 3 expression is associated with poor prognosis whereas high collagen 4A3, syndecan 4, or glypican 4 expression is associated with increased patient survival.	('glypican 4', 'Gene', (205, 215))	('syndecan', 'molecular_function', 'GO:0015023', ('107', '115'))	('fibronectin', 'Gene', '2335', (81, 92))	('high', 'Var', (57, 61))	('collagen', 'molecular_function', 'GO:0005202', ('176', '184'))	('syndecan', 'molecular_function', 'GO:0015023', ('190', '198'))	('syndecan 4', 'Gene', (190, 200))	('Human', 'Species', '9606', (18, 23))	('syndecan 3', 'Gene', '9672', (107, 117))	('glypican', 'molecular_function', 'GO:0015017', ('205', '213'))	('syndecan 4', 'Gene', '6385', (190, 200))	('fibronectin', 'Gene', (81, 92))	('increased', 'PosReg', (246, 255))	('syndecan 3', 'Gene', (107, 117))	('glypican 4', 'Gene', '2239', (205, 215))	('collagen', 'molecular_function', 'GO:0005202', ('62', '70'))	('patient', 'Species', '9606', (256, 263))
34515	32411604	Loss of VHL deregulates and constitutively activates hypoxia-inducible factor HIF1alpha and HIF2alpha.	('HIF2alpha', 'Gene', '2034', (92, 101))	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('HIF1alpha', 'Gene', '3091', (78, 87))	('deregulates', 'Reg', (12, 23))	('HIF2alpha', 'Gene', (92, 101))	('activates', 'PosReg', (43, 52))	('HIF1alpha', 'Gene', (78, 87))	('Loss', 'Var', (0, 4))	('VHL', 'Gene', (8, 11))
34518	32411604	Nevertheless, a recent meta-analysis study from Kim and colleagues found no correlation between VHL inactivation and patient survival in ccRCC.	('inactivation', 'Var', (100, 112))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Disease', (139, 142))	('VHL', 'Gene', (96, 99))	('patient', 'Species', '9606', (117, 124))
34539	32411604	RCC cells expressed FN1 and silencing its expression inhibits cell proliferation and invasion in vitro.	('cell proliferation', 'biological_process', 'GO:0008283', ('62', '80'))	('expression', 'MPA', (42, 52))	('FN1', 'Gene', (20, 23))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('inhibits', 'NegReg', (53, 61))	('silencing', 'Var', (28, 37))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('RCC', 'Disease', (0, 3))
34547	32411604	The human 786-O cell line is derived from ccRCC mutated on the VHL gene.	('human', 'Species', '9606', (4, 9))	('mutated', 'Var', (48, 55))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('VHL', 'Gene', (63, 66))
34586	32411604	Furthermore, patients with high Col 4A3 expression have better survival rate in ccRCC (Table 2).	('Col 4A3', 'Gene', '1285', (32, 39))	('patients', 'Species', '9606', (13, 21))	('survival', 'CPA', (63, 71))	('Col 4A3', 'Gene', (32, 39))	('high', 'Var', (27, 31))	('better', 'PosReg', (56, 62))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))
34590	32411604	However, high Col 4A3, syndecan 4, and glypican 4 expression is of good prognosis in RCC (Table 2).	('Col 4A3', 'Gene', '1285', (14, 21))	('glypican 4', 'Gene', (39, 49))	('Col 4A3', 'Gene', (14, 21))	('RCC', 'Phenotype', 'HP:0005584', (85, 88))	('glypican', 'molecular_function', 'GO:0015017', ('39', '47'))	('syndecan 4', 'Gene', '6385', (23, 33))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('RCC', 'Disease', (85, 88))	('syndecan 4', 'Gene', (23, 33))	('glypican 4', 'Gene', '2239', (39, 49))	('syndecan', 'molecular_function', 'GO:0015023', ('23', '31'))	('high', 'Var', (9, 13))
34615	32411604	Analysis of the 5-year patient survival in the The Human Protein Atlas reveals a negative correlation between ccRCC and pRCC and high Col 1 expression.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('negative', 'NegReg', (81, 89))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('expression', 'MPA', (140, 150))	('high', 'Var', (129, 133))	('RCC', 'Disease', (121, 124))	('Human', 'Species', '9606', (51, 56))	('RCC', 'Disease', (112, 115))	('RCC', 'Phenotype', 'HP:0005584', (112, 115))	('RCC', 'Disease', 'MESH:C538614', (112, 115))	('pRCC', 'Phenotype', 'HP:0006766', (120, 124))	('patient', 'Species', '9606', (23, 30))
34646	30986931	The Complex Interplay between Metabolic Reprogramming and Epigenetic Alterations in Renal Cell Carcinoma Renal cell carcinoma (RCC) is the most common malignancy affecting the kidney.	('Renal Cell Carcinoma', 'Disease', (84, 104))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('Carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('RC', 'Phenotype', 'HP:0009726', (127, 129))	('Renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('Epigenetic Alterations', 'Var', (58, 80))	('malignancy', 'Disease', (151, 161))	('malignancy affecting the kidney', 'Phenotype', 'HP:0009726', (151, 182))	('Renal cell carcinoma', 'Disease', (105, 125))	('Renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (84, 104))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('RCC', 'Disease', 'MESH:C538614', (127, 130))	('RCC', 'Disease', (127, 130))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (84, 104))
34648	30986931	Presently, metabolic reprograming and epigenetic alterations are recognized cancer hallmarks and their interactions are still in its infancy concerning RCC.	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('RCC', 'Disease', (152, 155))	('RCC', 'Phenotype', 'HP:0005584', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer hallmarks', 'Disease', (76, 92))	('cancer hallmarks', 'Disease', 'MESH:D009369', (76, 92))	('epigenetic alterations', 'Var', (38, 60))	('RC', 'Phenotype', 'HP:0009726', (152, 154))
34649	30986931	In this review, we explore RCC biology, highlighting genetic and epigenetic alterations that contribute to metabolic deregulation of tumor cells, including high glycolytic phenotype (Warburg effect).	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('high glycolytic phenotype', 'MPA', (156, 181))	('RC', 'Phenotype', 'HP:0009726', (27, 29))	('tumor', 'Disease', (133, 138))	('metabolic deregulation', 'MPA', (107, 129))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('epigenetic alterations', 'Var', (65, 87))
34650	30986931	Moreover, we critically discuss available data concerning epigenetic enzymes' regulation by aberrant metabolite accumulation and their consequences in RCC emergence and progression.	('regulation', 'biological_process', 'GO:0065007', ('78', '88'))	('aberrant', 'Var', (92, 100))	('RC', 'Phenotype', 'HP:0009726', (151, 153))	('regulation', 'MPA', (78, 88))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))
34659	30986931	Most familial ccRCC are associated with von Hippel Lindau disease, caused by von Hippel Lindau tumor suppressor gene (VHL) genetic alterations, at chromosome 3p (3p25-26).	('von Hippel Lindau disease', 'Disease', (40, 65))	('VHL', 'Gene', (118, 121))	('associated', 'Reg', (24, 34))	('RCC', 'Disease', 'MESH:C538614', (16, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('147', '157'))	('RCC', 'Disease', (16, 19))	('VHL', 'Gene', '7428', (118, 121))	('caused by', 'Reg', (67, 76))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('95', '111'))	('von Hippel Lindau disease', 'Disease', 'MESH:D006623', (40, 65))	('von Hippel Lindau tumor', 'Disease', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor suppressor', 'biological_process', 'GO:0051726', ('95', '111'))	('genetic alterations', 'Var', (123, 142))	('RC', 'Phenotype', 'HP:0009726', (16, 18))	('von Hippel Lindau tumor', 'Disease', 'MESH:D006623', (77, 100))
34660	30986931	Furthermore, BRCA1 associated protein 1 (BAP1) and succinate dehydrogenase (SDHB, SDHC and SDHD) gene mutations have also been associated with ccRCC hereditary forms.	('succinate', 'Chemical', 'MESH:D019802', (51, 60))	('SDHC', 'Gene', '6391', (82, 86))	('BAP1', 'Gene', (41, 45))	('SDHD', 'Gene', (91, 95))	('protein', 'cellular_component', 'GO:0003675', ('30', '37'))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (145, 148))	('associated', 'Reg', (127, 137))	('BRCA1 associated protein 1', 'Gene', '8314', (13, 39))	('RC', 'Phenotype', 'HP:0009726', (14, 16))	('mutations', 'Var', (102, 111))	('SDHC', 'Gene', (82, 86))	('hereditary forms', 'Disease', (149, 165))	('SDHB', 'Gene', '6390', (76, 80))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('RC', 'Phenotype', 'HP:0009726', (145, 147))	('BAP1', 'Gene', '8314', (41, 45))	('SDHB', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (91, 95))	('BRCA1 associated protein 1', 'Gene', (13, 39))
34662	30986931	Indeed, biallelic VHL inactivation caused by genetic mutations and/or by VHL promoter hypermethylation is considered a driving event in ccRCC carcinogenesis.	('carcinogenesis', 'Disease', (142, 156))	('VHL', 'Gene', (73, 76))	('hypermethylation', 'Var', (86, 102))	('RCC', 'Disease', (138, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('biallelic', 'Var', (8, 17))	('RCC', 'Disease', 'MESH:C538614', (138, 141))	('VHL', 'Gene', '7428', (18, 21))	('VHL', 'Gene', '7428', (73, 76))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('inactivation', 'NegReg', (22, 34))	('RC', 'Phenotype', 'HP:0009726', (138, 140))	('genetic mutations', 'Var', (45, 62))	('VHL', 'Gene', (18, 21))
34667	30986931	Along with VHL loss, mutations in other genes located at chromosome 3p have also been reported in ccRCC.	('VHL loss', 'Disease', 'MESH:D006623', (11, 19))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('reported', 'Reg', (86, 94))	('RC', 'Phenotype', 'HP:0009726', (100, 102))	('VHL loss', 'Disease', (11, 19))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('mutations', 'Var', (21, 30))
34668	30986931	These include mutations in chromatin remodeling genes, e.g., polybromo 1 (PBRM1), SET domain containing 2 (SETD2) and BAP1, as well as activating mutations in mammalian target of rapamycin (mTOR) pathway, which are prevalent in ccRCC and associated with worse clinical outcome.	('RC', 'Phenotype', 'HP:0009726', (230, 232))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('activating', 'PosReg', (135, 145))	('SETD2', 'Gene', '29072', (107, 112))	('mammalian target of rapamycin', 'Gene', (159, 188))	('BAP1', 'Gene', '8314', (118, 122))	('prevalent', 'Reg', (215, 224))	('mutations', 'Var', (14, 23))	('polybromo 1', 'Gene', '55193', (61, 72))	('mTOR', 'Gene', (190, 194))	('RCC', 'Disease', (230, 233))	('BAP1', 'Gene', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (230, 233))	('PBRM1', 'Gene', '55193', (74, 79))	('mTOR', 'Gene', '2475', (190, 194))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('27', '47'))	('polybromo 1', 'Gene', (61, 72))	('RCC', 'Disease', 'MESH:C538614', (230, 233))	('mammalian target of rapamycin', 'Gene', '2475', (159, 188))	('SETD2', 'Gene', (107, 112))	('PBRM1', 'Gene', (74, 79))
34673	30986931	Besides, it is typically associated with MET proto-oncogene, receptor tyrosine kinase (MET) amplification and overexpression.	('associated', 'Reg', (25, 35))	('amplification', 'Var', (92, 105))	('MET proto-oncogene, receptor tyrosine kinase', 'Gene', '4233', (41, 85))	('MET', 'Gene', (87, 90))	('overexpression', 'PosReg', (110, 124))
34674	30986931	On the other hand, hereditary papillary renal cancer (HPRC), the familiar form of pRCC Type I, is characterized by activating mutations in the tyrosine kinase domain of MET, which is located at chromosome 7p.	('chromosome', 'cellular_component', 'GO:0005694', ('194', '204'))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('pRCC', 'Gene', (82, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (40, 52))	('RC', 'Phenotype', 'HP:0009726', (56, 58))	('hereditary papillary renal cancer', 'Disease', (19, 52))	('RC', 'Phenotype', 'HP:0009726', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations in', 'Var', (126, 138))	('MET', 'Gene', (169, 172))	('pRCC', 'Gene', '5546', (82, 86))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (30, 52))	('hereditary papillary renal cancer', 'Disease', 'MESH:D007681', (19, 52))
34678	30986931	Sporadic Type II tumors are frequently associated with cyclin dependent kinase inhibitor (CDKN) 2A inactivation, either by mutation or promoter hypermethylation.	('cyclin dependent kinase inhibitor (CDKN) 2A', 'Gene', '1029', (55, 98))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutation', 'Var', (123, 131))	('promoter hypermethylation', 'Var', (135, 160))	('Sporadic Type II tumors', 'Disease', (0, 23))	('cyclin dependent kinase inhibitor', 'molecular_function', 'GO:0004861', ('55', '88'))	('Sporadic Type II tumors', 'Disease', 'MESH:D009369', (0, 23))	('associated', 'Reg', (39, 49))	('inactivation', 'NegReg', (99, 111))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('72', '88'))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
34679	30986931	Additionally, mutations of chromatin remodeling genes (SETD2, BAP1 and PBRM1 genes) described for ccRCC have also been found.	('PBRM1', 'Gene', (71, 76))	('mutations', 'Var', (14, 23))	('BAP1', 'Gene', '8314', (62, 66))	('PBRM1', 'Gene', '55193', (71, 76))	('BAP1', 'Gene', (62, 66))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))	('RC', 'Phenotype', 'HP:0009726', (100, 102))	('chromatin', 'cellular_component', 'GO:0000785', ('27', '36'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('27', '47'))	('SETD2', 'Gene', '29072', (55, 60))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))	('SETD2', 'Gene', (55, 60))
34680	30986931	The familiar form arises from hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome and it due to fumarate hydratase (FH) gene germline mutations.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('fumarate hydratase', 'Gene', '2271', (103, 121))	('hereditary leiomyoma renal cell carcinoma (HLRCC) syndrome', 'Disease', 'MESH:C535516', (30, 88))	('fumarate hydratase', 'Gene', (103, 121))	('FH', 'Gene', '2271', (123, 125))	('RC', 'Phenotype', 'HP:0009726', (75, 77))	('germline mutations', 'Var', (132, 150))
34705	30986931	As described in the previous section, RCC is characterized by mutations in genes related with cell metabolism, namely FH and SDH genes.	('RCC', 'Disease', (38, 41))	('metabolism', 'biological_process', 'GO:0008152', ('99', '109'))	('RC', 'Phenotype', 'HP:0009726', (38, 40))	('SDH', 'Gene', '6390', (125, 128))	('FH', 'Gene', '2271', (118, 120))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('SDH', 'Gene', (125, 128))	('mutations', 'Var', (62, 71))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
34716	30986931	Specifically, glucose-6-phosphate dehydrogenase (G6PD) overexpression increases PPP activity, which generates high nicotinamide adenine dinucleotide phosphate (NADPH) levels.	('glucose-6-phosphate dehydrogenase', 'Gene', (14, 47))	('high nicotinamide adenine dinucleotide phosphate', 'Phenotype', 'HP:0410206', (110, 158))	('PPP', 'Enzyme', (80, 83))	('G6PD', 'Gene', '2539', (49, 53))	('increases', 'PosReg', (70, 79))	('overexpression', 'Var', (55, 69))	('G6PD', 'Gene', (49, 53))	('activity', 'MPA', (84, 92))	('glucose-6-phosphate dehydrogenase', 'Gene', '2539', (14, 47))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (115, 158))	('high', 'PosReg', (110, 114))	('NADPH', 'Chemical', 'MESH:D009249', (160, 165))
34719	30986931	Remarkably, glutamine metabolism upregulation has been associated with MYC proto-oncogene (MYC) overexpression in RCC, inducing glutamine transporter and glutaminase (GLS) upregulation, followed by elevated glutamate and alpha-ketoglutarate levels, and lipid accumulation in RCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (221, 240))	('glutamine', 'Chemical', 'MESH:D005973', (12, 21))	('upregulation', 'PosReg', (33, 45))	('inducing', 'Reg', (119, 127))	('glutamate', 'Chemical', 'MESH:D018698', (207, 216))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('MYC', 'Gene', '4609', (91, 94))	('RC', 'Phenotype', 'HP:0009726', (275, 277))	('MYC', 'Gene', (71, 74))	('glutaminase', 'Gene', '2744', (154, 165))	('elevated glutamate', 'Phenotype', 'HP:0500149', (198, 216))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('overexpression', 'Var', (96, 110))	('glutamine', 'Chemical', 'MESH:D005973', (128, 137))	('RC', 'Phenotype', 'HP:0009726', (114, 116))	('lipid', 'Chemical', 'MESH:D008055', (253, 258))	('glutamine metabolism upregulation', 'Phenotype', 'HP:0003217', (12, 45))	('RCC tumors', 'Disease', (275, 285))	('upregulation', 'PosReg', (172, 184))	('MYC', 'Gene', '4609', (71, 74))	('elevated', 'PosReg', (198, 206))	('glutaminase', 'Gene', (154, 165))	('RCC tumors', 'Disease', 'MESH:C538614', (275, 285))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('12', '32'))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('MYC', 'Gene', (91, 94))	('lipid accumulation', 'MPA', (253, 271))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
34722	30986931	Accordingly, high lactate levels have been associated with poor prognosis, high risk for development of metastasis and high tumor recurrence in several solid tumors.	('lactate', 'Chemical', 'MESH:D019344', (18, 25))	('men', 'Species', '9606', (96, 99))	('tumor', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (152, 164))	('high', 'Var', (13, 17))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('solid tumors', 'Disease', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
34730	30986931	Epigenetic marks are crucial to maintain genomic stability, chromosome imprinting and cell differentiation in normal development.	('cell differentiation', 'biological_process', 'GO:0030154', ('86', '106'))	('cell differentiation', 'CPA', (86, 106))	('men', 'Species', '9606', (124, 127))	('Epigenetic marks', 'Var', (0, 16))	('chromosome', 'cellular_component', 'GO:0005694', ('60', '70'))
34737	30986931	Contrarily, cancer cells display global DNA hypomethylation resulting in genome instability with proto-oncogenes activation, loss of imprinting and high mutation rates.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('loss', 'NegReg', (125, 129))	('mutation', 'CPA', (153, 161))	('cancer', 'Disease', (12, 18))	('genome instability', 'MPA', (73, 91))	('DNA hypomethylation', 'biological_process', 'GO:0044028', ('40', '59'))	('activation', 'PosReg', (113, 123))	('DNA', 'cellular_component', 'GO:0005574', ('40', '43'))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('DNA hypomethylation', 'Var', (40, 59))	('resulting in', 'Reg', (60, 72))
34738	30986931	Furthermore, aberrant gene promoter hypermethylation in cancer is associated with tumor suppressor genes' transcription silencing.	('associated', 'Reg', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor suppressor', 'biological_process', 'GO:0051726', ('82', '98'))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('82', '98'))	('aberrant gene', 'Var', (13, 26))	('transcription', 'biological_process', 'GO:0006351', ('106', '119'))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('transcription', 'MPA', (106, 119))	('cancer', 'Disease', (56, 62))
34743	30986931	Additionally, H4K20me3, a repressive histone mark, is also frequently found in human cancers.	('human', 'Species', '9606', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('H4K20me3', 'Var', (14, 22))	('found', 'Reg', (70, 75))
34745	30986931	Contrarily, deacetylation leads to DNA condensation by restoring the positive charges of lysine, with consequent transcription abrogation.	('transcription', 'MPA', (113, 126))	('restoring', 'PosReg', (55, 64))	('DNA condensation', 'biological_process', 'GO:0006323', ('35', '51'))	('DNA condensation', 'biological_process', 'GO:0030261', ('35', '51'))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('DNA condensation', 'Disease', (35, 51))	('DNA', 'cellular_component', 'GO:0005574', ('35', '38'))	('positive charges of lysine', 'MPA', (69, 95))	('transcription', 'biological_process', 'GO:0006351', ('113', '126'))	('deacetylation', 'Var', (12, 25))
34748	30986931	HATs and HDACs enzymes' deregulation have been implicated in tumorigenesis and metastasis.	('deregulation', 'Var', (24, 36))	('implicated', 'Reg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('metastasis', 'CPA', (79, 89))	('tumor', 'Disease', (61, 66))
34750	30986931	Moreover, H3K9 hypoacetylation was associated with a high proliferative profile and higher recurrence rates in ependymal tumors.	('hypoacetylation', 'Var', (15, 30))	('recurrence rates', 'CPA', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('ependymal tumors', 'Disease', (111, 127))	('H3K9', 'Protein', (10, 14))	('high proliferative profile', 'CPA', (53, 79))	('ependymal tumors', 'Disease', 'MESH:D009369', (111, 127))	('higher', 'PosReg', (84, 90))
34751	30986931	Epigenetic mechanisms allow cell adaptation to environmental changes, but also fueling cancer cells phenotype by supporting cell proliferation and metabolic reprogramming.	('cancer', 'Disease', (87, 93))	('supporting', 'PosReg', (113, 123))	('cell proliferation', 'biological_process', 'GO:0008283', ('124', '142'))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metabolic reprogramming', 'CPA', (147, 170))	('men', 'Species', '9606', (54, 57))	('cell proliferation', 'CPA', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Epigenetic mechanisms', 'Var', (0, 21))
34754	30986931	In RCC, epigenetic silencing through gene promoter hypermethylation often downregulates genes related with Wnt/beta-catenin and transforming growth factor (TGF) beta pathway, pro-apoptotic genes, cell cycle regulator' genes and genes responsible for cell adhesion, implicated in cancer proliferation and metastization.	('cell', 'Gene', (196, 200))	('genes', 'Gene', (88, 93))	('downregulates', 'NegReg', (74, 87))	('Wnt/beta-catenin', 'Pathway', (107, 123))	('RC', 'Phenotype', 'HP:0009726', (3, 5))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('epigenetic silencing', 'Var', (8, 28))	('cell cycle regulator', 'molecular_function', 'GO:0003750', ('196', '216'))	('cell adhesion', 'biological_process', 'GO:0007155', ('250', '263'))	('cell cycle regulator', 'biological_process', 'GO:0051726', ('196', '216'))	('RCC', 'Disease', (3, 6))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
34756	30986931	BAP1-deficient ccRCC tumors are associated with poor prognosis, whereas loss of PBRM1 expression increases tumor aggressiveness.	('PBRM1', 'Gene', '55193', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('increases tumor aggressiveness', 'Disease', 'MESH:D009369', (97, 127))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('RC', 'Phenotype', 'HP:0009726', (17, 19))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('aggressiveness', 'Phenotype', 'HP:0000718', (113, 127))	('loss', 'Var', (72, 76))	('increases tumor aggressiveness', 'Disease', (97, 127))	('PBRM1', 'Gene', (80, 85))	('BAP1-deficient ccRCC tumors', 'Disease', 'MESH:D009369', (0, 27))	('BAP1-deficient ccRCC tumors', 'Disease', (0, 27))
34757	30986931	Moreover, inactivating mutations in SETD2, KDM5C and KMD6A were also found in RCC (mutated in approximately 5-15% of ccRCC cases).	('inactivating mutations', 'Var', (10, 32))	('KMD6A', 'Gene', (53, 58))	('SETD2', 'Gene', '29072', (36, 41))	('RC', 'Phenotype', 'HP:0009726', (78, 80))	('KDM5C', 'Gene', (43, 48))	('RC', 'Phenotype', 'HP:0009726', (119, 121))	('SETD2', 'Gene', (36, 41))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('KDM5C', 'Gene', '8242', (43, 48))	('RCC', 'Disease', (119, 122))	('RCC', 'Disease', 'MESH:C538614', (78, 81))
34758	30986931	As a result of HTMs and KDMs deregulation, RCC display a specific histone methylation profile.	('HTMs', 'Var', (15, 19))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('histone methylation profile', 'MPA', (66, 93))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('histone methylation', 'biological_process', 'GO:0016571', ('66', '85'))	('RC', 'Phenotype', 'HP:0009726', (43, 45))	('KDMs deregulation', 'Var', (24, 41))	('KDMs', 'Chemical', '-', (24, 28))
34766	30986931	Paradoxically, although ccRCC samples depict lower HDAC9 levels than normal adjacent tissues, high HDAC9 expression was associated with poor prognosis.	('RC', 'Phenotype', 'HP:0009726', (26, 28))	('HDAC9', 'Gene', (51, 56))	('RCC', 'Disease', (26, 29))	('RCC', 'Phenotype', 'HP:0005584', (26, 29))	('lower', 'NegReg', (45, 50))	('HDAC9', 'Gene', (99, 104))	('RCC', 'Disease', 'MESH:C538614', (26, 29))	('HDAC9', 'Gene', '9734', (99, 104))	('HDAC9', 'Gene', '9734', (51, 56))	('high', 'Var', (94, 98))
34790	30986931	In absence of glycolytic metabolism, beta-OHB is used as oxidative energy source instead of epigenetic regulator, inducing tumor growth.	('beta-OHB', 'Chemical', '-', (37, 45))	('tumor', 'Disease', (123, 128))	('inducing', 'PosReg', (114, 122))	('beta-OHB', 'Var', (37, 45))	('metabolism', 'biological_process', 'GO:0008152', ('25', '35'))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
34794	30986931	Thus, SIRTs inhibition seems to contribute to hyperacetylation and aberrant gene transcription, leading to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SIRTs', 'Protein', (6, 11))	('hyperacetylation', 'MPA', (46, 62))	('transcription', 'biological_process', 'GO:0006351', ('81', '94'))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('aberrant', 'Var', (67, 75))	('cancer', 'Disease', (107, 113))	('leading to', 'Reg', (96, 106))
34802	30986931	Additionally, acetyl-CoA generated from glutamine was shown to be involved in histone acetylation, inducing the expression of genes involved in lipid metabolism.	('lipid', 'Chemical', 'MESH:D008055', (144, 149))	('histone acetylation', 'biological_process', 'GO:0016573', ('78', '97'))	('glutamine', 'Chemical', 'MESH:D005973', (40, 49))	('lipid metabolism', 'biological_process', 'GO:0006629', ('144', '160'))	('glutamine', 'Var', (40, 49))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (14, 24))	('inducing', 'PosReg', (99, 107))	('expression', 'MPA', (112, 122))
34806	30986931	In tumors with SDH mutations, succinate accumulation associates with DNA hypermethylation phenotype.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('succinate accumulation', 'MPA', (30, 52))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('69', '89'))	('SDH', 'Gene', '6390', (15, 18))	('mutations', 'Var', (19, 28))	('DNA hypermethylation', 'MPA', (69, 89))	('succinate', 'Chemical', 'MESH:D019802', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('SDH', 'Gene', (15, 18))
34807	30986931	Inhibition of histone and DNA demethylases was associated with increased tumor aggressiveness and invasion potential, mediated by epigenetic silencing of genes involved in cell differentiation and epithelial mesenchymal transition (EMT).	('epigenetic silencing', 'Var', (130, 150))	('increased', 'PosReg', (63, 72))	('DNA', 'cellular_component', 'GO:0005574', ('26', '29'))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('epithelial mesenchymal transition', 'biological_process', 'GO:0001837', ('197', '230'))	('tumor aggressiveness', 'Disease', (73, 93))	('EMT', 'biological_process', 'GO:0001837', ('232', '235'))	('cell differentiation', 'biological_process', 'GO:0030154', ('172', '192'))	('Inhibition', 'Var', (0, 10))	('aggressiveness', 'Phenotype', 'HP:0000718', (79, 93))	('DNA', 'Protein', (26, 29))	('histone', 'Protein', (14, 21))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (73, 93))	('invasion potential', 'CPA', (98, 116))
34808	30986931	Moreover, fumarate was also associated with tumor aggressiveness.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (44, 64))	('aggressiveness', 'Phenotype', 'HP:0000718', (50, 64))	('associated', 'Reg', (28, 38))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('fumarate', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor aggressiveness', 'Disease', (44, 64))
34812	30986931	In RCC, increased L-2HG levels are mediated by L-2HG dehydrogenase (L2HGDH) reduced expression due to copy number loss.	('L-2HG levels', 'MPA', (18, 30))	('L2HGDH', 'Gene', (68, 74))	('L-2HG dehydrogenase', 'Gene', '79944', (47, 66))	('RC', 'Phenotype', 'HP:0009726', (3, 5))	('RCC', 'Phenotype', 'HP:0005584', (3, 6))	('L-2HG dehydrogenase', 'Gene', (47, 66))	('L2HGDH', 'Gene', '79944', (68, 74))	('reduced', 'NegReg', (76, 83))	('increased', 'PosReg', (8, 17))	('copy number loss', 'Var', (102, 118))	('RCC', 'Disease', (3, 6))	('expression', 'MPA', (84, 94))	('RCC', 'Disease', 'MESH:C538614', (3, 6))
34816	30986931	Hence, owing to mutations in FH, SDH and L2HGDH genes, which lead to TET and KMDs inhibition, aberrant accumulation of oncometabolites occurs in RCC, stimulating tumor growth and aggressiveness (Figure 5B).	('stimulating', 'PosReg', (150, 161))	('tumor', 'Disease', (162, 167))	('SDH', 'Gene', '6390', (33, 36))	('FH', 'Gene', '2271', (29, 31))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('RCC', 'Phenotype', 'HP:0005584', (145, 148))	('RCC', 'Disease', (145, 148))	('mutations', 'Var', (16, 25))	('L2HGDH', 'Gene', (41, 47))	('L2HGDH', 'Gene', '79944', (41, 47))	('oncometabolites', 'MPA', (119, 134))	('SDH', 'Gene', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RC', 'Phenotype', 'HP:0009726', (145, 147))	('accumulation', 'PosReg', (103, 115))	('TET', 'Chemical', '-', (69, 72))	('aggressiveness', 'Disease', (179, 193))	('aggressiveness', 'Phenotype', 'HP:0000718', (179, 193))	('aggressiveness', 'Disease', 'MESH:D001523', (179, 193))
34823	30986931	Cell metabolism deregulation, particularly Warburg effect, plays a major role in RCC development, contributing to accumulation of metabolites that regulate epigenetic factors.	('Warburg effect', 'Disease', (43, 57))	('RC', 'Phenotype', 'HP:0009726', (81, 83))	('metabolism', 'biological_process', 'GO:0008152', ('5', '15'))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('deregulation', 'Var', (16, 28))	('RCC', 'Disease', (81, 84))	('accumulation', 'PosReg', (114, 126))	('Cell metabolism', 'MPA', (0, 15))	('men', 'Species', '9606', (92, 95))	('metabolites', 'MPA', (130, 141))
34935	29208006	Different genetic alterations induce the development of renal tubules into RCCs of varying histological subtypes that exhibit different gene expression patterns or mutations, thus providing specific molecular candidates for targeted therapy (e.g., mTOR, VEGF, KIT, and checkpoint inhibitors).	('mTOR', 'Gene', '2475', (248, 252))	('alterations', 'Var', (18, 29))	('KIT', 'molecular_function', 'GO:0005020', ('260', '263'))	('mTOR', 'Gene', (248, 252))	('VEGF', 'Gene', '7422', (254, 258))	('RCC', 'Phenotype', 'HP:0005584', (75, 78))	('development', 'CPA', (41, 52))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('gene expression', 'biological_process', 'GO:0010467', ('136', '151'))	('VEGF', 'Gene', (254, 258))	('induce', 'Reg', (30, 36))
34950	29208006	Array-based gene expression profiling of 295 tissue samples obtained from six GEO data sets (GSE12090, GSE15641, GSE19949, GSE8271, GSE7023 and GSE19982) was mainly conducted on two different Affymetrix oligonucleotide microarray platforms, GeneChip Human Genome U133A Array and U133Plus 2.0 Array.	('Human', 'Species', '9606', (250, 255))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('GSE7023', 'Chemical', '-', (132, 139))	('GSE12090', 'Var', (93, 101))	('GSE19949', 'Var', (113, 121))	('GSE8271', 'Var', (123, 130))	('GSE15641', 'Var', (103, 111))	('GSE19982', 'Var', (144, 152))	('GSE7023', 'Var', (132, 139))	('GSE8271', 'Chemical', '-', (123, 130))
35007	25564569	The recent identification of mutations of chromatin remodeling genes in clear cell renal carcinoma (RCC), of genomic heterogeneity and of a Warburg-like metabolic phenotype in advanced disease has had a profound effect on our understanding of the evolution of clear cell RCC and on potential approaches to personalized therapy.	('chromatin remodeling', 'biological_process', 'GO:0006338', ('42', '62'))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (72, 98))	('renal carcinoma', 'Phenotype', 'HP:0005584', (83, 98))	('mutations', 'Var', (29, 38))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (72, 98))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('chromatin', 'cellular_component', 'GO:0000785', ('42', '51'))	('clear cell renal carcinoma', 'Disease', (72, 98))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('RCC', 'Disease', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('effect', 'Reg', (212, 218))	('RCC', 'Disease', (100, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
35011	25564569	CUL3 and Nrf2 mutations as well as an Nrf2 activation phenotype are found in sporadic type 2 papillary RCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('Nrf2', 'Gene', '4780', (38, 42))	('RCC', 'Disease', (103, 106))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('CUL3', 'Gene', '8452', (0, 4))	('CUL3', 'Gene', (0, 4))	('Nrf2', 'Gene', (38, 42))	('found', 'Reg', (68, 73))	('Nrf2', 'Gene', '4780', (9, 13))	('mutations', 'Var', (14, 23))	('Nrf2', 'Gene', (9, 13))
35015	25564569	However, in patients with advanced disease (T4 or M1), the two year survival was less than twenty percent before the advent of targeted agents directed against the HIF/VEGF pathway.	('patients', 'Species', '9606', (12, 20))	('VEGF', 'Gene', '7422', (168, 172))	('less', 'NegReg', (81, 85))	('M1', 'Var', (50, 52))	('VEGF', 'Gene', (168, 172))
35023	25564569	The VHL tumor suppressor gene, located on the short arm of chromosome 3, is the gene for the inherited form of clear cell renal cell carcinoma associated with von Hippel-Lindau and has been found to be mutated or methylated in a high percentage of tumors (~90%) from patients with clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (292, 312))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (248, 254))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (281, 312))	('clear cell renal cell carcinoma', 'Disease', (111, 142))	('associated', 'Reg', (143, 153))	('methylated', 'Var', (213, 223))	('patients', 'Species', '9606', (267, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (122, 142))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('chromosome', 'cellular_component', 'GO:0005694', ('59', '69'))	('von Hippel-Lindau', 'Disease', (159, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (111, 142))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (281, 312))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('8', '24'))	('VHL tumor', 'Disease', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('short arm', 'Phenotype', 'HP:0009824', (46, 55))	('VHL tumor', 'Disease', 'MESH:D006623', (4, 13))	('tumor suppressor', 'biological_process', 'GO:0051726', ('8', '24'))	('clear cell renal cell carcinoma', 'Disease', (281, 312))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (159, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
35035	25564569	Functional studies have long suggested that HIF2alpha (versus HIF1alpha) is the critical downstream target of VHL and that inhibition of HIF2alpha can suppress the ability of a VHL -/- tumor to form tumors in xenograft models and HIF2alpha single nucleotide polymorphisms have been linked to an increased risk of developing renal cell carcinoma.	('HIF2alpha', 'Gene', '2034', (230, 239))	('tumors', 'Disease', (199, 205))	('inhibition', 'Var', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('linked to', 'Reg', (282, 291))	('tumor', 'Disease', (185, 190))	('VHL', 'Gene', '7428', (110, 113))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (324, 344))	('HIF2alpha', 'Gene', (137, 146))	('HIF2alpha', 'Gene', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('suppress', 'NegReg', (151, 159))	('tumor', 'Disease', (199, 204))	('VHL', 'Gene', (177, 180))	('single nucleotide polymorphisms', 'Var', (240, 271))	('HIF2alpha', 'Gene', (230, 239))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('HIF1alpha', 'Gene', '3091', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('renal cell carcinoma', 'Disease', (324, 344))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (324, 344))	('HIF2alpha', 'Gene', '2034', (137, 146))	('HIF2alpha', 'Gene', '2034', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('VHL', 'Gene', '7428', (177, 180))	('HIF1alpha', 'Gene', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('VHL', 'Gene', (110, 113))
35036	25564569	Genetic and functional studies have implicated HIF1alpha as a chromosome 14q kidney cancer suppressor gene and chromosome 14q loss has been found to be associated with poor prognosis.	('HIF1alpha', 'Gene', (47, 56))	('kidney cancer', 'Phenotype', 'HP:0009726', (77, 90))	('kidney cancer', 'Disease', (77, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('62', '72'))	('HIF1alpha', 'Gene', '3091', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('loss', 'NegReg', (126, 130))	('kidney cancer', 'Disease', 'MESH:D007680', (77, 90))	('chromosome', 'Var', (111, 121))
35042	25564569	Additional approaches involving autophagic degradation of HIF2alpha, targeting proteosomal degradation of VHL missense mutations, and targeting the hypoxia associated factor (HAF)-mediated regulation of HIF2alpha-dependent transcription during hypoxia are being evaluated.	('degradation', 'biological_process', 'GO:0009056', ('43', '54'))	('degradation', 'biological_process', 'GO:0009056', ('91', '102'))	('HIF2alpha', 'Gene', (203, 212))	('transcription', 'biological_process', 'GO:0006351', ('223', '236'))	('missense mutations', 'Var', (110, 128))	('hypoxia associated factor', 'Gene', (148, 173))	('HIF2alpha', 'Gene', (58, 67))	('VHL', 'Gene', '7428', (106, 109))	('HIF2alpha', 'Gene', '2034', (203, 212))	('hypoxia', 'Disease', 'MESH:D000860', (148, 155))	('VHL', 'Gene', (106, 109))	('HAF', 'Gene', (175, 178))	('hypoxia', 'Disease', (244, 251))	('hypoxia', 'Disease', (148, 155))	('HIF2alpha', 'Gene', '2034', (58, 67))	('hypoxia', 'Disease', 'MESH:D000860', (244, 251))	('HAF', 'Gene', '2161', (175, 178))	('regulation', 'biological_process', 'GO:0065007', ('189', '199'))	('hypoxia associated factor', 'Gene', '2161', (148, 173))
35043	25564569	opened a new chapter in our understanding of the genetic basis of clear cell RCC and the role of systematic screens to determine genomic architecture when they reported the identification of inactivating mutations of genes involved in histone modification, such as the histone H3 lysine 36 methyltransferase SETD2, and the histone H3 lysine 4 demethylase KDM5C.	('KDM5C', 'Gene', '8242', (355, 360))	('SETD2', 'Gene', '29072', (308, 313))	('histone modification', 'biological_process', 'GO:0016570', ('235', '255'))	('SETD2', 'Gene', (308, 313))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('inactivating mutations', 'Var', (191, 213))	('KDM5C', 'Gene', (355, 360))
35044	25564569	This was followed shortly by the identification of truncating mutations of the SWI/SNF chromatin remodeling complex gene, PBRM1, and BAP1, a deubiquitase that is the catalytic subunit of the Polycomb repressive deubiquitinase complex, in clear cell RCC, highlighting the fundamental role of aberrant chromatin biology in this disease.	('Polycomb repressive deubiquitinase complex', 'cellular_component', 'GO:0035517', ('191', '233'))	('PBRM1', 'Gene', (122, 127))	('deubiquitinase', 'molecular_function', 'GO:0004843', ('211', '225'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('87', '107'))	('SWI/SNF', 'Gene', (79, 86))	('chromatin', 'cellular_component', 'GO:0000785', ('300', '309'))	('PBRM1', 'Gene', '55193', (122, 127))	('RCC', 'Phenotype', 'HP:0005584', (249, 252))	('RCC', 'Disease', 'MESH:C538614', (249, 252))	('BAP1', 'Gene', '8314', (133, 137))	('RCC', 'Disease', (249, 252))	('truncating mutations', 'Var', (51, 71))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('87', '115'))	('BAP1', 'Gene', (133, 137))
35046	25564569	Mutations in the chromatin regulators, SETD2, BAP1 and PBRM1 were each differentially associated with altered expression patterns with a distinct set of down stream effects, reflecting different roles for chromatin remodeling in the transcriptome.	('down stream', 'MPA', (153, 164))	('expression patterns', 'MPA', (110, 129))	('SETD2', 'Gene', (39, 44))	('SETD2', 'Gene', '29072', (39, 44))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('205', '225'))	('BAP1', 'Gene', '8314', (46, 50))	('chromatin', 'cellular_component', 'GO:0000785', ('17', '26'))	('associated', 'Reg', (86, 96))	('Mutations', 'Var', (0, 9))	('BAP1', 'Gene', (46, 50))	('PBRM1', 'Gene', (55, 60))	('chromatin', 'cellular_component', 'GO:0000785', ('205', '214'))	('PBRM1', 'Gene', '55193', (55, 60))	('altered', 'Reg', (102, 109))
35047	25564569	A number of findings have highlighted the importance of driver mutations of chromatin remodeling genes in ccRCC.	('mutations', 'Var', (63, 72))	('RCC', 'Disease', 'MESH:C538614', (108, 111))	('RCC', 'Disease', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (108, 111))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('76', '96'))	('chromatin', 'cellular_component', 'GO:0000785', ('76', '85'))
35048	25564569	In large studies somatic mutations of BAP1 have been correlated with decreased overall survival and a straightforward immunohistochemical assay has been developed to assess BAP1 levels.	('overall survival', 'CPA', (79, 95))	('BAP1', 'Gene', (38, 42))	('decreased', 'NegReg', (69, 78))	('BAP1', 'Gene', '8314', (173, 177))	('somatic mutations', 'Var', (17, 34))	('BAP1', 'Gene', (173, 177))	('BAP1', 'Gene', '8314', (38, 42))
35049	25564569	In addition, germline BAP1 mutations have been found to be the driver mutations in families characterized by an increased incidence of early onset, bilateral, multifocal clear cell renal carcinoma.	('mutations', 'Var', (27, 36))	('multifocal clear cell renal carcinoma', 'Disease', 'MESH:C538614', (159, 196))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (170, 196))	('multifocal clear cell renal carcinoma', 'Disease', (159, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('BAP1', 'Gene', '8314', (22, 26))	('renal carcinoma', 'Phenotype', 'HP:0005584', (181, 196))	('BAP1', 'Gene', (22, 26))
35050	25564569	Intensive efforts are currently underway to determine the functional consequences of inactivation of chromatin remodeling genes in clear cell renal cell carcinoma to provide the foundation for the development of effective forms of therapy targeting these gene pathways.	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (131, 162))	('clear cell renal cell carcinoma', 'Disease', (131, 162))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (142, 162))	('inactivation', 'Var', (85, 97))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('101', '121'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (131, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('chromatin', 'cellular_component', 'GO:0000785', ('101', '110'))
35051	25564569	have recently identified alterations in chromatin organization and transcript profiles in ccRCC associated with SETD2 mutations in a large cohort of primary human kidney tumors as a first step in developing actionable targets in SETD2-deficient clear cell RCC.	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('40', '49'))	('chromatin organization', 'MPA', (40, 62))	('SETD2', 'Gene', (112, 117))	('RCC', 'Disease', (256, 259))	('RCC', 'Phenotype', 'HP:0005584', (256, 259))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('kidney tumors', 'Phenotype', 'HP:0009726', (163, 176))	('kidney tumors', 'Disease', 'MESH:D007674', (163, 176))	('human', 'Species', '9606', (157, 162))	('kidney tumor', 'Phenotype', 'HP:0009726', (163, 175))	('chromatin organization', 'biological_process', 'GO:0006325', ('40', '62'))	('SETD2', 'Gene', '29072', (112, 117))	('SETD2', 'Gene', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (118, 127))	('transcript profiles', 'MPA', (67, 86))	('RCC', 'Disease', 'MESH:C538614', (256, 259))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('alterations', 'Reg', (25, 36))	('SETD2', 'Gene', '29072', (229, 234))	('SETD2-deficient clear cell RCC', 'Disease', (229, 259))	('kidney tumors', 'Disease', (163, 176))	('SETD2-deficient clear cell RCC', 'Disease', 'MESH:C538614', (229, 259))
35055	25564569	VHL gene mutation, which was found in each sample, was considered to be a "truncal" mutation as it was uniformly present in all segments.	('mutation', 'Var', (9, 17))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))
35056	25564569	PBRM1 was found to be mutated in a portion of the tumors and was also considered to be truncal in those subsets.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('mutated', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
35057	25564569	Other driver mutations, found in the chromatin remodeling genes BAP1, KDM5C and SETD2, genes in the phosphoinositide 3-kinase (PI3K)-mTOR pathway (mTOR, PIK3CA, TSC2, PTEN) and TP53 were found only in "branch" segments of the tumors and each portion of the tumors were found to have a unique spectrum of branch mutations.	('PIK3CA', 'Gene', '5290', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('PI3K', 'molecular_function', 'GO:0016303', ('127', '131'))	('TP53', 'Gene', '7157', (177, 181))	('mTOR', 'Gene', '2475', (147, 151))	('KDM5C', 'Gene', (70, 75))	('BAP1', 'Gene', (64, 68))	('chromatin', 'cellular_component', 'GO:0000785', ('37', '46'))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('PIK3CA', 'Gene', (153, 159))	('TSC2', 'Gene', '7249', (161, 165))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('SETD2', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('PTEN', 'Gene', (167, 171))	('mTOR', 'Gene', (133, 137))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', (177, 181))	('SETD2', 'Gene', '29072', (80, 85))	('KDM5C', 'Gene', '8242', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('TSC2', 'Gene', (161, 165))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', (257, 263))	('mTOR', 'Gene', '2475', (133, 137))	('BAP1', 'Gene', '8314', (64, 68))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('37', '57'))	('PTEN', 'Gene', '5728', (167, 171))	('mTOR', 'Gene', (147, 151))
35059	25564569	First, what is the best way to detect driver mutations in clear cell RCC?	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('mutations', 'Var', (45, 54))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))
35064	25564569	When more information about the effect of mutations in chromatin remodeling genes such as SETD2 and BAP1 becomes available, approaches targeting these pathways will be evaluated.	('BAP1', 'Gene', '8314', (100, 104))	('SETD2', 'Gene', (90, 95))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('55', '75'))	('chromatin', 'cellular_component', 'GO:0000785', ('55', '64'))	('BAP1', 'Gene', (100, 104))	('SETD2', 'Gene', '29072', (90, 95))	('mutations', 'Var', (42, 51))
35077	25564569	Kidney tumors from patients affected with both HPRC and sporadic papillary renal cell carcinoma are characterized by polysomy of chromosome 7 and non-random duplication of the mutant MET allele have been found in tumors from patients affected with HPRC.	('sporadic papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 95))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (75, 95))	('mutant', 'Var', (176, 182))	('sporadic papillary renal cell carcinoma', 'Disease', (56, 95))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('Kidney tumors', 'Disease', 'MESH:D007674', (0, 13))	('MET', 'Gene', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('chromosome', 'cellular_component', 'GO:0005694', ('129', '139'))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('Kidney tumors', 'Disease', (0, 13))	('tumors', 'Disease', (213, 219))	('Kidney tumors', 'Phenotype', 'HP:0009726', (0, 13))	('tumors', 'Disease', (7, 13))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (65, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('patients', 'Species', '9606', (19, 27))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (225, 233))	('tumors', 'Disease', 'MESH:D009369', (7, 13))
35078	25564569	Hereditary and sporadic type 1 papillary renal carcinoma share a distinct morphologic phenotype and MET mutations have been found in 13% of sporadic type 1 papillary tumors.	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (31, 56))	('mutations', 'Var', (104, 113))	('found', 'Reg', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('papillary tumors', 'Disease', 'MESH:D002291', (156, 172))	('papillary tumors', 'Disease', (156, 172))	('papillary renal carcinoma', 'Disease', (31, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('papillary tumors', 'Phenotype', 'HP:0007482', (156, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('renal carcinoma', 'Phenotype', 'HP:0005584', (41, 56))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (31, 56))
35079	25564569	The identification of oncogenic MET mutations in patients affected with hereditary papillary renal carcinoma and in a subset of patients with sporadic papillary RCC led the conduct of a multicenter phase II study of foretinib, an inhibitor of Met, VEGFR2, RON and AXL tyrosine kinases, in patients with sporadic as well as HPRC-associated papillary renal cell carcinoma.	('hereditary papillary renal carcinoma', 'Disease', (72, 108))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (339, 369))	('MET', 'Gene', (32, 35))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (83, 108))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (339, 369))	('renal carcinoma', 'Phenotype', 'HP:0005584', (93, 108))	('RCC', 'Disease', (161, 164))	('RCC', 'Phenotype', 'HP:0005584', (161, 164))	('VEGFR2', 'Gene', (248, 254))	('patients', 'Species', '9606', (289, 297))	('VEGFR2', 'Gene', '3791', (248, 254))	('papillary renal cell carcinoma', 'Disease', (339, 369))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (349, 369))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (128, 136))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:D007681', (72, 108))	('RON', 'Gene', (256, 259))	('mutations', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('RON', 'Gene', '4486', (256, 259))
35081	25564569	In a subgroup analysis, 5/10 (50%) of HPRC patients with germline MET mutations were found to have a partial response to therapy, versus 5/57 (9%) of non-HPRC patients.	('patients', 'Species', '9606', (43, 51))	('HPRC', 'Disease', (38, 42))	('patients', 'Species', '9606', (159, 167))	('mutations', 'Var', (70, 79))
35090	25564569	HLRCC is characterized by germline mutation of the gene for the Krebs cycle enzyme, fumarate hydratase.	('Krebs', 'Chemical', '-', (64, 69))	('RCC', 'Disease', (2, 5))	('RCC', 'Phenotype', 'HP:0005584', (2, 5))	('Krebs cycle', 'biological_process', 'GO:0006099', ('64', '75'))	('RCC', 'Disease', 'MESH:C538614', (2, 5))	('germline mutation', 'Var', (26, 43))	('fumarate hydratase', 'Gene', '2271', (84, 102))	('fumarate hydratase', 'Gene', (84, 102))
35093	25564569	In FH-deficient RCC, fumarate accumulates and inhibits HIF prolyl hydroxylase (PHD), resulting in accumulation of HIF1 and increased transcription of its targets such as VEGF and GLUT1, which lead to the increased vascularity and glucose transport needed to provide increased nutrients for rapid growth and proliferation and for ATP production needed in cells characterized by a decrease in oxidative phosphorylation (Fig.	('HIF1', 'Gene', (114, 118))	('GLUT1', 'Gene', (179, 184))	('FH-deficient RCC', 'Disease', (3, 19))	('increased', 'PosReg', (204, 213))	('inhibits', 'NegReg', (46, 54))	('VEGF', 'Gene', '7422', (170, 174))	('oxidative phosphorylation', 'MPA', (391, 416))	('transcription', 'MPA', (133, 146))	('PHD', 'molecular_function', 'GO:0050175', ('79', '82'))	('accumulation', 'PosReg', (98, 110))	('ATP', 'Chemical', 'MESH:D000255', (329, 332))	('VEGF', 'Gene', (170, 174))	('FH-deficient RCC', 'Disease', 'MESH:C538614', (3, 19))	('fumarate', 'Chemical', 'MESH:D005650', (21, 29))	('fumarate', 'Var', (21, 29))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('391', '416'))	('increased', 'PosReg', (123, 132))	('transcription', 'biological_process', 'GO:0006351', ('133', '146'))	('RCC', 'Phenotype', 'HP:0005584', (16, 19))	('vascularity', 'MPA', (214, 225))	('PHD', 'Disease', (79, 82))	('GLUT1', 'Gene', '6513', (179, 184))	('hydroxyl', 'Chemical', 'MESH:D017665', (66, 74))	('glucose transport', 'MPA', (230, 247))	('glucose transport', 'biological_process', 'GO:1904659', ('230', '247'))	('PHD', 'Disease', 'MESH:D011547', (79, 82))	('HIF1', 'Gene', '3091', (114, 118))	('glucose', 'Chemical', 'MESH:D005947', (230, 237))
35099	25564569	found a similar antioxidant response phenotype shared between hereditary and sporadic type 2 papillary RCC and that CUL2 and Nrf2 mutations confer an Nrf2 activation phenotype in sporadic type 2 papillary RCC.	('RCC', 'Disease', 'MESH:C538614', (103, 106))	('RCC', 'Disease', (103, 106))	('Nrf2', 'Gene', '4780', (150, 154))	('RCC', 'Phenotype', 'HP:0005584', (103, 106))	('RCC', 'Disease', (205, 208))	('RCC', 'Phenotype', 'HP:0005584', (205, 208))	('Nrf2', 'Gene', '4780', (125, 129))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('sporadic', 'Disease', (179, 187))	('antioxidant response', 'MPA', (16, 36))	('CUL2', 'Gene', (116, 120))	('Nrf2', 'Gene', (150, 154))	('mutations', 'Var', (130, 139))	('CUL2', 'Gene', '8453', (116, 120))	('Nrf2', 'Gene', (125, 129))	('activation', 'PosReg', (155, 165))
35102	25564569	LDHA inhibition has been shown to have anti-tumor activity against FH-deficient RCC cells and an effort is underway to identify clinically evaluable LDHA inhibitors.	('FH-deficient RCC cells', 'Disease', 'MESH:C538614', (67, 89))	('LDHA', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('LDHA', 'Gene', '3939', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FH-deficient RCC cells', 'Disease', (67, 89))	('LDHA', 'Gene', (149, 153))	('LDHA', 'Gene', '3939', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
35151	32583730	We further used the SCAN module in the TIMER platform to analyze the relationship between infiltration level and DAB2IP mutations in RCC.	('DAB2IP', 'Gene', (113, 119))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('RCC', 'Disease', (133, 136))	('mutations', 'Var', (120, 129))	('rat', 'Species', '10116', (96, 99))
35171	32583730	To analyze the relationship between gene mutations and immune infiltration, we compared the distribution of the abundance of tumor-infiltrating immune cells under different mutation states of the DAB2IP (Figure 5).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('rat', 'Species', '10116', (137, 140))	('DAB2IP', 'Gene', (196, 202))	('rat', 'Species', '10116', (68, 71))	('mutation', 'Var', (173, 181))
35198	32583730	Thirdly, our study found an association between DAB2IP mutations and immune infiltration cells, for example, the arm-level gain or deletion of DAB2IP might be the most statistically significant mutations in immune infiltration cells.	('mutations', 'Var', (55, 64))	('DAB2IP', 'Gene', (143, 149))	('rat', 'Species', '10116', (82, 85))	('rat', 'Species', '10116', (220, 223))	('DAB2IP', 'Gene', (48, 54))	('gain', 'PosReg', (123, 127))	('deletion', 'Var', (131, 139))
35199	32583730	A study found loss of DAB2IP in RCC cells enhances their sensitivities to growth factor stimulation and resistances to SMI (such as mammalian target of rapamycin [mTOR] inhibitors).	('sensitivities to growth factor stimulation', 'MPA', (57, 99))	('loss', 'Var', (14, 18))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('DAB2IP', 'Gene', (22, 28))	('mTOR', 'Gene', '2475', (163, 167))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('mTOR', 'Gene', (163, 167))	('mammalian target of rapamycin', 'Gene', '2475', (132, 161))	('enhances', 'PosReg', (42, 50))	('resistances to SMI', 'MPA', (104, 122))	('mammalian target of rapamycin', 'Gene', (132, 161))
35276	25027688	As a dichotomous variable, lymphopenia (<1,300 cells/mul) was associated with higher TNM stage (p=0.003).	('lymphopenia', 'Disease', 'MESH:D008231', (27, 38))	('TNM', 'Gene', (85, 88))	('lymphopenia', 'Phenotype', 'HP:0001888', (27, 38))	('<1,300', 'Var', (40, 46))	('higher', 'PosReg', (78, 84))	('lymphopenia', 'Disease', (27, 38))	('TNM', 'Gene', '10178', (85, 88))
35313	25027688	Potential confounders were consistent with our analysis of ccRCC cohort: age at surgery (<60 vs. 60>= years, (closest round figure to the median)), CCI (<2 vs. >= 2), pT stage (pT1p/T2 vs. pT3/pT4), N stage (N0 vs. N1), M stage (M0 vs. M1), PRCC type (I vs. II), and smoking history (ever vs. never).	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('pT1p', 'Gene', (177, 181))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('RCC', 'Disease', (242, 245))	('PRCC', 'Gene', '5546', (241, 245))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('pT3', 'Gene', '7694', (189, 192))	('pT3', 'Gene', (189, 192))	('PRCC', 'Gene', (241, 245))	('CCI', 'Disease', (148, 151))	('pT1p', 'Gene', '58492', (177, 181))	('RCC', 'Disease', (61, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('M0', 'Var', (229, 231))	('PRCC', 'Phenotype', 'HP:0006766', (241, 245))
