0	33397043	Whole Exome Sequencing Identifies Novel Genetic Alterations in Patients with Pheochromocytoma/Paraganglioma Pheochromocytoma and paragangliomas (PPGL) are known as tumors with the highest level of heritability, approximately 30% of all cases.	('paragangliomas', 'Phenotype', 'HP:0002668', (129, 143))	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('Genetic Alterations', 'Var', (40, 59))	('tumors', 'Disease', (164, 170))	('Pheochromocytoma/Paraganglioma', 'Disease', (77, 107))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (108, 124))	('Paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('Pheochromocytoma/Paraganglioma', 'Disease', 'MESH:D010673', (77, 107))	('Patients', 'Species', '9606', (63, 71))	('Pheochromocytoma and paragangliomas', 'Disease', 'MESH:D010673', (108, 143))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))
1	33397043	Clinical practice guidelines of PPGL recommend genetic testing for germline variants in all patients.	('PPGL', 'Gene', (32, 36))	('patients', 'Species', '9606', (92, 100))	('germline variants', 'Var', (67, 84))
2	33397043	Thirty-six tested negative for pathogenic variants in previous Sanger sequencing or targeted gene panel testing for PPGL underwent whole exome sequencing.	('PPGL', 'Gene', (116, 120))	('variants', 'Var', (42, 50))	('S', 'Chemical', 'MESH:D013455', (63, 64))
5	33397043	Among previously mutation undetected 36 patients, two likely pathogenic variants and 13 variants of uncertain significance (VUS) were detected in 32 pheochromocytoma-related genes.	('pheochromocytoma', 'Disease', (149, 165))	('patients', 'Species', '9606', (40, 48))	('pheochromocytoma', 'Disease', 'MESH:D010673', (149, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (149, 165))	('pathogenic', 'Reg', (61, 71))	('variants', 'Var', (72, 80))	('S', 'Chemical', 'MESH:D013455', (126, 127))
6	33397043	SDHA c.778G>A (p.Gly260Arg) was detected in a patient with head and neck paraganglioma, and KIF1B c.2787-2A>C in a patient with a bladder paraganglioma.	('bladder paraganglioma', 'Disease', 'MESH:D001745', (130, 151))	('patient', 'Species', '9606', (46, 53))	('p.Gly260Arg', 'Mutation', 'rs940845256', (15, 26))	('neck paraganglioma', 'Disease', 'MESH:D010235', (68, 86))	('SDHA', 'Gene', (0, 4))	('paraganglioma', 'Phenotype', 'HP:0002668', (138, 151))	('neck paraganglioma', 'Disease', (68, 86))	('c.778G>A', 'Var', (5, 13))	('c.2787-2A>C', 'Var', (98, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (73, 86))	('c.2787-2A>C', 'Mutation', 'c.2787-2A>C', (98, 109))	('bladder paraganglioma', 'Disease', (130, 151))	('KIF1B', 'Gene', (92, 97))	('SDHA', 'Gene', '6389', (0, 4))	('c.778G>A', 'Mutation', 'rs940845256', (5, 13))	('patient', 'Species', '9606', (115, 122))	('KIF1B', 'Gene', '23095', (92, 97))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (59, 86))
7	33397043	Additionally, a likely pathogenic variant in BRCA2, VUS in TP53, and VUS in NFU1 were detected.	('NFU1', 'Gene', (76, 80))	('BRCA2', 'Gene', (45, 50))	('TP53', 'Gene', (59, 63))	('BRCA2', 'Gene', '675', (45, 50))	('NFU1', 'Gene', '27247', (76, 80))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('S', 'Chemical', 'MESH:D013455', (71, 72))	('pathogenic', 'Reg', (23, 33))	('variant', 'Var', (34, 41))	('TP53', 'Gene', '7157', (59, 63))
8	33397043	Exome sequencing further identified genetic alterations by 5.6% in previously mutation undetected patients in PPGL.	('genetic alterations', 'Var', (36, 55))	('PPGL', 'Gene', (110, 114))	('patients', 'Species', '9606', (98, 106))
12	33397043	Another cluster is the kinase signaling group, consisting of germline or somatic variants in RET, NF1, HRAS, MAX, and TMEM127.	('HRAS', 'Gene', '3265', (103, 107))	('germline', 'Var', (61, 69))	('TMEM127', 'Gene', (118, 125))	('HRAS', 'Gene', (103, 107))	('RET', 'Gene', '5979', (93, 96))	('TMEM127', 'Gene', '55654', (118, 125))	('NF1', 'Gene', (98, 101))	('NF1', 'Gene', '4763', (98, 101))	('RET', 'Gene', (93, 96))
13	33397043	The third cluster is Wnt signaling group, which includes newly recognized somatic variants in CSDE1 as well as somatic gene fusions affecting MAML3.	('variants', 'Var', (82, 90))	('CSDE1', 'Gene', (94, 99))	('MAML3', 'Gene', '55534', (142, 147))	('CSDE1', 'Gene', '7812', (94, 99))	('MAML3', 'Gene', (142, 147))
15	33397043	Aside from those three syndromes, germline variants in the succinate dehydrogenase (SDH) genes are the most common cause of PPGL, occurring in up to 25% of all PPGL patients.	('occurring', 'Reg', (130, 139))	('succinate dehydrogenase', 'Gene', '6390', (59, 82))	('succinate dehydrogenase', 'Gene', (59, 82))	('PPGL', 'Disease', (124, 128))	('SDH', 'Gene', '6390', (84, 87))	('patients', 'Species', '9606', (165, 173))	('cause', 'Reg', (115, 120))	('germline variants', 'Var', (34, 51))	('SDH', 'Gene', (84, 87))
16	33397043	Clinical practice guidelines of PPGL recommend testing for germline variants in all patients by accredited laboratories.	('testing', 'Reg', (47, 54))	('PPGL', 'Gene', (32, 36))	('germline', 'Var', (59, 67))	('patients', 'Species', '9606', (84, 92))
18	33397043	In this study, whole exome sequencing (WES) was used to screen for novel causative variants associated with PPGL to improve the detection rate of rare genetic variants in our cohort.	('variants', 'Var', (83, 91))	('S', 'Chemical', 'MESH:D013455', (41, 42))	('PPGL', 'Gene', (108, 112))
19	33397043	Additional screening for variants in other genes related to cancerous disease or mitochondrial function was also performed.	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('variants', 'Var', (25, 33))	('cancerous disease', 'Disease', 'MESH:D009369', (60, 77))	('cancerous disease', 'Disease', (60, 77))
36	33397043	Allele frequencies in normal controls (gnomeAD) and in silico prediction results were considered (SIFT, PolyPhen2, and MutationTaster).	('S', 'Chemical', 'MESH:D013455', (98, 99))	('PolyPhen2', 'Var', (104, 113))	('SIFT', 'Var', (98, 102))	('MutationTaster', 'Var', (119, 133))
40	33397043	Genes related to other types of cancerous disease or encoding for mitochondria-localized proteins were screened for additional variants.	('variants', 'Var', (127, 135))	('cancerous disease', 'Disease', 'MESH:D009369', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancerous disease', 'Disease', (32, 49))
45	33397043	Among 36 patients, 14 patients were found to carry at least one variant of interest (VOI) in 32 pheochromocytoma-related genes.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (22, 30))	('variant', 'Var', (64, 71))	('pheochromocytoma', 'Disease', (96, 112))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('pheochromocytoma', 'Disease', 'MESH:D010673', (96, 112))
47	33397043	SDHA c.778G>A (p.Gly260Arg) was detected in a patient negative for SDHB, SDHD, VHL, and RET genes.	('VHL', 'Gene', '7428', (79, 82))	('patient', 'Species', '9606', (46, 53))	('p.Gly260Arg', 'Mutation', 'rs940845256', (15, 26))	('RET', 'Gene', (88, 91))	('SDHA', 'Gene', (0, 4))	('SDHB', 'Gene', '6390', (67, 71))	('c.778G>A', 'Var', (5, 13))	('SDHB', 'Gene', (67, 71))	('RET', 'Gene', '5979', (88, 91))	('SDHA', 'Gene', '6389', (0, 4))	('c.778G>A', 'Mutation', 'rs940845256', (5, 13))	('SDHD', 'Gene', (73, 77))	('VHL', 'Gene', (79, 82))	('SDHD', 'Gene', '6392', (73, 77))
49	33397043	KIF1B c.2787-2A>C, a likely pathogenic variant that had not been previously reported, was detected in a patient with a bladder paraganglioma.	('KIF1B', 'Gene', (0, 5))	('KIF1B', 'Gene', '23095', (0, 5))	('bladder paraganglioma', 'Disease', (119, 140))	('paraganglioma', 'Phenotype', 'HP:0002668', (127, 140))	('patient', 'Species', '9606', (104, 111))	('c.2787-2A>C', 'Mutation', 'c.2787-2A>C', (6, 17))	('bladder paraganglioma', 'Disease', 'MESH:D001745', (119, 140))	('c.2787-2A>C', 'Var', (6, 17))
50	33397043	Other variants detected in pheochromocytoma-related genes lacked strong supporting evidence for pathogenic classification.	('pheochromocytoma', 'Disease', 'MESH:D010673', (27, 43))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (27, 43))	('pheochromocytoma', 'Disease', (27, 43))	('variants', 'Var', (6, 14))
51	33397043	SDHC c.478G>A (p.Val160Met) has not been reported previously, but other missense variants near this amino acid residue such as p. Leu158Pro and p. Leu161Val had been detected in PPGL patients.	('c.478G>A', 'Mutation', 'rs377274728', (5, 13))	('Leu158Pro', 'SUBSTITUTION', 'None', (130, 139))	('p.Val160Met', 'Mutation', 'rs147022828', (15, 26))	('SDHC', 'Gene', (0, 4))	('detected', 'Reg', (166, 174))	('PPGL', 'Disease', (178, 182))	('Leu161Val', 'Var', (147, 156))	('SDHC', 'Gene', '6391', (0, 4))	('Leu158Pro', 'Var', (130, 139))	('Leu161Val', 'SUBSTITUTION', 'None', (147, 156))	('patients', 'Species', '9606', (183, 191))
52	33397043	FH c.418G>C (p.Val140Leu) had been submitted in ClinVar as a VUS, but c.419T>G (p. Val140Gly) involving the same amino acid residue has been reported in leiomyomatosis and renal cell cancer patients.	('S', 'Chemical', 'MESH:D013455', (63, 64))	('c.419T>G', 'Var', (70, 78))	('Val140Gly', 'Var', (83, 92))	('patients', 'Species', '9606', (190, 198))	('p.Val140Leu', 'Mutation', 'rs768637170', (13, 24))	('Val140Gly', 'SUBSTITUTION', 'None', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('renal cell cancer', 'Phenotype', 'HP:0005584', (172, 189))	('c.419T>G', 'Mutation', 'rs75642700', (70, 78))	('leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (153, 189))	('c.418G>C', 'Mutation', 'rs768637170', (3, 11))
53	33397043	In addition, a novel nonsense variant, c.914G>A (p.Trp305*) in DNMT3A, showed variant allele frequency of 18% in exome sequencing data, and subsequent validation by Sanger sequencing showed a small alternate peak in the region (Supplemental Fig.	('c.914G>A', 'Var', (39, 47))	('c.914G>A', 'Mutation', 'rs765341003', (39, 47))	('S', 'Chemical', 'MESH:D013455', (228, 229))	('p.Trp305*', 'Mutation', 'rs765341003', (49, 58))	('DNMT3A', 'Gene', (63, 69))	('S', 'Chemical', 'MESH:D013455', (165, 166))	('DNMT3A', 'Gene', '1788', (63, 69))
56	33397043	One likely pathogenic variant in BRCA2 and one VUS in TP53 were detected in cancer-related genes (Table 2).	('BRCA2', 'Gene', (33, 38))	('variant', 'Var', (22, 29))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (54, 58))	('BRCA2', 'Gene', '675', (33, 38))	('pathogenic', 'Reg', (11, 21))	('TP53', 'Gene', (54, 58))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
57	33397043	A BRCA2 splice-site variant, c.8488-1G>A, was detected in a 25-year-old male patient with early-onset paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('paraganglioma', 'Disease', (102, 115))	('BRCA2', 'Gene', (2, 7))	('c.8488-1G>A', 'Mutation', 'rs397507404', (29, 40))	('c.8488-1G>A', 'Var', (29, 40))	('paraganglioma', 'Disease', 'MESH:D010235', (102, 115))	('BRCA2', 'Gene', '675', (2, 7))	('patient', 'Species', '9606', (77, 84))
59	33397043	A patient with VUS in TP53, c.566C>T (p.Ala189Val), had previously been diagnosed with breast cancer, endometrial polyp and also had a brother who had been diagnosed with choriocarcinoma.	('choriocarcinoma', 'Disease', (171, 186))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (171, 186))	('S', 'Chemical', 'MESH:D013455', (17, 18))	('p.Ala189Val', 'Mutation', 'rs121912665', (38, 49))	('c.566C>T', 'Var', (28, 36))	('endometrial polyp', 'Disease', (102, 119))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('endometrial polyp', 'Disease', 'MESH:D011127', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('TP53', 'Gene', '7157', (22, 26))	('choriocarcinoma', 'Disease', 'MESH:D002822', (171, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('patient', 'Species', '9606', (2, 9))	('TP53', 'Gene', (22, 26))	('c.566C>T', 'Mutation', 'rs121912665', (28, 36))
60	33397043	Additionally, we found a missense VUS c.473G>A in NFU1, which is a causative gene of multiple mitochondrial dysfunctions syndrome 1 (MMDS1).	('c.473G>A', 'Var', (38, 46))	('NFU1', 'Gene', (50, 54))	('MMDS1', 'Gene', '27247', (133, 138))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('NFU1', 'Gene', '27247', (50, 54))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('c.473G>A', 'Mutation', 'rs1281276965', (38, 46))	('mitochondrial dysfunctions', 'Phenotype', 'HP:0003287', (94, 120))	('MMDS1', 'Gene', (133, 138))	('multiple mitochondrial dysfunctions syndrome', 'Disease', 'MESH:C565304', (85, 129))	('multiple mitochondrial dysfunctions syndrome', 'Disease', (85, 129))
62	33397043	SDHA c.778G>A (p.Gly260Arg) was shown to be a loss-of-function variant in functional studies in a yeast strain lacking Sdh1.	('Sdh1', 'Gene', '853709', (119, 123))	('p.Gly260Arg', 'Mutation', 'rs940845256', (15, 26))	('SDHA', 'Gene', (0, 4))	('yeast', 'Species', '4932', (98, 103))	('Sdh1', 'Gene', (119, 123))	('c.778G>A', 'Var', (5, 13))	('SDHA', 'Gene', '6389', (0, 4))	('c.778G>A', 'Mutation', 'rs940845256', (5, 13))	('loss-of-function', 'NegReg', (46, 62))
63	33397043	Pathogenic germline SDHA variants were previously identified in 7.6% of patients with PGL, with diagnosis occurring at a significantly younger age in patients carrying the SDHA variants.	('variants', 'Var', (25, 33))	('SDHA', 'Gene', (20, 24))	('Pathogenic', 'Reg', (0, 10))	('SDHA', 'Gene', (172, 176))	('patients', 'Species', '9606', (150, 158))	('SDHA', 'Gene', '6389', (20, 24))	('SDHA', 'Gene', '6389', (172, 176))	('variants', 'Var', (177, 185))	('PGL', 'Disease', (86, 89))	('patients', 'Species', '9606', (72, 80))
64	33397043	The patient carrying the likely pathogenic SDHA variant in this study was diagnosed with head and neck paraganglioma at the age of 20 and was the second youngest patient of our study cohort.	('diagnosed', 'Reg', (74, 83))	('neck paraganglioma', 'Disease', (98, 116))	('variant', 'Var', (48, 55))	('pathogenic', 'Reg', (32, 42))	('patient', 'Species', '9606', (4, 11))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (89, 116))	('neck paraganglioma', 'Disease', 'MESH:D010235', (98, 116))	('SDHA', 'Gene', '6389', (43, 47))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('patient', 'Species', '9606', (162, 169))	('SDHA', 'Gene', (43, 47))
65	33397043	Missense variants in the KIF1B gene had been previously detected in samples of pheochromocytoma, along with a splice site variant.	('pheochromocytoma', 'Disease', 'MESH:D010673', (79, 95))	('detected', 'Reg', (56, 64))	('KIF1B', 'Gene', (25, 30))	('KIF1B', 'Gene', '23095', (25, 30))	('Missense variants', 'Var', (0, 17))	('pheochromocytoma', 'Disease', (79, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (79, 95))
66	33397043	Yet, no previous reports of paraganglioma with a pathogenic KIF1B variant have been published.	('KIF1B', 'Gene', '23095', (60, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (28, 41))	('paraganglioma', 'Disease', (28, 41))	('variant', 'Var', (66, 73))	('paraganglioma', 'Disease', 'MESH:D010235', (28, 41))	('KIF1B', 'Gene', (60, 65))
67	33397043	Our patient carrying a KIF1B c.2787-2A>C had a bladder paraganglioma, which may be the first paraganglioma to be reported carrying a KIF1B variant.	('bladder paraganglioma', 'Disease', 'MESH:D001745', (47, 68))	('paraganglioma', 'Disease', 'MESH:D010235', (93, 106))	('c.2787-2A>C', 'Mutation', 'c.2787-2A>C', (29, 40))	('paraganglioma', 'Disease', 'MESH:D010235', (55, 68))	('c.2787-2A>C', 'Var', (29, 40))	('patient', 'Species', '9606', (4, 11))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('paraganglioma', 'Disease', (93, 106))	('paraganglioma', 'Phenotype', 'HP:0002668', (55, 68))	('bladder paraganglioma', 'Disease', (47, 68))	('KIF1B', 'Gene', (133, 138))	('KIF1B', 'Gene', '23095', (23, 28))	('KIF1B', 'Gene', (23, 28))	('paraganglioma', 'Disease', (55, 68))	('KIF1B', 'Gene', '23095', (133, 138))
68	33397043	The overall positive rate of pathogenic variants in the whole cohort of the apparently sporadic PPGL in our institution was 21.7% (35 among 161 PPGL patients).	('patients', 'Species', '9606', (149, 157))	('pathogenic', 'Reg', (29, 39))	('PPGL', 'Disease', (96, 100))	('positive', 'Reg', (12, 20))	('variants', 'Var', (40, 48))
71	33397043	Among the VUSs, a novel nonsense variant, c.914G>A (p.Trp305*) was detected in DNMT3A.	('p.Trp305*', 'Mutation', 'rs765341003', (52, 61))	('VUSs', 'Disease', 'None', (10, 14))	('DNMT3A', 'Gene', (79, 85))	('c.914G>A', 'Var', (42, 50))	('DNMT3A', 'Gene', '1788', (79, 85))	('c.914G>A', 'Mutation', 'rs765341003', (42, 50))	('VUSs', 'Disease', (10, 14))
73	33397043	Germline variants of DNMT3A previously reported in paraganglioma had been gain-of-function missense variants, while most of the likely hematopoietic somatic mosaic variants detected in multiple cancers were loss-of-function variants.	('gain-of-function', 'PosReg', (74, 90))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('paraganglioma', 'Disease', 'MESH:D010235', (51, 64))	('missense variants', 'Var', (91, 108))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('DNMT3A', 'Gene', (21, 27))	('DNMT3A', 'Gene', '1788', (21, 27))	('loss-of-function', 'NegReg', (207, 223))	('paraganglioma', 'Phenotype', 'HP:0002668', (51, 64))	('variants', 'Var', (9, 17))	('paraganglioma', 'Disease', (51, 64))
74	33397043	In other cancer-related genes, BRCA2 c.8488-1G>A, detected in a 25-year-old male patient with early-onset paraganglioma.	('cancer', 'Disease', (9, 15))	('BRCA2', 'Gene', (31, 36))	('patient', 'Species', '9606', (81, 88))	('paraganglioma', 'Disease', (106, 119))	('c.8488-1G>A', 'Mutation', 'rs397507404', (37, 48))	('BRCA2', 'Gene', '675', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('paraganglioma', 'Disease', 'MESH:D010235', (106, 119))	('c.8488-1G>A', 'Var', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))
76	33397043	Germline BRCA1/2 variants, most commonly associated genes in familial breast and ovarian cancer, are also known to be associated with other cancers such as prostate, colon, gastric, pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('variants', 'Var', (17, 25))	('pancreatic cancer', 'Disease', (182, 199))	('BRCA1/2', 'Gene', (9, 16))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('associated', 'Reg', (118, 128))	('prostate', 'Disease', (156, 164))	('familial breast and ovarian cancer', 'Disease', 'MESH:D000071298', (61, 95))	('gastric', 'Disease', (173, 180))	('BRCA1/2', 'Gene', '672;675', (9, 16))	('colon', 'Disease', (166, 171))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))
77	33397043	BRCA1/2 variants are not regarded as genetic causes for adrenal tumors, but there had been a previously reported case of pheochromocytoma who carried BRCA2 variants.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('pheochromocytoma', 'Disease', 'MESH:D010673', (121, 137))	('BRCA1/2', 'Gene', '672;675', (0, 7))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (121, 137))	('BRCA2', 'Gene', '675', (150, 155))	('adrenal tumors', 'Disease', 'MESH:D000310', (56, 70))	('variants', 'Var', (156, 164))	('BRCA2', 'Gene', (150, 155))	('BRCA1/2', 'Gene', (0, 7))	('adrenal tumors', 'Disease', (56, 70))	('pheochromocytoma', 'Disease', (121, 137))
82	33397043	Although the causative role of this variant for the diagnosis of pheochromocytoma cannot be proven, the BRCA2 germline variants may be associated with an increased risk for adrenal tumors.	('adrenal tumors', 'Disease', (173, 187))	('BRCA2', 'Gene', (104, 109))	('pheochromocytoma', 'Disease', 'MESH:D010673', (65, 81))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (65, 81))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('BRCA2', 'Gene', '675', (104, 109))	('associated', 'Reg', (135, 145))	('adrenal tumors', 'Disease', 'MESH:D000310', (173, 187))	('pheochromocytoma', 'Disease', (65, 81))	('variants', 'Var', (119, 127))
83	33397043	Another missense VUS, c.473G>A (p.Arg158Gln) in NFU1, was found in an individual who also carried a missense variant c.418G>C (p.Val140Leu) in FH.	('NFU1', 'Gene', (48, 52))	('c.418G>C', 'Mutation', 'rs768637170', (117, 125))	('p.Val140Leu', 'Mutation', 'rs768637170', (127, 138))	('p.Arg158Gln', 'Mutation', 'rs1281276965', (32, 43))	('c.473G>A', 'Mutation', 'rs1281276965', (22, 30))	('NFU1', 'Gene', '27247', (48, 52))	('S', 'Chemical', 'MESH:D013455', (19, 20))	('c.418G>C', 'Var', (117, 125))
85	33397043	Though this gene is known to be associated with MMDS1, which is inherited in an autosomal recessive pattern, a variant that affects the function of the protein may be involved with compromised SDH function.	('variant', 'Var', (111, 118))	('involved', 'Reg', (167, 175))	('MMDS1', 'Gene', (48, 53))	('function of', 'MPA', (136, 147))	('SDH', 'Gene', '6390', (193, 196))	('protein', 'Protein', (152, 159))	('MMDS1', 'Gene', '27247', (48, 53))	('associated', 'Reg', (32, 42))	('SDH', 'Gene', (193, 196))	('affects', 'Reg', (124, 131))
86	33397043	Association of the disease and the BRCA2 variant, as well as VUS detected in other genes, should be assessed in further studies.	('variant', 'Var', (41, 48))	('BRCA2', 'Gene', '675', (35, 40))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('BRCA2', 'Gene', (35, 40))
90	33397043	Likely pathogenic variants were detected in two patients, which led to a 5.6% increase in molecularly confirmed PPGL patients.	('PPGL', 'Disease', (112, 116))	('variants', 'Var', (18, 26))	('increase', 'PosReg', (78, 86))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (48, 56))
131	32408270	The genetic study for the mutations of succinate dehydrogenase (SDH)-B, D, and C subunits, MYC-associated factor X (MAX), Transmembrane protein 127 (TMEM 127), and Von Hippel-Lindau (VHL) were requested.	('Transmembrane protein 127', 'Gene', (122, 147))	('MAX', 'Gene', (116, 119))	('MAX', 'Gene', '4149', (116, 119))	('VHL', 'Gene', '7428', (183, 186))	('succinate dehydrogenase (SDH)-B', 'Gene', '6390', (39, 70))	('Transmembrane protein 127', 'Gene', '55654', (122, 147))	('TMEM 127', 'Gene', (149, 157))	('TMEM 127', 'Gene', '55654', (149, 157))	('Von Hippel-Lindau', 'Gene', '7428', (164, 181))	('mutations', 'Var', (26, 35))	('Von Hippel-Lindau', 'Gene', (164, 181))	('MYC-associated factor X', 'Gene', '4149', (91, 114))	('MYC-associated factor X', 'Gene', (91, 114))	('VHL', 'Gene', (183, 186))
132	32408270	PALB2 gene variant c.1408A>G, p (Thr470Ala) with unknown meaning was found when a genetic cause for her breast cancer was studied.	('c.1408A>G', 'Mutation', 'rs150636811', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PALB2', 'Gene', '79728', (0, 5))	('c.1408A>G', 'Var', (19, 28))	('Thr470Ala', 'Var', (33, 42))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('PALB2', 'Gene', (0, 5))	('breast cancer', 'Disease', (104, 117))	('Thr470Ala', 'SUBSTITUTION', 'None', (33, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
158	32408270	Most of hereditary paragangliomas arising in the skull base and neck have been linked to mutations in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complex.	('hereditary paragangliomas', 'Disease', (8, 33))	('paraganglioma', 'Phenotype', 'HP:0002668', (19, 32))	('linked', 'Reg', (79, 85))	('succinate dehydrogenase', 'Gene', '6390', (147, 170))	('succinate dehydrogenase', 'Gene', (147, 170))	('SDH', 'Gene', (172, 175))	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (8, 33))	('mutations', 'Var', (89, 98))	('paragangliomas', 'Phenotype', 'HP:0002668', (19, 33))	('SDH', 'Gene', '6390', (172, 175))
160	32408270	Most cases of hereditary paraganglioma are accounted for mutations in SDHD, SDHB, and SDHC, VHL, and NF1.	('SDHD', 'Gene', (70, 74))	('SDHD', 'Gene', '6392', (70, 74))	('SDHB', 'Gene', '6390', (76, 80))	('paraganglioma', 'Disease', 'MESH:D010235', (25, 38))	('NF1', 'Gene', (101, 104))	('SDHB', 'Gene', (76, 80))	('SDHC', 'Gene', '6391', (86, 90))	('NF1', 'Gene', '4763', (101, 104))	('VHL', 'Gene', (92, 95))	('paraganglioma', 'Phenotype', 'HP:0002668', (25, 38))	('paraganglioma', 'Disease', (25, 38))	('mutations', 'Var', (57, 66))	('VHL', 'Gene', '7428', (92, 95))	('SDHC', 'Gene', (86, 90))	('accounted', 'Reg', (43, 52))
174	32408270	There is a report of the possible involvement of the PALB2 gene in the etiology of paragangliomas as well as a report of a clinical case where a PALB2 mutation in metastatic pancreatic adenocarcinoma and neuroendocrine tumor was described.	('PALB2', 'Gene', '79728', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PALB2', 'Gene', (53, 58))	('pancreatic adenocarcinoma', 'Disease', (174, 199))	('PALB2', 'Gene', '79728', (53, 58))	('neuroendocrine tumor', 'Disease', (204, 224))	('paragangliomas', 'Disease', (83, 97))	('paragangliomas', 'Disease', 'MESH:D010235', (83, 97))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (174, 199))	('paragangliomas', 'Phenotype', 'HP:0002668', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('mutation', 'Var', (151, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (174, 199))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (204, 224))	('involvement', 'Reg', (34, 45))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (204, 224))	('PALB2', 'Gene', (145, 150))
181	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))
182	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
184	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
186	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
188	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
189	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
190	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
191	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('short', 'NegReg', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('associated', 'Reg', (113, 123))
193	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
195	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('rat', 'Species', '10116', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deregulation', 'MPA', (129, 141))	('amplification', 'Var', (112, 125))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('affects', 'Reg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (6, 15))
197	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('177-338aa', 'Var', (174, 183))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
199	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('cancer', 'Disease', (397, 403))	('activation', 'PosReg', (146, 156))	('promote', 'PosReg', (284, 291))	('proliferation', 'CPA', (292, 305))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('EGFR', 'Gene', (96, 100))	('dimerization', 'Var', (33, 45))	('survival', 'CPA', (319, 327))	('metastasis', 'CPA', (441, 451))	('growth', 'CPA', (307, 313))	('activates', 'PosReg', (218, 227))	('contribute', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('autophosphorylation', 'MPA', (161, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('rat', 'Species', '10116', (299, 302))
201	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
203	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
206	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
208	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
211	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
215	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))
225	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('alterations', 'Var', (30, 41))	('EGFR', 'Gene', (25, 29))	('rat', 'Species', '10116', (34, 37))
226	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
227	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
228	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
230	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
232	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
233	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', (86, 91))	('located', 'Reg', (71, 78))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
234	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
235	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
236	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
237	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
238	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
239	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('G598A', 'Var', (100, 105))	('G598E', 'Var', (159, 164))	('G598V', 'Var', (82, 87))
240	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
242	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('L858R', 'Var', (170, 175))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
246	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
248	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ESCA', 'Disease', (92, 96))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('rat', 'Species', '10116', (78, 81))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('HNSC', 'Disease', (106, 110))	('STAD', 'Disease', (119, 123))
250	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
251	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (155, 158))	('alterations', 'Var', (55, 66))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (141, 144))	('patient', 'Species', '9606', (80, 87))
252	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median', 'MPA', (100, 106))
253	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('shortened', 'NegReg', (115, 124))	('patients', 'Species', '9606', (125, 133))
254	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
255	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('short survival', 'MPA', (79, 93))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
257	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutation', 'Var', (287, 295))	('cancers', 'Disease', (128, 135))	('increased', 'PosReg', (337, 346))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (33, 39))	('EGFR expression', 'MPA', (347, 362))	('tumors', 'Disease', (232, 238))
277	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))
278	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
281	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
283	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))
286	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('alterations', 'Var', (35, 46))	('EGFR', 'Gene', (30, 34))	('alteration', 'Var', (122, 132))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
288	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
289	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
290	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
291	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
293	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
294	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
296	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (160, 165))
297	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))
298	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('amplification', 'Var', (5, 18))	('patient', 'Species', '9606', (74, 81))	('EGFR', 'Gene', (42, 46))	('short patient survival', 'CPA', (68, 90))
299	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
300	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))
301	32067422	However, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('high', 'Var', (9, 13))
303	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
308	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (152, 158))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
309	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
310	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))
355	31931809	performed a retrospective study which involved 99 patients with pheochromocytomas comparing TLA with PRA and stated that the mean operative time (117 vs 84 min) was significantly longer in the TLA group than in the PRA group, infering a similar result to our study.	('patients', 'Species', '9606', (50, 58))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (64, 81))	('longer', 'PosReg', (179, 185))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (64, 80))	('pheochromocytomas', 'Disease', (64, 81))	('pheochromocytomas', 'Disease', 'MESH:D010673', (64, 81))	('TLA', 'Var', (193, 196))
422	31849832	For example, in several cancers including endocrine pancreatic cancer cells, loss of fructose-1,6-bisphosphatase (FBP1) that catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate, is associated with increased cancer stem cell like phenotype and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (24, 30))	('metastasis', 'CPA', (269, 279))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('FBP1', 'Gene', '2203', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('loss', 'Var', (77, 81))	('cancers', 'Disease', (24, 31))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('endocrine pancreatic cancer', 'Disease', (42, 69))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('fructose 1,6-bisphosphate', 'Chemical', 'MESH:C029063', (153, 178))	('increased', 'PosReg', (223, 232))	('FBP1', 'Gene', (114, 118))	('endocrine pancreatic cancer', 'Disease', 'MESH:D010190', (42, 69))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('fructose 6-phosphate', 'Chemical', 'MESH:C027618', (182, 202))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (52, 69))
428	31849832	Similarly, Glut3 expression in non-small cell lung cancer is associated with increased glucose uptake, activation of EMT-TFs and tumor cell invasiveness.	('Glut3', 'Gene', '6515', (11, 16))	('glucose', 'Chemical', 'MESH:D005947', (87, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('Glut3', 'Gene', (11, 16))	('glucose uptake', 'CPA', (87, 101))	('EMT-TFs', 'CPA', (117, 124))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('increased glucose', 'Phenotype', 'HP:0003074', (77, 94))	('expression', 'Var', (17, 27))	('increased', 'PosReg', (77, 86))	('tumor', 'Disease', (129, 134))	('activation', 'PosReg', (103, 113))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
431	31849832	In intestinal-type gastric cancer cell lines, silencing LDHa downregulates Zeb2 and the synergistic decrease of LDHa and Zeb2 decreased cancer invasion, metastasis and poor prognosis.	('LDHa', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('downregulates', 'NegReg', (61, 74))	('silencing', 'Var', (46, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (19, 33))	('decrease', 'NegReg', (100, 108))	('cancer', 'Disease', (136, 142))	('intestinal-type gastric cancer', 'Disease', 'MESH:D013274', (3, 33))	('poor prognosis', 'CPA', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('Zeb2', 'Gene', (75, 79))	('Zeb2', 'Gene', '9839', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('Zeb2', 'Gene', '9839', (121, 125))	('Zeb2', 'Gene', (121, 125))	('decreased', 'NegReg', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('intestinal-type gastric cancer', 'Disease', (3, 33))	('LDHa', 'Gene', '3939', (112, 116))	('metastasis', 'CPA', (153, 163))	('LDHa', 'Gene', (112, 116))	('LDHa', 'Gene', '3939', (56, 60))	('cancer', 'Disease', (27, 33))
432	31849832	Also, in bladder cell lines, high levels of LDHa stimulated EMT leading to migration and invasion of the tumor cells and silencing Ldha inhibited tumorogenecity in pancreatic cells in vivo.	('stimulated', 'PosReg', (49, 59))	('Ldha', 'Gene', (131, 135))	('silencing', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('inhibited', 'NegReg', (136, 145))	('LDHa', 'Gene', (44, 48))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Ldha', 'Gene', '3939', (131, 135))	('pancreatic', 'Disease', 'MESH:D010195', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('EMT', 'CPA', (60, 63))	('migration', 'CPA', (75, 84))	('tumor', 'Disease', (105, 110))	('pancreatic', 'Disease', (164, 174))	('LDHa', 'Gene', '3939', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
438	31849832	For example, mutation of mtDNA encoding Complex I subunits of the ETC increases the propensity of oncocytic thyroid cancers.	('oncocytic thyroid cancers', 'Disease', 'MESH:D013964', (98, 123))	('mutation', 'Var', (13, 21))	('oncocytic thyroid cancers', 'Disease', (98, 123))	('increases', 'PosReg', (70, 79))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mtDNA', 'Gene', (25, 30))
439	31849832	The importance of mtDNA mutations to metastasis is highlighted by experiments using cybrid technology, to distinguish the contribution of mitochondrial genome to cancer metastasis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (24, 33))	('mtDNA', 'Gene', (18, 23))
441	31849832	ROS, a mitochondrial byproduct of the ETC, which can damage and mutate mtDNA, was also shown to induce metastasis of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutate', 'Var', (64, 70))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('tumor', 'Disease', (117, 122))	('induce', 'PosReg', (96, 102))	('mtDNA', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
452	31849832	Silencing Pgc-1alpha impaired the invasion and metastasis without affecting the proliferation of the primary tumor.	('Pgc-1alpha', 'Gene', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('impaired', 'NegReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('Pgc-1alpha', 'Gene', '10891', (10, 20))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (109, 114))
454	31849832	Evident in endocrine cancers are mutations of TCA cycle operational enzymes, which are linked to EMT.	('TCA cycle operational enzymes', 'Enzyme', (46, 75))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('endocrine cancers', 'Disease', (11, 28))	('linked', 'Reg', (87, 93))	('mutations', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('endocrine cancer', 'Phenotype', 'HP:0100568', (11, 27))	('TCA', 'Chemical', 'MESH:D014233', (46, 49))	('endocrine cancers', 'Disease', 'MESH:D004701', (11, 28))
455	31849832	The neuroendocrine tumors, pheochromocytoma and paragangliomas are associated with mutation of succinate dehydrogenase (SDH) that converts succinate to fumarate.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (4, 25))	('paragangliomas', 'Disease', 'MESH:D010235', (48, 62))	('paraganglioma', 'Phenotype', 'HP:0002668', (48, 61))	('paragangliomas', 'Phenotype', 'HP:0002668', (48, 62))	('mutation', 'Var', (83, 91))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (27, 61))	('SDH', 'Gene', '6390', (120, 123))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (4, 25))	('succinate', 'Chemical', 'MESH:D019802', (95, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (27, 43))	('succinate dehydrogenase', 'Gene', (95, 118))	('SDH', 'Gene', (120, 123))	('paragangliomas', 'Disease', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('neuroendocrine tumors', 'Disease', (4, 25))	('associated', 'Reg', (67, 77))	('endocrine tumor', 'Phenotype', 'HP:0100568', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('succinate', 'Chemical', 'MESH:D019802', (139, 148))	('fumarate', 'Chemical', 'MESH:D005650', (152, 160))	('succinate dehydrogenase', 'Gene', '6390', (95, 118))
456	31849832	In particular, a mutation of SDHb a subunit of SDH, is thought to alter glucose and glutamine utilization and cause epigenetic modifications that results in EMT.	('SDHb', 'Gene', '6390', (29, 33))	('results in', 'Reg', (146, 156))	('glucose', 'Chemical', 'MESH:D005947', (72, 79))	('SDH', 'Gene', (47, 50))	('mutation', 'Var', (17, 25))	('glutamine', 'Chemical', 'MESH:D005973', (84, 93))	('epigenetic modifications', 'MPA', (116, 140))	('alter', 'Reg', (66, 71))	('SDH', 'Gene', '6390', (29, 32))	('cause', 'Reg', (110, 115))	('EMT', 'CPA', (157, 160))	('SDH', 'Gene', '6390', (47, 50))	('SDHb', 'Gene', (29, 33))	('SDH', 'Gene', (29, 32))
457	31849832	Moreover, SDH mutation is hypothesized to cause consumption of extracellular pyruvate to maintain the Warburg effect conducive for cell growth and thus EMT potential.	('SDH', 'Gene', '6390', (10, 13))	('pyruvate', 'Chemical', 'MESH:D019289', (77, 85))	('EMT potential', 'CPA', (152, 165))	('SDH', 'Gene', (10, 13))	('cause', 'Reg', (42, 47))	('Warburg effect', 'MPA', (102, 116))	('mutation', 'Var', (14, 22))	('consumption of extracellular pyruvate', 'MPA', (48, 85))
460	31849832	SDHb mutations cause upregulation of metastatic genes and epigenetic silencing of cell adhesion protein, keratin 19, leading to EMT and rendering the tumor cells more aggressive and invasive.	('keratin 19', 'Gene', (105, 115))	('EMT', 'CPA', (128, 131))	('epigenetic silencing', 'Var', (58, 78))	('SDHb', 'Gene', (0, 4))	('SDHb', 'Gene', '6390', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('metastatic genes', 'Gene', (37, 53))	('upregulation', 'PosReg', (21, 33))	('keratin 19', 'Gene', '3880', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('aggressive', 'CPA', (167, 177))	('more', 'PosReg', (162, 166))	('invasive', 'CPA', (182, 190))	('tumor', 'Disease', (150, 155))
461	31849832	Mutation of another important enzyme of the TCA cycle, fumarate hydratase (FH), which converts fumarate to malate, is also implicated in metastasis of pheochromocytoma and paraganglioma.	('TCA', 'Chemical', 'MESH:D014233', (44, 47))	('paraganglioma', 'Phenotype', 'HP:0002668', (172, 185))	('Mutation', 'Var', (0, 8))	('fumarate', 'Chemical', 'MESH:D005650', (95, 103))	('FH', 'Gene', '2271', (75, 77))	('implicated', 'Reg', (123, 133))	('fumarate', 'Chemical', 'MESH:D005650', (55, 63))	('fumarate hydratase', 'Gene', '2271', (55, 73))	('metastasis of pheochromocytoma and paraganglioma', 'Disease', 'MESH:D009362', (137, 185))	('malate', 'Chemical', 'MESH:C030298', (107, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (151, 167))	('fumarate hydratase', 'Gene', (55, 73))
464	31849832	Recently, fumarate buildup in renal cancers has been shown to cause EMT by inhibiting Tet dioxygenase mediated demethyation of antimetastatic miR-200 which is a known activator of metastasis and EMT.	('renal cancers', 'Disease', (30, 43))	('inhibiting', 'NegReg', (75, 85))	('Tet', 'Chemical', 'MESH:C010349', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('EMT', 'Disease', (68, 71))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('cause', 'Reg', (62, 67))	('miR-200', 'Chemical', '-', (142, 149))	('Tet dioxygenase mediated demethyation', 'MPA', (86, 123))	('renal cancers', 'Disease', 'MESH:D007680', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('fumarate buildup', 'Var', (10, 26))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))
466	31849832	An oncometabolite formed due to mutation of isocitrate dehydrogenase, 2D hydroxyglutarate, induced metastasis and EMT in colorectal cancers by increasing Zeb1 expression.	('Zeb1', 'Gene', '6935', (154, 158))	('EMT', 'CPA', (114, 117))	('Zeb1', 'Gene', (154, 158))	('isocitrate dehydrogenase', 'Gene', (44, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('colorectal cancers', 'Disease', 'MESH:D015179', (121, 139))	('2D hydroxyglutarate', 'Chemical', '-', (70, 89))	('increasing', 'PosReg', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('isocitrate dehydrogenase', 'Gene', '3417', (44, 68))	('colorectal cancers', 'Disease', (121, 139))	('expression', 'MPA', (159, 169))	('metastasis', 'CPA', (99, 109))	('induced', 'PosReg', (91, 98))	('mutation', 'Var', (32, 40))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
484	31849832	High FASN expression levels in pancreatic cancer and papillary thyroid carcinoma patients is associated with poor survival rate, but its importance to EMT is unknown.	('survival', 'MPA', (114, 122))	('FASN', 'Gene', '2194', (5, 9))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (63, 80))	('papillary thyroid carcinoma', 'Disease', (53, 80))	('High', 'Var', (0, 4))	('poor', 'NegReg', (109, 113))	('expression levels', 'MPA', (10, 27))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('pancreatic cancer', 'Disease', (31, 48))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (53, 80))	('patients', 'Species', '9606', (81, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (53, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (31, 48))	('FASN', 'Gene', (5, 9))
490	31849832	Importantly, inhibition of SCD in prostate cancer blocked tumor gowth and survival.	('survival', 'CPA', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('SCD', 'Gene', (27, 30))	('blocked', 'NegReg', (50, 57))	('inhibition', 'Var', (13, 23))	('prostate cancer', 'Disease', (34, 49))	('SCD', 'Gene', '6319', (27, 30))	('tumor gowth', 'Disease', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (34, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (34, 49))	('tumor gowth', 'Disease', 'MESH:D009369', (58, 69))
495	31849832	The importance of PM composition affecting EMT is also reinforced by the influence of cholesterol, whereby altering cholesterol content of plasma membrane is associated with increased mesenchymal stem cell like phenotype.	('cholesterol content', 'MPA', (116, 135))	('mesenchymal stem cell like phenotype', 'CPA', (184, 220))	('cholesterol', 'Chemical', 'MESH:D002784', (116, 127))	('altering', 'Var', (107, 115))	('cholesterol', 'Chemical', 'MESH:D002784', (86, 97))	('increased', 'PosReg', (174, 183))
504	31620170	Frequent Mutations of VHL Gene and the Clinical Phenotypes in the Largest Chinese Cohort With Von Hippel-Lindau Disease Von Hippel-Lindau (VHL) disease is a rare autosomal-dominant inherited tumor syndrome.	('Mutations', 'Var', (9, 18))	('autosomal-dominant inherited tumor syndrome', 'Disease', (162, 205))	('VHL', 'Gene', (22, 25))	('VHL', 'Gene', (139, 142))	('Von Hippel-Lindau Disease', 'Disease', (94, 119))	('autosomal-dominant inherited tumor syndrome', 'Disease', 'None', (162, 205))	('VHL', 'Gene', '7428', (139, 142))	('VHL', 'Gene', '7428', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('Von Hippel-Lindau Disease', 'Disease', 'MESH:D006623', (94, 119))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (120, 151))
505	31620170	We screened 540 patients from 187 unrelated Chinese VHL families for 19 frequent VHL mutations.	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (16, 24))	('VHL', 'Gene', (81, 84))
509	31620170	193300) is an autosomal-dominant familial neoplastic condition that is caused by germline mutations in the VHL gene located on chromosome 3p25-26.	('mutations', 'Var', (90, 99))	('caused by', 'Reg', (71, 80))	('neoplastic condition', 'Phenotype', 'HP:0002664', (42, 62))	('familial neoplastic condition', 'Disease', 'MESH:C566834', (33, 62))	('familial neoplastic condition', 'Disease', (33, 62))	('VHL', 'Gene', (107, 110))
517	31620170	For example, a retrospective study that included 63 VHL patients from two large VHL kindreds (family 1: Y112H mutation and family 2: Y98H mutation) with pheochromocytoma/paraganglioma found that pheochromocytoma expressivity differed by genotype.	('patients', 'Species', '9606', (56, 64))	('pheochromocytoma', 'Disease', (153, 169))	('Y112H mutation', 'Var', (104, 118))	('Y98H mutation', 'Var', (133, 146))	('paraganglioma', 'Disease', 'MESH:D010235', (170, 183))	('Y112H', 'Mutation', 'p.Y112H', (104, 109))	('Y98H', 'Mutation', 'p.Y98H', (133, 137))	('pheochromocytoma', 'Disease', 'MESH:D010673', (153, 169))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (153, 169))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (195, 211))	('paraganglioma', 'Phenotype', 'HP:0002668', (170, 183))	('pheochromocytoma', 'Disease', (195, 211))	('paraganglioma', 'Disease', (170, 183))	('pheochromocytoma', 'Disease', 'MESH:D010673', (195, 211))
518	31620170	evaluated the genotype-phenotype correlations in 573 VHL patients and confirmed that pheochromocytoma was linked to VHL missense mutations.	('missense mutations', 'Var', (120, 138))	('patients', 'Species', '9606', (57, 65))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('VHL', 'Gene', (116, 119))	('pheochromocytoma', 'Disease', (85, 101))	('pheochromocytoma', 'Disease', 'MESH:D010673', (85, 101))	('linked', 'Reg', (106, 112))
519	31620170	Additionally, the age at onset for VHL syndrome was significantly earlier (P = 0.001) and the age-related risks of RA and RCC were higher (P = 0.022 and P = 0.0008, respectively) for individuals with nonsense or frameshift mutations compared to those with deletions.	('nonsense', 'Var', (200, 208))	('VHL syndrome', 'Disease', 'MESH:D006623', (35, 47))	('earlier', 'PosReg', (66, 73))	('RCC', 'Disease', 'MESH:D002292', (122, 125))	('VHL syndrome', 'Disease', (35, 47))	('frameshift mutations', 'Var', (212, 232))	('RCC', 'Disease', (122, 125))	('RA', 'Disease', 'MESH:D012173', (115, 117))	('higher', 'PosReg', (131, 137))
520	31620170	Due to the rarity of VHL disease, studies on the correlations between the frequent mutations of the VHL gene and clinical phenotypes are relatively scarce, with the majority being case reports or studies involving a limited number of VHL patients or families.	('mutations', 'Var', (83, 92))	('VHL disease', 'Disease', 'MESH:D006623', (21, 32))	('VHL', 'Gene', (100, 103))	('patients', 'Species', '9606', (238, 246))	('VHL disease', 'Disease', (21, 32))
523	31620170	This study improves our understanding of how frequent mutations of the VHL gene affect the age at onset for each susceptible organ and their impact on prognosis in a Chinese population and provides a more accurate resource for genetic counseling and the monitoring of VHL patients.	('affect', 'Reg', (80, 86))	('VHL', 'Gene', (71, 74))	('age at onset for each susceptible organ', 'MPA', (91, 130))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (272, 280))	('impact', 'Reg', (141, 147))
527	31620170	However, at least one patient from a family confirmed the presence of a VHL mutation through genetic testing.	('mutation', 'Var', (76, 84))	('patient', 'Species', '9606', (22, 29))	('VHL', 'Gene', (72, 75))
533	31620170	For each type of mutation, the mean age at onset of VHL-associated susceptible organs (CHB, RA, RCC, PCT, PHEO, and GS) and the mean age at death were calculated as the mean +- standard deviation.	('RCC', 'Disease', (96, 99))	('VHL-associated', 'Gene', (52, 66))	('RA', 'Disease', 'MESH:D012173', (92, 94))	('PHEO', 'Disease', 'MESH:D010673', (106, 110))	('mutation', 'Var', (17, 25))	('PHEO', 'Disease', (106, 110))	('GS', 'Disease', 'MESH:D011125', (116, 118))	('CHB', 'Phenotype', 'HP:0006880', (87, 90))	('RCC', 'Disease', 'MESH:D002292', (96, 99))
535	31620170	A total of 540 patients from 187 unrelated Chinese VHL families were included in our database, and 126 different types of VHL mutations were identified.	('VHL', 'Gene', (122, 125))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (126, 135))
539	31620170	For CHB, both the c.481C > T p.Arg161stop (group 16) and c.486C > G p.Cys162Trp (group 17) mutations had a high penetrance of approximately 80.0% (12/15).	('p.Arg161stop', 'Var', (29, 41))	('CHB', 'Gene', (4, 7))	('CHB', 'Phenotype', 'HP:0006880', (4, 7))	('c.481C > T p.Arg161stop', 'Mutation', 'c.481,161C>T,R,X', (18, 41))	('p.Cys162Trp', 'SUBSTITUTION', 'None', (68, 79))	('p.Cys162Trp', 'Var', (68, 79))	('c.481C > T p.Arg161stop', 'Var', (18, 41))
540	31620170	The mean age at onset of CHB for the c.481C > T p.Arg161stop (group 16) mutation was 27.4 +- 9.4 years (range = 14-40 years), while for the c.486C > G p.Cys162Trp (group 17) mutation, it was 31.4 +- 10.0 years (range = 12-49 years).	('c.486C > G', 'Var', (140, 150))	('c.481C > T p.Arg161stop', 'Var', (37, 60))	('CHB', 'Disease', (25, 28))	('CHB', 'Phenotype', 'HP:0006880', (25, 28))	('c.481C > T p.Arg161stop', 'Mutation', 'c.481,161C>T,R,X', (37, 60))	('p.Cys162Trp', 'SUBSTITUTION', 'None', (151, 162))	('p.Cys162Trp', 'Var', (151, 162))	('p.Arg161stop', 'Var', (48, 60))
541	31620170	For RCC, the mean ages at onset for the c.269A > T p.Asn90Ile (group 8) and c.486C > G p.Cys162Trp (group 17) mutations were 41.5 +- 15.5 years and 41.8 +- 10.3 years, while the penetrance was 26.7% (4/15) and 53.3% (8/15), respectively.	('p.Cys162Trp', 'SUBSTITUTION', 'None', (87, 98))	('p.Cys162Trp', 'Var', (87, 98))	('p.Asn90Ile', 'Var', (51, 61))	('c.486C > G', 'Var', (76, 86))	('p.Asn90Ile', 'SUBSTITUTION', 'None', (51, 61))	('c.269A > T', 'Var', (40, 50))	('RCC', 'Disease', (4, 7))	('RCC', 'Disease', 'MESH:D002292', (4, 7))
542	31620170	There were two types of missense mutations in group 1 located in the 194 mutation site, c.194C > T p.Ser65Leu and c.194C > G p.Ser65Trp, but the clinical phenotypes were different between these two mutational subgroups.	('p.Ser65Trp', 'SUBSTITUTION', 'None', (125, 135))	('p.Ser65Trp', 'Var', (125, 135))	('p.Ser65Leu', 'SUBSTITUTION', 'None', (99, 109))	('p.Ser65Leu', 'Var', (99, 109))	('c.194C > T', 'Var', (88, 98))
543	31620170	Six major VHL-related lesions (CHB, RA, RCC, PCT, PHEO, and GS) were observed in the c.194C > T p.Ser65Leu mutational subgroup, while only three VHL lesions (CHB, RCC, and PCT) presented in the c.194C > G p.Ser65Trp mutational subgroup.	('p.Ser65Leu', 'Var', (96, 106))	('PHEO', 'Disease', (50, 54))	('RCC', 'Disease', 'MESH:D002292', (163, 166))	('RCC', 'Disease', (163, 166))	('RA', 'Disease', 'MESH:D012173', (36, 38))	('p.Ser65Trp', 'SUBSTITUTION', 'None', (205, 215))	('CHB', 'Phenotype', 'HP:0006880', (158, 161))	('RCC', 'Disease', (40, 43))	('p.Ser65Trp', 'Var', (205, 215))	('p.Ser65Leu', 'SUBSTITUTION', 'None', (96, 106))	('GS', 'Disease', 'MESH:D011125', (60, 62))	('RCC', 'Disease', 'MESH:D002292', (40, 43))	('CHB', 'Phenotype', 'HP:0006880', (31, 34))	('VHL-related', 'Disease', (10, 21))	('PHEO', 'Disease', 'MESH:D010673', (50, 54))
544	31620170	The mean age at onset for the common VHL lesions in the c.194C > T p.Ser65Leu mutational subgroup was older than that of the c.194C > G p.Ser65Trp mutational subgroup ( Figures 2A-D ).	('common VHL lesions', 'Disease', (30, 48))	('p.Ser65Leu', 'Var', (67, 77))	('p.Ser65Trp', 'SUBSTITUTION', 'None', (136, 146))	('p.Ser65Trp', 'Var', (136, 146))	('p.Ser65Leu', 'SUBSTITUTION', 'None', (67, 77))
545	31620170	Both c.262T > C p.Trp88Arg and c.263G > C p.Trp88Ser were missense mutations, while c.263G > A p.Trp88Stop resulted in a nonsense mutation.	('p.Trp88Ser', 'Var', (42, 52))	('p.Trp88Arg', 'SUBSTITUTION', 'None', (16, 26))	('p.Trp88Ser', 'SUBSTITUTION', 'None', (42, 52))	('p.Trp88Arg', 'Var', (16, 26))	('p.Trp88Stop', 'SUBSTITUTION', 'None', (95, 106))	('p.Trp88Stop', 'Var', (95, 106))	('c.263G > C', 'Var', (31, 41))
546	31620170	A comparison was made between the mean age at onset for CHB in these three subgroups and found that the c.262T > C p.Trp88Arg mutational group was older than that of the c.263G > C p.Trp88Ser mutational subgroup (P = 0.0152) and the c.263G > A p.Trp88Stop mutational subgroup (P = 0.0232) ( Figure 2E ).	('p.Trp88Ser', 'Var', (181, 191))	('p.Trp88Ser', 'SUBSTITUTION', 'None', (181, 191))	('p.Trp88Stop', 'SUBSTITUTION', 'None', (244, 255))	('p.Trp88Arg', 'Var', (115, 125))	('p.Trp88Stop', 'Var', (244, 255))	('CHB', 'Phenotype', 'HP:0006880', (56, 59))	('p.Trp88Arg', 'SUBSTITUTION', 'None', (115, 125))
547	31620170	However, the CHB-associated age at onset for the c.263G > A p.Trp88Stop mutational subgroup was younger than the c.263G > C p.Trp88Ser mutational subgroup, but the difference was not significant (P = 0.481) ( Figure 2E ).	('CHB', 'Phenotype', 'HP:0006880', (13, 16))	('CHB-associated', 'Disease', (13, 27))	('p.Trp88Ser', 'SUBSTITUTION', 'None', (124, 134))	('p.Trp88Ser', 'Var', (124, 134))	('p.Trp88Stop', 'SUBSTITUTION', 'None', (60, 71))	('p.Trp88Stop', 'Var', (60, 71))
548	31620170	In groups 18 and 19, the c.499C > T p.Arg167Trp and c.500G > A p.Arg167Gln mutations were located in codon 167 (Arg).	('p.Arg167Gln', 'Var', (63, 74))	('p.Arg167Gln', 'SUBSTITUTION', 'None', (63, 74))	('p.Arg167Trp', 'Var', (36, 47))	('p.Arg167Trp', 'SUBSTITUTION', 'None', (36, 47))
550	31620170	Kaplan-Meier curves were used to describe the survival of patients with different VHL mutations, and the results are presented in  Figure 3A .	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (86, 95))	('VHL', 'Gene', (82, 85))
554	31620170	Screening for mutations in the VHL gene helps to clarify the diagnosis of asymptomatic first-degree relatives, thereby improving patient outcomes through early disease surveillance.	('VHL', 'Gene', (31, 34))	('patient', 'Species', '9606', (129, 136))	('mutations', 'Var', (14, 23))	('improving', 'PosReg', (119, 128))
556	31620170	In total, we screened 540 patients from 187 unrelated VHL families and identified 126 different VHL mutations.	('mutations', 'Var', (100, 109))	('VHL', 'Gene', (96, 99))	('patients', 'Species', '9606', (26, 34))
558	31620170	The mutation hotspots of the VHL gene that are already known include Leu178, Cys162, Arg167, Asn78, Pro86, and Tyr98 and have a frequency of approximately 3% to 17%.	('Asn78', 'Chemical', 'MESH:C010809', (93, 98))	('Tyr98', 'Var', (111, 116))	('Leu178', 'Var', (69, 75))	('Asn78', 'Var', (93, 98))	('VHL', 'Gene', (29, 32))	('Cys', 'Chemical', 'MESH:C046557', (77, 80))	('Cys162', 'Var', (77, 83))	('Pro86', 'Var', (100, 105))	('Arg167', 'Var', (85, 91))
559	31620170	reported that Glu70Lys was a high-frequency VHL germline mutation in the Korean population, with nine unrelated patients [16.4% (9/55)] who had the same amino-acid alteration at codon 70 (Glu70Lys) and exhibited VHL type 1 phenotypes.	('Glu70Lys', 'Var', (14, 22))	('VHL', 'Gene', (44, 47))	('Glu70Lys', 'Mutation', 'p.E70K', (188, 196))	('patients', 'Species', '9606', (112, 120))	('Glu70Lys', 'Mutation', 'p.E70K', (14, 22))	('Glu70Lys', 'Var', (188, 196))
560	31620170	Patients from different ethnic backgrounds that have the same VHL germline mutation may also develop distinct phenotypes.	('germline mutation', 'Var', (66, 83))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (62, 65))	('develop', 'Reg', (93, 100))
561	31620170	For example, found four mutations (Arg113Stop, Gln132Stop, Leu158Val, and Cys162Tyr) in Japanese families with the VHL type 2 phenotype, whereas reported that these mutations were associated with the VHL type 1 phenotype in Western populations.	('Gln132Stop', 'Var', (47, 57))	('Leu158Val', 'Var', (59, 68))	('VHL type', 'Disease', (115, 123))	('Arg113Stop', 'Var', (35, 45))	('Cys162Tyr', 'SUBSTITUTION', 'None', (74, 83))	('Gln132Stop', 'Mutation', 'p.Q132X', (47, 57))	('Arg113Stop', 'Mutation', 'p.R113X', (35, 45))	('Leu158Val', 'Chemical', 'MESH:C041390', (59, 68))	('Cys162Tyr', 'Var', (74, 83))
563	31620170	Studies in Western populations showed that the mutation of c.500G > A p.Arg167Gln was associated with RCC and renal cysts, indicating that this mutation was associated with the VHL type 1 phenotype.	('p.Arg167Gln', 'Var', (70, 81))	('renal cysts', 'Disease', (110, 121))	('associated', 'Reg', (86, 96))	('renal cysts', 'Disease', 'MESH:D007674', (110, 121))	('renal cyst', 'Phenotype', 'HP:0000107', (110, 120))	('RCC', 'Disease', 'MESH:D002292', (102, 105))	('RCC', 'Disease', (102, 105))	('renal cysts', 'Phenotype', 'HP:0000107', (110, 121))	('p.Arg167Gln', 'SUBSTITUTION', 'None', (70, 81))
564	31620170	However, according to our database, we found that this mutation was also related to PHEO (37.5%, 9 of 24), which indicated that the phenotype of the c.500G > A p.Arg167Gln mutation also differs in different ethnic backgrounds.	('PHEO', 'Disease', 'MESH:D010673', (84, 88))	('PHEO', 'Disease', (84, 88))	('p.Arg167Gln', 'Var', (160, 171))	('p.Arg167Gln', 'SUBSTITUTION', 'None', (160, 171))
565	31620170	For example, in group 1, two missense mutations occurred in the 194 mutation site, c.194C > T p.Ser65Leu and c.194C > G p.Ser65Trp.	('p.Ser65Leu', 'Var', (94, 104))	('p.Ser65Leu', 'SUBSTITUTION', 'None', (94, 104))	('p.Ser65Trp', 'SUBSTITUTION', 'None', (120, 130))	('p.Ser65Trp', 'Var', (120, 130))	('c.194C > T', 'Var', (83, 93))
566	31620170	Intriguingly, the six major VHL-related lesions (CHB, RA, RCC, PCT, PHEO, and GS) were observed in the c.194C > T p.Ser65Leu mutational subgroup, while only three VHL lesions (CHB, RCC, and PCT) presented in the c.194C > G p.Ser65Trp mutational subgroup.	('p.Ser65Trp', 'Var', (223, 233))	('VHL-related', 'Disease', (28, 39))	('RA', 'Disease', 'MESH:D012173', (54, 56))	('PHEO', 'Disease', 'MESH:D010673', (68, 72))	('p.Ser65Leu', 'Var', (114, 124))	('PHEO', 'Disease', (68, 72))	('PCT', 'Disease', (63, 66))	('GS', 'Disease', 'MESH:D011125', (78, 80))	('p.Ser65Leu', 'SUBSTITUTION', 'None', (114, 124))	('RCC', 'Disease', (58, 61))	('CHB', 'Phenotype', 'HP:0006880', (49, 52))	('CHB', 'Phenotype', 'HP:0006880', (176, 179))	('p.Ser65Trp', 'SUBSTITUTION', 'None', (223, 233))	('RCC', 'Disease', 'MESH:D002292', (58, 61))	('RCC', 'Disease', 'MESH:D002292', (181, 184))	('RCC', 'Disease', (181, 184))
568	31620170	also reported on the phenotypes of two distinct missense mutations in the same codon of the VHL gene (c.334T > A p.Tyr112Asn and c.334T > C p.Tyr112His).	('p.Tyr112Asn', 'Var', (113, 124))	('VHL', 'Gene', (92, 95))	('p.Tyr112Asn', 'SUBSTITUTION', 'None', (113, 124))	('p.Tyr112His', 'SUBSTITUTION', 'None', (140, 151))	('p.Tyr112His', 'Var', (140, 151))
569	31620170	Thirteen patients were found with the c.334T > A p.Tyr112Asn mutation, seven of whom had RCC, and one of these patients had a pheochromocytoma, which suggests that this type of mutation causes the VHL type 1 phenotype, as most of the patients presented with RCC.	('presented', 'Reg', (243, 252))	('RCC', 'Disease', (258, 261))	('RCC', 'Disease', 'MESH:D002292', (258, 261))	('patients', 'Species', '9606', (9, 17))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (126, 142))	('p.Tyr112Asn', 'SUBSTITUTION', 'None', (49, 60))	('RCC', 'Disease', (89, 92))	('causes', 'Reg', (186, 192))	('patients', 'Species', '9606', (234, 242))	('p.Tyr112Asn', 'Var', (49, 60))	('RCC', 'Disease', 'MESH:D002292', (89, 92))	('pheochromocytoma', 'Disease', (126, 142))	('pheochromocytoma', 'Disease', 'MESH:D010673', (126, 142))	('VHL type 1 phenotype', 'Disease', (197, 217))	('patients', 'Species', '9606', (111, 119))
570	31620170	Conversely, the c.334T > C p.Tyr112His mutation was associated with the VHL type 2A phenotype, as every affected individual in two families (22 patients) had PHEO but did not have RCC.	('p.Tyr112His', 'SUBSTITUTION', 'None', (27, 38))	('RCC', 'Disease', 'MESH:D002292', (180, 183))	('p.Tyr112His', 'Var', (27, 38))	('RCC', 'Disease', (180, 183))	('PHEO', 'Disease', 'MESH:D010673', (158, 162))	('patients', 'Species', '9606', (144, 152))	('PHEO', 'Disease', (158, 162))	('VHL type 2A', 'Disease', (72, 83))
571	31620170	evaluated the clinical presentation of 49 family members from three generations of a Turkish family and identified the VHL p.A149S mutation.	('VHL', 'Gene', (119, 122))	('p.A149S', 'Var', (123, 130))	('p.A149S', 'Mutation', 'p.A149S', (123, 130))
579	31620170	Recently, reported genotype-phenotype correlations in VHL disease based on the alteration of a HIF-alpha binding site in the VHL protein.	('VHL disease', 'Disease', (54, 65))	('HIF-alpha', 'Protein', (95, 104))	('VHL disease', 'Disease', 'MESH:D006623', (54, 65))	('alteration', 'Var', (79, 89))
580	31620170	analyzed the genotype-phenotype correlations of VHL syndrome in Korean families and concluded that missense mutations in the Hypoxia-inducible factor-alpha (HIF-alpha) binding site elevate the age-specific risk for CHB.	('missense mutations in', 'Var', (99, 120))	('elevate', 'PosReg', (181, 188))	('VHL syndrome', 'Disease', 'MESH:D006623', (48, 60))	('Hypoxia', 'Disease', 'MESH:D000860', (125, 132))	('CHB', 'Disease', (215, 218))	('Hypoxia', 'Disease', (125, 132))	('VHL syndrome', 'Disease', (48, 60))	('CHB', 'Phenotype', 'HP:0006880', (215, 218))
581	31620170	Von Hippel-Lindau disease is rare, the size of this cohort is relatively small, and the follow-up durations are not sufficiently long, which may influence the correlation analysis between the frequent mutations in the VHL gene and the clinical phenotypes.	('mutations', 'Var', (201, 210))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('VHL', 'Gene', (218, 221))	('Von Hippel-Lindau disease', 'Disease', (0, 25))	('influence', 'Reg', (145, 154))
588	31312622	These alterations stem from single mutations that lead to maladaptive overabsorption of electrolytes with fluid shift into the vasculature, and consequent hypertension.	('lead to', 'Reg', (50, 57))	('hypertension', 'Disease', 'MESH:D006973', (155, 167))	('fluid shift into the vasculature', 'MPA', (106, 138))	('hypertension', 'Phenotype', 'HP:0000822', (155, 167))	('overabsorption of electrolytes', 'MPA', (70, 100))	('hypertension', 'Disease', (155, 167))	('overabsorption of electrolytes', 'Phenotype', 'HP:0005579', (70, 100))	('mutations', 'Var', (35, 44))
595	31312622	These genetic forms of hypertension stem from gain- or loss-of-function mutations within the mineralocorticoid, glucocorticoid, or sympathetic pathways.	('mutations', 'Var', (72, 81))	('glucocorticoid', 'Pathway', (112, 126))	('hypertension', 'Disease', (23, 35))	('hypertension', 'Phenotype', 'HP:0000822', (23, 35))	('gain-', 'PosReg', (46, 51))	('loss-of-function', 'NegReg', (55, 71))	('hypertension', 'Disease', 'MESH:D006973', (23, 35))	('sympathetic pathways', 'Pathway', (131, 151))	('mineralocorticoid', 'Pathway', (93, 110))
620	31312622	Genetics and pathogenesis: Liddle Syndrome is caused by an autosomal dominant (AD), gain-of-function mutation of the epithelial sodium channel (ENaC) present in the collecting duct.	('Liddle Syndrome', 'Disease', (27, 42))	('gain-of-function', 'PosReg', (84, 100))	('ENaC', 'Gene', (144, 148))	('sodium', 'Chemical', 'MESH:D012964', (128, 134))	('mutation', 'Var', (101, 109))	('AD', 'Disease', 'MESH:D000544', (79, 81))	('AD', 'Disease', (79, 81))
622	31312622	Mutation of these subunits disrupts expression of proline-rich regions of the cytoplasmic carboxyl terminus and results in loss of regulatory binding sites for Nedd4-2, a ubiquitin ligase necessary for the breakdown of ENaC.	('regulatory', 'MPA', (131, 141))	('proline', 'Chemical', 'MESH:D011392', (50, 57))	('Nedd4-2', 'Gene', (160, 167))	('Mutation', 'Var', (0, 8))	('disrupts', 'NegReg', (27, 35))	('proline-rich regions of the cytoplasmic', 'MPA', (50, 89))	('loss', 'NegReg', (123, 127))	('expression', 'MPA', (36, 46))	('Nedd4-2', 'Gene', '23327', (160, 167))
628	31312622	Liddle's has an estimated prevalence of 1.5% with genetic testing in a Chinese population and was found to have a 6% prevalence in hypertensive patients among a study of US veterans in Louisiana.	('hypertensive', 'Disease', 'MESH:D006973', (131, 143))	('genetic', 'Var', (50, 57))	('patients', 'Species', '9606', (144, 152))	('hypertensive', 'Disease', (131, 143))
632	31312622	Random aldosterone/renin ratio can be used as a screening test, and a ratio >30 excludes the diagnosis (when expressed in ng/dL for aldosterone and ng/dL/h for renin).	('renin', 'Gene', '5972', (19, 24))	('excludes', 'NegReg', (80, 88))	('renin', 'Gene', '5972', (160, 165))	('aldosterone', 'Chemical', 'MESH:D000450', (7, 18))	('ratio >30', 'Var', (70, 79))	('renin', 'Gene', (19, 24))	('aldosterone', 'Chemical', 'MESH:D000450', (132, 143))	('renin', 'Gene', (160, 165))
636	31312622	Spironolactone is not useful as the genetically altered ENaC is independent of mineralocorticoid regulation.	('Spironolactone', 'Chemical', 'MESH:D013148', (0, 14))	('ENaC', 'Gene', (56, 60))	('genetically altered', 'Var', (36, 55))
645	31312622	The respective enzymes regulate different steps in steroid synthesis, but 11OHD and 17OHD deficiency both cause elevated deoxycortisol and deoxycorticosterone levels.	('11OHD', 'Var', (74, 79))	('17OHD deficiency', 'Disease', 'MESH:D007153', (84, 100))	('17OHD deficiency', 'Disease', (84, 100))	('elevated', 'PosReg', (112, 120))	('deoxycorticosterone levels', 'MPA', (139, 165))	('deoxycortisol', 'MPA', (121, 134))	('deoxycorticosterone', 'Chemical', 'MESH:D003900', (139, 158))	('steroid', 'Chemical', 'MESH:D013256', (51, 58))	('deoxycortisol', 'Chemical', 'MESH:D003350', (121, 134))	('elevated deoxycortisol and deoxycorticosterone', 'Phenotype', 'HP:0025436', (112, 158))
648	31312622	Genetics and Pathophysiology: CAH type IV, or loss of 11beta-hydroxylase, prevents conversion of deoxycortisone and deoxycortisol into corticosterone and cortisol, respectively.	('deoxycortisol', 'Chemical', 'MESH:D003350', (116, 129))	('conversion', 'MPA', (83, 93))	('corticosterone', 'Chemical', 'MESH:D003345', (135, 149))	('deoxycortisone', 'Chemical', 'MESH:D003350', (97, 111))	('deoxycortisol', 'MPA', (116, 129))	('prevents', 'NegReg', (74, 82))	('loss', 'Var', (46, 50))	('cortisol', 'Chemical', 'MESH:D006854', (154, 162))	('cortisol', 'Chemical', 'MESH:D006854', (121, 129))	('11beta-hydroxylase', 'Protein', (54, 72))
661	31312622	CAH type V, also known as P450C17alpha deficiency, manifests clinically as hypogonadism, hypokalemia, and hypertension.	('hypertension', 'Disease', 'MESH:D006973', (106, 118))	('hypogonadism', 'Phenotype', 'HP:0000135', (75, 87))	('hypokalemia', 'Disease', (89, 100))	('hypertension', 'Disease', (106, 118))	('hypogonadism', 'Disease', (75, 87))	('hypokalemia', 'Disease', 'MESH:D007008', (89, 100))	('hypogonadism', 'Disease', 'MESH:D007006', (75, 87))	('hypertension', 'Phenotype', 'HP:0000822', (106, 118))	('hypokalemia', 'Phenotype', 'HP:0002900', (89, 100))	('CAH', 'Var', (0, 3))
677	31312622	Genetics and pathophysiology: The syndrome of apparent mineralocorticoid excess (AME) is an autosomal recessive disease caused by an inactivating mutation of 11beta-hydroxysteroid dehydrogenase type 2 (HSD11B2).	('inactivating mutation', 'Var', (133, 154))	('autosomal recessive disease', 'Disease', (92, 119))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (92, 119))	('mineralocorticoid excess', 'Phenotype', 'HP:0000859', (55, 79))	('HSD11B2', 'Gene', (202, 209))	('caused by', 'Reg', (120, 129))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', '3291', (158, 200))	('HSD11B2', 'Gene', '3291', (202, 209))	('11beta-hydroxysteroid dehydrogenase type 2', 'Gene', (158, 200))
681	31312622	With this mutation, cortisol is not metabolized and is able to bind to the mineralocorticoid receptor, causing clinical features similar to pseudohyperaldosteronism (Figure 4).	('bind', 'Interaction', (63, 67))	('pseudohyperaldosteronism', 'Disease', (140, 164))	('mineralocorticoid receptor', 'Gene', (75, 101))	('causing', 'Reg', (103, 110))	('cortisol', 'Chemical', 'MESH:D006854', (20, 28))	('mutation', 'Var', (10, 18))	('mineralocorticoid receptor', 'Gene', '4306', (75, 101))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (146, 164))	('pseudohyperaldosteronism', 'Disease', 'MESH:D056929', (140, 164))
695	31312622	Genetic testing revealed a mutation of the mineralocorticoid receptor gene to confirm the diagnosis of Geller Syndrome.	('revealed', 'Reg', (16, 24))	('mineralocorticoid receptor', 'Gene', (43, 69))	('Geller Syndrome', 'Disease', 'MESH:D013577', (103, 118))	('Geller Syndrome', 'Disease', (103, 118))	('mutation', 'Var', (27, 35))	('mineralocorticoid receptor', 'Gene', '4306', (43, 69))
696	31312622	Geller syndrome, also referred to as constitutive activation of the mineralocorticoid receptor, results from a gain-of-function mutation on chromosome 4q31.	('Geller syndrome', 'Disease', (0, 15))	('mineralocorticoid receptor', 'Gene', (68, 94))	('Geller syndrome', 'Disease', 'MESH:D013577', (0, 15))	('mutation', 'Var', (128, 136))	('gain-of-function', 'PosReg', (111, 127))	('mineralocorticoid receptor', 'Gene', '4306', (68, 94))
698	31312622	This mutation within the mineralocorticoid receptor causes it to remain constitutively active due to changes to receptor sites that result in altered specificities to the steroid hormones.	('mineralocorticoid receptor', 'Gene', '4306', (25, 51))	('altered', 'Reg', (142, 149))	('steroid hormones', 'Chemical', 'MESH:D013256', (171, 187))	('mineralocorticoid receptor', 'Gene', (25, 51))	('specificities to the steroid hormones', 'MPA', (150, 187))	('mutation', 'Var', (5, 13))	('changes', 'Reg', (101, 108))
704	31312622	A clear diagnosis can be done by genetic testing for gene mutations in the mineralocorticoid receptor.	('mineralocorticoid receptor', 'Gene', (75, 101))	('mineralocorticoid receptor', 'Gene', '4306', (75, 101))	('gene mutations', 'Var', (53, 67))
714	31312622	PHAII type B is due to a loss-of-function mutation of the WNK4 gene on chromosome 17q21.2, while PHAII type C results from gain-of-function mutation of the WNK1 gene on chromosome 12p12.3.	('WNK1', 'Gene', '65125', (156, 160))	('WNK1', 'Gene', (156, 160))	('gain-of-function', 'PosReg', (123, 139))	('loss-of-function', 'NegReg', (25, 41))	('mutation', 'Var', (140, 148))	('WNK4', 'Gene', (58, 62))	('WNK4', 'Gene', '65266', (58, 62))	('PHAII type B', 'Disease', (0, 12))	('mutation', 'Var', (42, 50))
716	31312622	Mutation of the WNK genes leads to failure of endocytosis of the Na+-Cl- co-transporter (NCC).	('Mutation', 'Var', (0, 8))	('Na+-Cl- co-transporter', 'Gene', '6559', (65, 87))	('WNK', 'Gene', (16, 19))	('NCC', 'Gene', '6559', (89, 92))	('Na+-Cl- co-transporter', 'Gene', (65, 87))	('failure', 'NegReg', (35, 42))	('NCC', 'Gene', (89, 92))
729	31312622	Two additional genes, KLHL3 and CUL3, located at chromosome 5q31.2 and 2q36.2, respectively, have been identified as aiding WNK4 function; KLHL 3 mutations are implicated in PHAII type D, while CUL3 is implicated in PHAII type E. Activation of WNK1 stimulates SGK1 (serum- and glucocorticoid-inducible protein kinase 1), which activates the NCC, increasing sodium reabsorption, and leading to hypertension.	('SGK1', 'Gene', '6446', (260, 264))	('WNK1', 'Gene', (244, 248))	('hypertension', 'Disease', (393, 405))	('hypertension', 'Phenotype', 'HP:0000822', (393, 405))	('sodium reabsorption', 'MPA', (357, 376))	('CUL3', 'Gene', (194, 198))	('increasing', 'PosReg', (346, 356))	('leading to', 'Reg', (382, 392))	('SGK1', 'Gene', (260, 264))	('Activation', 'Var', (230, 240))	('aid', 'Gene', (117, 120))	('WNK1', 'Gene', '65125', (244, 248))	('KLHL 3', 'Gene', '26249', (139, 145))	('serum- and glucocorticoid-inducible protein kinase 1', 'Gene', '6446', (266, 318))	('CUL3', 'Gene', (32, 36))	('KLHL3', 'Gene', (22, 27))	('aid', 'Gene', '57379', (117, 120))	('NCC', 'Gene', (341, 344))	('KLHL 3', 'Gene', (139, 145))	('KLHL3', 'Gene', '26249', (22, 27))	('CUL3', 'Gene', '8452', (194, 198))	('activates', 'PosReg', (327, 336))	('WNK4', 'Gene', '65266', (124, 128))	('WNK4', 'Gene', (124, 128))	('NCC', 'Gene', '6559', (341, 344))	('hypertension', 'Disease', 'MESH:D006973', (393, 405))	('sodium', 'Chemical', 'MESH:D012964', (357, 363))	('CUL3', 'Gene', '8452', (32, 36))
750	31312622	Normally, aldosterone is secreted by the zona glomerulosa of the adrenal gland, but due to this chimeric gene, aldosterone is ectopically secreted from the adrenal zona fasciculata instead.	('adrenal zona fasciculata', 'Disease', (156, 180))	('chimeric gene', 'Var', (96, 109))	('adrenal zona fasciculata', 'Disease', 'MESH:D006562', (156, 180))	('aldosterone', 'Chemical', 'MESH:D000450', (10, 21))	('aldosterone', 'Chemical', 'MESH:D000450', (111, 122))
776	31312622	A recent study of patients diagnosed with FHT-II implicates gain-of-function mutations in the CLCN2 gene, encoding a chloride channel, ClC-2, located at chromosome 3q27.1.	('gain-of-function', 'PosReg', (60, 76))	('FHT-I', 'Phenotype', 'HP:0011739', (42, 47))	('ClC-2', 'Gene', (135, 140))	('CLCN2', 'Gene', '1181', (94, 99))	('ClC-2', 'Gene', '1181', (135, 140))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (18, 26))	('CLCN2', 'Gene', (94, 99))
777	31312622	The variant channels were shown in vitro to cause depolarization of adrenocortical cancer cell lines, leading to increased expression of aldosterone synthase and aldosterone production.	('aldosterone production', 'MPA', (162, 184))	('expression', 'MPA', (123, 133))	('aldosterone', 'Chemical', 'MESH:D000450', (162, 173))	('adrenocortical cancer', 'Disease', (68, 89))	('aldosterone production', 'Phenotype', 'HP:0000859', (162, 184))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('aldosterone', 'Chemical', 'MESH:D000450', (137, 148))	('aldosterone synthase', 'Gene', (137, 157))	('aldosterone synthase', 'Gene', '1585', (137, 157))	('increased expression of aldosterone', 'Phenotype', 'HP:0000859', (113, 148))	('increased', 'PosReg', (113, 122))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (68, 89))	('variant', 'Var', (4, 11))	('depolarization', 'MPA', (50, 64))
779	31312622	Genetic testing for CLCN2 mutations may prove helpful, though further work is needed to identify other possible causative genes.	('mutations', 'Var', (26, 35))	('CLCN2', 'Gene', '1181', (20, 25))	('CLCN2', 'Gene', (20, 25))
781	31312622	Familial hyperaldosteronism type 3 (FHT-III) is an autosomal dominant condition caused by gain-of-function mutations in the KCNJ5 gene located at locus 11q24.3.	('mutations', 'Var', (107, 116))	('KCNJ5', 'Gene', (124, 129))	('Familial hyperaldosteronism', 'Disease', 'MESH:C580087', (0, 27))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (0, 32))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (9, 27))	('KCNJ5', 'Gene', '3762', (124, 129))	('gain-of-function', 'PosReg', (90, 106))	('FHT-I', 'Phenotype', 'HP:0011739', (36, 41))	('Familial hyperaldosteronism', 'Disease', (0, 27))
782	31312622	KCNJ5 encodes a potassium channel, which loses its ionic selectivity in disease-causing variants to allow other cations, particularly sodium, to pass through.	('pass through', 'MPA', (145, 157))	('KCNJ5', 'Gene', '3762', (0, 5))	('loses', 'NegReg', (41, 46))	('potassium', 'Chemical', 'MESH:D011188', (16, 25))	('sodium', 'Chemical', 'MESH:D012964', (134, 140))	('ionic selectivity', 'MPA', (51, 68))	('variants', 'Var', (88, 96))	('KCNJ5', 'Gene', (0, 5))
785	31312622	Familial hyperaldosteronism type 4 (FHT-IV) is an autosomal dominant condition caused by gain-of-function mutations in the CACNA1H gene located at chromosome 16p13.3.	('hyperaldosteronism type 4', 'Phenotype', 'HP:0011741', (9, 34))	('CACNA1H', 'Gene', '8912', (123, 130))	('gain-of-function', 'PosReg', (89, 105))	('Familial hyperaldosteronism', 'Disease', 'MESH:C580087', (0, 27))	('Familial hyperaldosteronism type', 'Phenotype', 'HP:0011739', (0, 32))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (9, 27))	('mutations', 'Var', (106, 115))	('FHT-I', 'Phenotype', 'HP:0011739', (36, 41))	('Familial hyperaldosteronism', 'Disease', (0, 27))	('CACNA1H', 'Gene', (123, 130))
787	31312622	These changes allow for greater influx of calcium ions, stimulating adrenal cortical cells and subsequently activating aldosterone synthase.	('calcium', 'Chemical', 'MESH:D002118', (42, 49))	('greater', 'PosReg', (24, 31))	('adrenal cortical cells', 'CPA', (68, 90))	('aldosterone synthase', 'Gene', (119, 139))	('aldosterone synthase', 'Gene', '1585', (119, 139))	('changes', 'Var', (6, 13))	('activating', 'PosReg', (108, 118))	('stimulating', 'PosReg', (56, 67))	('influx of calcium ions', 'MPA', (32, 54))
799	31312622	The mutation is on chromosome 3p25.3 and is a tumor-suppressor gene defect that leads to disease.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mutation', 'Var', (4, 12))	('leads to', 'Reg', (80, 88))	('disease', 'Disease', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
804	31312622	Pheochromocytoma has also been associated with neurofibromatosis type I, caused by mutations in the NF1 gene, located at chromosome 17q11.2.	('Pheochromocytoma', 'Disease', (0, 16))	('mutations', 'Var', (83, 92))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('NF1', 'Gene', '4763', (100, 103))	('associated', 'Reg', (31, 41))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (47, 64))	('NF1', 'Gene', (100, 103))	('caused by', 'Reg', (73, 82))	('neurofibromatosis type I', 'Disease', (47, 71))	('neurofibromatosis type I', 'Disease', 'MESH:C537392', (47, 71))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))
805	31312622	Solitary pheochromocytomas have also been shown to contain mutations in the aforementioned genes.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (9, 26))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('pheochromocytomas', 'Disease', 'MESH:D010673', (9, 26))	('pheochromocytomas', 'Disease', (9, 26))	('mutations', 'Var', (59, 68))
806	31312622	One study of solitary tumors reported that 86% contained copy number alterations in genes associated with familial pheochromocytoma; changes in NF1 were found to be the most frequent at 26% of the tumors studied.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('NF1', 'Gene', (144, 147))	('solitary tumors', 'Disease', (13, 28))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (106, 131))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (115, 131))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('changes', 'Var', (133, 140))	('solitary tumors', 'Disease', 'MESH:D054364', (13, 28))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('familial pheochromocytoma', 'Disease', (106, 131))	('NF1', 'Gene', '4763', (144, 147))	('tumors', 'Disease', (197, 203))	('copy number alterations', 'Var', (57, 80))	('tumors', 'Disease', (22, 28))
815	31312622	Hypertension and brachydactyly (HTNB) describes an autosomal dominant syndrome caused by a mutation in the PDE3A gene located at chromosome 12p12.2; this gene encodes a phosphodiesterase that hydrolyzes cAMP.	('HTNB', 'Disease', (32, 36))	('PDE3A', 'Gene', '5139', (107, 112))	('mutation', 'Var', (91, 99))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (51, 78))	('autosomal dominant syndrome', 'Disease', (51, 78))	('brachydactyly', 'Phenotype', 'HP:0001156', (17, 30))	('brachydactyly', 'Disease', (17, 30))	('PDE3A', 'Gene', (107, 112))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('and', 'Disease', (13, 16))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('cAMP', 'Chemical', '-', (203, 207))	('brachydactyly', 'Disease', 'MESH:D059327', (17, 30))	('HTNB', 'Disease', 'MESH:C537095', (32, 36))	('caused by', 'Reg', (79, 88))	('Hypertension', 'Disease', (0, 12))
816	31312622	Variants of PDE3A that cause HTNB exhibit a gain-of-function due to altered enzyme phosphorylation.	('HTNB', 'Disease', (29, 33))	('HTNB', 'Disease', 'MESH:C537095', (29, 33))	('Variants', 'Var', (0, 8))	('gain-of-function', 'PosReg', (44, 60))	('enzyme phosphorylation', 'MPA', (76, 98))	('PDE3A', 'Gene', '5139', (12, 17))	('PDE3A', 'Gene', (12, 17))	('altered', 'Reg', (68, 75))
817	31312622	The mutant PDE3A enzymes consequently decrease cellular cAMP levels in vascular smooth muscle cells, allowing for proliferation.	('PDE3A', 'Gene', '5139', (11, 16))	('mutant', 'Var', (4, 10))	('allowing', 'Reg', (101, 109))	('PDE3A', 'Gene', (11, 16))	('enzymes', 'Protein', (17, 24))	('decrease', 'NegReg', (38, 46))	('proliferation', 'CPA', (114, 127))	('cAMP', 'Chemical', '-', (56, 60))
822	31312622	Monogenic hypertension refers to specific genetic mutations that interfere with normal renal and adrenal regulation of blood pressure.	('hypertension', 'Disease', 'MESH:D006973', (10, 22))	('mutations', 'Var', (50, 59))	('interfere', 'NegReg', (65, 74))	('hypertension', 'Disease', (10, 22))	('hypertension', 'Phenotype', 'HP:0000822', (10, 22))
873	31034483	One start codon variant of unknown clinical significance (VUS) (c.3G>A, p.Met1Ile) and one missense VUS (c.631A>C, p.Met211Leu) was found in VHL in a patient with RCC-onset at twenty-eight years of age but without other manifestations or family history of von Hippel-Lindau (VHL).	('c.3G>A', 'Mutation', 'rs578091032', (64, 70))	('RCC', 'Phenotype', 'HP:0005584', (163, 166))	('patient', 'Species', '9606', (150, 157))	('VHL', 'Gene', '7428', (141, 144))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (256, 273))	('VUS', 'Chemical', '-', (58, 61))	('VUS', 'Chemical', '-', (100, 103))	('RCC-onset', 'Disease', 'MESH:C538614', (163, 172))	('p.Met211Leu', 'Mutation', 'rs200019083', (115, 126))	('von Hippel-Lindau', 'Disease', (256, 273))	('c.631A>C', 'Var', (105, 113))	('c.3G>A', 'Var', (64, 70))	('VHL', 'Gene', (275, 278))	('RCC-onset', 'Disease', (163, 172))	('c.631A>C', 'Mutation', 'rs200019083', (105, 113))	('VHL', 'Gene', (141, 144))	('p.Met1Ile', 'Mutation', 'rs578091032', (72, 81))	('VHL', 'Gene', '7428', (275, 278))
874	31034483	Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('p.Ser501Asn', 'Mutation', 'rs587777964', (144, 155))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('BAP1', 'Gene', '8314', (68, 72))	('BAP1', 'Gene', (68, 72))	('c.1502G>A', 'Var', (133, 142))	('c.1502G>A', 'Mutation', 'rs587777964', (133, 142))
875	31034483	Finally, we found the known E318K-substitution in MITF in a RCC-affected member of a family with multiple melanomas.	('MITF', 'Gene', '4286', (50, 54))	('MITF', 'Gene', (50, 54))	('E318K-substitution', 'Var', (28, 46))	('E318K', 'Mutation', 'rs149617956', (28, 33))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('multiple melanomas', 'Disease', (97, 115))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('melanomas', 'Phenotype', 'HP:0002861', (106, 115))	('multiple melanomas', 'Disease', 'MESH:D008545', (97, 115))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))
877	31034483	Although we did find three VUS's in BAP1 in three families and a pathogenic variant in MITF in one family, pathogenic germline variants in BAP1, MITF or CDKN2B are not frequent causes of hereditary renal cancer in Denmark.	('MITF', 'Gene', '4286', (145, 149))	('variant', 'Var', (76, 83))	('CDKN2B', 'Gene', '1030', (153, 159))	('MITF', 'Gene', '4286', (87, 91))	('MITF', 'Gene', (145, 149))	('BAP1', 'Gene', '8314', (36, 40))	('MITF', 'Gene', (87, 91))	('variants', 'Var', (127, 135))	('hereditary renal cancer', 'Disease', 'MESH:D007680', (187, 210))	('hereditary renal cancer', 'Disease', (187, 210))	('BAP1', 'Gene', '8314', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	("VUS's", 'Disease', 'MESH:D010300', (27, 32))	('VUS', 'Disease', (27, 30))	('BAP1', 'Gene', (36, 40))	('CDKN2B', 'Gene', (153, 159))	('BAP1', 'Gene', (139, 143))	('renal cancer', 'Phenotype', 'HP:0009726', (198, 210))	('causes', 'Reg', (177, 183))
889	31034483	The majority of hereditary RCCs are caused by pathogenic germline variants in the VHL gene (OMIM #608537) that causes von Hippel-Lindau syndrome (VHL), while other predisposing syndromes include hereditary leiomyomatosis and RCC (FH, OMIM#136850), Birt-Hogg-Dube (FLCN, OMIM #607273), hereditary papillary RCC (MET, OMIM#164860), hereditary paraganglioma and RCC (SDHB, OMIM#185470) and constitutional chromosome 3 translocations of t(3;8)(p14.2;q24.1) (reviewed in, OMIM#14470).	('hereditary leiomyomatosis', 'Disease', 'MESH:D018231', (195, 220))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (330, 354))	('SDHB', 'Gene', '6390', (364, 368))	('causes', 'Reg', (111, 117))	('paraganglioma', 'Phenotype', 'HP:0002668', (341, 354))	('t(3;8)(p14.2;q24.1)', 'STRUCTURAL_ABNORMALITY', 'None', (433, 452))	('RCC', 'Disease', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (27, 30))	('RCC', 'Phenotype', 'HP:0005584', (306, 309))	('RCC', 'Disease', (225, 228))	('RCC', 'Disease', (306, 309))	('von Hippel-Lindau syndrome', 'Disease', (118, 144))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('variants', 'Var', (66, 74))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (118, 144))	('hereditary paraganglioma', 'Disease', (330, 354))	('RCC', 'Disease', 'MESH:C538614', (27, 30))	('SDHB', 'Gene', (364, 368))	('VHL', 'Gene', (146, 149))	('hereditary papillary RCC', 'Disease', 'MESH:C538614', (285, 309))	('RCC', 'Disease', 'MESH:C538614', (306, 309))	('RCC', 'Disease', (359, 362))	('RCC', 'Phenotype', 'HP:0005584', (359, 362))	('RCC', 'Disease', 'MESH:C538614', (225, 228))	('VHL', 'Gene', (82, 85))	('FLCN', 'Gene', '201163', (264, 268))	('hereditary leiomyomatosis', 'Disease', (195, 220))	('RCCs', 'Phenotype', 'HP:0005584', (27, 31))	('hereditary papillary RCC', 'Disease', (285, 309))	('RCC', 'Disease', 'MESH:C538614', (359, 362))	('FLCN', 'Gene', (264, 268))	('VHL', 'Gene', '7428', (146, 149))	('caused', 'Reg', (36, 42))	('VHL', 'Gene', '7428', (82, 85))
890	31034483	However, for several multi-case or early onset RCC families, screening for known pathogenic variants in the most frequent causative genes VHL, FH, FLCN, and MET yields no eligible explanation for the accumulation of RCC in the family, suggesting that unknown genes predisposing for RCC most likely exist.	('FLCN', 'Gene', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (282, 285))	('VHL', 'Gene', '7428', (138, 141))	('RCC', 'Disease', (282, 285))	('RCC', 'Phenotype', 'HP:0005584', (282, 285))	('FLCN', 'Gene', '201163', (147, 151))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RCC', 'Phenotype', 'HP:0005584', (47, 50))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('VHL', 'Gene', (138, 141))	('variants', 'Var', (92, 100))
893	31034483	A broad tumor spectrum accompanies BAP1 pathogenic germline variants and although this spectrum has not yet been fully elucidated, pathogenic variants in BAP1 is known to predispose to cutaneous and uveal melanoma and mesothelioma and is suspected of playing a role in the development of other cancers such as breast cancer, cholangiocarcinoma, cancer of the pancreas and basal cell carcinoma.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (372, 392))	('BAP1', 'Gene', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (383, 392))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('men', 'Species', '9606', (280, 283))	('BAP1', 'Gene', (35, 39))	('breast cancer', 'Disease', (310, 323))	('role', 'Reg', (261, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('basal cell carcinoma', 'Disease', (372, 392))	('uveal melanoma and mesothelioma', 'Disease', 'MESH:C536494', (199, 230))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('cancer of the pancreas', 'Disease', (345, 367))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer of the pancreas', 'Phenotype', 'HP:0002894', (345, 367))	('variants', 'Var', (142, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (325, 343))	('playing', 'Reg', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Disease', (8, 13))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('cholangiocarcinoma', 'Disease', (325, 343))	('BAP1', 'Gene', '8314', (154, 158))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (325, 343))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (372, 392))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('BAP1', 'Gene', '8314', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('predispose', 'Reg', (171, 181))	('variants', 'Var', (60, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))	('cancer of the pancreas', 'Disease', 'MESH:D010190', (345, 367))
894	31034483	Furthermore BAP1 has been found to be mutated in tissue from sporadic malignant renal tumors, which are associated with a high tumor grade and bad prognosis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutated', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('malignant renal tumors', 'Disease', 'MESH:D007674', (70, 92))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (86, 91))	('renal tumor', 'Phenotype', 'HP:0009726', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('BAP1', 'Gene', '8314', (12, 16))	('renal tumors', 'Phenotype', 'HP:0009726', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('BAP1', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('malignant renal tumors', 'Disease', (70, 92))
895	31034483	Pathogenic germline variants have been found to segregate with the disease in high risk RCC families in France and the US, indicating that RCC might be an integral part of the BAP1 tumor spectrum.	('variants', 'Var', (20, 28))	('tumor', 'Disease', (181, 186))	('BAP1', 'Gene', '8314', (176, 180))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('RCC', 'Disease', 'MESH:C538614', (88, 91))	('RCC', 'Disease', (88, 91))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('RCC', 'Phenotype', 'HP:0005584', (88, 91))	('RCC', 'Disease', (139, 142))	('BAP1', 'Gene', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
897	31034483	In 2011 Bertolotto et al discovered a germline amino acid substitution (E318K) in MITF (OMIM#156845) that occurred with a significantly higher frequency in patients with melanoma, RCC or both cancers when compared to controls.	('patients', 'Species', '9606', (156, 164))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('melanoma', 'Disease', (170, 178))	('RCC', 'Disease', (180, 183))	('RCC', 'Phenotype', 'HP:0005584', (180, 183))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('MITF', 'Gene', (82, 86))	('MITF', 'Gene', '4286', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('E318K', 'Mutation', 'rs149617956', (72, 77))	('E318K', 'Var', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
898	31034483	The E318K variant has been found to increase growth, proliferation and migration of melanocytes and renal cells, and although the full picture of MITFs contribution to oncogenesis is yet unknown, the variant is thought to enable MITF to act as an oncogene and thereby predispose to melanoma and RCC.	('melanoma', 'Disease', (282, 290))	('MITF', 'Gene', '4286', (229, 233))	('MITF', 'Gene', (229, 233))	('E318K', 'Mutation', 'rs149617956', (4, 9))	('melanoma', 'Disease', 'MESH:D008545', (282, 290))	('growth', 'CPA', (45, 51))	('increase', 'PosReg', (36, 44))	('E318K', 'Var', (4, 9))	('RCC', 'Phenotype', 'HP:0005584', (295, 298))	('enable', 'PosReg', (222, 228))	('RCC', 'Disease', 'MESH:C538614', (295, 298))	('predispose to', 'Reg', (268, 281))	('MITF', 'Gene', (146, 150))	('RCC', 'Disease', (295, 298))	('MITF', 'Gene', '4286', (146, 150))	('melanoma', 'Phenotype', 'HP:0002861', (282, 290))
899	31034483	CDKN2B (OMIM#600431) is located close to the tumor suppressor gene CDKN2A in region 9p21.3 on the short arm of chromosome 9; a region that often contains genetic alterations and is involved in the development of several types of tumors.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('CDKN2A', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('contains', 'Reg', (145, 153))	('tumor', 'Disease', (45, 50))	('CDKN2A', 'Gene', '1029', (67, 73))	('short arm', 'Phenotype', 'HP:0009824', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('involved', 'Reg', (181, 189))	('tumor', 'Disease', (229, 234))	('men', 'Species', '9606', (204, 207))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('genetic alterations', 'Var', (154, 173))	('CDKN2B', 'Gene', (0, 6))	('tumors', 'Disease', (229, 235))	('CDKN2B', 'Gene', '1030', (0, 6))
903	31034483	DNA was available from five family members of whom the variant was found in two affected brothers and not in three of their cancer free siblings.	('variant', 'Var', (55, 62))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
904	31034483	Furthermore, two novel missense variants in CDKN2B were found in a cohort of fifty individuals with features of nonsyndromic hereditary RCC.	('missense variants', 'Var', (23, 40))	('CDKN2B', 'Gene', (44, 50))	('nonsyndromic hereditary RCC', 'Disease', (112, 139))	('nonsyndromic hereditary RCC', 'Disease', 'MESH:C538614', (112, 139))	('RCC', 'Phenotype', 'HP:0005584', (136, 139))	('CDKN2B', 'Gene', '1030', (44, 50))	('found', 'Reg', (56, 61))
905	31034483	In this study we have examined whether pathogenic variants in BAP1, MITF or CDKN2B play a role in the development of RCC.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('BAP1', 'Gene', '8314', (62, 66))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('CDKN2B', 'Gene', '1030', (76, 82))	('MITF', 'Gene', '4286', (68, 72))	('MITF', 'Gene', (68, 72))	('BAP1', 'Gene', (62, 66))	('variants', 'Var', (50, 58))	('men', 'Species', '9606', (109, 112))	('CDKN2B', 'Gene', (76, 82))
906	31034483	In Denmark, patients with early onset RCC and families with accumulation of RCCs are usually screened for variants in four genes: VHL, FH, FLCN and MET.	('RCC', 'Disease', (38, 41))	('patients', 'Species', '9606', (12, 20))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('variants', 'Var', (106, 114))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCCs', 'Phenotype', 'HP:0005584', (76, 80))	('FLCN', 'Gene', (139, 143))	('VHL', 'Gene', (130, 133))	('VHL', 'Gene', '7428', (130, 133))	('MET', 'Gene', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('FLCN', 'Gene', '201163', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
907	31034483	At Copenhagen University Hospital SDHB-screening is also performed, since pathogenic variants in SDHB are correlated with an increased risk of paraganglioma, pheochromocytoma and RCC and standard chromosome analysis is performed to examine for the known chromosome translocation t(3;8)(p14.2;q24.1).	('SDHB', 'Gene', (97, 101))	('pheochromocytoma', 'Disease', 'MESH:D010673', (158, 174))	('SDHB', 'Gene', '6390', (97, 101))	('variants', 'Var', (85, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (143, 156))	('paraganglioma', 'Disease', (143, 156))	('pheochromocytoma', 'Disease', (158, 174))	('SDHB', 'Gene', '6390', (34, 38))	('t(3;8)(p14.2;q24.1)', 'STRUCTURAL_ABNORMALITY', 'None', (279, 298))	('SDHB', 'Gene', (34, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('paraganglioma', 'Disease', 'MESH:D010235', (143, 156))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
908	31034483	We have performed analyses of the aforementioned RCC causative genes and screened for variants in the putative RCC genes BAP1, MITF and CDKN2B.	('RCC', 'Disease', (49, 52))	('BAP1', 'Gene', '8314', (121, 125))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('MITF', 'Gene', '4286', (127, 131))	('MITF', 'Gene', (127, 131))	('CDKN2B', 'Gene', (136, 142))	('BAP1', 'Gene', (121, 125))	('variants', 'Var', (86, 94))	('CDKN2B', 'Gene', '1030', (136, 142))	('men', 'Species', '9606', (39, 42))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
913	31034483	Patients with a previously identified pathogenic variant in a renal cancer predisposition gene were not included.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('Patients', 'Species', '9606', (0, 8))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('variant', 'Var', (49, 56))
917	31034483	Cohort 1 comprises thirty-two families, who had already been through genetic counselling and hence been screened for variants in one or more of the RCC predisposition genes VHL, FH, FLCN and MET without identification of any pathogenic mutations.	('VHL', 'Gene', (173, 176))	('RCC', 'Disease', (148, 151))	('FLCN', 'Gene', (182, 186))	('VHL', 'Gene', '7428', (173, 176))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('variants', 'Var', (117, 125))	('FLCN', 'Gene', '201163', (182, 186))	('screened', 'Reg', (104, 112))
922	31034483	These patients only consented to screening for variants in BAP1 and the known E318K-variant in MITF, which was performed prior to this study.	('variants', 'Var', (47, 55))	('BAP1', 'Gene', (59, 63))	('MITF', 'Gene', '4286', (95, 99))	('MITF', 'Gene', (95, 99))	('patients', 'Species', '9606', (6, 14))	('E318K', 'Mutation', 'rs149617956', (78, 83))	('BAP1', 'Gene', '8314', (59, 63))	('E318K-variant', 'Var', (78, 91))
943	31034483	MITF was screened for the E318K variant by TaqMan analysis as recently described.	('E318K', 'Mutation', 'rs149617956', (26, 31))	('MITF', 'Gene', '4286', (0, 4))	('E318K', 'Var', (26, 31))	('MITF', 'Gene', (0, 4))
945	31034483	BAP1, MITF and VHL variants are numbered according to accession number NM_004656.3, NM_000248.3 and NM_000551.3, respectively, following the guidelines from the Human Genome Variation Society (http://www.hgvs.org/varnomen).	('Human', 'Species', '9606', (161, 166))	('BAP1', 'Gene', (0, 4))	('VHL', 'Gene', (15, 18))	('NM_000248.3', 'Var', (84, 95))	('VHL', 'Gene', '7428', (15, 18))	('BAP1', 'Gene', '8314', (0, 4))	('men', 'Species', '9606', (218, 221))	('MITF', 'Gene', '4286', (6, 10))	('MITF', 'Gene', (6, 10))	('NM_000551.3', 'Var', (100, 111))	('variants', 'Var', (19, 27))	('NM_004656.3', 'Var', (71, 82))
947	31034483	'Likely benign' and 'benign' variants have a low probability of actually being pathogenic (0.001-0.049 and lower than 0.001, respectively) and are treated as 'no mutation detected' for RCC.	('RCC', 'Disease', (185, 188))	('variants', 'Var', (29, 37))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('RCC', 'Disease', 'MESH:C538614', (185, 188))
955	31034483	Sixteen patients were screened for variants in one or more of the RCC predisposition genes VHL, FH, FLCN, MET or SDHB (Table 2).	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('FLCN', 'Gene', (100, 104))	('SDHB', 'Gene', '6390', (113, 117))	('MET', 'Gene', (106, 109))	('variants', 'Var', (35, 43))	('VHL', 'Gene', (91, 94))	('SDHB', 'Gene', (113, 117))	('VHL', 'Gene', '7428', (91, 94))	('FLCN', 'Gene', '201163', (100, 104))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))	('patients', 'Species', '9606', (8, 16))
956	31034483	No pathogenic variants were found in FH, FLCN, MET or SDHB, but we did find a start codon variant (c.3G>A, p.Met1Ile) and a missense variant (c.631A>C, p.Met211Leu) in VHL in a patient from cohort 2 (Fig 3).	('FLCN', 'Gene', (41, 45))	('c.631A>C', 'Var', (142, 150))	('SDHB', 'Gene', '6390', (54, 58))	('patient', 'Species', '9606', (177, 184))	('SDHB', 'Gene', (54, 58))	('VHL', 'Gene', (168, 171))	('p.Met211Leu', 'Mutation', 'rs200019083', (152, 163))	('c.3G>A', 'Var', (99, 105))	('c.631A>C', 'Mutation', 'rs200019083', (142, 150))	('FLCN', 'Gene', '201163', (41, 45))	('VHL', 'Gene', '7428', (168, 171))	('p.Met1Ile', 'Mutation', 'rs578091032', (107, 116))	('c.3G>A', 'Mutation', 'rs578091032', (99, 105))
957	31034483	Both VHL variants are classified as class 3 variants (VUS) according to the classification guidelines from IARC.	('variants', 'Var', (9, 17))	('VUS', 'Chemical', '-', (54, 57))	('VHL', 'Gene', (5, 8))	('VHL', 'Gene', '7428', (5, 8))
958	31034483	In three patients of forty-seven tested, we found variants in BAP1; two missense variants (c.944A>C, p.Glu315Ala, Fig 4) and (c.1502G>A, p.Ser501Asn, Fig 5) and one intron variant (c.1729+8T>C, Table 3).	('p.Ser501Asn', 'Mutation', 'rs587777964', (137, 148))	('patients', 'Species', '9606', (9, 17))	('BAP1', 'Gene', '8314', (62, 66))	('p.Glu315Ala', 'Mutation', 'rs149974450', (101, 112))	('c.944A>C', 'Var', (91, 99))	('c.1502G>A', 'Mutation', 'rs587777964', (126, 135))	('BAP1', 'Gene', (62, 66))	('c.1729+8T>C', 'Mutation', 'rs150945583', (181, 192))	('c.944A>C', 'Mutation', 'rs149974450', (91, 99))	('c.1502G>A', 'Var', (126, 135))
959	31034483	The missense variant c.944A>C, p.Glu315Ala is reported in the gnomAD database with a frequency of 0.016% in Europeans (non-Finnish).	('c.944A>C', 'Var', (21, 29))	('p.Glu315Ala', 'Var', (31, 42))	('p.Glu315Ala', 'Mutation', 'rs149974450', (31, 42))	('c.944A>C', 'Mutation', 'rs149974450', (21, 29))
960	31034483	The intron variant c.1729+8T>C (rs150945583), which is identified in the patient with two VHL variants, is reported in the gnomAD database with a frequency of 0.60% in Europeans (non-Finnish).	('VHL', 'Gene', '7428', (90, 93))	('rs150945583', 'Mutation', 'rs150945583', (32, 43))	('c.1729+8T>C', 'Mutation', 'rs150945583', (19, 30))	('patient', 'Species', '9606', (73, 80))	('VHL', 'Gene', (90, 93))	('c.1729+8T>C', 'Var', (19, 30))
961	31034483	Finally, the novel missense variant c.1502G>A, p.Ser501Asn is not reported in the gnomAD database and to our knowledge not in the literature, and is classified as a class 3 variant.	('p.Ser501Asn', 'Var', (47, 58))	('p.Ser501Asn', 'Mutation', 'rs587777964', (47, 58))	('c.1502G>A', 'Var', (36, 45))	('c.1502G>A', 'Mutation', 'rs587777964', (36, 45))
962	31034483	Sequencing for the E318K-variant in MITF was performed in forty-five patients with normal results.	('MITF', 'Gene', '4286', (36, 40))	('MITF', 'Gene', (36, 40))	('patients', 'Species', '9606', (69, 77))	('E318K', 'Mutation', 'rs149617956', (19, 24))	('E318K-variant', 'Var', (19, 32))
963	31034483	In one family, we were able to collect DNA from two relatives with RCC and both were screened for the E318K variant with normal results.	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('E318K', 'Mutation', 'rs149617956', (102, 107))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('E318K', 'Var', (102, 107))
964	31034483	In one family, the patient diagnosed with RCC was found to carry the E318K variant.	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('patient', 'Species', '9606', (19, 26))	('E318K', 'Mutation', 'rs149617956', (69, 74))	('E318K', 'Var', (69, 74))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))
966	31034483	Two daughters were diagnosed with melanoma, one of whom was a carrier of the E318K-variant.	('E318K-variant', 'Var', (77, 90))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))	('diagnosed', 'Reg', (19, 28))	('E318K', 'Mutation', 'rs149617956', (77, 82))
980	31034483	Forty-six families in the current study, including thirteen families with melanoma, have been screened for the known E318K-variant in MITF, but the variant has only been found in one family, which has previously been published.	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('E318K', 'Mutation', 'rs149617956', (117, 122))	('MITF', 'Gene', (134, 138))	('melanoma', 'Disease', (74, 82))	('E318K-variant', 'Var', (117, 130))	('MITF', 'Gene', '4286', (134, 138))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))
983	31034483	The c.1502G>A, p.Ser501Asn variant in BAP1 in family 1013 has not previously been reported.	('c.1502G>A', 'Var', (4, 13))	('p.Ser501Asn', 'Var', (15, 26))	('BAP1', 'Gene', (38, 42))	('c.1502G>A', 'Mutation', 'rs587777964', (4, 13))	('p.Ser501Asn', 'Mutation', 'rs587777964', (15, 26))	('BAP1', 'Gene', '8314', (38, 42))
984	31034483	Pathogenic clues include the highly conserved nucleotide and amino acid involved, and a SIFT and MutationTaster prediction as 'deleterious'.	('MutationTaster', 'Var', (97, 111))	('SIFT', 'Disease', (88, 92))	('SIFT', 'Disease', 'None', (88, 92))
985	31034483	However, the variant was not found in two cancer-free FFPE samples collected from the proband's brother also diagnosed with RCC (II:1, Fig 5) and thus did not segregate with RCC in the family.	('RCC', 'Disease', (124, 127))	('RCC', 'Phenotype', 'HP:0005584', (124, 127))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('variant', 'Var', (13, 20))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Disease', 'MESH:C538614', (174, 177))
988	31034483	The c.944A>C, p.Glu315Ala variant in BAP1 in family 5001 has not been reported in families with BAP1-associated cancers but has a population frequency of 0.016%.	('BAP1', 'Gene', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('c.944A>C', 'Var', (4, 12))	('p.Glu315Ala', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('c.944A>C', 'Mutation', 'rs149974450', (4, 12))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('BAP1', 'Gene', '8314', (37, 41))	('cancers', 'Disease', (112, 119))	('BAP1', 'Gene', (37, 41))	('p.Glu315Ala', 'Mutation', 'rs149974450', (14, 25))	('BAP1', 'Gene', '8314', (96, 100))
992	31034483	The start codon variant (c.3G>A, p.Met1Ile) and missense variant (c.631A>C, p.Met211Leu) in VHL in family 6002 was found in a patient (III:1, Fig 3), who was diagnosed with ccRCC at age twenty-eight, but neither he nor any family member have other VHL-manifestations.	('c.3G>A', 'Var', (25, 31))	('p.Met211Leu', 'Mutation', 'rs200019083', (76, 87))	('p.Met1Ile', 'Mutation', 'rs578091032', (33, 42))	('c.631A>C', 'Var', (66, 74))	('c.3G>A', 'Mutation', 'rs578091032', (25, 31))	('VHL', 'Gene', (92, 95))	('patient', 'Species', '9606', (126, 133))	('p.Met211Leu', 'Var', (76, 87))	('VHL', 'Gene', '7428', (92, 95))	('RCC', 'Disease', (175, 178))	('c.631A>C', 'Mutation', 'rs200019083', (66, 74))	('RCC', 'Phenotype', 'HP:0005584', (175, 178))	('VHL', 'Gene', (248, 251))	('RCC', 'Disease', 'MESH:C538614', (175, 178))	('VHL', 'Gene', '7428', (248, 251))
993	31034483	The start codon variant substitutes the initial methionine, thus skipping the native start codon with a yet unknown effect on VHL translation.	('variant', 'Var', (16, 23))	('methionine', 'Chemical', 'MESH:D008715', (48, 58))	('VHL', 'Gene', (126, 129))	('methionine', 'MPA', (48, 58))	('skipping', 'NegReg', (65, 73))	('VHL', 'Gene', '7428', (126, 129))
994	31034483	An alternative start codon at codon 54, which harbors the next methionine, is presumed to initiate VHL translation, thus forming an alternative protein product, which is thought to possess tumor suppressor properties partially similar to wildtype VHL.	('tumor', 'Disease', (189, 194))	('methionine', 'Var', (63, 73))	('VHL', 'Gene', (99, 102))	('VHL', 'Gene', '7428', (99, 102))	('VHL', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('VHL', 'Gene', '7428', (247, 250))	('methionine', 'Chemical', 'MESH:D008715', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
997	31034483	It is possible that mosaicism of a third, and pathogenic, variant in VHL could explain the mild VHL-phenotype.	('variant', 'Var', (58, 65))	('VHL', 'Gene', (96, 99))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', '7428', (96, 99))	('VHL', 'Gene', '7428', (69, 72))
1000	31034483	Evidence suggests that the E318K-variant plays a role in the development of melanoma but the role in the development of RCC is unclear.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('E318K', 'Mutation', 'rs149617956', (27, 32))	('E318K-variant', 'Var', (27, 40))	('RCC', 'Disease', 'MESH:C538614', (120, 123))	('RCC', 'Disease', (120, 123))	('RCC', 'Phenotype', 'HP:0005584', (120, 123))	('men', 'Species', '9606', (112, 115))	('men', 'Species', '9606', (68, 71))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
1001	31034483	Recent studies do not find an association between the E318K-variant and the development of RCC, neither does the current study.	('E318K', 'Mutation', 'rs149617956', (54, 59))	('men', 'Species', '9606', (83, 86))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('E318K-variant', 'Var', (54, 67))
1002	31034483	A possible association between the E318K-variant and the development of pheochromocytoma and paraganglioma has been proposed recently by Castro-Vega et al, illustrating that the cancer spectrum of the E318K-variant, if any, is not yet fully elucidated.	('pheochromocytoma', 'Disease', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pheochromocytoma', 'Disease', 'MESH:D010673', (72, 88))	('paraganglioma', 'Disease', 'MESH:D010235', (93, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (72, 88))	('E318K-variant', 'Var', (201, 214))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('E318K-variant', 'Var', (35, 48))	('paraganglioma', 'Disease', (93, 106))	('E318K', 'Mutation', 'rs149617956', (35, 40))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('men', 'Species', '9606', (64, 67))	('E318K', 'Mutation', 'rs149617956', (201, 206))
1003	31034483	Further studies should be performed in renal cancer families to elucidate the impact of the E318K-variant in the development of RCC.	('renal cancer', 'Disease', 'MESH:D007680', (39, 51))	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('renal cancer', 'Phenotype', 'HP:0009726', (39, 51))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('renal cancer', 'Disease', (39, 51))	('E318K', 'Mutation', 'rs149617956', (92, 97))	('E318K-variant', 'Var', (92, 105))	('men', 'Species', '9606', (120, 123))
1004	31034483	We found no variants in CDKN2B and are therefore not able to confirm the findings of Jafri et al regarding CDKN2B as a RCC predisposing gene.	('CDKN2B', 'Gene', '1030', (107, 113))	('RCC', 'Phenotype', 'HP:0005584', (119, 122))	('CDKN2B', 'Gene', (24, 30))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('variants', 'Var', (12, 20))	('RCC', 'Disease', (119, 122))	('CDKN2B', 'Gene', '1030', (24, 30))	('CDKN2B', 'Gene', (107, 113))
1005	31034483	Two different putative RCC-genes include PTEN known for its involvement in Cowden syndrome, in which patients have a genetic predisposition to RCC, and PBRM1 in which a heterozygote germline variant was found to segregate with RCC in four affected family members in a French RCC-family.	('involvement', 'Reg', (60, 71))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('PBRM1', 'Gene', (152, 157))	('Cowden syndrome', 'Disease', 'MESH:D006223', (75, 90))	('RCC', 'Disease', (227, 230))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('patients', 'Species', '9606', (101, 109))	('RCC', 'Phenotype', 'HP:0005584', (227, 230))	('variant', 'Var', (191, 198))	('PTEN', 'Gene', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (227, 230))	('Cowden syndrome', 'Disease', (75, 90))	('RCC', 'Phenotype', 'HP:0005584', (143, 146))	('RCC', 'Disease', (143, 146))	('PTEN', 'Gene', '5728', (41, 45))	('men', 'Species', '9606', (67, 70))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('RCC', 'Disease', (23, 26))	('RCC', 'Disease', 'MESH:C538614', (143, 146))	('PBRM1', 'Gene', '55193', (152, 157))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))
1006	31034483	The proband of one family in the current study was screened for variants in PTEN prior to inclusion, but in the remaining families PTEN screening was not considered relevant by the Departments of Clinical Genetics initially performing the genetic counselling.	('PTEN', 'Gene', (131, 135))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (131, 135))	('PTEN', 'Gene', '5728', (76, 80))	('men', 'Species', '9606', (187, 190))	('variants', 'Var', (64, 72))
1027	31034483	Here ten different histological subtypes of RCCs are described (clear cell, multilocular cystic, papillary, chromophobe, collecting duct carcinoma, medullary carcinoma, RCC associated with Xp11.2 translocations, RCC associated with neuroblastoma, mucinous, tubular and spindle cell carcinomas and the unclassified carcinomas).	('associated', 'Reg', (216, 226))	('neuroblastoma', 'Disease', (232, 245))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (212, 215))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('neuroblastoma', 'Phenotype', 'HP:0003006', (232, 245))	('RCC', 'Disease', 'MESH:C538614', (212, 215))	('carcinoma', 'Disease', 'MESH:D002277', (282, 291))	('RCC', 'Phenotype', 'HP:0005584', (169, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (232, 245))	('RCC', 'Disease', (169, 172))	('carcinoma', 'Disease', 'MESH:D002277', (314, 323))	('carcinomas', 'Disease', (282, 292))	('carcinomas', 'Disease', (314, 324))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('carcinoma', 'Disease', 'MESH:D002277', (137, 146))	('associated', 'Reg', (173, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Disease', (158, 167))	('RCC', 'Disease', 'MESH:C538614', (169, 172))	('mucinous', 'Disease', (247, 255))	('RCCs', 'Phenotype', 'HP:0005584', (44, 48))	('Xp11.2', 'Gene', (189, 195))	('translocations', 'Var', (196, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('carcinomas', 'Disease', 'MESH:D002277', (282, 292))	('carcinomas', 'Phenotype', 'HP:0030731', (282, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('carcinomas', 'Phenotype', 'HP:0030731', (314, 324))	('carcinoma', 'Disease', (282, 291))	('carcinomas', 'Disease', 'MESH:D002277', (314, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('RCC', 'Disease', (212, 215))	('carcinoma', 'Disease', (314, 323))	('carcinoma', 'Disease', (137, 146))
1032	31034483	Few E318K-carriers have been diagnosed with RCC, but the most prevalent histological subtype described in the literature is clear cell carcinoma.	('E318K', 'Mutation', 'rs149617956', (4, 9))	('carcinoma', 'Disease', 'MESH:D002277', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('E318K-carriers', 'Var', (4, 18))	('carcinoma', 'Disease', (135, 144))
1039	31034483	We screened forty-nine family members in forty-eight families for variants in one or more of the RCC causative genes VHL (n = 10), FH (n = 11), FLCN (n = 10), MET (n = 11) and SDHB (n = 9) and the putative RCC-genes BAP1 (n = 47), MITF (n = 46) and CDKN2B (n = 43).	('MITF', 'Gene', '4286', (231, 235))	('FLCN', 'Gene', (144, 148))	('BAP1', 'Gene', (216, 220))	('SDHB', 'Gene', (176, 180))	('MET', 'Gene', (159, 162))	('CDKN2B', 'Gene', '1030', (249, 255))	('VHL', 'Gene', (117, 120))	('MITF', 'Gene', (231, 235))	('variants', 'Var', (66, 74))	('RCC', 'Disease', (97, 100))	('RCC', 'Phenotype', 'HP:0005584', (97, 100))	('VHL', 'Gene', '7428', (117, 120))	('BAP1', 'Gene', '8314', (216, 220))	('RCC', 'Phenotype', 'HP:0005584', (206, 209))	('RCC', 'Disease', (206, 209))	('SDHB', 'Gene', '6390', (176, 180))	('RCC', 'Disease', 'MESH:C538614', (97, 100))	('FLCN', 'Gene', '201163', (144, 148))	('CDKN2B', 'Gene', (249, 255))	('RCC', 'Disease', 'MESH:C538614', (206, 209))
1041	31034483	Furthermore, we found three VUS's in BAP1, of which one was novel and non-segregating in the family, and the E318K variant in MITF in one patient of a family with melanoma and RCC.	('E318K', 'Mutation', 'rs149617956', (109, 114))	('RCC', 'Disease', (176, 179))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('melanoma', 'Disease', (163, 171))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('E318K', 'Var', (109, 114))	("VUS's", 'Disease', 'MESH:D010300', (28, 33))	('MITF', 'Gene', '4286', (126, 130))	('MITF', 'Gene', (126, 130))	('BAP1', 'Gene', '8314', (37, 41))	('patient', 'Species', '9606', (138, 145))	('BAP1', 'Gene', (37, 41))	('VUS', 'Disease', (28, 31))
1042	31034483	Since the BAP1 variants are classified as VUS's, a standardized surveillance program for variant carriers is not relevant.	('BAP1', 'Gene', (10, 14))	("VUS's", 'Disease', 'MESH:D010300', (42, 47))	('variants', 'Var', (15, 23))	('VUS', 'Disease', (42, 45))	('BAP1', 'Gene', '8314', (10, 14))
1043	31034483	A surveillance program has not been established for E318K variant carriers, but increased awareness of potentially malignant cutaneous lesions and symptoms of renal disease should be advised.	('renal disease', 'Disease', 'MESH:D007674', (159, 172))	('malignant cutaneous lesions', 'Disease', (115, 142))	('E318K', 'Mutation', 'rs149617956', (52, 57))	('malignant cutaneous lesions', 'Disease', 'MESH:D009369', (115, 142))	('renal disease', 'Disease', (159, 172))	('E318K', 'Var', (52, 57))	('renal disease', 'Phenotype', 'HP:0000112', (159, 172))
1045	31034483	The results of the study indicate that germline variants in BAP1, MITF and CDKN2B are not frequent in Danish families with suspected hereditary predisposition to renal cancer, and in the families of this study a possible genetic background of RCC is still unresolved.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('variants', 'Var', (48, 56))	('CDKN2B', 'Gene', (75, 81))	('renal cancer', 'Disease', (162, 174))	('BAP1', 'Gene', '8314', (60, 64))	('RCC', 'Disease', (243, 246))	('RCC', 'Disease', 'MESH:C538614', (243, 246))	('CDKN2B', 'Gene', '1030', (75, 81))	('renal cancer', 'Disease', 'MESH:D007680', (162, 174))	('renal cancer', 'Phenotype', 'HP:0009726', (162, 174))	('RCC', 'Phenotype', 'HP:0005584', (243, 246))	('MITF', 'Gene', '4286', (66, 70))	('MITF', 'Gene', (66, 70))	('BAP1', 'Gene', (60, 64))
1049	23714463	For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2).	('SDHC', 'Gene', (133, 137))	('BAP1', 'Gene', (99, 103))	('SDHD', 'Gene', (139, 143))	('SDH', 'Gene', '6390', (121, 124))	('SDHAF2', 'Gene', '54949', (145, 151))	('SDHAF2', 'Gene', (145, 151))	('SDH', 'Gene', (145, 148))	('SDHB', 'Gene', (127, 131))	('SDH', 'Gene', (115, 118))	('SDH', 'Gene', '6390', (127, 130))	('mutations', 'Var', (79, 88))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', (121, 124))	('TP53', 'Gene', (105, 109))	('SDH', 'Gene', '6390', (133, 136))	('SDHx', 'Chemical', '-', (115, 119))	('SDH', 'Gene', (127, 130))	('SDHC', 'Gene', '6391', (133, 137))	('BAP1', 'Gene', '8314', (99, 103))	('SDH', 'Gene', (133, 136))	('SDH', 'Gene', '6390', (145, 148))	('SDHD', 'Gene', '6392', (139, 143))	('SDHB', 'Gene', '6390', (127, 131))	('SDH', 'Gene', '6390', (115, 118))	('SDH', 'Gene', '6390', (139, 142))	('TP53', 'Gene', '7157', (105, 109))
1050	23714463	BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers.	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('benign atypical melanocytic tumors', 'Disease', (184, 218))	('BAP1', 'Gene', (114, 118))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (237, 256))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (237, 256))	('uveal melanoma', 'Phenotype', 'HP:0007716', (220, 234))	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('BAP1', 'Gene', (0, 4))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('cause', 'Reg', (119, 124))	('malignant mesotheliomas', 'Phenotype', 'HP:0100001', (258, 281))	('uveal melanomas', 'Disease', (220, 235))	('uveal melanomas', 'Phenotype', 'HP:0007716', (220, 235))	('cancer syndrome', 'Disease', 'MESH:D009369', (133, 148))	('melanomas', 'Phenotype', 'HP:0002861', (226, 235))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (258, 280))	('mutations', 'Var', (101, 110))	('cutaneous melanomas', 'Disease', (237, 256))	('cancer syndrome', 'Disease', (133, 148))	('malignant mesotheliomas', 'Disease', (258, 281))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (184, 218))	('melanoma', 'Phenotype', 'HP:0002861', (226, 234))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancers', 'Disease', (305, 312))	('BAP1', 'Gene', '8314', (114, 118))	('malignant mesotheliomas', 'Disease', 'MESH:C562839', (258, 281))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanomas', 'Phenotype', 'HP:0002861', (247, 256))	('uveal melanomas', 'Disease', 'MESH:C536494', (220, 235))	('BAP1', 'Gene', '8314', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
1051	23714463	TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancers', 'Disease', 'MESH:D001943', (155, 169))	('breast cancers', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('brain tumors', 'Disease', (171, 183))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('cause', 'Reg', (15, 20))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('multiple tumors', 'Disease', 'MESH:D009369', (100, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (155, 169))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (189, 214))	('adrenocortical carcinomas', 'Disease', (189, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('mutations', 'Var', (5, 14))	('cancer syndrome', 'Disease', 'MESH:D009369', (68, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (145, 152))	('multiple tumors', 'Disease', (100, 115))	('brain tumors', 'Disease', 'MESH:D001932', (171, 183))	('sarcomas', 'Disease', 'MESH:D012509', (145, 153))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (189, 214))	('brain tumors', 'Phenotype', 'HP:0030692', (171, 183))	('sarcomas', 'Phenotype', 'HP:0100242', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('sarcomas', 'Disease', (145, 153))	('cancer syndrome', 'Disease', (68, 83))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
1053	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers.	('succinate', 'MPA', (132, 141))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('SDH', 'Gene', (99, 102))	('cancers', 'Disease', (280, 287))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (223, 254))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (223, 254))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('SDH', 'Gene', '6390', (0, 3))	('TCA', 'Chemical', 'MESH:D014233', (74, 77))	('paragangliomas', 'Disease', 'MESH:D010235', (158, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (158, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (158, 172))	('mutations', 'Var', (104, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('pheochromocytomas', 'Disease', 'MESH:D010673', (174, 191))	('pheochromocytomas', 'Disease', (174, 191))	('increased', 'PosReg', (122, 131))	('RCC', 'Disease', (216, 219))	('RCC', 'Phenotype', 'HP:0005584', (216, 219))	('gastrointestinal stromal tumors', 'Disease', (223, 254))	('gliomas', 'Phenotype', 'HP:0009733', (165, 172))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (193, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('SDHx', 'Chemical', '-', (99, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('increased succinate', 'Phenotype', 'HP:0020149', (122, 141))	('renal cell carcinomas', 'Disease', (193, 214))	('SDH', 'Gene', '6390', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (216, 219))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (174, 191))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('paragangliomas', 'Disease', (158, 172))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (193, 214))	('succinate', 'Chemical', 'MESH:D019802', (132, 141))	('GISTs', 'Phenotype', 'HP:0100723', (256, 261))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (174, 190))	('RCCs', 'Phenotype', 'HP:0005584', (216, 220))
1061	23714463	Nearly 15 years later, Harbor and colleagues reported a high frequency of BAP1 mutations in metastasizing uveal melanoma (UM), including one that was germline in origin.	('uveal melanoma', 'Disease', 'MESH:C536494', (106, 120))	('BAP1', 'Gene', '8314', (74, 78))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('UM', 'Phenotype', 'HP:0007716', (122, 124))	('uveal melanoma', 'Phenotype', 'HP:0007716', (106, 120))	('uveal melanoma', 'Disease', (106, 120))	('BAP1', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
1063	23714463	In one report, germline inactivating mutations of BAP1 were discovered in two families with high incidence of malignant mesothelioma (MM), UM, and other cancers.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (110, 132))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('germline inactivating mutations', 'Var', (15, 46))	('cancers', 'Disease', (153, 160))	('malignant mesothelioma', 'Disease', (110, 132))	('discovered', 'Reg', (60, 70))	('BAP1', 'Gene', '8314', (50, 54))	('UM', 'Phenotype', 'HP:0007716', (139, 141))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (110, 132))	('BAP1', 'Gene', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
1064	23714463	In the second report, two families were described in which germline mutations in BAP1 predisposed to multiple melanocytic tumors ranging from epithelioid nevi to atypical melanocytic tumors, with some mutation carriers developing UM or cutaneous melanoma (CM).	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('epithelioid nevi', 'Disease', (142, 158))	('multiple melanocytic tumors', 'Disease', (101, 128))	('BAP1', 'Gene', (81, 85))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('cutaneous melanoma', 'Disease', (236, 254))	('melanocytic tumors', 'Disease', 'MESH:D009508', (110, 128))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (236, 254))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 254))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('predisposed to', 'Reg', (86, 100))	('melanocytic tumors', 'Disease', 'MESH:D009508', (171, 189))	('developing', 'PosReg', (219, 229))	('melanocytic tumors', 'Disease', (171, 189))	('nevi to atypical melanocytic tumors', 'Phenotype', 'HP:0000995', (154, 189))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('nevi', 'Phenotype', 'HP:0003764', (154, 158))	('UM', 'Phenotype', 'HP:0007716', (230, 232))	('germline mutations', 'Var', (59, 77))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (101, 128))	('BAP1', 'Gene', '8314', (81, 85))	('CM', 'Phenotype', 'HP:0012056', (256, 258))
1065	23714463	Below, we focus on the involvement of BAP1 mutations in a new cancer predisposition disorder, now known as the BAP1 cancer syndrome.	('BAP1', 'Gene', '8314', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BAP1', 'Gene', (38, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('involvement', 'Reg', (23, 34))	('cancer syndrome', 'Disease', 'MESH:D009369', (116, 131))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('men', 'Species', '9606', (30, 33))	('cancer syndrome', 'Disease', (116, 131))	('BAP1', 'Gene', '8314', (38, 42))
1066	23714463	Notably, however, somatic BAP1 mutations have also been reported in various sporadic tumors including MM, RCC, and a rare, distinct subset of melanocytic tumors known as atypical Spitz tumors (ASTs).	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('BAP1', 'Gene', (26, 30))	('Spitz tumors', 'Disease', (179, 191))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('melanocytic tumors', 'Disease', (142, 160))	('melanocytic tumors', 'Disease', 'MESH:D009508', (142, 160))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', (85, 91))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('reported', 'Reg', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', (154, 160))	('Spitz tumors', 'Disease', 'MESH:D018332', (179, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('BAP1', 'Gene', '8314', (26, 30))
1069	23714463	Historically, the understanding of MM pathogenesis was understood in the context of somatic genetic losses within chromosome arms 3p, 9p, and 22q, the latter two specifically affecting CDKN2A and NF2, suggesting a multistep cascade involving the inactivation of multiple tumor suppressors.	('genetic', 'Var', (92, 99))	('losses', 'NegReg', (100, 106))	('CDKN2A', 'Gene', '1029', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('affecting', 'Reg', (175, 184))	('NF2', 'Gene', '4771', (196, 199))	('tumor', 'Disease', (271, 276))	('CDKN2A', 'Gene', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('NF2', 'Gene', (196, 199))
1071	23714463	Bott and colleagues reported inactivating mutations in BAP1, a tumor suppressor gene located at 3p21.1, in 22% of sporadic MMs.	('tumor', 'Disease', (63, 68))	('BAP1', 'Gene', (55, 59))	('inactivating mutations', 'Var', (29, 51))	('MMs', 'Disease', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('BAP1', 'Gene', '8314', (55, 59))
1073	23714463	Moreover, heterozygous germline mutations of BAP1 were identified in two high-risk cancer families in which the predominant malignancy was MM; notably, one family also had two cases of UM, a tumor type previously shown to be associated with somatic BAP1 mutations.	('UM', 'Phenotype', 'HP:0007716', (185, 187))	('BAP1', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('identified', 'Reg', (55, 65))	('BAP1', 'Gene', '8314', (45, 49))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('BAP1', 'Gene', '8314', (249, 253))	('malignancy', 'Disease', (124, 134))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BAP1', 'Gene', (249, 253))	('mutations', 'Var', (254, 263))	('cancer', 'Disease', (83, 89))
1079	23714463	Intriguingly, germline BAP1 mutations were also found in 2 of 26 sporadic MMs tested, and both patients with mutant BAP1 were previously diagnosed with UM.	('BAP1', 'Gene', (23, 27))	('BAP1', 'Gene', (116, 120))	('patients', 'Species', '9606', (95, 103))	('MMs', 'Disease', (74, 77))	('BAP1', 'Gene', '8314', (23, 27))	('UM', 'Phenotype', 'HP:0007716', (152, 154))	('mutant', 'Var', (109, 115))	('found', 'Reg', (48, 53))	('BAP1', 'Gene', '8314', (116, 120))	('mutations', 'Var', (28, 37))
1080	23714463	Concurrent work by Wiesner and colleagues revealed inactivating germline BAP1 mutations in two families with multiple benign melanocytic tumors; some affected individuals developed UM or CM, and one family member was subsequently diagnosed with MM.	('BAP1', 'Gene', '8314', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BAP1', 'Gene', (73, 77))	('inactivating germline', 'Var', (51, 72))	('mutations', 'Var', (78, 87))	('melanocytic tumors', 'Disease', (125, 143))	('melanocytic tumors', 'Disease', 'MESH:D009508', (125, 143))	('CM', 'Phenotype', 'HP:0012056', (187, 189))	('developed', 'PosReg', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('UM', 'Phenotype', 'HP:0007716', (181, 183))	('germline', 'Var', (64, 72))
1081	23714463	The existence of a BAP1-related melanocytic disorder was confirmed by a report of germline BAP1 inactivation in families with metastatic UM or with both UM and CM; and some carriers also had atypical melanocytic tumors.	('BAP1', 'Gene', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('inactivation', 'Var', (96, 108))	('UM', 'Phenotype', 'HP:0007716', (153, 155))	('BAP1', 'Gene', '8314', (19, 23))	('melanocytic tumors', 'Disease', 'MESH:D009508', (200, 218))	('melanocytic disorder', 'Disease', 'MESH:D009508', (32, 52))	('melanocytic disorder', 'Disease', (32, 52))	('UM', 'Phenotype', 'HP:0007716', (137, 139))	('melanocytic tumors', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('BAP1', 'Gene', (19, 23))	('BAP1', 'Gene', '8314', (91, 95))	('metastatic UM', 'Disease', (126, 139))	('CM', 'Disease', (160, 162))	('CM', 'Phenotype', 'HP:0012056', (160, 162))
1082	23714463	Another group reported a germline BAP1 mutation in a family with a wide variety of cancers, including three MMs, three UMs, and three CMs.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('UM', 'Phenotype', 'HP:0007716', (119, 121))	('UMs', 'Disease', (119, 122))	('mutation', 'Var', (39, 47))	('BAP1', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('reported', 'Reg', (14, 22))	('germline', 'Var', (25, 33))	('CMs', 'Disease', (134, 137))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('BAP1', 'Gene', '8314', (34, 38))	('CM', 'Phenotype', 'HP:0012056', (134, 136))	('MMs', 'Disease', (108, 111))	('cancers', 'Disease', (83, 90))
1083	23714463	More recently, a germline BAP1 mutation was identified in a family in which MM was found in four members, none with a history of asbestos exposure; one member also had multiple melanocytic tumors.	('BAP1', 'Gene', (26, 30))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (168, 195))	('multiple melanocytic tumors', 'Disease', (168, 195))	('mutation', 'Var', (31, 39))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('BAP1', 'Gene', '8314', (26, 30))	('asbestos', 'Chemical', 'MESH:D001194', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
1085	23714463	The full tumor spectrum associated with germline BAP1 mutations has yet to be established, as suggested by recent report of a germline BAP1 splice mutation and truncating frameshift in a family with UM, CM, suspected MM, as well as paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (232, 245))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('paraganglioma', 'Disease', (232, 245))	('BAP1', 'Gene', (49, 53))	('BAP1', 'Gene', '8314', (135, 139))	('truncating frameshift', 'Var', (160, 181))	('mutations', 'Var', (54, 63))	('CM', 'Phenotype', 'HP:0012056', (203, 205))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('paraganglioma', 'Disease', 'MESH:D010235', (232, 245))	('BAP1', 'Gene', (135, 139))	('UM', 'Phenotype', 'HP:0007716', (199, 201))	('BAP1', 'Gene', '8314', (49, 53))
1091	23714463	Inactivating somatic mutations of BAP1 were identified in 26/31 (84%) metastasizing tumors, including one that was germline in origin.	('BAP1', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('identified', 'Reg', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('BAP1', 'Gene', '8314', (34, 38))	('Inactivating somatic mutations', 'Var', (0, 30))
1095	23714463	Biallelic inactivation of BAP1 has been documented in multiple tumors from these high-risk families, strongly suggesting that BAP1 acts as a classical tumor suppressor gene.	('tumor', 'Disease', (63, 68))	('BAP1', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('BAP1', 'Gene', (126, 130))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('Biallelic inactivation', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('BAP1', 'Gene', '8314', (26, 30))	('men', 'Species', '9606', (44, 47))	('multiple tumors', 'Disease', 'MESH:D009369', (54, 69))	('multiple tumors', 'Disease', (54, 69))	('BAP1', 'Gene', '8314', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
1105	23714463	Mutations of BAP1 and potentially genes encoding other PR-DUB components may alter the function of the holo-complex leading to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('BAP1', 'Gene', (13, 17))	('alter', 'Reg', (77, 82))	('tumor', 'Disease', (127, 132))	('Mutations', 'Var', (0, 9))	('function', 'MPA', (87, 95))	('BAP1', 'Gene', '8314', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
1106	23714463	Germane to this, somatic ASXL1/2 alterations have been detected in human myelodysplastic disorders and solid tumors, and a conditional, systemic knockout model in which Bap1 was homozygously deleted in adult mice recapitulated features of human myelodysplastic syndrome.	('ASXL1/2', 'Gene', (25, 32))	('human', 'Species', '9606', (239, 244))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('myelodysplastic disorders', 'Disease', (73, 98))	('Bap1', 'Gene', '8314', (169, 173))	('Bap1', 'Gene', (169, 173))	('myelodysplastic syndrome', 'Disease', (245, 269))	('ASXL1/2', 'Gene', '171023;55252', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('alterations', 'Var', (33, 44))	('mice', 'Species', '10090', (208, 212))	('detected', 'Reg', (55, 63))	('myelodysplastic disorders', 'Phenotype', 'HP:0002863', (73, 98))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (245, 269))	('solid tumors', 'Disease', (103, 115))	('myelodysplastic disorders', 'Disease', 'MESH:D009190', (73, 98))	('human', 'Species', '9606', (67, 72))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (245, 269))
1107	23714463	While the first two reports of germline inactivating BAP1 mutations focused on different disease entities:that is, one on families with a high incidence of MM, and the other on families with multiple melanocytic tumors:both studies found recurrent UMs as well.	('mutations', 'Var', (58, 67))	('UM', 'Phenotype', 'HP:0007716', (248, 250))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('multiple melanocytic tumors', 'Disease', 'MESH:D009508', (191, 218))	('UMs', 'Disease', (248, 251))	('BAP1', 'Gene', '8314', (53, 57))	('multiple melanocytic tumors', 'Disease', (191, 218))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('focused', 'Reg', (68, 75))	('BAP1', 'Gene', (53, 57))
1108	23714463	As proposed by Goldstein, current evidence supports the notion that these initial reports of germline BAP1 mutations were describing a single syndrome consisting of a range of tumors with varying penetrance.	('BAP1', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('BAP1', 'Gene', '8314', (102, 106))
1115	23714463	Moreover, why do BAP1 mutations predispose to cancer when present in the germ line, yet act as a late, somatic event in connection with UM metastasis?	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('predispose', 'Reg', (32, 42))	('BAP1', 'Gene', '8314', (17, 21))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('UM', 'Phenotype', 'HP:0007716', (136, 138))	('BAP1', 'Gene', (17, 21))
1116	23714463	It is also unclear if variations in the number of melanocytic tumors and incidence of MM among BAP1 mutation carriers reflect differences in genetic background of affected individuals or differences in exposure to carcinogens.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carriers', 'Reg', (109, 117))	('mutation', 'Var', (100, 108))	('BAP1', 'Gene', '8314', (95, 99))	('melanocytic tumors', 'Disease', (50, 68))	('melanocytic tumors', 'Disease', 'MESH:D009508', (50, 68))
1118	23714463	BAP1 mutation carriers should be regularly monitored for evidence of early malignancy, and preventive measures such as avoidance of exposure to asbestos and sun should be implemented.	('asbestos', 'Chemical', 'MESH:D001194', (144, 152))	('BAP1', 'Gene', (0, 4))	('men', 'Species', '9606', (176, 179))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('BAP1', 'Gene', '8314', (0, 4))	('malignancy', 'Disease', (75, 85))	('mutation', 'Var', (5, 13))
1121	23714463	In 1990, germline TP53 mutations were discovered to be the underlying cause of the majority of LFS cases.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('cause', 'Reg', (70, 75))	('LFS', 'Disease', (95, 98))
1123	23714463	Approximately 1,800 different somatic and germline TP53 mutations have been reported, with most localized to the DNA binding domain (DBD) (http://p53.iarc.fr).	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('p53', 'Gene', (146, 149))	('p53', 'Gene', '7157', (146, 149))	('TP53', 'Gene', '7157', (51, 55))
1124	23714463	Mutant p53 loss-of-function, dominant-negative and gain-of-function properties are all important for tumorigenesis in humans, with gain-of-function activities being particularly relevant.	('humans', 'Species', '9606', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p53', 'Gene', '7157', (7, 10))	('gain-of-function', 'PosReg', (51, 67))	('loss-of-function', 'NegReg', (11, 27))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
1133	23714463	Specific TP53 mutant genotype may influence age of onset and tumor spectrum.	('mutant', 'Var', (14, 20))	('age', 'MPA', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TP53', 'Gene', '7157', (9, 13))	('influence', 'Reg', (34, 43))	('TP53', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
1134	23714463	Birch and colleagues reported a significantly higher incidence and earlier age at cancer diagnosis for breast (p = 0.006) and brain cancers (p = 0.05) in families who carry missense mutations in the DBD.	('brain cancers', 'Disease', 'MESH:D001932', (126, 139))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('brain cancers', 'Disease', (126, 139))	('higher', 'PosReg', (46, 52))	('breast', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('missense mutations', 'Var', (173, 191))
1136	23714463	Furthermore, nonsense, frameshift, and splice mutations are associated with particularly early tumor onset.	('tumor', 'Disease', (95, 100))	('nonsense', 'Var', (13, 21))	('frameshift', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('splice mutations', 'Var', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('associated', 'Reg', (60, 70))
1137	23714463	However, these genotype:phenotype correlations are not consistent, as numerous families carrying the same mutation express widely divergent clinical manifestations of age of onset and cancer type.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('mutation', 'Var', (106, 114))
1139	23714463	The sensitivity and specificity of the Chompret criteria are 82% and 58%, respectively, making it perhaps the most rigorous and relevant definition to justify TP53 mutation analysis.	('TP53', 'Gene', (159, 163))	('mutation', 'Var', (164, 172))	('TP53', 'Gene', '7157', (159, 163))
1145	23714463	Almost 50% of children with CPC harbor germline TP53 mutations even in the absence of a typical LFS family history.	('children', 'Species', '9606', (14, 22))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('CPC', 'Disease', (28, 31))	('germline', 'Var', (39, 47))
1147	23714463	Approximately 20% to 30% of tumors in TP53 mutation carriers do not belong to the classical LFS tumor spectrum: Wilms tumor and phyllodes tumors of the breast are strongly associated, pancreatic cancer moderately associated, and neuroblastoma weakly associated with TP53 mutation carrier status.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TP53', 'Gene', (38, 42))	('LFS tumor', 'Disease', 'MESH:D016864', (92, 101))	('associated', 'Interaction', (172, 182))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('TP53', 'Gene', (266, 270))	('LFS tumor', 'Disease', (92, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('mutation', 'Var', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('neuroblastoma', 'Disease', (229, 242))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('Wilms tumor', 'Disease', 'MESH:D009396', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('TP53', 'Gene', '7157', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (28, 34))	('TP53', 'Gene', '7157', (266, 270))	('Wilms tumor', 'Phenotype', 'HP:0002667', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('pancreatic cancer', 'Disease', (184, 201))	('tumors', 'Disease', (138, 144))	('Wilms tumor', 'Disease', (112, 123))
1148	23714463	Carcinomas of the lung and gastrointestinal tract, lymphomas, and other neoplasms have been shown to occur in TP53 mutation carriers or first-degree relatives of carriers at much earlier ages than seen in the general population.	('carriers', 'Reg', (124, 132))	('lymphomas', 'Disease', (51, 60))	('lymphomas', 'Disease', 'MESH:D008223', (51, 60))	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('Carcinomas of the lung and gastrointestinal tract', 'Disease', 'MESH:D004067', (0, 49))	('neoplasms', 'Disease', 'MESH:D009369', (72, 81))	('neoplasms', 'Disease', (72, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (51, 60))	('mutation', 'Var', (115, 123))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (72, 81))
1149	23714463	Approximately 1% of heritable breast cancers arise due to a germline TP53 mutation.	('mutation', 'Var', (74, 82))	('breast cancers', 'Disease', 'MESH:D001943', (30, 44))	('breast cancers', 'Disease', (30, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('arise due to', 'Reg', (45, 57))	('breast cancers', 'Phenotype', 'HP:0003002', (30, 44))	('germline', 'Var', (60, 68))
1150	23714463	However, 7% of women who develop breast cancer under 30 years of age and have no first- or second-degree relatives with cancer carry a TP53 mutation; presence of first- or second-degree relatives with cancer raises this likelihood to well over 75%.	('breast cancer', 'Phenotype', 'HP:0003002', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('women', 'Species', '9606', (15, 20))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('TP53', 'Gene', '7157', (135, 139))	('cancer', 'Disease', (120, 126))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('TP53', 'Gene', (135, 139))	('breast cancer', 'Disease', 'MESH:D001943', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('breast cancer', 'Disease', (33, 46))
1153	23714463	In TP53 mutation carriers, the cumulative probability of a second cancer is 57% (+-10%) at 30 years.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutation', 'Var', (8, 16))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
1155	23714463	A unique R337H mutation exclusively found in LFS families from southeastern Brazil is a risk allele for pediatric ACC and, until recently, was thought to represent a unique example of a tissue-specific predisposing mutation.	('R337H', 'Var', (9, 14))	('R337H', 'Mutation', 'rs121912664', (9, 14))	('pediatric ACC', 'Disease', (104, 117))
1156	23714463	Nonbiased ascertainment of families with the R337H mutation shows that the cancer risk encompasses the full spectrum of tumors associated with LFS, in particular early-onset breast cancer (mean age at diagnosis below 40 years) and CPC.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('breast cancer', 'Disease', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CPC', 'Disease', (231, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Disease', (75, 81))	('R337H', 'Mutation', 'rs121912664', (45, 50))	('R337H', 'Var', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('men', 'Species', '9606', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (181, 187))
1157	23714463	Additionally, current data on overall cancer penetrance suggest that the age-related cancer risk is somewhat lower than in LFS associated with other TP53 mutations, with tumors detected in approximately 25% of carriers at the age of 30 and a lifetime risk of approximately 80%.	('cancer', 'Disease', (38, 44))	('lower', 'NegReg', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TP53', 'Gene', '7157', (149, 153))	('cancer', 'Disease', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TP53', 'Gene', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (154, 163))	('tumors', 'Disease', (170, 176))
1159	23714463	The PIN3 (16 bp duplication in intron 3) polymorphism has been associated with an increase in age of onset of tumors in TP53 mutation carriers.	('polymorphism', 'Var', (41, 53))	('PIN3', 'Gene', (4, 8))	('mutation', 'Var', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('increase', 'PosReg', (82, 90))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))
1160	23714463	A single nucleotide polymorphism (SNP) at codon 72 in exon 4 involves the substitution of an arginine for a proline base.	('arginine', 'MPA', (93, 101))	('proline', 'Chemical', 'MESH:D011392', (108, 115))	('arginine', 'Chemical', 'MESH:D001120', (93, 101))	('substitution', 'Var', (74, 86))
1161	23714463	The current consensus from a large number of studies is that R72 is more effective in inducing apoptosis than P72.	('P72', 'Gene', '10521', (110, 113))	('R72', 'Var', (61, 64))	('apoptosis', 'CPA', (95, 104))	('inducing', 'Reg', (86, 94))	('P72', 'Gene', (110, 113))
1162	23714463	On the other hand, the SNP309, rs2279744 T/G polymorphic substitution in the MDM2 gene appears to confer an earlier age of onset in LFS patients.	('rs2279744', 'Mutation', 'rs2279744', (31, 40))	('MDM2', 'Gene', '4193', (77, 81))	('MDM2', 'Gene', (77, 81))	('patients', 'Species', '9606', (136, 144))	('SNP309', 'Var', (23, 29))	('LFS', 'Disease', (132, 135))
1164	23714463	Interestingly, telomeres in peripheral blood leukocytes of TP53 mutation carriers are shorter than in normal individuals of corresponding age.	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('shorter', 'NegReg', (86, 93))	('telomeres', 'CPA', (15, 24))	('TP53', 'Gene', '7157', (59, 63))
1166	23714463	The accelerated telomere attrition in TP53 mutation carriers is postulated to lead to greater genomic instability and earlier age of cancer onset in successive generations.	('mutation', 'Var', (43, 51))	('telomere', 'MPA', (16, 24))	('greater', 'PosReg', (86, 93))	('genomic instability', 'CPA', (94, 113))	('TP53', 'Gene', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('accelerated', 'PosReg', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', '7157', (38, 42))
1167	23714463	Global copy number variation frequency and total structural variation are significantly increased in individuals with germline TP53 mutations (p = 0.01).	('mutations', 'Var', (132, 141))	('increased', 'PosReg', (88, 97))	('structural variation', 'MPA', (49, 69))	('germline', 'Var', (118, 126))	('TP53', 'Gene', '7157', (127, 131))	('Global copy number variation frequency', 'MPA', (0, 38))	('TP53', 'Gene', (127, 131))
1169	23714463	These findings, together with the accelerated telomere attrition data, support the notion that TP53 mutation carriers have inherently unstable genomes and harbor other genetic and genomic alterations that can directly modify the age phenotype.	('mutation', 'Var', (100, 108))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('modify', 'Reg', (218, 224))
1170	23714463	Recent evidence suggests that the "early" germline presence of TP53 mutations in a cell may induce early critical telomere length shortening, which in turn may be involved in chromothripsis:an event of catastrophic chromosome rearrangement that is frequently seen in LFS-associated tumors.	('involved', 'Reg', (163, 171))	('telomere length shortening', 'Phenotype', 'HP:0031413', (114, 140))	('TP53', 'Gene', '7157', (63, 67))	('LFS-associated', 'Disease', (267, 281))	('TP53', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('men', 'Species', '9606', (235, 238))	('mutations', 'Var', (68, 77))	('induce', 'Reg', (92, 98))	('chromothripsis', 'Disease', (175, 189))
1171	23714463	What the other genetic events are that modify the "driver" genotype conferred by the germline TP53 mutation are being actively explored and may ultimately lead to the development of more precise predictive algorithms of cancer phenotype and disease risk.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('algorithms of cancer', 'Disease', 'MESH:D009369', (206, 226))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('lead', 'Reg', (155, 159))	('mutation', 'Var', (99, 107))	('algorithms of cancer', 'Disease', (206, 226))	('men', 'Species', '9606', (174, 177))
1173	23714463	For female TP53 mutation carriers, the role of prophylactic mastectomy has not been carefully evaluated.	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))
1174	23714463	Ultimately, determining the exact nature of the TP53 mutation may be of prognostic significance and therefore important for the clinical management of these patients.	('TP53', 'Gene', '7157', (48, 52))	('mutation', 'Var', (53, 61))	('TP53', 'Gene', (48, 52))	('patients', 'Species', '9606', (157, 165))	('men', 'Species', '9606', (143, 146))
1176	23714463	Although FDG-PET/CT can identify new primary cancers in TP53 mutation carriers, repeated radiation exposure may accelerate the risk of secondary malignancies.	('malignancies', 'Disease', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('TP53', 'Gene', '7157', (56, 60))	('mutation', 'Var', (61, 69))	('TP53', 'Gene', (56, 60))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('accelerate', 'PosReg', (112, 122))
1179	23714463	Studies to improve the predictive value of genetic and genomic modifier effects on the mutant TP53-associated phenotype will inform development of more refined tumor screening protocols and lead to improved understanding of the biologic mechanisms of tumor formation in these patients.	('patients', 'Species', '9606', (276, 284))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('mutant', 'Var', (87, 93))	('men', 'Species', '9606', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
1187	23714463	However, in the presence of an underlying germline SDHx mutation, the tumor rate may be extraordinarily high with a penetrance approaching 80%.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('germline', 'Var', (42, 50))	('SDHx', 'Gene', (51, 55))	('SDHx', 'Chemical', '-', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
1191	23714463	Over the past several years, we have learned that germline mutations in each of these SDHx genes may lead to development of paragangliomas or pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('paragangliomas or pheochromocytomas', 'Disease', (124, 159))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (142, 159))	('germline mutations', 'Var', (50, 68))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('paragangliomas or pheochromocytomas', 'Disease', 'MESH:D010673', (124, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('SDHx', 'Gene', (86, 90))	('men', 'Species', '9606', (116, 119))	('SDHx', 'Chemical', '-', (86, 90))	('lead to', 'Reg', (101, 108))
1194	23714463	Germline mutations in other genes such as NF1, VHL, RET, TMEM127, and MAX also have been associated with the development of paragangliomas and pheochromocytomas.	('Germline mutations', 'Var', (0, 18))	('associated with', 'Reg', (89, 104))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (124, 160))	('VHL', 'Disease', 'MESH:D006623', (47, 50))	('VHL', 'Disease', (47, 50))	('gliomas', 'Phenotype', 'HP:0009733', (131, 138))	('RET', 'Gene', '5979', (52, 55))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('MAX', 'Gene', (70, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (143, 160))	('TMEM127', 'Gene', (57, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('TMEM127', 'Gene', '55654', (57, 64))	('RET', 'Gene', (52, 55))	('NF1', 'Gene', '4763', (42, 45))	('men', 'Species', '9606', (116, 119))	('NF1', 'Gene', (42, 45))
1195	23714463	Based on gene expression and pathway analysis, these tumors can be divided into two clusters corresponding to their underlying gene mutations: Cluster 1 (Cluster 1A: SDHx, Cluster 1B: VHL), associated with pseudohypoxia and aberrant VEGF signaling, and Cluster 2 (RET/NF1/TMEM127/MAX), associated with aberrant kinase signaling pathways.	('TMEM127', 'Gene', (272, 279))	('RET', 'Gene', '5979', (264, 267))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (190, 200))	('pseudohypoxia', 'Disease', (206, 219))	('pseudohypoxia', 'Disease', 'None', (206, 219))	('NF1', 'Gene', '4763', (268, 271))	('TMEM127', 'Gene', '55654', (272, 279))	('VEGF', 'Gene', '7422', (233, 237))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('RET', 'Gene', (264, 267))	('VEGF', 'Gene', (233, 237))	('VHL', 'Disease', (184, 187))	('tumors', 'Disease', (53, 59))	('NF1', 'Gene', (268, 271))	('kinase signaling pathways', 'Pathway', (311, 336))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (132, 141))	('SDHx', 'Chemical', '-', (166, 170))	('VHL', 'Disease', 'MESH:D006623', (184, 187))
1196	23714463	In the absence of SDHx mutations, paragangliomas (and sometimes pheochromocytomas) are benign and very slow growing tumors.	('SDHx', 'Chemical', '-', (18, 22))	('paragangliomas', 'Disease', (34, 48))	('very slow growing tumors', 'Disease', 'MESH:D000326', (98, 122))	('paragangliomas', 'Disease', 'MESH:D010235', (34, 48))	('paragangliomas', 'Phenotype', 'HP:0002668', (34, 48))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (64, 81))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (64, 80))	('SDHx', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('pheochromocytomas', 'Disease', (64, 81))	('very slow growing tumors', 'Disease', (98, 122))	('pheochromocytomas', 'Disease', 'MESH:D010673', (64, 81))
1198	23714463	However, when such tumors occur because of germline mutations in SDHx genes, paragangliomas and pheochromocytomas can transform to become highly aggressive and metastatic.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('germline mutations', 'Var', (43, 61))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (77, 113))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('metastatic', 'CPA', (160, 170))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('SDHx', 'Chemical', '-', (65, 69))	('SDHx', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('paragangliomas', 'Phenotype', 'HP:0002668', (77, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (96, 113))
1200	23714463	A recent study from the National Institutes of Health demonstrated that nearly 30% of nonmetastatic paragangliomas and pheochromocytomas are due to germline SDHx mutations, and that 44% of adults and 81% of children with metastatic disease are due to germline SDHx mutations.	('mutations', 'Var', (162, 171))	('gliomas', 'Phenotype', 'HP:0009733', (107, 114))	('children', 'Species', '9606', (207, 215))	('SDHx', 'Chemical', '-', (260, 264))	('SDHx', 'Chemical', '-', (157, 161))	('SDHx', 'Gene', (157, 161))	('paragangliomas', 'Phenotype', 'HP:0002668', (100, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (119, 136))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (100, 136))	('due', 'Reg', (141, 144))
1201	23714463	In fact, this study did not test for all of the known SDHx genes, so the actual prevalence of germline SDHx mutations in this disease may be higher.	('SDHx', 'Chemical', '-', (54, 58))	('SDHx', 'Chemical', '-', (103, 107))	('SDHx', 'Gene', (103, 107))	('mutations', 'Var', (108, 117))
1203	23714463	Each SDHx gene mutation leads to a slightly different disease phenotype and clinical presentation (see Table 2).	('mutation', 'Var', (15, 23))	('SDHx', 'Chemical', '-', (5, 9))	('SDHx', 'Gene', (5, 9))
1204	23714463	Interestingly, PGL-1 disease related to germline SDHD mutations is inherited in a maternally imprinted fashion with only the children of fathers: but not mothers: developing disease.	('children', 'Species', '9606', (125, 133))	('mutations', 'Var', (54, 63))	('PGL-1 disease', 'Disease', (15, 28))	('SDHD', 'Gene', '6392', (49, 53))	('PGL-1 disease', 'Disease', 'MESH:D010235', (15, 28))	('SDHD', 'Gene', (49, 53))
1206	23714463	This is also true for germline SDHAF2 mutations (PGL-2), which are also inherited as a maternally imprinted disease.	('SDHAF2', 'Gene', '54949', (31, 37))	('SDHAF2', 'Gene', (31, 37))	('PGL-2', 'Gene', '54949', (49, 54))	('mutations', 'Var', (38, 47))	('PGL-2', 'Gene', (49, 54))
1207	23714463	Disease caused by germline SDHB mutations (PGL-4) seems to be the most common and malignant of the clinical phenotypes in "Familial Paraganglioma and Pheochromocytoma Syndrome."	('PGL-4', 'Gene', '6390', (43, 48))	('Paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('caused', 'Reg', (8, 14))	('Familial Paraganglioma', 'Disease', 'MESH:D010235', (123, 145))	('Familial Paraganglioma', 'Disease', (123, 145))	('Pheochromocytoma Syndrome', 'Disease', (150, 175))	('mutations', 'Var', (32, 41))	('PGL-4', 'Gene', (43, 48))	('SDHB', 'Gene', '6390', (27, 31))	('Pheochromocytoma Syndrome', 'Disease', 'MESH:D010673', (150, 175))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('SDHB', 'Gene', (27, 31))
1208	23714463	Every germline SDHx mutation (except SDHAF2) has been associated with GISTs.	('SDHx', 'Chemical', '-', (15, 19))	('SDHx', 'Gene', (15, 19))	('GISTs', 'Phenotype', 'HP:0100723', (70, 75))	('mutation', 'Var', (20, 28))	('GISTs', 'Disease', (70, 75))	('SDHAF2', 'Gene', '54949', (37, 43))	('SDHAF2', 'Gene', (37, 43))	('associated', 'Reg', (54, 64))
1210	23714463	Previously, clinical testing for the specific inherited SDHx mutations was based on disease presentation.	('SDHx', 'Gene', (56, 60))	('mutations', 'Var', (61, 70))	('SDHx', 'Chemical', '-', (56, 60))
1211	23714463	For instance, a patient with metastatic paraganglioma that secretes catecholamine would first be tested for SDHB mutations, whereas a young patient with just familial head and neck paragangliomas might first be screened for SDHD or SDHC mutations.	('tested', 'Reg', (97, 103))	('mutations', 'Var', (113, 122))	('SDHD', 'Gene', (224, 228))	('SDHB', 'Gene', '6390', (108, 112))	('patient', 'Species', '9606', (16, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paragangliomas', 'Disease', 'MESH:D010235', (181, 195))	('SDHC', 'Gene', '6391', (232, 236))	('paragangliomas', 'Phenotype', 'HP:0002668', (181, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (181, 194))	('secretes catecholamine', 'MPA', (59, 81))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('SDHB', 'Gene', (108, 112))	('catecholamine', 'Chemical', 'MESH:D002395', (68, 81))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (176, 195))	('just familial head', 'Phenotype', 'HP:0001357', (153, 171))	('SDHC', 'Gene', (232, 236))	('paragangliomas', 'Disease', (181, 195))	('paraganglioma', 'Disease', (40, 53))	('paraganglioma', 'Disease', (181, 194))	('patient', 'Species', '9606', (140, 147))	('paraganglioma', 'Disease', 'MESH:D010235', (40, 53))	('SDHD', 'Gene', '6392', (224, 228))	('paraganglioma', 'Disease', 'MESH:D010235', (181, 194))
1212	23714463	In order to identify patients at risk for underlying germline SDHx mutations, it was observed several years ago that tumor tissues could be stained by immunohistochemistry (IHC) for the SDHB protein.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SDHB', 'Gene', (186, 190))	('tumor', 'Disease', (117, 122))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (21, 29))	('SDHx', 'Gene', (62, 66))	('SDHx', 'Chemical', '-', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('SDHB', 'Gene', '6390', (186, 190))
1219	23714463	Like LFS, we have learned that scheduled surveillance can detect early tumors in patients with underlying germline SDHx mutations.	('SDHx', 'Chemical', '-', (115, 119))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', (71, 77))	('SDHx', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
1225	23714463	Fractionated metanephrines are nearly always abnormal in individuals with a hereditary syndrome characterized by secreting tumors (elevated metanephrines for RET and NF1 mutations and elevated normetanephrines for SDHx and VHL mutations).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('SDHx', 'Chemical', '-', (214, 218))	('hereditary syndrome', 'Disease', (76, 95))	('NF1', 'Gene', '4763', (166, 169))	('normetanephrines', 'Chemical', 'MESH:D009647', (193, 209))	('VHL', 'Disease', 'MESH:D006623', (223, 226))	('hereditary syndrome', 'Disease', 'MESH:D009386', (76, 95))	('RET', 'Gene', '5979', (158, 161))	('NF1', 'Gene', (166, 169))	('elevated', 'PosReg', (131, 139))	('metanephrines', 'MPA', (140, 153))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('RET', 'Gene', (158, 161))	('elevated', 'PosReg', (184, 192))	('VHL', 'Disease', (223, 226))	('normetanephrines', 'MPA', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('metanephrines', 'Chemical', 'MESH:D008676', (140, 153))	('tumors', 'Disease', (123, 129))	('metanephrines', 'Chemical', 'MESH:D008676', (13, 26))	('SDHx', 'Gene', (214, 218))	('mutations', 'Var', (170, 179))	('metanephrines', 'Chemical', 'MESH:D008676', (196, 209))
1230	23714463	At the University of Utah, a recent prospective observational study of whole body, rapid sequence MRI in SDHx mutation carriers demonstrated MRI sensitivity of 88% and specificity of 95% to detect new tumors compared to biochemical testing sensitivity of 38% and specificity of 95% (K. Jasperson, personal communication, submitted).	('SDHx', 'Chemical', '-', (105, 109))	('SDHx', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutation', 'Var', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))
1231	23714463	The University of Utah now recommends whole body MRI (5-mm slices from skull base to pelvis) at least every two years for patients with underlying SDHx mutations, followed by PET scans for patients with abnormal MRI results.	('mutations', 'Var', (152, 161))	('SDHx', 'Gene', (147, 151))	('men', 'Species', '9606', (32, 35))	('SDHx', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (189, 197))
1232	23714463	As testing for SDHx mutations has become more widespread, we have learned more about the spectrum of other SDH-related tumors, including GISTs, renal tumors (RCC, oncocytoma), papillary thyroid cancer, pituitary tumors, and even neuroblastoma.	('SDHx', 'Chemical', '-', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('renal tumors', 'Phenotype', 'HP:0009726', (144, 156))	('GISTs', 'Phenotype', 'HP:0100723', (137, 142))	('oncocytoma', 'Disease', 'MESH:D018249', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('papillary thyroid cancer', 'Disease', (176, 200))	('SDH', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('GISTs', 'Disease', (137, 142))	('neuroblastoma', 'Disease', (229, 242))	('SDH', 'Gene', '6390', (15, 18))	('neuroblastoma', 'Phenotype', 'HP:0003006', (229, 242))	('pituitary tumors', 'Disease', 'MESH:D010911', (202, 218))	('neuroblastoma', 'Disease', 'MESH:D009447', (229, 242))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('oncocytoma', 'Disease', (163, 173))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (176, 200))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('tumors', 'Disease', (212, 218))	('RCC', 'Disease', (158, 161))	('RCC', 'Phenotype', 'HP:0005584', (158, 161))	('renal tumors', 'Disease', (144, 156))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (176, 200))	('mutations', 'Var', (20, 29))	('SDH', 'Gene', (15, 18))	('SDH', 'Gene', '6390', (107, 110))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('pituitary tumors', 'Disease', (202, 218))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('RCC', 'Disease', 'MESH:C538614', (158, 161))	('renal tumors', 'Disease', 'MESH:D007674', (144, 156))
1233	23714463	In fact, wild-type GISTs lacking somatic KIT or PDFRA mutations have been shown to be 100% SDH-deficient as measured by SDHB IHC.	('SDH-deficient', 'Disease', 'MESH:D007153', (91, 104))	('mutations', 'Var', (54, 63))	('SDHB', 'Gene', '6390', (120, 124))	('PDFRA', 'Gene', (48, 53))	('GISTs', 'Phenotype', 'HP:0100723', (19, 24))	('SDHB', 'Gene', (120, 124))	('SDH-deficient', 'Disease', (91, 104))
1236	23714463	Many recent reports have demonstrated germline SDHA mutations associated with SDH-deficient (wild-type KIT/PDFRA) GISTs, which can be detected by SDHA IHC.	('mutations', 'Var', (52, 61))	('SDH-deficient', 'Disease', 'MESH:D007153', (78, 91))	('SDH', 'Gene', (78, 81))	('associated', 'Reg', (62, 72))	('SDH', 'Gene', (47, 50))	('SDH', 'Gene', '6390', (146, 149))	('GISTs', 'Phenotype', 'HP:0100723', (114, 119))	('SDH', 'Gene', '6390', (47, 50))	('SDH', 'Gene', '6390', (78, 81))	('SDH-deficient', 'Disease', (78, 91))	('SDH', 'Gene', (146, 149))
1237	23714463	Germline SDHx mutations still account for less than half of SDH-deficient GISTs, and the search for underlying SDH-related genes continues for the majority of patients with SDH-deficient GISTs.	('SDH', 'Gene', (60, 63))	('mutations', 'Var', (14, 23))	('GISTs', 'Phenotype', 'HP:0100723', (187, 192))	('SDH-deficient', 'Disease', 'MESH:D007153', (173, 186))	('SDH', 'Gene', '6390', (111, 114))	('SDH', 'Gene', '6390', (173, 176))	('SDH', 'Gene', '6390', (9, 12))	('SDH-deficient', 'Disease', (173, 186))	('SDH-deficient', 'Disease', 'MESH:D007153', (60, 73))	('SDH', 'Gene', '6390', (60, 63))	('SDH-deficient', 'Disease', (60, 73))	('SDH', 'Gene', (173, 176))	('GISTs', 'Phenotype', 'HP:0100723', (74, 79))	('patients', 'Species', '9606', (159, 167))	('SDH', 'Gene', (111, 114))	('SDH', 'Gene', (9, 12))	('SDHx', 'Chemical', '-', (9, 13))
1238	23714463	It is now recommended that patients with SDH-deficient GISTs be referred for genetic evaluation for underlying SDHx mutations.	('SDH-deficient', 'Disease', (41, 54))	('SDH-deficient', 'Disease', 'MESH:D007153', (41, 54))	('men', 'Species', '9606', (15, 18))	('GISTs', 'Phenotype', 'HP:0100723', (55, 60))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (116, 125))	('SDHx', 'Gene', (111, 115))	('SDHx', 'Chemical', '-', (111, 115))
1239	23714463	If germline SDHx mutations are identified in patients with GISTs, they should be considered for biochemical and imaging surveillance due to risk for other tumors.	('SDHx', 'Gene', (12, 16))	('GISTs', 'Phenotype', 'HP:0100723', (59, 64))	('SDHx', 'Chemical', '-', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (17, 26))
1240	23714463	As familial tumors due to inherited SDHx mutations become better recognized, we will begin to learn more about the genetic, epigenetic, and metabolic alterations related to cancer risk.	('mutations', 'Var', (41, 50))	('SDHx', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('SDHx', 'Chemical', '-', (36, 40))	('cancer', 'Disease', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('familial tumors', 'Disease', 'MESH:D009386', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('familial tumors', 'Disease', (3, 18))
1248	23714463	BAP1 encodes a catalyzing enzyme that removes ubiquitin from protein substrates, and germline BAP1 mutations cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanoma, cutaneous melanoma, malignant mesothelioma, and potentially other cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (246, 268))	('benign atypical melanocytic tumors', 'Disease', 'MESH:D009508', (174, 208))	('uveal melanoma', 'Disease', 'MESH:C536494', (210, 224))	('BAP1', 'Gene', (0, 4))	('uveal melanoma', 'Disease', (210, 224))	('BAP1', 'Gene', '8314', (94, 98))	('malignant mesothelioma', 'Disease', (246, 268))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('cutaneous melanoma', 'Disease', (226, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (226, 244))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (226, 244))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (246, 268))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('benign atypical melanocytic tumors', 'Disease', (174, 208))	('uveal melanoma', 'Phenotype', 'HP:0007716', (210, 224))	('cause', 'Reg', (109, 114))	('melanoma', 'Phenotype', 'HP:0002861', (236, 244))	('cancer syndrome', 'Disease', 'MESH:D009369', (123, 138))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('mutations', 'Var', (99, 108))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('cancer syndrome', 'Disease', (123, 138))	('BAP1', 'Gene', '8314', (0, 4))
1249	23714463	BAP1 mutation carriers should have regular medical examinations in order to diagnose associated malignancies at an early, more treatable stage.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('BAP1', 'Gene', (0, 4))	('malignancies', 'Disease', (96, 108))	('BAP1', 'Gene', '8314', (0, 4))	('mutation', 'Var', (5, 13))
1250	23714463	TP53 mutations cause Li-Fraumeni syndrome with extremely high risk for sarcomas, breast cancer, brain tumors, adrenocortical carcinomas, and other tumors.	('breast cancer', 'Disease', (81, 94))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('brain tumors', 'Disease', 'MESH:D001932', (96, 108))	('brain tumors', 'Phenotype', 'HP:0030692', (96, 108))	('sarcomas', 'Disease', 'MESH:D012509', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('sarcomas', 'Phenotype', 'HP:0100242', (71, 79))	('cause', 'Reg', (15, 20))	('sarcomas', 'Disease', (71, 79))	('Li-Fraumeni syndrome', 'Disease', (21, 41))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('brain tumors', 'Disease', (96, 108))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (21, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('adrenocortical carcinomas', 'Phenotype', 'HP:0006744', (110, 135))	('mutations', 'Var', (5, 14))	('adrenocortical carcinomas', 'Disease', (110, 135))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('adrenocortical carcinomas', 'Disease', 'MESH:D018268', (110, 135))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
1252	23714463	SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid cycle, and SDHx mutations (SDHA, SDHB, SDHC, SDHD, and SDHAF2) lead to increased succinate and high risk for paragangliomas, pheochromocytomas, renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs), and other tumors.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (217, 237))	('SDH', 'Gene', '6390', (128, 131))	('GISTs', 'Phenotype', 'HP:0100723', (278, 283))	('succinate', 'MPA', (154, 163))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (198, 214))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('pheochromocytomas', 'Disease', 'MESH:D010673', (198, 215))	('SDH', 'Gene', '6390', (112, 115))	('pheochromocytomas', 'Disease', (198, 215))	('SDH', 'Gene', '6390', (0, 3))	('tumors', 'Disease', (270, 276))	('paragangliomas', 'Disease', 'MESH:D010235', (182, 196))	('SDHx', 'Chemical', '-', (84, 88))	('SDH', 'Gene', (106, 109))	('SDHC', 'Gene', '6391', (112, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (182, 195))	('SDHAF2', 'Gene', (128, 134))	('SDH', 'Gene', '6390', (118, 121))	('paragangliomas', 'Phenotype', 'HP:0002668', (182, 196))	('SDHAF2', 'Gene', '54949', (128, 134))	('SDH', 'Gene', (128, 131))	('renal cell carcinoma', 'Disease', (217, 237))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (217, 237))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (245, 276))	('SDH', 'Gene', (112, 115))	('SDH', 'Gene', '6390', (100, 103))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (245, 276))	('SDHD', 'Gene', '6392', (118, 122))	('SDH', 'Gene', (0, 3))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (54, 72))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('SDHB', 'Gene', '6390', (106, 110))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (198, 215))	('RCC', 'Disease', (239, 242))	('RCC', 'Phenotype', 'HP:0005584', (239, 242))	('increased succinate', 'Phenotype', 'HP:0020149', (144, 163))	('SDH', 'Gene', '6390', (84, 87))	('SDH', 'Gene', (118, 121))	('SDHC', 'Gene', (112, 116))	('increased', 'PosReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('paragangliomas', 'Disease', (182, 196))	('SDHD', 'Gene', (118, 122))	('SDH', 'Gene', (100, 103))	('gastrointestinal stromal tumors', 'Disease', (245, 276))	('tumors', 'Disease', (296, 302))	('RCC', 'Disease', 'MESH:C538614', (239, 242))	('succinate', 'Chemical', 'MESH:D019802', (154, 163))	('SDHB', 'Gene', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('SDH', 'Gene', (84, 87))	('SDH', 'Gene', '6390', (106, 109))
1253	23714463	Regular biochemical screening and imaging in patients with germline SDHx mutations can detect early cancer to improve patient outcome.	('SDHx', 'Chemical', '-', (68, 72))	('SDHx', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('improve', 'PosReg', (110, 117))	('patient', 'Species', '9606', (45, 52))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (118, 125))	('mutations', 'Var', (73, 82))
1260	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
1289	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
1306	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
1323	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('cytolytic levels', 'MPA', (156, 172))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
1348	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
1349	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('PRF1', 'Gene', (188, 192))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('cutaneous melanoma', 'Disease', (28, 46))
1353	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
1354	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('GSE13876', 'Var', (192, 200))	('TCGA-UCEC', 'Disease', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
1355	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
1356	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
1359	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
1361	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
1367	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('PRF1', 'Var', (120, 124))	('GSE10846', 'Var', (10, 18))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
1368	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
1406	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
1411	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('patients', 'Species', '9606', (95, 103))	('blockage', 'Var', (56, 64))	('non-small cell lung cancer', 'Disease', (139, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
1419	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
1425	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('tumor', 'Disease', (53, 58))	('Inhibition', 'Var', (0, 10))	('enhance', 'PosReg', (40, 47))
1439	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
1443	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
1450	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('THYM', 'Disease', (157, 161))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('LUAD/LUSC', 'Disease', (163, 172))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
1451	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('associated', 'Reg', (123, 133))	('GZMA', 'Gene', (90, 94))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
1520	29270506	False-negative results occur more commonly in small tumors, dopamine-producing tumors, and some tumors with SDHx mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('dopamine', 'Chemical', 'MESH:D004298', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (79, 85))	('mutations', 'Var', (113, 122))	('small tumors', 'Disease', 'MESH:D058405', (46, 58))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('SDHx', 'Chemical', '-', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('SDHx', 'Gene', (108, 112))	('small tumors', 'Disease', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
1527	29270506	Finally, MIBG scintigraphy has been reported to have low sensitivity in cases related to von Hippel-Lindau disease, SDHx mutations, or metastatic PPGLs.	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (89, 114))	('mutations', 'Var', (121, 130))	('SDHx', 'Chemical', '-', (116, 120))	('SDHx', 'Gene', (116, 120))	('MIBG', 'Chemical', 'MESH:D019797', (9, 13))	('PPGLs', 'Chemical', '-', (146, 151))	('von Hippel-Lindau disease', 'Disease', (89, 114))
1530	29270506	It is now recognized that the tumor genotype can ascertain metastatic potential; tumors with SDHB mutations carry a higher malignant risk.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('SDHB', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SDHB', 'Gene', '6390', (93, 97))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (81, 86))
1531	29270506	Deficient (abnormal) immunohistochemistry for SDHB is a sensitive and specific indicator of germline mutations in genes responsible for the assembly of the SDHB protein (SDHA, SDHB, SDHC, SDHD, and SDHAF2).	('SDHB', 'Gene', '6390', (156, 160))	('SDHB', 'Gene', '6390', (176, 180))	('SDHB', 'Gene', '6390', (46, 50))	('mutations', 'Var', (101, 110))	('SDHB', 'Gene', (176, 180))	('SDHB', 'Gene', (46, 50))	('SDHD', 'Gene', '6392', (188, 192))	('SDHA', 'Gene', '6389', (170, 174))	('SDHB', 'Gene', (156, 160))	('SDHC', 'Gene', (182, 186))	('SDHA', 'Gene', '6389', (198, 202))	('SDHD', 'Gene', (188, 192))	('SDHAF2', 'Gene', (198, 204))	('SDHC', 'Gene', '6391', (182, 186))	('SDHAF2', 'Gene', '54949', (198, 204))	('SDHA', 'Gene', (170, 174))	('SDHA', 'Gene', (198, 202))
1534	29270506	These include well-studied disorders such as von Hippel-Lindau (VHL), multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1), and the hereditary paraganglioma-pheochromocytoma caused by mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2.	('multiple endocrine neoplasia type 2', 'Disease', (70, 105))	('VHL', 'Disease', 'MESH:D006623', (64, 67))	('von Hippel-Lindau', 'Gene', (45, 62))	('SDHA', 'Gene', '6389', (247, 251))	('SDHAF2', 'Gene', (247, 253))	('SDHC', 'Gene', '6391', (231, 235))	('SDHAF2', 'Gene', '54949', (247, 253))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('von Hippel-Lindau', 'Gene', '7428', (45, 62))	('neurofibromatosis type 1', 'Gene', (114, 138))	('NF1', 'Gene', '4763', (140, 143))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (70, 105))	('SDHD', 'Gene', '6392', (237, 241))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (179, 195))	('neoplasia', 'Phenotype', 'HP:0002664', (89, 98))	('mutations', 'Var', (206, 215))	('SDHB', 'Gene', '6390', (225, 229))	('VHL', 'Disease', (64, 67))	('NF1', 'Gene', (140, 143))	('SDHC', 'Gene', (231, 235))	('hereditary paraganglioma-pheochromocytoma', 'Disease', (154, 195))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (79, 98))	('SDHD', 'Gene', (237, 241))	('SDHB', 'Gene', (225, 229))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (114, 131))	('SDHA', 'Gene', (219, 223))	('hereditary paraganglioma-pheochromocytoma', 'Disease', 'MESH:D010673', (154, 195))	('neurofibromatosis type 1', 'Gene', '4763', (114, 138))	('SDHA', 'Gene', '6389', (219, 223))	('caused by', 'Reg', (196, 205))	('SDHA', 'Gene', (247, 251))
1537	29270506	The highest frequency of mutations in PPGLs occur within VHL and SDHx genes.	('mutations', 'Var', (25, 34))	('VHL', 'Disease', (57, 60))	('VHL', 'Disease', 'MESH:D006623', (57, 60))	('PPGLs', 'Chemical', '-', (38, 43))	('SDHx', 'Chemical', '-', (65, 69))	('SDHx', 'Gene', (65, 69))	('PPGLs', 'Gene', (38, 43))
1538	29270506	In bladder PPGLs in particular, SDHB mutations have been reported in more than 50% of the patients.	('SDHB', 'Gene', '6390', (32, 36))	('SDHB', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('PPGLs', 'Chemical', '-', (11, 16))	('reported', 'Reg', (57, 65))	('patients', 'Species', '9606', (90, 98))
1539	29270506	This is important, because SDHB mutations demonstrate high metastatic potential.	('metastatic potential', 'CPA', (59, 79))	('mutations', 'Var', (32, 41))	('SDHB', 'Gene', (27, 31))	('SDHB', 'Gene', '6390', (27, 31))
1542	29270506	Although immunohistochemistry staining was not suggestive of an SDHx mutation, there are reports of interobserver variability.	('mutation', 'Var', (69, 77))	('SDHx', 'Chemical', '-', (64, 68))	('SDHx', 'Gene', (64, 68))
1543	29270506	Alternatively, a gene mutation in 1 of the newer genes such as EPAS1, KIF1B, and EGLN1 may be possible.	('EPAS1', 'Gene', '2034', (63, 68))	('KIF1B', 'Gene', (70, 75))	('EGLN1', 'Gene', (81, 86))	('EPAS1', 'Gene', (63, 68))	('KIF1B', 'Gene', '23095', (70, 75))	('gene mutation', 'Var', (17, 30))	('EGLN1', 'Gene', '54583', (81, 86))
1550	28752085	PCC and PGL are inherited in as much as 80% of pediatric cases, and all patients with mutations should be followed closely given the risk of recurrence and malignancy.	('mutations', 'Var', (86, 95))	('PGL', 'Gene', (8, 11))	('PCC', 'Gene', (0, 3))	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('malignancy', 'Disease', (156, 166))	('PCC', 'Phenotype', 'HP:0002666', (0, 3))	('PGL', 'Phenotype', 'HP:0002668', (8, 11))	('patients', 'Species', '9606', (72, 80))
1551	28752085	While the presentation of chromaffin cell tumors has been well described with multiple endocrine neoplasia, NF1, and Von Hippel-Lindau syndromes, the identification of new gene mutations leading to chromaffin cell tumors at a young age is changing the landscape of how clinicians approach such cases.	('Von Hippel-Lindau syndromes', 'Disease', (117, 144))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Von Hippel-Lindau syndromes', 'Disease', 'MESH:D006623', (117, 144))	('cell tumors', 'Disease', (37, 48))	('NF1', 'Gene', '4763', (108, 111))	('cell tumors', 'Disease', (209, 220))	('cell tumors', 'Disease', 'MESH:D005935', (37, 48))	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('cell tumors', 'Disease', 'MESH:D005935', (209, 220))	('NF', 'Phenotype', 'HP:0001067', (108, 110))	('NF1', 'Gene', (108, 111))	('chromaffin', 'Chemical', '-', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (78, 106))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (26, 48))	('chromaffin', 'Chemical', '-', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('multiple endocrine neoplasia', 'Disease', (78, 106))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (87, 106))	('leading to', 'Reg', (187, 197))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (198, 220))
1552	28752085	The paraganglioma-pheochromocytoma syndromes (SDHx) comprise familial gene mutations, of which the SDHB gene mutation carries a high rate of malignancy.	('paraganglioma-pheochromocytoma syndromes', 'Disease', (4, 44))	('SDHx', 'Chemical', '-', (46, 50))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (4, 17))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('paraganglioma-pheochromocytoma syndromes', 'Disease', 'MESH:D010673', (4, 44))	('malignancy', 'Disease', (141, 151))	('SDHB', 'Gene', '6390', (99, 103))	('SDHB', 'Gene', (99, 103))	('mutation', 'Var', (109, 117))
1575	28752085	The mass effect from non-functional head and neck paragangliomas (HNPGLs) can lead to dysphagia, hoarseness, hearing disturbances, and pain.	('hoarseness', 'Phenotype', 'HP:0001609', (97, 107))	('hearing disturbances', 'Phenotype', 'HP:0000365', (109, 129))	('lead to', 'Reg', (78, 85))	('dysphagia', 'Phenotype', 'HP:0002015', (86, 95))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (36, 64))	('neck paragangliomas', 'Disease', 'MESH:D010235', (45, 64))	('pain', 'Disease', (135, 139))	('hearing disturbances', 'Disease', 'MESH:D034381', (109, 129))	('hearing disturbances', 'Disease', (109, 129))	('non-functional', 'Var', (21, 35))	('pain', 'Phenotype', 'HP:0012531', (135, 139))	('PGL', 'Phenotype', 'HP:0002668', (68, 71))	('HNPGLs', 'Phenotype', 'HP:0002864', (66, 72))	('dysphagia', 'Disease', 'MESH:D003680', (86, 95))	('paraganglioma', 'Phenotype', 'HP:0002668', (50, 63))	('dysphagia', 'Disease', (86, 95))	('pain', 'Disease', 'MESH:D010146', (135, 139))	('neck paragangliomas', 'Disease', (45, 64))	('hoarseness', 'Disease', (97, 107))	('paragangliomas', 'Phenotype', 'HP:0002668', (50, 64))
1576	28752085	The European-American-Pheochromocytoma-Paraganglioma-Registry (EAPPR) followed 164 unrelated pediatric patients diagnosed with PCCs/PGLs, 80% of which had a germline mutation in a gene associated with such tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('germline mutation', 'Var', (157, 174))	('tumors', 'Disease', (206, 212))	('Pheochromocytoma-Paraganglioma', 'Disease', 'MESH:D010673', (22, 52))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('PCC', 'Phenotype', 'HP:0002666', (127, 130))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('Paraganglioma', 'Phenotype', 'HP:0002668', (39, 52))	('patients', 'Species', '9606', (103, 111))	('Pheochromocytoma-Paraganglioma', 'Disease', (22, 52))	('PGL', 'Phenotype', 'HP:0002668', (132, 135))
1577	28752085	In addition to the known syndromic presentations of MEN II, NF1, and VHL, germline succinate dehydrogenase gene mutations (SDHx) involving the mitochondrial enzyme complex (SDH) form part of the familial PGL-PCC syndromes.	('PGL', 'Phenotype', 'HP:0002668', (204, 207))	('syndromic', 'Disease', (25, 34))	('NF', 'Phenotype', 'HP:0001067', (60, 62))	('NF1', 'Gene', '4763', (60, 63))	('syndromic', 'Disease', 'MESH:D013577', (25, 34))	('NF1', 'Gene', (60, 63))	('VHL', 'Disease', 'MESH:D006623', (69, 72))	('SDHx', 'Chemical', '-', (123, 127))	('mutations', 'Var', (112, 121))	('familial PGL-PCC syndromes', 'Disease', (195, 221))	('VHL', 'Disease', (69, 72))	('PCC', 'Phenotype', 'HP:0002666', (208, 211))	('MEN', 'Species', '9606', (52, 55))
1588	28752085	Most patients have been found to carry germline mutations in SDHB, SDHC or SDHD.	('SDHC', 'Gene', '6391', (67, 71))	('germline mutations', 'Var', (39, 57))	('patients', 'Species', '9606', (5, 13))	('SDHD', 'Gene', '6392', (75, 79))	('SDHB', 'Gene', '6390', (61, 65))	('SDHD', 'Gene', (75, 79))	('SDHB', 'Gene', (61, 65))	('SDHC', 'Gene', (67, 71))
1594	28752085	Multiple other gene mutations associated with hereditary PCCs and PGLs have been identified in the past decade and include TMEM127 involved in the mTOR pathway, MAX that controls gene transcription as well as KIF 1B, EGLN1, IDH1, and FH, with unclear clinical significance.	('mutations', 'Var', (20, 29))	('associated', 'Reg', (30, 40))	('IDH1', 'Gene', '3417', (224, 228))	('TMEM127', 'Gene', '55654', (123, 130))	('EGLN1', 'Gene', '54583', (217, 222))	('hereditary PCC', 'Disease', 'OMIM:115700', (46, 60))	('KIF 1B', 'Gene', '23095', (209, 215))	('mTOR', 'Gene', '2475', (147, 151))	('EGLN1', 'Gene', (217, 222))	('KIF 1B', 'Gene', (209, 215))	('PGL', 'Phenotype', 'HP:0002668', (66, 69))	('hereditary PCC', 'Disease', (46, 60))	('IDH1', 'Gene', (224, 228))	('PCC', 'Phenotype', 'HP:0002666', (57, 60))	('TMEM127', 'Gene', (123, 130))	('involved', 'Reg', (131, 139))	('mTOR', 'Gene', (147, 151))
1595	28752085	Table 2 lists the syndromic as well as newer gene mutations associated with PCCs and PGLs and describes the biochemical profile of such tumors, including the earliest age of presentation as noted in the literature.	('tumors', 'Disease', (136, 142))	('PCCs', 'Disease', (76, 80))	('syndromic', 'Disease', (18, 27))	('PGLs', 'Disease', (85, 89))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('PCC', 'Phenotype', 'HP:0002666', (76, 79))	('mutations', 'Var', (50, 59))	('syndromic', 'Disease', 'MESH:D013577', (18, 27))	('PGL', 'Phenotype', 'HP:0002668', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('associated', 'Reg', (60, 70))
1598	28752085	Gene mutations in VHL, SDHx, and HIF2 confer a reduced oxidative response with angiogenesis and hypoxia and encompass cluster 1 tumors.	('oxidative response', 'MPA', (55, 73))	('HIF2', 'Gene', (33, 37))	('SDHx', 'Chemical', '-', (23, 27))	('SDHx', 'Gene', (23, 27))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('VHL', 'Disease', (18, 21))	('hypoxia', 'Disease', (96, 103))	('VHL', 'Disease', 'MESH:D006623', (18, 21))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('tumors', 'Disease', (128, 134))	('encompass', 'Reg', (108, 117))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('reduced', 'NegReg', (47, 54))
1599	28752085	Gene mutations in RET, NF1, KIF 1B, TMEM 127, and MAX were found to activate kinase signaling pathways leading to tumors with such features, termed cluster 2 tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('RET', 'Gene', '5979', (18, 21))	('kinase signaling pathways', 'Pathway', (77, 102))	('KIF 1B', 'Gene', (28, 34))	('NF1', 'Gene', '4763', (23, 26))	('KIF 1B', 'Gene', '23095', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('leading to', 'Reg', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('activate', 'PosReg', (68, 76))	('NF1', 'Gene', (23, 26))	('NF', 'Phenotype', 'HP:0001067', (23, 25))	('RET', 'Gene', (18, 21))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('mutations', 'Var', (5, 14))	('TMEM 127', 'Gene', '55654', (36, 44))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('TMEM 127', 'Gene', (36, 44))	('tumors', 'Disease', (114, 120))
1603	28752085	Those with SDHB mutations had the highest prevalence for malignancy with extra-adrenal and thoracic paraganglial tumors posing additional risk factors.	('malignancy', 'Disease', (57, 67))	('SDHB', 'Gene', (11, 15))	('paraganglial tumors', 'Disease', (100, 119))	('paraganglial tumors', 'Disease', 'MESH:D009369', (100, 119))	('mutations', 'Var', (16, 25))	('paraganglial tumors', 'Phenotype', 'HP:0002668', (100, 119))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('extra-adrenal', 'Disease', (73, 86))	('SDHB', 'Gene', '6390', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
1604	28752085	Adult studies have also shown that SDHB mutation carry a higher risk for malignancy at 13-23%.	('mutation', 'Var', (40, 48))	('SDHB', 'Gene', (35, 39))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('malignancy', 'Disease', (73, 83))	('SDHB', 'Gene', '6390', (35, 39))
1605	28752085	The European-American-Asian Pheochromocytoma-Paraganglioma Registry prospectively followed up on predominantly adult patients with the newer gene mutations SDHA, TMEM127, MAX, and SDHAF2 and determined that 12% (4/34) of SDHA mutation carriers and 10% (3/29) of TMEM127 mutation carriers had malignant tumors.	('Paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('TMEM127', 'Gene', '55654', (162, 169))	('mutation', 'Var', (226, 234))	('malignant tumors', 'Disease', (292, 308))	('patients', 'Species', '9606', (117, 125))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (28, 44))	('TMEM127', 'Gene', (262, 269))	('Pheochromocytoma-Paraganglioma', 'Disease', (28, 58))	('SDHA', 'Gene', (221, 225))	('SDHA', 'Gene', '6389', (221, 225))	('TMEM127', 'Gene', '55654', (262, 269))	('SDHAF2', 'Gene', '54949', (180, 186))	('SDHAF2', 'Gene', (180, 186))	('SDHA', 'Gene', (180, 184))	('SDHA', 'Gene', (156, 160))	('TMEM127', 'Gene', (162, 169))	('SDHA', 'Gene', '6389', (180, 184))	('SDHA', 'Gene', '6389', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('malignant tumors', 'Disease', 'MESH:D018198', (292, 308))	('Pheochromocytoma-Paraganglioma', 'Disease', 'MESH:D010673', (28, 58))
1610	28752085	While in the past one would consider the syndromes MEN2, VHL, NF1 or sporadic mutations as the cause of PCCs or PGLs, the discovery of new gene mutations that cause such tumors now needs to be incorporated into the diagnostic algorithm of patients thought to have a PCC or a PGL.	('VHL', 'Disease', 'MESH:D006623', (57, 60))	('PGL', 'Phenotype', 'HP:0002668', (112, 115))	('NF1', 'Gene', (62, 65))	('cause', 'Reg', (159, 164))	('NF', 'Phenotype', 'HP:0001067', (62, 64))	('mutations', 'Var', (144, 153))	('PGLs', 'Disease', (112, 116))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('PCC', 'Phenotype', 'HP:0002666', (104, 107))	('mutations', 'Var', (78, 87))	('PGL', 'Phenotype', 'HP:0002668', (275, 278))	('PCCs', 'Disease', (104, 108))	('VHL', 'Disease', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('PCC', 'Disease', (266, 269))	('patients', 'Species', '9606', (239, 247))	('PCC', 'Phenotype', 'HP:0002666', (266, 269))	('MEN', 'Species', '9606', (51, 54))	('NF1', 'Gene', '4763', (62, 65))	('tumors', 'Disease', (170, 176))
1613	28752085	demonstrated that SDHD mutations exhibit a weak diffuse staining pattern while SDHB mutations had a completely absent staining.	('SDHD', 'Gene', '6392', (18, 22))	('mutations', 'Var', (23, 32))	('SDHB', 'Gene', '6390', (79, 83))	('diffuse staining pattern', 'MPA', (48, 72))	('SDHD', 'Gene', (18, 22))	('SDHB', 'Gene', (79, 83))
1614	28752085	Thus, a positive staining would entail intact SDHx subunits while a negative/weakly positive staining would indicate a mutation in the SDHx subunits.	('SDHx', 'Chemical', '-', (46, 50))	('SDHx', 'Chemical', '-', (135, 139))	('mutation', 'Var', (119, 127))	('SDHx', 'Gene', (46, 50))	('SDHx', 'Gene', (135, 139))
1615	28752085	As can then be expected, syndromes that do not have a SDHx gene mutation, to include MEN II, VHL, and NF1, will stain positive for SDHx.	('SDHx', 'Gene', (54, 58))	('mutation', 'Var', (64, 72))	('MEN', 'Species', '9606', (85, 88))	('SDHx', 'Chemical', '-', (54, 58))	('NF1', 'Gene', (102, 105))	('positive', 'Reg', (118, 126))	('NF', 'Phenotype', 'HP:0001067', (102, 104))	('VHL', 'Disease', 'MESH:D006623', (93, 96))	('NF1', 'Gene', '4763', (102, 105))	('VHL', 'Disease', (93, 96))	('SDHx', 'Chemical', '-', (131, 135))
1625	28752085	Tumors can rarely secrete a predominance of dopamine; these are usually extra-adrenal PGLs with SDHx gene mutations.	('SDHx', 'Gene', (96, 100))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('PGL', 'Phenotype', 'HP:0002668', (86, 89))	('dopamine', 'Chemical', 'MESH:D004298', (44, 52))	('SDHx', 'Chemical', '-', (96, 100))	('mutations', 'Var', (106, 115))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
1629	28752085	Sensitivities and specificities of CgA and plasma metanephrines were 73.2/95.9 and 70.7/98.6%, respectively, in SDHB mutation carriers with PCCs and sympathetic PGLs.	('PGL', 'Phenotype', 'HP:0002668', (161, 164))	('SDHB', 'Gene', '6390', (112, 116))	('CgA', 'Gene', '1113', (35, 38))	('SDHB', 'Gene', (112, 116))	('sympathetic PGLs', 'Disease', (149, 165))	('metanephrines', 'Chemical', 'MESH:D008676', (50, 63))	('PCC', 'Phenotype', 'HP:0002666', (140, 143))	('PCCs', 'Disease', (140, 144))	('mutation', 'Var', (117, 125))	('CgA', 'Gene', (35, 38))
1640	28752085	These include 123metaiodobenzylguanidine (123I-MIBG) scan, positron emission tomography (PET) with [18F] fluorodopamine (FDA), [18F] fluorodeoxyglucose (FDG), and [18F] fluorodihydroxyphenylalanine (F-DOPA).	('123metaiodobenzylguanidine', 'MPA', (14, 40))	('F-DOPA', 'Chemical', '-', (199, 205))	('[18F] fluorodopamine', 'Chemical', '-', (99, 119))	('FDA', 'Chemical', '-', (121, 124))	('123I-MIBG', 'Chemical', 'MESH:D019797', (42, 51))	('FDG', 'Chemical', 'MESH:D019788', (153, 156))	('[18F] fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (127, 151))	('[18F] fluorodihydroxyphenylalanine', 'Chemical', 'MESH:C043437', (163, 197))	('[18F] fluorodihydroxyphenylalanine', 'Var', (163, 197))	('123metaiodobenzylguanidine', 'Chemical', '-', (14, 40))
1645	28752085	In contrast, [18F]-FDG PET has been the recommended functional imaging technique to evaluate malignant and metastatic PCCs/PGLs, particularly in SDHB mutation carriers in adults.	('SDHB', 'Gene', '6390', (145, 149))	('PCC', 'Phenotype', 'HP:0002666', (118, 121))	('PGL', 'Phenotype', 'HP:0002668', (123, 126))	('mutation', 'Var', (150, 158))	('SDHB', 'Gene', (145, 149))	('FDG', 'Chemical', 'MESH:D019788', (19, 22))	('malignant', 'Disease', (93, 102))	('carriers', 'Reg', (159, 167))
1646	28752085	Recent advances in functional imaging of PCCs/PGLs have led to the use of radiolabeled DOTA peptides, such as [68Ga]-DOTATATE PET, which has high affinity for somatostatin receptor 2.	('[68Ga]', 'Var', (110, 116))	('somatostatin receptor 2', 'Gene', (159, 182))	('DOTATATE', 'Chemical', '-', (117, 125))	('PCC', 'Phenotype', 'HP:0002666', (41, 44))	('PGL', 'Phenotype', 'HP:0002668', (46, 49))	('somatostatin receptor 2', 'Gene', '6752', (159, 182))
1647	28752085	Adult studies have demonstrated the superiority of [68Ga]-DOTATATE PET in localizing metastatic SDHB-associated PCCs/PGLs over the other functional imaging studies, excluding MIBG.	('DOTATATE', 'Chemical', '-', (58, 66))	('metastatic', 'Disease', (85, 95))	('PCC', 'Phenotype', 'HP:0002666', (112, 115))	('SDHB', 'Gene', '6390', (96, 100))	('PGL', 'Phenotype', 'HP:0002668', (117, 120))	('SDHB', 'Gene', (96, 100))	('[68Ga]-DOTATATE', 'Var', (51, 66))	('MIBG', 'Chemical', 'MESH:D019797', (175, 179))
1649	28752085	Another study confirmed the high detection rate of PCCs/PGLs using [68Ga]-DOTATATE PET but noted that [18F]-FDG PET had higher uptake than the former in cases of mutations involving the pseudohypoxic cluster and a dedifferentiated tumor with loss of SSTR expression.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('mutations', 'Var', (162, 171))	('[18F]-FDG', 'Var', (102, 111))	('FDG', 'Chemical', 'MESH:D019788', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('pseudohypoxic cluster', 'Disease', (186, 207))	('higher', 'PosReg', (120, 126))	('tumor', 'Disease', (231, 236))	('SSTR', 'Gene', (250, 254))	('PCC', 'Phenotype', 'HP:0002666', (51, 54))	('pseudohypoxic cluster', 'Disease', 'MESH:D003027', (186, 207))	('uptake', 'MPA', (127, 133))	('PGL', 'Phenotype', 'HP:0002668', (56, 59))	('DOTATATE', 'Chemical', '-', (74, 82))
1650	28752085	In addition, CT with 123I-MIBG proved to have a lower lesion detection rate than [68Ga]-DOTATATE PET and [18F]-FDG PET in identifying PCCs and PGLs.	('PGL', 'Phenotype', 'HP:0002668', (143, 146))	('lower', 'NegReg', (48, 53))	('lesion detection rate', 'MPA', (54, 75))	('123I-MIBG', 'Chemical', 'MESH:D019797', (21, 30))	('123I-MIBG', 'Var', (21, 30))	('FDG', 'Chemical', 'MESH:D019788', (111, 114))	('PCCs', 'Disease', (134, 138))	('PCC', 'Phenotype', 'HP:0002666', (134, 137))	('PGLs', 'Disease', (143, 147))	('DOTATATE', 'Chemical', '-', (88, 96))
1652	28752085	Beta blockade is instituted following alpha blockade to offset reflex tachycardia from alpha-2 receptor antagonism and should never precede alpha blockade.	('alpha-2 receptor', 'Protein', (87, 103))	('tachycardia', 'Phenotype', 'HP:0001649', (70, 81))	('tachycardia', 'Disease', (70, 81))	('tachycardia', 'Disease', 'MESH:D013610', (70, 81))	('antagonism', 'Var', (104, 114))
1670	28752085	The adult literature reviewed the efficacy of preoperative phenoxybenzamine, doxazosin, and prazosin in terms of having fewer hemodynamic fluctuations intraoperatively.	('prazosin', 'Chemical', 'MESH:D011224', (92, 100))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (59, 75))	('phenoxybenzamine', 'Var', (59, 75))	('doxazosin', 'Chemical', 'MESH:D017292', (77, 86))	('hemodynamic fluctuations', 'MPA', (126, 150))
1672	28752085	Monotherapy with an alpha blocker has been found to cause hemodynamic instability intraoperatively during tumor manipulation.	('hemodynamic instability', 'MPA', (58, 81))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cause', 'Reg', (52, 57))	('Monotherapy', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
1673	28752085	Metyrosine, a tyrosine hydroxylase inhibitor, prevents catecholamine synthesis and has been used in adults to prevent intraoperative BP fluctuations.	('prevents', 'NegReg', (46, 54))	('catecholamine synthesis', 'MPA', (55, 78))	('catecholamine', 'Chemical', 'MESH:D002395', (55, 68))	('tyrosine hydroxylase', 'Gene', (14, 34))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))	('tyrosine hydroxylase', 'Gene', '7054', (14, 34))
1674	28752085	The combination of phenoxybenzamine or prazosin and metyrosine in adults resulted in better BP control pre- and intraoperatively, with less need for pressure agents intraoperatively than when using phenoxybenzamine alone.	('better', 'PosReg', (85, 91))	('prazosin', 'Var', (39, 47))	('prazosin', 'Chemical', 'MESH:D011224', (39, 47))	('phenoxybenzamine', 'Var', (19, 35))	('metyrosine', 'Chemical', 'MESH:D019805', (52, 62))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (19, 35))	('BP control', 'MPA', (92, 102))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (198, 214))	('metyrosine', 'Var', (52, 62))
1676	28752085	They note their experience to be in agreement with the adult literature that metyrosine use is associated with a decreased need for intraoperative vasoactive medications, fluids, and decreased blood loss.	('metyrosine', 'Chemical', 'MESH:D019805', (77, 87))	('decreased blood loss', 'Disease', 'MESH:D006473', (183, 203))	('metyrosine', 'Var', (77, 87))	('decreased blood loss', 'Disease', (183, 203))	('decreased', 'NegReg', (113, 122))
1678	28752085	Although there were no significant differences in BPs pre-, intra- and postoperatively, careful review of patients showed that those who received metyrosine had more severe disease and more stable BPs intraoperatively.	('severe disease', 'Disease', 'MESH:D056729', (166, 180))	('metyrosine', 'Var', (146, 156))	('severe disease', 'Disease', (166, 180))	('patients', 'Species', '9606', (106, 114))	('more', 'PosReg', (185, 189))	('metyrosine', 'Chemical', 'MESH:D019805', (146, 156))
1699	28752085	The use of phenoxybenzamine is associated with postoperative hypotension from sustained alpha blockade for the 24 h following surgery.	('phenoxybenzamine', 'Var', (11, 27))	('hypotension', 'Disease', 'MESH:D007022', (61, 72))	('postoperative', 'MPA', (47, 60))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (11, 27))	('hypotension', 'Disease', (61, 72))	('hypotension', 'Phenotype', 'HP:0002615', (61, 72))
1710	28752085	Genetic testing was not available during that time period except for five patients who tested positive for a RET mutation (three patients) or an SDHD or SDHB mutation (two patients).	('mutation', 'Var', (113, 121))	('RET', 'Gene', (109, 112))	('SDHD', 'Gene', (145, 149))	('patients', 'Species', '9606', (129, 137))	('SDHB', 'Gene', (153, 157))	('patients', 'Species', '9606', (74, 82))	('mutation', 'Var', (158, 166))	('RET', 'Gene', '5979', (109, 112))	('patients', 'Species', '9606', (172, 180))	('positive', 'Reg', (94, 102))	('SDHD', 'Gene', '6392', (145, 149))	('SDHB', 'Gene', '6390', (153, 157))
1714	28752085	Three of the patients had VHL, three had SDHB mutations, two had NF1, and one SDHA with the cause of death being metastases in seven and cardiac failure in one patient.	('patients', 'Species', '9606', (13, 21))	('cardiac failure', 'Disease', (137, 152))	('cardiac failure', 'Disease', 'MESH:D006333', (137, 152))	('patient', 'Species', '9606', (160, 167))	('cardiac failure', 'Phenotype', 'HP:0001635', (137, 152))	('metastases', 'Disease', 'MESH:D009362', (113, 123))	('VHL', 'Disease', (26, 29))	('mutations', 'Var', (46, 55))	('metastases', 'Disease', (113, 123))	('death', 'Disease', (101, 106))	('SDHA', 'Gene', (78, 82))	('patient', 'Species', '9606', (13, 20))	('SDHA', 'Gene', '6389', (78, 82))	('SDHB', 'Gene', '6390', (41, 45))	('NF1', 'Gene', '4763', (65, 68))	('VHL', 'Disease', 'MESH:D006623', (26, 29))	('NF', 'Phenotype', 'HP:0001067', (65, 67))	('death', 'Disease', 'MESH:D003643', (101, 106))	('NF1', 'Gene', (65, 68))	('SDHB', 'Gene', (41, 45))
1725	28752085	Recurrences were significantly more common in patients with germline mutations than those with sporadic disease and tended to recur 10 years earlier, with a latency period of 23 versus 33 years, respectively.	('patients', 'Species', '9606', (46, 54))	('sporadic disease', 'Disease', (95, 111))	('sporadic disease', 'Disease', 'MESH:D004421', (95, 111))	('germline mutations', 'Var', (60, 78))	('common', 'Reg', (36, 42))
1726	28752085	The mutations seen with these recurrent tumors were associated with VHL and SDHD mutations.	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (76, 80))	('VHL', 'Disease', (68, 71))	('VHL', 'Disease', 'MESH:D006623', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (81, 90))	('mutations', 'Var', (4, 13))	('tumors', 'Disease', (40, 46))
1727	28752085	Within these gene-specific mutations, SDHD mutations had a recurrent tumor after 18 years of latency versus 21 years for VHL mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('VHL', 'Disease', 'MESH:D006623', (121, 124))	('mutations', 'Var', (43, 52))	('SDHD', 'Gene', '6392', (38, 42))	('SDHD', 'Gene', (38, 42))	('VHL', 'Disease', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
1728	28752085	HNPGLs recurred in 4% of pediatric patients and were caused by SDHD mutations at initial diagnosis and during recurrences.	('PGL', 'Phenotype', 'HP:0002668', (2, 5))	('caused by', 'Reg', (53, 62))	('SDHD', 'Gene', '6392', (63, 67))	('patients', 'Species', '9606', (35, 43))	('mutations', 'Var', (68, 77))	('HNPGLs', 'Phenotype', 'HP:0002864', (0, 6))	('SDHD', 'Gene', (63, 67))	('HNPGLs', 'Disease', (0, 6))
1729	28752085	Seven percent of patients had a third recurrence, with a time interval of 1-20 years (mean 5 years) from second to third tumor; they all had germline mutations.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('had', 'Reg', (137, 140))	('tumor', 'Disease', (121, 126))	('patients', 'Species', '9606', (17, 25))	('germline mutations', 'Var', (141, 159))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
1730	28752085	The prevalence of malignancy was highest in SDHB mutation-positive individuals, with extra-adrenal and thoracic PGLs posing added risk for malignancy.	('highest', 'Reg', (33, 40))	('SDHB', 'Gene', '6390', (44, 48))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('PGL', 'Phenotype', 'HP:0002668', (112, 115))	('SDHB', 'Gene', (44, 48))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('malignancy', 'Disease', (18, 28))	('mutation-positive', 'Var', (49, 66))	('malignancy', 'Disease', (139, 149))
1732	28752085	Of those, 72% (23 patients) had a germline mutation in SDHB, 9.4% (3 patients) had an SDHD mutation, and 6.3% (2 patients) had a VHL mutation, with the absence of a known mutation in the remainder (4 patients).	('SDHB', 'Gene', (55, 59))	('VHL', 'Disease', (129, 132))	('SDHB', 'Gene', '6390', (55, 59))	('SDHD', 'Gene', (86, 90))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (113, 121))	('germline mutation', 'Var', (34, 51))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (69, 77))	('VHL', 'Disease', 'MESH:D006623', (129, 132))	('SDHD', 'Gene', '6392', (86, 90))
1733	28752085	The study that established plasma methoxytyramine as a biomarker for metastatic PCCs and PGLs also recognized the association between extra-adrenal disease, tumor size >5 cm and SDHB mutation carriers associated with a high risk of malignancy.	('tumor', 'Disease', (157, 162))	('methoxytyramine', 'Chemical', 'MESH:C001746', (34, 49))	('PGL', 'Phenotype', 'HP:0002668', (89, 92))	('PCC', 'Phenotype', 'HP:0002666', (80, 83))	('adrenal disease', 'Phenotype', 'HP:0000834', (140, 155))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('adrenal disease', 'Disease', 'MESH:D000309', (140, 155))	('adrenal disease', 'Disease', (140, 155))	('malignancy', 'Disease', 'MESH:D009369', (232, 242))	('associated', 'Reg', (201, 211))	('mutation', 'Var', (183, 191))	('malignancy', 'Disease', (232, 242))	('SDHB', 'Gene', '6390', (178, 182))	('SDHB', 'Gene', (178, 182))
1736	28752085	For example, SDHB mutations have high risk of metastasis, VHL and SDHD mutation carriers have high recurrence rates, and SDHA and TMEM127 have now been identified to confer added risks of malignancy.	('SDHD', 'Gene', '6392', (66, 70))	('VHL', 'Disease', (58, 61))	('malignancy', 'Disease', (188, 198))	('VHL', 'Disease', 'MESH:D006623', (58, 61))	('SDHB', 'Gene', '6390', (13, 17))	('TMEM127', 'Gene', (130, 137))	('metastasis', 'CPA', (46, 56))	('SDHA', 'Gene', (121, 125))	('SDHB', 'Gene', (13, 17))	('TMEM127', 'Gene', '55654', (130, 137))	('SDHA', 'Gene', '6389', (121, 125))	('recurrence', 'MPA', (99, 109))	('malignancy', 'Disease', 'MESH:D009369', (188, 198))	('SDHD', 'Gene', (66, 70))	('mutations', 'Var', (18, 27))
1737	28752085	Recommendations of the EAPPR are to perform annual surveillance for the first 3 years after initial diagnosis of mutation carriers, this being the time frame where malignancy is apparent unless diagnosed at presentation, followed by lifelong follow-up.	('malignancy', 'Disease', (164, 174))	('mutation', 'Var', (113, 121))	('malignancy', 'Disease', 'MESH:D009369', (164, 174))
1740	28752085	The identification of new gene mutations and the determination of recurrence and malignancy rates have allowed clinicians to acquire a better understanding of this disease process.	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('mutations', 'Var', (31, 40))	('malignancy', 'Disease', (81, 91))
1742	28752085	All patients with genetic mutations should be followed throughout their lifetime given the risk of recurrence and malignancy.	('malignancy', 'Disease', 'MESH:D009369', (114, 124))	('genetic mutations', 'Var', (18, 35))	('patients', 'Species', '9606', (4, 12))	('malignancy', 'Disease', (114, 124))
1743	28752085	Those with SDHB gene mutations ought to be aggressively followed given the high risk of metastatic disease.	('SDHB', 'Gene', '6390', (11, 15))	('SDHB', 'Gene', (11, 15))	('mutations', 'Var', (21, 30))
1749	24449023	Screening for RET revealed a rare S891A mutation located in the intracellular tyrosine kinase domain.	('RET', 'Gene', '5979', (14, 17))	('S891A', 'Var', (34, 39))	('S891A', 'Mutation', 'rs75234356', (34, 39))	('RET', 'Gene', (14, 17))
1752	24449023	Our report suggests that cases with S891A mutation, akin to those with other RET mutations, require screening for pheochromocytoma.	('RET', 'Gene', (77, 80))	('pheochromocytoma', 'Disease', 'MESH:D010673', (114, 130))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (114, 130))	('S891A', 'Var', (36, 41))	('S891A', 'Mutation', 'rs75234356', (36, 41))	('RET', 'Gene', '5979', (77, 80))	('pheochromocytoma', 'Disease', (114, 130))
1756	24449023	Most of the mutations, found in the cysteine-rich extracellular domain, give rise to ligand-independent receptor dimerization and cross-phosphorylation, leading to constitutive activation of the downstream signal of the receptor.	('ligand-independent', 'MPA', (85, 103))	('constitutive', 'MPA', (164, 176))	('mutations', 'Var', (12, 21))	('activation', 'PosReg', (177, 187))	('dimerization', 'MPA', (113, 125))	('cysteine', 'Chemical', 'MESH:D003545', (36, 44))	('cross-phosphorylation', 'MPA', (130, 151))	('downstream signal', 'MPA', (195, 212))
1757	24449023	Mutation of the cysteine codon 634 constitutes 80-90 % of MEN2A cases, although those caused by mutations of the cysteine codon 611, 618, and 620 are also observed.	('MEN2A', 'Gene', '5979', (58, 63))	('caused', 'Reg', (86, 92))	('MEN2A', 'Gene', (58, 63))	('Mutation', 'Var', (0, 8))	('cysteine', 'Chemical', 'MESH:D003545', (113, 121))	('cysteine', 'Chemical', 'MESH:D003545', (16, 24))
1758	24449023	Although they are a minor subset, RET mutations in MEN2A cases are also identified within the intracellular domain, including those originally reported as mutations of familial medullary thyroid carcinoma (FMTC).	('thyroid carcinoma', 'Disease', 'MESH:D013964', (187, 204))	('RET', 'Gene', '5979', (34, 37))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (177, 204))	('MEN2A', 'Gene', (51, 56))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (187, 204))	('RET', 'Gene', (34, 37))	('thyroid carcinoma', 'Disease', (187, 204))	('MEN2A', 'Gene', '5979', (51, 56))	('MTC', 'Phenotype', 'HP:0002865', (207, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('mutations', 'Var', (38, 47))
1759	24449023	On the other hand, most cases with MEN2B carry M918T or A883F mutations in the tyrosine kinase domain, suggesting strong genotype-phenotype correlations.	('MEN2B', 'Gene', (35, 40))	('M918T', 'Mutation', 'rs74799832', (47, 52))	('MEN2B', 'Gene', '5979', (35, 40))	('A883F', 'Var', (56, 61))	('A883F', 'Mutation', 'rs377767429', (56, 61))	('M918T', 'Var', (47, 52))
1761	24449023	In particular, mutations at codons 609, 768, 790, 791, 804 and 891 are classified as level 1, having the lowest risk for aggressiveness among the three levels of MTC.	('lowest', 'NegReg', (105, 111))	('aggressiveness', 'Disease', 'MESH:D001523', (121, 135))	('mutations', 'Var', (15, 24))	('MTC', 'Phenotype', 'HP:0002865', (162, 165))	('aggressiveness', 'Disease', (121, 135))	('aggressiveness', 'Phenotype', 'HP:0000718', (121, 135))
1762	24449023	A rare mutation, S891A, has been associated solely with intermediate-risk FMTC.	('FMTC', 'Disease', (74, 78))	('S891A', 'Mutation', 'rs75234356', (17, 22))	('associated', 'Reg', (33, 43))	('MTC', 'Phenotype', 'HP:0002865', (75, 78))	('S891A', 'Var', (17, 22))
1763	24449023	For the carriers of such FMTC mutations, intensive screening for age-related development of pheochromocytoma need not be started until they are 20 years old.	('pheochromocytoma', 'Disease', (92, 108))	('FMTC', 'Gene', (25, 29))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (92, 108))	('mutations', 'Var', (30, 39))	('pheochromocytoma', 'Disease', 'MESH:D010673', (92, 108))	('MTC', 'Phenotype', 'HP:0002865', (26, 29))
1764	24449023	However, a rare case with a S891A mutation expressing MTC and pheochromocytoma was recently reported, suggesting the limitation of genotype-based predictions.	('S891A mutation', 'Var', (28, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (62, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('S891A', 'Mutation', 'rs75234356', (28, 33))	('MTC', 'Phenotype', 'HP:0002865', (54, 57))	('pheochromocytoma', 'Disease', (62, 78))
1765	24449023	In this manuscript, we report a rare case of a patient who was affected by bilateral pheochromocytomas as the first manifestation of MEN2A, whose subsequent screening for RET mutation identified S891A.	('patient', 'Species', '9606', (47, 54))	('RET', 'Gene', (171, 174))	('S891A', 'Mutation', 'rs75234356', (195, 200))	('RET', 'Gene', '5979', (171, 174))	('bilateral pheochromocytomas', 'Disease', (75, 102))	('S891A', 'Var', (195, 200))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (85, 102))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('MEN2A', 'Gene', '5979', (133, 138))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (75, 102))	('MEN2A', 'Gene', (133, 138))
1775	24449023	Finally, screening for the RET gene was performed after appropriate informed consent was obtained (approved by the Ethical Review Board for Human Genome Studies at Fujita Health University), and, unexpectedly, the S891A mutation was identified.	('Human', 'Species', '9606', (140, 145))	('S891A', 'Mutation', 'rs75234356', (214, 219))	('S891A', 'Var', (214, 219))	('RET', 'Gene', (27, 30))	('RET', 'Gene', '5979', (27, 30))
1781	24449023	The 27-year-old son requested RET mutation screening, and indeed, the S891A mutation was identified (Fig.	('S891A', 'Mutation', 'rs75234356', (70, 75))	('RET', 'Gene', (30, 33))	('RET', 'Gene', '5979', (30, 33))	('S891A', 'Var', (70, 75))
1783	24449023	S891A mutation constitutes 2 % of all RET mutations identified in MEN2/FMTC cases.	('RET', 'Gene', '5979', (38, 41))	('S891A', 'Mutation', 'rs75234356', (0, 5))	('MEN', 'Species', '9606', (66, 69))	('MEN2/FMTC', 'Disease', (66, 75))	('MTC', 'Phenotype', 'HP:0002865', (72, 75))	('RET', 'Gene', (38, 41))	('S891A mutation', 'Var', (0, 14))
1784	24449023	Early reports stress the association of this mutation with FMTC, but accumulating evidence shows the mutant's capacity to induce a wider spectrum of MEN2A.	('FMTC', 'Disease', (59, 63))	('mutant', 'Var', (101, 107))	('mutation', 'Var', (45, 53))	('MEN2A', 'Gene', '5979', (149, 154))	('MEN2A', 'Gene', (149, 154))	('induce', 'Reg', (122, 128))	('MTC', 'Phenotype', 'HP:0002865', (60, 63))
1785	24449023	S891A mutation causes MTC in 63.5 % of cases, pheochromocytoma in 4.1 % of cases and parathyroid hyperplasia in 4.1 % of cases.	('causes', 'Reg', (15, 21))	('pheochromocytoma', 'Disease', (46, 62))	('parathyroid hyperplasia', 'Disease', (85, 108))	('parathyroid hyperplasia', 'Phenotype', 'HP:0008208', (85, 108))	('pheochromocytoma', 'Disease', 'MESH:D010673', (46, 62))	('S891A', 'Mutation', 'rs75234356', (0, 5))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (46, 62))	('MTC', 'Phenotype', 'HP:0002865', (22, 25))	('S891A mutation', 'Var', (0, 14))	('parathyroid hyperplasia', 'Disease', 'MESH:D006965', (85, 108))	('MTC', 'Disease', (22, 25))
1786	24449023	Compilation of MEN2A-related clinical manifestation in patients with RETS891A mutation in previous reports is described in Table 2.	('mutation', 'Var', (78, 86))	('RETS891A', 'Gene', (69, 77))	('MEN2A', 'Gene', (15, 20))	('MEN2A', 'Gene', '5979', (15, 20))	('patients', 'Species', '9606', (55, 63))
1787	24449023	Indeed, the management guideline of medullary thyroid cancer by the American Thyroid Association categorizes pheochromocytoma in S891A mutation as 'rare'.	('S891A', 'Mutation', 'rs75234356', (129, 134))	('pheochromocytoma', 'Disease', (109, 125))	('thyroid cancer', 'Phenotype', 'HP:0002890', (46, 60))	('thyroid cancer', 'Disease', (46, 60))	('pheochromocytoma', 'Disease', 'MESH:D010673', (109, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (109, 125))	('thyroid cancer', 'Disease', 'MESH:D013964', (46, 60))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (36, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('S891A mutation', 'Var', (129, 143))
1788	24449023	None of ten Japanese cases with S891A mutation reported in a recent study had pheochromocytoma, but our case report combined with previous data indicates that S891A patients as well as other MEN2A patients require early detection of subclinical pheochromocytoma to prevent a potential hypertensive crisis In MEN2 patients, the gain-of-function mutation in the RET receptor tyrosine kinase gene constitutively activates the downstream signals, leading to transformation of the cells.	('patients', 'Species', '9606', (197, 205))	('hypertensive', 'Disease', 'MESH:D006973', (285, 297))	('pheochromocytoma', 'Disease', (78, 94))	('pheochromocytoma', 'Disease', (245, 261))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (245, 261))	('transformation of the cells', 'CPA', (454, 481))	('mutation', 'Var', (344, 352))	('patients', 'Species', '9606', (165, 173))	('MEN', 'Species', '9606', (191, 194))	('RET', 'Gene', (360, 363))	('activates', 'PosReg', (409, 418))	('S891A', 'Mutation', 'rs75234356', (159, 164))	('patients', 'Species', '9606', (313, 321))	('S891A', 'Mutation', 'rs75234356', (32, 37))	('MEN', 'Species', '9606', (308, 311))	('hypertensive', 'Disease', (285, 297))	('gain-of-function', 'PosReg', (327, 343))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (285, 304))	('pheochromocytoma', 'Disease', 'MESH:D010673', (245, 261))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))	('MEN2A', 'Gene', '5979', (191, 196))	('RET', 'Gene', '5979', (360, 363))	('MEN2A', 'Gene', (191, 196))
1789	24449023	Although the mutations in the cysteine-rich extracellular domain all target cysteine codons, inducing ligand-independent RET dimerization, the mutations located in the intracellular tyrosine kinase domain do not target cysteine codons.	('cysteine', 'Chemical', 'MESH:D003545', (219, 227))	('RET', 'Gene', '5979', (121, 124))	('inducing', 'Reg', (93, 101))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('RET', 'Gene', (121, 124))	('mutations', 'Var', (13, 22))	('cysteine', 'Chemical', 'MESH:D003545', (30, 38))
1790	24449023	These mutations, including S891A, are considered to give rise to structural changes in the protein facilitating the access of adenosine triphosphate and substrate to the catalytic site.	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (126, 148))	('S891A', 'Mutation', 'rs75234356', (27, 32))	('S891A', 'Var', (27, 32))	('access of adenosine triphosphate', 'MPA', (116, 148))
1791	24449023	The less constitutive RET kinase activation relative to mutations in the cysteine-rich extracellular domain might result in less neoplastic transforming capacity.	('RET', 'Gene', (22, 25))	('mutations', 'Var', (56, 65))	('cysteine', 'Chemical', 'MESH:D003545', (73, 81))	('activation', 'PosReg', (33, 43))	('neoplastic transforming capacity', 'CPA', (129, 161))	('RET', 'Gene', '5979', (22, 25))	('less', 'NegReg', (124, 128))
1792	24449023	The S891A mutation is classified as level 1 or level A, the lowest risk group among the three (level 1-3) or the four (level A-D) RET codon mutation stratification categories.	('S891A', 'Var', (4, 9))	('RET', 'Gene', (130, 133))	('S891A', 'Mutation', 'rs75234356', (4, 9))	('RET', 'Gene', '5979', (130, 133))
1793	24449023	The penetrance and aggressiveness of MTC arising in cases with S891A are variable, but MTC develops at a later age and grows more slowly than with the higher risk mutations.	('aggressiveness', 'Phenotype', 'HP:0000718', (19, 33))	('slowly', 'NegReg', (130, 136))	('MTC', 'Phenotype', 'HP:0002865', (87, 90))	('S891A', 'Mutation', 'rs75234356', (63, 68))	('aggressiveness', 'Disease', 'MESH:D001523', (19, 33))	('S891A', 'Var', (63, 68))	('MTC', 'Phenotype', 'HP:0002865', (37, 40))	('aggressiveness', 'Disease', (19, 33))
1795	24449023	According to the guidelines, cases with S891A mutation still need prophylactic resection, and some experts recommended thyroidectomy by the age of 5 years, while others suggest that thyroidectomy by the age of 10 years is appropriate with careful follow-up and periodic calcitonin testing.	('thyroidectomy', 'Disease', (119, 132))	('S891A mutation', 'Var', (40, 54))	('S891A', 'Mutation', 'rs75234356', (40, 45))
1801	24449023	Furthermore, this hypothesis implies that the patient with the S891A mutation carried slow-growing C-cell hyperplasia for a long period, during which time the decreased Ca2+ was compensated for by the secondary hyperparathyroidism.	('patient', 'Species', '9606', (46, 53))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (211, 230))	('hyperparathyroidism', 'Disease', (211, 230))	('C-cell hyperplasia', 'Disease', (99, 117))	('secondary hyperparathyroidism', 'Phenotype', 'HP:0000867', (201, 230))	('S891A', 'Mutation', 'rs75234356', (63, 68))	('Ca2+', 'Chemical', 'MESH:D000069285', (169, 173))	('S891A', 'Var', (63, 68))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (211, 230))	('C-cell hyperplasia', 'Disease', 'MESH:C537418', (99, 117))
1802	24449023	These data lend support to the concept that C-cell hyperplasia in the patient with S891A mutation, in spite of its slow growth speed, has a high chance of obtaining another hit for malignant transformation.	('C-cell hyperplasia', 'Disease', 'MESH:C537418', (44, 62))	('S891A mutation', 'Var', (83, 97))	('patient', 'Species', '9606', (70, 77))	('C-cell hyperplasia', 'Disease', (44, 62))	('slow growth', 'Phenotype', 'HP:0001510', (115, 126))	('S891A', 'Mutation', 'rs75234356', (83, 88))
1818	19875067	Although RF ablation is appealing as a minimally invasive targeted therapy for metastatic disease, its role in the treatment of metastatic pheochromocytoma has not been well described to date.	('ablation', 'Var', (12, 20))	('pheochromocytoma', 'Disease', (139, 155))	('pheochromocytoma', 'Disease', 'MESH:D010673', (139, 155))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (139, 155))	('RF', 'Chemical', '-', (9, 11))	('metastatic', 'Disease', (128, 138))
1924	20949656	The diagnosis of a pheochromocytoma was confirmed by concentrations of norepinephrine measuring 6109 pg/mL (reference range, 112 to 658) present in the blood with normal values of epinephrine and dopamine.	('norepinephrine', 'Chemical', 'MESH:D009638', (71, 85))	('epinephrine', 'Chemical', 'MESH:D004837', (74, 85))	('pheochromocytoma', 'Disease', (19, 35))	('pheochromocytoma', 'Disease', 'MESH:D010673', (19, 35))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (19, 35))	('6109 pg/mL', 'Var', (96, 106))	('epinephrine', 'Chemical', 'MESH:D004837', (180, 191))	('dopamine', 'Chemical', 'MESH:D004298', (196, 204))
1983	20842377	Over the past decade, systematic mutation analysis of apparently sporadic cases of pheochromocytomas and paragangliomas has elucidated the frequent presence of germ line mutations in one of five candidate genes, including RET, VHL, SDHB, SDHC, and SDHD.	('SDHD', 'Gene', (248, 252))	('RET', 'Gene', '5979', (222, 225))	('paragangliomas', 'Phenotype', 'HP:0002668', (105, 119))	('RET', 'Gene', (222, 225))	('SDHB', 'Gene', '6390', (232, 236))	('mutations', 'Var', (170, 179))	('VHL', 'Disease', (227, 230))	('SDHB', 'Gene', (232, 236))	('VHL', 'Disease', 'MESH:D006623', (227, 230))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (83, 119))	('SDHC', 'Gene', (238, 242))	('SDHD', 'Gene', '6392', (248, 252))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))	('paraganglioma', 'Phenotype', 'HP:0002668', (105, 118))	('SDHC', 'Gene', '6391', (238, 242))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))
1986	20842377	There was no staining of tumour cells with SDHB immunohistochemistry, indicative of an SDH mutation.	('mutation', 'Var', (91, 99))	('SDH', 'Gene', (43, 46))	('SDH', 'Gene', '6390', (87, 90))	('SDHB', 'Gene', '6390', (43, 47))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('SDHB', 'Gene', (43, 47))	('SDH', 'Gene', '6390', (43, 46))	('SDH', 'Gene', (87, 90))	('tumour', 'Disease', (25, 31))
1987	20842377	Mutation analysis demonstrated a germ line SDHD mutation (p.Val147Met).	('SDHD', 'Gene', '6392', (43, 47))	('p.Val147Met', 'Mutation', 'p.V147M', (58, 69))	('p.Val147Met', 'Var', (58, 69))	('SDHD', 'Gene', (43, 47))
1998	20842377	Between 12% and 24% of apparently sporadic paragangliomas have been shown over the past decade to have a hereditary basis, involving mutations in one of five different genes: the REarranged during Transfection (RET) proto-oncogene, the von Hippel-Lindau (VHL) gene, and the succinate dehydrogenase subunits B (SDHB), C (SDHC), and D (SDHD) genes,.	('RET', 'Gene', (211, 214))	('SDHB', 'Gene', '6390', (310, 314))	('SDHD', 'Gene', (334, 338))	('paragangliomas', 'Disease', (43, 57))	('SDHC', 'Gene', '6391', (320, 324))	('von Hippel-Lindau', 'Gene', (236, 253))	('SDHB', 'Gene', (310, 314))	('VHL', 'Disease', (255, 258))	('REarranged during Transfection', 'Gene', '5979', (179, 209))	('mutations', 'Var', (133, 142))	('REarranged during Transfection', 'Gene', (179, 209))	('von Hippel-Lindau', 'Gene', '7428', (236, 253))	('RET', 'Gene', '5979', (211, 214))	('SDHC', 'Gene', (320, 324))	('paragangliomas', 'Disease', 'MESH:D010235', (43, 57))	('paraganglioma', 'Phenotype', 'HP:0002668', (43, 56))	('paragangliomas', 'Phenotype', 'HP:0002668', (43, 57))	('succinate dehydrogenase subunits B', 'Gene', '6390', (274, 308))	('VHL', 'Disease', 'MESH:D006623', (255, 258))	('SDHD', 'Gene', '6392', (334, 338))	('succinate dehydrogenase subunits B', 'Gene', (274, 308))
2000	20842377	This was shown to be a useful tool in diagnosing paraganglioma patients with SDHx mutations; negative immunostaining was seen in paragangliomas with SDHx mutations, whereas paragangliomas without mutations are positive with SDHB immunohistochemistry.	('paraganglioma', 'Disease', (173, 186))	('paragangliomas', 'Phenotype', 'HP:0002668', (129, 143))	('SDHx', 'Gene', (77, 81))	('paraganglioma', 'Disease', 'MESH:D010235', (173, 186))	('paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('SDHx', 'Chemical', '-', (149, 153))	('paraganglioma', 'Disease', (129, 142))	('SDHx', 'Chemical', '-', (77, 81))	('paragangliomas', 'Disease', 'MESH:D010235', (173, 187))	('paraganglioma', 'Disease', 'MESH:D010235', (129, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (173, 186))	('paragangliomas', 'Phenotype', 'HP:0002668', (173, 187))	('paragangliomas', 'Disease', (129, 143))	('SDHB', 'Gene', '6390', (224, 228))	('paraganglioma', 'Disease', (49, 62))	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('paraganglioma', 'Disease', 'MESH:D010235', (49, 62))	('mutations', 'Var', (154, 163))	('paragangliomas', 'Disease', (173, 187))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (63, 71))	('SDHB', 'Gene', (224, 228))	('SDHx', 'Gene', (149, 153))	('paragangliomas', 'Disease', 'MESH:D010235', (129, 143))
2001	20842377	In this spermatic cord sympathetic paraganglioma, the negative immunostaining gave an important clue for the presence of an SDHx mutation, which was subsequently shown to be a previously unknown germ line SDHD mutation.	('SDHD', 'Gene', (205, 209))	('mutation', 'Var', (129, 137))	('paraganglioma', 'Disease', 'MESH:D010235', (35, 48))	('paraganglioma', 'Phenotype', 'HP:0002668', (35, 48))	('SDHx', 'Gene', (124, 128))	('SDHx', 'Chemical', '-', (124, 128))	('SDHD', 'Gene', '6392', (205, 209))	('paraganglioma', 'Disease', (35, 48))
2020	20842377	The mutation analysis that was performed by direct sequencing, on tumour tissue of this patient, showed an SDHD mutation in exon 4 (c.439 G T, p.Val147Met) (Fig.	('patient', 'Species', '9606', (88, 95))	('SDHD', 'Gene', (107, 111))	('p.Val147Met', 'Mutation', 'p.V147M', (143, 154))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('c.439 G T', 'Var', (132, 141))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('SDHD', 'Gene', '6392', (107, 111))	('p.Val147Met', 'Var', (143, 154))
2022	20842377	Because of negative immunostaining, an SDHx mutation was predicted and eventually shown to be a p.Val147Met SDHD mutation.	('SDHD', 'Gene', '6392', (108, 112))	('mutation', 'Var', (44, 52))	('SDHx', 'Chemical', '-', (39, 43))	('p.Val147Met', 'Mutation', 'p.V147M', (96, 107))	('p.Val147Met', 'Var', (96, 107))	('SDHx', 'Gene', (39, 43))	('SDHD', 'Gene', (108, 112))
2031	20842377	The finding of this mutation has important implications for further patient management, as it is known that patients with SDHD germ line mutations are at increased risk to develop further paragangliomas, either abdominal or head and neck, or even pheochromocytomas.	('abdominal', 'Disease', (211, 220))	('develop', 'PosReg', (172, 179))	('paraganglioma', 'Phenotype', 'HP:0002668', (188, 201))	('patient', 'Species', '9606', (68, 75))	('pheochromocytomas', 'Disease', 'MESH:D010673', (247, 264))	('paragangliomas', 'Phenotype', 'HP:0002668', (188, 202))	('pheochromocytomas', 'Disease', (247, 264))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (247, 263))	('mutations', 'Var', (137, 146))	('SDHD', 'Gene', (122, 126))	('SDHD', 'Gene', '6392', (122, 126))	('paragangliomas', 'Disease', 'MESH:D010235', (188, 202))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (247, 264))	('man', 'Species', '9606', (76, 79))	('men', 'Species', '9606', (82, 85))	('paragangliomas', 'Disease', (188, 202))
2074	20951316	MEN1 gene mutations have been identified in 80-90% of the MEN-1 cases.	('MEN1', 'Gene', '4221', (0, 4))	('MEN-1', 'Gene', '4221', (58, 63))	('MEN-1', 'Gene', (58, 63))	('mutations', 'Var', (10, 19))	('MEN1', 'Gene', (0, 4))
2081	20951316	Variants of MEN2 include familial MTC (FMTC), MEN2A or FMTC with Hirshsprung's disease and MEN2A with cutaneous lichen amyloidosis.	('MEN2', 'Gene', (12, 16))	('Variants', 'Var', (0, 8))	('cutaneous lichen amyloidosis', 'Phenotype', 'HP:0032346', (102, 130))	('MTC', 'Phenotype', 'HP:0002865', (56, 59))	('amyloidosis', 'Phenotype', 'HP:0011034', (119, 130))	("Hirshsprung's disease", 'Disease', 'MESH:D010300', (65, 86))	('MEN', 'Species', '9606', (46, 49))	('MEN2A', 'Gene', (91, 96))	('MEN2A', 'Gene', '5979', (91, 96))	('familial MTC', 'Disease', (25, 37))	('cutaneous lichen amyloidosis', 'Disease', (102, 130))	('MEN', 'Species', '9606', (12, 15))	('MEN', 'Species', '9606', (91, 94))	('cutaneous lichen amyloidosis', 'Disease', 'MESH:C562643', (102, 130))	('MTC', 'Phenotype', 'HP:0002865', (34, 37))	("Hirshsprung's disease", 'Phenotype', 'HP:0002251', (65, 86))	("Hirshsprung's disease", 'Disease', (65, 86))	('MEN2A', 'Gene', (46, 51))	('MEN2A', 'Gene', '5979', (46, 51))	('MTC', 'Phenotype', 'HP:0002865', (40, 43))
2089	20951316	RET activation can be caused by RET homodimerization in most MEN2A mutations or by RET kinase enzyme's catalytic site activation in MEN2B.	('MEN2A', 'Gene', (61, 66))	('RET', 'Gene', '5979', (0, 3))	('MEN2A', 'Gene', '5979', (61, 66))	('RET', 'Gene', '5979', (83, 86))	('mutations', 'Var', (67, 76))	('catalytic site activation', 'MPA', (103, 128))	('RET', 'Gene', (0, 3))	('RET', 'Gene', '5979', (32, 35))	('MEN2B', 'Gene', (132, 137))	('RET', 'Gene', (83, 86))	('MEN2B', 'Gene', '5979', (132, 137))	('homodimerization', 'MPA', (36, 52))	('activation', 'PosReg', (4, 14))	('RET', 'Gene', (32, 35))
2090	20951316	RET mutations lead to the activation of major intracellular oncogenic pathways, such as RAS/ERK, PI3K/AKT, nuclear factor kB (NFkB) and JUN kinase pathways.	('RET', 'Gene', '5979', (0, 3))	('JUN kinase pathways', 'Pathway', (136, 155))	('oncogenic pathways', 'Pathway', (60, 78))	('RET', 'Gene', (0, 3))	('activation', 'PosReg', (26, 36))	('AKT', 'Gene', '207', (102, 105))	('ERK', 'Gene', (92, 95))	('ERK', 'Gene', '2048', (92, 95))	('mutations', 'Var', (4, 13))	('AKT', 'Gene', (102, 105))
2092	20951316	The clinical behavior of MTC correlates with the type of MEN2 syndrome and with the mutated RET codon.	('MTC', 'Phenotype', 'HP:0002865', (25, 28))	('RET', 'Gene', '5979', (92, 95))	('RET', 'Gene', (92, 95))	('mutated', 'Var', (84, 91))	('MEN2 syndrome', 'Disease', (57, 70))	('MEN2 syndrome', 'Disease', 'MESH:D013577', (57, 70))
2098	20951316	Patients with specific germ-line RET mutations are stratified into specific risk groups based on reported age of onset and aggressiveness of the disease.	('aggressiveness of the disease', 'Disease', 'MESH:D001523', (123, 152))	('RET', 'Gene', (33, 36))	('aggressiveness of the disease', 'Disease', (123, 152))	('mutations', 'Var', (37, 46))	('rat', 'Species', '10116', (53, 56))	('Patients', 'Species', '9606', (0, 8))	('RET', 'Gene', '5979', (33, 36))	('aggressiveness', 'Phenotype', 'HP:0000718', (123, 137))
2101	20951316	Individuals with MEN 2A mutations (codons 611, 618, 620, and 634) are considered high risk (level II) and should have thyroidectomy performed before 5 years of age.	('MEN 2A', 'Gene', (17, 23))	('MEN 2A', 'Gene', '5979', (17, 23))	('codons 611', 'Var', (35, 45))
2102	20951316	Although RET codon 609, 768, 790, 791, 804 and 891 mutations are classified as level I or having the lowest risk among the three groups of RET mutations, the level I individuals should also undergo thyroidectomy by the age of 5 years.	('RET', 'Gene', (139, 142))	('mutations', 'Var', (51, 60))	('RET', 'Gene', '5979', (9, 12))	('thyroidectomy', 'Disease', (198, 211))	('RET', 'Gene', '5979', (139, 142))	('RET', 'Gene', (9, 12))	('undergo', 'Reg', (190, 197))
2106	20951316	Hereditary etiologies of pheochromocytoma include: MEN2A and MEN2B caused by RET mutations; von Hippel-Lindau disease caused by VHL gene mutations; mutations of the NF1 gene, responsible for neurofibromatosis; and familial paraganglioma syndromes caused by mutations in subunits B, C or D of the succinate dehydrogenase (SDH) complex (Table 3).	('MEN2B', 'Gene', '5979', (61, 66))	('mutations', 'Var', (257, 266))	('VHL', 'Gene', '7428', (128, 131))	('SDH', 'Gene', (321, 324))	('succinate dehydrogenase', 'Gene', (296, 319))	('paraganglioma', 'Phenotype', 'HP:0002668', (223, 236))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (191, 208))	('von Hippel-Lindau disease', 'Disease', (92, 117))	('mutations', 'Var', (81, 90))	('familial paraganglioma syndromes', 'Disease', (214, 246))	('NF1', 'Gene', '4763', (165, 168))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (214, 246))	('neurofibromatosis', 'Disease', 'MESH:C537392', (191, 208))	('RET', 'Gene', '5979', (77, 80))	('caused by', 'Reg', (247, 256))	('NF1', 'Gene', (165, 168))	('pheochromocytoma', 'Disease', 'MESH:D010673', (25, 41))	('mutations', 'Var', (148, 157))	('neurofibromatosis', 'Disease', (191, 208))	('succinate dehydrogenase', 'Gene', '6390', (296, 319))	('MEN2A', 'Gene', (51, 56))	('MEN2A', 'Gene', '5979', (51, 56))	('SDH', 'Gene', '6390', (321, 324))	('pheochromocytoma', 'Disease', (25, 41))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (25, 41))	('VHL', 'Gene', (128, 131))	('RET', 'Gene', (77, 80))	('caused by', 'Reg', (118, 127))	('mutations', 'Var', (137, 146))	('caused', 'Reg', (67, 73))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (92, 117))	('MEN2B', 'Gene', (61, 66))
2107	20951316	Germline mutations in the susceptibility genes for pheochromocytoma can also be found in about 25% of the non-syndromic cases.	('Germline mutations', 'Var', (0, 18))	('found', 'Reg', (80, 85))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (51, 67))	('pheochromocytoma', 'Disease', (51, 67))	('pheochromocytoma', 'Disease', 'MESH:D010673', (51, 67))
2108	20951316	Therefore, genetic screening for mutations of RET, VHL, SDHD and SDHB is indicated to identify pheochromocytoma-related syndromes in non-familial cases.	('SDHD', 'Gene', (56, 60))	('SDHD', 'Gene', '6392', (56, 60))	('VHL', 'Gene', '7428', (51, 54))	('pheochromocytoma', 'Disease', (95, 111))	('mutations', 'Var', (33, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (95, 111))	('SDHB', 'Gene', (65, 69))	('RET', 'Gene', '5979', (46, 49))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (95, 111))	('SDHB', 'Gene', '6390', (65, 69))	('VHL', 'Gene', (51, 54))	('RET', 'Gene', (46, 49))
2109	20951316	found 19% of germline mutations in 989 apparently nonsyndromic pheochromocytoma cases.	('pheochromocytoma', 'Disease', (63, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (63, 79))	('germline mutations', 'Var', (13, 31))	('pheochromocytoma', 'Disease', 'MESH:D010673', (63, 79))
2110	20951316	Predictors for presence of mutation are age < 45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (65, 81))	('extra-adrenal location', 'Disease', (83, 105))	('paraganglioma', 'Phenotype', 'HP:0002668', (134, 147))	('neck paraganglioma', 'Disease', (129, 147))	('mutation', 'Var', (27, 35))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (120, 147))	('multiple pheochromocytoma', 'Disease', 'MESH:D010673', (56, 81))	('neck paraganglioma', 'Disease', 'MESH:D010235', (129, 147))	('multiple pheochromocytoma', 'Disease', (56, 81))
2112	20951316	The diagnosis of head and neck paragangliomas is highly suggestive of SDHD mutations.	('SDHD', 'Gene', (70, 74))	('SDHD', 'Gene', '6392', (70, 74))	('neck paragangliomas', 'Disease', (26, 45))	('paragangliomas', 'Phenotype', 'HP:0002668', (31, 45))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (17, 45))	('paraganglioma', 'Phenotype', 'HP:0002668', (31, 44))	('mutations', 'Var', (75, 84))	('neck paragangliomas', 'Disease', 'MESH:D010235', (26, 45))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (17, 44))
2115	20951316	Pheochromocytoma has been found in kindreds with all RET mutations except those in codons 609, 768, 804 and 891.	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('RET', 'Gene', (53, 56))	('Pheochromocytoma', 'Disease', (0, 16))	('found', 'Reg', (26, 31))	('mutations', 'Var', (57, 66))	('RET', 'Gene', '5979', (53, 56))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))
2116	20951316	In addition, pheochromocytomas have been identified with codon 634 mutations as early as 5 and 10 years of age.	('pheochromocytomas', 'Disease', (13, 30))	('pheochromocytomas', 'Disease', 'MESH:D010673', (13, 30))	('codon 634 mutations', 'Var', (57, 76))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (13, 29))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (13, 30))
2117	20951316	VHL disease arises from de novo mutations without a family history in 20% of the cases.	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('VHL disease', 'Disease', (0, 11))	('mutations', 'Var', (32, 41))
2135	20951316	Paraganglioma syndromes are caused by mutations in the SDH genes: paraganglioma syndrome type 1 (SDHD), paraganglioma syndrome type 3 (SDHC), paraganglioma syndrome type 4 (SDHB).	('paraganglioma syndrome', 'Disease', (104, 126))	('SDH', 'Gene', '6390', (97, 100))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (66, 88))	('paraganglioma', 'Phenotype', 'HP:0002668', (142, 155))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('SDH', 'Gene', '6390', (55, 58))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (142, 164))	('SDHB', 'Gene', '6390', (173, 177))	('SDH', 'Gene', '6390', (173, 176))	('Paraganglioma syndromes', 'Disease', (0, 23))	('SDH', 'Gene', '6390', (135, 138))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (104, 126))	('SDH', 'Gene', (97, 100))	('mutations', 'Var', (38, 47))	('SDHC', 'Gene', (135, 139))	('paraganglioma syndrome type 1 (SDHD), paraganglioma syndrome', 'Disease', 'MESH:D010235', (66, 126))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('SDHC', 'Gene', '6391', (135, 139))	('Paraganglioma syndromes', 'Disease', 'MESH:D010235', (0, 23))	('SDHB', 'Gene', (173, 177))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', (173, 176))	('SDH', 'Gene', (135, 138))	('paraganglioma syndrome', 'Disease', (66, 88))	('paraganglioma', 'Phenotype', 'HP:0002668', (66, 79))	('caused by', 'Reg', (28, 37))	('paraganglioma syndrome', 'Disease', (142, 164))
2136	20951316	Hereditary head and neck paragangliomas are most exclusively caused with germline SDHB, SDHC and SDHD mutations.	('neck paragangliomas', 'Disease', 'MESH:D010235', (20, 39))	('SDHD', 'Gene', (97, 101))	('SDHB', 'Gene', '6390', (82, 86))	('paragangliomas', 'Phenotype', 'HP:0002668', (25, 39))	('paraganglioma', 'Phenotype', 'HP:0002668', (25, 38))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (11, 39))	('SDHB', 'Gene', (82, 86))	('mutations', 'Var', (102, 111))	('neck paragangliomas', 'Disease', (20, 39))	('caused', 'Reg', (61, 67))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (11, 38))	('SDHC', 'Gene', (88, 92))	('SDHD', 'Gene', '6392', (97, 101))	('SDHC', 'Gene', '6391', (88, 92))
2138	20951316	Germline SDHC mutations are a very rare cause of pheochromocytomas.	('cause', 'Reg', (40, 45))	('pheochromocytomas', 'Disease', 'MESH:D010673', (49, 66))	('pheochromocytomas', 'Disease', (49, 66))	('SDHC', 'Gene', (9, 13))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (49, 66))	('mutations', 'Var', (14, 23))	('SDHC', 'Gene', '6391', (9, 13))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (49, 65))
2139	20951316	Mutations of the SDHB gene are more frequently associated with malignant disease.	('malignant disease', 'Disease', 'MESH:D009369', (63, 80))	('SDHB', 'Gene', '6390', (17, 21))	('malignant disease', 'Disease', (63, 80))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (17, 21))	('associated', 'Reg', (47, 57))
2140	20951316	Recently, germline SDHB, SDHC and SDHD mutations were identified in patients with both gastrointestinal stromal tumors and paragangliomas.	('SDHC', 'Gene', '6391', (25, 29))	('SDHD', 'Gene', (34, 38))	('paragangliomas', 'Disease', (123, 137))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (68, 76))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (87, 117))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (87, 118))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (87, 118))	('SDHB', 'Gene', '6390', (19, 23))	('SDHC', 'Gene', (25, 29))	('identified', 'Reg', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('paragangliomas', 'Disease', 'MESH:D010235', (123, 137))	('paraganglioma', 'Phenotype', 'HP:0002668', (123, 136))	('gastrointestinal stromal tumors', 'Disease', (87, 118))	('paragangliomas', 'Phenotype', 'HP:0002668', (123, 137))	('SDHB', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SDHD', 'Gene', '6392', (34, 38))
2142	20951316	Germline SDHB, SDHC, and SDHD mutations were associated with familial gastrointestinal stromal tumors, but abdominal paragangliomas associated with gastrointestinal tumors were exclusively caused by SDHC mutations.	('SDHB', 'Gene', (9, 13))	('SDHC', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('SDHD', 'Gene', (25, 29))	('abdominal paragangliomas', 'Disease', 'MESH:D010235', (107, 131))	('abdominal paragangliomas', 'Disease', (107, 131))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (117, 131))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (70, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (117, 130))	('SDHC', 'Gene', '6391', (199, 203))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (148, 171))	('SDHC', 'Gene', '6391', (15, 19))	('familial gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (61, 101))	('mutations', 'Var', (204, 213))	('associated', 'Reg', (45, 55))	('mutations', 'Var', (30, 39))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (70, 100))	('SDHB', 'Gene', '6390', (9, 13))	('caused', 'Reg', (189, 195))	('SDHC', 'Gene', (199, 203))	('familial gastrointestinal stromal tumors', 'Disease', (61, 101))	('SDHD', 'Gene', '6392', (25, 29))	('gastrointestinal tumors', 'Disease', (148, 171))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (148, 171))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
2158	20951316	Inactivating mutations of the PRKAR1A gene coding for the regulatory type I-alpha (RIalpha) subunit of protein kinase A (PKA) are responsible for the disease in most CNC patients.	('patients', 'Species', '9606', (170, 178))	('PRKAR1A', 'Gene', (30, 37))	('responsible', 'Reg', (130, 141))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', '5573', (30, 37))	('CNC', 'Disease', (166, 169))
2159	20951316	The overall penetrance of CNC among PRKAR1A mutation carriers is near 98%.	('PRKAR1A', 'Gene', (36, 43))	('mutation', 'Var', (44, 52))	('CNC', 'Disease', (26, 29))	('PRKAR1A', 'Gene', '5573', (36, 43))
2160	20951316	Most PRKAR1A mutations result in premature stop codon generation and lead to nonsense-mediated mRNA decay.	('PRKAR1A', 'Gene', (5, 12))	('premature stop codon generation', 'MPA', (33, 64))	('result in', 'Reg', (23, 32))	('PRKAR1A', 'Gene', '5573', (5, 12))	('lead to', 'Reg', (69, 76))	('rat', 'Species', '10116', (58, 61))	('nonsense-mediated mRNA decay', 'MPA', (77, 105))	('mutations', 'Var', (13, 22))
2161	20951316	Phosphodiesterase-11A (the PDE11A gene) and -8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD.	('found', 'Reg', (80, 85))	('PPNAD', 'Disease', (179, 184))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (136, 152))	('Phosphodiesterase-11A', 'Gene', (0, 21))	('PDE11A gene) and -8B', 'Gene', '8622', (27, 47))	('isolated adrenal hyperplasia', 'Disease', 'MESH:C537027', (103, 131))	('PPNAD', 'Chemical', '-', (179, 184))	('Cushing syndrome', 'Disease', (136, 152))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (165, 173))	('PDE8B', 'Gene', '8622', (53, 58))	('isolated adrenal hyperplasia', 'Disease', (103, 131))	('Phosphodiesterase-11A', 'Gene', '50940', (0, 21))	('PDE8B', 'Gene', (53, 58))	('Cushing syndrome', 'Disease', 'MESH:D003480', (136, 152))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (112, 131))	('mutations', 'Var', (65, 74))
2165	20951316	VHL, RET, SDHD and SDHB mutations should also be screened in non-familial cases of pheochromocytomas and paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (105, 119))	('SDHB', 'Gene', '6390', (19, 23))	('RET', 'Gene', (5, 8))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (83, 119))	('SDHB', 'Gene', (19, 23))	('VHL', 'Gene', (0, 3))	('RET', 'Gene', '5979', (5, 8))	('SDHD', 'Gene', (10, 14))	('SDHD', 'Gene', '6392', (10, 14))	('screened', 'Reg', (49, 57))	('mutations', 'Var', (24, 33))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))	('paraganglioma', 'Phenotype', 'HP:0002668', (105, 118))	('VHL', 'Gene', '7428', (0, 3))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))
2194	33677926	Genomic instability such as DNA hypomethylation and chromosomal instability was associated with POU1F1/PIT1 lineage differentiation.	('PIT1', 'Gene', (103, 107))	('DNA hypomethylation', 'Var', (28, 47))	('chromosomal', 'CPA', (52, 63))	('PIT1', 'Gene', '5449', (103, 107))	('chromosomal instability', 'Phenotype', 'HP:0040012', (52, 75))	('POU1F1', 'Gene', '5449', (96, 102))	('associated', 'Reg', (80, 90))	('POU1F1', 'Gene', (96, 102))
2198	33677926	A somatic hotspot mutation in splicing factor 3 subunit B1 (SFB1R625H) was discovered by whole-genome sequencing in 21 patients with prolactinoma and validated by digital polymerase chain reaction in 227 prolactinomas.	('prolactinomas', 'Disease', (204, 217))	('prolactinoma', 'Disease', (204, 216))	('prolactinoma', 'Phenotype', 'HP:0040278', (204, 216))	('prolactinoma', 'Disease', (133, 145))	('patients', 'Species', '9606', (119, 127))	('prolactinoma', 'Disease', 'MESH:D015175', (204, 216))	('prolactinoma', 'Disease', 'MESH:D015175', (133, 145))	('prolactinoma', 'Phenotype', 'HP:0040278', (133, 145))	('prolactinomas', 'Disease', 'MESH:D015175', (204, 217))	('hotspot', 'PosReg', (10, 17))	('mutation', 'Var', (18, 26))	('SFB1R625H', 'Gene', (60, 69))
2363	32824391	Eleven patients were included in this trial, four (36%) with germline mutations and seven (64%) with hormonally active tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('germline mutations', 'Var', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('patients', 'Species', '9606', (7, 15))
2394	32824391	These mutations predispose patients to tumor pseudohypoxia, abnormal tumor cell replication, and tumor necrosis and angiogenesis and may prevent immune system recognition.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('abnormal tumor', 'Disease', 'MESH:D009369', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('prevent', 'NegReg', (137, 144))	('abnormal tumor', 'Phenotype', 'HP:0002664', (60, 74))	('angiogenesis', 'CPA', (116, 128))	('predispose', 'Reg', (16, 26))	('tumor pseudohypoxia', 'Disease', (39, 58))	('patients', 'Species', '9606', (27, 35))	('tumor necrosis', 'Disease', 'MESH:D009336', (97, 111))	('tumor pseudohypoxia', 'Disease', 'MESH:D009369', (39, 58))	('abnormal tumor', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor necrosis', 'Disease', (97, 111))	('mutations', 'Var', (6, 15))
2396	32824391	Deregulation of cellular energetics is a universal hallmark of cancer that interferes with T cell effector function, causes immune suppression and tolerance, impairs tumor infiltration by T cells, and induces resistance to cytotoxic T cells.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('immune suppression', 'CPA', (124, 142))	('impairs tumor', 'Disease', (158, 171))	('cellular energetics', 'MPA', (16, 35))	('resistance to cytotoxic T cells', 'CPA', (209, 240))	('T cell effector function', 'CPA', (91, 115))	('causes', 'Reg', (117, 123))	('tolerance', 'CPA', (147, 156))	('interferes', 'NegReg', (75, 85))	('induces', 'Reg', (201, 208))	('cancer', 'Disease', (63, 69))	('impairs tumor', 'Disease', 'MESH:D060825', (158, 171))
2412	32824391	Although the expression of PDL-1 in patients with non-small cell lung cancer is typically associated with a positive immunological response, this association is not clear in patients with other cancers.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('patients', 'Species', '9606', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PDL-1', 'Gene', '29126', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('lung cancer', 'Disease', (65, 76))	('associated', 'Reg', (90, 100))	('expression', 'Var', (13, 23))	('cancers', 'Disease', (194, 201))	('patients', 'Species', '9606', (174, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PDL-1', 'Gene', (27, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))
2453	32824391	Four patients (36%) had a germline mutation; two had paraganglioma syndrome type 4 (SDHB), one had a paraganglioma syndrome type 1 (SDHD), and one had Lynch syndrome (PMS2).	('PMS2', 'Gene', '5395', (167, 171))	('paraganglioma syndrome', 'Disease', (101, 123))	('Lynch syndrome', 'Disease', (151, 165))	('SDHD', 'Gene', (132, 136))	('patients', 'Species', '9606', (5, 13))	('SDHB', 'Gene', '6390', (84, 88))	('Lynch syndrome', 'Disease', 'MESH:D003123', (151, 165))	('paraganglioma syndrome', 'Disease', (53, 75))	('germline mutation', 'Var', (26, 43))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (101, 123))	('SDHB', 'Gene', (84, 88))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (53, 75))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('SDHD', 'Gene', '6392', (132, 136))	('PMS2', 'Gene', (167, 171))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))
2480	32824391	One patient with a metastatic head and neck paraganglioma that was associated with a germline SDHD mutation experienced SD for 24 months; during the last month of therapy with pembrolizumab, the patient developed a pathologic fracture of the spine that was related to tumor progression.	('paraganglioma', 'Phenotype', 'HP:0002668', (44, 57))	('SDHD', 'Gene', (94, 98))	('developed', 'PosReg', (203, 212))	('neck paraganglioma', 'Disease', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('pembrolizumab', 'Chemical', 'MESH:C582435', (176, 189))	('neck paraganglioma', 'Disease', 'MESH:D010235', (39, 57))	('patient', 'Species', '9606', (195, 202))	('tumor', 'Disease', (268, 273))	('patient', 'Species', '9606', (4, 11))	('pathologic fracture', 'Phenotype', 'HP:0002756', (215, 234))	('mutation', 'Var', (99, 107))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (30, 57))	('associated', 'Reg', (67, 77))	('SDHD', 'Gene', '6392', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
2518	32824391	The second patient carried an SDHB germline mutation and was treated with antibiotics for severe hand and foot syndrome that was complicated by an infection with Pseudomona aeruginosa.	('infection', 'Disease', (147, 156))	('foot syndrome', 'Disease', 'MESH:D005534', (106, 119))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('germline', 'Var', (35, 43))	('patient', 'Species', '9606', (11, 18))	('SDHB', 'Gene', '6390', (30, 34))	('SDHB', 'Gene', (30, 34))	('foot syndrome', 'Disease', (106, 119))
2529	32824391	MPPGs are associated with the highest rate of single germline mutations of any oncological disease; however, they have some of the lowest rates of somatic mutations among malignancies.	('malignancies', 'Disease', 'MESH:D009369', (171, 183))	('MPPGs', 'Chemical', '-', (0, 5))	('malignancies', 'Disease', (171, 183))	('single germline mutations', 'Var', (46, 71))	('MPPGs', 'Gene', (0, 5))	('oncological disease', 'Phenotype', 'HP:0002664', (79, 98))
2533	32824391	Previous analyses may have been performed in non-metastatic tumors; nevertheless, the presence of TILs does not seem to be predictive of the primary tumor's metastatic potential or response to pembrolizumab.	('presence', 'Var', (86, 94))	('primary tumor', 'Disease', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('pembrolizumab', 'Chemical', 'MESH:C582435', (193, 206))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('metastatic potential', 'CPA', (157, 177))	('primary tumor', 'Disease', 'MESH:D001932', (141, 154))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (60, 66))
2684	31196171	Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma Laryngeal squamous cell carcinoma (LSCC) is among the most common malignant tumors with poor prognosis.	('progression', 'CPA', (74, 85))	('malignant tumors', 'Disease', 'MESH:D018198', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 137))	('Aberrant methylation-mediated', 'Var', (0, 29))	('Laryngeal squamous cell carcinoma', 'Disease', (138, 171))	('malignant tumors', 'Disease', (204, 220))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', (90, 137))	('downregulation', 'NegReg', (30, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma Laryngeal squamous cell carcinoma', 'Phenotype', 'HP:0012118', (128, 171))	('SSTR5-AS1', 'Gene', (55, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('promotes', 'PosReg', (65, 73))	('methylation-mediated', 'Var', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('Laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 171))	('SSTR5-AS1', 'Gene', '146336;6755;5729', (55, 64))
2713	31196171	There are two transcripts of SSTR5, and the main transcript (NM_001053) is located at chr16: 1078781-1081454 (GRCh38/hg38).	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hg38', 'Gene', (117, 121))	('hg38', 'Gene', '8549', (117, 121))	('NM_001053', 'Var', (61, 70))
2732	31196171	3b, c, the expression levels of SSTR5 and SSTR5-AS1 were significantly increased in the 5-Aza-dC-, TSA-, 5-Aza-dC/TSA-treated laryngeal carcinoma cells, and the effect was more apparent in the 5-Aza-dC/TSA-treated cells, indicating that the expression of SSTR5 and SSTR5-AS1 might be co-regulated by DNA methylation and histone modification.	('SSTR5', 'Gene', (255, 260))	('SSTR5', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SSTR5', 'Gene', '6755', (255, 260))	('5-Aza-dC-', 'Var', (88, 97))	('TSA', 'Chemical', 'MESH:C012589', (99, 102))	('SSTR5', 'Gene', '6755', (32, 37))	('TSA', 'Chemical', 'MESH:C012589', (202, 205))	('laryngeal carcinoma', 'Disease', (126, 145))	('5-Aza-dC/TSA-treated', 'Var', (105, 125))	('TSA', 'Chemical', 'MESH:C012589', (114, 117))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (193, 201))	('TSA-', 'Var', (99, 103))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (105, 113))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (126, 145))	('SSTR5', 'Gene', (42, 47))	('SSTR5', 'Gene', (265, 270))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (88, 96))	('expression levels', 'MPA', (11, 28))	('SSTR5', 'Gene', '6755', (42, 47))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (126, 145))	('increased', 'PosReg', (71, 80))	('SSTR5', 'Gene', '6755', (265, 270))
2734	31196171	3d, frequent CpG sites methylation was observed in the exon 1 region of SSTR5, while frequent methylated CpG sites were located in the promoter region of SSTR5-AS1 (Fig.	('methylation', 'Var', (23, 34))	('SSTR5', 'Gene', '6755', (154, 159))	('SSTR5', 'Gene', (154, 159))	('SSTR5', 'Gene', '6755', (72, 77))	('SSTR5', 'Gene', (72, 77))
2741	31196171	The methylation status of promoter region of SSTR5 in LSCC tissues was not associated with any clinicopathologic characteristics, while the methylation status of exon 1 in LSCC tissues was associated with TNM stage and lymph node metastasis (P < 0.05) (Table 1).	('methylation', 'Var', (140, 151))	('TNM stage', 'CPA', (205, 214))	('associated', 'Reg', (189, 199))	('SSTR5', 'Gene', '6755', (45, 50))	('lymph node metastasis', 'CPA', (219, 240))	('SSTR5', 'Gene', (45, 50))
2742	31196171	The mRNA expression level of SSTR5 in LSCC tissues with hypermethylation of exon 1 was significantly decreased than that with unmethylation of this region (P < 0.05); however, the expression level of SSTR5 was not associated with methylation status of promoter region (P > 0.05) (Fig.	('SSTR5', 'Gene', (200, 205))	('mRNA expression level', 'MPA', (4, 25))	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hypermethylation', 'Var', (56, 72))	('decreased', 'NegReg', (101, 110))	('SSTR5', 'Gene', '6755', (200, 205))
2744	31196171	To determine the potential role of histone modifications on SSTR5 downregulation, the presence of active (H3K4me3, H3K9ac) and inactive (H3K9me2) histone modifications at SSTR5 promoter was further examined by chromatin immunoprecipitation assay in AMC-HN-8 cells (Fig.	('SSTR5', 'Gene', '6755', (171, 176))	('SSTR5', 'Gene', '6755', (60, 65))	('H3K4me3', 'Var', (106, 113))	('SSTR5', 'Gene', (171, 176))	('SSTR5', 'Gene', (60, 65))	('H3K9ac', 'Var', (115, 121))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (249, 257))
2746	31196171	Increased enrichment of H3K4me3 and decreased enrichment of H3K9me2 were detected in 5-Aza-dC-treated AMC-HN-8 cells, and significant increased enrichment of H3K9ac was detected in TSA-treated AMC-HN-8 cells, indicating that in addition to DNA methylation, histone modification is also involved in the regulation of SSTR5 expression.	('SSTR5', 'Gene', (316, 321))	('TSA', 'Chemical', 'MESH:C012589', (181, 184))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (102, 110))	('5-Aza-dC-treated', 'Var', (85, 101))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (85, 93))	('H3K4me3', 'Var', (24, 31))	('involved', 'Reg', (286, 294))	('enrichment', 'MPA', (10, 20))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (193, 201))	('enrichment', 'MPA', (46, 56))	('SSTR5', 'Gene', '6755', (316, 321))	('decreased', 'NegReg', (36, 45))
2774	31196171	Promoter CpG sites hypermethylation of E-cadherin is a recognized mechanism of its inactivation in numerous cancers.	('numerous cancers', 'Disease', 'MESH:D009369', (99, 115))	('inactivation', 'NegReg', (83, 95))	('E-cadherin', 'Gene', '999', (39, 49))	('E-cadherin', 'Gene', (39, 49))	('numerous cancers', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (19, 35))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
2778	31196171	The hMeDIP-qPCR assay was used to track the 5hmC change in the CpG-rich regions of E-cadherin promoters, and co-expression of SSTR5-AS1 and TET1 in AMC-HN-8 cells significantly increased 5hmC levels at the promoter regions of E-cadherin (Fig.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('TET1', 'Gene', '80312', (140, 144))	('SSTR5-AS1', 'Var', (126, 135))	('5hmC', 'Chemical', '-', (187, 191))	('increased', 'PosReg', (177, 186))	('5hmC levels', 'MPA', (187, 198))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (148, 156))	('E-cadherin', 'Gene', (226, 236))	('5hmC', 'Chemical', '-', (44, 48))	('E-cadherin', 'Gene', '999', (226, 236))	('TET1', 'Gene', (140, 144))
2790	31196171	AChE-AS represses AChE expression via epigenetic modification of the AChE promoter region and demonstrates an anti-apoptotic effect in hepatocellular carcinoma cells.	('AChE', 'Gene', '43', (0, 4))	('AChE', 'Gene', (18, 22))	('AChE', 'Gene', '43', (18, 22))	('AChE', 'Gene', '43', (69, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', (135, 159))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('represses', 'NegReg', (8, 17))	('epigenetic', 'Var', (38, 48))	('AChE', 'Gene', (0, 4))	('anti-apoptotic effect', 'CPA', (110, 131))	('AChE', 'Gene', (69, 73))
2792	31196171	Moreover, by genomic sequence analysis, obvious CpG islands were found in the promoter and exon 1 regions of SSTR5 and SSTR5-AS1, indicating the possible epigenetic regulation mechanisms on their expression regulation.	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', (109, 114))	('SSTR5', 'Gene', '6755', (119, 124))	('CpG', 'Var', (48, 51))	('SSTR5', 'Gene', (119, 124))
2796	31196171	In the present study, we verified the tumor suppressor role of SSTR5 and SSTR5-AS1 in LSCC progression; DNA hypermethylation and histone modification may co-regulate the expression of SSTR5 and SSTR5-AS1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SSTR5', 'Gene', '6755', (184, 189))	('SSTR5', 'Gene', '6755', (73, 78))	('SSTR5', 'Gene', (184, 189))	('SSTR5', 'Gene', (73, 78))	('SSTR5', 'Gene', '6755', (194, 199))	('SSTR5', 'Gene', (194, 199))	('SSTR5', 'Gene', '6755', (63, 68))	('co-regulate', 'Reg', (154, 165))	('DNA hypermethylation', 'Var', (104, 124))	('histone modification', 'Var', (129, 149))	('LSCC', 'Disease', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SSTR5', 'Gene', (63, 68))	('expression', 'MPA', (170, 180))
2809	31196171	In the process of laryngeal squamous cell carcinogenesis, when CpG sites hypermethylation occurs in the promoter region of E-cadherin, SSTR5-AS1 may also act as a tumor suppressor gene to upregulate the expression of E-cadherin by recruiting TET1 to E-cadherin to hydrolyze 5'-mc to 5'-hmc, thus inhibiting the occurrence of EMT.	('hypermethylation', 'Var', (73, 89))	('laryngeal squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (18, 56))	('TET1', 'Gene', (242, 246))	('tumor', 'Disease', (163, 168))	('laryngeal squamous cell carcinogenesis', 'Disease', (18, 56))	("hydrolyze 5'-mc to 5'-hmc", 'MPA', (264, 289))	('SSTR5-AS1', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('E-cadherin', 'Gene', (250, 260))	('E-cadherin', 'Gene', '999', (250, 260))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('inhibiting', 'NegReg', (296, 306))	('upregulate', 'PosReg', (188, 198))	('E-cadherin', 'Gene', (217, 227))	('E-cadherin', 'Gene', '999', (217, 227))	("5'-mc", 'Chemical', 'MESH:D044503', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TET1', 'Gene', '80312', (242, 246))	('recruiting', 'PosReg', (231, 241))	('expression', 'MPA', (203, 213))	("5'-hmc", 'Chemical', 'MESH:C011865', (283, 289))
2810	31196171	SSTR5 may act as a tumor suppressor gene in LSCC, and aberrant DNA hypermethylation of the CpG sites clustered in the exon 1 and histone modification on its promoter region may be epigenetic mechanisms for its inactivation.	('LSCC', 'Disease', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CpG', 'Gene', (91, 94))	('SSTR5', 'Gene', '6755', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('SSTR5', 'Gene', (0, 5))	('histone modification', 'Var', (129, 149))	('aberrant', 'Var', (54, 62))
2811	31196171	SSTR5-AS1 may play anti-tumor role in LSCC and may be regulated by hypermethylation of the same CpG sites with SSTR5.	('SSTR5', 'Gene', '6755', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SSTR5', 'Gene', (111, 116))	('tumor', 'Disease', (24, 29))	('LSCC', 'Disease', (38, 42))	('SSTR5', 'Gene', '6755', (0, 5))	('hypermethylation', 'Var', (67, 83))	('SSTR5', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
2848	31196171	Antibodies against H3K4me3, H3K9ac, H3K9me2, MLL3, and TET1 (Upstate, Millipore, MA, USA) were used for immunoprecipitation.	('H3K9me2', 'Var', (36, 43))	('TET1', 'Gene', (55, 59))	('H3K4me3', 'Var', (19, 26))	('H3K9ac', 'Var', (28, 34))	('MLL3', 'Gene', (45, 49))	('TET1', 'Gene', '80312', (55, 59))	('MLL3', 'Gene', '58508', (45, 49))
2866	26739108	In the present study, we show that ERK5, but not ERK1/2 regulates TH levels in rat sympathetic neurons.	('ERK1/2', 'Gene', '50689;116590', (49, 55))	('ERK1/2', 'Gene', (49, 55))	('ERK5', 'Var', (35, 39))	('regulates', 'Reg', (56, 65))	('TH', 'Gene', '25085', (66, 68))	('rat', 'Species', '10116', (79, 82))
2870	26739108	TH levels were reduced by ankrd1 knockdown with no changes in the mRNA levels, suggesting that ankrd1 was involved in stabilization of TH protein.	('ankrd1', 'Gene', (26, 32))	('TH', 'Gene', '25085', (135, 137))	('knockdown', 'Var', (33, 42))	('reduced', 'NegReg', (15, 22))	('TH', 'Gene', '25085', (0, 2))
2871	26739108	Interestingly, ubiquitination of TH was enhanced and catecholamine biosynthesis was reduced by ankrd1 knockdown.	('catecholamine biosynthesis', 'MPA', (53, 79))	('TH', 'Gene', '25085', (33, 35))	('ankrd1', 'Gene', (95, 101))	('knockdown', 'Var', (102, 111))	('reduced', 'NegReg', (84, 91))	('catecholamine', 'Chemical', 'MESH:D002395', (53, 66))	('ubiquitination', 'MPA', (15, 29))	('enhanced', 'PosReg', (40, 48))
2881	26739108	The ERK5 gene knockout is lethal at E9.5-10.5 due to cardiovascular defects.	('cardiovascular defects', 'Disease', 'MESH:D002318', (53, 75))	('ERK5', 'Gene', (4, 8))	('knockout', 'Var', (14, 22))	('cardiovascular defects', 'Disease', (53, 75))	('cardiovascular defects', 'Phenotype', 'HP:0001626', (53, 75))
2915	26739108	A day after being plated, explants were photographed and incubated with or without U0126 and BIX02189, and then photographed again 6 h later.	('BIX02189', 'Var', (93, 101))	('U0126', 'Var', (83, 88))	('U0126', 'Chemical', 'MESH:C113580', (83, 88))	('BIX02189', 'Chemical', 'MESH:C533207', (93, 101))
2919	26739108	Among them, genes whose expression was inhibited by more than 50% by U0126 and BIX02189 were defined as ERK1/2-dependent genes and ERK5-dependent genes, respectively.	('inhibited', 'NegReg', (39, 48))	('U0126', 'Chemical', 'MESH:C113580', (69, 74))	('expression', 'MPA', (24, 34))	('BIX02189', 'Var', (79, 87))	('ERK1/2', 'Gene', (104, 110))	('ERK1/2', 'Gene', '50689;116590', (104, 110))	('BIX02189', 'Chemical', 'MESH:C533207', (79, 87))	('U0126', 'Var', (69, 74))
2971	26739108	Cellular accumulation of ERK5 and ankrd1 was defined as positive cytoplasmic staining of more than 50% of tumor and adrenal medullary cells despite their staining intensity.	('ankrd1', 'Gene', (34, 40))	('ERK5', 'Var', (25, 29))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
2972	26739108	Previously, we have shown that NGF promotes both ERK5 and ERK1/2 phosphorylation in PC12 cells and ERK5 is responsible for neurite outgrowth and TH expression along with ERK1/2.	('ERK5', 'Var', (99, 103))	('TH', 'Gene', '25085', (145, 147))	('neurite outgrowth', 'CPA', (123, 140))	('promotes', 'PosReg', (35, 43))	('phosphorylation', 'MPA', (65, 80))	('ERK1/2', 'Gene', (170, 176))	('ERK1/2', 'Gene', '50689;116590', (58, 64))	('ERK1/2', 'Gene', '50689;116590', (170, 176))	('NGF', 'Gene', (31, 34))	('ERK5', 'Protein', (49, 53))	('ERK1/2', 'Gene', (58, 64))	('PC12 cells', 'CellLine', 'CVCL:0481', (84, 94))
2973	26739108	In that study, the role of ERK5 was examined using dominant-negative mutants of ERK5 or MEK5, or novel pharmacological inhibitors, BIX02188 or BIX02189.	('ERK5', 'Gene', (80, 84))	('BIX02189', 'Var', (143, 151))	('MEK5', 'Gene', '29568', (88, 92))	('mutants', 'Var', (69, 76))	('BIX02189', 'Chemical', 'MESH:C533207', (143, 151))	('MEK5', 'Gene', (88, 92))	('BIX02188', 'Var', (131, 139))	('BIX02188', 'Chemical', 'MESH:C533206', (131, 139))
2977	26739108	When these cells were cultured in the presence or absence of NGF (100 ng/ml) for a day, TH levels were selectively abolished by ERK5 knockdown in both basal and NGF-stimulated states, whereas other neuronal marker/cytoskeletal protein levels including neurofilament light chain, beta-tubulin, beta-actin and GAPDH were not affected at all by ERK5 knockdown (Fig.	('knockdown', 'Var', (347, 356))	('beta-actin', 'Gene', (293, 303))	('ERK5', 'Gene', (342, 346))	('beta-actin', 'Gene', '81822', (293, 303))	('abolished', 'NegReg', (115, 124))	('knockdown', 'Var', (133, 142))	('TH', 'Gene', '25085', (88, 90))	('ERK5', 'Gene', (128, 132))
2979	26739108	The loss of TH by ERK5 shRNA was greater than that by the biochemical interfering mutants and pharmacological inhibitors as observed in a previous study, suggesting that constitutive ERK5 knockdown can cause a more dramatic effect.	('knockdown', 'Var', (188, 197))	('ERK5', 'Gene', (18, 22))	('loss', 'NegReg', (4, 8))	('TH', 'Gene', '25085', (12, 14))
2984	26739108	NGF alone (2 ng/ml) promoted axon elongation at approximately 30 mum/h, and BIX02189 completely blocked axon elongation whereas U0126 did not in our condition (Figs.	('axon elongation', 'CPA', (29, 44))	('promoted', 'PosReg', (20, 28))	('blocked', 'NegReg', (96, 103))	('U0126', 'Chemical', 'MESH:C113580', (128, 133))	('BIX02189', 'Chemical', 'MESH:C533207', (76, 84))	('BIX02189', 'Var', (76, 84))	('axon elongation', 'CPA', (104, 119))
2986	26739108	Four days after ERK5 shRNA was transfected into the sympathetic neurons, TH levels were reduced significantly (Fig.	('TH', 'Gene', '25085', (73, 75))	('reduced', 'NegReg', (88, 95))	('transfected', 'Var', (31, 42))
2987	26739108	There was no change in TH levels in neurons incubated with U0126 (20 muM) for 1 or 3 days, although phosphorylation of ERK1/2 was inhibited (Fig.	('U0126', 'Chemical', 'MESH:C113580', (59, 64))	('inhibited', 'NegReg', (130, 139))	('phosphorylation', 'MPA', (100, 115))	('ERK1/2', 'Gene', '50689;116590', (119, 125))	('U0126', 'Var', (59, 64))	('TH', 'Gene', '25085', (23, 25))	('ERK1/2', 'Gene', (119, 125))
2991	26739108	Expression of 232 NGF-stimulated genes (62.0%) was attenuated by both U0126 and BIX02189 (i.e.	('U0126', 'Chemical', 'MESH:C113580', (70, 75))	('Expression', 'MPA', (0, 10))	('attenuated', 'NegReg', (51, 61))	('U0126', 'Var', (70, 75))	('BIX02189', 'Chemical', 'MESH:C533207', (80, 88))	('BIX02189', 'Var', (80, 88))
2992	26739108	ERK1/2 and ERK5-dependent genes), expression of 49 genes (13.1%) genes was inhibited by U0126 only (i.e.	('ERK5-dependent', 'Gene', (11, 25))	('expression', 'MPA', (34, 44))	('U0126', 'Var', (88, 93))	('ERK1/2', 'Gene', (0, 6))	('ERK1/2', 'Gene', '50689;116590', (0, 6))	('inhibited', 'NegReg', (75, 84))	('U0126', 'Chemical', 'MESH:C113580', (88, 93))
2993	26739108	ERK1/2-dependent genes), and induction of 46 genes (12.3%) was blocked by BIX02189 only (i.e.	('BIX02189', 'Var', (74, 82))	('BIX02189', 'Chemical', 'MESH:C533207', (74, 82))	('ERK1/2', 'Gene', '50689;116590', (0, 6))	('ERK1/2', 'Gene', (0, 6))
2994	26739108	We also checked the selectivity of BIX02189 and U0126 at the same time when the samples for microarray were prepared.	('U0126', 'Chemical', 'MESH:C113580', (48, 53))	('BIX02189', 'Var', (35, 43))	('BIX02189', 'Chemical', 'MESH:C533207', (35, 43))	('U0126', 'Var', (48, 53))	('checked', 'Reg', (8, 15))
3007	26739108	NGF induction of TH mRNA was blocked significantly by BIX02189, but U0126 also showed tendency to inhibit the expression although it was not significant in our condition.	('U0126', 'Chemical', 'MESH:C113580', (68, 73))	('U0126', 'Var', (68, 73))	('inhibit', 'NegReg', (98, 105))	('TH', 'Gene', '25085', (17, 19))	('BIX02189', 'Chemical', 'MESH:C533207', (54, 62))	('BIX02189', 'Var', (54, 62))
3018	26739108	In this condition, ankrd1 siRNA decreased basal TH levels (by 30.3%) and NGF (100 ng/ml, a day)-stimulated TH (decreased by 61.7%).	('TH', 'Gene', '25085', (48, 50))	('decreased', 'NegReg', (32, 41))	('TH', 'Gene', '25085', (107, 109))	('ankrd1', 'Var', (19, 25))
3034	26739108	Furthermore, ankrd1 knockdown did not decrease TH protein levels when proteasome activity was blocked by MG132 (Fig.	('knockdown', 'Var', (20, 29))	('ankrd1', 'Gene', (13, 19))	('MG132', 'Chemical', 'MESH:C072553', (105, 110))	('TH', 'Gene', '25085', (47, 49))
3037	26739108	NGF stimulated catecholamine biosynthesis in PC12 cells, and ERK5 knockdown decreased catecholamine biosynthesis (Fig.	('catecholamine', 'Chemical', 'MESH:D002395', (86, 99))	('decreased', 'NegReg', (76, 85))	('ERK5', 'Gene', (61, 65))	('catecholamine', 'Chemical', 'MESH:D002395', (15, 28))	('catecholamine biosynthesis', 'MPA', (86, 112))	('PC12 cells', 'CellLine', 'CVCL:0481', (45, 55))	('knockdown', 'Var', (66, 75))	('catecholamine biosynthesis', 'MPA', (15, 41))
3039	26739108	Furthermore, ankrd1 knockdown with siRNA prevented the NGF (100 ng/ml)-induced increase in catecholamine levels (Fig.	('increase', 'PosReg', (79, 87))	('ankrd1', 'Gene', (13, 19))	('prevented', 'NegReg', (41, 50))	('knockdown', 'Var', (20, 29))	('catecholamine levels', 'MPA', (91, 111))	('catecholamine', 'Chemical', 'MESH:D002395', (91, 104))
3041	26739108	NGF stimulated dopamine biosynthesis compared with drug-free control, and ankrd1 knockdown prevented the NGF-induced increase in dopamine compared to control siRNA with NGF.	('ankrd1', 'Gene', (74, 80))	('prevented', 'NegReg', (91, 100))	('dopamine', 'MPA', (129, 137))	('knockdown', 'Var', (81, 90))	('dopamine', 'Chemical', 'MESH:D004298', (15, 23))	('dopamine biosynthesis', 'MPA', (15, 36))	('dopamine', 'Chemical', 'MESH:D004298', (129, 137))
3042	26739108	For norepinephrine, ankrd1 knockdown prevented the norepinephrine levels compared to control siRNA with or without NGF (Fig.	('norepinephrine levels', 'MPA', (51, 72))	('knockdown', 'Var', (27, 36))	('ankrd1', 'Gene', (20, 26))	('norepinephrine', 'Chemical', 'MESH:D009638', (51, 65))	('norepinephrine', 'Chemical', 'MESH:D009638', (4, 18))	('prevented', 'NegReg', (37, 46))
3066	26739108	Furthermore, we first showed that ankrd1 induced by ERK5 but not ERK1/2 is involved in TH protein expression and catecholamine biosynthesis (Fig.	('involved', 'Reg', (75, 83))	('TH', 'Gene', '25085', (87, 89))	('ankrd1', 'Gene', (34, 40))	('ERK1/2', 'Gene', (65, 71))	('ERK1/2', 'Gene', '50689;116590', (65, 71))	('catecholamine biosynthesis', 'MPA', (113, 139))	('ERK5', 'Var', (52, 56))	('catecholamine', 'Chemical', 'MESH:D002395', (113, 126))
3069	26739108	We have previously showed that TH protein expression is reduced by dominant-negative mutants of ERK5 and MEK5 or a pharmacological inhibitor, BIX02189 .	('TH', 'Gene', '25085', (31, 33))	('reduced', 'NegReg', (56, 63))	('MEK5', 'Gene', (105, 109))	('BIX02189', 'Chemical', 'MESH:C533207', (142, 150))	('ERK5', 'Gene', (96, 100))	('mutants', 'Var', (85, 92))	('MEK5', 'Gene', '29568', (105, 109))
3070	26739108	In the present study, we used PC12 cells clones that stably express ERK5 shRNA to constitutively lower ERK5 protein levels.	('ERK5', 'Var', (68, 72))	('PC12 cells', 'CellLine', 'CVCL:0481', (30, 40))	('lower', 'NegReg', (97, 102))	('ERK5 protein levels', 'MPA', (103, 122))
3078	26739108	In our previous study, we observed dominant negative mutants of ERK5 and MEK5 and its pharmacological inhibitor attenuated the NGF-induced neurite outgrowth in PC12 cells.	('MEK5', 'Gene', (73, 77))	('PC12 cells', 'CellLine', 'CVCL:0481', (160, 170))	('ERK5', 'Gene', (64, 68))	('mutants', 'Var', (53, 60))	('MEK5', 'Gene', '29568', (73, 77))	('attenuated', 'NegReg', (112, 122))	('negative', 'NegReg', (44, 52))
3080	26739108	This was surprising because U0126 caused significant inhibitory effect on neurite outgrowth in PC12 cells and dissociated sympathetic neurons.	('U0126', 'Chemical', 'MESH:C113580', (28, 33))	('PC12 cells', 'CellLine', 'CVCL:0481', (95, 105))	('U0126', 'Var', (28, 33))	('neurite outgrowth', 'CPA', (74, 91))	('inhibitory', 'NegReg', (53, 63))
3084	26739108	Although other groups have also reported that U0126 does not block ERK5 efficiently at low doses as observed in our study, there are conflicting reports showing U0126 inhibits ERK5 in addition to ERK1/2.	('ERK1/2', 'Gene', '50689;116590', (196, 202))	('ERK1/2', 'Gene', (196, 202))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('ERK5', 'Enzyme', (176, 180))	('U0126', 'Var', (161, 166))	('U0126', 'Chemical', 'MESH:C113580', (161, 166))	('inhibits', 'NegReg', (167, 175))
3086	26739108	In fact, we observed lower band shift of phosho-ERK5 in U0126-treated cells although phosphorylation status of ERK5 at the TEY activation site was not blocked by U0126 (Figs.	('U0126', 'Chemical', 'MESH:C113580', (162, 167))	('U0126', 'Chemical', 'MESH:C113580', (56, 61))	('lower', 'NegReg', (21, 26))	('U0126-treated', 'Var', (56, 69))	('band shift', 'MPA', (27, 37))
3091	26739108	As a transcriptional modulator, ankrd1 binds to p53 tumor suppressor protein and enhances its transcriptional activity, whereas ankrd1 represses some cardiac gene expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p53', 'Gene', (48, 51))	('ankrd1', 'Var', (32, 38))	('tumor', 'Disease', (52, 57))	('transcriptional activity', 'MPA', (94, 118))	('enhances', 'PosReg', (81, 89))	('represses', 'NegReg', (135, 144))	('p53', 'Gene', '301300', (48, 51))	('binds', 'Interaction', (39, 44))	('cardiac', 'MPA', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
3096	26739108	Sp3 is also activated by phosphorylation by ERKs, suggesting these factors are involved in ERK5-mediated ankrd1 gene expression.	('Sp3', 'Gene', '367846', (0, 3))	('ERKs', 'Gene', '5594;50689;116590;50689', (44, 48))	('ERKs', 'Gene', (44, 48))	('phosphorylation', 'Var', (25, 40))	('Sp3', 'Gene', (0, 3))
3097	26739108	One unresolved findings is that ankrd1 expression is induced by only ERK5, and not ERK1/2.	('ankrd1', 'Gene', (32, 38))	('ERK1/2', 'Gene', (83, 89))	('ERK1/2', 'Gene', '50689;116590', (83, 89))	('ERK5', 'Var', (69, 73))	('expression', 'MPA', (39, 49))
3099	26739108	However, neurite outgrowth was neither affected by ankrd1 knockdown nor overexpression in PC12 cells (supplemental Fig.	('PC12 cells', 'CellLine', 'CVCL:0481', (90, 100))	('neurite outgrowth', 'CPA', (9, 26))	('knockdown', 'Var', (58, 67))	('ankrd1', 'Gene', (51, 57))
3101	26739108	In the present study, ankrd1 knockdown reduced TH protein levels and catecholamine biosynthesis without changing the mRNA levels (Fig.	('knockdown', 'Var', (29, 38))	('catecholamine', 'Chemical', 'MESH:D002395', (69, 82))	('TH', 'Gene', '25085', (47, 49))	('reduced', 'NegReg', (39, 46))	('catecholamine biosynthesis', 'MPA', (69, 95))	('ankrd1', 'Gene', (22, 28))
3105	26739108	5), therefore blockade of catecholamine biosynthesis by ankrd1 knockdown was partial whereas it was completely inhibited by ERK5 knockdown (Fig.	('knockdown', 'Var', (63, 72))	('ankrd1', 'Gene', (56, 62))	('catecholamine', 'Chemical', 'MESH:D002395', (26, 39))	('catecholamine biosynthesis', 'MPA', (26, 52))
3107	26739108	However, we revealed that this phosphorylation was ERK1/2-dependent but ERK5-independent, suggesting that ERK5 stabilizes TH protein using a distinct mechanism.	('ERK1/2', 'Gene', (51, 57))	('ERK1/2', 'Gene', '50689;116590', (51, 57))	('TH', 'Gene', '25085', (122, 124))	('ERK5', 'Var', (106, 110))
3116	26739108	At first, we hypothesized that ERK5 and ankrd1 were also overexpressed in adrenal pheochromocytomas because ERK5 signaling increased TH levels in PC12 cells and sympathetic neurons.	('increased', 'PosReg', (123, 132))	('ankrd1', 'Gene', (40, 46))	('PC12 cells', 'CellLine', 'CVCL:0481', (146, 156))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (74, 99))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (74, 99))	('adrenal pheochromocytomas', 'Disease', (74, 99))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (82, 99))	('ERK5', 'Var', (108, 112))	('TH', 'Gene', '25085', (133, 135))	('overexpressed', 'PosReg', (57, 70))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (74, 98))
3119	26739108	As mentioned above, loss of ERK5 causes down-regulation of TH in PC12 cells and sympathetic neurons, but this observation is not applied to the pathological conditions such as adrenal pheochromocytomas.	('loss', 'Var', (20, 24))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (184, 200))	('adrenal pheochromocytomas', 'Disease', (176, 201))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (184, 201))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (176, 200))	('down-regulation', 'NegReg', (40, 55))	('ERK5', 'Gene', (28, 32))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (176, 201))	('PC12 cells', 'CellLine', 'CVCL:0481', (65, 75))	('TH', 'Gene', '25085', (59, 61))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (176, 201))
3124	26739108	In addition, we found for the first time that ankrd1 gene expression was induced by ERK5 signaling, but not ERK1/2 signaling and ankrd1 was required for stabilization of TH protein and promotion of catecholamine biosynthesis.	('catecholamine biosynthesis', 'MPA', (198, 224))	('TH', 'Gene', '25085', (170, 172))	('expression', 'MPA', (58, 68))	('ERK1/2', 'Gene', (108, 114))	('ERK1/2', 'Gene', '50689;116590', (108, 114))	('ankrd1 gene', 'Gene', (46, 57))	('catecholamine', 'Chemical', 'MESH:D002395', (198, 211))	('ERK5', 'Var', (84, 88))
3170	30461634	3), the tumor was partly S-100(+), SyN(+), CgA(+), CD56(+), CD10(-), approximately 5% Ki67(+), and CK(-), and sustentacular cells were seen around chief cells, which is in accordance with PGL.	('SyN', 'Gene', '23336', (35, 38))	('SyN', 'Gene', (35, 38))	('CgA', 'Gene', '1113', (43, 46))	('CD56(+', 'Var', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('PGL', 'Phenotype', 'HP:0002668', (188, 191))	('CD10(-', 'Var', (60, 66))	('CgA', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('S-100(+', 'Var', (25, 32))	('tumor', 'Disease', (8, 13))	('Ki67', 'Var', (86, 90))
3200	30461634	The possibility of SDH mutation was also not ruled out in the present case because SDH mutations are most common in PCC/PGL, and the rate of malignancy is about 50% for SDHB-related sympathetic PGL.	('SDH', 'Gene', (19, 22))	('SDHB', 'Gene', '6390', (169, 173))	('PGL', 'Phenotype', 'HP:0002668', (194, 197))	('SDHB', 'Gene', (169, 173))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('SDH', 'Gene', '6390', (169, 172))	('SDH', 'Gene', '6390', (83, 86))	('malignancy', 'Disease', (141, 151))	('PGL', 'Phenotype', 'HP:0002668', (120, 123))	('PCC', 'Phenotype', 'HP:0002666', (116, 119))	('SDH', 'Gene', (83, 86))	('PCC/PGL', 'Disease', (116, 123))	('SDH', 'Gene', '6390', (19, 22))	('SDH', 'Gene', (169, 172))	('common', 'Reg', (106, 112))	('mutations', 'Var', (87, 96))
3201	30461634	Immunohistochemistry is progressively used as a screening tool prior to germline testing, and immunohistochemical staining for SDHB has been validated as a sensitive, reliable marker for germline mutation of any of the SDH subunit genes.	('SDH', 'Gene', '6390', (219, 222))	('SDH', 'Gene', (127, 130))	('SDHB', 'Gene', '6390', (127, 131))	('SDH', 'Gene', (219, 222))	('germline', 'Var', (187, 195))	('SDHB', 'Gene', (127, 131))	('SDH', 'Gene', '6390', (127, 130))
3369	28789448	Patients with identified germline mutations in subunit B of succinate dehydrogenase exhibit an increased likelihood of experiencing malignancy, multiple pheochromocytomas and recurrences.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (153, 170))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (153, 169))	('Patients', 'Species', '9606', (0, 8))	('germline mutations', 'Var', (25, 43))	('pheochromocytomas', 'Disease', 'MESH:D010673', (153, 170))	('malignancy', 'Disease', (132, 142))	('pheochromocytomas', 'Disease', (153, 170))
3401	19690028	Usefulness of 123I-MIBG Scintigraphy in the Evaluation of Patients with Known or Suspected Primary or Metastatic Pheochromocytoma or Paraganglioma: Results from a Prospective Multicenter Trial Although 123I-MIBG has been in clinical use for the imaging of pheochromocytoma for many years, a large multicenter evaluation of this agent has never been performed.	('pheochromocytoma', 'Disease', (256, 272))	('Primary or Metastatic Pheochromocytoma or Paraganglioma', 'Disease', 'MESH:D010673', (91, 146))	('pheochromocytoma', 'Disease', 'MESH:D010673', (256, 272))	('123I-MIBG', 'Var', (202, 211))	('123I-MIBG', 'Chemical', 'MESH:D019797', (14, 23))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (256, 272))	('123I-MIBG', 'Chemical', 'MESH:D019797', (202, 211))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (113, 129))	('Paraganglioma', 'Phenotype', 'HP:0002668', (133, 146))	('Patients', 'Species', '9606', (58, 66))
3412	19690028	During the past 25 y, both 123I-MIBG and 131I-MIBG have been extensively used in research and clinical imaging of pheochromocytoma, even though in the United States before September 2008, only 131I-MIBG was approved by the Food and Drug Administration (FDA) as a diagnostic imaging agent.	('131I-MIBG', 'Var', (193, 202))	('pheochromocytoma', 'Disease', 'MESH:D010673', (114, 130))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (114, 130))	('131I-MIBG', 'Chemical', '-', (41, 50))	('131I-MIBG', 'Chemical', '-', (193, 202))	('123I-MIBG', 'Chemical', 'MESH:D019797', (27, 36))	('pheochromocytoma', 'Disease', (114, 130))
3415	19690028	The objective of the present trial was to document the efficacy of 123I-MIBG scintigraphy for confirming or excluding the diagnosis of pheochromocytoma.	('123I-MIBG', 'Chemical', 'MESH:D019797', (67, 76))	('pheochromocytoma', 'Disease', (135, 151))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('123I-MIBG', 'Var', (67, 76))
3456	19690028	After the first reports of MIBG (labeled with 131I) results in pheochromocytoma in 1981, similar descriptions of experience using 123I-MIBG appeared within the next few years.	('MIBG', 'Var', (27, 31))	('MIBG', 'Chemical', 'MESH:D019797', (27, 31))	('123I-MIBG', 'Chemical', 'MESH:D019797', (130, 139))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (63, 79))	('131I', 'Chemical', 'MESH:C000614965', (46, 50))	('MIBG', 'Chemical', 'MESH:D019797', (135, 139))	('pheochromocytoma', 'Disease', (63, 79))	('results in', 'Reg', (52, 62))	('pheochromocytoma', 'Disease', 'MESH:D010673', (63, 79))
3459	19690028	Sensitivities for detecting primary pheochromocytoma using 123I-MIBG and 131I-MIBG have almost always been reported as greater than 80%.	('131I-MIBG', 'Chemical', '-', (73, 82))	('123I-MIBG', 'Chemical', 'MESH:D019797', (59, 68))	('pheochromocytoma', 'Disease', (36, 52))	('123I-MIBG', 'Var', (59, 68))	('pheochromocytoma', 'Disease', 'MESH:D010673', (36, 52))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('131I-MIBG', 'Var', (73, 82))
3472	19690028	Potential relationships between 123I-MIBG imaging results and genetic abnormalities associated with pheochromocytoma could not be explored because the trial did not include the collection of relevant historical and histopathology data.	('123I-MIBG', 'Var', (32, 41))	('pheochromocytoma', 'Disease', 'MESH:D010673', (100, 116))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('123I-MIBG', 'Chemical', 'MESH:D019797', (32, 41))	('genetic abnormalities', 'Disease', 'MESH:D030342', (62, 83))	('pheochromocytoma', 'Disease', (100, 116))	('genetic abnormalities', 'Disease', (62, 83))
3474	19690028	This prospective multicenter clinical trial confirmed the performance characteristics of 123I-MIBG scintigraphic imaging in a contemporary population of patients referred for assessment of known prior or suspected pheochromocytoma and paraganglioma, with sensitivities of 87%-90% for the former and 67%-100% for the latter.	('paraganglioma', 'Disease', (235, 248))	('123I-MIBG', 'Var', (89, 98))	('patients', 'Species', '9606', (153, 161))	('pheochromocytoma', 'Disease', (214, 230))	('123I-MIBG', 'Chemical', 'MESH:D019797', (89, 98))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (214, 230))	('paraganglioma', 'Disease', 'MESH:D010235', (235, 248))	('pheochromocytoma', 'Disease', 'MESH:D010673', (214, 230))	('paraganglioma', 'Phenotype', 'HP:0002668', (235, 248))
3597	25973288	Also, mutation in succinate dehydrogenase gene (SDH) may lead to familial paraganglioma.	('familial paraganglioma', 'Disease', 'MESH:D010235', (65, 87))	('SDH', 'Gene', '6390', (48, 51))	('mutation', 'Var', (6, 14))	('lead to', 'Reg', (57, 64))	('SDH', 'Gene', (48, 51))	('familial paraganglioma', 'Disease', (65, 87))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))
3598	25973288	Three subunits of SDH gene mutation have been described in the literature and 33% of patients with SDH subunit B mutation have a positive family history.	('mutation', 'Var', (113, 121))	('SDH', 'Gene', (99, 102))	('SDH', 'Gene', '6390', (18, 21))	('patients', 'Species', '9606', (85, 93))	('SDH', 'Gene', (18, 21))	('SDH', 'Gene', '6390', (99, 102))
3628	25973288	Encasement of abdominal aorta and/or IVC without luminal compression is highly suggestive of retroperitoneal lymphoma.	('retroperitoneal lymphoma', 'Disease', 'MESH:D012186', (93, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	('retroperitoneal lymphoma', 'Disease', (93, 117))	('Encasement', 'Var', (0, 10))	('men', 'Species', '9606', (6, 9))
3640	25109928	Ocular manifestations of HIF-2 alpha paraganglioma-somatostatinomapolycythemia syndrome A new syndrome of paraganglioma-somatostatinoma-polycythemia caused by somatic gain-of-function HIF2A mutations has been recently described.	('HIF2A', 'Gene', (184, 189))	('paraganglioma-somatostatinoma-polycythemia', 'Disease', 'MESH:D013005', (106, 148))	('gain-of-function', 'PosReg', (167, 183))	('mutations', 'Var', (190, 199))	('polycythemia', 'Phenotype', 'HP:0001901', (136, 148))	('HIF-2 alpha paraganglioma-somatostatinomapolycythemia syndrome', 'Disease', 'MESH:C566646', (25, 87))	('HIF2A', 'Gene', '2034', (184, 189))	('paraganglioma', 'Phenotype', 'HP:0002668', (37, 50))	('paraganglioma-somatostatinoma-polycythemia', 'Disease', (106, 148))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))	('polycythemia', 'Phenotype', 'HP:0001901', (66, 78))
3654	25109928	All patients had gain-of-function mutations in the EPAS1 gene (encoding HIF-2A peptide) detected in tumors but not in leukocyte DNA.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('gain-of-function', 'PosReg', (17, 33))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('EPAS1', 'Gene', '2034', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (4, 12))	('EPAS1', 'Gene', (51, 56))	('HIF-2A', 'Gene', (72, 78))	('mutations', 'Var', (34, 43))	('HIF-2A', 'Gene', '2034', (72, 78))
3655	25109928	Paraganglioma-somatostatinoma-polycythemia is a new syndrome, and the unique eye lesions clustered with the syndrome suggest that somatic gain-of-function HIF2A mutations play an important role in the pathogenesis of these eye lesions.	('Paraganglioma-somatostatinoma-polycythemia', 'Disease', (0, 42))	('polycythemia', 'Phenotype', 'HP:0001901', (30, 42))	('HIF2A', 'Gene', '2034', (155, 160))	('mutations', 'Var', (161, 170))	('gain-of-function', 'PosReg', (138, 154))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paraganglioma-somatostatinoma-polycythemia', 'Disease', 'MESH:D013005', (0, 42))	('HIF2A', 'Gene', (155, 160))
3660	25109928	HIF-2alpha alteration in a transgenic mouse model exhibits marked retinopathy.	('mouse', 'Species', '10090', (38, 43))	('retinopathy', 'Phenotype', 'HP:0000488', (66, 77))	('marked retinopathy', 'Phenotype', 'HP:0001141', (59, 77))	('alteration', 'Var', (11, 21))	('retinopathy', 'Disease', 'MESH:D012164', (66, 77))	('HIF-2alpha', 'Gene', (0, 10))	('retinopathy', 'Disease', (66, 77))
3662	25109928	Therefore, a HIF2A mutation, along with high erythropoietin levels, may affect the eye, especially the retina, resulting in the ocular abnormalities among patients.	('ocular abnormalities', 'Disease', (128, 148))	('mutation', 'Var', (19, 27))	('affect', 'Reg', (72, 78))	('erythropoietin', 'Gene', '2056', (45, 59))	('HIF2A', 'Gene', '2034', (13, 18))	('eye', 'MPA', (83, 86))	('patients', 'Species', '9606', (155, 163))	('HIF2A', 'Gene', (13, 18))	('resulting in', 'Reg', (111, 123))	('erythropoietin', 'Gene', (45, 59))	('ocular abnormalities', 'Disease', 'MESH:D005124', (128, 148))	('ocular abnormalities', 'Phenotype', 'HP:0000478', (128, 148))
3663	25109928	In addition to the HIF2A mutation, the genes affecting the HIF signaling pathway such as von Hippel-Lindau, succinate dehydrogenase, and prolyl hydroxylase can have mutations found to be associated with neural crest cell tumors, paragangliomas/pheochromocytomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (229, 243))	('paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (229, 261))	('paragangliomas/pheochromocytomas', 'Disease', (229, 261))	('HIF2A', 'Gene', (19, 24))	('HIF2A', 'Gene', '2034', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('mutation', 'Var', (25, 33))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('neural crest cell tumors', 'Disease', 'MESH:C536408', (203, 227))	('associated', 'Reg', (187, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (229, 242))	('mutations', 'Var', (165, 174))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (244, 261))	('von Hippel-Lindau', 'Disease', (89, 106))	('neural crest cell tumors', 'Disease', (203, 227))
3664	25109928	Dysregulation of the HIF signaling pathway initiates an activation cascade of genes, many of them participating in angiogenesis, abnormal apoptosis, cell migration, and development, processes that can lead to tumorigenesis and may affect tissue-specific development of various organs or structures (as indicated by the presence of a Marfanoid habitus and brain abnormalities), including the eye and retina.	('genes', 'Gene', (78, 83))	('Dysregulation', 'Var', (0, 13))	('tissue-specific development of', 'CPA', (238, 268))	('Marfanoid habitus and brain abnormalities', 'Disease', 'MESH:C565411', (333, 374))	('Marfanoid habitus', 'Phenotype', 'HP:0001519', (333, 350))	('affect', 'Reg', (231, 237))	('tumorigenesis', 'CPA', (209, 222))	('cell migration', 'CPA', (149, 163))	('brain abnormalities', 'Phenotype', 'HP:0012443', (355, 374))	('activation', 'PosReg', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('lead to', 'Reg', (201, 208))	('abnormal', 'CPA', (129, 137))
3665	25109928	As of the time of this report, over 20 patients have been described presenting with HIF2A mutations associated with paraganglioma and polycythemia.	('paraganglioma', 'Phenotype', 'HP:0002668', (116, 129))	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (39, 47))	('HIF2A', 'Gene', (84, 89))	('associated', 'Reg', (100, 110))	('paraganglioma and polycythemia', 'Disease', 'MESH:D011086', (116, 146))	('polycythemia', 'Phenotype', 'HP:0001901', (134, 146))	('HIF2A', 'Gene', '2034', (84, 89))
3666	25109928	Our series of cases (4 out of 7 examined cases) with somatic HIF2A mutations clearly document the existence of an additional phenotype of this syndrome, i.e.	('HIF2A', 'Gene', '2034', (61, 66))	('HIF2A', 'Gene', (61, 66))	('mutations', 'Var', (67, 76))
3678	23209036	However, germline mutations in 10 different genes have been shown to cause PPGLs, and at least 30% of these tumors are now known to be hereditary.	('PPGLs', 'Chemical', '-', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cause', 'Reg', (69, 74))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('PPGLs', 'Disease', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('germline mutations', 'Var', (9, 27))
3679	23209036	Importantly, genotype-phenotype correlations have been elucidated: different mutations are associated with specific clinical features and sites of disease, the production of certain catecholamines, and varying frequency of malignancy.	('production', 'MPA', (160, 170))	('malignancy', 'Disease', 'MESH:D009369', (223, 233))	('malignancy', 'Disease', (223, 233))	('mutations', 'Var', (77, 86))	('catecholamines', 'Chemical', 'MESH:D002395', (182, 196))	('associated', 'Reg', (91, 101))
3684	23209036	Populations at increased risk for PPGLs are those with germline mutations of the now identified 10 tumor-susceptibility genes.	('tumor', 'Disease', (99, 104))	('PPGLs', 'Disease', (34, 39))	('PPGLs', 'Chemical', '-', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('germline mutations', 'Var', (55, 73))
3690	23209036	the "Black Forest VHL gene mutation (p. Tyr98His)" that is common in south-western Germany is associated with a high risk of pheochromocytoma) may cause geographic variations in the frequency of specific inherited forms of PPGL.	('pheochromocytoma', 'Disease', (125, 141))	('Tyr98His', 'SUBSTITUTION', 'None', (40, 48))	('pheochromocytoma', 'Disease', 'MESH:D010673', (125, 141))	('Tyr98His', 'Var', (40, 48))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (125, 141))	('cause', 'Reg', (147, 152))	('PPGL', 'Disease', (223, 227))	('VHL', 'Disease', (18, 21))	('VHL', 'Disease', 'MESH:D006623', (18, 21))	('associated', 'Reg', (94, 104))	('PPGL', 'Chemical', '-', (223, 227))
3696	23209036	multiple endocrine neoplasia type 2, neurofibromatosis type 1, von Hippel Lindau syndrome, or succinate dehydrogenase mutations); a family history of pheochromocytoma; an incidentally discovered adrenal mass; pressor response to anesthesia, surgery, or angiography; onset of hypertension at a young age (e.g.	('pheochromocytoma', 'Disease', (150, 166))	('hypertension', 'Disease', 'MESH:D006973', (275, 287))	('mutations', 'Var', (118, 127))	('multiple endocrine neoplasia type 2, neurofibromatosis type 1', 'Gene', '4763', (0, 61))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('von Hippel Lindau syndrome', 'Disease', (63, 89))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (37, 54))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('hypertension', 'Disease', (275, 287))	('pheochromocytoma', 'Disease', 'MESH:D010673', (150, 166))	('von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (63, 89))	('hypertension', 'Phenotype', 'HP:0000822', (275, 287))
3700	23209036	This is the case for HNPGL in the Netherlands, given the founder mutations in succinate dehydrogenase subunit D (SDHD).	('succinate dehydrogenase subunit D', 'Gene', (78, 111))	('SDHD', 'Gene', (113, 117))	('SDHD', 'Gene', '6392', (113, 117))	('succinate dehydrogenase subunit D', 'Gene', '6392', (78, 111))	('mutations', 'Var', (65, 74))
3752	23209036	Large size is also a risk factor and together with extra-adrenal location accounts for the high risk of malignancy associated with mutations of the SDHB gene.	('mutations', 'Var', (131, 140))	('SDHB', 'Gene', (148, 152))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('malignancy', 'Disease', (104, 114))	('SDHB', 'Gene', '6390', (148, 152))
3758	23209036	Dr. Eamonn R Maher: In the absence of distant metastases, the presence of a germline SDHB mutation will significantly increase the prior risk of malignancy but cannot definitively inform whether an individual PPGL is malignant or not.	('increase', 'PosReg', (118, 126))	('metastases', 'Disease', (46, 56))	('malignancy', 'Disease', 'MESH:D009369', (145, 155))	('malignancy', 'Disease', (145, 155))	('PPGL', 'Chemical', '-', (209, 213))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('metastases', 'Disease', 'MESH:D009362', (46, 56))	('mutation', 'Var', (90, 98))
3762	23209036	Malignancy is rare in patients with multiple endocrine neoplasia type 2 or von Hippel Lindau syndrome, but is common in those with familial paraganglioma caused by mutations in SDHB.	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (36, 71))	('von Hippel Lindau syndrome', 'Disease', (75, 101))	('von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (75, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('familial paraganglioma', 'Disease', 'MESH:D010235', (131, 153))	('SDHB', 'Gene', '6390', (177, 181))	('common', 'Reg', (110, 116))	('multiple endocrine neoplasia type 2', 'Disease', (36, 71))	('SDHB', 'Gene', (177, 181))	('patients', 'Species', '9606', (22, 30))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (45, 64))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('caused by', 'Reg', (154, 163))	('Malignancy', 'Disease', (0, 10))	('mutations', 'Var', (164, 173))	('familial paraganglioma', 'Disease', (131, 153))	('Malignancy', 'Disease', 'MESH:D009369', (0, 10))
3763	23209036	Patients with SDHB mutations are more likely to develop malignant disease and nonparaganglioma neoplasms (e.g.	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('develop', 'PosReg', (48, 55))	('neoplasms', 'Phenotype', 'HP:0002664', (95, 104))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('malignant disease', 'Disease', 'MESH:D009369', (56, 73))	('SDHB', 'Gene', '6390', (14, 18))	('nonparaganglioma neoplasms', 'Disease', 'MESH:D009369', (78, 104))	('malignant disease', 'Disease', (56, 73))	('SDHB', 'Gene', (14, 18))	('nonparaganglioma neoplasms', 'Disease', (78, 104))
3788	23209036	Such patients and family members with identified mutations represent important groups who must be periodically screened for PPGLs and in who choice of specific tests, test interpretation and management of disease, including other manifestations, should be individualized according to the affected gene.	('PPGLs', 'Chemical', '-', (124, 129))	('patients', 'Species', '9606', (5, 13))	('PPGLs', 'Gene', (124, 129))	('mutations', 'Var', (49, 58))
3789	23209036	As an example, periodic biochemical testing in patients with mutations of the SDHB gene should include measurements of plasma methoxytyramine, with test interpretation concentrating on this analyte and normetanephrine.	('SDHB', 'Gene', '6390', (78, 82))	('methoxytyramine', 'Chemical', 'MESH:C001746', (126, 141))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (61, 70))	('SDHB', 'Gene', (78, 82))	('normetanephrine', 'Chemical', 'MESH:D009647', (202, 217))	('plasma methoxytyramine', 'MPA', (119, 141))
3818	23209036	Whilst some of these cases might ultimately prove to have a mutation in a currently known gene that cannot be detected by standard mutation detection methods, I strongly suspect that further inherited pheochromocytoma/paraganglioma genes will be identified in the next few years.	('paraganglioma', 'Phenotype', 'HP:0002668', (218, 231))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (201, 231))	('mutation', 'Var', (60, 68))	('inherited pheochromocytoma', 'Disease', 'MESH:D010673', (191, 217))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (201, 217))	('pheochromocytoma/paraganglioma', 'Disease', (201, 231))	('inherited pheochromocytoma', 'Disease', (191, 217))
3869	25083379	However, in our case, it was interesting that the embolization of tumor vessels decreased the plasma noradrenaline level (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('embolization', 'Var', (50, 62))	('tumor', 'Disease', (66, 71))	('noradrenaline', 'Chemical', 'MESH:D009638', (101, 114))	('decreased', 'NegReg', (80, 89))	('plasma noradrenaline level', 'MPA', (94, 120))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
3886	32957698	We tested 35 dog tumors to determine how likely SDH mutations were.	('mutations', 'Var', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('SDH', 'Gene', '6390', (48, 51))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('SDH', 'Gene', (48, 51))	('dog', 'Species', '9615', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
3887	32957698	While our data suggest significant numbers of SDH mutations, these mutations do not appear to be associated with tumor aggression.	('mutations', 'Var', (50, 59))	('tumor aggression', 'Disease', (113, 129))	('SDH', 'Gene', '6390', (46, 49))	('tumor aggression', 'Disease', 'MESH:D001523', (113, 129))	('aggression', 'Phenotype', 'HP:0000718', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SDH', 'Gene', (46, 49))	('associated', 'Reg', (97, 107))
3890	32957698	In humans, immunohistochemistry has proven valuable as a screening technique for SDH mutations.	('mutations', 'Var', (85, 94))	('SDH', 'Gene', '6390', (81, 84))	('SDH', 'Gene', (81, 84))	('humans', 'Species', '9606', (3, 9))
3891	32957698	Human PCs that lack succinate dehydrogenase B (SDHB) immunoreactivity have a high rate of mutation in the SDH family of genes, while human PCs lacking succinate dehydrogenase A (SDHA) immunoreactivity have mutations in the SDHA gene.	('Human', 'Species', '9606', (0, 5))	('mutations', 'Var', (206, 215))	('SDH', 'Gene', '6390', (223, 226))	('SDH', 'Gene', (178, 181))	('SDH', 'Gene', (106, 109))	('succinate dehydrogenase', 'Gene', (151, 174))	('SDH', 'Gene', (47, 50))	('succinate dehydrogenase', 'Gene', '6390', (151, 174))	('succinate dehydrogenase', 'Gene', '6390', (20, 43))	('succinate dehydrogenase', 'Gene', (20, 43))	('SDH', 'Gene', (223, 226))	('SDH', 'Gene', '6390', (178, 181))	('human', 'Species', '9606', (133, 138))	('mutation', 'Var', (90, 98))	('SDH', 'Gene', '6390', (47, 50))	('SDH', 'Gene', '6390', (106, 109))
3893	32957698	Interestingly, there was a loss of immunoreactivity for both SDHA and SDHB in four samples (11%), suggesting a mutation in SDHx including SDHA.	('SDH', 'Gene', (123, 126))	('SDH', 'Gene', (70, 73))	('SDH', 'Gene', '6390', (138, 141))	('SDH', 'Gene', (61, 64))	('SDH', 'Gene', '6390', (70, 73))	('SDH', 'Gene', (138, 141))	('mutation', 'Var', (111, 119))	('SDH', 'Gene', '6390', (123, 126))	('SDH', 'Gene', '6390', (61, 64))	('loss', 'NegReg', (27, 31))	('immunoreactivity', 'MPA', (35, 51))
3902	32957698	Frequently, these are associated with mutations in the succinate dehydrogenase (SDH) family of genes, with mutations in succinate dehydrogenase subunit B (SDHB) associated with a high likelihood of metastasis/malignancy.	('SDH', 'Gene', '6390', (155, 158))	('succinate dehydrogenase', 'Gene', (120, 143))	('malignancy', 'Disease', (209, 219))	('mutations', 'Var', (107, 116))	('associated with', 'Reg', (161, 176))	('succinate dehydrogenase', 'Gene', '6390', (55, 78))	('SDH', 'Gene', '6390', (80, 83))	('SDH', 'Gene', (155, 158))	('succinate dehydrogenase', 'Gene', (55, 78))	('mutations', 'Var', (38, 47))	('associated', 'Reg', (22, 32))	('SDH', 'Gene', (80, 83))	('succinate dehydrogenase', 'Gene', '6390', (120, 143))	('malignancy', 'Disease', 'MESH:D009369', (209, 219))
3904	32957698	Studies in human PCs have found that immunohistochemistry (IHC) is highly correlated with the SDH mutation status.	('mutation status', 'Var', (98, 113))	('SDH', 'Gene', '6390', (94, 97))	('SDH', 'Gene', (94, 97))	('human', 'Species', '9606', (11, 16))
3905	32957698	For instance, all samples with mutations in SDH family genes lacked SDHB immunoreactivity.	('SDH', 'Gene', (44, 47))	('mutations', 'Var', (31, 40))	('lacked', 'NegReg', (61, 67))	('SDH', 'Gene', (68, 71))	('SDH', 'Gene', '6390', (44, 47))	('SDH', 'Gene', '6390', (68, 71))
3909	32957698	Some mutations have been found in SDH family genes, which may indicate that mutations in these genes may initiate oncogenesis in a similar way to people.	('mutations', 'Var', (76, 85))	('SDH', 'Gene', (34, 37))	('initiate', 'Reg', (105, 113))	('mutations', 'Var', (5, 14))	('people', 'Species', '9606', (146, 152))	('oncogenesis', 'CPA', (114, 125))	('SDH', 'Gene', '6390', (34, 37))
3920	32957698	Human studies have found that 75% of samples with SDHA mutations lacked immunoreactivity for SDHA and SDHB and that 90% of samples with SDHB, C, D, or SDHAF2 mutations had immunoreactivity for SDHA and lacked immunoreactivity for SDHB.	('immunoreactivity', 'MPA', (172, 188))	('Human', 'Species', '9606', (0, 5))	('SDHAF2', 'Gene', (151, 157))	('mutations', 'Var', (55, 64))	('immunoreactivity', 'MPA', (72, 88))	('SDHAF2', 'Gene', '476065', (151, 157))	('lacked', 'NegReg', (65, 71))	('SDHA', 'Gene', (50, 54))	('SDHB', 'Gene', (136, 140))	('SDHA', 'MPA', (193, 197))	('mutations', 'Var', (158, 167))
3921	32957698	When this is applied to the samples in our study, these patterns suggest that 29 out of the 35 (82.8%) samples have a mutation in at least one of the SDH family genes (Figure 2).	('SDH', 'Gene', (150, 153))	('mutation', 'Var', (118, 126))	('SDH', 'Gene', '6390', (150, 153))
3923	32957698	However, as inactivation of SDHA does not lead to tumorigenesis, this may represent a somatic hypermethylation of the promoter region, leading to an accumulation of succinate and later an inhibition of demethylase enzymes.	('demethylase enzymes', 'Enzyme', (202, 221))	('succinate', 'MPA', (165, 174))	('SDHA', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('inhibition', 'NegReg', (188, 198))	('accumulation', 'PosReg', (149, 161))	('inactivation', 'Var', (12, 24))	('succinate', 'Chemical', 'MESH:D019802', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
3926	32957698	These findings do suggest that IHC has a similar utility in narrowing candidate mutations in pheochromocytomas in dogs; given, in particular, the relatively higher cost of sequencing, restricting the set of possible candidate genes using immunohistochemistry would be helpful in future sequencing studies.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('mutations', 'Var', (80, 89))	('pheochromocytomas', 'Disease', 'MESH:D010673', (93, 110))	('pheochromocytomas', 'Disease', (93, 110))	('dogs', 'Species', '9615', (114, 118))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (93, 110))
3927	32957698	However, determining the true utility of SDH immunohistochemistry would require sequencing information and additional case information; if immunohistochemistry is associated with specific mutations and/or mutations in specific genes are closely associated with clinical behavior, immunohistochemistry would become an important tool in case management.	('mutations', 'Var', (205, 214))	('SDH', 'Gene', (41, 44))	('associated', 'Reg', (245, 255))	('genes', 'Gene', (227, 232))	('mutations', 'Var', (188, 197))	('SDH', 'Gene', '6390', (41, 44))
3928	32957698	Canine pheochromocytomas have similar immunohistochemical characteristics to those previously reported in human tumors, with approximately 82% showing immunohistochemical evidence of an SDH family mutation.	('human', 'Species', '9606', (106, 111))	('Canine', 'Species', '9615', (0, 6))	('pheochromocytomas', 'Disease', (7, 24))	('pheochromocytomas', 'Disease', 'MESH:D010673', (7, 24))	('tumors', 'Disease', (112, 118))	('SDH', 'Gene', '6390', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (7, 23))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('SDH', 'Gene', (186, 189))	('mutation', 'Var', (197, 205))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (7, 24))
3932	32960387	Meta-[211At]astatobenzylguanidine (211At-MABG) has been proposed for the treatment of pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (86, 102))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (86, 102))	('211At-MABG', 'Chemical', 'MESH:C078685', (35, 45))	('Meta-[211At]astatobenzylguanidine', 'Chemical', 'MESH:C520658', (0, 33))	('Meta-[211At]', 'Var', (0, 12))	('pheochromocytoma', 'Disease', (86, 102))
3940	32960387	The absorbed doses of 211At-MABG in the adrenal glands, heart wall, and liver were higher than those of free 211At.	('211At', 'Chemical', '-', (22, 27))	('211At-MABG', 'Chemical', 'MESH:C078685', (22, 32))	('211At', 'Chemical', '-', (109, 114))	('higher', 'PosReg', (83, 89))	('211At-MABG', 'Var', (22, 32))
3941	32960387	The absorbed doses of 211At-MABG in organs expressing the norepinephrine transporter were higher than those of free 211At.	('211At', 'Chemical', '-', (22, 27))	('211At-MABG', 'Chemical', 'MESH:C078685', (22, 32))	('211At', 'Chemical', '-', (116, 121))	('higher', 'PosReg', (90, 96))	('211At-MABG', 'Var', (22, 32))
3950	32960387	131I-MIBG, an analog of guanethidine, concentrates in adrenergic tissue by the same mechanism as that of norepinephrine through the norepinephrine transporter (NET).	('norepinephrine', 'Chemical', 'MESH:D009638', (132, 146))	('guanethidine', 'Chemical', 'MESH:D006145', (24, 36))	('131I-MIBG', 'Var', (0, 9))	('norepinephrine', 'Chemical', 'MESH:D009638', (105, 119))	('131I-MIBG', 'Chemical', '-', (0, 9))	('norepinephrine transporter', 'MPA', (132, 158))	('concentrates in', 'MPA', (38, 53))	('rat', 'Species', '10116', (45, 48))
3956	32960387	Since the decay pathway is 100% alpha-particle emission (5.87 and 7.45 MeV in 42% and 58% of the decays, respectively) during the decay of 211At at a half-life of 7.2 h, 211At is one of the nuclides available for TAT.	('nuclides', 'Chemical', '-', (190, 198))	('211At', 'Chemical', '-', (170, 175))	('211At', 'Chemical', '-', (139, 144))	('alpha-particle emission', 'MPA', (32, 55))	('TAT', 'Chemical', '-', (213, 216))	('211At', 'Var', (139, 144))
3981	32960387	In this study, 211At refers to "free astatine," which likely consists not only of 211At-, but also, to some extent, other oxidation states.	('astatine', 'Chemical', 'MESH:D001246', (37, 45))	('211At', 'Var', (15, 20))	('211At', 'Chemical', '-', (15, 20))	('211At', 'Chemical', '-', (82, 87))	('211At-', 'Var', (82, 88))
4008	32960387	The stomach had a high concentration of free 211At for up to 24 h, with the highest activity concentration observed after 1 h.  On the other hand, the accumulation of 211At-MABG was higher than that of free 211At in the heart and adrenal glands.	('211At', 'Chemical', '-', (45, 50))	('accumulation', 'MPA', (151, 163))	('211At', 'Chemical', '-', (207, 212))	('rat', 'Species', '10116', (30, 33))	('211At-MABG', 'Chemical', 'MESH:C078685', (167, 177))	('higher', 'PosReg', (182, 188))	('211At', 'Chemical', '-', (167, 172))	('rat', 'Species', '10116', (100, 103))	('211At-MABG', 'Var', (167, 177))
4009	32960387	211At-MABG showed faster clearance in each organ as well as in blood and plasma.	('clearance', 'MPA', (25, 34))	('211At-MABG', 'Var', (0, 10))	('faster', 'PosReg', (18, 24))	('211At-MABG', 'Chemical', 'MESH:C078685', (0, 10))
4015	32960387	The dosimetric calculations for free 211At and 211At-MABG showed that the thyroid received the highest absorbed dose per injection activity, with free 211At = 15.1 Gy/MBq and 211At-MABG = 4.08 Gy/MBq followed by the stomach wall in the mouse model (Table 4).	('211At', 'Chemical', '-', (151, 156))	('211At-MABG =', 'Var', (175, 187))	('211At', 'Chemical', '-', (37, 42))	('211At-MABG', 'Chemical', 'MESH:C078685', (47, 57))	('free 211At', 'Var', (146, 156))	('211At', 'Chemical', '-', (47, 52))	('211At-MABG', 'Chemical', 'MESH:C078685', (175, 185))	('211At', 'Chemical', '-', (175, 180))	('mouse', 'Species', '10090', (236, 241))
4016	32960387	Relatively higher absorbed doses in extrathyroidal tissues and organs were found in the heart, lung, and stomach wall for free 211At than for 211At-MABG.	('211At', 'Chemical', '-', (142, 147))	('free 211At', 'Var', (122, 132))	('211At-MABG', 'Chemical', 'MESH:C078685', (142, 152))	('rat', 'Species', '10116', (39, 42))	('higher', 'PosReg', (11, 17))	('211At', 'Chemical', '-', (127, 132))	('absorbed doses', 'MPA', (18, 32))
4028	32960387	Previous studies also demonstrated higher activity concentrations of free 211At than of radioiodine in extrathyroidal organs and tissues, suggesting that the uptake/transport of free 211At is dependent on mechanisms other than the sodium iodide symporter (NIS).	('free 211At', 'Var', (178, 188))	('activity', 'MPA', (42, 50))	('uptake/transport', 'MPA', (158, 174))	('sodium iodide symporter', 'Gene', '114479', (231, 254))	('211At', 'Chemical', '-', (74, 79))	('211At', 'Chemical', '-', (183, 188))	('sodium iodide symporter', 'Gene', (231, 254))	('rat', 'Species', '10116', (29, 32))	('radioiodine', 'Chemical', 'MESH:C000614965', (88, 99))	('rat', 'Species', '10116', (58, 61))	('rat', 'Species', '10116', (106, 109))
4031	32960387	The mean absorbed dose in the thyroid was higher for free 211At than for 211At-MABG, which is explained by the much higher uptake of free 211At than of 211At-MABG.	('211At', 'Chemical', '-', (152, 157))	('211At-MABG', 'Chemical', 'MESH:C078685', (73, 83))	('absorbed dose', 'MPA', (9, 22))	('higher', 'PosReg', (116, 122))	('211At', 'Chemical', '-', (73, 78))	('211At-MABG', 'Chemical', 'MESH:C078685', (152, 162))	('higher', 'PosReg', (42, 48))	('free 211At', 'Var', (53, 63))	('211At', 'Chemical', '-', (138, 143))	('211At', 'Chemical', '-', (58, 63))
4036	32960387	The uptake of 211At-MABG was higher in the heart and adrenal gland, which have higher densities of NET than in other organs and glands.	('higher', 'PosReg', (29, 35))	('211At-MABG', 'Var', (14, 24))	('uptake', 'MPA', (4, 10))	('211At-MABG', 'Chemical', 'MESH:C078685', (14, 24))
4044	32960387	estimated the human-equivalent internal radiation absorbed doses of 124I-MIBG using PET/CT data in a murine xenograft model.	('124I-MIBG', 'Var', (68, 77))	('PET', 'Gene', (84, 87))	('human', 'Species', '9606', (14, 19))	('murine', 'Species', '10090', (101, 107))	('124I-MIBG', 'Chemical', '-', (68, 77))	('PET', 'Gene', '22095', (84, 87))
4047	32960387	211At-MABG is a promising radiopharmaceutical for the treatment of malignant pheochromocytoma.	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (67, 93))	('malignant pheochromocytoma', 'Disease', (67, 93))	('211At-MABG', 'Var', (0, 10))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('211At-MABG', 'Chemical', 'MESH:C078685', (0, 10))
4048	32960387	The distribution of 211At-MABG showed different uptakes in several organs compared with free 211At.	('211At', 'Chemical', '-', (93, 98))	('uptakes', 'MPA', (48, 55))	('211At-MABG', 'Var', (20, 30))	('211At-MABG', 'Chemical', 'MESH:C078685', (20, 30))	('211At', 'Chemical', '-', (20, 25))
4057	32132978	In recent years, temozolomide (TMZ) showed great promise in some MMP patients, especially those with SDHB germline mutation.	('MMP', 'Disease', (65, 68))	('SDHB', 'Gene', (101, 105))	('temozolomide', 'Chemical', 'MESH:D000077204', (17, 29))	('germline mutation', 'Var', (106, 123))	('patients', 'Species', '9606', (69, 77))	('SDHB', 'Gene', '6390', (101, 105))	('TMZ', 'Chemical', 'MESH:D000077204', (31, 34))
4063	32132978	Molecular profiling of the tumor tissue of the patient revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter and a negative immunostaining for MGMT.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patient', 'Species', '9606', (47, 54))	('MGMT', 'Gene', '4255', (128, 132))	('O6-methylguanine-DNA-methyltransferase', 'Gene', '4255', (88, 126))	('MGMT', 'Gene', (128, 132))	('tumor', 'Disease', (27, 32))	('O6-methylguanine-DNA-methyltransferase', 'Gene', (88, 126))	('MGMT', 'Gene', (177, 181))	('MGMT', 'Gene', '4255', (177, 181))	('immunostaining', 'MPA', (158, 172))	('hypermethylation', 'Var', (64, 80))	('negative', 'NegReg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
4065	32132978	TMZ is effective, especially in patients with SDHB mutation, which can be explained by the silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumors.	('MGMT', 'Gene', (104, 108))	('patients', 'Species', '9606', (32, 40))	('MGMT', 'Gene', '4255', (104, 108))	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SDHB', 'Gene', '6390', (174, 178))	('silencing', 'NegReg', (91, 100))	('mutation', 'Var', (51, 59))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('SDHB', 'Gene', (174, 178))	('MGMT', 'Gene', (140, 144))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('MGMT', 'Gene', '4255', (140, 144))
4066	32132978	Although, in general, patients with SDHB mutation or MGMT promoter hypermethylation have better response to TMZ, there are also exceptions.	('TMZ', 'Chemical', 'MESH:D000077204', (108, 111))	('better', 'PosReg', (89, 95))	('SDHB', 'Gene', '6390', (36, 40))	('response to TMZ', 'MPA', (96, 111))	('SDHB', 'Gene', (36, 40))	('patients', 'Species', '9606', (22, 30))	('mutation', 'Var', (41, 49))	('MGMT', 'Gene', (53, 57))	('MGMT', 'Gene', '4255', (53, 57))	('promoter hypermethylation', 'Var', (58, 83))
4075	32132978	Radionuclide therapy includes 131I-MIBG therapy and peptide receptor radionuclide therapy (PRRT, such as 177Lu-DOTATATE), which can only be used for the treatment of tumors with uptake of the tracer.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('131I-MIBG', 'Chemical', 'MESH:D019797', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('131I-MIBG', 'Var', (30, 39))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (105, 119))	('peptide', 'Protein', (52, 59))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