35325	25027688	As a dichotomous variable, lymphopenia (<1,300 cells/mul) was associated with higher pT stage (p=0.002), TNM stage (p=0.005), and CCI >=2 (p=0.004).	('TNM', 'Gene', (105, 108))	('lymphopenia', 'Disease', 'MESH:D008231', (27, 38))	('lymphopenia', 'Phenotype', 'HP:0001888', (27, 38))	('higher', 'PosReg', (78, 84))	('<1,300 cells/mul', 'Var', (40, 56))	('CCI >', 'CPA', (130, 135))	('TNM', 'Gene', '10178', (105, 108))	('lymphopenia', 'Disease', (27, 38))
35380	24568263	Dual color interphase fluorescence in situ hybridization was utilized to assess for deletion of chromosome 3p and trisomy of chromosomes 7 and 17 in all tumors.	('deletion', 'Var', (84, 92))	('interphase', 'biological_process', 'GO:0051325', ('11', '21'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('trisomy', 'Var', (114, 121))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('chromosome', 'cellular_component', 'GO:0005694', ('96', '106'))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
35383	24568263	Of metastatic PRCC, 75% showed trisomy of chromosomes 7 and/or 17.	('PRCC', 'Gene', '5546', (14, 18))	('trisomy', 'Var', (31, 38))	('RCC', 'Phenotype', 'HP:0005584', (15, 18))	('PRCC', 'Gene', (14, 18))	('PRCC', 'Phenotype', 'HP:0006766', (14, 18))
35384	24568263	Of the tumors not previously classified, 6% were positive for CK7, and 64% were positive for AMACR; 35% showed chromosome 3p deletion, and 16% showed trisomy of chromosomes 7 and/or 17.	('AMACR', 'Gene', '23600', (93, 98))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('chromosome', 'cellular_component', 'GO:0005694', ('111', '121'))	('trisomy', 'Var', (150, 157))	('CK7', 'Gene', (62, 65))	('CK7', 'Gene', '3855', (62, 65))	('AMACR', 'Gene', (93, 98))	('chromosome', 'Var', (111, 121))
35391	24568263	Defects in VHL expression result in constitutive activation of the hypoxia-inducible factor (HIF) pathway and overexpression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and other products.	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('VEGF', 'Gene', '7422', (164, 168))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('128', '162'))	('Defects', 'Var', (0, 7))	('PDGF', 'molecular_function', 'GO:0005161', ('203', '207'))	('VHL', 'Gene', (11, 14))	('overexpression', 'PosReg', (110, 124))	('vascular endothelial growth factor', 'Gene', (128, 162))	('VHL', 'Gene', '7428', (11, 14))	('platelet-derived growth factor', 'molecular_function', 'GO:0005161', ('171', '201'))	('VEGF', 'Gene', (164, 168))	('activation', 'PosReg', (49, 59))	('vascular endothelial growth factor', 'Gene', '7422', (128, 162))
35392	24568263	Inactivation of the VHL gene also enhances tumor cell growth though the mammalian target of rapamycin (mTOR) pathway .	('mTOR', 'Gene', (103, 107))	('cell growth', 'biological_process', 'GO:0016049', ('49', '60'))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('enhances', 'PosReg', (34, 42))	('mammalian target of rapamycin', 'Gene', '2475', (72, 101))	('VHL', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('VHL', 'Gene', '7428', (20, 23))	('mammalian target of rapamycin', 'Gene', (72, 101))	('Inactivation', 'Var', (0, 12))	('mTOR', 'Gene', '2475', (103, 107))
35403	24568263	PRCC frequently exhibits chromosomal polysomies, of which trisomy of chromosomes 7 and/or 17 are the most consistent and characteristic .	('PRCC', 'Gene', '5546', (0, 4))	('PRCC', 'Gene', (0, 4))	('RCC', 'Phenotype', 'HP:0005584', (1, 4))	('exhibits', 'Reg', (16, 24))	('PRCC', 'Phenotype', 'HP:0006766', (0, 4))	('trisomy of chromosomes', 'Var', (58, 80))
35417	24568263	Deletion of chromosome 3p was assessed using a probe cocktail containing BAC clone probe to chromosome 3p25 (RP11-572 M14, Green) and CEP3 (Orange).	('CEP3', 'Gene', '10602', (134, 138))	('CEP3', 'Gene', (134, 138))	('RP11-572 M14', 'Var', (109, 121))	('chromosome', 'cellular_component', 'GO:0005694', ('92', '102'))	('CEP', 'molecular_function', 'GO:0047849', ('134', '137'))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))
35423	24568263	Chromosome 3p deletion was considered to be characteristic of CCRCC, whereas trisomy of chromosomes 7 and/or 17 was considered characteristic of PRCC .	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('Chromosome 3p deletion', 'Var', (0, 22))	('PRCC', 'Gene', '5546', (145, 149))	('CCRCC', 'Phenotype', 'HP:0006770', (62, 67))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('PRCC', 'Gene', (145, 149))	('RCC', 'Disease', (64, 67))	('PRCC', 'Phenotype', 'HP:0006766', (145, 149))
35434	24568263	Of the CK7-positive tumors, 86% (6/7) also demonstrated trisomy of chromosomes 7 and/or 17 by FISH.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('trisomy', 'Var', (56, 63))	('CK7', 'Gene', (7, 10))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CK7', 'Gene', '3855', (7, 10))
35435	24568263	Chromosome 3p deletion was detected in 41% (42/103) of all metastatic RCC cases, and trisomy of chromosomes 7 and/or 17 was detected in 16% (16/103), of which 14 exhibited trisomy of chromosome 7 and 12 exhibited trisomy of chromosome 17 (Table  1).	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('trisomy', 'Var', (172, 179))	('exhibited', 'Reg', (162, 171))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('Chromosome 3p', 'Gene', (0, 13))	('Chromosome', 'cellular_component', 'GO:0005694', ('0', '10'))	('chromosome', 'cellular_component', 'GO:0005694', ('224', '234'))	('chromosome', 'cellular_component', 'GO:0005694', ('183', '193'))	('detected', 'Reg', (27, 35))
35436	24568263	Of the tumors originally classified as metastatic CCRCC, chromosome 3p deletion was detected in 63% (20/32).	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('RCC', 'Disease', (52, 55))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('57', '67'))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('detected', 'Reg', (84, 92))	('CCRCC', 'Phenotype', 'HP:0006770', (50, 55))	('chromosome 3p deletion', 'Var', (57, 79))
35437	24568263	Of the tumors originally classified as metastatic PRCC, 75% (6/8) showed trisomy of chromosome 7 and/or 17.	('RCC', 'Phenotype', 'HP:0005584', (51, 54))	('PRCC', 'Phenotype', 'HP:0006766', (50, 54))	('tumors', 'Disease', (7, 13))	('trisomy', 'Var', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('chromosome', 'cellular_component', 'GO:0005694', ('84', '94'))	('PRCC', 'Gene', '5546', (50, 54))	('PRCC', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
35438	24568263	Deletions of chromosome 3p and trisomy of chromosomes 7 and/or 17 were mutually exclusive findings in these metastatic CCRCC and PRCC cases.	('RCC', 'Phenotype', 'HP:0005584', (121, 124))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('chromosome', 'cellular_component', 'GO:0005694', ('13', '23'))	('RCC', 'Disease', (121, 124))	('trisomy', 'Var', (31, 38))	('PRCC', 'Phenotype', 'HP:0006766', (129, 133))	('CCRCC', 'Phenotype', 'HP:0006770', (119, 124))	('RCC', 'Disease', (130, 133))	('PRCC', 'Gene', '5546', (129, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('Deletions', 'Var', (0, 9))	('PRCC', 'Gene', (129, 133))
35439	24568263	Of the RCCs not previously classified, 35% (22/63) were found to have chromosome 3p deletion, and 16% (10/63) were found to have trisomy of chromosome 7 and/or 17 (Table  1).	('chromosome', 'Var', (70, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('70', '80'))	('chromosome', 'cellular_component', 'GO:0005694', ('140', '150'))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('RCC', 'Disease', (7, 10))	('RCC', 'Phenotype', 'HP:0005584', (7, 10))	('trisomy', 'Var', (129, 136))
35444	24568263	If this tumor is regarded as PRCC based on positivity for CK7, then 52% (33/63) of the metastatic RCCs that were not previously subtyped could be reclassified based on a combination of FISH and immunohistochemistry.	('PRCC', 'Phenotype', 'HP:0006766', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('RCC', 'Disease', (30, 33))	('PRCC', 'Gene', '5546', (29, 33))	('RCC', 'Disease', (98, 101))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (98, 101))	('CK7', 'Gene', (58, 61))	('tumor', 'Disease', (8, 13))	('RCC', 'Disease', 'MESH:C538614', (98, 101))	('positivity', 'Var', (43, 53))	('CK7', 'Gene', '3855', (58, 61))	('PRCC', 'Gene', (29, 33))
35463	24568263	For example, inhibition of targets in the HIF pathway has resulted in significant clinical responses in CCRCC .	('inhibition', 'Var', (13, 23))	('CCRCC', 'Phenotype', 'HP:0006770', (104, 109))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
35487	24568263	FISH analysis shows the characteristic chromosome 3p deletion in 60-90% of CCRCC cases .	('chromosome', 'Var', (39, 49))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('RCC', 'Disease', (77, 80))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('CCRCC', 'Phenotype', 'HP:0006770', (75, 80))
35488	24568263	In contrast, PRCC frequently exhibits chromosomal polysomies, of which trisomy of chromosomes 7 and/or 17 are the most consistent and characteristic .	('exhibits', 'Reg', (29, 37))	('PRCC', 'Gene', (13, 17))	('PRCC', 'Phenotype', 'HP:0006766', (13, 17))	('trisomy of chromosomes', 'Var', (71, 93))	('PRCC', 'Gene', '5546', (13, 17))	('RCC', 'Phenotype', 'HP:0005584', (14, 17))
35491	24568263	Of tumors originally diagnosed as metastatic PRCC, 75% (6/8) showed trisomy of chromosomes 7 or 17.	('PRCC', 'Gene', '5546', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('tumors', 'Disease', (3, 9))	('PRCC', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PRCC', 'Phenotype', 'HP:0006766', (45, 49))	('trisomy', 'Var', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
35492	24568263	Of the metastatic RCCs that were not originally classified, 35% (22/63) additionally exhibited chromosome 3p deletion, facilitating reclassification as metastatic CCRCC.	('RCC', 'Disease', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (18, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('95', '105'))	('chromosome', 'Var', (95, 105))	('CCRCC', 'Phenotype', 'HP:0006770', (163, 168))	('RCC', 'Phenotype', 'HP:0005584', (165, 168))	('exhibited', 'Reg', (85, 94))	('RCC', 'Disease', 'MESH:C538614', (165, 168))	('RCC', 'Disease', 'MESH:C538614', (18, 21))	('RCC', 'Disease', (165, 168))
35493	24568263	An additional 16% of these tumors (10/63) were found to have trisomy of chromosomes 7 and/or 17, supporting reclassification as metastatic PRCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('PRCC', 'Phenotype', 'HP:0006766', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('PRCC', 'Gene', '5546', (139, 143))	('RCC', 'Phenotype', 'HP:0005584', (140, 143))	('PRCC', 'Gene', (139, 143))	('trisomy', 'Var', (61, 68))
35499	24568263	However, a number of other RCC subtypes are now increasingly recognized , such as those associated with translocations involving MITF family genes .	('translocations', 'Var', (104, 118))	('MITF family genes', 'Gene', (129, 146))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))
35501	24568263	In contrast to the 3p deletions and trisomy of chromosomes 7 and 17 in CCRCC and PRCC, respectively, FISH analysis has assumed a key role in confirming rearrangements involving the TFE3 gene in such tumors  and to a lesser extent, the TFEB gene .	('PRCC', 'Gene', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (73, 76))	('RCC', 'Disease', (73, 76))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('CCRCC', 'Phenotype', 'HP:0006770', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('PRCC', 'Phenotype', 'HP:0006766', (81, 85))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))	('TFE3', 'Gene', (181, 185))	('RCC', 'Phenotype', 'HP:0005584', (82, 85))	('rearrangements', 'Var', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PRCC', 'Gene', '5546', (81, 85))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
35516	32973759	Manipulating these lipids and T cells may open new strategies for therapy of pediatric PRCCs.	('PRCC', 'Gene', '5546', (87, 91))	('Manipulating', 'Var', (0, 12))	('PRCC', 'Gene', (87, 91))	('lipids', 'Chemical', 'MESH:D008055', (19, 25))	('PRCC', 'Phenotype', 'HP:0006766', (87, 91))
35554	32973759	IM2473), Anti-TCR Pan gamma/delta-FITC (Cat.	('Cat', 'Gene', (40, 43))	('Cat', 'molecular_function', 'GO:0004096', ('40', '43'))	('delta-FITC', 'Chemical', '-', (28, 38))	('TCR', 'cellular_component', 'GO:0042101', ('14', '17'))	('Cat', 'Gene', '847', (40, 43))	('TCR', 'biological_process', 'GO:0006283', ('14', '17'))	('Anti-TCR Pan', 'Var', (9, 21))
35555	32973759	B49175) (all Beckman Coulter), Anti-iNKT-PE-Vio770  (Cat.	('Cat', 'Gene', '847', (53, 56))	('Anti-iNKT-PE-Vio770', 'Var', (31, 50))	('Cat', 'Gene', (53, 56))	('Cat', 'molecular_function', 'GO:0004096', ('53', '56'))
35573	32973759	sc-100289, Santa Cruz) and anti-CD1d ([NOR3.2 (NOR3.2/13.17)], Cat.	('NOR', 'cellular_component', 'GO:0005731', ('39', '42'))	('NOR', 'cellular_component', 'GO:0005731', ('47', '50'))	('Cat', 'molecular_function', 'GO:0004096', ('63', '66'))	('Cat', 'Gene', (63, 66))	('sc-100289', 'Chemical', '-', (0, 9))	('Cat', 'Gene', '847', (63, 66))	('anti-CD1d', 'Var', (27, 36))
35647	32973759	In some samples, the use of DMSO had a small effect on iNKT or gammadelta T cells, but this effect was much smaller than the effect of the lipid fractions.	('gammadelta T cells', 'CPA', (63, 81))	('iNKT', 'CPA', (55, 59))	('DMSO', 'Var', (28, 32))	('DMSO', 'Chemical', 'MESH:D004121', (28, 32))	('lipid', 'Chemical', 'MESH:D008055', (139, 144))
35686	32973759	Several vaccine and T cell therapies are based on immunogenic, mutated peptides resulting from genetic alterations within the tumor.	('mutated', 'Var', (63, 70))	('genetic alterations', 'Var', (95, 114))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
35769	32838750	Purines are involved in many biological processes, including immune responses and host-tumor interaction, and their metabolism changes continuously in response to cell demands; thus, it is a consequence that the alteration of the enzymes involved in this pathway, organized in dynamic multienzyme complexes called "purinosome", occurs in severe diseases.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Purines', 'Chemical', 'MESH:D011687', (0, 7))	('host-tumor', 'Disease', (82, 92))	('host-tumor', 'Disease', 'MESH:D006086', (82, 92))	('alteration', 'Var', (212, 222))	('metabolism', 'biological_process', 'GO:0008152', ('116', '126'))
35810	31655611	Deregulated gene expression, especially that related to epigenetic control mechanisms clearly contributes to the development of renal tumors.	('renal tumors', 'Disease', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('Deregulated', 'Var', (0, 11))	('renal tumor', 'Phenotype', 'HP:0009726', (128, 139))	('contributes', 'Reg', (94, 105))	('renal tumors', 'Phenotype', 'HP:0009726', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('gene expression', 'biological_process', 'GO:0010467', ('12', '27'))	('renal tumors', 'Disease', 'MESH:D007680', (128, 140))
35816	31655611	EMT is partially regulated by Wnt/beta-catenin signaling pathway, whose hallmark is membrane dissociation of ss-catenin and its translocation into the cytoplasm or nucleus, which then leads to N-cadherin overexpression and reduced E-cadherin expression.	('expression', 'MPA', (242, 252))	('N-cadherin', 'Gene', '1000', (193, 203))	('ss-catenin', 'Var', (109, 119))	('cadherin', 'molecular_function', 'GO:0008014', ('195', '203'))	('E-cadherin', 'Gene', (231, 241))	('E-cadherin', 'Gene', '999', (231, 241))	('beta-catenin', 'Gene', '1499', (34, 46))	('reduced', 'NegReg', (223, 230))	('EMT', 'biological_process', 'GO:0001837', ('0', '3'))	('signaling pathway', 'biological_process', 'GO:0007165', ('47', '64'))	('cadherin', 'molecular_function', 'GO:0008014', ('233', '241'))	('cytoplasm', 'cellular_component', 'GO:0005737', ('151', '160'))	('nucleus', 'cellular_component', 'GO:0005634', ('164', '171'))	('membrane', 'cellular_component', 'GO:0016020', ('84', '92'))	('N-cadherin', 'Gene', (193, 203))	('translocation', 'MPA', (128, 141))	('overexpression', 'PosReg', (204, 218))	('beta-catenin', 'Gene', (34, 46))
35818	31655611	Furthermore, it was shown that PRMT1 directly methylates Runt-related transcription factor 1 (RUNX1) and functions as a co-activator for RUNX1-dependent transcriptional activation in different hematopoietic cell lineages.	('activation', 'PosReg', (169, 179))	('RUNX1', 'Gene', (94, 99))	('RUNX1', 'Gene', '861', (94, 99))	('transcriptional', 'MPA', (153, 168))	('PRMT1', 'Gene', '3276', (31, 36))	('Runt-related transcription factor 1', 'Gene', (57, 92))	('PRMT1', 'Gene', (31, 36))	('Runt-related transcription factor 1', 'Gene', '861', (57, 92))	('transcription factor', 'molecular_function', 'GO:0000981', ('70', '90'))	('RUNX1', 'Gene', (137, 142))	('transcription', 'biological_process', 'GO:0006351', ('70', '83'))	('methylates', 'Var', (46, 56))	('RUNX1', 'Gene', '861', (137, 142))
35903	31655611	Among analyzed RCT types, aberrant ss-catenin cytoplasmic immunoreactivity was observed in 147 (71.7%) of cases, without nuclear positivity.	('aberrant', 'Var', (26, 34))	('ss-catenin', 'Protein', (35, 45))	('RCT', 'Disease', 'MESH:D002292', (15, 18))	('observed', 'Reg', (79, 87))	('RCT', 'Disease', (15, 18))
35908	31655611	E-cadherin loss was less frequent in RUNX1 positive than in RUNX1 negative ccRCC (p = 0.019).	('positive', 'Var', (43, 51))	('loss', 'NegReg', (11, 15))	('ccRCC', 'Disease', (75, 80))	('RUNX1', 'Gene', (37, 42))	('cadherin', 'molecular_function', 'GO:0008014', ('2', '10'))	('ccRCC', 'Disease', 'MESH:D002292', (75, 80))	('RUNX1', 'Gene', (60, 65))	('RUNX1', 'Gene', '861', (37, 42))	('E-cadherin', 'Gene', (0, 10))	('RUNX1', 'Gene', '861', (60, 65))	('E-cadherin', 'Gene', '999', (0, 10))
35913	31655611	In particular, the expression of PRMT1 and ZEB1 in ccRCC, as well as low-nuclear tumor grade and low-tumor stage were significantly associated with better cancer-specific survival (p = 0.029, p = 0.009, p < 0.001 and p < 0.001, respectively) (Fig.	('low-tumor', 'Disease', (97, 106))	('ZEB1', 'Gene', '6935', (43, 47))	('PRMT1', 'Gene', '3276', (33, 38))	('better', 'PosReg', (148, 154))	('low-tumor', 'Disease', 'MESH:D009800', (97, 106))	('PRMT1', 'Gene', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (81, 86))	('ZEB1', 'Gene', (43, 47))	('expression', 'Var', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('low-nuclear', 'Var', (69, 80))	('cancer', 'Disease', (155, 161))	('ccRCC', 'Disease', 'MESH:D002292', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ccRCC', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
35930	31655611	Furthermore, it has been widely accepted that epigenetic regulation plays an important role in many biological processes, including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('epigenetic regulation', 'Var', (46, 67))	('regulation', 'biological_process', 'GO:0065007', ('57', '67'))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))
35959	31655611	Thus, in breast carcinoma, PRMT1 methylates ZEB1 promoter, which then induces EMT and therefore implies ZEB1 as a negative prognostic parameter.	('PRMT1', 'Gene', '3276', (27, 32))	('induces', 'PosReg', (70, 77))	('breast carcinoma', 'Phenotype', 'HP:0003002', (9, 25))	('ZEB1', 'Gene', '6935', (44, 48))	('ZEB1', 'Gene', '6935', (104, 108))	('PRMT1', 'Gene', (27, 32))	('ZEB1', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('methylates', 'Var', (33, 43))	('EMT', 'CPA', (78, 81))	('breast carcinoma', 'Disease', 'MESH:D001943', (9, 25))	('breast carcinoma', 'Disease', (9, 25))	('ZEB1', 'Gene', (104, 108))	('EMT', 'biological_process', 'GO:0001837', ('78', '81'))
35961	31655611	Finally, in non-small lung carcinoma, PRMT1 methylates TWIST1 and induces EMT related aggressive cancer behavior.	('small lung carcinoma', 'Phenotype', 'HP:0030357', (16, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('PRMT1', 'Gene', '3276', (38, 43))	('cancer', 'Disease', (97, 103))	('EMT', 'biological_process', 'GO:0001837', ('74', '77'))	('methylates', 'Var', (44, 54))	('induces', 'Reg', (66, 73))	('non-small lung carcinoma', 'Disease', 'MESH:D002289', (12, 36))	('TWIST1', 'Gene', (55, 61))	('TWIST1', 'Gene', '7291', (55, 61))	('PRMT1', 'Gene', (38, 43))	('small lung', 'Phenotype', 'HP:0002089', (16, 26))	('EMT', 'CPA', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('non-small lung carcinoma', 'Disease', (12, 36))	('non-small lung carcinoma', 'Phenotype', 'HP:0030358', (12, 36))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
35968	31655611	This may suggest that PRMT1/ZEB1 co-expression may be significant in RO tumorigenesis and may serve as a helpful IHC tool in the diagnosis of RO.	('co-expression', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('RO', 'Disease', 'MESH:C537750', (69, 71))	('RO', 'Disease', 'MESH:C537750', (142, 144))	('tumor', 'Disease', (72, 77))	('significant', 'Reg', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('PRMT1', 'Gene', '3276', (22, 27))	('PRMT1', 'Gene', (22, 27))	('ZEB1', 'Gene', (28, 32))	('ZEB1', 'Gene', '6935', (28, 32))
35973	31655611	Therefore, we suggest that loss of PRMT1 in ccRCC could lead to TWIST1 cytoplasmic expression and more aggressive behavior.	('TWIST1', 'Gene', (64, 70))	('loss', 'Var', (27, 31))	('TWIST1', 'Gene', '7291', (64, 70))	('aggressive behavior', 'Phenotype', 'HP:0000718', (103, 122))	('more', 'PosReg', (98, 102))	('aggressive behavior', 'biological_process', 'GO:0002118', ('103', '122'))	('PRMT1', 'Gene', '3276', (35, 40))	('ccRCC', 'Disease', (44, 49))	('ccRCC', 'Disease', 'MESH:D002292', (44, 49))	('PRMT1', 'Gene', (35, 40))	('aggressive behavior', 'CPA', (103, 122))	('lead to', 'Reg', (56, 63))
35983	31655611	Heterogenous PRMT1 IHC expression may emphasize intratumor heterogeneity which should be extensively examined in further studies.	('PRMT1', 'Gene', '3276', (13, 18))	('PRMT1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Heterogenous', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
35999	29270287	The unique phenomenon of pseudo-hypoxia connected with vhl mutation was observed in clear-cell, but not in papillary RCC, and the treatment of this subtype of cancer is still challenging.	('cancer', 'Disease', (159, 165))	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('an', 'Gene', '84509', (160, 162))	('RCC', 'Disease', (117, 120))	('an', 'Gene', '84509', (122, 124))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('vhl', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('hypoxia', 'Disease', (32, 39))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('mutation', 'Var', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('clear-cell', 'Disease', (84, 94))
36017	29270287	RCC subtypes are defined by specific genetic abnormalities including von Hippel Lindau (vhl), hepatocyte growth factor receptor (c-met), Birt-Hogg-Dube (bhd) and fumarate hydratase (fh) gene mutations, which was confirmed in both classical genetics and in genomic studies.	('genetic abnormalities', 'Disease', 'MESH:D030342', (37, 58))	('c-met', 'Gene', '4233', (129, 134))	('an', 'Gene', '84509', (249, 251))	('von Hippel Lindau', 'Gene', '7428', (69, 86))	('fh', 'Gene', (182, 184))	('an', 'Gene', '84509', (158, 160))	('genetic abnormalities', 'Disease', (37, 58))	('mutations', 'Var', (191, 200))	('hepatocyte growth factor receptor', 'Gene', '4233', (94, 127))	('von Hippel Lindau', 'Gene', (69, 86))	('c-met', 'Gene', (129, 134))	('fumarate hydratase', 'Gene', '2271', (162, 180))	('RCC', 'Disease', 'MESH:C538614', (0, 3))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('94', '118'))	('RCC', 'Phenotype', 'HP:0005584', (0, 3))	('fumarate hydratase', 'Gene', (162, 180))	('hepatocyte growth factor receptor', 'Gene', (94, 127))	('RCC', 'Disease', (0, 3))
36044	29270287	Understanding these processes is especially significant because the hypoxia signaling pathway is frequently de-regulated in clear-cell renal cell carcinoma due to vhl mutations and limited information is available on intratumoral hypoxia-mediated signaling abnormalities in pRCC or ccRCC.	('pRCC', 'Gene', (274, 278))	('hypoxia', 'Disease', 'MESH:D000860', (68, 75))	('mutations', 'Var', (167, 176))	('vhl', 'Gene', (163, 166))	('RCC', 'Disease', 'MESH:C538614', (284, 287))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('an', 'Gene', '84509', (177, 179))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('hypoxia', 'Disease', (230, 237))	('signaling', 'biological_process', 'GO:0023052', ('247', '256'))	('signaling pathway', 'biological_process', 'GO:0007165', ('76', '93'))	('clear-cell renal cell carcinoma', 'Disease', (124, 155))	('an', 'Gene', '84509', (7, 9))	('hypoxia', 'Disease', 'MESH:D000860', (230, 237))	('pRCC', 'Gene', '5546', (274, 278))	('tumor', 'Disease', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('de-regulated', 'NegReg', (108, 120))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 155))	('hypoxia', 'Disease', (68, 75))	('RCC', 'Phenotype', 'HP:0005584', (284, 287))	('RCC', 'Disease', (284, 287))	('an', 'Gene', '84509', (52, 54))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
36074	29270287	Caki-1, human metastasis of clear-cell renal cell carcinoma to the skin, expresses wild-type vhl (vhl-proficient) and forms tumors in immunocompromised mice (ATCC  HTB-46 ), and 769-P, human primary clear-cell renal cell carcinoma with vhl mutation (vhl-deficient), which forms tumors in NOD/SCID mice (ATCC  CRL-1933 ), were cultured primarily in monolayer in RPMI 1640 supplemented with GlutaMAX -I (Gibco, Cat.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('human', 'Species', '9606', (185, 190))	('an', 'Gene', '84509', (11, 13))	('SCID', 'Disease', (292, 296))	('an', 'Gene', '84509', (114, 116))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (210, 230))	('forms tumors', 'Disease', (272, 284))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (199, 230))	('Caki-1', 'CellLine', 'CVCL:0234', (0, 6))	('forms tumors', 'Disease', 'MESH:D009369', (118, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('Cat', 'molecular_function', 'GO:0004096', ('409', '412'))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (240, 248))	('clear-cell renal cell carcinoma', 'Disease', (28, 59))	('mice', 'Species', '10090', (297, 301))	('human', 'Species', '9606', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('forms tumors', 'Disease', (118, 130))	('an', 'Gene', '84509', (174, 176))	('mice', 'Species', '10090', (152, 156))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (28, 59))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('an', 'Gene', '84509', (188, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('clear-cell renal cell carcinoma', 'Disease', (199, 230))	('SCID', 'Disease', 'MESH:D053632', (292, 296))	('vhl', 'Gene', (236, 239))	('forms tumors', 'Disease', 'MESH:D009369', (272, 284))
36086	29270287	For HKCSCs, 769-P and Caki-1 monolayer cell cultures, following drug concentrations were used in normoxia and in hypoxia for a primary screening of their response to drug treatment: sunitinib and sorafenib:C1 = 0.15 microM (maximum clinically relevant dose administered to patients), C2 = 1.5 microM, C3 = 15 microM, C4 = 150 microM; axitinib:C1 = 0.07 microM (maximum clinically relevant dose administered to patients), C2 = 0.15 microM, C3 = 1.5 microM, C4 = 15 microM.	('sunitinib', 'Chemical', 'MESH:D000077210', (182, 191))	('sorafenib', 'Chemical', 'MESH:D000077157', (196, 205))	('hypoxia', 'Disease', 'MESH:D000860', (113, 120))	('patients', 'Species', '9606', (273, 281))	('Caki-1', 'CellLine', 'CVCL:0234', (22, 28))	('patients', 'Species', '9606', (410, 418))	('C4 =', 'Var', (456, 460))	('hypoxia', 'Disease', (113, 120))	('an', 'Gene', '84509', (192, 194))	('an', 'Gene', '84509', (106, 108))	('an', 'Gene', '84509', (385, 387))	('C3 = 1.5', 'Var', (439, 447))	('response to drug', 'biological_process', 'GO:0042493', ('154', '170'))	('C1 = 0.07', 'Var', (343, 352))	('an', 'Gene', '84509', (18, 20))	('axitinib', 'Chemical', 'MESH:D000077784', (334, 342))	('an', 'Gene', '84509', (248, 250))	('C2 = 0.15 microM', 'Var', (421, 437))
36125	29270287	To increase the proteome coverage, each of the three MS/MS measurements covered different m/z ranges: 300-600, 600-900 or 900-2000 Th.	('300-600', 'Var', (102, 109))	('an', 'Gene', '84509', (95, 97))	('900-2000 Th', 'Var', (122, 133))	('600-900', 'Var', (111, 118))	('proteome coverage', 'MPA', (16, 33))	('increase', 'PosReg', (3, 11))
36199	29270287	HKCSCs cultured in normoxia were Ki67 positive (Ki67+) in 87% in comparison with HKCSCs cultured in hypoxia:74%, irrespective of TKI treatment (Fig.	('Ki67 positive', 'Var', (33, 46))	('hypoxia', 'Disease', (100, 107))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))
36240	29270287	Previously described alterations in map2k1 protein expression together with eif4b support the hypothesis that key proteins expression in hypoxic tumor niche is regulated mostly by oxygen tension.	('map2k1', 'Gene', (36, 42))	('eif4b', 'Gene', '1975', (76, 81))	('eif4b', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('map2k', 'molecular_function', 'GO:0004708', ('36', '41'))	('hypoxic tumor', 'Disease', (137, 150))	('oxygen', 'Chemical', 'MESH:D010100', (180, 186))	('eif4', 'cellular_component', 'GO:0008304', ('76', '80'))	('map2k1', 'Gene', '5604', (36, 42))	('protein', 'cellular_component', 'GO:0003675', ('43', '50'))	('hypoxic tumor', 'Disease', 'MESH:D009369', (137, 150))	('alterations', 'Var', (21, 32))	('protein', 'Protein', (43, 50))
36242	29270287	It was previously reported that inhibition of mek1 in the renal cell carcinoma xenograft model with acquired resistance to sunitinib successfully improved anti-tumor drug efficacy.	('sunitinib', 'Chemical', 'MESH:D000077210', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('inhibition', 'Var', (32, 42))	('an', 'Gene', '84509', (115, 117))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('an', 'Gene', '84509', (155, 157))	('improved', 'PosReg', (146, 154))	('mek1', 'molecular_function', 'GO:0004708', ('46', '50'))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('renal cell carcinoma xenograft', 'Disease', 'MESH:C538614', (58, 88))	('mek1', 'Gene', (46, 50))	('renal cell carcinoma xenograft', 'Disease', (58, 88))	('tumor', 'Disease', (160, 165))	('mek1', 'Gene', '5604', (46, 50))
36244	29270287	Our results confirm previously published clinical data, which showed eifs expression in advanced cancers inter alia in renal cell carcinomas.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('an', 'Gene', '84509', (98, 100))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (119, 140))	('cancers inter alia in renal cell carcinomas', 'Disease', (97, 140))	('cancers inter alia in renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 140))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('eifs', 'Var', (69, 73))	('an', 'Gene', '84509', (91, 93))
36258	29270287	Not only is papillary renal cancer cells' protein expression profile affected by hypoxic conditions, but 1% pO2 also impacts papillary RCC cells' proliferation rate, cell cycling and response to tyrosine kinase inhibitors, which we confirmed in both the 2D and 3D cell cultures.	('pO2', 'Var', (108, 111))	('hypoxic conditions', 'Disease', 'MESH:D009135', (81, 99))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('an', 'Gene', '84509', (257, 259))	('an', 'Gene', '84509', (179, 181))	('protein expression profile', 'MPA', (42, 68))	('response', 'MPA', (183, 191))	('renal cancer', 'Phenotype', 'HP:0009726', (22, 34))	('pO2', 'Chemical', 'MESH:C093415', (108, 111))	('cell cycling', 'CPA', (166, 178))	('affected', 'Reg', (69, 77))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (12, 34))	('tyrosine kinase', 'Gene', (195, 210))	('hypoxic conditions', 'Disease', (81, 99))	('tyrosine kinase', 'Gene', '7294', (195, 210))	('papillary renal cancer', 'Disease', 'MESH:D007681', (12, 34))	('papillary renal cancer', 'Disease', (12, 34))	('an', 'Gene', '84509', (29, 31))	('protein', 'cellular_component', 'GO:0003675', ('42', '49'))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', (135, 138))	('impacts', 'Reg', (117, 124))
36286	33371886	We hypothesized that the alterations of common upstream regulators as well as subtype-specific upstream regulators work together to affect the downstream pathway perturbations and drive cancer initialization and prognosis.	('alterations', 'Var', (25, 36))	('affect', 'Reg', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('drive', 'Reg', (180, 185))	('downstream pathway', 'Pathway', (143, 161))	('prognosis', 'CPA', (212, 221))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
36293	33371886	Genomic alterations lead to differential expression of genes and subsequently induce dysregulation of biological functions to promote tumorigenesis and development.	('induce', 'Reg', (78, 84))	('development', 'CPA', (152, 163))	('dysregulation of biological functions', 'MPA', (85, 122))	('expression of genes', 'MPA', (41, 60))	('promote', 'PosReg', (126, 133))	('alterations', 'Var', (8, 19))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lead to differential', 'Reg', (20, 40))	('tumor', 'Disease', (134, 139))
36307	33371886	In summary, our work explored the relationships among pathway alterations, upstream regulators as well as clinical outcome for different subtypes of RCC.	('RCC', 'Disease', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('alterations', 'Var', (62, 73))	('RCC', 'Disease', 'MESH:C538614', (149, 152))
36382	33371886	Thus, we hypothesize that the alteration of upstream regulators induced the downregulation of such kind of prognostic pathways, thus contributing to the tumorigenesis and progression of ccRCC.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('alteration', 'Var', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('progression', 'CPA', (171, 182))	('RCC', 'Disease', (188, 191))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))	('ccRCC', 'Phenotype', 'HP:0006770', (186, 191))	('RCC', 'Disease', 'MESH:C538614', (188, 191))	('contributing', 'Reg', (133, 145))	('downregulation', 'NegReg', (76, 90))
36391	33371886	We hypothesized that the dysregulation of recurrent upstream regulators as well as subtype-specific upstream regulators work together to affect pathway perturbations and further influence cancer prognosis among various RCC subtypes.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('influence', 'Reg', (178, 187))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('pathway perturbations', 'Pathway', (144, 165))	('dysregulation', 'Var', (25, 38))	('cancer', 'Disease', (188, 194))	('RCC', 'Disease', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (219, 222))	('affect', 'Reg', (137, 143))	('RCC', 'Disease', 'MESH:C538614', (219, 222))
36447	31547602	Dysregulation of the protein kinases may introduce dramatic changes in cellular processes that, in the worst case, may lead to the development of cancer or other diseases.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('changes', 'Reg', (60, 67))	('Dysregulation', 'Var', (0, 13))	('lead to', 'Reg', (119, 126))	('men', 'Species', '9606', (138, 141))	('protein kinases', 'Enzyme', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cellular processes', 'MPA', (71, 89))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))
36473	31547602	Inhibiting VEGFRs will also increase the circulating endothelin-1 (ET-1) concentration:a change that promotes vasoconstriction.	('endothelin-1', 'Gene', (53, 65))	('Inhibiting', 'Var', (0, 10))	('ET-1', 'Gene', '1906', (67, 71))	('rat', 'Species', '10116', (80, 83))	('endothelin-1', 'Gene', '1906', (53, 65))	('vasoconstriction', 'MPA', (110, 126))	('VEGFRs', 'Gene', (11, 17))	('ET-1', 'Gene', (67, 71))	('VEGFRs', 'Gene', '2321;2324;3791', (11, 17))	('promotes', 'PosReg', (101, 109))	('increase', 'PosReg', (28, 36))	('vasoconstriction', 'biological_process', 'GO:0042310', ('110', '126'))
36478	31547602	Blockage of the RTKs at the cell surface leads to inhibition of the intracellular phosphorylation cascade and the Raf/MEK/ERK and PI3K/AKT/mTOR pathways, thereby inhibiting the transcription of proteins involved in different functions.	('PI3K', 'molecular_function', 'GO:0016303', ('130', '134'))	('mTOR', 'Gene', (139, 143))	('AKT', 'Gene', (135, 138))	('MEK', 'Gene', (118, 121))	('inhibiting', 'NegReg', (162, 172))	('ERK', 'Gene', '5594', (122, 125))	('intracellular phosphorylation cascade', 'Pathway', (68, 105))	('Blockage', 'Var', (0, 8))	('ERK', 'molecular_function', 'GO:0004707', ('122', '125'))	('mTOR', 'Gene', '2475', (139, 143))	('proteins', 'Protein', (194, 202))	('ERK', 'Gene', (122, 125))	('MEK', 'Gene', '5609', (118, 121))	('AKT', 'Gene', '207', (135, 138))	('phosphorylation', 'biological_process', 'GO:0016310', ('82', '97'))	('inhibition', 'NegReg', (50, 60))	('cell surface', 'cellular_component', 'GO:0009986', ('28', '40'))	('intracellular', 'cellular_component', 'GO:0005622', ('68', '81'))	('transcription', 'biological_process', 'GO:0006351', ('177', '190'))	('transcription', 'MPA', (177, 190))
36497	31547602	SU12662 is further metabolised by CYP3A4 to an inactive metabolite.	('CYP3A4', 'Gene', (34, 40))	('SU12662', 'Chemical', 'MESH:C544393', (0, 7))	('CYP3A4', 'Gene', '1576', (34, 40))	('SU12662', 'Var', (0, 7))	('CYP3A4', 'molecular_function', 'GO:0033780', ('34', '40'))
36521	31547602	The median disease-free survival (DFS) was 6.8 years in patients treated with sunitinib (compared to 5.6 years in the placebo group).	('disease-free', 'Disease', (11, 23))	('patients', 'Species', '9606', (56, 64))	('sunitinib', 'Chemical', 'MESH:C473478', (78, 87))	('sunitinib', 'Var', (78, 87))
36537	31547602	The most common AEs in the axitinib arm were diarrhoea (55%), hypertension (40%) and fatigue (39%).	('fatigue', 'Phenotype', 'HP:0012378', (85, 92))	('diarrhoea', 'Disease', (45, 54))	('hypertension', 'Disease', 'MESH:D006973', (62, 74))	('axitinib', 'Chemical', 'MESH:C503983', (27, 35))	('fatigue', 'Disease', 'MESH:D005221', (85, 92))	('diarrhoea', 'Disease', 'MESH:D003967', (45, 54))	('diarrhoea', 'Phenotype', 'HP:0002014', (45, 54))	('fatigue', 'Disease', (85, 92))	('hypertension', 'Disease', (62, 74))	('axitinib', 'Var', (27, 35))	('hypertension', 'Phenotype', 'HP:0000822', (62, 74))
36540	31547602	Less than 1% of axitinib-treated patients suffered from hypertension-induced sequelae, and while axitinib caused hypertension more frequently than sorafenib, it rarely led to therapy discontinuation or cardiovascular complications.	('suffered', 'Reg', (42, 50))	('cardiovascular complications', 'Disease', 'MESH:D002318', (202, 230))	('caused', 'Reg', (106, 112))	('axitinib', 'Chemical', 'MESH:C503983', (16, 24))	('hypertension', 'Disease', (113, 125))	('cardiovascular complications', 'Disease', (202, 230))	('patients', 'Species', '9606', (33, 41))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))	('sorafenib', 'Chemical', 'MESH:C471405', (147, 156))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('axitinib', 'Var', (97, 105))	('hypertension', 'Disease', 'MESH:D006973', (56, 68))	('axitinib', 'Chemical', 'MESH:C503983', (97, 105))	('hypertension', 'Disease', (56, 68))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (202, 230))	('hypertension', 'Phenotype', 'HP:0000822', (56, 68))
36586	31547602	VEGFR-2 inhibition abrogates NO synthesis, VEGFR-1+2 inhibition reduces PGI2 synthesis and VEGFR-(1+2+3) inhibition promotes vessel rarefaction, all of which are mechanisms involved in hypertension development.	('VEGFR-2', 'Gene', (0, 7))	('NO synthesis', 'MPA', (29, 41))	('vessel rarefaction', 'CPA', (125, 143))	('VEGFR-1', 'Gene', (43, 50))	('promotes', 'PosReg', (116, 124))	('abrogates', 'NegReg', (19, 28))	('hypertension', 'Disease', 'MESH:D006973', (185, 197))	('hypertension', 'Disease', (185, 197))	('inhibition', 'Var', (8, 18))	('reduces', 'NegReg', (64, 71))	('VEGFR', 'Gene', '3791', (43, 48))	('VEGFR', 'Gene', '3791', (91, 96))	('VEGFR', 'Gene', (91, 96))	('VEGFR', 'Gene', (43, 48))	('men', 'Species', '9606', (205, 208))	('VEGFR-1', 'Gene', '2321', (43, 50))	('hypertension', 'Phenotype', 'HP:0000822', (185, 197))	('PGI2 synthesis', 'MPA', (72, 86))	('synthesis', 'biological_process', 'GO:0009058', ('32', '41'))	('VEGFR-2', 'Gene', '3791', (0, 7))	('inhibition', 'Var', (53, 63))	('VEGFR', 'Gene', '3791', (0, 5))	('synthesis', 'biological_process', 'GO:0009058', ('77', '86'))	('VEGFR', 'Gene', (0, 5))
36648	26185343	Discontinuity of this pseudocapsule generally indicates a high-grade tumor.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('indicates', 'Reg', (46, 55))	('Discontinuity', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
36757	33886004	Authors also showed that high expressions of FAP are associated with development of early metastases and worse cancer-specific survival.	('of', 'Gene', '6688', (81, 83))	('metastases', 'Disease', (90, 100))	('of', 'Gene', '6688', (42, 44))	('FAP', 'Gene', '2191', (45, 48))	('metastases', 'Disease', 'MESH:D009362', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('men', 'Species', '9606', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high', 'Var', (25, 29))	('associated', 'Reg', (53, 63))	('FAP', 'Gene', (45, 48))	('cancer', 'Disease', (111, 117))	('worse', 'NegReg', (105, 110))
36772	33886004	Authors showed that aberrant expression of ubiquitin-specific protease 2 mRNA acted as independent prognosticator for ccRCC (AUC: 0.89, p < 0.001).	('ubiquitin-specific', 'Protein', (43, 61))	('aberrant expression', 'Var', (20, 39))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('ubiquitin', 'molecular_function', 'GO:0031386', ('43', '52'))	('of', 'Gene', '6688', (40, 42))
36819	33886004	In particular, non-coding RNAs (ncRNAs), which included also microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been studied as possible biomarkers in several tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('non-coding', 'Var', (15, 25))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('art', 'Gene', '9048', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('art', 'Gene', (4, 7))
36869	32751108	Molecular studies have clearly shown that CCRCC is universally initiated by Von Hippel Lindau (VHL) gene dysregulation, followed by different types of additional genetic events involving epigenetic regulatory genes, dictating disease progression, aggressiveness, and differential response to treatments.	('Von Hippel Lindau', 'Gene', (76, 93))	('aggressiveness', 'Disease', 'MESH:D001523', (247, 261))	('VHL', 'Gene', (95, 98))	('aggressiveness', 'Disease', (247, 261))	('initiated by', 'Reg', (63, 75))	('Von Hippel Lindau', 'Gene', '7428', (76, 93))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('VHL', 'Gene', '7428', (95, 98))	('RCC', 'Disease', (44, 47))	('men', 'Species', '9606', (297, 300))	('aggressiveness', 'Phenotype', 'HP:0000718', (247, 261))	('dictating', 'Reg', (216, 225))	('gene dysregulation', 'Var', (100, 118))	('dysregulation', 'Var', (105, 118))
36885	32751108	Many autosomal dominant hereditary RCC syndromes have been reported and included those in which germline pathogenic mutations at the level of VHL, MET, FH, SDH A/B/C/D, FLCN, TSC1/TSC2, BAP1, CDC73, and MiTF are involved.	('CDC73', 'Gene', '79577', (192, 197))	('TSC2', 'Gene', '7249', (180, 184))	('MET', 'Gene', '79811', (147, 150))	('SDH A/B/C/D', 'Gene', '6389;6390;6391;6392', (156, 167))	('VHL', 'Gene', '7428', (142, 145))	('autosomal dominant hereditary RCC syndromes', 'Disease', (5, 48))	('TSC2', 'Gene', (180, 184))	('SDH A/B/C/D', 'Gene', (156, 167))	('BAP1', 'Gene', '8314', (186, 190))	('autosomal dominant hereditary RCC syndromes', 'Disease', 'MESH:C538614', (5, 48))	('mutations', 'Var', (116, 125))	('TSC1', 'Gene', (175, 179))	('MiTF', 'Gene', '4286', (203, 207))	('MET', 'Gene', (147, 150))	('TSC1', 'Gene', '7248', (175, 179))	('MiTF', 'Gene', (203, 207))	('FH', 'Gene', '2271', (152, 154))	('FLCN', 'Gene', (169, 173))	('BAP1', 'Gene', (186, 190))	('CDC73', 'Gene', (192, 197))	('VHL', 'Gene', (142, 145))
36890	32751108	The prevalence of germline mutations in known predisposition genes and other genes associated with cancer development was explored in 254 patients with advanced RCC; about 16% carried pathogenic or seemingly pathogenic germline variants at the level of 17 different cancer-predisposition genes: 5.5% of these patients carried mutations at the level of RCC-associated genes, such as FH, BAP1, VHL, MET, SDHA, and SDHB; 10.5% of these patients carried mutations in genes not clearly associated with RCC, including the CHEK2 gene.	('mutations', 'Var', (326, 335))	('RCC', 'Disease', (497, 500))	('men', 'Species', '9606', (113, 116))	('MET', 'Gene', (397, 400))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('RCC', 'Disease', (352, 355))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('BAP1', 'Gene', '8314', (386, 390))	('RCC', 'Disease', 'MESH:C538614', (497, 500))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('RCC', 'Disease', (161, 164))	('patients', 'Species', '9606', (433, 441))	('mutations', 'Var', (450, 459))	('SDHB', 'Gene', (412, 416))	('VHL', 'Gene', (392, 395))	('patients', 'Species', '9606', (138, 146))	('RCC', 'Disease', 'MESH:C538614', (352, 355))	('MET', 'Gene', '79811', (397, 400))	('CHEK2', 'Gene', (516, 521))	('BAP1', 'Gene', (386, 390))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('CHEK2', 'Gene', '11200', (516, 521))	('cancer', 'Disease', (266, 272))	('SDHA', 'Gene', (402, 406))	('VHL', 'Gene', '7428', (392, 395))	('cancer', 'Disease', (99, 105))	('FH', 'Gene', '2271', (382, 384))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('patients', 'Species', '9606', (309, 317))	('variants', 'Var', (228, 236))	('SDHA', 'Gene', '6389', (402, 406))
36895	32751108	Germline VHL gene mutations predispose affected subjects to the development of benign and malignant tumors located at the central nervous system and visceral organs.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('VHL', 'Gene', (9, 12))	('VHL', 'Gene', '7428', (9, 12))	('men', 'Species', '9606', (71, 74))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('malignant tumors', 'Disease', (90, 106))	('tumors located at the central nervous system', 'Phenotype', 'HP:0100006', (100, 144))	('malignant tumors', 'Disease', 'MESH:D009369', (90, 106))	('predispose', 'Reg', (28, 38))	('mutations', 'Var', (18, 27))
36898	32751108	The genotype correlates with the type of tumor risk observed in VHL syndrome: truncating or missense mutations are associated with type 1 and missense mutations with type 2.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('VHL syndrome', 'Disease', (64, 76))	('associated', 'Reg', (115, 125))	('VHL syndrome', 'Disease', 'MESH:D006623', (64, 76))	('truncating', 'MPA', (78, 88))	('missense mutations', 'Var', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('missense mutations', 'Var', (92, 110))
36899	32751108	Recent studies have explored the relationship between genotype and phenotype in VHL syndrome: G239T mutation was linked with VHL type 2B, associated with renal cell carcinoma, pheochromocytoma, and cerebellar hemangioma; A232T mutation was related to VHL type I, associated with renal cell carcinoma alone; G500A mutation was associated with VHL type II, characterized by pheochromocytoma and cerebellar, retina and spinal cord hemangioblastoma; A293G mutation was associated with pheochromocytoma and thus with type IIC VHL.	('pheochromocytoma', 'Disease', (372, 388))	('G500A', 'Var', (307, 312))	('VHL', 'Gene', (80, 83))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (279, 299))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (372, 388))	('G239T', 'Var', (94, 99))	('spinal cord hemangioblastoma', 'Disease', (416, 444))	('renal cell carcinoma', 'Disease', (154, 174))	('VHL', 'Gene', '7428', (342, 345))	('G500A', 'SUBSTITUTION', 'None', (307, 312))	('A293G', 'Var', (446, 451))	('VHL', 'Gene', (251, 254))	('A293G', 'SUBSTITUTION', 'None', (446, 451))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (154, 174))	('VHL syndrome', 'Disease', 'MESH:D006623', (80, 92))	('cerebellar hemangioma', 'Disease', (198, 219))	('VHL', 'Gene', (125, 128))	('pheochromocytoma', 'Disease', 'MESH:D010673', (481, 497))	('VHL', 'Gene', '7428', (80, 83))	('cerebellar hemangioma', 'Phenotype', 'HP:0006880', (198, 219))	('VHL', 'Gene', (521, 524))	('spinal cord hemangioblastoma', 'Phenotype', 'HP:0009713', (416, 444))	('A232T', 'Var', (221, 226))	('spinal cord hemangioblastoma', 'Disease', 'MESH:D018325', (416, 444))	('VHL', 'Gene', '7428', (251, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('renal cell carcinoma', 'Disease', (279, 299))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (279, 299))	('pheochromocytoma', 'Disease', (481, 497))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (481, 497))	('pheochromocytoma', 'Disease', 'MESH:D010673', (176, 192))	('VHL', 'Gene', '7428', (125, 128))	('VHL', 'Gene', '7428', (521, 524))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (428, 444))	('A232T', 'SUBSTITUTION', 'None', (221, 226))	('cerebellar hemangioma', 'Disease', 'MESH:D006391', (198, 219))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (154, 174))	('pheochromocytoma', 'Disease', (176, 192))	('G239T', 'SUBSTITUTION', 'None', (94, 99))	('associated', 'Reg', (465, 475))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (176, 192))	('pheochromocytoma', 'Disease', 'MESH:D010673', (372, 388))	('VHL syndrome', 'Disease', (80, 92))	('VHL', 'Gene', (342, 345))	('hemangioma', 'Phenotype', 'HP:0001028', (209, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
36900	32751108	The role of different types of germline VHL mutations classified as missense or truncating mutations and two subgroups of missense mutations subdivided according to mutations affecting the HIF-alpha binding site (HM) and mutations not affecting the HIF-alpha binding site (nHM) was also investigated.	('binding', 'molecular_function', 'GO:0005488', ('259', '266'))	('VHL', 'Gene', (40, 43))	('VHL', 'Gene', '7428', (40, 43))	('mutations', 'Var', (44, 53))	('mutations', 'Var', (165, 174))	('binding', 'molecular_function', 'GO:0005488', ('199', '206'))
36902	32751108	The results of this study showed that: (i) Missense mutations are associated with an increased risk of pheochromocytoma, but a lower risk of renal cancer than truncating mutations; among missense mutations, HM mutations conferred a higher risk than nHM mutations of developing renal cancer.	('pheochromocytoma', 'Disease', 'MESH:D010673', (103, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('renal cancer', 'Disease', 'MESH:D007680', (277, 289))	('mutations', 'Var', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (277, 289))	('renal cancer', 'Disease', (141, 153))	('Missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('renal cancer', 'Disease', 'MESH:D007680', (141, 153))	('renal cancer', 'Phenotype', 'HP:0009726', (141, 153))	('pheochromocytoma', 'Disease', (103, 119))	('renal cancer', 'Disease', (277, 289))
36904	32751108	Patients with VHL disease and asymptomatic family members carriers of the VHL mutation are annually screened for asymptomatic tumors and starting from the age of 16 years are controlled for RCC by magnetic resonance imaging, thus these patients undergo RCC removal when the tumor mass reaches 3 cm of diameter.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('RCC', 'Disease', 'MESH:C538614', (253, 256))	('VHL disease', 'Disease', 'MESH:D006623', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('VHL', 'Gene', (14, 17))	('tumor', 'Disease', (274, 279))	('VHL disease', 'Disease', (14, 25))	('tumors', 'Disease', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('patients', 'Species', '9606', (236, 244))	('Patients', 'Species', '9606', (0, 8))	('undergo', 'Reg', (245, 252))	('VHL', 'Gene', '7428', (14, 17))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('VHL', 'Gene', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (126, 131))	('mutation', 'Var', (78, 86))	('RCC', 'Disease', (190, 193))	('RCC', 'Disease', (253, 256))	('VHL', 'Gene', '7428', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (126, 131))
36906	32751108	Both in CCRCC with germline VHL mutation and in sporadic CCRCC, the most relevant copy number alterations occurred at the level of 3p deletion involving the VHL gene, p9 deletion involving CDKN2A and CDKN2B genes, and of 8q amplification involving the MYC gene amplification.	('CDKN2B', 'Gene', '1030', (200, 206))	('MYC', 'Gene', '4609', (252, 255))	('VHL', 'Gene', (157, 160))	('CDKN2A', 'Gene', '1029', (189, 195))	('RCC', 'Disease', (59, 62))	('VHL', 'Gene', '7428', (157, 160))	('amp', 'Chemical', 'MESH:D000249', (224, 227))	('VHL', 'Gene', (28, 31))	('RCC', 'Disease', (10, 13))	('mutation', 'Var', (32, 40))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('copy number', 'MPA', (82, 93))	('p9 deletion', 'Var', (167, 178))	('MYC', 'Gene', (252, 255))	('amp', 'Chemical', 'MESH:D000249', (261, 264))	('VHL', 'Gene', '7428', (28, 31))	('CDKN2B', 'Gene', (200, 206))	('RCC', 'Disease', 'MESH:C538614', (10, 13))	('CDKN2A', 'Gene', (189, 195))	('germline', 'Var', (19, 27))	('alterations', 'Reg', (94, 105))
36907	32751108	Several studies have explored the evolution at clonal level of RCCs developing in individuals with germline VHL mutations.	('RCC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('VHL', 'Gene', '7428', (108, 111))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', (108, 111))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
36908	32751108	The genomic analysis on multi-focal RCCs developing in an individual with germline VHL mutation showed that tumors arising in this multifocal context are clonally independent and harbor distinct secondary events, such as loss of chromosome 3p; despite this heterogeneity, the genetic alterations converge upon PI3K-AKT-mTOR signaling pathway; the tumors display only a minimal intratumoral heterogeneity.	('RCC', 'Disease', (36, 39))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('tumor', 'Disease', (108, 113))	('AKT', 'Gene', (315, 318))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('tumor', 'Disease', (382, 387))	('tumors', 'Disease', (347, 353))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mTOR', 'Gene', (319, 323))	('signaling pathway', 'biological_process', 'GO:0007165', ('324', '341'))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('VHL', 'Gene', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('AKT', 'Gene', '207', (315, 318))	('chromosome', 'cellular_component', 'GO:0005694', ('229', '239'))	('tumors', 'Disease', (108, 114))	('converge', 'Reg', (296, 304))	('PI3K', 'molecular_function', 'GO:0016303', ('310', '314'))	('mutation', 'Var', (87, 95))	('mTOR', 'Gene', '2475', (319, 323))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('VHL', 'Gene', '7428', (83, 86))	('tumor', 'Disease', (347, 352))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (347, 352))
36909	32751108	These observations suggested the development of RCC from germline VHL mutation, follow the evolutionary principles of complementary contingency and convergence.	('germline', 'Var', (57, 65))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('men', 'Species', '9606', (124, 127))	('men', 'Species', '9606', (40, 43))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (66, 69))	('RCC', 'Disease', (48, 51))
36911	32751108	The pattern of nucleotide substitution and the number and type of copy number alterations follow an individual pattern, thus suggesting that the genetic background and the environment plays a significant role in the types of secondary genetic alterations occurring during the development of RCCs with germline VHL mutations.	('men', 'Species', '9606', (179, 182))	('VHL', 'Gene', (310, 313))	('mutations', 'Var', (314, 323))	('VHL', 'Gene', '7428', (310, 313))	('RCC', 'Disease', (291, 294))	('men', 'Species', '9606', (283, 286))	('RCC', 'Disease', 'MESH:C538614', (291, 294))