4080	32132978	TMZ was effective in MPP patients, especially those with SDHB germline mutation.	('MPP', 'Disease', (21, 24))	('SDHB', 'Gene', '6390', (57, 61))	('patients', 'Species', '9606', (25, 33))	('SDHB', 'Gene', (57, 61))	('MPP', 'Disease', 'MESH:D010673', (21, 24))	('germline mutation', 'Var', (62, 79))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))
4117	32132978	Thirty five to forty percent of patients with PHEO/PGL have germline genetic mutation, and the rate is 50% in patients with MPP.	('PHEO', 'Disease', 'MESH:D010673', (46, 50))	('patients', 'Species', '9606', (32, 40))	('MPP', 'Disease', 'MESH:D010673', (124, 127))	('PHEO', 'Disease', (46, 50))	('PGL', 'Disease', 'MESH:D010235', (51, 54))	('PHEO', 'Phenotype', 'HP:0002666', (46, 50))	('germline genetic mutation', 'Var', (60, 85))	('MPP', 'Disease', (124, 127))	('PGL', 'Phenotype', 'HP:0002668', (51, 54))	('PGL', 'Disease', (51, 54))	('patients', 'Species', '9606', (110, 118))
4119	32132978	Mutations in SDHB are one of the most common causes of familial PHEO/PGL, and tend to be associated with MPPs, particularly MPPs that afflict younger patients.	('associated with', 'Reg', (89, 104))	('PHEO', 'Disease', 'MESH:D010673', (64, 68))	('PGL', 'Disease', 'MESH:D010235', (69, 72))	('MPP', 'Disease', 'MESH:D010673', (124, 127))	('PHEO', 'Disease', (64, 68))	('SDHB', 'Gene', '6390', (13, 17))	('MPP', 'Disease', 'MESH:D010673', (105, 108))	('causes', 'Reg', (45, 51))	('PGL', 'Phenotype', 'HP:0002668', (69, 72))	('Mutations', 'Var', (0, 9))	('MPP', 'Disease', (124, 127))	('SDHB', 'Gene', (13, 17))	('patients', 'Species', '9606', (150, 158))	('PHEO', 'Phenotype', 'HP:0002666', (64, 68))	('MPP', 'Disease', (105, 108))	('PGL', 'Disease', (69, 72))
4124	32132978	MGMT is a highly-efficient DNA repair enzyme, which can repair methylated DNA.	('MGMT', 'Gene', (0, 4))	('methylated', 'Var', (63, 73))	('MGMT', 'Gene', '4255', (0, 4))
4133	32132978	Ten patients had a SDHB germline mutation.	('germline', 'Var', (24, 32))	('SDHB', 'Gene', '6390', (19, 23))	('patients', 'Species', '9606', (4, 12))	('SDHB', 'Gene', (19, 23))
4135	32132978	PFS was significantly longer in patients with SDHB mutation than in patients without mutations (19.7 vs. 2.9 months), 80% of PR patients exhibited MGMT deficience.	('patients', 'Species', '9606', (32, 40))	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('exhibited', 'Reg', (137, 146))	('patients', 'Species', '9606', (68, 76))	('mutation', 'Var', (51, 59))	('MGMT', 'Gene', (147, 151))	('patients', 'Species', '9606', (128, 136))	('MGMT', 'Gene', '4255', (147, 151))
4136	32132978	In a separate cohort involving 190 PHEO/PGLs, SDHB mutation was associated with hypermethylation of the MGMT promoter and low expression of MGMT.	('PHEO', 'Disease', (35, 39))	('MGMT', 'Gene', (104, 108))	('MGMT', 'Gene', '4255', (104, 108))	('SDHB', 'Gene', '6390', (46, 50))	('hypermethylation', 'MPA', (80, 96))	('SDHB', 'Gene', (46, 50))	('expression', 'MPA', (126, 136))	('PGL', 'Phenotype', 'HP:0002668', (40, 43))	('PGL', 'Disease', (40, 43))	('PHEO', 'Phenotype', 'HP:0002666', (35, 39))	('low', 'NegReg', (122, 125))	('mutation', 'Var', (51, 59))	('PGL', 'Disease', 'MESH:D010235', (40, 43))	('PHEO', 'Disease', 'MESH:D010673', (35, 39))	('MGMT', 'Gene', (140, 144))	('MGMT', 'Gene', '4255', (140, 144))
4138	32132978	And the result can be explained by the silencing of MGMT expression as a consequence of MGMT promoter hypermethylation in SDHB-mutated tumors.	('MGMT', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('MGMT', 'Gene', '4255', (52, 56))	('SDHB', 'Gene', '6390', (122, 126))	('MGMT', 'Gene', (88, 92))	('silencing', 'NegReg', (39, 48))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('MGMT', 'Gene', '4255', (88, 92))	('SDHB', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('hypermethylation', 'Var', (102, 118))
4139	32132978	However, some other studies showed that, like our case, TMZ was also effective in patients with non-SDHB mutations.	('TMZ', 'Chemical', 'MESH:D000077204', (56, 59))	('patients', 'Species', '9606', (82, 90))	('mutations', 'Var', (105, 114))	('SDHB', 'Gene', '6390', (100, 104))	('SDHB', 'Gene', (100, 104))
4140	32132978	Tumors carrying mutations in Krebs cycle-related genes, such as SDHx and FH, exhibit CpG island hypermethylation, which was caused by the accumulation of specific metabolites.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SDHx', 'Chemical', '-', (64, 68))	('SDHx', 'Gene', (64, 68))	('mutations', 'Var', (16, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Krebs', 'Chemical', '-', (29, 34))	('hypermethylation', 'Var', (96, 112))
4142	32132978	Our patient did not have any known germline pathogenic genetic change, but showed MGMT promoter hypermethylation, suggesting that other factors might also contribute DNA hypermethylation.	('patient', 'Species', '9606', (4, 11))	('MGMT', 'Gene', (82, 86))	('MGMT', 'Gene', '4255', (82, 86))	('contribute', 'Reg', (155, 165))	('hypermethylation', 'Var', (96, 112))
4146	32132978	In contrast, in a patient with both SDHB mutation and MGMT promoter hypermethylation (patient 6), the partial response to TMZ lasted only 8 month.	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('MGMT', 'Gene', (54, 58))	('mutation', 'Var', (41, 49))	('patient', 'Species', '9606', (86, 93))	('MGMT', 'Gene', '4255', (54, 58))	('patient', 'Species', '9606', (18, 25))	('TMZ', 'Chemical', 'MESH:D000077204', (122, 125))
4147	32132978	Other two patients with SDHB mutation (patient 9 and patient 14) even had PD after TMZ treatment.	('mutation', 'Var', (29, 37))	('TMZ', 'Chemical', 'MESH:D000077204', (83, 86))	('patient', 'Species', '9606', (39, 46))	('patient', 'Species', '9606', (10, 17))	('SDHB', 'Gene', '6390', (24, 28))	('patients', 'Species', '9606', (10, 18))	('SDHB', 'Gene', (24, 28))	('patient', 'Species', '9606', (53, 60))
4149	32132978	In general, patients with SDHB mutation or MGMT promoter hypermethylation respond better to TMZ.	('patients', 'Species', '9606', (12, 20))	('better', 'PosReg', (82, 88))	('mutation', 'Var', (31, 39))	('SDHB', 'Gene', '6390', (26, 30))	('SDHB', 'Gene', (26, 30))	('MGMT', 'Gene', '4255', (43, 47))	('MGMT', 'Gene', (43, 47))	('TMZ', 'Chemical', 'MESH:D000077204', (92, 95))
4151	32132978	Patients whose tumors carried a methylated MGMT promoter benefited more from TMZ treatment.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('benefited', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('TMZ', 'Chemical', 'MESH:D000077204', (77, 80))	('Patients', 'Species', '9606', (0, 8))	('MGMT', 'Gene', '4255', (43, 47))	('MGMT', 'Gene', (43, 47))	('methylated', 'Var', (32, 42))	('tumors', 'Disease', (15, 21))
4167	32132978	A recent retrospective study showed that, in 12 MPP patients with SDHB gene mutation, all patients had tumor reduction (12-100% by RECIST) upon CVD, which suggests CVD therapy probably works better in patients with SDHB mutation.	('SDHB', 'Gene', (66, 70))	('SDHB', 'Gene', '6390', (215, 219))	('MPP', 'Disease', 'MESH:D010673', (48, 51))	('patients', 'Species', '9606', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SDHB', 'Gene', (215, 219))	('MPP', 'Disease', (48, 51))	('tumor reduction', 'Disease', (103, 118))	('SDHB', 'Gene', '6390', (66, 70))	('mutation', 'Var', (76, 84))	('patients', 'Species', '9606', (90, 98))	('tumor reduction', 'Disease', 'MESH:D009369', (103, 118))	('patients', 'Species', '9606', (52, 60))
4168	32132978	However, CVD is not effective in all patients with SDHB mutation (patient 1 and patient 2 in Table 1).	('patient', 'Species', '9606', (37, 44))	('patients', 'Species', '9606', (37, 45))	('patient', 'Species', '9606', (66, 73))	('SDHB', 'Gene', '6390', (51, 55))	('SDHB', 'Gene', (51, 55))	('mutation', 'Var', (56, 64))	('patient', 'Species', '9606', (80, 87))
4246	32049819	In our study, the number of extreme hypertensive or hypotensive episodes were similar between the 2 groups; however, the mean maximal systolic and diastolic BP was significantly higher in TPA during the operation.	('TPA', 'Chemical', '-', (188, 191))	('hypotensive', 'Disease', (52, 63))	('hypertensive', 'Disease', 'MESH:D006973', (36, 48))	('higher', 'PosReg', (178, 184))	('hypertensive', 'Disease', (36, 48))	('TPA', 'Var', (188, 191))	('hypotensive', 'Disease', 'MESH:D007022', (52, 63))
4387	31248124	Patients with high norepinephrine had higher systolic BP (cutoff = twice the upper reference value, p = 0.025, cutoff = 10 times the upper reference value (p = 0.013).	('systolic BP', 'MPA', (45, 56))	('high norepinephrine', 'Var', (14, 33))	('Patients', 'Species', '9606', (0, 8))	('high norepinephrine', 'Phenotype', 'HP:0003345', (14, 33))	('higher', 'PosReg', (38, 44))	('BP', 'Chemical', '-', (54, 56))	('norepinephrine', 'Chemical', 'MESH:D009638', (19, 33))	('higher systolic BP', 'Phenotype', 'HP:0004421', (38, 56))
4388	31248124	The tumor SUVmax and the tumor-to liver ratio was higher in patients with high norepinephrine (cutoff = 10 times the upper reference value, p = 0.009).	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('higher', 'PosReg', (50, 56))	('high', 'Var', (74, 78))	('tumor', 'Disease', (25, 30))	('patients', 'Species', '9606', (60, 68))	('high norepinephrine', 'Phenotype', 'HP:0003345', (74, 93))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('norepinephrine', 'Chemical', 'MESH:D009638', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
4468	31312604	performed a systemic review and meta-analysis of the role of this type of imaging in detecting paragangliomas and found that per-lesion detection rates of 68Ga-DOTA-SST PET were consistently higher (ranging from 92% to 100%) than other imaging modalities, including 18F-fluorohydroxyphenylalanine (18F-FDOPA) PET, 18F-FDG PET, and 123/131I-metaiodobenzylguanidine (123/131I-MIBG) scintigraphy.	('paragangliomas', 'Disease', (95, 109))	('higher', 'PosReg', (191, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('68Ga-DOTA-SST', 'Var', (155, 168))	('MIBG', 'Chemical', '-', (374, 378))	('68Ga-DOTA', 'Chemical', '-', (155, 164))	('paragangliomas', 'Disease', 'MESH:D010235', (95, 109))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))
4504	27022413	Multimodal Somatostatin Receptor Theranostics Using [64Cu]Cu-/[177Lu]Lu-DOTA-(Tyr3)octreotate and AN-238 in a Mouse Pheochromocytoma Model Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamine-producing chromaffin cell tumors.	('paragangliomas', 'Phenotype', 'HP:0002668', (175, 189))	('catecholamine', 'Chemical', 'MESH:D002395', (211, 224))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (139, 155))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (116, 132))	('Lu-DOTA-(Tyr3)octreotate', 'Chemical', '-', (69, 93))	('chromaffin', 'Chemical', '-', (235, 245))	('Cu', 'Chemical', 'MESH:D003300', (55, 57))	('Pheochromocytoma', 'Disease', (116, 132))	('177Lu', 'Chemical', 'MESH:C000615061', (63, 68))	('Somatostatin', 'Gene', '20604', (11, 23))	('Mouse', 'Species', '10090', (110, 115))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (139, 156))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('Pheochromocytomas', 'Disease', (139, 156))	('Pheochromocytoma', 'Disease', (139, 155))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (139, 155))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (161, 189))	('[64Cu]', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (235, 257))	('AN-238', 'Var', (98, 104))	('tumors', 'Disease', (251, 257))	('extra-adrenal paragangliomas', 'Disease', (161, 189))	('Somatostatin', 'Gene', (11, 23))	('AN', 'Chemical', 'MESH:D000431', (98, 100))	('PHEO', 'Gene', (191, 195))	('Cu', 'Chemical', 'MESH:D003300', (58, 60))	('PHEO', 'Gene', '114618', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (139, 156))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (116, 132))
4505	27022413	Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE) and AN-238.	('[177Lu]Lu-DOTA-', 'Var', (196, 211))	('PHEO', 'Gene', (59, 63))	('SSTR2', 'Gene', (49, 54))	('radionuclides', 'Chemical', 'MESH:D011868', (146, 159))	('AN-238', 'Chemical', 'MESH:C110845', (243, 249))	('DOTATATE', 'Chemical', '-', (229, 237))	('[177Lu]Lu-DOTA-(Tyr3)octreotate', 'Chemical', '-', (196, 227))	('PHEO', 'Gene', '114618', (59, 63))
4509	27022413	Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [177Lu]Lu-DOTATATE compared to AN-238 and doxorubicin.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mice', 'Species', '10090', (126, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (194, 205))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (69, 74))	('AN-238', 'Chemical', 'MESH:C110845', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('reduction', 'NegReg', (39, 48))	('monoamine', 'Chemical', '-', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('[177Lu]Lu-DOTATATE', 'Var', (152, 170))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (152, 170))
4519	27022413	Some support for the radionuclide approach is provided by clinical reports on [177Lu]Lu- and [90Y]Y-labeled somatostatin analogs leading to longer progression-free survival, mainly in gastroenteropancreatic neuroendocrine tumors, but also in metastatic neuroendocrine tumors, including PHEO/PGLs.	('PHEO', 'Gene', '114618', (286, 290))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('longer', 'PosReg', (140, 146))	('neuroendocrine tumors', 'Disease', (253, 274))	('[177Lu]Lu-', 'Var', (78, 88))	('[177Lu', 'Chemical', 'MESH:C000615061', (78, 84))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (184, 228))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (207, 228))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (207, 228))	('PHEO', 'Gene', (286, 290))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (184, 228))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (253, 274))	('radionuclide', 'Chemical', 'MESH:D011868', (21, 33))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (253, 274))
4525	27022413	This study had two objectives: 1. characterization of the MPC-mCherry tumor model for preclinical evaluation of somatostatin type 2 receptor (SSTR2)-targeting theranostic applications; and 2. use of the model for preclinical evaluation of receptor-targeted therapies using [177Lu]Lu-DOTA-(Tyr3)octreotate (DOTATATE) and AN-238 compared to systemic therapy using doxorubicin for the treatment of PHEO/PGLs.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('PHEO', 'Gene', (395, 399))	('tumor', 'Disease', (70, 75))	('[177Lu]Lu-DOTA-(Tyr3)octreotate', 'Chemical', '-', (273, 304))	('DOTATATE', 'Chemical', '-', (306, 314))	('PHEO', 'Gene', '114618', (395, 399))	('[177Lu]Lu-DOTA-(Tyr3', 'Var', (273, 293))	('doxorubicin', 'Chemical', 'MESH:D004317', (362, 373))	('AN-238', 'Chemical', 'MESH:C110845', (320, 326))
4535	27022413	Protein bands were detected using the primary antibodies anti-SSTR2 [UMB1, ab134152] (Abcam, Cambridge, UK), anti-chromogranin A [C-20, sc1488] (Santa Cruz Biotechnology, Heidelberg, Germany), anti-ss-actin [A5316] (Sigma-Aldrich).	('chromogranin A', 'Gene', (114, 128))	('anti-ss-actin', 'Var', (193, 206))	('chromogranin A', 'Gene', '12652', (114, 128))
4542	27022413	Endogenous peroxidase was blocked with PBS containing 0.3% (v/v) H2O2.	('PBS', 'Chemical', 'MESH:D007854', (39, 42))	('H2O2', 'Chemical', 'MESH:D006861', (65, 69))	('H2O2', 'Var', (65, 69))	('Endogenous peroxidase', 'Enzyme', (0, 21))
4597	27022413	Most importantly, by co-injection of somatostatin analogs, all imaging and distribution studies similarly showed significantly reduced radiotracer uptake in tumors (Figure 3 D-F) in the order of [natLu]Lu-DOTATATE > octreotide > AN-238.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('[natLu]Lu-DOTATATE', 'Chemical', '-', (195, 213))	('AN-238', 'Chemical', 'MESH:C110845', (229, 235))	('radiotracer uptake', 'MPA', (135, 153))	('octreotide', 'Chemical', 'MESH:D015282', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('reduced', 'NegReg', (127, 134))	('reduced radiotracer uptake', 'Phenotype', 'HP:0031219', (127, 153))	('[natLu]Lu-DOTATATE', 'Var', (195, 213))
4598	27022413	Ex vivo radiotracer distribution revealed octreotide and [natLu]Lu-DOTATATE to significantly inhibit radiotracer uptake also in pancreas due to physiologic mSSTR expression.	('inhibit', 'NegReg', (93, 100))	('[natLu]Lu-DOTATATE', 'Chemical', '-', (57, 75))	('[natLu]Lu-DOTATATE', 'Var', (57, 75))	('octreotide', 'Chemical', 'MESH:D015282', (42, 52))	('radiotracer uptake', 'MPA', (101, 119))
4601	27022413	Size and fluorescence intensity of tumors (Figure 4 A) appeared similar at therapy start (15 days pci) and reduced after treatment (30 days pci) with doxorubicin, AN-238, and [177Lu]Lu-DOTATATE compared to the control.	('AN-238', 'Chemical', 'MESH:C110845', (163, 169))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('reduced', 'NegReg', (107, 114))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('AN-238', 'Var', (163, 169))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('fluorescence intensity', 'MPA', (9, 31))	('[177Lu]Lu-DOTATATE', 'Var', (175, 193))
4603	27022413	After [177Lu]Lu-DOTATATE treatment, tumors declined continuously until 30 days pci (t1/2.= 2.8 days).	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (6, 24))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('declined', 'NegReg', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('[177Lu]Lu-DOTATATE', 'Var', (6, 24))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
4606	27022413	Notably, doubling time of tumor volume was significantly lower in animals treated with AN-238 compared to doxorubicin.	('doubling time', 'CPA', (9, 22))	('AN-238', 'Chemical', 'MESH:C110845', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('doxorubicin', 'Chemical', 'MESH:D004317', (106, 117))	('AN-238', 'Var', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('lower', 'NegReg', (57, 62))
4607	27022413	In relation to the control group, single treatment with doxorubicin, AN-238, or [177Lu]Lu-DOTATATE produced significant reduction of tumor growth in vivo (Table 2).	('AN-238', 'Chemical', 'MESH:C110845', (69, 75))	('[177Lu]Lu-DOTATATE', 'Var', (80, 98))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('reduction', 'NegReg', (120, 129))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (80, 98))	('tumor', 'Disease', (133, 138))	('doxorubicin', 'Chemical', 'MESH:D004317', (56, 67))
4608	27022413	Additionally, combinations of [177Lu]Lu-DOTATATE with doxorubicin (simultaneously) or AN-238 (consecutively) exerted similar effects on tumor growth compared to single [177Lu]Lu-DOTATATE treatment (Table 2, Figure S8 A-B, Table S4).	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (30, 48))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('combinations', 'Interaction', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (168, 186))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('[177Lu]Lu-DOTATATE', 'Var', (30, 48))	('tumor', 'Disease', (136, 141))	('AN-238', 'Chemical', 'MESH:C110845', (86, 92))
4610	27022413	After [177Lu]Lu-DOTATATE treatment of MPC-mCherry tumor-bearing animals, in vivo PLI and SPECT imaging (Figure 4 C-E) revealed strong accumulation of 177Lu activity in tumors and, to a lesser extent, in kidneys one day after therapy start (  16 days pci).	('177Lu activity', 'MPA', (150, 164))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('accumulation', 'PosReg', (134, 146))	('tumor', 'Disease', (168, 173))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (6, 24))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('[177Lu', 'Var', (6, 12))	('177Lu', 'Chemical', 'MESH:C000615061', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('177Lu', 'Chemical', 'MESH:C000615061', (7, 12))
4614	27022413	Additionally, combinations of [177Lu]Lu-DOTATATE with doxorubicin or AN-238 exerted similar effects on 177Lu activity in tumors compared to single [177Lu]Lu-DOTATATE treatment (Figure S8 D, Table S4).	('177Lu', 'Chemical', 'MESH:C000615061', (103, 108))	('177Lu', 'Chemical', 'MESH:C000615061', (31, 36))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (30, 48))	('177Lu', 'Chemical', 'MESH:C000615061', (148, 153))	('combinations', 'Interaction', (14, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('AN-238', 'Chemical', 'MESH:C110845', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('177Lu activity', 'MPA', (103, 117))	('tumors', 'Disease', (121, 127))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (147, 165))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('[177Lu]Lu-DOTATATE', 'Var', (30, 48))
4622	27022413	Notably, [177Lu]Lu-DOTATATE was 2-fold more effective in reducing the overall renal monoamine excretion compared to doxorubicin and AN-238.	('monoamine', 'Chemical', '-', (84, 93))	('AN-238', 'Chemical', 'MESH:C110845', (132, 138))	('[177Lu]Lu-DOTATATE', 'Var', (9, 27))	('doxorubicin', 'Chemical', 'MESH:D004317', (116, 127))	('renal monoamine excretion', 'MPA', (78, 103))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (9, 27))	('reducing', 'NegReg', (57, 65))
4628	27022413	The mSSTR2 pattern and morphology of AN-238-treated tumors appeared similar to control.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('AN-238-treated', 'Var', (37, 51))	('mSSTR2', 'Gene', '20606', (4, 10))	('AN-238', 'Chemical', 'MESH:C110845', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('mSSTR2', 'Gene', (4, 10))
4629	27022413	In contrast, [177Lu]Lu-DOTATATE-treated tumors showed condensed mSSTR2 spots irrespective of any membranous localization as well as a dispersed tumor cell structure with irregularly-shaped nuclei and large intercellular spaces.	('tumor', 'Disease', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('[177Lu', 'Var', (13, 19))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (13, 31))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mSSTR2', 'Gene', (64, 70))	('mSSTR2', 'Gene', '20606', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Disease', (40, 46))
4630	27022413	Notably, Western blot analysis revealed no significant differences in the relative mSSTR2 tumor levels per chromogranin A-positive tumor cells after AN-238 and [177Lu]Lu-DOTATATE treatment compared to control (Figure 6 B-C).	('mSSTR2', 'Gene', (83, 89))	('AN-238', 'Chemical', 'MESH:C110845', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mSSTR2', 'Gene', '20606', (83, 89))	('chromogranin A', 'Gene', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('[177Lu]Lu-DOTATATE', 'Var', (160, 178))	('tumor', 'Disease', (131, 136))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (160, 178))	('chromogranin A', 'Gene', '12652', (107, 121))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
4631	27022413	In therapy groups, body weight tended to decrease immediately after both doxorubicin and AN-238, but not after [177Lu]Lu-DOTATATE treatment.	('AN-238', 'Var', (89, 95))	('decrease', 'NegReg', (41, 49))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (111, 129))	('AN-238', 'Chemical', 'MESH:C110845', (89, 95))	('doxorubicin', 'Chemical', 'MESH:D004317', (73, 84))	('body weight', 'CPA', (19, 30))
4632	27022413	We found white blood cells to be significantly reduced to 1.7 x 106/mL after both doxorubicin and AN-238 treatment, but only non-significantly lowered to 2.4 x 106/mL after [177Lu]Lu-DOTATATE treatment.	('white blood cells', 'CPA', (9, 26))	('AN-238', 'Var', (98, 104))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('AN-238', 'Chemical', 'MESH:C110845', (98, 104))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (173, 191))	('reduced', 'NegReg', (47, 54))
4633	27022413	Additionally, combinations of [177Lu]Lu-DOTATATE with doxorubicin or AN-238 tended to increase adverse effects (Figure S8 E-F).	('adverse', 'MPA', (95, 102))	('increase', 'PosReg', (86, 94))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (30, 48))	('doxorubicin', 'Chemical', 'MESH:D004317', (54, 65))	('combinations', 'Interaction', (14, 26))	('AN-238', 'Chemical', 'MESH:C110845', (69, 75))	('AN-238', 'Gene', (69, 75))	('[177Lu]Lu-DOTATATE', 'Var', (30, 48))
4636	27022413	Most importantly, [177Lu]Lu-DOTATATE treatment was by far the most efficient therapeutic strategy in the MPC-mCherry model compared to AN-238 and doxorubicin.	('AN-238', 'Chemical', 'MESH:C110845', (135, 141))	('MPC-mCherry', 'Disease', (105, 116))	('[177Lu]Lu-DOTATATE', 'Var', (18, 36))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (18, 36))	('doxorubicin', 'Chemical', 'MESH:D004317', (146, 157))
4640	27022413	Moreover, small animal imaging and autoradiographic applications benefit from [64Cu]Cu-labeled radiotracers in terms of long radionuclide half-life and low maximal ss+ emission energy, allowing for higher imaging resolution and longer experimental durations.	('imaging', 'MPA', (205, 212))	('[64Cu]Cu-labeled', 'Var', (78, 94))	('64Cu', 'Chemical', 'MESH:C000615411', (79, 83))	('Cu', 'Chemical', 'MESH:D003300', (84, 86))	('radionuclide', 'Chemical', 'MESH:D011868', (125, 137))	('Cu', 'Chemical', 'MESH:D003300', (81, 83))	('higher', 'PosReg', (198, 204))
4645	27022413	However, a certain variation of mSSTR2-levels between tumors of different animals, as well as between clonal tumor cell sub-populations within individual lesions reflect the heterogeneity of MPC-mCherry tumors, as has been described for human PHEO/PGLs as a consequence of genetic lesions and epigenetic changes, as well as specific copy number alterations.	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('genetic lesions', 'Disease', 'MESH:D020022', (273, 288))	('PHEO', 'Gene', (243, 247))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('MPC-mCherry tumors', 'Disease', (191, 209))	('mSSTR2', 'Gene', (32, 38))	('MPC-mCherry tumors', 'Disease', 'MESH:D009369', (191, 209))	('PHEO', 'Gene', '114618', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('epigenetic changes', 'Var', (293, 311))	('tumors', 'Disease', (54, 60))	('copy number alterations', 'Var', (333, 356))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('human', 'Species', '9606', (237, 242))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('genetic lesions', 'Disease', (273, 288))	('mSSTR2', 'Gene', '20606', (32, 38))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (109, 114))
4654	27022413	In mice, PLI, PET and ex vivo radiotracer distribution studies using [64Cu]Cu-DOTATATE similarly showed that, after co-injection, [natLu]Lu-DOTATATE exhibit superior tumor targeting efficiency to octreotide and AN-238.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('AN-238', 'Chemical', 'MESH:C110845', (211, 217))	('64Cu', 'Chemical', 'MESH:C000615411', (70, 74))	('mice', 'Species', '10090', (3, 7))	('[natLu]Lu-DOTATATE', 'Chemical', '-', (130, 148))	('tumor', 'Disease', (166, 171))	('Cu-DOTATATE', 'Chemical', '-', (75, 86))	('superior', 'PosReg', (157, 165))	('octreotide', 'Chemical', 'MESH:D015282', (196, 206))	('[natLu]Lu-DOTATATE', 'Var', (130, 148))
4665	27022413	The superior therapeutic efficacy of [177Lu]Lu-DOTATATE reflects its ability for high-affinity mSSTR2 binding as well as for exerting 177Lu-related bystander and crossfire effects assumed to allow for overcoming tumor-specific escape strategies based on, e.g., multi-drug resistance, hypoxia, and irregular vascularization.	('hypoxia', 'Disease', 'MESH:D000860', (284, 291))	('177Lu', 'Chemical', 'MESH:C000615061', (38, 43))	('binding', 'Interaction', (102, 109))	('hypoxia', 'Disease', (284, 291))	('therapeutic efficacy', 'CPA', (13, 33))	('[177Lu]Lu-DOTATATE', 'Var', (37, 55))	('overcoming', 'PosReg', (201, 211))	('mSSTR2', 'Gene', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mSSTR2', 'Gene', '20606', (95, 101))	('177Lu', 'Chemical', 'MESH:C000615061', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (37, 55))	('tumor', 'Disease', (212, 217))	('drug resistance', 'Phenotype', 'HP:0020174', (267, 282))
4667	27022413	Supporting this, only [177Lu]Lu-DOTATATE therapy severely affected the histologic integrity of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('affected', 'Reg', (58, 66))	('[177Lu]Lu-DOTATATE', 'Var', (22, 40))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (22, 40))
4673	27022413	However, superior anti-tumor efficacy of AN-238 to 2-pyrrolinodoxorubicin on tumor cells with elevated SSTR2 levels has been demonstrated in many studies.	('AN-238', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('2-pyrrolinodoxorubicin', 'Chemical', 'MESH:C098751', (51, 73))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (23, 28))	('SSTR2', 'MPA', (103, 108))	('tumor', 'Disease', (77, 82))	('AN-238', 'Chemical', 'MESH:C110845', (41, 47))
4676	27022413	Reduced white blood cells result from the cytotoxic effects of doxorubicin on rapidly dividing multipotent hematopoietic progenitor cells as well as from the capability of AN-238 and [177Lu]Lu-DOTATATE for targeting mSSTR2 on lymphocytes and inflammatory cells.	('white blood cells', 'CPA', (8, 25))	('AN-238', 'Var', (172, 178))	('[177Lu]Lu-DOTATATE', 'Var', (183, 201))	('Reduced white blood cells', 'Phenotype', 'HP:0001882', (0, 25))	('AN-238', 'Chemical', 'MESH:C110845', (172, 178))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (183, 201))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('mSSTR2', 'Gene', '20606', (216, 222))	('cytotoxic effects', 'CPA', (42, 59))	('mSSTR2', 'Gene', (216, 222))
4677	27022413	Importantly, agonist-induced downregulation of mSSTR2 was not present in tumors after [177Lu]Lu-DOTATATE and AN-238 treatment.	('AN-238', 'Var', (109, 115))	('downregulation', 'NegReg', (29, 43))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('[177Lu]Lu-DOTATATE', 'Var', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('AN-238', 'Chemical', 'MESH:C110845', (109, 115))	('mSSTR2', 'Gene', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (86, 104))	('mSSTR2', 'Gene', '20606', (47, 53))	('tumors', 'Disease', (73, 79))
4679	27022413	However, our pilot studies on combining [177Lu]Lu-DOTATATE with doxorubicin (simultaneously) or AN-238 (in quick succession) revealed similar therapeutic effects compared to single [177Lu]Lu-DOTATATE, thereby tending to increase adverse effects.	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (40, 58))	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (181, 199))	('doxorubicin', 'Chemical', 'MESH:D004317', (64, 75))	('combining', 'Interaction', (30, 39))	('[177Lu]Lu-DOTATATE', 'Var', (40, 58))	('AN-238', 'Chemical', 'MESH:C110845', (96, 102))
4683	27022413	Nevertheless, the model does recapitulate the clinical situation in which [68Ga]Ga-DOTATATE has been shown to be a superior imaging agent compared to others for metastatic PHEO/PGLs due to mutations of the succinate dehydrogenase subunit 2 (SDHB) gene.	('SDHB', 'Gene', (241, 245))	('due to', 'Reg', (182, 188))	('PHEO', 'Gene', (172, 176))	('SDHB', 'Gene', '67680', (241, 245))	('succinate dehydrogenase subunit 2', 'Gene', (206, 239))	('succinate dehydrogenase subunit 2', 'Gene', '67680', (206, 239))	('Ga-DOTATATE', 'Chemical', '-', (80, 91))	('mutations', 'Var', (189, 198))	('PHEO', 'Gene', '114618', (172, 176))
4684	27022413	This is also in agreement with other findings of high SSTR2 expression in PHEO/PGLs due to SDHB mutations.	('PHEO', 'Gene', (74, 78))	('expression', 'MPA', (60, 70))	('SDHB', 'Gene', '67680', (91, 95))	('PHEO', 'Gene', '114618', (74, 78))	('SDHB', 'Gene', (91, 95))	('SSTR2', 'Gene', (54, 59))	('mutations', 'Var', (96, 105))
4685	27022413	These clinical findings support the possibility that utility of [177Lu]Lu-DOTATATE reported here in the MPC-mCherry model may indeed translate to the clinic, and particularly to metastatic PHEO/PGLs due to SDHB mutations, which carry a high metastatic risk responsible for 40-50% of all cases of malignant disease.	('[177Lu]Lu-DOTATATE', 'Chemical', '-', (64, 82))	('SDHB', 'Gene', '67680', (206, 210))	('mutations', 'Var', (211, 220))	('PHEO', 'Gene', (189, 193))	('malignant disease', 'Disease', 'MESH:D009369', (296, 313))	('malignant disease', 'Disease', (296, 313))	('SDHB', 'Gene', (206, 210))	('PHEO', 'Gene', '114618', (189, 193))
4691	26574647	Prior studies have identified gigantism as a feature of a number of monogenic disorders, including mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene, multiple endocrine neoplasia types 1 and 4, McCune Albright Syndrome, Carney Complex, and the paraganglioma, pheochromocytoma and pituitary adenoma association (3PA) due to succinate dehydrogenase defects.	('succinate dehydrogenase', 'Gene', '6390', (347, 370))	('pheochromocytoma', 'Disease', 'MESH:D010673', (283, 299))	('Carney Complex', 'Disease', (244, 258))	('paraganglioma', 'Phenotype', 'HP:0002668', (268, 281))	('pheochromocytoma', 'Disease', (283, 299))	('aryl hydrocarbon receptor interacting protein (AIP)', 'Gene', '9049', (116, 167))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (283, 299))	('glioma', 'Phenotype', 'HP:0009733', (275, 281))	('neoplasia', 'Phenotype', 'HP:0002664', (193, 202))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (174, 202))	('multiple endocrine neoplasia', 'Disease', (174, 202))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (183, 202))	('succinate dehydrogenase', 'Gene', (347, 370))	('pituitary adenoma', 'Disease', 'MESH:D010911', (304, 321))	('McCune Albright Syndrome', 'Disease', (218, 242))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (304, 321))	('pituitary adenoma', 'Disease', (304, 321))	('Carney Complex', 'Disease', 'MESH:D056733', (244, 258))	('mutations', 'Var', (99, 108))	('paraganglioma', 'Disease', (268, 281))	('aryl hydrocarbon receptor interacting protein (AIP', 'Gene', (116, 166))	('paraganglioma', 'Disease', 'MESH:D010235', (268, 281))
4699	26574647	When pituitary gigantism is suspected, the clinician should consider the presence of disorders known to be associated with GH-secreting pituitary tumors, including McCune Albright syndrome (MAS), Carney complex (CNC), multiple endocrine neoplasia types 1 and 4 (MEN 1, MEN 4), familial isolated pituitary adenoma (FIPA), the paraganglioma, pheochromocytoma and pituitary adenoma association (3PA) due to succinate dehydrogenase defects, and X-linked acrogigantism (X-LAG).	('pituitary adenoma', 'Phenotype', 'HP:0002893', (295, 312))	('pituitary adenoma', 'Disease', 'MESH:D010911', (295, 312))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (218, 246))	('pheochromocytoma', 'Disease', (340, 356))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (340, 356))	('succinate dehydrogenase', 'Gene', '6390', (404, 427))	('multiple endocrine neoplasia', 'Disease', (218, 246))	('MEN 1', 'Gene', '4221', (262, 267))	('paraganglioma', 'Phenotype', 'HP:0002668', (325, 338))	('glioma', 'Phenotype', 'HP:0009733', (332, 338))	('McCune Albright syndrome', 'Disease', (164, 188))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (286, 312))	('pituitary gigantism', 'Disease', 'MESH:D005877', (5, 24))	('familial isolated pituitary adenoma', 'Disease', 'MESH:C566321', (277, 312))	('MEN 1', 'Gene', (262, 267))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('MEN 4', 'Gene', (269, 274))	('GH-secreting pituitary tumors', 'Disease', 'MESH:D049912', (123, 152))	('pituitary adenoma', 'Disease', 'MESH:D010911', (361, 378))	('defects', 'Var', (428, 435))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (361, 378))	('succinate dehydrogenase', 'Gene', (404, 427))	('neoplasia', 'Phenotype', 'HP:0002664', (237, 246))	('paraganglioma', 'Disease', (325, 338))	('pituitary adenoma', 'Disease', (361, 378))	('paraganglioma', 'Disease', 'MESH:D010235', (325, 338))	('pituitary gigantism', 'Disease', (5, 24))	('McCune Albright syndrome', 'Disease', 'MESH:D005357', (164, 188))	('MEN 4', 'Gene', '1027', (269, 274))	('familial isolated pituitary adenoma', 'Disease', (277, 312))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (227, 246))	('pheochromocytoma', 'Disease', 'MESH:D010673', (340, 356))	('GH-secreting pituitary tumors', 'Disease', (123, 152))
4732	26574647	Activating mutations of Gsalpha, the stimulatory subunit of the heterotrimeric G protein complex responsible for intracellular signaling of G protein-coupled receptors (GPCRs), are the source of the clinical manifestations found in MAS.	('mutations', 'Var', (11, 20))	('GPCR', 'Gene', (169, 173))	('Activating', 'PosReg', (0, 10))	('GPCR', 'Gene', '442206', (169, 173))	('Gsalpha', 'Gene', (24, 31))	('MAS', 'Disease', (232, 235))	('Gsalpha', 'Gene', '2778', (24, 31))
4739	26574647	Mutations in the gene encoding for the tumor suppressor nuclear protein menin lead to the development of neoplasia.	('menin', 'Gene', (72, 77))	('lead to', 'Reg', (78, 85))	('neoplasia', 'Phenotype', 'HP:0002664', (105, 114))	('tumor suppressor', 'Gene', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('neoplasia', 'Disease', (105, 114))	('Mutations', 'Var', (0, 9))	('tumor suppressor', 'Gene', '7248', (39, 55))	('neoplasia', 'Disease', 'MESH:D009369', (105, 114))	('menin', 'Gene', '4221', (72, 77))
4745	26574647	Recently, a patient with pituitary gigantism was found to have a deletion in the 5'UTR of CDKN1B leading to reduced transcriptional activity of the gene.	('transcriptional activity', 'MPA', (116, 140))	('pituitary gigantism', 'Disease', (25, 44))	('pituitary gigantism', 'Disease', 'MESH:D005877', (25, 44))	('CDKN1B', 'Gene', (90, 96))	('reduced', 'NegReg', (108, 115))	('deletion in', 'Var', (65, 76))	('patient', 'Species', '9606', (12, 19))	('CDKN1B', 'Gene', '1027', (90, 96))
4747	26574647	Mutations in the gene encoding the regulatory subunit 1alpha of protein kinase A (PRKAR1A) are responsible for the majority of cases of CNC.	('CNC', 'Disease', (136, 139))	('PRKAR1A', 'Gene', (82, 89))	('responsible', 'Reg', (95, 106))	('PRKAR1A', 'Gene', '5573', (82, 89))	('Mutations', 'Var', (0, 9))
4749	26574647	Inactivating mutations in the gene encoding the aryl hydrocarbon receptor interacting protein (AIP) have been identified in about 20% of families with FIPA.	('identified', 'Reg', (110, 120))	('aryl hydrocarbon receptor interacting protein (AIP', 'Gene', (48, 98))	('aryl hydrocarbon receptor interacting protein (AIP)', 'Gene', '9049', (48, 99))	('Inactivating mutations', 'Var', (0, 22))
4750	26574647	Germline mutations in AIP are associated with large pituitary adenomas in children/adolescents and young adults, and usually are associated with somatotropinomas in 35% of the cases.	('Germline mutations', 'Var', (0, 18))	('somatotropinomas', 'Disease', (145, 161))	('associated', 'Reg', (129, 139))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (52, 70))	('AIP', 'Gene', '9049', (22, 25))	('AIP', 'Gene', (22, 25))	('somatotropinomas', 'Disease', 'MESH:D049912', (145, 161))	('pituitary adenomas', 'Disease', (52, 70))	('children', 'Species', '9606', (74, 82))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (52, 69))	('pituitary adenomas', 'Disease', 'MESH:D010911', (52, 70))	('associated with', 'Reg', (30, 45))
4751	26574647	A recent study compared 96 patients with germline AIP mutations and pituitary adenomas to 232 matched AIP-negative acromegaly controls.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (68, 86))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (68, 85))	('AIP', 'Gene', '9049', (50, 53))	('pituitary adenomas', 'Disease', (68, 86))	('acromegaly', 'Disease', (115, 125))	('mutations', 'Var', (54, 63))	('AIP', 'Gene', (50, 53))	('acromegaly', 'Phenotype', 'HP:0000845', (115, 125))	('patients', 'Species', '9606', (27, 35))	('AIP', 'Gene', '9049', (102, 105))	('AIP', 'Gene', (102, 105))	('acromegaly', 'Disease', 'MESH:D000172', (115, 125))	('pituitary adenomas', 'Disease', 'MESH:D010911', (68, 86))
4752	26574647	The population with AIP mutations was predominantly young and male with presentation during childhood.	('child', 'Species', '9606', (92, 97))	('mutations', 'Var', (24, 33))	('AIP', 'Gene', (20, 23))	('AIP', 'Gene', '9049', (20, 23))
4755	26574647	GH-secreting tumors associated with AIP mutations were more likely to cosecrete prolactin Another recent study examined AIP mutational status of FIPA and young pituitary adenoma patients, and found 37 FIPA families and 34 sporadic patients had AIP mutations.	('AIP', 'Gene', '9049', (244, 247))	('patients', 'Species', '9606', (231, 239))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('AIP', 'Gene', '9049', (36, 39))	('pituitary adenoma', 'Disease', (160, 177))	('GH-secreting tumors', 'Disease', 'MESH:D049912', (0, 19))	('AIP', 'Gene', (36, 39))	('patients', 'Species', '9606', (178, 186))	('pituitary adenoma', 'Disease', 'MESH:D010911', (160, 177))	('mutations', 'Var', (40, 49))	('prolactin', 'Gene', (80, 89))	('AIP', 'Gene', '9049', (120, 123))	('prolactin', 'Gene', '5617', (80, 89))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (160, 177))	('AIP', 'Gene', (120, 123))	('GH-secreting tumors', 'Disease', (0, 19))	('AIP', 'Gene', (244, 247))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
4756	26574647	One-quarter of the AIP mutation carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for patients carrying AIP mutations Patients with AIP mutations underwent more surgical interventions and had a poor response to somatostatin analogues with lower decreases in GH and IGF-I and less tumor shrinkage.	('Patients', 'Species', '9606', (193, 201))	('poor response to somatostatin', 'Phenotype', 'HP:0000824', (269, 298))	('AIP', 'Gene', '9049', (179, 182))	('somatostatin', 'Gene', '6750', (286, 298))	('pituitary disease', 'Phenotype', 'HP:0011747', (70, 87))	('somatostatin', 'Gene', (286, 298))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('mutations', 'Var', (183, 192))	('AIP', 'Gene', '9049', (19, 22))	('IGF-I', 'Gene', (340, 345))	('AIP', 'Gene', (179, 182))	('IGF-I', 'Gene', '3479', (340, 345))	('AIP', 'Gene', '9049', (207, 210))	('GH', 'Gene', '2688', (333, 335))	('decreases', 'NegReg', (320, 329))	('AIP', 'Gene', (19, 22))	('patients', 'Species', '9606', (161, 169))	('pituitary disease', 'Disease', 'MESH:D010900', (70, 87))	('AIP', 'Gene', (207, 210))	('mutations', 'Var', (211, 220))	('tumor', 'Disease', (355, 360))	('pituitary disease', 'Disease', (70, 87))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
4758	26574647	Germline mutations in genes coding for the succinate dehydrogenase (SDH) subunits A, B, C, and D have been identified in familial paragangliomas/pheochromocytomas and other tumors.	('Germline mutations', 'Var', (0, 18))	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('paraganglioma', 'Phenotype', 'HP:0002668', (130, 143))	('paragangliomas', 'Phenotype', 'HP:0002668', (130, 144))	('familial paragangliomas/pheochromocytomas', 'Disease', (121, 162))	('succinate dehydrogenase', 'Gene', (43, 66))	('SDH', 'Gene', (68, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (145, 162))	('identified', 'Reg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('familial paragangliomas/pheochromocytomas', 'Disease', 'MESH:C531777', (121, 162))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('SDH', 'Gene', '6390', (68, 71))	('succinate dehydrogenase', 'Gene', '6390', (43, 66))
4759	26574647	The first GH-secreting pituitary adenoma caused by a SDHD mutation in a patient with familial paragangliomas was described in 2012.	('familial paragangliomas', 'Disease', 'MESH:D010235', (85, 108))	('SDHD', 'Gene', (53, 57))	('SDHD', 'Gene', '6392', (53, 57))	('pituitary adenoma', 'Disease', (23, 40))	('mutation', 'Var', (58, 66))	('patient', 'Species', '9606', (72, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (94, 108))	('pituitary adenoma', 'Disease', 'MESH:D010911', (23, 40))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('familial paragangliomas', 'Disease', (85, 108))	('GH', 'Gene', '2688', (10, 12))	('caused by', 'Reg', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (101, 107))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (23, 40))
4760	26574647	A patient with an SDHB mutation, a somatotropinoma and paragangliomas was subsequently identified in addition to other patients with pituitary tumors and SDH defects.	('SDHB', 'Gene', (18, 22))	('SDHB', 'Gene', '6390', (18, 22))	('patient', 'Species', '9606', (119, 126))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('mutation', 'Var', (23, 31))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('patients', 'Species', '9606', (119, 127))	('paragangliomas', 'Disease', (55, 69))	('paragangliomas', 'Disease', 'MESH:D010235', (55, 69))	('pituitary tumors and SDH defects', 'Disease', 'MESH:D010911', (133, 165))	('paraganglioma', 'Phenotype', 'HP:0002668', (55, 68))	('paragangliomas', 'Phenotype', 'HP:0002668', (55, 69))	('somatotropinoma', 'Disease', 'MESH:D049912', (35, 50))	('somatotropinoma', 'Disease', (35, 50))	('patient', 'Species', '9606', (2, 9))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
4766	26574647	The Xq26.3 microduplications were initially identified by whole-genome array comparative genomic hybridization (aCGH) and subsequently confirmed by fluorescent in situ hybridization (FISH) and TaqMan copy number variant (CNV) assays.	('Xq26.3', 'Gene', (4, 10))	('GH', 'Gene', '2688', (114, 116))	('microduplications', 'Var', (11, 28))
4773	26574647	SRO1 (135,627,637-135,986,830) encompasses three protein-coding genes: CD40LG (MIM#300386), ARHGEF6 (MIM# 300267), and RBMX (MIM# 300199); while SRO2 (136,045,310-136,118,269) contains the sole GPR101 gene (MIM# 300393).	('CD40LG', 'Gene', (71, 77))	('ARHGEF6', 'Gene', (92, 99))	('RBMX', 'Gene', (119, 123))	('MIM# 300199);', 'Var', (125, 138))	('SRO2', 'Chemical', '-', (145, 149))	('MIM# 300393', 'Var', (207, 218))	('ARHGEF6', 'Gene', '9459', (92, 99))	('RBMX', 'Gene', '27316', (119, 123))	('GPR101', 'Gene', '83550', (194, 200))	('SRO1', 'Chemical', '-', (0, 4))	('MIM#300386', 'Var', (79, 89))	('GPR101', 'Gene', (194, 200))	('CD40LG', 'Gene', '959', (71, 77))	('MIM# 300267', 'Var', (101, 112))
4783	26574647	As X-LAG syndrome, although very rare, will be increasingly recognized by physicians all over the world, more giants with unknown genetic defects will be screened for Xq26.3 microduplications.	('X-LAG syndrome', 'Disease', 'MESH:D017566', (3, 17))	('genetic defects', 'Disease', (130, 145))	('genetic defects', 'Disease', 'MESH:D030342', (130, 145))	('microduplications', 'Var', (174, 191))	('X-LAG syndrome', 'Disease', (3, 17))
4787	26574647	The search for potential variants to explain pituitary tumor formation continue; a recently identified variation in immunoglobulin superfamily member 1 (IGSF1) has been described in the germline DNA of three patients with gigantism in the same family.	('patients', 'Species', '9606', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('immunoglobulin superfamily member 1', 'Gene', (116, 151))	('IGSF1', 'Gene', '3547', (153, 158))	('described', 'Reg', (169, 178))	('immunoglobulin superfamily member 1', 'Gene', '3547', (116, 151))	('variation', 'Var', (103, 112))	('pituitary tumor', 'Disease', (45, 60))	('IGSF1', 'Gene', (153, 158))	('pituitary tumor', 'Disease', 'MESH:D010911', (45, 60))
4788	26574647	This family was also found to harbor an Xq26.3 duplication, but this potentially functional IGSF1 variant might act as a disease-modifier.	('variant', 'Var', (98, 105))	('IGSF1', 'Gene', '3547', (92, 97))	('IGSF1', 'Gene', (92, 97))
4789	26574647	In the largest retrospective study of gigantism conducted so far, 143 patients were genetically tested and known genetic defects were identified in about half of them: 29% had AIP mutations/deletions associated with sporadic or familial (FIPA) cases of gigantism, 10% X-LAG syndrome, 5% MAS, 1.5% familial CNC, and one was a MEN 1-mutated case.	('mutations/deletions', 'Var', (180, 199))	('X-LAG syndrome', 'Disease', (268, 282))	('patients', 'Species', '9606', (70, 78))	('AIP', 'Gene', '9049', (176, 179))	('familial CNC', 'Disease', (297, 309))	('AIP', 'Gene', (176, 179))	('X-LAG syndrome', 'Disease', 'MESH:D017566', (268, 282))	('genetic defects', 'Disease', 'MESH:D030342', (113, 128))	('genetic defects', 'Disease', (113, 128))	('MEN 1', 'Gene', '4221', (325, 330))	('associated', 'Reg', (200, 210))	('gigantism', 'Disease', (253, 262))	('MEN 1', 'Gene', (325, 330))	('MAS', 'Disease', (287, 290))
4793	26574647	While mutations in the NF1 gene would most likely explain these cases, it is still unclear the origin of the GH excess, being the tumors that have been analyzed negative for GH, growth hormone releasing hormone (GHRH), and somatostatin expression.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('GHRH', 'Gene', '2691', (212, 216))	('GH', 'Gene', '2688', (109, 111))	('NF1', 'Gene', (23, 26))	('GH', 'Gene', '2688', (174, 176))	('growth hormone releasing hormone', 'Gene', '2691', (178, 210))	('growth hormone releasing hormone', 'Gene', (178, 210))	('GH', 'Gene', '2688', (212, 214))	('NF1', 'Gene', '4763', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('GHRH', 'Gene', (212, 216))	('somatostatin', 'Gene', '6750', (223, 235))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('mutations', 'Var', (6, 15))	('somatostatin', 'Gene', (223, 235))
4815	26229341	REarranged in Transfection (RET) gene mutations are proven to cause both of these conditions.	('REarranged in Transfection', 'Gene', (0, 26))	('cause', 'Reg', (62, 67))	('REarranged in Transfection', 'Gene', '5979', (0, 26))	('RET', 'Gene', (28, 31))	('mutations', 'Var', (38, 47))
4831	26229341	Paragangliomas, in general, are proven to have underlying germline (inherited) mutations in 40% cases in 12 genes so far, one of the important gene being RET.	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paragangliomas', 'Disease', (0, 14))	('mutations', 'Var', (79, 88))
4838	26229341	RET mutations are well-established cause of multiple endocrine neoplasia type 2 (MEN2) syndromes (medullary carcinoma thyroid, adrenal pheochromocytoma, ganglioneuromas).	('carcinoma thyroid', 'Disease', (108, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('neoplasia', 'Phenotype', 'HP:0002664', (63, 72))	('carcinoma thyroid', 'Phenotype', 'HP:0002890', (108, 125))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (127, 151))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (44, 79))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (53, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('ganglioneuromas', 'Disease', (153, 168))	('RET', 'Gene', (0, 3))	('adrenal pheochromocytoma', 'Disease', (127, 151))	('multiple endocrine neoplasia type 2', 'Disease', (44, 79))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (127, 151))	('medullary carcinoma thyroid', 'Phenotype', 'HP:0002865', (98, 125))	('cause', 'Reg', (35, 40))	('mutations', 'Var', (4, 13))	('ganglioneuromas', 'Disease', 'MESH:D005729', (153, 168))	('carcinoma thyroid', 'Disease', 'MESH:D013964', (108, 125))
4839	26229341	Incidence of RET mutation in paraganglioma is variably reported but estimated to be 5% in a recent review article.	('paraganglioma', 'Disease', (29, 42))	('RET', 'Gene', (13, 16))	('mutation', 'Var', (17, 25))	('paraganglioma', 'Disease', 'MESH:D010235', (29, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))
4841	26229341	For instance, loss of function mutation in RET gene causes defect in enteric nervous system (analogous to Hirschsprung disease), renal agenesis or congenital anomalies of urinary tract depending on combination of RET and Spry1 (another gene involved in renal development) in transgenic mice experimentally.	('congenital anomalies', 'Disease', (147, 167))	('defect in enteric nervous system', 'Phenotype', 'HP:0025028', (59, 91))	('enteric', 'Disease', (69, 76))	('loss of function', 'NegReg', (14, 30))	('mutation', 'Var', (31, 39))	('Spry1', 'Gene', '24063', (221, 226))	('renal agenesis', 'Disease', (129, 143))	('Hirschsprung disease', 'Disease', (106, 126))	('Spry1', 'Gene', (221, 226))	('RET gene', 'Gene', (43, 51))	('congenital anomalies', 'Disease', 'MESH:D000013', (147, 167))	('renal agenesis', 'Phenotype', 'HP:0000104', (129, 143))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (106, 126))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (106, 126))	('anomalies of urinary tract', 'Phenotype', 'HP:0000079', (158, 184))	('transgenic mice', 'Species', '10090', (275, 290))
4842	26229341	Clinically, evidence of RET mutation in renal agenesis is supported by a study of stillborn fetuses showing 20% RET mutation rate in unilateral renal agenesis.	('unilateral renal agenesis', 'Disease', (133, 158))	('mutation', 'Var', (116, 124))	('unilateral renal agenesis', 'Phenotype', 'HP:0000122', (133, 158))	('renal agenesis', 'Phenotype', 'HP:0000104', (40, 54))	('renal agenesis', 'Phenotype', 'HP:0000104', (144, 158))	('unilateral renal agenesis', 'Disease', 'MESH:D000075529', (133, 158))
4844	26229341	Experimental evidence for such mutation was found when a particular type of RET mutation was found to promote cellular proliferation but which impaired GDNF action on RET on cellular migration and differentiation in vitro Clinical support for paradox is found in a MEN2A case with renal agenesis, one of the three cases of renal agenesis with pheochromocytoma described previously.	('cellular proliferation', 'CPA', (110, 132))	('renal agenesis', 'Phenotype', 'HP:0000104', (323, 337))	('pheochromocytoma', 'Disease', (343, 359))	('action', 'MPA', (157, 163))	('GDNF', 'Gene', (152, 156))	('renal agenesis', 'Disease', (281, 295))	('MEN2A', 'Gene', (265, 270))	('MEN2A', 'Gene', '5979', (265, 270))	('promote', 'PosReg', (102, 109))	('GDNF', 'Gene', '2668', (152, 156))	('impaired', 'NegReg', (143, 151))	('pheochromocytoma', 'Disease', 'MESH:D010673', (343, 359))	('renal agenesis', 'Phenotype', 'HP:0000104', (281, 295))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (343, 359))	('mutation', 'Var', (80, 88))	('RET', 'Gene', (76, 79))
4845	26229341	Further, same gene mutation may manifest with only loss of function phenotype in one generation but with loss and gain of function mutation in a different generation, for example, familial renal agenesis with medullary carcinoma thyroid in a mother and with Hirschsprung disease in son.	('Hirschsprung disease', 'Disease', (258, 278))	('renal agenesis', 'Phenotype', 'HP:0000104', (189, 203))	('loss', 'NegReg', (105, 109))	('carcinoma thyroid', 'Disease', 'MESH:D013964', (219, 236))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (258, 278))	('familial renal agenesis', 'Disease', 'MESH:C536482', (180, 203))	('medullary carcinoma thyroid', 'Phenotype', 'HP:0002865', (209, 236))	('carcinoma thyroid', 'Disease', (219, 236))	('familial renal agenesis', 'Disease', (180, 203))	('gain of function', 'PosReg', (114, 130))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (258, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinoma thyroid', 'Phenotype', 'HP:0002890', (219, 236))	('mutation', 'Var', (131, 139))
4951	24707167	Genetic testing identified a 3p25-26 (c.482 G>A) VHL gene chromosomal mutation consistent with von Hippel-Lindau disease genotype.	('c.482 G>A', 'Mutation', 'rs730882035', (38, 47))	('c.482 G>A', 'Var', (38, 47))	('von Hippel-Lindau disease', 'Disease', (95, 120))	('VHL', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (49, 52))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (95, 120))
4968	24707167	The brain magnetic resonance imaging (MRI) with and without contrast revealed multiple high T2 and fluid-attenuated inversion-recovery (FLAIR) signal lesions found diffusely in the cortical and subcortical white matter region of the frontal and parietal lobes (Figure 3A).	('lesions', 'Var', (150, 157))	('parietal lobes', 'Disease', (245, 259))	('parietal lobes', 'Disease', 'MESH:C566826', (245, 259))	('high', 'Gene', (87, 91))
4985	24707167	Subsequent genetic testing identified a 3p25-26 (c.482 G>A) chromosomal mutation consistent with a mutation of the VHL gene.	('VHL', 'Gene', (115, 118))	('c.482 G>A', 'Mutation', 'rs730882035', (49, 58))	('c.482 G>A', 'Var', (49, 58))	('VHL', 'Gene', '7428', (115, 118))
5009	24707167	The patient was then lost to follow-up for 11 years, and subsequent genetic testing identified the VHL mutation.	('mutation', 'Var', (103, 111))	('VHL', 'Gene', (99, 102))	('patient', 'Species', '9606', (4, 11))	('VHL', 'Gene', '7428', (99, 102))
5028	24707167	VHL disease is only known to be caused by the mutations of the VHL gene on chromosome 3p25-26, and genetic testing can identify 90%-100% of affected individuals.	('VHL disease', 'Disease', (0, 11))	('mutations', 'Var', (46, 55))	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('caused', 'Reg', (32, 38))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', (63, 66))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (63, 66))
5029	24707167	VHL is an autosomal dominant disease; however, an estimated 20% have spontaneous de novo VHL gene mutations.	('autosomal dominant disease', 'Disease', 'MESH:D030342', (10, 36))	('VHL', 'Gene', (89, 92))	('mutations', 'Var', (98, 107))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (89, 92))	('VHL', 'Gene', '7428', (0, 3))	('autosomal dominant disease', 'Disease', (10, 36))
5118	24667359	The expression level of NCX isoforms and different types of VDCC was verified by qPCR and immunoblotting, and shown to be upregulated in cells with reduced level of PMCA2 or PMCA3 (Fig.	('NCX', 'Gene', (24, 27))	('upregulated', 'PosReg', (122, 133))	('PMCA3', 'Var', (174, 179))	('PMCA2', 'Var', (165, 170))	('NCX', 'Gene', '29715', (24, 27))
5121	24667359	Since over-activation of calcineurin in PMCA2- or PMCA3 reduced cells was reported previously, in this study we tested subcellular and activity of the Ca2+/calcineurin-dependent transcription factor, NFAT.	('PMCA2-', 'Var', (40, 46))	('Ca2', 'Gene', (151, 154))	('NFAT', 'Gene', '307820', (200, 204))	('NFAT', 'Gene', (200, 204))	('PMCA3', 'Var', (50, 55))	('over-activation', 'PosReg', (6, 21))	('Ca2', 'Gene', '54231', (151, 154))	('cells', 'CPA', (64, 69))
5137	24667359	Abnormality of calcium homeostasis could affect the secretory activity of PC12 cells.	('calcium homeostasis', 'MPA', (15, 34))	('Abnormality', 'Var', (0, 11))	('PC12', 'CellLine', 'CVCL:0481', (74, 78))	('calcium', 'Chemical', 'MESH:D002118', (15, 22))	('secretory activity', 'MPA', (52, 70))	('affect', 'Reg', (41, 47))
5139	24667359	The obtained results revealed that dopamine is released with a significant delay by cells with altered pattern of PMCA isoforms in comparison to control.	('delay', 'NegReg', (75, 80))	('released', 'MPA', (47, 55))	('dopamine', 'Chemical', 'MESH:D004298', (35, 43))	('PMCA', 'Gene', (114, 118))	('altered', 'Var', (95, 102))	('dopamine', 'MPA', (35, 43))
5182	24667359	In view of this fact one could expect that deficiency in these isoforms should increase dopamine secretion.	('increase', 'PosReg', (79, 87))	('dopamine', 'Chemical', 'MESH:D004298', (88, 96))	('deficiency', 'Var', (43, 53))	('dopamine secretion', 'MPA', (88, 106))
5192	24667359	Firstly, a store-operated Ca2+ entry, influencing directly the NFAT/calcineurin pathway was not inhibited with KB-R7943 in cardiomyocytes exhibiting an increased calcineurin-NFAT activation.	('NFAT', 'Gene', (63, 67))	('Ca2', 'Gene', '54231', (26, 29))	('NFAT', 'Gene', '307820', (174, 178))	('NFAT', 'Gene', '307820', (63, 67))	('Ca2', 'Gene', (26, 29))	('KB-R7943', 'Var', (111, 119))	('KB-R7943', 'Chemical', 'MESH:C101670', (111, 119))	('NFAT', 'Gene', (174, 178))
5198	24667359	However, it would be interesting to test in the future activation of NFAT upon KB-R7943 treatment and upon plasma membrane depolarization in PC12 cells.	('NFAT', 'Gene', (69, 73))	('KB-R7943', 'Chemical', 'MESH:C101670', (79, 87))	('KB-R7943', 'Var', (79, 87))	('PC12', 'CellLine', 'CVCL:0481', (141, 145))	('NFAT', 'Gene', '307820', (69, 73))	('test', 'Reg', (36, 40))	('activation', 'PosReg', (55, 65))
5202	24667359	Nonetheless, inhibition of VDCC did not alter [Ca2+]c at resting state, excluding its involvement in the observed increase in [Ca2+]c during resting conditions.	('VDCC', 'Protein', (27, 31))	('Ca2', 'Gene', '54231', (127, 130))	('inhibition', 'Var', (13, 23))	('Ca2', 'Gene', '54231', (47, 50))	('Ca2', 'Gene', (127, 130))	('Ca2', 'Gene', (47, 50))
5206	24667359	However, on the basis of literature it could be assumed that pharmacological inhibition of VDCC decreases NFAT activity during cell stimulation.	('decreases', 'NegReg', (96, 105))	('VDCC', 'Gene', (91, 95))	('pharmacological inhibition', 'Var', (61, 87))	('NFAT', 'Gene', '307820', (106, 110))	('NFAT', 'Gene', (106, 110))
5211	24667359	It was also shown that depolarization of neurons induced activation of NFAT3, and the effect was linked directly with L-type VDCC, but not with N- and P/Q-types of VDCC.	('NFAT', 'Gene', (71, 75))	('activation', 'PosReg', (57, 67))	('NFAT', 'Gene', '307820', (71, 75))	('depolarization', 'Var', (23, 37))
5231	24667359	Moreover, according to the literature, 11R-VIVIT was found to efficiently block transcriptional activity of NFAT, manifested by an arrested NFAT translocation, decreased NFAT expression in osteoclast differentiation, and by alterations of the expression pattern of genes being under its control.	('NFAT', 'Gene', (108, 112))	('expression', 'MPA', (175, 185))	('osteoclast differentiation', 'CPA', (189, 215))	('NFAT', 'Gene', '307820', (170, 174))	('11R-VIVIT', 'Chemical', '-', (39, 48))	('NFAT', 'Gene', (170, 174))	('11R-VIVIT', 'Var', (39, 48))	('NFAT', 'Gene', '307820', (108, 112))	('block', 'NegReg', (74, 79))	('NFAT', 'Gene', '307820', (140, 144))	('transcriptional activity', 'MPA', (80, 104))	('decreased', 'NegReg', (160, 169))	('arrested', 'NegReg', (131, 139))	('expression pattern of genes', 'MPA', (243, 270))	('alterations', 'Reg', (224, 235))	('NFAT', 'Gene', (140, 144))
5263	20664475	Genetic testing for RET mutations has allowed identification of familial cases and prophylactic thyroidectomy for cure.	('RET', 'Gene', (20, 23))	('mutations', 'Var', (24, 33))	('RET', 'Gene', '5979', (20, 23))
5283	20664475	At present it is estimated that at least 24-27% of pheochromocytomas or paragangliomas are associated with known genetic mutations, in children this prevalence may be as high as 40%.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (51, 68))	('mutations', 'Var', (121, 130))	('paragangliomas', 'Disease', (72, 86))	('paragangliomas', 'Disease', 'MESH:D010235', (72, 86))	('children', 'Species', '9606', (135, 143))	('pheochromocytomas', 'Disease', (51, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('paragangliomas', 'Phenotype', 'HP:0002668', (72, 86))	('pheochromocytomas', 'Disease', 'MESH:D010673', (51, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (51, 67))	('associated', 'Reg', (91, 101))
5286	20664475	Hereditary pheochromocytoma is associated with multiple endocrine neoplasia type 2 (MEN-2A or MEN-2B), neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL) syndrome, and familial paragangliomas and pheochromocytomas due to germ-line mutations of genes encoding succinate dehydrogenase subunits B, C, and D (SDHB, SDHC, SDHD) (Tables 1,2).	('neurofibromatosis', 'Phenotype', 'HP:0001067', (103, 120))	('MEN-2A', 'Gene', (84, 90))	('MEN-2B', 'Gene', (94, 100))	('SDHB', 'Gene', (311, 315))	('paragangliomas', 'Phenotype', 'HP:0002668', (183, 197))	('Hereditary pheochromocytoma', 'Disease', 'MESH:D010673', (0, 27))	('paraganglioma', 'Phenotype', 'HP:0002668', (183, 196))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (202, 219))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (47, 82))	('neoplasia', 'Phenotype', 'HP:0002664', (66, 75))	('MEN-2B', 'Gene', '5979', (94, 100))	('associated', 'Reg', (31, 41))	('SDHC', 'Gene', '6391', (317, 321))	('neurofibromatosis type 1 (NF-1), von Hippel-Lindau (VHL) syndrome', 'Disease', 'MESH:D006623', (103, 168))	('familial paragangliomas and pheochromocytomas', 'Disease', 'MESH:C531777', (174, 219))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (202, 218))	('mutations', 'Var', (237, 246))	('SDHD', 'Gene', '6392', (323, 327))	('MEN-2A', 'Gene', '5979', (84, 90))	('SDHD', 'Gene', (323, 327))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (11, 27))	('Hereditary pheochromocytoma', 'Disease', (0, 27))	('multiple endocrine neoplasia type 2', 'Disease', (47, 82))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (56, 75))	('SDHC', 'Gene', (317, 321))	('SDHB', 'Gene', '6390', (311, 315))
5291	20664475	In those patients with malignant disease secondary to an extra-adrenal paraganglioma, almost 50% had SDHB mutations.	('malignant disease', 'Disease', 'MESH:D009369', (23, 40))	('patients', 'Species', '9606', (9, 17))	('SDHB', 'Gene', (101, 105))	('extra-adrenal paraganglioma', 'Disease', (57, 84))	('malignant disease', 'Disease', (23, 40))	('mutations', 'Var', (106, 115))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (57, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))	('SDHB', 'Gene', '6390', (101, 105))
5293	20664475	Family history is often helpful in MEN-2, VHL, and NF-1 tumors but only 10% of the currently investigated patients with SDHB mutations have a positive family history for pheochromocytoma or paraganglioma (Table 1).	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (170, 186))	('NF-1 tumors', 'Disease', (51, 62))	('NF-1 tumors', 'Disease', 'MESH:C537392', (51, 62))	('VHL', 'Disease', (42, 45))	('SDHB', 'Gene', '6390', (120, 124))	('pheochromocytoma or paraganglioma', 'Disease', 'MESH:D010673', (170, 203))	('VHL', 'Disease', 'MESH:D006623', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('MEN', 'Species', '9606', (35, 38))	('pheochromocytoma or paraganglioma', 'Disease', (170, 203))	('patients', 'Species', '9606', (106, 114))	('SDHB', 'Gene', (120, 124))	('paraganglioma', 'Phenotype', 'HP:0002668', (190, 203))
5309	20664475	The superiority of [18F]-FDA PET imaging over [131I]-MIBG scintigraphy, especially in malignant tumors, has been reported.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('[18F]-FDA', 'Chemical', '-', (19, 28))	('malignant tumors', 'Disease', (86, 102))	('[131I]-MIBG', 'Chemical', '-', (46, 57))	('malignant tumors', 'Disease', 'MESH:D018198', (86, 102))	('[18F]-FDA', 'Var', (19, 28))
5320	20664475	Although follow-up is especially important for patients identified with mutations of disease-causing genes, there is currently no method based on pathological examination of a resected tumor to rule out potential for malignancy or recurrence.	('tumor', 'Disease', (185, 190))	('mutations', 'Var', (72, 81))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('malignancy', 'Disease', (217, 227))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
5341	20664475	The effect of [177-Lu-DOTA]-Octreotate in malignant paragangliomas or pheochromocytomas has only been described in case reports.	('[177-Lu-DOTA]-Octreotate', 'Chemical', 'MESH:C000608228', (14, 38))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (70, 87))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (70, 86))	('malignant paragangliomas', 'Disease', (42, 66))	('pheochromocytomas', 'Disease', (70, 87))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('paragangliomas', 'Phenotype', 'HP:0002668', (52, 66))	('pheochromocytomas', 'Disease', 'MESH:D010673', (70, 87))	('[177-Lu-DOTA]-Octreotate', 'Var', (14, 38))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (42, 66))
5358	20664475	Some variants of MEN2A are also associated with either cutaneous lichen amyloidosis or Hirschsprung's disease.	('MEN2A', 'Gene', (17, 22))	('MEN2A', 'Gene', '5979', (17, 22))	("Hirschsprung's disease", 'Disease', (87, 109))	('cutaneous lichen amyloidosis', 'Disease', (55, 83))	('amyloidosis', 'Phenotype', 'HP:0011034', (72, 83))	("Hirschsprung's disease", 'Phenotype', 'HP:0002251', (87, 109))	("Hirschsprung's disease", 'Disease', 'MESH:D006627', (87, 109))	('cutaneous lichen amyloidosis', 'Phenotype', 'HP:0032346', (55, 83))	('cutaneous lichen amyloidosis', 'Disease', 'MESH:C562643', (55, 83))	('variants', 'Var', (5, 13))	('associated', 'Reg', (32, 42))
5369	20664475	There is significant overlap in the genetic mutations that lead to either FMTC or MEN2A.	('FMTC', 'Disease', (74, 78))	('lead to', 'Reg', (59, 66))	('mutations', 'Var', (44, 53))	('MTC', 'Phenotype', 'HP:0002865', (75, 78))	('MEN2A', 'Gene', (82, 87))	('MEN2A', 'Gene', '5979', (82, 87))
5379	20664475	The most common germline mutation in MEN2A is in codon 634 (80% of patients).	('MEN2A', 'Gene', (37, 42))	('codon 634', 'Var', (49, 58))	('patients', 'Species', '9606', (67, 75))	('MEN2A', 'Gene', '5979', (37, 42))
5382	20664475	Family members of patients with a germline mutation of the RET gene have a 50% chance of inheriting the mutation.	('RET', 'Gene', (59, 62))	('germline mutation', 'Var', (34, 51))	('patients', 'Species', '9606', (18, 26))	('RET', 'Gene', '5979', (59, 62))
5383	20664475	In patients harboring a RET mutation, their lifetime risk of malignancy approaches 100%.	('RET', 'Gene', '5979', (24, 27))	('mutation', 'Var', (28, 36))	('RET', 'Gene', (24, 27))	('patients', 'Species', '9606', (3, 11))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))	('malignancy', 'Disease', (61, 71))
5386	20664475	The aggressiveness of the MTC in hereditary disease is dependent upon the specific RET mutation.	('RET', 'Gene', '5979', (83, 86))	('aggressiveness', 'Disease', 'MESH:D001523', (4, 18))	('MTC', 'Phenotype', 'HP:0002865', (26, 29))	('hereditary disease', 'Disease', 'MESH:D030342', (33, 51))	('hereditary disease', 'Disease', (33, 51))	('RET', 'Gene', (83, 86))	('aggressiveness', 'Disease', (4, 18))	('mutation', 'Var', (87, 95))	('aggressiveness', 'Phenotype', 'HP:0000718', (4, 18))
5390	20664475	Level 2 mutations (RET codons 611, 618, 620, and 634 mutations) are considered high risk for aggressive MTC.	('RET', 'Gene', (19, 22))	('MTC', 'Phenotype', 'HP:0002865', (104, 107))	('mutations', 'Var', (8, 17))	('RET', 'Gene', '5979', (19, 22))	('aggressive MTC', 'Disease', (93, 107))
5391	20664475	Patients with level 2 RET mutations should undergo thyroidectomy before age 5.	('mutations', 'Var', (26, 35))	('RET', 'Gene', (22, 25))	('RET', 'Gene', '5979', (22, 25))	('Patients', 'Species', '9606', (0, 8))
5393	20664475	In patients with level 1 RET mutations, MTC usually develops later in life and is more indolent.	('RET', 'Gene', '5979', (25, 28))	('mutations', 'Var', (29, 38))	('RET', 'Gene', (25, 28))	('patients', 'Species', '9606', (3, 11))	('MTC', 'Phenotype', 'HP:0002865', (40, 43))	('MTC', 'Disease', (40, 43))
5419	20664475	Hopefully as we gain a better understanding of the phenotype-genotype relationships amongst the RET mutations, we will be better able to predict when disease is likely to develop and therefore plan operative intervention prior to that time.	('mutations', 'Var', (100, 109))	('RET', 'Gene', (96, 99))	('RET', 'Gene', '5979', (96, 99))
5475	20664475	Genetic testing for RET mutations have allowed potential cure for the 25% of patients with hereditary MTC.	('RET', 'Gene', '5979', (20, 23))	('MTC', 'Disease', (102, 105))	('RET', 'Gene', (20, 23))	('patients', 'Species', '9606', (77, 85))	('mutations', 'Var', (24, 33))	('MTC', 'Phenotype', 'HP:0002865', (102, 105))
5509	21223554	High catecholamine level can cause direct myocardial damage with focal degeneration and contraction band necrosis of the myocytes, monocytic infiltration, medial thickening of small and medium size coronary arteries and interstitial fibrosis.	('High catecholamine', 'Var', (0, 18))	('myocardial damage', 'Disease', 'MESH:D009202', (42, 59))	('medial thickening', 'CPA', (155, 172))	('myocardial damage', 'Disease', (42, 59))	('High catecholamine level', 'Phenotype', 'HP:0003334', (0, 24))	('monocytic infiltration', 'CPA', (131, 153))	('focal degeneration and contraction band necrosis', 'Disease', 'MESH:D058745', (65, 113))	('interstitial fibrosis', 'Disease', (220, 241))	('catecholamine', 'Chemical', 'MESH:D002395', (5, 18))	('interstitial fibrosis', 'Disease', 'MESH:D005355', (220, 241))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (220, 241))	('cause', 'Reg', (29, 34))
5531	19243216	Pre-eclampsia may be associated with hyperuricaemia, deranged liver function, and signs of neurologic irritability such as headaches, hyper-reflexia, and seizures.	('liver function', 'MPA', (62, 76))	('hyper-reflexia', 'Phenotype', 'HP:0001347', (134, 148))	('hyper-reflexia', 'Disease', (134, 148))	('seizures', 'Disease', (154, 162))	('hyperuricaemia', 'Phenotype', 'HP:0002149', (37, 51))	('seizures', 'Disease', 'MESH:D012640', (154, 162))	('hyperuricaemia', 'Disease', 'None', (37, 51))	('Pre-eclampsia', 'Disease', (0, 13))	('deranged', 'Var', (53, 61))	('seizures', 'Phenotype', 'HP:0001250', (154, 162))	('neurologic irritability', 'Disease', 'MESH:D009422', (91, 114))	('hyper-reflexia', 'Disease', 'MESH:D053307', (134, 148))	('headaches', 'Disease', 'MESH:D006261', (123, 132))	('hyperuricaemia', 'Disease', (37, 51))	('eclampsia', 'Phenotype', 'HP:0100601', (4, 13))	('associated', 'Reg', (21, 31))	('neurologic irritability', 'Disease', (91, 114))	('Pre-eclampsia', 'Phenotype', 'HP:0100602', (0, 13))	('headaches', 'Phenotype', 'HP:0002315', (123, 132))	('irritability', 'Phenotype', 'HP:0000737', (102, 114))	('headache', 'Phenotype', 'HP:0002315', (123, 131))	('headaches', 'Disease', (123, 132))
5568	19243216	She was found to be heterozygous for c.449_453dup mutation of the succinate dehydrogenase subunit D (SDHD) gene (Figure 5).	('SDHD', 'Gene', '6392', (101, 105))	('SDHD', 'Gene', (101, 105))	('succinate dehydrogenase subunit D', 'Gene', '6392', (66, 99))	('c.449_453dup mutation', 'Var', (37, 58))	('succinate dehydrogenase subunit D', 'Gene', (66, 99))	('c.449_453dup', 'Mutation', 'c.449_453dup', (37, 49))
5569	19243216	This mutation is a novel frameshift mutation, and leads to SDHD deficiency (GenBank accession number: 1162563).	('SDHD deficiency', 'Disease', (59, 74))	('SDHD deficiency', 'Disease', 'MESH:D007153', (59, 74))	('leads to', 'Reg', (50, 58))	('mutation', 'Var', (5, 13))
5589	19243216	I131 or I123 MIBG scan is the imaging modality of choice.	('I131', 'Var', (0, 4))	('MIBG', 'Chemical', 'MESH:D019797', (13, 17))	('I123', 'Var', (8, 12))
5594	19243216	The main side-effects of phenoxybenzamine are postural hypotension and reflex tachycardia.	('tachycardia', 'Disease', (78, 89))	('tachycardia', 'Disease', 'MESH:D013610', (78, 89))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (25, 41))	('hypotension', 'Phenotype', 'HP:0002615', (55, 66))	('phenoxybenzamine', 'Var', (25, 41))	('postural hypotension', 'Phenotype', 'HP:0001278', (46, 66))	('hypotension', 'Disease', 'MESH:D007022', (55, 66))	('tachycardia', 'Phenotype', 'HP:0001649', (78, 89))	('hypotension', 'Disease', (55, 66))
5595	19243216	It is important to note that beta-blockers should not be used in isolation, since blockade of ss2-adrenoceptors, which have a vasodilatory effect, can cause unopposed vasoconstriction by a1-adrenoceptor stimulation and precipitate severe hypertension.	('hypertension', 'Phenotype', 'HP:0000822', (238, 250))	('precipitate', 'Reg', (219, 230))	('blockade', 'Var', (82, 90))	('ss2-adrenoceptors', 'Gene', (94, 111))	('a1-adrenoceptor', 'Protein', (187, 202))	('hypertension', 'Disease', 'MESH:D006973', (238, 250))	('cause', 'Reg', (151, 156))	('unopposed vasoconstriction', 'MPA', (157, 183))	('hypertension', 'Disease', (238, 250))
5603	19243216	Approximately one quarter of patients presenting with phaeochromocytoma may carry germline mutations, even in the absence of apparent family history.	('patients', 'Species', '9606', (29, 37))	('phaeochromocytoma', 'Disease', (54, 71))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (54, 71))	('carry', 'Reg', (76, 81))	('germline mutations', 'Var', (82, 100))
5606	19243216	Our patient has a novel frameshift mutation in the SDHD gene located at Chromosome 11q.	('SDHD', 'Gene', (51, 55))	('frameshift mutation', 'Var', (24, 43))	('patient', 'Species', '9606', (4, 11))	('SDHD', 'Gene', '6392', (51, 55))
5608	19243216	Characteristically, SDHD mutation is associated with head or neck non-functional paraganglioma, and infrequently, sympathetic paraganglioma or phaeochromocytoma.	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('paraganglioma', 'Phenotype', 'HP:0002668', (126, 139))	('paraganglioma or phaeochromocytoma', 'Disease', 'MESH:D010235', (126, 160))	('mutation', 'Var', (25, 33))	('paraganglioma', 'Disease', (81, 94))	('paraganglioma', 'Disease', (126, 139))	('SDHD', 'Gene', '6392', (20, 24))	('associated', 'Reg', (37, 47))	('paraganglioma', 'Disease', 'MESH:D010235', (81, 94))	('paraganglioma', 'Disease', 'MESH:D010235', (126, 139))	('SDHD', 'Gene', (20, 24))	('paraganglioma or phaeochromocytoma', 'Disease', (126, 160))
5609	19243216	Tumours associated with SDHD mutation are rarely malignant, in contrast to those arisen from mutation of the SDHB gene.	('mutation', 'Var', (29, 37))	('SDHB', 'Gene', '6390', (109, 113))	('SDHB', 'Gene', (109, 113))	('SDHD', 'Gene', '6392', (24, 28))	('SDHD', 'Gene', (24, 28))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
5610	19243216	Like all other syndromes of hereditary phaeochromocytoma, SDHD mutation is transmitted in an autosomal dominant fashion.	('hereditary phaeochromocytoma', 'Disease', (28, 56))	('mutation', 'Var', (63, 71))	('SDHD', 'Gene', '6392', (58, 62))	('hereditary phaeochromocytoma', 'Disease', 'MESH:D009386', (28, 56))	('hereditary phaeochromocytoma', 'Phenotype', 'HP:0002666', (28, 56))	('SDHD', 'Gene', (58, 62))
5611	19243216	However, not all carriers of the SDHD mutation develop tumours, and inheritance is further complicated by maternal imprinting in gene expression.	('tumours', 'Disease', (55, 62))	('SDHD', 'Gene', '6392', (33, 37))	('SDHD', 'Gene', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('mutation', 'Var', (38, 46))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
5613	19243216	Von Hippel-Lindau syndrome Multiple endocrine neoplasia type 2A and type 2B Neurofibromatosis type 1 Mutation of SDHB, SDHC, SDHD  Ataxia-telangiectasia Tuberous sclerosis Sturge-Weber syndrome Hypertension complicating pregnancy is a commonly encountered medical condition.	('telangiectasia', 'Phenotype', 'HP:0001009', (138, 152))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (36, 55))	('Tuberous sclerosis', 'Disease', 'MESH:D014402', (153, 171))	('Von Hippel-Lindau syndrome', 'Disease', (0, 26))	('Mutation', 'Var', (101, 109))	('SDHC', 'Gene', '6391', (119, 123))	('Multiple endocrine neoplasia type', 'Disease', (27, 60))	('Ataxia-telangiectasia', 'Disease', 'MESH:D001260', (131, 152))	('Multiple endocrine neoplasia type', 'Disease', 'MESH:D018761', (27, 60))	('SDHD', 'Gene', '6392', (125, 129))	('SDHB', 'Gene', '6390', (113, 117))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('Tuberous sclerosis', 'Disease', (153, 171))	('Weber syndrome', 'Phenotype', 'HP:0002277', (179, 193))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (0, 26))	('SDHD', 'Gene', (125, 129))	('Ataxia', 'Phenotype', 'HP:0001251', (131, 137))	('SDHC', 'Gene', (119, 123))	('Hypertension', 'Disease', 'MESH:D006973', (194, 206))	('Neurofibromatosis type', 'Disease', (76, 98))	('Ataxia-telangiectasia', 'Disease', (131, 152))	('Neurofibromatosis type', 'Disease', 'MESH:C537392', (76, 98))	('SDHB', 'Gene', (113, 117))	('Hypertension', 'Disease', (194, 206))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (76, 93))	('Hypertension', 'Phenotype', 'HP:0000822', (194, 206))
5622	32859697	The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model The conserved B-subunit of succinate dehydrogenase (SDH) participates in the tricarboxylic acid cycle (TCA) cycle and mitochondrial electron transport.	('SDH', 'Gene', '6390', (4, 7))	('Caenorhabditis elegans', 'Species', '6239', (86, 108))	('SDH', 'Gene', (167, 170))	('causing', 'Reg', (28, 35))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('SDH', 'Gene', (4, 7))	('succinate dehydrogenase', 'Gene', '6390', (142, 165))	('Arg230His', 'SUBSTITUTION', 'None', (9, 18))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (192, 210))	('familial paraganglioma alters glycolysis', 'Disease', (36, 76))	('succinate dehydrogenase', 'Gene', (142, 165))	('SDHB', 'Gene', '6390', (4, 8))	('familial paraganglioma alters glycolysis', 'Disease', 'MESH:C564972', (36, 76))	('SDHB', 'Gene', (4, 8))	('SDH', 'Gene', '6390', (167, 170))	('Arg230His', 'Var', (9, 18))
5623	32859697	The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (48, 64))	('PPGL', 'Chemical', '-', (80, 84))	('pheochromocytoma/paraganglioma', 'Disease', (48, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHB', 'Gene', '6390', (26, 30))	('Arg230His', 'Var', (4, 13))	('SDHB', 'Gene', (26, 30))	('causes', 'Reg', (31, 37))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (48, 78))	('Arg230His', 'SUBSTITUTION', 'None', (4, 13))
5624	32859697	In Caenorhabditis elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His), which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number.	('human', 'Species', '9606', (95, 100))	('SDHB-1', 'Gene', (63, 69))	('shortened', 'NegReg', (150, 159))	('Arg244His', 'SUBSTITUTION', 'None', (70, 79))	('Arg230His', 'SUBSTITUTION', 'None', (101, 110))	('lifespan', 'CPA', (160, 168))	('ATP', 'Chemical', 'MESH:D000255', (181, 184))	('reduced', 'NegReg', (200, 207))	('PPGL', 'Chemical', '-', (51, 55))	('SDHB-1', 'Gene', '174482', (63, 69))	('mitochondrial number', 'MPA', (208, 228))	('delayed development', 'Phenotype', 'HP:0001263', (129, 148))	('Caenorhabditis elegans', 'Species', '6239', (3, 25))	('attenuated', 'NegReg', (170, 180))	('Arg244His', 'Var', (70, 79))	('Arg230His', 'Var', (101, 110))	('reduced mitochondrial number', 'Phenotype', 'HP:0040013', (200, 228))	('ATP production', 'MPA', (181, 195))
5625	32859697	Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis, whereby only Arg244His (not null) worms demonstrate elevated lactate/pyruvate levels, pointing to a missense-induced, Warburg-like aberrant glycolysis.	('elevated', 'PosReg', (242, 250))	('succinate', 'MPA', (9, 18))	('elevated lactate/pyruvate levels', 'Phenotype', 'HP:0025435', (242, 274))	('succinate', 'Chemical', 'MESH:D019802', (9, 18))	('elevated', 'PosReg', (22, 30))	('lactate', 'Chemical', 'MESH:D019344', (251, 258))	('Arg244His', 'Var', (203, 212))	('lactate/pyruvate levels', 'MPA', (251, 274))	('mutants', 'Var', (71, 78))	('sdhb-1', 'Gene', (57, 63))	('sdhb-1', 'Gene', '174482', (57, 63))	('pyruvate', 'Chemical', 'MESH:D019289', (259, 267))	('succinate is elevated', 'Phenotype', 'HP:0020149', (9, 30))	('aberrant glycolysis', 'Phenotype', 'HP:0004366', (321, 340))	('Arg244His', 'SUBSTITUTION', 'None', (203, 212))
5626	32859697	In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter's remoteness from the mutation site.	('Arg230His', 'SUBSTITUTION', 'None', (69, 78))	('catalytic cleft', 'MPA', (92, 107))	('SDHA', 'Gene', '6389', (29, 33))	('Arg230His', 'Var', (69, 78))	('SDHA', 'Gene', (29, 33))	('modifies', 'Reg', (79, 87))
5627	32859697	We hypothesize that the Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer.	('metabolism', 'MPA', (56, 66))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rewires', 'Reg', (48, 55))	('Arg230His', 'Var', (24, 33))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('Arg230His', 'SUBSTITUTION', 'None', (24, 33))
5629	32859697	Summary: Heritable pheochromocytoma/paraganglioma follows the Arg230His missense mutation in SDHB in mitochondrial complex II.	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (19, 49))	('Arg230His', 'SUBSTITUTION', 'None', (62, 71))	('SDHB', 'Gene', (93, 97))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (19, 35))	('pheochromocytoma/paraganglioma', 'Disease', (19, 49))	('Arg230His', 'Var', (62, 71))	('SDHB', 'Gene', '6390', (93, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (36, 49))
5636	32859697	Several mutant genes have been associated with PPGL.	('PPGL', 'Chemical', '-', (47, 51))	('PPGL', 'Disease', (47, 51))	('mutant', 'Var', (8, 14))	('associated', 'Reg', (31, 41))
5637	32859697	These genes disrupt different signaling pathways  and can be classified into three groups: the pseudohypoxia group [including both tricarboxylic acid cycle (TCA)- and VHL/EPAS1-related genes]; the kinase signaling group; and the Wnt signaling group.	('hypoxia', 'Disease', (101, 108))	('EPAS1', 'Gene', (171, 176))	('disrupt', 'Reg', (12, 19))	('signaling pathways', 'Pathway', (30, 48))	('genes', 'Var', (6, 11))	('VHL', 'Gene', (167, 170))	('VHL', 'Gene', '7428', (167, 170))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (131, 149))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))	('EPAS1', 'Gene', '2034', (171, 176))
5647	32859697	SDH mutations are thought to cause malignant change by three principal mechanisms.	('SDH', 'Gene', (0, 3))	('malignant change', 'Phenotype', 'HP:0002664', (35, 51))	('mutations', 'Var', (4, 13))	('cause', 'Reg', (29, 34))	('SDH', 'Gene', '6390', (0, 3))
5648	32859697	Second, it is believed that in many such cancer-linked SDH mutations (now renamed SDHx), mitochondrial succinate accumulates.	('succinate', 'Chemical', 'MESH:D019802', (103, 112))	('SDH', 'Gene', '6390', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SDH', 'Gene', (82, 85))	('mitochondrial succinate', 'MPA', (89, 112))	('accumulates', 'PosReg', (113, 124))	('cancer-linked SDH', 'Disease', 'MESH:D009369', (41, 58))	('SDH', 'Gene', (55, 58))	('mutations', 'Var', (59, 68))	('cancer-linked SDH', 'Disease', (41, 58))	('SDH', 'Gene', '6390', (82, 85))
5653	32859697	It is curious that SDHA, SDHC and SDHD mutations typically cause benign tumors, whereas mutations in the gene encoding subunit B are, for unknown reasons, strongly associated with high metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SDHA', 'Gene', '6389', (19, 23))	('associated', 'Reg', (164, 174))	('benign tumors', 'Disease', (65, 78))	('SDHC', 'Gene', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('cause', 'Reg', (59, 64))	('mutations', 'Var', (39, 48))	('SDHC', 'Gene', '6391', (25, 29))	('SDHD', 'Gene', '6392', (34, 38))	('benign tumors', 'Disease', 'MESH:D009369', (65, 78))	('SDHA', 'Gene', (19, 23))	('SDHD', 'Gene', (34, 38))
5654	32859697	Additionally, significant numbers of SDHB-affected patients harbor germ line SDHB mutations and suffer from a particularly aggressive form of malignant PPGL, whereas other family members with identical SDH mutations remain free of metastatic disease (see modifier genes above and mev-1 below).	('SDH', 'Gene', (77, 80))	('SDH', 'Gene', '6390', (202, 205))	('PPGL', 'Chemical', '-', (152, 156))	('SDH', 'Gene', (37, 40))	('SDHB', 'Gene', '6390', (37, 41))	('SDHB', 'Gene', '6390', (77, 81))	('SDH', 'Gene', (202, 205))	('SDH', 'Gene', '6390', (77, 80))	('suffer from', 'Reg', (96, 107))	('SDHB', 'Gene', (37, 41))	('mutations', 'Var', (82, 91))	('SDHB', 'Gene', (77, 81))	('patients', 'Species', '9606', (51, 59))	('SDH', 'Gene', '6390', (37, 40))
5655	32859697	We hypothesized that a critical advance would be the establishment of a tractable animal model of an aggressive germ line form of SDHB mutation (see below).	('SDHB', 'Gene', '6390', (130, 134))	('mutation', 'Var', (135, 143))	('SDHB', 'Gene', (130, 134))
5661	32859697	When this Pro211 was mutated, which corresponds to Pro197 in the human SDHB protein, SDH assembly and function were impaired, leading to increased superoxide anion production and perturbed mitochondrial respiration.	('SDH', 'Gene', (71, 74))	('function', 'MPA', (102, 110))	('human', 'Species', '9606', (65, 70))	('increased superoxide anion', 'Phenotype', 'HP:0031836', (137, 163))	('assembly', 'MPA', (89, 97))	('SDH', 'Gene', (85, 88))	('mitochondrial respiration', 'MPA', (189, 214))	('SDHB', 'Gene', '6390', (71, 75))	('superoxide anion production', 'MPA', (147, 174))	('impaired', 'NegReg', (116, 124))	('SDH', 'Gene', '6390', (71, 74))	('perturbed', 'Reg', (179, 188))	('SDHB', 'Gene', (71, 75))	('Pro211', 'Var', (10, 16))	('increased', 'PosReg', (137, 146))	('superoxide anion', 'Chemical', 'MESH:D013481', (147, 163))	('SDH', 'Gene', '6390', (85, 88))	('Pro197', 'Var', (51, 57))
5662	32859697	Our interest in SDHx was prompted by a family with an Arg230His missense SDHB mutation that leads to a familial form of malignant PHEO.	('SDH', 'Gene', '6390', (73, 76))	('familial form of malignant PHEO', 'Disease', (103, 134))	('SDHB', 'Gene', '6390', (73, 77))	('SDH', 'Gene', '6390', (16, 19))	('Arg230His', 'SUBSTITUTION', 'None', (54, 63))	('SDH', 'Gene', (73, 76))	('leads to', 'Reg', (92, 100))	('Arg230His', 'Var', (54, 63))	('SDH', 'Gene', (16, 19))	('SDHB', 'Gene', (73, 77))
5664	32859697	It was found that her non-identical twin children (twins amongst four siblings) and her own adult brother also carried Arg230His.	('Arg230His', 'SUBSTITUTION', 'None', (119, 128))	('children', 'Species', '9606', (41, 49))	('Arg230His', 'Var', (119, 128))	('carried', 'Reg', (111, 118))
5666	32859697	The Arg230His mutation in this family corresponds to the C. elegans Arg244His SDHB-1 mutation.	('Arg244His', 'Var', (68, 77))	('SDHB-1', 'Gene', '174482', (78, 84))	('Arg230His', 'Var', (4, 13))	('SDHB-1', 'Gene', (78, 84))	('Arg244His', 'SUBSTITUTION', 'None', (68, 77))	('C. elegans', 'Species', '6239', (57, 67))	('Arg230His', 'SUBSTITUTION', 'None', (4, 13))
5667	32859697	First, we built nematode models of this SDHB mutation, where we used an existing sdhb-1(gk165) deletional worm and then generated two transgenic lines carrying either the above Arg244His mutation or its genomic wild-type SDHB as a control.	('SDHB', 'Gene', '6390', (40, 44))	('Arg244His', 'Var', (177, 186))	('SDHB', 'Gene', '6390', (221, 225))	('SDHB', 'Gene', (221, 225))	('SDHB', 'Gene', (40, 44))	('Arg244His', 'SUBSTITUTION', 'None', (177, 186))	('mutation', 'Var', (45, 53))	('sdhb-1', 'Gene', (81, 87))	('sdhb-1', 'Gene', '174482', (81, 87))
5668	32859697	Unexpectedly, our results showed that although fully deletional 'null' mutants arrest development soon after egg hatching at the L2 larval stage, the missense Arg244His point mutants develop much further, to the last larval L4 stage, but thereafter can only generate sterile adults.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('Arg244His', 'SUBSTITUTION', 'None', (159, 168))	('arrest', 'Disease', (79, 85))	('development', 'CPA', (86, 97))	('Arg244His', 'Var', (159, 168))
5669	32859697	Next, we analyzed the metabolic profile of the mutants using complementary metabolic and genetic approaches, finding that Arg244His mutant animals are metabolically very different from their SDHB-null counterparts in a manner that cannot be explained simply by their differential timing of developmental arrest.	('SDHB', 'Gene', (191, 195))	('developmental arrest', 'Disease', (290, 310))	('Arg244His', 'Var', (122, 131))	('developmental arrest', 'Disease', 'MESH:D006323', (290, 310))	('developmental arrest', 'Phenotype', 'HP:0007281', (290, 310))	('Arg244His', 'SUBSTITUTION', 'None', (122, 131))	('SDHB', 'Gene', '6390', (191, 195))
5670	32859697	The missense mutants (but not the null mutants) display aberrant glycolytic activity, principally manifesting as highly elevated lactate and pyruvate levels.	('lactate', 'Chemical', 'MESH:D019344', (129, 136))	('glycolytic activity', 'MPA', (65, 84))	('elevated', 'PosReg', (120, 128))	('pyruvate', 'Chemical', 'MESH:D019289', (141, 149))	('missense mutants', 'Var', (4, 20))
5671	32859697	Finally, bioinformatics analysis, alongside models of the SDH structure, led us to propose a pathway disorder following this missense mutation.	('SDH', 'Gene', (58, 61))	('missense mutation', 'Var', (125, 142))	('SDH', 'Gene', '6390', (58, 61))
5672	32859697	The combined data suggest the existence of a missense-mutation-dependent, rewired form of metabolism reminiscent of the Warburg effect metabolic reprogramming that is characteristic of tumor cells.	('tumor', 'Disease', (185, 190))	('metabolism', 'MPA', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('missense-mutation-dependent', 'Var', (45, 72))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
5673	32859697	Our animal model not only provides insight into a heritable SDH impairment, but also creates a useful tool that might help to not only decipher the enigmatic nature of other SDHx-associated pathologies, but also shed light on the genesis of aberrant glycolysis following just one missense mutation within complex II of mitochondria.	('SDH', 'Gene', (60, 63))	('SDH', 'Gene', (174, 177))	('glycolysis', 'MPA', (250, 260))	('SDH impairment', 'Disease', (60, 74))	('missense mutation', 'Var', (280, 297))	('aberrant glycolysis', 'Phenotype', 'HP:0004366', (241, 260))	('SDH', 'Gene', '6390', (60, 63))	('SDH impairment', 'Disease', 'MESH:D060825', (60, 74))	('SDH', 'Gene', '6390', (174, 177))
5677	32859697	In order to better understand the consequences of the familial p.Arg230His (SDHB c.689G>A), we generated the corresponding mutation, Arg244His (G731A in the cDNA) in the worm (Knudra Transgenics, Murray, UT, USA).	('G731A', 'Mutation', 'c.731G>A', (144, 149))	('p.Arg230His', 'Mutation', 'p.R230H', (63, 74))	('SDHB', 'Gene', '6390', (76, 80))	('Arg244His', 'Var', (133, 142))	('SDHB', 'Gene', (76, 80))	('Arg244His', 'SUBSTITUTION', 'None', (133, 142))	('c.689G>A', 'Mutation', 'c.689G>A', (81, 89))
5681	32859697	These transgenic strains each contain two corresponding transgenic sdhb-1 copies on their X chromosomes in addition to their endogenous copies on chromosome II.	('sdhb-1', 'Gene', '174482', (67, 73))	('copies', 'Var', (74, 80))	('sdhb-1', 'Gene', (67, 73))
5682	32859697	To create animals carrying only two transgenic wild-type or only two G731A point mutant copies, COP957 and COP952 strains were crossed into the sdhb-1(gk165) null background.	('G731A', 'Var', (69, 74))	('sdhb-1', 'Gene', (144, 150))	('sdhb-1', 'Gene', '174482', (144, 150))	('G731A', 'Mutation', 'c.731G>A', (69, 74))
5686	32859697	First, we crossed wild-type (COP957) and G731A point mutant (COP952) transgenic lines into sdhb-1(gk165) null mutant background and determined whether these transgenes were able to rescue the deletion caused by gk165.	('G731A', 'Var', (41, 46))	('G731A', 'Mutation', 'c.731G>A', (41, 46))	('gk165', 'Gene', (211, 216))	('sdhb-1', 'Gene', (91, 97))	('deletion', 'MPA', (192, 200))	('sdhb-1', 'Gene', '174482', (91, 97))
5687	32859697	In contrast, the G731A rescue generated sterile adults with a protruding vulva (the 'Pvl' phenotype; ); these phenotypes were not further analyzed.	('G731A', 'Mutation', 'c.731G>A', (17, 22))	('protruding vulva', 'MPA', (62, 78))	('G731A', 'Var', (17, 22))
5688	32859697	Henceforth, we refer to the G731A point mutant animals on a deletional background as R244H (Arg244His) (Fig.	('G731A', 'Mutation', 'c.731G>A', (28, 33))	('R244H', 'SUBSTITUTION', 'None', (85, 90))	('R244H', 'Var', (85, 90))	('Arg244His', 'SUBSTITUTION', 'None', (92, 101))	('G731A', 'Var', (28, 33))	('Arg244His', 'Var', (92, 101))
5689	32859697	To facilitate propagation, the R244H animals were also balanced using mIn1mIs14, as for gk165 deletional mutants.	('R244H', 'SUBSTITUTION', 'None', (31, 36))	('gk165', 'Gene', (88, 93))	('deletional mutants', 'Var', (94, 112))	('R244H', 'Var', (31, 36))	('mIn1', 'Gene', (70, 74))	('mIn1', 'Gene', '16258', (70, 74))
5690	32859697	Next, we compared the lifespan of homozygous sdhb-1(gk165) mutants against wild-type worms and observed that gk165 homozygotes survived about half as long as wild-type control N2 (WT) animals (Fig.	('gk165', 'Var', (109, 114))	('sdhb-1', 'Gene', (45, 51))	('mutants', 'Var', (59, 66))	('sdhb-1', 'Gene', '174482', (45, 51))
5692	32859697	R244H worms also showed a shortened lifespan compared to WT and WTR animals (Fig.	('R244H', 'Var', (0, 5))	('shortened', 'NegReg', (26, 35))	('R244H', 'SUBSTITUTION', 'None', (0, 5))	('lifespan', 'CPA', (36, 44))
5694	32859697	In contrast, R244H worms reached adulthood on only day 4-5, indicating delayed development (Fig.	('R244H', 'SUBSTITUTION', 'None', (13, 18))	('R244H', 'Var', (13, 18))	('delayed development', 'Phenotype', 'HP:0001263', (71, 90))	('delayed development', 'CPA', (71, 90))
5695	32859697	In order to investigate the proteins generated by the gk165 and Arg244His sdhb-1 mutant alleles, we performed Western capillary immunoassay (Wes) experiments using a human SDHB-specific antibody, which successfully cross-reacted with the worm SDHB-1 protein, likely due to the high level of conservation.	('SDHB', 'Gene', (172, 176))	('SDHB', 'Gene', '6390', (243, 247))	('SDHB', 'Gene', '6390', (172, 176))	('human', 'Species', '9606', (166, 171))	('Arg244His', 'Var', (64, 73))	('SDHB', 'Gene', (243, 247))	('SDHB-1', 'Gene', '174482', (243, 249))	('gk165', 'Var', (54, 59))	('Arg244His', 'SUBSTITUTION', 'None', (64, 73))	('sdhb-1', 'Gene', (74, 80))	('SDHB-1', 'Gene', (243, 249))	('sdhb-1', 'Gene', '174482', (74, 80))
5696	32859697	As expected, gk165 represents a null allele as no antibody specific band can be detected, whereas the same antibody recognized a single, well-defined band of 32 kDa, specific for SDHB-1 in all control samples (Fig.	('SDHB-1', 'Gene', '174482', (179, 185))	('SDHB-1', 'Gene', (179, 185))	('gk165', 'Var', (13, 18))
5698	32859697	Transcriptomics data verify Wes results at the mRNA level: we find that sdhb-1 mRNA lies below the detectable limit in gk165 mutants, whereas in R244H point mutants, sdhb-1 mRNA is transcribed, although at a decreased level (Fig.	('sdhb-1', 'Gene', (72, 78))	('sdhb-1', 'Gene', '174482', (72, 78))	('R244H', 'SUBSTITUTION', 'None', (145, 150))	('mutants', 'Var', (125, 132))	('sdhb-1', 'Gene', '174482', (166, 172))	('sdhb-1', 'Gene', (166, 172))	('R244H', 'Var', (145, 150))	('transcribed', 'MPA', (181, 192))	('gk165', 'Gene', (119, 124))	('mRNA', 'MPA', (79, 83))
5701	32859697	Metabolic characterization of sdhb-1 deletional and SDHB Arg244His point mutants shows elevated succinate-to-fumarate ratios and attenuated oxygen consumption with reduced mitochondrial and ATP content.	('succinate-to-fumarate ratios', 'MPA', (96, 124))	('attenuated', 'NegReg', (129, 139))	('Arg244His', 'Var', (57, 66))	('SDHB', 'Gene', (52, 56))	('oxygen', 'Chemical', 'MESH:D010100', (140, 146))	('ATP', 'Chemical', 'MESH:D000255', (190, 193))	('elevated succinate', 'Phenotype', 'HP:0020149', (87, 105))	('oxygen consumption', 'MPA', (140, 158))	('deletional', 'Var', (37, 47))	('Arg244His', 'SUBSTITUTION', 'None', (57, 66))	('succinate', 'Chemical', 'MESH:D019802', (96, 105))	('SDHB', 'Gene', '6390', (52, 56))	('sdhb-1', 'Gene', (30, 36))	('elevated', 'PosReg', (87, 95))	('fumarate', 'Chemical', 'MESH:D005650', (109, 117))	('sdhb-1', 'Gene', '174482', (30, 36))	('reduced', 'NegReg', (164, 171))
5703	32859697	Therefore, we compared TCA-related metabolite levels, glycolytic activity and the efficiency of stimulated mitochondrial oxygen consumption in sdhb-1(gk165) null mutants, R244H point mutants, WTR worms (which served as comparators for point mutants) and wild-type L2, L3 and L4 larvae as further stage-dependent controls.	('sdhb-1', 'Gene', '174482', (143, 149))	('R244H', 'Var', (171, 176))	('oxygen', 'Chemical', 'MESH:D010100', (121, 127))	('stimulated mitochondrial oxygen consumption', 'MPA', (96, 139))	('R244H', 'SUBSTITUTION', 'None', (171, 176))	('sdhb-1', 'Gene', (143, 149))	('TCA-related', 'MPA', (23, 34))
5708	32859697	As expected, succinate was elevated in the sdhb-1(gk165) deletional mutant, but, interestingly, R244H point mutants also showed an equivalent succinate rise (Fig.	('succinate', 'Chemical', 'MESH:D019802', (142, 151))	('R244H', 'SUBSTITUTION', 'None', (96, 101))	('succinate rise', 'MPA', (142, 156))	('succinate', 'MPA', (13, 22))	('R244H', 'Var', (96, 101))	('elevated', 'PosReg', (27, 35))	('sdhb-1', 'Gene', (43, 49))	('sdhb-1', 'Gene', '174482', (43, 49))	('succinate rise', 'Phenotype', 'HP:0020149', (142, 156))	('deletional mutant', 'Var', (57, 74))	('succinate', 'Chemical', 'MESH:D019802', (13, 22))
5709	32859697	The succinate-to-fumarate ratio was similarly elevated in both mutants despite their different developmental stages (Fig.	('elevated', 'PosReg', (46, 54))	('mutants', 'Var', (63, 70))	('fumarate', 'Chemical', 'MESH:D005650', (17, 25))	('succinate-to-fumarate ratio', 'MPA', (4, 31))	('succinate', 'Chemical', 'MESH:D019802', (4, 13))
5710	32859697	These data pointed to a complex metabolic phenotype dependent on the mutation status of SDHB.	('mutation', 'Var', (69, 77))	('SDHB', 'Gene', '6390', (88, 92))	('SDHB', 'Gene', (88, 92))
5711	32859697	For example, both aspartate and glutamate levels were decreased in R244H point mutants compared to wild-type and transgenic WTR L4 animals (Fig.	('R244H', 'Var', (67, 72))	('decreased', 'NegReg', (54, 63))	('aspartate', 'Chemical', 'MESH:D001224', (18, 27))	('R244H', 'SUBSTITUTION', 'None', (67, 72))	('glutamate', 'Chemical', 'MESH:D018698', (32, 41))
5712	32859697	Furthermore, R244H point mutants (but not null mutants) displayed significantly higher pyruvate and lactate levels compared to their larval stage-matched L4 controls (Fig.	('R244H', 'SUBSTITUTION', 'None', (13, 18))	('R244H', 'Var', (13, 18))	('higher', 'PosReg', (80, 86))	('pyruvate', 'Chemical', 'MESH:D019289', (87, 95))	('lactate', 'Chemical', 'MESH:D019344', (100, 107))
5713	32859697	Because the SDH complex plays a parallel role in complex II of the mitochondrial respiratory chain (see Introduction), we next determined the stimulated mitochondrial oxygen consumption rate (OCR) using the Seahorse technique in the above sdhb-1 deletional worms, point mutants and control strains.	('oxygen', 'Chemical', 'MESH:D010100', (167, 173))	('deletional', 'Var', (246, 256))	('SDH', 'Gene', '6390', (12, 15))	('mitochondrial oxygen consumption rate', 'MPA', (153, 190))	('SDH', 'Gene', (12, 15))	('sdhb-1', 'Gene', (239, 245))	('sdhb-1', 'Gene', '174482', (239, 245))
5715	32859697	We used this device to study the action of two mitochondrially active compounds, protonophore carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) and the complex IV (cytochrome oxidase) inhibitor sodium azide, to assess stimulated bioenergetics in sdhb-1 mutant worms and control strains (Fig.	('FCCP', 'Chemical', 'MESH:D002259', (149, 153))	('sdhb-1', 'Gene', (257, 263))	('sodium azide', 'Chemical', 'MESH:D019810', (205, 217))	('sdhb-1', 'Gene', '174482', (257, 263))	('mutant', 'Var', (264, 270))	('carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone', 'Chemical', 'MESH:D002259', (94, 147))
5716	32859697	There were no differences in either the unstimulated, basal OCR or the OCR following sodium azide addition between the mutants and control animals.	('OCR following sodium azide addition', 'MPA', (71, 106))	('sodium azide', 'Chemical', 'MESH:D019810', (85, 97))	('mutants', 'Var', (119, 126))
5718	32859697	In marked contrast, in gk165 deletional and R244H mutants, oxygen consumption was unchanged after FCCP injection, implying a loss of reserve capacity of respiration in these mutants (Fig.	('reserve capacity of respiration', 'MPA', (133, 164))	('loss', 'NegReg', (125, 129))	('deletional', 'Var', (29, 39))	('R244H', 'Var', (44, 49))	('gk165', 'Gene', (23, 28))	('FCCP', 'Chemical', 'MESH:D002259', (98, 102))	('oxygen', 'Chemical', 'MESH:D010100', (59, 65))	('oxygen consumption', 'MPA', (59, 77))	('R244H', 'SUBSTITUTION', 'None', (44, 49))
5719	32859697	As the SDH complex is an integral part of complex II of the mitochondrial electron transport system and its deficiency may hamper mitochondrial integrity and hence energy production, we next estimated the functional mitochondrial content using Mitotracker dye, the uptake of which is dependent on mitochondrial transmembrane potential and measured total ATP production, using a bioluminescent ATP assay.	('ATP', 'Chemical', 'MESH:D000255', (393, 396))	('energy production', 'CPA', (164, 181))	('SDH', 'Gene', (7, 10))	('mitochondrial integrity', 'CPA', (130, 153))	('ATP', 'Chemical', 'MESH:D000255', (354, 357))	('deficiency', 'Var', (108, 118))	('hamper', 'NegReg', (123, 129))	('SDH', 'Gene', '6390', (7, 10))
5720	32859697	We observed that deletional as well as point mutants of sdhb-1 had not only significantly fewer healthy mitochondria but also demonstrated downregulated ATP production, compared to wild-type and rescued strains (Fig.	('healthy mitochondria', 'MPA', (96, 116))	('sdhb-1', 'Gene', '174482', (56, 62))	('fewer', 'NegReg', (90, 95))	('sdhb-1', 'Gene', (56, 62))	('ATP production', 'MPA', (153, 167))	('point mutants', 'Var', (39, 52))	('deletional', 'Var', (17, 27))	('downregulated', 'NegReg', (139, 152))	('ATP', 'Chemical', 'MESH:D000255', (153, 156))
5721	32859697	The Arg244His mutation of C. elegans SDHB-1 corresponds to the Arg230His mutation of human SDHB, which leads to a familial form of malignant PPGL.	('PPGL', 'Chemical', '-', (141, 145))	('familial form of malignant PPGL', 'Disease', (114, 145))	('SDHB-1', 'Gene', '174482', (37, 43))	('SDHB', 'Gene', '6390', (37, 41))	('SDHB', 'Gene', '6390', (91, 95))	('SDHB-1', 'Gene', (37, 43))	('Arg244His', 'Var', (4, 13))	('leads to', 'Reg', (103, 111))	('Arg230His', 'Var', (63, 72))	('SDHB', 'Gene', (37, 41))	('SDHB', 'Gene', (91, 95))	('C. elegans', 'Species', '6239', (26, 36))	('Arg244His', 'SUBSTITUTION', 'None', (4, 13))	('human', 'Species', '9606', (85, 90))	('Arg230His', 'SUBSTITUTION', 'None', (63, 72))
5722	32859697	1A), that Arg230 plays an equivalent role across the SDHBs of these distant species.	('SDHB', 'Gene', (53, 57))	('Arg230', 'Chemical', '-', (10, 16))	('SDHB', 'Gene', '6390', (53, 57))	('Arg230', 'Var', (10, 16))
5723	32859697	In the X-ray structure (PDBID 4YTP) of the SDHB subunit of porcine heart, the guanidino group of Arg230 of SDHB forms two hydrogen bonds with the carboxyl oxygens of the side chain of Asp224.	('guanidino', 'Chemical', '-', (78, 87))	('Asp224', 'Chemical', '-', (184, 190))	('SDHB', 'Gene', (107, 111))	('Arg230', 'Chemical', '-', (97, 103))	('SDHB', 'Gene', '6390', (43, 47))	('oxygens', 'Chemical', 'MESH:D010100', (155, 162))	('hydrogen', 'Chemical', 'MESH:D006859', (122, 130))	('Arg230', 'Var', (97, 103))	('SDHB', 'Gene', (43, 47))	('SDHB', 'Gene', '6390', (107, 111))
5724	32859697	In addition, Arg230 is hydrogen bonded with the peptide backbone atoms of residues Glu154, Tyr156 and Phe226.	('Arg230', 'Var', (13, 19))	('Phe226', 'Var', (102, 108))	('Glu154', 'Chemical', '-', (83, 89))	('hydrogen', 'Chemical', 'MESH:D006859', (23, 31))	('Tyr156', 'Var', (91, 97))	('hydrogen bonded', 'Reg', (23, 38))	('Arg230', 'Chemical', '-', (13, 19))	('Tyr156', 'Chemical', '-', (91, 97))	('Phe226', 'Chemical', '-', (102, 108))	('Glu154', 'Var', (83, 89))
5726	32859697	Hence, substitution of Arg230 by other residues, such as His, Cys, Gly and Leu, is likely to disrupt the strong hydrogen bonding between residues 224 and 230, which might impair protein function (see Discussion).	('protein', 'Protein', (178, 185))	('impair', 'NegReg', (171, 177))	('His', 'Chemical', 'MESH:D006639', (57, 60))	('Gly', 'Var', (67, 70))	('hydrogen', 'Chemical', 'MESH:D006859', (112, 120))	('disrupt', 'NegReg', (93, 100))	('Leu', 'Var', (75, 78))	('strong hydrogen bonding', 'MPA', (105, 128))	('Arg230', 'Chemical', '-', (23, 29))	('Leu', 'Chemical', 'MESH:D007930', (75, 78))	('Cys', 'Var', (62, 65))	('Cys', 'Chemical', 'MESH:D003545', (62, 65))	('Gly', 'Chemical', 'MESH:D005998', (67, 70))	('Arg230', 'Var', (23, 29))
5727	32859697	In order to probe the effect of R230H mutation in human SDHB, we constructed homology models of the human SDHA/B complex for the wild type and R230H mutant, based on the above structure of the porcine SDHB subunit (Fig.	('SDHA', 'Gene', (106, 110))	('R230H', 'Var', (143, 148))	('SDHB', 'Gene', '6390', (201, 205))	('SDHB', 'Gene', (56, 60))	('SDHB', 'Gene', (201, 205))	('R230H', 'Mutation', 'p.R230H', (143, 148))	('SDHB', 'Gene', '6390', (56, 60))	('human', 'Species', '9606', (100, 105))	('R230H', 'Mutation', 'p.R230H', (32, 37))	('SDHA', 'Gene', '6389', (106, 110))	('human', 'Species', '9606', (50, 55))
5728	32859697	The difference in averaged pairwise contacts from wild type to R230H mutant indicates a reduction of about five inter-residue contacts upon the mutation (Fig.	('R230H', 'Mutation', 'p.R230H', (63, 68))	('reduction', 'NegReg', (88, 97))	('R230H', 'Var', (63, 68))
5731	32859697	We found that expression of genes encoding vitellogenins (such as vit-2, vit-5, vit-6) and genes required to build the cuticle (for example, col-140, col-122, col-123 or bli-6) were increased in the point mutant worms, consistent with their later developmental arrest point (point mutants develop to adulthood whereas null mutants arrest at L2).	('increased', 'PosReg', (182, 191))	('point mutant', 'Var', (199, 211))	('arrest', 'Disease', (261, 267))	('col-123', 'Gene', (159, 166))	('expression', 'MPA', (14, 24))	('arrest', 'Disease', 'MESH:D006323', (331, 337))	('developmental arrest', 'Disease', (247, 267))	('col-122', 'Gene', (150, 157))	('developmental arrest', 'Disease', 'MESH:D006323', (247, 267))	('arrest', 'Disease', (331, 337))	('col-140', 'Gene', (141, 148))	('bli-6', 'Gene', (170, 175))	('arrest', 'Disease', 'MESH:D006323', (261, 267))	('developmental arrest', 'Phenotype', 'HP:0007281', (247, 267))
5732	32859697	We observed that R244H point mutants also show a decreased expression of germline-specific genes (gld-1 or spch-1) when compared to wild-type worms, which might relate to the sterility of R244H animals.	('R244H', 'SUBSTITUTION', 'None', (188, 193))	('R244H', 'SUBSTITUTION', 'None', (17, 22))	('spch-1', 'Gene', '93986', (107, 113))	('gld-1', 'Gene', (98, 103))	('R244H', 'Var', (188, 193))	('sterility', 'Disease', (175, 184))	('R244H', 'Var', (17, 22))	('decreased', 'NegReg', (49, 58))	('spch-1', 'Gene', (107, 113))	('expression', 'MPA', (59, 69))
5733	32859697	Interestingly, given the neurological nature of the disease, in deletional mutants, some genes associated with the nervous system (for example, C06B3.6, B0205.13, F18E3.12, F09F7.6) are highly overexpressed, which requires further study (data not shown).	('B0205.13', 'Var', (153, 161))	('deletional mutants', 'Var', (64, 82))	('F18E3.12', 'Var', (163, 171))	('C06B3.6', 'Var', (144, 151))	('F09F7.6', 'CellLine', 'CVCL:L036', (173, 180))	('overexpressed', 'PosReg', (193, 206))	('F09F7.6', 'Var', (173, 180))
5734	32859697	Next, we focused on genes related to the observed differences in the metabolic profiles of sdhb-1 deletional and point mutants (Fig.	('deletional', 'Var', (98, 108))	('sdhb-1', 'Gene', (91, 97))	('point mutants', 'Var', (113, 126))	('sdhb-1', 'Gene', '174482', (91, 97))
5735	32859697	Because our LC-MS data revealed a differentially compromised TCA cycle in sdhb-1 null compared to point mutants (e.g.	('compromised', 'NegReg', (49, 60))	('sdhb-1', 'Gene', (74, 80))	('sdhb-1', 'Gene', '174482', (74, 80))	('null', 'Var', (81, 85))	('TCA cycle', 'MPA', (61, 70))
5737	32859697	First, we compared their expression levels in the null sdhb-1(gk165) and R244H mutants versus their stage-specific control strains (Fig.	('sdhb-1', 'Gene', (55, 61))	('expression levels', 'MPA', (25, 42))	('sdhb-1', 'Gene', '174482', (55, 61))	('R244H', 'SUBSTITUTION', 'None', (73, 78))	('R244H', 'Var', (73, 78))
5743	32859697	In deletional mutants, the relatively lowly expressed genes included sdha-1 and fum-1; the moderately expressed genes included glutamate dehydrogenase (gdh-1) and malic enzyme (men-1).	('hydrogen', 'Chemical', 'MESH:D006859', (139, 147))	('deletional mutants', 'Var', (3, 21))	('glutamate', 'Chemical', 'MESH:D018698', (127, 136))	('men-1', 'Gene', '4221', (177, 182))	('fum-1', 'Gene', (80, 85))	('gdh-1', 'Gene', '2746', (152, 157))	('sdha-1', 'Gene', (69, 75))	('men-1', 'Gene', (177, 182))	('gdh-1', 'Gene', (152, 157))
5744	32859697	In point mutants, highly selectively elevated expressed genes included idh-2 and ldh-1, compared to aco-2, icl-1, pyc-1 and pck-1/2, which were increased in both mutants (Fig.	('pyc-1', 'Gene', '260434', (114, 119))	('point mutants', 'Var', (3, 16))	('pyc-1', 'Gene', (114, 119))	('idh-2', 'Gene', (71, 76))	('aco-2', 'Gene', '50', (100, 105))	('elevated', 'PosReg', (37, 45))	('pck-1/2', 'Gene', (124, 131))	('ldh-1', 'Gene', (81, 86))	('idh-2', 'Gene', '3418', (71, 76))	('aco-2', 'Gene', (100, 105))	('expressed genes', 'MPA', (46, 61))	('pck-1/2', 'Gene', '5105;5106', (124, 131))
5745	32859697	Expression of icl-1, the bifunctional key enzyme of the glyoxylate shunt, showed the most remarkable change in both deletional and point mutants compared to the appropriate controls (~20-fold or 10-fold change in deletional and point mutants, respectively; Fig.	('Expression', 'MPA', (0, 10))	('deletional', 'Var', (116, 126))	('icl-1', 'Gene', (14, 19))	('point mutants', 'Var', (131, 144))	('glyoxylate', 'Chemical', 'MESH:C031150', (56, 66))	('change', 'Reg', (101, 107))
5746	32859697	qPCR data also confirmed results found in metabolic analysis: ldh-1, which generates lactate from pyruvate, was strongly and selectively increased in point mutant animals (Fig.	('ldh-1', 'Gene', (62, 67))	('pyruvate', 'Chemical', 'MESH:D019289', (98, 106))	('point mutant', 'Var', (150, 162))	('lactate', 'Chemical', 'MESH:D019344', (85, 92))	('lactate from pyruvate', 'MPA', (85, 106))	('increased', 'PosReg', (137, 146))
5747	32859697	Interestingly, only R244H mutants showed increased aco-2, idh-2, sdha-1, fum-1 and mdh-2 expression.	('idh-2', 'Gene', '3418', (58, 63))	('R244H', 'SUBSTITUTION', 'None', (20, 25))	('expression', 'MPA', (89, 99))	('increased', 'PosReg', (41, 50))	('aco-2', 'Gene', '50', (51, 56))	('R244H', 'Var', (20, 25))	('mdh-2', 'Gene', (83, 88))	('sdha-1', 'Gene', (65, 71))	('fum-1', 'Gene', (73, 78))	('idh-2', 'Gene', (58, 63))	('mdh-2', 'Gene', '4191', (83, 88))	('aco-2', 'Gene', (51, 56))
5749	32859697	Based on our metabolomic data, the glyoxylate cycle plays an important role in the metabolism of sdhb-1 mutants as we found that isocitrate lyase (icl-1) expression was significantly elevated in both mutant backgrounds (Fig.	('glyoxylate', 'Chemical', 'MESH:C031150', (35, 45))	('mutants', 'Var', (104, 111))	('isocitrate', 'MPA', (129, 139))	('mutant', 'Var', (200, 206))	('sdhb-1', 'Gene', (97, 103))	('expression', 'MPA', (154, 164))	('sdhb-1', 'Gene', '174482', (97, 103))	('isocitrate', 'Chemical', 'MESH:C034219', (129, 139))	('elevated', 'PosReg', (183, 191))
5750	32859697	We first attempted to attenuate the glyoxylate shunt by silencing ICL-1 activity by feeding sdhb-1 mutants with HT115 bacteria expressing double-stranded RNA (dsRNA) specific for icl-1 [icl-1(RNAi)].	('ICL-1 activity', 'MPA', (66, 80))	('sdhb-1', 'Gene', '174482', (92, 98))	('glyoxylate', 'Chemical', 'MESH:C031150', (36, 46))	('HT115', 'CellLine', 'CVCL:2520', (112, 117))	('sdhb-1', 'Gene', (92, 98))	('glyoxylate', 'MPA', (36, 46))	('mutants', 'Var', (99, 106))	('attenuate', 'NegReg', (22, 31))	('silencing', 'NegReg', (56, 65))
5751	32859697	This influenced the lifespan and viability of sdhb-1(-) null mutants as follows: icl-1(RNAi) treatment resulted in partially penetrant lethality of gk165 mutant embryos (Fig.	('mutant', 'Var', (154, 160))	('partially penetrant lethality', 'CPA', (115, 144))	('influenced', 'Reg', (5, 15))	('sdhb-1', 'Gene', (46, 52))	('sdhb-1', 'Gene', '174482', (46, 52))	('gk165', 'Gene', (148, 153))
5754	32859697	As point mutants showed a significant increase in lactate dehydrogenase (ldh-1) expression, we applied an inhibitor that targets the human LDH-1 homolog lactate dehydrogenase A (GSK2837808A) and is known to inhibit tumorigenesis in mouse models.	('ldh-1', 'Gene', (73, 78))	('inhibit', 'NegReg', (207, 214))	('lactate dehydrogenase A', 'Gene', '3939', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('lactate', 'MPA', (50, 57))	('GSK2837808A', 'Chemical', 'MESH:C000612070', (178, 189))	('increase', 'PosReg', (38, 46))	('hydrogen', 'Chemical', 'MESH:D006859', (60, 68))	('lactate dehydrogenase A', 'Gene', (153, 176))	('expression', 'MPA', (80, 90))	('human', 'Species', '9606', (133, 138))	('hydrogen', 'Chemical', 'MESH:D006859', (163, 171))	('LDH-1', 'Gene', (139, 144))	('tumor', 'Disease', (215, 220))	('lactate', 'Chemical', 'MESH:D019344', (153, 160))	('lactate', 'Chemical', 'MESH:D019344', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mouse', 'Species', '10090', (232, 237))	('GSK2837808A', 'Var', (178, 189))
5755	32859697	GSK2837808A arrested the development of R244H point mutants at an earlier time point, such that R244H mutant embryos grown on bacteria and the LDH-A inhibitor at 10 microM concentration arrested development at the L2/L3 larval stage in 12.4% of cases, whereas the untreated controls reached adulthood but remained sterile (Fig.	('LDH-A', 'Gene', (143, 148))	('arrest', 'Disease', 'MESH:D006323', (186, 192))	('R244H', 'Var', (40, 45))	('R244H', 'SUBSTITUTION', 'None', (96, 101))	('arrest', 'Disease', 'MESH:D006323', (12, 18))	('R244H', 'Var', (96, 101))	('arrest', 'Disease', (186, 192))	('GSK2837808A', 'Chemical', 'MESH:C000612070', (0, 11))	('arrest', 'Disease', (12, 18))	('LDH-A', 'Gene', '3939', (143, 148))	('R244H', 'SUBSTITUTION', 'None', (40, 45))	('development at the L2/L3 larval stage', 'CPA', (195, 232))
5758	32859697	Our second aim was to determine whether a worm model would enable a better understanding of the different biological backgrounds following different sdhb mutations, only some of which are associated with an increased risk of malignant PPGL.	('associated', 'Reg', (188, 198))	('PPGL', 'Chemical', '-', (235, 239))	('sdhb', 'Gene', '6390', (149, 153))	('sdhb', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))
5760	32859697	To that end, using bioinformatic tools, we also explored the structural consequences of one SDHB missense mutation that might affect the SDHA-SDHB interface.	('SDHB', 'Gene', (142, 146))	('SDHB', 'Gene', '6390', (92, 96))	('missense mutation', 'Var', (97, 114))	('SDHA', 'Gene', '6389', (137, 141))	('SDHB', 'Gene', (92, 96))	('affect', 'Reg', (126, 132))	('SDHB', 'Gene', '6390', (142, 146))	('SDHA', 'Gene', (137, 141))
5761	32859697	Amongst SDHB mutations, we focused on worms bearing the Arg230His missense mutation that is causal of a familial form of PPGL.	('PPGL', 'Chemical', '-', (121, 125))	('Arg230His', 'SUBSTITUTION', 'None', (56, 65))	('SDHB', 'Gene', '6390', (8, 12))	('SDHB', 'Gene', (8, 12))	('Arg230His', 'Var', (56, 65))	('mutations', 'Var', (13, 22))
5762	32859697	We generated two transgenic lines carrying the Arg244His missense mutation (corresponding to human Arg230His) and genomic wild-type sdhb-1.	('Arg244His', 'Var', (47, 56))	('Arg230His', 'Var', (99, 108))	('sdhb-1', 'Gene', (132, 138))	('human', 'Species', '9606', (93, 98))	('sdhb-1', 'Gene', '174482', (132, 138))	('Arg244His', 'SUBSTITUTION', 'None', (47, 56))	('Arg230His', 'SUBSTITUTION', 'None', (99, 108))
5764	32859697	As expected, only the wild-type SDHB transgene efficiently rescued the L2 larval arrest that is characteristic of the SDHB null mutant.	('SDHB', 'Gene', '6390', (118, 122))	('SDHB', 'Gene', '6390', (32, 36))	('SDHB', 'Gene', (118, 122))	('SDHB', 'Gene', (32, 36))	('mutant', 'Var', (128, 134))	('rescued', 'PosReg', (59, 66))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('arrest', 'Disease', (81, 87))
5765	32859697	In contrast, the point mutant corresponding to human Arg230His was unable to fully complement the deletional phenotype, producing only sterile adults with a significantly shortened lifespan of a similar degree to that of null mutants.	('Arg230His', 'Var', (53, 62))	('shortened', 'NegReg', (171, 180))	('Arg230His', 'SUBSTITUTION', 'None', (53, 62))	('human', 'Species', '9606', (47, 52))
5766	32859697	These data are consistent with known lifespan-shortening effects of mutations in the C. elegans SDHC mev-1 subunit.	('SDHC', 'Gene', (96, 100))	('SDHC', 'Gene', '6391', (96, 100))	('mutations', 'Var', (68, 77))	('lifespan-shortening', 'CPA', (37, 56))	('C. elegans', 'Species', '6239', (85, 95))
5767	32859697	To gain more insight into the nature of gk165 and Arg244His mutant alleles, we examined whether SDHB is transcribed and translated in these mutant backgrounds.	('Arg244His', 'SUBSTITUTION', 'None', (50, 59))	('gk165', 'Var', (40, 45))	('SDHB', 'Gene', '6390', (96, 100))	('SDHB', 'Gene', (96, 100))	('Arg244His', 'Var', (50, 59))
5769	32859697	We first confirmed that gk165 represents a true null allele as in this background SDHB-1 protein is absent.	('absent', 'NegReg', (100, 106))	('gk165', 'Var', (24, 29))	('SDHB-1', 'Gene', '174482', (82, 88))	('protein', 'Protein', (89, 96))	('SDHB-1', 'Gene', (82, 88))
5770	32859697	In Arg244His mutants, SDHB-1 is transcribed and translated, but at a lower level compared to the wild-type control.	('SDHB-1', 'Gene', '174482', (22, 28))	('SDHB-1', 'Gene', (22, 28))	('Arg244His', 'Var', (3, 12))	('translated', 'MPA', (48, 58))	('Arg244His', 'SUBSTITUTION', 'None', (3, 12))
5771	32859697	This result shows that the SDHB-1 R244H protein is stable enough to be detected, although it is functionally defective in the TCA cycle, given the elevated succinate-to-furmarate ratio.	('elevated succinate', 'Phenotype', 'HP:0020149', (147, 165))	('succinate-to-furmarate ratio', 'MPA', (156, 184))	('SDHB-1', 'Gene', (27, 33))	('furmarate', 'Chemical', '-', (169, 178))	('succinate', 'Chemical', 'MESH:D019802', (156, 165))	('TCA cycle', 'MPA', (126, 135))	('R244H', 'SUBSTITUTION', 'None', (34, 39))	('defective', 'NegReg', (109, 118))	('R244H', 'Var', (34, 39))	('elevated', 'PosReg', (147, 155))	('SDHB-1', 'Gene', '174482', (27, 33))
5772	32859697	However, we do not know whether the SDH complex stays intact in the mutant or whether soluble SDHA is released with an attenuated function described as 'CII low activity'.	('SDH', 'Gene', '6390', (94, 97))	('SDHA', 'Gene', '6389', (94, 98))	('SDH', 'Gene', '6390', (36, 39))	('SDHA', 'Gene', (94, 98))	('SDH', 'Gene', (94, 97))	('SDH', 'Gene', (36, 39))	('mutant', 'Var', (68, 74))
5773	32859697	The status of SDHA needs to be examined in both sdhb-1 deletional and point mutants in future studies.	('deletional', 'Var', (55, 65))	('sdhb-1', 'Gene', (48, 54))	('SDHA', 'Gene', (14, 18))	('point mutants', 'Var', (70, 83))	('sdhb-1', 'Gene', '174482', (48, 54))	('SDHA', 'Gene', '6389', (14, 18))
5775	32859697	Interestingly, point mutants showed an almost identically elevated succinate-to-fumarate ratio compared to deletional mutants, suggesting that point mutation also leads to loss of SDH activity in the TCA cycle.	('elevated succinate', 'Phenotype', 'HP:0020149', (58, 76))	('succinate-to-fumarate ratio', 'MPA', (67, 94))	('loss', 'NegReg', (172, 176))	('point mutation', 'Var', (143, 157))	('SDH', 'Gene', '6390', (180, 183))	('activity', 'MPA', (184, 192))	('succinate', 'Chemical', 'MESH:D019802', (67, 76))	('TCA cycle', 'Enzyme', (200, 209))	('elevated', 'PosReg', (58, 66))	('SDH', 'Gene', (180, 183))	('fumarate', 'Chemical', 'MESH:D005650', (80, 88))
5777	32859697	Clearly, in the null state, elevated succinate cannot be further metabolized in the TCA cycle, but we saw no corresponding reduction in SDHA mRNA in the point mutant worm.	('succinate', 'Chemical', 'MESH:D019802', (37, 46))	('SDHA', 'Gene', '6389', (136, 140))	('reduction', 'NegReg', (123, 132))	('point mutant', 'Var', (153, 165))	('elevated succinate', 'Phenotype', 'HP:0020149', (28, 46))	('SDHA', 'Gene', (136, 140))
5778	32859697	Stimulated oxygen consumption was also equivalently reduced in both deletional and point mutant animals and was accompanied by downregulated mitochondrial and total ATP content, consistent with the notion that this related manifestation of SDH activity was eliminated equally in both mutants.	('SDH', 'Gene', '6390', (240, 243))	('reduced', 'NegReg', (52, 59))	('point mutant', 'Var', (83, 95))	('ATP', 'Chemical', 'MESH:D000255', (165, 168))	('oxygen', 'Chemical', 'MESH:D010100', (11, 17))	('downregulated', 'NegReg', (127, 140))	('deletional', 'Var', (68, 78))	('SDH', 'Gene', (240, 243))	('oxygen consumption', 'MPA', (11, 29))
5779	32859697	These results are in line with published human data and our bioinformatic predictions suggesting that the Arg244His substitution induces a conformational change in the structure of SDHB-1 that might result in either an inactive or altered enzyme.	('inactive', 'MPA', (219, 227))	('enzyme', 'MPA', (239, 245))	('Arg244His', 'Var', (106, 115))	('human', 'Species', '9606', (41, 46))	('SDHB-1', 'Gene', '174482', (181, 187))	('conformational change', 'MPA', (139, 160))	('Arg244His', 'SUBSTITUTION', 'None', (106, 115))	('SDHB-1', 'Gene', (181, 187))
5780	32859697	Importantly, the guanidino group of Arg230 (Arg244 in worms) normally forms a conserved Asp224-Arg230 salt bridge that might be critical for the stability of SDHB proteins.	('Arg230', 'Chemical', '-', (36, 42))	('Asp224', 'Chemical', '-', (88, 94))	('guanidino', 'Chemical', '-', (17, 26))	('Arg230', 'Chemical', '-', (95, 101))	('SDHB', 'Gene', '6390', (158, 162))	('Arg230', 'Var', (36, 42))	('SDHB', 'Gene', (158, 162))	('Arg244', 'Chemical', '-', (44, 50))
5781	32859697	The importance of this salt bridge is also supported by the fact that not only the Arg230His mutation described in this work, but also missense mutation of the bridging partner's histidine Asp224His, is linked to hereditary PPGL.	('Arg230His', 'SUBSTITUTION', 'None', (83, 92))	('missense mutation', 'Var', (135, 152))	('histidine', 'Chemical', 'MESH:D006639', (179, 188))	('PPGL', 'Disease', (224, 228))	('Arg230His', 'Var', (83, 92))	('PPGL', 'Chemical', '-', (224, 228))	('Asp224His', 'SUBSTITUTION', 'None', (189, 198))	('linked', 'Reg', (203, 209))	('Asp224His', 'Var', (189, 198))
5782	32859697	Despite the above similarities in bioenergetics, the null and point mutants show significant developmental differences: the null worms show arrested development at the L2 larval stage, whereas point mutants develop further, eventually reaching adulthood, although they are then sterile.	('arrest', 'Disease', (140, 146))	('arrest', 'Disease', 'MESH:D006323', (140, 146))	('point mutants', 'Var', (193, 206))
5783	32859697	We found elevated isocitrate lyase (icl-1) expression in both mutants (confirmed by qPCR, below).	('elevated', 'PosReg', (9, 17))	('mutants', 'Var', (62, 69))	('isocitrate', 'MPA', (18, 28))	('isocitrate', 'Chemical', 'MESH:C034219', (18, 28))	('expression', 'MPA', (43, 53))
5790	32859697	The metabolic switch between the (early) glyoxylate shunt and the (later) TCA cycle pivots at the L2/L3 larval stage, exactly when we observed arrested development in sdhb-1(gk165) deletional mutants.	('deletional mutants', 'Var', (181, 199))	('glyoxylate', 'Chemical', 'MESH:C031150', (41, 51))	('arrest', 'Disease', (143, 149))	('sdhb-1', 'Gene', (167, 173))	('sdhb-1', 'Gene', '174482', (167, 173))	('arrest', 'Disease', 'MESH:D006323', (143, 149))
5791	32859697	Correspondingly, transcriptomic and qPCR data showed elevated icl-1 expression in deletional mutants, which arrest at L2 larval stage, in which the glyoxylate cycle is active.	('deletional mutants', 'Var', (82, 100))	('elevated', 'PosReg', (53, 61))	('expression', 'MPA', (68, 78))	('glyoxylate', 'Chemical', 'MESH:C031150', (148, 158))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('icl-1', 'Gene', (62, 67))	('arrest', 'Disease', (108, 114))
5792	32859697	icl-1 expression was also increased in Arg244His point mutants, which might compensate for the absence of SDH activity in the TCA cycle.	('icl-1 expression', 'MPA', (0, 16))	('Arg244His', 'Var', (39, 48))	('SDH', 'Gene', (106, 109))	('Arg244His', 'SUBSTITUTION', 'None', (39, 48))	('increased', 'PosReg', (26, 35))	('SDH', 'Gene', '6390', (106, 109))
5793	32859697	Interestingly, key enzymes of gluconeogenesis (pck-2, pyc-1) were not significantly different when point mutants were compared to the null state.	('pck-2', 'Gene', '5106', (47, 52))	('pyc-1', 'Gene', (54, 59))	('pyc-1', 'Gene', '260434', (54, 59))	('pck-2', 'Gene', (47, 52))	('point mutants', 'Var', (99, 112))
5794	32859697	Neither was the relative expression of the message for several TCA cycle enzymes (ogdh-1, suca-1, fum-1 and mdh-2) different in R244H worms compared to wild-type controls, which suggests that the point mutants can express key components of the TCA cycle in addition to the glyoxylate cycle.	('express', 'Reg', (214, 221))	('point', 'Var', (196, 201))	('gdh-1', 'Gene', '2746', (83, 88))	('glyoxylate', 'Chemical', 'MESH:C031150', (273, 283))	('R244H', 'SUBSTITUTION', 'None', (128, 133))	('mdh-2', 'Gene', (108, 113))	('gdh-1', 'Gene', (83, 88))	('R244H', 'Var', (128, 133))	('mdh-2', 'Gene', '4191', (108, 113))
5795	32859697	Increased expression of the message for the enzyme interconverting lactate and pyruvate (ldh-1) was confined to point mutants, consistent with our biochemical data, which showed high lactate levels only in the Arg244His point mutants.	('lactate levels', 'MPA', (183, 197))	('lactate', 'Chemical', 'MESH:D019344', (183, 190))	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('Arg244His', 'SUBSTITUTION', 'None', (210, 219))	('pyruvate', 'Chemical', 'MESH:D019289', (79, 87))	('Arg244His', 'Var', (210, 219))	('ldh-1', 'Gene', (89, 94))
5796	32859697	Together, the data suggest that Arg244His point mutants, which develop into sterile adults, exhibit a higher glycolytic activity alongside a partially functioning TCA cycle, where the glyoxylate shunt likely compensates for the absence of SDH activity.	('SDH', 'Gene', (239, 242))	('Arg244His', 'Var', (32, 41))	('glycolytic activity', 'MPA', (109, 128))	('glyoxylate', 'Chemical', 'MESH:C031150', (184, 194))	('higher', 'PosReg', (102, 108))	('Arg244His', 'SUBSTITUTION', 'None', (32, 41))	('SDH', 'Gene', '6390', (239, 242))
5798	32859697	In this respect, in Arg244His mutants, the glycolytic-oxphos metabolite concentrations/ratios were reminiscent of tumor cells undergoing Warburg effect, i.e.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Arg244His', 'Var', (20, 29))	('tumor', 'Disease', (114, 119))	('Arg244His', 'SUBSTITUTION', 'None', (20, 29))	('glycolytic-oxphos metabolite concentrations/ratios', 'MPA', (43, 93))
5800	32859697	In the work reported here, we have generated a novel nematode model for examining and evaluating the developmental and metabolic consequences of two clinically important SDHB mutations (null and point mutant).	('SDHB', 'Gene', '6390', (170, 174))	('mutations', 'Var', (175, 184))	('SDHB', 'Gene', (170, 174))	('point mutant', 'Var', (195, 207))
5801	32859697	We observed very different metabolic alterations as a result of sdhb-1 deletion in comparison to an equally cancer-proven but highly malignant (Arg230His) missense mutation.	('Arg230His', 'SUBSTITUTION', 'None', (144, 153))	('Arg230His', 'Var', (144, 153))	('deletion', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('metabolic alterations', 'MPA', (27, 48))	('sdhb-1', 'Gene', '174482', (64, 70))	('sdhb-1', 'Gene', (64, 70))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
5804	32859697	We found that icl-1(RNAi) treatment selectively acted on gk165 null mutants, caused a partially penetrant embryonic lethality and shortened lifespan.	('shortened', 'NegReg', (130, 139))	('embryonic lethality', 'Disease', 'MESH:D020964', (106, 125))	('embryonic lethality', 'Disease', (106, 125))	('gk165', 'Gene', (57, 62))	('acted', 'Reg', (48, 53))	('lifespan', 'CPA', (140, 148))	('mutants', 'Var', (68, 75))	('caused', 'Reg', (77, 83))
5805	32859697	These data are consistent with the idea that the glyoxylate cycle serves a critical role in null mutants by sustaining their development until the L2 stage.	('null mutants', 'Var', (92, 104))	('sustaining', 'PosReg', (108, 118))	('development', 'CPA', (125, 136))	('glyoxylate', 'Chemical', 'MESH:C031150', (49, 59))
5806	32859697	However, R244H point mutants, which are able to reach adulthood, specifically display an elevated lactate dehydrogenase (ldh-1) expression in addition to the increased icl-1 message.	('ldh-1', 'Gene', (121, 126))	('elevated lactate dehydrogenase', 'Phenotype', 'HP:0025435', (89, 119))	('lactate', 'Chemical', 'MESH:D019344', (98, 105))	('elevated', 'PosReg', (89, 97))	('lactate', 'MPA', (98, 105))	('R244H', 'SUBSTITUTION', 'None', (9, 14))	('expression', 'MPA', (128, 138))	('hydrogen', 'Chemical', 'MESH:D006859', (108, 116))	('icl-1 message', 'MPA', (168, 181))	('R244H', 'Var', (9, 14))	('increased', 'PosReg', (158, 167))
5808	32859697	LDH-1 inhibition resulted in an earlier than expected L2/L3 larval arrest of point mutants, showing that LDH-1 activity is indeed crucial in their development.	('LDH-1', 'Gene', (0, 5))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('point mutants', 'Var', (77, 90))	('inhibition', 'NegReg', (6, 16))	('arrest', 'Disease', (67, 73))	('earlier', 'CPA', (32, 39))
5810	32859697	Our modeling approach might also be of benefit to research groups studying other SDH mutations and different TCA cycle genes linked to metabolic diseases and cancer.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('SDH', 'Gene', (81, 84))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('metabolic diseases', 'Disease', (135, 153))	('cancer', 'Disease', (158, 164))	('mutations', 'Var', (85, 94))	('SDH', 'Gene', '6390', (81, 84))	('metabolic diseases', 'Disease', 'MESH:D008659', (135, 153))	('TCA cycle', 'Gene', (109, 118))
5818	32859697	]; R244H, sdhb-1(gk165)/ mIn1 [mIs14 [myo-2::gfp; pes-10::gfp] dpy-10(e128)] II.	('sdhb-1', 'Gene', (10, 16))	('R244H', 'SUBSTITUTION', 'None', (3, 8))	('sdhb-1', 'Gene', '174482', (10, 16))	('mIn1', 'Gene', (25, 29))	('R244H', 'Var', (3, 8))	('mIn1', 'Gene', '16258', (25, 29))
5822	32859697	In this study, we also used two transgenic strains generated by Knudra Transgene Service: sdhb-1 wild-type transgenic strain [sdhb-1p::SDHB-1(wt)::sdhb-1u] and a transgenic strain carrying the Arg244His missense mutation (caused by a G731A point mutation in the coding sequence) [sdhb-1p::SDHB-1(G731A)::sdhb-1u].	('sdhb-1', 'Gene', (147, 153))	('SDHB-1', 'Gene', '174482', (289, 295))	('sdhb-1', 'Gene', (90, 96))	('sdhb-1', 'Gene', '174482', (147, 153))	('sdhb-1', 'Gene', '174482', (90, 96))	('SDHB-1', 'Gene', (135, 141))	('Arg244His', 'SUBSTITUTION', 'None', (193, 202))	('sdhb-1', 'Gene', (280, 286))	('sdhb-1', 'Gene', (304, 310))	('sdhb-1', 'Gene', '174482', (280, 286))	('sdhb-1', 'Gene', '174482', (304, 310))	('SDHB-1', 'Gene', '174482', (135, 141))	('Arg244His', 'Var', (193, 202))	('sdhb-1', 'Gene', '174482', (126, 132))	('sdhb-1', 'Gene', (126, 132))	('G731A', 'Mutation', 'c.731G>A', (234, 239))	('SDHB-1', 'Gene', (289, 295))	('G731A', 'Mutation', 'c.731G>A', (296, 301))	('G731A', 'Var', (234, 239))
5830	32859697	Subsequently, transgenic worms were generated by biolistic transformation using the unc-119(ed3) mutant genetic background and the unc-119(+) gene as a co-transformation marker.	('unc-119', 'Gene', '9094', (131, 138))	('unc-119', 'Gene', (84, 91))	('unc-119', 'Gene', '9094', (84, 91))	('mutant', 'Var', (97, 103))	('unc-119', 'Gene', (131, 138))
5837	32859697	We used two compounds, FCCP at 10 microM final well concentration and sodium azide at 40 mM final well concentration, to assess bioenergetics in sdhb-1 mutant worms and control strains.	('sodium azide', 'Chemical', 'MESH:D019810', (70, 82))	('sdhb-1', 'Gene', (145, 151))	('sdhb-1', 'Gene', '174482', (145, 151))	('FCCP', 'Chemical', 'MESH:D002259', (23, 27))	('mutant', 'Var', (152, 158))
5850	32859697	The wild-type and R230H variants of human SDHA/B complex were constructed using homology modeling.	('R230H', 'Var', (18, 23))	('R230H', 'Mutation', 'p.R230H', (18, 23))	('SDHA', 'Gene', (42, 46))	('human', 'Species', '9606', (36, 41))	('SDHA', 'Gene', '6389', (42, 46))
5862	32859697	R244H animals were treated by LDH-A inhibitor GSK2837808A (Tocris) at 1 microM and 10 microM.	('R244H', 'SUBSTITUTION', 'None', (0, 5))	('GSK2837808A', 'Chemical', 'MESH:C000612070', (46, 57))	('R244H', 'Var', (0, 5))	('LDH-A', 'Gene', '3939', (30, 35))	('GSK2837808A', 'Var', (46, 57))	('LDH-A', 'Gene', (30, 35))
5863	32859697	R244H strain was synchronized by NaOH/hypochlorite treatment, and embryos were put on NGM plates with a seeded lawn of OP50 bacteria containing GSK2837808A at a final concentration of 1 microM and 10 microM.	('R244H', 'SUBSTITUTION', 'None', (0, 5))	('R244H', 'Var', (0, 5))	('GSK2837808A', 'Chemical', 'MESH:C000612070', (144, 155))	('NaOH', 'Chemical', '-', (33, 37))	('OP50', 'Species', '637912', (119, 123))	('hypochlorite', 'Chemical', 'MESH:D006997', (38, 50))	('GSK2837808A', 'Var', (144, 155))
5883	32130200	In patients with a known predisposition to bilateral PHEO, including those with von Hippel-Lindau (VHL), multiple endocrine neoplasia type 2 (MEN2), neurofibromatosis type 1 (NF1) and myc-associated factor X (MAX) gene mutations, the utility of 18F-FDOPA PET/CT for identifying PHEOs has been previously demonstrated.	('VHL', 'Disease', (99, 102))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (105, 140))	('PHEO', 'Disease', (53, 57))	('MEN2', 'Disease', (142, 146))	('myc-associated factor X', 'Gene', '4149', (184, 207))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (245, 254))	('NF1', 'Gene', (175, 178))	('PHEO', 'Phenotype', 'HP:0002666', (53, 57))	('neurofibromatosis type 1', 'Gene', (149, 173))	('von Hippel-Lindau', 'Gene', '7428', (80, 97))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (114, 133))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (149, 166))	('PHEO', 'Disease', 'MESH:D010673', (278, 282))	('MAX', 'Gene', '4149', (209, 212))	('VHL', 'Disease', 'MESH:D006623', (99, 102))	('multiple endocrine neoplasia type 2', 'Disease', (105, 140))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (219, 228))	('neurofibromatosis type 1', 'Gene', '4763', (149, 173))	('PHEO', 'Disease', (278, 282))	('PHEO', 'Disease', 'MESH:D010673', (53, 57))	('myc-associated factor X', 'Gene', (184, 207))	('PHEO', 'Phenotype', 'HP:0002666', (278, 282))	('MEN2', 'Disease', 'MESH:D018813', (142, 146))	('PHEOs', 'Chemical', '-', (278, 283))	('von Hippel-Lindau', 'Gene', (80, 97))	('NF1', 'Gene', '4763', (175, 178))	('MAX', 'Gene', (209, 212))
5902	32130200	Germline mutation testing by the Next Generation Sequencing (NGS) method revealed a heterozygous pathogenic variant MEN1 c.249_252delGTCT causing a frameshift mutation, also known as rs587776841.	('MEN1', 'Disease', 'MESH:D018761', (116, 120))	('MEN1', 'Disease', (116, 120))	('c.249_252delGTCT', 'Var', (121, 137))	('rs587776841', 'Mutation', 'rs587776841', (183, 194))	('c.249_252delGTCT', 'Mutation', 'rs587776841', (121, 137))
5916	32130200	In this report, we describe a patient with a confirmed germline MEN1 mutation and a clinically silent PHEO.	('MEN1', 'Disease', 'MESH:D018761', (64, 68))	('patient', 'Species', '9606', (30, 37))	('PHEO', 'Disease', 'MESH:D010673', (102, 106))	('PHEO', 'Disease', (102, 106))	('mutation', 'Var', (69, 77))	('germline', 'Var', (55, 63))	('PHEO', 'Phenotype', 'HP:0002666', (102, 106))	('MEN1', 'Disease', (64, 68))
5926	32130200	Similarly, a patient with a germline mutation in MEN1 was reported with clinical findings of both MEN1 and MEN2, including a PHEO.	('MEN1', 'Disease', 'MESH:D018761', (98, 102))	('MEN1', 'Disease', (98, 102))	('patient', 'Species', '9606', (13, 20))	('MEN2', 'Disease', (107, 111))	('PHEO', 'Phenotype', 'HP:0002666', (125, 129))	('MEN1', 'Disease', (49, 53))	('MEN2', 'Disease', 'MESH:D018813', (107, 111))	('MEN1', 'Disease', 'MESH:D018761', (49, 53))	('PHEO', 'Disease', 'MESH:D010673', (125, 129))	('germline mutation', 'Var', (28, 45))	('PHEO', 'Disease', (125, 129))
5927	32130200	This patient had a negative RET gene analysis of pathogenic variants but did have germline RET polymorphisms Gly691Ser and Arg982Cys.	('RET', 'Gene', (91, 94))	('Arg982Cys', 'Var', (123, 132))	('patient', 'Species', '9606', (5, 12))	('Gly691Ser', 'Var', (109, 118))	('RET', 'Gene', '5979', (28, 31))	('Arg982Cys', 'SUBSTITUTION', 'None', (123, 132))	('RET', 'Gene', '5979', (91, 94))	('RET', 'Gene', (28, 31))	('Gly691Ser', 'SUBSTITUTION', 'None', (109, 118))
5928	32130200	It remains unclear if either of these variants, individually or in combination, were working in synergy with the MEN1 germline mutation in that patient (1132delG) or with another gene to produce features of MEN2, including pheochromocytoma and thickened corneal nerves.	('pheochromocytoma', 'Disease', 'MESH:D010673', (223, 239))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (223, 239))	('variants', 'Var', (38, 46))	('thickened corneal nerves', 'Phenotype', 'HP:0010726', (244, 268))	('1132delG', 'Mutation', 'c.1132delG', (153, 161))	('1132delG', 'Var', (153, 161))	('MEN2', 'Disease', (207, 211))	('patient', 'Species', '9606', (144, 151))	('MEN2', 'Disease', 'MESH:D018813', (207, 211))	('MEN1', 'Disease', 'MESH:D018761', (113, 117))	('pheochromocytoma', 'Disease', (223, 239))	('thickened', 'CPA', (244, 253))	('MEN1', 'Disease', (113, 117))
5944	32130200	However, data on sporadic PHEO suggests that 18F-FDOPA PET/CT may have minimally better patient-based and lesion-based detection rates than 68Ga-DOTATATE PET/CT (100% vs 90% and 94% vs 81%, respectively).	('patient', 'Species', '9606', (88, 95))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (45, 54))	('PHEO', 'Disease', 'MESH:D010673', (26, 30))	('PHEO', 'Disease', (26, 30))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (140, 153))	('18F-FDOPA', 'Var', (45, 54))	('PHEO', 'Phenotype', 'HP:0002666', (26, 30))
5947	32130200	Cluster 1 PHEOs with pseudohypoxic Krebs cycle-related gene, for example, SDHx mutations are best seen on 68Ga-DOTATATE PET/CT, while PHEOs with pseudohypoxia VHL/EPAS1-related signaling mutations are best seen on 18F-FDOPA PET/CT.	('EPAS1', 'Gene', (163, 168))	('PHEOs', 'Chemical', '-', (134, 139))	('SDHx', 'Gene', (74, 78))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (106, 119))	('SDHx', 'Chemical', '-', (74, 78))	('PHEOs', 'Chemical', '-', (10, 15))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (214, 223))	('VHL', 'Disease', (159, 162))	('Krebs', 'Chemical', '-', (35, 40))	('EPAS1', 'Gene', '2034', (163, 168))	('PHEO', 'Phenotype', 'HP:0002666', (134, 138))	('mutations', 'Var', (79, 88))	('PHEO', 'Phenotype', 'HP:0002666', (10, 14))
5955	32130200	A recently described rare syndrome of pituitary adenomas plus PHEO/paraganglioma (3PAs) has been associated with mutations in SDHB (cluster 1) and RET (cluster 2), which are two of the most prevalent germline mutations in patients with PHEO/paraganglioma.	('PHEO', 'Phenotype', 'HP:0002666', (62, 66))	('pituitary adenomas', 'Disease', (38, 56))	('patients', 'Species', '9606', (222, 230))	('PHEO', 'Disease', (236, 240))	('RET', 'Gene', (147, 150))	('mutations', 'Var', (113, 122))	('SDHB', 'Gene', '6390', (126, 130))	('associated', 'Reg', (97, 107))	('PHEO', 'Phenotype', 'HP:0002666', (236, 240))	('syndrome', 'Disease', (26, 34))	('paraganglioma', 'Disease', (67, 80))	('paraganglioma', 'Disease', 'MESH:D010235', (67, 80))	('paraganglioma', 'Disease', (241, 254))	('SDHB', 'Gene', (126, 130))	('paraganglioma', 'Disease', 'MESH:D010235', (241, 254))	('PHEO', 'Disease', 'MESH:D010673', (62, 66))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('RET', 'Gene', '5979', (147, 150))	('PHEO', 'Disease', 'MESH:D010673', (236, 240))	('paraganglioma', 'Phenotype', 'HP:0002668', (241, 254))	('pituitary adenomas', 'Disease', 'MESH:D010911', (38, 56))	('PHEO', 'Disease', (62, 66))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (38, 56))
5956	32130200	A report of a 54-year-old male patient with acromegaly and incidentally identified bilateral PHEO had a heterozygous germline variant of uncertain significance in MEN1 (c.1618C > T; p.Pro540Ser).	('acromegaly', 'Disease', 'MESH:D000172', (44, 54))	('c.1618C > T; p.Pro540Ser', 'Var', (169, 193))	('c.1618C > T', 'Mutation', 'rs745404679', (169, 180))	('p.Pro540Ser', 'Mutation', 'rs745404679', (182, 193))	('PHEO', 'Phenotype', 'HP:0002666', (93, 97))	('patient', 'Species', '9606', (31, 38))	('MEN1', 'Disease', 'MESH:D018761', (163, 167))	('acromegaly', 'Phenotype', 'HP:0000845', (44, 54))	('PHEO', 'Disease', 'MESH:D010673', (93, 97))	('p.Pro540Ser', 'Var', (182, 193))	('acromegaly', 'Disease', (44, 54))	('MEN1', 'Disease', (163, 167))	('PHEO', 'Disease', (93, 97))
5963	32130200	In this study, we report a rare case of PHEO in a patient with a germline mutation in MEN1.	('PHEO', 'Disease', (40, 44))	('MEN1', 'Disease', 'MESH:D018761', (86, 90))	('PHEO', 'Phenotype', 'HP:0002666', (40, 44))	('germline mutation', 'Var', (65, 82))	('MEN1', 'Disease', (86, 90))	('patient', 'Species', '9606', (50, 57))	('PHEO', 'Disease', 'MESH:D010673', (40, 44))
5975	31240094	Laboratory studies showed significant elevation of plasma normetanephrines and 3-methoxytyramine while DNA molecular analysis confirmed pathogenic mutation in the SDHB gene and genetic transmission of PGL4.	('SDHB', 'Gene', '6390', (163, 167))	('SDHB', 'Gene', (163, 167))	('mutation', 'Var', (147, 155))	('normetanephrines', 'Chemical', 'MESH:D009647', (58, 74))	('elevation', 'PosReg', (38, 47))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (79, 96))	('plasma normetanephrines', 'MPA', (51, 74))	('3-methoxytyramine', 'MPA', (79, 96))	('PGL4', 'Gene', (201, 205))
5989	31240094	Ligation of the venous drainage of the abdominal tumour would typically cause severe hypotension and norepinephrine would be required to control the blood pressure.	('norepinephrine', 'Chemical', 'MESH:D009638', (101, 115))	('abdominal tumour', 'Disease', (39, 55))	('Ligation', 'Var', (0, 8))	('hypotension', 'Disease', 'MESH:D007022', (85, 96))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('hypotension', 'Disease', (85, 96))	('cause', 'Reg', (72, 77))	('abdominal tumour', 'Disease', 'MESH:D000008', (39, 55))	('hypotension', 'Phenotype', 'HP:0002615', (85, 96))
5992	31240094	Tumour excision caused a ventricular perforation with bleeding controlled by digital pressure.	('ventricular perforation', 'Disease', (25, 48))	('bleeding', 'Disease', 'MESH:D006470', (54, 62))	('Tumour excision', 'Var', (0, 15))	('bleeding', 'Disease', (54, 62))	('excision', 'Var', (7, 15))	('caused', 'Reg', (16, 22))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))
6000	31240094	PGL4 is associated with mutations in the SDHB at gene locus 1.p36.1-35.	('SDHB', 'Gene', '6390', (41, 45))	('associated', 'Reg', (8, 18))	('PGL4', 'Gene', (0, 4))	('mutations', 'Var', (24, 33))	('SDHB', 'Gene', (41, 45))
6031	31080465	The important risk factors for hypertension are high sodium intake, low potassium diet, overweight, and obesity in Chinese population.	('overweight', 'Phenotype', 'HP:0025502', (88, 98))	('low potassium', 'Phenotype', 'HP:0002900', (68, 81))	('overweight', 'Disease', (88, 98))	('sodium', 'Chemical', 'MESH:D012964', (53, 59))	('hypertension', 'Disease', 'MESH:D006973', (31, 43))	('low potassium diet', 'Phenotype', 'HP:0002900', (68, 86))	('obesity', 'Phenotype', 'HP:0001513', (104, 111))	('low', 'Var', (68, 71))	('hypertension', 'Disease', (31, 43))	('obesity', 'Disease', 'MESH:D009765', (104, 111))	('hypertension', 'Phenotype', 'HP:0000822', (31, 43))	('obesity', 'Disease', (104, 111))	('high sodium intake', 'Phenotype', 'HP:0003228', (48, 66))	('potassium', 'Chemical', 'MESH:D011188', (72, 81))
6065	31080465	Studies have shown that exposure to PM2.5, PM10, SO2, and O3 is associated with increased risk of hypertension and increased mortality from cardiovascular disease.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (140, 162))	('increased', 'PosReg', (115, 124))	('PM10', 'Var', (43, 47))	('SO2', 'Var', (49, 52))	('hypertension', 'Disease', (98, 110))	('cardiovascular disease', 'Disease', 'MESH:D002318', (140, 162))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('cardiovascular disease', 'Disease', (140, 162))	('PM2.5', 'Var', (36, 41))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))
6071	31080465	In the Asia Pacific cohort study (APCSC) which consists of 13 Chinese populations, clinic BP was closely associated with the risk of stroke and ischemic heart disease events, and the association between elevated BP and stroke or ischemic heart disease events in Asian populations was stronger than in Australia and New Zealand populations.	('stroke', 'Phenotype', 'HP:0001297', (133, 139))	('ischemic heart disease', 'Disease', 'MESH:D017202', (229, 251))	('stroke', 'Disease', (133, 139))	('ischemic heart disease', 'Disease', (229, 251))	('stroke', 'Phenotype', 'HP:0001297', (219, 225))	('clinic BP', 'Var', (83, 92))	('stroke', 'Disease', (219, 225))	('ischemic heart disease', 'Disease', 'MESH:D017202', (144, 166))	('ischemic heart disease', 'Disease', (144, 166))	('stroke', 'Disease', 'MESH:D020521', (133, 139))	('elevated BP', 'Phenotype', 'HP:0032263', (203, 214))	('associated', 'Reg', (105, 115))	('stroke', 'Disease', 'MESH:D020521', (219, 225))	('elevated', 'PosReg', (203, 211))
6074	31080465	Clinical follow-up data showed that the incidence of heart failure increased with BP level.	('heart failure', 'Phenotype', 'HP:0001635', (53, 66))	('heart failure', 'Disease', (53, 66))	('heart failure', 'Disease', 'MESH:D006333', (53, 66))	('BP level', 'Var', (82, 90))
6080	31080465	Long-term clinical follow-up studies revealed that the incidence of end-stage renal disease (ESRD) also increased significantly with clinic BP.	('end-stage renal disease', 'Disease', (68, 91))	('end-stage renal disease', 'Disease', 'MESH:D007676', (68, 91))	('renal disease', 'Phenotype', 'HP:0000112', (78, 91))	('ESRD', 'Disease', (93, 97))	('end-stage renal disease', 'Phenotype', 'HP:0003774', (68, 91))	('ESRD', 'Disease', 'MESH:D007676', (93, 97))	('clinic BP', 'Var', (133, 142))
6134	31080465	HBPM can be used to evaluate anti-hypertensive efficacy and long-term BP variation for days, weeks, months or even years, and can help to enhance patient's awareness of health participation, improve patient's compliance and adherence to treatment, and is suitable for long-term BP monitoring of patients.	('HBP', 'Gene', (0, 3))	('hypertensive', 'Disease', 'MESH:D006973', (34, 46))	('patient', 'Species', '9606', (295, 302))	('hypertensive', 'Disease', (34, 46))	('adherence', 'CPA', (224, 233))	('variation', 'Var', (73, 82))	('enhance', 'PosReg', (138, 145))	('patient', 'Species', '9606', (199, 206))	('HBP', 'Gene', '50865', (0, 3))	('patients', 'Species', '9606', (295, 303))	('men', 'Species', '9606', (242, 245))	('compliance', 'CPA', (209, 219))	('improve', 'PosReg', (191, 198))	('patient', 'Species', '9606', (146, 153))
6163	31080465	At present, normal (SBP < 120 mmHg and DBP < 80 mmHg), high normal (SBP 120-139 mmHg and/or DBP 80-89 mmHg) and hypertension (SBP >=140 mmHg and/or DBP >= 90 mmHg) are used to classify BP levels in China.	('hypertension', 'Disease', (112, 124))	('hypertension', 'Phenotype', 'HP:0000822', (112, 124))	('SBP', 'Var', (68, 71))	('hypertension', 'Disease', 'MESH:D006973', (112, 124))
6170	31080465	The diagnostic thresholds of hypertension based on HBPM >= 135/85 mmHg, which is corresponding to 140/90 mmHg of clinic BP.	('hypertension', 'Disease', (29, 41))	('HBP', 'Gene', (51, 54))	('hypertension', 'Phenotype', 'HP:0000822', (29, 41))	('>= 135/85 mmHg', 'Var', (56, 70))	('HBP', 'Gene', '50865', (51, 54))	('hypertension', 'Disease', 'MESH:D006973', (29, 41))
6249	31080465	Excessive drinking significantly increases the risk of developing hypertension, and its risk increases with the increasing consumption of alcohol.	('Excessive drinking', 'Phenotype', 'HP:0030082', (0, 18))	('Excessive drinking', 'Var', (0, 18))	('hypertension', 'Disease', 'MESH:D006973', (66, 78))	('alcohol', 'Chemical', 'MESH:D000438', (138, 145))	('hypertension', 'Disease', (66, 78))	('hypertension', 'Phenotype', 'HP:0000822', (66, 78))
6304	31080465	Clinical trials conducted in China (such as multivitamin treatment trials, meta-analysis of folic acid treatment trials and CSPPT-China stroke primary prevention trial) have shown that supplementation with folic acid can reduce plasma homocysteine concentration and reduce the risk of stroke.	('men', 'Species', '9606', (62, 65))	('stroke', 'Phenotype', 'HP:0001297', (136, 142))	('reduce', 'NegReg', (221, 227))	('plasma homocysteine concentration', 'MPA', (228, 261))	('reduce', 'NegReg', (266, 272))	('stroke', 'Disease', 'MESH:D020521', (285, 291))	('stroke', 'Disease', (136, 142))	('men', 'Species', '9606', (108, 111))	('homocysteine', 'Chemical', 'MESH:D006710', (235, 247))	('folic acid', 'Chemical', 'MESH:D005492', (206, 216))	('men', 'Species', '9606', (191, 194))	('stroke', 'Phenotype', 'HP:0001297', (285, 291))	('stroke', 'Disease', 'MESH:D020521', (136, 142))	('stroke', 'Disease', (285, 291))	('supplementation', 'Var', (185, 200))	('folic acid', 'Chemical', 'MESH:D005492', (92, 102))
6318	31080465	In previous large-scale clinical trials of antihypertensive therapy, dihydropyridine CCB was commonly used as the research agent, and it was confirmed that the antihypertensive treatment based on dihydropyridine CCB can significantly reduce the risk of stroke in hypertensives.	('stroke', 'Phenotype', 'HP:0001297', (253, 259))	('hypertensive', 'Disease', 'MESH:D006973', (164, 176))	('hypertensive', 'Disease', (47, 59))	('stroke', 'Disease', (253, 259))	('dihydropyridine CCB', 'Chemical', '-', (196, 215))	('hypertensive', 'Disease', (164, 176))	('hypertensives', 'Disease', 'MESH:D006973', (263, 276))	('hypertensives', 'Disease', (263, 276))	('dihydropyridine CCB', 'Chemical', '-', (69, 88))	('hypertensive', 'Disease', 'MESH:D006973', (263, 275))	('reduce', 'NegReg', (234, 240))	('stroke', 'Disease', 'MESH:D020521', (253, 259))	('dihydropyridine CCB', 'Var', (196, 215))	('hypertensive', 'Disease', (263, 275))	('men', 'Species', '9606', (182, 185))	('hypertensive', 'Disease', 'MESH:D006973', (47, 59))
6325	31080465	Gingival hyperplasia induced by non-dihydropyridine CCB sometimes occurs.	('Gingival hyperplasia', 'Disease', (0, 20))	('Gingival hyperplasia', 'Phenotype', 'HP:0000212', (0, 20))	('Gingival hyperplasia', 'Disease', 'MESH:D005885', (0, 20))	('non-dihydropyridine CCB', 'Var', (32, 55))	('dihydropyridine CCB', 'Chemical', '-', (36, 55))
6372	31080465	(7) Renin inhibitors: the mechanism of renin inhibitors is a direct inhibition of renin, to reduce the production of angiotensin II, which can significantly reduce BP levels in hypertensive patients.	('angiotensin II', 'Gene', (117, 131))	('hypertensive', 'Disease', (177, 189))	('renin', 'Gene', '5972', (39, 44))	('reduce', 'NegReg', (92, 98))	('patients', 'Species', '9606', (190, 198))	('renin', 'Gene', '5972', (82, 87))	('Renin', 'Gene', '5972', (4, 9))	('reduce', 'NegReg', (157, 163))	('BP levels', 'MPA', (164, 173))	('Renin', 'Gene', (4, 9))	('renin', 'Gene', (39, 44))	('inhibitors', 'Var', (45, 55))	('angiotensin II', 'Gene', '183', (117, 131))	('hypertensive', 'Disease', 'MESH:D006973', (177, 189))	('renin', 'Gene', (82, 87))
6376	31080465	(1) Indications for combination therapy: high-risk group of patients with BP >= 160/100 mmHg or 20/10 mmHg higher than that of the target BP often require two drugs for initial treatment.	('men', 'Species', '9606', (182, 185))	('require', 'Reg', (147, 154))	('patients', 'Species', '9606', (60, 68))	('20/10 mmHg', 'Var', (96, 106))
6384	31080465	a. ACEI/ARB+thiazide diuretic: ACEI and ARB can increase serum potassium slightly, and can antagonize side effects such as hypokalemia caused by long-term administration of thiazide diuretics.	('thiazide', 'Chemical', 'MESH:D049971', (12, 20))	('ACEI', 'Var', (31, 35))	('antagonize', 'NegReg', (91, 101))	('hypokalemia', 'Disease', (123, 134))	('thiazide', 'Chemical', 'MESH:D049971', (173, 181))	('increase serum potassium', 'Phenotype', 'HP:0002153', (48, 72))	('hypokalemia', 'Disease', 'MESH:D007008', (123, 134))	('potassium', 'Chemical', 'MESH:D011188', (63, 72))	('hypokalemia', 'Phenotype', 'HP:0002900', (123, 134))	('serum potassium', 'MPA', (57, 72))	('increase', 'PosReg', (48, 56))
6387	31080465	A common side effect that dihydropyridine CCB has is ankle edema, which can be alleviated or offset by ACEI or ARB.	('dihydropyridine', 'Var', (26, 41))	('ankle edema', 'Disease', (53, 64))	('ankle edema', 'Disease', 'MESH:D016512', (53, 64))	('edema', 'Phenotype', 'HP:0000969', (59, 64))	('dihydropyridine CCB', 'Chemical', '-', (26, 45))
6390	31080465	c. Dihydropyridine CCB+Thiazide diuretic: the FEVER study has confirmed that combination therapy of dihydropyridine CCB plus thiazide diuretic can reduce the risk of stroke in hypertensive patients.	('dihydropyridine CCB', 'Var', (100, 119))	('FEVER', 'Phenotype', 'HP:0001945', (46, 51))	('stroke', 'Disease', 'MESH:D020521', (166, 172))	('hypertensive', 'Disease', 'MESH:D006973', (176, 188))	('thiazide', 'Chemical', 'MESH:D049971', (125, 133))	('hypertensive', 'Disease', (176, 188))	('reduce', 'NegReg', (147, 153))	('dihydropyridine CCB', 'Chemical', '-', (100, 119))	('Dihydropyridine CCB', 'Chemical', '-', (3, 22))	('Thiazide', 'Chemical', 'MESH:D049971', (23, 31))	('patients', 'Species', '9606', (189, 197))	('stroke', 'Phenotype', 'HP:0001297', (166, 172))	('stroke', 'Disease', (166, 172))
6416	31080465	The Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults (Revised 2016) for the first time clarified that the ideal cholesterol level in the primary prevention population of Chinese ASCVD is LDL-C < 2.6 mmol/L (non-HDL-C < 3.4 mmol/L).	('LDL-C < 2.6 mmol/L', 'Var', (216, 234))	('cholesterol', 'Chemical', 'MESH:D002784', (141, 152))	('men', 'Species', '9606', (43, 46))	('Dyslipidemia', 'Phenotype', 'HP:0003119', (51, 63))	('Dyslipidemia', 'Disease', 'MESH:D050171', (51, 63))	('Dyslipidemia', 'Disease', (51, 63))
6456	31080465	(5) For new-onset diabetes with fasting blood glucose above 11 mmol/L or HbA1c over 9%, short-term intensive insulin therapy could be adopted so as to control blood glucose and preserve islet beta-cell function as soon as possible.	('over', 'Var', (79, 83))	('insulin', 'Gene', (109, 116))	('blood glucose', 'Chemical', 'MESH:D001786', (159, 172))	('diabetes', 'Disease', (18, 26))	('insulin', 'Gene', '3630', (109, 116))	('diabetes', 'Disease', 'MESH:D003920', (18, 26))	('HbA1', 'Gene', '3039', (73, 77))	('control blood glucose', 'MPA', (151, 172))	('blood glucose', 'Chemical', 'MESH:D001786', (40, 53))	('HbA1', 'Gene', (73, 77))
6481	31080465	Treatment of hypertension with elevation in homocysteine (HCY) level: nutrition intervention study in Lin County and CSPPT study suggest supplement of folic acid could reduce the risk of first stroke.	('hypertension', 'Disease', 'MESH:D006973', (13, 25))	('homocysteine', 'Chemical', 'MESH:D006710', (44, 56))	('stroke', 'Disease', 'MESH:D020521', (193, 199))	('hypertension', 'Disease', (13, 25))	('hypertension', 'Phenotype', 'HP:0000822', (13, 25))	('reduce', 'NegReg', (168, 174))	('HCY', 'Chemical', 'MESH:D006710', (58, 61))	('folic acid', 'Chemical', 'MESH:D005492', (151, 161))	('stroke', 'Phenotype', 'HP:0001297', (193, 199))	('men', 'Species', '9606', (5, 8))	('supplement', 'Var', (137, 147))	('men', 'Species', '9606', (143, 146))	('stroke', 'Disease', (193, 199))
6498	31080465	Elevation in SBP increases the risk of stroke, CHD and end stage renal disease.	('stroke', 'Disease', (39, 45))	('CHD and end stage renal disease', 'Disease', 'MESH:D007676', (47, 78))	('Elevation', 'Var', (0, 9))	('end stage renal disease', 'Phenotype', 'HP:0003774', (55, 78))	('stroke', 'Disease', 'MESH:D020521', (39, 45))	('stroke', 'Phenotype', 'HP:0001297', (39, 45))	('SBP', 'Gene', (13, 16))	('renal disease', 'Phenotype', 'HP:0000112', (65, 78))
6500	31080465	Fluctuation in BP affects treatment results and remarkably increases the risk of cardiovascular events.	('Fluctuation', 'Var', (0, 11))	('men', 'Species', '9606', (31, 34))	('cardiovascular', 'Disease', (81, 95))	('cardiovascular events', 'Phenotype', 'HP:0001626', (81, 102))	('affects', 'Reg', (18, 25))	('increases', 'PosReg', (59, 68))
6520	31080465	When given to the very elderly patients with postural BP variations, alpha-blockers should be used with caution and they may cause postural hypotension.	('hypotension', 'Disease', 'MESH:D007022', (140, 151))	('postural hypotension', 'Phenotype', 'HP:0001278', (131, 151))	('cause', 'Reg', (125, 130))	('patients', 'Species', '9606', (31, 39))	('hypotension', 'Disease', (140, 151))	('hypotension', 'Phenotype', 'HP:0002615', (140, 151))	('variations', 'Var', (57, 67))
6534	31080465	Other risk factors include parental hypertension history, low birth weight, premature birth, high salt intake, sleep insufficiency, and physical inactivity.	('salt', 'Chemical', 'MESH:D012492', (98, 102))	('physical inactivity', 'Disease', (136, 155))	('premature', 'Disease', (76, 85))	('low birth weight', 'Phenotype', 'HP:0001518', (58, 74))	('hypertension', 'Disease', (36, 48))	('low birth', 'Var', (58, 67))	('hypertension', 'Phenotype', 'HP:0000822', (36, 48))	('premature birth', 'Phenotype', 'HP:0001622', (76, 91))	('sleep insufficiency', 'Disease', (111, 130))	('sleep insufficiency', 'Disease', 'MESH:D012892', (111, 130))	('hypertension', 'Disease', 'MESH:D006973', (36, 48))	('sleep insufficiency', 'Phenotype', 'HP:0002360', (111, 130))
6558	31080465	Hypertension is diagnosed when SBP and/or DBP >= 95th percentile for sex, age, and height on all three occasions.	('diagnosed', 'Reg', (16, 25))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('DBP >=', 'Var', (42, 48))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('SBP', 'Disease', (31, 34))	('Hypertension', 'Disease', (0, 12))
6624	31080465	For patients with continuous elevation of BP, SBP >= 200 mmHg or DBP >= 110 mmHg, or with severe cardiac insufficiency, aortic dissection or hypertensive encephalopathy, antihypertensive agents should be given.	('elevation', 'PosReg', (29, 38))	('hypertensive', 'Disease', (174, 186))	('aortic dissection', 'Phenotype', 'HP:0002647', (120, 137))	('cardiac insufficiency', 'Disease', 'MESH:D006331', (97, 118))	('hypertensive encephalopathy', 'Disease', (141, 168))	('elevation of BP', 'Phenotype', 'HP:0032263', (29, 44))	('aortic dissection', 'Disease', (120, 137))	('cardiac insufficiency', 'Disease', (97, 118))	('hypertensive', 'Disease', 'MESH:D006973', (141, 153))	('hypertensive', 'Disease', (141, 153))	('hypertensive encephalopathy', 'Disease', 'MESH:D006973', (141, 168))	('SBP >= 200 mmHg', 'Var', (46, 61))	('patients', 'Species', '9606', (4, 12))	('hypertensive', 'Disease', 'MESH:D006973', (174, 186))	('encephalopathy', 'Phenotype', 'HP:0001298', (154, 168))	('cardiac insufficiency', 'Phenotype', 'HP:0001635', (97, 118))
6663	31080465	Hypertension caused by various CKD, which is called renal hypertension, is mainly divided into renal vascular hypertension and renal parenchyma hypertension.	('renal parenchyma hypertension', 'Disease', (127, 156))	('renal hypertension', 'Disease', 'MESH:D006977', (52, 70))	('renal vascular hypertension', 'Disease', (95, 122))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('hypertension', 'Phenotype', 'HP:0000822', (144, 156))	('hypertension', 'Phenotype', 'HP:0000822', (58, 70))	('renal vascular hypertension', 'Disease', 'MESH:D006977', (95, 122))	('hypertension', 'Phenotype', 'HP:0000822', (110, 122))	('renal parenchyma hypertension', 'Disease', 'MESH:D006977', (127, 156))	('CKD', 'Var', (31, 34))	('Hypertension', 'Disease', (0, 12))	('renal hypertension', 'Disease', (52, 70))
6667	31080465	The target of antihypertensive therapy is < 140/90 mmHg when urine albumin excretion < 30mg/24 h (or equivalence), and < 130/80 mmHg when albuminuria >= 30 mg/24 h (or equivalence).	('albuminuria', 'Phenotype', 'HP:0012592', (138, 149))	('< 140/90 mmHg', 'Var', (42, 55))	('hypertensive', 'Disease', 'MESH:D006973', (18, 30))	('albuminuria', 'Disease', 'MESH:D000419', (138, 149))	('hypertensive', 'Disease', (18, 30))	('urine albumin excretion', 'MPA', (61, 84))	('< 130/80 mmHg', 'Var', (119, 132))	('albuminuria', 'Disease', (138, 149))
6671	31080465	ACEI/ARB not only has antihypertensive effect, but also can reduce proteinuria, delay the decline of renal function, and improve the renal prognosis of CKD patients.	('patients', 'Species', '9606', (156, 164))	('decline of renal function', 'Disease', 'MESH:D007674', (90, 115))	('hypertensive', 'Disease', 'MESH:D006973', (26, 38))	('reduce', 'NegReg', (60, 66))	('renal', 'MPA', (133, 138))	('proteinuria', 'Disease', (67, 78))	('proteinuria', 'Phenotype', 'HP:0000093', (67, 78))	('decline of renal function', 'Disease', (90, 115))	('delay', 'NegReg', (80, 85))	('ACEI/ARB', 'Var', (0, 8))	('improve', 'PosReg', (121, 128))	('proteinuria', 'Disease', 'MESH:D011507', (67, 78))	('hypertensive', 'Disease', (26, 38))
6677	31080465	The combination of aldosterone antagonists with ACEI or ARB may accelerate the risk of renal function deterioration and hyperkalemia.	('hyperkalemia', 'Disease', 'MESH:D006947', (120, 132))	('aldosterone', 'Chemical', 'MESH:D000450', (19, 30))	('aldosterone', 'Protein', (19, 30))	('accelerate', 'PosReg', (64, 74))	('renal function deterioration', 'Disease', 'MESH:D058186', (87, 115))	('hyperkalemia', 'Phenotype', 'HP:0002153', (120, 132))	('ACEI', 'Var', (48, 52))	('hyperkalemia', 'Disease', (120, 132))	('renal function deterioration', 'Disease', (87, 115))	('combination', 'Interaction', (4, 15))
6686	31080465	The recommended target BP in patients with diabetes mellitus is less than 130/80 mmHg (II a, B).	('less', 'Var', (64, 68))	('patients', 'Species', '9606', (29, 37))	('men', 'Species', '9606', (9, 12))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (43, 60))	('diabetes mellitus', 'Disease', (43, 60))	('diabetes mellitus', 'Disease', 'MESH:D003920', (43, 60))
6687	31080465	Nonpharmacologic methods lasting less than three months can be instituted in diabetic patients with systolic BP 130-139 mmHg or diastolic BP 80-89 mmHg.	('diabetic', 'Disease', 'MESH:D003920', (77, 85))	('systolic', 'Var', (100, 108))	('diabetic', 'Disease', (77, 85))	('patients', 'Species', '9606', (86, 94))
6711	31080465	Among the combinations of metabolic syndrome components, abdominal obesity accompanied by hypertension and low HDL-C had the highest cardiovascular risk (increased by 5.25 times), and the risk is further increased by 16.58 times if hyperglycemia is added in.	('low HDL', 'Phenotype', 'HP:0003233', (107, 114))	('hyperglycemia', 'Disease', 'MESH:D006943', (232, 245))	('hypertension', 'Disease', (90, 102))	('abdominal obesity', 'Disease', (57, 74))	('cardiovascular', 'MPA', (133, 147))	('abdominal obesity', 'Phenotype', 'HP:0012743', (57, 74))	('obesity', 'Phenotype', 'HP:0001513', (67, 74))	('hyperglycemia', 'Disease', (232, 245))	('abdominal obesity', 'Disease', 'MESH:D056128', (57, 74))	('metabolic syndrome', 'Disease', 'MESH:D008659', (26, 44))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('metabolic syndrome', 'Disease', (26, 44))	('hyperglycemia', 'Phenotype', 'HP:0003074', (232, 245))	('HDL-C', 'Gene', (111, 116))	('low', 'Var', (107, 110))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))
6725	31080465	The BP targeting not only reduces the incidence of cardiovascular and cerebrovascular events in these patients, but also slows down the progression of the lesion, as well as reduces the amputation rate of the patients.	('slows down', 'NegReg', (121, 131))	('cerebrovascular events', 'Phenotype', 'HP:0001297', (70, 92))	('patients', 'Species', '9606', (102, 110))	('progression of', 'CPA', (136, 150))	('BP targeting', 'Var', (4, 16))	('patients', 'Species', '9606', (209, 217))	('amputation rate', 'CPA', (186, 201))	('reduces', 'NegReg', (26, 33))	('cardiovascular', 'CPA', (51, 65))	('reduces', 'NegReg', (174, 181))
6782	31080465	(1) Definition: perioperative hypertension refers to an elevation of BP (SBP, DBP or PP) over 30% of baseline between the decision of operation and the end of its related therapy, or SBP >= 140 mmHg and/or DBP >= 90 mmHg during this period.	('hypertension', 'Disease', 'MESH:D006973', (30, 42))	('elevation of BP', 'Phenotype', 'HP:0032263', (56, 71))	('SBP', 'Var', (183, 186))	('hypertension', 'Disease', (30, 42))	('hypertension', 'Phenotype', 'HP:0000822', (30, 42))	('elevation', 'PosReg', (56, 65))
6784	31080465	(2) Risk factors: patients with hypertension history, uncontrolled BP before operation, secondary hypertension or intracranial hypertension, psychological factors such as stress, anxiety, fearness or sleeping disorder, especially those with DBP > 110 mmHg, are prone to develop perioperative BP fluctuation.	('sleeping disorder', 'Phenotype', 'HP:0002360', (200, 217))	('develop', 'PosReg', (270, 277))	('fearness or sleeping disorder', 'Disease', 'MESH:D012893', (188, 217))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))	('intracranial hypertension', 'Disease', (114, 139))	('anxiety', 'Disease', (179, 186))	('intracranial hypertension', 'Phenotype', 'HP:0002516', (114, 139))	('hypertension', 'Disease', (98, 110))	('DBP > 110 mmHg', 'Var', (241, 255))	('anxiety', 'Disease', 'MESH:D001008', (179, 186))	('hypertension', 'Disease', 'MESH:D006973', (32, 44))	('hypertension', 'Disease', (32, 44))	('hypertension', 'Disease', 'MESH:D006973', (127, 139))	('BP fluctuation', 'MPA', (292, 306))	('hypertension', 'Disease', (127, 139))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('fearness or sleeping disorder', 'Disease', (188, 217))	('patients', 'Species', '9606', (18, 26))	('hypertension', 'Phenotype', 'HP:0000822', (32, 44))	('anxiety', 'Phenotype', 'HP:0000739', (179, 186))	('hypertension', 'Phenotype', 'HP:0000822', (127, 139))	('intracranial hypertension', 'Disease', 'MESH:D019586', (114, 139))
6887	31080465	The diagnosis of renal parenchymal hypertension depends on: history of kidney disease; proteinuria and hematuria; abnormal renal function; decreased eGFR; abnormal size and shape of kidney; and should take pathological biopsy of kidney when necessary.	('kidney disease', 'Phenotype', 'HP:0000112', (71, 85))	('shape of kidney', 'Phenotype', 'HP:0012210', (173, 188))	('abnormal renal function', 'Phenotype', 'HP:0012211', (114, 137))	('hematuria', 'Disease', (103, 112))	('GFR', 'Gene', (150, 153))	('GFR', 'Gene', '9771', (150, 153))	('abnormal renal function', 'Disease', (114, 137))	('abnormal', 'Var', (155, 163))	('kidney disease', 'Disease', (71, 85))	('renal parenchymal hypertension', 'Disease', 'MESH:D006977', (17, 47))	('hematuria', 'Disease', 'MESH:D006417', (103, 112))	('hypertension', 'Phenotype', 'HP:0000822', (35, 47))	('kidney disease', 'Disease', 'MESH:D007674', (71, 85))	('abnormal renal function', 'Disease', 'MESH:D007674', (114, 137))	('hematuria', 'Phenotype', 'HP:0000790', (103, 112))	('proteinuria', 'Disease', (87, 98))	('proteinuria', 'Disease', 'MESH:D011507', (87, 98))	('renal parenchymal hypertension', 'Disease', (17, 47))	('proteinuria', 'Phenotype', 'HP:0000093', (87, 98))	('decreased', 'NegReg', (139, 148))
6892	31080465	The main characteristic of renal artery stenosis is the stenosis at the main trunk or branch of renal artery, which leads to renal ischemia, significant increase of renin-angiotensin system activity thereby causing hypertension and renal hypofunction.	('renal ischemia', 'Phenotype', 'HP:0002637', (125, 139))	('branch of renal artery', 'Disease', 'MESH:D007674', (86, 108))	('renal hypofunction', 'Disease', (232, 250))	('renal hypofunction', 'Disease', 'MESH:D007674', (232, 250))	('renal artery stenosis', 'Phenotype', 'HP:0001920', (27, 48))	('renal artery stenosis', 'Disease', 'MESH:D012078', (27, 48))	('hypertension', 'Disease', 'MESH:D006973', (215, 227))	('renin', 'Gene', (165, 170))	('hypertension', 'Disease', (215, 227))	('branch of renal artery', 'Disease', (86, 108))	('renin', 'Gene', '5972', (165, 170))	('renal ischemia', 'Disease', 'MESH:D007511', (125, 139))	('leads to', 'Reg', (116, 124))	('artery stenosis', 'Phenotype', 'HP:0100545', (33, 48))	('hypertension', 'Phenotype', 'HP:0000822', (215, 227))	('renal ischemia', 'Disease', (125, 139))	('stenosis', 'Var', (56, 64))	('renal artery stenosis', 'Disease', (27, 48))	('increase of renin', 'Phenotype', 'HP:0000848', (153, 170))	('increase', 'PosReg', (153, 161))	('causing', 'Reg', (207, 214))
6945	31080465	The mutations of monogenic inherited hypertension are mostly associated with gene mutations on renal unit ion transporters or RAS components causing dysfunction.	('hypertension', 'Disease', (37, 49))	('hypertension', 'Phenotype', 'HP:0000822', (37, 49))	('mutations', 'Var', (4, 13))	('hypertension', 'Disease', 'MESH:D006973', (37, 49))	('associated', 'Reg', (61, 71))
6946	31080465	It can be divided into the following categories: (1) Gene mutations directly affect the function of related proteins in renal tubu-lar ion channel transport system: Liddle syndrome, Gordon syndrome, apparent mineralocortixoid excess, pregnancy-I resistancenduced hypertension caused by corticosteroid receptor mutations (2) abnormal steroid synthesis in the adrenal gland caused by Gene mutations: familial hyperaldosteronism (I, II, III), congenital adrenal hyperplasia (11beta-hydroxylase deficiency, 7 alpha-hydroxylase/17, 20-lyase deficiency, 17OHD), familial glucocorticoid resistance (3) Various neuroendocrine tumors, such as pheochromocytoma, hypertension with brachydactylia, multipleendocrineneoplasm (MEN) and Von Hippel-Lindau (VHL).	('tumors', 'Phenotype', 'HP:0002664', (618, 624))	('Liddle syndrome', 'Disease', 'MESH:D056929', (165, 180))	('pheochromocytoma', 'Disease', (634, 650))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (634, 650))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (440, 470))	('neoplasm', 'Phenotype', 'HP:0002664', (703, 711))	('tumor', 'Phenotype', 'HP:0002664', (618, 623))	('hypertension', 'Disease', 'MESH:D006973', (652, 664))	('VHL', 'Disease', (741, 744))	('neuroendocrine tumors', 'Disease', (603, 624))	('hyperaldosteronism', 'Disease', (407, 425))	('brachydactylia, multipleendocrineneoplasm', 'Disease', 'MESH:D059327', (670, 711))	('mineralocortixoid excess', 'Phenotype', 'HP:0000859', (208, 232))	('Gordon syndrome', 'Phenotype', 'HP:0030181', (182, 197))	('hypertension', 'Disease', (652, 664))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (407, 425))	('mutations', 'Var', (387, 396))	('11beta-hydroxylase deficiency', 'Disease', (472, 501))	('hypertension', 'Disease', 'MESH:D006973', (263, 275))	('MEN', 'Species', '9606', (713, 716))	('11beta-hydroxylase deficiency', 'Disease', 'MESH:D054882', (472, 501))	('hypertension', 'Disease', (263, 275))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (603, 624))	('glucocorticoid resistance', 'Phenotype', 'HP:0008163', (565, 590))	('Gordon syndrome', 'Disease', 'MESH:C537288', (182, 197))	('hypertension', 'Phenotype', 'HP:0000822', (652, 664))	('Von Hippel-Lindau', 'Gene', '7428', (722, 739))	('Von Hippel-Lindau', 'Gene', (722, 739))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (603, 624))	('VHL', 'Disease', 'MESH:D006623', (741, 744))	('hypertension', 'Phenotype', 'HP:0000822', (263, 275))	('hypertension with brachydactylia', 'Phenotype', 'HP:0001156', (652, 684))	('Gordon syndrome', 'Disease', (182, 197))	('pheochromocytoma', 'Disease', 'MESH:D010673', (634, 650))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (440, 470))	('hyperaldosteronism', 'Disease', 'MESH:D006929', (407, 425))	('congenital adrenal hyperplasia', 'Disease', (440, 470))	('Liddle syndrome', 'Disease', (165, 180))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (451, 470))
6951	30356369	Pheochromocytoma in Congenital Cyanotic Heart Disease Studies on genome-wide transcription patterns have shown that many genetic alterations implicated in pheochromocytoma-paraganglioma (P-PGL) syndromes cluster in a common cellular pathway leading to aberrant activation of molecular response to hypoxia in normoxic conditions (the pseudohypoxia hypothesis).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (155, 171))	('hypoxia', 'Disease', (297, 304))	('paraganglioma', 'Phenotype', 'HP:0002668', (172, 185))	('hypoxia', 'Disease', (339, 346))	('hypoxia', 'Disease', 'MESH:D000860', (339, 346))	('cellular pathway', 'Pathway', (224, 240))	('Pheochromocytoma in Congenital Cyanotic Heart Disease', 'Disease', 'MESH:D010673', (0, 53))	('alterations', 'Var', (129, 140))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('pheochromocytoma-paraganglioma (P-PGL) syndromes cluster', 'Disease', 'MESH:D010235', (155, 211))	('hypoxia', 'Disease', 'MESH:D000860', (297, 304))	('activation', 'PosReg', (261, 271))
6970	30356369	All these cardio-vascular alterations can lead to a more or less evident cyanosis with potential effects favoring the development of chromaffin cell alterations.	('cyanosis', 'Disease', 'MESH:D003490', (73, 81))	('alterations', 'Var', (26, 37))	('cardio-vascular alterations', 'Phenotype', 'HP:0001626', (10, 37))	('vascular alterations', 'Phenotype', 'HP:0002597', (17, 37))	('cyanosis', 'Phenotype', 'HP:0000961', (73, 81))	('lead to', 'Reg', (42, 49))	('cyanosis', 'Disease', (73, 81))	('chromaffin', 'Chemical', '-', (133, 143))
6973	30356369	Up to 35-40% of patients have disease-causing germline mutations and the likelihood increases in young patients.	('disease-causing', 'Reg', (30, 45))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (103, 111))	('germline mutations', 'Var', (46, 64))
6989	30356369	The P-PGL susceptibility genes VHL, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, MAX, and TMEM127 were analyzed for germline mutations and large deletions, via direct sequencing and multiplex ligation-dependent probe amplification methods; RET was only analyzed by direct sequencing.	('RET', 'Gene', (36, 39))	('SDHA', 'Gene', (41, 45))	('SDHD', 'Gene', (67, 71))	('TMEM127', 'Gene', '55654', (82, 89))	('SDHA', 'Gene', '6389', (41, 45))	('RET', 'Gene', (232, 235))	('VHL', 'Gene', '7428', (31, 34))	('SDHC', 'Gene', (61, 65))	('SDHB', 'Gene', (55, 59))	('deletions', 'Var', (137, 146))	('SDHAF2', 'Gene', '54949', (47, 53))	('SDHAF2', 'Gene', (47, 53))	('SDHA', 'Gene', (47, 51))	('RET', 'Gene', '5979', (36, 39))	('SDHA', 'Gene', '6389', (47, 51))	('P-PGL', 'Gene', (4, 9))	('SDHC', 'Gene', '6391', (61, 65))	('SDHD', 'Gene', '6392', (67, 71))	('RET', 'Gene', '5979', (232, 235))	('TMEM127', 'Gene', (82, 89))	('SDHB', 'Gene', '6390', (55, 59))	('VHL', 'Gene', (31, 34))
7001	30356369	In a recent letter to editor of New England Journal of Medicine Vaidya and colleagues report the identification of gain-of-function somatic mutations of EPAS1, which encodes for HIF-2alpha, in pheochromocytomas and paragangliomas in four of five patients who presented with cyanotic congenital heart disease.	('paragangliomas', 'Phenotype', 'HP:0002668', (215, 229))	('congenital heart disease', 'Phenotype', 'HP:0001627', (283, 307))	('cyanotic congenital heart disease', 'Disease', (274, 307))	('gain-of-function', 'PosReg', (115, 131))	('HIF-2alpha', 'Gene', '2034', (178, 188))	('patients', 'Species', '9606', (246, 254))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (193, 209))	('paragangliomas', 'Disease', 'MESH:D010235', (215, 229))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (193, 210))	('paraganglioma', 'Phenotype', 'HP:0002668', (215, 228))	('EPAS1', 'Gene', (153, 158))	('cyanotic congenital heart disease', 'Disease', 'MESH:D006331', (274, 307))	('EPAS1', 'Gene', '2034', (153, 158))	('HIF-2alpha', 'Gene', (178, 188))	('mutations', 'Var', (140, 149))	('pheochromocytomas', 'Disease', (193, 210))	('paragangliomas', 'Disease', (215, 229))	('pheochromocytomas', 'Disease', 'MESH:D010673', (193, 210))
7002	30356369	The authors concluded that the EPAS1 mutations endow chromaffin cells exposed to chronic hypoxia amplified the ability of development of the oncogenic properties of HIF-2alpha.	('hypoxia', 'Disease', (89, 96))	('hypoxia', 'Disease', 'MESH:D000860', (89, 96))	('HIF-2alpha', 'Gene', '2034', (165, 175))	('amplified', 'PosReg', (97, 106))	('EPAS1', 'Gene', '2034', (31, 36))	('mutations', 'Var', (37, 46))	('EPAS1', 'Gene', (31, 36))	('chromaffin', 'Chemical', '-', (53, 63))	('HIF-2alpha', 'Gene', (165, 175))
7007	30356369	Therefore, in the light of the above, the cooccurrence of CCHD (as well as in other numerous case of congenital heart defects that can cause cyanosis) and P-PGL in this patient could be explained by exposure to chronic hypoxia.	('P-PGL', 'Var', (155, 160))	('congenital heart defects', 'Phenotype', 'HP:0001627', (101, 125))	('congenital heart defects', 'Disease', (101, 125))	('CCHD', 'Disease', 'None', (58, 62))	('hypoxia', 'Disease', 'MESH:D000860', (219, 226))	('cyanosis', 'Disease', 'MESH:D003490', (141, 149))	('congenital heart defects', 'Disease', 'MESH:D006330', (101, 125))	('hypoxia', 'Disease', (219, 226))	('patient', 'Species', '9606', (169, 176))	('cyanosis', 'Phenotype', 'HP:0000961', (141, 149))	('heart defects', 'Phenotype', 'HP:0030680', (112, 125))	('cyanosis', 'Disease', (141, 149))	('CCHD', 'Disease', (58, 62))
7011	30356369	Clinicians should consider P-PGL as a possible and potentially curable cause of otherwise unexplained clinical deterioration (in this case a slight hypertensive crisis and worsening dyspnea) in CCHD patients, even in the absence of typical paroxysmal symptoms.	('hypertensive crisis', 'Phenotype', 'HP:0100735', (148, 167))	('hypertensive', 'Disease', 'MESH:D006973', (148, 160))	('CCHD', 'Disease', (194, 198))	('dyspnea', 'Phenotype', 'HP:0002094', (182, 189))	('hypertensive', 'Disease', (148, 160))	('CCHD', 'Disease', 'None', (194, 198))	('dyspnea', 'Disease', (182, 189))	('patients', 'Species', '9606', (199, 207))	('P-PGL', 'Var', (27, 32))	('dyspnea', 'Disease', 'MESH:D004417', (182, 189))
7017	29783778	Aeroplysinin-1 diminished the number of proliferating cells and reduced spheroid growth significantly.	('spheroid growth', 'CPA', (72, 87))	('rat', 'Species', '10116', (47, 50))	('Aeroplysinin-1', 'Var', (0, 14))	('number of proliferating cells', 'CPA', (30, 59))	('reduced', 'NegReg', (64, 71))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (0, 14))	('diminished', 'NegReg', (15, 25))
7018	29783778	Beside these anti-tumorigenic activity, Aeroplysinin-1 decreased the migration ability of the cells significantly (p = 0.01), whereas, the invasion capacity was not affected.	('rat', 'Species', '10116', (72, 75))	('tumor', 'Disease', (18, 23))	('Aeroplysinin-1', 'Var', (40, 54))	('decreased', 'NegReg', (55, 64))	('migration ability of the cells', 'CPA', (69, 99))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
7019	29783778	Aeroplysinin-1 diminished the high adhesion capacity of the MTT cells to collagen (p < 0.001) and, furthermore, reduced the ability to form spheroids significantly.	('MTT', 'Chemical', 'MESH:C070243', (60, 63))	('high adhesion', 'MPA', (30, 43))	('Aeroplysinin-1', 'Var', (0, 14))	('reduced', 'NegReg', (112, 119))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (0, 14))	('diminished', 'NegReg', (15, 25))
7036	29783778	In conclusion, Aeroplysinin-1 addresses four hallmarks of cancer; proliferation, inflammation, angiogenesis, and metastasis, but the underlying mechanism is mainly unclear.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Aeroplysinin-1', 'Var', (15, 29))	('angiogenesis', 'CPA', (95, 107))	('proliferation', 'CPA', (66, 79))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (15, 29))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('inflammation', 'Disease', 'MESH:D007249', (81, 93))	('inflammation', 'Disease', (81, 93))	('metastasis', 'CPA', (113, 123))	('cancer', 'Disease', (58, 64))	('rat', 'Species', '10116', (73, 76))
7047	29783778	Twenty-four hours of incubation under extrinsic hypoxia (1% oxygen) in the presence of Aeroplysinin-1 resulted in a slight decrease of the effect (EC50 = 12-15 microM).	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (87, 101))	('effect', 'MPA', (139, 145))	('oxygen', 'Chemical', 'MESH:D010100', (60, 66))	('decrease', 'NegReg', (123, 131))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('Aeroplysinin-1', 'Var', (87, 101))	('hypoxia', 'Disease', (48, 55))
7052	29783778	Aeroplysinin-1 induced apoptosis, analyzed by caspase (casp)-3 and casp-7 activity assay, in a concentration-dependent manner but predominant at lower concentrations (Figure 3A-C).	('apoptosis', 'CPA', (23, 32))	('caspase (casp)-3', 'Gene', '836', (46, 62))	('casp-7', 'Gene', (67, 73))	('Aeroplysinin-1', 'Var', (0, 14))	('caspase (casp)-3', 'Gene', (46, 62))	('rat', 'Species', '10116', (102, 105))	('rat', 'Species', '10116', (158, 161))	('casp-7', 'Gene', '840', (67, 73))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (0, 14))
7053	29783778	Furthermore, gene expression analysis demonstrated a reduction of casp-3 and casp-7 after treatment with 10 microM Aeroplysinin-1 in the MTT cells (Figure 3D).	('casp-3', 'Gene', (66, 72))	('casp-3', 'Gene', '836', (66, 72))	('MTT', 'Chemical', 'MESH:C070243', (137, 140))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (115, 129))	('reduction', 'NegReg', (53, 62))	('casp-7', 'Gene', (77, 83))	('casp-7', 'Gene', '840', (77, 83))	('rat', 'Species', '10116', (45, 48))	('Aeroplysinin-1', 'Var', (115, 129))
7059	29783778	Furthermore, Becn1 as a marker of autophagy was increased after Isofistularin-3 treatment (Figure 3G).	('increased', 'PosReg', (48, 57))	('Isofistularin-3', 'Var', (64, 79))	('Becn1', 'Gene', (13, 18))	('Isofistularin-3', 'Chemical', 'MESH:C000626294', (64, 79))
7064	29783778	A single treatment with 5-10 microM Aeroplysinin-1 diminished the spheroid growth significantly over a time period of 12 days (Figure 4A).	('Aeroplysinin-1', 'Var', (36, 50))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (36, 50))	('spheroid growth', 'CPA', (66, 81))	('diminished', 'NegReg', (51, 61))
7066	29783778	A single treatment with Aeroplysinin-1 resulted in a decelerated spheroid growth, but was not able to inhibit spheroid growth completely.	('decelerated', 'NegReg', (53, 64))	('Aeroplysinin-1', 'Var', (24, 38))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (24, 38))	('rat', 'Species', '10116', (59, 62))
7067	29783778	Treatment with Aeroplysinin-1 took place on day four, 8, 11, and 15 after spheroid generation and resulted in a full inhibition of spheroid growth at a concentration of 10 microM (Figure 4B).	('spheroid growth', 'CPA', (131, 146))	('Aeroplysinin-1', 'Var', (15, 29))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (15, 29))	('inhibition', 'NegReg', (117, 127))	('rat', 'Species', '10116', (159, 162))	('rat', 'Species', '10116', (87, 90))
7068	29783778	Moreover, even 5 microM Aeroplysinin-1 significantly decreased spheroid growth over the entire time period.	('decreased', 'NegReg', (53, 62))	('spheroid growth', 'CPA', (63, 78))	('Aeroplysinin-1', 'Var', (24, 38))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (24, 38))
7074	29783778	Aeroplysinin-1 decreased the migration ability of the cells significantly, whereas, the invasion capacity was not affected (Figure 5A,B).	('migration ability of the cells', 'CPA', (29, 59))	('rat', 'Species', '10116', (32, 35))	('Aeroplysinin-1', 'Var', (0, 14))	('decreased', 'NegReg', (15, 24))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (0, 14))
7078	29783778	In contrast, Aeroplysinin-1 significantly diminished the high adhesion capacity of the MTT cells to collagen.	('diminished', 'NegReg', (42, 52))	('high adhesion capacity', 'MPA', (57, 79))	('Aeroplysinin-1', 'Var', (13, 27))	('MTT', 'Chemical', 'MESH:C070243', (87, 90))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (13, 27))
7082	29783778	A concentration of 1 microM Aeroplysinin-1 significantly inhibits the ability of MTT cells to form spheroids (Figure 5E).	('MTT', 'Chemical', 'MESH:C070243', (81, 84))	('rat', 'Species', '10116', (9, 12))	('Aeroplysinin-1', 'Var', (28, 42))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (28, 42))	('inhibits', 'NegReg', (57, 65))
7096	29783778	demonstrated that Aeroplysinin-1 inhibits the proliferation of colon cancer cells by promoting beta-catenin degradation.	('Aeroplysinin-1', 'Var', (18, 32))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('promoting', 'PosReg', (85, 94))	('beta-catenin', 'Gene', (95, 107))	('proliferation', 'CPA', (46, 59))	('colon cancer', 'Disease', 'MESH:D015179', (63, 75))	('rat', 'Species', '10116', (7, 10))	('rat', 'Species', '10116', (53, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (63, 75))	('inhibits', 'NegReg', (33, 41))	('beta-catenin', 'Gene', '1499', (95, 107))	('colon cancer', 'Disease', (63, 75))
7097	29783778	Beta-catenin gene expression was significantly reduced after 48 h treatment with Aeroplysinin-1 (data not shown) indicating an impact of Aeroplysinin-1 on the Wnt/beta-catenin signaling.	('beta-catenin', 'Gene', (163, 175))	('Beta-catenin', 'Gene', (0, 12))	('Aeroplysinin-1', 'Var', (81, 95))	('beta-catenin', 'Gene', '1499', (163, 175))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (81, 95))	('Beta-catenin', 'Gene', '1499', (0, 12))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (137, 151))	('reduced', 'NegReg', (47, 54))
7105	29783778	Another sign in this direction is provided by the work from Stuhldreier et al., who demonstrate that Aeroplysinin-1 stimulates the phosphorylation of histone H2AX (gamma-H2AX), a marker for DNA damage, in acute myeloid (NOMO-1) and acute monocytic (THP-1) cells.	('acute myeloid', 'Disease', 'MESH:D015470', (205, 218))	('THP-1', 'CellLine', 'CVCL:0006', (249, 254))	('NOMO-1', 'Gene', '23420', (220, 226))	('stimulates', 'PosReg', (116, 126))	('rat', 'Species', '10116', (91, 94))	('NOMO-1', 'Gene', (220, 226))	('acute myeloid', 'Disease', (205, 218))	('Aeroplysinin-1', 'Var', (101, 115))	('histone H2AX', 'Gene', '3014', (150, 162))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (101, 115))	('histone H2AX', 'Gene', (150, 162))	('phosphorylation', 'MPA', (131, 146))
7110	29783778	Anti-angiogenic activity and the previously presented data underline the potential anti-tumorigenic activity of Aeroplysinin-1 on the one hand, but indicate an impact on normal blood vessel endothelial cells on the other hand.	('impact', 'Reg', (160, 166))	('Anti-angiogenic activity', 'CPA', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Aeroplysinin-1', 'Var', (112, 126))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
7113	29783778	Aeroplysinin-1 decreased the migration ability of pheochromocytoma cells significantly, whereas the invasion capacity was not affected.	('pheochromocytoma', 'Disease', (50, 66))	('rat', 'Species', '10116', (32, 35))	('pheochromocytoma', 'Disease', 'MESH:D010673', (50, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (50, 66))	('Aeroplysinin-1', 'Var', (0, 14))	('migration ability of', 'CPA', (29, 49))	('decreased', 'NegReg', (15, 24))	('Aeroplysinin-1', 'Chemical', 'MESH:C042151', (0, 14))
7128	29783778	This could be important especially for PPGLs with an activation in pseudohypoxic pathways, including those with mutations in HIF2alpha, VHL, PHD and particularly SDHB that carry a higher risk of malignancy.	('PPGLs', 'Chemical', '-', (39, 44))	('malignancy', 'Disease', (195, 205))	('SDHB', 'Gene', (162, 166))	('activation', 'PosReg', (53, 63))	('VHL', 'Disease', 'MESH:D006623', (136, 139))	('hypoxic', 'Disease', (73, 80))	('VHL', 'Disease', (136, 139))	('hypoxic', 'Disease', 'MESH:D000860', (73, 80))	('mutations', 'Var', (112, 121))	('PHD', 'Disease', 'MESH:D011547', (141, 144))	('HIF2alpha', 'Gene', '2034', (125, 134))	('PHD', 'Disease', (141, 144))	('SDHB', 'Gene', '6390', (162, 166))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))	('HIF2alpha', 'Gene', (125, 134))
7184	29783778	Membrane was incubated with primary antibodies anti-integrin beta 1 (1:500; ab179471; abcam plc., Cambridge, UK), anti-E cadherin (1:500, ab76319; abcam plc.	('integrin beta 1', 'Gene', '3688', (52, 67))	('1:500', 'Var', (131, 136))	('integrin beta 1', 'Gene', (52, 67))	('cadherin', 'Gene', '999;1000', (121, 129))	('cadherin', 'Gene', (121, 129))
7196	24390213	SDHB immunohistochemistry was used as a surrogate marker for the presence of succinate dehydrogenase mutations.	('succinate dehydrogenase', 'Gene', (77, 100))	('succinate dehydrogenase', 'Gene', '6390', (77, 100))	('mutations', 'Var', (101, 110))	('SDHB', 'Gene', (0, 4))
7197	24390213	The FGFR4 G388R SNP was also investigated.	('FGFR4', 'Gene', '2264', (4, 9))	('FGFR4', 'Gene', (4, 9))	('G388R', 'Mutation', 'rs351855', (10, 15))	('G388R', 'Var', (10, 15))
7206	24390213	The discovery of succinate dehydrogenase (SDH) mutations as a frequent underlying cause of paragangliomas in the year 2000 has launched a phase of accelerated gene discovery in these tumors; it is now known that a genetic predisposition is present in almost 30% of cases.	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('succinate dehydrogenase', 'Gene', '6390', (17, 40))	('cause', 'Reg', (82, 87))	('SDH', 'Gene', '6390', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('succinate dehydrogenase', 'Gene', (17, 40))	('rat', 'Species', '10116', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('mutations', 'Var', (47, 56))	('SDH', 'Gene', (42, 45))	('paragangliomas', 'Disease', 'MESH:D010235', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('paragangliomas', 'Disease', (91, 105))	('tumors', 'Disease', (183, 189))	('paragangliomas', 'Phenotype', 'HP:0002668', (91, 105))
7208	24390213	Numerous factors have been associated with malignancy, including the presence of SDHB mutations, high proliferative index and tumor size and location; however the only accepted criterion of malignancy is the presence of distant metastasis.	('mutations', 'Var', (86, 95))	('associated', 'Reg', (27, 37))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('rat', 'Species', '10116', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('malignancy', 'Disease', 'MESH:D009369', (43, 53))	('SDHB', 'Gene', (81, 85))	('malignancy', 'Disease', (190, 200))	('malignancy', 'Disease', (43, 53))	('tumor', 'Disease', (126, 131))
7211	24390213	RTKs and their ligands are known to be mutated or overexpressed in a variety of endocrine malignancies, including thyroid, pituitary, pancreas, pheochromocytomas and paragangliomas.	('pituitary', 'Disease', (123, 132))	('endocrine malignancies', 'Phenotype', 'HP:0100568', (80, 102))	('pancreas', 'Disease', (134, 142))	('RTKs', 'Gene', (0, 4))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (144, 180))	('mutated', 'Var', (39, 46))	('overexpressed', 'PosReg', (50, 63))	('thyroid', 'Disease', (114, 121))	('pituitary', 'Disease', 'MESH:D010900', (123, 132))	('paraganglioma', 'Phenotype', 'HP:0002668', (166, 179))	('paragangliomas', 'Phenotype', 'HP:0002668', (166, 180))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (144, 160))	('endocrine malignancies', 'Disease', (80, 102))	('endocrine malignancies', 'Disease', 'MESH:D009369', (80, 102))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (144, 161))
7212	24390213	Single nucleotide polymorphisms (SNPs) in RTK genes may also play a role in development or progression of tumors, as is the case with the common FGFR4 G388R SNP.	('RTK', 'Gene', (42, 45))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('progression', 'CPA', (91, 102))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('FGFR4', 'Gene', '2264', (145, 150))	('FGFR4', 'Gene', (145, 150))	('development', 'CPA', (76, 87))	('G388R', 'Var', (151, 156))	('play', 'Reg', (61, 65))	('role', 'Reg', (68, 72))	('G388R', 'Mutation', 'rs351855', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
7216	24390213	SDHB immunohistochemistry was used as a surrogate maker for SDH mutations and genotyping for the common FGFR4 G388R polymorphism was performed in order to assess a possible influence of this SNP on the development and progression of these tumors.	('SDH', 'Gene', (60, 63))	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('FGFR4', 'Gene', '2264', (104, 109))	('FGFR4', 'Gene', (104, 109))	('SDH', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('G388R', 'Mutation', 'rs351855', (110, 115))	('mutations', 'Var', (64, 73))	('SDH', 'Gene', '6390', (60, 63))	('G388R', 'Var', (110, 115))	('SDH', 'Gene', '6390', (0, 3))
7230	24390213	These are referred to as SDH-related, in accordance with the fact that they can be due to either mutations or epigenetic changes in SDHA, SDHB, SDHC or SDHD, or in genes involved in mitochondrial respiratory complex II assembly or regulation.	('mutations', 'Var', (97, 106))	('SDHD', 'Gene', '6392', (152, 156))	('SDH', 'Gene', '6390', (152, 155))	('SDH', 'Gene', (138, 141))	('SDHD', 'Gene', (152, 156))	('SDH', 'Gene', '6390', (144, 147))	('SDH', 'Gene', (25, 28))	('SDHC', 'Gene', '6391', (144, 148))	('SDH', 'Gene', (152, 155))	('epigenetic changes', 'Var', (110, 128))	('SDH', 'Gene', (144, 147))	('SDH', 'Gene', '6390', (132, 135))	('SDHA', 'Gene', (132, 136))	('due', 'Reg', (83, 86))	('SDHA', 'Gene', '6389', (132, 136))	('rat', 'Species', '10116', (201, 204))	('SDHC', 'Gene', (144, 148))	('SDH', 'Gene', '6390', (138, 141))	('SDH', 'Gene', (132, 135))	('SDH', 'Gene', '6390', (25, 28))
7236	24390213	Exon 9 of fgfr4 was PCR amplified and RFLP digested with BstN1 to distinguish three FGFR4 genotypes: wild type (Gly/Gly), heterozygous Gly388 (Gly/Arg) and homozygous Arg388 (Arg/Arg) as previously described.	('Gly388', 'Chemical', '-', (135, 141))	('Arg', 'Chemical', 'MESH:D001120', (175, 178))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))	('Gly', 'Chemical', 'MESH:D005998', (112, 115))	('Gly', 'Chemical', 'MESH:D005998', (116, 119))	('FGFR4', 'Gene', '2264', (84, 89))	('fgfr4', 'Gene', (10, 15))	('FGFR4', 'Gene', (84, 89))	('Gly', 'Chemical', 'MESH:D005998', (135, 138))	('Gly', 'Chemical', 'MESH:D005998', (143, 146))	('fgfr4', 'Gene', '2264', (10, 15))	('Gly388 (Gly/Arg', 'Var', (135, 150))	('Arg388', 'Chemical', '-', (167, 173))	('Arg', 'Chemical', 'MESH:D001120', (147, 150))	('Arg', 'Chemical', 'MESH:D001120', (167, 170))	('Arg388 (Arg/Arg', 'Var', (167, 182))
7260	24390213	It was also higher in tumors from patients with a positive family history of pheochromocytoma/paraganglioma (22.5 vs. 12.9, p=0.0031), patients with FGFR4 Gly/Gly genotype (17.2 vs. 11.7 in Gly/Arg patients, p=0.045) and was associated with an increased risk of metastasis (OR=1.04, 95% CI=1.01-1.09, p=0.043).	('patients', 'Species', '9606', (135, 143))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (77, 107))	('patients', 'Species', '9606', (198, 206))	('Arg', 'Chemical', 'MESH:D001120', (194, 197))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('Gly', 'Chemical', 'MESH:D005998', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('Gly', 'Chemical', 'MESH:D005998', (155, 158))	('tumors', 'Disease', (22, 28))	('higher', 'PosReg', (12, 18))	('FGFR4', 'Gene', '2264', (149, 154))	('patients', 'Species', '9606', (34, 42))	('pheochromocytoma/paraganglioma', 'Disease', (77, 107))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('FGFR4', 'Gene', (149, 154))	('Gly', 'Chemical', 'MESH:D005998', (159, 162))	('Gly/Gly', 'Var', (155, 162))	('metastasis', 'CPA', (262, 272))
7274	24390213	No association was found between FGFR4 genotype and FGFR4 levels of expression, nor with age, gender, bilateral/multiple tumors, family history, any individual outcomes or the combined outcome.	('multiple tumors', 'Disease', (112, 127))	('multiple tumors', 'Disease', 'MESH:D009369', (112, 127))	('FGFR4', 'Gene', '2264', (52, 57))	('FGFR4', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('genotype', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('levels of expression', 'MPA', (58, 78))	('FGFR4', 'Gene', '2264', (33, 38))	('FGFR4', 'Gene', (33, 38))
7306	24390213	We identified a higher FGFR1 score in SDH-related tumors; Dekker et al also showed higher staining intensity of FGFR1 and higher bFGF RNA levels in SDHD mutated versus sporadic tumors.	('FGFR1', 'Gene', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('FGFR1', 'Gene', (23, 28))	('staining intensity', 'MPA', (90, 108))	('bFGF RNA levels', 'MPA', (129, 144))	('SDHD', 'Gene', '6392', (148, 152))	('SDH', 'Gene', '6390', (38, 41))	('higher', 'PosReg', (122, 128))	('mutated', 'Var', (153, 160))	('FGFR1', 'Gene', '2260', (112, 117))	('SDH', 'Gene', '6390', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('higher', 'PosReg', (83, 89))	('SDHD', 'Gene', (148, 152))	('FGFR1', 'Gene', '2260', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('SDH', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SDH', 'Gene', (148, 151))	('tumors', 'Disease', (177, 183))	('tumors', 'Disease', (50, 56))
7313	24390213	Our finding that nuclear FGFR2 was associated with increased risk of metastasis and recurrence is not unprecedented.	('nuclear', 'Var', (17, 24))	('metastasis', 'CPA', (69, 79))	('FGFR2', 'Gene', (25, 30))	('FGFR2', 'Gene', '2263', (25, 30))
7321	24390213	FGFR3 expression was significantly lower in tumors that metastasized, with high levels of FGFR3 being associated with a decreased risk of aggressive behavior.	('decreased', 'NegReg', (120, 129))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('FGFR3', 'Gene', (0, 5))	('expression', 'MPA', (6, 16))	('FGFR3', 'Gene', '2261', (90, 95))	('lower', 'NegReg', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('aggressive behavior', 'CPA', (138, 157))	('high levels', 'Var', (75, 86))	('FGFR3', 'Gene', (90, 95))	('aggressive behavior', 'Phenotype', 'HP:0000718', (138, 157))	('FGFR3', 'Gene', '2261', (0, 5))
7327	24390213	Cytoplasmic relocalization has been shown to be one of the mechanisms tumor cells develop to inactivate p27.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('p27', 'Gene', '3429', (104, 107))	('p27', 'Gene', (104, 107))	('inactivate', 'Var', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
7330	24390213	The low percentage of p53 staining is in accordance with previous studies showing a very low frequency of p53 mutations in these tumors.	('p53', 'Gene', '7157', (106, 109))	('tumors', 'Disease', (129, 135))	('mutations', 'Var', (110, 119))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('p53', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (106, 109))
7332	24390213	These findings are consistent with a previous report of p16ink4a promoter hypermethylation in SDHB mutated and malignant tumors and with the observation that pheochromocytoma-prone mice with homozygous Ink4a/Arf inactivation often develop malignant tumors.	('mice', 'Species', '10090', (181, 185))	('inactivation', 'Var', (212, 224))	('pheochromocytoma', 'Disease', (158, 174))	('develop', 'PosReg', (231, 238))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('Ink4a', 'Gene', '12578', (202, 207))	('Ink4a', 'Gene', (202, 207))	('SDHB', 'Gene', (94, 98))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('malignant tumors', 'Disease', 'MESH:D018198', (239, 255))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('p16ink4a', 'Gene', (56, 64))	('malignant tumors', 'Disease', 'MESH:D018198', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('malignant tumors', 'Disease', (239, 255))	('malignant tumors', 'Disease', (111, 127))	('p16ink4a', 'Gene', '12578', (56, 64))	('pheochromocytoma', 'Disease', 'MESH:D010673', (158, 174))
7388	27076898	Methyldopa may worsen the symptoms of pheochromocytoma and not recommended.	('worsen', 'NegReg', (15, 21))	('Methyldopa', 'Var', (0, 10))	('symptoms', 'MPA', (26, 34))	('Methyldopa', 'Chemical', 'MESH:D008750', (0, 10))	('pheochromocytoma', 'Disease', (38, 54))	('pheochromocytoma', 'Disease', 'MESH:D010673', (38, 54))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (38, 54))
7405	27047799	Collectively, such groupings establish that inactivating germline changes in genes within pathways related to genomic repair can promote carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (137, 151))	('carcinogenesis', 'Disease', (137, 151))	('inactivating germline changes', 'Var', (44, 73))	('promote', 'PosReg', (129, 136))
7420	27047799	Pseudo-hypoxia may be achieved through inactivation of tumor-suppressor genes, such as the von Hippel-Lindau (VHL) tumor suppressor, E3 ubiquitin ligase gene (VHL); the genes associated with the succinate dehydrogenase (SDH) complex (the SDHx genes); and the fumarate hydratase (FH) gene.	('SDHx', 'Chemical', '-', (238, 242))	('SDH', 'Gene', '6390', (238, 241))	('tumor-suppressor', 'Gene', '7248', (55, 71))	('succinate dehydrogenase', 'Gene', '6390', (195, 218))	('VHL', 'Gene', '7428', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('hypoxia', 'Disease', (7, 14))	('fumarate hydratase', 'Gene', '2271', (259, 277))	('SDH', 'Gene', (238, 241))	('SDH', 'Gene', '6390', (220, 223))	('tumor-suppressor', 'Gene', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('hypoxia', 'Disease', 'MESH:D000860', (7, 14))	('von Hippel-Lindau (VHL) tumor', 'Disease', 'MESH:D006623', (91, 120))	('VHL', 'Gene', (159, 162))	('succinate dehydrogenase', 'Gene', (195, 218))	('FH', 'Gene', '2271', (279, 281))	('SDH', 'Gene', (220, 223))	('inactivation', 'Var', (39, 51))	('VHL', 'Gene', (110, 113))	('fumarate hydratase', 'Gene', (259, 277))	('VHL', 'Gene', '7428', (159, 162))
7422	27047799	Since these syndromes involve germline mutations associated with activation of the hypoxia pathway, and activation of this pathway may lead to aggressive and resistant sporadic tumors, this review will also compare clinical aspects of carcinogenesis, tumor growth, local/distant spread, and treatment resistance between syndrome-associated tumors and similar sporadic tumors.	('lead to', 'Reg', (135, 142))	('sporadic tumors', 'Disease', (359, 374))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', (368, 373))	('sporadic tumors', 'Disease', 'MESH:D009369', (359, 374))	('sporadic tumors', 'Disease', (168, 183))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('tumors', 'Disease', 'MESH:D009369', (368, 374))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('tumors', 'Disease', (177, 183))	('sporadic tumors', 'Disease', 'MESH:D009369', (168, 183))	('carcinogenesis', 'Disease', (235, 249))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('germline mutations', 'Var', (30, 48))	('tumor', 'Disease', (177, 182))	('activation', 'PosReg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('carcinogenesis', 'Disease', 'MESH:D063646', (235, 249))	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumors', 'Disease', (340, 346))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (368, 374))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', (340, 345))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('tumor', 'Disease', 'MESH:D009369', (340, 345))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (368, 374))	('hypoxia', 'Disease', (83, 90))
7423	27047799	von Hippel-Lindau disease is an autosomal-dominant hereditary cancer syndrome involving a germline mutation in VHL.	('germline mutation', 'Var', (90, 107))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('VHL', 'Gene', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('VHL', 'Gene', '7428', (111, 114))	('autosomal-dominant hereditary cancer syndrome', 'Disease', (32, 77))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (32, 77))	('involving', 'Reg', (78, 87))	('von Hippel-Lindau disease', 'Disease', (0, 25))
7427	27047799	von Hippel-Lindau disease is diagnosed in a patient who fulfills any one of the following four conditions: (1) two or more CNS hemangioblastomas; (2) one CNS hemangioblastoma and a disease-associated visceral tumor (i.e., RCC, PCC, pancreatic tumor or cysts, or broad ligament cystadenomas); (3) a family history of VHL disease and one of the following: (a) retinal angioma, (b) spinal or cerebellar hemangioblastoma, (c) PCC, (d) RCC, (e) or multiple renal and pancreatic cysts; or (4) a pathogenic VHL variant.	('hemangioblastomas', 'Disease', (127, 144))	('hemangioblastoma', 'Disease', 'MESH:D018325', (127, 143))	('VHL disease', 'Disease', (316, 327))	('hemangioblastoma', 'Disease', (400, 416))	('pathogenic', 'Reg', (489, 499))	('pancreatic tumor', 'Disease', (232, 248))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (400, 416))	('VHL', 'Gene', '7428', (500, 503))	('visceral tumor', 'Disease', 'MESH:D059265', (200, 214))	('cystadenomas', 'Disease', (277, 289))	('RCC', 'Disease', 'MESH:C538614', (222, 225))	('PCC', 'Gene', (227, 230))	('CNS hemangioblastomas', 'Phenotype', 'HP:0006880', (123, 144))	('pancreatic tumor', 'Disease', 'MESH:D010190', (232, 248))	('VHL', 'Gene', '7428', (316, 319))	('CNS hemangioblastoma', 'Phenotype', 'HP:0006880', (123, 143))	('CNS hemangioblastoma', 'Phenotype', 'HP:0006880', (154, 174))	('retinal angioma', 'Disease', (358, 373))	('cystadenomas', 'Disease', 'MESH:D003537', (277, 289))	('pancreatic cysts', 'Disease', (462, 478))	('PCC', 'Gene', (422, 425))	('hemangioblastoma', 'Disease', 'MESH:D018325', (158, 174))	('PCC', 'Gene', '1421', (227, 230))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (462, 478))	('RCC', 'Disease', (431, 434))	('hemangioblastoma', 'Disease', (127, 143))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (127, 143))	('hemangioblastomas', 'Disease', 'MESH:D018325', (127, 144))	('PCC', 'Gene', '1421', (422, 425))	('cerebellar hemangioblastoma', 'Disease', 'MESH:D018325', (389, 416))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('cerebellar hemangioblastoma', 'Disease', (389, 416))	('RCC', 'Disease', 'MESH:C538614', (431, 434))	('retinal angioma', 'Disease', 'MESH:D012173', (358, 373))	('hemangioblastoma', 'Disease', 'MESH:D018325', (400, 416))	('hemangioblastoma', 'Disease', (158, 174))	('von Hippel-Lindau disease', 'Disease', (0, 25))	('multiple renal and pancreatic cysts', 'Phenotype', 'HP:0005562', (443, 478))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (158, 174))	('patient', 'Species', '9606', (44, 51))	('visceral tumor', 'Disease', (200, 214))	('cerebellar hemangioblastoma', 'Phenotype', 'HP:0006880', (389, 416))	('VHL', 'Gene', (500, 503))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (232, 248))	('pancreatic cysts', 'Disease', 'MESH:D010181', (462, 478))	('variant', 'Var', (504, 511))	('VHL disease', 'Disease', 'MESH:D006623', (316, 327))	('VHL', 'Gene', (316, 319))	('RCC', 'Disease', (222, 225))	('spinal or', 'Disease', (379, 388))
7435	27047799	VHL disease requires a mutation or in-frame deletion/insertion of VHL that leads to loss of a functional protein.	('VHL disease', 'Disease', (0, 11))	('mutation', 'Var', (23, 31))	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('loss of', 'NegReg', (84, 91))	('VHL', 'Gene', (0, 3))	('in-frame deletion/insertion', 'Var', (35, 62))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (0, 3))	('a functional protein', 'MPA', (92, 112))	('VHL', 'Gene', '7428', (66, 69))
7436	27047799	Loss of functional pVHL leads to upregulation of HIF that increases expression of various proteins (e.g., vascular endothelial growth factor (VEGF), platelet-derived growth factor, matrix metalloproteinases, and transforming growth factor-alpha) involved in cancer growth and development.	('VEGF', 'Gene', (142, 146))	('increases', 'PosReg', (58, 67))	('vascular endothelial growth factor', 'Gene', (106, 140))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('expression', 'MPA', (68, 78))	('proteins', 'Protein', (90, 98))	('cancer', 'Disease', (258, 264))	('vascular endothelial growth factor', 'Gene', '7422', (106, 140))	('upregulation', 'PosReg', (33, 45))	('VEGF', 'Gene', '7422', (142, 146))	('pVHL', 'Gene', '7428', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('platelet-derived growth factor, matrix metalloproteinases, and transforming growth factor-alpha', 'Gene', '7039', (149, 244))	('pVHL', 'Gene', (19, 23))	('Loss', 'Var', (0, 4))
7444	27047799	Perhaps the potential higher response rate in VHL disease is not surprising, as a study of sporadic metastatic clear cell RCC indicated that patients with VHL inactivation have a higher, albeit not statistically significant different, response rate (41 versus 31%) to VEGF targeted therapy than did sporadic tumors with wild-type VHL.	('VHL disease', 'Disease', 'MESH:D006623', (46, 57))	('VHL', 'Gene', (46, 49))	('VEGF', 'Gene', (268, 272))	('VHL disease', 'Disease', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('VHL', 'Gene', (330, 333))	('patients', 'Species', '9606', (141, 149))	('VHL', 'Gene', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('VHL', 'Gene', '7428', (46, 49))	('VHL', 'Gene', '7428', (330, 333))	('RCC', 'Disease', (122, 125))	('VHL', 'Gene', '7428', (155, 158))	('inactivation', 'Var', (159, 171))	('higher', 'PosReg', (179, 185))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('sporadic tumors', 'Disease', (299, 314))	('response', 'MPA', (235, 243))	('VEGF', 'Gene', '7422', (268, 272))	('sporadic tumors', 'Disease', 'MESH:D009369', (299, 314))
7449	27047799	The former cluster includes mutations in genes related to SDH, known as the SDHx genes.	('SDHx', 'Chemical', '-', (76, 80))	('SDH', 'Gene', (58, 61))	('SDH', 'Gene', '6390', (76, 79))	('SDH', 'Gene', (76, 79))	('mutations', 'Var', (28, 37))	('SDH', 'Gene', '6390', (58, 61))
7450	27047799	The SDHx hereditary PGL/PCC syndromes are relatively newly described entities that involve a mutation in SDHA, SDHB, SDHC, SDHD, or SDHAF2.	('SDHB', 'Gene', (111, 115))	('PCC syndrome', 'Disease', (24, 36))	('SDHA', 'Gene', '6389', (105, 109))	('SDHD', 'Gene', (123, 127))	('SDHAF2', 'Gene', '54949', (132, 138))	('SDHC', 'Gene', (117, 121))	('SDHA', 'Gene', (132, 136))	('SDHAF2', 'Gene', (132, 138))	('PGL/PCC', 'Gene', (20, 27))	('SDHD', 'Gene', '6392', (123, 127))	('PCC syndrome', 'Disease', 'MESH:C565384', (24, 36))	('SDHC', 'Gene', '6391', (117, 121))	('SDHx', 'Chemical', '-', (4, 8))	('SDHA', 'Gene', (105, 109))	('PGL/PCC', 'Gene', '1421', (20, 27))	('mutation', 'Var', (93, 101))	('SDHA', 'Gene', '6389', (132, 136))	('SDHB', 'Gene', '6390', (111, 115))
7452	27047799	Since that time, in addition to PGL/PCC, the recognized tumor spectrum among patients with a mutation in one of the SDHx genes has been expanded to also include RCC, pituitary tumors, gastrointestinal stromal tumors, and pancreatic neuroendocrine tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('PGL/PCC', 'Gene', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SDHx', 'Gene', (116, 120))	('pituitary tumors', 'Disease', 'MESH:D010911', (166, 182))	('tumor', 'Disease', (209, 214))	('gastrointestinal stromal tumors', 'Disease', (184, 215))	('SDHx', 'Chemical', '-', (116, 120))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (77, 85))	('RCC', 'Disease', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (221, 253))	('pituitary tumors', 'Disease', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic neuroendocrine tumors', 'Disease', (221, 253))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('RCC', 'Disease', 'MESH:C538614', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (232, 253))	('PGL/PCC', 'Gene', '1421', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (184, 215))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (184, 215))	('mutation', 'Var', (93, 101))
7453	27047799	A meta-analysis of prevalence studies found the pooled risk for malignant PGL to be 13 and 4% for SDHB and SDHD mutations, respectively.	('SDHD', 'Gene', (107, 111))	('PGL', 'Disease', (74, 77))	('SDHB', 'Gene', '6390', (98, 102))	('mutations', 'Var', (112, 121))	('SDHB', 'Gene', (98, 102))	('PGL', 'Disease', 'MESH:D010235', (74, 77))	('SDHD', 'Gene', '6392', (107, 111))
7454	27047799	Penetrance may be affected by environmental oxygenation factors as patients with SDHD mutations who lived at lower (as opposed to higher) altitudes have less disease penetrance, have more findings of single (as opposed to multiple) tumors, and do not typically develop PCCs.	('mutations', 'Var', (86, 95))	('PCC', 'Gene', '1421', (269, 272))	('less', 'NegReg', (153, 157))	('patients', 'Species', '9606', (67, 75))	('develop', 'PosReg', (261, 268))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('SDHD', 'Gene', '6392', (81, 85))	('PCC', 'Gene', (269, 272))	('disease', 'CPA', (158, 165))	('SDHD', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (232, 238))	('oxygen', 'Chemical', 'MESH:D010100', (44, 50))
7463	27047799	PCCs with SDHB knockdown, like those in familial PGL/PCC, demonstrate HIF1-alpha stabilization despite normoxic conditions, consistent with pseudo-hypoxia.	('PCC', 'Gene', '1421', (0, 3))	('knockdown', 'Var', (15, 24))	('PCC', 'Gene', (53, 56))	('stabilization', 'MPA', (81, 94))	('hypoxia', 'Disease', (147, 154))	('PCC', 'Gene', (0, 3))	('HIF1-alpha', 'Gene', '3091', (70, 80))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('PCC', 'Gene', '1421', (53, 56))	('PGL/PCC', 'Gene', (49, 56))	('SDHB', 'Gene', '6390', (10, 14))	('SDHB', 'Gene', (10, 14))	('PGL/PCC', 'Gene', '1421', (49, 56))	('HIF1-alpha', 'Gene', (70, 80))
7464	27047799	This has been recapitulated in tumor specimens where dysfunction of SDH due to mutations in SDHx genes leads to events consistent with pseudo-hypoxia, including mitochondrial dysfunction; increased expression of HIF1-alpha by immunohistochemistry; increased expression of miR-210, a key regulator of response to hypoxia; and increased VEGF expression.	('SDH', 'Gene', (92, 95))	('SDH', 'Gene', (68, 71))	('hypoxia', 'Disease', (312, 319))	('increased VEGF expression', 'Phenotype', 'HP:0030269', (325, 350))	('increased', 'PosReg', (188, 197))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (161, 186))	('HIF1-alpha', 'Gene', (212, 222))	('mutations', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SDHx', 'Chemical', '-', (92, 96))	('mitochondrial dysfunction', 'Disease', (161, 186))	('hypoxia', 'Disease', 'MESH:D000860', (312, 319))	('expression', 'MPA', (198, 208))	('hypoxia', 'Disease', (142, 149))	('miR-210', 'Gene', '406992', (272, 279))	('increased', 'PosReg', (248, 257))	('HIF1-alpha', 'Gene', '3091', (212, 222))	('VEGF', 'Gene', '7422', (335, 339))	('VEGF', 'Gene', (335, 339))	('SDH', 'Gene', '6390', (92, 95))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('SDH', 'Gene', '6390', (68, 71))	('miR-210', 'Gene', (272, 279))	('expression', 'MPA', (258, 268))	('tumor', 'Disease', (31, 36))	('dysfunction', 'Var', (53, 64))	('increased', 'PosReg', (325, 334))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (161, 186))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
7467	27047799	Paragangliomas associated with SDHB mutations are more aggressive and resistant to treatment than sporadic PGLs.	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('SDHB', 'Gene', (31, 35))	('PGL', 'Disease', 'MESH:D010235', (107, 110))	('mutations', 'Var', (36, 45))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('SDHB', 'Gene', '6390', (31, 35))	('Paragangliomas', 'Disease', (0, 14))	('PGL', 'Disease', (107, 110))
7468	27047799	Malignant PGLs more frequently have SDHB mutations than do sporadic tumors.	('mutations', 'Var', (41, 50))	('PGL', 'Disease', 'MESH:D010235', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('sporadic tumors', 'Disease', 'MESH:D009369', (59, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PGL', 'Disease', (10, 13))	('sporadic tumors', 'Disease', (59, 74))
7469	27047799	In a retrospective study of 34 patients undergoing primary carotid body PGL resections, there was significantly worse disease-free survival among patients with a SDHB mutation than among patients without a SDHB mutation.	('patients', 'Species', '9606', (187, 195))	('PGL', 'Disease', (72, 75))	('SDHB', 'Gene', (162, 166))	('SDHB', 'Gene', '6390', (162, 166))	('SDHB', 'Gene', (206, 210))	('mutation', 'Var', (167, 175))	('PGL', 'Disease', 'MESH:D010235', (72, 75))	('SDHB', 'Gene', '6390', (206, 210))	('patients', 'Species', '9606', (31, 39))	('disease-free survival', 'CPA', (118, 139))	('patients', 'Species', '9606', (146, 154))	('worse', 'NegReg', (112, 117))
7470	27047799	In a cohort of patients with malignant PCC/PGL, there was an association of decreased survival for those patients with a SDHB mutation compared to others within this cohort.	('patients', 'Species', '9606', (15, 23))	('patients', 'Species', '9606', (105, 113))	('survival', 'MPA', (86, 94))	('PCC', 'Gene', (39, 42))	('SDHB', 'Gene', (121, 125))	('PGL', 'Disease', (43, 46))	('mutation', 'Var', (126, 134))	('decreased', 'NegReg', (76, 85))	('PCC', 'Gene', '1421', (39, 42))	('PGL', 'Disease', 'MESH:D010235', (43, 46))	('SDHB', 'Gene', '6390', (121, 125))
7471	27047799	Clinical trials (e.g., NCT02495103) are underway to explore targeted therapies for RCC associated with SDHx gene mutations.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('associated', 'Reg', (87, 97))	('mutations', 'Var', (113, 122))	('SDHx', 'Gene', (103, 107))	('SDHx', 'Chemical', '-', (103, 107))
7475	27047799	Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal-dominant hereditary cancer syndrome first associated with mutations in FH in 2002.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('autosomal-dominant hereditary cancer syndrome', 'Disease', (62, 107))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (0, 47))	('mutations', 'Var', (130, 139))	('associated', 'Reg', (114, 124))	('autosomal-dominant hereditary cancer syndrome', 'Disease', 'MESH:D009386', (62, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('FH', 'Gene', '2271', (143, 145))	('RCC', 'Disease', 'MESH:C538614', (51, 54))	('RCC', 'Disease', (51, 54))
7480	27047799	There is variable expression in HLRCC, with one study reporting 87% of patients with FH mutations having skin leiomyomata, 96% of females having uterine leiomyomata (typically younger in age than those with sporadic tumors), and 42% having RCC  - although a separate reviews put the risk of RCC between 15 and 20%.	('patients', 'Species', '9606', (71, 79))	('mutations', 'Var', (88, 97))	('RCC', 'Disease', (291, 294))	('FH', 'Gene', '2271', (85, 87))	('skin leiomyomata', 'Disease', 'MESH:C535516', (105, 121))	('sporadic tumors', 'Disease', (207, 222))	('RCC', 'Disease', 'MESH:C538614', (291, 294))	('uterine leiomyomata', 'Phenotype', 'HP:0000131', (145, 164))	('sporadic tumors', 'Disease', 'MESH:D009369', (207, 222))	('leiomyomata', 'Disease', 'MESH:C535516', (153, 164))	('RCC', 'Disease', (34, 37))	('RCC', 'Disease', (240, 243))	('leiomyomata', 'Disease', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', 'MESH:C538614', (34, 37))	('skin leiomyomata', 'Disease', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('skin leiomyomata', 'Phenotype', 'HP:0007620', (105, 121))	('leiomyomata', 'Disease', 'MESH:C535516', (110, 121))	('leiomyomata', 'Disease', (110, 121))
7481	27047799	A rare manifestation of germline FH mutations is PCC.	('PCC', 'Gene', (49, 52))	('FH', 'Gene', '2271', (33, 35))	('mutations', 'Var', (36, 45))	('PCC', 'Gene', '1421', (49, 52))
7493	27047799	There is a lack of evidence to date regarding HLRCC-associated tumors' responsiveness to therapy although clinical trials are underway to evaluate therapeutic options for patients with HLRCC-associated RCC (e.g., NCT01130519 and NCT02495103).	('NCT01130519', 'Var', (213, 224))	('RCC', 'Disease', 'MESH:C538614', (48, 51))	('RCC', 'Disease', (187, 190))	('RCC', 'Disease', 'MESH:C538614', (187, 190))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (171, 179))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('RCC', 'Disease', 'MESH:C538614', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('RCC', 'Disease', (202, 205))	('NCT02495103', 'Var', (229, 240))	('RCC', 'Disease', (48, 51))
7495	27047799	Both are relatively newly discovered heritable cancer syndromes that involve a germline mutation in a tumor-suppressor gene that is translated into a tricarboxylic acid cycle enzyme.	('cancer syndromes', 'Disease', (47, 63))	('tumor-suppressor', 'Gene', '7248', (102, 118))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (150, 168))	('germline mutation', 'Var', (79, 96))	('tumor-suppressor', 'Gene', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer syndromes', 'Disease', 'MESH:D009369', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
7573	24678933	Genetic analysis revealed a mutation of the VHL gene (exon2 TTT   TGT), indicating von Hippel-Lindau syndrome.	('von Hippel-Lindau syndrome', 'Disease', (83, 109))	('indicating', 'Reg', (72, 82))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (83, 109))	('TGT', 'Gene', (66, 69))	('revealed', 'Reg', (17, 25))	('VHL', 'Gene', (44, 47))	('VHL', 'Gene', '7428', (44, 47))	('mutation', 'Var', (28, 36))	('TGT', 'Gene', '81890', (66, 69))
7584	24678933	von Hippel-Lindau syndrome is an autosomal-dominant disorder, and mutation of one copy of the VHL tumor suppressor gene is associated with the development of the tumors.	('associated', 'Reg', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('VHL tumor', 'Disease', 'MESH:D006623', (94, 103))	('autosomal-dominant disorder', 'Disease', 'MESH:D030342', (33, 60))	('autosomal-dominant disorder', 'Disease', (33, 60))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('von Hippel-Lindau syndrome', 'Disease', (0, 26))	('mutation', 'Var', (66, 74))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('VHL tumor', 'Disease', (94, 103))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (0, 26))
7585	24678933	Recently, it has been reported that de novo mutations seem to play a greater role in von Hippel-Lindau syndrome than previously thought.	('von Hippel-Lindau syndrome', 'Disease', (85, 111))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (85, 111))	('mutations', 'Var', (44, 53))
7615	24523932	Thus, post-translational processing of CgA gives rise to vasostatin I and II, chromofungin, chromacin, pancreastatin, catestatin, parastatin, WE-14 and EL35 peptides.	('vasostatin', 'MPA', (57, 67))	('post-translational processing', 'Var', (6, 35))	('catestatin', 'Gene', (118, 128))	('parastatin', 'MPA', (130, 140))	('WE-14', 'Chemical', '-', (142, 147))	('CgA', 'Gene', (39, 42))	('chromofungin', 'MPA', (78, 90))	('pancreastatin', 'MPA', (103, 116))	('EL35 peptides', 'MPA', (152, 165))	('catestatin', 'Gene', '1113', (118, 128))	('chromacin', 'MPA', (92, 101))	('WE-14', 'MPA', (142, 147))	('CgA', 'Gene', '1113', (39, 42))
7626	24523932	Most of these neuroendocrine tumors occur sporadically, but the proportion of sporadic pheochromocytomas presenting genetic mutations that was initially estimated to about 24% may actually reach 30% or more.	('sporadic pheochromocytomas', 'Disease', 'MESH:D010673', (78, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (87, 103))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (14, 35))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (14, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('genetic mutations', 'Var', (116, 133))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('neuroendocrine tumors', 'Disease', (14, 35))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (87, 104))	('sporadic pheochromocytomas', 'Disease', (78, 104))
7627	24523932	The latest gene mutation discoveries brought to 11 the number of genes playing an important role in the pathogenesis of pheochromocytomas.	('pheochromocytomas', 'Disease', (120, 137))	('mutation', 'Var', (16, 24))	('pheochromocytomas', 'Disease', 'MESH:D010673', (120, 137))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (120, 137))
7646	24523932	Twenty-four tumors were apparently sporadic, whereas 3 tumors had a RET mutation, 2 a NF1 mutation, 3 a SDHB mutation, 4 a SDHD mutation and 1 a VHL mutation.	('RET', 'Gene', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('NF1', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (55, 61))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('VHL', 'Gene', (145, 148))	('mutation', 'Var', (90, 98))	('SDHD', 'Gene', '6392', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('SDHB', 'Gene', '6390', (104, 108))	('RET', 'Gene', '5979', (68, 71))	('tumors', 'Disease', (12, 18))	('VHL', 'Gene', '7428', (145, 148))	('mutation', 'Var', (109, 117))	('SDHD', 'Gene', (123, 127))	('NF1', 'Gene', '4763', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('SDHB', 'Gene', (104, 108))
7647	24523932	Of note, the seven patients with a SDH mutation had a paraganglioma and the five malignant tumors are of adrenomedullary origin (i.e.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('paraganglioma', 'Disease', (54, 67))	('SDH', 'Gene', '6390', (35, 38))	('mutation', 'Var', (39, 47))	('patients', 'Species', '9606', (19, 27))	('malignant tumors', 'Disease', (81, 97))	('paraganglioma', 'Disease', 'MESH:D010235', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SDH', 'Gene', (35, 38))	('malignant tumors', 'Disease', 'MESH:D018198', (81, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (54, 67))
7676	24523932	The Spearman's test was performed to analyze the correlations between plasma levels of WE-14 and CgA, WE-14 and EM66 or EM66 and CgA and between tumor size and CgA, WE-14 or EM66 plasma levels.	('EM66', 'Gene', (174, 178))	('CgA', 'Gene', (129, 132))	('CgA', 'Gene', (97, 100))	('CgA', 'Gene', (160, 163))	('tumor', 'Disease', (145, 150))	('EM66', 'Gene', '7857', (120, 124))	('EM66', 'Gene', '7857', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('WE-14', 'Var', (102, 107))	('EM66', 'Gene', '7857', (174, 178))	('EM66', 'Gene', (112, 116))	('EM66', 'Gene', (120, 124))	('CgA', 'Gene', '1113', (129, 132))	('WE-14', 'Chemical', '-', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CgA', 'Gene', '1113', (97, 100))	('WE-14', 'Chemical', '-', (102, 107))	('WE-14', 'Chemical', '-', (165, 170))	('CgA', 'Gene', '1113', (160, 163))
7713	24523932	For instance, whatever the characteristic of the tumor, WE-14 measurement always increased the diagnostic sensitivity.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('men', 'Species', '9606', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('WE-14', 'Chemical', '-', (56, 61))	('tumor', 'Disease', (49, 54))	('diagnostic sensitivity', 'MPA', (95, 117))	('WE-14', 'Var', (56, 61))	('increased', 'PosReg', (81, 90))
7718	24523932	The early detection of WE-14 during ontogeny and the elevated concentrations detected in neuroendocrine neoplasms suggested that WE-14 could exert a physiological and/or pathophysiological role.	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (89, 113))	('WE-14', 'Var', (129, 134))	('neoplasm', 'Phenotype', 'HP:0002664', (104, 112))	('WE-14', 'Chemical', '-', (23, 28))	('WE-14', 'Chemical', '-', (129, 134))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (89, 113))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (89, 112))	('neuroendocrine neoplasms', 'Disease', (89, 113))	('rat', 'Species', '10116', (69, 72))
7721	24523932	Because WE-14 is present in pheochromocytes, this peptide could also be released into the circulation of patients with pheochromocytoma.	('WE-14', 'Var', (8, 13))	('patients', 'Species', '9606', (105, 113))	('pheochromocytoma', 'Disease', (119, 135))	('released', 'MPA', (72, 80))	('WE-14', 'Chemical', '-', (8, 13))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('pheochromocytoma', 'Disease', 'MESH:D010673', (119, 135))
7743	24523932	Worthy of note, the patient with a VHL mutation had false-negative results for all three tests.	('patient', 'Species', '9606', (20, 27))	('VHL', 'Gene', '7428', (35, 38))	('mutation', 'Var', (39, 47))	('VHL', 'Gene', (35, 38))
7744	24523932	Similarly, one patient with a RET mutation also had negative results on CgA, WE-14 and EM66 assays, while the two other patients with this gene mutation had at least one false-negative result.	('patient', 'Species', '9606', (15, 22))	('RET', 'Gene', (30, 33))	('EM66', 'Gene', '7857', (87, 91))	('CgA', 'Gene', (72, 75))	('EM66', 'Gene', (87, 91))	('patient', 'Species', '9606', (120, 127))	('mutation', 'Var', (34, 42))	('RET', 'Gene', '5979', (30, 33))	('negative', 'NegReg', (52, 60))	('patients', 'Species', '9606', (120, 128))	('WE-14', 'Chemical', '-', (77, 82))	('CgA', 'Gene', '1113', (72, 75))
7745	24523932	Further studies should be performed on a larger group of pheochromocytoma patients with a VHL or RET gene mutation to confirm these observations.	('VHL', 'Gene', '7428', (90, 93))	('patients', 'Species', '9606', (74, 82))	('pheochromocytoma', 'Disease', (57, 73))	('mutation', 'Var', (106, 114))	('RET', 'Gene', '5979', (97, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('VHL', 'Gene', (90, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (57, 73))	('RET', 'Gene', (97, 100))
7752	24523932	Interestingly, all the tumors with a SDHB or SDHD mutation in our series corresponded to paragangliomas and, in this subgroup of patients, combined measurement of CgA, WE-14 and EM66 also provided 100% sensitivity.	('paraganglioma', 'Phenotype', 'HP:0002668', (89, 102))	('paragangliomas', 'Phenotype', 'HP:0002668', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('mutation', 'Var', (50, 58))	('EM66', 'Gene', '7857', (178, 182))	('SDHB', 'Gene', '6390', (37, 41))	('SDHD', 'Gene', '6392', (45, 49))	('CgA', 'Gene', '1113', (163, 166))	('paragangliomas', 'Disease', (89, 103))	('tumors', 'Disease', (23, 29))	('EM66', 'Gene', (178, 182))	('corresponded to', 'Reg', (73, 88))	('patients', 'Species', '9606', (129, 137))	('SDHB', 'Gene', (37, 41))	('SDHD', 'Gene', (45, 49))	('WE-14', 'Chemical', '-', (168, 173))	('men', 'Species', '9606', (155, 158))	('CgA', 'Gene', (163, 166))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('paragangliomas', 'Disease', 'MESH:D010235', (89, 103))
7822	23525329	Mutations of the genes SDHD, PGL2, SDHC and also MEN have been identified as involved in paragangliomas.	('paragangliomas', 'Disease', (89, 103))	('paraganglioma', 'Phenotype', 'HP:0002668', (89, 102))	('paragangliomas', 'Phenotype', 'HP:0002668', (89, 103))	('involved', 'Reg', (77, 85))	('SDHD', 'Gene', '6392', (23, 27))	('SDHD', 'Gene', (23, 27))	('Mutations', 'Var', (0, 9))	('SDHC', 'Gene', (35, 39))	('MEN', 'Species', '9606', (49, 52))	('PGL2', 'Gene', '54949', (29, 33))	('SDHC', 'Gene', '6391', (35, 39))	('paragangliomas', 'Disease', 'MESH:D010235', (89, 103))	('PGL2', 'Gene', (29, 33))
7971	19169894	As a result, seven genes were found to be part of a network including matrix metallopeptidase 14 (MMP14), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS1), Fyn-related kinase (FRK), GATA binding protein 2 (GATA2), keratin 8 (KRT8), matrix metallopeptidase 2 (MMP2), and neurotensin (NTS1).	('MMP14', 'Gene', '17387', (98, 103))	('NTS1', 'Gene', (294, 298))	('osteosarcoma viral', 'Disease', (123, 141))	('neurotensin', 'Gene', (281, 292))	('GATA binding protein 2', 'Gene', '14461', (193, 215))	('keratin 8', 'Gene', '16691', (225, 234))	('MMP2', 'Gene', '17390', (270, 274))	('Fyn-related kinase', 'Gene', '14302', (167, 185))	('murine', 'Species', '10090', (116, 122))	('Fyn-related kinase', 'Gene', (167, 185))	('v-fos FBJ', 'Var', (106, 115))	('MMP2', 'Gene', (270, 274))	('GATA2', 'Gene', '14461', (217, 222))	('matrix metallopeptidase 2', 'Gene', '17390', (243, 268))	('MMP14', 'Gene', (98, 103))	('FRK', 'Gene', '14302', (187, 190))	('KRT8', 'Gene', '16691', (236, 240))	('GATA binding protein 2', 'Gene', (193, 215))	('keratin 8', 'Gene', (225, 234))	('FRK', 'Gene', (187, 190))	('osteosarcoma', 'Phenotype', 'HP:0002669', (123, 135))	('KRT8', 'Gene', (236, 240))	('GATA2', 'Gene', (217, 222))	('neurotensin', 'Gene', '67405', (281, 292))	('matrix metallopeptidase 2', 'Gene', (243, 268))	('osteosarcoma viral', 'Disease', 'MESH:D012516', (123, 141))	('NTS1', 'Gene', '67405', (294, 298))
7982	19169894	In these groups, we found that injected MTT cells resulted in liver lesions visible by MRI on day 21 compared to day 30 in mice injected with MPC cells.	('MPC', 'Chemical', '-', (142, 145))	('liver lesions', 'Disease', 'MESH:D017093', (62, 75))	('liver lesions', 'Disease', (62, 75))	('MTT', 'Chemical', '-', (40, 43))	('MTT cells', 'Var', (40, 49))	('mice', 'Species', '10090', (123, 127))
8058	22548972	Among the variants of RCC, clear cell RCC is the main differential diagnosis as it shares several morphologic features with hemangioblastoma.	('hemangioblastoma', 'Disease', (124, 140))	('RCC', 'Disease', (38, 41))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (124, 140))	('variants', 'Var', (10, 18))	('RCC', 'Disease', (22, 25))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('hemangioblastoma', 'Disease', 'MESH:D018325', (124, 140))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))
8112	22303083	Mutations in the susceptibility genes (RET, VHL, SDHD and SDHB) associated with these hereditary syndromes are found in up to 25% of patients thought to have sporadic disease.	('found', 'Reg', (111, 116))	('RET', 'Gene', (39, 42))	('SDHB', 'Gene', (58, 62))	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('patients', 'Species', '9606', (133, 141))	('Mutations', 'Var', (0, 9))	('RET', 'Gene', '5979', (39, 42))	('SDHD', 'Gene', '6392', (49, 53))	('SDHB', 'Gene', '6390', (58, 62))	('SDHD', 'Gene', (49, 53))	('VHL', 'Disease', (44, 47))
8113	22303083	The germline mutation in the SDHD gene identified in this patient is inherited in an autosomal dominant fashion, and it yields a 50% risk of transmission of hereditary paraganglioma to the offspring.	('SDHD', 'Gene', '6392', (29, 33))	('hereditary paraganglioma', 'Disease', (157, 181))	('yields', 'Reg', (120, 126))	('SDHD', 'Gene', (29, 33))	('patient', 'Species', '9606', (58, 65))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (157, 181))	('paraganglioma', 'Phenotype', 'HP:0002668', (168, 181))	('germline mutation', 'Var', (4, 21))	('transmission', 'Reg', (141, 153))
8178	21188160	Genetic disorders involving mutations within the succinate dehydrogenase B and D units (SDHB, SDHD) and the von Hippel-Lindau (VHL) gene places an increased risk in the development of extra-adrenal paragangliomas and adrenal pheochromocytomas, respectively.	('Genetic disorders', 'Disease', (0, 17))	('SDHD', 'Gene', (94, 98))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (225, 242))	('SDHB', 'Gene', '6390', (88, 92))	('VHL', 'Disease', (127, 130))	('extra-adrenal paragangliomas and adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (184, 242))	('SDHB', 'Gene', (88, 92))	('von Hippel-Lindau', 'Gene', (108, 125))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (217, 242))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('Genetic disorders', 'Disease', 'MESH:D030342', (0, 17))	('mutations', 'Var', (28, 37))	('SDHD', 'Gene', '6392', (94, 98))	('paragangliomas', 'Phenotype', 'HP:0002668', (198, 212))	('von Hippel-Lindau', 'Gene', '7428', (108, 125))
8249	33628464	The growing deployment of genetic testing has shown that approximately 30% of pheochromocytoma and paraganglioma (PPGL) patients carry familial pathogenic germline mutations in known PPGL-susceptibility genes.	('paraganglioma', 'Phenotype', 'HP:0002668', (99, 112))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (78, 112))	('PPGL-susceptibility', 'Gene', (183, 202))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (164, 173))
8252	33628464	Eight out of the 16 siblings (50.0%) in the second generation of the reported family pedigree were carriers of the succinate dehydrogenase B:c.574T>C mutation, reflecting the autosomal dominant inheritance risk of paraganglioma and other associated tumors.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('paraganglioma', 'Disease', (214, 227))	('B:c.574T>C', 'SUBSTITUTION', 'None', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('B:c.574T>C', 'Var', (139, 149))	('paraganglioma', 'Disease', 'MESH:D010235', (214, 227))	('paraganglioma', 'Phenotype', 'HP:0002668', (214, 227))	('tumors', 'Disease', (249, 255))
8274	33628464	This revealed a heterozygous pathogenic succinate dehydrogenase B (SDHB) mutation:c.574T>C; p.Cys192Arg (coding reference: NM_00300.2).	('succinate dehydrogenase B', 'Gene', (40, 65))	('succinate dehydrogenase B', 'Gene', '6390', (40, 65))	('mutation:c.574T>C', 'SUBSTITUTION', 'None', (73, 90))	('SDHB', 'Gene', '6390', (67, 71))	('pathogenic', 'Reg', (29, 39))	('mutation:c.574T>C', 'Var', (73, 90))	('SDHB', 'Gene', (67, 71))	('p.Cys192Arg', 'Mutation', 'rs786202732', (92, 103))	('p.Cys192Arg', 'Var', (92, 103))
8275	33628464	As patients with mutations in the SDHB gene have a high risk of other malignancy like papillary thyroid cancer, a neck ultrasound was performed in the patient, which was normal.	('malignancy like papillary thyroid cancer', 'Disease', 'MESH:D000077273', (70, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('patient', 'Species', '9606', (3, 10))	('patient', 'Species', '9606', (151, 158))	('patients', 'Species', '9606', (3, 11))	('SDHB', 'Gene', '6390', (34, 38))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (86, 110))	('SDHB', 'Gene', (34, 38))	('malignancy like papillary thyroid cancer', 'Disease', (70, 110))	('mutations', 'Var', (17, 26))	('thyroid cancer', 'Phenotype', 'HP:0002890', (96, 110))
8293	33628464	Her four children tested negative for the SDHB:c.574T>C mutation.	('children', 'Species', '9606', (9, 17))	('negative', 'NegReg', (25, 33))	('SDHB:c.574T>C', 'SUBSTITUTION', 'None', (42, 55))	('SDHB:c.574T>C', 'Var', (42, 55))
8300	33628464	Eight out of the 16 siblings (50.0%) in the second generation of the reported family pedigree [Figure 1] were carriers of the SDHB:c.574T>C mutation, reflecting the autosomal dominant inheritance risk for paraganglioma and other associated tumors.	('paraganglioma', 'Disease', 'MESH:D010235', (205, 218))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (240, 246))	('SDHB:c.574T>C', 'Var', (126, 139))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('paraganglioma', 'Phenotype', 'HP:0002668', (205, 218))	('SDHB:c.574T>C', 'SUBSTITUTION', 'None', (126, 139))	('paraganglioma', 'Disease', (205, 218))
8358	33383673	Consequently, it was proposed that the blockade of PD-1/PD-L1 interaction could be a means to induce the reacquisition of antitumour activity by T cells.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('interaction', 'Interaction', (62, 73))	('blockade', 'Var', (39, 47))	('PD-1/PD-L1', 'Gene', (51, 61))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))
8375	33383673	Anti-PD-1 and anti-PD-L1 monoclonal antibodies, such as avelumab, are supposed to boost up and enhance said immune response.	('anti-PD-L1', 'Var', (14, 24))	('avelumab', 'Chemical', 'MESH:C000609138', (56, 64))	('boost', 'PosReg', (82, 87))	('Anti-PD-1', 'Var', (0, 9))	('immune response', 'CPA', (108, 123))	('enhance', 'PosReg', (95, 102))
8408	33383673	According to the protocol, participants aged 18 years and older with histologically confirmed unresectable/metastatic adrenocortical carcinoma (ACC), or unresectable malignant PHEO/PGL, are grouped in five different cohorts and receive EO2401 in combination with nivolumab at standard dose.	('nivolumab', 'Chemical', 'MESH:D000077594', (263, 272))	('EO2401', 'Var', (236, 242))	('participants', 'Species', '9606', (27, 39))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('EO2401', 'Chemical', '-', (236, 242))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (118, 142))	('adrenocortical carcinoma', 'Disease', (118, 142))
8409	33383673	The recommended dose of EO2401 is to be found in Cohort 1 and will be administered to the other cohorts of patients, respectively composed by previously treated ACCs, previously untreated ACCs, previously treated PHEO/PGL, and previously untreated PHEO/PGL.	('ACCs', 'Gene', (161, 165))	('ACCs', 'Gene', '84680', (161, 165))	('EO2401', 'Var', (24, 30))	('EO2401', 'Chemical', '-', (24, 30))	('ACCs', 'Gene', '84680', (188, 192))	('patients', 'Species', '9606', (107, 115))	('ACCs', 'Gene', (188, 192))
8463	33383673	As a final point, we should consider that PHEO/PGL patients harboring specific mutations might benefit the most from ICIs therapy.	('benefit', 'PosReg', (95, 102))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (79, 88))
8465	33383673	These mutations are classified in three clinically-relevant subgroups: pseudohypoxia, kinase signaling, and Wnt signaling.	('hypoxia', 'Disease', (77, 84))	('kinase signaling', 'Disease', (86, 102))	('Wnt signaling', 'Disease', (108, 121))	('mutations', 'Var', (6, 15))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
8466	33383673	The pseudohypoxia subgroup includes mutations in a highly significant number of genes, including succinate subunits A, B, C, D, fumarate hydratase, and von Hippel-Lindau tumour suppressor gene, encoding for proteins involved in the cell response induced by conditions of hypoxia.	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (152, 176))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (36, 45))	('hypoxia', 'Disease', 'MESH:D000860', (271, 278))	('von Hippel-Lindau tumour', 'Disease', (152, 176))	('hypoxia', 'Disease', 'MESH:D000860', (10, 17))	('succinate subunits A', 'Gene', (97, 117))	('hypoxia', 'Disease', (271, 278))	('hypoxia', 'Disease', (10, 17))	('fumarate hydratase', 'Gene', (128, 146))
8467	33383673	Of note, mutations in this subgroup of genes, although acting at different metabolic levels and on different substrates, ultimately cause the stabilization of the hypoxia-inducible factor (HIF).	('stabilization', 'MPA', (142, 155))	('mutations', 'Var', (9, 18))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('cause', 'Reg', (132, 137))	('hypoxia', 'Disease', (163, 170))
8469	33383673	Thus, the engagement of PD-1 signaling represents a novel pathway of T-cell suppression promoted by pseudohypoxia, and provides the rational basis for a more effective use of ICIs in the specific subgroup of PHEO/PGL patients bearing the above mentioned pseudohypoxia-related gene mutations.	('T-cell suppression', 'CPA', (69, 87))	('hypoxia', 'Disease', 'MESH:D000860', (260, 267))	('hypoxia', 'Disease', (260, 267))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('mutations', 'Var', (281, 290))	('patients', 'Species', '9606', (217, 225))
8472	30584686	Tumor multifocality with vagus nerve involvement as a phenotypic marker of SDHD mutation in patients with head and neck paragangliomas: A 18F-FDOPA PET/CT study 18F-FDOPA PET/CT was proved to be a highly sensitive imaging method for detecting head and neck paraganglioma (HNPGL).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('neck paraganglioma', 'Disease', 'MESH:D010235', (115, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('SDHD', 'Gene', (75, 79))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (106, 133))	('neck paragangliomas', 'Disease', (115, 134))	('HNPGL', 'Phenotype', 'HP:0002864', (272, 277))	('patients', 'Species', '9606', (92, 100))	('PGL', 'Phenotype', 'HP:0002668', (274, 277))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (138, 147))	('neck paraganglioma', 'Disease', (252, 270))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (106, 134))	('neck paragangliomas', 'Disease', 'MESH:D010235', (115, 134))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (161, 170))	('mutation', 'Var', (80, 88))	('SDHD', 'Gene', '6392', (75, 79))	('neck paraganglioma', 'Disease', 'MESH:D010235', (252, 270))	('paraganglioma', 'Phenotype', 'HP:0002668', (257, 270))	('vagus nerve involvement', 'Phenotype', 'HP:0002886', (25, 48))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (243, 270))	('paragangliomas', 'Phenotype', 'HP:0002668', (120, 134))
8478	30584686	The present study shows that tumor multifocality within the vagus nerve is a phenotypic marker of SDHD mutation.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SDHD', 'Gene', '6392', (98, 102))	('tumor', 'Disease', (29, 34))	('SDHD', 'Gene', (98, 102))	('mutation', 'Var', (103, 111))	('tumor multifocality within the vagus nerve', 'Phenotype', 'HP:0002886', (29, 71))
8482	30584686	The molecular genetics era of HNPGL began in 2000, with the description of the first succinate dehydrogenase subunit D (SDHD) gene mutation (PGL1 syndrome).	('succinate dehydrogenase subunit D', 'Gene', '6392', (85, 118))	('SDHD', 'Gene', '6392', (120, 124))	('PGL', 'Phenotype', 'HP:0002668', (141, 144))	('succinate dehydrogenase subunit D', 'Gene', (85, 118))	('SDHD', 'Gene', (120, 124))	('HNPGL', 'Phenotype', 'HP:0002864', (30, 35))	('PGL', 'Phenotype', 'HP:0002668', (32, 35))	('mutation', 'Var', (131, 139))
8483	30584686	Most of SDHD-mutation carriers that carry mutation from their father (maternal imprinting) will develop HNPGL that could possibly coexist with sympathetic pheochromocytoma and paraganglioma (PPGL).	('PPGL', 'Chemical', '-', (191, 195))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (155, 189))	('SDHD', 'Gene', '6392', (8, 12))	('develop', 'PosReg', (96, 103))	('HNPGL', 'Phenotype', 'HP:0002864', (104, 109))	('SDHD', 'Gene', (8, 12))	('PGL', 'Phenotype', 'HP:0002668', (192, 195))	('PGL', 'Phenotype', 'HP:0002668', (106, 109))	('mutation', 'Var', (42, 50))	('paraganglioma', 'Phenotype', 'HP:0002668', (176, 189))	('HNPGL', 'Disease', (104, 109))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (155, 171))
8484	30584686	Of all the known genetic mutations, SDHD mutations are currently the leading cause of hereditary HNPGLs, followed by SDHB and SDHC mutations.	('mutations', 'Var', (41, 50))	('SDHB', 'Gene', (117, 121))	('SDHC', 'Gene', (126, 130))	('SDHD', 'Gene', (36, 40))	('cause', 'Reg', (77, 82))	('SDHD', 'Gene', '6392', (36, 40))	('hereditary HNPGLs', 'Disease', 'MESH:D030342', (86, 103))	('PGL', 'Phenotype', 'HP:0002668', (99, 102))	('SDHC', 'Gene', '6391', (126, 130))	('HNPGL', 'Phenotype', 'HP:0002864', (97, 102))	('hereditary HNPGLs', 'Disease', (86, 103))	('SDHB', 'Gene', '6390', (117, 121))
8490	30584686	Based on our longstanding experience in 18F-FDOPA imaging and literature, false-positive findings in the head and neck region are seen in very rare situations and mainly be related to thyroid tumors of follicular origin, medullary thyroid carcinoma that can coexist with PPGL in the setting of MEN2 cases and prolactinomas that can be sporadic or related to SDHx mutations.	('SDH', 'Gene', '6390', (358, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('PPGL', 'Chemical', '-', (271, 275))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (40, 49))	('tumors of follicular origin', 'Phenotype', 'HP:0031548', (192, 219))	('mutations', 'Var', (363, 372))	('prolactinomas', 'Disease', (309, 322))	('SDH', 'Gene', (358, 361))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (231, 248))	('thyroid tumors', 'Disease', 'MESH:D013964', (184, 198))	('thyroid carcinoma', 'Disease', (231, 248))	('thyroid tumors', 'Disease', (184, 198))	('prolactinomas', 'Disease', 'MESH:D015175', (309, 322))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (231, 248))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (221, 248))	('PGL', 'Phenotype', 'HP:0002668', (272, 275))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('related', 'Reg', (173, 180))
8493	30584686	Among these patients, only those who fulfilled the following criteria were included: (1) final diagnosis of PGL (2) evaluation by 18F-DOPA PET/CT, and (3) genetic testing for at least germline mutations (including large deletions) in the SDHB, SDHD, and SDHC genes.	('testing', 'Reg', (163, 170))	('SDHB', 'Gene', '6390', (238, 242))	('patients', 'Species', '9606', (12, 20))	('SDHC', 'Gene', (254, 258))	('PGL', 'Phenotype', 'HP:0002668', (108, 111))	('SDHB', 'Gene', (238, 242))	('SDHC', 'Gene', '6391', (254, 258))	('SDHD', 'Gene', (244, 248))	('18F-DOPA', 'Chemical', 'MESH:C043437', (130, 138))	('SDHD', 'Gene', '6392', (244, 248))	('germline mutations', 'Var', (184, 202))
8505	30584686	Based on the clinical presentation and the Endocrine Society Clinical Practice Guideline (Lenders et al, JCEM 2014), the genetic testing of the SDHB (NM_003000.2), SDHC (NM_003001.3), and SDHD (NM_003002.3) genes was performed for all the index cases after that their informed consents were obtained.	('NM_003002.3', 'Var', (194, 205))	('NM_003001.3', 'Var', (170, 181))	('SDHC', 'Gene', (164, 168))	('NM_003000.2', 'Var', (150, 161))	('SDHD', 'Gene', '6392', (188, 192))	('SDHC', 'Gene', '6391', (164, 168))	('SDHD', 'Gene', (188, 192))	('SDHB', 'Gene', '6390', (144, 148))	('SDHB', 'Gene', (144, 148))
8506	30584686	The SDHB/SDHC/SDHD sequence variants were classified as pathogenic/likely pathogenic/variants of uncertain significance (VUS)/likely benign/benign according the ACMG-AMP Standards and guidelines for the interpretation of sequence variants.	('variants', 'Var', (28, 36))	('SDHB', 'Gene', (4, 8))	('ACMG-AMP', 'Chemical', '-', (161, 169))	('SDHD', 'Gene', '6392', (14, 18))	('SDHB', 'Gene', '6390', (4, 8))	('SDHC', 'Gene', (9, 13))	('SDHD', 'Gene', (14, 18))	('SDHC', 'Gene', '6391', (9, 13))
8509	30584686	Logistic regression model was used to find variables that were found to be associated with SDHD mutation status.	('SDHD', 'Gene', (91, 95))	('mutation status', 'Var', (96, 111))	('SDHD', 'Gene', '6392', (91, 95))
8514	30584686	Regarding the PGL associated with the vagus nerve (VP), they were diagnosed in 0% of the SDHB mutation carriers, 86.9% (n = 20) of the SDHD mutation carriers, 12.5% (n = 1) of the SDHC mutation carriers, and 23.1% (n = 15) of the sporadic cases (Table 1, Figure 1).	('SDHD', 'Gene', '6392', (135, 139))	('SDHD', 'Gene', (135, 139))	('mutation', 'Var', (94, 102))	('mutation', 'Var', (140, 148))	('SDHC', 'Gene', (180, 184))	('SDHB', 'Gene', '6390', (89, 93))	('PGL', 'Phenotype', 'HP:0002668', (14, 17))	('VP', 'Chemical', '-', (51, 53))	('SDHC', 'Gene', '6391', (180, 184))	('SDHB', 'Gene', (89, 93))	('VP', 'Phenotype', 'HP:0002886', (51, 53))
8515	30584686	69.5% (n =16) of SDHD mutations carrier patients had multifocal VP, whereas there were only 0%, 12.5% (n = 1), and 3.1% (n = 2) in SDHB, SDHC, and sporadic cases, respectively (Table 2).	('SDHB', 'Gene', '6390', (131, 135))	('SDHC', 'Gene', '6391', (137, 141))	('VP', 'Chemical', '-', (64, 66))	('SDHB', 'Gene', (131, 135))	('patients', 'Species', '9606', (40, 48))	('SDHD', 'Gene', '6392', (17, 21))	('multifocal VP', 'Disease', (53, 66))	('SDHD', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('VP', 'Phenotype', 'HP:0002886', (64, 66))	('SDHC', 'Gene', (137, 141))
8517	30584686	Eleven different variants were identified in SDHD mutation carriers.	('SDHD', 'Gene', (45, 49))	('SDHD', 'Gene', '6392', (45, 49))	('mutation', 'Var', (50, 58))
8518	30584686	Among them, two nucleotidic variants were over represented: c.169+5G>A and c.129G>A, both located in exon 2.	('c.129G>A', 'Var', (75, 83))	('c.129G>A', 'Mutation', 'rs104894308', (75, 83))	('c.169+5G>A', 'Mutation', 'c.169+5G>A', (60, 70))	('c.169+5G>A', 'Var', (60, 70))
8520	30584686	Focusing on the c.129G>A variant, it appears clear that this genotype is more likely to express a phenotype with a mediastinal vagus location (OR = 7.14; P = 5 X 10-21).	('c.129G>A', 'Var', (16, 24))	('express', 'Reg', (88, 95))	('c.129G>A', 'Mutation', 'rs104894308', (16, 24))
8521	30584686	Indeed, among the 104 patients with HNPGL, 6 out the 7 patients with a mediastinal vagus location are patients with SDHD having a c.129G>A variant (Table 3).	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (22, 30))	('SDHD', 'Gene', (116, 120))	('SDHD', 'Gene', '6392', (116, 120))	('patients', 'Species', '9606', (55, 63))	('PGL', 'Phenotype', 'HP:0002668', (38, 41))	('c.129G>A', 'Mutation', 'rs104894308', (130, 138))	('c.129G>A', 'Var', (130, 138))	('HNPGL', 'Phenotype', 'HP:0002864', (36, 41))
8522	30584686	The two most represented variants: c.169+5G>A (n = 6) and c.129G>A (n = 6) have previously been reported in the literature (Cascon, et al.	('c.169+5G>A', 'Mutation', 'c.169+5G>A', (35, 45))	('c.129G>A', 'Mutation', 'rs104894308', (58, 66))	('c.169+5G>A', 'Var', (35, 45))	('c.129G>A', 'Var', (58, 66))
8523	30584686	The c.169+5G>A variant has been described as potentially metastatic.	('metastatic', 'CPA', (57, 67))	('c.169+5G>A', 'Mutation', 'c.169+5G>A', (4, 14))	('c.169+5G>A', 'Var', (4, 14))
8524	30584686	Indeed, in our study, one out of the 6 c.169+5G>A variants (the only one among SDHD variants) presented distant metastasis at diagnosis, (Table 1) confirming that we should consider this variant as a potentially malignant condition.	('SDHD', 'Gene', (79, 83))	('c.169+5G>A', 'Mutation', 'c.169+5G>A', (39, 49))	('distant metastasis', 'CPA', (104, 122))	('SDHD', 'Gene', '6392', (79, 83))	('c.169+5G>A', 'Var', (39, 49))
8526	30584686	Four variants have never been reported in the literature: c.1A>G, c.446-449delinsA, c.64C>T, and c.433-438del (Table 3).	('c.64C>T', 'Var', (84, 91))	('c.1A>G', 'Mutation', 'rs104894307', (58, 64))	('c.433-438del', 'Var', (97, 109))	('c.446-449del', 'DELETION', 'None', (66, 78))	('c.446-449del', 'Var', (66, 78))	('c.433-438del', 'Mutation', 'c.433_438del', (97, 109))	('c.64C>T', 'Mutation', 'rs104894306', (84, 91))
8527	30584686	Ultimately, among the three nonsense mutations coding for truncated proteins: c.129G>A (n = 6), c.325C>T (n = 3), and c.64C>T (n = 1); 100% of them were VP with multifocality (Table 3).	('VP', 'Phenotype', 'HP:0002886', (153, 155))	('c.64C>T', 'Var', (118, 125))	('c.325C>T', 'Var', (96, 104))	('c.129G>A', 'Mutation', 'rs104894308', (78, 86))	('c.129G>A', 'Var', (78, 86))	('c.325C>T', 'Mutation', 'rs1060503770', (96, 104))	('c.64C>T', 'Mutation', 'rs104894306', (118, 125))	('VP', 'Chemical', '-', (153, 155))
8541	30584686	Although subtotal surgical approaches have been developed to limit cranial nerve morbidity, surgical resection of HNPGL may lead to severe, permanent surgery-induced injuries (ie, dysphagia, chronic aspiration, vocal cord paralysis) and may compromise subsequent operations.	('cranial nerve morbidity', 'Phenotype', 'HP:0001291', (67, 90))	('surgical resection', 'Var', (92, 110))	('paralysis', 'Disease', (222, 231))	('dysphagia', 'Disease', (180, 189))	('vocal cord paralysis', 'Phenotype', 'HP:0001605', (211, 231))	('PGL', 'Phenotype', 'HP:0002668', (116, 119))	('paralysis', 'Phenotype', 'HP:0003470', (222, 231))	('HNPGL', 'Phenotype', 'HP:0002864', (114, 119))	('chronic aspiration', 'Disease', (191, 209))	('HNPGL', 'Gene', (114, 119))	('paralysis', 'Disease', 'MESH:D010243', (222, 231))	('dysphagia', 'Phenotype', 'HP:0002015', (180, 189))	('cranial nerve', 'Phenotype', 'HP:0001291', (67, 80))	('aspiration', 'Phenotype', 'HP:0002835', (199, 209))	('lead to', 'Reg', (124, 131))	('dysphagia', 'Disease', 'MESH:D003680', (180, 189))
8544	30584686	As surgical management of HNPGL can be followed by secondarily neurological injuries, the presence of contralateral PGL especially VP may compromise further surgical and radiosurgical intervention.	('neurological injuries', 'Disease', (63, 84))	('VP', 'Phenotype', 'HP:0002886', (131, 133))	('presence', 'Var', (90, 98))	('HNPGL', 'Disease', (26, 31))	('PGL', 'Phenotype', 'HP:0002668', (116, 119))	('PGL', 'Phenotype', 'HP:0002668', (28, 31))	('HNPGL', 'Phenotype', 'HP:0002864', (26, 31))	('VP', 'Chemical', '-', (131, 133))	('neurological injuries', 'Disease', 'MESH:D009422', (63, 84))	('compromise', 'NegReg', (138, 148))
8562	30584686	Although, HNPGL can be related to SDH mutations, they are often sporadic.	('SDH', 'Gene', (34, 37))	('HNPGL', 'Disease', (10, 15))	('mutations', 'Var', (38, 47))	('PGL', 'Phenotype', 'HP:0002668', (12, 15))	('HNPGL', 'Phenotype', 'HP:0002864', (10, 15))	('SDH', 'Gene', '6390', (34, 37))
8600	32178651	During admission, her vital signs showed slight elevation of blood pressure (140\90-160\110) mmHg, thus 24-h urine metanephrine and normetanephrine were requested and the results revealed normal values.	('blood pressure', 'MPA', (61, 75))	('metanephrine', 'Chemical', 'MESH:D008676', (115, 127))	('metanephrine', 'Chemical', 'MESH:D008676', (135, 147))	('140\\90-160\\110', 'Var', (77, 91))	('elevation', 'PosReg', (48, 57))	('elevation of blood pressure', 'Phenotype', 'HP:0032263', (48, 75))	('normetanephrine', 'Chemical', 'MESH:D009647', (132, 147))
8610	32178651	PGLs tend to be sporadic and could be hereditary in approximately 30% of cases including germline mutations in Von Hippel-Lindau syndrome, succinate dehydrogenase subunits SDHx, RET, neurofibromatosis type 1 and multiple endocrine neoplasia (MEN2).	('RET', 'Gene', (178, 181))	('RET', 'Gene', '5979', (178, 181))	('multiple endocrine neoplasia', 'Disease', (212, 240))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (183, 200))	('PGL', 'Phenotype', 'HP:0002668', (0, 3))	('Von Hippel-Lindau syndrome', 'Disease', (111, 137))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (221, 240))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (111, 137))	('mutations', 'Var', (98, 107))	('neurofibromatosis type 1', 'Gene', '4763', (183, 207))	('neoplasia', 'Phenotype', 'HP:0002664', (231, 240))	('PGL', 'Disease', (0, 3))	('neurofibromatosis type 1', 'Gene', (183, 207))	('SDHx', 'Chemical', '-', (172, 176))	('SDHx', 'Gene', (172, 176))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (212, 240))	('PGL', 'Disease', 'MESH:D010235', (0, 3))
8611	32178651	There is obvious correlation between SDHB, SDHD mutations and PGLs.	('PGL', 'Disease', 'MESH:D010235', (62, 65))	('SDHD', 'Gene', '6392', (43, 47))	('SDHB', 'Gene', '6390', (37, 41))	('PGL', 'Phenotype', 'HP:0002668', (62, 65))	('SDHD', 'Gene', (43, 47))	('PGL', 'Disease', (62, 65))	('SDHB', 'Gene', (37, 41))	('mutations', 'Var', (48, 57))
8618	32178651	Physical examination showed slightly pale patient, pulse rate about (90-110) beat per minute (bpm) and blood pressure (BP) about (140\90-160\110) mmHg.	('patient', 'Species', '9606', (42, 49))	('blood pressure', 'MPA', (103, 117))	('140\\90-160\\110', 'Var', (130, 144))	('pulse rate', 'MPA', (51, 61))
8654	32178651	Biochemically silent PGL in patients with SDHB mutation is a potential other cause for normal plasma or urinary fractionated metanephrines.	('silent', 'NegReg', (14, 20))	('urinary fractionated metanephrines', 'MPA', (104, 138))	('PGL', 'Phenotype', 'HP:0002668', (21, 24))	('mutation', 'Var', (47, 55))	('SDHB', 'Gene', '6390', (42, 46))	('PGL', 'Disease', (21, 24))	('metanephrines', 'Chemical', 'MESH:D008676', (125, 138))	('patients', 'Species', '9606', (28, 36))	('PGL', 'Disease', 'MESH:D010235', (21, 24))	('SDHB', 'Gene', (42, 46))
8656	32178651	Consequently, such tumors with SDHB mutation can increase in size and manifest with symptoms of surrounding organ compression rather than the classic symptoms of catecholamine hypersecretion.	('tumors', 'Disease', (19, 25))	('increase', 'PosReg', (49, 57))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('SDHB', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('catecholamine', 'Chemical', 'MESH:D002395', (162, 175))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('SDHB', 'Gene', '6390', (31, 35))	('mutation', 'Var', (36, 44))
8669	32178651	As 24-h urine metanephrine and normetanephrine were normal in our large sized PGL, SDHB mutation should be assessed.	('mutation', 'Var', (88, 96))	('SDHB', 'Gene', (83, 87))	('PGL', 'Phenotype', 'HP:0002668', (78, 81))	('metanephrine', 'Chemical', 'MESH:D008676', (14, 26))	('metanephrine', 'Chemical', 'MESH:D008676', (34, 46))	('PGL', 'Disease', (78, 81))	('normetanephrine', 'Chemical', 'MESH:D009647', (31, 46))	('SDHB', 'Gene', '6390', (83, 87))	('PGL', 'Disease', 'MESH:D010235', (78, 81))
8679	31142060	A pseudohypoxic transcriptional signature characterizes pheochromocytomas and paragangliomas (PPGLs) of the cluster I, mainly represented by tumors with mutations in von Hippel-Lindau (VHL), endothelial PAS domain-containing protein 1 (EPAS1), or succinate dehydrogenase (SDH) subunit genes.	('SDH', 'Gene', '6390', (272, 275))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (56, 73))	('endothelial PAS domain-containing protein 1', 'Gene', (191, 234))	('paragangliomas', 'Phenotype', 'HP:0002668', (78, 92))	('succinate dehydrogenase', 'Gene', (247, 270))	('succinate dehydrogenase', 'Gene', '6390', (247, 270))	('EPAS1', 'Gene', (236, 241))	('mutations', 'Var', (153, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('PPGLs', 'Chemical', '-', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('SDH', 'Gene', (272, 275))	('endothelial PAS domain-containing protein 1', 'Gene', '2034', (191, 234))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (56, 92))	('pseudohypoxic transcriptional signature', 'MPA', (2, 41))
8680	31142060	The aim of this study was to investigate a possible association between underlying tumor driver mutations and COX-2 in PPGLs.	('PPGLs', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('COX-2', 'Gene', (110, 115))	('tumor', 'Disease', (83, 88))	('PPGLs', 'Chemical', '-', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('mutations', 'Var', (96, 105))
8681	31142060	COX-2 gene expression and immunoreactivity were examined in clinical specimens with documented mutations, as well as in spheroids and allografts derived from mouse pheochromocytoma (MPC) cells.	('pheochromocytoma', 'Disease', 'MESH:D010673', (164, 180))	('mouse', 'Species', '10090', (158, 163))	('clinical', 'Species', '191496', (60, 68))	('pheochromocytoma', 'Disease', (164, 180))	('mutations', 'Var', (95, 104))	('COX-2', 'Gene', (0, 5))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (164, 180))
8687	31142060	Over the past few decades, advances in genetic testing have substantially facilitated the identification of germline and somatic mutations in tumor susceptibility genes in about 60% of adrenal pheochromocytomas and their extra adrenal counterparts, paragangliomas (summarized as PPGLs).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (193, 209))	('tumor', 'Disease', (142, 147))	('mutations', 'Var', (129, 138))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (193, 210))	('paragangliomas', 'Disease', (249, 263))	('paragangliomas', 'Disease', 'MESH:D010235', (249, 263))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (185, 210))	('PPGLs', 'Chemical', '-', (279, 284))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (185, 210))	('paragangliomas', 'Phenotype', 'HP:0002668', (249, 263))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('adrenal pheochromocytomas', 'Disease', (185, 210))
8688	31142060	Gain-of-function mutations in proto-oncogenes such as rearranged during transfection (RET; germline or somatic), endothelial per-arnt-sim domain-containing protein 1 (EPAS1; somatic), and Harvey rat sarcoma viral oncogene homolog (HRAS; somatic); and loss-of-function mutations in tumor suppressor genes such as von Hippel-Lindau (VHL; germline or somatic), neurofibromin 1 (NF1; germline or somatic), transmembrane protein 127 (TMEM127; germline), and myc-associated factor X (MAX, germline or somatic), as well as mutations in all four succinate dehydrogenase subunits (SDHD, SDHC, SDHB, and SDHA; germline) and SDH assembly factor 2 (SDHAF2; germline) have been implicated in the tumorigenesis of PPGLs.	('PPGLs', 'Chemical', '-', (700, 705))	('Gain-of-function', 'PosReg', (0, 16))	('MAX', 'Gene', '60661', (478, 481))	('SDHC', 'Gene', (578, 582))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', (281, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('mutations', 'Var', (516, 525))	('MAX', 'Gene', (478, 481))	('SDHD', 'Gene', (572, 576))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('SDHA', 'Gene', (594, 598))	('mutations', 'Var', (268, 277))	('tumor', 'Disease', (683, 688))	('SDH assembly factor 2', 'Gene', '361726', (614, 635))	('transmembrane protein 127', 'Gene', (402, 427))	('myc-associated factor X', 'Gene', '60661', (453, 476))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('rat', 'Species', '10116', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (683, 688))	('transmembrane protein 127', 'Gene', '311405', (402, 427))	('myc-associated factor X', 'Gene', (453, 476))	('SDHB', 'Gene', (584, 588))	('succinate dehydrogenase subunits', 'Gene', (538, 570))	('PPGLs', 'Disease', (700, 705))	('neurofibromin 1', 'Gene', '24592', (358, 373))	('loss-of-function', 'NegReg', (251, 267))	('implicated', 'Reg', (665, 675))	('neurofibromin 1', 'Gene', (358, 373))	('SDH assembly factor 2', 'Gene', (614, 635))	('succinate dehydrogenase subunits', 'Gene', '363061', (538, 570))	('sarcoma', 'Disease', 'MESH:D012509', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (683, 688))	('sarcoma', 'Disease', (199, 206))
8690	31142060	Gene expression profiling provided the basis for classifying PPGLs according to their main transcriptional signatures underlying the aforementioned mutations: cluster I presents with activation of pseudohypoxic signaling pathways and includes mainly VHL-, EPAS1-, and SDHx-mutant cases; cluster II is enriched in kinase receptor signaling pathways and is comprised of RET-, NF1-, TMEM127-, MAX-, and HRAS-mutant cases.	('pseudohypoxic signaling pathways', 'Pathway', (197, 229))	('MAX', 'Gene', '60661', (390, 393))	('mutations', 'Var', (148, 157))	('activation', 'PosReg', (183, 193))	('PPGLs', 'Chemical', '-', (61, 66))	('SDHx-mutant', 'Gene', (268, 279))	('SDHx-mutant', 'Var', (268, 279))	('MAX', 'Gene', (390, 393))	('SDHx', 'Chemical', '-', (268, 272))	('VHL-', 'Gene', (250, 254))
8697	31142060	Endoradiotherapy, e.g., with [177Lu]Lu-DOTA-(Tyr3)octreotate (177Lu-DOTA-TATE) is currently investigated as a treatment option for inoperable or metastatic PPGLs, showing promising effects, but sometimes incomplete tumor remission in clinics as well as in preclinical PPGL models.	('[177Lu]Lu-DOTA-(Tyr3)octreotate', 'Chemical', '-', (29, 60))	('177Lu-DOTA-TATE', 'Chemical', 'MESH:C447941', (62, 77))	('PPGLs', 'Chemical', '-', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('clinical', 'Species', '191496', (259, 267))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PPGLs', 'Disease', (156, 161))	('tumor', 'Disease', (215, 220))	('[177Lu]Lu-DOTA-', 'Var', (29, 44))
8704	31142060	Furthermore, we characterized COX-2 immunoreactivity in tumor spheroids and allografts derived from mouse pheochromocytoma (MPC) cells with a heterozygous Nf1 knockout in order to assess the usefulness of these models for preclinical testing of COX-2-targeting adjuvant and, in particular, radiosensitizing treatments.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mouse', 'Species', '10090', (100, 105))	('Nf1', 'Gene', (155, 158))	('tumor', 'Disease', (56, 61))	('clinical', 'Species', '191496', (225, 233))	('pheochromocytoma', 'Disease', (106, 122))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (106, 122))	('Nf1', 'Gene', '18015', (155, 158))	('pheochromocytoma', 'Disease', 'MESH:D010673', (106, 122))	('knockout', 'Var', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
8705	31142060	COX-2 gene expression data were extracted from gene expression arrays of 70 PPGL samples with documented mutations in tumor susceptibility genes (Table 1).	('mutations', 'Var', (105, 114))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))
8707	31142060	Most of the tumors carried mutations in SDHx (23% comprising 5 SDHD, 2 SDHC, and 9 SDHB, cases) and RET (23%) followed by VHL (21%), EPAS1 (16%), HRAS (11%), and NF1 (5.7%).	('mutations', 'Var', (27, 36))	('SDHx', 'Chemical', '-', (40, 44))	('SDHx', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
8715	31142060	PPGLs carrying a VHL mutation showed the highest COX-2 expression (0.30 +- 0.28), followed by cases with SDHx (-0.13 +- 0.22), EPAS1 (-0.25 +- 0.13), HRAS (-0.55 +- 0.12), RET (-0.68 +- 0.14), and NF1 (-0.96 +- 0.16) mutations (Figure 1).	('SDHx', 'Chemical', '-', (105, 109))	('PPGLs', 'Chemical', '-', (0, 5))	('mutation', 'Var', (21, 29))	('expression', 'MPA', (55, 65))	('COX-2', 'Enzyme', (49, 54))	('VHL', 'Gene', (17, 20))
8721	31142060	This series included 96 PPGLs with a clinically documented mutation in tumor susceptibility genes (Table 2) and reflects the expected age, location, and metastatic disease, according to the mutations involved.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PPGLs', 'Chemical', '-', (24, 29))	('clinical', 'Species', '191496', (37, 45))	('mutation', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
8723	31142060	Most of the cases carried a mutation in SDHx (41% comprising 18 SDHD, 3 SDHC, 9 SDHB, 5 SDHA, and 4 SDHAF2 cases) followed by NF1 (22%), VHL (15%), RET (9.4%), EPAS1 (7.3%), and HRAS (6.3%).	('SDHx', 'Chemical', '-', (40, 44))	('mutation', 'Var', (28, 36))	('SDHx', 'Gene', (40, 44))
8725	31142060	Tumor diameters were significantly smaller in the SDHx subgroup (3.9 cm) and significantly higher in the RET subgroup (7.2 cm) compared to cases with other genetic backgrounds.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('higher', 'PosReg', (91, 97))	('smaller', 'NegReg', (35, 42))	('SDHx', 'Var', (50, 54))	('Tumor diameters', 'CPA', (0, 15))	('SDHx', 'Chemical', '-', (50, 54))
8735	31142060	In tissue samples with different genetic backgrounds, a trend was observed with highest COX-2 immunoreactivity in PPGLs due to VHL mutations (36% strong, 43% moderate), followed by NF1 (33% strong, 43% moderate), SDHx (23% strong, 41% moderate), HRAS (17% strong, 33% moderate), EPAS1 (14% strong, 29% moderate), and RET (all samples negative or weak) (Figure 3).	('mutations', 'Var', (131, 140))	('highest', 'PosReg', (80, 87))	('rat', 'Species', '10116', (162, 165))	('PPGLs', 'Chemical', '-', (114, 119))	('immunoreactivity', 'MPA', (94, 110))	('rat', 'Species', '10116', (306, 309))	('rat', 'Species', '10116', (239, 242))	('VHL', 'Gene', (127, 130))	('SDHx', 'Chemical', '-', (213, 217))	('COX-2', 'Enzyme', (88, 93))	('rat', 'Species', '10116', (206, 209))	('rat', 'Species', '10116', (272, 275))
8737	31142060	However, due to higher numbers of SDHD-mutant cases compared to the other subtypes, multiple regression analyses (Table S2) taking also into account the sex of the patients showed a significant positive relationship between SDHD mutation and COX-2 immunoreactivity (r = 0.867, p <= 0.001).	('mutation', 'Var', (229, 237))	('positive', 'PosReg', (194, 202))	('immunoreactivity', 'MPA', (248, 264))	('SDHD-mutant', 'Gene', (34, 45))	('SDHD', 'Gene', (224, 228))	('COX-2', 'Enzyme', (242, 247))	('patients', 'Species', '9606', (164, 172))
8741	31142060	Tumors with mutations in SDHx showed the highest proportion of COX-2 immunoreactivity with stromal cells involved (72%, pattern B+C), followed by VHL (45%, pattern B only), NF1 (38%, pattern B+C), HRAS (33%, pattern B only), and EPAS1 (0%).	('immunoreactivity', 'MPA', (69, 85))	('COX-2', 'Enzyme', (63, 68))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (12, 21))	('SDHx', 'Gene', (25, 29))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SDHx', 'Chemical', '-', (25, 29))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
8742	31142060	Pearson correlation showed a significant positive relationship between SDHx mutations and COX-2 immunoreactivity with stromal cells involved (r = 0.266, p = 0.009).	('mutations', 'Var', (76, 85))	('COX-2', 'Gene', (90, 95))	('SDHx', 'Chemical', '-', (71, 75))	('SDHx', 'Gene', (71, 75))	('positive', 'PosReg', (41, 49))	('immunoreactivity', 'MPA', (96, 112))
8743	31142060	We further assessed the COX-2 status of a commonly used preclinical model of mouse pheochromocytoma (MPC) cells with heterozygous Nf1 knockout.	('Nf1', 'Gene', (130, 133))	('knockout', 'Var', (134, 142))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))	('Nf1', 'Gene', '18015', (130, 133))	('pheochromocytoma', 'Disease', (83, 99))	('mouse', 'Species', '10090', (77, 82))	('clinical', 'Species', '191496', (59, 67))	('pheochromocytoma', 'Disease', 'MESH:D010673', (83, 99))
8746	31142060	Endoradiotherapy, e.g., with 177Lu-DOTA-TATE is currently investigated as a treatment option for inoperable or metastatic PPGLs, showing promising effects, but sometimes incomplete tumor remission in clinics as well as in preclinical models.	('tumor', 'Disease', (181, 186))	('PPGLs', 'Chemical', '-', (122, 127))	('clinical', 'Species', '191496', (225, 233))	('177Lu-DOTA-TATE', 'Var', (29, 44))	('177Lu-DOTA-TATE', 'Chemical', 'MESH:C447941', (29, 44))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('PPGLs', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
8747	31142060	Inhibition of COX-2 is considered a viable radiosensitization strategy.	('rat', 'Species', '10116', (64, 67))	('Inhibition', 'Var', (0, 10))	('COX-2', 'Gene', (14, 19))
8749	31142060	Expression of COX-2 was assessed on mRNA or protein level in two separate cohorts of PPGL patients with known tumor driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('PPGL', 'Gene', (85, 89))	('rat', 'Species', '10116', (69, 72))	('mutations', 'Var', (123, 132))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
8755	31142060	Amongst others, intratumoral differences in normoxic/hypoxic conditions, systemic chemotherapy, oxidative stress, or even tobacco smoking can interfere with COX-2 levels on gene expression and protein level, possibly masking a potential association with the pseudohypoxic signature of cluster I PPGLs.	('hypoxic conditions', 'Disease', 'MESH:D009135', (53, 71))	('tumor', 'Disease', (21, 26))	('tobacco', 'Species', '4097', (122, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('hypoxic conditions', 'Disease', (53, 71))	('PPGLs', 'Chemical', '-', (295, 300))	('rat', 'Species', '10116', (19, 22))	('COX-2 levels', 'MPA', (157, 169))	('differences', 'Var', (29, 40))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('interfere', 'NegReg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
8756	31142060	In cluster I PPGLs with loss-of-function mutations in VHL and SDHx, pseudohypoxic transcriptional phenotypes may contribute to COX-2 induction on gene expression and protein level.	('mutations', 'Var', (41, 50))	('VHL', 'Gene', (54, 57))	('loss-of-function', 'NegReg', (24, 40))	('induction', 'MPA', (133, 142))	('PPGLs', 'Chemical', '-', (13, 18))	('SDHx', 'Gene', (62, 66))	('pseudohypoxic transcriptional phenotypes', 'MPA', (68, 108))	('SDHx', 'Chemical', '-', (62, 66))	('COX-2', 'Gene', (127, 132))
8757	31142060	Functional defects of VHL, an E3 ubiquitin ligase, directly impair ubiquitin labeling of hypoxia-inducible factors (HIF-alpha) for regular proteasomal degradation.	('impair', 'NegReg', (60, 66))	('defects', 'Var', (11, 18))	('VHL', 'Gene', (22, 25))	('hypoxia', 'Disease', (89, 96))	('hypoxia', 'Disease', 'MESH:D000860', (89, 96))	('ubiquitin labeling of', 'MPA', (67, 88))	('regular proteasomal degradation', 'MPA', (131, 162))
8758	31142060	Functional defects of SDH indirectly impair ubiquitin-labeling of HIF-alpha caused by intracellular accumulation of succinate, an intrinsic inhibitor of prolyl hydroxylases.	('defects', 'Var', (11, 18))	('ubiquitin-labeling', 'MPA', (44, 62))	('intracellular accumulation of succinate', 'MPA', (86, 125))	('SDH', 'Gene', '6390', (22, 25))	('HIF-alpha', 'Protein', (66, 75))	('succinate', 'Chemical', 'MESH:D019802', (116, 125))	('impair', 'NegReg', (37, 43))	('SDH', 'Gene', (22, 25))
8759	31142060	Therefore, both VHL and SDH defects are associated with enhanced HIF-alpha signaling even under normoxic conditions, a metabolic state referred to as pseudohypoxia.	('defects', 'Var', (28, 35))	('SDH', 'Gene', '6390', (24, 27))	('VHL', 'Gene', (16, 19))	('pseudohypoxia', 'Disease', (150, 163))	('enhanced', 'PosReg', (56, 64))	('SDH', 'Gene', (24, 27))	('HIF-alpha signaling', 'MPA', (65, 84))	('pseudohypoxia', 'Disease', 'None', (150, 163))
8761	31142060	COX-2 mRNA levels as well as the percentage of moderate and high COX-2 immunoreactivity tended to be lower among cases carrying a gain-of function mutation in EPAS1, encoding the HIF-2alpha protein, compared to VHL- and SDHx-mutant cases.	('gain-of function', 'PosReg', (130, 146))	('HIF-2alpha', 'Gene', '2034', (179, 189))	('COX-2 mRNA levels', 'MPA', (0, 17))	('mutation', 'Var', (147, 155))	('lower', 'NegReg', (101, 106))	('SDHx', 'Chemical', '-', (220, 224))	('EPAS1', 'Gene', (159, 164))	('HIF-2alpha', 'Gene', (179, 189))	('rat', 'Species', '10116', (51, 54))
8763	31142060	In cluster II PPGLs with loss-of-function mutations in NF1 gene, the trend for a relatively high COX-2 immunoreactivity is consistent with another report on elevated COX-2 and prostaglandin E2 (PGE2) levels in NF1 malignant peripheral nerve sheath tumors.	('sheath tumors', 'Disease', (241, 254))	('high', 'PosReg', (92, 96))	('COX-2 immunoreactivity', 'MPA', (97, 119))	('loss-of-function', 'NegReg', (25, 41))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (214, 254))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('elevated', 'PosReg', (157, 165))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (176, 192))	('PPGLs', 'Chemical', '-', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('sheath tumors', 'Disease', 'MESH:D010524', (241, 254))	('NF1', 'Gene', (55, 58))	('mutations', 'Var', (42, 51))	('PGE2', 'Chemical', 'MESH:D015232', (194, 198))
8766	31142060	The lack of high COX-2 mRNA in the gene expression cohort might be due to the low number of NF1-mutant cases in this particular set of tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('NF1-mutant', 'Gene', (92, 102))	('NF1-mutant', 'Var', (92, 102))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
8767	31142060	Whether there is a relationship between germ line or somatic NF1 mutations and different COX-2 levels in PPGLs remains to be investigated.	('PPGLs', 'Chemical', '-', (105, 110))	('COX-2 levels', 'MPA', (89, 101))	('mutations', 'Var', (65, 74))	('NF1', 'Gene', (61, 64))
8768	31142060	In accordance with the observations in clinical PPGL samples, COX-2 immunoreactivity was also high in spheroids and subcutaneous allografts derived from mouse pheochromocytoma (MPC) cells with a heterozygous Nf1 knockout.	('COX-2', 'Gene', (62, 67))	('high', 'PosReg', (94, 98))	('pheochromocytoma', 'Disease', 'MESH:D010673', (159, 175))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (159, 175))	('Nf1', 'Gene', '18015', (208, 211))	('knockout', 'Var', (212, 220))	('clinical', 'Species', '191496', (39, 47))	('immunoreactivity', 'MPA', (68, 84))	('mouse', 'Species', '10090', (153, 158))	('Nf1', 'Gene', (208, 211))	('pheochromocytoma', 'Disease', (159, 175))
8770	31142060	Since we did not find a significant relationship between tumor driver mutations and COX-2 in clinical PPGL samples, molecular imaging could be applied in a personalized approach to pre-estimate whether a tumor is susceptible to COX-2-targeted treatment.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('clinical', 'Species', '191496', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
8773	31142060	In the case of HRAS and RET mutations, trends for lower COX-2 mRNA levels in PPGLs are in agreement with COX-2 immunoreactivity.	('lower', 'NegReg', (50, 55))	('mutations', 'Var', (28, 37))	('PPGLs', 'Chemical', '-', (77, 82))	('COX-2 mRNA levels', 'MPA', (56, 73))
8778	31142060	Significantly higher COX-2 mRNA levels in head and neck PPGLs compared to other tumor locations is related to the fact that all head and neck PPGLs in this series carried an SDHD mutation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('COX-2 mRNA levels', 'MPA', (21, 38))	('mutation', 'Var', (179, 187))	('tumor', 'Disease', (80, 85))	('SDHD', 'Gene', (174, 178))	('PPGLs', 'Chemical', '-', (56, 61))	('PPGLs', 'Chemical', '-', (142, 147))	('higher', 'PosReg', (14, 20))
8781	31142060	In our tissue series, head and neck PPGLs comprised of cases with different tumor driver mutations explaining why similar effects on COX-2 were not detected in this series.	('PPGLs', 'Chemical', '-', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
8787	31142060	A very strong relationship between both tumor COX-2 expression and tumor-to-stromal COX-2 ratio has been shown to be highly correlated with response to chemotherapy while, high COX-2 expression in the stroma was significantly associated with better survival, but failed to directly correlate with response to treatment.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('COX-2', 'Gene', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('expression', 'MPA', (183, 193))	('high', 'Var', (172, 176))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('better', 'PosReg', (242, 248))	('rat', 'Species', '10116', (90, 93))
8830	31368675	Among these, mutations in the subunits of succinate dehydrogenase complex (SDH) are the most common, causing around half of familial PPGL cases.	('succinate dehydrogenase', 'Gene', (42, 65))	('common', 'Reg', (93, 99))	('succinate dehydrogenase', 'Gene', '6390', (42, 65))	('SDH', 'Gene', '6390', (75, 78))	('causing', 'Reg', (101, 108))	('familial PPGL', 'Disease', (124, 137))	('mutations', 'Var', (13, 22))	('SDH', 'Gene', (75, 78))
8831	31368675	Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation.	('mutations', 'Var', (63, 72))	('SDHA', 'Gene', '6389', (142, 146))	('SDHD', 'Disease', 'None', (50, 54))	('variants', 'Var', (126, 134))	('SDHB', 'Gene', (35, 39))	('SDHC', 'Gene', (41, 45))	('SDHA', 'Gene', (142, 146))	('SDHC', 'Gene', '6391', (41, 45))	('SDHD', 'Disease', (50, 54))	('PPGLs', 'Chemical', '-', (14, 19))	('SDHB', 'Gene', '6390', (35, 39))	('linked', 'Reg', (165, 171))
8832	31368675	Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants were identified retrospectively.	('SDHA', 'Gene', '6389', (103, 107))	('SDHA', 'Gene', (103, 107))	('variants', 'Var', (108, 116))
8833	31368675	We report the case of an asymptomatic suspected carotid body tumour found during surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant.	('SDHA', 'Gene', (165, 169))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('carotid body tumour', 'Phenotype', 'HP:0002668', (48, 67))	('tumour', 'Disease', (61, 67))	('variant', 'Var', (181, 188))	('SDHA', 'Gene', '6389', (165, 169))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
8834	31368675	To our knowledge, this is the first screen that detected PPGL found in a previously identified SDHA pathogenic variant carrier, during surveillance imaging.	('SDHA', 'Gene', (95, 99))	('variant', 'Var', (111, 118))	('SDHA', 'Gene', '6389', (95, 99))	('PPGL', 'Gene', (57, 61))
8835	31368675	This finding supports the use of cascade genetic testing and surveillance screening in all carriers of a pathogenic SDHA variant.	('variant', 'Var', (121, 128))	('carriers', 'Reg', (91, 99))	('pathogenic', 'Reg', (105, 115))	('SDHA', 'Gene', '6389', (116, 120))	('SDHA', 'Gene', (116, 120))
8836	31368675	SDH mutations are important causes of PPGL disease.	('SDH', 'Gene', (0, 3))	('causes', 'Reg', (28, 34))	('PPGL disease', 'Disease', (38, 50))	('mutations', 'Var', (4, 13))	('SDH', 'Gene', '6390', (0, 3))
8840	31368675	Surveillance screening for SDH-related disease should be performed in identified carriers of a pathogenic SDHA variant.	('SDHA', 'Gene', (106, 110))	('variant', 'Var', (111, 118))	('SDH', 'Gene', (106, 109))	('pathogenic', 'Reg', (95, 105))	('SDH', 'Gene', (27, 30))	('SDHA', 'Gene', '6389', (106, 110))	('SDH', 'Gene', '6390', (27, 30))	('SDH', 'Gene', '6390', (106, 109))
8842	31368675	Mutations in genes that encode this complex have been associated with familial paraganglioma syndromes since 2000.	('familial paraganglioma syndromes', 'Disease', (70, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('Mutations', 'Var', (0, 9))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (70, 102))	('associated', 'Reg', (54, 64))
8843	31368675	Mutations in SDHA subunit, however, have only more recently been linked to causing paraganglioma disease.	('linked', 'Reg', (65, 71))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('paraganglioma disease', 'Disease', (83, 104))	('SDHA', 'Gene', '6389', (13, 17))	('Mutations', 'Var', (0, 9))	('paraganglioma disease', 'Disease', 'MESH:D010235', (83, 104))	('SDHA', 'Gene', (13, 17))
8844	31368675	All the cases described in SDHA mutation carriers have occurred in symptomatic index cases, following which the genetic variant was identified.	('SDHA', 'Gene', '6389', (27, 31))	('mutation', 'Var', (32, 40))	('SDHA', 'Gene', (27, 31))
8845	31368675	We report the first case of a paraganglioma being identified in an asymptomatic SDHA mutation carrier on their first surveillance screening, which highlights the importance that asymptomatic relatives should undergo surveillance screening.	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('SDHA', 'Gene', '6389', (80, 84))	('paraganglioma', 'Disease', (30, 43))	('mutation', 'Var', (85, 93))	('SDHA', 'Gene', (80, 84))	('paraganglioma', 'Disease', 'MESH:D010235', (30, 43))
8846	31368675	A 72-year-old female was referred to the endocrinology service following the identification of a pathogenic germline variant in the SDHA gene (c.91C>T, p.Arg31*) as part of a genetic panel for cardiomyopathy.	('p.Arg31*', 'Mutation', 'rs142441643', (152, 160))	('c.91C>T', 'Mutation', 'rs142441643', (143, 150))	('c.91C>T', 'Var', (143, 150))	('pathogenic', 'Reg', (97, 107))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (193, 207))	('cardiomyopathy', 'Disease', 'MESH:D009202', (193, 207))	('SDHA', 'Gene', (132, 136))	('p.Arg31*', 'Var', (152, 160))	('cardiomyopathy', 'Disease', (193, 207))	('SDHA', 'Gene', '6389', (132, 136))
8850	31368675	At this time a 218 gene cardiomyopathy genetic panel was performed, which included the SDHA gene due to reports of neonatal isolated dilated cardiomyopathy in certain SDHA variants.	('SDHA', 'Gene', (167, 171))	('dilated cardiomyopathy', 'Disease', 'MESH:D002311', (133, 155))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (141, 155))	('cardiomyopathy', 'Disease', 'MESH:D009202', (141, 155))	('dilated cardiomyopathy', 'Disease', (133, 155))	('SDHA', 'Gene', (87, 91))	('neonatal', 'Disease', (115, 123))	('cardiomyopathy', 'Disease', (24, 38))	('variants', 'Var', (172, 180))	('dilated cardiomyopathy', 'Phenotype', 'HP:0001644', (133, 155))	('SDHA', 'Gene', '6389', (167, 171))	('cardiomyopathy', 'Disease', (141, 155))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (24, 38))	('SDHA', 'Gene', '6389', (87, 91))	('cardiomyopathy', 'Disease', 'MESH:D009202', (24, 38))
8851	31368675	The pathogenic variant in the SDHA gene was subsequently identified, with all other genetic mutations negative.	('variant', 'Var', (15, 22))	('pathogenic', 'Reg', (4, 14))	('SDHA', 'Gene', '6389', (30, 34))	('SDHA', 'Gene', (30, 34))
8856	31368675	On identification of an SDH mutation all patients are reviewed in clinic and biochemistry is sent (plasma or 24 h urine metanephrines).	('metanephrines', 'Chemical', 'MESH:D008676', (120, 133))	('SDH', 'Gene', '6390', (24, 27))	('patients', 'Species', '9606', (41, 49))	('mutation', 'Var', (28, 36))	('SDH', 'Gene', (24, 27))
8867	31368675	If positive for the pathogenic variant, they will be entered into our SDH screening programme.	('variant', 'Var', (31, 38))	('SDH', 'Gene', '6390', (70, 73))	('positive', 'Reg', (3, 11))	('SDH', 'Gene', (70, 73))
8868	31368675	It is now widely accepted that patients who carry SDHB, SDHC and SDHD pathogenic variants should undergo surveillance screening.	('SDHD', 'Disease', (65, 69))	('SDHB', 'Gene', (50, 54))	('SDHC', 'Gene', (56, 60))	('patients', 'Species', '9606', (31, 39))	('SDHC', 'Gene', '6391', (56, 60))	('SDHD', 'Disease', 'None', (65, 69))	('variants', 'Var', (81, 89))	('SDHB', 'Gene', '6390', (50, 54))
8871	31368675	SDHA mutations are less common than SDHB and SDHD mutations and therefore there are fewer reported cases and a limited understanding of the best surveillance for these individuals.	('SDHB', 'Gene', '6390', (36, 40))	('SDHA', 'Gene', (0, 4))	('SDHB', 'Gene', (36, 40))	('mutations', 'Var', (5, 14))	('SDHA', 'Gene', '6389', (0, 4))	('SDHD', 'Disease', 'None', (45, 49))	('SDHD', 'Disease', (45, 49))
8872	31368675	Mutations in the SDHA gene were first associated with autosomal recessive inheritance of the mitochondrial disease Leigh syndrome (juvenile encephalopathy), and more recently, with severe neurological dysfunction and cardiomyopathy.	('SDHA', 'Gene', (17, 21))	('mitochondrial disease Leigh syndrome', 'Disease', (93, 129))	('associated with', 'Reg', (38, 53))	('neurological dysfunction', 'Disease', (188, 212))	('juvenile encephalopathy', 'Phenotype', 'HP:0005681', (131, 154))	('mitochondrial disease Leigh syndrome', 'Disease', 'MESH:D007888', (93, 129))	('juvenile encephalopathy', 'Disease', (131, 154))	('juvenile encephalopathy', 'Disease', 'MESH:D001927', (131, 154))	('cardiomyopathy', 'Disease', (217, 231))	('encephalopathy', 'Phenotype', 'HP:0001298', (140, 154))	('Mutations', 'Var', (0, 9))	('neurological dysfunction', 'Disease', 'MESH:D009422', (188, 212))	('SDHA', 'Gene', '6389', (17, 21))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (217, 231))	('cardiomyopathy', 'Disease', 'MESH:D009202', (217, 231))
8873	31368675	These rare cases of cardiomyopathy due to SDHA mutations occur in infancy with a high mortality due to congestive heart failure.	('cardiomyopathy', 'Disease', (20, 34))	('SDHA', 'Gene', (42, 46))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (20, 34))	('mutations', 'Var', (47, 56))	('congestive heart failure', 'Phenotype', 'HP:0001635', (103, 127))	('congestive heart failure', 'Disease', 'MESH:D006333', (103, 127))	('cardiomyopathy', 'Disease', 'MESH:D009202', (20, 34))	('SDHA', 'Gene', '6389', (42, 46))	('congestive heart failure', 'Disease', (103, 127))
8874	31368675	As an autosomal dominant inherited tumour suppressor gene, SDHA mutations were only proven to be associated with inherited familial PGL syndromes in 2010.	('SDHA', 'Gene', (59, 63))	('familial PGL syndromes', 'Disease', 'MESH:D010235', (123, 145))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('familial PGL syndromes', 'Disease', (123, 145))	('mutations', 'Var', (64, 73))	('SDHA', 'Gene', '6389', (59, 63))	('associated', 'Reg', (97, 107))	('tumour', 'Disease', (35, 41))
8875	31368675	SDHA mutations were originally estimated to be found in just 3% of all familial PPGL cases, but this is now thought to be higher, at 7.6%.	('SDHA', 'Gene', '6389', (0, 4))	('mutations', 'Var', (5, 14))	('SDHA', 'Gene', (0, 4))
8876	31368675	Penetrance figures are thought to be lower for SDHA mutation carriers compared to SDHB and SDHD, but the actual penetrance figures are unknown.	('SDHA', 'Gene', (47, 51))	('Penetrance figures', 'MPA', (0, 18))	('SDHB', 'Gene', '6390', (82, 86))	('SDHD', 'Disease', 'None', (91, 95))	('SDHA', 'Gene', '6389', (47, 51))	('SDHB', 'Gene', (82, 86))	('mutation', 'Var', (52, 60))	('lower', 'NegReg', (37, 42))	('SDHD', 'Disease', (91, 95))
8880	31368675	None of these relatives were known to carry an SDHA mutation before diagnosis.	('SDHA', 'Gene', (47, 51))	('SDHA', 'Gene', '6389', (47, 51))	('mutation', 'Var', (52, 60))
8881	31368675	The most common of which was c.91C>T, p.Arg31*, the same mutation identified in our patient.	('c.91C>T', 'Var', (29, 36))	('p.Arg31*', 'Var', (38, 46))	('p.Arg31*', 'Mutation', 'rs142441643', (38, 46))	('c.91C>T', 'Mutation', 'rs142441643', (29, 36))	('patient', 'Species', '9606', (84, 91))
8884	31368675	In our patient, as the tumour has not been surgically resected, we were unable to perform further analysis on the tumour tissue to confirm the pathogenicity of this mutation variant in the development of this PGL, and therefore, the possibility remains that the development of this PGL may be unrelated to the discovered SDHA germline variant.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', (114, 120))	('SDHA', 'Gene', (321, 325))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('patient', 'Species', '9606', (7, 14))	('SDHA', 'Gene', '6389', (321, 325))	('tumour', 'Disease', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('variant', 'Var', (174, 181))	('tumour', 'Disease', 'MESH:D009369', (114, 120))
8885	31368675	Previous reports have shown this SDHA variant to be pathogenic, with in silico analysis suggesting a truncated protein is produced, with loss of protein function demonstrated by negative staining with SDHA immunohistochemistry.	('SDHA', 'Gene', '6389', (201, 205))	('SDHA', 'Gene', '6389', (33, 37))	('variant', 'Var', (38, 45))	('SDHA', 'Gene', (201, 205))	('SDHA', 'Gene', (33, 37))
8886	31368675	Another paper used performed metabolic analysis on a PGL from a patient with the same mutation variant as our patient using MRI spectroscopy and identified a succinate peak in the tumour tissue, again providing supporting evidence to the pathogenicity of this mutation variant.	('patient', 'Species', '9606', (64, 71))	('variant', 'Var', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('patient', 'Species', '9606', (110, 117))	('succinate peak', 'MPA', (158, 172))	('succinate', 'Chemical', 'MESH:D019802', (158, 167))	('tumour', 'Disease', (180, 186))
8888	31368675	Mutations in the SDHA gene are rare causes of cardiomyopathy, and the authors are surprised that the SDHA gene is included in the panel test.	('SDHA', 'Gene', (17, 21))	('SDHA', 'Gene', '6389', (101, 105))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (46, 60))	('SDHA', 'Gene', (101, 105))	('cardiomyopathy', 'Disease', 'MESH:D009202', (46, 60))	('Mutations', 'Var', (0, 9))	('SDHA', 'Gene', '6389', (17, 21))	('cardiomyopathy', 'Disease', (46, 60))	('causes', 'Reg', (36, 42))
8889	31368675	However, secretory PPGLs are recognised as more common causes of cardiomyopathy and a more practical approach would be to screen for PPGLs with a single plasma or urine metanephrine measurement in patients with unexplained cardiomyopathies.	('PPGLs', 'Chemical', '-', (19, 24))	('cardiomyopathy', 'Disease', 'MESH:D009202', (65, 79))	('patients', 'Species', '9606', (197, 205))	('PPGLs', 'Chemical', '-', (133, 138))	('PPGLs', 'Gene', (133, 138))	('cardiomyopathy', 'Disease', (65, 79))	('unexplained cardiomyopathies', 'Disease', 'MESH:D009202', (211, 239))	('secretory', 'Var', (9, 18))	('metanephrine', 'Chemical', 'MESH:D008676', (169, 181))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (223, 239))	('causes', 'Reg', (55, 61))	('unexplained cardiomyopathies', 'Disease', (211, 239))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (65, 79))
8890	31368675	To our knowledge, we report the first case of a surveillance screen detected PPGL to be found in an asymptomatic individual with previously identified SDHA mutation status.	('SDHA', 'Gene', (151, 155))	('SDHA', 'Gene', '6389', (151, 155))	('PPGL', 'Gene', (77, 81))	('mutation', 'Var', (156, 164))
8894	31368675	Although the true penetrance rates are unknown in SDHA mutation carriers, especially for specific mutation variants, as per SDHB and SDHD carriers, accurate penetrance rates can only be established through long-term follow-up of asymptomatic carriers, and perhaps subsequent surveillance protocols need to be adapted to be more personalised taking into account factors such as the specific mutation variant, other relevant comorbidities (e.g.	('SDHB', 'Gene', (124, 128))	('SDHA', 'Gene', '6389', (50, 54))	('variants', 'Var', (107, 115))	('SDHD', 'Disease', 'None', (133, 137))	('SDHA', 'Gene', (50, 54))	('SDHD', 'Disease', (133, 137))	('SDHB', 'Gene', '6390', (124, 128))
8896	31368675	We believe therefore that this case highlights the potential importance of at least an initial surveillance screening in all newly identified SDHA mutation carriers.	('SDHA', 'Gene', '6389', (142, 146))	('mutation', 'Var', (147, 155))	('SDHA', 'Gene', (142, 146))
8924	31034925	Under hypoxic conditions, the lack of oxygen curtails PHD activity thereby leading to the stabilization of HIF.	('oxygen', 'Chemical', 'MESH:D010100', (38, 44))	('leading to', 'Reg', (75, 85))	('lack', 'Var', (30, 34))	('stabilization', 'MPA', (90, 103))	('curtails', 'NegReg', (45, 53))	('PHD', 'Disease', 'MESH:D011547', (54, 57))	('PHD', 'Disease', (54, 57))
8926	31034925	The corresponding hydroxylase is HIF1AN, which binds to the inhibitory domain of HIF-1alpha and is capable of hydroxylating N803 in the adjacent C-terminal domain.	('N803', 'Chemical', '-', (124, 128))	('HIF-1alpha', 'Gene', '3091', (81, 91))	('N803', 'Var', (124, 128))	('HIF-1alpha', 'Gene', (81, 91))	('hydroxylating', 'MPA', (110, 123))	('binds', 'Interaction', (47, 52))
8928	31034925	Given the important roles of oxygen sensing by HIF in development, homeostasis and diseases such as cancer, anemia or ischemic vascular disease, HIF1AN has been predicted to modulate all these physiological processes.	('anemia', 'Disease', (108, 114))	('anemia', 'Disease', 'MESH:D000740', (108, 114))	('ischemic vascular disease', 'Disease', 'MESH:D000783', (118, 143))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('anemia', 'Phenotype', 'HP:0001903', (108, 114))	('HIF1AN', 'Var', (145, 151))	('modulate', 'Reg', (174, 182))	('oxygen', 'Chemical', 'MESH:D010100', (29, 35))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('homeostasis and diseases', 'Disease', 'MESH:D003141', (67, 91))	('ischemic vascular disease', 'Disease', (118, 143))
8931	31034925	In addition, intracardial injection of shRNA directed against HIF1AN cooperated with downregulation of PHD2 during recovery after myocardial infarction in mice, resulting in improved stem cell mobilization and angiogenesis; this may represent another instance when HIF1AN constrains HIF function and perhaps hints at a role for the HIF1AN-HIF interaction in repair after injury rather than normal development.	('myocardial infarction', 'Disease', 'MESH:D009203', (130, 151))	('stem cell mobilization', 'CPA', (183, 205))	('downregulation', 'NegReg', (85, 99))	('myocardial infarction', 'Phenotype', 'HP:0001658', (130, 151))	('HIF1AN', 'Var', (265, 271))	('mice', 'Species', '10090', (155, 159))	('PHD2', 'Gene', '112405', (103, 107))	('HIF', 'MPA', (283, 286))	('angiogenesis', 'CPA', (210, 222))	('myocardial infarction', 'Disease', (130, 151))	('improved', 'PosReg', (174, 182))	('PHD2', 'Gene', (103, 107))
8936	31034925	While the relevance of those hydroxylation events is currently unresolved, HIF1AN-mediated hydroxylation of N242 within the cytoplasmic ankyrin repeat domain of the ion channel TRPV3 was shown to inhibit its in vitro function.	('in vitro function', 'CPA', (208, 225))	('N242', 'Chemical', '-', (108, 112))	('inhibit', 'NegReg', (196, 203))	('TRPV3', 'Gene', (177, 182))	('hydroxylation', 'MPA', (91, 104))	('TRPV3', 'Gene', '162514', (177, 182))	('N242', 'Var', (108, 112))
8939	31034925	Hence, HIF1AN inhibition is predicted to aggravate ovarian cancer progression and consistently, low levels of HIF1AN were associated with increased stage and reduced survival of ovarian cancer patients.	('patients', 'Species', '9606', (193, 201))	('increased', 'PosReg', (138, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('stage', 'CPA', (148, 153))	('aggravate', 'PosReg', (41, 50))	('low levels', 'Var', (96, 106))	('ovarian cancer', 'Disease', 'MESH:D010051', (178, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('HIF1AN', 'Gene', (7, 13))	('ovarian cancer', 'Disease', (178, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('HIF1AN', 'Gene', (110, 116))	('survival', 'CPA', (166, 174))	('reduced', 'NegReg', (158, 165))	('ovarian cancer', 'Disease', (51, 65))	('inhibition', 'NegReg', (14, 24))
8940	31034925	In contrast, HIF1AN may enhance breast cancer metastasis through asparagine hydroxylation and thereby inhibition of the E3 ubiquitin ligase HACE1, indicating that HIF1AN inhibition may also be beneficial in cancer therapy.	('HIF1AN', 'Var', (13, 19))	('breast cancer', 'Disease', (32, 45))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('HACE1', 'Gene', '57531', (140, 145))	('asparagine', 'Chemical', 'MESH:D001216', (65, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (207, 213))	('enhance', 'PosReg', (24, 31))	('HACE1', 'Gene', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('asparagine hydroxylation', 'MPA', (65, 89))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('inhibition', 'NegReg', (102, 112))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))
8942	31034925	Possibly, this entails a HIF1AN-dependent decrease of the levels of the p53 tumor suppressor, but how HIF1AN does so is an open question.	('tumor suppressor', 'Gene', (76, 92))	('tumor suppressor', 'Gene', '7248', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('levels of', 'MPA', (58, 67))	('HIF1AN-dependent', 'Var', (25, 41))	('decrease', 'NegReg', (42, 50))
8944	31034925	Asparagine hydroxylation of RIPK4 by HIF1AN resulted in enhanced beta-catenin-dependent transcription, presumably because RIPK4 kinase activity was stimulated, and HIF1AN may thereby widely promote neoplasia that beta-catenin is known to stimulate.	('beta-catenin', 'Gene', '1499', (65, 77))	('neoplasia', 'Disease', 'MESH:D009369', (198, 207))	('RIPK4', 'Gene', (28, 33))	('stimulated', 'PosReg', (148, 158))	('HIF1AN', 'Gene', (37, 43))	('neoplasia', 'Disease', (198, 207))	('activity', 'MPA', (135, 143))	('Asparagine hydroxylation', 'MPA', (0, 24))	('enhanced', 'PosReg', (56, 64))	('RIPK4', 'Gene', '54101', (28, 33))	('RIPK4', 'Gene', (122, 127))	('beta-catenin', 'Gene', (213, 225))	('promote', 'PosReg', (190, 197))	('HIF1AN', 'Var', (164, 170))	('beta-catenin', 'Gene', '1499', (213, 225))	('RIPK4', 'Gene', '54101', (122, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (198, 207))	('Asparagine', 'Chemical', 'MESH:D001216', (0, 10))	('beta-catenin', 'Gene', (65, 77))
8945	31034925	In mice, knockout of HIF1AN led to a hypermetabolic state, characterized by enlarged oxygen consumption and heat production, increased oxidative metabolism, decreased metabolic efficiency in skeletal muscle, hyperventilation and an increased heart rate.	('increased', 'PosReg', (125, 134))	('hypermetabolic state', 'MPA', (37, 57))	('increased heart rate', 'Phenotype', 'HP:0001649', (232, 252))	('heart rate', 'MPA', (242, 252))	('oxygen', 'Chemical', 'MESH:D010100', (85, 91))	('HIF1AN', 'Gene', (21, 27))	('heat', 'CPA', (108, 112))	('decreased', 'NegReg', (157, 166))	('knockout', 'Var', (9, 17))	('increased oxidative metabolism', 'Phenotype', 'HP:0025464', (125, 155))	('mice', 'Species', '10090', (3, 7))	('metabolic efficiency in skeletal muscle', 'MPA', (167, 206))	('enlarged', 'PosReg', (76, 84))	('increased', 'PosReg', (232, 241))	('oxidative metabolism', 'MPA', (135, 155))	('hyperventilation', 'Phenotype', 'HP:0002883', (208, 224))	('oxygen consumption', 'MPA', (85, 103))	('hyperventilation', 'MPA', (208, 224))	('increased heart', 'Phenotype', 'HP:0001640', (232, 247))
8946	31034925	Also, HIF1AN knockout mice displayed a reduced body mass, lower blood lipid levels and enhanced insulin sensitivity.	('enhanced insulin sensitivity', 'Phenotype', 'HP:0000855', (87, 115))	('lower', 'NegReg', (58, 63))	('body mass', 'CPA', (47, 56))	('knockout', 'Var', (13, 21))	('insulin sensitivity', 'CPA', (96, 115))	('lipid', 'Chemical', 'MESH:D008055', (70, 75))	('blood lipid levels', 'MPA', (64, 82))	('enhanced', 'PosReg', (87, 95))	('reduced', 'NegReg', (39, 46))	('HIF1AN', 'Gene', (6, 12))	('mice', 'Species', '10090', (22, 26))
8949	31034925	Possibly, HIF1AN's impact on metabolism involves asparagine hydroxylation of the deubiquitinase OTUB1 that seems to suppress binding to many proteins related to metabolic processes.	('asparagine', 'Chemical', 'MESH:D001216', (49, 59))	('OTUB1', 'Gene', '55611', (96, 101))	('metabolism', 'MPA', (29, 39))	('HIF1AN', 'Var', (10, 16))	('suppress', 'NegReg', (116, 124))	('proteins', 'Protein', (141, 149))	('binding', 'Interaction', (125, 132))	('asparagine hydroxylation', 'MPA', (49, 73))	('OTUB1', 'Gene', (96, 101))
8950	31034925	Mutations in ANKS6 and INVS can cause nephronophthisis, an autosomal recessive cystic kidney disease.	('ANKS6', 'Gene', (13, 18))	('ANKS6', 'Gene', '203286', (13, 18))	('INVS', 'Gene', (23, 27))	('nephronophthisis', 'Disease', 'MESH:C537699', (38, 54))	('nephronophthisis', 'Phenotype', 'HP:0000090', (38, 54))	('nephronophthisis', 'Disease', (38, 54))	('Mutations', 'Var', (0, 9))	('cystic kidney', 'Phenotype', 'HP:0000107', (79, 92))	('kidney disease', 'Phenotype', 'HP:0000112', (86, 100))	('autosomal recessive cystic kidney disease', 'Disease', 'MESH:D052177', (59, 100))	('autosomal recessive cystic kidney disease', 'Disease', (59, 100))	('cause', 'Reg', (32, 37))
8951	31034925	HIF1AN hydroxylates both proteins on asparagine residues and facilitates the formation of protein complexes containing both ANKS6 and INVS.	('HIF1AN', 'Var', (0, 6))	('protein', 'Protein', (90, 97))	('ANKS6', 'Gene', (124, 129))	('ANKS6', 'Gene', '203286', (124, 129))	('asparagine', 'Chemical', 'MESH:D001216', (37, 47))	('formation', 'Interaction', (77, 86))	('facilitates', 'PosReg', (61, 72))
8952	31034925	HIF1AN knockdown in Xenopus led to edema and renal tubular shortening, implying that HIF1AN contributes to kidney development through posttranslational modification of ANKS6 and INVS.	('edema', 'Phenotype', 'HP:0000969', (35, 40))	('contributes', 'PosReg', (92, 103))	('ANKS6', 'Gene', (168, 173))	('HIF1AN', 'Gene', (85, 91))	('tubular shortening', 'Phenotype', 'HP:0003026', (51, 69))	('edema and renal tubular shortening', 'Disease', 'MESH:D015499', (35, 69))	('kidney development', 'CPA', (107, 125))	('HIF1AN', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('Xenopus', 'Species', '8355', (20, 27))	('ANKS6', 'Gene', '203286', (168, 173))
8953	31034925	Nephronophthisis is just one of many ciliopathies, implicating that altered HIF1AN activity could contribute to their genesis through modulation of the primary cilia-associated ANKS6 and INVS proteins.	('activity', 'MPA', (83, 91))	('contribute', 'Reg', (98, 108))	('modulation', 'Reg', (134, 144))	('INVS proteins', 'Protein', (187, 200))	('ANKS6', 'Gene', (177, 182))	('Nephronophthisis', 'Disease', (0, 16))	('primary', 'Protein', (152, 159))	('ANKS6', 'Gene', '203286', (177, 182))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (0, 16))	('HIF1AN', 'Gene', (76, 82))	('altered', 'Var', (68, 75))
8954	31034925	In addition, HIF1AN may thereby also affect tumorigenesis, since primary cilia defects are correlated with both pro- and anti-tumor effects.	('HIF1AN', 'Var', (13, 19))	('cilia defects', 'Disease', (73, 86))	('affect', 'Reg', (37, 43))	('cilia defects', 'Disease', 'MESH:C536287', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (126, 131))
8963	31034925	In Drosophila, knockout of HSPBAP1 led to slower sedation upon first exposure to low ethanol doses and decreased ethanol tolerance upon repeated exposure.	('ethanol tolerance', 'MPA', (113, 130))	('knockout', 'Var', (15, 23))	('HSPBAP1', 'Gene', (27, 34))	('HSPBAP1', 'Gene', '79663', (27, 34))	('decreased', 'NegReg', (103, 112))	('slower', 'NegReg', (42, 48))	('Drosophila', 'Species', '7227', (3, 13))	('ethanol', 'Chemical', 'MESH:D000431', (85, 92))	('ethanol', 'Chemical', 'MESH:D000431', (113, 120))	('sedation', 'MPA', (49, 57))
8966	31034925	First, a fusion transcript of HSPBAP1 as a consequence of a chromosomal translocation was found in a case of familial renal cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('found', 'Reg', (90, 95))	('consequence', 'Reg', (43, 54))	('HSPBAP1', 'Gene', (30, 37))	('familial renal cell cancer', 'Disease', (109, 135))	('familial renal cell cancer', 'Disease', 'MESH:C538614', (109, 135))	('fusion', 'Var', (9, 15))	('chromosomal translocation', 'Var', (60, 85))	('HSPBAP1', 'Gene', '79663', (30, 37))	('renal cell cancer', 'Phenotype', 'HP:0005584', (118, 135))
8968	31034925	Accordingly, dysregulation of expression through placement of a novel promoter upstream of the HSPBAP1 gene rather than an inactivated HSPBAP1 protein may be involved in disease formation.	('expression', 'MPA', (30, 40))	('dysregulation', 'Var', (13, 26))	('involved', 'Reg', (158, 166))	('HSPBAP1', 'Gene', (135, 142))	('HSPBAP1', 'Gene', (95, 102))	('HSPBAP1', 'Gene', '79663', (135, 142))	('HSPBAP1', 'Gene', '79663', (95, 102))
8978	31034925	One group reported that such endoproteolytic activity occurs after monomethylated K4, K9, K27 and K36 on histone H3, with a preference for monomethylated K9, while the second group found histones H2, H3 and H4 as substrates when they were mono- or dimethylated (symmetrically or asymmetrically) on arginine residues.	('endoproteolytic activity', 'MPA', (29, 53))	('arginine', 'Chemical', 'MESH:D001120', (298, 306))	('K36', 'Gene', '8689', (98, 101))	('monomethylated K4', 'Var', (67, 84))	('K36', 'Gene', (98, 101))	('K27', 'Gene', '342574', (90, 93))	('K27', 'Gene', (90, 93))
8979	31034925	In support of cleavage after methylated arginine residues, ablation of JMJD5 led to increased H3R2me2 and H4R3me2 levels.	('arginine', 'Chemical', 'MESH:D001120', (40, 48))	('H4R3me2', 'Chemical', '-', (106, 113))	('H3R2me2', 'Chemical', '-', (94, 101))	('H4R3me2 levels', 'MPA', (106, 120))	('increased', 'PosReg', (84, 93))	('ablation', 'Var', (59, 67))	('JMJD5', 'Gene', (71, 76))
8982	31034925	One report indicated that 2OG had marginal impact on proteolytic activity, while the other showed that mutation of the 2OG binding site within the JmjC domain impaired it.	('binding', 'Interaction', (123, 130))	('2OG', 'Gene', (119, 122))	('proteolytic activity', 'MPA', (53, 73))	('2OG', 'Chemical', 'MESH:D007656', (26, 29))	('2OG', 'Chemical', 'MESH:D007656', (119, 122))	('mutation', 'Var', (103, 111))	('impaired', 'NegReg', (159, 167))
8987	31034925	In contrast, JMJD5 knockout in Arabidopsis or Drosophila was not lethal.	('Drosophila', 'Species', '7227', (46, 56))	('Arabidopsis', 'Species', '3702', (31, 42))	('JMJD5', 'Gene', (13, 18))	('knockout', 'Var', (19, 27))
8988	31034925	Notably, JMJD5 ablation in Arabidopsis, Drosophila or human U2OS osteosarcoma cells resulted into a short-period circadian phenotype and additionally a reduction in daytime sleep was observed in Drosophila.	('human', 'Species', '9606', (54, 59))	('ablation', 'Var', (15, 23))	('Drosophila', 'Species', '7227', (40, 50))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('short-period circadian phenotype', 'MPA', (100, 132))	('Arabidopsis', 'Species', '3702', (27, 38))	('JMJD5', 'Gene', (9, 14))	('Drosophila', 'Species', '7227', (195, 205))	('U2OS', 'CellLine', 'CVCL:0042', (60, 64))	('daytime sleep', 'MPA', (165, 178))	('reduction', 'NegReg', (152, 161))	('daytime sleep', 'Phenotype', 'HP:0002360', (165, 178))
8993	31034925	Embryonic lethality upon JMJD5 ablation was ameliorated by knockout of the cell cycle inhibitor p21 and even more so by knockout of the p53 tumor suppressor, but respective mouse embryos still died during gestation.	('Embryonic lethality', 'Disease', (0, 19))	('ameliorated', 'PosReg', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Embryonic lethality', 'Disease', 'MESH:D020964', (0, 19))	('knockout', 'Var', (120, 128))	('JMJD5', 'Gene', (25, 30))	('mouse', 'Species', '10090', (173, 178))	('knockout', 'Var', (59, 67))	('tumor suppressor', 'Gene', (140, 156))	('ablation', 'Var', (31, 39))	('tumor suppressor', 'Gene', '7248', (140, 156))	('p53', 'Gene', (136, 139))
8994	31034925	Similarly, JMJD5 downregulation in human embryonic stem cells led to p21 upregulation, and p21 shRNA rescued the loss of pluripotency and cell cycle defects caused by JMJD5 shRNA.	('cell cycle defects', 'CPA', (138, 156))	('loss of pluripotency', 'Disease', (113, 133))	('p21', 'Gene', (69, 72))	('human', 'Species', '9606', (35, 40))	('cell cycle defects', 'Phenotype', 'HP:0011018', (138, 156))	('downregulation', 'NegReg', (17, 31))	('loss of pluripotency', 'Disease', 'MESH:D014786', (113, 133))	('JMJD5', 'Var', (167, 172))	('p21 shRNA', 'Var', (91, 100))	('upregulation', 'PosReg', (73, 85))
9000	31034925	Within the cell nucleus, JMJD5 and PKM2 jointly regulated gene transcription in both breast and prostate cancer cells and promoted aerobic glycolysis.	('aerobic glycolysis', 'MPA', (131, 149))	('JMJD5', 'Var', (25, 30))	('gene transcription', 'MPA', (58, 76))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (85, 111))	('promoted', 'PosReg', (122, 130))	('PKM2', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PKM2', 'Gene', '5315', (35, 39))	('regulated', 'Reg', (48, 57))
9003	31034925	Likewise, JMJD5 shRNA impaired proliferation and invasion of Caco-2 colon cancer cells, and JMJD5 was overexpressed and correlated with lower survival in colorectal cancer patients.	('survival', 'MPA', (142, 150))	('JMJD5', 'Var', (10, 15))	('lower', 'NegReg', (136, 141))	('colorectal cancer', 'Disease', (154, 171))	('proliferation', 'CPA', (31, 44))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('JMJD5', 'Var', (92, 97))	('impaired', 'NegReg', (22, 30))	('Caco-2', 'CellLine', 'CVCL:0025', (61, 67))	('invasion', 'CPA', (49, 57))	('colon cancer', 'Disease', (68, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (154, 171))	('patients', 'Species', '9606', (172, 180))	('overexpressed', 'PosReg', (102, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (154, 171))
9005	31034925	Hence, one may imagine that loss of JMJD5 leads to inaccurate mitosis and the development of aneuploidy that is thought to be important for both cancer initiation and evolution.	('loss', 'Var', (28, 32))	('cancer initiation', 'Disease', (145, 162))	('aneuploidy', 'Disease', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('JMJD5', 'Gene', (36, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (93, 103))	('mitosis', 'Disease', (62, 69))	('mitosis', 'Disease', 'None', (62, 69))	('cancer initiation', 'Disease', 'MESH:D009369', (145, 162))
9007	31034925	In C. elegans, feeding with JMJD5 siRNA induced mutations in the germline and genetic ablation of JMJD5 led to hypersensitivity to ionizing radiation and impaired DNA double strand break repair through homologous recombination, while JMJD5 downregulation in NIH3T3 cells resulted in defective mismatch repair.	('mismatch repair', 'MPA', (293, 308))	('defective', 'NegReg', (283, 292))	('hypersensitivity to ionizing radiation', 'Disease', (111, 149))	('C. elegans', 'Species', '6239', (3, 13))	('NIH3T3', 'CellLine', 'CVCL:0594', (258, 264))	('homologous', 'MPA', (202, 212))	('DNA double strand break repair', 'MPA', (163, 193))	('impaired', 'NegReg', (154, 162))	('JMJD5', 'Gene', (98, 103))	('downregulation', 'NegReg', (240, 254))	('hypersensitivity to ionizing radiation', 'Disease', 'MESH:D004194', (111, 149))	('mutations', 'Var', (48, 57))
9012	31034925	Hydroxylation of DRG1\2 promoted their binding to RNA, but a corresponding biological relevance has not yet been established.	('RNA', 'Protein', (50, 53))	('DRG1\\2', 'Gene', (17, 23))	('promoted', 'PosReg', (24, 32))	('Hydroxylation', 'Var', (0, 13))	('binding', 'Interaction', (39, 46))	('DRG1\\2', 'Gene', '4733;1819', (17, 23))
9028	31034925	Consistently, deletion of RIOX1 in mesenchymal cells produced mice with an increased number of preosteoblasts and osteoblasts, a larger skeleton and higher bone mass.	('mice', 'Species', '10090', (62, 66))	('increased', 'PosReg', (75, 84))	('larger', 'PosReg', (129, 135))	('deletion', 'Var', (14, 22))	('higher', 'PosReg', (149, 155))	('RIOX1', 'Gene', (26, 31))	('bone mass', 'CPA', (156, 165))
9033	31034925	Unexpectedly, IL4 produced in response to house dust mites was less in RIOX2 knockout compared to wild-type mice.	('house dust mites', 'Phenotype', 'HP:0410325', (42, 58))	('IL4', 'Gene', (14, 17))	('knockout', 'Var', (77, 85))	('IL4', 'Gene', '16189', (14, 17))	('mice', 'Species', '10090', (108, 112))	('RIOX2', 'Gene', (71, 76))	('less', 'NegReg', (63, 67))	('dust mites', 'Phenotype', 'HP:0410324', (48, 58))
9035	31034925	Regardless, RIOX2 knockout mice, which are viable and fertile, displayed a reduced allergic response in an asthma model, while a single-nucleotide polymorphism in the RIOX2 gene was associated with the development of childhood asthma and increased IL4 levels.	('asthma', 'Disease', (227, 233))	('asthma', 'Disease', 'MESH:D001249', (107, 113))	('asthma', 'Disease', 'MESH:D001249', (227, 233))	('mice', 'Species', '10090', (27, 31))	('asthma', 'Disease', (107, 113))	('IL4', 'Gene', (248, 251))	('associated with', 'Reg', (182, 197))	('RIOX2', 'Gene', (167, 172))	('increased', 'PosReg', (238, 247))	('reduced', 'NegReg', (75, 82))	('IL4', 'Gene', '16189', (248, 251))	('single-nucleotide polymorphism', 'Var', (129, 159))	('allergic', 'Disease', 'MESH:D004342', (83, 91))	('increased IL4 levels', 'Phenotype', 'HP:0032300', (238, 258))	('asthma', 'Phenotype', 'HP:0002099', (107, 113))	('asthma', 'Phenotype', 'HP:0002099', (227, 233))	('allergic response', 'Phenotype', 'HP:0012393', (83, 100))	('allergic', 'Disease', (83, 91))
9037	31034925	Together, these data imply that inhibition of RIOX2 might be beneficial in the treatment of asthma and autoimmune diseases.	('asthma', 'Phenotype', 'HP:0002099', (92, 98))	('inhibition', 'Var', (32, 42))	('RIOX2', 'Gene', (46, 51))	('autoimmune diseases', 'Disease', 'MESH:D001327', (103, 122))	('autoimmune diseases', 'Disease', (103, 122))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (103, 122))	('beneficial', 'PosReg', (61, 71))	('asthma', 'Disease', 'MESH:D001249', (92, 98))	('asthma', 'Disease', (92, 98))
9038	31034925	Many reports have associated RIOX2 with colon cancer, esophageal squamous cell carcinoma, lung cancer, renal cell carcinoma, gastric adenocarcinoma, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer or glioblastoma, demonstrating that RIOX2 is overexpressed in tumor specimens compared to normal tissue, that high RIOX2 expression correlates with an adverse prognosis, and/or that RIOX2 downregulation impairs proliferation or survival of cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('tumor', 'Disease', (275, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (149, 173))	('RIOX2', 'Gene', (328, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Disease', (453, 459))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (453, 459))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 123))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (175, 193))	('cancer', 'Disease', (95, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (216, 228))	('expression', 'MPA', (334, 344))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (149, 173))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('high', 'Var', (323, 327))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (125, 147))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cholangiocarcinoma', 'Disease', (175, 193))	('pancreatic cancer', 'Disease', (195, 212))	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('cancer', 'Disease', (46, 52))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (175, 193))	('glioblastoma', 'Disease', (216, 228))	('lung cancer', 'Disease', (90, 101))	('hepatocellular carcinoma', 'Disease', (149, 173))	('RIOX2', 'Gene', (395, 400))	('proliferation', 'CPA', (424, 437))	('glioblastoma', 'Phenotype', 'HP:0012174', (216, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (453, 459))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('downregulation impairs', 'NegReg', (401, 423))	('renal cell carcinoma', 'Disease', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('colon cancer', 'Disease', (40, 52))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('gastric adenocarcinoma', 'Disease', (125, 147))
9046	31034925	Preventing hydroxylation of eRF1 resulted in reduced efficiency of transcriptional termination, but no physiological consequences were examined.	('reduced', 'NegReg', (45, 52))	('eRF1', 'Gene', '2107', (28, 32))	('hydroxylation', 'Var', (11, 24))	('eRF1', 'Gene', (28, 32))	('transcriptional termination', 'MPA', (67, 94))
9048	31034925	Further, similar to eRF1, JMJD4 is a predominantly cytoplasmic protein in HEK293T cells, which also holds true for Drosophila and human colon cells.	('eRF1', 'Gene', '2107', (20, 24))	('HEK293T', 'CellLine', 'CVCL:0063', (74, 81))	('eRF1', 'Gene', (20, 24))	('Drosophila', 'Species', '7227', (115, 125))	('JMJD4', 'Var', (26, 31))	('human', 'Species', '9606', (130, 135))