36912	32751108	Studies based on the analysis of early renal cancers derived from nephrectomies performed in VHL disease patients provided evidence that biallelic inactivation of VHL is observed in preneoplastic renal lesions, in association with HIF activation.	('VHL', 'Gene', '7428', (163, 166))	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('VHL', 'Gene', '7428', (93, 96))	('preneoplastic renal lesions', 'Disease', 'MESH:D007674', (182, 209))	('VHL disease', 'Disease', (93, 104))	('biallelic', 'Var', (137, 146))	('renal cancers', 'Disease', 'MESH:D007680', (39, 52))	('renal cancers', 'Disease', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('preneoplastic renal lesions', 'Disease', (182, 209))	('VHL disease', 'Disease', 'MESH:D006623', (93, 104))	('VHL', 'Gene', (93, 96))	('VHL', 'Gene', (163, 166))	('preneoplastic renal lesions', 'Phenotype', 'HP:0009726', (182, 209))	('S', 'Chemical', 'MESH:D013455', (0, 1))
36914	32751108	Biallelic VHL inactivation is also required for the development of sporadic renal cancer, but requires a longer time than in VHL disease since the two VHL alleles must be inactivated.	('sporadic renal cancer', 'Disease', (67, 88))	('VHL', 'Gene', '7428', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('VHL', 'Gene', (125, 128))	('VHL', 'Gene', '7428', (125, 128))	('VHL disease', 'Disease', (125, 136))	('inactivation', 'Var', (14, 26))	('VHL', 'Gene', (151, 154))	('sporadic renal cancer', 'Disease', 'MESH:D007680', (67, 88))	('VHL', 'Gene', (10, 13))	('renal cancer', 'Phenotype', 'HP:0009726', (76, 88))	('VHL', 'Gene', '7428', (151, 154))	('VHL disease', 'Disease', 'MESH:D006623', (125, 136))	('men', 'Species', '9606', (59, 62))
36915	32751108	Sporadic CCRCC displays loss of the short arm of chromosome 3 (observed in >=90% of patients), with a deletion region encompassing four tumor suppressor genes that are also frequent targets for inactivating point mutations on the other chromosomal allele: VHL (with point mutations in 60-70% of cases and epigenetic silencing in about 5-10% of patients), PBRM1 (40%), BAP1 (10%), and SETD2 (10%).	('SETD2', 'Gene', (384, 389))	('RCC', 'Disease', (11, 14))	('point mutations', 'Var', (266, 281))	('patients', 'Species', '9606', (84, 92))	('short arm', 'Phenotype', 'HP:0009824', (36, 45))	('chromosome', 'cellular_component', 'GO:0005694', ('49', '59'))	('SETD2', 'Gene', '29072', (384, 389))	('S', 'Chemical', 'MESH:D013455', (384, 385))	('epigenetic silencing', 'Var', (305, 325))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('tumor', 'Disease', (136, 141))	('patients', 'Species', '9606', (344, 352))	('PBRM1', 'Gene', '55193', (355, 360))	('BAP1', 'Gene', '8314', (368, 372))	('VHL', 'Gene', (256, 259))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('PBRM1', 'Gene', (355, 360))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('136', '152'))	('loss', 'NegReg', (24, 28))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('tumor suppressor', 'biological_process', 'GO:0051726', ('136', '152'))	('BAP1', 'Gene', (368, 372))	('VHL', 'Gene', '7428', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
36918	32751108	In VHL disease, one allele is altered through germline mutations and this explains the high penetrance and the accelerated RCC development observed in these patients.	('accelerated', 'PosReg', (111, 122))	('germline mutations', 'Var', (46, 64))	('VHL disease', 'Disease', 'MESH:D006623', (3, 14))	('patients', 'Species', '9606', (157, 165))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('VHL disease', 'Disease', (3, 14))	('men', 'Species', '9606', (134, 137))
36919	32751108	The retrospective study analysis of the natural history of RCC developing in VHL disease showed that: (i) The mean age of onset was 38.8 years, with a mean initial tumor size of 3.1 cm; (ii) the mean tumor growth rate was 0.49 cm/year; (iii) some factors, such as later age of onset, larger initial tumor size, missense mutation, mutations located at the level of exon 3, were associated with faster tumor growth; (iv) bilateral tumors, large initial tumors, fast tumor growth, and presence of metastases are high-risk factors for poor prognosis in germline VHL-related RCCs.	('tumor', 'Disease', (464, 469))	('VHL disease', 'Disease', 'MESH:D006623', (77, 88))	('tumor', 'Disease', (164, 169))	('tumors', 'Disease', (429, 435))	('VHL', 'Gene', (77, 80))	('tumor', 'Disease', (400, 405))	('VHL disease', 'Disease', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (464, 469))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('RCC', 'Disease', 'MESH:C538614', (570, 573))	('tumors', 'Phenotype', 'HP:0002664', (451, 457))	('metastases', 'Disease', 'MESH:D009362', (494, 504))	('RCC', 'Disease', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (400, 405))	('tumors', 'Disease', 'MESH:D009369', (429, 435))	('tumor', 'Disease', (200, 205))	('VHL', 'Gene', '7428', (77, 80))	('metastases', 'Disease', (494, 504))	('VHL', 'Gene', (558, 561))	('tumors', 'Disease', (451, 457))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('missense mutation', 'Var', (311, 328))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', (429, 434))	('tumor', 'Phenotype', 'HP:0002664', (400, 405))	('tumor', 'Disease', (451, 456))	('tumor', 'Disease', 'MESH:D009369', (429, 434))	('tumors', 'Disease', 'MESH:D009369', (451, 457))	('VHL', 'Gene', '7428', (558, 561))	('tumor', 'Disease', 'MESH:D009369', (451, 456))	('tumors', 'Phenotype', 'HP:0002664', (429, 435))	('mutations', 'Var', (330, 339))	('tumor', 'Disease', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('bilateral', 'Disease', (419, 428))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('RCC', 'Disease', (570, 573))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))
36921	32751108	Germline mutations located at the level of the tyrosine kinase domain of the hepatocyte growth factor receptor, c-Met, are responsible for hereditary papillary renal cell cancer (HPRCC) type I, a very rare form of familial kidney cancer.	('hepatocyte growth factor receptor', 'Gene', (77, 110))	('familial kidney cancer', 'Disease', 'MESH:D007680', (214, 236))	('responsible for', 'Reg', (123, 138))	('papillary renal cell cancer', 'Phenotype', 'HP:0006766', (150, 177))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('PRCC', 'Gene', '5546', (180, 184))	('familial kidney cancer', 'Disease', (214, 236))	('kidney cancer', 'Phenotype', 'HP:0009726', (223, 236))	('hereditary papillary renal cell cancer', 'Disease', 'MESH:C538614', (139, 177))	('Germline', 'Var', (0, 8))	('c-Met', 'Gene', (112, 117))	('hereditary papillary renal cell cancer', 'Disease', (139, 177))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('77', '101'))	('c-Met', 'Gene', '4233', (112, 117))	('hepatocyte growth factor receptor', 'Gene', '4233', (77, 110))	('PRCC', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('renal cell cancer', 'Phenotype', 'HP:0005584', (160, 177))
36922	32751108	The mutants c-Met observed in these patients in suitable cellular and animal models display enhanced and dysregulated kinase activity and induce cell transformation and tumorigenicity.	('kinase activity', 'molecular_function', 'GO:0016301', ('118', '133'))	('cell transformation', 'CPA', (145, 164))	('mutants', 'Var', (4, 11))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('induce', 'Reg', (138, 144))	('c-Met', 'Gene', (12, 17))	('tumor', 'Disease', (169, 174))	('c-Met', 'Gene', '4233', (12, 17))	('dysregulated kinase activity', 'MPA', (105, 133))	('enhanced', 'PosReg', (92, 100))
36923	32751108	A fundamental study by Schmidt and coworkers in 1997 led to the identification of missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRCC families, as well as in a subset of sporadic PRCCs.	('PRCC', 'Gene', '5546', (195, 199))	('missense mutations located in', 'Var', (82, 111))	('PRCC', 'Gene', (195, 199))	('MET', 'Gene', '79811', (146, 149))	('S', 'Chemical', 'MESH:D013455', (23, 24))	('PRCC', 'Gene', '5546', (245, 249))	('MET', 'Gene', (146, 149))	('men', 'Species', '9606', (7, 10))	('PRCC', 'Gene', (245, 249))
36924	32751108	The same authors in a study on PRCCs identified 13% of cases with c-MET mutations: half of these patients were found to harbor germline c-MET and the rest only somatic c-MET mutations.	('mutations', 'Var', (72, 81))	('c-MET', 'Gene', '4233', (136, 141))	('c-MET', 'Gene', (66, 71))	('PRCC', 'Gene', '5546', (31, 35))	('c-MET', 'Gene', '4233', (168, 173))	('c-MET', 'Gene', '4233', (66, 71))	('PRCC', 'Gene', (31, 35))	('c-MET', 'Gene', (136, 141))	('c-MET', 'Gene', (168, 173))	('patients', 'Species', '9606', (97, 105))
36926	32751108	MET mutations cause constitutive activation of the cytoplasmic domain of the receptor, stimulate cell growth, and represent the main pathogenetic event in the development of HPRCC.	('MET', 'Gene', '79811', (0, 3))	('activation', 'PosReg', (33, 43))	('cell growth', 'CPA', (97, 108))	('PRCC', 'Gene', (175, 179))	('cell growth', 'biological_process', 'GO:0016049', ('97', '108'))	('MET', 'Gene', (0, 3))	('cytoplasmic domain', 'MPA', (51, 69))	('men', 'Species', '9606', (166, 169))	('stimulate', 'PosReg', (87, 96))	('mutations', 'Var', (4, 13))	('PRCC', 'Gene', '5546', (175, 179))
36927	32751108	Direct DNA diagnosis in HPRCC is based on the identification of mutations at the level of MET exons 15-21, encoding the cytoplasmic domain of the receptor.	('PRCC', 'Gene', '5546', (25, 29))	('PRCC', 'Gene', (25, 29))	('MET', 'Gene', '79811', (90, 93))	('MET', 'Gene', (90, 93))	('mutations', 'Var', (64, 73))	('DNA', 'cellular_component', 'GO:0005574', ('7', '10'))
36929	32751108	Papillary renal neoplasms from both patients with hereditary or somatic c-MET mutations share the same histologic features typical of chromophil basophilic type I PRCC, including macrophages and psammoma bodies; a papillary and/or tubulopapillary architecture is observed in all these tumors; clear cells were commonly detected in variable proportions in all c-MET-mutated PRCCs.	('PRCC', 'Gene', (373, 377))	('PRCC', 'Gene', '5546', (373, 377))	('Papillary renal neoplasms', 'Disease', 'MESH:D007681', (0, 25))	('c-MET', 'Gene', (72, 77))	('c-MET', 'Gene', (359, 364))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('neoplasms', 'Phenotype', 'HP:0002664', (16, 25))	('mutations', 'Var', (78, 87))	('c-MET', 'Gene', '4233', (72, 77))	('tumors', 'Disease', (285, 291))	('Papillary renal neoplasms', 'Disease', (0, 25))	('PRCC', 'Gene', '5546', (163, 167))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('renal neoplasms', 'Phenotype', 'HP:0009726', (10, 25))	('c-MET', 'Gene', '4233', (359, 364))	('PRCC', 'Gene', (163, 167))
36931	32751108	Interestingly, a case of a family with HPRCC was reported with a novel germline missense mutation of c-MET with a histological pattern consisting in multiple adenomas and papillary renal cell carcinomas with focal clear cells and a mixture of type I and type II pattern.	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (171, 202))	('c-MET', 'Gene', (101, 106))	('papillary renal cell carcinomas', 'Disease', (171, 202))	('PRCC', 'Gene', '5546', (40, 44))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (181, 202))	('missense mutation', 'Var', (80, 97))	('adenomas', 'Disease', 'MESH:D000236', (158, 166))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (171, 202))	('c-MET', 'Gene', '4233', (101, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (181, 201))	('PRCC', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('adenomas', 'Disease', (158, 166))
36933	32751108	Thus, foretinib, a pan-kinase inhibitor of MET, VEGFR2, RON, and AXL, was evaluated in patients with PRCC, showing 50% of partial responses among patients with HPRCC and 20% in PRCC patients with somatic c-MET mutations.	('MET', 'Gene', (43, 46))	('mutations', 'Var', (210, 219))	('patients', 'Species', '9606', (182, 190))	('partial responses', 'MPA', (122, 139))	('PRCC', 'Gene', '5546', (177, 181))	('PRCC', 'Gene', (101, 105))	('RON', 'Gene', (56, 59))	('MET', 'Gene', (206, 209))	('VEGFR2', 'Gene', (48, 54))	('RON', 'Gene', '4486', (56, 59))	('AXL', 'Gene', '558', (65, 68))	('MET', 'Gene', '79811', (43, 46))	('c-MET', 'Gene', '4233', (204, 209))	('patients', 'Species', '9606', (146, 154))	('VEGFR2', 'Gene', '3791', (48, 54))	('c-MET', 'Gene', (204, 209))	('PRCC', 'Gene', (161, 165))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('23', '39'))	('PRCC', 'Gene', '5546', (101, 105))	('foretinib', 'Chemical', 'MESH:C544831', (6, 15))	('PRCC', 'Gene', (177, 181))	('MET', 'Gene', '79811', (206, 209))	('AXL', 'Gene', (65, 68))	('patients', 'Species', '9606', (87, 95))	('PRCC', 'Gene', '5546', (161, 165))
36935	32751108	The majority of patients with this syndrome were found to have germline mutations in PTEN.	('PTEN', 'Gene', '5728', (85, 89))	('germline mutations', 'Var', (63, 81))	('patients', 'Species', '9606', (16, 24))	('PTEN', 'Gene', (85, 89))
36941	32751108	A recent study reported an atypical presentation of Cowden syndrome in a subject with heterozygous mutation C1003T in the PTEN gene, who developed four primary onset carcinomas (one melanoma, two CCRCC, and a follicular variant of papillary thyroid carcinoma).	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('carcinomas', 'Disease', (166, 176))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (231, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('papillary thyroid carcinoma', 'Disease', (231, 258))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (231, 258))	('Cowden syndrome', 'Disease', 'MESH:D006223', (52, 67))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('PTEN', 'Gene', (122, 126))	('melanoma', 'Disease', (182, 190))	('carcinomas', 'Disease', 'MESH:D009369', (166, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('C1003T', 'Var', (108, 114))	('PTEN', 'Gene', '5728', (122, 126))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (241, 258))	('Cowden syndrome', 'Disease', (52, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('C1003T', 'SUBSTITUTION', 'None', (108, 114))	('RCC', 'Disease', (198, 201))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
36942	32751108	Interestingly, the analysis of family's genetic background identified deleterious variants in two candidate modifier genes: CECAM1 and MIB2; CECAM1 is a tumor suppressor gene which presents loss of expression in RCC.	('variants', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('MIB2', 'Gene', '142678', (135, 139))	('expression', 'MPA', (198, 208))	('tumor suppressor', 'biological_process', 'GO:0051726', ('153', '169'))	('loss', 'NegReg', (190, 194))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('153', '169'))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('RCC', 'Disease', (212, 215))	('MIB2', 'Gene', (135, 139))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('CECAM1', 'Gene', (124, 130))	('CECAM1', 'Gene', (141, 147))
36943	32751108	The BRCA1-associated protein1 (BAP1) syndrome is a tumor predisposition syndrome dependent on the presence of germline pathogenic variants at the level of the tumor suppressor gene BAP1 that predisposes to the development of various types of tumors including uveal melanoma, mesothelioma, cutaneous melanoma, and RCC.	('uveal melanoma', 'Phenotype', 'HP:0007716', (259, 273))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('predisposes to', 'Reg', (191, 205))	('BRCA1-associated protein1', 'Gene', '8314', (4, 29))	('tumor', 'Disease', (242, 247))	('BRCA1-associated protein1', 'Gene', (4, 29))	('BAP1', 'Gene', '8314', (181, 185))	('melanoma', 'Disease', 'MESH:D008545', (265, 273))	('RCC', 'Disease', (313, 316))	('protein', 'cellular_component', 'GO:0003675', ('21', '28'))	('variants', 'Var', (130, 138))	('men', 'Species', '9606', (217, 220))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('BAP1', 'Gene', '8314', (31, 35))	('tumor', 'Disease', (51, 56))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('159', '175'))	('melanoma', 'Phenotype', 'HP:0002861', (299, 307))	('melanoma', 'Disease', (299, 307))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor suppressor', 'biological_process', 'GO:0051726', ('159', '175'))	('RCC', 'Disease', 'MESH:C538614', (313, 316))	('BAP1', 'Gene', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (159, 164))	('BAP1', 'Gene', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (265, 273))	('melanoma', 'Disease', (265, 273))	('tumors', 'Disease', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mesothelioma', 'Disease', (275, 287))	('cutaneous melanoma', 'Disease', (289, 307))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (289, 307))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (289, 307))	('mesothelioma', 'Disease', 'MESH:D008654', (275, 287))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (299, 307))
36948	32751108	The three most frequently observed missense mutations in these patients are H94R, L100P, and T173C.	('T173C', 'SUBSTITUTION', 'None', (93, 98))	('L100P', 'Var', (82, 87))	('L100P', 'SUBSTITUTION', 'None', (82, 87))	('H94R', 'SUBSTITUTION', 'None', (76, 80))	('T173C', 'Var', (93, 98))	('patients', 'Species', '9606', (63, 71))	('H94R', 'Var', (76, 80))
36949	32751108	identified in a family prone to RCC a germline mutation of BAP1 gene (277A>G; Thr93Ala); furthermore, these authors screened 11 families that included individuals carrying germline deleterious BAP1 mutations and 6 of these families presented with RCC-affected individuals.	('277A>G', 'SUBSTITUTION', 'None', (70, 76))	('BAP1', 'Gene', (59, 63))	('BAP1', 'Gene', '8314', (193, 197))	('BAP1', 'Gene', '8314', (59, 63))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('mutations', 'Var', (198, 207))	('277A>G', 'Var', (70, 76))	('BAP1', 'Gene', (193, 197))	('Thr93Ala', 'Chemical', '-', (78, 86))	('RCC', 'Disease', 'MESH:C538614', (247, 250))	('RCC', 'Disease', (247, 250))
36950	32751108	reported a family with a BAP1 germline variant (41T>A; L14H), disrupting a highly conserved residue in the catalytic domain: 22% of the individuals of this family display RCC, mostly multifocal and of the clear cell type.	('L14H', 'SUBSTITUTION', 'None', (55, 59))	('BAP1', 'Gene', (25, 29))	('L14H', 'Var', (55, 59))	('41T>A', 'SUBSTITUTION', 'None', (48, 53))	('RCC', 'Disease', (171, 174))	('variant', 'Var', (39, 46))	('41T>A', 'Var', (48, 53))	('disrupting', 'NegReg', (62, 72))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('highly conserved residue in the catalytic domain', 'MPA', (75, 123))	('BAP1', 'Gene', '8314', (25, 29))
36953	32751108	Germline mutations of the genes encoding the SDH subunits result in hereditary syndromes associated with the development of paraganglioma-pheochromocytoma, gastrointestinal stromal tumors, and RCC.	('Germline mutations', 'Var', (0, 18))	('associated', 'Reg', (89, 99))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (138, 154))	('RCC', 'Disease', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('hereditary syndromes', 'Disease', 'MESH:D061325', (68, 88))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('RCC', 'Disease', 'MESH:C538614', (193, 196))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paraganglioma-pheochromocytoma', 'Disease', (124, 154))	('SDH', 'Gene', (45, 48))	('gastrointestinal stromal tumors', 'Disease', (156, 187))	('paraganglioma-pheochromocytoma', 'Disease', 'MESH:D010673', (124, 154))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (156, 187))	('result in', 'Reg', (58, 67))	('men', 'Species', '9606', (116, 119))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (156, 187))	('hereditary syndromes', 'Disease', (68, 88))
36955	32751108	Most of the renal tumors developing in individuals with SDH deficiency, particularly those associated with germline SDHB mutations, exhibit a distinctive morphology consisting in tumors composed by cuboidal cells with bubbly eosinophilic cytoplasm, arranged in solid nests or in tubules surrounding central spaces.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mutations', 'Var', (121, 130))	('renal tumors', 'Disease', (12, 24))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('renal tumor', 'Phenotype', 'HP:0009726', (12, 23))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('SDHB', 'Gene', (116, 120))	('SDH deficiency', 'Disease', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('renal tumors', 'Phenotype', 'HP:0009726', (12, 24))	('cytoplasm', 'cellular_component', 'GO:0005737', ('238', '247'))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('SDH deficiency', 'Disease', 'MESH:D007153', (56, 70))	('renal tumors', 'Disease', 'MESH:D007674', (12, 24))
36956	32751108	have reported SDH-deficient renal carcinomas from 27 patients and estimated that 0.05%-0.2% of all carcinomas are SDH deficient; 94% of these tumors displayed the typical morphology of SDH-deficient renal cancers; all the patients performing a genetic evaluation displayed germline SDHB mutations (only in one patient SDHA mutations were detected); a part of these patients had a metastatic disease, associated with high-grade nuclear atypia or coagulative necrosis.	('patients', 'Species', '9606', (365, 373))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SDH-deficient renal cancers', 'Disease', 'MESH:D007680', (185, 212))	('patients', 'Species', '9606', (222, 230))	('mutations', 'Var', (287, 296))	('necrosis', 'biological_process', 'GO:0008220', ('457', '465'))	('coagulative necrosis', 'Disease', (445, 465))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('SDHA', 'Gene', (318, 322))	('renal carcinomas', 'Phenotype', 'HP:0005584', (28, 44))	('patients', 'Species', '9606', (53, 61))	('SDH-deficient renal carcinomas', 'Disease', 'MESH:C538614', (14, 44))	('SDHA', 'Gene', '6389', (318, 322))	('necrosis', 'biological_process', 'GO:0070265', ('457', '465'))	('necrosis', 'biological_process', 'GO:0019835', ('457', '465'))	('tumors', 'Disease', (142, 148))	('necrosis', 'biological_process', 'GO:0001906', ('457', '465'))	('patient', 'Species', '9606', (310, 317))	('carcinomas', 'Disease', (34, 44))	('patient', 'Species', '9606', (53, 60))	('patient', 'Species', '9606', (365, 372))	('carcinomas', 'Disease', (99, 109))	('renal carcinoma', 'Phenotype', 'HP:0005584', (28, 43))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('patient', 'Species', '9606', (222, 229))	('metastatic disease', 'Disease', (380, 398))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('SDHB', 'Gene', (282, 286))	('coagulative necrosis', 'Disease', 'MESH:D001778', (445, 465))	('SDH-deficient renal carcinomas', 'Disease', (14, 44))	('renal cancer', 'Phenotype', 'HP:0009726', (199, 211))	('necrosis', 'biological_process', 'GO:0008219', ('457', '465'))	('coagulative necrosis', 'Phenotype', 'HP:0010885', (445, 465))	('carcinomas', 'Disease', 'MESH:D009369', (34, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Disease', 'MESH:D009369', (99, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('SDH-deficient renal cancers', 'Disease', (185, 212))
36957	32751108	reported the characterization of 11 SDH-deficient RCC and observed the common presence of intratumoral mast cells; the majority of patients with SDHB gene mutations exhibited also loss of the second allele.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (155, 164))	('SDHB', 'Gene', (145, 149))	('SDH-deficient RCC', 'Disease', (36, 53))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (36, 53))	('tumor', 'Disease', (95, 100))
36960	32751108	In some rare patients, SDH mutations may co-occur with Xp11 translocation RCC, characterized by TFE3 chromosomal translocations involving break points in the TFE3 gene; renal cell carcinomas with translocations make part of MiT family translocation renal cell carcinoma and are composed by eosinophilic cells, with cytoplasmic inclusions and prominent nucleoli.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (13, 21))	('TFE3', 'Gene', (96, 100))	('TFE3', 'Gene', '7030', (96, 100))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (169, 189))	('renal cell carcinoma', 'Disease', (249, 269))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (249, 269))	('RCC', 'Disease', (74, 77))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (169, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('renal cell carcinomas', 'Disease', (169, 190))	('TFE3', 'Gene', (158, 162))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('translocations', 'Var', (196, 210))	('TFE3', 'Gene', '7030', (158, 162))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (169, 190))	('SDH', 'Gene', (23, 26))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (169, 189))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (249, 269))
36963	32751108	The most commonly mutated gene was SDHB (with 137G>A being the most frequent mutation) and less frequently SDHC (380A>G being the most frequent mutation) and SDHA.	('380A>G', 'SUBSTITUTION', 'None', (113, 119))	('SDHA', 'Gene', (158, 162))	('137G>A', 'Var', (46, 52))	('SDHB', 'Gene', (35, 39))	('SDHC', 'Gene', (107, 111))	('SDHC', 'Gene', '6391', (107, 111))	('SDHA', 'Gene', '6389', (158, 162))	('137G>A', 'SUBSTITUTION', 'None', (46, 52))	('380A>G', 'Var', (113, 119))
36964	32751108	Rare cases of SDH-deficient renal cell cancers are related to alterations of the SDHA gene: Yakirevich et al.	('SDHA', 'Gene', (81, 85))	('SDH-deficient renal cell cancers', 'Disease', (14, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('SDH-deficient renal cell cancers', 'Disease', 'MESH:C538614', (14, 46))	('renal cell cancer', 'Phenotype', 'HP:0005584', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('SDHA', 'Gene', '6389', (81, 85))	('related', 'Reg', (51, 58))	('alterations', 'Var', (62, 73))
36965	32751108	reported a case of SDH-deficiency RCC, characterized by homozygous deletion of the SDHA gene (9 of the SDHA gene exons were deleted): at immunohistochemical level, the expression of both SDHA and SDHB was lost.	('SDH-deficiency RCC', 'Disease', (19, 37))	('SDHA', 'Gene', '6389', (83, 87))	('SDHA', 'Gene', '6389', (187, 191))	('SDH-deficiency RCC', 'Disease', 'MESH:C538614', (19, 37))	('expression', 'MPA', (168, 178))	('SDHA', 'Gene', (83, 87))	('SDHA', 'Gene', (103, 107))	('SDHA', 'Gene', (187, 191))	('deletion', 'Var', (67, 75))	('lost', 'NegReg', (205, 209))	('SDHB', 'Gene', (196, 200))	('SDHA', 'Gene', '6389', (103, 107))
36966	32751108	The characterization of an SDHB-deficient RCC cell line isolated from young patient carrying the SDHBR46Q mutation was used as a tool to elucidate the alterations of metabolism caused by SDH deficiency.	('SDH deficiency', 'Disease', (187, 201))	('SDH deficiency', 'Disease', 'MESH:D007153', (187, 201))	('mutation', 'Var', (106, 114))	('metabolism', 'biological_process', 'GO:0008152', ('166', '176'))	('SDHBR46Q', 'Gene', (97, 105))	('SDHB-deficient RCC', 'Disease', 'MESH:C538614', (27, 45))	('patient', 'Species', '9606', (76, 83))	('SDHB-deficient RCC', 'Disease', (27, 45))
36968	32751108	The SDH function and molecular organization require two conserved L(I)YR motifs present in SDHB; the SDHBR46Q mutation impairs one of these two L(I)YR motifs, by changing IYR to IYQ and thus determining an incapacity of SDHB to incorporate Fe-S cluster, with its consequent unstability.	('incapacity', 'NegReg', (206, 216))	('changing', 'Reg', (162, 170))	('impairs', 'NegReg', (119, 126))	('IYR', 'MPA', (171, 174))	('mutation', 'Var', (110, 118))	('SDHBR46Q', 'Gene', (101, 109))	('incorporate', 'MPA', (228, 239))	('Fe-S', 'Chemical', '-', (240, 244))
36970	32751108	As a consequence of SDHB degradation, SDHB-mutant cells displayed markedly decreased oxygen consumption, increased succinate levels, and pronounced use of glutamine as the main source of TCA cycle metabolites via reductive carboxylation (reduction of glutamine-derived alpha-ketoglutarate into citrate).	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (269, 288))	('glutamine', 'Chemical', 'MESH:D005973', (251, 260))	('succinate', 'Chemical', 'MESH:D019802', (115, 124))	('oxygen', 'Chemical', 'MESH:D010100', (85, 91))	('glutamine', 'Chemical', 'MESH:D005973', (155, 164))	('TCA cycle', 'biological_process', 'GO:0006099', ('187', '196'))	('degradation', 'biological_process', 'GO:0009056', ('25', '36'))	('degradation', 'Var', (25, 36))	('succinate levels', 'MPA', (115, 131))	('oxygen consumption', 'MPA', (85, 103))	('reductive carboxylation', 'MPA', (213, 236))	('increased', 'PosReg', (105, 114))	('SDHB-mutant', 'Gene', (38, 49))	('citrate', 'Chemical', 'MESH:D019343', (294, 301))	('TCA', 'Chemical', 'MESH:D014238', (187, 190))	('increased succinate levels', 'Phenotype', 'HP:0020149', (105, 131))	('SDHB', 'Gene', (20, 24))	('decreased', 'NegReg', (75, 84))
36972	32751108	Through the study of SDHB-ablated kidney mouse cells it was shown that lack of SDH activity induces the commitment of the cells to consume extracellular pyruvate, inducing Warburg-like bioenergetic features; pyruvate carboxylation shifts glucose-derived carbons into aspartate biosynthesis and, through this mechanism, sustains tumor cell growth.	('ablated kidney', 'Phenotype', 'HP:0000104', (26, 40))	('mouse', 'Species', '10090', (41, 46))	('tumor', 'Disease', (328, 333))	('glucose-derived carbons', 'MPA', (238, 261))	('lack', 'Var', (71, 75))	('carbons', 'Chemical', 'MESH:D002244', (254, 261))	('extracellular', 'cellular_component', 'GO:0005576', ('139', '152'))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('Warburg-like bioenergetic features', 'MPA', (172, 206))	('pyruvate', 'Chemical', 'MESH:D019289', (153, 161))	('pyruvate', 'Chemical', 'MESH:D019289', (208, 216))	('men', 'Species', '9606', (110, 113))	('sustains', 'PosReg', (319, 327))	('SDH', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('cell growth', 'biological_process', 'GO:0016049', ('334', '345'))	('glucose', 'Chemical', 'MESH:D005947', (238, 245))	('aspartate', 'Chemical', 'MESH:D001224', (267, 276))	('aspartate biosynthesis', 'biological_process', 'GO:0006532', ('267', '289'))	('inducing', 'Reg', (163, 171))
36973	32751108	SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite.	('inactivation', 'Var', (4, 16))	('SDH', 'Gene', (0, 3))	('succinate', 'MPA', (52, 61))	('accumulation', 'PosReg', (36, 48))	('succinate', 'Chemical', 'MESH:D019802', (52, 61))
36976	32751108	A pulsed proton magnetic resonance spectroscopy (1)H-MRS sequence was developed, optimized, and applied to imaging of patients with paraganglioma: a succinate peak was detected at 2.44 ppm in all paraganglioma patients carrying an SDHx gene mutation, but not in patients exempt of SDHx mutation.	('SDHx', 'Gene', (231, 235))	('paraganglioma', 'Disease', 'MESH:D010235', (196, 209))	('paraganglioma', 'Disease', (132, 145))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('S', 'Chemical', 'MESH:D013455', (231, 232))	('succinate', 'Chemical', 'MESH:D019802', (149, 158))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('paraganglioma', 'Disease', 'MESH:D010235', (132, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('paraganglioma', 'Disease', (196, 209))	('mutation', 'Var', (241, 249))	('patients', 'Species', '9606', (210, 218))	('S', 'Chemical', 'MESH:D013455', (281, 282))	('patients', 'Species', '9606', (262, 270))	('patients', 'Species', '9606', (118, 126))
36978	32751108	Succinate accumulated in individuals with germline SDHx mutations acts as an oncometabolite and is responsible at a large extent for the oncogenic effect mediated by SDH mutational deficiency.	('deficiency', 'Disease', (181, 191))	('mutations', 'Var', (56, 65))	('deficiency', 'Disease', 'MESH:D007153', (181, 191))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('oncometabolite', 'MPA', (77, 91))	('SDHx', 'Gene', (51, 55))	('SDH', 'Gene', (166, 169))
36984	32751108	Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata, and aggressive papillary renal cancer; according to these observations, it was proposed that FH acts as a tumor suppressor.	('Germline mutations', 'Var', (0, 18))	('FH', 'Gene', '2271', (22, 24))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('202', '218'))	('aggressive papillary renal cancer', 'Disease', (100, 133))	('skin leiomyomata', 'Disease', (78, 94))	('FH', 'Gene', '2271', (189, 191))	('tumor', 'Disease', (202, 207))	('tumor suppressor', 'biological_process', 'GO:0051726', ('202', '218'))	('skin leiomyomata', 'Phenotype', 'HP:0007620', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('dominantly inherited uterine fibroids', 'Disease', (39, 76))	('predispose', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('aggressive papillary renal cancer', 'Disease', 'MESH:D007680', (100, 133))	('FH acts', 'Disease', 'MESH:D006938', (189, 196))	('uterine fibroids', 'Phenotype', 'HP:0000131', (60, 76))	('renal cancer', 'Phenotype', 'HP:0009726', (121, 133))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('skin leiomyomata', 'Disease', 'MESH:C535516', (78, 94))	('papillary renal cancer', 'Phenotype', 'HP:0006766', (111, 133))	('FH acts', 'Disease', (189, 196))
36987	32751108	have investigated 13 patients with FH-deficient renal cancers and observed absent expression in 12/13 cases, germline FH mutations in seven cases, and somatic mutations of FH gene in the remaining four cases.	('FH-deficient renal cancers', 'Disease', 'MESH:D007680', (35, 61))	('FH', 'Gene', '2271', (35, 37))	('mutations', 'Var', (121, 130))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('expression', 'MPA', (82, 92))	('FH-deficient renal cancers', 'Disease', (35, 61))	('patients', 'Species', '9606', (21, 29))	('FH', 'Gene', '2271', (118, 120))	('renal cancer', 'Phenotype', 'HP:0009726', (48, 60))	('absent', 'NegReg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('FH', 'Gene', '2271', (172, 174))
36991	32751108	These four cases were FH-negative and 2SC-positive at immunohistochemical level and in 3/4 cases harbored germline FH mutations and in 1/4 somatic FH mutations.	('FH', 'Gene', '2271', (147, 149))	('mutations', 'Var', (118, 127))	('FH', 'Gene', '2271', (115, 117))	('S', 'Chemical', 'MESH:D013455', (39, 40))	('FH', 'Gene', '2271', (22, 24))	('harbored', 'Reg', (97, 105))
36992	32751108	Germline FH mutations are observed in about 90% of families with HLRCC.	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('mutations', 'Var', (12, 21))	('FH', 'Gene', '2271', (9, 11))	('RCC', 'Disease', (67, 70))
36994	32751108	In cases positive for FH mutations, the most frequent mutations located along the entire length of the coding region were represented by missense and frameshifts, and more rarely, by non-sense and splice site mutations.	('mutations', 'Var', (25, 34))	('FH', 'Gene', '2271', (22, 24))	('non-sense', 'Var', (183, 192))	('frameshifts', 'Var', (150, 161))	('missense', 'Var', (137, 145))
36995	32751108	In a large series of HLRCC patients, 68 different germline mutations of the FHG gene were identified: 18 truncating or frameshift mutations, 37 missense mutations, 9 splice-site, and 4 large deletions.	('missense mutations', 'Var', (144, 162))	('FH', 'Gene', '2271', (76, 78))	('truncating', 'MPA', (105, 115))	('splice-site', 'Var', (166, 177))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('patients', 'Species', '9606', (27, 35))	('frameshift mutations', 'Var', (119, 139))
36996	32751108	have explored the occurrence of FH gene mutations in a group of patients with phenotypic manifestations consistent with HLRCC reporting in the 13 families explored, 11 complete FH gene deletions, and 2 partial FH gene deletion; kidney cancer was diagnosed in 32% of these patients and in 54% of families possessing either complete or partial FH deletions.	('diagnosed', 'Reg', (246, 255))	('FH', 'Gene', '2271', (210, 212))	('patients', 'Species', '9606', (64, 72))	('kidney cancer', 'Disease', 'MESH:D007680', (228, 241))	('mutations', 'Var', (40, 49))	('FH', 'Gene', '2271', (177, 179))	('kidney cancer', 'Phenotype', 'HP:0009726', (228, 241))	('patients', 'Species', '9606', (272, 280))	('FH', 'Gene', '2271', (32, 34))	('FH', 'Gene', '2271', (342, 344))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('RCC', 'Disease', (122, 125))	('kidney cancer', 'Disease', (228, 241))
36997	32751108	These observations clearly indicate that FH gene deletions, as well as gene mutations are associated with the development of RCCs.	('mutations', 'Var', (76, 85))	('FH', 'Gene', '2271', (41, 43))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('RCC', 'Disease', (125, 128))	('men', 'Species', '9606', (117, 120))	('associated', 'Reg', (90, 100))	('deletions', 'Var', (49, 58))
37011	32751108	The glycolytic shift induced by fumarate deficiency induced several consequences at the level of the AMP-activated pathway (AMPK): (i) AMPK levels were decreased with consequent lowered expression of the iron transported DNMT1; (ii) in turn, reduced DNMT1 levels induced a condition of cytosolic iron deficiency, activating the iron regulatory proteins, IRP1 and IRP2, and increasing the expression of HIF-1alpha; (iii) activation of AMPK or silencing of HIF-1alpha decreases the invasive properties of FH-deficient renal cancer cells.	('AMPK', 'Gene', (434, 438))	('DNMT1', 'Gene', (221, 226))	('AMPK', 'molecular_function', 'GO:0004691', ('434', '438'))	('increasing', 'PosReg', (373, 383))	('DNMT1', 'Gene', '1786', (250, 255))	('decreases', 'NegReg', (466, 475))	('AMPK', 'molecular_function', 'GO:0047322', ('124', '128'))	('AMPK', 'Gene', '5562', (135, 139))	('iron deficiency', 'Disease', 'MESH:C562385', (296, 311))	('HIF-1alpha', 'Gene', (402, 412))	('AMPK', 'molecular_function', 'GO:0050405', ('135', '139'))	('HIF-1alpha', 'Gene', '3091', (455, 465))	('IRP2', 'Gene', (363, 367))	('deficiency', 'Disease', 'MESH:D007153', (41, 51))	('iron deficiency', 'Disease', (296, 311))	('silencing', 'Var', (442, 451))	('AMPK', 'molecular_function', 'GO:0047322', ('434', '438'))	('IRP2', 'Gene', '3658', (363, 367))	('FH-deficient renal cancer', 'Disease', 'MESH:D007680', (503, 528))	('iron', 'Chemical', 'MESH:D007501', (204, 208))	('AMPK', 'Gene', '5562', (124, 128))	('deficiency', 'Disease', 'MESH:D007153', (301, 311))	('AMPK', 'Gene', '5562', (434, 438))	('cancer', 'Phenotype', 'HP:0002664', (522, 528))	('deficiency', 'Disease', (41, 51))	('AMPK', 'molecular_function', 'GO:0004691', ('135', '139'))	('expression', 'MPA', (388, 398))	('DNMT1', 'Gene', '1786', (221, 226))	('DNMT1', 'Gene', (250, 255))	('FH-deficient renal cancer', 'Disease', (503, 528))	('HIF-1alpha', 'Gene', (455, 465))	('AMPK', 'molecular_function', 'GO:0050405', ('124', '128'))	('deficiency', 'Disease', (301, 311))	('iron', 'Chemical', 'MESH:D007501', (328, 332))	('AMPK', 'Gene', (135, 139))	('AMPK', 'molecular_function', 'GO:0050405', ('434', '438'))	('IRP1', 'Gene', (354, 358))	('iron', 'Chemical', 'MESH:D007501', (296, 300))	('IRP1', 'Gene', '48', (354, 358))	('AMPK', 'molecular_function', 'GO:0004691', ('124', '128'))	('AMPK', 'molecular_function', 'GO:0047322', ('135', '139'))	('renal cancer', 'Phenotype', 'HP:0009726', (516, 528))	('HIF-1alpha', 'Gene', '3091', (402, 412))	('activating', 'PosReg', (313, 323))	('fumarate', 'Chemical', 'MESH:D005650', (32, 40))	('AMPK', 'Gene', (124, 128))
37021	32751108	Through the study of numerous families inheriting the mutated gene responsible for BHD syndrome it is estimated an increased risk of developing RCC for BHD-affected family members of about 7-fold in comparison with unaffected individuals.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('BHD', 'Disease', 'MESH:C564185', (152, 155))	('BHD syndrome', 'Disease', 'MESH:C564185', (83, 95))	('BHD', 'Disease', (83, 86))	('mutated gene', 'Var', (54, 66))	('BHD', 'Disease', (152, 155))	('RCC', 'Disease', (144, 147))	('BHD syndrome', 'Disease', (83, 95))	('BHD', 'Disease', 'MESH:C564185', (83, 86))
37027	32751108	The majority of FLCN mutations identified in the germline of BHD patients are frameshift mutations (insertion/deletion), nonsense mutations that are predicted to truncate and to inactivate the FLCN protein.	('BHD', 'Disease', (61, 64))	('BHD', 'Disease', 'MESH:C564185', (61, 64))	('inactivate', 'NegReg', (178, 188))	('frameshift mutations', 'Var', (78, 98))	('FLCN protein', 'Protein', (193, 205))	('patients', 'Species', '9606', (65, 73))	('protein', 'cellular_component', 'GO:0003675', ('198', '205'))	('FLCN', 'Gene', (16, 20))	('protein', 'Protein', (198, 205))	('mutations', 'Var', (21, 30))
37029	32751108	These conclusions were supported by a study carried out by Vocke and coworkers on 77 renal tumors derived from 12 patients with germline FLCN mutations to identify somatic mutations in the second copy of BHD, showing FLCN somatic mutations in 53% of cases and loss-of-heterozygosity at the BHD locus in 17% of cases.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (172, 181))	('BHD', 'Disease', (290, 293))	('mutations', 'Var', (142, 151))	('renal tumors', 'Phenotype', 'HP:0009726', (85, 97))	('BHD', 'Disease', 'MESH:C564185', (290, 293))	('BHD', 'Disease', 'MESH:C564185', (204, 207))	('renal tumors', 'Disease', (85, 97))	('renal tumors', 'Disease', 'MESH:D007674', (85, 97))	('mutations', 'Var', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('FLCN', 'Gene', (137, 141))	('loss-of-heterozygosity', 'NegReg', (260, 282))	('patients', 'Species', '9606', (114, 122))	('BHD', 'Disease', (204, 207))	('renal tumor', 'Phenotype', 'HP:0009726', (85, 96))
37031	32751108	The study of some germline missense mutations in the folliculin gene, such as H255Y and K508R, observed in BHD patients with renal carcinomas has directly supported their pathogenic role: the FLCN H255Y mutant protein displayed a loss of its tumor suppressive function inducing kidney cell proliferation and the clinical manifestations of BHD, the FLCN K508R mutant protein exerted a dominant negative effect on the function of WT FLCN in the regulation of kidney cell proliferation.	('clinical manifestations', 'CPA', (312, 335))	('renal carcinomas', 'Disease', (125, 141))	('H255Y', 'SUBSTITUTION', 'None', (197, 202))	('renal carcinomas', 'Phenotype', 'HP:0005584', (125, 141))	('cell proliferation', 'biological_process', 'GO:0008283', ('464', '482'))	('K508R', 'Var', (353, 358))	('tumor', 'Disease', (242, 247))	('folliculin', 'Gene', (53, 63))	('protein', 'cellular_component', 'GO:0003675', ('210', '217'))	('K508R', 'Var', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('BHD', 'Disease', 'MESH:C564185', (339, 342))	('H255Y', 'Var', (78, 83))	('folliculin', 'Gene', '201163', (53, 63))	('K508R', 'SUBSTITUTION', 'None', (353, 358))	('FLCN', 'Gene', (348, 352))	('negative', 'NegReg', (393, 401))	('protein', 'cellular_component', 'GO:0003675', ('366', '373'))	('BHD', 'Disease', (339, 342))	('cell proliferation', 'biological_process', 'GO:0008283', ('285', '303'))	('H255Y', 'Var', (197, 202))	('K508R', 'SUBSTITUTION', 'None', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('renal carcinomas', 'Disease', 'MESH:C538614', (125, 141))	('BHD', 'Disease', 'MESH:C564185', (107, 110))	('loss', 'NegReg', (230, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('regulation', 'biological_process', 'GO:0065007', ('443', '453'))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('H255Y', 'SUBSTITUTION', 'None', (78, 83))	('BHD', 'Disease', (107, 110))	('kidney cell proliferation', 'CPA', (278, 303))	('renal carcinoma', 'Phenotype', 'HP:0005584', (125, 140))	('patients', 'Species', '9606', (111, 119))
37035	32751108	All patients displayed FLCN germline mutations; somatic FLCN mutations were observed in 25 out of the 29 kidney tumors: 20 tumors displayed frameshift/nonsense mutations or loss of heterozygosity at the level of the allele not affected by the germline mutation.	('kidney tumors', 'Phenotype', 'HP:0009726', (105, 118))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('kidney tumor', 'Phenotype', 'HP:0009726', (105, 117))	('FLCN', 'Gene', (56, 60))	('loss of', 'NegReg', (173, 180))	('mutations', 'Var', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('kidney tumors', 'Disease', (105, 118))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('kidney tumors', 'Disease', 'MESH:D007680', (105, 118))	('frameshift/nonsense mutations', 'Var', (140, 169))	('tumors', 'Disease', (112, 118))
37037	32751108	The number of somatic variants was similar in the various histological subtypes of BHD-associated kidney tumors; the frequency of gene mutations was usually low in these tumors, with variants in chromatin remodeling genes being frequently observed (59% of cases); furthermore, variants in genes associated with the mitochondrial pathway, lipid metabolism, and glycolytic pathway were observed in 28%, 24%, and 7% of cases, respectively.	('tumors', 'Disease', (105, 111))	('BHD-associated kidney tumors', 'Disease', 'MESH:C564185', (83, 111))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('195', '215'))	('lipid', 'Chemical', 'MESH:D008055', (338, 343))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('BHD-associated kidney tumors', 'Disease', (83, 111))	('kidney tumors', 'Phenotype', 'HP:0009726', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('low', 'NegReg', (157, 160))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('chromatin', 'cellular_component', 'GO:0000785', ('195', '204'))	('variants', 'Var', (277, 285))	('kidney tumor', 'Phenotype', 'HP:0009726', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('observed', 'Reg', (384, 392))	('tumors', 'Disease', (170, 176))	('lipid metabolism', 'biological_process', 'GO:0006629', ('338', '354'))
37039	32751108	It is of interest to note that at molecular level BHD-related hybrid oncocytic/chromophobe tumors can be differentiated from the sporadic counterpart of these tumors in that these last tumors have copy number losses in chromosomes 1 and XY, but lacks recurrent mutations.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BHD', 'Disease', 'MESH:C564185', (50, 53))	('copy number losses', 'Var', (197, 215))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('chromophobe tumors', 'Disease', (79, 97))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('BHD', 'Disease', (50, 53))	('chromophobe tumors', 'Disease', 'MESH:D000238', (79, 97))
37041	32751108	The protein folliculin is involved in numerous biological processes, such as membrane trafficking, energy and nutrient homeostasis, and lysosomal biogenesis, and the mutations affecting this protein generate different phenotypes, in relation with their cellular context.	('membrane', 'cellular_component', 'GO:0016020', ('77', '85'))	('mutations', 'Var', (166, 175))	('protein', 'cellular_component', 'GO:0003675', ('191', '198'))	('homeostasis', 'biological_process', 'GO:0042592', ('119', '130'))	('protein', 'cellular_component', 'GO:0003675', ('4', '11'))	('folliculin', 'Gene', '201163', (12, 22))	('folliculin', 'Gene', (12, 22))
37045	32751108	Thus, functional studies have shown that FNIP1 and FNIP2 act as tumor suppressors since mice deficient in FNIP1 and FNIP2 tumors display tumors developing at the level of several organs.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (137, 142))	('tumors display tumors', 'Disease', 'MESH:D009369', (122, 143))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('FNIP2', 'Gene', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FNIP1', 'Gene', (106, 111))	('deficient', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mice', 'Species', '10090', (88, 92))	('tumor', 'Disease', (122, 127))	('tumors display tumors', 'Disease', (122, 143))
37049	32751108	Studies in mice with the kidney-targeted FLCN inactivation develop polycystic kidneys and cystic tumors, exhibiting activation of mTORC1.	('cystic tumors', 'Disease', (90, 103))	('FLCN', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cystic tumors', 'Disease', 'MESH:D052177', (90, 103))	('mTORC1', 'Gene', (130, 136))	('polycystic kidneys', 'Disease', 'MESH:D007690', (67, 85))	('develop', 'Reg', (59, 66))	('mice', 'Species', '10090', (11, 15))	('mTORC1', 'cellular_component', 'GO:0031931', ('130', '136'))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('inactivation', 'Var', (46, 58))	('mTORC1', 'Gene', '382056', (130, 136))	('polycystic kidneys', 'Disease', (67, 85))	('polycystic kidneys', 'Phenotype', 'HP:0000113', (67, 85))	('S', 'Chemical', 'MESH:D013455', (0, 1))
37050	32751108	Homozygous deletion of FLCN in mice resulted in early embryonic lethality; FLCN heterozygous knockout (FLCN+/-) mice appeared normal at birth, but developed kidney cysts and solid tumors, as they aged, of different histologic types (oncocytic hybrid, oncocytoma, and clear cell carcinoma with concomitant loss of heterozygosity of FLCN); these tumors displayed increased mTORC1 and TORC2 activity.	('mTORC1', 'Gene', '382056', (371, 377))	('TORC2', 'Gene', '74343', (382, 387))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mice', 'Species', '10090', (31, 35))	('solid tumors', 'Disease', 'MESH:D009369', (174, 186))	('TORC2', 'Gene', (382, 387))	('FLCN', 'Gene', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('embryonic lethality', 'Disease', (54, 73))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (267, 287))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('kidney cysts', 'Disease', 'MESH:D007674', (157, 169))	('increased', 'PosReg', (361, 370))	('tumors', 'Disease', (180, 186))	('oncocytoma', 'Disease', (251, 261))	('TORC2', 'cellular_component', 'GO:0031932', ('382', '387'))	('embryonic lethality', 'Disease', 'MESH:D020964', (54, 73))	('kidney cysts', 'Phenotype', 'HP:0000107', (157, 169))	('kidney cysts', 'Disease', (157, 169))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('mice', 'Species', '10090', (112, 116))	('solid tumors', 'Disease', (174, 186))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumors', 'Disease', (344, 350))	('mTORC1', 'Gene', (371, 377))	('deletion', 'Var', (11, 19))	('oncocytoma', 'Disease', 'MESH:D018249', (251, 261))	('clear cell carcinoma', 'Disease', (267, 287))	('mTORC1', 'cellular_component', 'GO:0031931', ('371', '377'))
37051	32751108	The investigation of other mouse models further supported a role for FLCN as a positive regulator of TORC1 and provided evidence that inappropriate mTORC1 levels can be associated with renal cancerogenesis.	('mTORC1', 'Gene', (148, 154))	('TORC1', 'cellular_component', 'GO:0031931', ('101', '106'))	('inappropriate', 'Var', (134, 147))	('mouse', 'Species', '10090', (27, 32))	('renal cancerogenesis', 'Disease', 'MESH:D007674', (185, 205))	('renal cancer', 'Phenotype', 'HP:0009726', (185, 197))	('TORC1', 'Gene', (101, 106))	('mTORC1', 'cellular_component', 'GO:0031931', ('148', '154'))	('mTORC1', 'Gene', '382056', (148, 154))	('associated', 'Reg', (169, 179))	('renal cancerogenesis', 'Disease', (185, 205))	('TORC1', 'Gene', '382056', (101, 106))	('TORC1', 'Gene', '382056', (149, 154))	('TORC1', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
37056	32751108	Furthermore, various studies have shown that FLCN deficiency triggers AMPK activation; furthermore, FNIP1 mutations are associated with high AMPK activity.	('FNIP1', 'Gene', (100, 105))	('AMPK', 'Gene', (141, 145))	('associated', 'Reg', (120, 130))	('FLCN deficiency', 'Disease', (45, 60))	('FLCN deficiency', 'Disease', 'MESH:D007153', (45, 60))	('AMPK activity', 'molecular_function', 'GO:0004679', ('141', '154'))	('AMPK', 'molecular_function', 'GO:0050405', ('70', '74'))	('AMPK', 'molecular_function', 'GO:0004691', ('70', '74'))	('AMPK', 'molecular_function', 'GO:0047322', ('70', '74'))	('mutations', 'Var', (106, 115))	('AMPK', 'Gene', '5562', (141, 145))	('AMPK', 'Gene', '5562', (70, 74))	('AMPK', 'Gene', (70, 74))
37064	32751108	Subjects carrying a germline pathogenic variant of MITF have a more than five-fold increased risk of developing melanoma and renal cancer, as compared to the individuals not bearing these variants.	('melanoma and renal cancer', 'Disease', 'MESH:D007680', (112, 137))	('variant', 'Var', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MITF', 'Gene', (51, 55))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('renal cancer', 'Phenotype', 'HP:0009726', (125, 137))	('MITF', 'Gene', '4286', (51, 55))	('S', 'Chemical', 'MESH:D013455', (0, 1))
37065	32751108	The molecular characterization of these MITF oncogenic variants showed a mutation at the level of codon 318 (E318K), located at the level of a small-ubiquitin-like modifier (SUMO) consensus site (psiKXE), determining a strong impairment of SUMOylation of MITF.	('S', 'Chemical', 'MESH:D013455', (174, 175))	('E318K', 'SUBSTITUTION', 'None', (109, 114))	('impairment', 'NegReg', (226, 236))	('MITF', 'Gene', (40, 44))	('MITF', 'Gene', '4286', (40, 44))	('SUMOylation', 'biological_process', 'GO:0016925', ('240', '251'))	('psiKXE', 'Disease', (196, 202))	('E318K', 'Var', (109, 114))	('psiKXE', 'Disease', 'None', (196, 202))	('men', 'Species', '9606', (232, 235))	('MITF', 'Gene', '4286', (255, 259))	('MITF', 'Gene', (255, 259))	('SUMOylation', 'MPA', (240, 251))	('ubiquitin', 'molecular_function', 'GO:0031386', ('149', '158'))	('S', 'Chemical', 'MESH:D013455', (240, 241))
37066	32751108	The E318K mutation increased the binding to the HIF1alpha promoter and increased its transcriptional activity.	('binding', 'molecular_function', 'GO:0005488', ('33', '40'))	('E318K', 'SUBSTITUTION', 'None', (4, 9))	('transcriptional activity', 'MPA', (85, 109))	('E318K', 'Var', (4, 9))	('HIF1alpha', 'Gene', (48, 57))	('increased', 'PosReg', (19, 28))	('HIF1alpha', 'Gene', '3091', (48, 57))	('increased', 'PosReg', (71, 80))	('binding', 'Interaction', (33, 40))
37067	32751108	However, the MITF E318K mutation does not seem to be involved in sporadic RCC: in fact, in a screening based on the analysis of 403 sporadic RCCs only one MITF E318K mutation was detected.	('RCC', 'Disease', (141, 144))	('E318K', 'Var', (160, 165))	('MITF', 'Gene', '4286', (13, 17))	('MITF', 'Gene', (13, 17))	('RCC', 'Disease', (74, 77))	('E318K', 'SUBSTITUTION', 'None', (18, 23))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('E318K', 'Var', (18, 23))	('MITF', 'Gene', (155, 159))	('MITF', 'Gene', '4286', (155, 159))	('E318K', 'SUBSTITUTION', 'None', (160, 165))	('RCC', 'Disease', 'MESH:C538614', (141, 144))
37081	32751108	In addition to these typical chromosomal losses, CHRCCs display also copy number gains that were detected in chromosomes 4, 7, 11, 12, 14q, and 18q.	('gains', 'PosReg', (81, 86))	('CHRCCs', 'Disease', 'None', (49, 55))	('CHRCCs', 'Disease', (49, 55))	('copy number', 'Var', (69, 80))
37083	32751108	The analysis of gene copy number by next generation sequencing showed the occurrence of multiple abnormalities in CHRCC; this analysis showed that the two most frequent deletions involved the tumor suppressor genes RB1 and ERBB4.	('tumor', 'Disease', (192, 197))	('multiple abnormalities', 'Disease', (88, 110))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('multiple abnormalities', 'Disease', 'MESH:D000015', (88, 110))	('ERBB4', 'Gene', '2066', (223, 228))	('RB1', 'Gene', (215, 218))	('tumor suppressor', 'biological_process', 'GO:0051726', ('192', '208'))	('ERBB4', 'Gene', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('192', '208'))	('CHRCC', 'Disease', (114, 119))	('RB1', 'Gene', '5925', (215, 218))	('deletions', 'Var', (169, 178))	('CHRCC', 'Disease', 'None', (114, 119))