9050	31034925	This suggests, but does not prove, that JMJD4 promotes colon cancer formation.	('colon cancer', 'Phenotype', 'HP:0003003', (55, 67))	('JMJD4', 'Var', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('promotes', 'PosReg', (46, 54))	('colon cancer', 'Disease', 'MESH:D015179', (55, 67))	('colon cancer', 'Disease', (55, 67))
9053	31034925	But contrasting this, there were no obvious growth defects in vivo, since JMJD4 ablation did not affect embryogenesis or postnatal development in mice or Drosophila.	('ablation', 'Var', (80, 88))	('mice', 'Species', '10090', (146, 150))	('Drosophila', 'Species', '7227', (154, 164))	('JMJD4', 'Gene', (74, 79))
9060	31034925	Demethylation of H4R3me2 by JMJD6 was likewise shown in another report, but JMJD6-mediated histone arginine demethylation was also reported to be not reproducible.	('Demethylation', 'MPA', (0, 13))	('arginine', 'Chemical', 'MESH:D001120', (99, 107))	('JMJD6', 'Var', (28, 33))	('H4R3me2', 'Protein', (17, 24))	('H4R3me2', 'Chemical', '-', (17, 24))
9061	31034925	Additionally, in 2009, JMJD6 was shown to mediate lysine hydroxylation at the C5 position on U2AF65, and crystallographic studies supported such lysine hydroxylation over arginine demethylation.	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('U2AF65', 'Gene', '11338', (93, 99))	('arginine', 'Chemical', 'MESH:D001120', (171, 179))	('JMJD6', 'Var', (23, 28))	('lysine', 'Chemical', 'MESH:D008239', (50, 56))	('mediate', 'Reg', (42, 49))	('arginine demethylation', 'MPA', (171, 193))	('lysine hydroxylation', 'MPA', (50, 70))	('U2AF65', 'Gene', (93, 99))
9062	31034925	Consistent with a role of U2AF65 in RNA splicing, JMJD6 downregulation affected the alternative splicing of some, but not all tested genes; moreover, JMJD6 cooperated with U2AF65 in splicing of the vascular endothelial growth factor receptor 1, which may explain how JMJD6 facilitates angiogenic sprouting.	('U2AF65', 'Gene', (26, 32))	('JMJD6', 'Var', (267, 272))	('affected', 'Reg', (71, 79))	('JMJD6', 'Var', (150, 155))	('alternative splicing', 'MPA', (84, 104))	('U2AF65', 'Gene', (172, 178))	('cooperated', 'Reg', (156, 166))	('U2AF65', 'Gene', '11338', (26, 32))	('downregulation', 'NegReg', (56, 70))	('vascular endothelial growth factor receptor 1', 'Gene', (198, 243))	('angiogenic sprouting', 'CPA', (285, 305))	('splicing', 'MPA', (182, 190))	('vascular endothelial growth factor receptor 1', 'Gene', '2321', (198, 243))	('U2AF65', 'Gene', '11338', (172, 178))	('facilitates', 'PosReg', (273, 284))
9063	31034925	Subsequently, JMJD6-mediated lysine hydroxylation was also found in histones and the tumor suppressor p53.	('lysine', 'Chemical', 'MESH:D008239', (29, 35))	('JMJD6-mediated', 'Var', (14, 28))	('tumor suppressor', 'Gene', (85, 101))	('histones', 'Protein', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lysine hydroxylation', 'MPA', (29, 49))	('tumor suppressor', 'Gene', '7248', (85, 101))
9064	31034925	JMJD6 was also suggested to demethylate arginine residues in non-histone proteins, including estrogen receptoralpha, heat shock protein HSP70, tumor necrosis factor receptor-associated factor 6, transcription factor STAT1, and the stress granule nucleating protein G3BP1.	('arginine', 'Chemical', 'MESH:D001120', (40, 48))	('tumor necrosis factor', 'Gene', (143, 164))	('estrogen receptoralpha', 'Gene', (93, 115))	('STAT1', 'Gene', '6772', (216, 221))	('non-histone proteins', 'Protein', (61, 81))	('tumor necrosis factor', 'Gene', '7124', (143, 164))	('JMJD6', 'Gene', (0, 5))	('shock', 'Disease', 'MESH:D012769', (122, 127))	('demethylate', 'Var', (28, 39))	('shock', 'Disease', (122, 127))	('G3BP1', 'Gene', (265, 270))	('G3BP1', 'Gene', '10146', (265, 270))	('estrogen receptoralpha', 'Gene', '2099', (93, 115))	('shock', 'Phenotype', 'HP:0031273', (122, 127))	('STAT1', 'Gene', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
9066	31034925	This small nuclear RNA that is involved in transcription elongation is stabilized by the addition of a methyl group onto the gamma-phosphate at its 5'-end.	('addition', 'Reg', (89, 97))	('gamma-phosphate', 'Chemical', '-', (125, 140))	('methyl', 'Var', (103, 109))
9069	31034925	Although the JmjC domain was required for tyrosine kinase activity of JMJD6, it was not sufficient and in vitro kinase reactions with JMJD6 did not require 2OG and Fe2+, but rather ATP or GTP.	('GTP', 'Chemical', 'MESH:D006160', (188, 191))	('Fe2+', 'Chemical', '-', (164, 168))	('2OG', 'Chemical', 'MESH:D007656', (156, 159))	('ATP', 'Chemical', 'MESH:D000255', (181, 184))	('JMJD6', 'Var', (134, 139))	('JMJD6', 'Gene', (70, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))
9073	31034925	Of note, interruption of this interaction with a monoclonal antibody reduced fibrosis at the primary tumor site and lung metastasis in a mouse mammary tumor model.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('fibrosis', 'Disease', (77, 85))	('reduced', 'NegReg', (69, 76))	('mouse', 'Species', '10090', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('interruption', 'Var', (9, 21))	('interaction', 'Interaction', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('lung metastasis in a', 'CPA', (116, 136))
9074	31034925	In general, JMJD6 appears to be a tumor promoter.	('JMJD6', 'Var', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
9075	31034925	Overexpression of JMJD6 in various cancers and its correlation with decreased patient survival has been found, and JMJD6 reportedly enhanced tumor cell proliferation in vitro and in xenografts, increased cell invasion and metastasis, and promoted cancer stemness.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('patient', 'Species', '9606', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer stemness', 'Disease', 'MESH:D009369', (247, 262))	('tumor', 'Disease', (141, 146))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('increased', 'PosReg', (194, 203))	('cell invasion', 'CPA', (204, 217))	('enhanced', 'PosReg', (132, 140))	('cancer stemness', 'Disease', (247, 262))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('promoted', 'PosReg', (238, 246))	('JMJD6', 'Var', (115, 120))	('cancers', 'Disease', (35, 42))
9084	31034925	In addition, JMJD8 was shown to be required for invasion of squamous cell carcinoma cells, suggesting that JMJD8 stimulates metastasis.	('JMJD8', 'Var', (107, 112))	('metastasis', 'CPA', (124, 134))	('stimulates', 'PosReg', (113, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('squamous cell carcinoma', 'Disease', (60, 83))
9090	31034925	On the other hand, cancer cells often become addicted to glutamine as a carbon and nitrogen source and for energy production, and glutamine - after conversion to glutamate - can replenish 2OG (Fig.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('carbon', 'Chemical', 'MESH:D002244', (72, 78))	('glutamate', 'Chemical', 'MESH:D018698', (162, 171))	('2OG', 'Chemical', 'MESH:D007656', (188, 191))	('2OG', 'MPA', (188, 191))	('glutamine', 'Chemical', 'MESH:D005973', (57, 66))	('glutamine', 'Chemical', 'MESH:D005973', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('nitrogen', 'Chemical', 'MESH:D009584', (83, 91))	('glutamine', 'Var', (130, 139))
9096	31034925	In contrast, D-2-hydroxyglutarate generation from 2OG is catalyzed by neomorphic mutants of isocitrate dehydrogenase (IDH).	('2OG', 'Chemical', 'MESH:D007656', (50, 53))	('citrate', 'Chemical', 'MESH:D019343', (95, 102))	('mutants', 'Var', (81, 88))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (13, 33))	('D-2-hydroxyglutarate generation', 'MPA', (13, 44))
9098	31034925	In the same manner, succinate and fumarate repress JMJD catalytic activity, and enhanced levels of these molecules are observable upon mutation of succinate dehydrogenase (SDH) and fumarate hydratase (FH).	('JMJD catalytic activity', 'MPA', (51, 74))	('succinate dehydrogenase', 'Gene', '6390', (147, 170))	('levels of', 'MPA', (89, 98))	('fumarate', 'Chemical', 'MESH:D005650', (34, 42))	('fumarate hydratase', 'Gene', (181, 199))	('fumarate hydratase', 'Gene', '2271', (181, 199))	('succinate dehydrogenase', 'Gene', (147, 170))	('SDH', 'Gene', (172, 175))	('fumarate', 'Chemical', 'MESH:D005650', (181, 189))	('FH', 'Gene', '2271', (201, 203))	('succinate', 'Chemical', 'MESH:D019802', (20, 29))	('enhanced', 'PosReg', (80, 88))	('mutation', 'Var', (135, 143))	('repress', 'NegReg', (43, 50))	('SDH', 'Gene', '6390', (172, 175))	('succinate', 'Chemical', 'MESH:D019802', (147, 156))
9099	31034925	Gain-of-function mutations in IDH were discovered in low-grade glioma, glioblastoma, chondrosarcoma, cholangiocarcinoma or acute myeloid leukemia, while loss-of-function mutations in SDH were found in paraganglioma, pheochromocytoma, renal cell carcinoma, thyroid cancer or gastrointestinal stromal tumors, and mutated FH was detected in leiomyomatosis, renal cell cancer, paraganglioma, pheochromocytoma or neuroblastoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (101, 119))	('glioma', 'Phenotype', 'HP:0009733', (380, 386))	('paraganglioma', 'Phenotype', 'HP:0002668', (373, 386))	('neuroblastoma', 'Phenotype', 'HP:0003006', (408, 421))	('glioblastoma', 'Disease', (71, 83))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('SDH', 'Gene', '6390', (183, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('cholangiocarcinoma', 'Disease', (101, 119))	('Gain-of-function', 'PosReg', (0, 16))	('pheochromocytoma', 'Disease', (388, 404))	('gastrointestinal stromal tumors', 'Disease', (274, 305))	('leiomyomatosis, renal cell cancer', 'Disease', 'MESH:C535516', (338, 371))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('renal cell carcinoma', 'Disease', (234, 254))	('paraganglioma', 'Disease', (201, 214))	('mutations', 'Var', (17, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (234, 254))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (388, 404))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (101, 119))	('paraganglioma', 'Disease', 'MESH:D010235', (201, 214))	('glioma', 'Disease', (208, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('thyroid cancer', 'Disease', (256, 270))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('SDH', 'Gene', (183, 186))	('IDH', 'Gene', (30, 33))	('glioma', 'Disease', 'MESH:D005910', (208, 214))	('pheochromocytoma', 'Disease', 'MESH:D010673', (216, 232))	('loss-of-function', 'NegReg', (153, 169))	('chondrosarcoma', 'Disease', (85, 99))	('chondrosarcoma', 'Disease', 'MESH:D002813', (85, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('paraganglioma, pheochromocytoma or neuroblastoma', 'Disease', 'MESH:D010673', (373, 421))	('paraganglioma', 'Disease', (373, 386))	('acute myeloid leukemia', 'Disease', (123, 145))	('glioma', 'Disease', (380, 386))	('paraganglioma', 'Phenotype', 'HP:0002668', (201, 214))	('pheochromocytoma', 'Disease', (216, 232))	('renal cell cancer', 'Phenotype', 'HP:0005584', (354, 371))	('FH', 'Gene', '2271', (319, 321))	('paraganglioma', 'Disease', 'MESH:D010235', (373, 386))	('glioma', 'Phenotype', 'HP:0009733', (208, 214))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (216, 232))	('thyroid cancer', 'Disease', 'MESH:D013964', (256, 270))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (274, 305))	('glioma', 'Disease', (63, 69))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (274, 305))	('glioma', 'Disease', 'MESH:D005910', (380, 386))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (234, 254))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('mutations', 'Var', (170, 179))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (85, 99))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('thyroid cancer', 'Phenotype', 'HP:0002890', (256, 270))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('pheochromocytoma', 'Disease', 'MESH:D010673', (388, 404))
9100	31034925	Interestingly, mutations in MDH were also found in paraganglioma and pheochromocytoma patients.	('paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (51, 85))	('MDH', 'Gene', '4200', (28, 31))	('mutations', 'Var', (15, 24))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (51, 64))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (69, 85))	('found', 'Reg', (42, 47))	('MDH', 'Gene', (28, 31))	('patients', 'Species', '9606', (86, 94))
9101	31034925	Although it is presently not proven that malate directly inhibits JMJD proteins, malate accumulation upon MDH mutation was accompanied by elevated fumarate levels, possibly due to end product inhibition of FH.	('FH', 'Gene', '2271', (206, 208))	('malate', 'MPA', (81, 87))	('fumarate', 'Chemical', 'MESH:D005650', (147, 155))	('malate', 'Chemical', 'MESH:C030298', (81, 87))	('fumarate levels', 'MPA', (147, 162))	('MDH', 'Gene', '4200', (106, 109))	('MDH', 'Gene', (106, 109))	('mutation', 'Var', (110, 118))	('malate', 'Chemical', 'MESH:C030298', (41, 47))	('accumulation', 'PosReg', (88, 100))	('elevated', 'PosReg', (138, 146))
9103	31034925	On the other hand, MDH inactivating mutations should lead to less production of L-2-hydroxyglutarate and in that way to less inhibition of JMJD proteins.	('MDH', 'Gene', (19, 22))	('inhibition', 'MPA', (125, 135))	('L-2-hydroxyglutarate', 'Chemical', '-', (80, 100))	('less', 'NegReg', (61, 65))	('less', 'NegReg', (120, 124))	('inactivating mutations', 'Var', (23, 45))	('MDH', 'Gene', '4200', (19, 22))	('production of L-2-hydroxyglutarate', 'MPA', (66, 100))
9104	31034925	How these opposing consequences of MDH mutation are integrated into a net effect needs further study.	('MDH', 'Gene', '4200', (35, 38))	('mutation', 'Var', (39, 47))	('MDH', 'Gene', (35, 38))
9105	31034925	Regardless, mutations in Krebs cycle enzymes can profoundly affect JMJD activity, but in what way this precisely impinges on each of the small JMJD proteins and if this is crucial for the function of oncometabolites are open questions.	('JMJD activity', 'MPA', (67, 80))	('mutations', 'Var', (12, 21))	('Krebs', 'Chemical', '-', (25, 30))	('affect', 'Reg', (60, 66))
9114	31034925	ROS can induce the oxidation of macromolecules and Fe2+, which is predicted to reduce JMJD enzymatic activity.	('oxidation of macromolecules', 'MPA', (19, 46))	('ROS', 'Var', (0, 3))	('Fe2+', 'Chemical', '-', (51, 55))	('Fe2+', 'MPA', (51, 55))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('induce', 'Reg', (8, 14))
9118	31034925	A positive role of ascorbate (vitamin C) for the activity of hydroxylases has been firmly established ever since it was shown how lack of ascorbate causes scurvy through impaired collagen hydroxylation.	('impaired', 'NegReg', (170, 178))	('lack', 'Var', (130, 134))	('ascorbate', 'Chemical', 'MESH:D001205', (138, 147))	('collagen hydroxylation', 'MPA', (179, 201))	('ascorbate', 'Chemical', 'MESH:D001205', (19, 28))	('ascorbate', 'Protein', (138, 147))	('scurvy', 'Disease', (155, 161))	('vitamin C', 'Chemical', 'MESH:D001205', (30, 39))
9126	31034925	Accordingly, changes in Fe2+ should influence JMJD function, but in vivo evidence is acutely missing.	('Fe2+', 'Chemical', '-', (24, 28))	('Fe2+', 'MPA', (24, 28))	('JMJD function', 'CPA', (46, 59))	('influence', 'Reg', (36, 45))	('changes', 'Var', (13, 20))
9130	31034925	On the other hand, too much iron can also kill cancer cells through ferroptosis, an iron-dependent, non- apoptotic regulated cell death pathway that is triggered through excessive lipid peroxidation.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('iron', 'Chemical', 'MESH:D007501', (28, 32))	('ferroptosis', 'Disease', (68, 79))	('cancer', 'Disease', (47, 53))	('lipid', 'Chemical', 'MESH:D008055', (180, 185))	('too', 'Var', (19, 22))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('excessive lipid peroxidation', 'Phenotype', 'HP:0025464', (170, 198))
9132	31034925	Several heavy metals, including arsenic, cadmium, chromium and nickel, are carcinogenic and also induce other pathologies like allergies, hypertension, pulmonary disease, renal dysfunction, diabetes, paralysis, osteoporosis, ulcer formation and mental retardation.	('mental retardation', 'Disease', (245, 263))	('cadmium', 'Var', (41, 48))	('ulcer', 'Disease', 'MESH:D014456', (225, 230))	('hypertension', 'Disease', 'MESH:D006973', (138, 150))	('renal dysfunction', 'Phenotype', 'HP:0000083', (171, 188))	('osteoporosis', 'Disease', (211, 223))	('hypertension', 'Disease', (138, 150))	('pulmonary disease', 'Disease', 'MESH:D008171', (152, 169))	('chromium', 'Var', (50, 58))	('osteoporosis', 'Phenotype', 'HP:0000939', (211, 223))	('cadmium', 'Chemical', 'MESH:D002104', (41, 48))	('metal', 'Chemical', 'MESH:D008670', (14, 19))	('pulmonary disease', 'Disease', (152, 169))	('carcinogenic', 'Disease', (75, 87))	('nickel', 'Chemical', 'MESH:D009532', (63, 69))	('allergies', 'Phenotype', 'HP:0012393', (127, 136))	('ulcer', 'Disease', (225, 230))	('allergies', 'Disease', (127, 136))	('induce', 'Reg', (97, 103))	('arsenic', 'Chemical', 'MESH:D001151', (32, 39))	('osteoporosis', 'Disease', 'MESH:D010024', (211, 223))	('diabetes', 'Disease', (190, 198))	('hypertension', 'Phenotype', 'HP:0000822', (138, 150))	('paralysis', 'Phenotype', 'HP:0003470', (200, 209))	('renal dysfunction', 'Disease', 'MESH:D007674', (171, 188))	('carcinogenic', 'Disease', 'MESH:D063646', (75, 87))	('paralysis', 'Disease', 'MESH:D010243', (200, 209))	('arsenic', 'Var', (32, 39))	('chromium', 'Chemical', 'MESH:D002857', (50, 58))	('mental retardation', 'Phenotype', 'HP:0001249', (245, 263))	('allergies', 'Disease', 'MESH:D004342', (127, 136))	('mental retardation', 'Disease', 'MESH:D008607', (245, 263))	('diabetes', 'Disease', 'MESH:D003920', (190, 198))	('renal dysfunction', 'Disease', (171, 188))	('paralysis', 'Disease', (200, 209))
9135	31034925	And indeed, some JMJD lysine demethylases were shown to be inhibited upon replacement of Fe2+ by Ni2+.	('Fe2+', 'Chemical', '-', (89, 93))	('Fe2+', 'MPA', (89, 93))	('demethylase', 'Gene', (29, 40))	('Ni2+', 'Chemical', '-', (97, 101))	('demethylase', 'Gene', '8932', (29, 40))	('inhibited', 'NegReg', (59, 68))	('lysine', 'Chemical', 'MESH:D008239', (22, 28))	('replacement', 'Var', (74, 85))	('Ni2+', 'MPA', (97, 101))
9142	31034925	Indeed, cell culture and xenograft studies provided strong evidence that small JMJD proteins are affecting cancer cell function.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('small', 'Var', (73, 78))	('proteins', 'Protein', (84, 92))	('affecting', 'Reg', (97, 106))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
9148	31034925	And the utility of such inhibitors will not be limited to controlling malignancies; for instance, inhibition of HIF1AN or RIOX2 may also be useful to treat metabolic syndrome or asthma, respectively.	('inhibition', 'Var', (98, 108))	('asthma', 'Disease', 'MESH:D001249', (178, 184))	('HIF1AN', 'Gene', (112, 118))	('treat', 'Reg', (150, 155))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('asthma', 'Phenotype', 'HP:0002099', (178, 184))	('metabolic syndrome', 'Disease', (156, 174))	('RIOX2', 'Gene', (122, 127))	('metabolic syndrome', 'Disease', 'MESH:D024821', (156, 174))	('malignancies', 'Disease', (70, 82))	('asthma', 'Disease', (178, 184))
9149	31034925	In summary, the small JMJD proteins are involved in a myriad of physiological processes related to development, homeostasis and disease that highlights their wide-ranging biological importance.	('homeostasis and disease', 'Disease', 'MESH:D003141', (112, 135))	('small JMJD', 'Var', (16, 26))	('involved', 'Reg', (40, 48))
9155	28291009	In this case report, we present the findings of I-123 MIBG single-photon emission computerized tomography (SPECT/CT) and In-111 SRS SPECT/CT in three members of a family with VHLS.	('I-123 MIBG', 'Chemical', '-', (48, 58))	('VHLS', 'Disease', 'MESH:D006623', (175, 179))	('MIBG', 'Gene', (54, 58))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('VHLS', 'Disease', (175, 179))	('I', 'Chemical', 'MESH:D007455', (121, 122))	('I', 'Chemical', 'MESH:D007455', (55, 56))	('I-123', 'Var', (48, 53))	('I', 'Chemical', 'MESH:D007455', (48, 49))
9162	28291009	Here in, we present the findings of I-123 MIBG single photon emission computerized tomography (SPECT/CT) and In-111 SRS SPECT/CT in three members of a family with VHLS.	('I', 'Chemical', 'MESH:D007455', (43, 44))	('VHLS', 'Disease', (163, 167))	('I', 'Chemical', 'MESH:D007455', (109, 110))	('I', 'Chemical', 'MESH:D007455', (36, 37))	('VHLS', 'Disease', 'MESH:D006623', (163, 167))	('I-123 MIBG', 'Var', (36, 46))	('I-123 MIBG', 'Chemical', '-', (36, 46))
9174	28291009	Four years later, abdominal MRI revealed a mass between the liver and right adrenal gland (33x30x36 mm) and another one in the pancreatic tail (13x15x17 mm).	('33x30x36 mm', 'Var', (91, 102))	('pancreatic', 'Disease', 'MESH:D010195', (127, 137))	('pancreatic', 'Disease', (127, 137))	('I', 'Chemical', 'MESH:D007455', (30, 31))
9202	28291009	They demonstrated uptake of Ga-68 DOTA-NOC in all central nervous system and visceral tumors.	('uptake', 'MPA', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ga', 'Chemical', 'MESH:D005708', (28, 30))	('NOC', 'Chemical', '-', (39, 42))	('visceral tumors', 'Disease', 'MESH:D059265', (77, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('central nervous system', 'Disease', (50, 72))	('visceral tumors', 'Disease', (77, 92))	('Ga-68', 'Var', (28, 33))
9457	26206689	The analytes were detected in multiple-reaction monitoring mode by using positive electrospray ionization: MN, transition m/z 180.1 165.1; NMN, m/z 166.1 134.1.	('ionization', 'Disease', 'MESH:D004194', (95, 105))	('NMN', 'Chemical', 'MESH:D009647', (139, 142))	('ionization', 'Disease', (95, 105))	('m/z 166.1 134.1', 'Var', (144, 159))
9482	26206689	Calibrators were prepared with five concentrations of each analyte (0.04, 0.4, 2.0, 10.0, and 50.0 nmol/L for MN and 0.08, 0.8, 4.0, 20.0, and 100.0 nmol/L for NMN) and were stored at -70C until use.	('NMN', 'Chemical', 'MESH:D009647', (160, 163))	('0.04', 'Var', (68, 72))	('0.08', 'Var', (117, 121))
9490	26206689	The transitions of precursor ions to product ions (m/z 180.1 165.1, m/z 166.1 134.1, m/z 183.1 168.1, and m/z 169.0 137.1) were monitored for MN, NMN, d3-MN, and d3-NMN, respectively, with dwell time of 50 msec for each.	('m/z 166.1 134.1', 'Var', (68, 83))	('NMN', 'Chemical', 'MESH:D009647', (165, 168))	('m/z 180.1 165.1', 'Var', (51, 66))	('m/z 183.1 168.1', 'Var', (85, 100))	('d3-NMN', 'Var', (162, 168))	('NMN', 'Chemical', 'MESH:D009647', (146, 149))	('d3-MN', 'Var', (151, 156))	('m/z 169.0 137.1', 'Var', (106, 121))
9515	24625421	Succinate Dehydrogenase Deficiency Is Rare in Pituitary Adenomas Germline mutations in the succinate dehydrogenase genes (SDHA, SDHB, SDHC, and SDHD) are established as causes of pheochromocytoma/paraganglioma, renal carcinoma, and gastrointestinal stromal tumor.	('succinate dehydrogenase', 'Gene', (91, 114))	('SDHB', 'Gene', (128, 132))	('SDHC', 'Gene', (134, 138))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (179, 209))	('SDHD', 'Gene', '6392', (144, 148))	('SDHA', 'Gene', '6389', (122, 126))	('Pituitary Adenomas', 'Phenotype', 'HP:0002893', (46, 64))	('renal carcinoma', 'Disease', 'MESH:C538614', (211, 226))	('Pituitary Adenomas', 'Disease', 'MESH:D010911', (46, 64))	('renal carcinoma', 'Disease', (211, 226))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (232, 262))	('renal carcinoma', 'Phenotype', 'HP:0005584', (211, 226))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (232, 262))	('SDHD', 'Gene', (144, 148))	('succinate dehydrogenase', 'Gene', '6390', (91, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (179, 195))	('SDHC', 'Gene', '6391', (134, 138))	('gastrointestinal stromal tumor', 'Disease', (232, 262))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('SDHB', 'Gene', '6390', (128, 132))	('Dehydrogenase Deficiency', 'Disease', 'MESH:D005955', (10, 34))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('pheochromocytoma/paraganglioma', 'Disease', (179, 209))	('mutations', 'Var', (74, 83))	('Pituitary Adenomas', 'Disease', (46, 64))	('Dehydrogenase Deficiency', 'Disease', (10, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('causes', 'Reg', (169, 175))	('SDHA', 'Gene', (122, 126))
9517	24625421	We sought to determine the incidence of SDH mutation in pituitary adenomas.	('mutation', 'Var', (44, 52))	('pituitary adenomas', 'Disease', 'MESH:D010911', (56, 74))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (56, 74))	('pituitary adenomas', 'Disease', (56, 74))	('SDH', 'Gene', '6390', (40, 43))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (56, 73))	('SDH', 'Gene', (40, 43))
9519	24625421	In those patients with an abnormal pattern of staining, we then performed SDH mutation analysis on DNA extracted from paraffin-embedded tissue, fresh frozen tissue, and peripheral blood.	('SDH', 'Gene', (74, 77))	('patients', 'Species', '9606', (9, 17))	('mutation', 'Var', (78, 86))	('paraffin', 'Chemical', 'MESH:D010232', (118, 126))	('SDH', 'Gene', '6390', (74, 77))
9521	24625421	Examination of paraffin-embedded and frozen tissues confirmed double-hit inactivating somatic SDHA mutations (c.725_736del and c.989_990insTA).	('c.989_990insTA', 'Mutation', 'c.989_990insTA', (127, 141))	('SDHA', 'Gene', '6389', (94, 98))	('c.725_736del', 'Var', (110, 122))	('SDHA', 'Gene', (94, 98))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('c.725_736del', 'Mutation', 'c.725_736del', (110, 122))	('c.989_990insTA', 'Var', (127, 141))
9522	24625421	We conclude that, although pathogenic SDH mutation may occur in pituitary adenomas and can be identified by immunohistochemistry, it appears to be a very rare event and can occur in the absence of germline mutation.	('SDH', 'Gene', '6390', (38, 41))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (64, 81))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (64, 82))	('pituitary adenomas', 'Disease', (64, 82))	('occur', 'Reg', (55, 60))	('mutation', 'Var', (42, 50))	('SDH', 'Gene', (38, 41))	('pituitary adenomas', 'Disease', 'MESH:D010911', (64, 82))	('pathogenic', 'Reg', (27, 37))
9524	24625421	Unless suggested by family history and physical examination, it is difficult to justify screening for SDH mutations in pituitary adenomas.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (119, 137))	('SDH', 'Gene', (102, 105))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (119, 136))	('pituitary adenomas', 'Disease', (119, 137))	('pituitary adenomas', 'Disease', 'MESH:D010911', (119, 137))	('mutations', 'Var', (106, 115))	('SDH', 'Gene', '6390', (102, 105))
9525	24625421	Surveillance programs for patients with SDH mutation may be tailored to include the possibility of pituitary neoplasia; however, this is likely to be a low-yield strategy.	('mutation', 'Var', (44, 52))	('patients', 'Species', '9606', (26, 34))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (99, 118))	('SDH', 'Gene', '6390', (40, 43))	('pituitary neoplasia', 'Disease', (99, 118))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (99, 118))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('SDH', 'Gene', (40, 43))
9527	24625421	At least 5% are hereditary, and there are clear associations with multiple endocrine neoplasia type 1 (MEN1, associated with MEN1 mutation), familial isolated pituitary adenoma (often associated with AIP mutation), Carney complex (often associated with PRKAR1A mutation), and MEN4 (associated with CDKN1B mutation).	('familial isolated pituitary adenoma', 'Disease', (141, 176))	('MEN1', 'Gene', '4221', (103, 107))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (75, 94))	('multiple endocrine neoplasia type 1', 'Gene', (66, 101))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (159, 176))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (66, 101))	('CDKN1B', 'Gene', (298, 304))	('MEN1', 'Gene', (103, 107))	('mutation', 'Var', (130, 138))	('MEN1', 'Gene', '4221', (125, 129))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (150, 176))	('PRKAR1A', 'Gene', (253, 260))	('associations', 'Interaction', (48, 60))	('MEN1', 'Gene', (125, 129))	('familial isolated pituitary adenoma', 'Disease', 'MESH:C566321', (141, 176))	('CDKN1B', 'Gene', '1027', (298, 304))	('MEN4', 'Gene', '1027', (276, 280))	('PRKAR1A', 'Gene', '5573', (253, 260))	('Carney complex', 'Disease', (215, 229))	('associated', 'Reg', (184, 194))	('neoplasia', 'Phenotype', 'HP:0002664', (85, 94))	('MEN4', 'Gene', (276, 280))
9530	24625421	These genes also function as tumor-suppressor genes, and germline SDH mutations are associated with a tumor syndrome characterized by pheochromocytoma/paraganglioma, a unique subtype of gastrointestinal stromal tumor (GIST) known as SDH-deficient GIST and a distinctive type of renal carcinoma.	('renal carcinoma', 'Phenotype', 'HP:0005584', (278, 293))	('tumor syndrome', 'Disease', 'MESH:D009369', (102, 116))	('SDH', 'Gene', (233, 236))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (186, 216))	('SDH', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (233, 251))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))	('SDH-deficient GIST', 'Disease', (233, 251))	('gastrointestinal stromal tumor', 'Disease', (186, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (151, 164))	('associated', 'Reg', (84, 94))	('pheochromocytoma/paraganglioma', 'Disease', (134, 164))	('tumor-suppressor', 'Gene', '7248', (29, 45))	('mutations', 'Var', (70, 79))	('GIST', 'Phenotype', 'HP:0100723', (218, 222))	('GIST', 'Phenotype', 'HP:0100723', (247, 251))	('type of renal carcinoma', 'Disease', (270, 293))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('type of renal carcinoma', 'Disease', 'MESH:C538614', (270, 293))	('SDH', 'Gene', '6390', (233, 236))	('SDH', 'Gene', '6390', (66, 69))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (134, 164))	('tumor-suppressor', 'Gene', (29, 45))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (186, 216))	('tumor syndrome', 'Disease', (102, 116))
9531	24625421	It is noteworthy that loss of immunohistochemical (IHC) staining for SDHB has been consistently identified in pheochromocytomas/paragangliomas, GISTs, and renal carcinomas associated with SDH mutation regardless of which SDH subunit is mutated.	('renal carcinomas', 'Phenotype', 'HP:0005584', (155, 171))	('loss', 'NegReg', (22, 26))	('pheochromocytomas/paragangliomas', 'Disease', (110, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (128, 141))	('paragangliomas', 'Phenotype', 'HP:0002668', (128, 142))	('SDHB', 'Gene', '6390', (69, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('renal carcinoma', 'Phenotype', 'HP:0005584', (155, 170))	('GISTs', 'Disease', (144, 149))	('mutation', 'Var', (192, 200))	('SDH', 'Gene', '6390', (221, 224))	('SDH', 'Gene', '6390', (188, 191))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (110, 142))	('SDHB', 'Gene', (69, 73))	('SDH', 'Gene', '6390', (69, 72))	('associated', 'Reg', (172, 182))	('renal carcinomas', 'Disease', 'MESH:C538614', (155, 171))	('SDH', 'Gene', (221, 224))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (110, 127))	('SDH', 'Gene', (188, 191))	('GIST', 'Phenotype', 'HP:0100723', (144, 148))	('SDH', 'Gene', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (110, 126))	('renal carcinomas', 'Disease', (155, 171))
9532	24625421	In addition to loss of SDHB staining, negative staining for SDHA also occurs in pheochromocytomas/paragangliomas and GISTs associated with SDHA mutation.	('paragangliomas', 'Phenotype', 'HP:0002668', (98, 112))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (80, 112))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('SDHA', 'Gene', '6389', (139, 143))	('SDHB', 'Gene', '6390', (23, 27))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (80, 97))	('SDHA', 'Gene', '6389', (60, 64))	('mutation', 'Var', (144, 152))	('SDHB', 'Gene', (23, 27))	('SDHA', 'Gene', (139, 143))	('GIST', 'Phenotype', 'HP:0100723', (117, 121))	('pheochromocytomas/paragangliomas', 'Disease', (80, 112))	('SDHA', 'Gene', (60, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))
9533	24625421	To date, SDHA mutation has not been reported in association in with renal carcinoma.	('renal carcinoma', 'Disease', 'MESH:C538614', (68, 83))	('SDHA', 'Gene', '6389', (9, 13))	('renal carcinoma', 'Disease', (68, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('mutation', 'Var', (14, 22))	('renal carcinoma', 'Phenotype', 'HP:0005584', (68, 83))	('SDHA', 'Gene', (9, 13))
9534	24625421	Tumors that show negative staining for SDHB are known as succinate dehydrogenase deficient, and IHC for SDHB and SDHA is used routinely to screen patients presenting with compatible tumors for germline SDH mutation.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('SDHB', 'Gene', '6390', (39, 43))	('SDH', 'Gene', '6390', (104, 107))	('SDHA', 'Gene', '6389', (113, 117))	('SDH', 'Gene', (202, 205))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('succinate dehydrogenase', 'Gene', (57, 80))	('SDH', 'Gene', (113, 116))	('tumors', 'Disease', (182, 188))	('SDHB', 'Gene', (39, 43))	('Tumors', 'Disease', (0, 6))	('SDH', 'Gene', (104, 107))	('SDH', 'Gene', '6390', (39, 42))	('patients', 'Species', '9606', (146, 154))	('deficient', 'NegReg', (81, 90))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('mutation', 'Var', (206, 214))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('SDHB', 'Gene', '6390', (104, 108))	('succinate dehydrogenase', 'Gene', '6390', (57, 80))	('SDH', 'Gene', '6390', (202, 205))	('SDH', 'Gene', (39, 42))	('SDH', 'Gene', '6390', (113, 116))	('SDHA', 'Gene', (113, 117))	('SDHB', 'Gene', (104, 108))
9535	24625421	There is now emerging evidence that pituitary adenomas may also be associated with SDH mutation.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (36, 53))	('SDH', 'Gene', '6390', (83, 86))	('pituitary adenomas', 'Disease', 'MESH:D010911', (36, 54))	('associated', 'Reg', (67, 77))	('SDH', 'Gene', (83, 86))	('mutation', 'Var', (87, 95))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (36, 54))	('pituitary adenomas', 'Disease', (36, 54))
9536	24625421	Briefly, 35 cases of coexistent pheochromocytoma/paraganglioma and pituitary adenoma in individuals or kindreds have been reported, and second-hit inactivation has been demonstrated by either loss of heterozygosity or acquired mutation in 2 pituitary adenomas arising in the setting of germline SDH mutation.	('pituitary adenomas', 'Disease', 'MESH:D010911', (241, 259))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (32, 62))	('loss of heterozygosity', 'Var', (192, 214))	('pituitary adenoma', 'Disease', 'MESH:D010911', (241, 258))	('SDH', 'Gene', (295, 298))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (32, 48))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (241, 259))	('pituitary adenoma', 'Disease', (67, 84))	('pituitary adenomas', 'Disease', (241, 259))	('pituitary adenoma', 'Disease', 'MESH:D010911', (67, 84))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (241, 258))	('mutation', 'Var', (299, 307))	('paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('SDH', 'Gene', '6390', (295, 298))	('pheochromocytoma/paraganglioma', 'Disease', (32, 62))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (67, 84))
9537	24625421	However, to date, the evidence linking SDH mutation and pituitary neoplasia has been based on case reports, and the incidence and clinical significance of SDH mutation in pituitary adenomas is unknown.	('pituitary adenomas', 'Disease', (171, 189))	('SDH', 'Gene', (39, 42))	('SDH', 'Gene', '6390', (155, 158))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (171, 188))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (56, 75))	('mutation', 'Var', (43, 51))	('neoplasia', 'Phenotype', 'HP:0002664', (66, 75))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (56, 75))	('pituitary neoplasia', 'Disease', (56, 75))	('pituitary adenomas', 'Disease', 'MESH:D010911', (171, 189))	('SDH', 'Gene', (155, 158))	('SDH', 'Gene', '6390', (39, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (171, 189))
9538	24625421	In this study, we sought to estimate the incidence and clinicopathologic associations of SDH mutation in pituitary adenomas.	('SDH', 'Gene', (89, 92))	('pituitary adenomas', 'Disease', (105, 123))	('pituitary adenomas', 'Disease', 'MESH:D010911', (105, 123))	('SDH', 'Gene', '6390', (89, 92))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (105, 123))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (105, 122))	('mutation', 'Var', (93, 101))
9564	24625421	In both the FFPE and frozen tissue the same 2 inactivating mutations were identified:a deletion in exon 6 (c.725_736del) and an insertion in exon 8 (c.989_990insTA).	('c.989_990insTA', 'Mutation', 'c.989_990insTA', (149, 163))	('c.725_736del', 'Mutation', 'c.725_736del', (107, 119))	('c.989_990insTA', 'Var', (149, 163))	('c.725_736del', 'Var', (107, 119))
9567	24625421	There have been 8 previously reported cases of pituitary adenoma occurring in association with confirmed germline SDH mutation, comprising 1 adenoma associated with mutation of SDHA, 3 with SDHB mutation, 2 with SDHC mutation, and 2 with SDHD mutation (summarized in Table 1).	('SDHB', 'Gene', '6390', (190, 194))	('SDHC', 'Gene', (212, 216))	('SDH', 'Gene', '6390', (238, 241))	('SDH', 'Gene', (114, 117))	('SDHA', 'Gene', (177, 181))	('pituitary adenoma', 'Disease', 'MESH:D010911', (47, 64))	('SDH', 'Gene', (177, 180))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (47, 64))	('SDHD', 'Gene', '6392', (238, 242))	('adenoma', 'Disease', (57, 64))	('SDHB', 'Gene', (190, 194))	('SDHA', 'Gene', '6389', (177, 181))	('associated', 'Reg', (149, 159))	('pituitary adenoma', 'Disease', (47, 64))	('SDH', 'Gene', '6390', (190, 193))	('adenoma', 'Disease', (141, 148))	('SDH', 'Gene', (238, 241))	('adenoma', 'Disease', 'MESH:D000236', (57, 64))	('SDH', 'Gene', '6390', (212, 215))	('SDHD', 'Gene', (238, 242))	('SDHC', 'Gene', '6391', (212, 216))	('adenoma', 'Disease', 'MESH:D000236', (141, 148))	('mutation', 'Var', (118, 126))	('SDH', 'Gene', (190, 193))	('SDH', 'Gene', '6390', (114, 117))	('SDH', 'Gene', '6390', (177, 180))	('SDH', 'Gene', (212, 215))	('mutation', 'Var', (165, 173))
9570	24625421	Including this case, of the 9 pituitary adenomas reported in association with confirmed SDH mutation, the mean age has been 45 years (range, 30 to 62 y), and 6 have occurred in men.	('SDH', 'Gene', (88, 91))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (30, 48))	('mutation', 'Var', (92, 100))	('pituitary adenomas', 'Disease', (30, 48))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (30, 47))	('men', 'Species', '9606', (177, 180))	('SDH', 'Gene', '6390', (88, 91))	('pituitary adenomas', 'Disease', 'MESH:D010911', (30, 48))
9572	24625421	In addition, the clinically nonfunctioning pituitary macroadenoma arising in the setting of germline SDHA mutation, which we recently described, also demonstrated positive IHC staining for prolactin (previously unreported data).	('pituitary macroadenoma', 'Disease', (43, 65))	('SDHA', 'Gene', '6389', (101, 105))	('pituitary macroadenoma', 'Disease', 'MESH:D010900', (43, 65))	('mutation', 'Var', (106, 114))	('SDHA', 'Gene', (101, 105))	('prolactin', 'Gene', (189, 198))	('prolactin', 'Gene', '5617', (189, 198))	('nonfunctioning pituitary macroadenoma', 'Phenotype', 'HP:0011761', (28, 65))
9578	24625421	Furthermore, germline SDH mutation presenting with pituitary neoplasia is extremely rare (none in 309 consecutive adenomas).	('adenomas', 'Disease', (114, 122))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (51, 70))	('mutation', 'Var', (26, 34))	('pituitary neoplasia', 'Disease', (51, 70))	('SDH', 'Gene', '6390', (22, 25))	('neoplasia', 'Phenotype', 'HP:0002664', (61, 70))	('adenomas', 'Disease', 'MESH:D000236', (114, 122))	('SDH', 'Gene', (22, 25))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (51, 70))
9586	24625421	In the interim, we recommend that the possibility of pituitary disease, particularly associated with hyperprolactinemia, be specifically considered in the annual history and physical examination for patients with known SDH mutation.	('SDH', 'Gene', '6390', (219, 222))	('men', 'Species', '9606', (24, 27))	('hyperprolactinemia', 'Disease', (101, 119))	('pituitary disease', 'Disease', 'MESH:D010900', (53, 70))	('pituitary disease', 'Phenotype', 'HP:0011747', (53, 70))	('SDH', 'Gene', (219, 222))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (101, 119))	('mutation', 'Var', (223, 231))	('pituitary disease', 'Disease', (53, 70))	('patients', 'Species', '9606', (199, 207))	('hyperprolactinemia', 'Disease', 'MESH:D002640', (101, 119))	('associated', 'Reg', (85, 95))
9587	24625421	The occurrence of 2 somatic SDHA mutations in the absence of a germline mutation is very unusual.	('SDHA', 'Gene', '6389', (28, 32))	('mutations', 'Var', (33, 42))	('SDHA', 'Gene', (28, 32))
9589	24625421	In fact, we are only aware of 2 reports of somatic mutation in SDH occurring in pheochromocytoma/paraganglioma (1 SDHB and 1 SDHD) in the absence of germline mutation and none in GIST or renal cancer.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('SDHB', 'Gene', (114, 118))	('renal cancer', 'Disease', (187, 199))	('mutation', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('SDH', 'Gene', (114, 117))	('renal cancer', 'Phenotype', 'HP:0009726', (187, 199))	('SDH', 'Gene', '6390', (63, 66))	('GIST', 'Phenotype', 'HP:0100723', (179, 183))	('pheochromocytoma/paraganglioma', 'Disease', (80, 110))	('renal cancer', 'Disease', 'MESH:D007680', (187, 199))	('SDHD', 'Gene', '6392', (125, 129))	('SDH', 'Gene', '6390', (125, 128))	('SDH', 'Gene', (63, 66))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (80, 110))	('SDHD', 'Gene', (125, 129))	('SDH', 'Gene', '6390', (114, 117))	('SDHB', 'Gene', '6390', (114, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (97, 110))	('SDH', 'Gene', (125, 128))
9590	24625421	Although the identification of SDH mutation in a tumor is usually considered prima facie evidence of germline SDH mutation, we caution that this is not always the case and that inactivation of the SDH genes can occur as a truly somatic event.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('SDH', 'Gene', '6390', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('SDH', 'Gene', '6390', (110, 113))	('tumor', 'Disease', (49, 54))	('SDH', 'Gene', '6390', (197, 200))	('SDH', 'Gene', (31, 34))	('SDH', 'Gene', (110, 113))	('mutation', 'Var', (35, 43))	('SDH', 'Gene', (197, 200))
9592	24625421	In conclusion, it appears that pituitary adenomas are a legitimate albeit very rare component of the hereditary syndromes associated with SDH mutation, and therefore the possibility of pituitary neoplasia should be considered clinically in patients with SDH mutation who are under surveillance.	('component of the hereditary syndromes', 'Disease', 'MESH:D009386', (84, 121))	('pituitary neoplasia', 'Disease', (185, 204))	('pituitary neoplasia', 'Phenotype', 'HP:0040277', (185, 204))	('SDH', 'Gene', '6390', (254, 257))	('SDH', 'Gene', '6390', (138, 141))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (31, 49))	('neoplasia', 'Phenotype', 'HP:0002664', (195, 204))	('pituitary adenomas', 'Disease', (31, 49))	('SDH', 'Gene', (254, 257))	('SDH', 'Gene', (138, 141))	('patients', 'Species', '9606', (240, 248))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (31, 48))	('mutation', 'Var', (142, 150))	('component of the hereditary syndromes', 'Disease', (84, 121))	('pituitary adenomas', 'Disease', 'MESH:D010911', (31, 49))	('pituitary neoplasia', 'Disease', 'MESH:D009369', (185, 204))
9617	22584715	Owing to the need for genetic association studies for unequivocal cases of MEN type 2, higher risk mutations in codon 918 (the classic MEN2B mutation; American Thyroid Association/ATA D), codon 634 (the classic MEN2A mutation; ATA C) and codons 609, 611, 618, 620, and 630 (ATA B) were overrepresented in the International MEN2 Consortium.	('ATA C', 'Gene', '6375', (227, 232))	('MEN', 'Species', '9606', (75, 78))	('MEN', 'Species', '9606', (211, 214))	('codon 634', 'Var', (188, 197))	('MEN2B', 'Gene', (135, 140))	('codon', 'Gene', (112, 117))	('MEN', 'Species', '9606', (135, 138))	('mutations', 'Var', (99, 108))	('MEN2B', 'Gene', '5979', (135, 140))	('MEN', 'Species', '9606', (323, 326))	('MEN2A', 'Gene', '5979', (211, 216))	('ATA C', 'Gene', (227, 232))	('higher risk', 'PosReg', (87, 98))	('MEN2A', 'Gene', (211, 216))
9618	22584715	The subsequent scanning of the RET proto-oncogene for additional mutations identified more RET mutations in codons 768, 790, 791, 804, and 891 between 1995 and 1998 -.	('RET', 'Gene', (91, 94))	('RET', 'Gene', '5979', (31, 34))	('RET', 'Gene', (31, 34))	('RET', 'Gene', '5979', (91, 94))	('mutations in codons 768', 'Var', (95, 118))
9621	22584715	The constitutive (i.e., genetically encoded) activation of the mutated RET receptor protein is believed to cause, in decreasing frequency, hyperplasia of the parafollicular C-cells, adrenal medullary cells, and parathyroid chief cells.	('mutated', 'Var', (63, 70))	('hyperplasia', 'Disease', (139, 150))	('cause', 'Reg', (107, 112))	('RET', 'Gene', '5979', (71, 74))	('activation', 'PosReg', (45, 55))	('hyperplasia', 'Disease', 'MESH:D006965', (139, 150))	('RET', 'Gene', (71, 74))
9622	22584715	A second mutation in one of these neuroendocrine cells ("second hit") is thought to cause MTC (C-cell cancer), pheochromocytoma, and primary hyperparathyroidism.	('mutation', 'Var', (9, 17))	('pheochromocytoma', 'Disease', (111, 127))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('pheochromocytoma', 'Disease', 'MESH:D010673', (111, 127))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('primary hyperparathyroidism', 'Disease', 'MESH:D049950', (133, 160))	('C-cell cancer', 'Disease', (95, 108))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (133, 160))	('primary hyperparathyroidism', 'Disease', (133, 160))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (141, 160))	('C-cell cancer', 'Disease', 'MESH:D020216', (95, 108))	('cause', 'Reg', (84, 89))
9623	22584715	Because the acquisition of somatic mutations by these cells reflects the play of chance, the development of the various MEN2 components can vary tremendously even among members of the same family, compromising predictions regarding the age by which the various MEN2 components will have developed.	('MEN', 'Species', '9606', (120, 123))	('compromising', 'NegReg', (197, 209))	('MEN', 'Species', '9606', (261, 264))	('mutations', 'Var', (35, 44))
9624	22584715	As a rule, the weaker the transforming activity of the inherited RET mutation, the more variable will be the clinical presentation (phenotype) of the various MEN2 components,,, with steep gradients from highest risk ATA-D to very high-risk ATA-C, high-risk ATA-B, and lowest risk ATA-A mutations (Table 1).	('weaker', 'NegReg', (15, 21))	('RET', 'Gene', '5979', (65, 68))	('MEN', 'Species', '9606', (158, 161))	('ATA-C', 'Gene', (240, 245))	('RET', 'Gene', (65, 68))	('mutation', 'Var', (69, 77))	('ATA-C', 'Gene', '6375', (240, 245))	('transforming activity', 'MPA', (26, 47))
9625	22584715	A systematic review of the literature,-, focused on the youngest carrier age at which a given MEN2-related tumor was ever reported, yielded the following chart of earliest tumor development (Table 1): medullary thyroid cancer as early as age 2 months (carriers of mutations in codon 918), 10 months (carriers of mutations in codon 634), 12 months (carriers of mutations in codon 630), 4-7 years (carriers of mutations in codons 609, 611, 618 and 620) and 9-21 years (carriers of mutations in codons 533, 768, 790, 791, 804 and 891); pheochromocytoma as early as age 12 years (carriers of mutations in codon 918 and 634), 19-30 years (carriers of mutations in codons 609, 611, 618, and 620), and 28-59 years (carriers of mutations in codons 768, 790, 791, 804, and 891); primary hyperparathyroidism as early as 5 years (carriers of mutations in codon 634), 34-41 years (carriers of mutations in codons 609, 611, 618, and 620), and 38-54 years (carriers of mutations in codons 533, 768, 790, 791, 804, and 891), but for unknown reasons, never in MEN2B patients (carriers of mutations in codon 918).	('MEN2B', 'Gene', (1044, 1049))	('tumor', 'Disease', (107, 112))	('mutations', 'Var', (955, 964))	('tumor', 'Disease', (172, 177))	('MEN2B', 'Gene', '5979', (1044, 1049))	('thyroid cancer', 'Disease', (211, 225))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('primary hyperparathyroidism', 'Disease', (770, 797))	('mutations', 'Var', (881, 890))	('MEN', 'Species', '9606', (94, 97))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (201, 225))	('mutations', 'Var', (831, 840))	('thyroid cancer', 'Disease', 'MESH:D013964', (211, 225))	('primary hyperparathyroidism', 'Disease', 'MESH:D049950', (770, 797))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('pheochromocytoma', 'Disease', 'MESH:D010673', (533, 549))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('thyroid cancer', 'Phenotype', 'HP:0002890', (211, 225))	('patients', 'Species', '9606', (1050, 1058))	('pheochromocytoma', 'Disease', (533, 549))	('primary hyperparathyroidism', 'Phenotype', 'HP:0008200', (770, 797))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (533, 549))	('MEN', 'Species', '9606', (1044, 1047))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (778, 797))
9626	22584715	With more data set to be forthcoming, the current ATA assignments of the rare RET mutations in codon 630 (currently ATA-B) and 883 (currently ATA D) may need to be revised.	('RET', 'Gene', (78, 81))	('codon 630', 'Gene', (95, 104))	('mutations in', 'Var', (82, 94))	('RET', 'Gene', '5979', (78, 81))
9628	22584715	Barring rare exceptions, lymph node metastases have not yet developed before age 2 years (carriers of mutations in codon 918), not before age 5 years (carriers of mutations in codon 634) and 15 years (carriers of mutations in codons 630) and not before age 20 years in the remaining RET carriers.	('RET', 'Gene', (283, 286))	('mutations in codon 634', 'Var', (163, 185))	('mutations in codon 918', 'Var', (102, 124))	('RET', 'Gene', '5979', (283, 286))	('lymph node metastases', 'Disease', 'MESH:D009362', (25, 46))	('lymph node metastases', 'Disease', (25, 46))
9632	22584715	Although the respective RET mutation sets the stage for tumor development, defining a time corridor, this corridor often is too wide to be useful for individual decisions with regard to the timing of prophylactic thyroidectomy.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('RET', 'Gene', '5979', (24, 27))	('tumor', 'Disease', (56, 61))	('mutation', 'Var', (28, 36))	('RET', 'Gene', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
9646	22584715	This disruption delayed the diagnosis of hereditary MTC in the second index patient by 7 years in the C611F family (Figure 2a) and 19 years in the C620S family (Figure 2b).	('C620S', 'Var', (147, 152))	('C611F', 'Mutation', 'rs377767397', (102, 107))	('hereditary MTC', 'Disease', (41, 55))	('C611F', 'Var', (102, 107))	('patient', 'Species', '9606', (76, 83))	('delayed', 'NegReg', (16, 23))	('C620S', 'Mutation', 'rs77316810', (147, 152))
9650	22584715	DNA-based screening may occasionally uncover previously unknown RET sequence variants dubbed "variants of unknown significance" (VUS), which may represent harmless polymorphisms or pathogenic mutations.	('RET', 'Gene', (64, 67))	('variants', 'Var', (77, 85))	('RET', 'Gene', '5979', (64, 67))
9651	22584715	In this setting, functional characterization of RET mutant cells in vitro has been harnessed to generate ancillary evidence regarding the pathogenicity of unknown sequence variants in comparison with established RET mutations -.	('RET', 'Gene', '5979', (212, 215))	('mutant', 'Var', (52, 58))	('variants', 'Var', (172, 180))	('RET', 'Gene', '5979', (48, 51))	('RET', 'Gene', (212, 215))	('RET', 'Gene', (48, 51))
9661	22584723	Recently, PHEO was reported to be highly prevalent in MEN2A patients harboring the double 634/791 mutation in the RET proto-oncogene.	('MEN2A', 'Gene', (54, 59))	('RET', 'Gene', '5979', (114, 117))	('patients', 'Species', '9606', (60, 68))	('PHEO', 'Disease', (10, 14))	('RET', 'Gene', (114, 117))	('double 634/791', 'Var', (83, 97))	('MEN2A', 'Gene', '5979', (54, 59))	('prevalent', 'Reg', (41, 50))	('PHEO', 'Phenotype', 'HP:0002666', (10, 14))
9763	33842149	Mutations of the gene, which converts into a coded form the succinate dehydrogenase (SDH) enzymes SDHD, SDHA, SDHB, and SDHC, are known to cause familial head and neck paragangliomas.	('succinate dehydrogenase', 'Gene', (60, 83))	('SDH', 'Gene', '6390', (104, 107))	('SDHA', 'Gene', (104, 108))	('paraganglioma', 'Phenotype', 'HP:0002668', (168, 181))	('paragangliomas', 'Phenotype', 'HP:0002668', (168, 182))	('SDHD', 'Gene', (98, 102))	('SDHA', 'Gene', '6389', (104, 108))	('SDH', 'Gene', '6390', (120, 123))	('SDHB', 'Gene', (110, 114))	('SDH', 'Gene', (98, 101))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (154, 182))	('SDH', 'Gene', '6390', (110, 113))	('SDHC', 'Gene', '6391', (120, 124))	('familial head and neck paragangliomas', 'Disease', 'MESH:D006258', (145, 182))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (104, 107))	('SDH', 'Gene', '6390', (85, 88))	('succinate dehydrogenase', 'Gene', '6390', (60, 83))	('SDH', 'Gene', (120, 123))	('SDH', 'Gene', (110, 113))	('cause', 'Reg', (139, 144))	('SDHC', 'Gene', (120, 124))	('SDH', 'Gene', (85, 88))	('SDHD', 'Gene', '6392', (98, 102))	('SDHB', 'Gene', '6390', (110, 114))	('SDH', 'Gene', '6390', (98, 101))
9764	33842149	Mutations in the SDHB are the reason for familial adrenal pheochromocytoma and extra-adrenal paraganglioma in the thorax and abdomen region.	('extra-adrenal paraganglioma', 'Disease', (79, 106))	('familial adrenal pheochromocytoma', 'Disease', 'MESH:C531777', (41, 74))	('reason', 'Reg', (30, 36))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (79, 106))	('familial adrenal pheochromocytoma', 'Disease', (41, 74))	('SDHB', 'Gene', '6390', (17, 21))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('SDHB', 'Gene', (17, 21))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (50, 74))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))
9778	33842149	Genetic testing revealed no relationship with any SDH mutations.	('SDH', 'Gene', '6390', (50, 53))	('mutations', 'Var', (54, 63))	('SDH', 'Gene', (50, 53))
9783	33842149	Immunohistochemistry revealed the positivity of neoplastic cells (Figure 5) in synaptophysin, chromogranin (Figure 6), and S100 (Figure 7), whereas the markers pankeratin and CD10 were negative.	('chromogranin', 'Protein', (94, 106))	('S100', 'Gene', (123, 127))	('positivity', 'Var', (34, 44))	('S100', 'Gene', '6271', (123, 127))	('synaptophysin', 'Gene', (79, 92))	('CD10', 'Gene', '4311', (175, 179))	('CD10', 'Gene', (175, 179))	('synaptophysin', 'Gene', '6855', (79, 92))
9797	33842149	The entity of SDHB mutations should alert surgeons to proceed with early and extensive surgery, a fact of paramount importance for patient's safety and overall survival.	('SDHB', 'Gene', '6390', (14, 18))	('SDHB', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('patient', 'Species', '9606', (131, 138))
9798	33842149	Unfortunately, tumors related to SDH mutations display more aggressive behavior.	('tumors', 'Disease', (15, 21))	('aggressive behavior', 'CPA', (60, 79))	('SDH', 'Gene', (33, 36))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('aggressive behavior', 'Phenotype', 'HP:0000718', (60, 79))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SDH', 'Gene', '6390', (33, 36))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
9824	32342607	The pre-surgical evaluation of this colon carcinoma was type 2, T3N0M0, Stage IIA.	('colon carcinoma', 'Disease', 'MESH:D003110', (36, 51))	('T3N0M0', 'Var', (64, 70))	('colon carcinoma', 'Disease', (36, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
9843	32326947	In addition to their common tumoral manifestations, many of these diseases present clinical affection of bone tissues and/or mineral metabolism, both as secondary complications of primary tumors and as primary defects due to genetic mutation.	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('affection', 'Reg', (92, 101))	('genetic mutation', 'Var', (225, 241))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('bone tissues', 'CPA', (105, 117))	('primary tumors', 'Disease', (180, 194))	('tumoral', 'Disease', (28, 35))	('tumoral', 'Disease', 'MESH:D009369', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('primary tumors', 'Disease', 'MESH:D001932', (180, 194))	('mineral', 'CPA', (125, 132))
9845	32326947	In addition to their common manifestations, almost all inherited endocrine tumor syndromes present features of bone and mineral metabolism, either as secondary complications of primary tumors or as a primary consequence of gene mutation.	('primary tumors', 'Disease', 'MESH:D001932', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('endocrine tumor', 'Phenotype', 'HP:0100568', (65, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('primary tumors', 'Disease', (177, 191))	('gene mutation', 'Var', (223, 236))	('endocrine tumor syndromes', 'Disease', (65, 90))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('endocrine tumor syndromes', 'Disease', 'MESH:D004701', (65, 90))
9881	32326947	MEN2 is caused by germinal heterozygote activating point mutations of the proto-oncogene RET (REarranged during Transfection; 10q11.21) (Table 1], encoding the homonym trans-membrane tyrosine kinase receptor (RET) responsible for positive regulation of cell growth.	('MEN2', 'Disease', (0, 4))	('activating', 'PosReg', (40, 50))	('RET', 'Gene', (209, 212))	('RET', 'Gene', (89, 92))	('RET', 'Gene', '5979', (209, 212))	('caused', 'Reg', (8, 14))	('MEN', 'Species', '9606', (0, 3))	('point mutations', 'Var', (51, 66))	('REarranged during Transfection', 'Gene', (94, 124))	('RET', 'Gene', '5979', (89, 92))	('REarranged during Transfection', 'Gene', '5979', (94, 124))
9882	32326947	MEN2A patients have mutations at codons 634 (85% of cases), 609, 611, 618 and 620.	('MEN2A', 'Gene', '5979', (0, 5))	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (20, 29))	('MEN2A', 'Gene', (0, 5))
9883	32326947	Over 90% of MEN2B patients present the de novo M918T mutation; mutation at codon 883 (A883F) affects about 5% of MEN2B patients.	('MEN2B', 'Gene', (113, 118))	('MEN2B', 'Gene', '5979', (113, 118))	('patients', 'Species', '9606', (119, 127))	('A883F', 'Mutation', 'rs377767429', (86, 91))	('M918T', 'Mutation', 'rs74799832', (47, 52))	('patients', 'Species', '9606', (18, 26))	('MEN2B', 'Gene', (12, 17))	('M918T', 'Var', (47, 52))	('MEN2B', 'Gene', '5979', (12, 17))
9888	32326947	PTH normalization, following surgical removal of parathyroid adenoma, reverts the bone mass loss.	('parathyroid adenoma', 'Disease', (49, 68))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (49, 68))	('PTH', 'Gene', (0, 3))	('parathyroid adenoma', 'Disease', 'MESH:D010282', (49, 68))	('PTH', 'Gene', '5741', (0, 3))	('bone mass loss', 'CPA', (82, 96))	('normalization', 'Var', (4, 17))	('reverts', 'NegReg', (70, 77))
9894	32326947	Skeletal anomalies, manifesting in MEN2B form, can be ascribed to the specific RET mutations, affecting the intracellular domain of the protein and responsible for MEN2B phenotype.	('mutations', 'Var', (83, 92))	('RET', 'Gene', '5979', (79, 82))	('MEN2B', 'Gene', (164, 169))	('Skeletal anomalies', 'Disease', 'MESH:C535534', (0, 18))	('Skeletal anomalies', 'Phenotype', 'HP:0000924', (0, 18))	('MEN2B', 'Gene', '5979', (164, 169))	('Skeletal anomalies', 'Disease', (0, 18))	('MEN2B', 'Gene', (35, 40))	('RET', 'Gene', (79, 82))	('MEN2B', 'Gene', '5979', (35, 40))	('affecting', 'Reg', (94, 103))	('intracellular domain of the protein', 'MPA', (108, 143))	('responsible', 'Reg', (148, 159))
9899	32326947	Chm1 mutant mice showed increased bone deposition.	('Chm1', 'Gene', '11061', (0, 4))	('bone deposition', 'CPA', (34, 49))	('mutant', 'Var', (5, 11))	('Chm1', 'Gene', (0, 4))	('mice', 'Species', '10090', (12, 16))	('increased', 'PosReg', (24, 33))
9900	32326947	Altered expression of CHM1 is suspected to alter the bone growth plate, leading to the skeletal abnormalities observed in MEN2B patients.	('leading to', 'Reg', (72, 82))	('MEN2B', 'Gene', '5979', (122, 127))	('alter', 'Reg', (43, 48))	('skeletal abnormalities', 'Disease', (87, 109))	('Altered', 'Var', (0, 7))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (87, 109))	('patients', 'Species', '9606', (128, 136))	('CHM1', 'Gene', '11061', (22, 26))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (87, 109))	('CHM1', 'Gene', (22, 26))	('MEN2B', 'Gene', (122, 127))
9901	32326947	Activating mutations of the intracellular domain of RET could also be suspected to be responsible for the overexpression, in MEN2, of stanniocalcin-1 (STC1), a protein involved in the regulation of bone metabolism, by acting as an autocrine/paracrine regulator of calcium and phosphate homeostasis, with a role in early skeletal patterning and joint formation,.	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('STC1', 'Gene', (151, 155))	('phosphate', 'Chemical', 'MESH:D010710', (276, 285))	('MEN', 'Species', '9606', (125, 128))	('RET', 'Gene', '5979', (52, 55))	('stanniocalcin-1', 'Gene', (134, 149))	('overexpression', 'PosReg', (106, 120))	('stanniocalcin-1', 'Gene', '6781', (134, 149))	('RET', 'Gene', (52, 55))	('STC1', 'Gene', '6781', (151, 155))	('calcium', 'Chemical', 'MESH:D002118', (264, 271))
9905	32326947	MEN4 is caused by inactivating heterozygous mutations of the CDKN1B tumor suppressor gene (12p13.1) (Table 1], encoding the p27kip1 protein, a CDK2 cyclin-dependent kinase inhibitor, which acts as a negative regulator of cell cycle progression at G1-S checkpoint.	('tumor', 'Disease', (68, 73))	('caused by', 'Reg', (8, 17))	('MEN4', 'Gene', '1027', (0, 4))	('CDKN1B', 'Gene', '1027', (61, 67))	('MEN4', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDKN1B', 'Gene', (61, 67))	('inactivating heterozygous mutations', 'Var', (18, 53))
9907	32326947	Therapeutic approaches follow the same guidelines of MEN1, and no specific research about possible gene therapies in patients with CDKN1B mutations has been carried out yet.	('CDKN1B', 'Gene', '1027', (131, 137))	('CDKN1B', 'Gene', (131, 137))	('patients', 'Species', '9606', (117, 125))	('MEN1', 'Gene', '4221', (53, 57))	('MEN1', 'Gene', (53, 57))	('mutations', 'Var', (138, 147))
9913	32326947	At cellular level, p27-/- mice showed increased proliferative activity of bone marrow cells and formation of numerous osteoblastic colonies.	('p27-/-', 'Var', (19, 25))	('proliferative activity of bone marrow cells', 'CPA', (48, 91))	('numerous osteoblastic colonies', 'Disease', (109, 139))	('numerous osteoblastic colonies', 'Disease', 'MESH:C563990', (109, 139))	('osteoblastic colonies', 'Phenotype', 'HP:0025027', (118, 139))	('increased', 'PosReg', (38, 47))	('mice', 'Species', '10090', (26, 30))
9917	32326947	Homozygous mutant murine models for both p27Kip1 and Pthrp (p27-/-/Pthrp KI) showed an increase in body weight, lifespan and growth of long bones, due to a higher proliferative state of growth plate, when compared to wild type and mutant models for Pthrp (Pthrp KI) or p27Kip1 (p27-/-).	('Pthrp', 'Gene', '19227', (67, 72))	('mutant', 'Var', (11, 17))	('body weight', 'CPA', (99, 110))	('increase', 'PosReg', (87, 95))	('increase in body weight', 'Phenotype', 'HP:0004324', (87, 110))	('proliferative state', 'CPA', (163, 182))	('p27-/-/Pthrp KI', 'Gene', (60, 75))	('p27Kip1', 'Gene', (269, 276))	('growth of long bones', 'Phenotype', 'HP:0006392', (125, 145))	('Pthrp', 'Gene', (53, 58))	('growth of long bones', 'CPA', (125, 145))	('Pthrp', 'Gene', '19227', (256, 261))	('p27Kip1', 'Gene', '12576', (41, 48))	('Pthrp', 'Gene', (249, 254))	('Pthrp', 'Gene', (67, 72))	('higher', 'PosReg', (156, 162))	('p27-/-/Pthrp KI', 'Gene', '19227', (60, 75))	('lifespan', 'CPA', (112, 120))	('p27Kip1', 'Gene', '12576', (269, 276))	('Pthrp', 'Gene', '19227', (53, 58))	('Pthrp', 'Gene', (256, 261))	('p27Kip1', 'Gene', (41, 48))	('Pthrp', 'Gene', '19227', (249, 254))	('murine', 'Species', '10090', (18, 24))
9918	32326947	BMD, cortical, epiphyseal and trabecular bone volume, number of osteoblasts and bone areas positive for type I collagen and osteocalcin, were all significantly increased in p27-/- mice and significantly reduced in Pthrp KI and p27-/-/Pthrp KI mice, compared to wild-type mice.	('mice', 'Species', '10090', (271, 275))	('Pthrp', 'Gene', '19227', (214, 219))	('p27-/-', 'Var', (173, 179))	('increased', 'PosReg', (160, 169))	('reduced', 'NegReg', (203, 210))	('mice', 'Species', '10090', (243, 247))	('Pthrp', 'Gene', (234, 239))	('Pthrp', 'Gene', '19227', (234, 239))	('BMD', 'Disease', (0, 3))	('p27-/-/Pthrp KI', 'Gene', '19227', (227, 242))	('cortical', 'CPA', (5, 13))	('mice', 'Species', '10090', (180, 184))	('BMD', 'Disease', 'MESH:D020388', (0, 3))	('p27-/-/Pthrp KI', 'Gene', (227, 242))	('Pthrp', 'Gene', (214, 219))
9920	32326947	Pthrp, Igf-1 and Bmi-1 expression was increased in p27-/- mice and reduced in Pthrp KI and p27-/-/Pthrp KI mice with respect to wild type; expression of these three genes was increased in p27-/-/Pthrp KI mice compared to Pthrp KI mice.	('Pthrp', 'Gene', (78, 83))	('Pthrp', 'Gene', '19227', (98, 103))	('p27-/-', 'Var', (51, 57))	('p27-/-/Pthrp KI', 'Gene', (91, 106))	('mice', 'Species', '10090', (204, 208))	('Igf-1', 'Gene', (7, 12))	('Bmi-1', 'Gene', (17, 22))	('p27-/-/Pthrp KI', 'Gene', '19227', (188, 203))	('Pthrp', 'Gene', (195, 200))	('Pthrp', 'Gene', '19227', (0, 5))	('mice', 'Species', '10090', (107, 111))	('Pthrp', 'Gene', '19227', (221, 226))	('p27-/-/Pthrp KI', 'Gene', '19227', (91, 106))	('Pthrp', 'Gene', '19227', (78, 83))	('Pthrp', 'Gene', (98, 103))	('mice', 'Species', '10090', (58, 62))	('Igf-1', 'Gene', '16000', (7, 12))	('increased', 'PosReg', (175, 184))	('Bmi-1', 'Gene', '12151', (17, 22))	('expression', 'MPA', (23, 33))	('Pthrp', 'Gene', (0, 5))	('mice', 'Species', '10090', (230, 234))	('Pthrp', 'Gene', '19227', (195, 200))	('reduced', 'NegReg', (67, 74))	('p27-/-/Pthrp KI', 'Gene', (188, 203))	('Pthrp', 'Gene', (221, 226))	('expression', 'MPA', (139, 149))	('increased', 'PosReg', (38, 47))
9921	32326947	The number of colonies-forming units-fibroblasts (CFU-f) and CFU-f positive for alkaline phosphatase (ALP) increased in p27-/- mice with respect to wild-type mice, and in p27-/-/Pthrp KI mice compared to Pthrp KI mice.	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (213, 217))	('mice', 'Species', '10090', (158, 162))	('increased', 'PosReg', (107, 116))	('p27-/-/Pthrp KI', 'Gene', '19227', (171, 186))	('Pthrp', 'Gene', '19227', (204, 209))	('Pthrp', 'Gene', (178, 183))	('Pthrp', 'Gene', '19227', (178, 183))	('positive for alkaline phosphatase', 'Phenotype', 'HP:0003155', (67, 100))	('ALP', 'Gene', (102, 105))	('mice', 'Species', '10090', (187, 191))	('alkaline phosphatase', 'MPA', (80, 100))	('p27-/-', 'Var', (120, 126))	('p27-/-/Pthrp KI', 'Gene', (171, 186))	('colonies-forming units-fibroblasts', 'CPA', (14, 48))	('Pthrp', 'Gene', (204, 209))	('ALP', 'Gene', '250', (102, 105))
9923	32326947	p27-/- mice also showed an increase of RANKL/OPG ratio, presumably responsible for over-activation of osteoblast activity.	('p27-/-', 'Var', (0, 6))	('RANKL', 'Gene', (39, 44))	('OPG', 'Gene', '18383', (45, 48))	('OPG', 'Gene', (45, 48))	('mice', 'Species', '10090', (7, 11))	('RANKL', 'Gene', '21943', (39, 44))	('increase', 'PosReg', (27, 35))	('osteoblast activity', 'CPA', (102, 121))
9924	32326947	p27kip1 may be directly involved in the regulation of skeletal growth through its direct interaction with the C-terminal region and nuclear localization signals (NLSs) of PTHrP.	('PTHrP', 'Gene', (171, 176))	('NLSs', 'Disease', 'None', (162, 166))	('interaction', 'Interaction', (89, 100))	('skeletal growth', 'CPA', (54, 69))	('NLSs', 'Disease', (162, 166))	('p27kip1', 'Var', (0, 7))	('C-terminal', 'Protein', (110, 120))	('involved', 'Reg', (24, 32))	('nuclear localization', 'MPA', (132, 152))	('PTHrP', 'Gene', '19227', (171, 176))
9925	32326947	The deletion of p27kip1 in Pthrp KI mice appears to partially compensate for bone growth defect and restore osteoblastic differentiation, increasing endochondral ossification and osteogenesis (Table 1), suggesting a possible future use of NLS and C-terminal regions of PTHrP to promote bone growth.	('p27kip1', 'Gene', (16, 23))	('PTHrP', 'Gene', '19227', (269, 274))	('endochondral ossification', 'CPA', (149, 174))	('osteogenesis', 'Disease', 'MESH:D010013', (179, 191))	('bone growth defect', 'Disease', (77, 95))	('restore', 'PosReg', (100, 107))	('Pthrp', 'Gene', (27, 32))	('Pthrp', 'Gene', '19227', (27, 32))	('osteoblastic differentiation', 'Disease', (108, 136))	('PTHrP', 'Gene', (269, 274))	('osteogenesis', 'Disease', (179, 191))	('deletion', 'Var', (4, 12))	('mice', 'Species', '10090', (36, 40))	('osteoblastic differentiation', 'Disease', 'MESH:D012734', (108, 136))	('bone growth defect', 'Disease', 'MESH:D006130', (77, 95))	('increasing', 'PosReg', (138, 148))
9928	32326947	VHL is caused by inactivating mutations in the tumor suppressor gene VHL (3p25.3) (Table 1), encoding the homologous protein (pVHL), which can be totally absent or inactive.	('inactivating mutations', 'Var', (17, 39))	('VHL', 'Disease', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('VHL', 'Gene', (69, 72))	('caused by', 'Reg', (7, 16))	('tumor', 'Disease', (47, 52))
9930	32326947	Loss of wild type pVHL prevents degradation of HIF factors and induces responses to hypoxia, even when not physiologically required, inducing cell growth and formation of new vessels, thus favoring tumorigenesis.	('cell growth', 'CPA', (142, 153))	('hypoxia', 'Disease', (84, 91))	('favoring', 'PosReg', (189, 197))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('prevents', 'NegReg', (23, 31))	('pVHL', 'Gene', (18, 22))	('formation of new vessels', 'CPA', (158, 182))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('induces', 'Reg', (63, 70))	('degradation', 'MPA', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('inducing', 'PosReg', (133, 141))	('tumor', 'Disease', (198, 203))	('Loss', 'Var', (0, 4))
9936	32326947	Indeed, only the complete loss of pVHL in cartilage cells can alter the correct bone growth and metabolism, as reported by studies in murine models with selective inactivation of the Vhlh gene only in the cartilaginous cells (Vhlh-null mice).	('mice', 'Species', '10090', (236, 240))	('Vhlh', 'Gene', '22346', (226, 230))	('Vhlh', 'Gene', (226, 230))	('murine', 'Species', '10090', (134, 140))	('alter', 'Reg', (62, 67))	('bone growth', 'CPA', (80, 91))	('Vhlh', 'Gene', '22346', (183, 187))	('Vhlh', 'Gene', (183, 187))	('loss', 'Var', (26, 30))
9943	32326947	Homozygous mutations of SDHA gene (5p15) cause a clinical phenotype (Leigh syndrome) characterized by degenerative myeloencephalopathy.	('Leigh syndrome', 'Disease', (69, 83))	('Homozygous mutations', 'Var', (0, 20))	('SDHA', 'Gene', (24, 28))	('cause', 'Reg', (41, 46))	('Leigh syndrome', 'Disease', 'MESH:D007888', (69, 83))	('degenerative myeloencephalopathy', 'Disease', (102, 134))	('SDHA', 'Gene', '6389', (24, 28))	('degenerative myeloencephalopathy', 'Disease', 'MESH:D019636', (102, 134))
9945	32326947	Indeed, mutations of SDHx genes induce energy metabolism disorders and succinate accumulation, the last inhibits the activity of PHD2 and leads to increased activation of HIF-alpha.	('increased activation', 'PosReg', (147, 167))	('activity', 'MPA', (117, 125))	('PHD2', 'Gene', (129, 133))	('succinate accumulation', 'MPA', (71, 93))	('inhibits', 'NegReg', (104, 112))	('PHD2', 'Gene', '54583', (129, 133))	('HIF-alpha', 'Protein', (171, 180))	('mutations', 'Var', (8, 17))	('succinate', 'Chemical', 'MESH:D019802', (71, 80))	('SDHx', 'Gene', (21, 25))	('induce', 'Reg', (32, 38))	('metabolism disorders', 'Disease', 'MESH:D008659', (46, 66))	('metabolism disorders', 'Disease', (46, 66))
9951	32326947	To date, no studies on animal models with mutations of SDHx genes and bone diseases, nor specific studies that correlate the gene encoding components of the enzymatic succinate dehydrogenase complex or complex 2 of the mitochondrial respiratory chain with bone and/or mineral metabolism, have been published (Table 1).	('bone diseases', 'Disease', 'MESH:D001847', (70, 83))	('succinate', 'Chemical', 'MESH:D019802', (167, 176))	('SDHx genes', 'Gene', (55, 65))	('bone diseases', 'Disease', (70, 83))	('mutations', 'Var', (42, 51))
9955	32326947	HPT-JT is caused by inactivating germinal mutations of the HRPT2/CDC73 tumor suppressor gene (1q31.2); (Table 1), encoding a nuclear protein called parafibromin, a component of the PAF1 complex, that is responsible for H3K4 histone trimethylation and H3K79 histone methylation.	('HRPT2', 'Gene', '79577', (59, 64))	('HPT-JT', 'Gene', (0, 6))	('HRPT2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CDC73', 'Gene', '79577', (65, 70))	('HPT-JT', 'Gene', '79577', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('caused by', 'Reg', (10, 19))	('inactivating', 'Var', (20, 32))	('tumor', 'Disease', (71, 76))	('mutations', 'Var', (42, 51))	('CDC73', 'Gene', (65, 70))
9956	32326947	Mutations of CDC73 also cause CDC73-related isolated familial hyperparathyroidism and CDC73-related parathyroid carcinoma.	('CDC73', 'Gene', (86, 91))	('CDC73', 'Gene', '79577', (86, 91))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (104, 121))	('cause', 'Reg', (24, 29))	('parathyroid carcinoma', 'Disease', 'MESH:D010282', (100, 121))	('familial hyperparathyroidism', 'Disease', (53, 81))	('familial hyperparathyroidism', 'Disease', 'MESH:D006961', (53, 81))	('parathyroid carcinoma', 'Disease', (100, 121))	('CDC73', 'Gene', (30, 35))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (62, 81))	('CDC73', 'Gene', (13, 18))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (100, 121))	('CDC73', 'Gene', '79577', (30, 35))	('CDC73', 'Gene', '79577', (13, 18))
9964	32326947	Homozygous deletion of Cdc73 in MSCs resulted in embryos non-presenting mesenchymal development of the internal organs.	('resulted in', 'Reg', (37, 48))	('Cdc73', 'Gene', (23, 28))	('deletion', 'Var', (11, 19))	('Cdc73', 'Gene', '214498', (23, 28))
9972	32326947	Over 80% of CS patients have a PTEN mutation.	('PTEN', 'Gene', (31, 35))	('patients', 'Species', '9606', (15, 23))	('PTEN', 'Gene', '5728', (31, 35))	('mutation', 'Var', (36, 44))
9973	32326947	Mutations in SDHB, SDHD or KLLN genes were recently identified in CS patients, with or without PTEN mutations.	('identified', 'Reg', (52, 62))	('SDHD', 'Gene', '6392', (19, 23))	('SDHB', 'Gene', '6390', (13, 17))	('SDHD', 'Gene', (19, 23))	('KLLN', 'Gene', (27, 31))	('Mutations', 'Var', (0, 9))	('PTEN', 'Gene', (95, 99))	('SDHB', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (95, 99))	('patients', 'Species', '9606', (69, 77))	('KLLN', 'Gene', '100144748', (27, 31))
9984	32326947	Failure to express Pten induces stress of the endoplasmic reticulum and causes up-regulation of hypoxia-induced genes, including HIF-1alpha,; (Tab.1).	('Pten', 'Gene', '5728', (19, 23))	('Failure', 'Var', (0, 7))	('Pten', 'Gene', (19, 23))	('HIF-1alpha', 'Gene', '3091', (129, 139))	('induces', 'Reg', (24, 31))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('stress', 'Disease', (32, 38))	('stress', 'Disease', 'MESH:D000079225', (32, 38))	('HIF-1alpha', 'Gene', (129, 139))	('up-regulation', 'PosReg', (79, 92))
9985	32326947	PTEN function in chondrocytes is essential for inhibiting dyschondroplasia; this could explain how the loss of PTEN protein has a direct pathogenic role in skeletal manifestations observed in CS patients.	('PTEN', 'Gene', (111, 115))	('loss', 'Var', (103, 107))	('PTEN', 'Gene', '5728', (111, 115))	('dyschondroplasia', 'Disease', (58, 74))	('patients', 'Species', '9606', (195, 203))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('dyschondroplasia', 'Disease', 'MESH:D010009', (58, 74))	('protein', 'Protein', (116, 123))
9987	32326947	Based on these genetic alterations, CNC was subdivided into two subtypes: CNC1 (mutation on PRKAR1A gene at 17q22-24) and CNC2 (mutation at 2p16 locus).	('CNC2', 'Gene', (122, 126))	('CNC1', 'Gene', '5573', (74, 78))	('PRKAR1A', 'Gene', (92, 99))	('CNC2', 'Gene', '1257', (122, 126))	('CNC1', 'Gene', (74, 78))	('mutation', 'Var', (80, 88))
9988	32326947	Approximately 60% of CNC patients bear an inactivating germline mutation of the PRKAR1A tumor suppressor gene, encoding the I-alpha regulatory subunit of cAMP-dependent protein kinase (PKA).	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CNC', 'Disease', (21, 24))	('inactivating germline mutation', 'Var', (42, 72))	('cAMP', 'Chemical', '-', (154, 158))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('PRKAR1A', 'Gene', (80, 87))
9997	32326947	Over-activation of PKA signaling causes fibrous dysplasia, an immature expansion of osteoblast precursors leading to structurally immature and hyper-proliferative bone.	('PKA', 'Gene', (19, 22))	('hyper-proliferative bone', 'Phenotype', 'HP:0100774', (143, 167))	('fibrous dysplasia', 'Disease', 'MESH:D005357', (40, 57))	('fibrous dysplasia', 'Disease', (40, 57))	('Over-activation', 'Var', (0, 15))
10001	32326947	The loss of Prkar1a-encoded protein increases the activity of PKA, which inhibits the transcription of Runx2 and its action on the target genes, and negatively regulates osteoblast differentiation.	('Prkar1a', 'Gene', '19084', (12, 19))	('negatively', 'NegReg', (149, 159))	('Prkar1a', 'Gene', (12, 19))	('Runx2', 'Gene', (103, 108))	('Runx2', 'Gene', '860', (103, 108))	('PKA', 'Gene', (62, 65))	('inhibits', 'NegReg', (73, 81))	('action', 'MPA', (117, 123))	('transcription', 'MPA', (86, 99))	('activity', 'MPA', (50, 58))	('increases', 'PosReg', (36, 45))	('osteoblast differentiation', 'CPA', (170, 196))	('regulates', 'Reg', (160, 169))	('loss', 'Var', (4, 8))
10002	32326947	The PKA signaling pathway, a key signal transduction pathway downstream of the PTH receptor (PTH1R) and PKA hyper-activation, resulting from the loss of PRKAR1A, could influence the PTH response.	('PTH', 'Gene', '5741', (93, 96))	('PTH', 'Gene', (182, 185))	('PKA signaling pathway', 'Pathway', (4, 25))	('PTH', 'Gene', (79, 82))	('PTH1R', 'Gene', '5745', (93, 98))	('loss', 'Var', (145, 149))	('PTH', 'Gene', '5741', (182, 185))	('influence', 'Reg', (168, 177))	('PTH1R', 'Gene', (93, 98))	('PTH', 'Gene', (93, 96))	('PRKAR1A', 'Gene', (153, 160))	('PTH', 'Gene', '5741', (79, 82))
10007	32326947	TSC is caused by loss-of-function mutations, either of the TSC1 gene (9q34), encoding hamartin, or the TSC2 gene (16p13), encoding tuberin; (Table 1), with over half of the cases arising from non-inherited embryonal mutations.	('tuberin', 'Gene', '7249', (131, 138))	('loss-of-function', 'NegReg', (17, 33))	('TSC2', 'Gene', '7249', (103, 107))	('TSC2', 'Gene', (103, 107))	('TSC', 'Gene', (0, 3))	('tuberin', 'Gene', (131, 138))	('TSC1', 'Gene', '7248', (59, 63))	('TSC', 'Gene', '7248', (0, 3))	('TSC', 'Gene', (59, 62))	('TSC', 'Gene', '7248', (59, 62))	('TSC', 'Gene', '7248', (103, 106))	('TSC1', 'Gene', (59, 63))	('TSC', 'Gene', (103, 106))	('mutations', 'Var', (34, 43))
10009	32326947	Loss of one of the encoded proteins is sufficient for development of TSC, leading to a complete loss of hamartin-tuberin complex activity, with no inhibitory modulation on the mTOR signaling cascade and subsequent alteration of nutritional signal transduction and stimulation of cell growth.	('tuberin', 'Gene', '7249', (113, 120))	('alteration', 'Reg', (214, 224))	('TSC', 'Gene', (69, 72))	('tuberin', 'Gene', (113, 120))	('activity', 'MPA', (129, 137))	('loss', 'NegReg', (96, 100))	('TSC', 'Gene', '7248', (69, 72))	('Loss', 'Var', (0, 4))
10011	32326947	Recently, a study in a murine model of TSC with embryonic loss of Tsc1 in brain neurons, demonstrated the therapeutic efficacy of hamartin transfection by adenovirus vector, resulting in the normalization of neuron size and a decrease in markers of mTOR activation, with no side effects.	('TSC', 'Gene', (39, 42))	('normalization', 'MPA', (191, 204))	('TSC', 'Gene', '7248', (39, 42))	('embryonic loss', 'Disease', 'MESH:D020964', (48, 62))	('embryonic loss', 'Disease', (48, 62))	('neuron size', 'CPA', (208, 219))	('decrease', 'NegReg', (226, 234))	('murine', 'Species', '10090', (23, 29))	('Tsc1', 'Gene', (66, 70))	('Tsc1', 'Gene', '64930', (66, 70))	('markers of mTOR activation', 'MPA', (238, 264))	('transfection', 'Var', (139, 151))	('adenovirus', 'Species', '10508', (155, 165))
10018	32326947	However, the inactivation of the hamartin-tuberin complex causes hyper-activation of mTOR, resulting in uncontrolled cell proliferation and growth that could also occur in bone tissue.	('tuberin', 'Gene', (42, 49))	('inactivation', 'Var', (13, 25))	('uncontrolled', 'MPA', (104, 116))	('hyper-activation', 'MPA', (65, 81))	('tuberin', 'Gene', '7249', (42, 49))	('mTOR', 'Gene', (85, 89))	('growth', 'CPA', (140, 146))
10019	32326947	Only a small percentage (14%) of patients without TSC1 or TSC2 mutations showed SBLs, while mutated patients develop SBLs in 84% of cases (of these, 47.2% have a pathogenic variant of TSC1 and 52.8% of TSC2).	('mutations', 'Var', (63, 72))	('pathogenic', 'Reg', (162, 172))	('TSC1', 'Gene', (184, 188))	('variant', 'Var', (173, 180))	('TSC2', 'Gene', '7249', (58, 62))	('patients', 'Species', '9606', (33, 41))	('TSC2', 'Gene', (58, 62))	('SBLs', 'Disease', (80, 84))	('TSC1', 'Gene', (50, 54))	('patients', 'Species', '9606', (100, 108))	('TSC1', 'Gene', '7248', (50, 54))	('TSC1', 'Gene', '7248', (184, 188))	('TSC2', 'Gene', '7249', (202, 206))	('TSC2', 'Gene', (202, 206))
10020	32326947	Early post-natal treatment with rapamycin, a mTOR inhibitor, in mice with a neural crest-specific Tsc1 deletion, prevented the growth of aberrant bone mass, whereas late treatment did not have this effect.	('prevented', 'NegReg', (113, 122))	('growth of aberrant bone mass', 'CPA', (127, 155))	('rapamycin', 'Chemical', 'MESH:D020123', (32, 41))	('Tsc1', 'Gene', '64930', (98, 102))	('Tsc1', 'Gene', (98, 102))	('mice', 'Species', '10090', (64, 68))	('deletion', 'Var', (103, 111))
10025	32326947	NF1 is caused by inactivating mutations of the NF1 tumor-suppressor gene (17q11.2) (Table 1), encoding neurofibromin 1, a negative regulator of the RAS transduction pathway, which regulates basic functions, such as proliferation, differentiation and apoptosis.	('neurofibromin 1', 'Gene', '4763', (103, 118))	('inactivating mutations', 'Var', (17, 39))	('differentiation', 'CPA', (230, 245))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('apoptosis', 'CPA', (250, 259))	('tumor', 'Disease', (51, 56))	('NF1', 'Gene', (47, 50))	('NF1', 'Gene', '4763', (47, 50))	('neurofibromin 1', 'Gene', (103, 118))	('NF1', 'Gene', (0, 3))	('regulates', 'Reg', (180, 189))	('caused by', 'Reg', (7, 16))	('NF1', 'Gene', '4763', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
10032	32326947	Less common skeletal manifestations include local overgrowth, abnormalities of the rib cage, rib fusion, genu varum/valgum, lytic bone lesions, osteosclerosis, absence of the patella, and syndactyly.	('genu varum', 'Phenotype', 'HP:0002970', (105, 115))	('abnormalities', 'Var', (62, 75))	('abnormalities of the rib cage', 'Phenotype', 'HP:0001547', (62, 91))	('genu varum/valgum', 'Phenotype', 'HP:0002857', (105, 122))	('absence', 'Disease', (160, 167))	('genu', 'Disease', (105, 109))	('syndactyly', 'Phenotype', 'HP:0001159', (188, 198))	('rib fusion', 'CPA', (93, 103))	('lytic bone lesions', 'Disease', (124, 142))	('syndactyly', 'Disease', (188, 198))	('absence of the patella', 'Phenotype', 'HP:0006443', (160, 182))	('abnormalities of the rib', 'Phenotype', 'HP:0000772', (62, 86))	('osteosclerosis', 'Disease', (144, 158))	('osteosclerosis', 'Disease', 'MESH:D010026', (144, 158))	('osteosclerosis', 'Phenotype', 'HP:0011001', (144, 158))	('local overgrowth', 'CPA', (44, 60))	('lytic bone lesions', 'Disease', 'MESH:D001847', (124, 142))	('rib fusion', 'Phenotype', 'HP:0000902', (93, 103))	('overgrowth', 'Phenotype', 'HP:0001548', (50, 60))
10033	32326947	Bone lesions are mainly congenital and often associated with each other, strongly suggesting that NF1 has a direct effect on proper skeletal development and correct homeostasis of bone remodeling, and that its inactivating mutations are responsible for the development of NF1 bone complications.	('inactivating mutations', 'Var', (210, 232))	('effect', 'Reg', (115, 121))	('NF1', 'Gene', (98, 101))	('correct homeostasis of bone remodeling', 'MPA', (157, 195))	('bone', 'Disease', (276, 280))	('NF1', 'Gene', '4763', (98, 101))	('responsible', 'Reg', (237, 248))	('NF1', 'Gene', (272, 275))	('NF1', 'Gene', '4763', (272, 275))
10043	32326947	Mice with a conditional specific inactivation of Nf1 in limb skeleton (Nf1Prx1 mice) showed two main signs: bowing of the tibia and diminished growth, the first due to decreased fitness of the cortical bone, the latter to lower proliferation rates and differentiation defect of chondrocytes.	('Nf1', 'Gene', '18015', (49, 52))	('growth', 'CPA', (143, 149))	('decreased fitness', 'Disease', 'MESH:D012640', (168, 185))	('Nf1', 'Gene', '18015', (71, 74))	('Nf1', 'Gene', (49, 52))	('differentiation defect of chondrocytes', 'CPA', (252, 290))	('mice', 'Species', '10090', (79, 83))	('bowing of the tibia', 'Phenotype', 'HP:0002982', (108, 127))	('bowing of the tibia', 'CPA', (108, 127))	('decreased fitness', 'Disease', (168, 185))	('Nf1', 'Gene', (71, 74))	('Mice', 'Species', '10090', (0, 4))	('inactivation', 'Var', (33, 45))	('lower', 'NegReg', (222, 227))	('diminished', 'NegReg', (132, 142))
10046	32326947	All these data suggest that neurofibromin is an important modulator of skeletal development and growth, and that somatic loss of the wild type NF1 allele in osteoprogenitor cells is necessary to develop NF1-associated bone phenotypes.	('neurofibromin', 'Gene', '4763', (28, 41))	('loss', 'Var', (121, 125))	('neurofibromin', 'Gene', (28, 41))	('NF1', 'Gene', (143, 146))	('NF1', 'Gene', (203, 206))	('NF1', 'Gene', '4763', (143, 146))	('NF1', 'Gene', '4763', (203, 206))
10051	24169168	The Presence of SDHB Mutations Should Modify Surgical Indications for Carotid Body Paragangliomas The aim of this study was to determine whether the genetic background of the disease should be incorporated into treatment decision making.	('Paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('SDHB', 'Gene', '6390', (16, 20))	('Modify', 'Reg', (38, 44))	('SDHB', 'Gene', (16, 20))	('Carotid Body Paragangliomas', 'Disease', (70, 97))	('Mutations', 'Var', (21, 30))	('Carotid Body Paragangliomas', 'Phenotype', 'HP:0100635', (70, 97))	('Carotid Body Paragangliomas', 'Disease', 'MESH:D002345', (70, 97))	('Paragangliomas', 'Phenotype', 'HP:0002668', (83, 97))
10052	24169168	Carotid body paragangliomas are rare tumors that often affect patients with genetic mutations of the succinate dehydrogenase complex (SDHx).	('genetic mutations', 'Var', (76, 93))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('succinate', 'Chemical', 'MESH:D013386', (101, 110))	('Carotid body paragangliomas', 'Disease', (0, 27))	('paraganglioma', 'Phenotype', 'HP:0002668', (13, 26))	('paragangliomas', 'Phenotype', 'HP:0002668', (13, 27))	('Carotid body paragangliomas', 'Phenotype', 'HP:0100635', (0, 27))	('SDHx', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('Carotid body paragangliomas', 'Disease', 'MESH:D002345', (0, 27))	('tumors', 'Disease', (37, 43))	('patients', 'Species', '9606', (62, 70))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
10053	24169168	Despite growing evidence that germ line genetic mutations alter the aggressiveness of paragangliomas, treatment decisions are currently based only on clinical symptoms and tumor size in patients with carotid body paragangliomas.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('aggressiveness of paragangliomas', 'Disease', (68, 100))	('aggressiveness of paragangliomas', 'Disease', 'MESH:D001523', (68, 100))	('paragangliomas', 'Phenotype', 'HP:0002668', (213, 227))	('tumor', 'Disease', (172, 177))	('paraganglioma', 'Phenotype', 'HP:0002668', (213, 226))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('carotid body paragangliomas', 'Disease', (200, 227))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (200, 227))	('paragangliomas', 'Phenotype', 'HP:0002668', (86, 100))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (200, 226))	('alter', 'Reg', (58, 63))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (200, 227))	('aggressiveness', 'Phenotype', 'HP:0000718', (68, 82))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mutations', 'Var', (48, 57))	('patients', 'Species', '9606', (186, 194))
10058	24169168	Twelve patients had germ line mutations in SDHB, 17 in SDHD, and 5 carried no known mutation.	('SDHB', 'Gene', '6390', (43, 47))	('SDHB', 'Gene', (43, 47))	('mutations', 'Var', (30, 39))	('SDHD', 'Gene', '6392', (55, 59))	('patients', 'Species', '9606', (7, 15))	('SDHD', 'Gene', (55, 59))
10060	24169168	Tumor size at resection was significantly smaller in patients with SDHB mutations than in patients with non-SDHB mutations (2.1 vs 3.3 cm, P = 0.02).	('mutations', 'Var', (72, 81))	('SDHB', 'Gene', (108, 112))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SDHB', 'Gene', '6390', (67, 71))	('patients', 'Species', '9606', (53, 61))	('smaller', 'NegReg', (42, 49))	('SDHB', 'Gene', (67, 71))	('Tumor size', 'CPA', (0, 10))	('SDHB', 'Gene', '6390', (108, 112))	('patients', 'Species', '9606', (90, 98))
10061	24169168	Patients with a mutation in the SDHB gene also had significantly worse disease-free survival compared with patients without an SDHB gene mutation (P = 0.03).	('disease-free survival', 'CPA', (71, 92))	('mutation', 'Var', (16, 24))	('worse', 'NegReg', (65, 70))	('SDHB', 'Gene', '6390', (32, 36))	('SDHB', 'Gene', '6390', (127, 131))	('SDHB', 'Gene', (32, 36))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', (127, 131))	('patients', 'Species', '9606', (107, 115))
10062	24169168	Mutations in the SDHB gene are associated with worse disease- free survival after resection in patients with carotid body paragangliomas despite earlier intervention.	('disease-', 'Disease', (53, 61))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (109, 135))	('paraganglioma', 'Phenotype', 'HP:0002668', (122, 135))	('paragangliomas', 'Phenotype', 'HP:0002668', (122, 136))	('patients', 'Species', '9606', (95, 103))	('SDHB', 'Gene', '6390', (17, 21))	('associated', 'Reg', (31, 41))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (109, 136))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (17, 21))	('carotid body paragangliomas', 'Disease', (109, 136))	('worse', 'NegReg', (47, 52))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (109, 136))
10063	24169168	This suggests that a more aggressive surgical approach is warranted in patients with SDHB mutations.	('SDHB', 'Gene', '6390', (85, 89))	('patients', 'Species', '9606', (71, 79))	('SDHB', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))
10071	24169168	The development of carotid body paragangliomas is often associated with germ line genetic mutations, most commonly involving genes in the succinate dehydrogenase complex (SDHx).	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (19, 46))	('mutations', 'Var', (90, 99))	('succinate', 'Chemical', 'MESH:D013386', (138, 147))	('associated', 'Reg', (56, 66))	('SDHx', 'Gene', (171, 175))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (19, 45))	('carotid body paragangliomas', 'Disease', (19, 46))	('paragangliomas', 'Phenotype', 'HP:0002668', (32, 46))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (19, 46))
10072	24169168	Paraganglioma syndromes 1 through 4 are associated with mutations in SDHD, SDHAF2, SDHC, and SDHB, respectively.	('mutations', 'Var', (56, 65))	('SDHB', 'Gene', (93, 97))	('Paraganglioma syndromes', 'Disease', 'MESH:D010235', (0, 23))	('Paraganglioma syndromes', 'Disease', (0, 23))	('SDHC', 'Gene', (83, 87))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('SDHC', 'Gene', '6391', (83, 87))	('SDHD', 'Gene', '6392', (69, 73))	('SDHAF2', 'Gene', '54949', (75, 81))	('SDHAF2', 'Gene', (75, 81))	('SDHB', 'Gene', '6390', (93, 97))	('associated', 'Reg', (40, 50))	('SDHD', 'Gene', (69, 73))
10073	24169168	Mutation of the SDHA gene is also associated with paragangliomas but does not cause one of the traditional paraganglioma syndromes.	('paragangliomas', 'Disease', 'MESH:D010235', (50, 64))	('associated', 'Reg', (34, 44))	('Mutation', 'Var', (0, 8))	('SDHA', 'Gene', '6389', (16, 20))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (107, 130))	('paraganglioma', 'Phenotype', 'HP:0002668', (107, 120))	('paraganglioma syndromes', 'Disease', (107, 130))	('paraganglioma', 'Phenotype', 'HP:0002668', (50, 63))	('paragangliomas', 'Disease', (50, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (50, 64))	('SDHA', 'Gene', (16, 20))
10074	24169168	Overall, mutations in SDHB result in more aggressive disease with higher rates of metastasis compared with mutations in SDHD, whereas mutations in SDHD result in a higher incidence of head and neck paragangliomas and a comparatively lower incidence of pheochromocytomas.	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (184, 211))	('mutations', 'Var', (9, 18))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (252, 268))	('SDHD', 'Gene', '6392', (120, 124))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('paragangliomas', 'Phenotype', 'HP:0002668', (198, 212))	('aggressive disease', 'Disease', (42, 60))	('SDHB', 'Gene', '6390', (22, 26))	('aggressive disease', 'Disease', 'MESH:D001523', (42, 60))	('SDHD', 'Gene', (120, 124))	('mutations', 'Var', (134, 143))	('pheochromocytomas', 'Disease', 'MESH:D010673', (252, 269))	('pheochromocytomas', 'Disease', (252, 269))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (184, 212))	('SDHB', 'Gene', (22, 26))	('SDHD', 'Gene', '6392', (147, 151))	('higher', 'PosReg', (66, 72))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (184, 212))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (193, 212))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (252, 269))	('metastasis', 'CPA', (82, 92))	('SDHD', 'Gene', (147, 151))
10079	24169168	Patients underwent genetic testing for germ line mutations and deletions in SDHA, SDHB, SDHC, SDHD, SDHAF2, RET, VHL, and TMEM127.	('SDHA', 'Gene', '6389', (76, 80))	('TMEM127', 'Gene', '55654', (122, 129))	('SDHC', 'Gene', '6391', (88, 92))	('Patients', 'Species', '9606', (0, 8))	('SDHD', 'Gene', '6392', (94, 98))	('SDHA', 'Gene', (100, 104))	('RET', 'Gene', '5979', (108, 111))	('VHL', 'Gene', (113, 116))	('SDHB', 'Gene', '6390', (82, 86))	('deletions', 'Var', (63, 72))	('SDHC', 'Gene', (88, 92))	('SDHA', 'Gene', '6389', (100, 104))	('SDHD', 'Gene', (94, 98))	('SDHAF2', 'Gene', (100, 106))	('SDHAF2', 'Gene', '54949', (100, 106))	('SDHA', 'Gene', (76, 80))	('VHL', 'Gene', '7428', (113, 116))	('SDHB', 'Gene', (82, 86))	('RET', 'Gene', (108, 111))	('TMEM127', 'Gene', (122, 129))
10092	24169168	Seventeen patients (50%) were positive for an SDHD mutation and 12 patients (35.3%) were positive for an SDHB mutation.	('SDHD', 'Gene', '6392', (46, 50))	('SDHB', 'Gene', '6390', (105, 109))	('positive', 'Reg', (30, 38))	('patients', 'Species', '9606', (67, 75))	('SDHD', 'Gene', (46, 50))	('SDHB', 'Gene', (105, 109))	('mutation', 'Var', (51, 59))	('patients', 'Species', '9606', (10, 18))
10101	24169168	The average tumor size at the time of operation was 2.1 cm in patients with germ line SDHB mutations, 3.1 cm in patients with germ line SDHD mutations, and 3.5 cm inpatients without germ line mutations.	('SDHB', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('patients', 'Species', '9606', (112, 120))	('SDHD', 'Gene', (136, 140))	('SDHD', 'Gene', '6392', (136, 140))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('patients', 'Species', '9606', (165, 173))	('tumor', 'Disease', (12, 17))	('patients', 'Species', '9606', (62, 70))	('SDHB', 'Gene', '6390', (86, 90))
10102	24169168	When stratified by germ line mutation status, patients with SDHB mutations had significantly smaller tumors than patients without SDHB mutations (P = 0.02, Fig.	('patients', 'Species', '9606', (46, 54))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('SDHB', 'Gene', '6390', (60, 64))	('SDHB', 'Gene', '6390', (130, 134))	('patients', 'Species', '9606', (113, 121))	('SDHB', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SDHB', 'Gene', (130, 134))	('smaller', 'NegReg', (93, 100))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
10108	24169168	Among the clinical, genetic, and demographic parameters analyzed, germ line SDHB mutation status was the only variable significantly associated with disease-free interval (P = 0.03, Fig.	('SDHB', 'Gene', '6390', (76, 80))	('mutation', 'Var', (81, 89))	('SDHB', 'Gene', (76, 80))	('associated', 'Reg', (133, 143))
10109	24169168	When patients with synchronous noncarotid body paragangliomas were excluded, there was still a trend toward worse DFS in patients with SDHB mutations (P = 0.09).	('synchronous noncarotid body paragangliomas', 'Disease', 'MESH:D009378', (19, 61))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (34, 60))	('SDHB', 'Gene', '6390', (135, 139))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (34, 61))	('patients', 'Species', '9606', (5, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (47, 60))	('SDHB', 'Gene', (135, 139))	('synchronous noncarotid body paragangliomas', 'Disease', (19, 61))	('worse', 'NegReg', (108, 113))	('mutations', 'Var', (140, 149))	('DFS', 'MPA', (114, 117))	('patients', 'Species', '9606', (121, 129))	('paragangliomas', 'Phenotype', 'HP:0002668', (47, 61))
10110	24169168	Although not statistically significant, patients with SDHB mutations were more likely to develop recurrence (50% in SDHB vs 22.7% in non-SDHB, P = 0.10).	('patients', 'Species', '9606', (40, 48))	('SDHB', 'Gene', '6390', (54, 58))	('SDHB', 'Gene', '6390', (116, 120))	('SDHB', 'Gene', (54, 58))	('SDHB', 'Gene', '6390', (137, 141))	('recurrence', 'Disease', (97, 107))	('SDHB', 'Gene', (137, 141))	('SDHB', 'Gene', (116, 120))	('mutations', 'Var', (59, 68))	('develop', 'PosReg', (89, 96))
10116	24169168	Patients with germ line SDHB mutations also had shorter DFS after surgical resection than patients without SDHB mutations.	('SDHB', 'Gene', (24, 28))	('SDHB', 'Gene', (107, 111))	('mutations', 'Var', (29, 38))	('shorter', 'NegReg', (48, 55))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', '6390', (24, 28))	('DFS', 'MPA', (56, 59))	('patients', 'Species', '9606', (90, 98))	('SDHB', 'Gene', '6390', (107, 111))
10118	24169168	The most important finding in this study is the relatively poor DFS in patients with SDHB mutations after surgical resection of smaller tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (90, 99))	('DFS', 'MPA', (64, 67))	('patients', 'Species', '9606', (71, 79))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('poor', 'NegReg', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
10119	24169168	The lower DFS observed in this cohort is consistent with data indicating that germ line SDHB mutations are associated with more aggressive disease.	('mutations', 'Var', (93, 102))	('aggressive disease', 'Disease', (128, 146))	('lower', 'NegReg', (4, 9))	('associated', 'Reg', (107, 117))	('SDHB', 'Gene', '6390', (88, 92))	('SDHB', 'Gene', (88, 92))	('DFS', 'MPA', (10, 13))	('aggressive disease', 'Disease', 'MESH:D001523', (128, 146))
10120	24169168	However, it is remarkable that patients with germ line SDHB mutations had a lower DFS despite the fact that the tumors were resected at a smaller tumor size than patients without an SDHB mutation (Fig.	('patients', 'Species', '9606', (162, 170))	('SDHB', 'Gene', (55, 59))	('SDHB', 'Gene', '6390', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('DFS', 'MPA', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('lower', 'NegReg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('SDHB', 'Gene', '6390', (182, 186))	('tumor', 'Disease', (112, 117))	('mutations', 'Var', (60, 69))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))	('SDHB', 'Gene', (182, 186))
10121	24169168	The statistical significance of the tumor size difference at the time of operation is unlikely to reflect disease biology or tumor growth rate but rather it is likely due to active screening and a more aggressive surgical approach in patients with a preidentified SDHB mutations.	('SDHB', 'Gene', (264, 268))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (269, 278))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (125, 130))	('patients', 'Species', '9606', (234, 242))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SDHB', 'Gene', '6390', (264, 268))	('tumor', 'Disease', (36, 41))
10123	24169168	Thus, these data suggest that delaying resection until a predetermined size (2 cm or larger) does not provide optimal disease control in patients with known SDHB mutations.	('SDHB', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('patients', 'Species', '9606', (137, 145))	('SDHB', 'Gene', '6390', (157, 161))
10129	24169168	This indicates that aggressive resection of carotid body paragangliomas in patients with germ line SDHB mutations, regardless of size or clinical symptoms, would result in safer operations and that the earlier intervention is justified to reduce the risk of disease recurrence.	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (44, 71))	('mutations', 'Var', (104, 113))	('patients', 'Species', '9606', (75, 83))	('SDHB', 'Gene', '6390', (99, 103))	('SDHB', 'Gene', (99, 103))	('carotid body paragangliomas', 'Disease', (44, 71))	('paraganglioma', 'Phenotype', 'HP:0002668', (57, 70))	('paragangliomas', 'Phenotype', 'HP:0002668', (57, 71))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (44, 71))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (44, 70))
10131	24169168	Our results, however, suggest that a clinical trial comparing active surveillance with surgical treatment may be warranted in patients without germ line SDHB mutations.	('SDHB', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('patients', 'Species', '9606', (126, 134))	('SDHB', 'Gene', '6390', (153, 157))
10134	24169168	In addition, the presence of noncarotid body paragangliomas was not associated with reduced DFS, and when patients with synchronous noncarotid body tumors were excluded, there was still a trend toward worse DFS (due to local recurrence, P = 0.10) inpatients with SDHB mutations.	('DFS', 'MPA', (207, 210))	('SDHB', 'Gene', (263, 267))	('synchronous noncarotid body tumors', 'Disease', (120, 154))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (32, 59))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('carotid body tumors', 'Phenotype', 'HP:0002668', (135, 154))	('synchronous noncarotid body tumors', 'Disease', 'MESH:D009378', (120, 154))	('carotid body paragangliomas', 'Disease', (32, 59))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (268, 277))	('DFS', 'MPA', (92, 95))	('patients', 'Species', '9606', (249, 257))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('paragangliomas', 'Phenotype', 'HP:0002668', (45, 59))	('carotid body tumor', 'Phenotype', 'HP:0002668', (135, 153))	('patients', 'Species', '9606', (106, 114))	('worse', 'NegReg', (201, 206))	('noncarotid body tumors', 'Phenotype', 'HP:0002668', (132, 154))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (32, 59))	('SDHB', 'Gene', '6390', (263, 267))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (32, 58))
10135	24169168	The clinical applicability of these data is dependent on the patient having a known germ line SDHB mutation before developing a carotid body paraganglioma.	('patient', 'Species', '9606', (61, 68))	('SDHB', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (128, 154))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('carotid body paraganglioma', 'Disease', 'MESH:D002345', (128, 154))	('carotid body paraganglioma', 'Disease', (128, 154))	('SDHB', 'Gene', '6390', (94, 98))
10140	24169168	In summary, our results indicate that patients with carotid body paragangliomas in the setting of germ line SDHB mutations are more likely to develop locoregional recurrence or metastatic disease than patients with non-SDHB mutations.	('patients', 'Species', '9606', (201, 209))	('SDHB', 'Gene', (108, 112))	('metastatic disease', 'CPA', (177, 195))	('carotid body paragangliomas', 'Disease', (52, 79))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (52, 79))	('locoregional recurrence', 'CPA', (150, 173))	('paragangliomas', 'Phenotype', 'HP:0002668', (65, 79))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (52, 79))	('develop', 'PosReg', (142, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (52, 78))	('mutations', 'Var', (113, 122))	('SDHB', 'Gene', '6390', (219, 223))	('patients', 'Species', '9606', (38, 46))	('SDHB', 'Gene', '6390', (108, 112))	('SDHB', 'Gene', (219, 223))
10141	24169168	These outcomes are observed despite the fact that, on average, patients with SDHB mutations had surgical interventions for smaller tumors.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('SDHB', 'Gene', '6390', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (82, 91))	('patients', 'Species', '9606', (63, 71))	('SDHB', 'Gene', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
10142	24169168	Our data challenge the notion that only tumor size should drive operative decision making in the absence of symptoms and indicate that patients with SDHB mutations should be surgical candidates even when only small carotid body tumors are detected.	('patients', 'Species', '9606', (135, 143))	('SDHB', 'Gene', '6390', (149, 153))	('SDHB', 'Gene', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('carotid body tumors', 'Phenotype', 'HP:0002668', (215, 234))	('carotid body tumors', 'Disease', 'MESH:D002345', (215, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (228, 233))	('mutations', 'Var', (154, 163))	('carotid body tumors', 'Disease', (215, 234))	('tumor', 'Disease', (40, 45))	('carotid body tumor', 'Phenotype', 'HP:0002668', (215, 233))
10143	24169168	Conversely, more conservative management based on symptoms, tumor size, and absence of invasive imaging tumor characteristics may be justified in patients without germ line SDHB mutations.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SDHB', 'Gene', '6390', (173, 177))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SDHB', 'Gene', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('absence of invasive imaging tumor', 'Disease', 'MESH:C564543', (76, 109))	('absence of invasive imaging tumor', 'Disease', (76, 109))	('tumor', 'Disease', (60, 65))	('mutations', 'Var', (178, 187))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
10201	31397861	These findings suggest that cortical-sparing surgery may be the preferred approach for patients at risk for, or diagnosed with, bilateral pheochromocytomas, especially those harboring a germline mutation in one of the known predisposition genes.	('germline mutation', 'Var', (186, 203))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (138, 154))	('bilateral pheochromocytomas', 'Disease', (128, 155))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (128, 155))	('patients', 'Species', '9606', (87, 95))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (138, 155))
10208	31397861	In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]).	('VHL', 'Disease', (109, 112))	('VHL', 'Disease', 'MESH:D006623', (109, 112))	('germline mutations', 'Var', (37, 55))	('RET', 'Gene', '5979', (83, 86))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (21, 29))	('RET', 'Gene', (83, 86))	('patients', 'Species', '9606', (155, 163))	('detected', 'Reg', (61, 69))	('patients', 'Species', '9606', (118, 126))
10221	31397861	Bilateral pheochromocytomas are often heritable and have been shown to occur mainly in patients with multiple endocrine neoplasia type 2 (MEN 2) caused by germline mutations of the RET (rearranged during transfection) proto-oncogene, von Hippel-Lindau disease (VHL; VHL gene) and the paragangliomas syndromes types 1 and 4 caused by mutations in the succinate dehydrogenase (SDH) subunit D (SDHD) and B (SDHB) genes, respectively.	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (234, 259))	('SDHB', 'Gene', '6390', (404, 408))	('VHL', 'Disease', 'MESH:D006623', (261, 264))	('paragangliomas syndromes', 'Disease', 'MESH:D010235', (284, 308))	('SDH', 'Gene', (375, 378))	('paraganglioma', 'Phenotype', 'HP:0002668', (284, 297))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (10, 27))	('von Hippel-Lindau disease', 'Disease', (234, 259))	('succinate dehydrogenase', 'Gene', (350, 373))	('caused by', 'Reg', (145, 154))	('multiple endocrine neoplasia type 2', 'Disease', (101, 136))	('SDHB', 'Gene', (404, 408))	('SDH', 'Gene', (391, 394))	('SDH', 'Gene', '6390', (404, 407))	('neoplasia', 'Phenotype', 'HP:0002664', (120, 129))	('mutations', 'Var', (333, 342))	('paragangliomas', 'Phenotype', 'HP:0002668', (284, 298))	('VHL', 'Disease', 'MESH:D006623', (266, 269))	('RET', 'Gene', '5979', (181, 184))	('VHL', 'Disease', (261, 264))	('subunit D (SDHD) and B', 'Gene', '6392', (380, 402))	('Bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (0, 27))	('mutations', 'Var', (164, 173))	('succinate dehydrogenase', 'Gene', '6390', (350, 373))	('caused by', 'Reg', (323, 332))	('SDH', 'Gene', (404, 407))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (101, 136))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (10, 26))	('Bilateral pheochromocytomas', 'Disease', (0, 27))	('SDH', 'Gene', '6390', (375, 378))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (110, 129))	('paragangliomas syndromes', 'Disease', (284, 308))	('RET', 'Gene', (181, 184))	('MEN', 'Species', '9606', (138, 141))	('SDH', 'Gene', '6390', (391, 394))	('patients', 'Species', '9606', (87, 95))	('VHL', 'Disease', (266, 269))
10246	31397861	Registrants were classified as mutation negative if they had no pathogenic DNA variant in these 9 genes and no clinical evidence for NF-1.	('NF-1', 'Gene', '4763', (133, 137))	('variant', 'Var', (79, 86))	('NF-1', 'Gene', (133, 137))
10261	31397861	Mutations of RET were present in 282 patients, VHL in 184, NF1 in 17, MAX in 9, SDHD in 7, TMEM127 in 5, and SDHB in 1 (Table 1).	('VHL', 'Disease', 'MESH:D006623', (47, 50))	('SDHD', 'Gene', (80, 84))	('VHL', 'Disease', (47, 50))	('RET', 'Gene', (13, 16))	('SDHB', 'Gene', '6390', (109, 113))	('patients', 'Species', '9606', (37, 45))	('SDHB', 'Gene', (109, 113))	('TMEM127', 'Gene', (91, 98))	('TMEM127', 'Gene', '55654', (91, 98))	('MAX', 'Gene', '4149', (70, 73))	('MAX', 'Gene', (70, 73))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', (59, 62))	('RET', 'Gene', '5979', (13, 16))	('present', 'Reg', (22, 29))	('NF1', 'Gene', '4763', (59, 62))	('SDHD', 'Gene', '6392', (80, 84))
10279	31397861	Of the 8 patients with metastatic pheochromocytoma, 4 patients had germline mutation in VHL, 1 in MAX, and 1 in RET.	('patients', 'Species', '9606', (9, 17))	('germline mutation', 'Var', (67, 84))	('patients', 'Species', '9606', (54, 62))	('RET', 'Gene', (112, 115))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (34, 50))	('RET', 'Gene', '5979', (112, 115))	('pheochromocytoma', 'Disease', (34, 50))	('pheochromocytoma', 'Disease', 'MESH:D010673', (34, 50))	('MAX', 'Gene', '4149', (98, 101))	('VHL', 'Disease', (88, 91))	('MAX', 'Gene', (98, 101))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
10313	31397861	The most frequent mutations in our cohort involve RET leading to MEN 2 and VHL leading to VHL disease.	('VHL', 'Disease', (75, 78))	('RET', 'Gene', (50, 53))	('VHL disease', 'Disease', (90, 101))	('VHL', 'Disease', (90, 93))	('MEN', 'Species', '9606', (65, 68))	('VHL', 'Disease', 'MESH:D006623', (90, 93))	('VHL disease', 'Disease', 'MESH:D006623', (90, 101))	('RET', 'Gene', '5979', (50, 53))	('MEN', 'Gene', (65, 68))	('VHL', 'Disease', 'MESH:D006623', (75, 78))	('mutations', 'Var', (18, 27))
10314	31397861	Although personal and family histories are important in diagnosing heritable pheochromocytoma, patients with an underlying germline mutation often present without hallmark clinical features suggestive of a particular hereditary syndrome.	('particular hereditary syndrome', 'Disease', (206, 236))	('patients', 'Species', '9606', (95, 103))	('particular hereditary syndrome', 'Disease', 'MESH:D009386', (206, 236))	('pheochromocytoma', 'Disease', (77, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (77, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('germline mutation', 'Var', (123, 140))
10315	31397861	Availability of DNA sequencing provides a powerful diagnostic tool to identify such mutations in patients with apparently sporadic pheochromocytoma.	('pheochromocytoma', 'Disease', (131, 147))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (131, 147))	('pheochromocytoma', 'Disease', 'MESH:D010673', (131, 147))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (97, 105))
10329	31397861	Cortical-sparing adrenalectomy should be considered in patients with (1) bilateral pheochromocytomas, (2) tumor size less than 5 cm, or (3) high likelihood of a predisposing mutation leading to high risk of metachronous pheochromocytoma in the future.	('bilateral pheochromocytomas', 'Disease', (73, 100))	('mutation', 'Var', (174, 182))	('metachronous pheochromocytoma', 'Disease', (207, 236))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (73, 100))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (55, 63))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (220, 236))	('metachronous pheochromocytoma', 'Disease', 'MESH:D010673', (207, 236))	('tumor', 'Disease', (106, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))
10338	30214218	It is caused by mutations in the NF1 gene that lead to the production of nonfunctional neurofibromin that cannot regulate cell growth or division, which generates increased risk for various benign and malignant tumors.	('neurofibromin', 'Gene', '4763', (87, 100))	('malignant tumors', 'Disease', 'MESH:D018198', (201, 217))	('NF1', 'Gene', (33, 36))	('lead to', 'Reg', (47, 54))	('benign', 'CPA', (190, 196))	('mutations', 'Var', (16, 25))	('NF1', 'Gene', '4763', (33, 36))	('neurofibromin', 'Gene', (87, 100))	('production', 'MPA', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('caused by', 'Reg', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('malignant tumors', 'Disease', (201, 217))
10395	30214218	Vascular abnormalities that can occur in NF1 patients are stenosis, aneurysms, and arteriovenous malformations due to cellular proliferation, degeneration, healing, and smooth-muscle loss and fibrosis caused by deficiency in neurofibromin with proliferation of the vessel wall.	('patients', 'Species', '9606', (45, 53))	('stenosis', 'Disease', (58, 66))	('arteriovenous malformations', 'Disease', 'MESH:D001165', (83, 110))	('fibrosis', 'Disease', (192, 200))	('cellular proliferation', 'CPA', (118, 140))	('fibrosis', 'Disease', 'MESH:D005355', (192, 200))	('neurofibromin', 'Gene', '4763', (225, 238))	('aneurysms', 'Disease', 'MESH:D000783', (68, 77))	('aneurysms', 'Disease', (68, 77))	('Vascular abnormalities', 'Phenotype', 'HP:0002597', (0, 22))	('deficiency', 'Var', (211, 221))	('degeneration', 'CPA', (142, 154))	('loss', 'NegReg', (183, 187))	('aneurysms', 'Phenotype', 'HP:0002617', (68, 77))	('arteriovenous malformations', 'Disease', (83, 110))	('smooth-muscle', 'CPA', (169, 182))	('NF1', 'Gene', '4763', (41, 44))	('muscle loss', 'Phenotype', 'HP:0003202', (176, 187))	('arteriovenous malformations', 'Phenotype', 'HP:0100026', (83, 110))	('healing', 'CPA', (156, 163))	('Vascular abnormalities', 'Disease', 'MESH:D000783', (0, 22))	('Vascular abnormalities', 'Disease', (0, 22))	('NF1', 'Gene', (41, 44))	('neurofibromin', 'Gene', (225, 238))
10400	30214218	In our case, Doppler ultrasonography of the renal arteries suggested a diagnosis of renal artery stenosis, and MR angiography, considered an alternative to conventional angiography, revealed reduced caliber of the abdominal aorta and celiac trunk, stenosis of the upper mesenteric artery, and bilateral renal artery stenosis.	('renal artery stenosis', 'Disease', 'MESH:D012078', (84, 105))	('bilateral renal artery stenosis', 'Disease', 'MESH:D012078', (293, 324))	('stenosis', 'Var', (248, 256))	('celiac trunk', 'Phenotype', 'HP:0012327', (234, 246))	('bilateral renal artery stenosis', 'Disease', (293, 324))	('artery stenosis', 'Phenotype', 'HP:0100545', (309, 324))	('reduced', 'NegReg', (191, 198))	('artery stenosis', 'Phenotype', 'HP:0100545', (90, 105))	('renal artery stenosis', 'Phenotype', 'HP:0001920', (303, 324))	('renal artery stenosis', 'Disease', (84, 105))	('renal artery stenosis', 'Disease', 'MESH:D012078', (303, 324))	('caliber', 'MPA', (199, 206))	('renal artery stenosis', 'Phenotype', 'HP:0001920', (84, 105))
10471	30151422	Sudden release can cause congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular accidents.	('pulmonary edema', 'Phenotype', 'HP:0100598', (51, 66))	('edema', 'Phenotype', 'HP:0000969', (61, 66))	('pulmonary edema', 'Disease', (51, 66))	('congestive heart failure', 'Disease', (25, 49))	('cerebrovascular accidents', 'Phenotype', 'HP:0001297', (121, 146))	('cerebrovascular accidents', 'Disease', 'MESH:D020521', (121, 146))	('ventricular fibrillation', 'Phenotype', 'HP:0001663', (91, 115))	('heart failure', 'Phenotype', 'HP:0001635', (36, 49))	('ventricular fibrillation', 'Disease', 'MESH:D014693', (91, 115))	('Sudden release', 'Var', (0, 14))	('congestive heart failure', 'Phenotype', 'HP:0001635', (25, 49))	('congestive heart failure', 'Disease', 'MESH:D006333', (25, 49))	('cerebrovascular accidents', 'Disease', (121, 146))	('myocardial infarction', 'Disease', (68, 89))	('cause', 'Reg', (19, 24))	('ventricular fibrillation', 'Disease', (91, 115))	('myocardial infarction', 'Phenotype', 'HP:0001658', (68, 89))	('pulmonary edema', 'Disease', 'MESH:D011654', (51, 66))	('myocardial infarction', 'Disease', 'MESH:D009203', (68, 89))
10477	30151422	Genetic mutations are classified into 2 groups, mutations involving the kinase signaling pathway (RET and NF1) and those with increased activity of the hypoxia-induced factor 1 (HIF-1alpha) transcription factor (VHL, SDHA, SDHB, SDHC, SDHD, and SDHAF2).	('SDHA', 'Gene', (217, 221))	('HIF-1alpha', 'Gene', '3091', (178, 188))	('VHL', 'Gene', (212, 215))	('SDHA', 'Gene', '6389', (217, 221))	('SDHB', 'Gene', (223, 227))	('activity', 'MPA', (136, 144))	('mutations', 'Var', (48, 57))	('hypoxia', 'Disease', (152, 159))	('RET', 'Gene', (98, 101))	('kinase signaling pathway', 'Pathway', (72, 96))	('SDHA', 'Gene', (245, 249))	('VHL', 'Gene', '7428', (212, 215))	('SDHC', 'Gene', '6391', (229, 233))	('hypoxia', 'Disease', 'MESH:D000860', (152, 159))	('HIF-1alpha', 'Gene', (178, 188))	('SDHA', 'Gene', '6389', (245, 249))	('SDHD', 'Gene', '6392', (235, 239))	('NF1', 'Gene', '4763', (106, 109))	('SDHAF2', 'Gene', '54949', (245, 251))	('SDHAF2', 'Gene', (245, 251))	('SDHD', 'Gene', (235, 239))	('NF1', 'Gene', (106, 109))	('SDHB', 'Gene', '6390', (223, 227))	('SDHC', 'Gene', (229, 233))	('RET', 'Gene', '5979', (98, 101))
10478	30151422	Von Hippel-Lindau syndrome is associated with a mutation in the VHL tumor suppressor gene.	('associated', 'Reg', (30, 40))	('VHL tumor', 'Disease', (64, 73))	('mutation', 'Var', (48, 56))	('Von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (0, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Von Hippel-Lindau syndrome', 'Disease', (0, 26))	('VHL tumor', 'Disease', 'MESH:D006623', (64, 73))
10483	30151422	Multiple endocrine neoplasia type 2 (MEN 2) syndrome with a prevalence of 1/40 000 individuals is associated with a mutation in the RET proto-oncogene that encodes for a receptor tyrosine kinase for glial-derived neurotropic factor.	('mutation', 'Var', (116, 124))	('RET', 'Gene', '5979', (132, 135))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('Multiple endocrine neoplasia type 2 (MEN 2) syndrome', 'Disease', 'MESH:D018813', (0, 52))	('associated', 'Reg', (98, 108))	('RET', 'Gene', (132, 135))
10488	30151422	Neurofibromatosis type 1 syndrome has an approximate frequency of 1 in 3000 and is associated with a NF1 gene mutation that codes for the protein neurofibromin.	('Neurofibromatosis type 1 syndrome', 'Disease', (0, 33))	('NF1', 'Gene', (101, 104))	('neurofibromin', 'Gene', '4763', (146, 159))	('NF1', 'Gene', '4763', (101, 104))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('Neurofibromatosis type 1 syndrome', 'Disease', 'MESH:C537392', (0, 33))	('associated', 'Reg', (83, 93))	('neurofibromin', 'Gene', (146, 159))	('mutation', 'Var', (110, 118))
10494	30151422	Mutations involving these subunits affecting HIF-1alpha transcription factor lead to hereditary paraganglioma syndrome, a syndrome characterized by multiple paragangliomas and pheochromocytomas with a frequency of 1/300 000 (Table 3).	('paraganglioma', 'Phenotype', 'HP:0002668', (157, 170))	('lead to', 'Reg', (77, 84))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (176, 192))	('HIF-1alpha', 'Gene', '3091', (45, 55))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (176, 193))	('HIF-1alpha', 'Gene', (45, 55))	('paragangliomas', 'Phenotype', 'HP:0002668', (157, 171))	('a syndrome', 'Disease', 'MESH:D013577', (108, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('Mutations', 'Var', (0, 9))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (157, 193))	('a syndrome', 'Disease', 'MESH:D013577', (120, 130))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D010235', (85, 118))	('hereditary paraganglioma syndrome', 'Disease', (85, 118))	('a syndrome', 'Disease', (120, 130))
10495	30151422	Familial paraganglioma variants, types 1, 3, and 4 are associated with mutations in SDHD, SDHC, and SDHB genes, respectively.	('SDHB', 'Gene', '6390', (100, 104))	('SDHD', 'Gene', '6392', (84, 88))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('associated', 'Reg', (55, 65))	('SDHD', 'Gene', (84, 88))	('SDHC', 'Gene', (90, 94))	('mutations', 'Var', (71, 80))	('SDHC', 'Gene', '6391', (90, 94))	('variants', 'Var', (23, 31))	('Familial paraganglioma', 'Disease', (0, 22))	('Familial paraganglioma', 'Disease', 'MESH:D010235', (0, 22))	('SDHB', 'Gene', (100, 104))
10496	30151422	Familial paraganglioma type 5 is associated with mutation in SDHA and familial paraganglioma type 2 with mutation in SDHAF2 gene.	('SDHA', 'Gene', (61, 65))	('SDHA', 'Gene', '6389', (117, 121))	('mutation', 'Var', (105, 113))	('Familial paraganglioma type', 'Disease', 'MESH:D010235', (0, 27))	('SDHAF2', 'Gene', '54949', (117, 123))	('SDHAF2', 'Gene', (117, 123))	('familial paraganglioma type 2', 'Disease', (70, 99))	('familial paraganglioma type 2', 'Disease', 'MESH:C566646', (70, 99))	('SDHA', 'Gene', (117, 121))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('mutation', 'Var', (49, 57))	('Familial paraganglioma type', 'Disease', (0, 27))	('associated', 'Reg', (33, 43))	('SDHA', 'Gene', '6389', (61, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))
10500	30151422	Each of the above hereditary syndromes, involving mutations in the succinate dehydrogenase gene, must be considered when evaluating a patient with a pheochromocytoma and/or paraganglioma.	('paraganglioma', 'Disease', (173, 186))	('pheochromocytoma', 'Disease', (149, 165))	('mutations', 'Var', (50, 59))	('pheochromocytoma', 'Disease', 'MESH:D010673', (149, 165))	('paraganglioma', 'Disease', 'MESH:D010235', (173, 186))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (149, 165))	('paraganglioma', 'Phenotype', 'HP:0002668', (173, 186))	('patient', 'Species', '9606', (134, 141))
10501	30151422	Patients presenting at an early age with these neoplasms should be screened for mutations involving the succinate dehydrogenase gene.	('mutations', 'Var', (80, 89))	('neoplasms', 'Phenotype', 'HP:0002664', (47, 56))	('Patients', 'Species', '9606', (0, 8))	('neoplasms', 'Disease', 'MESH:D009369', (47, 56))	('neoplasms', 'Disease', (47, 56))
10502	30151422	Immunohistochemistry for SDHB has been used to screen for succinate dehydrogenase mutations.	('mutations', 'Var', (82, 91))	('SDHB', 'Gene', '6390', (25, 29))	('SDHB', 'Gene', (25, 29))
10508	30151422	Twenty to forty percent of paragangliomas are malignant and malignancy is more common in chromaffin tumors associated with germline mutations.	('malignancy', 'Disease', (60, 70))	('chromaffin', 'Chemical', '-', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('common', 'Reg', (79, 85))	('paragangliomas', 'Disease', 'MESH:D010235', (27, 41))	('associated', 'Reg', (107, 117))	('tumors', 'Disease', (100, 106))	('paragangliomas', 'Disease', (27, 41))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('germline mutations', 'Var', (123, 141))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('paragangliomas', 'Phenotype', 'HP:0002668', (27, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (27, 40))	('chromaffin tumors', 'Phenotype', 'HP:0002666', (89, 106))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))
10518	30151422	Genetic mutations are classified into 2 groups, mutations involving the kinase signaling pathway (RET and NF1) and those with increased activity of the HIF-1alpha transcription factor (VHL, SDHA, SDHB, SDHC, SDHD, and SDHAF2).	('RET', 'Gene', '5979', (98, 101))	('SDHD', 'Gene', '6392', (208, 212))	('SDHA', 'Gene', '6389', (218, 222))	('SDHB', 'Gene', '6390', (196, 200))	('mutations', 'Var', (48, 57))	('activity', 'MPA', (136, 144))	('SDHC', 'Gene', (202, 206))	('SDHD', 'Gene', (208, 212))	('RET', 'Gene', (98, 101))	('kinase signaling pathway', 'Pathway', (72, 96))	('SDHA', 'Gene', (190, 194))	('SDHB', 'Gene', (196, 200))	('HIF-1alpha', 'Gene', '3091', (152, 162))	('SDHA', 'Gene', '6389', (190, 194))	('VHL', 'Gene', (185, 188))	('NF1', 'Gene', '4763', (106, 109))	('SDHC', 'Gene', '6391', (202, 206))	('HIF-1alpha', 'Gene', (152, 162))	('NF1', 'Gene', (106, 109))	('SDHAF2', 'Gene', '54949', (218, 224))	('SDHAF2', 'Gene', (218, 224))	('VHL', 'Gene', '7428', (185, 188))	('SDHA', 'Gene', (218, 222))
10547	28974878	The risk factors for pediatric malignant pheochromocytoma include the extra-adrenal location, primary tumor >6 cm, sporadic nature, gland weight >250 g, and early onset postoperative hypertension.	('>250', 'Var', (145, 149))	('postoperative hypertension', 'Disease', 'MESH:D006973', (169, 195))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (31, 57))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (41, 57))	('malignant pheochromocytoma', 'Disease', (31, 57))	('pediatric', 'Disease', (21, 30))	('tumor', 'Disease', (102, 107))	('postoperative hypertension', 'Disease', (169, 195))	('hypertension', 'Phenotype', 'HP:0000822', (183, 195))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
10634	27561909	Phenoxybenzamine provides irreversible inhibition of both alpha-1 and alpha-2 receptors.	('alpha-2 receptors', 'Protein', (70, 87))	('alpha-1', 'Gene', (58, 65))	('Phenoxybenzamine', 'Var', (0, 16))	('inhibition', 'NegReg', (39, 49))	('Phenoxybenzamine', 'Chemical', 'MESH:D010643', (0, 16))	('alpha-1', 'Gene', '146', (58, 65))
10652	27561909	Additionally, patients receiving phenoxybenzamine were titrated to the point of developing orthostatic hypotension, which suggested loss of the baroreceptor reflex and achievement of complete blockade.	('orthostatic hypotension', 'Disease', 'MESH:D007024', (91, 114))	('phenoxybenzamine', 'Var', (33, 49))	('baroreceptor reflex', 'MPA', (144, 163))	('loss', 'NegReg', (132, 136))	('hypotension', 'Phenotype', 'HP:0002615', (103, 114))	('orthostatic hypotension', 'Disease', (91, 114))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (33, 49))	('patients', 'Species', '9606', (14, 22))	('orthostatic hypotension', 'Phenotype', 'HP:0001278', (91, 114))
10706	27561909	Intra-operative hypotension and increased post-operative support were associated with selective blockade, but complications and hospital stay were similar between those blocked selectively and non-selectively.	('hypotension', 'Disease', 'MESH:D007022', (16, 27))	('hypotension', 'Disease', (16, 27))	('selective blockade', 'Var', (86, 104))	('increased', 'PosReg', (32, 41))	('hypotension', 'Phenotype', 'HP:0002615', (16, 27))	('-operative hypotension', 'Phenotype', 'HP:0001278', (5, 27))
10718	24213114	The treatment of bulky tumors by radionuclides that emit high energy alpha or beta particles is the preferred approach (Tables 1 and 2); however, for the eradication of small clusters of cancer cells or small tumor deposits, radionuclides that emit Auger electrons are considered to be beneficial because of their high level of cytotoxicity and short-range biological effectiveness.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('tumor deposits', 'Disease', 'MESH:D000079822', (209, 223))	('tumors', 'Disease', (23, 29))	('cytotoxicity', 'Disease', (328, 340))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', (187, 193))	('radionuclide', 'Chemical', 'MESH:D011868', (225, 237))	('men', 'Species', '9606', (9, 12))	('tumor deposits', 'Disease', (209, 223))	('radionuclide', 'Chemical', 'MESH:D011868', (33, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (328, 340))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('radionuclides', 'Var', (225, 238))
10720	24213114	It aims at destroying residual microscopic tumor tissue to reduce the recurrence rate, ablating remaining thyroid tissue to optimize follow-up conditions (e.g., thyroglobulin measurement), and completing staging by a highly sensitive post-therapeutic whole-body scintigraphy.	('recurrence rate', 'MPA', (70, 85))	('thyroglobulin', 'Gene', (161, 174))	('thyroglobulin', 'Gene', '7038', (161, 174))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ablating', 'Var', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('reduce', 'NegReg', (59, 65))	('tumor', 'Disease', (43, 48))	('men', 'Species', '9606', (182, 185))
10747	24213114	The duration of hormone withdrawal symptoms can be shortened with T3 supplement during this period and weaned for only 8-10 days prior to treatment.	('men', 'Species', '9606', (75, 78))	('men', 'Species', '9606', (143, 146))	('hormone', 'Disease', (16, 23))	('T3 supplement', 'Var', (66, 79))
10787	24213114	Many studies demonstrated the efficacy of Y-90-ibritumomab tiuxetan and I-131 tositumomab to be similar in patients with chemotherapy- refractory low-grade relapsed NHL, with an overall response rate of 60%-83% and a complete response (CR) rate of 15-52%.	('Y-90-ibritumomab tiuxetan', 'Chemical', 'MESH:C422802', (42, 67))	('I-131 tositumomab', 'Disease', (72, 89))	('I-131 tositumomab', 'Disease', 'MESH:D020754', (72, 89))	('CR', 'Chemical', '-', (236, 238))	('Y-90-ibritumomab', 'Var', (42, 58))	('NHL', 'Phenotype', 'HP:0012539', (165, 168))	('patients', 'Species', '9606', (107, 115))
10788	24213114	Song et al., using Monte Carlo based dosimetry in patients with lung metastases, found that I-131 may provide a therapeutic advantage over Y-90, especially in tumors with a radius less than 2.0 cm, as well as with a lower tumor burden due to a shorter pathlength of the beta particle from I-131 radionuclide.	('therapeutic', 'MPA', (112, 123))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('I-131', 'Chemical', 'MESH:C000614965', (289, 294))	('Y-90', 'Chemical', 'MESH:C000615496', (139, 143))	('tumors', 'Disease', (159, 165))	('lung metastases', 'Disease', 'MESH:D009362', (64, 79))	('tumor', 'Disease', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('lung metastases', 'Disease', (64, 79))	('tumor', 'Disease', (222, 227))	('radionuclide', 'Chemical', 'MESH:D011868', (295, 307))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('I-131', 'Chemical', 'MESH:C000614965', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('I-131', 'Var', (92, 97))
10793	24213114	Radiolabeled monoclonal antibodies have been shown to be effective in patients with chemotherapy-refractory, low-grade, or transformed low-grade NHL.	('patients', 'Species', '9606', (70, 78))	('low-grade', 'Var', (109, 118))	('NHL', 'Phenotype', 'HP:0012539', (145, 148))	('chemotherapy-refractory', 'Disease', (84, 107))
10795	24213114	showed that advanced age, prior radiotherapy, less than a 75-cGy dose of total-body radiation, bulky disease (>=5 cm), prior anthracycline-containing chemotherapy regimens, and no response to the last chemotherapeutic regimen are predictive of a lower overall response rate.	('less', 'Var', (46, 50))	('anthracycline', 'Chemical', 'MESH:D018943', (125, 138))	('bulky', 'Disease', (95, 100))	('men', 'Species', '9606', (222, 225))	('overall response', 'MPA', (252, 268))	('men', 'Species', '9606', (167, 170))	('lower', 'NegReg', (246, 251))
10819	24213114	[Y-90-DOTA0,Tyr3]Octreotide demonstrated a higher affinity for somatostatin receptor subtype 2 with a greater stability than with an In-111 radionuclide.	('Tyr3]Octreotide', 'Chemical', 'MESH:C045210', (12, 27))	('[Y-90-DOTA0', 'Var', (0, 11))	('Tyr3]', 'Var', (12, 17))	('stability', 'MPA', (110, 119))	('affinity', 'Interaction', (50, 58))	('somatostatin', 'Gene', '6750', (63, 75))	('[Y-90-DOTA0', 'Chemical', '-', (0, 11))	('radionuclide', 'Chemical', 'MESH:D011868', (140, 152))	('somatostatin', 'Gene', (63, 75))
10836	24213114	Although results with [Y-90-DOTA0,Tyr3]octreotide and [Lu-177-DOTA0,Tyr3]octreotate appear promising, reported varied response rates.	('[Y-90-DOTA0', 'Chemical', '-', (22, 33))	('[Lu-177-DOTA0', 'Var', (54, 67))	('Tyr3]', 'Var', (34, 39))	('Tyr3]', 'Var', (68, 73))	('Tyr3]octreotide', 'Chemical', 'MESH:C045210', (34, 49))	('[Y-90-DOTA0', 'Var', (22, 33))	('[Lu-177-DOTA0,Tyr3]octreotate', 'Chemical', '-', (54, 83))
10857	24213114	In a phase II study by Matthay et al., a group of patients with refractory neuroblastoma were treated with 18 mCi/kg (0.66 GBq/kg) I-131 MIBG and one third of the patients demonstrated hematopoietic toxicity requiring autologous hematopoietic stem cell support.	('GBq', 'Chemical', '-', (123, 126))	('patients', 'Species', '9606', (163, 171))	('hematopoietic toxicity', 'Disease', (185, 207))	('patients', 'Species', '9606', (50, 58))	('I-131 MIBG', 'Chemical', '-', (131, 141))	('mCi', 'Gene', (110, 113))	('neuroblastoma', 'Disease', 'MESH:D009447', (75, 88))	('neuroblastoma', 'Disease', (75, 88))	('I-131', 'Var', (131, 136))	('neuroblastoma', 'Phenotype', 'HP:0003006', (75, 88))	('mCi', 'Gene', '622408', (110, 113))	('hematopoietic toxicity', 'Disease', 'MESH:D019337', (185, 207))
10860	24213114	In a retrospective study of 37 patients treated with I-131 MIBG in a total of 116 treatment sessions, the overall survival rate was 85% at five years and 70% at 10 years.	('men', 'Species', '9606', (87, 90))	('I-131 MIBG', 'Chemical', '-', (53, 63))	('patients', 'Species', '9606', (31, 39))	('MIBG', 'Gene', (59, 63))	('I-131', 'Var', (53, 58))
10863	24213114	Although treatment of NETs with I-131 MIBG appears to be effective in symptomatic relief, further randomized studies are needed to evaluate its usefulness against chemotherapeutic agents.	('MIBG', 'Gene', (38, 42))	('I-131 MIBG', 'Chemical', '-', (32, 42))	('I-131', 'Var', (32, 37))	('men', 'Species', '9606', (14, 17))
10867	24213114	Intravenous administration of Sr-89 chloride, Sm-153-lexidronam, and Re-186-etidronate have been approved in different countries for the treatment of bone pain arising from osteoblastic or mixed osseous metastases.	('pain', 'Phenotype', 'HP:0012531', (155, 159))	('men', 'Species', '9606', (142, 145))	('Sr-89 chloride', 'Chemical', '-', (30, 44))	('bone pain', 'Phenotype', 'HP:0002653', (150, 159))	('Sm-153-lexidronam', 'Chemical', '-', (46, 63))	('Re-186-etidronate', 'Chemical', '-', (69, 86))	('osteoblastic', 'Disease', 'None', (173, 185))	('bone pain', 'Disease', 'MESH:D010146', (150, 159))	('osteoblastic', 'Disease', (173, 185))	('osseous metastases', 'Disease', 'MESH:D009362', (195, 213))	('osseous metastases', 'Disease', (195, 213))	('Sm-153-lexidronam', 'Var', (46, 63))	('bone pain', 'Disease', (150, 159))
10871	24213114	In a comparison trial by Baczyk et al., with breast or prostate cancer patients, complete pain relief was seen in 40% of women and 40% of men treated using Sm-153, and 25% of women and 33% of men achieved complete relief with Sr-89, which appears to be similarly effective.	('pain', 'Phenotype', 'HP:0012531', (90, 94))	('men', 'Species', '9606', (138, 141))	('patients', 'Species', '9606', (71, 79))	('breast or prostate cancer', 'Disease', (45, 70))	('breast or prostate cancer', 'Disease', 'MESH:D011471', (45, 70))	('pain', 'Disease', 'MESH:D010146', (90, 94))	('prostate cancer', 'Phenotype', 'HP:0012125', (55, 70))	('pain', 'Disease', (90, 94))	('men', 'Species', '9606', (177, 180))	('Sm-153', 'Var', (156, 162))	('Sm-153', 'Chemical', 'MESH:C000615023', (156, 162))	('women', 'Species', '9606', (175, 180))	('Sr-89', 'Chemical', 'MESH:C025700', (226, 231))	('men', 'Species', '9606', (192, 195))	('men', 'Species', '9606', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('women', 'Species', '9606', (121, 126))
10873	24213114	compared the effect of treatment with Re-188-HEDP, Re-186-HEDP, Sm-153-EDTMP, and Sr-89 Chloride.	('Sm-153-EDTMP', 'Var', (64, 76))	('men', 'Species', '9606', (28, 31))	('HEDP', 'Chemical', 'MESH:D012968', (58, 62))	('HEDP', 'Chemical', 'MESH:D012968', (45, 49))	('Sr-89 Chloride', 'Chemical', '-', (82, 96))	('Re-186-HEDP', 'Var', (51, 62))	('Sm-153-EDTMP', 'Chemical', '-', (64, 76))	('Re-188-HEDP', 'Var', (38, 49))
10874	24213114	In total, 73% of patients reported pain relief (77% after Re-188, 67% after Re-186, 73% after Sm-153, and 72% after Sr-89; P = 0.268-0.846).	('pain', 'Phenotype', 'HP:0012531', (35, 39))	('Sm-153', 'Chemical', 'MESH:C000615023', (94, 100))	('Sm-153', 'Var', (94, 100))	('pain', 'Disease', 'MESH:D010146', (35, 39))	('pain', 'Disease', (35, 39))	('Sr-89', 'Chemical', 'MESH:C025700', (116, 121))	('patients', 'Species', '9606', (17, 25))
10905	23888270	Germline loss-of-function SDH mutations are associated with several tumors such as pheochromocytoma and paraganglioma, gastrointestinal stromal tumor (GIST), and renal cell carcinoma (Hensen & Bayley; Kantorovich et al.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('pheochromocytoma', 'Disease', 'MESH:D010673', (83, 99))	('SDH', 'Gene', (26, 29))	('renal cell carcinoma', 'Disease', (162, 182))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('loss-of-function', 'NegReg', (9, 25))	('pheochromocytoma', 'Disease', (83, 99))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (119, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('paraganglioma', 'Disease', (104, 117))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (119, 149))	('tumors', 'Disease', (68, 74))	('paraganglioma', 'Disease', 'MESH:D010235', (104, 117))	('GIST', 'Phenotype', 'HP:0100723', (151, 155))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (162, 182))	('gastrointestinal stromal tumor', 'Disease', (119, 149))	('SDH', 'Gene', '6390', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
10907	23888270	Although SDH germline mutation may be accurately evaluated by gene sequencing, a few recent studies have shown very high sensitivity for immunohistochemical detection of SDH mutation in GIST, pheochromocytoma, and paraganglioma (Van Nederveen et al.	('paraganglioma', 'Disease', (214, 227))	('mutation', 'Var', (174, 182))	('SDH', 'Gene', '6390', (9, 12))	('pheochromocytoma', 'Disease', (192, 208))	('paraganglioma', 'Disease', 'MESH:D010235', (214, 227))	('SDH', 'Gene', '6390', (170, 173))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (192, 208))	('paraganglioma', 'Phenotype', 'HP:0002668', (214, 227))	('GIST', 'Phenotype', 'HP:0100723', (186, 190))	('pheochromocytoma', 'Disease', 'MESH:D010673', (192, 208))	('SDH', 'Gene', (170, 173))	('SDH', 'Gene', (9, 12))
10946	23888270	Tumor negativity for SDHA correlated with earlier age at diagnosis of breast cancer (P = 0.012) and with lower histologic grade (P = 0.062).	('lower', 'NegReg', (105, 110))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SDHA', 'Gene', (21, 25))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('Tumor negativity', 'Var', (0, 16))	('breast cancer', 'Disease', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SDHA', 'Gene', '6389', (21, 25))
10951	23888270	Stromal SDHB negativity was associated with HER-2 negativity (P < 0.001, Table 6).	('SDHB', 'Gene', '6390', (8, 12))	('HER-2', 'Gene', '2064', (44, 49))	('negativity', 'Var', (13, 23))	('SDHB', 'Gene', (8, 12))	('HER-2', 'Gene', (44, 49))	('negativity', 'MPA', (50, 60))
10960	23888270	Germline defects in SDH, particularly in SDHA and SDHB, have been detected in several tumor types, including pheochromocytomas (Van Nederveen et al.	('SDHA', 'Gene', (41, 45))	('SDH', 'Gene', (20, 23))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (109, 125))	('pheochromocytomas', 'Disease', 'MESH:D010673', (109, 126))	('SDHA', 'Gene', '6389', (41, 45))	('pheochromocytomas', 'Disease', (109, 126))	('SDH', 'Gene', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('defects', 'Var', (9, 16))	('SDH', 'Gene', (41, 44))	('SDHB', 'Gene', '6390', (50, 54))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (109, 126))	('detected', 'Reg', (66, 74))	('SDH', 'Gene', '6390', (20, 23))	('SDHB', 'Gene', (50, 54))	('tumor', 'Disease', (86, 91))	('SDH', 'Gene', '6390', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('SDH', 'Gene', '6390', (41, 44))
10963	23888270	Until recently, the accurate detection of SDH mutation depended primarily on direct sequencing and western blotting, methods that a clinical laboratory may find too costly and time-consuming.	('SDH', 'Gene', (42, 45))	('mutation', 'Var', (46, 54))	('SDH', 'Gene', '6390', (42, 45))
10965	23888270	demonstrated the high sensitivity of immunohistochemical methods to detect germline mutations in SDH (Van Nederveen et al.).	('germline mutations', 'Var', (75, 93))	('SDH', 'Gene', '6390', (97, 100))	('SDH', 'Gene', (97, 100))
10966	23888270	While the tumors with SDHB, SDHC, or SDHD germline mutations exhibited a loss of SDHB immmunoexpression with intact SDHA expression, tumors with SDHA germline mutations exhibited a loss of expression of both SDHA and SDHB.	('mutations', 'Var', (51, 60))	('tumors', 'Disease', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('SDHA', 'Gene', (145, 149))	('SDHB', 'Gene', (81, 85))	('SDHA', 'Gene', (208, 212))	('immmunoexpression', 'MPA', (86, 103))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('SDHA', 'Gene', '6389', (145, 149))	('SDHC', 'Gene', (28, 32))	('SDHB', 'Gene', '6390', (22, 26))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('SDHA', 'Gene', '6389', (208, 212))	('loss', 'NegReg', (73, 77))	('tumors', 'Disease', (133, 139))	('SDHD', 'Gene', '6392', (37, 41))	('SDHB', 'Gene', (22, 26))	('SDHB', 'Gene', '6390', (217, 221))	('SDHA', 'Gene', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('SDHB', 'Gene', '6390', (81, 85))	('SDHD', 'Gene', (37, 41))	('expression', 'MPA', (189, 199))	('SDHA', 'Gene', '6389', (116, 120))	('SDHC', 'Gene', '6391', (28, 32))	('loss', 'NegReg', (181, 185))	('SDHB', 'Gene', (217, 221))
10967	23888270	Using similar methods in the present study, we found that 23 of 721 breast cancer patients (3.19%) had SDHA mutation (SDHA-/SDHB- expression) and one patient (0.1%) had an SDHB mutation (SHDA+/SDHB- expression; Table 7).	('SDHB', 'Gene', (124, 128))	('SDHB', 'Gene', (172, 176))	('patient', 'Species', '9606', (150, 157))	('SDHB', 'Gene', '6390', (193, 197))	('SDHB', 'Gene', (193, 197))	('patient', 'Species', '9606', (82, 89))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('patients', 'Species', '9606', (82, 90))	('SDHA', 'Gene', '6389', (118, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('SDHA', 'Gene', (103, 107))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SDHA', 'Gene', (118, 122))	('mutation', 'Var', (108, 116))	('SDHB', 'Gene', '6390', (172, 176))	('SDHA', 'Gene', '6389', (103, 107))	('SDHB', 'Gene', '6390', (124, 128))
10968	23888270	As few previous studies have evaluated SDH mutation in breast cancer, these findings provide a starting point for future investigations.	('SDH', 'Gene', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (43, 51))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('SDH', 'Gene', '6390', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))
10969	23888270	However, a previous study reported that SDH germline mutations or variants occur in some patients with Cowden syndrome (CS) who do not present the expected PTEN mutation.	('PTEN', 'Gene', (156, 160))	('PTEN', 'Gene', '5728', (156, 160))	('variants', 'Var', (66, 74))	('germline mutations', 'Var', (44, 62))	('patients', 'Species', '9606', (89, 97))	('SDH', 'Gene', '6390', (40, 43))	('Cowden syndrome', 'Disease', 'MESH:D006223', (103, 118))	('occur', 'Reg', (75, 80))	('Cowden syndrome', 'Disease', (103, 118))	('SDH', 'Gene', (40, 43))
10971	23888270	Therefore, some breast cancer patients may be expected to have SDH mutations.	('SDH', 'Gene', '6390', (63, 66))	('breast cancer', 'Disease', (16, 29))	('SDH', 'Gene', (63, 66))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
10972	23888270	Findings in this study may be limited in that the sensitivity of immunohistochemistry in detecting SDH mutation as compared to direct sequencing has not been tested in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('SDH', 'Gene', (99, 102))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('SDH', 'Gene', '6390', (99, 102))	('mutation', 'Var', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
10974	23888270	To confirm SDH mutation, loss of SDH expression should be tested throughout the entire tumor (Barletta & Hornick), whereas in this study, immunohistochemistry was performed on the tissue microarray only.	('mutation', 'Var', (15, 23))	('SDH', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SDH', 'Gene', (11, 14))	('tumor', 'Disease', (87, 92))	('SDH', 'Gene', '6390', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('expression', 'MPA', (37, 47))	('SDH', 'Gene', '6390', (11, 14))
10979	23888270	Several mechanisms have been proposed to explain the involvement of SDH mutation in tumorigenesis, among which a HIF-1alpha-pathway-dependent mechanism is the most famous.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('involvement', 'Reg', (53, 64))	('SDH', 'Gene', (68, 71))	('HIF-1alpha', 'Gene', '3091', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('HIF-1alpha', 'Gene', (113, 123))	('mutation', 'Var', (72, 80))	('SDH', 'Gene', '6390', (68, 71))
10980	23888270	Loss-of-function mutation of SDH could result in an intracellular SDH accumulation, which in turn inhibits prolyl 4-hydroxylase (PHD), a negative regulator of HIF-1alpha (Cardaci & Ciriolo; Barletta & Hornick).	('Loss-of-function', 'NegReg', (0, 16))	('SDH', 'Gene', '6390', (66, 69))	('HIF-1alpha', 'Gene', (159, 169))	('mutation', 'Var', (17, 25))	('SDH', 'Gene', (66, 69))	('prolyl 4-hydroxylase', 'MPA', (107, 127))	('SDH', 'Gene', '6390', (29, 32))	('HIF-1alpha', 'Gene', '3091', (159, 169))	('inhibits', 'NegReg', (98, 106))	('SDH', 'Gene', (29, 32))
10982	23888270	As loss-of-function mutations in SDH are predicted to stabilize HIF-1alpha and upregulate HIF-1 transcriptional activity, we examined the expression of HIF-1alpha along with SDHA/SDHB.	('HIF-1', 'Gene', '3091', (152, 157))	('loss-of-function', 'NegReg', (3, 19))	('SDH', 'Gene', (179, 182))	('HIF-1', 'Gene', (152, 157))	('SDH', 'Gene', '6390', (33, 36))	('HIF-1', 'Gene', (90, 95))	('SDH', 'Gene', '6390', (174, 177))	('SDHB', 'Gene', '6390', (179, 183))	('HIF-1', 'Gene', '3091', (64, 69))	('HIF-1alpha', 'Gene', '3091', (152, 162))	('SDH', 'Gene', (33, 36))	('HIF-1', 'Gene', (64, 69))	('SDHA', 'Gene', (174, 178))	('SDH', 'Gene', (174, 177))	('HIF-1alpha', 'Gene', '3091', (64, 74))	('SDHA', 'Gene', '6389', (174, 178))	('SDHB', 'Gene', (179, 183))	('mutations', 'Var', (20, 29))	('SDH', 'Gene', '6390', (179, 182))	('HIF-1alpha', 'Gene', (152, 162))	('upregulate', 'PosReg', (79, 89))	('HIF-1alpha', 'Gene', (64, 74))	('HIF-1', 'Gene', '3091', (90, 95))
10987	23888270	Based on these results, SDH mutation in breast cancer is associated with low histologic grade and a less aggressive molecular subtype.	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('SDH', 'Gene', '6390', (24, 27))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('mutation', 'Var', (28, 36))	('SDH', 'Gene', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
10989	23888270	In earlier studies of SDH mutations in renal cell carcinomas (Baysal), GISTs (Miettinen et al.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (39, 60))	('GIST', 'Phenotype', 'HP:0100723', (71, 75))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (39, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (39, 59))	('mutations', 'Var', (26, 35))	('renal cell carcinomas', 'Disease', (39, 60))	('SDH', 'Gene', '6390', (22, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('SDH', 'Gene', (22, 25))
11101	31689495	Molecular pathway elucidation, genomic studies, and systematic genetics screens reported over the last two decades have identified several FH-inactivation driven pathways alterations, as well as rationally conceived treatment strategies that specifically target FH-/- tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('FH', 'Gene', '2271', (139, 141))	('FH', 'Gene', '2271', (262, 264))	('alterations', 'Var', (171, 182))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
11122	31689495	Enzymatic assay confirmed that the mutations ablated FH enzymatic function and that the mutation follows the Knudson's two hit hypothesis.	('ablated', 'NegReg', (45, 52))	('FH', 'Gene', '2271', (53, 55))	('mutations', 'Var', (35, 44))
11126	31689495	Since the molecular mechanism of VHL syndrome was well characterized, it was hypothesized that FH, SDH, and VHL mutations all cause dysregulation to the same pathway.	('VHL', 'Gene', '7428', (108, 111))	('dysregulation', 'MPA', (132, 145))	('SDH', 'Gene', (99, 102))	('cause', 'Reg', (126, 131))	('VHL', 'Gene', (33, 36))	('VHL syndrome', 'Disease', (33, 45))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', '7428', (33, 36))	('SDH', 'Gene', '6390', (99, 102))	('VHL syndrome', 'Disease', 'MESH:D006623', (33, 45))	('FH', 'Gene', '2271', (95, 97))	('VHL', 'Gene', (108, 111))
11135	31689495	These results point to several inconsistencies as to why FH mutation is more effective at activating HIF1A in fibroids as opposed to renal tumors, and why SDH mutant HPGL tumors show more consistent HIF1A activation.	('mutation', 'Var', (60, 68))	('SDH', 'Gene', '6390', (155, 158))	('renal tumors', 'Disease', 'MESH:D007674', (133, 145))	('mutant', 'Var', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('FH', 'Gene', '2271', (57, 59))	('HPGL tumors', 'Disease', 'MESH:D009369', (166, 177))	('HIF1A', 'Gene', (101, 106))	('renal tumors', 'Disease', (133, 145))	('HPGL tumors', 'Disease', (166, 177))	('activating', 'MPA', (90, 100))	('SDH', 'Gene', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('renal tumors', 'Phenotype', 'HP:0009726', (133, 145))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
11136	31689495	To investigate tumorigenesis events that take place following biallelic FH inactivation, Pollard and co-workers developed a mouse model of Fh1 (mouse homolog of human FH) knockout.	('inactivation', 'Var', (75, 87))	('human', 'Species', '9606', (161, 166))	('mouse', 'Species', '10090', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('FH', 'Gene', '2271', (72, 74))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mouse', 'Species', '10090', (124, 129))	('knockout', 'Var', (171, 179))	('Fh1', 'Gene', (139, 142))	('tumor', 'Disease', (15, 20))	('FH', 'Gene', '2271', (167, 169))
11138	31689495	Thus, to investigate kidney tumorigenesis following Fh1 knockout, they conditionally knocked out Fh1 in the kidney using Ksp1.3/Cre.	('tumor', 'Disease', (28, 33))	('Fh1', 'Gene', (97, 100))	('knocked', 'Var', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
11140	31689495	None of the mice developed kidney tumors and immunohistochemical analyses showed an increase in nuclear HIF1A staining, and a moderate increase in nuclear HIF2A staining in the Fh1 knockout renal cyst.	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('increase', 'PosReg', (135, 143))	('kidney tumors', 'Disease', (27, 40))	('Fh1', 'Gene', (177, 180))	('renal cyst', 'Phenotype', 'HP:0000107', (190, 200))	('kidney tumors', 'Phenotype', 'HP:0009726', (27, 40))	('knockout', 'Var', (181, 189))	('nuclear HIF2A staining', 'MPA', (147, 169))	('kidney tumors', 'Disease', 'MESH:D007680', (27, 40))	('mice', 'Species', '10090', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
11142	31689495	Apart from the direct inhibition of prolyl hydroxylase by fumarate, it was also showed that FH inactivation increases cellular reactive oxygen species (ROS), which in turn drives constitutive HIF activation (Figure 2).	('constitutive HIF activation', 'MPA', (179, 206))	('increases', 'PosReg', (108, 117))	('cellular reactive oxygen species', 'MPA', (118, 150))	('drives', 'PosReg', (172, 178))	('fumarate', 'Chemical', 'MESH:D005650', (58, 66))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (127, 150))	('ROS', 'Chemical', 'MESH:D017382', (152, 155))	('FH', 'Gene', '2271', (92, 94))	('inactivation', 'Var', (95, 107))
11143	31689495	It is important to note that conditional Fh1 and Hif1a double knockout mice have been created, and the addition of the Hif1a knockout exacerbates the renal cyst development, suggesting that Hif1a activation is likely a compensatory mechanism and not a tumor promoting event.	('mice', 'Species', '10090', (71, 75))	('knockout', 'Var', (125, 133))	('renal cyst development', 'CPA', (150, 172))	('addition', 'Var', (103, 111))	('Hif1a', 'Gene', (49, 54))	('Hif1a', 'Gene', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('Hif1a', 'Gene', '15251', (119, 124))	('exacerbates', 'PosReg', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('Hif1a', 'Gene', '15251', (49, 54))	('tumor', 'Disease', (252, 257))	('Hif1a', 'Gene', (119, 124))	('renal cyst', 'Phenotype', 'HP:0000107', (150, 160))	('Hif1a', 'Gene', '15251', (190, 195))
11144	31689495	Genomic studies on HLRCC tumors begin with gene expression profiling of FH mutant and FH wild type uterine fibroids.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('FH', 'Gene', '2271', (86, 88))	('FH', 'Gene', '2271', (72, 74))	('HLRCC tumors', 'Disease', 'MESH:C535516', (19, 31))	('HLRCC tumors', 'Disease', (19, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('uterine fibroids', 'Phenotype', 'HP:0000131', (99, 115))	('mutant', 'Var', (75, 81))
11145	31689495	The study revealed that FH mutant fibroids over-expressed genes involved in carbohydrate metabolism, iron homeostasis, and oxidoreductases.	('FH', 'Gene', '2271', (24, 26))	('mutant', 'Var', (27, 33))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('genes', 'Gene', (58, 63))	('carbohydrate', 'Chemical', 'MESH:D002241', (76, 88))	('over-expressed', 'PosReg', (43, 57))
11146	31689495	Through the gene expression profiling analyses, a 7 gene classifier, consisting of LDHA, NQO1, LAMA2, BNIP3, MYO15B, CDKN1C and COL6A2, was able to accurately predict FH mutation status in fibroids, signifying that FH inactivation alters gene expression profile in a specific way.	('BNIP3', 'Gene', '664', (102, 107))	('COL6A2', 'Gene', '1292', (128, 134))	('MYO15B', 'Gene', '80022', (109, 115))	('mutation', 'Var', (170, 178))	('COL6A2', 'Gene', (128, 134))	('CDKN1C', 'Gene', '1028', (117, 123))	('LDHA', 'Gene', '3939', (83, 87))	('inactivation', 'Var', (218, 230))	('LAMA2', 'Gene', '3908', (95, 100))	('predict', 'Reg', (159, 166))	('LAMA2', 'Gene', (95, 100))	('FH', 'Gene', '2271', (167, 169))	('MYO15B', 'Gene', (109, 115))	('NQO1', 'Gene', '1728', (89, 93))	('CDKN1C', 'Gene', (117, 123))	('alters', 'Reg', (231, 237))	('BNIP3', 'Gene', (102, 107))	('LDHA', 'Gene', (83, 87))	('NQO1', 'Gene', (89, 93))	('FH', 'Gene', '2271', (215, 217))
11148	31689495	Similarly, gene expression profile analyses were performed to evaluate gene expression changes following Fh1 knockout in the kidney tissue of mice.	('Fh1', 'Gene', (105, 108))	('knockout', 'Var', (109, 117))	('mice', 'Species', '10090', (142, 146))
11152	31689495	As expected, ccRCC, paraganglioma, and pheochromocytoma tumors that were known to harbor either VHL or SDH mutations were enriched for HIF1A signature, but HLRCC and the morphologically similar sporadic PRCC2 tumors did not show the enrichment of the HIF1A signature.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('paraganglioma', 'Disease', (20, 33))	('tumors', 'Disease', (56, 62))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (39, 55))	('paraganglioma', 'Disease', 'MESH:D010235', (20, 33))	('pheochromocytoma tumors', 'Disease', 'MESH:D010673', (39, 62))	('pheochromocytoma tumors', 'Disease', (39, 62))	('SDH', 'Gene', '6390', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('paraganglioma', 'Phenotype', 'HP:0002668', (20, 33))	('ccRCC', 'Disease', (13, 18))	('VHL', 'Gene', (96, 99))	('SDH', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('mutations', 'Var', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('VHL', 'Gene', '7428', (96, 99))
11155	31689495	These computational findings were empirically validated, revealing that fumarate accumulated following FH inactivation, which in turn activates NRF2 by covalently modifying C151 and C288 of Kelch Like ECH Associated Protein 1 (KEAP1), the bonafide negative regulator of NRF2, leading to sustained NRF2 activation.	('FH', 'Gene', '2271', (103, 105))	('NRF2', 'Gene', (144, 148))	('Kelch Like ECH Associated Protein 1', 'Gene', (190, 225))	('inactivation', 'Var', (106, 118))	('Kelch Like ECH Associated Protein 1', 'Gene', '9817', (190, 225))	('modifying', 'Reg', (163, 172))	('C151', 'Var', (173, 177))	('activates', 'PosReg', (134, 143))	('fumarate', 'Chemical', 'MESH:D005650', (72, 80))	('C288', 'Var', (182, 186))	('NRF2', 'Gene', (297, 301))	('activation', 'PosReg', (302, 312))
11159	31689495	Around the same time, a mouse model study involving the development of an Fh1/Hif1a double knockout mouse model also identified that Fh1 inactivation in mice drives an Nrf2 activation phenotype, reinforcing that NRF2 activation is one of the main cellular alterations following FH inactivation.	('inactivation', 'Var', (137, 149))	('mouse', 'Species', '10090', (24, 29))	('FH', 'Gene', '2271', (278, 280))	('activation', 'PosReg', (173, 183))	('Nrf2', 'Gene', '18024', (168, 172))	('Hif1a', 'Gene', '15251', (78, 83))	('mouse', 'Species', '10090', (100, 105))	('Fh1', 'Gene', (133, 136))	('Nrf2', 'Gene', (168, 172))	('mice', 'Species', '10090', (153, 157))	('Hif1a', 'Gene', (78, 83))
11160	31689495	Unlike other subtypes of kidney cancer whereby the hereditary and sporadic forms of the tumors harbor mutations to the same tumor suppressor and oncogenes, the sporadic counterpart of HLRCC rarely harbors an FH mutation.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('kidney cancer', 'Disease', 'MESH:D007680', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (25, 38))	('tumor', 'Disease', (124, 129))	('kidney cancer', 'Disease', (25, 38))	('mutations', 'Var', (102, 111))	('FH', 'Gene', '2271', (208, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('HLRCC', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
11161	31689495	The answer to this question came to light when our group utilized exome sequencing on carefully curated cases of PRCC2 and found that those tumor cases harbored gain-of-function NRF2 mutations and loss-of-function mutations to CUL3.	('mutations', 'Var', (183, 192))	('NRF2', 'Gene', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('gain-of-function', 'PosReg', (161, 177))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('CUL3', 'Gene', '8452', (227, 231))	('loss-of-function', 'NegReg', (197, 213))	('CUL3', 'Gene', (227, 231))	('tumor', 'Disease', (140, 145))
11162	31689495	Functional studies confirmed the functional changes of the identified NRF2 and CUL3 mutations.	('mutations', 'Var', (84, 93))	('NRF2', 'Gene', (70, 74))	('CUL3', 'Gene', '8452', (79, 83))	('CUL3', 'Gene', (79, 83))
11163	31689495	Subsequently, The Cancer Genome Atlas (TCGA) reported in a larger cohort that mutations that drive sustained NRF2 activation, including NRF2 gain-of-function, KEAP1 loss-of-function, and CUL3 loss-of-function, were significantly enriched in sporadic PRCC2 cases, confirming our initial exome sequencing findings.	('activation', 'PosReg', (114, 124))	('PRCC2', 'Disease', (250, 255))	('loss-of-function', 'NegReg', (192, 208))	('loss-of-function', 'NegReg', (165, 181))	('mutations', 'Var', (78, 87))	('CUL3', 'Gene', '8452', (187, 191))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NRF2', 'Gene', (109, 113))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Disease', (18, 24))	('NRF2', 'Gene', (136, 140))	('CUL3', 'Gene', (187, 191))	('gain-of-function', 'PosReg', (141, 157))
11183	31689495	The succination alters cellular iron homeostasis in HLRCC and induces a pro-proliferative signaling in HLRCC cells.	('pro-proliferative signaling', 'MPA', (72, 99))	('cellular iron homeostasis', 'MPA', (23, 48))	('induces', 'Reg', (62, 69))	('succination', 'Var', (4, 15))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('alters', 'Reg', (16, 22))
11186	31689495	While this study did not find pKa of the sulfhydryl group to be predictive of reactivity to fumarate, protonation of fumarate in an acidic environment was shown to encourage 2-SC formation.	('2-SC', 'Chemical', 'MESH:C511650', (174, 178))	('fumarate', 'Chemical', 'MESH:D005650', (92, 100))	('iron', 'Chemical', 'MESH:D007501', (142, 146))	('2-SC formation', 'MPA', (174, 188))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('encourage', 'PosReg', (164, 173))	('protonation', 'Var', (102, 113))
11189	31689495	Tong and co-workers demonstrated that FH inactivation decreased the intracellular labile iron pool, which resulted in IRPs repression of HIF2A translation.	('iron', 'Chemical', 'MESH:D007501', (89, 93))	('inactivation', 'Var', (41, 53))	('translation', 'MPA', (143, 154))	('repression', 'NegReg', (123, 133))	('HIF2A', 'Gene', (137, 142))	('decreased', 'NegReg', (54, 63))	('intracellular labile iron pool', 'MPA', (68, 98))	('FH', 'Gene', '2271', (38, 40))
11190	31689495	Specifically, they showed that the absence of FH inactivates AMP-activated protein kinase (AMPK) which in turn suppresses divalent metal transporter 1 (DMT1) expression (Figure 4).	('divalent metal transporter 1', 'Gene', '4891', (122, 150))	('DMT1', 'Gene', (152, 156))	('DMT1', 'Gene', '4891', (152, 156))	('expression', 'MPA', (158, 168))	('divalent metal transporter 1', 'Gene', (122, 150))	('AMPK', 'Gene', (91, 95))	('AMP-activated protein kinase', 'Pathway', (61, 89))	('AMPK', 'Gene', '5564', (91, 95))	('FH', 'Gene', '2271', (46, 48))	('absence', 'Var', (35, 42))	('suppresses', 'NegReg', (111, 121))	('inactivates', 'NegReg', (49, 60))
11194	31689495	Interestingly, this differential HIF1A vs HIF2A activation is in discordance with the differential HIF1A vs HIF2A activation in ccRCC, which frequently harbors VHL loss-of-function mutations that lead to sustained HIF activation.	('ccRCC', 'Disease', (128, 133))	('VHL', 'Gene', (160, 163))	('loss-of-function', 'NegReg', (164, 180))	('VHL', 'Gene', '7428', (160, 163))	('mutations', 'Var', (181, 190))
11196	31689495	Accordingly, aggressive ccRCC often harbors HIF1A loss-of-function mutations that lead to selective activation of HIF2A alone, suggesting a tumor suppressive role of HIF1A in ccRCC.	('HIF1A', 'Gene', (44, 49))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('loss-of-function', 'NegReg', (50, 66))	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', (140, 145))
11206	31689495	As outlined in the earlier sections, biallelic FH inactivation imparts very significant changes to the transcriptome and the proteome.	('transcriptome', 'MPA', (103, 116))	('inactivation', 'Var', (50, 62))	('FH', 'Gene', '2271', (47, 49))	('changes', 'Reg', (88, 95))
11207	31689495	Since all cancer cells and only cancer cells in HLRCC patients harbor biallelic FH inactivation, biological changes driven by FH inactivation provide unique opportunities for targeted therapy.	('biallelic', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('patients', 'Species', '9606', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FH', 'Gene', '2271', (80, 82))	('FH', 'Gene', '2271', (126, 128))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
11209	31689495	Particularly FH inactivation increases cellular dependency on glycolysis for ATP production.	('cellular dependency on glycolysis', 'MPA', (39, 72))	('inactivation', 'Var', (16, 28))	('increases', 'PosReg', (29, 38))	('ATP', 'Chemical', 'MESH:D000255', (77, 80))	('FH', 'Gene', '2271', (13, 15))
11219	31689495	As such, heme biosynthesis and degradation serve to complete carbohydrate catabolism and glutaminolysis, while continually supplying the cells with NADH and biosynthetic precursors when the TCA cycle is truncated upon FH inactivation.	('TCA', 'Chemical', 'MESH:D014238', (190, 193))	('degradation', 'MPA', (31, 42))	('carbohydrate', 'Chemical', 'MESH:D002241', (61, 73))	('carbohydrate catabolism', 'MPA', (61, 84))	('heme', 'Chemical', 'MESH:D006418', (9, 13))	('NADH', 'Chemical', 'MESH:D009243', (148, 152))	('FH', 'Gene', '2271', (218, 220))	('inactivation', 'Var', (221, 233))	('glutaminolysis', 'MPA', (89, 103))	('heme', 'MPA', (9, 13))
11220	31689495	Inhibiting HMOX1 and heme biosynthesis stifled the cells' ability to complete carbohydrate and glutamine metabolism and resulted in conditional cell death (Figure 5).	('Inhibiting', 'Var', (0, 10))	('HMOX1', 'Gene', (11, 16))	('heme', 'Enzyme', (21, 25))	('heme', 'Chemical', 'MESH:D006418', (21, 25))	('HMOX1', 'Gene', '3162', (11, 16))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('carbohydrate', 'Chemical', 'MESH:D002241', (78, 90))	('death', 'Disease', 'MESH:D003643', (149, 154))	('death', 'Disease', (149, 154))
11223	31689495	Specifically, C94 of GPX4 is succinated in FH-inactivated cells and the succinated form of GPX4 has reduced activity (Figure 5).	('FH', 'Gene', '2271', (43, 45))	('activity', 'MPA', (108, 116))	('GPX4', 'Gene', (91, 95))	('GPX4', 'Gene', '2879', (91, 95))	('succinate', 'Chemical', 'MESH:D019802', (29, 38))	('GPX4', 'Gene', (21, 25))	('GPX4', 'Gene', '2879', (21, 25))	('C94', 'Var', (14, 17))	('succinate', 'Chemical', 'MESH:D019802', (72, 81))
11235	31689495	The screen identified the synthetic lethal combination of the pentose phosphate enzyme, phosphogluconate dehydrogenase (PGD) knockdown with FH-inactivation.	('phosphogluconate dehydrogenase', 'Gene', (88, 118))	('knockdown', 'Var', (125, 134))	('pentose phosphate', 'Chemical', 'MESH:D010428', (62, 79))	('PGD', 'Gene', (120, 123))	('phosphogluconate dehydrogenase', 'Gene', '5226', (88, 118))	('PGD', 'Gene', '5226', (120, 123))	('FH', 'Gene', '2271', (140, 142))
11236	31689495	Mechanistically, PGD inhibition blocks glycolysis, suppresses reductive carboxylation of glutamine, and increases the NADP+/NADPH ratio to disrupt redox homeostasis (Figure 5).	('blocks', 'NegReg', (32, 38))	('redox homeostasis', 'MPA', (147, 164))	('glycolysis', 'MPA', (39, 49))	('disrupt', 'Reg', (139, 146))	('NADPH', 'Gene', '1666', (124, 129))	('PGD', 'Gene', (17, 20))	('increases', 'PosReg', (104, 113))	('disrupt redox homeostasis', 'Phenotype', 'HP:0025463', (139, 164))	('reductive carboxylation of glutamine', 'MPA', (62, 98))	('inhibition', 'Var', (21, 31))	('NADPH', 'Gene', (124, 129))	('glutamine', 'Chemical', 'MESH:D005973', (89, 98))	('NADP+', 'Chemical', 'MESH:D009249', (118, 123))	('PGD', 'Gene', '5226', (17, 20))	('suppresses', 'NegReg', (51, 61))
11239	31689495	It is important to note that PGD loss-of-function mutation has been previously identified in the human population and is associated with occasional mild hemolytic anemia, suggesting that PGD inhibition should be well tolerated in human.	('PGD', 'Gene', '5226', (187, 190))	('PGD', 'Gene', (29, 32))	('hemolytic anemia', 'Disease', 'MESH:D000743', (153, 169))	('PGD', 'Gene', '5226', (29, 32))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (153, 169))	('human', 'Species', '9606', (97, 102))	('anemia', 'Phenotype', 'HP:0001903', (163, 169))	('mutation', 'Var', (50, 58))	('human', 'Species', '9606', (230, 235))	('hemolytic anemia', 'Disease', (153, 169))	('PGD', 'Gene', (187, 190))	('loss-of-function', 'NegReg', (33, 49))
11250	31689495	This is an important study because a significant subset of lung cancer tumors harbor either somatic loss-of-function mutations to KEAP1 or somatic gain-of-function mutation to NRF2.	('lung cancer tumors', 'Disease', (59, 77))	('mutations', 'Var', (117, 126))	('KEAP1', 'Gene', (130, 135))	('lung cancer tumors', 'Disease', 'MESH:D008175', (59, 77))	('loss-of-function', 'NegReg', (100, 116))	('gain-of-function', 'PosReg', (147, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('NRF2', 'Gene', (176, 180))	('mutation', 'Var', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
11251	31689495	The study utilized a small sgRNA library consisting of 65 sgRNA targeting 17 NRF2 target genes and found that tumors with sustained NRF2 activation is dependent on glutaminolysis for cellular bioenergetics, whereby inhibition of the glutaminase, GLS, could selectively kill cancer cells with sustained NRF2 activation (Figure 5).	('inhibition', 'Var', (215, 225))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('glutaminase', 'Gene', (233, 244))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('glutaminase', 'Gene', '2744', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
11252	31689495	This is relevant to HLRCC because (as it was outlined in the earlier section), FH inactivation drives sustained NRF2 activation, a phenotype that unifies HLRCC with its sporadic counterpart, PRCC2.	('HLRCC', 'Disease', (154, 159))	('FH', 'Gene', '2271', (79, 81))	('activation', 'PosReg', (117, 127))	('inactivation', 'Var', (82, 94))	('NRF2', 'Gene', (112, 116))
11258	31689495	Loss-of-heterozygosity is always detected in the tumor tissues indicating bialleic FH loss as the tumor initiating event.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('Loss-of-heterozygosity', 'NegReg', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FH loss', 'Disease', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('bialleic', 'Var', (74, 82))	('FH loss', 'Disease', 'MESH:D006938', (83, 90))
11260	31689495	It is measured that fumarate accumulates to millimolar concentration in HLRCC cells, and at this high concentration, fumarate directly alters various cellular signaling pathways including: increased HIF1A activity, increased NRF2 activity, and attenuated cellular iron homeostasis.	('cellular iron homeostasis', 'MPA', (255, 280))	('attenuated', 'NegReg', (244, 254))	('fumarate', 'Chemical', 'MESH:D005650', (20, 28))	('iron', 'Chemical', 'MESH:D007501', (264, 268))	('activity', 'MPA', (205, 213))	('increased', 'PosReg', (215, 224))	('HIF1A', 'Enzyme', (199, 204))	('activity', 'MPA', (230, 238))	('alters', 'Reg', (135, 141))	('fumarate', 'Chemical', 'MESH:D005650', (117, 125))	('fumarate', 'Var', (117, 125))	('cellular signaling pathways', 'Pathway', (150, 177))	('NRF2', 'Enzyme', (225, 229))	('increased', 'PosReg', (189, 198))
11366	30258932	For example, in breast cancer, overexpression of NEAT1 promotes EMT and invasion in vitro as well as dissemination and metastasis in vivo.	('breast cancer', 'Disease', (16, 29))	('overexpression', 'Var', (31, 45))	('promotes', 'PosReg', (55, 63))	('NEAT1', 'Gene', '283131', (49, 54))	('NEAT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dissemination', 'CPA', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
11367	30258932	Exogenous modulation of NEAT1 modulates gemcitabine sensitivity in cholangiocarcinoma.	('modulates', 'Reg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('modulation', 'Var', (10, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('gemcitabine sensitivity', 'MPA', (40, 63))	('NEAT1', 'Gene', '283131', (24, 29))	('NEAT1', 'Gene', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
11369	30258932	Moreover, in breast cancer, hepatocellular carcinoma, and papillary kidney cancer, whole-genome analysis indicates NEAT1 carries specific mutations that affect their expression levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('hepatocellular carcinoma', 'Disease', (28, 52))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('papillary kidney cancer', 'Disease', (58, 81))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('affect', 'Reg', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('expression levels', 'MPA', (166, 183))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (58, 81))	('NEAT1', 'Gene', (115, 120))	('NEAT1', 'Gene', '283131', (115, 120))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (58, 81))	('mutations', 'Var', (138, 147))
11370	30258932	rs512715 of NEAT1 is also associated with an increased risk of cervical cancer.	('rs512715', 'Mutation', 'rs512715', (0, 8))	('NEAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (63, 78))	('rs512715', 'Var', (0, 8))	('cervical cancer', 'Disease', (63, 78))	('NEAT1', 'Gene', '283131', (12, 17))	('associated', 'Reg', (26, 36))
11393	30258932	However, a recent study indicated that in breast invasive cancer, from TCGA datasets, NEAT1 was focally deleted in ~8% of breast cancers and its promoters carried various mutations, and three out of the four mutations they validated reproducibly decreased NEAT1 expression compared with the wild type sequence.	('NEAT1', 'Gene', '283131', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NEAT1', 'Gene', (256, 261))	('deleted', 'NegReg', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('expression', 'MPA', (262, 272))	('breast invasive cancer', 'Disease', (42, 64))	('mutations', 'Var', (208, 217))	('NEAT1', 'Gene', '283131', (86, 91))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('NEAT1', 'Gene', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (246, 255))
11406	30258932	In lung cancer, NEAT1 is up-regulated by the direct binding of Oct4, since knockdown of NEAT1 abolishes Oct4-mediated lung cancer cell growth and motility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('Oct4', 'Gene', '5460', (63, 67))	('lung cancer', 'Disease', (118, 129))	('abolishes', 'NegReg', (94, 103))	('NEAT1', 'Gene', (88, 93))	('Oct4', 'Gene', (104, 108))	('knockdown', 'Var', (75, 84))	('binding', 'Interaction', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NEAT1', 'Gene', (16, 21))	('lung cancer', 'Disease', (3, 14))	('Oct4', 'Gene', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NEAT1', 'Gene', '283131', (88, 93))	('up-regulated', 'PosReg', (25, 37))	('motility', 'CPA', (146, 154))	('NEAT1', 'Gene', '283131', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('Oct4', 'Gene', '5460', (104, 108))
11418	30258932	The aberrant expression of NEAT1 in certain types of cancer may be resulted from the cooperation and antagonism between different transcription factors.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('NEAT1', 'Gene', '283131', (27, 32))	('NEAT1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resulted from', 'Reg', (67, 80))
11425	30258932	In laryngeal squamous cell cancer, high expression of NEAT1 decreases miR-107 expression, thus regulating CDK6 level and exerting an oncogenic effect.	('decreases', 'NegReg', (60, 69))	('regulating', 'Reg', (95, 105))	('laryngeal squamous cell cancer', 'Disease', (3, 33))	('NEAT1', 'Gene', (54, 59))	('expression', 'MPA', (78, 88))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (3, 33))	('NEAT1', 'Gene', '283131', (54, 59))	('CDK6', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CDK6', 'Gene', '1021', (106, 110))	('oncogenic effect', 'CPA', (133, 149))	('high expression', 'Var', (35, 50))	('miR-107', 'Gene', '406901', (70, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (13, 33))	('miR-107', 'Gene', (70, 77))
11444	30258932	Recently, several studies have revealed the mutations and polymorphisms of NEAT1 are also closely correlated with the prognosis of cancers, which has added complexity to NEAT1-associated signaling and function.	('NEAT1', 'Gene', '283131', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('NEAT1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('polymorphisms', 'Var', (58, 71))	('correlated', 'Reg', (98, 108))	('mutations', 'Var', (44, 53))	('NEAT1', 'Gene', '283131', (170, 175))	('NEAT1', 'Gene', (170, 175))
11445	30258932	Moreover, since the two major isoforms of NEAT1 produced from alternative transcription have been reported to have different cellular location and tumor regulation properties, it is necessary to distinguish the exact expression and function of these two isoforms.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NEAT1', 'Gene', '283131', (42, 47))	('alternative transcription', 'Var', (62, 87))	('NEAT1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
11521	28197344	A 33-year-old G6P3 woman (weight 83.9 kg; height 1.6 m; body mass index 32.8 kg/m2) presented to our unit at 32 5/7 weeks of gestation with severe headache, palpitations, anxiety, abdominal pain, and hypertensive crisis (blood pressure (BP) 200-230/100-130 mmHg).	('headache', 'Disease', (147, 155))	('woman', 'Species', '9606', (19, 24))	('pain', 'Phenotype', 'HP:0012531', (190, 194))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (200, 219))	('palpitations', 'Disease', (157, 169))	('anxiety', 'Phenotype', 'HP:0000739', (171, 178))	('abdominal pain', 'Phenotype', 'HP:0002027', (180, 194))	('headache', 'Phenotype', 'HP:0002315', (147, 155))	('G6P3', 'Var', (14, 18))	('anxiety', 'Disease', 'MESH:D001008', (171, 178))	('hypertensive', 'Disease', 'MESH:D006973', (200, 212))	('abdominal pain', 'Disease', (180, 194))	('palpitations', 'Phenotype', 'HP:0001962', (157, 169))	('headache', 'Disease', 'MESH:D006261', (147, 155))	('hypertensive', 'Disease', (200, 212))	('anxiety', 'Disease', (171, 178))	('abdominal pain', 'Disease', 'MESH:D015746', (180, 194))
11586	28197344	Phenoxybenzamine is an irreversible adrenergic antagonist and has been suggested as the preferred treatment of choice in patients with pheochromocytoma or PGL.	('pheochromocytoma', 'Disease', (135, 151))	('Phenoxybenzamine', 'Var', (0, 16))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('PGL', 'Phenotype', 'HP:0002668', (155, 158))	('Phenoxybenzamine', 'Chemical', 'MESH:D010643', (0, 16))	('patients', 'Species', '9606', (121, 129))
11598	28197344	Referral for genetic testing is also essential given that a germline mutation in susceptibility genes is identified in approximately 40% of pheochromocytomas or paragangliomas cases, which can increase risk of tumor recurrence and also have implications for family members.	('pheochromocytomas', 'Disease', (140, 157))	('paraganglioma', 'Phenotype', 'HP:0002668', (161, 174))	('pheochromocytomas', 'Disease', 'MESH:D010673', (140, 157))	('increase', 'PosReg', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('paragangliomas', 'Disease', (161, 175))	('germline mutation', 'Var', (60, 77))	('paragangliomas', 'Disease', 'MESH:D010235', (161, 175))	('paragangliomas', 'Phenotype', 'HP:0002668', (161, 175))	('tumor', 'Disease', (210, 215))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (140, 157))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (140, 156))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
11604	15331017	No evidence for involvement of SDHD in neuroblastoma pathogenesis Deletions in the long arm of chromosome 11 are observed in a subgroup of advanced stage neuroblastomas with poor outcome.	('SDHD', 'Gene', (31, 35))	('Deletions', 'Var', (66, 75))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('neuroblastomas', 'Phenotype', 'HP:0003006', (154, 168))	('observed', 'Reg', (113, 121))	('neuroblastomas', 'Disease', 'MESH:D009447', (154, 168))	('neuroblastoma', 'Phenotype', 'HP:0003006', (154, 167))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Disease', 'MESH:D009447', (154, 167))	('SDHD', 'Gene', '6392', (31, 35))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('neuroblastoma', 'Disease', (154, 167))	('neuroblastomas', 'Disease', (154, 168))
11607	15331017	Analysis at the genomic level of 67 tumour samples and 37 cell lines revealed at least 2 bona-fide mutations in cell lines without allelic loss at 11q23: a 4bp-deletion causing skip of exon 3 resulting in a premature stop codon in cell line N206, and a Y93C mutation in cell line NMB located in a region affected by germline SDHD mutations causing hereditary paraganglioma.	('Y93C', 'Var', (253, 257))	('NMB', 'Gene', '4828', (280, 283))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', (36, 42))	('N206', 'CellLine', 'CVCL:C885', (241, 245))	('paraganglioma', 'Phenotype', 'HP:0002668', (359, 372))	('hereditary paraganglioma', 'Disease', (348, 372))	('NMB', 'Gene', (280, 283))	('Y93C', 'Mutation', 'rs142135772', (253, 257))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (348, 372))
11617	15331017	Both NB subgroups present with 17q-gain, but are distinguished by presence of MYCN amplification and 1p-deletion in subgroup 2B and 11q-deletion often in combination with 3p-deletion in subgroup 2A.	('17q-gain', 'MPA', (31, 39))	('NB', 'Phenotype', 'HP:0003006', (5, 7))	('11q-deletion', 'Var', (132, 144))	('MYCN', 'Gene', '4613', (78, 82))	('MYCN', 'Gene', (78, 82))	('1p-deletion', 'Var', (101, 112))	('17q-gain', 'PosReg', (31, 39))
11619	15331017	The recurrent finding of 11q-deletions in NB suggests the presence of a tumour suppressor gene residing on the long arm of chromosome 11.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('NB', 'Phenotype', 'HP:0003006', (42, 44))	('11q-deletions', 'Var', (25, 38))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
11620	15331017	Although both comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) studies indicate that the majority of the 11q-deletions are distal losses encompassing a large portion of the long arm, detection of rare small or interstitial deletions allowed the provisional localization of an SRO (shortest region of overlap) at 11q23.3 between markers D11S1340 and D11S1299, encompassing a distance of approximately 3 Mb.	('D11S1299', 'Var', (373, 381))	('D11S1340', 'Var', (360, 368))	('S1299', 'CellLine', 'CVCL:0060', (376, 381))	('SRO', 'Chemical', '-', (300, 303))
11621	15331017	When a single tumour with two small interstitial deletions is not taken into consideration, the SRO is defined by a small subset of tumours and spans 18 Mb between markers D11S898 and D11S1299 (according to UCSC Genome Browser, freeze version July 2003).	('SRO', 'Chemical', '-', (96, 99))	('tumour', 'Disease', (14, 20))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Disease', (132, 138))	('D11S898', 'Var', (172, 179))	('tumours', 'Disease', (132, 139))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('D11S1299', 'Var', (184, 192))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('S1299', 'CellLine', 'CVCL:0060', (187, 192))
11623	15331017	The first evidence for a role of SDHD in tumour development was obtained by the discovery of germline mutations in this gene as the cause for familial paraganglioma (PGL).	('familial paraganglioma', 'Disease', 'MESH:D010235', (142, 164))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('paraganglioma', 'Phenotype', 'HP:0002668', (151, 164))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (102, 111))	('PGL', 'Phenotype', 'HP:0002668', (166, 169))	('familial paraganglioma', 'Disease', (142, 164))	('tumour', 'Disease', (41, 47))	('cause', 'Reg', (132, 137))
11624	15331017	Somatic and occult germline SDHD mutations were also detected in patients with apparently sporadic pheochromocytoma (PC).	('SDHD', 'Gene', (28, 32))	('pheochromocytoma', 'Disease', (99, 115))	('mutations', 'Var', (33, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (99, 115))	('detected', 'Reg', (53, 61))	('PC', 'Phenotype', 'HP:0002666', (117, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (99, 115))	('patients', 'Species', '9606', (65, 73))
11626	15331017	It was shown that SDHD inactivation leads to a pseudo-hypoxic state and upregulation of hypoxia responsive genes, possibly through increased production of reactive oxygen species (ROS).	('inactivation', 'Var', (23, 35))	('upregulation', 'PosReg', (72, 84))	('hypoxia', 'Disease', 'MESH:D000860', (88, 95))	('increased', 'PosReg', (131, 140))	('hypoxia', 'Disease', (88, 95))	('increased production of reactive oxygen species', 'Phenotype', 'HP:0025464', (131, 178))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (155, 178))	('ROS', 'Chemical', 'MESH:D017382', (180, 183))	('leads to', 'Reg', (36, 44))	('SDHD', 'Gene', (18, 22))	('pseudo-hypoxic state', 'MPA', (47, 67))
11628	15331017	Consequently, inactivating SDHD mutations or reduced activity of SDHD might lead to impaired oxidative phosphorylation and hypoxia and thus contribute to NB oncogenesis.	('reduced', 'NegReg', (45, 52))	('NB', 'Phenotype', 'HP:0003006', (154, 156))	('oxidative phosphorylation', 'MPA', (93, 118))	('hypoxia', 'Disease', 'MESH:D000860', (123, 130))	('impaired', 'NegReg', (84, 92))	('contribute', 'Reg', (140, 150))	('hypoxia', 'Disease', (123, 130))	('activity', 'MPA', (53, 61))	('mutations', 'Var', (32, 41))	('SDHD', 'Gene', (27, 31))	('inactivating', 'Var', (14, 26))	('NB oncogenesis', 'Disease', (154, 168))	('NB oncogenesis', 'Disease', 'MESH:D063646', (154, 168))
11635	15331017	Cultures of NB cell lines N206, SK-N-AS, SK-N-SH, NMB, SK-N-FI, CLB-GA, LA-N-2 and NGP were treated with puromycine (100 mug/ml) during 6 hours in order to prevent possible nonsense mediated RNA decay of variant SDHD transcripts.	('CLB', 'Gene', (64, 67))	('N206', 'CellLine', 'CVCL:C885', (26, 30))	('NMB', 'Gene', '4828', (50, 53))	('variant', 'Var', (204, 211))	('SK-N-AS, SK-N-SH', 'Disease', 'MESH:C536108', (32, 48))	('SDHD', 'Gene', (212, 216))	('puromycine', 'Chemical', 'MESH:D011691', (105, 115))	('NB', 'Phenotype', 'HP:0003006', (12, 14))	('NMB', 'Gene', (50, 53))	('CLB', 'Gene', '171425', (64, 67))	('nonsense mediated RNA decay', 'MPA', (173, 200))
11637	15331017	All NB patients were analyzed with 4 microsatellite markers on 11q23: D11S1986 (11q23.1), D11S1998 (11q23.3), D11S1356 (11q23.3) and D11S1299 (11q23.3), of which D11S1986 and D11S1998 are immediately flanking the SDHD gene.	('D11S1299', 'Var', (133, 141))	('patients', 'Species', '9606', (7, 15))	('D11S1986', 'Var', (70, 78))	('S1299', 'CellLine', 'CVCL:0060', (136, 141))	('D11S1998', 'Var', (175, 183))	('D11S1986', 'Var', (162, 170))	('NB', 'Phenotype', 'HP:0003006', (4, 6))	('D11S1998', 'Var', (90, 98))	('SDHD', 'Gene', (213, 217))	('D11S1356', 'Var', (110, 118))
11638	15331017	In order to discriminate between whole chromosome loss, and unbalanced 11q loss (= partial 11q loss), two microsatellite markers on 11p (D11S922 on 11p15.5 and D11S1324 on 11p14.1) were analyzed in patients that showed allelic imbalance for all 11q markers (positions of the markers are according to the UCSC Genome Browser, freeze version July 2003).	('loss', 'NegReg', (75, 79))	('patients', 'Species', '9606', (198, 206))	('imbalance', 'Phenotype', 'HP:0002172', (227, 236))	('D11S1324', 'Var', (160, 168))
11654	15331017	For the screening of the g.7876A>G variant, multiplex PCR was performed using primers and probe of the normal allele of the above-mentioned SNP (IVS4-32T>C) and primers and probe for the variant allele g.7876A>G.	('PC', 'Phenotype', 'HP:0002666', (54, 56))	('g.7876A>G', 'Mutation', 'rs142135772', (25, 34))	('g.7876A>G', 'Mutation', 'rs142135772', (202, 211))	('g.7876A>G', 'Var', (202, 211))	('g.7876A>G', 'Var', (25, 34))	('IVS4-32T>C', 'Mutation', 'c.IVS4-32T>C', (145, 155))
11670	15331017	Sequencing analysis of SDHD on 11q23 demonstrated that the allelic imbalance in NMB does not cause loss of heterozygosity (see later).	('imbalance', 'Phenotype', 'HP:0002172', (67, 76))	('NMB', 'Gene', '4828', (80, 83))	('NMB', 'Gene', (80, 83))	('allelic imbalance', 'Var', (59, 76))
11671	15331017	In 20 of the 67 NB tumour samples, loss of heterozygosity (LOH) or allelic imbalance (AI) (AIF > 2) in the 11q23 region was found (Table 3): unbalanced 11q LOH (i.e.	('unbalanced 11q LOH', 'Var', (141, 159))	('NB tumour', 'Disease', (16, 25))	('imbalance', 'Phenotype', 'HP:0002172', (75, 84))	('NB tumour', 'Disease', 'MESH:D009369', (16, 25))	('NB', 'Phenotype', 'HP:0003006', (16, 18))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
11672	15331017	partial allelic loss of the long arm of chromosome 11) in 2/32 patients of the Ghent University Hospital (Ghent, Belgium) and in 7/35 patients of the Molecular Oncology Unit (Lyon, France) and loss of markers on both chromosome arms (indicating whole chromosome 11 loss, or co-occurrence of 11q and 11p allelic loss) in 3/32 patients of the Ghent University Hospital and 8/35 patients of the Molecular Oncology Unit (Table 3).	('patients', 'Species', '9606', (376, 384))	('partial allelic loss', 'Var', (0, 20))	('patients', 'Species', '9606', (325, 333))	('loss', 'NegReg', (265, 269))	('loss', 'Var', (193, 197))	('patients', 'Species', '9606', (134, 142))	('loss', 'NegReg', (311, 315))	('patients', 'Species', '9606', (63, 71))	('Oncology', 'Phenotype', 'HP:0002664', (402, 410))	('Oncology', 'Phenotype', 'HP:0002664', (160, 168))
11674	15331017	Denaturing high performance liquid chromatography (DHPLC) analysis and subsequent sequencing of the SDHD gene in 31 NB cell lines and 67 NB tumour samples revealed the presence of sequence variants in 5 NB cell lines and 4 NB tumour samples (Table 4).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('NB', 'Phenotype', 'HP:0003006', (116, 118))	('NB tumour', 'Disease', 'MESH:D009369', (223, 232))	('NB', 'Phenotype', 'HP:0003006', (137, 139))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('presence', 'Reg', (168, 176))	('NB tumour', 'Disease', (137, 146))	('NB', 'Phenotype', 'HP:0003006', (203, 205))	('NB', 'Phenotype', 'HP:0003006', (223, 225))	('DHPLC', 'Chemical', '-', (51, 56))	('sequence variants', 'Var', (180, 197))	('NB tumour', 'Disease', (223, 232))	('SDHD', 'Gene', (100, 104))	('NB tumour', 'Disease', 'MESH:D009369', (137, 146))
11675	15331017	The first, a Y93C missense mutation in cell line NMB, was not detected in 135 unrelated healthy individuals.	('Y93C missense', 'Var', (13, 26))	('NMB', 'Gene', '4828', (49, 52))	('NMB', 'Gene', (49, 52))	('Y93C', 'Mutation', 'rs142135772', (13, 17))
11682	15331017	This is also true for the G12S change found in tumour and constitutional DNA of patient F18.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('G12S', 'Var', (26, 30))	('F18', 'Gene', (88, 91))	('constitutional DNA', 'Disease', (58, 76))	('F18', 'Gene', '10046', (88, 91))	('tumour', 'Disease', (47, 53))	('G12S', 'Mutation', 'rs34677591', (26, 30))	('patient', 'Species', '9606', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
11683	15331017	The previously reported polymorphisms IVS3-29A>G and S68S were detected in cell lines NGP, NMB and SK-N-FI, in both tumour and constitutional DNA of patients F18 and F35, and in constitutional DNA of patient F22.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('NMB', 'Gene', '4828', (91, 94))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (149, 157))	('S68S', 'Mutation', 'rs9919552', (53, 57))	('tumour', 'Disease', (116, 122))	('F18', 'Gene', (158, 161))	('S68S', 'Var', (53, 57))	('IVS3-29A>G', 'Var', (38, 48))	('patient', 'Species', '9606', (149, 156))	('F18', 'Gene', '10046', (158, 161))	('NMB', 'Gene', (91, 94))	('IVS3-29A>G', 'Mutation', 'c.IVS3-29A>G', (38, 48))	('patient', 'Species', '9606', (200, 207))
11684	15331017	In all cases, these last two polymorphism (IVS3-29A>G and S68S) were present together with the IVS4-32T>C variant, previously described by Taschner and colleagues.	('S68S', 'Var', (58, 62))	('IVS3-29A>G', 'Var', (43, 53))	('IVS4-32T>C', 'Mutation', 'c.IVS4-32T>C', (95, 105))	('IVS3-29A>G', 'Mutation', 'c.IVS3-29A>G', (43, 53))	('IVS4-32T>C', 'Var', (95, 105))	('S68S', 'Mutation', 'rs9919552', (58, 62))
11687	15331017	The presence of the IVS3-29A>G, S68S and IVS4-32T>C variants in a cell line (NGP) and two tumours (F18 and F35), in which one of both SDHD alleles has been deleted, indicates that all three variants are located on the same allele, representing a low frequent haplotype.	('S68S', 'Mutation', 'rs9919552', (32, 36))	('F18', 'Gene', (99, 102))	('variants', 'Var', (52, 60))	('S68S', 'Var', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('IVS4-32T>C variants', 'Var', (41, 60))	('F18', 'Gene', '10046', (99, 102))	('IVS3-29A>G', 'Mutation', 'c.IVS3-29A>G', (20, 30))	('IVS4-32T>C', 'Mutation', 'c.IVS4-32T>C', (41, 51))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
11689	15331017	Amplification of the full-length SDHD cDNA showed that a 4 bp deletion in the intron-exon boundary in cell line N206 caused skipping of exon 3 leading to a premature stop codon.	('deletion', 'Var', (62, 70))	('premature stop codon', 'MPA', (156, 176))	('N206', 'CellLine', 'CVCL:C885', (112, 116))	('skipping', 'MPA', (124, 132))
11690	15331017	No alternative transcripts could be detected in cell lines NMB, SK-N-FI, NGP and LA-N-2 carrying basepair variants (and 3 control cell lines without sequence variants SK-N-SH, SK-N-AS and CLB-GA) when grown with or without puromycin (Figure 1).	('CLB', 'Gene', (188, 191))	('CLB', 'Gene', '171425', (188, 191))	('variants', 'Var', (106, 114))	('NMB', 'Gene', (59, 62))	('NMB', 'Gene', '4828', (59, 62))	('puromycin', 'Chemical', 'MESH:D011691', (223, 232))
11691	15331017	NMB and N206) (N = 9) compared to cell lines without 11q allelic loss (N = 22) (Mann-Whitney test: P = 1.49E-03).	('NMB', 'Gene', '4828', (0, 3))	('NMB', 'Gene', (0, 3))	('N206', 'CellLine', 'CVCL:C885', (8, 12))	('N206', 'Var', (8, 12))
11692	15331017	As the SDHD gene encodes the small subunit D of the mitochondrial respiratory chain complex II we decided to assess the effect of the basepair variants on the activity of complex II of the respiratory chain by spectrophotometrical measurements in 5 NB cell lines (N206, NMB, SK-N-FI, NGP and LA-N-2) and 3 control NB cell lines without sequence variants (SK-N-SH, SK-N-AS and CLB-GA).	('NB', 'Phenotype', 'HP:0003006', (249, 251))	('NMB', 'Gene', '4828', (270, 273))	('N206', 'CellLine', 'CVCL:C885', (264, 268))	('CLB', 'Gene', (376, 379))	('CLB', 'Gene', '171425', (376, 379))	('NB', 'Phenotype', 'HP:0003006', (314, 316))	('NMB', 'Gene', (270, 273))	('variants', 'Var', (143, 151))
11700	15331017	missense mutation Y93C in cell line NMB and a 4 bp deletion in cell line N206.	('NMB', 'Gene', '4828', (36, 39))	('N206', 'CellLine', 'CVCL:C885', (73, 77))	('Y93C', 'Mutation', 'rs142135772', (18, 22))	('Y93C', 'Var', (18, 22))	('NMB', 'Gene', (36, 39))
11702	15331017	The substituted amino-acid is located within a region of the SDHD protein frequently altered due to germline mutations in paraganglioma (PGL) families (loss of Y93 and two missense mutations, i.e.	('paraganglioma', 'Phenotype', 'HP:0002668', (122, 135))	('PGL', 'Phenotype', 'HP:0002668', (137, 140))	('paraganglioma', 'Disease', (122, 135))	('loss', 'Var', (152, 156))	('SDHD', 'Gene', (61, 65))	('paraganglioma', 'Disease', 'MESH:D010235', (122, 135))	('altered', 'Reg', (85, 92))	('PGL', 'Gene', (137, 140))	('Y93', 'Var', (160, 163))
11703	15331017	D92Y and L95P).	('L95P', 'Mutation', 'rs80338846', (9, 13))	('D92Y', 'Var', (0, 4))	('L95P', 'Var', (9, 13))	('D92Y', 'Mutation', 'rs80338845', (0, 4))
11704	15331017	The predicted truncated protein has another carboxyterminal amino-acid sequence from H56 on and its normal function is assumed to be impaired as carboxyterminal amino-acids involved in ubiquinone and heme b binding are missing (H71, D82 and Y83) and consequently the structure of the transmembrane subunit and/or association of the catalytic domain subunits SDHA and SDHB to the membrane would be disrupted.	('disrupted', 'NegReg', (397, 406))	('Y83', 'Var', (241, 244))	('heme', 'Chemical', 'MESH:D006418', (200, 204))	('ubiquinone', 'Chemical', 'MESH:D014451', (185, 195))	('SDHA', 'Gene', '6389', (358, 362))	('D82', 'Var', (233, 236))	('H56', 'Var', (85, 88))	('SDHA', 'Gene', (358, 362))	('H71', 'Var', (228, 231))	('association', 'Interaction', (313, 324))	('SDHB', 'Gene', '6390', (367, 371))	('H56', 'CellLine', 'CVCL:5768', (85, 88))	('SDHB', 'Gene', (367, 371))	('missing', 'NegReg', (219, 226))	('structure', 'MPA', (267, 276))
11707	15331017	Additional screening for homozygous deletions in all cell lines and methylation in cell lines and tumours were negative.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('deletions', 'Var', (36, 45))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))
11709	15331017	However, the finding of two apparently bona fide SDHD mutations in NB without allelic loss of distal 11q leaves the possibility open that the gene contributes to NB oncogenesis due to haplo-insufficiency, rather than functional inactivation of both alleles.	('NB oncogenesis', 'Disease', (162, 176))	('NB oncogenesis', 'Disease', 'MESH:D063646', (162, 176))	('mutations', 'Var', (54, 63))	('contributes', 'Reg', (147, 158))	('haplo-insufficiency', 'Disease', (184, 203))	('NB', 'Phenotype', 'HP:0003006', (162, 164))	('haplo-insufficiency', 'Disease', 'MESH:D000309', (184, 203))	('NB', 'Phenotype', 'HP:0003006', (67, 69))
11710	15331017	A similar correlation between 11q LOH and reduced SDHD expression was recently described in colorectal and gastric cancer.	('reduced', 'NegReg', (42, 49))	('SDHD', 'Gene', (50, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('11q LOH', 'Var', (30, 37))	('expression', 'MPA', (55, 65))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (92, 121))
11714	15331017	However, the finding of, albeit rare, bona fide mutations and reduced expression of SDHD in NB with 11q allelic loss hints at a possible haplo-insufficient contribution to tumour development.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('NB', 'Phenotype', 'HP:0003006', (92, 94))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('expression', 'MPA', (70, 80))	('tumour', 'Disease', (172, 178))	('loss', 'NegReg', (112, 116))	('SDHD in NB', 'Gene', (84, 94))	('mutations', 'Var', (48, 57))	('reduced', 'NegReg', (62, 69))
11717	15331017	In mouse models for some of these genes, loss or mutation of one allele increased tumour susceptibility despite expression of the remaining wild-type allele.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('increased', 'PosReg', (72, 81))	('mouse', 'Species', '10090', (3, 8))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('mutation', 'Var', (49, 57))	('tumour', 'Disease', (82, 88))	('loss', 'NegReg', (41, 45))
11720	15331017	However, further evidence is needed to support the haplo-insufficient involvement of SDHD in cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('haplo-insufficient', 'Var', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('SDHD', 'Gene', (85, 89))
11769	24289190	Additionally, 131I-metaiodobenzylguanidine (MIBG), a precursor of noradrenaline, scintigraphy has a sensitivity of 77%-90% and a specificity of 95%-100% in detecting paragangliomas .	('131I-metaiodobenzylguanidine', 'Chemical', '-', (14, 42))	('noradrenaline', 'Chemical', 'MESH:D009638', (66, 79))	('paragangliomas', 'Disease', (166, 180))	('paragangliomas', 'Disease', 'MESH:D010235', (166, 180))	('131I-metaiodobenzylguanidine', 'Var', (14, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (166, 179))	('paragangliomas', 'Phenotype', 'HP:0002668', (166, 180))	('MIBG', 'Chemical', '-', (44, 48))
11775	24289190	To date, I131-MIBG remains the only other non-surgical treatment that has produced tumor responses >30% .	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('MIBG', 'Chemical', '-', (14, 18))	('tumor', 'Disease', (83, 88))	('I131-MIBG', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
11778	24289190	have reported that 97% of patients with paraganglioma achieve tumor control through radiosurgery, the results are comparable to that of surgery .	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paraganglioma achieve tumor', 'Disease', (40, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (26, 34))	('radiosurgery', 'Var', (84, 96))	('paraganglioma achieve tumor', 'Disease', 'MESH:D010235', (40, 67))
11787	22261759	Elevated Plasma Succinate Among PTEN, SDHB and SDHD Mutation Positive Individuals Cowden Syndrome (CS) results from germline mutations in phosphatase and tensin homologue deleted on chromosome ten (PTEN) and from variants in succinate dehydrogenase (SDH) B and D subunits.	('SDH', 'Gene', (250, 253))	('Cowden Syndrome', 'Disease', (82, 97))	('Elevated', 'PosReg', (0, 8))	('PTEN', 'Gene', '5728', (198, 202))	('SDHB', 'Gene', '6390', (38, 42))	('succinate dehydrogenase', 'Gene', (225, 248))	('Plasma Succinate', 'MPA', (9, 25))	('Succinate', 'Chemical', 'MESH:D019802', (16, 25))	('SDHD', 'Gene', '6392', (47, 51))	('Cowden Syndrome', 'Disease', 'MESH:D006223', (82, 97))	('Mutation', 'Var', (52, 60))	('SDH', 'Gene', '6390', (47, 50))	('Elevated Plasma Succinate', 'Phenotype', 'HP:0020149', (0, 25))	('SDHB', 'Gene', (38, 42))	('mutations', 'Var', (125, 134))	('SDH', 'Gene', '6390', (38, 41))	('PTEN', 'Gene', (32, 36))	('SDH', 'Gene', '6390', (250, 253))	('SDHD', 'Gene', (47, 51))	('succinate dehydrogenase', 'Gene', '6390', (225, 248))	('variants', 'Var', (213, 221))	('SDH', 'Gene', (47, 50))	('PTEN', 'Gene', '5728', (32, 36))	('PTEN', 'Gene', (198, 202))	('SDH', 'Gene', (38, 41))
11788	22261759	We hypothesized that succinate accumulation may be common among individuals with SDH variants/mutations and those with PTEN mutations.	('common', 'Reg', (51, 57))	('variants/mutations', 'Var', (85, 103))	('PTEN', 'Gene', (119, 123))	('succinate accumulation', 'MPA', (21, 43))	('SDH', 'Gene', '6390', (81, 84))	('PTEN', 'Gene', '5728', (119, 123))	('succinate', 'Chemical', 'MESH:D019802', (21, 30))	('SDH', 'Gene', (81, 84))
11789	22261759	Urine and blood were collected from individuals meeting full or partial CS diagnostic criteria, those with paraganglioma or a known susceptibility PGL-associated gene mutation and succinate was measured.	('paraganglioma', 'Disease', 'MESH:D010235', (107, 120))	('succinate', 'Chemical', 'MESH:D019802', (180, 189))	('PGL-associated', 'Gene', (147, 161))	('mutation', 'Var', (167, 175))	('PGL', 'Phenotype', 'HP:0002668', (147, 150))	('paraganglioma', 'Phenotype', 'HP:0002668', (107, 120))	('paraganglioma', 'Disease', (107, 120))
11791	22261759	Elevated plasma succinate was observed in 13/21 (62%) individuals with germline PTEN, SDHB or SDHD mutations compared to 5/32 (16%) controls (p<0.001); 10/15 (67%) individuals with pathogenic PTEN mutations, but in <20% of mutation negative individuals meeting identical criteria; and among individuals with mutations in SDHB (1/1, 100%) and SDHD (2/5, 40%).	('PTEN', 'Gene', '5728', (80, 84))	('SDHD', 'Gene', '6392', (342, 346))	('Elevated', 'PosReg', (0, 8))	('SDHB', 'Gene', '6390', (86, 90))	('SDHD', 'Gene', (342, 346))	('succinate', 'Chemical', 'MESH:D019802', (16, 25))	('PTEN', 'Gene', (192, 196))	('Elevated plasma succinate', 'Phenotype', 'HP:0020149', (0, 25))	('SDHD', 'Gene', '6392', (94, 98))	('SDHB', 'Gene', (86, 90))	('mutations', 'Var', (197, 206))	('plasma succinate', 'MPA', (9, 25))	('SDHB', 'Gene', '6390', (321, 325))	('PTEN', 'Gene', '5728', (192, 196))	('SDHD', 'Gene', (94, 98))	('PTEN', 'Gene', (80, 84))	('SDHB', 'Gene', (321, 325))	('mutations', 'Var', (99, 108))	('pathogenic', 'Reg', (181, 191))
11792	22261759	Our data suggest that mutations in PTEN, SDHB and SDHD reduce catalytic activity of SDH and result in succinate accumulation and identify a common biochemical alteration between these two patient populations.	('SDHD', 'Gene', (50, 54))	('succinate accumulation', 'MPA', (102, 124))	('result in', 'Reg', (92, 101))	('reduce', 'NegReg', (55, 61))	('SDH', 'Gene', (50, 53))	('SDH', 'Gene', (41, 44))	('succinate', 'Chemical', 'MESH:D019802', (102, 111))	('patient', 'Species', '9606', (188, 195))	('PTEN', 'Gene', (35, 39))	('SDHB', 'Gene', '6390', (41, 45))	('SDH', 'Gene', '6390', (84, 87))	('catalytic activity', 'MPA', (62, 80))	('mutations', 'Var', (22, 31))	('SDHD', 'Gene', '6392', (50, 54))	('PTEN', 'Gene', '5728', (35, 39))	('SDH', 'Gene', '6390', (50, 53))	('SDHB', 'Gene', (41, 45))	('SDH', 'Gene', '6390', (41, 44))	('SDH', 'Gene', (84, 87))
11796	22261759	Germline mutations or deletions in phosphatase and tensin homologue deleted on chromosome ten (PTEN, OMIM +601728), a ubiquitously expressed tumour suppressor, have been identified in approximately 25% of individuals with CS, and somatic PTEN mutations have been variably observed in a large number of sporadic malignancies.	('deletions', 'Var', (22, 31))	('malignancies', 'Disease', 'MESH:D009369', (311, 323))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('PTEN', 'Gene', (238, 242))	('malignancies', 'Disease', (311, 323))	('identified', 'Reg', (170, 180))	('PTEN', 'Gene', (95, 99))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('PTEN', 'Gene', '5728', (238, 242))	('PTEN', 'Gene', '5728', (95, 99))	('tumour', 'Disease', (141, 147))
11800	22261759	Like PTEN, SDHx genes also function as tumour supressors and mutations in these genes result in mitochondrial dysfunction and tumourigenesis via upregulation of angiogenic and hypoxic pathways.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (96, 121))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('upregulation', 'PosReg', (145, 157))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', (39, 45))	('mitochondrial dysfunction', 'Disease', (96, 121))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('PTEN', 'Gene', (5, 9))	('mutations', 'Var', (61, 70))	('PTEN', 'Gene', '5728', (5, 9))	('SDHx genes', 'Gene', (11, 21))	('tumour', 'Disease', (126, 132))	('SDHx', 'Chemical', '-', (11, 15))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (96, 121))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
11801	22261759	Mutations in SDHA, SDHB, SDHC, SDHD and succinate dehyrogenase complex assembly factor 2 (SDHAF2) underlie most cases of familial paraganglioma (PGL) giving rise to paraganglioma syndromes type 4 (PGL-4, SDHB, OMIM 115310), type 3 (PGL-3, SDHC, OMIM 605373), type 1 (PGL-1, SDHD, OMIM 168000), and type 2 (PGL-2, SDHAF2, OMIM 601650) respectively.	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (165, 188))	('PGL-3', 'Gene', '6391', (232, 237))	('SDHAF2', 'Gene', '54949', (90, 96))	('SDHAF2', 'Gene', '54949', (313, 319))	('SDHAF2', 'Gene', (313, 319))	('SDHAF2', 'Gene', (90, 96))	('paraganglioma syndromes', 'Disease', (165, 188))	('SDHA', 'Gene', (90, 94))	('SDHC', 'Gene', '6391', (25, 29))	('PGL', 'Phenotype', 'HP:0002668', (197, 200))	('PGL-2', 'Gene', (306, 311))	('SDHC', 'Gene', '6391', (239, 243))	('SDHA', 'Gene', '6389', (90, 94))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('SDHB', 'Gene', '6390', (204, 208))	('PGL-3', 'Gene', (232, 237))	('Mutations', 'Var', (0, 9))	('PGL-4', 'Gene', (197, 202))	('SDHD', 'Gene', '6392', (31, 35))	('SDHA', 'Gene', (13, 17))	('familial paraganglioma', 'Disease', 'MESH:D010235', (121, 143))	('SDHB', 'Gene', '6390', (19, 23))	('PGL', 'Phenotype', 'HP:0002668', (267, 270))	('SDHD', 'Gene', '6392', (274, 278))	('SDHC', 'Gene', (25, 29))	('SDHB', 'Gene', (204, 208))	('SDHA', 'Gene', '6389', (13, 17))	('PGL', 'Phenotype', 'HP:0002668', (145, 148))	('PGL', 'Phenotype', 'HP:0002668', (306, 309))	('succinate dehyrogenase complex assembly factor 2', 'Gene', (40, 88))	('SDHC', 'Gene', (239, 243))	('PGL', 'Phenotype', 'HP:0002668', (232, 235))	('SDHD', 'Gene', (31, 35))	('paraganglioma', 'Phenotype', 'HP:0002668', (130, 143))	('PGL-4', 'Gene', '6390', (197, 202))	('succinate dehyrogenase complex assembly factor 2', 'Gene', '54949', (40, 88))	('SDHA', 'Gene', (313, 317))	('SDHD', 'Gene', (274, 278))	('SDHB', 'Gene', (19, 23))	('PGL-2', 'Gene', '54949', (306, 311))	('underlie', 'Reg', (98, 106))	('familial paraganglioma', 'Disease', (121, 143))	('SDHA', 'Gene', '6389', (313, 317))
11804	22261759	In addition to their recent association with paraganglioma in its heterozygous state, germline homozygous or compound heterozygous SDHA mutations have more commonly been associated with Leigh syndrome (OMIM 256000), a rare neurometabolic disorder.	('paraganglioma', 'Disease', 'MESH:D010235', (45, 58))	('Leigh syndrome', 'Disease', (186, 200))	('SDHA', 'Gene', '6389', (131, 135))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('paraganglioma', 'Disease', (45, 58))	('mutations', 'Var', (136, 145))	('SDHA', 'Gene', (131, 135))	('rare neurometabolic disorder', 'Disease', 'MESH:D035583', (218, 246))	('Leigh syndrome', 'Disease', 'MESH:D007888', (186, 200))	('associated', 'Reg', (170, 180))	('rare neurometabolic disorder', 'Disease', (218, 246))
11805	22261759	Succinate accumulation has been observed in SDHA mutant fibroblasts and in SDHB mutant tumor tissues and elevated urinary succinate has been associated with, but is not specific to, mitochondrial disorders, hypoxia and seizures.	('elevated urinary succinate', 'Phenotype', 'HP:0020149', (105, 131))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('seizures', 'Disease', 'MESH:D012640', (219, 227))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('Succinate', 'MPA', (0, 9))	('seizures', 'Phenotype', 'HP:0001250', (219, 227))	('mitochondrial disorders', 'Disease', 'MESH:D028361', (182, 205))	('hypoxia', 'Disease', (207, 214))	('mutant', 'Var', (49, 55))	('mutant', 'Var', (80, 86))	('accumulation', 'PosReg', (10, 22))	('urinary', 'MPA', (114, 121))	('associated', 'Reg', (141, 151))	('hypoxia', 'Disease', 'MESH:D000860', (207, 214))	('mitochondrial disorders', 'Disease', (182, 205))	('tumor', 'Disease', (87, 92))	('SDHB', 'Gene', '6390', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('SDHA', 'Gene', (44, 48))	('SDHA', 'Gene', '6389', (44, 48))	('succinate', 'Chemical', 'MESH:D019802', (122, 131))	('seizures', 'Disease', (219, 227))	('SDHB', 'Gene', (75, 79))
11807	22261759	We hypothesized that elevated succinate could be measured in urine and plasma from patients with SDHx mutations and also in individuals with PTEN mutations meeting full or partial CS diagnostic criteria.	('PTEN', 'Gene', (141, 145))	('succinate', 'Chemical', 'MESH:D019802', (30, 39))	('PTEN', 'Gene', '5728', (141, 145))	('succinate', 'MPA', (30, 39))	('elevated', 'PosReg', (21, 29))	('mutations', 'Var', (102, 111))	('patients', 'Species', '9606', (83, 91))	('SDHx', 'Gene', (97, 101))	('SDHx', 'Chemical', '-', (97, 101))	('elevated succinate', 'Phenotype', 'HP:0020149', (21, 39))
11814	22261759	Multiplex ligation dependent probe amplification (MLPA) was performed to identify PTEN, SDHB, SDHC, and SDHD gene duplications or deletions in select mutation negative individuals.	('gene duplications', 'Var', (109, 126))	('deletions', 'Var', (130, 139))	('SDHC', 'Gene', '6391', (94, 98))	('SDHB', 'Gene', '6390', (88, 92))	('SDHB', 'Gene', (88, 92))	('SDHC', 'Gene', (94, 98))	('SDHD', 'Gene', '6392', (104, 108))	('PTEN', 'Gene', (82, 86))	('PTEN', 'Gene', '5728', (82, 86))	('SDHD', 'Gene', (104, 108))
11824	22261759	Study participants whose phenotypes and family history were consistent with CS or CSL were screened for germline PTEN, SDHB, SDHC or SDHD mutations.	('CSL', 'Gene', '1444', (82, 85))	('SDHD', 'Gene', '6392', (133, 137))	('SDHB', 'Gene', '6390', (119, 123))	('SDHC', 'Gene', (125, 129))	('participants', 'Species', '9606', (6, 18))	('PTEN', 'Gene', (113, 117))	('SDHD', 'Gene', (133, 137))	('SDHC', 'Gene', '6391', (125, 129))	('SDHB', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (113, 117))	('CSL', 'Gene', (82, 85))	('mutations', 'Var', (138, 147))
11825	22261759	The majority of PTEN mutation negative CS and CSL individuals were also assessed for PTEN duplications and deletions.	('negative', 'NegReg', (30, 38))	('CSL', 'Gene', (46, 49))	('mutation', 'Var', (21, 29))	('PTEN', 'Gene', (16, 20))	('CSL', 'Gene', '1444', (46, 49))	('deletions', 'Var', (107, 116))	('PTEN', 'Gene', '5728', (16, 20))	('PTEN', 'Gene', (85, 89))	('PTEN', 'Gene', '5728', (85, 89))	('duplications', 'Var', (90, 102))
11827	22261759	Individuals who presented with paraganglioma, or a family history of a known SDH mutation, were screened for germline SDHB, SDHC, SDHD and PTEN mutations.	('paraganglioma', 'Disease', 'MESH:D010235', (31, 44))	('SDHC', 'Gene', (124, 128))	('SDHD', 'Gene', (130, 134))	('mutations', 'Var', (144, 153))	('SDHB', 'Gene', '6390', (118, 122))	('SDH', 'Gene', (130, 133))	('PTEN', 'Gene', (139, 143))	('SDH', 'Gene', '6390', (118, 121))	('SDH', 'Gene', '6390', (77, 80))	('paraganglioma', 'Phenotype', 'HP:0002668', (31, 44))	('SDH', 'Gene', '6390', (124, 127))	('mutation', 'Var', (81, 89))	('SDHB', 'Gene', (118, 122))	('PTEN', 'Gene', '5728', (139, 143))	('SDHC', 'Gene', '6391', (124, 128))	('SDH', 'Gene', (118, 121))	('SDH', 'Gene', (77, 80))	('SDHD', 'Gene', '6392', (130, 134))	('SDH', 'Gene', (124, 127))	('paraganglioma', 'Disease', (31, 44))	('SDH', 'Gene', '6390', (130, 133))
11828	22261759	In total, we enrolled 1 SDHB mutation positive individual, 5 SDHD mutation positive individuals, 10 individuals with paraganglioma with no identifiable mutations, duplications or deletions in SDHB, SDHC or SDHD (SDH mutation negative, PGL), 1 individual with a known VHL mutation, and 1 individual with a known TMEM127 SNP (Table 1).	('paraganglioma', 'Disease', 'MESH:D010235', (117, 130))	('SDH', 'Gene', (61, 64))	('deletions', 'Var', (179, 188))	('SDHD', 'Gene', '6392', (206, 210))	('TMEM127', 'Gene', '55654', (311, 318))	('duplications', 'Var', (163, 175))	('SDHB', 'Gene', (24, 28))	('SDH', 'Gene', '6390', (206, 209))	('SDH', 'Gene', '6390', (24, 27))	('SDH', 'Gene', (192, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (117, 130))	('SDH', 'Gene', '6390', (198, 201))	('SDHD', 'Gene', (206, 210))	('SDH', 'Gene', '6390', (212, 215))	('VHL', 'Disease', 'MESH:D006623', (267, 270))	('PGL', 'Phenotype', 'HP:0002668', (235, 238))	('SDHC', 'Gene', '6391', (198, 202))	('SDHD', 'Gene', '6392', (61, 65))	('SDHB', 'Gene', '6390', (192, 196))	('SDH', 'Gene', (206, 209))	('mutation positive', 'Reg', (29, 46))	('SDH', 'Gene', (24, 27))	('SDH', 'Gene', '6390', (61, 64))	('SDH', 'Gene', '6390', (192, 195))	('SDH', 'Gene', (198, 201))	('SDH', 'Gene', (212, 215))	('SDHD', 'Gene', (61, 65))	('TMEM127', 'Gene', (311, 318))	('SDHB', 'Gene', (192, 196))	('SDHB', 'Gene', '6390', (24, 28))	('paraganglioma', 'Disease', (117, 130))	('SDHC', 'Gene', (198, 202))	('VHL', 'Disease', (267, 270))
11829	22261759	Organic acid analyses revealed elevated plasma succinate in 13/21 (62%) individuals with germline mutations in any examined gene compared to 5/32 (16%) mutation negative controls (p<0.001).	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (31, 56))	('plasma succinate', 'MPA', (40, 56))	('mutations', 'Var', (98, 107))	('succinate', 'Chemical', 'MESH:D019802', (47, 56))	('elevated', 'PosReg', (31, 39))	('Organic acid', 'Chemical', '-', (0, 12))
11830	22261759	The majority of PTEN mutation positive individuals (10/15; 67%) had elevated plasma succinate, this finding was not observed in PTEN mutation negative CS individuals (3/15; 20%) or the PTEN mutation negative, CSL group (1/4; 25%) or in individuals with PTEN VUS (1/3; 33%) (Table 1).	('PTEN', 'Gene', '5728', (185, 189))	('CSL', 'Gene', '1444', (209, 212))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('succinate', 'Chemical', 'MESH:D019802', (84, 93))	('mutation', 'Var', (21, 29))	('elevated', 'PosReg', (68, 76))	('PTEN', 'Gene', (16, 20))	('PTEN', 'Gene', (253, 257))	('CSL', 'Gene', (209, 212))	('plasma succinate', 'MPA', (77, 93))	('PTEN', 'Gene', '5728', (16, 20))	('PTEN', 'Gene', '5728', (253, 257))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (68, 93))	('PTEN', 'Gene', (185, 189))
11831	22261759	Elevated plasma succinate was recorded in individuals with SDHB (1/1; 100%) and SDHD mutations (2/5; 40%), and in one individual harboring a TMEM127 SNP (1/1; 100%).	('TMEM127', 'Gene', (141, 148))	('TMEM127', 'Gene', '55654', (141, 148))	('SDHD', 'Gene', (80, 84))	('plasma succinate', 'MPA', (9, 25))	('Elevated', 'PosReg', (0, 8))	('mutations', 'Var', (85, 94))	('succinate', 'Chemical', 'MESH:D019802', (16, 25))	('SDHB', 'Gene', '6390', (59, 63))	('SDHB', 'Gene', (59, 63))	('Elevated plasma succinate', 'Phenotype', 'HP:0020149', (0, 25))	('SDHD', 'Gene', '6392', (80, 84))
11832	22261759	Elevated plasma succinate was not found in SDH mutation negative individuals with PGL (0/10; 0%), or in one individual with a mutation in VHL (0/1; 0%) (Table 1).	('SDH', 'Gene', (43, 46))	('PGL', 'Phenotype', 'HP:0002668', (82, 85))	('mutation', 'Var', (47, 55))	('plasma succinate', 'MPA', (9, 25))	('VHL', 'Disease', (138, 141))	('VHL', 'Disease', 'MESH:D006623', (138, 141))	('succinate', 'Chemical', 'MESH:D019802', (16, 25))	('SDH', 'Gene', '6390', (43, 46))	('Elevated plasma succinate', 'Phenotype', 'HP:0020149', (0, 25))
11835	22261759	This report demonstrates that elevated plasma succinate is a common finding among individuals with known pathogenic mutations in PTEN, SDHB, SDHD and TMEM127.	('SDHD', 'Gene', (141, 145))	('SDHB', 'Gene', '6390', (135, 139))	('succinate', 'Chemical', 'MESH:D019802', (46, 55))	('SDHB', 'Gene', (135, 139))	('PTEN', 'Gene', (129, 133))	('TMEM127', 'Gene', (150, 157))	('plasma succinate', 'MPA', (39, 55))	('mutations', 'Var', (116, 125))	('elevated', 'PosReg', (30, 38))	('PTEN', 'Gene', '5728', (129, 133))	('TMEM127', 'Gene', '55654', (150, 157))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (30, 55))	('SDHD', 'Gene', '6392', (141, 145))
11836	22261759	Previous studies have reported elevated succinate levels in tumor derived tissue from patients with SDHB mutations and in SDHA mutant fibroblasts, but to the best of our knowledge this is the first report demonstrating an elevation of succinate in plasma from patients with germline mutations in SDHB, SDHD, TMEM127 and PTEN.	('mutations', 'Var', (105, 114))	('SDHA', 'Gene', '6389', (122, 126))	('SDHB', 'Gene', '6390', (100, 104))	('tumor', 'Disease', (60, 65))	('patients', 'Species', '9606', (86, 94))	('SDHD', 'Gene', '6392', (302, 306))	('succinate levels', 'MPA', (40, 56))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('succinate', 'Chemical', 'MESH:D019802', (40, 49))	('patients', 'Species', '9606', (260, 268))	('TMEM127', 'Gene', (308, 315))	('SDHB', 'Gene', (100, 104))	('mutant', 'Var', (127, 133))	('SDHD', 'Gene', (302, 306))	('elevated succinate', 'Phenotype', 'HP:0020149', (31, 49))	('PTEN', 'Gene', (320, 324))	('succinate', 'Chemical', 'MESH:D019802', (235, 244))	('mutations', 'Var', (283, 292))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TMEM127', 'Gene', '55654', (308, 315))	('elevated', 'PosReg', (31, 39))	('SDHB', 'Gene', '6390', (296, 300))	('succinate', 'MPA', (235, 244))	('elevation of succinate in plasma', 'Phenotype', 'HP:0020149', (222, 254))	('elevation', 'PosReg', (222, 231))	('PTEN', 'Gene', '5728', (320, 324))	('SDHB', 'Gene', (296, 300))	('SDHA', 'Gene', (122, 126))
11837	22261759	Although elevated plasma succinate levels might be expected for individuals with SDHx mutations, it was unexpected for PTEN mutation positive individuals and implies that PTEN mutations somehow reduce the catalytic activity of the SDH protein complex.	('succinate', 'Chemical', 'MESH:D019802', (25, 34))	('mutations', 'Var', (86, 95))	('elevated', 'PosReg', (9, 17))	('mutations', 'Var', (176, 185))	('catalytic activity', 'MPA', (205, 223))	('plasma succinate levels', 'MPA', (18, 41))	('SDHx', 'Chemical', '-', (81, 85))	('SDH', 'Gene', '6390', (231, 234))	('PTEN', 'Gene', (119, 123))	('SDH', 'Gene', '6390', (81, 84))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (9, 34))	('PTEN', 'Gene', '5728', (119, 123))	('PTEN', 'Gene', (171, 175))	('PTEN', 'Gene', '5728', (171, 175))	('SDH', 'Gene', (231, 234))	('SDH', 'Gene', (81, 84))	('reduce', 'NegReg', (194, 200))
11838	22261759	Consistent with previous studies assessing succinate levels in tumor-derived tissue, more than half of our SDHD mutation positive individuals (3/5, 60%) did not demonstrate elevated plasma succinate.	('tumor', 'Disease', (63, 68))	('SDHD', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutation', 'Var', (112, 120))	('succinate', 'Chemical', 'MESH:D019802', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (173, 198))	('succinate', 'Chemical', 'MESH:D019802', (189, 198))	('SDHD', 'Gene', '6392', (107, 111))
11839	22261759	Similarly, 33% of PTEN mutation positive individuals did not exhibit elevated plasma succinate.	('PTEN', 'Gene', (18, 22))	('PTEN', 'Gene', '5728', (18, 22))	('mutation', 'Var', (23, 31))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (69, 94))	('plasma succinate', 'MPA', (78, 94))	('succinate', 'Chemical', 'MESH:D019802', (85, 94))
11842	22261759	It is possible some mutations and/or variants impair and/or enhance the reversibility of these reactions thereby reducing succinate to normal levels.	('enhance', 'PosReg', (60, 67))	('reversibility', 'MPA', (72, 85))	('succinate', 'MPA', (122, 131))	('succinate', 'Chemical', 'MESH:D019802', (122, 131))	('variants', 'Var', (37, 45))	('impair', 'NegReg', (46, 52))	('mutations', 'Var', (20, 29))	('reducing', 'NegReg', (113, 121))
11843	22261759	This is one possible explanation for the SDHD and PTEN mutation positive individuals who do not exhibit elevated plasma succinate.	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (104, 129))	('SDHD', 'Gene', (41, 45))	('PTEN', 'Gene', (50, 54))	('SDHD', 'Gene', '6392', (41, 45))	('PTEN', 'Gene', '5728', (50, 54))	('succinate', 'Chemical', 'MESH:D019802', (120, 129))	('mutation', 'Var', (55, 63))
11846	22261759	One of three patients harboring PTEN polymorphisms exhibited elevated succinate in both plasma and urine.	('polymorphisms', 'Var', (37, 50))	('succinate', 'Chemical', 'MESH:D019802', (70, 79))	('PTEN', 'Gene', (32, 36))	('patients', 'Species', '9606', (13, 21))	('elevated', 'PosReg', (61, 69))	('PTEN', 'Gene', '5728', (32, 36))	('succinate in', 'MPA', (70, 82))	('elevated succinate', 'Phenotype', 'HP:0020149', (61, 79))
11848	22261759	It is conceivable that this intronic variant c.210 -7del5, although currently classified as a polymorphism, may actually be a pathogenic mutation leading to splicing defects.	('leading to', 'Reg', (146, 156))	('-7del5', 'Var', (51, 57))	('splicing defects', 'MPA', (157, 173))	('-7del5', 'DELETION', 'None', (51, 57))	('pathogenic', 'Reg', (126, 136))
11849	22261759	One plausible explanation for the link between PTEN mutations and elevated plasma succinate is PTEN-induced kinase 1 (PINK1), a mitochondrial localized serine-threonine kinase, transcriptionally activated by PTEN.	('mutations', 'Var', (52, 61))	('PTEN-induced kinase 1', 'Gene', '65018', (95, 116))	('PTEN', 'Gene', '5728', (95, 99))	('PTEN', 'Gene', (208, 212))	('PTEN', 'Gene', '5728', (208, 212))	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (66, 91))	('succinate', 'Chemical', 'MESH:D019802', (82, 91))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', (95, 99))	('PTEN-induced kinase 1', 'Gene', (95, 116))	('PTEN', 'Gene', '5728', (47, 51))	('plasma succinate', 'MPA', (75, 91))	('elevated', 'PosReg', (66, 74))
11852	22261759	Therefore, mutations that affect the stability or activity of PTEN likely affect PINK1 transcription and downstream function of mitochondrial complex II.	('mutations', 'Var', (11, 20))	('PTEN', 'Gene', (62, 66))	('PINK1', 'Gene', (81, 86))	('PTEN', 'Gene', '5728', (62, 66))	('mitochondrial complex II', 'Enzyme', (128, 152))	('activity', 'MPA', (50, 58))	('affect', 'Reg', (74, 80))
11854	22261759	Estimated cost for PTEN sequencing, deletion and duplication analysis is approximately US$2,000 per sample.	('duplication analysis', 'Var', (49, 69))	('PTEN', 'Gene', (19, 23))	('deletion', 'Var', (36, 44))	('PTEN', 'Gene', '5728', (19, 23))
11855	22261759	Likewise, cost for SDHB, SDHC, and SDHD mutation analyses are approximately $1,000, $1,300 and $700, respectively.	('mutation', 'Var', (40, 48))	('SDHD', 'Gene', (35, 39))	('SDHD', 'Gene', '6392', (35, 39))	('SDHB', 'Gene', '6390', (19, 23))	('SDHC', 'Gene', (25, 29))	('SDHB', 'Gene', (19, 23))	('SDHC', 'Gene', '6391', (25, 29))
11859	22261759	Therefore, based upon our finding that a large proportion of individuals with pathogenic PTEN, SDHB and SDHD mutations exhibit elevated plasma succinate, we suggest that plasma organic acid analysis may be a useful and cost-effective preliminary screening tool to identify individuals for which more costly gene sequencing is warranted.	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (127, 152))	('plasma succinate', 'MPA', (136, 152))	('SDHB', 'Gene', '6390', (95, 99))	('organic acid', 'Chemical', '-', (177, 189))	('elevated', 'PosReg', (127, 135))	('pathogenic', 'Reg', (78, 88))	('SDHD', 'Gene', '6392', (104, 108))	('mutations', 'Var', (109, 118))	('SDHB', 'Gene', (95, 99))	('PTEN', 'Gene', (89, 93))	('SDHD', 'Gene', (104, 108))	('succinate', 'Chemical', 'MESH:D019802', (143, 152))	('PTEN', 'Gene', '5728', (89, 93))
11860	22261759	In conclusion, we have demonstrated that elevated plasma succinate is a common biochemical disturbance in the majority of PTEN, SDHB and SDHD mutation positive individuals and provides a plausible biochemical link for the shared phenotypic findings across these groups.	('elevated plasma succinate', 'Phenotype', 'HP:0020149', (41, 66))	('SDHB', 'Gene', (128, 132))	('mutation positive', 'Var', (142, 159))	('SDHD', 'Gene', (137, 141))	('SDHD', 'Gene', '6392', (137, 141))	('SDHB', 'Gene', '6390', (128, 132))	('succinate', 'Chemical', 'MESH:D019802', (57, 66))	('plasma succinate', 'MPA', (50, 66))	('elevated', 'PosReg', (41, 49))	('PTEN', 'Gene', (122, 126))	('PTEN', 'Gene', '5728', (122, 126))
11862	22261759	CSL Cowden syndrome-like              PTEN            phosphatase and tensin homologue deleted on chromosome ten SNP single nucleotide polymorphism              SDHB            succinate dehydrogenase B subunit              SDHC            succinate dehydrogenase C subunit              SDHD            succinate dehydrogenase D subunit SNP single nucleotide polymorphism              TMEM127            transmembrane protein 127              VHL            von Hippel-Lindau	('VHL', 'Disease', 'MESH:D006623', (443, 446))	('SDHD', 'Gene', '6392', (287, 291))	('SDHC', 'Gene', '6391', (224, 228))	('succinate dehydrogenase', 'Gene', (177, 200))	('PTEN', 'Gene', '5728', (38, 42))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (458, 475))	('CSL', 'Gene', '1444', (0, 3))	('SDHD', 'Gene', (287, 291))	('Cowden syndrome', 'Disease', 'MESH:D006223', (4, 19))	('succinate dehydrogenase', 'Gene', (240, 263))	('single nucleotide polymorphism', 'Var', (341, 371))	('succinate dehydrogenase', 'Gene', (303, 326))	('SDHC', 'Gene', (224, 228))	('VHL', 'Disease', (443, 446))	('SDHB', 'Gene', '6390', (161, 165))	('succinate dehydrogenase', 'Gene', '6390', (177, 200))	('Cowden syndrome', 'Disease', (4, 19))	('CSL', 'Gene', (0, 3))	('TMEM127', 'Gene', (385, 392))	('succinate dehydrogenase', 'Gene', '6390', (240, 263))	('succinate dehydrogenase', 'Gene', '6390', (303, 326))	('von Hippel-Lindau', 'Disease', (458, 475))	('SDHB', 'Gene', (161, 165))	('PTEN', 'Gene', (38, 42))	('TMEM127', 'Gene', '55654', (385, 392))
11874	23213586	Evaluation of fat planes is important in differentiating salivary from extrasalivary neoplasms, and the differences in MRI signal characteristics can further improve diagnostic accuracy for certain parapharyngeal space lesions.	('neoplasm', 'Phenotype', 'HP:0002664', (85, 93))	('improve', 'PosReg', (158, 165))	('differences', 'Var', (104, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (85, 94))	('extrasalivary neoplasms', 'Disease', (71, 94))	('extrasalivary neoplasms', 'Disease', 'MESH:D009369', (71, 94))	('parapharyngeal space lesions', 'Disease', (198, 226))	('MRI signal', 'MPA', (119, 129))
11938	19243052	The CR and CNR in the early phase microCT were 10.5+-1.25 and 0.1723+-0.004 and in the delayed phase CT was 15.36+-1.01 and 0.1625+-0.02, both substantially lower than MRI.	('0.1625+-0.02', 'Var', (124, 136))	('CR', 'Chemical', '-', (4, 6))	('lower', 'NegReg', (157, 162))	('0.1723+-0.004', 'Var', (62, 75))
12000	34046474	Its development is related to mutations in the VHL gene (a tumor suppressor gene, 3p25-26).	('tumor', 'Disease', (59, 64))	('related', 'Reg', (19, 26))	('VHL', 'Gene', (47, 50))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('VHL', 'Gene', '7428', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
12045	34046474	Dramatic changes in BP during the operation can change intracranial and intraocular pressure with the risk of vitreous hemorrhage, retinal detachment and cerebral hernia; thus, early detection of intracranial hemorrhage is important.	('intracranial hemorrhage', 'Phenotype', 'HP:0002170', (196, 219))	('changes', 'Var', (9, 16))	('retinal detachment and cerebral hernia', 'Disease', 'MESH:D012163', (131, 169))	('change', 'Reg', (48, 54))	('retinal detachment', 'Phenotype', 'HP:0000541', (131, 149))	('vitreous hemorrhage', 'Disease', (110, 129))	('intracranial hemorrhage', 'Disease', (196, 219))	('hernia', 'Phenotype', 'HP:0100790', (163, 169))	('vitreous hemorrhage', 'Disease', 'MESH:D014823', (110, 129))	('intracranial hemorrhage', 'Disease', 'MESH:D020300', (196, 219))	('vitreous hemorrhage', 'Phenotype', 'HP:0007902', (110, 129))
12099	31370003	For the purposes of this analysis and based on prior published evidence, we assumed that any PNM-PMN greater than twice the URL would be considered clinically as highly likely diagnostic of PPGL (i.e., a true positive result).	('PPGL', 'Chemical', '-', (190, 194))	('PNM-PMN', 'Chemical', '-', (93, 100))	('diagnostic', 'Reg', (176, 186))	('PNM-PMN', 'Var', (93, 100))	('PPGL', 'Disease', (190, 194))
12140	31370003	Note that the above suggestions do not apply to PPGL screening in patients at-risk for or with known germline PPGL mutations; in such patients with high pre-test probability, supine age-adjusted testing is mandatory for biochemical screening.	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (134, 142))	('PPGL', 'Chemical', '-', (48, 52))	('PPGL', 'Chemical', '-', (110, 114))	('PPGL', 'Gene', (110, 114))	('patients', 'Species', '9606', (66, 74))
12153	31370003	However, this is not intended as a study of sensitivity/specificity but rather an analysis of potential diagnostic actions that must follow any abnormal PNM test result; given the rarity of PPGL, the vast majority of positive (especially slightly positive) PNM will be false positive and the clinician will want to avoid sending a high number of patients through unnecessary and expensive imaging tests.	('PPGL', 'Gene', (190, 194))	('PNM', 'Chemical', '-', (257, 260))	('PPGL', 'Chemical', '-', (190, 194))	('patients', 'Species', '9606', (346, 354))	('PNM', 'Chemical', '-', (153, 156))	('PNM', 'Var', (257, 260))
12166	32152203	However, PCPGs with mutations in the succinate dehydrogenase B subunit (SDHB) have a poor prognosis and frequently develop metastatic lesions.	('metastatic lesions', 'CPA', (123, 141))	('SDHB', 'Gene', (72, 76))	('succinate dehydrogenase B subunit', 'Gene', (37, 70))	('succinate dehydrogenase B subunit', 'Gene', '67680', (37, 70))	('develop', 'Reg', (115, 122))	('mutations', 'Var', (20, 29))
12176	32152203	Cluster I PCPGs commonly exhibit abnormal activation of hypoxia signaling, particularly those carrying mutations in succinate dehydrogenase subunits (SDHx), von Hippel-Lindau (VHL), hypoxia-inducible factor 2A (HIF2A), or fumarate hydratase (FH).	('succinate dehydrogenase', 'Gene', (116, 139))	('von Hippel-Lindau', 'Gene', (157, 174))	('SDH', 'Gene', (150, 153))	('mutations', 'Var', (103, 112))	('hypoxia-inducible factor 2A', 'Gene', (182, 209))	('von Hippel-Lindau', 'Gene', '22346', (157, 174))	('hypoxia-inducible factor 2A', 'Gene', '13819', (182, 209))	('SDH', 'Gene', '30956', (150, 153))	('HIF2A', 'Gene', (211, 216))	('hypoxia', 'Disease', (182, 189))	('hypoxia', 'Disease', 'MESH:D000860', (182, 189))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('succinate dehydrogenase', 'Gene', '30956', (116, 139))	('activation', 'PosReg', (42, 52))	('FH', 'Disease', 'MESH:D006938', (242, 244))	('hypoxia', 'Disease', (56, 63))	('HIF2A', 'Gene', '13819', (211, 216))
12177	32152203	Cluster II PCPGs commonly show hyperactivation of protein kinase pathways, carry mutations in ret proto-oncogene (RET), neurofibromatosis type 1 (NF1), MYC-associated factor X (MAX), transmembrane protein 127 (TMEM127), or the kinesin family member 1B (KIF1B; refs.).	('kinesin family member 1B', 'Gene', (227, 251))	('MAX', 'Gene', (177, 180))	('RET', 'Gene', (114, 117))	('mutations', 'Var', (81, 90))	('neurofibromatosis type 1', 'Gene', '18015', (120, 144))	('KIF1B', 'Gene', (253, 258))	('kinesin family member 1B', 'Gene', '16561', (227, 251))	('MAX', 'Gene', '17187', (177, 180))	('TMEM127', 'Gene', '69470', (210, 217))	('NF1', 'Gene', '18015', (146, 149))	('MYC-associated factor X', 'Gene', '17187', (152, 175))	('RET', 'Gene', '19713', (114, 117))	('NF1', 'Gene', (146, 149))	('TMEM127', 'Gene', (210, 217))	('hyperactivation', 'PosReg', (31, 46))	('neurofibromatosis type 1', 'Gene', (120, 144))	('ret', 'Gene', '19713', (94, 97))	('KIF1B', 'Gene', '16561', (253, 258))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (120, 137))	('ret', 'Gene', (94, 97))	('MYC-associated factor X', 'Gene', (152, 175))	('protein kinase pathways', 'Pathway', (50, 73))
12179	32152203	Loss-of-function mutations in SDHx lead to substantial loss of the complex II activity and result in reprogramming of cellular metabolic pathways, as indicated by the accumulation of succinate, genome-wide hypermethylation, and a pseudohypoxia phenotype.	('complex II activity', 'MPA', (67, 86))	('SDH', 'Gene', (30, 33))	('Loss-of-function', 'NegReg', (0, 16))	('loss', 'NegReg', (55, 59))	('accumulation', 'PosReg', (167, 179))	('SDH', 'Gene', '30956', (30, 33))	('reprogramming', 'CPA', (101, 114))	('succinate', 'Chemical', 'MESH:D019802', (183, 192))	('cellular metabolic pathways', 'Pathway', (118, 145))	('pseudohypoxia', 'Disease', (230, 243))	('mutations', 'Var', (17, 26))	('pseudohypoxia', 'Disease', 'None', (230, 243))	('succinate', 'MPA', (183, 192))
12180	32152203	Furthermore, compromised mitochondrial complex II disrupts electron transfer to oxygen, leading to increased formation of reactive oxygen species (ROS) and redox imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (162, 171))	('electron transfer to oxygen', 'MPA', (59, 86))	('mitochondrial complex II', 'Enzyme', (25, 49))	('ROS', 'Chemical', 'MESH:D017382', (147, 150))	('formation of reactive oxygen species', 'MPA', (109, 145))	('compromised mitochondrial complex II', 'Phenotype', 'HP:0008314', (13, 49))	('redox imbalance', 'Phenotype', 'HP:0025463', (156, 171))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (122, 145))	('compromised', 'Var', (13, 24))	('oxygen', 'Chemical', 'MESH:D010100', (80, 86))	('oxygen', 'Chemical', 'MESH:D010100', (131, 137))	('increased', 'PosReg', (99, 108))	('redox imbalance', 'MPA', (156, 171))	('disrupts', 'NegReg', (50, 58))	('increased formation of reactive oxygen species', 'Phenotype', 'HP:0025464', (99, 145))
12242	32152203	The primary antibodies used included anti-HIF-1alpha, anti-HIF-2alpha, and anti-DMT1 (Abcam), and anti-TF and anti-TFR2 (Thermo Fisher Scientific).	('HIF-1alpha', 'Gene', (42, 52))	('TF', 'Gene', '22041', (115, 117))	('anti-DMT1', 'Var', (75, 84))	('TF', 'Gene', '22041', (103, 105))	('HIF-2alpha', 'Gene', '13819', (59, 69))	('HIF-2alpha', 'Gene', (59, 69))	('HIF-1alpha', 'Gene', '15251', (42, 52))
12256	32152203	Genetic defects in SDHx result in substantial loss of mitochondrial complex II (SDH and succinate-ubiquinone oxidoreductase activity) activity, leading to abnormal activation of the hypoxia signaling pathway and a switch to the pseudohypoxia phenotype.	('SDH', 'Gene', (19, 22))	('SDH', 'Gene', '30956', (80, 83))	('loss of mitochondrial complex II', 'Phenotype', 'HP:0008314', (46, 78))	('defects', 'Var', (8, 15))	('loss', 'NegReg', (46, 50))	('pseudohypoxia', 'Disease', (228, 241))	('SDH', 'Gene', '30956', (19, 22))	('succinate', 'Chemical', 'MESH:D019802', (88, 97))	('pseudohypoxia', 'Disease', 'None', (228, 241))	('mitochondrial', 'MPA', (54, 67))	('hypoxia', 'Disease', (182, 189))	('hypoxia', 'Disease', 'MESH:D000860', (182, 189))	('activation', 'PosReg', (164, 174))	('hypoxia', 'Disease', (234, 241))	('hypoxia', 'Disease', 'MESH:D000860', (234, 241))	('switch', 'Reg', (214, 220))	('activity', 'MPA', (134, 142))	('SDH', 'Gene', (80, 83))
12262	32152203	Consistent with the upregulation of iron transporters, we found elevated intracellular labile iron in SDHBKD cells compared with SDHBWT cells (Fig.	('elevated', 'PosReg', (64, 72))	('intracellular labile iron', 'MPA', (73, 98))	('iron', 'Chemical', 'MESH:D007501', (94, 98))	('SDHBKD', 'Var', (102, 108))	('iron', 'Chemical', 'MESH:D007501', (36, 40))	('upregulation', 'PosReg', (20, 32))
12270	32152203	Previous findings indicated that abnormal iron metabolism results in oxidative stress in a variety of malignancies, including SDHB-deficient ones.	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('iron', 'Chemical', 'MESH:D007501', (42, 46))	('abnormal iron metabolism', 'Phenotype', 'HP:0011031', (33, 57))	('malignancies', 'Disease', (102, 114))	('SDHB-deficient', 'Gene', (126, 140))	('abnormal', 'Var', (33, 41))	('iron metabolism', 'MPA', (42, 57))	('results in', 'Reg', (58, 68))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('oxidative stress', 'MPA', (69, 85))
12272	32152203	A MitoSOX assay confirmed increased ROS in the mitochondria of SDHBKD cells (Fig.	('SDHBKD', 'Var', (63, 69))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('ROS in the mitochondria', 'MPA', (36, 59))	('increased', 'PosReg', (26, 35))
12279	32152203	We hypothesized that pharmacologic concentrations of ascorbic acid could serve as an antitumor agent for SDHB-mutant PCPGs via synergism with the iron overload found in SDHBKD cells.	('ascorbic acid', 'Chemical', 'MESH:D001205', (53, 66))	('iron', 'Chemical', 'MESH:D007501', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('SDHB-mutant', 'Gene', (105, 116))	('SDHB-mutant', 'Var', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
12282	32152203	Consistently, both the ARE luciferase reporter assay and the MitoSOX Red assay showed increased ROS after ascorbic acid treatment in both cell lines, and higher ROS levels in SDHBKD compared with SDHBWT cells (Fig.	('ROS levels', 'MPA', (161, 171))	('increased', 'PosReg', (86, 95))	('ROS', 'Chemical', 'MESH:D017382', (161, 164))	('ascorbic acid', 'Chemical', 'MESH:D001205', (106, 119))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('higher', 'PosReg', (154, 160))	('SDHBKD', 'Var', (175, 181))	('ROS', 'MPA', (96, 99))
12284	32152203	To further probe whether iron metabolism underlies redox imbalance, we supplemented SDHBWT and SDHBKD cells with exogenous iron and ascorbic acid and found that iron enhanced ROS with ascorbic acid (Fig.	('iron', 'Chemical', 'MESH:D007501', (25, 29))	('iron', 'Var', (161, 165))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('iron', 'Chemical', 'MESH:D007501', (123, 127))	('imbalance', 'Phenotype', 'HP:0002172', (57, 66))	('enhanced', 'PosReg', (166, 174))	('ROS', 'MPA', (175, 178))	('redox imbalance', 'Phenotype', 'HP:0025463', (51, 66))	('ascorbic acid', 'Chemical', 'MESH:D001205', (184, 197))	('ascorbic acid', 'MPA', (184, 197))	('ascorbic acid', 'Chemical', 'MESH:D001205', (132, 145))	('iron', 'Chemical', 'MESH:D007501', (161, 165))
12285	32152203	Moreover, we found elevated labile iron in both SDHBWT and SDHBKD cells after ascorbic acid treatment, although labile iron in SDHBKD cells was higher than in wild-type cells, and knockdown of TF reduced labile iron (Supplementary Fig.	('knockdown', 'Var', (180, 189))	('ascorbic acid', 'Chemical', 'MESH:D001205', (78, 91))	('labile iron', 'MPA', (28, 39))	('labile iron', 'MPA', (204, 215))	('TF', 'Gene', '22041', (193, 195))	('elevated', 'PosReg', (19, 27))	('iron', 'Chemical', 'MESH:D007501', (35, 39))	('iron', 'Chemical', 'MESH:D007501', (211, 215))	('labile', 'MPA', (112, 118))	('iron', 'Chemical', 'MESH:D007501', (119, 123))	('reduced', 'NegReg', (196, 203))
12289	32152203	To further evaluate whether ascorbic acid is a therapeutic candidate for the treatment of cancers with mutated SDHB, we characterized concentration-dependent cytotoxicity.	('SDHB', 'Gene', (111, 115))	('cancers', 'Disease', (90, 97))	('mutated', 'Var', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ascorbic acid', 'Chemical', 'MESH:D001205', (28, 41))	('cytotoxicity', 'Disease', (158, 170))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cytotoxicity', 'Disease', 'MESH:D064420', (158, 170))
12296	32152203	Moreover, the trypan blue exclusion assay showed reduced cell number of SDHBKD cells compared with SDHBWT counterparts (Fig.	('trypan blue', 'Chemical', 'MESH:D014343', (14, 25))	('SDHBKD', 'Var', (72, 78))	('cell number', 'CPA', (57, 68))	('reduced', 'NegReg', (49, 56))
12317	32152203	Conversely, a missense mutation at a splice junction of SLC11A2 that impaired iron uptake in erythroid cells and led to iron deficiency-related anemia was discovered in a patient.	('impaired', 'NegReg', (69, 77))	('missense mutation', 'Var', (14, 31))	('deficiency-related anemia', 'Disease', (125, 150))	('iron uptake in erythroid cells', 'MPA', (78, 108))	('patient', 'Species', '9606', (171, 178))	('iron', 'Chemical', 'MESH:D007501', (78, 82))	('deficiency-related anemia', 'Disease', 'MESH:D000740', (125, 150))	('led to', 'Reg', (113, 119))	('anemia', 'Phenotype', 'HP:0001903', (144, 150))	('SLC11A2', 'Gene', (56, 63))	('iron', 'Chemical', 'MESH:D007501', (120, 124))
12324	32152203	Redox-active iron converts hydrogen peroxide largely to the highly toxic hydroxyl radical via the Fenton/Haber-Weiss reaction cycles (Fe2+ + H2O2   Fe3+ + HO  + OH-; Fe3+ + H2O2   Fe2+ + HOO  + H+; ref.).	('Fe2+', 'Chemical', '-', (134, 138))	('H2O2', 'Chemical', 'MESH:D006861', (141, 145))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (27, 44))	('Fe3+ +', 'Chemical', '-', (148, 154))	('Fe2+', 'Chemical', '-', (180, 184))	('Fe3+ +', 'Chemical', '-', (166, 172))	('H2O2', 'Chemical', 'MESH:D006861', (173, 177))	('HOO', 'Chemical', '-', (187, 190))	('hydrogen peroxide', 'MPA', (27, 44))	('hydroxyl radical', 'Chemical', 'MESH:D017665', (73, 89))	('Fe2+ + H2O2   Fe3+ + HO  + OH-; Fe3+ + H2O2   Fe2+', 'Var', (134, 184))	('iron', 'Chemical', 'MESH:D007501', (13, 17))
12327	32152203	Genetic silencing of TF reduced the labile iron pool as well as the ROS level indicating a close association between low levels of SDHB, iron overload, and oxidative stress, consistent with reports that showed a correlation between ROS accumulation and SDH dysfunction.	('ROS level', 'MPA', (68, 77))	('ROS', 'Chemical', 'MESH:D017382', (68, 71))	('reduced', 'NegReg', (24, 31))	('Genetic silencing', 'Var', (0, 17))	('SDH dysfunction', 'Disease', 'MESH:D009461', (253, 268))	('ROS', 'Chemical', 'MESH:D017382', (232, 235))	('labile iron pool', 'MPA', (36, 52))	('TF', 'Gene', '22041', (21, 23))	('iron', 'Chemical', 'MESH:D007501', (137, 141))	('oxidative stress', 'Phenotype', 'HP:0025464', (156, 172))	('iron', 'Chemical', 'MESH:D007501', (43, 47))	('SDH dysfunction', 'Disease', (253, 268))
12329	32152203	Moreover, blocking interception of electrons generated at SDHA by displacement of their acceptor, coenzyme Q, from the membrane part of cluster II by vitamin E succinate and, even more so, its mitochondria-targeted variant caused the massive formation of ROS with ensuing apoptosis induction.	('coenzyme Q', 'Chemical', 'MESH:D014451', (98, 108))	('caused', 'Reg', (223, 229))	('blocking', 'NegReg', (10, 18))	('ROS', 'Chemical', 'MESH:D017382', (255, 258))	('ROS', 'Protein', (255, 258))	('variant', 'Var', (215, 222))	('SDHA', 'Gene', (58, 62))	('apoptosis', 'CPA', (272, 281))	('SDHA', 'Gene', '66945', (58, 62))	('vitamin E succinate', 'Chemical', 'MESH:D024502', (150, 169))	('formation', 'MPA', (242, 251))
12332	32152203	SDH depletion leads to the accumulation of succinate, which serves as a competitive inhibitor of DNA/histone demethylases.	('accumulation', 'PosReg', (27, 39))	('succinate', 'MPA', (43, 52))	('SDH', 'Gene', (0, 3))	('depletion', 'Var', (4, 13))	('succinate', 'Chemical', 'MESH:D019802', (43, 52))	('SDH', 'Gene', '30956', (0, 3))
12350	32152203	Aberrant iron metabolism combined with redox disbalance induced by ascorbic acid, could be a promising therapeutic target for malignancies, especially those with "fragile" redox homeostasis.	('ascorbic acid', 'Chemical', 'MESH:D001205', (67, 80))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('redox disbalance', 'Phenotype', 'HP:0025463', (39, 55))	('Aberrant', 'Var', (0, 8))	('fragile', 'Disease', (163, 170))	('iron metabolism', 'MPA', (9, 24))	('Aberrant iron metabolism', 'Phenotype', 'HP:0011031', (0, 24))	('malignancies', 'Disease', (126, 138))	('fragile', 'Disease', 'MESH:D005600', (163, 170))	('redox disbalance', 'MPA', (39, 55))	('iron', 'Chemical', 'MESH:D007501', (9, 13))
12358	32152203	Ascorbate here was used as a single treatment agent, both for wild-type and mutant tumors in athymic mice.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Ascorbate', 'Chemical', 'MESH:D001205', (0, 9))	('mice', 'Species', '10090', (101, 105))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
12362	32152203	Disruption of this redox state by ascorbic acid may cause an overwhelming ROS burden, which presents a potential strategy toward this tumor type treatment.	('ascorbic acid', 'Chemical', 'MESH:D001205', (34, 47))	('ROS burden', 'MPA', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cause', 'Reg', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ROS', 'Chemical', 'MESH:D017382', (74, 77))	('tumor', 'Disease', (134, 139))	('Disruption', 'Var', (0, 10))
12395	32038491	Ten percent of CS cases are caused by ectopic ACTH production.	('CS', 'Phenotype', 'HP:0003118', (15, 17))	('ACTH', 'Gene', (46, 50))	('ectopic', 'Var', (38, 45))	('ACTH', 'Gene', '5443', (46, 50))	('CS', 'Disease', 'MESH:D003480', (15, 17))	('caused by', 'Reg', (28, 37))
12439	32038491	On the other hand, about 95% of paraganglioma patients with catecholamine hypersecretion presented with hypertension, while only 33.5% of paraganglioma patients without elevated catecholamine had hypertension.	('patients', 'Species', '9606', (46, 54))	('hypertension', 'Phenotype', 'HP:0000822', (196, 208))	('paraganglioma', 'Disease', (138, 151))	('catecholamine', 'Chemical', 'MESH:D002395', (60, 73))	('paraganglioma', 'Disease', 'MESH:D010235', (138, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('presented with', 'Reg', (89, 103))	('hypertension', 'Disease', 'MESH:D006973', (104, 116))	('hypertension', 'Disease', (104, 116))	('catecholamine hypersecretion', 'Var', (60, 88))	('catecholamine', 'Chemical', 'MESH:D002395', (178, 191))	('paraganglioma', 'Phenotype', 'HP:0002668', (138, 151))	('hypertension', 'Phenotype', 'HP:0000822', (104, 116))	('patients', 'Species', '9606', (152, 160))	('paraganglioma', 'Disease', (32, 45))	('hypertension', 'Disease', 'MESH:D006973', (196, 208))	('hypertension', 'Disease', (196, 208))	('elevated catecholamine', 'Phenotype', 'HP:0003334', (169, 191))	('paraganglioma', 'Disease', 'MESH:D010235', (32, 45))
12458	32038491	The hypersecretion of cortisol may result in hyperglycemia and suppression of the immune system.	('result in', 'Reg', (35, 44))	('cortisol', 'Chemical', 'MESH:D006854', (22, 30))	('immune system', 'CPA', (82, 95))	('hyperglycemia', 'Phenotype', 'HP:0003074', (45, 58))	('hyperglycemia', 'Disease', (45, 58))	('hyperglycemia', 'Disease', 'MESH:D006943', (45, 58))	('hypersecretion', 'Var', (4, 18))
12485	31214117	In a retrospective collaborative study conducted on behalf of the Italian Endocrine Society on 284 patients affected by a PPGL, only 60% presented hypertensive crises, about 20% presented a hypertension not different from that of patients with essential hypertension, and 21% resulted normotensive (Figure 1).	('hypertension', 'Disease', (190, 202))	('hypertensive', 'Disease', (147, 159))	('hypertension', 'Phenotype', 'HP:0000822', (190, 202))	('hypertension', 'Disease', 'MESH:D006973', (254, 266))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (99, 107))	('PPGL', 'Var', (122, 126))	('hypertension', 'Disease', (254, 266))	('hypertension', 'Phenotype', 'HP:0000822', (254, 266))	('hypertension', 'Disease', 'MESH:D006973', (190, 202))	('hypertensive', 'Disease', 'MESH:D006973', (147, 159))	('hypertensive crises', 'Phenotype', 'HP:0100735', (147, 166))
12490	31214117	Cluster 1 includes mainly tumors linked to mutations of VHL (von Hippel-Lindau) and SDHx (succinate-dehydrogenase) genes and characterized by the induction of a pseudohypoxia mechanism.	('SDHx', 'Gene', (84, 88))	('succinate', 'Chemical', 'MESH:D019802', (90, 99))	('SDHx', 'Chemical', '-', (84, 88))	('von Hippel-Lindau', 'Gene', '7428', (61, 78))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('pseudohypoxia', 'Disease', (161, 174))	('von Hippel-Lindau', 'Gene', (61, 78))	('linked', 'Reg', (33, 39))	('mutations', 'Var', (43, 52))	('VHL', 'Disease', (56, 59))	('VHL', 'Disease', 'MESH:D006623', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('pseudohypoxia', 'Disease', 'None', (161, 174))	('tumors', 'Disease', (26, 32))
12491	31214117	Cluster 2 includes tumors mainly linked to mutations of NF1 (neurofibromatosis type 1) and RET (responsible for the occurrence of Multiple Endocrine Neoplasia type 2) genes and characterized by the activation of tyrosine-kynase pathway.	('RET', 'Gene', (91, 94))	('tumors', 'Disease', (19, 25))	('NF1', 'Gene', '4763', (56, 59))	('Neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('linked', 'Reg', (33, 39))	('Multiple Endocrine Neoplasia type 2', 'Disease', (130, 165))	('tyrosine', 'Chemical', 'MESH:D014443', (212, 220))	('NF1', 'Gene', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (139, 158))	('neurofibromatosis type 1', 'Gene', (61, 85))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (61, 78))	('tyrosine-kynase pathway', 'Pathway', (212, 235))	('activation', 'PosReg', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('RET', 'Gene', '5979', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('neurofibromatosis type 1', 'Gene', '4763', (61, 85))	('Multiple Endocrine Neoplasia type 2', 'Disease', 'MESH:D018813', (130, 165))	('mutations', 'Var', (43, 52))
12494	31214117	In fact, in VHL tumors, the PNMT gene has been found hypermethylated and therefore downregulated.	('hypermethylated', 'Var', (53, 68))	('PNMT', 'Gene', '5409', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('downregulated', 'NegReg', (83, 96))	('VHL tumors', 'Disease', (12, 22))	('PNMT', 'Gene', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('VHL tumors', 'Disease', 'MESH:D006623', (12, 22))
12496	31214117	These biochemical differences explain why MEN2 patients result more symptomatic and have a higher incidence of hypertension, mainly paroxysmal in comparison with VHL patients.	('hypertension', 'Disease', (111, 123))	('MEN2', 'Var', (42, 46))	('hypertension', 'Phenotype', 'HP:0000822', (111, 123))	('paroxysmal', 'Disease', (132, 142))	('patients', 'Species', '9606', (47, 55))	('hypertension', 'Disease', 'MESH:D006973', (111, 123))	('VHL', 'Disease', (162, 165))	('VHL', 'Disease', 'MESH:D006623', (162, 165))	('patients', 'Species', '9606', (166, 174))
12500	31214117	Succinate, which is increased in SDHx mutated PPGL, causes an increase of plasma renin activity in rats but circulating succinate does not differ between hypertensive patients and normotensive controls.	('mutated', 'Var', (38, 45))	('increased', 'PosReg', (20, 29))	('SDHx', 'Gene', (33, 37))	('SDHx', 'Chemical', '-', (33, 37))	('hypertensive', 'Disease', (154, 166))	('rats', 'Species', '10116', (99, 103))	('increase of plasma renin activity', 'Phenotype', 'HP:0000841', (62, 95))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('patients', 'Species', '9606', (167, 175))	('Succinate', 'MPA', (0, 9))	('increase of plasma renin', 'Phenotype', 'HP:0000848', (62, 86))	('succinate', 'Chemical', 'MESH:D019802', (120, 129))	('plasma renin activity', 'MPA', (74, 95))	('hypertensive', 'Disease', 'MESH:D006973', (154, 166))	('increase', 'PosReg', (62, 70))
12501	31214117	Finally, the familial genetic screening permits the discovery of mutation carriers and the early diagnosis of small PPGL whose scanty releasing activity does not cause hypertension.	('small', 'Var', (110, 115))	('hypertension', 'Phenotype', 'HP:0000822', (168, 180))	('hypertension', 'Disease', 'MESH:D006973', (168, 180))	('hypertension', 'Disease', (168, 180))
12510	31214117	PPGL are among the causes of endocrine hypertension.	('causes', 'Reg', (19, 25))	('hypertension', 'Phenotype', 'HP:0000822', (39, 51))	('endocrine hypertension', 'Disease', (29, 51))	('PPGL', 'Var', (0, 4))	('endocrine hypertension', 'Disease', 'MESH:D006973', (29, 51))
12563	28634180	We identified seven candidate mutations in six genes that were further studied using 215 sporadic SI-NET patients.	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (30, 39))	('SI-NET', 'Disease', (98, 104))	('SI-NET', 'Disease', 'None', (98, 104))
12564	28634180	A heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was significantly enriched in SI-NET patients (minor allele frequencies 0.013 and 0.003 for patients and controls respectively) and resulted in odds ratio of 5.09 (95% confidence interval 1.56-14.74; P value = 0.0038).	('patients', 'Species', '9606', (205, 213))	('SI-NET', 'Disease', 'None', (143, 149))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (58, 71))	('SI-NET', 'Disease', (143, 149))	('patients', 'Species', '9606', (150, 158))	('p.(Gly396Asp', 'Var', (58, 70))
12566	28634180	The inactivation of this gene leads to specific increase of G:C- > T:A transversions in DNA sequence and has been shown to cause various cancers in humans and experimental animals.	('humans', 'Species', '9606', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('inactivation', 'Var', (4, 16))	('DNA sequence', 'MPA', (88, 100))	('cause', 'Reg', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('G:C- > T', 'MPA', (60, 68))	('increase', 'PosReg', (48, 56))
12567	28634180	Our results suggest that p.(Gly396Asp) in MUTYH, and potentially other mutations in additional members of the same DNA excision-repair pathway (such as the OGG1 gene) might be involved in driving the tumorigenesis leading to familial and sporadic SI-NETs.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('SI-NETs', 'Disease', (247, 254))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (25, 38))	('tumor', 'Disease', (200, 205))	('involved', 'Reg', (176, 184))	('p.(Gly396Asp', 'Var', (25, 37))	('SI-NETs', 'Disease', 'None', (247, 254))
12580	28634180	Frameshift and heterozygous mutations involving the CDKN1B gene, coding for the tumor suppressor p27, were recently described in approximately 8 and 14% of the analyzed tumors.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN1B', 'Gene', (52, 58))	('heterozygous mutations', 'Var', (15, 37))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('p27', 'Gene', '10671', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (80, 85))	('p27', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('Frameshift', 'Var', (0, 10))	('tumor', 'Disease', (169, 174))	('CDKN1B', 'Gene', '1027', (52, 58))	('tumors', 'Disease', (169, 175))	('described', 'Reg', (116, 125))
12581	28634180	About 50% of the tumors had deleted or mutated SMAD genes, suggesting an involvement of the TGF-beta pathway in tumor formation.	('involvement', 'Reg', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('SMAD', 'Gene', (47, 51))	('TGF-beta', 'Gene', '7040', (92, 100))	('mutated', 'Var', (39, 46))	('SMAD', 'Gene', '4086', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (112, 117))	('TGF-beta', 'Gene', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
12582	28634180	Single-nucleotide variants were found in MEN1, FGFR2, HOOK3, EZH2, MLF1, CARD11, VHL, NONO and SMAD1.	('MLF1', 'Gene', '4291', (67, 71))	('Single-nucleotide variants', 'Var', (0, 26))	('HOOK3', 'Gene', (54, 59))	('SMAD1', 'Gene', '4086', (95, 100))	('NONO', 'Gene', '4841', (86, 90))	('CARD11', 'Gene', (73, 79))	('MLF1', 'Gene', (67, 71))	('CARD11', 'Gene', '84433', (73, 79))	('HOOK3', 'Gene', '84376', (54, 59))	('VHL', 'Gene', (81, 84))	('FGFR2', 'Gene', (47, 52))	('MEN1', 'Gene', '4221', (41, 45))	('EZH2', 'Gene', (61, 65))	('EZH2', 'Gene', '2146', (61, 65))	('NONO', 'Gene', (86, 90))	('SMAD1', 'Gene', (95, 100))	('VHL', 'Gene', '7428', (81, 84))	('FGFR2', 'Gene', '2263', (47, 52))	('MEN1', 'Gene', (41, 45))
12583	28634180	The amplifications of AKT1 or AKT2 were the most common alterations detected in the cases with an alteration of the PI3K/Akt/mTOR signaling pathway.	('Akt', 'Gene', (121, 124))	('mTOR', 'Gene', '2475', (125, 129))	('AKT2', 'Gene', '208', (30, 34))	('mTOR', 'Gene', (125, 129))	('amplifications', 'Var', (4, 18))	('alteration', 'Reg', (98, 108))	('AKT2', 'Gene', (30, 34))	('Akt', 'Gene', '207', (121, 124))	('AKT1', 'Gene', '207', (22, 26))	('AKT1', 'Gene', (22, 26))
12586	28634180	We published a series of 10 families with SI-NETs and could show that deletion of chromosome 18 in tumors was less frequently found in these familial cases as compared to sporadic patients.	('deletion', 'Var', (70, 78))	('SI-NETs', 'Disease', 'None', (42, 49))	('SI-NETs', 'Disease', (42, 49))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (180, 188))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
12588	28634180	Furthermore, a group at NIH presented a series of 33 families, having at least two SI-NET patients, and could identify a 4-bp deletion in the inositol polyphosphate multikinase gene (IPMK) segregating in one large family.	('inositol polyphosphate multikinase', 'Gene', '253430', (142, 176))	('SI-NET', 'Disease', 'None', (83, 89))	('deletion', 'Var', (126, 134))	('IPMK', 'Gene', '253430', (183, 187))	('SI-NET', 'Disease', (83, 89))	('IPMK', 'Gene', (183, 187))	('patients', 'Species', '9606', (90, 98))	('inositol polyphosphate multikinase', 'Gene', (142, 176))
12617	28634180	After having identified candidate variants from WGS and WES experiments on familial SI-NETs cases, we designed validation primers for seven loci using PrimerZ, using the option 'Input SNPs or Positions' with default settings except for the product size ranges that was restricted to 100-400 base pairs (http://genepipe.ngc.sinica.edu.tw/primerz/).	('familial SI-NETs', 'Disease', 'MESH:D009394', (75, 91))	('familial SI-NETs', 'Disease', (75, 91))	('variants', 'Var', (34, 42))
12619	28634180	Paraffin-embedded tumor tissue specimens from SI-NET patients with and without verified mutations in MUTYH, OGG1 TERT, SDHB and SDHD were cut into approximately 4-microm thick sections and attached to positively charged glass slides (Superfrost Plus, Menzel Glaser, Braunschweig, Germany).	('SI-NET', 'Disease', (46, 52))	('Paraffin', 'Chemical', 'MESH:D010232', (0, 8))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', (18, 23))	('TERT', 'Gene', '7015', (113, 117))	('SDHB', 'Gene', '6390', (119, 123))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('SDHB', 'Gene', (119, 123))	('SDHD', 'Gene', '6392', (128, 132))	('MUTYH', 'Gene', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('SI-NET', 'Disease', 'None', (46, 52))	('TERT', 'Gene', (113, 117))	('OGG1', 'Gene', (108, 112))	('SDHD', 'Gene', (128, 132))
12630	28634180	We populated these lists with variants present in one (for families with only one affected subjects sequenced) or more cancer patients, prioritizing those reported as pathogenic (specifically cancer causing) in ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/) or predicted to be damaging by at least one of the three functional prediction algorithms: SIFT, Polyphen and MutationTaster.	('variants', 'Var', (30, 38))	('SIFT', 'Disease', (359, 363))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('patients', 'Species', '9606', (126, 134))	('SIFT', 'Disease', 'None', (359, 363))	('MutationTaster', 'Var', (378, 392))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
12631	28634180	The heterozygous missense variant in the telomerase reverse transcriptase gene (TERT) p.(Ala279Thr) was the most common DNA sequence variant identified among the 24 familial SI-NET patients and was observed in six patients from three families (subjects A1, A2, A6, A7, B3 and M2) (Fig.	('missense', 'Var', (17, 25))	('telomerase reverse transcriptase', 'Gene', (41, 73))	('patients', 'Species', '9606', (214, 222))	('telomerase reverse transcriptase', 'Gene', '7015', (41, 73))	('familial SI-NET', 'Disease', 'MESH:D009394', (165, 180))	('p.(Ala279Thr)', 'Mutation', 'rs61748181', (86, 99))	('familial SI-NET', 'Disease', (165, 180))	('patients', 'Species', '9606', (181, 189))	('TERT', 'Gene', (80, 84))	('TERT', 'Gene', '7015', (80, 84))
12632	28634180	Prediction of the phenotypic effect of this variant was discordant in SIFT, Polyphen and MutationTaster; reported as 'tolerated', 'probably damaging', and 'disease causing' respectively.	('SIFT', 'Disease', 'None', (70, 74))	('SIFT', 'Disease', (70, 74))	("'tolerated", 'PosReg', (117, 127))	('variant', 'Var', (44, 51))
12634	28634180	In addition, in two members of family A, an additional heterozygous variant of the TERT gene p.(His412Tyr) was uncovered.	('p.(His412Tyr', 'Var', (93, 105))	('p.(His412Tyr)', 'SUBSTITUTION', 'None', (93, 106))	('TERT', 'Gene', (83, 87))	('TERT', 'Gene', '7015', (83, 87))
12635	28634180	It was present in A4 (married to affected subject A1) and he passed on this allele to his affected son A2, who is therefore a compound heterozygote for two TERT gene variants; p.(Ala279Thr) and p.(His412Tyr).	('p.(His412Tyr)', 'SUBSTITUTION', 'None', (194, 207))	('p.(Ala279Thr)', 'Mutation', 'rs61748181', (176, 189))	('p.(His412Tyr', 'Var', (194, 206))	('TERT', 'Gene', (156, 160))	('p.(Ala279Thr', 'Var', (176, 188))	('TERT', 'Gene', '7015', (156, 160))
12636	28634180	SIFT, Polyphen and MutationTaster predicted this variant in a similar way as the former one (tolerated, probably damaging and disease causing respectively) (Table 3).	('variant', 'Var', (49, 56))	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))
12637	28634180	Both Ala279Thr and His412Tyr variants are described as pathogenic in ClinVar and were reported in patients affected with bone marrow failure, aplastic anemia and dyskeratosis congenita, a telomere-related disorder.	('Ala279Thr', 'Var', (5, 14))	('bone marrow failure', 'Disease', (121, 140))	('pathogenic', 'Reg', (55, 65))	('Ala279Thr', 'Chemical', '-', (5, 14))	('anemia', 'Phenotype', 'HP:0001903', (151, 157))	('aplastic anemia', 'Phenotype', 'HP:0001915', (142, 157))	('dyskeratosis congenita', 'Disease', (162, 184))	('His412Tyr', 'SUBSTITUTION', 'None', (19, 28))	('aplastic anemia', 'Disease', 'MESH:D000741', (142, 157))	('patients', 'Species', '9606', (98, 106))	('bone marrow failure', 'Disease', 'MESH:D000080983', (121, 140))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (162, 184))	('bone marrow failure', 'Phenotype', 'HP:0005528', (121, 140))	('His412Tyr', 'Var', (19, 28))	('aplastic anemia', 'Disease', (142, 157))	('ClinVar', 'Disease', (69, 76))
12638	28634180	This variant has been furthermore described in esophageal carcinomas, both in heterozygous and homozygous states.	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (47, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (47, 68))	('variant', 'Var', (5, 12))	('esophageal carcinomas', 'Disease', (47, 68))	('described', 'Reg', (34, 43))
12639	28634180	In comparison with normal ones, cells expressing the TERT A279T variant were shown to have shorter telomeres and impaired canonical and non-canonical telomerase functions.	('A279T', 'Var', (58, 63))	('impaired', 'NegReg', (113, 121))	('canonical', 'MPA', (122, 131))	('A279T', 'SUBSTITUTION', 'None', (58, 63))	('shorter', 'NegReg', (91, 98))
12640	28634180	NGS analysis of the whole-exome and whole-genome data on the familial cases also revealed four likely polymorphisms in three genes (SDHA, SDHB and SDHD) encoding different subunits of the mitochondrial succinate dehydrogenase complex (Fig.	('SDHB', 'Gene', (138, 142))	('SDHA', 'Gene', '6389', (132, 136))	('polymorphisms', 'Var', (102, 115))	('SDHA', 'Gene', (132, 136))	('SDHD', 'Gene', '6392', (147, 151))	('SDHD', 'Gene', (147, 151))	('SDHB', 'Gene', '6390', (138, 142))
12641	28634180	The SDHD His50Arg and Gly12Ser variants have previously described neuroendocrine tumors such as pheochromocytomas and paragangliomas, as well as midgut carcinoids and Merkel cell carcinomas.	('His50Arg', 'Var', (9, 17))	('Gly12Ser', 'Chemical', '-', (22, 30))	('midgut carcinoids', 'Disease', (145, 162))	('pheochromocytomas', 'Disease', 'MESH:D010673', (96, 113))	('pheochromocytomas', 'Disease', (96, 113))	('carcinoids', 'Phenotype', 'HP:0100570', (152, 162))	('His50Arg', 'SUBSTITUTION', 'None', (9, 17))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (66, 87))	('carcinoid', 'Phenotype', 'HP:0100570', (152, 161))	('paragangliomas', 'Disease', 'MESH:D010235', (118, 132))	('paraganglioma', 'Phenotype', 'HP:0002668', (118, 131))	('paragangliomas', 'Phenotype', 'HP:0002668', (118, 132))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (96, 113))	('Merkel cell carcinomas', 'Disease', 'MESH:D015266', (167, 189))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (66, 86))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (66, 87))	('SDHD', 'Gene', '6392', (4, 8))	('endocrine tumor', 'Phenotype', 'HP:0100568', (71, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('described', 'Reg', (56, 65))	('Merkel cell carcinomas', 'Disease', (167, 189))	('paragangliomas', 'Disease', (118, 132))	('SDHD', 'Gene', (4, 8))	('Gly12Ser', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('neuroendocrine tumors', 'Disease', (66, 87))
12642	28634180	The pathogenicity of SDHB Ser163Pro according to ClinVar is controversial, but this allele has previously been detected in familial cases of pheochromocytoma and paraganglioma.	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (141, 175))	('detected', 'Reg', (111, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('SDHB', 'Gene', '6390', (21, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('Ser163Pro', 'SUBSTITUTION', 'None', (26, 35))	('SDHB', 'Gene', (21, 25))	('Ser163Pro', 'Var', (26, 35))
12643	28634180	A polymorphism affecting the A subunit of the complex, SDHA Asp38Val, detected in two affected individuals of family G, G1 and G2, has been previously described in gastrointestinal stromal tumors.	('SDHA', 'Gene', '6389', (55, 59))	('described', 'Reg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (164, 195))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (164, 195))	('SDHA', 'Gene', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('Asp38Val', 'SUBSTITUTION', 'None', (60, 68))	('polymorphism', 'Var', (2, 14))	('Asp38Val', 'Var', (60, 68))	('gastrointestinal stromal tumors', 'Disease', (164, 195))
12644	28634180	The above studies describe homozygous inactivation as the most plausible mechanism of tumorigenesis for these variants of the mitochondrial SDHC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('variants', 'Var', (110, 118))	('mitochondrial SDHC', 'Gene', (126, 144))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
12646	28634180	Furthermore, a heterozygous variant causing an amino acid substitution p.(Gly396Asp) in the MutY DNA glycosylase gene (MUTYH) was observed in two SI-NET patients from different families (subjects O1 and No1) (Fig.	('SI-NET', 'Disease', (146, 152))	('patients', 'Species', '9606', (153, 161))	('p.(Gly396Asp', 'Var', (71, 83))	('SI-NET', 'Disease', 'None', (146, 152))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (71, 84))
12647	28634180	Germline biallelic variants of MUTYH (including Gly396Asp) have been previously described in patients affected with multiple colorectal adenomas and adenomatous polyposis, as well as pancreatic NETs.	('Gly396Asp', 'Var', (48, 57))	('adenomatous polyposis', 'Disease', (149, 170))	('described', 'Reg', (80, 89))	('pancreatic', 'Disease', (183, 193))	('multiple colorectal adenomas', 'Disease', 'MESH:C563924', (116, 144))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (149, 170))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (149, 170))	('Gly396Asp', 'SUBSTITUTION', 'None', (48, 57))	('MUTYH', 'Gene', (31, 36))	('multiple colorectal adenomas', 'Disease', (116, 144))	('patients', 'Species', '9606', (93, 101))	('pancreatic', 'Disease', 'MESH:D010195', (183, 193))
12648	28634180	Finally, in family M (subject M1), we also observed a variant in the 8-oxoguanine DNA glycosylase gene (OGG1) p.(Arg46Gln), which was predicted as damaging by all three methods, and this gene was therefore considered a candidate for further analysis.	('p.(Arg46Gln)', 'SUBSTITUTION', 'None', (110, 122))	('8-oxoguanine DNA glycosylase', 'Gene', '4968', (69, 97))	('8-oxoguanine DNA glycosylase', 'Gene', (69, 97))	('OGG1', 'Gene', (104, 108))	('p.(Arg46Gln', 'Var', (110, 121))
12649	28634180	A study of human kidney carcinomas has suggested that this variant might be a risk allele.	('human', 'Species', '9606', (11, 16))	('kidney carcinomas', 'Disease', (17, 34))	('kidney carcinomas', 'Disease', 'MESH:C538614', (17, 34))	('variant', 'Var', (59, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
12650	28634180	In summary, for the familial SI-NET patients, we analyzed 15 small families and identified seven heterozygous missense variants affecting six genes, which could be further tested in sporadic SI-NET patients (see below).	('missense variants', 'Var', (110, 127))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (198, 206))	('familial SI-NET', 'Disease', 'MESH:D009394', (20, 35))	('SI-NET', 'Disease', 'None', (191, 197))	('familial SI-NET', 'Disease', (20, 35))	('SI-NET', 'Disease', 'None', (29, 35))	('SI-NET', 'Disease', (29, 35))	('SI-NET', 'Disease', (191, 197))
12651	28634180	All identified variants were reported as involved in cancer in ClinVar and pinpointed as possible pathogenic by our unbiased filtering pipeline of NGS data; thus, both approaches converged on the same candidate mutations.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('involved', 'Reg', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('variants', 'Var', (15, 23))
12654	28634180	It should also be mentioned that we tested, with negative results (details not shown), our families for mutations in the inositol polyphosphate multikinase gene (IPMK), which has been reported in one large family with SI-NETs.	('inositol polyphosphate multikinase', 'Gene', (121, 155))	('SI-NETs', 'Disease', (218, 225))	('mutations', 'Var', (104, 113))	('IPMK', 'Gene', (162, 166))	('IPMK', 'Gene', '253430', (162, 166))	('SI-NETs', 'Disease', 'None', (218, 225))	('inositol polyphosphate multikinase', 'Gene', '253430', (121, 155))
12656	28634180	Samples obtained from 215 unrelated subjects affected with SI-NETs were screened for the seven candidate variants and the results are summarized in Table 3.	('SI-NETs', 'Disease', 'None', (59, 66))	('variants', 'Var', (105, 113))	('SI-NETs', 'Disease', (59, 66))
12663	28634180	A comparison of allele frequencies for the seven variants showed that the heterozygous variant causing amino acid substitution p.(Gly396Asp) in MUTYH was significantly enriched among the patients affected with SI-NETs, compared to all the control cohorts.	('patients', 'Species', '9606', (187, 195))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (127, 140))	('SI-NETs', 'Disease', 'None', (210, 217))	('SI-NETs', 'Disease', (210, 217))	('p.(Gly396Asp', 'Var', (127, 139))
12664	28634180	The minor allele frequencies (MAFs) for the MUTYH p.(Gly396Asp) variant were: 0.009, 0.004 and 0.003 for the Exac-, 1000 Genomes-, and EpiHealth cohort respectively.	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (50, 63))	('MAF', 'Gene', (30, 33))	('p.(Gly396Asp', 'Var', (50, 62))	('MAF', 'Gene', '4094', (30, 33))
12665	28634180	The overall minor allele frequency of this variant in our collection of affected subjects (sporadic and familial subjects) was 2-5 times higher (MAF = 0.016) when considering subjects harboring the variant in the germline.	('MAF', 'Gene', '4094', (145, 148))	('variant', 'Var', (43, 50))	('MAF', 'Gene', (145, 148))	('higher', 'PosReg', (137, 143))
12666	28634180	A similar situation was observed when studying variants found in any tissue (germline plus tumor samples) resulting in MAF = 0.013; 1.4-4 times higher than that in controls.	('MAF', 'Gene', '4094', (119, 122))	('variants', 'Var', (47, 55))	('MAF', 'Gene', (119, 122))	('germline plus tumor', 'Disease', (77, 96))	('higher', 'PosReg', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('germline plus tumor', 'Disease', 'MESH:D009369', (77, 96))
12668	28634180	Calculations of odds ratios (Fisher's exact test) for being affected with SI-NETs and having SNP causing amino acid substitution p.(Gly396Asp) in MUTYH were 6.19 (95% confidence interval (CI): 1.7-19.02, P value = 0.0034) and 5.09 (95% CI: 1.56-14.74, P value = 0.0038) (Table 3).	('SI-NETs', 'Disease', 'None', (74, 81))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (129, 142))	('SI-NETs', 'Disease', (74, 81))	('p.(Gly396Asp', 'Var', (129, 141))
12670	28634180	The 95% CIs for the odds ratios are wide, largely because of the low MAFs in controls, suggesting that future studies of p.(Gly396Asp) in MUTYH in SI-NET patients are necessary using a larger cohort of patients.	('p.(Gly396Asp', 'Var', (121, 133))	('SI-NET', 'Disease', 'None', (147, 153))	('patients', 'Species', '9606', (154, 162))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (121, 134))	('MAF', 'Gene', (69, 72))	('patients', 'Species', '9606', (202, 210))	('SI-NET', 'Disease', (147, 153))	('MAF', 'Gene', '4094', (69, 72))
12671	28634180	The monoallelic mutation MUTYH p.(Gly396Asp) was also uncovered in two samples of tumor DNA; i.e.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p.(Gly396Asp', 'Var', (31, 43))	('tumor', 'Disease', (82, 87))
12673	28634180	However, due to the unavailability of tumor specimens from the relevant patients, we have not been able to carefully study tumors from all patients for deletions on 1p (where MUTYH is located), with an aim to uncover the mechanism of inactivation of the other allele of the MUTYH gene.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('unavailability of tumor', 'Disease', 'MESH:D009369', (20, 43))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('deletions', 'Var', (152, 161))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('unavailability of tumor', 'Disease', (20, 43))	('patients', 'Species', '9606', (72, 80))
12675	28634180	The OGG1 mutation p.(Arg46Gln) was enriched in SI-NETs about two times, compared to EpiHealth, but our patient cohort would need to be considerably larger in order to reach the statistical significance, suggesting that future studies of OGG1 p.(Arg46Gln) candidate mutation in SI-NET patients are necessary.	('p.(Arg46Gln', 'Var', (242, 253))	('SI-NET', 'Disease', 'None', (277, 283))	('p.(Arg46Gln)', 'SUBSTITUTION', 'None', (18, 30))	('SI-NETs', 'Disease', (47, 54))	('SI-NET', 'Disease', (47, 53))	('patients', 'Species', '9606', (284, 292))	('SI-NET', 'Disease', 'None', (47, 53))	('SI-NET', 'Disease', (277, 283))	('p.(Arg46Gln)', 'SUBSTITUTION', 'None', (242, 254))	('OGG1', 'Gene', (4, 8))	('patient', 'Species', '9606', (103, 110))	('OGG1', 'Gene', (237, 241))	('SI-NETs', 'Disease', 'None', (47, 54))	('patient', 'Species', '9606', (284, 291))	('p.(Arg46Gln', 'Var', (18, 29))
12676	28634180	As for the mutation in MUTYH gene, also this variant in OGG1 was present in a single copy in all studied subjects, including one metastasis and one PT from apparently sporadic patients.	('OGG1', 'Gene', (56, 60))	('patients', 'Species', '9606', (176, 184))	('variant', 'Var', (45, 52))
12685	28634180	These results for the SDHB and SDHD genes may suggest that these mutations do not have an effect on the expression of proteins of the mitochondrial complex II, speaking against their possible role in this disease.	('SDHD', 'Gene', (31, 35))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('SDHD', 'Gene', '6392', (31, 35))	('mutations', 'Var', (65, 74))
12686	28634180	This is in contrast to observations in pheochromocytomas and paragangliomas, where it has been shown that pathogenic variants of these genes, present in tumors in two copies, lead to loss of expression with subsequent impaired enzymatic activity.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('enzymatic activity', 'MPA', (227, 245))	('loss', 'NegReg', (183, 187))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('of expression', 'MPA', (188, 201))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (39, 56))	('paragangliomas', 'Disease', 'MESH:D010235', (61, 75))	('impaired', 'NegReg', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('variants', 'Var', (117, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (39, 55))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('pheochromocytomas', 'Disease', (39, 56))	('paragangliomas', 'Disease', (61, 75))	('pheochromocytomas', 'Disease', 'MESH:D010673', (39, 56))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))
12689	28634180	Using analysis of germline DNA from family members affected with SI-NETs and sporadic SI-NET patients, we identified a monoallelic mutation causing an amino acid substitution p.(Gly396Asp) in MUTYH that was significantly enriched among the patients affected with SI-NETs, compared to the controls.	('SI-NET', 'Disease', (263, 269))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (175, 188))	('MUTYH', 'Gene', (192, 197))	('SI-NETs', 'Disease', 'None', (65, 72))	('SI-NETs', 'Disease', (65, 72))	('p.(Gly396Asp', 'Var', (175, 187))	('SI-NET', 'Disease', 'None', (86, 92))	('SI-NET', 'Disease', 'None', (263, 269))	('SI-NET', 'Disease', 'None', (65, 71))	('SI-NET', 'Disease', (65, 71))	('patients', 'Species', '9606', (240, 248))	('SI-NETs', 'Disease', 'None', (263, 270))	('SI-NET', 'Disease', (86, 92))	('SI-NETs', 'Disease', (263, 270))	('patients', 'Species', '9606', (93, 101))
12691	28634180	Although we have not reached statistical significance for enrichment of the mutation OGG1 p.(Arg46Gln) in patients vs controls, this variant should also be considered in future studies.	('p.(Arg46Gln)', 'SUBSTITUTION', 'None', (90, 102))	('patients', 'Species', '9606', (106, 114))	('p.(Arg46Gln', 'Var', (90, 101))	('OGG1', 'Gene', (85, 89))
12693	28634180	equal number of patients and controls from EpiHealth cohort, and assuming the same frequency of OGG1 p.(Arg46Gln) mutation in SI-NET patient cohort) would be sufficient.	('p.(Arg46Gln', 'Var', (101, 112))	('SI-NET', 'Disease', 'None', (126, 132))	('SI-NET', 'Disease', (126, 132))	('patient', 'Species', '9606', (133, 140))	('patients', 'Species', '9606', (16, 24))	('p.(Arg46Gln)', 'SUBSTITUTION', 'None', (101, 113))	('OGG1', 'Gene', (96, 100))	('patient', 'Species', '9606', (16, 23))
12694	28634180	Interestingly, a recent report on a related disease, pancreatic neuroendocrine tumors (PAN-NETs), has described mutations in the MUTYH gene.	('endocrine tumor', 'Phenotype', 'HP:0100568', (69, 84))	('mutations', 'Var', (112, 121))	('pancreatic neuroendocrine tumors', 'Disease', (53, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (53, 85))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (64, 84))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (64, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('MUTYH', 'Gene', (129, 134))
12695	28634180	Mutation p.(Gly396Asp) in MUTYH, along with other pathogenic variants in this gene, were reported.	('p.(Gly396Asp', 'Var', (9, 21))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (9, 22))	('MUTYH', 'Gene', (26, 31))
12702	28634180	Furthermore, previous analyses of gene copy number alterations in SI-NETs showed that chromosome 1p (where MUTYH is located) is rarely affected by tumor-specific deletions, which speaks against a frequent biallelic inactivation of this gene.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('alterations', 'Var', (51, 62))	('tumor', 'Disease', (147, 152))	('SI-NETs', 'Disease', 'None', (66, 73))	('SI-NETs', 'Disease', (66, 73))	('deletions', 'Var', (162, 171))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
12703	28634180	These results might suggest that biallelic inactivation of MUTYH might not be the only mechanism driving the tumor development of SI-NETs, as opposed to what was observed in PAN-NETs.	('biallelic', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SI-NETs', 'Disease', 'None', (130, 137))	('SI-NETs', 'Disease', (130, 137))	('tumor', 'Disease', (109, 114))
12708	28634180	Furthermore, these mutations have also been associated with extra-colonic tumors in subjects bearing two mutations in this gene.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (19, 28))	('extra-colonic tumors', 'Disease', (60, 80))	('extra-colonic tumors', 'Disease', 'MESH:D015179', (60, 80))	('associated with', 'Reg', (44, 59))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
12710	28634180	Notably, amino acid substitution p.(Gly396Asp) MUTYH is among the recessive germline mutations described so far in the MUTYH gene and likely causing the autosomal recessive form of adenomatous polyposis.	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (33, 46))	('causing', 'Reg', (141, 148))	('MUTYH', 'Gene', (119, 124))	('p.(Gly396Asp', 'Var', (33, 45))	('adenomatous polyposis', 'Disease', (181, 202))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (181, 202))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (181, 202))
12712	28634180	Interestingly, deficient excision of the mutagenic base 8-oxoguanine causes mutations in codon 12 of k-ras gene in mice and codon 12 mutations in human K-RAS have also been described as a somatic tumor-specific change in SI-NETs.	('mutations in', 'Var', (76, 88))	('tumor', 'Disease', (196, 201))	('K-RAS', 'Gene', '3845', (152, 157))	('excision', 'MPA', (25, 33))	('k-ras', 'Gene', (101, 106))	('K-RAS', 'Gene', (152, 157))	('SI-NETs', 'Disease', 'None', (221, 228))	('human', 'Species', '9606', (146, 151))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (56, 68))	('SI-NETs', 'Disease', (221, 228))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('k-ras', 'Gene', '16653', (101, 106))	('deficient', 'NegReg', (15, 24))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
12713	28634180	Considering the above, we hypothesize that a monoallelic mutation causing amino acid substitution p.(Gly396Asp) in MUTYH is conferring a mild functional impairment, affecting the excision-repair system of 8-oxoguanine (without disturbing the level of MUTYH protein expression), eventually leading to the development of SI-NETs.	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (98, 111))	('SI-NETs', 'Disease', (319, 326))	('leading to', 'Reg', (289, 299))	('affecting', 'Reg', (165, 174))	('p.(Gly396Asp', 'Var', (98, 110))	('8-oxoguanine', 'Chemical', 'MESH:C024829', (205, 217))	('SI-NETs', 'Disease', 'None', (319, 326))	('excision-repair system of 8-oxoguanine', 'MPA', (179, 217))
12715	28634180	The presence of one copy of the wild-type allele in patients with MUTYH p.(Gly396Asp) might temper the effect of the altered protein, giving SI-NET patient a mild phenotype, late onset and slow progression of the disease.	('MUTYH', 'Var', (66, 71))	('temper', 'NegReg', (92, 98))	('SI-NET', 'Disease', 'None', (141, 147))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (72, 85))	('patients', 'Species', '9606', (52, 60))	('patient', 'Species', '9606', (52, 59))	('effect', 'MPA', (103, 109))	('SI-NET', 'Disease', (141, 147))	('patient', 'Species', '9606', (148, 155))	('p.(Gly396Asp', 'Var', (72, 84))
12716	28634180	We speculate that in the presence of the biallelic MUTYH mutation (as is the case for autosomal recessive form of adenomatous polyposis), one might, for most of patients, never have time to observe the onset of SI-NETs, since other aggressive pathologies (such as colorectal cancer) might lead to the death of the patient.	('colorectal cancer', 'Disease', 'MESH:D015179', (264, 281))	('colorectal cancer', 'Phenotype', 'HP:0003003', (264, 281))	('patient', 'Species', '9606', (161, 168))	('adenomatous polyposis', 'Disease', (114, 135))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('biallelic MUTYH mutation', 'Var', (41, 65))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (114, 135))	('colorectal cancer', 'Disease', (264, 281))	('adenomatous polyposis', 'Disease', 'MESH:D011125', (114, 135))	('SI-NETs', 'Disease', 'None', (211, 218))	('patients', 'Species', '9606', (161, 169))	('SI-NETs', 'Disease', (211, 218))	('patient', 'Species', '9606', (314, 321))
12717	28634180	In this context, one could mention that heterozygous variant p.(Gly396Asp) in the MutY DNA glycosylase gene has been shown to be associated with an elevated risk of breast cancer also in a study on 930 Sephardi Jewish women of North African origin.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('associated', 'Reg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('MutY DNA glycosylase', 'Gene', (82, 102))	('p.(Gly396Asp', 'Var', (61, 73))	('women', 'Species', '9606', (218, 223))
12718	28634180	The p.(Gly396Asp) in MUTYH is, however, unlikely a single and sufficient event to cause the development of SI-NETs.	('SI-NETs', 'Disease', (107, 114))	('SI-NETs', 'Disease', 'None', (107, 114))	('p.(Gly396Asp', 'Var', (4, 16))	('p.(Gly396Asp)', 'SUBSTITUTION', 'None', (4, 17))
12719	28634180	The observed variants in TERT as well as in SDHA, SDHB and SDHD genes are actually the most common findings in our familial SI-NET patients, but these alleles are not enriched in frequency among all SI-NET patients, when compared to the control population.	('patients', 'Species', '9606', (131, 139))	('variants', 'Var', (13, 21))	('TERT', 'Gene', (25, 29))	('SDHB', 'Gene', (50, 54))	('SI-NET', 'Disease', 'None', (199, 205))	('SDHA', 'Gene', '6389', (44, 48))	('common', 'Reg', (92, 98))	('SI-NET', 'Disease', (199, 205))	('TERT', 'Gene', '7015', (25, 29))	('SDHD', 'Gene', '6392', (59, 63))	('patients', 'Species', '9606', (206, 214))	('familial SI-NET', 'Disease', 'MESH:D009394', (115, 130))	('SI-NET', 'Disease', 'None', (124, 130))	('SDHA', 'Gene', (44, 48))	('SDHD', 'Gene', (59, 63))	('SI-NET', 'Disease', (124, 130))	('familial SI-NET', 'Disease', (115, 130))	('SDHB', 'Gene', '6390', (50, 54))
12720	28634180	Furthermore, mutations in the SDHx genes have previously been implicated in cancer, and particularly, in forms related to SI-NETs, such as pheochromocytoma and paraganglioma.	('SI-NETs', 'Disease', 'None', (122, 129))	('SI-NETs', 'Disease', (122, 129))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (139, 173))	('paraganglioma', 'Phenotype', 'HP:0002668', (160, 173))	('SDHx', 'Gene', (30, 34))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('mutations', 'Var', (13, 22))	('implicated', 'Reg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
12721	28634180	Somatic, tumor-specific SDHD mutations have also been shown in SI-NETs.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (29, 38))	('SI-NETs', 'Disease', 'None', (63, 70))	('SI-NETs', 'Disease', (63, 70))	('tumor', 'Disease', (9, 14))	('SDHD', 'Gene', (24, 28))	('SDHD', 'Gene', '6392', (24, 28))
12724	28634180	We may only speculate that the variants we characterized could contribute to the development of tumors in some patients or in some families.	('variants', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('contribute', 'Reg', (63, 73))	('patients', 'Species', '9606', (111, 119))
12728	28634180	The only previously characterized mutation (4-bp deletion in the IPMK gene) predisposing to familial SI-NETs is apparently a private mutation, specific for one large family.	('familial SI-NETs', 'Disease', 'MESH:D009394', (92, 108))	('IPMK', 'Gene', (65, 69))	('IPMK', 'Gene', '253430', (65, 69))	('familial SI-NETs', 'Disease', (92, 108))	('4-bp deletion', 'Var', (44, 57))
12730	28634180	Moreover, in the large family reported by Sei and coworkers, only two individuals (out of 14 in the third generation with the IPMK gene mutation, Fig.	('IPMK', 'Gene', (126, 130))	('mutation', 'Var', (136, 144))	('IPMK', 'Gene', '253430', (126, 130))
12733	28634180	about 43% of clinically asymptomatic subjects (with the mutation) in this family had occult tumors, which is a very high number.	('occult tumors', 'Disease', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutation', 'Var', (56, 64))	('occult tumors', 'Disease', 'MESH:D009382', (85, 98))
12734	28634180	Thus, it appears that expressivity of the IPMK mutation in causing SI-NETs is variable and there are likely additional mutation carriers without clinical symptoms of the disease.	('mutation', 'Var', (47, 55))	('IPMK', 'Gene', '253430', (42, 46))	('IPMK', 'Gene', (42, 46))	('SI-NETs', 'Disease', 'None', (67, 74))	('SI-NETs', 'Disease', (67, 74))
12739	28634180	We have identified monoallelic germline mutations in MUTYH, involved in DNA repair following oxidative stress, which may be a candidate gene for predisposition to SI-NET.	('SI-NET', 'Disease', 'None', (163, 169))	('germline mutations', 'Var', (31, 49))	('oxidative stress', 'Phenotype', 'HP:0025464', (93, 109))	('MUTYH', 'Gene', (53, 58))	('SI-NET', 'Disease', (163, 169))
12765	28761619	Hypothyroidism was found in 33% of patients with ectopic thyroid and it was higher in patients without normal placed thyroid gland.	('Hypothyroidism', 'Disease', 'MESH:D007037', (0, 14))	('ectopic thyroid', 'Phenotype', 'HP:0100028', (49, 64))	('ectopic', 'Var', (49, 56))	('Hypothyroidism', 'Phenotype', 'HP:0000821', (0, 14))	('patients', 'Species', '9606', (35, 43))	('Hypothyroidism', 'Disease', (0, 14))	('patients', 'Species', '9606', (86, 94))
12824	28702269	Genetic testing of the RET, VHL, SDHB, and SDHD gene mutations is advocated in patients younger than fifty years.	('RET', 'Gene', (23, 26))	('SDHB', 'Gene', '6390', (33, 37))	('SDHD', 'Gene', '6392', (43, 47))	('SDHB', 'Gene', (33, 37))	('mutations', 'Var', (53, 62))	('SDHD', 'Gene', (43, 47))	('patients', 'Species', '9606', (79, 87))	('RET', 'Gene', '5979', (23, 26))	('VHL', 'Gene', (28, 31))	('VHL', 'Gene', '7428', (28, 31))
12842	27042633	Magnetic resonance showed destruction and hypersignal at T10 in the T1 sequence, and hypersignal in the T2 sequence, with significant spinal cord compression, causing edema (Figure 1, Figure 2, Figure 3, Figure 4).	('edema', 'Disease', (167, 172))	('causing', 'Reg', (159, 166))	('spinal cord compression', 'Phenotype', 'HP:0002176', (134, 157))	('hypersignal', 'Var', (42, 53))	('edema', 'Disease', 'MESH:D004487', (167, 172))	('edema', 'Phenotype', 'HP:0000969', (167, 172))	('hypersignal', 'Var', (85, 96))
12965	22708103	Second, it has been suggested that dopamine can lower blood pressure by itself.	('lower blood pressure', 'Phenotype', 'HP:0002615', (48, 68))	('dopamine', 'Chemical', 'MESH:D004298', (35, 43))	('blood pressure', 'MPA', (54, 68))	('lower', 'NegReg', (48, 53))	('dopamine', 'Var', (35, 43))
13035	19808327	Elimination of norepinephrine secretion in PC12-KO cells induced neither cardiac dilation (3.9+-1.8% increase vs. control) nor changes in (1.9+-0.4% reduction) fractional shortening compared to controls.	('PC12', 'CellLine', 'CVCL:0481', (43, 47))	('norepinephrine', 'Chemical', 'MESH:D009638', (15, 29))	('cardiac dilation', 'Disease', (73, 89))	('PC12-KO', 'Var', (43, 50))	('fractional', 'MPA', (160, 170))	('increase', 'PosReg', (101, 109))	('cardiac dilation', 'Disease', 'MESH:D002311', (73, 89))	('norepinephrine secretion', 'MPA', (15, 39))
13040	19808327	Excessive adrenergic stimulation can induce and exacerbate cardiovascular disease.	('exacerbate', 'PosReg', (48, 58))	('Excessive', 'Var', (0, 9))	('cardiovascular disease', 'Disease', (59, 81))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (59, 81))	('cardiovascular disease', 'Disease', 'MESH:D002318', (59, 81))	('induce', 'Reg', (37, 43))
13053	19808327	Rat pheochromocytoma cells (PC12, ATCC, VA) were maintained in F12K media (ATCC) with 10% horse serum (Hyclone, Logan, UT), 5% FBS (Hyclone) and 100 units/ml penicillin/streptomyocin (Invitrogen, CA).	('Rat', 'Species', '10116', (0, 3))	('F12K', 'SUBSTITUTION', 'None', (63, 67))	('F12K', 'Var', (63, 67))	('streptomyocin', 'Chemical', '-', (169, 182))	('FBS', 'Disease', 'MESH:D005198', (127, 130))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (4, 20))	('horse', 'Species', '9796', (90, 95))	('penicillin', 'Chemical', 'MESH:D010406', (158, 168))	('PC12', 'CellLine', 'CVCL:0481', (28, 32))	('pheochromocytoma', 'Disease', (4, 20))	('FBS', 'Disease', (127, 130))	('pheochromocytoma', 'Disease', 'MESH:D010673', (4, 20))
13099	19808327	Cardiac dilation was more pronounced in Pheo rats and mice (p<0.01 vs. control, p<0.01 vs. NE) compared to NE rats and mice (Figure 3A).	('Cardiac dilation', 'Disease', (0, 16))	('Cardiac dilation', 'Disease', 'MESH:D002311', (0, 16))	('mice', 'Species', '10090', (119, 123))	('rats', 'Species', '10116', (45, 49))	('Pheo', 'Chemical', '-', (40, 44))	('Pheo', 'Var', (40, 44))	('rats', 'Species', '10116', (110, 114))	('mice', 'Species', '10090', (54, 58))	('pronounced', 'PosReg', (26, 36))
13100	19808327	The hearts of Pheo rats were 47% larger than controls (p<0.01) and NE rats (p<0.01), the latter statistically indistinguishable from controls (Table 1).	('Pheo', 'Var', (14, 18))	('hearts', 'MPA', (4, 10))	('Pheo', 'Chemical', '-', (14, 18))	('larger', 'PosReg', (33, 39))	('rats', 'Species', '10116', (70, 74))	('rats', 'Species', '10116', (19, 23))
13102	19808327	Furthermore Pheo mice experienced a greater loss of cardiac function, evident in the 10.8+-1.9% (p<0.01 vs. control, p<0.05 vs. NE) decrease in fractional shortening (FS) compared to NE mice that experienced a 6.3+-2.9% (p<0.01) decrease in FS.	('loss of cardiac function', 'Phenotype', 'HP:0001635', (44, 68))	('fractional shortening', 'MPA', (144, 165))	('mice', 'Species', '10090', (17, 21))	('Pheo', 'Var', (12, 16))	('loss', 'NegReg', (44, 48))	('Pheo', 'Chemical', '-', (12, 16))	('mice', 'Species', '10090', (186, 190))	('cardiac function', 'MPA', (52, 68))	('decrease', 'NegReg', (132, 140))
13104	19808327	Of note, Pheo-KO mice did exhibit slight increase in cardiac dilation but no discernible loss of FS compared to controls (Table 2).	('mice', 'Species', '10090', (17, 21))	('Pheo', 'Chemical', '-', (9, 13))	('cardiac dilation', 'Disease', (53, 69))	('Pheo-KO', 'Var', (9, 16))	('increase', 'PosReg', (41, 49))	('cardiac dilation', 'Disease', 'MESH:D002311', (53, 69))
13105	19808327	Left ventricular end-systolic volume scaled linearly with norepinephrine levels (R2=0.916, p<0.0001) in control, pheo and pheo-KO mice but not in NE pump animals whose catecholamine levels were all at the upper limit and without correlative effect.	('Left ventricular end-systolic volume', 'MPA', (0, 36))	('mice', 'Species', '10090', (130, 134))	('catecholamine', 'Chemical', 'MESH:D002395', (168, 181))	('pheo', 'Chemical', '-', (113, 117))	('norepinephrine', 'Chemical', 'MESH:D009638', (58, 72))	('pheo', 'Chemical', '-', (122, 126))	('pheo-KO', 'Var', (122, 129))	('norepinephrine levels', 'MPA', (58, 79))
13111	19808327	This mechanism is further validated by the 96% and 36% increase in stroke volume for Pheo rats over controls and NE rats, respectively.	('stroke', 'Disease', (67, 73))	('increase', 'PosReg', (55, 63))	('rats', 'Species', '10116', (116, 120))	('stroke', 'Disease', 'MESH:D020521', (67, 73))	('rats', 'Species', '10116', (90, 94))	('Pheo', 'Var', (85, 89))	('stroke', 'Phenotype', 'HP:0001297', (67, 73))	('Pheo', 'Chemical', '-', (85, 89))
13114	19808327	Pheo-implants raised MMP3 (p<0.01), collagen-1 (p<0.05), CCL2 (p < 0.01) and reduced TIMP3 (p <0.01) mRNA levels compared to NE rats (Figure 6).	('CCL2', 'Gene', (57, 61))	('MMP3', 'Gene', '171045', (21, 25))	('collagen-1', 'MPA', (36, 46))	('Pheo-implants', 'Var', (0, 13))	('TIMP3', 'Gene', '25358', (85, 90))	('MMP3', 'Gene', (21, 25))	('rats', 'Species', '10116', (128, 132))	('reduced', 'NegReg', (77, 84))	('TIMP3', 'Gene', (85, 90))	('Pheo', 'Chemical', '-', (0, 4))	('CCL2', 'Gene', '24770', (57, 61))	('raised', 'PosReg', (14, 20))
13133	19808327	The altered balance of the cytoskeletal proteins, MMP3, TIMP3, and collagen, creates maladaptive myocardial remodeling that mediates the transition from compensated to decompensated heart failure.	('heart failure', 'Phenotype', 'HP:0001635', (182, 195))	('maladaptive myocardial remodeling', 'Disease', (85, 118))	('heart failure', 'Disease', (182, 195))	('altered', 'Var', (4, 11))	('MMP3', 'Gene', '171045', (50, 54))	('maladaptive myocardial remodeling', 'Disease', 'MESH:D020257', (85, 118))	('TIMP3', 'Gene', '25358', (56, 61))	('heart failure', 'Disease', 'MESH:D006333', (182, 195))	('TIMP3', 'Gene', (56, 61))	('MMP3', 'Gene', (50, 54))
13168	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))
13173	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))
13181	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))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('Pan-cancer', 'Disease', 'MESH:D009369', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('breast cancer', 'Disease', (39, 52))	('RING1', 'Gene', (111, 116))
13199	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))
13218	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))
13240	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))	('lose', 'NegReg', (96, 100))	('tumor', 'Disease', (81, 86))
13251	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))
13268	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))	('cell multiplication', 'CPA', (59, 78))	('promotes', 'PosReg', (32, 40))	('beta-catenin', 'Gene', (205, 217))	('beta-catenin', 'Gene', '1499', (205, 217))	('invasion', 'CPA', (83, 91))	('drives', 'PosReg', (145, 151))	('colony formation', 'CPA', (41, 57))	('activating', 'PosReg', (186, 196))	('RING1', 'Gene', (11, 16))	('malignant transformation', 'CPA', (158, 182))
13277	33644666	Cardiac paraganglioma with sulfur subunit B gene mutation: a case report Pheochromocytoma and paraganglioma is a rare disease with a prevalence of 0.2-0.6% in hypertensive patients from outpatient.	('hypertensive', 'Disease', 'MESH:D006973', (159, 171))	('Cardiac paraganglioma', 'Disease', (0, 21))	('hypertensive', 'Disease', (159, 171))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (73, 89))	('mutation', 'Var', (49, 57))	('Pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (73, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (8, 21))	('patients', 'Species', '9606', (172, 180))	('Cardiac paraganglioma', 'Disease', 'MESH:D006331', (0, 21))	('outpatient', 'Species', '9606', (186, 196))
13282	33644666	Subsequent genetic test suggested succinate dehydrogenase complex iron sulfur subunit B (SDHB) gene mutation.	('mutation', 'Var', (100, 108))	('SDHB', 'Gene', '6390', (89, 93))	('SDHB', 'Gene', (89, 93))
13285	33644666	Given a potential risk of developing malignancies, close follow-up is significant in patients with SDHB gene mutations.	('malignancies', 'Disease', (37, 49))	('SDHB', 'Gene', '6390', (99, 103))	('patients', 'Species', '9606', (85, 93))	('SDHB', 'Gene', (99, 103))	('mutations', 'Var', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))
13288	33644666	Patients with sulfur subunit B gene mutations are at high risk of developing malignancies and follow-up is required to monitoring relapse.	('sulfur subunit B', 'Gene', (14, 30))	('malignancies', 'Disease', (77, 89))	('mutations', 'Var', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
13292	33644666	Several genetic mutations such as succinate dehydrogenase complex iron sulfur subunit B (SDHB) mutations also occur in metastatic PPGL patients with increased risk for malignancy.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('patients', 'Species', '9606', (135, 143))	('malignancy', 'Disease', (168, 178))	('PPGL', 'Chemical', '-', (130, 134))	('occur', 'Reg', (110, 115))	('SDHB', 'Gene', '6390', (89, 93))	('metastatic PPGL', 'Disease', (119, 134))	('mutations', 'Var', (95, 104))	('SDHB', 'Gene', (89, 93))
13293	33644666	We herein reported a unique case of non-typical paraganglioma in heart identified with SDHB mutation.	('mutation', 'Var', (92, 100))	('paraganglioma', 'Phenotype', 'HP:0002668', (48, 61))	('paraganglioma', 'Disease', (48, 61))	('paraganglioma in heart', 'Phenotype', 'HP:0100544', (48, 70))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))	('paraganglioma', 'Disease', 'MESH:D010235', (48, 61))
13312	33644666	Immunohistochemical results presented CgA (+), S100 (+), NSE (+), CK (-), EMA (-), CD34 (-), calretinin (+), and CD68 (-).	('NSE', 'Gene', '2026', (57, 60))	('CD68', 'Var', (113, 117))	('S100', 'Gene', (47, 51))	('calretinin', 'Gene', (93, 103))	('S100', 'Gene', '6271', (47, 51))	('NSE', 'Gene', (57, 60))	('CgA', 'Gene', '1113', (38, 41))	('CD34', 'Var', (83, 87))	('CgA', 'Gene', (38, 41))	('calretinin', 'Gene', '794', (93, 103))
13313	33644666	The genetic test showed SDHB gene mutation, nucleotide mutation c.725G>A, and amino acid mutation p. Arg242His.	('c.725G>A', 'Var', (64, 72))	('Arg242His', 'Var', (101, 110))	('c.725G>A', 'Mutation', 'rs74315368', (64, 72))	('SDHB', 'Gene', '6390', (24, 28))	('SDHB', 'Gene', (24, 28))	('Arg242His', 'SUBSTITUTION', 'None', (101, 110))
13319	33644666	In addition, SDHB gene mutation was identified.	('SDHB', 'Gene', '6390', (13, 17))	('SDHB', 'Gene', (13, 17))	('mutation', 'Var', (23, 31))
13320	33644666	Previous studies have established 14 different genes susceptible in PPGLs, with SDHB mutations mainly in extra-adrenal tumours.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('SDHB', 'Gene', (80, 84))	('PPGLs', 'Chemical', '-', (68, 73))	('mutations', 'Var', (85, 94))	('adrenal tumours', 'Disease', (111, 126))	('adrenal tumours', 'Disease', 'MESH:D000310', (111, 126))	('SDHB', 'Gene', '6390', (80, 84))
13321	33644666	Of note, 30% of patients with metastatic PPGL appear with pathogenic SDHB mutations.	('SDHB', 'Gene', '6390', (69, 73))	('SDHB', 'Gene', (69, 73))	('patients', 'Species', '9606', (16, 24))	('mutations', 'Var', (74, 83))	('metastatic PPGL', 'Disease', (30, 45))	('PPGL', 'Chemical', '-', (41, 45))	('pathogenic', 'Reg', (58, 68))
13323	33644666	Remarkably, Pasini and Stratakis documented a prevalence of 36% of SDHB mutations in malignant PPGLs.	('SDHB', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('PPGLs', 'Chemical', '-', (95, 100))	('SDHB', 'Gene', '6390', (67, 71))
13324	33644666	A high risk of developing malignancy is thus implied in PPGL patients with SDHB gene mutations.	('patients', 'Species', '9606', (61, 69))	('SDHB', 'Gene', '6390', (75, 79))	('mutations', 'Var', (85, 94))	('SDHB', 'Gene', (75, 79))	('malignancy', 'Disease', (26, 36))	('malignancy', 'Disease', 'MESH:D009369', (26, 36))	('PPGL', 'Chemical', '-', (56, 60))
13325	33644666	Indeed, patients with metastatic disease should be tested for potential SDHB gene mutations.	('metastatic disease', 'Disease', (22, 40))	('SDHB', 'Gene', (72, 76))	('SDHB', 'Gene', '6390', (72, 76))	('mutations', 'Var', (82, 91))	('tested', 'Reg', (51, 57))	('patients', 'Species', '9606', (8, 16))
13409	32793847	These cases illustrate that if appropriate thyroid blockade is not performed, ETT concentrating radioiodine from mIBG can lead to falsely positive mIBG scans and unnecessary surgical procedures.	('radioiodine', 'Chemical', 'MESH:C000614965', (96, 107))	('mIBG', 'MPA', (147, 151))	('scans', 'MPA', (152, 157))	('lead to', 'Reg', (122, 129))	('mIBG', 'Chemical', '-', (113, 117))	('ETT', 'Var', (78, 81))	('mIBG', 'Chemical', '-', (147, 151))
13485	32793847	Friedman et al pointed out that in older patients there may be less concern for the long-term risk of thyroid neoplasia from the minimal amount of radiation exposure from 123I-mIBG.	('thyroid neoplasia', 'Phenotype', 'HP:0100031', (102, 119))	('thyroid neoplasia', 'Disease', 'MESH:D009369', (102, 119))	('123I-mIBG', 'Chemical', '-', (171, 180))	('123I-mIBG', 'Var', (171, 180))	('thyroid neoplasia', 'Disease', (102, 119))	('neoplasia', 'Phenotype', 'HP:0002664', (110, 119))	('patients', 'Species', '9606', (41, 49))
13522	32609829	To explore this hypothesis we applied a mass spectrometry-based method to measure 15 adrenal steroids in plasma of a cohort of patients with PPGLs compared with additional patients with primary hypertension.	('hypertension', 'Disease', (194, 206))	('hypertension', 'Phenotype', 'HP:0000822', (194, 206))	('steroids', 'Chemical', 'MESH:D013256', (93, 101))	('patients', 'Species', '9606', (127, 135))	('hypertension', 'Disease', 'MESH:D006973', (194, 206))	('PPGLs', 'Chemical', '-', (141, 146))	('patients', 'Species', '9606', (172, 180))	('PPGLs', 'Var', (141, 146))
13532	32609829	Among the patients with PPGLs, additional plasma samples were available from 100 patients at an interval between 12 and 36 months after surgical removal of tumors (88 with pheochromocytoma and 12 with paraganglioma).	('paraganglioma', 'Disease', 'MESH:D010235', (201, 214))	('PPGLs', 'Var', (24, 29))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PPGLs', 'Chemical', '-', (24, 29))	('paraganglioma', 'Phenotype', 'HP:0002668', (201, 214))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('patients', 'Species', '9606', (10, 18))	('paraganglioma', 'Disease', (201, 214))	('pheochromocytoma', 'Disease', (172, 188))	('tumors', 'Disease', (156, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (172, 188))	('pheochromocytoma', 'Disease', 'MESH:D010673', (172, 188))
13589	32609829	Cortisol has a particularly slow plasma clearance, in part due to the high proportion of the steroid that is bound to transcortin; thus, it is possible that differences in binding to transcortin could also decrease the clearance of glucocorticoids and through this action increase plasma concentrations.	('Cortisol', 'Chemical', 'MESH:D006854', (0, 8))	('increase', 'PosReg', (272, 280))	('plasma concentrations', 'MPA', (281, 302))	('differences', 'Var', (157, 168))	('binding', 'Interaction', (172, 179))	('transcortin', 'Gene', (118, 129))	('decrease', 'NegReg', (206, 214))	('transcortin', 'Gene', (183, 194))	('steroid', 'Chemical', 'MESH:D013256', (93, 100))	('increase plasma concentrations', 'Phenotype', 'HP:0020170', (272, 302))	('transcortin', 'Gene', '866', (118, 129))	('clearance of glucocorticoids', 'MPA', (219, 247))	('transcortin', 'Gene', '866', (183, 194))
13669	30952024	In the United States 90% to 95% of bladder cancers are pure UC, and the remaining 5%-10% consist of UC with aberrant differentiation or non-urothelial carcinoma.	('bladder cancers', 'Phenotype', 'HP:0009725', (35, 50))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('non-urothelial carcinoma', 'Disease', 'MESH:D002289', (136, 160))	('aberrant', 'Var', (108, 116))	('bladder cancers', 'Disease', 'MESH:D001749', (35, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('non-urothelial carcinoma', 'Disease', (136, 160))	('bladder cancers', 'Disease', (35, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
13694	29942926	Ectopic adrenocorticotropic hormone (ACTH) production is a rare cause of Cushing syndrome.	('adrenocorticotropic hormone', 'Gene', (8, 35))	('Cushing syndrome', 'Disease', 'MESH:D003480', (73, 89))	('cause', 'Reg', (64, 69))	('ACTH', 'Gene', (37, 41))	('ACTH', 'Gene', '5443', (37, 41))	('Ectopic', 'Var', (0, 7))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (73, 89))	('Cushing syndrome', 'Disease', (73, 89))	('adrenocorticotropic hormone', 'Gene', '5443', (8, 35))
13741	29942926	The majority (80%) of cases are due to oversecretion of ACTH, and the other 20% of cases originate from the adrenal glands as adenomas or, rarely, carcinomas.	('carcinomas', 'Disease', 'MESH:D002277', (147, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('originate', 'Reg', (89, 98))	('carcinomas', 'Disease', (147, 157))	('ACTH', 'Gene', '5443', (56, 60))	('oversecretion', 'Var', (39, 52))	('adenomas', 'Disease', 'MESH:D000236', (126, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('adenomas', 'Disease', (126, 134))	('ACTH', 'Gene', (56, 60))	('due to', 'Reg', (32, 38))
13787	29942926	Three were negative, including our own; one had a missense mutation in VHL that is nonpathogenic; and in the fifth case the patient refused testing.	('VHL', 'Gene', (71, 74))	('missense mutation', 'Var', (50, 67))	('patient', 'Species', '9606', (124, 131))	('VHL', 'Gene', '7428', (71, 74))
13846	25136447	The first two are associated with germline mutations in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('germline mutations', 'Var', (34, 52))	('associated', 'Reg', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
13847	25136447	VHL mutations, however, result in a pseudo-hypoxic state through decreased degradation of HIF (cluster 1 transcriptome) and PGLs are attributed to mutations in succinate dehydrogenase (SDH) subunit genes SDHB, SDHC, and SDHD that comprise portions of mitochondrial complex II.	('mutations', 'Var', (147, 156))	('SDH', 'Gene', '6390', (185, 188))	('decreased', 'NegReg', (65, 74))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('SDH', 'Gene', (210, 213))	('SDHB', 'Gene', '6390', (204, 208))	('SDHC', 'Gene', (210, 214))	('SDH', 'Gene', (185, 188))	('SDHD', 'Gene', '6392', (220, 224))	('degradation', 'MPA', (75, 86))	('PGLs', 'Phenotype', 'HP:0002668', (124, 128))	('SDH', 'Gene', '6390', (220, 223))	('succinate dehydrogenase', 'Gene', (160, 183))	('SDHB', 'Gene', (204, 208))	('VHL', 'Disease', (0, 3))	('pseudo-hypoxic state', 'MPA', (36, 56))	('SDH', 'Gene', '6390', (204, 207))	('mutations', 'Var', (4, 13))	('SDHD', 'Gene', (220, 224))	('SDH', 'Gene', '6390', (210, 213))	('SDH', 'Gene', (220, 223))	('SDHC', 'Gene', '6391', (210, 214))	('succinate dehydrogenase', 'Gene', '6390', (160, 183))	('SDH', 'Gene', (204, 207))
13850	25136447	It is caused by mutation or deletion of imprinted genes within the chromosome 11p15.5 region, which harbors the insulin-like growth factor 2 (IGF2) gene.	('insulin-like growth factor 2', 'Gene', (112, 140))	('IGF2', 'Gene', '3481', (142, 146))	('mutation', 'Var', (16, 24))	('insulin-like growth factor 2', 'Gene', '3481', (112, 140))	('IGF2', 'Gene', (142, 146))	('caused by', 'Reg', (6, 15))	('deletion', 'Var', (28, 36))
13875	25136447	Multiplex ligation-dependent probe analysis revealed no epigenetic alterations in 11p15.5, which included investigation for hypomethylation at KCNQ1OT1 and hypermethylation at ICR1, and also no 11p15.5 uniparental disomy (UPD) was found.	('ICR1', 'Gene', (176, 180))	('KCNQ1OT1', 'Gene', '10984', (143, 151))	('ICR1', 'Gene', '3388', (176, 180))	('uniparental disomy', 'Disease', (202, 220))	('hypermethylation', 'Var', (156, 172))	('KCNQ1OT1', 'Gene', (143, 151))	('uniparental disomy', 'Disease', 'MESH:D024182', (202, 220))	('hypomethylation', 'MPA', (124, 139))	('epigenetic', 'MPA', (56, 66))	('11p15.5', 'Gene', (82, 89))
13894	25136447	Screening for somatic and germline mutations in the VHL and RET genes in the adrenal tumor was also negative and methylation patterns for LIT1 (KCNQ1OT1) and H19 genes associated with BWS were normal.	('H19', 'Gene', (158, 161))	('adrenal tumor', 'Disease', 'MESH:D000310', (77, 90))	('adrenal tumor', 'Disease', (77, 90))	('KCNQ1OT1', 'Gene', '10984', (144, 152))	('BWS', 'Disease', (184, 187))	('RET', 'Gene', (60, 63))	('negative', 'NegReg', (100, 108))	('BWS', 'Disease', 'MESH:D001506', (184, 187))	('adrenal tumor', 'Phenotype', 'HP:0100631', (77, 90))	('LIT1', 'Gene', '10984', (138, 142))	('LIT1', 'Gene', (138, 142))	('RET', 'Gene', '5979', (60, 63))	('VHL', 'Disease', 'MESH:D006623', (52, 55))	('KCNQ1OT1', 'Gene', (144, 152))	('VHL', 'Disease', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('H19', 'Gene', '283120', (158, 161))	('mutations', 'Var', (35, 44))
13896	25136447	The fifth case involved early-onset bilateral pediatric pheochromocytomas caused by mosaic chromosome 11p15 paternal UPD, which was recently reported.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (56, 73))	('caused by', 'Reg', (74, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('mosaic chromosome 11p15 paternal', 'Var', (84, 116))	('bilateral pediatric pheochromocytomas', 'Disease', (36, 73))	('bilateral pediatric pheochromocytomas', 'Disease', 'MESH:D010673', (36, 73))
13906	25136447	CDKN1C mutations appear to be particularly associated with umbilical abnormalities, but not with increased predisposition to Wilms' tumor.	('umbilical abnormalities', 'Phenotype', 'HP:0001551', (59, 82))	("Wilms' tumor", 'Disease', (125, 137))	('mutations', 'Var', (7, 16))	('CDKN1C', 'Gene', '1028', (0, 6))	("Wilms' tumor", 'Phenotype', 'HP:0002667', (125, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('umbilical abnormalities', 'Disease', 'MESH:D014496', (59, 82))	('umbilical abnormalities', 'Disease', (59, 82))	('associated', 'Reg', (43, 53))	("Wilms' tumor", 'Disease', 'MESH:D009396', (125, 137))	('CDKN1C', 'Gene', (0, 6))
13907	25136447	Epigenetic factors have also been reported including UPD of 11p15, hypomethylation of KCNQ1OT1 gene, and hypermethylation of the genes H19, LIT1, and IGF2 .	('LIT1', 'Gene', '10984', (140, 144))	('LIT1', 'Gene', (140, 144))	('H19', 'Gene', '283120', (135, 138))	('UPD', 'PosReg', (53, 56))	('H19', 'Gene', (135, 138))	('IGF2', 'Gene', '3481', (150, 154))	('KCNQ1OT1', 'Gene', '10984', (86, 94))	('hypermethylation', 'Var', (105, 121))	('hypomethylation', 'Var', (67, 82))	('IGF2', 'Gene', (150, 154))	('KCNQ1OT1', 'Gene', (86, 94))	('11p15', 'Protein', (60, 65))
13908	25136447	Tested epigenetic alterations were not indicative of BWS in our patient.	('epigenetic alterations', 'Var', (7, 29))	('BWS', 'Disease', 'MESH:D001506', (53, 56))	('BWS', 'Disease', (53, 56))	('patient', 'Species', '9606', (64, 71))
13909	25136447	There may be a wide heterogeneity for epimutations regarding BWS, as the causative genetic factors are still unknown.	('BWS', 'Disease', 'MESH:D001506', (61, 64))	('BWS', 'Disease', (61, 64))	('epimutations', 'Var', (38, 50))
13917	24465590	A Conditional Mouse Mutant in the Tumor Suppressor SdhD Gene Unveils a Link between p21WAF1/Cip1 Induction and Mitochondrial Dysfunction Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors.	('MCI', 'Gene', (176, 179))	('Mutations', 'Var', (137, 146))	('SdhD', 'Gene', (51, 55))	('SdhD', 'Gene', '66925', (51, 55))	('Mouse', 'Species', '10090', (14, 19))	('MCI', 'Gene', '622408', (176, 179))	('familiar pheochromocytoma/paraganglioma tumors', 'Disease', 'MESH:D010673', (224, 270))	('Cip1', 'Gene', (92, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (233, 249))	('succinate dehydrogenase', 'Gene', (182, 205))	('paraganglioma', 'Phenotype', 'HP:0002668', (250, 263))	('familiar pheochromocytoma/paraganglioma tumors', 'Disease', (224, 270))	('Mitochondrial Dysfunction', 'Phenotype', 'HP:0003287', (111, 136))	('succinate dehydrogenase', 'Gene', '30956', (182, 205))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('cause', 'Reg', (218, 223))	('Tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Cip1', 'Gene', '12575', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))
13918	24465590	Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia-inducible factor 1alpha (Hif1alpha) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive".	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('oxygen', 'Chemical', 'MESH:D010100', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Sdh-mutation-induced', 'Var', (53, 73))	('tumor', 'Disease', (74, 79))	('hypoxia-inducible factor 1alpha', 'Gene', '15251', (163, 194))	('Sdh-mutation-induced', 'Gene', (53, 73))	('hypoxia-inducible factor 1alpha', 'Gene', (163, 194))
13925	24465590	This new and unprecedented evidence for a link between SdhD dysfunction and p21WAF1/Cip1 will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants.	('SdhD dysfunction', 'Disease', (55, 71))	('Sdh', 'Gene', (164, 167))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('p21WAF1/Cip1', 'Gene', '12575', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('p21WAF1/Cip1', 'Gene', (76, 88))	('SdhD dysfunction', 'Disease', 'MESH:D006331', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutants', 'Var', (168, 175))
13927	24465590	Germ-line mutations in the mitochondrial succinate dehydrogenase (Sdh) enzyme -also referred to as mitochondrial complex II (MCII)- or in its accessory units cause familial hereditary pheochromocytoma and paraganglioma.	('succinate dehydrogenase', 'Gene', '30956', (41, 64))	('Sdh', 'Gene', (66, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (184, 200))	('paraganglioma', 'Disease', 'MESH:D010235', (205, 218))	('MCI', 'Gene', (125, 128))	('cause', 'Reg', (158, 163))	('succinate dehydrogenase', 'Gene', (41, 64))	('MCI', 'Gene', '622408', (125, 128))	('paraganglioma', 'Phenotype', 'HP:0002668', (205, 218))	('mutations', 'Var', (10, 19))	('paraganglioma', 'Disease', (205, 218))	('familial hereditary pheochromocytoma', 'Disease', 'MESH:C531777', (164, 200))	('familial hereditary pheochromocytoma', 'Disease', (164, 200))
13932	24465590	Mutations on subunits B, C, A, as well as on the accessory protein SDHAF2, have subsequently also been implicated in paraganglioma, pheochromocytoma, renal cell carcinomas, and gastrointestinal tumors.	('pheochromocytoma', 'Disease', 'MESH:D010673', (132, 148))	('paraganglioma', 'Disease', 'MESH:D010235', (117, 130))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (150, 171))	('gastrointestinal tumors', 'Disease', (177, 200))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (177, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('pheochromocytoma', 'Disease', (132, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (132, 148))	('paraganglioma', 'Phenotype', 'HP:0002668', (117, 130))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('implicated in', 'Reg', (103, 116))	('SDHAF2', 'Gene', '66072', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (150, 170))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (177, 200))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (150, 171))	('SDHAF2', 'Gene', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('renal cell carcinomas', 'Disease', (150, 171))	('paraganglioma', 'Disease', (117, 130))
13933	24465590	Several mechanisms have been proposed to account for the tumorigenic role of MCII mutations.	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MCI', 'Gene', (77, 80))	('mutations', 'Var', (82, 91))	('MCI', 'Gene', '622408', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
13938	24465590	Hence, inhibition of PHDs could prevent Hif1alpha degradation in normoxic conditions, a situation termed to as "pseudo-hypoxia", which would favor tumor formation and progression.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('favor', 'PosReg', (141, 146))	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))	('progression', 'CPA', (167, 178))	('hypoxia', 'Disease', (119, 126))	('degradation', 'MPA', (50, 61))	('inhibition', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Hif1alpha', 'Protein', (40, 49))	('prevent', 'NegReg', (32, 39))
13940	24465590	Thus, impairment of electron transfer at MCII would lead to electron leakage and/or possibly to a biased accumulation of the semi-reduced form of ubiquinone, which ultimately may contribute to mitochondrial reactive oxygen species (ROS) generation.	('impairment', 'Var', (6, 16))	('electron leakage', 'MPA', (60, 76))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (207, 230))	('semi-reduced form of ubiquinone', 'MPA', (125, 156))	('contribute', 'Reg', (179, 189))	('MCI', 'Gene', '622408', (41, 44))	('ROS', 'Chemical', 'MESH:D017382', (232, 235))	('accumulation', 'PosReg', (105, 117))	('ubiquinone', 'Chemical', 'MESH:D014451', (146, 156))	('mitochondrial reactive oxygen species', 'MPA', (193, 230))	('lead to', 'Reg', (52, 59))	('electron transfer', 'MPA', (20, 37))	('MCI', 'Gene', (41, 44))
13948	24465590	Conditional and tissue-specific SdhD mutant strains generated by our group also failed to show an increased predisposition to tumor occurrence.	('mutant', 'Var', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SdhD', 'Gene', (32, 36))	('tumor', 'Disease', (126, 131))
13950	24465590	In patients, tumor formation in heterozygous, paternally inherited SDHD-mutation carriers requires the loss of the maternal allele in a phenomenon known as loss of heterozygosity.	('tumor', 'Disease', (13, 18))	('SDHD-mutation', 'Gene', (67, 80))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('SDHD-mutation', 'Var', (67, 80))
13956	24465590	Additionally, and given that none of the hypothesis has been definitively established, we performed large-scale gene expression analysis in SDHD-ESR adrenal medulla and kidney tissue soon after SdhD deletion.	('ESR', 'Gene', (145, 148))	('ESR', 'Gene', '109755', (145, 148))	('deletion', 'Var', (199, 207))	('SdhD', 'Gene', (194, 198))
13979	24465590	For immortalization, BMK cells were electroporated with the plasmids pCMVE1A containing the viral oncogene E1A, and p53DD containing a dominant negative mutant allele of p53 (kindly gifted by Dr. Eileen White) according to a previously reported protocol.	('negative', 'NegReg', (144, 152))	('p53', 'Gene', '22060', (116, 119))	('p53', 'Gene', (170, 173))	('mutant', 'Var', (153, 159))	('p53', 'Gene', '22060', (170, 173))	('p53', 'Gene', (116, 119))
13988	24465590	The microarrays were scanned in a GenePix  reader, with data acquired at wavelengths of 635 nm and 532 nm for Cy3 and Cy5, respectively.	('Cy3', 'Chemical', '-', (110, 113))	('Cy5', 'Chemical', '-', (118, 121))	('Cy3', 'Var', (110, 113))	('Cy5', 'Var', (118, 121))
14003	24465590	This tamoxifen dose-dependency was translated to the general phenotype of mutant SDHD-ESR individuals as these animals stopped gaining weight after administration of the drug, and with the higher dose, even lost weight after two weeks (Figure 1C).	('stopped', 'NegReg', (119, 126))	('gaining weight', 'Phenotype', 'HP:0004324', (127, 141))	('ESR', 'Gene', '109755', (86, 89))	('stopped gaining weight', 'Phenotype', 'HP:0001508', (119, 141))	('lost', 'NegReg', (207, 211))	('mutant', 'Var', (74, 80))	('ESR', 'Gene', (86, 89))	('gaining weight', 'MPA', (127, 141))	('tamoxifen', 'Chemical', 'MESH:D013629', (5, 14))
14005	24465590	Low-dose tamoxifen-treated mutants, although surviving longer than the high-dose treated animals, still had a shorter average life-span (7 weeks) than their wild-type littermates (Figure 1D).	('mutants', 'Var', (27, 34))	('shorter', 'NegReg', (110, 117))	('tamoxifen', 'Chemical', 'MESH:D013629', (9, 18))