37086	32751108	The results of this study showed: (i) The typical and frequent chromosome losses described in other studies, observed in all cases corresponding to the classic variant and in about 53% of cases corresponding to the eosinophilic variant; (ii) TP53 (32% of cases) and PTEN (9% of cases) were the only two genes frequently mutated in these tumors, while mutations of other cancer-relevant genes (such as MTOR, NRAS) were found at lower frequencies; (iii) the gene expression profile showed a high index of mRNA expression correlation for CHRCC with distal regions of the nephron; (iv) the analysis of mitochondrial DNA showed mutations at the level of genes involved in respiration and oxidative phosphorylation; (v) whole genome sequencing analysis showed the occurrence of kataegis (a mutational phenomenon involving highly localized substitution mutations, C > T or C > G), occurring at the level of some chromosome regions involved in rearrangements, involving also rearrangements occurring within the TERT promoter gene region (observed in 12% of cases) and associated with elevated TERT expression.	('elevated', 'PosReg', (1076, 1084))	('PTEN', 'Gene', (266, 270))	('TERT', 'Gene', (1085, 1089))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('TERT', 'Gene', '7015', (1085, 1089))	('rearrangements', 'Var', (967, 981))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('683', '708'))	('men', 'Species', '9606', (945, 948))	('NRAS', 'Gene', (407, 411))	('PTEN', 'Gene', '5728', (266, 270))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('gene expression', 'biological_process', 'GO:0010467', ('456', '471'))	('chromosome loss', 'Disease', (63, 78))	('kataegis', 'Disease', (772, 780))	('TP53', 'Gene', (242, 246))	('TERT', 'Gene', (1003, 1007))	('TERT', 'Gene', '7015', (1003, 1007))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('CHRCC', 'Disease', (535, 540))	('CHRCC', 'Disease', 'None', (535, 540))	('men', 'Species', '9606', (976, 979))	('C > T or C > G', 'Var', (857, 871))	('chromosome', 'cellular_component', 'GO:0005694', ('63', '73'))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('598', '615'))	('tumors', 'Disease', (337, 343))	('cancer', 'Disease', (370, 376))	('chromosome loss', 'Disease', 'MESH:D025063', (63, 78))	('respiration', 'biological_process', 'GO:0007585', ('667', '678'))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('men', 'Species', '9606', (800, 803))	('respiration', 'biological_process', 'GO:0045333', ('667', '678'))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('NRAS', 'Gene', '4893', (407, 411))	('chromosome', 'cellular_component', 'GO:0005694', ('905', '915'))	('MTOR', 'Gene', (401, 405))	('TP53', 'Gene', '7157', (242, 246))	('MTOR', 'Gene', '2475', (401, 405))
37089	32751108	Some of these mutations may play a relevant role in the pathogenesis of CHRCC.	('role', 'Reg', (44, 48))	('CHRCC', 'Disease', (72, 77))	('CHRCC', 'Disease', 'None', (72, 77))	('pathogenesis', 'biological_process', 'GO:0009405', ('56', '68'))	('play', 'Reg', (28, 32))	('mutations', 'Var', (14, 23))	('S', 'Chemical', 'MESH:D013455', (0, 1))
37090	32751108	Thus, the PDHB gene encodes the E1beta subunit of the pyruvate dehydrogenase complex (PDHc), catalyzing the conversion of pyruvate to acetyl-CoA, thus providing a link between glycolysis and the TCA cycle; the two mutations observed in CHRCC are reminiscent of those observed in a neurological condition associated with germline mutations of this gene and causing lactic acidosis.	('PDHB', 'Gene', '5162', (10, 14))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (134, 144))	('TCA cycle', 'biological_process', 'GO:0006099', ('195', '204'))	('lactic acidosis', 'Disease', 'MESH:D000140', (364, 379))	('pyruvate dehydrogenase complex', 'cellular_component', 'GO:0045254', ('54', '84'))	('causing', 'Reg', (356, 363))	('CHRCC', 'Disease', (236, 241))	('pyruvate', 'Chemical', 'MESH:D019289', (122, 130))	('CHRCC', 'Disease', 'None', (236, 241))	('mutations', 'Var', (214, 223))	('lactic acidosis', 'Disease', (364, 379))	('TCA', 'Chemical', 'MESH:D014238', (195, 198))	('acidosis', 'Phenotype', 'HP:0001941', (371, 379))	('glycolysis', 'biological_process', 'GO:0006096', ('176', '186'))	('neurological condition', 'Phenotype', 'HP:0000707', (281, 303))	('pyruvate', 'Chemical', 'MESH:D019289', (54, 62))	('PDHB', 'Gene', (10, 14))	('lactic acidosis', 'Phenotype', 'HP:0003128', (364, 379))	('E1beta subunit', 'Gene', (32, 46))	('E1beta subunit', 'Gene', '594', (32, 46))
37091	32751108	PRKAG2 encodes one of the three gamma subunits of AMPK, a key sensor of cellular metabolism; the mutations of this gene, observed at the level of the inhibitory pseudosubstrate sequence within AMPK gamma subunit, may lead to constitutive AMPK activation.	('mutations', 'Var', (97, 106))	('PRKAG2', 'Gene', (0, 6))	('AMPK', 'molecular_function', 'GO:0047322', ('193', '197'))	('AMPK', 'molecular_function', 'GO:0050405', ('50', '54'))	('AMPK', 'Gene', (193, 197))	('PRKAG2', 'Gene', '51422', (0, 6))	('AMPK', 'Gene', (50, 54))	('AMPK', 'Gene', '5562', (238, 242))	('lead to', 'Reg', (217, 224))	('AMPK', 'molecular_function', 'GO:0050405', ('238', '242'))	('AMPK', 'molecular_function', 'GO:0050405', ('193', '197'))	('AMPK', 'molecular_function', 'GO:0004691', ('50', '54'))	('AMPK', 'molecular_function', 'GO:0004691', ('238', '242'))	('AMPK', 'Gene', '5562', (193, 197))	('AMPK', 'Gene', '5562', (50, 54))	('AMPK', 'molecular_function', 'GO:0047322', ('50', '54'))	('AMPK', 'Gene', (238, 242))	('AMPK', 'molecular_function', 'GO:0004691', ('193', '197'))	('cellular metabolism', 'biological_process', 'GO:0044237', ('72', '91'))	('AMPK', 'molecular_function', 'GO:0047322', ('238', '242'))
37094	32751108	Some recurrent mutations have a prognostic impact in CHRCC patients: PTEN mutations correlated with decreased survival; CDKN2A alterations (including loss of the region of chromosome 9p encoding CDKN2A and promoter hypermethylation) correlated with a decreased survival.	('S', 'Chemical', 'MESH:D013455', (0, 1))	('PTEN', 'Gene', '5728', (69, 73))	('survival', 'MPA', (110, 118))	('CHRCC', 'Disease', 'None', (53, 58))	('PTEN', 'Gene', (69, 73))	('CDKN2A', 'Gene', (195, 201))	('CDKN2A', 'Gene', (120, 126))	('mutations', 'Var', (74, 83))	('decreased', 'NegReg', (251, 260))	('CDKN2A', 'Gene', '1029', (195, 201))	('decreased', 'NegReg', (100, 109))	('CDKN2A', 'Gene', '1029', (120, 126))	('patients', 'Species', '9606', (59, 67))	('chromosome', 'cellular_component', 'GO:0005694', ('172', '182'))	('alterations', 'Var', (127, 138))	('CHRCC', 'Disease', (53, 58))	('survival', 'MPA', (261, 269))
37099	32751108	This hyperdiploid pattern is due to either loss of the CHRCC-7 set-chromosomes, associated with duplication of the remaining genome or duplication of multiple chromosomes excluding the CHRCC-7 set-chromosomes: this condition was defined as imbalanced chromosome duplication (ICD).	('duplication', 'Var', (135, 146))	('hyperdiploid', 'Disease', (5, 17))	('CHRCC', 'Disease', (185, 190))	('CHRCC', 'Disease', 'None', (185, 190))	('imbalanced chromosome duplication', 'Disease', (240, 273))	('hyperdiploid', 'Disease', 'MESH:D054198', (5, 17))	('duplication', 'Var', (96, 107))	('loss', 'NegReg', (43, 47))	('CHRCC', 'Disease', (55, 60))	('chromosome', 'cellular_component', 'GO:0005694', ('251', '261'))	('CHRCC', 'Disease', 'None', (55, 60))
37100	32751108	The comparative analysis of metastatic and non-metastatic CHRCC showed among metastatic tumors increased frequencies of TP53 mutations, PTEN mutations, and ICD (observed at frequency of 55%, 27%, and 43%, respectively) compared with those observed in nonmetastatic CHRCC (25%, 7%, and 10%, respectively).	('mutations', 'Var', (125, 134))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (141, 150))	('ICD', 'Disease', (156, 159))	('CHRCC', 'Disease', (58, 63))	('PTEN', 'Gene', '5728', (136, 140))	('CHRCC', 'Disease', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('CHRCC', 'Disease', 'None', (58, 63))	('PTEN', 'Gene', (136, 140))	('CHRCC', 'Disease', 'None', (265, 270))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
37101	32751108	Phylogenetic studies of paired-primary-metastatic samples allowed to propose a tumor progression process, involving the nearly universal loss of CHRCC-7 set-chromosomes as the only driver event in the pathogenesis of CHRCC, followed by TP53 mutations that were detected in 82% of metastatic samples and then by ICD and PTEN mutations that were detected in 82% of metastatic samples and then by ICD and PTEN mutation, occurring in a mutually exclusive manner.	('PTEN', 'Gene', '5728', (319, 323))	('amp', 'Chemical', 'MESH:D000249', (51, 54))	('amp', 'Chemical', 'MESH:D000249', (375, 378))	('TP53', 'Gene', (236, 240))	('PTEN', 'Gene', (402, 406))	('pathogenesis', 'biological_process', 'GO:0009405', ('201', '213'))	('loss', 'NegReg', (137, 141))	('tumor', 'Disease', (79, 84))	('PTEN', 'Gene', '5728', (402, 406))	('CHRCC', 'Disease', (217, 222))	('CHRCC', 'Disease', 'None', (217, 222))	('amp', 'Chemical', 'MESH:D000249', (292, 295))	('CHRCC', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TP53', 'Gene', '7157', (236, 240))	('PTEN', 'Gene', (319, 323))	('CHRCC', 'Disease', 'None', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('mutations', 'Var', (241, 250))
37125	32751108	Whole exome sequencing performed in 157 PRCCs identified several somatic mutations, occurring with a significant frequency, at the level of tumor-related genes, such as MET, SETD2, NF2, KDM6A, SMARCB1, FAT1, BAP1, PBRM1, STAG2, NFE2L2, and TP53.	('TP53', 'Gene', '7157', (240, 244))	('STAG2', 'Gene', '10735', (221, 226))	('PRCC', 'Gene', '5546', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('FAT1', 'Gene', (202, 206))	('BAP1', 'Gene', (208, 212))	('NFE2L2', 'Gene', (228, 234))	('SMARCB1', 'Gene', '6598', (193, 200))	('PBRM1', 'Gene', '55193', (214, 219))	('SMARCB1', 'Gene', (193, 200))	('STAG2', 'Gene', (221, 226))	('MET', 'Gene', '79811', (169, 172))	('NF2', 'Gene', '4771', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('PBRM1', 'Gene', (214, 219))	('KDM6A', 'Gene', '7403', (186, 191))	('NF2', 'Gene', (181, 184))	('TP53', 'Gene', (240, 244))	('FAT1', 'Gene', '2195', (202, 206))	('SETD2', 'Gene', (174, 179))	('PRCC', 'Gene', (40, 44))	('BAP1', 'Gene', '8314', (208, 212))	('SETD2', 'Gene', '29072', (174, 179))	('KDM6A', 'Gene', (186, 191))	('MET', 'Gene', (169, 172))	('NFE2L2', 'Gene', '4780', (228, 234))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', (140, 145))
37127	32751108	However, some genetic alterations are specific to types of PRCCs: (1) MET mutations are much more frequent in type 1 than type 2 PRCCs (17% vs. 1.6%, respectively) and were observed in 11% of unclassified PRCCs; levels of MET mRNA and MET protein phosphorylation were higher in type 1 than type 2 tumors.	('type 2 tumors', 'Disease', (290, 303))	('MET', 'Gene', '79811', (70, 73))	('MET', 'Gene', '79811', (235, 238))	('type 2 tumors', 'Disease', 'MESH:C000657245', (290, 303))	('PRCC', 'Gene', (59, 63))	('PRCC', 'Gene', '5546', (205, 209))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))	('PRCC', 'Gene', (129, 133))	('higher', 'PosReg', (268, 274))	('protein phosphorylation', 'biological_process', 'GO:0006468', ('239', '262'))	('MET', 'Gene', (222, 225))	('observed', 'Reg', (173, 181))	('MET', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('PRCC', 'Gene', '5546', (59, 63))	('MET', 'Gene', (235, 238))	('mutations', 'Var', (74, 83))	('PRCC', 'Gene', '5546', (129, 133))	('MET', 'Gene', '79811', (222, 225))	('PRCC', 'Gene', (205, 209))	('protein', 'cellular_component', 'GO:0003675', ('239', '246'))
37128	32751108	(2) 8% type 2 PRCCs displayed 9p21 chromosomal focal loss with loss of CDKN2A locus; other type 2 PRCCs exhibited CDKN2A mutations or promoter hypermethylation, resulting in a total of 13% of tumors with CDKN2A alterations; CDKN2A loss was associated with low overall survival.	('mutations', 'Var', (121, 130))	('CDKN2A', 'Gene', '1029', (204, 210))	('tumors', 'Disease', (192, 198))	('PRCC', 'Gene', (14, 18))	('loss', 'NegReg', (53, 57))	('CDKN2A', 'Gene', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('promoter hypermethylation', 'Var', (134, 159))	('9p21', 'Gene', (30, 34))	('CDKN2A', 'Gene', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PRCC', 'Gene', '5546', (14, 18))	('PRCC', 'Gene', (98, 102))	('CDKN2A', 'Gene', '1029', (114, 120))	('CDKN2A', 'Gene', (71, 77))	('chromosomal focal loss', 'Phenotype', 'HP:0040012', (35, 57))	('loss', 'NegReg', (63, 67))	('CDKN2A', 'Gene', (204, 210))	('CDKN2A', 'Gene', '1029', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('CDKN2A', 'Gene', '1029', (71, 77))	('PRCC', 'Gene', '5546', (98, 102))
37129	32751108	(3) Type 2 PRCCs are associated with mutations in chromatin-modifying genes SETD2 (19.4%), BAP1 (10.4%), and PBRM1 (11.9%) which are frequently mutated in CCRCCs; mutations of BAP1 and PBRM1 were mutually exclusive, whereas SETD2 mutations co-occurred with PBMR1 mutations in most cases.	('SETD2', 'Gene', (76, 81))	('BAP1', 'Gene', (91, 95))	('PRCC', 'Gene', '5546', (11, 15))	('PBRM1', 'Gene', (185, 190))	('RCC', 'Disease', (12, 15))	('BAP1', 'Gene', (176, 180))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('SETD2', 'Gene', '29072', (76, 81))	('RCC', 'Disease', 'MESH:C538614', (12, 15))	('chromatin', 'cellular_component', 'GO:0000785', ('50', '59'))	('SETD2', 'Gene', (224, 229))	('associated', 'Reg', (21, 31))	('PRCC', 'Gene', (11, 15))	('PBRM1', 'Gene', '55193', (109, 114))	('PBMR1', 'Gene', (257, 262))	('mutations', 'Var', (37, 46))	('SETD2', 'Gene', '29072', (224, 229))	('BAP1', 'Gene', '8314', (91, 95))	('mutations', 'Var', (163, 172))	('PBRM1', 'Gene', (109, 114))	('BAP1', 'Gene', '8314', (176, 180))	('PBRM1', 'Gene', '55193', (185, 190))	('RCC', 'Disease', (157, 160))
37130	32751108	(4) Another feature of type 2 PRCCs consists in the increased expression of NRF2-associated response element (ARE) pathway; these findings were in line with other studies showing increased activation of the NRF2-ARE pathway in type 2 PRCCs and mutations in NRF2-ARE pathway genes NFE2L2, CUL3, KEAP1, and SRT1.	('NRF2', 'Gene', '4780', (76, 80))	('CUL3', 'Gene', (288, 292))	('NRF2', 'Gene', (257, 261))	('NRF2', 'Gene', '4780', (207, 211))	('PRCC', 'Gene', (30, 34))	('PRCC', 'Gene', (234, 238))	('men', 'Species', '9606', (104, 107))	('NRF2', 'Gene', (76, 80))	('S', 'Chemical', 'MESH:D013455', (305, 306))	('mutations', 'Var', (244, 253))	('NFE2L2', 'Gene', '4780', (280, 286))	('KEAP1', 'Gene', '9817', (294, 299))	('KEAP1', 'Gene', (294, 299))	('NRF2', 'Gene', (207, 211))	('type', 'Disease', (227, 231))	('PRCC', 'Gene', '5546', (30, 34))	('PRCC', 'Gene', '5546', (234, 238))	('CUL3', 'Gene', '8452', (288, 292))	('NFE2L2', 'Gene', (280, 286))	('activation', 'PosReg', (189, 199))	('NRF2', 'Gene', '4780', (257, 261))
37131	32751108	(5) A CpG island methylator phenotype (CIMP) was observed in a subgroup of type 2 PRCCs characterized by mutations of FH gene and poor survival.	('PRCC', 'Gene', (82, 86))	('FH', 'Gene', '2271', (118, 120))	('mutations', 'Var', (105, 114))	('observed', 'Reg', (49, 57))	('PRCC', 'Gene', '5546', (82, 86))
37132	32751108	Finally, from this study it emerges that unclassified PRCCs display molecular properties hybrid between type 1 and type 2 PRCCs; the frequency of chromosomal 7 gain in these tumors is intermediate (26%) between type 1 (85%) and type 2 (18%).	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('PRCC', 'Gene', (122, 126))	('gain', 'PosReg', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('chromosomal 7', 'Var', (146, 159))	('PRCC', 'Gene', '5546', (54, 58))	('PRCC', 'Gene', '5546', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('PRCC', 'Gene', (54, 58))
37133	32751108	in their study of molecular characterization of non-clear RCCs reported a detailed analysis of MET mutations occurring in PRCCs; particularly, they observed MET mutations in 15% of the PRCC samples: all these mutations, with just a single exception, affected the kinase domain of MET, all displaying elevated phosphorylation, suggesting their constitutive activation.	('PRCC', 'Gene', '5546', (185, 189))	('RCC', 'Disease', (123, 126))	('RCC', 'Disease', (58, 61))	('MET', 'Gene', (95, 98))	('phosphorylation', 'MPA', (309, 324))	('RCC', 'Disease', (186, 189))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('MET', 'Gene', '79811', (280, 283))	('RCC', 'Disease', 'MESH:C538614', (58, 61))	('amp', 'Chemical', 'MESH:D000249', (191, 194))	('PRCC', 'Gene', (122, 126))	('MET', 'Gene', (157, 160))	('PRCC', 'Gene', (185, 189))	('RCC', 'Disease', 'MESH:C538614', (186, 189))	('kinase domain', 'MPA', (263, 276))	('MET', 'Gene', '79811', (95, 98))	('affected', 'Reg', (250, 258))	('mutations', 'Var', (209, 218))	('phosphorylation', 'biological_process', 'GO:0016310', ('309', '324'))	('PRCC', 'Gene', '5546', (122, 126))	('MET', 'Gene', (280, 283))	('MET', 'Gene', '79811', (157, 160))	('elevated', 'PosReg', (300, 308))
37135	32751108	Particularly, in patients with type 1 PRCC the most commonly altered genes were MET (33%), TERT (30%), CDKN2A/B (18%), and EGFR (8%); in patients with type 2 PRCC the most recurrent gene mutations were CDKN2A/B (18%), TERT (18%), NF2 (13%), FH (13%), and MET (7%).	('EGFR', 'Gene', (123, 127))	('PRCC', 'Gene', (158, 162))	('MET', 'Gene', (255, 258))	('NF2', 'Gene', '4771', (230, 233))	('PRCC', 'Gene', (38, 42))	('CDKN2A/B', 'Gene', '1029;1030', (202, 210))	('NF2', 'Gene', (230, 233))	('CDKN2A/B', 'Gene', (103, 111))	('EGFR', 'Gene', '1956', (123, 127))	('TERT', 'Gene', (218, 222))	('PRCC', 'Gene', '5546', (158, 162))	('MET', 'Gene', (80, 83))	('MET', 'Gene', '79811', (255, 258))	('FH', 'Gene', '2271', (241, 243))	('PRCC', 'Gene', '5546', (38, 42))	('TERT', 'Gene', (91, 95))	('TERT', 'Gene', '7015', (218, 222))	('EGFR', 'molecular_function', 'GO:0005006', ('123', '127'))	('patients', 'Species', '9606', (137, 145))	('TERT', 'Gene', '7015', (91, 95))	('patients', 'Species', '9606', (17, 25))	('CDKN2A/B', 'Gene', '1029;1030', (103, 111))	('CDKN2A/B', 'Gene', (202, 210))	('mutations', 'Var', (187, 196))	('MET', 'Gene', '79811', (80, 83))
37139	32751108	Li and coworkers using this approach discovered mutations at the level of an intron of MET gene, connected to an oncogenically relevant splicing event; furthermore, in other cases a methylation dysregulation on nearby, leading to a cryptic promoter activation of the MET gene was identified.	('promoter', 'MPA', (240, 248))	('splicing', 'biological_process', 'GO:0045292', ('136', '144'))	('MET', 'Gene', '79811', (87, 90))	('methylation dysregulation', 'Var', (182, 207))	('methylation', 'biological_process', 'GO:0032259', ('182', '193'))	('MET', 'Gene', (87, 90))	('MET', 'Gene', '79811', (267, 270))	('mutations', 'Var', (48, 57))	('MET', 'Gene', (267, 270))
37140	32751108	Furthermore, it was identified the recurrent mutation of the long noncoding RNA NEAT1 and these mutations are associated with increased NEAT1 expression and negative outcome.	('NEAT1', 'Gene', (136, 141))	('RNA', 'cellular_component', 'GO:0005562', ('76', '79'))	('associated', 'Reg', (110, 120))	('NEAT1', 'Gene', '283131', (80, 85))	('mutation', 'Var', (45, 53))	('expression', 'MPA', (142, 152))	('NEAT1', 'Gene', (80, 85))	('increased', 'PosReg', (126, 135))	('NEAT1', 'Gene', '283131', (136, 141))
37142	32751108	Through the analysis of 29 patients at the level of various tumor regions (center and periphery of each tumor) the authors reached the important conclusion that, at variance with previous studies in CCRCC, in PRCC driver gene mutations and most arm-level somatic copy number alterations are clonal.	('PRCC', 'Gene', '5546', (209, 213))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PRCC', 'Gene', (209, 213))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('RCC', 'Disease', 'MESH:C538614', (210, 213))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mutations', 'Var', (226, 235))	('RCC', 'Disease', (210, 213))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
37157	32751108	The most frequent and typical genetic alteration of CCRCC is represented by biallelic inactivation on the VHL gene determined by allelic deletion or loss of heterogeneity on chromosome 3p (observed in >90% of cases), together with gene mutation (observed in about 50% of cases) or promoter hypermethylation (observed in 5-10% of cases).	('biallelic', 'Var', (76, 85))	('RCC', 'Disease', (54, 57))	('chromosome', 'cellular_component', 'GO:0005694', ('174', '184'))	('RCC', 'Disease', 'MESH:C538614', (54, 57))	('VHL', 'Gene', (106, 109))	('VHL', 'Gene', '7428', (106, 109))
37158	32751108	Other frequent genetic alterations are represented by mutations in genes involved in chromatin modification, such as PBRM1, SETD2, KDM5C, KDM6A, and BAP1.	('SETD2', 'Gene', (124, 129))	('KDM5C', 'Gene', '8242', (131, 136))	('chromatin modification', 'biological_process', 'GO:0016569', ('85', '107'))	('KDM6A', 'Gene', (138, 143))	('BAP1', 'Gene', '8314', (149, 153))	('mutations', 'Var', (54, 63))	('PBRM1', 'Gene', (117, 122))	('KDM6A', 'Gene', '7403', (138, 143))	('PBRM1', 'Gene', '55193', (117, 122))	('BAP1', 'Gene', (149, 153))	('chromatin', 'cellular_component', 'GO:0000785', ('85', '94'))	('chromatin modification', 'biological_process', 'GO:0006325', ('85', '107'))	('SETD2', 'Gene', '29072', (124, 129))	('KDM5C', 'Gene', (131, 136))
37160	32751108	Four (VHL, PBMR1, SETD2, and BPA1) of the five mutated genes in CCRCC are all located at the level of the 3p chromosomal region involved in LOH; 98% of the CRCC cases displaying LOH at 3p showed the remaining VHL allele altered by somatic mutation or promoter methylation.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('methylation', 'biological_process', 'GO:0032259', ('260', '271'))	('VHL', 'Gene', (209, 212))	('SETD2', 'Gene', '29072', (18, 23))	('VHL', 'Gene', '7428', (209, 212))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', '7428', (6, 9))	('SETD2', 'Gene', (18, 23))	('chromosomal region', 'cellular_component', 'GO:0098687', ('109', '127'))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('RCC', 'Disease', (157, 160))	('RCC', 'Disease', (66, 69))	('promoter methylation', 'Var', (251, 271))
37161	32751108	Almost all cases exhibiting PBMR1, SETD2, and BAP1 mutations occurred in CCRCC cases displaying VHL inactivation.	('mutations', 'Var', (51, 60))	('BAP1', 'Gene', '8314', (46, 50))	('RCC', 'Disease', 'MESH:C538614', (75, 78))	('RCC', 'Disease', (75, 78))	('PBMR1', 'Gene', (28, 33))	('occurred', 'Reg', (61, 69))	('VHL', 'Gene', (96, 99))	('BAP1', 'Gene', (46, 50))	('SETD2', 'Gene', '29072', (35, 40))	('VHL', 'Gene', '7428', (96, 99))	('SETD2', 'Gene', (35, 40))
37162	32751108	Importantly, SETD2 and BAP1 mutations displayed lower allelic burdens than coexisting VHL mutations, suggesting that these mutations are acquired at later times during tumor development.	('BAP1', 'Gene', (23, 27))	('allelic burdens', 'MPA', (54, 69))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('lower', 'NegReg', (48, 53))	('men', 'Species', '9606', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('BAP1', 'Gene', '8314', (23, 27))	('SETD2', 'Gene', '29072', (13, 18))	('SETD2', 'Gene', (13, 18))	('VHL', 'Gene', (86, 89))	('mutations', 'Var', (28, 37))	('VHL', 'Gene', '7428', (86, 89))
37163	32751108	PBRM1 mutations had no significant impact on overall survival, whereas BAP1 mutations, mutually exclusive with PBRM1 mutations, were associated with a shorter overall survival; finally, SETD2 mutations displayed a high relapse rate.	('SETD2', 'Gene', (186, 191))	('overall survival', 'MPA', (159, 175))	('mutations', 'Var', (76, 85))	('BAP1', 'Gene', (71, 75))	('shorter', 'NegReg', (151, 158))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', '8314', (71, 75))	('PBRM1', 'Gene', (111, 116))	('PBRM1', 'Gene', '55193', (111, 116))	('mutations', 'Var', (192, 201))	('SETD2', 'Gene', '29072', (186, 191))
37164	32751108	Interestingly, 5% of CCRCC patients displayed TCEB1 mutations, not associated with VHL gene alterations, but constantly associated with loss of chromosome 8; TCEB1 encodes a protein involved in the formation of the RNA polymerase II elongation factor complex but also involved in the VHL complex formation.	('mutations', 'Var', (52, 61))	('VHL complex', 'cellular_component', 'GO:0030891', ('284', '295'))	('VHL', 'Gene', '7428', (83, 86))	('VHL', 'Gene', (284, 287))	('TCEB1', 'Gene', '6921', (158, 163))	('chromosome', 'cellular_component', 'GO:0005694', ('144', '154'))	('TCEB1', 'Gene', (158, 163))	('VHL', 'Gene', '7428', (284, 287))	('RNA', 'cellular_component', 'GO:0005562', ('215', '218'))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('patients', 'Species', '9606', (27, 35))	('RCC', 'Disease', (23, 26))	('TCEB1', 'Gene', '6921', (46, 51))	('formation', 'biological_process', 'GO:0009058', ('296', '305'))	('TCEB1', 'Gene', (46, 51))	('formation', 'biological_process', 'GO:0009058', ('198', '207'))	('protein', 'cellular_component', 'GO:0003675', ('174', '181'))	('VHL', 'Gene', (83, 86))
37166	32751108	Therefore, CCRCC with VHL loss or with TCEB1 mutations accounts for 95.4% of the cases.	('TCEB1', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('VHL loss', 'Disease', 'MESH:D006623', (22, 30))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('TCEB1', 'Gene', '6921', (39, 44))	('VHL loss', 'Disease', (22, 30))
37167	32751108	Other genes recurrently mutated in CCRCC included TET2, KEAP1, and MTOR: TET2 mutations and deletions occurred in 16% of cases; mutually exclusive mutations in KEAP1, NRF2, and CUL3 occurred in 6.6% of cases; MTOR mutations were observed in 5.7% of cases.	('mutations', 'Var', (147, 156))	('CUL3', 'Gene', '8452', (177, 181))	('MTOR', 'Gene', (67, 71))	('RCC', 'Disease', (37, 40))	('MTOR', 'Gene', (209, 213))	('MTOR', 'Gene', '2475', (67, 71))	('MTOR', 'Gene', '2475', (209, 213))	('KEAP1', 'Gene', '9817', (56, 61))	('TET2', 'Gene', (50, 54))	('mutations', 'Var', (78, 87))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('NRF2', 'Gene', '4780', (167, 171))	('KEAP1', 'Gene', (56, 61))	('KEAP1', 'Gene', '9817', (160, 165))	('TET2', 'Gene', (73, 77))	('KEAP1', 'Gene', (160, 165))	('CUL3', 'Gene', (177, 181))	('NRF2', 'Gene', (167, 171))	('TET2', 'Gene', '54790', (50, 54))	('TET2', 'Gene', '54790', (73, 77))	('deletions', 'Var', (92, 101))
37172	32751108	reported among the CNAs the loss of 8p with or without loss of 8q (20% of cases), an abnormality frequently associated with TCEB1 mutations.	('TCEB1', 'Gene', '6921', (124, 129))	('mutations', 'Var', (130, 139))	('TCEB1', 'Gene', (124, 129))	('loss', 'NegReg', (28, 32))
37173	32751108	Integrative data analysis showed that the most frequently mutated network involved VHL and numerous interacting partners, leading to activation of the transcription factor program mediated by HIF1A/ARNT; the second most mutated network included PBRM1, ARID1A, and SMARCA4, key genes at the level of chromatin remodeling complex; the mutations of the chromatin regulators PBRM1, STD2, and BAP1 induce different patterns of altered gene expression in the context of a background caused by VHL loss; mutually exclusive alterations targeting multiple complexes of the PI3K/AKT/MTOR pathway occur in about 28% of the cases and suggest a potential therapeutic targeting.	('transcription factor', 'molecular_function', 'GO:0000981', ('151', '171'))	('ARNT', 'Gene', '405', (198, 202))	('HIF1A', 'Gene', (192, 197))	('SMARCA4', 'Gene', (264, 271))	('transcription', 'biological_process', 'GO:0006351', ('151', '164'))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('299', '319'))	('AKT', 'Gene', (569, 572))	('ARNT', 'Gene', (198, 202))	('S', 'Chemical', 'MESH:D013455', (378, 379))	('BAP1', 'Gene', '8314', (388, 392))	('PBRM1', 'Gene', '55193', (245, 250))	('MTOR', 'Gene', (573, 577))	('mutations', 'Var', (333, 342))	('VHL', 'Gene', (83, 86))	('PBRM1', 'Gene', (245, 250))	('VHL loss', 'Disease', (487, 495))	('S', 'Chemical', 'MESH:D013455', (264, 265))	('MTOR', 'Gene', '2475', (573, 577))	('BAP1', 'Gene', (388, 392))	('HIF1A', 'Gene', '3091', (192, 197))	('VHL', 'Gene', (487, 490))	('PBRM1', 'Gene', '55193', (371, 376))	('AKT', 'Gene', '207', (569, 572))	('gene expression', 'biological_process', 'GO:0010467', ('430', '445'))	('VHL loss', 'Disease', 'MESH:D006623', (487, 495))	('SMARCA4', 'Gene', '6597', (264, 271))	('ARID1A', 'Gene', (252, 258))	('VHL', 'Gene', '7428', (83, 86))	('PBRM1', 'Gene', (371, 376))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('299', '327'))	('VHL', 'Gene', '7428', (487, 490))	('PI3K', 'molecular_function', 'GO:0016303', ('564', '568'))	('chromatin', 'cellular_component', 'GO:0000785', ('350', '359'))	('ARID1A', 'Gene', '8289', (252, 258))
37175	32751108	evaluated all genetic alterations occurring in CCRCCC-inducing activation of PI3K signaling and estimated a frequency of 76% of cases exhibiting PI3K activation; furthermore, they reported also the frequent (40%) activation of p53 signaling.	('RCC', 'Disease', (49, 52))	('PI3K', 'molecular_function', 'GO:0016303', ('77', '81'))	('p53', 'Gene', (227, 230))	('genetic alterations', 'Var', (14, 33))	('p53', 'Gene', '7157', (227, 230))	('signaling', 'biological_process', 'GO:0023052', ('231', '240'))	('activation', 'PosReg', (213, 223))	('PI3K signaling', 'biological_process', 'GO:0014065', ('77', '91'))	('PI3K', 'molecular_function', 'GO:0016303', ('145', '149'))	('PI3K signaling', 'Pathway', (77, 91))	('activation', 'PosReg', (63, 73))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
37178	32751108	Copy number gains of chromosome 5q occurring in CCRCC drive overexpression of the gene SQSTM1; the p62 SQSMT1 protein is involved in activation of NRF2, and through this mechanism, in promotion of resistance to redox stress and in stimulation of renal cancer cell growth in vitro and in vivo.	('promotion', 'PosReg', (184, 193))	('Copy number', 'Var', (0, 11))	('SQSTM1', 'Gene', (87, 93))	('NRF2', 'Gene', (147, 151))	('stimulation', 'PosReg', (231, 242))	('protein', 'cellular_component', 'GO:0003675', ('110', '117'))	('overexpression', 'PosReg', (60, 74))	('protein', 'Protein', (110, 117))	('RCC', 'Disease', (50, 53))	('p62', 'Var', (99, 102))	('resistance to redox stress', 'MPA', (197, 223))	('SQSTM1', 'Gene', '8878', (87, 93))	('RCC', 'Disease', 'MESH:C538614', (50, 53))	('renal cancer', 'Disease', (246, 258))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('SQSMT1', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('renal cancer', 'Phenotype', 'HP:0009726', (246, 258))	('S', 'Chemical', 'MESH:D013455', (89, 90))	('S', 'Chemical', 'MESH:D013455', (103, 104))	('cell growth', 'biological_process', 'GO:0016049', ('259', '270'))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('activation', 'PosReg', (133, 143))	('chromosome', 'cellular_component', 'GO:0005694', ('21', '31'))	('NRF2', 'Gene', '4780', (147, 151))	('renal cancer', 'Disease', 'MESH:D007680', (246, 258))
37181	32751108	refined the analysis of molecular abnormalities of CCRCC performed by TCGA and showed that in these tumors: TP53 and BAP1 mutations and CDKN2A alterations were associated with decreased survival; at mRNA expression level an increased expression of the vasculature development signature, due to the activation of the VHL/HIF pathway, increased the immune response signature compared to other RCC types and increased ribose metabolism pathway, associated with poor survival.	('TP53', 'Gene', (108, 112))	('expression', 'MPA', (234, 244))	('ribose metabolism pathway', 'Pathway', (415, 440))	('decreased', 'NegReg', (176, 185))	('RCC', 'Disease', (53, 56))	('activation', 'PosReg', (298, 308))	('VHL', 'Gene', '7428', (316, 319))	('men', 'Species', '9606', (271, 274))	('BAP1', 'Gene', '8314', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('CDKN2A', 'Gene', (136, 142))	('ribose', 'Chemical', 'MESH:D012266', (415, 421))	('RCC', 'Disease', (391, 394))	('increased', 'PosReg', (224, 233))	('vasculature development', 'biological_process', 'GO:0001944', ('252', '275'))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TP53', 'Gene', '7157', (108, 112))	('tumors', 'Disease', (100, 106))	('CDKN2A', 'Gene', '1029', (136, 142))	('BAP1', 'Gene', (117, 121))	('RCC', 'Disease', 'MESH:C538614', (391, 394))	('alterations', 'Var', (143, 154))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('immune', 'MPA', (347, 353))	('mutations', 'Var', (122, 131))	('VHL', 'Gene', (316, 319))	('immune response', 'biological_process', 'GO:0006955', ('347', '362'))	('increased', 'PosReg', (333, 342))	('metabolism', 'biological_process', 'GO:0008152', ('422', '432'))
37189	32751108	The results of these two studies provided some fundamental data about intratumor heterogeneity of CCRCC: only a small fraction of genetic alterations display a clonal distribution, such as VHL loss and chromosome arm 3p loss, whereas other genes recurrently mutated such as SETD2 and BAP1 have a subclonal pattern of distribution within the tumor.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('men', 'Species', '9606', (52, 55))	('VHL loss', 'Disease', (189, 197))	('BAP1', 'Gene', '8314', (284, 288))	('SETD2', 'Gene', (274, 279))	('chromosome', 'cellular_component', 'GO:0005694', ('202', '212'))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('tumor', 'Disease', (75, 80))	('VHL loss', 'Disease', 'MESH:D006623', (189, 197))	('SETD2', 'Gene', '29072', (274, 279))	('alterations', 'Var', (138, 149))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('BAP1', 'Gene', (284, 288))	('chromosome', 'Var', (202, 212))	('tumor', 'Disease', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('RCC', 'Disease', (100, 103))	('loss', 'NegReg', (220, 224))
37190	32751108	It is of interest to note that the multi-region sequencing allowed the identification of a higher frequency of gene mutations and copy number alterations than by single tumor sampling.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('gene mutations', 'Var', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('copy number alterations', 'Var', (130, 153))	('amp', 'Chemical', 'MESH:D000249', (176, 179))
37196	32751108	Huang and coworkers have analyzed the clonal architectures of 473 CCRCC patients and showed that the evolution patterns of CCRCC have consistent inter-patient heterogeneity, with del(3p) being considered as the common earliest molecular event, followed by three most recurrent patterns of clonal evolution dictated by different molecular events: (i) VHL and PBRM1 mutations; (ii) del(14q); (iii) amp(7), del(1p), del(6q), amp(7q), del(3q).	('amp(7', 'Var', (396, 401))	('RCC', 'Disease', (125, 128))	('patient', 'Species', '9606', (72, 79))	('RCC', 'Disease', (68, 71))	('amp(7q', 'Var', (422, 428))	('VHL', 'Gene', '7428', (350, 353))	('del(1p', 'Gene', '10085', (404, 410))	('PBRM1', 'Gene', '55193', (358, 363))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('amp', 'Chemical', 'MESH:D000249', (422, 425))	('patient', 'Species', '9606', (151, 158))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('mutations', 'Var', (364, 373))	('PBRM1', 'Gene', (358, 363))	('del(14q)', 'Var', (380, 388))	('del(3q', 'Var', (431, 437))	('del(6q', 'Var', (413, 419))	('amp', 'Chemical', 'MESH:D000249', (396, 399))	('VHL', 'Gene', (350, 353))	('patients', 'Species', '9606', (72, 80))
37197	32751108	The analysis of these patients allowed to identify three prognostic subtypes of CCRCC with different clonal architectures and immune infiltrates: patients with a long-life expectancy are enriched with VHL, but depleted of BAP1 mutations, and have high levels of Th17 and CD8+T lymphocytes, while patients with a short survival are characterized by high burden of CNAs (frequent del(14q)), high levels of Tregs and Th2 cells.	('VHL', 'Gene', (201, 204))	('VHL', 'Gene', '7428', (201, 204))	('CD8', 'Gene', (271, 274))	('patients', 'Species', '9606', (22, 30))	('Th17', 'MPA', (262, 266))	('CD8', 'Gene', '925', (271, 274))	('depleted', 'NegReg', (210, 218))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('BAP1', 'Gene', '8314', (222, 226))	('RCC', 'Disease', (82, 85))	('del(14q', 'Var', (378, 385))	('patients', 'Species', '9606', (296, 304))	('patients', 'Species', '9606', (146, 154))	('BAP1', 'Gene', (222, 226))
37199	32751108	At arm level, 3p loss (93%) was the most frequent CNA, followed by 5q gain (54%), chromosome 14q loss (42%), chromosome 7 gain (34%), and chromosome 9 loss (21%); furthermore, about 13% of tumors displayed extensive copy number variations along all chromosomes, thus indicating a high degree of genomic instability.	('loss', 'NegReg', (97, 101))	('chromosome', 'cellular_component', 'GO:0005694', ('82', '92'))	('3p loss', 'Var', (14, 21))	('chromosome', 'cellular_component', 'GO:0005694', ('138', '148'))	('gain', 'PosReg', (70, 74))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('loss', 'NegReg', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gain', 'PosReg', (122, 126))	('copy number variations', 'Var', (216, 238))
37200	32751108	This analysis showed also that 61% of CCRCC cases displayed one or more translocations, mainly involving the chromosome 3p locus and chromosome 5 (20%).	('translocations', 'Var', (72, 86))	('RCC', 'Disease', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('chromosome', 'cellular_component', 'GO:0005694', ('109', '119'))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))
37201	32751108	This study confirmed the data on the frequency of most recurrence gene mutations and provided evidence that all the genetic alterations, including VHL, PBMR1, BAP1, KDM5C, and SETD2 are related to genetic events resulting in reduced expression of both mRNA and protein, thus indicating loss-of-function and supporting the classification of these genes as tumor suppressors.	('BAP1', 'Gene', '8314', (159, 163))	('expression', 'MPA', (233, 243))	('alterations', 'Var', (124, 135))	('reduced', 'NegReg', (225, 232))	('KDM5C', 'Gene', (165, 170))	('SETD2', 'Gene', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('protein', 'Protein', (261, 268))	('VHL', 'Gene', (147, 150))	('mutations', 'Var', (71, 80))	('SETD2', 'Gene', '29072', (176, 181))	('BAP1', 'Gene', (159, 163))	('mRNA and', 'MPA', (252, 260))	('loss-of-function', 'NegReg', (286, 302))	('VHL', 'Gene', '7428', (147, 150))	('KDM5C', 'Gene', '8242', (165, 170))	('PBMR1', 'Gene', (152, 157))	('tumor', 'Disease', (355, 360))	('protein', 'cellular_component', 'GO:0003675', ('261', '268'))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
37204	32751108	The proteomic analysis allowed the subdivision of CCRCC into three groups: CCRCC1 associated with higher tumor grade and stage and characterized by elevated adaptive immune response, N-linked glycosylation, OXPHOS protein expression and fatty acid metabolism and high frequency of BAP1 mutations and CIMP+ status; CCRCC2 and CCRCC3 were associated with lower tumor grade and stage: tumors in CCRCC2 were associated with tumor immunity, whereas tumors in CCRCC3 with glycolysis, mTOR signaling, and hypoxia and display higher frequency of PBRM1 mutations.	('BAP1', 'Gene', (281, 285))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('RCC', 'Disease', 'MESH:C538614', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (444, 449))	('tumors', 'Disease', (382, 388))	('OXPHOS', 'biological_process', 'GO:0002082', ('207', '213'))	('tumors', 'Disease', (444, 450))	('RCC', 'Disease', 'MESH:C538614', (394, 397))	('RCC', 'Disease', (456, 459))	('S', 'Chemical', 'MESH:D013455', (212, 213))	('glycosylation', 'biological_process', 'GO:0070085', ('192', '205'))	('mTOR', 'Gene', (478, 482))	('RCC', 'Disease', (52, 55))	('PBRM1', 'Gene', '55193', (538, 543))	('glycolysis', 'MPA', (466, 476))	('tumor', 'Disease', (382, 387))	('signaling', 'biological_process', 'GO:0023052', ('483', '492'))	('tumor', 'Disease', (359, 364))	('tumors', 'Disease', 'MESH:D009369', (444, 450))	('RCC', 'Disease', 'MESH:C538614', (456, 459))	('associated', 'Reg', (404, 414))	('tumor', 'Disease', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (382, 388))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('adaptive immune response', 'biological_process', 'GO:0002250', ('157', '181'))	('PBRM1', 'Gene', (538, 543))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('mTOR', 'Gene', '2475', (478, 482))	('RCC', 'Disease', (327, 330))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (420, 425))	('hypoxia', 'Disease', (498, 505))	('tumor', 'Disease', (444, 449))	('BAP1', 'Gene', '8314', (281, 285))	('RCC', 'Disease', (316, 319))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (444, 449))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('mutations', 'Var', (544, 553))	('RCC', 'Disease', 'MESH:C538614', (327, 330))	('RCC', 'Disease', (77, 80))	('RCC', 'Disease', (394, 397))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('protein', 'cellular_component', 'GO:0003675', ('214', '221'))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('glycolysis', 'biological_process', 'GO:0006096', ('466', '476'))	('tumors', 'Phenotype', 'HP:0002664', (444, 450))	('hypoxia', 'Disease', 'MESH:D000860', (498, 505))	('RCC', 'Disease', 'MESH:C538614', (316, 319))	('fatty acid metabolism', 'biological_process', 'GO:0006631', ('237', '258'))
37214	32751108	62% of these patients displayed VHL mutations and 44% PBMR1 mutations; angiogenesis-related gene expression signature was higher in VHL-mutated and PBRM1-mutated CCRCCs; within treatment evaluation showed that PBRM1 mutations were associated with improved PFS in the sunitinib arm; in the PBRM1-mutated patients atezolizumab+bevacizumab showed improved PFS compared to atezolizumab alone.	('PBRM1', 'Gene', '55193', (289, 294))	('S', 'Chemical', 'MESH:D013455', (355, 356))	('VHL', 'Gene', '7428', (32, 35))	('patients', 'Species', '9606', (13, 21))	('RCC', 'Disease', 'MESH:C538614', (164, 167))	('PBRM1', 'Gene', (210, 215))	('PBRM1', 'Gene', (289, 294))	('VHL', 'Gene', (132, 135))	('S', 'Chemical', 'MESH:D013455', (258, 259))	('angiogenesis', 'biological_process', 'GO:0001525', ('71', '83'))	('improved', 'PosReg', (247, 255))	('sunitinib', 'Chemical', 'MESH:D000077210', (267, 276))	('men', 'Species', '9606', (182, 185))	('PBRM1', 'Gene', '55193', (148, 153))	('VHL', 'Gene', '7428', (132, 135))	('PFS', 'Disease', (256, 259))	('PBRM1', 'Gene', (148, 153))	('patients', 'Species', '9606', (303, 311))	('VHL', 'Gene', (32, 35))	('gene expression', 'biological_process', 'GO:0010467', ('92', '107'))	('bevacizumab', 'Chemical', 'MESH:D000068258', (325, 336))	('atezolizumab', 'Chemical', 'MESH:C000594389', (312, 324))	('RCC', 'Disease', (164, 167))	('mutations', 'Var', (216, 225))	('atezolizumab', 'Chemical', 'MESH:C000594389', (369, 381))	('PBRM1', 'Gene', '55193', (210, 215))
37215	32751108	Whole genome sequencing studies performed in 35 metastatic CCRCC patients undergoing treatment with an anti-PD-1 blocking agent showed that clinical benefit to this treatment was significantly associated with mutations in the PBMR1 gene.	('men', 'Species', '9606', (90, 93))	('PBMR1', 'Gene', (226, 231))	('men', 'Species', '9606', (170, 173))	('PD-1', 'Gene', (108, 112))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('mutations', 'Var', (209, 218))	('RCC', 'Disease', (61, 64))	('PD-1', 'Gene', '5133', (108, 112))	('patients', 'Species', '9606', (65, 73))	('associated', 'Reg', (193, 203))
37221	32751108	Loss of SMARCB1 (also known as INI1) is a key diagnostic feature of these tumors: Calderaro et al.	('SMARCB1', 'Gene', '6598', (8, 15))	('SMARCB1', 'Gene', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('INI1', 'Gene', (31, 35))	('INI1', 'Gene', '6598', (31, 35))	('Loss', 'Var', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
37224	32751108	reported novel balanced translocations disrupting SMARCB1 in 4 of 5 cases studied; all these 4 cases occurred in patients with sickle cell trait or disease, whereas the remaining case displayed a homozygous deletion of SMARCB1 and presented in a patient with normal hemoglobin.	('patient', 'Species', '9606', (246, 253))	('balanced translocations', 'Var', (15, 38))	('patient', 'Species', '9606', (113, 120))	('sickle cell trait', 'Disease', (127, 144))	('SMARCB1', 'Gene', '6598', (50, 57))	('occurred', 'Reg', (101, 109))	('patients', 'Species', '9606', (113, 121))	('SMARCB1', 'Gene', (50, 57))	('SMARCB1', 'Gene', '6598', (219, 226))	('SMARCB1', 'Gene', (219, 226))	('disrupting', 'NegReg', (39, 49))
37228	32751108	Tumors pertaining to the three subsets associated with different FISH findings displayed comparable clinicopathologic features; the only peculiarity was related to the cases with homozygous SMARCB1 deletion being associated with the solid growth pattern, whereas tumor-bearing SMARCB1 translocations were more associated with reticular/cribiform growth.	('reticular/cribiform growth', 'Disease', (326, 352))	('associated', 'Reg', (310, 320))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('growth pattern', 'biological_process', 'GO:0007150', ('239', '253'))	('associated', 'Reg', (213, 223))	('deletion', 'Var', (198, 206))	('Tumors', 'Disease', (0, 6))	('S', 'Chemical', 'MESH:D013455', (67, 68))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('growth pattern', 'biological_process', 'GO:0040007', ('239', '253'))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SMARCB1', 'Gene', (190, 197))	('SMARCB1', 'Gene', '6598', (190, 197))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('SMARCB1', 'Gene', '6598', (277, 284))	('solid growth pattern', 'CPA', (233, 253))	('S', 'Chemical', 'MESH:D013455', (277, 278))	('SMARCB1', 'Gene', (277, 284))
37237	32751108	performed miRNA expression analysis and targeted next-generation sequencing mutational profiling on 13 cases of TCRCC: the expression profile of some miRs, such as miR-155 and miR-34a, that were downregulated was clearly different from that observed in PRCC; the gene sequencing showed recurrent mutations of ABL1 and PDGFRA genes, both genes being only rarely mutated in other RCC types.	('RCC', 'Disease', 'MESH:C538614', (378, 381))	('ABL1', 'Gene', '25', (309, 313))	('PRCC', 'Gene', (253, 257))	('RCC', 'Disease', (114, 117))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('miR-155', 'Gene', (164, 171))	('ABL1', 'Gene', (309, 313))	('miR-34a', 'Gene', '407040', (176, 183))	('miR-34a', 'Gene', (176, 183))	('PDGFRA', 'Gene', '5156', (318, 324))	('PDGFRA', 'Gene', (318, 324))	('PRCC', 'Gene', '5546', (253, 257))	('miR-155', 'Gene', '406947', (164, 171))	('RCC', 'Disease', (378, 381))	('RCC', 'Disease', 'MESH:C538614', (254, 257))	('mutations', 'Var', (296, 305))	('RCC', 'Disease', (254, 257))
37244	32751108	Initial studies have shown genetic abnormalities of WT1 gene, Wnt-activating mutations of CTNNB1 and WTX, abnormalities of 11p15 copy number, and methylation.	('11p15', 'Protein', (123, 128))	('CTNNB1', 'Gene', '1499', (90, 96))	('genetic abnormalities of WT1', 'Disease', (27, 55))	('WTX', 'Gene', '139285', (101, 104))	('genetic abnormalities of WT1', 'Disease', 'MESH:D030342', (27, 55))	('mutations', 'Var', (77, 86))	('abnormalities', 'Var', (106, 119))	('CTNNB1', 'Gene', (90, 96))	('methylation', 'Var', (146, 157))	('WTX', 'Gene', (101, 104))	('methylation', 'biological_process', 'GO:0032259', ('146', '157'))
37245	32751108	Subsequent genetic studies of large cohorts of WT patients have identified new mutations: recurrent mutations of the miRNA-processing gene DROSHA (observed in about 12% of cases) and non-recurrent mutations in other genes of this pathway (DICER1, DGCR8, XPO5, and TARBP2), associated with the downregulation of miRNA expression in a subset of WTs.	('XPO5', 'Gene', '57510', (254, 258))	('mutations', 'Var', (100, 109))	('DGCR8', 'Gene', '54487', (247, 252))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('patients', 'Species', '9606', (50, 58))	('TARBP2', 'Gene', '6895', (264, 270))	('TARBP2', 'Gene', (264, 270))	('DGCR8', 'Gene', (247, 252))	('miRNA-processing', 'biological_process', 'GO:0035196', ('117', '133'))	('miRNA expression', 'MPA', (311, 327))	('DROSHA', 'Gene', '29102', (139, 145))	('DROSHA', 'Gene', (139, 145))	('downregulation', 'NegReg', (293, 307))	('XPO5', 'Gene', (254, 258))	('DICER1', 'Gene', (239, 245))	('DICER1', 'Gene', '23405', (239, 245))	('S', 'Chemical', 'MESH:D013455', (0, 1))
37246	32751108	Recurrent mutations at the level of the homeodomain of SIX1 and SIX2 genes involved in the control of renal development, particularly frequent in WTs with blastemal histology (18% of cases), as well as DROSHA mutations (18% of cases); mutations of MYCN, SMARCA4, and ARID1A.	('MYCN', 'Gene', (248, 252))	('SMARCA4', 'Gene', (254, 261))	('mutations', 'Var', (235, 244))	('SIX2', 'Gene', (64, 68))	('men', 'Species', '9606', (115, 118))	('SMARCA4', 'Gene', '6597', (254, 261))	('DROSHA', 'Gene', (202, 208))	('MYCN', 'Gene', '4613', (248, 252))	('SIX2', 'Gene', '10736', (64, 68))	('DROSHA', 'Gene', '29102', (202, 208))	('SIX1', 'Gene', (55, 59))	('SIX1', 'Gene', '6495', (55, 59))	('mutations', 'Var', (10, 19))	('ARID1A', 'Gene', '8289', (267, 273))	('ARID1A', 'Gene', (267, 273))
37247	32751108	The most recurrent gene mutations occurring in high-risk subgroups of WT patients subdivided into those exhibiting a favorable histology (FHWT) that subsequently relapsed and those with diffuse anaplasia (DAWT) were defined: recurrent DROSHA, DGCR8, and SIX1/2 homeodomain genes were observed in FHWT; recurrent TP53 alterations are observed in DAWT, with 48% of cases showing TP53 mutations, 11% copy loss without mutation: patients with stage III/IV DAWTs had lower relapse and death rates than those with TP53 abnormalities.	('mutations', 'Var', (382, 391))	('DROSHA', 'Gene', '29102', (235, 241))	('TP53', 'Gene', (377, 381))	('death', 'Disease', 'MESH:D003643', (480, 485))	('TP53', 'Gene', '7157', (508, 512))	('DROSHA', 'Gene', (235, 241))	('DGCR8', 'Gene', (243, 248))	('SIX1/2', 'Gene', (254, 260))	('patients', 'Species', '9606', (425, 433))	('DGCR8', 'Gene', '54487', (243, 248))	('lower', 'NegReg', (462, 467))	('TP53', 'Gene', (312, 316))	('FH', 'Gene', '2271', (296, 298))	('FH', 'Gene', '2271', (138, 140))	('patients', 'Species', '9606', (73, 81))	('TP53', 'Gene', '7157', (377, 381))	('death', 'Disease', (480, 485))	('TP53', 'Gene', (508, 512))	('SIX1/2', 'Gene', '6495;10736', (254, 260))	('TP53', 'Gene', '7157', (312, 316))
37248	32751108	Another study showed the frequent occurrence of insertion/deletion MLTT1 (a gene known to be involved in transcriptional elongation during early development) mutations, associated with altered binding to acetylated histone tails: these tumors show an increase in MYC gene expression and HOX genes dysregulation.	('binding', 'molecular_function', 'GO:0005488', ('193', '200'))	('MYC', 'Gene', '4609', (263, 266))	('dysregulation', 'MPA', (297, 310))	('expression', 'MPA', (272, 282))	('HOX genes', 'Gene', (287, 296))	('men', 'Species', '9606', (152, 155))	('tumors', 'Disease', (236, 242))	('insertion/deletion', 'Var', (48, 66))	('gene expression', 'biological_process', 'GO:0010467', ('267', '282'))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('MYC', 'Gene', (263, 266))	('increase', 'PosReg', (251, 259))	('mutations', 'Var', (158, 167))	('MLTT1', 'Gene', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
37250	32751108	In addition to genes previously found to be mutated in WTs (WT1, CTNNB1, AMER1, DROSHA, DGCR8, XPO5, DICER1, SIX1, SIX2, MLLT1, MYCN, and TP53), this study discovered as frequently mutated in WTs also BCOR, BCORL1, NONO, MAX, COL6A3, ASXL1, MAP3K4, and ARID1A genes.	('WT1', 'Gene', (60, 63))	('BCORL1', 'Gene', (207, 213))	('ARID1A', 'Gene', '8289', (253, 259))	('BCOR', 'Gene', (201, 205))	('AMER1', 'Gene', (73, 78))	('MYCN', 'Gene', '4613', (128, 132))	('ASXL1', 'Gene', '171023', (234, 239))	('BCOR', 'Gene', '54880', (207, 211))	('XPO5', 'Gene', (95, 99))	('DICER1', 'Gene', '23405', (101, 107))	('WT1', 'Gene', '7490', (60, 63))	('mutated', 'Var', (181, 188))	('MAP3K', 'molecular_function', 'GO:0004709', ('241', '246'))	('SIX2', 'Gene', (115, 119))	('CTNNB1', 'Gene', '1499', (65, 71))	('COL6A3', 'Gene', (226, 232))	('BCOR', 'Gene', (207, 211))	('COL6A3', 'Gene', '1293', (226, 232))	('MAP3K4', 'Gene', '4216', (241, 247))	('NONO', 'Gene', (215, 219))	('TP53', 'Gene', (138, 142))	('MLLT1', 'Gene', '4298', (121, 126))	('DICER1', 'Gene', (101, 107))	('AMER1', 'Gene', '139285', (73, 78))	('ASXL1', 'Gene', (234, 239))	('DGCR8', 'Gene', (88, 93))	('SIX1', 'Gene', '6495', (109, 113))	('MYCN', 'Gene', (128, 132))	('MAP3K4', 'Gene', (241, 247))	('DGCR8', 'Gene', '54487', (88, 93))	('MAX', 'Gene', (221, 224))	('XPO5', 'Gene', '57510', (95, 99))	('DROSHA', 'Gene', '29102', (80, 86))	('CTNNB1', 'Gene', (65, 71))	('DROSHA', 'Gene', (80, 86))	('SIX1', 'Gene', (109, 113))	('ARID1A', 'Gene', (253, 259))	('TP53', 'Gene', '7157', (138, 142))	('SIX2', 'Gene', '10736', (115, 119))	('NONO', 'Gene', '4841', (215, 219))	('BCOR', 'Gene', '54880', (201, 205))	('MLLT1', 'Gene', (121, 126))	('BCORL1', 'Gene', '63035', (207, 213))
37251	32751108	TP53 was the most frequently mutated gene in the discovery set, enriched in DAWT histology; importantly, mutations in TP53 were significantly associated with DAWT histology (56/118 DAWT and 9/533 FHWT); frequently, TP53 mutations display a lower allelic fraction, consistent with the role of TP53 as a secondary mutation in WTs.	('TP53', 'Gene', '7157', (0, 4))	('FH', 'Gene', '2271', (196, 198))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (292, 296))	('TP53', 'Gene', (292, 296))	('lower', 'NegReg', (240, 245))	('allelic fraction', 'MPA', (246, 262))	('TP53', 'Gene', '7157', (215, 219))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('associated', 'Reg', (142, 152))	('mutations', 'Var', (105, 114))	('TP53', 'Gene', (215, 219))	('mutations', 'Var', (220, 229))
37252	32751108	CTNNB1 was the most frequently mutated gene with global frequency of 13.5%; CTNNB1 mutations were much more frequent among FHWT (16%) than among DWAT (1.7%); analysis of co-occurrence mutations showed a significant co-occurrence of CTNNB1 mutations WT1 (about 39% of tumors with CTNNB1 mutations also had WT1 mutations and about 74% of tumors with WT1 mutations also had CTNNB1 mutations).	('WT1', 'Gene', (305, 308))	('CTNNB1', 'Gene', (371, 377))	('tumors', 'Disease', (336, 342))	('CTNNB1', 'Gene', '1499', (232, 238))	('CTNNB1', 'Gene', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('WT1', 'Gene', '7490', (305, 308))	('CTNNB1', 'Gene', '1499', (279, 285))	('WT1', 'Gene', (249, 252))	('mutations', 'Var', (286, 295))	('tumors', 'Disease', 'MESH:D009369', (336, 342))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('FH', 'Gene', '2271', (123, 125))	('WT1', 'Gene', '7490', (249, 252))	('tumors', 'Disease', (267, 273))	('CTNNB1', 'Gene', (232, 238))	('CTNNB1', 'Gene', '1499', (0, 6))	('CTNNB1', 'Gene', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('CTNNB1', 'Gene', '1499', (371, 377))	('WT1', 'Gene', (348, 351))	('CTNNB1', 'Gene', '1499', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (336, 342))	('CTNNB1', 'Gene', (0, 6))	('WT1', 'Gene', '7490', (348, 351))
37253	32751108	A significant co-occurrence was also observed between DROSHA and SIX1/SIX2 mutations (15% of tumors with DROSHA mutations also had mutations in SIX1 or SIX2, and 23% tumors with SIX1 or SIX2 mutations also had DROSHA mutations).	('DROSHA', 'Gene', '29102', (54, 60))	('SIX2', 'Gene', '10736', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('DROSHA', 'Gene', (54, 60))	('mutations', 'Var', (112, 121))	('SIX1', 'Gene', '6495', (178, 182))	('SIX1', 'Gene', '6495', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('SIX2', 'Gene', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SIX1', 'Gene', (65, 69))	('SIX1', 'Gene', '6495', (144, 148))	('DROSHA', 'Gene', '29102', (210, 216))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SIX1', 'Gene', (178, 182))	('DROSHA', 'Gene', (210, 216))	('tumors', 'Disease', (166, 172))	('DROSHA', 'Gene', '29102', (105, 111))	('SIX2', 'Gene', (152, 156))	('DROSHA', 'Gene', (105, 111))	('SIX2', 'Gene', '10736', (70, 74))	('SIX1', 'Gene', (144, 148))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (131, 140))	('SIX2', 'Gene', '10736', (186, 190))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('SIX2', 'Gene', (70, 74))
37254	32751108	At the level of CNAs, WTs are characterized by gains and losses of entire chromosomes or chromosomal arms, such as gains of 1q, 6, and 12 and loss of 4q, 16q, 17p, 14, 11, and 22; gain of 1q was shown in about 48% of cases; gain of 1q was not concurrent with any recurrent mutation, suggesting a possible role as a secondary event; amplification of 2p24 including MYCN locus, was found in 11.5% of FHWTs and 25.5% DAWTs; loss of 17p correlated with TP53 mutations, as well as loss of 4q and 14q.	('loss of 17p', 'Var', (421, 432))	('FHWTs', 'Disease', 'None', (398, 403))	('MYCN', 'Gene', (364, 368))	('MYCN', 'Gene', '4613', (364, 368))	('FHWTs', 'Disease', (398, 403))	('TP53', 'Gene', '7157', (449, 453))	('amp', 'Chemical', 'MESH:D000249', (332, 335))	('loss', 'Var', (476, 480))	('TP53', 'Gene', (449, 453))	('mutations', 'Var', (454, 463))