14006	24465590	Since the treatment with the low dose of tamoxifen casts doubt about the efficient deletion of SdhD in all the tissues, the rest of experiments shown here were performed with the high dose.	('SdhD', 'Gene', (95, 99))	('tamoxifen', 'Chemical', 'MESH:D013629', (41, 50))	('deletion', 'Var', (83, 91))
14007	24465590	To address the possible activation of the "pseudo-hypoxic drive" mechanism, the expression of several HIF1alpha target genes was analyzed in wild-type (homozygous; +/+), heterozygous (+/-) and SDHD-ESR mutant tissues.	('HIF1alpha', 'Gene', (102, 111))	('ESR', 'Gene', (198, 201))	('HIF1alpha', 'Gene', '15251', (102, 111))	('ESR', 'Gene', '109755', (198, 201))	('mutant', 'Var', (202, 208))
14010	24465590	However, when the remaining functional copy of SdhD was deleted, a significant induction of Vegf was observed in the SDHD-ESR kidney only three weeks after the start of injections, whereas for Glut1 and Phd3 their mRNA levels did not significantly increase further (Figure 2B).	('SDHD-ESR kidney', 'Disease', 'MESH:D007674', (117, 132))	('SdhD', 'Gene', (47, 51))	('SDHD-ESR kidney', 'Disease', (117, 132))	('induction', 'PosReg', (79, 88))	('Glut1', 'Gene', (193, 198))	('deleted', 'Var', (56, 63))	('Vegf', 'Gene', '22339', (92, 96))	('Glut1', 'Gene', '20512', (193, 198))	('Vegf', 'Gene', (92, 96))
14013	24465590	Together, these data suggest that activation of "pseudo-hypoxic drive" as a consequence of MCII depletion does not take place in a general and obvious manner in the analyzed mouse tissues.	('MCI', 'Gene', (91, 94))	('MCI', 'Gene', '622408', (91, 94))	('depletion', 'Var', (96, 105))	('mouse', 'Species', '10090', (174, 179))
14014	24465590	As the diffusion kinetics of the drug throughout the mouse tissues could expand the SdhD deletion on time, thus hampering the detection of transitory Hif1alpha stabilization and the transcriptional activation of its target genes, we decided to establish cell lines from the SDHD-ESR mouse in which the accessibility of the cells to the drug is better controlled.	('SdhD', 'Gene', (84, 88))	('detection', 'MPA', (126, 135))	('ESR', 'Gene', '109755', (279, 282))	('deletion', 'Var', (89, 97))	('mouse', 'Species', '10090', (283, 288))	('hampering', 'NegReg', (112, 121))	('mouse', 'Species', '10090', (53, 58))	('transcriptional', 'MPA', (182, 197))	('ESR', 'Gene', (279, 282))
14019	24465590	Whereas in heterozygous lines no differences were found in either Hif1alpha or Glut1 protein levels with respect to the wild type, the SDHD-ESR mutant line underwent accumulation of both proteins, although with different kinetics of induction (Figure 3A-D).	('Glut1', 'Gene', '20512', (79, 84))	('ESR', 'Gene', '109755', (140, 143))	('ESR', 'Gene', (140, 143))	('accumulation', 'PosReg', (166, 178))	('mutant', 'Var', (144, 150))	('Glut1', 'Gene', (79, 84))	('Hif1alpha', 'MPA', (66, 75))
14022	24465590	With the aim of identifying alternative molecular pathways altered upon SdhD deletion, and to determine if some tissue-specific features could condition the transcriptional response to MCII depletion, we performed high-throughput gene expression analysis of kidney and adrenal medulla tissue.	('altered', 'Reg', (59, 66))	('MCI', 'Gene', '622408', (185, 188))	('deletion', 'Var', (77, 85))	('transcriptional', 'MPA', (157, 172))	('SdhD', 'Gene', (72, 76))	('MCI', 'Gene', (185, 188))
14024	24465590	The kidney was chosen not only because of the more intense effect on SdhD deletion exerted by tamoxifen, but also due to the finding that renal cell carcinoma, although much less frequently, is also associated with Sdh-mutations.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('associated', 'Reg', (199, 209))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (138, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('deletion', 'Var', (74, 82))	('Sdh-mutations', 'Gene', (215, 228))	('SdhD', 'Gene', (69, 73))	('tamoxifen', 'Chemical', 'MESH:D013629', (94, 103))	('renal cell carcinoma', 'Disease', (138, 158))
14034	24465590	Among them, Cdkn1a was significantly up-regulated and showed a log ratio of intensities >=1 in both the adrenal medulla and kidney of the SDHD-ESR mutant (table 2).	('mutant', 'Var', (147, 153))	('ESR', 'Gene', '109755', (143, 146))	('Cdkn1a', 'Gene', '12575', (12, 18))	('up-regulated', 'PosReg', (37, 49))	('Cdkn1a', 'Gene', (12, 18))	('ESR', 'Gene', (143, 146))
14037	24465590	In both cell types, p21WAF/Cip expression was strongly up-regulated in the mutant SDHD-ESR cell lines 4 hours after tamoxifen-induced SdhD deletion, and the amount of protein remained increased after 24 hours (Figure 6).	('up-regulated', 'PosReg', (55, 67))	('ESR', 'Gene', (87, 90))	('deletion', 'Var', (139, 147))	('Cip', 'Gene', '69642', (27, 30))	('tamoxifen', 'Chemical', 'MESH:D013629', (116, 125))	('increased', 'PosReg', (184, 193))	('p21WAF', 'Gene', (20, 26))	('SdhD', 'Gene', (134, 138))	('ESR', 'Gene', '109755', (87, 90))	('Cip', 'Gene', (27, 30))	('mutant', 'Var', (75, 81))	('p21WAF', 'Gene', '12575', (20, 26))
14038	24465590	In this study, we aimed to identify the molecular events triggered after the second hit of the process of MCII mutation-induced tumorigenesis by inducing loss of the second SdhD allele in vivo.	('mutation-induced', 'Var', (111, 127))	('SdhD', 'Gene', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('MCI', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inducing', 'Reg', (145, 153))	('tumor', 'Disease', (128, 133))	('loss', 'NegReg', (154, 158))	('MCI', 'Gene', '622408', (106, 109))
14048	24465590	Thus, any subsequent molecular event that causes the cell division machinery to by-pass this checkpoint would drive the cells to replicative catastrophe, accumulating mutations and eventually resulting in tumor transformation.	('resulting in', 'Reg', (192, 204))	('accumulating', 'PosReg', (154, 166))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mutations', 'Var', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('drive', 'Reg', (110, 115))	('replicative catastrophe', 'MPA', (129, 152))
14049	24465590	Previous reports in humans, based on gene expression profiling and unsupervised hierarchical clustering, demonstrate a tight association between pheochromocytomas with VHL and SDH mutations, which distinguishes them from pheochromocytomas with MEN2, RET, and NF1 mutations.	('RET', 'Gene', (250, 253))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (145, 162))	('VHL', 'Disease', 'MESH:D006623', (168, 171))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (221, 238))	('mutations', 'Var', (180, 189))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('VHL', 'Disease', (168, 171))	('NF1', 'Gene', (259, 262))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (221, 237))	('SDH', 'Gene', '6390', (176, 179))	('NF1', 'Gene', '4763', (259, 262))	('pheochromocytomas', 'Disease', 'MESH:D010673', (145, 162))	('pheochromocytomas', 'Disease', 'MESH:D010673', (221, 238))	('RET', 'Gene', '5979', (250, 253))	('pheochromocytomas', 'Disease', (145, 162))	('humans', 'Species', '9606', (20, 26))	('pheochromocytomas', 'Disease', (221, 238))	('SDH', 'Gene', (176, 179))
14054	24465590	It could be that the shorter life-span resulting from administration of the minimal effective dose of tamoxifen, i. e., the minimal amount tested to cause reliable deletion of the SdhD gene, does not allow subsequent tumorigenic events to occur.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tamoxifen', 'Chemical', 'MESH:D013629', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('SdhD', 'Gene', (180, 184))	('deletion', 'Var', (164, 172))
14062	24465590	It is also worth noting a study by Young et al., in which acute inactivation of pVHL -the ubiquitin ligase part of the proteasome that downregulates Hif1alpha under normoxic conditions- caused a senescent-like phenotype in MEFs, with overexpression of p27, another cyclin-kinase inhibitor.	('inactivation', 'Var', (64, 76))	('p27', 'Gene', '12576', (252, 255))	('caused', 'Reg', (186, 192))	('pVHL', 'Gene', (80, 84))	('Hif1alpha', 'Protein', (149, 158))	('MEFs', 'CellLine', 'CVCL:9115', (223, 227))	('downregulates', 'NegReg', (135, 148))	('senescent-like phenotype', 'CPA', (195, 219))	('overexpression', 'PosReg', (234, 248))	('pVHL', 'Gene', '22346', (80, 84))	('p27', 'Gene', (252, 255))
14073	24465590	One striking issue regarding tumors caused by mutations in MCII or associated proteins concerns tissue specificity.	('MCI', 'Gene', (59, 62))	('MCI', 'Gene', '622408', (59, 62))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('caused', 'Reg', (36, 42))	('proteins', 'Protein', (78, 86))
14076	24465590	The identification of p21WAF1/Cip1 as one molecule that responds in a general manner to complete SdhD deletion, together with its critical role in the cell cycle, senescence, and DNA integrity, paints a new picture of the molecular and cellular responses that take place after MCII dysfunction.	('p21WAF1/Cip1', 'Gene', (22, 34))	('MCII dysfunction', 'Disease', 'MESH:D006331', (277, 293))	('deletion', 'Var', (102, 110))	('p21WAF1/Cip1', 'Gene', '12575', (22, 34))	('SdhD', 'Gene', (97, 101))	('MCII dysfunction', 'Disease', (277, 293))
14084	31332495	However, PPGLs related to VHL and HIF2A mutations remain an exception to the rule and should be explored first by [18F]FDOPA.	('VHL', 'Gene', (26, 29))	('HIF2A', 'Gene', '2034', (34, 39))	('FDOPA', 'Chemical', 'MESH:C043437', (119, 124))	('VHL', 'Gene', '7428', (26, 29))	('mutations', 'Var', (40, 49))	('HIF2A', 'Gene', (34, 39))	('PPGLs', 'Chemical', '-', (9, 14))
14085	31332495	For sporadic phaeochromocytomas or those associated with mutations in NF1/RET/MAX, the use of [18F]FDOPA rather than [68Ga]SSTs is proposed, mainly due to the optimal tumourto-adrenal uptake ratio that facilitate their detection.	('NF1', 'Gene', '4763', (70, 73))	('associated', 'Reg', (41, 51))	('RET', 'Gene', (74, 77))	('tumourto-adrenal', 'Disease', (167, 183))	('FDOPA', 'Chemical', 'MESH:C043437', (99, 104))	('tumourto-adrenal', 'Disease', 'MESH:D000310', (167, 183))	('sporadic phaeochromocytomas', 'Disease', (4, 31))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (4, 31))	('RET', 'Gene', '5979', (74, 77))	('mutations', 'Var', (57, 66))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('NF1', 'Gene', (70, 73))
14088	31332495	They recommend using [18F]FDOPA or [68Ga]SSTs PET/CT as first intention in all situations (diagnosis, post-treatment evaluation, staging, suspicion of relapse), while highlighting the superiority of [68Ga]SSTs in SDHD-related head and neck PPGLs.	('[68Ga]SSTs', 'Var', (199, 209))	('PPGLs', 'Chemical', '-', (240, 245))	('[68Ga]', 'Var', (35, 41))	('FDOPA', 'Chemical', 'MESH:C043437', (26, 31))
14090	32460727	Identification of a novel SDHB c.563 T > C mutation responsible for Paraganglioma syndrome and genetic analysis of the SDHB gene in China: a case report Pheochromocytoma/paraganglioma (PPGL) is a rare neuroendocrine tumor.	('SDHB', 'Gene', (26, 30))	('SDHB', 'Gene', (119, 123))	('Pheochromocytoma/paraganglioma', 'Disease', (153, 183))	('PPGL', 'Chemical', '-', (185, 189))	('Paraganglioma', 'Phenotype', 'HP:0002668', (68, 81))	('neuroendocrine tumor', 'Disease', (201, 221))	('c.563 T > C', 'Var', (31, 42))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (201, 221))	('responsible', 'Reg', (52, 63))	('Paraganglioma syndrome', 'Disease', (68, 90))	('Pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (153, 183))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (153, 169))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (201, 221))	('paraganglioma', 'Phenotype', 'HP:0002668', (170, 183))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('PGL', 'Phenotype', 'HP:0002668', (186, 189))	('Paraganglioma syndrome', 'Disease', 'MESH:D010235', (68, 90))	('SDHB', 'Gene', '6390', (119, 123))	('SDHB', 'Gene', '6390', (26, 30))
14092	32460727	SDHB mutations play an important role in PPGL.	('PPGL', 'Disease', (41, 45))	('mutations', 'Var', (5, 14))	('role', 'Reg', (33, 37))	('SDHB', 'Gene', '6390', (0, 4))	('PGL', 'Phenotype', 'HP:0002668', (42, 45))	('PPGL', 'Chemical', '-', (41, 45))	('SDHB', 'Gene', (0, 4))
14094	32460727	We report a case of a 23-year-old woman with paraganglioma (PGL) caused by a novel missense SDHB mutation, c.563 T > C (p.Leu188Pro), who presented with paroxysmal hypertension.	('paroxysmal hypertension', 'Disease', (153, 176))	('p.Leu188Pro', 'SUBSTITUTION', 'None', (120, 131))	('PGL', 'Phenotype', 'HP:0002668', (60, 63))	('SDHB', 'Gene', '6390', (92, 96))	('paroxysmal hypertension', 'Disease', 'MESH:D006973', (153, 176))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('SDHB', 'Gene', (92, 96))	('woman', 'Species', '9606', (34, 39))	('paraganglioma', 'Disease', (45, 58))	('p.Leu188Pro', 'Var', (120, 131))	('paroxysmal hypertension', 'Phenotype', 'HP:0000875', (153, 176))	('hypertension', 'Phenotype', 'HP:0000822', (164, 176))	('caused by', 'Reg', (65, 74))	('paraganglioma', 'Disease', 'MESH:D010235', (45, 58))
14096	32460727	In addition, we searched the literature related to variations in SDHB genes in Chinese patients with PPGL using multiple online databases, including PubMed, China Hospital Knowledge Database and Wanfang Data.	('PPGL', 'Chemical', '-', (101, 105))	('PGL', 'Phenotype', 'HP:0002668', (102, 105))	('variations', 'Var', (51, 61))	('SDHB', 'Gene', '6390', (65, 69))	('PPGL', 'Disease', (101, 105))	('patients', 'Species', '9606', (87, 95))	('SDHB', 'Gene', (65, 69))
14099	32460727	The common genetic alterations of SDHB in China were c.136C > T (11.4%), c.18C > A (11.4%) and c.725G > A (8.5%).	('c.18C > A', 'Var', (73, 82))	('c.136C > T', 'Var', (53, 63))	('c.725G > A', 'Var', (95, 105))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))
14100	32460727	Some carriers of SDHB mutations (28.1%) developed metastatic PPGL, and a high frequency of head and neck PGLs (HNPGLs) (59.4%) was reported.	('PGL', 'Phenotype', 'HP:0002668', (113, 116))	('SDHB', 'Gene', '6390', (17, 21))	('PGL', 'Phenotype', 'HP:0002668', (62, 65))	('metastatic PPGL', 'Disease', (50, 65))	('high frequency of head', 'Phenotype', 'HP:0000256', (73, 95))	('PPGL', 'Chemical', '-', (61, 65))	('mutations', 'Var', (22, 31))	('HNPGLs', 'Chemical', '-', (111, 117))	('SDHB', 'Gene', (17, 21))	('PGL', 'Phenotype', 'HP:0002668', (105, 108))	('developed', 'Reg', (40, 49))
14101	32460727	We describe a classic case with a novel SDHB c.563 T > C mutation.	('c.563 T > C mutation', 'Var', (45, 65))	('SDHB', 'Gene', '6390', (40, 44))	('SDHB', 'Gene', (40, 44))
14102	32460727	Based on our literature review, common SDHB gene mutations in Chinese PPGL patients are c.136C > T, c.18C > A and c.725G > A. Paraganglioma (PGL) and pheochromocytoma (PCC) are also referred to as pheochromocytoma/paraganglioma (PPGL), which are rare neuroendocrine tumors.	('pheochromocytoma', 'Disease', (197, 213))	('SDHB', 'Gene', '6390', (39, 43))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (251, 272))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (197, 213))	('PGL', 'Phenotype', 'HP:0002668', (230, 233))	('PGL', 'Phenotype', 'HP:0002668', (141, 144))	('PCC', 'Phenotype', 'HP:0002666', (168, 171))	('paraganglioma', 'Phenotype', 'HP:0002668', (214, 227))	('c.136C > T', 'Var', (88, 98))	('c.725G > A.', 'Var', (114, 125))	('SDHB', 'Gene', (39, 43))	('Paraganglioma', 'Disease', 'MESH:D010235', (126, 139))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (251, 272))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('PPGL', 'Chemical', '-', (229, 233))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('pheochromocytoma', 'Disease', 'MESH:D010673', (150, 166))	('pheochromocytoma/paraganglioma', 'Disease', (197, 227))	('neuroendocrine tumors', 'Disease', (251, 272))	('Paraganglioma', 'Phenotype', 'HP:0002668', (126, 139))	('PPGL', 'Chemical', '-', (70, 74))	('Paraganglioma', 'Disease', (126, 139))	('pheochromocytoma', 'Disease', (150, 166))	('c.18C > A', 'Var', (100, 109))	('pheochromocytoma', 'Disease', 'MESH:D010673', (197, 213))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (150, 166))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (251, 271))	('PGL', 'Phenotype', 'HP:0002668', (71, 74))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (197, 227))
14109	32460727	In many cases, SDHB-related disease is characterized by a single tumor, and carriers of gene variants commonly develop extra-adrenal PGLs, PCCs and metastatic disease than do carriers of mutations in the other SDH subunits.	('SDH', 'Gene', '6390', (210, 213))	('SDHB', 'Gene', '6390', (15, 19))	('PCCs and metastatic disease', 'Disease', 'MESH:C538445', (139, 166))	('PGL', 'Phenotype', 'HP:0002668', (133, 136))	('tumor', 'Disease', (65, 70))	('PCC', 'Phenotype', 'HP:0002666', (139, 142))	('SDHB', 'Gene', (15, 19))	('variants', 'Var', (93, 101))	('SDH', 'Gene', (210, 213))	('extra-adrenal PGLs', 'Disease', (119, 137))	('develop', 'PosReg', (111, 118))	('SDH', 'Gene', '6390', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SDH', 'Gene', (15, 18))
14112	32460727	The aims of the study are to report a novel SDHB c.563 T > C mutation and to investigate SDHB variations in Chinese PPGL patients.	('SDHB', 'Gene', '6390', (44, 48))	('c.563 T > C', 'Var', (49, 60))	('PPGL', 'Chemical', '-', (116, 120))	('SDHB', 'Gene', (44, 48))	('SDHB', 'Gene', '6390', (89, 93))	('PGL', 'Phenotype', 'HP:0002668', (117, 120))	('patients', 'Species', '9606', (121, 129))	('SDHB', 'Gene', (89, 93))
14113	32460727	Therefore, we collected all literature related to SDHB variations in PPGL in Chinese people.	('SDHB', 'Gene', (50, 54))	('variations', 'Var', (55, 65))	('people', 'Species', '9606', (85, 91))	('PPGL', 'Gene', (69, 73))	('PGL', 'Phenotype', 'HP:0002668', (70, 73))	('PPGL', 'Chemical', '-', (69, 73))	('SDHB', 'Gene', '6390', (50, 54))
14126	32460727	Genetic testing demonstrated that the patient carried a missense mutation in exon 6 of the SDHB gene [c.563 T > C] (Fig.	('[c.563 T > C]', 'Var', (101, 114))	('SDHB', 'Gene', '6390', (91, 95))	('SDHB', 'Gene', (91, 95))	('patient', 'Species', '9606', (38, 45))
14132	32460727	Our study reports a novel SDHB c.563 T > C mutation.	('SDHB', 'Gene', (26, 30))	('c.563 T > C', 'Var', (31, 42))	('SDHB', 'Gene', '6390', (26, 30))
14133	32460727	To date, Human Gene Mutation Database (HGDM, http://www.hgmd.cf.ac.uk/) includes 254 SDHB gene mutations, but the c.563 T > C variant has not been reported.	('Human', 'Species', '9606', (9, 14))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('mutations', 'Var', (95, 104))
14140	32460727	In addition, 9/32 (28.1%) carriers of SDHB mutations developed metastatic PPGL, including 5 cases of head and neck paragangliomas (HNPGLs), 1 case of PCC and 3 cases of extra-adrenal sympathetic paraganglioma (sPGL).	('HNPGLs', 'Chemical', '-', (131, 137))	('PPGL', 'Chemical', '-', (74, 78))	('neck paragangliomas', 'Disease', 'MESH:D010235', (110, 129))	('SDHB', 'Gene', '6390', (38, 42))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (110, 129))	('developed', 'Reg', (53, 62))	('PGL', 'Phenotype', 'HP:0002668', (133, 136))	('PCC', 'Phenotype', 'HP:0002666', (150, 153))	('SDHB', 'Gene', (38, 42))	('PGL', 'Phenotype', 'HP:0002668', (211, 214))	('PGL', 'Phenotype', 'HP:0002668', (75, 78))	('metastatic PPGL', 'Disease', (63, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (195, 208))	('paraganglioma', 'Phenotype', 'HP:0002668', (115, 128))	('paragangliomas', 'Phenotype', 'HP:0002668', (115, 129))	('neck paragangliomas', 'Disease', (110, 129))	('adrenal sympathetic paraganglioma', 'Disease', (175, 208))	('mutations', 'Var', (43, 52))	('adrenal sympathetic paraganglioma', 'Disease', 'MESH:D010236', (175, 208))
14141	32460727	Although previous studies have shown much higher rates for the development of sPGLs (approximately 60%), the frequency of HNPGLs among SDHB mutation carriers was high in our study, at approximately 59.4%.	('SDHB', 'Gene', '6390', (135, 139))	('HNPGLs', 'Chemical', '-', (122, 128))	('mutation', 'Var', (140, 148))	('sPGLs', 'Chemical', '-', (78, 83))	('SDHB', 'Gene', (135, 139))	('PGL', 'Phenotype', 'HP:0002668', (79, 82))	('PGL', 'Phenotype', 'HP:0002668', (124, 127))
14142	32460727	Recently, French and Dutch groups published mutation studies of SDHB with proportions similar to those reported in our study, and the prevalence rates of PCC and sPGLs in their studies were 1.6 and 6.5% or 2.1 and 13.4%, respectively.	('mutation', 'Var', (44, 52))	('SDHB', 'Gene', '6390', (64, 68))	('SDHB', 'Gene', (64, 68))	('PCC', 'Phenotype', 'HP:0002666', (154, 157))	('PGL', 'Phenotype', 'HP:0002668', (163, 166))	('sPGLs', 'Chemical', '-', (162, 167))
14144	32460727	In addition, our review includes three HNPGL studies, which may increase the proportion of HNPGLs among SDHB mutation carriers.	('HNPGLs', 'Chemical', '-', (91, 97))	('mutation', 'Var', (109, 117))	('PGL', 'Phenotype', 'HP:0002668', (41, 44))	('SDHB', 'Gene', '6390', (104, 108))	('HNPGLs', 'Disease', (91, 97))	('PGL', 'Phenotype', 'HP:0002668', (93, 96))	('SDHB', 'Gene', (104, 108))
14145	32460727	In our study, 9/32 (28.1%) SDHB mutation carriers developed metastatic PGL/PCC, which included 5 cases of HNPGLs, 1 case of PCC and 3 cases of sPGLs.	('PCC', 'Phenotype', 'HP:0002666', (124, 127))	('metastatic PGL/PCC', 'Disease', (60, 78))	('PCC', 'Phenotype', 'HP:0002666', (75, 78))	('SDHB', 'Gene', (27, 31))	('SDHB', 'Gene', '6390', (27, 31))	('PGL', 'Phenotype', 'HP:0002668', (144, 147))	('HNPGLs', 'Chemical', '-', (106, 112))	('developed', 'Reg', (50, 59))	('sPGLs', 'Chemical', '-', (143, 148))	('PGL', 'Phenotype', 'HP:0002668', (108, 111))	('mutation', 'Var', (32, 40))	('PGL', 'Phenotype', 'HP:0002668', (71, 74))
14146	32460727	Some have proposed that selection bias in referral-based studies is a major reason for a very high rate of malignant PGL in SDHB mutation carriers.	('SDHB', 'Gene', (124, 128))	('PGL', 'Phenotype', 'HP:0002668', (117, 120))	('SDHB', 'Gene', '6390', (124, 128))	('mutation', 'Var', (129, 137))
14151	32460727	Moreover, a recent study reported that patients with SDH mutation have a higher risk of later development of metachronous tumors and recurrence than do patients without mutation in this gene.	('mutation', 'Var', (57, 65))	('SDH', 'Gene', (53, 56))	('metachronous tumors', 'Disease', 'MESH:D016609', (109, 128))	('patients', 'Species', '9606', (39, 47))	('recurrence', 'CPA', (133, 143))	('SDH', 'Gene', '6390', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('metachronous tumors', 'Disease', (109, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('patients', 'Species', '9606', (152, 160))
14152	32460727	In summary, radiological screening is very important among carriers of SDHB mutations, and follow-up of those patients, especially the head and neck region, should be undertaken.	('SDHB', 'Gene', '6390', (71, 75))	('SDHB', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))	('patients', 'Species', '9606', (110, 118))
14153	32460727	Of the 35 SDHB gene variants, we found 25 different mutations, and SDHB pathogenic mutations included missense mutations (n = 10), nonsense mutations (n = 6), frameshift mutations (n = 4), splice site mutations (n = 3), synonymous mutations (n = 1), and deletions of one or more exons (n = 1).	('mutations', 'Var', (83, 92))	('missense mutations', 'Var', (102, 120))	('variants', 'Var', (20, 28))	('SDHB', 'Gene', '6390', (67, 71))	('frameshift mutations', 'Var', (159, 179))	('nonsense mutations', 'Var', (131, 149))	('synonymous mutations', 'Var', (220, 240))	('splice site mutations', 'Var', (189, 210))	('SDHB', 'Gene', (67, 71))	('deletions of', 'Var', (254, 266))	('SDHB', 'Gene', '6390', (10, 14))	('SDHB', 'Gene', (10, 14))
14154	32460727	Common genetic alterations of SDHB in Chinese patients included c.136C > T (11.4%), c.18C > A (11.4%) and c.725G > A (8.5%).	('patients', 'Species', '9606', (46, 54))	('SDHB', 'Gene', '6390', (30, 34))	('c.18C > A', 'Var', (84, 93))	('SDHB', 'Gene', (30, 34))	('c.136C > T', 'Var', (64, 74))	('c.725G > A', 'Var', (106, 116))
14155	32460727	The c.136C > T (p.R46X) mutation and the c.725G > A (p.R242H) mutation occur in the first highly conserved (I44Y45R46) motif of SDHB and the second (L240Y241R240) motif, which are essential for incorporation of the Fe-S cluster into SDHB.	('SDHB', 'Gene', (128, 132))	('p.R46X', 'SUBSTITUTION', 'None', (16, 22))	('I44Y45R46', 'Var', (108, 117))	('p.R242H', 'SUBSTITUTION', 'None', (53, 60))	('SDHB', 'Gene', '6390', (128, 132))	('SDHB', 'Gene', '6390', (233, 237))	('Fe-S', 'Chemical', 'MESH:D007501', (215, 219))	('p.R242H', 'Var', (53, 60))	('SDHB', 'Gene', (233, 237))	('p.R46X', 'Var', (16, 22))	('c.725G > A', 'Var', (41, 51))	('c.136C > T', 'Var', (4, 14))
14156	32460727	Fe-S clusters are vitally important to electron transport and function, and this mutation completely abrogates SDH activity.	('abrogates', 'NegReg', (101, 110))	('Fe-S', 'Chemical', 'MESH:D007501', (0, 4))	('SDH', 'Gene', '6390', (111, 114))	('mutation', 'Var', (81, 89))	('activity', 'MPA', (115, 123))	('SDH', 'Gene', (111, 114))
14157	32460727	However, the c.18C > A (p.A6A) mutation is a synonymous mutation, and 3/4 of carriers of this variation have metastatic disease.	('p.A6A', 'Var', (24, 29))	('metastatic disease', 'Disease', (109, 127))	('c.18C > A', 'Var', (13, 22))	('p.A6A', 'SUBSTITUTION', 'None', (24, 29))
14158	32460727	Thus, we suggest that c.18C > A may be one of the phenotypic causes of HNPGLs.	('HNPGLs', 'Chemical', '-', (71, 77))	('c.18C > A', 'Var', (22, 31))	('PGL', 'Phenotype', 'HP:0002668', (73, 76))	('HNPGLs', 'Disease', (71, 77))
14159	32460727	Interestingly, in our results, three frameshift mutations (c.757delT, c.20-22delinsC and c.112delC) were associated with metastatic disease.	('c.20-22del', 'DELETION', 'None', (70, 80))	('c.112delC', 'Var', (89, 98))	('c.757delT', 'DELETION', 'None', (59, 68))	('c.757delT', 'Var', (59, 68))	('c.20-22del', 'Var', (70, 80))	('associated', 'Reg', (105, 115))	('metastatic disease', 'Disease', (121, 139))	('c.112delC', 'DELETION', 'None', (89, 98))
14160	32460727	This change may render PPGL caused by frameshift mutations prone to metastasis, which highlights the necessity of follow-up for those patients.	('PPGL', 'Disease', (23, 27))	('frameshift mutations', 'Var', (38, 58))	('PPGL', 'Chemical', '-', (23, 27))	('patients', 'Species', '9606', (134, 142))	('PGL', 'Phenotype', 'HP:0002668', (24, 27))	('metastasis', 'CPA', (68, 78))	('prone', 'Reg', (59, 64))
14161	32460727	On the other hand, we did not perform genomic analysis of family members, which limits our ability to assess the association of PPGL morbidity with SDHB mutations.	('SDHB', 'Gene', (148, 152))	('mutations', 'Var', (153, 162))	('PGL', 'Phenotype', 'HP:0002668', (129, 132))	('SDHB', 'Gene', '6390', (148, 152))	('PPGL', 'Chemical', '-', (128, 132))
14162	32460727	Moreover, without functional studies, we cannot determine the true pathogenicity of SDHB mutations.	('SDHB', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))	('SDHB', 'Gene', '6390', (84, 88))
14163	32460727	In conclusion, we report a novel SDHB c.563 T > C mutation and investigate SDHB mutations among PPGL patients in China in this literature review.	('c.563 T > C', 'Var', (38, 49))	('patients', 'Species', '9606', (101, 109))	('SDHB', 'Gene', '6390', (33, 37))	('SDHB', 'Gene', '6390', (75, 79))	('SDHB', 'Gene', (33, 37))	('SDHB', 'Gene', (75, 79))	('PGL', 'Phenotype', 'HP:0002668', (97, 100))	('PPGL', 'Chemical', '-', (96, 100))
14165	32460727	Large studies of SDHB mutations are needed to analyze the characteristics of these patients in China.	('patients', 'Species', '9606', (83, 91))	('SDHB', 'Gene', '6390', (17, 21))	('mutations', 'Var', (22, 31))	('SDHB', 'Gene', (17, 21))
14184	32188704	NCT02721732  Rare cancers pose many challenges.	('cancers', 'Disease', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('NCT02721732', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
14195	32188704	Recently, the FDA provided its first tissue-agnostic/site-agnostic drug approval:for pembrolizumab in patients with unresectable or metastatic microsatellite instability:high or mismatch repair deficient solid tumors.	('deficient solid tumors', 'Disease', 'MESH:D009369', (194, 216))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('patients', 'Species', '9606', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('deficient solid tumors', 'Disease', (194, 216))	('pembrolizumab', 'Chemical', 'MESH:C582435', (85, 98))	('mismatch repair', 'Var', (178, 193))
14327	32188704	Nevertheless, given that pembrolizumab has been approved for first-line treatment of advanced non-small cell lung cancer in patients with high PD-L1 expression according to an FDA-approved test in the absence of EGFR or ALK molecular alterations, PD-L1 expression likely reflects an immune-active tumor milieu that should be investigated further.	('pembrolizumab', 'Chemical', 'MESH:C582435', (25, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('non-small cell lung cancer', 'Disease', (94, 120))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('ALK', 'Gene', (220, 223))	('high', 'Var', (138, 142))	('expression', 'MPA', (149, 159))	('PD-L1', 'Gene', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ALK', 'Gene', '238', (220, 223))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (94, 120))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', (297, 302))	('EGFR', 'Gene', '1956', (212, 216))	('EGFR', 'Gene', (212, 216))
14342	31561209	Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics.	('PPGLs', 'Disease', (93, 98))	('SSA', 'Chemical', '-', (27, 30))	('patients', 'Species', '9606', (116, 124))	('131I-MIBG', 'Chemical', 'MESH:D019797', (168, 177))	('PPGLs', 'Chemical', '-', (93, 98))	('68Ga-labeled-SSAs', 'Var', (14, 31))	('PRRT', 'Chemical', '-', (129, 133))
14343	31561209	PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control.	('90Y/177Lu-DOTA-SSAs', 'Var', (11, 30))	('PPGLs', 'Disease', (66, 71))	('PRRT', 'Chemical', '-', (0, 4))	('177Lu-DOTA-SSA', 'Chemical', '-', (15, 29))	('improvement', 'PosReg', (77, 88))	('PPGLs', 'Chemical', '-', (66, 71))
14345	31561209	Such an approval has recently been obtained for high-specific-activity 131I-MIBG for inoperable/metastatic PPGL.	('inoperable/metastatic PPGL', 'Disease', (85, 111))	('PPGL', 'Chemical', '-', (107, 111))	('131I-MIBG', 'Chemical', 'MESH:D019797', (71, 80))	('131I-MIBG', 'Var', (71, 80))
14353	31561209	Kinase signaling group (cluster 2) consists of germline or somatic mutations in ret proto-oncogene (RET), neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and HRas proto-oncogene (HRAS).	('ret', 'Gene', '5979', (80, 83))	('MYC-associated factor X', 'Gene', (166, 189))	('NF1', 'Gene', '4763', (123, 126))	('MYC-associated factor X', 'Gene', '4149', (166, 189))	('HRas', 'Gene', '3265', (201, 205))	('MAX', 'Gene', (191, 194))	('RET', 'Gene', '5979', (100, 103))	('TMEM127', 'Gene', (156, 163))	('NF1', 'Gene', (123, 126))	('neurofibromin 1', 'Gene', '4763', (106, 121))	('HRas', 'Gene', (201, 205))	('neurofibromin 1', 'Gene', (106, 121))	('mutations', 'Var', (67, 76))	('TMEM127', 'Gene', '55654', (156, 163))	('HRAS', 'Gene', '3265', (222, 226))	('MAX', 'Gene', '4149', (191, 194))	('RET', 'Gene', (100, 103))	('HRAS', 'Gene', (222, 226))	('ret', 'Gene', (80, 83))
14354	31561209	Wnt signaling group (cluster 3) includes newly recognized somatic mutations in cold shock domain containing E1 (CSDE1), as well as somatic gene fusions affecting mastermind like transcriptional coactivator 3 (MAML3).	('mutations', 'Var', (66, 75))	('MAML3', 'Gene', '55534', (209, 214))	('shock', 'Phenotype', 'HP:0031273', (84, 89))	('MAML3', 'Gene', (209, 214))	('cold shock domain containing E1', 'Gene', (79, 110))	('CSDE1', 'Gene', (112, 117))	('mastermind like transcriptional coactivator 3', 'Gene', '55534', (162, 207))	('mastermind like transcriptional coactivator 3', 'Gene', (162, 207))	('CSDE1', 'Gene', '7812', (112, 117))	('cold shock domain containing E1', 'Gene', '7812', (79, 110))
14361	31561209	Furthermore, PPGL with an underlying SDHB mutation are associated with a higher risk of aggressive behavior than other hereditary PPGLs leading ultimately to death, particularly due to development of metastatic disease.	('aggressive behavior', 'Disease', (88, 107))	('SDHB', 'Gene', '6390', (37, 41))	('aggressive behavior', 'Disease', 'MESH:D001523', (88, 107))	('death', 'Disease', 'MESH:D003643', (158, 163))	('PPGLs', 'Chemical', '-', (130, 135))	('death', 'Disease', (158, 163))	('PPGL', 'Chemical', '-', (13, 17))	('PPGL', 'Chemical', '-', (130, 134))	('aggressive behavior', 'Phenotype', 'HP:0000718', (88, 107))	('mutation', 'Var', (42, 50))	('SDHB', 'Gene', (37, 41))	('metastatic disease', 'Disease', (200, 218))
14376	31561209	Also, per lesion detection rate of 68Ga-DOTATATE PET/CT was superior to 123I-MIBG scintigraphy (100 %, 29/27 vs. 6.9%, 2/27) in 10 extra-adrenal PGL patients.	('patients', 'Species', '9606', (149, 157))	('68Ga-DOTATATE', 'Var', (35, 48))	('123I-MIBG', 'Chemical', 'MESH:D019797', (72, 81))	('extra-adrenal PGL', 'Disease', (131, 148))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (35, 48))
14382	31561209	The elevated clinical value of 68Ga-DOTATATE was also observed in the pediatric population with SDHx mutation.	('mutation', 'Var', (101, 109))	('SDHx', 'Gene', (96, 100))	('clinical value', 'MPA', (13, 27))	('elevated', 'PosReg', (4, 12))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (31, 44))
14383	31561209	68Ga-DOTA-SSA PET/CT can therefore, be recommended for diagnosis, staging, and follow-up imaging of PPGL with underlying SDHx mutations.	('SSA', 'Chemical', '-', (10, 13))	('mutations', 'Var', (126, 135))	('PPGL', 'Chemical', '-', (100, 104))	('PPGL', 'Gene', (100, 104))	('SDHx', 'Gene', (121, 125))
14392	31561209	Such high risk-factors have been identified as: SDHB, SDHA germline mutations, ATRX mutation, male sex, patient with large primary tumors (various studies have identified that from >4.5-5 cm to >10 cm), noradrenergic or dopaminergic biochemical phenotype, older age at primary tumor diagnosis (>40-50 years), and high proliferative index (, Jha et al.	('primary tumor', 'Disease', (123, 136))	('SDHB', 'Gene', '6390', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('SDHA', 'Gene', '6389', (54, 58))	('primary tumor', 'Disease', (269, 282))	('primary tumor', 'Disease', 'MESH:D001932', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('ATRX', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('patient', 'Species', '9606', (104, 111))	('tumors', 'Disease', (131, 137))	('SDHA', 'Gene', (54, 58))	('mutations', 'Var', (68, 77))	('primary tumor', 'Disease', 'MESH:D001932', (269, 282))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('ATRX', 'Gene', '546', (79, 83))	('SDHB', 'Gene', (48, 52))	('mutation', 'Var', (84, 92))
14405	31561209	In the kinase signaling group, 18F-FDOPA is probably the best radiopharmaceutical due to its high tumor uptake together with a limited uptake in the remaining (unaffected) adrenal gland.	('uptake', 'MPA', (135, 141))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('18F-FDOPA', 'Var', (31, 40))	('tumor', 'Disease', (98, 103))
14409	31561209	For those associated with mutations in NF1/RET/MAX, 18F-FDOPA PET/CT should be recommended first due to the optimal tumor-to-adrenal uptake ratio that facilitate their detection.	('MAX', 'Gene', '4149', (47, 50))	('RET', 'Gene', (43, 46))	('NF1', 'Gene', (39, 42))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('NF1', 'Gene', '4763', (39, 42))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('RET', 'Gene', '5979', (43, 46))	('tumor', 'Disease', (116, 121))	('MAX', 'Gene', (47, 50))
14417	31561209	Initially, 123/131I-MIBG targeting norepinephrine transporter system and more recently 68Ga/90Y/177Lu-DOTA-SSA analogs targeting peptide (somatostatin) receptors have been introduced as theranostic agents for PPGLs.	('norepinephrine transporter', 'Gene', '6530', (35, 61))	('177Lu-DOTA-SSA', 'Chemical', '-', (96, 110))	('123/131I-MIBG', 'Var', (11, 24))	('PPGLs', 'Chemical', '-', (209, 214))	('131I-MIBG', 'Chemical', 'MESH:D019797', (15, 24))	('PPGLs', 'Disease', (209, 214))	('norepinephrine transporter', 'Gene', (35, 61))
14425	31561209	Myelodysplastic syndrome (MDS) and acute leukemias (ALs) have been reported in patients treated with large amounts of 131I-MIBG and chemotherapy (Carrasquillo et al.	('131I-MIBG', 'Var', (118, 127))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('acute leukemias', 'Phenotype', 'HP:0002488', (35, 50))	('Myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (0, 24))	('acute leukemias', 'Disease', 'MESH:D015470', (35, 50))	('acute leukemias', 'Disease', (35, 50))	('MDS', 'Disease', (26, 29))	('MDS', 'Disease', 'MESH:D009190', (26, 29))	('patients', 'Species', '9606', (79, 87))	('leukemias', 'Phenotype', 'HP:0001909', (41, 50))	('Myelodysplastic syndrome', 'Disease', (0, 24))	('131I-MIBG', 'Chemical', 'MESH:D019797', (118, 127))	('Myelodysplastic syndrome', 'Disease', 'MESH:D009190', (0, 24))
14433	31561209	Of the 68 patients who received at least one therapeutic dose of HSA 131I-MIBG, 17 (25%; 95% CI, 16-37%) had a durable reduction in baseline antihypertensive medication use.	('antihypertensive medication', 'Phenotype', 'HP:0000822', (141, 168))	('131I-MIBG', 'Chemical', 'MESH:D019797', (69, 78))	('hypertensive', 'Disease', 'MESH:D006973', (145, 157))	('hypertensive', 'Disease', (145, 157))	('patients', 'Species', '9606', (10, 18))	('reduction', 'NegReg', (119, 128))	('HSA', 'Chemical', '-', (65, 68))	('HSA', 'Var', (65, 68))
14444	31561209	Although effective, the use of HSA 131I-MIBG is associated with higher rate of hematologic toxicity which possibly got amplified due to previous cytotoxic therapies together with some individual susceptibilities.	('HSA 131I-MIBG', 'Var', (31, 44))	('HSA', 'Chemical', '-', (31, 34))	('131I-MIBG', 'Chemical', 'MESH:D019797', (35, 44))	('hematologic', 'Disease', (79, 90))	('toxicity', 'Disease', 'MESH:D064420', (91, 99))	('toxicity', 'Disease', (91, 99))
14452	31561209	Selection of good candidates is based on the use of a companion diagnostic agent corresponding to the same SSA labeled with 111Indium or 68Ga, which is now preferred for molecular imaging of PPGL.	('PPGL', 'Chemical', '-', (191, 195))	('SSA', 'Chemical', '-', (107, 110))	('111Indium', 'Var', (124, 133))	('68Ga', 'Var', (137, 141))	('111Indium', 'Chemical', 'MESH:C000615551', (124, 133))
14463	31561209	The main predictors of poor OS outcome after PRRT are non-specific and include high Ki-67 index (greater than 10%), high uptake on 18F-FDG, involvement of more than two organ systems, local vs. distant metastases, low Karnofsky performance score (<= 70%), high tumor burden, identified progressive disease after first PRRT, and when PRRT is delivered as salvage therapy after chemotherapy.	('metastases', 'Disease', 'MESH:D009362', (202, 212))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('high', 'Var', (116, 120))	('tumor', 'Disease', (261, 266))	('low', 'NegReg', (214, 217))	('PRRT', 'Chemical', '-', (45, 49))	('PRRT', 'Chemical', '-', (333, 337))	('involvement', 'Reg', (140, 151))	('Ki-67', 'Gene', (84, 89))	('18F-FDG', 'Chemical', 'MESH:D019788', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('PRRT', 'Chemical', '-', (318, 322))	('metastases', 'Disease', (202, 212))
14464	31561209	In another study, highly elevated maximum standardized uptake values (SUVmax) on pre-therapeutic 68Ga-DOTATOC were associated with tumor shrinkage, reduction of tumor markers, and improved overall clinical condition after PRRT with 90Y-DOTATOC.	('PRRT', 'Chemical', '-', (222, 226))	('reduction', 'NegReg', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('90Y-DOTA', 'Chemical', '-', (232, 240))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (131, 136))	('improved', 'PosReg', (180, 188))	('maximum standardized uptake values', 'MPA', (34, 68))	('elevated', 'PosReg', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('68Ga-DOTATOC', 'Var', (97, 109))
14466	31561209	Toxicity is limited, especially when using 177Lu due to its lower tissue penetration range compared with 90Y (Table 3).	('tissue penetration range', 'CPA', (66, 90))	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('177Lu', 'Chemical', 'MESH:C000615061', (43, 48))	('177Lu', 'Var', (43, 48))	('lower', 'NegReg', (60, 65))
14471	31561209	There have been large patient series that reported grade 3/4 nephrotoxicity ranging from 0% (0/343) with 177Lu; 0.3% (20/581) with 177Lu; 1.3% (1/74) with 177Lu; and to 1.5% (12/807) with 90Y, 177Lu, or 90Y+177Lu.	('90Y+177Lu', 'Var', (203, 212))	('177Lu', 'Chemical', 'MESH:C000615061', (155, 160))	('90Y', 'Var', (188, 191))	('177Lu', 'Chemical', 'MESH:C000615061', (131, 136))	('nephrotoxicity', 'Disease', (61, 75))	('177Lu', 'Var', (131, 136))	('nephrotoxicity', 'Disease', 'MESH:D007674', (61, 75))	('177Lu', 'Var', (155, 160))	('177Lu', 'Chemical', 'MESH:C000615061', (193, 198))	('177Lu', 'Chemical', 'MESH:C000615061', (105, 110))	('177Lu', 'Chemical', 'MESH:C000615061', (207, 212))	('177Lu', 'Var', (105, 110))	('177Lu', 'Var', (193, 198))	('patient', 'Species', '9606', (22, 29))
14474	31561209	The grade 3/4 hematotoxicty reported in large patient series ranged from 9.5% (77/807) with 90Y, 177Lu, or 90Y+177Lu; 10% (61/582) with 177Lu; 11% (34/320) with 177Lu; and to 11.3% (23/208) with 177Lu.	('patient', 'Species', '9606', (46, 53))	('90Y', 'Var', (92, 95))	('90Y+177Lu', 'Var', (107, 116))	('177Lu', 'Chemical', 'MESH:C000615061', (97, 102))	('177Lu', 'Chemical', 'MESH:C000615061', (111, 116))	('177Lu', 'Var', (97, 102))	('hematotoxicty', 'Disease', (14, 27))	('177Lu', 'Var', (136, 141))	('177Lu', 'Chemical', 'MESH:C000615061', (136, 141))	('177Lu', 'Chemical', 'MESH:C000615061', (161, 166))	('177Lu', 'Chemical', 'MESH:C000615061', (195, 200))	('hematotoxicty', 'Disease', 'None', (14, 27))	('177Lu', 'Var', (161, 166))
14477	31561209	Furthermore, MDS or AL were reported to range from 1.4% (3/208) with 177Lu; 2.0% (22/148) with 90Y or 177Lu; 2.2% (13/582) with 177Lu; and to 1.4% (32/2225) in the meta-analysis comprising 16 studies.	('177Lu', 'Chemical', 'MESH:C000615061', (69, 74))	('90Y', 'Var', (95, 98))	('177Lu', 'Var', (69, 74))	('177Lu', 'Chemical', 'MESH:C000615061', (128, 133))	('MDS', 'Disease', (13, 16))	('177Lu', 'Var', (128, 133))	('MDS', 'Disease', 'MESH:D009190', (13, 16))	('177Lu', 'Chemical', 'MESH:C000615061', (102, 107))	('177Lu', 'Var', (102, 107))
14481	31561209	Recently, grade 3/4 hepatotoxicity in NET patients with liver metastases was observed in 3% (20/581) with 177Lu and any hepatotoxicity in 10.8% (10/93) with either of 90Y or 177Lu or 90Y+177Lu based PRRT.	('177Lu', 'Var', (106, 111))	('hepatotoxicity', 'Disease', 'MESH:D056486', (120, 134))	('177Lu', 'Var', (174, 179))	('hepatotoxicity', 'Disease', 'MESH:D056486', (20, 34))	('90Y', 'Var', (167, 170))	('PRRT', 'Chemical', '-', (199, 203))	('177Lu', 'Chemical', 'MESH:C000615061', (187, 192))	('liver metastases', 'Disease', (56, 72))	('90Y+177Lu', 'Var', (183, 192))	('hepatotoxicity', 'Disease', (120, 134))	('177Lu', 'Chemical', 'MESH:C000615061', (106, 111))	('liver metastases', 'Disease', 'MESH:D009362', (56, 72))	('hepatotoxicity', 'Disease', (20, 34))	('patients', 'Species', '9606', (42, 50))	('177Lu', 'Chemical', 'MESH:C000615061', (174, 179))
14484	31561209	It was also observed that the frequency of nephrotoxicity and hematotoxicity was highest with 90Y followed by 90Y+177Lu and least with 177Lu based PRRT.	('nephrotoxicity and hematotoxicity', 'Disease', 'MESH:D007674', (43, 76))	('177Lu', 'Chemical', 'MESH:C000615061', (135, 140))	('PRRT', 'Chemical', '-', (147, 151))	('177Lu', 'Chemical', 'MESH:C000615061', (114, 119))	('90Y+177Lu', 'Var', (110, 119))	('90Y', 'Var', (94, 97))
14496	31561209	reported the response rates of PRRT using either 90Y-DOTATOC (25 patients) or 177Lu-DOTATOC (3 patients) in surgically unresectable PPGLs.	('90Y-DOTATOC', 'Var', (49, 60))	('patients', 'Species', '9606', (95, 103))	('177Lu', 'Chemical', 'MESH:C000615061', (78, 83))	('90Y-DOTA', 'Chemical', '-', (49, 57))	('PPGLs', 'Disease', (132, 137))	('patients', 'Species', '9606', (65, 73))	('PRRT', 'Chemical', '-', (31, 35))	('177Lu-DOTATOC', 'Var', (78, 91))	('PPGLs', 'Chemical', '-', (132, 137))
14529	31561209	had described the outcomes of 22 patients with progressive/metastatic PPGLs treated with either 131I-MIBG (11 patients), 90Y-DOTATATE (8 patients), 177Lu-DOTATATE (1 patient) or combination of 131I-MIBG with 90Y/177Lu-DOTATATE (2 patients).	('patient', 'Species', '9606', (137, 144))	('131I-MIBG', 'Var', (193, 202))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (148, 162))	('131I-MIBG', 'Chemical', 'MESH:D019797', (96, 105))	('131I-MIBG', 'Var', (96, 105))	('patient', 'Species', '9606', (33, 40))	('PPGLs', 'Disease', (70, 75))	('patient', 'Species', '9606', (230, 237))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (166, 173))	('90Y/177Lu-DOTATATE', 'Chemical', '-', (208, 226))	('patients', 'Species', '9606', (137, 145))	('PPGLs', 'Chemical', '-', (70, 75))	('patients', 'Species', '9606', (33, 41))	('177Lu-DOTATATE', 'Var', (148, 162))	('patients', 'Species', '9606', (230, 238))	('131I-MIBG', 'Chemical', 'MESH:D019797', (193, 202))	('90Y-DOTATATE', 'Chemical', '-', (121, 133))	('patients', 'Species', '9606', (110, 118))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (212, 226))
14531	31561209	In the subgroup of 15 patients with extradrenal PGLs (21 treatments, from which 13 were with PRRT and 8 with 131I-MIBG), PRRT performed significantly better than 131I-MIBG in terms of OS, PFS, and response to treatment.	('better', 'PosReg', (150, 156))	('PRRT', 'Var', (121, 125))	('PFS', 'MPA', (188, 191))	('patients', 'Species', '9606', (22, 30))	('PRRT', 'Chemical', '-', (121, 125))	('131I-MIBG', 'Chemical', 'MESH:D019797', (162, 171))	('PRRT', 'Chemical', '-', (93, 97))	('131I-MIBG', 'Chemical', 'MESH:D019797', (109, 118))
14532	31561209	Four patients (18.1%) developed renal toxicity related to radionuclide treatment, with grade 3 renal toxicity in a patient treated with 90Y-DOTATATE and 131I-MIBG.	('patient', 'Species', '9606', (5, 12))	('131I-MIBG', 'Var', (153, 162))	('patients', 'Species', '9606', (5, 13))	('renal toxicity', 'Disease', 'MESH:D007674', (32, 46))	('90Y-DOTATATE', 'Chemical', '-', (136, 148))	('renal toxicity', 'Disease', (32, 46))	('renal toxicity', 'Disease', (95, 109))	('131I-MIBG', 'Chemical', 'MESH:D019797', (153, 162))	('patient', 'Species', '9606', (115, 122))	('renal toxicity', 'Disease', 'MESH:D007674', (95, 109))
14540	31561209	One patient developed MDS after 45 months following 6 cycles of 177Lu-DOTATATE (including retreatment, cumulative dose 44.4 GBq) and died after 4.5 years of first cycle of PRRT due to complications.	('PRRT', 'Chemical', '-', (172, 176))	('patient', 'Species', '9606', (4, 11))	('MDS', 'Disease', (22, 25))	('GBq', 'Chemical', '-', (124, 127))	('died', 'Disease', (133, 137))	('MDS', 'Disease', 'MESH:D009190', (22, 25))	('died', 'Disease', 'MESH:D003643', (133, 137))	('177Lu-DOTATATE', 'Var', (64, 78))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (64, 78))	('ret', 'Gene', (90, 93))	('ret', 'Gene', '5979', (90, 93))
14581	31561209	Vagal nerve PGL is usually related to SDHx mutation (mainly SDHD) in approximately 40% of patients.	('mutation', 'Var', (43, 51))	('SDHD', 'Gene', (60, 64))	('Vagal nerve PGL', 'Disease', (0, 15))	('SDHD', 'Gene', '6392', (60, 64))	('SDHx', 'Gene', (38, 42))	('related', 'Reg', (27, 34))	('patients', 'Species', '9606', (90, 98))
14598	31561209	Therefore, surgical strategy should be tailored to each situation with the knowledge of the genetic status since upto 70% of patients with extraadrenal retroperitoneal PGL may carry germline mutations in SDHx or VHL genes.	('SDHx', 'Gene', (204, 208))	('ret', 'Gene', '5979', (152, 155))	('carry', 'Reg', (176, 181))	('germline mutations', 'Var', (182, 200))	('VHL', 'Gene', (212, 215))	('VHL', 'Gene', '7428', (212, 215))	('ret', 'Gene', (152, 155))	('patients', 'Species', '9606', (125, 133))
14599	31561209	Large PPGLs and those associated to SDHB mutation are associated with a higher risk for metastatic spread and imaging is required to fully localize the extent of disease at whole-body scale.	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('metastatic spread', 'CPA', (88, 105))	('PPGLs', 'Chemical', '-', (6, 11))	('mutation', 'Var', (41, 49))
14600	31561209	In patients with non- or incompletely resectable large PGL, a radiotherapeutic management could be considered (also as complementary therapy after debulking surgery), especially for patients with SDHB mutation which are prone to develop metastases and symptomatic patients (e.g.	('metastases', 'Disease', 'MESH:D009362', (237, 247))	('SDHB', 'Gene', '6390', (196, 200))	('mutation', 'Var', (201, 209))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (182, 190))	('develop', 'PosReg', (229, 236))	('patients', 'Species', '9606', (264, 272))	('SDHB', 'Gene', (196, 200))	('metastases', 'Disease', (237, 247))
14602	31561209	The use of PRRT using 177Lu-DOTA-SSA will be better suited to SDHx-related PPGL than 131I-MIBG.	('177Lu-DOTA-SSA', 'Var', (22, 36))	('131I-MIBG', 'Chemical', 'MESH:D019797', (85, 94))	('PPGL', 'Disease', (75, 79))	('SDHx-related PPGL', 'Disease', (62, 79))	('PPGL', 'Chemical', '-', (75, 79))	('177Lu-DOTA-SSA', 'Chemical', '-', (22, 36))	('PRRT', 'Chemical', '-', (11, 15))
14613	31561209	Additionally, combined 177Lu-DOTA-SSA and cold SSA can be considered in SSTR positive patients and its efficacy can be determined in future trials.	('SSA', 'Chemical', '-', (47, 50))	('SSA', 'Chemical', '-', (34, 37))	('177Lu-DOTA-SSA', 'Chemical', '-', (23, 37))	('177Lu-DOTA-SSA', 'Var', (23, 37))	('SSTR positive', 'Disease', (72, 85))	('patients', 'Species', '9606', (86, 94))
14614	31561209	Moreover, patients with tumor phenotype showing both or discordant molecular targets on various lesions may theoretically benefit from a combined or sequential radionuclide therapeutic approach using PRRT and 131I-MIBG, but further trials are required to assess efficacy and potential toxicity of this regimen.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('PRRT', 'Chemical', '-', (200, 204))	('131I-MIBG', 'Chemical', 'MESH:D019797', (209, 218))	('ret', 'Gene', (112, 115))	('tumor', 'Disease', (24, 29))	('toxicity', 'Disease', 'MESH:D064420', (285, 293))	('toxicity', 'Disease', (285, 293))	('ret', 'Gene', '5979', (112, 115))	('131I-MIBG', 'Var', (209, 218))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('benefit', 'PosReg', (122, 129))
14624	31561209	Preliminary results of a trial in NETs (P-PRRT, ) have shown that the use of patient-specific PRRT dosimetry might increase absorbed dose delivered to a tumor (median 1.26-fold; range: 0.47-2.7-fold) compared to fixed-dose regimen, without increased toxicity (oral communication OP-181, congress).	('toxicity', 'Disease', 'MESH:D064420', (250, 258))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('toxicity', 'Disease', (250, 258))	('PRRT', 'Var', (94, 98))	('increase', 'PosReg', (115, 123))	('PRRT', 'Chemical', '-', (42, 46))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('PRRT', 'Chemical', '-', (94, 98))	('patient', 'Species', '9606', (77, 84))
14650	31561209	IA PRRT resulted in a 4-fold higher intrahepatic tumor accumulation compared to intravenous infusion due to high first-pass extraction, decreasing to 1.3 times greater at 72 hours.	('higher', 'PosReg', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('intrahepatic tumor accumulation', 'Disease', 'MESH:D002780', (36, 67))	('PRRT', 'Chemical', '-', (3, 7))	('first-pass extraction', 'MPA', (113, 134))	('PRRT', 'Var', (3, 7))	('intrahepatic tumor accumulation', 'Disease', (36, 67))
14657	31561209	The effect of PPGL driver mutations on these parameters and response to immunotherapy would be of particular interest.	('PPGL', 'Chemical', '-', (14, 18))	('mutations', 'Var', (26, 35))	('PPGL', 'Gene', (14, 18))
14660	31561209	A preclinical study has shown that PRRT leads to increased infiltration of antigen-presenting cells and natural killer cells into tumors, suggesting a mechanistic role for the inflammatory response followed by increased innate immunity in the action of PRRT.	('tumors', 'Disease', (130, 136))	('PRRT', 'Chemical', '-', (253, 257))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('PRRT', 'Var', (35, 39))	('increased', 'PosReg', (49, 58))	('infiltration', 'MPA', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PRRT', 'Chemical', '-', (35, 39))
14662	31561209	More recently, there has been an evidence that radiolabeled SSTR2 antagonists generate higher tumor doses and more DNA double-strand breaks than agonists, resulting in better treatment efficacy despite poor internalisation.	('DNA double-strand breaks', 'MPA', (115, 139))	('internalisation', 'MPA', (207, 222))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SSTR2', 'Gene', '6752', (60, 65))	('better', 'PosReg', (168, 174))	('tumor', 'Disease', (94, 99))	('treatment efficacy', 'CPA', (175, 193))	('SSTR2', 'Gene', (60, 65))	('antagonists', 'Var', (66, 77))	('higher', 'PosReg', (87, 93))
14664	31561209	An evans blue (EB) modification of DOTA-octreotate, resulted in a radionuclide 177Lu-DOTA-EB-TATE which markedly increased binding to circulating serum albumin, a slower clearance through the urinary tract and thus, an increased half-life in blood was observed thereby increasing tumor retention.	('modification', 'Var', (19, 31))	('binding', 'Interaction', (123, 130))	('clearance through the urinary', 'MPA', (170, 199))	('serum albumin', 'Gene', '213', (146, 159))	('177Lu-DOTA-EB-TATE', 'Chemical', '-', (79, 97))	('serum albumin', 'Gene', (146, 159))	('tumor retention', 'Disease', (280, 295))	('DOTA-octreotate', 'Chemical', '-', (35, 50))	('evans blue', 'Chemical', 'MESH:D005070', (3, 13))	('half-life', 'MPA', (229, 238))	('tumor retention', 'Disease', 'MESH:D016055', (280, 295))	('EB', 'Chemical', 'MESH:D005070', (90, 92))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('slower', 'NegReg', (163, 169))	('increased', 'PosReg', (113, 122))	('increasing', 'PosReg', (269, 279))	('EB', 'Chemical', 'MESH:D005070', (15, 17))	('increased', 'PosReg', (219, 228))
14665	31561209	In a pilot study by Zhang et al in advanced NET patients, 177Lu-DOTA-EB-TATE demonstrated a 7.9-fold increase in delivered tumor doses when comparable total body effective doses of 177Lu-DOTATATE (0.174 millisievert/megabecquerel (mSv/MBq), 3 patients) and 177Lu-DOTA-EB-TATE (0.205 mSv/MBq, 5 patients).	('177Lu-DOTA-EB-TATE', 'Chemical', '-', (257, 275))	('tumor', 'Disease', (123, 128))	('patients', 'Species', '9606', (243, 251))	('patients', 'Species', '9606', (294, 302))	('increase', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (181, 195))	('patients', 'Species', '9606', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('177Lu-DOTA-EB-TATE', 'Var', (58, 76))	('177Lu-DOTA-EB-TATE', 'Chemical', '-', (58, 76))
14666	31561209	However, significant increase in dose delivery to the kidneys (3.2-fold) and bone marrow (18.2-fold) were noted in patients receiving 177Lu-DOTA-EB-TATE than those receiving 177Lu-DOTATATE (, JNM).	('patients', 'Species', '9606', (115, 123))	('177Lu-DOTA-EB-TATE', 'Chemical', '-', (134, 152))	('dose delivery', 'MPA', (33, 46))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (174, 188))	('177Lu-DOTA-EB-TATE', 'Var', (134, 152))	('increase', 'PosReg', (21, 29))
14743	31842905	There were more benign and nonfunctional LATs in the laparoscopic adrenalectomy group than in the open adrenalectomy group (P < 0.05).	('nonfunctional LATs', 'CPA', (27, 45))	('laparoscopic', 'Var', (53, 65))	('LATs', 'Chemical', '-', (41, 45))
14808	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
14815	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
14855	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
14873	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
14920	30538672	Mutations of genes that encode any of the subunits A, B, C, or D or the complex assembly factor 2 (AF2) account for a group of overlapping yet distinct hereditary syndromes termed SDHx.	('account for', 'Reg', (104, 115))	('factor 2', 'Gene', '8458', (89, 97))	('SDHx', 'Disease', (180, 184))	('Mutations', 'Var', (0, 9))	('factor 2', 'Gene', (89, 97))	('SDHx', 'Chemical', '-', (180, 184))
14925	30538672	This technique is especially useful in the context of suspected SDHx mutations.	('mutations', 'Var', (69, 78))	('SDHx', 'Chemical', '-', (64, 68))	('SDHx', 'Gene', (64, 68))
14934	30538672	More recently, a study of a cohort reported by the National Institutes of Health (NIH) revealed co-secreting dopamine (DA) tumors in some FH mutated patients.	('mutated', 'Var', (141, 148))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('patients', 'Species', '9606', (149, 157))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('DA', 'Chemical', 'MESH:D004298', (119, 121))	('FH', 'Gene', '2271', (138, 140))	('co-secreting', 'MPA', (96, 108))	('dopamine', 'Chemical', 'MESH:D004298', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
14936	30538672	were the first to identify a gain-of-function somatic mutation in exon 12 of EPAS1 (G1588A and C1589T) in patients with PPGLs.	('EPAS1', 'Gene', '2034', (77, 82))	('gain-of-function', 'PosReg', (29, 45))	('G1588A', 'Var', (84, 90))	('G1588A', 'Mutation', 'c.1588G>A', (84, 90))	('EPAS1', 'Gene', (77, 82))	('C1589T', 'Var', (95, 101))	('PPGLs', 'Chemical', '-', (120, 125))	('C1589T', 'Mutation', 'c.1589C>T', (95, 101))	('patients', 'Species', '9606', (106, 114))	('PGLs', 'Phenotype', 'HP:0002668', (121, 125))	('PPGLs', 'Disease', (120, 125))
14937	30538672	These mutations caused defects on the proline residues at the hydroxylation site of HIF-2alpha leading to its reduced degradation and stabilization.	('reduced', 'NegReg', (110, 117))	('degradation', 'MPA', (118, 129))	('HIF-2alpha', 'Gene', (84, 94))	('defects', 'NegReg', (23, 30))	('stabilization', 'MPA', (134, 147))	('proline', 'Chemical', 'MESH:D011392', (38, 45))	('proline residues at the', 'MPA', (38, 61))	('HIF-2alpha', 'Gene', '2034', (84, 94))	('mutations', 'Var', (6, 15))
14948	30538672	Pathogenic mutations in H-RAS were firstly identified in 2013.	('mutations', 'Var', (11, 20))	('H-RAS', 'Gene', (24, 29))	('H-RAS', 'Gene', '3265', (24, 29))
14949	30538672	WES of tumor DNA in four cases with phenotype suggesting an underlying pathogenic genetic variant revealed the presence of 2 hotspot mutations in H-RAS (G13R and Q61K) in two of them.	('Q61K', 'Mutation', 'rs28933406', (162, 166))	('tumor', 'Disease', (7, 12))	('H-RAS', 'Gene', (146, 151))	('G13R', 'Mutation', 'rs104894228', (153, 157))	('G13R', 'Var', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('H-RAS', 'Gene', '3265', (146, 151))	('Q61K', 'Var', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
14951	30538672	Further validation in a cohort of 58 additional samples obtained showed an accumulated frequency of 6.9% (4/58) of missense somatic mutations in H-RAS: G13R (n = 1), Q61K (n = 1), and Q61R (n = 2).	('Q61R', 'Var', (184, 188))	('H-RAS', 'Gene', (145, 150))	('Q61R', 'Mutation', 'rs121913233', (184, 188))	('G13R', 'Mutation', 'rs104894228', (152, 156))	('missense somatic', 'Var', (115, 131))	('Q61K', 'Mutation', 'rs28933406', (166, 170))	('G13R', 'Var', (152, 156))	('H-RAS', 'Gene', '3265', (145, 150))	('Q61K', 'Var', (166, 170))
14953	30538672	The association of CSDE1 to PPGL was recently described by TCGA group in a cohort study of 176 PPGL patients, in which four were found to have a somatic mutation: two frameshift, and two splice-site:, in CSDE1.	('CSDE1', 'Gene', (204, 209))	('CSDE1', 'Gene', '7812', (204, 209))	('frameshift', 'Var', (167, 177))	('CSDE1', 'Gene', (19, 24))	('CSDE1', 'Gene', '7812', (19, 24))	('patients', 'Species', '9606', (100, 108))	('PPGL', 'Disease', (28, 32))
14955	30538672	Mutations in this gene result in downregulation of the apoptosis protease activator protein 1 (APAF1), which controls apoptosis in PCC cells under normal conditions.	('PCC', 'Gene', '1421', (131, 134))	('Mutations', 'Var', (0, 9))	('APAF1', 'Gene', (95, 100))	('APAF1', 'Gene', '317', (95, 100))	('PCC', 'Gene', (131, 134))	('downregulation', 'NegReg', (33, 47))
14962	30538672	Finding UBTF-MAML3 fusion predicts a poor prognosis, as compared with other syndromic forms of PPGL.	('fusion', 'Var', (19, 25))	('MAML3', 'Gene', '55534', (13, 18))	('MAML3', 'Gene', (13, 18))	('UBTF', 'Gene', '7343', (8, 12))	('UBTF', 'Gene', (8, 12))
14968	30538672	were the first to report a case with a germline mutation in MDH2: a male patient diagnosed with multiple PGLs.	('PGLs', 'Phenotype', 'HP:0002668', (105, 109))	('germline mutation', 'Var', (39, 56))	('patient', 'Species', '9606', (73, 80))	('MDH2', 'Gene', '4191', (60, 64))	('MDH2', 'Gene', (60, 64))
14972	30538672	Deficiency of this enzyme prevents degradation of HIF-alpha and resulting in HIF stabilization leading to a global activation of signaling pathways that lead to tumorigenesis.	('HIF-alpha', 'Protein', (50, 59))	('activation', 'PosReg', (115, 125))	('degradation', 'MPA', (35, 46))	('HIF stabilization', 'MPA', (77, 94))	('signaling pathways', 'Pathway', (129, 147))	('prevents', 'NegReg', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('lead to', 'Reg', (153, 160))	('Deficiency', 'Var', (0, 10))
14974	30538672	were the first to describe the association of mutations in PHD2 with polycythemia and PPGLs.	('mutations', 'Var', (46, 55))	('PPGLs', 'Disease', (86, 91))	('association', 'Interaction', (31, 42))	('polycythemia', 'Disease', (69, 81))	('PHD2', 'Gene', (59, 63))	('PGLs', 'Phenotype', 'HP:0002668', (87, 91))	('PHD2', 'Gene', '54583', (59, 63))	('PPGLs', 'Chemical', '-', (86, 91))	('polycythemia', 'Phenotype', 'HP:0001901', (69, 81))	('polycythemia', 'Disease', 'MESH:D011086', (69, 81))
14978	30538672	In the patient with the mutation in PHD1 (EGLN2), sensitivity of erythroid progenitors to EPO and erythropoietin receptor (EpoR) activity were inappropriately increased and resulted in polycythemia with no or mild increase in EPO levels with increased EpoR expression.	('EpoR', 'Gene', '2057', (252, 256))	('resulted in', 'Reg', (173, 184))	('PHD1', 'Gene', '112398', (36, 40))	('expression', 'MPA', (257, 267))	('EPO', 'Gene', '2056', (226, 229))	('increase', 'PosReg', (214, 222))	('polycythemia', 'Phenotype', 'HP:0001901', (185, 197))	('EPO', 'Gene', '2056', (90, 93))	('EPO', 'Gene', (226, 229))	('sensitivity', 'MPA', (50, 61))	('EPO', 'Gene', (90, 93))	('patient', 'Species', '9606', (7, 14))	('increased', 'PosReg', (242, 251))	('EGLN2', 'Gene', '112398', (42, 47))	('EGLN2', 'Gene', (42, 47))	('erythropoietin receptor', 'Gene', '2057', (98, 121))	('polycythemia', 'Disease', (185, 197))	('mutation', 'Var', (24, 32))	('polycythemia', 'Disease', 'MESH:D011086', (185, 197))	('PHD1', 'Gene', (36, 40))	('EpoR', 'Gene', (252, 256))	('EpoR', 'Gene', (123, 127))	('increased', 'PosReg', (159, 168))	('EpoR', 'Gene', '2057', (123, 127))	('erythropoietin receptor', 'Gene', (98, 121))
14980	30538672	Thus, deficiency of IRP1 increases HIF2alpha by dissociating sequences of HIF2alpha mRNA from iron-responsive element and suppressing protein translation.	('IRP1', 'Gene', (20, 24))	('IRP1', 'Gene', '48', (20, 24))	('protein translation', 'MPA', (134, 153))	('HIF2alpha', 'Gene', (74, 83))	('sequences', 'MPA', (61, 70))	('deficiency', 'Var', (6, 16))	('suppressing', 'NegReg', (122, 133))	('HIF2alpha', 'Gene', '2034', (74, 83))	('HIF2alpha', 'Gene', '2034', (35, 44))	('iron', 'Chemical', 'MESH:D007501', (94, 98))	('dissociating', 'NegReg', (48, 60))	('HIF2alpha', 'Gene', (35, 44))
14983	30538672	in a patient with a medical history of polycythemia vera with a proven JAK2 mutation, hypertension, diaphoresis, and abdominal pain that led to the diagnosis of PCC years later.	('polycythemia vera', 'Disease', (39, 56))	('JAK2', 'Gene', '3717', (71, 75))	('patient', 'Species', '9606', (5, 12))	('abdominal pain', 'Phenotype', 'HP:0002027', (117, 131))	('diaphoresis', 'Phenotype', 'HP:0000975', (100, 111))	('JAK2', 'Gene', (71, 75))	('polycythemia', 'Phenotype', 'HP:0001901', (39, 51))	('PCC', 'Gene', (161, 164))	('abdominal pain', 'Disease', (117, 131))	('hypertension', 'Disease', 'MESH:D006973', (86, 98))	('abdominal pain', 'Disease', 'MESH:D015746', (117, 131))	('pain', 'Phenotype', 'HP:0012531', (127, 131))	('polycythemia vera', 'Disease', 'MESH:D011087', (39, 56))	('led to', 'Reg', (137, 143))	('hypertension', 'Disease', (86, 98))	('mutation', 'Var', (76, 84))	('hypertension', 'Phenotype', 'HP:0000822', (86, 98))	('PCC', 'Gene', '1421', (161, 164))
14985	30538672	Subsequent tumor DNA sequencing revealed a somatic, loss of function mutation in IRP1 located on exon 3 splicing site.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('IRP1', 'Gene', '48', (81, 85))	('tumor', 'Disease', (11, 16))	('loss of function', 'NegReg', (52, 68))	('mutation', 'Var', (69, 77))	('IRP1', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
14987	30538672	Defects in H3F3A have been linked with diffuse intrinsic pontine glioma (DIPG), chondroblastoma, and giant cell tumor of the bone (GCT).	('linked', 'Reg', (27, 33))	('DIPG', 'Chemical', '-', (73, 77))	('giant cell tumor', 'Disease', (101, 117))	('glioma', 'Disease', (65, 71))	('H3F3A', 'Gene', '3020', (11, 16))	('chondroblastoma', 'Disease', (80, 95))	('Defects', 'Var', (0, 7))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('chondroblastoma', 'Phenotype', 'HP:0030432', (80, 95))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('GCT', 'Phenotype', 'HP:0011847', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('giant cell tumor', 'Disease', 'MESH:D005870', (101, 117))	('chondroblastoma', 'Disease', 'MESH:D002804', (80, 95))	('H3F3A', 'Gene', (11, 16))	('tumor of the bone', 'Phenotype', 'HP:0010622', (112, 129))	('giant cell tumor of the bone', 'Phenotype', 'HP:0011847', (101, 129))
14988	30538672	analyzed 43 samples of 41 patients using exome or transcriptome sequencing and detected a postzygotic H3F3A mutation in three tumors from one patient with a history of recurrent GCT.	('patient', 'Species', '9606', (26, 33))	('H3F3A', 'Gene', '3020', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('H3F3A', 'Gene', (102, 107))	('patient', 'Species', '9606', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (26, 34))	('mutation', 'Var', (108, 116))	('GCT', 'Phenotype', 'HP:0011847', (178, 181))
14990	30538672	Further analysis showed that this mutation was identical to an oncogenic driver of sporadic GCT (c.103 G > T, p.G34W).	('c.103 G > T', 'Mutation', 'rs868820087', (97, 108))	('p.G34W', 'Mutation', 'rs868820087', (110, 116))	('GCT', 'Phenotype', 'HP:0011847', (92, 95))	('c.103 G > T', 'Var', (97, 108))	('p.G34W', 'Var', (110, 116))
14991	30538672	Furthermore, additional variants in other chromatin remodeling genes (KMT2B, EZH2, SETD2, ATRX, JMJD1C, KDM2B) were reported in this study.	('KMT2B', 'Gene', (70, 75))	('EZH2', 'Gene', (77, 81))	('variants', 'Var', (24, 32))	('JMJD1C', 'Gene', '221037', (96, 102))	('JMJD1C', 'Gene', (96, 102))	('KMT2B', 'Gene', '9757', (70, 75))	('SETD2', 'Gene', '29072', (83, 88))	('KDM2B', 'Gene', (104, 109))	('KDM2B', 'Gene', '84678', (104, 109))	('ATRX', 'Gene', (90, 94))	('SETD2', 'Gene', (83, 88))	('EZH2', 'Gene', '2146', (77, 81))	('ATRX', 'Gene', '546', (90, 94))
14993	30538672	Also, the investigators detected a somatic mutation in the main hotspot residue of the fibroblast growth factor receptor 1 gene, which is known to play a role in other cancers, such as glioblastomas.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutation', 'Var', (43, 51))	('glioblastomas', 'Phenotype', 'HP:0012174', (185, 198))	('fibroblast growth factor receptor 1', 'Gene', '2260', (87, 122))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('glioblastomas', 'Disease', 'MESH:D005909', (185, 198))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('glioblastomas', 'Disease', (185, 198))	('fibroblast growth factor receptor 1', 'Gene', (87, 122))
14996	30538672	Germline mutations in ATRX have been reported as a cause of X-linked alpha thalassemia mental retardation syndrome (ATRX syndrome).	('Germline mutations', 'Var', (0, 18))	('ATRX', 'Gene', (22, 26))	('ATRX', 'Gene', (116, 120))	('X-linked alpha thalassemia mental retardation syndrome', 'Disease', 'MESH:C538258', (60, 114))	('ATRX', 'Gene', '546', (116, 120))	('ATRX', 'Gene', '546', (22, 26))	('ATRX syndrome', 'Disease', (116, 129))	('cause', 'Reg', (51, 56))	('ATRX syndrome', 'Disease', 'MESH:C538258', (116, 129))	('mental retardation', 'Phenotype', 'HP:0001249', (87, 105))
14997	30538672	reported somatic ATRX mutations in two SDHB-related frozen tumors.	('ATRX', 'Gene', (17, 21))	('SDHB', 'Gene', '6390', (39, 43))	('ATRX', 'Gene', '546', (17, 21))	('SDHB', 'Gene', (39, 43))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
14998	30538672	They found somatic ATRX mutations in 12.6% of the samples, along with an alternative lengthening of telomeres seen on fluorescence in situ hybridization (FISH) and presenting with more aggressive disease.	('ATRX', 'Gene', '546', (19, 23))	('aggressive disease', 'Disease', 'MESH:D001523', (185, 203))	('lengthening', 'PosReg', (85, 96))	('mutations', 'Var', (24, 33))	('aggressive disease', 'Disease', (185, 203))	('ATRX', 'Gene', (19, 23))
14999	30538672	Later, the first case of an ATRX driver mutation was reported in a patient with a metastatic composite PCC-PGL, clinically with anemia, weight loss, and hepatic metastases.	('anemia', 'Disease', (128, 134))	('mutation', 'Var', (40, 48))	('hepatic metastases', 'Disease', 'MESH:D009362', (153, 171))	('weight loss', 'Phenotype', 'HP:0001824', (136, 147))	('anemia', 'Disease', 'MESH:D000740', (128, 134))	('PCC', 'Gene', '1421', (103, 106))	('ATRX', 'Gene', (28, 32))	('anemia', 'Phenotype', 'HP:0001903', (128, 134))	('weight loss', 'Disease', 'MESH:D015431', (136, 147))	('hepatic metastases', 'Disease', (153, 171))	('PCC', 'Gene', (103, 106))	('ATRX', 'Gene', '546', (28, 32))	('weight loss', 'Disease', (136, 147))	('patient', 'Species', '9606', (67, 74))
15001	30538672	Somatic mutations have been reported in association with co-existing mutations in the isocitrate dehydrogenase 1 and 2 (IDH 1/2) genes in both adult and pediatric patients with astrocytic tumors.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (163, 171))	('IDH 1/2', 'Gene', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('astrocytic tumors', 'Disease', (177, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('astrocytic tumors', 'Disease', 'MESH:D001254', (177, 194))	('IDH 1/2', 'Gene', '3417;3418', (120, 127))
15002	30538672	In addition, ATRX may play a driver mutation role for sporadic PPGL and truncated ATRX could potentially play a synergistic role with SDHx in tumor initiation and might be a predisposition for a more aggressive disease.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ATRX', 'Gene', (82, 86))	('aggressive disease', 'Disease', (200, 218))	('play', 'Reg', (105, 109))	('ATRX', 'Gene', (13, 17))	('predisposition', 'Reg', (174, 188))	('tumor initiation', 'Disease', 'MESH:D009369', (142, 158))	('ATRX', 'Gene', '546', (82, 86))	('ATRX', 'Gene', '546', (13, 17))	('SDHx', 'Chemical', '-', (134, 138))	('truncated', 'Var', (72, 81))	('tumor initiation', 'Disease', (142, 158))	('PPGL', 'Disease', (63, 67))	('aggressive disease', 'Disease', 'MESH:D001523', (200, 218))
15017	30538672	This phenotype is commonly seen in the cluster 1/ pseudohypoxia group, including both VHL and SDHx mutations.	('pseudohypoxia', 'Disease', (50, 63))	('pseudohypoxia', 'Disease', 'None', (50, 63))	('mutations', 'Var', (99, 108))	('VHL', 'Gene', (86, 89))	('SDHx', 'Chemical', '-', (94, 98))	('VHL', 'Gene', '7428', (86, 89))	('SDHx', 'Gene', (94, 98))
15029	30538672	Elevated levels of DA/3MT together with NE have been reported in approximately 65% of patients with SDHx mutations, especially in SDHB.	('DA', 'Chemical', 'MESH:D004298', (19, 21))	('SDHB', 'Gene', '6390', (130, 134))	('mutations', 'Var', (105, 114))	('SDHx', 'Gene', (100, 104))	('SDHB', 'Gene', (130, 134))	('SDHx', 'Chemical', '-', (100, 104))	('patients', 'Species', '9606', (86, 94))
15047	30538672	Regarding specific mutations, 68Ga-DOTATATE PET/CT resulted inferior in the evaluation of patients with polycythemia/PPGL: including both HIF2A and PHD1-related tumors:, FH or MAX mutations.	('polycythemia', 'Disease', 'MESH:D011086', (104, 116))	('68Ga-DOTATATE', 'Chemical', '-', (30, 43))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('HIF2A', 'Gene', '2034', (138, 143))	('mutations', 'Var', (19, 28))	('polycythemia', 'Disease', (104, 116))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('FH', 'Gene', '2271', (170, 172))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PHD1', 'Gene', '112398', (148, 152))	('HIF2A', 'Gene', (138, 143))	('polycythemia', 'Phenotype', 'HP:0001901', (104, 116))	('patients', 'Species', '9606', (90, 98))	('PHD1', 'Gene', (148, 152))
15048	30538672	In these patients: polycythemia associated to PPGL:, the combination of 18F-FDOPA PET/CT and 18F-FDA PET/CT resulted superior with a lesion-base detection rate of ~98%, vs. 35.3% for the 68Ga-DOTATATE PET/CT group (95% CI, 25.0-47.2%).	('18F-FDOPA', 'Chemical', '-', (72, 81))	('patients', 'Species', '9606', (9, 17))	('polycythemia', 'Phenotype', 'HP:0001901', (19, 31))	('polycythemia', 'Disease', 'MESH:D011086', (19, 31))	('lesion-base detection', 'MPA', (133, 154))	('18F-FDA', 'Chemical', '-', (93, 100))	('18F-FDA', 'Var', (93, 100))	('polycythemia', 'Disease', (19, 31))	('68Ga-DOTATATE', 'Chemical', '-', (187, 200))
15055	30538672	Thus, the use of more than one functional imaging modality is recommended in the pediatric group and the use of both 68Ga-DOTATATE and 18F-FDG PET/CT is highly recommended in children with small lesions, when there is a high likelihood of metastatic disease and in those patients with SDHx mutations.	('metastatic disease', 'CPA', (239, 257))	('68Ga-DOTATATE', 'Chemical', '-', (117, 130))	('SDHx', 'Chemical', '-', (285, 289))	('patients', 'Species', '9606', (271, 279))	('SDHx', 'Gene', (285, 289))	('mutations', 'Var', (290, 299))	('children', 'Species', '9606', (175, 183))	('18F-FDG', 'Chemical', 'MESH:D019788', (135, 142))
15061	30538672	When comparing PRRT with 131I-MIBG in 22 patients with metastatic/progressive PPGL, PRRT showed increased PFS and tumor response rate, as well as increased event-free and overall survival (OS).	('PPGL', 'Disease', (78, 82))	('increased', 'PosReg', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('131I-MIBG', 'Chemical', '-', (25, 34))	('overall survival', 'CPA', (171, 187))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PFS', 'CPA', (106, 109))	('PRRT', 'Var', (84, 88))	('tumor', 'Disease', (114, 119))	('patients', 'Species', '9606', (41, 49))	('event-free', 'CPA', (156, 166))
15063	30538672	A second-generation of SSTR2 antagonists that include DOTA-JR11 showed higher tumor uptake when combined with 68Ga-DOTA (1.3 times), or 68Ga-NODAGA (1.7 times) as compared with DOTA analogs.	('higher', 'PosReg', (71, 77))	('SSTR2', 'Gene', '6752', (23, 28))	('DOTA', 'Chemical', 'MESH:C071349', (177, 181))	('DA', 'Chemical', 'MESH:D004298', (143, 145))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('DOTA-JR11', 'Chemical', '-', (54, 63))	('SSTR2', 'Gene', (23, 28))	('DOTA', 'Chemical', 'MESH:C071349', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('DOTA', 'Chemical', 'MESH:C071349', (54, 58))	('DOTA-JR11', 'Var', (54, 63))
15064	30538672	In the preclinical setting, DOTA-JR11 was superior to 177Lu in H69 cell lines, and in vivo therapy experiments achieved a higher uptake, median survival rate, and a longer delay in tumor growth.	('DOTA-JR11', 'Chemical', '-', (28, 37))	('tumor', 'Disease', (181, 186))	('higher', 'PosReg', (122, 128))	('DOTA-JR11', 'Var', (28, 37))	('uptake', 'MPA', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('177Lu', 'Chemical', 'MESH:C000615061', (54, 59))	('median survival rate', 'CPA', (137, 157))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('H69', 'CellLine', 'CVCL:8121', (63, 66))
15139	29977594	SDHx mutation.	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
15164	28881853	Actually, succinate dehydrogenase gene mutations and abnormal succinate accumulation have been observed in a battery of hereditary and sporadic malignancies.	('succinate', 'Chemical', 'MESH:D019802', (62, 71))	('sporadic malignancies', 'Disease', (135, 156))	('observed', 'Reg', (95, 103))	('sporadic malignancies', 'Disease', 'MESH:D009369', (135, 156))	('succinate dehydrogenase', 'Gene', (10, 33))	('succinate dehydrogenase', 'Gene', '6390', (10, 33))	('mutations', 'Var', (39, 48))	('succinate accumulation', 'MPA', (62, 84))	('succinate', 'Chemical', 'MESH:D019802', (10, 19))
15170	28881853	Random mutation of SDH subunits by hereditary or acquired influences will contribute to the abnormal accumulation of succinate in the cytosol.	('succinate', 'Chemical', 'MESH:D019802', (117, 126))	('SDH', 'Gene', (19, 22))	('Random mutation', 'Var', (0, 15))	('contribute', 'Reg', (74, 84))	('accumulation of succinate in the cytosol', 'MPA', (101, 141))	('SDH', 'Gene', '6390', (19, 22))
15172	28881853	Mutations in SDH have been identified in specific cancers, both genetic and sporadic, such as familial paraganglioma/pheochromocytoma (PGL/PCC), renal carcinoma, thyroid cancer, ovarian cancer, neuroblastoma, gastrointestinal stromal tumor, and even testicular seminoma.	('familial paraganglioma/pheochromocytoma', 'Disease', (94, 133))	('neuroblastoma', 'Disease', 'MESH:D009447', (194, 207))	('identified', 'Reg', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('ovarian cancer', 'Disease', 'MESH:D010051', (178, 192))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (209, 239))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('PCC', 'Gene', (139, 142))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (209, 239))	('PGL', 'Disease', (135, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (117, 133))	('thyroid cancer', 'Disease', 'MESH:D013964', (162, 176))	('renal carcinoma', 'Disease', 'MESH:C538614', (145, 160))	('Mutations', 'Var', (0, 9))	('PCC', 'Gene', '1421', (139, 142))	('ovarian cancer', 'Disease', (178, 192))	('SDH', 'Gene', '6390', (13, 16))	('gastrointestinal stromal tumor', 'Disease', (209, 239))	('testicular seminoma', 'Disease', 'MESH:D018239', (250, 269))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('renal carcinoma', 'Disease', (145, 160))	('renal carcinoma', 'Phenotype', 'HP:0005584', (145, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('thyroid cancer', 'Phenotype', 'HP:0002890', (162, 176))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('SDH', 'Gene', (13, 16))	('neuroblastoma', 'Disease', (194, 207))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('testicular seminoma', 'Phenotype', 'HP:0100617', (250, 269))	('PGL', 'Disease', 'MESH:D010235', (135, 138))	('testicular seminoma', 'Disease', (250, 269))	('neuroblastoma', 'Phenotype', 'HP:0003006', (194, 207))	('familial paraganglioma/pheochromocytoma', 'Disease', 'MESH:C531777', (94, 133))	('thyroid cancer', 'Disease', (162, 176))
15185	28881853	In contrast, deletion of TRAP1 to prevent SDH inhibition delayed prostatic tumorigenesis.	('prostatic', 'Disease', (65, 74))	('delayed', 'NegReg', (57, 64))	('SDH', 'Gene', '6390', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('deletion', 'Var', (13, 21))	('SDH', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('TRAP1', 'Gene', '10131', (25, 30))	('TRAP1', 'Gene', (25, 30))	('tumor', 'Disease', (75, 80))
15192	28881853	Mutations of the gene encoding SDH result in the accumulation of succinate.	('SDH', 'Gene', '6390', (31, 34))	('accumulation of succinate', 'MPA', (49, 74))	('SDH', 'Gene', (31, 34))	('Mutations', 'Var', (0, 9))	('succinate', 'Chemical', 'MESH:D019802', (65, 74))
15194	28881853	Although succinate is known as a classic "housekeeping gene", SDH mutations are commonly found in a series of neoplasms and different subunit mutations can lead to different types of tumors.	('mutations', 'Var', (66, 75))	('SDH', 'Gene', '6390', (62, 65))	('lead to', 'Reg', (156, 163))	('succinate', 'Chemical', 'MESH:D019802', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('SDH', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('neoplasms', 'Disease', 'MESH:D009369', (110, 119))	('neoplasms', 'Disease', (110, 119))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))
15195	28881853	It is noteworthy that most mediastinal paragangliomas (PGLs) were related to SDHD gene mutations, whereas germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma.	('SDHB', 'Gene', (128, 132))	('PGL', 'Disease', 'MESH:D010235', (55, 58))	('SDHD', 'Gene', '6392', (77, 81))	('neck paraganglioma', 'Disease', (181, 199))	('SDHD', 'Gene', (77, 81))	('paraganglioma', 'Phenotype', 'HP:0002668', (186, 199))	('related', 'Reg', (66, 73))	('paragangliomas', 'Disease', (39, 53))	('paragangliomas', 'Disease', 'MESH:D010235', (39, 53))	('neck paraganglioma', 'Disease', 'MESH:D010235', (181, 199))	('SDHB', 'Gene', '6390', (128, 132))	('PGLs', 'Phenotype', 'HP:0002668', (55, 59))	('PGL', 'Disease', (55, 58))	('paragangliomas', 'Phenotype', 'HP:0002668', (39, 53))	('mutations', 'Var', (87, 96))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (172, 199))	('paraganglioma', 'Phenotype', 'HP:0002668', (39, 52))
15196	28881853	To date, the genomics research on PGL/PCC has demonstrated that mutations of SDHD and SDHC cause PGL1 and PGL3, while PGL4, PGL5, and PGL2 are associated with mutations in the large subunit genes SDHB, SDHA and SDHAF2, respectively.	('PGL', 'Disease', 'MESH:D010235', (134, 137))	('PGL', 'Disease', (97, 100))	('PGL', 'Disease', (106, 109))	('PCC', 'Gene', '1421', (38, 41))	('PGL2', 'Gene', '54949', (134, 138))	('PGL', 'Disease', 'MESH:D010235', (124, 127))	('SDHB', 'Gene', '6390', (196, 200))	('PGL3', 'Gene', (106, 110))	('SDHC', 'Gene', (86, 90))	('PGL5', 'Gene', (124, 128))	('associated', 'Reg', (143, 153))	('PGL', 'Disease', (118, 121))	('PGL3', 'Gene', '6391', (106, 110))	('PGL', 'Disease', (134, 137))	('mutations', 'Var', (64, 73))	('PGL5', 'Gene', '6389', (124, 128))	('SDHB', 'Gene', (196, 200))	('PGL', 'Disease', (124, 127))	('PGL', 'Disease', 'MESH:D010235', (106, 109))	('PGL', 'Disease', 'MESH:D010235', (34, 37))	('PGL4', 'Gene', (118, 122))	('SDHD', 'Gene', '6392', (77, 81))	('PGL4', 'Gene', '6390', (118, 122))	('PGL', 'Disease', 'MESH:D010235', (97, 100))	('SDHA', 'Gene', (211, 215))	('SDHAF2', 'Gene', '54949', (211, 217))	('SDHA', 'Gene', (202, 206))	('cause', 'Reg', (91, 96))	('SDHA', 'Gene', '6389', (211, 215))	('PGL2', 'Gene', (134, 138))	('PGL', 'Disease', 'MESH:D010235', (118, 121))	('SDHD', 'Gene', (77, 81))	('PCC', 'Gene', (38, 41))	('SDHA', 'Gene', '6389', (202, 206))	('PGL', 'Disease', (34, 37))	('SDHAF2', 'Gene', (211, 217))
15197	28881853	In the case of renal cell carcinoma and papillary thyroid cancer, dysfunction of the SDHB domain is the greatest risk factor.	('papillary thyroid cancer', 'Disease', (40, 64))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('dysfunction', 'Var', (66, 77))	('renal cell carcinoma', 'Disease', (15, 35))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (15, 35))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (40, 64))	('thyroid cancer', 'Phenotype', 'HP:0002890', (50, 64))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (15, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
15198	28881853	Additionally, mutations in SDHA, SDHB, and SDHC have also been implicated in gastrointestinal stromal tumors.	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (77, 108))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (77, 108))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (77, 107))	('SDHA', 'Gene', (27, 31))	('SDHB', 'Gene', '6390', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('gastrointestinal stromal tumors', 'Disease', (77, 108))	('SDHB', 'Gene', (33, 37))	('SDHA', 'Gene', '6389', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mutations', 'Var', (14, 23))	('implicated', 'Reg', (63, 73))	('SDHC', 'Gene', (43, 47))
15199	28881853	As previously described, SDH mutations have been observed in some hereditary and non-genetic tumors, such as PGL/PCC, thyroid cancer and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('observed', 'Reg', (49, 57))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('PCC', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('SDH', 'Gene', (25, 28))	('PGL', 'Disease', (109, 112))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PCC', 'Gene', '1421', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutations', 'Var', (29, 38))	('ovarian cancer', 'Disease', (137, 151))	('tumors', 'Disease', (93, 99))	('thyroid cancer', 'Disease', (118, 132))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('PGL', 'Disease', 'MESH:D010235', (109, 112))	('SDH', 'Gene', '6390', (25, 28))
15200	28881853	As it is a key enzyme involved in the TCA cycle, both inactivity and dysfunction of SDH can lead to succinate accumulation and low level of fumarate.	('low level of fumarate', 'MPA', (127, 148))	('succinate', 'Chemical', 'MESH:D019802', (100, 109))	('lead to', 'Reg', (92, 99))	('fumarate', 'Chemical', 'MESH:D005650', (140, 148))	('dysfunction', 'Var', (69, 80))	('inactivity', 'Var', (54, 64))	('TCA', 'Chemical', 'MESH:D014238', (38, 41))	('SDH', 'Gene', '6390', (84, 87))	('succinate accumulation', 'MPA', (100, 122))	('SDH', 'Gene', (84, 87))
15202	28881853	Mitochondrial respiratory disorder resulting from enzyme dysfunction has been shown to be directly responsible for the initiation of cancer, while mutations of SDH should bear most of the responsibility.	('SDH', 'Gene', (160, 163))	('mutations', 'Var', (147, 156))	('Mitochondrial respiratory disorder', 'Disease', (0, 34))	('responsible', 'Reg', (99, 110))	('initiation of cancer', 'Disease', (119, 139))	('Mitochondrial respiratory disorder', 'Disease', 'MESH:D012131', (0, 34))	('initiation of cancer', 'Disease', 'MESH:D009369', (119, 139))	('SDH', 'Gene', '6390', (160, 163))	('enzyme dysfunction', 'Disease', 'MESH:D008661', (50, 68))	('enzyme dysfunction', 'Disease', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
15214	28881853	In summary, the involvement of SDH mutations, glyoxylate shunt and the tumor-associated inflammatory response can indeed contribute to high concentrations of succinate in cancer (Figure 1).	('SDH', 'Gene', '6390', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('involvement', 'Reg', (16, 27))	('glyoxylate', 'Chemical', 'MESH:C031150', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Disease', (171, 177))	('SDH', 'Gene', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('high concentrations of succinate', 'MPA', (135, 167))	('contribute', 'Reg', (121, 131))	('succinate', 'Chemical', 'MESH:D019802', (158, 167))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mutations', 'Var', (35, 44))
15221	28881853	A concise summary, all these adjustments resulting in succinate accumulation in cancer cells will conversely facilitate cellular transformation and tumor evolvement.	('adjustments', 'Var', (29, 40))	('cancer', 'Disease', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('succinate accumulation', 'MPA', (54, 76))	('succinate', 'Chemical', 'MESH:D019802', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (148, 153))	('resulting in', 'Reg', (41, 53))	('cellular transformation', 'CPA', (120, 143))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('facilitate', 'PosReg', (109, 119))
15227	28881853	Abnormally accumulated succinate in mitochondria which causes by inherited or somatic mutations in random subunits of SDH will be freely transported to the cytosol via the dicarboxylic acid translocator in the mitochondrial inner membrane and the voltage-dependent anion channel (VDAC/porin) in the mitochondrial outer membrane.	('mutations', 'Var', (86, 95))	('dicarboxylic acid', 'Chemical', 'MESH:D003998', (172, 189))	('Abnormally accumulated succinate', 'Phenotype', 'HP:0020149', (0, 32))	('SDH', 'Gene', '6390', (118, 121))	('succinate', 'Chemical', 'MESH:D019802', (23, 32))	('porin', 'Gene', (285, 290))	('porin', 'Gene', '7416', (285, 290))	('causes', 'Reg', (55, 61))	('SDH', 'Gene', (118, 121))
15235	28881853	Subsequent studies showed that any defects in SDHB, SDHC, or SDHD, but not SDHA, will disrupt complex II enzymatic activity in mitochondria.	('SDHA', 'Gene', (75, 79))	('SDHB', 'Gene', '6390', (46, 50))	('disrupt', 'NegReg', (86, 93))	('SDHB', 'Gene', (46, 50))	('SDHD', 'Gene', '6392', (61, 65))	('SDHC', 'Gene', (52, 56))	('complex II enzymatic activity in mitochondria', 'MPA', (94, 139))	('SDHD', 'Gene', (61, 65))	('SDHA', 'Gene', '6389', (75, 79))	('defects', 'Var', (35, 42))
15236	28881853	Dysfunction of mitochondria stemming from TCA cycle enzyme inactivation leads to ROS overproduction directly and indirectly.	('inactivation', 'NegReg', (59, 71))	('Dysfunction', 'Var', (0, 11))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('TCA', 'Chemical', 'MESH:D014238', (42, 45))	('overproduction', 'PosReg', (85, 99))	('ROS', 'Protein', (81, 84))
15237	28881853	Once elevated in the cytosol, ROS can oxidize amino acid residues within fatty acids and proteins, and cause irreversible DNA damage and genomic instability, leading to carcinogenesis and tumorigenesis.	('tumor', 'Disease', (188, 193))	('oxidize amino acid residues', 'MPA', (38, 65))	('carcinogenesis', 'Disease', (169, 183))	('fatty acids', 'Chemical', 'MESH:D005227', (73, 84))	('DNA damage', 'MPA', (122, 132))	('leading to', 'Reg', (158, 168))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cause', 'Reg', (103, 108))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('genomic instability', 'CPA', (137, 156))	('ROS', 'Var', (30, 33))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
15238	28881853	In addition to the oxidative stress pathway, ROS production resulting from SDH defects can also act as signal transduction messengers to stabilize HIF-1alpha through oxidizing Fe2+ to Fe3+, as Fe2+ is a critical cofactor of PHD.	('Fe2+', 'Chemical', 'MESH:C038178', (176, 180))	('Fe2+', 'Chemical', 'MESH:C038178', (193, 197))	('oxidative stress', 'Phenotype', 'HP:0025464', (19, 35))	('defects', 'Var', (79, 86))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('HIF-1alpha', 'Gene', '3091', (147, 157))	('PHD', 'Disease', 'MESH:D011547', (224, 227))	('ROS production', 'MPA', (45, 59))	('SDH', 'Gene', '6390', (75, 78))	('PHD', 'Disease', (224, 227))	('stabilize', 'MPA', (137, 146))	('Fe3+', 'Chemical', '-', (184, 188))	('SDH', 'Gene', (75, 78))	('HIF-1alpha', 'Gene', (147, 157))	('oxidizing Fe2+ to Fe3+', 'MPA', (166, 188))
15258	28881853	Although the evidence of the relationship between SDH mutation and NRF2 activation is insufficient, SDH inhibition is more likely to induce NRF2 production, and this may depend on increased ROS production.	('mutation', 'Var', (54, 62))	('inhibition', 'NegReg', (104, 114))	('SDH', 'Gene', '6390', (100, 103))	('induce', 'PosReg', (133, 139))	('NRF2', 'Gene', '4780', (67, 71))	('increased ROS production', 'Phenotype', 'HP:0025464', (180, 204))	('SDH', 'Gene', (100, 103))	('SDH', 'Gene', '6390', (50, 53))	('insufficient', 'Disease', 'MESH:D000309', (86, 98))	('NRF2', 'Gene', (67, 71))	('insufficient', 'Disease', (86, 98))	('NRF2', 'Gene', '4780', (140, 144))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('SDH', 'Gene', (50, 53))	('NRF2', 'Gene', (140, 144))
15261	28881853	Taken together, accumulation of succinate in the tumor microenvironment finally enhances the tumor-associated inflammation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('enhances', 'PosReg', (80, 88))	('inflammation', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (49, 54))	('succinate', 'Chemical', 'MESH:D019802', (32, 41))	('accumulation', 'Var', (16, 28))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
15272	28881853	While SDH mutation is generally acknowledged as the culprit for the high level of succinate, the comprehensive mechanisms that contribute to its accumulation remain mysterious.	('high level of succinate', 'Phenotype', 'HP:0020149', (68, 91))	('SDH', 'Gene', (6, 9))	('mutation', 'Var', (10, 18))	('succinate', 'Chemical', 'MESH:D019802', (82, 91))	('SDH', 'Gene', '6390', (6, 9))
15396	27873108	MCT is caused by mutations in the RET proto-oncogene, and may be sporadic or inherited in an autosomal dominant pattern in approximately 25% of cases as part of multiple endocrine neoplasia (MEN2A and MEN2B) or familial MTC.	('RET', 'Gene', '5979', (34, 37))	('multiple endocrine neoplasia', 'Disease', (161, 189))	('MCT', 'Disease', (0, 3))	('familial MTC', 'Disease', (211, 223))	('neoplasia', 'Phenotype', 'HP:0002664', (180, 189))	('RET', 'Gene', (34, 37))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (170, 189))	('MEN2A', 'Gene', '5979', (191, 196))	('MEN2B', 'Gene', (201, 206))	('caused by', 'Reg', (7, 16))	('MEN2B', 'Gene', '5979', (201, 206))	('mutations', 'Var', (17, 26))	('MEN2A', 'Gene', (191, 196))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (161, 189))
15415	27873108	Endogenous Cushing syndrome is the result of chronic glucocorticoid excess from either an ACTH-secreting pituitary tumor, cortisol producing adenoma, adrenal hyperplasia, or ectopic production of ACTH and/or CRH from a neuroendocrine tumor.	('adrenal hyperplasia', 'Disease', (150, 169))	('CRH', 'Gene', (208, 211))	('neuroendocrine tumor', 'Disease', (219, 239))	('ACTH', 'Gene', '5443', (196, 200))	('ACTH', 'Gene', (90, 94))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (219, 239))	('Cushing syndrome', 'Disease', 'MESH:D003480', (11, 27))	('ectopic', 'Var', (174, 181))	('pituitary tumor', 'Disease', 'MESH:D010911', (105, 120))	('adenoma', 'Disease', (141, 148))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (11, 27))	('adrenal hyperplasia', 'Disease', 'MESH:D000312', (150, 169))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('pituitary tumor', 'Disease', (105, 120))	('Cushing syndrome', 'Disease', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (219, 239))	('adenoma', 'Disease', 'MESH:D000236', (141, 148))	('endocrine tumor', 'Phenotype', 'HP:0100568', (224, 239))	('ACTH', 'Gene', (196, 200))	('glucocorticoid', 'MPA', (53, 67))	('CRH', 'Gene', '1392', (208, 211))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (150, 169))	('ACTH', 'Gene', '5443', (90, 94))	('glucocorticoid excess', 'Phenotype', 'HP:0003118', (53, 74))	('ACTH-secreting pituitary tumor', 'Phenotype', 'HP:0008291', (90, 120))
15421	27873108	More than two thirds of perimenopausal women experience hot flashes which may represent a marker of underlying cardiovascular disease; a recent study examined the role of genetic variation in the tachykinin receptor 3 (TACR3) as a contributor to hot flashes.	('cardiovascular disease', 'Disease', 'MESH:D002318', (111, 133))	('TACR3', 'Gene', '6870', (219, 224))	('men', 'Species', '9606', (28, 31))	('women', 'Species', '9606', (39, 44))	('cardiovascular disease', 'Disease', (111, 133))	('hot flashes', 'Phenotype', 'HP:0031217', (246, 257))	('tachykinin receptor 3', 'Gene', (196, 217))	('hot flashes', 'Phenotype', 'HP:0031217', (56, 67))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (111, 133))	('tachykinin receptor 3', 'Gene', '6870', (196, 217))	('genetic variation', 'Var', (171, 188))	('TACR3', 'Gene', (219, 224))	('men', 'Species', '9606', (41, 44))	('amine', 'Chemical', 'MESH:D000588', (152, 157))
15494	25929929	PVS does not usually decrease the cardiac output or trigger cyclical blood pressure fluctuations itself, but it instead causes persistent hypotension that is difficult to correct or triggers high blood pressure.	('hypotension', 'Disease', (138, 149))	('causes', 'Reg', (120, 126))	('hypotension', 'Phenotype', 'HP:0002615', (138, 149))	('PVS', 'Var', (0, 3))	('triggers', 'Reg', (182, 190))	('high blood pressure', 'Phenotype', 'HP:0000822', (191, 210))	('cyclical blood pressure', 'Phenotype', 'HP:0000875', (60, 83))	('hypotension', 'Disease', 'MESH:D007022', (138, 149))	('cardiac', 'MPA', (34, 41))
15514	25874239	The combination therapy with I-131 MIBG and other modalities such as nonmyeloablative chemotherapy and myeloablative chemotherapy with HCT improved the therapeutic response in patients with refractory or relapsed neuroblastoma.	('patients', 'Species', '9606', (176, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (213, 226))	('I-131 MIBG', 'Chemical', '-', (29, 39))	('neuroblastoma', 'Disease', (213, 226))	('improved', 'PosReg', (139, 147))	('refractory', 'Disease', (190, 200))	('neuroblastoma', 'Disease', 'MESH:D009447', (213, 226))	('therapeutic', 'MPA', (152, 163))	('I-131', 'Var', (29, 34))	('MIBG', 'Gene', (35, 39))
15533	25874239	The uptake of MIBG in neuroendocrine cells such as normal adrenomedullary cells, neuroblastoma, and pheochromocytoma cells is similar to the uptake of NE.	('pheochromocytoma', 'Disease', 'MESH:D010673', (100, 116))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('MIBG', 'Var', (14, 18))	('MIBG', 'Chemical', 'MESH:D019797', (14, 18))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('neuroblastoma', 'Disease', (81, 94))	('pheochromocytoma', 'Disease', (100, 116))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))
15547	25874239	Relative contraindications are provided as uncontrollable medical risk and urinary incontinence by isolation and decreased renal function by glomerular filtration rate (GFR) less than 30 mL/min.	('less than 30', 'Var', (174, 186))	('urinary incontinence', 'Disease', 'MESH:D014549', (75, 95))	('urinary incontinence', 'Disease', (75, 95))	('urinary incontinence', 'Phenotype', 'HP:0000020', (75, 95))	('decreased renal function', 'Disease', (113, 137))	('decreased renal function', 'Disease', 'MESH:D051437', (113, 137))
15549	25874239	Typical acute toxicities usually seen within two or three days after I-131 MIBG administration are nausea and vomiting.	('toxicities', 'Disease', (14, 24))	('nausea', 'Disease', 'MESH:D009325', (99, 105))	('I-131 MIBG', 'Chemical', '-', (69, 79))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (99, 118))	('MIBG', 'Gene', (75, 79))	('I-131', 'Var', (69, 74))	('toxicities', 'Disease', 'MESH:D064420', (14, 24))	('vomiting', 'Phenotype', 'HP:0002013', (110, 118))	('vomiting', 'Disease', (110, 118))	('nausea', 'Phenotype', 'HP:0002018', (99, 105))	('nausea', 'Disease', (99, 105))	('vomiting', 'Disease', 'MESH:D014839', (110, 118))
15554	25874239	Table 1 shows acute toxicities in 40 patients with refractory or relapsed neuroblastoma treated with I-131 MIBG at a mean dose of 10.5 mCi/kg in our institution.	('toxicities', 'Disease', 'MESH:D064420', (20, 30))	('patients', 'Species', '9606', (37, 45))	('neuroblastoma', 'Disease', 'MESH:D009447', (74, 87))	('neuroblastoma', 'Disease', (74, 87))	('I-131 MIBG', 'Chemical', '-', (101, 111))	('I-131', 'Var', (101, 106))	('neuroblastoma', 'Phenotype', 'HP:0003006', (74, 87))	('toxicities', 'Disease', (20, 30))
15567	25874239	Venoocclusive liver disease (VOLD) is an important early complication in patients received I-131 MIBG therapy followed by myeloablative chemotherapy and HCT.	('MIBG', 'Gene', (97, 101))	('I-131', 'Var', (91, 96))	('Venoocclusive liver disease', 'Disease', 'MESH:D011668', (0, 27))	('VOLD', 'Disease', (29, 33))	('Venoocclusive liver disease', 'Disease', (0, 27))	('I-131 MIBG', 'Chemical', '-', (91, 101))	('VOLD', 'Disease', 'None', (29, 33))	('patients', 'Species', '9606', (73, 81))	('liver disease', 'Phenotype', 'HP:0001392', (14, 27))
15583	25874239	Since the first I-131 MIBG therapy for neuroblastoma were reported in 1986, many monotherapy trials with I-131 MIBG for refractory or relapsed neuroblastoma were reported and obtained objective responses (partial or complete response) in 0 to 66%.	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('I-131 MIBG', 'Chemical', '-', (16, 26))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('neuroblastoma', 'Disease', (39, 52))	('I-131 MIBG', 'Chemical', '-', (105, 115))	('neuroblastoma', 'Disease', (143, 156))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('I-131', 'Var', (105, 110))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))
15586	25874239	For instance, an Italian group treated 42 patients with refractory or relapsed neuroblastoma with 75 to 162 mCi of I-131 MIBG per each therapy.	('neuroblastoma', 'Phenotype', 'HP:0003006', (79, 92))	('I-131 MIBG', 'Chemical', '-', (115, 125))	('neuroblastoma', 'Disease', 'MESH:D009447', (79, 92))	('I-131', 'Var', (115, 120))	('neuroblastoma', 'Disease', (79, 92))	('patients', 'Species', '9606', (42, 50))	('MIBG', 'Gene', (121, 125))
15588	25874239	In the phase II study by a French group, 26 patients with refractory or relapsed neuroblastoma were treated with 30 to 108 mCi of I-131 MIBG per each therapy.	('I-131', 'Var', (130, 135))	('patients', 'Species', '9606', (44, 52))	('neuroblastoma', 'Disease', 'MESH:D009447', (81, 94))	('refractory', 'Disease', (58, 68))	('neuroblastoma', 'Disease', (81, 94))	('I-131 MIBG', 'Chemical', '-', (130, 140))	('neuroblastoma', 'Phenotype', 'HP:0003006', (81, 94))
15590	25874239	In a recent report from Israel, I-131 MIBG therapy at a dose of 5 mCi/kg (maximum dose 150 mCi) per each therapy acquired pain palliation in 90% of the first therapies and 87.5% of the second therapies in 10 symptomatic patients with refractory neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (245, 258))	('neuroblastoma', 'Disease', (245, 258))	('I-131 MIBG', 'Chemical', '-', (32, 42))	('patients', 'Species', '9606', (220, 228))	('neuroblastoma', 'Phenotype', 'HP:0003006', (245, 258))	('pain', 'Phenotype', 'HP:0012531', (122, 126))	('I-131', 'Var', (32, 37))	('pain', 'Disease', 'MESH:D010146', (122, 126))	('pain', 'Disease', (122, 126))
15591	25874239	Lower doses of I-131 MIBG obtain a few objective responses, whereas can achieve high-probability pain reduction (Figure 1).	('pain', 'Phenotype', 'HP:0012531', (97, 101))	('pain', 'Disease', 'MESH:D010146', (97, 101))	('I-131 MIBG', 'Chemical', '-', (15, 25))	('pain', 'Disease', (97, 101))	('MIBG', 'Gene', (21, 25))	('reduction', 'NegReg', (102, 111))	('I-131', 'Var', (15, 20))
15592	25874239	In a phase I study from UCSF, 30 patients with refractory or relapsed neuroblastoma were treated with I-131 MIBG at escalating doses of 3 to 18 mCi/kg per each therapy.	('I-131', 'Var', (102, 107))	('neuroblastoma', 'Disease', (70, 83))	('patients', 'Species', '9606', (33, 41))	('neuroblastoma', 'Phenotype', 'HP:0003006', (70, 83))	('refractory', 'Disease', (47, 57))	('I-131 MIBG', 'Chemical', '-', (102, 112))	('MIBG', 'Gene', (108, 112))	('neuroblastoma', 'Disease', 'MESH:D009447', (70, 83))
15610	25874239	On the basis of I-131 MIBG monotherapeutic results, some groups tried the combination therapy with I-131 MIBG and chemotherapy agents act as radiosensitizers for refractory or relapsed neuroblastoma.	('I-131', 'Var', (99, 104))	('neuroblastoma', 'Phenotype', 'HP:0003006', (185, 198))	('I-131 MIBG', 'Chemical', '-', (16, 26))	('refractory', 'Disease', (162, 172))	('neuroblastoma', 'Disease', 'MESH:D009447', (185, 198))	('I-131 MIBG', 'Chemical', '-', (99, 109))	('neuroblastoma', 'Disease', (185, 198))
15611	25874239	In a report from Italy, 4 patients with refractory or relapsed neuroblastoma were administered I-131 MIBG in combination with cisplatin.	('neuroblastoma', 'Phenotype', 'HP:0003006', (63, 76))	('I-131', 'Var', (95, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('patients', 'Species', '9606', (26, 34))	('neuroblastoma', 'Disease', 'MESH:D009447', (63, 76))	('I-131 MIBG', 'Chemical', '-', (95, 105))	('neuroblastoma', 'Disease', (63, 76))
15613	25874239	In addition, the same group treated 16 patients with 200 mCi I-131 MIBG plus cisplatin and cyclophosphamide with or without etoposide and vincristine.	('etoposide', 'Chemical', 'MESH:D005047', (124, 133))	('patients', 'Species', '9606', (39, 47))	('MIBG', 'Gene', (67, 71))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (91, 107))	('I-131 MIBG', 'Chemical', '-', (61, 71))	('vincristine', 'Chemical', 'MESH:D014750', (138, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('I-131', 'Var', (61, 66))
15620	25874239	In a phase I study from the NANT consortium, 24 patients with refractory or relapsed neuroblastoma treated with irinotecan which is another topoisomerase I inhibitor, vincristine, and I-131 MIBG at escalating doses of 8 to 18 mCi/kg.	('MIBG', 'Gene', (190, 194))	('vincristine', 'Chemical', 'MESH:D014750', (167, 178))	('irinotecan', 'Chemical', 'MESH:D000077146', (112, 122))	('I-131 MIBG', 'Chemical', '-', (184, 194))	('neuroblastoma', 'Disease', 'MESH:D009447', (85, 98))	('neuroblastoma', 'Disease', (85, 98))	('I-131', 'Var', (184, 189))	('patients', 'Species', '9606', (48, 56))	('NANT', 'Chemical', '-', (28, 32))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))
15623	25874239	A phase I study with a combination of I-131 MIBG and vorinostat for refractory or relapsed neuroblastoma is now examined by the NANT consortium (N2007-03).	('neuroblastoma', 'Disease', 'MESH:D009447', (91, 104))	('I-131 MIBG', 'Var', (38, 48))	('neuroblastoma', 'Disease', (91, 104))	('vorinostat', 'Chemical', 'MESH:D000077337', (53, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (91, 104))	('I-131 MIBG', 'Chemical', '-', (38, 48))	('NANT', 'Chemical', '-', (128, 132))
15629	25874239	In a phase I dose escalation study by the NANT consortium, 24 patients with refractory neuroblastoma were treated with I-131 MIBG at escalating doses of 12 to 18 mCi/kg on day -21 along with CEM on day -7 to day -4.	('MIBG', 'Gene', (125, 129))	('I-131', 'Var', (119, 124))	('CEM', 'Chemical', '-', (191, 194))	('neuroblastoma', 'Phenotype', 'HP:0003006', (87, 100))	('neuroblastoma', 'Disease', 'MESH:D009447', (87, 100))	('I-131 MIBG', 'Chemical', '-', (119, 129))	('patients', 'Species', '9606', (62, 70))	('NANT', 'Chemical', '-', (42, 46))	('neuroblastoma', 'Disease', (87, 100))
15635	25874239	Eight patients with refractory neuroblastoma were treated with 18 mCi/kg I-131 MIBG on day -13 and auto-HCT on day 0.	('neuroblastoma', 'Phenotype', 'HP:0003006', (31, 44))	('I-131 MIBG', 'Chemical', '-', (73, 83))	('I-131', 'Var', (73, 78))	('patients', 'Species', '9606', (6, 14))	('neuroblastoma', 'Disease', 'MESH:D009447', (31, 44))	('neuroblastoma', 'Disease', (31, 44))
15642	25874239	Two patients with relapsed neuroblastoma treated with I-131 MIBG and allo-HCT were reported in case reports from Japan.	('I-131', 'Var', (54, 59))	('neuroblastoma', 'Disease', (27, 40))	('neuroblastoma', 'Phenotype', 'HP:0003006', (27, 40))	('I-131 MIBG', 'Chemical', '-', (54, 64))	('patients', 'Species', '9606', (4, 12))	('neuroblastoma', 'Disease', 'MESH:D009447', (27, 40))
15649	25874239	Exposure of the neuroblastoma cells to hyperbaric oxygen (HBO) enhanced the effects of I-131 MIBG on decreasing cell proliferation and energy metabolism and increasing lipid peroxidation.	('cell proliferation', 'CPA', (112, 130))	('decreasing', 'NegReg', (101, 111))	('lipid', 'Chemical', 'MESH:D008055', (168, 173))	('neuroblastoma', 'Disease', 'MESH:D009447', (16, 29))	('I-131 MIBG', 'Chemical', '-', (87, 97))	('I-131', 'Var', (87, 92))	('increasing', 'PosReg', (157, 167))	('neuroblastoma', 'Disease', (16, 29))	('lipid peroxidation', 'MPA', (168, 186))	('neuroblastoma', 'Phenotype', 'HP:0003006', (16, 29))	('oxygen', 'Chemical', 'MESH:D010100', (50, 56))	('energy metabolism', 'MPA', (135, 152))	('MIBG', 'Gene', (93, 97))
15650	25874239	These effects may provide the positive effects on neuroblastoma patients treated with the combination of I-131 MIBG and HBO.	('neuroblastoma', 'Disease', 'MESH:D009447', (50, 63))	('patients', 'Species', '9606', (64, 72))	('positive', 'PosReg', (30, 38))	('neuroblastoma', 'Disease', (50, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (50, 63))	('I-131 MIBG', 'Chemical', '-', (105, 115))	('I-131', 'Var', (105, 110))
15674	25874239	A pilot study of intensive induction chemotherapy and I-131 MIBG undergoing HCT for newly diagnosed advanced neuroblastoma by the Children's Oncology Group is currently recruiting participants.	('Children', 'Species', '9606', (130, 138))	('Oncology', 'Phenotype', 'HP:0002664', (141, 149))	('I-131 MIBG', 'Var', (54, 64))	('neuroblastoma', 'Disease', 'MESH:D009447', (109, 122))	('I-131 MIBG', 'Chemical', '-', (54, 64))	('neuroblastoma', 'Disease', (109, 122))	('neuroblastoma', 'Phenotype', 'HP:0003006', (109, 122))	('participants', 'Species', '9606', (180, 192))
15675	25874239	Recently, a Dutch group reported the result of I-131 MIBG therapy in patients with unresectable localized neuroblastoma.	('localized neuroblastoma', 'Phenotype', 'HP:0006768', (96, 119))	('localized neuroblastoma', 'Disease', 'MESH:D009447', (96, 119))	('I-131 MIBG', 'Chemical', '-', (47, 57))	('patients', 'Species', '9606', (69, 77))	('neuroblastoma', 'Phenotype', 'HP:0003006', (106, 119))	('localized neuroblastoma', 'Disease', (96, 119))	('I-131', 'Var', (47, 52))
15676	25874239	Twenty-one patients with any organ dysfunctions were treated with I-131 MIBG for unresectable localized neuroblastoma.	('MIBG', 'Gene', (72, 76))	('dysfunctions', 'Disease', 'MESH:D006331', (35, 47))	('dysfunctions', 'Disease', (35, 47))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('localized neuroblastoma', 'Phenotype', 'HP:0006768', (94, 117))	('localized neuroblastoma', 'Disease', 'MESH:D009447', (94, 117))	('I-131', 'Var', (66, 71))	('patients', 'Species', '9606', (11, 19))	('localized neuroblastoma', 'Disease', (94, 117))	('I-131 MIBG', 'Chemical', '-', (66, 76))
15688	25874239	Dose-limiting toxicity was not observed in all of 3, 3, and 6 patients treated with 12, 15, and 18 mCi/kg I-131 MIBG.	('I-131', 'Var', (106, 111))	('toxicity', 'Disease', 'MESH:D064420', (14, 22))	('patients', 'Species', '9606', (62, 70))	('toxicity', 'Disease', (14, 22))	('I-131 MIBG', 'Chemical', '-', (106, 116))
15694	25874239	In phases I and II trials by the University of Michigan, 10 patients with refractory or relapsed neuroblastoma received I-125 MIBG therapy at a dose of 224 to 814 mCi.	('I-125', 'Var', (120, 125))	('refractory', 'Disease', (74, 84))	('neuroblastoma', 'Disease', (97, 110))	('I-125 MIBG', 'Chemical', '-', (120, 130))	('patients', 'Species', '9606', (60, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (97, 110))	('neuroblastoma', 'Disease', 'MESH:D009447', (97, 110))
15696	25874239	Further studies are needed, such as for macroscopic disease with a combination with I-125 MIBG and I-131 MIBG and for microscopic disease with I-125 MIBG.	('I-125', 'Var', (143, 148))	('I-131 MIBG', 'Var', (99, 109))	('I-125 MIBG', 'Chemical', '-', (143, 153))	('microscopic', 'Disease', (118, 129))	('macroscopic disease', 'Disease', (40, 59))	('I-125', 'Var', (84, 89))	('I-125 MIBG', 'Chemical', '-', (84, 94))	('I-131 MIBG', 'Chemical', '-', (99, 109))
15700	25874239	This pilot study demonstrated the regional administration of At-211-labeled antitenascin antibody was feasible, safe, and effective for malignant brain tumors.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('malignant brain tumors', 'Disease', (136, 158))	('malignant brain tumors', 'Disease', 'MESH:D001932', (136, 158))	('antitenascin', 'Protein', (76, 88))	('At-211-labeled', 'Var', (61, 75))	('At-211', 'Chemical', 'MESH:C000615146', (61, 67))	('brain tumors', 'Phenotype', 'HP:0030692', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
15703	25874239	A number of studies indicate the efficacy of I-131 MIBG therapy in patients with refractory or relapsed neuroblastoma.	('I-131 MIBG', 'Chemical', '-', (45, 55))	('patients', 'Species', '9606', (67, 75))	('neuroblastoma', 'Disease', (104, 117))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('refractory', 'Disease', (81, 91))	('I-131', 'Var', (45, 50))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
15704	25874239	In addition, I-131 MIBG therapy incorporated in the induction therapy is the feasible treatment strategy in patients with newly diagnosed neuroblastoma.	('neuroblastoma', 'Disease', (138, 151))	('patients', 'Species', '9606', (108, 116))	('I-131', 'Var', (13, 18))	('neuroblastoma', 'Phenotype', 'HP:0003006', (138, 151))	('I-131 MIBG', 'Chemical', '-', (13, 23))	('neuroblastoma', 'Disease', 'MESH:D009447', (138, 151))
15742	22571874	In general, [123I]MIBG is thought to be slightly more sensitive than [111In]octreotide for the site of primary disease and is often the radiotracer of choice.	('primary disease', 'Disease', 'MESH:D009202', (103, 118))	('[111In]octreotide', 'Chemical', 'MESH:C094279', (69, 86))	('primary disease', 'Disease', (103, 118))	('[123I]MIBG', 'Var', (12, 22))	('[123I]MIBG', 'Chemical', '-', (12, 22))
15746	22571874	Although [18F[FDG-PET has a high sensitivity for metastatic disease, the specificity is generally less than that of [123I]MIBG or [111In]octreotide.	('[123I]MIBG', 'Chemical', '-', (116, 126))	('[18F[FDG-PET', 'Var', (9, 21))	('[111In]octreotide', 'Chemical', 'MESH:C094279', (130, 147))	('FDG', 'Chemical', 'MESH:D019788', (14, 17))	('less', 'NegReg', (98, 102))	('metastatic disease', 'Disease', (49, 67))
15750	22571874	Current clinical management relies on a combination of surgical resection, [131I]MIBG therapy, and chemotherapy in malignant tumors.	('malignant tumors', 'Disease', 'MESH:D018198', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('[131I', 'Var', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('malignant tumors', 'Disease', (115, 131))	('MIBG', 'Chemical', 'MESH:D019797', (81, 85))
15753	22571874	Von Hippel-Lindau (VHL) is an autosomal dominant disease caused by VHL gene mutations that predisposes individuals to central nervous system hemangioblastomas, renal cysts, renal cell carcinoma, pancreatic cysts, retinal angiomas, and pheochromocytomas (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (118, 158))	('caused', 'Reg', (57, 63))	('autosomal dominant disease', 'Disease', (30, 56))	('VHL', 'Gene', (67, 70))	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (126, 158))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (235, 251))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (173, 193))	('pancreatic cysts', 'Disease', 'MESH:D010181', (195, 211))	('central nervous system hemangioblastomas', 'Disease', (118, 158))	('pheochromocytomas', 'Disease', 'MESH:D010673', (235, 252))	('pheochromocytomas', 'Disease', (235, 252))	('VHL', 'Gene', '7428', (67, 70))	('Von Hippel-Lindau', 'Gene', '7428', (0, 17))	('VHL', 'Gene', (19, 22))	('Von Hippel-Lindau', 'Gene', (0, 17))	('renal cysts', 'Disease', (160, 171))	('renal cell carcinoma', 'Disease', (173, 193))	('retinal angiomas', 'Disease', (213, 229))	('mutations', 'Var', (76, 85))	('renal cysts', 'Phenotype', 'HP:0000107', (160, 171))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (173, 193))	('pancreatic cysts', 'Disease', (195, 211))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (235, 252))	('VHL', 'Gene', '7428', (19, 22))	('retinal angiomas', 'Disease', 'MESH:D012173', (213, 229))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (195, 211))	('renal cysts', 'Disease', 'MESH:D007674', (160, 171))	('autosomal dominant disease', 'Disease', 'MESH:D030342', (30, 56))
15756	22571874	Genetic analysis has also linked mutations in the succinate dehydrogenase (SDH) genes to the development of parangangliomas and pheochromocytomas.	('succinate dehydrogenase', 'Gene', '6390', (50, 73))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (128, 144))	('mutations', 'Var', (33, 42))	('SDH', 'Gene', '6390', (75, 78))	('linked', 'Reg', (26, 32))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (128, 145))	('succinate dehydrogenase', 'Gene', (50, 73))	('SDH', 'Gene', (75, 78))	('parangangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (108, 145))
15757	22571874	At least 4 paraganglioma syndromes named paraganglioma syndrome I-IV have been linked to mutations in the SDHD, SDH5, SDHC, and SDHB, respectively.	('SDHB', 'Gene', (128, 132))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (11, 34))	('SDH5', 'Gene', (112, 116))	('linked', 'Reg', (79, 85))	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('paraganglioma syndromes', 'Disease', (11, 34))	('SDHD', 'Gene', '6392', (106, 110))	('paraganglioma', 'Phenotype', 'HP:0002668', (11, 24))	('SDHD', 'Gene', (106, 110))	('mutations', 'Var', (89, 98))	('SDH5', 'Gene', '54949', (112, 116))	('paraganglioma syndrome I-IV', 'Disease', (41, 68))	('SDHC', 'Gene', (118, 122))	('SDHB', 'Gene', '6390', (128, 132))	('paraganglioma syndrome I-IV', 'Disease', 'MESH:D010235', (41, 68))	('SDHC', 'Gene', '6391', (118, 122))
15784	21753790	First are those sarcomas with near-diploid karyotypes and simple genetic alterations including translocations or specific activating mutations.	('sarcomas', 'Disease', (16, 24))	('activating', 'PosReg', (122, 132))	('sarcomas', 'Disease', 'MESH:D012509', (16, 24))	('translocations', 'Var', (95, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (16, 24))
15790	21753790	Although well studied, the physiological roles of the individual genes in these fusions have seldom been directly linked to their respective sarcoma phenotypes, save perhaps for translocations of the myogenic transcription factor genes paired box 3 (PAX3) and PAX7 with forkhead box O1 (FOXO1) in alveolar rhabdomyosarcomas (ARMS; discussed below).	('FOXO1', 'Gene', (287, 292))	('ARMS', 'Phenotype', 'HP:0006779', (325, 329))	('sarcoma', 'Disease', (141, 148))	('sarcoma', 'Disease', 'MESH:D012509', (315, 322))	('alveolar rhabdomyosarcomas', 'Disease', (297, 323))	('sarcoma', 'Disease', (315, 322))	('PAX7', 'Gene', '5081', (260, 264))	('PAX7', 'Gene', (260, 264))	('sarcoma', 'Phenotype', 'HP:0100242', (141, 148))	('alveolar rhabdomyosarcomas', 'Disease', 'MESH:D018232', (297, 323))	('paired box 3', 'Gene', (236, 248))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (306, 322))	('sarcoma', 'Phenotype', 'HP:0100242', (315, 322))	('forkhead box O1', 'Gene', '2308', (270, 285))	('sarcomas', 'Phenotype', 'HP:0100242', (315, 323))	('forkhead box O1', 'Gene', (270, 285))	('PAX3', 'Gene', (250, 254))	('AR', 'Gene', '367', (325, 327))	('alveolar rhabdomyosarcomas', 'Phenotype', 'HP:0006779', (297, 323))	('paired box 3', 'Gene', '5077', (236, 248))	('translocations', 'Var', (178, 192))	('sarcoma', 'Disease', 'MESH:D012509', (141, 148))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (306, 323))
15796	21753790	The mechanisms that drive human sarcomagenesis fall into three broad categories: transcriptional dysregulation owing to aberrant fusion proteins resulting from genomic rearrangements (FIG.	('aberrant', 'Var', (120, 128))	('transcriptional dysregulation', 'MPA', (81, 110))	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('sarcoma', 'Disease', 'MESH:D012509', (32, 39))	('fusion proteins', 'Protein', (129, 144))	('sarcoma', 'Disease', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (32, 39))	('human', 'Species', '9606', (26, 31))
15802	21753790	Finally, regarding external risk factors, sarcoma translocations, in particular the t(X;18) of synovial sarcoma, may be rarely related to radiotherapy-induced DNA damage.	('sarcoma', 'Disease', (42, 49))	('sarcoma', 'Disease', (104, 111))	('synovial sarcoma', 'Disease', (95, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('t(X;18', 'Var', (84, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (95, 111))	('synovial sarcoma', 'Disease', 'MESH:D013584', (95, 111))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))
15811	21753790	As noted above, most recurrent tumor-type-specific translocations in sarcomas produce gene fusions that encode aberrant transcriptional proteins.	('translocations', 'Var', (51, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('gene fusions', 'Var', (86, 98))	('tumor', 'Disease', (31, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (69, 76))	('sarcomas', 'Disease', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('sarcomas', 'Disease', 'MESH:D012509', (69, 77))
15813	21753790	Likewise, general reviews of translocation-associated sarcomas, including comprehensive listings of recurrent gene fusions in sarcomas, have recently been published (FIG.	('sarcomas', 'Phenotype', 'HP:0100242', (126, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (126, 133))	('sarcomas', 'Disease', (126, 134))	('translocation-associated', 'Var', (29, 53))	('sarcomas', 'Disease', 'MESH:D012509', (54, 62))	('sarcomas', 'Phenotype', 'HP:0100242', (54, 62))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('sarcomas', 'Disease', 'MESH:D012509', (126, 134))	('sarcomas', 'Disease', (54, 62))
15824	21753790	This is typified by the MDM2SNP309 promoter polymorphism, which along with MDM2 amplification and TP53 deletion and mutation, represents another mechanism of aberrant p53 activity in a broad range of sarcomas.	('mutation', 'Var', (116, 124))	('MDM2', 'Gene', '4193', (75, 79))	('sarcomas', 'Disease', 'MESH:D012509', (200, 208))	('MDM2', 'Gene', (75, 79))	('MDM2', 'Gene', '4193', (24, 28))	('sarcomas', 'Phenotype', 'HP:0100242', (200, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MDM2', 'Gene', (24, 28))	('p53', 'Gene', '7157', (167, 170))	('TP53', 'Gene', (98, 102))	('sarcomas', 'Disease', (200, 208))	('TP53', 'Gene', '7157', (98, 102))	('p53', 'Gene', (167, 170))	('activity', 'MPA', (171, 179))	('deletion', 'Var', (103, 111))
15833	21753790	Microsatellites containing 6 or more GGAA repeats (the core ETS domain binding sequence) are associated with EWS-FLI1 target gene upregulation.	('EWS-FLI1', 'Gene', (109, 117))	('EWS-FLI1', 'Gene', '2130;2313', (109, 117))	('upregulation', 'PosReg', (130, 142))	('GGAA', 'Protein', (37, 41))	('Microsatellites', 'Var', (0, 15))
15839	21753790	Genes found to be directly up-regulated by specific aberrant sarcoma fusion proteins can be subjected to focused RNA interference (RNAi)-based screens to identify the genes most essential to the sarcoma in question (see Target Discovery below).	('up-regulated', 'PosReg', (27, 39))	('sarcoma', 'Disease', (195, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('sarcoma', 'Disease', 'MESH:D012509', (61, 68))	('aberrant', 'Var', (52, 60))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('sarcoma', 'Disease', (61, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))
15844	21753790	Silencing EWS-FLI1 in Ewing sarcoma cell lines produces an expression profile most similar to mesenchymal stem cells (MSCs) or mesenchymal progenitor cells and these can subsequently be induced to differentiate along adipogenic or osteoblastic lineages.	('induced', 'Reg', (186, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (28, 35))	('expression', 'Species', '29278', (59, 69))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (22, 35))	('osteoblastic', 'Disease', 'None', (231, 243))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (22, 35))	('EWS-FLI1', 'Gene', (10, 18))	('osteoblastic', 'Disease', (231, 243))	('expression profile', 'MPA', (59, 77))	('Silencing', 'Var', (0, 9))	('Ewing sarcoma', 'Disease', (22, 35))	('EWS-FLI1', 'Gene', '2130;2313', (10, 18))
15846	21753790	In the converse experiment, EWS-FLI1 expression in human MSCs induces a Ewing sarcoma gene expression profile, especially clear in MSCs derived from younger individuals.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('expression', 'Var', (37, 47))	('EWS-FLI1', 'Gene', '2130;2313', (28, 36))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('induces', 'Reg', (62, 69))	('human', 'Species', '9606', (51, 56))	('Ewing sarcoma', 'Disease', (72, 85))	('expression', 'Species', '29278', (37, 47))	('EWS-FLI1', 'Gene', (28, 36))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('expression', 'Species', '29278', (91, 101))
15850	21753790	Synovial sarcomas contain fusions of the SS18 (also known as SYT) gene with either SSX1 or SSX2.	('SYT', 'Gene', '6760', (61, 64))	('fusions', 'Var', (26, 33))	('SSX2', 'Gene', '6757', (91, 95))	('sarcomas', 'Disease', (9, 17))	('SSX1', 'Gene', '6756', (83, 87))	('SS18', 'Gene', '6760', (41, 45))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SS18', 'Gene', (41, 45))	('SYT', 'Gene', (61, 64))	('SSX1', 'Gene', (83, 87))	('SSX2', 'Gene', (91, 95))	('Synovial sarcomas', 'Phenotype', 'HP:0012570', (0, 17))
15851	21753790	In a striking analogy to the EWS-FLI1 data, synovial sarcoma cell lines also express POU5F1, SOX2 and NANOG, and silencing of SYT-SSX in these cell lines enhances their potential to differentiate along adipogenic, osteoblastic or chondrogenic lineages.	('SYT', 'Gene', '6760', (126, 129))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (44, 60))	('enhances', 'PosReg', (154, 162))	('chondrogenic lineages', 'CPA', (230, 251))	('EWS-FLI1', 'Gene', (29, 37))	('SSX', 'Gene', '6757', (130, 133))	('POU5F1', 'Gene', '5460', (85, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('osteoblastic', 'Disease', 'None', (214, 226))	('silencing', 'Var', (113, 122))	('EWS-FLI1', 'Gene', '2130;2313', (29, 37))	('SSX', 'Gene', (130, 133))	('SYT', 'Gene', (126, 129))	('osteoblastic', 'Disease', (214, 226))	('NANOG', 'Gene', '79923', (102, 107))	('synovial sarcoma', 'Disease', (44, 60))	('SOX2', 'Gene', (93, 97))	('SOX2', 'Gene', '6657', (93, 97))	('NANOG', 'Gene', (102, 107))	('POU5F1', 'Gene', (85, 91))	('synovial sarcoma', 'Disease', 'MESH:D013584', (44, 60))
15856	21753790	GIST, one of the more common human sarcoma types, is characterized by oncogenic mutations in KIT, or less often in platelet-derived growth factor receptor-alpha (PDGFRA), or rarely in BRAF .	('platelet-derived growth factor receptor-alpha', 'Gene', (115, 160))	('human', 'Species', '9606', (29, 34))	('KIT', 'Gene', (93, 96))	('BRAF', 'Gene', (184, 188))	('sarcoma', 'Disease', (35, 42))	('mutations', 'Var', (80, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (115, 160))	('GIST', 'Phenotype', 'HP:0100723', (0, 4))	('PDGFRA', 'Gene', (162, 168))	('PDGFRA', 'Gene', '5156', (162, 168))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))	('BRAF', 'Gene', '673', (184, 188))
15858	21753790	Nevertheless, oncogenic KIT mutations (in the activation domain; D816V in particular) are also found in tumors of diverse lineages including mastocytosis, acute myeloid leukemia, and germ cell tumors.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('D816V', 'Var', (65, 70))	('cell tumors', 'Disease', 'MESH:D005935', (188, 199))	('D816V', 'Mutation', 'rs121913507', (65, 70))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('tumors', 'Disease', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (183, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('acute myeloid leukemia', 'Disease', (155, 177))	('mastocytosis', 'Phenotype', 'HP:0100495', (141, 153))	('found', 'Reg', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('mutations', 'Var', (28, 37))	('mastocytosis', 'Disease', (141, 153))	('KIT', 'Gene', (24, 27))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (155, 177))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (161, 177))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (155, 177))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('mastocytosis', 'Disease', 'MESH:D008415', (141, 153))	('cell tumors', 'Disease', (188, 199))
15859	21753790	Approximately 10% of adult GISTs lack a KIT or PDGFRA mutation, a small subset (<1% of total GIST cases) harbor BRAF-V600E mutations (Table 1).	('mutation', 'Var', (54, 62))	('BRAF', 'Gene', '673', (112, 116))	('BRAF', 'Gene', (112, 116))	('GIST', 'Phenotype', 'HP:0100723', (27, 31))	('GIST', 'Phenotype', 'HP:0100723', (93, 97))	('KIT', 'Gene', (40, 43))	('PDGFRA', 'Gene', (47, 53))	('V600E', 'Mutation', 'rs113488022', (117, 122))	('PDGFRA', 'Gene', '5156', (47, 53))
15860	21753790	Most pediatric GISTs harbor no mutations in KIT, PDGFRA, or BRAF, although KIT pathway activity is high in pediatric cases and in adult cases lacking mutations.	('mutations', 'Var', (31, 40))	('activity', 'MPA', (87, 95))	('PDGFRA', 'Gene', (49, 55))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('KIT pathway', 'Pathway', (75, 86))	('PDGFRA', 'Gene', '5156', (49, 55))	('KIT', 'Gene', (44, 47))	('GIST', 'Phenotype', 'HP:0100723', (15, 19))
15861	21753790	In total, approximately 10% of adult and most pediatric GISTs harbor no mutations in KIT, PDGFRA, or BRAF, although KIT pathway activity is high.	('BRAF', 'Gene', (101, 105))	('mutations', 'Var', (72, 81))	('PDGFRA', 'Gene', '5156', (90, 96))	('PDGFRA', 'Gene', (90, 96))	('KIT', 'Gene', (85, 88))	('BRAF', 'Gene', '673', (101, 105))	('GIST', 'Phenotype', 'HP:0100723', (56, 60))
15863	21753790	In fact, pediatric tumors have mostly diploid genomes with few if any DNA copy-number alterations.	('pediatric tumors', 'Disease', 'MESH:D063766', (9, 25))	('diploid genomes', 'Var', (38, 53))	('pediatric tumors', 'Disease', (9, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
15866	21753790	In Carney-Stratakis syndrome, which is characterized by the co-occurrence of GIST and paraganglioma, germline mutations in genes encoding subunits of succinate dehydrogenase have been identified, as is also the case in familial paraganglioma.	('Carney-Stratakis syndrome', 'Disease', (3, 28))	('paraganglioma', 'Disease', 'MESH:D010235', (86, 99))	('mutations', 'Var', (110, 119))	('GIST', 'Phenotype', 'HP:0100723', (77, 81))	('paraganglioma', 'Disease', 'MESH:D010235', (228, 241))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (3, 28))	('familial paraganglioma', 'Disease', (219, 241))	('paraganglioma', 'Phenotype', 'HP:0002668', (228, 241))	('familial paraganglioma', 'Disease', 'MESH:D010235', (219, 241))	('paraganglioma', 'Disease', (86, 99))	('paraganglioma', 'Disease', (228, 241))
15869	21753790	Sequencing of these five genes revealed KDR mutations in about 10% of cases of angiosarcoma.	('angiosarcoma', 'Disease', (79, 91))	('KDR', 'Gene', '3791', (40, 43))	('angiosarcoma', 'Phenotype', 'HP:0200058', (79, 91))	('revealed', 'Reg', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('mutations', 'Var', (44, 53))	('angiosarcoma', 'Disease', 'MESH:D006394', (79, 91))	('KDR', 'Gene', (40, 43))
15870	21753790	The VEGFR2 mutant proteins, when expressed in COS-7 cells, showed ligand-independent activation.	('VEGFR2', 'Gene', '3791', (4, 10))	('mutant', 'Var', (11, 17))	('proteins', 'Protein', (18, 26))	('VEGFR2', 'Gene', (4, 10))	('activation', 'PosReg', (85, 95))	('COS-7', 'CellLine', 'CVCL:0224', (46, 51))
15871	21753790	A recent large-scale analysis of the genomic landscape of sarcomas encompassing seven major subtypes (myxoid/round-cell, dedifferentiated, and pleomorphic liposarcomas; myxofibrosarcoma, leiomyosarcoma, GIST, and synovial sarcoma) identified frequent mutations in TP53 (which encodes p53), NF1, and PI3K catalytic subunit-alpha (PIK3CA).	('synovial sarcoma', 'Phenotype', 'HP:0012570', (213, 229))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (187, 201))	('pleomorphic liposarcomas; myxofibrosarcoma', 'Disease', 'MESH:D008080', (143, 185))	('TP53', 'Gene', '7157', (264, 268))	('sarcoma', 'Phenotype', 'HP:0100242', (159, 166))	('liposarcomas', 'Phenotype', 'HP:0012034', (155, 167))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (187, 201))	('liposarcoma', 'Phenotype', 'HP:0012034', (155, 166))	('PIK3CA', 'Gene', (329, 335))	('NF1', 'Gene', '4763', (290, 293))	('p53', 'Gene', '7157', (284, 287))	('GIST', 'Phenotype', 'HP:0100723', (203, 207))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('leiomyosarcoma', 'Disease', (187, 201))	('pleomorphic liposarcomas; myxofibrosarcoma', 'Disease', (143, 185))	('TP53', 'Gene', (264, 268))	('NF1', 'Gene', (290, 293))	('p53', 'Gene', (284, 287))	('synovial sarcoma', 'Disease', (213, 229))	('sarcomas', 'Disease', 'MESH:D012509', (58, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('sarcomas', 'Disease', 'MESH:D012509', (159, 167))	('synovial sarcoma', 'Disease', 'MESH:D013584', (213, 229))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('mutations', 'Var', (251, 260))	('sarcomas', 'Phenotype', 'HP:0100242', (58, 66))	('sarcomas', 'Phenotype', 'HP:0100242', (159, 167))	('sarcomas', 'Disease', (58, 66))	('PIK3CA', 'Gene', '5290', (329, 335))	('sarcomas', 'Disease', (159, 167))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))
15872	21753790	TP53 mutations were identified in 17% of pleomorphic liposarcomas, consistent with these mutations being frequent in sarcomas with complex karyotypes.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('sarcomas', 'Disease', 'MESH:D012509', (117, 125))	('liposarcomas', 'Phenotype', 'HP:0012034', (53, 65))	('sarcomas', 'Phenotype', 'HP:0100242', (117, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('mutations', 'Var', (5, 14))	('sarcomas', 'Disease', (117, 125))	('pleomorphic liposarcomas', 'Disease', (41, 65))	('sarcomas', 'Disease', 'MESH:D012509', (57, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (53, 64))	('sarcomas', 'Phenotype', 'HP:0100242', (57, 65))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (41, 65))	('sarcomas', 'Disease', (57, 65))
15873	21753790	By contrast, in translocation-associated sarcomas secondary genetic alterations, such as TP53 mutations or homozygous deletions of cyclin-dependent kinase inhibitor 2A (CDKN2A), are less common but, when present, are associated with a highly aggressive clinical course.	('CDKN2A', 'Gene', (169, 175))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('sarcomas', 'Phenotype', 'HP:0100242', (41, 49))	('associated with', 'Reg', (217, 232))	('mutations', 'Var', (94, 103))	('sarcomas', 'Disease', (41, 49))	('CDKN2A', 'Gene', '1029', (169, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (41, 48))	('clinical', 'Species', '191496', (253, 261))	('sarcomas', 'Disease', 'MESH:D012509', (41, 49))
15874	21753790	The discovery of PIK3CA mutations in 18% of myxoid/round-cell liposarcomas (Table 1) raises the possibility that secondary mutations may cooperate with the FUS-CHOP fusion protein in oncogenesis.	('FUS', 'Gene', (156, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('liposarcomas', 'Disease', (62, 74))	('FUS', 'Gene', '2521', (156, 159))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('PIK3CA', 'Gene', (17, 23))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('PIK3CA', 'Gene', '5290', (17, 23))	('mutations', 'Var', (24, 33))	('liposarcomas', 'Disease', 'MESH:D008080', (62, 74))	('liposarcomas', 'Phenotype', 'HP:0012034', (62, 74))
15875	21753790	PIK3CA mutations clustered in the same two hot spots observed in epithelial tumors: the helical domain (E542K and E545K) and the kinase domain (H1047L and H1047R).	('H1047L', 'Var', (144, 150))	('E542K', 'Var', (104, 109))	('H1047R', 'Mutation', 'rs121913279', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('PIK3CA', 'Gene', (0, 6))	('epithelial tumors', 'Disease', (65, 82))	('E542K', 'Mutation', 'rs121913273', (104, 109))	('PIK3CA', 'Gene', '5290', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('epithelial tumor', 'Phenotype', 'HP:0031492', (65, 81))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('epithelial tumors', 'Disease', 'MESH:D002277', (65, 82))	('E545K', 'Var', (114, 119))	('H1047R', 'Var', (155, 161))	('H1047L', 'Mutation', 'rs121913279', (144, 150))
15876	21753790	Patients with helical domain mutations had a shorter disease-specific survival and increased AKT phosphorylation at both CREB-regulated transcription coactivator 2 (TORC2; also known as CRTC2) and pyruvate dehydrogenase kinase 1 (PDK1) phosphorylation sites than those with wild-type or kinase-domain-mutant tumors.	('CREB-regulated transcription coactivator 2', 'Gene', (121, 163))	('shorter', 'NegReg', (45, 52))	('pyruvate dehydrogenase kinase 1', 'Gene', '5163', (197, 228))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('helical domain mutations', 'Var', (14, 38))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('disease-specific survival', 'CPA', (53, 78))	('increased', 'PosReg', (83, 92))	('PDK1', 'Gene', '5163', (230, 234))	('AKT', 'Gene', (93, 96))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (308, 314))	('TORC2', 'Gene', (165, 170))	('CRTC2', 'Gene', '200186', (186, 191))	('AKT', 'Gene', '207', (93, 96))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('TORC2', 'Gene', '200186', (165, 170))	('CRTC2', 'Gene', (186, 191))	('PDK1', 'Gene', (230, 234))	('pyruvate dehydrogenase kinase 1', 'Gene', (197, 228))	('CREB-regulated transcription coactivator 2', 'Gene', '200186', (121, 163))
15877	21753790	Another novel finding is that of NF1 alterations (point mutations or deletions) in 10% of myxofibrosarcomas and 8% of pleomorphic liposarcomas (Table 1).	('pleomorphic liposarcomas', 'Disease', (118, 142))	('sarcomas', 'Phenotype', 'HP:0100242', (99, 107))	('NF1', 'Gene', (33, 36))	('myxofibrosarcomas', 'Disease', 'None', (90, 107))	('liposarcomas', 'Phenotype', 'HP:0012034', (130, 142))	('myxofibrosarcomas', 'Disease', (90, 107))	('NF1', 'Gene', '4763', (33, 36))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (118, 142))	('deletions', 'Var', (69, 78))	('liposarcoma', 'Phenotype', 'HP:0012034', (130, 141))	('alterations', 'Var', (37, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma', 'Phenotype', 'HP:0100242', (99, 106))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))
15878	21753790	NF1 germline and somatic mutations are typically associated with NF1 inactivation in sarcomas in individuals with neurofibromatosis type 1 syndrome, but NF1 mutations had not been previously described in sporadic sarcomas.	('NF1', 'Gene', (153, 156))	('associated', 'Reg', (49, 59))	('NF1', 'Gene', (0, 3))	('sarcomas', 'Disease', 'MESH:D012509', (213, 221))	('sporadic sarcomas', 'Disease', (204, 221))	('mutations', 'Var', (25, 34))	('sarcomas', 'Phenotype', 'HP:0100242', (213, 221))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('sarcomas', 'Disease', (213, 221))	('neurofibromatosis type 1 syndrome', 'Disease', 'MESH:C537392', (114, 147))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('sarcomas', 'Disease', (85, 93))	('neurofibromatosis type 1 syndrome', 'Disease', (114, 147))	('sporadic sarcomas', 'Disease', 'MESH:D012509', (204, 221))	('NF1', 'Gene', '4763', (65, 68))	('neurofibroma', 'Phenotype', 'HP:0001067', (114, 126))	('inactivation', 'NegReg', (69, 81))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (114, 131))	('NF1', 'Gene', '4763', (153, 156))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (0, 3))
15880	21753790	Sarcomas span a wide range of complexity among human malignancies in their copy-number alterations.	('copy-number alterations', 'Var', (75, 98))	('Sarcomas', 'Disease', 'MESH:D012509', (0, 8))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('malignancies', 'Disease', (53, 65))	('Sarcomas', 'Phenotype', 'HP:0100242', (0, 8))	('human', 'Species', '9606', (47, 52))	('Sarcomas', 'Disease', (0, 8))
15884	21753790	These three groups are genomically simple sarcomas, driven by pathognomonic translocations or point mutations; non-translocation-associated sarcomas of intermediate genomic complexity; and highly genomically complex sarcomas, while some subtypes may not fit so neatly in these broad groups, such as PAX7-FOXO1-positive ARMS.	('PAX7', 'Gene', '5081', (299, 303))	('sarcoma', 'Phenotype', 'HP:0100242', (216, 223))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('PAX7', 'Gene', (299, 303))	('non-translocation-associated', 'Disease', (111, 139))	('AR', 'Gene', '367', (319, 321))	('sarcomas', 'Disease', 'MESH:D012509', (140, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcomas', 'Disease', (140, 148))	('sarcomas', 'Disease', 'MESH:D012509', (216, 224))	('sarcomas', 'Disease', 'MESH:D012509', (42, 50))	('ARMS', 'Phenotype', 'HP:0006779', (319, 323))	('sarcomas', 'Phenotype', 'HP:0100242', (216, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcomas', 'Disease', (216, 224))	('translocations', 'Var', (76, 90))	('sarcomas', 'Disease', (42, 50))	('point mutations', 'Var', (94, 109))
15886	21753790	The first group, genomically simple sarcomas, harbor characteristic gene fusions or activating mutations thought to represent early events in their pathogenesis.	('sarcomas', 'Disease', 'MESH:D012509', (36, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (36, 44))	('sarcomas', 'Disease', (36, 44))	('activating', 'PosReg', (84, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (36, 43))	('gene fusions', 'Var', (68, 80))
15888	21753790	Intermediate complexity sarcomas are exemplified by well-differentiated and dedifferentiated liposarcomas, which are driven mainly by chromosome 12 alterations, often generating extra-chromosomal episomes, ring chromosomes and larger markers (FIG.	('sarcomas', 'Disease', 'MESH:D012509', (24, 32))	('sarcomas', 'Disease', 'MESH:D012509', (97, 105))	('alterations', 'Var', (148, 159))	('sarcomas', 'Phenotype', 'HP:0100242', (24, 32))	('sarcomas', 'Phenotype', 'HP:0100242', (97, 105))	('sarcoma', 'Phenotype', 'HP:0100242', (24, 31))	('liposarcoma', 'Phenotype', 'HP:0012034', (93, 104))	('sarcomas', 'Disease', (24, 32))	('extra-chromosomal episomes', 'MPA', (178, 204))	('sarcoma', 'Phenotype', 'HP:0100242', (97, 104))	('sarcomas', 'Disease', (97, 105))	('liposarcomas', 'Phenotype', 'HP:0012034', (93, 105))	('generating', 'Reg', (167, 177))	('liposarcomas', 'Disease', 'MESH:D008080', (93, 105))	('ring chromosomes', 'Var', (206, 222))	('liposarcomas', 'Disease', (93, 105))
15892	21753790	This genomic remodeling of chromosome 12 is likely the result of progressive rearrangement and amplification in an evolving amplicon rather than a single catastrophic event such as the recently proposed chromothripsis, seen in a subset of osteosarcomas and chordomas (Table 1).	('rearrangement', 'Var', (77, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (244, 252))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('amplification', 'Var', (95, 108))	('osteosarcomas and chordomas', 'Disease', 'MESH:D002817', (239, 266))	('osteosarcoma', 'Phenotype', 'HP:0002669', (239, 251))	('osteosarcomas', 'Phenotype', 'HP:0002669', (239, 252))
15897	21753790	Some targets of genomic amplification appear to be shared among a subset of both intermediate and highly complex sarcomas, including Yes-associated protein 1 (YAP1) and vestigial like 3 (VGLL3) on 11q22 and 3p12, respectively.	('sarcomas', 'Disease', (113, 121))	('intermediate', 'Disease', (81, 93))	('vestigial like 3', 'Gene', (169, 185))	('Yes-associated protein 1', 'Gene', '10413', (133, 157))	('VGLL3', 'Gene', (187, 192))	('sarcomas', 'Disease', 'MESH:D012509', (113, 121))	('YAP1', 'Gene', (159, 163))	('Yes-associated protein 1', 'Gene', (133, 157))	('vestigial like 3', 'Gene', '389136', (169, 185))	('YAP1', 'Gene', '10413', (159, 163))	('sarcomas', 'Phenotype', 'HP:0100242', (113, 121))	('VGLL3', 'Gene', '389136', (187, 192))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('genomic amplification', 'Var', (16, 37))
15899	21753790	Broad amplifications of several chromosome arms (such as 5p) often occur in combination with deletions affecting well-established tumor suppressors such as CDKN2A, CDKN2B, PTEN, retinoblastoma 1 (RB1), NF1 and TP53.	('PTEN', 'Gene', '5728', (172, 176))	('CDKN2A', 'Gene', (156, 162))	('TP53', 'Gene', '7157', (210, 214))	('TP53', 'Gene', (210, 214))	('retinoblastoma', 'Phenotype', 'HP:0009919', (178, 192))	('CDKN2A', 'Gene', '1029', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('retinoblastoma 1 (RB1', 'Gene', '5925', (178, 199))	('NF1', 'Gene', (202, 205))	('deletions', 'Var', (93, 102))	('CDKN2B', 'Gene', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('NF1', 'Gene', '4763', (202, 205))	('tumor', 'Disease', (130, 135))	('occur', 'Reg', (67, 72))	('CDKN2B', 'Gene', '1030', (164, 170))	('PTEN', 'Gene', (172, 176))
15901	21753790	In other subtypes, such as leiomyosarcoma, genomic deletions are more common than amplifications.	('common', 'Reg', (70, 76))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (27, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (34, 41))	('genomic deletions', 'Var', (43, 60))	('leiomyosarcoma', 'Disease', (27, 41))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (27, 41))
15902	21753790	Nevertheless, at least a subset of leiomyosarcomas depends on the specific amplification of myocardin (MYOCD), which encodes a smooth muscle-specific transcriptional coactivator of the serum response factor (SRF) (Table 1).	('serum response factor', 'Gene', '6722', (185, 206))	('MYOCD', 'Gene', (103, 108))	('serum response factor', 'Gene', (185, 206))	('sarcomas', 'Phenotype', 'HP:0100242', (42, 50))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('SRF', 'Gene', (208, 211))	('myocardin', 'Gene', '93649', (92, 101))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (35, 49))	('MYOCD', 'Gene', '93649', (103, 108))	('amplification', 'Var', (75, 88))	('myocardin', 'Gene', (92, 101))	('SRF', 'Gene', '6722', (208, 211))	('leiomyosarcomas depends', 'Disease', (35, 58))	('leiomyosarcomas depends', 'Disease', 'MESH:D007890', (35, 58))
15904	21753790	Therefore, while systematic catalogues of copy numbers alterations point to pathways potentially activated in specific subtypes, to precisely delineate genes involved in these events that drive sarcomagenesis it will be essential to annotate genomic characterization with high-throughput functional genetics for target discovery.	('alterations', 'Var', (55, 66))	('activated', 'Reg', (97, 106))	('sarcoma', 'Disease', 'MESH:D012509', (194, 201))	('sarcoma', 'Disease', (194, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (194, 201))	('copy numbers alterations', 'Var', (42, 66))
15919	21753790	Two such methods, Genomic Identification of Significant Targets in Cancer (GISTIC) and RAE, assign a statistical significance to candidate driver alterations emerging from a background of random, passenger abnormalities using their pattern of recurrence, amplitude, and extent, but also assign to individuals the set of CNAs they have undergone.	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('GIST', 'Phenotype', 'HP:0100723', (75, 79))	('alterations', 'Var', (146, 157))	('Cancer', 'Disease', (67, 73))
15924	21753790	Along these lines, we recently sought to functionally annotate the dedifferentiated liposarcoma genome by systematically knocking down genes altered by recurrent genomic amplification on 12q and elsewhere.	('liposarcoma', 'Disease', (84, 95))	('knocking', 'Var', (121, 129))	('liposarcoma', 'Disease', 'MESH:D008080', (84, 95))	('liposarcoma', 'Phenotype', 'HP:0012034', (84, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))
15943	21753790	For example, in leiomyosarcoma, the most prominent genetic alteration is chromosome 10 deletions affecting PTEN, but this may be a secondary alteration.	('PTEN', 'Gene', (107, 111))	('leiomyosarcoma', 'Disease', (16, 30))	('PTEN', 'Gene', '5728', (107, 111))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (16, 30))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (16, 30))	('deletions', 'Var', (87, 96))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))
15944	21753790	Nonetheless, this was modeled by genetically inactivating Pten in smooth muscle cells of mice, which led to leiomyosarcomagenesis.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (108, 122))	('mice', 'Species', '10090', (89, 93))	('genetically inactivating', 'Var', (33, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (115, 122))	('led to', 'Reg', (101, 107))	('leiomyosarcomagenesis', 'Disease', 'None', (108, 129))	('leiomyosarcomagenesis', 'Disease', (108, 129))	('Pten', 'Gene', (58, 62))	('Pten', 'Gene', '19211', (58, 62))
15945	21753790	Another recent mouse model introduced oncogenic Kras and mutant Trp53 in the muscle of mice; these changes were sufficient to generate high-grade sarcomas with myofibroblastic differentiation, but KRAS is rarely mutated in human sarcomas.	('Trp53', 'Gene', '22059', (64, 69))	('sarcomas', 'Disease', 'MESH:D012509', (229, 237))	('mutant', 'Var', (57, 63))	('KRAS', 'Gene', (197, 201))	('mouse', 'Species', '10090', (15, 20))	('sarcomas', 'Phenotype', 'HP:0100242', (229, 237))	('sarcomas', 'Disease', (229, 237))	('Trp53', 'Gene', (64, 69))	('human', 'Species', '9606', (223, 228))	('KRAS', 'Gene', '16653', (197, 201))	('Kras', 'Gene', (48, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('sarcomas', 'Disease', (146, 154))	('generate', 'Reg', (126, 134))	('Kras', 'Gene', '16653', (48, 52))	('mice', 'Species', '10090', (87, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))
15956	21753790	These responses to imatinib depend, however, on the specific site of mutation; tumors with activation loop mutations are generally insensitive.	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('imatinib', 'Chemical', 'MESH:D000068877', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
15959	21753790	For example, the recent success of Raf inhibitors in BRAF-V600E mutant melanoma suggests that responses may be elicited in other tumor types with a dependence on oncogenic Raf, a possible therapeutic option for the approximately 1% of adult GIST patients with BRAF-V600E mutation.	('Raf', 'Gene', '22882', (172, 175))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Disease', (129, 134))	('Raf', 'Gene', '22882', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('V600E', 'Mutation', 'rs113488022', (58, 63))	('V600E', 'Mutation', 'rs113488022', (265, 270))	('mutant', 'Var', (64, 70))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (260, 264))	('Raf', 'Gene', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('BRAF', 'Gene', (260, 264))	('GIST', 'Phenotype', 'HP:0100723', (241, 245))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('Raf', 'Gene', (35, 38))
15962	21753790	Among these are responses to imatinib in dermatofibrosarcoma protuberans (DFSP) and giant-cell tumors of the tendon sheath with collagen Ialpha1 (COL1A1)-platelet- derived growth factor-beta (PDGFB) and collagen Ivalpha3 (COL6A3)-colony-stimulating factor 1 (CSF1) fusions, respectively, MET inhibitor responses in ASPS and clear-cell sarcomas with ASPL-TFE3 and EWS-activating transcription factor 1 (ATF1) fusions, respectively, ALK inhibitor responses in inflammatory myofibroblastic tumors with ALK fusions, and IGF1R antibody responses in Ewing sarcoma with EWS-FLI1 or EWS-ERG fusions.	('sarcomas', 'Phenotype', 'HP:0100242', (335, 343))	('EWS', 'Gene', (575, 578))	('sarcomas', 'Disease', (335, 343))	('EWS-FLI1', 'Gene', (563, 571))	('EWS', 'Gene', '2130', (363, 366))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('giant-cell tumors of the tendon sheath', 'Disease', 'MESH:D000070779', (84, 122))	('Ewing sarcoma', 'Disease', (544, 557))	('EWS-activating transcription factor 1', 'Gene', '466', (363, 400))	('myofibroblastic tumors', 'Disease', 'MESH:D009369', (471, 493))	('PDGFB', 'Gene', (192, 197))	('CSF1', 'Gene', (259, 263))	('IGF1R', 'Gene', '3480', (516, 521))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('EWS-activating transcription factor 1', 'Gene', (363, 400))	('colony-stimulating factor 1', 'Gene', (230, 257))	('ASPL', 'Gene', (349, 353))	('ALK', 'Gene', '238', (431, 434))	('EWS', 'Gene', (563, 566))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (471, 493))	('dermatofibrosarcoma protuberans', 'Disease', (41, 72))	('giant-cell tumors of the tendon sheath', 'Disease', (84, 122))	('IGF1R', 'Gene', (516, 521))	('ASPS', 'Gene', (315, 319))	('EWS-FLI1', 'Gene', '2130;2313', (563, 571))	('ALK', 'Gene', (431, 434))	('CSF1', 'Gene', '1435', (259, 263))	('EWS', 'Gene', '2130', (575, 578))	('ATF1', 'Gene', (402, 406))	('COL1A1', 'Gene', '1277', (146, 152))	('fusions', 'Var', (503, 510))	('EWS', 'Gene', (363, 366))	('COL6A3', 'Gene', (222, 228))	('tumor', 'Phenotype', 'HP:0002664', (487, 492))	('COL6A3', 'Gene', '1293', (222, 228))	('TFE3', 'Gene', (354, 358))	('myofibroblastic tumors', 'Disease', (471, 493))	('ALK', 'Gene', '238', (499, 502))	('ASPL', 'Gene', '79058', (349, 353))	('dermatofibrosarcoma protuberans', 'Disease', 'MESH:D018223', (41, 72))	('DFSP', 'Disease', 'MESH:D018223', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (487, 493))	('ASPS', 'Gene', '79058', (315, 319))	('COL1A1', 'Gene', (146, 152))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (544, 557))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (544, 557))	('sarcoma', 'Phenotype', 'HP:0100242', (550, 557))	('TFE3', 'Gene', '7030', (354, 358))	('ATF1', 'Gene', '466', (402, 406))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('ASPS', 'Phenotype', 'HP:0012218', (315, 319))	('colony-stimulating factor 1', 'Gene', '1435', (230, 257))	('EWS', 'Gene', '2130', (563, 566))	('ALK', 'Gene', (499, 502))	('PDGFB', 'Gene', '5155', (192, 197))	('DFSP', 'Disease', (74, 78))	('sarcomas', 'Disease', 'MESH:D012509', (335, 343))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
15971	21753790	As NF1 inactivation leads to aberrant MAPK and mTOR pathway activity, the NF1 mutations and genomic deletions recently observed in pleomorphic liposarcomas and myxofibrosarcomas may identify a broader range of patients who might respond to either RAF/MEK inhibitors or rapamycin and its analogs (rapalogues).	('inactivation', 'Var', (7, 19))	('MEK', 'Gene', '5609', (251, 254))	('RAF', 'Gene', (247, 250))	('RAF', 'Gene', '22882', (247, 250))	('MEK', 'Gene', (251, 254))	('mutations', 'Var', (78, 87))	('NF1', 'Gene', '4763', (3, 6))	('patients', 'Species', '9606', (210, 218))	('MAPK', 'Pathway', (38, 42))	('sarcomas', 'Phenotype', 'HP:0100242', (147, 155))	('NF1', 'Gene', '4763', (74, 77))	('NF1', 'Gene', (3, 6))	('activity', 'MPA', (60, 68))	('mTOR', 'Gene', (47, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('rapamycin', 'Chemical', 'MESH:D020123', (269, 278))	('NF1', 'Gene', (74, 77))	('liposarcomas', 'Phenotype', 'HP:0012034', (143, 155))	('sarcoma', 'Phenotype', 'HP:0100242', (169, 176))	('mTOR', 'Gene', '2475', (47, 51))	('sarcomas', 'Phenotype', 'HP:0100242', (169, 177))	('liposarcoma', 'Phenotype', 'HP:0012034', (143, 154))	('pleomorphic liposarcomas and myxofibrosarcomas', 'Disease', 'MESH:D008080', (131, 177))
15972	21753790	In fact, deploying rapalogues in several complex subtypes could be justified on the basis of highly prevalent PTEN deletions, as in leiomyosarcoma.	('PTEN', 'Gene', '5728', (110, 114))	('leiomyosarcoma', 'Disease', (132, 146))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (132, 146))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (132, 146))	('sarcoma', 'Phenotype', 'HP:0100242', (139, 146))	('deletions', 'Var', (115, 124))	('PTEN', 'Gene', (110, 114))
15974	21753790	The finding of frequent PIK3CA mutations in myxoid/round-cell liposarcoma (Table 1) suggests that at least this molecular subset of patients might benefit from PI3K inhibitors; this is currently being tested in clinical trials.	('mutations', 'Var', (31, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('liposarcoma', 'Phenotype', 'HP:0012034', (62, 73))	('PIK3CA', 'Gene', (24, 30))	('clinical', 'Species', '191496', (211, 219))	('liposarcoma', 'Disease', (62, 73))	('PIK3CA', 'Gene', '5290', (24, 30))	('patients', 'Species', '9606', (132, 140))	('liposarcoma', 'Disease', 'MESH:D008080', (62, 73))
15980	21753790	For instance, GIST harboring the more common and imatinib-sensitive KIT exon 11 mutation tend to become resistant by acquiring a second-site KIT mutation in exon 11 rather than in exon 9.	('KIT exon 11', 'Gene', (68, 79))	('GIST', 'Phenotype', 'HP:0100723', (14, 18))	('mutation', 'Var', (80, 88))	('imatinib', 'Chemical', 'MESH:D000068877', (49, 57))	('mutation', 'Var', (145, 153))
15982	21753790	Another mechanism of resistance may involve alternative oncogenic pathways or rewiring of signaling networks, as experimental evidence suggests is the case for IGF1R inhibitors in rhabdomyosarcomas and Ewing sarcoma cell lines.	('sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('sarcomas', 'Phenotype', 'HP:0100242', (189, 197))	('IGF1R', 'Gene', (160, 165))	('rhabdomyosarcomas', 'Disease', 'MESH:D012208', (180, 197))	('sarcoma', 'Phenotype', 'HP:0100242', (189, 196))	('Ewing sarcoma', 'Disease', (202, 215))	('IGF1R', 'Gene', '3480', (160, 165))	('rhabdomyosarcomas', 'Disease', (180, 197))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (180, 196))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (202, 215))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (202, 215))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (180, 197))	('inhibitors', 'Var', (166, 176))
15983	21753790	This adaptive resistance is consistent with the lack of IGF1R mutations observed in cancer types where these therapies are active.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('IGF1R', 'Gene', '3480', (56, 61))	('adaptive resistance', 'MPA', (5, 24))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('IGF1R', 'Gene', (56, 61))	('mutations', 'Var', (62, 71))
15989	21753790	Considering therapeutic strategies aimed at the aberrant transcriptional proteins driving translocation sarcomas, we note that transcription factors are considered poorly druggable because their protein-protein and protein-DNA interactions have historically been difficult to inhibit with small molecules.	('sarcomas', 'Disease', 'MESH:D012509', (104, 112))	('protein-protein', 'Protein', (195, 210))	('sarcomas', 'Phenotype', 'HP:0100242', (104, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('aberrant', 'Var', (48, 56))	('sarcomas', 'Disease', (104, 112))
15994	21753790	In clear-cell sarcoma, EWS-ATF1 transactivates microphthalmia-associated transcription factor (MITF), which in turn directly activates MET transcription.	('activates', 'PosReg', (125, 134))	('sarcoma', 'Disease', (14, 21))	('EWS-ATF1', 'Gene', (23, 31))	('transactivates', 'Var', (32, 46))	('microphthalmia-associated transcription factor', 'Gene', (47, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('EWS-ATF1', 'Gene', '466;2130', (23, 31))	('microphthalmia', 'Phenotype', 'HP:0000568', (47, 61))	('MET transcription', 'MPA', (135, 152))	('MITF', 'Gene', '4286', (95, 99))	('MITF', 'Gene', (95, 99))	('microphthalmia-associated transcription factor', 'Gene', '4286', (47, 93))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
15999	21753790	These findings have in part provided the rationale for trials of IGF1R inhibitors in these sarcomas.	('inhibitors', 'Var', (71, 81))	('IGF1R', 'Gene', (65, 70))	('sarcomas', 'Disease', 'MESH:D012509', (91, 99))	('sarcomas', 'Phenotype', 'HP:0100242', (91, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (91, 98))	('sarcomas', 'Disease', (91, 99))	('IGF1R', 'Gene', '3480', (65, 70))
16005	21753790	Epigenetic approaches may lead to re-expression of pro-apoptotic molecules, rendering sarcomas sensitive to other agents, or itself induce apoptosis or senescence, although unknown at present.	('sarcomas', 'Disease', 'MESH:D012509', (86, 94))	('lead to', 'Reg', (26, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (86, 93))	('senescence', 'CPA', (152, 162))	('apoptosis', 'CPA', (139, 148))	('re-expression', 'MPA', (34, 47))	('sarcomas', 'Phenotype', 'HP:0100242', (86, 94))	('induce', 'Reg', (132, 138))	('expression', 'Species', '29278', (37, 47))	('sarcomas', 'Disease', (86, 94))	('Epigenetic approaches', 'Var', (0, 21))
16007	21753790	Targeting the p53-MDM2 pathway with nutlins is promising in tumors with MDM2 amplification (predominantly well- and dedifferentiated liposarcomas).	('sarcoma', 'Phenotype', 'HP:0100242', (137, 144))	('liposarcomas', 'Phenotype', 'HP:0012034', (133, 145))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('liposarcomas', 'Disease', 'MESH:D008080', (133, 145))	('liposarcomas', 'Disease', (133, 145))	('amplification', 'Var', (77, 90))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('liposarcoma', 'Phenotype', 'HP:0012034', (133, 144))	('MDM2', 'Gene', '4193', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('MDM2', 'Gene', '4193', (72, 76))	('MDM2', 'Gene', (18, 22))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('MDM2', 'Gene', (72, 76))	('tumors', 'Disease', (60, 66))
16012	21753790	Over the next few years, the catalog of mutations that drive all but the least common diseases will become known, thanks to large-scale efforts such as TCGA and the International Cancer Genome Consortium, as well as others.	('Cancer', 'Disease', 'MESH:D009369', (179, 185))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (179, 185))	('Cancer', 'Phenotype', 'HP:0002664', (179, 185))
16014	21753790	Translocation Structural rearrangement that juxtaposes distant genome sequences, resulting in aberrant gene expression or modified regulatory control of a gene (promoter substitution) or the formation of a fusion gene that encodes an aberrant, chimeric protein (gene fusion).	('resulting in', 'Reg', (81, 93))	('rearrangement', 'Var', (25, 38))	('expression', 'Species', '29278', (108, 118))	('gene expression', 'MPA', (103, 118))	('modified', 'Reg', (122, 130))	('aberrant', 'Var', (94, 102))	('regulatory control', 'MPA', (131, 149))
16020	21753790	Novel genomic findings from diverse approaches in sarcoma are identifying point mutations that co-occur with translocations, lineage-specific oncogenes, chromosomal remodeling events, and both genomic alterations and mutations that alter canonical signaling and differentiation pathways.	('alter', 'Reg', (232, 237))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('differentiation pathways', 'Pathway', (262, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('mutations', 'Var', (217, 226))	('translocations', 'Disease', (109, 123))
16091	21092109	A deletion of the succinate dehydrogenase subunit B gene has recently been associated with composite paraganglioma with neuroblastoma.	('paraganglioma', 'Disease', 'MESH:D010235', (101, 114))	('deletion', 'Var', (2, 10))	('succinate dehydrogenase subunit B', 'Gene', '6390', (18, 51))	('neuroblastoma', 'Phenotype', 'HP:0003006', (120, 133))	('succinate dehydrogenase subunit B', 'Gene', (18, 51))	('neuroblastoma', 'Disease', 'MESH:D009447', (120, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('neuroblastoma', 'Disease', (120, 133))	('associated', 'Reg', (75, 85))	('paraganglioma', 'Disease', (101, 114))
16115	20842251	131-MIBG and octreotide have high sensitivity and accuracy in diagosing extra-adrenal paraganglioma.	('131-MIBG', 'Var', (0, 8))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (72, 99))	('131-MIBG', 'Chemical', '-', (0, 8))	('octreotide', 'Chemical', 'MESH:D015282', (13, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('extra-adrenal paraganglioma', 'Disease', (72, 99))
16152	20842251	It is reported silent extra-adrenal PGL of retroperitoneum is probably due to mutations of the gene for succinate dehydrogenase-B (SDHB).	('SDHB', 'Gene', '6390', (131, 135))	('due', 'Reg', (71, 74))	('succinate dehydrogenase-B', 'Gene', '6390', (104, 129))	('succinate dehydrogenase-B', 'Gene', (104, 129))	('SDHB', 'Gene', (131, 135))	('mutations', 'Var', (78, 87))	('extra-adrenal PGL of', 'Disease', (22, 42))
16163	20842251	The sensitivity of 131I-MIBG for detecting PGLs ranges between 80 and 90%, with a specificity of 90-100%.	('PGLs', 'Protein', (43, 47))	('131I-MIBG', 'Var', (19, 28))	('PGLs', 'Phenotype', 'HP:0002668', (43, 47))	('131I-MIBG', 'Chemical', 'MESH:D019797', (19, 28))
16188	20842251	Treatment with therapeutic doses of 131I-MIBG or combination chemotherapy (cyclophosphamide, vincristine, and darcabazine) may induce (partial) responses to malignant PGLs.	('induce', 'Reg', (127, 133))	('PGLs', 'Phenotype', 'HP:0002668', (167, 171))	('131I-MIBG', 'Var', (36, 45))	('darcabazine', 'Chemical', '-', (110, 121))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (75, 91))	('vincristine', 'Chemical', 'MESH:D014750', (93, 104))	('men', 'Species', '9606', (5, 8))	('131I-MIBG', 'Chemical', 'MESH:D019797', (36, 45))	('responses', 'MPA', (144, 153))
16190	20842251	131I-MIBG and octreotide have high sensitivity and accuracy in diagnosing silent extra-adrenal PGL.	('131I-MIBG', 'Var', (0, 9))	('octreotide', 'Chemical', 'MESH:D015282', (14, 24))	('131I-MIBG', 'Chemical', 'MESH:D019797', (0, 9))	('silent extra-adrenal PGL', 'Disease', (74, 98))
16194	19596260	Loss of heterozygosity of succinate dehydrogenase B mutation by direct sequencing in synchronous paragangliomas Extraadrenal pheochromocytomas and paragangliomas are rare entities within the pediatric population.	('Extraadrenal pheochromocytomas', 'Phenotype', 'HP:0006737', (112, 142))	('paragangliomas', 'Disease', 'MESH:D010235', (97, 111))	('mutation', 'Var', (52, 60))	('paragangliomas', 'Phenotype', 'HP:0002668', (97, 111))	('succinate dehydrogenase', 'Gene', (26, 49))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (125, 141))	('paragangliomas', 'Disease', (147, 161))	('synchronous paragangliomas', 'Disease', (85, 111))	('synchronous paragangliomas', 'Disease', 'MESH:D009378', (85, 111))	('Loss', 'NegReg', (0, 4))	('Extraadrenal pheochromocytomas', 'Disease', (112, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('paragangliomas', 'Disease', (97, 111))	('succinate dehydrogenase', 'Gene', '6390', (26, 49))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (125, 142))	('paragangliomas', 'Disease', 'MESH:D010235', (147, 161))	('paragangliomas', 'Phenotype', 'HP:0002668', (147, 161))	('paraganglioma', 'Phenotype', 'HP:0002668', (97, 110))	('Extraadrenal pheochromocytomas', 'Disease', 'MESH:C565335', (112, 142))
16201	19596260	Germline mutation in SDHD at 11q23 predisposes to benign head and neck tumors.	('head and neck tumors', 'Phenotype', 'HP:0012288', (57, 77))	('SDHD', 'Gene', '6392', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SDHD', 'Gene', (21, 25))	('neck tumors', 'Disease', 'MESH:D006258', (66, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('Germline mutation', 'Var', (0, 17))	('neck tumors', 'Disease', (66, 77))	('predisposes', 'Reg', (35, 46))
16202	19596260	SDHC mutations at 1q21 are associated with solitary tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SDHC', 'Gene', (0, 4))	('associated', 'Reg', (27, 37))	('solitary tumors', 'Disease', 'MESH:D054364', (43, 58))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('solitary tumors', 'Disease', (43, 58))
16203	19596260	Mutations in the iron-sulfur protein catalytic subunit, SDHB at 1p36, commonly lead to extra-adrenal abdominal tumors, classically secreting norepinephrine.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('extra-adrenal abdominal tumors', 'Disease', 'MESH:D010236', (87, 117))	('Mutations', 'Var', (0, 9))	('norepinephrine', 'Chemical', 'MESH:D009638', (141, 155))	('extra-adrenal abdominal tumors', 'Disease', (87, 117))	('lead to', 'Reg', (79, 86))	('secreting norepinephrine', 'MPA', (131, 155))
16206	19596260	Pediatric paragangliomas represent early manifestations of hereditary disease due to germline mutations in the von Hippel Lindau susceptibility gene VHL, MEN-2-associated RET gene, or SDH genes.	('Pediatric paragangliomas', 'Disease', (0, 24))	('von Hippel Lindau', 'Disease', 'MESH:D006623', (111, 128))	('MEN', 'Species', '9606', (154, 157))	('mutations', 'Var', (94, 103))	('hereditary disease', 'Disease', (59, 77))	('paraganglioma', 'Phenotype', 'HP:0002668', (10, 23))	('RET', 'Gene', (171, 174))	('RET', 'Gene', '5979', (171, 174))	('Pediatric paragangliomas', 'Disease', 'MESH:D010235', (0, 24))	('hereditary disease', 'Disease', 'MESH:D030342', (59, 77))	('VHL', 'Disease', (149, 152))	('man', 'Species', '9606', (41, 44))	('VHL', 'Disease', 'MESH:D006623', (149, 152))	('SDH', 'Gene', '6390', (184, 187))	('paragangliomas', 'Phenotype', 'HP:0002668', (10, 24))	('von Hippel Lindau', 'Disease', (111, 128))	('SDH', 'Gene', (184, 187))
16207	19596260	Heterozygous germline SDH mutations resulting in loss of function confer tumor susceptibility.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('loss of function', 'NegReg', (49, 65))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (73, 78))	('SDH', 'Gene', '6390', (22, 25))	('SDH', 'Gene', (22, 25))
16209	19596260	Here we report a pediatric patient heterozygous for a SDHB mutation who presents with three simultaneous extra-adrenal paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (119, 133))	('SDHB', 'Gene', '6390', (54, 58))	('paraganglioma', 'Phenotype', 'HP:0002668', (119, 132))	('SDHB', 'Gene', (54, 58))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (105, 133))	('patient', 'Species', '9606', (27, 34))	('mutation', 'Var', (59, 67))	('extra-adrenal paragangliomas', 'Disease', (105, 133))
16228	19596260	DNA from peripheral blood leukocytes was sequenced initially for mutations in the VHL tumor suppressor gene and the RET oncogene, both of which were normal.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('VHL tumor', 'Disease', (82, 91))	('RET', 'Gene', (116, 119))	('VHL tumor', 'Disease', 'MESH:D006623', (82, 91))	('mutations', 'Var', (65, 74))	('RET', 'Gene', '5979', (116, 119))
16229	19596260	Subsequent sequencing of SDHD, SDHC, and SDHB genes revealed a previously reported heterozygous SDHB mutation, deletion of a cytosine at nucleotide 88 in exon 2 codon 30, causing a frameshift resulting in a translation stop at codon 76.	('cytosine', 'Chemical', 'MESH:D003596', (125, 133))	('SDHB', 'Gene', (96, 100))	('SDHC', 'Gene', (31, 35))	('SDHB', 'Gene', '6390', (41, 45))	('SDHD', 'Gene', '6392', (25, 29))	('SDHB', 'Gene', '6390', (96, 100))	('SDHC', 'Gene', '6391', (31, 35))	('SDHD', 'Gene', (25, 29))	('SDHB', 'Gene', (41, 45))	('deletion', 'Var', (111, 119))
16233	19596260	Sequencing of both tumors revealed the predominance of the nucleotides representing the mutated allele over the diminished peaks of the normal sequence, consistent with loss of heterozygosity of SDHB in both tumors (Fig 3, middle).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('loss', 'NegReg', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('nucleotides', 'Var', (59, 70))	('tumors', 'Disease', (208, 214))	('SDHB', 'Gene', '6390', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('SDHB', 'Gene', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
16234	19596260	Loss-of-function mutations as a cause of familial paraganglioma were first identified in the SDHD gene, and subsequently in the SDHC and SDHB genes.	('Loss-of-function', 'NegReg', (0, 16))	('SDHD', 'Gene', (93, 97))	('SDHB', 'Gene', '6390', (137, 141))	('SDHC', 'Gene', (128, 132))	('SDHB', 'Gene', (137, 141))	('familial paraganglioma', 'Disease', (41, 63))	('SDHC', 'Gene', '6391', (128, 132))	('paraganglioma', 'Phenotype', 'HP:0002668', (50, 63))	('SDHD', 'Gene', '6392', (93, 97))	('mutations', 'Var', (17, 26))	('familial paraganglioma', 'Disease', 'MESH:D010235', (41, 63))
16235	19596260	Mutations in SDHB, sometimes referred to as paraganglioma syndrome type 4 (PGL4), are notable for a higher incidence of abdominal tumors and potential for metastasis.	('paraganglioma', 'Phenotype', 'HP:0002668', (44, 57))	('SDHB', 'Gene', '6390', (13, 17))	('PGL4', 'Gene', '6390', (75, 79))	('abdominal tumors', 'Disease', (120, 136))	('PGL4', 'Gene', (75, 79))	('paraganglioma syndrome', 'Disease', (44, 66))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (44, 66))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('abdominal tumors', 'Disease', 'MESH:D015746', (120, 136))
16236	19596260	Single-nucleotide missense, nonsense, and frameshift mutations, as well as large deletions, have been identified in the SDHB gene.	('Single-nucleotide missense', 'Var', (0, 26))	('frameshift mutations', 'Var', (42, 62))	('SDHB', 'Gene', '6390', (120, 124))	('SDHB', 'Gene', (120, 124))	('nonsense', 'Var', (28, 36))
16237	19596260	Here we report the identification of a heterozygous c.88delC frameshift mutation in the germline of a child bearing three intra-abdominal, extra-adrenal paragangliomas, as well as in his asymptomatic father, along with corresponding loss of the normal allele (LOH) in the child's tumors by DNA sequence analysis.	('paragangliomas', 'Phenotype', 'HP:0002668', (153, 167))	('child', 'Species', '9606', (102, 107))	('c.88delC frameshift mutation', 'Var', (52, 80))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('c.88delC', 'Mutation', 'rs747198089', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (280, 286))	('tumors', 'Disease', (280, 286))	('child', 'Species', '9606', (272, 277))	('paraganglioma', 'Phenotype', 'HP:0002668', (153, 166))	('intra-abdominal, extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (122, 167))	('tumors', 'Disease', 'MESH:D009369', (280, 286))
16242	19596260	Loss-of-function mutations associated with cancer predisposition predict complete loss of tumor suppressor gene function in tumors resulting from loss of heterozygosity at the mutation site.	('Loss-of-function', 'NegReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('loss of tumor', 'Disease', 'MESH:D009369', (82, 95))	('cancer', 'Disease', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('loss of heterozygosity', 'Var', (146, 168))	('mutation', 'Var', (176, 184))	('loss of tumor', 'Disease', (82, 95))	('mutations', 'Var', (17, 26))	('function', 'MPA', (112, 120))
16243	19596260	LOH in SDHB tumors has been demonstrated by fluorescence in situ hybridization by using probes for chromosome 1 p in a nonfamilial malignant pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('probes', 'Var', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SDHB tumors', 'Disease', (7, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (131, 157))	('SDHB tumors', 'Disease', 'MESH:D009369', (7, 18))	('malignant pheochromocytoma', 'Disease', (131, 157))
16245	19596260	Our demonstration by sequence analysis of the predominance of the mutated SDHB allele over the normal allele in both abdominal tumors of this patient confirms loss of LOH as an important feature of paraganglioma pathogenesis in this tumor predisposition syndrome.	('paraganglioma', 'Disease', (198, 211))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutated', 'Var', (66, 73))	('abdominal tumors', 'Disease', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', (127, 132))	('SDHB', 'Gene', '6390', (74, 78))	('paraganglioma', 'Disease', 'MESH:D010235', (198, 211))	('SDHB', 'Gene', (74, 78))	('abdominal tumors', 'Disease', 'MESH:D015746', (117, 133))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('patient', 'Species', '9606', (142, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('tumor', 'Disease', 'MESH:D009369', (233, 238))
16261	33902135	Furthermore, Addison's disease or congenital adrenal hyperplasia (CAH) are respectively associated with insufficient or dysregulated adrenal hormone production, compromising the development of sex characteristics in patients with CAH  .	("Addison's disease", 'Disease', 'MESH:D000224', (13, 30))	('CAH', 'Phenotype', 'HP:0008258', (230, 233))	('CAH', 'Phenotype', 'HP:0008258', (66, 69))	("Addison's disease", 'Phenotype', 'HP:0008207', (13, 30))	('congenital adrenal hyperplasia', 'Phenotype', 'HP:0008258', (34, 64))	('congenital adrenal hyperplasia', 'Disease', 'MESH:D000312', (34, 64))	('congenital adrenal hyperplasia', 'Disease', (34, 64))	('compromising', 'NegReg', (161, 173))	('development of sex characteristics', 'CPA', (178, 212))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (45, 64))	('dysregulated', 'Var', (120, 132))	("Addison's disease", 'Disease', (13, 30))
16274	33902135	In brief, to a reaction mixture containing 920 mul 0.4 M Tris-HCl buffer (pH 8.5), 20 mul 2.5 mM d 3 -S-adenosyl methionine ( d 3 -SAM), 20 mul 2.5 mM norepinephrine, and 40 mul tissue/cell lysate were added to a reaction tube, and incubated for 20 minutes at 37 C. Enzyme activity was quenched by placing samples on ice.	('d 3 -S-adenosyl methionine', 'Chemical', '-', (97, 123))	('d 3 -S-adenosyl', 'Var', (97, 112))	('Tris-HCl', 'Chemical', '-', (57, 65))	('activity', 'MPA', (273, 281))	('d 3 -SAM', 'Chemical', '-', (126, 134))
16293	33902135	These include mutations in genes encoding for SDHx, fumarate hydratase and isocitrate dehydrogenase within the TCA cycle  .	('fumarate hydratase', 'Gene', '2271', (52, 70))	('mutations', 'Var', (14, 23))	('SDHx', 'Gene', (46, 50))	('fumarate hydratase', 'Gene', (52, 70))
16294	33902135	This is of importance for patients with mutations in the SDHB subunit, which bears a high risk for metastatic disease, requiring a fast and reliable identification to improve patient outcome    .	('metastatic disease', 'Disease', (99, 117))	('SDHB', 'Gene', '6390', (57, 61))	('mutations', 'Var', (40, 49))	('metastatic disease', 'Disease', 'MESH:C538445', (99, 117))	('SDHB', 'Gene', (57, 61))
16298	31887185	Mutations of metabolic enzymes in somatic tissues can cause cancers due to oncometabolite accumulation.	('cause', 'Reg', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('oncometabolite accumulation', 'MPA', (75, 102))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('Mutations', 'Var', (0, 9))
16302	31887185	Mitochondrial disorders can result from mutations affecting enzymes of oxidative metabolism.	('result from', 'Reg', (28, 39))	('Mitochondrial disorders', 'Disease', (0, 23))	('Mitochondrial disorders', 'Disease', 'MESH:D028361', (0, 23))	('mutations', 'Var', (40, 49))
16303	31887185	Interestingly and surprisingly, some cancers are caused by gain-of-function or loss-of-function mutations of genes encoding metabolic enzymes in susceptible tissues.	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('loss-of-function', 'NegReg', (79, 95))	('gain-of-function', 'PosReg', (59, 75))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancers', 'Disease', (37, 44))	('mutations', 'Var', (96, 105))
16308	31887185	The resulting TCA cycle dysfunction drives metabolic remodeling with dependence on glycolysis and a profound accumulation of succinate as defective SDH cannot oxidize this dicarboxylic acid to fumarate.	('dicarboxylic acid', 'Chemical', 'MESH:D003998', (172, 189))	('succinate', 'Chemical', 'MESH:D013386', (125, 134))	('TCA cycle', 'Enzyme', (14, 23))	('TCA', 'Chemical', 'MESH:C000589078', (14, 17))	('defective', 'Var', (138, 147))	('dysfunction', 'Reg', (24, 35))	('SDH', 'Gene', (148, 151))	('fumarate', 'Chemical', 'MESH:D005650', (193, 201))	('accumulation', 'PosReg', (109, 121))
16324	31887185	In principle, changes in C. elegans phenotype or behavior associated with mutations related to SDH and HIF function could create models for high-throughput screening of compounds that suppress or exacerbate these characteristics in intact animals.	('exacerbate', 'PosReg', (196, 206))	('behavior', 'MPA', (49, 57))	('C. elegans', 'Species', '6239', (25, 35))	('mutations', 'Var', (74, 83))	('changes', 'Reg', (14, 21))	('SDH', 'Gene', (95, 98))
16326	31887185	Inspiration for a C. elegans model of the molecular changes associated with SDH-loss disorders such as PPGL came from the previous fascinating observation that mutation of egl-9(sa307), the C. elegans ortholog of human PHD, unexpectedly causes increased egg retention in hermaphrodite worms.	('mutation', 'Var', (160, 168))	('human', 'Species', '9606', (213, 218))	('hermaphrodite worms', 'Disease', 'MESH:D012734', (271, 290))	('causes', 'Reg', (237, 243))	('hermaphrodite worms', 'Disease', (271, 290))	('C. elegans', 'Species', '6239', (18, 28))	('egl-9', 'Gene', (172, 177))	('C. elegans', 'Species', '6239', (190, 200))	('egg retention', 'CPA', (254, 267))	('SDH-loss', 'Gene', (76, 84))	('egl-9', 'Gene', '179461', (172, 177))	('increased', 'PosReg', (244, 253))
16328	31887185	The egg-laying defect is HIF-1-dependent, as egl-9(sa307):hif-1(ia4) double mutants and hif-1(ia4) single mutants both exhibit normal egg laying behavior.	('egg laying behavior', 'CPA', (134, 153))	('HIF-1', 'Gene', (25, 30))	('hif-1(ia4', 'Gene', '180359', (58, 67))	('egg-laying', 'CPA', (4, 14))	('egl-9', 'Gene', (45, 50))	('double mutants', 'Var', (69, 83))	('hif-1(ia4', 'Gene', '180359', (88, 97))	('egl-9', 'Gene', '179461', (45, 50))	('HIF-1', 'Gene', '180359', (25, 30))
16338	31887185	The C. elegans Punc-31 promoter was used to drive expression of Hif transgenes or RNA interference constructs for SDH subunit knockdown, allowing these effects to be limited to neurons known to be important for egg-laying.	('C. elegans', 'Species', '6239', (4, 14))	('unc-31', 'Gene', (16, 22))	('unc-31', 'Gene', '178233', (16, 22))	('SDH', 'Gene', (114, 117))	('knockdown', 'Var', (126, 135))
16346	31887185	A second round of Gibson assembly was used to insert the sense and antisense sdhb-1 segments into the SbfI-linearized plasmid, forming an inverted repeat encoding a long RNA hairpin for RNA interference.	('antisense', 'Var', (67, 76))	('sdhb-1', 'Gene', (77, 83))	('sdhb-1', 'Gene', '174482', (77, 83))
16359	31887185	Hermaphrodite worms homozygous for the egl-9(sa307) mutation retain eggs.	('eggs', 'CPA', (68, 72))	('egl-9', 'Gene', '179461', (39, 44))	('mutation', 'Var', (52, 60))	('egl-9', 'Gene', (39, 44))
16360	31887185	We found that Punc-31-driven expression of functional EGL-9 in egl-9(sa307) mutants significantly relieved egg retention from egl-9(sa307) mutant levels (P<2.62e-14) to near wild type levels (mean eggs per worm are 14.2 and 12.7 respectively; P = 0.007; Fig 1A).	('EGL-9', 'Gene', '179461', (54, 59))	('egl-9', 'Gene', (126, 131))	('egl-9', 'Gene', (63, 68))	('egl-9', 'Gene', '179461', (126, 131))	('EGL-9', 'Gene', (54, 59))	('unc-31', 'Gene', (15, 21))	('relieved', 'NegReg', (98, 106))	('mutants', 'Var', (76, 83))	('egl-9', 'Gene', '179461', (63, 68))	('unc-31', 'Gene', '178233', (15, 21))	('egg retention', 'CPA', (107, 120))
16365	31887185	Interestingly, in contrast to Punc-31, we found that Ptdc-1-driven expression of functional hif-1(+) in egl-9(sa307):hif-1(ia4) mutants was inadequate to induce egg retention (data not shown).	('unc-31', 'Gene', (31, 37))	('hif-1', 'Gene', '180359', (92, 97))	('hif-1', 'Gene', (117, 122))	('mutants', 'Var', (128, 135))	('hif-1(ia4', 'Gene', '180359', (117, 126))	('unc-31', 'Gene', '178233', (31, 37))	('tdc-1', 'Gene', '174327', (54, 59))	('egg retention', 'CPA', (161, 174))	('egl-9', 'Gene', (104, 109))	('hif-1', 'Gene', '180359', (117, 122))	('tdc-1', 'Gene', (54, 59))	('hif-1', 'Gene', (92, 97))	('egl-9', 'Gene', '179461', (104, 109))
16367	31887185	Based on these results, Punc-31 was chosen to drive cell-specific knockdown of SDHB-1 by RNA interference after injection of a plasmid containing an sdhb-1 inverted repeat (IR) under the control of Punc-31.	('unc-31', 'Gene', (25, 31))	('SDHB-1', 'Gene', (79, 85))	('unc-31', 'Gene', '178233', (25, 31))	('sdhb-1', 'Gene', (149, 155))	('RNA interference', 'MPA', (89, 105))	('sdhb-1', 'Gene', '174482', (149, 155))	('unc-31', 'Gene', '178233', (199, 205))	('unc-31', 'Gene', (199, 205))	('knockdown', 'Var', (66, 75))	('SDHB-1', 'Gene', '174482', (79, 85))
16368	31887185	Disruption of the SDH complex in unc-31-expressing cells is hypothesized to mimic essential biochemical phenotypes of SDH-loss disorders such as PPGL.	('unc-31', 'Gene', (33, 39))	('SDH-loss', 'Gene', (118, 126))	('unc-31', 'Gene', '178233', (33, 39))	('PPGL', 'Disease', (145, 149))	('Disruption', 'Var', (0, 10))
16371	31887185	We hypothesize that SDH knockdown results in intracellular succinate accumulation, known to inhibit 2-ketoglutarate-dependent dioxygenases such as EGL-9.	('SDH', 'Gene', (20, 23))	('EGL-9', 'Gene', '179461', (147, 152))	('2-ketoglutarate-dependent dioxygenases', 'MPA', (100, 138))	('intracellular succinate accumulation', 'MPA', (45, 81))	('results in', 'Reg', (34, 44))	('inhibit', 'NegReg', (92, 99))	('2-ketoglutarate', 'Chemical', 'MESH:C029743', (100, 115))	('oxygen', 'Chemical', 'MESH:D010100', (128, 134))	('EGL-9', 'Gene', (147, 152))	('knockdown', 'Var', (24, 33))	('succinate', 'Chemical', 'MESH:D013386', (59, 68))
16372	31887185	According to this model, EGL-9 inhibition prevents HIF-1 hydroxylation, stabilizing HIF-1 and promoting HIF-1 signaling and egg retention behavior in C. elegans.	('retention behavior', 'Disease', (128, 146))	('EGL-9', 'Gene', (25, 30))	('HIF-1', 'Gene', '180359', (104, 109))	('HIF-1', 'Gene', '180359', (51, 56))	('HIF-1', 'Gene', '180359', (84, 89))	('HIF-1', 'Gene', (104, 109))	('promoting', 'PosReg', (94, 103))	('HIF-1', 'Gene', (51, 56))	('HIF-1', 'Gene', (84, 89))	('EGL-9', 'Gene', '179461', (25, 30))	('inhibition', 'Var', (31, 41))	('retention behavior', 'Disease', 'MESH:D016055', (128, 146))	('C. elegans', 'Species', '6239', (150, 160))
16373	31887185	We note that global succinate accumulation in whole worms is not expected for SDH knockdown under these conditions, as effects would be limited to the small subset of cells where Punc-31 is active.	('SDH', 'Gene', (78, 81))	('unc-31', 'Gene', (180, 186))	('unc-31', 'Gene', '178233', (180, 186))	('knockdown', 'Var', (82, 91))	('succinate', 'Chemical', 'MESH:D013386', (20, 29))
16376	31887185	Previous studies have shown that mammalian cells treated with DMOG show an increase in transcription of HIF-1-responsive genes.	('HIF-1', 'Gene', '180359', (104, 109))	('DMOG', 'Var', (62, 66))	('HIF-1', 'Gene', (104, 109))	('mammalian', 'Species', '9606', (33, 42))	('transcription', 'MPA', (87, 100))	('DMOG', 'Chemical', 'None', (62, 66))	('increase', 'PosReg', (75, 83))
16377	31887185	Consistent with our observations for sdhb-1 knockdown, treatment of C. elegans hermaphrodites with DMOG induced egg retention in wild type N2 worms, but not in hif-1(ia4) worms (Fig 3).	('C. elegans', 'Species', '6239', (68, 78))	('DMOG', 'Chemical', 'None', (99, 103))	('egg retention', 'CPA', (112, 125))	('sdhb-1', 'Gene', (37, 43))	('hif-1(ia4', 'Gene', '180359', (160, 169))	('sdhb-1', 'Gene', '174482', (37, 43))	('DMOG', 'Var', (99, 103))
16379	31887185	Second, the inability of DMOG to affect egg laying in hif-1(ia4) mutants demonstrates the HIF-1-dependence of this chemical mechanism of egg retention in N2 worms.	('HIF-1', 'Gene', '180359', (90, 95))	('mutants', 'Var', (65, 72))	('DMOG', 'Chemical', 'None', (25, 29))	('egg laying', 'CPA', (40, 50))	('HIF-1', 'Gene', (90, 95))	('hif-1(ia4', 'Gene', '180359', (54, 63))
16380	31887185	This observation supports a model attributing egg retention in N2 worms to increased HIF-1 signaling resulting from DMOG inhibition of EGL-9.	('DMOG', 'Chemical', 'None', (116, 120))	('EGL-9', 'Gene', (135, 140))	('egg retention', 'CPA', (46, 59))	('increased HIF-1', 'Phenotype', 'HP:0030269', (75, 90))	('DMOG', 'Var', (116, 120))	('EGL-9', 'Gene', '179461', (135, 140))	('HIF-1', 'Gene', '180359', (85, 90))	('increased', 'PosReg', (75, 84))	('HIF-1', 'Gene', (85, 90))
16383	31887185	As hypothesized, DMOG treatment was observed to increase the girth of worms, and this effect was dose-dependent (Fig 4A).	('DMOG', 'Var', (17, 21))	('DMOG', 'Chemical', 'None', (17, 21))	('girth of worms', 'CPA', (61, 75))	('increase', 'PosReg', (48, 56))
16385	31887185	Thus, DMOG-treated worms were both wider and shorter than normal as evidenced by a reproducible dose-dependent decrease in width:length ratio (Fig 4C).	('DMOG-treated', 'Var', (6, 18))	('shorter', 'NegReg', (45, 52))	('DMOG', 'Chemical', 'None', (6, 10))	('width:length ratio', 'MPA', (123, 141))	('decrease', 'NegReg', (111, 119))
16395	31887185	We further show that worm body morphology changes in a dose-dependent manner with DMOG treatment, paralleling egg retention, and providing a possible future approach for high-content image screening of worm phenotypes if the methodologies can be optimized.	('worm body morphology', 'CPA', (21, 41))	('DMOG', 'Var', (82, 86))	('DMOG', 'Chemical', 'None', (82, 86))	('changes', 'Reg', (42, 49))
16482	31355591	In the case of pheochromocytoma located on a side wall nearby a ureteral orifice or distal part of the ureter, resection of the leasion may compel ureteral reimplantation into a normal bladder wall.	('pheochromocytoma', 'Disease', (15, 31))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (15, 31))	('resection', 'Var', (111, 120))	('compel', 'NegReg', (140, 146))	('pheochromocytoma', 'Disease', 'MESH:D010673', (15, 31))	('ureteral reimplantation into a normal bladder wall', 'CPA', (147, 197))
16519	30170467	Genetic investigation was negative for RET, VHL, SDHB, SDHC, SDHD mutations.	('mutations', 'Var', (66, 75))	('SDHB', 'Gene', (49, 53))	('RET', 'Gene', (39, 42))	('VHL', 'Disease', 'MESH:D006623', (44, 47))	('SDHD', 'Gene', '6392', (61, 65))	('SDHC', 'Gene', (55, 59))	('SDHD', 'Gene', (61, 65))	('RET', 'Gene', '5979', (39, 42))	('SDHC', 'Gene', '6391', (55, 59))	('SDHB', 'Gene', '6390', (49, 53))	('VHL', 'Disease', (44, 47))
16577	30170467	The improved survival benefited from reducing the tumor burden, decompressing the spinal stenosis to alleviate radiculopathy, and facilitating subsequent chemotherapy and radiation therapy.	('radiculopathy', 'Disease', 'MESH:D011843', (111, 124))	('radiculopathy', 'Disease', (111, 124))	('spinal stenosis', 'Disease', (82, 97))	('spinal stenosis', 'Disease', 'MESH:D013130', (82, 97))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('spinal stenosis', 'Phenotype', 'HP:0003416', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('decompressing', 'Var', (64, 77))	('tumor', 'Disease', (50, 55))
16646	30641325	Nonspecific alpha-antagonists such as phentolamine and phenoxybenzamine are commonly used for vasoconstrictive blockade and reduce complications from malignant hypertension to less than 3%.	('hypertension', 'Disease', (160, 172))	('phentolamine', 'Chemical', 'MESH:D010646', (38, 50))	('hypertension', 'Phenotype', 'HP:0000822', (160, 172))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (55, 71))	('phentolamine', 'Var', (38, 50))	('hypertension', 'Disease', 'MESH:D006973', (160, 172))	('vasoconstrictive blockade', 'MPA', (94, 119))	('reduce', 'NegReg', (124, 130))	('phenoxybenzamine', 'Var', (55, 71))
16671	30464530	Moreover, the high HOXD-AS1 expression indicated a poor overall survival (OS) rate and can be an independent predictive factor for OS.	('overall survival', 'MPA', (56, 72))	('expression', 'MPA', (28, 38))	('HOXD-AS1', 'Gene', (19, 27))	('high', 'Var', (14, 18))	('poor', 'NegReg', (51, 55))	('HOXD-AS1', 'Gene', '401022', (19, 27))
16672	30464530	The TCGA dataset, which included 9,502 cancer patients, showed that the expression of HOXD-AS1 was related to poor OS and disease-free survival.	('disease-free survival', 'CPA', (122, 143))	('patients', 'Species', '9606', (46, 54))	('poor', 'Disease', (110, 114))	('cancer', 'Disease', (39, 45))	('related', 'Reg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('HOXD-AS1', 'Gene', (86, 94))	('HOXD-AS1', 'Gene', '401022', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('expression', 'Var', (72, 82))
16702	30464530	Therefore, our results indicated that the high HOXD-AS1 expression significantly increased the risk of worse clinicopathologic features.	('high', 'Var', (42, 46))	('HOXD-AS1', 'Gene', (47, 55))	('HOXD-AS1', 'Gene', '401022', (47, 55))
16707	30464530	As shown in Table 3, all of the subgroup analyses demonstrated that the expression of HOXD-AS1 was related to worse OS according to sample size (Figure 5B), NOS score (Figure 5C), and HR estimation method (Figure 5D).	('expression', 'Var', (72, 82))	('worse OS', 'Disease', (110, 118))	('HOXD-AS1', 'Gene', (86, 94))	('HOXD-AS1', 'Gene', '401022', (86, 94))
16708	30464530	However, the subgroup analysis for tumor type indicated that the expression of HOXD-AS1 was only related to a worse OS in the digestive system (HR = 1.59, 95% CI = [1.25, 1.93], P<0.001, fixed effect, Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('HOXD-AS1', 'Gene', (79, 87))	('HOXD-AS1', 'Gene', '401022', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('expression', 'Var', (65, 75))
16711	30464530	The pooled results reported that the expression of HOXD-AS1 was an independent prognostic factor for the OS of patients (HR = 1.66, 95% CI = [1.12, 2.20], P<0.001, fixed effect, Figure 5B).	('HOXD-AS1', 'Gene', (51, 59))	('expression', 'Var', (37, 47))	('HOXD-AS1', 'Gene', '401022', (51, 59))	('OS of', 'Disease', (105, 110))	('patients', 'Species', '9606', (111, 119))
16717	30464530	The results indicated that the high expression of HOXD-AS1 denoted a worse OS (Figure 7A) and DFS (Figure 7B), confirming that an upregulated expression of HOXD-AS1 was associated with OS and DFS in cancer patients.	('upregulated', 'PosReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('DFS', 'Disease', (192, 195))	('DFS', 'CPA', (94, 97))	('HOXD-AS1', 'Gene', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('HOXD-AS1', 'Gene', '401022', (156, 164))	('HOXD-AS1', 'Gene', (50, 58))	('patients', 'Species', '9606', (206, 214))	('cancer', 'Disease', (199, 205))	('expression', 'MPA', (142, 152))	('high', 'Var', (31, 35))	('HOXD-AS1', 'Gene', '401022', (50, 58))
16722	30464530	On the contrary, the expression of HOXD-AS1 was associated with DFS in the female reproductive system (Figure 7N).	('HOXD-AS1', 'Gene', (35, 43))	('HOXD-AS1', 'Gene', '401022', (35, 43))	('DFS', 'Disease', (64, 67))	('associated', 'Reg', (48, 58))	('expression', 'Var', (21, 31))
16725	30464530	The results indicated that the risk of lymph node metastasis in high expression was 2.69 times higher than those in low HOXD-AS1 expression.	('high expression', 'Var', (64, 79))	('HOXD-AS1', 'Gene', (120, 128))	('HOXD-AS1', 'Gene', '401022', (120, 128))	('lymph node metastasis', 'CPA', (39, 60))
16727	30464530	The pooled results showed that the high expression of HOXD-AS1 was related to a worse OS, and HOXD-AS1 could be an independent role for the prognosis of cancers.	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('related', 'Reg', (67, 74))	('cancers', 'Disease', (153, 160))	('HOXD-AS1', 'Gene', (94, 102))	('worse OS', 'Disease', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HOXD-AS1', 'Gene', (54, 62))	('HOXD-AS1', 'Gene', '401022', (94, 102))	('HOXD-AS1', 'Gene', '401022', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('high', 'Var', (35, 39))
16733	30464530	Further, Wang et al indicated that the knockdown of HOXD-AS1 inhibited migration and invasion, and HOXD-AS1 could competitively bind to miR-130a-3p to prevent SOX4.	('HOXD-AS1', 'Gene', '401022', (99, 107))	('SOX4', 'Gene', (159, 163))	('bind', 'Interaction', (128, 132))	('inhibited', 'NegReg', (61, 70))	('HOXD-AS1', 'Gene', (52, 60))	('knockdown', 'Var', (39, 48))	('SOX4', 'Gene', '6659', (159, 163))	('miR', 'Gene', '220972', (136, 139))	('HOXD-AS1', 'Gene', '401022', (52, 60))	('miR', 'Gene', (136, 139))	('prevent', 'NegReg', (151, 158))	('HOXD-AS1', 'Gene', (99, 107))
16739	30464530	Xia et al reported that miR-133b was a downstream target of HOXD-AS1, and a knockdown of HOXD-AS1 could inhibit the proliferation, migration, and invasion of non-small-cell lung cancer cells.	('HOXD-AS1', 'Gene', '401022', (89, 97))	('miR-133b', 'Gene', '442890', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('migration', 'CPA', (131, 140))	('knockdown', 'Var', (76, 85))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (158, 184))	('miR-133b', 'Gene', (24, 32))	('invasion', 'CPA', (146, 154))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (162, 184))	('HOXD-AS1', 'Gene', (60, 68))	('proliferation', 'CPA', (116, 129))	('inhibit', 'NegReg', (104, 111))	('HOXD-AS1', 'Gene', '401022', (60, 68))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('HOXD-AS1', 'Gene', (89, 97))
16747	30464530	Despite the above limitations, this meta-analysis concluded that the high expression of HOXD-AS1 was associated with large tumor size, lower differentiation, increased lymph node metastasis, and advanced TNM stage.	('expression', 'MPA', (74, 84))	('TNM', 'Gene', (204, 207))	('tumor', 'Disease', (123, 128))	('HOXD-AS1', 'Gene', (88, 96))	('lower', 'NegReg', (135, 140))	('high', 'Var', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('TNM', 'Gene', '10178', (204, 207))	('HOXD-AS1', 'Gene', '401022', (88, 96))	('lymph node metastasis', 'CPA', (168, 189))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('increased', 'PosReg', (158, 167))
16762	28078324	The highest rate of metastases occurs in hereditary PGL syndromes and is associated with mutations of genes of the succinate dehydrogenase complex (SDH gene).	('hereditary PGL syndromes', 'Disease', (41, 65))	('SDH gene', 'Gene', (148, 156))	('associated', 'Reg', (73, 83))	('hereditary PGL syndromes', 'Disease', 'MESH:D010235', (41, 65))	('mutations', 'Var', (89, 98))	('metastases', 'Disease', (20, 30))	('PGL', 'Phenotype', 'HP:0002668', (52, 55))	('metastases', 'Disease', 'MESH:D009362', (20, 30))
16837	22399235	PPGLs occur sporadically or in association with familial poly-tumor syndromes: multiple endocrine neoplasia type 2 (MEN2); von Hippel-Lindau (VHL) syndrome; neurofibromatosis type 1 (NF1); and paraganglioma syndromes associated with mutations of genes encoding subunits of the succinate dehydrogenase (SDH) complex, in particular subunits B (SDHB) and D (SDHD).	('NF1', 'Gene', (183, 186))	('neurofibromatosis type 1', 'Gene', (157, 181))	('von Hippel-Lindau (VHL) syndrome', 'Disease', 'MESH:D006623', (123, 155))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (88, 114))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (157, 174))	('SDHB', 'Gene', (342, 346))	('SDH', 'Gene', '6390', (342, 345))	('neoplasia', 'Phenotype', 'HP:0002664', (98, 107))	('succinate dehydrogenase', 'Gene', '6390', (277, 300))	('endocrine neoplasia type 2', 'Disease', (88, 114))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SDH', 'Gene', '6390', (302, 305))	('PPGLs', 'Chemical', '-', (0, 5))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (193, 216))	('paraganglioma syndromes', 'Disease', (193, 216))	('SDHD', 'Gene', '6392', (355, 359))	('neurofibromatosis type 1', 'Gene', '4763', (157, 181))	('paraganglioma', 'Phenotype', 'HP:0002668', (193, 206))	('SDH', 'Gene', (342, 345))	('SDH', 'Gene', '6390', (355, 358))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (88, 107))	('SDH', 'Gene', (302, 305))	('SDHD', 'Gene', (355, 359))	('succinate dehydrogenase', 'Gene', (277, 300))	('NF1', 'Gene', '4763', (183, 186))	('associated', 'Reg', (217, 227))	('SDHB', 'Gene', '6390', (342, 346))	('tumor', 'Disease', (62, 67))	('mutations', 'Var', (233, 242))	('SDH', 'Gene', (355, 358))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
16838	22399235	Reported frequencies of germline mutations of the above genes among patients with PPGLs range from 27 % to 32 %, and are likely to increase as further tumor susceptibility genes are identified.	('PPGLs', 'Chemical', '-', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('PPGLs', 'Gene', (82, 87))	('tumor', 'Disease', (151, 156))	('patients', 'Species', '9606', (68, 76))	('germline mutations', 'Var', (24, 42))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
16839	22399235	Most recently, mutations of genes encoding the SDH complex assembly factor 2 (SDHAF2), transmembrane protein 127 (TMEM127), SDHA, and MYC associated factor X (MAX) have been identified as further hereditary causes of PPGLs, ranking PPGLs as tumors most commonly associated with known gene mutations [ - ].	('transmembrane protein 127', 'Gene', (87, 112))	('TMEM127', 'Gene', '55654', (114, 121))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('PPGLs', 'Chemical', '-', (217, 222))	('causes', 'Reg', (207, 213))	('PPGLs', 'Chemical', '-', (232, 237))	('MAX', 'Gene', (159, 162))	('mutations', 'Var', (15, 24))	('SDH complex assembly factor 2', 'Gene', '54949', (47, 76))	('SDHA', 'Gene', (78, 82))	('SDHA', 'Gene', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('SDHA', 'Gene', '6389', (78, 82))	('MYC associated factor X', 'Gene', (134, 157))	('SDHAF2', 'Gene', '54949', (78, 84))	('SDHAF2', 'Gene', (78, 84))	('SDHA', 'Gene', '6389', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('PPGLs', 'Disease', (217, 222))	('MAX', 'Gene', '4149', (159, 162))	('TMEM127', 'Gene', (114, 121))	('tumors', 'Disease', (241, 247))	('MYC associated factor X', 'Gene', '4149', (134, 157))	('transmembrane protein 127', 'Gene', '55654', (87, 112))	('SDH complex assembly factor 2', 'Gene', (47, 76))
16840	22399235	It is important to note that PPGLs with an underlying SDHB mutation are strongly associated with an aggressive behavior and the development of metastatic disease.	('aggressive behavior', 'Phenotype', 'HP:0000718', (100, 119))	('associated with', 'Reg', (81, 96))	('PPGLs', 'Chemical', '-', (29, 34))	('SDHB', 'Gene', '6390', (54, 58))	('SDHB', 'Gene', (54, 58))	('metastatic disease', 'CPA', (143, 161))	('mutation', 'Var', (59, 67))	('aggressive behavior', 'CPA', (100, 119))
16877	22399235	The use of 123I-MIBG is preferred over 131I-MIBG because of its higher sensitivity, lower radiation exposure, and improved imaging quality with SPECT.	('imaging', 'MPA', (123, 130))	('improved', 'PosReg', (114, 122))	('123I-MIBG', 'Var', (11, 20))	('123I-MIBG', 'Chemical', 'MESH:D019797', (11, 20))	('sensitivity', 'MPA', (71, 82))	('131I-MIBG', 'Chemical', '-', (39, 48))
16899	22399235	The sensitivity of somatostatin receptor scintigraphy with 111In-DTPA-pentetreotide is lower than that of 123I/131I-MIBG in PPGLs [ - ].	('lower', 'NegReg', (87, 92))	('111In-DTPA-pentetreotide', 'Var', (59, 83))	('PPGLs', 'Chemical', '-', (124, 129))	('111In-DTPA-pentetreotide', 'Chemical', 'MESH:C452379', (59, 83))
16913	22399235	SDHB mutations can lead to complete loss of SDH enzymatic activity in malignant PPGL, with upregulation of hypoxic-angiogenetic responsive genes.	('SDH', 'Gene', (44, 47))	('PPGL', 'Chemical', '-', (80, 84))	('upregulation', 'PosReg', (91, 103))	('SDH', 'Gene', (0, 3))	('loss', 'NegReg', (36, 40))	('mutations', 'Var', (5, 14))	('SDH', 'Gene', '6390', (44, 47))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('hypoxic-angiogenetic', 'MPA', (107, 127))	('SDH', 'Gene', '6390', (0, 3))
16975	26512333	It is recommended that patients with genetic cancer susceptibility conditions, such as medullary thyroid cancer or pheochromocytoma, and all patients with a personal history or family history of MEN 2 syndrome, should be offered germline RET mutation screening along with pre- and post-test genetic counseling.	('genetic cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('MEN 2 syndrome', 'Disease', (195, 209))	('pheochromocytoma', 'Disease', (115, 131))	('thyroid cancer', 'Disease', (97, 111))	('RET', 'Gene', '5979', (238, 241))	('MEN 2 syndrome', 'Disease', 'MESH:D018813', (195, 209))	('patients', 'Species', '9606', (23, 31))	('pheochromocytoma', 'Disease', 'MESH:D010673', (115, 131))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (87, 111))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (115, 131))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RET', 'Gene', (238, 241))	('genetic cancer', 'Disease', 'MESH:D030342', (37, 51))	('patients', 'Species', '9606', (141, 149))	('mutation', 'Var', (242, 250))
17000	23401807	Subsequent referral for genetic testing and sequencing of the von Hippel-Lindau gene showed a deleterious mutation (R167Q).	('R167Q', 'Mutation', 'rs147297806', (116, 121))	('von Hippel-Lindau', 'Disease', (62, 79))	('R167Q', 'Var', (116, 121))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (62, 79))
17015	23401807	If CAH is suspected, screening for adrenal insufficiency as well as mutation analysis for CYP21B is recommended.	('CAH', 'Phenotype', 'HP:0008258', (3, 6))	('adrenal insufficiency', 'Disease', (35, 56))	('mutation analysis', 'Var', (68, 85))	('CAH', 'Disease', (3, 6))	('CYP21B', 'Gene', '1589', (90, 96))	('CYP21B', 'Gene', (90, 96))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (35, 56))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (35, 56))
17018	23401807	Genetic syndromes of pheochromocytoma include multiple endocrine neoplasia type 2 (MEN2A and 2B), neurofibromatosis type 1 (NF1), the pheochromocytoma-paraganglioma syndrome (mutation of the SDHB or SDHD genes), and von Hippel-Lindau syndrome (VHL).	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (216, 242))	('SDHB', 'Gene', (191, 195))	('pheochromocytoma', 'Disease', (134, 150))	('pheochromocytoma', 'Disease', (21, 37))	('SDHD', 'Gene', '6392', (199, 203))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (21, 37))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))	('NF1', 'Gene', '4763', (124, 127))	('von Hippel-Lindau syndrome', 'Disease', (216, 242))	('neoplasia', 'Phenotype', 'HP:0002664', (65, 74))	('VHL', 'Disease', 'MESH:D006623', (244, 247))	('paraganglioma', 'Phenotype', 'HP:0002668', (151, 164))	('pheochromocytoma-paraganglioma syndrome', 'Disease', (134, 173))	('MEN2A and 2B', 'Gene', '5979', (83, 95))	('SDHD', 'Gene', (199, 203))	('NF1', 'Gene', (124, 127))	('neurofibromatosis type 1', 'Gene', (98, 122))	('mutation', 'Var', (175, 183))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (55, 81))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (98, 115))	('SDHB', 'Gene', '6390', (191, 195))	('endocrine neoplasia type 2', 'Disease', (55, 81))	('pheochromocytoma-paraganglioma syndrome', 'Disease', 'MESH:D010673', (134, 173))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (55, 74))	('VHL', 'Disease', (244, 247))	('pheochromocytoma', 'Disease', 'MESH:D010673', (134, 150))	('pheochromocytoma', 'Disease', 'MESH:D010673', (21, 37))	('neurofibromatosis type 1', 'Gene', '4763', (98, 122))
17021	23401807	Mutations in the SDHB or SDHD genes predispose patients to glomus tumors and occasionally pheochromocytomas.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (90, 107))	('patients', 'Species', '9606', (47, 55))	('SDHB', 'Gene', '6390', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('SDHB', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('glomus tumors', 'Disease', 'MESH:D005918', (59, 72))	('pheochromocytomas', 'Disease', 'MESH:D010673', (90, 107))	('SDHD', 'Gene', '6392', (25, 29))	('pheochromocytomas', 'Disease', (90, 107))	('predispose', 'Reg', (36, 46))	('SDHD', 'Gene', (25, 29))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (90, 106))	('glomus tumors', 'Disease', (59, 72))
17022	23401807	Patients with bilateral pheochromocytoma should be screened for mutations in the genes associated with the above syndromes depending on the clinical presentation and family history (Table 1).	('bilateral pheochromocytoma', 'Disease', (14, 40))	('bilateral pheochromocytoma', 'Disease', 'MESH:D010673', (14, 40))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (64, 73))	('screened', 'Reg', (51, 59))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (24, 40))
17067	22787353	A neuroendocrine work-up for the para-aortic mass demonstrated a normal catecholamine metabolites, normetanephrine (329 mcg/24 hours [reference range: 88-649 mcg/24 hours]) and metenephrine (164 mcg/24 hours [reference range: 58-203 mcg/24 hours]) on 24-hour urine.	('164 mcg/24', 'Var', (191, 201))	('metenephrine', 'Chemical', '-', (177, 189))	('catecholamine metabolites', 'MPA', (72, 97))	('normetanephrine', 'MPA', (99, 114))	('normetanephrine', 'Chemical', 'MESH:D009647', (99, 114))	('catecholamine', 'Chemical', 'MESH:D002395', (72, 85))	('metenephrine', 'MPA', (177, 189))
17083	22787353	Treatment of associated hypertension is with phenoxybenzamine, an irreversible alpha-blocker with a long half-life.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (45, 61))	('hypertension', 'Disease', 'MESH:D006973', (24, 36))	('phenoxybenzamine', 'Var', (45, 61))	('hypertension', 'Disease', (24, 36))	('hypertension', 'Phenotype', 'HP:0000822', (24, 36))
17092	21082267	The identification of the first gene related to paraganglioma, SDHD, encoding a subunit of mitochondrial succinate dehydrogenase (SDH), was quickly followed by the identification of mutations in SDHC and SDHB.	('succinate dehydrogenase', 'Gene', '6389', (105, 128))	('paraganglioma', 'Phenotype', 'HP:0002668', (48, 61))	('SDH', 'Gene', (195, 198))	('SDHD', 'Gene', '6392', (63, 67))	('succinate dehydrogenase', 'Gene', (105, 128))	('SDHC', 'Gene', (195, 199))	('SDH', 'Gene', '6390', (63, 66))	('SDH', 'Gene', (130, 133))	('SDHB', 'Gene', '6390', (204, 208))	('SDHD', 'Gene', (63, 67))	('mutations', 'Var', (182, 191))	('SDHB', 'Gene', (204, 208))	('SDH', 'Gene', (63, 66))	('SDH', 'Gene', '6390', (204, 207))	('paraganglioma', 'Disease', (48, 61))	('SDH', 'Gene', '6390', (195, 198))	('paraganglioma', 'Disease', 'MESH:D010235', (48, 61))	('SDHC', 'Gene', '6391', (195, 199))	('SDH', 'Gene', '6390', (130, 133))	('SDH', 'Gene', (204, 207))
17098	21082267	In addition to these recent discoveries, new techniques related to mutation analysis, including genetic analysis algorithms, SDHB immunohistochemistry, and deletion analysis by MLPA have improved the efficiency and accuracy of genetic analysis.	('MLPA', 'Gene', (177, 181))	('SDHB', 'Gene', (125, 129))	('improved', 'PosReg', (187, 195))	('deletion analysis', 'Var', (156, 173))	('SDHB', 'Gene', '6390', (125, 129))
17099	21082267	However, many intriguing questions remain, such as the striking differences in the clinical phenotype of genes that encode proteins with an apparently very close functional relationship, and the lack of expression of SDHD and SDHAF2 mutations when inherited via the maternal line.	('SDHAF2', 'Gene', (226, 232))	('SDHD', 'Gene', (217, 221))	('mutations', 'Var', (233, 242))	('SDHD', 'Gene', '6392', (217, 221))	('SDHAF2', 'Gene', '54949', (226, 232))
17101	21082267	Prior to the year 2000, knowledge of the genetics of paraganglioma and pheochromocytoma was confined to mutations of the VHL, RET and NF1 genes.	('VHL', 'Gene', '7428', (121, 124))	('mutations', 'Var', (104, 113))	('paraganglioma', 'Disease', (53, 66))	('pheochromocytoma', 'Disease', (71, 87))	('NF1', 'Gene', (134, 137))	('RET', 'Gene', (126, 129))	('paraganglioma', 'Disease', 'MESH:D010235', (53, 66))	('pheochromocytoma', 'Disease', 'MESH:D010673', (71, 87))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (71, 87))	('NF1', 'Gene', '4763', (134, 137))	('VHL', 'Gene', (121, 124))	('RET', 'Gene', '5979', (126, 129))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))
17102	21082267	The identification of mutations in the succinate dehydrogenase subunit D gene (SDHD) in patients with head and neck paraganglioma was therefore a major breakthrough.	('neck paraganglioma', 'Disease', 'MESH:D010235', (111, 129))	('paraganglioma', 'Phenotype', 'HP:0002668', (116, 129))	('SDHD', 'Gene', '6392', (79, 83))	('succinate dehydrogenase', 'Gene', '6389', (39, 62))	('patients', 'Species', '9606', (88, 96))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (102, 129))	('mutations', 'Var', (22, 31))	('neck paraganglioma', 'Disease', (111, 129))	('SDHD', 'Gene', (79, 83))	('succinate dehydrogenase', 'Gene', (39, 62))
17103	21082267	The association of paraganglioma with mutations in SDHD, and later with mutations in other SDH subunits, has helped elucidate both the role of the mitochondrial SDH complex and intermediary metabolism in tumorigenesis.	('SDH', 'Gene', '6390', (51, 54))	('SDH', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('paraganglioma', 'Disease', (19, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (19, 32))	('association', 'Interaction', (4, 15))	('SDH', 'Gene', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('SDH', 'Gene', '6390', (91, 94))	('paraganglioma', 'Disease', 'MESH:D010235', (19, 32))	('SDH', 'Gene', (51, 54))	('tumor', 'Disease', (204, 209))	('SDHD', 'Gene', '6392', (51, 55))	('mutations', 'Var', (38, 47))	('SDHD', 'Gene', (51, 55))	('SDH', 'Gene', '6390', (161, 164))
17104	21082267	The subsequent discovery of SDH mutations in patients with pheochromocytomas and extra-adrenal paragangliomas led to a recognition that paragangliomas and pheochromocytomas share not only similar cellular origins, but can also have a comparable genetic basis.	('paraganglioma', 'Phenotype', 'HP:0002668', (136, 149))	('paragangliomas', 'Phenotype', 'HP:0002668', (136, 150))	('SDH', 'Gene', (28, 31))	('patients', 'Species', '9606', (45, 53))	('paragangliomas', 'Disease', 'MESH:D010235', (95, 109))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (155, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (81, 109))	('mutations', 'Var', (32, 41))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('paragangliomas', 'Disease', (136, 150))	('extra-adrenal paragangliomas', 'Disease', (81, 109))	('pheochromocytomas', 'Disease', 'MESH:D010673', (59, 76))	('pheochromocytomas', 'Disease', (59, 76))	('pheochromocytomas', 'Disease', (155, 172))	('pheochromocytomas', 'Disease', 'MESH:D010673', (155, 172))	('paragangliomas', 'Disease', (95, 109))	('SDH', 'Gene', '6390', (28, 31))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (59, 76))	('paragangliomas', 'Disease', 'MESH:D010235', (136, 150))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (155, 172))
17111	21082267	Presently, causative gene mutations can be identified in around 32% of paraganglioma-pheochromocytomas.	('paraganglioma-pheochromocytomas', 'Disease', (71, 102))	('mutations', 'Var', (26, 35))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (85, 102))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))	('paraganglioma-pheochromocytomas', 'Disease', 'MESH:D010673', (71, 102))
17112	21082267	Hereditary tumor syndromes which have pheochromocytoma within their spectrum include the multiple endocrine neoplasia syndromes, MEN2A and MEN2B, caused by mutations of the RET (Rearranged in Transfection) proto-oncogene, subtypes of von Hippel-Lindau (VHL) disease, caused by mutations of the VHL tumor suppressor gene, and neurofibromatosis type 1 (NF1) resulting from mutations of the NF1 tumor suppressor gene.	('caused by', 'Reg', (146, 155))	('neoplasia', 'Phenotype', 'HP:0002664', (108, 117))	('tumor syndromes', 'Disease', (11, 26))	('tumor', 'Disease', (392, 397))	('multiple endocrine neoplasia syndromes', 'Disease', 'MESH:D009377', (89, 127))	('MEN2B', 'Gene', (139, 144))	('NF1', 'Gene', (388, 391))	('pheochromocytoma', 'Disease', (38, 54))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (234, 265))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (325, 342))	('MEN2B', 'Gene', '5979', (139, 144))	('neurofibromatosis type 1', 'Gene', '4763', (325, 349))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (38, 54))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('Rearranged in Transfection', 'Gene', (178, 204))	('tumor', 'Disease', (298, 303))	('RET', 'Gene', '5979', (173, 176))	('tumor', 'Disease', (11, 16))	('VHL tumor', 'Disease', (294, 303))	('mutations', 'Var', (277, 286))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('mutations', 'Var', (371, 380))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (98, 117))	('VHL tumor', 'Disease', 'MESH:D006623', (294, 303))	('tumor syndromes', 'Disease', 'MESH:D009369', (11, 26))	('MEN2A', 'Gene', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('MEN2A', 'Gene', '5979', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('mutations', 'Var', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('RET', 'Gene', (173, 176))	('NF1', 'Gene', '4763', (351, 354))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('neurofibromatosis type 1', 'Gene', (325, 349))	('Hereditary tumor', 'Disease', (0, 16))	('caused by', 'Reg', (267, 276))	('multiple endocrine neoplasia syndromes', 'Disease', (89, 127))	('Rearranged in Transfection', 'Gene', '5979', (178, 204))	('Hereditary tumor', 'Disease', 'MESH:D009386', (0, 16))	('NF1', 'Gene', '4763', (388, 391))	('NF1', 'Gene', (351, 354))	('pheochromocytoma', 'Disease', 'MESH:D010673', (38, 54))
17114	21082267	More recently, mutations in genes associated with the mitochondrial succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, SDHD and SDHAF2) have been shown to cause head and neck paragangliomas, extra-adrenal paragangliomas, and pheochromocytomas (Table 1).	('SDHA', 'Gene', '6389', (107, 111))	('succinate dehydrogenase', 'Gene', (68, 91))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (167, 194))	('neck paragangliomas', 'Disease', (176, 195))	('SDH', 'Gene', '6390', (119, 122))	('SDH', 'Gene', (107, 110))	('SDH', 'Gene', (113, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (181, 194))	('paragangliomas', 'Phenotype', 'HP:0002668', (181, 195))	('SDHC', 'Gene', '6391', (119, 123))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (231, 248))	('mutations', 'Var', (15, 24))	('paraganglioma', 'Phenotype', 'HP:0002668', (211, 224))	('SDHAF2', 'Gene', '54949', (134, 140))	('SDHAF2', 'Gene', (134, 140))	('SDHD', 'Gene', '6392', (125, 129))	('SDH', 'Gene', '6390', (134, 137))	('SDH', 'Gene', (119, 122))	('SDHA', 'Gene', (134, 138))	('SDHB', 'Gene', '6390', (113, 117))	('neck paragangliomas', 'Disease', 'MESH:D010235', (176, 195))	('SDH', 'Gene', '6390', (93, 96))	('SDH', 'Gene', '6390', (125, 128))	('SDHA', 'Gene', '6389', (134, 138))	('paragangliomas', 'Phenotype', 'HP:0002668', (211, 225))	('SDHD', 'Gene', (125, 129))	('SDHC', 'Gene', (119, 123))	('cause', 'Reg', (161, 166))	('SDH', 'Gene', '6390', (107, 110))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (197, 225))	('SDH', 'Gene', (134, 137))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (167, 195))	('SDHB', 'Gene', (113, 117))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (231, 247))	('SDHA', 'Gene', (107, 111))	('succinate dehydrogenase', 'Gene', '6389', (68, 91))	('pheochromocytomas', 'Disease', (231, 248))	('SDH', 'Gene', '6390', (113, 116))	('extra-adrenal paragangliomas', 'Disease', (197, 225))	('pheochromocytomas', 'Disease', 'MESH:D010673', (231, 248))	('SDH', 'Gene', (93, 96))	('SDH', 'Gene', (125, 128))
17120	21082267	Despite the fact that SDH proteins are all components of the same protein complex, mutations lead to clear differences in clinical phenotype.	('mutations', 'Var', (83, 92))	('differences', 'Reg', (107, 118))	('SDH', 'Gene', (22, 25))	('SDH', 'Gene', '6390', (22, 25))
17122	21082267	Such populations facilitate the proliferation of founder mutations, one of them being the well-known Dutch SDHD founder mutation, p. Asp92Tyr.	('Asp92Tyr', 'Var', (133, 141))	('Asp92Tyr', 'SUBSTITUTION', 'None', (133, 141))	('SDHD', 'Gene', '6392', (107, 111))	('SDHD', 'Gene', (107, 111))
17123	21082267	The increased prevalence of this and other SDHD founder mutations, relative to SDHB mutations, facilitated the initial mapping of the SDHD locus.	('mutations', 'Var', (56, 65))	('SDHD', 'Gene', '6392', (43, 47))	('SDHD', 'Gene', (43, 47))	('SDHD', 'Gene', (134, 138))	('SDHD', 'Gene', '6392', (134, 138))	('SDHB', 'Gene', '6390', (79, 83))	('SDHB', 'Gene', (79, 83))
17126	21082267	Mutations in SDHD most frequently result in benign head and neck paragangliomas and are much less commonly associated with sympathetic paragangliomas and adrenal pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('paragangliomas and adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (135, 179))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (162, 179))	('neck paragangliomas', 'Disease', (60, 79))	('associated', 'Reg', (107, 117))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (154, 179))	('paragangliomas', 'Phenotype', 'HP:0002668', (65, 79))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHD', 'Gene', (13, 17))	('SDHD', 'Gene', '6392', (13, 17))	('Mutations', 'Var', (0, 9))	('neck paragangliomas', 'Disease', 'MESH:D010235', (60, 79))	('paraganglioma', 'Phenotype', 'HP:0002668', (135, 148))	('paragangliomas', 'Phenotype', 'HP:0002668', (135, 149))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (51, 79))	('result in', 'Reg', (34, 43))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (154, 178))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (51, 78))
17127	21082267	The proportion of SDHD mutation carriers that will develop a tumor (penetrance) is high (87-100%), although not all carriers with a tumor will develop additional tumor-related symptoms.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('develop', 'PosReg', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mutation', 'Var', (23, 31))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('SDHD', 'Gene', '6392', (18, 22))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SDHD', 'Gene', (18, 22))	('tumor', 'Disease', (61, 66))
17128	21082267	The identification of mutations in SDHD as a cause of hereditary paraganglioma syndrome quickly led to the discovery of the role of other SDH subunits.	('SDH', 'Gene', '6390', (35, 38))	('SDHD', 'Gene', (35, 39))	('SDHD', 'Gene', '6392', (35, 39))	('SDH', 'Gene', '6390', (138, 141))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D010235', (54, 87))	('hereditary paraganglioma syndrome', 'Disease', (54, 87))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDH', 'Gene', (138, 141))	('SDH', 'Gene', (35, 38))	('mutations', 'Var', (22, 31))	('cause', 'Reg', (45, 50))
17130	21082267	Since its discovery, SDHB has been found to be the dominant gene in hereditary paraganglioma syndrome in many parts of the world, despite a relatively low penetrance of SDHB mutations of 25-40%.	('SDHB', 'Gene', '6390', (169, 173))	('SDHB', 'Gene', (169, 173))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('SDHB', 'Gene', '6390', (21, 25))	('hereditary paraganglioma syndrome', 'Disease', (68, 101))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D010235', (68, 101))	('mutations', 'Var', (174, 183))	('SDHB', 'Gene', (21, 25))
17131	21082267	Due to their lower penetrance, SDHB mutations are often found in apparently sporadic patients.	('lower penetrance', 'MPA', (13, 29))	('SDHB', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (85, 93))	('SDHB', 'Gene', '6390', (31, 35))
17132	21082267	SDHB mutations primarily predispose to sPGLs, and around 20% of SDHB mutation carriers will develop metastatic disease.	('metastatic', 'CPA', (100, 110))	('SDHB', 'Gene', '6390', (64, 68))	('mutations', 'Var', (5, 14))	('mutation', 'Var', (69, 77))	('SDHB', 'Gene', (64, 68))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('sPGLs', 'Disease', (39, 44))	('develop', 'PosReg', (92, 99))	('predispose', 'Reg', (25, 35))
17134	21082267	Paragangliomas due to mutations in SDHC are much rarer than SDHB- and SDHD-related paragangliomas, accounting for less than 1% of all patients in a recent study.	('SDHD', 'Gene', (70, 74))	('SDHD', 'Gene', '6392', (70, 74))	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('SDHB-', 'Gene', '6390', (60, 65))	('SDHB-', 'Gene', (60, 65))	('paragangliomas', 'Disease', (83, 97))	('paragangliomas', 'Disease', 'MESH:D010235', (83, 97))	('paragangliomas', 'Phenotype', 'HP:0002668', (83, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('patients', 'Species', '9606', (134, 142))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('SDHC', 'Gene', (35, 39))	('mutations', 'Var', (22, 31))	('SDHC', 'Gene', '6391', (35, 39))	('Paragangliomas', 'Disease', (0, 14))
17135	21082267	SDHC mutations result primarily in head and neck paragangliomas, but have also been identified in patients with sympathetic paragangliomas.	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (35, 62))	('result', 'Reg', (15, 21))	('neck paragangliomas', 'Disease', (44, 63))	('SDHC', 'Gene', (0, 4))	('paragangliomas', 'Disease', (124, 138))	('paragangliomas', 'Disease', (49, 63))	('mutations', 'Var', (5, 14))	('paragangliomas', 'Disease', 'MESH:D010235', (49, 63))	('paragangliomas', 'Disease', 'MESH:D010235', (124, 138))	('SDHC', 'Gene', '6391', (0, 4))	('patients', 'Species', '9606', (98, 106))	('neck paragangliomas', 'Disease', 'MESH:D010235', (44, 63))	('paragangliomas', 'Phenotype', 'HP:0002668', (49, 63))	('paragangliomas', 'Phenotype', 'HP:0002668', (124, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (35, 63))
17138	21082267	While the approximate location of this paraganglioma-associated gene had been known for over a decade, referred to as PGL2 locus, a yeast screen of respiration deficient mutants facilitated the fortuitous discovery of a conserved mitochondrial protein of unknown function that physically associated with the SDHA flavoprotein.	('respiration deficient', 'Phenotype', 'HP:0002093', (148, 169))	('paraganglioma', 'Disease', (39, 52))	('SDHA', 'Gene', '6389', (308, 312))	('mutants', 'Var', (170, 177))	('paraganglioma', 'Disease', 'MESH:D010235', (39, 52))	('SDHA', 'Gene', (308, 312))	('yeast', 'Species', '4932', (132, 137))	('paraganglioma', 'Phenotype', 'HP:0002668', (39, 52))
17140	21082267	A missense mutation of SDHAF2 c.232G>A (p.Gly78Arg) identified in a large Dutch head and neck paraganglioma kindred results in the loss of SDHA flavination and activity of the SDH complex.	('neck paraganglioma', 'Disease', (89, 107))	('p.Gly78Arg', 'Mutation', 'rs113560320', (40, 50))	('SDH', 'Gene', '6390', (176, 179))	('activity', 'MPA', (160, 168))	('c.232G>A', 'Var', (30, 38))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (80, 107))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', '6390', (23, 26))	('neck paraganglioma', 'Disease', 'MESH:D010235', (89, 107))	('SDH', 'Gene', (176, 179))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('missense', 'Var', (2, 10))	('loss of SDHA flavination', 'Disease', 'MESH:C562935', (131, 155))	('SDHAF2', 'Gene', '54949', (23, 29))	('SDHAF2', 'Gene', (23, 29))	('SDH', 'Gene', (23, 26))	('c.232G>A', 'Mutation', 'rs113560320', (30, 38))	('SDH', 'Gene', '6390', (139, 142))	('loss of SDHA flavination', 'Disease', (131, 155))
17141	21082267	In a follow-up study with the joint aims of identifying new mutation carriers and assessing the frequency of SDHAF2 mutations amongst 443 paraganglioma and pheochromocytoma patients, it became clear that mutations in this gene make a very modest contribution to the overall genetic burden in these syndromes.	('paraganglioma', 'Disease', 'MESH:D010235', (138, 151))	('pheochromocytoma', 'Disease', (156, 172))	('patients', 'Species', '9606', (173, 181))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (156, 172))	('mutations', 'Var', (204, 213))	('pheochromocytoma', 'Disease', 'MESH:D010673', (156, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (138, 151))	('mutations', 'Var', (116, 125))	('paraganglioma', 'Disease', (138, 151))	('SDHAF2', 'Gene', '54949', (109, 115))	('SDHAF2', 'Gene', (109, 115))
17143	21082267	Only one additional SDHAF2-related family was identified, which interestingly carried the exact mutation, p.Gly78Arg, previously found in the Netherlands, but without evidence of a familial relationship to the Dutch kindred.	('SDHAF2', 'Gene', '54949', (20, 26))	('SDHAF2', 'Gene', (20, 26))	('p.Gly78Arg', 'Var', (106, 116))	('p.Gly78Arg', 'Mutation', 'rs113560320', (106, 116))
17144	21082267	Although apparently a simple loss of function mutation in yeast, the recurrence of this mutation and absence of other mutations may suggest that the SDHAF2 protein with the specific p.Gly78Arg mutation retains residual activity, allowing the protein to participate in other, currently unknown, cellular activities, most feasibly the addition of FAD prosthetic groups to other flavoproteins.	('activity', 'MPA', (219, 227))	('FAD', 'Chemical', 'MESH:D005182', (345, 348))	('SDHAF2', 'Gene', (149, 155))	('allowing', 'Reg', (229, 237))	('participate', 'Reg', (253, 264))	('p.Gly78Arg', 'Var', (182, 192))	('SDHAF2', 'Gene', '54949', (149, 155))	('yeast', 'Species', '4932', (58, 63))	('protein', 'Protein', (156, 163))	('p.Gly78Arg', 'Mutation', 'rs113560320', (182, 192))
17145	21082267	A striking aspect of SDHAF2 mutations, and the probable explanation for the rapid identification of all mutation carriers, is the very high penetrance.	('SDHAF2', 'Gene', '54949', (21, 27))	('mutations', 'Var', (28, 37))	('SDHAF2', 'Gene', (21, 27))
17147	21082267	Seven mutation carriers are known to have inherited the mutation via the maternal line, and are not thought to be at risk of tumor development (see "Inheritance" below).	('tumor', 'Disease', (125, 130))	('mutation', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))
17148	21082267	The studies above suggest that SDHAF2 mutation screening should only be considered in patients who suffer exclusively from head and neck paragangliomas, who have familial antecedents, multiple tumors, or a very young age of onset, and in whom the SDHB, SDHC and SDHD genes have been shown to be negative for mutations and deletions by sequencing and multiplex ligation-dependent probe amplification (MLPA).	('deletions', 'Var', (322, 331))	('paragangliomas', 'Phenotype', 'HP:0002668', (137, 151))	('SDHD', 'Gene', '6392', (262, 266))	('patients', 'Species', '9606', (86, 94))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (123, 151))	('neck paragangliomas', 'Disease', 'MESH:D010235', (132, 151))	('multiple tumors', 'Disease', (184, 199))	('SDHD', 'Gene', (262, 266))	('SDHC', 'Gene', '6391', (253, 257))	('SDHAF2', 'Gene', '54949', (31, 37))	('SDHAF2', 'Gene', (31, 37))	('SDHB', 'Gene', '6390', (247, 251))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('paraganglioma', 'Phenotype', 'HP:0002668', (137, 150))	('negative', 'NegReg', (295, 303))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (123, 150))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('multiple tumors', 'Disease', 'MESH:D009369', (184, 199))	('SDHB', 'Gene', (247, 251))	('mutation', 'Var', (38, 46))	('SDHC', 'Gene', (253, 257))	('neck paragangliomas', 'Disease', (132, 151))
17152	21082267	Recently the first SDHA mutation was reported, (c.1765C>T, p.Arg589Trp:exon 13) in a patient with a catecholamine secreting extra-adrenal paraganglioma.	('c.1765C>T', 'Var', (48, 57))	('patient', 'Species', '9606', (85, 92))	('extra-adrenal paraganglioma', 'Disease', (124, 151))	('SDHA', 'Gene', '6389', (19, 23))	('catecholamine', 'Chemical', 'MESH:D002395', (100, 113))	('paraganglioma', 'Phenotype', 'HP:0002668', (138, 151))	('p.Arg589Trp', 'Mutation', 'rs387906780', (59, 70))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (124, 151))	('SDHA', 'Gene', (19, 23))	('c.1765C>T', 'Mutation', 'rs387906780', (48, 57))
17154	21082267	It remains unclear why SDHA mutations in paragangliomas are so rare, but the patient above may suggest that SDHA mutations show reduced penetrance and most mutation carriers escape the development of clinical symptoms.	('SDHA', 'Gene', '6389', (108, 112))	('penetrance', 'MPA', (136, 146))	('paragangliomas', 'Disease', (41, 55))	('paragangliomas', 'Disease', 'MESH:D010235', (41, 55))	('reduced', 'NegReg', (128, 135))	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('SDHA', 'Gene', (108, 112))	('SDHA', 'Gene', '6389', (23, 27))	('paragangliomas', 'Phenotype', 'HP:0002668', (41, 55))	('mutations', 'Var', (113, 122))	('patient', 'Species', '9606', (77, 84))	('escape', 'NegReg', (174, 180))	('SDHA', 'Gene', (23, 27))	('development of clinical symptoms', 'CPA', (185, 217))
17155	21082267	Equally, and as suggested above for SDHAF2, the scarcity of SDHA mutations could be attributable to a secondary cellular function of SDHA, leading to intolerance for missense and truncating mutations that eliminate all enzyme activity.	('SDHA', 'Gene', '6389', (36, 40))	('SDHA', 'Gene', '6389', (60, 64))	('SDHA', 'Gene', '6389', (133, 137))	('enzyme activity', 'MPA', (219, 234))	('eliminate', 'NegReg', (205, 214))	('truncating mutations', 'Var', (179, 199))	('missense', 'Var', (166, 174))	('SDHAF2', 'Gene', (36, 42))	('SDHA', 'Gene', (36, 40))	('SDHA', 'Gene', (60, 64))	('SDHAF2', 'Gene', '54949', (36, 42))	('mutations', 'Var', (65, 74))	('SDHA', 'Gene', (133, 137))
17161	21082267	Mutations seen in these patients are generally missense and the only known truncating mutation in a patient was found together with a missense mutation on the opposing allele, suggesting that complete loss of SDHA function may not be compatible with life.	('SDHA', 'Gene', (209, 213))	('missense', 'Var', (47, 55))	('patient', 'Species', '9606', (24, 31))	('patient', 'Species', '9606', (100, 107))	('Mutations', 'Var', (0, 9))	('SDHA', 'Gene', '6389', (209, 213))	('patients', 'Species', '9606', (24, 32))	('function', 'MPA', (214, 222))
17163	21082267	will prove to be first of many paraganglioma cases related to SDHA mutations is presently unclear.	('paraganglioma', 'Disease', 'MESH:D010235', (31, 44))	('SDHA', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('paraganglioma', 'Phenotype', 'HP:0002668', (31, 44))	('paraganglioma', 'Disease', (31, 44))	('SDHA', 'Gene', '6389', (62, 66))
17167	21082267	Identified in consanguineous families of Turkish and Italian origin, homozygous mutations of the SDHAF1 gene result in infantile leukoencephalopathy in affected children, and symptoms include rapidly progressive psychomotor regression beginning in the first year of life, reminiscent of the clinical symptoms seen in homozygous SDHA mutations carriers.	('SDHA', 'Gene', '6389', (97, 101))	('SDHAF1', 'Gene', '644096', (97, 103))	('psychomotor', 'Disease', (212, 223))	('SDHAF1', 'Gene', (97, 103))	('mutations', 'Var', (80, 89))	('infantile leukoencephalopathy', 'Disease', 'MESH:D056784', (119, 148))	('psychomotor', 'Disease', 'MESH:D011596', (212, 223))	('infantile leukoencephalopathy', 'Phenotype', 'HP:0007105', (119, 148))	('psychomotor regression', 'Phenotype', 'HP:0002376', (212, 234))	('result in', 'Reg', (109, 118))	('SDHA', 'Gene', (97, 101))	('SDHA', 'Gene', '6389', (328, 332))	('children', 'Species', '9606', (161, 169))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (129, 148))	('infantile leukoencephalopathy', 'Disease', (119, 148))	('SDHA', 'Gene', (328, 332))
17169	21082267	Disruption of the homologous gene or expression of the mutated gene in yeast caused SDH deficiency and failure of oxidative phosphorylation-dependent growth.	('SDH deficiency and failure', 'Disease', 'MESH:D006333', (84, 110))	('caused', 'Reg', (77, 83))	('yeast', 'Species', '4932', (71, 76))	('Disruption', 'Var', (0, 10))
17172	21082267	The explanation for the lack of tumor development in these mutation carriers and heterozygous SDHA mutation carriers may lie in the biochemical activity of SDH-complex II.	('SDH', 'Gene', '6390', (94, 97))	('SDHA', 'Gene', '6389', (94, 98))	('SDH', 'Gene', '6390', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (99, 107))	('SDHA', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SDH', 'Gene', (94, 97))	('tumor', 'Disease', (32, 37))	('SDH', 'Gene', (156, 159))
17173	21082267	SDHA homozygous mutation carriers generally show retention of complex II activity of at least 20% (range 20-61%), and likewise, homozygous SDHAF1 mutation carriers show 20-30% residual activity.	('SDHAF1', 'Gene', (139, 145))	('mutation', 'Var', (16, 24))	('SDHA', 'Gene', (0, 4))	('activity', 'MPA', (73, 81))	('SDHA', 'Gene', '6389', (139, 143))	('complex II', 'Enzyme', (62, 72))	('SDHA', 'Gene', (139, 143))	('SDHA', 'Gene', '6389', (0, 4))	('SDHAF1', 'Gene', '644096', (139, 145))
17175	21082267	As SDHAF1 and most SDHA mutations do not eliminate all enzyme function, even allowing for LOH in a specific cell, a residual activity of 10-30% is apparently sufficient to prevent the development of paragangliomas.	('paragangliomas', 'Disease', 'MESH:D010235', (199, 213))	('SDHA', 'Gene', (3, 7))	('SDHA', 'Gene', '6389', (19, 23))	('paragangliomas', 'Phenotype', 'HP:0002668', (199, 213))	('paraganglioma', 'Phenotype', 'HP:0002668', (199, 212))	('SDHAF1', 'Gene', '644096', (3, 9))	('mutations', 'Var', (24, 33))	('SDHAF1', 'Gene', (3, 9))	('SDHA', 'Gene', (19, 23))	('SDHA', 'Gene', '6389', (3, 7))	('paragangliomas', 'Disease', (199, 213))
17176	21082267	A further interesting aspect of the biochemical profile of SDHAF1 and SDHA mutation carriers is the accumulation of succinate.	('accumulation of succinate', 'MPA', (100, 125))	('SDHA', 'Gene', '6389', (70, 74))	('SDHA', 'Gene', (59, 63))	('mutation', 'Var', (75, 83))	('SDHA', 'Gene', (70, 74))	('succinate', 'Chemical', 'MESH:D019802', (116, 125))	('SDHAF1', 'Gene', '644096', (59, 65))	('SDHA', 'Gene', '6389', (59, 63))	('SDHAF1', 'Gene', (59, 65))
17178	21082267	The nuclear translocation of HIF-1 may be an important mechanism in triggering tumorigenesis in paraganglioma progenitor cells, but its occurrence in SDHAF1 and SDHA mutation carriers may suggest that complete loss of SDH activity is required to achieve levels of succinate accumulation sufficient to drive HIF-1 translocation to the extent needed to initiate tumorigenesis.	('SDHA', 'Gene', (161, 165))	('SDHAF1', 'Gene', '644096', (150, 156))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('translocation', 'MPA', (313, 326))	('SDHA', 'Gene', '6389', (161, 165))	('SDH', 'Gene', '6390', (150, 153))	('loss', 'NegReg', (210, 214))	('SDH', 'Gene', (218, 221))	('tumor', 'Disease', (360, 365))	('SDH', 'Gene', (161, 164))	('SDHAF1', 'Gene', (150, 156))	('activity', 'MPA', (222, 230))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('SDH', 'Gene', (150, 153))	('tumor', 'Disease', (79, 84))	('SDHA', 'Gene', (150, 154))	('HIF-1', 'Gene', '3091', (29, 34))	('HIF-1', 'Gene', (29, 34))	('SDHA', 'Gene', '6389', (150, 154))	('paraganglioma', 'Disease', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mutation', 'Var', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('paraganglioma', 'Disease', 'MESH:D010235', (96, 109))	('HIF-1', 'Gene', '3091', (307, 312))	('HIF-1', 'Gene', (307, 312))	('SDH', 'Gene', '6390', (218, 221))	('SDH', 'Gene', '6390', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('succinate', 'Chemical', 'MESH:D019802', (264, 273))
17187	21082267	Tumors linked to NF1 or RET mutations show an upregulation of biological pathways including genes that mediate translation initiation, protein synthesis, and kinase signaling, and are both associated with the RAS/RAF/MAP kinase signaling pathway.	('RET', 'Gene', '5979', (24, 27))	('upregulation', 'PosReg', (46, 58))	('associated', 'Reg', (189, 199))	('biological pathways', 'Pathway', (62, 81))	('kinase', 'MPA', (158, 164))	('NF1', 'Gene', (17, 20))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('RET', 'Gene', (24, 27))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('NF1', 'Gene', '4763', (17, 20))	('RAF', 'Gene', '22882', (213, 216))	('RAF', 'Gene', (213, 216))	('mutations', 'Var', (28, 37))
17190	21082267	The authors focused on the mammalian target of rapamycin (mTOR), which is deregulated on loss of NF1, and could show that the C1 mTOR complex is specifically affected by TMEM127 knockdown, leading to increased phosphorylation of targets of mTORC1.	('NF1', 'Gene', (97, 100))	('loss', 'Var', (89, 93))	('TMEM127', 'Gene', '55654', (170, 177))	('mTOR', 'Gene', (129, 133))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', (58, 62))	('mammalian target of rapamycin', 'Gene', '2475', (27, 56))	('mTOR', 'Gene', '2475', (129, 133))	('affected', 'Reg', (158, 166))	('knockdown', 'Var', (178, 187))	('mTORC1', 'Gene', (240, 246))	('mTOR', 'Gene', '2475', (58, 62))	('mTOR', 'Gene', '2475', (240, 244))	('mTORC1', 'Gene', '382056', (240, 246))	('increased', 'PosReg', (200, 209))	('mammalian target of rapamycin', 'Gene', (27, 56))	('NF1', 'Gene', '4763', (97, 100))	('TMEM127', 'Gene', (170, 177))	('phosphorylation', 'MPA', (210, 225))
17191	21082267	Knockdown of TMEM127 also resulted in larger cells with higher rates of proliferation.	('Knockdown', 'Var', (0, 9))	('proliferation', 'CPA', (72, 85))	('higher rates', 'PosReg', (56, 68))	('TMEM127', 'Gene', (13, 20))	('TMEM127', 'Gene', '55654', (13, 20))
17192	21082267	Pheochromocytomas carrying a TMEM127 mutation showed hyperphosphorylation of mTOR effector proteins, all these data together indicating that TMEM127 is a negative regulator of mTOR.	('TMEM127', 'Gene', (141, 148))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('TMEM127', 'Gene', '55654', (141, 148))	('mutation', 'Var', (37, 45))	('mTOR', 'Gene', '2475', (176, 180))	('mTOR', 'Gene', (176, 180))	('TMEM127', 'Gene', (29, 36))	('mTOR', 'Gene', '2475', (77, 81))	('Pheochromocytomas', 'Disease', (0, 17))	('TMEM127', 'Gene', '55654', (29, 36))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('mTOR', 'Gene', (77, 81))
17194	21082267	Of the seven distinct germline mutations identified, six were truncating, and the deletion of the wild-type allele in tumor DNA indicates that this is a bone fide tumor suppressor gene.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('deletion', 'Var', (82, 90))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (163, 168))	('truncating', 'MPA', (62, 72))
17199	21082267	The recognition of this phenomenon was made possible by the same social and demographic factors in the Netherlands that facilitated the initial mapping of the SDHD locus, and specifically by the increased prevalence of SDHD mutations, relative to SDHB mutations.	('SDHD', 'Gene', (159, 163))	('SDHB', 'Gene', '6390', (247, 251))	('SDHB', 'Gene', (247, 251))	('SDHD', 'Gene', '6392', (219, 223))	('mutations', 'Var', (224, 233))	('SDHD', 'Gene', (219, 223))	('SDHD', 'Gene', '6392', (159, 163))
17200	21082267	Although mutations in SDHD and SDHAF2 can be inherited via the maternal and paternal lines, tumor formation following maternal transmission of a mutation is extremely rare.	('SDHAF2', 'Gene', '54949', (31, 37))	('SDHAF2', 'Gene', (31, 37))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('SDHD', 'Gene', '6392', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SDHD', 'Gene', (22, 26))	('tumor', 'Disease', (92, 97))
17213	21082267	A number of studies have linked the central mediator of cellular hypoxia, HIF-1, to defects in succinate dehydrogenase.	('succinate dehydrogenase', 'Gene', (95, 118))	('HIF-1', 'Gene', '3091', (74, 79))	('succinate dehydrogenase', 'Gene', '6389', (95, 118))	('defects', 'Var', (84, 91))	('HIF-1', 'Gene', (74, 79))	('hypoxia', 'Disease', (65, 72))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))
17218	21082267	identified a family with two SDHB-linked cases of high altitude paraganglioma, residing at elevations of up to 2,200 m. These are the first cases to link high altitude paraganglioma to mutations of the succinate dehydrogenase genes.	('paraganglioma', 'Disease', 'MESH:D010235', (168, 181))	('paraganglioma', 'Disease', (64, 77))	('succinate dehydrogenase', 'Gene', (202, 225))	('paraganglioma', 'Phenotype', 'HP:0002668', (168, 181))	('paraganglioma', 'Disease', 'MESH:D010235', (64, 77))	('paraganglioma', 'Disease', (168, 181))	('succinate dehydrogenase', 'Gene', '6389', (202, 225))	('mutations', 'Var', (185, 194))	('SDHB-', 'Gene', '6390', (29, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (64, 77))	('SDHB-', 'Gene', (29, 34))
17222	21082267	In addition, both patients developed head and neck tumors, while abdominal tumors occur much more frequently in SDHB mutation carriers.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('head and neck tumors', 'Phenotype', 'HP:0012288', (37, 57))	('neck tumors', 'Disease', 'MESH:D006258', (46, 57))	('developed', 'Reg', (27, 36))	('neck tumors', 'Disease', (46, 57))	('abdominal tumors', 'Disease', 'MESH:D015746', (65, 81))	('SDHB', 'Gene', (112, 116))	('SDHB', 'Gene', '6390', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patients', 'Species', '9606', (18, 26))	('mutation', 'Var', (117, 125))	('carriers', 'Reg', (126, 134))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('abdominal tumors', 'Disease', (65, 81))
17223	21082267	The identification of SDHB mutations in high altitude paraganglioma may serve to renew interest in this fascinating but underappreciated field of paraganglioma research, and refocus attention on the role of oxygen levels in the initiation and development of these tumors.	('mutations', 'Var', (27, 36))	('oxygen', 'Chemical', 'MESH:D010100', (207, 213))	('paraganglioma', 'Disease', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('paraganglioma', 'Disease', 'MESH:D010235', (146, 159))	('SDHB', 'Gene', '6390', (22, 26))	('paraganglioma', 'Disease', 'MESH:D010235', (54, 67))	('SDHB', 'Gene', (22, 26))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('paraganglioma', 'Phenotype', 'HP:0002668', (146, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (54, 67))	('paraganglioma', 'Disease', (146, 159))
17227	21082267	Both MLPA and similar multiplex PCR methods have been applied in SDH deletion analysis, and have led to the recognition that deletions can represent up to 10% of all mutations.	('SDH', 'Gene', '6390', (65, 68))	('SDH', 'Gene', (65, 68))	('deletions', 'Var', (125, 134))
17230	21082267	who showed that in a series of 220 paragangliomas and pheochromocytomas, 102 tumors with known mutation of one of the SDH genes were negative for SDHB staining while RET, VHL and NF1 cases were uniformly positive.	('negative', 'NegReg', (133, 141))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (54, 70))	('pheochromocytomas', 'Disease', (54, 71))	('pheochromocytomas', 'Disease', 'MESH:D010673', (54, 71))	('SDH', 'Gene', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('RET', 'Gene', '5979', (166, 169))	('paragangliomas', 'Disease', (35, 49))	('VHL', 'Gene', (171, 174))	('SDH', 'Gene', '6390', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SDHB', 'Gene', '6390', (146, 150))	('NF1', 'Gene', '4763', (179, 182))	('mutation', 'Var', (95, 103))	('tumors', 'Disease', (77, 83))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (54, 71))	('VHL', 'Gene', '7428', (171, 174))	('NF1', 'Gene', (179, 182))	('RET', 'Gene', (166, 169))	('SDH', 'Gene', (118, 121))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('SDHB', 'Gene', (146, 150))	('paragangliomas', 'Disease', 'MESH:D010235', (35, 49))	('SDH', 'Gene', '6390', (146, 149))	('paragangliomas', 'Phenotype', 'HP:0002668', (35, 49))	('paraganglioma', 'Phenotype', 'HP:0002668', (35, 48))
17241	21082267	The identification of mutations in SDHAF2 has revealed that proteins ancillary to succinate dehydrogenase can also be tumorigenic, and the belated identification of a mutation in SDHA in a paraganglioma patient has demonstrated that no SDH-related gene can be entirely excluded from consideration when thinking about the genetics of these tumor syndromes.	('tumor', 'Disease', (339, 344))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('SDHAF2', 'Gene', '54949', (35, 41))	('SDH', 'Gene', (179, 182))	('SDHAF2', 'Gene', (35, 41))	('SDHA', 'Gene', (35, 39))	('SDH', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('succinate dehydrogenase', 'Gene', '6389', (82, 105))	('tumor syndromes', 'Disease', 'MESH:D009369', (339, 354))	('succinate dehydrogenase', 'Gene', (82, 105))	('SDHA', 'Gene', '6389', (35, 39))	('paraganglioma', 'Phenotype', 'HP:0002668', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SDH', 'Gene', '6390', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('mutation', 'Var', (167, 175))	('mutations', 'Var', (22, 31))	('SDH', 'Gene', (236, 239))	('SDH', 'Gene', '6390', (179, 182))	('SDHA', 'Gene', (179, 183))	('tumor syndromes', 'Disease', (339, 354))	('SDH', 'Gene', '6390', (35, 38))	('patient', 'Species', '9606', (203, 210))	('paraganglioma', 'Disease', (189, 202))	('tumor', 'Disease', (118, 123))	('SDHA', 'Gene', '6389', (179, 183))	('paraganglioma', 'Disease', 'MESH:D010235', (189, 202))
17318	33971553	Cardiac examination revealed crackles Killip II with no signs of right heart failure.	('crackles', 'Phenotype', 'HP:0030830', (29, 37))	('right heart failure', 'Disease', 'MESH:D006333', (65, 84))	('revealed', 'Reg', (20, 28))	('heart failure', 'Phenotype', 'HP:0001635', (71, 84))	('crackles', 'Var', (29, 37))	('right heart failure', 'Phenotype', 'HP:0001708', (65, 84))	('right heart failure', 'Disease', (65, 84))
17364	33846792	A dual-luciferase reporter gene assay was performed to verify the combination of miR-29a-3p and IGF-1.	('IGF-1', 'Gene', (96, 101))	('miR-29a-3p', 'Var', (81, 91))	('miR-29a-3p', 'Chemical', '-', (81, 91))
17368	33846792	Overexpression miR-29a-3p inhibited IGF-1 mRNA and protein expression.	('IGF-1', 'Gene', (36, 41))	('miR-29a-3p', 'Chemical', '-', (15, 25))	('miR-29a-3p', 'Var', (15, 25))	('inhibited', 'NegReg', (26, 35))
17369	33846792	miR-29a-3p inhibited cell proliferation and PRL and GH expression, and promoted apoptosis by inhibiting IGF-1.	('miR-29a-3p', 'Chemical', '-', (0, 10))	('PRL', 'CPA', (44, 47))	('promoted', 'PosReg', (71, 79))	('cell proliferation', 'CPA', (21, 39))	('rat', 'Species', '10116', (33, 36))	('inhibited', 'NegReg', (11, 20))	('inhibiting', 'NegReg', (93, 103))	('apoptosis', 'CPA', (80, 89))	('miR-29a-3p', 'Var', (0, 10))	('IGF-1', 'Gene', (104, 109))
17371	33846792	To conclude, miR-29a-3p inhibited the proliferation and secretory abilities of prolactinoma cells by inhibiting nuclear translocation of beta-catenin via a molecular mechanism that is inseparable from IGF-1.	('secretory', 'MPA', (56, 65))	('beta-catenin', 'Gene', '84353', (137, 149))	('proliferation', 'CPA', (38, 51))	('inhibited', 'NegReg', (24, 33))	('prolactinoma', 'Disease', (79, 91))	('miR-29a-3p', 'Var', (13, 23))	('prolactinoma', 'Phenotype', 'HP:0040278', (79, 91))	('beta-catenin', 'Gene', (137, 149))	('prolactinoma', 'Disease', 'MESH:D015175', (79, 91))	('miR-29a-3p', 'Chemical', '-', (13, 23))	('rat', 'Species', '10116', (45, 48))	('inhibiting', 'NegReg', (101, 111))
17378	33846792	In prolactinoma, miRNAs, such as miR-93-5p, miR-145-5p and miR-1299, have regulatory functions.	('miR-1299', 'Var', (59, 67))	('miR-93', 'Gene', '100314154', (33, 39))	('regulatory', 'MPA', (74, 84))	('miR-145', 'Gene', (44, 51))	('miR-145', 'Gene', '100314036', (44, 51))	('prolactinoma', 'Phenotype', 'HP:0040278', (3, 15))	('prolactinoma', 'Disease', (3, 15))	('miR-93', 'Gene', (33, 39))	('prolactinoma', 'Disease', 'MESH:D015175', (3, 15))
17380	33846792	Moreover, miR-29 can affect the growth of rats by inhibiting the expression of IGF-1.	('inhibiting', 'NegReg', (50, 60))	('rats', 'Species', '10116', (42, 46))	('miR-29', 'Chemical', '-', (10, 16))	('miR-29', 'Var', (10, 16))	('expression', 'MPA', (65, 75))	('growth', 'CPA', (32, 38))	('IGF-1', 'Gene', (79, 84))	('affect', 'Reg', (21, 27))
17382	33846792	Therefore, the aim of the present study was to determine the effects of miR-29a-3p on the proliferation and apoptosis of prolactinoma cells, as well as the secretion of PRL and GH via the IGF-1 and beta-catenin pathways.	('prolactinoma', 'Phenotype', 'HP:0040278', (121, 133))	('rat', 'Species', '10116', (97, 100))	('miR-29a-3p', 'Var', (72, 82))	('miR-29a-3p', 'Chemical', '-', (72, 82))	('prolactinoma', 'Disease', 'MESH:D015175', (121, 133))	('beta-catenin', 'Gene', (198, 210))	('IGF-1', 'Pathway', (188, 193))	('secretion', 'MPA', (156, 165))	('beta-catenin', 'Gene', '84353', (198, 210))	('effects', 'Reg', (61, 68))	('apoptosis', 'CPA', (108, 117))	('prolactinoma', 'Disease', (121, 133))	('PRL', 'Protein', (169, 172))
17423	33846792	In order to preliminarily analyze the significance of miR-29a-3p in prolactinoma, analysis of TCGA database showed that low expression of miR-29a-3p was associated with poor prognosis of patients with pheochromocytomas and paragangliomas (P=0.02, Fig.	('patients', 'Species', '9606', (187, 195))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (201, 218))	('miR-29a-3p', 'Chemical', '-', (138, 148))	('miR-29a-3p', 'Var', (138, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (201, 217))	('prolactinoma', 'Disease', (68, 80))	('paragangliomas', 'Phenotype', 'HP:0002668', (223, 237))	('paraganglioma', 'Phenotype', 'HP:0002668', (223, 236))	('prolactinoma', 'Phenotype', 'HP:0040278', (68, 80))	('low', 'NegReg', (120, 123))	('miR-29a-3p', 'Chemical', '-', (54, 64))	('prolactinoma', 'Disease', 'MESH:D015175', (68, 80))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (201, 237))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))
17424	33846792	The prediction results showed that there were binding sites between miR-29a-3p and the 3'-UTR of IGF-1 mRNA, and both are conserved (Fig.	('miR-29a-3p', 'Chemical', '-', (68, 78))	('miR-29a-3p', 'Var', (68, 78))	('IGF-1', 'Gene', (97, 102))	('binding', 'Interaction', (46, 53))
17426	33846792	1C and D), transfection with miR-29a-3p mimic and Wt-IGF-1 decreased the relative luciferase activity in MMQ and GH3 cells, thereby confirming targeted binding (Fig.	('miR-29a-3p mimic', 'Var', (29, 45))	('decreased', 'NegReg', (59, 68))	('activity', 'MPA', (93, 101))	('miR-29a-3p', 'Chemical', '-', (29, 39))	('luciferase', 'Enzyme', (82, 92))	('binding', 'Interaction', (152, 159))
17429	33846792	The aforementioned data suggested that miR-29a-3p targeted IGF-1 and may play an important regulatory role in prolactinoma.	('prolactinoma', 'Disease', 'MESH:D015175', (110, 122))	('prolactinoma', 'Phenotype', 'HP:0040278', (110, 122))	('miR-29a-3p', 'Var', (39, 49))	('miR-29a-3p', 'Chemical', '-', (39, 49))	('targeted', 'Reg', (50, 58))	('prolactinoma', 'Disease', (110, 122))	('play', 'Reg', (73, 77))	('IGF-1', 'Gene', (59, 64))
17430	33846792	To further analyze the effects of miR-29a-3p/IGF-1 on prolactinoma, MMQ and GH3 cells were divided into four treatment groups: NC, mimic, mimic + IGF-1, and IGF-1.	('prolactinoma', 'Disease', (54, 66))	('prolactinoma', 'Phenotype', 'HP:0040278', (54, 66))	('prolactinoma', 'Disease', 'MESH:D015175', (54, 66))	('miR-29a-3p', 'Chemical', '-', (34, 44))	('mimic +', 'Var', (138, 145))
17431	33846792	The results showed that overexpression of miR-29a-3p significantly inhibited the mRNA and protein levels of IGF-1 (P<0.05), while transfection of IGF-1 pcDNA3.1 blocked the inhibitory effects of miR-29a-3p on IGF-1 (Fig.	('inhibited', 'NegReg', (67, 76))	('overexpression', 'PosReg', (24, 38))	('miR-29a-3p', 'Chemical', '-', (42, 52))	('IGF-1', 'MPA', (108, 113))	('miR-29a-3p', 'Chemical', '-', (195, 205))	('miR-29a-3p', 'Var', (42, 52))
17432	33846792	These findings suggested that miR-29a-3p strongly inhibited IGF-1 expression at the mRNA and protein levels in MMQ and GH3 cells.	('IGF-1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('miR-29a-3p', 'Chemical', '-', (30, 40))	('miR-29a-3p', 'Var', (30, 40))	('inhibited', 'NegReg', (50, 59))
17434	33846792	The results showed that overexpression of miR-29a-3p inhibited the viability and proliferation of MMQ and GH3 cells.	('inhibited', 'NegReg', (53, 62))	('miR-29a-3p', 'Var', (42, 52))	('rat', 'Species', '10116', (88, 91))	('overexpression', 'PosReg', (24, 38))	('miR-29a-3p', 'Chemical', '-', (42, 52))	('viability', 'CPA', (67, 76))
17436	33846792	Moreover, increased expression of miR-29a-3p significantly increased the apoptosis rates of MMQ and GH3 cells, while overexpression of IGF-1 had an opposite effect on apoptosis by neutralizing the effect of miR-29a-3p (P<0.05, Fig.	('rat', 'Species', '10116', (83, 86))	('apoptosis rates', 'CPA', (73, 88))	('MMQ', 'CPA', (92, 95))	('miR-29a-3p', 'Chemical', '-', (207, 217))	('miR-29a-3p', 'Chemical', '-', (34, 44))	('miR-29a-3p', 'Var', (34, 44))	('increased', 'PosReg', (59, 68))	('increased', 'PosReg', (10, 19))
17437	33846792	Correspondingly, the levels of apoptosis marker proteins caspase-3 and Bax increased correspondingly after miR-29a-3p was overexpressed.	('miR-29a-3p', 'Var', (107, 117))	('caspase-3', 'Gene', '25402', (57, 66))	('Bax', 'Gene', '24887', (71, 74))	('Bax', 'Gene', (71, 74))	('caspase-3', 'Gene', (57, 66))	('increased', 'PosReg', (75, 84))	('overexpressed', 'PosReg', (122, 135))	('miR-29a-3p', 'Chemical', '-', (107, 117))
17439	33846792	These results suggested that miR-29a-3p inhibited proliferation and induced apoptosis of prolactinoma cells, which was closely related to the inhibition of IGF-1.	('inhibited', 'NegReg', (40, 49))	('induced', 'Reg', (68, 75))	('proliferation', 'CPA', (50, 63))	('miR-29a-3p', 'Var', (29, 39))	('prolactinoma', 'Disease', (89, 101))	('miR-29a-3p', 'Chemical', '-', (29, 39))	('rat', 'Species', '10116', (57, 60))	('prolactinoma', 'Disease', 'MESH:D015175', (89, 101))	('apoptosis', 'CPA', (76, 85))	('prolactinoma', 'Phenotype', 'HP:0040278', (89, 101))
17441	33846792	Overexpression of miR-29a-3p significantly lowered GH mRNA levels in GH3 cells and GH concentration in the medium as compared with the NC group.	('GH concentration in the', 'MPA', (83, 106))	('lowered', 'NegReg', (43, 50))	('miR-29a-3p', 'Chemical', '-', (18, 28))	('miR-29a-3p', 'Var', (18, 28))	('GH mRNA levels', 'MPA', (51, 65))	('rat', 'Species', '10116', (93, 96))
17443	33846792	These results suggested that miR-29a-3p inhibited the expression and secretion of PRL and/or GH in MMQ and GH3 cells by inhibiting IGF-1.	('expression', 'MPA', (54, 64))	('inhibiting', 'NegReg', (120, 130))	('inhibited', 'NegReg', (40, 49))	('PRL', 'Protein', (82, 85))	('miR-29a-3p', 'Chemical', '-', (29, 39))	('miR-29a-3p', 'Var', (29, 39))	('secretion', 'MPA', (69, 78))	('IGF-1', 'MPA', (131, 136))
17444	33846792	To further analyze the mechanism used by miR-29a-3p/IGF-1 to regulate the progression and secretion of prolactinoma, beta-catenin levels were measured.	('miR-29a-3p', 'Chemical', '-', (41, 51))	('beta-catenin', 'Gene', (117, 129))	('prolactinoma', 'Disease', 'MESH:D015175', (103, 115))	('beta-catenin', 'Gene', '84353', (117, 129))	('miR-29a-3p/IGF-1', 'Var', (41, 57))	('prolactinoma', 'Disease', (103, 115))	('prolactinoma', 'Phenotype', 'HP:0040278', (103, 115))
17447	33846792	In addition, overexpression of IGF-1 reversed the inhibitory effects of miR-29a-3p on beta-catenin (P<0.05, Fig.	('miR-29a-3p', 'Chemical', '-', (72, 82))	('miR-29a-3p', 'Var', (72, 82))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '84353', (86, 98))	('IGF-1', 'Gene', (31, 36))
17448	33846792	Collectively, these results suggested that the effects of miR-29a-3p/IGF-1 on the proliferation, metastasis and secretion of MMQ and GH3 cells were related to beta-catenin.	('beta-catenin', 'Gene', (159, 171))	('secretion', 'MPA', (112, 121))	('metastasis', 'CPA', (97, 107))	('MMQ', 'Protein', (125, 128))	('beta-catenin', 'Gene', '84353', (159, 171))	('rat', 'Species', '10116', (89, 92))	('proliferation', 'CPA', (82, 95))	('miR-29a-3p/IGF-1', 'Var', (58, 74))	('effects', 'Reg', (47, 54))	('miR-29a-3p', 'Chemical', '-', (58, 68))
17452	33846792	In a rat model of prolactinoma induced by 17-beta estradiol, inhibition of IGF-1 alleviated serum levels of PRL and reduced the blood vessel density of prolactinoma.	('prolactinoma', 'Disease', 'MESH:D015175', (18, 30))	('prolactinoma', 'Phenotype', 'HP:0040278', (152, 164))	('inhibition', 'Var', (61, 71))	('serum levels of PRL', 'MPA', (92, 111))	('IGF-1', 'Gene', (75, 80))	('prolactinoma', 'Disease', 'MESH:D015175', (152, 164))	('rat', 'Species', '10116', (5, 8))	('blood vessel', 'MPA', (128, 140))	('alleviated', 'NegReg', (81, 91))	('prolactinoma', 'Phenotype', 'HP:0040278', (18, 30))	('prolactinoma', 'Disease', (18, 30))	('reduced', 'NegReg', (116, 123))	('17-beta estradiol', 'Chemical', 'MESH:D004958', (42, 59))	('prolactinoma', 'Disease', (152, 164))
17455	33846792	The results of the present study suggested that inhibition of IGF-1 by exogenous methods could inhibit the growth of prolactinoma and reduce the secretion of PRL and GH.	('reduce', 'NegReg', (134, 140))	('inhibit', 'NegReg', (95, 102))	('prolactinoma', 'Phenotype', 'HP:0040278', (117, 129))	('inhibition', 'Var', (48, 58))	('growth', 'MPA', (107, 113))	('prolactinoma', 'Disease', (117, 129))	('prolactinoma', 'Disease', 'MESH:D015175', (117, 129))	('IGF-1', 'Gene', (62, 67))
17456	33846792	In polycystic ovary syndrome, IGF-1 is targeted by miR-323-3p and miR-323-3p/IGF-1 is involved in the regulation of steroid secretion and human cumulus cell function.	('miR-323-3p', 'Var', (51, 61))	('polycystic ovary', 'Phenotype', 'HP:0000147', (3, 19))	('steroid', 'Chemical', 'MESH:D013256', (116, 123))	('polycystic ovary syndrome', 'Disease', (3, 28))	('human', 'Species', '9606', (138, 143))	('miR-323-3p/IGF-1', 'Gene', (66, 82))	('ovary syndrome', 'Phenotype', 'HP:0000137', (14, 28))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (3, 28))	('IGF-1', 'Gene', (30, 35))	('involved', 'Reg', (86, 94))	('targeted', 'Reg', (39, 47))	('steroid secretion', 'MPA', (116, 133))	('miR-323-3p/IGF-1', 'Var', (66, 82))
17457	33846792	miR-135a inhibits the proliferation and metastasis of lung cancer cells by targeting IGF-1 to inhibit the AKT pathway.	('AKT', 'Gene', (106, 109))	('miR-135a', 'Var', (0, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('targeting', 'Reg', (75, 84))	('miR-135a', 'Chemical', '-', (0, 8))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inhibits', 'NegReg', (9, 17))	('IGF-1', 'Gene', (85, 90))	('AKT', 'Gene', '207', (106, 109))	('metastasis of lung cancer', 'Disease', (40, 65))	('inhibit', 'NegReg', (94, 101))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (40, 65))
17459	33846792	Moreover, it was predicted and verified that miR-29a-3p was an upstream regulator of IGF-1 and, thus, presents a possible target to reduce IGF-1 mRNA and protein levels.	('IGF-1', 'Gene', (139, 144))	('miR-29a-3p', 'Chemical', '-', (45, 55))	('IGF-1', 'Gene', (85, 90))	('reduce', 'NegReg', (132, 138))	('miR-29a-3p', 'Var', (45, 55))
17460	33846792	These results also suggested that miR-29a-3p might play a role in the development and progression of prolactinoma by regulating IGF-1.	('IGF-1', 'Gene', (128, 133))	('prolactinoma', 'Disease', 'MESH:D015175', (101, 113))	('prolactinoma', 'Phenotype', 'HP:0040278', (101, 113))	('regulating', 'Reg', (117, 127))	('play', 'Reg', (51, 55))	('miR-29a-3p', 'Chemical', '-', (34, 44))	('miR-29a-3p', 'Var', (34, 44))	('prolactinoma', 'Disease', (101, 113))
17461	33846792	In order to further analyze the effects of miR-29a-3p/IGF-1 on prolactinoma, miR-29a-3p and/or IGF-1 was overexpressed in MMQ and GH3 cells.	('prolactinoma', 'Phenotype', 'HP:0040278', (63, 75))	('miR-29a-3p', 'Var', (77, 87))	('IGF-1', 'Gene', (95, 100))	('prolactinoma', 'Disease', (63, 75))	('miR-29a-3p', 'Chemical', '-', (43, 53))	('miR-29a-3p', 'Chemical', '-', (77, 87))	('prolactinoma', 'Disease', 'MESH:D015175', (63, 75))
17462	33846792	The results showed that miR-29a-3p inhibited the proliferation and induced apoptosis of prolactinoma cells, while IGF-1 blocked the inhibitory effects of miR-29a-3p.	('miR-29a-3p', 'Chemical', '-', (24, 34))	('induced', 'Reg', (67, 74))	('rat', 'Species', '10116', (56, 59))	('prolactinoma', 'Disease', (88, 100))	('proliferation', 'CPA', (49, 62))	('apoptosis', 'CPA', (75, 84))	('prolactinoma', 'Disease', 'MESH:D015175', (88, 100))	('prolactinoma', 'Phenotype', 'HP:0040278', (88, 100))	('inhibited', 'NegReg', (35, 44))	('miR-29a-3p', 'Chemical', '-', (154, 164))	('miR-29a-3p', 'Var', (24, 34))
17465	33846792	Taken together, the results of the present and previous studies indicate that miR-29a-3p can inhibit the proliferation and induce apoptosis of prolactinoma cells, and these functions are related to the targeted inhibition of IGF-1 expression.	('inhibit', 'NegReg', (93, 100))	('IGF-1', 'Gene', (225, 230))	('induce', 'PosReg', (123, 129))	('apoptosis', 'CPA', (130, 139))	('prolactinoma', 'Disease', (143, 155))	('proliferation', 'CPA', (105, 118))	('rat', 'Species', '10116', (112, 115))	('prolactinoma', 'Disease', 'MESH:D015175', (143, 155))	('prolactinoma', 'Phenotype', 'HP:0040278', (143, 155))	('miR-29a-3p', 'Chemical', '-', (78, 88))	('miR-29a-3p', 'Var', (78, 88))
17467	33846792	Inhibition of Wnt/beta-catenin can reduce PRL secretion by MMQ cells.	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '84353', (18, 30))	('PRL secretion', 'MPA', (42, 55))	('Inhibition', 'Var', (0, 10))	('reduce', 'NegReg', (35, 41))
17469	33846792	The results of the present study showed that increasing the expression of miR-29a-3p inhibited the nuclear translocation of beta-catenin in MMQ and GH3 cells, while inhibiting the secretion of PRL and/or GH.	('expression', 'MPA', (60, 70))	('beta-catenin', 'Gene', (124, 136))	('inhibited', 'NegReg', (85, 94))	('beta-catenin', 'Gene', '84353', (124, 136))	('inhibiting', 'NegReg', (165, 175))	('increasing', 'PosReg', (45, 55))	('miR-29a-3p', 'Var', (74, 84))	('miR-29a-3p', 'Chemical', '-', (74, 84))	('secretion of PRL', 'MPA', (180, 196))	('nuclear translocation', 'MPA', (99, 120))
17470	33846792	Overexpression of IGF-1 restored the retention of beta-catenin in the cytoplasm caused by miR-29a-3p.	('miR-29a-3p', 'Chemical', '-', (90, 100))	('miR-29a-3p', 'Var', (90, 100))	('beta-catenin', 'Gene', (50, 62))	('retention', 'MPA', (37, 46))	('IGF-1', 'Gene', (18, 23))	('beta-catenin', 'Gene', '84353', (50, 62))
17475	33846792	In conclusion, the level of miR-29a-3p in prolactinoma was suppressed, thus increasing miR-29a-3p expression may inhibit the proliferation of prolactinoma cells and the secretion of PRL and GH by targeting IGF-1 via mechanisms that may be related to the beta-catenin pathway.	('prolactinoma', 'Disease', 'MESH:D015175', (142, 154))	('targeting', 'Reg', (196, 205))	('prolactinoma', 'Phenotype', 'HP:0040278', (42, 54))	('beta-catenin', 'Gene', (254, 266))	('miR-29a-3p', 'Chemical', '-', (87, 97))	('proliferation', 'CPA', (125, 138))	('PRL', 'Protein', (182, 185))	('increasing', 'PosReg', (76, 86))	('prolactinoma', 'Disease', (42, 54))	('miR-29a-3p', 'Chemical', '-', (28, 38))	('prolactinoma', 'Phenotype', 'HP:0040278', (142, 154))	('miR-29a-3p', 'Var', (87, 97))	('rat', 'Species', '10116', (132, 135))	('beta-catenin', 'Gene', '84353', (254, 266))	('prolactinoma', 'Disease', (142, 154))	('prolactinoma', 'Disease', 'MESH:D015175', (42, 54))	('inhibit', 'NegReg', (113, 120))	('secretion', 'MPA', (169, 178))	('IGF-1', 'Gene', (206, 211))
17476	33846792	However, further studies are needed to elucidate the relationship between miR-29a-3p and prolactinoma, and the underlying mechanism regulating IGF-1/beta-catenin in prolactinoma cells must be verified in vivo.	('beta-catenin', 'Gene', (149, 161))	('prolactinoma', 'Disease', (89, 101))	('prolactinoma', 'Disease', (165, 177))	('prolactinoma', 'Phenotype', 'HP:0040278', (165, 177))	('miR-29a-3p', 'Chemical', '-', (74, 84))	('miR-29a-3p', 'Var', (74, 84))	('prolactinoma', 'Disease', 'MESH:D015175', (89, 101))	('beta-catenin', 'Gene', '84353', (149, 161))	('prolactinoma', 'Disease', 'MESH:D015175', (165, 177))	('prolactinoma', 'Phenotype', 'HP:0040278', (89, 101))
17485	33714404	Heart Failure (HF) is a clinical syndrome characterized by the following features: typical symptoms (breathlessness at rest or on exercise, fatigue, tiredness, ankle swelling) and signs (tachycardia, tachypnea, pulmonary rales, pleural effusion, raised jugular venous pressure, peripheral edema, hepatomegaly) and objective evidence of a structural or functional abnormality of the heart at rest (cardiomegaly, third heart sound, cardiac murmurs, abnormality on the echocardiogram, raised natriuretic peptide concentration).	('tiredness', 'Disease', (149, 158))	('third heart sound', 'Phenotype', 'HP:0031658', (411, 428))	('hepatomegaly', 'Disease', (296, 308))	('tiredness', 'Disease', 'MESH:D005221', (149, 158))	('rales', 'Phenotype', 'HP:0030830', (221, 226))	('raised natriuretic peptide concentration', 'Phenotype', 'HP:0020183', (482, 522))	('ankle swelling', 'Disease', 'MESH:D016512', (160, 174))	('Heart Failure', 'Phenotype', 'HP:0001635', (0, 13))	('tachypnea', 'Phenotype', 'HP:0002789', (200, 209))	('Heart Failure', 'Disease', 'MESH:D006333', (0, 13))	('hepatomegaly', 'Disease', 'MESH:D006529', (296, 308))	('cardiac murmurs', 'CPA', (430, 445))	('third heart sound', 'CPA', (411, 428))	('cardiac murmurs', 'Phenotype', 'HP:0030148', (430, 445))	('cardiomegaly', 'Disease', 'MESH:D006332', (397, 409))	('cardiomegaly', 'Disease', (397, 409))	('abnormality of the heart', 'Phenotype', 'HP:0001627', (363, 387))	('tachycardia', 'Phenotype', 'HP:0001649', (187, 198))	('raised jugular venous pressure', 'MPA', (246, 276))	('hepatomegaly', 'Phenotype', 'HP:0002240', (296, 308))	('pleural effusion', 'Disease', (228, 244))	('tachycardia', 'Disease', 'MESH:D013610', (187, 198))	('tachycardia', 'Disease', (187, 198))	('fatigue', 'Disease', (140, 147))	('fatigue', 'Phenotype', 'HP:0012378', (140, 147))	('ankle swelling', 'Disease', (160, 174))	('abnormality', 'Var', (447, 458))	('ankle swelling', 'Phenotype', 'HP:0001785', (160, 174))	('peripheral edema', 'Phenotype', 'HP:0012398', (278, 294))	('edema', 'Phenotype', 'HP:0000969', (289, 294))	('raised jugular venous pressure', 'Phenotype', 'HP:0030848', (246, 276))	('pleural effusion', 'Disease', 'MESH:D010996', (228, 244))	('cardiomegaly', 'Phenotype', 'HP:0001640', (397, 409))	('tachypnea', 'Disease', 'MESH:D059246', (200, 209))	('tiredness', 'Phenotype', 'HP:0012378', (149, 158))	('pulmonary rales', 'Disease', (211, 226))	('abnormality on the echocardiogram', 'Phenotype', 'HP:0003116', (447, 480))	('edema', 'Disease', 'MESH:D004487', (289, 294))	('Heart Failure', 'Disease', (0, 13))	('edema', 'Disease', (289, 294))	('fatigue', 'Disease', 'MESH:D005221', (140, 147))	('pleural effusion', 'Phenotype', 'HP:0002202', (228, 244))	('tachypnea', 'Disease', (200, 209))
17518	33714404	The same study also showed significant correlation of high TSH (subclinical hypothyroidism), high free T4 and low total T3 levels with increased mortality over 4 years.	('hypothyroidism', 'Disease', 'MESH:D007037', (76, 90))	('hypothyroidism', 'Phenotype', 'HP:0000821', (76, 90))	('T3', 'Chemical', 'MESH:D014284', (120, 122))	('mortality', 'Disease', (145, 154))	('high', 'Var', (54, 58))	('TSH', 'MPA', (59, 62))	('subclinical hypothyroidism', 'Phenotype', 'HP:0008223', (64, 90))	('hypothyroidism', 'Disease', (76, 90))	('free T4', 'MPA', (98, 105))	('high TSH', 'Phenotype', 'HP:0002925', (54, 62))	('mortality', 'Disease', 'MESH:D003643', (145, 154))	('low', 'NegReg', (110, 113))
17571	33714404	T2-hyperintensity in Cardiac Magnetic Resonance (CMR) may represent edema associated with acromegaly which predicts reversibility with treatment.	('acromegaly', 'Disease', 'MESH:D000172', (90, 100))	('edema', 'Disease', (68, 73))	('acromegaly', 'Disease', (90, 100))	('acromegaly', 'Phenotype', 'HP:0000845', (90, 100))	('hyperintensity in Cardiac Magnetic Resonance', 'Phenotype', 'HP:0030890', (3, 47))	('edema', 'Disease', 'MESH:D004487', (68, 73))	('edema', 'Phenotype', 'HP:0000969', (68, 73))	('T2-hyperintensity', 'Var', (0, 17))	('Cardiac Magnetic', 'MPA', (21, 37))
17592	33714404	Carney complex is an autosomal dominant disorder due to mutation in protein regulatory kinase subunit (PRKR 1 alpha).	('autosomal dominant disorder', 'Disease', (21, 48))	('Carney complex', 'Disease', (0, 14))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (21, 48))	('mutation', 'Var', (56, 64))	('PRKR 1 alpha', 'Gene', (103, 115))
17622	33714404	However, results of a preliminary intervention study still do not clearly prove the therapeutic benefits of inhibiting prolactin production to expedite the recovery.	('prolactin', 'Gene', '5617', (119, 128))	('inhibiting', 'Var', (108, 118))	('prolactin', 'Gene', (119, 128))
17635	33714404	It is caused by loss of function mutation of HSD11B2 gene.	('HSD11B2', 'Gene', '3291', (45, 52))	('HSD11B2', 'Gene', (45, 52))	('mutation', 'Var', (33, 41))	('loss of function', 'NegReg', (16, 32))
17636	33714404	However, mutations in the HSD11B2 gene (at different alleles) can result in milder phenotypes that are difficult to distinguish from essential hypertension.	('hypertension', 'Disease', 'MESH:D006973', (143, 155))	('mutations', 'Var', (9, 18))	('hypertension', 'Disease', (143, 155))	('HSD11B2', 'Gene', '3291', (26, 33))	('hypertension', 'Phenotype', 'HP:0000822', (143, 155))	('result in', 'Reg', (66, 75))	('HSD11B2', 'Gene', (26, 33))
17654	33714404	The action of excess progesterone on the mutant mineralocorticoid receptor has been implicated as the cause of exacerbation of this condition during pregnancy.	('excess progesterone', 'Phenotype', 'HP:0031216', (14, 33))	('mutant', 'Var', (41, 47))	('mineralocorticoid receptor', 'Gene', (48, 74))	('progesterone', 'Chemical', 'MESH:D011374', (21, 33))	('mineralocorticoid receptor', 'Gene', '4306', (48, 74))
17699	32887459	Assessing miR-451a to miR-23a-3p ratio no red blood cell (RBC) contamination was detected in any of our samples.MiRNAs which are considered indicating red-blood-cell or platelet cellular contamination also showed low variance (0.4 for miR-142-3p and 0.3 for miR451a/miR-23a-3p, respectively).	('miR451a', 'Gene', (258, 265))	('miR-451a', 'Gene', '574411', (10, 18))	('miR-451a', 'Gene', (10, 18))	('miR451a', 'Gene', '574411', (258, 265))	('miR-142-3p', 'Var', (235, 245))
17705	32887459	Of the 33 significantly differently expressed miRNAs between controls and tumor sera samples we selected 6 underexpressed miRNAs (let-7b-5p, let-7i-5p; miR-143-3p; miR-30d-5p; miR-451a; miR-486-5p) in pNET/PPGL samples compared to controls) based on miRNA abundance for further investigation.	('miR-30d', 'Gene', '407033', (164, 171))	('miR-486-5p', 'Var', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('let-7b', 'Gene', (130, 136))	('let-7i', 'Gene', '406891', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miR-486-5p', 'Chemical', '-', (186, 196))	('tumor', 'Disease', (74, 79))	('miR-451a', 'Gene', (176, 184))	('miR-30d', 'Gene', (164, 171))	('miR-451a', 'Gene', '574411', (176, 184))	('NET', 'Phenotype', 'HP:0100634', (202, 205))	('let-7i', 'Gene', (141, 147))	('let-7b', 'Gene', '406884', (130, 136))
17707	32887459	After dissecting tumor groups, the underexpression of miR-30d-5p, miR-451a, and miR-486-5p was significant in pNET patients with high CgA levels and let-7b-5p in PPGL cases compared to healthy controls without PPI treatment (Figure 2B).	('NET', 'Phenotype', 'HP:0100634', (111, 114))	('pNET', 'Disease', (110, 114))	('miR-486-5p', 'Var', (80, 90))	('patients', 'Species', '9606', (115, 123))	('tumor', 'Disease', (17, 22))	('CgA', 'Gene', '1113', (134, 137))	('miR-486-5p', 'Chemical', '-', (80, 90))	('miR-451a', 'Gene', '574411', (66, 74))	('miR-451a', 'Gene', (66, 74))	('miR-30d', 'Gene', (54, 61))	('CgA', 'Gene', (134, 137))	('PPGL', 'Disease', (162, 166))	('let-7b', 'Gene', '406884', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('let-7b', 'Gene', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('miR-30d', 'Gene', '407033', (54, 61))
17709	32887459	However, let-7b-5p, let-7i-5p; miR-143-3p; miR-30d-5p; miR-451a and miR-486-5p showed lower expression in samples with high (>100 ng/mL) CgA levels compared to samples with normal CgA level (<=100 ng/mL) (Figure 3A).	('let-7i', 'Gene', '406891', (20, 26))	('CgA', 'Gene', (180, 183))	('miR-30d', 'Gene', '407033', (43, 50))	('CgA', 'Gene', '1113', (137, 140))	('miR-451a', 'Gene', '574411', (55, 63))	('miR-451a', 'Gene', (55, 63))	('lower', 'NegReg', (86, 91))	('miR-486-5p', 'Var', (68, 78))	('let-7i', 'Gene', (20, 26))	('CgA', 'Gene', (137, 140))	('let-7b', 'Gene', '406884', (9, 15))	('CgA', 'Gene', '1113', (180, 183))	('miR-486-5p', 'Chemical', '-', (68, 78))	('miR-30d', 'Gene', (43, 50))	('expression', 'MPA', (92, 102))	('let-7b', 'Gene', (9, 15))
17713	32887459	In samples obtained from PPGL patients only miR-486-5p showed an inverse correlation with CgA (Table 2).	('CgA', 'Gene', (90, 93))	('CgA', 'Gene', '1113', (90, 93))	('miR-486-5p', 'Var', (44, 54))	('patients', 'Species', '9606', (30, 38))	('miR-486-5p', 'Chemical', '-', (44, 54))
17714	32887459	We found that in serum samples obtained from PPGL patients with germline mutations (SDHB, RET, VHL, or NF1) miR-486-5p and miR-30d-5p were downregulated compared to sporadic patients (Figure 3C).	('miR-486-5p', 'Var', (108, 118))	('RET', 'Gene', (90, 93))	('NF1', 'Gene', '4763', (103, 106))	('miR-30d', 'Gene', '407033', (123, 130))	('VHL', 'Gene', (95, 98))	('SDHB', 'Gene', '6390', (84, 88))	('patients', 'Species', '9606', (50, 58))	('RET', 'Gene', '5979', (90, 93))	('VHL', 'Gene', '7428', (95, 98))	('miR-486-5p', 'Chemical', '-', (108, 118))	('patients', 'Species', '9606', (174, 182))	('SDHB', 'Gene', (84, 88))	('downregulated', 'NegReg', (139, 152))	('miR-30d', 'Gene', (123, 130))	('NF1', 'Gene', (103, 106))
17715	32887459	In patients with SDHB germline mutation beside the underexpression of miR-30d-5p and miR-486-5p, let-7b-5p and let-7i-5p also showed downregulation compared to serum samples of patients with SDHB wild type (Figure 3D).	('SDHB', 'Gene', (191, 195))	('miR-30d', 'Gene', '407033', (70, 77))	('patients', 'Species', '9606', (177, 185))	('miR-486-5p', 'Var', (85, 95))	('SDHB', 'Gene', '6390', (191, 195))	('SDHB', 'Gene', '6390', (17, 21))	('let-7i', 'Gene', '406891', (111, 117))	('downregulation', 'NegReg', (133, 147))	('patients', 'Species', '9606', (3, 11))	('SDHB', 'Gene', (17, 21))	('let-7b', 'Gene', '406884', (97, 103))	('let-7b', 'Gene', (97, 103))	('let-7i', 'Gene', (111, 117))	('miR-30d', 'Gene', (70, 77))	('miR-486-5p', 'Chemical', '-', (85, 95))
17718	32887459	Altogether 6 miRNAs (let-7b-5p, let-7i-5p, miR-143-3p, miR-30d-5p, miR-451a, and miR-486-5p) were assessed individually and in combinations (Table 3).	('let-7i', 'Gene', (32, 38))	('miR-30d', 'Gene', (55, 62))	('miR-486-5p', 'Var', (81, 91))	('miR-143-3p', 'Var', (43, 53))	('let-7b', 'Gene', '406884', (21, 27))	('miR-30d', 'Gene', '407033', (55, 62))	('let-7b', 'Gene', (21, 27))	('let-7i', 'Gene', '406891', (32, 38))	('miR-451a', 'Gene', '574411', (67, 75))	('miR-451a', 'Gene', (67, 75))	('miR-486-5p', 'Chemical', '-', (81, 91))
17719	32887459	In the pNET group compared to CgA the use of individual let-7b-5p, miR-30d-5p, miR-451a, and miR-486-5p in ROC analysis resulted in better discrimination (Table 3).	('discrimination', 'MPA', (139, 153))	('NET', 'Phenotype', 'HP:0100634', (8, 11))	('miR-451a', 'Gene', '574411', (79, 87))	('miR-451a', 'Gene', (79, 87))	('CgA', 'Gene', (30, 33))	('miR-30d', 'Gene', (67, 74))	('miR-486-5p', 'Chemical', '-', (93, 103))	('let-7b', 'Gene', '406884', (56, 62))	('CgA', 'Gene', '1113', (30, 33))	('let-7b', 'Gene', (56, 62))	('better', 'PosReg', (132, 138))	('miR-30d', 'Gene', '407033', (67, 74))	('miR-486-5p', 'Var', (93, 103))
17723	32887459	The use of the individual expression of let-7b-5p or miR-143-3p yielded better discrimination from healthy controls compared to CgA alone (Table 3).	('let-7b', 'Gene', '406884', (40, 46))	('let-7b', 'Gene', (40, 46))	('CgA', 'Gene', '1113', (128, 131))	('miR-143-3p', 'Var', (53, 63))	('CgA', 'Gene', (128, 131))
17726	32887459	Using binary logistic regression model the combination of CgA with 3 miRNAs (let-7b-5p, miR-143-3p and miR-486-5p) yielded higher specificity compared to CgA alone with 83.6% accuracy in discrimination of normal samples from PPGL samples, however, with lower sensitivity (AUC: 0.862; 85% sensitivity; 82.7% specificity) (Table 3).	('CgA', 'Gene', '1113', (154, 157))	('CgA', 'Gene', '1113', (58, 61))	('let-7b', 'Gene', '406884', (77, 83))	('let-7b', 'Gene', (77, 83))	('miR-486-5p', 'Chemical', '-', (103, 113))	('higher', 'PosReg', (123, 129))	('CgA', 'Gene', (154, 157))	('miR-143-3p', 'Var', (88, 98))	('miR-486-5p', 'Var', (103, 113))	('CgA', 'Gene', (58, 61))	('specificity', 'MPA', (130, 141))
17728	32887459	In PPGL, while miR-101-3p showed higher expression in malignant vs. benign PPGLs, in serum, it was downregulated compared to controls.	('expression', 'MPA', (40, 50))	('higher', 'PosReg', (33, 39))	('downregulated', 'NegReg', (99, 112))	('PPGLs', 'Gene', (75, 80))	('miR-101-3p', 'Var', (15, 25))	('miR-101-3p', 'Chemical', '-', (15, 25))
17729	32887459	However, miR-16-5p and miR-451a as putative tumor suppressor miRNAs were downregulated in both tissue and serum (Table 4).	('miR-16-5p', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('downregulated', 'NegReg', (73, 86))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('miR-451a', 'Gene', '574411', (23, 31))	('miR-451a', 'Gene', (23, 31))	('tumor', 'Disease', (44, 49))
17732	32887459	Our data revealed a low global miRNA expression (abundance) in sera of patients with pNET/PPGL compared to normal controls.	('low', 'NegReg', (20, 23))	('NET', 'Phenotype', 'HP:0100634', (86, 89))	('pNET/PPGL', 'Var', (85, 94))	('patients', 'Species', '9606', (71, 79))
17741	32887459	Similarly, to our findings, in breast cancer, the same miR-203a-3p was overexpressed both on a tissue level and in exosomes secreted by tumor cells.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ret', 'Gene', (127, 130))	('breast cancer', 'Disease', (31, 44))	('overexpressed', 'PosReg', (71, 84))	('ret', 'Gene', '5979', (127, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('miR-203a-3p', 'Var', (55, 66))	('tumor', 'Disease', (136, 141))
17743	32887459	These data raise the possibility that miR-203a-3p may potentially be originated from tumor cells and can be considered as an oncomiR.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('miR-203a-3p', 'Var', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
17759	32887459	Let-7i-5p is a well-known tumor suppressor miRNA which expression is negatively correlated with prognosis.	('negatively', 'NegReg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('expression', 'MPA', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Let-7i-5p', 'Var', (0, 9))
17769	32887459	Let-7b-5p, let-7i-5p, miR-30d-5p, and miR-486-5p were downregulated in SDHB mutant cases compared to SDHB wild type cases indicating that the etiology of PPGL may influence the circulating miRNA pool.	('influence', 'Reg', (163, 172))	('circulating miRNA pool', 'MPA', (177, 199))	('Let-7b', 'Gene', '406884', (0, 6))	('SDHB', 'Gene', (101, 105))	('let-7i', 'Gene', '406891', (11, 17))	('miR-486-5p', 'Chemical', '-', (38, 48))	('SDHB', 'Gene', '6390', (71, 75))	('mutant', 'Var', (76, 82))	('Let-7b', 'Gene', (0, 6))	('miR-30d', 'Gene', (22, 29))	('SDHB', 'Gene', (71, 75))	('miR-486-5p', 'Var', (38, 48))	('let-7i', 'Gene', (11, 17))	('miR-30d', 'Gene', '407033', (22, 29))	('downregulated', 'NegReg', (54, 67))	('SDHB', 'Gene', '6390', (101, 105))
17780	32887459	Low-CgA (<100 ng/mL) pNET group consisted of 9, high-CgA (>100 ng/mL) pNET group consisted of 16 patients.	('NET', 'Phenotype', 'HP:0100634', (71, 74))	('NET', 'Phenotype', 'HP:0100634', (22, 25))	('CgA', 'Gene', '1113', (4, 7))	('CgA', 'Gene', (53, 56))	('<100', 'Var', (9, 13))	('patients', 'Species', '9606', (97, 105))	('CgA', 'Gene', (4, 7))	('CgA', 'Gene', '1113', (53, 56))
17806	30589099	Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle.	('succinate dehydrogenase', 'Gene', (95, 118))	('succinate', 'Chemical', 'MESH:D013386', (146, 155))	('fumarate', 'Chemical', 'MESH:D005650', (256, 264))	('SDH', 'Gene', (171, 174))	('succinate', 'Chemical', 'MESH:D013386', (243, 252))	('succinate dehydrogenase', 'Gene', '6390', (146, 169))	('phaeochromocytoma and paraganglioma', 'Disease', 'MESH:D010235', (45, 80))	('carriers', 'Var', (133, 141))	('succinate', 'Chemical', 'MESH:D013386', (95, 104))	('succinate dehydrogenase', 'Gene', (146, 169))	('SDH', 'Gene', '6390', (171, 174))	('citric acid', 'Chemical', 'MESH:D019343', (272, 283))	('succinate dehydrogenase', 'Gene', '6390', (95, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('mutation carriers', 'Var', (124, 141))
17807	30589099	Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis.	('cellular accumulation of', 'MPA', (51, 75))	('succinate', 'Chemical', 'MESH:D013386', (95, 104))	('Inactivation', 'Var', (0, 12))	('results in', 'Reg', (36, 46))
17809	30589099	Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours.	('SDH', 'Gene', (194, 197))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('SDH deficient (dSDH) tumours', 'Disease', 'MESH:C535803', (178, 206))	('SDH', 'Gene', '6390', (124, 127))	('SDH', 'Gene', (178, 181))	('SDH', 'Gene', (137, 140))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('SDH', 'Gene', '6390', (194, 197))	('Biallelic inactivation', 'Var', (0, 22))	('cause', 'Reg', (168, 173))	('SDHA', 'Gene', '6389', (137, 141))	('SDH', 'Gene', (124, 127))	('SDH', 'Gene', '6390', (178, 181))	('SDH', 'Gene', '6390', (137, 140))	('SDHA', 'Gene', (137, 141))
17810	30589099	Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours.	('Germline mutations', 'Var', (0, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('tumours', 'Disease', (162, 169))	('PPGL', 'Disease', (120, 124))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('type gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (132, 169))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('tumours', 'Disease', 'MESH:D009369', (234, 241))	('tumours', 'Disease', (65, 72))	('SDH', 'Gene', (26, 29))	('type gastrointestinal stromal tumours', 'Disease', (132, 169))	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (199, 219))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('pituitary tumour', 'Phenotype', 'HP:0002893', (224, 240))	('pituitary tumours', 'Disease', 'MESH:D010911', (224, 241))	('PPGL', 'Disease', 'MESH:D010235', (120, 124))	('renal cell carcinoma', 'Disease', (199, 219))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (199, 219))	('paraganglioma', 'Phenotype', 'HP:0002668', (105, 118))	('predispose', 'Reg', (37, 47))	('SDH', 'Gene', '6390', (26, 29))	('pituitary tumours', 'Disease', (224, 241))	('phaeochromocytoma and paraganglioma', 'Disease', 'MESH:D010235', (83, 118))	('tumours', 'Disease', (234, 241))
17811	30589099	Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5-year mortality of 50%.	('SDHB', 'Gene', (55, 59))	('SDH', 'Gene', (30, 33))	('SDH', 'Gene', '6390', (55, 58))	('PPGL', 'Disease', (102, 106))	('PPGL', 'Disease', 'MESH:D010235', (102, 106))	('associated', 'Reg', (117, 127))	('SDH', 'Gene', '6390', (30, 33))	('SDH', 'Gene', (55, 58))	('predispose', 'Reg', (61, 71))	('SDHB', 'Gene', '6390', (55, 59))	('mutations', 'Var', (13, 22))
17812	30589099	There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours.	('mutations', 'Var', (125, 134))	('dSDH tumours', 'Disease', (220, 232))	('dSDH tumours', 'Disease', 'MESH:D009369', (220, 232))	('SDH', 'Gene', '6390', (221, 224))	('SDH', 'Gene', '6390', (115, 118))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('SDH', 'Gene', (115, 118))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))	('reduce', 'NegReg', (169, 175))	('SDH', 'Gene', (221, 224))
17814	30589099	Here, we address the question: "What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?".	('PPGL', 'Disease', 'MESH:D010235', (104, 108))	('SDH', 'Gene', (136, 139))	('PPGL', 'Disease', (104, 108))	('mutation', 'Var', (141, 149))	('SDH', 'Gene', '6390', (136, 139))
17816	30589099	However the recent molecular revolution has brought with it an understanding that PPGL have a rich hereditary background, as 30% of PPGL are now known to be familial.1 Germline mutations in the SDHx genes account for 30-40% of hereditary PPGL cases and mutations in the SDHB gene in particular predict a higher risk of malignant potential.2 Although there is is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with SDH deficient tumours,3 there is at present no consensus on when and how surveillance should be performed in children and young adults.	('mutations', 'Var', (478, 487))	('PPGL', 'Disease', 'MESH:D010235', (132, 136))	('SDHB', 'Gene', (270, 274))	('reduce', 'NegReg', (522, 528))	('SDH', 'Gene', '6390', (270, 273))	('PPGL', 'Disease', (238, 242))	('SDH', 'Gene', (194, 197))	('SDH', 'Gene', '6390', (468, 471))	('SDH', 'Gene', (573, 576))	('tumours', 'Disease', (587, 594))	('PPGL', 'Disease', 'MESH:D010235', (82, 86))	('PPGL', 'Disease', (132, 136))	('SDH', 'Gene', (270, 273))	('tumours', 'Phenotype', 'HP:0002664', (587, 594))	('SDH', 'Gene', (468, 471))	('tumours', 'Disease', 'MESH:D009369', (587, 594))	('children', 'Species', '9606', (682, 690))	('tumour', 'Phenotype', 'HP:0002664', (587, 593))	('PPGL', 'Disease', (82, 86))	('SDHB', 'Gene', '6390', (270, 274))	('PPGL', 'Disease', 'MESH:D010235', (238, 242))	('SDH', 'Gene', '6390', (194, 197))	('SDH', 'Gene', '6390', (573, 576))
17819	30589099	Whilst there are several reports of tumour development in paediatric SDHx mutation carriers, the prevalence of disease among paediatric nonprobands remains low.	('mutation', 'Var', (74, 82))	('SDH', 'Gene', '6390', (69, 72))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('SDH', 'Gene', (69, 72))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
17820	30589099	A review of the genotype information demonstrated that 77 (73.3%) patients had a germline pathogenic SDHB variant, 25 (23.8%) cases a pathogenic SDHD variant and three cases (2.9%) a pathogenic SDHC variant (Figure 1).	('SDHC', 'Gene', '6391', (194, 198))	('pathogenic', 'Reg', (90, 100))	('SDHB', 'Gene', (101, 105))	('SDHD', 'Gene', (145, 149))	('variant', 'Var', (150, 157))	('pathogenic', 'Reg', (134, 144))	('variant', 'Var', (106, 113))	('SDHC', 'Gene', (194, 198))	('SDHB', 'Gene', '6390', (101, 105))	('patients', 'Species', '9606', (66, 74))	('SDHD', 'Gene', '6392', (145, 149))
17821	30589099	The variant type was available for 93 patients and included 20 (21.6%) nonsense variants, 28 (30.1%) missense variants, 13 (13.9%) splice site variants, 26 (27.9%) frameshift variants.	('frameshift variants', 'Var', (164, 183))	('patients', 'Species', '9606', (38, 46))	('missense variants', 'Var', (101, 118))
17823	30589099	There was no significant difference in the mean age at presentation with PPGL in those patients with germline SDHB variants (13.1 years) compared to those with SDHC (13.3 years) or SDHD variants (14.6 years) (P = 0.78), and there was no significant difference in the mean age at presentation of those patients presenting with malignant tumours vs those presenting with localized tumours (12.8 vs 13.4 years, P = 0.9).	('localized tumours', 'Disease', 'MESH:D009364', (369, 386))	('patients', 'Species', '9606', (301, 309))	('variants', 'Var', (115, 123))	('SDHC', 'Gene', '6391', (160, 164))	('SDHB', 'Gene', (110, 114))	('tumours', 'Phenotype', 'HP:0002664', (336, 343))	('SDHD', 'Gene', '6392', (181, 185))	('localized tumours', 'Disease', (369, 386))	('PPGL', 'Disease', 'MESH:D010235', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (336, 342))	('SDHC', 'Gene', (160, 164))	('SDHD', 'Gene', (181, 185))	('tumours', 'Phenotype', 'HP:0002664', (379, 386))	('malignant tumours', 'Disease', 'MESH:D009369', (326, 343))	('malignant tumours', 'Disease', (326, 343))	('PPGL', 'Disease', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (379, 385))	('SDHB', 'Gene', '6390', (110, 114))	('patients', 'Species', '9606', (87, 95))
17828	30589099	Malignant tumours were reported in 26 patients (24.8%), and the majority of malignant cases were identified in patients with a pathogenic SDHB germline variant (22 patients, 84.6%).	('SDHB', 'Gene', (138, 142))	('Malignant tumours', 'Disease', (0, 17))	('variant', 'Var', (152, 159))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('Malignant tumours', 'Disease', 'MESH:D009369', (0, 17))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (164, 172))	('SDHB', 'Gene', '6390', (138, 142))	('patients', 'Species', '9606', (111, 119))
17829	30589099	Of note, this is a lower figure than what King et al4 found in their study of metastatic PPGL related to primary tumour development in childhood and adolescence, where 85.2% (n = 23) of their paediatric and adolescent patients with SDHB mutations developed metastatic disease.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('developed', 'Reg', (247, 256))	('SDHB', 'Gene', '6390', (232, 236))	('patients', 'Species', '9606', (218, 226))	('primary tumour', 'Disease', (105, 119))	('PPGL', 'Disease', (89, 93))	('SDHB', 'Gene', (232, 236))	('metastatic disease', 'CPA', (257, 275))	('primary tumour', 'Disease', 'MESH:D009369', (105, 119))	('PPGL', 'Disease', 'MESH:D010235', (89, 93))	('mutations', 'Var', (237, 246))	('child', 'Species', '9606', (135, 140))
17832	30589099	The Endocrine Society recommends that surveillance should comprise annual biochemistry (urinary or plasma metanephrines) and sporadic cross-sectional imaging of the skull base, neck, thorax, abdomen and pelvis (MRI is the preferred radiation sparing imaging modality).3 There are no recommendations as to the lower age limit of genetic testing of children in SDHx mutation families.	('metanephrines', 'Chemical', 'MESH:D008676', (106, 119))	('children', 'Species', '9606', (347, 355))	('SDH', 'Gene', '6390', (359, 362))	('mutation', 'Var', (364, 372))	('SDH', 'Gene', (359, 362))
17833	30589099	In the UK, genetic testing for inherited neoplasia syndromes is usually conducted around the time when clinical, biochemical and radiological surveillance would begin.53 It is also important to note that as SDHD variants have a preferential paternal transmission pattern of inheritance, clinical surveillance is only recommended for those carriers that inherit an SDHD variant from their father.	('SDHD', 'Gene', (207, 211))	('SDHD', 'Gene', '6392', (207, 211))	('inherited neoplasia syndromes', 'Disease', 'MESH:D009369', (31, 60))	('neoplasia', 'Phenotype', 'HP:0002664', (41, 50))	('inherited neoplasia syndromes', 'Disease', (31, 60))	('time', 'Disease', 'MESH:D000377', (93, 97))	('SDHD', 'Gene', (364, 368))	('time', 'Disease', (93, 97))	('paternal transmission', 'CPA', (241, 262))	('variants', 'Var', (212, 220))	('SDHD', 'Gene', '6392', (364, 368))
17834	30589099	To our knowledge, no guidance exists to inform the most appropriate starting age for clinical, biochemical and radiological surveillance in paediatric SDHx mutation carriers.	('SDH', 'Gene', '6390', (151, 154))	('SDH', 'Gene', (151, 154))	('mutation', 'Var', (156, 164))
17837	30589099	Recent studies, focused on more accurately predicting the clinical penetrance of SDHx genes, have adopted methods to control for ascertainment bias and suggest an estimated clinical penetrance of around 20% by age 50 years for SDHB mutation carriers.64  In the largest study of SDHB and SDHD mutation carriers yet reported, Andrews et al65 estimated the risks of PPGL and head and neck paraganglioma (HNPGL) by ages at 5, 10, 16 and 18 years in SDHB mutation carriers (n = 598 with clinical information available) and in SDHD carriers (n = 137 with clinical information available) (Table 2).	('SDH', 'Gene', (521, 524))	('SDHB', 'Gene', (445, 449))	('SDHD', 'Gene', '6392', (287, 291))	('SDH', 'Gene', '6390', (445, 448))	('SDH', 'Gene', (227, 230))	('SDH', 'Gene', '6390', (287, 290))	('head and neck paraganglioma', 'Disease', 'MESH:D006258', (372, 399))	('SDH', 'Gene', (81, 84))	('SDHB', 'Gene', (278, 282))	('PPGL', 'Disease', (363, 367))	('SDH', 'Gene', '6390', (278, 281))	('HNPGL', 'Disease', (401, 406))	('SDHD', 'Gene', (287, 291))	('paraganglioma', 'Phenotype', 'HP:0002668', (386, 399))	('SDH', 'Gene', (445, 448))	('SDHB', 'Gene', '6390', (227, 231))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (372, 399))	('SDH', 'Gene', (287, 290))	('SDHD', 'Gene', '6392', (521, 525))	('SDH', 'Gene', (278, 281))	('SDH', 'Gene', '6390', (521, 524))	('SDHB', 'Gene', (227, 231))	('SDHB', 'Gene', '6390', (445, 449))	('HNPGL', 'Disease', 'MESH:D006258', (401, 406))	('SDH', 'Gene', '6390', (227, 230))	('mutation', 'Var', (450, 458))	('SDH', 'Gene', '6390', (81, 84))	('SDHD', 'Gene', (521, 525))	('PPGL', 'Disease', 'MESH:D010235', (363, 367))	('SDHB', 'Gene', '6390', (278, 282))
17839	30589099	Using a different methodology, Benn et al recently estimated the lifetime penetrance of pathogenic SDHA, SDHB and SDHC variants by adopting an algorithm which compared allelic frequencies in 1815 cases (including cases from ref.	('SDHA', 'Gene', (99, 103))	('SDHB', 'Gene', '6390', (105, 109))	('pathogenic', 'Reg', (88, 98))	('SDHB', 'Gene', (105, 109))	('SDHA', 'Gene', '6389', (99, 103))	('time', 'Disease', 'MESH:D000377', (69, 73))	('SDHC', 'Gene', '6391', (114, 118))	('SDHC', 'Gene', (114, 118))	('time', 'Disease', (69, 73))	('variants', 'Var', (119, 127))
17840	30589099	The estimated lifetime penetrance of pathogenic SDHA and SDHC variants was low (1.7% and 8.3%, respectively), whilst the penetrance for SDHB was similar to that previously reported at 20.2%.66 The authors also speculated that SDHx gene penetrance may be directly proportional to the risk of multifocal tumours as SDHB gene mutations are more commonly associated with multifocal tumours compared to SDHA gene mutations.	('multifocal tumours', 'Disease', 'MESH:D009369', (367, 385))	('tumour', 'Phenotype', 'HP:0002664', (378, 384))	('SDH', 'Gene', (226, 229))	('tumours', 'Phenotype', 'HP:0002664', (378, 385))	('SDH', 'Gene', (313, 316))	('SDHB', 'Gene', (136, 140))	('multifocal tumours', 'Disease', (291, 309))	('SDH', 'Gene', '6390', (57, 60))	('SDH', 'Gene', '6390', (136, 139))	('SDHC', 'Gene', '6391', (57, 61))	('SDHA', 'Gene', (398, 402))	('SDH', 'Gene', '6390', (48, 51))	('SDH', 'Gene', (398, 401))	('SDHA', 'Gene', (48, 52))	('tumours', 'Phenotype', 'HP:0002664', (302, 309))	('SDHB', 'Gene', '6390', (313, 317))	('time', 'Disease', (18, 22))	('multifocal tumours', 'Disease', 'MESH:D009369', (291, 309))	('SDHA', 'Gene', '6389', (398, 402))	('SDHA', 'Gene', '6389', (48, 52))	('mutations', 'Var', (323, 332))	('SDH', 'Gene', (57, 60))	('SDH', 'Gene', (136, 139))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('SDH', 'Gene', (48, 51))	('time', 'Disease', 'MESH:D000377', (18, 22))	('SDHB', 'Gene', (313, 317))	('SDHC', 'Gene', (57, 61))	('SDH', 'Gene', '6390', (226, 229))	('multifocal tumours', 'Disease', (367, 385))	('SDH', 'Gene', '6390', (313, 316))	('SDHB', 'Gene', '6390', (136, 140))	('associated', 'Reg', (351, 361))	('SDH', 'Gene', '6390', (398, 401))
17841	30589099	Several factors complicate the decision when surveillance should be commenced in paediatric SDHx mutation carriers.	('SDH', 'Gene', '6390', (92, 95))	('SDH', 'Gene', (92, 95))	('mutation', 'Var', (97, 105))
17842	30589099	Important considerations include the growing awareness that the lifetime penetrance of SDHB mutations is significantly lower (see above) than that estimated when the gene was first identified (originally estimated at 70%-80%).	('time', 'Disease', 'MESH:D000377', (68, 72))	('lower', 'NegReg', (119, 124))	('time', 'Disease', (68, 72))	('mutations', 'Var', (92, 101))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))
17846	30589099	Incidental findings may be associated with a psychological burden and additional health costs.68 Finally, there is extremely limited information on the specificity and sensitivity of surveillance modalities for child and adolescent SDHx mutation carriers.	('mutation', 'Var', (237, 245))	('SDH', 'Gene', '6390', (232, 235))	('child', 'Species', '9606', (211, 216))	('SDH', 'Gene', (232, 235))
17847	30589099	Rijken et al64 started surveillance in a 7-year-old SDHB mutation carrier by urinary catecholamines measurements, allowing for surveillance to commence without the stress of imaging or phlebotomy.	('mutation', 'Var', (57, 65))	('SDHB', 'Gene', (52, 56))	('urinary catecholamines', 'Phenotype', 'HP:0011976', (77, 99))	('catecholamines', 'Chemical', 'MESH:D002395', (85, 99))	('urinary', 'MPA', (77, 84))	('SDHB', 'Gene', '6390', (52, 56))
17851	30589099	However it must also be considered that ultrasound has a lower sensitivity and specificity compared with MRI in PPGL detection.3  The Endocrine Society clearly state that the morbidity associated with SDHB gene mutations requires particular attention,3 and therefore, more stringent screening efforts may be necessary in order to reduce the morbidity and mortality associated with SDHB-mutated PPGL.	('SDHB', 'Gene', '6390', (201, 205))	('PPGL', 'Disease', (112, 116))	('PPGL', 'Disease', 'MESH:D010235', (394, 398))	('SDHB', 'Gene', (201, 205))	('mutations', 'Var', (211, 220))	('PPGL', 'Disease', (394, 398))	('SDHB', 'Gene', '6390', (381, 385))	('PPGL', 'Disease', 'MESH:D010235', (112, 116))	('SDHB', 'Gene', (381, 385))
17855	30589099	The absolute risks of a "clinical PPGL" in the paediatric age group are estimated to exceed 1% and 5% at ages 10 years and 16 years in SDHB mutation carriers and ages 16 and 18 years in SDHD carriers, respectively.65 Reviewing those paediatric index cases with SDHx variants reported in the literature, 9.5% (10/105) of cases presented before the age of 10 years and 70% of those cases were SDHB gene mutation carriers.	('SDH', 'Gene', '6390', (261, 264))	('SDHD', 'Gene', (186, 190))	('SDHD', 'Gene', '6392', (186, 190))	('SDHB', 'Gene', '6390', (135, 139))	('PPGL', 'Disease', 'MESH:D010235', (34, 38))	('SDH', 'Gene', (391, 394))	('SDHB', 'Gene', (135, 139))	('SDH', 'Gene', (261, 264))	('PPGL', 'Disease', (34, 38))	('SDH', 'Gene', '6390', (135, 138))	('SDHB', 'Gene', (391, 395))	('SDH', 'Gene', '6390', (186, 189))	('variants', 'Var', (266, 274))	('SDHB', 'Gene', '6390', (391, 395))	('SDH', 'Gene', (135, 138))	('SDH', 'Gene', '6390', (391, 394))	('SDH', 'Gene', (186, 189))
17857	30589099	Importantly, this data would suggest that the approach to clinical surveillance should be tailored to the SDHx subunit gene affected, as recent studies would suggest a higher risk of PPGL (and possibly of synchronous and multifocal tumours) with SDHB gene mutations.	('PPGL', 'Disease', 'MESH:D010235', (183, 187))	('SDHB', 'Gene', '6390', (246, 250))	('synchronous and multifocal tumours', 'Disease', 'MESH:D009378', (205, 239))	('SDH', 'Gene', (106, 109))	('SDH', 'Gene', '6390', (246, 249))	('PPGL', 'Disease', (183, 187))	('SDHB', 'Gene', (246, 250))	('mutations', 'Var', (256, 265))	('SDH', 'Gene', (246, 249))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))	('SDH', 'Gene', '6390', (106, 109))
17858	30589099	Based on the available data reviewed herein both for asymptomatic SDHx carriers and index cases, we propose that for SDHB mutation carriers annual physical examination (with blood pressure) and biochemical screening should generally commence at the age of 5 years and at age 10 years for SDHA, SDHC and SDHD carriers.	('SDH', 'Gene', '6390', (303, 306))	('SDHA', 'Gene', '6389', (288, 292))	('SDH', 'Gene', (66, 69))	('SDH', 'Gene', '6390', (294, 297))	('SDHB', 'Gene', '6390', (117, 121))	('SDHD', 'Gene', (303, 307))	('SDH', 'Gene', (288, 291))	('SDHC', 'Gene', '6391', (294, 298))	('mutation', 'Var', (122, 130))	('SDH', 'Gene', (303, 306))	('SDHB', 'Gene', (117, 121))	('SDH', 'Gene', '6390', (117, 120))	('SDH', 'Gene', (294, 297))	('SDHC', 'Gene', (294, 298))	('SDHD', 'Gene', '6392', (303, 307))	('SDH', 'Gene', '6390', (66, 69))	('SDH', 'Gene', '6390', (288, 291))	('SDHA', 'Gene', (288, 292))	('SDH', 'Gene', (117, 120))
17862	30589099	Finally, this clinical review has highlighted the need for a large prospective multicentre study to better inform existing surveillance and management strategies for paediatric and adolescent SDHx mutation carriers.	('SDH', 'Gene', (192, 195))	('mutation', 'Var', (197, 205))	('SDH', 'Gene', '6390', (192, 195))
17989	29041921	Her medical history included dyspnea on exertion and persistent hypertension(150-160/90-100 mmHg).Her serum adrenaline, noradrenaline and dopamine levels were 0.617 pmol/ml(normal,0.05-1.39 pmol/ml),97.417 pmol/ml(normal,0.51-3.62 pmol/ml)and0.046 pmol/ml(normal,0.07-0.68 pmol/ml).	('adrenaline', 'Chemical', 'MESH:D004837', (123, 133))	('noradrenaline', 'Chemical', 'MESH:D009638', (120, 133))	('dopamine', 'Chemical', 'MESH:D004298', (138, 146))	('hypertension', 'Disease', (64, 76))	('serum adrenaline', 'MPA', (102, 118))	('hypertension', 'Phenotype', 'HP:0000822', (64, 76))	('dyspnea', 'Disease', (29, 36))	('dyspnea', 'Disease', 'MESH:D004417', (29, 36))	('adrenaline', 'Chemical', 'MESH:D004837', (108, 118))	('0.617', 'Var', (159, 164))	('hypertension', 'Disease', 'MESH:D006973', (64, 76))	('dyspnea', 'Phenotype', 'HP:0002094', (29, 36))
18196	20066070	This patient also had coexistent Pentalogy of Fallots along with transposition of pulmonary trunk to the left ventricle, a very rare congenital cyanotic heart disease.	('patient', 'Species', '9606', (5, 12))	('transposition', 'Var', (65, 78))	('Pentalogy of Fallot', 'Phenotype', 'HP:0001636', (33, 52))	('Pentalogy of Fallots', 'Disease', (33, 53))	('congenital cyanotic heart disease', 'Disease', (133, 166))	('Pentalogy of Fallots', 'Phenotype', 'HP:0001636', (33, 53))	('congenital cyanotic heart disease', 'Disease', 'MESH:D006331', (133, 166))
18235	20066070	The presence of paraganglioma worsens the hemodynamic state in patients with congenital heart disease regardless of whether radical surgery for congenital heart disease had been performed.	('congenital heart disease', 'Disease', (144, 168))	('paraganglioma', 'Disease', (16, 29))	('congenital heart disease', 'Phenotype', 'HP:0001627', (144, 168))	('worsens', 'NegReg', (30, 37))	('congenital heart disease', 'Disease', (77, 101))	('congenital heart disease', 'Disease', 'MESH:D006331', (144, 168))	('paraganglioma', 'Disease', 'MESH:D010235', (16, 29))	('congenital heart', 'Phenotype', 'HP:0001627', (77, 93))	('patients', 'Species', '9606', (63, 71))	('congenital heart disease', 'Phenotype', 'HP:0001627', (77, 101))	('presence', 'Var', (4, 12))	('congenital heart disease', 'Disease', 'MESH:D006331', (77, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (16, 29))	('congenital heart', 'Phenotype', 'HP:0001627', (144, 160))	('hemodynamic state', 'MPA', (42, 59))
18236	20066070	In conclusion, we report a very rare and unusual case of cardiac paraganglioma associated with Pentalogy of Fallot and transposition of pulmonary trunk to the left ventricle.	('cardiac paraganglioma', 'Disease', 'MESH:D010235', (57, 78))	('associated', 'Reg', (79, 89))	('Pentalogy of Fallot', 'Phenotype', 'HP:0001636', (95, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('Pentalogy of Fallot', 'Disease', (95, 114))	('Fallot and transposition', 'Phenotype', 'HP:0011540', (108, 132))	('cardiac paraganglioma', 'Disease', (57, 78))	('transposition', 'Var', (119, 132))
18238	20066070	The presence of both the pathologies together worsen the patients condition and turned out to be fatal in some cases as in this case.	('presence', 'Var', (4, 12))	('worsen', 'PosReg', (46, 52))	('patients', 'Species', '9606', (57, 65))
18245	32256452	Hypersecreted catecholamines may result in myocardial injury via its direct toxic effect on cardiomyocytes or mediating vasoconstriction which will reduce coronary blood flow in this special setting.	('myocardial injury', 'Disease', 'MESH:D009202', (43, 60))	('coronary blood flow', 'MPA', (155, 174))	('result in', 'Reg', (33, 42))	('myocardial injury', 'Disease', (43, 60))	('reduce', 'NegReg', (148, 154))	('Hypersecreted', 'Var', (0, 13))	('catecholamines', 'Chemical', 'MESH:D002395', (14, 28))
18273	32256452	He underwent thrombophilia screening studies (including antiphospholipid antibodies, protein S or C deficiency, factor V Leiden mutation, prothrombin gene mutation, antithrombin III deficiency, and elevated factor VIII), without any positive results.	('factor V Leiden', 'Gene', '2153', (112, 127))	('thrombophilia', 'Disease', 'MESH:D019851', (13, 26))	('antiphospholipid', 'Reg', (56, 72))	('III deficiency', 'Disease', 'MESH:C537189', (178, 192))	('protein S or C deficiency', 'Disease', (85, 110))	('thrombophilia', 'Disease', (13, 26))	('prothrombin', 'Gene', (138, 149))	('antiphospholipid antibodies', 'Phenotype', 'HP:0003613', (56, 83))	('prothrombin', 'Gene', '2147', (138, 149))	('elevated factor VIII', 'Phenotype', 'HP:0030977', (198, 218))	('antithrombin III deficiency', 'Phenotype', 'HP:0001976', (165, 192))	('protein S or C deficiency', 'Disease', 'MESH:D018455', (85, 110))	('factor V Leiden', 'Gene', (112, 127))	('mutation', 'Var', (128, 136))	('III deficiency', 'Disease', (178, 192))	('thrombophilia', 'Phenotype', 'HP:0100724', (13, 26))
18289	32256452	Third, the coronary slow flow, possibly caused by microvascular dysfunction following vasospasm due to aberrant catecholamines secretion, may also participate in this pathologic process.	('catecholamines', 'Chemical', 'MESH:D002395', (112, 126))	('vasospasm', 'Disease', 'MESH:D020301', (86, 95))	('aberrant', 'Var', (103, 111))	('vasospasm', 'Phenotype', 'HP:0025637', (86, 95))	('aberrant catecholamines', 'Phenotype', 'HP:0012099', (103, 126))	('microvascular dysfunction', 'Disease', 'MESH:D017566', (50, 75))	('vasospasm', 'Disease', (86, 95))	('microvascular dysfunction', 'Disease', (50, 75))	('participate', 'Reg', (147, 158))	('coronary', 'Disease', (11, 19))
18312	32190664	PPGL with pathological invasion of the local blood vessels, lymph node and fatty infiltration, or tumor necrosis was regarded as potentially malignant.	('fatty infiltration', 'Disease', 'MESH:D008067', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor necrosis', 'Disease', 'MESH:D009336', (98, 112))	('PPGL', 'Var', (0, 4))	('fatty infiltration', 'Disease', (75, 93))	('tumor necrosis', 'Disease', (98, 112))
18319	32190664	Furthermore, in the reported literature, up to 50% of patients with metastatic PPGLs carry hereditary germline mutations, mainly in the SDHB gene.	('mutations', 'Var', (111, 120))	('SDHB', 'Gene', '6390', (136, 140))	('metastatic PPGLs', 'Disease', (68, 84))	('SDHB', 'Gene', (136, 140))	('PGLs', 'Phenotype', 'HP:0002668', (80, 84))
18332	31035382	Impact of Extrinsic and Intrinsic Hypoxia on Catecholamine Biosynthesis in Absence or Presence of Hif2alpha in Pheochromocytoma Cells Pheochromocytomas and paragangliomas (PPGLs) with activated pseudohypoxic pathways are associated with an immature catecholamine phenotype and carry a higher risk for metastasis.	('Pheochromocytoma', 'Disease', (134, 150))	('Catecholamine Biosynthesis', 'MPA', (45, 71))	('metastasis', 'CPA', (301, 311))	('Hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('Hypoxia', 'Disease', (34, 41))	('catecholamine', 'Chemical', 'MESH:D002395', (249, 262))	('Presence', 'Var', (86, 94))	('Catecholamine', 'Chemical', 'MESH:D002395', (45, 58))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (111, 127))	('immature catecholamine phenotype', 'MPA', (240, 272))	('Pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (134, 170))	('paragangliomas', 'Phenotype', 'HP:0002668', (156, 170))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (134, 150))	('Hif2alpha', 'Gene', '29452', (98, 107))	('Pheochromocytoma', 'Disease', (111, 127))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('PPGLs', 'Chemical', '-', (172, 177))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (134, 151))	('Hif2alpha', 'Gene', (98, 107))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))
18333	31035382	For improved understanding of the underlying mechanisms we investigated the impact of hypoxia and pseudohypoxia on catecholamine biosynthesis in pheochromocytoma cells naturally lacking Hif2alpha (MPC and MTT) or expressing both Hif1alpha and Hif2alpha (PC12).	('lacking', 'NegReg', (178, 185))	('pheochromocytoma', 'Disease', (145, 161))	('Hif2alpha', 'Protein', (186, 195))	('Hif1alpha', 'Gene', (229, 238))	('Hif1alpha', 'Gene', '29560', (229, 238))	('pseudohypoxia', 'Disease', (98, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('PC12', 'CellLine', 'CVCL:0481', (254, 258))	('pheochromocytoma', 'Disease', 'MESH:D010673', (145, 161))	('catecholamine', 'Chemical', 'MESH:D002395', (115, 128))	('Hif2alpha', 'Var', (243, 252))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('hypoxia', 'Disease', (104, 111))	('catecholamine biosynthesis', 'MPA', (115, 141))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('pseudohypoxia', 'Disease', 'None', (98, 111))	('MTT', 'Chemical', 'MESH:C070243', (205, 208))
18338	31035382	A specific knockdown of Hif1alpha in PC12 diminished these effects.	('PC12', 'CellLine', 'CVCL:0481', (37, 41))	('diminished', 'NegReg', (42, 52))	('Hif1alpha', 'Gene', '29560', (24, 33))	('knockdown', 'Var', (11, 20))	('Hif1alpha', 'Gene', (24, 33))
18343	31035382	PPGLs with activated pseudohypoxic pathways (cluster 1), including those with mutations in genes encoding hypoxia-inducible factor (HIF) 2alpha (also known as EPAS1), von Hippel-Lindau tumor suppressor (VHL), prolyl hydroxylase domain (PHD), fumarate hydratase, and succinate dehydrogenase subunits (SDHx) are characterized by an immature catecholamine phenotype and higher risk of metastasis particularly prevalent in SDHx-mutated tumors.	('VHL', 'Gene', '24874', (203, 206))	('prevalent', 'Reg', (406, 415))	('tumors', 'Disease', 'MESH:D009369', (432, 438))	('SDHx', 'Chemical', '-', (419, 423))	('SDHx', 'Chemical', '-', (300, 304))	('fumarate hydratase', 'Gene', (242, 260))	('catecholamine', 'Chemical', 'MESH:D002395', (339, 352))	('PPGLs', 'Chemical', '-', (0, 5))	('mutations', 'Var', (78, 87))	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (167, 190))	('VHL', 'Gene', (203, 206))	('activated', 'PosReg', (11, 20))	('tumors', 'Phenotype', 'HP:0002664', (432, 438))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PHD', 'Disease', (236, 239))	('fumarate hydratase', 'Gene', '24368', (242, 260))	('tumor', 'Phenotype', 'HP:0002664', (432, 437))	('tumors', 'Disease', (432, 438))	('hypoxia-inducible factor (HIF) 2alpha', 'Gene', '29452', (106, 143))	('PHD', 'Disease', 'MESH:D011547', (236, 239))	('von Hippel-Lindau tumor', 'Disease', (167, 190))
18344	31035382	In contrast, PPGLs with genetic alterations associated with activated kinase signaling pathways (cluster 2) are mostly benign and show a mature catecholamine phenotype with strong expression of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine (NEpi) to epinephrine (Epi).	('genetic alterations', 'Var', (24, 43))	('epinephrine', 'Chemical', 'MESH:D004837', (291, 302))	('norepinephrine', 'Chemical', 'MESH:D009638', (266, 280))	('NEpi', 'Chemical', 'MESH:D009638', (282, 286))	('rat', 'Species', '10116', (36, 39))	('PPGLs', 'Chemical', '-', (13, 18))	('phenylethanolamine N-methyltransferase', 'Gene', '24661', (194, 232))	('phenylethanolamine N-methyltransferase', 'Gene', (194, 232))	('PNMT', 'Gene', '24661', (234, 238))	('epinephrine', 'Chemical', 'MESH:D004837', (269, 280))	('PNMT', 'Gene', (234, 238))	('catecholamine', 'Chemical', 'MESH:D002395', (144, 157))
18354	31035382	A specific knockdown of Hif2alpha by RNA interference had no effect on Th mRNA expression in a rat adrenomedullary chromaffin cell line; in contrast, an influence on DOPA decarboxylase (Ddc), the enzyme responsible for conversion of L-DOPA to dopamine (DA), was established by changes in mRNA expression.	('DOPA decarboxylase', 'Gene', (166, 184))	('DA', 'Chemical', 'MESH:D004298', (253, 255))	('DOPA decarboxylase', 'Gene', '24311', (166, 184))	('Hif2alpha', 'Gene', (24, 33))	('L-DOPA', 'Chemical', 'MESH:D007980', (233, 239))	('Th', 'Chemical', 'MESH:D013910', (71, 73))	('Ddc', 'Gene', '24311', (186, 189))	('rat', 'Species', '10116', (95, 98))	('RNA interference', 'MPA', (37, 53))	('changes', 'Reg', (277, 284))	('chromaffin', 'Chemical', '-', (115, 125))	('dopamine', 'Chemical', 'MESH:D004298', (243, 251))	('Ddc', 'Gene', (186, 189))	('knockdown', 'Var', (11, 20))
18376	31035382	Furthermore, alterations in hypoxia-associated genes in pseudohypoxic cluster 1 PPGLs are associated with an immature catecholamine phenotype.	('PPGLs', 'Gene', (80, 85))	('immature catecholamine phenotype', 'MPA', (109, 141))	('rat', 'Species', '10116', (17, 20))	('associated', 'Reg', (90, 100))	('catecholamine', 'Chemical', 'MESH:D002395', (118, 131))	('hypoxia', 'Disease', (28, 35))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('alterations', 'Var', (13, 24))	('PPGLs', 'Chemical', '-', (80, 85))
18389	31035382	To clarify whether Hif1alpha or Hif2alpha drives the induction of catecholamine biosynthesis under extrinsic hypoxia, we analyzed cellular catecholamines of the rat PC12 cell line expressing both Hif1alpha and Hif2alpha.	('rat PC12', 'CellLine', 'CVCL:4695', (161, 169))	('catecholamines', 'Chemical', 'MESH:D002395', (139, 153))	('hypoxia', 'Disease', (109, 116))	('Hif1alpha', 'Gene', '29560', (196, 205))	('hypoxia', 'Disease', 'MESH:D000860', (109, 116))	('Hif1alpha', 'Gene', (19, 28))	('catecholamine', 'Chemical', 'MESH:D002395', (66, 79))	('Hif1alpha', 'Gene', '29560', (19, 28))	('catecholamine', 'Chemical', 'MESH:D002395', (139, 152))	('Hif1alpha', 'Gene', (196, 205))	('Hif2alpha', 'Var', (210, 219))
18397	31035382	No differences in cellular DA and NEpi content between MTT H2A cells and MTT control cells were observed.	('NEpi', 'Chemical', 'MESH:D009638', (34, 38))	('cellular DA', 'CPA', (18, 29))	('MTT', 'Var', (55, 58))	('DA', 'Chemical', 'MESH:D004298', (27, 29))	('MTT', 'Chemical', 'MESH:C070243', (55, 58))	('MTT', 'Chemical', 'MESH:C070243', (73, 76))
18402	31035382	In the presence of Hif2alpha (pseudohypoxia), the exposure to extrinsic hypoxia only had a negligible effect on the TH phosphorylation.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('Hif2alpha', 'Var', (19, 28))	('hypoxia', 'Disease', (36, 43))	('TH', 'Gene', '25085', (116, 118))	('pseudohypoxia', 'Disease', (30, 43))	('hypoxia', 'Disease', (72, 79))	('hypoxia', 'Disease', 'MESH:D000860', (72, 79))	('pseudohypoxia', 'Disease', 'None', (30, 43))
18410	31035382	A stable knockdown efficiency of 42.1 +- 5.7% was achieved over at least 72 h, also under extrinsic hypoxia (Figure 5B,C).	('hypoxia', 'Disease', (100, 107))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('knockdown', 'Var', (9, 18))
18412	31035382	Specific knockdown of Hif1alpha reduced hypoxia-induced DA content of PC12 cells significantly (Figure 5C).	('hypoxia', 'Disease', (40, 47))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('knockdown', 'Var', (9, 18))	('DA', 'Chemical', 'MESH:D004298', (56, 58))	('reduced', 'NegReg', (32, 39))	('Hif1alpha', 'Gene', (22, 31))	('Hif1alpha', 'Gene', '29560', (22, 31))	('PC12', 'CellLine', 'CVCL:0481', (70, 74))
18413	31035382	Moreover, specific knockdown of Hif1alpha led to reduced phosphorylation of TH at Ser40, while the total TH protein amount remained unaffected (Figure 5D).	('Ser40', 'Chemical', '-', (82, 87))	('TH', 'Gene', '25085', (76, 78))	('reduced', 'NegReg', (49, 56))	('knockdown', 'Var', (19, 28))	('Hif1alpha', 'Gene', (32, 41))	('Hif1alpha', 'Gene', '29560', (32, 41))	('TH', 'Gene', '25085', (105, 107))	('phosphorylation', 'MPA', (57, 72))
18418	31035382	Similar to other pseudohypoxic cluster 1 (5 VHL, 4 SDHB, 3 SDHD) PPGLs, tumors with a somatic gain-of-function mutation in EPAS1/HIF2alpha (n = 3) showed an increased expression of HIF2alpha compared to cluster 2 tumors (4 NF1, 6 MEN2), confirming previous results in the present cohort (Figure 6A,C).	('NF1, 6 MEN2', 'Gene', '24592', (223, 234))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('SDHB', 'Gene', '67680', (51, 55))	('tumors', 'Disease', (72, 78))	('SDHD', 'Disease', 'None', (59, 63))	('PPGLs', 'Chemical', '-', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('expression', 'MPA', (167, 177))	('gain-of-function', 'PosReg', (94, 110))	('tumors', 'Disease', (213, 219))	('VHL', 'Gene', (44, 47))	('cluster 2 tumors', 'Disease', 'MESH:D003027', (203, 219))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('HIF2alpha', 'Protein', (181, 190))	('mutation', 'Var', (111, 119))	('SDHB', 'Gene', (51, 55))	('SDHD', 'Disease', (59, 63))	('EPAS1/HIF2alpha', 'Gene', (123, 138))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('increased', 'PosReg', (157, 166))	('VHL', 'Gene', '24874', (44, 47))	('cluster 2 tumors', 'Disease', (203, 219))
18420	31035382	The three patients with EPAS1/HIF2alpha mutation consistently showed a doubling of NEpi in comparison to other cluster 1 tumors (Figure 6B).	('mutation', 'Var', (40, 48))	('NEpi', 'Chemical', 'MESH:D009638', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('EPAS1/HIF2alpha', 'Gene', (24, 39))	('NEpi', 'MPA', (83, 87))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (10, 18))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('doubling', 'PosReg', (71, 79))
18435	31035382	Different protein kinases and protein phosphatases mediate the phosphorylation of TH at serine residues Ser8, Ser19, Ser31 and Ser40.	('Ser31', 'Var', (117, 122))	('Ser8', 'Var', (104, 108))	('protein', 'Enzyme', (10, 17))	('Ser40', 'Chemical', '-', (127, 132))	('Ser31', 'Chemical', '-', (117, 122))	('Ser19', 'Chemical', '-', (110, 115))	('TH', 'Gene', '25085', (82, 84))	('phosphorylation', 'MPA', (63, 78))	('Ser40', 'Var', (127, 132))	('Ser19', 'Var', (110, 115))	('serine', 'Chemical', 'MESH:D012694', (88, 94))	('Ser8', 'Chemical', '-', (104, 108))	('protein phosphatases', 'Enzyme', (30, 50))
18436	31035382	TH activity is nevertheless predominantly dependent on the phosphorylation at Ser40; phosphorylation at Ser31 also enhances TH activity but to a much lesser extent than for Ser40, and phosphorylation at Ser19 or Ser8 has no effect on the enzyme activity.	('TH', 'Gene', '25085', (124, 126))	('Ser31', 'Chemical', '-', (104, 109))	('phosphorylation', 'Var', (85, 100))	('Ser8', 'Chemical', '-', (212, 216))	('Ser40', 'Chemical', '-', (173, 178))	('TH', 'Gene', '25085', (0, 2))	('Ser19', 'Chemical', '-', (203, 208))	('Ser40', 'Chemical', '-', (78, 83))	('enhances', 'PosReg', (115, 123))
18437	31035382	Protein kinase (PK) A, PKG, and PKC are primarily responsible for the phosphorylation of Ser40, whereas dephosphorylation is regulated by protein phosphatase 2A and 2C.	('PK', 'Gene', '64030', (16, 18))	('responsible', 'Reg', (50, 61))	('PK', 'Gene', '64030', (23, 25))	('Ser40', 'Chemical', '-', (89, 94))	('dephosphorylation', 'MPA', (104, 121))	('Ser40', 'Var', (89, 94))	('phosphorylation', 'MPA', (70, 85))	('PKC', 'Gene', (32, 35))	('Protein kinase', 'Gene', '64030', (0, 14))	('Protein kinase', 'Gene', (0, 14))	('PKC', 'Gene', '5580', (32, 35))	('PK', 'Gene', '64030', (32, 34))
18446	31035382	The three tumors bearing a mutation in EPAS1/HIF2alpha consistently showed a doubling of NEpi in comparison to other cluster 1 PPGLs.	('NEpi', 'Chemical', 'MESH:D009638', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('EPAS1/HIF2alpha', 'Gene', (39, 54))	('NEpi', 'MPA', (89, 93))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('mutation', 'Var', (27, 35))	('PPGLs', 'Chemical', '-', (127, 132))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('doubling', 'PosReg', (77, 85))
18450	31035382	Furthermore, expression of Hif2alpha in MPC-mCherry cells enhanced hypoxia-stimulated expression of Ddc (Figure 4).	('Hif2alpha', 'Protein', (27, 36))	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('enhanced', 'PosReg', (58, 66))	('Ddc', 'Gene', (100, 103))	('expression', 'Var', (13, 23))	('Ddc', 'Gene', '24311', (100, 103))
18452	31035382	This could be responsible for the enhanced Ddc expression in presence of Hif1alpha and Hif2alpha.	('Hif1alpha', 'Gene', (73, 82))	('Hif1alpha', 'Gene', '29560', (73, 82))	('enhanced', 'PosReg', (34, 42))	('Ddc', 'Gene', '24311', (43, 46))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('Hif2alpha', 'Var', (87, 96))	('Ddc', 'Gene', (43, 46))
18453	31035382	The present study allows for the first time a differentiation between HIF1alpha- and HIF2alpha-driven effects on the catecholamine biosynthesis under hypoxic conditions (Figure 7).	('hypoxic conditions', 'Disease', 'MESH:D009135', (150, 168))	('catecholamine', 'Chemical', 'MESH:D002395', (117, 130))	('HIF2alpha-driven', 'Var', (85, 101))	('HIF1alpha-', 'Var', (70, 80))	('catecholamine biosynthesis', 'MPA', (117, 143))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('hypoxic conditions', 'Disease', (150, 168))
18455	31035382	A specific knockdown of Hif1alpha reduced hypoxia-induced dopamine synthesis and diminished TH phosphorylation significantly (Figure 5), while the expression of Hif2alpha had no additional effect (Figure 4).	('diminished', 'NegReg', (81, 91))	('reduced', 'NegReg', (34, 41))	('dopamine', 'Chemical', 'MESH:D004298', (58, 66))	('TH', 'Gene', '25085', (92, 94))	('hypoxia', 'Disease', (42, 49))	('hypoxia', 'Disease', 'MESH:D000860', (42, 49))	('Hif1alpha', 'Gene', '29560', (24, 33))	('knockdown', 'Var', (11, 20))	('Hif1alpha', 'Gene', (24, 33))