37256	32751108	Chromosomal loss at 9q22 caused recurrent loss of MIRLET7A gene family: MIRLET7A1 (5%), MIRLET7A2 (18%), MIRLET7A3 (/21%).	('Chromosomal loss', 'Var', (0, 16))	('MIRLET7A3', 'Gene', (105, 114))	('MIRLET7A2', 'Gene', '406882', (88, 97))	('MIRLET7A1', 'Gene', (72, 81))	('MIRLET7A gene family', 'Gene', (50, 70))	('MIRLET7A3', 'Gene', '406883', (105, 114))	('MIRLET7A1', 'Gene', '406881', (72, 81))	('MIRLET7A2', 'Gene', (88, 97))	('loss', 'NegReg', (42, 46))
37258	32751108	This study showed that WTs: (i) Derive from the cooperation of multiple genetic events; (ii) display different genetic alterations, associated with differential gene expression profiles; (iii) have multiple driver genes, the majority being altered in <5% of tumors; (iv) display mutations at the level of genes with common functions, mainly represented by genes involved in early renal development or epigenetic regulation.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mutations', 'Var', (279, 288))	('regulation', 'biological_process', 'GO:0065007', ('412', '422'))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', (258, 264))	('men', 'Species', '9606', (393, 396))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('gene expression', 'biological_process', 'GO:0010467', ('161', '176'))
37261	32751108	Using human and mouse cellular models, evidence was provided that ENL mutants induce gene expression changes that promote a premalignant condition and in nephrogenesis models induce the formation of undifferentiated cellular structures resembling those observed in WTs.	('premalignant condition', 'Disease', (124, 146))	('induce', 'Reg', (175, 181))	('human', 'Species', '9606', (6, 11))	('gene expression', 'biological_process', 'GO:0010467', ('85', '100'))	('mutants', 'Var', (70, 77))	('formation', 'biological_process', 'GO:0009058', ('186', '195'))	('nephrogenesis', 'biological_process', 'GO:0072006', ('154', '167'))	('nephrogenesis', 'biological_process', 'GO:0001822', ('154', '167'))	('ENL', 'Gene', (66, 69))	('formation', 'CPA', (186, 195))	('mouse', 'Species', '10090', (16, 21))	('gene expression changes', 'MPA', (85, 108))	('nephrogenesis', 'Disease', (154, 167))	('nephrogenesis', 'Disease', 'None', (154, 167))	('promote', 'PosReg', (114, 121))
37262	32751108	At mechanistic level, these ENL mutations exhibit a function similar to their normal counterpart, occupying similar target genomic loci, but with a clearly increased occupancy, leading to a pronounced increase in the recruitment and activity of transcription elongation machinery, thus enforcing the rate and the level of gene transcription of these target genes.	('men', 'Species', '9606', (224, 227))	('activity', 'MPA', (233, 241))	('transcription', 'biological_process', 'GO:0006351', ('245', '258'))	('increase', 'PosReg', (201, 209))	('transcription', 'biological_process', 'GO:0006351', ('327', '340'))	('transcription elongation', 'CPA', (245, 269))	('increased', 'PosReg', (156, 165))	('mutations', 'Var', (32, 41))	('ENL', 'Gene', (28, 31))	('recruitment', 'MPA', (217, 228))
37266	32751108	To perform this analysis, these investigators initially investigated some children with unilateral WTs and sampled tumor, blood and normal kidney tissue specimens from the same individuals: in two of the three cases analyzed, mosaic mutations in normal kidneys that were present in the corresponding tumor, but absent from blood were observed.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (115, 120))	('children', 'Species', '9606', (74, 82))	('mutations', 'Var', (233, 242))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('amp', 'Chemical', 'MESH:D000249', (108, 111))	('men', 'Species', '9606', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
37271	32751108	sRCC is not a distinct RCC subtype, but represents a shift in the epithelial differentiation to mesenchymal differentiation in the context of pre-existing RCC; this conclusion is supported by two lines of observations: both an epithelial and a mesenchymal component is present in these tumors; both the epithelial and sarcomatoid components share the large majority of gene mutations, copy number alterations, and X-chromosome inactivation patterns.	('RCC', 'Disease', (155, 158))	('sarcomatoid', 'Disease', 'MESH:C538614', (318, 329))	('copy number alterations', 'Var', (385, 408))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('pre', 'molecular_function', 'GO:0003904', ('142', '145'))	('RCC', 'Disease', 'MESH:C538614', (1, 4))	('gene mutations', 'Var', (369, 383))	('tumors', 'Disease', (286, 292))	('RCC', 'Disease', (1, 4))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('sarcomatoid', 'Disease', (318, 329))	('RCC', 'Disease', (23, 26))	('X-chromosome', 'cellular_component', 'GO:0000805', ('414', '426'))	('X-chromosome inactivation', 'biological_process', 'GO:0009048', ('414', '439'))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
37275	32751108	The most recurrent mutations in these patients involved VHL (72%), chromatin remodeling genes SETD2 (40%), PBMR1 (34%) and BAP1 (26%), TERT promoter (18%), PTEN (14%), TSC2 (12%), and Hippo pathway members NF2 (10%) and FAT1 (10%).	('VHL', 'Gene', (56, 59))	('TERT', 'Gene', '7015', (135, 139))	('PTEN', 'Gene', (156, 160))	('TSC2', 'Gene', (168, 172))	('chromatin', 'cellular_component', 'GO:0000785', ('67', '76'))	('NF2', 'Gene', '4771', (206, 209))	('patients', 'Species', '9606', (38, 46))	('NF2', 'Gene', (206, 209))	('VHL', 'Gene', '7428', (56, 59))	('PTEN', 'Gene', '5728', (156, 160))	('PBMR1', 'Gene', (107, 112))	('BAP1', 'Gene', '8314', (123, 127))	('FAT1', 'Gene', '2195', (220, 224))	('FAT1', 'Gene', (220, 224))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('67', '87'))	('BAP1', 'Gene', (123, 127))	('TSC2', 'Gene', '7249', (168, 172))	('SETD2', 'Gene', (94, 99))	('mutations', 'Var', (19, 28))	('SETD2', 'Gene', '29072', (94, 99))	('TERT', 'Gene', (135, 139))
37277	32751108	It is of interest to note that concerning the chromatin remodeling genes, in addition to SETD2, PBRM1, and BAP1 mutations, were observed also mutations of ARID1A and ARID1B genes and of several genes acting as epigenetic regulators.	('mutations', 'Var', (142, 151))	('BAP1', 'Gene', '8314', (107, 111))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('46', '66'))	('SETD2', 'Gene', '29072', (89, 94))	('BAP1', 'Gene', (107, 111))	('ARID1B', 'Gene', (166, 172))	('mutations', 'Var', (112, 121))	('SETD2', 'Gene', (89, 94))	('ARID1A', 'Gene', '8289', (155, 161))	('PBRM1', 'Gene', (96, 101))	('ARID1A', 'Gene', (155, 161))	('PBRM1', 'Gene', '55193', (96, 101))	('chromatin', 'cellular_component', 'GO:0000785', ('46', '55'))	('ARID1B', 'Gene', '57492', (166, 172))
37278	32751108	In 23 patients the genomic profiles of paired epithelial and mesenchymal components were compared, showing that: SETD2 and TERT alterations markedly differed between the two components; one tumor harbored NF2 and CDKN2A mutations exclusively in the mesenchymal component; two tumors harbored TP53 mutations exclusively in the mesenchymal component.	('TP53', 'Gene', (292, 296))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('NF2', 'Gene', '4771', (205, 208))	('TERT', 'Gene', (123, 127))	('TERT', 'Gene', '7015', (123, 127))	('SETD2', 'Gene', (113, 118))	('NF2', 'Gene', (205, 208))	('mutations', 'Var', (220, 229))	('tumors', 'Disease', (276, 282))	('TP53', 'Gene', '7157', (292, 296))	('SETD2', 'Gene', '29072', (113, 118))	('CDKN2A', 'Gene', (213, 219))	('tumor', 'Disease', (276, 281))	('tumor', 'Disease', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('CDKN2A', 'Gene', '1029', (213, 219))
37280	32751108	Hippo-mutant sRCCs showed YAP/TAZ upregulation, thus showing that Hippo pathway is activated in these tumors; furthermore, Hippo pathway inhibition or restoration of normal NF2 expression inhibited the proliferation and invasiveness of sRCC.	('TAZ', 'Gene', '6901', (30, 33))	('RCC', 'Disease', (14, 17))	('TAZ', 'Gene', (30, 33))	('inhibited', 'NegReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('expression', 'MPA', (177, 187))	('NF2', 'Gene', '4771', (173, 176))	('RCC', 'Disease', 'MESH:C538614', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('NF2', 'Gene', (173, 176))	('Hippo pathway', 'Pathway', (123, 136))	('tumors', 'Disease', (102, 108))	('YAP', 'Gene', '55249', (26, 29))	('RCC', 'Disease', (237, 240))	('YAP', 'Gene', (26, 29))	('proliferation', 'CPA', (202, 215))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('Hippo-mutant', 'Var', (0, 12))	('inhibition', 'NegReg', (137, 147))	('RCC', 'Disease', 'MESH:C538614', (237, 240))	('upregulation', 'PosReg', (34, 46))
37281	32751108	Ito and coworkers reported a detailed analysis on CNAs occurring in 17 sRCCs, showing that these tumors are associated with a high rate of chromosomal abnormalities involving losses of 9q, 15q, 18p/q, and 22q and gains of 1q and 8q occurring at significantly higher frequencies compared to the corresponding non-sarcomatoid RCCs.	('RCC', 'Disease', 'MESH:C538614', (324, 327))	('RCC', 'Disease', 'MESH:C538614', (72, 75))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (139, 164))	('RCC', 'Disease', (72, 75))	('non-sarcomatoid', 'Disease', 'MESH:C538614', (308, 323))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('18p/q', 'Var', (194, 199))	('sarcomatoid RCCs', 'Disease', (312, 328))	('sarcomatoid RCCs', 'Disease', 'MESH:C538614', (312, 328))	('15q', 'Var', (189, 192))	('tumors', 'Disease', (97, 103))	('chromosomal abnormalities', 'Disease', (139, 164))	('losses', 'NegReg', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('gains', 'PosReg', (213, 218))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('non-sarcomatoid', 'Disease', (308, 323))	('RCC', 'Disease', (324, 327))
37284	32751108	reported the extensive molecular characterization of 62 primary high-grade uRCCs: sequencing analysis showed recurrent mutations at the level of 29 genes, the most frequent being NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), MTOR (8%), PTEN (7%), and TSC1 (7%); integrated molecular analyses showed the existence of a subset (26% of uRCCs) characterized by NF2 loss, dysregulated Hippo-YAP pathway and poor survival and of another subset (21% of uRCCs), characterized by recurrent mutations of MTOR, TSC1, TSC2, or PTEN, hyperactive MT OR signaling and a better clinical outcome.	('RCC', 'Disease', 'MESH:C538614', (450, 453))	('mutations', 'Var', (484, 493))	('RCC', 'Disease', (337, 340))	('RCC', 'Disease', (76, 79))	('TSC1', 'Gene', (503, 507))	('PTEN', 'Gene', (518, 522))	('SETD2', 'Gene', (190, 195))	('BAP1', 'Gene', '8314', (203, 207))	('RCC', 'Disease', 'MESH:C538614', (337, 340))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('TSC2', 'Gene', '7249', (509, 513))	('TSC1', 'Gene', '7248', (503, 507))	('dysregulated', 'Reg', (370, 382))	('KMT2C', 'Gene', (215, 220))	('KMT2C', 'Gene', '58508', (215, 220))	('poor', 'NegReg', (405, 409))	('PTEN', 'Gene', '5728', (518, 522))	('NF2', 'Gene', '4771', (179, 182))	('PTEN', 'Gene', (239, 243))	('TSC1', 'Gene', (254, 258))	('YAP', 'Gene', '55249', (389, 392))	('SETD2', 'Gene', '29072', (190, 195))	('NF2', 'Gene', (179, 182))	('YAP', 'Gene', (389, 392))	('TSC2', 'Gene', (509, 513))	('MTOR', 'Gene', (228, 232))	('BAP1', 'Gene', (203, 207))	('hyperactive MT', 'Disease', (524, 538))	('hyperactive MT', 'Disease', 'MESH:D006948', (524, 538))	('MTOR', 'Gene', (497, 501))	('NF2', 'Gene', '4771', (360, 363))	('TSC1', 'Gene', '7248', (254, 258))	('MTOR', 'Gene', '2475', (228, 232))	('signaling', 'biological_process', 'GO:0023052', ('542', '551'))	('MTOR', 'Gene', '2475', (497, 501))	('PTEN', 'Gene', '5728', (239, 243))	('RCC', 'Disease', (450, 453))	('loss', 'NegReg', (364, 368))	('NF2', 'Gene', (360, 363))
37285	32751108	The frequent NF2 abnormalities and the consequent dysregulation of the Hippo pathway represent a common feature of both sRCC and uRCC and support the targeting of this pathway for the therapy of a subset of these aggressive RCCs.	('RCC', 'Disease', (224, 227))	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('NF2', 'Gene', '4771', (13, 16))	('RCC', 'Disease', (121, 124))	('Hippo pathway', 'Pathway', (71, 84))	('aggressive RCCs', 'Disease', (213, 228))	('aggressive RCCs', 'Disease', 'MESH:D001523', (213, 228))	('RCC', 'Disease', (130, 133))	('abnormalities', 'Var', (17, 30))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('NF2', 'Gene', (13, 16))	('dysregulation', 'Reg', (50, 63))	('RCC', 'Disease', 'MESH:C538614', (224, 227))
37296	32751108	These various types of RCC have been defined on the basis of their histological appearance, the presence of distinct driver mutations, varying clinical course, and different responses to therapy.	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('mutations', 'Var', (124, 133))
37301	32751108	Thus, molecular studies in CCRCC have defined the dysregulation of the VHL gene as an almost universal initial, founding event, followed by different types of additional genetic events involving PBRM1, KDM5C, SETD2, or BAP1 that differentially dictate disease progression and aggressiveness.	('aggressiveness', 'Disease', (276, 290))	('KDM5C', 'Gene', '8242', (202, 207))	('aggressiveness', 'Phenotype', 'HP:0000718', (276, 290))	('BAP1', 'Gene', (219, 223))	('VHL', 'Gene', (71, 74))	('SETD2', 'Gene', '29072', (209, 214))	('PBRM1', 'Gene', (195, 200))	('RCC', 'Disease', (29, 32))	('PBRM1', 'Gene', '55193', (195, 200))	('VHL', 'Gene', '7428', (71, 74))	('RCC', 'Disease', 'MESH:C538614', (29, 32))	('SETD2', 'Gene', (209, 214))	('aggressiveness', 'Disease', 'MESH:D001523', (276, 290))	('dictate', 'Reg', (244, 251))	('dysregulation', 'Var', (50, 63))	('KDM5C', 'Gene', (202, 207))	('BAP1', 'Gene', '8314', (219, 223))
37302	32751108	CCRCC tumors with PBRM1 mutations respond to targeted therapy differently than tumors with BAP1 mutations.	('BAP1', 'Gene', (91, 95))	('CCRCC tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CCRCC tumors', 'Disease', (0, 12))	('PBRM1', 'Gene', (18, 23))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BAP1', 'Gene', '8314', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PBRM1', 'Gene', '55193', (18, 23))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
37311	32751108	The rationale for their use was related to the very frequent VHL alterations observed in RCCs and responsible for activation of hypoxia signaling pathway in these tumors.	('activation', 'PosReg', (114, 124))	('alterations', 'Var', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('RCC', 'Disease', (89, 92))	('tumors', 'Disease', (163, 169))	('VHL', 'Gene', (61, 64))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('RCC', 'Disease', 'MESH:C538614', (89, 92))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('VHL', 'Gene', '7428', (61, 64))	('signaling pathway', 'biological_process', 'GO:0007165', ('136', '153'))	('hypoxia', 'Disease', (128, 135))
37328	32751108	showed the preliminary results of a phase II study (NCT 03401788) involving the treatment of 61 patients with germline VHL mutant, localized/nonmetastatic CCRCC, common lesions outside the kidney (non-RCC tumors such as hemangioblastomas (80%) and pancreatic lesions (50%)); about 28% of the patients displayed objective responses and about 87% of patients showed decrease in the size of target lesions.	('patients', 'Species', '9606', (348, 356))	('RCC tumors', 'Disease', (201, 211))	('mutant', 'Var', (123, 129))	('VHL', 'Gene', '7428', (119, 122))	('decrease', 'NegReg', (364, 372))	('RCC tumors', 'Disease', 'MESH:C538614', (201, 211))	('RCC', 'Disease', 'MESH:C538614', (157, 160))	('patients', 'Species', '9606', (292, 300))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('RCC', 'Disease', (201, 204))	('pancreatic lesions', 'Disease', (248, 266))	('germline', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('hemangioblastomas', 'Disease', 'MESH:D018325', (220, 237))	('pancreatic lesions', 'Disease', 'MESH:D010195', (248, 266))	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('men', 'Species', '9606', (85, 88))	('patients', 'Species', '9606', (96, 104))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (220, 236))	('VHL', 'Gene', (119, 122))	('RCC', 'Disease', (157, 160))	('hemangioblastomas', 'Disease', (220, 237))
37460	30995092	The American Urological Association guidelines for management of renal masses considers AS as a potential option for select patients with T1a (<= 4 cm) or T1b (> 4 and <= 7 cm) RCC, particularly those with comorbidities or limited life expectancy.	('As', 'Gene', '112935892', (24, 26))	('as', 'Gene', '112935892', (72, 74))	('AS', 'Gene', '112935892', (88, 90))	('RCC', 'Disease', 'MESH:C538614', (177, 180))	('RCC', 'Disease', (177, 180))	('RCC', 'Phenotype', 'HP:0005584', (177, 180))	('T1a (<= 4 cm', 'Var', (138, 150))	('as', 'Gene', '112935892', (91, 93))	('renal masses', 'Phenotype', 'HP:0009726', (65, 77))	('> 4', 'Var', (160, 163))	('patients', 'Species', '9606', (124, 132))
37538	30995092	Intratumoral areas of hypointense signal on shorter-TE opposed-phase images relative to longer-TE in-phase images are secondary to intracytoplasmic microscopic fat and are present in many ccRCCs.	('fat', 'Gene', (160, 163))	('as', 'Gene', '112935892', (103, 105))	('as', 'Gene', '112935892', (65, 67))	('fat', 'Gene', '2195', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('RCC', 'Disease', 'MESH:C538614', (190, 193))	('as', 'Gene', '112935892', (142, 144))	('RCC', 'Disease', (190, 193))	('RCC', 'Phenotype', 'HP:0005584', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('as', 'Gene', '112935892', (16, 18))	('tumor', 'Disease', (5, 10))	('hypointense', 'Var', (22, 33))
37546	30995092	found that the presence of SEI at mpMRI was an independent predictor for the diagnosis of oncocytoma (odds ratio = 16.21; 95% CI, 1.0-275.4), but the CI was wide (approaching 1) and the interobserver agreement was only moderate(kappa = 0.49).	('as', 'Gene', '112935892', (41, 43))	('oncocytoma', 'Disease', (90, 100))	('oncocytoma', 'Disease', 'MESH:D018249', (90, 100))	('presence', 'Var', (15, 23))	('as', 'Gene', '112935892', (211, 213))	('as', 'Gene', '112935892', (154, 156))	('mpMRI', 'Gene', (34, 39))
37547	30995092	reported SEI in both oncocytomas and chrRCCs, making the distinction between these two subtypes based on this imaging finding alone not reliable.	('SEI', 'Var', (9, 12))	('RCC', 'Disease', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('as', 'Gene', '112935892', (97, 99))	('oncocytomas', 'Disease', (21, 32))	('oncocytomas', 'Disease', 'MESH:D018249', (21, 32))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('as', 'Gene', '112935892', (30, 32))
37549	30995092	The hypointensity on T2-weighted imaging also is common with pRCC, but some differences exist that help in differentiation.	('pRCC', 'Gene', (61, 65))	('hypointensity', 'Var', (4, 17))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('pRCC', 'Gene', '5546', (61, 65))
37563	30995092	However, DWI may aid in the differentiation of some histologic subtypes, particularly when included in a comprehensive mpMRI assessment (discussed later), and may help in estimating tumor grade.	('help', 'Reg', (163, 167))	('as', 'Gene', '112935892', (125, 127))	('tumor', 'Disease', (182, 187))	('aid', 'Gene', (17, 20))	('DWI', 'Var', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('aid', 'Gene', '57379', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
37568	30995092	The first step in the algorithm by Kay and Pedrosa assesses the signal intensity on T2-weighted images and determines whether the lesion is hyper-, iso-, or hypointense relative to renal cortex.	('as', 'Gene', '112935892', (51, 53))	('signal intensity', 'MPA', (64, 80))	('hypointense', 'Var', (157, 168))	('hyper-', 'Var', (140, 146))	('iso-', 'Var', (148, 152))
37576	30995092	Among T2-isointense masses, ccRCC is suspected if the mass is heterogeneous or has microscopic fat, oncocytoma is suspected if SEI is present, chrRCC is suspected if moderately enhancing and homogeneous, and pRCC is suspected if there is mild progressive enhancement.	('fat', 'Gene', (95, 98))	('pRCC', 'Gene', '5546', (208, 212))	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (209, 212))	('RCC', 'Disease', (209, 212))	('RCC', 'Disease', (146, 149))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (209, 212))	('oncocytoma', 'Disease', (100, 110))	('pRCC', 'Gene', (208, 212))	('T2-isointense', 'Var', (6, 19))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('as', 'Gene', '112935892', (80, 82))	('as', 'Gene', '112935892', (55, 57))	('fat', 'Gene', '2195', (95, 98))	('heterogeneous', 'MPA', (62, 75))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('oncocytoma', 'Disease', 'MESH:D018249', (100, 110))	('as', 'Gene', '112935892', (21, 23))
37583	30995092	For example, a mass showing hyperintense signal on T2-weighted images, intense enhancement, and microscopic fat would receive a ccLS of 5 (highly likely ccRCC), whereas a mass showing hypointense signal on T2-weighted images and mild progressive enhancement would be designated a ccLS of 1 (very unlikely ccRCC).	('enhancement', 'PosReg', (79, 90))	('RCC', 'Disease', (155, 158))	('as', 'Gene', '112935892', (172, 174))	('RCC', 'Disease', 'MESH:C538614', (307, 310))	('ccLS', 'Chemical', '-', (128, 132))	('RCC', 'Disease', (307, 310))	('RCC', 'Phenotype', 'HP:0005584', (307, 310))	('as', 'Gene', '112935892', (166, 168))	('ccLS', 'Chemical', '-', (280, 284))	('as', 'Gene', '112935892', (16, 18))	('fat', 'Gene', (108, 111))	('ccLS', 'Var', (128, 132))	('fat', 'Gene', '2195', (108, 111))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
37603	30995092	Incorporation of mpMRI into the workup of an indeterminate renal mass could reduce the number of biopsies, expedite treatment in high-risk patients, minimize complications, and potentially reduce the cost of care.	('as', 'Gene', '112935892', (66, 68))	('Incorporation', 'Var', (0, 13))	('patients', 'Species', '9606', (139, 147))	('reduce', 'NegReg', (76, 82))	('reduce', 'NegReg', (189, 195))	('mpMRI', 'Gene', (17, 22))
37627	32555180	In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal.	('mutations', 'Var', (63, 72))	('RCC', 'Disease', (46, 49))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('pRCC', 'Gene', (45, 49))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('pRCC', 'Gene', '5546', (45, 49))
37650	32555180	The average SNV and indel rates across tumors were 1.21/Mb and 0.18/Mb, respectively: on average, 1.00/Mb and 0.18/Mb for pRCC1; 1.46/Mb and 0.21/Mb for pRCC2.	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('pRCC', 'Gene', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('pRCC', 'Gene', '5546', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SNV', 'Var', (12, 15))	('pRCC', 'Gene', (153, 157))	('tumors', 'Disease', (39, 45))	('pRCC', 'Gene', '5546', (122, 126))
37656	32555180	In pRCC2 tumors, we observed a SMARCB1 driver mutation in one pRCC2; TERT promoter in two pRCC2; SETD2, PBRM1 and NF2 in one pRCC2 tumor each.	('pRCC', 'Gene', '5546', (3, 7))	('pRCC', 'Gene', '5546', (90, 94))	('tumor', 'Disease', (131, 136))	('TERT', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('PBRM1', 'Gene', '55193', (104, 109))	('SETD2', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', (9, 15))	('pRCC', 'Gene', (3, 7))	('tumor', 'Disease', (9, 14))	('PBRM1', 'Gene', (104, 109))	('pRCC', 'Gene', (90, 94))	('SETD2', 'Gene', '29072', (97, 102))	('pRCC', 'Gene', '5546', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('pRCC', 'Gene', '5546', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('NF2', 'Gene', '4771', (114, 117))	('SMARCB1', 'Gene', '6598', (31, 38))	('mutation', 'Var', (46, 54))	('SMARCB1', 'Gene', (31, 38))	('NF2', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('pRCC', 'Gene', (125, 129))	('pRCC', 'Gene', (62, 66))
37657	32555180	We also found clonal indels in NF2 in two tumors (cdRCC and mixRCC), and MET (mixRCC), SMARCB1 (pRCC1) and ROS1 (pRCC2) indels in one tumor each.	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('NF2', 'Gene', '4771', (31, 34))	('ROS1', 'Gene', '6098', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('pRCC', 'Gene', (113, 117))	('RCC', 'Disease', (114, 117))	('NF2', 'Gene', (31, 34))	('tumor', 'Disease', (42, 47))	('RCC', 'Disease', (52, 55))	('RCC', 'Disease', (81, 84))	('pRCC', 'Gene', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('RCC', 'Disease', (97, 100))	('pRCC', 'Gene', '5546', (96, 100))	('RCC', 'Disease', 'MESH:C538614', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('ROS1', 'Gene', (107, 111))	('indels', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SMARCB1', 'Gene', '6598', (87, 94))	('tumor', 'Disease', (134, 139))	('RCC', 'Disease', (63, 66))	('SMARCB1', 'Gene', (87, 94))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('tumors', 'Disease', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('pRCC', 'Gene', '5546', (113, 117))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
37658	32555180	We found no mutations in TP53, mutated in a high proportion of cases across cancer types, and no mutations in the 5'UTR region of TERT, which has been reported as mutated in a sizeable fraction of ccRCC (Fig.	('TP53', 'Gene', (25, 29))	('TERT', 'Gene', (130, 134))	('TERT', 'Gene', '7015', (130, 134))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (25, 29))	('RCC', 'Disease', (199, 202))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
37662	32555180	In these tumors, SNVs in other genes or other genomic alterations yet to be defined are the likely driver events.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('SNVs', 'Var', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
37663	32555180	An analysis of the germline sequencing data provided evidence of rare, potentially deleterious, germline variants in known cancer susceptibility genes ("Methods" section).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('variants', 'Var', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
37664	32555180	These include two different variants in POLE in two different tumors; two different variants in CHEK2 in two different tumors; one variant in BRIP1 and PTCH1 both in a single tumor; and additional rare variants, one per tumor (e.g., TP53, MET, EGFR, among others, Supplementary Data 6).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (220, 225))	('BRIP1', 'Gene', '83990', (142, 147))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('EGFR', 'Gene', '1956', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', (62, 68))	('MET', 'Var', (239, 242))	('BRIP1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (175, 180))	('PTCH1', 'Gene', '5727', (152, 157))	('TP53', 'Gene', (233, 237))	('CHEK2', 'Gene', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (119, 124))	('EGFR', 'Gene', (244, 248))	('CHEK2', 'Gene', '11200', (96, 101))	('tumor', 'Disease', (62, 67))	('PTCH1', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('EGFR', 'molecular_function', 'GO:0005006', ('244', '248'))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('TP53', 'Gene', '7157', (233, 237))
37665	32555180	This is consistent with a report on the relatively high frequency of germline mutations in cancer susceptibility genes in non-clear cell renal cell carcinomas.	('non-clear cell renal cell carcinomas', 'Disease', (122, 158))	('non-clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (122, 158))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (137, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (126, 158))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (126, 157))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('germline mutations', 'Var', (69, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
37678	32555180	1c and 2), which most likely originated in the primary tumor region T02 or T10, share the same driver mutations in PBRM1 and SMARCB1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SMARCB1', 'Gene', '6598', (125, 132))	('SMARCB1', 'Gene', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (102, 111))	('PBRM1', 'Gene', (115, 120))	('PBRM1', 'Gene', '55193', (115, 120))
37690	32555180	In both of our metastatic cases (stage 4 at diagnosis), pRCC2_1824_13 and rSRC_1697_10, intermixing of subclones has extended to metastatic sites, pointing to the occurrence of polyclonal seeding as previously observed in metastatic prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (233, 248))	('prostate cancer', 'Phenotype', 'HP:0012125', (233, 248))	('pRCC', 'Gene', '5546', (56, 60))	('rSRC_1697_10', 'Var', (74, 86))	('pRCC', 'Gene', (56, 60))	('prostate cancer', 'Disease', (233, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
37703	32555180	Metastatic lesions shared most SCNAs with their primary tumors, but also displayed metastasis-specific SCNAs (e.g., hemizygous deletion loss of heterozygosity in 4q of pRCC2_1824_13, Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('pRCC', 'Gene', '5546', (168, 172))	('metastasis-specific SCNAs', 'Disease', (83, 108))	('tumors', 'Disease', (56, 62))	('pRCC', 'Gene', (168, 172))	('deletion', 'Var', (127, 135))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('loss', 'NegReg', (136, 140))
37704	32555180	Among the rarer subtypes, both rSRC and cdRCC had clonal focal homozygous deletions of CDKN2A at 9p21.3 (Fig.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('deletions', 'Var', (74, 83))	('CDKN2A', 'Gene', '1029', (87, 93))	('RCC', 'Disease', (42, 45))	('CDKN2A', 'Gene', (87, 93))
37705	32555180	For example, the SMARCB1 p.R373T mutation occurred earlier than the 22q LOH in pRCC2_1824_13_T08, and the truncated mutation KMT2C p.S789* occurred later than the chr7 amplification in pRCC2_1494.	('KMT2C', 'Gene', '58508', (125, 130))	('p.S789*', 'Var', (131, 138))	('p.R373T', 'Mutation', 'p.R373T', (25, 32))	('pRCC', 'Gene', (79, 83))	('pRCC', 'Gene', (185, 189))	('p.R373T', 'Var', (25, 32))	('SMARCB1', 'Gene', (17, 24))	('p.S789*', 'Mutation', 'p.S789*', (131, 138))	('SMARCB1', 'Gene', '6598', (17, 24))	('KMT2C', 'Gene', (125, 130))	('pRCC', 'Gene', '5546', (79, 83))	('pRCC', 'Gene', '5546', (185, 189))
37709	32555180	1c), including a deletion within MET in one pRCC2, and several fusions involving genes previously reported in renal cancer or other tumors.	('pRCC', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('renal cancer', 'Disease', (110, 122))	('renal cancer', 'Disease', 'MESH:D007680', (110, 122))	('renal cancer', 'Phenotype', 'HP:0009726', (110, 122))	('deletion', 'Var', (17, 25))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('pRCC', 'Gene', '5546', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('MET', 'Gene', (33, 36))	('fusions', 'Reg', (63, 70))
37721	32555180	At least three transposon insertions could have potentially affected the expression of proteins involved in chromatin regulation and chromosome structural maintenance and, in turn, the maintenance of genome integrity in this tumor (Supplementary Method).	('insertions', 'Var', (26, 36))	('affected', 'Reg', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('chromatin', 'cellular_component', 'GO:0000785', ('108', '117'))	('proteins', 'Protein', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('regulation', 'biological_process', 'GO:0065007', ('118', '128'))	('chromosome structural', 'CPA', (133, 154))	('transposon', 'Gene', (15, 25))	('tumor', 'Disease', (225, 230))	('maintenance of genome integrity', 'biological_process', 'GO:0051276', ('185', '216'))	('expression', 'MPA', (73, 83))	('chromosome', 'cellular_component', 'GO:0005694', ('133', '143'))
37729	32555180	We also observed a small proportion of mutations attributed to the clock-like mutational signature 1(3.5% of total SNVs) and signature 8 (1.4%), which has unknown etiology.	('clock', 'Gene', '9575', (67, 72))	('clock', 'Gene', (67, 72))	('mutations', 'Var', (39, 48))
37739	32555180	Multi-region whole-genome sequencing demonstrates that papillary renal cell carcinomas and rarer renal cancer subtypes generally have much less driver gene mutation and copy number alteration intra-tumor heterogeneity than clear cell renal cell carcinomas.	('less', 'NegReg', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (234, 254))	('intra-tumor', 'Disease', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (223, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('copy number alteration', 'Var', (169, 191))	('clear cell renal cell carcinomas', 'Disease', (223, 255))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (234, 255))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (55, 86))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (223, 254))	('renal cancer', 'Disease', (97, 109))	('driver gene', 'MPA', (144, 155))	('intra-tumor', 'Disease', 'MESH:D009369', (192, 203))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (65, 86))	('renal cancer', 'Phenotype', 'HP:0009726', (97, 109))	('papillary renal cell carcinomas', 'Disease', (55, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (55, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (55, 85))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (223, 255))	('renal cancer', 'Disease', 'MESH:D007680', (97, 109))
37741	32555180	Large-scale copy number aberrations, often associated with inter-chromosomal translocations, were frequently clonal across all samples from a tumor.	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('copy number aberrations', 'Var', (12, 35))
37742	32555180	In support of this hypothesis, bulk- and single-cell based copy number and sequencing studies of breast and prostate cancers have suggested that complex aneuploid copy number changes may occur in only a few cell divisions at the earliest stages of tumor progression, leading to punctuated evolution.	('copy number changes', 'Var', (163, 182))	('aneuploid', 'Disease', (153, 162))	('tumor', 'Disease', (248, 253))	('breast and prostate cancers', 'Disease', 'MESH:D001943', (97, 124))	('leading to', 'Reg', (267, 277))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('punctuated evolution', 'MPA', (278, 298))	('aneuploid', 'Disease', 'MESH:D000782', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('prostate cancers', 'Phenotype', 'HP:0012125', (108, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
37744	32555180	Thus, our data indicate that papillary renal cell carcinomas initiate through a combination of large clonal SCNAs and mutations in different driver genes, while tumor progression is further promoted by additional SNVs, small scale SCNAs and SVs.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (39, 60))	('papillary renal cell carcinomas', 'Disease', (29, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('mutations', 'Var', (118, 127))	('papillary renal cell carcinomas', 'Disease', 'MESH:C538614', (29, 60))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (29, 59))	('tumor', 'Disease', (161, 166))	('papillary renal cell carcinomas', 'Phenotype', 'HP:0006766', (29, 60))
37749	32555180	Signatures SBS5 and SBS40 accounted for 92.5% of all somatic mutations observed in pRCC.	('pRCC', 'Gene', '5546', (83, 87))	('SBS40', 'Var', (20, 25))	('pRCC', 'Gene', (83, 87))
37750	32555180	High frequency of signature SBS40 has been found in kidney cancer in previous studies, possibly due to the organ's cells constant contact with mutagens during the blood filtration process.	('kidney cancer', 'Phenotype', 'HP:0009726', (52, 65))	('SBS40', 'Gene', (28, 33))	('kidney cancer', 'Disease', 'MESH:D007680', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('kidney cancer', 'Disease', (52, 65))	('signature', 'Var', (18, 27))
37757	32555180	Although based on a limited number of tumors, the observed clonal patterns of both large scale SCNAs and SNVs/indels in driver genes suggest a single tumor biopsy would be sufficient to characterize these changes.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SNVs/indels', 'Var', (105, 116))	('tumor', 'Disease', (150, 155))
37760	32555180	Further therapeutic challenges for the renal cell tumors we studied are provided by the subclonal nature of SVs as well as the low mutation burden and the notable lack of TP53 mutations, both of which may hinder response to immune checkpoint inhibitors.	('TP53', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('renal cell tumors', 'Disease', 'MESH:C538614', (39, 56))	('response to', 'MPA', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('hinder', 'NegReg', (205, 211))	('renal cell tumors', 'Disease', (39, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('TP53', 'Gene', '7157', (171, 175))
37768	32555180	For example, trisomies 7 and 17 are frequent in pRCC1 but can be also found, less frequently, in pRCC2.	('pRCC', 'Gene', '5546', (48, 52))	('pRCC', 'Gene', '5546', (97, 101))	('trisomies', 'Var', (13, 22))	('pRCC', 'Gene', (48, 52))	('pRCC', 'Gene', (97, 101))
37790	32555180	Putative driver mutations were defined if they met one of the following requirements: (i) if the variant was predicted to be deleterious, including stop-gain, frameshift and splicing mutation, and had a SIFT score < 0.05 or a PolyPhen score >0.995 or a CCAD score >0.99; or (ii) If the variant was identified as a recurrent hotspot (statistically significant, http://cancerhotspots.org) or a 3D clustered hotspot (http://3dhotspots.org) in a population-scale cohort of tumor samples of various cancer types using a previously described methodology.	('variant', 'Var', (97, 104))	('frameshift', 'Var', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (469, 474))	('cancer', 'Disease', 'MESH:D009369', (494, 500))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('cancer', 'Disease', (494, 500))	('cancer', 'Disease', (367, 373))	('tumor', 'Phenotype', 'HP:0002664', (469, 474))	('tumor', 'Disease', (469, 474))	('splicing', 'biological_process', 'GO:0045292', ('174', '182'))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))
37806	32555180	The MALAT-TFEB and EWSR1-PATZ1 fusions were validated and confirmed by Sanger sequencing.	('TFEB', 'Gene', '7942', (10, 14))	('PATZ1', 'Gene', (25, 30))	('TFEB', 'Gene', (10, 14))	('EWSR1', 'Gene', (19, 24))	('PATZ1', 'Gene', '23598', (25, 30))	('EWSR1', 'Gene', '2130', (19, 24))	('fusions', 'Var', (31, 38))
37823	31130944	Bioinformatics Analysis Involving Human Carcinomas C1q is the first subcomponent of the classical pathway of the complement system and belongs to the C1q/Tumor Necrosis Factor superfamily.	('Tumor Necrosis Factor', 'molecular_function', 'GO:0005164', ('154', '175'))	('C1q', 'Var', (51, 54))	('Necrosis', 'biological_process', 'GO:0008219', ('160', '168'))	('Tumor Necrosis Factor', 'Disease', (154, 175))	('Human', 'Species', '9606', (34, 39))	('Tumor Necrosis Factor', 'Disease', 'MESH:C536657', (154, 175))	('Necrosis', 'biological_process', 'GO:0019835', ('160', '168'))	('C1q', 'cellular_component', 'GO:0062167', ('150', '153'))	('Carcinomas', 'Disease', (40, 50))	('Carcinomas', 'Disease', 'MESH:D002277', (40, 50))	('Carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('Necrosis', 'biological_process', 'GO:0001906', ('160', '168'))	('Necrosis', 'biological_process', 'GO:0070265', ('160', '168'))	('C1q', 'cellular_component', 'GO:0062167', ('51', '54'))	('Tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Necrosis', 'biological_process', 'GO:0008220', ('160', '168'))
37826	31130944	In the current study, we performed a bioinformatics analysis to investigate whether C1q can serve as a potential prognostic marker for human carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Disease', (141, 150))	('human', 'Species', '9606', (135, 140))	('C1q', 'Var', (84, 87))	('C1q', 'cellular_component', 'GO:0062167', ('84', '87'))
37828	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer for disease-free survival, and in HER2-positive breast cancer for overall survival, while it showed a pro-tumorigenic role of C1q in lung adenocarcinoma, and in clear cell renal cell carcinoma.	('HER2-positive breast cancer', 'Disease', (139, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('tumor', 'Disease', (211, 216))	('high', 'Var', (24, 28))	('C1q', 'cellular_component', 'GO:0062167', ('231', '234'))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (266, 297))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('C1q', 'Var', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 297))	('lung adenocarcinoma', 'Disease', (238, 257))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', (91, 104))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (139, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('clear cell renal cell carcinoma', 'Disease', (266, 297))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (277, 297))	('C1q', 'cellular_component', 'GO:0062167', ('39', '42'))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
37832	31130944	C1q associates with the Ca2+-dependent C1r2-C1s2 tetramer, of about 360 kDa, to form the soluble pentameric C1 complex.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('C1r', 'Gene', '715', (39, 42))	('Ca2+', 'Chemical', 'MESH:D000069285', (24, 28))	('C1r', 'Gene', (39, 42))	('C1s', 'Gene', '716', (44, 47))	('soluble', 'cellular_component', 'GO:0005625', ('89', '96'))	('C1s', 'Gene', (44, 47))	('associates', 'Interaction', (4, 14))
37838	31130944	C1q expressed in the stroma and vascular endothelium of several human malignant tumors acted as a tumor-promoting factor by favoring adhesion, migration and proliferation of cancer cells as well as angiogenesis and metastasis.	('malignant tumors', 'Disease', 'MESH:D018198', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('metastasis', 'CPA', (215, 225))	('angiogenesis', 'biological_process', 'GO:0001525', ('198', '210'))	('tumor', 'Disease', (98, 103))	('adhesion', 'CPA', (133, 141))	('migration', 'CPA', (143, 152))	('proliferation', 'CPA', (157, 170))	('malignant tumors', 'Disease', (70, 86))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('human', 'Species', '9606', (64, 69))	('favoring', 'PosReg', (124, 132))	('angiogenesis', 'CPA', (198, 210))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (174, 180))
37840	31130944	Recently, we demonstrated that C1q is abundantly present in malignant pleural mesothelioma (MPM), where it can combine with hyaluronic acid (HA), which is a principal component of the TME, and enhance the tumor growth by promoting cell adhesion and proliferation.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (60, 90))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (70, 90))	('C1q', 'Var', (31, 34))	('cell adhesion', 'biological_process', 'GO:0007155', ('231', '244'))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('malignant pleural mesothelioma', 'Disease', (60, 90))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (124, 139))	('HA', 'Chemical', 'MESH:D006820', (141, 143))	('promoting', 'PosReg', (221, 230))	('C1q', 'cellular_component', 'GO:0062167', ('31', '34'))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cell adhesion', 'CPA', (231, 244))	('enhance', 'PosReg', (193, 200))	('combine', 'Interaction', (111, 118))
37843	31130944	In the current study, we performed a bioinformatics analysis, using Oncomine database and the survival analysis platforms Kaplan-Meier plotter, in order to investigate whether C1q can serve as a potential prognostic marker for human carcinoma, i.e., tumors of epithelial origin.	('carcinoma', 'Disease', (233, 242))	('C1q', 'Var', (176, 179))	('human', 'Species', '9606', (227, 232))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('C1q', 'cellular_component', 'GO:0062167', ('176', '179'))	('Oncomine', 'Chemical', '-', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
37844	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer (BLBC) and in HER-2 positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('high levels', 'Var', (24, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('C1q', 'cellular_component', 'GO:0062167', ('39', '42'))	('C1q', 'MPA', (39, 42))	('HER-2', 'Gene', '2064', (119, 124))	('HER-2', 'Gene', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
37863	31130944	We only investigated carcinomas in which all the three C1q chains showed a significant prognostic effect by Kaplan-Meier plotter analysis.	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('carcinomas', 'Disease', (21, 31))	('carcinomas', 'Disease', 'MESH:D002277', (21, 31))	('C1q', 'Var', (55, 58))	('C1q', 'cellular_component', 'GO:0062167', ('55', '58'))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
37865	31130944	These data appear to suggest that C1q can have pro- or anti-tumorigenic implications, depending on the carcinoma types (Table 1).	('C1q', 'cellular_component', 'GO:0062167', ('34', '37'))	('carcinoma', 'Disease', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumor', 'Disease', (60, 65))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('C1q', 'Var', (34, 37))
37882	31130944	C1q is present in colon, lung, breast, pancreatic carcinoma, and melanoma.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('lung', 'Disease', (25, 29))	('breast', 'Disease', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('colon', 'Disease', (18, 23))	('pancreatic carcinoma', 'Disease', (39, 59))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (39, 59))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
37883	31130944	C1q can promote adhesion, proliferation and migration of melanoma cells.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('adhesion', 'CPA', (16, 24))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('migration', 'CPA', (44, 53))	('proliferation', 'CPA', (26, 39))	('promote', 'PosReg', (8, 15))
37885	31130944	C1q bound high and low molecular weight HA and acted as a tumor-promoting factor.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('bound', 'Interaction', (4, 9))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('high', 'Protein', (10, 14))	('HA', 'Chemical', 'MESH:D006820', (40, 42))
37886	31130944	In addition, C1q exerted a protective effect against apoptosis, suggesting an overall pro-tumorigenic activity.	('apoptosis', 'CPA', (53, 62))	('protective effect', 'CPA', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('C1q', 'cellular_component', 'GO:0062167', ('13', '16'))	('apoptosis', 'biological_process', 'GO:0097194', ('53', '62'))	('apoptosis', 'biological_process', 'GO:0006915', ('53', '62'))	('C1q', 'Var', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
37888	31130944	C1q was able to induce apoptosis and growth suppression of human prostate DU145 cells, through direct activation of the tumor suppressor WW-domain containing oxidoreductase (WOX1).	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('human', 'Species', '9606', (59, 64))	('C1q', 'Var', (0, 3))	('tumor suppressor', 'biological_process', 'GO:0051726', ('120', '136'))	('DU145', 'CellLine', 'CVCL:0105', (74, 79))	('apoptosis', 'CPA', (23, 32))	('WOX1', 'Gene', (174, 178))	('WW-domain containing oxidoreductase', 'Gene', (137, 172))	('apoptosis', 'biological_process', 'GO:0097194', ('23', '32'))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('120', '136'))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('activation', 'PosReg', (102, 112))	('apoptosis', 'biological_process', 'GO:0006915', ('23', '32'))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('growth suppression', 'CPA', (37, 55))	('WW-domain containing oxidoreductase', 'Gene', '51741', (137, 172))	('tumor', 'Disease', (120, 125))	('WOX1', 'Gene', '51741', (174, 178))
37889	31130944	C1q also have a pro-apoptotic effect on an ovarian cell line, SKOV3, acting via a TNF-alpha induced apoptosis pathway that involves upregulation of Bax and Fas.	('Bax', 'Gene', (148, 151))	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('apoptosis pathway', 'Pathway', (100, 117))	('C1q', 'Var', (0, 3))	('Fas', 'Protein', (156, 159))	('upregulation', 'PosReg', (132, 144))	('apoptosis', 'biological_process', 'GO:0097194', ('100', '109'))	('TNF-alpha', 'Gene', '7124', (82, 91))	('Bax', 'Gene', '581', (148, 151))	('apoptosis', 'biological_process', 'GO:0006915', ('100', '109'))	('TNF-alpha', 'Gene', (82, 91))	('SKOV3', 'CellLine', 'CVCL:0532', (62, 67))
37894	31130944	We selected the carcinomas that showed all the three chains of human C1q statistically significant for the prognosis; in several cases, the prognosis was differentially linked to the C1q chains, or limited to one or two C1q chains.	('human', 'Species', '9606', (63, 68))	('linked', 'Reg', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('C1q', 'cellular_component', 'GO:0062167', ('183', '186'))	('carcinomas', 'Disease', (16, 26))	('carcinomas', 'Disease', 'MESH:D002277', (16, 26))	('C1q', 'cellular_component', 'GO:0062167', ('220', '223'))	('C1q', 'cellular_component', 'GO:0062167', ('69', '72'))	('C1q chains', 'Var', (183, 193))
37897	31130944	Our bioinformatics analysis highlighted that high levels of C1q have a favorable prognostic index in BLBCs for DFS and HER2+ breast cancer for OS, (Graphical Abstract) consistent with the in vivo studies by Bandini et al.	('BLBCs', 'Disease', (101, 106))	('HER2+', 'Var', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('C1q', 'cellular_component', 'GO:0062167', ('60', '63'))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('high', 'Var', (45, 49))	('C1q', 'Var', (60, 63))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('OS', 'Chemical', '-', (143, 145))
37900	31130944	One possible explanation for the observed positive association between C1q expression and favorable prognostic index could be due to the correlation between the presence of C1q and dendritic cells (CD11c positive cells) in TME.	('CD11c', 'Gene', (198, 203))	('C1q', 'Gene', (173, 176))	('C1q', 'cellular_component', 'GO:0062167', ('173', '176'))	('C1q', 'Gene', (71, 74))	('C1q', 'cellular_component', 'GO:0062167', ('71', '74'))	('presence', 'Var', (161, 169))	('CD11c', 'Gene', '3687', (198, 203))
37901	31130944	High CD11c expression in BLBCs is associated with a significantly higher OS (p = 0.047) as compared to low CD11c expression.	('CD11c', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (73, 75))	('CD11c', 'Gene', (107, 112))	('CD11c', 'Gene', '3687', (107, 112))	('higher', 'PosReg', (66, 72))	('CD11c', 'Gene', '3687', (5, 10))
37905	31130944	The analysis of publicly available data sets revealed that the genes encoding for the C1q chains were associated with a poor prognosis in BLBC using the TCGA dataset (504 patients).	('C1q', 'cellular_component', 'GO:0062167', ('86', '89'))	('C1q', 'Var', (86, 89))	('BLBC', 'Disease', (138, 142))	('patients', 'Species', '9606', (171, 179))
37910	31130944	The expression of C1q in kidney cancer is increased as compared to normal kidney tissue (Figure 3A) and C1q has a negative prognostic effect in the case of CCRCC (Figure 3B); no association was evident for PRCC.	('increased', 'PosReg', (42, 51))	('PRCC', 'Gene', '5546', (206, 210))	('CCRCC', 'Phenotype', 'HP:0006770', (156, 161))	('kidney cancer', 'Disease', 'MESH:D007680', (25, 38))	('C1q', 'Var', (104, 107))	('C1q', 'Gene', (18, 21))	('PRCC', 'Gene', (206, 210))	('kidney cancer', 'Phenotype', 'HP:0009726', (25, 38))	('C1q', 'cellular_component', 'GO:0062167', ('104', '107'))	('expression', 'MPA', (4, 14))	('C1q', 'cellular_component', 'GO:0062167', ('18', '21'))	('negative', 'NegReg', (114, 122))	('kidney cancer', 'Disease', (25, 38))	('PRCC', 'Phenotype', 'HP:0006766', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCRCC', 'Disease', (156, 161))
37913	31130944	We can hypothesize that C1q can also participate in promoting angiogenic processes in this particular tumor.	('promoting', 'PosReg', (52, 61))	('C1q', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('C1q', 'cellular_component', 'GO:0062167', ('24', '27'))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('angiogenic processes', 'CPA', (62, 82))
37914	31130944	C1q has a negative prognostic value in lung tumors limited to adenocarcinomas, the most common form of lung cancer (Figure 3D).	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('C1q', 'Var', (0, 3))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung tumors', 'Disease', (39, 50))	('adenocarcinomas', 'Disease', (62, 77))	('lung tumors', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('lung cancer', 'Disease', (103, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung tumors', 'Disease', 'MESH:D008175', (39, 50))
37918	31130944	C1q interaction with the ECM components can adversely interrupt its putative functions, as is the case with HA.	('C1q', 'cellular_component', 'GO:0062167', ('0', '3'))	('C1q', 'Var', (0, 3))	('interaction', 'Interaction', (4, 15))	('ECM', 'Gene', '22915', (25, 28))	('HA', 'Chemical', 'MESH:D006820', (108, 110))	('ECM', 'Gene', (25, 28))	('putative functions', 'MPA', (68, 86))	('interrupt', 'NegReg', (54, 63))
37947	32102400	Regarding molecular analyses, the issue remains incomplete when considering VHL gene malfunctions as the hallmark of CCRCC, and the trisomy of chromosomes 7 and 17 as the signature for PRCC.	('VHL', 'Gene', (76, 79))	('VHL', 'Gene', '7428', (76, 79))	('PRCC', 'Disease', 'MESH:C538614', (185, 189))	('CCRCC', 'Disease', (117, 122))	('trisomy', 'Var', (132, 139))	('CCRCC', 'Phenotype', 'HP:0006770', (117, 122))	('PRCC', 'Phenotype', 'HP:0006766', (185, 189))	('CCRCC', 'Disease', 'MESH:C538614', (117, 122))	('malfunctions', 'Var', (85, 97))	('PRCC', 'Disease', (185, 189))
37978	33628782	Generally, tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intrapatient heterogeneity, and the subpopulation of cancer cells with distinct phenotypic and molecular features within a tumor is regarded as intratumor heterogeneity.	('patient', 'Species', '9606', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumor', 'Disease', (43, 48))	('cancer', 'Disease', (271, 277))	('variations', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('patient', 'Species', '9606', (223, 230))	('patient', 'Species', '9606', (94, 101))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Disease', (367, 372))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', (43, 49))	('patient', 'Species', '9606', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
38028	33628782	The dysregulation of m6A regulators can affect cell proliferation, cell self-renewal and differentiation capacity, control of heat shock response, DNA damage response, tissue development, cell death, and development of multiple forms of human diseases, including cancer.	('death', 'Disease', (193, 198))	('cancer', 'Disease', (263, 269))	('dysregulation', 'Var', (4, 17))	('DNA', 'cellular_component', 'GO:0005574', ('147', '150'))	('DNA damage response', 'biological_process', 'GO:0006974', ('147', '166'))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cell proliferation', 'biological_process', 'GO:0008283', ('47', '65'))	('cell self-renewal', 'CPA', (67, 84))	('tissue development', 'CPA', (168, 186))	('m6A', 'Gene', '56339', (21, 24))	('cell death', 'biological_process', 'GO:0008219', ('188', '198'))	('m6A', 'Gene', (21, 24))	('cell proliferation', 'CPA', (47, 65))	('death', 'Disease', 'MESH:D003643', (193, 198))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('human', 'Species', '9606', (237, 242))	('differentiation capacity', 'CPA', (89, 113))	('shock', 'Phenotype', 'HP:0031273', (131, 136))	('tissue development', 'biological_process', 'GO:0009888', ('168', '186'))	('affect', 'Reg', (40, 46))
38049	33628782	HNRNPC was highly expressed in bladder cancer, and the HNRNPC knockdown reduced the proliferation of breast cancer cells.	('reduced', 'NegReg', (72, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (31, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('HNRNPC', 'Gene', '3183', (0, 6))	('HNRNPC', 'Gene', (55, 61))	('knockdown', 'Var', (62, 71))	('proliferation', 'CPA', (84, 97))	('HNRNPC', 'Gene', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', (101, 114))	('HNRNPC', 'Gene', '3183', (55, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (31, 45))	('bladder cancer', 'Disease', (31, 45))