18466	31035382	Targeted inhibition of HIF2alpha possibly provides an excellent therapeutic approach for advanced PPGLs and is moreover able to modulate catecholamine biosynthesis within the tumor cells.	('modulate', 'Reg', (128, 136))	('tumor', 'Disease', (175, 180))	('PPGLs', 'Chemical', '-', (98, 103))	('HIF2alpha', 'Gene', (23, 32))	('catecholamine biosynthesis', 'MPA', (137, 163))	('Targeted inhibition', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('PPGLs', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('catecholamine', 'Chemical', 'MESH:D002395', (137, 150))
18515	31035382	After centrifugation at 4  C, pellets were washed twice with PBS and stored at -80  C. Sixty spheroids were transferred to each Eppendorf tube, washed three times with PBS and stored at -80  C. Lysates were prepared on ice using CellLyticTM M (Sigma-Aldrich, C2978) with protease inhibitors (1:100, Sigma-Aldrich; P8340).	('P8340', 'Var', (314, 319))	('PBS', 'Disease', 'MESH:D011535', (61, 64))	('PBS', 'Disease', (61, 64))	('PBS', 'Disease', 'MESH:D011535', (168, 171))	('PBS', 'Disease', (168, 171))	('C2978', 'CellLine', 'CVCL:9U73', (259, 264))
18534	31035382	; writing:original draft preparation, N.B., I.P., V.S., C.G., M.U., N.Q., A.W., M.P., M.R., K.P., J.P., S.R.	('M.P.', 'Var', (80, 84))	('M.R.', 'Var', (86, 90))	('rat', 'Species', '10116', (30, 33))	('K.P.', 'Var', (92, 96))
18566	31179416	Patients with a mutation in the B subunit of SDH, known as SDHB, are more likely to have metastatic disease.	('SDH', 'Gene', '6390', (59, 62))	('mutation in', 'Var', (16, 27))	('metastatic disease', 'CPA', (89, 107))	('SDH', 'Gene', (45, 48))	('SDH', 'Gene', (59, 62))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', '6390', (59, 63))	('SDHB', 'Gene', (59, 63))	('SDH', 'Gene', '6390', (45, 48))
18569	31179416	Each syndrome is distinguished by a different mutated subunit of SDH and has a characteristic incidence of PPGLs as well as renal cell carcinomas, gastrointestinal stromal tumors, pituitary tumors, and thyroid cancers.	('SDH', 'Gene', '6390', (65, 68))	('renal cell carcinomas', 'Disease', (124, 145))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutated', 'Var', (46, 53))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (124, 145))	('gastrointestinal stromal tumors', 'Disease', (147, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('thyroid cancers', 'Disease', 'MESH:D013964', (202, 217))	('PPGLs', 'Chemical', '-', (107, 112))	('pituitary tumors', 'Disease', 'MESH:D010911', (180, 196))	('SDH', 'Gene', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PPGLs', 'Disease', (107, 112))	('pituitary tumors', 'Disease', (180, 196))	('thyroid cancers', 'Disease', (202, 217))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (147, 178))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (147, 178))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (124, 145))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))
18576	31179416	After engaging in shared decision making, genetic testing for SDH mutations may be recommended as well.	('mutations', 'Var', (66, 75))	('SDH', 'Gene', (62, 65))	('SDH', 'Gene', '6390', (62, 65))
18602	31179416	In terms of radiotherapy options, 131I-MIBG, a norepinephrine analog labeled with a radioactive isotope, can be used for both diagnosis and treatment of metastatic PPGLs.	('norepinephrine', 'Chemical', 'MESH:D009638', (47, 61))	('131I-MIBG', 'Chemical', 'MESH:D019797', (34, 43))	('PPGLs', 'Chemical', '-', (164, 169))	('metastatic PPGLs', 'Disease', (153, 169))	('131I-MIBG', 'Var', (34, 43))
18603	31179416	One meta-analysis of 243 patients with metastatic PPGL treated with varying doses of 131I-MIBG demonstrated 3% complete response, 27% partial responsive, and 52% stable disease.	('131I-MIBG', 'Chemical', 'MESH:D019797', (85, 94))	('PPGL', 'Chemical', '-', (50, 54))	('131I-MIBG', 'Var', (85, 94))	('patients', 'Species', '9606', (25, 33))	('partial', 'NegReg', (134, 141))
18607	31179416	Currently, randomized control trials are underway looking at a variety of biological molecules including sunitinib (NCT01371201), as well as cabozantinib (NCT02302833), lenvatinib (NCT03008369), pembrolizumab (NCT02721732), ipilimumab/nivolumab (NCT02834013), and dovitinib (NCT01635907) for the treatment of metastatic PPGLs.	('metastatic PPGLs', 'Disease', (309, 325))	('nivolumab', 'Chemical', 'MESH:D000077594', (235, 244))	('NCT02834013', 'Var', (246, 257))	('ipilimumab', 'Chemical', 'MESH:D000074324', (224, 234))	('sunitinib', 'Chemical', 'MESH:D000077210', (105, 114))	('NCT03008369', 'Var', (181, 192))	('NCT01635907', 'Var', (275, 286))	('cabozantinib', 'Chemical', 'MESH:C558660', (141, 153))	('pembrolizumab', 'Chemical', 'MESH:C582435', (195, 208))	('NCT02721732', 'Var', (210, 221))	('NCT02302833', 'Var', (155, 166))	('PPGLs', 'Chemical', '-', (320, 325))	('dovitinib', 'Chemical', 'MESH:C500007', (264, 273))	('NCT01371201', 'Var', (116, 127))	('lenvatinib', 'Chemical', 'MESH:C531958', (169, 179))
18641	30693873	In such rare circumstances, specific genetic mutations result in VHL disease or familial pheochromocytoma and RCC syndrome have been proposed.	('RCC', 'Disease', (110, 113))	('result in', 'Reg', (55, 64))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('mutations', 'Var', (45, 54))	('VHL disease', 'Disease', (65, 76))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('familial pheochromocytoma', 'Disease', (80, 105))	('VHL disease', 'Disease', 'MESH:D006623', (65, 76))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (80, 105))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (89, 105))
18642	30693873	The negative results of VHL gene mutation and unremarkable family history in our patient make the diagnosis of these two diseases less likely.	('mutation', 'Var', (33, 41))	('patient', 'Species', '9606', (81, 88))	('negative', 'NegReg', (4, 12))	('VHL', 'Disease', 'MESH:D006623', (24, 27))	('VHL', 'Disease', (24, 27))
18710	30631823	Once MIBG is tagged with either 123I or 131I, it can be taken up by functional paragangliomas.	('123I', 'Var', (32, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('paragangliomas', 'Phenotype', 'HP:0002668', (79, 93))	('functional paragangliomas', 'Disease', 'MESH:D010235', (68, 93))	('MIBG', 'Chemical', 'MESH:D019797', (5, 9))	('functional paragangliomas', 'Disease', (68, 93))	('131I', 'Var', (40, 44))
18748	30405919	They suggest testing for succinate dehydrogenase (SDH) mutations and that patients with metastatic disease should undergo testing for SDHB mutations.	('mutations', 'Var', (55, 64))	('mutations', 'Var', (139, 148))	('succinate dehydrogenase', 'Gene', '6390', (25, 48))	('patients', 'Species', '9606', (74, 82))	('succinate dehydrogenase', 'Gene', (25, 48))	('testing', 'Reg', (13, 20))	('SDHB', 'Gene', (134, 138))	('SDH', 'Gene', (50, 53))
18750	30405919	Multiple paragangliomas have been identified in 66.9 percent of the SDHD mutation carriers; but malignant paragangliomas are more commonly seen in SDHB mutation carriers, 37.5 percent, as opposed to 3.1 percent of the SDHD, and none of the SDHC mutation carriers.	('malignant paragangliomas', 'Disease', (96, 120))	('Multiple paragangliomas', 'Disease', 'MESH:D010235', (0, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (96, 120))	('SDHB', 'Gene', (147, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('paragangliomas', 'Phenotype', 'HP:0002668', (9, 23))	('Multiple paragangliomas', 'Disease', (0, 23))	('mutation', 'Var', (152, 160))	('paragangliomas', 'Phenotype', 'HP:0002668', (106, 120))
18760	30405919	These gene mutations have been identified as part of Von Hipple Lindau syndrome, multiple endocrine neoplasia, neurofibromatosis type 1, and paragangliomas syndrome.	('mutations', 'Var', (11, 20))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (111, 128))	('multiple endocrine neoplasia', 'Disease', (81, 109))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (90, 109))	('identified', 'Reg', (31, 41))	('Von Hipple Lindau syndrome', 'Disease', 'MESH:D006623', (53, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (100, 109))	('paragangliomas syndrome', 'Disease', (141, 164))	('Von Hipple Lindau syndrome', 'Disease', (53, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (141, 155))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (81, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('neurofibromatosis type 1', 'Gene', '4763', (111, 135))	('neurofibromatosis type 1', 'Gene', (111, 135))	('paragangliomas syndrome', 'Disease', 'MESH:D010235', (141, 164))
18761	30405919	It consisted of four female patients, one of them with synchronous PTC and PGL; 2 had heterozygous germline variants in SDHB and the four of them had -79 T>C CDKN1B gene polymorphism (3 homozygous and 1 in heterozygous state).	('PTC', 'Phenotype', 'HP:0002895', (67, 70))	('variants', 'Var', (108, 116))	('PGL; 2', 'Gene', (75, 81))	('CDKN1B', 'Gene', '1027', (158, 164))	('SDHB', 'Gene', (120, 124))	('PGL; 2', 'Gene', '54949', (75, 81))	('-79 T>C', 'Mutation', 'rs34330', (150, 157))	('CDKN1B', 'Gene', (158, 164))
18876	29623209	The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines.	('NF-1', 'Gene', '4763', (52, 56))	('urinary fractionated metanephrines', 'MPA', (97, 131))	('plasma-free metanephrines', 'MPA', (68, 93))	('PPGL', 'Var', (44, 48))	('metanephrines', 'Chemical', 'MESH:D008676', (80, 93))	('NF-1', 'Gene', (52, 56))	('PGL', 'Phenotype', 'HP:0002668', (45, 48))	('metanephrines', 'Chemical', 'MESH:D008676', (118, 131))
18879	29623209	Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.	('exacerbate', 'PosReg', (28, 38))	('metabolic bone defect', 'Disease', 'MESH:D001851', (43, 64))	('PHPT', 'Var', (11, 15))	('patients', 'Species', '9606', (74, 82))	('metabolic bone defect', 'Disease', (43, 64))	('PHPT', 'Phenotype', 'HP:0008200', (11, 15))
18884	29623209	Loss of neurofibromin results in hyperactivation of the RAS proto-oncogene, which is a key signalling molecule of cell growth.	('neurofibromin', 'Gene', '4763', (8, 21))	('hyperactivation', 'PosReg', (33, 48))	('Loss', 'Var', (0, 4))	('neurofibromin', 'Gene', (8, 21))	('RAS proto-oncogene', 'Gene', (56, 74))
18885	29623209	Therefore, NF-1 is now recognized as a form of RASopathy, where dysregulated RAS-MAPK signalling pathway causes cancer predisposition.	('RAS-MAPK signalling pathway', 'Pathway', (77, 104))	('causes', 'Reg', (105, 111))	('NF-1', 'Gene', '4763', (11, 15))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('RASopathy', 'Disease', (47, 56))	('NF-1', 'Gene', (11, 15))	('dysregulated', 'Var', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('RASopathy', 'Disease', 'None', (47, 56))
18955	29623209	The presence of PHPT may further exacerbate the bone diseases in these patients and when it is recognised, treatment should be considered based on the current guidelines.	('patients', 'Species', '9606', (71, 79))	('PHPT', 'Phenotype', 'HP:0008200', (16, 20))	('exacerbate', 'PosReg', (33, 43))	('presence', 'Var', (4, 12))	('bone diseases', 'Disease', (48, 61))	('PHPT', 'Gene', (16, 20))	('bone diseases', 'Disease', 'MESH:D001847', (48, 61))
18971	29308445	To use the Exome Aggregation Consortium (ExAC) data set to determine the background population frequencies of rare germline coding-region variants in genes associated with hereditary endocrine disease and to evaluate the clinical utility of these data.	('hereditary endocrine disease', 'Disease', (172, 200))	('hereditary endocrine disease', 'Disease', 'MESH:D030342', (172, 200))	('endocrine disease', 'Phenotype', 'HP:0000818', (183, 200))	('variants', 'Var', (138, 146))
18973	29308445	The utility of gene-level and variant-level metrics of tolerability was assessed, and the pathogenicity and penetrance of germline variants previously associated with endocrine disease evaluated.	('associated', 'Reg', (151, 161))	('endocrine disease', 'Phenotype', 'HP:0000818', (167, 184))	('variants', 'Var', (131, 139))	('endocrine disease', 'Disease', (167, 184))	('endocrine disease', 'Disease', 'MESH:D004700', (167, 184))
18974	29308445	Genes associated with dominant monogenic endocrine disorders typically harbored fewer rare missense and/or loss-of-function variants than expected.	('endocrine disorders', 'Disease', 'MESH:D004700', (41, 60))	('endocrine disorders', 'Phenotype', 'HP:0000818', (41, 60))	('loss-of-function', 'NegReg', (107, 123))	('endocrine disorders', 'Disease', (41, 60))	('missense', 'Var', (91, 99))
18975	29308445	The frequency of several endocrine disease-associated variants in the ExAC cohort far exceeded estimates of disease prevalence, indicating either misclassification or overestimation of disease penetrance.	('variants', 'Var', (54, 62))	('endocrine disease', 'Disease', 'MESH:D004700', (25, 42))	('endocrine disease', 'Phenotype', 'HP:0000818', (25, 42))	('endocrine disease', 'Disease', (25, 42))
18980	29308445	The detailed genetic characterization of large population cohorts provides an unbiased resource to reevaluate the role of germline genetic variation in hereditary disease, as illustrated by results from the exome variant server and 1000 Genomes Project cohorts, which identified a surprising high degree of rare coding-region variation as well as demonstrating that many disease-associated variants reported as pathogenic were instead observed with improbably high frequencies in apparently healthy individuals, indicating likely misclassification.	('hereditary disease', 'Disease', 'MESH:D030342', (152, 170))	('hereditary disease', 'Disease', (152, 170))	('variation', 'Var', (326, 335))	('variants', 'Var', (390, 398))
18986	29308445	Indications for genetic testing include the evaluation of individuals at risk for monogenic disease [e.g., multiple endocrine neoplasia type 1 (MEN1)]; sporadic clinical presentations associated with a high prevalence of germline mutations [e.g., pheochromocytoma/paraganglioma (PPGL)]; or investigative studies for clinical presentations in which a genetic etiology is suspected.	('pheochromocytoma/paraganglioma', 'Disease', (247, 277))	('MEN1', 'Gene', '4221', (144, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (126, 135))	('germline mutations', 'Var', (221, 239))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (247, 277))	('multiple endocrine neoplasia type 1', 'Gene', '4221', (107, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (264, 277))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (116, 135))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (247, 263))	('multiple endocrine neoplasia type 1', 'Gene', (107, 142))	('MEN1', 'Gene', (144, 148))
18987	29308445	Therefore, to address these challenges, we used the ExAC cohort to quantify the spectrum and frequency of rare germline missense and loss-of-function (LOF) SNVs in 38 genes associated with hereditary endocrine disease and explored the utility of these data when applied to several clinical settings.	('hereditary endocrine disease', 'Disease', 'MESH:D030342', (189, 217))	('missense', 'Var', (120, 128))	('loss-of-function', 'NegReg', (133, 149))	('endocrine disease', 'Phenotype', 'HP:0000818', (200, 217))	('SNVs', 'Var', (156, 160))	('hereditary endocrine disease', 'Disease', (189, 217))
18988	29308445	All high-quality nonsynonymous SNVs were identified in the 38 genes selected for study, including those predicted to result in missense or nonsense amino acid changes and those directly disrupting donor or acceptor splice sites.	('missense', 'Var', (127, 135))	('donor', 'Species', '9606', (197, 202))	('donor or acceptor splice sites', 'MPA', (197, 227))	('nonsense amino acid changes', 'Var', (139, 166))	('result', 'Reg', (117, 123))	('disrupting', 'NegReg', (186, 196))
18993	29308445	A separate subanalysis of only LOF SNVs was performed (i.e., single-nucleotide substitution predicting either a nonsense amino acid change or directly affecting a donor or acceptor splice site).	('nonsense amino acid', 'MPA', (112, 131))	('affecting', 'Reg', (151, 160))	('donor', 'Species', '9606', (163, 168))	('single-nucleotide substitution', 'Var', (61, 91))
18996	29308445	SIFT, Polyphen2, and Combined Annotation Dependent Depletion (CADD) scores were evaluated for all missense SNVs with an AF <0.5% in a subset of 12 genes (downloaded from http://cadd.gs.washington.edu/).	('AF', 'Disease', 'MESH:D001281', (120, 122))	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))	('missense', 'Var', (98, 106))
18997	29308445	Variants were categorized as deleterious if they met all of the following criteria: AF <0.5%; SIFT score <=0.05; a Polyphen2 description of probably damaging; and a scaled CADD score >20.	('Variants', 'Var', (0, 8))	('SIFT', 'Disease', 'None', (94, 98))	('AF', 'Disease', 'MESH:D001281', (84, 86))	('SIFT', 'Disease', (94, 98))
18998	29308445	Variants were considered possibly deleterious when they had an AF <0.5% and either a SIFT score <=0.05 and/or a Polyphen2 classification of probably damaging or possibly damaging.	('SIFT', 'Disease', 'None', (85, 89))	('SIFT', 'Disease', (85, 89))	('Variants', 'Var', (0, 8))	('AF', 'Disease', 'MESH:D001281', (63, 65))
19000	29308445	In a separate analysis, the ExAC data set was screened for actionable variants in MEN1, RET, VHL, SDHB, SDHC, SDHD, and SDHAF2 (as recommended by the American College of Medical Genetics and Genomics (ACMG) guidelines).	('RET', 'Gene', (88, 91))	('SDHC', 'Gene', (104, 108))	('SDHB', 'Gene', '6390', (98, 102))	('MEN1', 'Gene', (82, 86))	('SDHB', 'Gene', (98, 102))	('variants', 'Var', (70, 78))	('SDHAF2', 'Gene', (120, 126))	('VHL', 'Disease', 'MESH:D006623', (93, 96))	('RET', 'Gene', '5979', (88, 91))	('VHL', 'Disease', (93, 96))	('SDHD', 'Gene', '6392', (110, 114))	('SDHC', 'Gene', '6391', (104, 108))	('SDHAF2', 'Gene', '54949', (120, 126))	('SDHD', 'Gene', (110, 114))	('MEN1', 'Gene', '4221', (82, 86))
19001	29308445	Individual and cumulative frequencies of all missense AIP SNVs with an AF <0.5% were established for the ExAC cohort and compared with those observed in 1866 individuals with apparently sporadic pituitary tumors reported in nine earlier studies.	('missense', 'Var', (45, 53))	('AIP', 'Gene', '9049', (54, 57))	('pituitary tumors', 'Disease', (195, 211))	('AIP', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('AF', 'Disease', 'MESH:D001281', (71, 73))	('pituitary tumors', 'Disease', 'MESH:D010911', (195, 211))
19003	29308445	Thirty-eight genes were selected for study, representing a range of endocrine disorders reported to be associated with heterozygous germline missense and/or LOF SNVs (Table 1).	('endocrine disorders', 'Phenotype', 'HP:0000818', (68, 87))	('SNVs', 'Disease', (161, 165))	('endocrine disorders', 'Disease', (68, 87))	('germline', 'Var', (132, 140))	('endocrine disorders', 'Disease', 'MESH:D004700', (68, 87))	('LOF', 'NegReg', (157, 160))
19004	29308445	The identification of all nonsynonymous SNVs (i.e., single-nucleotide substitutions resulting in missense or nonsense amino acid changes or directly affecting donor or acceptor splice sites) in each of the 38 genes revealed that the overwhelming majority were rare, with ~60% occurring as singletons (i.e., observed only once in the ExAC cohort), whereas ~92% of gene-specific SNVs had an AF <0.05% (i.e., observed in <=1 in 1000 individuals) (Fig.	('donor', 'Species', '9606', (159, 164))	('nonsense amino acid', 'MPA', (109, 128))	('missense', 'Var', (97, 105))	('AF', 'Disease', 'MESH:D001281', (389, 391))	('single-nucleotide substitutions', 'Var', (52, 83))	('affecting', 'Reg', (149, 158))
19005	29308445	For example, chromodomain helicase DNA-binding protein 7 (CHD7) and neurofibromin (NF1) demonstrated the highest frequencies of singleton variants (affecting approximately one in 100 and approximately one in 200 of the cohort, respectively), whereas the lowest frequency was observed for adaptor-related protein complex 2 sigma 1 subunit (AP2S1) (affecting approximately one in 12,000 individuals).	('NF1', 'Gene', '4763', (83, 86))	('AP2S1', 'Gene', (339, 344))	('chromodomain helicase DNA-binding protein 7', 'Gene', '55636', (13, 56))	('CHD7', 'Gene', (58, 62))	('CHD7', 'Gene', '55636', (58, 62))	('variants', 'Var', (138, 146))	('neurofibromin', 'Gene', (68, 81))	('adaptor-related protein complex 2 sigma 1 subunit', 'Gene', (288, 337))	('adaptor-related protein complex 2 sigma 1 subunit', 'Gene', '1175', (288, 337))	('AP2S1', 'Gene', '1175', (339, 344))	('chromodomain helicase DNA-binding protein 7', 'Gene', (13, 56))	('NF1', 'Gene', (83, 86))	('neurofibromin', 'Gene', '4763', (68, 81))
19008	29308445	To further investigate gene-level differences in rare variant frequency, we evaluated the utility of recently reported metrics of constraint, which aim to quantify the deviation between observed and expected numbers of rare nonsynonymous SNVs resulting in either a missense amino acid change or an LOF (i.e., nonsense or donor/acceptor splice site change) .	('missense', 'Var', (265, 273))	('donor', 'Species', '9606', (321, 326))	('SNVs', 'Var', (238, 242))	('LOF', 'NegReg', (298, 301))	('nonsense', 'Var', (309, 317))
19010	29308445	In contrast, many disease-associated genes were categorized as missense and/or LOF tolerant, including several in which the role of heterozygous variation and endocrine disease is less established [e.g., growth hormone receptor (GHR)] or was previously associated with reduced disease penetrance [e.g., succinate dehydrogenase A (SDHA), succinate dehydrogenase B (SDHB)].	('endocrine disease', 'Phenotype', 'HP:0000818', (159, 176))	('succinate dehydrogenase A', 'Gene', '6389', (303, 328))	('missense', 'Var', (63, 71))	('growth hormone receptor', 'Gene', (204, 227))	('succinate dehydrogenase A', 'Gene', (303, 328))	('SDHA', 'Gene', (330, 334))	('growth hormone receptor', 'Gene', '2690', (204, 227))	('endocrine disease', 'Disease', (159, 176))	('succinate dehydrogenase B', 'Gene', (337, 362))	('succinate dehydrogenase B', 'Gene', '6390', (337, 362))	('endocrine disease', 'Disease', 'MESH:D004700', (159, 176))	('GHR', 'Gene', (229, 232))	('SDHB', 'Gene', '6390', (364, 368))	('GHR', 'Gene', '2690', (229, 232))	('SDHA', 'Gene', '6389', (330, 334))	('SDHB', 'Gene', (364, 368))	('LOF', 'NegReg', (79, 82))
19013	29308445	Although many genes displayed an absence or very low number of LOF SNV alleles consistent with their known haploinsufficiency function (e.g., MEN1, CDC73), some genes harbored cumulative LOF SNV frequencies considerably higher than the associated disease phenotype (e.g., SDHA and PPGL), indicating a reduced penetrance of such variants.	('LOF', 'NegReg', (187, 190))	('CDC73', 'Gene', (148, 153))	('MEN1', 'Gene', '4221', (142, 146))	('CDC73', 'Gene', '79577', (148, 153))	('SDHA', 'Gene', (272, 276))	('haploinsufficiency function', 'Disease', (107, 134))	('MEN1', 'Gene', (142, 146))	('haploinsufficiency function', 'Disease', 'MESH:D058495', (107, 134))	('higher', 'PosReg', (220, 226))	('SNV', 'Var', (191, 194))	('SDHA', 'Gene', '6389', (272, 276))
19015	29308445	Similarly, small indels resulting in an LOF (i.e., frameshift) were absent or very rare in the majority of genes (i.e., 21 of 38 genes harboring <=1 affected individual), although higher frequencies were observed in several genes in which LOF indels would be anticipated to be disease causing, including NF1 (~1:5000 individuals), CASR (~1:15,000 individuals), SDHB (~1:30,000), and CDC73 (~1:30,000) .	('SDHB', 'Gene', '6390', (361, 365))	('SDHB', 'Gene', (361, 365))	('NF1', 'Gene', (304, 307))	('CDC73', 'Gene', (383, 388))	('LOF', 'NegReg', (239, 242))	('CDC73', 'Gene', '79577', (383, 388))	('indels', 'Var', (243, 249))	('CASR', 'Gene', '846', (331, 335))	('NF1', 'Gene', '4763', (304, 307))	('CASR', 'Gene', (331, 335))
19016	29308445	Computational tools are frequently used to predict the functional effects of missense SNVs on protein function and are often used as an adjunct alongside other clinical and genetic data to provide supporting evidence of variant pathogenicity (e.g., as part of the ACMG algorithm for interpretation of sequence variants).	('ret', 'Gene', '5979', (289, 292))	('missense SNVs', 'Var', (77, 90))	('ret', 'Gene', (289, 292))	('protein function', 'MPA', (94, 110))	('effects', 'Reg', (66, 73))
19017	29308445	To assess the potential utility of such tools, we analyzed SIFT, Polyphen2, and CADD scores of all rare missense SNVs in a subset of 12 genes.	('missense SNVs', 'Var', (104, 117))	('SIFT', 'Disease', 'None', (59, 63))	('SIFT', 'Disease', (59, 63))
19018	29308445	For example, ~1:2000 ExAC individuals harbored a rare MEN1 missense SNV predicted to be deleterious using all three tools, compared with the estimated population prevalence of MEN1 of 1:30,000.	('missense SNV', 'Var', (59, 71))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('MEN1', 'Gene', (54, 58))	('MEN1', 'Gene', '4221', (54, 58))
19019	29308445	First, we examined the ExAC cohort for variants previously reported as disease-causing in six genes associated with penetrant monogenic disorders (i.e., FHH, MEN1 and MEN2, hyperparathyroidism-jaw tumor syndrome, NF1, and VHL).	('MEN1', 'Gene', '4221', (158, 162))	('VHL', 'Disease', 'MESH:D006623', (222, 225))	('FHH', 'Gene', (153, 156))	('VHL', 'Disease', (222, 225))	('disease-causing', 'Reg', (71, 86))	('MEN', 'Species', '9606', (158, 161))	('MEN', 'Species', '9606', (167, 170))	('hyperparathyroidism-jaw tumor syndrome', 'Disease', 'MESH:C563273', (173, 211))	('jaw tumor', 'Phenotype', 'HP:0030792', (193, 202))	('NF1', 'Gene', (213, 216))	('MEN1', 'Gene', (158, 162))	('NF1', 'Gene', '4763', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('FHH', 'Gene', '846', (153, 156))	('MEN2', 'Disease', (167, 171))	('hyperparathyroidism-jaw tumor syndrome', 'Disease', (173, 211))	('variants', 'Var', (39, 47))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (173, 192))
19023	29308445	Thirteen of 22 RET mutation carriers harbored the moderate-risk p.Val804Met variant, indicating that this allele is likely associated with low disease penetrance.	('p.Val804Met', 'Var', (64, 75))	('RET', 'Gene', '5979', (15, 18))	('low disease', 'Disease', (139, 150))	('p.Val804Met', 'Mutation', 'rs79658334', (64, 75))	('low disease', 'Disease', 'MESH:D009800', (139, 150))	('RET', 'Gene', (15, 18))
19024	29308445	Excluding the p.Val804Met variant, approximately one in 6000 individuals carried moderate- or high-risk RET mutations, indicating that the disease penetrance of these alleles may also require reevaluation.	('RET', 'Gene', (104, 107))	('p.Val804Met', 'Mutation', 'rs79658334', (14, 25))	('RET', 'Gene', '5979', (104, 107))	('p.Val804Met', 'Var', (14, 25))
19025	29308445	An apparent similar overrepresentation of disease alleles was observed for the calcium sensing receptor (CASR), in which approximately one in 3500 individuals harbored a variant previously associated with FHH type 1 (estimated prevalence: 1:15 to 30,000), although in this setting it is plausible that the condition is more prevalent than currently recognized because of its typically asymptomatic phenotype.	('CASR', 'Gene', (105, 109))	('FHH type', 'Disease', (205, 213))	('variant', 'Var', (170, 177))	('FHH type', 'Disease', 'MESH:C537145', (205, 213))	('calcium sensing receptor', 'Gene', '846', (79, 103))	('CASR', 'Gene', '846', (105, 109))	('calcium sensing receptor', 'Gene', (79, 103))
19026	29308445	In contrast, the higher-than-expected occurrence of potentially pathogenic MEN1 and VHL variants in the ExAC cohort indicates that several of these variants were likely misclassified.	('VHL', 'Disease', (84, 87))	('pathogenic', 'Reg', (64, 74))	('MEN1', 'Gene', (75, 79))	('variants', 'Var', (88, 96))	('MEN1', 'Gene', '4221', (75, 79))	('VHL', 'Disease', 'MESH:D006623', (84, 87))
19027	29308445	However, it is important to note that in the case of VHL, four of the six likely pathogenic variants occurred in individuals from the TCGA cohort, which included 344 patients with a history of sporadic renal clear cell carcinoma who may be at an increased risk of harboring such germline variants .	('VHL', 'Disease', (53, 56))	('VHL', 'Disease', 'MESH:D006623', (53, 56))	('occurred', 'Reg', (101, 109))	('patients', 'Species', '9606', (166, 174))	('sporadic renal clear cell carcinoma', 'Disease', 'MESH:C538614', (193, 228))	('sporadic renal clear cell carcinoma', 'Disease', (193, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('variants', 'Var', (92, 100))
19028	29308445	Next, the ExAC cohort was evaluated for individuals harboring clinically-actionable variants in one of seven hereditary endocrine tumor predisposition genes currently included in the ACMG guidelines.	('endocrine tumor', 'Phenotype', 'HP:0100568', (120, 135))	('hereditary endocrine tumor', 'Disease', 'MESH:D004701', (109, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('variants', 'Var', (84, 92))	('hereditary endocrine tumor', 'Disease', (109, 135))
19029	29308445	Germline mutations in AIP are reported in familial isolated pituitary adenoma kindreds but are associated with reduced penetrance, making it difficult to differentiate between hereditary and sporadic forms.	('Germline mutations', 'Var', (0, 18))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (60, 77))	('familial isolated pituitary adenoma', 'Disease', (42, 77))	('AIP', 'Gene', '9049', (22, 25))	('AIP', 'Gene', (22, 25))	('familial isolated pituitary adenoma', 'Disease', 'MESH:C566321', (42, 77))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (51, 77))
19030	29308445	Germline AIP variants have also been reported in individuals with apparent sporadic pituitary tumors, although ascribing pathogenicity may be challenging because several AIP variants are observed in both disease and control populations.	('variants', 'Var', (13, 21))	('pituitary tumors', 'Disease', (84, 100))	('AIP', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('AIP', 'Gene', '9049', (170, 173))	('AIP', 'Gene', '9049', (9, 12))	('AIP', 'Gene', (170, 173))	('pituitary tumors', 'Disease', 'MESH:D010911', (84, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('reported', 'Reg', (37, 45))
19031	29308445	To investigate the role of AIP in this setting, we compared the frequencies of rare germline missense AIP variants in 1866 individuals with sporadic pituitary adenomas (reported in nine previous studies; ) with those observed in the ExAC cohort.	('AIP', 'Gene', (102, 105))	('variants', 'Var', (106, 114))	('sporadic pituitary adenomas', 'Disease', (140, 167))	('sporadic pituitary adenomas', 'Disease', 'MESH:D010911', (140, 167))	('missense', 'Var', (93, 101))	('AIP', 'Gene', '9049', (102, 105))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (149, 167))	('AIP', 'Gene', (27, 30))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (149, 166))	('AIP', 'Gene', '9049', (27, 30))	('sporadic pituitary adenomas', 'Phenotype', 'HP:0011761', (140, 167))
19032	29308445	Of note, only a small excess of rare missense AIP variants was observed in the tumor cohort compared with the ExAC cohort (odds ratio, 1.4; confidence interval: 1.0 to 2.0), whereas no overall excess was identified when compared with the European ExAC subpopulation, selected to represent the most relevant cohort for comparison (Table 3).	('AIP', 'Gene', '9049', (46, 49))	('tumor', 'Disease', (79, 84))	('AIP', 'Gene', (46, 49))	('variants', 'Var', (50, 58))	('missense', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
19033	29308445	Furthermore, no overrepresentation of several missense AIP variants previously reported as pathogenic (e.g., Arg304Gln) were observed in the tumor group, indicating that such variants are most likely benign or associated with very low penetrance (i.e., <1%).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('Arg304Gln', 'SUBSTITUTION', 'None', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('AIP', 'Gene', '9049', (55, 58))	('Arg304Gln', 'Var', (109, 118))	('AIP', 'Gene', (55, 58))
19036	29308445	For example, the pretest likelihood of identifying at least one rare missense/LOF SNV (AF <0.5%) when employing a 15-gene panel for PPGL was estimated at ~14% (i.e., one in every seven individuals), with ~3% of control individuals harboring a novel singleton variant (i.e., one in every 31 individuals).	('AF', 'Disease', 'MESH:D001281', (87, 89))	('missense/LOF', 'Var', (69, 81))	('ret', 'Gene', (18, 21))	('PPGL', 'Gene', (132, 136))	('ret', 'Gene', '5979', (18, 21))
19039	29308445	Recent studies have highlighted the occurrence of widespread variant misclassification in association with several disorders, which have frequently arisen as a result of ascertainment and reporting bias, a failure to genetically characterize sufficiently large patient and control cohorts, and an overreliance on SNV rarity per se and computational tools in predicting pathogenicity.	('variant misclassification', 'Var', (61, 86))	('association', 'Interaction', (90, 101))	('patient', 'Species', '9606', (261, 268))
19040	29308445	In this study, we used the ExAC cohort to quantify the spectrum and frequency of rare nonsynonymous germline variants occurring in a broad range of genes associated with hereditary endocrine diseases and illustrate the potential utility of this information for improved variant interpretation, both in ascribing potential pathogenicity and in reevaluating estimates of disease penetrance.	('ret', 'Gene', (284, 287))	('ret', 'Gene', '5979', (284, 287))	('hereditary endocrine diseases', 'Disease', 'MESH:D030342', (170, 199))	('endocrine disease', 'Phenotype', 'HP:0000818', (181, 198))	('hereditary endocrine diseases', 'Disease', (170, 199))	('variants', 'Var', (109, 117))
19042	29308445	Although consensus guidelines have been established by the ACMG for the clinical interpretation of germline sequence variants, in many instances an unambiguous assignment of pathogenicity is not possible.	('variants', 'Var', (117, 125))	('ret', 'Gene', (87, 90))	('ret', 'Gene', '5979', (87, 90))
19043	29308445	Although these approaches in isolation do not provide sufficient evidence to categorize variants as pathogenic/likely pathogenic (i.e., enabling categorization only as a variant of uncertain significance), they are frequently cited as supporting evidence of pathogenicity and may ultimately result in a patient being managed as if the variant is disease causing.	('variants', 'Var', (88, 96))	('result in', 'Reg', (291, 300))	('patient', 'Species', '9606', (303, 310))
19044	29308445	Our analyses indicate that variant rarity (i.e., the absence or very low AF of a variant in a control database) together with computational prediction tools frequently have a low specificity for ascribing clinically relevant effects and that relying on such features likely overestimates pathogenicity.	('variant', 'Var', (81, 88))	('variant', 'Var', (27, 34))	('AF', 'Disease', 'MESH:D001281', (73, 75))	('low', 'NegReg', (175, 178))
19046	29308445	For example, variants in genes associated with very low rates of rare variation and intolerant constraint metrics are more likely to be pathogenic than those in genes with greater tolerance of variation, and such information may be useful to the clinician in deciding how to counsel/follow-up a patient with an ambiguous test result (e.g., a variant of uncertain significance).	('patient', 'Species', '9606', (295, 302))	('variants', 'Var', (13, 21))	('pathogenic', 'Reg', (136, 146))
19047	29308445	In the current study, we observed improbably high frequencies of variants reported as pathogenic in several genes (e.g., RET, VHL, and MEN1), indicating their likely prior misclassification and/or overestimates of disease penetrance.	('VHL', 'Disease', (126, 129))	('VHL', 'Disease', 'MESH:D006623', (126, 129))	('RET', 'Gene', '5979', (121, 124))	('variants', 'Var', (65, 73))	('MEN1', 'Gene', (135, 139))	('MEN1', 'Gene', '4221', (135, 139))	('RET', 'Gene', (121, 124))	('pathogenic', 'Reg', (86, 96))
19048	29308445	Indeed, the need to define allele-specific estimates of disease penetrance is an important concept, as recently illustrated for prion disease in which the disease-penetrance of individual PRNP variants ranged from <0.1% to ~100%.	('PRNP', 'Gene', (188, 192))	('variants', 'Var', (193, 201))	('prion', 'Species', '36469', (128, 133))	('prion disease', 'Disease', (128, 141))
19049	29308445	Our studies suggest that similar dynamic ranges of penetrance are likely to occur for alleles associated with endocrine disease (e.g., RET), and quantifying these is essential to enable appropriate patient care (e.g., appropriate guidance on the timing/requirement for prophylactic thyroidectomy in individuals with RET variants associated with MEN2/familial medullary thyroid cancer.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('associated', 'Reg', (329, 339))	('endocrine disease', 'Phenotype', 'HP:0000818', (110, 127))	('RET', 'Gene', '5979', (316, 319))	('patient', 'Species', '9606', (198, 205))	('thyroid cancer', 'Phenotype', 'HP:0002890', (369, 383))	('thyroid cancer', 'Disease', (369, 383))	('variants', 'Var', (320, 328))	('endocrine disease', 'Disease', (110, 127))	('RET', 'Gene', (316, 319))	('RET', 'Gene', '5979', (135, 138))	('thyroid cancer', 'Disease', 'MESH:D013964', (369, 383))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (359, 383))	('endocrine disease', 'Disease', 'MESH:D004700', (110, 127))	('MEN', 'Species', '9606', (345, 348))	('RET', 'Gene', (135, 138))
19050	29308445	For example, the failure to demonstrate enrichment of several individual AIP variants (e.g., Arg304Gln) in a large pituitary tumor cohort compared with the ExAC population cannot exclude an etiological role in disease, although it suggests that any disease relationship is associated with extremely low penetrance and that the overwhelming majority of such variant carriers will not manifest clinical features.	('AIP', 'Gene', (73, 76))	('pituitary tumor', 'Disease', 'MESH:D010911', (115, 130))	('AIP', 'Gene', '9049', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Arg304Gln', 'Var', (93, 102))	('Arg304Gln', 'SUBSTITUTION', 'None', (93, 102))	('pituitary tumor', 'Disease', (115, 130))
19052	29308445	Our results reveal that approximately one in 900 individuals in the ExAC cohort harbored an apparent clinically actionable missense/LOF SNV in one of seven endocrine tumor predisposition genes currently included in the ACMG guidelines for the reporting of incidental genetic findings in clinical exome and genome data, which is considerably higher than the combined prevalence of the associated disorders (estimated to be 1:10,000).	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SNV', 'Var', (136, 139))	('endocrine tumor', 'Disease', 'MESH:D004701', (156, 171))	('endocrine tumor', 'Disease', (156, 171))	('missense/LOF SNV', 'Var', (123, 139))	('endocrine tumor', 'Phenotype', 'HP:0100568', (156, 171))
19054	29308445	This not only highlights the potential clinical burden that increased genetic testing may bring but also emphasizes the need for accurate estimates of variant pathogenicity and penetrance because the potential for patient harm arising through tumor surveillance programs is not insignificant.	('patient', 'Species', '9606', (214, 221))	('genetic testing', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
19058	29308445	For example, the reliability of sequence data for genes with multiple pseudogenes (e.g., SDHA) may be reduced, although in these instances, visual inspection of individual sequence reads covering regions adjacent to the SNVs enabled increased confidence in the variant call .	('variant', 'Var', (261, 268))	('SDHA', 'Gene', '6389', (89, 93))	('increased', 'PosReg', (233, 242))	('SDHA', 'Gene', (89, 93))
19064	28464318	Germline mutations cause congenital central hypoventilation syndrome and predispose to neuroblastoma and Hirschsprung disease.	('Germline mutations', 'Var', (0, 18))	('cause', 'Reg', (19, 24))	('congenital central hypoventilation syndrome', 'Disease', (25, 68))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (105, 125))	('neuroblastoma', 'Phenotype', 'HP:0003006', (87, 100))	('predispose', 'Reg', (73, 83))	('congenital central hypoventilation syndrome', 'Disease', 'MESH:C536209', (25, 68))	('neuroblastoma and Hirschsprung disease', 'Disease', 'MESH:C538119', (87, 125))	('central hypoventilation', 'Phenotype', 'HP:0007110', (36, 59))	('hypoventilation', 'Phenotype', 'HP:0002791', (44, 59))
19078	28464318	Germline PHOX2B mutations cause congenital central hypoventilation syndrome and predispose to neuroblastoma and Hirschsprung disease.	('cause', 'Reg', (26, 31))	('predispose', 'Reg', (80, 90))	('mutations', 'Var', (16, 25))	('hypoventilation', 'Phenotype', 'HP:0002791', (51, 66))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (112, 132))	('PHOX2B', 'Gene', (9, 15))	('neuroblastoma', 'Phenotype', 'HP:0003006', (94, 107))	('congenital central hypoventilation syndrome', 'Disease', (32, 75))	('congenital central hypoventilation syndrome', 'Disease', 'MESH:C536209', (32, 75))	('PHOX2B', 'Gene', '8929', (9, 15))	('neuroblastoma and Hirschsprung disease', 'Disease', 'MESH:C538119', (94, 132))	('central hypoventilation', 'Phenotype', 'HP:0007110', (43, 66))
19296	27729064	The sensitivity of iodine123-MIBG scintigraphy for detecting pheochromocytoma is approximately 90 %, and known factors responsible for false-negative results include extra-adrenal or small adrenal pheochromocytoma, succinate dehydrogenase subunit B (SDHB) gene mutations, drug interference, and extensive necrosis in the tumor.	('pheochromocytoma', 'Disease', (197, 213))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (197, 213))	('pheochromocytoma', 'Disease', 'MESH:D010673', (61, 77))	('tumor', 'Disease', (321, 326))	('extra-adrenal or small adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (166, 213))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('pheochromocytoma', 'Disease', (61, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (61, 77))	('mutations', 'Var', (261, 270))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (189, 213))	('extra-adrenal or small adrenal pheochromocytoma', 'Disease', (166, 213))	('SDHB', 'Gene', '6390', (250, 254))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('succinate dehydrogenase subunit B', 'Gene', '6390', (215, 248))	('necrosis', 'Disease', 'MESH:D009336', (305, 313))	('pheochromocytoma', 'Disease', 'MESH:D010673', (197, 213))	('SDHB', 'Gene', (250, 254))	('small adrenal', 'Phenotype', 'HP:0000835', (183, 196))	('iodine123-MIBG', 'Chemical', '-', (19, 33))	('succinate dehydrogenase subunit B', 'Gene', (215, 248))	('necrosis', 'Disease', (305, 313))
19322	27270552	reported that catecholamines cause myocardial necrosis, focal myofibrillar degeneration, and subsequent fibrous scar formation.	('myocardial necrosis', 'Phenotype', 'HP:0001700', (35, 54))	('myocardial necrosis', 'Disease', 'MESH:D009202', (35, 54))	('focal myofibrillar degeneration', 'Disease', (56, 87))	('catecholamines', 'Var', (14, 28))	('focal myofibrillar degeneration', 'Disease', 'MESH:C580316', (56, 87))	('myocardial necrosis', 'Disease', (35, 54))	('scar', 'Phenotype', 'HP:0100699', (112, 116))	('myofibrillar degeneration', 'Phenotype', 'HP:0003715', (62, 87))	('catecholamines', 'Chemical', 'MESH:D002395', (14, 28))	('fibrous scar formation', 'CPA', (104, 126))
19324	27270552	Moreover, long-term high catecholamine levels can lead to myocardial hypertrophy and heart failure.	('lead to', 'Reg', (50, 57))	('heart failure', 'Disease', (85, 98))	('catecholamine', 'Chemical', 'MESH:D002395', (25, 38))	('high catecholamine levels', 'Phenotype', 'HP:0003334', (20, 45))	('high', 'Var', (20, 24))	('heart failure', 'Phenotype', 'HP:0001635', (85, 98))	('heart failure', 'Disease', 'MESH:D006333', (85, 98))	('myocardial hypertrophy', 'Disease', 'MESH:D006332', (58, 80))	('myocardial hypertrophy', 'Disease', (58, 80))
19336	21958851	[18F]-DA detected less metastatic lesions compared to [18F]-DOPA.	('[18F]-DOPA', 'Chemical', '-', (54, 64))	('metastatic lesions', 'CPA', (23, 41))	('[18F]-DA', 'Chemical', '-', (0, 8))	('[18F]-DA', 'Var', (0, 8))	('less', 'NegReg', (18, 22))
19337	21958851	TLR values for liver metastases were 2.26-2.71 for [18F]-DOPA and 1.83-2.83 for [18F]-DA.	('[18F]-DOPA', 'Var', (51, 61))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('[18F]-DA', 'Chemical', '-', (80, 88))	('[18F]-DA', 'Var', (80, 88))	('metastases', 'Disease', (21, 31))	('[18F]-DOPA', 'Chemical', '-', (51, 61))
19341	21958851	We confirmed [18F]-DA's high affinity for the NET for its uptake and VMAT1 and VMAT2 for its storage and retention in pheochromocytoma cell vesicles.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (118, 134))	('pheochromocytoma', 'Disease', 'MESH:D010673', (118, 134))	('[18F]-DA', 'Chemical', '-', (13, 21))	('uptake', 'MPA', (58, 64))	('[18F]-DA', 'Var', (13, 21))	('pheochromocytoma', 'Disease', (118, 134))
19344	21958851	[18F]-DOPA had overall better sensitivity than [18F]-DA for the detection of metastases.	('better', 'PosReg', (23, 29))	('metastases', 'Disease', (77, 87))	('[18F]-DA', 'Chemical', '-', (47, 55))	('[18F]-DOPA', 'Chemical', '-', (0, 10))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('[18F', 'Var', (0, 4))
19345	21958851	Subcutaneous tumors were localized only with [18F]-DOPA, a finding that may reflect differences in expression of VMAT1 and VMAT2, perhaps similar to some patients with pheochromocytoma where [18F]-DOPA provides better visualization of lesions than [18F]-DA.	('[18F]-DOPA', 'Var', (45, 55))	('pheochromocytoma', 'Disease', 'MESH:D010673', (168, 184))	('VMAT1', 'Gene', (113, 118))	('Subcutaneous tumors', 'Phenotype', 'HP:0001482', (0, 19))	('Subcutaneous tumors', 'Disease', 'MESH:D013352', (0, 19))	('[18F]-DOPA', 'Chemical', '-', (191, 201))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('[18F]-DOPA', 'Chemical', '-', (45, 55))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (168, 184))	('VMAT2', 'Gene', (123, 128))	('patients', 'Species', '9606', (154, 162))	('Subcutaneous tumors', 'Disease', (0, 19))	('pheochromocytoma', 'Disease', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('[18F]-DA', 'Chemical', '-', (248, 256))
19351	21958851	Functional imaging studies with [18F]-DA and [18F]-DOPA have the advantage over anatomical imaging of superior specificity for identification of pheochromocytomas.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (145, 162))	('[18F]-DA', 'Chemical', '-', (32, 40))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('[18F]-DA', 'Var', (32, 40))	('pheochromocytomas', 'Disease', 'MESH:D010673', (145, 162))	('pheochromocytomas', 'Disease', (145, 162))	('[18F]-DOPA', 'Chemical', '-', (45, 55))
19354	21958851	[18F]-DOPA, an analogue of the dopamine precursor, DOPA, is incorporated into tumor cells via the aromatic amino acid transporter.	('rat', 'Species', '10116', (67, 70))	('dopamine', 'Chemical', 'MESH:D004298', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('[18F]-DOPA', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DOPA', 'Chemical', 'MESH:D004295', (6, 10))	('DOPA', 'Chemical', 'MESH:D004295', (51, 55))	('[18F]-DOPA', 'Var', (0, 10))
19411	21958851	For all sections, primary antibodies were detected with species-specific secondary antibodies consisting of donkey anti-rabbit Cy3, anti-goat FITC and anti-sheep DyLight.	('FITC', 'Chemical', 'MESH:D016650', (142, 146))	('anti-sheep DyLight', 'Var', (151, 169))	('goat', 'Species', '9925', (137, 141))	('donkey', 'Species', '9793', (108, 114))	('sheep', 'Species', '9940', (156, 161))	('anti-goat', 'Var', (132, 141))	('rabbit', 'Species', '9986', (120, 126))	('Cy3', 'Chemical', '-', (127, 130))	('detected', 'Reg', (42, 50))
19444	21958851	Thirty to forty liver lesions were localized using [18F]-DA PET in eight out of nine animals, while [18F]-DOPA PET localized more than 50 liver lesions in nine animals (Table 1).	('[18F]-DA', 'Var', (51, 59))	('liver lesions', 'Disease', (16, 29))	('liver lesions', 'Disease', 'MESH:D017093', (138, 151))	('liver lesions', 'Disease', (138, 151))	('[18F]-DOPA', 'Chemical', '-', (100, 110))	('[18F]-DA', 'Chemical', '-', (51, 59))	('liver lesions', 'Disease', 'MESH:D017093', (16, 29))
19445	21958851	Eight adrenal lesions were detected with [18F]-DA in four out of nine animals compared to nine detected in five out of nine with [18F]-DOPA.	('[18F]-DA', 'Chemical', '-', (41, 49))	('[18F]-DOPA', 'Chemical', '-', (129, 139))	('adrenal', 'Disease', (6, 13))	('[18F]-DA', 'Var', (41, 49))
19447	21958851	Desipramine had a stronger inhibiting effect compared to reserpine on accumulation of [18F]-DA during the initial 10-min uptake phase (P<.05; Fig.	('Desipramine', 'Chemical', 'MESH:D003891', (0, 11))	('[18F]-DA', 'Chemical', '-', (86, 94))	('reserpine', 'Chemical', 'MESH:D012110', (57, 66))	('Desipramine', 'Var', (0, 11))	('inhibiting', 'NegReg', (27, 37))	('accumulation', 'MPA', (70, 82))
19453	21958851	Relative to control cells, uptake of [18F]-DOPA after the 10-min incubation period was decreased (P<.001) to 67.37% after desipramine, 14.03% after reserpine, 17.87% after tetrabenazine and 13.47% after the combination of desipramine and reserpine (Fig.	('[18F]-DOPA', 'Chemical', '-', (37, 47))	('decreased', 'NegReg', (87, 96))	('desipramine', 'Chemical', 'MESH:D003891', (222, 233))	('desipramine', 'Chemical', 'MESH:D003891', (122, 133))	('uptake of [18F]-DOPA', 'MPA', (27, 47))	('desipramine', 'Var', (122, 133))	('reserpine', 'Chemical', 'MESH:D012110', (148, 157))	('tetrabenazine', 'Chemical', 'MESH:D013747', (172, 185))	('reserpine', 'Chemical', 'MESH:D012110', (238, 247))
19463	21958851	While [18F]-DA and [18F]-DOPA PET performed equally well for the detection of ovarian metastatic tumors, [18F]-DOPA PET showed superiority to [18F]-DA PET in the detection of liver, lung and s.c. tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('lung', 'Disease', (182, 186))	('[18F]-DOPA', 'Chemical', '-', (105, 115))	('ovarian metastatic tumors', 'Disease', (78, 103))	('[18F]-DOPA', 'Chemical', '-', (19, 29))	('tumors', 'Disease', (196, 202))	('[18F]-DOPA', 'Var', (105, 115))	('liver', 'Disease', (175, 180))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ovarian metastatic tumors', 'Disease', 'MESH:D010051', (78, 103))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('[18F]-DA', 'Chemical', '-', (6, 14))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('[18F]-DA', 'Chemical', '-', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
19464	21958851	In particular, s.c. tumors were detected only with [18F]-DOPA PET.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (20, 26))	('[18F]-DOPA', 'Var', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('[18F]-DOPA', 'Chemical', '-', (51, 61))
19468	21958851	As supported by several clinical studies functional imaging using [18F]-DA and [18F]-DOPA PET is a useful tool for diagnostic localization of pheochromocytomas and paragangliomas (extra-adrenal pheochromocytomas).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('[18F]-DA', 'Chemical', '-', (66, 74))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (142, 159))	('paragangliomas', 'Phenotype', 'HP:0002668', (164, 178))	('extra-adrenal pheochromocytomas', 'Disease', (180, 211))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (194, 211))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (194, 210))	('extra-adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (180, 211))	('[18F]-DOPA', 'Chemical', '-', (79, 89))	('[18F]-DOPA', 'Var', (79, 89))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (142, 178))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (186, 211))
19474	21958851	For example, in patients with malignant paragangliomas due to succinate dehydrogenase subunit B mutations, [18F]-DA is superior to [18F]-DOPA for localization of metastases (reverse to the present animal model of pheochromocytoma), whereas in other patients with so called 'head-and-neck' paragangliomas, [18F]-DOPA is superior to [18F]-DA.	('metastases', 'Disease', (162, 172))	('patients', 'Species', '9606', (16, 24))	('malignant paragangliomas', 'Disease', (30, 54))	('paragangliomas', 'Disease', 'MESH:D010235', (40, 54))	('pheochromocytoma', 'Disease', (213, 229))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (213, 229))	('mutations', 'Var', (96, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (40, 54))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (30, 54))	('paragangliomas', 'Disease', (289, 303))	('[18F]-DOPA', 'Chemical', '-', (131, 141))	('[18F]-DOPA', 'Chemical', '-', (305, 315))	('patients', 'Species', '9606', (249, 257))	('localization', 'MPA', (146, 158))	('paragangliomas', 'Disease', (40, 54))	('[18F]-DA', 'Chemical', '-', (331, 339))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('succinate', 'Gene', (62, 71))	('paragangliomas', 'Disease', 'MESH:D010235', (289, 303))	('paragangliomas', 'Phenotype', 'HP:0002668', (289, 303))	('pheochromocytoma', 'Disease', 'MESH:D010673', (213, 229))	('[18F]-DA', 'Chemical', '-', (107, 115))
19487	21958851	This is well documented from previous studies where the uptake of [18F]-DOPA in the central nervous dopaminergic system depended on the presence VMAT2.	('dopamine', 'Chemical', 'MESH:D004298', (100, 108))	('presence', 'Var', (136, 144))	('depended', 'Reg', (120, 128))	('[18F]-DOPA', 'Chemical', '-', (66, 76))
19489	21958851	Second, we did not study any presence and function of the cell membrane amino acid transporter system that is known to allow l-DOPA to enter a pheochromocytoma cell; lastly, the absence of in vivo experiments manipulating (e.g., inhibiting) NET, VMAT1 and VMAT2, and amino acid transporters.	('inhibiting', 'NegReg', (229, 239))	('VMAT1', 'MPA', (246, 251))	('NET', 'MPA', (241, 244))	('manipulating', 'Var', (209, 221))	('pheochromocytoma', 'Disease', (143, 159))	('pheochromocytoma', 'Disease', 'MESH:D010673', (143, 159))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('l-DOPA', 'Chemical', 'MESH:D007980', (125, 131))	('VMAT2', 'Enzyme', (256, 261))	('amino acid transporters', 'MPA', (267, 290))
19491	21958851	In summary, this is the first study to compare multi-imaging modalities with [18F]-DOPA and [18F]-DA PET, microCT and MRI for detection of organ metastatic and s.c. lesions in nude mice model of pheochromocytoma.	('[18F]-DOPA', 'Chemical', '-', (77, 87))	('[18F]-DA', 'Chemical', '-', (92, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (195, 211))	('[18F]-DA', 'Var', (92, 100))	('pheochromocytoma', 'Disease', (195, 211))	('pheochromocytoma', 'Disease', 'MESH:D010673', (195, 211))	('nude mice', 'Species', '10090', (176, 185))	('organ metastatic', 'CPA', (139, 155))
19547	24616770	Surrounding the tumour lobules were several spindle cells S-100+ (sustentacular cells).	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Disease', 'MESH:D009369', (16, 22))	('tumour', 'Disease', (16, 22))	('S-100+', 'Var', (58, 64))
19563	24616770	Owing to the high prevalence of mutations in the SDH gene in people suffering from paraganglioma, genetic testing is mandatory.	('SDH', 'Gene', '10993', (49, 52))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('SDH', 'Gene', (49, 52))	('paraganglioma', 'Disease', (83, 96))	('mutations', 'Var', (32, 41))	('people', 'Species', '9606', (61, 67))	('paraganglioma', 'Disease', 'MESH:D010235', (83, 96))
19636	19432956	Mutations in 3 of the 4 genes encoding subunits of succinate dehydrogenase (SDH, complex II in the mitochondrial respiratory chain) have been implicated in the familial forms of the disease: SDHB, SDHC, and SDHD .	('SDHC', 'Gene', '6391', (197, 201))	('SDHD', 'Gene', (207, 211))	('SDHD', 'Gene', '6392', (207, 211))	('implicated', 'Reg', (142, 152))	('SDHB', 'Gene', (191, 195))	('succinate dehydrogenase', 'Gene', '6390', (51, 74))	('SDH', 'Gene', '6390', (76, 79))	('SDH', 'Gene', '6390', (207, 210))	('SDH', 'Gene', '6390', (191, 194))	('SDH', 'Gene', '6390', (197, 200))	('succinate dehydrogenase', 'Gene', (51, 74))	('Mutations', 'Var', (0, 9))	('SDHC', 'Gene', (197, 201))	('SDH', 'Gene', (76, 79))	('SDH', 'Gene', (191, 194))	('SDH', 'Gene', (197, 200))	('SDHB', 'Gene', '6390', (191, 195))	('SDH', 'Gene', (207, 210))
19640	19432956	Mutations in SDHB, SDHC and SDHD are also implicated in the formation of phaeochromocytomas, tumors arising in cells derived from the neural crest in the adrenal medulla.	('SDHD', 'Gene', (28, 32))	('SDHC', 'Gene', '6391', (19, 23))	('SDHD', 'Gene', '6392', (28, 32))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (73, 91))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SDHB', 'Gene', '6390', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('tumors', 'Disease', (93, 99))	('phaeochromocytomas', 'Disease', (73, 91))	('implicated', 'Reg', (42, 52))	('SDHC', 'Gene', (19, 23))
19656	19432956	Eighteen paraganglioma cases were selected: 7 cases with a known D92Y founder mutation in the SDHD gene, 6 cases from the family with significant linkage tot the PGL2 locus on 11q13, and 5 sporadic cases.	('paraganglioma', 'Disease', (9, 22))	('SDHD', 'Gene', (94, 98))	('D92Y', 'Var', (65, 69))	('paraganglioma', 'Disease', 'MESH:D010235', (9, 22))	('PGL2', 'Gene', '54949', (162, 166))	('D92Y', 'Mutation', 'rs80338845', (65, 69))	('PGL2', 'Gene', (162, 166))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('SDHD', 'Gene', '6392', (94, 98))
19657	19432956	The latter were defined as 'sporadic' because mutation scanning of SDHB, SDHC, and SDHD was negative, while the family histories of these cases were negative for HN-paraganglioma or any of the other clinical stigmata that would suggest the involvement of VHL, NF1 or the RET gene.	('HN-paraganglioma', 'Disease', (162, 178))	('SDHB', 'Gene', '6390', (67, 71))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('SDHC', 'Gene', (73, 77))	('NF1', 'Gene', (260, 263))	('RET', 'Gene', '5979', (271, 274))	('SDHB', 'Gene', (67, 71))	('RET', 'Gene', (271, 274))	('NF1', 'Gene', '4763', (260, 263))	('SDHC', 'Gene', '6391', (73, 77))	('VHL', 'Gene', (255, 258))	('SDHD', 'Gene', '6392', (83, 87))	('involvement', 'Reg', (240, 251))	('mutation', 'Var', (46, 54))	('VHL', 'Gene', '7428', (255, 258))	('SDHD', 'Gene', (83, 87))	('HN-paraganglioma', 'Disease', 'MESH:D010235', (162, 178))
19658	19432956	SDHB, SDHC, and SDHD genes were scanned for the presence of mutations at the laboratory for DNA diagnostics at the LUMC.	('SDHC', 'Gene', (6, 10))	('SDHD', 'Gene', '6392', (16, 20))	('SDHC', 'Gene', '6391', (6, 10))	('SDHD', 'Gene', (16, 20))	('SDHB', 'Gene', '6390', (0, 4))	('mutations', 'Var', (60, 69))	('SDHB', 'Gene', (0, 4))
19659	19432956	All exonic regions of these genes were tested by direct sequencing using the Sanger method on an ABI 3177 Genetic Analyzer, starting with the exon containing the known Dutch founder mutations in SDHD followed by exons that had previously been found to contain pathogenic mutations in SDHD, SDHB, and SDHC (in that order) in the Dutch population.	('SDHD', 'Gene', '6392', (284, 288))	('SDHB', 'Gene', '6390', (290, 294))	('SDHD', 'Gene', (284, 288))	('pathogenic', 'Reg', (260, 270))	('SDHB', 'Gene', (290, 294))	('SDHD', 'Gene', (195, 199))	('SDHD', 'Gene', '6392', (195, 199))	('SDHC', 'Gene', (300, 304))	('SDHC', 'Gene', '6391', (300, 304))	('mutations', 'Var', (271, 280))	('mutations', 'Var', (182, 191))
19660	19432956	More recently, the sporadic, mutation-negative cases were also examined by MLPA for the presence of large deletions in SDHB, SDHC, and SDHD.	('SDHD', 'Gene', '6392', (135, 139))	('deletions', 'Var', (106, 115))	('SDHD', 'Gene', (135, 139))	('SDHB', 'Gene', '6390', (119, 123))	('SDHC', 'Gene', (125, 129))	('SDHC', 'Gene', '6391', (125, 129))	('SDHB', 'Gene', (119, 123))
19710	19432956	The mechanism of HIF1alpha induction in tumors with SDH mutations has recently been shown to be succinate accumulation resulting from loss of SDH function, leading to inhibition of HIF-alpha-prolyl hydroxylases and thus to elevated HIF1alpha activity.	('SDH', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('succinate', 'Chemical', 'MESH:D019802', (96, 105))	('tumors', 'Disease', (40, 46))	('mutations', 'Var', (56, 65))	('SDH', 'Gene', '6390', (142, 145))	('HIF1alpha', 'Gene', '3091', (232, 241))	('HIF1alpha', 'Gene', '3091', (17, 26))	('loss', 'NegReg', (134, 138))	('HIF1alpha', 'Gene', (232, 241))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('HIF1alpha', 'Gene', (17, 26))	('activity', 'MPA', (242, 250))	('HIF-alpha-prolyl hydroxylases', 'Enzyme', (181, 210))	('SDH', 'Gene', (142, 145))	('elevated', 'PosReg', (223, 231))	('SDH', 'Gene', '6390', (52, 55))	('inhibition', 'NegReg', (167, 177))	('function', 'MPA', (146, 154))	('succinate accumulation', 'MPA', (96, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
19713	19432956	PGL2 - and SDHD -linked tumors also appear to share the features of increased HIF1alpha activity and upregulation of HIF1alpha targets that results from SDH inactivity.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('inactivity', 'Var', (157, 167))	('upregulation', 'PosReg', (101, 113))	('HIF1alpha', 'Gene', '3091', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('SDH', 'Gene', (11, 14))	('SDHD -linked tumors', 'Disease', 'MESH:D009369', (11, 30))	('SDHD -linked tumors', 'Disease', (11, 30))	('PGL2', 'Gene', '54949', (0, 4))	('SDH', 'Gene', (153, 156))	('activity', 'MPA', (88, 96))	('PGL2', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (153, 156))	('HIF1alpha', 'Gene', (117, 126))	('HIF1alpha', 'Gene', '3091', (117, 126))	('HIF1alpha', 'Gene', (78, 87))	('increased', 'PosReg', (68, 77))	('SDH', 'Gene', '6390', (11, 14))
19714	19432956	These findings may hold important clues for the function of the yet unidentified PGL2 gene on 11q13, as a defect in the yet unidentified PGL2 gene seems to have consequences similar to a mutation in the SDHD gene.	('PGL2', 'Gene', '54949', (81, 85))	('PGL2', 'Gene', (137, 141))	('PGL2', 'Gene', '54949', (137, 141))	('PGL2', 'Gene', (81, 85))	('SDHD', 'Gene', '6392', (203, 207))	('SDHD', 'Gene', (203, 207))	('defect', 'Var', (106, 112))
19730	19432956	This suggests that a defect in the yet unidentified PGL2 gene, like a mutation in the SDHD gene, disrupts normal SDH function.	('SDH', 'Gene', (113, 116))	('SDH', 'Gene', '6390', (86, 89))	('SDHD', 'Gene', (86, 90))	('PGL2', 'Gene', '54949', (52, 56))	('SDH', 'Gene', (86, 89))	('disrupts', 'NegReg', (97, 105))	('PGL2', 'Gene', (52, 56))	('SDH', 'Gene', '6390', (113, 116))	('mutation', 'Var', (70, 78))	('SDHD', 'Gene', '6392', (86, 90))
19750	33920661	Notably, the two unique cell lines PTJ64i and PTJ86i were previously established in our laboratory from two patients with paraganglioma, a rare tumor that is poorly responsive to standard chemotherapy, for which new therapeutic agents are urgently needed, and which may benefit from an orphan designation.	('tumor', 'Disease', (144, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (122, 135))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('paraganglioma', 'Disease', (122, 135))	('PTJ86i', 'Var', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('paraganglioma', 'Disease', 'MESH:D010235', (122, 135))	('patients', 'Species', '9606', (108, 116))	('PTJ64i', 'Var', (35, 41))
19756	33920661	The effects of 15 benzimidazole-based anthelmintics (Figure 1) on the viability of six cancer cell lines (AsPC-1, BxPC-3, PTJ64i, PTJ86i, HT-29 and SW480) were analyzed by MTT.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('PTJ64i', 'Var', (122, 128))	('BxPC-3', 'CellLine', 'CVCL:0186', (114, 120))	('MTT', 'Chemical', 'MESH:C070243', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SW480', 'CellLine', 'CVCL:0546', (148, 153))	('HT-29', 'CellLine', 'CVCL:0320', (138, 143))	('benzimidazole', 'Chemical', 'MESH:C031000', (18, 31))	('AsPC-1', 'CellLine', 'CVCL:0152', (106, 112))	('PTJ86i', 'Var', (130, 136))
19780	33920661	In addition, (R)-oxfendazole was also consistently active in reducing the viability of PTJ64i e PTJ86i paraganglioma cell lines, with IC50 values of 10.02 muM and 12.41 muM, respectively, and in HT-29 colorectal cancer cell line, displaying an IC50 of 10.02 muM.	('reducing', 'NegReg', (61, 69))	('(R)-oxfendazole', 'Chemical', '-', (13, 28))	('paraganglioma', 'Disease', 'MESH:D010235', (103, 116))	('PTJ86i', 'Var', (96, 102))	('HT-29 colorectal cancer', 'Disease', 'MESH:D015179', (195, 218))	('HT-29 colorectal cancer', 'Disease', (195, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('paraganglioma', 'Disease', (103, 116))	('viability', 'CPA', (74, 83))	('PTJ64i', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
19805	33920661	So, the inhibition of the VEGF-2 receptor could be effective in impairing tumor vascularization, also promoting a "normal" vasculature within the tumor and leading to the efficient delivery of antitumor drugs.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('impairing tumor', 'Disease', 'MESH:D060825', (64, 79))	('VEGF-2', 'Gene', (26, 32))	('leading to', 'Reg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('impairing tumor', 'Disease', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('promoting', 'PosReg', (102, 111))	('inhibition', 'Var', (8, 18))	('tumor', 'Disease', (197, 202))	('delivery of', 'MPA', (181, 192))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
19822	33920661	IC50 values of the six less active benzimidazoles on pancreatic (AsPC-1, BxPC-3), paraganglioma (PTJ64i, PTJ86i), and colorectal (HT-29, SW480) cancer cell lines.	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('BxPC-3', 'CellLine', 'CVCL:0186', (73, 79))	('colorectal', 'Disease', (118, 128))	('pancreatic', 'Disease', 'MESH:D010195', (53, 63))	('AsPC-1', 'CellLine', 'CVCL:0152', (65, 71))	('paraganglioma', 'Disease', (82, 95))	('pancreatic', 'Disease', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('SW480', 'CellLine', 'CVCL:0546', (137, 142))	('colorectal', 'Disease', 'MESH:D015179', (118, 128))	('HT-29', 'CellLine', 'CVCL:0320', (130, 135))	('cancer', 'Disease', (144, 150))	('paraganglioma', 'Disease', 'MESH:D010235', (82, 95))	('benzimidazoles', 'Chemical', 'MESH:D001562', (35, 49))	('PTJ86i', 'Var', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('IC50', 'MPA', (0, 4))
19931	33157340	One month after surgery, the blood pressure remained normal without any antihypertensive therapy, the patient had less invalid intermittent claudication with a walking perimeter >200 m but still have intermittent abdominal pain.	('intermittent abdominal pain', 'Phenotype', 'HP:0002574', (200, 227))	('abdominal pain', 'Phenotype', 'HP:0002027', (213, 227))	('>200', 'Var', (178, 182))	('abdominal pain', 'Disease', (213, 227))	('patient', 'Species', '9606', (102, 109))	('hypertensive', 'Disease', 'MESH:D006973', (76, 88))	('abdominal pain', 'Disease', 'MESH:D015746', (213, 227))	('intermittent claudication', 'Phenotype', 'HP:0004417', (127, 152))	('hypertensive', 'Disease', (76, 88))	('pain', 'Phenotype', 'HP:0012531', (223, 227))
19948	33157340	On the other hand, irrecognition of renal artery stenosis in a patient with pheochromocytoma may lead to persistent hypertension after tumoral resection.	('irrecognition', 'Var', (19, 32))	('tumoral', 'Disease', 'MESH:D009369', (135, 142))	('hypertension', 'Disease', 'MESH:D006973', (116, 128))	('pheochromocytoma', 'Disease', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('renal artery stenosis', 'Disease', 'MESH:D012078', (36, 57))	('artery stenosis', 'Phenotype', 'HP:0100545', (42, 57))	('pheochromocytoma', 'Disease', 'MESH:D010673', (76, 92))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (76, 92))	('hypertension', 'Disease', (116, 128))	('hypertension', 'Phenotype', 'HP:0000822', (116, 128))	('patient', 'Species', '9606', (63, 70))	('renal artery stenosis', 'Disease', (36, 57))	('lead to', 'Reg', (97, 104))	('renal artery stenosis', 'Phenotype', 'HP:0001920', (36, 57))	('tumoral', 'Disease', (135, 142))
19970	31996412	Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known.	('VHL', 'Gene', (54, 57))	('paraganglioma', 'Phenotype', 'HP:0002668', (309, 322))	('VHL', 'Gene', (275, 278))	('tumours of von Hippel-Lindau disease', 'Disease', (80, 116))	('VHL', 'Gene', '7428', (230, 233))	('tumours of von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (80, 116))	('patients', 'Species', '9606', (242, 250))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (256, 287))	('paraganglioma', 'Phenotype', 'HP:0002668', (134, 147))	('VHL', 'Gene', '7428', (54, 57))	('mutations', 'Var', (174, 183))	('VHL', 'Gene', '7428', (275, 278))	('paraganglioma or pheochromocytoma', 'Disease', (309, 342))	('paraganglioma or pheochromocytoma', 'Disease', 'MESH:D010673', (309, 342))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('paraganglioma', 'Disease', (309, 322))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('paraganglioma', 'Disease', 'MESH:D010235', (309, 322))	('patients', 'Species', '9606', (66, 74))	('patients', 'Species', '9606', (295, 303))	('paraganglioma', 'Disease', (134, 147))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (326, 342))	('VHL', 'Gene', (230, 233))	('paraganglioma', 'Disease', 'MESH:D010235', (134, 147))
19975	31996412	VHL E1' cryptic exon mutations contribute to 1.32% (1/76) of 'VHL-like' cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL.	('VHL', 'Gene', (177, 180))	('VHL', 'Gene', '7428', (177, 180))	('VHL', 'Gene', (0, 3))	('PPGL', 'Disease', (272, 276))	('VHL', 'Gene', (62, 65))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (62, 65))	('patients', 'Species', '9606', (141, 149))	('mutations', 'Var', (21, 30))
19980	31996412	Indeed, to date, approximately 17 susceptibility genes have been reported but two thirds of identified mutations are found in SDHB, SDHD and VHL genes.	('mutations', 'Var', (103, 112))	('SDHD', 'Gene', (132, 136))	('VHL', 'Gene', '7428', (141, 144))	('SDHB', 'Gene', '6390', (126, 130))	('SDHB', 'Gene', (126, 130))	('SDHD', 'Gene', '6392', (132, 136))	('VHL', 'Gene', (141, 144))
19989	31996412	Germline DNA from 'VHL-like', 'Multiple VHL tumours' and 'Single VHL tumour' cohorts had been previously tested for VHL gene by Sanger sequencing or Next Generation Sequencing and large rearrangements by MLPA or QMPSF.	('VHL', 'Gene', '7428', (65, 68))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('VHL', 'Gene', (40, 43))	('VHL tumours', 'Disease', (40, 51))	('VHL', 'Gene', (19, 22))	('VHL', 'Gene', '7428', (40, 43))	('VHL', 'Gene', (116, 119))	('rearrangements', 'Var', (186, 200))	('VHL', 'Gene', '7428', (19, 22))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('VHL', 'Gene', '7428', (116, 119))	('VHL tumours', 'Disease', 'MESH:D006623', (40, 51))	('Single VHL tumour', 'Disease', (58, 75))	('VHL', 'Gene', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('Single VHL tumour', 'Disease', 'MESH:D006623', (58, 75))
19994	31996412	Loss of heterozygosity (LOH) was evaluated by (1) Sanger sequencing of the E1' cryptic exon of VHL by mutation-specific primers and (2) microsatellite analysis on D3S1537, D3S1038, D3S1317 D3S3547, D3S3727 as previously described.	('VHL', 'Gene', (95, 98))	('VHL', 'Gene', '7428', (95, 98))	('D3S1038', 'Var', (172, 179))	('D3S3727', 'Var', (198, 205))	('D3S1317 D3S3547', 'Var', (181, 196))	('D3S1537', 'Var', (163, 170))
19995	31996412	VHL gene deletion on tumour DNA was assessed with the SALSA MLPA P016 VHL probemix (MRC-Holland).	('VHL', 'Gene', (70, 73))	('VHL', 'Gene', '7428', (70, 73))	('deletion', 'Var', (9, 17))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('MRC', 'CellLine', 'CVCL:0440', (84, 87))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('VHL', 'Gene', (0, 3))	('tumour', 'Disease', (21, 27))	('VHL', 'Gene', '7428', (0, 3))
19998	31996412	RNA was extracted from paraffin embedded tumours of six control PPGL (3 NF1-related, 2 RET-related and 1 TMEM127-related PPGL), 5 VHL- related PPGL (all carrying a missense mutation in VHL gene) and patients #3 and #10 PPGL by using the Maxwell 16 LEV RNA FFPE Purification Kit (Promega).	('missense mutation', 'Var', (164, 181))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('VHL', 'Gene', (130, 133))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('VHL', 'Gene', (185, 188))	('patients', 'Species', '9606', (199, 207))	('VHL', 'Gene', '7428', (130, 133))	('paraffin', 'Chemical', 'MESH:D010232', (23, 31))	('tumours', 'Disease', (41, 48))	('VHL', 'Gene', '7428', (185, 188))
20006	31996412	We identified a rare germline genetic variant (minor allele frequency <1%) in the E1' VHL cryptic exon in 12 patients (1%).	('variant', 'Var', (38, 45))	("E1' VHL", 'Gene', '6080;7428', (82, 89))	("E1' VHL", 'Gene', (82, 89))	('patients', 'Species', '9606', (109, 117))
20009	31996412	None of these variants was found in a control cohort of 198 European subjects without VHL manifestations.	('VHL', 'Gene', (86, 89))	('variants', 'Var', (14, 22))	('VHL', 'Gene', '7428', (86, 89))
20010	31996412	Seven patients (patients #2 to #8) (0.6%) carried the same rare variant of uncertain significance (VUS), c.340+578C>T which is referenced in dbSNP as rs139622356 and has been previously reported in the Genome Aggregation Database (gnomAD).	('c.340+578C>T', 'Mutation', 'rs139622356', (105, 117))	('c.340+578C>T', 'Var', (105, 117))	('rs139622356', 'Var', (150, 161))	('rs139622356', 'Mutation', 'rs139622356', (150, 161))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (6, 14))
20015	31996412	None of the four patients with a PPGL and an E1' VUS have developed VHL spectrum tumour(s) during their follow-up and none of them had family history of VHL disease (table 2); however, segregation analysis was only performed in patient #9.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('VHL', 'Gene', (153, 156))	('PPGL', 'Var', (33, 37))	('VHL disease', 'Disease', (153, 164))	('VHL', 'Gene', '7428', (153, 156))	('patient', 'Species', '9606', (17, 24))	('VHL', 'Gene', (68, 71))	('tumour', 'Disease', (81, 87))	('patients', 'Species', '9606', (17, 25))	('VHL', 'Gene', '7428', (68, 71))	('VHL disease', 'Disease', 'MESH:D006623', (153, 164))	('patient', 'Species', '9606', (228, 235))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
20016	31996412	The proband's mother did carry the variant and had a pancreatic cyst and multiple vertebral body haemangiomas which both are evocating of VHL disease.	('VHL disease', 'Disease', (138, 149))	('pancreatic cyst and multiple vertebral body haemangiomas', 'Disease', 'MESH:D010181', (53, 109))	('variant', 'Var', (35, 42))	('VHL disease', 'Disease', 'MESH:D006623', (138, 149))	('pancreatic cyst', 'Phenotype', 'HP:0001737', (53, 68))
20019	31996412	In tumour DNA of patient #10, which harbours the c.340+682T>C variant, we identified a second variant in the exon 3 of VHL (c.482G>A; p.Arg161Gln), known to be pathogenic (figure 1).	('c.482G>A', 'Mutation', 'rs760434926', (124, 132))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('c.340+682T>C', 'Var', (49, 61))	('VHL', 'Gene', (119, 122))	('patient', 'Species', '9606', (17, 24))	('c.482G>A; p.Arg161Gln', 'Var', (124, 145))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('VHL', 'Gene', '7428', (119, 122))	('tumour', 'Disease', (3, 9))	('c.340+682T>C', 'Mutation', 'c.340+682T>C', (49, 61))	('p.Arg161Gln', 'Mutation', 'rs730882035', (134, 145))
20021	31996412	In the absence of LOH, this exon 3 variant may function as the second VHL hit in this tumour.	('VHL', 'Gene', (70, 73))	('VHL', 'Gene', '7428', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('variant', 'Var', (35, 42))	('tumour', 'Disease', (86, 92))
20031	31996412	We assessed the expression of two different VHL mRNA: the mRNA containing the exons 1 and 2 (E1-E2), which will lead with the exon 3 to the expression of the two main VHL proteins (pVHL213 and pVHL160) and VHL mRNA containing the exon 1 and E1' (E1-E1'), which was previously described as increased in tumour or in lymphoblastoid cell lines of patients with E1' mutation.	('exon', 'Var', (230, 234))	('VHL', 'Gene', (194, 197))	('increased', 'PosReg', (289, 298))	('VHL', 'Gene', (44, 47))	('VHL', 'Gene', (182, 185))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	("E1'", 'Var', (241, 244))	('VHL', 'Gene', '7428', (194, 197))	('VHL', 'Gene', (206, 209))	('VHL', 'Gene', (167, 170))	('VHL', 'Gene', '7428', (44, 47))	('VHL', 'Gene', '7428', (182, 185))	('tumour', 'Disease', 'MESH:D009369', (302, 308))	('VHL', 'Gene', '7428', (167, 170))	('patients', 'Species', '9606', (344, 352))	('tumour', 'Disease', (302, 308))	('VHL', 'Gene', '7428', (206, 209))
20032	31996412	In normal condition, this VHL E1-E1' mRNA is degraded by nonsense-mediated decay (NMD), and in this pathological condition, NMD may be overwhelmed.	('nonsense-mediated decay', 'Var', (57, 80))	('degraded', 'NegReg', (45, 53))	('VHL', 'Gene', (26, 29))	('VHL', 'Gene', '7428', (26, 29))
20035	31996412	Altogether, these data provide evidence that this VHL E1' mutation (c.340+682T>C) is a pathogenic mutation that combined with the second mutation (c.482G>A; p.Arg161Gln) induce tumorigenesis.	('p.Arg161Gln', 'Mutation', 'rs730882035', (157, 168))	('tumorigenesis', 'CPA', (177, 190))	('VHL', 'Gene', (50, 53))	('c.482G>A; p.Arg161Gln', 'Var', (147, 168))	('VHL', 'Gene', '7428', (50, 53))	('c.340+682T>C', 'Mutation', 'c.340+682T>C', (68, 80))	('c.482G>A', 'Mutation', 'rs760434926', (147, 155))	('c.340+682T>C', 'Var', (68, 80))	('induce', 'PosReg', (170, 176))
20036	31996412	Finally, 23 patients carry the c.340+648T>C (rs73024533) variant, previously described in dbSNP, at an heterozygous state.	('patients', 'Species', '9606', (12, 20))	('rs73024533', 'Mutation', 'rs73024533', (45, 55))	('c.340+648T>C (rs73024533', 'Var', (31, 55))	('c.340+648T>C', 'Mutation', 'rs73024533', (31, 43))	('rs73024533', 'Var', (45, 55))
20038	31996412	E1' mutations were previously described by Lenglet et al in eight families, either with erythrocytosis or VHL disease.	("E1'", 'Gene', (0, 3))	('erythrocytosis', 'Phenotype', 'HP:0001901', (88, 102))	('erythrocytosis or VHL disease', 'Disease', 'MESH:D006623', (88, 117))	('mutations', 'Var', (4, 13))	('erythrocytosis or VHL disease', 'Disease', (88, 117))
20039	31996412	These mutations led to an abnormal VHL mRNA with the insertion of the E1' in the transcript and to mRNA degradation by NMD and to global defect in VHL protein expression.	('defect', 'NegReg', (137, 143))	('insertion', 'Var', (53, 62))	('led to', 'Reg', (16, 22))	('expression', 'MPA', (159, 169))	('VHL', 'Gene', (147, 150))	('VHL', 'Gene', (35, 38))	('VHL', 'Gene', '7428', (147, 150))	('mRNA degradation', 'MPA', (99, 115))	('VHL', 'Gene', '7428', (35, 38))
20040	31996412	In our large international study, we identified four new germline variants in E1' VHL gene and we classified two of them as pathogenic, representing 1.3% of 'VHL-like' cohort (1/76 patients) and 0.11% of 'PPGL' cohort (1/946 patients).	('patients', 'Species', '9606', (225, 233))	("E1' VHL", 'Gene', '6080;7428', (78, 85))	("E1' VHL", 'Gene', (78, 85))	('variants', 'Var', (66, 74))	('VHL', 'Gene', (82, 85))	('VHL', 'Gene', (158, 161))	('patients', 'Species', '9606', (181, 189))	('VHL', 'Gene', '7428', (82, 85))	('VHL', 'Gene', '7428', (158, 161))
20043	31996412	Interestingly, multiple vertebral body haemangiomas are rare in VHL disease but have been described in patients with Chuvash polycythemia, a disease secondary to a recurrent germline biallelic mutation in VHL gene (c.598C>T, p.Arg200Trp).	('polycythemia', 'Phenotype', 'HP:0001901', (125, 137))	('VHL', 'Gene', (205, 208))	('VHL disease', 'Disease', 'MESH:D006623', (64, 75))	('vertebral body haemangiomas', 'Disease', (24, 51))	('p.Arg200Trp', 'Mutation', 'rs28940298', (225, 236))	('VHL', 'Gene', '7428', (205, 208))	('Chuvash polycythemia', 'Disease', 'MESH:C563918', (117, 137))	('VHL', 'Gene', (64, 67))	('vertebral body haemangiomas', 'Disease', 'MESH:C536543', (24, 51))	('c.598C>T', 'Var', (215, 223))	('p.Arg200Trp', 'Var', (225, 236))	('c.598C>T', 'Mutation', 'rs28940298', (215, 223))	('VHL', 'Gene', '7428', (64, 67))	('VHL disease', 'Disease', (64, 75))	('patients', 'Species', '9606', (103, 111))	('Chuvash polycythemia', 'Disease', (117, 137))
20044	31996412	Our data suggest incomplete penetrance of E1' VHL mutations, as it was previously described for the SDHA gene-another PPGL susceptibility gene- mutations that exhibit a relatively high allele frequency in gnomAD.	('SDHA', 'Gene', (100, 104))	('mutations', 'Var', (50, 59))	("E1' VHL", 'Gene', (42, 49))	("E1' VHL", 'Gene', '6080;7428', (42, 49))	('SDHA', 'Gene', '6389', (100, 104))
20045	31996412	We have identified the same variant c.340+578C>T (rs139622356) in seven patients, but our tumour analyses were not able lead to the classification of this variant in a pathogenic variant.	('c.340+578C>T', 'Mutation', 'rs139622356', (36, 48))	('rs139622356', 'Mutation', 'rs139622356', (50, 61))	('c.340+578C>T', 'Var', (36, 48))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))	('patients', 'Species', '9606', (72, 80))
20046	31996412	Indeed in one tumour with this variant, we identified the E1-E1' mRNA which suggest that the variant is pathogenic.	('tumour', 'Disease', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumour', 'Disease', 'MESH:D009369', (14, 20))	('variant', 'Var', (31, 38))	('variant', 'Var', (93, 100))
20049	31996412	All these data suggest that this variant could be either a pathogenic variant that is not implicated in the PPGL of our patient because of the lack of LOH/second VHL mutation, or a modifier variant contributing potentially to an 8.5-fold risk (95% CI 4.4 to 14.3, p<0.0001) for development of PPGL or VHL tumours.	('VHL', 'Gene', (162, 165))	('VHL', 'Gene', (301, 304))	('VHL', 'Gene', '7428', (162, 165))	('VHL tumours', 'Disease', (301, 312))	('patient', 'Species', '9606', (120, 127))	('VHL', 'Gene', '7428', (301, 304))	('variant', 'Var', (33, 40))	('VHL tumours', 'Disease', 'MESH:D006623', (301, 312))	('PPGL', 'Disease', (293, 297))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('tumours', 'Phenotype', 'HP:0002664', (305, 312))
20051	31996412	Our study demonstrates that E1' VHL variants are rare events in 'VHL-like' and 'PPGL' patients, but nearly as frequent as the VHL mutation rate in exons 1 and 2 in patients with PPGL (in the molecular genetic laboratory of Hopital Europeen Georges Pompidou-Paris-France VHL mutation rate in exon 1 has been reported to be 0.74% (p=0.062), in exon 2: 0.18% (p=0.99) and in exon 3: 0.92% (p=0.0264), or as frequent as in exons of other PPGL susceptibility genes (for instance, the mutation rate in exon 1 of SDHD is 0.43%).	('mutation', 'Var', (274, 282))	('VHL', 'Gene', (32, 35))	('VHL', 'Gene', '7428', (65, 68))	('SDHD', 'Gene', (506, 510))	('VHL', 'Gene', (270, 273))	('VHL', 'Gene', '7428', (32, 35))	("E1' VHL", 'Gene', (28, 35))	('VHL', 'Gene', '7428', (270, 273))	("E1' VHL", 'Gene', '6080;7428', (28, 35))	('VHL', 'Gene', (126, 129))	('variants', 'Var', (36, 44))	('patients', 'Species', '9606', (164, 172))	('VHL', 'Gene', '7428', (126, 129))	('VHL', 'Gene', (65, 68))	('SDHD', 'Gene', '6392', (506, 510))	('patients', 'Species', '9606', (86, 94))
20053	31996412	As the identification of VHL variants has important implications for management and follow-up of patients and relatives, we suggest that E1' cryptic exon should be added to NGS diagnostic panels.	('VHL', 'Gene', '7428', (25, 28))	('VHL', 'Gene', (25, 28))	('variants', 'Var', (29, 37))	('patients', 'Species', '9606', (97, 105))
20054	31996412	Considering the genetic heterogeneity of PPGLs and the high rate of detectable driver mutations in these tumours, a low frequency of variants in any given new gene/exons is not unexpected.	('PPGLs', 'Gene', (41, 46))	('mutations', 'Var', (86, 95))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (105, 112))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
20056	32150977	Mutations in the SDHB subunit of succinate dehydrogenase (SDH) predispose patients to malignant disease with limited therapeutic options and poor prognosis.	('predispose', 'Reg', (63, 73))	('SDH', 'Gene', (58, 61))	('SDH', 'Gene', (17, 20))	('patients', 'Species', '9606', (74, 82))	('succinate', 'Chemical', 'MESH:D019802', (33, 42))	('malignant disease', 'Disease', 'MESH:D009369', (86, 103))	('Mutations', 'Var', (0, 9))	('malignant disease', 'Disease', (86, 103))	('SDH', 'Gene', '6390', (58, 61))	('SDH', 'Gene', '6390', (17, 20))
20067	32150977	In the past decade, enzymes of the tricarboxylic acid (TCA) cycle became the center of attention, because variants of genes encoding the subunits of succinate dehydrogenase enzyme, fumarate hydratase, malate dehydrogenase type 2, and aspartate aminotransferase enzymes have been associated with development of Pheo/PGL.	('variants', 'Var', (106, 114))	('rat', 'Species', '10116', (193, 196))	('succinate', 'Chemical', 'MESH:D019802', (149, 158))	('TCA', 'Chemical', 'MESH:D014233', (55, 58))	('associated with', 'Reg', (279, 294))	('aspartate', 'Chemical', 'MESH:D001224', (234, 243))	('fumarate', 'Chemical', 'MESH:D005650', (181, 189))	('Pheo', 'Gene', '114618', (310, 314))	('Pheo', 'Gene', (310, 314))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (35, 53))	('rat', 'Species', '10116', (185, 188))	('malate', 'Chemical', 'MESH:C030298', (201, 207))
20068	32150977	The most widely accepted assumption is that defects of tricarboxylic acid (TCA) cycle may result in accumulation of certain, so called oncometabolites (such as succinate, fumarate, D-2-hydroxyglutarate) which contribute to cancer development.	('tricarboxylic', 'MPA', (55, 68))	('TCA', 'Chemical', 'MESH:D014233', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('succinate', 'Chemical', 'MESH:D019802', (160, 169))	('accumulation', 'PosReg', (100, 112))	('fumarate', 'Chemical', 'MESH:D005650', (171, 179))	('defects', 'Var', (44, 51))	('fumarate', 'MPA', (171, 179))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('D-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (181, 201))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (55, 73))	('cancer', 'Disease', (223, 229))	('succinate', 'MPA', (160, 169))
20071	32150977	In addition, chronic hypoxia (i.e., high altitudes) increases the incidence of sporadic PGLs and it has been demonstrated that it has a phenotype modifier effect on germline SDHB and SDHD mutant PGLs.	('increases', 'PosReg', (52, 61))	('SDHD', 'Gene', '363061', (183, 187))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('hypoxia', 'Disease', (21, 28))	('sporadic PGLs', 'Disease', (79, 92))	('rat', 'Species', '10116', (116, 119))	('SDHB', 'Gene', (174, 178))	('SDHD', 'Gene', (183, 187))	('mutant', 'Var', (188, 194))
20072	32150977	Even though germline mutations of genes encoding for SDH subunits have been shown to predispose susceptibility for the development of familial Pheo/PGL, only mutations of the SDHB gene have been often associated with high rate of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (230, 240))	('Pheo', 'Gene', (143, 147))	('SDH', 'Gene', (53, 56))	('SDH', 'Gene', (175, 178))	('malignancy', 'Disease', (230, 240))	('SDH', 'Gene', '6390', (175, 178))	('susceptibility', 'Reg', (96, 110))	('rat', 'Species', '10116', (222, 225))	('SDH', 'Gene', '6390', (53, 56))	('associated', 'Reg', (201, 211))	('mutations', 'Var', (158, 167))	('Pheo', 'Gene', '114618', (143, 147))	('mutations', 'Var', (21, 30))
20073	32150977	Metastatic disease can be observed in more than 17-40% of patients with SDHB mutations, but the mechanisms leading to the malignant phenotype are still unclear.	('SDHB', 'Gene', (72, 76))	('observed', 'Reg', (26, 34))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (58, 66))	('Metastatic disease', 'Disease', (0, 18))
20083	32150977	SDHx mutant tumors were shown to accumulate lower levels of glutamate, and SDHB knockout cells were shown to be more sensitive to GLS-1 inhibitors.	('lower', 'NegReg', (44, 49))	('glutamate', 'Chemical', 'MESH:D018698', (60, 69))	('SDH', 'Gene', (0, 3))	('GLS-1', 'Gene', (130, 135))	('accumulate', 'PosReg', (33, 43))	('SDH', 'Gene', '6390', (75, 78))	('GLS-1', 'Gene', '2744', (130, 135))	('lower levels of glutamate', 'Phenotype', 'HP:0500150', (44, 69))	('mutant', 'Var', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('levels of glutamate', 'MPA', (50, 69))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('SDH', 'Gene', (75, 78))	('SDH', 'Gene', '6390', (0, 3))
20101	32150977	SDH activity was effectively reduced after siSdhb transfection compared to mock transfected and untreated cells (Figure 1A-D).	('SDH', 'Gene', (0, 3))	('siSdhb', 'Disease', (43, 49))	('reduced', 'NegReg', (29, 36))	('siSdhb', 'Disease', 'None', (43, 49))	('transfection', 'Var', (50, 62))	('SDH', 'Gene', '6390', (0, 3))
20102	32150977	siSdhb transfection showed similar potential in inhibiting SDH activity to atpenin, a potent and known SDH inhibitor (Figure 1D).	('SDH', 'Gene', '6390', (103, 106))	('inhibiting', 'NegReg', (48, 58))	('atpenin', 'Chemical', '-', (75, 82))	('siSdhb', 'Disease', 'None', (0, 6))	('SDH', 'Gene', (59, 62))	('transfection', 'Var', (7, 19))	('SDH', 'Gene', (103, 106))	('siSdhb', 'Disease', (0, 6))	('SDH', 'Gene', '6390', (59, 62))
20103	32150977	Succinate/fumarate ratio increased significantly in cells transfected with siRNA against Sdhb compared to cells transfected with mock siRNA (p < 0.0001) (Figure 1G).	('siRNA', 'Var', (75, 80))	('increased', 'PosReg', (25, 34))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('Sdhb', 'Gene', (89, 93))	('fumarate', 'Chemical', 'MESH:D005650', (10, 18))	('rat', 'Species', '10116', (19, 22))	('Succinate/fumarate ratio', 'MPA', (0, 24))	('rat', 'Species', '10116', (14, 17))
20108	32150977	Sdhb knockdown significantly increased PC12 cells' viability after 72 h (p = 0.04) compared to mock transfected cells whereas significant differences were not observed at 24 and 48 h. (Figure 2A).	('knockdown', 'Var', (5, 14))	('Sdhb', 'Gene', (0, 4))	('PC12', 'CellLine', 'CVCL:0481', (39, 43))	('increased', 'PosReg', (29, 38))
20111	32150977	Cell proliferation of PC12 cells measured with SRB assay was not affected by SDH impairment either with Sdhb knockdown or itaconate/atpenin treatment (Figure 2D-F).	('PC12', 'CellLine', 'CVCL:0481', (22, 26))	('rat', 'Species', '10116', (12, 15))	('SDH impairment', 'Disease', (77, 91))	('atpenin', 'Chemical', '-', (132, 139))	('Sdhb', 'Gene', (104, 108))	('SDH impairment', 'Disease', 'MESH:D060825', (77, 91))	('knockdown', 'Var', (109, 118))	('SRB', 'Chemical', 'MESH:C022027', (47, 50))	('itaconate', 'Chemical', 'MESH:C005229', (122, 131))	('Cell proliferation', 'CPA', (0, 18))
20116	32150977	In PC12 cells metabolite concentrations measured after Sdhb knockdown clustered together to those measured after itaconate treatment (Figure 4B).	('itaconate', 'Chemical', 'MESH:C005229', (113, 122))	('rat', 'Species', '10116', (32, 35))	('Sdhb', 'Gene', (55, 59))	('PC12', 'CellLine', 'CVCL:0481', (3, 7))	('knockdown', 'Var', (60, 69))	('metabolite concentrations', 'MPA', (14, 39))
20118	32150977	Sdhb knockdown significantly decreased glutamate concentrations (p < 0.0001) (Figure 4C), while lactate did not show accumulation (Figure 4D and Table S1).	('glutamate', 'Chemical', 'MESH:D018698', (39, 48))	('decreased glutamate', 'Phenotype', 'HP:0500150', (29, 48))	('rat', 'Species', '10116', (56, 59))	('decreased glutamate concentrations', 'Phenotype', 'HP:0500150', (29, 63))	('knockdown', 'Var', (5, 14))	('Sdhb', 'Gene', (0, 4))	('glutamate concentrations', 'MPA', (39, 63))	('lactate', 'Chemical', 'MESH:D019344', (96, 103))	('decreased', 'NegReg', (29, 38))
20121	32150977	Contrary to PC12 cells, glutamate (p = 0.004) and lactate (p = 0.013) concentrations significantly increased in HeLa cells treated with itaconic acid compared to vehicle treatment after 24 h incubation.	('PC12', 'CellLine', 'CVCL:0481', (12, 16))	('rat', 'Species', '10116', (77, 80))	('lactate', 'Chemical', 'MESH:D019344', (50, 57))	('glutamate', 'Chemical', 'MESH:D018698', (24, 33))	('HeLa', 'CellLine', 'CVCL:0030', (112, 116))	('itaconic acid', 'Chemical', 'MESH:C005229', (136, 149))	('increased', 'PosReg', (99, 108))	('itaconic', 'Var', (136, 144))
20127	32150977	A significant increase in GLS-1 expression after Sdhb knockout (fold change: 1.53 +- 0.3, p = 0.002) was observed in PC12 cells A significant increase in GLS-1 expression was observed after itaconate treatment of PC12 cells after 24 h (fold change: 1.2 +- 0.03, p = 0.015) and 48 h (fold change 1.48 +- 0.13, p = 0.002).	('expression', 'MPA', (160, 170))	('increase', 'PosReg', (142, 150))	('knockout', 'Var', (54, 62))	('increase', 'PosReg', (14, 22))	('PC12', 'CellLine', 'CVCL:0481', (213, 217))	('Sdhb', 'Gene', (49, 53))	('itaconate', 'Chemical', 'MESH:C005229', (190, 199))	('GLS-1', 'Gene', '2744', (154, 159))	('GLS-1', 'Gene', '2744', (26, 31))	('PC12', 'CellLine', 'CVCL:0481', (117, 121))	('GLS-1', 'Gene', (154, 159))	('expression', 'MPA', (32, 42))	('GLS-1', 'Gene', (26, 31))
20145	32150977	In case of the benign sporadic samples, out of the four samples with low SDHB scores two were accompanied by high GLS-1 immunostaining scores (Table 1).	('scores', 'Var', (78, 84))	('GLS-1', 'Gene', '2744', (114, 119))	('GLS-1', 'Gene', (114, 119))	('low', 'NegReg', (69, 72))	('SDHB', 'Gene', (73, 77))
20153	32150977	The effects of Sdhb knockdown were compared to mock transfected cells whereas the consequences of itaconate and atpenin treatment were compared to control (untreated) PC12 cells.	('PC12', 'CellLine', 'CVCL:0481', (167, 171))	('atpenin', 'Chemical', '-', (112, 119))	('knockdown', 'Var', (20, 29))	('itaconate', 'Chemical', 'MESH:C005229', (98, 107))	('Sdhb', 'Gene', (15, 19))
20156	32150977	Compared to control PC12 cells, itaconate yielded a significantly higher basal respiration (p = 0.007) whereas Sdhb knockdown resulted in significantly lower basal respiration rate compared to mock transfected cells (p = 0.0079).	('rat', 'Species', '10116', (169, 172))	('basal respiration rate', 'MPA', (158, 180))	('rat', 'Species', '10116', (176, 179))	('basal respiration', 'MPA', (73, 90))	('rat', 'Species', '10116', (84, 87))	('PC12', 'CellLine', 'CVCL:0481', (20, 24))	('knockdown', 'Var', (116, 125))	('lower', 'NegReg', (152, 157))	('higher', 'PosReg', (66, 72))	('Sdhb', 'Gene', (111, 115))	('itaconate', 'Chemical', 'MESH:C005229', (32, 41))
20160	32150977	BPTES treatment only had a significant effect on Sdhb silenced cells when their basal oxygen consumption was compared to the OCR after glutamine admission (p = 0.0079).	('glutamine', 'Chemical', 'MESH:D005973', (135, 144))	('BPTES', 'Chemical', '-', (0, 5))	('Sdhb', 'Gene', (49, 53))	('oxygen', 'Chemical', 'MESH:D010100', (86, 92))	('silenced', 'Var', (54, 62))
20164	32150977	Itaconate treatment and siSdhb knockdown significantly increased maximal respiration (p = 0.0079).	('Itaconate', 'Chemical', 'MESH:C005229', (0, 9))	('siSdhb', 'Disease', 'None', (24, 30))	('increased', 'PosReg', (55, 64))	('rat', 'Species', '10116', (78, 81))	('maximal respiration', 'MPA', (65, 84))	('siSdhb', 'Disease', (24, 30))	('knockdown', 'Var', (31, 40))
20170	32150977	A total of 40% of these neuro-endocrine tumors are inherited in an autosomal dominant manner due to mutations in one of the 17 Pheo/PGL-associated genes.	('mutations', 'Var', (100, 109))	('neuro-endocrine tumors', 'Disease', 'MESH:D004700', (24, 46))	('inherited', 'Reg', (51, 60))	('neuro-endocrine tumors', 'Disease', (24, 46))	('due to', 'Reg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('Pheo', 'Gene', (127, 131))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('Pheo', 'Gene', '114618', (127, 131))
20172	32150977	Mutations of the SDHB gene represent a strong susceptibility for malignancy.	('malignancy', 'Disease', 'MESH:D009369', (65, 75))	('malignancy', 'Disease', (65, 75))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (17, 21))	('susceptibility', 'Reg', (46, 60))
20173	32150977	The precise pathomechanism behind the SDHx mutations and especially the malignant potential of SDHB mutations is still unknown despite the several observations made through the last decades.	('mutations', 'Var', (100, 109))	('SDH', 'Gene', '6390', (38, 41))	('mutations', 'Var', (43, 52))	('SDH', 'Gene', '6390', (95, 98))	('SDH', 'Gene', (38, 41))	('SDH', 'Gene', (95, 98))
20174	32150977	Several novel approaches were introduced recently to address the lack of therapeutic options: the inhibition of glutathione synthesis was shown to contribute to the DNA damage as a result of the increased level of reactive oxygen species in SDHB mutant tumors.	('SDHB', 'Gene', (241, 245))	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('glutathione', 'Chemical', 'MESH:D005978', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('inhibition', 'NegReg', (98, 108))	('oxygen', 'Chemical', 'MESH:D010100', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('mutant', 'Var', (246, 252))	('level of reactive oxygen species', 'MPA', (205, 237))	('increased', 'PosReg', (195, 204))	('glutathione synthesis', 'MPA', (112, 133))
20175	32150977	Inhibition of complex I made complex II impaired tumors more sensitive to DNA damaging chemotherapeutic agents while it has been also demonstrated that elevated succinate and fumarate levels suppress the homologous recombination DNA pathway, rendering these tumors vulnerable to poly(ADP)-ribose polymerase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('fumarate', 'Chemical', 'MESH:D005650', (175, 183))	('tumors', 'Disease', (49, 55))	('rat', 'Species', '10116', (141, 144))	('poly(ADP)', 'Chemical', '-', (279, 288))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('suppress', 'NegReg', (191, 199))	('elevated succinate', 'Phenotype', 'HP:0020149', (152, 170))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('homologous recombination DNA pathway', 'Pathway', (204, 240))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('elevated', 'PosReg', (152, 160))	('tumors', 'Disease', (258, 264))	('sensitive', 'MPA', (61, 70))	('II impaired tumors', 'Disease', (37, 55))	('Inhibition', 'Var', (0, 10))	('rat', 'Species', '10116', (179, 182))	('II impaired tumors', 'Disease', 'MESH:D060825', (37, 55))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('succinate', 'Chemical', 'MESH:D019802', (161, 170))
20178	32150977	The succinate accumulation in SDHx mutant tumors can inhibit the alpha-ketoglutarate-dependent prolyl hydroxylases, which have an important role in the degradation of HIF1alpha and HIF2alpha under normoxia.	('alpha-ketoglutarate-dependent', 'MPA', (65, 94))	('HIF1alpha', 'Gene', (167, 176))	('SDH', 'Gene', (30, 33))	('inhibit', 'NegReg', (53, 60))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('HIF2alpha', 'Gene', '29452', (181, 190))	('succinate accumulation', 'MPA', (4, 26))	('mutant', 'Var', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HIF2alpha', 'Gene', (181, 190))	('HIF1alpha', 'Gene', '29560', (167, 176))	('SDH', 'Gene', '6390', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('succinate', 'Chemical', 'MESH:D019802', (4, 13))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (65, 84))
20179	32150977	Mutations in the SDHB subunit beside the HIF1alpha stabilization, shift the cellular metabolism towards reductive glutamine catabolism.	('glutamine', 'Chemical', 'MESH:D005973', (114, 123))	('reductive glutamine catabolism', 'MPA', (104, 134))	('cellular metabolism', 'MPA', (76, 95))	('Mutations', 'Var', (0, 9))	('HIF1alpha', 'Gene', (41, 50))	('SDHB', 'Gene', (17, 21))	('shift', 'Reg', (66, 71))	('HIF1alpha', 'Gene', '29560', (41, 50))
20180	32150977	reported that both loss of complex I and complex II activity are necessary to mimic the metabolic phenotype of SDH mutant tumors based on reductive glutamine metabolism, sole SDHA or SDHB inhibition failed to do so in their study.	('SDHA', 'Gene', '157074', (175, 179))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('reductive glutamine metabolism', 'MPA', (138, 168))	('glutamine', 'Chemical', 'MESH:D005973', (148, 157))	('SDH', 'Gene', (175, 178))	('SDH', 'Gene', '6390', (183, 186))	('SDH', 'Gene', '6390', (111, 114))	('mutant', 'Var', (115, 121))	('SDH', 'Gene', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('SDH', 'Gene', (111, 114))	('SDH', 'Gene', '6390', (175, 178))	('SDHA', 'Gene', (175, 179))
20183	32150977	Increased succinate to fumarate ratio also characteristic for SDH mutant Pheo/PGLs.	('succinate to fumarate ratio', 'MPA', (10, 37))	('SDH', 'Gene', '6390', (62, 65))	('fumarate', 'Chemical', 'MESH:D005650', (23, 31))	('rat', 'Species', '10116', (32, 35))	('mutant', 'Var', (66, 72))	('Pheo', 'Gene', '114618', (73, 77))	('SDH', 'Gene', (62, 65))	('Increased succinate', 'Phenotype', 'HP:0020149', (0, 19))	('Pheo', 'Gene', (73, 77))	('Increased', 'PosReg', (0, 9))	('rat', 'Species', '10116', (27, 30))	('succinate', 'Chemical', 'MESH:D019802', (10, 19))
20188	32150977	Based on these data we assume that the impairment of SDH activity (either by itaconate or atpenin treatments or Sdhb knockdown) has a cell type-specific effect on the viability of cells.	('SDH', 'Gene', (53, 56))	('atpenin', 'Chemical', '-', (90, 97))	('Sdhb', 'Gene', (112, 116))	('SDH', 'Gene', '6390', (53, 56))	('activity', 'MPA', (57, 65))	('itaconate', 'Chemical', 'MESH:C005229', (77, 86))	('knockdown', 'Var', (117, 126))
20193	32150977	In general, inhibition of SDH shifts cellular metabolism to anaerobic glycolysis, and administration of itaconate is also associated with lactate accumulation.	('associated', 'Reg', (122, 132))	('rat', 'Species', '10116', (94, 97))	('inhibition', 'Var', (12, 22))	('itaconate', 'Chemical', 'MESH:C005229', (104, 113))	('lactate accumulation', 'MPA', (138, 158))	('SDH', 'Gene', '6390', (26, 29))	('shifts', 'Reg', (30, 36))	('lactate', 'Chemical', 'MESH:D019344', (138, 145))	('cellular metabolism', 'MPA', (37, 56))	('SDH', 'Gene', (26, 29))
20194	32150977	However, in contrary to HeLa and H295R cell lines, the expected increase in lactate concentrations was absent in PC12 cells after itaconate treatment and after Sdhb knockout.	('lactate concentrations', 'MPA', (76, 98))	('PC12', 'CellLine', 'CVCL:0481', (113, 117))	('lactate', 'Chemical', 'MESH:D019344', (76, 83))	('absent', 'NegReg', (103, 109))	('rat', 'Species', '10116', (91, 94))	('itaconate', 'Chemical', 'MESH:C005229', (130, 139))	('increase', 'PosReg', (64, 72))	('HeLa', 'CellLine', 'CVCL:0030', (24, 28))	('knockout', 'Var', (165, 173))	('Sdhb', 'Gene', (160, 164))	('H295R', 'CellLine', 'CVCL:0458', (33, 38))
20195	32150977	Sdhb knockdown significantly decreased glutamate concentrations which is in line with the data demonstrating that SDHx mutant tumors also accumulate lower levels of glutamate, and SDHB mutation associated with increased glutamine metabolism.	('decreased glutamate', 'Phenotype', 'HP:0500150', (29, 48))	('increased glutamine', 'Phenotype', 'HP:0003217', (210, 229))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('SDH', 'Gene', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('glutamate', 'Chemical', 'MESH:D018698', (39, 48))	('glutamate', 'Chemical', 'MESH:D018698', (165, 174))	('tumors', 'Disease', (126, 132))	('rat', 'Species', '10116', (56, 59))	('levels of glutamate', 'MPA', (155, 174))	('mutation', 'Var', (185, 193))	('rat', 'Species', '10116', (102, 105))	('mutant', 'Var', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('accumulate', 'PosReg', (138, 148))	('SDH', 'Gene', '6390', (180, 183))	('increased', 'PosReg', (210, 219))	('decreased glutamate concentrations', 'Phenotype', 'HP:0500150', (29, 63))	('lower levels of glutamate', 'Phenotype', 'HP:0500150', (149, 174))	('decreased', 'NegReg', (29, 38))	('glutamine', 'Chemical', 'MESH:D005973', (220, 229))	('SDH', 'Gene', '6390', (114, 117))	('glutamate concentrations', 'MPA', (39, 63))	('lower', 'NegReg', (149, 154))	('SDH', 'Gene', (180, 183))	('glutamine metabolism', 'MPA', (220, 240))
20196	32150977	In addition, glutamine was shown to be the main source in SDHB-mutated UOK269 cells and this metabolite linked HIF-1alpha stabilization and DNA methylator phenotype.	('UOK269', 'CellLine', 'CVCL:B686', (71, 77))	('HIF-1alpha', 'Gene', '29560', (111, 121))	('HIF-1alpha', 'Gene', (111, 121))	('SDHB-mutated', 'Gene', (58, 70))	('glutamine', 'Chemical', 'MESH:D005973', (13, 22))	('SDHB-mutated', 'Var', (58, 70))
20200	32150977	Itaconate but not atpenin had the same effect, it increased the basal respiration of PC12 cells whereas it did not have a significant impact on lactate concentration further supporting its capability to serve as a model for Sdhb mutant Pheo/PGLs.	('Pheo', 'Gene', '114618', (236, 240))	('basal', 'CPA', (64, 69))	('Itaconate', 'Chemical', 'MESH:C005229', (0, 9))	('atpenin', 'Chemical', '-', (18, 25))	('PC12', 'CellLine', 'CVCL:0481', (85, 89))	('rat', 'Species', '10116', (75, 78))	('increased', 'PosReg', (50, 59))	('Sdhb', 'Gene', (224, 228))	('lactate', 'Chemical', 'MESH:D019344', (144, 151))	('mutant', 'Var', (229, 235))	('rat', 'Species', '10116', (159, 162))	('Pheo', 'Gene', (236, 240))
20203	32150977	We may hypothesize that in SDH deficient cells a rapid metabolic adaptation occurs which allows these cells to survive by either shifting its metabolism to the use of the alternative fuel glutamine or going into a reversible, more quiescent state.	('metabolism', 'MPA', (142, 152))	('SDH', 'Gene', (27, 30))	('deficient', 'Var', (31, 40))	('glutamine', 'Chemical', 'MESH:D005973', (188, 197))	('SDH', 'Gene', '6390', (27, 30))
20204	32150977	Glutamate has an extensive role in cell metabolism and disruption of the TCA cycle makes the cells more dependent on reductive carboxylation of glutamine instead of the oxidative metabolism of the TCA cycle.	('TCA', 'Chemical', 'MESH:D014233', (73, 76))	('Glutamate', 'Chemical', 'MESH:D018698', (0, 9))	('glutamine', 'Chemical', 'MESH:D005973', (144, 153))	('reductive carboxylation', 'MPA', (117, 140))	('disruption', 'Var', (55, 65))	('TCA', 'Chemical', 'MESH:D014233', (197, 200))	('oxidative metabolism', 'MPA', (169, 189))
20207	32150977	PC12 cells exhibited significantly increased GLS-1 expression upon Sdhb knockdown and SDH inhibition with itaconate too.	('inhibition', 'NegReg', (90, 100))	('GLS-1', 'Gene', '2744', (45, 50))	('increased', 'PosReg', (35, 44))	('SDH', 'Gene', '6390', (86, 89))	('PC12', 'CellLine', 'CVCL:0481', (0, 4))	('GLS-1', 'Gene', (45, 50))	('SDH', 'Gene', (86, 89))	('itaconate', 'Chemical', 'MESH:C005229', (106, 115))	('expression', 'MPA', (51, 61))	('knockdown', 'Var', (72, 81))	('Sdhb', 'Gene', (67, 71))
20213	32150977	These results indicate that SDH inhibition exhibits cell line and inhibitory method specific consequences and the dynamism of metabolic changes varies among cell types, but in PC12 cells both Sdhb knockdown and itaconate treatment increased its expression suggesting that these cells might be dependent on this enzyme.	('Sdhb', 'Gene', (192, 196))	('SDH', 'Gene', '6390', (28, 31))	('increased', 'PosReg', (231, 240))	('knockdown', 'Var', (197, 206))	('SDH', 'Gene', (28, 31))	('itaconate', 'Chemical', 'MESH:C005229', (211, 220))	('expression', 'MPA', (245, 255))	('PC12', 'CellLine', 'CVCL:0481', (176, 180))
20231	32150977	The heterogeneous phenotype associated with Sdhb mutations is highlighted in an in vivo model of Sdhb mutation developed in Caenorhabditis elegans, where the deleted mutant arrested in development, while the point mutant form was viable and it presented only infertility.	('Caenorhabditis elegans', 'Species', '6239', (124, 146))	('mutation', 'Var', (102, 110))	('infertility', 'Disease', 'MESH:D007247', (259, 270))	('infertility', 'Phenotype', 'HP:0000789', (259, 270))	('Sdhb', 'Gene', (97, 101))	('infertility', 'Disease', (259, 270))
20232	32150977	In conclusion, we assume that GLS-1 contributes to SDHB-mutant malignant tumor growth and we presume that the evaluation of GLS-1 expression before therapy might yield valuable information for the management of the disease.	('SDHB-mutant', 'Gene', (51, 62))	('SDHB-mutant', 'Var', (51, 62))	('malignant tumor', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GLS-1', 'Gene', '2744', (124, 129))	('malignant tumor', 'Disease', 'MESH:D009369', (63, 78))	('GLS-1', 'Gene', (124, 129))	('GLS-1', 'Gene', '2744', (30, 35))	('GLS-1', 'Gene', (30, 35))
20239	32150977	HeLa cells (human cervix carcinoma cell line) were grown in 75-cm2 flasks in Dulbecco's modified Eagle medium/HamF12 (DMEM/F12) (#11330032, Thermo Fisher Scientific, Waltham, MA, USA) containing 10% FBS (#10270106, Thermo Fisher Scientific, Waltham, MA, USA) and 1% penicillin-streptomycin (LM-A4118/100, Biosera, Nouille, France).	('#11330032', 'Var', (129, 138))	('cervix carcinoma', 'Disease', 'MESH:D002583', (18, 34))	('penicillin', 'Chemical', 'MESH:D010406', (266, 276))	('#10270106', 'Var', (204, 213))	('F12', 'Chemical', 'MESH:C007782', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('cervix carcinoma', 'Disease', (18, 34))	('F12', 'Chemical', 'MESH:C007782', (123, 126))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (18, 34))	('streptomycin', 'Chemical', 'MESH:D013307', (277, 289))	('human', 'Species', '9606', (12, 17))	('DMEM', 'Chemical', '-', (118, 122))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (77, 109))
20240	32150977	H295R cells (human adrenocortical carcinoma) were grown in 75-cm2 flasks in Dulbecco's modified Eagle medium/HamF12 (DMEM/F12) containing HEPES buffer, l-glutamine, and pyridoxine HCl (#11330032, Thermo Fisher Scientific, Waltham, MA, USA).	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('pyridoxine HCl', 'Chemical', 'MESH:D011736', (169, 183))	('human', 'Species', '9606', (13, 18))	('carcinoma', 'Disease', (34, 43))	('H295R', 'CellLine', 'CVCL:0458', (0, 5))	('carcinoma', 'Disease', 'MESH:D009369', (34, 43))	('DMEM', 'Chemical', '-', (117, 121))	('#11330032', 'Var', (185, 194))	('HEPES', 'Chemical', 'MESH:D006531', (138, 143))	("Dulbecco's modified Eagle medium", 'Chemical', '-', (76, 108))	('F12', 'Chemical', 'MESH:C007782', (112, 115))	('F12', 'Chemical', 'MESH:C007782', (122, 125))	('l-glutamine', 'Chemical', 'MESH:D005973', (152, 163))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (19, 43))
20241	32150977	Additional supplements were added to the medium, including 0.00625 mg/mL insulin (#I9278, Sigma, St. Louis, MO, USA), 0,00625 mg/mL human transferrin (#T5391, Sigma, St. Louis, MO, USA), and 6.25 ng/mL selenous acid (#S9133, Sigma, St. Louis, MO, USA) 1.25 mg/mL bovine serum albumine (#A9647, Sigma, St. Louis, MO, USA), 2.5% nu-serum (Zenon Bio Kft.	('transferrin', 'Gene', '7018', (138, 149))	('serum albumin', 'Gene', '24186', (270, 283))	('transferrin', 'Gene', (138, 149))	('human', 'Species', '9606', (132, 137))	('serum albumin', 'Gene', (270, 283))	('#A9647', 'Var', (286, 292))
20245	32150977	Total protein was separated by 10-15% SDS polyacrylamide gel electrophoresis, transferred to a PVDF membrane, and incubated overnight with primary antibody against SDHB (5 mug/mL; anti-SDHB, ab14714, Abcam, Cambridge, United Kingdom).	('rat', 'Species', '10116', (22, 25))	('anti-SDHB', 'Var', (180, 189))	('polyacrylamide', 'Chemical', 'MESH:C016679', (42, 56))	('SDS', 'Chemical', 'MESH:D012967', (38, 41))	('SDHB', 'Gene', (164, 168))	('PVDF', 'Chemical', 'MESH:C024865', (95, 99))
20311	32150977	In summary, we demonstrated for the first time that SDH inhibition either with itaconate, atpenin, or SDHB knockdown had a positive effect on cell viability of chromaffin cells but not on other cell lines which may be related to the glutamine/glutamate metabolism.	('knockdown', 'Var', (107, 116))	('inhibition', 'NegReg', (56, 66))	('atpenin', 'Chemical', '-', (90, 97))	('SDH', 'Gene', (102, 105))	('itaconate', 'Chemical', 'MESH:C005229', (79, 88))	('SDH', 'Gene', '6390', (52, 55))	('rat', 'Species', '10116', (22, 25))	('cell viability of chromaffin cells', 'CPA', (142, 176))	('SDH', 'Gene', (52, 55))	('glutamine', 'Chemical', 'MESH:D005973', (233, 242))	('glutamate', 'Chemical', 'MESH:D018698', (243, 252))	('SDH', 'Gene', '6390', (102, 105))	('chromaffin', 'Chemical', '-', (160, 170))
20313	32150977	SDHB expression in some SDHB-mutant Pheo/PGL tissues suggests that tumor heterogeneity occurs even in SDHB-associated tumors.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('Pheo', 'Gene', '114618', (36, 40))	('tumor', 'Disease', (67, 72))	('tumors', 'Disease', (118, 124))	('Pheo', 'Gene', (36, 40))	('SDHB-mutant', 'Gene', (24, 35))	('SDHB', 'Gene', (0, 4))	('SDHB-mutant', 'Var', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
20315	32150977	All together these data suggest that some SDH activity is still maintained in these tumors, therefore knockdown of SDHB by siRNA provides a feasible model for the disease.	('SDH', 'Gene', '6390', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('SDH', 'Gene', '6390', (115, 118))	('knockdown', 'Var', (102, 111))	('SDH', 'Gene', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('SDH', 'Gene', (115, 118))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
20321	32150977	The following are available online at , Figure S1: SDHB knockdown by Sdhb targeting siRNAs, Figure S2: Succinate to fumarate ratios in cell lines after itaconate or vehicle treatment, Figure S3: Normalized succinate levels after atpenin vs. vehicle treatment: veh: vehicle; suc: succinate, Figure S4: HeatMap, Table S1: Intracellular normalized concentrations of all measured metabolites (micromol/microg), Table S2: Intracellular normalized concentrations of all measured metabolites (micromol/microg).	('succinate', 'Chemical', 'MESH:D019802', (206, 215))	('rat', 'Species', '10116', (125, 128))	('rat', 'Species', '10116', (352, 355))	('fumarate', 'Chemical', 'MESH:D005650', (116, 124))	('succinate', 'Chemical', 'MESH:D019802', (279, 288))	('rat', 'Species', '10116', (449, 452))	('atpenin', 'Chemical', '-', (229, 236))	('itaconate', 'Chemical', 'MESH:C005229', (152, 161))	('Sdhb', 'Gene', (69, 73))	('Succinate', 'Chemical', 'MESH:D019802', (103, 112))	('rat', 'Species', '10116', (120, 123))	('SDHB', 'Gene', (51, 55))	('knockdown', 'Var', (56, 65))
20324	32150977	; performed clinical evaluation of patients: B.S., I.K., J.P., L.C., M.L., A.P.	('J.P.', 'Disease', (57, 61))	('L.C.', 'Disease', (63, 67))	('M.L.', 'Var', (69, 73))	('patients', 'Species', '9606', (35, 43))
20334	31261748	Subgroup analysis showed Ki-67 <15% associated with longer OS (p = 0.013) and PFS (p = 0.005).	('OS', 'Chemical', '-', (59, 61))	('<15%', 'Var', (31, 35))	('Ki-67 <15%', 'Var', (25, 35))	('PFS', 'Disease', (78, 81))	('associated', 'Reg', (36, 46))	('longer OS', 'Disease', (52, 61))	('Ki-67', 'Chemical', '-', (25, 30))
20345	31261748	Furthermore, encouraging results of PRRT have been shown in small cohorts of PCC/PGL patients treated with 90Y- DOTATOC and with 177Lu-DOTATATE.	('90Y- DOTATOC', 'Var', (107, 119))	('PCC/PGL', 'Disease', (77, 84))	('TOC', 'Chemical', '-', (116, 119))	('patients', 'Species', '9606', (85, 93))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (129, 143))
20395	31261748	Patient 20 had an SDHD mutation, whereas the other patient was not tested for a genetic profile.	('mutation', 'Var', (23, 31))	('patient', 'Species', '9606', (51, 58))	('SDHD', 'Gene', (18, 22))	('SDHD', 'Gene', '6392', (18, 22))	('Patient', 'Species', '9606', (0, 7))
20398	31261748	Ki-67 <15% compared to Ki-67 >=15% (p = 0.013) and PRRT received as first-line therapy compared to PPRT received because of tumor progression (p = 0.041) were associated with longer OS (Figure 2A,B).	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('Ki-67 >=15%', 'Var', (23, 34))	('OS', 'Chemical', '-', (182, 184))	('Ki-67', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (124, 129))	('Ki-67 <15%', 'Var', (0, 10))	('longer OS', 'Disease', (175, 184))	('PRRT', 'Var', (51, 55))	('Ki-67', 'Chemical', '-', (23, 28))
20401	31261748	Ki-67 <15% (p = 0.005) was associated with longer PFS, whereas PRRT received as first-line therapy, tumor type, visual response on scintigraphy (>=50%), biochemical response, number of cycles, administered activity, and previous therapies (surgery, radiotherapy, chemotherapy, 131I-MIBG) were all factors unrelated to PFS.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('<15%', 'Var', (6, 10))	('131I-MIBG', 'Chemical', 'MESH:D019797', (277, 286))	('tumor', 'Disease', (100, 105))	('Ki-67', 'Chemical', '-', (0, 5))	('PFS', 'Disease', (50, 53))	('Ki-67 <15%', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
20417	31261748	With 177Lu-DOTATATE, we experienced no kidney toxicity and only grade 1 (n = 10) and 2 (n = 6) hematological toxicity.	('kidney toxicity', 'Disease', 'MESH:D007674', (39, 54))	('hematological toxicity', 'Disease', 'MESH:D006402', (95, 117))	('177Lu-DOTATATE', 'Var', (5, 19))	('kidney toxicity', 'Disease', (39, 54))	('hematological toxicity', 'Disease', (95, 117))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (5, 19))
20419	31261748	Additionally, Kong et al., who in half of their patients combined 177Lu-DOTATATE with fluorouracil, reported mainly grade 2 lymphopenia.	('lymphopenia', 'Disease', (124, 135))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (66, 80))	('lymphopenia', 'Phenotype', 'HP:0001888', (124, 135))	('lymphopenia', 'Disease', 'MESH:D008231', (124, 135))	('patients', 'Species', '9606', (48, 56))	('177Lu-DOTATATE', 'Var', (66, 80))	('fluorouracil', 'Chemical', 'MESH:D005472', (86, 98))
20433	31261748	With 90Y-DOTATOC, biochemical responses were reported in 2/11 (18%) and 4/28 (14%) PCC and PGL patients, respectively.	('biochemical', 'MPA', (18, 29))	('TOC', 'Chemical', '-', (13, 16))	('patients', 'Species', '9606', (95, 103))	('90Y-DOTATOC', 'Var', (5, 16))	('PCC', 'Disease', (83, 86))
20442	31261748	With 177Lu/90Y-DOTATATE/TOC therapy, the tumors need to show sufficient somatostatin receptor expression on imaging, usually Krenning grade 3 or 4 (higher than that of the liver) or at lease grade 2 (similar to that of the liver) in order to be eligible for PRRT.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('somatostatin', 'MPA', (72, 84))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TOC', 'Chemical', '-', (24, 27))	('177Lu/90Y-DOTATATE/TOC', 'Var', (5, 27))	('expression', 'MPA', (94, 104))	('DOTATATE', 'Chemical', '-', (15, 23))	('higher', 'PosReg', (148, 154))
20446	31261748	The sensitivity of 123I-MIBG scintigraphy is particularly low in head and neck PGLs (HNPGL) (18-50%).	('123I-MIBG', 'Chemical', 'MESH:D019797', (19, 28))	('123I-MIBG', 'Var', (19, 28))	('low', 'NegReg', (58, 61))
20453	31261748	Interestingly, we found such a correlation and Ki-67 >=15% was shown to be a predictor for worse OS and PFS.	('Ki-67', 'Chemical', '-', (47, 52))	('PFS', 'Disease', (104, 107))	('Ki-67 >=15%', 'Var', (47, 58))	('>=15%', 'Var', (53, 58))	('worse OS', 'Disease', (91, 99))	('OS', 'Chemical', '-', (97, 99))
20455	31261748	We were however unable to show any predictive value for tumor type (PCC or PGL), visual response on scintigraphy, or previous therapies (surgery, radiotherapy, chemotherapy, 131I-MIBG), which were all factors unrelated to OS and PFS.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('131I-MIBG', 'Chemical', 'MESH:D019797', (174, 183))	('tumor', 'Disease', (56, 61))	('131I-MIBG', 'Var', (174, 183))	('OS', 'Chemical', '-', (222, 224))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
20467	31261748	Inclusion criteria for PRRT were patients with pheochromocytoma or paraganglioma confirmed by histopathological examination, and a tumor uptake higher than that of the normal liver (Krenning scores 3 and 4) on somatostatin receptor scintigraphy (SRS), life expectancy > 3 months, white blood cell count (WBC) > 3.0 x 109/L, platelet count > 100 x 109/L, bilirubin < 40 micromol /L, albumin > 25 g/L, ASAT and ALAT less than 5 times upper limit, creatinine < 110 micromol/L or, if higher, GFR (cystatin-C) > 50 mL/min/1.73 m2.	('cystatin-C', 'Gene', (493, 503))	('ASAT', 'Gene', (400, 404))	('platelet', 'MPA', (324, 332))	('pheochromocytoma', 'Disease', (47, 63))	('tumor', 'Disease', (131, 136))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (47, 63))	('ALAT', 'Disease', (409, 413))	('less', 'NegReg', (414, 418))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('paraganglioma', 'Disease', (67, 80))	('bilirubin', 'MPA', (354, 363))	('paraganglioma', 'Disease', 'MESH:D010235', (67, 80))	('albumin', 'MPA', (382, 389))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('creatinine', 'MPA', (445, 455))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('GFR', 'Gene', (488, 491))	('patients', 'Species', '9606', (33, 41))	('GFR', 'Gene', '9771', (488, 491))	('cystatin-C', 'Gene', '1471', (493, 503))	('> 25 g/L', 'Var', (390, 398))	('pheochromocytoma', 'Disease', 'MESH:D010673', (47, 63))	('creatinine', 'Chemical', 'MESH:D003404', (445, 455))	('SRS', 'Disease', 'MESH:C536678', (246, 249))	('> 100 x', 'Var', (339, 346))	('SRS', 'Disease', (246, 249))	('ASAT', 'Gene', '22', (400, 404))	('ALAT', 'Disease', 'None', (409, 413))
20489	31261748	In conclusion, PRRT with 177Lu-DOTATATE was associated with a favorable outcome and low toxicity.	('177Lu-DOTATATE', 'Var', (25, 39))	('177Lu-DOTATATE', 'Chemical', 'MESH:C447941', (25, 39))	('low toxicity', 'Disease', (84, 96))	('low toxicity', 'Disease', 'MESH:D009800', (84, 96))
20492	31308404	SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice The enzyme succinate dehydrogenase (SDH) functions in the citric acid cycle and loss of function predisposes to the development of phaeochromocytoma/paraganglioma (PPGL), wild type gastrointestinal stromal tumour (wtGIST) and renal cell carcinoma.	('phaeochromocytoma/paraganglioma', 'Disease', (234, 265))	('renal cell carcinoma', 'Disease', (329, 349))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (234, 265))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (329, 349))	('tumours', 'Disease', (74, 81))	('glioma', 'Phenotype', 'HP:0009733', (259, 265))	('succinate dehydrogenase', 'Gene', (114, 137))	('SDH', 'Gene', '6390', (0, 3))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (29, 61))	('SDH', 'Gene', (139, 142))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('SDHC', 'Gene', '6391', (0, 4))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (29, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('type gastrointestinal stromal tumour', 'Disease', 'MESH:D046152', (279, 315))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (284, 315))	('paraganglioma', 'Phenotype', 'HP:0002668', (252, 265))	('SDH', 'Gene', (0, 3))	('tumours', 'Disease', (54, 61))	('succinate dehydrogenase', 'Gene', '6390', (114, 137))	('type gastrointestinal stromal tumour', 'Disease', (279, 315))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (329, 349))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('gastrointestinal stromal tumours', 'Disease', (29, 61))	('loss', 'Var', (183, 187))	('SDHC', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (309, 315))	('SDH', 'Gene', '6390', (139, 142))	('citric acid', 'Chemical', 'MESH:D019343', (161, 172))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
20493	31308404	SDH-deficient tumours are most commonly associated with a germline SDH subunit gene (SDHA/B/C/D) mutation but can also be associated with epigenetic silencing of the SDHC gene.	('SDH-deficient tumours', 'Disease', 'MESH:D009369', (0, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('associated', 'Reg', (40, 50))	('SDH', 'Gene', '6390', (0, 3))	('SDH', 'Gene', '6390', (166, 169))	('SDH', 'Gene', '6390', (85, 88))	('mutation', 'Var', (97, 105))	('SDHC', 'Gene', '6391', (166, 170))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', '6390', (67, 70))	('epigenetic silencing', 'Var', (138, 158))	('SDH-deficient tumours', 'Disease', (0, 21))	('SDH', 'Gene', (166, 169))	('associated', 'Reg', (122, 132))	('SDHA', 'Gene', (85, 89))	('SDH', 'Gene', (85, 88))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('SDHA', 'Gene', '6389', (85, 89))	('SDHC', 'Gene', (166, 170))	('SDH', 'Gene', (67, 70))
20495	31308404	The objective of this study was to investigate the indications for and the optimum diagnostic pathways for the detection of SDHC epimutations in clinical practice.	('epimutations', 'Var', (129, 141))	('SDHC', 'Gene', '6391', (124, 128))	('SDHC', 'Gene', (124, 128))
20497	31308404	SDHC promoter methylation was identified in 6 (18.7%) tumours.	('SDHC', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('SDHC', 'Gene', '6391', (0, 4))	('methylation', 'Var', (14, 25))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
20498	31308404	All 6 SDHC epimutation cases presented with SDH deficient wtGIST and 3/6 cases had multiple primary tumours.	('SDH', 'Gene', (44, 47))	('SDHC', 'Gene', (6, 10))	('SDH', 'Gene', (6, 9))	('multiple primary tumours', 'Disease', 'MESH:D009378', (83, 107))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('SDHC', 'Gene', '6391', (6, 10))	('SDH', 'Gene', '6390', (44, 47))	('presented with', 'Reg', (29, 43))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('multiple primary tumours', 'Disease', (83, 107))	('epimutation', 'Var', (11, 22))	('SDH', 'Gene', '6390', (6, 9))
20500	31308404	Whole genome sequencing of germline DNA from three wtGIST cases with an SDHC epimutation, did not reveal any causative sequence anomalies.	('epimutation', 'Var', (77, 88))	('SDHC', 'Gene', '6391', (72, 76))	('SDHC', 'Gene', (72, 76))
20501	31308404	Herein, we recommend a diagnostic workflow for the detection of an SDHC epimutation in a service setting.	('SDHC', 'Gene', '6391', (67, 71))	('SDHC', 'Gene', (67, 71))	('epimutation', 'Var', (72, 83))
20504	31308404	Biallelic inactivation of one of the four SDH subunit genes (SDHA, SDHB, SDHC, SDHD) is the most common mechanism causing SDH deficient (dSDH) tumours.	('SDH', 'Gene', '6390', (42, 45))	('SDH', 'Gene', '6390', (73, 76))	('SDH', 'Gene', (61, 64))	('SDHC', 'Gene', '6391', (73, 77))	('SDH', 'Gene', (138, 141))	('SDHD', 'Gene', '6392', (79, 83))	('SDH', 'Gene', '6390', (79, 82))	('SDH', 'Gene', (122, 125))	('SDH', 'Gene', '6390', (122, 125))	('SDH', 'Gene', (42, 45))	('SDH', 'Gene', (73, 76))	('SDHD', 'Gene', (79, 83))	('SDHB', 'Gene', '6390', (67, 71))	('SDH deficient (dSDH) tumours', 'Disease', 'MESH:D009369', (122, 150))	('SDHC', 'Gene', (73, 77))	('SDH', 'Gene', '6390', (67, 70))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('causing', 'Reg', (114, 121))	('Biallelic inactivation', 'Var', (0, 22))	('SDH', 'Gene', (79, 82))	('SDH', 'Gene', '6390', (61, 64))	('SDHA', 'Gene', (61, 65))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('SDH', 'Gene', '6390', (138, 141))	('SDHB', 'Gene', (67, 71))	('SDHA', 'Gene', '6389', (61, 65))	('SDH', 'Gene', (67, 70))
20505	31308404	Germline genetic testing for germline SDHx mutations is now considered best practice for patients presenting with i) PPGL, ii) wild type gastrointestinal stromal tumours (wtGIST) and iii) specific histopathological subtypes of renal cell carcinoma.	('type gastrointestinal stromal tumours', 'Disease', (132, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (227, 247))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (227, 247))	('gastrointestinal stromal tumour', 'Phenotype', 'HP:0100723', (137, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('SDHx', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('type gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (132, 169))	('PPGL', 'Disease', (117, 121))	('SDHx', 'Chemical', '-', (38, 42))	('patients', 'Species', '9606', (89, 97))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('renal cell carcinoma', 'Disease', (227, 247))
20506	31308404	wtGIST are defined as GIST that are negative for KIT and PDGFRA somatic gene mutations and account for 15% of adult and 85% of paediatric GIST.	('mutations', 'Var', (77, 86))	('PDGFRA', 'Gene', (57, 63))	('PDGFRA', 'Gene', '5156', (57, 63))	('negative', 'NegReg', (36, 44))	('KIT', 'Gene', (49, 52))
20507	31308404	Biallelic inactivation of any of the SDHx genes, most commonly results in destabilisation of the SDH enzyme complex, which can be detected by loss of staining for the SDHB protein on IH and therefore wtGIST can be further classified based on the loss or preservation of SDHB protein expression on immunohistochemistry as a surrogate marker for loss of function of the SDH complex.	('SDH', 'Gene', (270, 273))	('loss', 'NegReg', (142, 146))	('SDH', 'Gene', (37, 40))	('destabilisation', 'MPA', (74, 89))	('SDHB', 'Gene', '6390', (270, 274))	('SDH', 'Gene', (167, 170))	('SDHB', 'Gene', (270, 274))	('SDH', 'Gene', '6390', (97, 100))	('SDHB', 'Gene', '6390', (167, 171))	('SDH', 'Gene', '6390', (368, 371))	('SDHx', 'Chemical', '-', (37, 41))	('SDHB', 'Gene', (167, 171))	('SDH', 'Gene', (368, 371))	('SDH', 'Gene', '6390', (270, 273))	('SDH', 'Gene', '6390', (37, 40))	('SDH', 'Gene', (97, 100))	('SDH', 'Gene', '6390', (167, 170))	('Biallelic', 'Var', (0, 9))
20509	31308404	Identification of a germline pathogenic variant in SDHB informs a higher risk of a malignant PPGL and detection of a germline SDHx mutation facilitates personalised surveillance, family screening and potentially the choice of therapy for metastatic disease.	('malignant PPGL', 'Disease', (83, 97))	('pathogenic', 'Reg', (29, 39))	('variant', 'Var', (40, 47))	('SDHx', 'Gene', (126, 130))	('SDHx', 'Chemical', '-', (126, 130))	('SDHB', 'Gene', '6390', (51, 55))	('SDHB', 'Gene', (51, 55))	('facilitates', 'PosReg', (140, 151))
20510	31308404	In addition to testing for germline SDHx variants, immunostaining for SDHB and SDHA is a valuable approach for identifying dSDH tumours.	('SDHx', 'Gene', (36, 40))	('variants', 'Var', (41, 49))	('SDHB', 'Gene', '6390', (70, 74))	('SDHB', 'Gene', (70, 74))	('SDHx', 'Chemical', '-', (36, 40))	('SDHA', 'Gene', (79, 83))	('dSDH tumours', 'Disease', 'MESH:D009369', (123, 135))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('SDHA', 'Gene', '6389', (79, 83))	('dSDH tumours', 'Disease', (123, 135))
20511	31308404	It is now recognized that in a subset of dSDH tumours, SDH inactivation results from promoter hypermethylation and epigenetic silencing of the SDHC gene.	('promoter', 'MPA', (85, 93))	('SDH', 'Gene', '6390', (55, 58))	('inactivation', 'NegReg', (59, 71))	('SDH', 'Gene', '6390', (42, 45))	('SDHC', 'Gene', '6391', (143, 147))	('dSDH tumours', 'Disease', (41, 53))	('SDH', 'Gene', (143, 146))	('dSDH tumours', 'Disease', 'MESH:D009369', (41, 53))	('SDH', 'Gene', (42, 45))	('epigenetic silencing', 'Var', (115, 135))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', '6390', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('SDHC', 'Gene', (143, 147))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
20513	31308404	Distinguishing dSDH tumours with germline SDHx mutations from those with SDHC hypermethylation only is beneficial because i) the relatives of patients with a germline SDHx mutation are at increased tumour risk and ii) an SDHC epimutation is potentially reversible (clinical trials have been initiated to investigate demethylating agents in such cases (ClinicalTrials.gov Identifier: NCT03165721)).	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('Distinguishing dSDH tumours', 'Disease', 'MESH:D009369', (0, 27))	('tumour', 'Disease', (20, 26))	('mutation', 'Var', (172, 180))	('SDHC', 'Gene', '6391', (73, 77))	('tumours', 'Phenotype', 'HP:0002664', (20, 27))	('mutations', 'Var', (47, 56))	('SDHx', 'Gene', (42, 46))	('SDHC', 'Gene', '6391', (221, 225))	('SDHC', 'Gene', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('SDHx', 'Chemical', '-', (42, 46))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('tumour', 'Disease', (198, 204))	('SDHx', 'Chemical', '-', (167, 171))	('SDHC', 'Gene', (221, 225))	('Distinguishing dSDH tumours', 'Disease', (0, 27))	('patients', 'Species', '9606', (142, 150))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
20514	31308404	SDHC epimutations appear to be unique to specific tumour types (e.g wtGIST and PPGL) but further study is required to determine whether SDHC epimutations might occur in tumours with an associated hypermethylation phenotype other than SDH deficient wt GIST and PPGL.	('tumours', 'Disease', (169, 176))	('SDH', 'Gene', (234, 237))	('hypermethylation', 'MPA', (196, 212))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('SDH', 'Gene', '6390', (136, 139))	('tumours', 'Disease', 'MESH:D009369', (169, 176))	('SDH', 'Gene', '6390', (0, 3))	('SDHC', 'Gene', '6391', (136, 140))	('epimutations', 'Var', (141, 153))	('SDHC', 'Gene', '6391', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (169, 175))	('tumour', 'Disease', (50, 56))	('SDH', 'Gene', (136, 139))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', '6390', (234, 237))	('SDHC', 'Gene', (136, 140))	('SDHC', 'Gene', (0, 4))
20515	31308404	IDH1 mutant gliomas have previously been associated with a global hypermethylation phenotype due to inhibition of alpha ketoglutarate dependent de-methylation enzymes and therefore IDH1mutant gliomas are a useful tumour type to test the hypothesis that SDHC promoter hypermethylation is unique to specific tumour types.	('gliomas', 'Disease', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (306, 312))	('tumour', 'Disease', 'MESH:D009369', (306, 312))	('IDH1', 'Gene', (0, 4))	('tumour', 'Disease', (306, 312))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('gliomas', 'Disease', (192, 199))	('IDH1', 'Gene', (181, 185))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('inhibition', 'NegReg', (100, 110))	('IDH1', 'Gene', '3417', (0, 4))	('alpha', 'MPA', (114, 119))	('SDHC', 'Gene', '6391', (253, 257))	('global hypermethylation', 'MPA', (59, 82))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (192, 199))	('IDH1', 'Gene', '3417', (181, 185))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('tumour', 'Disease', (213, 219))	('mutant', 'Var', (5, 11))	('gliomas', 'Phenotype', 'HP:0009733', (192, 199))	('SDHC', 'Gene', (253, 257))	('alpha ketoglutarate', 'Chemical', 'MESH:D007656', (114, 133))
20516	31308404	Despite the implications for patient management and family testing and screening, diagnostic testing for SDHC epimutations has not been adopted as routine clinical practice because the indications for testing and a suitable methodology for a clinical service laboratory have not been well defined.	('patient', 'Species', '9606', (29, 36))	('SDHC', 'Gene', '6391', (105, 109))	('SDHC', 'Gene', (105, 109))	('epimutations', 'Var', (110, 122))
20517	31308404	The aims of this study were; i) to investigate a pyrosequencing-based assay for the diagnosis of SDHC promoter methylation and ii) to determine the role for SDHC epimutation testing in a clinical diagnostic pathway using pooled data from this study and available literature.	('SDHC', 'Gene', (157, 161))	('epimutation', 'Var', (162, 173))	('SDHC', 'Gene', '6391', (157, 161))	('SDHC', 'Gene', (97, 101))	('SDHC', 'Gene', '6391', (97, 101))
20525	31308404	Tumour samples with evidence of SDHB preservation on SDHB IH were included in SDHC promoter methylation analysis in order to confirm if SDHB IH was a sensitive triaging test for the diagnosis of an SDHC epimutation.	('SDHC', 'Gene', '6391', (78, 82))	('SDHC', 'Gene', '6391', (198, 202))	('SDHB', 'Gene', '6390', (32, 36))	('SDHB', 'Gene', '6390', (53, 57))	('SDHB', 'Gene', '6390', (136, 140))	('SDHB', 'Gene', (32, 36))	('SDHB', 'Gene', (53, 57))	('SDHB', 'Gene', (136, 140))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('SDHC', 'Gene', (78, 82))	('SDHC', 'Gene', (198, 202))	('epimutation', 'Var', (203, 214))
20527	31308404	SDHC expression analysis was performed on RNA extracted from FFPE tumour and matched normal tissue and finally sequencing of tumour DNA was performed to identify somatic SDHx mutations.	('SDHx', 'Gene', (170, 174))	('FFPE tumour', 'Disease', (61, 72))	('SDHC', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('SDHC', 'Gene', '6391', (0, 4))	('mutations', 'Var', (175, 184))	('FFPE tumour', 'Disease', 'MESH:D009369', (61, 72))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (66, 72))	('tumour', 'Disease', (125, 131))	('SDHx', 'Chemical', '-', (170, 174))
20528	31308404	A further 17 IDH1 mutant glioma samples (anonymised tumour DNA from consented patients provided by Professor Colin Watts) were included in the study.	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (25, 31))	('mutant', 'Var', (18, 24))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (78, 86))	('IDH1', 'Gene', (13, 17))	('glioma', 'Phenotype', 'HP:0009733', (25, 31))	('IDH1', 'Gene', '3417', (13, 17))	('tumour', 'Disease', (52, 58))	('glioma', 'Disease', (25, 31))
20563	31308404	All cases identified as having an SDHC epimutation in this study had a dSDH wtGIST as the presenting phenotype.	('SDH', 'Gene', '6390', (72, 75))	('SDHC', 'Gene', (34, 38))	('SDH', 'Gene', (34, 37))	('SDHC', 'Gene', '6391', (34, 38))	('epimutation', 'Var', (39, 50))	('SDH', 'Gene', (72, 75))	('SDH', 'Gene', '6390', (34, 37))
20564	31308404	Comparing 6 tumours with evidence of SDHC hypermethylation to those with low methylation revealed statistically significant associations with wtGIST (6/15 versus 0/17 PPGL; P = 0.005), female sex (6/19 versus 0/13 males; P = 0.02); metastatic disease (5/6 versus 5/26 (P = 0.035), younger age at diagnosis (mean age 24 years versus mean age 39.2 years) (P = 0.0002) and multiple primary tumours (3/6 versus 2/26, P = 0.03).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('hypermethylation', 'Var', (42, 58))	('SDHC', 'Gene', '6391', (37, 41))	('associations', 'Interaction', (124, 136))	('metastatic disease', 'Disease', (232, 250))	('tumour', 'Phenotype', 'HP:0002664', (387, 393))	('tumours', 'Phenotype', 'HP:0002664', (387, 394))	('multiple primary tumours', 'Disease', (370, 394))	('tumours', 'Disease', (12, 19))	('tumours', 'Disease', 'MESH:D009369', (387, 394))	('tumours', 'Disease', (387, 394))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('SDHC', 'Gene', (37, 41))	('multiple primary tumours', 'Disease', 'MESH:D009378', (370, 394))
20570	31308404	ROC curve analysis (see Supplementary Data and statistical methods) demonstrated that a methylation of >8.5% separated the cases with an identified epimutation and silencing of SDHC from those without (AUC 1.0, p = < 0.0001).	('silencing', 'Var', (164, 173))	('SDHC', 'Gene', (177, 181))	('epimutation', 'Var', (148, 159))	('methylation', 'MPA', (88, 99))	('SDHC', 'Gene', '6391', (177, 181))
20572	31308404	In 5/5 tumour samples with SDHC hypermethylation the mean fold difference was -6.41(SD 5.4) (Fig.	('SDHC', 'Gene', (27, 31))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('SDHC', 'Gene', '6391', (27, 31))	('hypermethylation', 'Var', (32, 48))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))
20574	31308404	Tumour sequencing was performed on 4/6 (#001, #002, #003, #004) cases with evidence of SDHC hypermethylation and no somatic SDHx variants were detected.	('SDHC', 'Gene', (87, 91))	('SDHC', 'Gene', '6391', (87, 91))	('hypermethylation', 'Var', (92, 108))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('SDHx', 'Chemical', '-', (124, 128))
20575	31308404	SDHB immunohistochemistry was performed on all tumours and loss of SDHB expression was confirmed in all 6 cases with SDHC hypermethylation (Table 1, examples for #001 and #003 displayed in Fig.	('SDHB', 'Gene', '6390', (67, 71))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('SDHC', 'Gene', (117, 121))	('expression', 'MPA', (72, 82))	('SDHB', 'Gene', (67, 71))	('SDHB', 'Gene', '6390', (0, 4))	('tumours', 'Disease', (47, 54))	('SDHC', 'Gene', '6391', (117, 121))	('loss', 'NegReg', (59, 63))	('hypermethylation', 'Var', (122, 138))	('SDHB', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
20577	31308404	No candidate pathogenic structural or single nucleotide variants were identified in these three cases in the SDHC locus (between 161314257-161375340) containing the SDHC promoter, exons and 3'UTR.	('SDHC', 'Gene', '6391', (109, 113))	('SDHC', 'Gene', (165, 169))	('between 161314257-161375340', 'Var', (121, 148))	('SDHC', 'Gene', '6391', (165, 169))	('SDHC', 'Gene', (109, 113))
20578	31308404	In the absence of an in cis genetic cause, additional analysis for potential pathogenic variants in genes implicated in genome methylation (TET1, TET2, TET3, DNMT3B, DNMT3A, DNMT1), was performed.	('DNMT3A', 'Gene', '1788', (166, 172))	('TET1', 'Gene', '80312', (140, 144))	('variants', 'Var', (88, 96))	('TET2', 'Gene', (146, 150))	('TET3', 'Gene', '200424', (152, 156))	('DNMT3B', 'Gene', (158, 164))	('DNMT3B', 'Gene', '1789', (158, 164))	('TET2', 'Gene', '54790', (146, 150))	('DNMT1', 'Gene', (174, 179))	('DNMT1', 'Gene', '1786', (174, 179))	('TET1', 'Gene', (140, 144))	('TET3', 'Gene', (152, 156))	('DNMT3A', 'Gene', (166, 172))
20580	31308404	None of the variants identified in the SDHC methylation cases were considered to be pathogenic by ACMG criteria.	('SDHC', 'Gene', (39, 43))	('variants', 'Var', (12, 20))	('methylation', 'Var', (44, 55))	('SDHC', 'Gene', '6391', (39, 43))
20581	31308404	A missense variant of uncertain significance in TET2 (p.Ile1762Val) was identified in all three cases with SDHC promoter hypermethylation, but this variant was absent from 1000 genomes and UK10K databases and was identified in 1876/4053 controls (Table S2).	('TET2', 'Gene', (48, 52))	('p.Ile1762Val', 'Mutation', 'rs2454206', (54, 66))	('SDHC', 'Gene', (107, 111))	('SDHC', 'Gene', '6391', (107, 111))	('TET2', 'Gene', '54790', (48, 52))	('p.Ile1762Val', 'Var', (54, 66))
20583	31308404	Firstly we undertook SDHC promoter methylation analysis on 17 IDH1 mutant glioma samples.	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('SDHC', 'Gene', (21, 25))	('IDH1', 'Gene', '3417', (62, 66))	('SDHC', 'Gene', '6391', (21, 25))	('glioma', 'Disease', (74, 80))	('mutant', 'Var', (67, 73))	('IDH1', 'Gene', (62, 66))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
20584	31308404	IDH1 mutant gliomas have previously been associated with a global hypermethylation phenotype due to inhibition of alpha ketoglutarate dependent de-methylating enzymes.	('associated', 'Reg', (41, 51))	('gliomas', 'Disease', (12, 19))	('gliomas', 'Disease', 'MESH:D005910', (12, 19))	('global hypermethylation', 'MPA', (59, 82))	('gliomas', 'Phenotype', 'HP:0009733', (12, 19))	('alpha', 'Protein', (114, 119))	('mutant', 'Var', (5, 11))	('IDH1', 'Gene', (0, 4))	('glioma', 'Phenotype', 'HP:0009733', (12, 18))	('alpha ketoglutarate', 'Chemical', 'MESH:D007656', (114, 133))	('inhibition', 'NegReg', (100, 110))	('IDH1', 'Gene', '3417', (0, 4))
20585	31308404	The mean SDHC promoter methylation in the IDH1 mutant glioma samples was 2% (+-SD 1.28, range 1-4%) (Fig.	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('IDH1', 'Gene', '3417', (42, 46))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('glioma', 'Disease', (54, 60))	('SDHC', 'Gene', (9, 13))	('IDH1', 'Gene', (42, 46))	('mutant', 'Var', (47, 53))	('SDHC', 'Gene', '6391', (9, 13))	('methylation', 'MPA', (23, 34))
20589	31308404	A search of PubMed (using the terms SDHC and methylation or epimutation) identified 8 publications containing 34 cases of SDHC promoter region hypermethylation in a variety of tumour types including dSDH wtGIST, sympathetic (PGL) and parasympathetic (HNPGL) paragangliomas (Table S5).	('paragangliomas', 'Disease', (258, 272))	('SDHC', 'Gene', '6391', (122, 126))	('SDH', 'Gene', '6390', (200, 203))	('SDHC', 'Gene', (36, 40))	('hypermethylation', 'Var', (143, 159))	('SDH', 'Gene', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('SDH', 'Gene', (200, 203))	('tumour', 'Disease', (176, 182))	('SDHC', 'Gene', (122, 126))	('paragangliomas', 'Disease', 'MESH:D010235', (258, 272))	('paragangliomas', 'Phenotype', 'HP:0002668', (258, 272))	('glioma', 'Phenotype', 'HP:0009733', (265, 271))	('paraganglioma', 'Phenotype', 'HP:0002668', (258, 271))	('SDH', 'Gene', '6390', (36, 39))	('SDHC', 'Gene', '6391', (36, 40))	('gliomas', 'Phenotype', 'HP:0009733', (265, 272))	('parasympathetic', 'Disease', (234, 249))	('sympathetic', 'Disease', (212, 223))	('SDH', 'Gene', (36, 39))	('SDH', 'Gene', '6390', (122, 125))
20590	31308404	The majority of patients (94%, 32/34) identified with SDHC hypermethylation had a dSDH-wtGIST and 53% (18/34) of these cases also had an additional tumour(s) (Table S5).	('tumour', 'Disease', (148, 154))	('hypermethylation', 'Var', (59, 75))	('SDH', 'Gene', '6390', (83, 86))	('patients', 'Species', '9606', (16, 24))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('SDH', 'Gene', '6390', (54, 57))	('SDH', 'Gene', (83, 86))	('SDHC', 'Gene', (54, 58))	('tumour', 'Disease', 'MESH:D009369', (148, 154))	('SDHC', 'Gene', '6391', (54, 58))	('SDH', 'Gene', (54, 57))
20591	31308404	We identified SDHC promoter region methylation in 6/15 wtGIST (all 6 cases were dSDH-wtGIST) but none of the 17 PPGL or SDH-preserved-wtGIST (3/15 wtGIST).	('SDH', 'Gene', '6390', (14, 17))	('SDHC', 'Gene', (14, 18))	('SDH', 'Gene', (120, 123))	('SDHC', 'Gene', '6391', (14, 18))	('SDH', 'Gene', (14, 17))	('SDH', 'Gene', '6390', (81, 84))	('methylation', 'Var', (35, 46))	('SDH', 'Gene', (81, 84))	('SDH', 'Gene', '6390', (120, 123))
20592	31308404	All SDHC hypermethylation cases were female and were significantly younger than patients without an SDHC epimutation.	('patients', 'Species', '9606', (80, 88))	('SDHC', 'Gene', (4, 8))	('SDHC', 'Gene', (100, 104))	('SDHC', 'Gene', '6391', (4, 8))	('SDHC', 'Gene', '6391', (100, 104))	('hypermethylation', 'Var', (9, 25))
20594	31308404	Rare reports of isolated sympathetic and parasympathetic PGL with an SDHC epimutation have also been published (Table S5).	('epimutation', 'Var', (74, 85))	('SDHC', 'Gene', '6391', (69, 73))	('SDHC', 'Gene', (69, 73))
20595	31308404	In two of the cases reported here, somatic SDHC promoter methylation was detected in the presence of a germline pathogenic SDHC variant.	('variant', 'Var', (128, 135))	('SDHC', 'Gene', '6391', (123, 127))	('SDHC', 'Gene', '6391', (43, 47))	('detected', 'Reg', (73, 81))	('SDHC', 'Gene', (123, 127))	('SDHC', 'Gene', (43, 47))
20596	31308404	This would be consistent (though not proven) with a two hit model of tumourigenesis in which SDHC hypermethylation resulted in silencing of the wild-type allele in the tumour.	('tumour', 'Disease', (69, 75))	('silencing', 'MPA', (127, 136))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('SDHC', 'Gene', (93, 97))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('tumour', 'Disease', (168, 174))	('SDHC', 'Gene', '6391', (93, 97))	('hypermethylation', 'Var', (98, 114))
20597	31308404	Two of the cases with a germline SDHC mutation had multiple tumours including case #004 (Fig.	('SDHC', 'Gene', '6391', (33, 37))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('multiple tumour', 'Disease', (51, 66))	('tumours', 'Disease', (60, 67))	('multiple tumour', 'Disease', 'MESH:D009369', (51, 66))	('mutation', 'Var', (38, 46))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('SDHC', 'Gene', (33, 37))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
20599	31308404	Although it was previously suggested that PCHO occurred exclusively in CT (a non-inherited disorder), this study and others have demonstrated that the triad of wtGIST, PPGL and PCHO can occur in association with a germline SDHx mutation and highlights the overlapping features of CT and CSS.	('PCHO', 'Disease', (177, 181))	('mutation', 'Var', (228, 236))	('association', 'Interaction', (195, 206))	('PCHO', 'CellLine', 'None', (177, 181))	('wtGIST', 'Disease', (160, 166))	('CSS', 'Disease', (287, 290))	('PPGL', 'Disease', (168, 172))	('CSS', 'Disease', 'MESH:C536436', (287, 290))	('SDHx', 'Chemical', '-', (223, 227))	('non-inherited disorder', 'Disease', 'MESH:D030342', (77, 99))	('SDHx', 'Gene', (223, 227))	('PCHO', 'CellLine', 'None', (42, 46))	('non-inherited disorder', 'Disease', (77, 99))
20604	31308404	In the case of the mismatch repair gene MLH1, somatic MLH1 promoter methylation is relatively common in older individuals with colorectal cancer with microsatellite instability but there are rare cases of patients with a constitutional MLH1 epimutation who present at a younger age.	('MLH1', 'Gene', '4292', (54, 58))	('patients', 'Species', '9606', (205, 213))	('MLH1', 'Gene', '4292', (236, 240))	('common', 'Reg', (94, 100))	('MLH1', 'Gene', (54, 58))	('MLH1', 'Gene', (236, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('microsatellite instability', 'Var', (150, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('MLH1', 'Gene', '4292', (40, 44))	('epimutation', 'Var', (241, 252))	('MLH1', 'Gene', (40, 44))
20606	31308404	In the absence of a detectable in cis or in trans genetic variant in these cases, low level postzygotic tissue mosaicism for SDHC promoter hypermethylation, provides an alternative hypothesis for this multiple tumour phenotype at a young age.	('SDHC', 'Gene', (125, 129))	('hypermethylation', 'Var', (139, 155))	('multiple tumour', 'Disease', (201, 216))	('multiple tumour', 'Disease', 'MESH:D009369', (201, 216))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('SDHC', 'Gene', '6391', (125, 129))
20610	31308404	We found that the methylation status of 12 CpG's in CpG27 in the promoter region of the SDHC gene could be accurately assessed and that detection of hypermethylation of the SDHC promoter correlated with reduced SDHC mRNA on mRNA extracted from the same FFPE tissue block.	('SDHC', 'Gene', '6391', (211, 215))	('CpG27', 'Gene', (52, 57))	('SDHC', 'Gene', '6391', (173, 177))	('reduced', 'NegReg', (203, 210))	('hypermethylation', 'Var', (149, 165))	('SDHC', 'Gene', (211, 215))	('SDHC', 'Gene', (88, 92))	('SDHC', 'Gene', (173, 177))	('SDHC', 'Gene', '6391', (88, 92))
20613	31308404	The authors recommend that whenever possible, cases with SDHC promoter hypermethylation should be analysed by RT-PCR of both tumour and adjacent normal tissue to confirm silencing of SDHC in the tumour tissue.	('promoter hypermethylation', 'Var', (62, 87))	('SDHC', 'Gene', '6391', (57, 61))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('SDHC', 'Gene', (183, 187))	('tumour', 'Disease', (195, 201))	('silencing', 'MPA', (170, 179))	('SDHC', 'Gene', '6391', (183, 187))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('SDHC', 'Gene', (57, 61))
20616	31308404	If germline genetic testing (including MLPA) is negative and SDHB IH suggests loss of SDHB protein expression, the first step for PPGL should be somatic sequencing to investigate for somatic SDHx or VHL mutations, which can account for loss of SDHB protein expression.	('expression', 'MPA', (99, 109))	('SDHB', 'Gene', (86, 90))	('SDHB', 'Gene', '6390', (61, 65))	('VHL', 'Gene', '7428', (199, 202))	('SDHx', 'Chemical', '-', (191, 195))	('protein', 'Protein', (91, 98))	('loss', 'NegReg', (78, 82))	('VHL', 'Gene', (199, 202))	('SDHB', 'Gene', (61, 65))	('SDHB', 'Gene', '6390', (244, 248))	('SDHB', 'Gene', (244, 248))	('mutations', 'Var', (203, 212))	('SDHx', 'Gene', (191, 195))	('SDHB', 'Gene', '6390', (86, 90))
20617	31308404	However, as SDHC epimutations are more frequent in wtGIST than in PPGL, we recommend SDHC promoter methylation analysis as the next step after germline genetic testing for wtGIST (Fig.	('SDHC', 'Gene', (85, 89))	('SDHC', 'Gene', '6391', (85, 89))	('SDHC', 'Gene', (12, 16))	('epimutations', 'Var', (17, 29))	('SDHC', 'Gene', '6391', (12, 16))
20618	31308404	If an SDHC epimutation is diagnosed, somatic tumour sequencing should be performed to identify a co-existing somatic SDHx mutation, which may affect the efficacy of any potential demethylating therapy (Fig.	('affect', 'Reg', (142, 148))	('efficacy', 'MPA', (153, 161))	('SDHC', 'Gene', (6, 10))	('mutation', 'Var', (122, 130))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('SDHC', 'Gene', '6391', (6, 10))	('SDHx', 'Chemical', '-', (117, 121))	('SDHx', 'Gene', (117, 121))	('tumour', 'Disease', (45, 51))
20621	31308404	In conclusion, the results from our literature review, experimental studies and interrogation of the TCGA data, suggest that SDHC epimutations are rare in tumours other than wtGIST and PPGL.	('tumours', 'Disease', (155, 162))	('SDHC', 'Gene', (125, 129))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('SDHC', 'Gene', '6391', (125, 129))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('epimutations', 'Var', (130, 142))
20622	31308404	Improving the accessibility of clinical diagnostic testing for SDHC promoter methylation will facilitate the management of patients with wtGIST by enabling stratification for personalised therapeutic strategies and defining risks for other family members, according to the presence or absence of a germline SDHx mutation and or a SDHC epimutation.	('mutation', 'Var', (312, 320))	('SDHC', 'Gene', (330, 334))	('SDHC', 'Gene', (63, 67))	('patients', 'Species', '9606', (123, 131))	('facilitate', 'PosReg', (94, 104))	('SDHC', 'Gene', '6391', (330, 334))	('SDHC', 'Gene', '6391', (63, 67))	('epimutation', 'Var', (335, 346))	('SDHx', 'Chemical', '-', (307, 311))	('SDHx', 'Gene', (307, 311))
20653	29084607	Only a few tumor cells showed positive immunolabeling for Ki67.	('Ki67', 'Var', (58, 62))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))
20678	28471419	Half of these inherited cases are intriguingly caused by mutations in genes encoding tricarboxylic acid enzymes, namely SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, encoding succinate dehydrogenase and its assembly protein, FH encoding fumarate hydratase, and MDH2 encoding malate dehydrogenase.	('malate dehydrogenase', 'Gene', (271, 291))	('succinate dehydrogenase', 'Gene', (171, 194))	('FH', 'Gene', '2271', (221, 223))	('mutations', 'Var', (57, 66))	('SDHC', 'Gene', (132, 136))	('SDHB', 'Gene', '6390', (126, 130))	('SDHA', 'Gene', (120, 124))	('MDH2', 'Gene', (257, 261))	('fumarate hydratase', 'Gene', (233, 251))	('SDHA', 'Gene', '6389', (120, 124))	('SDHB', 'Gene', (126, 130))	('succinate dehydrogenase', 'Gene', '6390', (171, 194))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (85, 103))	('SDHA', 'Gene', (148, 152))	('caused by', 'Reg', (47, 56))	('SDHC', 'Gene', '6391', (132, 136))	('SDHD', 'Gene', '6392', (138, 142))	('SDHA', 'Gene', '6389', (148, 152))	('MDH2', 'Gene', '4191', (257, 261))	('malate dehydrogenase', 'Gene', '10873', (271, 291))	('SDHAF2', 'Gene', '54949', (148, 154))	('fumarate hydratase', 'Gene', '2271', (233, 251))	('SDHAF2', 'Gene', (148, 154))	('SDHD', 'Gene', (138, 142))
20679	28471419	These mutations may also predispose to other type of cancers, such as renal cancer, leiomyomas, or gastro-intestinal stromal tumours.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('gastro-intestinal stromal tumours', 'Phenotype', 'HP:0100723', (99, 132))	('gastro-intestinal stromal tumour', 'Phenotype', 'HP:0100723', (99, 131))	('leiomyomas', 'Disease', 'MESH:D007889', (84, 94))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('renal cancer', 'Disease', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('gastro-intestinal stromal tumours', 'Disease', (99, 132))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('leiomyomas', 'Disease', (84, 94))	('gastro-intestinal stromal tumours', 'Disease', 'MESH:D007414', (99, 132))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('renal cancer', 'Disease', 'MESH:D007680', (70, 82))	('renal cancer', 'Phenotype', 'HP:0009726', (70, 82))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('predispose', 'Reg', (25, 35))	('mutations', 'Var', (6, 15))
20689	28471419	Approximately 40% of patients with PPGLs carry a germline mutation in one of the 13 PPGL predisposing genes identified so far, including the RET proto-oncogene and the NF1, VHL, and SDHx genes.	('VHL', 'Gene', (173, 176))	('RET', 'Gene', '5979', (141, 144))	('VHL', 'Gene', '7428', (173, 176))	('PPGL', 'Gene', (84, 88))	('PPGLs', 'Disease', (35, 40))	('patients', 'Species', '9606', (21, 29))	('NF1', 'Gene', (168, 171))	('RET', 'Gene', (141, 144))	('SDHx', 'Chemical', '-', (182, 186))	('germline mutation', 'Var', (49, 66))	('SDHx', 'Gene', (182, 186))	('NF1', 'Gene', '4763', (168, 171))	('PGLs', 'Phenotype', 'HP:0002668', (36, 40))
20690	28471419	Other rare cases involve germline mutations in the FH, TMEM127, MAX, and MDH2 genes.	('TMEM127', 'Gene', (55, 62))	('TMEM127', 'Gene', '55654', (55, 62))	('MDH2', 'Gene', '4191', (73, 77))	('FH', 'Gene', '2271', (51, 53))	('MDH2', 'Gene', (73, 77))	('germline mutations', 'Var', (25, 43))	('MAX', 'Gene', (64, 67))
20692	28471419	Predisposing mutations can occur in apparently sporadic tumours (12-15%) or in the context of a hereditary cancer syndrome mostly represented by the following three genetic syndromes: multiple endocrine neoplasia type 2, Von Hippel-Lindau disease, and neurofibromatosis type I. Activating mutations in the RET proto-oncogene lead to multiple endocrine neoplasia type 2 (MEN2), characterized by the development of medullary thyroid carcinoma, often associated with PCCs and hyperparathyroidism.	('neoplasia', 'Phenotype', 'HP:0002664', (203, 212))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (473, 492))	('mutations', 'Var', (289, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (431, 440))	('neurofibromatosis type I', 'Disease', (252, 276))	('hereditary cancer syndrome', 'Disease', 'MESH:D009386', (96, 122))	('sporadic tumours', 'Disease', 'MESH:D009369', (47, 63))	('RET', 'Gene', (306, 309))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (473, 492))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (193, 212))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (252, 269))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (333, 368))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (342, 361))	('PC', 'Gene', '18563', (464, 466))	('sporadic tumours', 'Disease', (47, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (423, 440))	('neoplasia', 'Phenotype', 'HP:0002664', (352, 361))	('neurofibromatosis type I', 'Disease', 'MESH:C537392', (252, 276))	('multiple endocrine neoplasia type 2', 'Disease', (184, 219))	('Von Hippel-Lindau disease', 'Disease', (221, 246))	('thyroid carcinoma', 'Disease', (423, 440))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (413, 440))	('genetic syndromes', 'Disease', (165, 182))	('genetic syndromes', 'Disease', 'MESH:D030342', (165, 182))	('hereditary cancer syndrome', 'Disease', (96, 122))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (221, 246))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (423, 440))	('Activating', 'PosReg', (278, 288))	('lead to', 'Reg', (325, 332))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RET', 'Gene', '5979', (306, 309))	('PCCs', 'Phenotype', 'HP:0002666', (464, 468))	('hyperparathyroidism', 'Disease', (473, 492))	('multiple endocrine neoplasia type 2', 'Disease', (333, 368))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (184, 219))
20694	28471419	Mutations in this gene cause neurofibromatosis type 1, also known as Von Recklinghausen disease, a frequent autosomal disorder (prevalence of 1 in 3000 to 1 in 4000 people in the general population and a high penetrance) characterized by pigmentary abnormalities and neoplastic growth of neural crest-derived cells, such as multiple dermal neurofibromas and very rarely PCCs (0.1-5.7% of patients with NF1).	('Von Recklinghausen disease', 'Disease', (69, 95))	('pigmentary abnormalities', 'Disease', (238, 262))	('neurofibromas', 'Phenotype', 'HP:0001067', (340, 353))	('PC', 'Gene', '18563', (370, 372))	('patients', 'Species', '9606', (388, 396))	('NF1', 'Gene', '4763', (402, 405))	('cause', 'Reg', (23, 28))	('neurofibromatosis type 1', 'Gene', (29, 53))	('Von Recklinghausen disease', 'Disease', 'MESH:C537392', (69, 95))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (29, 46))	('Mutations', 'Var', (0, 9))	('NF1', 'Gene', (402, 405))	('multiple dermal neurofibromas', 'Disease', 'MESH:C537392', (324, 353))	('pigmentary abnormalities', 'Phenotype', 'HP:0001000', (238, 262))	('neurofibromatosis type 1', 'Gene', '4763', (29, 53))	('pigmentary abnormalities', 'Disease', 'MESH:C536859', (238, 262))	('multiple dermal neurofibromas', 'Disease', (324, 353))	('people', 'Species', '9606', (165, 171))	('PCCs', 'Phenotype', 'HP:0002666', (370, 374))	('autosomal disorder', 'Disease', 'MESH:D030342', (108, 126))	('autosomal disorder', 'Disease', (108, 126))
20695	28471419	The Von Hippel Lindau disease is a hereditary neoplastic syndrome caused by mutations in the VHL tumour suppressor gene, which are responsible for a predisposition to renal cell carcinoma (RCC), retinal or central nervous system hemangioblastomas, pancreatic cysts, and PCCs.	('central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (206, 246))	('VHL tumour', 'Disease', (93, 103))	('neoplastic syndrome', 'Phenotype', 'HP:0002664', (46, 65))	('VHL tumour', 'Disease', 'MESH:D006623', (93, 103))	('pancreatic cysts', 'Disease', (248, 264))	('RCC', 'Disease', 'MESH:C538614', (189, 192))	('caused by', 'Reg', (66, 75))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (248, 264))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (167, 187))	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (214, 246))	('PCCs', 'Phenotype', 'HP:0002666', (270, 274))	('Von Hippel Lindau disease', 'Disease', 'MESH:D006623', (4, 29))	('central nervous system hemangioblastomas', 'Disease', (206, 246))	('hereditary neoplastic syndrome', 'Disease', (35, 65))	('Von Hippel Lindau disease', 'Disease', (4, 29))	('retinal', 'Disease', (195, 202))	('retinal', 'Disease', 'MESH:D012173', (195, 202))	('renal cell carcinoma', 'Disease', (167, 187))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (167, 187))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatic cysts', 'Disease', 'MESH:D010181', (248, 264))	('mutations', 'Var', (76, 85))	('PC', 'Gene', '18563', (270, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('hereditary neoplastic syndrome', 'Disease', 'MESH:D009386', (35, 65))	('RCC', 'Disease', (189, 192))	('RCC', 'Phenotype', 'HP:0005584', (189, 192))
20700	28471419	In 2000, the description of the first mutations in the SDHD gene in patients with PPGL was a major breakthrough, not only in the understanding of PPGL tumorigenesis but in cancer in general.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('SDHD', 'Gene', '6392', (55, 59))	('cancer', 'Disease', (172, 178))	('mutations', 'Var', (38, 47))	('SDHD', 'Gene', (55, 59))
20708	28471419	Hence, patients carry a germline heterozygous loss-of-function mutation and subsequent loss of heterozygosity (LOH) at somatic level, leads to the complete inactivation of the gene.	('loss', 'NegReg', (87, 91))	('inactivation', 'MPA', (156, 168))	('mutation', 'Var', (63, 71))	('loss-of-function', 'NegReg', (46, 62))	('patients', 'Species', '9606', (7, 15))
20710	28471419	Previous studies have reported that germline mutations in one of the SDHx genes lead to PPGL predisposition in patients, which is transmitted in an autosomal dominant fashion for SDHA, SDHB, and SDHC genes mutations and in an autosomal dominant fashion with maternal imprinting for SDHD and SDHAF2 genes.	('SDHB', 'Gene', (185, 189))	('SDHD', 'Gene', (282, 286))	('lead to', 'Reg', (80, 87))	('SDHx', 'Chemical', '-', (69, 73))	('SDHC', 'Gene', (195, 199))	('transmitted', 'Reg', (130, 141))	('mutations', 'Var', (206, 215))	('SDHB', 'Gene', '6390', (185, 189))	('SDHAF2', 'Gene', (291, 297))	('SDHD', 'Gene', '6392', (282, 286))	('SDHAF2', 'Gene', '54949', (291, 297))	('SDHA', 'Gene', (291, 295))	('SDHA', 'Gene', (179, 183))	('PPGL predisposition', 'Gene', (88, 107))	('SDHC', 'Gene', '6391', (195, 199))	('SDHA', 'Gene', '6389', (291, 295))	('SDHA', 'Gene', '6389', (179, 183))	('SDHx', 'Gene', (69, 73))	('patients', 'Species', '9606', (111, 119))
20714	28471419	SDHD germline mutations have a penetrance of 86% at the age of 50 and are frequently associated with the development of multiple head and neck PGL and with family history of PPGLs in the paternal branch.	('associated with', 'Reg', (85, 100))	('PGLs', 'Phenotype', 'HP:0002668', (175, 179))	('SDHD', 'Gene', '6392', (0, 4))	('SDHD', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
20716	28471419	On the contrary, malignant PPGLs are only found in 5% of SDHD or SDHC mutation carriers.	('SDHD', 'Gene', '6392', (57, 61))	('SDHC', 'Gene', (65, 69))	('SDHD', 'Gene', (57, 61))	('SDHC', 'Gene', '6391', (65, 69))	('PGLs', 'Phenotype', 'HP:0002668', (28, 32))	('mutation', 'Var', (70, 78))
20717	28471419	Germline SDHB mutations are found in 36% of all malignant PPGLs, and SDHB-related malignant PPGLs have a worst prognosis than all other types of malignant PPGL.	('SDHB', 'Gene', '6390', (9, 13))	('SDHB', 'Gene', (69, 73))	('SDHB', 'Gene', (9, 13))	('PGLs', 'Phenotype', 'HP:0002668', (59, 63))	('SDHB', 'Gene', '6390', (69, 73))	('PGLs', 'Phenotype', 'HP:0002668', (93, 97))	('mutations', 'Var', (14, 23))
20719	28471419	The reason for this phenotypic characteristic of SDHB mutants is still unclear.	('SDHB', 'Gene', (49, 53))	('mutants', 'Var', (54, 61))	('SDHB', 'Gene', '6390', (49, 53))
20720	28471419	Germline mutation in SDHC gene are rare and may be associated with any type of PPGL.	('SDHC', 'Gene', (21, 25))	('SDHC', 'Gene', '6391', (21, 25))	('PPGL', 'Disease', (79, 83))	('associated', 'Reg', (51, 61))	('Germline mutation', 'Var', (0, 17))
20721	28471419	Finally, SDHA and SDHAF2 mutations have been described in only few patients and predispose to abdominal PPGL and head and neck PGL, respectively.	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (67, 75))	('SDHA', 'Gene', '6389', (9, 13))	('SDHA', 'Gene', (18, 22))	('SDHAF2', 'Gene', (18, 24))	('abdominal PPGL', 'Disease', (94, 108))	('SDHAF2', 'Gene', '54949', (18, 24))	('SDHA', 'Gene', (9, 13))	('predispose to', 'Reg', (80, 93))	('SDHA', 'Gene', '6389', (18, 22))
20722	28471419	Because of the genetic complexity of PPGL and of the large number of variants of unknown significance (VUS) identified in patients, immunochemical analyses of SDHA, SDHB, and SDHD are now used in pathology department worldwide to validate the genetic analyses.	('variants', 'Var', (69, 77))	('PPGL', 'Gene', (37, 41))	('SDHA', 'Gene', '6389', (159, 163))	('SDHB', 'Gene', '6390', (165, 169))	('SDHD', 'Gene', (175, 179))	('SDHD', 'Gene', '6392', (175, 179))	('patients', 'Species', '9606', (122, 130))	('SDHA', 'Gene', (159, 163))	('SDHB', 'Gene', (165, 169))
20723	28471419	Germline mutations in SDHx genes have also been implicated in other tumours such as renal cell carcinoma (RCC) and gastro-intestinal stromal tumour (GIST) (Table 1).	('Germline mutations', 'Var', (0, 18))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('SDHx', 'Gene', (22, 26))	('renal cell carcinoma', 'Disease', (84, 104))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (84, 104))	('gastro-intestinal stromal tumour', 'Disease', (115, 147))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('GIST', 'Phenotype', 'HP:0100723', (149, 153))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('SDHx', 'Chemical', '-', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('RCC', 'Disease', (106, 109))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))	('implicated', 'Reg', (48, 58))	('gastro-intestinal stromal tumour', 'Disease', 'MESH:D007414', (115, 147))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (84, 104))	('RCC', 'Disease', 'MESH:C538614', (106, 109))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumours', 'Disease', (68, 75))	('gastro-intestinal stromal tumour', 'Phenotype', 'HP:0100723', (115, 147))
20725	28471419	Since, SDHx genes mutations have been implicated in 0.05 to 0.2% of renal cancers, and SDHB mutations are the most frequent.	('renal cancers', 'Disease', (68, 81))	('renal cancer', 'Phenotype', 'HP:0009726', (68, 80))	('SDHB', 'Gene', '6390', (87, 91))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('SDHx genes', 'Gene', (7, 17))	('mutations', 'Var', (92, 101))	('SDHx', 'Chemical', '-', (7, 11))	('implicated', 'Reg', (38, 48))	('renal cancers', 'Disease', 'MESH:D007680', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('SDHB', 'Gene', (87, 91))	('mutations', 'Var', (18, 27))
20728	28471419	In patients carrying the SDHB gene mutation, the lifetime risk of RCC has been estimated as 14%.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('SDHB', 'Gene', '6390', (25, 29))	('patients', 'Species', '9606', (3, 11))	('mutation', 'Var', (35, 43))	('SDHB', 'Gene', (25, 29))	('RCC', 'Disease', (66, 69))	('RCC', 'Phenotype', 'HP:0005584', (66, 69))
20730	28471419	In these WT GISTs, more than 85% are secondary to an SDHx gene mutation.	('GIST', 'Phenotype', 'HP:0100723', (12, 16))	('SDHx', 'Chemical', '-', (53, 57))	('SDHx', 'Gene', (53, 57))	('mutation', 'Var', (63, 71))	('secondary', 'Reg', (37, 46))
20731	28471419	The great majority are germline mutation (82%) and SDHA mutations represent more than a half of the identified mutations.	('SDHA', 'Gene', (51, 55))	('mutations', 'Var', (56, 65))	('germline mutation', 'Var', (23, 40))	('SDHA', 'Gene', '6389', (51, 55))
20734	28471419	Recently, epimutations of the SDHC gene promoter have been proposed as a new mechanism of SDH loss of function in WT GIST with a negative SDHB immunochemistry and without any mutations in germline or somatic DNA.	('SDHB', 'Gene', (138, 142))	('SDHC', 'Gene', (30, 34))	('epimutations', 'Var', (10, 22))	('SDHC', 'Gene', '6391', (30, 34))	('SDH', 'Gene', (90, 93))	('GIST', 'Phenotype', 'HP:0100723', (117, 121))	('loss of function', 'NegReg', (94, 110))	('SDHB', 'Gene', '6390', (138, 142))	('negative', 'NegReg', (129, 137))
20737	28471419	They are characterized by an SDHC promoter-specific CpG island hypermethylation associated with subsequent gene silencing.	('SDHC', 'Gene', (29, 33))	('SDHC', 'Gene', '6391', (29, 33))	('hypermethylation', 'Var', (63, 79))
20738	28471419	Recently, a patient with multiple PPGL has been described with an epimutation of the SDHC promotor.	('patient', 'Species', '9606', (12, 19))	('SDHC', 'Gene', '6391', (85, 89))	('SDHC', 'Gene', (85, 89))	('epimutation', 'Var', (66, 77))
20741	28471419	Germline mutations in this tumour suppressor gene were first described in the predisposition to HRLCC syndrome (hereditary leiomyomatosis and renal cell cancer) also known as Reed Syndrome.	('Germline mutations', 'Var', (0, 18))	('HRLCC syndrome', 'Disease', (96, 110))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('Reed Syndrome', 'Disease', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (112, 159))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('HRLCC syndrome', 'Disease', 'MESH:D013577', (96, 110))	('renal cell cancer', 'Phenotype', 'HP:0005584', (142, 159))	('tumour', 'Disease', (27, 33))
20744	28471419	More recently, it was demonstrated that FH gene germline mutations can also predispose to PPGL and lead to malignant or multiple forms of the disease.	('predispose', 'Reg', (76, 86))	('lead to', 'Reg', (99, 106))	('PPGL', 'Disease', (90, 94))	('FH', 'Gene', '2271', (40, 42))	('germline mutations', 'Var', (48, 66))	('malignant', 'Disease', (107, 116))
20747	28471419	Until now, this is the only case of MDH2 mutation ever described in the predisposition to cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutation', 'Var', (41, 49))	('MDH2', 'Gene', '4191', (36, 40))	('MDH2', 'Gene', (36, 40))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
20748	28471419	In 2000, the demonstration of SDHD being a tumour suppressor gene showed that Warburg view was actually true, at least in these very specific cases of inherited cancer predisposition, and that a defect in a central metabolic function could be the origin of cancer.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('tumour', 'Disease', (43, 49))	('SDHD', 'Gene', (30, 34))	('SDHD', 'Gene', '6392', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('defect', 'Var', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (257, 263))	('central metabolic function', 'MPA', (207, 233))
20751	28471419	One explanation is that patients affected with Leigh syndrome or fumarate hydratase deficiency carry homozygous germline mutations that maintain some residual enzymatic activity, allowing these mutations to be viable and mediating the neurologic phenotype.	('mutations', 'Var', (121, 130))	('mutations', 'Var', (194, 203))	('Leigh syndrome', 'Disease', (47, 61))	('fumarate hydratase deficiency', 'Disease', (65, 94))	('patients', 'Species', '9606', (24, 32))	('fumarate hydratase deficiency', 'Disease', 'MESH:C538191', (65, 94))	('fumarate hydratase deficiency', 'Phenotype', 'HP:0003536', (65, 94))	('Leigh syndrome', 'Disease', 'MESH:D007888', (47, 61))
20752	28471419	In contrast, mutations predisposing to cancer susceptibility are heterozygous, require a second somatic genetic event (most generally the loss of the chromosomal region harbouring the wild-type allele), and then lead to the complete and selective loss of the enzymatic activity.	('loss', 'NegReg', (138, 142))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('enzymatic activity', 'MPA', (259, 277))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('loss', 'NegReg', (247, 251))	('mutations', 'Var', (13, 22))
20753	28471419	The first key allowing understanding the tumorigenesis pathways associated with TCA cycle mutations was the description, in the first French family of SDHD-related PGL, of increased angiogenesis and overexpression of the hypoxia inducible factor 2alpha (HIF2alpha) and one of its target, the vascular endothelial growth factor (VEGF).	('VEGF', 'Gene', '7422', (328, 332))	('mutations', 'Var', (90, 99))	('increased', 'PosReg', (172, 181))	('hypoxia inducible factor 2alpha', 'Gene', (221, 252))	('HIF2alpha', 'Gene', '2034', (254, 263))	('TCA cycle', 'Gene', (80, 89))	('vascular endothelial growth factor', 'Gene', (292, 326))	('overexpression', 'PosReg', (199, 213))	('angiogenesis', 'CPA', (182, 194))	('vascular endothelial growth factor', 'Gene', '7422', (292, 326))	('SDHD', 'Gene', (151, 155))	('VEGF', 'Gene', (328, 332))	('SDHD', 'Gene', '6392', (151, 155))	('hypoxia inducible factor 2alpha', 'Gene', '2034', (221, 252))	('TCA', 'Chemical', 'MESH:D014233', (80, 83))	('HIF2alpha', 'Gene', (254, 263))
20754	28471419	Transcriptomic studies further confirmed this initial observation by demonstrating that unsupervised classification of PPGL tumours allowed separating them into two major clusters of expression: cluster 1, characterized by a hypoxic signature, which comprised all TCA cycle mutations (cluster 1A) on one side and VHL and HIF2A mutated tumours (cluster 1B) on the other side, and cluster 2, regrouping RET, NF1, MAX, and TMEM127 related tumours, as well as most of the sporadic cases.	('RET', 'Gene', (401, 404))	('NF1', 'Gene', (406, 409))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Disease', (335, 342))	('HIF2A', 'Gene', '2034', (321, 326))	('tumours', 'Phenotype', 'HP:0002664', (335, 342))	('HIF2A', 'Gene', (321, 326))	('PPGL tumours', 'Disease', 'MESH:D009369', (119, 131))	('TMEM127', 'Gene', (420, 427))	('tumours', 'Disease', 'MESH:D009369', (335, 342))	('TCA', 'Chemical', 'MESH:D014233', (264, 267))	('tumours', 'Disease', (436, 443))	('VHL', 'Gene', (313, 316))	('tumour', 'Phenotype', 'HP:0002664', (335, 341))	('tumours', 'Phenotype', 'HP:0002664', (436, 443))	('PPGL tumours', 'Disease', (119, 131))	('TMEM127', 'Gene', '55654', (420, 427))	('tumours', 'Disease', 'MESH:D009369', (436, 443))	('RET', 'Gene', '5979', (401, 404))	('tumours', 'Disease', (124, 131))	('VHL', 'Gene', '7428', (313, 316))	('TCA cycle', 'Gene', (264, 273))	('tumour', 'Phenotype', 'HP:0002664', (436, 442))	('NF1', 'Gene', '4763', (406, 409))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('mutations', 'Var', (274, 283))	('tumours', 'Disease', 'MESH:D009369', (124, 131))
20766	28471419	Hence, SDH mutant cells, by reprogramming the transcriptome at the whole genome scale, foster tumorigenesis by repressing the expression of genes that promote cancer stem cell identity, and Epithelial-to-Mesenchymal Transition (EMT).	('cancer', 'Disease', (159, 165))	('mutant', 'Var', (11, 17))	('repressing', 'NegReg', (111, 121))	('Epithelial-to-Mesenchymal Transition', 'CPA', (190, 226))	('expression', 'MPA', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SDH', 'Gene', (7, 10))	('promote', 'PosReg', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('foster', 'PosReg', (87, 93))	('tumorigenesis', 'CPA', (94, 107))
20768	28471419	Because of their central role in the acquisition of tumour hallmarks by SDH- and FH-deficient cells, succinate and fumarate are now referred to as "oncometabolites", as 2-hydroxyglutarate, the organic acid generated by mutant isocitrate dehydrogenase mutants in gliomas and acute myeloid leukaemia.	('gliomas', 'Disease', 'MESH:D005910', (262, 269))	('FH-deficient', 'Disease', 'MESH:D006938', (81, 93))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour hallmarks', 'Disease', 'MESH:D009369', (52, 68))	('isocitrate dehydrogenase', 'Gene', '3417', (226, 250))	('acute myeloid leukaemia', 'Disease', (274, 297))	('gliomas', 'Phenotype', 'HP:0009733', (262, 269))	('tumour hallmarks', 'Disease', (52, 68))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (169, 187))	('succinate', 'Chemical', 'MESH:D019802', (101, 110))	('organic acid', 'Chemical', '-', (193, 205))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (280, 297))	('isocitrate dehydrogenase', 'Gene', (226, 250))	('fumarate', 'Chemical', 'MESH:D005650', (115, 123))	('mutant', 'Var', (219, 225))	('gliomas', 'Disease', (262, 269))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (274, 297))	('FH-deficient', 'Disease', (81, 93))	('mutants', 'Var', (251, 258))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (274, 297))
20769	28471419	As discussed earlier, SDHx mutation carriers are at risk of developing multiple PPGLs, and SDHB-mutation carriers are predisposed to metastatic forms of the disease.	('SDHx', 'Gene', (22, 26))	('SDHB', 'Gene', '6390', (91, 95))	('SDHx', 'Chemical', '-', (22, 26))	('PGLs', 'Phenotype', 'HP:0002668', (81, 85))	('mutation', 'Var', (27, 35))	('SDHB', 'Gene', (91, 95))	('metastatic', 'CPA', (133, 143))
20772	28471419	One promising strategy is based on an antiangiogenic approach that appears appropriate regarding the highly vascularized pattern and the activation of a VEFG-dependant angiogenesis of PPGL carrying SDHx mutations.	('PPGL', 'Gene', (184, 188))	('SDHx', 'Gene', (198, 202))	('mutations', 'Var', (203, 212))	('SDHx', 'Chemical', '-', (198, 202))
20773	28471419	The first six case reports of metastatic PPGLs treated with sunitinib were published almost simultaneously by four different teams showing extended partial response in patients carrying SDHB mutations.	('SDHB', 'Gene', (186, 190))	('mutations', 'Var', (191, 200))	('patients', 'Species', '9606', (168, 176))	('PGLs', 'Phenotype', 'HP:0002668', (42, 46))	('sunitinib', 'Chemical', 'MESH:D000077210', (60, 69))	('SDHB', 'Gene', '6390', (186, 190))
20774	28471419	The most comprehensive study reported so far is a retrospective review of medical records of 17 patients (including eight with an SDHB mutation and one VHL patient) with metastatic PPGLs who were treated with sunitinib.	('VHL', 'Gene', (152, 155))	('VHL', 'Gene', '7428', (152, 155))	('SDHB', 'Gene', '6390', (130, 134))	('patient', 'Species', '9606', (96, 103))	('PGLs', 'Phenotype', 'HP:0002668', (182, 186))	('SDHB', 'Gene', (130, 134))	('patients', 'Species', '9606', (96, 104))	('mutation', 'Var', (135, 143))	('patient', 'Species', '9606', (156, 163))	('sunitinib', 'Chemical', 'MESH:D000077210', (209, 218))
20776	28471419	Partial response or stable disease were observed in the patient with a VHL mutation and five of the six evaluable patients with an SDHB mutation, suggesting that patients with cluster 1 disease might be better responders to antiangiogenic treatments than patients with cluster 2 tumours.	('patient', 'Species', '9606', (255, 262))	('VHL', 'Gene', '7428', (71, 74))	('mutation', 'Var', (75, 83))	('tumours', 'Phenotype', 'HP:0002664', (279, 286))	('patient', 'Species', '9606', (56, 63))	('patients', 'Species', '9606', (114, 122))	('SDHB', 'Gene', '6390', (131, 135))	('patients', 'Species', '9606', (162, 170))	('cluster 1 disease', 'Disease', (176, 193))	('mutation', 'Var', (136, 144))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('cluster 1 disease', 'Disease', 'MESH:D003027', (176, 193))	('patients', 'Species', '9606', (255, 263))	('cluster 2 tumours', 'Disease', (269, 286))	('VHL', 'Gene', (71, 74))	('SDHB', 'Gene', (131, 135))	('cluster 2 tumours', 'Disease', 'MESH:D003027', (269, 286))	('patient', 'Species', '9606', (114, 121))	('patient', 'Species', '9606', (162, 169))
20780	28471419	Recently, two independent teams published the results of PT2399, a selective HIF-2 antagonist, in a preclinical model of clear cell renal carcinoma (ccRCC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (121, 147))	('PT2399', 'Var', (57, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (132, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('PT2399', 'Chemical', 'MESH:C000614278', (57, 63))	('clear cell renal carcinoma', 'Disease', (121, 147))	('RCC', 'Disease', 'MESH:C538614', (151, 154))	('RCC', 'Disease', (151, 154))	('RCC', 'Phenotype', 'HP:0005584', (151, 154))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (121, 147))
20781	28471419	Epigenetic alterations play major roles in establishing and maintaining aberrant gene expression profiles in cancer cells and in particular in the hypermethylated cluster M1 involving all PPGL with SDHx and FH mutations.	('SDHx', 'Gene', (198, 202))	('mutations', 'Var', (210, 219))	('SDHx', 'Chemical', '-', (198, 202))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('PPGL', 'Gene', (188, 192))	('cancer', 'Disease', (109, 115))	('FH', 'Gene', '2271', (207, 209))	('aberrant gene expression profiles', 'MPA', (72, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
20782	28471419	Targeting epigenetic alterations in cancer cells (epigenetic therapy) is a new frontier in drug discovery.	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('epigenetic alterations', 'Var', (10, 32))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (36, 42))
20783	28471419	Reversion of DNA methylation by epidrugs such as 5-aza-2'-deoxycytidine (Decitabine) or histone methylation by histone methyl transferase inhibitors, is clearly an attractive strategy for carriers of SDHx or FH mutations.	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (49, 71))	('mutations', 'Var', (211, 220))	('FH', 'Gene', '2271', (208, 210))	('Decitabine', 'Chemical', 'MESH:D000077209', (73, 83))	('histone', 'MPA', (88, 95))	('SDHx', 'Chemical', '-', (200, 204))	('SDHx', 'Gene', (200, 204))
20789	28471419	Indeed, in the first report involving a small retrospective cohort of 15 patients with progressive metastatic PPGL, temozolomide treatment was more effective in patients carrying SDHB mutations than in those without SDHB mutations.	('temozolomide', 'Chemical', 'MESH:D000077204', (116, 128))	('mutations', 'Var', (184, 193))	('SDHB', 'Gene', '6390', (179, 183))	('SDHB', 'Gene', '6390', (216, 220))	('patients', 'Species', '9606', (161, 169))	('SDHB', 'Gene', (179, 183))	('SDHB', 'Gene', (216, 220))	('patients', 'Species', '9606', (73, 81))
20791	28471419	During the last decade, many studies have shown that the majority of oncogenes and tumour suppressor genes are involved in cell metabolism and that mutations in these genes facilitate cell survival and proliferation by promoting the use of nutrients.	('tumour', 'Disease', (83, 89))	('mutations', 'Var', (148, 157))	('promoting', 'PosReg', (219, 228))	('proliferation', 'CPA', (202, 215))	('cell survival', 'CPA', (184, 197))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('facilitate', 'PosReg', (173, 183))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('oncogenes', 'Gene', (69, 78))	('use of nutrients', 'MPA', (233, 249))
20792	28471419	As a central metabolic actor, alterations of enzymes in the TCA cycle result in important metabolic re-wiring in order to respond to bioenergetics and anabolic requests of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('alterations', 'Var', (30, 41))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('metabolic re-wiring', 'MPA', (90, 109))	('result in', 'Reg', (70, 79))	('TCA', 'Chemical', 'MESH:D014233', (60, 63))
20794	28471419	Hence, mutations in SDHx genes were demonstrated to mediate a rise in contribution of glucose to ATP production and glutamine to TCA cycle intermediates in an ovarian cancer model.	('ovarian cancer', 'Disease', (159, 173))	('TCA', 'Chemical', 'MESH:D014233', (129, 132))	('contribution', 'MPA', (70, 82))	('rise', 'PosReg', (62, 66))	('glucose', 'MPA', (86, 93))	('SDHx', 'Gene', (20, 24))	('glutamine', 'Chemical', 'MESH:D005973', (116, 125))	('SDHx', 'Chemical', '-', (20, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('ATP', 'Chemical', 'MESH:D000255', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ovarian cancer', 'Disease', 'MESH:D010051', (159, 173))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('glutamine to TCA cycle intermediates', 'MPA', (116, 152))	('mutations', 'Var', (7, 16))
20795	28471419	Recently, two independent studies demonstrated that loss of SDH activity through Sdhb deletion in a mouse cellular model results in their dependence on the pyruvate carboxylase (PC) enzyme, responsible for pyruvate carboxylation to synthesize oxaloacetate (OAA) (Figure 1).	('SDH', 'Gene', (60, 63))	('pyruvate carboxylase', 'Gene', '18563', (156, 176))	('dependence', 'MPA', (138, 148))	('loss', 'NegReg', (52, 56))	('OAA', 'Chemical', 'MESH:D062907', (257, 260))	('Sdhb', 'Gene', (81, 85))	('mouse', 'Species', '10090', (100, 105))	('pyruvate', 'Chemical', 'MESH:D019289', (206, 214))	('PC', 'Gene', '18563', (178, 180))	('Sdhb', 'Gene', '67680', (81, 85))	('activity', 'MPA', (64, 72))	('oxaloacetate', 'Chemical', 'MESH:D062907', (243, 255))	('pyruvate', 'Chemical', 'MESH:D019289', (156, 164))	('pyruvate carboxylase', 'Gene', (156, 176))	('deletion', 'Var', (86, 94))
20796	28471419	Despite the TCA cycle truncation, cells can use OAA as a TCA cycle intermediate in order to produce aspartate, a key metabolic pivot in the cell (the main precursor for protein and nucleotide biosynthesis).	('TCA', 'Chemical', 'MESH:D014233', (57, 60))	('aspartate', 'MPA', (100, 109))	('OAA', 'Chemical', 'MESH:D062907', (48, 51))	('truncation', 'Var', (22, 32))	('TCA', 'Chemical', 'MESH:D014233', (12, 15))	('aspartate', 'Chemical', 'MESH:D001224', (100, 109))
20797	28471419	Moreover, in vitro silencing of PC resulted in complete ablation of proliferation and loss of viability.	('proliferation', 'CPA', (68, 81))	('loss', 'NegReg', (86, 90))	('PC', 'Gene', '18563', (32, 34))	('ablation', 'NegReg', (56, 64))	('silencing', 'Var', (19, 28))	('viability', 'CPA', (94, 103))
20798	28471419	Although it is unlikely that PC targeting would be appropriate in patients, deciphering the metabolic pathways associated with TCA cycle mutations may reveal important and novel therapeutic targets for the management of these tumours.	('TCA cycle', 'Gene', (127, 136))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('TCA', 'Chemical', 'MESH:D014233', (127, 130))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('mutations', 'Var', (137, 146))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('tumours', 'Disease', (226, 233))	('patients', 'Species', '9606', (66, 74))	('PC', 'Gene', '18563', (29, 31))
20805	28471419	18F-FDG PET/CT is therefore already considered a standard examination for complete staging in patients with an SDHx mutation and for the evaluation of early response to treatment.	('patients', 'Species', '9606', (94, 102))	('mutation', 'Var', (116, 124))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('SDHx', 'Gene', (111, 115))	('SDHx', 'Chemical', '-', (111, 115))
20807	28471419	SDH inactivation leads to a massive accumulation of succinate, acting as an oncometabolite, and its levels, assessed on surgically resected tissues, are a highly specific biomarker of SDHx-mutated tumours.	('inactivation', 'Var', (4, 16))	('tumours', 'Disease', 'MESH:D009369', (197, 204))	('tumours', 'Disease', (197, 204))	('SDH', 'Gene', (0, 3))	('SDHx', 'Chemical', '-', (184, 188))	('succinate', 'MPA', (52, 61))	('accumulation', 'PosReg', (36, 48))	('tumours', 'Phenotype', 'HP:0002664', (197, 204))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('succinate', 'Chemical', 'MESH:D019802', (52, 61))
20811	28471419	The majority (50-86%) of gliomas diagnosed in younger adults (<45 years old) have recurrent somatic mutations in one of the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) leading to the overproduction of 2-hydroxyglutarate, an oncometabolite that plays a key role in malignant transformation and is interestingly detectable in vivo by 1H-MRS. A pulse 1H-MRS sequence was previously developed to measure succinate in an allografted mouse model of Sdhb-deficient tumours and used in a pilot study performed in nine patients with PPGL (five with SDHx mutations and four sporadic cases).	('mutations', 'Var', (557, 566))	('PPGL', 'Gene', (536, 540))	('SDHx', 'Gene', (552, 556))	('IDH2', 'Gene', (174, 178))	('IDH2', 'Gene', '3418', (174, 178))	('patients', 'Species', '9606', (522, 530))	('isocitrate dehydrogenase', 'Gene', '3417', (139, 163))	('SDHx', 'Chemical', '-', (552, 556))	('IDH1', 'Gene', (165, 169))	('tumours', 'Phenotype', 'HP:0002664', (470, 477))	('Sdhb-deficient tumours', 'Disease', 'MESH:D009369', (455, 477))	('gliomas', 'Disease', (25, 32))	('succinate', 'Chemical', 'MESH:D019802', (412, 421))	('tumour', 'Phenotype', 'HP:0002664', (470, 476))	('Sdhb-deficient tumours', 'Disease', (455, 477))	('IDH1', 'Gene', '3417', (165, 169))	('gliomas', 'Disease', 'MESH:D005910', (25, 32))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (213, 231))	('1H', 'Chemical', '-', (360, 362))	('isocitrate dehydrogenase', 'Gene', (139, 163))	('mouse', 'Species', '10090', (440, 445))	('1H', 'Chemical', '-', (344, 346))	('gliomas', 'Phenotype', 'HP:0009733', (25, 32))
20812	28471419	That pilot study demonstrated the feasibility of detecting succinate in vivo by 1H-MRS as a very specific biomarker of SDHx mutations.	('mutations', 'Var', (124, 133))	('SDHx', 'Chemical', '-', (119, 123))	('succinate', 'MPA', (59, 68))	('SDHx', 'Gene', (119, 123))	('1H', 'Chemical', '-', (80, 82))	('succinate', 'Chemical', 'MESH:D019802', (59, 68))
20855	21098082	Its efficacy depends on the [131I]-MIBG concentration reached within the tumor through its uptake via the norepinephrine transporter and retention in neurosecretory granules.	('norepinephrine transporter', 'Gene', '20538', (106, 132))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('norepinephrine transporter', 'Gene', (106, 132))	('uptake', 'MPA', (91, 97))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (28, 39))	('tumor', 'Disease', (73, 78))	('[131I]-MIBG', 'Var', (28, 39))
20863	21098082	These results suggest that HDAC inhibitors could enhance the therapeutic efficacy of [131I]-MIBG treatment in patients with malignant pheochromocytoma.	('HDAC', 'Gene', '9734', (27, 31))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))	('enhance', 'PosReg', (49, 56))	('-MIBG', 'Gene', (91, 96))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (85, 96))	('[131I', 'Var', (85, 90))	('therapeutic', 'MPA', (61, 72))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (124, 150))	('malignant pheochromocytoma', 'Disease', (124, 150))	('patients', 'Species', '9606', (110, 118))	('HDAC', 'Gene', (27, 31))
20868	21098082	[131I]-MIBG is one of the most effective therapies because it specifically targets chromaffin and pheochromocytoma cells.	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (0, 11))	('pheochromocytoma', 'Disease', (98, 114))	('chromaffin', 'Chemical', '-', (83, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (98, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (98, 114))	('[131I]-MIBG', 'Var', (0, 11))	('chromaffin', 'Disease', (83, 93))
20883	21098082	We examined the effects of HDAC inhibition on proliferation, uptake of [3H]-norepinephrine, [123I]-MIBG, and [18F]-fluorodopamine, and norepinephrine transporter expression in MPC cells.	('norepinephrine transporter', 'Gene', (135, 161))	('HDAC', 'Gene', '9734', (27, 31))	('amine', 'Chemical', 'MESH:D000588', (5, 10))	('[18F]-fluorodopamine', 'Chemical', '-', (109, 129))	('uptake of [3H]-norepinephrine', 'MPA', (61, 90))	('[123I]-MIBG', 'Chemical', 'MESH:D019797', (92, 103))	('[3H]-norepinephrine', 'Chemical', '-', (71, 90))	('[123I]-MIBG', 'Var', (92, 103))	('norepinephrine transporter', 'Gene', '20538', (135, 161))	('amine', 'Chemical', 'MESH:D000588', (124, 129))	('HDAC', 'Gene', (27, 31))
20974	21098082	Figure 4 demonstrates no relationship between tumor size and uptake of either [18F]-fluorodopamine or [123I]-MIBG in both the control and HDAC inhibitor-treated groups.	('HDAC', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('HDAC', 'Gene', '9734', (138, 142))	('uptake', 'MPA', (61, 67))	('tumor', 'Disease', (46, 51))	('[18F]-fluorodopamine', 'Chemical', '-', (78, 98))	('[123I]-MIBG', 'Chemical', 'MESH:D019797', (102, 113))	('[123I]-MIBG', 'Var', (102, 113))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
20975	21098082	If the increased uptake of [18F]-fluorodopamine and [123I]-MIBG by liver tumors is independent of tumor size, it must be an effect of increased expression of the norepinephrine transporter.	('norepinephrine transporter', 'Gene', (162, 188))	('increased', 'PosReg', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('liver tumors', 'Disease', (67, 79))	('liver tumors', 'Phenotype', 'HP:0002896', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('liver tumor', 'Phenotype', 'HP:0002896', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('norepinephrine transporter', 'Gene', '20538', (162, 188))	('[123I', 'Var', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('uptake', 'MPA', (17, 23))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('[18F]-fluorodopamine', 'Chemical', '-', (27, 47))	('liver tumors', 'Disease', 'MESH:D008113', (67, 79))	('[123I]-MIBG', 'Chemical', 'MESH:D019797', (52, 63))
20984	21098082	HDAC inhibitors can induce growth arrest, differentiation and/or apoptosis in various tumor cell lines.	('HDAC', 'Gene', (0, 4))	('induce', 'Reg', (20, 26))	('differentiation', 'CPA', (42, 57))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HDAC', 'Gene', '9734', (0, 4))	('growth arrest', 'Phenotype', 'HP:0001510', (27, 40))	('tumor', 'Disease', (86, 91))	('inhibitors', 'Var', (5, 15))	('apoptosis', 'CPA', (65, 74))	('growth arrest', 'Disease', 'MESH:D006323', (27, 40))	('growth arrest', 'Disease', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
20991	21098082	Response rates are increased with higher doses of [131I]-MIBG, but higher doses are associated with greater toxicity.	('[131I]-MIBG', 'Var', (50, 61))	('Response', 'MPA', (0, 8))	('toxicity', 'Disease', 'MESH:D064420', (108, 116))	('toxicity', 'Disease', (108, 116))	('increased', 'PosReg', (19, 28))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (50, 61))
20993	21098082	High doses of [131I]-MIBG increase the long term risk of a second malignant neoplasm.	('malignant neoplasm', 'Disease', 'MESH:D009369', (66, 84))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (14, 25))	('neoplasm', 'Phenotype', 'HP:0002664', (76, 84))	('[131I]-MIBG', 'Var', (14, 25))	('malignant neoplasm', 'Disease', (66, 84))
20994	21098082	One way of increasing the efficacy of [131I]-MIBG, while at the same time decreasing nonspecific uptake in non-target tissues, is to increase the expression of the norepinephrine transporter in the tumor cells.	('norepinephrine transporter', 'Gene', '20538', (164, 190))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('decreasing', 'NegReg', (74, 84))	('[131I]-MIBG', 'Var', (38, 49))	('efficacy', 'MPA', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('norepinephrine transporter', 'Gene', (164, 190))	('increasing', 'PosReg', (11, 21))	('increase', 'PosReg', (133, 141))	('nonspecific uptake in non-target tissues', 'MPA', (85, 125))	('tumor', 'Disease', (198, 203))	('expression', 'MPA', (146, 156))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (38, 49))
21007	21098082	Increased uptake of both [18F]-fluorodopamine and [123I]-MIBG in inhibitor-treated liver tumors compared to that in control liver tumors in vivo confirmed our in vitro findings.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('liver tumor', 'Phenotype', 'HP:0002896', (83, 94))	('[123I', 'Var', (50, 55))	('[123I]-MIBG', 'Chemical', 'MESH:D019797', (50, 61))	('liver tumor', 'Phenotype', 'HP:0002896', (124, 135))	('liver tumors', 'Disease', 'MESH:D008113', (83, 95))	('liver tumors', 'Disease', 'MESH:D008113', (124, 136))	('liver tumors', 'Disease', (83, 95))	('Increased', 'PosReg', (0, 9))	('liver tumors', 'Phenotype', 'HP:0002896', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('liver tumors', 'Disease', (124, 136))	('[18F]-fluorodopamine', 'Chemical', '-', (25, 45))	('liver tumors', 'Phenotype', 'HP:0002896', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('uptake', 'MPA', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
21024	21098082	First, our results need to be confirmed with [123\131I]-MIBG scintigraphy coupled with dosimetry measurements in patients with metastatic pheochromocytoma.	('pheochromocytoma', 'Disease', (138, 154))	('pheochromocytoma', 'Disease', 'MESH:D010673', (138, 154))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (138, 154))	('patients', 'Species', '9606', (113, 121))	('[123\\131I]-MIBG', 'Chemical', '-', (45, 60))	('[123\\131I]', 'Var', (45, 55))
21027	21098082	However, there is also a possibility that such results could also be more impressive, as [131I]-MIBG may exhibit greater uptake due to increased expression of the norepinephrine transporter.	('norepinephrine transporter', 'Gene', (163, 189))	('[131I]-MIBG', 'Chemical', 'MESH:D019797', (89, 100))	('[131I]-MIBG', 'Var', (89, 100))	('increased', 'PosReg', (135, 144))	('expression', 'MPA', (145, 155))	('norepinephrine transporter', 'Gene', '20538', (163, 189))	('greater', 'PosReg', (113, 120))	('uptake', 'MPA', (121, 127))
21101	24235841	For instance, one could assume that mutations or alterations to the genomic profile of our patient's tumor made it especially sensitive to sorafenib.	('alterations', 'Reg', (49, 60))	('sorafenib', 'Chemical', 'MESH:D000077157', (139, 148))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (36, 45))	('sensitive', 'MPA', (126, 135))	('patient', 'Species', '9606', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
21106	33252357	Certainly, depending on the mutated gene, and the activated intracellular signalling pathways, as well as their metastatic potential, each tumour is immensely different.	('tumour', 'Disease', (139, 145))	('mutated', 'Var', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('metastatic potential', 'CPA', (112, 132))	('tumour', 'Disease', 'MESH:D009369', (139, 145))
21121	33252357	Mutations have been identified in more than 15 genes and, based on gene profiling, PPGLs can be assigned to three different 'clusters' (for recent reviews on the genetic/phenotype correlations of PPGLs see:).	('PGLs', 'Phenotype', 'HP:0002668', (197, 201))	('PGLs', 'Phenotype', 'HP:0002668', (84, 88))	('PPGLs', 'Chemical', '-', (196, 201))	('Mutations', 'Var', (0, 9))	('PPGLs', 'Chemical', '-', (83, 88))	('PPGLs', 'Gene', (83, 88))
21122	33252357	PPGLs with mutations in genes encoding the hypoxia-inducible factor (HIF) 2alpha, von Hippel-Lindau tumour suppressor (VHL), prolyl hydroxylase domain (PHD), fumarate hydratase (FH), and succinate dehydrogenase subunits (SDHx) are included in cluster 1.	('mutations', 'Var', (11, 20))	('rat', 'Species', '10116', (162, 165))	('FH', 'Disease', 'MESH:D006938', (178, 180))	('VHL', 'Gene', (119, 122))	('rat', 'Species', '10116', (170, 173))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('PPGLs', 'Chemical', '-', (0, 5))	('VHL', 'Gene', '22346', (119, 122))	('succinate', 'Chemical', 'MESH:D019802', (187, 196))	('fumarate', 'Chemical', 'MESH:D005650', (158, 166))	('von Hippel-Lindau tumour', 'Disease', 'MESH:D006623', (82, 106))	('PHD', 'Disease', 'MESH:D011547', (152, 155))	('PHD', 'Disease', (152, 155))	('von Hippel-Lindau tumour', 'Disease', (82, 106))	('hypoxia-inducible factor (HIF) 2alpha', 'Gene', '13819', (43, 80))	('PGLs', 'Phenotype', 'HP:0002668', (1, 5))
21124	33252357	Intriguingly, tumours mutated in one of the enzymes involved in the Krebs cycle are more aggressive than others, showing an elevated metastatic potential.	('Krebs', 'Chemical', '-', (68, 73))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('mutated', 'Var', (22, 29))	('metastatic potential', 'CPA', (133, 153))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('elevated', 'PosReg', (124, 132))	('aggressive', 'CPA', (89, 99))
21125	33252357	Cluster 2 includes PPGLs with mutations in the RE arranged during Transfection (RET) proto-oncogene, Neurofibromatosis type 1 (NF1) tumour suppressor gene, TransMEMbrane protein (TMEM127) gene, Harvey rat sarcoma viral oncogene homolog (HRAS) and MYC Associated Factor X (MAX) gene.	('PPGLs', 'Chemical', '-', (19, 24))	('NF1', 'Gene', '18015', (127, 130))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('HRAS', 'Gene', (237, 241))	('sarcoma', 'Disease', (205, 212))	('MYC Associated Factor X', 'Gene', (247, 270))	('TMEM127', 'Gene', '311405', (179, 186))	('MAX', 'Gene', '60661', (272, 275))	('NF1', 'Gene', (127, 130))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('tumour', 'Disease', (132, 138))	('MAX', 'Gene', (272, 275))	('Neurofibromatosis type 1', 'Disease', (101, 125))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('HRAS', 'Gene', '293621', (237, 241))	('Neurofibromatosis type 1', 'Disease', 'MESH:C537392', (101, 125))	('MYC Associated Factor X', 'Gene', '60661', (247, 270))	('PGLs', 'Phenotype', 'HP:0002668', (20, 24))	('mutations', 'Var', (30, 39))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (101, 118))	('TMEM127', 'Gene', (179, 186))	('rat', 'Species', '10116', (201, 204))
21127	33252357	Recently, introducing also a cluster 3 has been suggested, which includes tumours associated with mutations in the Mastermind Like Transcriptional Coactivator 3 (MAML3) gene, which is involved in the Wnt signalling pathway.	('Mastermind Like Transcriptional Coactivator 3', 'Gene', '433586', (115, 160))	('Mastermind Like Transcriptional Coactivator 3', 'Gene', (115, 160))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('MAML3', 'Gene', '433586', (162, 167))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('mutations', 'Var', (98, 107))	('MAML3', 'Gene', (162, 167))	('tumours', 'Disease', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
21135	33252357	Mutations in some of the susceptibility genes cause an impairment of the Krebs cycle, resulting in an accumulation of the oncometabolites succinate, fumarate, or 2-hydroxyglutarate, that in turn leads to the inhibition of PHD1/2.	('fumarate', 'MPA', (149, 157))	('inhibition', 'NegReg', (208, 218))	('accumulation', 'PosReg', (102, 114))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (162, 180))	('impairment', 'NegReg', (55, 65))	('oncometabolites succinate', 'MPA', (122, 147))	('PHD1/2', 'Gene', (222, 228))	('Mutations', 'Var', (0, 9))	('2-hydroxyglutarate', 'MPA', (162, 180))	('Krebs cycle', 'Enzyme', (73, 84))	('PHD1/2', 'Gene', '112406;112405', (222, 228))	('fumarate', 'Chemical', 'MESH:D005650', (149, 157))	('Krebs', 'Chemical', '-', (73, 78))	('succinate', 'Chemical', 'MESH:D019802', (138, 147))
21136	33252357	Inactivation of PHD1/2 results in a decrease of HIF-alpha hydroxylation that cannot be degraded any longer.	('PHD1/2', 'Gene', (16, 22))	('HIF-alpha hydroxylation', 'MPA', (48, 71))	('PHD1/2', 'Gene', '112406;112405', (16, 22))	('Inactivation', 'Var', (0, 12))	('decrease', 'NegReg', (36, 44))
21137	33252357	Therefore, cluster 1 mutations promote angiogenesis, tumour invasion, and metastasis.	('tumour invasion', 'Disease', 'MESH:D009361', (53, 68))	('tumour invasion', 'Disease', (53, 68))	('angiogenesis', 'CPA', (39, 51))	('cluster 1', 'Gene', (11, 20))	('metastasis', 'CPA', (74, 84))	('promote', 'PosReg', (31, 38))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (21, 30))
21138	33252357	Mutations of genes belonging to cluster 2 lead to activation of the phosphatidylinositol-3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTORC1)/p70S6 kinase (p70S6K), and RAS/RAF/ERK signalling pathways, which in turn promote cell proliferation, survival, cancer development and angiogenesis.	('AKT', 'Gene', '207', (105, 108))	('p70S6K', 'Gene', '6198', (163, 169))	('mammalian target of rapamycin', 'Gene', (110, 139))	('survival', 'CPA', (251, 259))	('activation', 'PosReg', (50, 60))	('phosphatidylinositol-3-kinase', 'Gene', '5290', (68, 97))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (261, 267))	('promote', 'PosReg', (223, 230))	('cell proliferation', 'CPA', (231, 249))	('angiogenesis', 'CPA', (284, 296))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('rat', 'Species', '10116', (243, 246))	('ERK', 'Gene', (184, 187))	('RAF', 'Gene', '109880', (180, 183))	('AKT', 'Gene', (105, 108))	('phosphatidylinositol-3-kinase', 'Gene', (68, 97))	('p70S6K', 'Gene', (163, 169))	('mTORC1', 'Gene', (141, 147))	('ERK', 'Gene', '2048', (184, 187))	('mTORC1', 'Gene', '382056', (141, 147))	('RAF', 'Gene', (180, 183))	('mammalian target of rapamycin', 'Gene', '2475', (110, 139))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
21140	33252357	Conversely, cluster 1 tumours, even those occurring in the adrenal gland, which are often associated with VHL mutations, do not produce significant A. Tumours mutated for the Cold Shock Domain-containing E1 (CSDE1) and the MAML3 fusion genes belong to cluster 3.	('CSDE1', 'Gene', '229663', (208, 213))	('MAML3', 'Gene', '433586', (223, 228))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('mutated', 'Var', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('VHL', 'Gene', '22346', (106, 109))	('Cold Shock Domain-containing E1', 'Gene', (175, 206))	('tumours', 'Disease', (22, 29))	('CSDE1', 'Gene', (208, 213))	('Shock', 'Phenotype', 'HP:0031273', (180, 185))	('VHL', 'Gene', (106, 109))	('MAML3', 'Gene', (223, 228))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('Cold Shock Domain-containing E1', 'Gene', '229663', (175, 206))	('Tumours', 'Phenotype', 'HP:0002664', (151, 158))
21141	33252357	MAML3 mutations lead to over-activation of Wnt and Hedgehog signalling and MAML3-mutated PPGLs showed elevated Ki-67 expression, aggressive behaviour and early metastatic spread.	('MAML3', 'Gene', (75, 80))	('Ki-67', 'Gene', '17345', (111, 116))	('expression', 'MPA', (117, 127))	('elevated', 'PosReg', (102, 110))	('MAML3', 'Gene', (0, 5))	('early metastatic spread', 'CPA', (154, 177))	('Ki-67', 'Gene', (111, 116))	('PPGLs', 'Chemical', '-', (89, 94))	('over-activation', 'PosReg', (24, 39))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (129, 149))	('MAML3', 'Gene', '433586', (75, 80))	('PPGLs', 'Gene', (89, 94))	('PGLs', 'Phenotype', 'HP:0002668', (90, 94))	('MAML3', 'Gene', '433586', (0, 5))	('aggressive behaviour', 'CPA', (129, 149))	('mutations', 'Var', (6, 15))
21142	33252357	CSDE1 mutations lead to over-activation of beta-catenin, a target of Wnt signalling, and favour tumour proliferation, invasion, and metastases.	('rat', 'Species', '10116', (110, 113))	('beta-catenin', 'Gene', '12387', (43, 55))	('tumour', 'Disease', (96, 102))	('metastases', 'Disease', (132, 142))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('over-activation', 'PosReg', (24, 39))	('CSDE1', 'Gene', '229663', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('metastases', 'Disease', 'MESH:D009362', (132, 142))	('favour', 'PosReg', (89, 95))	('invasion', 'CPA', (118, 126))	('beta-catenin', 'Gene', (43, 55))	('mutations', 'Var', (6, 15))	('CSDE1', 'Gene', (0, 5))
21159	33252357	constructed a mouse strain with a knock-out (KO) mutation of Nf1, the murine counterpart of NF1.	('mouse', 'Species', '10090', (14, 19))	('Nf1', 'Gene', '18015', (61, 64))	('mutation', 'Var', (49, 57))	('NF1', 'Gene', (92, 95))	('murine', 'Species', '10090', (70, 76))	('NF1', 'Gene', '18015', (92, 95))	('Nf1', 'Gene', (61, 64))
21162	33252357	A few years later, in the same laboratory, five mouse PCC cell lines (MPC) were stabilised from primary cultures of PCCs arising in mice with a Nf1 heterozygous KO mutation.	('PCC', 'Gene', (54, 57))	('MPC', 'Chemical', '-', (70, 73))	('mouse', 'Species', '10090', (48, 53))	('Nf1', 'Gene', '18015', (144, 147))	('PCCs', 'Phenotype', 'HP:0002666', (116, 120))	('PCC', 'Gene', (116, 119))	('Nf1', 'Gene', (144, 147))	('KO mutation', 'Var', (161, 172))	('mice', 'Species', '10090', (132, 136))	('PCC', 'Gene', '1421', (54, 57))	('rat', 'Species', '10116', (35, 38))	('PCC', 'Gene', '1421', (116, 119))
21174	33252357	Several cell lines were then derived from MPC and MTT to improve and diversify research studies, with a particular interest in SDHB mutations, because mutations in this gene represent a high-risk factor for malignancy and poor prognosis.	('MPC', 'Chemical', '-', (42, 45))	('mutations', 'Var', (132, 141))	('MTT', 'Chemical', '-', (50, 53))	('malignancy', 'Disease', 'MESH:D009369', (207, 217))	('SDHB', 'Gene', (127, 131))	('malignancy', 'Disease', (207, 217))	('mutations', 'Var', (151, 160))
21175	33252357	To assess possible associations between SDHB gene mutations and invasiveness, Richter and colleagues established an MTT SDHB knockdown by viral transduction with lentiviral particles.	('MTT', 'Chemical', '-', (116, 119))	('knockdown', 'Var', (125, 134))	('SDHB', 'Gene', (40, 44))	('SDHB', 'Gene', (120, 124))
21176	33252357	Of note, one of the shortcomings of silencing the SDHB subunit in an Nf1 heterozygous KO mouse is the mixing of the phenotypes of clusters 1 and 2.	('SDHB', 'Gene', (50, 54))	('Nf1', 'Gene', (69, 72))	('silencing', 'Var', (36, 45))	('Nf1', 'Gene', '18015', (69, 72))	('mouse', 'Species', '10090', (89, 94))
21192	33252357	Subsequently, chromaffin cells were isolated from the adrenal medulla, and deleted for SDHB by Cre-mediated recombination.	('chromaffin', 'Chemical', '-', (14, 24))	('SDHB', 'Gene', (87, 91))	('deleted', 'Var', (75, 82))
21194	33252357	Later on, Morin et al demonstrated that, in these SDHB-deficient cells, hypermethylation and pseudohypoxia act synergistically leading to the acquisition of metastatic treats.	('pseudohypoxia', 'Disease', 'None', (93, 106))	('rat', 'Species', '10116', (29, 32))	('hypermethylation', 'Var', (72, 88))	('SDHB-deficient', 'Gene', (50, 64))	('metastatic treats', 'CPA', (157, 174))	('leading to', 'Reg', (127, 137))	('acquisition', 'PosReg', (142, 153))	('pseudohypoxia', 'Disease', (93, 106))
21195	33252357	developed two cell lines of SDH-deficient chromaffin cells from rats with a heterozygous germline SDHB mutation.	('mutation', 'Var', (103, 111))	('SDHB', 'Gene', (98, 102))	('chromaffin', 'Chemical', '-', (42, 52))	('rats', 'Species', '10116', (64, 68))
21196	33252357	Heterozygous Sdhb+/- founder rats were generated with various deletions in the rat SDHB gene: offspring were irradiated and maintained until they were killed.	('SDHB', 'Gene', (83, 87))	('Sdhb', 'Gene', (13, 17))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (43, 46))	('Sdhb', 'Gene', '298596', (13, 17))	('deletions', 'Var', (62, 71))	('rat', 'Species', '10116', (79, 82))	('rats', 'Species', '10116', (29, 33))
21203	33252357	The genome, transcriptome and metabolome of RS0 closely resemble those of SDHB-mutated human PPGLs, representing the only real cell model deriving from cluster 1 tumours.	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('tumours', 'Disease', (162, 169))	('RS0', 'Var', (44, 47))	('human', 'Species', '9606', (87, 92))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('PPGLs', 'Chemical', '-', (93, 98))	('PGLs', 'Phenotype', 'HP:0002668', (94, 98))
21208	33252357	In fact, genetically engineered mice with SDHB mutations have failed to develop SDH-deficient PPGLs.	('SDH-deficient PPGLs', 'Disease', 'MESH:D007153', (80, 99))	('PGLs', 'Phenotype', 'HP:0002668', (95, 99))	('mutations', 'Var', (47, 56))	('SDH-deficient PPGLs', 'Disease', (80, 99))	('mice', 'Species', '10090', (32, 36))	('SDHB', 'Gene', (42, 46))
21233	33252357	Indeed, patients harbouring RET gain of function mutations develop MEN 2 syndrome.	('MEN 2 syndrome', 'Disease', (67, 81))	('gain of function', 'PosReg', (32, 48))	('mutations', 'Var', (49, 58))	('MEN', 'Species', '9606', (67, 70))	('patients', 'Species', '9606', (8, 16))
21234	33252357	PCCs in Pten KO mice show consistent deletions in mouse chromosome 4, which is homologous to human chromosome 1p, the most frequent deletion in human PCCs.	('deletions', 'Var', (37, 46))	('PCC', 'Gene', '1421', (0, 3))	('human', 'Species', '9606', (144, 149))	('PCC', 'Gene', (150, 153))	('Pten', 'Gene', (8, 12))	('human', 'Species', '9606', (93, 98))	('Pten', 'Gene', '19211', (8, 12))	('PCCs', 'Phenotype', 'HP:0002666', (150, 154))	('PCC', 'Gene', (0, 3))	('PCCs', 'Phenotype', 'HP:0002666', (0, 4))	('PCC', 'Gene', '1421', (150, 153))	('mouse', 'Species', '10090', (50, 55))	('mice', 'Species', '10090', (16, 20))
21235	33252357	ErbB2 and B-Raf proto-oncogenes mutated mice are also able to develop PCCs, as well as those mutated in Rb, Trp53, VHL, and InK4a tumour suppressor genes.	('PCC', 'Gene', '1421', (70, 73))	('ErbB2', 'Gene', '13866', (0, 5))	('InK4a', 'Gene', '12578', (124, 129))	('B-Raf', 'Gene', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('develop', 'PosReg', (62, 69))	('mutated', 'Var', (93, 100))	('tumour', 'Disease', (130, 136))	('B-Raf', 'Gene', '109880', (10, 15))	('Trp53', 'Gene', '22059', (108, 113))	('VHL', 'Gene', (115, 118))	('ErbB2', 'Gene', (0, 5))	('Trp53', 'Gene', (108, 113))	('mice', 'Species', '10090', (40, 44))	('PCCs', 'Phenotype', 'HP:0002666', (70, 74))	('Rb', 'Gene', '19645', (104, 106))	('InK4a', 'Gene', (124, 129))	('VHL', 'Gene', '22346', (115, 118))	('mutated', 'Var', (32, 39))	('PCC', 'Gene', (70, 73))
21239	33252357	RS0 is, in fact, a new xenograft and cell line model of SDH-deficient PCC from rats with a heterozygous germline SDHB mutation.	('SDH-deficient PCC', 'Disease', (56, 73))	('SDH-deficient PCC', 'Disease', 'OMIM:115700', (56, 73))	('SDHB', 'Gene', (113, 117))	('rats', 'Species', '10116', (79, 83))	('mutation', 'Var', (118, 126))
21250	33252357	In contrast, PC12 are noradrenergic and become excitable following NGF treatment.	('PC12', 'CellLine', 'CVCL:0481', (13, 17))	('PC12', 'Var', (13, 17))	('excitable', 'MPA', (47, 56))
21256	33252357	On the contrary, the rat PC12 cell lines express both HIF1alpha and HIF2alpha.	('HIF1alpha', 'Var', (54, 63))	('rat PC12', 'CellLine', 'CVCL:4695', (21, 29))	('HIF2alpha', 'Var', (68, 77))
21365	30366175	Most genetic studies on paraganglioma patients have highlighted the germline mutations in the RET, NFI and SDH mutations.	('RET', 'Gene', '5979', (94, 97))	('SDH', 'Gene', '6390', (107, 110))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('NFI', 'Gene', '4782', (99, 102))	('paraganglioma', 'Disease', (24, 37))	('germline mutations', 'Var', (68, 86))	('RET', 'Gene', (94, 97))	('NFI', 'Gene', (99, 102))	('patients', 'Species', '9606', (38, 46))	('SDH', 'Gene', (107, 110))	('paraganglioma', 'Disease', 'MESH:D010235', (24, 37))
21366	30366175	According to Piccini et al., the gene mutations responsible for head and neck paraganglioma occurs mostly in genes encoding the subunits of succinate dehydrogenase or mitochondrial complex II which includes SDHD which located on 11q2 chromosome.	('SDHD', 'Gene', '6392', (207, 211))	('SDHD', 'Gene', (207, 211))	('neck paraganglioma', 'Disease', 'MESH:D010235', (73, 91))	('mutations', 'Var', (38, 47))	('neck paraganglioma', 'Disease', (73, 91))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))
21368	30366175	The SDH mutations have been associated with clinical paraganglioma syndrome.	('SDH', 'Gene', '6390', (4, 7))	('associated', 'Reg', (28, 38))	('SDH', 'Gene', (4, 7))	('paraganglioma syndrome', 'Disease', (53, 75))	('mutations', 'Var', (8, 17))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (53, 75))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))
21369	30366175	documented that individual who is more likely to have SDH mutations are those who present with a family history of paragangliomas, a previous phaechromocytoma, multiple head and neck paragangliomas, age less than 40 years old and a male.	('mutations', 'Var', (58, 67))	('paragangliomas', 'Disease', (115, 129))	('paragangliomas', 'Disease', 'MESH:D010235', (115, 129))	('neck paragangliomas', 'Disease', (178, 197))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (178, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (115, 128))	('paragangliomas', 'Disease', (183, 197))	('SDH', 'Gene', '6390', (54, 57))	('paragangliomas', 'Disease', 'MESH:D010235', (183, 197))	('paragangliomas', 'Phenotype', 'HP:0002668', (115, 129))	('paragangliomas', 'Phenotype', 'HP:0002668', (183, 197))	('neck paragangliomas', 'Disease', 'MESH:D010235', (178, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (183, 196))	('SDH', 'Gene', (54, 57))
21375	30109021	Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia-inducible factor inhibitors Inactivating mutations of the succinate dehydrogenase subunit B ( SDHB) gene and the subsequent stabilization and activation of the hypoxia-inducible factor 2-alpha (HIF2alpha) unit are recognized hallmarks associated with the development of metastatic pheochromocytomas and paragangliomas (MPPG).	('Inactivating mutations', 'Var', (148, 170))	('hypoxia', 'Disease', (280, 287))	('hypoxia-inducible factor 2-alpha', 'Gene', '2034', (280, 312))	(' SDHB', 'Gene', (213, 218))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (47, 63))	('succinate dehydrogenase subunit B', 'Gene', '6390', (178, 211))	('MPPG', 'Chemical', '-', (439, 443))	('hypoxia', 'Disease', 'MESH:D000860', (280, 287))	('hypoxia', 'Disease', (112, 119))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (401, 437))	('activation', 'PosReg', (262, 272))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (401, 417))	('succinate dehydrogenase subunit B', 'Gene', (178, 211))	('hypoxia', 'Disease', 'MESH:D000860', (112, 119))	('malignant pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (37, 81))	('paraganglioma', 'Phenotype', 'HP:0002668', (68, 81))	('hypoxia-inducible factor 2-alpha', 'Gene', (280, 312))	('paragangliomas', 'Phenotype', 'HP:0002668', (423, 437))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (401, 418))	('paraganglioma', 'Phenotype', 'HP:0002668', (423, 436))
21390	30109021	Treatment options are limited to chemotherapy and low-specific activity 131meta-iodo-benzyl-guanidine (MIBG) and usually fail to produce a prolonged remission , .	('131meta-iodo-benzyl-guanidine', 'Var', (72, 101))	('MIBG', 'Chemical', 'MESH:D019797', (103, 107))	('low-specific', 'NegReg', (50, 62))
21396	30109021	These mutations prevent the oxidative catabolism of succinate to fumarate and electron transportation through the internal mitochondrial membrane.	('oxidative catabolism of succinate to fumarate', 'MPA', (28, 73))	('fumarate', 'Chemical', 'MESH:D005650', (65, 73))	('prevent', 'NegReg', (16, 23))	('mutations', 'Var', (6, 15))	('succinate', 'Chemical', 'MESH:D019802', (52, 61))
21401	30109021	Although the genetic causes of many MPPG (mainly SDHB mutations) and the molecular events leading to the metastatic transformation of chromaffin cells (stabilization and activation of HIF2alpha, DNA hypermethylation)  were determined several years ago, the development of therapeutics against MPPG has been very slow for three main reasons: (a) difficulty of patient enrollment in large clinical trials, (b) lack of preclinical animal models, and (c) lack of efficient, targeted drugs.	('SDHB', 'Gene', (49, 53))	('chromaffin', 'Chemical', '-', (134, 144))	('MPPG', 'Chemical', '-', (293, 297))	('mutations', 'Var', (54, 63))	('MPPG', 'Chemical', '-', (36, 40))	('MPPG', 'Disease', (36, 40))	('patient', 'Species', '9606', (359, 366))
21408	30109021	In addition, TKIs can inhibit other tyrosine kinase receptors that are universally involved in processes such as cancer cell growth, tumor spread, and development of resistance ,  ( Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('TKIs', 'Var', (13, 17))	('inhibit', 'NegReg', (22, 29))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', (113, 119))	('tumor', 'Disease', (133, 138))	('tyrosine kinase receptors', 'Enzyme', (36, 61))
21422	30109021	Positive responses were noticed in carriers of SDHB mutations as well as patients with apparently sporadic tumors.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('SDHB', 'Gene', (47, 51))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('patients', 'Species', '9606', (73, 81))
21443	30109021	In addition to inhibiting the VEGFRs, cabozantinib inhibits the c-met receptor pathways which are involved in tumor growth and spread and the development of resistance to anti-angiogenesis .	('cabozantinib', 'Var', (38, 50))	('VEGFR', 'Gene', '3791', (30, 35))	('c-met', 'Gene', '4233', (64, 69))	('cabozantinib', 'Chemical', 'MESH:C558660', (38, 50))	('inhibits', 'NegReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('VEGFR', 'Gene', (30, 35))	('inhibiting', 'NegReg', (15, 25))	('c-met', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
21475	30109021	It is also important to remember that patients with MPPG may have easier-to-control blood pressure after primary tumor resection (if possible) because of a decreased catecholamine surge .	('tumor', 'Disease', (113, 118))	('MPPG', 'Chemical', '-', (52, 56))	('catecholamine surge', 'Phenotype', 'HP:0003334', (166, 185))	('easier-to-control', 'PosReg', (66, 83))	('catecholamine surge', 'MPA', (166, 185))	('decreased', 'NegReg', (156, 165))	('catecholamine', 'Chemical', 'MESH:D002395', (166, 179))	('MPPG', 'Var', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
21477	30109021	Patients who receive TKIs frequently complain of constitutional symptoms, hand and foot syndrome, pain exacerbation, and gastrointestinal irritability among other symptoms.	('foot syndrome', 'Disease', (83, 96))	('constitutional symptoms', 'Disease', (49, 72))	('hand', 'Disease', (74, 78))	('irritability', 'Phenotype', 'HP:0000737', (138, 150))	('constitutional symptoms', 'Phenotype', 'HP:0025142', (49, 72))	('TKIs', 'Var', (21, 25))	('hand', 'Disease', 'MESH:D006230', (74, 78))	('gastrointestinal irritability', 'Disease', (121, 150))	('gastrointestinal irritability', 'Disease', 'MESH:D005767', (121, 150))	('Patients', 'Species', '9606', (0, 8))	('foot syndrome', 'Disease', 'MESH:D005534', (83, 96))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('pain', 'Disease', 'MESH:D010146', (98, 102))	('pain', 'Disease', (98, 102))	('complain', 'Reg', (37, 45))
21487	30109021	In addition to SDHB mutations leading to HIF2alpha activation, mutations in the HIF2alpha-encoding gene ( EPAS1) have been identified and functionally characterized in PPGL .	('mutations', 'Var', (63, 72))	('EPAS1', 'Gene', '2034', (106, 111))	('EPAS1', 'Gene', (106, 111))	('PPG', 'Chemical', '-', (168, 171))	('SDHB', 'Gene', (15, 19))	('activation', 'PosReg', (51, 61))	('PPGL', 'Gene', (168, 172))	('mutations', 'Var', (20, 29))
21488	30109021	These validated findings, implicating the disruption of genes involved in the response to hypoxia, have spearheaded the initiation of therapeutic strategies to directly tackle HIF2alpha ( Figure 1).	('disruption', 'Var', (42, 52))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('hypoxia', 'Disease', (90, 97))
21497	30109021	These therapies include radiopharmaceutical medications such as high-specific activity MIBG and peptide receptor radionuclide therapy (PRRT).	('MIBG', 'Gene', (87, 91))	('high-specific', 'Var', (64, 77))	('MIBG', 'Chemical', 'MESH:D019797', (87, 91))
21532	29644041	Immunohistochemistry revealed positivity for chromogranin and synaptofisin, compatible with paraganglioma (Figs 4-6).	('positivity', 'Var', (30, 40))	('paraganglioma', 'Disease', (92, 105))	('synaptofisin', 'Protein', (62, 74))	('paraganglioma', 'Disease', 'MESH:D010235', (92, 105))	('chromogranin', 'Protein', (45, 57))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))
21542	29644041	While PGGL secret almost exclusively noradrenaline (except PGGL of organ of Zuckerkandl), Pheos may secrete adrenaline, noradrenaline and dopamine due to the expression of phenyletanolamine-N-metyltransferase.	('adrenaline', 'Chemical', 'MESH:D004837', (123, 133))	('dopamine', 'Chemical', 'MESH:D004298', (138, 146))	('phenyletanolamine-N-metyltransferase', 'Var', (172, 208))	('secrete adrenaline', 'MPA', (100, 118))	('noradrenaline', 'Chemical', 'MESH:D009638', (37, 50))	('Pheos', 'Phenotype', 'HP:0002666', (90, 95))	('adrenaline', 'Chemical', 'MESH:D004837', (108, 118))	('PGGL', 'Phenotype', 'HP:0002668', (6, 10))	('PGGL', 'Phenotype', 'HP:0002668', (59, 63))	('noradrenaline', 'MPA', (37, 50))	('noradrenaline', 'Chemical', 'MESH:D009638', (120, 133))	('adrenaline', 'Chemical', 'MESH:D004837', (40, 50))
21548	29644041	Functional imaging with 123I-MIBG or 18F-FDG PET/CT are also acceptable if no lesion can be identified by morphological cross sectional imaging, if metastatic disease is suspected or if a paraganglioma is discovered.	('paraganglioma', 'Phenotype', 'HP:0002668', (188, 201))	('123I-MIBG', 'Var', (24, 33))	('paraganglioma', 'Disease', (188, 201))	('123I-MIBG', 'Chemical', 'MESH:D019797', (24, 33))	('paraganglioma', 'Disease', 'MESH:D010235', (188, 201))	('18F-FDG', 'Var', (37, 44))
21550	29644041	18F-FDG-PET, 18F-DOPA and Octreoscan are superior to MIBG in the investigation of PGGL, especially if malignant and harboring a SDHB mutation.	('mutation', 'Var', (133, 141))	('SDHB', 'Gene', (128, 132))	('PGGL', 'Phenotype', 'HP:0002668', (82, 86))	('18F-DOPA', 'Chemical', 'MESH:C043437', (13, 21))	('MIBG', 'Chemical', 'MESH:D019797', (53, 57))	('SDHB', 'Gene', '6390', (128, 132))
21712	26624503	Those with non-functioning retroperitoneal paragangliomas may be diagnosed incidentally or present with compressive symptoms such as abdominal pain that may be associated with nausea, vomiting, abdominal distension and weight loss.	('vomiting', 'Disease', (184, 192))	('retroperitoneal paragangliomas', 'Phenotype', 'HP:0006729', (27, 57))	('weight loss', 'Disease', (219, 230))	('nausea', 'Disease', (176, 182))	('retroperitoneal paragangliomas', 'Disease', (27, 57))	('associated', 'Reg', (160, 170))	('abdominal pain', 'Disease', (133, 147))	('abdominal pain', 'Disease', 'MESH:D015746', (133, 147))	('pain', 'Phenotype', 'HP:0012531', (143, 147))	('nausea', 'Disease', 'MESH:D009325', (176, 182))	('retroperitoneal paraganglioma', 'Phenotype', 'HP:0006729', (27, 56))	('retroperitoneal paragangliomas', 'Disease', 'MESH:D012186', (27, 57))	('abdominal distension', 'Disease', (194, 214))	('abdominal distension', 'Phenotype', 'HP:0003270', (194, 214))	('compressive symptoms', 'Phenotype', 'HP:0000716', (104, 124))	('paraganglioma', 'Phenotype', 'HP:0002668', (43, 56))	('paragangliomas', 'Phenotype', 'HP:0002668', (43, 57))	('weight loss', 'Disease', 'MESH:D015431', (219, 230))	('vomiting', 'Disease', 'MESH:D014839', (184, 192))	('non-functioning', 'Var', (11, 26))	('nausea', 'Phenotype', 'HP:0002018', (176, 182))	('weight loss', 'Phenotype', 'HP:0001824', (219, 230))	('vomiting', 'Phenotype', 'HP:0002013', (184, 192))	('abdominal pain', 'Phenotype', 'HP:0002027', (133, 147))
21744	23891076	Factors not associated with biochemical response to surgery include gender, family history, SDHB mutation status, systemic therapy, and preoperative biochemical profile.	('SDHB', 'Gene', (92, 96))	('SDHB', 'Gene', '6390', (92, 96))	('mutation', 'Var', (97, 105))
21752	23891076	The most well defined genetic risk factor for malignant disease is a mutation in the SDHB gene, which is clinically associated with an earlier onset of disease and more aggressive malignancy.	('mutation', 'Var', (69, 77))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('malignant disease', 'Disease', 'MESH:D009369', (46, 63))	('aggressive malignancy', 'Disease', 'MESH:D009369', (169, 190))	('aggressive malignancy', 'Disease', (169, 190))	('malignant disease', 'Disease', (46, 63))	('associated', 'Reg', (116, 126))
21757	23891076	All patients underwent genetic testing for mutations and deletions in SDHA, SDHB, SDHC, SDHD, SDHAF2, RET, VHL, and TMEM127.	('SDHC', 'Gene', '6391', (82, 86))	('SDHD', 'Gene', '6392', (88, 92))	('SDHD', 'Gene', (88, 92))	('patients', 'Species', '9606', (4, 12))	('RET', 'Gene', '5979', (102, 105))	('VHL', 'Gene', (107, 110))	('SDHC', 'Gene', (82, 86))	('deletions', 'Var', (57, 66))	('SDHB', 'Gene', '6390', (76, 80))	('SDHAF2', 'Gene', (94, 100))	('SDHA', 'Gene', (70, 74))	('SDHAF2', 'Gene', '54949', (94, 100))	('SDHA', 'Gene', (94, 98))	('TMEM127', 'Gene', (116, 123))	('VHL', 'Gene', '7428', (107, 110))	('SDHA', 'Gene', '6389', (70, 74))	('SDHB', 'Gene', (76, 80))	('RET', 'Gene', (102, 105))	('SDHA', 'Gene', '6389', (94, 98))	('mutations', 'Var', (43, 52))	('TMEM127', 'Gene', '55654', (116, 123))
21774	23891076	Twelve (40%) patients had a germline mutation in the SDHB gene, with one patient positive for SDHD.	('SDHD', 'Gene', (94, 98))	('SDHB', 'Gene', '6390', (53, 57))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('SDHB', 'Gene', (53, 57))	('patient', 'Species', '9606', (73, 80))	('germline mutation', 'Var', (28, 45))	('SDHD', 'Gene', '6392', (94, 98))
21788	23891076	Patients with SDHB mutations appeared to demonstrate a less durable biochemical response, but this result did not achieve statistical significance (P = 0.021, Figure 2).	('mutations', 'Var', (19, 28))	('biochemical response', 'MPA', (68, 88))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', '6390', (14, 18))	('SDHB', 'Gene', (14, 18))
21799	23891076	The analysis also showed a statistical trends towards worse operative outcomes in patients with SDHB mutations (Figure 2) and in patients whose initial presentation involved the classic symptom triad of headache, palpitations, and diaphoresis.	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (82, 90))	('headache', 'Disease', (203, 211))	('palpitations', 'Disease', (213, 225))	('headache', 'Phenotype', 'HP:0002315', (203, 211))	('palpitations', 'Phenotype', 'HP:0001962', (213, 225))	('diaphoresis', 'Phenotype', 'HP:0000975', (231, 242))	('diaphoresis', 'Disease', (231, 242))	('SDHB', 'Gene', '6390', (96, 100))	('SDHB', 'Gene', (96, 100))	('headache', 'Disease', 'MESH:D006261', (203, 211))	('worse', 'NegReg', (54, 59))
21987	22983831	Mutations in succinate dehydrogenase (SDH) gene or mitochondrial complex 2 gene are responsible for most cases of hereditary paragangliomas.	('succinate dehydrogenase', 'Gene', '6390', (13, 36))	('SDH', 'Gene', '6390', (38, 41))	('succinate dehydrogenase', 'Gene', (13, 36))	('responsible', 'Reg', (84, 95))	('paragangliomas', 'Phenotype', 'HP:0002668', (125, 139))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (38, 41))	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (114, 139))	('paraganglioma', 'Phenotype', 'HP:0002668', (125, 138))	('hereditary paragangliomas', 'Disease', (114, 139))
22106	22222147	For surgery of primary pheochromocytoma, it has been shown that catecholamine release can be triggered by direct manipulation during dissection/extirpation of the tumor and by increase of pressure of the abdominal cavity, as it can occur by induction of a pneumoperitoneum for laparoscopy or palpation of the abdomen.	('increase', 'PosReg', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('catecholamine release', 'MPA', (64, 85))	('manipulation', 'Var', (113, 125))	('pheochromocytoma', 'Disease', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('tumor', 'Disease', (163, 168))	('catecholamine', 'Chemical', 'MESH:D002395', (64, 77))	('pheochromocytoma', 'Disease', 'MESH:D010673', (23, 39))
22112	22222147	In particular, tumors predominantly containing norepinephrine are characterized by poorly differentiated secretory pathways resulting in unregulated catecholamine release, in contrast to tumors that predominantly produce epinephrine or metanephrine.	('unregulated catecholamine release', 'MPA', (137, 170))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('norepinephrine', 'Chemical', 'MESH:D009638', (47, 61))	('norepinephrine', 'Var', (47, 61))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('catecholamine', 'Chemical', 'MESH:D002395', (149, 162))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('epinephrine', 'Chemical', 'MESH:D004837', (221, 232))	('epinephrine', 'Chemical', 'MESH:D004837', (50, 61))	('tumors', 'Disease', (15, 21))	('metanephrine', 'Chemical', 'MESH:D008676', (236, 248))
22155	18707631	Familial syndromes with pheochromocytomas/paragangliomas include multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) syndrome, neuroectodermal dysplasias (neurofibromatosis type 1 [NF-1], tuberous sclerosis and Sturge-Weber syndrome) and other familial paragangliomas (especially those related to succinate dehydrogenase (SDH) gene mutations; see below).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (24, 40))	('endocrine neoplasia type 2', 'Disease', (74, 100))	('tuberous sclerosis', 'Disease', (205, 223))	('pheochromocytomas/paragangliomas', 'Disease', (24, 56))	('NF-1', 'Gene', '4763', (198, 202))	('NF-1', 'Gene', (198, 202))	('familial paragangliomas', 'Disease', (261, 284))	('paragangliomas', 'Phenotype', 'HP:0002668', (270, 284))	('paraganglioma', 'Phenotype', 'HP:0002668', (270, 283))	('neuroectodermal dysplasias', 'Disease', (144, 170))	('neurofibromatosis type 1', 'Gene', (172, 196))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (74, 93))	('succinate dehydrogenase', 'Gene', '6390', (314, 337))	('SDH', 'Gene', '6390', (339, 342))	('mutations', 'Var', (349, 358))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (24, 56))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (24, 41))	('Sturge-Weber syndrome', 'Disease', 'MESH:D013341', (228, 249))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (172, 189))	('MEN', 'Species', '9606', (102, 105))	('familial paragangliomas', 'Disease', 'MESH:D010235', (261, 284))	('neuroectodermal dysplasias', 'Disease', 'MESH:D020752', (144, 170))	('Sturge-Weber syndrome', 'Disease', (228, 249))	('von Hippel-Lindau (VHL) syndrome', 'Disease', 'MESH:D006623', (110, 142))	('neuroectodermal dysplasias', 'Phenotype', 'HP:0030061', (144, 170))	('paragangliomas', 'Phenotype', 'HP:0002668', (42, 56))	('SDH', 'Gene', (339, 342))	('paraganglioma', 'Phenotype', 'HP:0002668', (42, 55))	('Weber syndrome', 'Phenotype', 'HP:0002277', (235, 249))	('neurofibromatosis type 1', 'Gene', '4763', (172, 196))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (74, 100))	('succinate dehydrogenase', 'Gene', (314, 337))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (205, 223))
22156	18707631	Activating germline mutations in the RET (REarranged during Transfection) protooncogene (usually in codons 634 or 918; 10q11.2) are implicated in the abnormal cellular proliferation of the MEN 2 syndrome.	('Activating', 'PosReg', (0, 10))	('RET', 'Gene', (37, 40))	('REarranged during Transfection', 'Gene', (42, 72))	('MEN 2 syndrome', 'Disease', (189, 203))	('MEN', 'Species', '9606', (189, 192))	('germline mutations', 'Var', (11, 29))	('RET', 'Gene', '5979', (37, 40))	('REarranged during Transfection', 'Gene', '5979', (42, 72))	('abnormal cellular proliferation', 'Phenotype', 'HP:0031377', (150, 181))
22158	18707631	Commonly missense mutations in the VHL tumor suppressor gene (usually in codon 167; 3p25-26) are implicated in the pathogenesis of VHL syndrome, with 25%-50% of subjects having mostly benign pheochromocytomas (and slightly less than 50% with bilateral disease).	('VHL syndrome', 'Disease', (131, 143))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (191, 207))	('implicated', 'Reg', (97, 107))	('VHL tumor', 'Disease', 'MESH:D006623', (35, 44))	('benign pheochromocytomas', 'Disease', (184, 208))	('benign pheochromocytomas', 'Disease', 'MESH:D010673', (184, 208))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (191, 208))	('VHL tumor', 'Disease', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('VHL syndrome', 'Disease', 'MESH:D006623', (131, 143))	('missense mutations', 'Var', (9, 27))
22159	18707631	The genetic background of pheochromocytomas observed in subjects with neuroectodermal dysplasias is yet to be elucidated, although mutations in the NF-1 tumor suppressor gene - associated with von Recklinghausen's disease - have been observed (17q11.2; in 90% of cases).	("von Recklinghausen's disease", 'Disease', (193, 221))	('mutations', 'Var', (131, 140))	('pheochromocytomas', 'Disease', (26, 43))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NF-1', 'Gene', '4763', (148, 152))	("von Recklinghausen's disease", 'Disease', 'MESH:C537392', (193, 221))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (26, 42))	('neuroectodermal dysplasias', 'Phenotype', 'HP:0030061', (70, 96))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (26, 43))	('neuroectodermal dysplasias', 'Disease', (70, 96))	('NF-1', 'Gene', (148, 152))	('neuroectodermal dysplasias', 'Disease', 'MESH:D020752', (70, 96))	('associated', 'Reg', (177, 187))	('pheochromocytomas', 'Disease', 'MESH:D010673', (26, 43))
22161	18707631	Familial pheochromocytomas or head/neck paragangliomas are seen in subjects with germline mutations in subunits B, C and D of the SDH gene; the risk of extraadrenal and/or malignant disease is high for SDHB mutation carriers.	('mutations', 'Var', (90, 99))	('extraadrenal', 'Disease', (152, 164))	('SDH', 'Gene', (202, 205))	('malignant disease', 'Disease', 'MESH:D009369', (172, 189))	('neck paragangliomas', 'Disease', (35, 54))	('malignant disease', 'Disease', (172, 189))	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paragangliomas', 'Phenotype', 'HP:0002668', (40, 54))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (9, 26))	('SDH', 'Gene', (130, 133))	('SDHB', 'Gene', '6390', (202, 206))	('mutation', 'Var', (207, 215))	('Familial pheochromocytomas', 'Disease', (0, 26))	('head/neck paragangliomas', 'Phenotype', 'HP:0002864', (30, 54))	('neck paragangliomas', 'Disease', 'MESH:D010235', (35, 54))	('SDHB', 'Gene', (202, 206))	('SDH', 'Gene', '6390', (202, 205))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('Familial pheochromocytomas', 'Disease', 'MESH:C531777', (0, 26))	('SDH', 'Gene', '6390', (130, 133))
22163	18707631	10% extraadrenal, 10% malignant or 10% hereditary is in flux, since mutations in the SDHB, SDHD, VHL or RET genes have been identified in 12%-25% of patients with apparently sporadic pheochromocytomas.	('RET', 'Gene', '5979', (104, 107))	('VHL', 'Gene', '7428', (97, 100))	('patients', 'Species', '9606', (149, 157))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (183, 199))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (183, 200))	('identified', 'Reg', (124, 134))	('mutations', 'Var', (68, 77))	('SDHD', 'Gene', (91, 95))	('SDHB', 'Gene', '6390', (85, 89))	('SDHD', 'Gene', '6392', (91, 95))	('SDHB', 'Gene', (85, 89))	('pheochromocytomas', 'Disease', 'MESH:D010673', (183, 200))	('VHL', 'Gene', (97, 100))	('pheochromocytomas', 'Disease', (183, 200))	('RET', 'Gene', (104, 107))
22187	18707631	The sensitivity of [123I]MIBG is 83%-100% versus 77%-90% of [131I]MIBG (sensitivity is lower for extra-adrenal and/or metastatic disease); their specificity is 95%-100%.	('[123I]MIBG', 'Chemical', 'MESH:D019797', (19, 29))	('lower', 'NegReg', (87, 92))	('metastatic', 'CPA', (118, 128))	('[131I]MIBG', 'Chemical', '-', (60, 70))	('extra-adrenal', 'Disease', (97, 110))	('[123I]MIBG', 'Var', (19, 29))
22231	18707631	Mainly gastric carcinoids are found in 10% of individuals with Multiple Endocrine Neoplasia (MEN) type 1, which is an autosomal dominant disorder caused by deletion of the MEN1 suppressor gene on chromosome 11q13.	('caused by', 'Reg', (146, 155))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (118, 145))	('MEN1', 'Gene', (172, 176))	('MEN1', 'Gene', '4221', (172, 176))	('Neoplasia', 'Phenotype', 'HP:0002664', (82, 91))	('MEN', 'Species', '9606', (172, 175))	('gastric carcinoids', 'Disease', (7, 25))	('autosomal dominant disorder', 'Disease', (118, 145))	('MEN', 'Species', '9606', (93, 96))	('Multiple Endocrine Neoplasia', 'Disease', (63, 91))	('carcinoid', 'Phenotype', 'HP:0100570', (15, 24))	('gastric carcinoids', 'Disease', 'MESH:D002276', (7, 25))	('Multiple Endocrine Neoplasia', 'Disease', 'MESH:D009377', (63, 91))	('carcinoids', 'Phenotype', 'HP:0100570', (15, 25))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (72, 91))	('deletion', 'Var', (156, 164))
22232	18707631	Forty to eighty percent of patients with sporadic carcinoids also harbor loss of heterozygozity in chromosome 11 or deletion of the MEN1 gene.	('loss', 'NegReg', (73, 77))	('carcinoids', 'Phenotype', 'HP:0100570', (50, 60))	('MEN1', 'Gene', (132, 136))	('MEN1', 'Gene', '4221', (132, 136))	('deletion', 'Var', (116, 124))	('patients', 'Species', '9606', (27, 35))	('carcinoid', 'Phenotype', 'HP:0100570', (50, 59))
22233	18707631	Pulmonary carcinoids are associated with mutations in the p53 suppressor gene and variability in bcl-2 expression.	('mutations', 'Var', (41, 50))	('carcinoid', 'Phenotype', 'HP:0100570', (10, 19))	('associated', 'Reg', (25, 35))	('expression', 'MPA', (103, 113))	('Pulmonary carcinoids', 'Disease', (0, 20))	('carcinoids', 'Phenotype', 'HP:0100570', (10, 20))	('bcl-2', 'Gene', (97, 102))	('p53', 'Gene', (58, 61))	('Pulmonary carcinoids', 'Phenotype', 'HP:0030445', (0, 20))	('bcl-2', 'Gene', '596', (97, 102))	('p53', 'Gene', '7157', (58, 61))
22247	18707631	Scintigraphy with [131I]MIBG has 55%-85% sensitivity and 95% specificity in localizing carcinoids and the combination of SRS and MIBG scintigraphy results may provide even better localizing sensitivity.	('MIBG', 'Chemical', 'MESH:D019797', (24, 28))	('[131I]MIBG', 'Chemical', '-', (18, 28))	('carcinoid', 'Phenotype', 'HP:0100570', (87, 96))	('carcinoids', 'Disease', (87, 97))	('MIBG', 'Chemical', 'MESH:D019797', (129, 133))	('carcinoids', 'Phenotype', 'HP:0100570', (87, 97))	('[131I]', 'Var', (18, 24))
22258	18707631	Other PET ligands, such as [68Ga]DOTANOC (with affinity for ST-R-2 and -5) are being evaluated for neuroendocrine tumors, including carcinoids.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (99, 120))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (99, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('neuroendocrine tumors', 'Disease', (99, 120))	('[68Ga]DOTANOC', 'Var', (27, 40))	('carcinoids', 'Disease', (132, 142))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('carcinoids', 'Phenotype', 'HP:0100570', (132, 142))	('carcinoid', 'Phenotype', 'HP:0100570', (132, 141))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (99, 119))
22336	31292390	On admission, her consciousness level was at Glasgow Coma Scale (GCS) E3V5M6, temperature was 36.1oC, blood pressure was 167/117 mmHg, heart rate was 118 bpm, respiratory rate was 22 breaths/min, and peripheral capillary oxygen saturation (SpO2) was 97% (room air).	('heart', 'MPA', (135, 140))	('Coma', 'Phenotype', 'HP:0001259', (53, 57))	('SpO2', 'Chemical', 'MESH:C064029', (240, 244))	('oxygen', 'Chemical', 'MESH:D010100', (221, 227))	('E3V5M6', 'Var', (70, 76))
22422	29680948	germline BAP1 mutations), there is limited information regarding the lifetime RCC risks and the most appropriate screening modalities.	('BAP1', 'Gene', '8314', (9, 13))	('RCC', 'Disease', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('BAP1', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
22424	29680948	International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis, surveillance protocols and management of these rare conditions.	('variant', 'Var', (49, 56))	('inherited RCC', 'Disease', 'MESH:C538614', (30, 43))	('inherited RCC', 'Disease', (30, 43))
22427	29680948	However, patients harbouring a mutation in a gene predisposing to RCC do not necessarily have a family history of RCC (the mutation may have arisen de novo in the proband or the mutation may be non-penetrant in a carrier parent.	('RCC', 'Disease', 'MESH:C538614', (66, 69))	('RCC', 'Disease', 'MESH:C538614', (114, 117))	('patients', 'Species', '9606', (9, 17))	('RCC', 'Disease', (114, 117))	('mutation', 'Var', (31, 39))	('RCC', 'Disease', (66, 69))
22433	29680948	This rare autosomal dominantly inherited disorder has an incidence of approximately 1 in 30,000 and is caused by constitutional mutations in the VHL tumour suppressor gene (TSG).	('autosomal dominantly inherited disorder', 'Disease', 'MESH:D030342', (10, 49))	('TSG', 'Gene', (173, 176))	('mutations', 'Var', (128, 137))	('VHL tumour', 'Disease', (145, 155))	('VHL tumour', 'Disease', 'MESH:D006623', (145, 155))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('TSG', 'Gene', '57045', (173, 176))	('caused by', 'Reg', (103, 112))	('autosomal dominantly inherited disorder', 'Disease', (10, 49))
22437	29680948	More than 95% of patients with VHL disease will have a detectable VHL gene mutation and well-defined genotype-phenotype mean that the nature of the mutation may predict likely tumour risks (e.g.	('VHL', 'Gene', '7428', (31, 34))	('predict', 'Reg', (161, 168))	('tumour', 'Disease', 'MESH:D009369', (176, 182))	('VHL disease', 'Disease', (31, 42))	('mutation', 'Var', (75, 83))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('VHL disease', 'Disease', 'MESH:D006623', (31, 42))	('patients', 'Species', '9606', (17, 25))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', (31, 34))	('tumour', 'Disease', (176, 182))	('VHL', 'Gene', '7428', (66, 69))
22438	29680948	risk of phaeochromocytoma is small with truncating mutations and exonic deletions).	('truncating mutations', 'Var', (40, 60))	('phaeochromocytoma', 'Disease', (8, 25))	('exonic deletions', 'Var', (65, 81))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (8, 25))
22440	29680948	sunitinib/sorafenib) in sporadic RCC, as most clear cell RCC have somatic mutations in the VHL TSG.	('sorafenib', 'Chemical', 'MESH:D000077157', (10, 19))	('VHL', 'Gene', (91, 94))	('TSG', 'Gene', (95, 98))	('mutations', 'Var', (74, 83))	('RCC', 'Disease', 'MESH:C538614', (33, 36))	('RCC', 'Disease', (33, 36))	('VHL', 'Gene', '7428', (91, 94))	('RCC', 'Disease', 'MESH:C538614', (57, 60))	('RCC', 'Disease', (57, 60))	('TSG', 'Gene', '57045', (95, 98))	('sunitinib', 'Chemical', 'MESH:D000077210', (0, 9))
22445	29680948	Germline inactivating mutations in the FLCN TSG can cause both BHD syndrome and non-syndromic familial pneumothorax.	('non-syndromic familial pneumothorax', 'Disease', (80, 115))	('BHD syndrome', 'Disease', 'MESH:D058249', (63, 75))	('pneumothorax', 'Phenotype', 'HP:0002107', (103, 115))	('FLCN', 'Gene', '201163', (39, 43))	('familial pneumothorax', 'Phenotype', 'HP:0004876', (94, 115))	('non-syndromic familial pneumothorax', 'Disease', 'MESH:D011030', (80, 115))	('Germline inactivating mutations', 'Var', (0, 31))	('TSG', 'Gene', (44, 47))	('cause', 'Reg', (52, 57))	('BHD syndrome', 'Disease', (63, 75))	('FLCN', 'Gene', (39, 43))	('TSG', 'Gene', '57045', (44, 47))
22446	29680948	The function of the FLCN gene product has not been fully elucidated; however, inactivation leads to activation of the mTOR pathway.	('inactivation', 'Var', (78, 90))	('FLCN', 'Gene', (20, 24))	('FLCN', 'Gene', '201163', (20, 24))	('mTOR', 'Gene', (118, 122))	('mTOR', 'Gene', '2475', (118, 122))	('activation', 'PosReg', (100, 110))
22448	29680948	This very rare disorder (incidence approximately 1 in 200,000) is caused by inactivating mutations in the FH gene which encodes fumarate hydratase, a key component of the tricarboxylic acid (Krebs) cycle.	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (171, 189))	('inactivating mutations', 'Var', (76, 98))	('rare disorder', 'Disease', (10, 23))	('rare disorder', 'Disease', 'MESH:D035583', (10, 23))	('fumarate hydratase', 'Gene', '2271', (128, 146))	('caused by', 'Reg', (66, 75))	('Krebs', 'Chemical', '-', (191, 196))	('fumarate hydratase', 'Gene', (128, 146))
22449	29680948	Affected females may present with early-onset multiple uterine leiomyomas (fibroids) and FH mutations are a rare cause of inherited phaeochromocytoma/paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (150, 163))	('uterine leiomyomas', 'Phenotype', 'HP:0000131', (55, 73))	('inherited phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (122, 163))	('leiomyomas', 'Disease', (63, 73))	('mutations', 'Var', (92, 101))	('inherited phaeochromocytoma/paraganglioma', 'Disease', (122, 163))	('leiomyomas', 'Disease', 'MESH:D007889', (63, 73))
22453	29680948	Germline mutations in these SDHx were initially described in association with phaeochromocytoma/paraganglioma and head and neck paraganglioma (HNPGL), but the tumour spectrum has since expanded to include gastrointestinal stromal tumours, pituitary tumours and RCC.	('Germline mutations', 'Var', (0, 18))	('RCC', 'Disease', 'MESH:C538614', (261, 264))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (205, 237))	('pituitary tumours', 'Disease', (239, 256))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('SDHx', 'Gene', (28, 32))	('neck paraganglioma', 'Disease', 'MESH:D010235', (123, 141))	('paraganglioma', 'Phenotype', 'HP:0002668', (128, 141))	('tumours', 'Phenotype', 'HP:0002664', (249, 256))	('association', 'Reg', (61, 72))	('SDHx', 'Chemical', '-', (28, 32))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('gastrointestinal stromal tumours', 'Disease', (205, 237))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumour', 'Disease', (249, 255))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('RCC', 'Disease', (261, 264))	('phaeochromocytoma/paraganglioma', 'Disease', (78, 109))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (78, 109))	('tumour', 'Disease', (159, 165))	('pituitary tumours', 'Disease', 'MESH:D010911', (239, 256))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('neck paraganglioma', 'Disease', (123, 141))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('tumour', 'Disease', (230, 236))
22455	29680948	Though RCC has been associated with mutations in each of the subunits, the most commonly associated gene is SDHB.	('associated', 'Reg', (89, 99))	('SDHB', 'Gene', (108, 112))	('associated', 'Reg', (20, 30))	('RCC', 'Disease', 'MESH:C538614', (7, 10))	('mutations', 'Var', (36, 45))	('SDHB', 'Gene', '6390', (108, 112))	('RCC', 'Disease', (7, 10))
22456	29680948	Germline mutations in SDHB may present with a familial RCC-only phenotype.	('Germline mutations', 'Var', (0, 18))	('present', 'Reg', (31, 38))	('SDHB', 'Gene', '6390', (22, 26))	('familial RCC-only', 'Disease', (46, 63))	('SDHB', 'Gene', (22, 26))	('familial RCC-only', 'Disease', 'MESH:C538614', (46, 63))
22457	29680948	The lifetime risk of RCC in SDHB mutation carriers is not well defined, but likely less than 10-15%; however, annual or biannual renal surveillance by MRI can be combined with screening for phaeochromocytoma/paraganglioma (which commences in older children).	('children', 'Species', '9606', (248, 256))	('mutation', 'Var', (33, 41))	('RCC', 'Disease', (21, 24))	('phaeochromocytoma/paraganglioma', 'Disease', (190, 221))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (190, 221))	('RCC', 'Disease', 'MESH:C538614', (21, 24))	('SDHB', 'Gene', '6390', (28, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (208, 221))	('SDHB', 'Gene', (28, 32))
22458	29680948	Activating mutations in the MET proto-oncogene predispose to Type 1 hereditary papillary RCC (HPRC).	('MET proto-oncogene', 'Gene', (28, 46))	('Type 1 hereditary papillary RCC', 'Disease', (61, 92))	('Activating mutations', 'Var', (0, 20))	('predispose', 'Reg', (47, 57))	('Type 1 hereditary papillary RCC', 'Disease', 'MESH:C538614', (61, 92))
22461	29680948	Following reports of germline BAP1 mutations in familial uveal melanoma, cutaneous melanoma and mesothelioma, it was recognised that RCCs are also part of the BAP1 tumour syndrome spectrum.	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('cutaneous melanoma', 'Disease', (73, 91))	('BAP1', 'Gene', '8314', (159, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (73, 91))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('tumour syndrome', 'Disease', (164, 179))	('mesothelioma', 'Disease', (96, 108))	('tumour syndrome', 'Disease', 'MESH:D009369', (164, 179))	('mesothelioma', 'Disease', 'MESH:D008654', (96, 108))	('BAP1', 'Gene', '8314', (30, 34))	('BAP1', 'Gene', (159, 163))	('uveal melanoma', 'Phenotype', 'HP:0007716', (57, 71))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('familial uveal melanoma', 'Disease', 'MESH:C536494', (48, 71))	('familial uveal melanoma', 'Disease', (48, 71))	('BAP1', 'Gene', (30, 34))	('RCC', 'Disease', (133, 136))	('mutations', 'Var', (35, 44))
22462	29680948	Though germline BAP1 mutations have been described in patients with familial RCC and no other BAP1-related tumours, such cases are rare and BAP1 mutation analysis is not yet performed in all cases of inherited RCC.	('familial RCC', 'Disease', 'MESH:C538614', (68, 80))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('BAP1', 'Gene', '8314', (94, 98))	('BAP1', 'Gene', (140, 144))	('inherited RCC', 'Disease', (200, 213))	('familial RCC', 'Disease', (68, 80))	('patients', 'Species', '9606', (54, 62))	('inherited RCC', 'Disease', 'MESH:C538614', (200, 213))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (94, 98))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('BAP1', 'Gene', '8314', (140, 144))	('BAP1', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
22464	29680948	Constitutional chromosome 3 translocations are a rare, but well-validated cause of familial RCC.	('Constitutional chromosome 3 translocations', 'Var', (0, 42))	('familial RCC', 'Disease', 'MESH:C538614', (83, 95))	('familial RCC', 'Disease', (83, 95))
22470	29680948	Germline VHL, SDHx and FH mutations may predispose to phaeochromocytoma/paraganglioma and RCC, and on rare occasions renal tumours have been reported in association with mutations in the phaeochromocytoma genes TMEM127 and MAX.	('phaeochromocytoma', 'Disease', 'MESH:D010673', (54, 71))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('VHL', 'Gene', '7428', (9, 12))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('mutations', 'Var', (26, 35))	('SDHx', 'Chemical', '-', (14, 18))	('renal tumours', 'Disease', 'MESH:D007680', (117, 130))	('RCC', 'Disease', (90, 93))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('phaeochromocytoma', 'Disease', (187, 204))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (187, 204))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('renal tumours', 'Disease', (117, 130))	('TMEM127', 'Gene', (211, 218))	('MAX', 'Gene', (223, 226))	('predispose', 'Reg', (40, 50))	('phaeochromocytoma/paraganglioma', 'Disease', (54, 85))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (54, 85))	('phaeochromocytoma', 'Disease', (54, 71))	('VHL', 'Gene', (9, 12))	('mutations', 'Var', (170, 179))	('TMEM127', 'Gene', '55654', (211, 218))	('SDHx', 'Gene', (14, 18))
22471	29680948	Germline mutations in CDC73 are associated with hyperparathyroidism-jaw tumour syndrome, a very rare disorder that has been associated with Wilms tumour and, on one occasion, papillary RCC.	('Germline mutations', 'Var', (0, 18))	('hyperparathyroidism-jaw tumour syndrome', 'Disease', (48, 87))	('RCC', 'Disease', (185, 188))	('Wilms tumour', 'Disease', (140, 152))	('Wilms tumour', 'Disease', 'MESH:D009396', (140, 152))	('Wilms tumour', 'Phenotype', 'HP:0002667', (140, 152))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('a very rare disorder', 'Disease', (89, 109))	('CDC73', 'Gene', (22, 27))	('associated', 'Reg', (124, 134))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (48, 67))	('CDC73', 'Gene', '79577', (22, 27))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('associated', 'Reg', (32, 42))	('hyperparathyroidism-jaw tumour syndrome', 'Disease', 'MESH:C563273', (48, 87))	('jaw tumour', 'Phenotype', 'HP:0030792', (68, 78))	('RCC', 'Disease', 'MESH:C538614', (185, 188))	('a very rare disorder', 'Disease', 'MESH:D035583', (89, 109))
22478	29680948	Germline SDHB and FLCN mutations have also been described in non-syndromic early-onset or bilateral RCC cases with no family history.	('SDHB', 'Gene', '6390', (9, 13))	('described', 'Reg', (48, 57))	('FLCN', 'Gene', (18, 22))	('SDHB', 'Gene', (9, 13))	('non-syndromic early-onset', 'Disease', (61, 86))	('mutations', 'Var', (23, 32))	('FLCN', 'Gene', '201163', (18, 22))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('RCC', 'Disease', (100, 103))
22481	29680948	For less well studied genes such as BAP1 variant, interpretation can be more challenging.	('BAP1', 'Gene', (36, 40))	('variant', 'Var', (41, 48))	('BAP1', 'Gene', '8314', (36, 40))
22482	29680948	Therefore, as suggested for diagnostic testing of hereditary phaeochromocytoma and paraganglioma, the establishment of agreed gene panels and curated databases of inherited RCC-associated gene variants would facilitate expert genetic testing.	('inherited RCC', 'Disease', 'MESH:C538614', (163, 176))	('hereditary phaeochromocytoma', 'Phenotype', 'HP:0002666', (50, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('variants', 'Var', (193, 201))	('hereditary phaeochromocytoma and paraganglioma', 'Disease', 'MESH:D010235', (50, 96))	('inherited RCC', 'Disease', (163, 176))
22484	29680948	The mean age at diagnosis of symptomatic RCC in VHL disease was around 45 years compared to an average age of > 60 years in sporadic cases, but there is not an agreed age threshold at which earlier-onset cases should be tested for RCC predisposition mutations.	('RCC', 'Disease', (231, 234))	('VHL disease', 'Disease', (48, 59))	('RCC', 'Disease', 'MESH:C538614', (231, 234))	('mutations', 'Var', (250, 259))	('VHL disease', 'Disease', 'MESH:D006623', (48, 59))	('RCC', 'Disease', 'MESH:C538614', (41, 44))	('RCC', 'Disease', (41, 44))
22487	29680948	Over the past 25 years, the identification and surveillance of large numbers of VHL mutation carriers has led to a broad consensus to how they should be investigated and managed.	('VHL', 'Gene', '7428', (80, 83))	('VHL', 'Gene', (80, 83))	('mutation', 'Var', (84, 92))
22492	29680948	Consequently, individuals with germline FH mutations undergo annual MRI surveillance even though most will not develop a renal lesion and surgical intervention is indicated for small screen-detected lesions.	('renal lesion', 'Disease', 'MESH:D007674', (121, 133))	('mutations', 'Var', (43, 52))	('renal lesion', 'Disease', (121, 133))
22493	29680948	For individuals with a germline BAP1 mutation, there is very limited information on the lifetime risks of RCC and the most appropriate screening modalities.	('germline', 'Var', (23, 31))	('mutation', 'Var', (37, 45))	('BAP1', 'Gene', '8314', (32, 36))	('BAP1', 'Gene', (32, 36))	('RCC', 'Disease', (106, 109))	('RCC', 'Disease', 'MESH:C538614', (106, 109))
22494	29680948	International data sharing of inherited RCC gene variant information and multicentre collaboration to pool results of natural history and screening protocols for mutation carriers are required to enable evidence-based surveillance programmes to be designed.	('variant', 'Var', (49, 56))	('inherited RCC', 'Disease', 'MESH:C538614', (30, 43))	('inherited RCC', 'Disease', (30, 43))
22496	29680948	However, the tumour risks in SDHB mutation carriers are significantly less than originally thought and so there is (as in FH mutation carriers) a tension between over-investigation and early detection.	('less', 'NegReg', (70, 74))	('SDHB', 'Gene', '6390', (29, 33))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('mutation', 'Var', (34, 42))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('SDHB', 'Gene', (29, 33))	('tumour', 'Disease', (13, 19))
22503	29680948	Hence, it could be hypothesised that ablation of such tumourlets by administration of a synthetically lethal compound to young adults with VHL disease might reduce the risk of RCC at a later age.	('VHL disease', 'Disease', 'MESH:D006623', (139, 150))	('RCC', 'Disease', (176, 179))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('tumour', 'Disease', (54, 60))	('ablation', 'Var', (37, 45))	('reduce', 'NegReg', (157, 163))	('VHL disease', 'Disease', (139, 150))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
22504	29680948	The development of novel therapeutic approaches to inherited RCC will require a deeper knowledge of the normal function of inherited RCC gene products and the consequences of mutations in the relevant pathways.	('inherited RCC', 'Disease', 'MESH:C538614', (51, 64))	('inherited RCC', 'Disease', 'MESH:C538614', (123, 136))	('mutations', 'Var', (175, 184))	('inherited RCC', 'Disease', (123, 136))	('inherited RCC', 'Disease', (51, 64))
22505	29680948	However, a likely outcome of such research would be the potential for translating the knowledge of the pathogenesis of inherited RCC into novel treatments for sporadic RCC (as exemplified in VHL disease and the involvement of VHL inactivation in sporadic clear cell RCC).	('VHL', 'Gene', '7428', (226, 229))	('VHL', 'Gene', (191, 194))	('inactivation', 'Var', (230, 242))	('VHL', 'Gene', '7428', (191, 194))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('VHL disease', 'Disease', (191, 202))	('RCC', 'Disease', (266, 269))	('RCC', 'Disease', 'MESH:C538614', (129, 132))	('inherited RCC', 'Disease', (119, 132))	('RCC', 'Disease', (129, 132))	('VHL', 'Gene', (226, 229))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('RCC', 'Disease', (168, 171))	('VHL disease', 'Disease', 'MESH:D006623', (191, 202))	('inherited RCC', 'Disease', 'MESH:C538614', (119, 132))
22511	29680948	International data sharing of inherited RCC gene variant information may enable evidence-based improvements in the diagnosis and management of these rare conditions.	('variant', 'Var', (49, 56))	('inherited RCC', 'Disease', 'MESH:C538614', (30, 43))	('inherited RCC', 'Disease', (30, 43))
22517	29636949	It is generally believed that biochemical screening for pheochromocytoma is crucial to prevent the potentially catastrophic effects of a hypertensive crisis caused by manipulation of the adrenal mass 3, 4.	('pheochromocytoma', 'Disease', (56, 72))	('pheochromocytoma', 'Disease', 'MESH:D010673', (56, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('manipulation', 'Var', (167, 179))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (137, 156))	('hypertensive', 'Disease', (137, 149))	('hypertensive', 'Disease', 'MESH:D006973', (137, 149))
22523	29636949	Subsequently, a fluorodeoxyglucose (FDG) positron emission tomography (PET) scan showed high FDG uptake in both adrenal glands (left 7.5 x 6.4 x 4.6 cm, right 8.1 x 5.8 x 3.9 cm; Figure 1), without evidence for a primary tumor elsewhere.	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (16, 34))	('FDG', 'Chemical', 'MESH:D019788', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('FDG', 'Chemical', 'MESH:D019788', (36, 39))	('FDG', 'Var', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
22549	29636949	Blood pressure was normal (133/87 mmHg), and laboratory examination revealed a severe microcytic anemia (hemoglobin 3.5 mmol/L, NR 7.4-9.9 mmol/L (equal to 5.64 g/dL; NR 12-18 g/dL); MCV 67 fL, NR 80-100 fL), elevated liver enzymes (alkaline phosphatase 405 U/L, aspartate aminotransferase 46 U/L, gamma-glutamyl transpeptidase 109 U/L; NR: <120 U/l, <30 U/L, and <40 U/L, respectively), and a lactate dehydrogenase of 1757 U/L.	('MCV', 'Var', (183, 186))	('lactate dehydrogenase', 'Enzyme', (394, 415))	('anemia', 'Disease', 'MESH:D000740', (97, 103))	('anemia', 'Disease', (97, 103))	('liver enzymes', 'Enzyme', (218, 231))	('gamma-glutamyl transpeptidase', 'Enzyme', (298, 327))	('elevated liver enzymes', 'Phenotype', 'HP:0002910', (209, 231))	('anemia', 'Phenotype', 'HP:0001903', (97, 103))	('elevated', 'PosReg', (209, 217))	('microcytic anemia', 'Phenotype', 'HP:0001935', (86, 103))	('aspartate aminotransferase', 'Enzyme', (263, 289))
22564	29636949	This may be an overestimation because of publication bias, however, even small size PAL may cause adrenal insufficiency, probably due to diffuse infiltration and complete destruction of the adrenal tissue architecture 5, 6, 7.	('cause', 'Reg', (92, 97))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (98, 119))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (98, 119))	('adrenal insufficiency', 'Disease', (98, 119))	('PAL', 'Var', (84, 87))	('PAL', 'Phenotype', 'HP:0030069', (84, 87))
22586	29636949	Nevertheless, for the purpose of localizing pheochromocytoma, 1.23I-MIBG scanning is preferred over FDG-PET scanning because of its higher sensitivity (85-94% and 76%, respectively 4).	('FDG', 'Chemical', 'MESH:D019788', (100, 103))	('pheochromocytoma', 'Disease', (44, 60))	('pheochromocytoma', 'Disease', 'MESH:D010673', (44, 60))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('1.23I-MIBG', 'Chemical', '-', (62, 72))	('1.23I-MIBG', 'Var', (62, 72))
22735	28128698	Germline genetic testing revealed no clinically significant alteration in the SDHB, SDHC or SDHD genes; however, a variant of unknown clinical significance, p.H50R or c.149A>G, in exon 2 of the SDHD gene was identified.	('p.H50R', 'Var', (157, 163))	('SDHD', 'Gene', '6392', (194, 198))	('SDHD', 'Gene', '6392', (92, 96))	('SDHC', 'Gene', '6391', (84, 88))	('c.149A>G', 'Var', (167, 175))	('SDHB', 'Gene', '6390', (78, 82))	('SDHD', 'Gene', (194, 198))	('SDHD', 'Gene', (92, 96))	('SDHB', 'Gene', (78, 82))	('c.149A>G', 'Mutation', 'rs11214077', (167, 175))	('p.H50R', 'Mutation', 'rs11214077', (157, 163))	('SDHC', 'Gene', (84, 88))
22786	28128698	A recent study demonstrated that 53% of patients with at least one extra-adrenal paraganglioma had an identified germline mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('germline mutation', 'Var', (113, 130))	('patients', 'Species', '9606', (40, 48))	('paraganglioma', 'Disease', (81, 94))	('paraganglioma', 'Disease', 'MESH:D010235', (81, 94))
22788	28128698	In patients with SDHB mutations, primary tumor size has been found to be an age-independent predictor of patient survival and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('patient', 'Species', '9606', (105, 112))	('tumor', 'Disease', (41, 46))	('patient', 'Species', '9606', (3, 10))	('SDHB', 'Gene', '6390', (17, 21))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('SDHB', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
22790	28128698	Thus, in order to achieve the best possible clinical outcome, patients discovered to have any SDHB mutation are recommended to undergo genetic counseling and early and regular evaluations for the development of PCC/PGL.	('SDHB', 'Gene', (94, 98))	('mutation', 'Var', (99, 107))	('PCC', 'Gene', '1421', (211, 214))	('patients', 'Species', '9606', (62, 70))	('SDHB', 'Gene', '6390', (94, 98))	('PCC', 'Gene', (211, 214))
22876	27869719	In a series of in vitro, animal, and human studies, these workers demonstrated 123I-iodometomidate's high binding specificity in tissues of adrenocortical origin, similar pharmacodynamic properties to etomidate/metomidate, lack of toxicity or mutagenicity, and excellent imaging properties in both mice and patients.	('etomidate', 'Chemical', 'MESH:D005045', (201, 210))	('mice', 'Species', '10090', (298, 302))	('metomidate', 'Chemical', 'MESH:C084586', (88, 98))	('binding', 'Interaction', (106, 113))	('adrenocortical', 'Disease', 'MESH:D018268', (140, 154))	('metomidate', 'Chemical', 'MESH:C084586', (211, 221))	('123I-iodometomidate', 'Var', (79, 98))	('etomidate', 'Chemical', 'MESH:D005045', (212, 221))	('etomidate', 'Chemical', 'MESH:D005045', (89, 98))	('human', 'Species', '9606', (37, 42))	('patients', 'Species', '9606', (307, 315))	('toxicity', 'Disease', 'MESH:D064420', (231, 239))	('123I-iodometomidate', 'Chemical', 'MESH:C529450', (79, 98))	('toxicity', 'Disease', (231, 239))	('adrenocortical', 'Disease', (140, 154))
22989	27069748	The tumor is usually isointense or hypointense on T1-weighted and hyperintense on T2-weighted, with a great enhancement after a gadolinium injection.	('tumor', 'Disease', (4, 9))	('enhancement', 'PosReg', (108, 119))	('hypointense', 'Var', (35, 46))	('hyperintense', 'Var', (66, 78))	('gadolinium', 'Chemical', 'MESH:D005682', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
23032	26645353	Moreover, creatinine kinase and lactose dehydrogenase increased rapidly to 7066 and 609 IU/L, respectively.	('lactose dehydrogenase increased', 'Phenotype', 'HP:0025435', (32, 63))	('7066', 'Var', (75, 79))	('lactose dehydrogenase', 'Enzyme', (32, 53))	('creatinine', 'Chemical', 'MESH:D003404', (10, 20))	('increased', 'PosReg', (54, 63))	('creatinine kinase', 'MPA', (10, 27))
23087	24765414	Germline mutations have been identified in these diseases in, respectively, the proto-oncogene RET, and the tumor suppressor genes VHL and NF1.	('Germline mutations', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('RET', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('NF1', 'Gene', (139, 142))	('NF1', 'Gene', '4763', (139, 142))	('tumor', 'Disease', (108, 113))	('identified', 'Reg', (29, 39))	('VHL', 'Disease', 'MESH:D006623', (131, 134))	('RET', 'Gene', '5979', (95, 98))	('VHL', 'Disease', (131, 134))
23149	20726977	All operations were performed after at least two weeks of our standard pre-operative blockade with phenoxybenzamine 10 mg BID and metyrosine 250 mg TID.	('BID', 'Gene', (122, 125))	('metyrosine 250 mg', 'Var', (130, 147))	('BID', 'Gene', '637', (122, 125))	('metyrosine', 'Chemical', 'MESH:D019805', (130, 140))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (99, 115))
23217	21444676	Aberrant mTOR activation is a frequent event in cancer, that commonly results from heterozygous loss of PTEN.	('activation', 'PosReg', (14, 24))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mTOR', 'Gene', (9, 13))	('heterozygous', 'Var', (83, 95))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('results from', 'Reg', (70, 82))	('PTEN', 'Gene', (104, 108))
23218	21444676	Here, we show for the first time a differential protein expression between S6K1 and S6K2 in both mouse and human tissues.	('S6K2', 'Var', (84, 88))	('protein expression', 'MPA', (48, 66))	('human', 'Species', '9606', (107, 112))	('differential', 'Reg', (35, 47))	('mouse', 'Species', '10090', (97, 102))	('S6K1', 'Var', (75, 79))
23219	21444676	Additionally, the inactivation of S6k1 in the context of Pten heterozygosity (Pten+/-) suggests a differential requirement for this protein across multiple tissues.	('inactivation', 'Var', (18, 30))	('Pten+/-)', 'Gene', '19211', (78, 86))	('S6k1', 'Gene', (34, 38))	('S6k1', 'Gene', '72508', (34, 38))	('Pten+/-', 'Gene', (78, 85))
23220	21444676	Accordingly, we find that deletion of S6k1 markedly impairs Pten+/- mediated adrenal tumorigenesis, specifically due to low expression of S6k2.	('tumor', 'Disease', (85, 90))	('S6k2', 'Protein', (138, 142))	('deletion', 'Var', (26, 34))	('low', 'NegReg', (120, 123))	('S6k1', 'Gene', '72508', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('expression', 'MPA', (124, 134))	('S6k1', 'Gene', (38, 42))	('impairs', 'NegReg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
23234	21444676	In addition, knockout mice for S6k1 or S6k2 alone demonstrate that there is redundancy between both genes, and it has also been suggested that inactivation of one may be compensated for through upregulation of the other.	('inactivation', 'Var', (143, 155))	('upregulation', 'PosReg', (194, 206))	('redundancy', 'MPA', (76, 86))	('rat', 'Species', '10116', (57, 60))	('S6k1', 'Gene', (31, 35))	('S6k1', 'Gene', '72508', (31, 35))	('mice', 'Species', '10090', (22, 26))
23236	21444676	However, overexpression of both S6K1 and S6K2 have been reported in breast cancer, while a recent report showed that only S6k1 is required for insulinoma formation induced by expression of constitutively active Akt1 in the mouse pancreas.	('overexpression', 'PosReg', (9, 23))	('mouse', 'Species', '10090', (223, 228))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('reported', 'Reg', (56, 64))	('Akt1', 'Gene', '11651', (211, 215))	('S6k1', 'Gene', '72508', (122, 126))	('breast cancer', 'Disease', (68, 81))	('S6k1', 'Gene', (122, 126))	('S6K1', 'Var', (32, 36))	('Akt1', 'Gene', (211, 215))	('S6K2', 'Var', (41, 45))	('insulinoma', 'Phenotype', 'HP:0012197', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('insulinoma', 'Disease', (143, 153))	('insulinoma', 'Disease', 'MESH:D007340', (143, 153))
23237	21444676	Here we show that S6k1 genetic deletion can suppress phenotypes mediated by Pten haploinsufficiency in an exquisite tissue-specific fashion.	('haploinsufficiency', 'Disease', 'MESH:D058495', (81, 99))	('phenotypes', 'MPA', (53, 63))	('suppress', 'NegReg', (44, 52))	('haploinsufficiency', 'Disease', (81, 99))	('S6k1', 'Gene', '72508', (18, 22))	('S6k1', 'Gene', (18, 22))	('genetic deletion', 'Var', (23, 39))	('Pten', 'Gene', (76, 80))
23247	21444676	The following antibodies were used for western blot analysis: GAPDH (14C10 Cell Signaling Technology); S6K1 (Cell Signaling Technology, 49D7 Rabbit mAb); S6K2 [p70 S6 kinase beta (C-19) Santa Cruz Biotechnology]; phospho-S6 (S235/S236) (Cell Signaling Technology); total S6 (Cell Signaling Technology); Pten (Cell Signaling Technology).	('GAPDH', 'Gene', '100009074', (62, 67))	('phospho-S6 (S235/S236', 'Var', (213, 234))	('GAPDH', 'Gene', (62, 67))	('S6 kinase', 'Gene', '72508', (164, 173))	('Rabbit', 'Species', '9986', (141, 147))	('S6 kinase', 'Gene', (164, 173))
23253	21444676	Amino acid sequences for human (Homo sapiens): RPS6Kbeta1 (NP_003152.1), RPS6Kbeta2 (NP_003943.2); cow (Bos taurus): RPS6Kbeta1 (NP_991385.1), RPS6Kbeta2 (XP_582478.4); rat (Rattus norvegicus): RPS6Kbeta1 (NP_114191.1), RPS6Kbeta2 (NP_001010962); mouse (Mus musculus): RPS6Kbeta1 (NP_001107806), RPS6Kbeta2 (NP_067460.1); rabbit (O cuniculus): RPS6Kbeta1 (NP_001095160); chicken (Gallus gallus): RPS6K (NP_001025892.1); zebrafish (Danio rerio): RPS6K (NP_998241.1); frog (Xenopus laevis): RPS6Kb-1 (NP_001080935).	('rat', 'Species', '10116', (169, 172))	('mouse', 'Species', '10090', (247, 252))	('NP_001080935', 'Var', (499, 511))	('chicken', 'Species', '9031', (371, 378))	('Xenopus laevis', 'Species', '8355', (472, 486))	('rabbit', 'Species', '9986', (322, 328))	('Homo sapiens', 'Species', '9606', (32, 44))	('human', 'Species', '9606', (25, 30))	('cow', 'Species', '9913', (99, 102))	('Rattus norvegicus', 'Species', '10116', (174, 191))	('zebrafish', 'Species', '7955', (420, 429))	('Gallus gallus', 'Species', '9031', (380, 393))	('Bos taurus', 'Species', '9913', (104, 114))	('Mus musculus', 'Species', '10090', (254, 266))	('Danio rerio', 'Species', '7955', (431, 442))	('RPS6Kb-1', 'Gene', '394276', (489, 497))	('RPS6Kb-1', 'Gene', (489, 497))
23255	21444676	In particular, we have focused on 4 specific genotypes for our study: wild-type (wt), S6k1-/-, Pten+/-, and S6k1-/-;Pten+/- mice.	('Pten+/- mice', 'Gene', (116, 128))	('S6k1-', 'Gene', '72508', (108, 113))	('Pten+/- mice', 'Gene', '19211', (116, 128))	('Pten+/-', 'Var', (95, 102))	('S6k1-', 'Gene', (108, 113))	('S6k1-', 'Gene', (86, 91))	('S6k1-', 'Gene', '72508', (86, 91))
23259	21444676	Indeed, the lymph nodes from Pten+/- and S6k1-/-;Pten+/- mice were found to be indistinguishable in composition, with lymph nodes from both genotypes exhibiting an expansion of B- and T-lymphocytes as characterized by immunohistochemical staining (IHC) with the B-lymphocyte specific marker B220 and the T-lymphocyte marker CD3 (Fig.	('B220', 'Gene', '19264', (291, 295))	('B220', 'Gene', (291, 295))	('Pten+/- mice', 'Gene', (49, 61))	('CD3', 'Gene', (324, 327))	('Pten+/- mice', 'Gene', '19211', (49, 61))	('Pten+/-', 'Var', (29, 36))	('CD3', 'Gene', '12501', (324, 327))	('S6k1-', 'Gene', (41, 46))	('S6k1-', 'Gene', '72508', (41, 46))
23260	21444676	Furthermore, lymph nodes from Pten+/- and S6k1-/-;Pten+/- mice showed no significant differences in positive staining for the cell proliferation marker Ki-67, (Fig.	('rat', 'Species', '10116', (138, 141))	('Pten+/-', 'Var', (30, 37))	('S6k1-', 'Gene', (42, 47))	('Pten+/- mice', 'Gene', (50, 62))	('S6k1-', 'Gene', '72508', (42, 47))	('Pten+/- mice', 'Gene', '19211', (50, 62))
23261	21444676	Thus, these data suggest that S6k1 deletion does not impact the increased lymph node proliferation triggered by Pten heterozygous loss.	('lymph node proliferation', 'CPA', (74, 98))	('Pten', 'Gene', (112, 116))	('S6k1', 'Gene', (30, 34))	('rat', 'Species', '10116', (92, 95))	('S6k1', 'Gene', '72508', (30, 34))	('deletion', 'Var', (35, 43))
23263	21444676	Taken together, our data suggest that S6k1 deletion has little impact on the proliferative advantage conferred by Pten heterozygous loss, consistent with the comparable survival rates between Pten+/- and S6k1-/-;Pten+/- cohorts of mice.	('Pten', 'Gene', (114, 118))	('S6k1', 'Gene', '72508', (204, 208))	('S6k1', 'Gene', (204, 208))	('proliferative advantage', 'CPA', (77, 100))	('S6k1-', 'Gene', '72508', (204, 209))	('deletion', 'Var', (43, 51))	('rat', 'Species', '10116', (84, 87))	('S6k1', 'Gene', '72508', (38, 42))	('S6k1', 'Gene', (38, 42))	('mice', 'Species', '10090', (231, 235))	('rat', 'Species', '10116', (178, 181))	('S6k1-', 'Gene', (204, 209))
23265	21444676	In order to further characterize the S6k1-/-;Pten+/- mice we examined the impact of S6k1 genetic deletion in tumorigenesis driven by Pten heterozygous loss.	('S6k1', 'Gene', (84, 88))	('S6k1', 'Gene', (37, 41))	('S6k1-', 'Gene', (37, 42))	('genetic deletion', 'Var', (89, 105))	('S6k1-', 'Gene', '72508', (37, 42))	('S6k1', 'Gene', '72508', (84, 88))	('S6k1', 'Gene', '72508', (37, 41))	('Pten+/- mice', 'Gene', '19211', (45, 57))	('Pten+/- mice', 'Gene', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
23267	21444676	However, some of the tumors driven by Pten heterozygosity occur after a long latency and at incomplete penetrance.	('heterozygosity', 'Var', (43, 57))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('Pten', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
23274	21444676	At 13-15 months of age the S6k1-/-;Pten+/- still showed a markedly lower penetrance of the tumor phenotype compared to Pten+/- mice (40% in S6k1-/-;Pten+/- versus 100% in Pten+/-) (Fig.	('Pten+/- mice', 'Gene', '19211', (119, 131))	('Pten+/-', 'Var', (148, 155))	('tumor', 'Disease', (91, 96))	('S6k1-', 'Gene', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Pten+/-)', 'Gene', '19211', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('S6k1-', 'Gene', '72508', (140, 145))	('S6k1-', 'Gene', (27, 32))	('penetrance', 'MPA', (73, 83))	('Pten+/-', 'Gene', (171, 178))	('lower', 'NegReg', (67, 72))	('S6k1-', 'Gene', '72508', (27, 32))	('Pten+/- mice', 'Gene', (119, 131))
23275	21444676	We also identified a profound suppression of proliferation as characterized by Ki-67 staining in the adrenal medullas of the S6k1-/-;Pten+/- versus those of the Pten+/- mice (Fig.	('rat', 'Species', '10116', (52, 55))	('Pten+/- mice', 'Gene', '19211', (161, 173))	('Pten+/- mice', 'Gene', (161, 173))	('proliferation', 'CPA', (45, 58))	('Pten+/-', 'Var', (133, 140))	('suppression', 'NegReg', (30, 41))	('S6k1-', 'Gene', (125, 130))	('S6k1-', 'Gene', '72508', (125, 130))
23276	21444676	In addition, deletion of S6k1 in the Pten+/- background resulted in a notable reduction in phoshpo-S6 in these adrenal glands (Fig.	('phoshpo-S6', 'MPA', (91, 101))	('reduction', 'NegReg', (78, 87))	('S6k1', 'Gene', (25, 29))	('deletion', 'Var', (13, 21))	('S6k1', 'Gene', '72508', (25, 29))
23279	21444676	Interestingly, an analysis of the effect of S6k1 inactivation on uterine tumor formation in Pten+/- female mice, a less penetrant phenotype in this background, leads to a mildly reduced penetrance when compared with Pten+/- females alone (supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('S6k1', 'Gene', '72508', (44, 48))	('S6k1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('inactivation', 'Var', (49, 61))	('tumor', 'Disease', (73, 78))	('mice', 'Species', '10090', (107, 111))	('uterine tumor', 'Phenotype', 'HP:0010784', (65, 78))	('penetrance', 'MPA', (186, 196))	('reduced', 'NegReg', (178, 185))
23281	21444676	In order to understand the molecular basis underlying the tissue specific differential response to deletion of S6k1, we decided to analyze in depth the expression status of both S6k1 and S6k2 across a panel of tissues.	('S6k1', 'Gene', '72508', (111, 115))	('deletion', 'Var', (99, 107))	('S6k1', 'Gene', (178, 182))	('S6k1', 'Gene', '72508', (178, 182))	('S6k1', 'Gene', (111, 115))
23282	21444676	Previously published data have reported the mRNA for S6k1 and S6k2 to be ubiquitously expressed in all tissues analyzed.	('S6k1', 'Gene', '72508', (53, 57))	('S6k1', 'Gene', (53, 57))	('S6k2', 'Var', (62, 66))
23285	21444676	Additionally, we carried out western analysis on adrenal glands from wt, Pten+/- and S6k1-/-;Pten+/- mice and observed that S6k2 protein levels did not increase in the S6k1-/-;Pten+/- glands (Fig.	('Pten+/-', 'Var', (73, 80))	('S6k2 protein levels', 'MPA', (124, 143))	('S6k1-', 'Gene', (85, 90))	('S6k1-', 'Gene', (168, 173))	('S6k1-', 'Gene', '72508', (168, 173))	('Pten+/- mice', 'Gene', '19211', (93, 105))	('Pten+/- mice', 'Gene', (93, 105))	('S6k1-', 'Gene', '72508', (85, 90))
23287	21444676	Taken together, these data offer an explanation why S6k1 deletion has a differential impact on the phenotypes dictated by Pten heterozygosity.	('deletion', 'Var', (57, 65))	('S6k1', 'Gene', '72508', (52, 56))	('impact', 'Reg', (85, 91))	('S6k1', 'Gene', (52, 56))
23288	21444676	The minimal effect of S6k1 loss on uterine tumor formation and the lack of an effect on lymph node proliferation may be accounted for through compensation and redundancy with S6k2, while S6k1 deletion has a pronounced effect on the pheochromocytoma incidence due to low protein expression of S6k2 in the adrenal gland.	('S6k1', 'Gene', '72508', (187, 191))	('low', 'NegReg', (266, 269))	('S6k1', 'Gene', (22, 26))	('pheochromocytoma', 'Disease', (232, 248))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('S6k1', 'Gene', '72508', (22, 26))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (232, 248))	('deletion', 'Var', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('pheochromocytoma', 'Disease', 'MESH:D010673', (232, 248))	('rat', 'Species', '10116', (106, 109))	('tumor', 'Disease', (43, 48))	('uterine tumor', 'Phenotype', 'HP:0010784', (35, 48))	('S6k1', 'Gene', (187, 191))	('protein expression', 'MPA', (270, 288))
23290	21444676	It has been previously reported that both S6K1 and S6K2 are ubiquitously expressed in humans at the mRNA level.	('S6K1', 'Var', (42, 46))	('S6K2', 'Var', (51, 55))	('humans', 'Species', '9606', (86, 92))
23305	21444676	Specifically, our data constitute the rationale to develop an S6K1-specific inhibitor to target tumors triggered by loss of PTEN in tissues having low expression of S6K2.	('PTEN', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('rat', 'Species', '10116', (38, 41))	('loss', 'Var', (116, 120))
23307	21444676	An excellent example for such an S6K1 targeted therapy is represented by the treatment of pheochromocytoma, as is clearly demonstrated through our genetic inactivation of S6k1 in the adrenal gland of Pten+/- mice and our concomitant human data.	('pheochromocytoma', 'Disease', 'MESH:D010673', (90, 106))	('human', 'Species', '9606', (233, 238))	('pheochromocytoma', 'Disease', (90, 106))	('genetic inactivation', 'Var', (147, 167))	('S6k1', 'Gene', (171, 175))	('rat', 'Species', '10116', (129, 132))	('S6k1', 'Gene', '72508', (171, 175))	('Pten+/- mice', 'Gene', '19211', (200, 212))	('Pten+/- mice', 'Gene', (200, 212))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (90, 106))
23328	18437026	Cardiac enzyme showed myocardial damage; creatine kinase (CK) 667 IU/L (normal <250), CK-MB 34.6 ng/mL (normal <5), and myoglobin 1,462 ng/mL (normal <110) (Fig.	('CK-MB', 'Var', (86, 91))	('myoglobin', 'MPA', (120, 129))	('creatine kinase', 'MPA', (41, 56))	('myocardial damage', 'Disease', (22, 39))	('myocardial damage', 'Disease', 'MESH:D009202', (22, 39))
23367	18437026	Preoperative preparation with volume replacement and alpha-adrenergic blockades (usually prazocin or phenoxylbenzamine) have accounted for the most significant reductions in perioperative mortality.	('reductions', 'NegReg', (160, 170))	('alpha-adrenergic blockades', 'Protein', (53, 79))	('prazocin', 'Chemical', '-', (89, 97))	('phenoxylbenzamine', 'Chemical', '-', (101, 118))	('perioperative', 'MPA', (174, 187))	('phenoxylbenzamine', 'Var', (101, 118))
23395	32561571	Third, 49 of the 570 variants of unknown significance (VUSs) were selected to undergo gene products expression analyses.	('variants', 'Var', (21, 29))	('VUSs', 'Disease', 'None', (55, 59))	('VUSs', 'Disease', (55, 59))
23404	32561571	Variants were classified as five categories: (1) pathogenic, (2) likely pathogenic, (3) benign, (4) likely benign and (5) VUSs.	('VUSs', 'Disease', 'None', (122, 126))	('VUSs', 'Disease', (122, 126))	('Variants', 'Var', (0, 8))
23407	32561571	293A cells were transfected with recombinant plasmids of Flag-gene (wild type) and Flag-gene (mutant) using Lipofectamine 3000 Reagent (ThermoFisher) according to the manufacturer's instructions.	('293A', 'CellLine', 'CVCL:6910', (0, 4))	('Flag-gene', 'Gene', (57, 66))	('Lipofectamine 3000', 'Chemical', '-', (108, 126))	('mutant', 'Var', (94, 100))	('Flag-gene', 'Gene', (83, 92))
23415	32561571	According to ACMG guidelines, 21 variants were found to be pathogenic or likely pathogenic (table 2), which may be responsible for monogenic forms of hypertension.	('pathogenic', 'Reg', (59, 69))	('hypertension', 'Disease', 'MESH:D006973', (150, 162))	('hypertension', 'Disease', (150, 162))	('hypertension', 'Phenotype', 'HP:0000822', (150, 162))	('variants', 'Var', (33, 41))
23416	32561571	Five hundred and seventy variants were considered to be VUSs, whose clinical significance remained unknown.	('VUSs', 'Disease', (56, 60))	('variants', 'Var', (25, 33))	('VUSs', 'Disease', 'None', (56, 60))
23418	32561571	LoF variants in all of the six genes are known mechanism of hypertension.	('hypertension', 'Disease', (60, 72))	('variants', 'Var', (4, 12))	('hypertension', 'Phenotype', 'HP:0000822', (60, 72))	('LoF', 'NegReg', (0, 3))	('hypertension', 'Disease', 'MESH:D006973', (60, 72))
23419	32561571	Additionally, in four of the six genes (ARMC5,  SDHD, MEN1  and VHL ), stop-gain or frame-shift variants were proved to be targets of nonsense-mediated mRNA decay.	('nonsense-mediated mRNA decay', 'Var', (134, 162))	('VHL', 'Gene', (64, 67))	('ARMC5', 'Gene', '79798', (40, 45))	('ARMC5', 'Gene', (40, 45))	('frame-shift variants', 'Var', (84, 104))	('VHL', 'Gene', '7428', (64, 67))	('MEN1', 'Gene', (54, 58))	('SDHD', 'Gene', '6392', (48, 52))	('MEN1', 'Gene', '4221', (54, 58))	('SDHD', 'Gene', (48, 52))
23421	32561571	The first patient was a compound heterozygote of two CYP17A1 variants with 17-alpha-hydroxylase deficiency manifestations.	('patient', 'Species', '9606', (10, 17))	('CYP17A1', 'Gene', (53, 60))	('CYP17A1', 'Gene', '1586', (53, 60))	('hydroxylase deficiency', 'Disease', 'MESH:D054882', (84, 106))	('hydroxylase deficiency', 'Disease', (84, 106))	('variants', 'Var', (61, 69))
23422	32561571	She also carried a predicted deleterious heterozygous SCNN1B variant.	('SCNN1B', 'Gene', (54, 60))	('SCNN1B', 'Gene', '6338', (54, 60))	('variant', 'Var', (61, 68))
23425	32561571	The second patient carried a heterozygous variant of SCNN1G and a heterozygous variant of ARMC5 with Cushing syndrome manifestations.	('ARMC5', 'Gene', '79798', (90, 95))	('ARMC5', 'Gene', (90, 95))	('SCNN1G', 'Gene', (53, 59))	('Cushing syndrome', 'Disease', (101, 117))	('SCNN1G', 'Gene', '6340', (53, 59))	('Cushing syndrome', 'Disease', 'MESH:D003480', (101, 117))	('patient', 'Species', '9606', (11, 18))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (101, 117))	('variant', 'Var', (42, 49))
23428	32561571	The third patient carried a heterozygous variant of CACNA1H and a heterozygous variant of WNK4 with pseudohypoaldosteronism, type IIB manifestations except for normal blood potassium.	('potassium', 'Chemical', 'MESH:D011188', (173, 182))	('pseudohypoaldosteronism', 'Disease', 'MESH:D011546', (100, 123))	('patient', 'Species', '9606', (10, 17))	('CACNA1H', 'Gene', (52, 59))	('WNK4', 'Gene', '65266', (90, 94))	('WNK4', 'Gene', (90, 94))	('pseudohypoaldosteronism', 'Disease', (100, 123))	('CACNA1H', 'Gene', '8912', (52, 59))	('pseudohypoaldosteronism', 'Phenotype', 'HP:0008242', (100, 123))	('variant', 'Var', (41, 48))
23432	32561571	Although some variants were predicted to be LoF variants, expression analyses were still performed to confirm their roles in 293A cell lines.	('LoF', 'NegReg', (44, 47))	('variants', 'Var', (14, 22))	('293A', 'CellLine', 'CVCL:6910', (125, 129))
23433	32561571	However, two stop gain variants in ARMC5 and VHL resulted in significantly reduced mRNA levels (online supplementary figure 3), which may be due to the nonsense-mediated mRNA decay.	('VHL', 'Gene', '7428', (45, 48))	('ARMC5', 'Gene', '79798', (35, 40))	('mRNA levels', 'MPA', (83, 94))	('reduced', 'NegReg', (75, 82))	('variants', 'Var', (23, 31))	('VHL', 'Gene', (45, 48))	('ARMC5', 'Gene', (35, 40))
23435	32561571	Therefore, 27 variants were regarded as potential functional VUSs (online supplementary table 8).	('variants', 'Var', (14, 22))	('VUSs', 'Disease', (61, 65))	('VUSs', 'Disease', 'None', (61, 65))
23437	32561571	Their phenotypes were all consistent with the clinical manifestations of the potential functional variants but not related with VUSs they harboured (online supplementary table 11).	('VUSs', 'Disease', (128, 132))	('variants', 'Var', (98, 106))	('VUSs', 'Disease', 'None', (128, 132))
23438	32561571	We totally identified 33 individuals with pathogenic or likely pathogenic variants, 49 individuals with potential functional variants, 572 individuals with VUSs, and one person with a benign variant (figure 3A, table 2).	('VUSs', 'Disease', (156, 160))	('variants', 'Var', (74, 82))	('variants', 'Var', (125, 133))	('pathogenic', 'Reg', (42, 52))	('pathogenic', 'Reg', (63, 73))	('VUSs', 'Disease', 'None', (156, 160))
23439	32561571	Diseases that harboured the greatest burden of pathogenic, likely pathogenic or potential functional variants were PA and PPGL (figure 3B).	('PPGL', 'Chemical', '-', (122, 126))	('variants', 'Var', (101, 109))	('PA', 'Phenotype', 'HP:0011736', (115, 117))	('PPGL', 'Disease', (122, 126))
23441	32561571	Pedigree analyses uncovered a known pathogenic variant responsible for MEN2B (Family 1, RET c.T2753C), two novel pathogenic variants for pre-eclampsia (Families 2 and 3, CACNA1D c.A920G and c.G4370A p.R1457Q), a novel pathogenic variant for Liddle syndrome (Family 4, SCNN1B c.C1513T) and a known pathogenic variant for 17alpha-hydroxylase deficiency syndrome (Family 5, CYP17A1 c.985_987delinsAA).	('c.985_987delinsAA', 'Mutation', 'c.985_987delinsAA', (379, 396))	('c.A920G', 'Var', (178, 185))	('RET', 'Gene', '5979', (88, 91))	('-hydroxylase deficiency syndrome', 'Disease', 'MESH:D054882', (327, 359))	('c.G4370A', 'Mutation', 'rs781726820', (190, 198))	('eclampsia', 'Disease', (141, 150))	('Liddle syndrome', 'Disease', (241, 256))	('Liddle syndrome', 'Disease', 'MESH:D056929', (241, 256))	('p.R1457Q', 'Var', (199, 207))	('c.A920G', 'Mutation', 'c.920A>G', (178, 185))	('c.G4370A p.R1457Q', 'Var', (190, 207))	('eclampsia', 'Phenotype', 'HP:0100601', (141, 150))	('c.C1513T', 'Var', (275, 283))	('CYP17A1', 'Gene', (371, 378))	('c.C1513T', 'Mutation', 'rs766620267', (275, 283))	('CYP17A1', 'Gene', '1586', (371, 378))	('RET', 'Gene', (88, 91))	('-hydroxylase deficiency syndrome', 'Disease', (327, 359))	('SCNN1B', 'Gene', (268, 274))	('p.R1457Q', 'Mutation', 'rs781726820', (199, 207))	('MEN2B', 'Gene', (71, 76))	('MEN2B', 'Gene', '5979', (71, 76))	('pre-eclampsia', 'Phenotype', 'HP:0100602', (137, 150))	('SCNN1B', 'Gene', '6338', (268, 274))	('CACNA1D', 'Gene', '776', (170, 177))	('CACNA1D', 'Gene', (170, 177))	('eclampsia', 'Disease', 'MESH:D004461', (141, 150))	('c.T2753C', 'Mutation', 'rs74799832', (92, 100))
23442	32561571	CACNA1D variants have been well documented to be a causative gene responsible for PA.	('CACNA1D', 'Gene', '776', (0, 7))	('PA', 'Phenotype', 'HP:0011736', (82, 84))	('CACNA1D', 'Gene', (0, 7))	('variants', 'Var', (8, 16))
23443	32561571	However, in family 2 and family 3, the probands and their affected relatives with CACNA1D mutations cannot be diagnosed as PA for failing to surpass the screening test ARR or confirmatory test.	('PA', 'Phenotype', 'HP:0011736', (123, 125))	('CACNA1D', 'Gene', (82, 89))	('mutations', 'Var', (90, 99))	('CACNA1D', 'Gene', '776', (82, 89))
23444	32561571	This suggest that CACNA1D variants identified in the current study may be responsible for pre-eclampsia rather than PA.	('CACNA1D', 'Gene', '776', (18, 25))	('CACNA1D', 'Gene', (18, 25))	('responsible', 'Reg', (74, 85))	('PA', 'Phenotype', 'HP:0011736', (116, 118))	('pre-eclampsia', 'Phenotype', 'HP:0100602', (90, 103))	('eclampsia', 'Phenotype', 'HP:0100601', (94, 103))	('eclampsia', 'Disease', 'MESH:D004461', (94, 103))	('eclampsia', 'Disease', (94, 103))	('variants', 'Var', (26, 34))
23449	32561571	Sometimes, even the diagnoses have been achieved, genetic testing is still recommended for disease classification and targeted treatment because the hereditary pattern, complicated diseases, growth characteristics and malignancy of monogenic hypertension are largely determined by gene mutation.	('hypertension', 'Disease', (242, 254))	('hypertension', 'Phenotype', 'HP:0000822', (242, 254))	('gene mutation', 'Var', (281, 294))	('hypertension', 'Disease', 'MESH:D006973', (242, 254))	('malignancy', 'Disease', 'MESH:D009369', (218, 228))	('malignancy', 'Disease', (218, 228))	('determined by', 'Reg', (267, 280))
23451	32561571	It is not rare to see hypertensive individuals with hypokalemia and adrenal imaging abnormalities have critical ARR values or confirmatory test results.	('hypertensive', 'Disease', (22, 34))	('adrenal imaging abnormalities', 'Phenotype', 'HP:0000834', (68, 97))	('hypokalemia', 'Phenotype', 'HP:0002900', (52, 63))	('abnormalities', 'Var', (84, 97))	('hypokalemia', 'Disease', 'MESH:D007008', (52, 63))	('adrenal', 'Gene', (68, 75))	('hypertensive', 'Disease', 'MESH:D006973', (22, 34))	('hypokalemia', 'Disease', (52, 63))
23457	32561571	Among the 523 individuals with no variant, 83 (15.87%) were suspected to have specific forms of monogenic hypertension.	('hypertension', 'Phenotype', 'HP:0000822', (106, 118))	('hypertension', 'Disease', 'MESH:D006973', (106, 118))	('hypertension', 'Disease', (106, 118))	('variant', 'Var', (34, 41))
23458	32561571	Targeted sequencing combined with gene product expression analyses uncovered a number of disease causing variants and potential functional variants that were newly associated with monogenic hypertension.	('hypertension', 'Disease', (190, 202))	('hypertension', 'Phenotype', 'HP:0000822', (190, 202))	('associated', 'Reg', (164, 174))	('variants', 'Var', (105, 113))	('variants', 'Var', (139, 147))	('hypertension', 'Disease', 'MESH:D006973', (190, 202))
23460	32561571	However, for the three genes that do not lead to completely abolished expression of mutant proteins (NOS3, KCNJ5 and SDHC), dose-dependent effects were observed in animal models through in vivo and in vitro experiments.	('KCNJ5', 'Gene', (107, 112))	('NOS3', 'Gene', (101, 105))	('KCNJ5', 'Gene', '3762', (107, 112))	('SDHC', 'Gene', (117, 121))	('mutant', 'Var', (84, 90))	('effects', 'Reg', (139, 146))	('SDHC', 'Gene', '6391', (117, 121))	('NOS3', 'Gene', '4846', (101, 105))
23461	32561571	Blended phenotypes resulting from multilocus variants can be mistaken for new disorders or newly identified phenotypes of known disorders.	('new disorders', 'Disease', (74, 87))	('multilocus', 'Var', (34, 44))	('new disorders', 'Disease', 'MESH:C000657245', (74, 87))
23462	32561571	The identification of multiple locus variants provided useful information on the patients' diagnoses and treatments since therapeutic strategy merely targets a single disorder were not sufficient to control the symptoms resulted from multiple genetic disorder.	('variants', 'Var', (37, 45))	('patients', 'Species', '9606', (81, 89))	('multiple genetic disorder', 'Disease', 'MESH:D030342', (234, 259))	('multiple genetic disorder', 'Disease', (234, 259))
23464	32561571	Most of the pathogenic or potential disease causing mutations were found in CACNA1H and CACNA1D genes.	('mutations', 'Var', (52, 61))	('disease causing', 'Reg', (36, 51))	('pathogenic', 'Reg', (12, 22))	('CACNA1D', 'Gene', '776', (88, 95))	('CACNA1H', 'Gene', (76, 83))	('CACNA1D', 'Gene', (88, 95))	('CACNA1H', 'Gene', '8912', (76, 83))
23466	32561571	Approximately 40% of PPGL cases carry a germline mutation in one of 12 known causative genes.	('PPGL', 'Chemical', '-', (21, 25))	('germline mutation', 'Var', (40, 57))	('PPGL', 'Gene', (21, 25))
23467	32561571	Similarly, in this study, 76 individuals were included for suspicion of having PPGL and PPGL variants were identified from 24 of them (31.58%).	('PPGL', 'Chemical', '-', (88, 92))	('PPGL', 'Gene', (88, 92))	('variants', 'Var', (93, 101))	('PPGL', 'Chemical', '-', (79, 83))	('PPGL', 'Gene', (79, 83))
23469	32561571	Our results generally showed a similar pattern, with causative variants being most frequently clustered in RET, VHL, SDHB and NF1, suggesting the necessity for screening these frequently mutated genes in clinical settings.	('SDHB', 'Gene', (117, 121))	('variants', 'Var', (63, 71))	('RET', 'Gene', '5979', (107, 110))	('VHL', 'Gene', (112, 115))	('NF1', 'Gene', (126, 129))	('VHL', 'Gene', '7428', (112, 115))	('NF1', 'Gene', '4763', (126, 129))	('RET', 'Gene', (107, 110))	('SDHB', 'Gene', '6390', (117, 121))
23472	32561571	Since the codon 918 mutations in family one has been implicated to have high penetrance of pheochromocytoma and medullary thyroid carcinoma, children who harbour this mutation have been recommended to have more aggressive treatment regimens.	('codon 918 mutations', 'Var', (10, 29))	('pheochromocytoma', 'Disease', (91, 107))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (112, 139))	('children', 'Species', '9606', (141, 149))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (122, 139))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (91, 107))	('pheochromocytoma', 'Disease', 'MESH:D010673', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (122, 139))	('thyroid carcinoma', 'Disease', (122, 139))
23474	32561571	In our study, there were two pre-eclampsia probands which had several family members who harbour CACNA1D variants and presented with either pre-eclampsia or early onset hypertension.	('pre-eclampsia', 'Phenotype', 'HP:0100602', (140, 153))	('hypertension', 'Disease', (169, 181))	('CACNA1D', 'Gene', (97, 104))	('eclampsia', 'Disease', 'MESH:D004461', (144, 153))	('hypertension', 'Phenotype', 'HP:0000822', (169, 181))	('CACNA1D', 'Gene', '776', (97, 104))	('eclampsia', 'Phenotype', 'HP:0100601', (144, 153))	('eclampsia', 'Disease', (144, 153))	('variants', 'Var', (105, 113))	('hypertension', 'Disease', 'MESH:D006973', (169, 181))	('pre-eclampsia', 'Phenotype', 'HP:0100602', (29, 42))	('eclampsia', 'Phenotype', 'HP:0100601', (33, 42))	('eclampsia', 'Disease', 'MESH:D004461', (33, 42))	('eclampsia', 'Disease', (33, 42))
23475	32561571	CACNA1D variants have been well documented to cause PA; however, no evidence implicates the direct correlation between CACNA1D and pre-eclampsia.	('PA', 'Disease', (52, 54))	('variants', 'Var', (8, 16))	('CACNA1D', 'Gene', '776', (119, 126))	('CACNA1D', 'Gene', (119, 126))	('CACNA1D', 'Gene', (0, 7))	('eclampsia', 'Phenotype', 'HP:0100601', (135, 144))	('cause', 'Reg', (46, 51))	('CACNA1D', 'Gene', '776', (0, 7))	('pre-eclampsia', 'Phenotype', 'HP:0100602', (131, 144))	('PA', 'Phenotype', 'HP:0011736', (52, 54))	('eclampsia', 'Disease', 'MESH:D004461', (135, 144))	('eclampsia', 'Disease', (135, 144))
23478	32561571	Thus, our study reports for the first time that CACNA1D mutations may cause pre-eclampsia.	('mutations', 'Var', (56, 65))	('CACNA1D', 'Gene', (48, 55))	('CACNA1D', 'Gene', '776', (48, 55))	('pre-eclampsia', 'Phenotype', 'HP:0100602', (76, 89))	('cause', 'Reg', (70, 75))	('eclampsia', 'Disease', 'MESH:D004461', (80, 89))	('eclampsia', 'Phenotype', 'HP:0100601', (80, 89))	('eclampsia', 'Disease', (80, 89))
23502	32151355	Additional immunohistochemical support for a diagnosis of poorly differentiated neuroendocrine carcinoma in this setting would include dot-like/perinuclear keratin positivity, thyroid transcription factor 1 (TTF-1) positivity (80%-90% of small cell lung cancers; 40% of extrapulmonary visceral poorly differentiated neuroendocrine carcinomas), and Rb loss (90% of small cell lung cancers; 50% of extrapulmonary visceral neuroendocrine carcinomas).	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (420, 445))	('small cell lung cancers', 'Disease', 'MESH:D055752', (364, 387))	('visceral neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (411, 445))	('extrapulmonary', 'Disease', (396, 410))	('lung cancer', 'Phenotype', 'HP:0100526', (375, 386))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (364, 387))	('small cell lung cancers', 'Disease', (364, 387))	('Rb loss', 'Disease', (348, 355))	('lung cancer', 'Phenotype', 'HP:0100526', (249, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (316, 341))	('positivity', 'Var', (164, 174))	('cancers', 'Phenotype', 'HP:0002664', (380, 387))	('lung cancers', 'Phenotype', 'HP:0100526', (249, 261))	('neuroendocrine carcinoma', 'Disease', (80, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('lung cancers', 'Phenotype', 'HP:0100526', (375, 387))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (238, 260))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (420, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('Rb loss', 'Disease', 'MESH:D014786', (348, 355))	('small cell lung cancers', 'Disease', 'MESH:D055752', (238, 261))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (364, 386))	('carcinomas', 'Phenotype', 'HP:0030731', (435, 445))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (316, 340))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (238, 261))	('small cell lung cancers', 'Disease', (238, 261))	('thyroid transcription factor 1', 'Gene', (176, 206))	('visceral neuroendocrine carcinomas', 'Disease', (411, 445))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (316, 340))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (316, 341))	('neuroendocrine carcinomas', 'Disease', (316, 341))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (80, 104))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (420, 444))	('TTF-1', 'Gene', (208, 213))	('carcinomas', 'Phenotype', 'HP:0030731', (331, 341))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (420, 444))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (80, 104))	('thyroid transcription factor 1', 'Gene', '7080', (176, 206))	('positivity', 'Var', (215, 225))
23505	32151355	It was introduced to the diagnostic pathology community by Rosenbaum and colleagues in 2015, who demonstrated INSM1 positivity in 88% of 129 neuroendocrine neoplasms from diverse anatomic sites and only 1 of 24 nonneuroendocrine tumors.	('positivity', 'Var', (116, 126))	('neuroendocrine neoplasms', 'Disease', (141, 165))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (141, 165))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('INSM1', 'Gene', '3642', (110, 115))	('neoplasm', 'Phenotype', 'HP:0002664', (156, 164))	('nonneuroendocrine tumors', 'Disease', 'MESH:D009369', (211, 235))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (141, 165))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (214, 234))	('INSM1', 'Gene', (110, 115))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (141, 164))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (214, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('neoplasms', 'Phenotype', 'HP:0002664', (156, 165))	('nonneuroendocrine tumors', 'Disease', (211, 235))
23508	32151355	For example, Rooper and colleagues reported INSM1 positivity in 95% of 39 small cell lung cancers with an average H-score of 154 (note: H-score is the product of intensity*percent cells staining and ranges from 0 to 300), while synaptophysin and chromogranin A were positive in only 62% (average H-score 60) and 49% (average H-score 85), respectively.	('synaptophysin', 'Gene', (228, 241))	('INSM1', 'Gene', (44, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small cell lung cancers', 'Disease', (74, 97))	('small cell lung cancers', 'Disease', 'MESH:D055752', (74, 97))	('chromogranin A', 'Gene', '1113', (246, 260))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (74, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('synaptophysin', 'Gene', '6855', (228, 241))	('lung cancers', 'Phenotype', 'HP:0100526', (85, 97))	('chromogranin A', 'Gene', (246, 260))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('positivity', 'Var', (50, 60))	('INSM1', 'Gene', '3642', (44, 49))
23517	32151355	Succinate dehydrogenase subunit B (SDHB) immunohistochemistry is highly recommended in pheochromocytoma/paraganglioma to screen for SDH deficiency due to inactivation of any SDH subunit, with SDHB loss (seen in 30% of thoracoabdominal and >=15% of head and neck paragangliomas and 5% of pheochromocytomas) suggesting the possibility of a hereditary tumor (ie, hereditary paraganglioma-pheochromocytoma syndrome, Carney-Stratakis syndrome) and associated with adverse prognosis (Fig.	('pheochromocytomas', 'Disease', (287, 304))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (87, 103))	('hereditary tumor', 'Disease', 'MESH:D030342', (338, 354))	('SDHB', 'Gene', (35, 39))	('paraganglioma', 'Phenotype', 'HP:0002668', (262, 275))	('paragangliomas', 'Phenotype', 'HP:0002668', (262, 276))	('neck paragangliomas', 'Disease', (257, 276))	('paraganglioma', 'Phenotype', 'HP:0002668', (104, 117))	('SDH', 'Gene', (35, 38))	('hereditary tumor', 'Disease', (338, 354))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('hereditary paraganglioma-pheochromocytoma syndrome', 'Disease', 'MESH:D010673', (360, 410))	('SDH', 'Gene', '6390', (174, 177))	('SDH deficiency', 'Disease', (132, 146))	('paraganglioma', 'Phenotype', 'HP:0002668', (371, 384))	('SDH', 'Gene', (192, 195))	('pheochromocytoma/paraganglioma', 'Disease', (87, 117))	('SDH deficiency', 'Disease', 'MESH:D007153', (132, 146))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (287, 304))	('Succinate dehydrogenase subunit B', 'Gene', '6390', (0, 33))	('hereditary paraganglioma-pheochromocytoma syndrome', 'Disease', (360, 410))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (385, 401))	('Carney-Stratakis syndrome', 'Disease', (412, 437))	('neck paragangliomas', 'Disease', 'MESH:D010235', (257, 276))	('SDH', 'Gene', (174, 177))	('inactivation', 'Var', (154, 166))	('SDHB', 'Gene', '6390', (192, 196))	('SDHB loss', 'Disease', 'MESH:D014786', (192, 201))	('SDH', 'Gene', '6390', (132, 135))	('Succinate dehydrogenase subunit B', 'Gene', (0, 33))	('SDHB loss', 'Disease', (192, 201))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (87, 117))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (257, 276))	('SDH', 'Gene', '6390', (192, 195))	('SDHB', 'Gene', '6390', (35, 39))	('SDH', 'Gene', '6390', (35, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (287, 303))	('SDHB', 'Gene', (192, 196))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (412, 437))	('SDH', 'Gene', (132, 135))	('pheochromocytomas', 'Disease', 'MESH:D010673', (287, 304))
23576	32151355	The poorly differentiated neuroendocrine carcinoma types are analogous, although the mitotic threshold is lower in the lung (>10 per 2 mm2) than in the GI tract (>20 per 10 HPF).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lower', 'NegReg', (106, 111))	('>10', 'Var', (125, 128))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (26, 50))	('GI', 'Gene', '2770', (152, 154))	('neuroendocrine carcinoma', 'Disease', (26, 50))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (26, 50))	('mitotic threshold', 'MPA', (85, 102))
23622	32151355	SATB2, which is typically used in diagnostic pathology as a marker of adenocarcinoma of lower GI origin, has emerged as the preferred marker of lower GI well-differentiated neuroendocrine tumors; I recently found moderate-tostrong expression in 92% of 25 rectosigmoid, 55% of 33 appendical, and 0% of 331 other well-differentiated neuroendocrine neoplasms from diverse anatomic sites.	('moderate-tostrong', 'Var', (213, 230))	('neoplasms', 'Phenotype', 'HP:0002664', (346, 355))	('appendical', 'Disease', (279, 289))	('adenocarcinoma', 'Disease', (70, 84))	('GI', 'Gene', '2770', (150, 152))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (173, 194))	('neoplasm', 'Phenotype', 'HP:0002664', (346, 354))	('neuroendocrine neoplasm', 'Phenotype', 'HP:0100634', (331, 354))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('GI', 'Gene', '2770', (94, 96))	('SATB2', 'Gene', (0, 5))	('SATB2', 'Gene', '23314', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (331, 355))	('neuroendocrine tumors', 'Disease', (173, 194))	('rectosigmoid', 'Disease', (255, 267))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (173, 193))	('neuroendocrine neoplasms', 'Disease', (331, 355))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (331, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (173, 194))
23628	32151355	Frequent ATRX inactivation (10%-20%) was noted in recent studies defining the molecular genetic landscape of pancreatic neuroendocrine tumors and not in jejunoileal or bronchopulmonary tumors.	('ATRX', 'Gene', '546', (9, 13))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (120, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('bronchopulmonary tumors', 'Disease', 'MESH:D001997', (168, 191))	('bronchopulmonary tumors', 'Disease', (168, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('inactivation', 'Var', (14, 26))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (109, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('pancreatic neuroendocrine tumors', 'Disease', (109, 141))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ATRX', 'Gene', (9, 13))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (120, 140))
23630	32151355	Of note, inactivation was also recently found in 3% of 103 pheochromocytomas/paragangliomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('pheochromocytomas/paragangliomas', 'Disease', (59, 91))	('inactivation', 'Var', (9, 21))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (59, 76))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (59, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('paragangliomas', 'Phenotype', 'HP:0002668', (77, 91))
23632	32151355	I found clusterin positivity in 82% of 148 nonjejunoileal tumors (average H-score 183) and only 8% of 107 jejunoileal tumors (average H-score 31).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('jejunoileal tumors', 'Disease', 'MESH:D009369', (46, 64))	('jejunoileal tumors', 'Disease', 'MESH:D009369', (106, 124))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('clusterin', 'Gene', (8, 17))	('clusterin', 'Gene', '1191', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('jejunoileal tumors', 'Disease', (46, 64))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('positivity', 'Var', (18, 28))	('jejunoileal tumors', 'Disease', (106, 124))
23641	32151355	As a note of caution, many pathology laboratories have shifted to performing monoclonal PAX8 immunohistochemistry (a fact your pathologist may be unaware of), which is negative in pancreatic well-differentiated neuroendocrine tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('PAX8', 'Gene', (88, 92))	('monoclonal', 'Var', (77, 87))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (211, 231))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (211, 232))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('PAX8', 'Gene', '7849', (88, 92))	('pancreatic well-differentiated neuroendocrine tumors', 'Disease', 'MESH:D018358', (180, 232))
23646	32151355	Up to 80% of Merkel cell carcinomas are driven by a polyomavirus (ie, Merkel cell polyomavirus), and I was initially excited about immunohistochemistry to the virus's large T antigen (clone CM2B4) to increase the accuracy of the TTF-1/CK20 classifier.	('polyomavirus', 'Var', (52, 64))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (13, 34))	('carcinomas', 'Disease', (25, 35))	('Merkel cell polyomavirus', 'Species', '493803', (70, 94))	('Merkel cell carcinoma', 'Disease', (13, 34))	('polyomavirus', 'Species', '36362', (52, 64))	('CK20', 'Gene', (235, 239))	('CK20', 'Gene', '54474', (235, 239))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))	('polyomavirus', 'Species', '36362', (82, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('driven by', 'Reg', (40, 49))	('carcinomas', 'Disease', 'MESH:D009369', (25, 35))
23648	32151355	The immunostain is useful, though, in distinguishing Merkel cell carcinoma (CM2B4+) from poorly differentiated neuroendocrine carcinoma of major salivary gland origin (CM2B4-).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (53, 74))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (111, 135))	('Merkel cell carcinoma', 'Disease', (53, 74))	('CM2B4+', 'Var', (76, 82))	('neuroendocrine carcinoma', 'Disease', (111, 135))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (111, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
23653	32151355	The molecular genetic hallmark of small cell lung cancer is biallelic inactivation of TP53 and RB1.	('TP53', 'Gene', '7157', (86, 90))	('RB1', 'Gene', (95, 98))	('TP53', 'Gene', (86, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('hallmark of small cell lung cancer', 'Disease', 'MESH:D055752', (22, 56))	('RB1', 'Gene', '5925', (95, 98))	('hallmark of small cell lung cancer', 'Disease', (22, 56))	('biallelic inactivation', 'Var', (60, 82))
23656	32151355	I recently found mutant-pattern p53 staining (missense or null patterns) in 71% of 31 small cell lung and 76% of extrapulmonary visceral, Rb loss in 85% of small cell lung and 52% of extrapulmonary visceral, and mutant-patten p53 and/or Rb loss in 97% and 81% of small cell lung cancers and extrapulmonary visceral poorly differentiated neuroendocrine carcinomas, respectively.	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('neuroendocrine carcinomas', 'Disease', (337, 362))	('Rb loss', 'Disease', (237, 244))	('lung cancers', 'Phenotype', 'HP:0100526', (274, 286))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (337, 362))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('carcinomas', 'Phenotype', 'HP:0030731', (352, 362))	('p53', 'Gene', '7157', (32, 35))	('Rb loss', 'Disease', 'MESH:D014786', (138, 145))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('mutant-pattern', 'Var', (17, 31))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (263, 285))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('p53', 'Gene', (32, 35))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (337, 361))	('mutant-patten', 'Var', (212, 225))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (337, 362))	('small cell lung cancers', 'Disease', (263, 286))	('small cell lung cancers', 'Disease', 'MESH:D055752', (263, 286))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (263, 286))	('Rb loss', 'Disease', 'MESH:D014786', (237, 244))	('small cell lung', 'Disease', (86, 101))	('Rb loss', 'Disease', (138, 145))	('p53', 'Gene', '7157', (226, 229))	('p53', 'Gene', (226, 229))
23671	32151355	Immunohistochemistry is useful for determining the site of origin of metastatic well-differentiated neuroendocrine tumor of occult origin, most of which arise from the jejunoileum (CDX2+) or pancreas (islet 1+), and for distinguishing morphologically ambiguous well-differentiated neuroendocrine tumor G3 (p53 wild-type pattern, Rb intact) from large cell neuroendocrine carcinoma (p53 mutant pattern and/or Rb lost).	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (356, 380))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (100, 120))	('p53', 'Gene', (306, 309))	('p53', 'Gene', '7157', (382, 385))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (100, 120))	('p53', 'Gene', (382, 385))	('neuroendocrine tumor', 'Disease', (281, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (345, 380))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (281, 301))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cell neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (351, 380))	('mutant pattern', 'Var', (386, 400))	('CDX2', 'Gene', '1045', (181, 185))	('islet 1', 'Gene', '3670', (201, 208))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (281, 301))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cell neuroendocrine carcinoma', 'Disease', (351, 380))	('p53', 'Gene', '7157', (306, 309))	('CDX2', 'Gene', (181, 185))	('neuroendocrine tumor', 'Disease', (100, 120))	('islet 1', 'Gene', (201, 208))
23673	30880007	Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations.	('cancer', 'Disease', (344, 350))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('transcription', 'MPA', (248, 261))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('sequences', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('transposons', 'Species', '2387', (226, 237))	('impacting', 'Reg', (238, 247))
23675	30880007	By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53.	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (257, 262))	('mutations', 'Var', (269, 278))	('Mutations', 'Var', (84, 93))	('occur', 'Reg', (248, 253))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Disease', (282, 287))	('TP53', 'Gene', '7157', (314, 318))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('transposons', 'Species', '2387', (221, 232))	('TP53', 'Gene', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
23678	30880007	Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutation loads', 'Var', (69, 83))	('cancer', 'Disease', (188, 194))
23680	30880007	Genomic instability, increased proliferation and escape from apoptosis are hallmarks of cancer.	('increased', 'PosReg', (21, 30))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('proliferation', 'CPA', (31, 44))	('escape', 'CPA', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Genomic', 'Var', (0, 7))
23681	30880007	A recent survey of >11000 tumor samples identified ~300 genes (cancer-driver genes) whose somatic mutations in terms of base substitutions are directly linked to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('linked', 'Reg', (152, 158))	('base substitutions', 'Var', (120, 138))	('malignancy', 'Disease', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('cancer', 'Disease', (63, 69))
23682	30880007	Another ~1100 genes may support tumorigenesis through alterations in their expression profiles as a consequence of copy-number alterations, gene fusions, and other types of genomic rearrangements.	('gene fusions', 'Var', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('expression profiles', 'MPA', (75, 94))	('alterations', 'Reg', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('copy-number alterations', 'Var', (115, 138))	('support', 'PosReg', (24, 31))
23686	30880007	Such genomic alterations are seen not only in adult but also in pediatric tumors, implicating DNA mutations and epigenetic changes in steering a normal cell into a malignant phenotype.	('epigenetic changes', 'Var', (112, 130))	('DNA', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('steering', 'PosReg', (134, 142))	('tumors', 'Disease', (74, 80))
23687	30880007	Somatic mutations in driver genes are often instigated by predisposing germline variants, such as in BRCA1 and BRCA2, and impinge on 8 major cellular processes, with alterations in genes involved in maintaining genome integrity, such as the Fanconi anemia pathway, and in 10 signaling pathways (RTK/RAS, Nrf2, PI3K, TGFbeta, Wnt, Myc, TP53, cell cycle, Hippo, Notch) as being among the most commonly altered.	('alterations', 'Reg', (166, 177))	('TGFbeta', 'Gene', (316, 323))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (241, 255))	('impinge', 'Reg', (122, 129))	('TP53', 'Gene', '7157', (335, 339))	('BRCA2', 'Gene', (111, 116))	('TGFbeta', 'Gene', '7039', (316, 323))	('Nrf2', 'Gene', (304, 308))	('Myc', 'Gene', (330, 333))	('mutations', 'Var', (8, 17))	('cell cycle', 'CPA', (341, 351))	('BRCA2', 'Gene', '675', (111, 116))	('signaling pathways', 'Pathway', (275, 293))	('variants', 'Var', (80, 88))	('Fanconi anemia', 'Disease', (241, 255))	('anemia', 'Phenotype', 'HP:0001903', (249, 255))	('TP53', 'Gene', (335, 339))	('BRCA1', 'Gene', '672', (101, 106))	('Fanconi anemia', 'Disease', 'MESH:D005199', (241, 255))	('Myc', 'Gene', '4609', (330, 333))	('altered', 'Reg', (400, 407))	('BRCA1', 'Gene', (101, 106))	('Nrf2', 'Gene', '4780', (304, 308))
23689	30880007	By extracting patterns of base changes in cancer genomes, ~30 distinct signatures have been catalogued, which inform on molecular processes likely to lead to mutations from either extrinsic (ultraviolet light, smoking, chemicals) or intrinsic (APOBEC misediting, DNA repair deficiencies, defective polymerase epsilon) sources.	('mutations', 'Var', (158, 167))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
23690	30880007	Patterns of base substitutions have also been associated with direct damage to DNA bases by oxidants, such as reactive oxygen and nitrogen species (ROS and RNS respectively), which rise in tumor cells following glucose deprivation, deregulation of the mitochondrial electron transport chain and other organelles (endoplasmic reticulum, lysosomes and peroxisomes).	('rise', 'PosReg', (181, 185))	('deregulation', 'Reg', (232, 244))	('base substitutions', 'Var', (12, 30))	('tumor', 'Disease', (189, 194))	('glucose', 'Chemical', 'MESH:D005947', (211, 218))	('nitrogen', 'Chemical', 'MESH:D009584', (130, 138))	('RNS', 'Chemical', 'MESH:D011886', (156, 159))	('mitochondrial', 'Enzyme', (252, 265))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
23691	30880007	This sustained proliferation contributes to a condition referred to as "replication stress", a potent inducer of genomic instability triggered by a buildup of ssDNA from RPA depletion, the accumulation of secondary DNA structures, R-loops, collisions between replication and transcription, and other factors.	('RPA', 'Gene', '6117', (170, 173))	('collisions', 'Var', (240, 250))	('R-loops', 'Var', (231, 238))	('accumulation', 'PosReg', (189, 201))	('stress', 'Disease', 'MESH:D000079225', (84, 90))	('RPA', 'Gene', (170, 173))	('secondary DNA structures', 'Protein', (205, 229))	('stress', 'Disease', (84, 90))
23696	30880007	Tumor samples with translocation breakpoints at G4 DNA-forming sequences are also more likely to carry mutations in TP53 and less likely to harbor pathologic mutations in KRAS and CTNNB1, supporting a role for TP53 mutations in G4 DNA-induced instability.	('TP53', 'Gene', (116, 120))	('mutations', 'Var', (103, 112))	('CTNNB1', 'Gene', '1499', (180, 186))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', (210, 214))	('G4 DNA-forming', 'Var', (48, 62))	('CTNNB1', 'Gene', (180, 186))	('KRAS', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (116, 120))	('KRAS', 'Gene', '3845', (171, 175))	('TP53', 'Gene', '7157', (210, 214))
23699	30880007	Thus, correlation analyses of G4 DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate sources of genomic instability in cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutation loads', 'Var', (72, 86))
23716	30880007	single base substitutions and small insertion/deletions in exons genome-wide specific to the tumor but not the matched normal samples.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('insertion/deletions', 'Var', (36, 55))	('single base substitutions', 'Var', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
23730	30880007	In conclusion, our analysis shows that translocation breakpoints in cancer occur at G4 DNA-forming repeats more often than expected by chance alone.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('translocation breakpoints', 'Var', (39, 64))	('cancer', 'Disease', (68, 74))
23732	30880007	First, we assessed the genome-wide load of translocations in each patient; we found that the group of patients with G4-associated breakpoints carried more translocations than the group of patients without G4-associated breakpoints (57.9 +- 59.7 vs. 17.3 +- 20.7; Fig.	('G4-associated', 'Var', (116, 129))	('breakpoints', 'Var', (130, 141))	('patient', 'Species', '9606', (188, 195))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('patient', 'Species', '9606', (66, 73))	('patients', 'Species', '9606', (188, 196))	('translocations', 'MPA', (155, 169))
23733	30880007	Second, even though tumor samples with and without G4-associated breakpoints carried pathologic mutations in cancer-related genes, such as TP53, KRAS, PIK3CA, etc.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('KRAS', 'Gene', (145, 149))	('pathologic', 'Reg', (85, 95))	('PIK3CA', 'Gene', (151, 157))	('cancer', 'Disease', (109, 115))	('TP53', 'Gene', '7157', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('KRAS', 'Gene', '3845', (145, 149))	('PIK3CA', 'Gene', '5290', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', (20, 25))
23734	30880007	(Figs 2C and D), samples with G4-containing breakpoints displayed a greater frequency of mutations at TP53, PTPRD and GATA3 than the alternate group.	('TP53', 'Gene', (102, 106))	('GATA3', 'Gene', (118, 123))	('PTPRD', 'Gene', '5789', (108, 113))	('PTPRD', 'Gene', (108, 113))	('mutations', 'Var', (89, 98))	('GATA3', 'Gene', '2625', (118, 123))	('TP53', 'Gene', '7157', (102, 106))	('G4-containing', 'Var', (30, 43))
23735	30880007	By contrast, the likelihood of harboring pathologic mutations at KRAS and CTNNB1 was significantly reduced (Fig.	('mutations', 'Var', (52, 61))	('CTNNB1', 'Gene', (74, 80))	('KRAS', 'Gene', '3845', (65, 69))	('CTNNB1', 'Gene', '1499', (74, 80))	('reduced', 'NegReg', (99, 106))	('KRAS', 'Gene', (65, 69))
23736	30880007	3E), in accordance with the expectation that mutations in the TP53, RTK/RAS and Wnt pathways are mutually exclusive.	('RTK/RAS', 'Pathway', (68, 75))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('Wnt pathways', 'Pathway', (80, 92))
23737	30880007	We conclude that strand breaks at or near G4 DNA-forming sequences occur generally in tumors with high genetic instability, which is promoted in part by mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (153, 162))	('strand', 'Var', (17, 23))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('TP53', 'Gene', '7157', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
23746	30880007	In conclusion, translocation breakpoints are more likely to be found at G4 DNA located in SVA elements than in L1 transposons; furthermore, it is possible that a subset of SVA elements in the human genome might be particularly unstable, yielding recurrent strand breaks in cancer.	('cancer', 'Disease', (273, 279))	('human', 'Species', '9606', (192, 197))	('transposons', 'Species', '2387', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('yielding', 'Reg', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SVA', 'Gene', (172, 175))	('elements', 'Var', (176, 184))	('strand breaks', 'MPA', (256, 269))	('recurrent strand breaks', 'Phenotype', 'HP:0040012', (246, 269))
23747	30880007	Recognizing that G4 DNA likely impacts transcription, we employed a separate set of analyses to assess the extent to which the cellular transcriptome and its regulation are associated with mutation loads in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('G4 DNA', 'Var', (17, 23))	('mutation loads', 'Var', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('associated', 'Reg', (173, 183))	('impacts', 'Reg', (31, 38))	('transcription', 'MPA', (39, 52))
23749	30880007	Thus, an S-plot of all P-values allowed for a direct comparison across all tumors, which revealed a strong variability on tissue-dependent origin in the extent to which gene expression correlates with mutation loads.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (201, 209))	('gene expression', 'MPA', (169, 184))
23757	30880007	Of the 10 top genes most negatively correlated with mutation loads, the strongest association was found for MLH1 in ESCA (Fig.	('ESCA', 'Disease', (116, 120))	('MLH1', 'Gene', '4292', (108, 112))	('MLH1', 'Gene', (108, 112))	('mutation', 'Var', (52, 60))
23758	30880007	Mutations in MLH1 or its low expression are known for their role in tumorigenesis, however none of the other 9 genes were listed in the COSMIC cancer gene census.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MLH1', 'Gene', (13, 17))	('MLH1', 'Gene', '4292', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
23761	30880007	In summary, the top genes most strongly correlated with mutations loads reveal strong associations between deregulation of gene expression and poor survival in cancer.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('poor survival', 'CPA', (143, 156))	('cancer', 'Disease', (160, 166))	('deregulation', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
23762	30880007	To further explore the involvement of the top genes correlated with mutations in tumorigenesis, we focused on two genes: MYBL2 for the positive correlations and SDHAF3 for the negative correlations.	('MYBL2', 'Gene', '4605', (121, 126))	('SDHAF3', 'Gene', '57001', (161, 167))	('MYBL2', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (68, 77))	('SDHAF3', 'Gene', (161, 167))	('tumor', 'Disease', (81, 86))
23768	30880007	Poor prognosis was associated with high MYBL2 expression in 11/32 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('MYBL2', 'Gene', '4605', (40, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('MYBL2', 'Gene', (40, 45))
23776	30880007	In PRAD, where SDHAF3 displayed the strongest negative correlation between expression and mutation of all tumors, the gene was overexpressed relative to matched controls (not shown); however, SDHD was strongly downregulated.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('SDHAF3', 'Gene', '57001', (15, 21))	('tumors', 'Disease', (106, 112))	('overexpressed', 'PosReg', (127, 140))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PRAD', 'Disease', (3, 7))	('SDHAF3', 'Gene', (15, 21))	('SDHD', 'Gene', (192, 196))	('SDHD', 'Gene', '6392', (192, 196))	('downregulated', 'NegReg', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('negative', 'NegReg', (46, 54))	('mutation', 'Var', (90, 98))	('expression', 'MPA', (75, 85))
23780	30880007	Having established the validity of our analyses in uncovering genes whose deregulation seem to predict poor clinical outcome, we then conducted a systematic assessment of gene enrichment for a pool of genes with strong correlations in each tumor type.	('deregulation', 'Var', (74, 86))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))
23787	30880007	We also conducted the gene enrichment analysis for the 270 genes (in each tumor type), whose expression was most negatively correlated with mutations, but did not find any enriched term.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (140, 149))	('negatively', 'NegReg', (113, 123))
23789	30880007	Therefore, our correlation analysis of gene expression versus mutation loads identified pathways that are commonly altered in different types of cancer.	('cancer', 'Disease', (145, 151))	('pathways', 'Pathway', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutation', 'Var', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
23790	30880007	In LUAD, although not in KICH and PRAD, the main pathways for the repair of base mismatch and base lesions, i.e.	('KICH', 'Disease', 'None', (25, 29))	('base mismatch', 'Var', (76, 89))	('KICH', 'Disease', (25, 29))
23792	30880007	In addition, ALKBH3 (R = -0.22, P = 4.0x10-7) for alkylation damage reversal, RRM2B (R = -0.24, P = 2.7 x 10-8), which supplies dNTPs during DNA repair synthesis, POLK (R = -0.22, P = 3.9 x 10-7) for translesion DNA synthesis and UBE2B (R = -0.22, P = 4.9 x 10-7), involved in ubiquitination of PCNA also displayed negative correlations with mutational loads (Fig.	('RRM2B', 'Gene', (78, 83))	('ALKBH3', 'Gene', (13, 19))	('ALKBH3', 'Gene', '221120', (13, 19))	('PCNA', 'Gene', (295, 299))	('negative', 'NegReg', (315, 323))	('UBE2B', 'Gene', '7320', (230, 235))	('RRM2B', 'Gene', '50484', (78, 83))	('mutational', 'Var', (342, 352))	('PCNA', 'Gene', '5111', (295, 299))	('POLK', 'Gene', (163, 167))	('POLK', 'Gene', '51426', (163, 167))	('UBE2B', 'Gene', (230, 235))
23795	30880007	Translocation breakpoints were enriched at sequences with the potential to form G4 DNA structures in tumor samples that were characterized by elevated genetic instability and frequent mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TP53', 'Gene', '7157', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', (229, 233))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
23799	30880007	Genes whose expression is positively correlated with mutations were enriched in selected KEGG terms in more than one cancer type, which provides a platform for addressing the contribution of specific pathways to somatic mutation in cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (232, 238))	('expression', 'MPA', (12, 22))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', (117, 123))
23802	30880007	Nevertheless, our estimates are in line with determinations of mutations at non-B DNA-forming motifs in cancer genomes and strengthens the concept, both from genome-wide and targeted studies, that non-B DNA structures contribute to mutagenesis, both in cancer and in genetic disease.	('mutations', 'Var', (63, 72))	('genetic disease', 'Disease', (267, 282))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('mutagenesis', 'MPA', (232, 243))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genetic disease', 'Disease', 'MESH:D030342', (267, 282))
23803	30880007	The prevalence of G4-associated translocation breakpoints with tumor samples carrying extensive genomic alterations is consistent with reports that TP53 mutant tumors are associated with high rates of genomic instability (reviewed in).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', (63, 68))	('translocation breakpoints', 'Var', (32, 57))	('G4-associated', 'Gene', (18, 31))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mutant', 'Var', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (160, 165))	('genomic instability', 'MPA', (201, 220))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
23804	30880007	TP53 mutants have been reported to sequester DNA repair factors, such as MRE11, away from double-strand breaks and at stalled replication forks, leading to an accumulation of translocations.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('MRE11', 'Gene', '4361', (73, 78))	('accumulation', 'PosReg', (159, 171))	('MRE11', 'Gene', (73, 78))	('translocations', 'MPA', (175, 189))	('mutants', 'Var', (5, 12))
23806	30880007	Changes in gene expression, which we show here are extensive and impact cancer mutagenesis, are also likely to influence G4 DNA structure-induced genetic instability.	('influence', 'Reg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Changes', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('impact', 'Reg', (65, 71))	('cancer', 'Disease', (72, 78))
23807	30880007	We are also learning how replication and repair proteins, such as FEN1, can act in trans to greatly impact mutations so molecular mechanisms are expected to be key to improve predictions.	('impact', 'Reg', (100, 106))	('FEN1', 'Gene', (66, 70))	('FEN1', 'Gene', '2237', (66, 70))	('mutations', 'Var', (107, 116))
23814	30880007	MLH1 mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal.	('protein-protein', 'Protein', (14, 29))	('MLH1', 'Gene', '4292', (0, 4))	('MLH1', 'Gene', (0, 4))	('mediates', 'Reg', (5, 13))	('mismatch recognition', 'Var', (50, 70))	('strand discrimination', 'Var', (72, 93))
23815	30880007	In colon and rectal cancers hypermutation has been linked in part to MLH1 hypermethylation, and in esophageal squamous cell carcinoma MLH1 promoter methylation correlates with weak expression and poor survival.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (181, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('linked', 'Reg', (51, 57))	('esophageal squamous cell carcinoma', 'Disease', (99, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('weak', 'NegReg', (176, 180))	('MLH1', 'Gene', '4292', (134, 138))	('MLH1', 'Gene', (134, 138))	('MLH1', 'Gene', '4292', (69, 73))	('hypermethylation', 'Var', (74, 90))	('MLH1', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('hypermutation', 'Var', (28, 41))	('colon and rectal cancers', 'Disease', 'MESH:D015179', (3, 27))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (99, 133))
23820	30880007	The polymeric immunoglobulin receptor (the PIGR gene product) pIgR plays an important role in protecting small airways of the lung from airborne antigens and microorganisms; PIGR-/- mice develop chronic obstructive pulmonary disease (COMP)-like pathology with age and persistent activation of innate immune response to the lung microbiome.	('chronic obstructive pulmonary disease', 'Disease', (195, 232))	('pIgR', 'Gene', (62, 66))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (195, 232))	('mice', 'Species', '10090', (182, 186))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (203, 232))	('pIgR', 'Gene', '18703', (62, 66))	('PIGR-/-', 'Var', (174, 181))	('develop', 'Reg', (187, 194))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (195, 232))
23821	30880007	Loss of PIGR is an early event in lung tumorigenesis, and it is plausible that the association of low PIGR with high mutation rates we observe reflects a role for the ensuing inflammation in mutagenesis, in part through the release of ROS and reactive nitrogen intermediates.	('nitrogen', 'Chemical', 'MESH:D009584', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('release', 'MPA', (224, 231))	('low', 'NegReg', (98, 101))	('PIGR', 'Gene', (8, 12))	('ROS', 'MPA', (235, 238))	('reactive nitrogen intermediates', 'MPA', (243, 274))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('inflammation', 'Disease', 'MESH:D007249', (175, 187))	('inflammation', 'Disease', (175, 187))	('PIGR', 'Gene', (102, 106))	('Loss', 'Var', (0, 4))	('ROS', 'Chemical', 'MESH:D017382', (235, 238))
23829	30880007	A causal association between MYBL2 expression and mutation loads has recently been reported, and involves transactivation of the APOBEC3B gene whose product (apolipoprotein B mRNA cytosine deaminase, A3B) generates ectopic C>U>T transitions and genomic hypermutation when overproduced.	('APOBEC3B', 'Gene', (129, 137))	('genomic hypermutation', 'CPA', (245, 266))	('apolipoprotein B', 'Gene', (158, 174))	('APOBEC3B', 'Gene', '9582', (129, 137))	('MYBL2', 'Gene', '4605', (29, 34))	('apolipoprotein B', 'Gene', '338', (158, 174))	('A3B', 'Gene', '9582', (200, 203))	('ectopic C', 'MPA', (215, 224))	('MYBL2', 'Gene', (29, 34))	('mutation', 'Var', (50, 58))	('A3B', 'Gene', (200, 203))
23830	30880007	The strong correlation of the SDH accessory factor SDHAF3 with mutations was of particular interest since a germline c.157T>C (p.Phe53Leu) substitution in this gene was recently associated with increased prevalence of familiar and sporadic pheochromocytoma and paraganglioma, which are characteristic of SDH-deficiency.	('SDHAF3', 'Gene', (51, 57))	('associated with', 'Reg', (178, 193))	('SDH', 'Gene', (51, 54))	('c.157T>C', 'Mutation', 'rs62624461', (117, 125))	('sporadic pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (231, 274))	('SDH', 'Gene', (304, 307))	('c.157T>C', 'Var', (117, 125))	('paraganglioma', 'Phenotype', 'HP:0002668', (261, 274))	('p.Phe53Leu', 'Mutation', 'rs62624461', (127, 137))	('familiar', 'Disease', (218, 226))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('SDH', 'Gene', '6390', (30, 33))	('SDH-deficiency', 'Disease', 'MESH:D007153', (304, 318))	('SDH-deficiency', 'Disease', (304, 318))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (240, 256))	('SDH', 'Gene', '6390', (51, 54))	('SDH', 'Gene', (30, 33))	('SDH', 'Gene', '6390', (304, 307))	('SDHAF3', 'Gene', '57001', (51, 57))
23832	30880007	The fundamental importance of Fe-S clusters and control of superoxide support the observed connections of the SDHB subunit with mutational load.	('SDHB', 'Gene', (110, 114))	('superoxide', 'Chemical', 'MESH:D013481', (59, 69))	('Fe-S', 'Chemical', 'MESH:D007501', (30, 34))	('mutational load', 'Var', (128, 143))	('SDHB', 'Gene', '6390', (110, 114))	('connections', 'Interaction', (91, 102))
23835	30880007	Thus, anticorrelation between SDHAF3 expression and mutations may stem from SDH deficiency.	('mutations', 'Var', (52, 61))	('stem from', 'Reg', (66, 75))	('SDH deficiency', 'Disease', 'MESH:D007153', (76, 90))	('SDHAF3', 'Gene', '57001', (30, 36))	('SDHAF3', 'Gene', (30, 36))	('expression', 'MPA', (37, 47))	('SDH deficiency', 'Disease', (76, 90))
23837	30880007	The clustering encompassing KICH, LUAD, PRAD and LGG is centered on cell cycle, DNA replication and DNA repair genes, and the positive correlations with mutations likely arise from replication stress, excessive DNA damage (such as A3B activation) and its escape from repair.	('A3B', 'Gene', (231, 234))	('DNA', 'MPA', (211, 214))	('mutations', 'Var', (153, 162))	('KICH', 'Disease', (28, 32))	('stress', 'Disease', 'MESH:D000079225', (193, 199))	('A3B', 'Gene', '9582', (231, 234))	('stress', 'Disease', (193, 199))	('KICH', 'Disease', 'None', (28, 32))	('arise from', 'Reg', (170, 180))
23839	30880007	Thus, we propose that the association of mitochondrial gene expression with mutations likely stems from direct damage to DNA by increased ROS and other oxidants.	('ROS', 'MPA', (138, 141))	('mutations', 'Var', (76, 85))	('mitochondrial gene', 'Gene', (41, 59))	('increased', 'PosReg', (128, 137))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))
23842	30880007	The ectopic expression and upregulation of olfactory receptors in melanoma (SKCM) is a potential source of malignant transformation, and it will be useful to assess their role in mutagenesis.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('olfactory receptors', 'Protein', (43, 62))	('upregulation', 'PosReg', (27, 39))	('ectopic expression', 'Var', (4, 22))
23847	30880007	We found that G4 DNA-forming sequences are enriched twofold at translocation breakpoints, strengthening the view that G4 DNA structures contribute to genomic instability in cancer; many such structures are likely to originate from L1 and SVA retrotransposons and contribute to instability.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('genomic instability', 'MPA', (150, 169))	('contribute', 'Reg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('transposons', 'Species', '2387', (247, 258))	('G4 DNA', 'Var', (118, 124))
23848	30880007	Mutations in TP53 increase the chance of G4 DNA-induced translocations, possibly through defects in homologous recombination following replication fork stalling at G4 DNA.	('TP53', 'Gene', (13, 17))	('homologous', 'MPA', (100, 110))	('defects', 'NegReg', (89, 96))	('Mutations', 'Var', (0, 9))	('translocations', 'MPA', (56, 70))	('TP53', 'Gene', '7157', (13, 17))
23850	30880007	Transcriptome analyses identify two distinct branches though which alterations in gene expression may lead to an accumulation of single base substitutions in cancer: 1) activation of cell cycle/DNA repair; and 2) loss of homeostatic control of mitochondrial respiration.	('homeostatic control of mitochondrial respiration', 'MPA', (221, 269))	('activation', 'PosReg', (169, 179))	('cell cycle/DNA repair', 'CPA', (183, 204))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('alterations', 'Var', (67, 78))	('cancer', 'Disease', (158, 164))	('single base substitutions', 'Var', (129, 154))	('loss', 'NegReg', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
23853	30880007	Tumor-specific alterations in gene expression associated with mutation loads also include the ectopic expression of olfactory receptor genes in skin cancer, exacerbation of the ER unfolded protein response in breast cancer and altered HLA gene expression in cervical cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('alterations', 'Reg', (15, 26))	('ER unfolded protein response', 'MPA', (177, 205))	('HLA', 'Protein', (235, 238))	('cancer', 'Disease', (216, 222))	('gene expression', 'MPA', (30, 45))	('skin cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutation loads', 'Var', (62, 76))	('cancer', 'Disease', (149, 155))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('cancer', 'Disease', (267, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('ectopic expression', 'MPA', (94, 112))	('olfactory receptor genes', 'Gene', (116, 140))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('altered', 'Reg', (227, 234))	('breast cancer', 'Disease', (209, 222))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('exacerbation', 'PosReg', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
23855	30880007	The second is to clarify how deregulation of the mitochondrial respiratory chain and its link to the TCA cycle through the SDH complex elicits mutations.	('SDH', 'Gene', (123, 126))	('deregulation', 'MPA', (29, 41))	('mitochondrial respiratory chain', 'Enzyme', (49, 80))	('elicits', 'Reg', (135, 142))	('SDH', 'Gene', '6390', (123, 126))	('TCA', 'Chemical', 'MESH:D014233', (101, 104))	('mutations', 'Var', (143, 152))
23876	31330766	Approximately 40-50% of MPPGs are associated with germline mutations of the succinate dehydrogenase subunit B (SDHB) gene.	('MPPGs', 'Disease', (24, 29))	('associated', 'Reg', (34, 44))	('SDHB', 'Gene', (111, 115))	('germline mutations', 'Var', (50, 68))	('succinate dehydrogenase subunit B', 'Gene', '6390', (76, 109))	('MPPGs', 'Chemical', '-', (24, 29))	('succinate dehydrogenase subunit B', 'Gene', (76, 109))	('SDHB', 'Gene', '6390', (111, 115))
23905	31330766	However, I-123 offers better imaging characteristics than I-131 with conventional gamma cameras and is the preferred radioisotope for diagnostic purposes.	('I-131', 'Chemical', 'MESH:C000614965', (58, 63))	('I', 'Chemical', 'MESH:D007455', (9, 10))	('I-123', 'Var', (9, 14))	('imaging characteristics', 'MPA', (29, 52))	('I', 'Chemical', 'MESH:D007455', (58, 59))
23909	31330766	For diagnostic purposes, I-123-MIBG and I-131-MIBG are provided at a dose of 5 mCi (185 MBq).	('I-131-MIBG', 'Var', (40, 50))	('I-123-MIBG', 'Chemical', '-', (25, 35))	('I-131-MIBG', 'Chemical', '-', (40, 50))	('I-123-MIBG', 'Var', (25, 35))
23910	31330766	At a high dose level, I-131-MIBG may emit enough beta (primarily) and gamma (secondarily) radiation to cause lethal cellular damage.	('At', 'Chemical', 'MESH:D001246', (0, 2))	('cause', 'Reg', (103, 108))	('I-131-MIBG', 'Chemical', '-', (22, 32))	('I-131-MIBG', 'Var', (22, 32))
23916	31330766	I-131-MIBG may therefore control one of the most important hallmarks of cancer, sustained replicative signaling.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('sustained replicative signaling', 'MPA', (80, 111))	('I-131-MIBG', 'Chemical', '-', (0, 10))	('I-131-MIBG', 'Var', (0, 10))	('control', 'Reg', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
23930	31330766	However, clinical experience and observations derived from phase 2 clinical trials for patients with MPPGs treated with radiolabeled MIBG indicate that patients with SDHB mutations may respond very well to therapy.	('SDHB', 'Gene', '6390', (166, 170))	('SDHB', 'Gene', (166, 170))	('MIBG', 'Chemical', 'MESH:D019797', (133, 137))	('MPPGs', 'Chemical', '-', (101, 106))	('mutations', 'Var', (171, 180))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (152, 160))
23935	31330766	Isotopic exchange yields in a considerable amount of cold carrier MIBG in the final solution.	('I', 'Chemical', 'MESH:D007455', (67, 68))	('MIBG', 'Chemical', 'MESH:D019797', (66, 70))	('Isotopic', 'Var', (0, 8))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('cold carrier MIBG', 'MPA', (53, 70))	('yields', 'Reg', (18, 24))
23942	31330766	HSA-I-131-MIBG results in an increased cellular uptake of lethal radioactivity, approximately 100-200 times higher than that of LSA-I-131-MIBG.	('HSA-I-131-MIBG', 'Var', (0, 14))	('cellular uptake of lethal radioactivity', 'MPA', (39, 78))	('LSA-I-131-MIBG', 'Chemical', '-', (128, 142))	('increased', 'PosReg', (29, 38))	('HSA-I-131-MIBG', 'Chemical', '-', (0, 14))	('higher', 'PosReg', (108, 114))
23943	31330766	Compared with LSA-I-131-MIBG, HSA-I-131-MIBG is less likely to saturate the NET and subsequently may cause fewer hormonal complications.	('saturate the NET', 'MPA', (63, 79))	('LSA-I-131-MIBG', 'Chemical', '-', (14, 28))	('HSA-I-131-MIBG', 'Var', (30, 44))	('HSA-I-131-MIBG', 'Chemical', '-', (30, 44))	('cause', 'Reg', (101, 106))	('hormonal', 'Disease', (113, 121))
23959	31330766	Second treatment dose reduction is recommended in the settings of measured platelet count less than 25,000 microL or less than 50,000 microL with active bleeding, ANC less than 500/microL or febrile neutropenia, and life-threatening anemia (hemoglobin less than 6.5 g/dL) for more than seven days.	('less', 'NegReg', (90, 94))	('anemia', 'Phenotype', 'HP:0001903', (233, 239))	('less than 500/microL', 'Var', (167, 187))	('anemia', 'Disease', (233, 239))	('active bleeding', 'Disease', 'MESH:D006470', (146, 161))	('neutropenia', 'Phenotype', 'HP:0001875', (199, 210))	('anemia', 'Disease', 'MESH:D000740', (233, 239))	('febrile neutropenia', 'Disease', (191, 210))	('febrile neutropenia', 'Disease', 'MESH:D009503', (191, 210))	('active bleeding', 'Disease', (146, 161))
23973	31330766	These publications suggest that LSA-1-131-MIBG could be an effective treatment for some patients with MPPG.	('MPPG', 'Disease', (102, 106))	('patients', 'Species', '9606', (88, 96))	('131-MIBG', 'Chemical', '-', (38, 46))	('MPPG', 'Chemical', '-', (102, 106))	('LSA-1-131-MIBG', 'Var', (32, 46))
23979	31330766	The study also confirmed that patients with MIBG-avid tumors (as demonstrated by pretreatment MIBG scanning), but not patients with tumors that are not MIBG avid, may benefit from LSA-I-131-MIBG.	('MIBG-avid tumors', 'Disease', 'MESH:D009369', (44, 60))	('MIBG', 'Chemical', 'MESH:D019797', (94, 98))	('MIBG', 'Chemical', 'MESH:D019797', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('benefit', 'PosReg', (167, 174))	('LSA-I-131-MIBG', 'Var', (180, 194))	('LSA-I-131-MIBG', 'Chemical', '-', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('MIBG', 'Chemical', 'MESH:D019797', (152, 156))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('MIBG', 'Chemical', 'MESH:D019797', (190, 194))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (118, 126))	('MIBG-avid tumors', 'Disease', (44, 60))
23981	31330766	After treatment with LSA-I-131-MIBG, 30% of patients exhibited an objective tumor response, including 4% of patients with tumor disappearance or complete responses (CRs) and 26% of patients with partial responses (PRs).	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (44, 52))	('PRs', 'Chemical', '-', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('LSA-I-131-MIBG', 'Var', (21, 35))	('LSA-I-131-MIBG', 'Chemical', '-', (21, 35))	('tumor', 'Disease', (122, 127))	('CRs', 'Chemical', '-', (165, 168))	('disappearance', 'NegReg', (128, 141))
23989	31330766	This study also suggested that LSA-I-131-MIBG may improve overall survival (OS).	('overall survival', 'MPA', (58, 74))	('OS', 'Chemical', '-', (76, 78))	('LSA-I-131-MIBG', 'Chemical', '-', (31, 45))	('improve', 'PosReg', (50, 57))	('LSA-I-131-MIBG', 'Var', (31, 45))
23991	31330766	Less heterogeneous retrospective studies from referral centers have also suggested that low doses of LSA-I-131-MIBG (median <200 mCi) may bring clinical benefits and minimal toxicity for patients with MPPGs.	('patients', 'Species', '9606', (187, 195))	('MPPGs', 'Chemical', '-', (201, 206))	('benefits', 'PosReg', (153, 161))	('clinical', 'MPA', (144, 152))	('toxicity', 'Disease', (174, 182))	('LSA-I-131-MIBG', 'Var', (101, 115))	('LSA-I-131-MIBG', 'Chemical', '-', (101, 115))	('toxicity', 'Disease', 'MESH:D064420', (174, 182))
23999	31330766	published the largest single-institution retrospective study of single low doses of LSA-I-131-MIBG for the treatment of MPPG.	('LSA-I-131-MIBG', 'Var', (84, 98))	('MPPG', 'Chemical', '-', (120, 124))	('LSA-I-131-MIBG', 'Chemical', '-', (84, 98))	('MPPG', 'Disease', (120, 124))
24002	31330766	The results of this study suggested that small, single doses of LSA-I-131-MIBG have a limited antineoplastic benefit.	('LSA-I-131-MIBG', 'Chemical', '-', (64, 78))	('antineoplastic benefit', 'CPA', (94, 116))	('LSA-I-131-MIBG', 'Var', (64, 78))
24003	31330766	The retrospective studies discussed above indicated that the major toxicity associated with small doses of LSA-I-131-MIBG was a reversible bone marrow insufficiency.	('LSA-I-131-MIBG', 'Chemical', '-', (107, 121))	('bone marrow insufficiency', 'Phenotype', 'HP:0005528', (139, 164))	('bone marrow insufficiency', 'Disease', 'MESH:D000081003', (139, 164))	('LSA-I-131-MIBG', 'Var', (107, 121))	('bone marrow insufficiency', 'Disease', (139, 164))	('toxicity', 'Disease', 'MESH:D064420', (67, 75))	('toxicity', 'Disease', (67, 75))
24010	31330766	Patients whose disease responded to LSA-I-131-MIBG had significantly longer OS when compared with those whose disease did not (4.7 versus 1.8 years, p < 0.01).	('OS', 'Chemical', '-', (76, 78))	('LSA-I-131-MIBG', 'Var', (36, 50))	('LSA-I-131-MIBG', 'Chemical', '-', (36, 50))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (69, 75))
24023	31330766	All patients with MPPGs and germline SDHB mutations exhibited clinical benefits.	('MPPGs', 'Disease', (18, 23))	('SDHB', 'Gene', '6390', (37, 41))	('benefits', 'PosReg', (71, 79))	('SDHB', 'Gene', (37, 41))	('MPPGs', 'Chemical', '-', (18, 23))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (42, 51))
24024	31330766	The study did not report whether the other patients were tested for susceptibility genes; therefore, it was not possible to determine if SDHB status could predict OS.	('status', 'Var', (142, 148))	('patients', 'Species', '9606', (43, 51))	('OS', 'Chemical', '-', (163, 165))	('SDHB', 'Gene', '6390', (137, 141))	('SDHB', 'Gene', (137, 141))	('predict', 'Reg', (155, 162))
24028	31330766	Two patients developed lethal myelodysplasia after two and three treatments with high doses of LSA-I-131-MIBG.	('developed', 'Reg', (13, 22))	('myelodysplasia', 'Disease', 'MESH:D009190', (30, 44))	('myelodysplasia', 'Disease', (30, 44))	('LSA-I-131-MIBG', 'Var', (95, 109))	('LSA-I-131-MIBG', 'Chemical', '-', (95, 109))	('patients', 'Species', '9606', (4, 12))	('myelodysplasia', 'Phenotype', 'HP:0002863', (30, 44))
24029	31330766	Of interest, 10 patients had hypertension during the infusion of LSA-I-131-MIB, including seven patients who had severe (grade 3) hypertension.	('hypertension', 'Disease', 'MESH:D006973', (130, 142))	('hypertension', 'Disease', (29, 41))	('hypertension', 'Phenotype', 'HP:0000822', (29, 41))	('LSA-I-131-MIB', 'Chemical', '-', (65, 78))	('hypertension', 'Disease', (130, 142))	('patients', 'Species', '9606', (16, 24))	('hypertension', 'Phenotype', 'HP:0000822', (130, 142))	('LSA-I-131-MIB', 'Var', (65, 78))	('patients', 'Species', '9606', (96, 104))	('hypertension', 'Disease', 'MESH:D006973', (29, 41))
24041	31330766	Therefore, the lack of tumor progression that was observed in some patients after treatment may not be related to the antineoplastic effects of LSA-I-131-MIBG.	('patients', 'Species', '9606', (67, 75))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('LSA-I-131-MIBG', 'Var', (144, 158))	('LSA-I-131-MIBG', 'Chemical', '-', (144, 158))
24046	31330766	Although some studies suggest that patients with MPPGs treated with LSA-I-131-MIBG had an improvement of their clinical manifestations, none of these studies used standardized instruments to evaluate quality of life.	('improvement', 'PosReg', (90, 101))	('MPPGs', 'Disease', (49, 54))	('clinical manifestations', 'MPA', (111, 134))	('patients', 'Species', '9606', (35, 43))	('LSA-I-131-MIBG', 'Var', (68, 82))	('MPPGs', 'Chemical', '-', (49, 54))	('LSA-I-131-MIBG', 'Chemical', '-', (68, 82))
24049	31330766	In fact, severe cardiovascular and pulmonary adverse events were mainly seen in patients treated with a high dose rather than a low or intermediate dose of LSA-I-131-MIBG.	('patients', 'Species', '9606', (80, 88))	('seen', 'Reg', (72, 76))	('cardiovascular', 'Disease', (16, 30))	('I', 'Chemical', 'MESH:D007455', (167, 168))	('I', 'Chemical', 'MESH:D007455', (160, 161))	('LSA-I-131-MIBG', 'Var', (156, 170))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('LSA-I-131-MIBG', 'Chemical', '-', (156, 170))
24057	31330766	Approximately 80% of the medication was excreted unaltered in the urine over a period no longer than 120 h. This finding was similar to those of an organ dosimetry study showing that organ distribution and whole-body retention of HSA-I-123-MIBG in cancer-free individuals were similar to that of LSA-I-123-MIBG.	('I-123-MIBG', 'Chemical', '-', (234, 244))	('cancer-free', 'Disease', (248, 259))	('I-123-MIBG', 'Chemical', '-', (300, 310))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('HSA-I-123-MIBG', 'Chemical', '-', (230, 244))	('HSA-I-123-MIBG', 'Var', (230, 244))	('cancer-free', 'Disease', 'MESH:D009369', (248, 259))
24058	31330766	An open label, multicenter, dose-escalation, phase 1 clinical trial for 21 patients with metastatic and/or unresectable PPGs was designed to determine the maximum tolerated dose of HSA-I-131-MIBG.	('HSA-I-131-MIBG', 'Var', (181, 195))	('patients', 'Species', '9606', (75, 83))	('PPGs', 'Disease', (120, 124))	('PPGs', 'Chemical', '-', (120, 124))	('HSA-I-131-MIBG', 'Chemical', '-', (181, 195))
24086	31330766	The number of PRs increased over time, an observation that suggests that HSA-I-131-MIBG has persistent antitumor effects (Figure 4).	('PRs', 'CPA', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('HSA-I-131-MIBG', 'Chemical', '-', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('PRs', 'Chemical', '-', (14, 17))	('HSA-I-131-MIBG', 'Var', (73, 87))
24117	31330766	Therefore, the surgical resection of the primary tumor and/or metastasectomy, if possible, should be considered in preparation for therapy with I-131-MIBG.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('I-131-MIBG', 'Chemical', '-', (144, 154))	('tumor', 'Disease', (49, 54))	('I-131-MIBG', 'Var', (144, 154))
24121	31330766	Like radiolabeled MIBG, CVD may cause bone marrow insufficiency and (rarely) predispose patients to secondary hematological malignancies (e.g., myelodysplasia, acute myelogenous leukemia).	('myelodysplasia', 'Phenotype', 'HP:0002863', (144, 158))	('hematological malignancies', 'Phenotype', 'HP:0004377', (110, 136))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (166, 186))	('CVD', 'Chemical', '-', (24, 27))	('myelodysplasia', 'Disease', 'MESH:D009190', (144, 158))	('CVD', 'Var', (24, 27))	('cause', 'Reg', (32, 37))	('hematological malignancies', 'Disease', (110, 136))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (160, 186))	('MIBG', 'Chemical', 'MESH:D019797', (18, 22))	('myelodysplasia', 'Disease', (144, 158))	('acute myelogenous leukemia', 'Disease', (160, 186))	('bone marrow insufficiency', 'Disease', (38, 63))	('patients', 'Species', '9606', (88, 96))	('bone marrow insufficiency', 'Phenotype', 'HP:0005528', (38, 63))	('predispose', 'Reg', (77, 87))	('hematological malignancies', 'Disease', 'MESH:D019337', (110, 136))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (160, 186))	('bone marrow insufficiency', 'Disease', 'MESH:D000081003', (38, 63))
24137	31330766	In fact, a recent publication described a MPPG patient treated with sunitinib and LSA-I-131-MIBG who had a CR with a remission that lasted for nine months.	('patient', 'Species', '9606', (47, 54))	('LSA-I-131-MIBG', 'Chemical', '-', (82, 96))	('CR', 'Chemical', '-', (107, 109))	('MPPG', 'Disease', (42, 46))	('I', 'Chemical', 'MESH:D007455', (93, 94))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('LSA-I-131-MIBG', 'Var', (82, 96))	('sunitinib', 'Chemical', 'MESH:D000077210', (68, 77))	('I', 'Chemical', 'MESH:D007455', (86, 87))	('MPPG', 'Chemical', '-', (42, 46))
24138	31330766	A reduction of the tumor burden with medications such as cabozantinib or sunitinib may increase the efficacy of I-131-MIBG.	('I-131-MIBG', 'Var', (112, 122))	('increase', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('reduction', 'NegReg', (2, 11))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('efficacy', 'MPA', (100, 108))	('I-131-MIBG', 'Chemical', '-', (112, 122))	('cabozantinib', 'Chemical', 'MESH:C558660', (57, 69))
24153	31330766	In contrast, I-131-MIBG may enhance a systemic response to immunotherapy.	('I-131-MIBG', 'Chemical', '-', (13, 23))	('I-131-MIBG', 'Var', (13, 23))	('enhance', 'PosReg', (28, 35))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('I', 'Chemical', 'MESH:D007455', (20, 21))	('I', 'Chemical', 'MESH:D007455', (13, 14))	('systemic response to immunotherapy', 'CPA', (38, 72))
24158	31330766	Unlike iodine-labeled MIBG, At-211-MABG decays by emitting alpha particles.	('emitting alpha particles', 'MPA', (50, 74))	('iodine', 'Chemical', 'MESH:D007455', (7, 13))	('decays', 'MPA', (40, 46))	('At-211-MABG', 'Var', (28, 39))	('MIBG', 'Chemical', 'MESH:D019797', (22, 26))	('At', 'Chemical', 'MESH:D001246', (28, 30))
24161	31330766	The use of At-211-MABG in a PC12 mouse model caused a substantial reduction of pheochromocytomas with mild detrimental effects on bone marrow cells.	('pheochromocytomas', 'Disease', 'MESH:D010673', (79, 96))	('a PC12', 'CellLine', 'CVCL:0481', (26, 32))	('pheochromocytomas', 'Disease', (79, 96))	('At-211-MABG', 'Var', (11, 22))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (79, 96))	('mouse', 'Species', '10090', (33, 38))	('At', 'Chemical', 'MESH:D001246', (11, 13))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (79, 95))	('reduction', 'NegReg', (66, 75))
24162	31330766	At-211-MABG may therefore be a potential treatment for patients with MPPG.	('MPPG', 'Disease', (69, 73))	('At-211-MABG', 'Var', (0, 11))	('patients', 'Species', '9606', (55, 63))	('At', 'Chemical', 'MESH:D001246', (0, 2))	('MPPG', 'Chemical', '-', (69, 73))
24165	31330766	In patients with neuroblastoma, positive responses have been noted in approximately 60% of those treated with LSA-I-131-MIBG.	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('I', 'Chemical', 'MESH:D007455', (114, 115))	('LSA-I-131-MIBG', 'Var', (110, 124))	('LSA-I-131-MIBG', 'Chemical', '-', (110, 124))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('patients', 'Species', '9606', (3, 11))	('neuroblastoma', 'Disease', (17, 30))	('I', 'Chemical', 'MESH:D007455', (121, 122))
24228	30087781	Some of the hereditary paragangliomas that are located in the head and neck, have mutations in the genes encoding succinate dehydrogenase (SDH) enzyme complex subunits.	('paraganglioma', 'Phenotype', 'HP:0002668', (23, 36))	('SDH', 'Gene', (139, 142))	('succinate dehydrogenase', 'Gene', '6390', (114, 137))	('SDH', 'Gene', '6390', (139, 142))	('mutations', 'Var', (82, 91))	('succinate dehydrogenase', 'Gene', (114, 137))	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (12, 37))	('paragangliomas', 'Phenotype', 'HP:0002668', (23, 37))	('hereditary paragangliomas', 'Disease', (12, 37))
24245	29978154	Pathogenicity and Penetrance of Germline SDHA Variants in Pheochromocytoma and Paraganglioma (PPGL) Germline SDHA mutations are reported in a minority of pheochromocytoma/paraganglioma (PPGL) cases but are associated with an increased risk of malignancy, leading some to advocate cascade genetic testing and surveillance screening of "at-risk" first-degree relatives.	('paraganglioma', 'Phenotype', 'HP:0002668', (171, 184))	('SDHA', 'Gene', (41, 45))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))	('mutations', 'Var', (114, 123))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (154, 184))	('SDHA', 'Gene', '6389', (109, 113))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (58, 92))	('pheochromocytoma/paraganglioma', 'Disease', (154, 184))	('Variants', 'Var', (46, 54))	('Paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('SDHA', 'Gene', '6389', (41, 45))	('malignancy', 'Disease', 'MESH:D009369', (243, 253))	('SDHA', 'Gene', (109, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (154, 170))	('malignancy', 'Disease', (243, 253))
24246	29978154	Thus, the aim of the current study was to evaluate the pathogenicity and penetrance of SDHA variants reported in literature-based PPGL cases by comparing their frequency to those occurring in the Genome Aggregation Database (GnomAD) data set, which provides high-quality DNA sequence data on 138,632 individuals.	('SDHA', 'Gene', (87, 91))	('SDHA', 'Gene', '6389', (87, 91))	('variants', 'Var', (92, 100))
24247	29978154	In total, 39 different missense or loss-of-function (LOF) SDHA variants were identified in 95 PPGL index cases.	('SDHA', 'Gene', '6389', (58, 62))	('variants', 'Var', (63, 71))	('loss-of-function', 'NegReg', (35, 51))	('SDHA', 'Gene', (58, 62))	('missense', 'Var', (23, 31))
24248	29978154	Notably, many of the PPGL-associated SDHA alleles were observed at an unexpectedly high frequency in the GnomAD cohort, with ~1% and ~0.1% of the background population harboring a rare missense or LOF variant, respectively.	('PPGL-associated', 'Gene', (21, 36))	('LOF', 'NegReg', (197, 200))	('missense', 'Var', (185, 193))	('SDHA', 'Gene', '6389', (37, 41))	('SDHA', 'Gene', (37, 41))
24250	29978154	Thus, although this study provides support for the etiological role of SDHA in PPGL formation, it suggests that most variant carriers will not manifest PPGLs and are unlikely to benefit from periodic surveillance screening.	('SDHA', 'Gene', '6389', (71, 75))	('variant', 'Var', (117, 124))	('SDHA', 'Gene', (71, 75))
24251	29978154	Germline SDHA variants are enriched in patients with pheochromocytoma/paraganglioma but are associated with very low disease penetrance such that most variant carriers will not manifest disease.	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (53, 83))	('patients', 'Species', '9606', (39, 47))	('SDHA', 'Gene', '6389', (9, 13))	('variants', 'Var', (14, 22))	('paraganglioma', 'Phenotype', 'HP:0002668', (70, 83))	('very low disease', 'Disease', 'MESH:D009800', (108, 124))	('SDHA', 'Gene', (9, 13))	('pheochromocytoma/paraganglioma', 'Disease', (53, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('very low disease', 'Disease', (108, 124))
24252	29978154	Pheochromocytomas and paragangliomas (PPGLs) are highly heritable tumors but display marked genetic heterogeneity such that ~35% of cases harbor germline mutations in one of >=15 genes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (0, 36))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('germline mutations', 'Var', (145, 163))	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))
24254	29978154	Indeed, the identification of a germline mutation in one of the PPGL susceptibility genes may not only have important clinical implications for the patient but may also facilitate cascade testing and periodic surveillance of "at-risk" first-degree relatives, although the appropriate implementation of such screening programs relies on accurate estimates of variant pathogenicity and disease penetrance.	('patient', 'Species', '9606', (148, 155))	('PPGL', 'Gene', (64, 68))	('facilitate', 'PosReg', (169, 179))	('germline mutation', 'Var', (32, 49))
24255	29978154	In particular, mutations in SDHB and SDHD have been established in large numbers of PPGL cases, providing unequivocal evidence of pathogenicity.	('PPGL', 'Disease', (84, 88))	('SDHD', 'Gene', '6392', (37, 41))	('mutations', 'Var', (15, 24))	('SDHD', 'Gene', (37, 41))	('SDHB', 'Gene', '6390', (28, 32))	('SDHB', 'Gene', (28, 32))
24256	29978154	Furthermore, the evaluation of cohorts of SDHB and SDHD variant carriers has facilitated reliable estimates of disease penetrance (i.e., ~20% and ~45% by age 60 years for SDHB and SDHD, respectively), thereby supporting the likely effectiveness of periodic surveillance of "at-risk" individuals.	('SDHD', 'Gene', (180, 184))	('variant', 'Var', (56, 63))	('SDHD', 'Gene', '6392', (180, 184))	('SDHB', 'Gene', '6390', (171, 175))	('SDHD', 'Gene', '6392', (51, 55))	('SDHB', 'Gene', (171, 175))	('SDHB', 'Gene', '6390', (42, 46))	('SDHD', 'Gene', (51, 55))	('SDHB', 'Gene', (42, 46))
24257	29978154	In comparison with SDHB and SDHD, mutations in the SDHA subunit have only relatively recently been described in patients with PPGLs and are reported to occur at a markedly lower frequency.	('SDHD', 'Gene', (28, 32))	('SDHD', 'Gene', '6392', (28, 32))	('SDHB', 'Gene', '6390', (19, 23))	('SDHA', 'Gene', (51, 55))	('patients', 'Species', '9606', (112, 120))	('SDHB', 'Gene', (19, 23))	('SDHA', 'Gene', '6389', (51, 55))	('mutations', 'Var', (34, 43))	('PPGLs', 'Disease', (126, 131))
24258	29978154	However, patients with PPGLs harboring SDHA mutations are also reported to have an increased risk of malignancy, leading several experts to advocate cascade genetic testing in first-degree relatives to facilitate downstream surveillance screening.	('patients', 'Species', '9606', (9, 17))	('SDHA', 'Gene', '6389', (39, 43))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))	('mutations', 'Var', (44, 53))	('malignancy', 'Disease', (101, 111))	('SDHA', 'Gene', (39, 43))
24259	29978154	Such an approach appears to be supported by the recent reporting of large PPGL series in which 3% to 7% of PPGL cases harbored SDHA variants, with estimates of disease penetrance in variant carriers ranging from 10% to 30%.	('to 7', 'Species', '1214577', (98, 102))	('SDHA', 'Gene', '6389', (127, 131))	('variants', 'Var', (132, 140))	('harbored', 'Reg', (118, 126))	('SDHA', 'Gene', (127, 131))
24260	29978154	Indeed, these approaches have enabled the reevaluation of genetic variants associated with several monogenic disease phenotypes, including cardiomyopathy, prion disease, and, more recently, hereditary endocrine disorders.	('hereditary endocrine disorders', 'Disease', 'MESH:D030342', (190, 220))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (139, 153))	('cardiomyopathy', 'Disease', 'MESH:D009202', (139, 153))	('variants', 'Var', (66, 74))	('hereditary endocrine disorders', 'Disease', (190, 220))	('endocrine disorders', 'Phenotype', 'HP:0000818', (201, 220))	('cardiomyopathy', 'Disease', (139, 153))	('prion disease', 'Disease', 'MESH:D017096', (155, 168))	('prion disease', 'Disease', (155, 168))
24261	29978154	Thus, in the current study, we aimed to use the Genome Aggregation Database (GnomAD), which provides high-quality genetic data on 138,632 individuals, to evaluate the pathogenicity and penetrance of germline SDHA variants reported in prior studies of PPGLs.	('SDHA', 'Gene', (208, 212))	('SDHA', 'Gene', '6389', (208, 212))	('variants', 'Var', (213, 221))
24262	29978154	PubMed was used to identify PPGL cases reported in the literature in association with heterozygous germline SDHA variants (up to February 2018).	('SDHA', 'Gene', '6389', (108, 112))	('variants', 'Var', (113, 121))	('SDHA', 'Gene', (108, 112))	('PPGL', 'Gene', (28, 32))
24265	29978154	The overall frequency of germline SDHA variants in PPGL cases was estimated from cohorts reporting germline SDHA sequencing results for >=50 individuals.	('SDHA', 'Gene', '6389', (108, 112))	('SDHA', 'Gene', (34, 38))	('SDHA', 'Gene', (108, 112))	('PPGL', 'Gene', (51, 55))	('SDHA', 'Gene', '6389', (34, 38))	('variants', 'Var', (39, 47))
24266	29978154	All SDHA missense and loss-of-function (LOF) variants in the GnomAD cohort were identified (accessed July 2017 to January 2018).	('SDHA', 'Gene', (4, 8))	('missense', 'Var', (9, 17))	('variants', 'Var', (45, 53))	('SDHA', 'Gene', '6389', (4, 8))	('loss-of-function', 'NegReg', (22, 38))
24267	29978154	LOF variants comprised all single-nucleotide variants predicted to result in nonsense amino acid changes or disruption to canonical donor or acceptor splice sites, as well as small insertions and/or deletions (indels) predicting a frameshift in the encoded protein.	('result', 'Reg', (67, 73))	('nonsense amino acid', 'MPA', (77, 96))	('variants', 'Var', (4, 12))	('donor', 'Species', '9606', (132, 137))	('deletions', 'Var', (199, 208))	('frameshift', 'Var', (231, 241))	('predicting', 'Reg', (218, 228))	('disruption', 'MPA', (108, 118))	('single-nucleotide', 'Var', (27, 44))
24268	29978154	Rare SDHA variants were defined as having an allele frequency (AF) <0.05% (i.e., affecting <=1 in 1000 of the population).	('affecting', 'Reg', (81, 90))	('variants', 'Var', (10, 18))	('SDHA', 'Gene', '6389', (5, 9))	('AF', 'Disease', 'MESH:D001281', (63, 65))	('SDHA', 'Gene', (5, 9))
24269	29978154	Each of the GnomAD missense SDHA variants (n = 357) was evaluated using the computational tools SIFT (http://sift.jcvi.org), Provean (http://provean.jcvi.org), and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2).	('SIFT', 'Disease', 'None', (96, 100))	('SDHA', 'Gene', (28, 32))	('SDHA', 'Gene', '6389', (28, 32))	('variants', 'Var', (33, 41))	('SIFT', 'Disease', (96, 100))
24270	29978154	The frequency of the literature-based PPGL SDHA variants, together with those reported as pathogenic/likely pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/), was ascertained in the GnomAD data set.	('SDHA', 'Gene', '6389', (43, 47))	('variants', 'Var', (48, 56))	('SDHA', 'Gene', (43, 47))
24271	29978154	Finally, manual visualization of the variant sequences alongside a multiple-sequence alignment file was used to minimize the possibility that SDHA variants represented false-positive artifacts from known pseudogenes (SDHAP1, SDHAP2, SDHAP3).	('SDHAP3', 'Gene', '728609', (233, 239))	('SDHA', 'Gene', '6389', (142, 146))	('variants', 'Var', (147, 155))	('SDHA', 'Gene', (217, 221))	('SDHA', 'Gene', '6389', (225, 229))	('SDHAP1', 'Gene', (217, 223))	('SDHA', 'Gene', (233, 237))	('SDHA', 'Gene', (142, 146))	('SDHAP1', 'Gene', '255812', (217, 223))	('SDHAP3', 'Gene', (233, 239))	('SDHAP2', 'Gene', '727956', (225, 231))	('SDHA', 'Gene', '6389', (233, 237))	('SDHA', 'Gene', (225, 229))	('SDHA', 'Gene', '6389', (217, 221))	('SDHAP2', 'Gene', (225, 231))
24272	29978154	Notably, all rare (AF < 0.05%) missense and LOF SDHA variants observed in the GnomAD database occurred only in the heterozygous state.	('missense', 'Var', (31, 39))	('LOF', 'NegReg', (44, 47))	('SDHA', 'Gene', (48, 52))	('SDHA', 'Gene', '6389', (48, 52))	('variants', 'Var', (53, 61))	('AF', 'Disease', 'MESH:D001281', (19, 21))
24273	29978154	Odds ratios (together with 95% CIs) comparing the frequency of SDHA variants between PPGL and GnomAD cohorts were calculated at http://www.hutchon.net/confidor.htm.	('variants', 'Var', (68, 76))	('SDHA', 'Gene', '6389', (63, 67))	('SDHA', 'Gene', (63, 67))	('PPGL', 'Gene', (85, 89))
24275	29978154	A total of 95 PPGL index cases with rare heterozygous SDHA variants were identified with equal sex distribution and mean age of 40 years (range, 15 to 81 years) (Table 1, Supplemental Table 1).	('SDHA', 'Gene', '6389', (54, 58))	('variants', 'Var', (59, 67))	('SDHA', 'Gene', (54, 58))
24278	29978154	Among the 95 index cases, 39 different germline heterozygous SDHA variants were observed.	('SDHA', 'Gene', (61, 65))	('SDHA', 'Gene', '6389', (61, 65))	('variants', 'Var', (66, 74))
24279	29978154	No patients were observed to harbor homozygous or compound heterozygous SDHA mutations.	('SDHA', 'Gene', '6389', (72, 76))	('mutations', 'Var', (77, 86))	('SDHA', 'Gene', (72, 76))	('compound heterozygous', 'Var', (50, 71))	('patients', 'Species', '9606', (3, 11))
24280	29978154	Overall, 62% of individuals harbored LOF SDHA variants (i.e., nonsense, splice site, or frameshift), with the remainder expressing missense variants.	('SDHA', 'Gene', (41, 45))	('splice site', 'Var', (72, 83))	('frameshift', 'Var', (88, 98))	('LOF', 'NegReg', (37, 40))	('SDHA', 'Gene', '6389', (41, 45))	('nonsense', 'Var', (62, 70))	('missense variants', 'Var', (131, 148))
24282	29978154	Several additional recurrent SDHA mutations were observed, including both LOF and missense variants, although most individual SDHA variants [28/39 (72%)] were observed in only single PPGL cases (Supplemental Fig.	('SDHA', 'Gene', (126, 130))	('missense variants', 'Var', (82, 99))	('SDHA', 'Gene', '6389', (29, 33))	('SDHA', 'Gene', (29, 33))	('SDHA', 'Gene', '6389', (126, 130))	('mutations', 'Var', (34, 43))
24283	29978154	To establish the frequency of germline SDHA variants in patients with PPGL, we identified cohorts of >50 PPGL index cases in which complete SDHA sequencing was reported (Supplemental Table 2).	('patients', 'Species', '9606', (56, 64))	('SDHA', 'Gene', (140, 144))	('SDHA', 'Gene', '6389', (39, 43))	('SDHA', 'Gene', '6389', (140, 144))	('SDHA', 'Gene', (39, 43))	('variants', 'Var', (44, 52))
24284	29978154	In this combined cohort, 3.6% of all patients with PPGLs harbored a heterozygous SDHA variant, although the frequency varied markedly between series (range, 0% to 7.6%).	('harbored', 'Reg', (57, 65))	('SDHA', 'Gene', (81, 85))	('patients', 'Species', '9606', (37, 45))	('SDHA', 'Gene', '6389', (81, 85))	('to 7', 'Species', '1214577', (160, 164))	('variant', 'Var', (86, 93))
24285	29978154	When evaluated by tumor site, the highest frequency of SDHA variants was observed in individuals with head and neck paraganglioma (overall, 6.3%; range, 0% to 12.1%), whereas the lowest frequency was observed in patients with adrenal pheochromocytoma (overall, 0.9%; range, 0% to 2.1%) (Supplemental Table 2).	('SDHA', 'Gene', '6389', (55, 59))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (226, 250))	('neck paraganglioma', 'Disease', 'MESH:D010235', (111, 129))	('paraganglioma', 'Phenotype', 'HP:0002668', (116, 129))	('tumor', 'Disease', (18, 23))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (234, 250))	('SDHA', 'Gene', (55, 59))	('patients', 'Species', '9606', (212, 220))	('adrenal pheochromocytoma', 'Disease', (226, 250))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (102, 129))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (226, 250))	('neck paraganglioma', 'Disease', (111, 129))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('variants', 'Var', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
24286	29978154	A high cumulative frequency of SDHA rare coding-region variation was observed in the GnomAD population, with ~1% of individuals in the cohort harboring a rare heterozygous SDHA missense variant (i.e., AF <0.05%), whereas strikingly, ~1 in every 1000 individuals carried a heterozygous LOF SDHA allele.	('SDHA', 'Gene', '6389', (289, 293))	('SDHA', 'Gene', '6389', (31, 35))	('SDHA', 'Gene', (172, 176))	('SDHA', 'Gene', (289, 293))	('SDHA', 'Gene', (31, 35))	('AF', 'Disease', 'MESH:D001281', (201, 203))	('variation', 'Var', (55, 64))	('SDHA', 'Gene', '6389', (172, 176))	('LOF', 'NegReg', (285, 288))	('missense variant', 'Var', (177, 193))
24287	29978154	Notably, when all GnomAD missense SDHA variants were evaluated using SIFT, Polyphen2, and Provean computational tools (n = 357), >75% were predicted to be potentially damaging (i.e., by one or more programs), with only ~22% predicted benign by each of SIFT, Polyphen-2, and Provean.	('SIFT', 'Disease', (69, 73))	('SIFT', 'Disease', 'None', (252, 256))	('SDHA', 'Gene', (34, 38))	('SIFT', 'Disease', 'None', (69, 73))	('SIFT', 'Disease', (252, 256))	('SDHA', 'Gene', '6389', (34, 38))	('variants', 'Var', (39, 47))
24288	29978154	Next, the number of expected individuals at risk for PPGLs due to SDHA mutations in the GnomAD cohort was established.	('mutations', 'Var', (71, 80))	('SDHA', 'Gene', (66, 70))	('PPGLs', 'Disease', (53, 58))	('SDHA', 'Gene', '6389', (66, 70))
24289	29978154	Thus, using the upper and lower bounds of PPGL disease incidence (i.e., 2 to 5/1,000,000/y) and SDHA mutation frequency in PPGL cases (i.e., 1% to 7%), a maximum of ~4 cases (range, 0.4 to 3.8) were predicted (Supplemental Table 3).	('to 7', 'Species', '1214577', (144, 148))	('SDHA', 'Gene', (96, 100))	('PPGL', 'Gene', (123, 127))	('PPGL', 'Disease', (42, 46))	('SDHA', 'Gene', '6389', (96, 100))	('mutation', 'Var', (101, 109))
24290	29978154	However, when the GnomAD data set was examined for individuals harboring PPGL-associated SDHA variants, the number observed was several orders of magnitude higher than predicted, with ~1 in every 750 of the GnomAD cohort carrying a potentially pathogenic variant.	('pathogenic', 'Reg', (244, 254))	('PPGL-associated', 'Gene', (73, 88))	('SDHA', 'Gene', (89, 93))	('variants', 'Var', (94, 102))	('SDHA', 'Gene', '6389', (89, 93))
24291	29978154	In total, 15 of 39 (40%) of the different PPGL-associated SDHA alleles were observed in individuals in the GnomAD cohort, of which the p.Arg31Ter occurred at the highest frequency (Fig.	('SDHA', 'Gene', '6389', (58, 62))	('p.Arg31Ter', 'Var', (135, 145))	('SDHA', 'Gene', (58, 62))	('p.Arg31Ter', 'Mutation', 'rs142441643', (135, 145))	('PPGL-associated', 'Gene', (42, 57))
24293	29978154	Having observed the high background frequency of individuals harboring potentially pathogenic SDHA variants in the GnomAD population, we next evaluated whether there was a significant excess of SDHA variants in the literature-based PPGL disease cohort relative to the GnomAD controls.	('PPGL', 'Disease', (232, 236))	('pathogenic', 'Reg', (83, 93))	('variants', 'Var', (199, 207))	('variants', 'Var', (99, 107))	('SDHA', 'Gene', '6389', (94, 98))	('SDHA', 'Gene', '6389', (194, 198))	('SDHA', 'Gene', (94, 98))	('SDHA', 'Gene', (194, 198))	('excess', 'PosReg', (184, 190))
24294	29978154	We initially focused these studies on p.Arg31Ter as this PPGL-associated variant was observed at the highest frequency in both disease and control cohorts (Fig.	('p.Arg31Ter', 'Mutation', 'rs142441643', (38, 48))	('p.Arg31Ter', 'Var', (38, 48))	('PPGL-associated', 'Gene', (57, 72))
24295	29978154	Thus, using the combined cohort of 1959 PPGL cases (Supplemental Table 2), a significant excess of the p.Arg31Ter variant was observed in the disease population relative to the GnomAD controls (Supplemental Table 4), whereas a similar excess was demonstrated in individual PPGL cohorts compared with both "Global" and "European" GnomAD populations, although the extent of enrichment varied between series (Supplemental Table 4).	('excess', 'PosReg', (89, 95))	('p.Arg31Ter', 'Mutation', 'rs142441643', (103, 113))	('p.Arg31Ter', 'Var', (103, 113))
24296	29978154	Similarly, a marked excess of LOF SDHA variants was observed in the PPGL cohorts when evaluated cumulatively, despite the high number of individuals harboring LOF alleles in the GnomAD population (Supplemental Table 4).	('SDHA', 'Gene', (34, 38))	('SDHA', 'Gene', '6389', (34, 38))	('LOF', 'NegReg', (30, 33))	('variants', 'Var', (39, 47))
24298	29978154	Finally, we established variant-level estimates of disease penetrance using the allele frequencies of the respective SDHA variants observed in disease (i.e., literature-based cohort) and control populations (i.e., GnomAD-based cohorts) (Supplemental Tables 5 and 6).	('SDHA', 'Gene', '6389', (117, 121))	('variants', 'Var', (122, 130))	('SDHA', 'Gene', (117, 121))
24299	29978154	For example, the highest estimates of penetrance were observed for the nonsense p.Arg31Ter variant in the PPGL cohort reported by van der Tuin et al.	('p.Arg31Ter', 'Var', (80, 90))	('PPGL', 'Gene', (106, 110))	('p.Arg31Ter', 'Mutation', 'rs142441643', (80, 90))
24302	29978154	Most notably, these studies provide support for the role of SDHA in PPGL tumorigenesis while simultaneously demonstrating that variants in SDHA are likely associated with a much lower disease penetrance than those reported for other components of the succinate dehydrogenase complex (i.e., SDHB/SDHD).	('variants', 'Var', (127, 135))	('PPGL', 'Disease', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SDHB', 'Gene', '6390', (290, 294))	('lower', 'NegReg', (178, 183))	('disease penetrance', 'MPA', (184, 202))	('SDHA', 'Gene', '6389', (139, 143))	('SDHA', 'Gene', '6389', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SDHB', 'Gene', (290, 294))	('SDHD', 'Gene', (295, 299))	('tumor', 'Disease', (73, 78))	('SDHA', 'Gene', (139, 143))	('SDHD', 'Gene', '6392', (295, 299))	('SDHA', 'Gene', (60, 64))
24305	29978154	Thus, future studies should aim to define the full range of tumor phenotypes associated with SDHA mutation, which likely extend beyond PPGLs and GISTs.	('SDHA', 'Gene', '6389', (93, 97))	('mutation', 'Var', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SDHA', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('GIST', 'Phenotype', 'HP:0100723', (145, 149))
24307	29978154	Although this may partly reflect the makeup of the specific populations under study (i.e., a high number of p.Arg31Ter cases from the Netherlands), it suggests there may be variant-specific factors that increase tumor risk (e.g., cis-acting genetic elements not captured in the current study or influences of the truncating variant on expression of the wild-type allele).	('influences', 'Reg', (295, 305))	('variant-specific', 'Var', (173, 189))	('increase tumor', 'Disease', (203, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('p.Arg31Ter', 'Mutation', 'rs142441643', (108, 118))	('increase tumor', 'Disease', 'MESH:D009369', (203, 217))
24308	29978154	The current analysis only allowed penetrance estimates for SDHA variants observed in both disease and control cohorts, with the most reliable estimates (i.e., narrow CIs) obtained for those observed multiple times.	('SDHA', 'Gene', (59, 63))	('SDHA', 'Gene', '6389', (59, 63))	('variants', 'Var', (64, 72))
24309	29978154	Thus, although 15 of 39 unique PPGL-associated SDHA variants occurred in the GnomAD population, the remaining 24 variants were not observed.	('SDHA', 'Gene', (47, 51))	('SDHA', 'Gene', '6389', (47, 51))	('variants', 'Var', (52, 60))
24310	29978154	However, ~80% (19/24) of these variants were observed in single patients with PPGLs, and the appropriate interpretation of such variants remains challenging.	('variants', 'Var', (31, 39))	('PPGLs', 'Disease', (78, 83))	('patients', 'Species', '9606', (64, 72))	('observed', 'Reg', (45, 53))
24311	29978154	For example, ~50% of the different nonsynonymous SDHA variants observed in the GnomAD population occurred in single individuals, and consequently, it may not be possible to distinguish disease-causing mutations from those very rare "background" coding variants identified incidentally.	('variants', 'Var', (54, 62))	('SDHA', 'Gene', (49, 53))	('SDHA', 'Gene', '6389', (49, 53))
24312	29978154	Thus, the high background frequency of rare missense SDHA variants observed in GnomAD indicates that some of the PPGL-associated missense variants may have been susceptible to misclassification.	('variants', 'Var', (58, 66))	('SDHA', 'Gene', (53, 57))	('PPGL-associated', 'Gene', (113, 128))	('SDHA', 'Gene', '6389', (53, 57))
24313	29978154	Furthermore, we demonstrate the limited specificity of the computational tools frequently used in support of variant pathogenicity, with most GnomAD missense SDHA variants predicted to be deleterious by at least one of the prediction programs.	('SDHA', 'Gene', '6389', (158, 162))	('missense', 'Var', (149, 157))	('variants', 'Var', (163, 171))	('SDHA', 'Gene', (158, 162))
24314	29978154	Thus, any high-volume genetic testing for SDHA should anticipate the identification of rare missense SDHA variants, including those not previously observed in control cohorts, which will remain problematic for interpretation.	('SDHA', 'Gene', '6389', (101, 105))	('variants', 'Var', (106, 114))	('SDHA', 'Gene', (42, 46))	('SDHA', 'Gene', (101, 105))	('SDHA', 'Gene', '6389', (42, 46))	('missense', 'Var', (92, 100))
24316	29978154	However, several of the larger cohorts excluded individuals with mutations in more common PPGL-associated genes, which in turn will overstate the frequency of SDHA variants in unselected PPGL cases (i.e., the true denominator will be underrepresented).	('PPGL', 'Gene', (187, 191))	('PPGL-associated', 'Gene', (90, 105))	('SDHA', 'Gene', '6389', (159, 163))	('variants', 'Var', (164, 172))	('overstate', 'PosReg', (132, 141))	('SDHA', 'Gene', (159, 163))	('mutations', 'Var', (65, 74))
24317	29978154	Thus, each of these potential limitations will likely overestimate the SDHA mutation frequency in cases, and as a consequence, our low estimates of disease penetrance may in fact be overstated.	('SDHA', 'Gene', '6389', (71, 75))	('mutation', 'Var', (76, 84))	('SDHA', 'Gene', (71, 75))	('overestimate', 'PosReg', (54, 66))
24410	29293508	Imbalances and collapse of cellular proteostasis capacity, the capacity to buffer against cytotoxic damage and stress, is increasingly implicated in some of the most challenging diseases of our time, including neurodegeneration and cancers.	('neurodegeneration', 'Phenotype', 'HP:0002180', (210, 227))	('cellular proteostasis capacity', 'MPA', (27, 57))	('implicated', 'Reg', (135, 145))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('cancers', 'Disease', (232, 239))	('neurodegeneration', 'Disease', (210, 227))	('cytotoxic damage', 'Disease', (90, 106))	('neurodegeneration', 'Disease', 'MESH:D019636', (210, 227))	('Imbalances', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cytotoxic damage', 'Disease', 'MESH:D064420', (90, 106))
24418	29293508	Increasing awareness of the fundamental role of the PN in cellular health, its relevance in diseases and potential as a therapeutic target of proteostasis regulator (PR) drugs call for a systematic and systems-level assessment of PN deregulation throughout the human diseasome, towards improved understanding of diseases of proteostasis deficiency and rationalized network-informed approaches to therapeutic proteostasis re-adjustment.	('diseases of proteostasis deficiency', 'Disease', 'MESH:D057165', (312, 347))	('deregulation', 'Var', (233, 245))	('human', 'Species', '9606', (261, 266))	('diseases of proteostasis deficiency', 'Disease', (312, 347))
24423	29293508	In cancers, mutations and genomic instability inevitably entail alterations of proteome composition and balance that are far less well explored than the consequences of nucleic acid sequence alterations.	('genomic instability', 'Var', (26, 45))	('proteome composition', 'MPA', (79, 99))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('alterations', 'Reg', (64, 75))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('balance', 'MPA', (104, 111))	('entail', 'Reg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
24500	29293508	Loss of complex subunits induces cell death and a decline of pluripotency of hESCs and induced pluripotent stem cells (iPSCs).	('complex subunits', 'Protein', (8, 24))	('death', 'Disease', 'MESH:D003643', (38, 43))	('decline of pluripotency of hESCs', 'Disease', (50, 82))	('death', 'Disease', (38, 43))	('decline of pluripotency of hESCs', 'Disease', 'MESH:D003072', (50, 82))	('pluripotent', 'MPA', (95, 106))	('Loss', 'Var', (0, 4))
24517	29293508	In light of the diverse signatures of differential chaperome deregulation observed across cancers (Fig 2), and motivated by the increasing amount of genomics datasets available for cancers and other human diseases, we aimed at reducing data complexity by extracting quantitative indicators of chaperome differential cancer gene expression alterations, in order to gain insights through reduced complexity while retaining maximum information content.	('cancers', 'Disease', (90, 97))	('human', 'Species', '9606', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('alterations', 'Var', (339, 350))	('cancers', 'Disease', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', (316, 322))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
24552	29293508	Here we exemplify a systematic analysis of differential chaperome gene expression alterations in cancers and neurodegenerative diseases.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (109, 135))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (109, 134))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('alterations', 'Var', (82, 93))	('neurodegenerative diseases', 'Disease', (109, 135))	('differential', 'Protein', (43, 55))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (109, 135))
24560	29293508	Cancer prevalence, genetic complexity and heterogeneity represent unmet medical need and a significant challenge to personalized medicine, calling for genome-informed therapeutic intervention strategies.	('Cancer', 'Disease', (0, 6))	('genetic complexity', 'Var', (19, 37))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
24564	29293508	Here, we focused on the human chaperome, a central PN component, and highly conserved facilitator and safeguard of the healthy folded proteome using an expert-curated human chaperome functional gene ontology comprising an ensemble of 332 chaperone and co-chaperone genes to systematically characterize chaperome alterations in a representative clinically relevant dataset of 22 human solid cancers with matching healthy tissue, corresponding to over 10,000 patient biopsy samples provided through the TCGA consortium.	('cancers', 'Phenotype', 'HP:0002664', (390, 397))	('human', 'Species', '9606', (24, 29))	('human', 'Species', '9606', (378, 383))	('cancers', 'Disease', (390, 397))	('cancers', 'Disease', 'MESH:D009369', (390, 397))	('human', 'Species', '9606', (167, 172))	('patient', 'Species', '9606', (457, 464))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('alterations', 'Var', (312, 323))
24572	29293508	The cellular safeguarding functions of chaperones are subverted during oncogenesis to facilitate malignant transformation in light of increased translational flux and aberrant protein species in cancer cells.	('translational flux', 'MPA', (144, 162))	('aberrant', 'Var', (167, 175))	('facilitate', 'PosReg', (86, 96))	('cancer', 'Disease', (195, 201))	('malignant transformation', 'CPA', (97, 121))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('protein', 'Protein', (176, 183))	('increased', 'PosReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
24582	29293508	Overexpression of the TRiC/CCT subunit CCT8 protects against hsf-1 knockdown in C. elegans, consistent with a regulatory connection between TRiC/CCT and HSF1.	('HSF1', 'Gene', '3297', (153, 157))	('hsf-1', 'Gene', (61, 66))	('CCT', 'Gene', '907', (145, 148))	('TRiC', 'Gene', '153562', (140, 144))	('TRiC', 'Gene', '153562', (22, 26))	('TRiC', 'Gene', (22, 26))	('CCT', 'Gene', (27, 30))	('knockdown', 'Var', (67, 76))	('CCT', 'Gene', '907', (39, 42))	('hsf-1', 'Gene', '173078', (61, 66))	('C. elegans', 'Species', '6239', (80, 90))	('TRiC', 'Gene', (140, 144))	('CCT', 'Gene', (145, 148))	('CCT', 'Gene', '907', (27, 30))	('HSF1', 'Gene', (153, 157))	('CCT', 'Gene', (39, 42))
24588	29293508	The collective damage caused by oncoprotein expression, compromised DNA repair, genomic instability, reactive oxygen species (ROS), elevated global translation and chaperome overload triggers stress response mechanisms in light of a challenged cellular proteostasis capacity.	('elevated', 'PosReg', (132, 140))	('compromised', 'Var', (56, 67))	('oncoprotein', 'Protein', (32, 43))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (101, 124))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('DNA repair', 'MPA', (68, 78))	('genomic instability', 'CPA', (80, 99))	('global translation', 'MPA', (141, 159))	('reactive oxygen species', 'MPA', (101, 124))	('triggers', 'Reg', (183, 191))
24594	29293508	In summary, our study showcases a systematic profiling of the extent of chaperome deregulation, as a central PN functional arm, in a panel of human cancers and three major neurodegenerative disorders, accompanied by a resource of quantitative multi-dimensional maps with reduced complexity.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (172, 199))	('neurodegenerative disorders', 'Disease', (172, 199))	('cancers', 'Disease', (148, 155))	('functional arm', 'Phenotype', 'HP:0003484', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (142, 147))	('chaperome', 'Protein', (72, 81))	('deregulation', 'Var', (82, 94))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (172, 199))
24880	23487352	In a study by Mann et al, both C-11 HED and F-18 FDG were able to localize more lesions in a more timely fashion than I-131 MIBG.	('I-131 MIBG', 'Chemical', 'MESH:D019797', (118, 128))	('FDG', 'Chemical', 'MESH:D019788', (49, 52))	('C-11', 'Var', (31, 35))	('HED', 'Disease', 'MESH:D053359', (36, 39))	('F-18', 'Var', (44, 48))	('HED', 'Disease', (36, 39))
24885	23154831	Acquired hypermethylation of the P16INK4A promoter in abdominal paraganglioma: relation to adverse tumor phenotype and predisposing mutation Recurrent alterations in promoter methylation of tumor suppressor genes (TSGs) and LINE1 (L1RE1) repeat elements were previously reported in pheochromocytoma and abdominal paraganglioma.	('adverse tumor', 'Disease', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('P16INK4A', 'Gene', '1029', (33, 41))	('abdominal paraganglioma', 'Disease', (303, 326))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (54, 77))	('tumor', 'Disease', (99, 104))	('pheochromocytoma', 'Disease', 'MESH:D010673', (282, 298))	('L1RE1', 'Gene', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('abdominal paraganglioma', 'Disease', (54, 77))	('pheochromocytoma', 'Disease', (282, 298))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (282, 298))	('L1RE1', 'Gene', '4029', (231, 236))	('promoter methylation', 'MPA', (166, 186))	('paraganglioma', 'Phenotype', 'HP:0002668', (313, 326))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('alterations', 'Var', (151, 162))	('TSG', 'Gene', '57045', (214, 217))	('adverse tumor', 'Disease', 'MESH:D064420', (91, 104))	('P16INK4A', 'Gene', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (303, 326))	('TSG', 'Gene', (214, 217))	('paraganglioma', 'Phenotype', 'HP:0002668', (64, 77))
24889	23154831	Z-scores for overall TSG, and individual TSG methylation levels, but not LINE1, were significantly correlated with metastatic disease, paraganglioma, disease predisposition, or outcome.	('TSG', 'Gene', '57045', (41, 44))	('paraganglioma', 'Disease', 'MESH:D010235', (135, 148))	('TSG', 'Gene', '57045', (21, 24))	('TSG', 'Gene', (21, 24))	('methylation', 'Var', (45, 56))	('correlated', 'Reg', (99, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (135, 148))	('TSG', 'Gene', (41, 44))	('metastatic disease', 'Disease', (115, 133))	('paraganglioma', 'Disease', (135, 148))
24890	23154831	Most strikingly, P16 hypermethylation was strongly associated with SDHB mutation as opposed to RET/MEN2, VHL/VHL, or NF1-related disease.	('hypermethylation', 'Var', (21, 37))	('VHL', 'Disease', (109, 112))	('NF1', 'Gene', '4763', (117, 120))	('RET', 'Gene', (95, 98))	('VHL', 'Disease', 'MESH:D006623', (109, 112))	('SDHB', 'Gene', '6390', (67, 71))	('P16', 'Gene', (17, 20))	('P16', 'Gene', '1029', (17, 20))	('SDHB', 'Gene', (67, 71))	('associated', 'Reg', (51, 61))	('RET', 'Gene', '5979', (95, 98))	('mutation', 'Var', (72, 80))	('VHL', 'Disease', 'MESH:D006623', (105, 108))	('NF1', 'Gene', (117, 120))	('VHL', 'Disease', (105, 108))
24891	23154831	Parallel analyses of constitutional, tumor, and metastasis DNA implicate an order of events where constitutional SDHB mutations are followed by TSG hypermethylation and 1p loss in primary tumors, later transferred to metastatic tissue.	('tumor', 'Disease', (188, 193))	('SDHB', 'Gene', '6390', (113, 117))	('loss', 'NegReg', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('TSG', 'Gene', '57045', (144, 147))	('mutations', 'Var', (118, 127))	('SDHB', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('primary tumors', 'Disease', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('primary tumors', 'Disease', 'MESH:D009369', (180, 194))	('TSG', 'Gene', (144, 147))
24892	23154831	In the combined material, P16 hypermethylation was prevalent in SDHB-mutated samples and was associated with short disease-related survival.	('P16', 'Gene', (26, 29))	('prevalent', 'Reg', (51, 60))	('SDHB', 'Gene', '6390', (64, 68))	('P16', 'Gene', '1029', (26, 29))	('associated', 'Reg', (93, 103))	('SDHB', 'Gene', (64, 68))	('hypermethylation', 'Var', (30, 46))
24893	23154831	The findings verify the previously reported importance of P16 and other TSG hypermethylation in an independent tumor series.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('TSG', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('P16', 'Gene', (58, 61))	('hypermethylation', 'Var', (76, 92))	('tumor', 'Disease', (111, 116))	('TSG', 'Gene', '57045', (72, 75))	('P16', 'Gene', '1029', (58, 61))
24894	23154831	Furthermore, a constitutional SDHB mutation is proposed to predispose for an epigenetic tumor phenotype occurring before the emanation of clinically recognized malignancy.	('malignancy', 'Disease', (160, 170))	('predispose', 'Reg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('clinical', 'Species', '191496', (138, 146))	('SDHB', 'Gene', '6390', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('SDHB', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))	('tumor', 'Disease', (88, 93))
24897	23154831	There is an increasing appreciation for the hereditary background of these tumors; indeed, known predisposing gene variations are present in more than 25% of pheochromocytoma and paraganglioma patients.	('patients', 'Species', '9606', (193, 201))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('paraganglioma', 'Phenotype', 'HP:0002668', (179, 192))	('variations', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (158, 192))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('tumors', 'Disease', (75, 81))
24900	23154831	Others and we have previously shown that promoter hypermethylation in tumor suppressor genes (TSGs) is a prominent feature of pheochromocytoma and paraganglioma.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TSG', 'Gene', (94, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('tumor', 'Disease', (70, 75))	('TSG', 'Gene', '57045', (94, 97))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (126, 160))	('promoter hypermethylation', 'Var', (41, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (126, 142))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
24902	23154831	Knocking out the mouse equivalent of the INK4A locus, Ink4a/Arf, causes a substantial increase in the severity of the disease phenotype in pheochromocytoma-prone mice.	('INK4A', 'Gene', (41, 46))	('increase', 'PosReg', (86, 94))	('mouse', 'Species', '10090', (17, 22))	('pheochromocytoma', 'Disease', (139, 155))	('Ink4a/Arf', 'Gene', (54, 63))	('pheochromocytoma', 'Disease', 'MESH:D010673', (139, 155))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (139, 155))	('INK4A', 'Gene', '12578', (41, 46))	('mice', 'Species', '10090', (162, 166))	('Ink4a/Arf', 'Gene', '12578', (54, 63))	('Knocking', 'Var', (0, 8))
24903	23154831	While this region is rarely lost in human pheochromocytomas and paragangliomas, we found that hypermethylation of the residing P16 gene is strongly associated with malignancy - 4/5 cases with P16 hypermethylation were classified as malignant, while only 1/44 tumors without evidence of malignancy harbored P16 hypermethylation.	('P16', 'Gene', (192, 195))	('malignancy', 'Disease', (286, 296))	('P16', 'Gene', '1029', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (42, 59))	('malignancy', 'Disease', 'MESH:D009369', (164, 174))	('paragangliomas', 'Phenotype', 'HP:0002668', (64, 78))	('P16', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('hypermethylation', 'Var', (196, 212))	('malignancy', 'Disease', (164, 174))	('hypermethylation', 'Var', (94, 110))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (42, 78))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('P16', 'Gene', '1029', (306, 309))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (42, 58))	('malignancy', 'Disease', 'MESH:D009369', (286, 296))	('P16', 'Gene', '1029', (192, 195))	('associated with', 'Reg', (148, 163))	('P16', 'Gene', (306, 309))	('human', 'Species', '9606', (36, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (64, 77))
24906	23154831	Interestingly, CIMP was associated with malignancy (4/5 cases with CIMP had developed metastases) and with SDHB mutation (SDHB mutation was detected in 4/5 cases with CIMP, and).	('metastases', 'Disease', (86, 96))	('associated', 'Reg', (24, 34))	('SDHB', 'Gene', (107, 111))	('mutation', 'Var', (112, 120))	('metastases', 'Disease', 'MESH:D009362', (86, 96))	('CIMP', 'Chemical', '-', (67, 71))	('CIMP', 'Chemical', '-', (15, 19))	('SDHB', 'Gene', '6390', (122, 126))	('CIMP', 'Chemical', '-', (167, 171))	('SDHB', 'Gene', (122, 126))	('malignancy', 'Disease', 'MESH:D009369', (40, 50))	('SDHB', 'Gene', '6390', (107, 111))	('CIMP', 'Disease', (15, 19))	('malignancy', 'Disease', (40, 50))
24909	23154831	Notably and as our previous findings indicated a presence of CIMP in strong association with malignant paragangliomas with SDHB mutation, the present panel included additional cases with known mutation in predisposing genes and/or associated syndromes, paragangliomas, and metastatic disease.	('paragangliomas', 'Disease', (103, 117))	('paragangliomas', 'Disease', 'MESH:D010235', (103, 117))	('paragangliomas', 'Phenotype', 'HP:0002668', (103, 117))	('malignant paragangliomas', 'Disease', (93, 117))	('association', 'Interaction', (76, 87))	('CIMP', 'Chemical', '-', (61, 65))	('SDHB', 'Gene', '6390', (123, 127))	('SDHB', 'Gene', (123, 127))	('paraganglioma', 'Phenotype', 'HP:0002668', (103, 116))	('paragangliomas', 'Disease', 'MESH:D010235', (253, 267))	('mutation', 'Var', (128, 136))	('paragangliomas', 'Disease', (253, 267))	('paraganglioma', 'Phenotype', 'HP:0002668', (253, 266))	('paragangliomas', 'Phenotype', 'HP:0002668', (253, 267))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (93, 117))
24911	23154831	Our aims were to i) verify the occurrence of TSG hypermethylation in an independent tumor series; ii) assess the temporal relation of methylation to tumor development; iii) determine the chronological relation to genetic alterations; iv) evaluate the relation to mutations in predisposing genes; and v) assess associations to metastatic disease.	('TSG', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('metastatic disease', 'Disease', (326, 344))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('hypermethylation', 'Var', (49, 65))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TSG', 'Gene', '57045', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (84, 89))	('associations', 'Interaction', (310, 322))	('tumor', 'Disease', (149, 154))
24915	23154831	Tumor series A (Tables 1 and 2) constituted of 38 primary tumors and two metastases was analyzed for promoter methylation and SDHB/D mutation in this study (Table 2).	('primary tumors', 'Disease', 'MESH:D009369', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutation', 'Var', (133, 141))	('metastases', 'Disease', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('primary tumors', 'Disease', (50, 64))	('metastases', 'Disease', 'MESH:D009362', (73, 83))	('SDHB', 'Gene', '6390', (126, 130))	('SDHB', 'Gene', (126, 130))
24924	23154831	In addition, non-tumorous DNA was sequenced in five cases in Series B with previously reported SDHB tumor mutations to assess whether mutations were constitutional or not.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('SDHB tumor', 'Disease', 'MESH:D009369', (95, 105))	('SDHB tumor', 'Disease', (95, 105))	('mutations', 'Var', (106, 115))	('tumorous', 'Disease', 'MESH:D009369', (17, 25))	('tumorous', 'Disease', (17, 25))
24926	23154831	Cases with a hereditary form of the disease were identified by mutation screening of constitutional DNA or in some cases based on the clinical presentation as reported in and.	('constitutional DNA', 'Disease', (85, 103))	('clinical', 'Species', '191496', (134, 142))	('mutation screening', 'Var', (63, 81))
24927	23154831	In addition, cases with SDHB mutations were identified by sequencing of tumor DNA and by verification of constitutional mutations in samples from blood or normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('mutations', 'Var', (29, 38))	('SDHB', 'Gene', '6390', (24, 28))	('SDHB', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
24942	23154831	exhibited increased MetI for three or more genes (AG-9, -14, and -20; Table 2).	('MetI', 'Chemical', '-', (20, 24))	('MetI', 'Var', (20, 24))	('increased', 'PosReg', (10, 19))
24943	23154831	Hypermethylation with MetI above cutoff was observed for all genes except NORE1A, and in addition, some tumors exhibited increased methylation at >=1 CpG without raising the MetI above cutoff (Table 2).	('NORE1A', 'Gene', (74, 80))	('MetI', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('increased', 'PosReg', (121, 130))	('Hypermethylation', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('MetI', 'Chemical', '-', (22, 26))	('MetI', 'Chemical', '-', (174, 178))	('tumors', 'Disease', (104, 110))	('NORE1A', 'Gene', '83593', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('methylation', 'MPA', (131, 142))
24944	23154831	Increased MetI was identified in three primary tumors for DCR2, three tumors for CDH1, five tumors for P16, one tumor for RARB, and five tumors for RASSF1A.	('tumors', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('RASSF1A', 'Gene', (148, 155))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MetI', 'Chemical', '-', (10, 14))	('P16', 'Gene', '1029', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (47, 53))	('DCR2', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('P16', 'Gene', (103, 106))	('tumors', 'Disease', (70, 76))	('primary tumors', 'Disease', (39, 53))	('RARB', 'Gene', (122, 126))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', (92, 98))	('RARB', 'Gene', '5915', (122, 126))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('MetI', 'Var', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('primary tumors', 'Disease', 'MESH:D009369', (39, 53))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', (47, 52))	('CDH1', 'Gene', '999', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('DCR2', 'Gene', '8793', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (92, 97))	('CDH1', 'Gene', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('RASSF1A', 'Gene', '11186', (148, 155))
24950	23154831	Importantly, higher mean Z-score was significantly associated with mutation (SDHB), tumor type (paraganglioma), metastatic disease, death of disease, and CIMP (Fig.	('paraganglioma', 'Disease', 'MESH:D010235', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('metastatic disease', 'Disease', (112, 130))	('mutation', 'Var', (67, 75))	('Z-score', 'MPA', (25, 32))	('death of disease', 'Disease', (132, 148))	('CIMP', 'Disease', (154, 158))	('SDHB', 'Gene', '6390', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('higher', 'PosReg', (13, 19))	('tumor', 'Disease', (84, 89))	('SDHB', 'Gene', (77, 81))	('paraganglioma', 'Disease', (96, 109))	('CIMP', 'Chemical', '-', (154, 158))	('death of disease', 'Disease', 'MESH:D003643', (132, 148))
24951	23154831	High Z-scores for individual TSG promoters were also significantly associated with different clinical and genetic features including SDHB mutation (all save NORE1A), paraganglioma tumor type (all), metastasis (all), and death of disease (all except RARB, with RASSF1A being highly significant) (Table 3).	('SDHB', 'Gene', '6390', (133, 137))	('metastasis', 'CPA', (198, 208))	('TSG', 'Gene', (29, 32))	('paraganglioma tumor', 'Disease', (166, 185))	('mutation', 'Var', (138, 146))	('paraganglioma', 'Phenotype', 'HP:0002668', (166, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('RARB', 'Gene', (249, 253))	('NORE1A', 'Gene', (157, 163))	('RARB', 'Gene', '5915', (249, 253))	('SDHB', 'Gene', (133, 137))	('clinical', 'Species', '191496', (93, 101))	('associated', 'Reg', (67, 77))	('death of disease', 'Disease', (220, 236))	('paraganglioma tumor', 'Disease', 'MESH:D010235', (166, 185))	('RASSF1A', 'Gene', '11186', (260, 267))	('death of disease', 'Disease', 'MESH:D003643', (220, 236))	('NORE1A', 'Gene', '83593', (157, 163))	('RASSF1A', 'Gene', (260, 267))	('TSG', 'Gene', '57045', (29, 32))
24952	23154831	3 illustrates the patterns of TSG hypermethylation in cases with different forms of heritable disease.	('TSG', 'Gene', (30, 33))	('hypermethylation', 'Var', (34, 50))	('TSG', 'Gene', '57045', (30, 33))
24958	23154831	Taken together, the combined observations in Series A+B strongly support an association between SDHB mutation and TSG hypermethylation, with P16 being the most frequently involved.	('TSG', 'Gene', (114, 117))	('hypermethylation', 'Var', (118, 134))	('P16', 'Gene', (141, 144))	('TSG', 'Gene', '57045', (114, 117))	('SDHB', 'Gene', '6390', (96, 100))	('P16', 'Gene', '1029', (141, 144))	('SDHB', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))
24964	23154831	Hence, SDHB mutations were present constitutionally, while TSG hypermethylation and CIMP were acquired events first observed in primary tumors together with loss of chromosomal region 1p encompassing the SDHB locus, and subsequently retained to metastatic tissue.	('TSG', 'Gene', (59, 62))	('SDHB', 'Gene', (7, 11))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('SDHB', 'Gene', '6390', (204, 208))	('mutations', 'Var', (12, 21))	('SDHB', 'Gene', (204, 208))	('CIMP', 'Chemical', '-', (84, 88))	('TSG', 'Gene', '57045', (59, 62))	('primary tumors', 'Disease', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SDHB', 'Gene', '6390', (7, 11))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))	('loss', 'NegReg', (157, 161))
24965	23154831	MetI levels for LINE1 repeat elements varied from 46 to 80% in the 39 primary tumors in Series A, and the values at the individual CpGs ranged from 37 to 83% (Table 2).	('LINE1', 'Var', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('primary tumors', 'Disease', (70, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MetI', 'MPA', (0, 4))	('MetI', 'Chemical', '-', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (70, 84))
24973	23154831	Indeed, individual TSG hypermethylation was salient in paragangliomas, being especially prominent in tumors classified as malignant.	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('paragangliomas', 'Disease', (55, 69))	('paragangliomas', 'Disease', 'MESH:D010235', (55, 69))	('TSG', 'Gene', (19, 22))	('paraganglioma', 'Phenotype', 'HP:0002668', (55, 68))	('paragangliomas', 'Phenotype', 'HP:0002668', (55, 69))	('hypermethylation', 'Var', (23, 39))	('TSG', 'Gene', '57045', (19, 22))	('tumors', 'Disease', (101, 107))
24974	23154831	In the combined Series A+B, 7/11 metastasized paragangliomas exhibited MetI above cutoff in two or more of the assessed TSG promoters (Fig.	('paragangliomas', 'Disease', (46, 60))	('MetI above cutoff', 'Var', (71, 88))	('TSG', 'Gene', '57045', (120, 123))	('MetI', 'Chemical', '-', (71, 75))	('paragangliomas', 'Disease', 'MESH:D010235', (46, 60))	('paraganglioma', 'Phenotype', 'HP:0002668', (46, 59))	('exhibited', 'Reg', (61, 70))	('TSG', 'Gene', (120, 123))	('paragangliomas', 'Phenotype', 'HP:0002668', (46, 60))
24975	23154831	Further, 4/12 paragangliomas without metastases carried SDHB mutations - strongly linked to malignant behavior and metastatic potential - three of which also exhibited MetI above cutoff for two or more TSGs (Fig.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('malignant behavior', 'CPA', (92, 110))	('mutations -', 'Var', (61, 72))	('TSG', 'Gene', '57045', (202, 205))	('metastases', 'Disease', (37, 47))	('paraganglioma', 'Phenotype', 'HP:0002668', (14, 27))	('linked to', 'Reg', (82, 91))	('metastatic potential -', 'CPA', (115, 137))	('paragangliomas', 'Disease', (14, 28))	('paragangliomas', 'Disease', 'MESH:D010235', (14, 28))	('paragangliomas', 'Phenotype', 'HP:0002668', (14, 28))	('MetI', 'Chemical', '-', (168, 172))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('TSG', 'Gene', (202, 205))
24976	23154831	In contrast, TSG hypermethylation proved infrequent in pheochromocytomas; 5/54 cases featured MetI above cutoff in a single TSG each (Fig.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (55, 72))	('TSG', 'Gene', (124, 127))	('TSG', 'Gene', '57045', (13, 16))	('TSG', 'Gene', '57045', (124, 127))	('pheochromocytomas', 'Disease', 'MESH:D010673', (55, 72))	('pheochromocytomas', 'Disease', (55, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (55, 71))	('TSG', 'Gene', (13, 16))	('MetI', 'Var', (94, 98))	('MetI', 'Chemical', '-', (94, 98))
24977	23154831	The most frequently hypermethylated genes were DCR2 (eight tumors), P16 (11 tumors (AG-6 exhibited elevated MetI, but was nonetheless.	('P16', 'Gene', (68, 71))	('P16', 'Gene', '1029', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('DCR2', 'Gene', (47, 51))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', (59, 65))	('elevated', 'PosReg', (99, 107))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('hypermethylated', 'Var', (20, 35))	('MetI', 'MPA', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MetI', 'Chemical', '-', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('DCR2', 'Gene', '8793', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
24978	23154831	Five percentage points too low to reach cutoff)), and RASSF1A (nine tumors), indicating that epigenetic modifications of these genes is an important facet of malignancy in paragangliomas.	('RASSF1A', 'Gene', '11186', (54, 61))	('malignancy in paragangliomas', 'Disease', 'MESH:C565335', (158, 186))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('paraganglioma', 'Phenotype', 'HP:0002668', (172, 185))	('paragangliomas', 'Phenotype', 'HP:0002668', (172, 186))	('epigenetic modifications', 'Var', (93, 117))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RASSF1A', 'Gene', (54, 61))	('malignancy in paragangliomas', 'Disease', (158, 186))
24979	23154831	We found a very strong association between SDHB mutation and hypermethylation of several TSGs in the novel Series A (Fig.	('SDHB', 'Gene', '6390', (43, 47))	('hypermethylation', 'MPA', (61, 77))	('TSG', 'Gene', (89, 92))	('mutation', 'Var', (48, 56))	('SDHB', 'Gene', (43, 47))	('TSG', 'Gene', '57045', (89, 92))
24981	23154831	2, grouped by syndrome/mutation, further highlight the over-representation of TSG CpG methylation coinciding with SDHB mutation compared with other genetic variants.	('mutation', 'Var', (119, 127))	('over-representation', 'PosReg', (55, 74))	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('TSG', 'Gene', (78, 81))	('TSG', 'Gene', '57045', (78, 81))
24982	23154831	P16 hypermethylation was most frequently seen with and was unequivocally associated with SDHB mutation (Fig.	('SDHB', 'Gene', (89, 93))	('P16', 'Gene', (0, 3))	('associated', 'Reg', (73, 83))	('SDHB', 'Gene', '6390', (89, 93))	('P16', 'Gene', '1029', (0, 3))	('mutation', 'Var', (94, 102))	('hypermethylation', 'Var', (4, 20))
24983	23154831	Furthermore, for the paraganglioma AG-6 with SDHB mutation, the MetI for P16 was elevated and close to the nominal 10% cutoff value, and hypermethylation above cutoff was observed for individual CpGs.	('paraganglioma', 'Disease', 'MESH:D010235', (21, 34))	('MetI', 'MPA', (64, 68))	('MetI', 'Chemical', '-', (64, 68))	('elevated', 'PosReg', (81, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (21, 34))	('P16', 'Gene', (73, 76))	('SDHB', 'Gene', '6390', (45, 49))	('paraganglioma', 'Disease', (21, 34))	('SDHB', 'Gene', (45, 49))	('P16', 'Gene', '1029', (73, 76))	('mutation', 'Var', (50, 58))
24986	23154831	By contrast, MetI levels for P16 were very low (1 or 2%) in tumors without detectable SDHB mutation.	('P16', 'Gene', (29, 32))	('MetI levels', 'MPA', (13, 24))	('SDHB', 'Gene', (86, 90))	('mutation', 'Var', (91, 99))	('P16', 'Gene', '1029', (29, 32))	('MetI', 'Chemical', '-', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('SDHB', 'Gene', '6390', (86, 90))	('tumors', 'Disease', (60, 66))
24987	23154831	Figure 3 further illustrates that in the combined Series A+B, concerted epigenetic events occur in relation to SDHB mutation but are not observed in association with other predisposing syndromes.	('mutation', 'Var', (116, 124))	('SDHB', 'Gene', (111, 115))	('SDHB', 'Gene', '6390', (111, 115))
24988	23154831	Survival analyses of combined Series A+B demonstrated significantly shorter survival in patients with primary tumors that displayed P16 MetI >10% compared with those with MetI below cutoff (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (102, 116))	('MetI >10%', 'Var', (136, 145))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('MetI', 'Chemical', '-', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('P16', 'Gene', '1029', (132, 135))	('MetI', 'Chemical', '-', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('P16', 'Gene', (132, 135))	('primary tumors', 'Disease', (102, 116))	('shorter', 'NegReg', (68, 75))
24989	23154831	In Series A as well as in combined Series A+B, hypermethylation of TSGs was found in association with paraganglioma tumor type, development of metastases, and mutation of the predisposing gene SDHB.	('SDHB', 'Gene', '6390', (193, 197))	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('TSG', 'Gene', (67, 70))	('SDHB', 'Gene', (193, 197))	('association', 'Reg', (85, 96))	('TSG', 'Gene', '57045', (67, 70))	('mutation', 'Var', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('paraganglioma tumor', 'Disease', 'MESH:D010235', (102, 121))	('metastases', 'Disease', (143, 153))	('hypermethylation', 'Var', (47, 63))	('paraganglioma tumor', 'Disease', (102, 121))
24990	23154831	While metastasis and SDHB mutations are known to be correlated, the question arises whether hypermethylation also occurs in SDHB wild-type metastatic tumors.	('SDHB', 'Gene', (124, 128))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SDHB', 'Gene', (21, 25))	('SDHB', 'Gene', '6390', (124, 128))
24992	23154831	Among these, only two paragangliomas had hypermethylation.	('hypermethylation', 'Var', (41, 57))	('paragangliomas', 'Disease', 'MESH:D010235', (22, 36))	('paragangliomas', 'Disease', (22, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))
24993	23154831	Significant methylation in RASSF1A alone was detected when analyzing TSG methylation in all metastatic tumors without apparent SDHB involvement (P>=0.02).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RASSF1A', 'Gene', (27, 34))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('TSG', 'Gene', '57045', (69, 72))	('SDHB', 'Gene', '6390', (127, 131))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('SDHB', 'Gene', (127, 131))	('RASSF1A', 'Gene', '11186', (27, 34))	('methylation', 'Var', (12, 23))	('TSG', 'Gene', (69, 72))
24994	23154831	Hence, increased TSG methylation does not appear to be frequently involved in sporadic, malignant cases or in conjunction with other predisposing mutations.	('TSG', 'Gene', (17, 20))	('increased', 'PosReg', (7, 16))	('TSG', 'Gene', '57045', (17, 20))	('methylation', 'Var', (21, 32))
24995	23154831	However, it is presently unknown whether metastatic tumors with mutations other than SDHB harbor TSG methylation.	('harbor', 'Reg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TSG', 'Gene', (97, 100))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SDHB', 'Gene', '6390', (85, 89))	('TSG', 'Gene', '57045', (97, 100))	('SDHB', 'Gene', (85, 89))	('mutations', 'Var', (64, 73))
24997	23154831	SDHB mutations are known to be frequently associated with malignant forms of paraganglioma, raising questions about causes and consequences in relation to these abnormalities and their clinical effects.	('clinical', 'Species', '191496', (185, 193))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('associated', 'Reg', (42, 52))	('paraganglioma', 'Disease', (77, 90))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('paraganglioma', 'Disease', 'MESH:D010235', (77, 90))	('SDHB', 'Gene', (0, 4))
24998	23154831	In four cases with constitutional SDHB mutations in Series B, TSG hypermethylation was absent in constitutional DNA - indicating that the TSG hypermethylation is tumor-specific - and first observed in primary tumors in conjunction with loss of 1p encompassing the SDHB gene locus (Fig.	('SDHB', 'Gene', (264, 268))	('TSG', 'Gene', (138, 141))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('TSG', 'Gene', '57045', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (162, 167))	('TSG', 'Gene', '57045', (138, 141))	('mutations', 'Var', (39, 48))	('primary tumors', 'Disease', (201, 215))	('SDHB', 'Gene', '6390', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('SDHB', 'Gene', (34, 38))	('SDHB', 'Gene', '6390', (264, 268))	('TSG', 'Gene', (62, 65))	('primary tumors', 'Disease', 'MESH:D009369', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
24999	23154831	Furthermore, acquired TSG hypermethylation was observed in four malignant primary paragangliomas before the development of metastasis and one case where metastasis had not developed before surgery (BS-10; Fig.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('TSG', 'Gene', (22, 25))	('observed', 'Reg', (47, 55))	('hypermethylation', 'Var', (26, 42))	('TSG', 'Gene', '57045', (22, 25))	('paragangliomas', 'Disease', 'MESH:D010235', (82, 96))	('paragangliomas', 'Disease', (82, 96))
25000	23154831	Importantly, these findings implicate that TSG hypermethylation is not a secondary consequence of a malignant tumor state.	('malignant tumor', 'Disease', (100, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('malignant tumor', 'Disease', 'MESH:D018198', (100, 115))	('TSG', 'Gene', (43, 46))	('TSG', 'Gene', '57045', (43, 46))	('hypermethylation', 'Var', (47, 63))
25002	23154831	However, it is a theoretical possibility that heterozygous SDHB inactivation could lead to TSG hypermethylation in cancer progenitor cells of the target tissue and subsequently be selected for at tumor transformation.	('inactivation', 'Var', (64, 76))	('cancer', 'Disease', (115, 121))	('tumor', 'Disease', (196, 201))	('hypermethylation', 'MPA', (95, 111))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TSG', 'Gene', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('SDHB', 'Gene', '6390', (59, 63))	('lead to', 'Reg', (83, 90))	('SDHB', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('TSG', 'Gene', '57045', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
25003	23154831	The data presented here strongly indicate that SDHB inactivation and TSG CpG hypermethylation are associated; an attractive possibility being that SDHB inactivation in fact causes TSG hypermethylation.	('TSG', 'Gene', (180, 183))	('TSG', 'Gene', '57045', (69, 72))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('inactivation', 'Var', (152, 164))	('SDHB', 'Gene', '6390', (147, 151))	('SDHB', 'Gene', (147, 151))	('TSG', 'Gene', '57045', (180, 183))	('causes', 'Reg', (173, 179))	('TSG', 'Gene', (69, 72))
25009	23154831	This specific methylative inactivation of apoptotic and antiproliferative genes might instead mirror a physiological attempt to counter the state of pseudo-hypoxia, induced by SDH dysfunction and described in and.	('hypoxia', 'Disease', (156, 163))	('methylative', 'Var', (14, 25))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('SDH dysfunction', 'Disease', (176, 191))	('SDH dysfunction', 'Disease', 'MESH:D006331', (176, 191))	('inactivation', 'NegReg', (26, 38))
25010	23154831	Indeed, recent immunohistochemical studies have shown that tumors from patients with SDHB, SDHC, and SDHD mutations lack SDHB immunoreactivity and that SDH activity is abolished in SDHB- and SDHD-mutated cases but not in connection with SDHC.	('lack', 'NegReg', (116, 120))	('SDH', 'Gene', (91, 94))	('SDHD', 'Gene', '6392', (191, 195))	('SDHB', 'Gene', (121, 125))	('SDHC', 'Gene', '6391', (91, 95))	('SDH', 'Gene', '6390', (121, 124))	('patients', 'Species', '9606', (71, 79))	('SDH', 'Gene', '6390', (191, 194))	('SDHC', 'Gene', (237, 241))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('SDH', 'Gene', '6390', (152, 155))	('SDHB', 'Gene', '6390', (181, 185))	('SDH', 'Gene', '6390', (237, 240))	('SDHD', 'Gene', (191, 195))	('abolished', 'NegReg', (168, 177))	('SDHB', 'Gene', '6390', (85, 89))	('SDH', 'Gene', (121, 124))	('SDH', 'Gene', '6390', (85, 88))	('SDHB', 'Gene', (181, 185))	('SDH', 'Gene', (191, 194))	('SDH', 'Gene', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('SDH', 'Gene', '6390', (181, 184))	('SDHC', 'Gene', (91, 95))	('SDHD', 'Gene', '6392', (101, 105))	('SDH', 'Gene', (237, 240))	('activity', 'MPA', (156, 164))	('SDH', 'Gene', '6390', (101, 104))	('SDH', 'Gene', '6390', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('SDHB', 'Gene', (85, 89))	('SDHC', 'Gene', '6391', (237, 241))	('SDHB', 'Gene', '6390', (121, 125))	('immunoreactivity', 'MPA', (126, 142))	('SDHD', 'Gene', (101, 105))	('SDH', 'Gene', (85, 88))	('SDH', 'Gene', (181, 184))	('tumors', 'Disease', (59, 65))	('mutations', 'Var', (106, 115))	('SDH', 'Gene', (101, 104))
25012	23154831	Based on the results, the authors recommended that screening for SDH gene mutations should be carried out in cases with negative SDHB immunohistochemistry.	('SDH', 'Gene', '6390', (65, 68))	('SDH', 'Gene', (129, 132))	('SDHB', 'Gene', '6390', (129, 133))	('SDHB', 'Gene', (129, 133))	('mutations', 'Var', (74, 83))	('SDH', 'Gene', (65, 68))	('SDH', 'Gene', '6390', (129, 132))
25015	23154831	The findings presented here suggest that methylation quantification for P16 promoter CpGs could be a valuable clinical tool in the assessment of paragangliomas and that cases with P16 hypermethylation should be genetically screened for SDHB mutations.	('P16', 'Gene', '1029', (72, 75))	('clinical', 'Species', '191496', (110, 118))	('SDHB', 'Gene', '6390', (236, 240))	('paragangliomas', 'Disease', (145, 159))	('hypermethylation', 'Var', (184, 200))	('paragangliomas', 'Disease', 'MESH:D010235', (145, 159))	('paragangliomas', 'Phenotype', 'HP:0002668', (145, 159))	('P16', 'Gene', (180, 183))	('SDHB', 'Gene', (236, 240))	('P16', 'Gene', (72, 75))	('paraganglioma', 'Phenotype', 'HP:0002668', (145, 158))	('P16', 'Gene', '1029', (180, 183))	('mutations', 'Var', (241, 250))
25016	23154831	In summary, our results associated mutation of the SDHB gene to alterations in TSG methylation in paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (98, 112))	('TSG', 'Gene', (79, 82))	('associated', 'Reg', (24, 34))	('methylation', 'MPA', (83, 94))	('TSG', 'Gene', '57045', (79, 82))	('paragangliomas', 'Disease', 'MESH:D010235', (98, 112))	('alterations', 'Reg', (64, 75))	('SDHB', 'Gene', '6390', (51, 55))	('mutation', 'Var', (35, 43))	('paragangliomas', 'Disease', (98, 112))	('SDHB', 'Gene', (51, 55))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))
25017	23154831	We here propose that epigenetic inactivation of TSGs is an important component in familial paraganglioma syndrome and suggest inquiries into the use of demethylating agents as a means to combat malignant paragangliomas.	('TSG', 'Gene', (48, 51))	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (194, 218))	('epigenetic inactivation', 'Var', (21, 44))	('familial paraganglioma syndrome', 'Disease', 'MESH:D010235', (82, 113))	('TSG', 'Gene', '57045', (48, 51))	('component', 'Reg', (69, 78))	('paragangliomas', 'Phenotype', 'HP:0002668', (204, 218))	('malignant paragangliomas', 'Disease', (194, 218))	('paraganglioma', 'Phenotype', 'HP:0002668', (204, 217))	('familial paraganglioma syndrome', 'Disease', (82, 113))
25019	23154831	We further propose the use of P16 methylation assessment as an additive tool in identification of patients for SDHB mutation screenings.	('SDHB', 'Gene', (111, 115))	('P16', 'Gene', '1029', (30, 33))	('mutation', 'Var', (116, 124))	('patients', 'Species', '9606', (98, 106))	('P16', 'Gene', (30, 33))	('SDHB', 'Gene', '6390', (111, 115))
25145	23226643	Excision of the pheochromocytoma would lower the blood pressure, thus significantly decreasing the blood flow across the stenotic lesion.	('decreasing', 'NegReg', (84, 94))	('lower the blood pressure', 'Phenotype', 'HP:0002615', (39, 63))	('pheochromocytoma', 'Disease', (16, 32))	('stenotic lesion', 'Disease', 'MESH:D051437', (121, 136))	('pheochromocytoma', 'Disease', 'MESH:D010673', (16, 32))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (16, 32))	('stenotic lesion', 'Disease', (121, 136))	('blood pressure', 'MPA', (49, 63))	('Excision', 'Var', (0, 8))	('lower', 'NegReg', (39, 44))
25217	22691888	The study of families with genetically inherited mutations in pheochromocytoma susceptibility genes has greatly enhanced our understanding of the pathophysiology and mechanisms of oncogenesis of the disease, and consequently changed our clinical approach.	('enhanced', 'PosReg', (112, 120))	('pheochromocytoma', 'Disease', 'MESH:D010673', (62, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('oncogenesis of the disease', 'Disease', 'MESH:D063646', (180, 206))	('mutations', 'Var', (49, 58))	('changed', 'Reg', (225, 232))	('oncogenesis of the disease', 'Disease', (180, 206))	('pheochromocytoma', 'Disease', (62, 78))
25218	22691888	Such mutations are responsible for the dysregulation of metabolic pathways involved in oxygen and nutrient sensing, apoptosis regulation, cell proliferation, migration and invasion.	('metabolic pathways', 'Pathway', (56, 74))	('apoptosis', 'CPA', (116, 125))	('responsible', 'Reg', (19, 30))	('mutations', 'Var', (5, 14))	('invasion', 'CPA', (172, 180))	('oxygen', 'Chemical', 'MESH:D010100', (87, 93))	('cell proliferation', 'CPA', (138, 156))	('migration', 'CPA', (158, 167))
25230	22691888	One cluster is the tumors with VHL and SDHx mutant genes and the other cluster contains tumors with RET and NF1 mutant genes.	('VHL', 'Gene', '7428', (31, 34))	('tumors', 'Disease', (19, 25))	('mutant genes', 'Var', (44, 56))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('SDHx', 'Chemical', '-', (39, 43))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('SDHx', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutant', 'Var', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('VHL', 'Gene', (31, 34))	('NF1', 'Gene', (108, 111))
25232	22691888	As newer genes were discovered further microarray studies tried to classify them into these two clusters and mutations in KIF1Bbeta, TMEM127 and MAX clustered with RET/NF1 and SDHAF2 and SDHA clustered with SDHx/VHL.	('SDHx', 'Chemical', '-', (207, 211))	('SDHA', 'Gene', '6389', (176, 180))	('SDHA', 'Gene', '6389', (187, 191))	('SDHAF2', 'Gene', (176, 182))	('KIF1Bbeta', 'Gene', (122, 131))	('MAX', 'Gene', (145, 148))	('MAX', 'Gene', '4149', (145, 148))	('SDHAF2', 'Gene', '54949', (176, 182))	('SDHA', 'Gene', (176, 180))	('SDHA', 'Gene', (187, 191))	('VHL', 'Gene', (212, 215))	('clustered', 'Reg', (149, 158))	('TMEM127', 'Gene', (133, 140))	('mutations', 'Var', (109, 118))	('TMEM127', 'Gene', '55654', (133, 140))	('VHL', 'Gene', '7428', (212, 215))
25236	22691888	The basis underlying this association seems to be confirmed with the pseudo hypoxia hypothesis for tumorigenesis caused due to VHL and SDHx mutations.	('tumor', 'Disease', (99, 104))	('SDHx', 'Chemical', '-', (135, 139))	('hypoxia', 'Disease', (76, 83))	('VHL', 'Gene', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('VHL', 'Gene', '7428', (127, 130))	('mutations', 'Var', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('hypoxia', 'Disease', 'MESH:D000860', (76, 83))	('SDHx', 'Gene', (135, 139))
25237	22691888	Mutations in these genes lead to accumulation and stabilization of hypoxia inducible factor alpha.	('hypoxia', 'Disease', (67, 74))	('hypoxia', 'Disease', 'MESH:D000860', (67, 74))	('Mutations', 'Var', (0, 9))	('stabilization', 'MPA', (50, 63))	('accumulation', 'PosReg', (33, 45))
25241	22691888	If the VHL gene is mutated the protein is not formed and HIF-alpha cannot be degraded and it accumulates.	('accumulates', 'PosReg', (93, 104))	('VHL', 'Gene', '7428', (7, 10))	('VHL', 'Gene', (7, 10))	('mutated', 'Var', (19, 26))
25242	22691888	Succinate dehydrogenase enzymes convert succinate to fumarate and its mutation leads to accumulation of succinate.	('succinate', 'Chemical', 'MESH:D019802', (104, 113))	('fumarate', 'Chemical', 'MESH:D005650', (53, 61))	('leads to', 'Reg', (79, 87))	('Succinate dehydrogenase', 'Gene', (0, 23))	('succinate', 'Chemical', 'MESH:D019802', (40, 49))	('mutation', 'Var', (70, 78))	('succinate', 'MPA', (104, 113))	('Succinate dehydrogenase', 'Gene', '6390', (0, 23))	('accumulation', 'PosReg', (88, 100))
25244	22691888	Therefore VHL and SDHx mutations both lead to induction of genes that would have also been induced via hypoxia and lead to tumor development by different mechanisms through the same pathway.	('tumor', 'Disease', (123, 128))	('SDHx', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('mutations', 'Var', (23, 32))	('induction', 'PosReg', (46, 55))	('VHL', 'Gene', (10, 13))	('hypoxia', 'Disease', (103, 110))	('SDHx', 'Chemical', '-', (18, 22))	('VHL', 'Gene', '7428', (10, 13))	('hypoxia', 'Disease', 'MESH:D000860', (103, 110))
25245	22691888	A mutation in the prolyl hydroxylase domain-2 (PHD2) gene has recently been implicated in a case of recurrent paragangliomas and erythrocytosis.	('paragangliomas and erythrocytosis', 'Disease', 'MESH:D011086', (110, 143))	('mutation', 'Var', (2, 10))	('prolyl hydroxylase domain-2', 'Gene', (18, 45))	('PHD2', 'Gene', (47, 51))	('prolyl hydroxylase domain-2', 'Gene', '54583', (18, 45))	('PHD2', 'Gene', '54583', (47, 51))	('erythrocytosis', 'Phenotype', 'HP:0001901', (129, 143))	('paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('paragangliomas', 'Phenotype', 'HP:0002668', (110, 124))	('implicated in', 'Reg', (76, 89))
25246	22691888	This mutation affects PHD2 function and stabilizes HIF-alpha proteins.	('function', 'MPA', (27, 35))	('PHD2', 'Gene', '54583', (22, 26))	('PHD2', 'Gene', (22, 26))	('HIF-alpha proteins', 'Protein', (51, 69))	('affects', 'Reg', (14, 21))	('stabilizes', 'MPA', (40, 50))	('mutation', 'Var', (5, 13))
25247	22691888	Also loss of heterozygosity could be indicative that the PHD2 could be a tumor-suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PHD2', 'Gene', '54583', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PHD2', 'Gene', (57, 61))	('tumor', 'Disease', (73, 78))	('loss', 'Var', (5, 9))
25255	22691888	More recently, pheochromocytoma susceptibility has been associated with mutations in the succinate dehydrogenase (SDH) gene.	('mutations', 'Var', (72, 81))	('succinate dehydrogenase', 'Gene', '6390', (89, 112))	('SDH', 'Gene', '6390', (114, 117))	('pheochromocytoma', 'Disease', (15, 31))	('succinate dehydrogenase', 'Gene', (89, 112))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (15, 31))	('associated', 'Reg', (56, 66))	('pheochromocytoma', 'Disease', 'MESH:D010673', (15, 31))	('SDH', 'Gene', (114, 117))
25259	22691888	In particular mutation in the SDHB subunit has been associated with a high likelihood of malignancy.	('malignancy', 'Disease', (89, 99))	('associated', 'Reg', (52, 62))	('mutation', 'Var', (14, 22))	('SDHB', 'Gene', '6390', (30, 34))	('SDHB', 'Gene', (30, 34))	('malignancy', 'Disease', 'MESH:D009369', (89, 99))
25264	22691888	Shortly after, mutations in genes that code for sub-units B (SDHB) and C (SDHC) were identified as genes of susceptibility.	('mutations', 'Var', (15, 24))	('SDHB', 'Gene', '6390', (61, 65))	('SDHB', 'Gene', (61, 65))	('SDHC', 'Gene', (74, 78))	('SDHC', 'Gene', '6391', (74, 78))
25265	22691888	The familial paragangliomas syndromes (PGL) type 1 to 4 have been found to be associated with gene mutations in these SDH subunits namely - PGL-1 (SDHD), PGL-2 (SDHAF2/SDH5), PGL-3 (SDHC) and PGL-4 (SDHB).	('SDH', 'Gene', (147, 150))	('SDHC', 'Gene', (182, 186))	('PGL-3', 'Gene', '6391', (175, 180))	('SDH5', 'Gene', (168, 172))	('SDHB', 'Gene', (199, 203))	('SDH', 'Gene', '6390', (182, 185))	('SDH', 'Gene', '6390', (199, 202))	('SDHAF2', 'Gene', '54949', (161, 167))	('SDHAF2', 'Gene', (161, 167))	('SDH', 'Gene', (161, 164))	('SDH', 'Gene', (168, 171))	('PGL-2', 'Gene', (154, 159))	('familial paragangliomas syndromes', 'Disease', (4, 37))	('SDH', 'Gene', '6390', (118, 121))	('SDH', 'Gene', '6390', (161, 164))	('PGL-4', 'Gene', '6390', (192, 197))	('PGL-3', 'Gene', (175, 180))	('SDH5', 'Gene', '54949', (168, 172))	('familial paragangliomas syndromes', 'Disease', 'MESH:D010235', (4, 37))	('associated', 'Reg', (78, 88))	('SDH', 'Gene', (182, 185))	('paraganglioma', 'Phenotype', 'HP:0002668', (13, 26))	('paragangliomas', 'Phenotype', 'HP:0002668', (13, 27))	('SDH', 'Gene', (199, 202))	('SDHD', 'Gene', '6392', (147, 151))	('SDHC', 'Gene', '6391', (182, 186))	('SDH', 'Gene', (118, 121))	('SDH', 'Gene', '6390', (147, 150))	('mutations', 'Var', (99, 108))	('SDHB', 'Gene', '6390', (199, 203))	('SDHD', 'Gene', (147, 151))	('SDH', 'Gene', '6390', (168, 171))	('PGL-4', 'Gene', (192, 197))	('PGL-2', 'Gene', '54949', (154, 159))
25266	22691888	Missense, frame-shift and nonsense mutations predisposing to pheochromocytoma have been identified in all the subunits of the SDH complex, including more recently in the SDHA subunit and in the SDH5/SDHAF2 gene, identified in patients with head and neck paragangliomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (254, 267))	('paragangliomas', 'Phenotype', 'HP:0002668', (254, 268))	('SDHA', 'Gene', '6389', (170, 174))	('SDH5', 'Gene', '54949', (194, 198))	('pheochromocytoma', 'Disease', 'MESH:D010673', (61, 77))	('Missense', 'Var', (0, 8))	('SDH', 'Gene', (170, 173))	('SDHAF2', 'Gene', (199, 205))	('SDH', 'Gene', (194, 197))	('SDH', 'Gene', '6390', (199, 202))	('neck paragangliomas', 'Disease', (249, 268))	('SDHAF2', 'Gene', '54949', (199, 205))	('SDHA', 'Gene', (199, 203))	('pheochromocytoma', 'Disease', (61, 77))	('frame-shift', 'Var', (10, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (61, 77))	('patients', 'Species', '9606', (226, 234))	('SDHA', 'Gene', '6389', (199, 203))	('SDH', 'Gene', '6390', (126, 129))	('SDH', 'Gene', (199, 202))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (240, 268))	('neck paragangliomas', 'Disease', 'MESH:D010235', (249, 268))	('SDH5', 'Gene', (194, 198))	('SDH', 'Gene', (126, 129))	('SDH', 'Gene', '6390', (194, 197))	('SDH', 'Gene', '6390', (170, 173))	('SDHA', 'Gene', (170, 174))
25269	22691888	RET and NF1 mutations lead to activation of the RAS/RAF/MAPK and the PI3K/AKT/mTOR signaling pathways.	('NF1', 'Gene', (8, 11))	('mutations', 'Var', (12, 21))	('AKT', 'Gene', '207', (74, 77))	('activation', 'PosReg', (30, 40))	('RAF', 'Gene', '22882', (52, 55))	('RET', 'Gene', (0, 3))	('RAF', 'Gene', (52, 55))	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (78, 82))	('AKT', 'Gene', (74, 77))
25270	22691888	TMEM127 mutant tumors clusters with the RET/NF1 group and they enhance mTOR activity independent of the above two kinase pathways.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('TMEM127', 'Gene', '55654', (0, 7))	('enhance', 'PosReg', (63, 70))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('mutant', 'Var', (8, 14))	('mTOR', 'Gene', '2475', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mTOR', 'Gene', (71, 75))	('TMEM127', 'Gene', (0, 7))	('tumors', 'Disease', (15, 21))
25271	22691888	Microarray expression analysis of KIF1Bbeta mutant tumors also groups with RET/NF1 tumors though its potential role in kinase pathways is not yet known.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('NF1 tumors', 'Disease', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('KIF1Bbeta', 'Gene', (34, 43))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('NF1 tumors', 'Disease', 'MESH:C537392', (79, 89))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('groups', 'Reg', (63, 69))	('mutant', 'Var', (44, 50))
25272	22691888	While the recently discovered MAX gene mutation, which leads to dysregulation of the MYC-MAX-MXD1 network, is grouped with this cluster for its connection with mTOR pathway.	('mutation', 'Var', (39, 47))	('MXD1', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (160, 164))	('dysregulation', 'MPA', (64, 77))	('mTOR', 'Gene', (160, 164))	('MAX', 'Gene', (30, 33))	('MXD1', 'Gene', '4084', (93, 97))	('MAX', 'Gene', '4149', (30, 33))	('MAX', 'Gene', '4149', (89, 92))	('MAX', 'Gene', (89, 92))
25273	22691888	(Figure 2) The study of families with MEN2 A and B, which develop pheochromocytomas among other tumors, allowed the discovery of mutations in the RET (Rearranged during Transfection) proto-oncogene.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (66, 83))	('Rearranged during Transfection', 'Gene', '5979', (151, 181))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (66, 82))	('MEN2 A and B', 'Gene', '5979', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutations', 'Var', (129, 138))	('tumors', 'Disease', (96, 102))	('pheochromocytomas', 'Disease', (66, 83))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('pheochromocytomas', 'Disease', 'MESH:D010673', (66, 83))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('RET', 'Gene', (146, 149))	('Rearranged during Transfection', 'Gene', (151, 181))
25281	22691888	Gain-of-function point mutations in RET, causing ligand-independent activation of the gene product, is the initial oncogenic event in the hereditary cancer syndrome multiple endocrine neoplasia type 2 (MEN 2), which recognize three subtypes based on clinical presentation: 1) MEN 2A; 2) MEN 2B; and 3) familial medullary thyroid carcinoma (FMTC).	('RET', 'Gene', (36, 39))	('MEN 2A', 'Gene', (276, 282))	('MEN 2A', 'Gene', '5979', (276, 282))	('hereditary cancer syndrome multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (138, 200))	('MEN', 'Species', '9606', (287, 290))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (321, 338))	('MEN', 'Species', '9606', (202, 205))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (311, 338))	('neoplasia', 'Phenotype', 'HP:0002664', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('point mutations', 'Var', (17, 32))	('Gain-of-function', 'PosReg', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('MEN 2B; and 3', 'Gene', '5979', (287, 300))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (321, 338))	('thyroid carcinoma', 'Disease', (321, 338))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (174, 193))	('MEN', 'Species', '9606', (276, 279))
25282	22691888	Trisomy 10 with duplication of the mutant RET allele, loss of wild-type RET allele and tandem duplication with amplification of the mutant RET, are among the "second hit" mechanisms identified that favor tumor development in these patients.	('RET', 'Gene', (139, 142))	('duplication', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('patients', 'Species', '9606', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutant', 'Var', (132, 138))	('favor', 'PosReg', (198, 203))	('tumor', 'Disease', (204, 209))	('RET', 'Gene', (42, 45))	('Trisomy', 'Disease', (0, 7))	('Trisomy', 'Disease', 'MESH:D014314', (0, 7))	('tandem duplication', 'Var', (87, 105))
25284	22691888	For example, in MEN 2A pheochromocytomas occur more frequently in patients with RET mutations in codon 634 and less frequently when the mutation involves codons 618, 620 or 791.	('MEN 2A', 'Gene', (16, 22))	('MEN 2A', 'Gene', '5979', (16, 22))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (23, 40))	('mutations in codon 634', 'Var', (84, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('pheochromocytomas', 'Disease', 'MESH:D010673', (23, 40))	('pheochromocytomas', 'Disease', (23, 40))	('patients', 'Species', '9606', (66, 74))
25285	22691888	Loss-of-function mutations in the RET gene are responsible for a different congenital disorder, known as Hirschsprung's disease (or aganglionic megacolon) in which normal enteric nerves are absent.	('Loss-of-function', 'NegReg', (0, 16))	('aganglionic megacolon', 'Phenotype', 'HP:0002251', (132, 153))	('congenital disorder', 'Disease', (75, 94))	('RET', 'Gene', (34, 37))	('congenital disorder', 'Disease', 'MESH:D000013', (75, 94))	("Hirschsprung's disease", 'Phenotype', 'HP:0002251', (105, 127))	("Hirschsprung's disease", 'Disease', (105, 127))	('mutations', 'Var', (17, 26))	("Hirschsprung's disease", 'Disease', 'MESH:D006627', (105, 127))
25286	22691888	Several groups have suggested that mutant RET in MEN 2B activates additional aberrant signaling pathways, which account for the more aggressive phenotype in patients with this syndrome compared to patients affected by MEN 2A.	('MEN 2B', 'Gene', '5979', (49, 55))	('activates', 'PosReg', (56, 65))	('MEN 2A', 'Gene', '5979', (218, 224))	('MEN 2A', 'Gene', (218, 224))	('patients', 'Species', '9606', (197, 205))	('mutant', 'Var', (35, 41))	('patients', 'Species', '9606', (157, 165))	('RET', 'Gene', (42, 45))	('MEN 2B', 'Gene', (49, 55))	('aberrant signaling pathways', 'Pathway', (77, 104))
25287	22691888	Interestingly, also RET mutations in MEN 2A occur mainly in the extracellular domain cysteine residue, causing alterations in receptor dimerization, while MEN 2B RET mutation are predominantly located in the intracellular domain, resulting in activation of different signaling pathways and consequent expression of different target genes.	('signaling pathways', 'Pathway', (267, 285))	('MEN 2B', 'Gene', '5979', (155, 161))	('receptor dimerization', 'MPA', (126, 147))	('MEN 2A', 'Gene', '5979', (37, 43))	('alterations', 'Reg', (111, 122))	('activation', 'PosReg', (243, 253))	('expression', 'MPA', (301, 311))	('mutations', 'Var', (24, 33))	('MEN 2B', 'Gene', (155, 161))	('cysteine', 'Chemical', 'MESH:D003545', (85, 93))	('MEN 2A', 'Gene', (37, 43))
25290	22691888	In patients with mutation in this gene, in conjunction with other tumors, pheochromocytoma is present in up to 5% of cases and it is frequently diagnosed later in life.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (17, 25))	('tumors', 'Disease', (66, 72))	('pheochromocytoma', 'Disease', (74, 90))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('pheochromocytoma', 'Disease', 'MESH:D010673', (74, 90))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('patients', 'Species', '9606', (3, 11))
25293	22691888	Studies on transgenic mice with NF1 mutations have clearly linked this gene with the development of pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (100, 116))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('linked', 'Reg', (59, 65))	('NF1', 'Gene', (32, 35))	('mutations', 'Var', (36, 45))	('pheochromocytoma', 'Disease', (100, 116))	('transgenic mice', 'Species', '10090', (11, 26))
25298	22691888	Interestingly, tumor samples from patient with TMEM127 mutations have an increased activation of mTORC1.	('mTORC1', 'Gene', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('patient', 'Species', '9606', (34, 41))	('tumor', 'Disease', (15, 20))	('mTORC1', 'Gene', '382056', (97, 103))	('TMEM127', 'Gene', (47, 54))	('TMEM127', 'Gene', '55654', (47, 54))	('activation', 'PosReg', (83, 93))
25299	22691888	Patients with TMEM127 mutation tend to have benign, bilateral adrenal pheochromocytomas; a clear association with development of other tumors in these patients still needs to be clarified.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (70, 87))	('TMEM127', 'Gene', (14, 21))	('mutation', 'Var', (22, 30))	('bilateral adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (52, 87))	('TMEM127', 'Gene', '55654', (14, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('patients', 'Species', '9606', (151, 159))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (135, 141))	('benign', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (62, 87))	('bilateral adrenal pheochromocytomas', 'Disease', (52, 87))
25300	22691888	were able to identify MAX gene mutations in three independent familial cases of pheochromocytoma; the inactivating nature of the germline mutation points to a tumor suppression function for this gene.	('pheochromocytoma', 'Disease', (80, 96))	('mutations', 'Var', (31, 40))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('pheochromocytoma', 'Disease', 'MESH:D010673', (80, 96))	('tumor', 'Disease', (159, 164))	('MAX', 'Gene', '4149', (22, 25))	('MAX', 'Gene', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
25305	22691888	According to this model the germline mutations in RET, VHL, NF1 and SDHx prevent apoptosis of the neuronal progenitor cells.	('RET', 'Gene', (50, 53))	('SDHx', 'Chemical', '-', (68, 72))	('SDHx', 'Gene', (68, 72))	('apoptosis of the neuronal progenitor cells', 'CPA', (81, 123))	('germline mutations', 'Var', (28, 46))	('NF1', 'Gene', (60, 63))	('VHL', 'Gene', (55, 58))	('prevent', 'NegReg', (73, 80))	('VHL', 'Gene', '7428', (55, 58))
25307	22691888	The recognition that germline mutations in the genes described above are important in the pathogenesis and clinical presentation of patients with pheochromocytoma, provide a solid justification for genetic testing as an important part of patient management.	('important', 'Reg', (73, 82))	('pheochromocytoma', 'Disease', 'MESH:D010673', (146, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (146, 162))	('germline mutations', 'Var', (21, 39))	('patient', 'Species', '9606', (132, 139))	('patient', 'Species', '9606', (238, 245))	('patients', 'Species', '9606', (132, 140))	('pheochromocytoma', 'Disease', (146, 162))
25324	22691888	Phenoxybenzamine is associated with elevation in norepinephrine and normetanephrine and can lead to high false positive rates.	('Phenoxybenzamine', 'Var', (0, 16))	('normetanephrine', 'MPA', (68, 83))	('elevation', 'PosReg', (36, 45))	('norepinephrine', 'MPA', (49, 63))	('normetanephrine', 'Chemical', 'MESH:D009647', (68, 83))	('Phenoxybenzamine', 'Chemical', 'MESH:D010643', (0, 16))	('norepinephrine', 'Chemical', 'MESH:D009638', (49, 63))
25332	22691888	Such patients have increased likelihood of SDHB positivity, tumor size (>5 cm) and extra-adrenal location of their tumor all predictors for higher likelihood of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (5, 13))	('malignancy', 'Disease', (161, 171))	('SDHB', 'Gene', '6390', (43, 47))	('positivity', 'Var', (48, 58))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('increased', 'PosReg', (19, 28))	('SDHB', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
25336	22691888	Since clonidine decreases resting plasma catecholamines by inhibition of centrally mediated stimulatory adrenergic influences it would not be expected to suppress catecholamine release in pheochromocytoma.	('inhibition', 'NegReg', (59, 69))	('catecholamine', 'Chemical', 'MESH:D002395', (41, 54))	('resting plasma catecholamines', 'MPA', (26, 55))	('pheochromocytoma', 'Disease', (188, 204))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (188, 204))	('catecholamine', 'Chemical', 'MESH:D002395', (163, 176))	('clonidine', 'Var', (6, 15))	('pheochromocytoma', 'Disease', 'MESH:D010673', (188, 204))	('catecholamines', 'Chemical', 'MESH:D002395', (41, 55))	('decreases', 'NegReg', (16, 25))	('clonidine', 'Chemical', 'MESH:D003000', (6, 15))	('catecholamine', 'MPA', (163, 176))
25358	22691888	MIBG scanning may be carried out with either 123I or 131I-MIBG scanning with 123I offers a number of advantages over 131I like much better sensitivity, additional utility for imaging by SPECT and shorter half-life hence higher doses can be used.	('MIBG', 'Chemical', 'MESH:D019797', (0, 4))	('123I', 'Chemical', 'MESH:C000614958', (77, 81))	('123I', 'Var', (77, 81))	('MIBG', 'Chemical', 'MESH:D019797', (58, 62))	('131I', 'Chemical', 'MESH:C000614965', (117, 121))	('123I', 'Chemical', 'MESH:C000614958', (45, 49))	('better', 'PosReg', (132, 138))	('131I', 'Chemical', 'MESH:C000614965', (53, 57))	('131I-MIBG', 'Chemical', 'MESH:D019797', (53, 62))
25364	22691888	Adrenal tumors associated with a VHL gene mutation are best imaged by 18F-DA PET.	('Adrenal tumors', 'Disease', 'MESH:D000310', (0, 14))	('VHL', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('associated', 'Reg', (15, 25))	('VHL', 'Gene', '7428', (33, 36))	('mutation', 'Var', (42, 50))	('Adrenal tumors', 'Disease', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('18F-DA', 'Chemical', '-', (70, 76))
25372	22691888	About 40-50% patients with malignant pheochromocytoma will have mutations in SDHB (~35 %), VHL (~5%) and SDHD (~1%) and hence should be offered testing for at least these 3 genes.	('SDHD', 'Gene', '6392', (105, 109))	('VHL', 'Gene', (91, 94))	('SDHD', 'Gene', (105, 109))	('SDHB', 'Gene', '6390', (77, 81))	('patients', 'Species', '9606', (13, 21))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (37, 53))	('VHL', 'Gene', '7428', (91, 94))	('SDHB', 'Gene', (77, 81))	('mutations', 'Var', (64, 73))	('malignant pheochromocytoma', 'Disease', (27, 53))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (27, 53))
25374	22691888	In an individual with SDHB positive immunohistochemistry staining one should test for VHL, RET or NF1 mutations.	('RET', 'Gene', (91, 94))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('NF1', 'Gene', (98, 101))	('mutations', 'Var', (102, 111))	('VHL', 'Gene', (86, 89))	('test', 'Reg', (77, 81))	('VHL', 'Gene', '7428', (86, 89))
25376	22691888	SDHB immunohistochemistry has a sensitivity of about 100% and a specificity of about 84% in a prospective series to detect the presence of an SDH mutation.	('SDH', 'Gene', '6390', (142, 145))	('SDH', 'Gene', (0, 3))	('SDHB', 'Gene', '6390', (0, 4))	('SDH', 'Gene', (142, 145))	('mutation', 'Var', (146, 154))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))
25377	22691888	SDHA immunohistochemistry has recently been shown to reveal the presence of SDHA mutations in about 3% of patients who are affected by apparently sporadic tumors.	('SDHA', 'Gene', '6389', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SDHA', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('SDHA', 'Gene', (76, 80))	('apparently sporadic tumors', 'Disease', 'MESH:C536023', (135, 161))	('SDHA', 'Gene', '6389', (0, 4))	('apparently sporadic tumors', 'Disease', (135, 161))	('mutations', 'Var', (81, 90))	('patients', 'Species', '9606', (106, 114))	('presence', 'Reg', (64, 72))
25399	22691888	Metyrosine a competitive inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis decreases production of catecholamines thus making pre and intra operative blood pressure control easier.	('catecholamine', 'Chemical', 'MESH:D002395', (134, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (38, 46))	('catecholamines', 'Chemical', 'MESH:D002395', (134, 148))	('decreases', 'NegReg', (110, 119))	('catecholamine', 'Chemical', 'MESH:D002395', (86, 99))	('tyrosine', 'Chemical', 'MESH:D014443', (2, 10))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))	('production of catecholamines', 'MPA', (120, 148))
25435	22691888	CVD therapy can cause a hypertensive crisis due to catecholamine release during treatment and hence patients should be blocked beforehand.	('hypertensive', 'Disease', 'MESH:D006973', (24, 36))	('hypertensive', 'Disease', (24, 36))	('catecholamine release', 'MPA', (51, 72))	('catecholamine', 'Chemical', 'MESH:D002395', (51, 64))	('patients', 'Species', '9606', (100, 108))	('CVD therapy', 'Var', (0, 11))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (24, 43))	('cause', 'Reg', (16, 21))
25451	22691888	Symptomatic improvement may occur with all radiolabeled somatostatin analogues though tumor size reduction is achieved with 90Y and 177Lu.	('reduction', 'NegReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('90Y', 'Var', (124, 127))	('177Lu', 'Var', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
25454	22691888	The median duration of the therapy response for [90Y-DOTA(0),Tyr(3)]octreotide is 30 months and for [177Lu-DOTA(0),Tyr(3)]octreotate it is more than 36 months.	('[177Lu-DOTA', 'Chemical', '-', (100, 111))	('octreotate', 'Chemical', '-', (122, 132))	('[90Y-DOTA', 'Chemical', '-', (48, 57))	('Tyr(3)]', 'Var', (61, 68))	('[90Y-DOTA', 'Var', (48, 57))	('octreotide', 'Chemical', 'MESH:D015282', (68, 78))	('Tyr', 'Chemical', 'MESH:D014443', (115, 118))	('Tyr', 'Chemical', 'MESH:D014443', (61, 64))
25459	19252526	VHL Type 2B gene mutation moderates HIF dosage in vitro and in vivo Von Hippel-Lindau (VHL) disease is caused by germline mutations in the VHL tumor suppressor gene, with Type 2B missense VHL mutations predisposing to renal cell carcinoma, hemangioblastoma, and pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (262, 278))	('missense', 'Var', (179, 187))	('VHL', 'Gene', (188, 191))	('mutations', 'Var', (192, 201))	('hemangioblastoma', 'Disease', (240, 256))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (68, 99))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (240, 256))	('mutation', 'Var', (17, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('renal cell carcinoma', 'Disease', (218, 238))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('caused by', 'Reg', (103, 112))	('predisposing to', 'Reg', (202, 217))	('VHL tumor', 'Disease', (139, 148))	('VHL Type 2B', 'Disease', 'MESH:D006623', (0, 11))	('pheochromocytoma', 'Disease', 'MESH:D010673', (262, 278))	('hemangioblastoma', 'Disease', 'MESH:D018325', (240, 256))	('VHL tumor', 'Disease', 'MESH:D006623', (139, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (218, 238))	('pheochromocytoma', 'Disease', (262, 278))	('VHL Type 2B', 'Disease', (0, 11))
25460	19252526	Type 2B mutant pVHL is predicted to be defective in hypoxia inducible factor (HIF)-alpha regulation.	('defective', 'NegReg', (39, 48))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('mutant', 'Var', (8, 14))	('pVHL', 'Gene', (15, 19))	('hypoxia', 'Disease', (52, 59))
25461	19252526	Murine embryonic stem (ES) cells in which the endogenous wild-type Vhl gene was replaced with the representative Type 2B VHL hotspot mutation R167Q (Vhl2B/2B) displayed preserved physiologic regulation of both HIF factors with slightly more normoxic dysregulation of HIF-2alpha.	('R167Q', 'Mutation', 'rs5030821', (142, 147))	('Vhl', 'Gene', (67, 70))	('physiologic regulation', 'MPA', (179, 201))	('ES', 'Chemical', '-', (23, 25))	('R167Q', 'Var', (142, 147))	('more', 'PosReg', (236, 240))	('Murine', 'Species', '10090', (0, 6))	('normoxic dysregulation', 'MPA', (241, 263))
25463	19252526	Vhl2B/2B mice displayed mid-gestational embryonic lethality, while adult Vhl2B/+ mice exhibited susceptibility to carcinogen-promoted renal neoplasia compared with wild-type littermates at twelve months.	('neoplasia', 'Phenotype', 'HP:0002664', (140, 149))	('mice', 'Species', '10090', (81, 85))	('renal neoplasia', 'Phenotype', 'HP:0009726', (134, 149))	('Vhl2B/2B', 'Var', (0, 8))	('renal neoplasia', 'Disease', (134, 149))	('renal neoplasia', 'Disease', 'MESH:D007674', (134, 149))	('susceptibility', 'Reg', (96, 110))	('mid-gestational embryonic lethality', 'Disease', (24, 59))	('mid-gestational embryonic lethality', 'Disease', 'MESH:D020964', (24, 59))	('mice', 'Species', '10090', (9, 13))
25464	19252526	Our experiments support a model in which the representative Type 2B R167Q mutant pVhl produces a unique profile of HIF dysregulation, thereby promoting tissue-specific effects on cell growth, development, and tumor predisposition.	('tumor', 'Disease', (209, 214))	('promoting', 'PosReg', (142, 151))	('HIF dysregulation', 'Disease', 'MESH:D021081', (115, 132))	('development', 'CPA', (192, 203))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('R167Q', 'Mutation', 'rs5030821', (68, 73))	('pVhl', 'Gene', (81, 85))	('cell growth', 'CPA', (179, 190))	('HIF dysregulation', 'Disease', (115, 132))	('R167Q', 'Var', (68, 73))
25465	19252526	Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited cancer susceptibility syndrome resulting from germline mutation of the VHL tumor suppressor gene which affects 1 in 36,000 live births in the US.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('autosomal dominant inherited cancer', 'Disease', 'MESH:D009386', (38, 73))	('VHL tumor', 'Disease', 'MESH:D006623', (138, 147))	('germline mutation', 'Var', (113, 130))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (0, 31))	('VHL tumor', 'Disease', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('autosomal dominant inherited cancer', 'Disease', (38, 73))	('resulting from', 'Reg', (98, 112))
25466	19252526	Specific classes of VHL mutations predispose to different spectrums of morbidity- and mortality-causing clinical phenotypes of VHL disease: retinal and central nervous system (CNS) hemangioblastoma, pheochromocytoma/paraganglioma, and renal cell carcinoma with clear cell histology (ccRCC).	('retinal and central nervous system (CNS) hemangioblastoma, pheochromocytoma/paraganglioma', 'Disease', 'MESH:D018325', (140, 229))	('VHL disease', 'Disease', 'MESH:D006623', (127, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (216, 229))	('renal cell carcinoma', 'Disease', (235, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (235, 255))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (199, 215))	('mutations', 'Var', (24, 33))	('VHL', 'Gene', (20, 23))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (235, 255))	('clear cell', 'Disease', (261, 271))	('renal cell carcinoma with clear cell histology', 'Phenotype', 'HP:0006770', (235, 281))	('VHL disease', 'Disease', (127, 138))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (181, 197))	('RCC', 'Disease', 'MESH:C538614', (285, 288))	('RCC', 'Disease', (285, 288))
25467	19252526	Type 1 VHL mutations predispose to ccRCC and hemangioblastoma.	('predispose', 'Reg', (21, 31))	('mutations', 'Var', (11, 20))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (45, 61))	('hemangioblastoma', 'Disease', 'MESH:D018325', (45, 61))	('RCC', 'Disease', 'MESH:C538614', (37, 40))	('RCC', 'Disease', (37, 40))	('VHL', 'Gene', (7, 10))	('hemangioblastoma', 'Disease', (45, 61))
25468	19252526	Type 2 missense VHL mutations predispose to pheochromocytoma, either alone (Type 2C) or in combination with hemangioblastoma and a high (Type 2B) or low (Type 2A) risk of ccRCC.	('hemangioblastoma', 'Disease', (108, 124))	('RCC', 'Disease', (173, 176))	('VHL', 'Gene', (16, 19))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (108, 124))	('pheochromocytoma', 'Disease', (44, 60))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('missense', 'Var', (7, 15))	('predispose to', 'Reg', (30, 43))	('hemangioblastoma', 'Disease', 'MESH:D018325', (108, 124))	('pheochromocytoma', 'Disease', 'MESH:D010673', (44, 60))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('mutations', 'Var', (20, 29))
25475	19252526	HIF-1alpha and HIF-2alpha target gene sets overlap in a highly context-dependent manner, but HIF-1alpha uniquely activates glycolytic enzymes.	('HIF-1alpha', 'Var', (93, 103))	('activates', 'PosReg', (113, 122))	('glycolytic enzymes', 'MPA', (123, 141))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (0, 25))
25477	19252526	First, biallelic inactivation of VHL and over-expression of HIF targets is observed in both VHL disease-associated renal lesions and also 70-90% of sporadic ccRCC tumors.	('RCC', 'Disease', 'MESH:C538614', (159, 162))	('VHL disease', 'Disease', 'MESH:D006623', (92, 103))	('over-expression', 'PosReg', (41, 56))	('renal lesions', 'Disease', 'MESH:D007674', (115, 128))	('VHL', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('renal lesions', 'Disease', (115, 128))	('observed', 'Reg', (75, 83))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('VHL disease', 'Disease', (92, 103))	('biallelic', 'Var', (7, 16))	('RCC', 'Disease', (159, 162))
25481	19252526	In vitro studies of cDNA expressed Type 2A and Type 2B mutant pVHL models revealed graded dysregulation of HIF-1alpha and HIF-2alpha, correlating with the degree of risk for ccRCC (Type 1>= Type 2B > Type 2A).	('RCC', 'Disease', (176, 179))	('RCC', 'Disease', 'MESH:C538614', (176, 179))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (107, 132))	('pVHL', 'Gene', (62, 66))	('mutant', 'Var', (55, 61))	('dysregulation', 'MPA', (90, 103))
25484	19252526	A Vhl gene replacement model of Chuvash Polycythemia, however, was viable and conferred erythrocytosis in a milieu of very mild HIF-2alpha stabilization.	('Polycythemia', 'Phenotype', 'HP:0001901', (40, 52))	('Vhl', 'Gene', (2, 5))	('Chuvash Polycythemia', 'Disease', (32, 52))	('Chuvash Polycythemia', 'Disease', 'MESH:C563918', (32, 52))	('erythrocytosis', 'Phenotype', 'HP:0001901', (88, 102))	('conferred', 'Reg', (78, 87))	('erythrocytosis', 'MPA', (88, 102))	('gene replacement', 'Var', (6, 22))
25485	19252526	To examine the activities of mutant pVHL relevant to human cancer, particularly with respect to missense mutation-specific effects on HIF regulation, we undertook a gene replacement approach to study Type 2B VHL disease in a mouse model.	('mutant', 'Var', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mouse', 'Species', '10090', (225, 230))	('human', 'Species', '9606', (53, 58))	('Type 2B VHL disease', 'Disease', (200, 219))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('Type 2B VHL disease', 'Disease', 'MESH:D006623', (200, 219))
25486	19252526	This model provides the first opportunity to examine the effect of a VHL disease-causing missense mutations in its pre-malignant context and under endogenous transcriptional, translational, and post-translational regulation.	('missense mutations', 'Var', (89, 107))	('VHL disease', 'Disease', 'MESH:D006623', (69, 80))	('VHL disease', 'Disease', (69, 80))
25487	19252526	Murine ES cells homozygous for a representative mutant 2B Vhl allele displayed mild HIF-2alpha stabilization but functionally preserved HIF-1alpha suppression.	('mutant', 'Var', (48, 54))	('HIF-2alpha stabilization', 'MPA', (84, 108))	('HIF-1alpha suppression', 'MPA', (136, 158))	('Murine ES', 'CellLine', 'CVCL:B288', (0, 9))	('Vhl', 'Gene', (58, 61))
25488	19252526	In vivo, while homozygosity for the mutant 2B Vhl allele conferred mid-gestational embryonic lethality, heterozygous Vhl2B/+ mice were viable and susceptible to carcinogen-promoted renal adenocarcinoma.	('mid-gestational embryonic lethality', 'Disease', (67, 102))	('Vhl', 'Gene', (46, 49))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (181, 201))	('conferred', 'PosReg', (57, 66))	('mid-gestational embryonic lethality', 'Disease', 'MESH:D020964', (67, 102))	('mice', 'Species', '10090', (125, 129))	('mutant', 'Var', (36, 42))	('susceptible', 'Reg', (146, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('renal adenocarcinoma', 'Disease', (181, 201))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (181, 201))
25489	19252526	Our genetic knock-in mouse model thus provides a species-congruent cellular system and in vivo model in which to further examine the contributions of Type 2B VHL missense mutation to VHL disease-associated cancers.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mouse', 'Species', '10090', (21, 26))	('missense mutation', 'Var', (162, 179))	('VHL disease', 'Disease', (183, 194))	('VHL', 'Gene', (158, 161))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('VHL disease', 'Disease', 'MESH:D006623', (183, 194))
25490	19252526	The Arginine 167   Glutamine (R167Q) missense mutation is a hotspot in the human VHL gene with a tight genotype-phenotype correlation to Type 2B disease.	('Arginine 167   Glutamine', 'Mutation', 'rs5030821', (4, 28))	('Arginine', 'Var', (4, 12))	('Type 2B disease', 'Disease', 'MESH:C536043', (137, 152))	('R167Q', 'Mutation', 'rs5030821', (30, 35))	('human', 'Species', '9606', (75, 80))	('R167Q', 'Var', (30, 35))	('Type 2B disease', 'Disease', (137, 152))
25494	19252526	Quantitative RT-PCR analysis in Vhl2B/2B ES cells confirmed that 2B mutant Vhl was transcribed at wild-type levels (Figure 2A).	('Vhl', 'Gene', (75, 78))	('ES', 'Chemical', '-', (41, 43))	('mutant', 'Var', (68, 74))
25496	19252526	The R167Q human pVHL mutation is predicted to destabilize the pVhl protein and to disrupt pVhl recruitment of Elongin C, resulting in HIF factor dysregulation.	('HIF factor dysregulation', 'MPA', (134, 158))	('human', 'Species', '9606', (10, 15))	('disrupt', 'NegReg', (82, 89))	('pVhl protein', 'Protein', (62, 74))	('pVhl recruitment', 'MPA', (90, 106))	('R167Q', 'Mutation', 'rs5030821', (4, 9))	('pVHL', 'Gene', (16, 20))	('destabilize', 'NegReg', (46, 57))	('R167Q', 'Var', (4, 9))
25505	19252526	Mirroring the qRT-PCR results, Vhl-/- ES cells secreted robust levels of Vegf protein (4.4-fold) compared to wild-type (p<0.01), while Vhl2B/2B ES cells did not secrete measurable Vegf (Figure 2F).	('ES', 'Chemical', '-', (38, 40))	('ES', 'Chemical', '-', (144, 146))	('Vhl-/- ES', 'Var', (31, 40))	('Vegf protein', 'MPA', (73, 85))	('secreted', 'MPA', (47, 55))
25506	19252526	To observe the functional effects of Type 2B Vhl mutation, we differentiated our panel of ES cells in a teratoma assay.	('teratoma', 'Phenotype', 'HP:0009792', (104, 112))	('teratoma', 'Disease', 'MESH:D013724', (104, 112))	('mutation', 'Var', (49, 57))	('ES', 'Chemical', '-', (90, 92))	('Vhl', 'Gene', (45, 48))	('teratoma', 'Disease', (104, 112))
25508	19252526	In contrast, the presence of one or two Type 2B Vhl alleles conferred a persistent growth advantage, such that Vhl2B/2B-derived teratomas grew faster than Vhl2B/+-derived teratomas, which in turn grew faster than wild-type teratomas (Figure 3A).	('teratoma', 'Phenotype', 'HP:0009792', (223, 231))	('Vhl2B/2B-derived', 'Var', (111, 127))	('teratomas', 'Disease', 'MESH:D013724', (223, 232))	('grew', 'CPA', (196, 200))	('teratomas', 'Disease', 'MESH:D013724', (128, 137))	('growth advantage', 'CPA', (83, 99))	('teratomas', 'Phenotype', 'HP:0009792', (171, 180))	('faster', 'PosReg', (143, 149))	('teratomas', 'Disease', (223, 232))	('teratomas', 'Disease', (128, 137))	('teratoma', 'Phenotype', 'HP:0009792', (171, 179))	('grew', 'CPA', (138, 142))	('teratomas', 'Disease', 'MESH:D013724', (171, 180))	('teratomas', 'Disease', (171, 180))	('teratoma', 'Phenotype', 'HP:0009792', (128, 136))	('teratomas', 'Phenotype', 'HP:0009792', (223, 232))	('faster', 'PosReg', (201, 207))	('teratomas', 'Phenotype', 'HP:0009792', (128, 137))	('presence', 'Var', (17, 25))	('Vhl', 'Gene', (48, 51))
25509	19252526	At harvest, J1, Vhl-/-, and Vhl2B/+ teratomas were well-encapsulated, while Vhl2B/2B teratomas adhered to the overlying skin (not shown).	('teratomas', 'Phenotype', 'HP:0009792', (85, 94))	('teratomas', 'Disease', 'MESH:D013724', (85, 94))	('teratomas', 'Disease', (85, 94))	('teratoma', 'Phenotype', 'HP:0009792', (36, 44))	('2B teratomas', 'Disease', 'MESH:D013724', (82, 94))	('2B teratomas', 'Disease', (82, 94))	('teratomas', 'Phenotype', 'HP:0009792', (36, 45))	('teratomas', 'Disease', 'MESH:D013724', (36, 45))	('teratoma', 'Phenotype', 'HP:0009792', (85, 93))	('Vhl2B/+', 'Var', (28, 35))	('teratomas', 'Disease', (36, 45))
25512	19252526	To determine whether Type 2B mutant pVhl preserves HIF regulation in vivo, teratomas were analyzed for HIF-1alpha and HIF-2alpha protein expression by immunoblot, confirming low levels of both HIF factors (Supplemental Figure 2).	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (103, 128))	('teratomas', 'Disease', (75, 84))	('mutant', 'Var', (29, 35))	('pVhl', 'Gene', (36, 40))	('HIF regulation', 'MPA', (51, 65))	('teratoma', 'Phenotype', 'HP:0009792', (75, 83))	('teratomas', 'Phenotype', 'HP:0009792', (75, 84))	('teratomas', 'Disease', 'MESH:D013724', (75, 84))
25515	19252526	In contrast to ES cells, the Vhl2B/2B-derived teratoma exhibited significant over-expression of both EglN3 (1.46-fold, p<0.05) and Vegf (1.87-fold, p<0.001) but failed to over-express the HIF-1alpha-specific target Pfk1.	('ES', 'Chemical', '-', (15, 17))	('Pfk1', 'Gene', (215, 219))	('teratoma', 'Phenotype', 'HP:0009792', (46, 54))	('teratoma', 'Disease', 'MESH:D013724', (46, 54))	('EglN3', 'Var', (101, 106))	('Pfk1', 'Gene', '5213', (215, 219))	('over-expression', 'PosReg', (77, 92))	('teratoma', 'Disease', (46, 54))
25519	19252526	To examine 2B mutant pVhl function in murine development in vivo, we derived Vhl2B/+ knock-in mice from our targeted murine ES cells.	('mutant', 'Var', (14, 20))	('ES', 'Chemical', '-', (124, 126))	('mice', 'Species', '10090', (94, 98))	('murine', 'Species', '10090', (38, 44))	('murine', 'Species', '10090', (117, 123))	('pVhl', 'Gene', (21, 25))
25520	19252526	Because reliance switches from yolk sac to placenta around E9.5, Vhl2B/2B embryonic lethality observed at E9.5-E10.5 implicates placental failure.	('placental failure', 'Disease', (128, 145))	('placental failure', 'Disease', 'MESH:D010922', (128, 145))	('E9.5-E10.5', 'Var', (106, 116))	('embryonic lethality', 'CPA', (74, 93))	('Vhl2B/2B', 'Gene', (65, 73))
25521	19252526	To visualize whether the 2B mutant Vhl allele acts similarly to the null allele in the placenta, we compared wild-type (not shown), Vhl2B/+, and Vhl2B/2B placentas by H&E for morphology and IHC for pVhl and the HIF target Vegfa.	('H&E', 'Chemical', '-', (167, 170))	('Vegfa', 'Gene', '22339', (222, 227))	('Vhl2B/2B', 'Var', (145, 153))	('Vegfa', 'Gene', (222, 227))
25522	19252526	By H&E, representative E9.5 Vhl2B/+ (Figure 5A) and Vhl2B/2B (Figure 5D) placentas displayed comparable chorionic villous fold formation and maternal red blood cell content in the spongiotrophoblast layer, but allantoic vessels, demarcated by the presence of nucleated fetal red blood cells (*), invaded the chorionic villi to a lesser extent in the Vhl2B/2B placenta.	('H&E', 'Chemical', '-', (3, 6))	('representative', 'Var', (8, 22))	('the', 'Var', (346, 349))	('villous fold formation', 'Phenotype', 'HP:0011473', (114, 136))	('E9.5', 'Var', (23, 27))
25525	19252526	Quantitative RT-PCR on three Vhl2B/2B E9.5 embryos showed significant (p<0.05) over-expression of the four HIF target genes studied relative to a Vhl2B/+ E9.5 embryo, paralleling the effect of Vhl mutation on HIF-regulated signaling observed in the differentiated teratoma model system (Figure 5G): Vegf (average 1.54-fold), Glut1 (average 2.60-fold), EglN3 (average 3.53-fold), and Pfk1 (average 1.88-fold).	('teratoma', 'Phenotype', 'HP:0009792', (264, 272))	('teratoma', 'Disease', 'MESH:D013724', (264, 272))	('over-expression', 'PosReg', (79, 94))	('teratoma', 'Disease', (264, 272))	('Pfk1', 'Gene', '5213', (383, 387))	('mutation', 'Var', (197, 205))	('Pfk1', 'Gene', (383, 387))
25529	19252526	Similar to prior models, Vhl2B/+ mice displayed frequent enlarged vessels (angiectasis) in the kidney and adrenal gland (Figure 6B, *) and renal cortical microcysts (3%, Figure 6A, Cy).	('enlarged', 'PosReg', (57, 65))	('angiectasis', 'Disease', (75, 86))	('renal cortical microcysts', 'Disease', (139, 164))	('renal cortical microcysts', 'Disease', 'MESH:D007674', (139, 164))	('Vhl2B/+', 'Var', (25, 32))	('mice', 'Species', '10090', (33, 37))	('angiectasis', 'Disease', 'None', (75, 86))	('renal cortical microcysts', 'Phenotype', 'HP:0004734', (139, 164))
25531	19252526	We hypothesized that accelerating somatic mutations via mutagenesis might reveal predisposition to cancer development in Vhl2B/+ mice.	('predisposition', 'Reg', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutagenesis', 'Var', (56, 67))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mice', 'Species', '10090', (129, 133))	('mutations', 'Var', (42, 51))
25532	19252526	Transplacental N-ethyl-N-nitrosourea (ENU) mutagenesis has been used successfully to augment renal cystogenesis in mouse models of Tuberous Sclerosis, another renal tumor predisposition syndrome, and therefore was an ideal method for accelerating progression in our model.	('Tuberous Sclerosis', 'Disease', 'MESH:D014402', (131, 149))	('augment', 'NegReg', (85, 92))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (15, 36))	('renal tumor', 'Disease', 'MESH:D007674', (159, 170))	('mouse', 'Species', '10090', (115, 120))	('renal tumor', 'Phenotype', 'HP:0009726', (159, 170))	('renal cystogenesis', 'MPA', (93, 111))	('renal cyst', 'Phenotype', 'HP:0000107', (93, 103))	('renal tumor', 'Disease', (159, 170))	('mutagenesis', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Tuberous Sclerosis', 'Disease', (131, 149))
25533	19252526	Renal lesions observed in mutagenized mice are summarized in Table 2.	('mice', 'Species', '10090', (38, 42))	('Renal lesions', 'Disease', 'MESH:D007674', (0, 13))	('Renal lesions', 'Disease', (0, 13))	('mutagenized', 'Var', (26, 37))
25534	19252526	At four months, both wild-type (2/4) and Vhl2B/+ (6/8) mutagenized mice displayed macroscopic subpleural lung nodules, indicating successful ENU mutagenesis.	('subpleural lung nodules', 'Disease', (94, 117))	('subpleural lung nodules', 'Disease', 'MESH:D016606', (94, 117))	('mutagenized', 'Var', (55, 66))	('subpleural lung nodules', 'Phenotype', 'HP:0001482', (94, 117))	('Vhl2B/+', 'Var', (41, 48))	('mice', 'Species', '10090', (67, 71))
25535	19252526	Both wild-type and Vhl2B/+ mutagenized mice displayed simple and papillary cortical renal microcysts on H&E-stained sections, suggesting that ENU mutagenesis effectively promotes benign renal cyst formation in this C57BL/6 genetic background.	('ENU', 'Var', (142, 145))	('simple and papillary', 'Phenotype', 'HP:0007482', (54, 74))	('cortical renal microcysts', 'Phenotype', 'HP:0004734', (75, 100))	('that', 'Gene', (137, 141))	('renal cyst', 'Phenotype', 'HP:0000107', (186, 196))	('promotes benign renal cyst', 'CPA', (170, 196))	('papillary cortical renal microcysts', 'Disease', 'MESH:D007681', (65, 100))	('H&E', 'Chemical', '-', (104, 107))	('effectively', 'PosReg', (158, 169))	('mice', 'Species', '10090', (39, 43))	('papillary cortical renal microcysts', 'Disease', (65, 100))
25538	19252526	However, Vhl2B/+ mutagenized mice (2/10) developed pathological findings typical of VHL disease.	('VHL disease', 'Disease', 'MESH:D006623', (84, 95))	('mutagenized', 'Var', (17, 28))	('developed', 'Reg', (41, 50))	('VHL disease', 'Disease', (84, 95))	('mice', 'Species', '10090', (29, 33))
25541	19252526	Statistical analysis suggested that Vhl mutation correlated with or trended toward development of neoplasia at 12 months (Pearson's chi2 p=0.037, Fisher's exact test p=0.101).	('mutation', 'Var', (40, 48))	('Vhl', 'Gene', (36, 39))	('neoplasia', 'Disease', 'MESH:D009369', (98, 107))	('neoplasia', 'Disease', (98, 107))	('neoplasia', 'Phenotype', 'HP:0002664', (98, 107))
25542	19252526	Germline Type 2B missense mutations in VHL predispose to ccRCC, CNS and retinal hemangioblastoma, and pheochromocytoma and paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (123, 136))	('missense mutations', 'Var', (17, 35))	('VHL', 'Gene', (39, 42))	('predispose', 'Reg', (43, 53))	('retinal hemangioblastoma', 'Disease', (72, 96))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (102, 136))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (80, 96))	('CNS', 'Disease', (64, 67))	('retinal hemangioblastoma', 'Phenotype', 'HP:0009711', (72, 96))	('retinal hemangioblastoma', 'Disease', 'MESH:D018325', (72, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (102, 118))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))
25543	19252526	In our murine gene replacement system, which models one VHL type 2B disease mutation, R167Q, generated a unique pattern of HIF-1alpha and HIF-2alpha dysregulation, differing from Vhl-null both in degree and ratio of HIF stabilization as well as in functional outcome in in vitro and in vivo studies.	('R167Q', 'Mutation', 'rs5030821', (86, 91))	('HIF-1alpha and HIF-2alpha dysregulation', 'Disease', 'MESH:D021081', (123, 162))	('R167Q', 'Var', (86, 91))	('VHL type 2B disease', 'Disease', 'MESH:D006623', (56, 75))	('murine', 'Species', '10090', (7, 13))	('VHL type 2B disease', 'Disease', (56, 75))
25545	19252526	We observed reduced levels of 2B mutant pVhl protein in homozygous ES cells, supporting the hypothesis that ccRCC-predisposing VHL missense mutations produce less stable proteins, as posited on the basis of structure analysis.	('RCC', 'Disease', (110, 113))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('protein', 'Protein', (45, 52))	('proteins', 'Protein', (170, 178))	('reduced', 'NegReg', (12, 19))	('pVhl', 'Gene', (40, 44))	('VHL', 'Gene', (127, 130))	('less', 'NegReg', (158, 162))	('missense mutations', 'Var', (131, 149))	('ES', 'Chemical', '-', (67, 69))
25550	19252526	Genetic knock-out of HIF-1alpha or replacement of HIF-1alpha with HIF-2alpha in teratomas enhances tumor growth and implicates HIF-1alpha as the growth-suppressive factor in this assay.	('HIF-1alpha', 'Gene', (21, 31))	('knock-out', 'Var', (8, 17))	('teratoma', 'Phenotype', 'HP:0009792', (80, 88))	('replacement', 'Var', (35, 46))	('HIF-1alpha', 'Gene', (50, 60))	('HIF-2alpha in teratomas enhances tumor', 'Disease', (66, 104))	('teratomas', 'Phenotype', 'HP:0009792', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('HIF-2alpha in teratomas enhances tumor', 'Disease', 'MESH:D013724', (66, 104))
25551	19252526	In our studies, Vhl-/- teratomas likewise displayed a growth disadvantage relative to wild-type and additionally featured over-expression of the joint HIF targets Vegfa and EglN3 and the HIF-1alpha-specific target Pfk1, all indicating HIF-1alpha and HIF-2alpha stabilization.	('teratomas', 'Disease', (23, 32))	('over-expression', 'PosReg', (122, 137))	('Pfk1', 'Gene', (214, 218))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (235, 260))	('teratoma', 'Phenotype', 'HP:0009792', (23, 31))	('Vegfa', 'Gene', '22339', (163, 168))	('teratomas', 'Phenotype', 'HP:0009792', (23, 32))	('EglN3', 'Var', (173, 178))	('teratomas', 'Disease', 'MESH:D013724', (23, 32))	('Pfk1', 'Gene', '5213', (214, 218))	('Vegfa', 'Gene', (163, 168))	('growth disadvantage', 'CPA', (54, 73))
25553	19252526	The placental failure and lethality observed in Vhl2B/2B embryos at E9.5-E10.5 was consistent with severely hypomorphic mutant pVhl function in the embryonic allantoic endothelium.	('placental failure', 'Disease', 'MESH:D010922', (4, 21))	('E9.5-E10.5', 'Var', (68, 78))	('lethality', 'CPA', (26, 35))	('placental failure', 'Disease', (4, 21))	('pVhl', 'Gene', (127, 131))	('mutant', 'Var', (120, 126))
25557	19252526	At twelve months post-ENU, renal adenocarcinoma was observed in mutagenized Vhl2B/+ mice, representing the first demonstration of this tumor in a genetically-predisposed mouse model and validating Vhl mutation as a tumor-initiating event in the development of RCC.	('observed', 'Reg', (52, 60))	('mutagenized', 'Var', (64, 75))	('renal adenocarcinoma', 'Disease', (27, 47))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (27, 47))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('Vhl', 'Gene', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (27, 47))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('mouse', 'Species', '10090', (170, 175))	('RCC', 'Disease', (260, 263))	('tumor', 'Disease', (215, 220))	('mutation', 'Var', (201, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
25558	19252526	Our gene replacement model of the representative Type 2B R167Q Vhl mutation bolsters emerging evidence that relative HIF-1alpha and HIF-2alpha protein abundance modulates the VHL Disease clinical phenotype and provides motivation for identifying the relevant genetic events involved in progressing Vhl-initiated tumors to invasive disease.	('tumors', 'Disease', (312, 318))	('modulates', 'Reg', (161, 170))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (117, 142))	('invasive disease', 'Disease', 'MESH:D009362', (322, 338))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('VHL Disease', 'Disease', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('R167Q', 'Mutation', 'rs5030821', (57, 62))	('invasive disease', 'Disease', (322, 338))	('R167Q', 'Var', (57, 62))	('Vhl', 'Gene', (63, 66))
25559	19252526	More broadly, our Vhl gene replacement model provides a comprehensive species-congruent system for future investigations of mutant pVhl HIF and non-HIF functions underpinning human VHL Disease both in vitro and in vivo.	('human', 'Species', '9606', (175, 180))	('mutant', 'Var', (124, 130))	('pVhl', 'Gene', (131, 135))
25565	19252526	The ES cells were screened at each stage by Southern blot for in vitro and in vivo studies of Type 2B mutant pVhl function.	('mutant', 'Var', (102, 108))	('ES', 'Chemical', '-', (4, 6))	('pVhl', 'Gene', (109, 113))
25570	19252526	All subsequent generations were genotyped by restriction PCR utilizing PCR primers flanking a novel HpyIV restriction site introduced by the G518A Vhl mutation (Figure 1D).	('G518A', 'SUBSTITUTION', 'None', (141, 146))	('G518A', 'Var', (141, 146))	('Vhl', 'Gene', (147, 150))
25579	19252526	Immunoblot primary antibodies used were: pVhl (M20 and FL181, Santa Cruz Biotechnology, Santa Cruz, CA, USA), HIF-1alpha (10006421, Cayman Chemical, Ann Arbor, MI, USA), HIF-2alpha (NB100-122, Novus Biologicals, Littleton, CO, USA), and eEF2 (Cell Signaling Technology, Danvers, MA, USA).	('10006421', 'Var', (122, 130))	('eEF2', 'Gene', '13629', (237, 241))	('eEF2', 'Gene', (237, 241))
25589	19252526	Pearson's chi2 test and Fisher's exact test were used to compare development of neoplasia in wild-type versus Vhl-mutant mutagenized mice.	('mice', 'Species', '10090', (133, 137))	('neoplasia', 'Disease', (80, 89))	('mutagenized', 'Var', (121, 132))	('neoplasia', 'Disease', 'MESH:D009369', (80, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (80, 89))	('Vhl-mutant mutagenized', 'Var', (110, 132))	('Vhl-mutant', 'Gene', (110, 120))
25591	16103922	We show here a functional link between tumors with VHL mutations and those with disruption of the genes encoding for succinate dehydrogenase (SDH) subunits B (SDHB) and D (SDHD).	('succinate', 'Chemical', 'MESH:D019802', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (55, 64))	('SDH', 'Gene', '66925', (172, 175))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('SDH', 'Gene', (172, 175))	('SDH', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SDHD', 'Gene', '66925', (172, 176))	('SDH', 'Gene', '66925', (159, 162))	('SDH', 'Gene', '66925', (142, 145))	('SDH', 'Gene', (142, 145))	('VHL', 'Gene', (51, 54))	('tumors', 'Disease', (39, 45))	('SDHD', 'Gene', (172, 176))
25594	16103922	The decrease in SDHB is also noted in tumors with SDHD mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('SDHD', 'Gene', (50, 54))	('tumors', 'Disease', (38, 44))	('mutations', 'Var', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('SDHB', 'Gene', (16, 20))	('decrease', 'NegReg', (4, 12))	('SDHD', 'Gene', '66925', (50, 54))
25596	16103922	These findings explain the shared features of pheochromocytomas with VHL and SDH mutations and suggest an additional mechanism for increased HIF1alpha activity in tumors.	('SDH', 'Gene', (77, 80))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (46, 63))	('increased', 'PosReg', (131, 140))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('pheochromocytomas', 'Disease', (46, 63))	('tumors', 'Disease', (163, 169))	('pheochromocytomas', 'Disease', 'MESH:D010673', (46, 63))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (81, 90))	('VHL', 'Gene', (69, 72))	('activity', 'MPA', (151, 159))	('SDH', 'Gene', '66925', (77, 80))
25597	16103922	Pheochromocytomas (also known as paragangliomas) are highly vascular tumors that arise from mutations in a diverse and apparently unrelated group of tumor suppressor genes and oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (69, 74))	('vascular tumors', 'Phenotype', 'HP:0100742', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (92, 101))	('Pheochromocytomas', 'Disease', (0, 17))	('tumors', 'Disease', (69, 75))	('paragangliomas', 'Disease', (33, 47))	('tumor', 'Disease', (149, 154))	('paragangliomas', 'Disease', 'MESH:D010235', (33, 47))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('paraganglioma', 'Phenotype', 'HP:0002668', (33, 46))	('paragangliomas', 'Phenotype', 'HP:0002668', (33, 47))
25602	16103922	The authors found that loss of two genes that cause two distinct pheochromocytoma syndromes (the genes SDHB and SDHD, which encode the subunits B and D of succinate dehydrogenase, a component enzyme of the energy and respiratory system in mitochondria) also triggers a HIF1alpha response.	('SDHD', 'Gene', '66925', (112, 116))	('SDHB', 'Gene', (103, 107))	('pheochromocytoma', 'Disease', 'MESH:D010673', (65, 81))	('succinate', 'Chemical', 'MESH:D019802', (155, 164))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (65, 81))	('SDHD', 'Gene', (112, 116))	('rat', 'Species', '10116', (222, 225))	('triggers', 'Reg', (258, 266))	('pheochromocytoma', 'Disease', (65, 81))	('loss', 'Var', (23, 27))	('HIF1alpha response', 'MPA', (269, 287))
25606	16103922	Pheochromocytomas can arise as a result of mutations in the following disease-associated genes: RET in multiple endocrine neoplasia type 2 (MEN2); VHL in von Hippel-Lindau disease (VHL); NF1 in neurofibromatosis type 1 (NF1); and succinate dehydrogenase (SDH) subunits B, C, or D in familial paraganglioma syndromes type 4 (PGL4), type 3 (PGL3), and type 1 (PGL1), respectively.	('familial paraganglioma syndromes', 'Disease', (283, 315))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (103, 138))	('succinate', 'Chemical', 'MESH:D019802', (230, 239))	('neoplasia', 'Phenotype', 'HP:0002664', (122, 131))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (154, 179))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('NF1', 'Gene', '18015', (220, 223))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (283, 315))	('paraganglioma', 'Phenotype', 'HP:0002668', (292, 305))	('NF1', 'Gene', '18015', (187, 190))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (112, 131))	('SDH', 'Gene', (255, 258))	('VHL', 'Gene', (147, 150))	('RET', 'Gene', (96, 99))	('NF1', 'Gene', (220, 223))	('neurofibromatosis type 1', 'Gene', (194, 218))	('von Hippel-Lindau disease', 'Disease', (154, 179))	('NF1', 'Gene', (187, 190))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (194, 211))	('Pheochromocytomas', 'Disease', (0, 17))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('multiple endocrine neoplasia type 2', 'Disease', (103, 138))	('SDH', 'Gene', '66925', (255, 258))	('neurofibromatosis type 1', 'Gene', '18015', (194, 218))	('mutations', 'Var', (43, 52))	('RET', 'Gene', '19713', (96, 99))
25607	16103922	The various pheochromocytoma susceptibility genes modulate a variety of signaling pathways that are superficially unrelated to one another.	('modulate', 'Reg', (50, 58))	('pheochromocytoma', 'Disease', 'MESH:D010673', (12, 28))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (12, 28))	('genes', 'Var', (44, 49))	('signaling pathways', 'Pathway', (72, 90))	('pheochromocytoma', 'Disease', (12, 28))
25613	16103922	Familial paragangliomas associated with SDHB and SDHD mutations resemble the carotid body growths that occur as a result of chronic hypoxia exposure in individuals living at high altitudes.	('hypoxia', 'Disease', (132, 139))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('mutations', 'Var', (54, 63))	('SDHB', 'Gene', (40, 44))	('SDHD', 'Gene', '66925', (49, 53))	('Familial paragangliomas', 'Disease', (0, 23))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('paragangliomas', 'Phenotype', 'HP:0002668', (9, 23))	('Familial paragangliomas', 'Disease', 'MESH:D010235', (0, 23))	('SDHD', 'Gene', (49, 53))
25614	16103922	These clinical observations and the finding of increased expression of HIF targets in tumors with SDH mutations have suggested the possibility that the VHL and SDH syndromes intersect at the molecular level.	('SDH', 'Gene', (160, 163))	('expression', 'MPA', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SDH', 'Gene', (98, 101))	('SDH', 'Gene', '66925', (98, 101))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('increased', 'PosReg', (47, 56))	('mutations', 'Var', (102, 111))	('SDH', 'Gene', '66925', (160, 163))
25616	16103922	We show here that pheochromocytomas with VHL and SDHB or SDHD mutations form a tight cluster with a clear hypoxia and reduced oxidoreductase signature.	('SDHB', 'Gene', (49, 53))	('SDHD', 'Gene', '66925', (57, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('oxidoreductase', 'MPA', (126, 140))	('pheochromocytomas', 'Disease', (18, 35))	('reduced', 'NegReg', (118, 125))	('pheochromocytomas', 'Disease', 'MESH:D010673', (18, 35))	('hypoxia', 'Disease', (106, 113))	('SDHD', 'Gene', (57, 61))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('VHL', 'Gene', (41, 44))	('mutations', 'Var', (62, 71))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (18, 35))
25617	16103922	This observation led to the identification of suppressed SDHB protein in tumors with VHL mutation and to the genetic demonstration that this effect is HIF-dependent.	('rat', 'Species', '10116', (124, 127))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('protein', 'Protein', (62, 69))	('VHL', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutation', 'Var', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SDHB', 'Gene', (57, 61))	('tumors', 'Disease', (73, 79))	('suppressed', 'NegReg', (46, 56))
25618	16103922	Our findings link pheochromocytomas with mutations in distinct genes:VHL, SDHB, and SDHD:and suggest that mitochondrial complex II inhibition contributes to development of pheochromocytomas with VHL mutation.	('mutations', 'Var', (41, 50))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (172, 189))	('SDHD', 'Gene', '66925', (84, 88))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (172, 188))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (18, 35))	('pheochromocytomas', 'Disease', (18, 35))	('pheochromocytomas', 'Disease', (172, 189))	('SDHB', 'Gene', (74, 78))	('SDHD', 'Gene', (84, 88))	('mutation', 'Var', (199, 207))	('pheochromocytomas', 'Disease', 'MESH:D010673', (18, 35))	('pheochromocytomas', 'Disease', 'MESH:D010673', (172, 189))	('VHL', 'Gene', (69, 72))	('VHL', 'Gene', (195, 198))	('mitochondrial complex II', 'Enzyme', (106, 130))	('inhibition', 'NegReg', (131, 141))
25625	16103922	Next, we sequenced all familial samples and also 20 of the sporadic tumors for mutations in known pheochromocytoma-associated genes.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('pheochromocytoma', 'Disease', (98, 114))	('sporadic tumors', 'Disease', 'MESH:D009369', (59, 74))	('pheochromocytoma', 'Disease', 'MESH:D010673', (98, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (98, 114))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sporadic tumors', 'Disease', (59, 74))	('mutations', 'Var', (79, 88))
25626	16103922	We detected novel VHL, SDHB, and RET mutations in six samples derived from four independent families (Table 1).	('RET', 'Gene', (33, 36))	('RET', 'Gene', '19713', (33, 36))	('mutations', 'Var', (37, 46))	('SDHB', 'Gene', (23, 27))	('VHL', 'Gene', (18, 21))
25628	16103922	Likewise, gene predictors were also created by comparing MEN2 and another component of Cluster 1, SDH tumors (including both SDHB and SDHD mutants).	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('SDHD', 'Gene', '66925', (134, 138))	('SDH tumors', 'Disease', 'MESH:D009369', (98, 108))	('SDHD', 'Gene', (134, 138))	('mutants', 'Var', (139, 146))	('SDH tumors', 'Disease', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
25636	16103922	The similar transcription profile of pheochromocytomas with mutations in SDH subunits indicates that the mechanism by which these tumors develop also involves the hypoxia-sensing pathway.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (37, 54))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SDH', 'Gene', '66925', (73, 76))	('pheochromocytomas', 'Disease', 'MESH:D010673', (37, 54))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('SDH', 'Gene', (73, 76))	('mutations', 'Var', (60, 69))	('pheochromocytomas', 'Disease', (37, 54))	('hypoxia', 'Disease', (163, 170))
25641	16103922	Mitochondrial complex II is a component of the electron transport chain, and mutations of SDHB or SDHD genes that abrogate the oxidoreductase function of complex II can cause pheochromocytomas.	('abrogate', 'NegReg', (114, 122))	('SDHD', 'Gene', '66925', (98, 102))	('pheochromocytomas', 'Disease', 'MESH:D010673', (175, 192))	('SDHB', 'Gene', (90, 94))	('pheochromocytomas', 'Disease', (175, 192))	('cause', 'Reg', (169, 174))	('mutations', 'Var', (77, 86))	('SDHD', 'Gene', (98, 102))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (175, 192))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (175, 191))	('oxidoreductase function', 'MPA', (127, 150))
25642	16103922	Because of the role of SDH subunits as tumor suppressors, we reasoned that the oxidoreductase signature observed in pheochromocytomas from Cluster 1 (Table 2) might indicate that complex II disruption could contribute to other tumors besides those with SDH mutations.	('mutations', 'Var', (257, 266))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('SDH', 'Gene', '66925', (23, 26))	('SDH', 'Gene', '66925', (253, 256))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('oxidoreductase', 'MPA', (79, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (116, 132))	('pheochromocytomas', 'Disease', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('pheochromocytomas', 'Disease', 'MESH:D010673', (116, 133))	('tumors', 'Disease', (227, 233))	('tumor', 'Disease', (39, 44))	('SDH', 'Gene', (253, 256))	('SDH', 'Gene', (23, 26))	('contribute', 'Reg', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (116, 133))
25643	16103922	This prompted us to examine the link between pheochromocytomas with VHL and SDH mutations in our series by first determining the protein expression of the catalytic unit of complex II, SDHB.	('pheochromocytomas', 'Disease', 'MESH:D010673', (45, 62))	('mutations', 'Var', (80, 89))	('pheochromocytomas', 'Disease', (45, 62))	('SDH', 'Gene', (185, 188))	('VHL', 'Gene', (68, 71))	('SDH', 'Gene', '66925', (185, 188))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (45, 62))	('SDH', 'Gene', (76, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (45, 61))	('SDH', 'Gene', '66925', (76, 79))
25644	16103922	We found that the expression of SDHB is reduced in all tumors with SDH (both SDHB and SDHD) mutations in this cohort (Figure 3A), indicating that low SDHB expression functions as a surrogate for disruption of complex II.	('SDH', 'Gene', '66925', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SDH', 'Gene', '66925', (86, 89))	('SDH', 'Gene', '66925', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('reduced', 'NegReg', (40, 47))	('tumors', 'Disease', (55, 61))	('expression', 'MPA', (18, 28))	('SDH', 'Gene', (67, 70))	('SDH', 'Gene', (32, 35))	('SDH', 'Gene', '66925', (67, 70))	('SDHD', 'Gene', '66925', (86, 90))	('SDH', 'Gene', (150, 153))	('mutations', 'Var', (92, 101))	('SDH', 'Gene', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('SDH', 'Gene', (77, 80))	('SDHD', 'Gene', (86, 90))	('SDH', 'Gene', '66925', (32, 35))
25645	16103922	Importantly, suppressed SDHB levels were also found in the majority of tumors with VHL mutations and sporadic pheochromocytomas from Cluster 1 tested by immunoblots (Figure 3B).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (110, 126))	('suppressed', 'NegReg', (13, 23))	('SDHB levels', 'MPA', (24, 35))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (110, 127))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('pheochromocytomas', 'Disease', 'MESH:D010673', (110, 127))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('pheochromocytomas', 'Disease', (110, 127))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (87, 96))	('VHL', 'Gene', (83, 86))
25653	16103922	Further, transient expression of a mutant, nondegradable form of HIF1alpha, HIF1alphaP402A/P564A, was able to downregulate SDHB (Figure 4B).	('SDHB', 'Gene', (123, 127))	('downregulate', 'NegReg', (110, 122))	('HIF1alphaP402A/P564A', 'Var', (76, 96))	('P564A', 'Mutation', 'p.P564A', (91, 96))
25657	16103922	Transcription profiling of a large series of primary pheochromocytomas reveals that tumors with VHL and SDH mutations are closely linked.	('mutations', 'Var', (108, 117))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (53, 70))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('SDH', 'Gene', (104, 107))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('VHL', 'Gene', (96, 99))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('pheochromocytomas', 'Disease', 'MESH:D010673', (53, 70))	('SDH', 'Gene', '66925', (104, 107))	('pheochromocytomas', 'Disease', (53, 70))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))
25658	16103922	The hypoxia-angiogenesis signature identified by our analysis of primary tumors with SDHB or SDHD mutations confirms and extends recent observations on the role of SDH proteins in cultured cell lines.	('SDHD', 'Gene', (93, 97))	('SDH', 'Gene', '66925', (85, 88))	('SDH', 'Gene', '66925', (164, 167))	('SDH', 'Gene', (85, 88))	('SDH', 'Gene', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SDHD', 'Gene', '66925', (93, 97))	('primary tumors', 'Disease', (65, 79))	('primary tumors', 'Disease', 'MESH:D009369', (65, 79))	('mutations', 'Var', (98, 107))	('hypoxia', 'Disease', 'MESH:D000860', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SDH', 'Gene', '66925', (93, 96))	('hypoxia', 'Disease', (4, 11))	('SDH', 'Gene', (93, 96))
25659	16103922	Our data show that mitochondrial complex II mutations lead to upregulation of HIF1alpha targets in human tumor tissue and indicate an additional level of interplay between the SDHB and HIF1alpha proteins, i.e., a reciprocal effect of HIF1alpha in modulating components of the mitochondrial complex II.	('mitochondrial complex II', 'Gene', (19, 43))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('interplay', 'Interaction', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', (105, 110))	('human', 'Species', '9606', (99, 104))	('upregulation', 'PosReg', (62, 74))
25664	16103922	One provocative possibility suggested by these findings is that the tumorigenic effects of VHL mutations in chromaffin tissue might involve dysfunction of mitochondrial complex II.	('tumor', 'Disease', (68, 73))	('dysfunction', 'MPA', (140, 151))	('mitochondrial complex II', 'Enzyme', (155, 179))	('VHL', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('chromaffin', 'Chemical', '-', (108, 118))	('mutations', 'Var', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
25666	16103922	The effects of HIF1alpha in our model were less marked than those observed with hypoxia-mimetic agents, which inhibit prolyl hydroxylases.	('hypoxia', 'Disease', (80, 87))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))	('HIF1alpha', 'Var', (15, 24))
25668	16103922	Also, clinical similarities besides pheochromocytoma have been noted in families with germline mutations of VHL and SDHB.	('pheochromocytoma', 'Disease', (36, 52))	('pheochromocytoma', 'Disease', 'MESH:D010673', (36, 52))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('SDHB', 'Gene', (116, 120))	('mutations', 'Var', (95, 104))	('VHL', 'Gene', (108, 111))
25670	16103922	We also showed that this distribution has high predictive value, as determined by the identification of previously undetected mutations in tumor samples segregating with the appropriate cluster.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutations', 'Var', (126, 135))
25672	16103922	Of interest, in a recent study, immunohistochemistry of head and neck paragangliomas with SDHB and SDHD mutations revealed similar suppression of SDHB, which was accompanied by morphologically abnormal mitochondria.	('neck paragangliomas', 'Disease', 'MESH:D010235', (65, 84))	('mutations', 'Var', (104, 113))	('SDHB', 'Gene', (90, 94))	('SDHB', 'Gene', (146, 150))	('SDHD', 'Gene', '66925', (99, 103))	('suppression', 'NegReg', (131, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (70, 83))	('paragangliomas', 'Phenotype', 'HP:0002668', (70, 84))	('neck paragangliomas', 'Disease', (65, 84))	('SDHD', 'Gene', (99, 103))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (56, 84))
25674	16103922	This study also describes a number of sporadic head and neck paragangliomas with low SDHB staining; these tumors might correspond with Cluster 1 pheochromocytomas for which no detectable mutation was identified and that also appear to arise from disruption of related pathways.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (145, 162))	('low', 'NegReg', (81, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('staining', 'Var', (90, 98))	('neck paragangliomas', 'Disease', 'MESH:D010235', (56, 75))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (47, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('pheochromocytomas', 'Disease', 'MESH:D010673', (145, 162))	('SDHB', 'Gene', (85, 89))	('pheochromocytomas', 'Disease', (145, 162))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('neck paragangliomas', 'Disease', (56, 75))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))
25675	16103922	It remains to be tested whether the predominant hypoxic-angiogenic profile of pheochromocytomas with VHL and SDH mutations will render these tumors targets for antiangiogenic therapies.	('VHL', 'Gene', (101, 104))	('SDH', 'Gene', '66925', (109, 112))	('SDH', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (78, 95))	('mutations', 'Var', (113, 122))	('pheochromocytomas', 'Disease', (78, 95))	('pheochromocytomas', 'Disease', 'MESH:D010673', (78, 95))
25682	16103922	In all, 76 catecholamine-secreting pheochromocytomas or paragangliomas representing well-characterized hereditary variants cited above, familial tumors of undetermined genetic cause, and sporadic tumors were included in this study (see Dataset S1).	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('catecholamine', 'Chemical', 'MESH:D002395', (11, 24))	('sporadic tumors', 'Disease', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('paragangliomas', 'Phenotype', 'HP:0002668', (56, 70))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('variants', 'Var', (114, 122))	('familial tumors', 'Disease', 'MESH:D009386', (136, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('pheochromocytomas or paragangliomas', 'Disease', (35, 70))	('familial tumors', 'Disease', (136, 151))	('pheochromocytomas or paragangliomas', 'Disease', 'MESH:D010673', (35, 70))	('sporadic tumors', 'Disease', 'MESH:D009369', (187, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (35, 51))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (35, 52))
25686	16103922	No head or neck paragangliomas or tumors with SDHC mutations were included in this series.	('SDHC', 'Gene', '66052', (46, 50))	('mutations', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('neck paragangliomas or tumors', 'Disease', 'MESH:D010235', (11, 40))	('head or neck paragangliomas', 'Phenotype', 'HP:0002864', (3, 30))	('neck paragangliomas or tumors', 'Disease', (11, 40))	('SDHC', 'Gene', (46, 50))	('paraganglioma', 'Phenotype', 'HP:0002668', (16, 29))	('paragangliomas', 'Phenotype', 'HP:0002668', (16, 30))
25714	16103922	A HIF1alpha double mutant (P402A/P564A) that is resistant to VHL-mediated proteasome degradation was generated by site-directed mutagenesis (Quick Change, Stratagene, La Jolla, California, United States) and cloned into p3X-FLAG vector (Sigma).	('HIF1alpha', 'Gene', (2, 11))	('P564A', 'Mutation', 'p.P564A', (33, 38))	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (157, 160))	('P402A', 'Var', (27, 32))	('P402A', 'SUBSTITUTION', 'None', (27, 32))
25715	16103922	HEK293 cells were transfected with the HIF1alpha P402A/P564A double mutant or an empty vector using Lipofectamine 2000, as recommended by the manufacturer (Invitrogen).	('HIF1alpha', 'Gene', (39, 48))	('P564A', 'Mutation', 'p.P564A', (55, 60))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (100, 118))	('P402A', 'SUBSTITUTION', 'None', (49, 54))	('P402A', 'Var', (49, 54))
25719	16103922	A2058 melanoma cells stably expressing HIF1alpha shRNA (FSIPPW-HIF) or control pEGFP shRNA (FSIPPW-EGFP) were cultured in DMEM, 10% FBS, and 2 mug/ml puromycin.	('DMEM', 'Chemical', '-', (122, 126))	('FSIPPW-HIF', 'Disease', 'None', (56, 66))	('A2058', 'CellLine', 'CVCL:1059', (0, 5))	('HIF1alpha shRNA', 'Var', (39, 54))	('puromycin', 'Chemical', 'MESH:D011691', (150, 159))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('FSIPPW-HIF', 'Disease', (56, 66))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
25751	33820394	PPGLs associated with SDHB mutation have a high risk of metastases (B).	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('PPGLs', 'Chemical', '-', (0, 5))	('SDHB', 'Gene', (22, 26))	('mutation', 'Var', (27, 35))	('metastases', 'Disease', (56, 66))	('PGLs', 'Phenotype', 'HP:0002668', (1, 5))
25760	33820394	If not recognized, PPGLs can severely affect the cardiovascular, gastrointestinal, and other systems, and can threaten patients by causing such as fatal arrhythmia, myocardial infarction, cerebrovascular events, and sudden death.	('PPGLs', 'Chemical', '-', (19, 24))	('threaten', 'Reg', (110, 118))	('cerebrovascular events', 'Phenotype', 'HP:0001297', (188, 210))	('sudden death', 'Disease', (216, 228))	('gastrointestinal', 'MPA', (65, 81))	('sudden death', 'Disease', 'MESH:D003645', (216, 228))	('myocardial infarction', 'Disease', (165, 186))	('causing', 'Reg', (131, 138))	('cardiovascular', 'MPA', (49, 63))	('PGLs', 'Phenotype', 'HP:0002668', (20, 24))	('myocardial infarction', 'Phenotype', 'HP:0001658', (165, 186))	('arrhythmia', 'Disease', 'MESH:D001145', (153, 163))	('arrhythmia', 'Phenotype', 'HP:0011675', (153, 163))	('arrhythmia', 'Disease', (153, 163))	('myocardial infarction', 'Disease', 'MESH:D009203', (165, 186))	('patients', 'Species', '9606', (119, 127))	('cerebrovascular events', 'Disease', (188, 210))	('PPGLs', 'Var', (19, 24))	('affect', 'Reg', (38, 44))
25829	33820394	In addition, succinate dehydrogenase B (SDHB) mutant PPGL showed increased production of dopamine in the tumor metabolomics and had high plasma and urinary dopamine and plasma 3-methoxytyramine levels.	('succinate dehydrogenase B', 'Gene', (13, 38))	('increased', 'PosReg', (65, 74))	('dopamine', 'Chemical', 'MESH:D004298', (89, 97))	('succinate dehydrogenase B', 'Gene', '6390', (13, 38))	('PPGL', 'Chemical', '-', (53, 57))	('SDHB', 'Gene', (40, 44))	('PPGL', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('dopamine', 'Chemical', 'MESH:D004298', (156, 164))	('mutant', 'Var', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (176, 193))	('tumor', 'Disease', (105, 110))	('high', 'PosReg', (132, 136))
25830	33820394	SDHB mutation confers a high risk of metastases, which, at least partly, explains the high risk of metastases in PPGL with elevated dopamine and 3-methoxytyramine.	('dopamine', 'MPA', (132, 140))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (145, 162))	('PPGL', 'Chemical', '-', (113, 117))	('metastases', 'Disease', (37, 47))	('dopamine', 'Chemical', 'MESH:D004298', (132, 140))	('elevated', 'PosReg', (123, 131))	('metastases', 'Disease', (99, 109))	('SDHB', 'Gene', (0, 4))	('metastases', 'Disease', 'MESH:D009362', (37, 47))	('mutation', 'Var', (5, 13))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('3-methoxytyramine', 'MPA', (145, 162))
25839	33820394	CT is preferred to MRI for the detection of lung metastases, while MRI shows better sensitivity between 90% and 95% for detecting skull base and neck PGLs than CT. MRI is also preferred in patients with an allergy to CT contrast agent, and in patients in whom radiation exposure should be limited (i.e., children, pregnant women, patients with known germline mutations, and those with recent excessive radiation exposure).	('patients', 'Species', '9606', (243, 251))	('germline mutations', 'Var', (350, 368))	('children', 'Species', '9606', (304, 312))	('PGLs', 'Phenotype', 'HP:0002668', (150, 154))	('allergy', 'Disease', (206, 213))	('lung metastases', 'Disease', (44, 59))	('patients', 'Species', '9606', (330, 338))	('lung metastases', 'Disease', 'MESH:D009362', (44, 59))	('allergy', 'Phenotype', 'HP:0012393', (206, 213))	('patients', 'Species', '9606', (189, 197))	('women', 'Species', '9606', (323, 328))	('allergy', 'Disease', 'MESH:D004342', (206, 213))
25846	33820394	The elevated clinical value of 68Ga-DOTA-SSA PET/CT is also observed in extra-adrenal PGLs and head and neck PGLs.	('68Ga-DOTA-SSA', 'Chemical', '-', (31, 44))	('PGLs', 'Phenotype', 'HP:0002668', (109, 113))	('68Ga-DOTA-SSA', 'Var', (31, 44))	('PGLs', 'Phenotype', 'HP:0002668', (86, 90))	('extra-adrenal PGLs', 'Disease', (72, 90))
25848	33820394	In PPGLs with underlying SDHx mutations, 68Ga-DOTA-SSA PET/CT can be recommended.	('SDH', 'Gene', (25, 28))	('PGLs', 'Phenotype', 'HP:0002668', (4, 8))	('mutations', 'Var', (30, 39))	('PPGLs', 'Chemical', '-', (3, 8))	('68Ga-DOTA-SSA', 'Chemical', '-', (41, 54))	('SDH', 'Gene', '6390', (25, 28))
25849	33820394	In contrast to SDHx-related PPGLs, 18F-DOPA PET/CT showed high tumor uptake in von Hippel-Lindau (VHL), rearranged during transfection (RET), neurofibromatosis 1 (NF1), myc-associated protein X (MAX), hypoxia-inducible factor (HIF) 2A, prolyl hydroxylase (PHD)1/2, and fumarate hydratase (FH) mutated PPGLs.	('neurofibromatosis 1', 'Gene', '4763', (142, 161))	('MAX', 'Gene', (195, 198))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (142, 159))	('mutated', 'Var', (293, 300))	('von Hippel-Lindau', 'Gene', '7428', (79, 96))	('PGLs', 'Phenotype', 'HP:0002668', (302, 306))	('SDH', 'Gene', '6390', (15, 18))	('neurofibromatosis 1', 'Gene', (142, 161))	('PPGLs', 'Gene', (301, 306))	('fumarate hydratase', 'Gene', '2271', (269, 287))	('PGLs', 'Phenotype', 'HP:0002668', (29, 33))	('tumor', 'Disease', (63, 68))	('PPGLs', 'Chemical', '-', (301, 306))	('FH', 'Gene', '2271', (289, 291))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('prolyl hydroxylase (PHD)1/2', 'Gene', '112398;54583', (236, 263))	('hypoxia-inducible factor (HIF) 2A', 'Gene', '2034', (201, 234))	('prolyl hydroxylase (PHD)1/2', 'Gene', (236, 263))	('SDH', 'Gene', (15, 18))	('von Hippel-Lindau', 'Gene', (79, 96))	('MAX', 'Gene', '60661', (195, 198))	('PPGLs', 'Chemical', '-', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('fumarate hydratase', 'Gene', (269, 287))	('18F-DOPA', 'Chemical', 'MESH:C043437', (35, 43))
25856	33820394	177Lu, 90Y, 225Ac-labeled DOTA-D-Phe1-Tyr3-octreotide (TOC) and DOTA-0-Tyr3-octreotate (TATE) is the currently available PRRT as compassionate or off-label use.	('TATE', 'Chemical', '-', (88, 92))	('DOTA-D-Phe1-Tyr3-octreotide', 'Chemical', '-', (26, 53))	('225Ac', 'Chemical', 'MESH:C000615155', (12, 17))	('DOTA-D-Phe1-Tyr3-octreotide', 'Var', (26, 53))	('90Y', 'Var', (7, 10))	('TOC', 'Chemical', '-', (55, 58))	('DOTA-0-Tyr3-octreotate', 'Chemical', '-', (64, 86))
25874	33820394	Pathogenic germline variants in any of the SDHx subunit genes (SDHA/B/C/D) have been implicated in hereditary tumorigenesis of PPGLs.	('SDH', 'Gene', '6390', (63, 66))	('variants', 'Var', (20, 28))	('SDH', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('SDH', 'Gene', (63, 66))	('implicated', 'Reg', (85, 95))	('PPGLs', 'Chemical', '-', (127, 132))	('hereditary tumor', 'Disease', 'MESH:D030342', (99, 115))	('SDH', 'Gene', '6390', (43, 46))	('PGLs', 'Phenotype', 'HP:0002668', (128, 132))	('hereditary tumor', 'Disease', (99, 115))	('PPGLs', 'Disease', (127, 132))
25876	33820394	Germline mutations of SDHB have been widely accepted as a high-risk factor for metastases, leading to metastatic PPGLs in 40% or more of affected patients.	('Germline mutations', 'Var', (0, 18))	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('PGLs', 'Phenotype', 'HP:0002668', (114, 118))	('leading to', 'Reg', (91, 101))	('PPGLs', 'Chemical', '-', (113, 118))	('SDHB', 'Gene', (22, 26))	('metastases', 'Disease', (79, 89))	('metastatic PPGLs', 'Disease', (102, 118))	('patients', 'Species', '9606', (146, 154))
25877	33820394	Furthermore, SDHB germline mutation is a poor prognostic factor in patients with metastatic PPGLs.	('PPGLs', 'Chemical', '-', (92, 97))	('metastatic PPGLs', 'Disease', (81, 97))	('patients', 'Species', '9606', (67, 75))	('SDHB', 'Gene', (13, 17))	('PGLs', 'Phenotype', 'HP:0002668', (93, 97))	('germline mutation', 'Var', (18, 35))
25878	33820394	In terms of the 5-year probability of survival after the diagnosis of the first metastases were 0.36 (0.15 to 0.57) in SDHB mutation carriers and 0.67 (0.47 to 0.81) in the absence of SDHB mutation (relative risk, 2.6; P=0.019).	('metastases', 'Disease', (80, 90))	('SDHB', 'Gene', (184, 188))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('SDHB', 'Gene', (119, 123))	('mutation', 'Var', (124, 132))
25880	33820394	Therefore, loss of SDHB IHC staining in tumoral tissue suggests the presence of germline mutations in one of the SDHx genes with 100% sensitivity and 84% specificity.	('SDH', 'Gene', (113, 116))	('SDH', 'Gene', (19, 22))	('tumoral', 'Disease', (40, 47))	('tumoral', 'Disease', 'MESH:D009369', (40, 47))	('mutations', 'Var', (89, 98))	('SDH', 'Gene', '6390', (113, 116))	('SDH', 'Gene', '6390', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))
25889	33820394	Second, about 40% or more of patients with SDHB mutation have metastatic phenotype as the principal predictor of malignancy in PPGL patients.	('malignancy', 'Disease', (113, 123))	('patients', 'Species', '9606', (29, 37))	('PPGL', 'Chemical', '-', (127, 131))	('mutation', 'Var', (48, 56))	('SDHB', 'Gene', (43, 47))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))	('patients', 'Species', '9606', (132, 140))
25891	33820394	Fourth, about 11% to 13% of patients with apparently sporadic PPGLs such as single benign PPGL without a family history have a mutation in susceptibility genes according to a meta-analysis.	('PPGL', 'Chemical', '-', (90, 94))	('PPGLs', 'Disease', (62, 67))	('mutation', 'Var', (127, 135))	('PGLs', 'Phenotype', 'HP:0002668', (63, 67))	('PPGLs', 'Chemical', '-', (62, 67))	('PPGL', 'Chemical', '-', (62, 66))	('patients', 'Species', '9606', (28, 36))
25897	33820394	Moreover, as techniques for genetic testing have been advanced, higher mutation discovery rates and a better understanding of the clinical phenotypes of PPGLs have been achieved.	('PPGLs', 'Chemical', '-', (153, 158))	('PPGLs', 'Gene', (153, 158))	('mutation', 'Var', (71, 79))	('higher', 'PosReg', (64, 70))	('PGLs', 'Phenotype', 'HP:0002668', (154, 158))	('rat', 'Species', '10116', (90, 93))
25906	33820394	A study about the diagnostic methods of PPGLs demonstrated that NGS assay significantly improved the performances of PPGL genetic testing compared with conventional methods with a higher rate of the identified mutation.	('PPGL', 'Gene', (117, 121))	('rat', 'Species', '10116', (187, 190))	('PPGL', 'Chemical', '-', (40, 44))	('genetic testing', 'Var', (122, 137))	('performances', 'MPA', (101, 113))	('PPGLs', 'Chemical', '-', (40, 45))	('PGLs', 'Phenotype', 'HP:0002668', (41, 45))	('rat', 'Species', '10116', (53, 56))	('improved', 'PosReg', (88, 96))	('PPGL', 'Chemical', '-', (117, 121))
25909	33820394	Recently, a study with the largest number of Korean PPGL patients (n=161) reported that approximately 21% of sporadic PPGLs without any family history still harbored germline mutation of the PPGL-related genes.	('PPGL', 'Chemical', '-', (191, 195))	('PPGLs', 'Chemical', '-', (118, 123))	('PPGL', 'Chemical', '-', (118, 122))	('harbored', 'Reg', (157, 165))	('patients', 'Species', '9606', (57, 65))	('PGLs', 'Phenotype', 'HP:0002668', (119, 123))	('PPGL-related', 'Gene', (191, 203))	('germline mutation', 'Var', (166, 183))	('PPGL', 'Chemical', '-', (52, 56))
25912	33820394	In this study, among 57 patients with PPGLs, 28 different germline mutations were identified in 11 susceptibility genes (EPAS1, KIF1B, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, TMEM127, and VHL).	('VHL', 'Gene', (187, 190))	('PGLs', 'Phenotype', 'HP:0002668', (39, 43))	('SDHA', 'Gene', (150, 154))	('SDHB', 'Gene', (156, 160))	('mutations', 'Var', (67, 76))	('SDHC', 'Gene', (162, 166))	('NF1', 'Gene', (140, 143))	('PPGLs', 'Chemical', '-', (38, 43))	('MAX', 'Gene', (135, 138))	('TMEM127', 'Gene', (174, 181))	('KIF1B', 'Gene', (128, 133))	('patients', 'Species', '9606', (24, 32))	('EPAS1', 'Gene', (121, 126))	('SDHD', 'Gene', (168, 172))	('MAX', 'Gene', '60661', (135, 138))
25940	33364876	In the recent prospective randomized study, although phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability than doxazosin, it was not been established whether this was related to better clinical outcomes.	('doxazosin', 'Chemical', 'MESH:D017292', (147, 156))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (53, 69))	('preventing intraoperative hemodynamic instability', 'MPA', (92, 141))	('phenoxybenzamine', 'Var', (53, 69))
25946	33364876	However, recent data suggest that the use of metyrosine in combination with preoperative phenoxybenzamine may reduce intraoperative hemodynamic instability and postoperative cardiovascular problems.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (89, 105))	('cardiovascular problems', 'Phenotype', 'HP:0001626', (174, 197))	('metyrosine', 'Chemical', 'MESH:D019805', (45, 55))	('postoperative cardiovascular problems', 'Disease', 'MESH:D002318', (160, 197))	('intraoperative hemodynamic instability', 'MPA', (117, 155))	('postoperative cardiovascular problems', 'Disease', (160, 197))	('metyrosine', 'Var', (45, 55))	('reduce', 'NegReg', (110, 116))
25952	33364876	Tachycardia is less common in those who use selective alpha-blockers, but especially in patients who use phenoxybenzamine, additional beta-adrenergic receptor blockade is often required for tachycardia control.	('tachycardia', 'Disease', 'MESH:D013610', (190, 201))	('Tachycardia', 'Phenotype', 'HP:0001649', (0, 11))	('patients', 'Species', '9606', (88, 96))	('phenoxybenzamine', 'Var', (105, 121))	('Tachycardia', 'Disease', 'MESH:D013610', (0, 11))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (105, 121))	('tachycardia', 'Phenotype', 'HP:0001649', (190, 201))	('tachycardia', 'Disease', (190, 201))	('Tachycardia', 'Disease', (0, 11))
25973	33364876	Reactive hypoglycemia may occur after PPGL resections, although not very often.	('hypoglycemia', 'Phenotype', 'HP:0001943', (9, 21))	('resections', 'Var', (43, 53))	('PGL', 'Phenotype', 'HP:0002668', (39, 42))	('hypoglycemia', 'Disease', (9, 21))	('hypoglycemia', 'Disease', 'MESH:D007003', (9, 21))	('PPGL', 'Chemical', '-', (38, 42))	('PPGL', 'Gene', (38, 42))	('Reactive hypoglycemia', 'Phenotype', 'HP:0012051', (0, 21))
25994	33364876	Preoperative knowledge of the type of preoperative germline mutation in PPGL affects the type of surgical approach and the extension of adrenalectomy.	('germline mutation', 'Var', (51, 68))	('affects', 'Reg', (77, 84))	('PPGL', 'Chemical', '-', (72, 76))	('PGL', 'Phenotype', 'HP:0002668', (73, 76))	('PPGL', 'Gene', (72, 76))
25995	33364876	Open adrenalectomy may be preferred in patients with SDHB, TMEM127 or FH germline mutations, as the risk of extra-adrenal disease, metastatic disease or recurrence risk is higher than in patients with NF1, RET or VHL germline mutations.	('RET', 'Gene', '5979', (206, 209))	('NF1', 'Gene', '4763', (201, 204))	('patients', 'Species', '9606', (187, 195))	('SDHB', 'Gene', '6390', (53, 57))	('patients', 'Species', '9606', (39, 47))	('extra-adrenal disease', 'Disease', (108, 129))	('metastatic', 'CPA', (131, 141))	('FH', 'Disease', 'MESH:D006938', (70, 72))	('RET', 'Gene', (206, 209))	('SDHB', 'Gene', (53, 57))	('VHL', 'Gene', (213, 216))	('mutations', 'Var', (82, 91))	('VHL', 'Gene', '7428', (213, 216))	('extra-adrenal disease', 'Disease', 'MESH:D010236', (108, 129))	('TMEM127', 'Gene', '55654', (59, 66))	('adrenal disease', 'Phenotype', 'HP:0000834', (114, 129))	('NF1', 'Gene', (201, 204))	('TMEM127', 'Gene', (59, 66))
25997	33364876	In metastatic diseases, metastases occur primarily in lymph nodes; therefore, locoregional lymph node dissection should be performed together with primary tumor during laparotomy, in patients in whom lymph node metastasis is detected in preoperative imaging or during the intraoperative evaluation, or in patients with a high risk of lymph node metastasis, such as SDHB germline mutation.	('SDHB', 'Gene', '6390', (365, 369))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('metastases', 'Disease', 'MESH:D009362', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SDHB', 'Gene', (365, 369))	('tumor', 'Disease', (155, 160))	('germline mutation', 'Var', (370, 387))	('metastatic', 'Disease', (3, 13))	('patients', 'Species', '9606', (305, 313))	('metastases', 'Disease', (24, 34))	('patients', 'Species', '9606', (183, 191))
26003	33364876	Apparently, germline mutation is less than 20% in patients with sporadic tumors and much higher in patients with family history.	('sporadic tumors', 'Disease', 'MESH:D009369', (64, 79))	('patients', 'Species', '9606', (50, 58))	('germline mutation', 'Var', (12, 29))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('sporadic tumors', 'Disease', (64, 79))	('patients', 'Species', '9606', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('higher', 'Reg', (89, 95))
26004	33364876	PGLs associated with SDHB mutations have a high risk of metastasis.	('metastasis', 'CPA', (56, 66))	('PGL', 'Phenotype', 'HP:0002668', (0, 3))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (26, 35))	('SDHB', 'Gene', (21, 25))
26007	33364876	SDHx mutations are the most common and are associated with paraganglioma syndromes from 1 to 4 (SDHD, SDHAF2, SDHC and SDHB mutations, respectively).	('SDHAF2', 'Gene', '54949', (102, 108))	('SDHB', 'Gene', '6390', (119, 123))	('SDHC', 'Gene', (110, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (59, 72))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (110, 114))	('SDHx', 'Gene', (0, 4))	('SDHB', 'Gene', (119, 123))	('paraganglioma', 'Disease', (59, 72))	('associated', 'Reg', (43, 53))	('paraganglioma', 'Disease', 'MESH:D010235', (59, 72))	('SDHD', 'Gene', '6392', (96, 100))	('SDHD', 'Gene', (96, 100))	('SDHAF2', 'Gene', (102, 108))
26008	33364876	While SDHB mutations cause more aggressive disease and metastasize more than SDHD mutations, SDHD mutations cause head and neck PGLs with higher rates and PCC with lower rates.	('aggressive disease', 'Disease', 'MESH:D001523', (32, 50))	('PGL', 'Phenotype', 'HP:0002668', (128, 131))	('mutations', 'Var', (11, 20))	('SDHD', 'Gene', (93, 97))	('metastasize', 'CPA', (55, 66))	('PCC', 'Phenotype', 'HP:0002666', (155, 158))	('aggressive disease', 'Disease', (32, 50))	('SDHD', 'Gene', '6392', (77, 81))	('SDHD', 'Gene', (77, 81))	('cause', 'Reg', (21, 26))	('mutations', 'Var', (98, 107))	('SDHB', 'Gene', '6390', (6, 10))	('cause', 'Reg', (108, 113))	('SDHD', 'Gene', '6392', (93, 97))	('PCC', 'Disease', (155, 158))	('SDHB', 'Gene', (6, 10))
26009	33364876	revealed that carotid body PGLs with SDHB mutation was associated with worse disease-free survival after resection despite early intervention, and a more aggressive surgical approach is required in these patients.	('patients', 'Species', '9606', (204, 212))	('disease-free survival', 'CPA', (77, 98))	('SDHB', 'Gene', '6390', (37, 41))	('PGL', 'Phenotype', 'HP:0002668', (27, 30))	('mutation', 'Var', (42, 50))	('SDHB', 'Gene', (37, 41))	('worse', 'NegReg', (71, 76))
26010	33364876	However, in the carotid body PGLs without SDHB mutation, they reported that if the lesion is asymptomatic, its diameter is less than 2 cm and not biochemically hormone-active, the follow-up option can be considered.	('PGL', 'Phenotype', 'HP:0002668', (29, 32))	('SDHB', 'Gene', '6390', (42, 46))	('mutation', 'Var', (47, 55))	('SDHB', 'Gene', (42, 46))
26030	33364876	Biochemical and clinical responses can be obtained with advanced somatostatin analogs, such as 90 Y-DOTATATE or 177 Lu-DOTATATE in somatostatin receptor-positive metastases in advanced PPGLs.	('metastases', 'Disease', (162, 172))	('Lu-DOTATATE', 'Chemical', '-', (116, 127))	('Y-DOTATATE', 'Chemical', '-', (98, 108))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('somatostatin', 'MPA', (131, 143))	('PPGLs', 'Chemical', '-', (185, 190))	('177 Lu-DOTATATE', 'Var', (112, 127))	('PGL', 'Phenotype', 'HP:0002668', (186, 189))
26033	33364876	Information about signal paths and mutations in PPGL can guide targeted treatments.	('PGL', 'Phenotype', 'HP:0002668', (49, 52))	('PPGL', 'Chemical', '-', (48, 52))	('PPGL', 'Gene', (48, 52))	('mutations', 'Var', (35, 44))
26037	33364876	Lifelong follow-up is recommended for high-risk PCC patients (germline mutation, young age (<20 years), large tumor (>5-6 cm), SDHB carriers) and all PGL patients.	('PCC', 'Disease', (48, 51))	('PGL', 'Phenotype', 'HP:0002668', (150, 153))	('SDHB', 'Gene', '6390', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('patients', 'Species', '9606', (154, 162))	('PCC', 'Phenotype', 'HP:0002666', (48, 51))	('SDHB', 'Gene', (127, 131))	('germline mutation', 'Var', (62, 79))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
26042	33364876	Chromogranin A test should be performed annually in patients with negative metanephrine and 3-MT tests, and positive chromogranin A.	('Chromogranin A', 'Gene', (0, 14))	('chromogranin A', 'Gene', (117, 131))	('Chromogranin A', 'Gene', '1113', (0, 14))	('chromogranin A', 'Gene', '1113', (117, 131))	('positive', 'Var', (108, 116))	('metanephrine', 'Chemical', 'MESH:D008676', (75, 87))	('3-MT tests', 'MPA', (92, 102))	('patients', 'Species', '9606', (52, 60))	('metanephrine', 'MPA', (75, 87))
26051	33364876	PPGL increases cardiovascular morbidity and mortality.	('cardiovascular morbidity', 'CPA', (15, 39))	('PGL', 'Phenotype', 'HP:0002668', (1, 4))	('mortality', 'Disease', 'MESH:D003643', (44, 53))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (15, 39))	('increases', 'PosReg', (5, 14))	('mortality', 'Disease', (44, 53))	('PPGL', 'Var', (0, 4))	('PPGL', 'Chemical', '-', (0, 4))
26073	33193100	Such genetic alterations are mainly involved in the pathogenesis of pseudohypoxia, Wnt, and kinase signaling, and other intracellular signaling cascades.	('pseudohypoxia', 'Disease', (68, 81))	('involved', 'Reg', (36, 44))	('pseudohypoxia', 'Disease', 'None', (68, 81))	('genetic alterations', 'Var', (5, 24))
26074	33193100	In addition, recurrent somatic mutations are frequently detected and overlapped with the presence of genetic alterations associated with hereditary diseases.	('hereditary diseases', 'Disease', (137, 156))	('hereditary diseases', 'Disease', 'MESH:D030342', (137, 156))	('mutations', 'Var', (31, 40))
26081	33193100	Among the genes above, the presence of SDHX mutations is reported to increase the risks of developing aggressive disease behavior by altering intracellular metabolism, especially the tricarboxylic acid (TCA) cycle.	('altering', 'Reg', (133, 141))	('aggressive disease behavior', 'Disease', (102, 129))	('SDHX', 'Gene', (39, 43))	('aggressive disease behavior', 'Disease', 'MESH:D001523', (102, 129))	('TCA', 'Chemical', 'MESH:D014233', (203, 206))	('intracellular metabolism', 'MPA', (142, 166))	('mutations', 'Var', (44, 53))	('presence', 'Var', (27, 35))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (183, 201))
26086	33193100	Pathogenic variants with genetic alterations in relevant genes are generally exclusive to each other, but it is also true that somatically mutated driver genes are involved in further development of PPGLs in a minor population with germline mutations, which is considered unique to this tumor.	('variants', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('involved', 'Reg', (164, 172))	('PPGLs', 'Chemical', '-', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))
26087	33193100	further demonstrated that 27% of PPGLs have germline mutations, 39% somatic mutations (with 5%-10% overlap with germline mutations), 7% gene fusions, and 89% copy number alterations.	('PPGLs', 'Chemical', '-', (33, 38))	('copy number alterations', 'Var', (158, 181))	('PPGLs', 'Gene', (33, 38))	('somatic mutations', 'CPA', (68, 85))	('germline mutations', 'Var', (44, 62))	('gene fusions', 'Var', (136, 148))
26089	33193100	The most prevalent subtype is the "pseudohypoxia type", with genetic alterations in SDHX families, FH, VHL, and EPAS1.	('pseudohypoxia', 'Disease', (35, 48))	('EPAS1', 'Gene', (112, 117))	('VHL', 'Gene', '7428', (103, 106))	('pseudohypoxia', 'Disease', 'None', (35, 48))	('SDHX families', 'Gene', (84, 97))	('prevalent', 'Reg', (9, 18))	('genetic alterations', 'Var', (61, 80))	('FH', 'Disease', 'MESH:D006938', (99, 101))	('EPAS1', 'Gene', '2034', (112, 117))	('VHL', 'Gene', (103, 106))
26090	33193100	The second is the "Wnt-signal type" associated with somatic alterations in genes involved in Wnt-signaling pathways, including CSDE1 mutation and MAML3 gene transfusion.	('CSDE1', 'Gene', (127, 132))	('mutation', 'Var', (133, 141))	('MAML3', 'Gene', '55534', (146, 151))	('MAML3', 'Gene', (146, 151))	('alterations', 'Var', (60, 71))
26095	33193100	However, genetic alterations in genes encoding catalyzing enzymes involved in the TCA cycle, such as succinate dehydrogenase, are known to result in loss of their physiological functions.	('loss', 'NegReg', (149, 153))	('genetic alterations', 'Var', (9, 28))	('TCA', 'Chemical', 'MESH:D014233', (82, 85))	('physiological functions', 'MPA', (163, 186))
26096	33193100	These altered genes subsequently promote anaerobic metabolism by tumor cells, shifting ATP resources from the TCA cycle into the system of metabolic glycolysis.	('promote', 'PosReg', (33, 40))	('tumor', 'Disease', (65, 70))	('anaerobic metabolism', 'MPA', (41, 61))	('TCA', 'Chemical', 'MESH:D014233', (110, 113))	('genes', 'Var', (14, 19))	('ATP', 'Chemical', 'MESH:D000255', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('shifting', 'Reg', (78, 86))
26098	33193100	These intracellular changes also enable tumor cells to efficiently synthesize ATP, although the amounts of ATP synthesized from glycolysis per reaction does not reach the same levels as those from the TCA cycle.	('ATP', 'Chemical', 'MESH:D000255', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('synthesize ATP', 'MPA', (67, 81))	('ATP', 'Chemical', 'MESH:D000255', (107, 110))	('TCA', 'Chemical', 'MESH:D014233', (201, 204))	('changes', 'Var', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
26103	33193100	The activation of Wnt-related signals is not necessarily specific for PPGLs, but the presence of this particular type of genetic abnormality has been reported to result in relatively frequent distant metastasis or recurrence, especially in cases involving MAML3 gene fusions.	('MAML3', 'Gene', '55534', (256, 261))	('recurrence', 'CPA', (214, 224))	('MAML3', 'Gene', (256, 261))	('genetic abnormality', 'Disease', 'MESH:D030342', (121, 140))	('PPGLs', 'Chemical', '-', (70, 75))	('genetic abnormality', 'Disease', (121, 140))	('distant metastasis', 'CPA', (192, 210))	('presence', 'Var', (85, 93))	('result in', 'Reg', (162, 171))
26104	33193100	Somatic mutations of the CSDE1 gene and transfusion of MAML3 are both classified as exhibiting this phenotype.	('transfusion', 'Var', (40, 51))	('CSDE1', 'Gene', (25, 30))	('MAML3', 'Gene', '55534', (55, 60))	('MAML3', 'Gene', (55, 60))
26105	33193100	CSDE1 frameshift and splice-site mutations have been reported in a minor population of PPGLs with previously known germline mutations, including VHL, NF1, and RET.	('splice-site mutations', 'Var', (21, 42))	('NF1', 'Gene', (150, 153))	('RET', 'Gene', '5979', (159, 162))	('NF1', 'Gene', '4763', (150, 153))	('RET', 'Gene', (159, 162))	('PPGLs', 'Chemical', '-', (87, 92))	('VHL', 'Gene', (145, 148))	('frameshift', 'Var', (6, 16))	('CSDE1', 'Gene', (0, 5))	('VHL', 'Gene', '7428', (145, 148))
26106	33193100	The functional roles of mutated variants of CSDE1 were also previously validated by microarray analysis using mouse embryonic stem cells.	('mouse', 'Species', '10090', (110, 115))	('variants', 'Var', (32, 40))	('mutated variants', 'Var', (24, 40))	('CSDE1', 'Gene', (44, 49))
26108	33193100	Comprehensive genetic analysis revealed that the UBTF-MAML3 fusion gene activates Wnt-Shh signaling, but only a small number of studies have investigated the clinical significance of this chimeric fusion gene.	('activates', 'PosReg', (72, 81))	('fusion', 'Var', (60, 66))	('UBTF', 'Gene', '7343', (49, 53))	('MAML3', 'Gene', (54, 59))	('Shh', 'Gene', '6469', (86, 89))	('UBTF', 'Gene', (49, 53))	('Shh', 'Gene', (86, 89))	('MAML3', 'Gene', '55534', (54, 59))
26110	33193100	Familial PHEOs with TMEM127 or MAX mutations are also categorized into this subtype.	('MAX', 'Gene', (31, 34))	('Familial PHEOs', 'Disease', (0, 14))	('TMEM127', 'Gene', (20, 27))	('TMEM127', 'Gene', '55654', (20, 27))	('mutations', 'Var', (35, 44))
26111	33193100	Among them, the gain-of-function caused by RET gene mutation has been studied in the most detail.	('RET', 'Gene', '5979', (43, 46))	('RET', 'Gene', (43, 46))	('mutation', 'Var', (52, 60))	('gain-of-function', 'PosReg', (16, 32))
26113	33193100	RET mutations detected in MEN2A are reported to cause homodimerization, which subsequently activates PI3K-AKT, RAS, p38-MAPK, and JUN N-terminal kinase pathways in a ligand-independent manner, promoting abnormal cell proliferation.	('AKT', 'Gene', (106, 109))	('RAS', 'Pathway', (111, 114))	('MEN2A', 'Gene', (26, 31))	('RET', 'Gene', '5979', (0, 3))	('cell proliferation', 'CPA', (212, 230))	('MEN2A', 'Gene', '5979', (26, 31))	('RET', 'Gene', (0, 3))	('cause', 'Reg', (48, 53))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (203, 230))	('activates', 'PosReg', (91, 100))	('JUN N-terminal kinase', 'Gene', '5599', (130, 151))	('promoting', 'PosReg', (193, 202))	('AKT', 'Gene', '207', (106, 109))	('JUN N-terminal kinase', 'Gene', (130, 151))	('mutations', 'Var', (4, 13))	('p38-MAPK', 'Pathway', (116, 124))	('homodimerization', 'MPA', (54, 70))
26117	33193100	Among these somatic gene abnormalities, aberrant telomere maintenance mechanism (TMM), which is caused by TERT (telomerase reverse transcriptase) structural rearrangement, genetic abnormalities, and ATRX mutations, has been reported to be associated with poor clinical outcomes in patients.	('associated', 'Reg', (239, 249))	('telomerase reverse transcriptase', 'Gene', '7015', (112, 144))	('TERT', 'Gene', (106, 110))	('mutations', 'Var', (204, 213))	('ATRX', 'Gene', (199, 203))	('TERT', 'Gene', '7015', (106, 110))	('patients', 'Species', '9606', (281, 289))	('genetic abnormalities', 'Disease', 'MESH:D030342', (172, 193))	('genetic abnormalities', 'Disease', (172, 193))	('ATRX', 'Gene', '546', (199, 203))	('telomerase reverse transcriptase', 'Gene', (112, 144))	('telomere maintenance mechanism', 'Disease', (49, 79))	('aberrant', 'Var', (40, 48))
26118	33193100	Structural rearrangement of TERT has also been reported to result in its over-expression as a result of the placement of enhancers proximal to the TERT promoter.	('TERT', 'Gene', (147, 151))	('rearrangement', 'Var', (11, 24))	('TERT', 'Gene', (28, 32))	('TERT', 'Gene', '7015', (147, 151))	('Structural rearrangement', 'Var', (0, 24))	('over-expression', 'MPA', (73, 88))	('enhancers', 'PosReg', (121, 130))	('TERT', 'Gene', '7015', (28, 32))
26119	33193100	The presence of somatic mutations detected in the TERT promoter is not necessarily concordant with TERT overexpression, but a specific hot-spot, C228T, is reported to be associated with adverse clinical outcomes in patients.	('patients', 'Species', '9606', (215, 223))	('TERT', 'Gene', '7015', (50, 54))	('TERT', 'Gene', (99, 103))	('C228T', 'Var', (145, 150))	('TERT', 'Gene', '7015', (99, 103))	('associated', 'Reg', (170, 180))	('TERT', 'Gene', (50, 54))	('C228T', 'Mutation', 'rs1450906770', (145, 150))
26135	33193100	The sensitivity of GAPP and M-GAPP is relatively high, while their specificity only reaches 50%-60% in terms of predicting distant metastasis in PPGL patients.	('M-GAPP', 'Var', (28, 34))	('patients', 'Species', '9606', (150, 158))	('distant metastasis', 'CPA', (123, 141))	('GAPP', 'Var', (19, 23))	('PPGL', 'Disease', (145, 149))
26136	33193100	The area under the curve (AUC) of these scoring systems resulted in 0.822 for M-GAPP, 0.728 for GAPP, and 0.753 for PASS, and there were no differences among the predictive values for patients.	('M-GAPP', 'Disease', (78, 84))	('GAPP', 'Var', (96, 100))	('PASS', 'Disease', (116, 120))	('patients', 'Species', '9606', (184, 192))
26145	33193100	Finally, COPPs were defined according to the following criteria: three clinicopathological parameters (tumor size > 7 cm, necrosis, and vascular invasion), loss of S-100 immunoreactivity (loss of intervening sustentacular cells), and loss of SDHB immunoreactivity (suggesting SDHB mutation) ( Figure 1E ).	('SDHB', 'Gene', '6390', (276, 280))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SDHB', 'Gene', '6390', (242, 246))	('necrosis', 'Disease', 'MESH:D009336', (122, 130))	('SDHB', 'Gene', (276, 280))	('tumor', 'Disease', (103, 108))	('mutation', 'Var', (281, 289))	('loss of SDHB immunoreactivity', 'Disease', (234, 263))	('loss', 'NegReg', (156, 160))	('SDHB', 'Gene', (242, 246))	('S-100 immunoreactivity', 'Protein', (164, 186))	('loss of SDHB immunoreactivity', 'Disease', 'MESH:C537505', (234, 263))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('necrosis', 'Disease', (122, 130))
26149	33193100	SDHB IHC has been employed to detect SDHB gene mutations with relatively high concordance (sensitivity: 100% [95% CI: 87%-100%], specificity: 84% [95% CI: 60%-97%]) as demonstrated by the total absence of immunoreactivity, with positive immunoreactivity in endothelial cells as a positive IHC control.	('SDHB', 'Gene', '6390', (37, 41))	('mutations', 'Var', (47, 56))	('SDHB', 'Gene', (37, 41))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))
26162	33193100	Of particular interest, pseudohypoxic PPGLs are generally negative for PNMT, and have silent clinical and hormonal phenotypes, which could delay therapeutic intervention in such patients.	('patients', 'Species', '9606', (178, 186))	('PNMT', 'Gene', (71, 75))	('negative', 'NegReg', (58, 66))	('PNMT', 'Gene', '5409', (71, 75))	('PPGLs', 'Chemical', '-', (38, 43))	('pseudohypoxic', 'Var', (24, 37))
26181	33193100	Among them, SDHX mutations are the most frequently detected, resulting in pseudohypoxic status of tumor cells and which correlate with patient clinical outcomes, especially in detecting metastatic potential.	('resulting in', 'Reg', (61, 73))	('patient', 'Species', '9606', (135, 142))	('pseudohypoxic status of', 'MPA', (74, 97))	('SDHX', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('metastatic potential', 'CPA', (186, 206))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('mutations', 'Var', (17, 26))
26251	32106822	Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing von Hippel-Lindau (VHL) disease is a familial neoplasia syndrome that results from the germline mutation of VHL.	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('familial neoplasia syndrome', 'Disease', 'MESH:D009369', (176, 203))	('VHL', 'Gene', '7428', (158, 161))	('c.414A > G', 'Var', (40, 50))	('VHL', 'Gene', (26, 29))	('c.414A > G', 'Mutation', 'rs869025648', (40, 50))	('p.Pro138Pro', 'Mutation', 'rs869025648', (52, 63))	('familial neoplasia syndrome', 'Disease', (176, 203))	('VHL', 'Gene', '7428', (26, 29))	('VHL', 'Gene', (247, 250))	('VHL', 'Gene', (158, 161))	('causes', 'Reg', (65, 71))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (139, 170))	('familial hemangioblastoma', 'Disease', 'MESH:D018325', (83, 108))	('VHL', 'Gene', '7428', (247, 250))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (92, 108))	('familial hemangioblastoma', 'Disease', (83, 108))
26252	32106822	Pathogenic VHL mutations include deletion, frameshift, nonsense and missense mutations.	('Pathogenic', 'Reg', (0, 10))	('deletion', 'Var', (33, 41))	('frameshift', 'Var', (43, 53))	('missense mutations', 'Var', (68, 86))	('VHL', 'Gene', (11, 14))	('VHL', 'Gene', '7428', (11, 14))	('nonsense', 'Var', (55, 63))
26253	32106822	Synonymous mutations are expected to be phenotypically silent and their role in VHL disease remains poorly understood.	('Synonymous mutations', 'Var', (0, 20))	('VHL disease', 'Disease', 'MESH:D006623', (80, 91))	('VHL disease', 'Disease', (80, 91))
26254	32106822	We report a Caucasian male with a family history of pheochromocytoma and the synonymous VHL mutation c.414A > G (p.Pro138Pro).	('c.414A > G', 'Mutation', 'rs869025648', (101, 111))	('pheochromocytoma', 'Disease', 'MESH:D010673', (52, 68))	('p.Pro138Pro', 'Mutation', 'rs869025648', (113, 124))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (52, 68))	('VHL', 'Gene', (88, 91))	('VHL', 'Gene', '7428', (88, 91))	('pheochromocytoma', 'Disease', (52, 68))	('c.414A > G', 'Var', (101, 111))
26258	32106822	Two of three of the proband's children inherited the mutation and both presented with retinal hemangioblastomas without pheochromocytoma at age 7: one twin needed four laser treatments.	('mutation', 'Var', (53, 61))	('children', 'Species', '9606', (30, 38))	('retinal hemangioblastoma', 'Phenotype', 'HP:0009711', (86, 110))	('retinal hemangioblastomas', 'Disease', 'MESH:D018325', (86, 111))	('inherited', 'Reg', (39, 48))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (94, 110))	('pheochromocytoma', 'Disease', (120, 136))	('retinal hemangioblastomas', 'Phenotype', 'HP:0009711', (86, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('presented with', 'Reg', (71, 85))	('pheochromocytoma', 'Disease', 'MESH:D010673', (120, 136))	('retinal hemangioblastomas', 'Disease', (86, 111))
26260	32106822	Mutant fibroblasts downregulated full-length VHL mRNA and protein, and upregulated the short VHL mRNA isoform (a result of exon 2 skipping in splicing) at the mRNA level but not at the protein level.	('VHL', 'Gene', '7428', (45, 48))	('full-length', 'MPA', (33, 44))	('VHL', 'Gene', '7428', (93, 96))	('Mutant', 'Var', (0, 6))	('VHL', 'Gene', (45, 48))	('VHL', 'Gene', (93, 96))	('downregulated', 'NegReg', (19, 32))	('upregulated', 'PosReg', (71, 82))
26261	32106822	Our study shows that the synonymous VHL mutation c.414A > G can within 7 years induce pediatric retinal hemangioblastoma in absence of pheochromocytoma.	('hemangioblastoma', 'Phenotype', 'HP:0010797', (104, 120))	('VHL', 'Gene', (36, 39))	('pheochromocytoma', 'Disease', (135, 151))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('VHL', 'Gene', '7428', (36, 39))	('retinal hemangioblastoma', 'Phenotype', 'HP:0009711', (96, 120))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('induce', 'PosReg', (79, 85))	('pediatric retinal hemangioblastoma', 'Disease', 'MESH:D018325', (86, 120))	('c.414A > G', 'Mutation', 'rs869025648', (49, 59))	('mutation c.414A > G', 'Var', (40, 59))	('pediatric retinal hemangioblastoma', 'Disease', (86, 120))
26262	32106822	This highlights the need to include splicing-altering synonymous mutations into the screening for VHL disease.	('VHL disease', 'Disease', 'MESH:D006623', (98, 109))	('VHL disease', 'Disease', (98, 109))	('splicing-altering synonymous mutations', 'Var', (36, 74))
26263	32106822	This is also the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts.	('VHL', 'Gene', (71, 74))	('patient', 'Species', '9606', (90, 97))	('mutation', 'Var', (75, 83))	('VHL', 'Gene', '7428', (71, 74))
26264	32106822	The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2.	('skipping', 'NegReg', (125, 133))	('splicing', 'MPA', (113, 121))	('c.414A > G', 'Var', (13, 23))	('c.414A > G', 'Mutation', 'rs869025648', (13, 23))	('causes', 'Reg', (97, 103))	('p.Pro138Pro', 'Mutation', 'rs869025648', (38, 49))
26267	32106822	Germline mutations in the VHL gene lead to the development of benign or malignant tumors in many organ systems.	('Germline mutations', 'Var', (0, 18))	('malignant tumors', 'Disease', 'MESH:D009369', (72, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('VHL', 'Gene', (26, 29))	('development', 'CPA', (47, 58))	('VHL', 'Gene', '7428', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lead to', 'Reg', (35, 42))	('malignant tumors', 'Disease', (72, 88))
26271	32106822	VHL disease has a characteristic genotype-phenotype correlation: Type 1 has a very low risk of PHEO and is most commonly caused by VHL exon deletion, truncation, frameshift and nonsense mutations; Type 2 has a higher risk of PHEO and is characterized by VHL missense mutations.	('VHL disease', 'Disease', (0, 11))	('caused', 'Reg', (121, 127))	('frameshift', 'Var', (162, 172))	('truncation', 'Var', (150, 160))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', '7428', (254, 257))	('PHEO', 'Disease', (225, 229))	('PHEO', 'Phenotype', 'HP:0002666', (225, 229))	('nonsense mutations', 'Var', (177, 195))	('VHL', 'Gene', (131, 134))	('PHEO', 'Disease', 'MESH:D010673', (95, 99))	('VHL', 'Gene', '7428', (131, 134))	('PHEO', 'Disease', (95, 99))	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('VHL', 'Gene', (0, 3))	('exon deletion', 'Var', (135, 148))	('VHL', 'Gene', (254, 257))	('PHEO', 'Disease', 'MESH:D010673', (225, 229))	('PHEO', 'Phenotype', 'HP:0002666', (95, 99))
26278	32106822	However, increasing evidence indicates that synonymous mutations may not be merely passenger events; instead, they can actively contribute to human cancers, often through alternation of pre-mRNA splicing.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('contribute', 'Reg', (128, 138))	('cancers', 'Disease', (148, 155))	('alternation', 'Reg', (171, 182))	('human', 'Species', '9606', (142, 147))	('pre-mRNA splicing', 'MPA', (186, 203))	('synonymous mutations', 'Var', (44, 64))
26279	32106822	For example, recurrent synonymous mutations in the tumor suppressor gene TP53 were found to impair the wild type splice sites and activate cryptic splice sites.	('synonymous mutations', 'Var', (23, 43))	('activate', 'PosReg', (130, 138))	('wild type splice sites', 'MPA', (103, 125))	('TP53', 'Gene', '7157', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TP53', 'Gene', (73, 77))	('tumor', 'Disease', (51, 56))	('cryptic splice sites', 'MPA', (139, 159))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('impair', 'NegReg', (92, 98))
26281	32106822	E1E2E3 encodes a longer protein of 213 amino acids (pVHL213) and a shorter protein of 160 amino acids (pVHL160) due to translation initiation from an internal start site.	('pVHL', 'Gene', '7428', (52, 56))	('pVHL', 'Gene', '7428', (103, 107))	('pVHL', 'Gene', (52, 56))	('pVHL', 'Gene', (103, 107))	('E1E2E3', 'Var', (0, 6))
26283	32106822	E1E3 encodes a protein of 172 amino acids (pVHL172) with generally low expression abundance and a possible lack of the tumor suppressor function due to the disruption of the HIF-binding domain.	('disruption', 'Var', (156, 166))	('tumor', 'Disease', (119, 124))	('HIF-binding', 'Protein', (174, 185))	('lack', 'NegReg', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('expression abundance', 'MPA', (71, 91))	('pVHL', 'Gene', '7428', (43, 47))	('E1E3', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('pVHL', 'Gene', (43, 47))	('low', 'NegReg', (67, 70))
26284	32106822	Recent studies suggest that synonymous mutations of VHL can also lead to dysregulated splicing.	('VHL', 'Gene', '7428', (52, 55))	('dysregulated splicing', 'MPA', (73, 94))	('lead to', 'Reg', (65, 72))	('synonymous mutations', 'Var', (28, 48))	('VHL', 'Gene', (52, 55))
26286	32106822	Here, we provide an independent line of evidence to demonstrate that a synonymous mutation in exon 2 of VHL that shifts the pattern of splicing and expression of VHL at the cellular level is pathogenic to cause HGB both with and without PHEO.	('VHL', 'Gene', (162, 165))	('VHL', 'Gene', '7428', (104, 107))	('VHL', 'Gene', '7428', (162, 165))	('HGB', 'Disease', (211, 214))	('PHEO', 'Phenotype', 'HP:0002666', (237, 241))	('pathogenic', 'Reg', (191, 201))	('mutation in', 'Var', (82, 93))	('HGB', 'Phenotype', 'HP:0010797', (211, 214))	('PHEO', 'Disease', 'MESH:D010673', (237, 241))	('VHL', 'Gene', (104, 107))	('PHEO', 'Disease', (237, 241))	('cause', 'Reg', (205, 210))	('HGB', 'Disease', 'MESH:D018325', (211, 214))
26290	32106822	The proband's test results revealed a heterozygous mutation from A to G at the nucleotide position 414 in the coding sequence of VHL transcript NM_000551, which surprisingly is a synonymous mutation that does not change the coded amino acid (p.Pro138Pro) of the protein pVHL.	('VHL', 'Gene', (129, 132))	('pVHL', 'Gene', (270, 274))	('pVHL', 'Gene', '7428', (270, 274))	('VHL', 'Gene', '7428', (129, 132))	('VHL', 'Gene', (271, 274))	('mutation', 'Var', (51, 59))	('p.Pro138Pro', 'Mutation', 'rs869025648', (242, 253))	('VHL', 'Gene', '7428', (271, 274))
26305	32106822	Children underwent genetic testing and confirmed that the son had wild type VHL and the twins both inherited the c.414A > G mutation.	('VHL', 'Gene', (76, 79))	('Children', 'Species', '9606', (0, 8))	('VHL', 'Gene', '7428', (76, 79))	('c.414A > G', 'Var', (113, 123))	('c.414A > G', 'Mutation', 'rs869025648', (113, 123))
26323	32106822	To examine whether this mutation affects splicing and gene expression, we first performed Reverse Transcriptase PCR (RT-PCR) on the 5 fibroblast cell lines using primers that locate in Exon 1 (F1: 5'-GCGTCGTGCTGCCCGTATG-3') and Exon 3 (R1: 5'-TTCTGCACATTTGGGTGGTCTT-3') of VHL transcript (shown schematically in Fig.	('affects', 'Reg', (33, 40))	('VHL', 'Gene', '7428', (273, 276))	('VHL', 'Gene', (273, 276))	('mutation', 'Var', (24, 32))
26324	32106822	We saw a significant change in the pattern of expressed VHL transcripts, with a higher expression level of the E1E3 mRNA at the expense of lower level of E1E2E3 mRNA for Proband, Twin 1 and Twin 2 fibroblasts relative to the two VHLWT fibroblasts (Fig.	('VHL', 'Gene', (56, 59))	('expression level', 'MPA', (87, 103))	('VHL', 'Gene', '7428', (56, 59))	('VHL', 'Gene', (229, 232))	('VHL', 'Gene', '7428', (229, 232))	('higher', 'PosReg', (80, 86))	('E1E3', 'Var', (111, 115))
26326	32106822	Consistent with downregulated E1E2E3 transcript, pVHL213 was downregulated in mutant fibroblasts compared with WT fibroblasts (Fig.	('transcript', 'MPA', (37, 47))	('pVHL', 'Gene', '7428', (49, 53))	('downregulated', 'NegReg', (61, 74))	('E1E2E3', 'Gene', (30, 36))	('pVHL', 'Gene', (49, 53))	('mutant', 'Var', (78, 84))	('downregulated', 'NegReg', (16, 29))
26327	32106822	Contrary to our expectation, pVHL172 was also downregulated in mutant fibroblasts (Fig.	('pVHL', 'Gene', (29, 33))	('downregulated', 'NegReg', (46, 59))	('mutant', 'Var', (63, 69))	('pVHL', 'Gene', '7428', (29, 33))
26328	32106822	Our study shows that the synonymous VHL mutation c.414A > G can induce pediatric retinal HGB in the absence of PHEO.	('induce', 'Reg', (64, 70))	('VHL', 'Gene', (36, 39))	('PHEO', 'Phenotype', 'HP:0002666', (111, 115))	('VHL', 'Gene', '7428', (36, 39))	('pediatric retinal HGB', 'Disease', 'MESH:D018325', (71, 92))	('HGB', 'Phenotype', 'HP:0010797', (89, 92))	('PHEO', 'Disease', 'MESH:D010673', (111, 115))	('c.414A > G', 'Mutation', 'rs869025648', (49, 59))	('pediatric retinal HGB', 'Disease', (71, 92))	('PHEO', 'Disease', (111, 115))	('mutation c.414A > G', 'Var', (40, 59))
26329	32106822	In the adult proband, the mutation caused the development of HGB with PHEO.	('HGB', 'Phenotype', 'HP:0010797', (61, 64))	('HGB', 'Disease', 'MESH:D018325', (61, 64))	('mutation', 'Var', (26, 34))	('PHEO', 'Phenotype', 'HP:0002666', (70, 74))	('caused', 'Reg', (35, 41))	('HGB', 'Disease', (61, 64))	('PHEO', 'Disease', 'MESH:D010673', (70, 74))	('PHEO', 'Disease', (70, 74))
26332	32106822	Although this variant was shown to be associated with PHEO, the clinical information on its role in HGB was limited.	('associated', 'Reg', (38, 48))	('PHEO', 'Disease', (54, 58))	('HGB', 'Phenotype', 'HP:0010797', (100, 103))	('HGB', 'Disease', 'MESH:D018325', (100, 103))	('PHEO', 'Phenotype', 'HP:0002666', (54, 58))	('HGB', 'Disease', (100, 103))	('variant', 'Var', (14, 21))	('PHEO', 'Disease', 'MESH:D010673', (54, 58))
26334	32106822	In this report, the natural history indicates that this variant can be causal for assertive development of HGB in brain and retina needing multiple interventions, strongly recommending that affected asymptomatic patients undergo regular brain, spine and abdominal MRI screenings and ophthalmologic exams.	('variant', 'Var', (56, 63))	('HGB', 'Disease', (107, 110))	('HGB', 'Phenotype', 'HP:0010797', (107, 110))	('patients', 'Species', '9606', (212, 220))	('HGB', 'Disease', 'MESH:D018325', (107, 110))
26335	32106822	This is the first report on detecting and validating a synonymous VHL mutation using patient-derived fibroblasts.	('mutation', 'Var', (70, 78))	('patient', 'Species', '9606', (85, 92))	('VHL', 'Gene', '7428', (66, 69))	('VHL', 'Gene', (66, 69))
26336	32106822	The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because the mutation causes aberrant splicing by skipping exon 2.	('skipping', 'NegReg', (135, 143))	('c.414A > G', 'Var', (13, 23))	('c.414A > G', 'Mutation', 'rs869025648', (13, 23))	('causes', 'Reg', (107, 113))	('p.Pro138Pro', 'Mutation', 'rs869025648', (38, 49))
26340	32106822	Using the fibroblasts derived from three patients and two healthy individuals, we confirmed that the c.414A > G mutation led to VHL exon 2 skipping and generated less E1E2E3 but more E1E3, consistent with previous reports.	('c.414A > G', 'Mutation', 'rs869025648', (101, 111))	('VHL', 'Gene', '7428', (128, 131))	('skipping', 'NegReg', (139, 147))	('E1E2E3', 'MPA', (167, 173))	('patients', 'Species', '9606', (41, 49))	('E1E3', 'MPA', (183, 187))	('VHL', 'Gene', (128, 131))	('c.414A > G', 'Var', (101, 111))
26341	32106822	Mechanistically, c.414A > G mutation may dysregulate the exonic splicing enhancer in exon 2 and cause exon 2 skipping.	('exonic splicing enhancer in', 'MPA', (57, 84))	('dysregulate', 'Reg', (41, 52))	('c.414A > G', 'Var', (17, 27))	('exon 2 skipping', 'MPA', (102, 117))	('cause', 'Reg', (96, 101))	('c.414A > G', 'Mutation', 'rs869025648', (17, 27))
26342	32106822	To our surprise, we observed lower protein levels for both pVHL213 (encoded by E1E2E3) and pVHL172 (encoded by E1E3) in mutant fibroblasts compared with wild type fibroblasts.	('pVHL', 'Gene', '7428', (59, 63))	('pVHL', 'Gene', (59, 63))	('mutant', 'Var', (120, 126))	('pVHL', 'Gene', '7428', (91, 95))	('lower', 'NegReg', (29, 34))	('pVHL', 'Gene', (91, 95))	('protein levels', 'MPA', (35, 49))
26343	32106822	This result strengthens a similar finding using lymphoblastoid cell lines carrying the c.414A > G mutation and suggest that there may be unidentified mechanisms regulating the translation or protein stability of pVHL172 so that this isoform level remains in proportionally lower abundance relative to the combined pVHL213 and pVHL160 level.	('protein', 'MPA', (191, 198))	('pVHL', 'Gene', '7428', (326, 330))	('abundance', 'MPA', (279, 288))	('pVHL', 'Gene', (212, 216))	('pVHL', 'Gene', '7428', (314, 318))	('pVHL', 'Gene', (314, 318))	('c.414A > G', 'Var', (87, 97))	('pVHL', 'Gene', '7428', (212, 216))	('c.414A > G', 'Mutation', 'rs869025648', (87, 97))	('lower', 'NegReg', (273, 278))	('pVHL', 'Gene', (326, 330))
26347	32106822	The findings from this study and others, strongly advocate changing the status of VHL c.414A > G variant from "Uncertain significance" to "Pathogenic" for VHL disease in human variant databases (e.g.	('VHL', 'Gene', '7428', (155, 158))	('VHL disease', 'Disease', (155, 166))	('c.414A > G', 'Var', (86, 96))	('VHL', 'Gene', (82, 85))	('VHL disease', 'Disease', 'MESH:D006623', (155, 166))	('human variant', 'Species', '9606', (170, 183))	('VHL', 'Gene', '7428', (82, 85))	('c.414A > G', 'Mutation', 'rs869025648', (86, 96))	('VHL', 'Gene', (155, 158))
26348	32106822	An unresolved issue is the mechanism how the exon 2 skipping mechanism causes the Type 2A disease phenotype which typically involves missense mutations.	('missense mutations', 'Var', (133, 151))	('Type 2A disease', 'Disease', 'MESH:C536464', (82, 97))	('Type 2A disease', 'Disease', (82, 97))	('causes', 'Reg', (71, 77))	('exon 2 skipping mechanism', 'Var', (45, 70))
26349	32106822	Clinically, the PHEO tumors in patients carrying c.414A > G mutation lost the other WT allele, demonstrating LOH as described in classic VHL disease.	('PHEO', 'Disease', 'MESH:D010673', (16, 20))	('VHL disease', 'Disease', 'MESH:D006623', (137, 148))	('other WT allele', 'MPA', (78, 93))	('tumors', 'Disease', (21, 27))	('PHEO', 'Disease', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('PHEO', 'Phenotype', 'HP:0002666', (16, 20))	('c.414A > G', 'Var', (49, 59))	('patients', 'Species', '9606', (31, 39))	('c.414A > G', 'Mutation', 'rs869025648', (49, 59))	('VHL disease', 'Disease', (137, 148))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
26350	32106822	Therefore, it is conceivable that this hypomorphic mutation in the backdrop of LOH creates a residual amount of pVHL activity that makes cells in the adrenal glands and CNS, but not kidney, susceptible to tumorigenesis.	('pVHL', 'Gene', (112, 116))	('activity', 'MPA', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('makes', 'Reg', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('mutation', 'Var', (51, 59))	('pVHL', 'Gene', '7428', (112, 116))
26374	30073909	The advent of these techniques has facilitated the identification of causative genes in rare diseases, and of gene variants that confer a relatively low disease risk.	('low disease', 'Disease', (149, 160))	('rare diseases', 'Disease', (88, 101))	('variants', 'Var', (115, 123))	('low disease', 'Disease', 'MESH:D009800', (149, 160))
26375	30073909	For gene variant carriers, the following notation is used: the age at diagnosis of the disease is denoted by T with cumulative distribution F and density f, and the age at the end of the study (collection of the data), or the age at death (whichever occurs first) by C, with distribution G and density g. It is assumed that T and C are independent.	('death', 'Disease', 'MESH:D003643', (233, 238))	('variant', 'Var', (9, 16))	('death', 'Disease', (233, 238))
26393	30073909	The development of the method described in this paper was inspired by a study that was aimed at estimating the risk of developing a paraganglioma or pheochromocytoma (rare, usually benign neuroendocrine neoplasms) in carriers of germline SDHB gene variant.	('SDHB', 'Gene', '6390', (238, 242))	('variant', 'Var', (248, 255))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('paraganglioma or pheochromocytoma', 'Disease', (132, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (149, 165))	('SDHB', 'Gene', (238, 242))	('neoplasms', 'Phenotype', 'HP:0002664', (203, 212))	('benign neuroendocrine neoplasms', 'Disease', 'MESH:D018358', (181, 212))	('paraganglioma or pheochromocytoma', 'Disease', 'MESH:D010673', (132, 165))	('benign neuroendocrine neoplasms', 'Disease', (181, 212))	('neuroendocrine neoplasms', 'Phenotype', 'HP:0100634', (188, 212))
26395	30073909	All individuals had consented to DNA testing, and all included individuals were identified as carriers of a SDHB gene variant predisposing to paraganglioma/pheochromocytoma.	('SDHB', 'Gene', (108, 112))	('variant', 'Var', (118, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (156, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (142, 155))	('paraganglioma/pheochromocytoma', 'Disease', (142, 172))	('paraganglioma/pheochromocytoma', 'Disease', 'MESH:D010673', (142, 172))	('SDHB', 'Gene', '6390', (108, 112))
26400	30073909	For some diseases the age-at-onset distribution may depend on genetic characteristics, like the variant at the disease-susceptibility gene or the number of repeat units (for instance for the disease FSHD).	('FSHD', 'Gene', (199, 203))	('variant', 'Var', (96, 103))	('FSHD', 'Gene', '2489', (199, 203))	('depend', 'Reg', (52, 58))
26401	30073909	The estimation of the penetrance of pathogenic gene variants is ideally based on a large number of affected pedigrees, collected in a study with clear ascertainment rules, with a high uptake of DNA tests by family members and detailed descriptions of the phenotype of all variant carriers.	('eta', 'Gene', '1909', (227, 230))	('eta', 'Gene', (227, 230))	('variants', 'Var', (52, 60))
26437	31328636	An alteration in neurohormonal signaling may act as candidate pathogenic contributor to the progressive pulmonary vascular remodeling process and the development of right heart failure.	('right heart failure', 'Disease', 'MESH:D006333', (165, 184))	('pulmonary vascular remodeling process', 'CPA', (104, 141))	('alteration', 'Var', (3, 13))	('neurohormonal signaling', 'MPA', (17, 40))	('heart failure', 'Phenotype', 'HP:0001635', (171, 184))	('right heart failure', 'Phenotype', 'HP:0001708', (165, 184))	('right heart failure', 'Disease', (165, 184))	('men', 'Species', '9606', (157, 160))	('development of right heart', 'Phenotype', 'HP:0010954', (150, 176))
26502	31328636	The main advantage of 123I-MIBG imaging is related to its organ-specificity in detecting cardiac alterations secondary to sympathetic system activation.	('123I-MIBG', 'Chemical', '-', (22, 31))	('cardiac alterations', 'MPA', (89, 108))	('123I-MIBG', 'Var', (22, 31))
26528	31328636	Despite the growing evidence of the important role of cardiac 123I-MIBG as a tool to evaluate organ-specific sympathetic nervous dysfunction, its clinical use has remained very limited because of economic concerns relative to reimbursement and funding.	('123I-MIBG', 'Var', (62, 71))	('nervous dysfunction', 'Disease', 'MESH:D009422', (121, 140))	('men', 'Species', '9606', (235, 238))	('sympathetic nervous dysfunction', 'Phenotype', 'HP:0012332', (109, 140))	('123I-MIBG', 'Chemical', '-', (62, 71))	('nervous dysfunction', 'Disease', (121, 140))
26590	31011769	Of these 45 patients, DNA analysis revealed germ-line mutations in the following genes: MEN2A in seven patients, SDHA in four patients, MAX in two patients, and NF-1 in one patient.	('MAX', 'Gene', (136, 139))	('patients', 'Species', '9606', (12, 20))	('NF-1', 'Gene', (161, 165))	('patient', 'Species', '9606', (147, 154))	('patient', 'Species', '9606', (173, 180))	('mutations', 'Var', (54, 63))	('SDHA', 'Gene', '6389', (113, 117))	('patient', 'Species', '9606', (12, 19))	('patient', 'Species', '9606', (126, 133))	('patient', 'Species', '9606', (103, 110))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (126, 134))	('SDHA', 'Gene', (113, 117))	('MEN2A', 'Gene', '5979', (88, 93))	('patients', 'Species', '9606', (103, 111))	('MEN2A', 'Gene', (88, 93))
26630	30135421	HIF-2alpha-pVHL complex reveals broad genotype-phenotype correlations in HIF-2alpha-driven disease It is definitively established that mutations in transcription factor HIF-2alpha are causative of both neuroendocrine tumors (class 1 disease) and polycythemia (class 2 disease).	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (202, 223))	('HIF-2alpha', 'Gene', '2034', (169, 179))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (202, 222))	('polycythemia', 'Phenotype', 'HP:0001901', (246, 258))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (202, 223))	('mutations', 'Var', (135, 144))	('HIF-2alpha', 'Gene', '2034', (73, 83))	('HIF-2alpha', 'Gene', '2034', (0, 10))	('HIF-2alpha', 'Gene', (169, 179))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('neuroendocrine tumors', 'Disease', (202, 223))	('causative', 'Reg', (184, 193))	('polycythemia', 'Disease', (246, 258))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('HIF-2alpha', 'Gene', (73, 83))	('polycythemia', 'Disease', 'MESH:D011086', (246, 258))	('pVHL', 'Gene', '7428', (11, 15))	('pVHL', 'Gene', (11, 15))	('HIF-2alpha', 'Gene', (0, 10))
26631	30135421	Here, we report the structure of HIF-2alpha peptide bound to pVHL-elongin B-elongin C (VBC) heterotrimeric complex, which shows topographical demarcation of class 1 and 2 mutations affecting residues predicted, and demonstrated via biophysical analyses, to differentially impact HIF-2alpha-pVHL interaction interface stability.	('interaction', 'Interaction', (295, 306))	('elongin C', 'Gene', (76, 85))	('VBC', 'Chemical', '-', (87, 90))	('elongin B', 'Gene', '6923', (66, 75))	('elongin B', 'Gene', (66, 75))	('peptide', 'Chemical', 'MESH:D010455', (44, 51))	('elongin C', 'Gene', '6921', (76, 85))	('impact', 'Reg', (272, 278))	('pVHL', 'Gene', '7428', (290, 294))	('pVHL', 'Gene', '7428', (61, 65))	('mutations', 'Var', (171, 180))	('pVHL', 'Gene', (290, 294))	('pVHL', 'Gene', (61, 65))
26632	30135421	Concordantly, biochemical experiments showed that class 1 mutations disrupt pVHL affinity to HIF-2alpha more adversely than class 2 mutations directly or indirectly via impeding PHD2-mediated hydroxylation.	('mutations', 'Var', (58, 67))	('pVHL', 'Gene', '7428', (76, 80))	('pVHL', 'Gene', (76, 80))	('impeding', 'NegReg', (169, 177))	('affinity', 'Interaction', (81, 89))	('PHD2', 'Gene', (178, 182))	('PHD2', 'Gene', '54583', (178, 182))	('disrupt', 'NegReg', (68, 75))
26634	30135421	Hypoxia inducible factor (HIF)-2alpha transcription factor is mutated in polycythemia and various neuroendocrine tumors.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (98, 119))	('Hypoxia inducible factor (HIF)-2alpha', 'Gene', '2034', (0, 37))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('neuroendocrine tumors', 'Disease', (98, 119))	('polycythemia', 'Phenotype', 'HP:0001901', (73, 85))	('polycythemia', 'Disease', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutated', 'Var', (62, 69))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (98, 118))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (98, 119))	('polycythemia', 'Disease', 'MESH:D011086', (73, 85))
26635	30135421	Here the authors present the crystal structure of a HIF-2alpha peptide bound to the pVHL-elongin B-elongin C (VBC) heterotrimeric complex and propose a classification scheme for HIF-2alpha mutations that helps to predict disease phenotype outcome.	('HIF-2alpha', 'Gene', (52, 62))	('VBC', 'Chemical', '-', (110, 113))	('elongin C', 'Gene', '6921', (99, 108))	('elongin C', 'Gene', (99, 108))	('pVHL', 'Gene', '7428', (84, 88))	('HIF-2alpha', 'Gene', (178, 188))	('pVHL', 'Gene', (84, 88))	('elongin B', 'Gene', '6923', (89, 98))	('mutations', 'Var', (189, 198))	('peptide', 'Chemical', 'MESH:D010455', (63, 70))	('elongin B', 'Gene', (89, 98))
26636	30135421	Recent discoveries have established that mutations in EPAS1, the gene encoding hypoxia-inducible factor (HIF)-2alpha transcription factor, are causative of familial and sporadic instances of polycythemia, as well as various neuroendocrine tumors.	('mutations', 'Var', (41, 50))	('polycythemia', 'Phenotype', 'HP:0001901', (191, 203))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (224, 244))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('EPAS1', 'Gene', (54, 59))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (224, 245))	('polycythemia', 'Disease', 'MESH:D011086', (191, 203))	('causative', 'Reg', (143, 152))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (224, 245))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('familial', 'Disease', (156, 164))	('neuroendocrine tumors', 'Disease', (224, 245))	('hypoxia', 'Disease', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('polycythemia', 'Disease', (191, 203))	('EPAS1', 'Gene', '2034', (54, 59))
26641	30135421	In studies featuring large cohorts of patients, EPAS1 mutations were identified in 5.7% of patients presenting with sporadic PPGLs (18/315, range of 2.3-12%), establishing EPAS1 mutations as a major driver of PPGL.	('patients', 'Species', '9606', (91, 99))	('PPGLs', 'Disease', (125, 130))	('EPAS1', 'Gene', '2034', (48, 53))	('mutations', 'Var', (54, 63))	('EPAS1', 'Gene', '2034', (172, 177))	('EPAS1', 'Gene', (48, 53))	('EPAS1', 'Gene', (172, 177))	('patients', 'Species', '9606', (38, 46))
26642	30135421	EPAS1 mutations have been shown, regardless of associated phenotype, to result in an increase in HIF-2alpha stability, by disrupting negative regulation via prolyl hydroxylase domain containing enzyme (PHD) and/or von Hippel-Lindau protein (pVHL) affinity to HIF-2alpha.	('EPAS1', 'Gene', '2034', (0, 5))	('pVHL', 'Gene', '7428', (241, 245))	('pVHL', 'Gene', (241, 245))	('EPAS1', 'Gene', (0, 5))	('disrupting', 'NegReg', (122, 132))	('HIF-2alpha stability', 'Disease', (97, 117))	('von Hippel-Lindau', 'Disease', (214, 231))	('increase', 'PosReg', (85, 93))	('HIF-2alpha stability', 'Disease', 'MESH:D043171', (97, 117))	('affinity', 'Interaction', (247, 255))	('negative regulation', 'MPA', (133, 152))	('mutations', 'Var', (6, 15))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (214, 231))
26646	30135421	Mutations in both VHL and EGLN1 (encodes PHD2) are known to cause both polycythemia and PPGL.	('polycythemia', 'Disease', (71, 83))	('VHL', 'Gene', '7428', (18, 21))	('cause', 'Reg', (60, 65))	('EGLN1', 'Gene', (26, 31))	('polycythemia', 'Disease', 'MESH:D011086', (71, 83))	('polycythemia', 'Phenotype', 'HP:0001901', (71, 83))	('PHD2', 'Gene', '54583', (41, 45))	('Mutations', 'Var', (0, 9))	('EGLN1', 'Gene', '54583', (26, 31))	('PHD2', 'Gene', (41, 45))	('VHL', 'Gene', (18, 21))	('PPGL', 'Disease', (88, 92))
26647	30135421	VHL mutation associated with PGL, polycythemia, and somatostatinoma has also been reported.	('associated', 'Reg', (13, 23))	('somatostatinoma', 'Disease', 'MESH:D013005', (52, 67))	('somatostatinoma', 'Disease', (52, 67))	('polycythemia', 'Disease', (34, 46))	('mutation', 'Var', (4, 12))	('PGL', 'Disease', (29, 32))	('VHL', 'Gene', (0, 3))	('polycythemia', 'Phenotype', 'HP:0001901', (34, 46))	('polycythemia', 'Disease', 'MESH:D011086', (34, 46))	('VHL', 'Gene', '7428', (0, 3))
26648	30135421	However, pheochromocytoma-associated VHL mutations have previously been suspected of triggering oncogenesis in a HIF-independent manner.	('mutations', 'Var', (41, 50))	('pheochromocytoma', 'Disease', (9, 25))	('VHL', 'Gene', (37, 40))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('VHL', 'Gene', '7428', (37, 40))	('pheochromocytoma', 'Disease', 'MESH:D010673', (9, 25))
26649	30135421	It has been noted that EPAS1 mutations associated with ECYT4 are genetically distinct from those that are associated with neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (122, 143))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (122, 143))	('ECYT4', 'Gene', '2034', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (29, 38))	('ECYT4', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('neuroendocrine tumors', 'Disease', (122, 143))	('associated', 'Reg', (39, 49))	('EPAS1', 'Gene', '2034', (23, 28))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (122, 142))	('EPAS1', 'Gene', (23, 28))
26650	30135421	However, to date, HIF-2alpha activating mutations associated with different phenotypes (ECYT4, Pacak-Zhuang Syndrome, sporadic PPGL) have not been studied in parallel.	('HIF-2alpha', 'Gene', (18, 28))	('Pacak-Zhuang Syndrome', 'Disease', (95, 116))	('ECYT4', 'Gene', '2034', (88, 93))	('mutations', 'Var', (40, 49))	('ECYT4', 'Gene', (88, 93))
26652	30135421	In one exceptional case, mutation of EPAS1 was associated with central nervous system hemangioblastoma.	('central nervous system hemangioblastoma', 'Phenotype', 'HP:0006880', (63, 102))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (86, 102))	('central nervous system hemangioblastoma', 'Disease', 'MESH:D018325', (63, 102))	('mutation', 'Var', (25, 33))	('central nervous system hemangioblastoma', 'Disease', (63, 102))	('EPAS1', 'Gene', '2034', (37, 42))	('associated', 'Reg', (47, 57))	('EPAS1', 'Gene', (37, 42))
26655	30135421	Others have also categorized diseases associated with EPAS1 mutations in a similar fashion, and class 2 disease has been previously described as ECYT4 while classes 1a and 1b have been jointly described as Pacak-Zhuang syndrome.	('EPAS1', 'Gene', (54, 59))	('ECYT4', 'Gene', '2034', (145, 150))	('Pacak-Zhuang syndrome', 'Disease', (206, 227))	('ECYT4', 'Gene', (145, 150))	('mutations', 'Var', (60, 69))	('EPAS1', 'Gene', '2034', (54, 59))
26658	30135421	Conversely, class 2 disease patients present with germline mutations and as families in 60% of reported cases (Table 1).	('germline mutations', 'Var', (50, 68))	('patients', 'Species', '9606', (28, 36))	('class 2 disease', 'Disease', (12, 27))
26659	30135421	Mutations associated with class 1 disease are typically located between amino acid residues 529 and 532, which contain proline 531, the primary hydroxylation site of HIF-2alpha (Fig.	('class 1 disease', 'Disease', (26, 41))	('associated', 'Reg', (10, 20))	('Mutations', 'Var', (0, 9))	('proline', 'Chemical', 'MESH:D011392', (119, 126))
26660	30135421	However, this topographical segregation is not absolute, as mutations of D539 are found in patients of all disease classes.	('mutations', 'Var', (60, 69))	('found', 'Reg', (82, 87))	('D539', 'Gene', (73, 77))	('patients', 'Species', '9606', (91, 99))
26661	30135421	Interestingly, there is no overlap in the specific mutations associated with class 1 and class 2 disease, as the mutations affecting D539 are not the same among class 1 and class 2 (D539N in class 1a and 1b, D539Y in class 1c, D539E in class 2; Fig.	('D539N', 'Var', (182, 187))	('D539Y', 'Var', (208, 213))	('D539Y', 'Mutation', 'p.D539Y', (208, 213))	('D539', 'Gene', (133, 137))	('D539N', 'Mutation', 'p.D539N', (182, 187))	('D539E', 'Mutation', 'p.D539E', (227, 232))	('D539E', 'Var', (227, 232))
26662	30135421	For example, the A530V mutation has been reported in patients with class 1a, class 1b, and class 1c disease (Fig.	('class 1c disease', 'Disease', (91, 107))	('reported', 'Reg', (41, 49))	('class 1b', 'Disease', (77, 85))	('class 1a', 'Disease', (67, 75))	('patients', 'Species', '9606', (53, 61))	('A530V', 'Mutation', 'p.A530V', (17, 22))	('A530V', 'Var', (17, 22))
26663	30135421	Thus, the broad phenotypic differences between class 1 and class 2 disease stem from genetic differences while the differences between subclasses of class 1 disease might be related to the presence of additional mutations or the occurrence of EPAS1 mutations during embryonic development or later in life.	('EPAS1', 'Gene', '2034', (243, 248))	('EPAS1', 'Gene', (243, 248))	('mutations', 'Var', (249, 258))	('related', 'Reg', (174, 181))	('stem from', 'Reg', (75, 84))
26664	30135421	Our first approach for testing the differences between class 1 and class 2 EPAS1 mutations was to employ a suite of mutation prediction software, including PolyPhen-2, SIFT, MutationTaster2, and PROVEAN.	('EPAS1', 'Gene', (75, 80))	('SIFT', 'Disease', 'None', (168, 172))	('mutations', 'Var', (81, 90))	('EPAS1', 'Gene', '2034', (75, 80))	('SIFT', 'Disease', (168, 172))
26665	30135421	MutationTaster2 annotated all class 1 mutations as disease causing while SIFT and Polyphen-2 classified 77.8% (14/18) and 83.3% (15/18) of class 1 mutations as probably damaging, respectively.	('mutations', 'Var', (38, 47))	('disease causing', 'Reg', (51, 66))	('SIFT', 'Disease', (73, 77))	('SIFT', 'Disease', 'None', (73, 77))
26667	30135421	The two notable sites of non-conservation are HIF-1alpha Met561/HIF-2alpha Thr528 and the insertion of HIF-2alpha Gly537, which is not present in HIF-1alpha.	('Thr528', 'Var', (75, 81))	('Thr528', 'Chemical', '-', (75, 81))	('Met561/HIF-2alpha', 'Var', (57, 74))	('Met561', 'Chemical', '-', (57, 63))	('Gly537', 'Chemical', '-', (114, 120))	('HIF-2alpha', 'Gene', (103, 113))
26668	30135421	Intriguingly, G537 is the most commonly mutated residue in HIF-2alpha driven disease while the substitution of the non-polar, sulfur-containing Met residue with a polar Thr residue supports the notion that HIF-2alpha peptide might not bind pVHL with an identical motif as HIF-1alpha.	('pVHL', 'Gene', '7428', (240, 244))	('pVHL', 'Gene', (240, 244))	('G537', 'Var', (14, 18))	('substitution', 'Var', (95, 107))	('sulfur', 'Chemical', 'MESH:D013455', (126, 132))	('peptide', 'Chemical', 'MESH:D010455', (217, 224))	('HIF-2alpha driven disease', 'Disease', (59, 84))	('HIF-2alpha driven disease', 'Disease', 'MESH:D004194', (59, 84))	('Thr', 'Chemical', 'MESH:D013912', (169, 172))	('mutated', 'Reg', (40, 47))
26674	30135421	The HIF-2alpha peptide binds to pVHL as an extended strand with N-terminal (residues 527-534) and C-terminal (residues 539-540) pVHL contact sites (Fig.	('pVHL', 'Gene', '7428', (128, 132))	('residues 539-540', 'Var', (110, 126))	('residues 527-534', 'Var', (76, 92))	('peptide', 'Chemical', 'MESH:D010455', (15, 22))	('pVHL', 'Gene', (128, 132))	('pVHL', 'Gene', '7428', (32, 36))	('pVHL', 'Gene', (32, 36))
26677	30135421	Further, RMSD of Calpha atoms of the HIF-2alpha peptide compared with HIF-1alpha peptide from previously reported co-crystal structures also revealed rather minor changes in conformation (0.78 A with 1LM8, 0.85 A with 1LQB).	('peptide', 'Chemical', 'MESH:D010455', (48, 55))	('0.78', 'Var', (188, 192))	('peptide', 'Chemical', 'MESH:D010455', (81, 88))	('1LM8', 'Var', (200, 204))	('RMSD of Calpha atoms', 'Disease', (9, 29))	('conformation', 'MPA', (174, 186))	('changes', 'Reg', (163, 170))	('RMSD of Calpha atoms', 'Disease', 'MESH:C564286', (9, 29))
26678	30135421	The substitution of the amino acid three residues N-terminal of the primary hydroxylation site (Met561/Thr528) had no effect on the local conformation, with both residues packed against pVHL F91 (Fig.	('local conformation', 'MPA', (132, 150))	('pVHL', 'Gene', '7428', (186, 190))	('Met561', 'Chemical', '-', (96, 102))	('pVHL', 'Gene', (186, 190))	('Met561/Thr528', 'Var', (96, 109))	('Thr528', 'Chemical', '-', (103, 109))
26679	30135421	The insertion of Gly537, seen in HIF-2alpha, results in an increased sinusoidal nature of the HIF-2alpha peptide but that only results in local conformational changes (Fig.	('Gly537', 'Chemical', '-', (17, 23))	('conformational changes', 'MPA', (144, 166))	('peptide', 'Chemical', 'MESH:D010455', (105, 112))	('Gly537', 'Var', (17, 23))	('sinusoidal nature', 'MPA', (69, 86))	('increased', 'PosReg', (59, 68))
26681	30135421	The hydroxylated P531 (Hyp531) is almost completely buried in a highly complementary pVHL pocket composed of residues W88, Y98, I109, S111, Y112, H115, and W117 (Fig.	('pVHL', 'Gene', (85, 89))	('H115', 'Var', (146, 150))	('W88', 'Var', (118, 121))	('I109', 'Var', (128, 132))	('W117', 'Var', (156, 160))	('Y112', 'Var', (140, 144))	('Y98', 'Var', (123, 126))	('S111', 'Var', (134, 138))	('pVHL', 'Gene', '7428', (85, 89))
26683	30135421	The carbonyl oxygen of HIF-2alpha E527 hydrogen bonds to the side chain of both pVHL N67 and pVHL R69 (Fig.	('oxygen', 'Chemical', 'MESH:D010100', (13, 19))	('E527', 'Var', (34, 38))	('hydrogen', 'Chemical', 'MESH:D006859', (39, 47))	('hydrogen', 'Reg', (39, 47))	('pVHL', 'Gene', '7428', (93, 97))	('pVHL', 'Gene', '7428', (80, 84))	('pVHL', 'Gene', (93, 97))	('pVHL', 'Gene', (80, 84))	('HIF-2alpha', 'Gene', (23, 33))
26686	30135421	F540 serves as a C-terminal anchor, contacting pVHL G106, that re-establishes contact between pVHL and HIF-2alpha (Fig.	('contact', 'Interaction', (78, 85))	('pVHL', 'Gene', '7428', (94, 98))	('pVHL', 'Gene', (94, 98))	('pVHL', 'Gene', '7428', (47, 51))	('F540', 'Var', (0, 4))	('pVHL', 'Gene', (47, 51))
26687	30135421	Interestingly, the majority of reported class 2 mutations (82%) are localized to the kink region whereas class 1 mutations affect residues making contact with pVHL (Fig.	('class 2', 'Gene', (40, 47))	('residues', 'Protein', (130, 138))	('pVHL', 'Gene', '7428', (159, 163))	('pVHL', 'Gene', (159, 163))	('affect', 'Reg', (123, 129))	('mutations', 'Var', (48, 57))
26688	30135421	Thus, a prediction based on our structural analysis is that class 1 mutations would have a greater negative impact on pVHL-HIF-2alpha interaction than class 2 mutations.	('negative', 'NegReg', (99, 107))	('pVHL', 'Gene', '7428', (118, 122))	('pVHL', 'Gene', (118, 122))	('mutations', 'Var', (68, 77))	('interaction', 'Interaction', (134, 145))
26689	30135421	To test our hypothesis that class 1 mutations have a more adverse effect on pVHL affinity (referring specifically to the strength of interaction between HIF-2alpha peptide or protein and pVHL), we conducted both steady-state and kinetic binding experiments.	('interaction', 'Interaction', (133, 144))	('pVHL', 'Gene', '7428', (76, 80))	('pVHL', 'Gene', (76, 80))	('mutations', 'Var', (36, 45))	('pVHL', 'Gene', '7428', (187, 191))	('peptide', 'Chemical', 'MESH:D010455', (164, 171))	('pVHL', 'Gene', (187, 191))	('adverse', 'NegReg', (58, 65))
26690	30135421	Previous ELISA-based experiments with polycythemia-associated HIF-2alpha mutants suggested that class 2 mutants had no effect on VBC affinity.	('mutants', 'Var', (104, 111))	('VBC', 'Protein', (129, 132))	('mutants', 'Var', (73, 80))	('polycythemia', 'Disease', (38, 50))	('VBC', 'Chemical', '-', (129, 132))	('polycythemia', 'Phenotype', 'HP:0001901', (38, 50))	('polycythemia', 'Disease', 'MESH:D011086', (38, 50))	('HIF-2alpha', 'Gene', (62, 72))
26691	30135421	Similarly, we show that steady-state ELISA experiments conducted with HIF-2alphaOH (amino acids 523-541) peptides (i.e., hydroxyl group synthetically added to P531) and purified VBC complex suggested that both class 1 and class 2 mutations had negligible or minimal effect on pVHL affinity (Fig.	('peptide', 'Chemical', 'MESH:D010455', (105, 112))	('pVHL', 'Gene', '7428', (276, 280))	('pVHL', 'Gene', (276, 280))	('mutations', 'Var', (230, 239))	('VBC', 'Chemical', '-', (178, 181))	('HIF-2alphaOH', 'Gene', (70, 82))
26692	30135421	4a), with the exception of the P531A mutant, which completely abolished binding to VBC as expected.	('abolished', 'NegReg', (62, 71))	('VBC', 'Chemical', '-', (83, 86))	('binding', 'Interaction', (72, 79))	('P531A', 'Mutation', 'p.P531A', (31, 36))	('P531A', 'Var', (31, 36))	('VBC', 'Protein', (83, 86))
26693	30135421	However, we found that class 1 mutations, in general, have a more deleterious effect on pVHL affinity than class 2 mutations when analyzed via pull-down experiments using in vitro transcribed and translated (IVTT) pVHL under both stringent and mild buffer conditions (Fig.	('mutations', 'Var', (31, 40))	('pVHL', 'Gene', '7428', (88, 92))	('pVHL', 'Gene', '7428', (214, 218))	('pVHL', 'Gene', (88, 92))	('pVHL', 'Gene', (214, 218))	('effect', 'Reg', (78, 84))	('affinity', 'MPA', (93, 101))
26694	30135421	Intriguingly, HIF-2alphaOH A530V class 1 peptide consistently bound to pVHL or VBC with an affinity similar to that of HIF-2alphaOH WT peptide and other class 2 mutants, such as M535I.	('VBC', 'Chemical', '-', (79, 82))	('peptide', 'Chemical', 'MESH:D010455', (135, 142))	('bound', 'Interaction', (62, 67))	('A530V', 'Mutation', 'p.A530V', (27, 32))	('peptide', 'Chemical', 'MESH:D010455', (41, 48))	('M535I', 'Var', (178, 183))	('pVHL', 'Gene', '7428', (71, 75))	('pVHL', 'Gene', (71, 75))	('M535I', 'Mutation', 'p.M535I', (178, 183))	('HIF-2alphaOH', 'Gene', (14, 26))
26695	30135421	To gain further quantitative insight, we next analyzed the effect of HIF-2alpha mutations on the kinetics of HIF-2alpha peptide binding to pVHL via biolayer interferometry (BLI), which measures the rate of association and dissociation of an analyte molecule (purified VBC complex) to and from an immobilized bait molecule (biotinylated HIF-2alphaOH peptide).	('HIF-2alpha', 'Gene', (69, 79))	('mutations', 'Var', (80, 89))	('VBC', 'Chemical', '-', (268, 271))	('association', 'Interaction', (206, 217))	('peptide', 'Chemical', 'MESH:D010455', (349, 356))	('pVHL', 'Gene', '7428', (139, 143))	('pVHL', 'Gene', (139, 143))	('dissociation', 'MPA', (222, 234))	('peptide', 'Chemical', 'MESH:D010455', (120, 127))
26698	30135421	Most mutant HIF-2alphaOH peptides displayed decreased binding to VBC, consistent with steady-state pull down experiments (Table 2).	('VBC', 'Chemical', '-', (65, 68))	('HIF-2alphaOH', 'Gene', (12, 24))	('peptides', 'Protein', (25, 33))	('mutant', 'Var', (5, 11))	('VBC', 'Protein', (65, 68))	('peptide', 'Chemical', 'MESH:D010455', (25, 32))	('binding', 'Interaction', (54, 61))	('decreased', 'NegReg', (44, 53))
26699	30135421	The four mutations with the most deleterious effect on pVHL affinity all belonged to class 1 (L529P, A530T, P531A, Y532C; Fig.	('pVHL', 'Gene', '7428', (55, 59))	('pVHL', 'Gene', (55, 59))	('A530T', 'Var', (101, 106))	('L529P', 'Mutation', 'p.L529P', (94, 99))	('A530T', 'Mutation', 'c.530A>T', (101, 106))	('Y532C', 'Var', (115, 120))	('P531A', 'Mutation', 'p.P531A', (108, 113))	('L529P', 'Var', (94, 99))	('Y532C', 'Mutation', 'p.Y532C', (115, 120))	('P531A', 'Var', (108, 113))
26700	30135421	The L529P mutation possibly results in steric clash with pVHL N67, resulting in a disruption of its hydrogen bond to HIF-2alpha E527.	('L529P', 'Var', (4, 9))	('hydrogen bond', 'MPA', (100, 113))	('hydrogen', 'Chemical', 'MESH:D006859', (100, 108))	('disruption', 'NegReg', (82, 92))	('results in', 'Reg', (28, 38))	('pVHL', 'Gene', '7428', (57, 61))	('pVHL', 'Gene', (57, 61))	('L529P', 'Mutation', 'p.L529P', (4, 9))
26701	30135421	Y532 normally packs against the sidechain of pVHL H110 and the Y532C mutation would result in diminished van der Waals interaction.	('pVHL', 'Gene', '7428', (45, 49))	('Y532C', 'Var', (63, 68))	('pVHL', 'Gene', (45, 49))	('van der Waals interaction', 'MPA', (105, 130))	('Y532C', 'Mutation', 'p.Y532C', (63, 68))	('diminished', 'NegReg', (94, 104))	('Y532', 'Var', (0, 4))
26702	30135421	The P531A mutation would result in the loss of important hydrogen bonds, shown in Fig.	('hydrogen', 'Chemical', 'MESH:D006859', (57, 65))	('P531A', 'Mutation', 'p.P531A', (4, 9))	('P531A', 'Var', (4, 9))	('hydrogen bonds', 'MPA', (57, 71))	('loss', 'NegReg', (39, 43))
26703	30135421	Interestingly, and consistent with our steady-state observations, the A530V (Kd = 219 nM) and A530T (Kd = 513 nM) mutations had different effects on pVHL affinity, despite affecting the same residue.	('affecting', 'Reg', (172, 181))	('pVHL', 'Gene', '7428', (149, 153))	('A530T', 'Mutation', 'c.530A>T', (94, 99))	('A530V', 'Mutation', 'p.A530V', (70, 75))	('pVHL', 'Gene', (149, 153))	('A530V', 'Var', (70, 75))
26704	30135421	The A530V HIF-2alphaOH peptide dissociated more slowly from VBC than WT (kd = 5.8 x 10-3 s-1) whereas the A530T HIF-2alphaOH peptide (kd = 18 x 10-3 s-1) behaved similarly to the other class 1 mutant peptides.	('peptide', 'Chemical', 'MESH:D010455', (200, 207))	('peptide', 'Chemical', 'MESH:D010455', (125, 132))	('A530V', 'Mutation', 'p.A530V', (4, 9))	('A530V', 'Var', (4, 9))	('dissociated', 'MPA', (31, 42))	('peptide', 'Chemical', 'MESH:D010455', (23, 30))	('VBC', 'Chemical', '-', (60, 63))	('slowly', 'NegReg', (48, 54))	('kd = 5', 'Species', '752783', (73, 79))	('A530T', 'Var', (106, 111))	('A530T', 'Mutation', 'c.530A>T', (106, 111))
26705	30135421	Due to the extensive hydrogen bond network involving HIF-2alpha Hyp531, it is possible that the polar nature of the A530T mutation results in a degree of interference.	('hydrogen', 'Chemical', 'MESH:D006859', (21, 29))	('A530T', 'Var', (116, 121))	('A530T', 'Mutation', 'c.530A>T', (116, 121))	('interference', 'MPA', (154, 166))	('hydrogen bond network', 'MPA', (21, 42))
26706	30135421	Specifically, A530 points toward pVHL Y98, which hydrogen bonds to the Hyp531 carbonyl oxygen atom (Fig.	('A530', 'Var', (14, 18))	('hydrogen', 'Chemical', 'MESH:D006859', (49, 57))	('pVHL', 'Gene', '7428', (33, 37))	('hydrogen', 'Reg', (49, 57))	('oxygen', 'Chemical', 'MESH:D010100', (87, 93))	('pVHL', 'Gene', (33, 37))
26707	30135421	Hydrogen bonding between the A530T mutant residue and pVHL Y98 may disrupt the Hyp531 pocket, promoting dissociation of pVHL.	('Hydrogen', 'Chemical', 'MESH:D006859', (0, 8))	('Y98', 'Var', (59, 62))	('promoting', 'PosReg', (94, 103))	('A530T', 'Var', (29, 34))	('disrupt', 'NegReg', (67, 74))	('Hyp531 pocket', 'MPA', (79, 92))	('A530T', 'Mutation', 'c.530A>T', (29, 34))	('pVHL', 'Gene', '7428', (54, 58))	('pVHL', 'Gene', '7428', (120, 124))	('pVHL', 'Gene', (54, 58))	('dissociation', 'MPA', (104, 116))	('pVHL', 'Gene', (120, 124))
26708	30135421	The decreased dissociation rate seen with the A530V (Table 2) mutation lends a degree of support to this argument, as the nonpolar mutation would possibly result in increased van der Waals interactions with the adjacent pVHL W88 residue without possibly hydrogen bonding to pVHL Y98.	('pVHL', 'Gene', '7428', (220, 224))	('decreased', 'NegReg', (4, 13))	('pVHL', 'Gene', (220, 224))	('interactions', 'Interaction', (189, 201))	('dissociation rate', 'MPA', (14, 31))	('van der Waals', 'MPA', (175, 188))	('A530V', 'Mutation', 'p.A530V', (46, 51))	('hydrogen', 'Chemical', 'MESH:D006859', (254, 262))	('pVHL', 'Gene', '7428', (274, 278))	('A530V', 'Var', (46, 51))	('pVHL', 'Gene', (274, 278))	('increased', 'PosReg', (165, 174))
26709	30135421	Interestingly, the G537R class 2 mutation (Kd = 348 nM; ka = 3.0 x 104 Ms-1; kd = 10 x 10-3 s-1) had a near identical effect on the kinetics of binding to VBC as did the F540L class 2 mutation (Kd = 345 nM; ka = 3.1 x 104 Ms-1; kd = 10 x 10-3 s-1), despite being localized to the kink region that does not make any significant contacts with pVHL.	('G537R', 'Mutation', 'rs137853036', (19, 24))	('pVHL', 'Gene', '7428', (341, 345))	('binding', 'Interaction', (144, 151))	('pVHL', 'Gene', (341, 345))	('F540L', 'Mutation', 'p.F540L', (170, 175))	('G537R', 'Var', (19, 24))	('VBC', 'Protein', (155, 158))	('VBC', 'Chemical', '-', (155, 158))
26711	30135421	3a), mutation of G537 to a bulkier amino acid (tryptophan or arginine; class 2 mutations) is predicted to result in steric clash with pVHL R108.	('steric clash', 'Disease', (116, 128))	('pVHL', 'Gene', '7428', (134, 138))	('arginine', 'Chemical', 'MESH:D001120', (61, 69))	('result in', 'Reg', (106, 115))	('tryptophan', 'Chemical', 'MESH:D014364', (47, 57))	('G537', 'Var', (17, 21))	('pVHL', 'Gene', (134, 138))
26712	30135421	This is an important observation as G537 is not conserved in HIF-1alpha and is also the most commonly mutated residue in HIF-2alpha driven disease (Fig.	('HIF-2alpha driven disease', 'Disease', (121, 146))	('G537', 'Var', (36, 40))	('HIF-2alpha driven disease', 'Disease', 'MESH:D004194', (121, 146))
26713	30135421	Other class 2 mutant peptides (M535I, D539E) bound to VBC with little defect, as compared to WT (Fig.	('M535I', 'Mutation', 'p.M535I', (31, 36))	('VBC', 'Protein', (54, 57))	('bound', 'Interaction', (45, 50))	('VBC', 'Chemical', '-', (54, 57))	('D539E', 'Mutation', 'p.D539E', (38, 43))	('peptide', 'Chemical', 'MESH:D010455', (21, 28))	('D539E', 'Var', (38, 43))	('M535I', 'Var', (31, 36))
26714	30135421	Thus, although BLI kinetic analysis revealed a distinguishable kinetic trend between class 1 and class 2 mutations, the disease class associated with HIF-2alpha mutations could not be absolutely predicted solely by determining affinity for pVHL due to outliers like A530V.	('A530V', 'Mutation', 'p.A530V', (266, 271))	('pVHL', 'Gene', '7428', (240, 244))	('pVHL', 'Gene', (240, 244))	('A530V', 'Var', (266, 271))	('HIF-2alpha', 'Gene', (150, 160))
26715	30135421	Considering that prolyl hydroxylation is indispensable for HIF-2alpha binding to pVHL, we next examined the notion that the A530V mutation negatively influences hydroxylation of HIF-2alpha via PHD2, which would attenuate HIF-2alpha A530V binding affinity for pVHL.	('PHD2', 'Gene', (193, 197))	('PHD2', 'Gene', '54583', (193, 197))	('binding affinity', 'Interaction', (238, 254))	('negatively', 'NegReg', (139, 149))	('pVHL', 'Gene', '7428', (81, 85))	('pVHL', 'Gene', (259, 263))	('pVHL', 'Gene', '7428', (259, 263))	('A530V', 'Mutation', 'p.A530V', (124, 129))	('hydroxylation', 'MPA', (161, 174))	('A530V', 'Mutation', 'p.A530V', (232, 237))	('A530V', 'Var', (124, 129))	('attenuate', 'NegReg', (211, 220))	('influences', 'Reg', (150, 160))	('pVHL', 'Gene', (81, 85))
26719	30135421	4b), M535I class 2 mutant still retained affinity for pVHL following incubation with HIS6-PHD2 (Fig.	('PHD2', 'Gene', (90, 94))	('PHD2', 'Gene', '54583', (90, 94))	('M535I', 'Var', (5, 10))	('M535I', 'Mutation', 'p.M535I', (5, 10))	('affinity', 'MPA', (41, 49))	('pVHL', 'Gene', '7428', (54, 58))	('pVHL', 'Gene', (54, 58))
26720	30135421	However, A530V peptide was only minimally able to bind pVHL, much like the A530T mutant (Fig.	('pVHL', 'Gene', '7428', (55, 59))	('peptide', 'Chemical', 'MESH:D010455', (15, 22))	('bind', 'Interaction', (50, 54))	('pVHL', 'Gene', (55, 59))	('A530V', 'Mutation', 'p.A530V', (9, 14))	('A530T', 'Var', (75, 80))	('A530V', 'Var', (9, 14))	('A530T', 'Mutation', 'c.530A>T', (75, 80))
26721	30135421	These results suggest that the A530V mutation impedes PHD2-mediated hydroxylation of P531, which negatively impacts HIF-2alpha binding affinity for pVHL.	('HIF-2alpha', 'Protein', (116, 126))	('negatively impacts', 'NegReg', (97, 115))	('binding', 'Interaction', (127, 134))	('PHD2', 'Gene', (54, 58))	('pVHL', 'Gene', '7428', (148, 152))	('PHD2', 'Gene', '54583', (54, 58))	('pVHL', 'Gene', (148, 152))	('P531', 'Gene', (85, 89))	('A530V', 'Mutation', 'p.A530V', (31, 36))	('A530V', 'Var', (31, 36))	('impedes', 'NegReg', (46, 53))
26722	30135421	Due to the importance of L574 for hydroxylation of HIF-1alpha, the fact that this residue is conserved in HIF-2alpha (L542), and the observation that the residue is mutated in class 1 disease (L542P, patient 7 in Supplementary Data 1), we posited that this mutation specifically affects hydroxylation but not pVHL affinity per se, similar to the A530V class 1 mutation.	('L542P', 'Mutation', 'p.L542P', (193, 198))	('pVHL', 'Gene', '7428', (309, 313))	('pVHL', 'Gene', (309, 313))	('mutation', 'Var', (257, 265))	('hydroxylation', 'MPA', (287, 300))	('affects', 'Reg', (279, 286))	('patient', 'Species', '9606', (200, 207))	('A530V', 'Mutation', 'p.A530V', (346, 351))
26724	30135421	However, synthetic addition of a hydroxyl group to P531 in HIF-2alphaOH L542 peptide rescued binding to pVHL with an affinity similar to HIF-2alphaOH WT peptide, confirming that the L542P mutation specifically abolishes PHD2-catalyzed hydroxylation (Fig.	('L542P', 'Var', (182, 187))	('pVHL', 'Gene', '7428', (104, 108))	('pVHL', 'Gene', (104, 108))	('rescued', 'PosReg', (85, 92))	('PHD2', 'Gene', (220, 224))	('peptide', 'Chemical', 'MESH:D010455', (77, 84))	('binding', 'Interaction', (93, 100))	('PHD2', 'Gene', '54583', (220, 224))	('L542P', 'Mutation', 'p.L542P', (182, 187))	('HIF-2alphaOH', 'Gene', (59, 71))	('peptide', 'Chemical', 'MESH:D010455', (153, 160))	('abolishes', 'NegReg', (210, 219))
26725	30135421	These results demonstrate that a subset of class 1 mutations specifically disrupt PHD2-mediated regulation, which ultimately leads to a severe reduction in pVHL binding.	('class 1', 'Gene', (43, 50))	('mutations', 'Var', (51, 60))	('binding', 'Interaction', (161, 168))	('pVHL', 'Gene', '7428', (156, 160))	('PHD2', 'Gene', (82, 86))	('PHD2', 'Gene', '54583', (82, 86))	('pVHL', 'Gene', (156, 160))	('reduction', 'NegReg', (143, 152))	('disrupt', 'NegReg', (74, 81))
26726	30135421	The presence of class 1 HIF-2alpha mutants that bind pVHL like WT when synthetically hydroxylated but fail to be hydroxylated by PHD2 suggested to us that class 1 and class 2 mutations may differentially affect PHD2 binding.	('binding', 'Interaction', (216, 223))	('PHD2', 'Gene', (211, 215))	('PHD2', 'Gene', '54583', (211, 215))	('PHD2', 'Gene', (129, 133))	('affect', 'Reg', (204, 210))	('mutants', 'Var', (35, 42))	('PHD2', 'Gene', '54583', (129, 133))	('pVHL', 'Gene', '7428', (53, 57))	('mutations', 'Var', (175, 184))	('pVHL', 'Gene', (53, 57))	('HIF-2alpha', 'Gene', (24, 34))
26727	30135421	To first test this hypothesis, we performed steady-state pull-down experiments with HIF-2alpha peptides (523-542) and purified HIS6-PHD2 (181-426).	('PHD2', 'Gene', (132, 136))	('523-542', 'Var', (105, 112))	('HIF-2alpha', 'Gene', (84, 94))	('peptide', 'Chemical', 'MESH:D010455', (95, 102))	('PHD2', 'Gene', '54583', (132, 136))
26731	30135421	We observed that all tested HIF-2alpha mutations result in decreased affinity for PHD2 (Supplementary Figure 6a).	('decreased', 'NegReg', (59, 68))	('PHD2', 'Gene', (82, 86))	('mutations', 'Var', (39, 48))	('PHD2', 'Gene', '54583', (82, 86))	('affinity', 'MPA', (69, 77))	('HIF-2alpha', 'Gene', (28, 38))
26732	30135421	However, the M535I class 2 mutant was not as deleterious in this regard, which is consistent with its ability to be hydroxylated by PHD2 in vitro (Fig.	('PHD2', 'Gene', (132, 136))	('M535I', 'Mutation', 'p.M535I', (13, 18))	('PHD2', 'Gene', '54583', (132, 136))	('M535I', 'Var', (13, 18))
26733	30135421	Next, we co-transfected HEK293a cells with 3xFLAG-HIF-2alpha ODD and HA-PHD2 constructs.	('3xFLAG-HIF-2alpha', 'Var', (43, 60))	('PHD2', 'Gene', '54583', (72, 76))	('PHD2', 'Gene', (72, 76))	('HEK293a', 'CellLine', 'CVCL:0045', (24, 31))
26734	30135421	Immunoprecipitation of 3xFLAG revealed that all HIF-2alpha mutant ODD constructs bound less PHD2 than WT HIF-2alpha ODD (Supplementary Figure 6b).	('bound', 'Interaction', (81, 86))	('WT HIF-2alpha ODD', 'Disease', 'MESH:C563160', (102, 119))	('PHD2', 'Gene', '54583', (92, 96))	('mutant', 'Var', (59, 65))	('PHD2', 'Gene', (92, 96))	('HIF-2alpha', 'Gene', (48, 58))	('less', 'NegReg', (87, 91))	('WT HIF-2alpha ODD', 'Disease', (102, 119))
26735	30135421	The increased binding of the M535I mutant to PHD2 was not observed in this experiment.	('PHD2', 'Gene', (45, 49))	('M535I', 'Mutation', 'p.M535I', (29, 34))	('PHD2', 'Gene', '54583', (45, 49))	('M535I', 'Var', (29, 34))
26736	30135421	Thus, the residual PHD2 binding observed among HIF-2alpha mutants may partially be driven by the P405 site, which may mask differential PHD2 binding among the HIF-2alpha mutant ODD constructs.	('P405', 'Var', (97, 101))	('PHD2', 'Gene', '54583', (19, 23))	('mask', 'NegReg', (118, 122))	('PHD2', 'Gene', (19, 23))	('binding', 'Interaction', (24, 31))	('binding', 'Interaction', (141, 148))	('PHD2', 'Gene', '54583', (136, 140))	('driven by', 'Reg', (83, 92))	('HIF-2alpha', 'Gene', (47, 57))	('PHD2', 'Gene', (136, 140))	('mutants', 'Var', (58, 65))
26737	30135421	To further evaluate the negative effect of HIF-2alpha mutations on pVHL affinity, we transiently expressed full-length HIF-2alpha (WT and representative class 1 and class 2 mutants) in combination with FLAG-pVHL in human embryonic kidney epithelial HEK293a cells that express endogenous PHD2.	('embryonic kidney epithelial', 'Disease', 'MESH:D007674', (221, 248))	('mutations', 'Var', (54, 63))	('PHD2', 'Gene', (287, 291))	('pVHL', 'Gene', (207, 211))	('PHD2', 'Gene', '54583', (287, 291))	('pVHL', 'Gene', '7428', (207, 211))	('HEK293a', 'CellLine', 'CVCL:0045', (249, 256))	('pVHL', 'Gene', '7428', (67, 71))	('HIF-2alpha', 'Gene', (119, 129))	('pVHL', 'Gene', (67, 71))	('embryonic kidney epithelial', 'Disease', (221, 248))	('human', 'Species', '9606', (215, 220))
26738	30135421	We observed that under this experimental condition, class 1 mutants bound lower levels of pVHL than class 2 mutants (Fig.	('levels', 'MPA', (80, 86))	('pVHL', 'Gene', '7428', (90, 94))	('pVHL', 'Gene', (90, 94))	('mutants', 'Var', (60, 67))	('lower', 'NegReg', (74, 79))
26739	30135421	Notably, A530V class 1 mutant bound poorly to pVHL in our cellular system, which corroborated our earlier in vitro binding assay following in vitro PHD2-mediated hydroxylation (Fig.	('poorly', 'NegReg', (36, 42))	('pVHL', 'Gene', '7428', (46, 50))	('A530V', 'Mutation', 'p.A530V', (9, 14))	('pVHL', 'Gene', (46, 50))	('A530V', 'Var', (9, 14))	('PHD2', 'Gene', '54583', (148, 152))	('bound', 'Interaction', (30, 35))	('PHD2', 'Gene', (148, 152))
26740	30135421	These results collectively support the notion that the observed differential impact on hydroxylation via PHD2 and/or binding affinity to pVHL by class 1 versus class 2 HIF-2alpha mutations underlies the emerging genotype-phenotype relationships seen in patients.	('PHD2', 'Gene', '54583', (105, 109))	('hydroxylation', 'MPA', (87, 100))	('PHD2', 'Gene', (105, 109))	('binding', 'Interaction', (117, 124))	('HIF-2alpha', 'Gene', (168, 178))	('patients', 'Species', '9606', (253, 261))	('mutations', 'Var', (179, 188))	('pVHL', 'Gene', (137, 141))	('pVHL', 'Gene', '7428', (137, 141))
26741	30135421	Loss-of-function mutations in VHL, which encodes the tumor suppressor pVHL, cause VHL disease, an autosomal dominant cancer disorder with predisposition to central nervous system hemangioblastoma, PPGL, and clear cell renal cell carcinoma (ccRCC) as well as polycythemia, and the majority of sporadic cases of hemangioblastoma and ccRCC.	('central nervous system hemangioblastoma', 'Phenotype', 'HP:0006880', (156, 195))	('autosomal dominant cancer disorder', 'Disease', 'MESH:D001859', (98, 132))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (207, 238))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('VHL', 'Gene', (30, 33))	('ccRCC', 'Phenotype', 'HP:0006770', (240, 245))	('VHL', 'Gene', '7428', (71, 74))	('hemangioblastoma', 'Disease', 'MESH:D018325', (310, 326))	('mutations', 'Var', (17, 26))	('autosomal dominant cancer disorder', 'Disease', (98, 132))	('pVHL', 'Gene', '7428', (70, 74))	('clear cell renal cell carcinoma', 'Disease', (207, 238))	('pVHL', 'Gene', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('polycythemia', 'Disease', (258, 270))	('VHL', 'Gene', '7428', (30, 33))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (218, 238))	('ccRCC', 'Disease', (331, 336))	('polycythemia', 'Disease', 'MESH:D011086', (258, 270))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hemangioblastoma', 'Disease', 'MESH:D018325', (179, 195))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (310, 326))	('hemangioblastoma', 'Disease', (310, 326))	('VHL disease', 'Disease', 'MESH:D006623', (82, 93))	('VHL', 'Gene', (82, 85))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (207, 238))	('ccRCC', 'Phenotype', 'HP:0006770', (331, 336))	('central nervous system hemangioblastoma', 'Disease', (156, 195))	('VHL disease', 'Disease', (82, 93))	('Loss-of-function', 'NegReg', (0, 16))	('VHL', 'Gene', (71, 74))	('central nervous system hemangioblastoma', 'Disease', 'MESH:D018325', (156, 195))	('VHL', 'Gene', '7428', (82, 85))	('tumor', 'Disease', (53, 58))	('hemangioblastoma', 'Disease', (179, 195))	('polycythemia', 'Phenotype', 'HP:0001901', (258, 270))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (179, 195))
26742	30135421	These diseases are thought to be driven, in part or wholly, by deregulation of HIF-alpha, the best characterized target of pVHL-mediated negative regulation.	('HIF-alpha', 'Protein', (79, 88))	('deregulation', 'Var', (63, 75))	('pVHL', 'Gene', '7428', (123, 127))	('pVHL', 'Gene', (123, 127))
26743	30135421	Concordantly, it is now known that mutations in EPAS1, which encodes HIF-2alpha, also cause polycythemia, PPGL, and somatostatinoma.	('polycythemia', 'Disease', (92, 104))	('PPGL', 'Disease', (106, 110))	('polycythemia', 'Phenotype', 'HP:0001901', (92, 104))	('EPAS1', 'Gene', '2034', (48, 53))	('EPAS1', 'Gene', (48, 53))	('somatostatinoma', 'Disease', 'MESH:D013005', (116, 131))	('cause', 'Reg', (86, 91))	('polycythemia', 'Disease', 'MESH:D011086', (92, 104))	('somatostatinoma', 'Disease', (116, 131))	('mutations', 'Var', (35, 44))
26744	30135421	Upon analyzing every reported case (66 as of 1 January 2018) of EPAS1 mutations in the aforementioned diseases, we propose the following classification system for HIF-2alpha-driven disease with class 1 disease featuring PPGL, which is subcategorized into class 1a featuring PPGL with somatostatinoma and polycythemia, class 1b featuring PPGL and polycythemia (classes 1a and 1b are also jointly known as Pacak-Zhuang syndrome), and class 1c featuring only PPGL.	('polycythemia', 'Disease', (304, 316))	('EPAS1', 'Gene', '2034', (64, 69))	('mutations', 'Var', (70, 79))	('somatostatinoma and polycythemia', 'Disease', 'MESH:D013005', (284, 316))	('polycythemia', 'Disease', (346, 358))	('EPAS1', 'Gene', (64, 69))	('polycythemia', 'Phenotype', 'HP:0001901', (304, 316))	('polycythemia', 'Disease', 'MESH:D011086', (304, 316))	('polycythemia', 'Phenotype', 'HP:0001901', (346, 358))	('polycythemia', 'Disease', 'MESH:D011086', (346, 358))
26747	30135421	Of the five individuals, four were found to have somatic EPAS1 mutations, all of which resulted in mutation of either amino acid residue A530 or P531 (P531S (x2), P531R, A530P).	('mutations', 'Var', (63, 72))	('EPAS1', 'Gene', (57, 62))	('P531', 'Var', (145, 149))	('P531R', 'Mutation', 'p.P531R', (163, 168))	('P531S', 'Mutation', 'p.P531S', (151, 156))	('A530P', 'Var', (170, 175))	('mutation', 'Var', (99, 107))	('A530P', 'Mutation', 'p.A530P', (170, 175))	('resulted in', 'Reg', (87, 98))	('P531R', 'Var', (163, 168))	('EPAS1', 'Gene', '2034', (57, 62))
26748	30135421	Thus, continued study of patients with PPGL affirms the emergence of EPAS1 mutations as a major driver of neuroendocrine tumor pathogenesis and solidifies the importance of systemic hypoxia or pseudohypoxia in PPGL tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (121, 126))	('EPAS1', 'Gene', '2034', (69, 74))	('hypoxia', 'Disease', (199, 206))	('hypoxia', 'Disease', (182, 189))	('neuroendocrine tumor', 'Disease', (106, 126))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (106, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('hypoxia', 'Disease', 'MESH:D000860', (199, 206))	('hypoxia', 'Disease', 'MESH:D000860', (182, 189))	('patients', 'Species', '9606', (25, 33))	('tumor', 'Disease', (215, 220))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('pseudohypoxia', 'Disease', (193, 206))	('pseudohypoxia', 'Disease', 'None', (193, 206))	('EPAS1', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))
26749	30135421	Co-crystal structure of hydroxylated HIF-2alpha peptide encompassing residues 523-541, which cover over 90% of bona fide disease-causing EPAS1 mutations identified to date, bound to VBC complex revealed that class 1 mutations affect residues contacting pVHL while the vast majority of reported class 2 mutations are localized to a non-contacting kink region (residues 535-538; Fig.	('peptide', 'Chemical', 'MESH:D010455', (48, 55))	('EPAS1', 'Gene', '2034', (137, 142))	('EPAS1', 'Gene', (137, 142))	('pVHL', 'Gene', '7428', (253, 257))	('affect', 'Reg', (226, 232))	('VBC', 'Chemical', '-', (182, 185))	('pVHL', 'Gene', (253, 257))	('mutations', 'Var', (216, 225))	('mutations', 'Var', (143, 152))
26751	30135421	When considering both the kink region and the mobile C-terminal region, almost 90% of class 2 mutations affect residues predicted to contribute marginally to pVHL-HIF-2alpha interface stability.	('affect', 'Reg', (104, 110))	('pVHL', 'Gene', (158, 162))	('mutations', 'Var', (94, 103))	('class 2', 'Gene', (86, 93))	('residues', 'Protein', (111, 119))	('pVHL', 'Gene', '7428', (158, 162))
26752	30135421	Conversely, over 80% of class 1 mutations affect residues that make substantial contact with pVHL (i.e.	('affect', 'Reg', (42, 48))	('pVHL', 'Gene', '7428', (93, 97))	('pVHL', 'Gene', (93, 97))	('class 1', 'Gene', (24, 31))	('mutations', 'Var', (32, 41))	('residues', 'Protein', (49, 57))	('contact', 'Interaction', (80, 87))
26753	30135421	In keeping with these structural data-based predictions, we found that the HIF-2alpha peptides with the lowest affinity for pVHL are indeed class 1 mutants (L529P, A530T, P531A, Y532C; Fig.	('Y532C', 'Var', (178, 183))	('A530T', 'Var', (164, 169))	('P531A', 'Mutation', 'p.P531A', (171, 176))	('L529P', 'Var', (157, 162))	('A530T', 'Mutation', 'c.530A>T', (164, 169))	('P531A', 'Var', (171, 176))	('Y532C', 'Mutation', 'p.Y532C', (178, 183))	('pVHL', 'Gene', '7428', (124, 128))	('pVHL', 'Gene', (124, 128))	('peptide', 'Chemical', 'MESH:D010455', (86, 93))	('L529P', 'Mutation', 'p.L529P', (157, 162))
26754	30135421	Interestingly, the trend of greater loss of pVHL affinity associated with class 1 mutants was apparent when conducting kinetic binding experiments with purified VBC (Fig.	('loss', 'NegReg', (36, 40))	('pVHL', 'Gene', '7428', (44, 48))	('pVHL', 'Gene', (44, 48))	('VBC', 'Chemical', '-', (161, 164))	('mutants', 'Var', (82, 89))
26756	30135421	In light of the BLI-measured dissociation constants (Kd) for WT and mutant HIF-2alphaOH peptides (200-500 nM; Table 2), it is clear that the minimum concentrations required to obtain a detectable signal during an ELISA experiment (575 nM) are saturating.	('HIF-2alphaOH', 'Gene', (75, 87))	('peptide', 'Chemical', 'MESH:D010455', (88, 95))	('mutant', 'Var', (68, 74))
26757	30135421	As previously mentioned, prior attempts to characterize class 2 mutants by ELISA failed to identify any change in VBC affinity, when compared to WT HIF-2alphaOH peptide.	('VBC', 'Protein', (114, 117))	('peptide', 'Chemical', 'MESH:D010455', (161, 168))	('mutants', 'Var', (64, 71))	('VBC', 'Chemical', '-', (114, 117))
26758	30135421	Although the majority of class 2 mutations are localized to the non-contacting kink region or flexible C-terminal region, mutations of I533 and P534 are also reported to cause polycythemia in the absence of neuroendocrine tumor development (Fig.	('polycythemia in the absence of neuroendocrine tumor', 'Disease', 'MESH:D018358', (176, 227))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (207, 227))	('P534', 'Gene', (144, 148))	('mutations', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('cause', 'Reg', (170, 175))	('I533', 'Gene', (135, 139))	('polycythemia', 'Phenotype', 'HP:0001901', (176, 188))
26759	30135421	These residues are proximal to Hyp531, make contacts with pVHL, and are predicted to contribute to the stability of the pVHL-HIF-2alpha interface.	('Hyp531', 'Var', (31, 37))	('pVHL', 'Gene', '7428', (58, 62))	('pVHL', 'Gene', (58, 62))	('stability', 'MPA', (103, 112))	('contribute', 'Reg', (85, 95))	('contacts', 'Interaction', (44, 52))	('pVHL', 'Gene', '7428', (120, 124))	('pVHL', 'Gene', (120, 124))
26760	30135421	In particular, I533 binds pVHL more deeply than any other residue, aside from Hyp531 (Supplementary Figure 3, 7).	('binds', 'Interaction', (20, 25))	('deeply', 'Interaction', (36, 42))	('pVHL', 'Gene', '7428', (26, 30))	('pVHL', 'Gene', (26, 30))	('I533', 'Var', (15, 19))
26761	30135421	However, the disease-causing mutations affecting these residues, I533V and P534L, are conserved mutations that can be accommodated at the pVHL-HIF-2alpha interface without introducing steric clash and with the loss of only minimal van der Waal interactions, which likely explains why these mutations are associated with class 2 disease phenotype despite affecting residues that make significant contact with pVHL.	('pVHL', 'Gene', '7428', (408, 412))	('pVHL', 'Gene', '7428', (138, 142))	('class 2 disease', 'Disease', (320, 335))	('P534L', 'Mutation', 'p.P534L', (75, 80))	('I533V', 'Mutation', 'p.I533V', (65, 70))	('pVHL', 'Gene', (408, 412))	('pVHL', 'Gene', (138, 142))	('disease-causing', 'Reg', (13, 28))	('I533V', 'Var', (65, 70))	('associated', 'Reg', (304, 314))	('P534L', 'Var', (75, 80))	('affecting', 'Reg', (354, 363))
26762	30135421	As a corollary, a prediction is that a bulky substitution at either of these sites, such as an I533F (C.1597 A > T) or P534R (C.1601C > G) missense mutation, would introduce steric clash that would destabilize the HIF-2alpha-pVHL binding interface.	('I533F', 'Mutation', 'p.I533F', (95, 100))	('P534R', 'Mutation', 'p.P534R', (119, 124))	('destabilize', 'NegReg', (198, 209))	('I533F (C.1597 A > T', 'Var', (95, 114))	('C.1601C > G', 'Mutation', 'c..1601C,C>G', (126, 137))	('pVHL', 'Gene', '7428', (225, 229))	('C.1597 A > T', 'Mutation', 'c..1597C,A>T', (102, 114))	('introduce', 'Reg', (164, 173))	('steric clash', 'MPA', (174, 186))	('pVHL', 'Gene', (225, 229))	('P534R (C.1601C > G', 'Var', (119, 137))
26763	30135421	Although not yet reported in literature, any patient confirmed to carry these de novo mutations should be monitored for neuroendocrine tumors, as they would be predicted to have or develop class 1 disease.	('mutations', 'Var', (86, 95))	('develop', 'PosReg', (181, 188))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (120, 141))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (120, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('neuroendocrine tumors', 'Disease', (120, 141))	('class 1 disease', 'Disease', (189, 204))	('patient', 'Species', '9606', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (120, 140))
26767	30135421	An intriguing speculation, therefore, is that class 2 mutations do not result in sufficient HIF-2alpha activation to overcome repression of HIF-2alpha during embryogenesis, while class 1 mutations result in sufficient HIF-2alpha activation via attenuation of pVHL-mediated degradation to transactivate HIF-2alpha targets, such as Oct4, necessary for PPGL pathogenesis.	('Oct4', 'Gene', (330, 334))	('mutations', 'Var', (54, 63))	('activation', 'PosReg', (229, 239))	('mutations', 'Var', (187, 196))	('pVHL', 'Gene', (259, 263))	('pVHL', 'Gene', '7428', (259, 263))	('Oct4', 'Gene', '5460', (330, 334))	('HIF-2alpha', 'MPA', (218, 228))	('transactivate', 'PosReg', (288, 301))	('attenuation', 'NegReg', (244, 255))
26768	30135421	Concordantly, a subset of class 1 mutations likely occur during embryogenesis despite being sporadic in nature, due to the presence of multiple neuroendocrine tumors of distinct cellular lineages (PPGL, somatostatinoma) and congenital polycythemia in patients with class 1a and class 1b diseases (Table 1).	('somatostatinoma', 'Disease', (203, 218))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (144, 164))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (144, 165))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (144, 165))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('polycythemia', 'Phenotype', 'HP:0001901', (235, 247))	('congenital polycythemia', 'Disease', 'MESH:D011086', (224, 247))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (251, 259))	('neuroendocrine tumors', 'Disease', (144, 165))	('congenital polycythemia', 'Disease', (224, 247))	('somatostatinoma', 'Disease', 'MESH:D013005', (203, 218))	('class 1', 'Gene', (26, 33))	('mutations', 'Var', (34, 43))
26769	30135421	Moreover, some patients present with HIF-2alpha mutations in tissues not affected by disease at detectable but non-heterozygous (i.e.	('patients', 'Species', '9606', (15, 23))	('HIF-2alpha', 'Gene', (37, 47))	('mutations', 'Var', (48, 57))
26770	30135421	Our hypothesis is consistent with the observation that VHL mutations that specifically cause pheochromocytoma appear to disrupt neuronal culling during embryogenesis via dysregulation of atypical protein kinase C in a HIF-independent process.	('disrupt', 'NegReg', (120, 127))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('dysregulation', 'MPA', (170, 183))	('atypical protein kinase C', 'Enzyme', (187, 212))	('pheochromocytoma', 'Disease', 'MESH:D010673', (93, 109))	('cause', 'Reg', (87, 92))	('mutations', 'Var', (59, 68))	('VHL', 'Gene', (55, 58))	('VHL', 'Gene', '7428', (55, 58))	('neuronal culling', 'CPA', (128, 144))	('pheochromocytoma', 'Disease', (93, 109))
26775	30135421	Here, we reveal the molecular basis underlying the broad class segregation emerging in HIF-2alpha-driven disease in which EPAS1 mutations that cause significant disturbance to the HIF-2alpha-pVHL interaction interface are associated with class 1 disease while those causing a mild disturbance are associated with class 2 disease.	('disturbance', 'MPA', (161, 172))	('EPAS1', 'Gene', '2034', (122, 127))	('associated with', 'Reg', (222, 237))	('EPAS1', 'Gene', (122, 127))	('mutations', 'Var', (128, 137))	('pVHL', 'Gene', '7428', (191, 195))	('pVHL', 'Gene', (191, 195))	('class 1 disease', 'Disease', (238, 253))
26777	30135421	Notably, the structure-guided information presented here would be powerful in predicting the broad class phenotype of de novo EPAS1 mutations in patients.	('patients', 'Species', '9606', (145, 153))	('EPAS1', 'Gene', (126, 131))	('EPAS1', 'Gene', '2034', (126, 131))	('mutations', 'Var', (132, 141))
26778	30135421	Missense mutations of EPAS1 (UniProt ascension number: Q99814; Genbank transcript ID: NM_001430; Protein Ensembl ENSP ID: ENSP00000263734) identified in patients with disease were analyzed using the Polyphen-2, SIFT, MutationTaster2, and PROVEAN prediction software.	('EPAS1', 'Gene', (22, 27))	('patients', 'Species', '9606', (153, 161))	('SIFT', 'Disease', (211, 215))	('EPAS1', 'Gene', '2034', (22, 27))	('SIFT', 'Disease', 'None', (211, 215))	('Missense mutations', 'Var', (0, 18))
26787	30135421	Anti-tubulin (T5168; 1:5000 western blot), anti-vinculin (V9264, 1:10,000 dilution western blot) and anti-FLAG (F1804; 1:5000 dilution western blot; 1:1000 dilution immunoprecipitation) were obtained from Sigma-Aldrich.	('vinculin', 'Gene', '7414', (48, 56))	('vinculin', 'Gene', (48, 56))	('V9264', 'CellLine', 'CVCL:U048', (58, 63))	('T5168', 'Var', (14, 19))
26790	30135421	For hydroxylation assays, or studies involving the L542P mutant, the following WT HIF-2alpha peptide, containing amino acid residues 523-542, was used: ELDLETLA[Hyp/P]YIPMDGEDFQL.	('L542P', 'Var', (51, 56))	('L542P', 'Mutation', 'p.L542P', (51, 56))	('hydroxylation', 'MPA', (4, 17))	('peptide', 'Chemical', 'MESH:D010455', (93, 100))
26811	30135421	Residues 523-526 and 541 of the HIF-2alpha peptide are disordered and not modeled, while the sidechain of D539 is disordered and built as a Cbeta stub.	('D539', 'Var', (106, 110))	('disordered', 'Disease', (55, 65))	('disordered', 'Disease', (114, 124))	('peptide', 'Chemical', 'MESH:D010455', (43, 50))	('disordered', 'Disease', 'MESH:D030342', (55, 65))	('disordered', 'Disease', 'MESH:D030342', (114, 124))
26824	30135421	L1170) and incubated with 2 mug of biotinylated HIF-2alphaOH peptide (WT or mutant), immobilized on streptavidin agarose beads, in either 500 muL of EBC buffer (50 mM Tris-HCl pH 8.0, 120 mM NaCl, 0.5% (v/v) NP-40; stringent buffer conditions) or buffer A supplemented with 0.02% (v/v) Tween-20 (mild buffer conditions) for 2 h at 4  C. Following incubation, beads were either washed 5x with NETN buffer (20 mM Tris-HCl pH 8.0, 100 mM NaCl, 1 mM EDTA, 0.5% (v/v) NP-40; stringent) or buffer A supplemented with 0.1% (v/v) Tween-20 (mild).	('NETN buffer', 'Chemical', '-', (392, 403))	('agarose', 'Chemical', 'MESH:D012685', (113, 120))	('NaCl', 'Chemical', 'MESH:D012965', (435, 439))	('mutant', 'Var', (76, 82))	('Tween-20', 'Chemical', 'MESH:D011136', (522, 530))	('EBC', 'Chemical', '-', (149, 152))	('Tween-20', 'Chemical', 'MESH:D011136', (286, 294))	('peptide', 'Chemical', 'MESH:D010455', (61, 68))	('NaCl', 'Chemical', 'MESH:D012965', (191, 195))	('Tris-HCl', 'Chemical', '-', (167, 175))	('Tris-HCl', 'Chemical', '-', (411, 419))	('HIF-2alphaOH', 'Gene', (48, 60))
26827	30135421	5 mug of biotinylated HIF-2alpha peptide (WT or mutant) was immobilized on streptavidin agarose beads and incubated with a 50 mug/muL solution of purified HIS6-PHD2 (181-426) in 50 mM Tris-HCl pH 7.5, 0.005% (v/v) Tween-20 buffer supplemented with or without 1 mM MnCl2 and 1 mM NOG, for 2 h at 4  C. Beads were washed 2x with the same buffer.	('PHD2', 'Gene', (160, 164))	('PHD2', 'Gene', '54583', (160, 164))	('mutant', 'Var', (48, 54))	('agarose', 'Chemical', 'MESH:D012685', (88, 95))	('peptide', 'Chemical', 'MESH:D010455', (33, 40))	('Tris-HCl', 'Chemical', '-', (184, 192))	('HIF-2alpha', 'Gene', (22, 32))	('Tween-20', 'Chemical', 'MESH:D011136', (214, 222))	('NOG', 'Chemical', 'MESH:C040947', (279, 282))	('MnCl2', 'Chemical', 'MESH:C025340', (264, 269))
26832	30135421	Following hydroxylation, beads were washed 5x with EBC buffer and peptides were incubated with IVTT HA-VHL30 under the stringent buffer conditions described above.	('VHL', 'Gene', '7428', (103, 106))	('EBC', 'Chemical', '-', (51, 54))	('hydroxylation', 'Var', (10, 23))	('peptide', 'Chemical', 'MESH:D010455', (66, 73))	('VHL', 'Gene', (103, 106))
26901	29922019	As we continue to improve long-term survival for single-ventricle patients, attention has shifted to long-term morbidities.	('improve', 'PosReg', (18, 25))	('single-ventricle', 'Phenotype', 'HP:0001750', (49, 65))	('patients', 'Species', '9606', (66, 74))	('single-ventricle', 'Var', (49, 65))
26913	27742784	The discovery of the genetic mutations causing the MEN1 and MEN2 syndromes has clarified much about the molecular biology of the syndromes and their component tumors, and in many cases has led to improved methods of diagnosis and treatment.	('MEN1', 'Gene', (51, 55))	('MEN1', 'Gene', '4221', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (29, 38))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('component tumors', 'Disease', (149, 165))	('MEN', 'Species', '9606', (51, 54))	('MEN2 syndromes', 'Disease', (60, 74))	('component tumors', 'Disease', 'MESH:D009369', (149, 165))	('MEN', 'Species', '9606', (60, 63))
26940	27742784	The Cancer Genome Atlas study of ACC confirmed and expanded the Weiss classification by integrating tumor subsets identified across the DNA copy-number and mutations, DNA-methylation, mRNA-expression, and miRNA-expression platforms.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (156, 165))	('tumor', 'Disease', (100, 105))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
26955	27742784	Interestingly, the partial responses only occurred in patients with SDHB mutations.	('patients', 'Species', '9606', (54, 62))	('SDHB', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('SDHB', 'Gene', '6390', (68, 72))
26957	27742784	Most patients who had a clinical benefit carried the SDHB mutation.	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (5, 13))	('SDHB', 'Gene', '6390', (53, 57))	('SDHB', 'Gene', (53, 57))
26960	27742784	In 65% of pheochromocyctomas, mutations have been discovered in 19 mutually exclusive susceptibility genes.	('pheochromocyctomas', 'Disease', 'None', (10, 28))	('pheochromocyctomas', 'Disease', (10, 28))	('mutations', 'Var', (30, 39))
26963	27742784	Pheochromocytomas can be divided into 3 clusters, depending on whether they have mutations in genes that alter proteins constituting the Krebs cycle (SDHA, SDHB, SDHC, SDHD, SDHAF2, MDH2, and FH), in genes associated with the hypoxic response (VHL and EPAS1), or in genes linked to signaling in the RAS/RAF, MAPK or mTOR pathways.	('EPAS1', 'Gene', (252, 257))	('RAF', 'Gene', '22882', (303, 306))	('FH', 'Gene', (192, 194))	('mTOR', 'Gene', '2475', (316, 320))	('MDH2', 'Gene', (182, 186))	('mutations', 'Var', (81, 90))	('SDHD', 'Gene', '6392', (168, 172))	('SDHB', 'Gene', '6390', (156, 160))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('alter', 'Reg', (105, 110))	('RAF', 'Gene', (303, 306))	('VHL', 'Disease', 'MESH:D006623', (244, 247))	('SDHC', 'Gene', (162, 166))	('SDHD', 'Gene', (168, 172))	('SDHAF2', 'Gene', '54949', (174, 180))	('SDHAF2', 'Gene', (174, 180))	('EPAS1', 'Gene', '2034', (252, 257))	('SDHA', 'Gene', (174, 178))	('SDHA', 'Gene', (150, 154))	('SDHB', 'Gene', (156, 160))	('MDH2', 'Gene', '4191', (182, 186))	('Krebs', 'Chemical', '-', (137, 142))	('Pheochromocytomas', 'Disease', (0, 17))	('SDHA', 'Gene', '6389', (150, 154))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('SDHA', 'Gene', '6389', (174, 178))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('mTOR', 'Gene', (316, 320))	('proteins', 'Protein', (111, 119))	('VHL', 'Disease', (244, 247))	('SDHC', 'Gene', '6391', (162, 166))
26965	27742784	Pheochromocytoma was the first human tumor shown to be caused by a germline mutation of SDHD, a gene that encodes a metabolic enzyme, and also the first human tumor shown to have activating mutations in HIF2A.	('Pheochromocytoma', 'Disease', (0, 16))	('caused by', 'Reg', (55, 64))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('HIF2A', 'Gene', '2034', (203, 208))	('SDHD', 'Gene', (88, 92))	('SDHD', 'Gene', '6392', (88, 92))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('human', 'Species', '9606', (31, 36))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('human', 'Species', '9606', (153, 158))	('HIF2A', 'Gene', (203, 208))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
26978	27742784	Prior work demonstrated mutually exclusive clonal mutations in papillary thyroid carcinoma (BRAF; 60%, RAS; 15%, and chromosomal rearrangements involving RET, and NTRK1; 5 to 40%), follicular thyroid carcinoma (RAS; 40 to 55%, and rearranged PPARG1; 25 to 60%), poorly differentiated thyroid carcinoma (BRAF; 0 to 13%, RAS; 20 to 30%, CTNNB1; 0 to 5%, and TP53; 17 to 40%), and anaplastic thyroid carcinoma (BRAF; 10 to 35%, RAS; 20 to 60%, CTNNB1; 66%, and TP53; 67 to 90%).	('TP53', 'Gene', (356, 360))	('RET', 'Gene', (154, 157))	('NTRK1', 'Gene', '4914', (163, 168))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (389, 406))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (284, 301))	('NTRK1', 'Gene', (163, 168))	('PPARG1', 'Gene', (242, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CTNNB1', 'Gene', '1499', (335, 341))	('TP53', 'Gene', (458, 462))	('anaplastic thyroid carcinoma', 'Disease', (378, 406))	('CTNNB1', 'Gene', (441, 447))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (192, 209))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (63, 90))	('rearranged', 'Var', (231, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (397, 406))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (73, 90))	('papillary thyroid carcinoma', 'Disease', (63, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('TP53', 'Gene', '7157', (356, 360))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (63, 90))	('BRAF', 'Gene', '673', (92, 96))	('PPARG1', 'Gene', '5468', (242, 248))	('CTNNB1', 'Gene', (335, 341))	('BRAF', 'Gene', (92, 96))	('TP53', 'Gene', '7157', (458, 462))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (192, 209))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (181, 209))	('RET', 'Gene', '5979', (154, 157))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (378, 406))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (378, 406))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (181, 209))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (389, 406))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (284, 301))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (73, 90))	('mutations', 'Var', (50, 59))	('thyroid carcinoma', 'Disease', (284, 301))	('CTNNB1', 'Gene', '1499', (441, 447))	('follicular thyroid carcinoma', 'Disease', (181, 209))	('BRAF', 'Gene', '673', (408, 412))	('BRAF', 'Gene', '673', (303, 307))	('BRAF', 'Gene', (408, 412))	('BRAF', 'Gene', (303, 307))
26979	27742784	A recent Cancer Genome Atlas study of 496 papillary thyroid carcinomas identified new mutations in EIFIAX, PPM1D, CHEK2 genes, and novel chromosomal rearrangements of BRAF, RET, NTRK, and ALK, thereby reducing the number of unknown driver mutations from 25% to 3.5%.	('EIFIAX', 'Gene', (99, 105))	('ALK', 'Gene', (188, 191))	('BRAF', 'Gene', (167, 171))	('BRAF', 'Gene', '673', (167, 171))	('NTRK', 'Gene', (178, 182))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('RET', 'Gene', '5979', (173, 176))	('CHEK2', 'Gene', (114, 119))	('mutations', 'Var', (86, 95))	('papillary thyroid carcinomas', 'Disease', (42, 70))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (42, 70))	('PPM1D', 'Gene', '8493', (107, 112))	('NTRK', 'Gene', '4914;4916', (178, 182))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (52, 69))	('CHEK2', 'Gene', '11200', (114, 119))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (52, 70))	('RET', 'Gene', (173, 176))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (42, 69))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (42, 70))	('PPM1D', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('ALK', 'Gene', '238', (188, 191))
26980	27742784	The Cancer Genome Atlas study investigators were able to divide papillary thyroid carcinomas into 3 molecular subtypes with mutually exclusive mutations and variable degrees of differentiation: (1) recurrent mutations in genes; the most prominent being BRAF (59.7%), NRAS and HRAS, (14.0, (2) gene fusions of BRAF, RET, PPARG, NTRK1, NTRK3, ALK, LTK, MET, FGFR2, and THDA (15.3%), and (3) somatic copy number alterations.	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (64, 92))	('NTRK3', 'Gene', '4916', (334, 339))	('gene fusions', 'Var', (293, 305))	('THDA', 'Chemical', '-', (367, 371))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (74, 92))	('mutations', 'Var', (208, 217))	('NTRK3', 'Gene', (334, 339))	('MET', 'Gene', (351, 354))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRAF', 'Gene', '673', (309, 313))	('BRAF', 'Gene', (309, 313))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('NTRK1', 'Gene', '4914', (327, 332))	('PPARG', 'Gene', '5468', (320, 325))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (64, 91))	('BRAF', 'Gene', '673', (253, 257))	('PPARG', 'Gene', (320, 325))	('NTRK1', 'Gene', (327, 332))	('BRAF', 'Gene', (253, 257))	('LTK', 'Gene', '4058', (346, 349))	('RET', 'Gene', '5979', (315, 318))	('NRAS', 'Gene', '4893', (267, 271))	('LTK', 'Gene', (346, 349))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (74, 91))	('papillary thyroid carcinomas', 'Disease', (64, 92))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (64, 92))	('FGFR2', 'Gene', (356, 361))	('HRAS', 'Gene', '3265', (276, 280))	('RET', 'Gene', (315, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('NRAS', 'Gene', (267, 271))	('ALK', 'Gene', '238', (341, 344))	('HRAS', 'Gene', (276, 280))	('FGFR2', 'Gene', '2263', (356, 361))	('ALK', 'Gene', (341, 344))
26981	27742784	The investigators also found that BRAFV600E mutated PTCs signal preferentially through the MAPK pathway, while RAS mutated PTCs signal through either the MAPK pathway or the PI3K pathway.	('BRAFV600E', 'Mutation', 'rs113488022', (34, 43))	('PTCs', 'Gene', (52, 56))	('MAPK pathway', 'Pathway', (91, 103))	('PI3K pathway', 'Pathway', (174, 186))	('BRAFV600E mutated', 'Var', (34, 51))	('preferentially', 'PosReg', (64, 78))	('MAPK pathway', 'Pathway', (154, 166))
26989	27742784	Approximately 50% of sporadic medullary thyroid carcinomas have somatic RET mutations, and a lesser number have RAS mutations.	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (30, 58))	('mutations', 'Var', (76, 85))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (40, 58))	('thyroid carcinomas', 'Disease', (40, 58))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (30, 57))	('RET', 'Gene', '5979', (72, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (40, 57))	('RET', 'Gene', (72, 75))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (40, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
26990	27742784	Virtually all hereditary medullary thyroid carcinomas have germline RET mutations, and there is a strong genotype-phenotype relationship in patients with MEN2A and MEN2B, not only regarding the range of disease expression, but also the severity of disease.	('mutations', 'Var', (72, 81))	('MEN2A', 'Gene', (154, 159))	('MEN2A', 'Gene', '5979', (154, 159))	('MEN2B', 'Gene', (164, 169))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (35, 52))	('MEN2B', 'Gene', '5979', (164, 169))	('RET', 'Gene', (68, 71))	('germline', 'Var', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (25, 53))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (35, 53))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (25, 52))	('patients', 'Species', '9606', (140, 148))	('RET', 'Gene', '5979', (68, 71))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (35, 53))	('thyroid carcinomas', 'Disease', (35, 53))
27007	27742784	No MEN1 mutation is found in 10 to 30% of typical MEN1 kindreds (probably the result of current DNA sequencing strategies) and 10% of the mutations are de novo, there being no family history.	('MEN1', 'Gene', '4221', (3, 7))	('MEN1', 'Gene', (3, 7))	('MEN1', 'Gene', (50, 54))	('MEN1', 'Gene', '4221', (50, 54))	('mutation', 'Var', (8, 16))	('mutations', 'Var', (138, 147))
27008	27742784	MEN1 is also the most common mutation in sporadic pancreatic neuroendocrine tumors, followed by mutations in DAXX/ATRX (Death-Domain Associated Protein/Mental Retardation Syndrome X-Linked Genes) and the mTOR (Molecular Target of Rapamycin) pathway.	('MEN1', 'Gene', '4221', (0, 4))	('DAXX', 'Gene', '1616', (109, 113))	('Mental Retardation Syndrome', 'Disease', (152, 179))	('mTOR', 'Gene', '2475', (204, 208))	('common', 'Reg', (22, 28))	('pancreatic neuroendocrine tumors', 'Disease', (50, 82))	('mutations', 'Var', (96, 105))	('MEN1', 'Gene', (0, 4))	('Mental Retardation Syndrome', 'Disease', 'MESH:D008607', (152, 179))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (61, 82))	('endocrine tumor', 'Phenotype', 'HP:0100568', (66, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Molecular Target of Rapamycin', 'Gene', '2475', (210, 239))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ATRX', 'Gene', (114, 118))	('Molecular Target of Rapamycin', 'Gene', (210, 239))	('ATRX', 'Gene', '546', (114, 118))	('Mental Retardation', 'Phenotype', 'HP:0001249', (152, 170))	('mTOR', 'Gene', (204, 208))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (50, 82))	('DAXX', 'Gene', (109, 113))
27036	27742784	The term, MEN4, applies to rare patients with the MEN1 phenotype, who have germline mutations in CDKN1B, not MEN1.	('patients', 'Species', '9606', (32, 40))	('CDKN1B', 'Gene', '1027', (97, 103))	('MEN4', 'Gene', '1027', (10, 14))	('mutations', 'Var', (84, 93))	('MEN1', 'Gene', (50, 54))	('MEN1', 'Gene', (109, 113))	('CDKN1B', 'Gene', (97, 103))	('MEN4', 'Gene', (10, 14))	('MEN1', 'Gene', '4221', (50, 54))	('MEN1', 'Gene', '4221', (109, 113))
27037	27742784	The Carney complex, characterized by multiple skin lesions cardiac myxoma, acromegaly, schwannoma, thyroid tumors, and pigmented nodular adrenocortical disease, is caused by germline mutations in CNC1 which encodes the regulatory subunit of the protein kinase A (PRKAR1A).	('acromegaly', 'Disease', 'MESH:D000172', (75, 85))	('thyroid tumors', 'Disease', 'MESH:D013959', (99, 113))	('germline mutations', 'Var', (174, 192))	('schwannoma', 'Disease', 'MESH:D009442', (87, 97))	('acromegaly', 'Disease', (75, 85))	('acromegaly', 'Phenotype', 'HP:0000845', (75, 85))	('skin lesions cardiac myxoma', 'Disease', (46, 73))	('PRKAR1A', 'Gene', (263, 270))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('pigmented nodular adrenocortical disease', 'Disease', 'MESH:C566469', (119, 159))	('Carney complex', 'Disease', (4, 18))	('thyroid tumors', 'Disease', (99, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pigmented nodular adrenocortical disease', 'Disease', (119, 159))	('pigmented nodular adrenocortical disease', 'Phenotype', 'HP:0001580', (119, 159))	('PRKAR1A', 'Gene', '5573', (263, 270))	('schwannoma', 'Phenotype', 'HP:0100008', (87, 97))	('CNC1', 'Gene', (196, 200))	('CNC1', 'Gene', '5573', (196, 200))	('cardiac myxoma', 'Phenotype', 'HP:0011672', (59, 73))	('schwannoma', 'Disease', (87, 97))	('caused by', 'Reg', (164, 173))	('skin lesions cardiac myxoma', 'Disease', 'MESH:D006331', (46, 73))
27038	27742784	Approximately 65% of patients have mutations in PRKARIA and 20% have mutations in the putative CNC2 gene located on chromosome 2; however, the specific gene has not been identified.	('mutations', 'Var', (69, 78))	('PRKARIA', 'Gene', (48, 55))	('patients', 'Species', '9606', (21, 29))	('CNC2', 'Gene', '1257', (95, 99))	('CNC2', 'Gene', (95, 99))	('mutations', 'Var', (35, 44))
27040	27742784	The large majority of pituitary tumors are sporadic, and not associated with any known syndrome; however, germline AIP mutations are found in 4% of them; the incidence being higher in children and in young adults with macroadenomas or gigantism.	('pituitary tumors', 'Disease', (22, 38))	('AIP', 'Gene', '9049', (115, 118))	('AIP', 'Gene', (115, 118))	('macroadenomas', 'Disease', 'None', (218, 231))	('children', 'Species', '9606', (184, 192))	('macroadenomas', 'Disease', (218, 231))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('pituitary tumors', 'Disease', 'MESH:D010911', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (119, 128))	('gigantism', 'Disease', (235, 244))
27041	27742784	Sporadic tumors with AIP mutations, compared to those without AIP mutations, are more common in males, are larger and invasive, and secrete growth hormone, or prolactin.	('mutations', 'Var', (25, 34))	('common', 'Reg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('growth hormone', 'Gene', (140, 154))	('Sporadic tumors', 'Disease', 'MESH:D009369', (0, 15))	('AIP', 'Gene', '9049', (62, 65))	('Sporadic tumors', 'Disease', (0, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('growth hormone', 'Gene', '2688', (140, 154))	('AIP', 'Gene', (21, 24))	('prolactin', 'MPA', (159, 168))	('AIP', 'Gene', '9049', (21, 24))	('AIP', 'Gene', (62, 65))
27042	27742784	Germline mutations in MEN1 are found in 0.6 to 2.6% of very young patients with isolated pituitary tumors.	('Germline mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MEN1', 'Gene', (22, 26))	('isolated pituitary tumors', 'Disease', 'MESH:D010911', (80, 105))	('MEN1', 'Gene', '4221', (22, 26))	('patients', 'Species', '9606', (66, 74))	('isolated pituitary tumors', 'Disease', (80, 105))
27043	27742784	There are few reports of CDKN1B mutations, and no reports of PRKAR1A mutations in sporadic pituitary tumors.	('pituitary tumors', 'Disease', (91, 107))	('CDKN1B', 'Gene', (25, 31))	('PRKAR1A', 'Gene', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('pituitary tumors', 'Disease', 'MESH:D010911', (91, 107))	('mutations', 'Var', (32, 41))	('PRKAR1A', 'Gene', '5573', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('CDKN1B', 'Gene', '1027', (25, 31))
27044	27742784	Although the subject of intense investigation, the role of epigenetic regulation on the pathogenesis of pituitary adenomas, is unclear and merits further investigation.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (104, 122))	('pituitary adenomas', 'Disease', (104, 122))	('epigenetic regulation', 'Var', (59, 80))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (104, 121))	('pituitary adenomas', 'Disease', 'MESH:D010911', (104, 122))