38051	33628782	Therefore, modulating m6A RNA methylation modifications might be a novel strategy to guide the targeted therapy for pRCC patients.	('RNA', 'cellular_component', 'GO:0005562', ('26', '29'))	('pRCC', 'Gene', (116, 120))	('m6A', 'Gene', (22, 25))	('RNA methylation', 'biological_process', 'GO:0001510', ('26', '41'))	('m6A', 'Gene', '56339', (22, 25))	('pRCC', 'Phenotype', 'HP:0006766', (116, 120))	('pRCC', 'Gene', '5546', (116, 120))	('modulating', 'Var', (11, 21))	('patients', 'Species', '9606', (121, 129))
38090	29963177	Commonly accepted BMI ranges in Chinese people are normal weight (18.5-23.9 kg/m2), overweight (24-27.9 kg/m2) and obesity (over 28 kg/m2).	('obesity', 'Disease', (115, 122))	('over 28', 'Var', (124, 131))	('overweight', 'Disease', (84, 94))	('obesity', 'Phenotype', 'HP:0001513', (115, 122))	('people', 'Species', '9606', (40, 46))	('24-27.9', 'Var', (96, 103))	('obesity', 'Disease', 'MESH:D009765', (115, 122))	('overweight', 'Phenotype', 'HP:0025502', (84, 94))
38096	29963177	The immunohistochemistry results (CK7, C10, AMACR, CA IX and RCC maker) were interpreted as negative, weak (<30% staining), moderate (30-70% staining) and strong (>70% staining).	('C10', 'Gene', '3226', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))	('30-70', 'Var', (134, 139))	('AMACR', 'Gene', '23600', (44, 49))	('AMACR', 'Gene', (44, 49))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('CK7', 'Gene', (34, 37))	('C10', 'Gene', (39, 42))	('RCC', 'Disease', (61, 64))	('CA IX', 'Gene', '768', (51, 56))	('CK7', 'Gene', '3855', (34, 37))	('CA IX', 'Gene', (51, 56))
38142	29963177	2I, 3B and D. According to the results of Ki67 LI, the expression of Ki67 in CCPRCC was much lower than that in CCRCC (2.19 vs. 7.07%, P<0.001; Fig.	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('PRCC', 'Gene', '5546', (79, 83))	('RCC', 'Disease', (114, 117))	('RCC', 'Phenotype', 'HP:0005584', (114, 117))	('CCRCC', 'Phenotype', 'HP:0006770', (112, 117))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('expression', 'MPA', (55, 65))	('Ki67', 'Var', (69, 73))	('lower', 'NegReg', (93, 98))	('PRCC', 'Gene', (79, 83))	('CCPRCC', 'Phenotype', 'HP:0006770', (77, 83))	('PRCC', 'Phenotype', 'HP:0006766', (79, 83))
38144	29963177	However, although the expression of Ki67 in CCRCC was still higher than that in PRCC (7.07 vs. 6.65%, P=0.848; Fig.	('CCRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('higher', 'PosReg', (60, 66))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('PRCC', 'Gene', '5546', (80, 84))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('RCC', 'Disease', (81, 84))	('PRCC', 'Gene', (80, 84))	('Ki67', 'Var', (36, 40))	('PRCC', 'Phenotype', 'HP:0006766', (80, 84))	('expression', 'MPA', (22, 32))
38186	29963177	Coincidentally, previous studies have documented that most of CCRCC have VHL gene mutations, which can also lead to overexpression of HIF pathway associated proteins, whereas CCPRCC lack these characteristic chromosomal abnormalities.	('VHL', 'Gene', '7428', (73, 76))	('overexpression', 'PosReg', (116, 130))	('CCRCC', 'Phenotype', 'HP:0006770', (62, 67))	('lead to', 'Reg', (108, 115))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('PRCC', 'Gene', '5546', (177, 181))	('HIF pathway', 'Pathway', (134, 145))	('chromosomal abnormalities', 'Disease', (208, 233))	('men', 'Species', '9606', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('RCC', 'Disease', (64, 67))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (208, 233))	('PRCC', 'Gene', (177, 181))	('VHL', 'Gene', (73, 76))	('PRCC', 'Phenotype', 'HP:0006766', (177, 181))	('mutations', 'Var', (82, 91))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('proteins', 'Protein', (157, 165))	('CCPRCC', 'Phenotype', 'HP:0006770', (175, 181))
38203	29963177	Many studies have indicated that Ki67 is a prognostic marker in several neoplasms, including kidney cancer.	('kidney cancer', 'Disease', 'MESH:D007680', (93, 106))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('neoplasms', 'Disease', (72, 81))	('kidney cancer', 'Phenotype', 'HP:0009726', (93, 106))	('neoplasm', 'Phenotype', 'HP:0002664', (72, 80))	('kidney cancer', 'Disease', (93, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))	('Ki67', 'Var', (33, 37))
38204	29963177	In this study, the Ki67 LI is significantly lower than that in CCRCC (P<0.001) or that in PRCC (P<0.001).	('RCC', 'Phenotype', 'HP:0005584', (65, 68))	('lower', 'NegReg', (44, 49))	('PRCC', 'Phenotype', 'HP:0006766', (90, 94))	('CCRCC', 'Phenotype', 'HP:0006770', (63, 68))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('PRCC', 'Gene', '5546', (90, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('Ki67 LI', 'Var', (19, 26))	('PRCC', 'Gene', (90, 94))	('RCC', 'Disease', 'MESH:C538614', (65, 68))	('RCC', 'Disease', (65, 68))
38259	31747386	We further revealed the differential landscape of somatic tumor mutation burden (TMB) between two nomogram-score groups and observed that TMB was also a prognostic biomarker; patients with high MAGs-nomogram scores suffered from a higher TMB, potentially leading to worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TMB', 'MPA', (238, 241))	('higher', 'PosReg', (231, 237))	('TMB', 'Chemical', '-', (138, 141))	('MAGs', 'Chemical', '-', (194, 198))	('high', 'Var', (189, 193))	('TMB', 'Chemical', '-', (238, 241))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TMB', 'Chemical', '-', (81, 84))
38270	31747386	Intensive studies have been conducted to identify numerous biomarkers associated with the survival of ccRCC for predicting prognosis, including mutated drivers, cancer-related noncoding RNA, risk methylated loci, and immune signatures in the tumor microenvironment.	('mutated', 'Var', (144, 151))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('ccRCC', 'Phenotype', 'HP:0006770', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('RNA', 'cellular_component', 'GO:0005562', ('186', '189'))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (242, 247))	('cancer', 'Disease', (161, 167))	('RCC', 'Disease', (104, 107))
38275	31747386	successfully utilized single-cell exome sequencing and found that KCP, LOC440040, and LOC440563 mutations are novel renal cancer stem cell drivers.	('KCP', 'Gene', '375616', (66, 69))	('renal cancer', 'Phenotype', 'HP:0009726', (116, 128))	('cancer', 'Disease', (122, 128))	('LOC440040', 'Gene', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('LOC440563 mutations', 'Var', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('LOC440040', 'Gene', '440040', (71, 80))	('KCP', 'Gene', (66, 69))
38288	31747386	In addition, Kaplan-Meier analysis indicated that patients with high MAG scores suffered significantly worse OS outcomes (P = 2.904e-08), which was validated consistently in the testing cohort with P = 1.031e-10.	('MAG scores', 'Gene', (69, 79))	('high', 'Var', (64, 68))	('MAG', 'Chemical', '-', (69, 72))	('patients', 'Species', '9606', (50, 58))	('worse', 'NegReg', (103, 108))
38289	31747386	Overall, we further integrated the MAG signature with survival analysis in the total TCGA-KIRC cohort, and distribution plots suggested that high MAG risk scores correlated with more cases of death or recurrence/ progression (Figure 3G, 3H and 3I).	('MAG', 'Chemical', '-', (35, 38))	('death', 'Disease', 'MESH:D003643', (192, 197))	('death', 'Disease', (192, 197))	('MAG', 'Chemical', '-', (146, 149))	('recurrence/', 'CPA', (201, 212))	('high', 'Var', (141, 145))	('MAG', 'Gene', (146, 149))
38292	31747386	Moreover, the MAG signature possessed superior significance in predicting 5-year PFS with an AUC of 0.752 in the total TCGA-KIRC cohort (Figure 4F), and patients with high MAG scores were proven to have greater hazards regarding tumor recurrence or progression with a log-rank test P = 0 (Figure 4G).	('progression', 'CPA', (249, 260))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('MAG', 'Chemical', '-', (172, 175))	('patients', 'Species', '9606', (153, 161))	('MAG', 'Chemical', '-', (14, 17))	('high', 'Var', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PFS', 'Disease', (81, 84))	('tumor', 'Disease', (229, 234))
38301	31747386	In addition, we calculated the differential mutation rate of mutants distributed in more than 5% of the samples, and the chi-square test revealed that SETD2, BAP1 and MTOR especially harbored more mutants in the high-risk group than in the low-risk group (Figure 6A).	('BAP1', 'Gene', '8314', (158, 162))	('BAP1', 'Gene', (158, 162))	('mutants', 'Var', (197, 204))	('MTOR', 'Gene', (167, 171))	('SETD2', 'Gene', '29072', (151, 156))	('harbored', 'Reg', (183, 191))	('MTOR', 'Gene', '2475', (167, 171))	('SETD2', 'Gene', (151, 156))
38302	31747386	Additionally, the Wilcoxon rank-sum test suggested that the MAG nomogram risk scores were significantly higher in the high TMB group than in the low TMB group (P = 2.875e-05).	('high', 'Var', (118, 122))	('TMB', 'Chemical', '-', (149, 152))	('MAG nomogram', 'Gene', (60, 72))	('MAG', 'Chemical', '-', (60, 63))	('higher', 'PosReg', (104, 110))	('TMB', 'Chemical', '-', (123, 126))
38304	31747386	We accordingly speculated that ccRCC patients with high MAG nomogram scores suffered from higher TMB levels which was also proven to be a risk factor in ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (153, 158))	('RCC', 'Disease', (155, 158))	('patients', 'Species', '9606', (37, 45))	('TMB', 'Chemical', '-', (97, 100))	('MAG', 'Chemical', '-', (56, 59))	('RCC', 'Disease', (33, 36))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('high', 'Var', (51, 55))	('ccRCC', 'Phenotype', 'HP:0006770', (31, 36))	('TMB levels', 'MPA', (97, 107))	('higher', 'PosReg', (90, 96))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
38306	31747386	We observed that oxidative phosphorylation, the Wnt signaling pathway, the MAPK signaling pathway and renal cell carcinoma crosstalk were upregulated in the high-risk group.	('signaling pathway', 'biological_process', 'GO:0007165', ('80', '97'))	('MAPK signaling', 'biological_process', 'GO:0000165', ('75', '89'))	('MAPK', 'molecular_function', 'GO:0004707', ('75', '79'))	('oxidative phosphorylation', 'MPA', (17, 42))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('48', '69'))	('high-risk', 'Var', (157, 166))	('Wnt signaling pathway', 'Pathway', (48, 69))	('MAPK signaling pathway', 'Pathway', (75, 97))	('renal cell carcinoma crosstalk', 'Disease', (102, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('upregulated', 'PosReg', (138, 149))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('17', '42'))	('renal cell carcinoma crosstalk', 'Disease', 'MESH:C538614', (102, 132))
38322	31747386	performed genome-wide association studies and identified the RCC risk allele at 12p12.1, a hazard variant in an enhancer that upregulates the expression of BHLHE41, in turn inducing IL-11 to promote tumor growth.	('tumor', 'Disease', (199, 204))	('BHLHE41', 'Gene', '79365', (156, 163))	('IL-11', 'Gene', (182, 187))	('variant', 'Var', (98, 105))	('IL-11', 'Gene', '3589', (182, 187))	('inducing', 'PosReg', (173, 181))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('expression', 'MPA', (142, 152))	('BHLHE41', 'Gene', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('upregulates', 'PosReg', (126, 137))	('promote', 'PosReg', (191, 198))	('IL-11', 'molecular_function', 'GO:0005142', ('182', '187'))
38328	31747386	For population validation, we utilized another ICGC cohort as the external data set to further test our MAG signature and found the clinical value of MAGs in predicting OS or PFS.	('MAG', 'Chemical', '-', (104, 107))	('MAGs', 'Chemical', '-', (150, 154))	('MAGs', 'Var', (150, 154))	('MAG', 'Chemical', '-', (150, 153))	('PFS', 'Disease', (175, 178))
38332	31747386	We accordingly speculated that the four tumor-driver mutants might promote the progression of ccRCC and that a high TMB was also proven to be a potential risk factor associated with MAGs.	('RCC', 'Disease', (96, 99))	('TMB', 'Chemical', '-', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutants', 'Var', (53, 60))	('ccRCC', 'Phenotype', 'HP:0006770', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('MAGs', 'Chemical', '-', (182, 186))	('RCC', 'Disease', 'MESH:C538614', (96, 99))	('promote', 'PosReg', (67, 74))
38333	31747386	TMB or mutational signatures revealed the process of mutation accumulation in tumors and were demonstrated to be effective predictors of the response to immunotherapy.	('revealed', 'Reg', (29, 37))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutation', 'Var', (53, 61))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
38359	31747386	We wrote a Perl script to extract all mutation data from 337 patients in the TCGA-KIRC cohort consisting of deletions, insertions, and substitutions across bases and divided the data into two groups according to the MAG nomogram risk scores.	('insertions', 'Var', (119, 129))	('MAG', 'Chemical', '-', (216, 219))	('substitutions', 'Var', (135, 148))	('patients', 'Species', '9606', (61, 69))	('deletions', 'Var', (108, 117))
38367	29617669	Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes.	('DNA', 'cellular_component', 'GO:0005574', ('163', '166'))	('altered', 'Reg', (48, 55))	('metabolic pathways', 'Pathway', (56, 74))	('survival', 'MPA', (118, 126))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('163', '183'))	('gene expression', 'biological_process', 'GO:0010467', ('225', '240'))	('CDKN2A', 'Gene', (134, 140))	('increased', 'PosReg', (153, 162))	('PBRM1', 'Gene', '55193', (28, 33))	('survival', 'MPA', (277, 285))	('decreased', 'NegReg', (267, 276))	('DNA', 'MPA', (163, 166))	('BAP1', 'Gene', (22, 26))	('alteration', 'Var', (8, 18))	('increases', 'PosReg', (189, 198))	('PBRM1', 'Gene', (28, 33))	('decreased', 'NegReg', (108, 117))	('PTEN', 'Gene', (39, 43))	('alteration', 'Var', (141, 151))
38369	29617669	Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes.	('alteration', 'Var', (8, 18))	('DNA', 'cellular_component', 'GO:0005574', ('136', '139'))	('survival', 'MPA', (101, 109))	('PBRM1', 'Gene', (28, 33))	('hypermethylation', 'Var', (140, 156))	('metabolic pathways', 'Pathway', (39, 57))	('DNA hypermethylation', 'biological_process', 'GO:0044026', ('136', '156'))	('PBRM1', 'Gene', '55193', (28, 33))	('CDKN2A', 'Gene', (117, 123))	('alteration', 'Var', (124, 134))	('decreased', 'NegReg', (198, 207))	('decreased', 'NegReg', (91, 100))	('BAP1', 'Gene', (22, 26))
38384	29617669	Similarly, PBRM1 mutation, which has been shown to not correlate with survival in ccRCC, was found to correlate with decreased survival in PRCC (p = 0.0008) that was specific to type 1 PRCC (p < 0.0001) (Figures 2A and S2B).	('PRCC', 'Disease', (139, 143))	('decreased', 'NegReg', (117, 126))	('mutation', 'Var', (17, 25))	('PBRM1', 'Gene', (11, 16))	('PBRM1', 'Gene', '55193', (11, 16))	('survival', 'MPA', (127, 135))
38385	29617669	CDKN2A mutation, hypermethylation, or deletion was found in 15.8% of tumors, with alterations in each RCC subtype accounting for 16.2% of ccRCC, 5.0% of type 1 PRCC, 18.6% of type 2 PRCC, 100% of CIMP-PRCC, and 19.8% of ChRCC (Figure 2B).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('hypermethylation', 'Var', (17, 33))	('CIMP-PRCC', 'Disease', (196, 205))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('CIMP', 'Chemical', '-', (196, 200))	('tumors', 'Disease', (69, 75))	('mutation', 'Var', (7, 15))	('alterations', 'Var', (82, 93))	('CDKN2A', 'Gene', (0, 6))	('ccRCC', 'Disease', (138, 143))	('type 2 PRCC', 'Disease', (175, 186))	('deletion', 'Var', (38, 46))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('ChRCC', 'Disease', (220, 225))	('found', 'Reg', (51, 56))
38387	29617669	Pathogenic SMG mutations were not detected in several tumors, particularly PRCC and ChRCC.	('ChRCC', 'Disease', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (15, 24))	('PRCC', 'Disease', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SMG', 'Gene', (11, 14))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
38388	29617669	In the VHL/HIF pathway, TCEB1 and CUL2 mutations in ccRCC were mutually exclusive with VHL mutation (Figure S2D).	('CUL2', 'Gene', '8453', (34, 38))	('ccRCC', 'Gene', (52, 57))	('VHL', 'Disease', 'MESH:D006623', (7, 10))	('VHL', 'Disease', (7, 10))	('TCEB1', 'Gene', (24, 29))	('mutations', 'Var', (39, 48))	('VHL', 'Disease', 'MESH:D006623', (87, 90))	('VHL', 'Disease', (87, 90))	('CUL2', 'Gene', (34, 38))
38389	29617669	Mutations of SWI/SNF complex genes, including PBRM1, ARID1A, and SMARCA4, were the most common chromatin remodeling complex alterations within ccRCC (47.1%), followed by mutation of the histone methyltransferases including SETD2 and MLL3 (23.8%), the histone demethylases including KDM5C (13.0%), the BAP1/ASXL1 histone de-ubiquitinase complex (12.1%), and the histone acetyltransferases (4.8%), compared with frequencies of 24.1%, 23.7%, 17.3%, 6.8%, and 7.5%, respectively, in PRCCs (Figure 2D).	('SWI/SNF complex', 'cellular_component', 'GO:0016514', ('13', '28'))	('MLL3', 'Gene', '58508', (233, 237))	('chromatin remodeling complex', 'cellular_component', 'GO:0016585', ('95', '123'))	('ASXL1', 'Gene', (306, 311))	('alterations', 'Var', (124, 135))	('SMARCA4', 'Gene', (65, 72))	('chromatin remodeling', 'biological_process', 'GO:0006338', ('95', '115'))	('Mutations', 'Var', (0, 9))	('SWI/SNF complex genes', 'Gene', (13, 34))	('MLL3', 'Gene', (233, 237))	('PBRM1', 'Gene', (46, 51))	('SETD2', 'Gene', '29072', (223, 228))	('SETD2', 'Gene', (223, 228))	('ASXL1', 'Gene', '171023', (306, 311))	('PBRM1', 'Gene', '55193', (46, 51))	('mutation', 'Var', (170, 178))
38395	29617669	Increased hypermethylation was associated with higher-stage disease in ccRCC, PRCC (with or without CIMP), and ChRCC (all p < 0.0001) and was associated with SETD2 mutation in ccRCC (p < 0.0001), either PBRM1 mutation or SETD2 mutation in type 2 PRCC (p = 0.0053, p = 0.0270, respectively), and TP53 mutation in ChRCC (p = 0.0119) (Figure S3B).	('higher-stage disease', 'Disease', (47, 67))	('mutation', 'Var', (164, 172))	('mutation', 'Var', (227, 235))	('CIMP', 'Chemical', '-', (100, 104))	('ccRCC', 'Disease', (71, 76))	('mutation', 'Var', (209, 217))	('associated', 'Reg', (142, 152))	('SETD2', 'Gene', (221, 226))	('associated with', 'Reg', (31, 46))	('Increased', 'PosReg', (0, 9))	('PBRM1', 'Gene', '55193', (203, 208))	('hypermethylation', 'MPA', (10, 26))	('SETD2', 'Gene', (158, 163))	('SETD2', 'Gene', '29072', (221, 226))	('TP53', 'Gene', (295, 299))	('PRCC', 'Disease', (78, 82))	('SETD2', 'Gene', '29072', (158, 163))	('PBRM1', 'Gene', (203, 208))	('mutation', 'Var', (300, 308))
38396	29617669	Previous studies have identified hypermethylation of the WNT pathway regulatory genes, SFRP1 and DKK1, in ccRCC.	('SFRP1', 'Gene', (87, 92))	('ccRCC', 'Disease', (106, 111))	('hypermethylation', 'Var', (33, 49))	('DKK1', 'Gene', '22943', (97, 101))	('DKK1', 'Gene', (97, 101))
38397	29617669	Increased methylation of probes for these two genes (DKK1, cg07684796; SFRP1, cg15839448) was observed in the methylated cluster 1 samples (Figure S3C), and hypermethylation of either of these genes correlated with poorer survival in ccRCC, PRCC, and ChRCC (p = 0.0015, p < 0.0001, and p = 0.0021, respectively) and in PRCC excluding the CIMP-RCC tumors (p = 0.0035) (Figures 3C and S3D).	('PRCC', 'Disease', (241, 245))	('DKK1', 'Gene', (53, 57))	('DKK1', 'Gene', '22943', (53, 57))	('methylation', 'MPA', (10, 21))	('cg07684796', 'Chemical', '-', (59, 69))	('CIMP-RCC tumors', 'Disease', 'MESH:C538614', (338, 353))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('cg15839448', 'Chemical', '-', (78, 88))	('CIMP-RCC tumors', 'Disease', (338, 353))	('survival', 'MPA', (222, 230))	('Increased', 'PosReg', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('ccRCC', 'Disease', (234, 239))	('ChRCC', 'Disease', (251, 256))	('hypermethylation', 'Var', (157, 173))	('methylation', 'biological_process', 'GO:0032259', ('10', '21'))	('poorer', 'NegReg', (215, 221))
38413	29617669	In the present study, comprehensive genetic and genomic analysis demonstrated that different histologically defined RCC subtypes are characterized by distinctive mutations, chromosomal copy number alterations, and expression patterns of mRNA, miRNA, and lncRNA, and that the combination of histology plus genomics provides unique insight into patient-centered management.	('mutations', 'Var', (162, 171))	('patient', 'Species', '9606', (343, 350))	('miRNA', 'MPA', (243, 248))	('lncRNA', 'Protein', (254, 260))	('alterations', 'Var', (197, 208))	('RCC', 'Disease', (116, 119))	('expression', 'MPA', (214, 224))	('mRNA', 'MPA', (237, 241))
38415	29617669	Loss of CDKN2A is known to correlate with poor outcome in ccRCC, PRCC, and other cancer types, but this demonstrates that it is a universal feature of RCC and is potentially targetable with CDK4/6 inhibitors that target the downstream effects of p16 loss.	('CDKN2A', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('ccRCC', 'Disease', (58, 63))	('PRCC', 'Disease', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Loss', 'Var', (0, 4))	('CDK', 'molecular_function', 'GO:0004693', ('190', '193'))
38416	29617669	This study highlighted hypermethylation of WNT pathway regulatory genes and demonstrated that analysis of hypermethylation in two specific WNT regulatory genes, SFRP1 and DKK1, recapitulated the correlation with decreased survival in ccRCC, PRCC, and ChRCC.	('decreased', 'NegReg', (212, 221))	('survival', 'CPA', (222, 230))	('PRCC', 'Disease', (241, 245))	('SFRP1', 'Gene', (161, 166))	('DKK1', 'Gene', '22943', (171, 175))	('DKK1', 'Gene', (171, 175))	('ccRCC', 'Disease', (234, 239))	('ChRCC', 'Disease', (251, 256))	('hypermethylation', 'Var', (23, 39))	('hypermethylation', 'Var', (106, 122))
38417	29617669	Increased DNA methylation was associated with SETD2 mutation, which is known to alter DNA methylation patterns, in ccRCC and PRCC, and increased DNA methylation was similarly associated with PBRM1 mutation in PRCC.	('SETD2', 'Gene', (46, 51))	('PBRM1', 'Gene', (191, 196))	('PBRM1', 'Gene', '55193', (191, 196))	('DNA', 'cellular_component', 'GO:0005574', ('145', '148'))	('DNA methylation', 'biological_process', 'GO:0006306', ('10', '25'))	('SETD2', 'Gene', '29072', (46, 51))	('DNA', 'cellular_component', 'GO:0005574', ('10', '13'))	('Increased', 'PosReg', (0, 9))	('DNA methylation', 'MPA', (10, 25))	('mutation', 'Var', (52, 60))	('DNA', 'cellular_component', 'GO:0005574', ('86', '89'))	('DNA methylation', 'biological_process', 'GO:0006306', ('86', '101'))	('alter', 'Reg', (80, 85))	('DNA methylation', 'biological_process', 'GO:0006306', ('145', '160'))	('ccRCC', 'Disease', (115, 120))
38418	29617669	Hypermethylation of SFRP1 and DKK1 could provide a prognostic biomarker for RCC and has been previously proposed in ccRCC.	('SFRP1', 'Gene', (20, 25))	('RCC', 'Disease', (76, 79))	('Hypermethylation', 'Var', (0, 16))	('ccRCC', 'Disease', (116, 121))	('DKK1', 'Gene', (30, 34))	('DKK1', 'Gene', '22943', (30, 34))
38420	29617669	Previous studies using TCGA data and other cohorts have shown that BAP1 mutation, but not PBRM1 mutation, correlates with poor survival in ccRCC and these correlations were confirmed in a mixed cohort of ccRCC and PRCC TCGA tumors.	('ccRCC', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('PRCC', 'Disease', (214, 218))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('poor', 'NegReg', (122, 126))	('mutation', 'Var', (72, 80))	('PBRM1', 'Gene', (90, 95))	('ccRCC', 'Disease', (204, 209))	('PBRM1', 'Gene', '55193', (90, 95))	('BAP1', 'Gene', (67, 71))
38421	29617669	By analysis of the histologic subtype of RCC, we confirmed these correlations in ccRCC and showed that while BAP1 mutations did not correlate with survival in PRCC, PBRM1 mutations did associate with poor survival in type 1 PRCC.	('poor', 'NegReg', (200, 204))	('ccRCC', 'Disease', (81, 86))	('mutations', 'Var', (114, 123))	('PBRM1', 'Gene', (165, 170))	('type 1 PRCC', 'Disease', (217, 228))	('PBRM1', 'Gene', '55193', (165, 170))	('mutations', 'Var', (171, 180))	('BAP1', 'Gene', (109, 113))
38427	29617669	While we observed the same general pattern as previously seen with PRCC overall demonstrating little expression of the immune signature associated with ccRCC, we found CIMP-RCC to have an increased immune signature expression for select immune gene signatures, including the Th2 gene signature, like that seen in ccRCC.	('immune gene signatures', 'MPA', (237, 259))	('CIMP', 'Chemical', '-', (168, 172))	('Th2 gene', 'Gene', (275, 283))	('ccRCC', 'Disease', (152, 157))	('immune signature expression', 'MPA', (198, 225))	('CIMP-RCC', 'Var', (168, 176))	('increased', 'PosReg', (188, 197))
38431	29617669	The MD-ChRCC had decreased Krebs cycle, ETC, and AMPK gene expression and increased ribose metabolism gene expression similar to higher-stage ccRCCs.	('gene expression', 'biological_process', 'GO:0010467', ('102', '117'))	('MD-ChRCC', 'Var', (4, 12))	('AMPK', 'MPA', (49, 53))	('decreased', 'NegReg', (17, 26))	('AMPK', 'molecular_function', 'GO:0047322', ('49', '53'))	('ribose metabolism gene expression', 'MPA', (84, 117))	('Krebs cycle', 'MPA', (27, 38))	('increased', 'PosReg', (74, 83))	('Krebs', 'Chemical', '-', (27, 32))	('Krebs cycle', 'biological_process', 'GO:0006099', ('27', '38'))	('AMPK', 'molecular_function', 'GO:0004691', ('49', '53'))	('metabolism', 'biological_process', 'GO:0008152', ('91', '101'))	('gene expression', 'biological_process', 'GO:0010467', ('54', '69'))	('ETC', 'MPA', (40, 43))	('ribose', 'Chemical', 'MESH:D012266', (84, 90))	('AMPK', 'molecular_function', 'GO:0050405', ('49', '53'))
38464	29617669	Unsupervised clustering was performed based on cancer-specific autosomal loci, which were defined as unmethylated probes in all normal tissue types as well as sorted blood populations (mean beta value < 0.2), but methylated (beta value > 0.3) in more than 5% samples within any of the kidney tumor type (for tumor type with less than 100 samples, we require the portion of methylated samples to be greater than 10% instead).	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('methylated', 'Var', (213, 223))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('kidney tumor', 'Disease', (285, 297))	('tumor', 'Disease', (292, 297))	('cancer', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('kidney tumor', 'Disease', 'MESH:D007674', (285, 297))	('tumor', 'Disease', (308, 313))	('kidney tumor', 'Phenotype', 'HP:0009726', (285, 297))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
38466	29617669	The DNA methylation level as interrogated by cg07684796, cg15839448 was used for DKK1, and SFRP1, respectively, with a beta value of 0.3 or more considered evidence for epigenetic silencing.	('DNA methylation level', 'MPA', (4, 25))	('cg07684796', 'Var', (45, 55))	('cg07684796', 'Chemical', '-', (45, 55))	('DKK1', 'Gene', '22943', (81, 85))	('DKK1', 'Gene', (81, 85))	('cg15839448', 'Chemical', '-', (57, 67))	('DNA methylation', 'biological_process', 'GO:0006306', ('4', '19'))	('DNA', 'cellular_component', 'GO:0005574', ('4', '7'))	('cg15839448', 'Var', (57, 67))
38468	29617669	BAM files were used as input of the MToolBox pipeline, that includes GSNAP, MUSCLE, and SAMtools, to align reads to the Revised Cambridge Reference Sequence (rCRS) for human mitochondrial DNA, extract variant alleles, quantify their heteroplasmy levels and related confidence intervals, and obtain functional annotation of the identified variants.	('human', 'Species', '9606', (168, 173))	('variant', 'Var', (201, 208))	('mitochondrial DNA', 'cellular_component', 'GO:0000262', ('174', '191'))	('heteroplasmy levels', 'MPA', (233, 252))
38559	33139776	The multivariate analysis revealed mRNA expression of PINK1 and PARK2 as well as PINK1 protein expression as independent prognostic factors for shorter overall survival.	('PINK1', 'Gene', (54, 59))	('PARK2', 'Gene', (64, 69))	('mRNA expression', 'Var', (35, 50))	('PINK1', 'Gene', (81, 86))	('overall survival', 'MPA', (152, 168))	('shorter', 'NegReg', (144, 151))	('protein', 'Protein', (87, 94))	('PINK1', 'Gene', '65018', (81, 86))	('PINK1', 'Gene', '65018', (54, 59))	('protein', 'cellular_component', 'GO:0003675', ('87', '94'))	('PARK2', 'Gene', '5071', (64, 69))
38567	33139776	Type 1 pRCC (basophilic pRCC) often carries MET gene alterations, whereas type 2 (eosinophilic) tumors are associated with CDKN2A silencing, SETD2 mutations, and an increased expression of the NRF2-antioxidant response element (ARE) pathway.	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('carries', 'Reg', (36, 43))	('NRF2', 'Gene', '4780', (193, 197))	('tumors', 'Disease', (96, 102))	('CDKN2A', 'Gene', (123, 129))	('MET', 'Gene', '79811', (44, 47))	('pRCC', 'Gene', '5546', (24, 28))	('expression', 'MPA', (175, 185))	('silencing', 'NegReg', (130, 139))	('NRF2', 'Gene', (193, 197))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('CDKN2A', 'Gene', '1029', (123, 129))	('pRCC', 'Gene', '5546', (7, 11))	('pRCC', 'Phenotype', 'HP:0006766', (24, 28))	('RCC', 'Phenotype', 'HP:0005584', (8, 11))	('pRCC', 'Gene', (24, 28))	('SETD2', 'Gene', (141, 146))	('MET', 'Gene', (44, 47))	('pRCC', 'Phenotype', 'HP:0006766', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pRCC', 'Gene', (7, 11))	('SETD2', 'Gene', '29072', (141, 146))	('increased', 'PosReg', (165, 174))
38573	33139776	Von Hippel-Lindau (VHL) gene inactivation is the most common alteration in sporadic ccRCC.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('Von Hippel-Lindau', 'Gene', '7428', (0, 17))	('VHL', 'Gene', (19, 22))	('Von Hippel-Lindau', 'Gene', (0, 17))	('VHL', 'Gene', '7428', (19, 22))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('RCC', 'Disease', (86, 89))	('inactivation', 'Var', (29, 41))
38580	33139776	Mitochondrial depolarization causes PINK1 accumulation on the outer mitochondrial membrane, which induces (cytosolic) PARK2 recruitment.	('Mitochondrial depolarization', 'biological_process', 'GO:0051882', ('0', '28'))	('PINK1', 'Gene', (36, 41))	('recruitment', 'MPA', (124, 135))	('induces', 'Reg', (98, 105))	('accumulation', 'PosReg', (42, 54))	('depolarization', 'Var', (14, 28))	('Mitochondrial depolarization', 'Var', (0, 28))	('outer mitochondrial membrane', 'cellular_component', 'GO:0005741', ('62', '90'))	('PARK2', 'Gene', (118, 123))	('PARK2', 'Gene', '5071', (118, 123))	('PINK1', 'Gene', '65018', (36, 41))
38623	33139776	Patients with an increased PINK1 and PARK2 expression (using cutoff dichotomization) had a significantly longer overall survival compared to patients with downregulated PINK1 and PARK2 levels in Kaplan Meier and univariate Cox-analysis (Fig.	('increased', 'PosReg', (17, 26))	('PARK2', 'Gene', '5071', (179, 184))	('longer', 'PosReg', (105, 111))	('PINK1', 'Gene', '65018', (27, 32))	('PARK2', 'Gene', (179, 184))	('expression', 'Var', (43, 53))	('PINK1', 'Gene', (27, 32))	('PINK1', 'Gene', '65018', (169, 174))	('Patients', 'Species', '9606', (0, 8))	('PARK2', 'Gene', '5071', (37, 42))	('PARK2', 'Gene', (37, 42))	('overall survival', 'CPA', (112, 128))	('PINK1', 'Gene', (169, 174))	('patients', 'Species', '9606', (141, 149))
38656	33139776	The consequences of PARK2 and PINK1 dysregulation in cancer are not fully elucidated.	('dysregulation', 'Var', (36, 49))	('PINK1', 'Gene', (30, 35))	('PARK2', 'Gene', (20, 25))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PINK1', 'Gene', '65018', (30, 35))	('PARK2', 'Gene', '5071', (20, 25))
38658	33139776	PARK2 mutations affect the PINK1/PARK2 mitophagy axis in lung cancer due to slower clearance of damaged mitochondria.	('PINK1', 'Gene', '65018', (27, 32))	('PARK2', 'Gene', (0, 5))	('mitophagy', 'biological_process', 'GO:0000423', ('39', '48'))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('mitochondria', 'cellular_component', 'GO:0005739', ('104', '116'))	('clearance of damaged mitochondria', 'MPA', (83, 116))	('PINK1', 'Gene', (27, 32))	('PARK2', 'Gene', '5071', (33, 38))	('affect', 'Reg', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('slower', 'NegReg', (76, 82))	('PARK2', 'Gene', (33, 38))	('mitophagy', 'biological_process', 'GO:0000422', ('39', '48'))	('lung cancer', 'Disease', (57, 68))	('PARK2', 'Gene', '5071', (0, 5))	('mutations', 'Var', (6, 15))
38659	33139776	Morever, dysregulation of the PINK1/PARK2 axis accelerates KRAS-mediated carcinogenesis in pancreatic cancer.	('KRAS', 'Gene', '3845', (59, 63))	('dysregulation', 'Var', (9, 22))	('PINK1', 'Gene', (30, 35))	('carcinogenesis', 'Disease', (73, 87))	('KRAS', 'Gene', (59, 63))	('accelerates', 'PosReg', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('PARK2', 'Gene', '5071', (36, 41))	('pancreatic cancer', 'Disease', (91, 108))	('PARK2', 'Gene', (36, 41))	('PINK1', 'Gene', '65018', (30, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
38681	29340018	Clinically, patients with other RCC subtypes tend to have desirable outcomes; however, patients with KIRP were more likely to experience obviously worse clinical courses.	('patients', 'Species', '9606', (12, 20))	('RCC', 'Phenotype', 'HP:0005584', (32, 35))	('RCC', 'Disease', 'MESH:C538614', (32, 35))	('RCC', 'Disease', (32, 35))	('patients', 'Species', '9606', (87, 95))	('KIRP', 'Var', (101, 105))
38682	29340018	Currently, several biomarkers for KIRC that have been detected include von Hippel-Lindau (VHL), vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX), and hypoxia-inducible factor 1 alpha/2 alpha (HIF1a/2a) mutations, some of which were able to forecast the medical effectiveness and outcomes.	('carbonic anhydrase IX', 'Gene', '768', (139, 160))	('VEGF', 'Gene', (132, 136))	('HIF1a', 'Gene', (215, 220))	('mutations', 'Var', (225, 234))	('CAIX', 'Gene', '768', (162, 166))	('von Hippel-Lindau', 'Gene', '7428', (71, 88))	('HIF1a', 'Gene', '3091', (215, 220))	('VHL', 'Disease', (90, 93))	('VHL', 'Disease', 'MESH:D006623', (90, 93))	('VEGF', 'Gene', '7422', (132, 136))	('vascular endothelial growth factor', 'Gene', (96, 130))	('vascular endothelial growth factor', 'molecular_function', 'GO:0005172', ('96', '130'))	('carbonic anhydrase IX', 'Gene', (139, 160))	('vascular endothelial growth factor', 'Gene', '7422', (96, 130))	('hypoxia-inducible factor 1 alpha/2 alpha', 'Gene', '3091;2034', (173, 213))	('von Hippel-Lindau', 'Gene', (71, 88))	('CAIX', 'Gene', (162, 166))	('hypoxia-inducible factor 1 alpha/2 alpha', 'Gene', (173, 213))
38697	29340018	On the contrary, in the low risk group, the enrichment was seen in 21 pathways, including some cancer-related pathways like KEGG_OXIDATIVE_PHOSPHORYLATION (Figure 11B, Figure 13), KEGG_REGULATION_OF_AUTOPHAGY.	('REGULATION_OF_AUTOPHAGY', 'biological_process', 'GO:0010506', ('185', '208'))	('OXIDATIVE', 'Disease', (129, 138))	('KEGG_REGULATION_OF_AUTOPHAGY', 'Var', (180, 208))	('OXIDATIVE', 'Disease', 'MESH:D004194', (129, 138))	('OS', 'Chemical', '-', (141, 143))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('OXIDATIVE_PHOSPHORYLATION', 'biological_process', 'GO:0006119', ('129', '154'))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
38698	29340018	Finally, only GSE2748 and GSE48352 were found to contain AFAP1-AS1 or GAS6-AS1 expression.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (57, 66))	('GSE2748', 'Var', (14, 21))	('GSE2748', 'Chemical', '-', (14, 21))	('GSE48352', 'Var', (26, 34))	('contain', 'Reg', (49, 56))	('AFAP1-AS1', 'Gene', (57, 66))	('GAS6-AS1', 'Gene', '650669;2621;5729', (70, 78))	('GAS', 'molecular_function', 'GO:0034005', ('70', '73'))	('GAS6-AS1', 'Gene', (70, 78))
38699	29340018	The expression level of AFAP1-AS1 from GSE48352 was higher in papillary renal cell carcinoma (PRCC) than in that of normal controls (P = 0.0318) (Figure 14E).	('expression level', 'MPA', (4, 20))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (72, 92))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 92))	('PRCC', 'Gene', '5546', (94, 98))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (62, 92))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (24, 33))	('papillary renal cell carcinoma', 'Disease', (62, 92))	('PRCC', 'Gene', (94, 98))	('higher', 'PosReg', (52, 58))	('AFAP1-AS1', 'Gene', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('PRCC', 'Phenotype', 'HP:0006766', (94, 98))	('GSE48352', 'Var', (39, 47))
38709	29340018	Moreover, enrichment of cluster C2 was carried out for 9p deletion and chromatin remodeler BAP1 somatic mutations.	('BAP1', 'Gene', '8314', (91, 95))	('chromatin', 'cellular_component', 'GO:0000785', ('71', '80'))	('BAP1', 'Gene', (91, 95))	('mutations', 'Var', (104, 113))
38713	29340018	The clinical and prognostic value of lncRNAs AFAP1-AS1 and GAS6-AS1 could be partially verified by GSE2748 and GSE48352.	('AFAP1-AS1', 'Gene', (45, 54))	('GSE2748', 'Chemical', '-', (99, 106))	('GAS6-AS1', 'Gene', '650669;2621;5729', (59, 67))	('GSE48352', 'Var', (111, 119))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (45, 54))	('GAS6-AS1', 'Gene', (59, 67))	('GAS', 'molecular_function', 'GO:0034005', ('59', '62'))	('GSE2748', 'Var', (99, 106))
38717	29340018	The knockdown of AFAP1-AS1 significantly prohibited cell migration and invasion in nasopharyngeal carcinoma (NPC) and lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cell migration', 'CPA', (52, 66))	('nasopharyngeal carcinoma (NPC) and lung cancer', 'Disease', 'MESH:D009303', (83, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('invasion', 'CPA', (71, 79))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (17, 26))	('NPC', 'Phenotype', 'HP:0100630', (109, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (83, 107))	('cell migration', 'biological_process', 'GO:0016477', ('52', '66'))	('NPC', 'cellular_component', 'GO:0005643', ('109', '112'))	('prohibited', 'NegReg', (41, 51))	('knockdown', 'Var', (4, 13))	('AFAP1-AS1', 'Gene', (17, 26))
38718	29340018	Silencing of AFAP1-AS1 markedly reduced hepatocellular carcinoma (HCC) cell proliferation and invasion and decreased tumor growth in a murine allograft model in vivo.	('invasion', 'CPA', (94, 102))	('decreased tumor', 'Disease', 'MESH:D009369', (107, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cell proliferation', 'biological_process', 'GO:0008283', ('71', '89'))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('decreased tumor', 'Disease', (107, 122))	('reduced', 'NegReg', (32, 39))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (13, 22))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (40, 64))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('hepatocellular carcinoma', 'Disease', (40, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 64))	('Silencing', 'Var', (0, 9))	('murine', 'Species', '10090', (135, 141))	('AFAP1-AS1', 'Gene', (13, 22))
38720	29340018	Silencing AFAP1-AS1 would inhibit the pancreatic ductal adenocarcinoma (PDAC) cell proliferation, migration, and invasion, while aberrantly-expressed AFAP1-AS1 accelerated cell proliferation, migration, and invasion.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (150, 159))	('cell proliferation', 'biological_process', 'GO:0008283', ('172', '190'))	('accelerated', 'PosReg', (160, 171))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (38, 70))	('Silencing', 'Var', (0, 9))	('invasion', 'CPA', (113, 121))	('AFAP1-AS1', 'Gene', (10, 19))	('invasion', 'CPA', (207, 215))	('cell proliferation', 'biological_process', 'GO:0008283', ('78', '96'))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (10, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('migration', 'CPA', (98, 107))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (38, 70))	('cell proliferation', 'CPA', (172, 190))	('inhibit', 'NegReg', (26, 33))	('AFAP1-AS1', 'Gene', (150, 159))	('pancreatic ductal adenocarcinoma', 'Disease', (38, 70))	('PDAC', 'Phenotype', 'HP:0006725', (72, 76))	('migration', 'CPA', (192, 201))
38721	29340018	The knockdown of AFAP1-AS1 decelerated the intrahepatic cholangiocarcinoma (CCA) cell proliferation and migration.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (17, 26))	('cell proliferation', 'biological_process', 'GO:0008283', ('81', '99'))	('decelerated', 'NegReg', (27, 38))	('CCA', 'Phenotype', 'HP:0030153', (76, 79))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (43, 74))	('knockdown', 'Var', (4, 13))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('AFAP1-AS1', 'Gene', (17, 26))	('intrahepatic cholangiocarcinoma', 'Disease', (43, 74))
38722	29340018	In addition, silencing AFAP1-AS1 prohibited cell migration in part due to reduced expression of MMP-2 and MMP-9.	('MMP-9', 'Gene', (106, 111))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (23, 32))	('MMP-2', 'Gene', '4313', (96, 101))	('prohibited', 'NegReg', (33, 43))	('expression', 'MPA', (82, 92))	('MMP-2', 'Gene', (96, 101))	('MMP-9', 'molecular_function', 'GO:0004229', ('106', '111'))	('cell migration', 'biological_process', 'GO:0016477', ('44', '58'))	('AFAP1-AS1', 'Gene', (23, 32))	('MMP-2', 'molecular_function', 'GO:0004228', ('96', '101'))	('MMP-9', 'Gene', '4318', (106, 111))	('reduced', 'NegReg', (74, 81))	('cell migration', 'CPA', (44, 58))	('silencing', 'Var', (13, 22))
38724	29340018	AFAP1-AS1 accelerated ovarian cancer cell proliferation, and AFAP1-AS1 knockdown significantly promoted ovarian cancer cell and esophageal squamous cell carcinoma (ESCC) cell apoptosis.	('cell proliferation', 'biological_process', 'GO:0008283', ('37', '55'))	('AFAP1-AS1 accelerated ovarian cancer', 'Disease', (0, 36))	('promoted', 'PosReg', (95, 103))	('AFAP1-AS1 accelerated ovarian cancer', 'Disease', 'OMIM:607277', (0, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('AFAP1-AS1', 'Gene', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (61, 70))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('AFAP1-AS1', 'Gene', (0, 9))	('accelerated ovarian cancer', 'Phenotype', 'HP:0008209', (10, 36))	('apoptosis', 'biological_process', 'GO:0097194', ('175', '184'))	('apoptosis', 'biological_process', 'GO:0006915', ('175', '184'))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('ovarian cancer', 'Disease', (104, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('knockdown', 'Var', (71, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))
38725	29340018	AFAP1-AS1 depletion suppressed SW480 cell and colorectal carcinoma (CRC) cell proliferation and colony formation.	('cell proliferation', 'biological_process', 'GO:0008283', ('73', '91'))	('colorectal carcinoma', 'Disease', (46, 66))	('suppressed', 'NegReg', (20, 30))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('depletion', 'Var', (10, 19))	('formation', 'biological_process', 'GO:0009058', ('103', '112'))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (46, 66))	('colony formation', 'CPA', (96, 112))	('SW480', 'CellLine', 'CVCL:0546', (31, 36))	('AFAP1-AS1', 'Gene', (0, 9))	('SW480 cell', 'CPA', (31, 41))	('CRC', 'Phenotype', 'HP:0030731', (68, 71))
38740	29340018	It was found that high expression of AFAP1-AS1 rendered cancer patients more vulnerable to lymph node metastasis and distant metastasis.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('AFAP1-AS1 rendered cancer', 'Disease', 'OMIM:607277', (37, 62))	('vulnerable', 'CPA', (77, 87))	('patients', 'Species', '9606', (63, 71))	('more', 'PosReg', (72, 76))	('high expression', 'Var', (18, 33))	('AFAP1-AS1 rendered cancer', 'Disease', (37, 62))
38750	29340018	Aberrant GAS6-AS1 expression could participate in the development of NSCLC via affecting of its host gene, rendering it possible in becoming a diagnosis target in NSCLC patients.	('GAS6-AS1', 'Gene', (9, 17))	('patients', 'Species', '9606', (169, 177))	('GAS', 'molecular_function', 'GO:0034005', ('9', '12'))	('Aberrant', 'Var', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))	('NSCLC', 'Disease', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('NSCLC', 'Disease', (163, 168))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('affecting', 'Reg', (79, 88))	('expression', 'MPA', (18, 28))	('GAS6-AS1', 'Gene', '650669;2621;5729', (9, 17))	('participate', 'Reg', (35, 46))
38754	29340018	TCGA has been a major source of valuable data for 33 types of tumors, including for mRNA expression, protein expression, various mutations, amplifications, etc.	('mRNA expression', 'MPA', (84, 99))	('amplifications', 'Var', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('mutations', 'Var', (129, 138))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('protein expression', 'MPA', (101, 119))	('protein', 'cellular_component', 'GO:0003675', ('101', '108'))
38846	27462141	The VHL protein plays a major role in RCC, being downregulated due to gene inactivation or epigenetic silencing.	('RCC', 'Disease', (38, 41))	('protein', 'cellular_component', 'GO:0003675', ('8', '15'))	('gene inactivation', 'Var', (70, 87))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('VHL', 'Gene', (4, 7))	('downregulated', 'NegReg', (49, 62))	('epigenetic silencing', 'Var', (91, 111))	('VHL', 'Gene', '7428', (4, 7))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
38848	27462141	This effect on VEGF can explain the angiogenic drive of clear-cell RCC (ccRCC), and expression of MET or AXL can be associated with an invasive tumor phenotype and poor prognosis.	('AXL', 'Gene', '558', (105, 108))	('expression', 'Var', (84, 94))	('associated with', 'Reg', (116, 131))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('VEGF', 'Gene', (15, 19))	('invasive tumor', 'Disease', (135, 149))	('RCC', 'Disease', (74, 77))	('RCC', 'Phenotype', 'HP:0005584', (74, 77))	('AXL', 'Gene', (105, 108))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('angiogenic drive', 'MPA', (36, 52))	('invasive tumor', 'Disease', 'MESH:D009369', (135, 149))	('VEGF', 'Gene', '3791', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
38858	27462141	Furthermore, it plays an important role in RCC where MET expression is associated with poor prognosis and higher Fuhrman grade as well as advanced disease.	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('MET expression', 'Var', (53, 67))	('RCC', 'Disease', (43, 46))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))
38859	27462141	The results of MET signaling pathway activated from several mechanisms, including chromosomal rearrangement, germline or somatic mutations, gene amplification, MET protein overexpression, and increased HGF expression, or by alternate activation of other pathways affecting MET.	('increased HGF expression', 'Phenotype', 'HP:0030269', (192, 216))	('HGF', 'Protein', (202, 205))	('MET signaling pathway', 'Pathway', (15, 36))	('activated', 'PosReg', (37, 46))	('expression', 'MPA', (206, 216))	('increased', 'PosReg', (192, 201))	('men', 'Species', '9606', (103, 106))	('protein', 'cellular_component', 'GO:0003675', ('164', '171'))	('MET signaling pathway', 'biological_process', 'GO:0048012', ('15', '36'))	('overexpression', 'PosReg', (172, 186))	('MET protein', 'Protein', (160, 171))	('gene amplification', 'Var', (140, 158))
38860	27462141	Moreover, MET along with VEGFR-2 plays a synergistic role in promoting tumor angiogenesis and metastatic phenotype.	('MET', 'Var', (10, 13))	('VEGFR-2', 'Gene', '3791', (25, 32))	('metastatic phenotype', 'CPA', (94, 114))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('angiogenesis', 'biological_process', 'GO:0001525', ('77', '89'))	('VEGFR-2', 'Gene', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promoting', 'PosReg', (61, 70))	('tumor', 'Disease', (71, 76))
38861	27462141	Mutations in the HGF and MET genes are associated with bilateral type I papillary renal carcinoma (pRCC) in hereditary pRCC syndrome that generally has a better prognosis.	('MET', 'Gene', (25, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('pRCC', 'Gene', '5546', (119, 123))	('bilateral type I papillary renal carcinoma', 'Disease', 'MESH:C538614', (55, 97))	('pRCC', 'Phenotype', 'HP:0006766', (99, 103))	('hereditary pRCC syndrome', 'Disease', (108, 132))	('HGF', 'Gene', (17, 20))	('pRCC', 'Gene', (99, 103))	('Mutations', 'Var', (0, 9))	('hereditary pRCC syndrome', 'Disease', 'MESH:D009386', (108, 132))	('pRCC', 'Phenotype', 'HP:0006766', (119, 123))	('bilateral type I papillary renal carcinoma', 'Disease', (55, 97))	('pRCC', 'Gene', (119, 123))	('renal carcinoma', 'Phenotype', 'HP:0005584', (82, 97))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (72, 97))	('associated with', 'Reg', (39, 54))	('pRCC', 'Gene', '5546', (99, 103))	('RCC', 'Phenotype', 'HP:0005584', (100, 103))
38863	27462141	The trisomy of chromosome 7 is a common occurrence in pRCC, and several activating missense mutations of the MET gene have been described, both in sporadic and hereditary forms.	('MET', 'Gene', (109, 112))	('chromosome', 'cellular_component', 'GO:0005694', ('15', '25'))	('missense mutations', 'Var', (83, 101))	('activating', 'PosReg', (72, 82))	('pRCC', 'Gene', '5546', (54, 58))	('pRCC', 'Phenotype', 'HP:0006766', (54, 58))	('RCC', 'Phenotype', 'HP:0005584', (55, 58))	('trisomy of chromosome 7', 'Disease', (4, 27))	('pRCC', 'Gene', (54, 58))
38865	27462141	Moreover, mutations or loss of the VHL gene under hypoxic conditions lead to accumulation of HIFs: as a result, different HIF target genes are upregulated, including VEGF, PDGF, TGF-a, and MET.	('TGF-a', 'Gene', '7039', (178, 183))	('TGF-a', 'Gene', (178, 183))	('hypoxic condition', 'Disease', (50, 67))	('accumulation', 'PosReg', (77, 89))	('VEGF', 'Gene', (166, 170))	('hypoxic condition', 'Disease', 'MESH:D009135', (50, 67))	('upregulated', 'PosReg', (143, 154))	('PDGF', 'molecular_function', 'GO:0005161', ('172', '176'))	('VEGF', 'Gene', '3791', (166, 170))	('loss', 'NegReg', (23, 27))	('VHL', 'Gene', (35, 38))	('mutations', 'Var', (10, 19))	('VHL', 'Gene', '7428', (35, 38))
38877	27462141	Hypoxic conditions due to VEGF pathway inhibition can induce c-Met expression, which may eventually promote tumor invasion, survival, and metastasis.	('c-Met', 'Protein', (61, 66))	('inhibition', 'Var', (39, 49))	('metastasis', 'CPA', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Hypoxic conditions', 'Disease', 'MESH:D009135', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Hypoxic conditions', 'Disease', (0, 18))	('tumor', 'Disease', (108, 113))	('VEGF', 'Gene', (26, 30))	('survival', 'CPA', (124, 132))	('promote', 'PosReg', (100, 107))	('VEGF', 'Gene', '3791', (26, 30))	('induce', 'PosReg', (54, 60))
38913	27462141	Stable disease occurred as the best response in 62% of patients in each group, while progressive disease occurred in 14% of patients treated with cabozantinib and 27% of patients treated with everolimus.	('patients', 'Species', '9606', (170, 178))	('cabozantinib', 'Chemical', 'MESH:C558660', (146, 158))	('cabozantinib', 'Var', (146, 158))	('Stable disease', 'Disease', (0, 14))	('everolimus', 'Chemical', 'MESH:D000068338', (192, 202))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (124, 132))
38915	27462141	The median OS was 21.4 months for patients receiving cabozantinib versus 16.5 months for those receiving everolimus (HR =0.66, 95% CI 0.53-0.83, P=0.0003) with a 34% reduction in the rate of death (Table 1).	('reduction', 'NegReg', (166, 175))	('everolimus', 'Chemical', 'MESH:D000068338', (105, 115))	('cabozantinib', 'Var', (53, 65))	('cabozantinib', 'Chemical', 'MESH:C558660', (53, 65))	('patients', 'Species', '9606', (34, 42))
38929	27462141	Treatment discontinuation due to AEs occurred in 9% of subjects receiving cabozantinib and in 10% of those receiving everolimus.	('AEs', 'Disease', (33, 36))	('cabozantinib', 'Var', (74, 86))	('men', 'Species', '9606', (5, 8))	('cabozantinib', 'Chemical', 'MESH:C558660', (74, 86))	('everolimus', 'Chemical', 'MESH:D000068338', (117, 127))
39017	23323104	Renal carcinomas associated with Xp11.2 translocations are less commonly encountered in a differential diagnosis of CCPRCC.	('PRCC', 'Gene', (118, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (6, 16))	('Xp11.2', 'Gene', (33, 39))	('PRCC', 'Gene', '5546', (118, 122))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('Renal carcinomas', 'Disease', 'MESH:C538614', (0, 16))	('Renal carcinomas', 'Phenotype', 'HP:0005584', (0, 16))	('translocations', 'Var', (40, 54))	('CCPRCC', 'Phenotype', 'HP:0006770', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('Renal carcinomas', 'Disease', (0, 16))
39018	23323104	Renal carcinomas associated with Xp11.2 translocations can show a papillary architecture and clear cells, and immunohistochemical staining for TFE3 and translocation studies can lead to a correct diagnosis.	('carcinomas', 'Phenotype', 'HP:0030731', (6, 16))	('Xp11.2', 'Gene', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('lead to', 'Reg', (178, 185))	('TFE3', 'Gene', (143, 147))	('Renal carcinomas', 'Disease', 'MESH:C538614', (0, 16))	('Renal carcinomas', 'Phenotype', 'HP:0005584', (0, 16))	('translocations', 'Var', (40, 54))	('TFE3', 'Gene', '7030', (143, 147))	('Renal carcinomas', 'Disease', (0, 16))
39053	23323104	A genetic study of the VHL gene mutation may show interesting results.	('VHL', 'Disease', (23, 26))	('mutation', 'Var', (32, 40))	('VHL', 'Disease', 'MESH:D006623', (23, 26))
39059	23323104	The loss of chromosome 3p, where the VHL gene and polybromo-1 (PBRM1) gene are located, is associated with CCRCC.	('VHL', 'Disease', (37, 40))	('polybromo-1', 'Gene', '55193', (50, 61))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('PBRM1', 'Gene', (63, 68))	('RCC', 'Disease', (109, 112))	('associated', 'Reg', (91, 101))	('PBRM1', 'Gene', '55193', (63, 68))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('polybromo-1', 'Gene', (50, 61))	('VHL', 'Disease', 'MESH:D006623', (37, 40))	('chromosome', 'cellular_component', 'GO:0005694', ('12', '22'))	('loss', 'Var', (4, 8))
39061	23323104	In PRCC cases, trisomy or tetrasomy of chromosome 7, trisomy 17, and a loss of the Y chromosome are characteristic features.	('PRCC', 'Gene', '5546', (3, 7))	('tetrasomy', 'Var', (26, 35))	('trisomy 17', 'Var', (53, 63))	('Y chromosome', 'cellular_component', 'GO:0000806', ('83', '95'))	('PRCC', 'Gene', (3, 7))	('trisomy', 'Var', (15, 22))	('loss', 'NegReg', (71, 75))	('Y chromosome', 'CPA', (83, 95))	('chromosome', 'cellular_component', 'GO:0005694', ('39', '49'))	('RCC', 'Phenotype', 'HP:0005584', (4, 7))
39064	23323104	reported low copy number gains at chromosomes 7 and 17 in one case of CCPRCC among 36 cases.	('CCPRCC', 'Phenotype', 'HP:0006770', (70, 76))	('PRCC', 'Gene', '5546', (72, 76))	('PRCC', 'Gene', (72, 76))	('low copy number gains', 'Var', (9, 30))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
39065	23323104	found polysomy for chromosome 7 and monosomy for chromosomes 17, 16, and 20 in one CCPRCC case.	('monosomy', 'Var', (36, 44))	('polysomy', 'Var', (6, 14))	('PRCC', 'Gene', (85, 89))	('CCPRCC', 'Phenotype', 'HP:0006770', (83, 89))	('PRCC', 'Gene', '5546', (85, 89))	('chromosome', 'cellular_component', 'GO:0005694', ('19', '29'))	('RCC', 'Phenotype', 'HP:0005584', (86, 89))
39074	31804603	In addition, proteasomal inhibition lowered the expression of the glutaminases GLS and GLS2, which support glutamine metabolism and the maintenance of the redox balance.	('redox', 'MPA', (155, 160))	('lowered', 'NegReg', (36, 43))	('GLS2', 'Gene', '27165', (87, 91))	('glutamine', 'Chemical', 'MESH:D005973', (107, 116))	('glutamine metabolism', 'MPA', (107, 127))	('expression', 'MPA', (48, 58))	('proteasomal', 'Protein', (13, 24))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('107', '127'))	('inhibition', 'Var', (25, 35))	('GLS2', 'Gene', (87, 91))	('GLS', 'Gene', (79, 82))
39075	31804603	Thus, in HLRCC cells, proteasome inhibition disrupts glucose and glutamine metabolism, restricting nutrients and lowering the cells' anti-oxidant response capacity.	('inhibition', 'Var', (33, 43))	('glutamine', 'Chemical', 'MESH:D005973', (65, 74))	('nutrients', 'MPA', (99, 108))	('disrupts glucose', 'Disease', (44, 60))	('oxidant response', 'Phenotype', 'HP:0025464', (138, 154))	('restricting', 'NegReg', (87, 98))	('proteasome', 'Protein', (22, 32))	('lowering', 'NegReg', (113, 121))	('proteasome', 'molecular_function', 'GO:0004299', ('22', '32'))	('proteasome', 'cellular_component', 'GO:0000502', ('22', '32'))	('anti-oxidant response capacity', 'MPA', (133, 163))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('65', '85'))	('disrupts glucose', 'Disease', 'MESH:D019958', (44, 60))
39086	31804603	This discovery led to the identification of mutations and amplification of MET in sporadic Type 1 PRCC, and to the development of therapeutic approaches targeting the MET pathway in hereditary and sporadic PRCC.	('RCC', 'Phenotype', 'HP:0005584', (207, 210))	('RCC', 'Disease', 'MESH:C538614', (207, 210))	('RCC', 'Disease', (207, 210))	('PRCC', 'Phenotype', 'HP:0006766', (98, 102))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('PRCC', 'Phenotype', 'HP:0006766', (206, 210))	('mutations', 'Var', (44, 53))	('RCC', 'Disease', (99, 102))	('amplification', 'Var', (58, 71))	('MET', 'Gene', (75, 78))
39088	31804603	It is characterized by a germline mutation of the gene for the TCA cycle enzyme fumarate hydratase (FH) and subsequent loss of the wild-type FH allele that results in complete inactivation of the fumarate hydratase enzyme (FH) in tumors.	('FH', 'Gene', '2271', (223, 225))	('FH', 'Gene', '2271', (141, 143))	('TCA cycle', 'biological_process', 'GO:0006099', ('63', '72'))	('FH', 'Gene', '2271', (100, 102))	('inactivation', 'NegReg', (176, 188))	('fumarate hydratase', 'Gene', '2271', (196, 214))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('TCA', 'Chemical', 'MESH:D014238', (63, 66))	('fumarate hydratase', 'Gene', '2271', (80, 98))	('fumarate hydratase', 'Gene', (196, 214))	('germline mutation', 'Var', (25, 42))	('loss', 'NegReg', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('fumarate hydratase', 'Gene', (80, 98))
39093	31804603	This results in HIF1alpha stabilization which leads to the aberrant expression of HIF transcriptional target genes that promote glycolysis and angiogenesis.	('HIF1alpha', 'Gene', (16, 25))	('glycolysis', 'MPA', (128, 138))	('expression', 'MPA', (68, 78))	('aberrant', 'Var', (59, 67))	('HIF1alpha', 'Gene', '3091', (16, 25))	('promote', 'PosReg', (120, 127))	('angiogenesis', 'biological_process', 'GO:0001525', ('143', '155'))	('angiogenesis', 'CPA', (143, 155))	('glycolysis', 'biological_process', 'GO:0006096', ('128', '138'))
39108	31804603	The HLRCC-derived FH-deficient cell line UOK262 and its fumarate hydratase (FH)-restored counterpart, UOK262WT, were treated with a concentration range of bortezomib or marizomib for 48 h. UOK262 cells, but not UOK262WT, were highly sensitive to both proteasome inhibitors with comparable IC50 (IC50~5-6 nM, Fig.	('proteasome', 'cellular_component', 'GO:0000502', ('251', '261'))	('UOK262WT', 'Chemical', '-', (211, 219))	('FH-deficient', 'Disease', (18, 30))	('IC50', 'MPA', (289, 293))	('UOK262WT', 'Chemical', '-', (102, 110))	('proteasome', 'molecular_function', 'GO:0004299', ('251', '261'))	('FH', 'Gene', '2271', (76, 78))	('FH', 'Gene', '2271', (18, 20))	('FH-deficient', 'Disease', 'MESH:D006938', (18, 30))	('marizomib', 'Chemical', 'MESH:C475865', (169, 178))	('fumarate hydratase', 'Gene', '2271', (56, 74))	('sensitive', 'MPA', (233, 242))	('bortezomib', 'Chemical', 'MESH:D000069286', (155, 165))	('UOK262', 'Var', (189, 195))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('fumarate hydratase', 'Gene', (56, 74))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
39136	31804603	A study from Valencia and collaborators showed that decreased p62 levels resulted in downregulation of c-Myc that alters glycolysis by decreasing c-Myc-induced transcription of LDHA.	('alters', 'Reg', (114, 120))	('c-Myc', 'Gene', '4609', (146, 151))	('transcription', 'biological_process', 'GO:0006351', ('160', '173'))	('p62', 'Var', (62, 65))	('downregulation', 'NegReg', (85, 99))	('decreased', 'NegReg', (52, 61))	('c-Myc', 'Gene', (103, 108))	('c-Myc', 'Gene', (146, 151))	('c-Myc', 'Gene', '4609', (103, 108))	('LDHA', 'Gene', '3939', (177, 181))	('glycolysis', 'MPA', (121, 131))	('glycolysis', 'biological_process', 'GO:0006096', ('121', '131'))	('LDHA', 'Gene', (177, 181))	('decreasing', 'NegReg', (135, 145))
39139	31804603	Silencing of either p62 (SQSTM1) or c-Myc (MYC) significantly, but not completely, decreased UOK262 cell viability (Fig.	('UOK262 cell viability', 'CPA', (93, 114))	('SQSTM1', 'Gene', '8878', (25, 31))	('decreased', 'NegReg', (83, 92))	('SQSTM1', 'Gene', (25, 31))	('p62', 'Var', (20, 23))	('MYC', 'Gene', '4609', (43, 46))	('c-Myc', 'Gene', '4609', (36, 41))	('MYC', 'Gene', (43, 46))	('Silencing', 'Var', (0, 9))	('c-Myc', 'Gene', (36, 41))
39140	31804603	Silencing of SQSTM1 expression resulted in downregulation of both MYC and LDHA mRNA expression, while silencing of MYC only reduced LDHA mRNA expression without altering SQSTM1 expression (Fig.	('SQSTM1', 'Gene', (170, 176))	('MYC', 'Gene', (66, 69))	('downregulation', 'NegReg', (43, 57))	('Silencing', 'Var', (0, 9))	('LDHA', 'Gene', (132, 136))	('LDHA', 'Gene', '3939', (74, 78))	('SQSTM1', 'Gene', '8878', (170, 176))	('MYC', 'Gene', (115, 118))	('LDHA', 'Gene', '3939', (132, 136))	('MYC', 'Gene', '4609', (66, 69))	('SQSTM1', 'Gene', (13, 19))	('SQSTM1', 'Gene', '8878', (13, 19))	('LDHA', 'Gene', (74, 78))	('MYC', 'Gene', '4609', (115, 118))
39144	31804603	Finally, silencing of p62 and c-Myc both significantly reduced ECAR in UOK262 cells (Fig.	('p62', 'Protein', (22, 25))	('reduced', 'NegReg', (55, 62))	('silencing', 'Var', (9, 18))	('c-Myc', 'Gene', '4609', (30, 35))	('ECAR', 'CPA', (63, 67))	('c-Myc', 'Gene', (30, 35))
39162	31804603	Similar to bortezomib, marizomib was found to have a significant cytotoxic effect against the FH-deficient HLRCC cell line model, UOK262.	('FH-deficient', 'Disease', (94, 106))	('bortezomib', 'Chemical', 'MESH:D000069286', (11, 21))	('cytotoxic effect', 'CPA', (65, 81))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('marizomib', 'Chemical', 'MESH:C475865', (23, 32))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('FH-deficient', 'Disease', 'MESH:D006938', (94, 106))	('marizomib', 'Var', (23, 32))
39175	31804603	Transient silencing of MYC only partially recapitulated the metabolic effects of the proteasome inhibitors suggesting that this global metabolic effect was both c-Myc-dependent and c-Myc-independent.	('MYC', 'Gene', '4609', (23, 26))	('c-Myc', 'Gene', '4609', (161, 166))	('proteasome', 'molecular_function', 'GO:0004299', ('85', '95'))	('proteasome', 'cellular_component', 'GO:0000502', ('85', '95'))	('c-Myc', 'Gene', (161, 166))	('MYC', 'Gene', (23, 26))	('c-Myc', 'Gene', '4609', (181, 186))	('silencing', 'Var', (10, 19))	('c-Myc', 'Gene', (181, 186))
39177	31804603	Proteasome inhibition disrupted glucose and glutamine metabolism, restricting nutrients and lowering the cells' anti-oxidant response capacity.	('nutrients', 'MPA', (78, 87))	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('lowering', 'NegReg', (92, 100))	('oxidant response', 'Phenotype', 'HP:0025464', (117, 133))	('disrupted', 'NegReg', (22, 31))	('Proteasome', 'Protein', (0, 10))	('inhibition', 'Var', (11, 21))	('anti-oxidant response capacity', 'MPA', (112, 142))	('glutamine', 'Chemical', 'MESH:D005973', (44, 53))	('glutamine metabolism', 'biological_process', 'GO:0006541', ('44', '64'))	('restricting', 'NegReg', (66, 77))
39209	31804603	The primers and fluorogenic probe Taqman  Gene Expression Assays used are: LDHA (Hs01378790_g1), SQSTM1 (Hs01061917_g1), MYC (Hs00153408_m1), GLS (Hs01014020_m1), GLS2 (Hs00998733_m1).	('Hs01378790_g1', 'Var', (81, 94))	('SQSTM1', 'Gene', (97, 103))	('LDHA', 'Gene', '3939', (75, 79))	('Hs00153408_m1', 'Var', (126, 139))	('MYC', 'Gene', (121, 124))	('GLS2', 'Gene', '27165', (163, 167))	('SQSTM1', 'Gene', '8878', (97, 103))	('Gene Expression', 'biological_process', 'GO:0010467', ('42', '57'))	('Hs00998733_m1', 'Var', (169, 182))	('Hs01014020_m1', 'Var', (147, 160))	('MYC', 'Gene', '4609', (121, 124))	('LDHA', 'Gene', (75, 79))	('GLS2', 'Gene', (163, 167))	('Hs01061917_g1', 'Var', (105, 118))
39227	30596034	Recently, the International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia recognized ccpRCC as a distinct epithelial tumor that could be distinguished from ccRCC and pRCC by genetic differences in the von Hippel-Lindau (VHL)tumor suppressor gene mutation and 3p loss status and the extreme rarity of gains in chromosomes 7 and 17 or the loss of chromosome Y, despite significant morphological, immunohistochemical, and genetic similarities among the three tumors.	('loss', 'NegReg', (299, 303))	('mutation', 'Var', (283, 291))	('pRCC', 'Phenotype', 'HP:0006766', (203, 207))	('RCC', 'Disease', (125, 128))	('RCC', 'Disease', (204, 207))	('tumors', 'Disease', 'MESH:D009369', (493, 499))	('RCC', 'Disease', (195, 198))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('Neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('ccpRCC', 'Phenotype', 'HP:0006770', (122, 128))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('261', '277'))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('gains', 'PosReg', (337, 342))	('epithelial tumor', 'Disease', (143, 159))	('tumor suppressor', 'biological_process', 'GO:0051726', ('261', '277'))	('epithelial tumor', 'Disease', 'MESH:D002277', (143, 159))	('epithelial tumor', 'Phenotype', 'HP:0031492', (143, 159))	('tumors', 'Phenotype', 'HP:0002664', (493, 499))	('Classification of Renal Neoplasia', 'Disease', 'MESH:D007674', (77, 110))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('chromosome', 'cellular_component', 'GO:0005694', ('382', '392'))	('loss', 'NegReg', (374, 378))	('pRCC', 'Phenotype', 'HP:0006766', (124, 128))	('chromosome', 'Gene', (382, 392))	('Renal Neoplasia', 'Phenotype', 'HP:0009726', (95, 110))	('von Hippel-Lindau (VHL)tumor', 'Disease', 'MESH:D006623', (238, 266))	('tumor', 'Phenotype', 'HP:0002664', (493, 498))	('Classification of Renal Neoplasia', 'Disease', (77, 110))	('tumors', 'Disease', (493, 499))
39234	30596034	Subsequent pathology revealed a tumor measuring 1.7 cm x 1.4 cm x 1.0 cm with a capsule abutting, leading to a diagnosis of a grade 2 ccpRCC without necrosis and a final pathologic stage of T1aN x M0 (Figure 2).	('pRCC', 'Phenotype', 'HP:0006766', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('necrosis', 'biological_process', 'GO:0070265', ('149', '157'))	('necrosis', 'biological_process', 'GO:0008219', ('149', '157'))	('necrosis', 'Disease', (149, 157))	('necrosis', 'biological_process', 'GO:0019835', ('149', '157'))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('necrosis', 'biological_process', 'GO:0001906', ('149', '157'))	('necrosis', 'biological_process', 'GO:0008220', ('149', '157'))	('capsule', 'cellular_component', 'GO:0042603', ('80', '87'))	('ccpRCC', 'Phenotype', 'HP:0006770', (134, 140))	('T1aN x M0', 'Var', (190, 199))	('necrosis', 'Disease', 'MESH:D009336', (149, 157))	('tumor', 'Disease', (32, 37))
39249	30596034	Although VHL mutation is a hallmark of ccRCC, mutations in this gene have been described in 15%-30% of ccpRCC cases.	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('ccRCC', 'Phenotype', 'HP:0006770', (39, 44))	('ccpRCC', 'Phenotype', 'HP:0006770', (103, 109))	('mutations', 'Var', (46, 55))	('mutation', 'Var', (13, 21))	('pRCC', 'Phenotype', 'HP:0006766', (105, 109))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('RCC', 'Disease', (106, 109))	('VHL', 'Disease', (9, 12))	('RCC', 'Disease', (41, 44))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('described', 'Reg', (79, 88))
39250	30596034	Rather than VHL alterations, pRCC is known to harbor trisomies of chromosomes 7 and 17 and losses of Y, whereas ccpRCC does not exhibit these changes.	('trisomies', 'Var', (53, 62))	('losses', 'NegReg', (91, 97))	('pRCC', 'Phenotype', 'HP:0006766', (114, 118))	('ccpRCC', 'Phenotype', 'HP:0006770', (112, 118))	('pRCC', 'Phenotype', 'HP:0006766', (29, 33))	('pRCC', 'Disease', (29, 33))	('VHL', 'Disease', 'MESH:D006623', (12, 15))	('VHL', 'Disease', (12, 15))
39341	25922552	Moreover, genetic mutations of proteins involved in stabilization of HIF factors, such as Von Hippel-Lindau (VHL) protein, are considered the primary events responsible for the occurrence of the majority of clear cell RCC.	('VHL', 'Disease', (109, 112))	('VHL', 'Disease', 'MESH:D006623', (109, 112))	('HIF', 'Disease', (69, 72))	('protein', 'cellular_component', 'GO:0003675', ('114', '121'))	('RCC', 'Disease', 'MESH:C538614', (218, 221))	('RCC', 'Disease', (218, 221))	('HIF', 'Disease', 'None', (69, 72))	('RCC', 'Phenotype', 'HP:0005584', (218, 221))	('genetic mutations', 'Var', (10, 27))	('Von Hippel-Lindau', 'Gene', '7428', (90, 107))	('Von Hippel-Lindau', 'Gene', (90, 107))
39386	30854133	Overexpression of FZD1 is Associated with a Good Prognosis and Resistance of Sunitinib in Clear Cell Renal Cell Carcinoma Frizzled class receptor 1 (FZD1), a receptor for Wnt signaling pathway.	('FZD1', 'Gene', (149, 153))	('Wnt signaling pathway', 'biological_process', 'GO:0016055', ('171', '192'))	('FZD1', 'Gene', '8321', (149, 153))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Clear Cell Renal Cell Carcinoma', 'Phenotype', 'HP:0006770', (90, 121))	('Sunitinib', 'Chemical', 'MESH:D000077210', (77, 86))	('Clear Cell Renal Cell Carcinoma', 'Disease', (90, 121))	('Clear Cell Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (90, 121))	('Overexpression', 'Var', (0, 14))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (101, 121))	('FZD1', 'Gene', '8321', (18, 22))	('FZD1', 'Gene', (18, 22))
39387	30854133	Overexpression of FZD1 has been detected in many cancer tissues and cells resulting in tumor development and drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('FZD1', 'Gene', '8321', (18, 22))	('drug resistance', 'biological_process', 'GO:0042493', ('109', '124'))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (87, 92))	('drug resistance', 'biological_process', 'GO:0009315', ('109', '124'))	('detected', 'Reg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('drug resistance', 'CPA', (109, 124))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('FZD1', 'Gene', (18, 22))	('cancer', 'Disease', (49, 55))	('resulting in', 'Reg', (74, 86))
39394	30854133	Both univariate and multivariate cox regression analysis indicated that high FZD1 level was an independent predictor of good prognosis for OS (HR 0.569, P=0.001) and DFS (HR 0.559, P=0.036) in ccRCC patients.	('cox', 'Gene', '1351', (33, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('RCC', 'Disease', (195, 198))	('OS', 'Chemical', '-', (139, 141))	('FZD1', 'Gene', '8321', (77, 81))	('cox', 'Gene', (33, 36))	('FZD1', 'Gene', (77, 81))	('patients', 'Species', '9606', (199, 207))	('RCC', 'Phenotype', 'HP:0005584', (195, 198))	('DFS', 'Disease', (166, 169))	('RCC', 'Disease', 'MESH:C538614', (195, 198))	('high', 'Var', (72, 76))
39395	30854133	Using cBioportal program, less than 1% mutation in the patients with renal cancer was observed, the alterations in FZD1 were correlated with better OS (P=0.0404) in ccRCC patients.	('FZD1', 'Gene', '8321', (115, 119))	('renal cancer', 'Disease', (69, 81))	('FZD1', 'Gene', (115, 119))	('OS', 'Chemical', '-', (148, 150))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ccRCC', 'Phenotype', 'HP:0006770', (165, 170))	('renal cancer', 'Disease', 'MESH:D007680', (69, 81))	('RCC', 'Disease', 'MESH:C538614', (167, 170))	('renal cancer', 'Phenotype', 'HP:0009726', (69, 81))	('RCC', 'Disease', (167, 170))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))	('patients', 'Species', '9606', (55, 63))	('alterations', 'Var', (100, 111))
39410	30854133	A previous report that ccRCC patients even within the same tumor stage may have different clinical features because mutation or dysregulation of different genes.	('patients', 'Species', '9606', (29, 37))	('ccRCC', 'Phenotype', 'HP:0006770', (23, 28))	('tumor', 'Disease', (59, 64))	('mutation', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('dysregulation', 'Var', (128, 141))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('RCC', 'Disease', (25, 28))
39451	30854133	The database query was based on mutation and altered expression of the FZD1 in ccRCC (U Tokyo, Nat Genet 2013; TCGA, Nature 2013; TCGA, Provisional), pRCC (TCGA, Provisional) and nccRCC (Genentech, Nat Genet 2014).	('RCC', 'Phenotype', 'HP:0005584', (81, 84))	('ccRCC', 'Phenotype', 'HP:0006770', (79, 84))	('RCC', 'Disease', (81, 84))	('pRCC', 'Gene', '5546', (150, 154))	('mutation', 'Var', (32, 40))	('altered', 'Reg', (45, 52))	('FZD1', 'Gene', '8321', (71, 75))	('RCC', 'Disease', 'MESH:C538614', (81, 84))	('FZD1', 'Gene', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('expression', 'MPA', (53, 63))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Disease', (182, 185))	('pRCC', 'Phenotype', 'HP:0006766', (150, 154))	('pRCC', 'Gene', (150, 154))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', 'MESH:C538614', (182, 185))
39452	30854133	Catalogue of Somatic Mutations in Cancer (COSMIC) database (http://www.sanger.ac.uk/cosmic/) was utilized for assessment of FZD1 mutations in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('mutations', 'Var', (129, 138))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('OS', 'Chemical', '-', (43, 45))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('FZD1', 'Gene', '8321', (124, 128))	('RCC', 'Disease', (144, 147))	('RCC', 'Phenotype', 'HP:0005584', (144, 147))	('FZD1', 'Gene', (124, 128))
39471	30854133	Overexpression of FZD1 significantly correlated with lower T stage (P<0.0001; Figure 2C), negative lymph node metastasis (P=0.0353; Figure 2D), negative distant metastasis (P=0.0068; Figure 2E), pathological stage (P<0.0001; Figure 2F), Grade stage (P=0.0001; Figure 2G) in ccRCC patients.	('patients', 'Species', '9606', (280, 288))	('negative', 'NegReg', (144, 152))	('RCC', 'Disease', 'MESH:C538614', (276, 279))	('ccRCC', 'Phenotype', 'HP:0006770', (274, 279))	('RCC', 'Disease', (276, 279))	('RCC', 'Phenotype', 'HP:0005584', (276, 279))	('pathological stage', 'CPA', (195, 213))	('negative lymph node metastasis', 'CPA', (90, 120))	('T stage', 'CPA', (59, 66))	('Overexpression', 'Var', (0, 14))	('FZD1', 'Gene', '8321', (18, 22))	('Grade', 'CPA', (237, 242))	('lower', 'NegReg', (53, 58))	('FZD1', 'Gene', (18, 22))
39483	30854133	Our results showed that upregulated FZD1 level could be a potential prognostic factor for ccRCC patients with Age<60 years (P=0.0021), Age>=60 years (P<0.0001), Female (P<0.0001), Male (P=0.0029), T3+T4 stage (P=0.0009), N0 stage (P<0.0001), Non-metastasis (P=0.0019), Metastasis (P=0.0011), Pathological (III+IV) stage (P=0.0006), G3+G4 stage (P<0.0001) and Non-neoadjuvant treatment (P<0.0001), which all were significantly related to better OS.	('Non-metastasis (P=0.0019), Metastasis', 'Disease', 'MESH:D009362', (242, 279))	('FZD1', 'Gene', '8321', (36, 40))	('FZD1', 'Gene', (36, 40))	('OS', 'Chemical', '-', (444, 446))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('upregulated', 'PosReg', (24, 35))	('RCC', 'Disease', 'MESH:C538614', (92, 95))	('patients', 'Species', '9606', (96, 104))	('ccRCC', 'Phenotype', 'HP:0006770', (90, 95))	('G3+G4 stage', 'Var', (332, 343))	('better OS', 'Disease', (437, 446))
39486	30854133	High expression of FZD1 had better DFS than low FZD1 expression group (log-rank test, P=0.0033; Figure 5A).	('High expression', 'Var', (0, 15))	('FZD1', 'Gene', '8321', (19, 23))	('better', 'PosReg', (28, 34))	('FZD1', 'Gene', (19, 23))	('DFS', 'MPA', (35, 38))	('FZD1', 'Gene', (48, 52))	('FZD1', 'Gene', '8321', (48, 52))
39494	30854133	We also found that FZD1 expression was a risk factor for DFS in the ccRCC patients by univariate cox regression analysis (HR 0.588; P=0.004).	('RCC', 'Disease', 'MESH:C538614', (70, 73))	('RCC', 'Disease', (70, 73))	('RCC', 'Phenotype', 'HP:0005584', (70, 73))	('FZD1', 'Gene', '8321', (19, 23))	('cox', 'Gene', (97, 100))	('patients', 'Species', '9606', (74, 82))	('DFS', 'Disease', (57, 60))	('FZD1', 'Gene', (19, 23))	('ccRCC', 'Phenotype', 'HP:0006770', (68, 73))	('risk', 'Reg', (41, 45))	('cox', 'Gene', '1351', (97, 100))	('expression', 'Var', (24, 34))
39495	30854133	By adjusting multivariate analysis, high FZD1 expression was still considered as an independent predictor of good prognosis for DFS in ccRCC (HR 0.559; P=0.036).	('FZD1', 'Gene', (41, 45))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('FZD1', 'Gene', '8321', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('ccRCC', 'Phenotype', 'HP:0006770', (135, 140))	('RCC', 'Disease', (137, 140))	('high', 'Var', (36, 40))
39498	30854133	Univariate analysis indicated that FZD1 expression was identified as a risk factor for OS in pRCC patients (HR 0.424; P=0.008).	('risk', 'Reg', (71, 75))	('RCC', 'Phenotype', 'HP:0005584', (94, 97))	('FZD1', 'Gene', (35, 39))	('pRCC', 'Gene', '5546', (93, 97))	('expression', 'Var', (40, 50))	('OS', 'Chemical', '-', (87, 89))	('pRCC', 'Phenotype', 'HP:0006766', (93, 97))	('patients', 'Species', '9606', (98, 106))	('pRCC', 'Gene', (93, 97))	('FZD1', 'Gene', '8321', (35, 39))
39501	30854133	Using COSMIC database, the pie chart described the mutations information including substitution nonsense, missense, synonymous, deletion frame and insertion frame shift.	('OS', 'Chemical', '-', (7, 9))	('missense', 'Var', (106, 114))	('deletion frame', 'Var', (128, 142))	('substitution nonsense', 'Var', (83, 104))	('insertion frame shift', 'Var', (147, 168))	('synonymous', 'Var', (116, 126))
39502	30854133	Substitution missense rate was 100% of mutation samples of ccRCC (Figure 6A).	('Substitution missense', 'Var', (0, 21))	('ccRCC', 'Phenotype', 'HP:0006770', (59, 64))	('RCC', 'Disease', 'MESH:C538614', (61, 64))	('RCC', 'Disease', (61, 64))	('RCC', 'Phenotype', 'HP:0005584', (61, 64))
39503	30854133	Alteration frequency of FZD1 mutation in renal cancer was analyzed by cBioportal program.	('mutation', 'Var', (29, 37))	('renal cancer', 'Disease', (41, 53))	('renal cancer', 'Disease', 'MESH:D007680', (41, 53))	('renal cancer', 'Phenotype', 'HP:0009726', (41, 53))	('FZD1', 'Gene', '8321', (24, 28))	('FZD1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
39505	30854133	After analyzed by Kaplan-Meier plot and log-rank test, the alterations in FZD1 were associated with better OS in ccRCC patients (P=0.0404; Figure 6C).	('alterations', 'Var', (59, 70))	('FZD1', 'Gene', '8321', (74, 78))	('OS', 'Chemical', '-', (107, 109))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('FZD1', 'Gene', (74, 78))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('RCC', 'Disease', (115, 118))	('patients', 'Species', '9606', (119, 127))	('ccRCC', 'Phenotype', 'HP:0006770', (113, 118))	('better', 'PosReg', (100, 106))
39506	30854133	However, there was no significant difference between DFS in ccRCC patients with/without FZD1 alterations (P=0.328; Figure 6D).	('FZD1', 'Gene', '8321', (88, 92))	('alterations', 'Var', (93, 104))	('FZD1', 'Gene', (88, 92))	('ccRCC', 'Phenotype', 'HP:0006770', (60, 65))	('RCC', 'Disease', 'MESH:C538614', (62, 65))	('RCC', 'Disease', (62, 65))	('RCC', 'Phenotype', 'HP:0005584', (62, 65))	('patients', 'Species', '9606', (66, 74))
39518	30854133	Overexpression of FZD1 in pancreatic cancer were associated with invasion, metastasis and shorter overall survival.	('FZD1', 'Gene', '8321', (18, 22))	('shorter', 'NegReg', (90, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))	('metastasis', 'CPA', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Overexpression', 'Var', (0, 14))	('invasion', 'CPA', (65, 73))	('pancreatic cancer', 'Disease', (26, 43))	('overall', 'MPA', (98, 105))	('FZD1', 'Gene', (18, 22))
39521	30854133	The high FZD1 level was strongly associated with indolent and non-recurrent characteristics of ccRCC.	('RCC', 'Disease', (97, 100))	('FZD1', 'Gene', '8321', (9, 13))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('FZD1', 'Gene', (9, 13))	('ccRCC', 'Phenotype', 'HP:0006770', (95, 100))	('associated', 'Reg', (33, 43))	('high', 'Var', (4, 8))
39522	30854133	Genetic mutations and epigenetic alterations are very important for tumorigenesis, also impose vital impact as independent prognostic markers on therapeutic strategies for cancer patients.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (172, 178))	('epigenetic alterations', 'Var', (22, 44))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Genetic mutations', 'Var', (0, 17))
39523	30854133	In ccRCC, although somatic VHL mutations have been described for some time, more recent cancer genomic studies have identified new mutations in ccRCC, including PBRM1, SETD2, BAP1, MTOR and CKAP4 that were associated with aggressive clinical features.	('cancer', 'Disease', (88, 94))	('PBRM1', 'Gene', (161, 166))	('VHL', 'Disease', (27, 30))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('RCC', 'Phenotype', 'HP:0005584', (5, 8))	('CKAP4', 'Gene', '10970', (190, 195))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('BAP1', 'Gene', (175, 179))	('RCC', 'Disease', (146, 149))	('associated', 'Reg', (206, 216))	('RCC', 'Phenotype', 'HP:0005584', (146, 149))	('ccRCC', 'Phenotype', 'HP:0006770', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('SETD2', 'Gene', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('CKAP4', 'Gene', (190, 195))	('RCC', 'Disease', 'MESH:C538614', (146, 149))	('VHL', 'Disease', 'MESH:D006623', (27, 30))	('SETD2', 'Gene', '29072', (168, 173))	('MTOR', 'Gene', (181, 185))	('MTOR', 'Gene', '2475', (181, 185))	('mutations', 'Var', (131, 140))	('PBRM1', 'Gene', '55193', (161, 166))	('BAP1', 'Gene', '8314', (175, 179))
39524	30854133	FZD1 was mutated at frequency ranged from 4% to 2%, involved in cell migration and invasion in neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (95, 108))	('involved in', 'Reg', (52, 63))	('neuroblastoma', 'Disease', 'MESH:D009447', (95, 108))	('mutated', 'Var', (9, 16))	('neuroblastoma', 'Disease', (95, 108))	('invasion', 'CPA', (83, 91))	('FZD1', 'Gene', '8321', (0, 4))	('cell migration', 'biological_process', 'GO:0016477', ('64', '78'))	('FZD1', 'Gene', (0, 4))	('cell migration', 'CPA', (64, 78))
39525	30854133	FZD1 was also frequently methylated and whose methylation was associated with inactivation of gene expression in prostate cancer cell lines.	('methylation', 'biological_process', 'GO:0032259', ('46', '57'))	('gene expression', 'biological_process', 'GO:0010467', ('94', '109'))	('associated', 'Reg', (62, 72))	('methylated', 'Var', (25, 35))	('prostate cancer', 'Disease', (113, 128))	('methylation', 'MPA', (46, 57))	('FZD1', 'Gene', '8321', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('FZD1', 'Gene', (0, 4))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('inactivation', 'NegReg', (78, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
39526	30854133	We found less than 1% mutation in the patients with renal cancer was observed and the alterations in FZD1 were associated with better OS in ccRCC patients.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('FZD1', 'Gene', (101, 105))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('associated', 'Reg', (111, 121))	('renal cancer', 'Disease', (52, 64))	('better OS', 'Disease', (127, 136))	('renal cancer', 'Phenotype', 'HP:0009726', (52, 64))	('OS', 'Chemical', '-', (134, 136))	('patients', 'Species', '9606', (38, 46))	('renal cancer', 'Disease', 'MESH:D007680', (52, 64))	('patients', 'Species', '9606', (146, 154))	('FZD1', 'Gene', '8321', (101, 105))	('alterations', 'Var', (86, 97))
39527	30854133	The exact mechanism of FZD1 alteration with longer OS in ccRCC patients needs more investigations.	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('OS', 'Chemical', '-', (51, 53))	('FZD1', 'Gene', '8321', (23, 27))	('alteration', 'Var', (28, 38))	('FZD1', 'Gene', (23, 27))	('patients', 'Species', '9606', (63, 71))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
39533	30854133	We also identified new mutated genes that are involved in the pathogenesis of ccRCC, which help identify clinic patients.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('RCC', 'Disease', (80, 83))	('RCC', 'Phenotype', 'HP:0005584', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('patients', 'Species', '9606', (112, 120))	('pathogenesis', 'biological_process', 'GO:0009405', ('62', '74'))	('mutated', 'Var', (23, 30))
39540	30854133	FZD1 is overexpressed in the multidrug resistant breast cancer cell, when FZD1 silencing induced down-regulation of MDR1/P-gp through the Wnt/beta-catenin signaling, restored sensitivity to chemotherapy drugs.	('down-regulation', 'NegReg', (97, 112))	('MDR1', 'Gene', (116, 120))	('FZD1', 'Gene', '8321', (74, 78))	('MDR', 'molecular_function', 'GO:0004745', ('116', '119'))	('FZD1', 'Gene', (74, 78))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('beta-catenin', 'Gene', (142, 154))	('regulation', 'biological_process', 'GO:0065007', ('102', '112'))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('beta-catenin', 'Gene', '1499', (142, 154))	('P-gp', 'Gene', '283871', (121, 125))	('restored', 'PosReg', (166, 174))	('FZD1', 'Gene', '8321', (0, 4))	('sensitivity to chemotherapy drugs', 'MPA', (175, 208))	('P-gp', 'Gene', (121, 125))	('FZD1', 'Gene', (0, 4))	('MDR1', 'Gene', '5243', (116, 120))	('signaling', 'biological_process', 'GO:0023052', ('155', '164'))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('silencing', 'Var', (79, 88))
39542	30854133	Hippo signaling dysregulation underlies various human diseases including cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('human', 'Species', '9606', (48, 53))	('Hippo signaling', 'MPA', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Hippo signaling', 'biological_process', 'GO:0035329', ('0', '15'))	('dysregulation', 'Var', (16, 29))
39583	30446580	2C), and P504S and negative for cytokeratin (CK) 7, thyroid transcription factor (TTF)-1, thyroglobulin, high-molecular weight CK (34betaE12), and CD10.	('P504S', 'Var', (9, 14))	('transcription', 'biological_process', 'GO:0006351', ('60', '73'))	('transcription factor', 'molecular_function', 'GO:0000981', ('60', '80'))	('cytokeratin (CK) 7', 'Gene', (32, 50))	('CD10', 'molecular_function', 'GO:0004245', ('147', '151'))	('thyroglobulin', 'Gene', '7038', (90, 103))	('thyroid transcription factor (TTF)-1', 'Gene', '7270', (52, 88))	('thyroglobulin', 'Gene', (90, 103))	('CD10', 'Gene', (147, 151))	('P504S', 'Mutation', 'p.P504S', (9, 14))	('cytokeratin (CK) 7', 'Gene', '3855', (32, 50))	('CD10', 'Gene', '4311', (147, 151))
39589	30446580	Comparison of the genomic sequencing results from the tumor against the peripheral blood (normal) sample detected a total of 25 somatic nonsynonymous single nucleotide variants (SNVs) and two truncating insertion/deletion events (indels) within coding regions.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('gain', 'Disease', (61, 65))	('gain', 'Disease', 'MESH:D015430', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('single nucleotide variants', 'Var', (150, 176))	('tumor', 'Disease', (54, 59))
39591	30446580	Six somatic variants of uncertain significance (VUSs) were detected in known cancer-related genes including KRAS, I187T; CAT, F185I; CEP290, Q284H; and CSDE1, D767N.	('KRAS', 'Gene', (108, 112))	('CSDE1', 'Gene', (152, 157))	('D767N', 'Var', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('AT', 'Disease', 'None', (122, 124))	('Q284H', 'Mutation', 'p.Q284H', (141, 146))	('CSDE1', 'Gene', '7812', (152, 157))	('Q284H', 'Var', (141, 146))	('D767N', 'Mutation', 'p.D767N', (159, 164))	('I187T', 'Mutation', 'rs1452019494', (114, 119))	('CEP290', 'Gene', '80184', (133, 139))	('cancer', 'Disease', (77, 83))	('I187T', 'Var', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('F185I', 'Mutation', 'p.F185I', (126, 131))	('CAT', 'molecular_function', 'GO:0004096', ('121', '124'))	('CEP290', 'Gene', (133, 139))	('F185I', 'Var', (126, 131))	('KRAS', 'Gene', '3845', (108, 112))	('CEP', 'molecular_function', 'GO:0047849', ('133', '136'))
39607	30446580	Blood genome sequences were analyzed to detect germline mutations, copy-number changes, and SVs in 98 genes previously linked to hereditary cancer.	('SVs', 'Var', (92, 95))	('copy-number changes', 'Var', (67, 86))	('hereditary cancer', 'Disease', 'MESH:D009369', (129, 146))	('hereditary cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
39618	30446580	Although both cases lacked VHL mutations, concurrent mutations in PBRM1, SETD2, and TSC1 supported the diagnosis of RCC.	('SETD2', 'Gene', (73, 78))	('TSC1', 'Gene', '7248', (84, 88))	('VHL', 'Disease', 'MESH:D006623', (27, 30))	('TSC1', 'Gene', (84, 88))	('VHL', 'Disease', (27, 30))	('mutations', 'Var', (53, 62))	('PBRM1', 'Gene', (66, 71))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('SETD2', 'Gene', '29072', (73, 78))	('RCC', 'Disease', (116, 119))	('PBRM1', 'Gene', '55193', (66, 71))
39633	30446580	Another case of TLFRCC showed monosomies in Chromosomes 7 and 17.	('monosomies', 'Var', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (19, 22))	('RCC', 'Disease', (19, 22))
39640	30446580	Messenger RNA selection was performed using NEBNext Oligod(T)25 beads (NEB) with incubation at 65 C for 5 min followed by snap-chilling at 4 C to denature RNA and facilitate binding of poly(A) mRNA to the beads.	('RNA', 'cellular_component', 'GO:0005562', ('10', '13'))	('binding', 'Interaction', (174, 181))	('binding', 'molecular_function', 'GO:0005488', ('174', '181'))	('-chilling', 'Phenotype', 'HP:0025143', (126, 135))	('facilitate', 'PosReg', (163, 173))	('RNA', 'Protein', (155, 158))	('snap', 'molecular_function', 'GO:0005483', ('122', '126'))	('poly(A)', 'Chemical', 'MESH:D011061', (185, 192))	('poly(A) mRNA', 'Protein', (185, 197))	('RNA', 'cellular_component', 'GO:0005562', ('155', '158'))	('denature', 'Var', (146, 154))
39646	30446580	Having sequenced both blood and tumor samples, variants identified from aligning the first sample were labeled as germline.	('tumor', 'Disease', (32, 37))	('variants', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))
39648	30446580	Heterozygosity and regions of copy loss and gain were assessed using hidden Markov model- based approaches, CNAseq (v0.0.6) and APOLLOH (v0.1.1).	('copy', 'Var', (30, 34))	('gain', 'Disease', (44, 48))	('gain', 'Disease', 'MESH:D015430', (44, 48))
39661	30111351	It was found that except for BRAF (22/28) mutations (c.1799 T > A, p.V600E), NF1 (6/28), NOTCH1 (5/28), SPEN (5/28), AKT2 (4/28), APC (4/28), ATRX (3/28), and ETV4 (3/28) mutations could also be detected.	('AKT2', 'Gene', (117, 121))	('APC', 'Gene', (130, 133))	('APC', 'cellular_component', 'GO:0005680', ('130', '133'))	('NF1', 'Gene', '4763', (77, 80))	('c.1799 T > A', 'Mutation', 'rs113488022', (53, 65))	('NOTCH1', 'Gene', '4851', (89, 95))	('ETV4', 'Gene', (159, 163))	('p.V600E', 'Mutation', 'rs113488022', (67, 74))	('p.V600E', 'Var', (67, 74))	('NF1', 'Gene', (77, 80))	('ETV4', 'Gene', '2118', (159, 163))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('SPEN', 'Gene', '23013', (104, 108))	('APC', 'Gene', '324', (130, 133))	('AKT2', 'Gene', '208', (117, 121))	('NOTCH1', 'Gene', (89, 95))	('c.1799 T > A', 'Var', (53, 65))	('ATRX', 'Gene', (142, 146))	('ATRX', 'Gene', '546', (142, 146))	('SPEN', 'Gene', (104, 108))
39673	30111351	It was demonstrated that missense mutation of BRAF V600E could be detected in approximately 90% of this kidney tumor subtype.	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('missense mutation', 'Var', (25, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('detected', 'Reg', (66, 74))	('tumor', 'Disease', (111, 116))	('kidney tumor', 'Phenotype', 'HP:0009726', (104, 116))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('rat', 'Species', '10116', (14, 17))
39674	30111351	In addition, other somatic mutations at BRAF exon 15, including a V600D missense mutation and a V600D and K601 L double mutation were also reported.	('BRAF', 'Gene', '673', (40, 44))	('K601 L', 'Var', (106, 112))	('V600D missense', 'Var', (66, 80))	('BRAF', 'Gene', (40, 44))	('K601 L', 'Mutation', 'p.K601L', (106, 112))	('V600D', 'Mutation', 'rs121913377', (96, 101))	('V600D', 'Mutation', 'rs121913377', (66, 71))	('V600D', 'Var', (96, 101))
39676	30111351	However, the BRAF V600E mutation could improve BRAF kinase activity and sustain the activation of downstream kinase MEK, which occurs in some human malignancies, such as melanoma, papillary thyroid carcinoma, colonic adenocarcinoma, pulmonary cancer, Langerhans cell histiocytosis, and pleomorphic xanthoastrocytomas to stimulate tumor growth.	('pulmonary cancer', 'Disease', (233, 249))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (190, 207))	('tumor', 'Disease', (330, 335))	('histiocytosis', 'Phenotype', 'HP:0100727', (267, 280))	('activation', 'MPA', (84, 94))	('Langerhans cell histiocytosis', 'Disease', (251, 280))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (209, 231))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('improve', 'PosReg', (39, 46))	('BRAF', 'Gene', '673', (13, 17))	('MEK', 'Gene', '5609', (116, 119))	('BRAF', 'Gene', (47, 51))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('BRAF', 'Gene', '673', (47, 51))	('colonic adenocarcinoma', 'Disease', (209, 231))	('human', 'Species', '9606', (142, 147))	('BRAF', 'Gene', (13, 17))	('pleomorphic xanthoastrocytomas', 'Disease', 'MESH:D008228', (286, 316))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (180, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('papillary thyroid carcinoma', 'Disease', (180, 207))	('kinase activity', 'molecular_function', 'GO:0016301', ('52', '67'))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (180, 207))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('MEK', 'Gene', (116, 119))	('pulmonary cancer', 'Disease', 'MESH:D008175', (233, 249))	('malignancies', 'Disease', 'MESH:D009369', (148, 160))	('malignancies', 'Disease', (148, 160))	('pulmonary cancer', 'Phenotype', 'HP:0100526', (233, 249))	('pleomorphic xanthoastrocytomas', 'Disease', (286, 316))	('V600E', 'Var', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('stimulate', 'PosReg', (320, 329))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
39691	30111351	Instances of the BRAF V600E mutation were confirmed using the ADx-ARMS BRAF Mutation Assay Kit (AmoyDx, China) by ARMS (Amplification Refractory Mutation System) and Scorpions technologies.	('BRAF', 'Gene', '673', (71, 75))	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', (17, 21))	('V600E', 'Var', (22, 27))
39694	30111351	Commercially available BRAF V600E-mutated or wild-type human genomic DNA were utilized as positive and negative controls respectively.	('DNA', 'cellular_component', 'GO:0005574', ('69', '72'))	('BRAF', 'Gene', '673', (23, 27))	('human', 'Species', '9606', (55, 60))	('BRAF', 'Gene', (23, 27))	('V600E-mutated', 'Var', (28, 41))	('V600E', 'Mutation', 'rs113488022', (28, 33))
39698	30111351	Over 50% of the tumor cells stained positivity were scored as diffuse and strong (3+); 26 to 50% were evaluated as intermediate and moderate (2+); and between 1 and 25% were scored as focal and weak (1+).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('rat', 'Species', '10116', (136, 139))	('positivity', 'Var', (36, 46))
39701	30111351	The remainders, two cases of PRCC and one case of Wilms tumor, which exerted similar morphological features with MA, were further identified by immunohistochemical study and BRAF mutations detection using qPCR.	('PRCC', 'Phenotype', 'HP:0006766', (29, 33))	('Wilms tumor', 'Disease', 'MESH:D009396', (50, 61))	('Wilms tumor', 'Phenotype', 'HP:0002667', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Wilms tumor', 'Disease', (50, 61))	('BRAF', 'Gene', '673', (174, 178))	('PRCC', 'Gene', '5546', (29, 33))	('BRAF', 'Gene', (174, 178))	('mutations', 'Var', (179, 188))	('PRCC', 'Gene', (29, 33))
39715	30111351	In this study, we found 22 MA patients possessing a p.V600E mutation of BRAF exon 15, a substitution of thymidine by adenine (GTG   GAG) at codon 600.	('BRAF', 'Gene', (72, 76))	('p.V600E', 'Var', (52, 59))	('adenine', 'Chemical', 'MESH:D000225', (117, 124))	('thymidine', 'Chemical', 'MESH:D013936', (104, 113))	('patients', 'Species', '9606', (30, 38))	('GAG', 'Chemical', 'MESH:D006025', (132, 135))	('GTG', 'Chemical', 'MESH:D006160', (126, 129))	('p.V600E', 'Mutation', 'rs113488022', (52, 59))	('BRAF', 'Gene', '673', (72, 76))
39718	30111351	All BRAF mutations have been confirmed using RT-PCR and Sanger sequencing (data not shown).	('mutations', 'Var', (9, 18))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
39721	30111351	In addition, tumor size in BRAF wild-type cases ranged from 2 to 5.5 cm (median = 2.2); this value was also less than that in BRAF V600E-mutated patients (p < 0.05, Table 4).	('V600E-mutated', 'Var', (131, 144))	('tumor', 'Disease', (13, 18))	('V600E', 'Mutation', 'rs113488022', (131, 136))	('patients', 'Species', '9606', (145, 153))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('BRAF', 'Gene', '673', (126, 130))	('BRAF', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
39723	30111351	In addition, it should be noticed that one germline BRCA1 (NM_007300.3) mutation which was likely pathogenic (c.2286A > T (p.Arg762Ser)) was found in a male MA patient.	('c.2286A > T', 'Mutation', 'rs273898682', (110, 121))	('BRCA1', 'Gene', '672', (52, 57))	('Ser', 'cellular_component', 'GO:0005790', ('131', '134'))	('BRCA1', 'Gene', (52, 57))	('p.Arg762Ser', 'Mutation', 'rs273898682', (123, 134))	('patient', 'Species', '9606', (160, 167))	('c.2286A > T', 'Var', (110, 121))
39724	30111351	This patient also had a somatic BRAF V600E, APC L662I, and FANCD2 N791S missense mutation.	('APC', 'Gene', (44, 47))	('BRAF', 'Gene', '673', (32, 36))	('FANCD2', 'Gene', (59, 65))	('patient', 'Species', '9606', (5, 12))	('APC', 'Gene', '324', (44, 47))	('N791S', 'Mutation', 'rs758718558', (66, 71))	('BRAF', 'Gene', (32, 36))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('V600E', 'Var', (37, 42))	('APC', 'cellular_component', 'GO:0005680', ('44', '47'))	('L662I', 'Var', (48, 53))	('L662I', 'Mutation', 'rs756859993', (48, 53))	('FANCD2', 'Gene', '2177', (59, 65))
39731	30111351	Meanwhile, in BRAF V600E-mutated MA, BCL2-positive cases were significantly higher than those in BRAF wild-type patients (Table 4).	('BCL2', 'Gene', (37, 41))	('V600E-mutated', 'Var', (19, 32))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('patients', 'Species', '9606', (112, 120))	('BRAF', 'Gene', '673', (14, 18))	('BCL2', 'Gene', '596', (37, 41))	('BCL2', 'molecular_function', 'GO:0015283', ('37', '41'))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (14, 18))	('higher', 'PosReg', (76, 82))	('BRAF', 'Gene', (97, 101))
39735	30111351	Moreover, p16 (INK4alpha)-positive cases were significantly higher in BRAF V600E-mutated MA cases in comparison with those in the BRAF wild-type cases (Table 4).	('higher', 'PosReg', (60, 66))	('BRAF', 'Gene', '673', (130, 134))	('V600E-mutated', 'Var', (75, 88))	('V600E', 'Mutation', 'rs113488022', (75, 80))	('p16', 'Gene', (10, 13))	('BRAF', 'Gene', (130, 134))	('INK4alpha', 'Gene', '1029', (15, 24))	('INK4alpha', 'Gene', (15, 24))	('BRAF', 'Gene', '673', (70, 74))	('p16', 'Gene', '1029', (10, 13))	('BRAF', 'Gene', (70, 74))
39736	30111351	Because of the high frequency of BRAF mutations in MA, we further investigated the status of MAPK signaling, the expression of phosphorylated MEK (p-MEK), total MEK (t-MEK), phosphorylated ERK (p-ERK), and total ERK (t-ERK).	('BRAF', 'Gene', '673', (33, 37))	('MAPK signaling', 'biological_process', 'GO:0000165', ('93', '107'))	('ERK', 'molecular_function', 'GO:0004707', ('189', '192'))	('BRAF', 'Gene', (33, 37))	('MEK', 'Gene', (149, 152))	('ERK', 'molecular_function', 'GO:0004707', ('219', '222'))	('MEK', 'Gene', (142, 145))	('ERK', 'Gene', (219, 222))	('mutations', 'Var', (38, 47))	('MEK', 'Gene', '5609', (168, 171))	('ERK', 'molecular_function', 'GO:0004707', ('196', '199'))	('MEK', 'Gene', '5609', (161, 164))	('ERK', 'Gene', '5594', (212, 215))	('ERK', 'Gene', '5594', (196, 199))	('ERK', 'Gene', '5594', (189, 192))	('ERK', 'molecular_function', 'GO:0004707', ('212', '215'))	('MAPK', 'molecular_function', 'GO:0004707', ('93', '97'))	('MEK', 'Gene', (168, 171))	('MEK', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (142, 145))	('MEK', 'Gene', '5609', (149, 152))	('ERK', 'Gene', '5594', (219, 222))	('ERK', 'Gene', (212, 215))	('ERK', 'Gene', (196, 199))	('ERK', 'Gene', (189, 192))
39745	30111351	However, no significant difference in p-ERK nor DUSP6 was found between BRAF V600E-mutated and BRAF wild-type MA cases (Table 5).	('ERK', 'molecular_function', 'GO:0004707', ('40', '43'))	('BRAF', 'Gene', (72, 76))	('ERK', 'Gene', '5594', (40, 43))	('V600E-mutated', 'Var', (77, 90))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', '673', (95, 99))	('ERK', 'Gene', (40, 43))	('BRAF', 'Gene', (95, 99))	('BRAF', 'Gene', '673', (72, 76))
39750	30111351	However, except for approximately 10% of the wild-type genotype, other BRAF mutation sites such as V600D, V600 K, V600R, and K601 L also exist in MA patients.	('V600D', 'Mutation', 'rs121913377', (99, 104))	('patients', 'Species', '9606', (149, 157))	('V600R', 'Mutation', 'rs121913227', (114, 119))	('BRAF', 'Gene', '673', (71, 75))	('K601 L', 'Var', (125, 131))	('V600R', 'Var', (114, 119))	('BRAF', 'Gene', (71, 75))	('V600 K', 'Mutation', 'rs121913227', (106, 112))	('K601 L', 'Mutation', 'p.K601L', (125, 131))	('V600D', 'Var', (99, 104))	('V600 K', 'Var', (106, 112))
39752	30111351	All five cases of MA which had negative BRAF mutation showed typical morphologic features of MA.	('BRAF', 'Gene', '673', (40, 44))	('mutation', 'Var', (45, 53))	('BRAF', 'Gene', (40, 44))
39753	30111351	Meanwhile, their immunophenotyping were WT-1 +, CD57 +, CK7 -, AMACR -, which were also accorded with the diagnosis of MA.	('CK7', 'Gene', (56, 59))	('CK7', 'Gene', '3855', (56, 59))	('WT-1 +', 'Var', (40, 46))	('CD57', 'Gene', (48, 52))	('AMACR', 'Gene', (63, 68))	('CD57', 'Gene', '27087', (48, 52))	('AMACR', 'Gene', '23600', (63, 68))
39755	30111351	We also detected copy number variations of 7, 17 and Y chromosomes by FISH technology, and found no abnormities among these five cases of MA, which is characteristic of type 1 PRCC (data not shown).	('PRCC', 'Phenotype', 'HP:0006766', (176, 180))	('detected', 'Reg', (8, 16))	('PRCC', 'Gene', '5546', (176, 180))	('PRCC', 'Gene', (176, 180))	('copy number variations', 'Var', (17, 39))
39757	30111351	However, although negative BRAF exists in MA, considered the high frequency of BRAF mutation improves the diagnosis of MA.	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (27, 31))	('BRAF', 'Gene', (79, 83))	('improves', 'PosReg', (93, 101))	('mutation', 'Var', (84, 92))
39760	30111351	Similar to previous studies mainly conducted on Caucasian MA patients, it was found that MA patients from Asian populations also have a high rate of mutation in the BRAF V600E site.	('V600E', 'Mutation', 'rs113488022', (170, 175))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (92, 100))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (165, 169))	('rat', 'Species', '10116', (141, 144))	('mutation', 'Var', (149, 157))
39769	30111351	Although it was confirmed that there was no copy number gain in chromosomes 3, 7, 17, and Y in those 28 MA cases by FISH analysis (data not shown), which is frequently existed in type 1 PRCC, NGS results still suggested that approximately 8.1% copy number gain occurred in total mutations.	('PRCC', 'Phenotype', 'HP:0006766', (186, 190))	('GS', 'Disease', 'MESH:D011125', (193, 195))	('PRCC', 'Gene', '5546', (186, 190))	('PRCC', 'Gene', (186, 190))	('copy number', 'Var', (244, 255))
39770	30111351	As it was known, the copy number variants were highly associated with the development of malignancy, such as type 1 PRCC.	('malignancy', 'Disease', (89, 99))	('copy number variants', 'Var', (21, 41))	('PRCC', 'Gene', (116, 120))	('PRCC', 'Phenotype', 'HP:0006766', (116, 120))	('PRCC', 'Gene', '5546', (116, 120))	('associated with', 'Reg', (54, 69))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
39773	30111351	Interestingly, a rare germline BRCA1 mutation was found in one male MA patient without a personal or family history of breast cancer, prostatic cancer, or pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (155, 172))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('mutation', 'Var', (37, 45))	('prostatic cancer', 'Disease', (134, 150))	('breast cancer', 'Disease', (119, 132))	('BRCA1', 'Gene', '672', (31, 36))	('prostatic cancer', 'Disease', 'MESH:D011471', (134, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('found', 'Reg', (50, 55))	('pancreatic cancer', 'Disease', (155, 172))	('prostatic cancer', 'Phenotype', 'HP:0012125', (134, 150))	('BRCA1', 'Gene', (31, 36))	('pancreatic cancer', 'Disease', 'MESH:D010190', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
39775	30111351	And certain mutations of BRCA1/2 often lead to increasing the risk of breast and ovarian cancer in women.	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('lead to', 'Reg', (39, 46))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (70, 95))	('increasing', 'PosReg', (47, 57))	('mutations', 'Var', (12, 21))	('BRCA1/2', 'Gene', '672;675', (25, 32))	('women', 'Species', '9606', (99, 104))	('BRCA1/2', 'Gene', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
39778	30111351	Because this sole case cannot establish the relationship between this germline BRCA1 mutation and tumor development as MA, the role of this famous tumor suppressor gene in MA requires further evaluation.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('BRCA1', 'Gene', '672', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('BRCA1', 'Gene', (79, 84))	('tumor suppressor', 'biological_process', 'GO:0051726', ('147', '163'))	('mutation', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor suppressor', 'molecular_function', 'GO:0008181', ('147', '163'))	('tumor', 'Disease', (98, 103))
39782	30111351	Thus, as well as in other indolent neoplasms such as melanocytic nevi, the reason for why MA remains benign in the presence of a BRAF V600E mutation attracted our attention.	('nevi', 'Phenotype', 'HP:0003764', (65, 69))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('neoplasm', 'Phenotype', 'HP:0002664', (35, 43))	('neoplasms', 'Disease', 'MESH:D009369', (35, 44))	('neoplasms', 'Disease', (35, 44))	('V600E', 'Mutation', 'rs113488022', (134, 139))	('melanocytic', 'Disease', 'MESH:D009508', (53, 64))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (53, 69))	('melanocytic', 'Disease', (53, 64))	('V600E', 'Var', (134, 139))	('neoplasms', 'Phenotype', 'HP:0002664', (35, 44))
39792	30111351	Not only p16 (INK4alpha), but other senescence markers such as acidic beta-galactosidase and PAI-1, could also be involved in cell senescence induced by a BRAF mutation.	('mutation', 'Var', (160, 168))	('BRAF', 'Gene', (155, 159))	('INK4alpha', 'Gene', '1029', (14, 23))	('INK4alpha', 'Gene', (14, 23))	('senescence', 'biological_process', 'GO:0010149', ('36', '46'))	('senescence', 'biological_process', 'GO:0010149', ('131', '141'))	('PAI-1', 'Gene', (93, 98))	('p16', 'Gene', '1029', (9, 12))	('involved', 'Reg', (114, 122))	('acidic beta-galactosidase', 'Disease', 'MESH:D016537', (63, 88))	('cell senescence', 'CPA', (126, 141))	('BRAF', 'Gene', '673', (155, 159))	('acidic beta-galactosidase', 'Disease', (63, 88))	('PAI-1', 'Gene', '5054', (93, 98))	('p16', 'Gene', (9, 12))
39799	30111351	Besides, the p-ERK positivity was no different between the BRAF-mutated and wild-type MA cases, suggesting that a BRAF mutation causes an irrelevant pathway that blocks the MAPK signal, which may be another important reason for the indolence of MA.	('ERK', 'molecular_function', 'GO:0004707', ('15', '18'))	('mutation', 'Var', (119, 127))	('BRAF', 'Gene', (114, 118))	('irrelevant pathway', 'Pathway', (138, 156))	('ERK', 'Gene', '5594', (15, 18))	('blocks', 'NegReg', (162, 168))	('BRAF', 'Gene', '673', (114, 118))	('MAPK signal', 'MPA', (173, 184))	('ERK', 'Gene', (15, 18))	('MAPK', 'molecular_function', 'GO:0004707', ('173', '177'))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('causes', 'Reg', (128, 134))
39813	29925043	The genetic alterations of TSC1 or TSC2 are responsible for the development of TSC.	('genetic alterations', 'Var', (4, 23))	('responsible', 'Reg', (44, 55))	('TSC2', 'Gene', '7249', (35, 39))	('TSC1', 'Gene', '7248', (27, 31))	('TSC', 'Gene', (27, 30))	('TSC', 'Gene', '7248', (27, 30))	('TSC2', 'Gene', (35, 39))	('TSC', 'Gene', (79, 82))	('TSC1', 'Gene', (27, 31))	('TSC', 'Gene', (35, 38))	('TSC', 'Gene', '7248', (79, 82))	('TSC', 'Gene', '7248', (35, 38))
39818	29925043	The mTOR pathway activation and the germline mutations of TSC2 were identified in both TSC-RCC cases.	('TSC2', 'Gene', '7249', (58, 62))	('TSC2', 'Gene', (58, 62))	('germline mutations', 'Var', (36, 54))	('TSC', 'Gene', (58, 61))	('TSC', 'Gene', '7248', (58, 61))	('TSC', 'Gene', '7248', (87, 90))	('mTOR', 'Gene', (4, 8))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('activation', 'PosReg', (17, 27))	('TSC', 'Gene', (87, 90))	('mTOR', 'Gene', '2475', (4, 8))
39819	29925043	The WES revealed several cancer gene alterations.	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('alterations', 'Var', (37, 48))
39821	29925043	In Case 2, genetic alterations of IWS1 and TSC2 were identified.	('IWS1', 'Gene', '55677', (34, 38))	('TSC2', 'Gene', '7249', (43, 47))	('IWS1', 'Gene', (34, 38))	('genetic alterations', 'Var', (11, 30))	('TSC2', 'Gene', (43, 47))
39832	29925043	The disease is caused by alterations in TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively.	('alterations', 'Var', (25, 36))	('tuberin', 'Gene', (86, 93))	('TSC1', 'Gene', (40, 44))	('caused by', 'Reg', (15, 24))	('TSC2', 'Gene', '7249', (48, 52))	('TSC2', 'Gene', (48, 52))	('hamartin', 'Gene', '7248', (73, 81))	('tuberin', 'Gene', '7249', (86, 93))	('hamartin', 'Gene', (73, 81))	('TSC1', 'Gene', '7248', (40, 44))
39841	29925043	In this study, we assessed the activation of the mTOR pathway and the genetic alterations in two cases of TSC-RCC by immunohistochemistry and whole exome sequencing (WES).	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('TSC', 'Gene', (106, 109))	('TSC', 'Gene', '7248', (106, 109))	('activation', 'PosReg', (31, 41))	('genetic alterations', 'Var', (70, 89))
39879	29925043	We regarded identical mutations on both normal and cancer tissues as germline mutations.	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
39880	29925043	In Case 1, a TSC2 c.4707C > A (p.Tyr1569*) mutation was identified, and in Case 2, a TSC2 c.2548+ 2 T > G mutation was seen (Table 1 and Supplementary Figure 2), which were stop gained effect and a splice donor variant, respectively.	('TSC2', 'Gene', (13, 17))	('2 T > G', 'SUBSTITUTION', 'None', (98, 105))	('donor variant', 'Species', '9606', (205, 218))	('c.4707C > A', 'Mutation', 'rs397514999', (18, 29))	('p.Tyr1569*', 'Mutation', 'rs397514999', (31, 41))	('2 T > G', 'Var', (98, 105))	('TSC2', 'Gene', '7249', (13, 17))	('c.4707C > A', 'Var', (18, 29))	('TSC2', 'Gene', '7249', (85, 89))	('TSC2', 'Gene', (85, 89))
39889	29925043	In both TSC-RCCs, there were no megabase-scale amplification or deletion.	('TSC', 'Gene', '7248', (8, 11))	('deletion', 'Var', (64, 72))	('RCC', 'Phenotype', 'HP:0005584', (12, 15))	('TSC', 'Gene', (8, 11))
39906	29925043	The mTOR activation has been thought to be one of the pathogenic alterations in TSC-RCC because alterations of TSC1 or TSC2 genes were responsible for the development of TSC.	('TSC1', 'Gene', (111, 115))	('alterations', 'Var', (96, 107))	('TSC', 'Gene', '7248', (80, 83))	('TSC', 'Gene', '7248', (111, 114))	('responsible', 'Reg', (135, 146))	('TSC', 'Gene', (119, 122))	('TSC', 'Gene', '7248', (119, 122))	('RCC', 'Phenotype', 'HP:0005584', (84, 87))	('mTOR', 'Gene', (4, 8))	('TSC', 'Gene', '7248', (170, 173))	('TSC2', 'Gene', '7249', (119, 123))	('TSC2', 'Gene', (119, 123))	('TSC1', 'Gene', '7248', (111, 115))	('mTOR', 'Gene', '2475', (4, 8))	('TSC', 'Gene', (80, 83))	('TSC', 'Gene', (111, 114))	('TSC', 'Gene', (170, 173))
39912	29925043	In TSC-associated papillary RCC cases, there were second-hit mutations (3 SNVs, 1 indel, and 1 LOH) in TSC2, and somatic mutations of PROS1, NPFFR2, TLL2, and RASA1 were identified.	('RASA1', 'Gene', '5921', (159, 164))	('PROS1', 'Gene', '5627', (134, 139))	('TSC2', 'Gene', '7249', (103, 107))	('RASA1', 'Gene', (159, 164))	('TSC2', 'Gene', (103, 107))	('TLL2', 'Gene', (149, 153))	('TSC', 'Gene', (3, 6))	('mutations', 'Var', (61, 70))	('TSC', 'Gene', '7248', (3, 6))	('TLL2', 'Gene', '7093', (149, 153))	('NPFFR2', 'Gene', '10886', (141, 147))	('PROS1', 'Gene', (134, 139))	('TSC', 'Gene', '7248', (103, 106))	('TSC', 'Gene', (103, 106))	('NPFFR2', 'Gene', (141, 147))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