27046	27742784	They also describe a number of somatic mutations associated with sporadic pituitary tumors, but note that the role of these mutations in tumor pathogenesis and progression is unclear.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (137, 142))	('pituitary tumors', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (84, 89))	('pituitary tumors', 'Disease', 'MESH:D010911', (74, 90))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
27050	27785149	Mediastinal paragangliomas related to SDHx gene mutations Paragangliomas (PGLs) related to hereditary syndromes are rare mediastinal tumors.	('PGLs', 'Phenotype', 'HP:0002668', (74, 78))	('Mediastinal paragangliomas', 'Disease', (0, 26))	('SDHx gene', 'Gene', (38, 47))	('Paragangliomas', 'Disease', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Paraganglioma', 'Phenotype', 'HP:0002668', (58, 71))	('paraganglioma', 'Phenotype', 'HP:0002668', (12, 25))	('Paragangliomas', 'Disease', 'MESH:D010235', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Mediastinal paragangliomas', 'Disease', 'MESH:D008480', (0, 26))	('mediastinal tumors', 'Disease', 'MESH:D008480', (121, 139))	('hereditary syndromes', 'Disease', 'MESH:D009386', (91, 111))	('Paragangliomas', 'Phenotype', 'HP:0002668', (58, 72))	('mediastinal tumors', 'Disease', (121, 139))	('hereditary syndromes', 'Disease', (91, 111))	('paragangliomas', 'Phenotype', 'HP:0002668', (12, 26))	('mutations', 'Var', (48, 57))
27051	27785149	Paragangliomas are caused by mutations in genes encoding subunits of succinate dehydrogenase enzyme (SDH).	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('caused by', 'Reg', (19, 28))	('mutations', 'Var', (29, 38))	('SDH', 'Gene', '6390', (101, 104))	('succinate dehydrogenase', 'Gene', '6390', (69, 92))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('succinate dehydrogenase', 'Gene', (69, 92))	('SDH', 'Gene', (101, 104))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paragangliomas', 'Disease', (0, 14))
27052	27785149	To evaluate clinical, anatomical and functional characteristics of mediastinal paragangliomas related to SDHx gene mutations.	('SDHx', 'Chemical', '-', (105, 109))	('mutations', 'Var', (115, 124))	('paragangliomas', 'Disease', (79, 93))	('SDHx', 'Gene', (105, 109))	('paragangliomas', 'Disease', 'MESH:D010235', (79, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('paragangliomas', 'Phenotype', 'HP:0002668', (79, 93))	('related', 'Reg', (94, 101))
27053	27785149	Retrospective analysis of 75 patients with confirmed SDHx gene mutations (24 patients with SDHB, 5 SDHC, 46 with SDHD mutations) was performed.	('mutations', 'Var', (63, 72))	('patients', 'Species', '9606', (29, 37))	('SDHx', 'Chemical', '-', (53, 57))	('SDHD', 'Gene', (113, 117))	('SDHD', 'Gene', '6392', (113, 117))	('SDHB', 'Gene', '6390', (91, 95))	('SDHC', 'Gene', '6391', (99, 103))	('patients', 'Species', '9606', (77, 85))	('SDHB', 'Gene', (91, 95))	('SDHx gene', 'Gene', (53, 62))	('SDHC', 'Gene', (99, 103))
27055	27785149	Out of 75 patients, 16 (21%) patients (1 SDHB, 15 SDHD mutations) had 17 PGLs localized in the mediastinum.	('patients', 'Species', '9606', (29, 37))	('SDHD', 'Gene', (50, 54))	('SDHD', 'Gene', '6392', (50, 54))	('mutations', 'Var', (55, 64))	('SDHB', 'Gene', '6390', (41, 45))	('PGLs', 'Phenotype', 'HP:0002668', (73, 77))	('patients', 'Species', '9606', (10, 18))	('SDHB', 'Gene', (41, 45))
27060	27785149	All PGLs were benign except in 1 patient with the SDHB mutation and PGL detected in the posterior mediastinum, who had a metastatic disease.	('patient', 'Species', '9606', (33, 40))	('SDHB', 'Gene', (50, 54))	('PGLs', 'Phenotype', 'HP:0002668', (4, 8))	('mutation', 'Var', (55, 63))	('SDHB', 'Gene', '6390', (50, 54))
27064	27785149	Most cases of familial paragangliomas are caused by mutations in the genes encoding A, B, C, D subunits of mitochondrial complex II enzyme succinate dehydrogenase (SDH).	('mutations', 'Var', (52, 61))	('familial paragangliomas', 'Disease', (14, 37))	('A, B, C, D subunits of mitochondrial complex II enzyme succinate dehydrogenase', 'Gene', '10058', (84, 162))	('paraganglioma', 'Phenotype', 'HP:0002668', (23, 36))	('caused by', 'Reg', (42, 51))	('SDH', 'Gene', (164, 167))	('familial paragangliomas', 'Disease', 'MESH:D010235', (14, 37))	('SDH', 'Gene', '6390', (164, 167))	('paragangliomas', 'Phenotype', 'HP:0002668', (23, 37))
27065	27785149	Predominantly, PGL syndromes are associated with SDHD and SDHB mutations.	('mutations', 'Var', (63, 72))	('SDHB', 'Gene', (58, 62))	('PGL syndromes', 'Disease', (15, 28))	('associated', 'Reg', (33, 43))	('SDHD', 'Gene', '6392', (49, 53))	('SDHB', 'Gene', '6390', (58, 62))	('SDHD', 'Gene', (49, 53))
27066	27785149	SDHC mutation is rare, and typically patients have benign, solitary head and neck paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('patients', 'Species', '9606', (37, 45))	('SDHC', 'Gene', (0, 4))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (68, 96))	('SDHC', 'Gene', '6391', (0, 4))	('neck paragangliomas', 'Disease', 'MESH:D010235', (77, 96))	('mutation', 'Var', (5, 13))	('neck paragangliomas', 'Disease', (77, 96))
27067	27785149	SDHD mutation carriers most frequently develop multifocal head and neck paragangliomas; adrenal and extraadrenal PGLs occur less frequently.	('PGLs', 'Phenotype', 'HP:0002668', (113, 117))	('neck paragangliomas', 'Disease', (67, 86))	('neck paragangliomas', 'Disease', 'MESH:D010235', (67, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('paragangliomas', 'Phenotype', 'HP:0002668', (72, 86))	('SDHD', 'Gene', '6392', (0, 4))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (58, 86))	('multifocal', 'Disease', (47, 57))	('SDHD', 'Gene', (0, 4))	('develop', 'PosReg', (39, 46))	('mutation', 'Var', (5, 13))
27068	27785149	SDHB mutation carriers are at risk of malignant and extraadrenal abdominal and thoracic paragangliomas.	('thoracic paragangliomas', 'Disease', 'MESH:D010235', (79, 102))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('thoracic paragangliomas', 'Disease', (79, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))	('mutation', 'Var', (5, 13))
27082	27785149	The aim of the study was to evaluate clinical, biochemical and imaging characteristics of mediastinal paragangliomas related to SDHx gene mutations.	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('paragangliomas', 'Phenotype', 'HP:0002668', (102, 116))	('paragangliomas', 'Disease', 'MESH:D010235', (102, 116))	('SDHx', 'Chemical', '-', (128, 132))	('SDHx', 'Gene', (128, 132))	('related', 'Reg', (117, 124))	('paragangliomas', 'Disease', (102, 116))	('mutations', 'Var', (138, 147))
27083	27785149	We retrospectively analyzed the patients with SDHx mutations confirmed by genetic testing and registered in the Polish Pheochromocytoma-Paraganglioma Registry.	('SDHx', 'Chemical', '-', (46, 50))	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (51, 60))	('Pheochromocytoma-Paraganglioma', 'Disease', (119, 149))	('Pheochromocytoma-Paraganglioma', 'Disease', 'MESH:D010673', (119, 149))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('Paraganglioma', 'Phenotype', 'HP:0002668', (136, 149))	('SDHx', 'Gene', (46, 50))
27087	27785149	Overall, 75 patients were enrolled in the study (24 patients with SDHB mutations, 5 with SDHC, 46 with SDHD mutations); 16 patients had PGLs localized in the mediastinum.	('SDHB', 'Gene', (66, 70))	('patients', 'Species', '9606', (12, 20))	('PGLs', 'Phenotype', 'HP:0002668', (136, 140))	('SDHC', 'Gene', (89, 93))	('patients', 'Species', '9606', (123, 131))	('SDHC', 'Gene', '6391', (89, 93))	('mutations', 'Var', (71, 80))	('SDHB', 'Gene', '6390', (66, 70))	('SDHD', 'Gene', '6392', (103, 107))	('patients', 'Species', '9606', (52, 60))	('SDHD', 'Gene', (103, 107))
27094	27785149	Carriers of the SDHx gene mutations with paragangliomas detected by CT examination were subsequently screened by somatostatin receptor scintigraphy (SRS) and mIBG scintigraphy as additional functional imaging modalities.	('SDHx', 'Gene', (16, 20))	('paragangliomas', 'Disease', 'MESH:D010235', (41, 55))	('paragangliomas', 'Disease', (41, 55))	('SDHx', 'Chemical', '-', (16, 20))	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('SRS', 'Chemical', '-', (149, 152))	('paragangliomas', 'Phenotype', 'HP:0002668', (41, 55))	('mutations', 'Var', (26, 35))	('mIBG', 'Chemical', '-', (158, 162))
27097	27785149	In each case after thyroid suppression using Lugol's solution, one day before the study, the patients received an injection of 300-370 MBq of 123I mIBG.	('thyroid suppression', 'Phenotype', 'HP:0008245', (19, 38))	('mIBG', 'Gene', (147, 151))	('123I', 'Var', (142, 146))	('patients', 'Species', '9606', (93, 101))	('mIBG', 'Chemical', '-', (147, 151))
27103	27785149	All patients with SDHD mutations, except 1, had a C11X nonsense mutation, which was recognized as a founding mutation, and 1 patient had an exon deletion.	('patient', 'Species', '9606', (4, 11))	('SDHD', 'Gene', '6392', (18, 22))	('mutations', 'Var', (23, 32))	('C11X', 'Var', (50, 54))	('patients', 'Species', '9606', (4, 12))	('patient', 'Species', '9606', (125, 132))	('SDHD', 'Gene', (18, 22))	('C11X', 'SUBSTITUTION', 'None', (50, 54))
27104	27785149	In 1 SDHB carrier, we observed a missense mutation.	('missense mutation', 'Var', (33, 50))	('SDHB', 'Gene', '6390', (5, 9))	('SDHB', 'Gene', (5, 9))
27105	27785149	One patient with SDHB mutation had a malignant disease with metastasis to the lung, bone and lymph nodes.	('malignant disease', 'Disease', 'MESH:D009369', (37, 54))	('malignant disease', 'Disease', (37, 54))	('mutation', 'Var', (22, 30))	('SDHB', 'Gene', '6390', (17, 21))	('patient', 'Species', '9606', (4, 11))	('metastasis to the lung', 'Disease', (60, 82))	('metastasis to the lung', 'Disease', 'MESH:D009362', (60, 82))	('SDHB', 'Gene', (17, 21))
27127	27785149	One SDHB gene mutation carrier had a metastatic disease at the time of the diagnosis of a posterior mediastinal paraganglioma.	('metastatic disease', 'Disease', (37, 55))	('paraganglioma', 'Disease', (112, 125))	('mutation', 'Var', (14, 22))	('paraganglioma', 'Disease', 'MESH:D010235', (112, 125))	('SDHB', 'Gene', '6390', (4, 8))	('SDHB', 'Gene', (4, 8))	('paraganglioma', 'Phenotype', 'HP:0002668', (112, 125))
27130	27785149	Paragangliomas related to SDHx gene mutations are mainly localized in the head and neck region, and extraadrenally in the abdomen.	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('SDHx', 'Gene', (26, 30))	('SDHx', 'Chemical', '-', (26, 30))	('mutations', 'Var', (36, 45))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paragangliomas', 'Disease', (0, 14))
27134	27785149	Their findings similar to Ghayee underline that mediastinal paragangliomas are closely related to SDHx mutations and are often malignant.	('paragangliomas', 'Disease', (60, 74))	('paragangliomas', 'Disease', 'MESH:D010235', (60, 74))	('mutations', 'Var', (103, 112))	('paragangliomas', 'Phenotype', 'HP:0002668', (60, 74))	('SDHx', 'Gene', (98, 102))	('SDHx', 'Chemical', '-', (98, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (60, 73))
27139	27785149	All patients were carriers of SDHx mutations, and the majority of our patients underwent a CT evaluation of the chest as a screening test after detecting SDHx gene mutations.	('patients', 'Species', '9606', (70, 78))	('SDHx', 'Gene', (30, 34))	('SDHx', 'Chemical', '-', (154, 158))	('SDHx', 'Gene', (154, 158))	('SDHx', 'Chemical', '-', (30, 34))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (35, 44))
27140	27785149	We found that the prevalence of mediastinal PGLs may be higher in carriers of SDHx mutations than previously reported, especially in SDHD gene mutations.	('mutations', 'Var', (83, 92))	('carriers', 'Reg', (66, 74))	('PGLs', 'Phenotype', 'HP:0002668', (44, 48))	('SDHx', 'Chemical', '-', (78, 82))	('SDHx', 'Gene', (78, 82))	('SDHD', 'Gene', '6392', (133, 137))	('SDHD', 'Gene', (133, 137))	('mediastinal PGLs', 'Disease', (32, 48))	('higher', 'PosReg', (56, 62))
27142	27785149	Among 75 patients with SDHx gene mutations, 16 (21%) patients had paragangliomas located in the mediastinum, but only 3 patients (with paragangliomas located in the posterior mediastinum) had symptoms associated with catecholamine hypersecretion, while the remaining patients were asymptomatic.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (267, 275))	('SDHx', 'Chemical', '-', (23, 27))	('paragangliomas', 'Disease', (66, 80))	('paragangliomas', 'Disease', 'MESH:D010235', (66, 80))	('SDHx', 'Gene', (23, 27))	('patients', 'Species', '9606', (53, 61))	('catecholamine', 'Chemical', 'MESH:D002395', (217, 230))	('mutations', 'Var', (33, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (66, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (66, 80))	('paragangliomas', 'Disease', (135, 149))	('paragangliomas', 'Disease', 'MESH:D010235', (135, 149))	('catecholamine', 'MPA', (217, 230))	('patients', 'Species', '9606', (120, 128))	('paragangliomas', 'Phenotype', 'HP:0002668', (135, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (135, 148))
27152	27785149	In our report, the prevalence of mediastinal paragangliomas was higher (8.2%) than in other reports, mainly due to SDHD gene mutations and with a benign course.	('mutations', 'Var', (125, 134))	('SDHD', 'Gene', '6392', (115, 119))	('SDHD', 'Gene', (115, 119))	('paragangliomas', 'Disease', (45, 59))	('paragangliomas', 'Disease', 'MESH:D010235', (45, 59))	('paragangliomas', 'Phenotype', 'HP:0002668', (45, 59))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))
27156	27785149	It is SDHD p.C11X, which was recognized as a Polish founder mutation.	('p.C11X', 'Mutation', 'rs104894309', (11, 17))	('SDHD', 'Gene', (6, 10))	('SDHD', 'Gene', '6392', (6, 10))	('p.C11X', 'Var', (11, 17))
27158	27785149	Most mediastinal paragangliomas were related to SDHD gene mutations, were asymptomatic, and were localized intrapericardially.	('mutations', 'Var', (58, 67))	('paragangliomas', 'Disease', (17, 31))	('paragangliomas', 'Disease', 'MESH:D010235', (17, 31))	('paraganglioma', 'Phenotype', 'HP:0002668', (17, 30))	('related', 'Reg', (37, 44))	('paragangliomas', 'Phenotype', 'HP:0002668', (17, 31))	('SDHD', 'Gene', '6392', (48, 52))	('SDHD', 'Gene', (48, 52))
27159	27785149	None of the PGLs related to SDHD mutations were malignant, and during the follow-up no metastases were detected.	('SDHD', 'Gene', (28, 32))	('metastases', 'Disease', (87, 97))	('mutations', 'Var', (33, 42))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('SDHD', 'Gene', '6392', (28, 32))	('PGLs', 'Phenotype', 'HP:0002668', (12, 16))
27160	27785149	Only one mediastinal PGL related to SDHB mutation was malignant.	('mutation', 'Var', (41, 49))	('SDHB', 'Gene', (36, 40))	('SDHB', 'Gene', '6390', (36, 40))
27161	27785149	The results of our study show that the prevalence of mediastinal paragangliomas in asymptomatic SDHx mutation carriers may be higher than previously believed.	('paragangliomas', 'Disease', (65, 79))	('paragangliomas', 'Disease', 'MESH:D010235', (65, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (65, 79))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHx', 'Gene', (96, 100))	('SDHx', 'Chemical', '-', (96, 100))	('mutation', 'Var', (101, 109))
27223	19889235	131I-Metaiodobenzylguanidine (131I-MIBG) scintigraphic scan tomography was performed and the retroperitoneal tumor accumulated 131I-MIBG 48 hours after radioisotope injection (Fig.	('131I-Metaiodobenzylguanidine', 'Chemical', '-', (0, 28))	('131I-MIBG', 'Chemical', 'MESH:D019797', (30, 39))	('131I-MIBG', 'Chemical', 'MESH:D019797', (127, 136))	('retroperitoneal tumor', 'Disease', 'MESH:D012186', (93, 114))	('retroperitoneal tumor', 'Disease', (93, 114))	('131I-MIBG', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
27246	19889235	In the present case, diagnostic images obtained by contrast-enhanced CT scan, MRI and 131I-MIBG scintigraphic scan tomography were compatible with paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('paraganglioma', 'Disease', (147, 160))	('131I-MIBG', 'Chemical', 'MESH:D019797', (86, 95))	('paraganglioma', 'Disease', 'MESH:D010235', (147, 160))	('131I-MIBG', 'Var', (86, 95))
27282	31903598	Over time, non-physiologic and excessive release of these hormones can lead to cardiovascular complications, decompensation and death.	('lead to', 'Reg', (71, 78))	('non-physiologic', 'Var', (11, 26))	('death', 'Disease', (128, 133))	('cardiovascular complications', 'Disease', 'MESH:D002318', (79, 107))	('cardiovascular complications', 'Disease', (79, 107))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (79, 107))	('decompensation', 'Disease', (109, 123))	('release', 'MPA', (41, 48))	('cardiovascular complication', 'Phenotype', 'HP:0001626', (79, 106))	('death', 'Disease', 'MESH:D003643', (128, 133))
27283	31903598	Intraoperative manipulation of the tumour can elicit hypertensive crises, which historically have been regarded as responsible for perioperative mortality rates of up to 48%.	('elicit', 'Reg', (46, 52))	('mortality', 'Disease', (145, 154))	('manipulation', 'Var', (15, 27))	('hypertensive crises', 'Phenotype', 'HP:0100735', (53, 72))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('hypertensive', 'Disease', 'MESH:D006973', (53, 65))	('mortality', 'Disease', 'MESH:D003643', (145, 154))	('hypertensive', 'Disease', (53, 65))	('tumour', 'Disease', (35, 41))
27398	33329398	Genetic testing for SDHB, SHDC, and SDHD gene mutations by aCGH (ExonArrayDx) did not detect any disease-associated mutations in exons 1-8 of the SDHB gene, exons 1-6 of the SDHC gene, exons 1-4 of the SDHD gene, or the c.232 G>A in exon 3 of the SDHAF2 gene (required for flavination of the SDHA subunit).	('SDHA', 'Gene', '6389', (292, 296))	('SDHAF2', 'Gene', '54949', (247, 253))	('SDHD', 'Gene', (36, 40))	('SDHB', 'Gene', (146, 150))	('SDHC', 'Gene', (174, 178))	('SDHD', 'Gene', '6392', (36, 40))	('c.232 G>A', 'Mutation', 'rs113560320', (220, 229))	('SDHC', 'Gene', '6391', (174, 178))	('SDHA', 'Gene', (292, 296))	('SDHB', 'Gene', (20, 24))	('SDHD', 'Gene', '6392', (202, 206))	('c.232 G>A', 'Var', (220, 229))	('SDHA', 'Gene', '6389', (247, 251))	('SDHB', 'Gene', '6390', (20, 24))	('SDHD', 'Gene', (202, 206))	('SDHB', 'Gene', '6390', (146, 150))	('SDHA', 'Gene', (247, 251))	('SDHAF2', 'Gene', (247, 253))
27404	33329398	The tumors showed I131-MIBG uptake.	('I131-MIBG', 'Chemical', '-', (18, 27))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('I131-MIBG', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
27434	33329398	With increasing dose levels, I131-MIBG emits sufficient radiation to lead to cellular damage.	('I131-MIBG', 'Var', (29, 38))	('cellular damage', 'CPA', (77, 92))	('lead to', 'Reg', (69, 76))	('I131-MIBG', 'Chemical', '-', (29, 38))
27436	33329398	In the pivotal phase II study of HSA I131-MIBG, the primary endpoint was the reduction in the number of anti-hypertensives and anti-hypertensive dose by greater than or equal to 50%.	('HSA I131-MIBG', 'Var', (33, 46))	('reduction', 'NegReg', (77, 86))	('hypertensive', 'Disease', 'MESH:D006973', (132, 144))	('hypertensives', 'Disease', 'MESH:D006973', (109, 122))	('anti-hypertensives', 'Phenotype', 'HP:0000822', (104, 122))	('hypertensives', 'Disease', (109, 122))	('hypertensive', 'Disease', (132, 144))	('I131-MIBG', 'Chemical', '-', (37, 46))	('hypertensive', 'Disease', 'MESH:D006973', (109, 121))	('hypertensive', 'Disease', (109, 121))
27449	33329398	Patients with PPGL already have elevated blood pressure due to catecholamine excess.	('elevated blood pressure', 'Phenotype', 'HP:0032263', (32, 55))	('elevated', 'PosReg', (32, 40))	('catecholamine', 'Chemical', 'MESH:D002395', (63, 76))	('catecholamine excess', 'MPA', (63, 83))	('Patients', 'Species', '9606', (0, 8))	('catecholamine excess', 'Phenotype', 'HP:0003334', (63, 83))	('blood pressure', 'MPA', (41, 55))	('PPGL', 'Chemical', '-', (14, 18))	('PPGL', 'Var', (14, 18))
27611	32195067	Exogenous infusion of norepinephrine has been reported to induce myocardial necrosis and leukocyte infiltration with degenerative changes.	('myocardial necrosis', 'Phenotype', 'HP:0001700', (65, 84))	('myocardial necrosis', 'Disease', 'MESH:D009202', (65, 84))	('norepinephrine', 'Chemical', 'MESH:D009638', (22, 36))	('leukocyte infiltration', 'CPA', (89, 111))	('norepinephrine', 'Var', (22, 36))	('myocardial necrosis', 'Disease', (65, 84))	('degenerative changes', 'Phenotype', 'HP:0002180', (117, 137))
27644	32195067	Mutations in the RYR2 receptor are not unique to CPVT and can occur in long QT syndrome.	('long QT syndrome', 'Disease', 'MESH:D008133', (71, 87))	('CPVT', 'Phenotype', 'HP:0004758', (49, 53))	('occur', 'Reg', (62, 67))	('Mutations', 'Var', (0, 9))	('RYR2', 'Gene', (17, 21))	('long QT syndrome', 'Disease', (71, 87))	('long QT syndrome', 'Phenotype', 'HP:0001657', (71, 87))
27651	32195067	It should be noted that CPVT can be frequently linked to aberrant sinus node function and may also contribute to atrial tachyarrhythmias.	('arrhythmias', 'Phenotype', 'HP:0011675', (125, 136))	('aberrant sinus node', 'Phenotype', 'HP:0011704', (57, 76))	('atrial tachyarrhythmias', 'Disease', (113, 136))	('CPVT', 'Phenotype', 'HP:0004758', (24, 28))	('contribute', 'Reg', (99, 109))	('atrial tachyarrhythmias', 'Disease', 'MESH:D013617', (113, 136))	('atrial tachyarrhythmias', 'Phenotype', 'HP:0001692', (113, 136))	('linked', 'Reg', (47, 53))	('arrhythmia', 'Phenotype', 'HP:0011675', (125, 135))	('CPVT', 'Disease', (24, 28))	('aberrant', 'Var', (57, 65))
27663	32133432	Tinnitus With Unexpected Spanish Roots: Head and Neck Paragangliomas Caused by SDHAF2 Mutation It is estimated that up to 40% of all head and neck paragangliomas (HNPGL) have a hereditary background with the most common mutations being found in the succinate dehydrogenase (SDH) genes.	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (133, 161))	('neck paragangliomas', 'Disease', 'MESH:D010235', (142, 161))	('HNPGL', 'Phenotype', 'HP:0002864', (163, 168))	('Mutation', 'Var', (86, 94))	('succinate dehydrogenase', 'Gene', (249, 272))	('SDH', 'Gene', '6390', (79, 82))	('Neck Paragangliomas', 'Disease', (49, 68))	('Head and Neck Paragangliomas', 'Phenotype', 'HP:0002864', (40, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('SDHAF2', 'Gene', '54949', (79, 85))	('Caused by', 'Reg', (69, 78))	('SDHAF2', 'Gene', (79, 85))	('Paragangliomas', 'Phenotype', 'HP:0002668', (54, 68))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (133, 160))	('SDH', 'Gene', (79, 82))	('SDH', 'Gene', '6390', (274, 277))	('succinate dehydrogenase', 'Gene', '6390', (249, 272))	('neck paragangliomas', 'Disease', (142, 161))	('Tinnitus', 'Phenotype', 'HP:0000360', (0, 8))	('paragangliomas', 'Phenotype', 'HP:0002668', (147, 161))	('Neck Paragangliomas', 'Disease', 'MESH:D010235', (49, 68))	('SDH', 'Gene', (274, 277))
27664	32133432	SDHAF2 mutation leads to the rare paraganglioma syndrome 2.	('leads to', 'Reg', (16, 24))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (34, 56))	('SDHAF2', 'Gene', '54949', (0, 6))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('SDHAF2', 'Gene', (0, 6))	('paraganglioma syndrome', 'Disease', (34, 56))	('mutation', 'Var', (7, 15))
27668	32133432	Genetic testing revealed a rare germline, loss-of-function mutation in the SDHAF2 gene, previously described to cause hereditary paraganglioma syndrome 2.	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('hereditary paraganglioma syndrome', 'Disease', (118, 151))	('mutation', 'Var', (59, 67))	('loss-of-function', 'NegReg', (42, 58))	('SDHAF2', 'Gene', '54949', (75, 81))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D061325', (118, 151))	('SDHAF2', 'Gene', (75, 81))
27677	32133432	The most common mutations are found in the succinate dehydrogenase (SDH) genes with the highest prevalence of mutations in SDHD, followed by SDHB and SDHC.	('SDHC', 'Gene', (150, 154))	('SDH', 'Gene', (150, 153))	('SDH', 'Gene', '6390', (141, 144))	('SDH', 'Gene', (123, 126))	('succinate dehydrogenase', 'Gene', (43, 66))	('mutations', 'Var', (110, 119))	('SDH', 'Gene', (68, 71))	('SDHB', 'Gene', (141, 145))	('SDHD', 'Gene', (123, 127))	('SDHD', 'Gene', '6392', (123, 127))	('SDHC', 'Gene', '6391', (150, 154))	('SDH', 'Gene', (141, 144))	('SDH', 'Gene', '6390', (150, 153))	('SDH', 'Gene', '6390', (123, 126))	('SDH', 'Gene', '6390', (68, 71))	('SDHB', 'Gene', '6390', (141, 145))	('succinate dehydrogenase', 'Gene', '6390', (43, 66))
27679	32133432	The enzymes of the tricarboxylic acid cycle in general are considered tumor suppressors, and mutations in the corresponding genes are associated with tumorigenesis in different tissues.	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (19, 37))	('associated', 'Reg', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
27680	32133432	Several of the mutations associated with hereditary Pheo/PGL cause a disturbed cellular response to hypoxia, leading to a condition called pseudohypoxia.	('cause', 'Reg', (61, 66))	('Pheo/PGL', 'Disease', (52, 60))	('pseudohypoxia', 'Disease', (139, 152))	('disturbed', 'Reg', (69, 78))	('mutations', 'Var', (15, 24))	('Pheo/PGL', 'Disease', 'MESH:D010673', (52, 60))	('leading to', 'Reg', (109, 119))	('pseudohypoxia', 'Disease', 'None', (139, 152))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('hypoxia', 'Disease', (145, 152))	('hypoxia', 'Disease', 'MESH:D000860', (145, 152))	('hypoxia', 'Disease', (100, 107))
27692	32133432	DNA from peripheral blood (leukocytes) was isolated and targeted next-generation sequencing of 27 (neuro-)endocrine tumor-related (including the SDHx) genes revealed no pathogenic mutation in the SDHD and SDHC genes but a germline mutation in the SDHAF2 gene (NM_017841.2; c.232G>A).	('tumor', 'Disease', (116, 121))	('SDHAF2', 'Gene', '54949', (247, 253))	('c.232G>A', 'SUBSTITUTION', 'None', (273, 281))	('NM_017841.2', 'Var', (260, 271))	('endocrine tumor', 'Phenotype', 'HP:0100568', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SDHD', 'Gene', '6392', (196, 200))	('SDHC', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SDHD', 'Gene', (196, 200))	('SDHC', 'Gene', '6391', (205, 209))	('c.232G>A', 'Var', (273, 281))	('SDHx', 'Chemical', '-', (145, 149))	('SDHAF2', 'Gene', (247, 253))
27699	32133432	Immunohistochemical staining for SDHB was negative; this investigation is a reasonable first screening, as a loss of SDHB expression is seen in the case of any SDHx mutation, but not in other hereditary tumor syndromes.	('SDHx', 'Chemical', '-', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('SDHB', 'Gene', (117, 121))	('expression', 'MPA', (122, 132))	('hereditary tumor syndrome', 'Disease', 'MESH:D009386', (192, 217))	('SDHB', 'Gene', '6390', (33, 37))	('loss', 'NegReg', (109, 113))	('mutation', 'Var', (165, 173))	('SDHB', 'Gene', (33, 37))	('hereditary tumor syndrome', 'Disease', (192, 217))	('SDHB', 'Gene', '6390', (117, 121))	('SDHx', 'Gene', (160, 164))
27700	32133432	He was found to have a germline, missense mutation of the SDHAF2 gene on chromosome 11 in position 12.2 at site 232 with an exchange of guanine to adenine (11q12.2 c232 G>A).	('11q12.2 c232 G>A', 'Var', (156, 172))	('adenine', 'Chemical', 'MESH:D000225', (147, 154))	('SDHAF2', 'Gene', '54949', (58, 64))	('SDHAF2', 'Gene', (58, 64))	('guanine', 'Chemical', 'MESH:D006147', (136, 143))
27701	32133432	This mutation is known to cause a loss of SDHAF2 function, leading to the hereditary paraganglioma syndrome 2 (PGL2), first discovered in 1982 by van Baars et al.	('paraganglioma', 'Phenotype', 'HP:0002668', (85, 98))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D061325', (74, 107))	('SDHAF2', 'Gene', (42, 48))	('SDHAF2', 'Gene', '54949', (42, 48))	('hereditary paraganglioma syndrome', 'Disease', (74, 107))	('mutation', 'Var', (5, 13))
27703	32133432	3, it inserts Flavin adenine dinucleotide (FAD) into SDHA, a step necessary for a fully functional and stable SDH complex.	('SDH', 'Gene', (53, 56))	('SDH', 'Gene', '6390', (110, 113))	('FAD', 'Chemical', 'MESH:D005182', (43, 46))	('SDHA', 'Gene', '6389', (53, 57))	('SDH', 'Gene', '6390', (53, 56))	('Flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (14, 41))	('SDH', 'Gene', (110, 113))	('inserts', 'Var', (6, 13))	('SDHA', 'Gene', (53, 57))
27720	32133432	According to the particular mutation and its specific tumor risk, the imaging modality and the examined body region can be adapted.	('tumor', 'Disease', (54, 59))	('mutation', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
27721	32133432	Because there is only a small number of PGL2 patients, the recommendations for patients with SDHD mutation can be applied, for instance an MRI of the head and neck region every 18 months and 3 yearly an MRI scans from head to pelvis.	('SDHD', 'Gene', (93, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (79, 87))	('SDHD', 'Gene', '6392', (93, 97))
27767	31275775	Resection usually leads to resolution of diabetes unless other predisposing factors are present.	('Resection', 'Var', (0, 9))	('diabetes', 'Disease', 'MESH:D003920', (41, 49))	('resolution', 'Disease', (27, 37))	('diabetes', 'Disease', (41, 49))
27774	31275775	Sagalowsky indicated that preoperative alpha-blockade without concomitant beta-blockade may predispose to hypoglycemia following tumor removal.	('hypoglycemia following tumor removal', 'Disease', (106, 142))	('predispose to hypoglycemia', 'Phenotype', 'HP:0001988', (92, 118))	('hypoglycemia following tumor removal', 'Disease', 'MESH:D007003', (106, 142))	('hypoglycemia', 'Phenotype', 'HP:0001943', (106, 118))	('predispose', 'Reg', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('alpha-blockade', 'Var', (39, 53))
27849	31211069	The largest study comparing marker-negative and marker-positive patients showed that the most common symptom in marker-positive patients was sustained hypertension (49%), versus abdominal/flank pain (57%) in marker-negative patients.	('patients', 'Species', '9606', (64, 72))	('hypertension', 'Disease', 'MESH:D006973', (151, 163))	('pain', 'Phenotype', 'HP:0012531', (194, 198))	('flank pain', 'Phenotype', 'HP:0030157', (188, 198))	('hypertension', 'Phenotype', 'HP:0000822', (151, 163))	('flank pain', 'Disease', (188, 198))	('patients', 'Species', '9606', (224, 232))	('hypertension', 'Disease', (151, 163))	('patients', 'Species', '9606', (128, 136))	('marker-positive', 'Var', (112, 127))	('flank pain', 'Disease', 'MESH:D021501', (188, 198))
27903	30963018	The incidence of familial paragangliomas is approximately 10%, and about 30% of them are caused by mutations in succinate dehydrogenase (SDH) gene.	('paraganglioma', 'Phenotype', 'HP:0002668', (26, 39))	('paragangliomas', 'Phenotype', 'HP:0002668', (26, 40))	('familial paragangliomas', 'Disease', 'MESH:D010235', (17, 40))	('SDH', 'Gene', (137, 140))	('caused by', 'Reg', (89, 98))	('mutations', 'Var', (99, 108))	('SDH', 'Gene', '6390', (137, 140))	('familial paragangliomas', 'Disease', (17, 40))	('succinate dehydrogenase', 'Gene', (112, 135))	('succinate dehydrogenase', 'Gene', '6390', (112, 135))
27906	30963018	None of our patients was tested for SDH mutations, as this was not routinely performed in our unit during that period.	('SDH', 'Gene', '6390', (36, 39))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (12, 20))	('SDH', 'Gene', (36, 39))
27940	30963018	In the same session, balloon occlusion of the internal carotid artery can be performed to determine if the patient can tolerate blockage of the vessel in case of ligation, clamping, or shunting.	('clamping', 'Var', (172, 180))	('patient', 'Species', '9606', (107, 114))	('balloon occlusion', 'Disease', 'MESH:D054549', (21, 38))	('balloon occlusion', 'Disease', (21, 38))
27944	27838885	Pathological and genetic characterization of bilateral adrenomedullary hyperplasia in a patient with germline MAX mutation In recent years, familial pheochromocytoma (PHEO) with germline mutations in the MAX (MYC Associated Factor X) gene has been reported in a few cases.	('MAX', 'Gene', '4149', (204, 207))	('patient', 'Species', '9606', (88, 95))	('bilateral adrenomedullary hyperplasia', 'Disease', 'MESH:D006965', (45, 82))	('bilateral adrenomedullary hyperplasia', 'Disease', (45, 82))	('MYC Associated Factor X', 'Gene', (209, 232))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (149, 165))	('MAX', 'Gene', '4149', (110, 113))	('MAX', 'Gene', (110, 113))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (140, 165))	('germline mutations', 'Var', (178, 196))	('familial pheochromocytoma', 'Disease', (140, 165))	('MAX', 'Gene', (204, 207))	('PHEO', 'Phenotype', 'HP:0002666', (167, 171))	('MYC Associated Factor X', 'Gene', '4149', (209, 232))
27945	27838885	Here we investigated a 25 years old patient with multiple PHEOs associated with a non-sense germline MAX mutation.	('associated', 'Reg', (64, 74))	('PHEO', 'Phenotype', 'HP:0002666', (58, 62))	('PHEOs', 'Phenotype', 'HP:0002666', (58, 63))	('MAX', 'Gene', (101, 104))	('MAX', 'Gene', '4149', (101, 104))	('patient', 'Species', '9606', (36, 43))	('non-sense', 'Var', (82, 91))
27950	27838885	Nevertheless, immunohistochemistry demonstrated loss of protein MAX expression in all samples including diffuse hyperplasia, suggesting a causative role of MAX mutation for both PHEOs and AMH.	('loss', 'NegReg', (48, 52))	('PHEO', 'Phenotype', 'HP:0002666', (178, 182))	('mutation', 'Var', (160, 168))	('hyperplasia', 'Disease', 'MESH:D006965', (112, 123))	('expression', 'MPA', (68, 78))	('PHEOs', 'Phenotype', 'HP:0002666', (178, 183))	('protein', 'Protein', (56, 63))	('MAX', 'Gene', (156, 159))	('AMH', 'Phenotype', 'HP:0008239', (188, 191))	('hyperplasia', 'Disease', (112, 123))	('MAX', 'Gene', '4149', (156, 159))	('MAX', 'Gene', '4149', (64, 67))	('MAX', 'Gene', (64, 67))
27954	27838885	Patients with bilateral PHEOs and/or family history, carry germline mutations in most cases.	('Patients', 'Species', '9606', (0, 8))	('PHEOs', 'Phenotype', 'HP:0002666', (24, 29))	('bilateral PHEOs', 'Disease', (14, 29))	('germline mutations', 'Var', (59, 77))	('PHEO', 'Phenotype', 'HP:0002666', (24, 28))
27955	27838885	Hereditary PHEO primarily develops in the context of several familial tumor syndromes: von Hippel-Lindau disease (VHL), Multiple Endocrine Neoplasia type 2 (MEN2), Neurofibromatosis 1 (NF1), respectively due to mutation in the VHL, RET or NF1 genes, or familial PPGL associated with mutations in one of the genes encoding for the succinate dehydrogenase complex (SDHA-D, collectively named SDHx).	('NF1', 'Gene', (239, 242))	('Neurofibromatosis 1', 'Gene', '4763', (164, 183))	('Multiple Endocrine Neoplasia type 2', 'Disease', 'MESH:D018813', (120, 155))	('VHL', 'Disease', (227, 230))	('VHL', 'Disease', (114, 117))	('familial tumor', 'Disease', (61, 75))	('Neoplasia', 'Phenotype', 'HP:0002664', (139, 148))	('RET', 'Gene', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SDHA-D', 'Gene', (363, 369))	('Multiple Endocrine Neoplasia type 2', 'Disease', (120, 155))	('associated', 'Reg', (267, 277))	('familial tumor', 'Disease', 'MESH:D009386', (61, 75))	('PHEO', 'Phenotype', 'HP:0002666', (11, 15))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (129, 148))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (87, 112))	('mutations', 'Var', (283, 292))	('VHL', 'Disease', 'MESH:D006623', (227, 230))	('VHL', 'Disease', 'MESH:D006623', (114, 117))	('NF1', 'Gene', '4763', (185, 188))	('SDHx', 'Chemical', '-', (390, 394))	('von Hippel-Lindau disease', 'Disease', (87, 112))	('Neurofibromatosis 1', 'Gene', (164, 183))	('mutation', 'Var', (211, 219))	('NF1', 'Gene', '4763', (239, 242))	('RET', 'Gene', '5979', (232, 235))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (164, 181))	('NF1', 'Gene', (185, 188))	('familial', 'Disease', (253, 261))
27956	27838885	Diffuse and nodular adrenal medullary hyperplasia (AMH) has been described as a precursor of PHEO in MEN2 as well as familial PPGL due to mutation in SDHB .	('PHEO', 'Phenotype', 'HP:0002666', (93, 97))	('adrenal medullary hyperplasia', 'Phenotype', 'HP:0008239', (20, 49))	('nodular adrenal medullary hyperplasia', 'Disease', (12, 49))	('SDHB', 'Gene', '6390', (150, 154))	('nodular adrenal medullary hyperplasia', 'Disease', 'MESH:D020518', (12, 49))	('SDHB', 'Gene', (150, 154))	('due to', 'Reg', (131, 137))	('mutation', 'Var', (138, 146))	('Diffuse', 'Disease', (0, 7))	('AMH', 'Phenotype', 'HP:0008239', (51, 54))	('familial PPGL', 'Disease', (117, 130))
27958	27838885	In these cases there is a loss of MAX protein in the tumors most often caused by Loss-of-Heterozygosity (LOH), deleting the wild-type allele (uniparental disomy, partial deletions).	('deleting', 'NegReg', (111, 119))	('MAX', 'Gene', '4149', (34, 37))	('MAX', 'Gene', (34, 37))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('uniparental disomy', 'Disease', (142, 160))	('loss', 'NegReg', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('Loss-of-Heterozygosity', 'Var', (81, 103))	('tumors', 'Disease', (53, 59))	('uniparental disomy', 'Disease', 'MESH:D024182', (142, 160))
27960	27838885	This brief report first described a patient with MAX germline mutation causing both bilateral PHEOs and nodular or diffuse AMH with an extensive histopathological and molecular analysis.	('germline mutation', 'Var', (53, 70))	('MAX', 'Gene', (49, 52))	('MAX', 'Gene', '4149', (49, 52))	('nodular', 'Disease', (104, 111))	('PHEO', 'Phenotype', 'HP:0002666', (94, 98))	('bilateral PHEOs', 'Disease', (84, 99))	('AMH', 'Phenotype', 'HP:0008239', (123, 126))	('causing', 'Reg', (71, 78))	('PHEOs', 'Phenotype', 'HP:0002666', (94, 99))	('patient', 'Species', '9606', (36, 43))
27961	27838885	A 25-year old asymptomatic adopted Caucasian man with no relevant background medical history had been screened in 2013 for a hereditary mutation of the MAX gene.	('man', 'Species', '9606', (45, 48))	('mutation', 'Var', (136, 144))	('MAX', 'Gene', '4149', (152, 155))	('MAX', 'Gene', (152, 155))
27964	27838885	The genetic test was positive for a non-sense heterozygous mutation in MAX (c.97C>T, p.Arg33* ; NM_002382.3 ; primers available upon request) previously reported in one study.	('p.Arg33*', 'SUBSTITUTION', 'None', (85, 93))	('c.97C>T', 'Mutation', 'rs387906651', (76, 83))	('positive', 'Reg', (21, 29))	('c.97C>T', 'Var', (76, 83))	('MAX', 'Gene', (71, 74))	('p.Arg33*', 'Var', (85, 93))	('MAX', 'Gene', '4149', (71, 74))
27990	27838885	Since the protein MAX antagonizes MYC activity, ablation of MAX's transcriptional repression of MYC could lead to MYC-dependent cell transformation .	('MYC', 'Gene', (34, 37))	('MYC', 'Gene', (96, 99))	('MAX', 'Gene', '4149', (18, 21))	('MAX', 'Gene', (18, 21))	('MYC', 'Gene', (114, 117))	('MYC', 'Gene', '4609', (34, 37))	('lead to', 'Reg', (106, 113))	('MYC', 'Gene', '4609', (96, 99))	('ablation', 'Var', (48, 56))	('MAX', 'Gene', '4149', (60, 63))	('MAX', 'Gene', (60, 63))	('MYC', 'Gene', '4609', (114, 117))
27992	27838885	The non-sense heterozygous MAX mutation found in our patient leads to a premature stop codon with subsequent degradation of the mRNA transcript or a truncated protein with complete disruption of the MAX/MYC interaction (Supplemental Figure 1).	('MAX', 'Gene', (27, 30))	('MAX', 'Gene', '4149', (199, 202))	('MAX', 'Gene', (199, 202))	('MYC', 'Gene', (203, 206))	('MAX', 'Gene', '4149', (27, 30))	('mutation', 'Var', (31, 39))	('degradation', 'MPA', (109, 120))	('MYC', 'Gene', '4609', (203, 206))	('mRNA transcript', 'MPA', (128, 143))	('patient', 'Species', '9606', (53, 60))
27993	27838885	The largest screening study performed on 1,694 PPGL patients without mutations in major susceptibility genes has reported pathogenic MAX mutations in 1.3% of patients with a mean age of occurrence of 32 years.	('mutations', 'Var', (137, 146))	('pathogenic', 'Reg', (122, 132))	('patients', 'Species', '9606', (158, 166))	('MAX', 'Gene', '4149', (133, 136))	('MAX', 'Gene', (133, 136))	('patients', 'Species', '9606', (52, 60))
28007	27838885	It has been reported that tumors carrying truncating MAX mutations can be identified on the basis of a negative immunohistochemical staining for MAX.	('MAX', 'Gene', '4149', (145, 148))	('MAX', 'Gene', (145, 148))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (57, 66))	('MAX', 'Gene', (53, 56))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MAX', 'Gene', '4149', (53, 56))	('tumors', 'Disease', (26, 32))
28034	16119530	In the molecular genetic analysis for MEN2A, direct mutation analysis showed that he was not a carrier of a mutation in exon 11, which includes codon 634 of the RET proto-oncogene.	('RET', 'Gene', '5979', (161, 164))	('MEN2A', 'Gene', '5979', (38, 43))	('MEN2A', 'Gene', (38, 43))	('RET', 'Gene', (161, 164))	('codon 634', 'Var', (144, 153))	('mutation in', 'Var', (108, 119))
28050	16119530	Data from the international RET consortium indicates that the preponderance of MEN2A mutations are in codon 634.	('MEN2A', 'Gene', (79, 84))	('RET', 'Gene', '5979', (28, 31))	('MEN2A', 'Gene', '5979', (79, 84))	('mutations', 'Var', (85, 94))	('RET', 'Gene', (28, 31))
28051	16119530	In 20 cases from 74 families, 97% had RET mutations with 87% having a mutation at codon 634, 6.4% at codon 918, 3.5% at codon 618, 2.1% at codon 611 and 0% at codon 918.	('RET', 'Gene', (38, 41))	('RET', 'Gene', '5979', (38, 41))	('codon 918', 'Var', (101, 110))
28215	25143914	found that younger age at presentation was significantly associated with germline mutations of MEN2 and VHL.	('VHL', 'Disease', 'MESH:D006623', (104, 107))	('germline mutations', 'Var', (73, 91))	('MEN2', 'Gene', (95, 99))	('VHL', 'Disease', (104, 107))
28216	25143914	found that younger age was associated with the VHL missense mutation.	('missense mutation', 'Var', (51, 68))	('VHL', 'Disease', 'MESH:D006623', (47, 50))	('VHL', 'Disease', (47, 50))
28244	22988529	Physical examination revealed severe hypertension (240/150 mmHg), tachycardia (150 bpm), and diaphoresis.	('240/150 mmHg', 'Var', (51, 63))	('tachycardia', 'Phenotype', 'HP:0001649', (66, 77))	('hypertension', 'Disease', (37, 49))	('diaphoresis', 'Phenotype', 'HP:0000975', (93, 104))	('tachycardia', 'Disease', (66, 77))	('hypertension', 'Phenotype', 'HP:0000822', (37, 49))	('tachycardia', 'Disease', 'MESH:D013610', (66, 77))	('diaphoresis', 'Disease', (93, 104))	('hypertension', 'Disease', 'MESH:D006973', (37, 49))
28261	22988529	This resulted in a marked decrease in plasma CgA (1531 mug/L) (Figure 5) and 24-hour urine excretion of VMA (202 mumol/d) and total free CATH and Metanephrines (102074 nmol/d) (Figure 6).	('decrease', 'NegReg', (26, 34))	('CgA', 'Gene', (45, 48))	('CgA', 'Gene', '1113', (45, 48))	('102074 nmol/d', 'Var', (161, 174))
28371	22629039	Hematological analysis confirmed normocytic anemia with hemoglobin 11.3 gm/dl, a raised erythrocyte sedimentation rate (ESR) (130 mm fall in the first hour), while the total and differential leukocyte counts were normal.	('raised erythrocyte', 'Phenotype', 'HP:0001901', (81, 99))	('fall', 'Phenotype', 'HP:0002527', (133, 137))	('normocytic anemia', 'Phenotype', 'HP:0001897', (33, 50))	('anemia', 'Disease', (44, 50))	('raised', 'PosReg', (81, 87))	('anemia', 'Disease', 'MESH:D000740', (44, 50))	('raised erythrocyte sedimentation', 'Phenotype', 'HP:0003565', (81, 113))	('hemoglobin', 'Var', (56, 66))	('anemia', 'Phenotype', 'HP:0001903', (44, 50))	('erythrocyte sedimentation rate', 'MPA', (88, 118))
28482	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
28492	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (26, 34))
28528	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
28529	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('TCGA', 'Disease', (75, 79))	('mutations', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
28530	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('BLCA', 'Disease', (76, 80))	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('SKCM', 'Disease', (58, 62))
28541	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
28542	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('hypermethylation', 'Var', (56, 72))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
28543	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
28544	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
28545	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
28546	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('TC2N', 'Gene', '123036', (12, 16))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', (12, 16))
28555	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
28559	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
28560	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('non-synonymous mutation', 'Var', (23, 46))	('BLCA', 'Disease', (88, 92))	('pathogenic', 'Reg', (12, 22))	('SKCM', 'Disease', (70, 74))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
28561	33247676	Whether these genetic mutations are causative or a sequel of cancer processes needs to be investigated.	('genetic mutations', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
28562	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('cancer', 'Disease', (29, 35))	('susceptibility', 'MPA', (257, 271))	('mutations', 'Var', (80, 89))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('metabolic wiring', 'CPA', (194, 210))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('altered', 'Reg', (186, 193))	('tumour', 'Disease', (161, 167))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
28571	31350093	Update on mutations in the HIF: EPO pathway and their role in erythrocytosis Identification of the underlying defects in congenital erythrocytosis has provided mechanistic insights into the regulation of erythropoiesis and oxygen homeostasis.	('erythrocytosis', 'Disease', (62, 76))	('erythrocytosis', 'Phenotype', 'HP:0001901', (132, 146))	('congenital erythrocytosis', 'Disease', 'MESH:C536842', (121, 146))	('erythrocytosis', 'Disease', 'MESH:D011086', (62, 76))	('EPO', 'Gene', (32, 35))	('oxygen', 'Chemical', 'MESH:D010100', (223, 229))	('erythrocytosis', 'Disease', 'MESH:D011086', (132, 146))	('erythrocytosis', 'Disease', (132, 146))	('congenital erythrocytosis', 'Disease', (121, 146))	('mutations', 'Var', (10, 19))	('EPO', 'Gene', '2056', (32, 35))	('erythrocytosis', 'Phenotype', 'HP:0001901', (62, 76))
28576	31350093	Loss of function mutations in PHD2 and VHL, as well as gain of function mutations in HIF-2alpha and EPOR, are well established causes of erythrocytosis.	('EPOR', 'Gene', '2057', (100, 104))	('mutations', 'Var', (72, 81))	('erythrocytosis', 'Disease', 'MESH:D011086', (137, 151))	('VHL', 'Gene', (39, 42))	('PHD2', 'Gene', (30, 34))	('Loss', 'NegReg', (0, 4))	('VHL', 'Gene', '7428', (39, 42))	('HIF-2alpha', 'Gene', (85, 95))	('HIF-2alpha', 'Gene', '2034', (85, 95))	('erythrocytosis', 'Phenotype', 'HP:0001901', (137, 151))	('gain of function', 'PosReg', (55, 71))	('mutations', 'Var', (17, 26))	('erythrocytosis', 'Disease', (137, 151))	('EPOR', 'Gene', (100, 104))
28578	31350093	Specifically, novel mutations have been identified that either change amino acids in the zinc finger domain of PHD2 or alter splicing of the VHL gene.	('VHL', 'Gene', '7428', (141, 144))	('VHL', 'Gene', (141, 144))	('alter', 'Reg', (119, 124))	('change', 'Reg', (63, 69))	('amino acids in the zinc finger domain', 'MPA', (70, 107))	('splicing', 'MPA', (125, 133))	('mutations', 'Var', (20, 29))	('PHD2', 'Gene', (111, 115))
28579	31350093	In addition, continued study of HIF-2alpha mutations has revealed a distinctive genotype-phenotype correlation.	('mutations', 'Var', (43, 52))	('HIF-2alpha', 'Gene', (32, 42))	('HIF-2alpha', 'Gene', '2034', (32, 42))
28591	31350093	Primary erythrocytosis can be due to defects in the JAK2 or EPOR genes.	('due', 'Reg', (30, 33))	('erythrocytosis', 'Phenotype', 'HP:0001901', (8, 22))	('Primary erythrocytosis', 'Disease', 'MESH:D011086', (0, 22))	('EPOR', 'Gene', '2057', (60, 64))	('JAK2', 'Gene', '3717', (52, 56))	('EPOR', 'Gene', (60, 64))	('defects', 'Var', (37, 44))	('JAK2', 'Gene', (52, 56))	('Primary erythrocytosis', 'Disease', (0, 22))
28594	31350093	These causes include mutations in genes that affect hemoglobin function, such as those encoding for hemoglobin alpha (HBA), hemoglobin beta (HBB), or 2,3-bisphosphoglycerate mutase (BPGM), which synthesizes BPG, a metabolite that decreases hemoglobin affinity for oxygen.	('decreases', 'NegReg', (230, 239))	('HBB', 'Gene', '3043', (141, 144))	('HBA', 'Gene', (118, 121))	('BPGM', 'Gene', '669', (182, 186))	('hemoglobin beta', 'Gene', (124, 139))	('hemoglobin beta', 'Gene', '3043', (124, 139))	('HBB', 'Gene', (141, 144))	('hemoglobin affinity for oxygen', 'MPA', (240, 270))	('BPG', 'Chemical', '-', (207, 210))	('2,3-bisphosphoglycerate mutase', 'Gene', '669', (150, 180))	('BPG', 'Chemical', '-', (182, 185))	('BPGM', 'Gene', (182, 186))	('oxygen', 'Chemical', 'MESH:D010100', (264, 270))	('causes', 'Reg', (6, 12))	('decreases hemoglobin affinity', 'Phenotype', 'HP:0020062', (230, 259))	('decreases hemoglobin', 'Phenotype', 'HP:0001903', (230, 250))	('mutations', 'Var', (21, 30))
28595	31350093	The end result of these mutations is increased hemoglobin affinity for oxygen.	('hemoglobin affinity for oxygen', 'MPA', (47, 77))	('increased hemoglobin', 'Phenotype', 'HP:0001900', (37, 57))	('increased', 'PosReg', (37, 46))	('mutations', 'Var', (24, 33))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))	('increased hemoglobin affinity', 'Phenotype', 'HP:0004825', (37, 66))
28597	31350093	However, it should be recognized that certain forms of secondary erythrocytosis, such as that due to PHD2 mutations, can be associated with normal EPO levels.	('PHD2', 'Gene', (101, 105))	('EPO levels', 'MPA', (147, 157))	('secondary erythrocytosis', 'Disease', (55, 79))	('mutations', 'Var', (106, 115))	('secondary erythrocytosis', 'Disease', 'MESH:D011086', (55, 79))	('erythrocytosis', 'Phenotype', 'HP:0001901', (65, 79))
28598	31350093	The evaluation of patients for erythrocytosis involves tests that include serum EPO measurements, imaging studies, oximetry, P50 measurements, and sequencing of candidate genes.	('P50', 'MPA', (125, 128))	('erythrocytosis', 'Disease', 'MESH:D011086', (31, 45))	('erythrocytosis', 'Disease', (31, 45))	('men', 'Species', '9606', (91, 94))	('patients', 'Species', '9606', (18, 26))	('sequencing', 'Var', (147, 157))	('men', 'Species', '9606', (136, 139))	('erythrocytosis', 'Phenotype', 'HP:0001901', (31, 45))	('serum EPO measurements', 'MPA', (74, 96))
28601	31350093	In pioneering work, de la Chapelle and colleagues carried out linkage analysis in a large family with known clinical and genealogical features, using a highly informative simple sequence repeat polymorphism in the 5' region of the EPOR gene.	('EPOR', 'Gene', '2057', (231, 235))	('simple sequence repeat polymorphism in', 'Var', (171, 209))	('EPOR', 'Gene', (231, 235))
28602	31350093	They found a highly significant linkage pointing to a mutation in the EPOR as the most probable cause of the disease phenotype in the family.	('cause', 'Reg', (96, 101))	('mutation', 'Var', (54, 62))	('EPOR', 'Gene', '2057', (70, 74))	('EPOR', 'Gene', (70, 74))
28604	31350093	Other EPOR mutations have recently been reviewed elsewhere.	('EPOR', 'Gene', (6, 10))	('mutations', 'Var', (11, 20))	('EPOR', 'Gene', '2057', (6, 10))
28605	31350093	This was the first disorder in humans to be ascribed to a mutation in either EPO or EPOR, and provided an impetus to uncover mutations in other genes that might be involved in erythrocytosis.	('erythrocytosis', 'Disease', 'MESH:D011086', (176, 190))	('erythrocytosis', 'Disease', (176, 190))	('EPOR', 'Gene', '2057', (84, 88))	('EPOR', 'Gene', (84, 88))	('EPO', 'Gene', (77, 80))	('mutation', 'Var', (58, 66))	('humans', 'Species', '9606', (31, 37))	('erythrocytosis', 'Phenotype', 'HP:0001901', (176, 190))
28607	31350093	Erythrocytosis arising in sporadic patients and families with mutations in the genes encoding VHL, PHD2 and HIF-2alpha has provided important insights into their role in the hypoxia sensing pathway and as regulators of red cell mass in humans.	('HIF-2alpha', 'Gene', (108, 118))	('VHL', 'Gene', '7428', (94, 97))	('Erythrocytosis', 'Phenotype', 'HP:0001901', (0, 14))	('hypoxia', 'Disease', (174, 181))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('humans', 'Species', '9606', (236, 242))	('PHD2', 'Gene', (99, 103))	('HIF-2alpha', 'Gene', '2034', (108, 118))	('Erythrocytosis', 'Disease', (0, 14))	('patients', 'Species', '9606', (35, 43))	('Erythrocytosis', 'Disease', 'MESH:D011086', (0, 14))	('mutations', 'Var', (62, 71))	('VHL', 'Gene', (94, 97))
28608	31350093	The first erythrocytosis-associated mutation in the pathway was identified in the VHL gene followed by a mutation in the PHD2 gene and subsequently by a mutation of the HIF2A (also known as EPAS1) gene in a family with hereditary erythrocytosis.	('PHD2', 'Gene', (121, 125))	('erythrocytosis', 'Phenotype', 'HP:0001901', (10, 24))	('mutation', 'Var', (105, 113))	('HIF2A', 'Gene', (169, 174))	('erythrocytosis', 'Disease', (10, 24))	('hereditary erythrocytosis', 'Disease', (219, 244))	('mutation', 'Var', (36, 44))	('EPAS1', 'Gene', (190, 195))	('erythrocytosis', 'Disease', 'MESH:D011086', (10, 24))	('VHL', 'Gene', (82, 85))	('hereditary erythrocytosis', 'Disease', 'MESH:C536842', (219, 244))	('erythrocytosis', 'Phenotype', 'HP:0001901', (230, 244))	('VHL', 'Gene', '7428', (82, 85))	('EPAS1', 'Gene', '2034', (190, 195))	('HIF2A', 'Gene', '2034', (169, 174))	('erythrocytosis', 'Disease', (230, 244))	('mutation', 'Var', (153, 161))	('erythrocytosis', 'Disease', 'MESH:D011086', (230, 244))
28612	31350093	In contrast, mice with homozygous knockout of the Phd1 or Phd3 genes are viable.	('mice', 'Species', '10090', (13, 17))	('Phd3', 'Gene', (58, 62))	('Phd3', 'Gene', '112407', (58, 62))	('Phd1', 'Gene', '112406', (50, 54))	('knockout', 'Var', (34, 42))	('Phd1', 'Gene', (50, 54))
28617	31350093	A mutation in the gene PHD2 in a family with erythrocytosis resulted in a marked decrease in PHD2 enzyme activity and segregated with phenotype.	('mutation', 'Var', (2, 10))	('decrease', 'NegReg', (81, 89))	('erythrocytosis', 'Disease', 'MESH:D011086', (45, 59))	('erythrocytosis', 'Disease', (45, 59))	('PHD2', 'Gene', (23, 27))	('activity', 'MPA', (105, 113))	('PHD2 enzyme', 'Enzyme', (93, 104))	('erythrocytosis', 'Phenotype', 'HP:0001901', (45, 59))
28619	31350093	Peptide binding, enzymatic activity and HRE reporter gene studies pointed to a marked loss of PHD2 function arising from the P317R mutation (Fig.	('PHD2', 'Gene', (94, 98))	('loss', 'NegReg', (86, 90))	('function', 'MPA', (99, 107))	('P317R', 'Mutation', 'rs80358193', (125, 130))	('P317R', 'Var', (125, 130))
28621	31350093	Familial erythrocytosis caused by mutations in the PHD2 gene has been designated as ECYT3 in the Mendelian Inheritance in Man classification (MIM) #: 609820.	('erythrocytosis', 'Phenotype', 'HP:0001901', (9, 23))	('Familial erythrocytosis', 'Disease', (0, 23))	('Familial erythrocytosis', 'Disease', 'MESH:C536842', (0, 23))	('PHD2', 'Gene', (51, 55))	('mutations', 'Var', (34, 43))	('caused', 'Reg', (24, 30))
28622	31350093	Subsequently, it was found that mice with acute global deletion of Phd2, but not Phd1 nor Phd3 display a dramatic erythrocytosis.	('Phd1', 'Gene', (81, 85))	('Phd2', 'Gene', '112405', (67, 71))	('erythrocytosis', 'Phenotype', 'HP:0001901', (114, 128))	('Phd3', 'Gene', (90, 94))	('erythrocytosis', 'Disease', (114, 128))	('mice', 'Species', '10090', (32, 36))	('Phd3', 'Gene', '112407', (90, 94))	('global deletion', 'Var', (48, 63))	('erythrocytosis', 'Disease', 'MESH:D011086', (114, 128))	('Phd1', 'Gene', '112406', (81, 85))	('Phd2', 'Gene', (67, 71))
28623	31350093	A mouse model for the P317R PHD2 mutation (P294R in the mouse) recapitulated the erythrocytosis and was consistent with haploinsufficiency as the mechanism for this particular mutation.	('P294R', 'Var', (43, 48))	('haploinsufficiency', 'Disease', 'MESH:D058495', (120, 138))	('P294R', 'Mutation', 'p.P294R', (43, 48))	('mouse', 'Species', '10090', (56, 61))	('P317R', 'Mutation', 'rs80358193', (22, 27))	('erythrocytosis', 'Phenotype', 'HP:0001901', (81, 95))	('haploinsufficiency', 'Disease', (120, 138))	('mouse', 'Species', '10090', (2, 7))	('PHD2', 'Gene', (28, 32))	('P317R', 'Var', (22, 27))	('erythrocytosis', 'Disease', 'MESH:D011086', (81, 95))	('erythrocytosis', 'Disease', (81, 95))
28624	31350093	These studies have also revealed interesting aspects of the original P317R PHD2 mutant, namely, that it displays no activity towards the N-terminal oxygen dependent degradation domain (which contains one of the two sites of hydroxylation, Pro-402) of HIF-1alpha, and that its activity towards the C-terminal oxygen dependent degradation domain (which contains the other site of hydroxylation, Pro-564) is substantially weaker with respect to HIF-2alpha as compared to HIF-1alpha.	('P317R', 'Mutation', 'rs80358193', (69, 74))	('oxygen', 'Chemical', 'MESH:D010100', (308, 314))	('HIF-2alpha', 'Gene', '2034', (442, 452))	('HIF-2alpha', 'Gene', (442, 452))	('Pro', 'Chemical', 'MESH:D011392', (239, 242))	('activity', 'MPA', (276, 284))	('P317R', 'Var', (69, 74))	('PHD2', 'Gene', (75, 79))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('weaker', 'NegReg', (419, 425))	('activity', 'MPA', (116, 124))	('N-terminal oxygen dependent degradation domain', 'MPA', (137, 183))	('C-terminal oxygen dependent degradation domain', 'MPA', (297, 343))	('Pro', 'Chemical', 'MESH:D011392', (393, 396))
28625	31350093	Over twenty erythrocytosis-associated PHD2 mutations, which comprise heterozygous missense, nonsense, and frameshift mutations, have been reported.	('nonsense', 'Var', (92, 100))	('erythrocytosis', 'Phenotype', 'HP:0001901', (12, 26))	('erythrocytosis', 'Disease', (12, 26))	('mutations', 'Var', (43, 52))	('PHD2', 'Gene', (38, 42))	('erythrocytosis', 'Disease', 'MESH:D011086', (12, 26))	('frameshift mutations', 'Var', (106, 126))	('missense', 'Var', (82, 90))
28629	31350093	Recently Sinnema and colleagues reported a PHD2 zinc finger mutation associated with congenital erythrocytosis in a 14 year old daughter of consanguineous parents.	('erythrocytosis', 'Phenotype', 'HP:0001901', (96, 110))	('mutation', 'Var', (60, 68))	('congenital erythrocytosis', 'Disease', (85, 110))	('associated', 'Reg', (69, 79))	('PHD2', 'Gene', (43, 47))	('congenital erythrocytosis', 'Disease', 'MESH:C536842', (85, 110))	('Sinnema', 'Disease', 'None', (9, 16))	('Sinnema', 'Disease', (9, 16))
28630	31350093	Whole exome sequencing using the parent-offspring trio approach revealed a homozygous missense variant in the PHD2 gene; EGLN1; Chr1 (GRCh37):g.231557511A>G; NM_022051.2: c.124T>C (p.Cys42Arg).	('EGLN1', 'Gene', '54583', (121, 126))	('p.Cys42Arg', 'Mutation', 'p.C42R', (181, 191))	('g.231557511A>G', 'Var', (142, 156))	('c.124T>C', 'SUBSTITUTION', 'None', (171, 179))	('c.124T>C', 'Var', (171, 179))	('EGLN1', 'Gene', (121, 126))	('PHD2', 'Gene', (110, 114))	('g.231557511A>G', 'Mutation', 'g.231557511A>G', (142, 156))
28632	31350093	Cys-42, the residue affected by the mutation lies within the zinc finger, and is 1 of 8 evolutionarily conserved zinc-chelating residues.	('mutation', 'Var', (36, 44))	('Cys', 'Chemical', 'MESH:D003545', (0, 3))	('Cys-42', 'Var', (0, 6))
28634	31350093	The functional effect of the C42R PHD2 mutation on binding was examined by coexpressing wild type or C42R PHD2 (residues 1-196) with p23 in HEK293FT cells.	('C42R', 'Chemical', '-', (101, 105))	('p23', 'Gene', (133, 136))	('PHD2', 'Gene', (106, 110))	('C42R', 'Chemical', '-', (29, 33))	('p23', 'Gene', '8851', (133, 136))	('HEK293FT', 'CellLine', 'CVCL:6911', (140, 148))	('C42R', 'Var', (101, 105))
28635	31350093	The wild-type PHD2 was found to coimmunoprecipitate with p23 but this interaction was abolished by the C42R mutation.	('C42R', 'Chemical', '-', (103, 107))	('coimmunoprecipitate', 'Interaction', (32, 51))	('p23', 'Gene', (57, 60))	('p23', 'Gene', '8851', (57, 60))	('C42R', 'Var', (103, 107))
28637	31350093	In HRE reporter gene assays the mutant C42R PHD2 was significantly less effective than wild-type PHD2 in suppressing hypoxia-induced HRE reporter activity gene activity.	('suppressing', 'NegReg', (105, 116))	('C42R', 'Var', (39, 43))	('PHD2', 'Gene', (44, 48))	('less', 'NegReg', (67, 71))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('C42R', 'Chemical', '-', (39, 43))	('hypoxia', 'Disease', (117, 124))	('mutant C42R', 'Var', (32, 43))
28638	31350093	Interestingly, additional erythrocytosis-associated mutations in the zinc finger domain of PHD2 were recently reported as variants of unknown significance, but not functionally characterized.	('PHD2', 'Gene', (91, 95))	('erythrocytosis', 'Phenotype', 'HP:0001901', (26, 40))	('erythrocytosis', 'Disease', 'MESH:D011086', (26, 40))	('erythrocytosis', 'Disease', (26, 40))	('mutations in', 'Var', (52, 64))
28639	31350093	Subsequent examination of one of these, Y41C, which changes a highly conserved residue was also found to abrogate PHD2 binding to p23 and was defective in its capacity to down-regulate hypoxia-induced HRE activity.	('down-regulate', 'NegReg', (171, 184))	('abrogate', 'NegReg', (105, 113))	('PHD2', 'Protein', (114, 118))	('hypoxia', 'Disease', (185, 192))	('hypoxia', 'Disease', 'MESH:D000860', (185, 192))	('Y41C', 'SUBSTITUTION', 'None', (40, 44))	('p23', 'Gene', (130, 133))	('Y41C', 'Var', (40, 44))	('defective', 'NegReg', (142, 151))	('p23', 'Gene', '8851', (130, 133))	('binding', 'Interaction', (119, 126))
28640	31350093	The genetic and functional studies are consistent with the proposition that the homozygous C42R mutation in PHD2 is the cause of the erythrocytosis in the 2 affected siblings.	('erythrocytosis', 'Disease', 'MESH:D011086', (133, 147))	('erythrocytosis', 'Disease', (133, 147))	('cause', 'Reg', (120, 125))	('C42R', 'Var', (91, 95))	('erythrocytosis', 'Phenotype', 'HP:0001901', (133, 147))	('C42R', 'Chemical', '-', (91, 95))	('PHD2', 'Gene', (108, 112))
28641	31350093	Characterization of knock-in mice bearing a C36S/C42S double mutation in the Phd2 allele that targets two of the predicted zinc chelating residues showed that the mice homozygous for the C36S/C42S mutation, but not heterozygous, display erythrocytosis.	('Phd2', 'Gene', (77, 81))	('C42S', 'SUBSTITUTION', 'None', (192, 196))	('erythrocytosis', 'Disease', (237, 251))	('C36S', 'Var', (187, 191))	('Phd2', 'Gene', '112405', (77, 81))	('erythrocytosis', 'Disease', 'MESH:D011086', (237, 251))	('C36S', 'SUBSTITUTION', 'None', (44, 48))	('C42S', 'SUBSTITUTION', 'None', (49, 53))	('C36S', 'Var', (44, 48))	('C42S', 'Var', (192, 196))	('mice', 'Species', '10090', (163, 167))	('erythrocytosis', 'Phenotype', 'HP:0001901', (237, 251))	('mice', 'Species', '10090', (29, 33))	('C42S', 'Var', (49, 53))	('C36S', 'SUBSTITUTION', 'None', (187, 191))
28642	31350093	The mouse Cys42 mutation affects the same residue as the human Cys42 mutation.	('mouse', 'Species', '10090', (4, 9))	('Cys42', 'Chemical', '-', (10, 15))	('Cys42', 'Gene', (10, 15))	('mutation', 'Var', (16, 24))	('Cys42', 'Chemical', '-', (63, 68))	('affects', 'Reg', (25, 32))	('human', 'Species', '9606', (57, 62))
28643	31350093	The observation that 2 mutant alleles are required to produce erythrocytosis could account for its relative rarity as a cause of erythrocytosis, compared to defects affecting the catalytic site of PHD2 which are sufficient to produce a phenotype in the heterozygous state.	('erythrocytosis', 'Disease', (62, 76))	('mutant', 'Var', (23, 29))	('erythrocytosis', 'Disease', 'MESH:D011086', (62, 76))	('erythrocytosis', 'Phenotype', 'HP:0001901', (129, 143))	('erythrocytosis', 'Disease', 'MESH:D011086', (129, 143))	('erythrocytosis', 'Disease', (129, 143))	('erythrocytosis', 'Phenotype', 'HP:0001901', (62, 76))
28644	31350093	Interestingly, the Y41C mutation is heterozygous, suggesting either that a single copy of certain zinc finger mutations is sufficient to cause the phenotype, or alternatively, that there is an as yet uncharacterized mutation in the HIF or other pathways that impact EPO production in the patient.	('impact', 'Reg', (259, 265))	('patient', 'Species', '9606', (288, 295))	('EPO production', 'MPA', (266, 280))	('mutations', 'Var', (110, 119))	('cause', 'Reg', (137, 142))	('Y41C', 'Var', (19, 23))	('Y41C', 'SUBSTITUTION', 'None', (19, 23))
28645	31350093	The phenotype of the zinc finger mutations provides genetic evidence that the zinc finger has a positive regulatory function in the oxygen-sensing pathway that controls erythropoiesis.	('mutations', 'Var', (33, 42))	('oxygen-sensing pathway', 'Pathway', (132, 154))	('zinc finger', 'Gene', (21, 32))	('oxygen', 'Chemical', 'MESH:D010100', (132, 138))	('positive regulatory', 'PosReg', (96, 115))	('erythropoiesis', 'MPA', (169, 183))
28646	31350093	As with HIF2A and VHL (see below), mutations in PHD2 can be associated not only with erythrocytosis, but also with cancer.	('PHD2', 'Gene', (48, 52))	('cancer', 'Disease', (115, 121))	('VHL', 'Gene', '7428', (18, 21))	('HIF2A', 'Gene', (8, 13))	('erythrocytosis', 'Disease', 'MESH:D011086', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('erythrocytosis', 'Phenotype', 'HP:0001901', (85, 99))	('erythrocytosis', 'Disease', (85, 99))	('VHL', 'Gene', (18, 21))	('HIF2A', 'Gene', '2034', (8, 13))	('associated', 'Reg', (60, 70))	('mutations', 'Var', (35, 44))
28648	31350093	Sequencing of germline DNA revealed a heterozygous H374R mutation in the PHD2 gene, while sequencing of the tumor and other studies revealed the presence of the mutant allele and loss of the wild type allele (loss of heterozygosity).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('H374R', 'Var', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('PHD2', 'Gene', (73, 77))	('H374R', 'Mutation', 'rs119476045', (51, 56))
28649	31350093	A P317S mutation in PHD2 that impairs activity has been identified in a melanoma tumor sample.	('melanoma tumor', 'Disease', 'MESH:D008545', (72, 86))	('activity', 'MPA', (38, 46))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('impairs', 'NegReg', (30, 37))	('P317S', 'Var', (2, 7))	('P317S', 'Mutation', 'p.P317S', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('melanoma tumor', 'Disease', (72, 86))	('PHD2', 'Gene', (20, 24))
28650	31350093	While it is difficult to draw genotype-phenotype correlations from the limited available data, it is worth noting that the H374R mutation affects an essential iron chelating residue, which in combination with loss of heterozygosity would be predicted to lead to essentially complete loss of PHD2 activity in the tumor.	('activity', 'MPA', (296, 304))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('loss', 'NegReg', (283, 287))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('iron', 'Chemical', 'MESH:D007501', (159, 163))	('H374R', 'Mutation', 'rs119476045', (123, 128))	('H374R', 'Var', (123, 128))	('tumor', 'Disease', (312, 317))	('affects', 'Reg', (138, 145))	('PHD2', 'Enzyme', (291, 295))
28653	31350093	Mice with homozygous Hif-1alpha deletion were found to die in utero from defective neurodevelopment and cardiovascular malformations, whereas mice lacking both copies of Hif-2alpha died in utero or around birth from severe vascular defects, disturbed catecholamine homeostasis, and abnormal lung maturation.	('deletion', 'Var', (32, 40))	('Hif-1alpha', 'Gene', '15251', (21, 31))	('Hif-2alpha', 'Gene', (170, 180))	('Hif-1alpha', 'Gene', (21, 31))	('vascular defects', 'Disease', (223, 239))	('Mice', 'Species', '10090', (0, 4))	('catecholamine', 'Chemical', 'MESH:D002395', (251, 264))	('lung maturation', 'CPA', (291, 306))	('Hif-2alpha', 'Gene', '13819', (170, 180))	('abnormal lung', 'Phenotype', 'HP:0002088', (282, 295))	('cardiovascular malformations', 'Phenotype', 'HP:0030680', (104, 132))	('defective neurodevelopment', 'Phenotype', 'HP:0012758', (73, 99))	('men', 'Species', '9606', (95, 98))	('cardiovascular malformations', 'Disease', 'MESH:D018376', (104, 132))	('disturbed catecholamine homeostasis', 'Phenotype', 'HP:0012099', (241, 276))	('disturbed', 'Reg', (241, 250))	('cardiovascular malformations', 'Disease', (104, 132))	('catecholamine homeostasis', 'MPA', (251, 276))	('vascular defects', 'Disease', 'MESH:D000783', (223, 239))	('mice', 'Species', '10090', (142, 146))
28655	31350093	Deletion of Hif-2alpha caused pancytopenia and hypocellular bone marrow.	('hypocellular bone marrow', 'Disease', 'MESH:D001855', (47, 71))	('Hif-2alpha', 'Gene', '13819', (12, 22))	('pancytopenia', 'Disease', (30, 42))	('Hif-2alpha', 'Gene', (12, 22))	('pancytopenia', 'Disease', 'MESH:D010198', (30, 42))	('hypocellular bone marrow', 'Phenotype', 'HP:0005528', (47, 71))	('hypocellular bone marrow', 'Disease', (47, 71))	('caused', 'Reg', (23, 29))	('pancytopenia', 'Phenotype', 'HP:0001876', (30, 42))	('Deletion', 'Var', (0, 8))
28657	31350093	Erythrocytosis induced by conditional liver knockout of Vhl is rescued by concurrent deletion of the Hif2a, but not the Hif1a, gene, demonstrating that hepatic regulation of Epo is dependent on Hif-2alpha.	('Hif-2alpha', 'Gene', '13819', (194, 204))	('Hif-2alpha', 'Gene', (194, 204))	('Hif1a', 'Gene', '3091', (120, 125))	('Hif2a', 'Gene', '2034', (101, 106))	('Erythrocytosis', 'Phenotype', 'HP:0001901', (0, 14))	('Epo', 'Gene', (174, 177))	('Epo', 'Gene', '13856', (174, 177))	('Erythrocytosis', 'Disease', (0, 14))	('deletion', 'Var', (85, 93))	('Hif1a', 'Gene', (120, 125))	('Erythrocytosis', 'Disease', 'MESH:D011086', (0, 14))	('Hif2a', 'Gene', (101, 106))	('Vhl', 'Gene', '7428', (56, 59))	('Vhl', 'Gene', (56, 59))
28660	31350093	These findings set the stage for identifying the genes responsible for erythrocytosis in humans by studies of specific mutations in patients with inherited forms of secondary erythrocytosis.	('erythrocytosis', 'Disease', 'MESH:D011086', (175, 189))	('erythrocytosis', 'Phenotype', 'HP:0001901', (71, 85))	('secondary erythrocytosis', 'Disease', (165, 189))	('erythrocytosis', 'Disease', (71, 85))	('secondary erythrocytosis', 'Disease', 'MESH:D011086', (165, 189))	('humans', 'Species', '9606', (89, 95))	('erythrocytosis', 'Phenotype', 'HP:0001901', (175, 189))	('erythrocytosis', 'Disease', 'MESH:D011086', (71, 85))	('mutations', 'Var', (119, 128))	('erythrocytosis', 'Disease', (175, 189))	('patients', 'Species', '9606', (132, 140))
28661	31350093	A study of the HIF2A gene in 3 generations of one family with erythrocytosis uncovered a novel G537W mutation located close to the hydroxylacceptor P531.	('HIF2A', 'Gene', (15, 20))	('erythrocytosis', 'Disease', (62, 76))	('erythrocytosis', 'Disease', 'MESH:D011086', (62, 76))	('G537W', 'Mutation', 'rs137853036', (95, 100))	('HIF2A', 'Gene', '2034', (15, 20))	('G537W', 'Var', (95, 100))	('erythrocytosis', 'Phenotype', 'HP:0001901', (62, 76))
28662	31350093	Functional characterization of the erythrocytosis-associated G537W HIF-2alpha mutant showed that a mutant G537W HIF-2alpha peptide binds less tightly to PHD2 and is less efficiently hydroxylated by PHD2 than wild-type peptide.	('erythrocytosis', 'Phenotype', 'HP:0001901', (35, 49))	('erythrocytosis', 'Disease', (35, 49))	('binds', 'Interaction', (131, 136))	('G537W', 'Mutation', 'rs137853036', (61, 66))	('HIF-2alpha', 'Gene', (67, 77))	('HIF-2alpha', 'Gene', (112, 122))	('erythrocytosis', 'Disease', 'MESH:D011086', (35, 49))	('less', 'NegReg', (137, 141))	('G537W', 'Var', (61, 66))	('hydroxylated', 'MPA', (182, 194))	('G537W', 'Mutation', 'rs137853036', (106, 111))	('less', 'NegReg', (165, 169))	('HIF-2alpha', 'Gene', '2034', (67, 77))	('tightly', 'Interaction', (142, 149))	('G537W', 'Var', (106, 111))	('HIF-2alpha', 'Gene', '2034', (112, 122))
28663	31350093	Additional studies showed that the mutation also affected subsequent recognition of HIF-2alpha by VHL (Fig.	('recognition', 'MPA', (69, 80))	('HIF-2alpha', 'Gene', (84, 94))	('VHL', 'Gene', (98, 101))	('affected', 'Reg', (49, 57))	('VHL', 'Gene', '7428', (98, 101))	('HIF-2alpha', 'Gene', '2034', (84, 94))	('mutation', 'Var', (35, 43))
28664	31350093	A mouse model for the G537W mutation (G536W in the mouse) demonstrated erythrocytosis in mice heterozygous for the mutation that was accentuated in mice homozygous for it.	('G536W', 'Mutation', 'p.G536W', (38, 43))	('G537W', 'Mutation', 'rs137853036', (22, 27))	('mice', 'Species', '10090', (89, 93))	('mouse', 'Species', '10090', (51, 56))	('erythrocytosis', 'Phenotype', 'HP:0001901', (71, 85))	('G537W', 'Var', (22, 27))	('erythrocytosis', 'Disease', (71, 85))	('mice', 'Species', '10090', (148, 152))	('mouse', 'Species', '10090', (2, 7))	('erythrocytosis', 'Disease', 'MESH:D011086', (71, 85))
28665	31350093	In vitro functional assays of three further erythrocytosis-associated mutations of HIF-2alpha located C-terminal to the highly conserved LXXLAP motif that contains the hyroxylacceptor proline, viz.	('erythrocytosis', 'Disease', 'MESH:D011086', (44, 58))	('HIF-2alpha', 'Gene', (83, 93))	('mutations', 'Var', (70, 79))	('HIF-2alpha', 'Gene', '2034', (83, 93))	('erythrocytosis', 'Phenotype', 'HP:0001901', (44, 58))	('proline', 'Chemical', 'MESH:D011392', (184, 191))	('erythrocytosis', 'Disease', (44, 58))
28666	31350093	M535V, P534L and G537R, revealed that all three mutants stabilized HIF-2alpha, but did so in nonidentical ways; P534L and G537R impaired binding to both PHD2 and VHL, but M535V impaired binding only to PHD2.	('VHL', 'Gene', (162, 165))	('binding', 'Interaction', (137, 144))	('M535V', 'Mutation', 'rs137853037', (171, 176))	('VHL', 'Gene', '7428', (162, 165))	('M535V', 'Mutation', 'rs137853037', (0, 5))	('P534L', 'Mutation', 'p.P534L', (112, 117))	('HIF-2alpha', 'Gene', (67, 77))	('impaired', 'NegReg', (128, 136))	('PHD2', 'Protein', (153, 157))	('P534L', 'Mutation', 'p.P534L', (7, 12))	('binding', 'Interaction', (186, 193))	('M535V', 'Var', (171, 176))	('HIF-2alpha', 'Gene', '2034', (67, 77))	('G537R', 'Mutation', 'rs137853036', (122, 127))	('P534L', 'Var', (112, 117))	('G537R', 'Mutation', 'rs137853036', (17, 22))	('G537R', 'Var', (122, 127))
28667	31350093	This suggests that the M535V mutation is pathogenic mainly through effects on PHD2 binding and catalytic hydroxylation, and that impairment of the PHD2/HIF2 interaction alone is sufficient to induce erythrocytosis.	('interaction', 'Interaction', (157, 168))	('PHD2', 'Protein', (78, 82))	('induce', 'Reg', (192, 198))	('catalytic hydroxylation', 'MPA', (95, 118))	('binding', 'Interaction', (83, 90))	('M535V', 'Var', (23, 28))	('effects', 'Reg', (67, 74))	('men', 'Species', '9606', (135, 138))	('erythrocytosis', 'Phenotype', 'HP:0001901', (199, 213))	('M535V', 'Mutation', 'rs137853037', (23, 28))	('erythrocytosis', 'Disease', 'MESH:D011086', (199, 213))	('erythrocytosis', 'Disease', (199, 213))
28668	31350093	This accords with the finding that mutations in PHD2 alone are a distinct cause of erythrocytosis.	('erythrocytosis', 'Disease', (83, 97))	('erythrocytosis', 'Disease', 'MESH:D011086', (83, 97))	('PHD2', 'Gene', (48, 52))	('erythrocytosis', 'Phenotype', 'HP:0001901', (83, 97))	('cause', 'Reg', (74, 79))	('mutations', 'Var', (35, 44))
28669	31350093	The existence of erythrocytosis-associated VHL mutations confirms that impairment of the HIF-alpha/VHL interaction alone is sufficient to induce erythrocytosis.	('erythrocytosis', 'Disease', 'MESH:D011086', (17, 31))	('erythrocytosis', 'Disease', (17, 31))	('erythrocytosis', 'Phenotype', 'HP:0001901', (145, 159))	('VHL', 'Gene', (43, 46))	('VHL', 'Gene', (99, 102))	('erythrocytosis', 'Disease', (145, 159))	('mutations', 'Var', (47, 56))	('men', 'Species', '9606', (77, 80))	('induce', 'Reg', (138, 144))	('VHL', 'Gene', '7428', (43, 46))	('VHL', 'Gene', '7428', (99, 102))	('erythrocytosis', 'Disease', 'MESH:D011086', (145, 159))	('erythrocytosis', 'Phenotype', 'HP:0001901', (17, 31))
28670	31350093	Decreased degradation leads to stabilization of HIF-2alpha, a gain-of-function phenotype, and it argues against the possibility that a dominant negative mechanism involving increased mutant binding to PHD2 leading to impaired hydroxylation of wild type HIF-2alpha, or increased mutant binding to VHL, could be responsible for the erythrocytosis.	('erythrocytosis', 'Phenotype', 'HP:0001901', (330, 344))	('erythrocytosis', 'Disease', (330, 344))	('increased', 'PosReg', (173, 182))	('HIF-2alpha', 'Gene', (253, 263))	('mutant', 'Var', (278, 284))	('HIF-2alpha', 'Gene', '2034', (48, 58))	('mutant', 'Var', (183, 189))	('VHL', 'Gene', (296, 299))	('stabilization', 'MPA', (31, 44))	('impaired', 'NegReg', (217, 225))	('PHD2', 'Gene', (201, 205))	('HIF-2alpha', 'Gene', (48, 58))	('VHL', 'Gene', '7428', (296, 299))	('degradation', 'MPA', (10, 21))	('HIF-2alpha', 'Gene', '2034', (253, 263))	('erythrocytosis', 'Disease', 'MESH:D011086', (330, 344))	('binding', 'Interaction', (285, 292))	('hydroxylation', 'MPA', (226, 239))	('binding', 'Interaction', (190, 197))
28671	31350093	To date no mutations in the HIF1A gene have been found to be associated with erythrocytosis in humans.	('mutations', 'Var', (11, 20))	('HIF1A', 'Gene', (28, 33))	('HIF1A', 'Gene', '3091', (28, 33))	('humans', 'Species', '9606', (95, 101))	('erythrocytosis', 'Phenotype', 'HP:0001901', (77, 91))	('associated', 'Reg', (61, 71))	('erythrocytosis', 'Disease', 'MESH:D011086', (77, 91))	('erythrocytosis', 'Disease', (77, 91))
28672	31350093	Familial erythrocytosis caused by a gain-of-function mutation in the HIF2A gene is an autosomal dominant disorder, and has been designated as ECYT4 in the MIM classification #: 611783.	('gain-of-function', 'PosReg', (36, 52))	('mutation', 'Var', (53, 61))	('autosomal dominant disorder', 'Disease', (86, 113))	('erythrocytosis', 'Phenotype', 'HP:0001901', (9, 23))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (86, 113))	('Familial erythrocytosis', 'Disease', (0, 23))	('HIF2A', 'Gene', '2034', (69, 74))	('ECYT4', 'Gene', (142, 147))	('Familial erythrocytosis', 'Disease', 'MESH:C536842', (0, 23))	('HIF2A', 'Gene', (69, 74))	('ECYT4', 'Gene', '2034', (142, 147))
28673	31350093	Somatic HIF-2alpha gain-of-function mutations were subsequently established as a cause of neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', (90, 111))	('gain-of-function', 'PosReg', (19, 35))	('HIF-2alpha', 'Gene', (8, 18))	('mutations', 'Var', (36, 45))	('HIF-2alpha', 'Gene', '2034', (8, 18))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (90, 111))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (90, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
28674	31350093	Additional HIF-2alpha mutations associated with erythrocytosis, neuroendocrine tumors, or both have been reported.	('erythrocytosis', 'Disease', (48, 62))	('HIF-2alpha', 'Gene', '2034', (11, 21))	('erythrocytosis', 'Disease', 'MESH:D011086', (48, 62))	('neuroendocrine tumors', 'Disease', (64, 85))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (64, 85))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (64, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (32, 42))	('HIF-2alpha', 'Gene', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('erythrocytosis', 'Phenotype', 'HP:0001901', (48, 62))
28677	31350093	The location of the HIF-2alpha mutations is shown in Fig.	('HIF-2alpha', 'Gene', (20, 30))	('HIF-2alpha', 'Gene', '2034', (20, 30))	('mutations', 'Var', (31, 40))
28678	31350093	HIF-2alpha gain-of-function mutations in class 1a-c and ECYT4 share a common feature, an increase in HIF-2alpha stability, but differ in the location of the mutations.	('stability', 'MPA', (112, 121))	('ECYT4', 'Gene', '2034', (56, 61))	('HIF-2alpha', 'Gene', '2034', (0, 10))	('ECYT4', 'Gene', (56, 61))	('HIF-2alpha', 'Gene', (101, 111))	('HIF-2alpha', 'Gene', '2034', (101, 111))	('gain-of-function', 'PosReg', (11, 27))	('mutations', 'Var', (28, 37))	('HIF-2alpha', 'Gene', (0, 10))	('increase', 'PosReg', (89, 97))
28679	31350093	Overall, the majority of HIF-2alpha mutations are missense mutations located between amino acids 519 and 545.	('missense mutations', 'Var', (50, 68))	('HIF-2alpha', 'Gene', (25, 35))	('mutations', 'Var', (36, 45))	('HIF-2alpha', 'Gene', '2034', (25, 35))
28680	31350093	Whereas all of the ECYT4 mutations described so far lie between amino acids 533 and 540, most of the class 1a-c mutations lie between 529 and 532 (containing proline 531, the primary hydroxylation site of HIF-2alpha ) and another small group between 539 and 544.	('mutations', 'Var', (25, 34))	('proline', 'Chemical', 'MESH:D011392', (158, 165))	('ECYT4', 'Gene', '2034', (19, 24))	('HIF-2alpha', 'Gene', (205, 215))	('mutations', 'Var', (112, 121))	('ECYT4', 'Gene', (19, 24))	('HIF-2alpha', 'Gene', '2034', (205, 215))	('class 1a-c', 'Gene', (101, 111))
28682	31350093	have recently reported three somatic HIF-2alpha mutations (p.A530V, p.P531S, and p.D539N) identified in DNA from paragangliomas (PGLs) of three patients.	('paragangliomas', 'Disease', (113, 127))	('p.A530V', 'Var', (59, 66))	('p.P531S', 'Var', (68, 75))	('paragangliomas', 'Disease', 'MESH:D010235', (113, 127))	('paragangliomas', 'Phenotype', 'HP:0002668', (113, 127))	('p.D539N', 'Mutation', 'p.D539N', (81, 88))	('PGLs', 'Phenotype', 'HP:0002668', (129, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('p.P531S', 'Mutation', 'p.P531S', (68, 75))	('p.A530V', 'Mutation', 'p.A530V', (59, 66))	('HIF-2alpha', 'Gene', (37, 47))	('patients', 'Species', '9606', (144, 152))	('HIF-2alpha', 'Gene', '2034', (37, 47))	('p.D539N', 'Var', (81, 88))
28686	31350093	Class 1 mutations affect residues that make contact with VHL, whereas the majority of the ECYT4 mutations are localized to the kink region between the N-terminal and C-terminal segments.	('ECYT4', 'Gene', '2034', (90, 95))	('affect', 'Reg', (18, 24))	('mutations', 'Var', (8, 17))	('residues', 'Protein', (25, 33))	('VHL', 'Gene', (57, 60))	('ECYT4', 'Gene', (90, 95))	('men', 'Species', '9606', (180, 183))	('VHL', 'Gene', '7428', (57, 60))	('mutations', 'Var', (96, 105))
28687	31350093	Based on temperature factor analysis residues N-terminal to the kink region (as defined by Tarade and colleagues, in their Figure 3) have a lower temperature factor and bind in a more rigid manner, raising the possibility that class 1 mutations would have a greater negative impact on the VHL-HIF-2alpha interaction than ECYT4 mutations.	('lower', 'NegReg', (140, 145))	('HIF-2alpha', 'Gene', (293, 303))	('VHL', 'Gene', '7428', (289, 292))	('mutations', 'Var', (235, 244))	('bind', 'Interaction', (169, 173))	('ECYT4', 'Gene', '2034', (321, 326))	('HIF-2alpha', 'Gene', '2034', (293, 303))	('temperature factor', 'MPA', (146, 164))	('negative', 'NegReg', (266, 274))	('interaction', 'Interaction', (304, 315))	('ECYT4', 'Gene', (321, 326))	('VHL', 'Gene', (289, 292))
28688	31350093	This was confirmed by steady-state and kinetic binding experiments which showed that class 1 mutations predominantly have a more deleterious effect on VHL affinity than ECYT4 mutations.	('mutations', 'Var', (93, 102))	('ECYT4', 'Gene', '2034', (169, 174))	('ECYT4', 'Gene', (169, 174))	('VHL', 'Gene', (151, 154))	('men', 'Species', '9606', (61, 64))	('VHL', 'Gene', '7428', (151, 154))
28690	31350093	Small increases in HIF-2alpha caused by mild disruption are sufficient to elicit erythrocytosis, but more serious disruption, leading to higher levels of HIF-2alpha, can be pathogenic for neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (188, 209))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (188, 209))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('elicit', 'Reg', (74, 80))	('HIF-2alpha', 'Gene', '2034', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('higher', 'PosReg', (137, 143))	('neuroendocrine tumors', 'Disease', (188, 209))	('HIF-2alpha', 'Gene', (19, 29))	('erythrocytosis', 'Phenotype', 'HP:0001901', (81, 95))	('HIF-2alpha', 'Gene', (154, 164))	('disruption', 'Var', (45, 55))	('HIF-2alpha', 'Gene', '2034', (154, 164))	('erythrocytosis', 'Disease', 'MESH:D011086', (81, 95))	('erythrocytosis', 'Disease', (81, 95))	('increases', 'PosReg', (6, 15))
28693	31350093	VHL mutations are also associated with benign tumors.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('benign tumors', 'Disease', 'MESH:D009369', (39, 52))	('benign tumors', 'Disease', (39, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('associated', 'Reg', (23, 33))
28695	31350093	A group of homozygous VHL gene mutations cause erythrocytosis that is not associated with any malignant or benign VHL syndrome.	('mutations', 'Var', (31, 40))	('VHL', 'Gene', (22, 25))	('VHL', 'Gene', '7428', (114, 117))	('VHL', 'Gene', '7428', (22, 25))	('erythrocytosis', 'Phenotype', 'HP:0001901', (47, 61))	('cause', 'Reg', (41, 46))	('erythrocytosis', 'Disease', (47, 61))	('malignant or benign VHL syndrome', 'Disease', (94, 126))	('erythrocytosis', 'Disease', 'MESH:D011086', (47, 61))	('malignant or benign VHL syndrome', 'Disease', 'MESH:D006623', (94, 126))	('VHL', 'Gene', (114, 117))
28698	31350093	Interactions between the mutated protein and HIF-1alpha or HIF-2alpha are impaired leading to increased expression of their target genes including EPO and vascular endothelial growth factor (VEGF).	('VEGF', 'Gene', (191, 195))	('HIF-2alpha', 'Gene', '2034', (59, 69))	('impaired', 'NegReg', (74, 82))	('increased', 'PosReg', (94, 103))	('vascular endothelial growth factor', 'Gene', '7422', (155, 189))	('EPO', 'Gene', (147, 150))	('Interactions', 'Interaction', (0, 12))	('expression', 'MPA', (104, 114))	('vascular endothelial growth factor', 'Gene', (155, 189))	('VEGF', 'Gene', '7422', (191, 195))	('protein', 'Protein', (33, 40))	('mutated', 'Var', (25, 32))	('HIF-2alpha', 'Gene', (59, 69))
28702	31350093	Two other homozygous VHL mutations, H191D and P138L, and several compound heterozygotes--three in combination with the R200W mutation, have been reported to cause congenital erythrocytosis but not cancer.	('erythrocytosis', 'Phenotype', 'HP:0001901', (174, 188))	('cause', 'Reg', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('H191D', 'Mutation', 'rs28940301', (36, 41))	('congenital erythrocytosis', 'Disease', 'MESH:C536842', (163, 188))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('R200W', 'Mutation', 'rs28940298', (119, 124))	('congenital erythrocytosis', 'Disease', (163, 188))	('VHL', 'Gene', (21, 24))	('H191D', 'Var', (36, 41))	('P138L', 'Mutation', 'rs780178275', (46, 51))	('VHL', 'Gene', '7428', (21, 24))	('P138L', 'Var', (46, 51))
28706	31350093	Both VHL213 and VHL160 are involved in the regulation of the oxygen sensing pathway and mutations would appear to have the potential to lead to the development of erythrocytosis or tumors.	('oxygen', 'Chemical', 'MESH:D010100', (61, 67))	('men', 'Species', '9606', (155, 158))	('VHL', 'Gene', (16, 19))	('erythrocytosis', 'Phenotype', 'HP:0001901', (163, 177))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('lead to', 'Reg', (136, 143))	('VHL', 'Gene', '7428', (16, 19))	('VHL', 'Gene', (5, 8))	('mutations', 'Var', (88, 97))	('involved', 'Reg', (27, 35))	('VHL', 'Gene', '7428', (5, 8))	('oxygen sensing pathway', 'Pathway', (61, 83))	('erythrocytosis or tumors', 'Disease', (163, 187))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('erythrocytosis or tumors', 'Disease', 'MESH:D011086', (163, 187))
28707	31350093	That being stated, there are individuals with homozygous M54I mutations that abolishes the internal translation start site (and hence the production of VHL160) who display erythrocytosis, extremely high EPO levels, but no tumors, suggesting that VHL213 and VHL160 do not have identical functions.	('erythrocytosis', 'Disease', (172, 186))	('VHL', 'Gene', '7428', (246, 249))	('VHL', 'Gene', '7428', (152, 155))	('M54I mutations', 'Var', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Disease', (222, 228))	('M54I', 'Mutation', 'p.M54I', (57, 61))	('EPO levels', 'MPA', (203, 213))	('abolishes', 'NegReg', (77, 86))	('VHL', 'Gene', (257, 260))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('high', 'PosReg', (198, 202))	('VHL', 'Gene', '7428', (257, 260))	('VHL', 'Gene', (246, 249))	('VHL', 'Gene', (152, 155))	('internal translation start site', 'MPA', (91, 122))	('erythrocytosis', 'Disease', 'MESH:D011086', (172, 186))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('erythrocytosis', 'Phenotype', 'HP:0001901', (172, 186))
28708	31350093	Particular mutations of VHL are generally linked to either erythrocytosis or the development of tumors.	('mutations', 'Var', (11, 20))	('VHL', 'Gene', '7428', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('erythrocytosis', 'Disease', 'MESH:D011086', (59, 73))	('erythrocytosis', 'Disease', (59, 73))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('men', 'Species', '9606', (88, 91))	('VHL', 'Gene', (24, 27))	('linked to', 'Reg', (42, 51))	('erythrocytosis', 'Phenotype', 'HP:0001901', (59, 73))
28709	31350093	The mechanisms that govern the phenotype-genotype relationship of VHL-driven disease have been characterized for some but not all mutations, so it is of interest that Lenglet and colleagues have recently identified a novel cryptic exon in intron 1 of the VHL gene (E1') and synonymous mutations in VHL exon 2 that affected splicing in both congenital erythrocytosis and typical VHL disease.	('mutations', 'Var', (285, 294))	('congenital erythrocytosis', 'Disease', (340, 365))	('VHL disease', 'Disease', (378, 389))	('VHL', 'Gene', '7428', (378, 381))	('VHL', 'Gene', (298, 301))	('VHL', 'Gene', '7428', (66, 69))	('erythrocytosis', 'Phenotype', 'HP:0001901', (351, 365))	('VHL', 'Gene', '7428', (298, 301))	('VHL', 'Gene', '7428', (255, 258))	('VHL disease', 'Disease', 'MESH:D006623', (378, 389))	('VHL', 'Gene', (255, 258))	('VHL', 'Gene', (378, 381))	('congenital erythrocytosis', 'Disease', 'MESH:C536842', (340, 365))	('splicing', 'MPA', (323, 331))	('VHL', 'Gene', (66, 69))	('affected', 'Reg', (314, 322))
28710	31350093	They investigated a patient with erythrocytosis with a known synonymous VHL c.429C>T p.Asp143Asp (D143D) mutation in the heterozygous state, and no other mutations in the 3 VHL canonical exons.	('VHL', 'Gene', (173, 176))	('VHL', 'Gene', '7428', (72, 75))	('p.Asp143Asp', 'Mutation', 'rs773556807', (85, 96))	('c.429C>T p.Asp143Asp', 'Var', (76, 96))	('VHL', 'Gene', '7428', (173, 176))	('erythrocytosis', 'Phenotype', 'HP:0001901', (33, 47))	('c.429C>T', 'Mutation', 'rs773556807', (76, 84))	('erythrocytosis', 'Disease', (33, 47))	('patient', 'Species', '9606', (20, 27))	('D143D', 'Mutation', 'rs773556807', (98, 103))	('erythrocytosis', 'Disease', 'MESH:D011086', (33, 47))	('p.Asp143Asp', 'Var', (85, 96))	('VHL', 'Gene', (72, 75))
28715	31350093	Investigation of six additional families with hereditary erythrocytosis revealed the presence of more E1' mutations.	("E1'", 'Gene', (102, 105))	('erythrocytosis', 'Phenotype', 'HP:0001901', (57, 71))	('mutations', 'Var', (106, 115))	('hereditary erythrocytosis', 'Disease', (46, 71))	('hereditary erythrocytosis', 'Disease', 'MESH:C536842', (46, 71))
28716	31350093	In five of the families, the affected family members were compound heterozygotes in which one VHL allele contained the E1' mutation while the other VHL allele contained a coding sequence mutation.	('VHL', 'Gene', (148, 151))	('VHL', 'Gene', '7428', (94, 97))	("E1'", 'Var', (119, 122))	('VHL', 'Gene', '7428', (148, 151))	('VHL', 'Gene', (94, 97))
28717	31350093	E1' mutations were also detected in typical VHL disease lacking alteration in the canonical VHL coding sequence exons.	('detected', 'Reg', (24, 32))	('VHL disease', 'Disease', 'MESH:D006623', (44, 55))	('VHL', 'Gene', (44, 47))	('VHL', 'Gene', (92, 95))	('VHL', 'Gene', '7428', (44, 47))	('VHL', 'Gene', '7428', (92, 95))	('VHL disease', 'Disease', (44, 55))	('mutations', 'Var', (4, 13))
28718	31350093	Sequencing of the new E1' cryptic exon in a large family with hereditary hemangioblastoma, clear cell renal cell carcinoma and pheochromocytoma identified 2 heterozygous variants, a previously unknown variant, c.340+617C>G and a c.340+648T>C variant originally reported as a rare polymorphism.	('c.340+617C>G', 'Mutation', 'c.340+617C>G', (210, 222))	('c.340+617C>G', 'Var', (210, 222))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (73, 89))	('c.340+648T>C', 'Var', (229, 241))	('c.340+648T>C', 'Mutation', 'rs73024533', (229, 241))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 122))	('clear cell renal cell carcinoma', 'Disease', (91, 122))	('pheochromocytoma', 'Disease', (127, 143))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (91, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('hereditary hemangioblastoma', 'Disease', (62, 89))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (127, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('pheochromocytoma', 'Disease', 'MESH:D010673', (127, 143))	('hereditary hemangioblastoma', 'Disease', 'MESH:D018325', (62, 89))
28719	31350093	These variants cosegregated in 6 patients who developed VHL disease, but were absent in the four healthy descendants tested, indicating their presence on a single disease-associated allele.	('variants', 'Var', (6, 14))	('patients', 'Species', '9606', (33, 41))	('VHL disease', 'Disease', (56, 67))	('developed', 'Reg', (46, 55))	('VHL disease', 'Disease', 'MESH:D006623', (56, 67))
28720	31350093	All of the new E1' mutations caused complex dysregulation of VHL splicing with excessive retention of E1', and significantly, were associated with downregulation of VHL protein expression.	("E1'", 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('dysregulation', 'MPA', (44, 57))	('downregulation', 'NegReg', (147, 161))	('VHL', 'Gene', (61, 64))	('VHL', 'Gene', (165, 168))	('VHL', 'Gene', '7428', (61, 64))	('VHL', 'Gene', '7428', (165, 168))
28723	31350093	In particular, the synonymous variants D143D and P138P should be considered as pathogenic mutations.	('P138P', 'Var', (49, 54))	('D143D', 'Mutation', 'rs773556807', (39, 44))	('D143D', 'Var', (39, 44))	('P138P', 'Mutation', 'rs869025648', (49, 54))
28725	31350093	Depending on the mutation in this region, the impact could be moderate (D143D, G144R and P138L) or severe (P138P) correlating with the severity of the disease, vis-a-vis congenital erythrocytosis and cancer.	('vis-a-vis congenital erythrocytosis', 'Disease', (160, 195))	('D143D', 'Mutation', 'rs773556807', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('P138P', 'Var', (107, 112))	('P138L', 'Mutation', 'rs780178275', (89, 94))	('G144R', 'Mutation', 'rs869025650', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('P138P', 'Mutation', 'rs869025648', (107, 112))	('erythrocytosis', 'Phenotype', 'HP:0001901', (181, 195))	('P138L', 'Var', (89, 94))	('D143D', 'Var', (72, 77))	('G144R', 'Var', (79, 84))	('vis-a-vis congenital erythrocytosis', 'Disease', 'MESH:D028243', (160, 195))	('cancer', 'Disease', (200, 206))
28727	31350093	Mutations identified in E1' in association with erythropoiesis had less severe impact on splicing than the mutations associated with cancer, confirming that erythrocytosis was associated with VHL hypomorphic mutations.	('erythrocytosis', 'Disease', 'MESH:D011086', (157, 171))	('VHL hypomorphic', 'Disease', 'MESH:D006623', (192, 207))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('splicing', 'MPA', (89, 97))	('associated', 'Reg', (176, 186))	("E1'", 'Gene', (24, 27))	('cancer', 'Disease', (133, 139))	('Mutations', 'Var', (0, 9))	('erythrocytosis', 'Phenotype', 'HP:0001901', (157, 171))	('VHL hypomorphic', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('erythrocytosis', 'Disease', (157, 171))
28728	31350093	Recently Zmajkovic and colleagues identified a mutation in the EPO gene that cosegregated with the disorder in a large family with autosomal dominant erythrocytosis (Fig.	('EPO', 'Gene', (63, 66))	('autosomal dominant erythrocytosis', 'Disease', 'MESH:D011086', (131, 164))	('mutation', 'Var', (47, 55))	('erythrocytosis', 'Phenotype', 'HP:0001901', (150, 164))	('cosegregated', 'Reg', (77, 89))	('autosomal dominant erythrocytosis', 'Disease', (131, 164))
28731	31350093	To investigate how DeltaG, an apparent loss-of-function variant of EPO, produces EPO the authors searched for alternative EPO mRNAs.	('DeltaG', 'Mutation', 'c.delG', (19, 25))	('DeltaG', 'Var', (19, 25))	('EPO', 'Gene', (67, 70))	('EPO', 'Disease', (81, 84))	('loss-of-function', 'NegReg', (39, 55))
28733	31350093	Cells transfected with DeltaG P2 produced more EPO than those transfected with wild-type P1 cDNA and the EPO was biologically active.	('more', 'PosReg', (42, 46))	('EPO', 'MPA', (47, 50))	('DeltaG', 'Mutation', 'c.delG', (23, 29))	('DeltaG P2', 'Var', (23, 32))
28734	31350093	Overall the results indicate that the EPO DeltaG mutation terminates translation of EPO P1 transcripts prematurely, but paradoxically alters the normally non-coding P2 transcripts so that AUG2, which ordinarily is out of frame with respect to the canonical EPO reading frame, initiates translation of the EPO coding sequence due to the frameshift, and produces an excess of biologically active EPO.	('translation', 'MPA', (286, 297))	('alters', 'Reg', (134, 140))	('DeltaG', 'Mutation', 'c.delG', (42, 48))	('EPO DeltaG', 'Gene', (38, 48))	('initiates', 'PosReg', (276, 285))	('mutation', 'Var', (49, 57))	('EPO P1', 'Gene', (84, 90))	('biologically active EPO', 'MPA', (374, 397))	('excess', 'PosReg', (364, 370))	('frameshift', 'Var', (336, 346))	('AUG2', 'Gene', (188, 192))	('terminates', 'NegReg', (58, 68))	('translation', 'MPA', (69, 80))
28735	31350093	A comparison of translated protein in this situation with that produced under normal circumstances, as well as the proposed mechanism for EPO overproduction by the DeltaG single-nucleotide deletion in Exon 2 of EPO is depicted in Fig.	('overproduction', 'PosReg', (142, 156))	('DeltaG', 'Mutation', 'c.delG', (164, 170))	('EPO', 'MPA', (138, 141))	('single-nucleotide deletion in', 'Var', (171, 200))
28738	31350093	The P2 transcripts with the DeltaC mutation produced high amounts of biologically active EPO, demonstrating that the EPO DeltaC causes erythrocytosis by the same mechanism as the EPO DeltaG mutation.	('EPO', 'Gene', (117, 120))	('erythrocytosis', 'Phenotype', 'HP:0001901', (135, 149))	('erythrocytosis', 'Disease', (135, 149))	('erythrocytosis', 'Disease', 'MESH:D011086', (135, 149))	('mutation', 'Var', (35, 43))	('causes', 'Reg', (128, 134))	('DeltaG', 'Mutation', 'c.delG', (183, 189))	('DeltaC', 'Var', (121, 127))
28739	31350093	Familial erythrocytosis caused by mutations in the EPO gene has now been designated as ECYT5 in the MIM classification #: 617907.	('EPO', 'Gene', (51, 54))	('erythrocytosis', 'Phenotype', 'HP:0001901', (9, 23))	('Familial erythrocytosis', 'Disease', (0, 23))	('Familial erythrocytosis', 'Disease', 'MESH:C536842', (0, 23))	('mutations', 'Var', (34, 43))	('caused', 'Reg', (24, 30))
28743	31350093	This variant is distinct from the aforementioned coding sequence mutation in the EPO gene, raising the possibility that it may cause erythrocytosis by a different mechanism.	('erythrocytosis', 'Disease', 'MESH:D011086', (133, 147))	('erythrocytosis', 'Disease', (133, 147))	('cause', 'Reg', (127, 132))	('variant', 'Var', (5, 12))	('erythrocytosis', 'Phenotype', 'HP:0001901', (133, 147))	('men', 'Species', '9606', (39, 42))
28751	31350093	Included among these are mutations in genes of the HIF: EPO pathway, including PHD2, HIF2A, VHL, and EPO.	('mutations', 'Var', (25, 34))	('HIF2A', 'Gene', '2034', (85, 90))	('VHL', 'Gene', (92, 95))	('EPO', 'Gene', (101, 104))	('HIF2A', 'Gene', (85, 90))	('VHL', 'Gene', '7428', (92, 95))	('EPO pathway', 'Pathway', (56, 67))	('PHD2', 'Gene', (79, 83))
28752	31350093	Genetic lesions in the HIF: EPO pathway should be particularly considered as a cause of erythrocytosis in patients with normal to elevated EPO levels, a family history of erythrocytosis, or in situations in which other secondary causes of erythrocytosis, such as high affinity hemoglobin, EPO-producing tumors, or right to left cardiac shunts, have been ruled out.	('erythrocytosis', 'Phenotype', 'HP:0001901', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('erythrocytosis', 'Disease', 'MESH:D011086', (239, 253))	('cardiac shunts', 'Phenotype', 'HP:0001693', (328, 342))	('erythrocytosis', 'Phenotype', 'HP:0001901', (88, 102))	('erythrocytosis', 'Phenotype', 'HP:0001901', (239, 253))	('cause', 'Reg', (79, 84))	('erythrocytosis', 'Disease', (88, 102))	('tumors', 'Disease', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('erythrocytosis', 'Disease', 'MESH:D011086', (171, 185))	('EPO levels', 'MPA', (139, 149))	('erythrocytosis', 'Disease', (171, 185))	('erythrocytosis', 'Disease', 'MESH:D011086', (88, 102))	('Genetic lesions', 'Var', (0, 15))	('erythrocytosis', 'Disease', (239, 253))	('patients', 'Species', '9606', (106, 114))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
28753	31350093	Gain further insight into genotype: phenotype correlations in erythrocytosis-associated mutations in genes of the HIF: EPO pathway.	('erythrocytosis', 'Disease', 'MESH:D011086', (62, 76))	('erythrocytosis', 'Disease', (62, 76))	('mutations', 'Var', (88, 97))	('erythrocytosis', 'Phenotype', 'HP:0001901', (62, 76))
28762	31469413	Stratification of PCPG patients with a risk-score formulated using multivariate analysis of lincRNA expression profiles, presence of key driver mutations, tumor location, and hormone secretion profiles showed significant differences in metastasis-free survival.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('metastasis-free survival', 'CPA', (236, 260))	('presence', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', (155, 160))	('differences', 'Reg', (221, 232))	('mutations', 'Var', (144, 153))
28768	31469413	Pseudohypoxic tumors can be further grouped into two distinct clusters: SDHx-mutated (including all cases with mutations in genes related to the tricarboxylic acid cycle) as well as non-SDHx-mutated (related to aberrations in VHL/EPAS1).	('mutations', 'Var', (111, 120))	('Pseudohypoxic tumors', 'Disease', (0, 20))	('EPAS1', 'Gene', '2034', (230, 235))	('Pseudohypoxic tumors', 'Disease', 'MESH:D009369', (0, 20))	('SDHx-mutated', 'Disease', (72, 84))	('EPAS1', 'Gene', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('VHL', 'Gene', (226, 229))	('VHL', 'Gene', '7428', (226, 229))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (145, 163))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
28769	31469413	PCPGs belonging to the subcluster SDHx-mutated pseudohypoxia; and most predominantly SDHB mutation, are associated with metastatic disease.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('metastatic disease', 'Disease', (120, 138))	('associated', 'Reg', (104, 114))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('mutation', 'Var', (90, 98))
28771	31469413	Other factors reported to be associated with metastasis in PCPG are somatic mutations in ATRX or telomerase activation, which generally co-occur with SDHB mutation.	('mutations', 'Var', (76, 85))	('telomerase', 'CPA', (97, 107))	('ATRX', 'Gene', (89, 93))	('SDHB', 'Gene', '6390', (150, 154))	('ATRX', 'Gene', '546', (89, 93))	('SDHB', 'Gene', (150, 154))	('mutation', 'Var', (155, 163))
28780	31469413	For calculation of the combined prognostic index (PI), expression levels of 18 marker lincRNAs, expression of TERT, and the following 6 clinical parameters were combined in a multivariate Cox regression model: (i) germline SDHB mutation; (ii) nonadrenal tumor location; (iii) ATRX somatic mutation; secretion of (iv) normetanephrine or norepinephrine; (v) epinephrine or metanephrine; and (vi) methoxytyramine, or dopamine (details of all statistical tests in Supporting Information).	('ATRX', 'Gene', '546', (276, 280))	('mutation', 'Var', (228, 236))	('norepinephrine', 'MPA', (336, 350))	('adrenal tumor', 'Phenotype', 'HP:0100631', (246, 259))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('TERT', 'Gene', (110, 114))	('SDHB', 'Gene', '6390', (223, 227))	('epinephrine', 'MPA', (356, 367))	('TERT', 'Gene', '7015', (110, 114))	('SDHB', 'Gene', (223, 227))	('adrenal tumor', 'Disease', (246, 259))	('ATRX', 'Gene', (276, 280))	('secretion of', 'MPA', (299, 311))	('methoxytyramine', 'MPA', (394, 409))	('adrenal tumor', 'Disease', 'MESH:D000310', (246, 259))
28801	31469413	Until now, the most relevant molecular markers for aggressive or metastatic PCPG have been the SDHB and ATRX mutations.	('ATRX', 'Gene', (104, 108))	('SDHB', 'Gene', '6390', (95, 99))	('aggressive or metastatic PCPG', 'Disease', (51, 80))	('mutations', 'Var', (109, 118))	('SDHB', 'Gene', (95, 99))	('ATRX', 'Gene', '546', (104, 108))
28809	31469413	In all of these cases, underexpression of the lincRNAs showed better metastasis-free survival in tumors from the corresponding molecular subtype, making them interesting candidates as possible new targets for treating patients diagnosed with the particular subtype.	('underexpression', 'Var', (23, 38))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('better', 'PosReg', (62, 68))	('metastasis-free survival', 'CPA', (69, 93))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
28874	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
28888	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('malignant tumors', 'Disease', (55, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
28896	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
28906	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('TRIM44', 'Gene', '54765', (18, 24))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('hallmark characteristics of', 'MPA', (70, 97))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
28908	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
28910	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
28911	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (111, 117))	('cyclin', 'Gene', '5111', (125, 131))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('cyclin', 'Gene', (125, 131))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (111, 117))
28913	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('TRIM44', 'Gene', '54765', (14, 20))	('p27', 'Gene', '10671', (64, 67))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('inhibited', 'NegReg', (91, 100))	('TRIM44', 'Gene', (14, 20))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
28914	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('glioma', 'Disease', (112, 118))	('activated', 'PosReg', (99, 108))	('p21', 'Gene', (22, 25))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
28915	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
28916	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
28927	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('knockdown', 'Var', (39, 48))	('DDIT4', 'Gene', (130, 135))	('CADM1', 'Gene', (103, 108))	('NUPR1', 'Gene', (89, 94))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', '54765', (32, 38))	('TNFSF10', 'Gene', '8743', (117, 124))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('CDK19', 'Gene', '23097', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
28936	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
28943	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
28969	32335823	IDH1 mutation was significantly associated with high-SST2 status.	('SST', 'Gene', '6750', (53, 56))	('associated', 'Reg', (32, 42))	('IDH1', 'Gene', (0, 4))	('SST', 'Gene', (53, 56))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
28977	32335823	In particular, several radioligands targeting SST have been developed, such as 68Ga-DOTATOC and 68Ga-DOTATATE, which are now commonly used in the diagnosis of neuroendocrine tumors (NETs) via positron emission tomography (PET).	('neuroendocrine tumors', 'Disease', (159, 180))	('SST', 'Gene', '6750', (46, 49))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (159, 180))	('68Ga-DOTATATE', 'Var', (96, 109))	('DOTATOC', 'Chemical', '-', (84, 91))	('NETs', 'Phenotype', 'HP:0100634', (182, 186))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (159, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('SST', 'Gene', (46, 49))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
29019	32335823	Mutational profiles were significantly associated with high-SST2 status in LGG, which showed the highest proportion of high-SST tumors, including isocitrate dehydrogenase 1 (IDH1), capicua transcriptional repressor (CIC), and far upstream element binding protein 1 (FUBP1) mutations.	('FUBP1', 'Gene', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('associated', 'Reg', (39, 49))	('tumors', 'Disease', (128, 134))	('CIC', 'Gene', '23152', (216, 219))	('isocitrate dehydrogenase 1', 'Gene', (146, 172))	('isocitrate dehydrogenase 1', 'Gene', '3417', (146, 172))	('SST', 'Gene', (124, 127))	('IDH1', 'Gene', (174, 178))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('capicua transcriptional repressor', 'Gene', '23152', (181, 214))	('FUBP1', 'Gene', '8880', (266, 271))	('far upstream element binding protein 1', 'Gene', '8880', (226, 264))	('SST', 'Gene', (60, 63))	('IDH1', 'Gene', '3417', (174, 178))	('CIC', 'Gene', (216, 219))	('SST', 'Gene', '6750', (124, 127))	('SST', 'Gene', '6750', (60, 63))	('mutations', 'Var', (273, 282))	('capicua transcriptional repressor', 'Gene', (181, 214))	('far upstream element binding protein 1', 'Gene', (226, 264))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
29020	32335823	In contrast, epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and tumor protein 53 (TP53) mutations were more common in low-SST2 tumors than in high-SST2 tumors (Fig.	('mutations', 'Var', (121, 130))	('common', 'Reg', (141, 147))	('PTEN', 'Gene', (86, 90))	('tumor protein 53', 'Gene', (97, 113))	('tumors', 'Disease', (185, 191))	('tumor protein 53', 'Gene', '7157', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', '1956', (47, 51))	('tumors', 'Disease', (160, 166))	('epidermal growth factor receptor', 'Gene', (13, 45))	('PTEN', 'Gene', '5728', (86, 90))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('SST', 'Gene', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('TP53', 'Gene', (115, 119))	('SST', 'Gene', (180, 183))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('SST', 'Gene', '6750', (155, 158))	('EGFR', 'Gene', (47, 51))	('phosphatase and tensin homolog', 'Gene', '5728', (54, 84))	('SST', 'Gene', '6750', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
29021	32335823	In pancreatic adenocarcinoma (PAAD), Kirsten rat sarcoma (KRAS) and TP53 mutations were associated with low-SST2 status.	('KRAS', 'Gene', (58, 62))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('SST', 'Gene', '6750', (108, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('KRAS', 'Gene', '24525', (58, 62))	('pancreatic adenocarcinoma', 'Disease', (3, 28))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('PAAD', 'Phenotype', 'HP:0006725', (30, 34))	('SST', 'Gene', (108, 111))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 28))	('associated', 'Reg', (88, 98))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('rat', 'Species', '10116', (45, 48))	('sarcoma', 'Disease', (49, 56))
29022	32335823	In uterine corpus endometrial carcinoma (UCEC), catenin beta 1 (CTNNB1) mutation showed an association with low-SST2 status.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('SST', 'Gene', (112, 115))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (18, 39))	('CTNNB1', 'Gene', (64, 70))	('catenin beta 1', 'Gene', (48, 62))	('endometrial carcinoma', 'Disease', (18, 39))	('SST', 'Gene', '6750', (112, 115))	('CTNNB1', 'Gene', '1499', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('mutation', 'Var', (72, 80))	('catenin beta 1', 'Gene', '1499', (48, 62))	('association', 'Interaction', (91, 102))
29023	32335823	When high-SST2 tumors were defined with the expression level in PCPG as a reference value, SST2-based tumor subtypes were not significantly associated with gene alterations in other cancer subtypes, including BRCA, PCPG, and KIRC.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SST', 'Gene', '6750', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('KIRC', 'Disease', (225, 229))	('cancer', 'Disease', (182, 188))	('rat', 'Species', '10116', (165, 168))	('SST', 'Gene', (91, 94))	('tumors', 'Disease', (15, 21))	('BRCA', 'Gene', '672', (209, 213))	('alterations', 'Var', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (140, 150))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BRCA', 'Gene', (209, 213))	('SST', 'Gene', '6750', (91, 94))	('SST', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('PCPG', 'Disease', (215, 219))
29026	32335823	The SST2 level in G2 grade tumors was significantly higher than that in G3 grade tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('G2 grade', 'Var', (18, 26))	('SST', 'Gene', (4, 7))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SST', 'Gene', '6750', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
29034	32335823	In addition, SST2 status showed prognostic impact in thymoma and glioblastoma when the level of expression in normal kidney tissue was defined as the reference (Supplementary fig.	('SST', 'Gene', (13, 16))	('impact', 'Reg', (43, 49))	('thymoma', 'Phenotype', 'HP:0100522', (53, 60))	('prognostic', 'Reg', (32, 42))	('SST', 'Gene', '6750', (13, 16))	('thymoma and glioblastoma', 'Disease', 'MESH:D013945', (53, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('status', 'Var', (18, 24))
29040	32335823	Additionally, we revealed that fourteen of the 32 cancer subtypes had more than 5% of tumors with high-SST2 expression when SST2 expression in normal kidney tissue was used as the reference.	('SST', 'Gene', '6750', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SST', 'Gene', '6750', (103, 106))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', (86, 92))	('SST', 'Gene', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SST', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('expression', 'Var', (108, 118))
29053	32335823	Several gene mutations were noted to have a correlation with SST2 expression in LGG.	('SST', 'Gene', (61, 64))	('SST', 'Gene', '6750', (61, 64))	('expression', 'MPA', (66, 76))	('correlation', 'Reg', (44, 55))	('mutations', 'Var', (13, 22))
29054	32335823	In particular, the IDH1 mutation was revealed to be associated with SST2 expression, which is supported by a previous study.	('IDH1', 'Gene', (19, 23))	('associated', 'Reg', (52, 62))	('IDH1', 'Gene', '3417', (19, 23))	('expression', 'MPA', (73, 83))	('SST', 'Gene', '6750', (68, 71))	('mutation', 'Var', (24, 32))	('SST', 'Gene', (68, 71))
29055	32335823	The close association between IDH1 mutation and SST2 expression was also verified by the association of high-SST2 with good prognosis in LGG.	('IDH1', 'Gene', '3417', (30, 34))	('IDH1', 'Gene', (30, 34))	('SST', 'Gene', (48, 51))	('SST', 'Gene', '6750', (109, 112))	('mutation', 'Var', (35, 43))	('SST', 'Gene', '6750', (48, 51))	('SST', 'Gene', (109, 112))	('LGG', 'Disease', (137, 140))	('association', 'Interaction', (89, 100))
29056	32335823	The presence of IDH1 mutation is the most common factor used to classify tumor subtypes in terms of disparate molecular pathogenesis and favorable prognosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('rat', 'Species', '10116', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', (16, 20))	('tumor', 'Disease', (73, 78))	('IDH1', 'Gene', '3417', (16, 20))
29057	32335823	Additionally, not only IDH1 but also CIC and FUBP1 mutations demonstrated a positive association with SST2 expression.	('SST', 'Gene', (102, 105))	('mutations', 'Var', (51, 60))	('CIC', 'Gene', '23152', (37, 40))	('FUBP1', 'Gene', '8880', (45, 50))	('IDH1', 'Gene', (23, 27))	('expression', 'MPA', (107, 117))	('CIC', 'Gene', (37, 40))	('rat', 'Species', '10116', (68, 71))	('SST', 'Gene', '6750', (102, 105))	('FUBP1', 'Gene', (45, 50))	('IDH1', 'Gene', '3417', (23, 27))	('positive', 'PosReg', (76, 84))
29058	32335823	This finding is also consistent with previous studies that showed an association between IDH1, CIC, and FUBP1 mutations and a favorable prognosis.	('CIC', 'Gene', '23152', (95, 98))	('mutations', 'Var', (110, 119))	('FUBP1', 'Gene', '8880', (104, 109))	('CIC', 'Gene', (95, 98))	('IDH1', 'Gene', (89, 93))	('FUBP1', 'Gene', (104, 109))	('IDH1', 'Gene', '3417', (89, 93))
29059	32335823	In contrast, EGFR, PTEN, and TP53 mutations showed a negative association with SST2 expression.	('SST', 'Gene', '6750', (79, 82))	('SST', 'Gene', (79, 82))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('TP53', 'Gene', (29, 33))	('negative', 'NegReg', (53, 61))	('expression', 'MPA', (84, 94))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (34, 43))
29064	32335823	Considering the association between gene mutations and SST2 expression, a high level of SST2 expression can be deemed a strong alternative to favorable prognostic markers, such as IDH1 mutation or tumor grade.	('mutations', 'Var', (41, 50))	('SST', 'Gene', (88, 91))	('IDH1', 'Gene', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('IDH1', 'Gene', '3417', (180, 184))	('SST', 'Gene', '6750', (88, 91))	('mutation', 'Var', (185, 193))	('SST', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SST', 'Gene', '6750', (55, 58))	('tumor', 'Disease', (197, 202))
29078	32335823	Second, therapeutic radiopharmaceuticals, including Lu-177-labeled DOTATATE, may be a feasible option for high-SST2 tumors regardless of the organ-based subtypes.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('SST', 'Gene', '6750', (111, 114))	('Lu-177', 'Chemical', 'MESH:C000615061', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SST', 'Gene', (111, 114))	('Lu-177-labeled', 'Var', (52, 66))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('DOTATATE', 'Chemical', '-', (67, 75))
29079	32335823	Despite IDH1 mutations and hormone receptor expression being good prognostic factors, recurrence of brain tumor patients with IDH1 mutations and breast cancer patients with hormone receptor expression is frequently observed in the clinical setting.	('IDH1', 'Gene', '3417', (126, 130))	('mutations', 'Var', (131, 140))	('IDH1', 'Gene', (8, 12))	('patients', 'Species', '9606', (112, 120))	('brain tumor', 'Disease', (100, 111))	('IDH1', 'Gene', '3417', (8, 12))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('IDH1', 'Gene', (126, 130))	('brain tumor', 'Disease', 'MESH:D001932', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('breast cancer', 'Disease', (145, 158))	('patients', 'Species', '9606', (159, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('brain tumor', 'Phenotype', 'HP:0030692', (100, 111))
29099	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
29101	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
29109	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
29128	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
29129	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
29130	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
29132	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
29133	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('E59K', 'Var', (0, 4))	('cancers', 'Disease', (85, 92))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
29134	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
29135	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('R238C', 'Var', (117, 122))	('NTNG1', 'Gene', '22854', (33, 38))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
29136	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
29137	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('patients', 'Species', '9606', (76, 84))	('NTN3', 'Gene', '4917', (224, 228))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
29138	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('patient', 'Species', '9606', (75, 82))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (35, 43))	('NTNG1', 'Gene', '22854', (104, 109))	('patients', 'Species', '9606', (118, 126))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
29139	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (84, 91))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('NTNG2', 'Gene', '84628', (204, 209))	('NTN1', 'Gene', '9423', (195, 199))
29140	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
29141	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
29142	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
29143	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
29144	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
29145	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
29146	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('NTN4', 'Gene', (42, 46))	('NTN3', 'Gene', '4917', (36, 40))	('NTN5', 'Gene', '126147', (52, 56))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
29147	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('NTNG1', 'Gene', (7, 12))
29148	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
29158	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('cancer', 'Disease', (118, 124))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MLK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('epigenetic activation', 'Var', (66, 87))	('transcription', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MMP9', 'Gene', '4318', (91, 95))	('enhanced', 'PosReg', (19, 27))
29193	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTNG1', 'Gene', '22854', (255, 260))	('NTN1', 'Gene', '9423', (57, 61))	('NTN1', 'Gene', (57, 61))	('NTN1', 'Gene', '9423', (238, 242))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
29196	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
29198	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('methylation', 'Var', (31, 42))	('associated', 'Reg', (55, 65))	('NTN4', 'Gene', '59277', (46, 50))	('NTN4', 'Gene', (46, 50))
29199	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
29201	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('radiation therapy', 'Disease', (49, 66))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
29202	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', (15, 19))	('associated', 'Reg', (24, 34))	('NTN3', 'Gene', '4917', (15, 19))
29203	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('associated', 'Reg', (104, 114))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
29204	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
29208	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('EZH2', 'Gene', '2146', (102, 106))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
29223	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
29229	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('eQTL', 'Var', (39, 43))	('affected', 'Reg', (27, 35))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
29232	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('AIDS', 'Disease', (55, 59))	('non-obstructive azoospermia', 'Disease', (96, 123))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
29235	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('MYC', 'Gene', (96, 99))	('EBF1', 'Gene', '1879', (108, 112))	('TCF12', 'Gene', '6938', (101, 106))	('rs9894790', 'Var', (22, 31))	('TCF12', 'Gene', (101, 106))	('EGR1', 'Gene', (114, 118))	('MYC', 'Gene', '4609', (96, 99))	('NR2F2', 'Gene', '7026', (124, 129))	('affect', 'Reg', (74, 80))	('EGR1', 'Gene', '1958', (114, 118))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('NR2F2', 'Gene', (124, 129))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs9901637', 'Var', (33, 42))	('EBF1', 'Gene', (108, 112))	('binding', 'Interaction', (85, 92))
29236	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('high', 'Var', (14, 18))	('NTN1', 'Gene', '9423', (33, 37))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
29244	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
29256	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('GPX4', 'Gene', '2879', (99, 103))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
29265	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
29268	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Netrin', 'Gene', (112, 118))
29269	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
29270	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('NTR', 'Gene', (215, 218))	('Laminin', 'Protein', (104, 111))
29273	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
29281	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
29289	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('methylation', 'Var', (36, 47))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (150, 156))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('NTNG1', 'Gene', (51, 56))
29290	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
29292	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
29293	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
29297	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
29341	32099962	At the molecular level, the dysregulation of myocardial beta2-adrenergic receptors, resulting in specific wall motion abnormalities with left ventricular apical hypokinesia and ballooning, is considered to be responsible.	('left ventricular apical hypokinesia and ballooning', 'Disease', 'MESH:D054549', (137, 187))	('specific wall motion abnormalities', 'Phenotype', 'HP:0012667', (97, 131))	('motion abnormalities', 'Disease', (111, 131))	('motion abnormalities', 'Disease', 'MESH:D009041', (111, 131))	('dysregulation', 'Var', (28, 41))	('myocardial beta2-adrenergic receptors', 'Protein', (45, 82))	('hypokinesia', 'Phenotype', 'HP:0002375', (161, 172))	('specific', 'MPA', (97, 105))
29444	32053635	Moreover, even when the all the samples were analyzed, participants with U-NM concentration above the cut-off value were significantly at risk for increased insulin resistance after adjustment for the confounding factors (OR: 2.73, p = 0.006, 95%CI: 1.34-5.57).	('U-NM', 'Var', (73, 77))	('increased', 'PosReg', (147, 156))	('U-NM', 'Chemical', '-', (73, 77))	('U-NM', 'Phenotype', 'HP:0003345', (73, 77))	('insulin resistance', 'Phenotype', 'HP:0000855', (157, 175))	('insulin', 'Gene', (157, 164))	('participants', 'Species', '9606', (55, 67))	('insulin', 'Gene', '3630', (157, 164))	('men', 'Species', '9606', (188, 191))
29448	32053635	In these patients, CA concentrations has been shown to be positively associated with both insulin resistance and impairment of insulin secretion, both of which have been shown to be primary causes of the impaired glucose tolerance in such patients.	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (204, 230))	('patients', 'Species', '9606', (9, 17))	('insulin resistance', 'Phenotype', 'HP:0000855', (90, 108))	('impaired glucose tolerance', 'Disease', (204, 230))	('impairment of insulin secretion', 'Disease', 'MESH:D007333', (113, 144))	('CA concentrations', 'Var', (19, 36))	('associated', 'Reg', (69, 79))	('impairment of insulin secretion', 'Disease', (113, 144))	('patients', 'Species', '9606', (239, 247))	('insulin', 'Gene', (127, 134))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (204, 230))	('insulin', 'Gene', (90, 97))	('insulin', 'Gene', '3630', (127, 134))	('insulin', 'Gene', '3630', (90, 97))
29451	32053635	A previous study of patients with pheochromocytoma found that U-NM and U-M concentrations are differently associated with insulin resistance and insulin secretion: U-M is positively associated with impairment in insulin secretion, but not with insulin resistance, while U-NM is negatively associated with impairment of insulin secretion and positively associated with insulin resistance.	('impairment of insulin secretion', 'Disease', 'MESH:D007333', (305, 336))	('insulin', 'Gene', '3630', (145, 152))	('insulin', 'Gene', '3630', (368, 375))	('insulin', 'Gene', (212, 219))	('insulin', 'Gene', '3630', (319, 326))	('insulin', 'Gene', (244, 251))	('insulin', 'Gene', '3630', (122, 129))	('insulin resistance', 'Phenotype', 'HP:0000855', (244, 262))	('U-NM', 'Phenotype', 'HP:0003345', (62, 66))	('U-NM', 'Chemical', '-', (270, 274))	('insulin resistance', 'Phenotype', 'HP:0000855', (122, 140))	('patients', 'Species', '9606', (20, 28))	('insulin', 'Gene', (368, 375))	('insulin', 'Gene', (145, 152))	('pheochromocytoma', 'Disease', 'MESH:D010673', (34, 50))	('insulin resistance', 'Phenotype', 'HP:0000855', (368, 386))	('impairment in insulin secretion', 'Disease', 'MESH:D007333', (198, 229))	('insulin', 'Gene', (319, 326))	('insulin', 'Gene', (122, 129))	('insulin', 'Gene', '3630', (212, 219))	('pheochromocytoma', 'Disease', (34, 50))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (34, 50))	('insulin', 'Gene', '3630', (244, 251))	('impairment of insulin secretion', 'Disease', (305, 336))	('U-NM', 'Chemical', '-', (62, 66))	('impairment in insulin secretion', 'Disease', (198, 229))	('U-NM', 'Phenotype', 'HP:0003345', (270, 274))	('U-M', 'Var', (164, 167))
29452	32053635	In the current study of people with CA concentrations within the physiologic range, the relationship between CAs and HOMA indices also differed according to the type of CA, with U-NM concentrations being significantly associated with insulin resistance, but no other association being identified.	('associated with', 'Reg', (218, 233))	('U-NM', 'Chemical', '-', (178, 182))	('U-NM', 'Phenotype', 'HP:0003345', (178, 182))	('CAs', 'Chemical', 'MESH:D002395', (109, 112))	('HOMA', 'Chemical', '-', (117, 121))	('insulin resistance', 'Phenotype', 'HP:0000855', (234, 252))	('insulin', 'Gene', (234, 241))	('insulin', 'Gene', '3630', (234, 241))	('differed', 'Reg', (135, 143))	('people', 'Species', '9606', (24, 30))	('U-NM', 'Var', (178, 182))
29543	32025984	Although desflurane elicits sympathetic activation, hypertension, and tachycardia when its inspired concentration exceeds 1.0 minimum alveolar concentration (MAC), it provides faster and tighter hemodynamic control than other volatile agents at lower than 1.0 MAC, suggesting that desflurane might be safely used during anesthesia for resection of pheochromocytomas.	('desflurane', 'Chemical', 'MESH:C053562', (281, 291))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (348, 364))	('elicits', 'Reg', (20, 27))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (348, 365))	('desflurane', 'Var', (9, 19))	('tachycardia', 'Phenotype', 'HP:0001649', (70, 81))	('tachycardia', 'Disease', (70, 81))	('hemodynamic control', 'MPA', (195, 214))	('hypertension', 'Disease', 'MESH:D006973', (52, 64))	('sympathetic activation', 'MPA', (28, 50))	('tachycardia', 'Disease', 'MESH:D013610', (70, 81))	('desflurane', 'Chemical', 'MESH:C053562', (9, 19))	('pheochromocytomas', 'Disease', 'MESH:D010673', (348, 365))	('hypertension', 'Disease', (52, 64))	('pheochromocytomas', 'Disease', (348, 365))	('hypertension', 'Phenotype', 'HP:0000822', (52, 64))
29576	32025984	Increased plasma catecholamine levels, an extra-adrenal mass at computed tomography, and uptake of 123I-MIBG lead to the diagnosis.	('uptake', 'CPA', (89, 95))	('catecholamine', 'Chemical', 'MESH:D002395', (17, 30))	('123I-MIBG', 'Chemical', 'MESH:D019797', (99, 108))	('123I-MIBG', 'Var', (99, 108))	('plasma catecholamine levels', 'MPA', (10, 37))	('Increased', 'PosReg', (0, 9))	('Increased plasma catecholamine', 'Phenotype', 'HP:0003334', (0, 30))
29587	32025984	Another study showed that peripheral sympathetic activity was significantly increased after pheochromocytoma surgery, despite decreased blood pressure, heart rate, and circulating catecholamine levels compared with those before surgery.	('decreased blood pressure', 'Phenotype', 'HP:0002615', (126, 150))	('decreased', 'NegReg', (126, 135))	('heart rate', 'MPA', (152, 162))	('increased', 'PosReg', (76, 85))	('pheochromocytoma', 'Disease', (92, 108))	('blood pressure', 'MPA', (136, 150))	('peripheral sympathetic activity', 'MPA', (26, 57))	('circulating catecholamine levels', 'MPA', (168, 200))	('catecholamine', 'Chemical', 'MESH:D002395', (180, 193))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (92, 108))	('pheochromocytoma', 'Disease', 'MESH:D010673', (92, 108))	('surgery', 'Var', (109, 116))
29598	31856921	Paragangliomas and pheochromocytomas can be sporadic or familial, the latter frequently being multifocal and possibly due to succinate dehydrogenase complex genes mutations.	('mutations', 'Var', (163, 172))	('succinate dehydrogenase', 'Gene', '6390', (125, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (19, 35))	('succinate dehydrogenase', 'Gene', (125, 148))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (19, 36))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('Paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (0, 36))
29599	31856921	In addition, 12% of sporadic paragangliomas are related to covered succinate dehydrogenase complex mutations.	('mutations', 'Var', (99, 108))	('paragangliomas', 'Disease', (29, 43))	('paragangliomas', 'Disease', 'MESH:D010235', (29, 43))	('succinate dehydrogenase', 'Gene', '6390', (67, 90))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('paragangliomas', 'Phenotype', 'HP:0002668', (29, 43))	('succinate dehydrogenase', 'Gene', (67, 90))	('related', 'Reg', (48, 55))
29600	31856921	The importance of identifying succinate dehydrogenase complex mutations is related to the risk for these patients of developing multiple tumors, including non-endocrine ones, showing an aggressive clinical presentation.	('succinate dehydrogenase', 'Gene', (30, 53))	('succinate dehydrogenase', 'Gene', '6390', (30, 53))	('tumors', 'Disease', (137, 143))	('patients', 'Species', '9606', (105, 113))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutations', 'Var', (62, 71))
29602	31856921	He was found to carry a germline Succinate dehydrogenase subunit B gene (SDHB) mutation.	('Succinate dehydrogenase', 'Gene', '6390', (33, 56))	('mutation', 'Var', (79, 87))	('SDHB', 'Gene', '6390', (73, 77))	('Succinate dehydrogenase', 'Gene', (33, 56))	('SDHB', 'Gene', (73, 77))
29603	31856921	It is crucial to look for a second malignancy in the case of a paraganglioma demonstrating succinate dehydrogenase complex germline mutations.	('succinate dehydrogenase', 'Gene', (91, 114))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('paraganglioma', 'Phenotype', 'HP:0002668', (63, 76))	('malignancy', 'Disease', (35, 45))	('paraganglioma', 'Disease', (63, 76))	('germline mutations', 'Var', (123, 141))	('succinate dehydrogenase', 'Gene', '6390', (91, 114))	('paraganglioma', 'Disease', 'MESH:D010235', (63, 76))
29606	31856921	Succinate dehydrogenase (SDH) germline mutations represent a possible cause of hereditary PPGL, but have also been reported in 12% of sporadic cases.	('SDH', 'Gene', (25, 28))	('Succinate dehydrogenase', 'Gene', (0, 23))	('germline mutations', 'Var', (30, 48))	('cause', 'Reg', (70, 75))	('PPGL', 'Disease', (90, 94))	('Succinate dehydrogenase', 'Gene', '6390', (0, 23))	('PGL', 'Phenotype', 'HP:0002668', (91, 94))	('SDH', 'Gene', '6390', (25, 28))
29610	31856921	This case report describes the association of a neck PGL with a follicular lymphoma in a patient with a germline SDHB mutation.	('SDHB', 'Gene', '6390', (113, 117))	('patient', 'Species', '9606', (89, 96))	('PGL', 'Phenotype', 'HP:0002668', (53, 56))	('lymphoma', 'Disease', 'MESH:D008223', (75, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (75, 83))	('association', 'Interaction', (31, 42))	('SDHB', 'Gene', (113, 117))	('mutation', 'Var', (118, 126))	('neck PGL', 'Disease', (48, 56))	('lymphoma', 'Disease', (75, 83))
29618	31856921	According to current guidelines, our patient was submitted to genetic testing, including investigation for germline RET and succinate dehydrogenase complex (SDHx) mutations.	('mutations', 'Var', (163, 172))	('patient', 'Species', '9606', (37, 44))	('SDH', 'Gene', (157, 160))	('RET', 'Gene', (116, 119))	('succinate dehydrogenase', 'Gene', (124, 147))	('succinate dehydrogenase', 'Gene', '6390', (124, 147))	('SDH', 'Gene', '6390', (157, 160))	('RET', 'Gene', '5979', (116, 119))
29620	31856921	Germline SDHx mutation testing was performed on leukocyte DNA by a next-generation sequencing (NGS) method based on capture technology (probe; IDT), evaluating the presence of point mutations, small deletions, or insertion mutations in the coding region of the SDHB, SDHA, SDHD, SDHAF2, SDHC genes and flanking intronic regions by amplification and direct sequencing.	('small deletions', 'Var', (193, 208))	('SDH', 'Gene', (267, 270))	('insertion mutations', 'Var', (213, 232))	('SDHA', 'Gene', (279, 283))	('SDHD', 'Gene', (273, 277))	('SDH', 'Gene', '6390', (9, 12))	('SDH', 'Gene', '6390', (287, 290))	('SDHA', 'Gene', '6389', (279, 283))	('SDHB', 'Gene', '6390', (261, 265))	('SDHC', 'Gene', '6391', (287, 291))	('SDH', 'Gene', (273, 276))	('SDH', 'Gene', '6390', (261, 264))	('SDHAF2', 'Gene', (279, 285))	('SDHAF2', 'Gene', '54949', (279, 285))	('SDH', 'Gene', (279, 282))	('SDH', 'Gene', (9, 12))	('SDHB', 'Gene', (261, 265))	('SDH', 'Gene', (287, 290))	('SDH', 'Gene', (261, 264))	('SDH', 'Gene', '6390', (267, 270))	('SDHA', 'Gene', (267, 271))	('SDHC', 'Gene', (287, 291))	('point mutations', 'Var', (176, 191))	('SDHD', 'Gene', '6392', (273, 277))	('SDHA', 'Gene', '6389', (267, 271))	('SDH', 'Gene', '6390', (273, 276))	('SDH', 'Gene', '6390', (279, 282))
29621	31856921	The results of the genetic test of our patient showed the presence of a germline mutation in exon 7 of the SDHB gene.	('patient', 'Species', '9606', (39, 46))	('SDHB', 'Gene', (107, 111))	('presence', 'Reg', (58, 66))	('germline mutation in', 'Var', (72, 92))	('SDHB', 'Gene', '6390', (107, 111))
29623	31856921	This variant causes the replacement of the amino acid arginine with a histidine at SDHB protein codon 230.	('arginine', 'Chemical', 'MESH:D001120', (54, 62))	('SDHB', 'Gene', (83, 87))	('histidine', 'Chemical', 'MESH:D006639', (70, 79))	('replacement', 'Var', (24, 35))	('causes', 'Reg', (13, 19))	('SDHB', 'Gene', '6390', (83, 87))
29627	31856921	Due to the presence of a germline SDHB gene mutation, a second malignancy was suspected; therefore, accurate histology examination was also pursued for the neck lymph nodes resected during surgery.	('mutation', 'Var', (44, 52))	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('malignancy', 'Disease', (63, 73))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))
29633	31856921	A carotid PGL in a SDHB gene mutation carrier is rarely the first manifestation, since SDHB-related PGLs are usually found in extra-adrenal abdominal sites.	('mutation', 'Var', (29, 37))	('SDHB', 'Gene', '6390', (19, 23))	('SDHB', 'Gene', (19, 23))	('PGL', 'Phenotype', 'HP:0002668', (10, 13))	('PGL', 'Phenotype', 'HP:0002668', (100, 103))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))
29645	31856921	Among the reported malignancies associated with SDHx mutations, the presence of a malignant B cell lymphoma has been reported only in one Japanese patient bearing a G106D alteration in exon 4 of the SDHD gene, who developed the disease 5 years after PGL surgery.	('G106D alteration in', 'Var', (165, 184))	('SDH', 'Gene', '6390', (199, 202))	('G106D', 'Mutation', 'p.G106D', (165, 170))	('malignancies', 'Disease', (19, 31))	('SDH', 'Gene', '6390', (48, 51))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (92, 107))	('patient', 'Species', '9606', (147, 154))	('malignant B cell lymphoma', 'Disease', (82, 107))	('SDH', 'Gene', (199, 202))	('SDHD', 'Gene', (199, 203))	('mutations', 'Var', (53, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('SDH', 'Gene', (48, 51))	('SDHD', 'Gene', '6392', (199, 203))	('malignant B cell lymphoma', 'Disease', 'MESH:D016393', (82, 107))	('malignancies', 'Disease', 'MESH:D009369', (19, 31))	('developed', 'Reg', (214, 223))	('PGL', 'Phenotype', 'HP:0002668', (250, 253))
29646	31856921	In addition, genetic derangements in the SDHD gene have been found in other cases: a silent single nucleotide polymorphism was identified in three Burkitt's lymphoma cell lines and in one Burkitt's lymphoma sample.	('lymphoma', 'Phenotype', 'HP:0002665', (198, 206))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (147, 165))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (188, 206))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (147, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (157, 165))	('SDHD', 'Gene', '6392', (41, 45))	("Burkitt's lymphoma", 'Disease', (188, 206))	("Burkitt's lymphoma", 'Disease', (147, 165))	('SDHD', 'Gene', (41, 45))	('single nucleotide polymorphism', 'Var', (92, 122))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (188, 206))
29651	31856921	To date, studies reporting a predisposition to lymphoid malignancies in patients with SDHx mutations are still lacking; also, SDHx genes are not routinely evaluated in individuals with non-endocrine cancers.	('SDH', 'Gene', '6390', (126, 129))	('SDH', 'Gene', '6390', (86, 89))	('non-endocrine cancers', 'Disease', (185, 206))	('SDH', 'Gene', (126, 129))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (47, 68))	('lymphoid malignancies', 'Disease', (47, 68))	('SDH', 'Gene', (86, 89))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (47, 68))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('non-endocrine cancers', 'Disease', 'MESH:D004701', (185, 206))	('patients', 'Species', '9606', (72, 80))
29687	31574816	Genetic investigation was negative for RET proto-oncogene, Von Hippel-Lindau, succinate dehydrogenase B, succinate dehydrogenase C, and succinate dehydrogenase D mutations.	('RET', 'Gene', (39, 42))	('mutations', 'Var', (162, 171))	('succinate', 'Chemical', 'MESH:D013386', (78, 87))	('succinate', 'Chemical', 'MESH:D013386', (105, 114))	('succinate', 'Chemical', 'MESH:D013386', (136, 145))	('RET', 'Gene', '5979', (39, 42))	('Von Hippel-Lindau', 'Disease', 'MESH:D006623', (59, 76))	('Von Hippel-Lindau', 'Disease', (59, 76))
16577	31574816	The improved survival benefited from reducing the tumor burden, decompressing the spinal stenosis to alleviate radiculopathy, and facilitating subsequent chemotherapy and radiation therapy.	('radiculopathy', 'Disease', 'MESH:D011843', (111, 124))	('radiculopathy', 'Disease', (111, 124))	('spinal stenosis', 'Disease', (82, 97))	('spinal stenosis', 'Disease', 'MESH:D013130', (82, 97))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('spinal stenosis', 'Phenotype', 'HP:0003416', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('decompressing', 'Var', (64, 77))	('tumor', 'Disease', (50, 55))
29726	30291194	Efficacy and Safety of High-Specific-Activity 131I-MIBG Therapy in Patients with Advanced Pheochromocytoma or Paraganglioma Patients with metastatic or unresectable (advanced) pheochromocytoma and paraganglioma (PPGL) have poor prognoses and few treatment options.	('131I-MIBG', 'Var', (46, 55))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (176, 192))	('paraganglioma', 'Phenotype', 'HP:0002668', (197, 210))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (90, 106))	('Advanced Pheochromocytoma or Paraganglioma', 'Disease', (81, 123))	('Patients', 'Species', '9606', (67, 75))	('Paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('131I-MIBG', 'Chemical', '-', (46, 55))	('Advanced Pheochromocytoma or Paraganglioma', 'Disease', 'MESH:D010673', (81, 123))	('Patients', 'Species', '9606', (124, 132))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (176, 210))	('men', 'Species', '9606', (251, 254))
29742	30291194	Shorter survival has been correlated with synchronous metastases, large primary tumor size, dependence on primary tumor location, germline mutations of the succinate dehydrogenase subunit B gene, and unresectable primary tumor.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('germline mutations', 'Var', (130, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (114, 119))	('synchronous metastases', 'Disease', 'MESH:D009362', (42, 64))	('Shorter', 'NegReg', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('synchronous metastases', 'Disease', (42, 64))
29785	30291194	A reduction in antihypertensive medication was considered if the patient's systolic and diastolic BP values were less than 140 mm Hg and less than 90 mm Hg, respectively, as measured with a manual mercury sphygmomanometer.	('less', 'NegReg', (113, 117))	('less', 'Var', (137, 141))	('reduction', 'NegReg', (2, 11))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (15, 42))	('systolic', 'MPA', (75, 83))	('diastolic BP values', 'MPA', (88, 107))	('hypertensive', 'Disease', 'MESH:D006973', (19, 31))	('patient', 'Species', '9606', (65, 72))	('hypertensive', 'Disease', (19, 31))
29850	30291194	Our findings show that HSA 131I-MIBG conferred sustained control of catecholamine-associated hypertension in 25% of patients and had persistent antitumor effects in 22% of patients with advanced PPGL.	('hypertension', 'Phenotype', 'HP:0000822', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('control', 'MPA', (57, 64))	('catecholamine', 'Chemical', 'MESH:D002395', (68, 81))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', (148, 153))	('HSA 131I-MIBG', 'Chemical', '-', (23, 36))	('hypertension', 'Disease', 'MESH:D006973', (93, 105))	('HSA 131I-MIBG', 'Var', (23, 36))	('patients', 'Species', '9606', (172, 180))	('hypertension', 'Disease', (93, 105))
29870	30291194	Furthermore, among patients who received at least 1 therapeutic dose, the proportion of those who had PRs increased from 6% at 3 mo to 23% at 12 mo, indicating that HSA 131I-MIBG has persistent antitumor effects.	('patients', 'Species', '9606', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('PRs', 'Chemical', '-', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('HSA 131I-MIBG', 'Chemical', '-', (165, 178))	('HSA 131I-MIBG', 'Var', (165, 178))
29874	30291194	In addition, effects observed with HSA 131I-MIBG during the long-term follow-up phase, including myelodysplastic syndrome and secondary malignancies such as acute myeloid leukemia and acute lymphocytic leukemia, are also known to occur after cytotoxic therapies, including high-dose conventional 131I-MIBG and peptide receptor radionuclide therapy.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (163, 179))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (157, 179))	('131I-MIBG', 'Var', (39, 48))	('131I-MIBG', 'Chemical', '-', (296, 305))	('HSA 131I-MIBG', 'Chemical', '-', (35, 48))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (97, 121))	('acute myeloid leukemia', 'Disease', (157, 179))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (184, 210))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('acute lymphocytic leukemia', 'Disease', (184, 210))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (157, 179))	('myelodysplastic syndrome', 'Disease', (97, 121))	('secondary malignancies', 'Disease', 'MESH:D009369', (126, 148))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (97, 121))	('131I-MIBG', 'Chemical', '-', (39, 48))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (184, 210))	('secondary malignancies', 'Disease', (126, 148))
29883	30291194	The findings of the present study demonstrate that HSA 131I-MIBG can provide a clinical benefit to patients with advanced PPGL, as evidenced by improved BP control and by durable tumor and biochemical tumor marker responses.	('improved', 'PosReg', (144, 152))	('PPGL', 'Disease', (122, 126))	('HSA 131I-MIBG', 'Chemical', '-', (51, 64))	('HSA 131I-MIBG', 'Var', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('patients', 'Species', '9606', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (201, 206))	('BP control', 'MPA', (153, 163))	('tumor', 'Disease', (179, 184))
29888	30291194	Furthermore, HSA 131I-MIBG was associated with BP improvement and an acceptable safety profile.	('HSA 131I-MIBG', 'Chemical', '-', (13, 26))	('men', 'Species', '9606', (57, 60))	('HSA 131I-MIBG', 'Var', (13, 26))	('improvement', 'PosReg', (50, 61))
29899	28685506	As nearly half of all pheochromocytoma patients harbor a mutation in one of the 14 tumor susceptibility genes, genetic testing and counseling should at least be considered in all patients with a proven tumor.	('mutation', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (83, 88))	('pheochromocytoma', 'Disease', (22, 38))	('pheochromocytoma', 'Disease', 'MESH:D010673', (22, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
29912	28685506	PPGLs in childhood have a preponderance of extra-adrenal and multifocal tumors and carry an increased prevalence of mutations in one of the PPGL susceptibility genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('extra-adrenal', 'Disease', (43, 56))	('PPGLs', 'Chemical', '-', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('PPGL', 'Chemical', '-', (140, 144))	('PPGL', 'Gene', (140, 144))	('PPGL', 'Chemical', '-', (0, 4))	('multifocal tumors', 'Disease', (61, 78))	('multifocal tumors', 'Disease', 'None', (61, 78))
29919	28685506	The overall prevalence of metastatic disease among patients with PPGLs is 10% to 15%, but may amount to 30% to 40% in the presence of specific risk factors: young age, genetic background in particular succinate dehydrogenase B (SDHB) mutations, large tumor size, dopaminergic phenotype, multifocal tumors, and extra-adrenal location.	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', (298, 303))	('metastatic disease', 'Disease', (26, 44))	('SDHB', 'Gene', '6390', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('SDHB', 'Gene', (228, 232))	('PPGLs', 'Chemical', '-', (65, 70))	('succinate dehydrogenase B', 'Gene', '6390', (201, 226))	('succinate dehydrogenase B', 'Gene', (201, 226))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('dopamine', 'Chemical', 'MESH:D004298', (263, 271))	('multifocal tumors', 'Disease', (287, 304))	('mutations', 'Var', (234, 243))	('multifocal tumors', 'Disease', 'None', (287, 304))
29927	28685506	Exceptions are rare patients with biochemically silent tumors who carry an SDHB mutation.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SDHB', 'Gene', '6390', (75, 79))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('patients', 'Species', '9606', (20, 28))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumors', 'Disease', (55, 61))	('SDHB', 'Gene', (75, 79))	('mutation', 'Var', (80, 88))
29973	28685506	The sensitivity of 123I-MIBG SPECT for detection of adrenal pheochromocytoma is excellent (nearly 100%), but is unacceptably low for extra-adrenal paragangliomas (56% to 75%) and metastases, particularly when associated with underlying succinate dehydrogenase (SDHx) mutations (<50%).	('to 7', 'Species', '1214577', (167, 171))	('extra-adrenal paragangliomas', 'Disease', (133, 161))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('paragangliomas', 'Phenotype', 'HP:0002668', (147, 161))	('mutations', 'Var', (267, 276))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (52, 76))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (52, 76))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (133, 161))	('metastases', 'Disease', (179, 189))	('SDHx', 'Gene', (261, 265))	('SDHx', 'Chemical', '-', (261, 265))	('123I-MIBG', 'Chemical', 'MESH:D019797', (19, 28))	('adrenal pheochromocytoma', 'Disease', (52, 76))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
29982	28685506	About 40% of all patients with a PPGL have a germline mutation in one of the 12 susceptibility genes and in 11% to 13% of all apparent sporadic cases a germline mutation can be detected.	('PPGL', 'Disease', (33, 37))	('germline mutation', 'Var', (45, 62))	('patients', 'Species', '9606', (17, 25))	('PPGL', 'Chemical', '-', (33, 37))
29986	28685506	The genes most frequently mutated are SDHB and VHL while MAX, TMEM127, MDH2, SDHAF2, and FH are least frequently mutated.	('MAX', 'Gene', (57, 60))	('TMEM127', 'Gene', '55654', (62, 69))	('MDH2', 'Gene', '4191', (71, 75))	('MAX', 'Gene', '4149', (57, 60))	('VHL', 'Gene', (47, 50))	('mutated', 'Var', (26, 33))	('FH', 'Gene', '2271', (89, 91))	('SDHAF2', 'Gene', '54949', (77, 83))	('SDHB', 'Gene', '6390', (38, 42))	('VHL', 'Gene', '7428', (47, 50))	('SDHAF2', 'Gene', (77, 83))	('SDHB', 'Gene', (38, 42))	('MDH2', 'Gene', (71, 75))	('TMEM127', 'Gene', (62, 69))
29987	28685506	Mutations of SDHB gene are associated with an increased risk of development of metastatic disease (40% to 60%) and mutation testing for this gene is particularly indicated in patients with extra-adrenal tumors (paragangliomas), particularly when large tumors or when producing 3-methoxytyramine.	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (277, 294))	('SDHB', 'Gene', '6390', (13, 17))	('adrenal tumor', 'Phenotype', 'HP:0100631', (195, 208))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('paragangliomas', 'Disease', (211, 225))	('extra-adrenal tumors', 'Disease', (189, 209))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('SDHB', 'Gene', (13, 17))	('paraganglioma', 'Phenotype', 'HP:0002668', (211, 224))	('indicated', 'Reg', (162, 171))	('tumors', 'Disease', (252, 258))	('extra-adrenal tumors', 'Disease', 'MESH:D010236', (189, 209))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('paragangliomas', 'Disease', 'MESH:D010235', (211, 225))	('paragangliomas', 'Phenotype', 'HP:0002668', (211, 225))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('metastatic disease', 'CPA', (79, 97))	('patients', 'Species', '9606', (175, 183))
29989	28685506	Cluster 1 tumors develop in patients with germline or somatic mutations in VHL, SDHB, SDHD, SDHC, SDHAF2, SDHAF2, hypoxia inducible factor 2alpha (HIF2alpha), prolyl hydroxylase 2 (PHD2), MDH2, FH genes and involve activation of hypoxia-angiogenic pathways.	('MDH2', 'Gene', (188, 192))	('hypoxia inducible factor 2alpha', 'Gene', '2034', (114, 145))	('tumors', 'Disease', (10, 16))	('PHD2', 'Gene', (181, 185))	('hypoxia', 'Disease', 'MESH:D000860', (114, 121))	('SDHC', 'Gene', (92, 96))	('SDHAF2', 'Gene', '54949', (106, 112))	('SDHAF2', 'Gene', '54949', (98, 104))	('SDHAF2', 'Gene', (106, 112))	('SDHAF2', 'Gene', (98, 104))	('VHL', 'Gene', (75, 78))	('SDHB', 'Gene', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('prolyl hydroxylase 2', 'Gene', (159, 179))	('PHD2', 'Gene', '54583', (181, 185))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (62, 71))	('SDHD', 'Gene', '6392', (86, 90))	('HIF2alpha', 'Gene', (147, 156))	('MDH2', 'Gene', '4191', (188, 192))	('hypoxia', 'Disease', (229, 236))	('activation', 'PosReg', (215, 225))	('VHL', 'Gene', '7428', (75, 78))	('FH', 'Gene', '2271', (194, 196))	('hypoxia inducible factor 2alpha', 'Gene', (114, 145))	('prolyl hydroxylase 2', 'Gene', '54583', (159, 179))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('SDHC', 'Gene', '6391', (92, 96))	('hypoxia', 'Disease', 'MESH:D000860', (229, 236))	('SDHD', 'Gene', (86, 90))	('HIF2alpha', 'Gene', '2034', (147, 156))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('hypoxia', 'Disease', (114, 121))	('SDHB', 'Gene', '6390', (80, 84))
29990	28685506	Cluster 2 tumors develop in patients with mutations in RET, NF1, TMEM127, and MAX and involve RAS and kinase signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('RET', 'Gene', '5979', (55, 58))	('develop', 'Reg', (17, 24))	('NF1', 'Gene', '4763', (60, 63))	('tumors', 'Disease', (10, 16))	('kinase signaling pathways', 'Pathway', (102, 127))	('NF1', 'Gene', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('RET', 'Gene', (55, 58))	('involve', 'Reg', (86, 93))	('TMEM127', 'Gene', '55654', (65, 72))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (42, 51))	('TMEM127', 'Gene', (65, 72))
29991	28685506	Cluster 1 tumors are usually noradrenergic while cluster 2 tumors have an adrenergic phenotype except those with a MAX mutation, which are mixed adrenergic/noradrenergic.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutation', 'Var', (119, 127))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('noradrenergic', 'MPA', (29, 42))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', (59, 65))	('MAX', 'Gene', '4149', (115, 118))	('adrenergic', 'MPA', (74, 84))	('MAX', 'Gene', (115, 118))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
29992	28685506	Tumors with SDHB and SDHD mutation may also produce additional 3-methoxytyramine.	('mutation', 'Var', (26, 34))	('SDHB', 'Gene', '6390', (12, 16))	('SDHB', 'Gene', (12, 16))	('3-methoxytyramine', 'MPA', (63, 80))	('SDHD', 'Gene', '6392', (21, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (63, 80))	('SDHD', 'Gene', (21, 25))
29994	28685506	Genetic testing should at least be considered in all patients and is strongly indicated in specific patients such as those with a positive family history of PPGLs or carriers of tumor susceptibility gene mutations, and those with syndromic features or metastatic disease.	('tumor', 'Disease', (178, 183))	('patients', 'Species', '9606', (53, 61))	('syndromic features', 'Disease', (230, 248))	('mutations', 'Var', (204, 213))	('PPGLs', 'Chemical', '-', (157, 162))	('PPGLs', 'Gene', (157, 162))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('syndromic features', 'Disease', 'MESH:D000013', (230, 248))
29996	28685506	Identification of a gene mutation in these patients might result in earlier detection of PPGLs and other neoplasms; thereby, reducing morbidity and improving survival.	('improving', 'PosReg', (148, 157))	('earlier', 'PosReg', (68, 75))	('patients', 'Species', '9606', (43, 51))	('mutation', 'Var', (25, 33))	('PPGLs', 'Chemical', '-', (89, 94))	('neoplasms', 'Phenotype', 'HP:0002664', (105, 114))	('reducing', 'NegReg', (125, 133))	('neoplasms', 'Disease', (105, 114))	('detection', 'MPA', (76, 85))	('morbidity', 'MPA', (134, 143))	('PPGLs', 'Disease', (89, 94))	('neoplasms', 'Disease', 'MESH:D009369', (105, 114))	('survival', 'MPA', (158, 166))
29998	28685506	A typical example are the patients with SDHB mutations who carry a high risk for developing metastatic PPGLs.	('SDHB', 'Gene', '6390', (40, 44))	('mutations', 'Var', (45, 54))	('SDHB', 'Gene', (40, 44))	('patients', 'Species', '9606', (26, 34))	('PPGLs', 'Chemical', '-', (103, 108))
30016	28685506	The underlying pathogenetic mutations in these syndromes drive however a certain risk of tumor recurrence in the remnant tissue after adrenal sparing surgery of 0% to 21%.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
30024	28685506	In patients at high-risk for recurrent disease such as the young ones, those who with a germline mutation, and those with an extra-adrenal or large tumor, follow-up should be continued lifelong.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('germline mutation', 'Var', (88, 105))	('tumor', 'Disease', (148, 153))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
30031	27831464	We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.	('presence', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('heterochromatin', 'Protein', (30, 45))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNAs', 'Disease', (114, 118))	('cancer', 'Disease', (137, 143))
30033	27831464	There are several different types of DNA alterations and one that is frequently seen in cancer cells is known as a "copy number alteration" (or CNA for short).	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('alterations', 'Var', (41, 52))
30037	27831464	Analysing datasets from almost 6000 patients with 20 different types of cancer showed that mutations in several genes are linked to a higher or lower number of CNAs in patients.	('patients', 'Species', '9606', (36, 44))	('lower', 'NegReg', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (91, 100))	('CNAs', 'Disease', (160, 164))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
30045	27831464	It has also been observed that DNA contact points in genome-wide chromosome conformation capture (HiC) proximity maps are more likely to become CNA breakpoints.	('HiC', 'Gene', '29969', (98, 101))	('DNA contact points', 'Var', (31, 49))	('HiC', 'Gene', (98, 101))
30046	27831464	The observation that certain genes tend to be mutated in CNA-rich (TP53 and SPOP) or CNA-poor (CTCF and ARID1A) cancers implies that, besides epigenetic factors, the genetic background of the cell influences CNA variation.	('SPOP', 'Gene', '8405', (76, 80))	('CTCF', 'Gene', '10664', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('mutated', 'Var', (46, 53))	('CNA-rich', 'Disease', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('SPOP', 'Gene', (76, 80))	('ARID1A', 'Gene', '8289', (104, 110))	('cancers', 'Disease', (112, 119))	('ARID1A', 'Gene', (104, 110))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('influences', 'Reg', (197, 207))	('CTCF', 'Gene', (95, 99))
30048	27831464	We identify mutations in genes that are statistically linked to the number of CNAs in cancer patients.	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CNAs', 'Disease', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('linked', 'Reg', (54, 60))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', (86, 92))
30059	27831464	Mutations in 62 of these genes are associated with significantly fewer CNAs, whereas one gene (TP53) is associated with a significantly higher number of CNAs (see Supplementary file 1 for the full gene list and Figure 2A for two examples).	('CNAs', 'Disease', (71, 75))	('Mutations', 'Var', (0, 9))	('fewer', 'NegReg', (65, 70))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
30062	27831464	We contemplated whether mutations in the remaining 48 genes contribute to the progression of the cancer or are just a by-product of the increased mutation rates found in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (170, 176))	('contribute', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
30063	27831464	Accordingly, we used functional impact scores to estimate the pathogenicity of the mutations found in CONIM genes that had not been previously implicated in cancer progression.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('CONIM genes', 'Gene', (102, 113))	('cancer', 'Disease', (157, 163))
30064	27831464	To estimate the temporal order of somatic events, we compared the variant allele fractions (VAFs) of mutations in non-cancer CONIM genes to the VAFs of mutations from equally often mutated genes.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('non-cancer', 'Disease', (114, 124))	('mutations', 'Var', (101, 110))	('non-cancer', 'Disease', 'MESH:D009369', (114, 124))
30065	27831464	We found that in two out of five cancer types tested, mutations in CONIM genes were associated with a lower VAF (Figure 2:figure supplement 1).	('lower', 'NegReg', (102, 107))	('cancer', 'Disease', (33, 39))	('CONIM genes', 'Gene', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (54, 63))	('VAF', 'CPA', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
30066	27831464	To investigate the potential mechanisms through which mutations in genes encoding CONIM proteins affect the amount of CNAs in a tumor, we explored the functions of the CONIM gene set.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('affect', 'Reg', (97, 103))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CONIM', 'Gene', (82, 87))	('tumor', 'Disease', (128, 133))	('amount of CNAs in a', 'MPA', (108, 127))
30075	27831464	The overlap between the mutated genes found in samples with a differential CNA length and those found in samples with a differential CNA number was larger than expected by chance (p < e-16; chi-square test).	('e-16', 'Gene', (184, 188))	('e-16', 'Gene', '26766', (184, 188))	('differential', 'Var', (62, 74))
30077	27831464	Mutations in components of the SWI/SNF complex have been observed in different tumor types, but their contribution to carcinogenesis is only poorly understood.	('carcinogenesis', 'Disease', (118, 132))	('tumor', 'Disease', (79, 84))	('SWI/SNF', 'Gene', (31, 38))	('observed', 'Reg', (57, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
30080	27831464	Instead, we explicitly tested whether epigenetic marks around breakpoints are enriched in those tissues where the breakpoint frequently occurs during cancer development versus those tissues where the breakpoint does not occur.	('tested', 'Reg', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('epigenetic marks', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
30084	27831464	We found that non-silent mutations in these genes affect a greater proportion of samples in cancer types (luad, lusc, lihc and skcm) that show a strong H3K9me3 enrichment (> 2-fold change in 10 kb windows around breakpoints; p < 0.05; Mann-Whitney-Wilcoxon test) in their tissue-of-origin (p < e-6; chi-square test).	('mutations', 'Var', (25, 34))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('affect', 'Reg', (50, 56))	('H3K9me3', 'Protein', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('non-silent mutations', 'Var', (14, 34))
30090	27831464	Mutations in NIPBL have been associated with chromatin decompaction and, indeed, mutations that are predicted to have a more severe effect on NIPBL exhibit a stronger effect on chromatin.	('NIPBL', 'Gene', '25836', (13, 18))	('NIPBL', 'Gene', (13, 18))	('NIPBL', 'Gene', '25836', (142, 147))	('stronger effect', 'PosReg', (158, 173))	('NIPBL', 'Gene', (142, 147))	('Mutations', 'Var', (0, 9))	('chromatin decompaction', 'MPA', (45, 67))	('mutations', 'Var', (81, 90))	('associated', 'Reg', (29, 39))	('chromatin', 'MPA', (177, 186))
30091	27831464	We therefore tested whether mutations in the HEAT domain, which is necessary to target NIPBL to sites of DNA damage, have a stronger effect on CNA number in cancers than do other missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CNA number', 'MPA', (143, 153))	('NIPBL', 'Gene', '25836', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('NIPBL', 'Gene', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('effect', 'Reg', (133, 139))	('mutations', 'Var', (28, 37))
30092	27831464	We also checked whether cancers with truncating mutations in the N-terminus of NIPBL are associated with a significantly lower CNA number as compared to those with truncating mutations in the C-terminus (Figure 5B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NIPBL', 'Gene', '25836', (79, 84))	('CNA number', 'CPA', (127, 137))	('NIPBL', 'Gene', (79, 84))	('lower', 'NegReg', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('truncating mutations in', 'Var', (37, 60))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
30093	27831464	In both cases, we observed a significant difference, with mutations that have an anticipated stronger functional or structural impact on NIPBL being associated with fewer CNAs.	('mutations', 'Var', (58, 67))	('CNAs', 'Disease', (171, 175))	('NIPBL', 'Gene', '25836', (137, 142))	('NIPBL', 'Gene', (137, 142))	('fewer', 'NegReg', (165, 170))
30103	27831464	One explanation for this observation could be that mutations in CONIM genes tend to occur late during cancer development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (51, 60))	('CONIM genes', 'Gene', (64, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
30107	27831464	Inactivation of TP53 decreases sensitivity to apoptosis, and therefore more DNA damage (including CNAs) is tolerated.	('decreases', 'NegReg', (21, 30))	('sensitivity to apoptosis', 'MPA', (31, 55))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
30109	27831464	The CNA-rich group has been associated with recurrent mutations in TP53 and the mutation-rich (and CNA-depleted) group with mutations in ARID1A and CTCF.	('ARID1A', 'Gene', '8289', (137, 143))	('mutations', 'Var', (124, 133))	('ARID1A', 'Gene', (137, 143))	('associated', 'Reg', (28, 38))	('mutations', 'Var', (54, 63))	('CTCF', 'Gene', (148, 152))	('TP53', 'Gene', '7157', (67, 71))	('CTCF', 'Gene', '10664', (148, 152))	('TP53', 'Gene', (67, 71))
30116	27831464	ATM is required for the repair of DNA double-strand breaks in heterochromatic regions, a process which is characterised by slow repair kinetics.	('ATM', 'Gene', (0, 3))	('DNA double-strand breaks', 'Var', (34, 58))	('ATM', 'Gene', '472', (0, 3))
30117	27831464	ATM-mediated phosphorylation of KAP1 (KRAB-associated protein 1) triggers local decondensation of heterochromatin and thereby facilitates efficient repair.	('facilitates', 'PosReg', (126, 137))	('KAP1', 'Gene', (32, 36))	('heterochromatin', 'Protein', (98, 113))	('KRAB-associated protein 1', 'Gene', (38, 63))	('repair', 'MPA', (148, 154))	('local decondensation', 'MPA', (74, 94))	('KAP1', 'Gene', '10155', (32, 36))	('phosphorylation', 'Var', (13, 28))	('ATM', 'Gene', (0, 3))	('KRAB-associated protein 1', 'Gene', '10155', (38, 63))	('ATM', 'Gene', '472', (0, 3))
30120	27831464	These factors are governed by the properties of the tissue-of-origin (which contribute to the variability in the number, length and distribution of CNAs over cancer types) and could be influenced by abnormal activity of epigenetic modifiers through mutation or differential expression (contributing to the variation on the patient-level).	('influenced by', 'Reg', (185, 198))	('mutation', 'Var', (249, 257))	('differential expression', 'Var', (261, 284))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('patient', 'Species', '9606', (323, 330))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
30122	27831464	In accordance with previous studies, we show that TP53 deficiency is strongly associated with high CNA numbers.	('associated', 'Reg', (78, 88))	('TP53', 'Gene', '7157', (50, 54))	('high CNA numbers', 'CPA', (94, 110))	('deficiency', 'Var', (55, 65))	('TP53', 'Gene', (50, 54))
30123	27831464	In summary, our observations suggest that the epigenome impacts CNA occurrence in a tissue- and patient-specific manner.	('epigenome', 'Var', (46, 55))	('CNA', 'Disease', (64, 67))	('patient', 'Species', '9606', (96, 103))	('impacts', 'Reg', (56, 63))
30139	27831464	We computed VAFs as the read count supporting mutation divided by the total read count for each mutation in ucec, hnsc, luad, brca and skcm, as these cancer types had at least 100 mutations in non-cancer CONIM genes (considering genes with at least 15 non-silent mutations), read count information and cancer gene classification available.	('brca', 'Gene', '672', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (180, 189))	('brca', 'Gene', (126, 130))	('non-cancer', 'Disease', 'MESH:D009369', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', (197, 203))	('non-cancer', 'Disease', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
30179	27831464	Since ovarian cancer has frequent TP53 mutations, the question was raised as to whether TP53-mutatant cancers exhibit the same relations between heterochromatin and CNA burden.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (6, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (6, 20))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', '7157', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TP53', 'Gene', (88, 92))	('ovarian cancer', 'Disease', (6, 20))	('TP53', 'Gene', '7157', (34, 38))
30182	27831464	"The manuscript is improved but the primary result-that 62 genes are associated with decreased CNA rates and only one (TP53) was associated with increased rates-raises the concern that a confounder continues to drive much of the association between mutation rates in specific genes and lack of CNAs.	('mutation', 'Var', (249, 257))	('CNA rates', 'CPA', (95, 104))	('decreased', 'NegReg', (85, 94))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
30194	27831464	We see that in the previous version of the manuscript 1) the motivation was not very well explained, 2) presenting the two pipelines at different positions of the manuscript was confusing and 3) combining the single cancer p-values with the Fisher Method also suppresses cancer type-specific effects.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('suppresses', 'NegReg', (260, 270))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (216, 222))	('p-values', 'Var', (223, 231))	('cancer', 'Disease', (271, 277))
30204	27831464	We agree with the reviewers that ovarian cancer may not show the same behavior like other cancer types due to frequent TP53 mutations and we include a corresponding paragraph in the Discussion section.	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (124, 133))	('ovarian cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('TP53', 'Gene', '7157', (119, 123))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', (119, 123))
30209	27831464	This suggests that even though we have a variation in dependence of the specific algorithmic details or the underlying data, we observe a robust functional enrichment towards epigenetic modifiers and a higher number of genes associated with lower CNA number (with exception of the cancer type-specific pipeline where the second effect is less pronounced).	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('CNA', 'MPA', (247, 250))	('cancer', 'Disease', (281, 287))	('lower', 'NegReg', (241, 246))	('epigenetic', 'Var', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
30213	27831464	We again observed elevated mutation frequencies in cancer types that correspond to H3K9me3-enriched tissues.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('elevated', 'PosReg', (18, 26))
30214	27831464	Also, we do not filter genes that do not give a signal in single cancer types or those that are also associated with silent mutations.	('cancer', 'Disease', (65, 71))	('silent mutations', 'Var', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
30271	22346222	NF1 infact is caused by a mutation of the NF1 gene, that has been mapped on chromosome 17.	('mutation', 'Var', (26, 34))	('NF1', 'Gene', (0, 3))	('caused by', 'Reg', (14, 23))	('NF1', 'Gene', '4763', (42, 45))	('NF1', 'Gene', '4763', (0, 3))	('NF1', 'Gene', (42, 45))
30276	22346222	These criteria are satisfied when a patient presents two or more of the following features, in the absence of another diagnosis: Six or more cafe-au-lait spots >5mm in the greatest diameter in the prepubertals, and >15 mm in the postpubertals; Two or more neurofibromas of any type or one plexiform neurofibroma; Freckling in the axillary or the inguinal regions; Optic glioma; Two or more Lisch nodules; A typical osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis; or A first degree relative affected by NF1 as defined above.	('neurofibroma', 'Disease', (299, 311))	('glioma', 'Disease', 'MESH:D005910', (370, 376))	('Optic glioma', 'Phenotype', 'HP:0009734', (364, 376))	('osseous lesion', 'Disease', (415, 429))	('NF1', 'Gene', (522, 525))	('Freckling', 'Disease', (313, 322))	('tibial pseudarthrosis', 'Disease', 'MESH:D011542', (460, 481))	('sphenoid dysplasia', 'Disease', 'MESH:D015524', (438, 456))	('glioma', 'Phenotype', 'HP:0009733', (370, 376))	('cafe-au-lait spots', 'Phenotype', 'HP:0000957', (141, 159))	('neurofibroma', 'Disease', 'MESH:D009455', (256, 268))	('>15 mm', 'Var', (215, 221))	('tibial pseudarthrosis', 'Disease', (460, 481))	('Freckling', 'Phenotype', 'HP:0001480', (313, 322))	('neurofibromas', 'Disease', (256, 269))	('>5mm', 'Var', (160, 164))	('neurofibroma', 'Disease', 'MESH:D009455', (299, 311))	('Lisch nodules', 'Phenotype', 'HP:0009737', (390, 403))	('neurofibroma', 'Disease', (256, 268))	('patient', 'Species', '9606', (36, 43))	('sphenoid dysplasia', 'Disease', (438, 456))	('plexiform neurofibroma', 'Phenotype', 'HP:0009732', (289, 311))	('neurofibromas', 'Phenotype', 'HP:0001067', (256, 269))	('osseous lesion', 'Disease', 'MESH:D010001', (415, 429))	('glioma', 'Disease', (370, 376))	('neurofibromas', 'Disease', 'MESH:D009455', (256, 269))	('NF1', 'Gene', '4763', (522, 525))
30295	21139908	Genetic analysis revealed a germline heterozygous missense mutation (Pro81Leu) in the succinate dehydrogenase subunit D (SDHD) gene.	('SDHD', 'Gene', (121, 125))	('revealed', 'Reg', (17, 25))	('succinate dehydrogenase subunit D', 'Gene', '6392', (86, 119))	('Pro81Leu', 'Var', (69, 77))	('Pro81Leu', 'Mutation', 'rs80338844', (69, 77))	('succinate dehydrogenase subunit D', 'Gene', (86, 119))	('SDHD', 'Gene', '6392', (121, 125))
30296	21139908	We discuss the clinical presentations of the familial paraganglioma syndrome type 1, which is caused by mutations in SDHD, and the implications for the clinical diagnosis and care of such patients.	('caused by', 'Reg', (94, 103))	('mutations', 'Var', (104, 113))	('familial paraganglioma syndrome type 1', 'Disease', 'MESH:D010235', (45, 83))	('patients', 'Species', '9606', (188, 196))	('SDHD', 'Gene', (117, 121))	('familial paraganglioma syndrome type 1', 'Disease', (45, 83))	('paraganglioma', 'Phenotype', 'HP:0002668', (54, 67))	('SDHD', 'Gene', '6392', (117, 121))
30311	21139908	Up to a third of paragangliomas and pheochromoctyomas are associated with hereditary causes; i.e., mutations in VHL, RET (causing multiple endocrine neoplasia type 2A-MEN2A), NF1, and the SDH complex genes SDHB, -C and -D. The SDH complex is bound to the inner mitochondrial membrane and participates in both the electron-transport chain and the Krebs cycle as part of complex II.	('Krebs', 'Chemical', '-', (346, 351))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (139, 158))	('paraganglioma', 'Phenotype', 'HP:0002668', (17, 30))	('paragangliomas', 'Phenotype', 'HP:0002668', (17, 31))	('SDH', 'Gene', (227, 230))	('VHL', 'Gene', '7428', (112, 115))	('NF1', 'Gene', (175, 178))	('SDHB', 'Gene', (206, 210))	('SDH', 'Gene', '6390', (206, 209))	('neoplasia', 'Disease', 'MESH:D009369', (149, 158))	('SDH', 'Gene', '6390', (188, 191))	('neoplasia', 'Disease', (149, 158))	('RET', 'Gene', '5979', (117, 120))	('participates', 'Reg', (288, 300))	('SDH', 'Gene', (206, 209))	('MEN2A', 'Gene', (167, 172))	('MEN2A', 'Gene', '5979', (167, 172))	('associated', 'Reg', (58, 68))	('SDH', 'Gene', (188, 191))	('SDH', 'Gene', '6390', (227, 230))	('VHL', 'Gene', (112, 115))	('neoplasia', 'Phenotype', 'HP:0002664', (149, 158))	('mutations', 'Var', (99, 108))	('SDHB', 'Gene', '6390', (206, 210))	('NF1', 'Gene', '4763', (175, 178))	('RET', 'Gene', (117, 120))	('paragangliomas and pheochromoctyomas', 'Disease', 'MESH:D010235', (17, 53))
30312	21139908	It consists of four subunits A-D. Mutations in subunits B, C, and D are associated with hereditary pheochromocytomas and paragangliomas: the PGL1 syndrome with mutations in SDHD, PGL3 with mutations in SDHC, and PGL4 with mutations in SDHB.	('mutations', 'Var', (160, 169))	('associated', 'Reg', (72, 82))	('PGL3', 'Gene', '6391', (179, 183))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (99, 116))	('Mutations', 'Var', (34, 43))	('SDHB', 'Gene', '6390', (235, 239))	('PGL1 syndrome', 'Disease', (141, 154))	('SDHC', 'Gene', (202, 206))	('PGL4', 'Gene', '6390', (212, 216))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (99, 115))	('PGL4', 'Gene', (212, 216))	('mutations', 'Var', (222, 231))	('mutations', 'Var', (189, 198))	('SDHD', 'Gene', '6392', (173, 177))	('SDHB', 'Gene', (235, 239))	('hereditary pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (88, 135))	('SDHC', 'Gene', '6391', (202, 206))	('SDHD', 'Gene', (173, 177))	('paragangliomas', 'Phenotype', 'HP:0002668', (121, 135))	('paraganglioma', 'Phenotype', 'HP:0002668', (121, 134))	('PGL3', 'Gene', (179, 183))	('PGL1 syndrome', 'Disease', 'MESH:D010235', (141, 154))
30316	21139908	Activation of HIF pathways with SDH subunit inactivation has been linked to accumulation of succinate and resulting inhibition of the prolyl hydroxylase enzymes that are necessary for HIF-alpha subunit modification and proteosomal degradation, as pVHL is unable to bind the unmodified sub-units.	('HIF pathways', 'Pathway', (14, 26))	('succinate', 'MPA', (92, 101))	('succinate', 'Chemical', 'MESH:D019802', (92, 101))	('SDH', 'Gene', '6390', (32, 35))	('inhibition', 'NegReg', (116, 126))	('prolyl hydroxylase enzymes', 'Enzyme', (134, 160))	('accumulation', 'PosReg', (76, 88))	('Activation', 'PosReg', (0, 10))	('pVHL', 'Gene', '7428', (247, 251))	('SDH', 'Gene', (32, 35))	('inactivation', 'Var', (44, 56))	('pVHL', 'Gene', (247, 251))
30317	21139908	In addition, animal models of SDH inactivation suggest that reactive oxygen species may be increased and also might provoke a pseudohypoxic state.	('reactive oxygen species', 'MPA', (60, 83))	('SDH', 'Gene', (30, 33))	('inactivation', 'Var', (34, 46))	('pseudohypoxic state', 'MPA', (126, 145))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (60, 83))	('provoke', 'Reg', (116, 123))	('increased', 'PosReg', (91, 100))	('SDH', 'Gene', '6390', (30, 33))
30318	21139908	Therefore SDHB/D mutations may predispose to a failure of normal developmental apoptosis of sympathetic neuronal cells leading to persistence of "pheochromocytoma precursor cells".	('developmental apoptosis', 'CPA', (65, 88))	('pheochromocytoma', 'Disease', 'MESH:D010673', (146, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (146, 162))	('SDHB', 'Gene', '6390', (10, 14))	('SDHB', 'Gene', (10, 14))	('mutations', 'Var', (17, 26))	('pheochromocytoma', 'Disease', (146, 162))
30326	21139908	Depending on the clinical presentation, mutation analysis of VHL, SDHB, SDHC, SDHD, and/or RET genes may be indicated.	('RET', 'Gene', (91, 94))	('SDHB', 'Gene', (66, 70))	('mutation analysis', 'Var', (40, 57))	('SDHD', 'Gene', (78, 82))	('SDHD', 'Gene', '6392', (78, 82))	('VHL', 'Gene', (61, 64))	('RET', 'Gene', '5979', (91, 94))	('SDHC', 'Gene', (72, 76))	('SDHB', 'Gene', '6390', (66, 70))	('VHL', 'Gene', '7428', (61, 64))	('SDHC', 'Gene', '6391', (72, 76))
30330	21139908	However, he will require genetic screening when he is older, because if he is a carrier of the SDHD mutation, then his children may be at risk.	('mutation', 'Var', (100, 108))	('children', 'Species', '9606', (119, 127))	('SDHD', 'Gene', (95, 99))	('SDHD', 'Gene', '6392', (95, 99))
30340	20059341	Hereditary Leiomyomatosis Renal Cell Carcinoma, a hereditary form of type 2 papillary renal carcinoma, is caused by inactivation of the Krebs cycle enzyme, fumarate hydratase (fumarase, FH).	('Carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (76, 101))	('Krebs', 'Chemical', '-', (136, 141))	('fumarate hydratase', 'Gene', (156, 174))	('inactivation', 'Var', (116, 128))	('type 2 papillary renal carcinoma', 'Phenotype', 'HP:0006732', (69, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('Hereditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', (0, 46))	('papillary renal carcinoma', 'Disease', (76, 101))	('caused by', 'Reg', (106, 115))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (26, 46))	('fumarase', 'Gene', '2271', (176, 184))	('Hereditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (0, 46))	('fumarate hydratase', 'Gene', '2271', (156, 174))	('fumarase', 'Gene', (176, 184))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (76, 101))
30362	20059341	The VHL gene was identified on the short arm of chromosome 3 and mutation of this gene was found in the germline of individuals affected with von Hippel Lindau.	('von Hippel Lindau', 'Disease', 'MESH:D006623', (142, 159))	('VHL', 'Disease', (4, 7))	('VHL', 'Disease', 'MESH:D006623', (4, 7))	('found', 'Reg', (91, 96))	('mutation', 'Var', (65, 73))	('short arm', 'Phenotype', 'HP:0009824', (35, 44))	('von Hippel Lindau', 'Disease', (142, 159))
30363	20059341	With improved detection methods mutation of the VHL gene is now found in nearly 100% of VHL families.	('VHL', 'Disease', (48, 51))	('VHL', 'Disease', 'MESH:D006623', (48, 51))	('found', 'Reg', (64, 69))	('mutation', 'Var', (32, 40))	('VHL', 'Disease', (88, 91))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
30364	20059341	When tumor tissue from patients with kidney cancer was tested for alteration of the VHL gene, mutations were detected in a high percentage of patients with clear cell kidney cancer.	('VHL', 'Disease', (84, 87))	('kidney cancer', 'Disease', (37, 50))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (156, 180))	('kidney cancer', 'Disease', 'MESH:D007680', (167, 180))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('kidney cancer', 'Phenotype', 'HP:0009726', (167, 180))	('VHL', 'Disease', 'MESH:D006623', (84, 87))	('mutations', 'Var', (94, 103))	('clear cell kidney cancer', 'Disease', (156, 180))	('kidney cancer', 'Disease', 'MESH:D007680', (37, 50))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (156, 180))	('detected', 'Reg', (109, 117))	('tumor', 'Disease', (5, 10))	('kidney cancer', 'Phenotype', 'HP:0009726', (37, 50))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
30366	20059341	detected mutation or methylation of the VHL gene in 91% of tumors from patients with clear cell kidney cancer.	('mutation', 'Var', (9, 17))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (85, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (85, 109))	('patients', 'Species', '9606', (71, 79))	('kidney cancer', 'Phenotype', 'HP:0009726', (96, 109))	('methylation', 'Var', (21, 32))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('clear cell kidney cancer', 'Disease', (85, 109))	('VHL', 'Disease', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('VHL', 'Disease', 'MESH:D006623', (40, 43))
30372	20059341	When there is mutation of the VHL gene in clear cell kidney cancer, either in the alpha domain that binds elongin C/B and Cul2, or in the beta domain that targets HIF for degradation, HIF is not degraded and over-accumulates.	('VHL', 'Disease', 'MESH:D006623', (30, 33))	('clear cell kidney cancer', 'Disease', (42, 66))	('binds', 'Interaction', (100, 105))	('clear cell kidney cancer', 'Disease', 'MESH:D008649', (42, 66))	('clear cell kidney cancer', 'Phenotype', 'HP:0006770', (42, 66))	('Cul2', 'Gene', (122, 126))	('elongin C/B', 'Gene', (106, 117))	('mutation', 'Var', (14, 22))	('elongin C/B', 'Gene', '6921;6923', (106, 117))	('kidney cancer', 'Phenotype', 'HP:0009726', (53, 66))	('Cul2', 'Gene', '8453', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('VHL', 'Disease', (30, 33))
30375	20059341	In this three arm randomized trial, patients treated with high dose bevacizumab had a significantly increased progression free survival compared with those treated with placebo.	('increased', 'PosReg', (100, 109))	('patients', 'Species', '9606', (36, 44))	('bevacizumab', 'Chemical', 'MESH:D000068258', (68, 79))	('high dose', 'Var', (58, 67))	('progression free survival', 'CPA', (110, 135))
30428	20059341	Mutation of the VHL gene was found to up-regulate these transmembrane enzymes which are critical for the regulation of pH in the extracellular microenvironment.	('transmembrane enzymes', 'Enzyme', (56, 77))	('up-regulate', 'PosReg', (38, 49))	('Mutation', 'Var', (0, 8))	('VHL', 'Disease', (16, 19))	('VHL', 'Disease', 'MESH:D006623', (16, 19))
30434	20059341	This technique provides a potential molecular diagnostic to differentiate tumors with VHL gene mutations from other types of kidney cancer.	('kidney cancer', 'Disease', 'MESH:D007680', (125, 138))	('VHL', 'Disease', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('VHL', 'Disease', 'MESH:D006623', (86, 89))	('tumors', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('kidney cancer', 'Phenotype', 'HP:0009726', (125, 138))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (95, 104))	('kidney cancer', 'Disease', (125, 138))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
30440	20059341	Activity has been observed with this agent in papillary RCC, notably in tumors with MET mutations (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('RCC', 'Disease', (56, 59))	('RCC', 'Disease', 'MESH:C538614', (56, 59))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('Activity', 'MPA', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('MET mutations', 'Var', (84, 97))
30444	20059341	Germline BHD gene mutations have been found in over 90% of BHD kindreds.	('BHD', 'Gene', (59, 62))	('BHD', 'Gene', '50947', (9, 12))	('BHD', 'Gene', (9, 12))	('BHD', 'Gene', '50947', (59, 62))	('mutations', 'Var', (18, 27))
30456	20059341	Mutations of the fumarate hydratase gene are found in over 90% of HLRCC families.	('fumarate hydratase', 'Gene', '2271', (17, 35))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('Mutations', 'Var', (0, 9))	('fumarate hydratase', 'Gene', (17, 35))	('RCC', 'Disease', (68, 71))	('found', 'Reg', (45, 50))
30462	20059341	Familial paraganglioma/pheochromocytoma kindreds have been found to have germline mutations in the mitochondrial complex II genes, SDHB, SDHC, and SDHB.	('SDHB', 'Gene', '6390', (131, 135))	('Familial paraganglioma/pheochromocytoma', 'Disease', (0, 39))	('SDHB', 'Gene', (131, 135))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('mutations', 'Var', (82, 91))	('SDHB', 'Gene', '6390', (147, 151))	('SDHB', 'Gene', (147, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('SDHC', 'Gene', (137, 141))	('Familial paraganglioma/pheochromocytoma', 'Disease', 'MESH:C531777', (0, 39))
30463	20059341	Renal carcinoma, along with pheochromocytoma/paraganglioma, has been found to be a component of the familial pheochromocytoma/paraganglioma complex and a recent report described germline SDHB mutations in a family with renal cancer with no history of pheochromocytoma.	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (109, 139))	('pheochromocytoma', 'Disease', (109, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (109, 125))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (28, 58))	('pheochromocytoma', 'Disease', (251, 267))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutations', 'Var', (192, 201))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (251, 267))	('pheochromocytoma', 'Disease', 'MESH:D010673', (28, 44))	('SDHB', 'Gene', '6390', (187, 191))	('Renal carcinoma', 'Disease', 'MESH:C538614', (0, 15))	('renal cancer', 'Disease', (219, 231))	('paraganglioma', 'Phenotype', 'HP:0002668', (126, 139))	('renal cancer', 'Phenotype', 'HP:0009726', (219, 231))	('pheochromocytoma', 'Disease', (28, 44))	('Renal carcinoma', 'Disease', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (6, 15))	('Renal carcinoma', 'Phenotype', 'HP:0005584', (0, 15))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (28, 44))	('SDHB', 'Gene', (187, 191))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('renal cancer', 'Disease', 'MESH:D007680', (219, 231))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (100, 125))	('pheochromocytoma/paraganglioma', 'Disease', (109, 139))	('pheochromocytoma/paraganglioma', 'Disease', (28, 58))	('described', 'Reg', (168, 177))	('pheochromocytoma', 'Disease', 'MESH:D010673', (109, 125))	('familial pheochromocytoma', 'Disease', (100, 125))	('pheochromocytoma', 'Disease', 'MESH:D010673', (251, 267))
30464	20059341	The tuberous sclerosis complex is an autosomal dominant disorder associated with mutation of either the TSC1 or TSC2 gene.	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (37, 64))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (4, 22))	('mutation', 'Var', (81, 89))	('associated', 'Reg', (65, 75))	('TSC1', 'Gene', '7248', (104, 108))	('autosomal dominant disorder', 'Disease', (37, 64))	('TSC1', 'Gene', (104, 108))	('tuberous sclerosis', 'Disease', (4, 22))	('TSC2', 'Gene', '7249', (112, 116))	('TSC2', 'Gene', (112, 116))
30486	20059341	A clear cell renal carcinoma in a patient affected with VHL has a mutation of the VHL gene as well as loss of the second allele (i.e., biallelic inactivation of the VHL gene).	('clear cell renal carcinoma', 'Disease', (2, 28))	('VHL', 'Disease', (82, 85))	('VHL', 'Disease', 'MESH:D006623', (82, 85))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (2, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('biallelic inactivation', 'Var', (135, 157))	('VHL', 'Disease', 'MESH:D006623', (165, 168))	('VHL', 'Disease', (165, 168))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (2, 28))	('patient', 'Species', '9606', (34, 41))	('VHL', 'Disease', (56, 59))	('renal carcinoma', 'Phenotype', 'HP:0005584', (13, 28))	('mutation', 'Var', (66, 74))	('VHL', 'Disease', 'MESH:D006623', (56, 59))
30487	20059341	A sporadic clear cell renal tumor with a VHL mutation has loss of the second allele as well (i.e., biallelic inactivation of the VHL gene).	('renal tumor', 'Disease', (22, 33))	('VHL', 'Disease', (129, 132))	('VHL', 'Disease', 'MESH:D006623', (41, 44))	('VHL', 'Disease', (41, 44))	('clear cell renal tumor', 'Phenotype', 'HP:0006770', (11, 33))	('mutation', 'Var', (45, 53))	('renal tumor', 'Disease', 'MESH:D007674', (22, 33))	('renal tumor', 'Phenotype', 'HP:0009726', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('VHL', 'Disease', 'MESH:D006623', (129, 132))	('biallelic inactivation', 'Var', (99, 121))
30488	20059341	The histology of the VHL clear cell renal tumor and the histology of the sporadic clear cell renal tumor with a VHL gene mutation are identical.	('VHL', 'Disease', (112, 115))	('VHL', 'Disease', 'MESH:D006623', (112, 115))	('VHL', 'Disease', 'MESH:D006623', (21, 24))	('clear cell renal tumor', 'Phenotype', 'HP:0006770', (82, 104))	('VHL clear cell renal tumor', 'Disease', 'MESH:C538614', (21, 47))	('VHL', 'Disease', (21, 24))	('VHL clear cell renal tumor', 'Disease', (21, 47))	('renal tumor', 'Disease', 'MESH:D007674', (93, 104))	('renal tumor', 'Phenotype', 'HP:0009726', (93, 104))	('clear cell renal tumor', 'Phenotype', 'HP:0006770', (25, 47))	('mutation', 'Var', (121, 129))	('renal tumor', 'Phenotype', 'HP:0009726', (36, 47))	('renal tumor', 'Disease', 'MESH:D007674', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('renal tumor', 'Disease', (93, 104))
30505	20059341	Clear cell kidney cancer and kidney cancer associated with von Hippel-Lindau are caused by mutation of the VHL gene, which results in a disorder of oxygen sensing.	('kidney cancer', 'Disease', (29, 42))	('mutation', 'Var', (91, 99))	('kidney cancer', 'Disease', 'MESH:D007680', (11, 24))	('von Hippel-Lindau', 'Gene', (59, 76))	('kidney cancer', 'Phenotype', 'HP:0009726', (11, 24))	('Clear cell kidney cancer', 'Disease', 'MESH:D008649', (0, 24))	('kidney cancer', 'Disease', 'MESH:D007680', (29, 42))	('von Hippel-Lindau', 'Gene', '7428', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('results in', 'Reg', (123, 133))	('caused by', 'Reg', (81, 90))	('VHL', 'Disease', 'MESH:D006623', (107, 110))	('kidney cancer', 'Phenotype', 'HP:0009726', (29, 42))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('VHL', 'Disease', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('disorder of oxygen sensing', 'MPA', (136, 162))	('Clear cell kidney cancer', 'Disease', (0, 24))
30506	20059341	Hereditary papillary renal cell carcinoma and a subset of sporadic type 1 papillary kidney cancers are caused by mutation of the MET gene.	('MET', 'Gene', (129, 132))	('mutation', 'Var', (113, 121))	('papillary kidney cancers', 'Disease', 'MESH:D007681', (74, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (74, 97))	('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))	('kidney cancers', 'Phenotype', 'HP:0009726', (84, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('kidney cancer', 'Phenotype', 'HP:0009726', (84, 97))	('papillary kidney cancers', 'Disease', (74, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (21, 41))	('caused by', 'Reg', (103, 112))	('Hereditary papillary renal cell carcinoma', 'Disease', (0, 41))
30507	20059341	The hereditary form of chromophobe kidney cancer associated with Birt-Hogg-Dube is caused by mutation of the BHD gene, which is involved with the AMPK/mTOR pathway.	('Birt-Hogg-Dube', 'Gene', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('associated', 'Reg', (49, 59))	('kidney cancer', 'Phenotype', 'HP:0009726', (35, 48))	('Birt-Hogg-Dube', 'Gene', '50947', (65, 79))	('BHD', 'Gene', '50947', (109, 112))	('chromophobe kidney cancer', 'Disease', 'MESH:D007680', (23, 48))	('chromophobe kidney cancer', 'Disease', (23, 48))	('BHD', 'Gene', (109, 112))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('mutation', 'Var', (93, 101))	('caused by', 'Reg', (83, 92))
30508	20059341	The hereditary form of kidney cancer associated with Hereditary Leiomyomatosis Renal Cell Carcinoma is caused by mutation of the gene for the Krebs cycle enzyme, fumarate hydratase.	('kidney cancer', 'Disease', (23, 36))	('mutation', 'Var', (113, 121))	('Hereditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', (53, 99))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (79, 99))	('fumarate hydratase', 'Gene', '2271', (162, 180))	('Krebs', 'Chemical', '-', (142, 147))	('Hereditary Leiomyomatosis Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (53, 99))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('Carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('associated', 'Reg', (37, 47))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('fumarate hydratase', 'Gene', (162, 180))	('caused by', 'Reg', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
30509	20059341	The hereditary form of kidney cancer associated with familial pheochromocytoma/paraganglioma results from mutations of the gene for the Krebs cycle enzyme, succinate dehydrogenase B.	('kidney cancer', 'Disease', (23, 36))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (53, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('pheochromocytoma/paraganglioma', 'Disease', (62, 92))	('Krebs', 'Chemical', '-', (136, 141))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('familial pheochromocytoma', 'Disease', (53, 78))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (62, 92))	('succinate dehydrogenase B', 'Gene', '6390', (156, 181))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('results from', 'Reg', (93, 105))	('mutations', 'Var', (106, 115))	('associated', 'Reg', (37, 47))	('succinate dehydrogenase B', 'Gene', (156, 181))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
30510	20059341	The hereditary form of angiomyolipoma results from mutations of the TSC1 and TSC2 genes, which are involved in the AMPK/mTOR pathway.	('mutations', 'Var', (51, 60))	('TSC1', 'Gene', '7248', (68, 72))	('TSC1', 'Gene', (68, 72))	('results from', 'Reg', (38, 50))	('angiomyolipoma', 'Disease', 'MESH:D018207', (23, 37))	('TSC2', 'Gene', '7249', (77, 81))	('angiomyolipoma', 'Disease', (23, 37))	('mTOR', 'Gene', (120, 124))	('TSC2', 'Gene', (77, 81))	('mTOR', 'Gene', '2475', (120, 124))	('angiomyolipoma', 'Phenotype', 'HP:0006772', (23, 37))
30587	20205783	The importance of genetic testing for mutations in the SHDB, SDHC, and SHDD genes has recently been highlighted.	('SHDB', 'Gene', (55, 59))	('SDHC', 'Gene', (61, 65))	('SDHC', 'Gene', '6391', (61, 65))	('mutations', 'Var', (38, 47))	('SHDD', 'Gene', (71, 75))
30588	20205783	Mutations in the VHL and NF1 genes are also associated with inherited paragangliomas.	('associated', 'Reg', (44, 54))	('inherited paragangliomas', 'Disease', 'MESH:D010235', (60, 84))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', (17, 20))	('paragangliomas', 'Phenotype', 'HP:0002668', (70, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (70, 83))	('NF1', 'Gene', (25, 28))	('inherited paragangliomas', 'Disease', (60, 84))	('VHL', 'Gene', '7428', (17, 20))	('NF1', 'Gene', '4763', (25, 28))
30589	20205783	In particular, patients with SDHB mutations are at higher risk for developing malignant paragangliomas.	('patients', 'Species', '9606', (15, 23))	('SDHB', 'Gene', '6390', (29, 33))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (78, 102))	('SDHB', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))	('malignant paragangliomas', 'Disease', (78, 102))
30591	20205783	Though these particular patients did not undergo genetic testing, it is probable that gene mutations were the cause of multiple paragangliomas.	('cause', 'Reg', (110, 115))	('gene mutations', 'Var', (86, 100))	('multiple paragangliomas', 'Disease', 'MESH:D010235', (119, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (128, 141))	('patients', 'Species', '9606', (24, 32))	('paragangliomas', 'Phenotype', 'HP:0002668', (128, 142))	('multiple paragangliomas', 'Disease', (119, 142))
30704	31582983	Risk factors of malignancy include size >5 cm, extra-adrenal locations, SDH gene mutations, and local invasiveness.	('SDH', 'Gene', '10993', (72, 75))	('malignancy', 'Disease', 'MESH:D009369', (16, 26))	('SDH', 'Gene', (72, 75))	('mutations', 'Var', (81, 90))	('malignancy', 'Disease', (16, 26))
30795	31205467	Activation of effector molecules in pseudohypoxia signaling is triggered by genetic mutations involving the degradation of hypoxia-inducible factor 1/2alpha or Krebs cycle function, such as succinate dehydrogenase genes (SDHx), VHL, or EPAS1.	('SDHx', 'Chemical', '-', (221, 225))	('EPAS1', 'Gene', '2034', (236, 241))	('Krebs', 'Chemical', '-', (160, 165))	('degradation', 'MPA', (108, 119))	('EPAS1', 'Gene', (236, 241))	('pseudohypoxia', 'Disease', (36, 49))	('hypoxia-inducible factor 1/2alpha', 'Gene', '2034', (123, 156))	('hypoxia-inducible factor 1/2alpha', 'Gene', (123, 156))	('mutations', 'Var', (84, 93))	('Activation', 'PosReg', (0, 10))	('pseudohypoxia', 'Disease', 'None', (36, 49))	('VHL', 'Disease', (228, 231))	('VHL', 'Disease', 'MESH:D006623', (228, 231))	('SDHx', 'Gene', (221, 225))
30796	31205467	Hyperactive kinase signaling is induced by mutations involving genes associated with mitogen-activated protein kinase, such as tumor suppressor genes (NF1, TMEM127, MAX, and KIF1Bbeta), RET, or HRAS, which promoted growth independence of extracellular signals.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('RET', 'Gene', (186, 189))	('Hyperactive kinase signaling', 'MPA', (0, 28))	('tumor', 'Disease', (127, 132))	('TMEM127', 'Gene', (156, 163))	('HRAS', 'Gene', '3265', (194, 198))	('NF1', 'Gene', (151, 154))	('mutations', 'Var', (43, 52))	('TMEM127', 'Gene', '55654', (156, 163))	('RET', 'Gene', '5979', (186, 189))	('NF1', 'Gene', '4763', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('HRAS', 'Gene', (194, 198))	('induced', 'Reg', (32, 39))
30797	31205467	Additionally, upregulated WNT signaling has been recently reported in genetic alterations of MAML3 and CSDE1.	('CSDE1', 'Gene', (103, 108))	('CSDE1', 'Gene', '7812', (103, 108))	('MAML3', 'Gene', '55534', (93, 98))	('MAML3', 'Gene', (93, 98))	('upregulated', 'PosReg', (14, 25))	('WNT signaling', 'Pathway', (26, 39))	('genetic alterations', 'Var', (70, 89))
30806	31205467	Comprehensive analyses have implicated germline mutations involving SDHB, FH, MAX, and SLC25A11 in the origin and development of malignant PC/PG.	('SLC25A11', 'Gene', (87, 95))	('SLC25A11', 'Gene', '8402', (87, 95))	('PG', 'Phenotype', 'HP:0002668', (142, 144))	('SDHB', 'Gene', '6390', (68, 72))	('SDHB', 'Gene', (68, 72))	('FH', 'Disease', 'MESH:D006938', (74, 76))	('mutations', 'Var', (48, 57))	('PC', 'Phenotype', 'HP:0002666', (139, 141))
30807	31205467	It is generally recognized that PC/PG carrying germline mutations of SDHB show a higher rate of metastasis.	('SDHB', 'Gene', (69, 73))	('metastasis', 'CPA', (96, 106))	('germline mutations', 'Var', (47, 65))	('PC', 'Phenotype', 'HP:0002666', (32, 34))	('SDHB', 'Gene', '6390', (69, 73))	('PG', 'Phenotype', 'HP:0002668', (35, 37))
30808	31205467	The SDHB mutation in Krebs cycle impairs glucose metabolism, leading to inhibition of 2-oxoglutarate-dependent histone and DNA demethylase enzymes.	('mutation', 'Var', (9, 17))	('impairs glucose metabolism', 'Disease', (33, 59))	('Krebs', 'Chemical', '-', (21, 26))	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (86, 100))	('SDHB', 'Gene', '6390', (4, 8))	('SDHB', 'Gene', (4, 8))	('impairs glucose metabolism', 'Disease', 'MESH:D044882', (33, 59))	('inhibition', 'NegReg', (72, 82))	('DNA demethylase enzymes', 'Enzyme', (123, 146))
30809	31205467	The germline mutation of SDHB was significantly susceptible to malignancy in TCGA and COMETE cohort (p = 0.0049 and p < 0.001, respectively).	('malignancy', 'Disease', 'MESH:D009369', (63, 73))	('malignancy', 'Disease', (63, 73))	('SDHB', 'Gene', '6390', (25, 29))	('germline mutation', 'Var', (4, 21))	('SDHB', 'Gene', (25, 29))	('susceptible', 'Reg', (48, 59))
30810	31205467	Mutations involving SDHx or FH lead to DNA hypermethylation, explaining both the tumor-suppressive role of these genes and the phenotypic characteristics.	('DNA hypermethylation', 'MPA', (39, 59))	('FH', 'Disease', 'MESH:D006938', (28, 30))	('SDHx', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Mutations', 'Var', (0, 9))	('SDHx', 'Chemical', '-', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
30811	31205467	In particular, the malignancy of SDHB mutation is attributed to severe epigenetic silencing of genes involved in cell differentiation and epithelial-to-mesenchymal transition.	('malignancy', 'Disease', (19, 29))	('SDHB', 'Gene', '6390', (33, 37))	('SDHB', 'Gene', (33, 37))	('malignancy', 'Disease', 'MESH:D009369', (19, 29))	('mutation', 'Var', (38, 46))	('epigenetic silencing', 'Var', (71, 91))
30812	31205467	RDBP hypermethylation may alter transcriptional networks involving apoptosis, invasion, and maintenance of DNA integrity.	('apoptosis', 'CPA', (67, 76))	('invasion', 'CPA', (78, 86))	('alter', 'Reg', (26, 31))	('RDBP', 'Gene', '7936', (0, 4))	('hypermethylation', 'Var', (5, 21))	('transcriptional networks', 'MPA', (32, 56))	('RDBP', 'Gene', (0, 4))
30823	30444046	However, epigenetic changes, such as DNA methylation and histone modifications, play a pivotal role in the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('DNA methylation', 'Var', (37, 52))	('cancer', 'Disease', (137, 143))	('histone', 'MPA', (57, 64))	('play', 'Reg', (80, 84))
30825	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('inactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (16, 21))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
30826	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hypermethylation', 'Var', (11, 27))	('histone H3', 'Protein', (99, 109))	('H3K9me3', 'Protein', (181, 188))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
30841	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
30871	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('MDA-MB468', 'Var', (177, 186))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('HER2', 'Gene', '2064', (193, 197))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
30893	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('multiple cancer', 'Disease', (181, 196))	('reduced', 'NegReg', (82, 89))	('expression', 'MPA', (90, 100))	('altered', 'Var', (53, 60))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('upregulation', 'PosReg', (165, 177))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))
30927	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('aberrant splicing', 'Var', (3, 20))	('cancer', 'Disease', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))
30930	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
30931	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
30932	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
30937	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
30942	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
31000	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
31001	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
31003	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
31018	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
31019	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('ZNF', 'Gene', (188, 191))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
31030	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
31047	28973655	Literature review revealed evidence of an association, in addition to VHL disease, between germline mutations in SDHB, SDHC, SDHD, TMEM127, and MAX genes and RAPTAS [defined here as the co-occurrence of tumors from both classes (PC/PGL/HNPGL and renal tumors) in the same individual or in first-degree relatives].	('VHL disease', 'Disease', (70, 81))	('renal tumor', 'Phenotype', 'HP:0009726', (246, 257))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('SDHC', 'Gene', '6391', (119, 123))	('PC', 'Phenotype', 'HP:0002666', (229, 231))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('SDHD', 'Gene', '6392', (125, 129))	('tumors', 'Disease', (252, 258))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('renal tumors', 'Disease', (246, 258))	('PGL', 'Phenotype', 'HP:0002668', (232, 235))	('TMEM127', 'Chemical', '-', (131, 138))	('renal tumors', 'Disease', 'MESH:D007674', (246, 258))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('mutations', 'Var', (100, 109))	('SDHC', 'Gene', (119, 123))	('SDHD', 'Gene', (125, 129))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('TMEM127', 'Gene', (131, 138))	('association', 'Interaction', (42, 53))	('SDHB', 'Gene', (113, 117))	('VHL disease', 'Disease', 'MESH:D006623', (70, 81))	('renal tumors', 'Phenotype', 'HP:0009726', (246, 258))	('PGL', 'Phenotype', 'HP:0002668', (238, 241))	('HNPGL', 'Phenotype', 'HP:0002864', (236, 241))
31048	28973655	In both the literature review and our case series of 22 probands with non-VHL RAPTAS, SDHB mutations were the most frequent cause of non-VHL RAPTAS.	('VHL', 'Gene', (74, 77))	(', SDHB', 'Gene', '6390', (84, 90))	('VHL', 'Gene', (137, 140))	('VHL', 'Gene', '7428', (74, 77))	('frequent cause', 'Reg', (115, 129))	('mutations', 'Var', (91, 100))	('VHL', 'Gene', '7428', (137, 140))
31050	28973655	We report a case of MAX-associated renal cell carcinoma and confirm the role of TMEM127 mutations with renal cell carcinoma predisposition.	('renal cell carcinoma', 'Disease', (103, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (35, 55))	('TMEM127', 'Chemical', '-', (80, 87))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('TMEM127', 'Gene', (80, 87))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (35, 55))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (103, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('mutations', 'Var', (88, 97))	('renal cell carcinoma', 'Disease', (35, 55))
31087	28973655	All cases were tested for germline mutations in VHL, and SDHB and 8/12 (67%) of probands from group A and 6/10 (60%) of probands from cohort B were also tested for mutations in SDHA, SDHC, SDHD, SDHAF2, FH, MAX, and TMEM127.	('FH', 'Disease', 'MESH:D006938', (203, 205))	('SDHB', 'Gene', (57, 61))	('SDHA', 'Chemical', '-', (177, 181))	('SDHC', 'Gene', '6391', (183, 187))	('VHL', 'Gene', (48, 51))	('SDHA', 'Gene', (177, 181))	('VHL', 'Gene', '7428', (48, 51))	('tested', 'Reg', (15, 21))	('MAX', 'Gene', (207, 210))	('SDHD', 'Gene', '6392', (189, 193))	('SDHC', 'Gene', (183, 187))	('SDHD', 'Gene', (189, 193))	('mutations', 'Var', (164, 173))	('SDHAF2', 'Gene', (195, 201))	('SDHA', 'Chemical', '-', (195, 199))	('tested', 'Reg', (153, 159))	('TMEM127', 'Chemical', '-', (216, 223))	('TMEM127', 'Gene', (216, 223))	('mutations', 'Var', (35, 44))
31088	28973655	One proband was diagnosed with a variant in SDHD (c.34G>A, p.Gly12Ser) that was not considered pathogenic and did not prompt family screening.	('SDHD', 'Gene', (44, 48))	('SDHD', 'Gene', '6392', (44, 48))	('c.34G>A', 'Var', (50, 57))	('c.34G>A', 'Mutation', 'rs34677591', (50, 57))	('p.Gly12Ser', 'Mutation', 'rs34677591', (59, 69))
31089	28973655	One proband presenting with RCC and unilateral PC age 43 years had a truncating mutation in the MAX gene (Table 1).	('RCC', 'Disease', 'MESH:C538614', (28, 31))	('MAX', 'Gene', (96, 99))	('PC', 'Phenotype', 'HP:0002666', (47, 49))	('truncating mutation', 'Var', (69, 88))	('RCC', 'Disease', (28, 31))	('RCC', 'Phenotype', 'HP:0005584', (28, 31))
31090	28973655	Another proband from group A was found to have a truncating mutation in TMEM127 (Table 1).	('truncating mutation', 'Var', (49, 68))	('TMEM127', 'Gene', (72, 79))	('TMEM127', 'Chemical', '-', (72, 79))
31091	28973655	No statistically significant correlation was identified for younger age at first tumor diagnosis, PGL, renal oncocytoma or malignant PGL, and the identification of a genetic mutation (P > 0.05 for all associations).	('renal oncocytoma', 'Phenotype', 'HP:0011798', (103, 119))	('renal oncocytoma', 'Disease', (103, 119))	('PGL', 'Phenotype', 'HP:0002668', (133, 136))	('PGL', 'Phenotype', 'HP:0002668', (98, 101))	('genetic mutation', 'Var', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PGL', 'Disease', (98, 101))	('malignant PGL', 'Disease', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('renal oncocytoma', 'Disease', 'MESH:C537750', (103, 119))	('tumor', 'Disease', (81, 86))
31092	28973655	The mean MTS value in group A patients with a mutation was 3.6 compared with 1.8 in those without a mutation (P = 0.09).	('patients', 'Species', '9606', (30, 38))	('MTS', 'MPA', (9, 12))	('mutation', 'Var', (46, 54))
31094	28973655	Analysis of DNA extracted from the PC and RCC tumors from case 10 with the germline mutation in the MAX gene (c.97C>T p. Arg33*) revealed loss of heterozygosity , with higher reads in the mutant allele identified in the PC [reads wild-type/mutant: 77/151 (depth 228) and RCC (reads: 60/179, depth 239) compared with the germline (157/157, depth 314) [germline.v's.PC P = 0.0002; germline.v's.RCC P < 0.0001 (Fisher's exact test)].	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RCC tumors', 'Disease', 'MESH:C538614', (42, 52))	('reads', 'MPA', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('RCC', 'Phenotype', 'HP:0005584', (392, 395))	('RCC', 'Disease', (392, 395))	('Arg33', 'Chemical', '-', (121, 126))	('PC', 'Phenotype', 'HP:0002666', (364, 366))	('RCC', 'Disease', (271, 274))	('RCC', 'Phenotype', 'HP:0005584', (271, 274))	('PC', 'Phenotype', 'HP:0002666', (220, 222))	('RCC', 'Disease', (42, 45))	('RCC', 'Phenotype', 'HP:0005584', (42, 45))	('RCC', 'Disease', 'MESH:C538614', (392, 395))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('PC', 'Phenotype', 'HP:0002666', (35, 37))	('mutant', 'Var', (188, 194))	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('higher', 'PosReg', (168, 174))	('c.97C>T', 'Mutation', 'rs1295386976', (110, 117))	('RCC tumors', 'Disease', (42, 52))
31097	28973655	No somatic mutation in SDHA/SDHB/SDHC/SDHD was identified in either tumor, but a somatic variant (not present in the germline) in VHL (c.245G>T p Arg82Leu) was identified in the PC tumor but not the RCC from case 2.	('Arg82Leu', 'SUBSTITUTION', 'None', (146, 154))	('PC tumor', 'Disease', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (68, 73))	('SDHC', 'Gene', '6391', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SDHA', 'Chemical', '-', (23, 27))	('SDHD', 'Gene', '6392', (38, 42))	('VHL', 'Gene', (130, 133))	('PC', 'Phenotype', 'HP:0002666', (178, 180))	('SDHD', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RCC', 'Disease', (199, 202))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('SDHC', 'Gene', (33, 37))	('tumor', 'Disease', (181, 186))	('PC tumor', 'Disease', 'MESH:D015324', (178, 186))	('Arg82Leu', 'Var', (146, 154))	('c.245G>T', 'Mutation', 'rs890210469', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('VHL', 'Gene', '7428', (130, 133))	('RCC', 'Disease', 'MESH:C538614', (199, 202))
31098	28973655	Germline mutations in at least 25 different genes have been reported to predispose to PC/PGL/HNPGL or RCC (NF1, RET, MAX, EGLN1, EGLN2, MSH2, KIFIB, SDHAF2,MEN1, BAP1, CDC73, CDKN2B, FLCN, MET, PBRM1, PTEN, TSC1, TSC2, FH, SDHA, SDHB, SDHC, SDHD, TMEM127, and VHL).	('PGL', 'Phenotype', 'HP:0002668', (95, 98))	('FH', 'Disease', 'MESH:D006938', (219, 221))	('MSH2', 'Gene', (136, 140))	('VHL', 'Gene', (260, 263))	('mutations', 'Var', (9, 18))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('CDKN2', 'Gene', '1017', (175, 180))	('SDHC', 'Gene', (235, 239))	('CDC73', 'Gene', '79577', (168, 173))	('PC', 'Phenotype', 'HP:0002666', (86, 88))	('SDHD', 'Gene', (241, 245))	('SDHA', 'Chemical', '-', (223, 227))	('TSC2', 'Gene', (213, 217))	('SDHA', 'Gene', (223, 227))	('PTEN', 'Gene', (201, 205))	('MSH2', 'Gene', '4436', (136, 140))	('SDHB', 'Gene', (229, 233))	('VHL', 'Gene', '7428', (260, 263))	('PC/PGL/HNPGL', 'Disease', (86, 98))	('predispose', 'Reg', (72, 82))	('BAP1', 'Gene', '8314', (162, 166))	('SDHA', 'Chemical', '-', (149, 153))	(', FLCN', 'Gene', '201163', (181, 187))	('SDHC', 'Gene', '6391', (235, 239))	('HNPGL', 'Phenotype', 'HP:0002864', (93, 98))	('PGL', 'Phenotype', 'HP:0002668', (89, 92))	('CDKN2', 'Gene', (175, 180))	('TMEM127', 'Chemical', '-', (247, 254))	('BAP1', 'Gene', (162, 166))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('SDHD', 'Gene', '6392', (241, 245))	('CDC73', 'Gene', (168, 173))
31099	28973655	However, with the exception of VHL disease and, to a lesser extent, SDHB mutations, other reported genetic causes of RAPTAS (as defined here) are rare.	('VHL disease', 'Disease', (31, 42))	('RAPTAS', 'Disease', (117, 123))	(', SDHB', 'Gene', '6390', (66, 72))	('VHL disease', 'Disease', 'MESH:D006623', (31, 42))	('mutations', 'Var', (73, 82))
31103	28973655	Metastatic RCC was reported in five patients with SDHB mutations, one patient with an SDHC mutation, and one patient with an SDHD mutation.	('patient', 'Species', '9606', (36, 43))	('patient', 'Species', '9606', (109, 116))	('patients', 'Species', '9606', (36, 44))	('mutations', 'Var', (55, 64))	('SDHB', 'Gene', (50, 54))	('patient', 'Species', '9606', (70, 77))	('SDHD', 'Gene', '6392', (125, 129))	('SDHC', 'Gene', (86, 90))	('reported', 'Reg', (19, 27))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('SDHC', 'Gene', '6391', (86, 90))	('RCC', 'Disease', (11, 14))	('SDHD', 'Gene', (125, 129))
31106	28973655	Renal oncocytoma was described as part of three cases of RAPTAS (two with an SDHB mutation and one with a MAX mutation) (Table 3).	('Renal oncocytoma', 'Disease', 'MESH:C537750', (0, 16))	('Renal oncocytoma', 'Disease', (0, 16))	('mutation', 'Var', (82, 90))	('Renal oncocytoma', 'Phenotype', 'HP:0011798', (0, 16))	('SDHB', 'Gene', (77, 81))	('RAPTAS', 'Disease', (57, 63))
31107	28973655	In addition to patients with RAPTAS, separate case reports of PC/PGL/HNPGL or renal tumors have been reported in association with the six genes described in Table 3, as well as with mutations in FH and SDHA (although no cases of coexisting PC/PGL and RCC in the same patient had been reported in conjunction with a mutation in FH/SDHA).	('patients', 'Species', '9606', (15, 23))	('renal tumors', 'Disease', 'MESH:D007674', (78, 90))	('PC', 'Phenotype', 'HP:0002666', (62, 64))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('RCC', 'Disease', 'MESH:C538614', (251, 254))	('renal tumors', 'Phenotype', 'HP:0009726', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PC/PGL/HNPGL', 'Disease', (62, 74))	('renal tumor', 'Phenotype', 'HP:0009726', (78, 89))	('mutations', 'Var', (182, 191))	('patient', 'Species', '9606', (15, 22))	('SDHA', 'Chemical', '-', (330, 334))	('PGL', 'Phenotype', 'HP:0002668', (243, 246))	('FH', 'Disease', 'MESH:D006938', (327, 329))	('SDHA', 'Chemical', '-', (202, 206))	('patient', 'Species', '9606', (267, 274))	('SDHA', 'Gene', (202, 206))	('HNPGL', 'Phenotype', 'HP:0002864', (69, 74))	('association', 'Reg', (113, 124))	('renal tumors', 'Disease', (78, 90))	('PGL', 'Phenotype', 'HP:0002668', (65, 68))	('RCC', 'Disease', (251, 254))	('RCC', 'Phenotype', 'HP:0005584', (251, 254))	('PC', 'Phenotype', 'HP:0002666', (240, 242))	('PGL', 'Phenotype', 'HP:0002668', (71, 74))	('FH', 'Disease', 'MESH:D006938', (195, 197))
31111	28973655	Also, germline mutations in MET cause familial type 1 papillary RCC and recently MET variants have been linked to PC/PGL susceptibility.	('linked', 'Reg', (104, 110))	('variants', 'Var', (85, 93))	('familial type 1 papillary RCC', 'Disease', 'MESH:C538614', (38, 67))	('germline mutations', 'Var', (6, 24))	('RCC', 'Phenotype', 'HP:0005584', (64, 67))	('MET', 'Gene', (28, 31))	('PGL', 'Phenotype', 'HP:0002668', (117, 120))	('familial type 1 papillary RCC', 'Disease', (38, 67))	('cause', 'Reg', (32, 37))	('PC', 'Phenotype', 'HP:0002666', (114, 116))
31112	28973655	In both the literature review and case series, SDHB mutations were the most common identified cause of non-VHL RAPTAS.	('mutations', 'Var', (52, 61))	('VHL', 'Gene', '7428', (107, 110))	(', SDHB', 'Gene', '6390', (45, 51))	('cause', 'Reg', (94, 99))	('VHL', 'Gene', (107, 110))
31113	28973655	Less frequently, RAPTAS was associated with mutations in other SDHx genes and mutations in TMEM127 and MAX.	('TMEM127', 'Chemical', '-', (91, 98))	('RAPTAS', 'Disease', (17, 23))	('associated', 'Reg', (28, 38))	('TMEM127', 'Gene', (91, 98))	('mutations', 'Var', (78, 87))	('SDHx genes', 'Gene', (63, 73))	('mutations', 'Var', (44, 53))	('SDHx', 'Chemical', '-', (63, 67))
31116	28973655	described a germline MAX mutation (a large, complex genomic alteration encompassing the intragenic and promoter regions of MAX and FUT8) in a patient with renal oncocytoma, bilateral PC, and erythrocytosis and two siblings with bilateral PC.	('MAX', 'Gene', (21, 24))	('PC', 'Phenotype', 'HP:0002666', (238, 240))	('mutation', 'Var', (25, 33))	('erythrocytosis', 'Phenotype', 'HP:0001901', (191, 205))	('renal oncocytoma', 'Disease', 'MESH:C537750', (155, 171))	('erythrocytosis', 'Disease', (191, 205))	('patient', 'Species', '9606', (142, 149))	('erythrocytosis', 'Disease', 'MESH:D011086', (191, 205))	('renal oncocytoma', 'Disease', (155, 171))	('PC', 'Phenotype', 'HP:0002666', (183, 185))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (155, 171))
31117	28973655	In this study, we report the association of RCC with a germline MAX mutation (c.97C>T p. Arg33*).	('c.97C>T p. Arg33*', 'Var', (78, 95))	('c.97C>T', 'Mutation', 'rs1295386976', (78, 85))	('Arg33', 'Chemical', '-', (89, 94))	('association', 'Reg', (29, 40))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))
31119	28973655	This finding expands the phenotype associated with MAX mutations and raises the intriguing possibility that MAX may be a candidate gene for inherited RCC [SDHB mutations were originally described in association with PC/PGL/HNPGL, then with RAPTAS, and then familial RCC-only phenotypes].	('HNPGL', 'Phenotype', 'HP:0002864', (223, 228))	('mutations', 'Var', (160, 169))	('SDHB', 'Gene', (155, 159))	('RCC', 'Disease', 'MESH:C538614', (266, 269))	('RCC', 'Disease', (266, 269))	('RCC', 'Disease', 'MESH:C538614', (150, 153))	('RCC', 'Disease', (150, 153))	('PGL', 'Phenotype', 'HP:0002668', (219, 222))	('RCC', 'Phenotype', 'HP:0005584', (150, 153))	('RCC', 'Phenotype', 'HP:0005584', (266, 269))	('PC/PGL/HNPGL', 'Disease', (216, 228))	('PC', 'Phenotype', 'HP:0002666', (216, 218))	('association', 'Reg', (199, 210))	('PGL', 'Phenotype', 'HP:0002668', (225, 228))
31120	28973655	Although mutations in all RAPTAS genes are inherited in autosomal dominant manner, mutations in MAX and SDHD show a parent-of-origin-dependent tumorigenesis, and tumors occur almost exclusively following paternal transmission of the mutation.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (143, 148))	('MAX', 'Gene', (96, 99))	('tumor', 'Disease', (162, 167))	('RAPTAS', 'Gene', (26, 32))	('SDHD', 'Gene', '6392', (104, 108))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('SDHD', 'Gene', (104, 108))	('parent-of-origin-dependent', 'CPA', (116, 142))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
31121	28973655	Hence the clinical management and genetic counseling of RAPTAS kindreds with SDHD and MAX mutations will differ from those with mutations in other RAPTAS genes.	('SDHD', 'Gene', (77, 81))	('MAX', 'Gene', (86, 89))	('SDHD', 'Gene', '6392', (77, 81))	('mutations', 'Var', (90, 99))
31122	28973655	We describe the second reported case of a patient with RAPTAS resulting from a mutation in TMEM127.	('TMEM127', 'Chemical', '-', (91, 98))	('resulting from', 'Reg', (62, 76))	('TMEM127', 'Gene', (91, 98))	('RAPTAS', 'Disease', (55, 61))	('patient', 'Species', '9606', (42, 49))	('mutation', 'Var', (79, 87))
31124	28973655	A germline deletion mutation in TMEM127 (c.308delG) and an additional germline variant in SDHB (159_*184delins25) was identified in this patient, but SDHB immunohistochemistry showed preservation of SDHB expression in both tumors.	('TMEM127', 'Chemical', '-', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('SDHB', 'Gene', (90, 94))	('patient', 'Species', '9606', (137, 144))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('c.308delG', 'Var', (41, 50))	('TMEM127', 'Gene', (32, 39))	('159_*184delins25', 'Mutation', 'c.159_*184delins25', (96, 112))	('c.308delG', 'Mutation', 'c.308delG', (41, 50))	('159_*184delins25', 'Var', (96, 112))	('expression', 'MPA', (204, 214))
31125	28973655	Histology of the RCC in RAPTAS patient 11 with a TMEM127 mutation demonstrated a clear-cell RCC.	('mutation', 'Var', (57, 65))	('TMEM127', 'Gene', (49, 56))	('RCC', 'Phenotype', 'HP:0005584', (17, 20))	('RCC', 'Disease', (92, 95))	('RCC', 'Phenotype', 'HP:0005584', (92, 95))	('patient', 'Species', '9606', (31, 38))	('TMEM127', 'Chemical', '-', (49, 56))	('RCC', 'Disease', 'MESH:C538614', (17, 20))	('RCC', 'Disease', (17, 20))	('RCC', 'Disease', 'MESH:C538614', (92, 95))
31127	28973655	Clear-cell RCC, PC (less often PGL and rarely HNPGL), and retinal and central nervous system hemangioblastomas (or the presence of pancreatic or renal cysts) should prompt genetic testing for VHL mutations.	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (78, 110))	('PC', 'Phenotype', 'HP:0002666', (16, 18))	('pancreatic or renal cysts', 'Disease', 'MESH:D010181', (131, 156))	('HNPGL', 'Phenotype', 'HP:0002864', (46, 51))	('renal cysts', 'Phenotype', 'HP:0000107', (145, 156))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (93, 109))	('VHL', 'Gene', (192, 195))	('pancreatic or renal cysts', 'Disease', (131, 156))	('PGL', 'Phenotype', 'HP:0002668', (31, 34))	('PGL', 'Phenotype', 'HP:0002668', (48, 51))	('retinal and central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (58, 110))	('RCC', 'Phenotype', 'HP:0005584', (11, 14))	('VHL', 'Gene', '7428', (192, 195))	('central nervous system hemangioblastoma', 'Phenotype', 'HP:0006880', (70, 109))	('RCC', 'Disease', 'MESH:C538614', (11, 14))	('RCC', 'Disease', (11, 14))	('mutations', 'Var', (196, 205))
31128	28973655	The occurrence of HNPGL, abdominal PGL, and malignant PPGL or the co-occurrence of wild-type gastrointestinal stromal tumors suggests a possible SDHx mutation.	('SDHx', 'Gene', (145, 149))	('HNPGL', 'Phenotype', 'HP:0002864', (18, 23))	('gastrointestinal stromal tumors', 'Disease', (93, 124))	('mutation', 'Var', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('abdominal PGL', 'Disease', (25, 38))	('PGL', 'Phenotype', 'HP:0002668', (20, 23))	('PGL', 'Phenotype', 'HP:0002668', (35, 38))	('PGL', 'Phenotype', 'HP:0002668', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('HNPGL', 'Disease', (18, 23))	('malignant PPGL', 'Disease', (44, 58))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (93, 124))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (93, 124))	('SDHx', 'Chemical', '-', (145, 149))
31135	28973655	For example, VHL mutations are almost invariably associated with clear-cell RCC, and a unique morphology consisting of solid architecture, distinctive intracytoplasmic inclusions, and intratumor mast cells is characteristic of SDHB-deficient RCC (Fig.	('tumor', 'Disease', (189, 194))	('RCC', 'Disease', 'MESH:C538614', (76, 79))	('RCC', 'Disease', (76, 79))	('RCC', 'Phenotype', 'HP:0005584', (76, 79))	('RCC', 'Disease', 'MESH:C538614', (242, 245))	('RCC', 'Disease', (242, 245))	('RCC', 'Phenotype', 'HP:0005584', (242, 245))	('associated', 'Reg', (49, 59))	('VHL', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('VHL', 'Gene', '7428', (13, 16))	('SDHB-deficient RCC', 'Disease', 'MESH:C538614', (227, 245))	('SDHB-deficient RCC', 'Disease', (227, 245))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutations', 'Var', (17, 26))
31139	28973655	Sequencing of both the PC and RCC tumors in case 2 revealed a somatic mutation in VHL (c.245G>T p Arg82Leu) in the PC but not the RCC, with no evidence of mutation in SDHA/SDHB/SDHC/SDHD genes.	('RCC', 'Disease', 'MESH:C538614', (30, 33))	('Arg82Leu', 'SUBSTITUTION', 'None', (98, 106))	('SDHA', 'Chemical', '-', (167, 171))	('SDHC', 'Gene', '6391', (177, 181))	('PC', 'Phenotype', 'HP:0002666', (23, 25))	('RCC', 'Disease', (130, 133))	('RCC', 'Phenotype', 'HP:0005584', (130, 133))	('SDHD', 'Gene', '6392', (182, 186))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('RCC tumors', 'Disease', (30, 40))	('VHL', 'Gene', (82, 85))	('RCC', 'Disease', 'MESH:C538614', (130, 133))	('SDHC', 'Gene', (177, 181))	('SDHD', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('RCC tumors', 'Disease', 'MESH:C538614', (30, 40))	('PC', 'Phenotype', 'HP:0002666', (115, 117))	('c.245G>T', 'Mutation', 'rs890210469', (87, 95))	('RCC', 'Disease', (30, 33))	('RCC', 'Phenotype', 'HP:0005584', (30, 33))	('VHL', 'Gene', '7428', (82, 85))	('Arg82Leu', 'Var', (98, 106))
31140	28973655	False-positive results using SDHB immunohistochemistry (as apparently occurred in this case) have been reported for patients with germline VHL mutations (Fig.	('VHL', 'Gene', (139, 142))	('patients', 'Species', '9606', (116, 124))	('VHL', 'Gene', '7428', (139, 142))	('SDHB', 'Gene', (29, 33))	('mutations', 'Var', (143, 152))
31141	28973655	A potential alternative explanation for the discrepant SDHB immunohistochemistry results in case 2 is that the first hit is an undetected germline VHL mutation (e.g., intronic mutation, copy number alteration) and that the somatic VHL missense mutation in the PCC was the "second hit."	('intronic mutation', 'Var', (167, 184))	('VHL', 'Gene', (231, 234))	('copy number alteration', 'Var', (186, 208))	('VHL', 'Gene', '7428', (231, 234))	('mutation', 'Var', (151, 159))	('PC', 'Phenotype', 'HP:0002666', (260, 262))	('VHL', 'Gene', (147, 150))	('missense mutation', 'Var', (235, 252))	('VHL', 'Gene', '7428', (147, 150))
31144	28973655	Nevertheless, it is important to consider that VHL mutations can lead to false-positive results on SDHB immunohistochemistry; therefore, we recommend that those patients with RAPTAS, without a detectable germline mutation in SDHx, but with loss of SDHB immunoexpression on tumor studies, undergo genetic screening for VHL mutations (Fig.	('SDHx', 'Chemical', '-', (225, 229))	('RAPTAS', 'Disease', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('mutations', 'Var', (322, 331))	('VHL', 'Gene', (318, 321))	('VHL', 'Gene', (47, 50))	('VHL', 'Gene', '7428', (318, 321))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('VHL', 'Gene', '7428', (47, 50))	('SDHx', 'Gene', (225, 229))
31147	28973655	SDHx and FH inactivation leads to the accumulation of oncometabolites such as succinate and fumarate that inhibit alpha ketoglutarate dependant dioxygenase enzymes, promoting stabilization of hypoxia inducible factor complex and inhibiting histone and DNA demethylation enzymes, resulting in DNA hypermethylation.	('fumarate', 'Chemical', 'MESH:D005650', (92, 100))	('inhibiting', 'NegReg', (229, 239))	('hypoxia', 'Disease', 'MESH:D000860', (192, 199))	('accumulation', 'PosReg', (38, 50))	('stabilization', 'MPA', (175, 188))	('hypoxia', 'Disease', (192, 199))	('succinate', 'Chemical', 'MESH:D019802', (78, 87))	('alpha ketoglutarate dependant dioxygenase enzymes', 'Enzyme', (114, 163))	('inhibit', 'NegReg', (106, 113))	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))	('DNA hypermethylation', 'MPA', (292, 312))	('inactivation', 'Var', (12, 24))	('FH', 'Disease', 'MESH:D006938', (9, 11))	('promoting', 'PosReg', (165, 174))
31148	28973655	Cluster two gene mutations (RET, NF1, TMEM127, MAX) activate the MAPK and phosphatidylinositol 3-kinase-AKT-mTOR pathways.	('activate', 'PosReg', (52, 60))	('TMEM127', 'Chemical', '-', (38, 45))	('RET', 'Gene', (28, 31))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (74, 94))	('mutations', 'Var', (17, 26))
31160	25371412	Genetic evidence of a precisely tuned dysregulation in the hypoxia signaling pathway during oncogenesis The classic model of tumor suppression implies that malignant transformation requires full 'two-hit' inactivation of a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor suppressor', 'Gene', '7248', (223, 239))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('dysregulation', 'Var', (38, 51))	('hypoxia', 'Disease', (59, 66))	('hypoxia', 'Disease', 'MESH:D000860', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor suppressor', 'Gene', (223, 239))
31162	25371412	Mutations in the tumor suppressor gene VHL are associated with a complex spectrum of conditions.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('VHL', 'Gene', (39, 42))	('tumor suppressor', 'Gene', (17, 33))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (47, 57))	('tumor suppressor', 'Gene', '7248', (17, 33))
31163	25371412	Homozygotes or compound heterozygotes for the R200W germline mutation in VHL have Chuvash polycythemia, whereas heterozygous carriers are free of disease.	('R200W', 'Mutation', 'rs28940298', (46, 51))	('VHL', 'Gene', (73, 76))	('polycythemia', 'Phenotype', 'HP:0001901', (90, 102))	('free of disease', 'Disease', 'MESH:D015673', (138, 153))	('Chuvash polycythemia', 'Disease', (82, 102))	('R200W', 'Var', (46, 51))	('Chuvash polycythemia', 'Disease', 'MESH:C563918', (82, 102))	('free of disease', 'Disease', (138, 153))
31164	25371412	Individuals with classic, heterozygous VHL mutations have von Hippel-Lindau disease and are at high risk of multiple tumors (e.g.	('von Hippel-Lindau disease', 'Disease', (58, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (58, 83))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('multiple tumors', 'Disease', 'MESH:D009369', (108, 123))	('VHL', 'Gene', (39, 42))	('multiple tumors', 'Disease', (108, 123))	('mutations', 'Var', (43, 52))
31166	25371412	We report here an atypical family bearing two VHL gene mutations in cis (R200W and R161Q), together with phenotypic analysis, structural modeling, functional and transcriptomic studies of these mutants in comparison to classical mutants involved in the different VHL phenotypes.	('R200W', 'Mutation', 'rs28940298', (73, 78))	('mutations', 'Var', (55, 64))	('R161Q', 'Mutation', 'rs730882035', (83, 88))	('VHL gene', 'Gene', (46, 54))	('R161Q', 'Var', (83, 88))
31168	25371412	Thus, by studying naturally occurring familial mutations, our work validates in humans the "continuum" model of tumor suppression.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('humans', 'Species', '9606', (80, 86))
31169	25371412	Over the past 30 years, the genetics of inherited cancer syndromes associated with germline mutations in tumor suppressor genes (TSG) have been dominated by Knudson's "two-hit" model.	('TSG', 'Gene', '57045', (129, 132))	('tumor suppressor', 'Gene', (105, 121))	('inherited cancer syndromes', 'Disease', 'MESH:D009386', (40, 66))	('inherited cancer syndromes', 'Disease', (40, 66))	('tumor suppressor', 'Gene', '7248', (105, 121))	('TSG', 'Gene', (129, 132))	('associated', 'Reg', (67, 77))	('germline mutations', 'Var', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
31171	25371412	The first genetic event is inherited and, in a second step, the loss of the wild type allele is acquired and induces further steps of oncogenesis, with somatic events and emergence of cancer.	('cancer', 'Disease', (184, 190))	('somatic events', 'CPA', (152, 166))	('oncogenesis', 'CPA', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('loss', 'Var', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('induces', 'Reg', (109, 116))
31175	25371412	One puzzling case of inherited cancer syndrome is the von Hippel-Lindau (VHL) disease associated with VHL mutations.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('associated', 'Reg', (86, 96))	('VHL', 'Gene', (102, 105))	('inherited cancer syndrome', 'Disease', (21, 46))	('mutations', 'Var', (106, 115))	('inherited cancer syndrome', 'Disease', 'MESH:D009386', (21, 46))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (54, 85))
31177	25371412	Depending on the mutation, patients are predisposed to multiple tumors, including renal cancers (that have lost the wild type allele), and/or pheochromocytomas (that do not always lose the second allele), and in cases with particular mutations, patients are free of cancer.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (88, 94))	('patients', 'Species', '9606', (245, 253))	('multiple tumors', 'Disease', 'MESH:D009369', (55, 70))	('pheochromocytomas', 'Disease', (142, 159))	('pheochromocytomas', 'Disease', 'MESH:D010673', (142, 159))	('predisposed', 'Reg', (40, 51))	('renal cancers', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('and/or', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('mutation', 'Var', (17, 25))	('patients', 'Species', '9606', (27, 35))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('renal cancer', 'Phenotype', 'HP:0009726', (82, 94))	('multiple tumors', 'Disease', (55, 70))	('renal cancers', 'Disease', 'MESH:D007680', (82, 95))	('mutations', 'Var', (234, 243))	('cancer', 'Disease', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
31184	25371412	Heterozygous mutations predispose to VHL disease, the leading cause of hereditary kidney cancer.	('hereditary kidney cancer', 'Disease', (71, 95))	('hereditary kidney cancer', 'Disease', 'MESH:D007680', (71, 95))	('VHL disease', 'Disease', 'MESH:D006623', (37, 48))	('kidney cancer', 'Phenotype', 'HP:0009726', (82, 95))	('Heterozygous mutations', 'Var', (0, 22))	('VHL disease', 'Disease', (37, 48))	('predispose', 'Reg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
31188	25371412	VHL Type-2 disease is associated with VHL missense mutations that lead to severe (Types-2A and 2B) or weaker (Type-2C) alterations in pVHL function.	('VHL Type-2 disease', 'Disease', 'MESH:D006623', (0, 18))	('alterations', 'MPA', (119, 130))	('missense mutations', 'Var', (42, 60))	('VHL', 'Gene', (38, 41))	('pVHL', 'Gene', '7428', (134, 138))	('VHL Type-2 disease', 'Disease', (0, 18))	('pVHL', 'Gene', (134, 138))
31189	25371412	In contrast, VHL Type-1 disease is associated with mutations that strongly impair the structure of pVHL or result in the complete absence of the protein (truncated proteins or total gene deletion).	('the protein', 'Protein', (141, 152))	('absence', 'NegReg', (130, 137))	('pVHL', 'Gene', (99, 103))	('mutations', 'Var', (51, 60))	('protein', 'Protein', (145, 152))	('structure', 'MPA', (86, 95))	('VHL Type-1 disease', 'Disease', (13, 31))	('VHL Type-1 disease', 'Disease', 'MESH:D006623', (13, 31))	('pVHL', 'Gene', '7428', (99, 103))	('impair', 'NegReg', (75, 81))
31190	25371412	The analysis of cases with gene deletions demonstrated that VHL-loss alone is sufficient to predispose to ccRCC development, and that the loss of a larger region (encompassing the HSPCC300 gene) would have a protective role.	('deletions', 'Var', (32, 41))	('HSPCC300', 'Gene', (180, 188))	('VHL-loss', 'Disease', 'MESH:D006623', (60, 68))	('ccRCC development', 'Disease', (106, 123))	('predispose', 'Reg', (92, 102))	('VHL-loss', 'Disease', (60, 68))	('R', 'Chemical', 'MESH:D001120', (108, 109))
31191	25371412	Whereas germline mutations in the VHL gene commonly predispose patients to the development of multiple tumors, a third category of phenotype has been described in Russian patients from the Chuvash region.	('germline mutations', 'Var', (8, 26))	('predispose', 'Reg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('multiple tumors', 'Disease', 'MESH:D009369', (94, 109))	('patients', 'Species', '9606', (171, 179))	('multiple tumors', 'Disease', (94, 109))	('VHL', 'Gene', (34, 37))	('patients', 'Species', '9606', (63, 71))	('R', 'Chemical', 'MESH:D001120', (163, 164))
31193	25371412	Survival in the Chuvash patients was found to be reduced compared to control groups due to higher rates of arterial and venous thromboses, and to haemorrhagic events.	('reduced', 'NegReg', (49, 56))	('Survival', 'CPA', (0, 8))	('venous thromboses', 'Disease', 'MESH:D020246', (120, 137))	('venous thromboses', 'Disease', (120, 137))	('venous thromboses', 'Phenotype', 'HP:0004936', (120, 137))	('patients', 'Species', '9606', (24, 32))	('Chuvash', 'Var', (16, 23))
31194	25371412	This specific VHL-R200W mutation has also been identified in combination with other VHL mutations (compound heterozygosity) (Supplementary Table S1) and, since then, other missenses VHL mutations have been described (always different from the VHL mutation involved in severe von Hippel-Lindau disease) (Table S2).	('von Hippel-Lindau disease', 'Disease', (275, 300))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (275, 300))	('VHL', 'Gene', (182, 185))	('missenses', 'Var', (172, 181))	('VHL-R200W', 'Gene', (14, 23))	('R200W', 'Mutation', 'rs28940298', (18, 23))
31198	25371412	The absence of tumor development in patients carrying the R200W mutation raised the possibility of the presence of a protective element within this core haplotype.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('patients', 'Species', '9606', (36, 44))	('R200W', 'Var', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('absence', 'NegReg', (4, 11))	('R200W', 'Mutation', 'rs28940298', (58, 63))
31200	25371412	In order to better understand the absence of tumors in the heterozygous carriers of the VHL-R200W mutation and to determine the cause of cancer development in this family (loss of a protective event or presence an additional event), we have carried out an in-depth study of family members and compared our findings to what is observed with classic VHL mutations.	('absence of tumors', 'Disease', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutation', 'Var', (98, 106))	('VHL-R200W', 'Gene', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('R200W', 'Mutation', 'rs28940298', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('absence of tumors', 'Disease', 'MESH:D004832', (34, 51))	('cancer', 'Disease', (137, 143))
31218	25371412	Gene expression was quantified using TaqMan quantitative RT-PCR (Life Technologies) on the 786.O clones expressing the different VHL mutants used in the microarray study and on two additional independent clones.	('mutants', 'Var', (133, 140))	('R', 'Chemical', 'MESH:D001120', (62, 63))	('VHL', 'Gene', (129, 132))	('R', 'Chemical', 'MESH:D001120', (57, 58))
31222	25371412	1A) was originally identified as a heterozygous carrier of a single c.598C>T, p.Arg200Trp (R200W) mutation in the VHL gene.	('p.Arg200Trp (R200W', 'Var', (78, 96))	('R200W', 'Mutation', 'rs28940298', (91, 96))	('p.Arg200Trp', 'Mutation', 'rs28940298', (78, 89))	('c.598C>T', 'Mutation', 'rs28940298', (68, 76))	('VHL', 'Gene', (114, 117))
31229	25371412	To determine if the VHL disease occurred in the genetic context of the particular Chuvash core haplotype, we analyzed the single nucleotide polymorphisms (SNP) of the VHL region (Table 1).	('single nucleotide polymorphisms', 'Var', (122, 153))	('VHL disease', 'Disease', 'MESH:D006623', (20, 31))	('VHL disease', 'Disease', (20, 31))
31231	25371412	Remarkably, we found a second heterozygous germline mutation, c.482G>A, p.Arg161Gln (R161Q) (Fig.	('R161Q', 'Mutation', 'rs730882035', (85, 90))	('c.482G>A', 'Mutation', 'rs730882035', (62, 70))	('R', 'Chemical', 'MESH:D001120', (85, 86))	('p.Arg161Gln', 'Mutation', 'rs730882035', (72, 83))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('p.Arg161Gln (R161Q', 'Var', (72, 90))	('c.482G>A', 'Var', (62, 70))
31232	25371412	The impact of the single mutations (R200W and R161Q), and the double mutation (R200W+R161Q), on the structure and dynamic behavior of pVHL was studied by molecular dynamics (MD) simulations.	('R161Q', 'Mutation', 'rs730882035', (46, 51))	('R200W', 'Var', (36, 41))	('R161Q', 'Mutation', 'rs730882035', (85, 90))	('R200W+R161Q', 'Var', (79, 90))	('R200W', 'Mutation', 'rs28940298', (36, 41))	('R200W', 'Mutation', 'rs28940298', (79, 84))	('pVHL', 'Gene', '7428', (134, 138))	('R161Q', 'Var', (46, 51))	('pVHL', 'Gene', (134, 138))
31236	25371412	Analysis of non-covalent contacts indicates that each mutation, R200 and R161, taken separately decreases the stabilizing inter-domains interactions, while these interactions are increased in the double mutant R200W+R161Q (Fig.	('R200W', 'Mutation', 'rs28940298', (210, 215))	('stabilizing inter-domains interactions', 'MPA', (110, 148))	('R', 'Chemical', 'MESH:D001120', (73, 74))	('decreases', 'NegReg', (96, 105))	('R200W+R161Q', 'Var', (210, 221))	('R161Q', 'Mutation', 'rs730882035', (216, 221))	('R161', 'Var', (73, 77))	('R', 'Chemical', 'MESH:D001120', (64, 65))	('R200', 'Var', (64, 68))	('R', 'Chemical', 'MESH:D001120', (210, 211))	('R', 'Chemical', 'MESH:D001120', (216, 217))	('increased', 'PosReg', (179, 188))
31240	25371412	To evaluate the impact of these different mutations on HIF regulation, we performed a functional in vitro analysis by measuring the ability of the mutants to bind to a proline-hydroxylated HIF-1alpha peptide (HIF-OH).	('HIF-1alpha', 'Gene', (189, 199))	('proline', 'Chemical', 'MESH:D011392', (168, 175))	('mutants', 'Var', (147, 154))	('HIF-1alpha', 'Gene', '3091', (189, 199))	('bind', 'Interaction', (158, 162))	('HIF-OH', 'Disease', (209, 215))	('HIF-OH', 'Disease', 'MESH:C566945', (209, 215))
31241	25371412	The R200W mutation had no effect on the ability of pVHL to bind to HIF-OH compared to the wild type protein (Fig.	('pVHL', 'Gene', '7428', (51, 55))	('pVHL', 'Gene', (51, 55))	('R200W', 'Var', (4, 9))	('HIF-OH', 'Disease', (67, 73))	('R200W', 'Mutation', 'rs28940298', (4, 9))	('HIF-OH', 'Disease', 'MESH:C566945', (67, 73))	('bind', 'Interaction', (59, 63))
31242	25371412	In contrast, R161Q moderately affected this binding and R200W+R161Q completely prevented it.	('R161Q', 'Mutation', 'rs730882035', (13, 18))	('affected', 'Reg', (30, 38))	('prevented', 'NegReg', (79, 88))	('R161Q', 'Var', (13, 18))	('R200W+R161Q', 'Var', (56, 67))	('R161Q', 'Mutation', 'rs730882035', (62, 67))	('binding', 'Interaction', (44, 51))	('R200W', 'Mutation', 'rs28940298', (56, 61))
31244	25371412	Each VHL mutant construct harboring missense mutation was then reintroduced into the VHL-defective renal cancer cell line 786.O, which over-expresses HIF-2alpha.	('VHL-defective renal cancer', 'Disease', 'MESH:D007680', (85, 111))	('renal cancer', 'Phenotype', 'HP:0009726', (99, 111))	('HIF-2alpha', 'Gene', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('missense mutation', 'Var', (36, 53))	('over-expresses', 'PosReg', (135, 149))	('VHL-defective renal cancer', 'Disease', (85, 111))	('HIF-2alpha', 'Gene', '2034', (150, 160))
31245	25371412	Many attempts were unsuccessful to reintroduce classical VHL constructions in the cells, stably or transiently, toxicity and non reproducible results being observed, especially for the wild type and the VHL-R200W vectors.	('VHL-R200W', 'Var', (203, 212))	('R200W', 'Mutation', 'rs28940298', (207, 212))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))	('toxicity', 'Disease', (112, 120))
31248	25371412	Immunoblotting of clones expressing the wild-type or various mutated pVHL showed that the HIF-2alpha protein was differentially stabilized by the different mutants in the same order of severity (Fig.	('pVHL', 'Gene', '7428', (69, 73))	('HIF-2alpha', 'Gene', (90, 100))	('pVHL', 'Gene', (69, 73))	('HIF-2alpha', 'Gene', '2034', (90, 100))	('mutants', 'Var', (156, 163))	('mutated', 'Var', (61, 68))	('stabilized', 'MPA', (128, 138))
31251	25371412	To pursue this further, transcriptomic profiles from cells expressing the main representative mutants of each type of VHL disease (C162F [Type-1], R167Q [Type-2B], Y98H [Type-2A], L188V [Type-2C]) were obtained by microarray analysis.	('Y98H', 'Var', (164, 168))	('C162F', 'Var', (131, 136))	('L188V', 'Mutation', 'rs5030824', (180, 185))	('VHL disease', 'Disease', (118, 129))	('VHL disease', 'Disease', 'MESH:D006623', (118, 129))	('L188V', 'Var', (180, 185))	('Y98H', 'Mutation', 'rs5030809', (164, 168))	('R167Q', 'Mutation', 'rs5030821', (147, 152))	('C162F', 'Mutation', 'rs397516444', (131, 136))	('R167Q [', 'Var', (147, 154))
31257	25371412	We tested the expression level of 10 genes randomly selected from this set in different 786.0 clones in which VHL mutants had been reintroduced (R200W and R161Q mutations, individually or in association, in which three independent clones with equivalent expression of VHL were obtained) (Fig.	('R161Q mutations', 'Var', (155, 170))	('R200W', 'Mutation', 'rs28940298', (145, 150))	('mutants', 'Var', (114, 121))	('R161Q', 'Mutation', 'rs730882035', (155, 160))	('R200W', 'Var', (145, 150))	('VHL', 'Gene', (110, 113))
31262	25371412	The expression profiles of our 30 candidate genes were studied in VHL mutated ccRCC compared to normal kidney tissues.	('ccRCC', 'Disease', (78, 83))	('mutated', 'Var', (70, 77))	('R', 'Chemical', 'MESH:D001120', (80, 81))
31264	25371412	We show that the R200W mutation alone is definitely not associated with the disease because the family actually carries another pathogenic mutation, R161Q, on the same VHL allele, and the double mutated allele segregates with disease.	('R161Q', 'Var', (149, 154))	('R200W', 'Var', (17, 22))	('R200W', 'Mutation', 'rs28940298', (17, 22))	('disease', 'Disease', (226, 233))	('R161Q', 'Mutation', 'rs730882035', (149, 154))
31266	25371412	We can thus conclude that this haplotype does not contain any protective elements against cancer development and that the VHL mutations are, by themselves, predominantly responsible for manifestations of the VHL disease.	('VHL disease', 'Disease', 'MESH:D006623', (208, 219))	('responsible', 'Reg', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('VHL', 'Gene', (122, 125))	('VHL disease', 'Disease', (208, 219))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
31267	25371412	The family under study is VHL Type-2B (pheochromocytoma and high risk of kidney cancer), and the disease is caused by the combination of two germline mutations which, when considered separately, are associated with different phenotypes: R200W (either no symptoms or erythrocytosis) and R161Q (VHL Type-2A, pheochromocytomas and low risk of kidney cancer).	('pheochromocytomas', 'Phenotype', 'HP:0002666', (306, 323))	('caused by', 'Reg', (108, 117))	('VHL Type-2B', 'Disease', (26, 37))	('kidney cancer', 'Disease', 'MESH:D007680', (73, 86))	('pheochromocytoma', 'Disease', (39, 55))	('erythrocytosis', 'Phenotype', 'HP:0001901', (266, 280))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (39, 55))	('R161Q', 'Var', (286, 291))	('erythrocytosis', 'Disease', (266, 280))	('pheochromocytoma', 'Disease', 'MESH:D010673', (306, 322))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('kidney cancer', 'Phenotype', 'HP:0009726', (73, 86))	('VHL Type-2', 'Disease', (293, 303))	('kidney cancer', 'Disease', (73, 86))	('VHL Type-2', 'Disease', 'MESH:D006623', (26, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (340, 353))	('pheochromocytoma', 'Disease', (306, 322))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (306, 322))	('VHL Type-2B', 'Disease', 'MESH:D006623', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('pheochromocytomas', 'Disease', (306, 323))	('R161Q', 'Mutation', 'rs730882035', (286, 291))	('pheochromocytomas', 'Disease', 'MESH:D010673', (306, 323))	('kidney cancer', 'Phenotype', 'HP:0009726', (340, 353))	('R200W', 'Mutation', 'rs28940298', (237, 242))	('VHL Type-2', 'Disease', 'MESH:D006623', (293, 303))	('R200W', 'Var', (237, 242))	('kidney cancer', 'Disease', (340, 353))	('pheochromocytoma', 'Disease', 'MESH:D010673', (39, 55))	('erythrocytosis', 'Disease', 'MESH:D011086', (266, 280))
31268	25371412	Although it is not excluded that this family carry other genetic alterations (linked or not to VHL), we conducted a comprehensive functional and comparative analysis of these VHL mutations in order to clarify the complexity of genotype/phenotype correlations, and to understand the basis of either tumor development in patients with VHL disease or absence of cancer in carriers of the VHL-R200W mutation.	('R200W', 'Mutation', 'rs28940298', (389, 394))	('absence of cancer', 'Disease', (348, 365))	('tumor', 'Disease', (298, 303))	('VHL-R200W', 'Gene', (385, 394))	('VHL disease', 'Disease', 'MESH:D006623', (333, 344))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('absence of cancer', 'Disease', 'MESH:D004832', (348, 365))	('patients', 'Species', '9606', (319, 327))	('VHL', 'Gene', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('mutations', 'Var', (179, 188))	('VHL disease', 'Disease', (333, 344))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
31269	25371412	The molecular dynamics simulations of the pVHL mutants revealed a highly constrained and reduced inter-domain mobility of the double mutant compared to the single one.	('inter-domain mobility', 'MPA', (97, 118))	('pVHL', 'Gene', '7428', (42, 46))	('pVHL', 'Gene', (42, 46))	('double mutant', 'Var', (126, 139))	('reduced', 'NegReg', (89, 96))	('mutants', 'Var', (47, 54))
31270	25371412	The results show a gradient in the loss of function of the different mutants with an additive effect of the double mutant: R200W+R161Q > R161Q > R200W >=wt.	('R200W', 'Mutation', 'rs28940298', (145, 150))	('R200W+R161Q > R161Q > R200W >', 'Var', (123, 152))	('loss', 'NegReg', (35, 39))	('R161Q', 'Mutation', 'rs730882035', (137, 142))	('R200W', 'Mutation', 'rs28940298', (123, 128))	('R161Q', 'Mutation', 'rs730882035', (129, 134))
31273	25371412	We did not identify any relevant candidate genes differentially regulated by the different mutants that may explain the occurrence of tumors or not.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('mutants', 'Var', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
31275	25371412	We identified a set of genes directly regulated by the pVHL/HIF-2alpha pathway, and observed a distinct and graded ability of the different VHL mutants to regulate these genes: the more important the pVHL loss of function is, the more dysregulated the HIF-2alpha target genes are.	('mutants', 'Var', (144, 151))	('pVHL', 'Gene', '7428', (55, 59))	('pVHL', 'Gene', (55, 59))	('VHL loss', 'Disease', 'MESH:D006623', (201, 209))	('pVHL', 'Gene', '7428', (200, 204))	('HIF-2alpha', 'Gene', (252, 262))	('pVHL', 'Gene', (200, 204))	('VHL loss', 'Disease', (201, 209))	('VHL', 'Gene', (140, 143))	('HIF-2alpha', 'Gene', (60, 70))	('HIF-2alpha', 'Gene', '2034', (252, 262))	('HIF-2alpha', 'Gene', '2034', (60, 70))	('dysregulated', 'MPA', (235, 247))
31281	25371412	Altogether, our results show a gradual loss of function of the different VHL mutants that could explain the different associated phenotypes: (i) no tumor for R200W mutant with a function similar close to wild-type pVHL, (ii) an intermediate dysfunction leading to low risk of developing ccRCC for the R161Q mutant, (iii) and VHL Type-2B disease with high risk of ccRCC, as described in the present family where R200W+R161Q is associated with a severe loss of function.	('R', 'Chemical', 'MESH:D001120', (365, 366))	('R', 'Chemical', 'MESH:D001120', (301, 302))	('ccRCC', 'Disease', (287, 292))	('R', 'Chemical', 'MESH:D001120', (411, 412))	('pVHL', 'Gene', '7428', (214, 218))	('R', 'Chemical', 'MESH:D001120', (158, 159))	('pVHL', 'Gene', (214, 218))	('R200W+R161Q', 'Var', (411, 422))	('R161Q', 'Mutation', 'rs730882035', (417, 422))	('VHL Type-2B disease', 'Disease', 'MESH:D006623', (325, 344))	('ccRCC', 'Disease', (363, 368))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('R161Q', 'Var', (301, 306))	('R', 'Chemical', 'MESH:D001120', (417, 418))	('R200W', 'Mutation', 'rs28940298', (411, 416))	('R200W', 'Mutation', 'rs28940298', (158, 163))	('R', 'Chemical', 'MESH:D001120', (289, 290))	('R161Q', 'Mutation', 'rs730882035', (301, 306))	('R200W', 'Var', (158, 163))	('tumor', 'Disease', (148, 153))	('mutants', 'Var', (77, 84))	('VHL Type-2B disease', 'Disease', (325, 344))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
31284	25371412	Our description of combined mutations in VHL, each proportionally impacting the patients phenotype, validates this model for the first time in humans and indicates that precisely-defined quantitative aspects of structural and functional dysregulation are key to tumor predisposition.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', (262, 267))	('impacting', 'Reg', (66, 75))	('humans', 'Species', '9606', (143, 149))	('VHL', 'Gene', (41, 44))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
31286	25371412	(i) heterozygous carriers of germline VHL mutations with a weak effect (like R200W) never develop tumors (except for two isolated cases of CNS hemangioblastomas).	('CNS hemangioblastomas', 'Phenotype', 'HP:0006880', (139, 160))	('tumors', 'Disease', (98, 104))	('R200W', 'Var', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('develop', 'PosReg', (90, 97))	('R200W', 'Mutation', 'rs28940298', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CNS hemangioblastoma', 'Phenotype', 'HP:0006880', (139, 159))	('hemangioblastomas', 'Disease', 'MESH:D018325', (143, 160))	('VHL', 'Gene', (38, 41))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (143, 159))	('hemangioblastomas', 'Disease', (143, 160))
31288	25371412	In these patients, the exact mechanisms of the occurrence of erythrocytosis (achievement of a threshold that induces HIF and EPO production and/ or direct effect on erythroid progenitors proliferation due to particular properties of the VHL mutations) and occurrence of thrombotic events or PAH still need to be determined.	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (241, 250))	('HIF', 'MPA', (117, 120))	('EPO', 'Gene', (125, 128))	('erythrocytosis', 'Phenotype', 'HP:0001901', (61, 75))	('VHL', 'Gene', (237, 240))	('thrombotic events', 'Phenotype', 'HP:0001907', (270, 287))	('erythrocytosis', 'Disease', (61, 75))	('thrombotic events', 'Disease', 'MESH:D013927', (270, 287))	('EPO', 'Gene', '2056', (125, 128))	('erythrocytosis', 'Disease', 'MESH:D011086', (61, 75))	('thrombotic events', 'Disease', (270, 287))
31295	25371412	We can therefore conclude that, in pheochromocytoma, pVHL mutations function as hypomorphs, not as dominant negative alleles.	('mutations', 'Var', (58, 67))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (35, 51))	('pVHL', 'Gene', '7428', (53, 57))	('pVHL', 'Gene', (53, 57))	('pheochromocytoma', 'Disease', (35, 51))	('pheochromocytoma', 'Disease', 'MESH:D010673', (35, 51))
31297	25371412	A gradient of predisposition depending on the VHL mutation has already been suggested in ccRCC.	('VHL', 'Gene', (46, 49))	('R', 'Chemical', 'MESH:D001120', (91, 92))	('ccRCC', 'Disease', (89, 94))	('mutation', 'Var', (50, 58))
31298	25371412	The threshold of pVHL loss of activity could be reached with VHL Type-2A mutants (the typical Y98H mutation predispose to ccRCC in 3% of cases) and a maximal risk of ccRCC development occurs with Type-2B mutants (severe pVHL loss of function) and Type-1 mutations (total VHL loss of function).	('Y98H', 'Var', (94, 98))	('VHL loss', 'Disease', 'MESH:D006623', (221, 229))	('ccRCC', 'Disease', (166, 171))	('pVHL', 'Gene', '7428', (220, 224))	('pVHL', 'Gene', (220, 224))	('VHL Type-2', 'Disease', (61, 71))	('R', 'Chemical', 'MESH:D001120', (124, 125))	('Y98H', 'Mutation', 'rs5030809', (94, 98))	('VHL loss', 'Disease', (271, 279))	('mutants', 'Var', (73, 80))	('VHL loss', 'Disease', (18, 26))	('pVHL', 'Gene', '7428', (17, 21))	('VHL loss', 'Disease', 'MESH:D006623', (271, 279))	('pVHL', 'Gene', (17, 21))	('VHL loss', 'Disease', 'MESH:D006623', (18, 26))	('ccRCC', 'Disease', (122, 127))	('VHL Type-2', 'Disease', 'MESH:D006623', (61, 71))	('VHL loss', 'Disease', (221, 229))	('R', 'Chemical', 'MESH:D001120', (168, 169))
31299	25371412	It is remarkable that VHL mutations in erythrocytosis patients are different to those identified in patients with VHL (Supplementary Table S2).	('VHL', 'Gene', (22, 25))	('patients', 'Species', '9606', (54, 62))	('erythrocytosis', 'Phenotype', 'HP:0001901', (39, 53))	('erythrocytosis', 'Disease', (39, 53))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (100, 108))	('erythrocytosis', 'Disease', 'MESH:D011086', (39, 53))
31300	25371412	There are a few exceptions: for example, Y175C and L188V have been associated with both erythrocytosis and pheochromocytoma.	('erythrocytosis and pheochromocytoma', 'Disease', 'MESH:D010673', (88, 123))	('Y175C', 'Mutation', 'rs193922613', (41, 46))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (107, 123))	('Y175C', 'Var', (41, 46))	('erythrocytosis', 'Phenotype', 'HP:0001901', (88, 102))	('associated', 'Reg', (67, 77))	('L188V', 'Var', (51, 56))	('L188V', 'Mutation', 'rs5030824', (51, 56))
31301	25371412	These mutations may be considered as "borderline", with a loss of function insufficient to induce renal cancer but still capable to cause pheochromocytoma.	('pheochromocytoma', 'Disease', (138, 154))	('renal cancer', 'Disease', 'MESH:D007680', (98, 110))	('renal cancer', 'Phenotype', 'HP:0009726', (98, 110))	('pheochromocytoma', 'Disease', 'MESH:D010673', (138, 154))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (138, 154))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('loss of function insufficient', 'Disease', 'MESH:D000309', (58, 87))	('cause', 'Reg', (132, 137))	('loss of function insufficient', 'Disease', (58, 87))	('mutations', 'Var', (6, 15))	('renal cancer', 'Disease', (98, 110))
31302	25371412	The L188V mutant illustrates perfectly this threshold: it is a typical VHL Type-2C mutation, its loss of function is difficult to assess and it has been described in rare patients with no symptoms or with erythrocytosis.	('VHL Type-2', 'Disease', 'MESH:D006623', (71, 81))	('patients', 'Species', '9606', (171, 179))	('L188V', 'Var', (4, 9))	('erythrocytosis', 'Phenotype', 'HP:0001901', (205, 219))	('L188V', 'Mutation', 'rs5030824', (4, 9))	('erythrocytosis', 'Disease', (205, 219))	('erythrocytosis', 'Disease', 'MESH:D011086', (205, 219))	('VHL Type-2', 'Disease', (71, 81))
31303	25371412	Finally, our results suggest that the dysregulation of HIF may play a key role in the continuum model of tumor suppression by VHL.	('dysregulation', 'Var', (38, 51))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
31304	25371412	This model may be of major importance in our understanding of tumor risk in patients carrying mutations in other genes belonging the HIF pathway.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (94, 103))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
31305	25371412	Indeed, patients with germline mutations in PHD2/EGLN1 and HIF2A/EPAS1 can develop pheochromocytomas or paragangliomas (equivalent to extra-adrenal pheochromocytomas).	('HIF2A', 'Gene', '2034', (59, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (104, 118))	('HIF2A', 'Gene', (59, 64))	('EGLN1', 'Gene', '54583', (49, 54))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (148, 164))	('germline mutations', 'Var', (22, 40))	('PHD2', 'Gene', (44, 48))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (140, 165))	('EPAS1', 'Gene', (65, 70))	('extra-adrenal pheochromocytomas', 'Disease', (134, 165))	('EGLN1', 'Gene', (49, 54))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))	('PHD2', 'Gene', '54583', (44, 48))	('develop', 'PosReg', (75, 82))	('patients', 'Species', '9606', (8, 16))	('extra-adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (134, 165))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (148, 165))	('EPAS1', 'Gene', '2034', (65, 70))	('pheochromocytomas or paragangliomas', 'Disease', (83, 118))	('pheochromocytomas or paragangliomas', 'Disease', 'MESH:D010673', (83, 118))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))
31306	25371412	A comparative study of PHD2 mutations showed a differential regulation of HIF that perfectly fits with the model described here.	('PHD2', 'Gene', '54583', (23, 27))	('fits', 'Disease', 'MESH:D012640', (93, 97))	('PHD2', 'Gene', (23, 27))	('HIF', 'MPA', (74, 77))	('fits', 'Disease', (93, 97))	('mutations', 'Var', (28, 37))
31307	25371412	The absence of renal cancer in patients with PHD2 and HIF2A mutations could be explained by an only partial inactivation of PHD2 (possibly compensated by PHD1 and 3), and by the persistence of some HIF-2alpha degradation (the germline activating mutations described in HIF2A gene being always outside of the major hydroxylated prolines).	('absence of renal cancer', 'Disease', 'MESH:D007680', (4, 27))	('HIF2A', 'Gene', (269, 274))	('HIF2A', 'Gene', (54, 59))	('PHD2', 'Gene', (45, 49))	('PHD2', 'Gene', (124, 128))	('absence of renal cancer', 'Disease', (4, 27))	('HIF-2alpha degradation', 'Disease', 'MESH:D055959', (198, 220))	('PHD2', 'Gene', '54583', (45, 49))	('PHD2', 'Gene', '54583', (124, 128))	('PHD1 and 3', 'Gene', '112398;112399', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('inactivation', 'NegReg', (108, 120))	('HIF2A', 'Gene', '2034', (269, 274))	('prolines', 'Chemical', 'MESH:D011392', (327, 335))	('patients', 'Species', '9606', (31, 39))	('mutations', 'Var', (60, 69))	('HIF-2alpha degradation', 'Disease', (198, 220))	('HIF2A', 'Gene', '2034', (54, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (15, 27))
31308	25371412	In conclusion, the unique concurrence of two mutations that interact positively to perturb a specific structural feature of pVHL has allowed functional - clinical correlates, improving as a result our understanding of the genotype-phenotype associations in VHL disease.	('mutations', 'Var', (45, 54))	('VHL disease', 'Disease', (257, 268))	('pVHL', 'Gene', '7428', (124, 128))	('pVHL', 'Gene', (124, 128))	('improving', 'PosReg', (175, 184))	('VHL disease', 'Disease', 'MESH:D006623', (257, 268))	('perturb', 'Reg', (83, 90))
31330	28341846	Pre-operatively, subjects in the group with SH/LA had larger tumors but a lower incidence of comorbid diabetes mellitus than those in the group with normolactatemia.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('SH/LA', 'Var', (44, 49))	('lactate', 'Chemical', 'MESH:D019344', (154, 161))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (102, 119))	('diabetes mellitus', 'Disease', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('LA', 'Phenotype', 'HP:0003128', (47, 49))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('diabetes mellitus', 'Disease', 'MESH:D003920', (102, 119))
31332	28341846	The SH/LA group had a greater proportion of epinephrine-secreting tumors than the normolactatemia group (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('epinephrine', 'Chemical', 'MESH:D004837', (44, 55))	('SH/LA', 'Var', (4, 9))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('LA', 'Phenotype', 'HP:0003128', (7, 9))	('lactate', 'Chemical', 'MESH:D019344', (87, 94))
31333	28341846	Intra-operatively, patients in the normolactatemia group experienced lower maximum heart rate and shorter anesthetic time than those in the MH groups, while the SH/LA group had a longer operative time than the normolactatemia group (Table 3).	('lactate', 'Chemical', 'MESH:D019344', (40, 47))	('patients', 'Species', '9606', (19, 27))	('maximum heart rate', 'Phenotype', 'HP:0001649', (75, 93))	('anesthetic time', 'MPA', (106, 121))	('MH', 'Chemical', '-', (140, 142))	('lactate', 'Chemical', 'MESH:D019344', (215, 222))	('lower', 'NegReg', (69, 74))	('normolactatemia', 'Var', (35, 50))	('LA', 'Phenotype', 'HP:0003128', (164, 166))	('maximum heart rate', 'MPA', (75, 93))	('shorter', 'NegReg', (98, 105))
31334	28341846	Post-operatively, subjects in the group with SH/LA had a longer mechanical ventilation time, greater maximum heart rate, and longer length of hospitalization than those in the normolactatemia group.	('LA', 'Phenotype', 'HP:0003128', (48, 50))	('longer', 'PosReg', (57, 63))	('mechanical ventilation time', 'MPA', (64, 91))	('SH/LA', 'Var', (45, 50))	('lactate', 'Chemical', 'MESH:D019344', (181, 188))	('maximum heart rate', 'MPA', (101, 119))	('maximum heart rate', 'Phenotype', 'HP:0001649', (101, 119))
31338	28341846	According to the results, patients with post-operative SH/LA are likely to experience a longer post-operative hospitalization, a higher post-operative maximum heart rate, and a longer duration of mechanical ventilation than those with normolactatemia.	('post-operative', 'Var', (40, 54))	('higher', 'PosReg', (129, 135))	('patients', 'Species', '9606', (26, 34))	('SH/LA', 'Var', (55, 60))	('maximum heart rate', 'Phenotype', 'HP:0001649', (151, 169))	('lactate', 'Chemical', 'MESH:D019344', (240, 247))	('LA', 'Phenotype', 'HP:0003128', (58, 60))
31344	28341846	Therefore, anaerobic glycolysis is the most common cause of hyperlactatemia or even lactic acidosis.	('lactic acidosis', 'Disease', (84, 99))	('lactic acidosis', 'Disease', 'MESH:D000140', (84, 99))	('hyperlactatemia', 'Disease', (60, 75))	('hyperlactatemia', 'Disease', 'MESH:D065906', (60, 75))	('acidosis', 'Phenotype', 'HP:0001941', (91, 99))	('cause', 'Reg', (51, 56))	('lactic acidosis', 'Phenotype', 'HP:0003128', (84, 99))	('anaerobic', 'Var', (11, 20))
31386	28341846	Unexpectedly, the incidence of diabetes mellitus in the SH/LA group was lower than that in the normolactatemia group.	('diabetes mellitus', 'Phenotype', 'HP:0000819', (31, 48))	('diabetes mellitus', 'Disease', (31, 48))	('lower', 'NegReg', (72, 77))	('diabetes mellitus', 'Disease', 'MESH:D003920', (31, 48))	('SH/LA', 'Var', (56, 61))	('lactate', 'Chemical', 'MESH:D019344', (100, 107))	('LA', 'Phenotype', 'HP:0003128', (59, 61))
31397	28341846	Second, excessive catecholamine secretion as a result of pheochromocytoma resection may induce SH/LA, and the effect of epinephrine might be stronger than that of norepinephrine.	('excessive catecholamine', 'Phenotype', 'HP:0003334', (8, 31))	('SH/LA', 'Disease', (95, 100))	('excessive', 'PosReg', (8, 17))	('catecholamine secretion', 'MPA', (18, 41))	('pheochromocytoma', 'Disease', (57, 73))	('catecholamine', 'Chemical', 'MESH:D002395', (18, 31))	('epinephrine', 'Chemical', 'MESH:D004837', (120, 131))	('resection', 'Var', (74, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('pheochromocytoma', 'Disease', 'MESH:D010673', (57, 73))	('LA', 'Phenotype', 'HP:0003128', (98, 100))	('induce', 'PosReg', (88, 94))	('epinephrine', 'Chemical', 'MESH:D004837', (166, 177))	('norepinephrine', 'Chemical', 'MESH:D009638', (163, 177))
31440	15225350	Of note, a positive LR above 10 and negative LR below 0.1 has been noted to generate large changes from pre-test to post-test probability of disease, often resulting in a large change in patient management; whereas positive LRs between 5 and 10 and negative LRs between 0.1 and 0.2 are considered to generate moderate shifts in pre-test to post-test probability of disease.	('changes', 'Reg', (91, 98))	('resulting', 'Reg', (156, 165))	('patient management', 'MPA', (187, 205))	('positive', 'Var', (11, 19))	('change', 'Reg', (177, 183))	('patient', 'Species', '9606', (187, 194))
31533	26419235	Microscopically, samples from the adrenal tumor revealed diffuse large B cell lymphoma (DLBCL) with the following immunophenotype: CD20(+), CD45(+), CD3(-), Ki67-50 %, CD5(-), CD10(-), BCL6(-), MUM1(-), and cyclin D1(-) (Fig.	('CD45', 'Gene', '5788', (140, 144))	('adrenal tumor', 'Disease', (34, 47))	('cyclin D1(-', 'Gene', (207, 218))	('BCL6', 'Gene', '604', (185, 189))	('CD20', 'Gene', (131, 135))	('MUM1', 'Gene', '84939', (194, 198))	('B cell lymphoma', 'Disease', 'MESH:D016393', (71, 86))	('CD10', 'Gene', '4311', (176, 180))	('adrenal tumor', 'Phenotype', 'HP:0100631', (34, 47))	('CD20', 'Gene', '54474', (131, 135))	('cyclin D1(-)', 'Gene', '595', (207, 219))	('CD5', 'Gene', (168, 171))	('CD3(-', 'Var', (149, 154))	('adrenal tumor', 'Disease', 'MESH:D000310', (34, 47))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (71, 86))	('Ki67-50 %', 'Var', (157, 166))	('MUM1', 'Gene', (194, 198))	('CD10', 'Gene', (176, 180))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('diffuse', 'Disease', (57, 64))	('large B cell', 'Phenotype', 'HP:0005404', (65, 77))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BCL6', 'Gene', (185, 189))	('B cell lymphoma', 'Disease', (71, 86))	('CD5', 'Gene', '921', (168, 171))	('CD45', 'Gene', (140, 144))
31535	26419235	The microscopic picture of brown focus was consistent with the diagnosis of pheochromocytoma (chromogranin A(+) and S-100(+); Fig.	('pheochromocytoma', 'Disease', (76, 92))	('chromogranin A', 'Gene', (94, 108))	('pheochromocytoma', 'Disease', 'MESH:D010673', (76, 92))	('S-100', 'Var', (116, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (76, 92))	('chromogranin A', 'Gene', '1113', (94, 108))
31623	23668927	Moreover, tumors that contain a large number of aneuploid or tetraploid cells are more likely to recur.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('aneuploid', 'Var', (48, 57))	('recur', 'CPA', (97, 102))	('tetraploid cells', 'Var', (61, 77))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))
31654	23668927	Such unresectable tumors may be treated with palliative chemotherapy with cyclophosphamide, dacarbazine, and vincristine, external beam radiotherapy for bony metastases, or 131I-labeled MIBG.	('vincristine', 'Chemical', 'MESH:D014750', (109, 120))	('bony metastases', 'Disease', 'MESH:D009362', (153, 168))	('dacarbazine', 'Chemical', 'MESH:D003606', (92, 103))	('MIBG', 'Chemical', 'MESH:D019797', (186, 190))	('tumors', 'Disease', (18, 24))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (74, 90))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('131I-labeled', 'Var', (173, 185))	('131I', 'Chemical', 'MESH:C000614965', (173, 177))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('bony metastases', 'Disease', (153, 168))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('MIBG', 'Gene', (186, 190))
31670	23457505	Pheochromocytoma also presents in familial syndromes associated with germline mutations of the genes encoding VHL, RET, NF1, SDH-A, B, C, and D, SDHAF2, TMEM127, and MAX .	('Pheochromocytoma', 'Disease', (0, 16))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('TMEM127', 'Gene', (153, 160))	('VHL', 'Gene', '7428', (110, 113))	('TMEM127', 'Gene', '55654', (153, 160))	('SDHAF2', 'Gene', '54949', (145, 151))	('mutations', 'Var', (78, 87))	('NF1', 'Gene', (120, 123))	('SDHAF2', 'Gene', (145, 151))	('familial syndromes', 'Disease', (34, 52))	('RET', 'Gene', '5979', (115, 118))	('associated', 'Reg', (53, 63))	('NF1', 'Gene', '4763', (120, 123))	('SDH-A, B, C, and D', 'Gene', '6389;6390;6391;6392', (125, 143))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('VHL', 'Gene', (110, 113))	('RET', 'Gene', (115, 118))
31673	23457505	Among the established subtypes, tumors with SDH-B mutation have a particularly high propensity to metastasize.	('SDH-B', 'Gene', '6390', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('metastasize', 'CPA', (98, 109))	('SDH-B', 'Gene', (44, 49))	('tumors', 'Disease', (32, 38))	('mutation', 'Var', (50, 58))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
31682	23457505	Currently no inhibitor has received regulatory approval but recent phase II studies with clinical responses that meet RECIST criteria suggest strategies for further development in several settings including HER2-positive breast cancer patients progressing on or resistant to trastuzumab, or non-small cell lung cancer patients with ALK mutations progressing on or resistant to crizotinib.	('ALK', 'Gene', (332, 335))	('HER2', 'Gene', '2064', (207, 211))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (221, 234))	('rat', 'Species', '10116', (144, 147))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (291, 317))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('patients', 'Species', '9606', (235, 243))	('trastuzumab', 'Chemical', 'MESH:D000068878', (275, 286))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (295, 317))	('crizotinib', 'Chemical', 'MESH:D000077547', (377, 387))	('HER2', 'Gene', (207, 211))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (291, 317))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (318, 326))	('non-small cell lung cancer', 'Disease', (291, 317))	('mutations', 'Var', (336, 345))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('ALK', 'Gene', '238', (332, 335))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))
31739	23457505	We tested the effect of Hsp90 inhibitor treatment on cell migration in the metastatic pheochromocytoma cell line MTT and found that 17-AAG reduced serum-stimulated migration (Fig.	('pheochromocytoma', 'Disease', 'MESH:D010673', (86, 102))	('17-AAG', 'Var', (132, 138))	('Hsp90', 'Gene', (24, 29))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (86, 102))	('MTT', 'Chemical', 'MESH:C070243', (113, 116))	('Hsp90', 'Gene', '3320', (24, 29))	('serum-stimulated migration', 'CPA', (147, 173))	('rat', 'Species', '10116', (61, 64))	('reduced', 'NegReg', (139, 146))	('rat', 'Species', '10116', (167, 170))	('pheochromocytoma', 'Disease', (86, 102))
31769	23457505	As shown in Figure 6, treatment with ganetespib for 10 days, with drug washout and readministration every two days resulted in a dose-dependent decrease in pheochromocytoma cell number.	('pheochromocytoma', 'Disease', (156, 172))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (156, 172))	('decrease', 'NegReg', (144, 152))	('ganetespib', 'Var', (37, 47))	('pheochromocytoma', 'Disease', 'MESH:D010673', (156, 172))	('rat', 'Species', '10116', (93, 96))	('ganetespib', 'Chemical', 'MESH:C533237', (37, 47))
31772	23457505	It has been suggested that these mutations can be divided into distinct molecular pathways causing errors in the HIF hypoxia-driven pathway (VHL, SDHB and SDHD) and errors in RNA synthesis and metabolism (RET, NF1, MAX, and TMEM127), while KIF1BBeta is thought to impact both pathways.	('TMEM127', 'Gene', (224, 231))	('SDHD', 'Gene', (155, 159))	('mutations', 'Var', (33, 42))	('RNA synthesis', 'MPA', (175, 188))	('TMEM127', 'Gene', '55654', (224, 231))	('VHL', 'Gene', '7428', (141, 144))	('HIF hypoxia', 'Disease', (113, 124))	('metabolism', 'MPA', (193, 203))	('RET', 'Gene', '5979', (205, 208))	('HIF hypoxia', 'Disease', 'MESH:D000860', (113, 124))	('SDHB', 'Gene', '6390', (146, 150))	('NF1', 'Gene', '4763', (210, 213))	('impact', 'Reg', (264, 270))	('NF1', 'Gene', (210, 213))	('SDHD', 'Gene', '6392', (155, 159))	('RET', 'Gene', (205, 208))	('errors', 'Var', (165, 171))	('SDHB', 'Gene', (146, 150))	('errors', 'Var', (99, 105))	('VHL', 'Gene', (141, 144))
31773	23457505	VHL targets HIF to the proteasome under normoxic conditions and loss of VHL results in HIF overexpression and angiogenesis.	('VHL', 'Gene', '7428', (72, 75))	('overexpression', 'PosReg', (91, 105))	('VHL', 'Gene', (0, 3))	('loss', 'Var', (64, 68))	('HIF', 'CPA', (87, 90))	('VHL', 'Gene', '7428', (0, 3))	('angiogenesis', 'CPA', (110, 122))	('VHL', 'Gene', (72, 75))
31774	23457505	SDHB and SDHD mutations result in accumulation of succinate, which inhibits HIF prolyl hydroxylation, and in the absence of prolyl-hydroxylated HIF VHL cannot recognize HIF and target it for degradation, and thus HIF is overexpressed via a different but complementary mechanism from VHL mutation.	('VHL', 'Gene', (148, 151))	('HIF VHL', 'Disease', (144, 151))	('VHL', 'Gene', '7428', (148, 151))	('SDHD', 'Gene', (9, 13))	('SDHD', 'Gene', '6392', (9, 13))	('HIF prolyl hydroxylation', 'MPA', (76, 100))	('VHL', 'Gene', (283, 286))	('succinate', 'Chemical', 'MESH:D019802', (50, 59))	('accumulation', 'PosReg', (34, 46))	('VHL', 'Gene', '7428', (283, 286))	('SDHB', 'Gene', '6390', (0, 4))	('inhibits', 'NegReg', (67, 75))	('HIF VHL', 'Disease', 'MESH:D006623', (144, 151))	('mutations', 'Var', (14, 23))	('SDHB', 'Gene', (0, 4))	('succinate', 'MPA', (50, 59))
31787	23457505	Clinical experience has demonstrated that targeted therapies can elicit the formation of secondary mutations in target molecules, leading to formation of drug resistance.	('drug resistance', 'MPA', (154, 169))	('elicit', 'Reg', (65, 71))	('mutations', 'Var', (99, 108))	('formation', 'Reg', (141, 150))	('drug resistance', 'Phenotype', 'HP:0020174', (154, 169))	('rat', 'Species', '10116', (31, 34))
31803	23457505	In this context, the first generation Hsp90 inhibitors have been shown to be very active against subcutaneous xenografts but to increase growth of prostatic and breast carcinoma cells in bone.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('Hsp90', 'Gene', (38, 43))	('increase', 'PosReg', (128, 136))	('inhibitors', 'Var', (44, 54))	('breast carcinoma', 'Disease', (161, 177))	('Hsp90', 'Gene', '3320', (38, 43))	('growth', 'MPA', (137, 143))	('breast carcinoma', 'Disease', 'MESH:D001943', (161, 177))	('breast carcinoma', 'Phenotype', 'HP:0003002', (161, 177))	('rat', 'Species', '10116', (31, 34))
31807	23457505	In our experiments using primary human cell cultures, we observed a dose-dependent reduction in tumor cells after treatment with ganetespib, further emphasizing the efficacy of this compound on pheochromocytoma tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (194, 210))	('ganetespib', 'Chemical', 'MESH:C533237', (129, 139))	('tumor', 'Disease', (96, 101))	('pheochromocytoma tumor', 'Disease', 'MESH:D010673', (194, 216))	('human', 'Species', '9606', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('reduction', 'NegReg', (83, 92))	('ganetespib', 'Var', (129, 139))	('pheochromocytoma tumor', 'Disease', (194, 216))
31816	22655253	Agents that bind somatostatin receptors include 111In-pentetreotide and 68Ga-labeled somatostatin analog peptides (68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE).	('somatostatin', 'Gene', '6750', (85, 97))	('somatostatin', 'Gene', '6750', (17, 29))	('somatostatin', 'Gene', (17, 29))	('somatostatin', 'Gene', (85, 97))	('68Ga-DOTA-TOC', 'Var', (115, 128))
31831	22655253	Patients with an inherited predisposition often develop multiple, bilateral, and early onset paragangliomas (as a result of germline mutations in the predisposing genes; Amar et al.,).	('Patients', 'Species', '9606', (0, 8))	('paragangliomas', 'Disease', 'MESH:D010235', (93, 107))	('paragangliomas', 'Disease', (93, 107))	('paragangliomas', 'Phenotype', 'HP:0002668', (93, 107))	('mutations', 'Var', (133, 142))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))
31833	22655253	These syndromes are caused by mutations in the RET, VHL, NF1, and succinate dehydrogenase (SDH) -B, -C, and -D genes, respectively (Bryant et al.,).	('VHL', 'Gene', '7428', (52, 55))	('RET', 'Gene', (47, 50))	('NF1', 'Gene', (57, 60))	('NF1', 'Gene', '4763', (57, 60))	('mutations', 'Var', (30, 39))	('caused by', 'Reg', (20, 29))	('RET', 'Gene', '5979', (47, 50))	('VHL', 'Gene', (52, 55))	('succinate dehydrogenase (SDH) -B', 'Gene', '6390', (66, 98))
31835	22655253	SDHB gene mutations are known to be associated with extra-adrenal localization, overproduction of norepinephrine and dopamine, and a high risk of malignancy with a poor prognosis (Gimenez-Roqueplo et al.,; Neumann et al.,; Amar et al.,; Timmers et al.,).	('norepinephrine', 'Chemical', 'MESH:D009638', (98, 112))	('overproduction', 'PosReg', (80, 94))	('dopamine', 'Chemical', 'MESH:D004298', (117, 125))	('associated', 'Reg', (36, 46))	('malignancy', 'Disease', 'MESH:D009369', (146, 156))	('SDHB', 'Gene', '6390', (0, 4))	('mutations', 'Var', (10, 19))	('malignancy', 'Disease', (146, 156))	('extra-adrenal localization', 'MPA', (52, 78))	('SDHB', 'Gene', (0, 4))
31836	22655253	In contrast to the high malignant potential of tumors related to SDHB germline mutations, patients with NF1,RET, VHL, and SDHD mutations rarely develop metastases (Amar et al.,; Gimenez-Roqueplo et al.,).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('RET', 'Gene', '5979', (108, 111))	('VHL', 'Gene', (113, 116))	('metastases', 'Disease', (152, 162))	('SDHD', 'Disease', 'None', (122, 126))	('NF1', 'Gene', '4763', (104, 107))	('VHL', 'Gene', '7428', (113, 116))	('SDHB', 'Gene', (65, 69))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('RET', 'Gene', (108, 111))	('SDHB', 'Gene', '6390', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (90, 98))	('SDHD', 'Disease', (122, 126))	('NF1', 'Gene', (104, 107))
31837	22655253	All these underlying mutations can lead to various tumor locations (with the possibility of multifocal disease), biochemical phenotypes, and malignant potentials: thus paragangliomas are exemplary for functional imaging.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('paragangliomas', 'Disease', (168, 182))	('paragangliomas', 'Disease', 'MESH:D010235', (168, 182))	('tumor', 'Disease', (51, 56))	('paraganglioma', 'Phenotype', 'HP:0002668', (168, 181))	('paragangliomas', 'Phenotype', 'HP:0002668', (168, 182))	('lead to', 'Reg', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('multifocal disease', 'Disease', (92, 110))	('multifocal disease', 'Disease', 'None', (92, 110))	('mutations', 'Var', (21, 30))
31845	22655253	An analog of norepinephrine, MIBG enters cells through the cell membrane norepinephrine transporter (NET) and is then transported and stored in neurosecretory granules via the vesicular monoamine transporter (VMAT; Eisenhofer,).	('norepinephrine transporter', 'Gene', (73, 99))	('NET', 'Gene', (101, 104))	('norepinephrine transporter', 'Gene', '6530', (73, 99))	('norepinephrine', 'Chemical', 'MESH:D009638', (13, 27))	('MIBG', 'Var', (29, 33))	('MIBG', 'Chemical', 'MESH:D019797', (29, 33))	('norepinephrine', 'Chemical', 'MESH:D009638', (73, 87))	('NET', 'Gene', '6530', (101, 104))
31847	22655253	Although 131I-labeled MIBG was initially used for scintigraphy, the superiority of 123I-labeledMIBG has been demonstrated (Lynn et al.,; Shulkin et al.,), due to its higher sensitivity, lower radiation exposure, and improved imaging quality with the possibility of SPECT imaging.	('higher', 'PosReg', (166, 172))	('imaging', 'MPA', (225, 232))	('improved', 'PosReg', (216, 224))	('123I-labeledMIBG', 'Var', (83, 99))	('123I', 'Chemical', 'MESH:C000614958', (83, 87))	('sensitivity', 'MPA', (173, 184))	('131I', 'Chemical', 'MESH:C000614965', (9, 13))	('MIBG', 'Chemical', 'MESH:D019797', (22, 26))	('MIBG', 'Chemical', 'MESH:D019797', (95, 99))
31859	22655253	To summarize, 123I-MIBG has high sensitivity for primary sympathetic paragangliomas, but poor sensitivity for metastases; therefore it is only useful in metastatic patients to evaluate whether they qualify for 131I-MIBG treatment.	('metastases', 'Disease', (110, 120))	('131I-MIBG', 'Chemical', '-', (210, 219))	('paraganglioma', 'Phenotype', 'HP:0002668', (69, 82))	('123I-MIBG', 'Var', (14, 23))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('paragangliomas', 'Disease', (69, 83))	('123I-MIBG', 'Chemical', 'MESH:D019797', (14, 23))	('paragangliomas', 'Disease', 'MESH:D010235', (69, 83))	('paragangliomas', 'Phenotype', 'HP:0002668', (69, 83))	('patients', 'Species', '9606', (164, 172))
31866	22655253	However, 123I-MIBG does have a high sensitivity and must be considered as a useful tracer in cases of adrenal non-metastatic paragangliomas.	('paragangliomas', 'Disease', 'MESH:D010235', (125, 139))	('paragangliomas', 'Disease', (125, 139))	('paragangliomas', 'Phenotype', 'HP:0002668', (125, 139))	('paraganglioma', 'Phenotype', 'HP:0002668', (125, 138))	('123I-MIBG', 'Var', (9, 18))	('123I-MIBG', 'Chemical', 'MESH:D019797', (9, 18))
31890	22655253	In a cohort of VHL mutation carriers, 18F-FDA was demonstrated to be superior to 131/123I-MIBG (Kaji et al.,).	('mutation', 'Var', (19, 27))	('18F-FDA', 'Chemical', '-', (38, 45))	('123I-MIBG', 'Chemical', 'MESH:D019797', (85, 94))	('VHL', 'Gene', (15, 18))	('VHL', 'Gene', '7428', (15, 18))
31894	22655253	Preferred 18F-FDA indications would be sympathetic non-head and neck paragangliomas, except those related to the SDHB mutation.	('SDHB', 'Gene', '6390', (113, 117))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (55, 83))	('18F-FDA', 'Chemical', '-', (10, 17))	('neck paragangliomas', 'Disease', (64, 83))	('paraganglioma', 'Phenotype', 'HP:0002668', (69, 82))	('SDHB', 'Gene', (113, 117))	('mutation', 'Var', (118, 126))	('paragangliomas', 'Phenotype', 'HP:0002668', (69, 83))	('neck paragangliomas', 'Disease', 'MESH:D010235', (64, 83))
31898	22655253	In particular, a recent prospective study published by King et al.,; on 10 patients carrying SDHx mutation, with a total of 26 head and neck paragangliomas) found a 100% sensitivity of 18F-FDOPA.	('mutation', 'Var', (98, 106))	('neck paragangliomas', 'Disease', (136, 155))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (127, 155))	('patients', 'Species', '9606', (75, 83))	('paragangliomas', 'Phenotype', 'HP:0002668', (141, 155))	('neck paragangliomas', 'Disease', 'MESH:D010235', (136, 155))	('sensitivity', 'MPA', (170, 181))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('18F-FDOPA', 'MPA', (185, 194))	('SDHx', 'Chemical', '-', (93, 97))	('18F-FDOPA', 'Chemical', '-', (185, 194))	('SDHx', 'Gene', (93, 97))
31903	22655253	Timmers' study of patients with and without SDHB mutations found a high sensitivity for non-SDHB-related paragangliomas, but poor sensitivity for SDHB-related paragangliomas, especially for metastatic paragangliomas (Timmers et al.,).	('paragangliomas', 'Phenotype', 'HP:0002668', (105, 119))	('paragangliomas', 'Disease', 'MESH:D010235', (159, 173))	('paraganglioma', 'Phenotype', 'HP:0002668', (159, 172))	('paragangliomas', 'Phenotype', 'HP:0002668', (159, 173))	('SDHB', 'Gene', '6390', (44, 48))	('mutations', 'Var', (49, 58))	('SDHB', 'Gene', '6390', (92, 96))	('paragangliomas', 'Disease', (201, 215))	('paragangliomas', 'Disease', (105, 119))	('SDHB', 'Gene', '6390', (146, 150))	('SDHB', 'Gene', (44, 48))	('paragangliomas', 'Disease', (159, 173))	('SDHB', 'Gene', (92, 96))	('paraganglioma', 'Phenotype', 'HP:0002668', (201, 214))	('patients', 'Species', '9606', (18, 26))	('paraganglioma', 'Phenotype', 'HP:0002668', (105, 118))	('SDHB', 'Gene', (146, 150))	('paragangliomas', 'Disease', 'MESH:D010235', (201, 215))	('paragangliomas', 'Phenotype', 'HP:0002668', (201, 215))	('paragangliomas', 'Disease', 'MESH:D010235', (105, 119))
31917	22655253	In parallel, basic science studies have found that oncogenetic signals resulting from mutations are present in both benign and malignant tumors.	('mutations', 'Var', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('malignant tumors', 'Disease', (127, 143))	('malignant tumors', 'Disease', 'MESH:D018198', (127, 143))	('oncogenetic signals', 'MPA', (51, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
31924	22655253	Mutation of the SDHB gene results in a loss of function of the SDH complex.	('SDH', 'Gene', '6390', (63, 66))	('SDHB', 'Gene', '6390', (16, 20))	('Mutation', 'Var', (0, 8))	('SDH', 'Gene', (63, 66))	('SDHB', 'Gene', (16, 20))	('SDH', 'Gene', '6390', (16, 19))	('SDH', 'Gene', (16, 19))	('loss of function', 'NegReg', (39, 55))
31936	22655253	Newer somatostatin analogs, 68Ga-DOTA-Tyr3-octreotide (DOTATOC; Buchmann et al.,; Kroiss et al.,), 68Ga-DOTANOC (Wild et al.,), and 68Ga-DOTA-TATE (Win et al.,; Naji et al.,) have shown favorable characteristics in imaging, with a high affinity for SSRs and a stable and easy process of labeling.	('68Ga-DOTANOC', 'Var', (99, 111))	('somatostatin', 'Gene', (6, 18))	('68Ga-DOTA-TATE', 'Var', (132, 146))	('somatostatin', 'Gene', '6750', (6, 18))
31953	22655253	In the meantime, we suggest the first-line exam choice to be as follows: for SDHB-related paragangliomas, 18F-FDG; for non-SDHB sympathetic paragangliomas, 18F-FDA (or 18F-FDOPA in adrenal paragangliomas); and for parasympathetic head and neck paragangliomas, 18F-FDOPA.	('paragangliomas', 'Disease', (140, 154))	('paragangliomas', 'Disease', (244, 258))	('paragangliomas', 'Disease', 'MESH:D010235', (189, 203))	('SDHB', 'Gene', '6390', (77, 81))	('paragangliomas', 'Disease', (90, 104))	('paragangliomas', 'Phenotype', 'HP:0002668', (189, 203))	('paraganglioma', 'Phenotype', 'HP:0002668', (189, 202))	('SDHB', 'Gene', '6390', (123, 127))	('paraganglioma', 'Phenotype', 'HP:0002668', (244, 257))	('18F-FDG', 'Chemical', '-', (106, 113))	('18F-FDOPA', 'Chemical', '-', (260, 269))	('paragangliomas', 'Disease', 'MESH:D010235', (140, 154))	('neck paragangliomas', 'Disease', (239, 258))	('paragangliomas', 'Phenotype', 'HP:0002668', (140, 154))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('paragangliomas', 'Disease', 'MESH:D010235', (244, 258))	('paragangliomas', 'Phenotype', 'HP:0002668', (244, 258))	('SDHB', 'Gene', (123, 127))	('SDHB', 'Gene', (77, 81))	('paragangliomas', 'Disease', (189, 203))	('adrenal paragangliomas', 'Disease', (181, 203))	('paragangliomas', 'Disease', 'MESH:D010235', (90, 104))	('18F-FDA', 'Chemical', '-', (156, 163))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (230, 258))	('neck paragangliomas', 'Disease', 'MESH:D010235', (239, 258))	('adrenal paragangliomas', 'Disease', 'MESH:D010236', (181, 203))	('paragangliomas', 'Phenotype', 'HP:0002668', (90, 104))	('paraganglioma', 'Phenotype', 'HP:0002668', (90, 103))	('18F-FDA', 'Var', (156, 163))	('18F-FDOPA', 'Chemical', '-', (168, 177))
32003	22145136	In some cases, no definite abnormality is seen on CT or MRI, and 123I-MIBG scans are negative in around 15% of pheochromocytomas and in up to 50% of malignant tumors because of relatively lower afinity of 123I-MIBG to the norepinephrine transporters in comparison to newer compounds, the lack of storage granules or the loss of transporters by tumor cell dedifferentiation.	('lower', 'NegReg', (188, 193))	('malignant tumors', 'Disease', 'MESH:D018198', (149, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('pheochromocytomas', 'Disease', 'MESH:D010673', (111, 128))	('pheochromocytomas', 'Disease', (111, 128))	('123I-MIBG', 'Var', (205, 214))	('123I-MIBG', 'Chemical', '-', (205, 214))	('malignant tumors', 'Disease', (149, 165))	('tumor', 'Disease', (344, 349))	('afinity', 'MPA', (194, 201))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (111, 128))	('loss', 'NegReg', (320, 324))	('norepinephrine transporter', 'Gene', (222, 248))	('tumor', 'Disease', (159, 164))	('123I-MIBG', 'Chemical', '-', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('norepinephrine transporter', 'Gene', '6530', (222, 248))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))
32010	22145136	PET radiotracers that have been successfully used in the investigation of pheochromocytoma include 18F-DOPA, 18FDA, DOTA-Tyr3-octreotide (DOTATOC) and DOTA-Nal-octreotide (DOTANOC), and 18F-FDG.	('18F-DOPA', 'Chemical', '-', (99, 107))	('DOTA-Tyr3-octreotide', 'Var', (116, 136))	('DOTA-Tyr3-octreotide', 'Chemical', 'MESH:C106246', (116, 136))	('pheochromocytoma', 'Disease', (74, 90))	('pheochromocytoma', 'Disease', 'MESH:D010673', (74, 90))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('DOTA-Nal-octreotide', 'Chemical', '-', (151, 170))	('18FDA', 'Chemical', '-', (109, 114))	('18F-FDG', 'Chemical', 'MESH:D019788', (186, 193))
32023	22145136	Factors favoring phenoxybenzamine use are its long duration of action leading to twice daily dosing and that it causes noncompetitive blockade of alpha-receptors; thus it prevents episodic surges of catecholamine releases during pre- and post-operative period.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (17, 33))	('catecholamine', 'Chemical', 'MESH:D002395', (199, 212))	('prevents', 'NegReg', (171, 179))	('episodic', 'Disease', (180, 188))	('phenoxybenzamine', 'Var', (17, 33))	('alpha-receptors', 'Protein', (146, 161))	('episodic', 'Disease', 'MESH:C580065', (180, 188))	('noncompetitive blockade', 'MPA', (119, 142))
32024	22145136	However, disadvantages of phenoxybenzamine include tachycardia, persistent postoperative hypotension in view of covalent, noncompetitive binding to the alpha-receptor, somnolence, stuffiness of nose, headache, and postural hypotension requiring intravenous fluid replacement.	('stuffiness', 'Disease', 'None', (180, 190))	('persistent postoperative hypotension', 'Phenotype', 'HP:0001278', (64, 100))	('hypotension', 'Disease', (89, 100))	('somnolence', 'Disease', 'MESH:D006970', (168, 178))	('hypotension', 'Disease', (223, 234))	('headache', 'Phenotype', 'HP:0002315', (200, 208))	('somnolence', 'Disease', (168, 178))	('phenoxybenzamine', 'Var', (26, 42))	('hypotension', 'Disease', 'MESH:D007022', (89, 100))	('alpha-receptor', 'Protein', (152, 166))	('hypotension', 'Disease', 'MESH:D007022', (223, 234))	('headache', 'Disease', (200, 208))	('hypotension', 'Phenotype', 'HP:0002615', (89, 100))	('hypotension', 'Phenotype', 'HP:0002615', (223, 234))	('tachycardia', 'Phenotype', 'HP:0001649', (51, 62))	('tachycardia', 'Disease', (51, 62))	('stuffiness of nose', 'Phenotype', 'HP:0001742', (180, 198))	('tachycardia', 'Disease', 'MESH:D013610', (51, 62))	('stuffiness', 'Disease', (180, 190))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (26, 42))	('headache', 'Disease', 'MESH:D006261', (200, 208))	('postural hypotension', 'Phenotype', 'HP:0001278', (214, 234))	('postural', 'Disease', (214, 222))
32040	22145136	Metyrosine and alpha-blockers when used together result in less labile blood pressure during anesthesia and surgery, reduced intraoperative blood loss, and reduced volume replacement during surgery compared with the use of alpha-blockers alone.	('volume replacement', 'MPA', (164, 182))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (125, 150))	('reduced', 'NegReg', (117, 124))	('alpha-blockers', 'Protein', (15, 29))	('reduced', 'NegReg', (156, 163))	('less', 'NegReg', (59, 63))	('intraoperative blood loss', 'Disease', (125, 150))	('labile blood pressure', 'MPA', (64, 85))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))
32078	22145136	The large tumor size (5.5 cm) and minimally elevated 24-hour urinary vanillylmandelic acid (<= 2.1 mg/day/cm2) are significantly associated with a higher probability of a malignant pheochromocytoma portending a lower metastasis-free survival and mandates more rigorous follow-up after surgery.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (171, 197))	('malignant pheochromocytoma', 'Disease', (171, 197))	('tumor', 'Disease', (10, 15))	('<=', 'Var', (92, 94))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (181, 197))	('urinary vanillylmandelic acid', 'Phenotype', 'HP:0011978', (61, 90))	('vanillylmandelic acid', 'Chemical', 'MESH:D014642', (69, 90))	('lower', 'NegReg', (211, 216))
32081	22145136	In a group of 28 patients shown to have sufficient uptake of 131I MIBG, objective partial responses were observed in 29% of the patients, and biochemical improvement was noted in 43% of the patients.	('131I MIBG', 'Chemical', '-', (61, 70))	('patients', 'Species', '9606', (190, 198))	('131I', 'Var', (61, 65))	('patients', 'Species', '9606', (17, 25))	('MIBG', 'Gene', (66, 70))	('patients', 'Species', '9606', (128, 136))
32115	33643901	One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.	('reduce', 'NegReg', (130, 136))	('tumor', 'Disease', (28, 33))	('circulating levels', 'MPA', (137, 155))	('neutralize', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('antibodies', 'Protein', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ENO1', 'Gene', (73, 77))	('ENO1', 'Gene', '2023', (73, 77))
32126	33643901	In this study, the cBio Cancer Genomics Portal (; accessed by April 30, 2020), which is a web tool for mutation analysis and visualization through TCGA cancer genomics profiles, was used for mutation analysis of ENO1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (24, 30))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ENO1', 'Gene', (212, 216))	('ENO1', 'Gene', '2023', (212, 216))	('mutation', 'Var', (191, 199))
32141	33643901	The highest ENO1 expression was found in EBV-transformed lymphocytes, whereas the lowest was observed in the left ventricle of the heart.	('EBV-transformed', 'Var', (41, 56))	('expression', 'MPA', (17, 27))	('ENO1', 'Gene', (12, 16))	('ENO1', 'Gene', '2023', (12, 16))	('highest', 'PosReg', (4, 11))
32148	33643901	The expression of ENO1 was significantly associated with the prognosis of eight types of cancers, including HNSC (HR = 1.32, P = 0.04), CESC (HR = 1.47, P = 0.04), BLCA (HR = 1.23, P = 0.04), LUAD (HR = 1.36, P = 0.01), SARC (HR = 1.36, P = 0.00), PAAD (HR = 1.65, P = 0.00), KICH (HR = 4.60, P = 0.00), and LIHC (HR = 1.63, P = 0.00), suggesting that high ENO1 expression might be an independent risk factor for these cancers (all HR > 1.00, P < 0.05).	('associated', 'Reg', (41, 51))	('high', 'Var', (352, 356))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', (89, 96))	('KICH', 'Disease', (276, 280))	('LUAD', 'Disease', (192, 196))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CESC', 'Disease', (136, 140))	('BLCA', 'Disease', (164, 168))	('ENO1', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('ENO1', 'Gene', (357, 361))	('cancers', 'Disease', (419, 426))	('ENO1', 'Gene', '2023', (18, 22))	('KICH', 'Disease', 'None', (276, 280))	('HNSC', 'Disease', (108, 112))	('SARC', 'Disease', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('ENO1', 'Gene', '2023', (357, 361))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
32150	33643901	High ENO1 expression was significantly associated with worse OS in CESC (log-rank P = 0.04), BLCA (log-rank P = 0.03), KICH (log-rank P = 0.01), LIHC (log-rank P = 0.00), and SARC (log-rank P = 0.04), and worse DFS in KICH (log-rank P = 0.03) and SARC (log-rank P = 0.07).	('SARC', 'Disease', (175, 179))	('LIHC', 'Disease', (145, 149))	('BLCA', 'Disease', (93, 97))	('KICH', 'Disease', 'None', (218, 222))	('High', 'Var', (0, 4))	('ENO1', 'Gene', '2023', (5, 9))	('expression', 'MPA', (10, 20))	('CESC', 'Disease', (67, 71))	('ENO1', 'Gene', (5, 9))	('KICH', 'Disease', 'None', (119, 123))	('KICH', 'Disease', (218, 222))	('KICH', 'Disease', (119, 123))	('SARC', 'Disease', (247, 251))
32155	33643901	Evidently, 195 samples in the altered group and 10,772 samples in the unaltered group were included for ENO1 mutation analysis.	('ENO1', 'Gene', '2023', (104, 108))	('ENO1', 'Gene', (104, 108))	('mutation', 'Var', (109, 117))
32156	33643901	The results demonstrated that ENO1 was altered in 1.8% of all the included samples, including inframe mutation, missense mutation, truncating mutation, fusion, amplification, and deep deletion ( Figure 6 ).	('truncating', 'MPA', (131, 141))	('amplification', 'Var', (160, 173))	('ENO1', 'Gene', (30, 34))	('deep deletion', 'Var', (179, 192))	('ENO1', 'Gene', '2023', (30, 34))	('altered', 'Reg', (39, 46))	('fusion', 'Var', (152, 158))	('missense mutation', 'Var', (112, 129))
32157	33643901	Furthermore, the prognostic significance of ENO1 mutation was estimated via Kaplan-Meier method.	('ENO1', 'Gene', (44, 48))	('ENO1', 'Gene', '2023', (44, 48))	('mutation', 'Var', (49, 57))
32189	33643901	These findings are consistent with a previous study showing that high ENO1 expression is significantly correlated with DNA replication and cell cycle in hepatocellular carcinoma.	('DNA replication', 'CPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('ENO1', 'Gene', (70, 74))	('ENO1', 'Gene', '2023', (70, 74))	('expression', 'MPA', (75, 85))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('cell cycle', 'CPA', (139, 149))	('high', 'Var', (65, 69))	('hepatocellular carcinoma', 'Disease', (153, 177))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('correlated', 'Reg', (103, 113))
32197	33643901	Furthermore, the knockdown of ENO1 has been shown to promote apoptosis and induce the arrest of cell cycle in gastric cancer cells.	('gastric cancer', 'Disease', (110, 124))	('apoptosis', 'CPA', (61, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ENO1', 'Gene', (30, 34))	('ENO1', 'Gene', '2023', (30, 34))	('knockdown', 'Var', (17, 26))	('induce', 'Reg', (75, 81))	('promote', 'PosReg', (53, 60))
32202	33643901	Additionally, mutation of ENO1 was analysis, for it was proved that mutation could affect tumor progression; however, ENO1 mutation (1.8%) did not impact on prognosis in this study.	('affect', 'Reg', (83, 89))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ENO1', 'Gene', (118, 122))	('tumor', 'Disease', (90, 95))	('ENO1', 'Gene', '2023', (118, 122))	('ENO1', 'Gene', (26, 30))	('ENO1', 'Gene', '2023', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
32206	33643901	In consonance with our results, ENO1 expression was higher in late stages (stages III and IV), particularly that in KICH ( Figure 5E ), meanwhile, high ENO1 expression was significantly associated with worse OS in KICH ( Figure 4I ).	('worse OS', 'Disease', (202, 210))	('expression', 'MPA', (157, 167))	('ENO1', 'Gene', (152, 156))	('ENO1', 'Gene', '2023', (152, 156))	('KICH', 'Disease', 'None', (214, 218))	('ENO1', 'Gene', '2023', (32, 36))	('ENO1', 'Gene', (32, 36))	('KICH', 'Disease', 'None', (116, 120))	('high', 'Var', (147, 151))	('associated', 'Reg', (186, 196))	('higher', 'PosReg', (52, 58))	('KICH', 'Disease', (214, 218))	('expression', 'MPA', (37, 47))	('KICH', 'Disease', (116, 120))
32234	33028297	Intraoperatively, the RARLA group had a lower incidence of haemodynamic instability (26.3% vs. 56.2%, P = 0.038) and less intraoperative blood loss (100 ml vs. Two hundred milliliter, P = 0.042) than the RLA group.	('haemodynamic instability', 'MPA', (59, 83))	('RLA', 'Chemical', '-', (204, 207))	('intraoperative blood loss', 'Disease', (122, 147))	('RARLA', 'Chemical', '-', (22, 27))	('RARLA', 'Var', (22, 27))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (122, 147))	('RLA', 'Chemical', '-', (24, 27))	('lower', 'NegReg', (40, 45))	('less', 'NegReg', (117, 121))
32235	33028297	Postoperatively, the time to diet resumption, time to ambulation, time to drainage removal and postoperative hospital stay were shorter in the RARLA group than in the RLA group (1 d vs. 2 d, P = 0.027; 1 d vs. 2 d, P = 0.034; 3 d vs. 5 d, P = 0.002; 5 d vs. 6 d, P = 0.02, respectively).	('shorter', 'NegReg', (128, 135))	('RLA', 'Chemical', '-', (167, 170))	('RLA', 'Chemical', '-', (145, 148))	('RARLA', 'Chemical', '-', (143, 148))	('RARLA', 'Var', (143, 148))
32271	33028297	The time to oral food intake, the time to ambulation, the time to removal of the drainage tube and postoperative hospitalization days were shorter in the RARLA group than in the RLA group, and the difference was statistically significant (1 d vs 2 d, P = 0.027; 1 d vs 2 d, P = 0.034; 4 d vs 5 d, P = 0.002 and 5 d vs 6 d, P = 0.02, respectively).	('RLA', 'Chemical', '-', (156, 159))	('RLA', 'Chemical', '-', (178, 181))	('RARLA', 'Chemical', '-', (154, 159))	('RARLA', 'Var', (154, 159))	('shorter', 'NegReg', (139, 146))
32280	33028297	An exciting finding in our study is that the RARLA group had less blood loss and a lower transfusion rate than the RLA group, although no statistically significant difference in the intraoperative transfusion rate was identified between the two groups.	('blood loss', 'Disease', 'MESH:D006473', (66, 76))	('RARLA', 'Chemical', '-', (45, 50))	('RARLA', 'Var', (45, 50))	('transfusion rate', 'MPA', (89, 105))	('blood loss', 'Disease', (66, 76))	('lower', 'NegReg', (83, 88))	('RLA', 'Chemical', '-', (47, 50))	('less', 'NegReg', (61, 65))	('RLA', 'Chemical', '-', (115, 118))
32289	33028297	Compared with RLA for the treatment of large PHEOs, RARLA can result in more stable intraoperative haemodynamics, less intraoperative blood loss, and a faster postoperative recovery while achieving a similar BP improvement rate.	('PHEO', 'Phenotype', 'HP:0002666', (45, 49))	('RLA', 'Chemical', '-', (54, 57))	('RLA', 'Chemical', '-', (14, 17))	('intraoperative blood loss', 'Disease', (119, 144))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (119, 144))	('PHEOs', 'Phenotype', 'HP:0002666', (45, 50))	('more', 'PosReg', (72, 76))	('RARLA', 'Chemical', '-', (52, 57))	('RARLA', 'Var', (52, 57))
32295	31479526	PPGL related to succinate dehydrogenase subunits mutations (SDHx mutations) are less differentiated than other subgroups and therefore may lack to concentrate 18F-FDOPA, a precursor of catecholamines biosynthesis.	('SDHx', 'Gene', (60, 64))	('concentrate 18F-FDOPA', 'MPA', (147, 168))	('mutations', 'Var', (49, 58))	('18F-FDOPA', 'Chemical', '-', (159, 168))	('lack to concentrate', 'Phenotype', 'HP:0031987', (139, 158))	('catecholamines', 'Chemical', 'MESH:D002395', (185, 199))	('succinate', 'Chemical', 'MESH:D019802', (16, 25))	('lack', 'NegReg', (139, 143))	('PPGL', 'Chemical', '-', (0, 4))
32304	31479526	One of the most frequent and fascinating causes is linked to mutations in the SDH genes (SDHA-D and SDHAF2, collectively named SDHx) that encode for subunits of the succinate dehydrogenase (SDH), a key respiratory enzyme complex that converts succinate to fumarate in tricarboxylic acid (TCA) cycle and also functions in the mitochondrial electron transport chain.	('SDH', 'Gene', (78, 81))	('SDHAF2', 'Gene', (100, 106))	('fumarate', 'Chemical', 'MESH:D005650', (256, 264))	('mutations', 'Var', (61, 70))	('succinate', 'Chemical', 'MESH:D019802', (243, 252))	('succinate', 'Chemical', 'MESH:D019802', (165, 174))	('SDHA-D', 'Gene', (89, 95))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (268, 286))	('functions', 'Reg', (308, 317))	('TCA', 'Chemical', 'MESH:D014233', (288, 291))
32305	31479526	SDHx mutations result in SDH deficiency, disruption of the TCA cycle with subsequent accumulation of succinate and metabolic reprogramming that promotes tumorigenesis.	('succinate', 'Chemical', 'MESH:D019802', (101, 110))	('metabolic reprogramming', 'CPA', (115, 138))	('result in', 'Reg', (15, 24))	('tumorigenesis', 'CPA', (153, 166))	('TCA cycle', 'MPA', (59, 68))	('promotes', 'PosReg', (144, 152))	('mutations', 'Var', (5, 14))	('TCA', 'Chemical', 'MESH:D014233', (59, 62))	('SDHx', 'Gene', (0, 4))	('SDH deficiency', 'Disease', (25, 39))	('disruption', 'Reg', (41, 51))	('SDH deficiency', 'Disease', 'MESH:D007153', (25, 39))
32308	31479526	In the setting of PPGL, 18F-fluorodeoxyglucose (18F-FDG) avidity was found to be associated to SDHx mutations, possibly due to the effects of succinate on stabilization of hypoxia-inducible factors and/or on microenvironment metabolism.	('succinate', 'Chemical', 'MESH:D019802', (142, 151))	('mutations', 'Var', (100, 109))	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('SDHx', 'Gene', (95, 99))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (24, 46))	('hypoxia', 'Disease', (172, 179))	('18F-FDG', 'Chemical', 'MESH:D019788', (48, 55))	('PPGL', 'Chemical', '-', (18, 22))	('associated', 'Reg', (81, 91))
32310	31479526	18F-FDOPA PET/CT was found to be a sensitive imaging tool for sporadic and SDHx-related HNPGL (mostly linked to SDHD mutations).	('mutations', 'Var', (117, 126))	('HNPGL', 'Disease', (88, 93))	('SDHD', 'Disease', 'None', (112, 116))	('HNPGL', 'Phenotype', 'HP:0002864', (88, 93))	('18F-FDOPA', 'Chemical', '-', (0, 9))	('SDHD', 'Disease', (112, 116))	('linked', 'Reg', (102, 108))
32323	31479526	Thirty three patients (40%) carried mutations in one of the SDH genes (5 SDHB, 8 SDHC, 20 SDHD).	('SDH', 'Gene', (60, 63))	('SDHD', 'Disease', (90, 94))	('mutations', 'Var', (36, 45))	('SDHB', 'Disease', (73, 77))	('SDHD', 'Disease', 'None', (90, 94))
32328	31479526	SDHC-related HNPGL was found to have higher 18F-FDOPA-derived uptake parameters compared to their non-SDHx counterparts (P = .033 for SUVmax, P = .031 for SUVmean and P = .004 for TL) and higher TL compared to SDHD (P = .033; Figure 2).	('SDHD', 'Disease', (210, 214))	('18F-FDOPA-derived uptake parameters', 'MPA', (44, 79))	('higher', 'PosReg', (37, 43))	('SDHC-related', 'Var', (0, 12))	('higher', 'PosReg', (188, 194))	('TL', 'Chemical', '-', (195, 197))	('18F-FDOPA', 'Chemical', '-', (44, 53))	('SDHD', 'Disease', 'None', (210, 214))	('HNPGL', 'Phenotype', 'HP:0002864', (13, 18))	('TL', 'Chemical', '-', (180, 182))
32329	31479526	In the three metastatic patients included, the tumours exhibited highly elevated uptake values with SUVmax, SUVmean, MTV42% and TL of 33.5 +- 34.3; 20 +- 20.4, 2.5 +- 2.5 and 33.7 +- 39.6, respectively.	('elevated', 'PosReg', (72, 80))	('TL', 'Chemical', '-', (128, 130))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('uptake', 'MPA', (81, 87))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('MTV42%', 'Var', (117, 123))	('tumours', 'Disease', (47, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
32337	31479526	The inter- and intra-patient differences observed on 18F-FDOPA PET/CT in SDHx mutation carriers is still unexplainable.	('mutation', 'Var', (78, 86))	('SDHx', 'Gene', (73, 77))	('18F-FDOPA', 'Chemical', '-', (53, 62))
32338	31479526	The presented data suggest that presence of SDH mutations is not enough to drive the 18F-FDOPA imaging phenotype in all PPGL but can influence tumour metabolism in a certain cell lineage of tumours equipped with catecholamine biosynthesis/storage/turnover.	('drive', 'Reg', (75, 80))	('SDH', 'Gene', (44, 47))	('tumour metabolism', 'Disease', 'MESH:D009369', (143, 160))	('tumour metabolism', 'Disease', (143, 160))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('influence', 'Reg', (133, 142))	('tumours', 'Disease', 'MESH:D009369', (190, 197))	('tumours', 'Disease', (190, 197))	('PPGL', 'Chemical', '-', (120, 124))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))	('18F-FDOPA', 'Chemical', '-', (85, 94))	('18F-FDOPA imaging phenotype', 'MPA', (85, 112))	('catecholamine', 'Chemical', 'MESH:D002395', (212, 225))	('mutations', 'Var', (48, 57))
32339	31479526	It was shown that SDHx mutated tumours are classically associated with lack of uptake of specific radiopharmaceuticals such as 18F-FDOPA or 123I-MIBG.	('uptake', 'MPA', (79, 85))	('123I-MIBG', 'Chemical', 'MESH:D019797', (140, 149))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('mutated', 'Var', (23, 30))	('SDHx', 'Gene', (18, 22))	('18F-FDOPA', 'Chemical', '-', (127, 136))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))
32382	32095152	A new marker, Tyrosine hydroxylase, as an enzyme in catecholamine synthetic pathway is also positive in PGs.	('positive', 'Reg', (92, 100))	('PGs', 'Var', (104, 107))	('Tyrosine hydroxylase', 'Gene', '7054', (14, 34))	('Tyrosine hydroxylase', 'Gene', (14, 34))	('catecholamine', 'Chemical', 'MESH:D002395', (52, 65))	('PGs', 'Chemical', 'MESH:D010715', (104, 107))	('PG', 'Phenotype', 'HP:0002668', (104, 106))
32394	31579262	The Impact Of Succinate Dehydrogenase Gene (SDH) Mutations In Renal Cell Carcinoma (RCC): A Systematic Review Renal cell cancer (RCC) syndrome is linked to Krebs cycle compartments and their coding genes' alterations like succinate dehydrogenase genes (SDHx).	('SDH', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RCC', 'Disease', (84, 87))	('RCC', 'Disease', 'MESH:D002292', (84, 87))	('RCC', 'Disease', (129, 132))	('SDH', 'Gene', '6390', (253, 256))	('Renal Cell Carcinoma', 'Disease', (62, 82))	('Mutations', 'Var', (49, 58))	('succinate dehydrogenase', 'Gene', (222, 245))	('Succinate Dehydrogenase', 'Gene', (14, 37))	('Renal cell cancer (RCC) syndrome', 'Disease', 'MESH:D002292', (110, 142))	('Renal Cell Carcinoma', 'Disease', 'MESH:D002292', (62, 82))	('SDH', 'Gene', '6390', (44, 47))	('Succinate Dehydrogenase', 'Gene', '6390', (14, 37))	('RCC', 'Disease', 'MESH:D002292', (129, 132))	('Carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Renal cell cancer', 'Phenotype', 'HP:0005584', (110, 127))	('SDH', 'Gene', (253, 256))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (62, 82))	('succinate dehydrogenase', 'Gene', '6390', (222, 245))
32395	31579262	Here we present a systematic review of the SDH genes' mutations and their impact on both RCC diagnosis and prognosis.	('SDH', 'Gene', (43, 46))	('mutations', 'Var', (54, 63))	('RCC', 'Disease', (89, 92))	('SDH', 'Gene', '6390', (43, 46))	('RCC', 'Disease', 'MESH:D002292', (89, 92))
32396	31579262	This systematic review includes any study in which tissue samples of RCC are considered in correlation with the SDHx mutations, microsatellite instability (MSI), and protein expression.	('RCC', 'Disease', 'MESH:D002292', (69, 72))	('mutations', 'Var', (117, 126))	('RCC', 'Disease', (69, 72))	('SDH', 'Gene', (112, 115))	('microsatellite instability', 'MPA', (128, 154))	('SDH', 'Gene', '6390', (112, 115))	('MSI', 'Disease', 'MESH:D053842', (156, 159))	('MSI', 'Disease', (156, 159))
32397	31579262	The final selected nineteen studies investigating the SDHx role in RCC tumor genesis were included, among which fifteen were mutation analysis, three were just SDHx protein expression, and two were MSI and mutation analysis studies.	('SDH', 'Gene', (160, 163))	('mutation analysis', 'Var', (125, 142))	('MSI', 'Disease', 'MESH:D053842', (198, 201))	('MSI', 'Disease', (198, 201))	('RCC', 'Disease', 'MESH:D002292', (67, 70))	('RCC', 'Disease', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('SDH', 'Gene', '6390', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SDH', 'Gene', '6390', (54, 57))	('tumor', 'Disease', (71, 76))	('SDH', 'Gene', (54, 57))
32398	31579262	A total of 432 RCC patients were reported by SDH mutations, and 64 patients with MSI and SDH expression change were reported in 514 surgically resected renal epithelial tumors.	('MSI', 'Disease', 'MESH:D053842', (81, 84))	('SDH', 'Gene', (89, 92))	('MSI', 'Disease', (81, 84))	('patients', 'Species', '9606', (19, 27))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (67, 75))	('RCC', 'Disease', 'MESH:D002292', (15, 18))	('RCC', 'Disease', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('renal epithelial tumors', 'Disease', (152, 175))	('SDH', 'Gene', (45, 48))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('SDH', 'Gene', '6390', (89, 92))	('renal epithelial tumors', 'Disease', 'MESH:D007680', (152, 175))	('SDH', 'Gene', '6390', (45, 48))
32399	31579262	The most common mutation was the single nucleotide variant rs772551056 (c.137G>A) of SDHB.	('c.137G>A', 'Var', (72, 80))	('common', 'Reg', (9, 15))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('rs772551056 (c.137G>A', 'Var', (59, 80))	('rs772551056', 'Mutation', 'rs772551056', (59, 70))	('c.137G>A', 'Mutation', 'rs772551056', (72, 80))
32400	31579262	For SDHC, c.380A>G presented in 48 RCC patients, and for SDHA a novel germline mutation c.2T>C: p.M1T in an occasional case of gastrointestinal stromal tumor intricate with RCC.	('RCC', 'Disease', 'MESH:D002292', (35, 38))	('RCC', 'Disease', (35, 38))	('RCC', 'Disease', (173, 176))	('SDHC', 'Gene', (4, 8))	('c.380A>G', 'Var', (10, 18))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (127, 157))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('RCC', 'Disease', 'MESH:D002292', (173, 176))	('SDHC', 'Gene', '6391', (4, 8))	('c.2T>C: p.M1T', 'Var', (88, 101))	('c.380A>G', 'Mutation', 'c.380A>G', (10, 18))	('SDHA', 'Gene', '6389', (57, 61))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (127, 157))	('c.2T>C', 'Mutation', 'rs864622194', (88, 94))	('gastrointestinal stromal tumor', 'Disease', (127, 157))	('SDHA', 'Gene', (57, 61))	('p.M1T', 'Mutation', 'rs864622194', (96, 101))
32402	31579262	It was shown recently that the succinate dehydrogenase gene variations can provide this diagnostic and prognostic biomarker.	('succinate dehydrogenase', 'Gene', (31, 54))	('succinate dehydrogenase', 'Gene', '6390', (31, 54))	('variations', 'Var', (60, 70))
32403	31579262	For this purpose, SDHB rs772551056 associated with its protein expression alterations can be taken into account.	('SDHB', 'Gene', (18, 22))	('rs772551056', 'Var', (23, 34))	('protein expression alterations', 'MPA', (55, 85))	('rs772551056', 'Mutation', 'rs772551056', (23, 34))	('SDHB', 'Gene', '6390', (18, 22))
32404	31579262	It is possible that a novel mutation of SDHA (c.2T>C: p.M1T) can provide evidence of GIST associated with RCC as well.	('c.2T>C:', 'Var', (46, 53))	('SDHA', 'Gene', '6389', (40, 44))	('p.M1T', 'Mutation', 'rs864622194', (54, 59))	('associated', 'Reg', (90, 100))	('SDHA', 'Gene', (40, 44))	('RCC', 'Disease', (106, 109))	('c.2T>C', 'Mutation', 'rs864622194', (46, 52))	('RCC', 'Disease', 'MESH:D002292', (106, 109))
32413	31579262	Patients with mutations in the SDH genes are under the risk of autonomic nervous system tumors like pheochromocytomas and paragangliomas (PPGLs), both head and neck, and in the thorax and abdomen, gastrointestinal stromal tumors (GISTs), and renal cell carcinoma (RCC).	('pheochromocytomas', 'Phenotype', 'HP:0002666', (100, 117))	('GISTs', 'Disease', 'MESH:D046152', (230, 235))	('renal cell carcinoma', 'Disease', (242, 262))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (242, 262))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('autonomic nervous system tumors like pheochromocytomas and paragangliomas', 'Disease', 'MESH:D009423', (63, 136))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('GISTs', 'Disease', (230, 235))	('SDH', 'Gene', '6390', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('Patients', 'Species', '9606', (0, 8))	('PGL', 'Disease', 'MESH:D010235', (139, 142))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (197, 228))	('mutations', 'Var', (14, 23))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (197, 228))	('RCC', 'Disease', (264, 267))	('SDH', 'Gene', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('nervous system tumors', 'Phenotype', 'HP:0004375', (73, 94))	('RCC', 'Disease', 'MESH:D002292', (264, 267))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (242, 262))	('paragangliomas', 'Phenotype', 'HP:0002668', (122, 136))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (197, 227))	('paraganglioma', 'Phenotype', 'HP:0002668', (122, 135))	('PGL', 'Disease', (139, 142))	('gastrointestinal stromal tumors', 'Disease', (197, 228))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
32415	31579262	Succinate dehydrogenase mutation in PPGL and GIST tumor cells had a microscopic result of predominantly epithelioid morphology, and epithelioid morphology, but not in RCC.	('Succinate dehydrogenase', 'Gene', (0, 23))	('PGL', 'Disease', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('epithelioid morphology', 'CPA', (104, 126))	('PGL', 'Disease', 'MESH:D010235', (37, 40))	('RCC', 'Disease', 'MESH:D002292', (167, 170))	('RCC', 'Disease', (167, 170))	('mutation', 'Var', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('epithelioid morphology', 'CPA', (132, 154))	('Succinate dehydrogenase', 'Gene', '6390', (0, 23))	('tumor', 'Disease', (50, 55))
32417	31579262	RCCs with additional histologic presence have been described in patients with germline mutations of succinate dehydrogenase genes, contrary to some limited histological types of RCCs with no succinate dehydrogenase mutation.	('RCC', 'Disease', (0, 3))	('patients', 'Species', '9606', (64, 72))	('succinate dehydrogenase', 'Gene', (100, 123))	('succinate dehydrogenase', 'Gene', '6390', (100, 123))	('succinate dehydrogenase', 'Gene', '6390', (191, 214))	('RCC', 'Disease', 'MESH:D002292', (178, 181))	('RCC', 'Disease', (178, 181))	('succinate dehydrogenase', 'Gene', (191, 214))	('RCC', 'Disease', 'MESH:D002292', (0, 3))	('mutations', 'Var', (87, 96))
32419	31579262	Interestingly, germline mutations of the genes coding for the succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) have been identified in patients with a combination of gastrointestinal stromal tumors (GISTs) and paraganglioma (PGL).	('SDHC', 'Gene', (102, 106))	('succinate dehydrogenase', 'Gene', '6390', (62, 85))	('SDHD', 'Gene', '6392', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (142, 150))	('identified', 'Reg', (128, 138))	('SDHD', 'Gene', (112, 116))	('GISTs', 'Disease', 'MESH:D046152', (206, 211))	('PGL', 'Disease', 'MESH:D010235', (232, 235))	('paraganglioma', 'Disease', (217, 230))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (173, 204))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (173, 204))	('paraganglioma', 'Disease', 'MESH:D010235', (217, 230))	('SDHC', 'Gene', '6391', (102, 106))	('succinate dehydrogenase', 'Gene', (62, 85))	('GISTs', 'Disease', (206, 211))	('SDHB', 'Gene', '6390', (96, 100))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (173, 203))	('PGL', 'Disease', (232, 235))	('paraganglioma', 'Phenotype', 'HP:0002668', (217, 230))	('gastrointestinal stromal tumors', 'Disease', (173, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('SDHB', 'Gene', (96, 100))