39913	29925043	In sporadic cases of eosinophilic/macrocystic RCC, copy number gain of 16p-q, 7p-q, 13q, 19p, 1p, and 10q; copy number loss of Xp, 22q, 19p,19q, and Xq; and LOH in 16p, Xq, 11p, and 9q were identified.	('copy number loss', 'Var', (107, 123))	('eosinophilic/macrocystic RCC', 'Disease', (21, 49))	('gain', 'PosReg', (63, 67))	('RCC', 'Phenotype', 'HP:0005584', (46, 49))	('eosinophilic/macrocystic RCC', 'Disease', 'MESH:D004802', (21, 49))	('copy number', 'Var', (51, 62))
39915	29925043	For the development of tumors related to TSC, biallelic TSC2 inactivation is needed.	('inactivation', 'Var', (61, 73))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('TSC', 'Gene', '7248', (56, 59))	('TSC2', 'Gene', '7249', (56, 60))	('TSC2', 'Gene', (56, 60))	('TSC', 'Gene', (41, 44))	('TSC', 'Gene', '7248', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TSC', 'Gene', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
39916	29925043	However, we could not find additional TSC2 mutations or LOH in Case 1.	('mutations', 'Var', (43, 52))	('TSC2', 'Gene', '7249', (38, 42))	('TSC2', 'Gene', (38, 42))
39917	29925043	There is the possibility that other types of mutations (large indel or epigenetic alterations), not detected in WES, may exist in the Case 1 patient or TSC2 inactivation was not responsible for mTOR activation, and tumor progression as histopathologic feature of Case 1 was truly unclassifiable.	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('epigenetic alterations', 'Var', (71, 93))	('TSC2', 'Gene', '7249', (152, 156))	('patient', 'Species', '9606', (141, 148))	('mTOR', 'Gene', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mTOR', 'Gene', '2475', (194, 198))	('TSC2', 'Gene', (152, 156))	('tumor', 'Disease', (215, 220))
39921	29925043	The USP34 and NDE1 alteration in TSC-associated papillary RCC was found in Case 1 and 2, respectively.	('TSC', 'Gene', (33, 36))	('TSC', 'Gene', '7248', (33, 36))	('alteration', 'Var', (19, 29))	('USP34', 'Gene', '9736', (4, 9))	('NDE1', 'Gene', '54820', (14, 18))	('USP34', 'Gene', (4, 9))	('USP', 'molecular_function', 'GO:0051748', ('4', '7'))	('RCC', 'Phenotype', 'HP:0005584', (58, 61))	('NDE1', 'Gene', (14, 18))
39925	29925043	CHD8 c.2368C > T, p.R790C mutation was previously reported in malignant melanoma and is considered pathogenic based upon FATHMM.	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('malignant melanoma', 'Phenotype', 'HP:0002861', (62, 80))	('CHD8', 'Gene', (0, 4))	('CHD8', 'Gene', '57680', (0, 4))	('malignant melanoma', 'Disease', 'MESH:D008545', (62, 80))	('malignant melanoma', 'Disease', (62, 80))	('c.2368C > T', 'Mutation', 'rs776528619', (5, 16))	('reported', 'Reg', (50, 58))	('p.R790C', 'Mutation', 'rs776528619', (18, 25))	('p.R790C', 'Var', (18, 25))
39927	29925043	CRISPLD1 c.1363C > T, p.R455* was in LCCL domain and has not been previously reported.	('p.R455*', 'Mutation', 'p.R455*', (22, 29))	('p.R455*', 'Var', (22, 29))	('CRISPLD1', 'Gene', '83690', (0, 8))	('CRISPLD1', 'Gene', (0, 8))	('c.1363C > T', 'Mutation', 'rs149361480', (9, 20))	('c.1363C > T', 'Var', (9, 20))
39928	29925043	Also, EPB41L4A c.1618C > T, p.R540C mutation has not been previously reported.	('EPB41L4A', 'Gene', '64097', (6, 14))	('p.R540C', 'Mutation', 'rs774150056', (28, 35))	('p.R540C', 'Var', (28, 35))	('c.1618C > T', 'Var', (15, 26))	('c.1618C > T', 'Mutation', 'rs774150056', (15, 26))	('EPB41L4A', 'Gene', (6, 14))
39930	29925043	GNA11 c.604C > T, p.R202W mutation located in G-alpha domain has not been previously reported.	('GNA11', 'Gene', (0, 5))	('c.604C > T', 'Mutation', 'c.604C>T', (6, 16))	('GNA11', 'Gene', '2767', (0, 5))	('p.R202W', 'Var', (18, 25))	('p.R202W', 'Mutation', 'p.R202W', (18, 25))
39932	29925043	NOTCH3 c.1194C > T, p.G398G mutation in EGF_CA domain has previously been reported in urothelial carcinoma of urinary bladder, hepatocellular carcinoma, and cutaneous malignant melanoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('NOTCH3', 'Gene', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('malignant melanoma', 'Phenotype', 'HP:0002861', (167, 185))	('c.1194C > T', 'Mutation', 'rs140368657', (7, 18))	('cutaneous malignant melanoma', 'Disease', (157, 185))	('reported', 'Reg', (74, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Disease', (127, 151))	('p.G398G', 'SUBSTITUTION', 'None', (20, 27))	('urothelial carcinoma of urinary bladder', 'Disease', (86, 125))	('p.G398G', 'Var', (20, 27))	('EGF', 'molecular_function', 'GO:0005154', ('40', '43'))	('EGF_CA domain', 'Gene', (40, 53))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (157, 185))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (157, 185))	('NOTCH3', 'Gene', '4854', (0, 6))	('urothelial carcinoma of urinary bladder', 'Disease', 'MESH:D001749', (86, 125))
39934	29925043	PBRM1 c.49G > A, p.G17R mutation was previously reported in prostate adenocarcinoma.	('c.49G > A', 'Mutation', 'rs764436452', (6, 15))	('p.G17R', 'Mutation', 'rs764436452', (17, 23))	('PBRM1', 'Gene', (0, 5))	('reported', 'Reg', (48, 56))	('c.49G > A', 'Var', (6, 15))	('PBRM1', 'Gene', '55193', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('prostate adenocarcinoma', 'Disease', (60, 83))	('p.G17R', 'Var', (17, 23))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (60, 83))
39936	29925043	PTPRU c.1412G > A, p.R471H mutation was not previously reported.	('p.R471H', 'Mutation', 'rs35745442', (19, 26))	('p.R471H', 'Var', (19, 26))	('PTPRU', 'Gene', (0, 5))	('PTPRU', 'Gene', '10076', (0, 5))	('c.1412G > A', 'Mutation', 'rs35745442', (6, 17))	('c.1412G > A', 'Var', (6, 17))
39938	29925043	RGS12 c.4073C > T, p.P1358L mutation was in RGS12_usC domain and was not previously reported.	('RGS12', 'Gene', '6002', (44, 49))	('RGS12', 'Gene', '6002', (0, 5))	('p.P1358L', 'Mutation', 'rs140022951', (19, 27))	('c.4073C > T', 'Mutation', 'rs140022951', (6, 17))	('RGS', 'molecular_function', 'GO:0016299', ('44', '47'))	('p.P1358L', 'Var', (19, 27))	('RGS12', 'Gene', (44, 49))	('RGS', 'molecular_function', 'GO:0016299', ('0', '3'))	('RGS12', 'Gene', (0, 5))
39940	29925043	SETBP1 c.2572G > A, p.E858K mutation was previously reported in esophageal carcinoma, cutaneous malignant melanoma, esophagus-stomach cancer, and hematopoietic neoplasm.	('p.E858K', 'Var', (20, 27))	('cutaneous malignant melanoma', 'Disease', (86, 114))	('reported', 'Reg', (52, 60))	('c.2572G > A', 'Mutation', 'rs1178702025', (7, 18))	('hematopoietic neoplasm', 'Disease', 'MESH:D019337', (146, 168))	('stomach cancer', 'Phenotype', 'HP:0012126', (126, 140))	('esophagus-stomach cancer', 'Disease', (116, 140))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('hematopoietic neoplasm', 'Phenotype', 'HP:0004377', (146, 168))	('malignant melanoma', 'Phenotype', 'HP:0002861', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (86, 114))	('SETBP1', 'Gene', '26040', (0, 6))	('hematopoietic neoplasm', 'Disease', (146, 168))	('SETBP1', 'Gene', (0, 6))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (86, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (64, 84))	('esophagus-stomach cancer', 'Disease', 'MESH:D004938', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('p.E858K', 'Mutation', 'rs1178702025', (20, 27))	('c.2572G > A', 'Var', (7, 18))	('esophageal carcinoma', 'Disease', (64, 84))
39942	29925043	SMARCA4 c.3067G > A, p.E1023K mutation was in SNF2_N domain and previously reported in colorectal adenocarcinoma and lung cancer.	('SMARCA4', 'Gene', (0, 7))	('c.3067G > A', 'Mutation', 'c.3067G>A', (8, 19))	('SMARCA4', 'Gene', '6597', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('colorectal adenocarcinoma and lung cancer', 'Disease', 'MESH:D015179', (87, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('c.3067G > A', 'Var', (8, 19))	('p.E1023K', 'Var', (21, 29))	('reported', 'Reg', (75, 83))	('p.E1023K', 'Mutation', 'p.E1023K', (21, 29))
39944	29925043	STMN1 c.235G > A, p.E79K was in Stathmin domain and has not been reported previously.	('STMN1', 'Gene', (0, 5))	('p.E79K', 'Mutation', 'p.E79K', (18, 24))	('p.E79K', 'Var', (18, 24))	('c.235G > A', 'Mutation', 'c.235G>A', (6, 16))	('STMN1', 'Gene', '3925', (0, 5))	('c.235G > A', 'Var', (6, 16))
39946	29925043	ZNRF3 c.1361G > A, p.R454H has not been previously reported.	('c.1361G > A', 'Var', (6, 17))	('p.R454H', 'Mutation', 'rs761341292', (19, 26))	('ZNRF3', 'Gene', '84133', (0, 5))	('ZNRF3', 'Gene', (0, 5))	('c.1361G > A', 'Mutation', 'rs1210755528', (6, 17))
39949	29925043	IWS1 c.2048A > G, p.N683S mutation was in Med26 domain and was not previously reported.	('c.2048A > G', 'Var', (5, 16))	('IWS1', 'Gene', '55677', (0, 4))	('IWS1', 'Gene', (0, 4))	('p.N683S', 'Var', (18, 25))	('c.2048A > G', 'Mutation', 'c.2048A>G', (5, 16))	('p.N683S', 'Mutation', 'p.N683S', (18, 25))
39951	29925043	TSC2 c.1372C > T, p.R458* was in DUF3384 domain and was previously reported in sporadic pulmonary lymphangioleiomyomatosis.	('TSC2', 'Gene', '7249', (0, 4))	('c.1372C > T', 'Var', (5, 16))	('TSC2', 'Gene', (0, 4))	('c.1372C > T', 'Mutation', 'rs45517169', (5, 16))	('lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (98, 122))	('p.R458*', 'Var', (18, 25))	('pulmonary lymphangioleiomyomatosis', 'Phenotype', 'HP:0012798', (88, 122))	('sporadic pulmonary lymphangioleiomyomatosis', 'Disease', 'MESH:D018192', (79, 122))	('sporadic pulmonary lymphangioleiomyomatosis', 'Disease', (79, 122))	('p.R458*', 'Mutation', 'p.R458*', (18, 25))
39959	29925043	The NOTCH3 mRNA expression with our mutation was 26 percentile in hepatocellular carcinoma and 56 percentile in melanoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('NOTCH3', 'Gene', (4, 10))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('NOTCH3', 'Gene', '4854', (4, 10))	('melanoma', 'Disease', (112, 120))	('mutation', 'Var', (36, 44))
39961	29925043	The SETBP1 mRNA expression with our mutation was 60 percentile in esophageal carcinoma and 97 percentile in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', (108, 116))	('SETBP1', 'Gene', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mRNA expression', 'MPA', (11, 26))	('esophageal carcinoma', 'Disease', (66, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (66, 86))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (66, 86))	('SETBP1', 'Gene', '26040', (4, 10))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('mutation', 'Var', (36, 44))
40045	21139840	Immunostain for racemase (P504s) was negative in the tumor.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('P504s', 'Var', (26, 31))	('tumor', 'Disease', (53, 58))
40063	31433528	Genetic Diversity in Alveolar Soft Part Sarcoma: A Subset Contain Variant Fusion Genes, Highlighting Broader Molecular Kinship with Other MiT Family Tumors Alveolar soft part sarcoma (ASPS) is a rare malignancy that, since its initial description, remains a neoplasm of uncertain histogenesis.	('sarcoma', 'Disease', (175, 182))	('neoplasm', 'Disease', (258, 266))	('Alveolar Soft Part Sarcoma', 'Disease', (21, 47))	('Variant Fusion Genes', 'Var', (66, 86))	('Sarcoma', 'Phenotype', 'HP:0100242', (40, 47))	('Tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ASPS', 'Gene', '79058', (184, 188))	('ASPS', 'Phenotype', 'HP:0012218', (184, 188))	('sarcoma', 'Phenotype', 'HP:0100242', (175, 182))	('histogenesis', 'biological_process', 'GO:0009888', ('280', '292'))	('neoplasm', 'Phenotype', 'HP:0002664', (258, 266))	('Tumors', 'Disease', (149, 155))	('malignancy', 'Disease', 'MESH:D009369', (200, 210))	('Alveolar Soft Part Sarcoma', 'Phenotype', 'HP:0012218', (21, 47))	('Soft Part Sarcoma', 'Phenotype', 'HP:0030448', (30, 47))	('Tumors', 'Disease', 'MESH:D009369', (149, 155))	('Alveolar Soft Part Sarcoma', 'Disease', 'MESH:D018234', (21, 47))	('Alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (156, 182))	('ASPS', 'Gene', (184, 188))	('neoplasm', 'Disease', 'MESH:D009369', (258, 266))	('malignancy', 'Disease', (200, 210))	('sarcoma', 'Disease', 'MESH:D012509', (175, 182))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (165, 182))
40070	31433528	The latter two fusions have previously been identified in renal cell carcinoma; to our knowledge this is the first report of a HNRNPH3-TFE3 gene fusion.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (58, 78))	('TFE3', 'Gene', (135, 139))	('HNRNPH3', 'Gene', '3189', (127, 134))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (58, 78))	('TFE3', 'Gene', '7030', (135, 139))	('fusion', 'Var', (145, 151))	('HNRNPH3', 'Gene', (127, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('renal cell carcinoma', 'Disease', (58, 78))
40078	31433528	ASPS has heretofore been reported to be genetically defined by der(17)t(X;17)(p11;q25), resulting in an ASPSCR1-TFE3 fusion gene.	('ASPS', 'Gene', (104, 108))	('der(17)t(X;17)(p11;q25)', 'STRUCTURAL_ABNORMALITY', 'None', (63, 86))	('ASPSCR1', 'Gene', '79058', (104, 111))	('ASPS', 'Gene', '79058', (0, 4))	('ASPS', 'Gene', '79058', (104, 108))	('TFE3', 'Gene', (112, 116))	('ASPSCR1', 'Gene', (104, 111))	('der(17)t', 'Var', (63, 71))	('ASPS', 'Phenotype', 'HP:0012218', (0, 4))	('ASPS', 'Phenotype', 'HP:0012218', (104, 108))	('TFE3', 'Gene', '7030', (112, 116))	('ASPS', 'Gene', (0, 4))
40079	31433528	Herein we report three cases of alveolar soft part sarcoma containing TFE3 gene fusion partners other than ASPSCR1.	('TFE3', 'Gene', (70, 74))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('TFE3', 'Gene', '7030', (70, 74))	('ASPSCR1', 'Gene', '79058', (107, 114))	('fusion partners', 'Var', (80, 95))	('alveolar soft part sarcoma', 'Disease', 'MESH:D018234', (32, 58))	('alveolar soft part sarcoma', 'Disease', (32, 58))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (32, 58))	('ASPSCR1', 'Gene', (107, 114))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (41, 58))	('ASPS', 'Phenotype', 'HP:0012218', (107, 111))
40098	31433528	Routine diagnostic RNA-Seq revealed an HNRNPH3-TFE3 gene fusion in the tumor from the index patient; this was in-frame and occurred between HNRNPH3 (NCBI Reference Sequence: NM_012207) partial exon 10 and TFE3 (NM_006521) exon 3.	('patient', 'Species', '9606', (92, 99))	('HNRNPH3', 'Gene', '3189', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TFE3', 'Gene', (47, 51))	('TFE3', 'Gene', '7030', (205, 209))	('NM_006521', 'Var', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('RNA', 'cellular_component', 'GO:0005562', ('19', '22'))	('HNRNPH3', 'Gene', (39, 46))	('occurred', 'Reg', (123, 131))	('TFE3', 'Gene', '7030', (47, 51))	('tumor', 'Disease', (71, 76))	('HNRNPH3', 'Gene', (140, 147))	('HNRNPH3', 'Gene', '3189', (39, 46))	('TFE3', 'Gene', (205, 209))
40099	31433528	Patient 2's tumor was found to have rearrangement of both the DVL2 and TFE3 genes by FISH, while lacking abnormalities in ASPSCR1, PRCC, CLTC and SFPQ genes; a bring-together FISH assay was subsequently used to confirm the juxtaposition of the two genes as a DVL2-TFE3 fusion.	('CLTC', 'Gene', '1213', (137, 141))	('ASPSCR1', 'Gene', (122, 129))	('ASPS', 'Phenotype', 'HP:0012218', (122, 126))	('TFE3', 'Gene', (264, 268))	('tumor', 'Disease', (12, 17))	('rearrangement', 'Var', (36, 49))	('DVL2', 'Gene', '1856', (62, 66))	('TFE3', 'Gene', '7030', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CLTC', 'Gene', (137, 141))	('DVL2', 'Gene', '1856', (259, 263))	('PRCC', 'Gene', (131, 135))	('DVL2', 'Gene', (62, 66))	('DVL2', 'Gene', (259, 263))	('TFE3', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TFE3', 'Gene', '7030', (71, 75))	('ASPSCR1', 'Gene', '79058', (122, 129))	('SFPQ', 'Gene', '6421', (146, 150))	('SFPQ', 'Gene', (146, 150))	('PRCC', 'Gene', '5546', (131, 135))	('Patient', 'Species', '9606', (0, 7))
40104	31433528	The disease-defining molecular event underpinning the diagnosis of ASPS is the ASPSCR1-TFE3 gene fusion which, for almost two decades, was considered the sole driver for this neoplasm.	('ASPS', 'Gene', (79, 83))	('neoplasm', 'Disease', 'MESH:D009369', (175, 183))	('TFE3', 'Gene', '7030', (87, 91))	('neoplasm', 'Phenotype', 'HP:0002664', (175, 183))	('ASPSCR1', 'Gene', '79058', (79, 86))	('ASPS', 'Phenotype', 'HP:0012218', (67, 71))	('ASPS', 'Gene', '79058', (79, 83))	('ASPS', 'Gene', (67, 71))	('ASPSCR1', 'Gene', (79, 86))	('fusion', 'Var', (97, 103))	('ASPS', 'Phenotype', 'HP:0012218', (79, 83))	('neoplasm', 'Disease', (175, 183))	('TFE3', 'Gene', (87, 91))	('ASPS', 'Gene', '79058', (67, 71))
40114	31433528	that discovered that the translocation fuses ASPSCR1 (formerly ASPL) to TFE3, a finding consistently confirmed in many subsequent series.	('TFE3', 'Gene', (72, 76))	('translocation', 'Var', (25, 38))	('fuses', 'Var', (39, 44))	('ASPSCR1', 'Gene', (45, 52))	('TFE3', 'Gene', '7030', (72, 76))	('ASPL', 'Gene', '79058', (63, 67))	('ASPS', 'Phenotype', 'HP:0012218', (45, 49))	('ASPL', 'Gene', (63, 67))	('ASPSCR1', 'Gene', '79058', (45, 52))
40121	31433528	Assuming the potential for broader molecular overlap between ASPS and renal cell carcinoma - not to mention PEComa, a subset of which likewise harbor TFE3 rearrangement - it is presumed additional fusion genes may exist in ASPS.	('renal cell carcinoma', 'Disease', (70, 90))	('TFE3', 'Gene', '7030', (150, 154))	('ASPS', 'Gene', '79058', (61, 65))	('PEComa', 'Disease', 'MESH:D054973', (108, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('ASPS', 'Gene', '79058', (223, 227))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('ASPS', 'Phenotype', 'HP:0012218', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('TFE3', 'Gene', (150, 154))	('ASPS', 'Phenotype', 'HP:0012218', (223, 227))	('rearrangement -', 'Var', (155, 170))	('ASPS', 'Gene', (61, 65))	('PEComa', 'Disease', (108, 114))	('ASPS', 'Gene', (223, 227))
40124	31433528	One patient was identified following routine diagnostic testing using break-apart FISH probes for DVL2 and TFE3, which suggested rearrangement of both genes; a bring-together FISH assay was subsequently used to confirm the juxtaposition of the two genes in a DVL2-TFE3 fusion.	('TFE3', 'Gene', '7030', (264, 268))	('DVL2', 'Gene', (259, 263))	('TFE3', 'Gene', '7030', (107, 111))	('patient', 'Species', '9606', (4, 11))	('DVL2', 'Gene', (98, 102))	('DVL2', 'Gene', '1856', (259, 263))	('fusion', 'Var', (269, 275))	('TFE3', 'Gene', (264, 268))	('DVL2', 'Gene', '1856', (98, 102))	('TFE3', 'Gene', (107, 111))
40126	31433528	TFE3 fusions involving DVL2 and PRCC have previously been reported in renal cell carcinoma; in addition, the former has also been identified in a TFE3-rearranged PEComa.	('renal cell carcinoma', 'Disease', (70, 90))	('TFE3', 'Gene', '7030', (0, 4))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('reported', 'Reg', (58, 66))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('fusions', 'Var', (5, 12))	('TFE3', 'Gene', '7030', (146, 150))	('PEComa', 'Disease', 'MESH:D054973', (162, 168))	('PRCC', 'Gene', '5546', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('DVL2', 'Gene', (23, 27))	('TFE3', 'Gene', (0, 4))	('identified', 'Reg', (130, 140))	('PRCC', 'Gene', (32, 36))	('DVL2', 'Gene', '1856', (23, 27))	('TFE3', 'Gene', (146, 150))	('PEComa', 'Disease', (162, 168))
40127	31433528	However, to our knowledge, this represents the first report of the fusion of TFE3 to HNRNPH3, which appears to represent an altogether novel gene pairing.	('HNRNPH3', 'Gene', '3189', (85, 92))	('TFE3', 'Gene', (77, 81))	('HNRNPH3', 'Gene', (85, 92))	('TFE3', 'Gene', '7030', (77, 81))	('fusion', 'Var', (67, 73))
40132	31433528	Similar to ASPSCR1-TFE3, fusion of PRCC (proline rich mitotic checkpoint control factor) and TFE3 result in the formation of a more potent activator than TFE3, thereby leading to aberrant expression of TFE3 targets in renal cell carcinoma.	('TFE3', 'Gene', '7030', (202, 206))	('mitotic checkpoint', 'biological_process', 'GO:0007093', ('54', '72'))	('TFE3', 'Gene', (19, 23))	('proline rich mitotic checkpoint control factor', 'Gene', (41, 87))	('PRCC', 'Gene', '5546', (35, 39))	('TFE3', 'Gene', (154, 158))	('TFE3', 'Gene', '7030', (19, 23))	('leading to', 'Reg', (168, 178))	('ASPS', 'Phenotype', 'HP:0012218', (11, 15))	('TFE3', 'Gene', '7030', (154, 158))	('formation', 'biological_process', 'GO:0009058', ('112', '121'))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('renal cell carcinoma', 'Disease', (218, 238))	('activator', 'MPA', (139, 148))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('proline rich mitotic checkpoint control factor', 'Gene', '5546', (41, 87))	('ASPSCR1', 'Gene', '79058', (11, 18))	('fusion', 'Var', (25, 31))	('PRCC', 'Gene', (35, 39))	('TFE3', 'Gene', (93, 97))	('expression', 'MPA', (188, 198))	('TFE3', 'Gene', '7030', (93, 97))	('ASPSCR1', 'Gene', (11, 18))	('TFE3', 'Gene', (202, 206))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))
40134	31433528	This, to our knowledge, represents the first report of a tumor harboring a HNRNPH3-TFE3 fusion gene.	('TFE3', 'Gene', '7030', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('HNRNPH3', 'Gene', (75, 82))	('fusion gene', 'Var', (88, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('TFE3', 'Gene', (83, 87))	('tumor', 'Disease', (57, 62))	('HNRNPH3', 'Gene', '3189', (75, 82))
40141	31433528	These findings reveal a genetic diversity that has heretofore been underrecognized in ASPS; furthermore, this highlights an even greater degree of molecular kinship amongst ASPS and MiT family translocation renal cell carcinoma, as well as PEComa.	('ASPS', 'Phenotype', 'HP:0012218', (86, 90))	('PEComa', 'Disease', 'MESH:D054973', (240, 246))	('renal cell carcinoma', 'Disease', (207, 227))	('MiT', 'Var', (182, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (207, 227))	('ASPS', 'Phenotype', 'HP:0012218', (173, 177))	('ASPS', 'Gene', (86, 90))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('ASPS', 'Gene', '79058', (86, 90))	('ASPS', 'Gene', (173, 177))	('PEComa', 'Disease', (240, 246))	('ASPS', 'Gene', '79058', (173, 177))
40151	25401301	Ectopic expression of the ACTG1-MITF fusion led to cellular transformation and induced the expression of downstream target genes.	('MITF', 'Gene', '4286', (32, 36))	('expression of', 'MPA', (91, 104))	('induced', 'PosReg', (79, 86))	('led to', 'Reg', (44, 50))	('fusion', 'Var', (37, 43))	('cellular transformation', 'CPA', (51, 74))	('MITF', 'Gene', (32, 36))
40162	25401301	An understanding of the genetic basis of nccRCCs has come from familial studies where germline mutations have been identified in MET in pRCC (type I), FH in pRCC (type II) and FLCN in the chRCC and renal oncocytoma tumor types.	('MET', 'Gene', (129, 132))	('pRCC', 'Disease', (136, 140))	('FH', 'Disease', 'MESH:D006938', (151, 153))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (198, 214))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('FLCN', 'Gene', (176, 180))	('FLCN', 'Gene', '201163', (176, 180))	('mutations', 'Var', (95, 104))	('renal oncocytoma tumor', 'Disease', (198, 220))	('chRCC', 'Disease', (188, 193))	('renal oncocytoma tumor', 'Disease', 'MESH:C537750', (198, 220))
40163	25401301	In addition to predisposing germline mutations in VHL in ccRCC, pathogenic variants in TSC1, TSC2, PTEN, SDHB, SDHC, SDHD, MITF and BAP1 have been associated with predisposition to kidney cancer subtypes.	('TSC2', 'Gene', '7249', (93, 97))	('variants', 'Var', (75, 83))	('BAP1', 'Gene', '8314', (132, 136))	('TSC2', 'Gene', (93, 97))	('PTEN', 'Gene', (99, 103))	('SDHC', 'Gene', '6391', (111, 115))	('kidney cancer', 'Disease', 'MESH:D007680', (181, 194))	('SDHD', 'Gene', '6392', (117, 121))	('SDHB', 'Gene', '6390', (105, 109))	('VHL', 'Gene', (50, 53))	('MITF', 'Gene', '4286', (123, 127))	('BAP1', 'Gene', (132, 136))	('PTEN', 'Gene', '5728', (99, 103))	('kidney cancer', 'Phenotype', 'HP:0009726', (181, 194))	('TSC1', 'Gene', (87, 91))	('SDHD', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('associated', 'Reg', (147, 157))	('MITF', 'Gene', (123, 127))	('VHL', 'Gene', '7428', (50, 53))	('kidney cancer', 'Disease', (181, 194))	('SDHB', 'Gene', (105, 109))	('SDHC', 'Gene', (111, 115))	('TSC1', 'Gene', '7248', (87, 91))
40164	25401301	Although somatic mutations in MET in sporadic pRCC and translocations involving the microphthalmia family (MiTF) members TFE3 and TFEB in tRCCs are known, alterations driving other sporadic forms of nccRCC remain to be identified.	('MiTF', 'Gene', '4286', (107, 111))	('TFEB', 'Gene', '7942', (130, 134))	('microphthalmia', 'Phenotype', 'HP:0000568', (84, 98))	('TFEB', 'Gene', (130, 134))	('TFE3', 'Gene', '7030', (121, 125))	('microphthalmia', 'Disease', 'MESH:D008850', (84, 98))	('microphthalmia', 'Disease', (84, 98))	('pRCC', 'Disease', (46, 50))	('MiTF', 'Gene', (107, 111))	('mutations', 'Var', (17, 26))	('TFE3', 'Gene', (121, 125))	('MET', 'Gene', (30, 33))
40165	25401301	We identified significantly mutated genes that include MET in pRCC and TP53 in chRCC.	('MET', 'Var', (55, 58))	('pRCC', 'Disease', (62, 66))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('chRCC', 'Disease', (79, 84))
40167	25401301	Additionally, we describe the identification of previously unreported gene fusions, including a transforming ACTG1-MITF fusion.	('fusion', 'Var', (120, 126))	('MITF', 'Gene', '4286', (115, 119))	('MITF', 'Gene', (115, 119))
40175	25401301	and J.S.G., B. Fischer and W. Huber, unpublished data), we identified five distinct mutational signatures (S1, S2, S3, S4 and S5) in the cancer types analyzed (Supplementary Figs.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('S1', 'Var', (107, 109))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
40179	25401301	In pRCC, chRCC and renal oncocytoma, we identified somatic protein-altering mutations in 2,364, 781 and 509 genes, respectively.	('mutations', 'Var', (76, 85))	('protein-altering', 'Reg', (59, 75))	('chRCC', 'Disease', (9, 14))	('renal oncocytoma', 'Disease', 'MESH:C537750', (19, 35))	('pRCC', 'Disease', (3, 7))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (19, 35))	('renal oncocytoma', 'Disease', (19, 35))	('protein', 'cellular_component', 'GO:0003675', ('59', '66'))
40180	25401301	We assessed the impact of protein-altering single-nucleotide variants on gene function using SIFT, PolyPhen and Condel, finding that 53% (1,140/2,164) of the mutations in pRCC, 50% (346/698) of the mutations in chRCC and 48% (211/441) of the mutations in renal oncocytoma were likely to result in functionally relevant alterations according to at least 2 of the 3 methods used for functional assessment (Supplementary Table 3).	('result', 'Reg', (287, 293))	('chRCC', 'Gene', (211, 216))	('SIFT', 'Disease', (93, 97))	('pRCC', 'Gene', (171, 175))	('mutations', 'Var', (242, 251))	('mutations', 'Var', (198, 207))	('renal oncocytoma', 'Disease', 'MESH:C537750', (255, 271))	('PolyPhen', 'Chemical', '-', (99, 107))	('SIFT', 'Disease', 'None', (93, 97))	('protein', 'cellular_component', 'GO:0003675', ('26', '33'))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (255, 271))	('mutations', 'Var', (158, 167))	('renal oncocytoma', 'Disease', (255, 271))
40181	25401301	6), suggesting an enrichment for pathogenic variants in the tumors.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', (60, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('variants', 'Var', (44, 52))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
40182	25401301	We further examined the data for enrichment of deleterious mutations by performing a simulation (Online Methods), finding that deleterious mutations, with the exception of those in renal oncocytoma (P = 0.548), were significantly enriched in pRCC (P < 0.0001) or trending toward significance in chRCC (P = 0.075), similar to ccRCC (P = 0.086; Supplementary Fig.	('mutations', 'Var', (139, 148))	('ccRCC', 'Disease', (325, 330))	('pRCC', 'Disease', (242, 246))	('renal oncocytoma', 'Disease', 'MESH:C537750', (181, 197))	('renal oncocytoma', 'Disease', (181, 197))	('chRCC', 'Disease', (295, 300))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (181, 197))
40184	25401301	Except for a single mutation mapping to the extracellular domain (ECD), all the mutations affected the kinase domain of MET (Fig.	('MET', 'Protein', (120, 123))	('kinase domain', 'MPA', (103, 116))	('mutations', 'Var', (80, 89))	('ECD', 'Disease', 'MESH:C574275', (66, 69))	('extracellular', 'cellular_component', 'GO:0005576', ('44', '57'))	('ECD', 'Disease', (66, 69))	('affected', 'Reg', (90, 98))
40185	25401301	Four previously unreported mutations of oncogenic relevance, including three kinase domain alterations (p.Val1088Ala, p.Ile1095Thr and the recurrent p.Phe1218Ile substitution) and an ECD alteration, p.Asp153Tyr, were identified (Fig.	('p.Phe1218Ile', 'Var', (149, 161))	('p.Phe1218Ile', 'Mutation', 'p.F1218I', (149, 161))	('p.Ile1095Thr', 'Var', (118, 130))	('ECD', 'Disease', 'MESH:C574275', (183, 186))	('p.Val1088Ala', 'Mutation', 'p.V1088A', (104, 116))	('p.Val1088Ala', 'Var', (104, 116))	('p.Asp153Tyr', 'Var', (199, 210))	('ECD', 'Disease', (183, 186))	('p.Asp153Tyr', 'Mutation', 'p.D153Y', (199, 210))	('p.Ile1095Thr', 'Mutation', 'p.I1095T', (118, 130))
40186	25401301	Mapping these alterations onto the crystal structures of the MET kinase domain and beta chain (Protein Data Bank (PDB), 1R0P and 1SHY; Fig.	('alterations', 'Var', (14, 25))	('PDB', 'Gene', (114, 117))	('PDB', 'Gene', '5131', (114, 117))
40187	25401301	We tested the transforming ability of the MET mutants by stably expressing them in NIH3T3 cells and found that they promoted a significant increase in anchorage-independent growth when compared to ectopically expressed wild-type MET (Fig.	('tested', 'Reg', (3, 9))	('NIH3T3', 'CellLine', 'CVCL:0594', (83, 89))	('increase', 'PosReg', (139, 147))	('mutants', 'Var', (46, 53))	('anchorage-independent growth', 'CPA', (151, 179))
40188	25401301	Cells expressing MET Asp153Tyr showed increased proliferation in comparison to those expressing wild-type MET at the concentrations of hepatocyte growth factor (HGF) ligand tested (Supplementary Fig.	('hepatocyte growth factor', 'Gene', '3082', (135, 159))	('hepatocyte growth factor', 'molecular_function', 'GO:0005171', ('135', '159'))	('HGF', 'Gene', (161, 164))	('proliferation', 'CPA', (48, 61))	('HGF', 'Gene', '3082', (161, 164))	('ligand', 'molecular_function', 'GO:0005488', ('166', '172'))	('hepatocyte growth factor', 'Gene', (135, 159))	('Asp153Tyr', 'Var', (21, 30))	('Asp153Tyr', 'SUBSTITUTION', 'None', (21, 30))	('increased', 'PosReg', (38, 47))
40189	25401301	MET mutations in pRCC were mutually exclusive with mutations in NF2, PTEN, TSC1 and MTOR, although they were not statistically significant given their low frequencies (Supplementary Fig.	('PTEN', 'Gene', '5728', (69, 73))	('TSC1', 'Gene', '7248', (75, 79))	('pRCC', 'Gene', (17, 21))	('NF2', 'Gene', '4771', (64, 67))	('MTOR', 'Gene', (84, 88))	('TSC1', 'Gene', (75, 79))	('MTOR', 'Gene', '2475', (84, 88))	('mutations', 'Var', (4, 13))	('NF2', 'Gene', (64, 67))	('PTEN', 'Gene', (69, 73))
40191	25401301	We note that Slc5a3 knockout mice show upregulation of genes involved in the mitochondrial electron transfer chain, indicating a role for SLC5A3 mutations in mitochondrial alterations that might contribute to the development or maintenance of pRCC.	('electron transfer', 'biological_process', 'GO:0006118', ('91', '108'))	('SLC5A3', 'Gene', (138, 144))	('mutations', 'Var', (145, 154))	('contribute', 'Reg', (195, 205))	('electron transfer', 'biological_process', 'GO:0022904', ('91', '108'))	('genes', 'MPA', (55, 60))	('Slc5a3', 'Gene', (13, 19))	('upregulation', 'PosReg', (39, 51))	('mitochondrial', 'Enzyme', (77, 90))	('mitochondrial alterations', 'Phenotype', 'HP:0012103', (158, 183))	('mitochondrial', 'MPA', (158, 171))	('pRCC', 'Disease', (243, 247))	('mice', 'Species', '10090', (29, 33))	('Slc5a3', 'Gene', '53881', (13, 19))
40195	25401301	Human germline PDHB (E1beta) mutations lead to lactic acidosis and heterogeneous neurological dysfunction.	('Human', 'Species', '9606', (0, 5))	('lead to', 'Reg', (39, 46))	('lactic acidosis', 'Disease', (47, 62))	('E1beta', 'Gene', '594', (21, 27))	('neurological dysfunction', 'Disease', 'MESH:D009422', (81, 105))	('mutations', 'Var', (29, 38))	('acidosis', 'Phenotype', 'HP:0001941', (54, 62))	('PDHB', 'Gene', (15, 19))	('E1beta', 'Gene', (21, 27))	('lactic acidosis', 'Disease', 'MESH:D000140', (47, 62))	('heterogeneous', 'Disease', (67, 80))	('PDHB', 'Gene', '5162', (15, 19))	('neurological dysfunction', 'Disease', (81, 105))	('lactic acidosis', 'Phenotype', 'HP:0003128', (47, 62))
40196	25401301	Of the two mutations identified in PDHB in chRCC, one would lead to a truncated protein (p.Phe222fs*35) and the second would result in the substitution of arginine at codon 105 with leucine (p.Arg105Leu) (Supplementary Fig.	('p.Arg105Leu', 'Mutation', 'p.R105L', (191, 202))	('mutations', 'Var', (11, 20))	('result in', 'Reg', (125, 134))	('p.Phe222fs*35', 'Var', (89, 102))	('substitution', 'Reg', (139, 151))	('arginine at codon 105 with leucine', 'Mutation', 'p.R105L', (155, 189))	('lead to', 'Reg', (60, 67))	('p.Phe222fs*35', 'FRAMESHIFT', 'None', (89, 102))	('protein', 'cellular_component', 'GO:0003675', ('80', '87'))	('PDHB', 'Gene', (35, 39))	('protein', 'Protein', (80, 87))	('PDHB', 'Gene', '5162', (35, 39))	('truncated', 'MPA', (70, 79))
40198	25401301	13b) that was also reported to be mutated (p.Arg105Gln) in an individual with lactic acidosis.	('lactic acidosis', 'Phenotype', 'HP:0003128', (78, 93))	('p.Arg105Gln', 'Var', (43, 54))	('lactic acidosis', 'Disease', (78, 93))	('lactic acidosis', 'Disease', 'MESH:D000140', (78, 93))	('p.Arg105Gln', 'Mutation', 'rs868788199', (43, 54))	('acidosis', 'Phenotype', 'HP:0001941', (85, 93))
40199	25401301	PDHB alterations, like the fumarate hydratase (FH) and succinate dehydrogenase (SDHB, SDHC and SDHD) mutations known in kidney cancer, potentially allow the tumor to favor glycolysis over oxidative phosphorylation for energy production.	('PDHB', 'Gene', (0, 4))	('favor', 'PosReg', (166, 171))	('FH', 'Disease', 'MESH:D006938', (47, 49))	('alterations', 'Var', (5, 16))	('SDHC', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('kidney cancer', 'Disease', 'MESH:D007680', (120, 133))	('SDHB', 'Gene', (80, 84))	('PDHB', 'Gene', '5162', (0, 4))	('SDHD', 'Gene', '6392', (95, 99))	('allow', 'Reg', (147, 152))	('glycolysis', 'MPA', (172, 182))	('kidney cancer', 'Phenotype', 'HP:0009726', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (101, 110))	('kidney cancer', 'Disease', (120, 133))	('SDHD', 'Gene', (95, 99))	('SDHC', 'Gene', '6391', (86, 90))	('tumor', 'Disease', (157, 162))	('glycolysis', 'biological_process', 'GO:0006096', ('172', '182'))	('oxidative phosphorylation', 'biological_process', 'GO:0006119', ('188', '213'))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('SDHB', 'Gene', '6390', (80, 84))
40200	25401301	Among the nccRCC samples analyzed, TP53 mutations were found to be significantly enriched in the chRCC classic subtype (P = 2.3 x 10-5).	('mutations', 'Var', (40, 49))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('chRCC classic subtype', 'Disease', (97, 118))
40201	25401301	ARID1A, a known tumor-suppressor gene, and PRKAG2 (encoding the AMP kinase (AMPK) gamma subunit), although not achieving statistical significance, were recurrently mutated in chRCC.	('tumor-suppressor', 'biological_process', 'GO:0051726', ('16', '32'))	('AMPK', 'molecular_function', 'GO:0047322', ('76', '80'))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('ARID1A', 'Gene', '8289', (0, 6))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('16', '32'))	('AMP kinase', 'Gene', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('AMPK', 'molecular_function', 'GO:0004691', ('76', '80'))	('PRKAG2', 'Gene', (43, 49))	('AMPK', 'molecular_function', 'GO:0050405', ('76', '80'))	('ARID1A', 'Gene', (0, 6))	('tumor', 'Disease', (16, 21))	('mutated', 'Var', (164, 171))	('chRCC', 'Disease', (175, 180))	('AMPK', 'Gene', '5562', (76, 80))	('AMP kinase', 'Gene', '5562', (64, 74))	('AMPK', 'Gene', (76, 80))
40202	25401301	In addition, chRCC samples had mutations in TSC1, TSC2 or MTOR, which might signal addiction to the mTORC1 pathway and responsiveness to mTORC1 inhibitors.	('TSC1', 'Gene', '7248', (44, 48))	('mutations', 'Var', (31, 40))	('signal', 'Reg', (76, 82))	('mTORC1', 'Gene', '382056', (137, 143))	('MTOR', 'Gene', '2475', (58, 62))	('mTORC1', 'cellular_component', 'GO:0031931', ('100', '106'))	('mTORC1', 'cellular_component', 'GO:0031931', ('137', '143'))	('TSC2', 'Gene', '7249', (50, 54))	('TSC1', 'Gene', (44, 48))	('mTORC1', 'Gene', '382056', (100, 106))	('addiction', 'MPA', (83, 92))	('mTORC1', 'Gene', (137, 143))	('TSC2', 'Gene', (50, 54))	('MTOR', 'Gene', (58, 62))	('mTORC1', 'Gene', (100, 106))
40203	25401301	In renal oncocytoma, the q-score analysis identified ERCC2, a nucleotide excision repair pathway gene, and C2CD4C, a C2 calcium-dependent domain-containing protein, as significantly mutated (Fig.	('mutated', 'Var', (182, 189))	('C2CD4C', 'Gene', '126567', (107, 113))	('nucleotide excision repair', 'biological_process', 'GO:0006289', ('62', '88'))	('ERCC2', 'Gene', '2068', (53, 58))	('renal oncocytoma', 'Disease', 'MESH:C537750', (3, 19))	('C2CD4C', 'Gene', (107, 113))	('calcium', 'Chemical', 'MESH:D002118', (120, 127))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (3, 19))	('renal oncocytoma', 'Disease', (3, 19))	('ERCC2', 'Gene', (53, 58))	('protein', 'cellular_component', 'GO:0003675', ('156', '163'))
40207	25401301	Mutations mapping to the pseudosubstrate sequence lead to constitutive activation of AMPK.	('AMPK', 'molecular_function', 'GO:0050405', ('85', '89'))	('AMPK', 'molecular_function', 'GO:0004691', ('85', '89'))	('AMPK', 'Gene', '5562', (85, 89))	('constitutive activation', 'MPA', (58, 81))	('AMPK', 'Gene', (85, 89))	('AMPK', 'molecular_function', 'GO:0047322', ('85', '89'))	('Mutations', 'Var', (0, 9))
40208	25401301	Among the mutations identified in PRKAG2 in chRCC, the encoded p.Ile388Val substitution was present in the pseudosubstrate sequence within the second cystathionine-beta synthase (CBS) motif (Supplementary Fig.	('PRKAG2', 'Gene', (34, 40))	('cystathionine-beta synthase', 'Gene', '875', (150, 177))	('p.Ile388Val', 'Var', (63, 74))	('p.Ile388Val', 'Mutation', 'p.I388V', (63, 74))	('cystathionine-beta synthase', 'Gene', (150, 177))
40210	25401301	A second mutation in PRKAG2, encoding p.Arg531Gln, was observed in two tumor samples.	('PRKAG2', 'Gene', (21, 27))	('p.Arg531Gln', 'Mutation', 'rs121908991', (38, 49))	('p.Arg531Gln', 'Var', (38, 49))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
40211	25401301	In a recent chRCC data set, we found a mutation encoding p.Arg299Gln in PRKAG1 (Supplementary Fig.	('PRKAG1', 'Gene', '5571', (72, 78))	('p.Arg299Gln', 'Mutation', 'p.R299Q', (57, 68))	('p.Arg299Gln', 'Var', (57, 68))	('PRKAG1', 'Gene', (72, 78))
40212	25401301	This mutation is analogous to the PRKAG2 mutation encoding p.Arg531Gln previously reported in sporadic lethal congenital glycogen storage cardiomyopathy (GSC).	('cardiomyopathy', 'Disease', 'MESH:D009202', (138, 152))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (138, 152))	('p.Arg531Gln', 'Mutation', 'rs121908991', (59, 70))	('GSC', 'cellular_component', 'GO:0032593', ('154', '157'))	('storage', 'biological_process', 'GO:0051235', ('130', '137'))	('p.Arg531Gln', 'Var', (59, 70))	('glycogen', 'Chemical', 'MESH:D006003', (121, 129))	('storage cardiomyopathy', 'Phenotype', 'HP:0005152', (130, 152))	('cardiomyopathy', 'Disease', (138, 152))
40213	25401301	Arg531 is a conserved residue located within non-exchangeable AMP-binding site 4 (CBS4) of AMPK that makes contact with AMP, and the p.Arg531Gln substitution is predicted to affect AMP binding (Fig.	('Arg531', 'Chemical', '-', (0, 6))	('AMPK', 'molecular_function', 'GO:0050405', ('91', '95'))	('Arg531', 'Chemical', '-', (135, 141))	('p.Arg531Gln', 'Mutation', 'rs121908991', (133, 144))	('AMP-binding', 'molecular_function', 'GO:0016208', ('62', '73'))	('AMP binding', 'MPA', (181, 192))	('AMPK', 'molecular_function', 'GO:0004691', ('91', '95'))	('p.Arg531Gln', 'Var', (133, 144))	('AMPK', 'Gene', '5562', (91, 95))	('AMPK', 'Gene', (91, 95))	('AMP', 'Chemical', 'MESH:D000249', (91, 94))	('AMPK', 'molecular_function', 'GO:0047322', ('91', '95'))	('affect', 'Reg', (174, 180))	('AMP', 'Chemical', 'MESH:D000249', (120, 123))	('AMP', 'Chemical', 'MESH:D000249', (62, 65))	('AMP binding', 'molecular_function', 'GO:0016208', ('181', '192'))	('AMP', 'Chemical', 'MESH:D000249', (181, 184))
40214	25401301	A mouse transgenic model expressing the PRKAG2 Arg531Gly mutant showed a cardiac phenotype and glycogen accumulation in the heart, although no elevation in mutant AMPK activity was detected.	('AMPK', 'Gene', (163, 167))	('cardiac phenotype', 'CPA', (73, 90))	('AMPK activity', 'molecular_function', 'GO:0004679', ('163', '176'))	('Arg531Gly', 'Var', (47, 56))	('glycogen accumulation', 'MPA', (95, 116))	('mouse', 'Species', '10090', (2, 7))	('glycogen', 'Chemical', 'MESH:D006003', (95, 103))	('Arg531Gly', 'SUBSTITUTION', 'None', (47, 56))	('AMPK', 'Gene', '5562', (163, 167))
40216	25401301	Interestingly, kidney proximal tube-specific expression of a mutant hypoxia-inducible factor (HIF)-1alpha protein that is not targeted for degradation by pVHL (a frequently inactivated protein in ccRCC) promotes the accumulation of glycogen.	('pVHL', 'Gene', (154, 158))	('glycogen', 'Chemical', 'MESH:D006003', (232, 240))	('protein', 'cellular_component', 'GO:0003675', ('106', '113'))	('protein', 'cellular_component', 'GO:0003675', ('185', '192'))	('accumulation', 'MPA', (216, 228))	('promotes', 'PosReg', (203, 211))	('degradation', 'biological_process', 'GO:0009056', ('139', '150'))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (68, 105))	('mutant', 'Var', (61, 67))	('glycogen', 'MPA', (232, 240))	('pVHL', 'Gene', '7428', (154, 158))
40217	25401301	Although AMPK is primarily thought to have a tumor-suppressor role owing to the loss-of-function mutations identified in its upstream activator STK11 (also known as LKB1) in cancers, recent evidence suggest that, under energy-limiting conditions, AMPK can support cell survival through inhibition of the ACC1 and ACC2 enzymes involved in fatty acid biosynthesis and thereby help conserve nicotinamide adenine dinucleotide phosphate (NADPH).	('mutations', 'Var', (97, 106))	('AMPK', 'Gene', '5562', (9, 13))	('LKB1', 'Gene', (165, 169))	('fatty acid', 'Chemical', 'MESH:D005227', (338, 348))	('AMPK', 'molecular_function', 'GO:0047322', ('247', '251'))	('ACC2', 'Gene', (313, 317))	('tumor', 'Disease', (45, 50))	('support', 'PosReg', (256, 263))	('AMPK', 'molecular_function', 'GO:0004691', ('9', '13'))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('STK11', 'molecular_function', 'GO:0033868', ('144', '149'))	('ACC1', 'Gene', (304, 308))	('cell survival', 'CPA', (264, 277))	('ACC2', 'Gene', '597', (313, 317))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('AMPK', 'Gene', (247, 251))	('cancers', 'Disease', (174, 181))	('ACC1', 'Gene', '597', (304, 308))	('AMPK', 'molecular_function', 'GO:0050405', ('247', '251'))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fatty acid biosynthesis', 'biological_process', 'GO:0006633', ('338', '361'))	('tumor-suppressor', 'molecular_function', 'GO:0008181', ('45', '61'))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('AMPK', 'Gene', (9, 13))	('AMPK', 'molecular_function', 'GO:0047322', ('9', '13'))	('STK11', 'Gene', (144, 149))	('nicotinamide adenine dinucleotide phosphate', 'Chemical', 'MESH:D009249', (388, 431))	('LKB1', 'Gene', '6794', (165, 169))	('tumor-suppressor', 'biological_process', 'GO:0051726', ('45', '61'))	('loss-of-function', 'NegReg', (80, 96))	('nicotinamide adenine dinucleotide phosphate', 'MPA', (388, 431))	('AMPK', 'molecular_function', 'GO:0004691', ('247', '251'))	('NADPH', 'Chemical', 'MESH:D009249', (433, 438))	('AMPK', 'Gene', '5562', (247, 251))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('STK11', 'Gene', '6794', (144, 149))	('AMPK', 'molecular_function', 'GO:0050405', ('9', '13'))	('inhibition', 'NegReg', (286, 296))
40218	25401301	Consistent with the fact that kidney cancers have been associated with prominent metabolic alterations and the role of AMPKs in energy sensing, the mutations identified in PRKAG2 along with those in PDHB potentially identify a subtype of chRCC in which metabolic deregulation contributes to pathogenesis.	('kidney cancers', 'Phenotype', 'HP:0009726', (30, 44))	('mutations', 'Var', (148, 157))	('PDHB', 'Gene', (199, 203))	('AMPK', 'Gene', '5562', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('PRKAG2', 'Gene', (172, 178))	('PDHB', 'Gene', '5162', (199, 203))	('AMPK', 'Gene', (119, 123))	('identify', 'Reg', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('kidney cancer', 'Phenotype', 'HP:0009726', (30, 43))	('kidney cancers', 'Disease', 'MESH:D007680', (30, 44))	('pathogenesis', 'biological_process', 'GO:0009405', ('291', '303'))	('kidney cancers', 'Disease', (30, 44))
40219	25401301	In addition to the mutational hotspots observed in TP53, MET and PRKAG2 (Supplementary Table 9), mutational meta-analysis using data from COSMIC identified 78 additional hotspot mutations in 60 genes (Supplementary Table 10), which included drug targets such as IDH2, JAK2 and MTOR.	('IDH2', 'Gene', '3418', (262, 266))	('TP53', 'Gene', (51, 55))	('JAK', 'molecular_function', 'GO:0004713', ('268', '271'))	('JAK2', 'Gene', (268, 272))	('MTOR', 'Gene', (277, 281))	('JAK2', 'Gene', '3717', (268, 272))	('MTOR', 'Gene', '2475', (277, 281))	('mutations', 'Var', (178, 187))	('TP53', 'Gene', '7157', (51, 55))	('IDH2', 'Gene', (262, 266))
40237	25401301	Renal oncocytomas showed very few copy number alterations, with chromosome 1 deletion being the most frequent (Supplementary Fig.	('frequent', 'Reg', (101, 109))	('Renal oncocytomas', 'Phenotype', 'HP:0011798', (0, 17))	('chromosome', 'cellular_component', 'GO:0005694', ('64', '74'))	('deletion', 'Var', (77, 85))	('Renal oncocytomas', 'Disease', (0, 17))	('Renal oncocytomas', 'Disease', 'MESH:C537750', (0, 17))	('chromosome 1', 'Gene', (64, 76))
40240	25401301	20b), indicating that, in addition to previously known TFEB translocations in tRCCs, amplification might be a cancer-relevant TFEB alteration.	('cancer', 'Disease', (110, 116))	('TFEB', 'Gene', '7942', (126, 130))	('TFEB', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('amplification', 'Var', (85, 98))	('TFEB', 'Gene', '7942', (55, 59))	('TFEB', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tRCCs', 'Disease', (78, 83))
40242	25401301	TFEB translocations are low-frequency events and are often missed in the clinic.	('translocations', 'Var', (5, 19))	('TFEB', 'Gene', (0, 4))	('TFEB', 'Gene', '7942', (0, 4))
40243	25401301	Of the samples classified as tRCC on the basis of morphology and TFE3 immunohistochemistry, we found evidence for the previously reported ASPSCR1-TFE3 fusion and PRCC-TFE3 fusion.	('TFE3', 'Gene', '7030', (65, 69))	('ASPSCR1', 'Gene', '79058', (138, 145))	('PRCC', 'Gene', '5546', (162, 166))	('fusion', 'Var', (151, 157))	('TFE3', 'Gene', (167, 171))	('TFE3', 'Gene', '7030', (146, 150))	('PRCC', 'Gene', (162, 166))	('ASPSCR1', 'Gene', (138, 145))	('TFE3', 'Gene', (65, 69))	('TFE3', 'Gene', '7030', (167, 171))	('TFE3', 'Gene', (146, 150))
40259	25401301	We identified an ACTG1-MITF gene fusion (Fig.	('MITF', 'Gene', '4286', (23, 27))	('MITF', 'Gene', (23, 27))	('fusion', 'Var', (33, 39))
40263	25401301	We found that the tumor expressing the fusion had a higher level of MITF expression than the matched normal sample (Fig.	('tumor', 'Disease', (18, 23))	('MITF', 'Gene', '4286', (68, 72))	('MITF', 'Gene', (68, 72))	('higher', 'PosReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('fusion', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
40265	25401301	Expression of the ACTG1-MITF fusion resulted in a significant induction in HIF1A, MET and APEX1 transcript levels in comparison to wild-type MITF (P < 0.01; Fig.	('APEX1', 'Gene', '328', (90, 95))	('APEX1', 'Gene', (90, 95))	('induction', 'PosReg', (62, 71))	('HIF1A', 'Gene', '3091', (75, 80))	('MITF', 'Gene', '4286', (24, 28))	('MITF', 'Gene', (24, 28))	('fusion', 'Var', (29, 35))	('APEX', 'cellular_component', 'GO:0097683', ('90', '94'))	('HIF1A', 'Gene', (75, 80))	('MITF', 'Gene', '4286', (141, 145))	('MITF', 'Gene', (141, 145))
40266	25401301	Given that RCC-predisposing mutation in MITF is thought to function by increasing its stability, we assessed the stability of the ACTG1-MITF fusion protein by analyzing its turnover in cells.	('increasing', 'PosReg', (71, 81))	('MITF', 'Gene', '4286', (40, 44))	('MITF', 'Gene', (40, 44))	('protein', 'cellular_component', 'GO:0003675', ('148', '155'))	('MITF', 'Gene', '4286', (136, 140))	('MITF', 'Gene', (136, 140))	('stability', 'MPA', (86, 95))	('mutation', 'Var', (28, 36))	('RCC-predisposing', 'Disease', (11, 27))
40270	25401301	Taken together, these data suggest that the MITF fusion, like the TFE3 and TFEB fusions, can contribute to tumorigenesis in nccRCC.	('nccRCC', 'Disease', (124, 130))	('contribute', 'Reg', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('MITF', 'Gene', (44, 48))	('TFEB', 'Gene', '7942', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TFE3', 'Gene', '7030', (66, 70))	('MITF', 'Gene', '4286', (44, 48))	('TFEB', 'Gene', (75, 79))	('fusion', 'Var', (49, 55))	('TFE3', 'Gene', (66, 70))
40272	25401301	Thus, we assessed the samples with MiTF fusion or amplification for genes upregulated in common between them that could serve as drug targets.	('fusion', 'Var', (40, 46))	('MiTF', 'Gene', '4286', (35, 39))	('amplification', 'Var', (50, 63))	('upregulated', 'PosReg', (74, 85))	('MiTF', 'Gene', (35, 39))
40273	25401301	We found that a majority (6/7) of the samples with MiTF fusion or amplification had elevated BIRC7 expression (Supplementary Fig.	('amplification', 'Var', (66, 79))	('BIRC7', 'Gene', '79444', (93, 98))	('elevated', 'PosReg', (84, 92))	('MiTF', 'Gene', (51, 55))	('fusion', 'Var', (56, 62))	('BIRC7', 'Gene', (93, 98))	('MiTF', 'Gene', '4286', (51, 55))
40276	25401301	Small molecule BIRC7 inhibitors that sensitize cancer cells to apoptosis are in clinical development and might prove effective in treating tumors positive for MiTF fusion or overexpressing MiTF, which currently remain intractable.	('BIRC7', 'Gene', (15, 20))	('MiTF', 'Gene', '4286', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('fusion', 'Var', (164, 170))	('cancer', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('apoptosis', 'biological_process', 'GO:0006915', ('63', '72'))	('MiTF', 'Gene', (189, 193))	('BIRC7', 'Gene', '79444', (15, 20))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('apoptosis', 'biological_process', 'GO:0097194', ('63', '72'))	('MiTF', 'Gene', '4286', (189, 193))	('MiTF', 'Gene', (159, 163))
40282	25401301	In particular, in pRCC, a majority of the tumors carried MET alterations that included mutation, amplification and/or overexpression (Supplementary Figs.	('overexpression', 'PosReg', (118, 132))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('pRCC', 'Disease', (18, 22))	('amplification', 'MPA', (97, 110))	('mutation', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
40283	25401301	Given these observations, it would be relevant to stratify patients on the basis of MET alterations in trials involving MET inhibitors, as patients with pRCC who have germline MET mutations were responsive to a broad-spectrum tyrosine kinase inhibitor.	('responsive to a', 'MPA', (195, 210))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (180, 189))	('MET', 'Gene', (176, 179))	('patients', 'Species', '9606', (59, 67))	('kinase inhibitor', 'biological_process', 'GO:0033673', ('235', '251'))
40284	25401301	Analysis of chRCC identified frequent TP53 mutations that were exclusive to the chRCC classic type, building on previous findings.	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (38, 42))
40286	25401301	Further, we demonstrate the usefulness of RNA-seq data for the detection of known and new MiTF gene fusions.	('fusions', 'Var', (100, 107))	('MiTF', 'Gene', (90, 94))	('MiTF', 'Gene', '4286', (90, 94))	('RNA', 'cellular_component', 'GO:0005562', ('42', '45'))
40287	25401301	Our data suggest that the tRCC subtype might need to be broadened to incorporate tumors with MITF translocations, as well as possibly other modes of activation of MiTF family members, including direct activation through amplification, indirect activation through fusions involving genes such as SBNO2 or yet to be defined mechanisms in fusion-negative TFE3-overexpressing samples.	('activation', 'PosReg', (201, 211))	('SBNO2', 'Gene', (295, 300))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('MiTF', 'Gene', '4286', (163, 167))	('fusions', 'Var', (263, 270))	('TFE3', 'Gene', (352, 356))	('translocations', 'Var', (98, 112))	('amplification', 'MPA', (220, 233))	('SBNO2', 'Gene', '22904', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('TFE3', 'Gene', '7030', (352, 356))	('MiTF', 'Gene', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('MITF', 'Gene', '4286', (93, 97))	('MITF', 'Gene', (93, 97))
40288	25401301	This suggests that tumors with MiTF gene fusions, encompassing the tRCCs, and/or MiTF gene (MITF, TFE3 or TFEB) overexpression likely form a distinct nccRCC 'MiTF-high' subtype.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('MITF', 'Gene', '4286', (92, 96))	('MITF', 'Gene', (92, 96))	('overexpression', 'PosReg', (112, 126))	('TFEB', 'Gene', '7942', (106, 110))	('MiTF', 'Gene', (81, 85))	('TFEB', 'Gene', (106, 110))	('TFE3', 'Gene', (98, 102))	('MiTF', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MiTF', 'Gene', '4286', (81, 85))	('MiTF', 'Gene', '4286', (158, 162))	('TFE3', 'Gene', '7030', (98, 102))	('fusions', 'Var', (41, 48))	('MiTF', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('MiTF', 'Gene', '4286', (31, 35))
40289	25401301	Overall, these data emphasize the importance of integrative histogenomics in the diagnosis of samples with MiTF family alterations.	('alterations', 'Var', (119, 130))	('MiTF', 'Gene', '4286', (107, 111))	('MiTF', 'Gene', (107, 111))
40340	25401301	Cell lysates from NIH3T3 cells (5 x 106) stably expressing either wild-type or mutant protein were prepared and used for protein blotting as described previously.	('protein', 'Protein', (86, 93))	('mutant', 'Var', (79, 85))	('NIH3T3', 'CellLine', 'CVCL:0594', (18, 24))	('protein', 'cellular_component', 'GO:0003675', ('121', '128'))	('protein', 'cellular_component', 'GO:0003675', ('86', '93'))
40343	25401301	Briefly, 20,000 NIH3T3 cells stably expressing Flag-tagged wild-type MET, MET mutants, ACTG1, MITF or ACTG1-MITF were mixed with 0.35% agar in DMEM (high glucose) and plated in triplicate on 0.5% base agar in a 6-well plate.	('MITF', 'Gene', (94, 98))	('ACTG1', 'Gene', (87, 92))	('high glucose', 'Phenotype', 'HP:0003074', (149, 161))	('MET', 'Gene', (69, 72))	('glucose', 'Chemical', 'MESH:D005947', (154, 161))	('agar', 'Chemical', 'MESH:D000362', (201, 205))	('NIH3T3', 'CellLine', 'CVCL:0594', (16, 22))	('mutants', 'Var', (78, 85))	('agar', 'Chemical', 'MESH:D000362', (135, 139))	('MITF', 'Gene', '4286', (108, 112))	('MITF', 'Gene', (108, 112))	('MET', 'Gene', (74, 77))	('DMEM', 'Chemical', '-', (143, 147))	('MITF', 'Gene', '4286', (94, 98))
40347	25401301	The primer and probe sets used include GAPDH (Hs02758991_g1), MITF (Hs01117294_m1), HIF1A (Hs00153153_m1), MET (Hs01565584_m1) and APEX1 (Hs00959050_g1).	('Hs00959050_g1', 'Var', (138, 151))	('HIF1A', 'Gene', '3091', (84, 89))	('Hs01117294_m1', 'Var', (68, 81))	('APEX1', 'Gene', (131, 136))	('APEX', 'cellular_component', 'GO:0097683', ('131', '135'))	('GAPDH', 'Gene', '2597', (39, 44))	('Hs02758991_g1', 'Var', (46, 59))	('MITF', 'Gene', '4286', (62, 66))	('MITF', 'Gene', (62, 66))	('HIF1A', 'Gene', (84, 89))	('GAPDH', 'Gene', (39, 44))	('APEX1', 'Gene', '328', (131, 136))	('Hs01565584_m1', 'Var', (112, 125))	('Hs00153153_m1', 'Var', (91, 104))