32420	31579262	The co-occurrence of RCC with paraganglioma or pheochromocytoma suggested a succinate dehydrogenase gene mutation presence.	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('paraganglioma', 'Disease', (30, 43))	('succinate dehydrogenase', 'Gene', '6390', (76, 99))	('pheochromocytoma', 'Disease', (47, 63))	('succinate dehydrogenase', 'Gene', (76, 99))	('pheochromocytoma', 'Disease', 'MESH:D010673', (47, 63))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (47, 63))	('mutation presence', 'Var', (105, 122))	('paraganglioma', 'Disease', 'MESH:D010235', (30, 43))	('RCC', 'Disease', 'MESH:D002292', (21, 24))	('RCC', 'Disease', (21, 24))
32422	31579262	In spite of the fact that recently the focus of scientists is on RCC genetic and epigenetic modifications, knowledge of the clinical features and management of patients associated with the SDH mutations is limited.	('patients', 'Species', '9606', (160, 168))	('SDH', 'Gene', '6390', (189, 192))	('SDH', 'Gene', (189, 192))	('mutations', 'Var', (193, 202))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('RCC', 'Disease', (65, 68))
32423	31579262	The current systematic review study is run with the purpose of delivering the first meticulous summary of all the available primary research over the SDH mutations, expression, and microsatellite instability (MSI) in RCC management and screening recommendations.	('SDH', 'Gene', (150, 153))	('RCC', 'Disease', (217, 220))	('RCC', 'Disease', 'MESH:D002292', (217, 220))	('MSI', 'Disease', 'MESH:D053842', (209, 212))	('MSI', 'Disease', (209, 212))	('SDH', 'Gene', '6390', (150, 153))	('mutations', 'Var', (154, 163))
32427	31579262	Studies were excluded if they: 1) analyzed SDHx mutations or expression in animals (in vivo studies); 2) studied them in cell culture (in vitro studies); or (3) did not have an appropriate explanation of selected case groups.	('mutations', 'Var', (48, 57))	('SDH', 'Gene', '6390', (43, 46))	('expression', 'MPA', (61, 71))	('SDH', 'Gene', (43, 46))
32430	31579262	A total of sixteen studies were mainly focused on SDHx mutations, three studied the SDHx protein expression without mutation analysis, and two targeted SDHx MSI with or without mutation (Table 1).	('mutations', 'Var', (55, 64))	('MSI', 'Disease', 'MESH:D053842', (157, 160))	('MSI', 'Disease', (157, 160))	('SDH', 'Gene', '6390', (152, 155))	('SDH', 'Gene', '6390', (50, 53))	('SDH', 'Gene', '6390', (84, 87))	('SDH', 'Gene', (152, 155))	('SDH', 'Gene', (50, 53))	('SDH', 'Gene', (84, 87))
32433	31579262	In these studies, several mutations of SDHB were checked including exonic mutations (c.137G>A), splice site acceptor or donor mutations (c.72+1G T), exon 1 splice acceptor site or c.268C>T (p. Arg90X) in exon 3 splice site mutation, and (c.136C>T Stop) mutation of stop codons which are resulting in truncated inactive forms of the protein.	('Arg90X', 'Var', (193, 199))	('SDHB', 'Gene', '6390', (39, 43))	('Arg90X', 'SUBSTITUTION', 'None', (193, 199))	('c.137G>A', 'Mutation', 'rs772551056', (85, 93))	('c.72+1G T', 'Var', (137, 146))	('SDHB', 'Gene', (39, 43))	('donor', 'Species', '9606', (120, 125))	('c.136C>T Stop', 'Var', (238, 251))	('c.268C>T', 'Mutation', 'c.268C>T', (180, 188))	('c.137G>A', 'Var', (85, 93))	('c.136C>T', 'Mutation', 'c.136C>T', (238, 246))
32434	31579262	Five studies were mainly focused on SDHC in which loss of heterozygosity (LOH) in two telomeric regions (D3S369, D3S1597) and five centromeric regions (D3SVHL3, D3S1337, D3SVHL7, D3SVHL8, D3S3611) more than c.380A>G mutations were tested.	('D3SVHL3', 'Var', (152, 159))	('D3S1337', 'Var', (161, 168))	('D3S369', 'Var', (105, 111))	('D3S1597', 'Var', (113, 120))	('loss', 'NegReg', (50, 54))	('c.380A>G', 'Var', (207, 215))	('D3SVHL7', 'Var', (170, 177))	('D3SVHL8', 'Var', (179, 186))	('D3S3611', 'Var', (188, 195))	('SDHC', 'Gene', (36, 40))	('D3S1597', 'Chemical', 'MESH:C571787', (113, 120))	('c.380A>G', 'Mutation', 'c.380A>G', (207, 215))	('SDHC', 'Gene', '6391', (36, 40))
32435	31579262	Especially, in an aggressive example of the Warburg Effect in succinate dehydrogenase kidney cancer (SDH-RCC), the germline SDHC mutation (R133X) (NM_003001.3-c.397C>T (p. Arg133Ter)) was identified.	('succinate dehydrogenase', 'Gene', '6390', (62, 85))	('SDHC', 'Gene', (124, 128))	('R133X', 'Mutation', 'p.R133X', (139, 144))	('Arg133Ter', 'Var', (172, 181))	('R133X) (NM_003001.3-c.397C>T', 'Var', (139, 167))	('dehydrogenase kidney cancer', 'Disease', 'MESH:D007680', (72, 99))	('NM_003001.3-c.397C>T', 'Var', (147, 167))	('RCC', 'Disease', (105, 108))	('dehydrogenase kidney cancer', 'Disease', (72, 99))	('c.397C>T', 'Mutation', 'c.397C>T', (159, 167))	('SDH', 'Gene', '6390', (124, 127))	('succinate dehydrogenase', 'Gene', (62, 85))	('SDH', 'Gene', '6390', (101, 104))	('RCC', 'Disease', 'MESH:D002292', (105, 108))	('SDHC', 'Gene', '6391', (124, 128))	('Arg133Ter', 'SUBSTITUTION', 'None', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('kidney cancer', 'Phenotype', 'HP:0009726', (86, 99))	('SDH', 'Gene', (124, 127))	('SDH', 'Gene', (101, 104))
32436	31579262	Two studies were related to SDHA (c.2T>C: p.M1T/rs864622194) resulting in substitution of Methionine with Threonine in a NM_006493.2:c.2T>C missense variant that change the amino acid sequence in protein and resulted in non-functional protein (https://www.ncbi.nlm.nih.gov/clinvar/variation/219649/).	('c.2T>C', 'Mutation', 'rs864622194', (133, 139))	('amino acid sequence in protein', 'MPA', (173, 203))	('resulted in', 'Reg', (208, 219))	('non-functional protein', 'MPA', (220, 242))	('c.2T>C', 'Mutation', 'rs864622194', (34, 40))	('substitution', 'Var', (74, 86))	('NM_006493.2:c.2T>C', 'Var', (121, 139))	('SDHA', 'Gene', (28, 32))	('NM_006493.2:c.2T>C', 'SUBSTITUTION', 'None', (121, 139))	('rs864622194', 'Mutation', 'rs864622194', (48, 59))	('p.M1T', 'Mutation', 'rs864622194', (42, 47))	('Threonine', 'Chemical', 'MESH:C061951', (106, 115))	('Methionine', 'Chemical', 'MESH:D008715', (90, 100))	('SDHA', 'Gene', '6389', (28, 32))	('change', 'Reg', (162, 168))
32438	31579262	Except for one study in sporadic RCC indicating no mutations in the three FH, FIH-1, and SDHB, others mainly suggested early-onset RCC with unusual histology (e.g., solid) must be observed to take an extended family history and SDHB mutant-related RCC in the way of better diagnosis and prognosis.	('FIH-1', 'Gene', '55662', (78, 83))	('FIH-1', 'Gene', (78, 83))	('RCC', 'Disease', 'MESH:D002292', (248, 251))	('RCC', 'Disease', (248, 251))	('SDHB', 'Gene', '6390', (228, 232))	('RCC', 'Disease', 'MESH:D002292', (131, 134))	('RCC', 'Disease', (131, 134))	('RCC', 'Disease', 'MESH:D002292', (33, 36))	('RCC', 'Disease', (33, 36))	('mutant-related', 'Var', (233, 247))	('SDHB', 'Gene', (228, 232))	('SDHB', 'Gene', '6390', (89, 93))	('FH', 'Gene', '2271', (74, 76))	('SDHB', 'Gene', (89, 93))
32440	31579262	The most common mutation was the single nucleotide variant rs772551056 (c.137G>A) of SDHB with genomic location Chr1: 17044824 resulting in protein change R46Q which was reported in 106 RCC patients.	('R46Q', 'Mutation', 'rs772551056', (155, 159))	('R46Q', 'Var', (155, 159))	('patients', 'Species', '9606', (190, 198))	('RCC', 'Disease', 'MESH:D002292', (186, 189))	('RCC', 'Disease', (186, 189))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('protein change', 'MPA', (140, 154))	('rs772551056', 'Mutation', 'rs772551056', (59, 70))	('c.137G>A', 'Mutation', 'rs772551056', (72, 80))
32441	31579262	After that, two mutations of c.32G>A and c.136C>T Stop were the most with 79 reported RCC patients.	('c.32G>A', 'Var', (29, 36))	('c.136C>T Stop', 'Var', (41, 54))	('c.32G>A', 'Mutation', 'c.32G>A', (29, 36))	('c.136C>T', 'Mutation', 'c.136C>T', (41, 49))	('RCC', 'Disease', 'MESH:D002292', (86, 89))	('RCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))
32442	31579262	The mutation of c.423+1G>A was in 44 RCC patients and c.72+1G T in 20 patients.	('c.72+1G T', 'Var', (54, 63))	('patients', 'Species', '9606', (70, 78))	('c.423+1G>A', 'Mutation', 'c.423+1G>A', (16, 26))	('RCC', 'Disease', 'MESH:D002292', (37, 40))	('RCC', 'Disease', (37, 40))	('patients', 'Species', '9606', (41, 49))	('c.423+1G>A', 'Var', (16, 26))
32443	31579262	The SDHC c.380A>G (p. His127Arg) was in 48 RCC, 18 PPGLs, and 11 GIST.	('c.380A>G', 'Mutation', 'c.380A>G', (9, 17))	('PGL', 'Disease', (52, 55))	('SDHC', 'Gene', (4, 8))	('PGL', 'Disease', 'MESH:D010235', (52, 55))	('SDHC', 'Gene', '6391', (4, 8))	('His127Arg', 'SUBSTITUTION', 'None', (22, 31))	('c.380A>G', 'Var', (9, 17))	('RCC', 'Disease', 'MESH:D002292', (43, 46))	('RCC', 'Disease', (43, 46))	('His127Arg', 'Var', (22, 31))
32444	31579262	The rs786201095 (c.380T>G (p. Ile127Ser)) with chromosome location Chr1: 17028643 is the common mutation found in RCC in addition to GIST and PPGL.	('c.380T>G', 'Var', (17, 25))	('RCC', 'Disease', (114, 117))	('RCC', 'Disease', 'MESH:D002292', (114, 117))	('PGL', 'Disease', (143, 146))	('Ile127Ser', 'SUBSTITUTION', 'None', (30, 39))	('PGL', 'Disease', 'MESH:D010235', (143, 146))	('Ile127Ser', 'Var', (30, 39))	('c.380T>G', 'Mutation', 'rs786201095', (17, 25))	('rs786201095', 'Mutation', 'rs786201095', (4, 15))
32446	31579262	The novel germline mutation of chromosome X rs864622194 (c.2T>C: p.M1T) with genomic locus ChrX: 103776997 in SDHA was recognized in a rare case of gastrointestinal stromal tumor complicated with RCC.	('c.2T>C', 'Mutation', 'rs864622194', (57, 63))	('p.M1T', 'Mutation', 'rs864622194', (65, 70))	('RCC', 'Disease', (196, 199))	('SDHA', 'Gene', (110, 114))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (148, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (148, 178))	('RCC', 'Disease', 'MESH:D002292', (196, 199))	('rs864622194', 'Var', (44, 55))	('rs864622194', 'Mutation', 'rs864622194', (44, 55))	('gastrointestinal stromal tumor', 'Disease', (148, 178))	('SDHA', 'Gene', '6389', (110, 114))
32451	31579262	Recently the importance of SDH subunit mutations has been highlighted in different malignancies including RCC.	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('SDH', 'Gene', (27, 30))	('mutations', 'Var', (39, 48))	('RCC', 'Disease', (106, 109))	('malignancies', 'Disease', (83, 95))	('SDH', 'Gene', '6390', (27, 30))	('RCC', 'Disease', 'MESH:D002292', (106, 109))
32456	31579262	Common genetic alterations of SDHB consist of a nonsense mutation (c.268C>T p.Arg90X), four missense mutations (c.137G>A p.Arg46Gln, c.286G>A p.Gly96Ser, c.379A>C p.Ile127Leu, c.689G>A p.Arg230His), two splice site altering mutations (c.286+2T>A, c.541-2A>G), and three complete deletions of the first exon of SDHB.	('SDHB', 'Gene', '6390', (310, 314))	('c.286G>A', 'SUBSTITUTION', 'None', (133, 141))	('c.379A>C', 'SUBSTITUTION', 'None', (154, 162))	('p.Arg230His', 'Var', (185, 196))	('p.Gly96Ser', 'SUBSTITUTION', 'None', (142, 152))	('p.Arg46Gln', 'SUBSTITUTION', 'None', (121, 131))	('SDHB', 'Gene', (310, 314))	('p.Ile127Leu', 'Var', (163, 174))	('c.286+2T>A', 'Var', (235, 245))	('SDHB', 'Gene', '6390', (30, 34))	('c.286+2T>A', 'Mutation', 'c.286+2T>A', (235, 245))	('c.541-2A>G', 'Mutation', 'c.541-2A>G', (247, 257))	('p.Ile127Leu', 'SUBSTITUTION', 'None', (163, 174))	('c.689G>A', 'SUBSTITUTION', 'None', (176, 184))	('p.Arg46Gln', 'Var', (121, 131))	('c.379A>C', 'Var', (154, 162))	('c.689G>A', 'Var', (176, 184))	('c.137G>A', 'SUBSTITUTION', 'None', (112, 120))	('c.137G>A', 'Var', (112, 120))	('p.Gly96Ser', 'Var', (142, 152))	('SDHB', 'Gene', (30, 34))	('p.Arg90X', 'SUBSTITUTION', 'None', (76, 84))	('c.268C>T', 'SUBSTITUTION', 'None', (67, 75))	('c.268C>T', 'Var', (67, 75))	('p.Arg230His', 'SUBSTITUTION', 'None', (185, 196))	('c.286G>A', 'Var', (133, 141))	('p.Arg90X', 'Var', (76, 84))
32457	31579262	The mutation c.72+1G T which is in the exon 1 splice acceptor site resulting in production of a truncated inactive form of the protein was in RCC with giant mitochondria.	('RCC', 'Disease', 'MESH:D002292', (142, 145))	('RCC', 'Disease', (142, 145))	('giant mitochondria', 'Disease', (151, 169))	('giant mitochondria', 'Disease', 'MESH:C564971', (151, 169))	('c.72+1G T', 'Var', (13, 22))
32458	31579262	SDHB mutation results in distinctive morphology of RCC and these RCCs have a respectable prognosis subsequently of whole excision unless there is sarcomatoid dedifferentiation.	('RCC', 'Disease', (51, 54))	('RCC', 'Disease', 'MESH:D002292', (65, 68))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('results in', 'Reg', (14, 24))	('mutation', 'Var', (5, 13))	('RCC', 'Disease', 'MESH:D002292', (51, 54))	('RCC', 'Disease', (65, 68))
32459	31579262	The involvement of SDHB mutations in RCC recommends that SDHB mutations must be checked when renal tumors are presented in families with other tumors consistent with hereditary paraganglioma syndrome.	('renal tumors', 'Disease', (93, 105))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('hereditary paraganglioma syndrome', 'Disease', (166, 199))	('RCC', 'Disease', (37, 40))	('SDHB', 'Gene', (57, 61))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Disease', (143, 149))	('renal tumors', 'Phenotype', 'HP:0009726', (93, 105))	('RCC', 'Disease', 'MESH:D002292', (37, 40))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D061325', (166, 199))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('SDHB', 'Gene', '6390', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('renal tumor', 'Phenotype', 'HP:0009726', (93, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (99, 105))	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (19, 23))	('renal tumors', 'Disease', 'MESH:D007680', (93, 105))	('paraganglioma', 'Phenotype', 'HP:0002668', (177, 190))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
32460	31579262	The two mutations c.541-2A>G (Splice) and c.689G>A (pArg230His) have a role in impairing iron-sulfur cluster delivery and are highlighted in several cancers.	('iron-sulfur cluster delivery', 'MPA', (89, 117))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('c.689G>A', 'Var', (42, 50))	('c.541-2A>G', 'Mutation', 'c.541-2A>G', (18, 28))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('c.541-2A>G', 'Var', (18, 28))	('c.689G>A', 'Mutation', 'c.689G>A', (42, 50))	('iron-sulfur', 'Chemical', 'MESH:D013455', (89, 100))	('impairing', 'NegReg', (79, 88))	('pArg230His', 'Chemical', 'MESH:C042459', (52, 62))
32461	31579262	According to our result the most common SDHB mutation was the single nucleotide variant rs772551056 (c.137G>A).	('SDHB', 'Gene', '6390', (40, 44))	('SDHB', 'Gene', (40, 44))	('rs772551056 (c.137G>A', 'Var', (88, 109))	('rs772551056', 'Mutation', 'rs772551056', (88, 99))	('c.137G>A', 'Mutation', 'rs772551056', (101, 109))
32463	31579262	Importantly, the c.137G>A (p.Arg46Gln or R46Q) mutation occurs in the first L(I)YR motif of SDHB and can be detected in familial paraganglioma/pheochromocytoma/GIST/renal cell carcinoma tumor syndromes.	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('detected', 'Reg', (108, 116))	('SDHB', 'Gene', '6390', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('familial paraganglioma/pheochromocytoma/GIST/renal cell carcinoma tumor', 'Disease', 'MESH:C536851', (120, 191))	('c.137G>A', 'Mutation', 'rs772551056', (17, 25))	('p.Arg46Gln', 'Mutation', 'rs772551056', (27, 37))	('SDHB', 'Gene', (92, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('R46Q', 'Mutation', 'rs772551056', (41, 45))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (165, 185))	('R46Q', 'Var', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
32466	31579262	Possible succinate-induced modifications contain stabilization of HIF-alpha propyl hydroxylase and hypermethylation of histones and DNA.	('propyl', 'Chemical', 'MESH:C033205', (76, 82))	('modifications', 'Var', (27, 40))	('succinate', 'Chemical', 'MESH:D013386', (9, 18))	('hypermethylation', 'MPA', (99, 115))	('histones', 'Protein', (119, 127))	('HIF-alpha', 'Protein', (66, 75))	('DNA', 'MPA', (132, 135))	('stabilization', 'MPA', (49, 62))
32469	31579262	Moreover, the SDHD mutations together with SDHB mutations were reported in familial PCC and HPGL.	('reported', 'Reg', (63, 71))	('PGL', 'Disease', 'MESH:D010235', (93, 96))	('SDHB', 'Gene', '6390', (43, 47))	('PCC', 'Disease', (84, 87))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))	('PCC', 'Disease', 'MESH:D010673', (84, 87))	('SDHB', 'Gene', (43, 47))	('SDHD', 'Gene', (14, 18))	('PGL', 'Disease', (93, 96))
32471	31579262	Germline mutation c.380A>G (p.His127Arg) of SDHC is the important mutation of this gene which is reported as a recurrent biomarker of SDH-deficient GIST and renal carcinoma.	('SDHC', 'Gene', '6391', (44, 48))	('SDH', 'Gene', (44, 47))	('c.380A>G', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('SDH', 'Gene', (134, 137))	('SDH', 'Gene', '6390', (44, 47))	('renal carcinoma', 'Disease', (157, 172))	('renal carcinoma', 'Disease', 'MESH:D002292', (157, 172))	('c.380A>G', 'Mutation', 'c.380A>G', (18, 26))	('renal carcinoma', 'Phenotype', 'HP:0005584', (157, 172))	('p.His127Arg', 'Mutation', 'p.H127R', (28, 39))	('SDHC', 'Gene', (44, 48))	('SDH', 'Gene', '6390', (134, 137))
32475	31579262	SDHC c.380A>G happens at a conserved protein region through different species and is located at the metal attachment site for iron and in the helical transmembrane topological domain.	('iron', 'Chemical', 'MESH:D007501', (126, 130))	('SDHC', 'Gene', (0, 4))	('SDHC', 'Gene', '6391', (0, 4))	('c.380A>G', 'Var', (5, 13))	('c.380A>G', 'Mutation', 'c.380A>G', (5, 13))
32476	31579262	In silico analyses predict that this polymorphism can perhaps change the protein structure and function, and suggested novel mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma.	('mutations', 'Var', (125, 134))	('paraganglioma', 'Phenotype', 'HP:0002668', (188, 201))	('paraganglioma', 'Phenotype', 'HP:0002668', (161, 174))	('neck paraganglioma and familial paraganglioma', 'Disease', 'MESH:D010235', (156, 201))	('change', 'Reg', (62, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (209, 225))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (147, 174))	('pheochromocytoma', 'Disease', (209, 225))	('function', 'MPA', (95, 103))	('pheochromocytoma', 'Disease', 'MESH:D010673', (209, 225))	('protein structure', 'MPA', (73, 90))
32477	31579262	Based on the currently available evidence, SDHC c.380A>G can be considered the RCC pathogenic variant.	('SDHC', 'Gene', '6391', (43, 47))	('RCC', 'Disease', (79, 82))	('c.380A>G', 'Var', (48, 56))	('c.380A>G', 'Mutation', 'c.380A>G', (48, 56))	('RCC', 'Disease', 'MESH:D002292', (79, 82))	('SDHC', 'Gene', (43, 47))
32478	31579262	These are conflicting because germline SDHC mutations are comparatively uncommon, so it was supposed that carriers of mutations of the SDHC gene have aspecial risk for head and neck paragangliomas more than a risk for adrenal pheochromocytoma.	('SDHC', 'Gene', '6391', (39, 43))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (168, 195))	('mutations', 'Var', (118, 127))	('adrenal pheochromocytoma', 'Disease', (218, 242))	('paragangliomas', 'Phenotype', 'HP:0002668', (182, 196))	('paraganglioma', 'Phenotype', 'HP:0002668', (182, 195))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (218, 242))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (168, 196))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (226, 242))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (218, 242))	('SDHC', 'Gene', (135, 139))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (168, 196))	('SDHC', 'Gene', (39, 43))	('SDHC', 'Gene', '6391', (135, 139))
32479	31579262	Therefore, not only the SDHC mutations but also the LOH and MSI were taken into consideration in RCC patients.	('MSI', 'Disease', (60, 63))	('RCC', 'Disease', (97, 100))	('patients', 'Species', '9606', (101, 109))	('SDHC', 'Gene', (24, 28))	('RCC', 'Disease', 'MESH:D002292', (97, 100))	('mutations', 'Var', (29, 38))	('SDHC', 'Gene', '6391', (24, 28))	('MSI', 'Disease', 'MESH:D053842', (60, 63))
32480	31579262	Two telomeric (D3S3691, D3S1597) and five centromeric (D3SVHL3, D3S1337, D3SVHL7, D3SVHL8, D3S3611) were evaluated and renal carcinoma.	('D3SVHL3', 'Var', (55, 62))	('D3S1597', 'Chemical', 'MESH:C571787', (24, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('D3S3611', 'Var', (91, 98))	('D3SVHL7', 'Var', (73, 80))	('D3SVHL8', 'Var', (82, 89))	('renal carcinoma', 'Disease', (119, 134))	('renal carcinoma', 'Disease', 'MESH:D002292', (119, 134))	('renal carcinoma', 'Phenotype', 'HP:0005584', (119, 134))	('D3S3691', 'Var', (15, 22))	('D3S1597', 'Var', (24, 31))	('D3S1337', 'Var', (64, 71))
32481	31579262	It was reported by Malinoc et al that for the clear cell renal carcinoma LOH was established in D3S3691 and, D3S1597 as the telomeric ones and in two centromeric signs (D3SVHL3 and D3S3611) in comparison with undesirable controls so it might be a new molecular indicator for the pathogenesis of RCC and ought to be checked in both heritable and sporadic forms.	('D3S3691', 'Var', (96, 103))	('renal carcinoma', 'Disease', (57, 72))	('renal carcinoma', 'Phenotype', 'HP:0005584', (57, 72))	('renal carcinoma', 'Disease', 'MESH:D002292', (57, 72))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (46, 72))	('D3S1597', 'Var', (109, 116))	('D3S1597', 'Chemical', 'MESH:C571787', (109, 116))	('RCC', 'Disease', 'MESH:D002292', (295, 298))	('RCC', 'Disease', (295, 298))	('D3S3611', 'Var', (181, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
32483	31579262	There was another described patient of an RCC linked with an SDHA mutation.	('SDHA', 'Gene', (61, 65))	('RCC', 'Disease', 'MESH:D002292', (42, 45))	('patient', 'Species', '9606', (28, 35))	('linked', 'Reg', (46, 52))	('SDHA', 'Gene', '6389', (61, 65))	('mutation', 'Var', (66, 74))	('RCC', 'Disease', (42, 45))
32484	31579262	As the main catalytic subunit of SDH complex, the (c.2T>C: p.M1T) mutation certainly deactivates the entire SDH complex.	('SDH', 'Gene', (33, 36))	('SDH', 'Gene', '6390', (108, 111))	('deactivates', 'NegReg', (85, 96))	('SDH', 'Gene', '6390', (33, 36))	('c.2T>C', 'Mutation', 'rs864622194', (51, 57))	('c.2T>C: p.M1T) mutation', 'Var', (51, 74))	('SDH', 'Gene', (108, 111))	('p.M1T', 'Mutation', 'rs864622194', (59, 64))
32486	31579262	Nevertheless, SDHA mutation does not result in loss of SDHA protein expression, which directs that the role of the other allele is normal, so SDHA in addition to SDHB have been recommended as diagnostic biomarkers for screening for potential SDH mutations in RCC cases.	('RCC', 'Disease', (259, 262))	('SDH', 'Gene', (162, 165))	('SDH', 'Gene', '6390', (55, 58))	('mutation', 'Var', (19, 27))	('SDH', 'Gene', '6390', (142, 145))	('SDHA', 'Gene', (55, 59))	('SDHA', 'Gene', (142, 146))	('RCC', 'Disease', 'MESH:D002292', (259, 262))	('mutations', 'Var', (246, 255))	('SDHB', 'Gene', '6390', (162, 166))	('SDHA', 'Gene', '6389', (55, 59))	('SDHA', 'Gene', '6389', (142, 146))	('SDH', 'Gene', '6390', (14, 17))	('SDHA', 'Gene', (14, 18))	('SDH', 'Gene', '6390', (242, 245))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', (142, 145))	('SDHA', 'Gene', '6389', (14, 18))	('SDHB', 'Gene', (162, 166))	('SDH', 'Gene', '6390', (162, 165))	('SDH', 'Gene', (14, 17))	('SDH', 'Gene', (242, 245))
32491	31579262	To our knowledge, as the first systematic review on the succinate dehydrogenase genetic alterations, we can say that the most frequently detected mutation is SDHB rs772551056 and its protein expression.	('rs772551056', 'Mutation', 'rs772551056', (163, 174))	('succinate dehydrogenase', 'Gene', '6390', (56, 79))	('succinate dehydrogenase', 'Gene', (56, 79))	('SDHB', 'Gene', '6390', (158, 162))	('rs772551056', 'Var', (163, 174))	('SDHB', 'Gene', (158, 162))
32492	31579262	Moreover, the c.380A>G mutation with four MSI markers (D3S3691, D3S1597, D3SVHL3, D3S3611) of SDHC can bring a morphologically distinct entity of RCC and be a predictor of its recurrence and aggressive behavior.	('aggressive behavior', 'Disease', (191, 210))	('aggressive behavior', 'Disease', 'MESH:D001523', (191, 210))	('RCC', 'Disease', 'MESH:D002292', (146, 149))	('RCC', 'Disease', (146, 149))	('c.380A>G', 'Var', (14, 22))	('D3S3691', 'Var', (55, 62))	('D3S1597', 'Var', (64, 71))	('aggressive behavior', 'Phenotype', 'HP:0000718', (191, 210))	('D3S3611', 'Var', (82, 89))	('MSI', 'Disease', 'MESH:D053842', (42, 45))	('MSI', 'Disease', (42, 45))	('c.380A>G', 'Mutation', 'c.380A>G', (14, 22))	('SDHC', 'Gene', (94, 98))	('D3S1597', 'Chemical', 'MESH:C571787', (64, 71))	('SDHC', 'Gene', '6391', (94, 98))	('D3SVHL3', 'Var', (73, 80))
32493	31579262	The newly suggested mutation of SDHA (c.2T>C: p.M1T) can provide evidence of GIST associated with RCC as well.	('c.2T>C: p.M1T', 'Var', (38, 51))	('associated', 'Reg', (82, 92))	('SDHA', 'Gene', '6389', (32, 36))	('c.2T>C', 'Mutation', 'rs864622194', (38, 44))	('RCC', 'Disease', (98, 101))	('RCC', 'Disease', 'MESH:D002292', (98, 101))	('SDHA', 'Gene', (32, 36))	('p.M1T', 'Mutation', 'rs864622194', (46, 51))
32502	31540433	The relevance of such mutations in tumorigenesis and catecholamine biosynthesis and secretion are also presented with special emphasis on the role of hypoxia-inducible factors on the regulation of phosphorylation of tyrosine hydroxylase.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('catecholamine biosynthesis', 'MPA', (53, 79))	('hypoxia', 'Disease', (150, 157))	('hypoxia', 'Disease', 'MESH:D000860', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tyrosine', 'Chemical', 'None', (216, 224))	('catecholamine', 'Chemical', 'MESH:D002395', (53, 66))	('mutations', 'Var', (22, 31))
32507	31540433	More specifically for head and neck PGL and metastatic cases, [68Ga]-DOTATATE PET/CT has become the best available imaging modality.	('PGL', 'Disease', (36, 39))	('metastatic', 'Disease', (44, 54))	('PGL', 'Disease', 'MESH:D010235', (36, 39))	('[68Ga', 'Var', (62, 67))	('[68Ga]-DOTATATE', 'Chemical', 'MESH:C513399', (62, 77))	('PGL', 'Phenotype', 'HP:0002668', (36, 39))
32515	31540433	To achieve these goals, preclinical models are needed, such as transgenic mice (e.g., Epas1 Gain-of-Function Mutation), canine models that carry similar genomic alterations to humans, or patient-derived tumor xenografts (PDXs).	('Mutation', 'Var', (109, 117))	('humans', 'Species', '9606', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('Gain-of-Function', 'PosReg', (92, 108))	('Epas1', 'Gene', '13819', (86, 91))	('canine', 'Species', '9615', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('patient', 'Species', '9606', (187, 194))	('transgenic mice', 'Species', '10090', (63, 78))	('Epas1', 'Gene', (86, 91))
32518	31540433	One original article shows a significant reduction or complete eradication of subcutaneous and metastatic lesions in a pheochromocytoma mouse model after immunotherapy using Mannan-BAM, TLR ligands, and anti-CD40.	('eradication', 'NegReg', (63, 74))	('anti-CD40', 'Var', (203, 212))	('pheochromocytoma', 'Disease', (119, 135))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('Mannan-BAM', 'Chemical', 'MESH:D008351', (174, 184))	('pheochromocytoma', 'Disease', 'MESH:D010673', (119, 135))	('mouse', 'Species', '10090', (136, 141))	('reduction', 'NegReg', (41, 50))
32590	31110198	Twelve weeks after 131I-mIBG injection, examinations for the evaluation of therapeutic effects was performed in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST).	('131I-mIBG', 'Var', (19, 28))	('Tumours', 'Phenotype', 'HP:0002664', (170, 177))	('131I-mIBG', 'Chemical', 'MESH:D019797', (19, 28))	('Solid Tumours', 'Disease', (164, 177))
32600	31110198	This phase I trial in a multi-center setting was conducted to assess the safety, dose-limiting toxicity (DLT), and efficacy of 131I-mIBG therapy in patients with refractory PPGL.	('patients', 'Species', '9606', (148, 156))	('131I-mIBG', 'Var', (127, 136))	('131I-mIBG', 'Chemical', 'MESH:D019797', (127, 136))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
32626	31110198	In this phase I multi-institutional clinical trial, along with the standardized treatment protocol, we evaluated the safety and efficacy of 131I-mIBG therapy for 20 patients with refractory PPGLs.	('131I-mIBG', 'Var', (140, 149))	('131I-mIBG', 'Chemical', 'MESH:D019797', (140, 149))	('PPGLs', 'Disease', (190, 195))	('patients', 'Species', '9606', (165, 173))	('PPGLs', 'Chemical', '-', (190, 195))
32629	31110198	Although selection bias might have occurred in retrospective cohort studies:especially for rare diseases:those studies revealed that the incidence of grade 3 or higher adverse reactions was quite low and grade 4 hematological toxicity had never occurred at the fixed dose of 7.4 GBq of 131I-mIBG.	('GBq', 'Chemical', '-', (279, 282))	('131I-mIBG', 'Var', (286, 295))	('131I-mIBG', 'Chemical', 'MESH:D019797', (286, 295))	('hematological toxicity', 'Disease', 'MESH:D006402', (212, 234))	('hematological toxicity', 'Disease', (212, 234))
32711	30445560	Association of prolactin receptor (PRLR) variants with prolactinomas Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans.	('prolactin receptor', 'Gene', (15, 33))	('prolactinomas', 'Disease', 'MESH:D015175', (55, 68))	('Association', 'Interaction', (0, 11))	('variants', 'Var', (41, 49))	('Prolactinomas', 'Disease', (69, 82))	('PRLR', 'Gene', '5618', (35, 39))	('prolactinoma', 'Phenotype', 'HP:0040278', (55, 67))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('humans', 'Species', '9606', (187, 193))	('pituitary tumors', 'Disease', 'MESH:D010911', (113, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('prolactinomas', 'Disease', (55, 68))	('prolactin receptor', 'Gene', '5618', (15, 33))	('intracranial neoplasms', 'Disease', 'MESH:D001932', (161, 183))	('prolactinomas Prolactinomas', 'Phenotype', 'HP:0040278', (55, 82))	('Prolactinomas', 'Disease', 'MESH:D015175', (69, 82))	('neoplasms', 'Phenotype', 'HP:0002664', (174, 183))	('PRLR', 'Gene', (35, 39))	('intracranial neoplasms', 'Disease', (161, 183))	('pituitary tumors', 'Disease', (113, 129))
32714	30445560	This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants.	('Arg453Trp', 'Chemical', '-', (101, 110))	('Ile76Val', 'Chemical', '-', (158, 166))	('Asn492Ile', 'SUBSTITUTION', 'None', (115, 124))	('Arg453Trp', 'Var', (101, 110))	('Ile76Val', 'Var', (158, 166))	('Ile146Leu', 'Var', (168, 177))	('Glu376Gln', 'Var', (90, 99))	('Gly57Ser', 'SUBSTITUTION', 'None', (80, 88))	('Glu376Gln', 'SUBSTITUTION', 'None', (90, 99))	('Gly57Ser', 'Var', (80, 88))	('Ile146Leu', 'Chemical', '-', (168, 177))	('PRLR', 'Gene', (29, 33))	('Asn492Ile', 'Var', (115, 124))
32715	30445560	The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank.	('prolactinoma', 'Disease', (204, 216))	('prolactinoma', 'Phenotype', 'HP:0040278', (204, 216))	('Asn492Ile', 'Var', (33, 42))	('prolactinoma', 'Disease', 'MESH:D015175', (204, 216))	('Asn492Ile', 'SUBSTITUTION', 'None', (33, 42))	('Glu376Gln', 'SUBSTITUTION', 'None', (19, 28))	('higher frequencies', 'PosReg', (169, 187))	('patients', 'Species', '9606', (217, 225))	('Glu376Gln', 'Var', (19, 28))
32716	30445560	In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling.	('Asn492Ile', 'SUBSTITUTION', 'None', (61, 70))	('proliferation', 'CPA', (206, 219))	('rat', 'Species', '10116', (46, 49))	('increased prolactin', 'Phenotype', 'HP:0000870', (137, 156))	('Akt', 'Gene', (166, 169))	('Asn492Ile', 'Var', (61, 70))	('rat', 'Species', '10116', (213, 216))	('increased', 'PosReg', (137, 146))	('Glu376Gln', 'Var', (88, 97))	('Glu376Gln', 'SUBSTITUTION', 'None', (88, 97))	('Akt', 'Gene', '207', (166, 169))
32717	30445560	Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels.	('Akt', 'Gene', '207', (77, 80))	('Asn492Ile', 'SUBSTITUTION', 'None', (98, 107))	('reduced', 'NegReg', (90, 97))	('Asn492Ile', 'Var', (98, 107))	('rat', 'Species', '10116', (129, 132))	('Akt', 'Gene', (77, 80))	('Akt', 'Gene', '207', (27, 30))	('everolimus', 'Chemical', 'MESH:D000068338', (47, 57))	('men', 'Species', '9606', (5, 8))	('proliferation', 'CPA', (122, 135))	('Akt', 'Gene', (27, 30))
32718	30445560	Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.	('prolactinoma', 'Phenotype', 'HP:0040278', (86, 98))	('gain-of-function', 'PosReg', (52, 68))	('variant', 'Var', (74, 81))	('neoplasms', 'Phenotype', 'HP:0002664', (171, 180))	('prolactinomas', 'Disease', 'MESH:D015175', (86, 99))	('PRLR', 'Gene', (69, 73))	('prolactinomas', 'Disease', (86, 99))	('neoplasms', 'Disease', 'MESH:D009369', (171, 180))	('neoplasms', 'Disease', (171, 180))
32723	30445560	Prolactinomas in ~5% of patients may occur as a hereditary disorder and be due to germline mutations of the multiple endocrine neoplasia type-1 (MEN1) or aryl hydrocarbon receptor interacting protein (AIP) genes.	('aryl hydrocarbon receptor interacting protein', 'Gene', '9049', (154, 199))	('neoplasia', 'Phenotype', 'HP:0002664', (127, 136))	('AIP', 'Gene', (201, 204))	('due', 'Reg', (75, 78))	('hereditary disorder', 'Disease', (48, 67))	('Prolactinomas', 'Disease', 'MESH:D015175', (0, 13))	('MEN1', 'Gene', (145, 149))	('MEN1', 'Gene', '4221', (145, 149))	('multiple endocrine neoplasia type-1', 'Gene', '4221', (108, 143))	('multiple endocrine neoplasia type-1', 'Gene', (108, 143))	('mutations', 'Var', (91, 100))	('Prolactinomas', 'Disease', (0, 13))	('aryl hydrocarbon receptor interacting protein', 'Gene', (154, 199))	('patients', 'Species', '9606', (24, 32))	('hereditary disorder', 'Disease', 'MESH:D030342', (48, 67))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (117, 136))
32725	30445560	The PRLR, which functions as a dimer, is a class I cytokine receptor that has a multi-domain structure consisting of a ligand-binding extracellular domain (ECD, residues 1-210), a single transmembrane segment (residues 211-234) and an intracellular domain (ICD, residues 235-598) (Supplementary Material, Fig.	('men', 'Species', '9606', (204, 207))	('men', 'Species', '9606', (287, 290))	('ICD', 'Disease', 'OMIM:252500', (257, 260))	('residues 211-234', 'Var', (210, 226))	('ICD', 'Disease', (257, 260))
32726	30445560	The ECD comprises two subdomains designated D1 (residues 1-101) and D2 (residues 109-210), which are important in ligand binding and subsequent PRLR activation, and the ICD is involved in activation of signaling pathways that include the JAK2-STAT5 pathway, as well as the PI3K/Akt and MAPK pathways (Supplementary Material, Fig.	('Akt', 'Gene', (278, 281))	('ICD', 'Disease', 'OMIM:252500', (169, 172))	('men', 'Species', '9606', (307, 310))	('ICD', 'Disease', (169, 172))	('signaling pathways', 'Pathway', (202, 220))	('residues', 'Var', (72, 80))	('MAPK pathways', 'Pathway', (286, 299))	('Akt', 'Gene', '207', (278, 281))	('activation', 'PosReg', (188, 198))	('JAK2-STAT5 pathway', 'Pathway', (238, 256))
32733	30445560	For example, two low-frequency [defined as having a minor allele frequency (MAF) of 1-5%] PRLR variants, Ile76Val and Ile146Leu, have been reported to result in a gain of function with constitutive activity and to occur in 15% of a cohort of French women with multiple fibroadenomas of the breast (OMIM #615554).	('constitutive activity', 'MPA', (185, 206))	('Ile76Val', 'Chemical', '-', (105, 113))	('fibroadenomas of the breast', 'Phenotype', 'HP:0010619', (269, 296))	('women', 'Species', '9606', (249, 254))	('Ile146Leu', 'Chemical', '-', (118, 127))	('gain', 'PosReg', (163, 167))	('multiple fibroadenomas of the breast', 'Disease', 'OMIM:615554', (260, 296))	('multiple fibroadenomas of the breast', 'Disease', (260, 296))	('Ile146Leu', 'Var', (118, 127))	('PRLR', 'Gene', (90, 94))	('Ile76Val', 'Var', (105, 113))
32735	30445560	In addition, a loss-of-function PRLR mutation His188Arg mutation (H188R), which is located in the ECD and abolishes JAK2/STAT5 signaling, has been reported to occur in one family with autosomal dominant hyperprolactinemia (OMIM #615555) and to be associated with oligomenorrhea and infertility.	('autosomal dominant hyperprolactinemia', 'Disease', (184, 221))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (203, 221))	('JAK2/STAT5 signaling', 'MPA', (116, 136))	('His188Arg', 'SUBSTITUTION', 'None', (46, 55))	('infertility', 'Phenotype', 'HP:0000789', (282, 293))	('oligomenorrhea and infertility', 'Disease', 'MESH:D009839', (263, 293))	('abolishes', 'NegReg', (106, 115))	('His188Arg', 'Var', (46, 55))	('oligomenorrhea', 'Phenotype', 'HP:0000876', (263, 277))	('autosomal dominant hyperprolactinemia', 'Disease', 'MESH:D002640', (184, 221))	('loss-of-function', 'NegReg', (15, 31))	('H188R', 'Mutation', 'rs398122522', (66, 71))
32738	30445560	Furthermore, neuron-specific conditional Prlr knockout mice have also been reported to develop hyperprolactinemia and abnormalities of the estrous cycle, with lactotroph-specific conditional Prlr knockout mice having normal circulating prolactin levels and estrous cycles, but impaired dopaminergic tone.	('circulating prolactin levels', 'Phenotype', 'HP:0000870', (224, 252))	('knockout', 'Var', (46, 54))	('develop', 'PosReg', (87, 94))	('estrous', 'CPA', (257, 264))	('circulating prolactin levels', 'MPA', (224, 252))	('dopamine', 'Chemical', 'MESH:D004298', (286, 294))	('mice', 'Species', '10090', (55, 59))	('hyperprolactinemia and abnormalities of the estrous', 'Disease', 'MESH:D002640', (95, 146))	('mice', 'Species', '10090', (205, 209))	('impaired', 'NegReg', (277, 285))	('dopaminergic tone', 'MPA', (286, 303))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (95, 113))
32740	30445560	We therefore investigated the hypothesis that PRLR variants, resulting in aberrant PRLR signaling, may be associated with prolactinoma and hyperprolactinaemia in humans.	('PRLR signaling', 'MPA', (83, 97))	('hyperprolactinaemia', 'Disease', 'MESH:D002640', (139, 158))	('humans', 'Species', '9606', (162, 168))	('associated', 'Reg', (106, 116))	('variants', 'Var', (51, 59))	('prolactinoma', 'Disease', (122, 134))	('hyperprolactinaemia', 'Phenotype', 'HP:0000870', (139, 158))	('hyperprolactinaemia', 'Disease', (139, 158))	('prolactinoma', 'Disease', 'MESH:D015175', (122, 134))	('prolactinoma', 'Phenotype', 'HP:0040278', (122, 134))	('PRLR', 'Gene', (46, 50))
32741	30445560	Surprisingly, a previous French study has reported an absence of an association between PRLR variants and prolactinomas in humans.	('PRLR', 'Gene', (88, 92))	('variants', 'Var', (93, 101))	('prolactinomas', 'Disease', (106, 119))	('humans', 'Species', '9606', (123, 129))	('prolactinoma', 'Phenotype', 'HP:0040278', (106, 118))	('prolactinomas', 'Disease', 'MESH:D015175', (106, 119))
32742	30445560	However, here we show that germline Glu376Gln and Asn492Ile PRLR ICD variants, which are rare variants (defined as having a MAF <1%) and in complete linkage disequilibrium (LD), are significantly associated with occurrence of prolactinomas in humans.	('Asn492Ile', 'Var', (50, 59))	('ICD', 'Disease', (65, 68))	('Glu376Gln', 'SUBSTITUTION', 'None', (36, 45))	('associated with', 'Reg', (196, 211))	('prolactinomas', 'Disease', (226, 239))	('humans', 'Species', '9606', (243, 249))	('prolactinoma', 'Phenotype', 'HP:0040278', (226, 238))	('ICD', 'Disease', 'OMIM:252500', (65, 68))	('Glu376Gln', 'Var', (36, 45))	('Asn492Ile', 'SUBSTITUTION', 'None', (50, 59))	('prolactinomas', 'Disease', 'MESH:D015175', (226, 239))
32743	30445560	In addition, we show that the Asn492Ile PRLR variant is associated with increased signaling by the Akt pathway and that everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is effective in normalizing this gain of Akt activity.	('signaling', 'MPA', (82, 91))	('Akt', 'Gene', (223, 226))	('increased', 'PosReg', (72, 81))	('Asn492Ile', 'SUBSTITUTION', 'None', (30, 39))	('Akt', 'Gene', '207', (99, 102))	('activity', 'MPA', (227, 235))	('everolimus', 'Chemical', 'MESH:D000068338', (120, 130))	('Akt', 'Gene', (99, 102))	('mammalian', 'Species', '9606', (134, 143))	('Asn492Ile', 'Var', (30, 39))	('Akt', 'Gene', '207', (223, 226))	('mTOR', 'Gene', (165, 169))	('mTOR', 'Gene', '2475', (165, 169))	('PRLR', 'Gene', (40, 44))
32746	30445560	This identified the presence of six germline PRLR coding variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) with a MAF of <1% and two low-frequency variants (Ile76Val and Ile146Leu) with a MAF of 1-5% (Figs 1 and 2).	('Glu376Gln', 'SUBSTITUTION', 'None', (113, 122))	('Arg453Trp', 'Chemical', '-', (124, 133))	('Ile146Leu', 'Var', (212, 221))	('Ile76Val', 'Var', (199, 207))	('Gly57Ser', 'SUBSTITUTION', 'None', (103, 111))	('Arg453Trp', 'Var', (124, 133))	('PRLR', 'Gene', (45, 49))	('Ile146Leu', 'Chemical', '-', (212, 221))	('Gly57Ser', 'Var', (103, 111))	('Asn492Ile', 'SUBSTITUTION', 'None', (138, 147))	('Ile76Val', 'Chemical', '-', (199, 207))	('Glu376Gln', 'Var', (113, 122))	('Asn492Ile', 'Var', (138, 147))
32747	30445560	Combined analyses of leucocyte and prolactinoma DNA from 4 patients and that of 11 tumor DNA samples did not identify any additional tumor-specific PRLR variants, thereby indicating that these PRLR variants are germline and that somatic PRLR mutations are unlikely to be involved in the development of prolactinomas in humans (Fig.	('prolactinoma', 'Disease', 'MESH:D015175', (302, 314))	('tumor', 'Disease', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('prolactinoma', 'Disease', (35, 47))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PRLR', 'Gene', (237, 241))	('men', 'Species', '9606', (294, 297))	('patients', 'Species', '9606', (59, 67))	('prolactinoma', 'Disease', 'MESH:D015175', (35, 47))	('prolactinomas', 'Disease', (302, 315))	('prolactinoma', 'Phenotype', 'HP:0040278', (302, 314))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (133, 138))	('variants', 'Var', (198, 206))	('prolactinoma', 'Disease', (302, 314))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('prolactinomas', 'Disease', 'MESH:D015175', (302, 315))	('mutations', 'Var', (242, 251))	('humans', 'Species', '9606', (319, 325))	('prolactinoma', 'Phenotype', 'HP:0040278', (35, 47))
32748	30445560	Three of the PRLR variants (Gly57Ser, Ile76Val and Ile146Leu) were located in the ECD, while the other three (Glu376Gln, Arg453Trp and Asn492Ile) were located in the ICD (Supplementary Material, Fig.	('ICD', 'Disease', 'OMIM:252500', (166, 169))	('Arg453Trp', 'Chemical', '-', (121, 130))	('Asn492Ile', 'Var', (135, 144))	('Gly57Ser', 'SUBSTITUTION', 'None', (28, 36))	('Glu376Gln', 'SUBSTITUTION', 'None', (110, 119))	('Arg453Trp', 'Var', (121, 130))	('ICD', 'Disease', (166, 169))	('men', 'Species', '9606', (177, 180))	('Glu376Gln', 'Var', (110, 119))	('Ile76Val', 'Var', (38, 46))	('Gly57Ser', 'Var', (28, 36))	('Ile146Leu', 'Var', (51, 60))	('Ile76Val', 'Chemical', '-', (38, 46))	('Asn492Ile', 'SUBSTITUTION', 'None', (135, 144))	('Ile146Leu', 'Chemical', '-', (51, 60))
32749	30445560	Each of the three PRLR ICD rare variants (Glu376Gln, Arg453Trp and Asn492Ile) were observed at significantly higher frequencies in the 46 prolactinoma patients when compared to their frequencies in the Exome Aggregation Consortium (ExAc) cohort (Fig.	('prolactinoma', 'Disease', 'MESH:D015175', (138, 150))	('Asn492Ile', 'SUBSTITUTION', 'None', (67, 76))	('prolactinoma', 'Phenotype', 'HP:0040278', (138, 150))	('Glu376Gln', 'Var', (42, 51))	('Asn492Ile', 'Var', (67, 76))	('Glu376Gln', 'SUBSTITUTION', 'None', (42, 51))	('higher', 'PosReg', (109, 115))	('ICD', 'Disease', 'OMIM:252500', (23, 26))	('Arg453Trp', 'Chemical', '-', (53, 62))	('patients', 'Species', '9606', (151, 159))	('ICD', 'Disease', (23, 26))	('Arg453Trp', 'Var', (53, 62))	('prolactinoma', 'Disease', (138, 150))
32750	30445560	The Glu376Gln and Asn492Ile variants were found not to occur in the four patients with familial prolactinoma.	('familial prolactinoma', 'Disease', (87, 108))	('Glu376Gln', 'Var', (4, 13))	('Glu376Gln', 'SUBSTITUTION', 'None', (4, 13))	('Asn492Ile', 'SUBSTITUTION', 'None', (18, 27))	('familial prolactinoma', 'Disease', 'MESH:D015175', (87, 108))	('prolactinoma', 'Phenotype', 'HP:0040278', (96, 108))	('patients', 'Species', '9606', (73, 81))	('Asn492Ile', 'Var', (18, 27))
32751	30445560	The Arg453Trp variant, which was observed in four samples (two leucocyte and two tumors) from unrelated individuals, was absent in the ExAc database, and hence represented a novel variant.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('Arg453Trp', 'Var', (4, 13))	('Arg453Trp', 'Chemical', '-', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
32753	30445560	In addition, the co-occurrence of the Glu376Gln and Asn492Ile in nine individuals in the prolactinoma cohort indicated that these two rare variants are in a high degree of LD.	('prolactinoma cohort', 'Disease', 'MESH:D015175', (89, 108))	('Glu376Gln', 'Var', (38, 47))	('Glu376Gln', 'SUBSTITUTION', 'None', (38, 47))	('prolactinoma cohort', 'Disease', (89, 108))	('Asn492Ile', 'SUBSTITUTION', 'None', (52, 61))	('prolactinoma', 'Phenotype', 'HP:0040278', (89, 101))	('Asn492Ile', 'Var', (52, 61))
32754	30445560	This is supported by the observation that identical numbers of individuals of European descent harboured each of the Glu376Gln and Asn492Ile variants in the ExAC population, while the variants were also observed in perfect LD (r2 = 1/D' = 1) in the Oxford Biobank (OBB) cohort.	('Glu376Gln', 'SUBSTITUTION', 'None', (117, 126))	('Asn492Ile', 'Var', (131, 140))	('Asn492Ile', 'SUBSTITUTION', 'None', (131, 140))	('Glu376Gln', 'Var', (117, 126))
32755	30445560	The frequencies of the co-occurring Glu376Gln and Asn492Ile PRLR ICD rare variants were significantly higher in the prolactinoma patients than in the OBB cohort, thereby confirming the association between these two ICD PRLR variants and prolactinomas (Table 1).	('ICD', 'Disease', 'OMIM:252500', (215, 218))	('prolactinomas', 'Disease', 'MESH:D015175', (237, 250))	('prolactinoma', 'Disease', (116, 128))	('Asn492Ile', 'SUBSTITUTION', 'None', (50, 59))	('prolactinoma', 'Disease', 'MESH:D015175', (237, 249))	('higher', 'PosReg', (102, 108))	('prolactinoma', 'Disease', 'MESH:D015175', (116, 128))	('Glu376Gln', 'Var', (36, 45))	('Asn492Ile', 'Var', (50, 59))	('PRLR', 'Gene', (60, 64))	('patients', 'Species', '9606', (129, 137))	('prolactinomas', 'Disease', (237, 250))	('prolactinoma', 'Phenotype', 'HP:0040278', (237, 249))	('ICD', 'Disease', (65, 68))	('ICD', 'Disease', (215, 218))	('prolactinoma', 'Disease', (237, 249))	('prolactinoma', 'Phenotype', 'HP:0040278', (116, 128))	('ICD', 'Disease', 'OMIM:252500', (65, 68))	('Glu376Gln', 'SUBSTITUTION', 'None', (36, 45))
32756	30445560	Furthermore, ~90% (8/9) of the Glu376Gln and Asn492Ile PRLR variants occurred in male prolactinoma patients (Fig.	('prolactinoma', 'Phenotype', 'HP:0040278', (86, 98))	('Glu376Gln', 'SUBSTITUTION', 'None', (31, 40))	('male prolactinoma', 'Disease', (81, 98))	('Glu376Gln', 'Var', (31, 40))	('patients', 'Species', '9606', (99, 107))	('male prolactinoma', 'Disease', 'MESH:D015175', (81, 98))	('Asn492Ile', 'SUBSTITUTION', 'None', (45, 54))	('Asn492Ile', 'Var', (45, 54))	('occurred', 'Reg', (69, 77))
32757	30445560	1), and in 40% (6/15) of patients who had required pituitary surgery, indicating that these two PRLR variants may be associated with aggressive or medically non-responsive prolactinomas.	('prolactinomas', 'Disease', 'MESH:D015175', (172, 185))	('associated with', 'Reg', (117, 132))	('prolactinomas', 'Disease', (172, 185))	('variants', 'Var', (101, 109))	('patients', 'Species', '9606', (25, 33))	('prolactinoma', 'Phenotype', 'HP:0040278', (172, 184))
32758	30445560	These associations between prolactinomas and the two ICD PRLR rare variants (Glu376Gln and Asn492Ile) remained significant in separate sub-analyses of leucocyte and tumor DNA from 35 and 15 patients, respectively (Table 1).	('prolactinomas', 'Disease', (27, 40))	('tumor', 'Disease', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Asn492Ile', 'SUBSTITUTION', 'None', (91, 100))	('prolactinomas', 'Disease', 'MESH:D015175', (27, 40))	('patients', 'Species', '9606', (190, 198))	('ICD', 'Disease', 'OMIM:252500', (53, 56))	('Asn492Ile', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('rat', 'Species', '10116', (130, 133))	('prolactinoma', 'Phenotype', 'HP:0040278', (27, 39))	('ICD', 'Disease', (53, 56))	('Glu376Gln', 'SUBSTITUTION', 'None', (77, 86))	('Glu376Gln', 'Var', (77, 86))
32759	30445560	The three PRLR ICD rare variants (Glu376Gln, Arg453Trp and Asn492Ile) were predicted by SIFT and/or PolyPhen-2 to be damaging and to have partial evolutionary conservation (Figs 2 and 3).	('Arg453Trp', 'Chemical', '-', (45, 54))	('Glu376Gln', 'Var', (34, 43))	('Glu376Gln', 'SUBSTITUTION', 'None', (34, 43))	('ICD', 'Disease', 'OMIM:252500', (15, 18))	('Asn492Ile', 'SUBSTITUTION', 'None', (59, 68))	('Arg453Trp', 'Var', (45, 54))	('ICD', 'Disease', (15, 18))	('SIFT', 'Disease', (88, 92))	('Asn492Ile', 'Var', (59, 68))	('SIFT', 'Disease', 'None', (88, 92))
32760	30445560	Weaker and variable associations between the prolactinomas and the PRLR ECD variants (Gly57Ser, Ile76Val and Ile146Leu) were also observed (Table 1).	('PRLR', 'Gene', (67, 71))	('prolactinoma', 'Phenotype', 'HP:0040278', (45, 57))	('Ile76Val', 'Var', (96, 104))	('Gly57Ser', 'SUBSTITUTION', 'None', (86, 94))	('prolactinomas', 'Disease', 'MESH:D015175', (45, 58))	('Ile146Leu', 'Chemical', '-', (109, 118))	('Ile76Val', 'Chemical', '-', (96, 104))	('Gly57Ser', 'Var', (86, 94))	('prolactinomas', 'Disease', (45, 58))	('Ile146Leu', 'Var', (109, 118))
32761	30445560	The ECD Gly57Ser rare variant was predicted, by SIFT and/or PolyPhen-2, to be damaging, while the ECD Ile76Val and Ile146Leu low-frequency variants were predicted to be benign (Fig.	('SIFT', 'Disease', (48, 52))	('Ile76Val', 'Var', (102, 110))	('Ile76Val', 'Chemical', '-', (102, 110))	('Gly57Ser', 'SUBSTITUTION', 'None', (8, 16))	('SIFT', 'Disease', 'None', (48, 52))	('Gly57Ser', 'Var', (8, 16))	('Ile146Leu', 'Var', (115, 124))	('Ile146Leu', 'Chemical', '-', (115, 124))
32762	30445560	The PRLR can signal by STAT5 and PI3K/Akt and the effects of the six PRLR variants on these signaling pathways were therefore assessed by studying the following: the cellular expression of the PRLR; the immediate effects of prolactin binding on pSTAT5 and pAkt activation; and the later downstream effects of receptor activation on transcription of the STAT5 target gene cytokine inducible SH2-containing protein (CISH), cellular proliferation and apoptosis (Fig.	('CISH', 'Gene', '1154', (414, 418))	('apoptosis', 'CPA', (448, 457))	('cytokine inducible SH2-containing protein', 'Gene', '1154', (371, 412))	('cellular proliferation', 'CPA', (421, 443))	('rat', 'Species', '10116', (437, 440))	('CISH', 'Gene', (414, 418))	('Akt', 'Gene', (257, 260))	('Akt', 'Gene', '207', (257, 260))	('Akt', 'Gene', '207', (38, 41))	('variants', 'Var', (74, 82))	('cytokine inducible SH2-containing protein', 'Gene', (371, 412))	('Akt', 'Gene', (38, 41))
32764	30445560	The effects on PRLR signaling were assessed together with that of the His188Arg mutant PRLR ECD that has been reported to result in a loss of function in association with familial hyperprolactinaemia.	('His188Arg', 'Var', (70, 79))	('hyperprolactinaemia', 'Phenotype', 'HP:0000870', (180, 199))	('familial hyperprolactinaemia', 'Disease', (171, 199))	('PRLR', 'Gene', (87, 91))	('His188Arg', 'SUBSTITUTION', 'None', (70, 79))	('familial hyperprolactinaemia', 'Disease', 'MESH:D002640', (171, 199))
32767	30445560	In contrast, the loss-of-function PRLR ECD mutant His188Arg abolished pSTAT5 expression (Figs 4B and 5B) and CISH transcription (Figs 4D and 5D), consistent with previous reports, and impaired the pAkt response (Figs 4C and 5C), but did not affect proliferation (Figs 4E and 5E).	('His188Arg', 'SUBSTITUTION', 'None', (50, 59))	('abolished', 'NegReg', (60, 69))	('expression', 'MPA', (77, 87))	('pSTAT5', 'Gene', (70, 76))	('impaired', 'NegReg', (184, 192))	('loss-of-function', 'NegReg', (17, 33))	('Akt', 'Gene', '207', (198, 201))	('CISH', 'Gene', '1154', (109, 113))	('rat', 'Species', '10116', (255, 258))	('CISH', 'Gene', (109, 113))	('Akt', 'Gene', (198, 201))	('transcription', 'MPA', (114, 127))	('His188Arg', 'Var', (50, 59))
32768	30445560	Cells expressing the prolactinoma-associated PRLR ECD variant Ile76Val (Fig.	('prolactinoma', 'Disease', (21, 33))	('Ile76Val', 'Var', (62, 70))	('prolactinoma', 'Phenotype', 'HP:0040278', (21, 33))	('prolactinoma', 'Disease', 'MESH:D015175', (21, 33))	('Ile76Val', 'Chemical', '-', (62, 70))
32769	30445560	4B-E) and the ICD variants Glu376Gln and Arg453Trp (Fig.	('ICD', 'Disease', (14, 17))	('Arg453Trp', 'Var', (41, 50))	('Glu376Gln', 'Var', (27, 36))	('Glu376Gln', 'SUBSTITUTION', 'None', (27, 36))	('Arg453Trp', 'Chemical', '-', (41, 50))	('ICD', 'Disease', 'OMIM:252500', (14, 17))
32771	30445560	Cells expressing the Gly57Ser and Ile146Leu PRLR ECD variants showed decreased transcription of CISH (Fig.	('CISH', 'Gene', (96, 100))	('Ile146Leu', 'Var', (34, 43))	('Gly57Ser', 'Var', (21, 29))	('decreased', 'NegReg', (69, 78))	('transcription', 'MPA', (79, 92))	('CISH', 'Gene', '1154', (96, 100))	('Ile146Leu', 'Chemical', '-', (34, 43))	('Gly57Ser', 'SUBSTITUTION', 'None', (21, 29))	('variants', 'Var', (53, 61))
32774	30445560	In contrast, cells expressing the ICD variant Asn492Ile showed increased pAkt expression (Fig.	('Akt', 'Gene', '207', (74, 77))	('increased', 'PosReg', (63, 72))	('Asn492Ile', 'Var', (46, 55))	('Asn492Ile', 'SUBSTITUTION', 'None', (46, 55))	('Akt', 'Gene', (74, 77))	('ICD', 'Disease', 'OMIM:252500', (34, 37))	('ICD', 'Disease', (34, 37))
32777	30445560	This increased proliferation of cells expressing the Asn492Ile PRLR variant was confirmed by measuring BrdU incorporation (Fig.	('Asn492Ile', 'SUBSTITUTION', 'None', (53, 62))	('rat', 'Species', '10116', (115, 118))	('Asn492Ile', 'Var', (53, 62))	('rat', 'Species', '10116', (22, 25))	('proliferation', 'CPA', (15, 28))	('BrdU', 'MPA', (103, 107))	('increased', 'PosReg', (5, 14))	('BrdU', 'Chemical', 'MESH:D001973', (103, 107))
32778	30445560	Apoptosis, assessed using a Caspase-Glo-3/7 assay, was not altered in cells expressing the Asn492Ile variant, when compared to those expressing WT PRLR, but was significantly increased in cells expressing the His188Arg mutant PRLR following 96 h of treatment with 200 ng/mL PRL (Fig.	('PRL', 'Gene', (274, 277))	('His188Arg', 'Var', (209, 218))	('men', 'Species', '9606', (254, 257))	('Asn492Ile', 'SUBSTITUTION', 'None', (91, 100))	('PRL', 'Gene', '5617', (274, 277))	('PRL', 'Gene', (147, 150))	('PRL', 'Gene', (226, 229))	('Asn492Ile', 'Var', (91, 100))	('His188Arg', 'SUBSTITUTION', 'None', (209, 218))	('PRL', 'Gene', '5617', (147, 150))	('PRL', 'Gene', '5617', (226, 229))	('Apoptosis', 'CPA', (0, 9))	('increased', 'PosReg', (175, 184))
32779	30445560	These results indicate that the Asn492Ile PRLR is most likely to be a rare pathogenic variant with a role in the etiology of prolactinomas (Supplementary Material, Table S1).	('prolactinoma', 'Phenotype', 'HP:0040278', (125, 137))	('Asn492Ile', 'SUBSTITUTION', 'None', (32, 41))	('Asn492Ile', 'Var', (32, 41))	('men', 'Species', '9606', (146, 149))	('prolactinomas', 'Disease', 'MESH:D015175', (125, 138))	('prolactinomas', 'Disease', (125, 138))
32780	30445560	The finding that the prolactinoma-associated Asn492Ile PRLR variant resulted in a gain of function that increased pAkt signaling, which is known to have a role in the etiology of other neoplasms (e.g.	('Akt', 'Gene', '207', (115, 118))	('neoplasms', 'Disease', 'MESH:D009369', (185, 194))	('neoplasms', 'Disease', (185, 194))	('increased', 'PosReg', (104, 113))	('Akt', 'Gene', (115, 118))	('prolactinoma', 'Disease', (21, 33))	('PRLR', 'Gene', (55, 59))	('prolactinoma', 'Disease', 'MESH:D015175', (21, 33))	('neoplasms', 'Phenotype', 'HP:0002664', (185, 194))	('Asn492Ile', 'SUBSTITUTION', 'None', (45, 54))	('prolactinoma', 'Phenotype', 'HP:0040278', (21, 33))	('gain', 'PosReg', (82, 86))	('Asn492Ile', 'Var', (45, 54))
32786	30445560	Moreover, the prolactin-induced elevations in pAkt activity and proliferation that were associated with the Asn492Ile mutant PRLR could also be reduced to similar levels to those of cells expressing WT PRLR, by a concentration of 10 mum Akt1/2 inhibitor or 20 nM everolimus (Fig.	('Asn492Ile', 'Var', (108, 117))	('reduced', 'NegReg', (144, 151))	('prolactin-induced', 'MPA', (14, 31))	('rat', 'Species', '10116', (71, 74))	('elevations', 'PosReg', (32, 42))	('Akt', 'Gene', '207', (47, 50))	('everolimus', 'Chemical', 'MESH:D000068338', (263, 273))	('Akt', 'Gene', '207', (237, 240))	('proliferation', 'CPA', (64, 77))	('rat', 'Species', '10116', (220, 223))	('Asn492Ile', 'SUBSTITUTION', 'None', (108, 117))	('Akt', 'Gene', (47, 50))	('Akt', 'Gene', (237, 240))
32787	30445560	In contrast, everolimus had no effect on the pSTAT5 pathway in WT or mutant Asn492Ile PRLR-expressing cells, thereby demonstrating its specificity for the pAkt pathway (Fig.	('rat', 'Species', '10116', (124, 127))	('Asn492Ile', 'Var', (76, 85))	('mutant', 'Var', (69, 75))	('Akt', 'Gene', (156, 159))	('pSTAT5 pathway', 'Pathway', (45, 59))	('everolimus', 'Chemical', 'MESH:D000068338', (13, 23))	('Asn492Ile', 'SUBSTITUTION', 'None', (76, 85))	('Akt', 'Gene', '207', (156, 159))
32790	30445560	Glu376Gln and Asn492Ile) (Table 1) in patients with prolactinomas, together with our previous observation that individuals harboring a loss-of-function mutant Arg188His PRLR developed hyperprolactinemia, led us to hypothesize that asymptomatic, healthy (i.e.	('Arg188His', 'Var', (159, 168))	('Glu376Gln', 'Var', (0, 9))	('prolactinoma', 'Phenotype', 'HP:0040278', (52, 64))	('hyperprolactinemia', 'Phenotype', 'HP:0000870', (184, 202))	('prolactinomas', 'Disease', 'MESH:D015175', (52, 65))	('patients', 'Species', '9606', (38, 46))	('hyperprolactinemia', 'Disease', 'MESH:D002640', (184, 202))	('Asn492Ile', 'SUBSTITUTION', 'None', (14, 23))	('Arg188His', 'SUBSTITUTION', 'None', (159, 168))	('Asn492Ile', 'Var', (14, 23))	('prolactinomas', 'Disease', (52, 65))	('Glu376Gln', 'SUBSTITUTION', 'None', (0, 9))	('hyperprolactinemia', 'Disease', (184, 202))
32791	30445560	normal) individuals with such PRLR variants may have alterations in serum prolactin concentrations.	('serum prolactin concentrations', 'MPA', (68, 98))	('rat', 'Species', '10116', (91, 94))	('variants', 'Var', (35, 43))	('alterations', 'Reg', (53, 64))	('rat', 'Species', '10116', (57, 60))
32793	30445560	Examination of the available exome chip data revealed the occurrence of four of the six PRLR variants identified in the prolactinoma patient cohort (Ile76Val, Ile146Leu, Glu376Gln and Asn492Ile) in >1 individual (Table 1 and Fig.	('Asn492Ile', 'Var', (184, 193))	('Ile76Val', 'Chemical', '-', (149, 157))	('PRLR', 'Gene', (88, 92))	('Ile146Leu', 'Chemical', '-', (159, 168))	('patient', 'Species', '9606', (133, 140))	('occurrence', 'Reg', (58, 68))	('prolactinoma', 'Disease', (120, 132))	('Glu376Gln', 'SUBSTITUTION', 'None', (170, 179))	('Ile146Leu', 'Var', (159, 168))	('prolactinoma', 'Phenotype', 'HP:0040278', (120, 132))	('Glu376Gln', 'Var', (170, 179))	('Ile76Val', 'Var', (149, 157))	('Asn492Ile', 'SUBSTITUTION', 'None', (184, 193))	('prolactinoma', 'Disease', 'MESH:D015175', (120, 132))
32794	30445560	Thus, >400 individuals were heterozygous for the PRLR ECD variants (Ile76Val, n = 404, and Ile146Leu, n = 402) and <10 individuals were homozygous for the minor allele (Ile76Val, n = 7; Ile146Leu n = 10).	('Ile146Leu', 'Chemical', '-', (186, 195))	('Ile146Leu', 'Var', (91, 100))	('Ile76Val', 'Var', (68, 76))	('Ile76Val', 'Chemical', '-', (169, 177))	('Ile146Leu', 'Chemical', '-', (91, 100))	('Ile76Val', 'Chemical', '-', (68, 76))	('Ile76Val', 'Var', (169, 177))
32795	30445560	However, measurement of prolactin from available sera revealed that neither the homozygous nor the heterozygous individuals for these Ile76Val or Ile146Leu PRLR variants had significant alterations in serum prolactin concentrations (Fig.	('Ile146Leu', 'Chemical', '-', (146, 155))	('variants', 'Var', (161, 169))	('Ile76Val', 'Var', (134, 142))	('rat', 'Species', '10116', (190, 193))	('alterations', 'Reg', (186, 197))	('Ile146Leu', 'Var', (146, 155))	('men', 'Species', '9606', (16, 19))	('Ile76Val', 'Chemical', '-', (134, 142))	('serum prolactin concentrations', 'MPA', (201, 231))	('rat', 'Species', '10116', (224, 227))
32796	30445560	Similarly, individuals heterozygous for the rare ICD PRLR variants, Glu376Gln (n = 17) and Asn492Ile (n = 17), did not have significant alterations in serum prolactin concentrations when compared to those without the variant (Fig.	('PRLR', 'Gene', (53, 57))	('ICD', 'Disease', (49, 52))	('Glu376Gln', 'Var', (68, 77))	('Asn492Ile', 'SUBSTITUTION', 'None', (91, 100))	('serum prolactin concentrations', 'MPA', (151, 181))	('Asn492Ile', 'Var', (91, 100))	('alterations', 'Reg', (136, 147))	('rat', 'Species', '10116', (174, 177))	('rat', 'Species', '10116', (140, 143))	('ICD', 'Disease', 'OMIM:252500', (49, 52))	('Glu376Gln', 'SUBSTITUTION', 'None', (68, 77))
32797	30445560	8) together with the observed effects on pSTAT5 and pAkt signaling (Figs 4 and 5 and Supplementary Material, Table S1) of these variants indicate that the ICD rare variant Glu376Gln and the ECD low-frequency variants Ile76Val and Ile146Leu are likely benign polymorphisms and that the ICD rare variant Asn492Ile may be a likely low penetrance risk allele for the occurrence of prolactinoma.	('ICD', 'Disease', (155, 158))	('Ile146Leu', 'Var', (230, 239))	('Akt', 'Gene', '207', (53, 56))	('ICD', 'Disease', (285, 288))	('Glu376Gln', 'SUBSTITUTION', 'None', (172, 181))	('prolactinoma', 'Disease', (377, 389))	('Asn492Ile', 'SUBSTITUTION', 'None', (302, 311))	('Glu376Gln', 'Var', (172, 181))	('men', 'Species', '9606', (91, 94))	('Ile76Val', 'Var', (217, 225))	('prolactinoma', 'Disease', 'MESH:D015175', (377, 389))	('Akt', 'Gene', (53, 56))	('Ile146Leu', 'Chemical', '-', (230, 239))	('prolactinoma', 'Phenotype', 'HP:0040278', (377, 389))	('Ile76Val', 'Chemical', '-', (217, 225))	('ICD', 'Disease', 'OMIM:252500', (285, 288))	('ICD', 'Disease', 'OMIM:252500', (155, 158))	('Asn492Ile', 'Var', (302, 311))
32798	30445560	Our study has (1) identified an association between the occurrence of prolactinoma and two germline PRLR variants, Glu376Gln and Asn492Ile, which are rare and in complete LD (Table 1 and Fig.	('prolactinoma', 'Disease', 'MESH:D015175', (70, 82))	('Asn492Ile', 'Var', (129, 138))	('Glu376Gln', 'SUBSTITUTION', 'None', (115, 124))	('Glu376Gln', 'Var', (115, 124))	('prolactinoma', 'Disease', (70, 82))	('Asn492Ile', 'SUBSTITUTION', 'None', (129, 138))	('prolactinoma', 'Phenotype', 'HP:0040278', (70, 82))
32799	30445560	1); (2) shown that the Asn492Ile PRLR variant results in a gain of function, with increased signaling by the Akt pathway and proliferation (Fig.	('Asn492Ile', 'SUBSTITUTION', 'None', (23, 32))	('Akt', 'Gene', '207', (109, 112))	('rat', 'Species', '10116', (132, 135))	('Asn492Ile', 'Var', (23, 32))	('proliferation', 'CPA', (125, 138))	('PRLR', 'Gene', (33, 37))	('increased', 'PosReg', (82, 91))	('Akt', 'Gene', (109, 112))	('signaling', 'MPA', (92, 101))	('gain', 'PosReg', (59, 63))
32800	30445560	5); and (3) shown that an Akt inhibitor and everolimus, an mTOR inhibitor, can normalize the increased activity associated with the Asn492Ile PRLR variant (Fig.	('Asn492Ile', 'Var', (132, 141))	('activity', 'MPA', (103, 111))	('Akt', 'Gene', '207', (26, 29))	('increased', 'PosReg', (93, 102))	('everolimus', 'Chemical', 'MESH:D000068338', (44, 54))	('Akt', 'Gene', (26, 29))	('mTOR', 'Gene', '2475', (59, 63))	('Asn492Ile', 'SUBSTITUTION', 'None', (132, 141))	('mTOR', 'Gene', (59, 63))
32802	30445560	Our findings of an association between PRLR variants and prolactinoma (Table 1) differ from those reported by a French study that did not find an association between PRLR variants and prolactinomas in 88 patients.	('patients', 'Species', '9606', (204, 212))	('prolactinoma', 'Disease', (184, 196))	('prolactinoma', 'Phenotype', 'HP:0040278', (184, 196))	('PRLR', 'Gene', (39, 43))	('prolactinoma', 'Disease', (57, 69))	('prolactinoma', 'Disease', 'MESH:D015175', (184, 196))	('prolactinoma', 'Phenotype', 'HP:0040278', (57, 69))	('prolactinomas', 'Disease', 'MESH:D015175', (184, 197))	('prolactinoma', 'Disease', 'MESH:D015175', (57, 69))	('prolactinomas', 'Disease', (184, 197))	('variants', 'Var', (44, 52))	('variants', 'Var', (171, 179))
32803	30445560	Importantly, the French study did not identify any of the three PRLR ICD rare variants (Glu376Gln, Arg453Trp and Asn492Ile) that were found in our study to have the strongest association with prolactinomas (Table 1).	('Arg453Trp', 'Var', (99, 108))	('ICD', 'Disease', (69, 72))	('prolactinomas', 'Disease', 'MESH:D015175', (192, 205))	('Asn492Ile', 'SUBSTITUTION', 'None', (113, 122))	('prolactinoma', 'Phenotype', 'HP:0040278', (192, 204))	('prolactinomas', 'Disease', (192, 205))	('Asn492Ile', 'Var', (113, 122))	('association', 'Reg', (175, 186))	('Arg453Trp', 'Chemical', '-', (99, 108))	('Glu376Gln', 'Var', (88, 97))	('Glu376Gln', 'SUBSTITUTION', 'None', (88, 97))	('ICD', 'Disease', 'OMIM:252500', (69, 72))
32806	30445560	Thus, in these patients, the frequency of succinate dehydrogenase complex, subunit A (SDHA) variants, was reported to differ markedly between PPGL cohorts, with the highest frequency observed in the Dutch population, which may potentially be due to the presence of a founder mutation Arg31Stop in SDHA.	('SDHA', 'Gene', '6389', (86, 90))	('patients', 'Species', '9606', (15, 23))	('Arg31Stop', 'SUBSTITUTION', 'None', (284, 293))	('SDHA', 'Gene', '6389', (297, 301))	('SDHA', 'Gene', (86, 90))	('SDHA', 'Gene', (297, 301))	('Arg31Stop', 'Var', (284, 293))	('variants', 'Var', (92, 100))
32807	30445560	Our results, which show a role for a PRLR mutation in the development of human prolactinomas (Table 1, Figs 1, 5, 6 and 7), are in agreement with the findings from mouse studies, which have reported that conventional Prlr knockout mice develop prolactinomas, although there is an apparent paradox in that both gain of function (in humans) and loss of function (in mouse) of PRLR can lead to prolactinoma formation.	('prolactinomas', 'Disease', 'MESH:D015175', (244, 257))	('PRLR', 'Gene', (374, 378))	('prolactinoma', 'Phenotype', 'HP:0040278', (391, 403))	('prolactinoma', 'Disease', 'MESH:D015175', (244, 256))	('loss of function', 'NegReg', (343, 359))	('mouse', 'Species', '10090', (364, 369))	('men', 'Species', '9606', (65, 68))	('human', 'Species', '9606', (73, 78))	('prolactinoma', 'Disease', (391, 403))	('mutation', 'Var', (42, 50))	('prolactinomas', 'Disease', (79, 92))	('prolactinoma', 'Phenotype', 'HP:0040278', (79, 91))	('men', 'Species', '9606', (136, 139))	('mouse', 'Species', '10090', (164, 169))	('humans', 'Species', '9606', (331, 337))	('human', 'Species', '9606', (331, 336))	('prolactinoma', 'Disease', (79, 91))	('mice', 'Species', '10090', (231, 235))	('prolactinomas', 'Disease', (244, 257))	('prolactinoma', 'Disease', 'MESH:D015175', (391, 403))	('prolactinoma', 'Phenotype', 'HP:0040278', (244, 256))	('gain of function', 'PosReg', (310, 326))	('prolactinomas', 'Disease', 'MESH:D015175', (79, 92))	('prolactinoma', 'Disease', (244, 256))	('prolactinoma', 'Disease', 'MESH:D015175', (79, 91))
32810	30445560	For example, deletion of Prlr in different subtypes of TIDA neurons (i.e.	('deletion', 'Var', (13, 21))	('TIDA', 'Chemical', '-', (55, 59))	('Prlr', 'Gene', (25, 29))
32813	30445560	Analysis of data available from the OBB cohort of healthy individuals revealed that four (Ile76Val, Ile146Leu, Glu376Gln and Asn492Ile) of the six germline PRLR variants identified in the prolactinoma patients (Table 1 and Supplementary Material, Table S1) occurred in >1 individual.	('Asn492Ile', 'Var', (125, 134))	('Ile76Val', 'Chemical', '-', (90, 98))	('patients', 'Species', '9606', (201, 209))	('Ile146Leu', 'Chemical', '-', (100, 109))	('prolactinoma', 'Disease', (188, 200))	('Glu376Gln', 'Var', (111, 120))	('Glu376Gln', 'SUBSTITUTION', 'None', (111, 120))	('Ile146Leu', 'Var', (100, 109))	('men', 'Species', '9606', (229, 232))	('Asn492Ile', 'SUBSTITUTION', 'None', (125, 134))	('Ile76Val', 'Var', (90, 98))	('prolactinoma', 'Disease', 'MESH:D015175', (188, 200))	('prolactinoma', 'Phenotype', 'HP:0040278', (188, 200))	('PRLR', 'Gene', (156, 160))	('occurred', 'Reg', (257, 265))
32814	30445560	However, these PRLR variants were not associated with alterations in serum prolactin concentrations in healthy individuals (Fig.	('rat', 'Species', '10116', (92, 95))	('variants', 'Var', (20, 28))	('rat', 'Species', '10116', (58, 61))	('serum prolactin concentrations', 'MPA', (69, 99))
32815	30445560	The low-frequency PRLR variants Ile76Val and Ile146Leu, which did not alter PRLR function or only altered PRLR function at supraphysiological prolactin concentrations (Fig.	('Ile76Val', 'Chemical', '-', (32, 40))	('Ile146Leu', 'Var', (45, 54))	('Ile76Val', 'Var', (32, 40))	('PRLR', 'Gene', (18, 22))	('rat', 'Species', '10116', (159, 162))	('Ile146Leu', 'Chemical', '-', (45, 54))
32817	30445560	The rare Glu376Gln PRLR variant, which did not alter PRLR function (Fig.	('Glu376Gln', 'SUBSTITUTION', 'None', (9, 18))	('Glu376Gln', 'Var', (9, 18))	('PRLR', 'Gene', (19, 23))
32818	30445560	5) but is in complete LD with the gain-of-function Asn492Ile mutant PRLR, is also likely to be a benign polymorphism, despite its highly significant association with prolactinomas (Table 1).	('prolactinoma', 'Phenotype', 'HP:0040278', (166, 178))	('PRLR', 'Gene', (68, 72))	('prolactinomas', 'Disease', 'MESH:D015175', (166, 179))	('gain-of-function', 'PosReg', (34, 50))	('prolactinomas', 'Disease', (166, 179))	('Asn492Ile', 'SUBSTITUTION', 'None', (51, 60))	('Asn492Ile', 'Var', (51, 60))
32819	30445560	However, the possibility remains that this and other rare variants may have an effect on other pathways, such as the Ras/Raf MAPK and Src kinase pathways, which have been reported to be involved in PRLR signaling.	('variants', 'Var', (58, 66))	('effect', 'Reg', (79, 85))	('Raf', 'Gene', '22882', (121, 124))	('Src kinase pathways', 'Pathway', (134, 153))	('Raf', 'Gene', (121, 124))
32820	30445560	In addition, these PRLR variants may have effects on receptor trafficking and degradation, which were not investigated by our study, and it therefore remains a possibility that these PRLR variants may have subtle effects on prolactinoma development in vivo that may not have been detectable by our in vitro assays.	('variants', 'Var', (188, 196))	('men', 'Species', '9606', (244, 247))	('prolactinoma', 'Phenotype', 'HP:0040278', (224, 236))	('variants', 'Var', (24, 32))	('effects', 'Reg', (42, 49))	('prolactinoma', 'Disease', (224, 236))	('receptor trafficking', 'MPA', (53, 73))	('degradation', 'MPA', (78, 89))	('PRLR', 'Gene', (183, 187))	('prolactinoma', 'Disease', 'MESH:D015175', (224, 236))	('effects', 'Reg', (213, 220))	('PRLR', 'Gene', (19, 23))
32821	30445560	The absence of elevated prolactin levels in individuals who have the rare Asn492Ile gain-of-function mutant PRLR in the OBB cohort indicates that this allele likely represents a low penetrance risk allele for the occurrence of prolactinoma and that the majority of individuals harboring this variant will remain asymptomatic.	('prolactinoma', 'Disease', 'MESH:D015175', (227, 239))	('prolactinoma', 'Phenotype', 'HP:0040278', (227, 239))	('gain-of-function', 'PosReg', (84, 100))	('Asn492Ile', 'Var', (74, 83))	('prolactin levels', 'MPA', (24, 40))	('PRLR', 'Gene', (108, 112))	('elevated prolactin', 'Phenotype', 'HP:0000870', (15, 33))	('prolactinoma', 'Disease', (227, 239))	('Asn492Ile', 'SUBSTITUTION', 'None', (74, 83))
32823	30445560	the SDHA in paraganglioma and cadherin-related 23 in pituitary adenomas) in which rare germline heterozygous coding variants are overrepresented in cases relative to controls but are associated with apparent low-disease penetrance.	('pituitary adenomas', 'Disease', (53, 71))	('variants', 'Var', (116, 124))	('paraganglioma', 'Phenotype', 'HP:0002668', (12, 25))	('overrepresented', 'PosReg', (129, 144))	('SDHA', 'Gene', (4, 8))	('paraganglioma', 'Disease', (12, 25))	('pituitary adenomas', 'Disease', 'MESH:D010911', (53, 71))	('low-disease', 'Disease', 'MESH:D009800', (208, 219))	('low-disease', 'Disease', (208, 219))	('paraganglioma', 'Disease', 'MESH:D010235', (12, 25))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (53, 71))	('SDHA', 'Gene', '6389', (4, 8))	('cadherin-related 23', 'Gene', (30, 49))	('cadherin-related 23', 'Gene', '64072', (30, 49))
32824	30445560	Our studies have highlighted that a gain of functional activity within the pAkt pathway may be an important mechanism in pituitary tumorigenesis in patients with the Asn492Ile PRLR, and this may be analogous to the increased pAkt signaling that has been reported to have an etiological role in other neoplasms (e.g.	('patients', 'Species', '9606', (148, 156))	('functional activity', 'MPA', (44, 63))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('neoplasms', 'Phenotype', 'HP:0002664', (300, 309))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Akt', 'Gene', (76, 79))	('neoplasms', 'Disease', 'MESH:D009369', (300, 309))	('neoplasms', 'Disease', (300, 309))	('gain', 'PosReg', (36, 40))	('tumor', 'Disease', (131, 136))	('Akt', 'Gene', '207', (226, 229))	('Akt', 'Gene', '207', (76, 79))	('Asn492Ile', 'SUBSTITUTION', 'None', (166, 175))	('Akt', 'Gene', (226, 229))	('Asn492Ile', 'Var', (166, 175))
32826	30445560	Furthermore, our results demonstrated that inhibition of this pathway by pAkt or mTOR inhibition can normalize signaling and decrease proliferation of cells expressing the Asn492Ile variant.	('Asn492Ile', 'Var', (172, 181))	('Akt', 'Gene', '207', (74, 77))	('mTOR', 'Gene', '2475', (81, 85))	('rat', 'Species', '10116', (141, 144))	('rat', 'Species', '10116', (32, 35))	('inhibition', 'NegReg', (43, 53))	('Asn492Ile', 'SUBSTITUTION', 'None', (172, 181))	('Akt', 'Gene', (74, 77))	('mTOR', 'Gene', (81, 85))	('normalize signaling', 'MPA', (101, 120))	('decrease', 'NegReg', (125, 133))	('proliferation', 'CPA', (134, 147))
32828	30445560	Indeed, our observations that the PRLR Asn492Ile gain-of-function mutation was frequently observed in prolactinoma patients requiring pituitary surgery suggest a potential personalized treatment approach for patients whose prolactinomas are aggressive or do not respond to dopamine-agonist therapy.	('patients', 'Species', '9606', (115, 123))	('Asn492Ile', 'SUBSTITUTION', 'None', (39, 48))	('patients', 'Species', '9606', (208, 216))	('Asn492Ile', 'Var', (39, 48))	('prolactinomas', 'Disease', 'MESH:D015175', (223, 236))	('prolactinoma', 'Disease', (102, 114))	('prolactinomas', 'Disease', (223, 236))	('men', 'Species', '9606', (190, 193))	('prolactinoma', 'Disease', (223, 235))	('dopamine', 'Chemical', 'MESH:D004298', (273, 281))	('prolactinoma', 'Disease', 'MESH:D015175', (102, 114))	('gain-of-function', 'PosReg', (49, 65))	('prolactinoma', 'Phenotype', 'HP:0040278', (102, 114))	('prolactinoma', 'Phenotype', 'HP:0040278', (223, 235))	('prolactinoma', 'Disease', 'MESH:D015175', (223, 235))
32831	30445560	In summary, our studies have identified that a gain-of-function PRLR mutation, which activates pAkt signaling, is associated with prolactinomas and that everolimus may represent a potential effective treatment in patients with prolactinomas resistant to currently used medical treatments.	('PRLR', 'Gene', (64, 68))	('prolactinoma', 'Phenotype', 'HP:0040278', (227, 239))	('gain-of-function', 'PosReg', (47, 63))	('prolactinomas', 'Disease', 'MESH:D015175', (227, 240))	('prolactinomas', 'Disease', (130, 143))	('everolimus', 'Chemical', 'MESH:D000068338', (153, 163))	('men', 'Species', '9606', (282, 285))	('men', 'Species', '9606', (205, 208))	('mutation', 'Var', (69, 77))	('Akt', 'Gene', '207', (96, 99))	('prolactinoma', 'Phenotype', 'HP:0040278', (130, 142))	('prolactinomas', 'Disease', (227, 240))	('patients', 'Species', '9606', (213, 221))	('activates', 'PosReg', (85, 94))	('prolactinomas', 'Disease', 'MESH:D015175', (130, 143))	('Akt', 'Gene', (96, 99))
32837	30445560	SIFT (http://sift.jcvi.org/) and Polyphen-2 (http://genetics.bwh.harvard.edu/pph2/) were used to predict the effect of amino acid substitutions.	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))	('amino acid substitutions', 'Var', (119, 143))
32838	30445560	Comparisons between the frequency of variants in the ExAc cohort and the prolactinoma cohort were performed by Fisher's exact test, and Bonferroni correction performed for multiple testing, using GraphPad Prism.	('variants', 'Var', (37, 45))	('prolactinoma', 'Phenotype', 'HP:0040278', (73, 85))	('prolactinoma cohort', 'Disease', 'MESH:D015175', (73, 92))	('prolactinoma cohort', 'Disease', (73, 92))
32844	30445560	Comparisons between the frequency of variants in the prolactinoma cohort and the OBB cohorts were performed using Fisher's exact test and Bonferroni correction for multiple comparisons.	('variants', 'Var', (37, 45))	('prolactinoma', 'Phenotype', 'HP:0040278', (53, 65))	('prolactinoma cohort', 'Disease', 'MESH:D015175', (53, 72))	('prolactinoma cohort', 'Disease', (53, 72))
32876	30445560	Comparisons between the frequency of variants in the prolactinoma cohort and the ExAC and OBB cohorts were performed using Fisher's exact test.	('variants', 'Var', (37, 45))	('prolactinoma', 'Phenotype', 'HP:0040278', (53, 65))	('prolactinoma cohort', 'Disease', 'MESH:D015175', (53, 72))	('prolactinoma cohort', 'Disease', (53, 72))
32877	30445560	Mean prolactin values from patients with each of the PRLR variants were compared with values from patients with the WT alleles by Student's t-test.	('variants', 'Var', (58, 66))	('patients', 'Species', '9606', (27, 35))	('prolactin', 'MPA', (5, 14))	('patients', 'Species', '9606', (98, 106))
32959	30460037	Chances for malignant paraganglioma increase with a mutation in the succinate dehydrogenase (SDHB) gene.	('malignant paraganglioma increase', 'Disease', (12, 44))	('SDHB', 'Gene', (93, 97))	('malignant paraganglioma increase', 'Disease', 'MESH:C565335', (12, 44))	('mutation', 'Var', (52, 60))	('SDHB', 'Gene', '6390', (93, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))
32968	30105105	Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation Von Hippel-Lindau (VHL) disease, caused by germline mutations in the VHL gene, is characterized by metachronously occurring tumors including pheochromocytoma, renal cell carcinoma (RCC), and hemangioblastoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (220, 236))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (238, 258))	('RCC', 'Disease', 'MESH:C538614', (260, 263))	('Bilateral Pheochromocytomas', 'Disease', (0, 27))	('pheochromocytoma', 'Disease', (220, 236))	('Von Hippel-Lindau', 'Gene', '7428', (52, 69))	('Mutation', 'Var', (70, 78))	('Von Hippel-Lindau', 'Gene', (52, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (220, 236))	('VHL', 'Gene', (148, 151))	('Bilateral Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 27))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('Y175C', 'Var', (46, 51))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (270, 286))	('hemangioblastoma', 'Disease', (270, 286))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (10, 27))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('renal cell carcinoma', 'Disease', (238, 258))	('VHL', 'Gene', '7428', (148, 151))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (238, 258))	('tumors', 'Disease', (203, 209))	('Von Hippel-Lindau', 'Gene', '7428', (79, 96))	('VHL', 'Gene', (98, 101))	('Von Hippel-Lindau', 'Gene', (79, 96))	('Y175C', 'Mutation', 'rs193922613', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (79, 110))	('RCC', 'Phenotype', 'HP:0005584', (260, 263))	('Patient', 'Species', '9606', (33, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('RCC', 'Disease', (260, 263))	('VHL', 'Gene', '7428', (98, 101))	('hemangioblastoma', 'Disease', 'MESH:D018325', (270, 286))
32971	30105105	VHL mutants with more severely reduced HIF degrading function carry a high risk of RCC, while mutants with preserved HIF degrading capacity do not cause RCC but still lead to other tumors.	('RCC', 'Disease', 'MESH:C538614', (83, 86))	('RCC', 'Disease', (83, 86))	('RCC', 'Phenotype', 'HP:0005584', (83, 86))	('reduced', 'NegReg', (31, 38))	('mutants', 'Var', (4, 11))	('tumors', 'Disease', (181, 187))	('lead to', 'Reg', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('RCC', 'Disease', (153, 156))	('HIF degrading function', 'MPA', (39, 61))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
32973	30105105	We report a case of bilateral pheochromocytomas and no other VHL-related tumors in a patient with Y175C VHL and show that this mutant preserves the ability to degrade HIF in normal oxygen conditions but, similar to the wild-type VHL protein, loses its ability to degrade HIF under hypoxic conditions.	('VHL', 'Gene', '7428', (104, 107))	('VHL', 'Gene', (229, 232))	('degrade HIF', 'MPA', (263, 274))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (73, 79))	('bilateral pheochromocytomas', 'Disease', (20, 47))	('hypoxic conditions', 'Disease', (281, 299))	('VHL', 'Gene', '7428', (229, 232))	('oxygen', 'Chemical', 'MESH:D010100', (181, 187))	('VHL', 'Gene', (61, 64))	('Y175C', 'Mutation', 'rs193922613', (98, 103))	('loses', 'NegReg', (242, 247))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (30, 46))	('patient', 'Species', '9606', (85, 92))	('VHL', 'Gene', '7428', (61, 64))	('VHL', 'Gene', (104, 107))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (20, 47))	('ability', 'MPA', (252, 259))	('hypoxic conditions', 'Disease', 'MESH:D009135', (281, 299))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (30, 47))	('Y175C', 'Var', (98, 103))	('degrade HIF', 'MPA', (159, 170))
32974	30105105	This study adds to the current understanding of the structure-function relationship of VHL mutations, which is important for risk stratification of future tumor development in the patients.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('VHL', 'Gene', '7428', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('mutations', 'Var', (91, 100))	('VHL', 'Gene', (87, 90))	('patients', 'Species', '9606', (180, 188))
32976	30105105	Germline mutations in VHL occur with a frequency of 1:36,000 in Europe and a 20% de novo rate.	('Germline mutations', 'Var', (0, 18))	('VHL', 'Gene', '7428', (22, 25))	('VHL', 'Gene', (22, 25))
32977	30105105	People with VHL mutations metachronously develop various benign and malignant tumors.	('VHL', 'Gene', (12, 15))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('malignant tumors', 'Disease', (68, 84))	('develop', 'PosReg', (41, 48))	('VHL', 'Gene', '7428', (12, 15))	('malignant tumors', 'Disease', 'MESH:D018198', (68, 84))	('mutations', 'Var', (16, 25))	('People', 'Species', '9606', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))
32988	30105105	Studies of over a dozen different VHL mutations have identified several phenotypic subtypes revealing a structure-function relationship in which the severity of the mutation predicts the likelihood of RCC.	('RCC', 'Disease', 'MESH:C538614', (201, 204))	('RCC', 'Disease', (201, 204))	('RCC', 'Phenotype', 'HP:0005584', (201, 204))	('mutation', 'Var', (165, 173))	('VHL', 'Gene', '7428', (34, 37))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (38, 47))
32989	30105105	VHL mutants that retain the ability to downregulate HIFalpha are less likely to be associated with RCC than those that lose that ability.	('downregulate', 'NegReg', (39, 51))	('mutants', 'Var', (4, 11))	('RCC', 'Phenotype', 'HP:0005584', (99, 102))	('VHL', 'Gene', (0, 3))	('associated', 'Reg', (83, 93))	('RCC', 'Disease', (99, 102))	('RCC', 'Disease', 'MESH:C538614', (99, 102))	('VHL', 'Gene', '7428', (0, 3))
32990	30105105	Patients with type 1 VHL have deletion or truncation mutations that completely abolish any functional protein expression.	('truncation mutations', 'Var', (42, 62))	('abolish', 'NegReg', (79, 86))	('functional protein expression', 'MPA', (91, 120))	('deletion', 'Var', (30, 38))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (21, 24))	('VHL', 'Gene', '7428', (21, 24))
32995	30105105	By contrast, type 2C mutations retain their ability to fully downregulate HIFalpha and present with only pheochromocytomas, indicating that HIFalpha-independent mechanisms are at play in the pathogenesis of VHL-related pheochromocytomas.	('VHL', 'Gene', (207, 210))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (105, 122))	('pheochromocytomas', 'Disease', 'MESH:D010673', (219, 236))	('downregulate', 'NegReg', (61, 73))	('pheochromocytomas', 'Disease', (219, 236))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (105, 121))	('VHL', 'Gene', '7428', (207, 210))	('pheochromocytomas', 'Disease', 'MESH:D010673', (105, 122))	('pheochromocytomas', 'Disease', (105, 122))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (219, 236))	('HIFalpha', 'Protein', (74, 82))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (219, 235))	('mutations', 'Var', (21, 30))
32996	30105105	Some in vitro studies suggest that type 2C VHL mutants cause defective fibronectin matrix assembly, while retaining the ability to suppress HIFalpha and stop the growth of RCC cells in culture.	('fibronectin', 'Gene', '2335', (71, 82))	('defective', 'NegReg', (61, 70))	('stop', 'NegReg', (153, 157))	('suppress', 'NegReg', (131, 139))	('HIFalpha', 'MPA', (140, 148))	('VHL', 'Gene', (43, 46))	('growth', 'CPA', (162, 168))	('fibronectin', 'Gene', (71, 82))	('VHL', 'Gene', '7428', (43, 46))	('defective fibronectin matrix', 'Phenotype', 'HP:0032463', (61, 89))	('RCC', 'Disease', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('mutants', 'Var', (47, 54))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))
33019	30105105	The patient was found to have a heterozygous germline mutation, c.524A>G in the VHL gene, corresponding to the Y175C substitution in the protein.	('c.524A>G', 'Mutation', 'rs193922613', (64, 72))	('VHL', 'Gene', (80, 83))	('Y175C', 'Var', (111, 116))	('Y175C', 'Mutation', 'rs193922613', (111, 116))	('VHL', 'Gene', '7428', (80, 83))	('patient', 'Species', '9606', (4, 11))	('c.524A>G', 'Var', (64, 72))
33021	30105105	In order to better define the risk of RCC in this patient and others with this mutation, we assessed the ability of Y175C VHL to degrade HIFalpha in vitro.	('RCC', 'Disease', (38, 41))	('RCC', 'Disease', 'MESH:C538614', (38, 41))	('degrade', 'NegReg', (129, 136))	('VHL', 'Gene', (122, 125))	('Y175C', 'Mutation', 'rs193922613', (116, 121))	('VHL', 'Gene', '7428', (122, 125))	('Y175C', 'Var', (116, 121))	('RCC', 'Phenotype', 'HP:0005584', (38, 41))	('patient', 'Species', '9606', (50, 57))	('HIFalpha', 'MPA', (137, 145))
33022	30105105	Stable wild-type (WT) or Y175C VHL-expressing cells lines were generated by transfection and clonal selection of VHL-null 786-O cells derived from a human RCC as previously described.	('VHL', 'Gene', '7428', (31, 34))	('RCC', 'Disease', (155, 158))	('Y175C', 'Mutation', 'rs193922613', (25, 30))	('Y175C', 'Var', (25, 30))	('VHL', 'Gene', (113, 116))	('VHL', 'Gene', '7428', (113, 116))	('human', 'Species', '9606', (149, 154))	('VHL', 'Gene', (31, 34))	('RCC', 'Phenotype', 'HP:0005584', (155, 158))	('WT', 'Disease', 'MESH:C536751', (18, 20))	('RCC', 'Disease', 'MESH:C538614', (155, 158))
33023	30105105	We detected HIF2alpha expression in the control VHL-null cell line, while stable overexpression of either WT or Y175C VHL resulted in the disappearance of HIF2alpha (Figure 2, left panel).	('VHL', 'Gene', '7428', (48, 51))	('VHL', 'Gene', (118, 121))	('HIF2alpha', 'Gene', (155, 164))	('HIF2alpha', 'Gene', (12, 21))	('VHL', 'Gene', '7428', (118, 121))	('overexpression', 'PosReg', (81, 95))	('HIF2alpha', 'Gene', '2034', (155, 164))	('Y175C', 'Mutation', 'rs193922613', (112, 117))	('WT', 'Disease', 'MESH:C536751', (106, 108))	('disappearance', 'NegReg', (138, 151))	('Y175C', 'Var', (112, 117))	('VHL', 'Gene', (48, 51))	('HIF2alpha', 'Gene', '2034', (12, 21))
33024	30105105	To further characterize the function of Y175C VHL under hypoxic conditions, the cells were placed into a hypoxia incubator at 1% O2 for 24 hours.	('VHL', 'Gene', (46, 49))	('hypoxia', 'Disease', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('VHL', 'Gene', '7428', (46, 49))	('hypoxic conditions', 'Disease', (56, 74))	('Y175C', 'Mutation', 'rs193922613', (40, 45))	('hypoxic conditions', 'Disease', 'MESH:D009135', (56, 74))	('O2', 'Chemical', 'MESH:D010100', (129, 131))	('Y175C', 'Var', (40, 45))
33026	30105105	The Y175C VHL similarly did not reduce HIF2alpha abundance in hypoxia.	('HIF2alpha', 'Gene', '2034', (39, 48))	('abundance', 'MPA', (49, 58))	('HIF2alpha', 'Gene', (39, 48))	('hypoxia', 'Disease', 'MESH:D000860', (62, 69))	('hypoxia', 'Disease', (62, 69))	('VHL', 'Gene', (10, 13))	('Y175C', 'Mutation', 'rs193922613', (4, 9))	('VHL', 'Gene', '7428', (10, 13))	('Y175C', 'Var', (4, 9))
33027	30105105	HIF2alpha abundance was also similar in WT and Y175C VHL-expressing cells after 6 hours and 12 hours of hypoxia (data not shown).	('HIF2alpha', 'Gene', '2034', (0, 9))	('WT', 'Disease', 'MESH:C536751', (40, 42))	('VHL', 'Gene', (53, 56))	('VHL', 'Gene', '7428', (53, 56))	('HIF2alpha', 'Gene', (0, 9))	('Y175C', 'Var', (47, 52))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('hypoxia', 'Disease', (104, 111))	('Y175C', 'Mutation', 'rs193922613', (47, 52))
33028	30105105	Thus, under both normoxic and hypoxic conditions, Y175C VHL functions similarly to the WT with regard to HIFalpha degradation.	('VHL', 'Gene', (56, 59))	('hypoxic conditions', 'Disease', 'MESH:D009135', (30, 48))	('VHL', 'Gene', '7428', (56, 59))	('Y175C', 'Var', (50, 55))	('Y175C', 'Mutation', 'rs193922613', (50, 55))	('WT', 'Disease', 'MESH:C536751', (87, 89))	('HIFalpha degradation', 'MPA', (105, 125))	('hypoxic conditions', 'Disease', (30, 48))
33030	30105105	Germline mutations in known susceptibility genes including SDHB (succinate dehydrogenase complex B) and others are identified in 11-13% of patients with sporadic pheochromocytomas.	('Germline mutations', 'Var', (0, 18))	('succinate dehydrogenase complex B', 'Gene', '6390', (65, 98))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (162, 179))	('patients', 'Species', '9606', (139, 147))	('identified', 'Reg', (115, 125))	('succinate dehydrogenase complex B', 'Gene', (65, 98))	('SDHB', 'Gene', '6390', (59, 63))	('SDHB', 'Gene', (59, 63))	('sporadic pheochromocytomas', 'Disease', 'MESH:D010673', (153, 179))	('sporadic pheochromocytomas', 'Disease', (153, 179))
33033	30105105	Although Y175C VHL has been reported in another family with a similar phenotype, its molecular function has not been studied to date.	('VHL', 'Gene', (15, 18))	('Y175C', 'Var', (9, 14))	('Y175C', 'Mutation', 'rs193922613', (9, 14))	('VHL', 'Gene', '7428', (15, 18))
33034	30105105	We have shown that the Y175C mutation preserves the ability of VHL to degrade HIFalpha under normal oxygen conditions.	('oxygen', 'Chemical', 'MESH:D010100', (100, 106))	('Y175C', 'Var', (23, 28))	('Y175C', 'Mutation', 'rs193922613', (23, 28))	('VHL', 'Gene', (63, 66))	('degrade HIFalpha', 'MPA', (70, 86))	('ability', 'MPA', (52, 59))	('VHL', 'Gene', '7428', (63, 66))
33036	30105105	This is the first reported molecular study of Y175C VHL and it adds to the growing body of knowledge about various VHL mutants.	('VHL', 'Gene', (115, 118))	('VHL', 'Gene', '7428', (52, 55))	('Y175C', 'Mutation', 'rs193922613', (46, 51))	('VHL', 'Gene', '7428', (115, 118))	('Y175C', 'Var', (46, 51))	('VHL', 'Gene', (52, 55))
33038	30105105	Previously reported type 2C VHL mutants with pheochromocytoma as the only notable disease manifestation include L188V and V84L.	('L188V', 'Var', (112, 117))	('V84L', 'Mutation', 'rs5030827', (122, 126))	('L188V', 'Mutation', 'rs5030824', (112, 117))	('V84L', 'Var', (122, 126))	('man', 'Species', '9606', (90, 93))	('pheochromocytoma', 'Disease', (45, 61))	('VHL', 'Gene', (28, 31))	('pheochromocytoma', 'Disease', 'MESH:D010673', (45, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (45, 61))	('VHL', 'Gene', '7428', (28, 31))
33039	30105105	Our case is similar to a previously described Spanish cohort with the same mutation that presented with pheochromocytomas in mutation carriers and no other VHL-associated tumors.	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (104, 121))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutation', 'Var', (75, 83))	('VHL', 'Gene', '7428', (156, 159))	('pheochromocytomas', 'Disease', 'MESH:D010673', (104, 121))	('pheochromocytomas', 'Disease', (104, 121))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (104, 120))	('tumors', 'Disease', (171, 177))	('VHL', 'Gene', (156, 159))
33040	30105105	The authors of that study calculated the folding energy of Y175C VHL and found that it was only slightly higher than that of the wild-type, indicating that Y175C VHL is predicted to be fairly stable.	('VHL', 'Gene', (162, 165))	('VHL', 'Gene', '7428', (65, 68))	('VHL', 'Gene', '7428', (162, 165))	('Y175C', 'Mutation', 'rs193922613', (156, 161))	('Y175C', 'Var', (156, 161))	('VHL', 'Gene', (65, 68))	('Y175C', 'Var', (59, 64))	('folding', 'MPA', (41, 48))	('Y175C', 'Mutation', 'rs193922613', (59, 64))
33042	30105105	Although HIFalpha degradation is better characterized, many studies have shown that VHL is also important in extracellular matrix assembly and cell membrane structure through regulating fibronectin and integrins, and loss of this function leads to tumor development as well.	('loss', 'Var', (217, 221))	('tumor', 'Disease', (248, 253))	('regulating', 'Reg', (175, 185))	('VHL', 'Gene', (84, 87))	('integrins', 'Protein', (202, 211))	('VHL', 'Gene', '7428', (84, 87))	('fibronectin', 'Gene', (186, 197))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('man', 'Species', '9606', (55, 58))	('leads to', 'Reg', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('fibronectin', 'Gene', '2335', (186, 197))
33044	30105105	Mutants that escape this modification are involved in tumorigenesis despite adequate HIFalpha suppression.	('HIFalpha', 'MPA', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('involved', 'Reg', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('Mutants', 'Var', (0, 7))
33053	29333259	PPGLs are genetically heterogeneous tumours caused by mutations in over 20 distinct genes .	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mutations', 'Var', (54, 63))	('caused by', 'Reg', (44, 53))	('tumours', 'Disease', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('PPGLs', 'Disease', (0, 5))
33054	29333259	A pathogenic mutation, either germline or somatic, can be identified in two-thirds of the tumours largely in a mutually exclusive manner .	('mutation', 'Var', (13, 21))	('pathogenic', 'Reg', (2, 12))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
33065	29333259	In addition, since hereditary PPGLs often present as part of multi-tumour syndromes, mutation detection can also lead to planned surveillance and early diagnosis of co-occurring cancers in probands and in their mutation-carrier relatives .	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('mutation', 'Var', (85, 93))	('cancers', 'Disease', (178, 185))	('multi-tumour syndromes', 'Disease', (61, 83))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('PPGLs', 'Disease', (30, 35))	('multi-tumour syndromes', 'Disease', 'MESH:D015140', (61, 83))
33090	29333259	The best-known genetic predictor of malignancy is the presence of a germline mutation of the succinate dehydrogenase subunit B gene, SDHB  ( Table 2).	('SDHB', 'Gene', '6390', (133, 137))	('presence', 'Var', (54, 62))	('SDHB', 'Gene', (133, 137))	('malignancy', 'Disease', 'MESH:D009369', (36, 46))	('malignancy', 'Disease', (36, 46))
33092	29333259	Most patients with a germline SDHB mutation have extra-adrenal disease and approximately 50% of these patients progress to metastatic disease .	('extra-adrenal disease', 'Disease', (49, 70))	('patients', 'Species', '9606', (5, 13))	('patients', 'Species', '9606', (102, 110))	('metastatic disease', 'CPA', (123, 141))	('extra-adrenal disease', 'Disease', 'MESH:D010236', (49, 70))	('SDHB', 'Gene', '6390', (30, 34))	('adrenal disease', 'Phenotype', 'HP:0000834', (55, 70))	('SDHB', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))	('progress', 'Reg', (111, 119))
33093	29333259	In addition, patients with SDHB mutant malignant PPGLs have shorter median overall survival than non- SDHB mutant metastatic PPGLs (42 versus 244 months after the diagnosis of the first metastasis, respectively) .	('patients', 'Species', '9606', (13, 21))	('SDHB', 'Gene', '6390', (102, 106))	('SDHB', 'Gene', '6390', (27, 31))	('mutant', 'Var', (32, 38))	('SDHB', 'Gene', (102, 106))	('overall survival', 'MPA', (75, 91))	('shorter', 'NegReg', (60, 67))	('SDHB', 'Gene', (27, 31))
33094	29333259	Mutations in other SDH component genes: SDHA, SDHC, SDHD, and SDHAF2:also lead to paragangliomas or phaeochromocytomas or both; however, malignancy is rarely associated with these tumours.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('malignancy', 'Disease', (137, 147))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('SDH', 'Gene', (52, 55))	('SDH', 'Gene', '6390', (40, 43))	('SDHA', 'Gene', (40, 44))	('SDHD', 'Disease', 'None', (52, 56))	('SDH', 'Gene', '6390', (62, 65))	('SDH', 'Gene', (19, 22))	('SDHA', 'Gene', '6389', (40, 44))	('SDH', 'Gene', '6390', (46, 49))	('Mutations', 'Var', (0, 9))	('SDHC', 'Gene', '6391', (46, 50))	('SDH', 'Gene', (40, 43))	('SDHAF2', 'Gene', (62, 68))	('lead to', 'Reg', (74, 81))	('SDHA', 'Gene', (62, 66))	('SDHAF2', 'Gene', '54949', (62, 68))	('SDH', 'Gene', (62, 65))	('SDH', 'Gene', (46, 49))	('SDHA', 'Gene', '6389', (62, 66))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('tumours', 'Disease', (180, 187))	('SDHD', 'Disease', (52, 56))	('paragangliomas or phaeochromocytomas', 'Disease', (82, 118))	('SDH', 'Gene', '6390', (52, 55))	('paragangliomas or phaeochromocytomas', 'Disease', 'MESH:D010235', (82, 118))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('SDH', 'Gene', '6390', (19, 22))	('SDHC', 'Gene', (46, 50))
33095	29333259	SDH mutations cause a metabolic imbalance that leads to a DNA and histone hypermethylation phenotype; genes targeted by aberrant methylation are thought to be required for tumour development in these models .	('leads to', 'Reg', (47, 55))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('SDH', 'Gene', (0, 3))	('cause', 'Reg', (14, 19))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('imbalance', 'Phenotype', 'HP:0002172', (32, 41))	('tumour', 'Disease', (172, 178))	('mutations', 'Var', (4, 13))	('metabolic imbalance', 'MPA', (22, 41))	('SDH', 'Gene', '6390', (0, 3))	('DNA and histone hypermethylation phenotype', 'MPA', (58, 100))
33096	29333259	However, why mutations in SDHB, but not in the other SDH genes, specifically confer increased risk of malignancy is not known.	('SDH', 'Gene', (53, 56))	('malignancy', 'Disease', (102, 112))	('SDHB', 'Gene', '6390', (26, 30))	('SDH', 'Gene', '6390', (53, 56))	('SDHB', 'Gene', (26, 30))	('SDH', 'Gene', '6390', (26, 29))	('mutations', 'Var', (13, 22))	('malignancy', 'Disease', 'MESH:D009369', (102, 112))	('SDH', 'Gene', (26, 29))
33097	29333259	Notably, despite its unquestionable role as an independent risk factor for malignancy, two-thirds of metastatic PPGLs do not have SDHB mutations, implying the existence of other markers of poor prognosis .	('SDHB', 'Gene', '6390', (130, 134))	('not', 'NegReg', (121, 124))	('mutations', 'Var', (135, 144))	('SDHB', 'Gene', (130, 134))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('malignancy', 'Disease', (75, 85))
33099	29333259	A recent integrated analysis of PPGLs as part of The Cancer Genome Atlas (TCGA) using genomic, mRNA, and microRNA expression, methylation profiling, and protein expression arrays identified new pathogenic lesions in PPGLs .	('Cancer Genome Atlas', 'Disease', (53, 72))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pathogenic', 'Reg', (194, 204))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('PPGLs', 'Gene', (216, 221))	('lesions', 'Var', (205, 212))
33101	29333259	Those included SDHB mutation, inclusion in the hypermethylation subtype, and inclusion in the pseudohypoxia subtype; the latter two are the groups that contain SDHB mutant tumours.	('SDHB', 'Gene', '6390', (15, 19))	('SDHB', 'Gene', '6390', (160, 164))	('mutant', 'Var', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('SDHB', 'Gene', (160, 164))	('mutation', 'Var', (20, 28))	('SDHB', 'Gene', (15, 19))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', 'MESH:D009369', (172, 179))	('pseudohypoxia subtype', 'Disease', 'MESH:C535673', (94, 115))	('pseudohypoxia subtype', 'Disease', (94, 115))	('tumours', 'Disease', (172, 179))
33102	29333259	Importantly, novel molecular markers were found: MAML3 (mastermind-like protein 3) fusions, SETD2 (SET domain containing 2) or ATRX somatic mutations, and WNT-related expression subtype, which comprise the tumours with MAML3 fusion tumours .	('SETD2', 'Gene', '29072', (92, 97))	('tumours', 'Disease', (232, 239))	('MAML3 fusion tumours', 'Disease', 'MESH:D000069337', (219, 239))	('MAML3', 'Gene', '55534', (49, 54))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))	('tumours', 'Disease', 'MESH:D009369', (232, 239))	('mastermind-like protein 3', 'Gene', '55534', (56, 81))	('MAML3', 'Gene', (219, 224))	('mastermind-like protein 3', 'Gene', (56, 81))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumours', 'Disease', (206, 213))	('fusions', 'Var', (83, 90))	('MAML3', 'Gene', '55534', (219, 224))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('mutations', 'Var', (140, 149))	('MAML3 fusion tumours', 'Disease', (219, 239))	('ATRX', 'Gene', (127, 131))	('ATRX', 'Gene', '546', (127, 131))	('SETD2', 'Gene', (92, 97))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('MAML3', 'Gene', (49, 54))
33103	29333259	Interestingly, almost all tumours carrying this fusion were phaeochromocytomas, in contrast with the predominant paraganglioma location of SDHB mutants, and represented a biological group distinct from the latter.	('mutants', 'Var', (144, 151))	('SDHB', 'Gene', '6390', (139, 143))	('phaeochromocytomas', 'Disease', (60, 78))	('SDHB', 'Gene', (139, 143))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('paraganglioma', 'Disease', (113, 126))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (60, 78))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('paraganglioma', 'Disease', 'MESH:D010235', (113, 126))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
33105	29333259	Genes targeted by methylation that may associate with metastatic tumours, including RBDP, have also been identified and will need to be independently verified .	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('associate', 'Reg', (39, 48))	('methylation', 'Var', (18, 29))	('RBDP', 'Disease', (84, 88))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumours', 'Disease', (65, 72))
33109	29333259	However, as not all patients with an SDHB mutation develop metastatic disease, even within the same family (that is, carriers of the same mutation), other risk factors, either inherited through different alleles or acquired, might exist .	('SDHB', 'Gene', '6390', (37, 41))	('develop', 'Reg', (51, 58))	('mutation', 'Var', (42, 50))	('SDHB', 'Gene', (37, 41))	('patients', 'Species', '9606', (20, 28))	('metastatic disease', 'Disease', (59, 77))
33137	29163991	Her vital signs briefly appeared to "normalize" with BP 120/80 mmHg and HR 90 bpm before tumor removal so both clevidipine and esmolol infusions were discontinued.	('BP 120/80 mmHg', 'Var', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('clevidipine', 'Chemical', 'MESH:C118563', (111, 122))	('tumor removal', 'Disease', 'MESH:D009369', (89, 102))	('esmolol', 'Chemical', 'MESH:C036604', (127, 134))	('vital signs', 'MPA', (4, 15))	('tumor removal', 'Disease', (89, 102))
33177	29163991	Despite premedication of most patients with phenoxybenzamine and a beta-blocker, varying degrees of intraoperative hemodynamic lability occurred.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (44, 60))	('phenoxybenzamine', 'Var', (44, 60))	('patients', 'Species', '9606', (30, 38))	('intraoperative hemodynamic lability', 'Disease', (100, 135))	('intraoperative hemodynamic lability', 'Disease', 'MESH:D005166', (100, 135))
33180	29163991	It should never be started prior to alpha blockade because blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to hypertensive crisis.	('lead to', 'Reg', (178, 185))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (186, 205))	('hypertensive', 'Disease', 'MESH:D006973', (186, 198))	('blockade', 'Var', (59, 67))	('hypertensive', 'Disease', (186, 198))
33231	26997629	The patient was discharged to home on enalapril 2.5 mg PO BID ( by mouth two times daily )and phenoxybenzamine 2.5 mg PO TID (by mouth three times daily) for blood pressure control, as well as potassium supplementation for hypokalemia.	('potassium', 'Chemical', 'MESH:D011188', (193, 202))	('phenoxybenzamine', 'Var', (94, 110))	('hypokalemia', 'Disease', (223, 234))	('TID', 'Disease', (121, 124))	('patient', 'Species', '9606', (4, 11))	('hypokalemia', 'Disease', 'MESH:D007008', (223, 234))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (94, 110))	('TID', 'Disease', 'None', (121, 124))	('enalapril', 'Chemical', 'MESH:D004656', (38, 47))	('hypokalemia', 'Phenotype', 'HP:0002900', (223, 234))
33331	26912984	Increased uptake of fluorodeoxyglucose (FDG) on 18F FDG PET/CT is not specific to paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (20, 38))	('FDG', 'Chemical', 'MESH:D019788', (52, 55))	('FDG', 'Chemical', 'MESH:D019788', (40, 43))	('Increased', 'PosReg', (0, 9))	('uptake of fluorodeoxyglucose', 'MPA', (10, 38))	('paragangliomas', 'Disease', 'MESH:D010235', (82, 96))	('FDG', 'Var', (52, 55))	('paragangliomas', 'Disease', (82, 96))
33612	21507561	Dissection into an incorrect plane may produce troublesome bleeding.	('troublesome bleeding', 'Disease', (47, 67))	('troublesome bleeding', 'Phenotype', 'HP:0001892', (47, 67))	('Dissection', 'Var', (0, 10))	('produce', 'Reg', (39, 46))	('troublesome bleeding', 'Disease', 'MESH:D006470', (47, 67))
33632	21507561	With these modifications, we typically do not have to mobilize the bowel on the right side and minimize bowel mobilization on the left.	('bowel', 'Disease', (67, 72))	('modifications', 'Var', (11, 24))	('bowel', 'Disease', 'MESH:D015212', (104, 109))	('bowel', 'Disease', (104, 109))	('bowel', 'Disease', 'MESH:D015212', (67, 72))
33662	21507561	Other studies have demonstrated that laparoscopic approaches for adrenal surgery are associated with decreased blood loss, shortened convalescent time, and decreased need for postoperative analgesia, as compared with open adrenalectomy, and we have observed the same benefits in the current series compared with our open experience.	('convalescent', 'CPA', (133, 145))	('adrenal', 'Disease', (65, 72))	('decreased blood loss', 'Disease', 'MESH:D006473', (101, 121))	('decreased', 'NegReg', (156, 165))	('laparoscopic', 'Var', (37, 49))	('decreased blood loss', 'Disease', (101, 121))
33663	21507561	While this current report describing our technique does not yet demonstrate long-term oncologic efficacy, recent evidence suggests that partial adrenalectomy for pheochromocytoma may provide excellent, long-term, oncologic and functional outcomes.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('partial', 'Var', (136, 143))	('pheochromocytoma', 'Disease', 'MESH:D010673', (162, 178))	('adrenalectomy for pheochromocytoma', 'Phenotype', 'HP:0006748', (144, 178))	('pheochromocytoma', 'Disease', (162, 178))
33740	33680468	Both blood and urine metanephrines were ordered and found to be abnormal: urine total, blood metanephrines, and blood normetanephrines were elevated at 9841 mcg/24 h (lab reference range: normal 33-185 mcg/24 h), serum 13 nmol/L (lab reference range <0.5 nmol/L), and 5.8 nmol/L (lab reference range <0.9 nmol/L), respectively.	('serum', 'MPA', (213, 218))	('urine total', 'MPA', (74, 85))	('metanephrines', 'Chemical', 'MESH:D008676', (21, 34))	('normetanephrines', 'Chemical', 'MESH:D009647', (118, 134))	('metanephrines', 'Chemical', 'MESH:D008676', (93, 106))	('metanephrines', 'Chemical', 'MESH:D008676', (121, 134))	('elevated', 'PosReg', (140, 148))	('blood metanephrines', 'Disease', (87, 106))	('9841 mcg/24', 'Var', (152, 163))	('blood metanephrines', 'Disease', 'MESH:D007022', (87, 106))	('blood normetanephrines', 'MPA', (112, 134))
33741	33680468	The patient was subsequently referred to endocrinology with eventual tumor resection after treatment with phenoxybenzamine to 50 mg QID and metyrosine to 500 mg for 1 month prior to surgery.	('metyrosine', 'Chemical', 'MESH:D019805', (140, 150))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (106, 122))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('patient', 'Species', '9606', (4, 11))	('phenoxybenzamine', 'Var', (106, 122))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
33742	33680468	Genetic testing revealed the patient was heterozygous for a pathogenic variant in RET (c.1826G>A (p. Cys609Tyr)) consistent with multiple endocrine neoplasia, type 2A (MEN2A).	('patient', 'Species', '9606', (29, 36))	('c.1826G>A', 'Mutation', 'rs77939446', (87, 96))	('RET', 'Gene', (82, 85))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (138, 157))	('MEN2A', 'Gene', (168, 173))	('MEN2A', 'Gene', '5979', (168, 173))	('neoplasia', 'Phenotype', 'HP:0002664', (148, 157))	('pathogenic', 'Reg', (60, 70))	('c.1826G>A', 'Var', (87, 96))	('Cys609Tyr', 'SUBSTITUTION', 'None', (101, 110))	('RET', 'Gene', '5979', (82, 85))	('Cys609Tyr', 'Var', (101, 110))	('multiple endocrine neoplasia, type 2A', 'Gene', '5979', (129, 166))
33770	33680468	Although testing was helpful in this case, inexperienced labs or personnel should proceed with caution as severe hypertension (>250 mmHg systolic or 125 mmHg diastolic, or blood pressure higher than can be measure by equipment) is an indication to discontinue a test or not test at all as it could lead to patient decompensation.	('hypertension', 'Disease', (113, 125))	('hypertension', 'Phenotype', 'HP:0000822', (113, 125))	('lead', 'Reg', (298, 302))	('>250 mmHg', 'Var', (127, 136))	('blood pressure', 'MPA', (172, 186))	('hypertension', 'Disease', 'MESH:D006973', (113, 125))	('patient', 'Species', '9606', (306, 313))
33775	33443647	However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [68 Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('Ga', 'Chemical', 'MESH:D005708', (93, 95))	('SSTR', 'Gene', (32, 36))	('Ga', 'Chemical', 'MESH:D005708', (90, 92))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('Ga-DOTATATE', 'Chemical', '-', (93, 104))	('[68 Ga]Ga-DOTATATE', 'Var', (86, 104))
33781	33443647	However, [68 Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST.	('[68 Ga]Ga-DOTATATE', 'Var', (9, 27))	('metachronous paraganglioma', 'Disease', 'MESH:D016609', (119, 145))	('Ga-DOTATATE', 'Chemical', '-', (16, 27))	('synchronous paraganglioma', 'Disease', (75, 100))	('synchronous paraganglioma', 'Disease', 'MESH:D009378', (75, 100))	('metachronous paraganglioma', 'Disease', (119, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (87, 100))	('Ga', 'Chemical', 'MESH:D005708', (16, 18))	('tracer uptake', 'MPA', (56, 69))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('Ga', 'Chemical', 'MESH:D005708', (13, 15))
33784	33443647	Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract, and the majority of adult onset GIST, so-called 'tyrosine kinase mutant' GIST (TK-mutant GIST), are driven by activating somatic mutations in the KIT or PDGFRA genes.	('Gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (0, 32))	('Gastrointestinal stromal tumours', 'Disease', (0, 32))	('PDGFRA', 'Gene', (264, 270))	('adult onset GIST', 'Disease', (131, 147))	('mutations', 'Var', (240, 249))	('mesenchymal tumours', 'Disease', 'MESH:D009369', (60, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('PDGFRA', 'Gene', '5156', (264, 270))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('mesenchymal tumours', 'Disease', (60, 79))	('KIT', 'Gene', '3815', (257, 260))	('activating', 'PosReg', (221, 231))	('KIT', 'Gene', (257, 260))	('tumours of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (72, 109))
33785	33443647	Wild-type GIST (wtGIST) refers to tumours that are negative for KIT and PDGFRA gene mutations and account for 15% of adult and 85% of paediatric GIST.	('PDGFRA', 'Gene', '5156', (72, 78))	('PDGFRA', 'Gene', (72, 78))	('KIT', 'Gene', '3815', (64, 67))	('mutations', 'Var', (84, 93))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('KIT', 'Gene', (64, 67))	('tumours', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
33788	33443647	SDH deficient (dSDH) wtGIST is the most common subcategory of wtGIST, and these tumours are driven by inherited germline mutations in one of the SDHx genes (SDHA/B/C/D) or can occur sporadically following epigenetic silencing of the SDHC gene.	('mutations', 'Var', (121, 130))	('SDH', 'Gene', (233, 236))	('SDH', 'Gene', (145, 148))	('SDH', 'Gene', '6390', (16, 19))	('epigenetic silencing', 'Var', (205, 225))	('SDHC', 'Gene', '6391', (233, 237))	('SDH', 'Gene', '6390', (0, 3))	('SDH', 'Gene', '6390', (157, 160))	('SDH', 'Gene', (16, 19))	('SDHA', 'Gene', (157, 161))	('SDHC', 'Gene', (233, 237))	('tumours', 'Disease', (80, 87))	('SDH', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('SDHA', 'Gene', '6389', (157, 161))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('SDH', 'Gene', '6390', (233, 236))	('SDH', 'Gene', '6390', (145, 148))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('SDH deficient (dSDH) wtGIST', 'Disease', 'MESH:D007153', (0, 27))	('SDH', 'Gene', (157, 160))
33790	33443647	Rarely, renal cell carcinoma and pituitary tumours can also develop in patients with germline SDHx gene mutations.	('pituitary tumours', 'Disease', 'MESH:D010911', (33, 50))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (8, 28))	('SDH', 'Gene', '6390', (94, 97))	('mutations', 'Var', (104, 113))	('tumours', 'Phenotype', 'HP:0002664', (43, 50))	('pituitary tumours', 'Disease', (33, 50))	('patients', 'Species', '9606', (71, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (8, 28))	('SDH', 'Gene', (94, 97))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('renal cell carcinoma', 'Disease', (8, 28))
33797	33443647	Recent case reports evaluating genetically profiled tumours indicate that high SSTR2 receptor overexpression can be found in KIT mutant GIST as well as in dSDH wtGIST.	('overexpression', 'PosReg', (94, 108))	('SSTR2', 'Gene', (79, 84))	('tumours', 'Disease', (52, 59))	('KIT', 'Gene', (125, 128))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('SDH', 'Gene', '6390', (156, 159))	('SSTR2', 'Gene', '6752', (79, 84))	('tumours', 'Disease', 'MESH:D009369', (52, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('KIT', 'Gene', '3815', (125, 128))	('SDH', 'Gene', (156, 159))	('mutant', 'Var', (129, 135))
33821	33443647	Five patients (41.6%) had a pathogenic germline SDHx variant, one patient had a variant of uncertain significance in the SDHA gene, and two patients had a confirmed SDHC epimutation.	('SDH', 'Gene', '6390', (165, 168))	('patient', 'Species', '9606', (5, 12))	('SDHC', 'Gene', (165, 169))	('patients', 'Species', '9606', (5, 13))	('SDH', 'Gene', '6390', (48, 51))	('SDH', 'Gene', '6390', (121, 124))	('variant', 'Var', (53, 60))	('SDHC', 'Gene', '6391', (165, 169))	('SDH', 'Gene', (165, 168))	('patient', 'Species', '9606', (140, 147))	('patient', 'Species', '9606', (66, 73))	('SDHA', 'Gene', (121, 125))	('SDH', 'Gene', (48, 51))	('SDH', 'Gene', (121, 124))	('patients', 'Species', '9606', (140, 148))	('pathogenic', 'Reg', (28, 38))	('SDHA', 'Gene', '6389', (121, 125))
33823	33443647	Tumour tissue for SSTR2 IHC was performed on 54 tumour samples and this included tumour samples from 8/12 (66.6%) patients who had [68 Ga]Ga-DOTATATE PET/CT imaging and 47 tumour samples from individuals who did not have [68 Ga]Ga-DOTATATE PET/CT imaging.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('SSTR2', 'Gene', (18, 23))	('Ga', 'Chemical', 'MESH:D005708', (135, 137))	('SSTR2', 'Gene', '6752', (18, 23))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('tumour', 'Disease', (172, 178))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Ga-DOTATATE', 'Chemical', '-', (138, 149))	('Ga', 'Chemical', 'MESH:D005708', (228, 230))	('patients', 'Species', '9606', (114, 122))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('[68 Ga]Ga-DOTATATE', 'Var', (131, 149))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('Ga-DOTATATE', 'Chemical', '-', (228, 239))	('Ga', 'Chemical', 'MESH:D005708', (138, 140))	('Ga', 'Chemical', 'MESH:D005708', (225, 227))
33847	33443647	Notably, SSTR2 expression was also found to be low or absent in an additional 46 tumour samples, including 23 TK-mutant GIST and an additional 23 wtGIST samples.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('TK-mutant', 'Var', (110, 119))	('tumour', 'Disease', (81, 87))	('SSTR2', 'Gene', (9, 14))	('expression', 'MPA', (15, 25))	('absent', 'NegReg', (54, 60))	('SSTR2', 'Gene', '6752', (9, 14))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
33848	33443647	A previous study investigating the expression of SSTR1-5 in TK-mutant GIST demonstrated expression of SSTR1-5 using both quantitative real-time polymerase chain reaction (qPCR) and IHC.	('SSTR1-5', 'Gene', '6751;6752;6753;6754;6755', (102, 109))	('SSTR1-5', 'Gene', '6751;6752;6753;6754;6755', (49, 56))	('SSTR1-5', 'Gene', (102, 109))	('SSTR1-5', 'Gene', (49, 56))	('expression', 'MPA', (88, 98))	('TK-mutant', 'Var', (60, 69))
33861	33443647	Patients with dSDH wtGIST due to a germline variant in SDHx or SDHC epimutations are at risk of multiple tumours including multifocal PPGL, pulmonary chondroma and renal cell carcinoma.	('pulmonary chondroma', 'Phenotype', 'HP:0031474', (140, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('renal cell carcinoma', 'Disease', (164, 184))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (164, 184))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('SDH', 'Gene', '6390', (63, 66))	('SDH', 'Gene', '6390', (55, 58))	('SDH', 'Gene', '6390', (15, 18))	('pulmonary chondroma', 'Disease', 'MESH:D002812', (140, 159))	('pulmonary chondroma', 'Disease', (140, 159))	('Patients', 'Species', '9606', (0, 8))	('SDHC', 'Gene', '6391', (63, 67))	('multiple tumours', 'Disease', 'MESH:D009369', (96, 112))	('germline variant', 'Var', (35, 51))	('epimutations', 'Var', (68, 80))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('SDH', 'Gene', (63, 66))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', (15, 18))	('multiple tumours', 'Disease', (96, 112))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (164, 184))	('SDHC', 'Gene', (63, 67))	('multifocal PPGL', 'Disease', (123, 138))
33866	33443647	Notably, the location of PPGL in patients with germline SDHx mutations or SDHC epimutations can be anywhere from the skull base to the pelvis and dSDH PPGL also have a high malignant potential, increasing the risk for synchronous malignant primary tumours in one individual.	('SDH', 'Gene', (74, 77))	('synchronous malignant primary tumours', 'Disease', (218, 255))	('epimutations', 'Var', (79, 91))	('patients', 'Species', '9606', (33, 41))	('SDH', 'Gene', (147, 150))	('SDH', 'Gene', '6390', (56, 59))	('mutations', 'Var', (61, 70))	('malignant potential', 'CPA', (173, 192))	('synchronous malignant primary tumours', 'Disease', 'MESH:D009378', (218, 255))	('PPGL', 'Gene', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('SDH', 'Gene', '6390', (74, 77))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('SDH', 'Gene', (56, 59))	('SDHC', 'Gene', (74, 78))	('SDH', 'Gene', '6390', (147, 150))	('SDHC', 'Gene', '6391', (74, 78))
33867	33443647	Therefore, as [18F]FDG PET/CT lacks the ability to differentiate between at risk tumour types in patients with SDHx mutations, there is an unmet need for sensitive and specific imaging modalities which are able to distinguish PPGL from wtGIST in this patient population in order to avoid multiple biopsies and inform appropriate management with proper use of molecular imaging.	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('SDH', 'Gene', '6390', (111, 114))	('patient', 'Species', '9606', (251, 258))	('tumour', 'Disease', (81, 87))	('mutations', 'Var', (116, 125))	('patient', 'Species', '9606', (97, 104))	('SDH', 'Gene', (111, 114))	('patients', 'Species', '9606', (97, 105))
33919	32997281	In addition, genetic testing for succinate dehydrogenase mutations is recommended, because paragangliomas are potentially hereditary.	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('mutations', 'Var', (57, 66))	('paragangliomas', 'Disease', 'MESH:D010235', (91, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (91, 105))	('paragangliomas', 'Disease', (91, 105))
33936	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
33976	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
33980	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
33990	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
34000	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
34006	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
34016	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
34021	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('YIF1B', 'Gene', (108, 113))	('tumor', 'Disease', (159, 164))	('LIHC', 'Disease', (64, 68))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (89, 97))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('YIF1B', 'Gene', '90522', (108, 113))
34023	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('YIF1B', 'Gene', '90522', (33, 38))	('YIF1B', 'Gene', '90522', (308, 313))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
34026	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('HTR', 'Gene', (33, 36))	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('specific proteins', 'MPA', (130, 147))	('YIF1B', 'Gene', (87, 92))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('encephalopathy', 'Disease', (175, 189))
34041	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('high MSI', 'Var', (32, 40))	('COAD', 'Disease', (13, 17))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
34053	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
34068	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('interact', 'Reg', (54, 62))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
34104	32201516	COSMIC provided information on Siglec-15 mutations in different cancers, which included substitution missense, nonsense and synonymous mutations, and the results are depicted in pie charts.	('mutations', 'Var', (41, 50))	('Siglec-15', 'Gene', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('substitution missense', 'Var', (88, 109))	('nonsense', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
34105	32201516	Nonsense substitutions were found in biliary tract cancer (33.33%), breast cancer (25%) and lung cancer (16.67%), while substitution missense mutations were observed in biliary tract cancer (33.33%), breast cancer (75%), central nervous system cancer (33.33%), hematopoietic and lymphoid cancer (100%), endometrial cancer (100%), large intestine cancer (68.42%), liver cancer (25%), lung cancer (83.33%), esophageal cancer (75%), prostate cancer (100%), skin cancer (100%), stomach cancer (75%), thyroid cancer (100%) and upper aerodigestive tract cancer (60%).	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('stomach cancer', 'Disease', (474, 488))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('biliary tract cancer', 'Disease', (37, 57))	('cancer', 'Disease', 'MESH:D009369', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (388, 394))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (279, 294))	('missense mutations', 'Var', (133, 151))	('cancer', 'Disease', (315, 321))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (221, 250))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (37, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('biliary tract cancer', 'Disease', 'MESH:D001661', (37, 57))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (504, 510))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Disease', (416, 422))	('liver cancer', 'Phenotype', 'HP:0002896', (363, 375))	('liver cancer', 'Disease', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('lymphoid cancer', 'Disease', 'MESH:D009369', (279, 294))	('upper aerodigestive tract cancer', 'Disease', (522, 554))	('cancer', 'Disease', (288, 294))	('thyroid cancer', 'Disease', (496, 510))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('prostate cancer', 'Disease', 'MESH:D011471', (430, 445))	('prostate cancer', 'Phenotype', 'HP:0012125', (430, 445))	('cancer', 'Disease', (97, 103))	('central nervous system cancer', 'Disease', (221, 250))	('thyroid cancer', 'Disease', 'MESH:D013964', (496, 510))	('biliary tract cancer', 'Disease', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', (459, 465))	('nervous system cancer', 'Phenotype', 'HP:0004375', (229, 250))	('esophageal cancer', 'Disease', (405, 422))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (369, 375))	('substitutions', 'Var', (9, 22))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (169, 189))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('skin cancer', 'Disease', 'MESH:D012878', (454, 465))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (51, 57))	('biliary tract cancer', 'Disease', 'MESH:D001661', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (522, 554))	('cancer', 'Disease', (548, 554))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('skin cancer', 'Disease', (454, 465))	('prostate cancer', 'Disease', (430, 445))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Disease', 'MESH:D013274', (474, 488))	('lymphoid cancer', 'Disease', (279, 294))	('lung cancer', 'Disease', (92, 103))	('large intestine cancer', 'Phenotype', 'HP:0100834', (330, 352))	('stomach cancer', 'Phenotype', 'HP:0012126', (474, 488))	('cancer', 'Disease', (346, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (496, 510))	('central nervous system cancer', 'Disease', 'MESH:D002494', (221, 250))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('cancer', 'Disease', (439, 445))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('esophageal cancer', 'Disease', 'MESH:D004938', (405, 422))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('skin cancer', 'Phenotype', 'HP:0008069', (454, 465))	('hematopoietic and', 'Disease', (261, 278))	('lung cancer', 'Disease', (383, 394))	('liver cancer', 'Disease', 'MESH:D006528', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('breast cancer', 'Disease', (68, 81))
34106	32201516	Additionally, synonymous substitution mutations appeared in biliary tract cancer (33.33%), central nervous system cancer (66.67%), large intestine cancer (36.84%), liver cancer (75%), esophageal cancer (25%), parathyroid cancer (100%), stomach cancer (25%) and upper aerodigestive tract cancer (40%).	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (287, 293))	('liver cancer', 'Disease', 'MESH:D006528', (164, 176))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('upper aerodigestive tract cancer', 'Disease', (261, 293))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('thyroid cancer', 'Phenotype', 'HP:0002890', (213, 227))	('synonymous substitution mutations', 'Var', (14, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('nervous system cancer', 'Phenotype', 'HP:0004375', (99, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (164, 176))	('biliary tract cancer', 'Disease', (60, 80))	('liver cancer', 'Disease', (164, 176))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (261, 293))	('stomach cancer', 'Disease', 'MESH:D013274', (236, 250))	('stomach cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('parathyroid cancer', 'Disease', 'MESH:D010282', (209, 227))	('large intestine cancer', 'Phenotype', 'HP:0100834', (131, 153))	('parathyroid cancer', 'Disease', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (60, 80))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('central nervous system cancer', 'Disease', (91, 120))	('biliary tract cancer', 'Disease', 'MESH:D001661', (60, 80))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (209, 227))	('appeared', 'Reg', (48, 56))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (91, 120))	('cancer', 'Disease', (147, 153))	('stomach cancer', 'Disease', (236, 250))	('central nervous system cancer', 'Disease', 'MESH:D002494', (91, 120))	('cancer', 'Disease', (114, 120))
34107	32201516	C>T and G>A mutations were most common in the Siglec-15 coding strand, both of which were observed in eleven cancer types.	('G>A mutations', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('C>T', 'Var', (0, 3))	('cancer', 'Disease', (109, 115))	('common', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
34108	32201516	A>T and T>A mutations in Siglec-15 were not found in the TCGA cancer samples.	('T>A', 'Var', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Siglec-15', 'Gene', (25, 34))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
34109	32201516	Other types of base mutations occurred sporadically in different cancers (Figure 3a).	('base mutations', 'Var', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('occurred', 'Reg', (30, 38))	('cancers', 'Disease', (65, 72))
34123	32201516	Several lines of evidence have shown that interactions with sialic acid-binding receptors can influence cancer progression; for example, hypersialylation can induce changes in the physical properties of tumor cells and potentiate the evasion of apoptosis in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('hypersialylation', 'Var', (137, 153))	('influence', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('potentiate', 'PosReg', (219, 229))	('sialic acid', 'Chemical', 'MESH:D019158', (60, 71))	('interactions', 'Interaction', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (258, 264))	('induce changes', 'Reg', (158, 172))	('cancer', 'Disease', (104, 110))	('evasion', 'MPA', (234, 241))
34131	32201516	Additionally, knockdown of Siglec-15 expression did not cause obvious physical abnormalities but did inhibit tumor growth.	('Siglec-15', 'Gene', (27, 36))	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', (109, 114))
34132	32201516	Since no previous studies have focused on Siglec-15 mutations in human cancers, we explored this topic with the help of COSMIC and cBioPortal.	('mutations', 'Var', (52, 61))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Siglec-15', 'Gene', (42, 51))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
34133	32201516	As shown in Figure 3, the results from TCGA demonstrated that Siglec-15 mutations occurred widely in human cancers.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Siglec-15', 'Gene', (62, 71))	('human', 'Species', '9606', (101, 106))	('occurred', 'Reg', (82, 90))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
34134	32201516	The most common type of Siglec-15 mutation was missense substitution, which could be observed in all tumors with mutations.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Siglec-15', 'Gene', (24, 33))	('missense substitution', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))
34135	32201516	At the base-pair level, C>T and G>A mutations were the most widely observed in tumors.	('observed', 'Reg', (67, 75))	('C>T', 'Var', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('G>A mutations', 'Var', (32, 45))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
34139	32201516	Alterations in the expression of Siglec-15 may cause a variety of gene changes across different cancers, which could lead to remarkably different results.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cause', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Alterations', 'Var', (0, 11))	('gene changes', 'MPA', (66, 78))	('Siglec-15', 'Gene', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
34143	32201516	For cutaneous melanoma patients, high Siglec-15 expression indicates a high risk of tumor aggressiveness and adverse clinical outcomes.	('high', 'Var', (33, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('Siglec-15', 'Protein', (38, 47))	('tumor aggressiveness', 'Disease', (84, 104))	('cutaneous melanoma', 'Disease', (4, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (4, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 22))
34171	32042879	The patient is a 37-year-old G3P0030 with past medical history significant for hairy cell leukemia, diagnosed at age 32 and treated with one cycle of cladribine, with no evidence of disease since that time.	('cladribine', 'Chemical', 'MESH:D017338', (150, 160))	('hairy cell leukemia', 'Disease', (79, 98))	('hairy cell leukemia', 'Disease', 'MESH:D007943', (79, 98))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('G3P0030', 'Var', (29, 36))
34288	30352413	It is noteworthy that postoperative SBP was significantly lower in suspected finding group, with 115 +- 19.0 mmHg in incidental finding group and 107 +- 14.2 mmHg in suspected finding group (P < 0.001), but both of them were within the normal range of SBP.	('lower', 'NegReg', (58, 63))	('SBP', 'Gene', '8991', (252, 255))	('SBP', 'Gene', '8991', (36, 39))	('SBP', 'Gene', (36, 39))	('suspected', 'Var', (67, 76))	('SBP', 'Gene', (252, 255))
34321	30352413	MEN2 is known to associate with a mutation on the RET gene.	('associate with', 'Reg', (17, 31))	('RET', 'Gene', (50, 53))	('mutation', 'Var', (34, 42))	('MEN2', 'Gene', (0, 4))	('RET', 'Gene', '5979', (50, 53))
34334	28070496	Utility of the succinate:fumarate ratio for assessing SDH dysfunction in different tumor types Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('gastrointestinal stromal tumors', 'Disease', (244, 275))	('tumor', 'Disease', (83, 88))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('paraganglioma', 'Phenotype', 'HP:0002668', (221, 234))	('RCCs', 'Phenotype', 'HP:0005584', (311, 315))	('succinate', 'Chemical', 'MESH:D019802', (144, 153))	('GISTs', 'Phenotype', 'HP:0100723', (277, 282))	('SDH', 'Gene', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (200, 234))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (288, 309))	('succinate dehydrogenase', 'Gene', (144, 167))	('SDH dysfunction', 'Disease', 'MESH:D006331', (54, 69))	('succinate', 'Chemical', 'MESH:D019802', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('RCC', 'Disease', (311, 314))	('tumors', 'Disease', (269, 275))	('SDH', 'Gene', '6390', (54, 57))	('renal cell carcinomas', 'Disease', (288, 309))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (288, 309))	('Mutations', 'Var', (95, 104))	('RCC', 'Disease', 'MESH:C538614', (311, 314))	('pheochromocytoma', 'Disease', 'MESH:D010673', (200, 216))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (244, 275))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (244, 275))	('paraganglioma', 'Disease', (221, 234))	('SDH', 'Gene', (54, 57))	('pheochromocytoma', 'Disease', (200, 216))	('succinate dehydrogenase', 'Gene', '6390', (144, 167))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (200, 216))	('paraganglioma', 'Disease', 'MESH:D010235', (221, 234))	('PPGLs', 'Chemical', '-', (236, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (299, 309))	('SDH', 'Gene', '6390', (169, 172))	('fumarate', 'Chemical', 'MESH:D005650', (25, 33))	('tumor', 'Disease', (269, 274))	('associated', 'Reg', (184, 194))	('SDH dysfunction', 'Disease', (54, 69))
34337	28070496	Sections of FFPE tumor specimens from 18 PPGL, 10 GIST and 11 RCC patients with known SDHx mutation status for SDH deficiency were collected for mass spectrometric analysis of succinate and fumarate.	('mutation', 'Var', (91, 99))	('deficiency', 'Var', (115, 125))	('SDHx', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('SDHx', 'Chemical', '-', (86, 90))	('patients', 'Species', '9606', (66, 74))
34340	28070496	Analyzing biochemical imbalances preserved in FFPE specimens with mass spectrometry expands the method and sample type repertoire available for characterisation of multiple neoplasias associated with SDH deficiency.	('imbalance', 'Phenotype', 'HP:0002172', (22, 31))	('neoplasias', 'Disease', 'MESH:D009369', (173, 183))	('associated', 'Reg', (184, 194))	('neoplasias', 'Phenotype', 'HP:0002664', (173, 183))	('SDH', 'Gene', (200, 203))	('deficiency', 'Var', (204, 214))	('imbalances', 'Phenotype', 'HP:0002172', (22, 32))	('neoplasias', 'Disease', (173, 183))
34342	28070496	Mutations in genes encoding subunits of succinate dehydrogenase (SDH) leading to loss or dysfunction of the mitochondrial enzyme involved in both the Krebs cycle and electron transport chain have been associated with multiple neoplasias.	('loss or dysfunction', 'Disease', (81, 100))	('Krebs', 'Chemical', '-', (150, 155))	('multiple neoplasias', 'Disease', (217, 236))	('neoplasias', 'Phenotype', 'HP:0002664', (226, 236))	('SDH', 'Gene', (65, 68))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (201, 211))	('loss or dysfunction', 'Disease', 'MESH:D015431', (81, 100))
34359	28070496	Interestingly among SDH-sufficient samples, those with highest succinate:fumarate ratios were from specimens with germline VHL mutations.	('mutations', 'Var', (127, 136))	('VHL', 'Gene', '7428', (123, 126))	('VHL', 'Gene', (123, 126))	('succinate:fumarate ratios', 'MPA', (63, 88))
34364	28070496	PPGL tumor specimens with VHL gene mutations have been associated with variably impaired SDHB protein expression, and although the mechanism for this is unknown several hypotheses have been advanced including pseudohypoxic expression of miR-210 that in turns downregulates SDHD expression.	('downregulates', 'NegReg', (259, 272))	('expression', 'MPA', (102, 112))	('expression', 'MPA', (278, 288))	('VHL gene', 'Gene', (26, 34))	('impaired', 'NegReg', (80, 88))	('SDHD', 'Gene', (273, 277))	('protein', 'Protein', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('miR-210', 'Gene', (237, 244))	('miR-210', 'Gene', '406992', (237, 244))	('SDHB', 'Gene', (89, 93))	('mutations', 'Var', (35, 44))
34366	28070496	Elevated succinate:fumarate appears to have at least three potential causes: (a) inactivation by germline mutation in SDHx gene (together with somatic loss of the other allele) herein shown to be true for SDHx-mutated RCCs as well for PPGLs; (b) hypermethylation of the SDHC promoter, as first described in Carney triad and more recently in PPGL by Richter et al., and which is possibly also the mechanism for SDH-deficiency in at least some of our GIST samples; and (c) by germline VHL mutation which is associated with variably impaired SDH function.	('mutation', 'Var', (487, 495))	('VHL', 'Gene', (483, 486))	('Carney', 'Disease', (307, 313))	('SDHC', 'Gene', (270, 274))	('RCCs', 'Phenotype', 'HP:0005584', (218, 222))	('Elevated succinate', 'Phenotype', 'HP:0020149', (0, 18))	('SDHC', 'Gene', '6391', (270, 274))
34367	28070496	indistinguishable from SDH-sufficient samples) contained SDHB mutation c.380T > G, p.Ile127Ser.	('c.380T > G', 'Var', (71, 81))	('p.Ile127Ser', 'Var', (83, 94))	('SDHB', 'Gene', (57, 61))	('p.Ile127Ser', 'Mutation', 'rs786201095', (83, 94))	('c.380T > G', 'Mutation', 'rs786201095', (71, 81))
34374	27992508	Nineteen patients with recurrent PPGLs consisted of ones with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations.	('PPGLs', 'Chemical', '-', (33, 38))	('patients', 'Species', '9606', (9, 17))	('VHL', 'Gene', '7428', (124, 127))	('PPGLs', 'Disease', (72, 77))	('RET', 'Gene', '5979', (132, 135))	('PPGLs', 'Chemical', '-', (102, 107))	('mutations', 'Var', (136, 145))	('PPGLs', 'Disease', (33, 38))	('PPGLs', 'Chemical', '-', (72, 77))	('VHL', 'Gene', (124, 127))	('RET', 'Gene', (132, 135))
34380	27992508	PPGL patients with characteristic pathologic findings and PASS >=4 or germline mutations require close follow-up.	('PPGL', 'Gene', (0, 4))	('patients', 'Species', '9606', (5, 13))	('germline mutations', 'Var', (70, 88))
34393	27992508	Recently, germline mutations in the SDHB and SDHD genes have been reported to be independent risk factors for metastasis.	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('metastasis', 'CPA', (110, 120))	('SDHD', 'Gene', '6392', (45, 49))	('germline mutations', 'Var', (10, 28))	('SDHD', 'Gene', (45, 49))	('risk factors', 'Reg', (93, 105))
34399	27992508	Clinical information included i) sex and age at initial diagnosis; ii) clinical symptoms/signs including headache, sweating, palpitation, pain (neck, chest, abdomen, or bone), palpable mass, and hypertension (new onset, paroxysmal, or uncontrolled); iii) secreted hormones (plasma/24 hours urine): epinephrine, norepinephrine, metanephrine, normetanephrine and dopamine; iv) tumor size; v) PASS; vi) genetic mutations; vii) recurrence; and viii) metastasis.	('metastasis', 'CPA', (446, 456))	('palpitation', 'Phenotype', 'HP:0001962', (125, 136))	('pain', 'Phenotype', 'HP:0012531', (138, 142))	('epinephrine', 'Chemical', 'MESH:D004837', (314, 325))	('hypertension', 'Disease', 'MESH:D006973', (195, 207))	('metanephrine', 'Chemical', 'MESH:D008676', (327, 339))	('dopamine', 'Chemical', 'MESH:D004298', (361, 369))	('hypertension', 'Disease', (195, 207))	('headache', 'Disease', (105, 113))	('genetic mutations', 'Var', (400, 417))	('normetanephrine', 'MPA', (341, 356))	('pain', 'Disease', 'MESH:D010146', (138, 142))	('norepinephrine', 'Chemical', 'MESH:D009638', (311, 325))	('tumor', 'Disease', (375, 380))	('hypertension', 'Phenotype', 'HP:0000822', (195, 207))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('headache', 'Disease', 'MESH:D006261', (105, 113))	('norepinephrine', 'MPA', (311, 325))	('normetanephrine', 'Chemical', 'MESH:D009647', (341, 356))	('sweating', 'Phenotype', 'HP:0000975', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('PASS', 'MPA', (390, 394))	('pain', 'Disease', (138, 142))	('metanephrine', 'Chemical', 'MESH:D008676', (344, 356))	('epinephrine', 'Chemical', 'MESH:D004837', (298, 309))	('metanephrine', 'MPA', (327, 339))	('epinephrine', 'MPA', (298, 309))	('headache', 'Phenotype', 'HP:0002315', (105, 113))
34403	27992508	Tumors with a PASS >4 reportedly exhibit more malignant tendencies.	('PASS >4', 'Var', (14, 21))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('malignant tendencies', 'CPA', (46, 66))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
34431	27992508	Median PASS values for malignant PPGLs were significantly higher than those for benign tumors (8 vs. 3 points respectively; p<0.001).	('PPGLs', 'Chemical', '-', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('benign tumors', 'Disease', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('malignant', 'Var', (23, 32))	('higher', 'PosReg', (58, 64))	('PASS', 'MPA', (7, 11))	('benign tumors', 'Disease', 'MESH:D009369', (80, 93))
34432	27992508	All patients with malignant PPGLs showed PASS >=4, while 42 (38.5%) of benign PPGL patients also presented with PASS >=4.	('PPGLs', 'Disease', (28, 33))	('PPGLs', 'Chemical', '-', (28, 33))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (83, 91))	('PASS', 'Var', (41, 45))
34438	27992508	PASS data were available for 116 patients with initially benign PPGLs; in these patients, necrosis, capsular invasion, vascular invasion, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were predictive factors for malignancy.	('atypical', 'Var', (152, 160))	('capsular invasion', 'CPA', (100, 117))	('malignancy', 'Disease', 'MESH:D009369', (233, 243))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (33, 41))	('malignancy', 'Disease', (233, 243))	('necrosis', 'Disease', (90, 98))	('hyperchromasia', 'Disease', 'None', (190, 204))	('high mitosis', 'Disease', 'MESH:D008228', (138, 150))	('PPGLs', 'Chemical', '-', (64, 69))	('necrosis', 'Disease', 'MESH:D009336', (90, 98))	('vascular invasion', 'CPA', (119, 136))	('high mitosis', 'Disease', (138, 150))	('hyperchromasia', 'Disease', (190, 204))
34440	27992508	Two of these patients, both of whom had VHL and RET mutations, experienced recurrence at the adrenal gland; this was not a criterion for malignancy.	('mutations', 'Var', (52, 61))	('experienced', 'Reg', (63, 74))	('malignancy', 'Disease', (137, 147))	('VHL', 'Gene', (40, 43))	('RET', 'Gene', '5979', (48, 51))	('patients', 'Species', '9606', (13, 21))	('VHL', 'Gene', '7428', (40, 43))	('RET', 'Gene', (48, 51))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
34447	27992508	SDHB mutation did not predict malignancy, whereas 12 variables of PASS, necrosis, capsular invasion, vascular invasion, cellular monotony, high mitosis, atypical mitotic figures, and nuclear hyperchromasia were predictive of malignancy in PPGLs that did not present with metastases at diagnosis.	('PPGLs', 'Chemical', '-', (239, 244))	('malignancy', 'Disease', (30, 40))	('hyperchromasia', 'Disease', (191, 205))	('metastases', 'Disease', 'MESH:D009362', (271, 281))	('predictive of', 'Reg', (211, 224))	('high mitosis', 'Disease', (139, 151))	('necrosis', 'Disease', (72, 80))	('mutation', 'Var', (5, 13))	('high mitosis', 'Disease', 'MESH:D008228', (139, 151))	('PPGLs', 'Disease', (239, 244))	('hyperchromasia', 'Disease', 'None', (191, 205))	('SDHB', 'Gene', (0, 4))	('malignancy', 'Disease', 'MESH:D009369', (30, 40))	('malignancy', 'Disease', 'MESH:D009369', (225, 235))	('SDHB', 'Gene', '6390', (0, 4))	('necrosis', 'Disease', 'MESH:D009336', (72, 80))	('malignancy', 'Disease', (225, 235))	('metastases', 'Disease', (271, 281))
34452	27992508	Two patients had recurrence in their adrenal glands, which was not a criterion for malignancy; these patients also had germline mutations.	('patients', 'Species', '9606', (101, 109))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('germline mutations', 'Var', (119, 137))	('malignancy', 'Disease', (83, 93))	('patients', 'Species', '9606', (4, 12))
34454	27992508	As recommended by European Society of Endocrinology guideline, only high-risk patients such as those who are young and those with germline mutations and large tumors should be followed for more than 10 years.	('germline mutations', 'Var', (130, 148))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('patients', 'Species', '9606', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
34470	27992508	found that tumors with a PASS >4 exhibited increased metastatic potential.	('PASS >4', 'Var', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('metastatic potential', 'CPA', (53, 73))	('increased', 'PosReg', (43, 52))
34475	27992508	Furthermore, high mitotic figures, atypical mitotic figures, and nuclear hyperchromasia were additional predictors of malignancy, as shown in other studies.	('high mitotic figures', 'CPA', (13, 33))	('hyperchromasia', 'Disease', 'None', (73, 87))	('malignancy', 'Disease', 'MESH:D009369', (118, 128))	('atypical', 'Var', (35, 43))	('malignancy', 'Disease', (118, 128))	('hyperchromasia', 'Disease', (73, 87))
34480	27992508	Nineteen patients with recurrent PPGLs included those with malignant PPGLs (n = 17) and multifocal PPGLs (n = 2) who had VHL and RET mutations.	('PPGLs', 'Chemical', '-', (33, 38))	('patients', 'Species', '9606', (9, 17))	('VHL', 'Gene', '7428', (121, 124))	('RET', 'Gene', (129, 132))	('PPGLs', 'Disease', (69, 74))	('PPGLs', 'Chemical', '-', (99, 104))	('PPGLs', 'Chemical', '-', (69, 74))	('PPGLs', 'Disease', (33, 38))	('mutations', 'Var', (133, 142))	('RET', 'Gene', '5979', (129, 132))	('VHL', 'Gene', (121, 124))
34481	27992508	The presence of an SDHB mutation is associated with an increased risk of metastasis, and up to 40% of patients with an SDHB mutation will develop distant metastasis.	('SDHB', 'Gene', '6390', (19, 23))	('metastasis', 'CPA', (73, 83))	('distant metastasis', 'CPA', (146, 164))	('patients', 'Species', '9606', (102, 110))	('SDHB', 'Gene', '6390', (119, 123))	('develop', 'PosReg', (138, 145))	('SDHB', 'Gene', (19, 23))	('SDHB', 'Gene', (119, 123))	('mutation', 'Var', (124, 132))	('mutation', 'Var', (24, 32))
34482	27992508	Because of the lack of genetic testing in malignant PPGLs, we did not investigate the proportion of SDHB mutations in malignant PPGLs.	('PPGLs', 'Chemical', '-', (128, 133))	('SDHB', 'Gene', '6390', (100, 104))	('mutations', 'Var', (105, 114))	('PPGLs', 'Chemical', '-', (52, 57))	('SDHB', 'Gene', (100, 104))
34485	27992508	The follow-up duration was relatively shorter in patients with non-metastatic PPGLs (n = 17) than those with metastatic ones (n = 194) (34.0 [18.1-69.0] vs. 85.3 [49.6-100.2], p value = 0.009).	('PPGLs', 'Chemical', '-', (78, 83))	('shorter', 'NegReg', (38, 45))	('PPGLs', 'Disease', (78, 83))	('patients', 'Species', '9606', (49, 57))	('non-metastatic', 'Var', (63, 77))
34489	27992508	PPGLs with PASS <4 have a benign clinical course without recurrence or malignancy regardless of tumor size.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PASS <4', 'Var', (11, 18))	('malignancy regardless of tumor', 'Disease', 'MESH:D018198', (71, 101))	('malignancy regardless of tumor', 'Disease', (71, 101))	('PPGLs', 'Chemical', '-', (0, 5))
34557	23083876	Succinate Dehydrogenase Kidney Cancer (SDH-RCC): An Aggressive Example of the Warburg Effect in Cancer Recently, a new renal cell cancer (RCC) syndrome has been linked to germline mutation of multiple subunits (SDHB/C/D) of the Krebs cycle enzyme, succinate dehydrogenase.	('SDH-RCC', 'Disease', (39, 46))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))	('renal cell cancer (RCC) syndrome', 'Disease', 'MESH:C538614', (119, 151))	('RCC', 'Phenotype', 'HP:0005584', (138, 141))	('Succinate Dehydrogenase', 'Gene', (0, 23))	('linked', 'Reg', (161, 167))	('SDHB', 'Gene', '6390', (211, 215))	('Kidney Cancer', 'Disease', (24, 37))	('Succinate Dehydrogenase', 'Gene', '6390', (0, 23))	('RCC', 'Phenotype', 'HP:0005584', (43, 46))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('succinate dehydrogenase', 'Gene', (248, 271))	('Kidney Cancer', 'Phenotype', 'HP:0009726', (24, 37))	('SDHB', 'Gene', (211, 215))	('renal cell cancer', 'Phenotype', 'HP:0005584', (119, 136))	('SDH-RCC', 'Disease', 'MESH:C538614', (39, 46))	('germline mutation', 'Var', (171, 188))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer', 'Disease', (96, 102))	('Kidney Cancer', 'Disease', 'MESH:D007680', (24, 37))	('succinate dehydrogenase', 'Gene', '6390', (248, 271))	('Cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Cancer', 'Disease', 'MESH:D009369', (96, 102))	('Krebs', 'Chemical', '-', (228, 233))
34560	23083876	Individuals from families with germline SDHB, SDHC and SDHD mutations and kidney cancer underwent comprehensive clinical and genetic evaluation.	('SDHB', 'Gene', '6390', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SDHB', 'Gene', (40, 44))	('SDHC', 'Gene', (46, 50))	('kidney cancer', 'Phenotype', 'HP:0009726', (74, 87))	('kidney cancer', 'Disease', 'MESH:D007680', (74, 87))	('SDHD', 'Gene', '6392', (55, 59))	('mutations', 'Var', (60, 69))	('kidney cancer', 'Disease', (74, 87))	('SDHD', 'Gene', (55, 59))	('SDHC', 'Gene', '6391', (46, 50))
34561	23083876	Fourteen patients from twelve SDHB mutation families were evaluated.	('patients', 'Species', '9606', (9, 17))	('SDHB', 'Gene', '6390', (30, 34))	('SDHB', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
34563	23083876	An additional family with six individuals found to have clear cell RCC that presented at a young average age, 47 yrs (range 40-53yrs), was identified with a germline SDHC mutation (R133X), two of which developed metastatic disease.	('developed', 'PosReg', (202, 211))	('R133X', 'Var', (181, 186))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('R133X', 'Mutation', 'rs764575966', (181, 186))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('metastatic disease', 'CPA', (212, 230))	('SDHC', 'Gene', (166, 170))	('SDHC', 'Gene', '6391', (166, 170))
34564	23083876	A patient with a history of carotid body paragangliomas and a very aggressive form of kidney cancer was evaluated from a family with germline SDHD mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('mutation', 'Var', (147, 155))	('kidney cancer', 'Disease', 'MESH:D007680', (86, 99))	('carotid body paragangliomas', 'Disease', (28, 55))	('carotid body paragangliomas', 'Disease', 'MESH:D002345', (28, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('kidney cancer', 'Phenotype', 'HP:0009726', (86, 99))	('paragangliomas', 'Phenotype', 'HP:0002668', (41, 55))	('carotid body paragangliomas', 'Phenotype', 'HP:0100635', (28, 55))	('kidney cancer', 'Disease', (86, 99))	('patient', 'Species', '9606', (2, 9))	('SDHD', 'Gene', '6392', (142, 146))	('SDHD', 'Gene', (142, 146))
34569	23083876	Germline mutation of the Krebs cycle (tricarboxylic acid cycle) enzyme, fumarate hydratase, is associated with an aggressive form of type II papillary kidney cancer in patients affected with Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC).	('type II papillary kidney cancer', 'Disease', 'MESH:D007681', (133, 164))	('RCC', 'Disease', 'MESH:C538614', (245, 248))	('fumarate hydratase', 'Gene', '2271', (72, 90))	('type II papillary kidney cancer', 'Phenotype', 'HP:0006732', (133, 164))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (38, 56))	('associated with', 'Reg', (95, 110))	('type II papillary kidney cancer', 'Disease', (133, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Hereditary Leiomyomatosis and Renal Cell Carcinoma', 'Disease', 'MESH:C535516', (191, 241))	('Krebs', 'Chemical', '-', (25, 30))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (141, 164))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (221, 241))	('fumarate hydratase', 'Gene', (72, 90))	('Germline mutation', 'Var', (0, 17))	('Carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('kidney cancer', 'Phenotype', 'HP:0009726', (151, 164))	('RCC', 'Disease', (245, 248))	('RCC', 'Phenotype', 'HP:0005584', (245, 248))	('patients', 'Species', '9606', (168, 176))
34572	23083876	A second form of inherited kidney cancer characterized by a Krebs cycle gene mutation was initially reported by Vanharanta, et al., who described three patients with kidney cancer in families with a germline mutation of succinate dehydrogenase B (SDHB) also associated with hereditary paraganglioma (PGL), a group of diseases associated with head and neck PGL that can include a history of pheochromocytoma (PCC).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('inherited kidney cancer', 'Disease', 'MESH:D007680', (17, 40))	('mutation', 'Var', (77, 85))	('kidney cancer', 'Disease', 'MESH:D007680', (27, 40))	('associated with', 'Reg', (258, 273))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (274, 298))	('Krebs', 'Chemical', '-', (60, 65))	('kidney cancer', 'Phenotype', 'HP:0009726', (27, 40))	('succinate dehydrogenase B', 'Gene', (220, 245))	('PGL', 'Phenotype', 'HP:0002668', (356, 359))	('kidney cancer', 'Disease', 'MESH:D007680', (166, 179))	('paraganglioma', 'Phenotype', 'HP:0002668', (285, 298))	('PGL', 'Phenotype', 'HP:0002668', (300, 303))	('hereditary paraganglioma', 'Disease', (274, 298))	('mutation', 'Var', (208, 216))	('SDHB', 'Gene', '6390', (247, 251))	('succinate dehydrogenase B', 'Gene', '6390', (220, 245))	('kidney cancer', 'Phenotype', 'HP:0009726', (166, 179))	('pheochromocytoma', 'Disease', 'MESH:D010673', (390, 406))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('kidney cancer', 'Disease', (166, 179))	('patients', 'Species', '9606', (152, 160))	('pheochromocytoma', 'Disease', (390, 406))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (390, 406))	('PCC', 'Phenotype', 'HP:0002666', (408, 411))	('SDHB', 'Gene', (247, 251))	('inherited kidney cancer', 'Disease', (17, 40))
34576	23083876	Multiple reports identified the presence of RCC in patients with SDHB mutations either with or without a personal or family history of PGL and/or PCC.	('mutations', 'Var', (70, 79))	('PCC', 'Phenotype', 'HP:0002666', (146, 149))	('RCC', 'Disease', 'MESH:C538614', (44, 47))	('RCC', 'Disease', (44, 47))	('RCC', 'Phenotype', 'HP:0005584', (44, 47))	('SDHB', 'Gene', '6390', (65, 69))	('presence', 'Reg', (32, 40))	('patients', 'Species', '9606', (51, 59))	('PGL', 'Phenotype', 'HP:0002668', (135, 138))	('SDHB', 'Gene', (65, 69))
34577	23083876	Furthermore, a recent investigation describing 2 individuals with Cowden or Cowden-like syndromic features including RCC, but no PTEN mutation, reported SDHD gene variants that affected the AKT and/or MAPK pathways.	('RCC', 'Disease', 'MESH:C538614', (117, 120))	('affected', 'Reg', (177, 185))	('RCC', 'Disease', (117, 120))	('RCC', 'Phenotype', 'HP:0005584', (117, 120))	('SDHD', 'Gene', (153, 157))	('SDHD', 'Gene', '6392', (153, 157))	('AKT', 'Gene', '207', (190, 193))	('PTEN', 'Gene', (129, 133))	('PTEN', 'Gene', '5728', (129, 133))	('variants', 'Var', (163, 171))	('MAPK pathways', 'Pathway', (201, 214))	('AKT', 'Gene', (190, 193))
34578	23083876	reported an individual patient with a germline SDHC gene mutation with personal and family history of PGL who was found to have RCC tumors with loss of the wild-type SDHC allele.	('mutation', 'Var', (57, 65))	('RCC tumors', 'Disease', (128, 138))	('RCC', 'Phenotype', 'HP:0005584', (128, 131))	('SDHC', 'Gene', '6391', (47, 51))	('PGL', 'Phenotype', 'HP:0002668', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('SDHC', 'Gene', (166, 170))	('RCC tumors', 'Disease', 'MESH:C538614', (128, 138))	('SDHC', 'Gene', '6391', (166, 170))	('SDHC', 'Gene', (47, 51))	('patient', 'Species', '9606', (23, 30))
34585	23083876	DNA was extracted from whole blood and mutation analyses were performed by direct sequencing on all coding exons of the SDHB (NM_003000.2), SDHC (NM_003001.3) and SDHD (NM_003002.2) genes.	('SDHD', 'Gene', (163, 167))	('NM_003001.3', 'Var', (146, 157))	('SDHC', 'Gene', (140, 144))	('SDHD', 'Gene', '6392', (163, 167))	('SDHC', 'Gene', '6391', (140, 144))	('SDHB', 'Gene', '6390', (120, 124))	('NM_003000.2', 'Var', (126, 137))	('SDHB', 'Gene', (120, 124))
34587	23083876	Members of affected kindreds with SDHB, SDHC or SDHD mutations that had clinical manifestations such as RCC or pheochromocytoma/paraganglioma were offered evaluation.	('RCC', 'Phenotype', 'HP:0005584', (104, 107))	('RCC', 'Disease', (104, 107))	('pheochromocytoma', 'Disease', (111, 127))	('RCC', 'Disease', 'MESH:C538614', (104, 107))	('pheochromocytoma', 'Disease', 'MESH:D010673', (111, 127))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('paraganglioma', 'Disease', 'MESH:D010235', (128, 141))	('SDHD', 'Gene', '6392', (48, 52))	('mutations', 'Var', (53, 62))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))	('SDHC', 'Gene', (40, 44))	('SDHD', 'Gene', (48, 52))	('paraganglioma', 'Phenotype', 'HP:0002668', (128, 141))	('SDHC', 'Gene', '6391', (40, 44))	('paraganglioma', 'Disease', (128, 141))
34589	23083876	Patient information was evaluated in addition to individual and familial manifestations of SDH mutation.	('SDH', 'Gene', (91, 94))	('SDH', 'Gene', '6390', (91, 94))	('Patient', 'Species', '9606', (0, 7))	('mutation', 'Var', (95, 103))
34592	23083876	Fourteen patients from 12 families with germline SDHB mutations were evaluated.	('SDHB', 'Gene', (49, 53))	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (54, 63))	('SDHB', 'Gene', '6390', (49, 53))
34598	23083876	Preoperative imaging was available for ten SDHB mutation patients.	('patients', 'Species', '9606', (57, 65))	('mutation', 'Var', (48, 56))	('SDHB', 'Gene', '6390', (43, 47))	('SDHB', 'Gene', (43, 47))
34606	23083876	Four SDHB mutation patients were found to have metastatic disease, three (UOB-1 III:1 and III:3, UOB-4 III:2) at the time of initial presentation and one patient (UOB-10 III:1) with T1a disease that recurred in the liver three years post-operatively (Figure 3E and 3F).	('metastatic disease', 'Disease', (47, 65))	('patient', 'Species', '9606', (19, 26))	('SDHB', 'Gene', '6390', (5, 9))	('patient', 'Species', '9606', (154, 161))	('patients', 'Species', '9606', (19, 27))	('SDHB', 'Gene', (5, 9))	('mutation', 'Var', (10, 18))
34607	23083876	The pathologic tumor stage for available cases was T1/T2 (Figure 3A and 3B) in 12/13 cases (92.3%) and T3a in the remaining case (UOB-4 III:2, Figure 3C).	('T3a', 'Var', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('T1/T2', 'Disease', (51, 56))	('tumor', 'Disease', (15, 20))
34609	23083876	All the SDHB mutations, except SDHB p.Ile127Leu, have been previously shown to be associated with PGL and/or PCC, and thus were considered pathogenic (LOVD v2.0 TCA Cycle Gene Mutation Database).	('associated', 'Reg', (82, 92))	('SDHB', 'Gene', (31, 35))	('pathogenic', 'Reg', (139, 149))	('SDHB', 'Gene', '6390', (8, 12))	('p.Ile127Leu', 'Mutation', 'rs201372280', (36, 47))	('PGL', 'Phenotype', 'HP:0002668', (98, 101))	('PCC', 'Disease', (109, 112))	('SDHB', 'Gene', (8, 12))	('PGL', 'Disease', (98, 101))	('PCC', 'Phenotype', 'HP:0002666', (109, 112))	('mutations', 'Var', (13, 22))	('SDHB', 'Gene', '6390', (31, 35))
34610	23083876	The novel p.Ile127Leu alters an amino acid that has alternative variants (p.Ile127Asn, p.Ile127Ser) that have been shown to be associated with PGL and/or PCC, and was thus considered pathogenic.	('p.Ile127Leu', 'Var', (10, 21))	('associated', 'Reg', (127, 137))	('PGL', 'Phenotype', 'HP:0002668', (143, 146))	('p.Ile127Asn', 'Mutation', 'p.I127N', (74, 85))	('PCC', 'Disease', (154, 157))	('PGL', 'Disease', (143, 146))	('PCC', 'Phenotype', 'HP:0002666', (154, 157))	('p.Ile127Ser', 'Var', (87, 98))	('p.Ile127Ser', 'Mutation', 'rs786201095', (87, 98))	('p.Ile127Asn', 'Var', (74, 85))	('p.Ile127Leu', 'Mutation', 'rs201372280', (10, 21))
34611	23083876	Alterations were observed throughout the length of the SDHB gene consisting of 1 nonsense (c.268C>T p.Arg90X), 4 missense (c.137G>A p.Arg46Gln, c.286G>A, p.Gly96Ser, c.379A>C p.Ile127Leu, c.689G>A p.Arg230His), 2 splice site altering mutations (c.286+2T>A, c.541-2A>G) and three complete deletions of exon 1.	('c.689G>A', 'Mutation', 'rs587782604', (188, 196))	('c.268C>T', 'Mutation', 'rs74315366', (91, 99))	('c.541-2A>G', 'Var', (257, 267))	('c.268C>T p.Arg90X', 'Var', (91, 108))	('p.Ile127Leu', 'Mutation', 'rs201372280', (175, 186))	('c.286+2T>A', 'Mutation', 'rs587781270', (245, 255))	('c.286G>A', 'Mutation', 'rs587782243', (144, 152))	('SDHB', 'Gene', (55, 59))	('p.Gly96Ser', 'Mutation', 'rs587782243', (154, 164))	('p.Arg90X', 'Mutation', 'rs74315366', (100, 108))	('c.137G>A', 'Mutation', 'rs772551056', (123, 131))	('c.286G>A', 'Var', (144, 152))	('c.689G>A p.Arg230His', 'Var', (188, 208))	('c.286+2T>A', 'Var', (245, 255))	('c.541-2A>G', 'Mutation', 'rs786201161', (257, 267))	('p.Arg230His', 'Mutation', 'rs587782604', (197, 208))	('c.379A>C', 'Mutation', 'rs201372280', (166, 174))	('c.137G>A p.Arg46Gln', 'Var', (123, 142))	('SDHB', 'Gene', '6390', (55, 59))	('c.379A>C', 'Var', (166, 174))	('p.Gly96Ser', 'Var', (154, 164))	('p.Arg46Gln', 'Mutation', 'rs772551056', (132, 142))
34612	23083876	Mutations occurred along the length of the SDHB protein including all three critical regulatory sites (Figure 4A and 4B).	('SDHB', 'Gene', '6390', (43, 47))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (43, 47))	('occurred', 'Reg', (10, 18))
34614	23083876	While no germline mutations were detected in known familial RCC genes such as VHL, FLCN, FH, SDHB and SDHD, mutation analysis of SDHC revealed a c.397C>T germline mutation in the proband, her affected cousin and two of her offspring.	('VHL', 'Disease', 'MESH:D006623', (78, 81))	('SDHC', 'Gene', '6391', (129, 133))	('c.397C>T', 'Mutation', 'rs764575966', (145, 153))	('SDHB', 'Gene', (93, 97))	('VHL', 'Disease', (78, 81))	('FLCN', 'Gene', (83, 87))	('RCC', 'Disease', (60, 63))	('RCC', 'Phenotype', 'HP:0005584', (60, 63))	('c.397C>T', 'Var', (145, 153))	('SDHD', 'Gene', (102, 106))	('RCC', 'Disease', 'MESH:C538614', (60, 63))	('FLCN', 'Gene', '201163', (83, 87))	('SDHD', 'Gene', '6392', (102, 106))	('SDHC', 'Gene', (129, 133))	('SDHB', 'Gene', '6390', (93, 97))
34622	23083876	Strikingly, all seven renal tumors from this family (UOB-13) with germline SDHC mutation were found to be classic clear cell RCC (Figure 6B and 6H).	('SDHC', 'Gene', (75, 79))	('RCC', 'Disease', 'MESH:C538614', (125, 128))	('SDHC', 'Gene', '6391', (75, 79))	('RCC', 'Disease', (125, 128))	('renal tumors', 'Disease', 'MESH:D007674', (22, 34))	('RCC', 'Phenotype', 'HP:0005584', (125, 128))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('renal tumors', 'Disease', (22, 34))	('renal tumor', 'Phenotype', 'HP:0009726', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mutation', 'Var', (80, 88))	('renal tumors', 'Phenotype', 'HP:0009726', (22, 34))
34625	23083876	The germline heterozygous SDHC nonsense mutation (c.397C>T p.Arg133X) identified in UOB-13 was previously associated with PGL/PCC.	('UOB-13', 'Gene', (84, 90))	('c.397C>T p.Arg133X', 'Var', (50, 68))	('SDHC', 'Gene', '6391', (26, 30))	('c.397C>T', 'Mutation', 'rs764575966', (50, 58))	('associated', 'Reg', (106, 116))	('PGL', 'Phenotype', 'HP:0002668', (122, 125))	('p.Arg133X', 'Mutation', 'rs764575966', (59, 68))	('PGL/PCC', 'Disease', (122, 129))	('PCC', 'Phenotype', 'HP:0002666', (126, 129))	('p.Arg133X', 'Var', (59, 68))	('SDHC', 'Gene', (26, 30))
34626	23083876	This mutation would be predicted to result in the loss of full-length protein production, which is also the case of the single SDHC mutation previously associated with RCC, pMet1Ile.	('SDHC', 'Gene', (127, 131))	('full-length protein production', 'MPA', (58, 88))	('SDHC', 'Gene', '6391', (127, 131))	('loss', 'NegReg', (50, 54))	('RCC', 'Phenotype', 'HP:0005584', (168, 171))	('RCC', 'Disease', 'MESH:C538614', (168, 171))	('associated', 'Reg', (152, 162))	('RCC', 'Disease', (168, 171))	('mutation', 'Var', (132, 140))	('mutation', 'Var', (5, 13))
34632	23083876	Both he and his son were found to have an SDHD mutation (c.239G>T p.Leu80Arg) that has been previously shown to associate with PGL/PCC.	('PGL', 'Phenotype', 'HP:0002668', (127, 130))	('c.239G>T', 'Mutation', 'c.239G>T', (57, 65))	('PCC', 'Phenotype', 'HP:0002666', (131, 134))	('p.Leu80Arg', 'Mutation', 'p.L80R', (66, 76))	('PGL/PCC', 'Disease', (127, 134))	('associate', 'Reg', (112, 121))	('SDHD', 'Gene', (42, 46))	('c.239G>T p.Leu80Arg', 'Var', (57, 76))	('SDHD', 'Gene', '6392', (42, 46))
34635	23083876	When considering germline SDH testing, a personal or family history of PGL, PCC, or a GIST should raise awareness of possible SDHB, SDHC or SDHD alterations, however RCC can present as the sole finding in these families.	('RCC', 'Disease', 'MESH:C538614', (166, 169))	('PCC', 'Phenotype', 'HP:0002666', (76, 79))	('SDH', 'Gene', (140, 143))	('SDHC', 'Gene', (132, 136))	('SDHB', 'Gene', '6390', (126, 130))	('SDH', 'Gene', (26, 29))	('alterations', 'Var', (145, 156))	('SDHB', 'Gene', (126, 130))	('SDH', 'Gene', '6390', (126, 129))	('SDH', 'Gene', '6390', (132, 135))	('SDHD', 'Gene', '6392', (140, 144))	('SDHC', 'Gene', '6391', (132, 136))	('SDH', 'Gene', '6390', (140, 143))	('RCC', 'Disease', (166, 169))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('SDH', 'Gene', (126, 129))	('SDHD', 'Gene', (140, 144))	('SDH', 'Gene', '6390', (26, 29))	('SDH', 'Gene', (132, 135))	('PGL', 'Phenotype', 'HP:0002668', (71, 74))
34636	23083876	Early age of onset of RCC has been previously observed in patients with SDHB mutations.	('RCC', 'Disease', (22, 25))	('SDHB', 'Gene', (72, 76))	('RCC', 'Phenotype', 'HP:0005584', (22, 25))	('RCC', 'Disease', 'MESH:C538614', (22, 25))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (58, 66))	('SDHB', 'Gene', '6390', (72, 76))
34658	23083876	Germline mutations in SDHB, SDHC and SDHD are not only associated with hereditary paraganglioma syndromes but also with hereditary kidney cancer.	('Germline mutations', 'Var', (0, 18))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('hereditary paraganglioma syndromes', 'Disease', (71, 105))	('SDHD', 'Gene', '6392', (37, 41))	('SDHC', 'Gene', (28, 32))	('associated', 'Reg', (55, 65))	('SDHB', 'Gene', '6390', (22, 26))	('SDHD', 'Gene', (37, 41))	('SDHB', 'Gene', (22, 26))	('hereditary kidney cancer', 'Disease', 'MESH:D007680', (120, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('hereditary kidney cancer', 'Disease', (120, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (131, 144))	('SDHC', 'Gene', '6391', (28, 32))	('hereditary paraganglioma syndromes', 'Disease', 'MESH:D010235', (71, 105))
34659	23083876	We have characterized the clinical manifestations and management of SDHB-, SDHC- and SDHD mutation-associated RCC.	('RCC', 'Disease', (110, 113))	('RCC', 'Phenotype', 'HP:0005584', (110, 113))	('SDHC', 'Gene', (75, 79))	('mutation-associated', 'Var', (90, 109))	('RCC', 'Disease', 'MESH:C538614', (110, 113))	('SDHC', 'Gene', '6391', (75, 79))	('SDHB', 'Gene', '6390', (68, 72))	('SDHD', 'Gene', '6392', (85, 89))	('SDHB', 'Gene', (68, 72))	('SDHD', 'Gene', (85, 89))
34675	23776912	Biological hyperthyroidism was evident with TSHus < 0.05 muUI/ml (normal range: 0.25 to 5), T3 = 24.37 pmol/l (normal range: 4 to 8.3), and T4 > 70 pmol/l (normal range: 9 to 20).	('T3 = 24.37', 'Var', (92, 102))	('TSHus < 0.05 muUI/ml', 'Var', (44, 64))	('hyperthyroidism', 'Disease', (11, 26))	('T4 > 70 pmol/l', 'Var', (140, 154))	('hyperthyroidism', 'Disease', 'MESH:D006980', (11, 26))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (11, 26))
34724	21584168	Germ line mutations in the succinate dehydrogenase (SDH) subunit genes sdh b, sdh c, sdh d, and sdh af2 predispose carriers to tumors of the paraganglia.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sdh', 'Gene', (85, 88))	('sdh', 'Gene', '6390', (71, 74))	('sdh', 'Gene', (78, 81))	('predispose', 'Reg', (104, 114))	('tumors of the paraganglia', 'Disease', (127, 152))	('sdh', 'Gene', '6390', (78, 81))	('sdh', 'Gene', '6390', (85, 88))	('succinate dehydrogenase', 'Gene', '6390', (27, 50))	('SDH', 'Gene', '6390', (52, 55))	('succinate dehydrogenase', 'Gene', (27, 50))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('sdh', 'Gene', (96, 99))	('sdh', 'Gene', '6390', (96, 99))	('SDH', 'Gene', (52, 55))	('tumors of the paraganglia', 'Disease', 'MESH:D009369', (127, 152))	('mutations', 'Var', (10, 19))	('sdh', 'Gene', (71, 74))
34815	32993074	The sensitivity (Figure 3, below the dashed line) of the pair of P-MN and P-NMN (51 of 54 PPGL detected) was higher (p <= 0.02) than that of the pair of U-A and U-NA (42 of 54 PPGL detected), but not (p = n.s.)	('PPGL', 'Chemical', '-', (90, 94))	('PGL', 'Phenotype', 'HP:0002668', (177, 180))	('P-MN', 'Chemical', '-', (65, 69))	('P-NMN', 'Chemical', '-', (74, 79))	('sensitivity', 'MPA', (4, 15))	('higher', 'PosReg', (109, 115))	('U-NA', 'Chemical', '-', (161, 165))	('P-NMN', 'Var', (74, 79))	('P-MN', 'Var', (65, 69))	('PGL', 'Phenotype', 'HP:0002668', (91, 94))	('PPGL', 'Chemical', '-', (176, 180))
34817	32993074	Specificity (Figure 3, above the dashed line) was highest with the combined P-MN and P-NMN (no false positives of 889 patients without PPGL), and higher (p < 0.001) than that of the pair of 24 h-urinary metanephrines (236 false positive) and of plasma-free metanephrines (46 false positive), when using the corrected ULN as proposed by others.	('higher', 'PosReg', (146, 152))	('P-MN', 'Var', (76, 80))	('P-NMN', 'Var', (85, 90))	('metanephrines', 'Chemical', 'MESH:D008676', (203, 216))	('PPGL', 'Chemical', '-', (135, 139))	('P-MN', 'Chemical', '-', (76, 80))	('PGL', 'Phenotype', 'HP:0002668', (136, 139))	('P-NMN', 'Chemical', '-', (85, 90))	('metanephrines', 'Chemical', 'MESH:D008676', (257, 270))	('Specificity', 'MPA', (0, 11))	('patients', 'Species', '9606', (118, 126))
34824	32993074	When the combined models were considered, both the AUC of the pairs of P-MN and P-NMN (0.989, 95% CI: 0.972-1.000), and of U-MN and U-NMN (0.995, 95% CI: 0.980-1.000), were larger (p < 0.05) than that of the pair of U-A and U-NA (0.956, 95% CI: 0.930-0.975), but not different (p = n.s.)	('P-NMN', 'Chemical', '-', (80, 85))	('U-NMN', 'Chemical', '-', (132, 137))	('U-NMN', 'Var', (132, 137))	('P-MN', 'Var', (71, 75))	('P-NMN', 'Var', (80, 85))	('U-NA', 'Chemical', '-', (224, 228))	('P-MN', 'Chemical', '-', (71, 75))	('U-MN', 'CellLine', 'CVCL:U508', (123, 127))	('U-MN', 'Var', (123, 127))
34832	32993074	The use of downward corrected ULN of the former, as proposed by others, resulted in a slight improvement of sensitivity, at the cost of a decrease in specificity to the extent to become lower than that of both, U-MNs and U-CATs.	('specificity', 'MPA', (150, 161))	('ULN', 'Gene', (30, 33))	('improvement', 'PosReg', (93, 104))	('U-MNs', 'Chemical', '-', (211, 216))	('U-CATs', 'Phenotype', 'HP:0011976', (221, 227))	('sensitivity', 'MPA', (108, 119))	('lower', 'NegReg', (186, 191))	('decrease', 'NegReg', (138, 146))	('downward corrected', 'Var', (11, 29))	('CATs', 'Species', '9685', (223, 227))
34834	32993074	Whether a larger number of PPGL would result in a significantly increased sensitivity remains to be determined.	('increased', 'PosReg', (64, 73))	('PGL', 'Phenotype', 'HP:0002668', (28, 31))	('PPGL', 'Chemical', '-', (27, 31))	('PPGL', 'Var', (27, 31))	('sensitivity', 'MPA', (74, 85))
34841	32993074	Further quality control studies have found that the linearity of the assay for P-MN exceeded the manufacturer's claim of precision (that of P-NMN was in accord), and that both P-MN and P-NMN underestimated the Royal College of Pathologists Australasia Quality Assurance Program target value by 15.6% and 18.3%, respectively.	('P-NMN', 'Var', (185, 190))	('underestimated', 'NegReg', (191, 205))	('P-MN', 'Chemical', '-', (79, 83))	('P-MN', 'Var', (176, 180))	('P-MN', 'Chemical', '-', (176, 180))	('P-NMN', 'Chemical', '-', (140, 145))	('P-NMN', 'Chemical', '-', (185, 190))	('linearity', 'MPA', (52, 61))
34892	32993074	Post-test probabilities of PPGL given a positive and negative test result of P-MNs were almost 100% and 0%, respectively, with P-MNs, but only 18% and 0% with U-MNs.	('U-MNs', 'Chemical', '-', (159, 164))	('P-MNs', 'Chemical', '-', (77, 82))	('P-MNs', 'Disease', (77, 82))	('P-MNs', 'Var', (127, 132))	('PGL', 'Phenotype', 'HP:0002668', (28, 31))	('PPGL', 'Chemical', '-', (27, 31))	('P-MNs', 'Chemical', '-', (127, 132))
34913	29450723	Currently, a well-characterized syndromic presentation includes the existence of other tumor types associated with the presence of a PGL (e.g., renal cell carcinoma, gastrointestinal stromal tumor, pituitary adenoma can also be related to SDHx mutations) (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('pituitary adenoma', 'Disease', 'MESH:D010911', (198, 215))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('presence', 'Var', (119, 127))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (198, 215))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('pituitary adenoma', 'Disease', (198, 215))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (166, 196))	('mutations', 'Var', (244, 253))	('SDHx', 'Gene', (239, 243))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (166, 196))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('renal cell carcinoma', 'Disease', (144, 164))	('PGL', 'Gene', (133, 136))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('gastrointestinal stromal tumor', 'Disease', (166, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (191, 196))
34915	29450723	They can also be revealed by screening patients who harbor mutations in one of the PHEO/PGL susceptibility genes.	('PHEO/PGL', 'Gene', (83, 91))	('patients', 'Species', '9606', (39, 47))	('mutations', 'Var', (59, 68))
34920	29450723	There are a few true single pathognomonic findings that will allow for definitive diagnosis of MEN2 by clinical inspection, including the presence of nostalgia paraesthetica (posterior pigmented pruritic patch and nostalgia) in MEN2A with codon 634 mutation or marfanoid body habitus (excessively long arms and legs) and thickened protruding lips due to multiple mucosal neuromas (also present on the distal portion of the tongue and gingiva) in MEN2B.	('marfanoid body habitus', 'Phenotype', 'HP:0001519', (261, 283))	('MEN2A', 'Gene', (228, 233))	('MEN2B', 'Gene', '5979', (446, 451))	('multiple mucosal neuromas', 'Disease', (354, 379))	('multiple mucosal neuromas', 'Phenotype', 'HP:0031023', (354, 379))	('protruding lips due', 'Phenotype', 'HP:0012471', (331, 350))	('nostalgia paraesthetica', 'Disease', 'MESH:C563590', (150, 173))	('pigmented pruritic patch and nostalgia', 'Disease', 'MESH:D010859', (185, 223))	('neuromas', 'Phenotype', 'HP:0030430', (371, 379))	('nostalgia paraesthetica', 'Disease', (150, 173))	('codon 634 mutation', 'Var', (239, 257))	('MEN2A', 'Gene', '5979', (228, 233))	('multiple mucosal neuromas', 'Disease', 'MESH:D018814', (354, 379))	('MEN2B', 'Gene', (446, 451))
34925	29450723	Norepinephrine-secreting tumors are characteristic for extra-adrenal PGLs, either sporadic, or those with hereditary background, mainly including mutations in succinate dehydrogenase subunits (SDHx), VHL, and fuma-rate dehydrogenase (FH).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('VHL', 'Gene', (200, 203))	('mutations', 'Var', (146, 155))	('adrenal PGLs', 'Disease', (61, 73))	('succinate', 'Chemical', 'MESH:D019802', (159, 168))	('FH', 'Gene', (234, 236))	('tumors', 'Disease', (25, 31))	('VHL', 'Gene', '7428', (200, 203))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('PGLs', 'Phenotype', 'HP:0002668', (69, 73))	('adrenal PGLs', 'Disease', 'MESH:D000310', (61, 73))	('ret', 'Gene', (18, 21))	('SDHx', 'Gene', (193, 197))	('Norepinephrine', 'Chemical', 'MESH:D009638', (0, 14))	('ret', 'Gene', '5979', (18, 21))
34927	29450723	They can be sporadic or hereditary, including mutations in ret.	('mutations', 'Var', (46, 55))	('ret', 'Gene', '5979', (59, 62))	('ret', 'Gene', (59, 62))
34930	29450723	Usually, dopamine or MTY elevation is associated with an increase in norepinephrine or normetanephrine, which is commonly seen in patients with SDHx mutations (Table 1).	('mutations', 'Var', (149, 158))	('dopamine', 'MPA', (9, 17))	('MTY elevation', 'MPA', (21, 34))	('dopamine', 'Chemical', 'MESH:D004298', (9, 17))	('norepinephrine', 'MPA', (69, 83))	('SDHx', 'Gene', (144, 148))	('patients', 'Species', '9606', (130, 138))	('increase', 'PosReg', (57, 65))	('MTY', 'Chemical', 'MESH:C001746', (21, 24))	('normetanephrine', 'MPA', (87, 102))	('normetanephrine', 'Chemical', 'MESH:D009647', (87, 102))	('norepinephrine', 'Chemical', 'MESH:D009638', (69, 83))
34946	29450723	To circumvent these limitations and drawbacks, the use of 124I-MIBG could provide higher resolution images with potential additional benefits of prospective dosimetry for radionuclide therapy.	('124I-MIBG', 'Var', (58, 67))	('higher', 'PosReg', (82, 88))	('124I-MIBG', 'Chemical', '-', (58, 67))
34967	29450723	Recent studies suggest that the accumulation of succinate due to the TCA defect plays a major role in glucose uptake by PHEO cells, not only via stabilization of hypoxia-inducibal factors (HIFs) proteins (pseudohypoxia) but also by endothelial cells via hormone-like action.	('succinate', 'Chemical', 'MESH:D019802', (48, 57))	('HIFs', 'Disease', (189, 193))	('glucose', 'Chemical', 'MESH:D005947', (102, 109))	('TCA', 'Gene', (69, 72))	('defect', 'Var', (73, 79))	('glucose uptake', 'MPA', (102, 116))	('hypoxia', 'Disease', 'MESH:D000860', (211, 218))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('TCA', 'Chemical', 'MESH:D014238', (69, 72))	('succinate', 'MPA', (48, 57))	('accumulation', 'PosReg', (32, 44))	('proteins', 'Protein', (195, 203))	('HIFs', 'Disease', 'None', (189, 193))	('hypoxia', 'Disease', (162, 169))	('stabilization', 'MPA', (145, 158))	('hypoxia', 'Disease', (211, 218))
34980	29450723	In metastatic PPGLs, 131I-MIBG provides symptomatic relief in approximately 75% of cases, and a partial radio-logical response in about 30%, with relatively limited side effects.	('symptomatic', 'MPA', (40, 51))	('131I-MIBG', 'Var', (21, 30))	('PPGLs', 'Chemical', '-', (14, 19))	('MIBG', 'Chemical', 'MESH:D019797', (26, 30))	('PGLs', 'Phenotype', 'HP:0002668', (15, 19))
34992	31666924	Mutational profile and genotype/phenotype correlation of non-familial pheochromocytoma and paraganglioma About 30%-40% of patients with pheochromocytoma (PCC) and paraganglioma (PGL) have underlying germline mutations in certain susceptibility genes despite absent family history of these tumors.	('pheochromocytoma', 'Disease', 'MESH:D010673', (70, 86))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('paraganglioma', 'Disease', (163, 176))	('pheochromocytoma', 'Disease', (70, 86))	('PGL', 'Disease', 'MESH:D010235', (178, 181))	('paraganglioma', 'Disease', 'MESH:D010235', (163, 176))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (70, 86))	('paraganglioma', 'Disease', (91, 104))	('paraganglioma', 'Disease', 'MESH:D010235', (91, 104))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('PGL', 'Disease', (178, 181))	('PCC', 'Disease', 'MESH:D010673', (154, 157))	('patients', 'Species', '9606', (122, 130))	('paraganglioma', 'Phenotype', 'HP:0002668', (163, 176))	('pheochromocytoma', 'Disease', 'MESH:D010673', (136, 152))	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('pheochromocytoma', 'Disease', (136, 152))	('PCC', 'Disease', (154, 157))	('germline mutations', 'Var', (199, 217))	('tumors', 'Disease', (289, 295))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (136, 152))
34994	31666924	Results: Of 101 cases with PPGL, 37/101 (36.6%) had germline mutations.	('PPGL', 'Disease', (27, 31))	('germline mutations', 'Var', (52, 70))	('PPGL', 'Disease', 'MESH:D010673', (27, 31))
34995	31666924	The most commonly mutated gene was SDHB (21/101 cases, 20.8%) and the most common SDHB mutation was c.268C>T, p.R90X occurring in 12/21 (57%) cases.	('p.R90X', 'Mutation', 'p.R90X', (110, 116))	('SDHB', 'Gene', (35, 39))	('SDHB', 'Gene', '6390', (82, 86))	('c.268C>T', 'Var', (100, 108))	('c.268C>T', 'Mutation', 'c.268C>T', (100, 108))	('SDHB', 'Gene', (82, 86))	('SDHB', 'Gene', '6390', (35, 39))	('p.R90X', 'Var', (110, 116))
34996	31666924	Mutations also occurred in SDHC (4/101, 3.96%), SDHD (3/101, 3%), VHL (2/101, 2%) and MAX (2/101, 2%) genes.	('SDHC', 'Gene', (27, 31))	('MAX', 'Gene', (86, 89))	('occurred', 'Reg', (15, 23))	('SDHD', 'Gene', '6392', (48, 52))	('SDHC', 'Gene', '6391', (27, 31))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', (66, 69))	('SDHD', 'Gene', (48, 52))	('VHL', 'Gene', '7428', (66, 69))
34997	31666924	The following genes were mutated in 1 patient each (1%), RET, SDHA, SDHAF2, TMEM127 and NF1.	('SDHAF2', 'Gene', '54949', (68, 74))	('NF1', 'Gene', (88, 91))	('SDHA', 'Gene', '6389', (62, 66))	('SDHA', 'Gene', (62, 66))	('SDHA', 'Gene', '6389', (68, 72))	('NF1', 'Gene', '4763', (88, 91))	('TMEM127', 'Gene', (76, 83))	('RET', 'Gene', (57, 60))	('TMEM127', 'Gene', '55654', (76, 83))	('patient', 'Species', '9606', (38, 45))	('RET', 'Gene', '5979', (57, 60))	('mutated', 'Var', (25, 32))	('SDHA', 'Gene', (68, 72))	('SDHAF2', 'Gene', (68, 74))
34998	31666924	Metastatic PPGL occurred in 6/21 cases (28.6%) with SDHB mutations and in 1 case with SDHAF2 mutation.	('SDHB', 'Gene', (52, 56))	('SDHAF2', 'Gene', (86, 92))	('Metastatic PPGL', 'Disease', (0, 15))	('SDHAF2', 'Gene', '54949', (86, 92))	('Metastatic PPGL', 'Disease', 'MESH:D010673', (0, 15))	('occurred', 'Reg', (16, 24))	('mutations', 'Var', (57, 66))	('SDHB', 'Gene', '6390', (52, 56))
35001	31666924	Conclusion: About 37% of PPGL without family history of such tumors harbor germline mutations.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('germline mutations', 'Var', (75, 93))	('PPGL', 'Disease', (25, 29))	('harbor', 'Reg', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('PPGL', 'Disease', 'MESH:D010673', (25, 29))
35003	31666924	SDHB mutations were associated with metastatic PPGL in more than a quarter of cases.	('associated', 'Reg', (20, 30))	('PPGL', 'Disease', (47, 51))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('PPGL', 'Disease', 'MESH:D010673', (47, 51))	('SDHB', 'Gene', (0, 4))
35005	31666924	While having been considered mostly sporadic for long time, it has become clear over the last 2 decades that 30-40% of these tumors are due to underlying germline mutations in one of several susceptibility genes.	('due to', 'Reg', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('germline mutations', 'Var', (154, 172))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (125, 131))
35016	31666924	SDHD, VHL and MAX genes were mutated in 3 (3%), 2 (2%) and 2 (2%) cases, respectively.	('MAX genes', 'Gene', (14, 23))	('SDHD', 'Gene', '6392', (0, 4))	('mutated', 'Var', (29, 36))	('VHL', 'Gene', (6, 9))	('VHL', 'Gene', '7428', (6, 9))	('SDHD', 'Gene', (0, 4))
35017	31666924	The majority of cases with SDHB mutations presented with abdominal PGL (14/21 cases, 66.7%) (Table 3) including one patient with combined abdominal and head and neck PGL.	('PGL', 'Disease', (166, 169))	('presented with', 'Reg', (42, 56))	('PGL', 'Disease', (67, 70))	('patient', 'Species', '9606', (116, 123))	('PGL', 'Disease', 'MESH:D010235', (67, 70))	('PGL', 'Disease', 'MESH:D010235', (166, 169))	('SDHB', 'Gene', '6390', (27, 31))	('mutations', 'Var', (32, 41))	('SDHB', 'Gene', (27, 31))
35018	31666924	Five cases presented with head/neck PGL of whom one case had bilateral carotid body tumors associated with the c.689G>A, p.R230H mutation.	('p.R230H', 'Mutation', 'p.R230H', (121, 128))	('PGL', 'Disease', (36, 39))	('c.689G>A', 'Var', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('presented', 'Reg', (11, 20))	('p.R230H', 'Var', (121, 128))	('PGL', 'Disease', 'MESH:D010235', (36, 39))	('carotid body tumors', 'Phenotype', 'HP:0002668', (71, 90))	('carotid body tumor', 'Phenotype', 'HP:0002668', (71, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('bilateral carotid body tumors', 'Disease', (61, 90))	('bilateral carotid body tumors', 'Disease', 'MESH:D002345', (61, 90))	('c.689G>A', 'Mutation', 'c.689G>A', (111, 119))	('associated', 'Reg', (91, 101))
35021	31666924	The non-sense mutation c.268C>T, p.R90X was the most frequent mutation occurring in 12 out of 21 cases (57%) with SDHB mutations.	('p.R90X', 'Var', (33, 39))	('c.268C>T', 'Var', (23, 31))	('c.268C>T', 'Mutation', 'c.268C>T', (23, 31))	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('p.R90X', 'Mutation', 'p.R90X', (33, 39))	('mutations', 'Var', (119, 128))
35022	31666924	Four patients had SDHC mutations.	('mutations', 'Var', (23, 32))	('SDHC', 'Gene', '6391', (18, 22))	('SDHC', 'Gene', (18, 22))	('patients', 'Species', '9606', (5, 13))
35025	31666924	The most common variant found was c.34G>A, p. G12S occurring in 7/10 cases with SDHD variants (70%).	('SDHD', 'Gene', (80, 84))	('G12S', 'SUBSTITUTION', 'None', (46, 50))	('G12S', 'Var', (46, 50))	('c.34G>A', 'Mutation', 'c.34G>A', (34, 41))	('SDHD', 'Gene', '6392', (80, 84))	('c.34G>A', 'Var', (34, 41))
35029	31666924	Interestingly, a case with the nonsense mutation c.15G>A, p.W5X presented with multiple recurrent head and neck PGLs (Table 4).	('p.W5X', 'Mutation', 'p.W5X', (58, 63))	('c.15G>A', 'Var', (49, 56))	('PGLs', 'Disease', 'MESH:D010235', (112, 116))	('PGLs', 'Disease', (112, 116))	('c.15G>A', 'Mutation', 'c.15G>A', (49, 56))
35030	31666924	Only one patient without family or personal history of multiple endocrine neoplasia type 2 presented with abdominal PGL and his genetic testing revealed the well-known c.1900T>C, p.C634R (Table 4).	('c.1900T>C', 'Mutation', 'c.1900T>C', (168, 177))	('p.C634R', 'Mutation', 'p.C634R', (179, 186))	('c.1900T>C', 'Var', (168, 177))	('endocrine neoplasia type', 'Disease', 'MESH:D018813', (64, 88))	('endocrine neoplasia type', 'Disease', (64, 88))	('PGL', 'Disease', (116, 119))	('neoplasia', 'Phenotype', 'HP:0002664', (74, 83))	('p.C634R', 'Var', (179, 186))	('patient', 'Species', '9606', (9, 16))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (64, 83))	('PGL', 'Disease', 'MESH:D010235', (116, 119))
35031	31666924	In addition, the c.2071G>A, p.G691S variant is a single nucleotide polymorphism (SNP) that was quite common occurring in 6 cases (5 PCC and 1 abdominal PGL).	('c.2071G>A', 'Var', (17, 26))	('p.G691S', 'Var', (28, 35))	('PCC', 'Disease', (132, 135))	('PGL', 'Disease', (152, 155))	('PCC', 'Disease', 'MESH:D010673', (132, 135))	('p.G691S', 'Mutation', 'rs1799939', (28, 35))	('PGL', 'Disease', 'MESH:D010235', (152, 155))	('c.2071G>A', 'Mutation', 'c.2071G>A', (17, 26))
35033	31666924	VHL mutations were detected in 2 cases (Table 4).	('mutations', 'Var', (4, 13))	('detected', 'Reg', (19, 27))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))
35035	31666924	MAX gene was mutated in 2 cases both of whom presented with bilateral PCC.	('MAX gene', 'Gene', (0, 8))	('PCC', 'Disease', (70, 73))	('PCC', 'Disease', 'MESH:D010673', (70, 73))	('presented', 'Reg', (45, 54))	('mutated', 'Var', (13, 20))
35036	31666924	A novel SDHAF2 variant was found in one case of metastatic PCC.	('variant', 'Var', (15, 22))	('SDHAF2', 'Gene', '54949', (8, 14))	('SDHAF2', 'Gene', (8, 14))	('found', 'Reg', (27, 32))	('PCC', 'Disease', (59, 62))	('PCC', 'Disease', 'MESH:D010673', (59, 62))
35039	31666924	The patient with NF1 variant does not have features of neurofibromatosis.	('neurofibromatosis', 'Phenotype', 'HP:0001067', (55, 72))	('neurofibromatosis', 'Disease', 'MESH:D017253', (55, 72))	('patient', 'Species', '9606', (4, 11))	('NF1', 'Gene', (17, 20))	('variant', 'Var', (21, 28))	('NF1', 'Gene', '4763', (17, 20))	('neurofibromatosis', 'Disease', (55, 72))
35043	31666924	In one unusual case with metastatic PCC, the underlying mutation was a novel SDHAF2 variant that is likely pathogenic (Tables 4 and 5).	('PCC', 'Disease', (36, 39))	('PCC', 'Disease', 'MESH:D010673', (36, 39))	('variant', 'Var', (84, 91))	('SDHAF2', 'Gene', '54949', (77, 83))	('metastatic', 'Disease', (25, 35))	('SDHAF2', 'Gene', (77, 83))
35048	31666924	Germline mutations were found in 29 of 69 (42%) of these PGLs while 40 cases were negative for any underlying mutation.	('Germline mutations', 'Var', (0, 18))	('found', 'Reg', (24, 29))	('PGLs', 'Disease', 'MESH:D010235', (57, 61))	('PGLs', 'Disease', (57, 61))
35049	31666924	These cases with positive mutations include 17 cases of abdominal PGL (5 metastatic), 11 cases of head and neck PGL (two bilateral) and one case of abdominal and head and neck PGLs (Table 5).	('PGLs', 'Disease', 'MESH:D010235', (176, 180))	('PGL', 'Disease', (176, 179))	('PGL', 'Disease', 'MESH:D010235', (66, 69))	('PGL', 'Disease', 'MESH:D010235', (176, 179))	('PGLs', 'Disease', (176, 180))	('PGL', 'Disease', (112, 115))	('mutations', 'Var', (26, 35))	('PGL', 'Disease', 'MESH:D010235', (112, 115))	('PGL', 'Disease', (66, 69))
35052	31666924	Two patients had metastatic PCC (one had no mutation and one had an SDHAF2 mutation) (Tables 4 and 5).	('PCC', 'Disease', (28, 31))	('SDHAF2', 'Gene', '54949', (68, 74))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (4, 12))	('PCC', 'Disease', 'MESH:D010673', (28, 31))	('SDHAF2', 'Gene', (68, 74))
35053	31666924	Six patients had abdominal PGL and SDHB mutations; one of them had both abdominal and head and neck PGLs (Table 3) and 2 patients had metastatic head and neck PGL (both negative for mutations).	('SDHB', 'Gene', '6390', (35, 39))	('PGL', 'Disease', 'MESH:D010235', (100, 103))	('PGLs', 'Disease', (100, 104))	('SDHB', 'Gene', (35, 39))	('PGL', 'Disease', 'MESH:D010235', (159, 162))	('mutations', 'Var', (40, 49))	('PGL', 'Disease', (27, 30))	('PGL', 'Disease', (100, 103))	('patients', 'Species', '9606', (4, 12))	('PGLs', 'Disease', 'MESH:D010235', (100, 104))	('patients', 'Species', '9606', (121, 129))	('PGL', 'Disease', (159, 162))	('PGL', 'Disease', 'MESH:D010235', (27, 30))
35065	31666924	Overall, we found a high rate (36.6%) of germline mutations in this series of patients with PPGL without family history of these tumors.	('PPGL', 'Disease', (92, 96))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (78, 86))	('PPGL', 'Disease', 'MESH:D010673', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('germline mutations', 'Var', (41, 59))
35066	31666924	In our study, SDHB mutations are the most common mutations in PPGL (20.8%) in general and in PGL in particular (30.4%).	('PGL', 'Disease', 'MESH:D010235', (63, 66))	('PGL', 'Disease', 'MESH:D010235', (93, 96))	('PPGL', 'Disease', 'MESH:D010673', (62, 66))	('mutations', 'Var', (19, 28))	('PPGL', 'Disease', (62, 66))	('SDHB', 'Gene', '6390', (14, 18))	('PGL', 'Disease', (63, 66))	('SDHB', 'Gene', (14, 18))	('PGL', 'Disease', (93, 96))
35067	31666924	SDHC and SDHD mutations are much less common occurring in 3.9% and 3% respectively.	('SDHD', 'Gene', '6392', (9, 13))	('SDHD', 'Gene', (9, 13))	('SDHC', 'Gene', (0, 4))	('SDHC', 'Gene', '6391', (0, 4))	('mutations', 'Var', (14, 23))
35069	31666924	Metastatic PPGL occurred in about 28.6% of patients (6/21) with SDHB mutations and in a patient with SDHAF2 mutation.	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (88, 95))	('SDHB', 'Gene', '6390', (64, 68))	('patient', 'Species', '9606', (43, 50))	('Metastatic PPGL', 'Disease', (0, 15))	('patients', 'Species', '9606', (43, 51))	('Metastatic PPGL', 'Disease', 'MESH:D010673', (0, 15))	('SDHB', 'Gene', (64, 68))	('occurred', 'Reg', (16, 24))	('SDHAF2', 'Gene', '54949', (101, 107))	('SDHAF2', 'Gene', (101, 107))
35073	31666924	Our study showed that most mutations involve the pseudohypoxemia group with the vast majority occurring in SDHB and to a lesser extent in SDHC and SDHD.	('pseudohypoxemia', 'Disease', (49, 64))	('mutations', 'Var', (27, 36))	('SDHB', 'Gene', (107, 111))	('pseudohypoxemia', 'Disease', 'None', (49, 64))	('involve', 'Reg', (37, 44))	('SDHC', 'Gene', (138, 142))	('SDHD', 'Gene', '6392', (147, 151))	('SDHC', 'Gene', '6391', (138, 142))	('SDHD', 'Gene', (147, 151))	('occurring', 'Reg', (94, 103))	('SDHB', 'Gene', '6390', (107, 111))
35074	31666924	These mutations occurred commonly in PGL but very rarely in PCC.	('PGL', 'Disease', (37, 40))	('PCC', 'Disease', 'MESH:D010673', (60, 63))	('PCC', 'Disease', (60, 63))	('occurred', 'Reg', (16, 24))	('PGL', 'Disease', 'MESH:D010235', (37, 40))	('mutations', 'Var', (6, 15))
35075	31666924	SDHB was the most commonly mutated gene (56.8% of patients with positive mutations and 20.8% of all cases studied) and c.268C>T, p.R90X was the most common mutation (Tables 2 and 3).	('c.268C>T', 'Var', (119, 127))	('c.268C>T', 'Mutation', 'c.268C>T', (119, 127))	('patients', 'Species', '9606', (50, 58))	('p.R90X', 'Var', (129, 135))	('SDHB', 'Gene', '6390', (0, 4))	('p.R90X', 'Mutation', 'p.R90X', (129, 135))	('SDHB', 'Gene', (0, 4))
35076	31666924	By contrast, in the recently published TCGA data from an international consortium population, SDHB germline mutations occurred only in 9.8% (17/173 cases) and the p.R90X mutation occurred only in 1/17 cases.	('SDHB', 'Gene', (94, 98))	('p.R90X', 'Mutation', 'p.R90X', (163, 169))	('p.R90X', 'Var', (163, 169))	('SDHB', 'Gene', '6390', (94, 98))
35077	31666924	The most frequent SDHB mutation in TCGA data was p.I127S (5/17 cases), which was not found in our patients.	('SDHB', 'Gene', (18, 22))	('p.I127S', 'Var', (49, 56))	('patients', 'Species', '9606', (98, 106))	('p.I127S', 'Mutation', 'p.I127S', (49, 56))	('SDHB', 'Gene', '6390', (18, 22))
35079	31666924	By contrast, in the original report of germline mutations in non-syndromic PCC from Europe, SDHB mutations were found in 12 of 271 (4.4%) apparently sporadic PPGL (mostly PCC) which is not much different from our study in which 2 out of 32 (6.3%) PCC carry SDHB mutations.	('mutations', 'Var', (97, 106))	('syndromic', 'Disease', (65, 74))	('SDHB', 'Gene', '6390', (92, 96))	('found', 'Reg', (112, 117))	('PCC', 'Disease', (75, 78))	('PPGL', 'Disease', (158, 162))	('PCC', 'Disease', 'MESH:D010673', (75, 78))	('SDHB', 'Gene', (92, 96))	('syndromic', 'Disease', 'MESH:D061325', (65, 74))	('PCC', 'Disease', (171, 174))	('SDHB', 'Gene', '6390', (257, 261))	('PCC', 'Disease', (247, 250))	('SDHB', 'Gene', (257, 261))	('PCC', 'Disease', 'MESH:D010673', (247, 250))	('PPGL', 'Disease', 'MESH:D010673', (158, 162))	('PCC', 'Disease', 'MESH:D010673', (171, 174))
35080	31666924	A more recent report from Spain in which 329 sporadic single non-familial PPGL were tested for mutations showed an overall prevalence of germline mutations of 14%.	('pain', 'Disease', 'MESH:D010146', (27, 31))	('pain', 'Disease', (27, 31))	('PPGL', 'Disease', 'MESH:D010673', (74, 78))	('germline mutations', 'Var', (137, 155))	('pain', 'Phenotype', 'HP:0012531', (27, 31))	('PPGL', 'Disease', (74, 78))
35081	31666924	Similar to our study, PGL were more commonly mutated (28.7% vs. 42% in our study) and most mutations occurred in SDHB (63% vs. 56.8% in our study) followed by SDHD (13% vs. 8% in our study) and SDHC (4.3% vs. 10.8% in our study) with other genes being rarely mutated.	('SDHC', 'Gene', '6391', (194, 198))	('SDHB', 'Gene', '6390', (113, 117))	('SDHD', 'Gene', (159, 163))	('PGL', 'Disease', (22, 25))	('occurred', 'Reg', (101, 109))	('SDHB', 'Gene', (113, 117))	('PGL', 'Disease', 'MESH:D010235', (22, 25))	('mutations', 'Var', (91, 100))	('SDHC', 'Gene', (194, 198))	('SDHD', 'Gene', '6392', (159, 163))
35082	31666924	In another study from USA, a review of 129 cases of PPGL who underwent surgery was undertaken and of 42 patients that were tested, 21 (50%) were positive for germline mutations.	('PPGL', 'Disease', 'MESH:D010673', (52, 56))	('germline mutations', 'Var', (158, 176))	('PPGL', 'Disease', (52, 56))	('positive', 'Reg', (145, 153))	('patients', 'Species', '9606', (104, 112))
35087	31666924	In the current study, SDHC mutations were the second most common mutations in PGL occurring in 4 out of 37 cases (10.8%) with positive mutations.	('mutations', 'Var', (27, 36))	('SDHC', 'Gene', (22, 26))	('SDHC', 'Gene', '6391', (22, 26))	('PGL', 'Disease', (78, 81))	('PGL', 'Disease', 'MESH:D010235', (78, 81))
35089	31666924	In a review of a number of series with more than 3000 patients with PPGL, SDHC mutations occurred only in 1% of cases (31/3193 cases).	('PPGL', 'Disease', (68, 72))	('patients', 'Species', '9606', (54, 62))	('PPGL', 'Disease', 'MESH:D010673', (68, 72))	('SDHC', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('SDHC', 'Gene', '6391', (74, 78))
35091	31666924	Similarly, in a recent report from Europe, SDHC mutations were not found in 87 cases of PCC.	('SDHC', 'Gene', '6391', (43, 47))	('PCC', 'Disease', (88, 91))	('PCC', 'Disease', 'MESH:D010673', (88, 91))	('mutations', 'Var', (48, 57))	('SDHC', 'Gene', (43, 47))
35092	31666924	An SDHC founder mutation (c.397C>T, p. Arg133Ter) was detected in about 70% of a cohort of 29 French Canadian patients presenting mostly (70%) with head and neck PGL and with distant metastasis in 30% of them.	('Arg133Ter', 'Var', (39, 48))	('PGL', 'Disease', (162, 165))	('SDHC', 'Gene', (3, 7))	('PGL', 'Disease', 'MESH:D010235', (162, 165))	('SDHC', 'Gene', '6391', (3, 7))	('distant metastasis', 'CPA', (175, 193))	('Arg133Ter', 'SUBSTITUTION', 'None', (39, 48))	('c.397C>T', 'Mutation', 'c.397C>T', (26, 34))	('c.397C>T', 'Var', (26, 34))	('patients', 'Species', '9606', (110, 118))
35096	31666924	SDHD mutations occurred in three cases with head and neck PGL, two unilateral and one bilateral.	('occurred', 'Reg', (15, 23))	('mutations', 'Var', (5, 14))	('SDHD', 'Gene', '6392', (0, 4))	('PGL', 'Disease', (58, 61))	('SDHD', 'Gene', (0, 4))	('PGL', 'Disease', 'MESH:D010235', (58, 61))
35097	31666924	Apart from these 3 cases, the most common SDHD variant found in this study was the c.34G>A, p.G12S occurring in 7 cases.	('c.34G>A', 'Mutation', 'c.34G>A', (83, 90))	('p.G12S', 'Mutation', 'p.G12S', (92, 98))	('c.34G>A', 'Var', (83, 90))	('SDHD', 'Gene', '6392', (42, 46))	('SDHD', 'Gene', (42, 46))	('p.G12S', 'Var', (92, 98))
35098	31666924	If considered pathogenic, SDHD mutations would be the second most common mutations after SDHB (10/48, 20.8%).	('mutations', 'Var', (31, 40))	('common', 'Reg', (66, 72))	('SDHD', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (26, 30))	('SDHB', 'Gene', '6390', (89, 93))	('SDHB', 'Gene', (89, 93))
35100	31666924	In fact, all SDHD mutations were also rare in the TCGA data occurring only in 3 out of 173 cases (2%).	('SDHD', 'Gene', (13, 17))	('SDHD', 'Gene', '6392', (13, 17))	('mutations', 'Var', (18, 27))
35102	31666924	SDHA mutations occurred only once in a patient with carotid body tumor (Table 4).	('carotid body tumor', 'Disease', 'MESH:D002345', (52, 70))	('patient', 'Species', '9606', (39, 46))	('SDHA', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHA', 'Gene', '6389', (0, 4))	('carotid body tumor', 'Disease', (52, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('carotid body tumor', 'Phenotype', 'HP:0002668', (52, 70))
35103	31666924	Mutations in this gene are rare but can be associated with aggressive metastatic PGL similar to those of SDHB.	('associated with', 'Reg', (43, 58))	('SDHB', 'Gene', '6390', (105, 109))	('PGL', 'Disease', (81, 84))	('SDHB', 'Gene', (105, 109))	('Mutations', 'Var', (0, 9))	('PGL', 'Disease', 'MESH:D010235', (81, 84))
35104	31666924	One patient had an SDHAF2 variant of unknown significance and presented with metastatic PCC.	('PCC', 'Disease', (88, 91))	('variant', 'Var', (26, 33))	('PCC', 'Disease', 'MESH:D010673', (88, 91))	('patient', 'Species', '9606', (4, 11))	('SDHAF2', 'Gene', '54949', (19, 25))	('SDHAF2', 'Gene', (19, 25))
35105	31666924	SDHAF2 mutations are extremely rare and their association with metastatic PPGL has not been reported.	('SDHAF2', 'Gene', '54949', (0, 6))	('SDHAF2', 'Gene', (0, 6))	('PPGL', 'Disease', 'MESH:D010673', (74, 78))	('PPGL', 'Disease', (74, 78))	('mutations', 'Var', (7, 16))
35107	31666924	SDHAF2 mutations were not also reported in TCGA data.	('SDHAF2', 'Gene', (0, 6))	('SDHAF2', 'Gene', '54949', (0, 6))	('mutations', 'Var', (7, 16))
35108	31666924	VHL mutations were detected in two patients; one with unilateral and one with bilateral PCC.	('PCC', 'Disease', (88, 91))	('PCC', 'Disease', 'MESH:D010673', (88, 91))	('detected', 'Reg', (19, 27))	('VHL', 'Gene', (0, 3))	('patients', 'Species', '9606', (35, 43))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
35109	31666924	VHL mutations have been commonly reported in hereditary PPGL and can be associated with unilateral or bilateral PCC or less frequently with PGL.	('PGL', 'Disease', 'MESH:D010235', (140, 143))	('PPGL', 'Disease', 'MESH:D010673', (56, 60))	('associated', 'Reg', (72, 82))	('PCC', 'Disease', 'MESH:D010673', (112, 115))	('PGL', 'Disease', (140, 143))	('VHL', 'Gene', (0, 3))	('PGL', 'Disease', (57, 60))	('PCC', 'Disease', (112, 115))	('PPGL', 'Disease', (56, 60))	('reported', 'Reg', (33, 41))	('unilateral', 'Disease', (88, 98))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('PGL', 'Disease', 'MESH:D010235', (57, 60))
35113	31666924	In a study of 972 cases from the European-American-Asian Pheochromocytoma and Paraganglioma Registry without mutations in the common PPGL genes, 58 had mutations in less commonly mutated genes (SDHA, TMEM127, SDHAF2) including 8 cases of PCC with MAX mutations.	('SDHA', 'Gene', (209, 213))	('SDHAF2', 'Gene', (209, 215))	('PCC', 'Disease', (238, 241))	('PCC', 'Disease', 'MESH:D010673', (238, 241))	('PPGL', 'Disease', (133, 137))	('mutations', 'Var', (152, 161))	('TMEM127', 'Gene', (200, 207))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('SDHA', 'Gene', '6389', (194, 198))	('TMEM127', 'Gene', '55654', (200, 207))	('Paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))	('SDHA', 'Gene', '6389', (209, 213))	('PPGL', 'Disease', 'MESH:D010673', (133, 137))	('SDHA', 'Gene', (194, 198))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (57, 91))	('SDHAF2', 'Gene', '54949', (209, 215))
35115	31666924	We also found one case with a TMEM127 mutation in an abdominal PGL.	('PGL', 'Disease', 'MESH:D010235', (63, 66))	('TMEM127', 'Gene', '55654', (30, 37))	('TMEM127', 'Gene', (30, 37))	('mutation', 'Var', (38, 46))	('PGL', 'Disease', (63, 66))
35116	31666924	TMEM127 mutations are generally more frequent than MAX mutations and may present with PCC, abdominal or head and neck PGL.	('abdominal', 'Disease', (91, 100))	('PGL', 'Disease', (118, 121))	('TMEM127', 'Gene', '55654', (0, 7))	('mutations', 'Var', (8, 17))	('PGL', 'Disease', 'MESH:D010235', (118, 121))	('present', 'Reg', (73, 80))	('PCC', 'Disease', (86, 89))	('PCC', 'Disease', 'MESH:D010673', (86, 89))	('TMEM127', 'Gene', (0, 7))
35119	31666924	SDHB mutations have been associated with increased risk of distant metastasis.	('distant metastasis', 'CPA', (59, 77))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
35120	31666924	In this study, SDHB mutations remain the most frequently associated mutations with distant metastasis occurring in 6 out of 21 cases (28.6%).	('SDHB', 'Gene', '6390', (15, 19))	('SDHB', 'Gene', (15, 19))	('distant metastasis', 'CPA', (83, 101))	('mutations', 'Var', (20, 29))	('associated', 'Reg', (57, 67))
35121	31666924	Only one additional case with an SDHAF2 variant developed distant metastasis.	('distant metastasis', 'CPA', (58, 76))	('SDHAF2', 'Gene', '54949', (33, 39))	('variant', 'Var', (40, 47))	('SDHAF2', 'Gene', (33, 39))
35123	31666924	Some previously reported mutations are somatic, particularly the WNT-related MAML4 fusion and HRAS mutations.	('MAML4', 'Gene', (77, 82))	('mutations', 'Var', (99, 108))	('HRAS', 'Gene', (94, 98))	('HRAS', 'Gene', '3265', (94, 98))
35130	31666924	SDHC and SDHD mutations are the second most common genetic alterations in PGL.	('SDHD', 'Gene', (9, 13))	('SDHD', 'Gene', '6392', (9, 13))	('SDHC', 'Gene', (0, 4))	('PGL', 'Disease', (74, 77))	('SDHC', 'Gene', '6391', (0, 4))	('common', 'Reg', (44, 50))	('PGL', 'Disease', 'MESH:D010235', (74, 77))	('mutations', 'Var', (14, 23))
35131	31666924	VHL and MAX mutations occur mainly in PCC and tend to present with bilateral disease.	('bilateral disease', 'Disease', 'MESH:D003638', (67, 84))	('PCC', 'Disease', 'MESH:D010673', (38, 41))	('bilateral disease', 'Disease', (67, 84))	('mutations', 'Var', (12, 21))	('MAX', 'Gene', (8, 11))	('present with', 'Reg', (54, 66))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('occur', 'Reg', (22, 27))	('PCC', 'Disease', (38, 41))
35143	31666924	We performed polymerase chain reaction (PCR) and direct Sanger sequencing using Big Dye terminator v3.1 cycle sequencing reaction kit and an ABI PRISM 3730XL genetic analyzer (Applied Biosystems) to detect mutations in RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX and TMEM127.	('SDHA', 'Gene', (224, 228))	('SDHD', 'Gene', (242, 246))	('SDHA', 'Gene', (248, 252))	('RET', 'Gene', (219, 222))	('SDHA', 'Gene', '6389', (224, 228))	('SDHB', 'Gene', (230, 234))	('SDHA', 'Gene', '6389', (248, 252))	('TMEM127', 'Gene', (269, 276))	('SDHC', 'Gene', (236, 240))	('SDHAF2', 'Gene', '54949', (248, 254))	('SDHAF2', 'Gene', (248, 254))	('mutations', 'Var', (206, 215))	('TMEM127', 'Gene', '55654', (269, 276))	('VHL', 'Gene', (256, 259))	('SDHD', 'Gene', '6392', (242, 246))	('RET', 'Gene', '5979', (219, 222))	('SDHC', 'Gene', '6391', (236, 240))	('SDHB', 'Gene', '6390', (230, 234))	('VHL', 'Gene', '7428', (256, 259))
35156	31027285	CGA is elevated in PPGLs, as well as in other neuroendocrine or non-neuroendocrine neoplasia and under clinical conditions increasing adrenergic activity.	('CGA', 'Gene', (0, 3))	('PPGLs', 'Chemical', '-', (19, 24))	('neoplasia', 'Phenotype', 'HP:0002664', (83, 92))	('increasing', 'PosReg', (123, 133))	('PGL', 'Phenotype', 'HP:0002668', (20, 23))	('CGA', 'Gene', '1113', (0, 3))	('adrenergic activity', 'MPA', (134, 153))	('non-neuroendocrine neoplasia', 'Disease', 'MESH:D018358', (64, 92))	('neuroendocrine neoplasia', 'Phenotype', 'HP:0100634', (68, 92))	('PPGLs', 'Var', (19, 24))	('non-neuroendocrine neoplasia', 'Disease', (64, 92))	('elevated', 'PosReg', (7, 15))
35173	31027285	The pseudohypoxia group is characterized by somatic or germline mutations and silent or dopaminergic and/or noradrenergic secretory profiles in the tricarboxylic acid cycle related to succinate dehydrogenase subunits SDHA, SDHB, SDHC, SDHD, SDHAF1, SDHAF2 (together SDHx) or in fumarate hydratase (FH), a second enzyme in the tricarboxylic acid cycle, in von Hippel-Lindau disease (VHL), endothelial PAS domain 1 (EPAS10, also known as hypoxia-inducible factor 2alpha (HIF2A)), and prolylhydroxylases PHD1 and PHD2.	('SDHA', 'Gene', (217, 221))	('SDHA', 'Gene', (241, 245))	('SDHA', 'Gene', '6389', (249, 253))	('von Hippel-Lindau disease', 'Disease', (355, 380))	('fumarate hydratase', 'Gene', '2271', (278, 296))	('PHD1', 'Gene', (501, 505))	('SDHA', 'Gene', '6389', (217, 221))	('SDHAF2', 'Gene', '54949', (249, 255))	('SDHB', 'Gene', (223, 227))	('SDHA', 'Gene', '6389', (241, 245))	('SDHAF2', 'Gene', (249, 255))	('hypoxia-inducible factor 2alpha', 'Gene', '2034', (436, 467))	('PHD1', 'Gene', '112398', (501, 505))	('pseudohypoxia', 'Disease', (4, 17))	('mutations', 'Var', (64, 73))	('FH', 'Gene', '2271', (298, 300))	('VHL', 'Disease', (382, 385))	('SDHC', 'Gene', '6391', (229, 233))	('pseudohypoxia', 'Disease', 'None', (4, 17))	('PHD2', 'Gene', (510, 514))	('SDHD', 'Gene', '6392', (235, 239))	('SDHAF1', 'Gene', '644096', (241, 247))	('fumarate hydratase', 'Gene', (278, 296))	('PHD2', 'Gene', '54583', (510, 514))	('SDHD', 'Gene', (235, 239))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (355, 380))	('hypoxia-inducible factor 2alpha', 'Gene', (436, 467))	('SDHB', 'Gene', '6390', (223, 227))	('SDHA', 'Gene', (249, 253))	('SDHAF1', 'Gene', (241, 247))	('VHL', 'Disease', 'MESH:D006623', (382, 385))	('SDHC', 'Gene', (229, 233))
35174	31027285	The wnt signaling group includes somatic mutations in cold shock domain containing E1 (CSDE1), alpha thalassemia/mental retardation syndrome X-linked (ATRX) and mastermind-like transcriptional coactivator (3MAML3) with mixed noradrenergic and adrenergic secretory phenotype.	('mutations', 'Var', (41, 50))	('CSDE1', 'Gene', (87, 92))	('CSDE1', 'Gene', '7812', (87, 92))	('thalassemia/mental retardation syndrome X-linked', 'Disease', (101, 149))	('mental retardation', 'Phenotype', 'HP:0001249', (113, 131))	('thalassemia/mental retardation syndrome X-linked', 'Disease', 'MESH:C538258', (101, 149))	('shock', 'Phenotype', 'HP:0031273', (59, 64))
35175	31027285	The kinase signaling group consists of germline or somatic mutations in RET proto-oncogene (syndrome MEN 2A, 2B), neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), kinesin-like protein (KIF1BB), receptor tyrosine kinase (MET) and GTPase, Harvey rat sarcoma viral oncogene homolog (HRAS) with adrenergic or mixed noradrenergic and adrenergic secretory profiles.	('MAX', 'Gene', '4149', (199, 202))	('HRAS', 'Gene', (322, 326))	('MYC-associated factor X', 'Gene', '4149', (174, 197))	('rat', 'Species', '10116', (286, 289))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('MEN 2A, 2B', 'Gene', '5979', (101, 111))	('RET', 'Gene', '5979', (72, 75))	('TMEM127', 'Gene', (164, 171))	('sarcoma', 'Disease', (290, 297))	('neurofibromin 1', 'Gene', '4763', (114, 129))	('MAX', 'Gene', (199, 202))	('NF1', 'Gene', '4763', (131, 134))	('HRAS', 'Gene', '293621', (322, 326))	('neurofibromin 1', 'Gene', (114, 129))	('mutations', 'Var', (59, 68))	('TMEM127', 'Gene', '55654', (164, 171))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('RET', 'Gene', (72, 75))	('NF1', 'Gene', (131, 134))	('MYC-associated factor X', 'Gene', (174, 197))
35176	31027285	Mutations in the mitochondrial succinate dehydrogenase enzyme complex subunit B (SDHB) and the tumor suppressor gene Von Hippel-Lindau (VHL) are mainly associated with malignancy.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('malignancy', 'Disease', (168, 178))	('VHL', 'Disease', 'MESH:D006623', (136, 139))	('VHL', 'Disease', (136, 139))	('SDHB', 'Gene', '6390', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('Von Hippel-Lindau', 'Gene', '7428', (117, 134))	('Mutations', 'Var', (0, 9))	('Von Hippel-Lindau', 'Gene', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SDHB', 'Gene', (81, 85))	('associated', 'Reg', (152, 162))	('tumor', 'Disease', (95, 100))
35244	31027285	Five of these patients had a tumor volume less than 20 mm3, and in one PCC patient diagnosed in 2002 with VHL gene mutation, recurrence was observed in 2003, 2005 and 2014.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('VHL', 'Disease', (106, 109))	('VHL', 'Disease', 'MESH:D006623', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PCC', 'Phenotype', 'HP:0002666', (71, 74))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Disease', (29, 34))	('mutation', 'Var', (115, 123))	('patient', 'Species', '9606', (75, 82))	('patients', 'Species', '9606', (14, 22))
35316	31027285	The CGA is elevated in PPGLs, however, as well as in other neuroendocrine or non-neuroendocrine neoplasia and in clinical conditions with increased adrenergic activity.	('CGA', 'Gene', (4, 7))	('PPGLs', 'Chemical', '-', (23, 28))	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('non-neuroendocrine neoplasia', 'Disease', 'MESH:D018358', (77, 105))	('PGL', 'Phenotype', 'HP:0002668', (24, 27))	('neuroendocrine neoplasia', 'Phenotype', 'HP:0100634', (81, 105))	('CGA', 'Gene', '1113', (4, 7))	('non-neuroendocrine neoplasia', 'Disease', (77, 105))	('elevated', 'PosReg', (11, 19))	('PPGLs', 'Var', (23, 28))
35321	31027285	In the PCC group, mutations in the RET gene were found in seven patients, three were diagnosed with MEN2A and MTC, four had MEN2B and MTC.	('mutations', 'Var', (18, 27))	('RET', 'Gene', '5979', (35, 38))	('patients', 'Species', '9606', (64, 72))	('MEN2A', 'Gene', (100, 105))	('MEN2A', 'Gene', '5979', (100, 105))	('MEN2B', 'Gene', (124, 129))	('MTC', 'Phenotype', 'HP:0002865', (110, 113))	('MEN2B', 'Gene', '5979', (124, 129))	('RET', 'Gene', (35, 38))	('MTC', 'Disease', (110, 113))	('PCC', 'Phenotype', 'HP:0002666', (7, 10))	('MTC', 'Phenotype', 'HP:0002865', (134, 137))	('found', 'Reg', (49, 54))
35322	31027285	Mutations in the VHL gene were observed in five patients, in three patients were mutations in the NF1 gene, two patients had mutations in the MAX gene, one patient in the MET gene, and in 50 patients the mutations were not determined.	('patients', 'Species', '9606', (191, 199))	('patient', 'Species', '9606', (112, 119))	('patients', 'Species', '9606', (67, 75))	('VHL', 'Disease', (17, 20))	('patient', 'Species', '9606', (191, 198))	('MAX', 'Gene', (142, 145))	('patient', 'Species', '9606', (67, 74))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('patients', 'Species', '9606', (112, 120))	('MAX', 'Gene', '4149', (142, 145))	('NF1', 'Gene', (98, 101))	('mutations', 'Reg', (81, 90))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (48, 55))	('NF1', 'Gene', '4763', (98, 101))	('observed', 'Reg', (31, 39))	('patients', 'Species', '9606', (48, 56))	('patient', 'Species', '9606', (156, 163))
35323	31027285	In the PGL group, mutations in the SDHB gene were found in two patients, while mutation in the SDHD gene was observed in one patient.	('SDHB', 'Gene', (35, 39))	('SDHD', 'Gene', '6392', (95, 99))	('found', 'Reg', (50, 55))	('PGL', 'Phenotype', 'HP:0002668', (7, 10))	('SDHD', 'Gene', (95, 99))	('patient', 'Species', '9606', (63, 70))	('patient', 'Species', '9606', (125, 132))	('patients', 'Species', '9606', (63, 71))	('SDHB', 'Gene', '6390', (35, 39))	('mutations', 'Var', (18, 27))
35355	30106970	Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies Succinate dehydrogenase subunit B and D (SDHB and SDHD) mutations represent the most frequent cause of hereditary pheochromocytoma and paraganglioma (PPGL).	('paraganglioma', 'Phenotype', 'HP:0002668', (311, 324))	('mutations', 'Var', (232, 241))	('Succinate dehydrogenase', 'Gene', (176, 199))	('SDHB', 'Gene', '6390', (45, 49))	('SDHD', 'Gene', '6392', (55, 59))	('hereditary pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (279, 324))	('Mathematical modeling of disease', 'Disease', 'MESH:D004195', (0, 32))	('Succinate dehydrogenase', 'Gene', '6390', (176, 199))	('cause', 'Reg', (270, 275))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (290, 306))	('paraganglioma', 'Disease', (68, 81))	('SDHB', 'Gene', (45, 49))	('Mathematical modeling of disease', 'Disease', (0, 32))	('paraganglioma', 'Disease', 'MESH:D010235', (68, 81))	('hereditary tumor', 'Disease', (113, 129))	('SDHD', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('paraganglioma', 'Disease', (311, 324))	('SDHD', 'Gene', '6392', (226, 230))	('SDHB', 'Gene', '6390', (217, 221))	('paraganglioma', 'Disease', 'MESH:D010235', (311, 324))	('hereditary tumor', 'Disease', 'MESH:D009386', (113, 129))	('paraganglioma', 'Phenotype', 'HP:0002668', (68, 81))	('SDHD', 'Gene', (226, 230))	('SDHB', 'Gene', (217, 221))
35356	30106970	Although truncation of the succinate dehydrogenase complex is thought to be the disease causing mechanism in both disorders, SDHB and SDHD patients exihibit different phenotypes.	('truncation', 'Var', (9, 19))	('SDHB', 'Gene', (125, 129))	('patients', 'Species', '9606', (139, 147))	('succinate dehydrogenase', 'Gene', '6390', (27, 50))	('succinate dehydrogenase', 'Gene', (27, 50))	('SDHD', 'Gene', (134, 138))	('SDHD', 'Gene', '6392', (134, 138))	('SDHB', 'Gene', '6390', (125, 129))
35369	30106970	described the first PGL syndrome related to deficiency in succinate dehydrogenase (SDH) enzyme activity due to mutations in SDH subunit D (SDHD), part of mitochondrial complex II and the tricarboxylic acid (TCA) cycle.	('PGL syndrome', 'Disease', 'MESH:D010235', (20, 32))	('SDHD', 'Gene', (139, 143))	('succinate dehydrogenase', 'Gene', (58, 81))	('activity', 'MPA', (95, 103))	('SDH', 'Gene', (83, 86))	('deficiency', 'Disease', (44, 54))	('mutations', 'Var', (111, 120))	('SDH', 'Gene', (139, 142))	('SDH subunit D', 'Gene', (124, 137))	('PGL syndrome', 'Disease', (20, 32))	('TCA', 'Chemical', 'MESH:D014233', (207, 210))	('SDH', 'Gene', '6390', (124, 127))	('succinate dehydrogenase', 'Gene', '6390', (58, 81))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (187, 205))	('SDH subunit D', 'Gene', '6392', (124, 137))	('SDHD', 'Gene', '6392', (139, 143))	('related', 'Reg', (33, 40))	('SDH', 'Gene', '6390', (83, 86))	('SDH', 'Gene', '6390', (139, 142))	('SDH', 'Gene', (124, 127))	('deficiency', 'Disease', 'MESH:D007153', (44, 54))
35370	30106970	Association between the TCA cycle and PPGL was later confirmed by the identification of mutations in other genes encoding subunits B, C, and A of the SDH complex or its flavination factor (SDHAF2) and more recently, mutations in fumarate hydratase and malate dehydrogenase type 2.	('SDH', 'Gene', (150, 153))	('SDH', 'Gene', '6390', (189, 192))	('fumarate hydratase', 'Gene', (229, 247))	('SDHAF2', 'Gene', (189, 195))	('SDHAF2', 'Gene', '54949', (189, 195))	('mutations', 'Var', (88, 97))	('TCA', 'Chemical', 'MESH:D014233', (24, 27))	('SDH', 'Gene', (189, 192))	('SDH', 'Gene', '6390', (150, 153))	('malate dehydrogenase type 2', 'Enzyme', (252, 279))	('PPGL', 'Gene', (38, 42))	('mutations', 'Var', (216, 225))	('fumarate hydratase', 'Gene', '2271', (229, 247))
35371	30106970	These genes are related to the TCA cycle and they are considered tumor supressors with biallelic inactivation of the healthy allele through a somatic event in paraganglial cells.	('tumor', 'Disease', (65, 70))	('biallelic inactivation', 'Var', (87, 109))	('TCA', 'Disease', (31, 34))	('TCA', 'Chemical', 'MESH:D014233', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
35374	30106970	Currently, SDHB and SDHD mutations represent the most frequent cause of hereditary PPGLs associated with TCA defects.	('associated', 'Reg', (89, 99))	('mutations', 'Var', (25, 34))	('SDHB', 'Gene', (11, 15))	('PPGLs', 'Disease', (83, 88))	('SDHB', 'Gene', '6390', (11, 15))	('SDHD', 'Gene', '6392', (20, 24))	('TCA defects', 'Disease', (105, 116))	('TCA', 'Chemical', 'MESH:D014233', (105, 108))	('SDHD', 'Gene', (20, 24))	('frequent cause', 'Reg', (54, 68))
35378	30106970	PGLs with underlying SDHB mutations are associated with a higher risk of aggressive behavior, development of metastatic disease, and ultimately, death.	('aggressive behavior', 'Phenotype', 'HP:0000718', (73, 92))	('metastatic disease', 'CPA', (109, 127))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (26, 35))	('SDHB', 'Gene', (21, 25))	('aggressive behavior', 'Disease', 'MESH:D001523', (73, 92))	('associated', 'Reg', (40, 50))	('aggressive behavior', 'Disease', (73, 92))
35382	30106970	SDHD-related mutations (paternally inherited) have very high penetrance (90-100%), in contrast to SDHB ones that have an estimated penetrance of only 20-40%.	('SDHB', 'Gene', '6390', (98, 102))	('SDHB', 'Gene', (98, 102))	('SDHD', 'Gene', '6392', (0, 4))	('mutations', 'Var', (13, 22))	('SDHD', 'Gene', (0, 4))
35393	30106970	A first model was parameterized to simulate SDHD disease dynamics with the following set of Pdobsv = [0.00, 0.75, 0.20, 0.05], where the superscript "d" stands for SDHD (i.e, 100% penetrance if the mutation is inherited from the father, 75% HNPGL and 20% sympathetic PPGL, 5% metastatic disease).	('SDHD disease', 'Disease', (44, 56))	('sympathetic PPGL', 'Disease', (255, 271))	('SDHD', 'Gene', (44, 48))	('SDHD', 'Gene', '6392', (44, 48))	('SDHD', 'Gene', '6392', (164, 168))	('SDHD disease', 'Disease', 'MESH:D004194', (44, 56))	('SDHD', 'Gene', (164, 168))	('mutation', 'Var', (198, 206))
35403	30106970	Nevertheless, through an integration of current knowledge of PPGL tumorigenesis, we attempted to integrate our findings into two major knolwedges related to SDHB- and SDHD-PPGL tumorigenesis: a genetic background, here the presence of SDHB or SDHD mutations, and embryological development from either sympathetic of parasympathetic paraganglia.	('mutations', 'Var', (248, 257))	('SDHD', 'Gene', '6392', (167, 171))	('SDHB', 'Gene', '6390', (157, 161))	('parasympathetic paraganglia', 'Disease', 'MESH:D001342', (316, 343))	('SDHB', 'Gene', '6390', (235, 239))	('tumor', 'Disease', (66, 71))	('SDHD', 'Gene', (167, 171))	('SDHB', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (177, 182))	('SDHB-', 'Gene', '6390', (157, 162))	('parasympathetic paraganglia', 'Disease', (316, 343))	('SDHB', 'Gene', (235, 239))	('SDHB-', 'Gene', (157, 162))	('SDHD', 'Gene', '6392', (243, 247))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SDHD', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))
35404	30106970	Here, genetics stipulates that biallelic inactivation of SDHB or SDHD loci is not enough to cause PPGL.	('cause', 'Reg', (92, 97))	('biallelic inactivation', 'Var', (31, 53))	('PPGL', 'Disease', (98, 102))	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (57, 61))	('SDHD', 'Gene', '6392', (65, 69))	('SDHD', 'Gene', (65, 69))
35409	30106970	It is, therefore, possible that chromosome 11p loss is necessary and sufficient to trigger SDHD and SDHAF2 tumorigenesis, whereas SDHB tumors require more complex changes with amplification or deletion of multiple driver genes located on different chromosomes, especially 1p.	('deletion', 'Var', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('SDHAF2', 'Gene', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SDHB tumors', 'Disease', (130, 141))	('SDHAF2', 'Gene', '54949', (100, 106))	('tumor', 'Disease', (135, 140))	('SDHD', 'Gene', (91, 95))	('loss', 'NegReg', (47, 51))	('SDHD', 'Gene', '6392', (91, 95))	('SDHB tumors', 'Disease', 'MESH:D009369', (130, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
35419	30106970	We acknowledge that this theory is still only supported by indirect evidence from genetic data that also fails to explain the absence of somatic biallelic SDH inactivation.	('biallelic', 'Var', (145, 154))	('SDH', 'Gene', '6390', (155, 158))	('SDH', 'Gene', (155, 158))
35456	28867159	Pseudohypoxia group (cluster 1) can be divided into at least two subgroups: tricarboxylic acid (TCA) cycle-related, containing germline mutations in succinate dehydrogenase subunits (SDHx) and fumarate hydratase (FH), a second enzyme in the tricarboxylic acid (TCA) cycle.	('fumarate hydratase', 'Gene', (193, 211))	('TCA', 'Chemical', 'MESH:D014233', (96, 99))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (241, 259))	('TCA', 'Chemical', 'MESH:D014233', (261, 264))	('hypoxia', 'Disease', 'MESH:D000860', (6, 13))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (76, 94))	('FH', 'Gene', '2271', (213, 215))	('succinate dehydrogenase', 'Gene', (149, 172))	('succinate dehydrogenase', 'Gene', '6390', (149, 172))	('mutations', 'Var', (136, 145))	('hypoxia', 'Disease', (6, 13))	('SDHx', 'Chemical', '-', (183, 187))	('SDHx', 'Gene', (183, 187))	('fumarate hydratase', 'Gene', '2271', (193, 211))
35458	28867159	Wnt signaling group includes newly recognized somatic mutations in CSDE1, as well as somatic gene fusions affecting MAML3.	('MAML3', 'Gene', '55534', (116, 121))	('MAML3', 'Gene', (116, 121))	('mutations', 'Var', (54, 63))	('fusions', 'Var', (98, 105))	('CSDE1', 'Gene', (67, 72))	('CSDE1', 'Gene', '7812', (67, 72))
35463	28867159	SDHx mutations also predispose patients to other tumors, particularly gastrointestinal stromal tumors (GISTs), renal cell carcinoma (RCC), and pituitary adenomas.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (143, 161))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('pituitary adenomas', 'Disease', (143, 161))	('tumors', 'Disease', (49, 55))	('RCC', 'Disease', 'MESH:C538614', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 131))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (70, 101))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (70, 101))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (5, 14))	('SDHx', 'Gene', (0, 4))	('gastrointestinal stromal tumors', 'Disease', (70, 101))	('renal cell carcinoma', 'Disease', (111, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('SDHx', 'Chemical', '-', (0, 4))	('patients', 'Species', '9606', (31, 39))	('RCC', 'Disease', (133, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('predispose', 'Reg', (20, 30))	('pituitary adenomas', 'Disease', 'MESH:D010911', (143, 161))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
35465	28867159	Patients with SDHB mutations present more frequently with sympathetic (mostly extra-adrenal) PPGLs compared to patients with SDHD mutations who more commonly present with head and neck PGLs (HNPGLs) with concomitant thoracoabdominal PGLs in only about 10% of cases.	('sympathetic', 'Disease', (58, 69))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (125, 129))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', '6390', (14, 18))	('PPGLs', 'Chemical', '-', (93, 98))	('SDHB', 'Gene', (14, 18))	('SDHD', 'Gene', (125, 129))	('patients', 'Species', '9606', (111, 119))
35466	28867159	Patients with SDHC mutations typically harbor PGLs originating from the parasympathetic cervical or thoracic paraganglia.	('PGLs', 'Protein', (46, 50))	('SDHC', 'Gene', (14, 18))	('harbor', 'Reg', (39, 45))	('mutations', 'Var', (19, 28))	('SDHC', 'Gene', '6391', (14, 18))	('Patients', 'Species', '9606', (0, 8))
35473	28867159	In contrast, PPGLs linked to somatic HIF2A mutations occur sporadically.	('HIF2A', 'Gene', (37, 42))	('mutations', 'Var', (43, 52))	('PPGLs', 'Chemical', '-', (13, 18))	('HIF2A', 'Gene', '2034', (37, 42))
35474	28867159	Exclusive to females, patients with somatic HIF2A mutations present with polycythemia, multiple PPGLs (sympathetic), and duodenal somatostatinomas.	('HIF2A', 'Gene', '2034', (44, 49))	('mutations', 'Var', (50, 59))	('HIF2A', 'Gene', (44, 49))	('patients', 'Species', '9606', (22, 30))	('somatostatinomas', 'Disease', 'MESH:D013005', (130, 146))	('polycythemia', 'Disease', (73, 85))	('PPGLs', 'Chemical', '-', (96, 101))	('multiple PPGLs', 'Disease', (87, 101))	('somatostatinomas', 'Disease', (130, 146))	('polycythemia', 'Phenotype', 'HP:0001901', (73, 85))	('polycythemia', 'Disease', 'MESH:D011086', (73, 85))
35476	28867159	In recent years, other than the aforementioned SDHx mutations, the presence of mutations in other Tricarboxylic Acid (TCA) cycle (also called Krebs cycle) enzymes (Fumarate Hydratase (FH), Malate Dehydrogenase 2 (MDH2), Isocitrate Dehydrogenase 1 and 2 (IDH1/2)) have been identified in various cancers, signifying that these metabolic changes constitute an emerging metabolic hallmark of cancer.	('MDH2', 'Gene', (213, 217))	('Malate Dehydrogenase 2', 'Gene', (189, 211))	('SDHx', 'Chemical', '-', (47, 51))	('cancer', 'Disease', (295, 301))	('Malate Dehydrogenase 2', 'Gene', '4191', (189, 211))	('Fumarate Hydratase', 'Gene', '2271', (164, 182))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Disease', (389, 395))	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('Fumarate Hydratase', 'Gene', (164, 182))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('cancers', 'Disease', (295, 302))	('IDH1/2))', 'Gene', '3417;3418', (254, 262))	('MDH2', 'Gene', '4191', (213, 217))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('FH', 'Gene', '2271', (184, 186))	('Tricarboxylic Acid', 'Chemical', 'MESH:D014233', (98, 116))	('IDH1/2)', 'Gene', (254, 261))	('Krebs', 'Chemical', '-', (142, 147))	('TCA', 'Chemical', 'MESH:D014233', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('identified', 'Reg', (273, 283))	('cancers', 'Disease', 'MESH:D009369', (295, 302))
35477	28867159	Importantly, disruption of the TCA cycle is associated with accumulation of its intermediates that alter various cellular and extra-cellular functions.	('TCA cycle', 'Gene', (31, 40))	('disruption', 'Var', (13, 23))	('alter', 'Reg', (99, 104))	('TCA', 'Chemical', 'MESH:D014233', (31, 34))	('accumulation', 'PosReg', (60, 72))
35481	28867159	DNA hypermethylation also silences key genes involved in neuroendocrine differentiation (such as Phenylethanolamine N-Methyltransferase (PNMT)), leading to a noradrenergic secretory profile.	('silences', 'NegReg', (26, 34))	('leading to', 'Reg', (145, 155))	('PNMT', 'Gene', (137, 141))	('Phenylethanolamine N-Methyltransferase', 'Gene', (97, 135))	('noradrenergic secretory profile', 'MPA', (158, 189))	('PNMT', 'Gene', '5409', (137, 141))	('Phenylethanolamine N-Methyltransferase', 'Gene', '5409', (97, 135))	('hypermethylation', 'Var', (4, 20))
35493	28867159	The accumulation of succinate observed in SDHx-mutated PPGL inhibits PHDs.	('accumulation', 'PosReg', (4, 16))	('SDHx', 'Chemical', '-', (42, 46))	('PHD', 'Disease', 'MESH:D011547', (69, 72))	('SDHx-mutated', 'Var', (42, 54))	('PHD', 'Disease', (69, 72))	('inhibits', 'NegReg', (60, 68))	('PPGL', 'Gene', (55, 59))	('succinate', 'Chemical', 'MESH:D019802', (20, 29))
35494	28867159	Thus, PHD inhibition by succinate or VHL/HIF2A mutations creates a pseudohypoxic state resulting in upregulation of HIF target genes (Box 1).	('VHL', 'Gene', (37, 40))	('HIF2A', 'Gene', '2034', (41, 46))	('VHL', 'Gene', '7428', (37, 40))	('mutations', 'Var', (47, 56))	('PHD', 'Disease', 'MESH:D011547', (6, 9))	('PHD', 'Disease', (6, 9))	('pseudohypoxic state', 'MPA', (67, 86))	('upregulation', 'PosReg', (100, 112))	('succinate', 'Chemical', 'MESH:D019802', (24, 33))	('HIF2A', 'Gene', (41, 46))
35496	28867159	The importance of the HIF signaling pathway in angiogenesis and tumorigenesis is also demonstrated by the association between PPGLs and mutations in the key proteins of the oxygen sensing pathway (i.e., VHL, EPAS1/HIF2A, FH, PHD1/EGLN2, PHD2/EGLN1) and MDH2).	('EGLN1', 'Gene', (242, 247))	('PHD1', 'Gene', (225, 229))	('FH', 'Gene', '2271', (221, 223))	('mutations', 'Var', (136, 145))	('oxygen', 'Chemical', 'MESH:D010100', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PHD2', 'Gene', (237, 241))	('PHD1', 'Gene', '112398', (225, 229))	('PPGLs', 'Gene', (126, 131))	('VHL', 'Gene', (203, 206))	('PHD2', 'Gene', '54583', (237, 241))	('MDH2', 'Gene', '4191', (253, 257))	('EPAS1', 'Gene', (208, 213))	('PPGLs', 'Chemical', '-', (126, 131))	('angiogenesis', 'CPA', (47, 59))	('EGLN2', 'Gene', '112398', (230, 235))	('HIF2A', 'Gene', '2034', (214, 219))	('VHL', 'Gene', '7428', (203, 206))	('EGLN2', 'Gene', (230, 235))	('tumor', 'Disease', (64, 69))	('association', 'Interaction', (106, 117))	('HIF2A', 'Gene', (214, 219))	('EGLN1', 'Gene', '54583', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('EPAS1', 'Gene', '2034', (208, 213))	('MDH2', 'Gene', (253, 257))
35500	28867159	Most of these tumors carry somatic VHL inactivation (in >90% of cases); however, they often fail to concentrate 18F-FDG.	('18F-FDG', 'Chemical', 'MESH:D019788', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('VHL', 'Gene', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('inactivation', 'Var', (39, 51))	('fail to concentrate', 'Phenotype', 'HP:0031987', (92, 111))	('VHL', 'Gene', '7428', (35, 38))
35502	28867159	Fluxomic studies that determine the rates of metabolic reactions show that pharmocological inhibition of SDH or SDH knockdown alone does not impair cellular respiration because it is still sustained in redox equivalents by glutaminolysis and succinate secretion flux.	('succinate secretion flux', 'MPA', (242, 266))	('SDH', 'Gene', (105, 108))	('glutaminolysis', 'MPA', (223, 237))	('SDH', 'Gene', (112, 115))	('succinate', 'Chemical', 'MESH:D019802', (242, 251))	('knockdown', 'Var', (116, 125))	('SDH', 'Gene', '6390', (105, 108))	('cellular', 'MPA', (148, 156))	('SDH', 'Gene', '6390', (112, 115))	('redox equivalents', 'MPA', (202, 219))
35503	28867159	Beyond succinate accumulation, it has been shown that SDH knockout cells rely on increased pyruvate carboxylase (PC)-dependent aspartate production and reductive glutamine metabolism.	('glutamine', 'Chemical', 'MESH:D005973', (162, 171))	('increased pyruvate', 'Phenotype', 'HP:0003542', (81, 99))	('increased pyruvate carboxylase', 'Phenotype', 'HP:0003209', (81, 111))	('reductive glutamine metabolism', 'MPA', (152, 182))	('aspartate', 'Chemical', 'MESH:D001224', (127, 136))	('SDH', 'Gene', '6390', (54, 57))	('pyruvate carboxylase', 'Gene', '5091', (91, 111))	('increased', 'PosReg', (81, 90))	('knockout', 'Var', (58, 66))	('succinate', 'Chemical', 'MESH:D019802', (7, 16))	('pyruvate carboxylase', 'Gene', (91, 111))	('SDH', 'Gene', (54, 57))
35512	28867159	Therefore, it was hypothesized that succinate could be the connecting hub between SDHx mutation status and 18F-FDG uptake.	('SDHx', 'Chemical', '-', (82, 86))	('SDHx', 'Gene', (82, 86))	('succinate', 'Chemical', 'MESH:D019802', (36, 45))	('mutation', 'Var', (87, 95))	('18F-FDG', 'Chemical', 'MESH:D019788', (107, 114))
35513	28867159	This effect would be mediated by a succinate efflux for SDHx mutated cells.	('succinate', 'Chemical', 'MESH:D019802', (35, 44))	('succinate efflux', 'MPA', (35, 51))	('mutated', 'Var', (61, 68))	('SDHx', 'Gene', (56, 60))	('mediated by', 'Reg', (21, 32))	('SDHx', 'Chemical', '-', (56, 60))
35514	28867159	Analyses of compartmentalized levels of TCA cycle metabolites have revealed that yeast with sdhDelta mutations may aberrantly efflux succinate from the mitochondria to the cytosol.	('efflux succinate from the mitochondria', 'MPA', (126, 164))	('mutations', 'Var', (101, 110))	('yeast', 'Species', '4932', (81, 86))	('succinate', 'Chemical', 'MESH:D019802', (133, 142))	('sdhDelta', 'Gene', (92, 100))	('aberrantly', 'MPA', (115, 125))	('TCA', 'Chemical', 'MESH:D014233', (40, 43))
35515	28867159	Other studies have even reported that succinate could be excreted into the medium during cultivation of yeast sdhDelta mutants.	('yeast sdhDelta', 'Gene', (104, 118))	('succinate', 'MPA', (38, 47))	('succinate', 'Chemical', 'MESH:D019802', (38, 47))	('mutants', 'Var', (119, 126))	('yeast', 'Species', '4932', (104, 109))
35528	28867159	Unlike 123I-MIBG/11C-HED/18F-FDA which enter the cells via norepinephrine transporter, 18F-FDOPA is taken up via neutral amino acid transporter system L (Figure 1).	('18F-FDA', 'Chemical', '-', (25, 32))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (87, 96))	('123I-MIBG', 'Chemical', 'MESH:D019797', (7, 16))	('11C-HED', 'Chemical', '-', (17, 24))	('norepinephrine transporter', 'Gene', (59, 85))	('18F-FDOPA', 'Var', (87, 96))	('norepinephrine transporter', 'Gene', '6530', (59, 85))	('neutral amino acid transporter system', 'MPA', (113, 150))
35545	28867159	Surprisingly, metastatic PPGLs associated with SDHB mutations, which are more aggressive than their sporadic counterparts, exhibit intense uptake of 68Ga-labeled-SSAs.	('mutations', 'Var', (52, 61))	('uptake of 68Ga-labeled-SSAs', 'MPA', (139, 166))	('metastatic', 'CPA', (14, 24))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('PPGLs', 'Chemical', '-', (25, 30))
35548	28867159	EPAS1 mutations remain an exception among susceptibility genes since they lead to PPGLs that concentrate less 68Ga-labeled-SSA in contrast to SDHx-related PPGLs.	('EPAS1', 'Gene', '2034', (0, 5))	('68Ga-labeled-SSA', 'MPA', (110, 126))	('PPGLs', 'Chemical', '-', (82, 87))	('lead to', 'Reg', (74, 81))	('EPAS1', 'Gene', (0, 5))	('less', 'NegReg', (105, 109))	('SDHx', 'Chemical', '-', (142, 146))	('PPGLs', 'Chemical', '-', (155, 160))	('mutations', 'Var', (6, 15))
35550	28867159	For detecting multifocality or metastases, both SDHx and non-SDHx PPGLs, are better visualized by 68Ga-DOTA-SSA than 18F-FDOPA PET/CT or even 18F-FDG PET/CT.	('18F-FDOPA', 'Chemical', 'MESH:C043437', (117, 126))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('SDHx', 'Chemical', '-', (61, 65))	('SDHx PPGLs', 'Chemical', '-', (61, 71))	('68Ga-DOTA-SSA', 'Chemical', '-', (98, 111))	('18F-FDG', 'Chemical', 'MESH:D019788', (142, 149))	('SDHx', 'Chemical', '-', (48, 52))	('68Ga-DOTA-SSA', 'Var', (98, 111))	('metastases', 'Disease', (31, 41))
35557	28867159	Interestingly, a recent study has shown that succinate has pro-angiogenic functions (chemotactic motility, tube-like structure formation and proliferation) and also upregulates vascular endothelial growth factor expression.	('succinate', 'Chemical', 'MESH:D019802', (45, 54))	('vascular endothelial growth factor', 'Gene', (177, 211))	('vascular endothelial growth factor', 'Gene', '7422', (177, 211))	('tube-like structure formation', 'CPA', (107, 136))	('succinate', 'Var', (45, 54))	('pro-angiogenic functions', 'CPA', (59, 83))	('upregulates', 'PosReg', (165, 176))
35568	28867159	Stabilization of HIF-alpha subunits is related to deregulation of the ubiquitin/proteasome system (SDHx, von Hippel-Lindau-VHL, or Endothelial PAS Domain Protein 1-EPAS-1 (also called Hypoxia-Inducible Factor 2 Alpha-HIF2A) mutations.	('Endothelial PAS Domain Protein 1', 'Gene', (131, 163))	('EPAS-1', 'Gene', (164, 170))	('HIF2A', 'Gene', '2034', (217, 222))	('deregulation', 'MPA', (50, 62))	('VHL', 'Gene', (123, 126))	('SDHx', 'Chemical', '-', (99, 103))	('VHL', 'Gene', '7428', (123, 126))	('EPAS-1', 'Gene', '2034', (164, 170))	('mutations', 'Var', (224, 233))	('HIF2A', 'Gene', (217, 222))	('Endothelial PAS Domain Protein 1', 'Gene', '2034', (131, 163))
35580	28867159	described the first PGL syndrome (PGL1) related to a SDH deficiency, due to a mutation in the SDHD.	('PGL syndrome', 'Disease', 'MESH:D010235', (20, 32))	('SDHD', 'Gene', (94, 98))	('mutation', 'Var', (78, 86))	('related', 'Reg', (40, 47))	('SDH deficiency', 'Disease', (53, 67))	('SDH deficiency', 'Disease', 'MESH:D007153', (53, 67))	('PGL syndrome', 'Disease', (20, 32))	('SDHD', 'Gene', '6392', (94, 98))
35581	28867159	Later, several familial clusters of PPGLs related to deleterious mutations in any of SDHx were described and defined as PGL syndromes PGL1 through PGL4.	('PPGLs', 'Chemical', '-', (36, 41))	('SDHx', 'Gene', (85, 89))	('SDHx', 'Chemical', '-', (85, 89))	('PGL4', 'Gene', (147, 151))	('PGL4', 'Gene', '6390', (147, 151))	('PGL syndrome', 'Disease', (120, 132))	('related', 'Reg', (42, 49))	('PPGLs', 'Disease', (36, 41))	('PGL syndrome', 'Disease', 'MESH:D010235', (120, 132))	('mutations', 'Var', (65, 74))
35584	28867159	Succinate leads to a set of distinct features that enhance tumor growth and survival via HIF proteins stabilization with increased expression of HIF-target genes (angiogenesis), hypermethylation profile that is viewed as a contributing factor to both tumor aggressiveness (epithelial to mesenchymal transition) and loss of chromaffin-specific patterns of gene expression.	('tumor aggressiveness', 'Disease', (251, 271))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', (59, 64))	('increased', 'PosReg', (121, 130))	('enhance', 'PosReg', (51, 58))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('aggressiveness', 'Phenotype', 'HP:0000718', (257, 271))	('HIF proteins', 'Protein', (89, 101))	('expression', 'MPA', (131, 141))	('hypermethylation profile', 'Var', (178, 202))	('chromaffin', 'Chemical', '-', (323, 333))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (251, 271))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('survival', 'CPA', (76, 84))	('stabilization', 'NegReg', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
35655	26943426	Zero to 15 % show identifiable somatic CKIT or platelet-derived growth factor receptor-alpha (PDGFRA) mutations in GIST.	('GIST', 'Gene', (115, 119))	('CKIT', 'Gene', '3815', (39, 43))	('PDGFRA', 'Gene', '5156', (94, 100))	('PDGFRA', 'Gene', (94, 100))	('platelet-derived growth factor receptor-alpha', 'Gene', (47, 92))	('CKIT', 'Gene', (39, 43))	('mutations', 'Var', (102, 111))	('GIST', 'Phenotype', 'HP:0100723', (115, 119))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (47, 92))
35673	25298897	In children less than 18 years of age approximately 60% of pheochromocytomas and paragangliomas are associated with a germline mutation.	('children', 'Species', '9606', (3, 11))	('pheochromocytomas', 'Disease', 'MESH:D010673', (59, 76))	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('germline mutation', 'Var', (118, 135))	('pheochromocytomas', 'Disease', (59, 76))	('associated', 'Reg', (100, 110))	('paragangliomas', 'Disease', 'MESH:D010235', (81, 95))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (59, 76))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('paragangliomas', 'Disease', (81, 95))	('paragangliomas', 'Phenotype', 'HP:0002668', (81, 95))
35674	25298897	We present an 11-year-old child with an abdominal paraganglioma related to a succinate dehydrogenase subunit B gene mutation whose father had a previously resected abdominal paraganglioma and was found to carry the same mutation.	('abdominal paraganglioma', 'Disease', (164, 187))	('paraganglioma', 'Phenotype', 'HP:0002668', (174, 187))	('mutation', 'Var', (116, 124))	('related', 'Reg', (64, 71))	('child', 'Species', '9606', (26, 31))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (40, 63))	('abdominal paraganglioma', 'Disease', (40, 63))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (164, 187))	('paraganglioma', 'Phenotype', 'HP:0002668', (50, 63))
35680	25298897	It has been reported that over half of all PCC and PGL in patients <18 years old are associated with a germline mutation and that this percentage seems to increase with decreasing age at diagnosis.	('patients', 'Species', '9606', (58, 66))	('PCC', 'Disease', (43, 46))	('PCC', 'Phenotype', 'HP:0002666', (43, 46))	('PGL', 'Phenotype', 'HP:0002668', (51, 54))	('germline mutation', 'Var', (103, 120))	('PGL', 'Disease', (51, 54))	('associated', 'Reg', (85, 95))
35695	25298897	Despite gradual increases in alpha- and beta-blockade with phenoxybenzamine, atenolol, and propranolol, he ultimately required an esmolol infusion to maintain the heart rate less than 100 beats per minute.	('atenolol', 'Chemical', 'MESH:D001262', (77, 85))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (59, 75))	('esmolol', 'Chemical', 'MESH:C036604', (130, 137))	('propranolol', 'Chemical', 'MESH:D011433', (91, 102))	('phenoxybenzamine', 'Var', (59, 75))	('increases', 'PosReg', (16, 25))	('heart rate', 'MPA', (163, 173))
35701	25298897	After discharge, a serum genetic panel returned positive for a heterozygous deleterious mutation in the succinate dehydrogenase complex subunit B (SDHB) gene.	('mutation', 'Var', (88, 96))	('succinate dehydrogenase complex subunit B', 'Gene', (104, 145))	('succinate dehydrogenase complex subunit B', 'Gene', '6390', (104, 145))	('positive', 'Reg', (48, 56))	('SDHB', 'Gene', '6390', (147, 151))	('SDHB', 'Gene', (147, 151))
35730	25298897	Although some cases of pediatric PCC/PGL are sporadic, it has been reported that 59% of those occurring in children <18 years old and up to 70% of those occurring in children <10 years old are associated with a germline mutation.	('PGL', 'Phenotype', 'HP:0002668', (37, 40))	('germline mutation', 'Var', (211, 228))	('children', 'Species', '9606', (107, 115))	('children', 'Species', '9606', (166, 174))	('PCC', 'Phenotype', 'HP:0002666', (33, 36))	('associated', 'Reg', (193, 203))
35736	25298897	While SDH subunit gene mutations have been shown to be associated with neoplasia and cause susceptibility to familial PCC/PGL syndromes, an exact causal mechanism is still unclear.	('PCC', 'Phenotype', 'HP:0002666', (118, 121))	('neoplasia', 'Disease', (71, 80))	('SDH', 'Gene', (6, 9))	('PGL', 'Phenotype', 'HP:0002668', (122, 125))	('associated', 'Reg', (55, 65))	('familial PCC', 'Disease', 'MESH:C565384', (109, 121))	('familial PCC', 'Disease', (109, 121))	('mutations', 'Var', (23, 32))	('neoplasia', 'Phenotype', 'HP:0002664', (71, 80))	('neoplasia', 'Disease', 'MESH:D009369', (71, 80))	('susceptibility', 'Reg', (91, 105))	('SDH', 'Gene', '6390', (6, 9))
35737	25298897	Hereditary PCC/PGL syndromes have an autosomal dominant mode of inheritance, and approximately 40% of patients with SDHB mutations may go on to develop malignant disease.	('PGL', 'Phenotype', 'HP:0002668', (15, 18))	('Hereditary PCC/PGL syndromes', 'Disease', (0, 28))	('mutations', 'Var', (121, 130))	('develop', 'PosReg', (144, 151))	('SDHB', 'Gene', '6390', (116, 120))	('patients', 'Species', '9606', (102, 110))	('SDHB', 'Gene', (116, 120))	('malignant disease', 'Disease', 'MESH:D009369', (152, 169))	('PCC', 'Phenotype', 'HP:0002666', (11, 14))	('malignant disease', 'Disease', (152, 169))
35738	25298897	Overall SDHB mutations are associated with a higher malignancy rate than mutations in the SDHD or SDHC genes and in fact account for 50% or more of malignant PCC and PGL.	('PGL', 'Disease', (166, 169))	('SDHD', 'Gene', (90, 94))	('SDHD', 'Gene', '6392', (90, 94))	('malignant PCC', 'Disease', (148, 161))	('SDHB', 'Gene', '6390', (8, 12))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('SDHC', 'Gene', '6391', (98, 102))	('malignancy', 'Disease', (52, 62))	('SDHB', 'Gene', (8, 12))	('PCC', 'Phenotype', 'HP:0002666', (158, 161))	('PGL', 'Phenotype', 'HP:0002668', (166, 169))	('mutations', 'Var', (13, 22))	('SDHC', 'Gene', (98, 102))
35739	25298897	SDHB mutations usually correlate with disease in the thorax, abdomen, or pelvis while SDHD mutations often manifest as head or neck tumors that are typically benign.	('disease', 'Disease', (38, 45))	('SDHD', 'Gene', (86, 90))	('manifest', 'Reg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('neck tumors', 'Disease', (127, 138))	('mutations', 'Var', (5, 14))	('neck tumors', 'Disease', 'MESH:D006258', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('SDHB', 'Gene', '6390', (0, 4))	('head or neck tumors', 'Phenotype', 'HP:0012288', (119, 138))	('SDHB', 'Gene', (0, 4))	('SDHD', 'Gene', '6392', (86, 90))
35741	25298897	Routine genetic counseling and testing are recommended, however, after the diagnosis of PGL in a child regardless of family history particularly since certain mutations can indicate multisite disease or higher probability of malignancy.	('child', 'Species', '9606', (97, 102))	('PGL', 'Phenotype', 'HP:0002668', (88, 91))	('indicate', 'Reg', (173, 181))	('mutations', 'Var', (159, 168))	('PGL', 'Disease', (88, 91))	('malignancy', 'Disease', 'MESH:D009369', (225, 235))	('malignancy', 'Disease', (225, 235))	('multisite disease', 'Disease', (182, 199))
35774	25057243	SDHD and SDHB mutations are very important for head and neck paragangliomas.	('SDHB', 'Gene', '6390', (9, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('neck paragangliomas', 'Disease', 'MESH:D010235', (56, 75))	('SDHB', 'Gene', (9, 13))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (47, 75))	('SDHD', 'Gene', '6392', (0, 4))	('SDHD', 'Gene', (0, 4))	('neck paragangliomas', 'Disease', (56, 75))	('mutations', 'Var', (14, 23))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))
35776	25057243	Although many familial cases that are often associated with the abovementioned germline mutations go unrecognized, germline mutations have been reported in 7.5%-24% of patients with pheochromocytomas or paragangliomas, and with their sporadic presentation.	('reported', 'Reg', (144, 152))	('paragangliomas', 'Disease', 'MESH:D010235', (203, 217))	('pheochromocytomas', 'Disease', 'MESH:D010673', (182, 199))	('pheochromocytomas', 'Disease', (182, 199))	('paragangliomas', 'Disease', (203, 217))	('paragangliomas', 'Phenotype', 'HP:0002668', (203, 217))	('paraganglioma', 'Phenotype', 'HP:0002668', (203, 216))	('patients', 'Species', '9606', (168, 176))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (182, 199))	('germline', 'Var', (115, 123))
35786	25057243	There is founded some malignant histologic criteria that necrosis, perineural invasion (Figure 3), increased mitotic activity, atypical mitotic figures in pathologic specimen.	('mitotic activity', 'CPA', (109, 125))	('atypical', 'Var', (127, 135))	('perineural invasion', 'CPA', (67, 86))	('increased', 'PosReg', (99, 108))	('necrosis', 'Disease', (57, 65))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
35789	25057243	Immunohiystochemical studies did not reveal any SDHD or SDHB mutations.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('mutations', 'Var', (61, 70))	('SDHD', 'Gene', '6392', (48, 52))	('SDHD', 'Gene', (48, 52))
35905	26523625	Seventy-three (55%) patients had SDHB mutations; 59 (45%) patients had apparently sporadic tumors (AST).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SDHB', 'Gene', '6390', (33, 37))	('SDHB', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (38, 47))
35914	26523625	In children, metastatic PHEOs/PGLs are mainly due to SDHB mutations; in adults they are equally distributed between in SDHB mutations and AST, with better 5- and 10-year survival rates for ASTs.	('mutations', 'Var', (58, 67))	('children', 'Species', '9606', (3, 11))	('mutations', 'Var', (124, 133))	('due', 'Reg', (46, 49))	('SDHB', 'Gene', '6390', (53, 57))	('SDHB', 'Gene', '6390', (119, 123))	('metastatic PHEOs/PGLs', 'Disease', (13, 34))	('PHEOs', 'Chemical', '-', (24, 29))	('SDHB', 'Gene', (53, 57))	('SDHB', 'Gene', (119, 123))
35920	26523625	Currently, about 35 to 40% of PHEOs/PGLs occur in the context of several major inherited tumor syndromes, mainly including multiple endocrine neoplasia type 2 (MEN2, with rearranged during transfection (RET) mutations), von Hippel-Lindau (VHL) disease (caused by mutations in VHL), neurofibromatosis type 1 (NF1, with NF1 mutations), and mutations in succinate dehydrogenase subunits (SDHx).	('VHL', 'Gene', (276, 279))	('NF1', 'Gene', (318, 321))	('mutations', 'Var', (263, 272))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (132, 151))	('VHL', 'Gene', '7428', (239, 242))	('NF1', 'Gene', '4763', (308, 311))	('RET', 'Gene', (203, 206))	('SDHx', 'Gene', (385, 389))	('PHEOs', 'Chemical', '-', (30, 35))	('inherited tumor syndrome', 'Disease', (79, 103))	('NF1', 'Gene', (308, 311))	('VHL', 'Gene', '7428', (276, 279))	('inherited tumor syndrome', 'Disease', 'None', (79, 103))	('endocrine neoplasia', 'Disease', (132, 151))	('neurofibromatosis type 1', 'Gene', (282, 306))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (282, 299))	('neoplasia', 'Phenotype', 'HP:0002664', (142, 151))	('mutations', 'Var', (322, 331))	('RET', 'Gene', '5979', (203, 206))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (132, 151))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (220, 251))	('mutations', 'Var', (338, 347))	('VHL', 'Gene', (239, 242))	('NF1', 'Gene', '4763', (318, 321))	('neurofibromatosis type 1', 'Gene', '4763', (282, 306))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
35922	26523625	Newly discovered mutations in transmembrane protein 127 (TMEM127) and myc-associated factor X (MAX) genes are also associated with PHEO/PGL, currently without a specific syndromic presentation.	('myc-associated factor X', 'Gene', (70, 93))	('transmembrane protein 127', 'Gene', '55654', (30, 55))	('PHEO/PGL', 'Disease', (131, 139))	('myc-associated factor X', 'Gene', '4149', (70, 93))	('associated', 'Reg', (115, 125))	('TMEM127', 'Gene', (57, 64))	('MAX', 'Gene', '4149', (95, 98))	('MAX', 'Gene', (95, 98))	('TMEM127', 'Gene', '55654', (57, 64))	('mutations', 'Var', (17, 26))	('transmembrane protein 127', 'Gene', (30, 55))
35923	26523625	Most recently, somatic gain-of-function mutations in the gene encoding hypoxia-inducible factor 2alpha (HIF2A) have been discovered, mainly in patients presenting with a new syndrome of multiple PGLs and duodenal somatostatinomas associated with polycythemia in females.	('hypoxia-inducible factor 2alpha', 'Gene', (71, 102))	('HIF2A', 'Gene', (104, 109))	('polycythemia', 'Phenotype', 'HP:0001901', (246, 258))	('polycythemia', 'Disease', 'MESH:D011086', (246, 258))	('gain-of-function', 'PosReg', (23, 39))	('hypoxia-inducible factor 2alpha', 'Gene', '2034', (71, 102))	('HIF2A', 'Gene', '2034', (104, 109))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (143, 151))	('polycythemia', 'Disease', (246, 258))	('duodenal somatostatinomas', 'Disease', (204, 229))	('duodenal somatostatinomas', 'Disease', 'MESH:D013005', (204, 229))	('multiple PGLs', 'Disease', (186, 199))
35924	26523625	Five pathogenic germline mutations in the FH gene encoding fumarate hydratase were identified.	('fumarate hydratase', 'Gene', (59, 77))	('mutations', 'Var', (25, 34))	('pathogenic', 'Reg', (5, 15))	('fumarate hydratase', 'Gene', '2271', (59, 77))
35928	26523625	SDHB mutations are associated with more aggressive tumor behavior and a higher rate of malignancy than other PHEO/PGL types, in some studies with rates up to 50 to 90%.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('malignancy', 'Disease', 'MESH:D009369', (87, 97))	('mutations', 'Var', (5, 14))	('malignancy', 'Disease', (87, 97))	('SDHB', 'Gene', '6390', (0, 4))	('aggressive tumor', 'Disease', 'MESH:D001523', (40, 56))	('SDHB', 'Gene', (0, 4))	('aggressive tumor', 'Disease', (40, 56))
35929	26523625	Mutations in the MAX and FH genes were also found to be associated with a higher rate of metastatic PHEO/PGL.	('MAX', 'Gene', '4149', (17, 20))	('MAX', 'Gene', (17, 20))	('associated', 'Reg', (56, 66))	('metastatic PHEO/PGL', 'Disease', (89, 108))	('Mutations', 'Var', (0, 9))
35930	26523625	In addition to the presence of SDHB mutations, several other independent factors exist that seem to be closely associated with metastatic behavior of primary tumors, including their location (extra-adrenal), size (mainly over 5-6 cm), the presence of high levels of methoxytyramine, and likely some histopathological criteria (e.g., necrosis, a high mitotic rate).	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('SDHB', 'Gene', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('associated', 'Reg', (111, 121))	('mutations', 'Var', (36, 45))	('necrosis', 'Disease', 'MESH:D009336', (333, 341))	('methoxytyramine', 'MPA', (266, 281))	('methoxytyramine', 'Chemical', 'MESH:C001746', (266, 281))	('SDHB', 'Gene', '6390', (31, 35))	('metastatic behavior', 'CPA', (127, 146))	('necrosis', 'Disease', (333, 341))
35939	26523625	Genetic testing for mutations in major PHEO/PGL susceptibility genes (SDHB, SDHC, SDHD, VHL, RET, MAX, and TMEM127) was performed at either the NIH, Mayo Medical Laboratories (Rochester, MN), the Division of Molecular Diagnostics at the University of Pittsburgh Medical Center, or the Department of Genetics of the Children's Hospital of Philadelphia.	('SDHB', 'Gene', '6390', (70, 74))	('Children', 'Species', '9606', (315, 323))	('SDHB', 'Gene', (70, 74))	('TMEM127', 'Gene', (107, 114))	('VHL', 'Gene', (88, 91))	('RET', 'Gene', '5979', (93, 96))	('PHEO/PGL', 'Gene', (39, 47))	('TMEM127', 'Gene', '55654', (107, 114))	('SDHD', 'Gene', (82, 86))	('VHL', 'Gene', '7428', (88, 91))	('SDHC', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (82, 86))	('Mayo', 'Species', '162683', (149, 153))	('SDHC', 'Gene', '6391', (76, 80))	('RET', 'Gene', (93, 96))	('MAX', 'Gene', '4149', (98, 101))	('mutations', 'Var', (20, 29))	('MAX', 'Gene', (98, 101))
35964	26523625	Overall, 73 (55%) patients had mutations in SDHB, and 59 (45%) patients presented with apparently sporadic tumors (AST), no mutations in SDHC, SDHD, RET, or VHL were included.	('mutations', 'Var', (31, 40))	('RET', 'Gene', '5979', (149, 152))	('SDHB', 'Gene', '6390', (44, 48))	('SDHC', 'Gene', '6391', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('SDHD', 'Gene', (143, 147))	('SDHB', 'Gene', (44, 48))	('VHL', 'Gene', (157, 160))	('presented', 'Reg', (72, 81))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('SDHD', 'Gene', '6392', (143, 147))	('VHL', 'Gene', '7428', (157, 160))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (63, 71))	('RET', 'Gene', (149, 152))	('SDHC', 'Gene', (137, 141))
35965	26523625	In children, 22 (81%) had mutations in SDHB (90% were PGLs); in adults, 51 (49%) had mutations in SDHB (80% were PGLs).	('children', 'Species', '9606', (3, 11))	('SDHB', 'Gene', '6390', (39, 43))	('SDHB', 'Gene', '6390', (98, 102))	('SDHB', 'Gene', (39, 43))	('mutations', 'Var', (26, 35))	('mutations', 'Var', (85, 94))	('SDHB', 'Gene', (98, 102))
35981	26523625	In patients with SDHB mutations, 15% and 35% of primary tumors were smaller than 4.5 or 6 cm, respectively; 74% and 54% were equal to or larger than 4.5 or 6 cm, respectively; and 11% were of an unknown size.	('smaller', 'NegReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SDHB', 'Gene', '6390', (17, 21))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('SDHB', 'Gene', (17, 21))
35986	26523625	In patients with SDHB mutations, metastases were most often found in the bones (78%), lungs and mediastinum (45%), lymph nodes (36%), and liver (35%); only 1 patient had metastases detected only in lymph nodes.	('metastases', 'Disease', (33, 43))	('patient', 'Species', '9606', (158, 165))	('patient', 'Species', '9606', (3, 10))	('SDHB', 'Gene', '6390', (17, 21))	('metastases', 'Disease', (170, 180))	('found', 'Reg', (60, 65))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('metastases', 'Disease', 'MESH:D009362', (170, 180))	('SDHB', 'Gene', (17, 21))
35993	26523625	In patients with SDHB mutations, 46 (73%) of patients with extraadrenal PGLs had noradrenergic) phenotype; 16 (35%) of these patients also had elevated DA.	('noradrenergic) phenotype', 'MPA', (81, 105))	('SDHB', 'Gene', '6390', (17, 21))	('elevated', 'PosReg', (143, 151))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (22, 31))	('SDHB', 'Gene', (17, 21))	('DA', 'Chemical', 'MESH:D004298', (152, 154))	('patients', 'Species', '9606', (125, 133))
35999	26523625	In 73 patients with SDHB mutations, 41 (65%) of the 63 PGLs were noradrenergic; 12 (29%) of these SDHB patients also had elevated DA.	('DA', 'Chemical', 'MESH:D004298', (130, 132))	('mutations', 'Var', (25, 34))	('SDHB', 'Gene', '6390', (98, 102))	('SDHB', 'Gene', (98, 102))	('SDHB', 'Gene', '6390', (20, 24))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (103, 111))	('SDHB', 'Gene', (20, 24))
36035	26523625	Twenty-nine of these patients had SDHB mutations; 10 were AST patients.	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (21, 29))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))	('patients', 'Species', '9606', (62, 70))
36036	26523625	There was a statistically significant difference in survival between patients with SDHB mutations and those with AST (P = .006, Fig.	('SDHB', 'Gene', (83, 87))	('survival', 'MPA', (52, 60))	('mutations', 'Var', (88, 97))	('significant difference', 'Reg', (26, 48))	('patients', 'Species', '9606', (69, 77))	('SDHB', 'Gene', '6390', (83, 87))
36037	26523625	Kaplan-Meier estimates of 5- and 10-year survival rates were 91.8% (95% confidence interval [CI]: 82.696.2%) and 75.5% (95% CI: 63.5-84.1%) in the SDHB mutation group and 94.8% (95% CI: 84.8-98.3%) and 86.3% (95% CI: 73.1-93.3%) in the group of patients with AST, respectively.	('SDHB', 'Gene', '6390', (147, 151))	('mutation', 'Var', (152, 160))	('SDHB', 'Gene', (147, 151))	('patients', 'Species', '9606', (245, 253))
36046	26523625	First, we did not find any major differences in the frequency of SDHB versus AST adult patients with metastatic disease, suggesting that other genetic and epigenetic factors besides SDHB mutations play an important role in the pathogenesis of metastatic PHEO/PGL.	('SDHB', 'Gene', (182, 186))	('mutations', 'Var', (187, 196))	('metastatic PHEO/PGL', 'Disease', (243, 262))	('SDHB', 'Gene', '6390', (65, 69))	('SDHB', 'Gene', '6390', (182, 186))	('patients', 'Species', '9606', (87, 95))	('SDHB', 'Gene', (65, 69))
36047	26523625	In contrast, in children, there were five times more patients with SDHB mutations than with AST.	('mutations', 'Var', (72, 81))	('patients', 'Species', '9606', (53, 61))	('SDHB', 'Gene', '6390', (67, 71))	('SDHB', 'Gene', (67, 71))	('children', 'Species', '9606', (16, 24))
36048	26523625	Second, we found that adult patients with SDHB mutations had statistically worse survival than those without them.	('SDHB', 'Gene', '6390', (42, 46))	('mutations', 'Var', (47, 56))	('survival', 'MPA', (81, 89))	('patients', 'Species', '9606', (28, 36))	('worse', 'NegReg', (75, 80))	('SDHB', 'Gene', (42, 46))
36053	26523625	These include: SDHB gene mutation, older age at initial diagnosis, location of primary lesions, tumor size/weight, and a noradrenergic and/or dopaminergic biochemical phenotype.	('SDHB', 'Gene', '6390', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('noradrenergic and/or', 'MPA', (121, 141))	('dopamine', 'Chemical', 'MESH:D004298', (142, 150))	('mutation', 'Var', (25, 33))	('SDHB', 'Gene', (15, 19))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
36054	26523625	Currently, SDHB mutations, although associated with a low penetrance, are considered one of the most important risk factors for developing metastatic PHEO/PGL with a poor prognosis, including in children.	('SDHB', 'Gene', (11, 15))	('metastatic PHEO/PGL', 'Disease', (139, 158))	('developing', 'PosReg', (128, 138))	('mutations', 'Var', (16, 25))	('SDHB', 'Gene', '6390', (11, 15))	('children', 'Species', '9606', (195, 203))
36055	26523625	In a paper by Amar et al, it was found that patients with PHEOs/PGLs with SDHB mutations have a high relative risk (71.4%) of developing metastatic tumors, which was later confirmed by several other investigators.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('patients', 'Species', '9606', (44, 52))	('SDHB', 'Gene', '6390', (74, 78))	('SDHB', 'Gene', (74, 78))	('PHEOs', 'Chemical', '-', (58, 63))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('developing', 'PosReg', (126, 136))	('mutations', 'Var', (79, 88))
36056	26523625	Furthermore, Brouwers et al found that SDHB mutations are responsible for about 50% of all metastases originating from primary extra-adrenal abdominal PGLs.	('SDHB', 'Gene', '6390', (39, 43))	('metastases', 'Disease', (91, 101))	('SDHB', 'Gene', (39, 43))	('mutations', 'Var', (44, 53))	('responsible', 'Reg', (58, 69))	('metastases', 'Disease', 'MESH:D009362', (91, 101))
36058	26523625	In the present study, in adult patients, we did not find a more frequent association between the presence of SDHB-related metastatic PHEO/PGL versus AST (Table 3).	('SDHB', 'Gene', '6390', (109, 113))	('presence', 'Var', (97, 105))	('SDHB', 'Gene', (109, 113))	('patients', 'Species', '9606', (31, 39))	('metastatic PHEO/PGL', 'Disease', (122, 141))
36060	26523625	Thus, we believe that the present results on this large population of patients with metastatic PHEO/PGL suggest that there are additional important factors besides SDHB mutations, including other genetic and epigenetic mechanisms, that play a crucial role in the development of metastases, at least in adults.	('patients', 'Species', '9606', (70, 78))	('metastases', 'Disease', 'MESH:D009362', (278, 288))	('mutations', 'Var', (169, 178))	('SDHB', 'Gene', '6390', (164, 168))	('metastases', 'Disease', (278, 288))	('SDHB', 'Gene', (164, 168))
36061	26523625	Other than the presence of SDHB mutations, the size and location of the primary tumor were also found to play an important and most likely independent role in the devolopment of metastases in the present study, as described below.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('SDHB', 'Gene', '6390', (27, 31))	('mutations', 'Var', (32, 41))	('metastases', 'Disease', (178, 188))	('SDHB', 'Gene', (27, 31))
36066	26523625	Furthermore, the primary tumor size of both PHEOs and PGLs was also found to be larger in patients with SDHB PHEO/PGL than in patients with AST.	('larger', 'PosReg', (80, 86))	('PHEOs', 'Chemical', '-', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('SDHB', 'Gene', '6390', (104, 108))	('patients', 'Species', '9606', (126, 134))	('PHEO/PGL', 'Var', (109, 117))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('SDHB', 'Gene', (104, 108))
36096	26523625	In children, 81% had mutations in SDHB (90% PGLs); in adults, only 49% had mutations in SDHB (80% PGLs).	('children', 'Species', '9606', (3, 11))	('SDHB', 'Gene', '6390', (88, 92))	('SDHB', 'Gene', (88, 92))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))	('mutations', 'Var', (21, 30))
36099	26523625	This supports the establishment of certain recommendations for practicing oncologists and other physicians: carefully examine patients who present with PHEO/PGL in childhood, including testing all of them for SDHB mutations and following them for many years due to the late development of metastases; increase the follow-up frequency for patients with tumor sizes over 4.5 cm and consider performing whole-body imaging, especially in SDHB patients since one-fifth of patients present with metastatic disease at the initial diagnosis, mainly in bones; increase follow-up frequency in older patients; assure patients that with appropriate follow-up and treatment the 10-year survival rates are currently 75% or 86% for SDHB and AST types, respectively; and follow-up visits should preferably be done in a collaborative oncology-endocrinology combined practice.	('metastases', 'Disease', 'MESH:D009362', (289, 299))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (467, 475))	('patients', 'Species', '9606', (338, 346))	('SDHB', 'Gene', '6390', (434, 438))	('metastases', 'Disease', (289, 299))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', (352, 357))	('patients', 'Species', '9606', (606, 614))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('oncology', 'Phenotype', 'HP:0002664', (817, 825))	('SDHB', 'Gene', (434, 438))	('SDHB', 'Gene', '6390', (717, 721))	('patients', 'Species', '9606', (439, 447))	('SDHB', 'Gene', '6390', (209, 213))	('child', 'Species', '9606', (164, 169))	('late development', 'Phenotype', 'HP:0001263', (269, 285))	('metastatic disease', 'Disease', (489, 507))	('patients', 'Species', '9606', (589, 597))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('SDHB', 'Gene', (717, 721))	('SDHB', 'Gene', (209, 213))
36117	31672301	Recently documented germline mutations characteristic of familial pheochromocytoma/paraganglioma syndromes have increased the percentage of heritable lesions to more than 30%.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (66, 82))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('germline mutations', 'Var', (20, 38))	('increased', 'PosReg', (112, 121))	('familial pheochromocytoma/paraganglioma syndromes', 'Disease', (57, 106))	('familial pheochromocytoma/paraganglioma syndromes', 'Disease', 'MESH:C531777', (57, 106))
36125	31672301	Watery diarrhea, hypokalemia, and achlorhydria syndrome caused by vasoactive intestinal peptide production, and polycythemia arising from erythropoietin (EPO) oversecretion or oversensitivity of EPO receptors, can also occur.	('EPO', 'Gene', '2056', (154, 157))	('achlorhydria syndrome', 'Disease', 'MESH:D000126', (34, 55))	('hypokalemia', 'Disease', (17, 28))	('EPO', 'Gene', '2056', (195, 198))	('diarrhea', 'Disease', (7, 15))	('EPO', 'Gene', (154, 157))	('EPO', 'Gene', (195, 198))	('achlorhydria syndrome', 'Disease', (34, 55))	('polycythemia', 'Phenotype', 'HP:0001901', (112, 124))	('oversensitivity', 'Var', (176, 191))	('diarrhea', 'Disease', 'MESH:D003967', (7, 15))	('hypokalemia', 'Phenotype', 'HP:0002900', (17, 28))	('erythropoietin', 'Gene', (138, 152))	('vasoactive intestinal peptide production', 'MPA', (66, 106))	('erythropoietin', 'Gene', '2056', (138, 152))	('achlorhydria', 'Phenotype', 'HP:0032448', (34, 46))	('hypokalemia', 'Disease', 'MESH:D007008', (17, 28))	('polycythemia', 'Disease', (112, 124))	('oversecretion', 'Var', (159, 172))	('diarrhea', 'Phenotype', 'HP:0002014', (7, 15))	('polycythemia', 'Disease', 'MESH:D011086', (112, 124))
36164	31672301	The remaining features of vascular invasion, capsular invasion, profound nuclear pleomorphism, and nuclear hyperchromasia score 1 point each.	('hyperchromasia', 'Disease', 'None', (107, 121))	('profound nuclear', 'Var', (64, 80))	('vascular invasion', 'CPA', (26, 43))	('hyperchromasia', 'Disease', (107, 121))	('capsular invasion', 'CPA', (45, 62))
36176	31672301	Although most PPGLs arise sporadically, germline mutations in known susceptibility genes are identified in up to 24% of sporadic-appearing PPGL cases.	('PPGLs', 'Disease', (14, 19))	('PPGL', 'Chemical', '-', (139, 143))	('germline mutations', 'Var', (40, 58))	('PPGLs', 'Chemical', '-', (14, 19))	('PPGL', 'Chemical', '-', (14, 18))	('PPGL', 'Disease', (139, 143))
36178	31672301	NF1 mutations, the most commonly mutated gene, are present in more than 25% of sporadic PPGLs, followed by VHL (9%) and RET (5%).	('VHL', 'Gene', '7428', (107, 110))	('PPGLs', 'Chemical', '-', (88, 93))	('NF1', 'Gene', '4763', (0, 3))	('RET', 'Gene', (120, 123))	('PPGLs', 'Disease', (88, 93))	('RET', 'Gene', '5979', (120, 123))	('NF1', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', (107, 110))
36179	31672301	In addition, some tumors harbor gain-of-function EPAS1 mutations.	('gain-of-function', 'PosReg', (32, 48))	('mutations', 'Var', (55, 64))	('tumors', 'Disease', (18, 24))	('EPAS1', 'Gene', '2034', (49, 54))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EPAS1', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
36181	31672301	The first cluster is associated with pseudohypoxic signaling and is subdivided into 2 subgroups: tricarboxylic acid (TCA) cycle-related mutations, involving germline mutations in all 5 of the succinate dehydrogenase (SDH) subunits (SDHA, SDHB, SDHC, SDHD, and SDHAF2) and fumarate hydratase (FH), also an enzyme in the TCA cycle; and VHL/EPAS1-related mutations.	('SDH', 'Gene', (250, 253))	('SDHB', 'Gene', '6390', (238, 242))	('SDH', 'Gene', '6390', (217, 220))	('SDHC', 'Gene', (244, 248))	('SDH', 'Gene', '6390', (238, 241))	('FH', 'Gene', '2271', (292, 294))	('mutations', 'Var', (352, 361))	('SDHD', 'Gene', (250, 254))	('mutations', 'Var', (136, 145))	('EPAS1', 'Gene', (338, 343))	('SDHA', 'Gene', (232, 236))	('SDH', 'Gene', (232, 235))	('TCA', 'Chemical', 'MESH:D014233', (319, 322))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (97, 115))	('mutations', 'Var', (166, 175))	('succinate dehydrogenase', 'Gene', (192, 215))	('SDHB', 'Gene', (238, 242))	('SDH', 'Gene', (217, 220))	('SDHA', 'Gene', '6389', (232, 236))	('SDH', 'Gene', '6390', (260, 263))	('fumarate hydratase', 'Gene', (272, 290))	('SDH', 'Gene', (238, 241))	('SDH', 'Gene', '6390', (244, 247))	('associated', 'Reg', (21, 31))	('SDH', 'Gene', '6390', (250, 253))	('EPAS1', 'Gene', '2034', (338, 343))	('SDHC', 'Gene', '6391', (244, 248))	('VHL', 'Gene', (334, 337))	('SDHAF2', 'Gene', '54949', (260, 266))	('SDHAF2', 'Gene', (260, 266))	('SDH', 'Gene', (260, 263))	('succinate dehydrogenase', 'Gene', '6390', (192, 215))	('SDHA', 'Gene', (260, 264))	('SDHD', 'Gene', '6392', (250, 254))	('fumarate hydratase', 'Gene', '2271', (272, 290))	('SDH', 'Gene', '6390', (232, 235))	('SDH', 'Gene', (244, 247))	('TCA', 'Chemical', 'MESH:D014233', (117, 120))	('SDHA', 'Gene', '6389', (260, 264))	('VHL', 'Gene', '7428', (334, 337))
36183	31672301	The second group is characterized by Wnt signaling and includes newly recognized CSDE1 somatic mutations as well as MAML3 somatic gene fusion events.	('MAML3', 'Gene', '55534', (116, 121))	('MAML3', 'Gene', (116, 121))	('mutations', 'Var', (95, 104))	('CSDE1', 'Gene', (81, 86))	('CSDE1', 'Gene', '7812', (81, 86))
36185	31672301	The last group consists of abnormalities of tyrosine kinase signaling pathways and encompass germline or somatic mutations in RET, NF1, TMEM127, MAX, and HRAS genes.	('NF1', 'Gene', (131, 134))	('HRAS', 'Gene', (154, 158))	('NF1', 'Gene', '4763', (131, 134))	('TMEM127', 'Gene', (136, 143))	('RET', 'Gene', (126, 129))	('mutations', 'Var', (113, 122))	('tyrosine kinase signaling pathways', 'Pathway', (44, 78))	('TMEM127', 'Gene', '55654', (136, 143))	('RET', 'Gene', '5979', (126, 129))	('HRAS', 'Gene', '3265', (154, 158))	('abnormalities', 'Var', (27, 40))
36188	31672301	It was formerly thought that 10% of pheochromocytomas were associated with familial syndromes; however, it is now known that up to 24% of sporadic-appearing PPGLs harbor germline mutations.	('pheochromocytomas', 'Disease', (36, 53))	('familial syndromes', 'Disease', (75, 93))	('PPGLs', 'Chemical', '-', (157, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (36, 53))	('associated', 'Reg', (59, 69))	('PPGLs', 'Disease', (157, 162))	('pheochromocytomas', 'Disease', 'MESH:D010673', (36, 53))	('germline mutations', 'Var', (170, 188))
36190	31672301	Hereditary PPGLs are often associated with the emergence of other neoplasms.	('PPGLs', 'Disease', (11, 16))	('neoplasms', 'Disease', 'MESH:D009369', (66, 75))	('associated', 'Reg', (27, 37))	('neoplasms', 'Disease', (66, 75))	('neoplasm', 'Phenotype', 'HP:0002664', (66, 74))	('PPGLs', 'Chemical', '-', (11, 16))	('Hereditary', 'Var', (0, 10))	('neoplasms', 'Phenotype', 'HP:0002664', (66, 75))
36197	31672301	Ninety percent of mutations with MEN2A develop medullary thyroid carcinoma, 50% develop pheochromocytomas, and 20% to 30% have hyperparathyroidism secondary to parathyroid hyperplasia.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('parathyroid hyperplasia', 'Phenotype', 'HP:0008208', (160, 183))	('develop', 'Reg', (80, 87))	('develop', 'Reg', (39, 46))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (88, 105))	('hyperparathyroidism', 'Disease', (127, 146))	('parathyroid hyperplasia', 'Disease', 'MESH:D006965', (160, 183))	('hyperparathyroidism secondary', 'Phenotype', 'HP:0000867', (127, 156))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (127, 146))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (57, 74))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (47, 74))	('MEN2A', 'Gene', (33, 38))	('thyroid carcinoma', 'Disease', (57, 74))	('MEN2A', 'Gene', '5979', (33, 38))	('parathyroid hyperplasia', 'Disease', (160, 183))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (127, 146))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (88, 104))	('pheochromocytomas', 'Disease', 'MESH:D010673', (88, 105))	('pheochromocytomas', 'Disease', (88, 105))	('mutations', 'Var', (18, 27))
36201	31672301	VHL syndrome is a rare genetic disorder caused by germline mutations in the VHL tumor suppressor gene located on chromosome 3p25.3.	('VHL syndrome', 'Disease', 'MESH:D006623', (0, 12))	('genetic disorder', 'Disease', (23, 39))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('germline mutations', 'Var', (50, 68))	('VHL tumor', 'Disease', 'MESH:D006623', (76, 85))	('caused by', 'Reg', (40, 49))	('genetic disorder', 'Disease', 'MESH:D030342', (23, 39))	('VHL syndrome', 'Disease', (0, 12))	('VHL tumor', 'Disease', (76, 85))
36205	31672301	As consequence, more than 90% of gene-carrying patients manifest 1 or more of the clinical sequelae of the syndrome by age 65 years and up to 30% develop PPGL at a mean patient age of 30 years.	('patient', 'Species', '9606', (47, 54))	('gene-carrying', 'Var', (33, 46))	('patients', 'Species', '9606', (47, 55))	('PPGL', 'Chemical', '-', (154, 158))	('PPGL', 'Gene', (154, 158))	('develop', 'Reg', (146, 153))	('patient', 'Species', '9606', (169, 176))
36210	31672301	In less than 10% of cases, sporadic PPGL may also present with VHL germline mutation without being part of a hereditary syndrome.	('germline mutation', 'Var', (67, 84))	('PPGL', 'Chemical', '-', (36, 40))	('hereditary syndrome', 'Disease', 'MESH:D061325', (109, 128))	('VHL', 'Gene', (63, 66))	('hereditary syndrome', 'Disease', (109, 128))	('PPGL', 'Disease', (36, 40))	('present', 'Reg', (50, 57))	('VHL', 'Gene', '7428', (63, 66))
36212	31672301	NF1 is an autosomal dominant syndrome caused by mutations in the NF1 gene on chromosome 17q11.2.	('autosomal dominant syndrome', 'Disease', (10, 37))	('caused by', 'Reg', (38, 47))	('NF1', 'Gene', '4763', (65, 68))	('NF1', 'Gene', (0, 3))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (0, 3))	('mutations', 'Var', (48, 57))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (10, 37))
36217	31672301	Familial pheochromocytoma/paraganglioma syndromes are a group of inherited genetic disorders caused by mutations of the succinate dehydrogenase (SDH) gene complex.	('caused by', 'Reg', (93, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (26, 39))	('mutations', 'Var', (103, 112))	('succinate dehydrogenase', 'Gene', (120, 143))	('SDH', 'Gene', '6390', (145, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('Familial pheochromocytoma/paraganglioma syndromes', 'Disease', (0, 49))	('Familial pheochromocytoma/paraganglioma syndromes', 'Disease', 'MESH:C531777', (0, 49))	('genetic disorders', 'Disease', (75, 92))	('SDH', 'Gene', (145, 148))	('genetic disorders', 'Disease', 'MESH:D030342', (75, 92))	('succinate dehydrogenase', 'Gene', '6390', (120, 143))
36218	31672301	Germline mutations in SDH genes are responsible for approximately 10% of sporadic PPGLs, 30% of pediatric cases, and more than 80% of familial collections of PPGLs.	('Germline mutations', 'Var', (0, 18))	('responsible', 'Reg', (36, 47))	('PPGLs', 'Chemical', '-', (82, 87))	('PPGLs', 'Chemical', '-', (158, 163))	('SDH', 'Gene', '6390', (22, 25))	('PPGLs', 'Disease', (82, 87))	('SDH', 'Gene', (22, 25))
36221	31672301	Among these, the major PGL syndromes are caused by mutations of the SDHB (PGL4), SDHD (PGL1) and SDHC (PGL3) subunits.	('mutations', 'Var', (51, 60))	('PGL4', 'Gene', (74, 78))	('SDHB', 'Gene', '6390', (68, 72))	('PGL4', 'Gene', '6390', (74, 78))	('SDHD', 'Gene', '6392', (81, 85))	('SDHC', 'Gene', (97, 101))	('SDHC', 'Gene', '6391', (97, 101))	('PGL3', 'Gene', '6391', (103, 107))	('SDHB', 'Gene', (68, 72))	('PGL syndromes', 'Disease', (23, 36))	('SDHD', 'Gene', (81, 85))	('PGL3', 'Gene', (103, 107))	('caused by', 'Reg', (41, 50))
36225	31672301	The risk of malignancy varies significantly based on the mutated SDH subunit.	('SDH', 'Gene', '6390', (65, 68))	('SDH', 'Gene', (65, 68))	('malignancy', 'Disease', 'MESH:D009369', (12, 22))	('malignancy', 'Disease', (12, 22))	('mutated', 'Var', (57, 64))
36226	31672301	In PGL4-related tumors, mutation in SDHB is associated with the worst prognosis because at least 30% of these neoplasms metastasize or show extensive multifocality (Fig.	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('SDHB', 'Gene', '6390', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('SDHB', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('neoplasm', 'Phenotype', 'HP:0002664', (110, 118))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mutation', 'Var', (24, 32))	('PGL4', 'Gene', '6390', (3, 7))	('PGL4', 'Gene', (3, 7))	('tumors', 'Disease', (16, 22))	('neoplasms metastasize', 'Disease', 'MESH:D009362', (110, 131))	('neoplasms metastasize', 'Disease', (110, 131))
36228	31672301	Among them, catecholamine hypersecretion, histologic parameters, SDHB mutation, methylation patterns, infiltrative growth, incomplete resection, and metastatic disease all contribute to increased morbidity and mortality.	('catecholamine hypersecretion', 'MPA', (12, 40))	('mortality', 'Disease', (210, 219))	('methylation', 'MPA', (80, 91))	('increased', 'PosReg', (186, 195))	('mortality', 'Disease', 'MESH:D003643', (210, 219))	('SDHB', 'Gene', '6390', (65, 69))	('catecholamine', 'Chemical', 'MESH:D002395', (12, 25))	('mutation', 'Var', (70, 78))	('metastatic disease', 'CPA', (149, 167))	('SDHB', 'Gene', (65, 69))
36229	31672301	The presence of metastases worsens the prognosis by decreasing the overall 5-year survival rate to less than 60%.	('presence', 'Var', (4, 12))	('decreasing', 'NegReg', (52, 62))	('metastases', 'Disease', 'MESH:D009362', (16, 26))	('metastases', 'Disease', (16, 26))
36241	32511227	MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens.	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (19, 49))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promote', 'PosReg', (50, 57))	('MYO5B', 'Gene', (0, 5))	('paraganglioma', 'Phenotype', 'HP:0002668', (213, 226))	('PPGL', 'Chemical', '-', (228, 232))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (19, 35))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (106, 112))	('MYO5B', 'Gene', '4645', (0, 5))	('pheochromocytoma/paraganglioma', 'Disease', (19, 49))	('paraganglioma', 'Phenotype', 'HP:0002668', (36, 49))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (192, 226))	('cancer', 'Disease', (58, 64))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (192, 208))	('mutations', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
36242	32511227	We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL.	('MYO5B', 'Gene', (68, 73))	('metastatic PPGL', 'Disease', (82, 97))	('nonsynonymous mutations', 'Var', (37, 60))	('PPGL', 'Chemical', '-', (93, 97))
36243	32511227	Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status.	('mutations', 'Var', (55, 64))	('PPGL tumor', 'Disease', 'MESH:D009369', (107, 117))	('MYO5B', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PPGL tumor', 'Disease', (107, 117))
36245	32511227	In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation.	('paraganglioma', 'Disease', (198, 211))	('protein', 'Protein', (47, 54))	('altered', 'Reg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MYO5B:p.G1611S', 'Var', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('paraganglioma', 'Disease', 'MESH:D010235', (198, 211))	('tumors', 'Disease', (117, 123))	('MYO5B', 'Gene', (41, 46))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('MYO5B:p.G1611S', 'SUBSTITUTION', 'None', (232, 246))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('subcellular localization', 'MPA', (13, 37))
36246	32511227	In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A.	('MYO5A', 'Gene', '4644', (190, 195))	('mutations', 'Var', (160, 169))	('MYO5B', 'Gene', (42, 47))	('PPGL', 'Chemical', '-', (83, 87))	('MYO5A', 'Gene', (190, 195))	('mutations', 'Var', (48, 57))
36247	32511227	The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293).	('neuroblastoma', 'Disease', 'MESH:D009447', (211, 224))	('p.L587P', 'Mutation', 'rs750054708', (71, 78))	('embryonic kidney', 'Disease', 'MESH:D007674', (245, 261))	('p.R1641C', 'Var', (93, 101))	('neuroblastoma', 'Disease', (211, 224))	('MYO5B', 'Gene', (10, 15))	('p.G1611S', 'Var', (80, 88))	('p.L587P', 'Var', (71, 78))	('p.G1611S', 'Mutation', 'rs748242455', (80, 88))	('neuroblastoma', 'Phenotype', 'HP:0003006', (211, 224))	('embryonic kidney', 'Disease', (245, 261))	('HEK293', 'CellLine', 'CVCL:0045', (269, 275))	('SK-N-AS', 'Chemical', '-', (232, 239))	('human', 'Species', '9606', (205, 210))	('p.R1641C', 'Mutation', 'rs780999931', (93, 101))
36248	32511227	In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones.	('rat', 'Species', '10116', (56, 59))	('mutated', 'Var', (87, 94))	('proliferation rate', 'CPA', (49, 67))	('increased', 'PosReg', (39, 48))	('rat', 'Species', '10116', (63, 66))	('MYO5B', 'Gene', (81, 86))
36249	32511227	The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate.	('rat', 'Species', '10116', (103, 106))	('migration rate', 'CPA', (93, 107))	('p.G1611S', 'Var', (51, 59))	('p.L587P', 'Mutation', 'rs750054708', (39, 46))	('increase', 'PosReg', (80, 88))	('p.G1611S', 'Mutation', 'rs748242455', (51, 59))	('p.L587P', 'Var', (39, 46))	('rat', 'Species', '10116', (96, 99))
36250	32511227	Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis.	('migration', 'CPA', (126, 135))	('glucose metabolism', 'Disease', (167, 185))	('rat', 'Species', '10116', (129, 132))	('rat', 'Species', '10116', (144, 147))	('rat', 'Species', '10116', (74, 77))	('mutants', 'Var', (29, 36))	('glucose metabolism', 'Disease', 'MESH:D044882', (167, 185))	('MYO5B', 'Gene', (23, 28))	('proliferation', 'CPA', (137, 150))
36251	32511227	Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.	('proliferation', 'CPA', (68, 81))	('MYO5', 'Gene', '4644', (49, 53))	('migration', 'CPA', (86, 95))	('mutations', 'Var', (55, 64))	('rat', 'Species', '10116', (75, 78))	('MYO5', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('rat', 'Species', '10116', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('MYO5', 'Gene', (113, 117))	('MYO5', 'Gene', '4644', (113, 117))	('involved', 'Reg', (132, 140))	('PPGL tumors', 'Disease', (178, 189))	('PPGL tumors', 'Disease', 'MESH:D009369', (178, 189))
36254	32511227	We have recently discovered novel missense mutations in the non-conventional myosin 5 gene (MYO5B), an endosomal transport protein, which we now show enhances progression and migration in PPGLs.	('myosin', 'Gene', '79784', (77, 83))	('missense mutations', 'Var', (34, 52))	('enhances', 'PosReg', (150, 158))	('PPGLs', 'Chemical', '-', (188, 193))	('rat', 'Species', '10116', (178, 181))	('MYO5B', 'Gene', (92, 97))	('myosin', 'Gene', (77, 83))
36255	32511227	MYO5B mutations were preferentially found in patients with metastatic disease and SDH deficiency (germline SDHB-mutations).	('MYO5B', 'Gene', (0, 5))	('SDHB', 'Gene', (107, 111))	('found', 'Reg', (36, 41))	('metastatic disease and SDH deficiency', 'Disease', 'MESH:C538445', (59, 96))	('patients', 'Species', '9606', (45, 53))	('SDHB', 'Gene', '6390', (107, 111))	('mutations', 'Var', (6, 15))
36257	32511227	Since the MYO5B mutations were found to drive progression through downstream up-regulation of glucose metabolism genes, e.g.	('MYO5B', 'Gene', (10, 15))	('mutations', 'Var', (16, 25))	('glucose metabolism', 'Disease', 'MESH:D044882', (94, 112))	('up-regulation', 'PosReg', (77, 90))	('glucose metabolism', 'Disease', (94, 112))
36258	32511227	glucagon, we hypothesize that these mutations may fuel the pseudohypoxic state by altering glucose uptake in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('glucose uptake', 'MPA', (91, 105))	('glucagon', 'Gene', '2641', (0, 8))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (36, 45))	('pseudohypoxic state', 'MPA', (59, 78))	('glucose', 'Chemical', 'MESH:D005947', (91, 98))	('fuel', 'PosReg', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('glucagon', 'Gene', (0, 8))	('altering', 'Reg', (82, 90))
36268	32511227	Inherited mutations have been identified in more than 14 genes, most commonly in VHL, SDHB, SDHD, NF1, and RET.	('SDHB', 'Gene', (86, 90))	('SDHD', 'Gene', '6392', (92, 96))	('VHL', 'Gene', (81, 84))	('RET', 'Gene', '5979', (107, 110))	('SDHD', 'Gene', (92, 96))	('VHL', 'Gene', '7428', (81, 84))	('NF1', 'Gene', (98, 101))	('NF1', 'Gene', '4763', (98, 101))	('RET', 'Gene', (107, 110))	('mutations', 'Var', (10, 19))	('SDHB', 'Gene', '6390', (86, 90))
36269	32511227	The most frequently mutated genes in PPGL belong to a wide range of functional classes, including kinase receptor and signaling (RET, NF1, HRAS, and MAX); energy metabolism (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH); cellular response to hypoxia (VHL, and EPAS1 (also known as HIF2A)); endosomal signaling (TMEM127), and chromatin remodeling (ATRX).	('hypoxia', 'Disease', (232, 239))	('TMEM127', 'Gene', (301, 308))	('SDHD', 'Gene', (192, 196))	('NF1', 'Gene', '4763', (134, 137))	('hypoxia', 'Disease', 'MESH:D000860', (232, 239))	('SDHB', 'Gene', '6390', (180, 184))	('RET', 'Gene', (129, 132))	('EPAS1', 'Gene', (250, 255))	('HRAS', 'Gene', '3265', (139, 143))	('SDHAF2', 'Gene', (198, 204))	('NF1', 'Gene', (134, 137))	('TMEM127', 'Gene', '55654', (301, 308))	('SDHAF2', 'Gene', '54949', (198, 204))	('ATRX', 'Gene', (337, 341))	('SDHC', 'Gene', (186, 190))	('HRAS', 'Gene', (139, 143))	('VHL', 'Gene', (241, 244))	('ATRX', 'Gene', '546', (337, 341))	('SDHA', 'Gene', (198, 202))	('mutated', 'Var', (20, 27))	('SDHA', 'Gene', (174, 178))	('endosomal signaling', 'MPA', (280, 299))	('SDHB', 'Gene', (180, 184))	('SDHA', 'Gene', '6389', (198, 202))	('HIF2A', 'Gene', '2034', (271, 276))	('SDHA', 'Gene', '6389', (174, 178))	('cellular', 'MPA', (211, 219))	('HIF2A', 'Gene', (271, 276))	('VHL', 'Gene', '7428', (241, 244))	('EPAS1', 'Gene', '2034', (250, 255))	('PPGL', 'Gene', (37, 41))	('PPGL', 'Chemical', '-', (37, 41))	('SDHD', 'Gene', '6392', (192, 196))	('chromatin remodeling', 'CPA', (315, 335))	('RET', 'Gene', '5979', (129, 132))	('SDHC', 'Gene', '6391', (186, 190))	('energy metabolism', 'MPA', (155, 172))
36271	32511227	Several additional genes have been recently reported, and the identification of more tumor-driving genes and mutations in PPGL could facilitate diagnosis, treatment decision, and may provide new therapeutic options for patients.	('tumor', 'Disease', (85, 90))	('PPGL', 'Chemical', '-', (122, 126))	('PPGL', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('facilitate', 'PosReg', (133, 143))
36272	32511227	Through large-scale sequencing of PPGLs, we recently reported recurrent mutations in the actin-dependent motor Myosin Vb gene; MYO5B (Fig 1).	('mutations', 'Var', (72, 81))	('Myosin Vb', 'Gene', (111, 120))	('MYO5B', 'Gene', (127, 132))	('; MYO5B', 'Gene', (125, 132))	('PPGLs', 'Chemical', '-', (34, 39))	('Myosin Vb', 'Gene', '4645', (111, 120))	('PPGLs', 'Gene', (34, 39))	('reported', 'Reg', (53, 61))
36273	32511227	Out of five novel nonsynonymous mutations identified, two somatically derived MYO5B variants (NP_001073936: p.L587P and p.G1611S) were found in metastatic sympathetic PGL cases from our data set.	('p.G1611S', 'Mutation', 'rs748242455', (120, 128))	('found', 'Reg', (135, 140))	('p.L587P', 'Var', (108, 115))	('p.L587P', 'SUBSTITUTION', 'None', (108, 115))	('metastatic sympathetic PGL', 'Disease', (144, 170))	('MYO5B', 'Gene', (78, 83))	('p.G1611S', 'Var', (120, 128))
36274	32511227	Further screening of two public PPGL data sets revealed three additional MYO5B mutations; one germline mutation in a metastatic PCC (p.R1641C), and two mutations in PCC tumor cases with metastatic potential (PASS score = 10) or metastasized disease (p.V1261G and p.D530E respectively).	('PCC', 'Gene', '1421', (165, 168))	('mutations', 'Var', (79, 88))	('metastasized disease', 'Disease', 'MESH:D009362', (228, 248))	('p.V1261G', 'Mutation', 'rs925774656', (250, 258))	('p.R1641C', 'Mutation', 'rs780999931', (133, 141))	('PPGL', 'Chemical', '-', (32, 36))	('metastatic potential', 'CPA', (186, 206))	('PCC', 'Gene', (128, 131))	('p.R1641C', 'Var', (133, 141))	('PCC tumor', 'Disease', 'OMIM:115700', (165, 174))	('PCC', 'Gene', '1421', (128, 131))	('p.D530E', 'Mutation', 'rs200469007', (263, 270))	('MYO5B', 'Gene', (73, 78))	('p.V1261G', 'Var', (250, 258))	('PCC tumor', 'Disease', (165, 174))	('metastasized disease', 'Disease', (228, 248))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PCC', 'Gene', (165, 168))	('p.D530E', 'Var', (263, 270))
36275	32511227	In addition, a novel somatic nonsynonymous mutation in isoform MYO5A (NP_000250.3: p.E926G) was discovered in a PCC tumor sample of our data set.	('MYO5A', 'Gene', (63, 68))	('p.E926G', 'Var', (83, 90))	('MYO5A', 'Gene', '4644', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PCC tumor', 'Disease', (112, 121))	('p.E926G', 'SUBSTITUTION', 'None', (83, 90))	('PCC tumor', 'Disease', 'OMIM:115700', (112, 121))
36279	32511227	Loss-of-function mutations in MYO5B are common in microvillus inclusion disease (MVID) and cause disruption of cell polarity.	('Loss-of-function', 'NegReg', (0, 16))	('MVID', 'Disease', (81, 85))	('MVID', 'Disease', 'MESH:C537470', (81, 85))	('microvillus inclusion disease', 'Disease', (50, 79))	('mutations', 'Var', (17, 26))	('MYO5B', 'Gene', (30, 35))
36281	32511227	For example, MYO5A expression is increased in a number of highly metastatic cancer cell lines and metastatic colorectal cancer tissues, and epigenetic downregulation of MYO5B has been reported to promote proliferation, invasion and migration in gastric cancer.	('MYO5A', 'Gene', (13, 18))	('gastric cancer', 'Disease', (245, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (120, 126))	('epigenetic downregulation', 'Var', (140, 165))	('invasion', 'CPA', (219, 227))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (19, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (245, 259))	('proliferation', 'CPA', (204, 217))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('MYO5A', 'Gene', '4644', (13, 18))	('MYO5B', 'Gene', (169, 174))	('colorectal cancer', 'Disease', (109, 126))	('rat', 'Species', '10116', (211, 214))	('rat', 'Species', '10116', (235, 238))	('promote', 'PosReg', (196, 203))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (245, 259))	('increased', 'PosReg', (33, 42))	('cancer', 'Disease', (253, 259))	('cancer', 'Disease', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('migration', 'CPA', (232, 241))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))
36282	32511227	Additionally, MYO5B mutations and methylation-independent loss of MYO5B expression that matched disease progression was recently reported in colorectal cancer.	('loss', 'NegReg', (58, 62))	('MYO5B', 'Gene', (14, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('expression', 'MPA', (72, 82))	('MYO5B', 'Gene', (66, 71))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (20, 29))
36283	32511227	Mutations identified in PPGL cases are located in three domains of the MYO5B protein; the ATP dependent actin binding motor domain (p.D530E and p.L587P), coiled-coil rod domain mediating dimerization of motor protein and RAB8 binding (p.V1261G), and at the C-terminal globular tail domain that mediates cargo interactions and RAB11 binding (p.G1611S and p.R1641C).	('binding', 'Interaction', (332, 339))	('p.D530E', 'Mutation', 'rs200469007', (132, 139))	('p.G1611S', 'Var', (341, 349))	('p.G1611S', 'Mutation', 'rs748242455', (341, 349))	('mediates', 'Reg', (294, 302))	('RAB11', 'Gene', (326, 331))	('RAB8', 'Gene', '4218', (221, 225))	('globular tail', 'Phenotype', 'HP:0002825', (268, 281))	('binding', 'Interaction', (226, 233))	('p.L587P', 'Var', (144, 151))	('p.D530E', 'Var', (132, 139))	('p.L587P', 'Mutation', 'rs750054708', (144, 151))	('RAB11', 'Gene', '8766', (326, 331))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('PPGL', 'Chemical', '-', (24, 28))	('p.R1641C', 'Mutation', 'rs780999931', (354, 362))	('PPGL', 'Gene', (24, 28))	('p.V1261G', 'Var', (235, 243))	('p.R1641C', 'Var', (354, 362))	('interactions', 'Interaction', (309, 321))	('RAB8', 'Gene', (221, 225))	('p.V1261G', 'Mutation', 'rs925774656', (235, 243))
36284	32511227	By functional prediction software, all five missense mutations were predicted to have an impact on the protein function, and none of the PPGL mutations were overlapping with previous reported MYO5B mutation spectra in colorectal cancer or MVID (Fig 1).	('colorectal cancer', 'Disease', (218, 235))	('missense mutations', 'Var', (44, 62))	('MVID', 'Disease', 'MESH:C537470', (239, 243))	('PPGL', 'Chemical', '-', (137, 141))	('impact', 'Reg', (89, 95))	('PPGL', 'Gene', (137, 141))	('protein function', 'MPA', (103, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (218, 235))	('colorectal cancer', 'Phenotype', 'HP:0003003', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('MVID', 'Disease', (239, 243))
36290	32511227	The strongest and most aberrant MYO5B expression pattern was observed in case CPN8 harboring the p.G1611S MYO5B mutation (Fig 2A).	('MYO5B', 'Protein', (32, 37))	('expression', 'MPA', (38, 48))	('p.G1611S', 'Var', (97, 105))	('p.G1611S', 'Mutation', 'rs748242455', (97, 105))	('MYO5B', 'Gene', (106, 111))
36294	32511227	This difference was mainly due to two metastatic cases (CPN4 and CPN8) showing a 10-fold higher MYO5B expression than the non-metastatic cases, and interestingly, these were the same two cases showing an aberrant membranous staining by IHC (Fig 2B).	('CPN8', 'Var', (65, 69))	('expression', 'MPA', (102, 112))	('MYO5B', 'Protein', (96, 101))	('higher', 'PosReg', (89, 95))	('CPN4', 'Gene', '131034', (56, 60))	('CPN4', 'Gene', (56, 60))
36296	32511227	Mutation analysis of 40 genes by exome sequencing, and complementary Multiplex Ligation-dependent Probe Amplification (MLPA) analysis of 6 genes, identified a causative PPGL mutation in 23 out of 30 cases; 6 RET-mutated, 3 NF1-mutated, 4 VHL-mutated, 2 HRAS-mutated, 6 SDHx-mutated (SDHA, -B, -C, and -D), and 2 EPAS1-mutated tumors (Table 1; S1 Table and S2 Table).	('NF1', 'Gene', '4763', (223, 226))	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('VHL', 'Gene', '7428', (238, 241))	('RET', 'Gene', '5979', (208, 211))	('SDHx-mutated (SDHA, -B, -C, and -D', 'Gene', '6389', (269, 303))	('NF1', 'Gene', (223, 226))	('tumors', 'Disease', (326, 332))	('EPAS1', 'Gene', (312, 317))	('PPGL', 'Gene', (169, 173))	('PPGL', 'Chemical', '-', (169, 173))	('RET', 'Gene', (208, 211))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (326, 332))	('VHL', 'Gene', (238, 241))	('EPAS1', 'Gene', '2034', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('causative', 'Reg', (159, 168))	('HRAS', 'Gene', '3265', (253, 257))	('HRAS', 'Gene', (253, 257))
36298	32511227	Mutations in RET, NF1, VHL, and HRAS were solely found in patients with PCC tumors, while mutations in SDH-genes were mainly found in patients with PGL tumors or metastatic PCC (Table 1).	('VHL', 'Gene', (23, 26))	('PGL tumors', 'Disease', (148, 158))	('patients', 'Species', '9606', (134, 142))	('PGL tumors', 'Disease', 'MESH:D010235', (148, 158))	('SDH', 'Gene', '6390', (103, 106))	('PCC tumors', 'Disease', 'OMIM:115700', (72, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', '7428', (23, 26))	('RET', 'Gene', '5979', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('found', 'Reg', (49, 54))	('HRAS', 'Gene', '3265', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HRAS', 'Gene', (32, 36))	('SDH', 'Gene', (103, 106))	('patients', 'Species', '9606', (58, 66))	('PCC', 'Gene', (72, 75))	('PCC', 'Gene', (173, 176))	('NF1', 'Gene', '4763', (18, 21))	('found', 'Reg', (125, 130))	('RET', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('PCC', 'Gene', '1421', (72, 75))	('PCC', 'Gene', '1421', (173, 176))	('PCC tumors', 'Disease', (72, 82))	('NF1', 'Gene', (18, 21))
36301	32511227	This pattern could either be due to loss of the SDHB-region, or chromosome 1p-deletion which is a classical somatic event in PPGL.	('loss', 'NegReg', (36, 40))	('chromosome 1p-deletion', 'Var', (64, 86))	('SDHB', 'Gene', '6390', (48, 52))	('PPGL', 'Chemical', '-', (125, 129))	('SDHB', 'Gene', (48, 52))
36302	32511227	Also, in CPN93 presenting syndromic NF1, a deletion of the whole NF1 gene was detected, This is most probably a secondary inactivation event occurring after a primary NF1 mutation, whichever could not be detected in the current analysis.	('NF1', 'Gene', (36, 39))	('NF1', 'Gene', '4763', (36, 39))	('deletion', 'Var', (43, 51))	('NF1', 'Gene', (167, 170))	('NF1', 'Gene', '4763', (167, 170))	('NF1', 'Gene', (65, 68))	('NF1', 'Gene', '4763', (65, 68))
36303	32511227	In sample CPN81, a RET mutation (p.C609Y) was found at an allele frequency (AF) of 0.98, indicating a loss of heterozygosity of the wild type allele in the tumor tissue.	('RET', 'Gene', (19, 22))	('p.C609Y', 'Mutation', 'rs77939446', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AF', 'Disease', 'MESH:D001281', (76, 78))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('RET', 'Gene', '5979', (19, 22))	('tumor', 'Disease', (156, 161))	('p.C609Y', 'Var', (33, 40))
36305	32511227	Somatic mutations in 8 cases (CPN1-9) have been previously reported, and in the current study including 22 additional cases the following new mutations were identified: ARNT:p.Q391K, MYO5A:p.P1194Q, MYO9B:p.H1726Y and SLC25A11:p.A200S.	('MYO5A:p.P1194Q', 'Var', (183, 197))	('MYO9B:p.H1726Y', 'Var', (199, 213))	('CPN1-9', 'Gene', (30, 36))	('ARNT:p.Q391K', 'Var', (169, 181))	('CPN1-9', 'Gene', '1369;1370;8895;131034;57699', (30, 36))	('MYO5A:p.P1194Q', 'SUBSTITUTION', 'None', (183, 197))	('ARNT:p.Q391K', 'SUBSTITUTION', 'None', (169, 181))	('MYO9B:p.H1726Y', 'SUBSTITUTION', 'None', (199, 213))	('SLC25A11:p.A200S', 'Var', (218, 234))	('SLC25A11:p.A200S', 'SUBSTITUTION', 'None', (218, 234))
36306	32511227	Hence, by this study we have also identified the MYO5A gene as recurrently mutated in PPGLs; MYO5A:p.E926G previously identified in case CPN1 (somatic, AF = 0.29,) and MYO5A:p.P1194Q identified in case CPN29 (somatic, AF = 0.25; S2 Table).	('MYO5A:p.E926G', 'SUBSTITUTION', 'None', (93, 106))	('MYO5A', 'Gene', (168, 173))	('MYO5A', 'Gene', (93, 98))	('CPN1', 'Gene', '1369', (137, 141))	('CPN1', 'Gene', (137, 141))	('MYO5A', 'Gene', (49, 54))	('MYO5A', 'Gene', '4644', (168, 173))	('MYO5A', 'Gene', '4644', (49, 54))	('AF', 'Disease', 'MESH:D001281', (218, 220))	('PPGLs', 'Chemical', '-', (86, 91))	('AF', 'Disease', 'MESH:D001281', (152, 154))	('MYO5A', 'Gene', '4644', (93, 98))	('MYO5A:p.P1194Q', 'Var', (168, 182))	('MYO5A:p.P1194Q', 'SUBSTITUTION', 'None', (168, 182))	('MYO5A:p.E926G', 'Var', (93, 106))
36307	32511227	In addition, a third MYO5A missense mutation, NM_000259.3: c.5065G>A, p.V1689I was identified in case CPN15 (germline, AF = 0.51), but this variant was filtered out due to presence in normal population (AF = 0.23% in Genome Aggregation Database (gnomAD) ALL).	('AF', 'Disease', 'MESH:D001281', (119, 121))	('AF', 'Disease', 'MESH:D001281', (203, 205))	('c.5065G>A', 'SUBSTITUTION', 'None', (59, 68))	('MYO5A', 'Gene', (21, 26))	('CPN1', 'Gene', '1369', (102, 106))	('c.5065G>A', 'Var', (59, 68))	('CPN1', 'Gene', (102, 106))	('MYO5A', 'Gene', '4644', (21, 26))	('p.V1689I', 'Var', (70, 78))	('p.V1689I', 'Mutation', 'rs143298463', (70, 78))
36308	32511227	All three MYO5A mutations were predicted to be damaging by at least 2 out of 3 functional prediction algorithms (i.e.	('MYO5A', 'Gene', (10, 15))	('MYO5A', 'Gene', '4644', (10, 15))	('mutations', 'Var', (16, 25))
36311	32511227	In addition, the CPN4 case, harboring a SDHA promoter mutation, showed a unique expression profile which did not fit well into any of the major PPGL expression subgroups (S2 Fig).	('mutation', 'Var', (54, 62))	('SDHA', 'Gene', '6389', (40, 44))	('CPN4', 'Gene', (17, 21))	('expression', 'MPA', (80, 90))	('SDHA', 'Gene', (40, 44))	('PPGL', 'Chemical', '-', (144, 148))	('CPN4', 'Gene', '131034', (17, 21))
36312	32511227	The SDHA promotor mutation (c.-7A>C, p.?	('c.-7A>C', 'Mutation', 'rs751633537', (28, 35))	('SDHA', 'Gene', (4, 8))	('SDHA', 'Gene', '6389', (4, 8))	('c.-7A>C', 'Var', (28, 35))
36313	32511227	Three previously identified MYO5B missense mutations were selected based on theoretical prediction as damaging/deleterious/disease causing; c.1760T>C, p.L597P; c.4831G>A, p.G1611S; c.4921C>T, p.R1641C (NM_001080467) (Fig 1).	('MYO5B', 'Gene', (28, 33))	('p.R1641C', 'Mutation', 'rs780999931', (192, 200))	('p.G1611S; c.4921C>T', 'Var', (171, 190))	('c.4921C>T', 'Var', (181, 190))	('c.1760T>C', 'Var', (140, 149))	('c.1760T>C', 'Mutation', 'rs750054708', (140, 149))	('c.4831G>A', 'Mutation', 'rs748242455', (160, 169))	('p.L597P', 'Mutation', 'rs750054708', (151, 158))	('p.R1641C', 'Var', (192, 200))	('c.4921C>T', 'Mutation', 'rs780999931', (181, 190))	('p.G1611S', 'Mutation', 'rs748242455', (171, 179))	('c.4831G>A', 'Var', (160, 169))
36314	32511227	Stable clones of MYO5B mutants, MYO5B wildtype (WT) and empty vector constructs were generated in SK-N-AS and HEK293 cells.	('SK-N-AS', 'Chemical', '-', (98, 105))	('MYO5B', 'Gene', (17, 22))	('rat', 'Species', '10116', (89, 92))	('HEK293', 'CellLine', 'CVCL:0045', (110, 116))	('mutants', 'Var', (23, 30))
36315	32511227	Western blot analysis of constructs showed a 230 kDa band representing endogenous expressed MYO5B protein, and 260 kDa band corresponding the additional size of the Myc-DKK-tag in transfected wildtype and mutated MYO5B proteins (Fig 3A).	('Myc', 'Gene', '4609', (165, 168))	('Myc', 'Gene', (165, 168))	('mutated', 'Var', (205, 212))
36317	32511227	By immunofluorescence the protein expression of mutated MYO5B (FLAG-tagged) showed a scattered cytoplasmic staining in small punctate spots, presumably localized to endosomal vesicles, in HEK293 cells (Fig 3B).	('HEK293', 'CellLine', 'CVCL:0045', (188, 194))	('MYO5B', 'Gene', (56, 61))	('mutated', 'Var', (48, 55))
36318	32511227	In order to assess the functional impact of the three MYO5B mutations in cultured, stably transfected cell lines, we investigated their ability to affect proliferation, migration and endosomal recycling.	('MYO5B', 'Gene', (54, 59))	('endosomal recycling', 'CPA', (183, 202))	('migration', 'CPA', (169, 178))	('rat', 'Species', '10116', (172, 175))	('rat', 'Species', '10116', (161, 164))	('mutations', 'Var', (60, 69))	('proliferation', 'CPA', (154, 167))	('affect', 'Reg', (147, 153))
36319	32511227	A significant increased proliferation (p<0.05) was found in all the three MYO5B mutations at 48h (p.L587P 1.8 fold; p.G1611S 1.6 fold; p.R1641C 1.7 fold), and the first and second mutations were also significant at 72h (p.L587P 2.1 fold; p.G1611S 1.9 fold) compared to MYO5BWT and empty vector clones (Fig 4A).	('increased', 'PosReg', (14, 23))	('proliferation', 'CPA', (24, 37))	('mutations', 'Var', (80, 89))	('p.G1611S', 'Var', (238, 246))	('p.R1641C', 'Var', (135, 143))	('p.L587P', 'Mutation', 'rs750054708', (98, 105))	('p.G1611S', 'Mutation', 'rs748242455', (238, 246))	('p.L587P', 'Mutation', 'rs750054708', (220, 227))	('MYO5B', 'Gene', (74, 79))	('p.G1611S', 'Var', (116, 124))	('p.R1641C', 'Mutation', 'rs780999931', (135, 143))	('rat', 'Species', '10116', (31, 34))	('p.G1611S', 'Mutation', 'rs748242455', (116, 124))
36320	32511227	The scratch-wound assay showed an increased migration rate of p.L587P and p.G1611S mutants with only 10% of the wound starting area remaining after 24 h, compared to MYO5BWT cells having 22% of the wound starting area remaining (Fig 4B).	('p.L587P', 'Var', (62, 69))	('rat', 'Species', '10116', (54, 57))	('rat', 'Species', '10116', (47, 50))	('p.G1611S', 'Var', (74, 82))	('migration rate', 'CPA', (44, 58))	('p.L587P', 'Mutation', 'rs750054708', (62, 69))	('rat', 'Species', '10116', (6, 9))	('p.G1611S', 'Mutation', 'rs748242455', (74, 82))	('increased', 'PosReg', (34, 43))
36323	32511227	By visual inspection and fluorescence measurement of transferrin (Tf), the MYO5B mutations displayed a somewhat higher transferrin uptake (1.5-2 fold), most apparent in the cells harboring the p.L587P and p.G1611S mutations (Fig 4C).	('p.L587P', 'Mutation', 'rs750054708', (193, 200))	('higher', 'PosReg', (112, 118))	('p.G1611S', 'Var', (205, 213))	('transferrin', 'Gene', '7018', (53, 64))	('p.L587P', 'Var', (193, 200))	('p.G1611S', 'Mutation', 'rs748242455', (205, 213))	('transferrin', 'Gene', (53, 64))	('Tf', 'Gene', '7018', (66, 68))	('mutations', 'Var', (81, 90))	('transferrin', 'Gene', '7018', (119, 130))	('MYO5B', 'Gene', (75, 80))	('transferrin', 'Gene', (119, 130))
36324	32511227	However, by relating the transferrin uptake to its receptor (TfR), the p.G1611S and p.R1641C mutants were found to express the transferrin receptor in almost the same proportion as transferrin, leaving p.L587P as the only mutation with slight impact on endosomal transport of transferrin (Fig 4C).	('p.R1641C', 'Mutation', 'rs780999931', (84, 92))	('transferrin', 'Gene', '7018', (127, 138))	('transferrin', 'Gene', '7018', (25, 36))	('transferrin', 'Gene', '7018', (181, 192))	('transferrin', 'Gene', (25, 36))	('transferrin', 'Gene', (181, 192))	('transferrin', 'Gene', '7018', (276, 287))	('endosomal transport', 'MPA', (253, 272))	('TfR', 'Gene', (61, 64))	('p.R1641C', 'Var', (84, 92))	('transferrin', 'Gene', (276, 287))	('p.L587P', 'Mutation', 'rs750054708', (202, 209))	('p.G1611S', 'Var', (71, 79))	('p.G1611S', 'Mutation', 'rs748242455', (71, 79))	('TfR', 'Gene', '7037', (61, 64))	('transferrin', 'Gene', (127, 138))	('p.L587P', 'Var', (202, 209))
36325	32511227	To elucidate the signaling pathways associated with MYO5B mutations in more detail, a transcriptome microarray analysis was performed in SK-N-AS constructs from three time points of proliferation (24h, 48h, and 72h) and from two replicated experiments.	('MYO5B', 'Gene', (52, 57))	('mutations', 'Var', (58, 67))	('SK-N-AS', 'Chemical', '-', (137, 144))	('rat', 'Species', '10116', (189, 192))
36326	32511227	Next, the top-ranked differentially expressed genes from all three MYO5B mutants were filtered out, and analyzed for enrichment of cellular processes using the Gene Ontology tool GOrilla (http://cbl-gorilla.cs.technion.ac.il) (S5 Table).	('GOrilla', 'Disease', (179, 186))	('gorilla', 'Species', '9593', (199, 206))	('GOrilla', 'Disease', 'None', (179, 186))	('mutants', 'Var', (73, 80))	('MYO5B', 'Gene', (67, 72))
36329	32511227	Moreover, Gene Set Enrichment Analysis (GSEA) was performed on each MYO5B mutant's merged gene list (ranked after mean fold change) analyzing 236 Hallmark and KEGG curated gene sets from the Molecular Signature database (http://software.broadinstitute.org/gsea/msigdb/index.jsp).	('MYO5B', 'Gene', (68, 73))	('rat', 'Species', '10116', (166, 169))	('msigdb', 'Disease', (261, 267))	('mutant', 'Var', (74, 80))	('msigdb', 'Disease', 'None', (261, 267))
36330	32511227	The most enriched gene sets in the three MYO5B mutants were the following four up-regulated: "Hallmark Myc targets v1", "KEGG Base excision repair", "KEGG Basal transcription factors", "Hallmark E2F targets", and four down-regulated: "Hallmark TNFA Signaling via NFKB", "Hallmark Inflammatory response", "KEGG ECM Receptor interaction", "KEGG Arrhythmogenic right ventricular cardiomyopathy ARVC" (S7 Table).	('ventricular cardiomyopathy ARVC', 'Disease', 'MESH:C566255', (364, 395))	('up-regulated', 'PosReg', (79, 91))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (376, 390))	('Myc', 'Gene', '4609', (103, 106))	('MYO5B', 'Gene', (41, 46))	('ventricular cardiomyopathy ARVC', 'Disease', (364, 395))	('Myc', 'Gene', (103, 106))	('right ventricular cardiomyopathy', 'Phenotype', 'HP:0011663', (358, 390))	('mutants', 'Var', (47, 54))	('down-regulated', 'NegReg', (218, 232))
36333	32511227	The highest fold change (DeltaDeltaCt >1.5 in at least 3/4 passages) for all three MYO5B mutants was found in three up-regulated genes: ARMCX2 (armadillo repeat containing X-linked 2), GCG (glucagon), INSM2 (insulin transcriptional repressor 2); and in four down-regulated genes: COL4A1 (Collagen Type IV Alpha 1 Chain), DLX5 (distal-less homeobox 5), IGFBP7 (insulin like growth factor binding protein 7), and POSTN (Periostin) (Fig 5; Table 2).	('COL4A1', 'Gene', (280, 286))	('MYO5B', 'Gene', (83, 88))	('IGFBP7', 'Gene', (352, 358))	('Collagen Type IV Alpha 1 Chain', 'Gene', (288, 318))	('DLX5', 'Gene', '1749', (321, 325))	('insulin', 'Gene', '3630', (360, 367))	('Periostin', 'Gene', '10631', (418, 427))	('insulin', 'Gene', '3630', (208, 215))	('mutants', 'Var', (89, 96))	('up-regulated', 'PosReg', (116, 128))	('INSM2', 'Gene', '84684', (201, 206))	('IGFBP7', 'Gene', '3490', (352, 358))	('Periostin', 'Gene', (418, 427))	('ARMCX2', 'Gene', (136, 142))	('distal-less homeobox 5', 'Gene', '1749', (327, 349))	('armadillo repeat containing X-linked 2', 'Gene', (144, 182))	('distal-less homeobox 5', 'Gene', (327, 349))	('glucagon', 'Gene', (190, 198))	('COL4A1', 'Gene', '1282', (280, 286))	('armadillo repeat containing X-linked 2', 'Gene', '9823', (144, 182))	('insulin like growth factor binding protein 7', 'Gene', (360, 404))	('POSTN', 'Gene', (411, 416))	('insulin', 'Gene', (360, 367))	('insulin like growth factor binding protein 7', 'Gene', '3490', (360, 404))	('Collagen Type IV Alpha 1 Chain', 'Gene', '1282', (288, 318))	('INSM2', 'Gene', (201, 206))	('ARMCX2', 'Gene', '9823', (136, 142))	('insulin', 'Gene', (208, 215))	('DLX5', 'Gene', (321, 325))	('POSTN', 'Gene', '10631', (411, 416))	('GCG', 'Gene', '2641', (185, 188))	('glucagon', 'Gene', '2641', (190, 198))	('GCG', 'Gene', (185, 188))
36334	32511227	Glucagon (GCG) and the insulin transcriptional repressor 2 (INSM2) were undoubtedly the two most up-regulated genes in all the three MYO5B mutants, with mean fold change of 7 and 14 respectively (Table 2).	('Glucagon', 'Gene', '2641', (0, 8))	('INSM2', 'Gene', '84684', (60, 65))	('INSM2', 'Gene', (60, 65))	('insulin', 'Gene', (23, 30))	('up-regulated', 'PosReg', (97, 109))	('insulin', 'Gene', '3630', (23, 30))	('GCG', 'Gene', '2641', (10, 13))	('mutants', 'Var', (139, 146))	('Glucagon', 'Gene', (0, 8))	('MYO5B', 'Gene', (133, 138))	('GCG', 'Gene', (10, 13))
36335	32511227	Analyzing GCG or INSM2 in primary tumors harboring MYO5B mutations (i.e.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('INSM2', 'Gene', (17, 22))	('MYO5B', 'Gene', (51, 56))	('INSM2', 'Gene', '84684', (17, 22))	('mutations', 'Var', (57, 66))	('GCG', 'Gene', '2641', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('GCG', 'Gene', (10, 13))
36338	32511227	However, a heat map of the MYO5B mutation associated gene transcripts revealed a differential expression between the two major subtypes of PPGLs (S3A Fig).	('PPGLs', 'Chemical', '-', (139, 144))	('differential', 'Reg', (81, 93))	('mutation', 'Var', (33, 41))	('MYO5B', 'Gene', (27, 32))	('expression', 'MPA', (94, 104))
36343	32511227	We have previously published a study identifying novel recurrent MYO5B mutations in metastatic PPGL.	('metastatic PPGL', 'Disease', (84, 99))	('PPGL', 'Chemical', '-', (95, 99))	('mutations', 'Var', (71, 80))	('MYO5B', 'Gene', (65, 70))
36344	32511227	Here, we functionally verified the tumorigenic properties of three of these mutations by in-vitro studies in SK-N-AS and HEK293 cell lines.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('HEK293', 'CellLine', 'CVCL:0045', (121, 127))	('SK-N-AS', 'Chemical', '-', (109, 116))
36346	32511227	Also, analyses in primary tumors revealed differential expression and altered sub-cellular localization of the MYO5B protein in metastatic PPGL, and mutation screening of additional PPGL cases identified recurrent mutations in the MYO5A paralog.	('MYO5A', 'Gene', '4644', (231, 236))	('altered', 'Reg', (70, 77))	('PPGL', 'Chemical', '-', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (214, 223))	('sub-cellular localization', 'MPA', (78, 103))	('MYO5A', 'Gene', (231, 236))	('expression', 'MPA', (55, 65))	('MYO5B', 'Gene', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PPGL', 'Chemical', '-', (182, 186))	('mutation', 'Var', (149, 157))	('PPGL', 'Gene', (182, 186))	('tumors', 'Disease', (26, 32))
36348	32511227	Mutations in MYO5B have been shown to disrupt cellular polarity in MVID.	('MYO5B', 'Gene', (13, 18))	('disrupt', 'NegReg', (38, 45))	('cellular polarity', 'CPA', (46, 63))	('MVID', 'Disease', 'MESH:C537470', (67, 71))	('Mutations', 'Var', (0, 9))	('MVID', 'Disease', (67, 71))
36353	32511227	Low protein levels of MYO5B has been shown to be associated with motility of gastric cells, and expression level and mutations in MYO5B has been reported as a powerful prognostic biomarker in colorectal cancer, which might help to stratifying patients for adjuvant therapy.	('mutations', 'Var', (117, 126))	('protein levels', 'MPA', (4, 18))	('colorectal cancer', 'Disease', (192, 209))	('patients', 'Species', '9606', (243, 251))	('associated', 'Reg', (49, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (192, 209))	('colorectal cancer', 'Disease', 'MESH:D015179', (192, 209))	('rat', 'Species', '10116', (233, 236))	('expression level', 'MPA', (96, 112))	('motility of gastric cells', 'CPA', (65, 90))	('Low', 'NegReg', (0, 3))	('MYO5B', 'Gene', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
36355	32511227	Moreover, an altered subcellular localization of the MYO5B protein to the membrane was observed in three metastatic cases, and the most prominent abnormal pattern was observed in the tumor case harboring the p.G1611S mutation.	('subcellular localization', 'MPA', (21, 45))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('MYO5B protein', 'Protein', (53, 66))	('p.G1611S', 'Var', (208, 216))	('p.G1611S', 'Mutation', 'rs748242455', (208, 216))	('altered', 'Reg', (13, 20))
36357	32511227	The tumorigenic properties of the MYO5B mutations were demonstrated by a significantly increased proliferation rate for all three missense mutations (p.L587P, p.G1611S and p.R1641C).	('tumor', 'Disease', (4, 9))	('increased', 'PosReg', (87, 96))	('rat', 'Species', '10116', (111, 114))	('p.R1641C', 'Var', (172, 180))	('p.G1611S', 'Var', (159, 167))	('MYO5B', 'Gene', (34, 39))	('p.L587P', 'Mutation', 'rs750054708', (150, 157))	('p.G1611S', 'Mutation', 'rs748242455', (159, 167))	('proliferation rate', 'CPA', (97, 115))	('p.R1641C', 'Mutation', 'rs780999931', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('p.L587P', 'Var', (150, 157))	('rat', 'Species', '10116', (62, 65))	('rat', 'Species', '10116', (104, 107))
36358	32511227	Furthermore, the p.L587P and p.G1611S mutations both showed increased migratory properties, and consistently the most significantly enriched GO-term among the differentially expressed genes in MYO5B-mutants was "positive regulation of migration".	('p.L587P', 'Mutation', 'rs750054708', (17, 24))	('p.G1611S', 'Var', (29, 37))	('MYO5B-mutants', 'Gene', (193, 206))	('p.G1611S', 'Mutation', 'rs748242455', (29, 37))	('migratory properties', 'CPA', (70, 90))	('p.L587P', 'Var', (17, 24))	('increased', 'PosReg', (60, 69))	('rat', 'Species', '10116', (73, 76))	('rat', 'Species', '10116', (238, 241))
36359	32511227	With regard to the p.R1641C, it appears that this mutation had less effect on proliferation compared to the other two MYO5B mutations, and also did not increase migration.	('increase', 'PosReg', (152, 160))	('rat', 'Species', '10116', (85, 88))	('p.R1641C', 'Var', (19, 27))	('rat', 'Species', '10116', (164, 167))	('migration', 'CPA', (161, 170))	('p.R1641C', 'Mutation', 'rs780999931', (19, 27))
36360	32511227	This is possibly due to the fact that p.R1641C was identified as a germline mutation in the primary case, while p.L587P and p.G1611S were originally discovered as somatic mutations.	('p.R1641C', 'Var', (38, 46))	('p.G1611S', 'Var', (124, 132))	('p.L587P', 'Mutation', 'rs750054708', (112, 119))	('p.G1611S', 'Mutation', 'rs748242455', (124, 132))	('p.R1641C', 'Mutation', 'rs780999931', (38, 46))	('p.L587P', 'Var', (112, 119))
36362	32511227	Although a moderately higher transferrin uptake in all three MYO5B mutants was observed, only p.L587P showed a slight effect on transferrin uptake after normalization to the transferrin receptor expression.	('higher', 'PosReg', (22, 28))	('rat', 'Species', '10116', (15, 18))	('p.L587P', 'Var', (94, 101))	('transferrin', 'Gene', '7018', (128, 139))	('transferrin', 'Gene', (128, 139))	('transferrin', 'Gene', '7018', (29, 40))	('p.L587P', 'Mutation', 'rs750054708', (94, 101))	('transferrin', 'Gene', (29, 40))	('transferrin', 'Gene', '7018', (174, 185))	('transferrin', 'Gene', (174, 185))	('MYO5B', 'Gene', (61, 66))
36363	32511227	Since the p.L587P is located in the actin binding myosin head, while p.G1611S and p.R1641C are located in the tail domain mediating Rab11 binding, the mechanisms may differ, which could also explain the different influence on transferrin receptor expression.	('myosin', 'Gene', (50, 56))	('p.G1611S', 'Var', (69, 77))	('p.R1641C', 'Mutation', 'rs780999931', (82, 90))	('p.L587P', 'Var', (10, 17))	('p.G1611S', 'Mutation', 'rs748242455', (69, 77))	('myosin', 'Gene', '79784', (50, 56))	('binding', 'Interaction', (138, 145))	('Rab11', 'Gene', '8766', (132, 137))	('p.R1641C', 'Var', (82, 90))	('p.L587P', 'Mutation', 'rs750054708', (10, 17))	('Rab11', 'Gene', (132, 137))
36364	32511227	Taken together, the functional in vitro studies of MYO5B mutations suggests a gain of function or a dominant negative role of the mutants, enhancing mainly proliferation and migration.	('rat', 'Species', '10116', (163, 166))	('gain of function', 'PosReg', (78, 94))	('rat', 'Species', '10116', (177, 180))	('proliferation', 'CPA', (156, 169))	('MYO5B', 'Gene', (51, 56))	('mutations', 'Var', (57, 66))	('enhancing', 'PosReg', (139, 148))	('migration', 'CPA', (174, 183))
36365	32511227	The downstream transcriptome analysis of transfected SK-N-AS MYO5B-mutants showed a differential expression of genes involved in cell growth and proliferation, cell migration, cell adhesion, endosomal transport and glucose metabolism.	('MYO5B-mutants', 'Var', (61, 74))	('rat', 'Species', '10116', (152, 155))	('glucose metabolism', 'Disease', (215, 233))	('SK-N-AS', 'Chemical', '-', (53, 60))	('cell growth', 'CPA', (129, 140))	('cell adhesion', 'CPA', (176, 189))	('rat', 'Species', '10116', (168, 171))	('MYO5B-mutants', 'Gene', (61, 74))	('cell migration', 'CPA', (160, 174))	('glucose metabolism', 'Disease', 'MESH:D044882', (215, 233))	('expression', 'MPA', (97, 107))
36367	32511227	Also, IGFBP7 (insulin-like growth factor binding protein 7), has been reported as epigenetically down-regulated and an independent prognostic factor in gastric cancer, leading to increased cell growth, invasion and migration.	('cell growth', 'CPA', (189, 200))	('IGFBP7', 'Gene', (6, 12))	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('gastric cancer', 'Disease', (152, 166))	('insulin-like growth factor binding protein 7', 'Gene', (14, 58))	('epigenetically', 'Var', (82, 96))	('IGFBP7', 'Gene', '3490', (6, 12))	('insulin-like growth factor binding protein 7', 'Gene', '3490', (14, 58))	('rat', 'Species', '10116', (218, 221))	('invasion', 'CPA', (202, 210))	('migration', 'CPA', (215, 224))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('increased', 'PosReg', (179, 188))	('down-regulated', 'NegReg', (97, 111))
36368	32511227	Moreover, deletion of IGFBP7 was found to increase proliferation in hepatocellular carcinoma by a constitutively active IGF signaling.	('IGFBP7', 'Gene', '3490', (22, 28))	('increase', 'PosReg', (42, 50))	('IGFBP7', 'Gene', (22, 28))	('proliferation', 'CPA', (51, 64))	('IGF signaling', 'MPA', (120, 133))	('rat', 'Species', '10116', (58, 61))	('deletion', 'Var', (10, 18))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (68, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('hepatocellular carcinoma', 'Disease', (68, 92))
36372	32511227	Most conspicuous was the 14-fold increase in expression of INSM2 (insulin transcriptional repressor 2) and the 7-fold increase in expression of GCG (glucagon) in all three MYO5B mutants.	('expression', 'MPA', (130, 140))	('glucagon', 'Gene', (149, 157))	('increase', 'PosReg', (118, 126))	('INSM2', 'Gene', '84684', (59, 64))	('INSM2', 'Gene', (59, 64))	('MYO5B', 'Gene', (172, 177))	('increase', 'PosReg', (33, 41))	('insulin', 'Gene', (66, 73))	('expression', 'MPA', (45, 55))	('GCG', 'Gene', '2641', (144, 147))	('glucagon', 'Gene', '2641', (149, 157))	('insulin', 'Gene', '3630', (66, 73))	('mutants', 'Var', (178, 185))	('GCG', 'Gene', (144, 147))
36374	32511227	Deletion of Insm2 in mice resulted in reduced insulin secretion and glucose intolerance.	('Insm2', 'Gene', (12, 17))	('glucose intolerance', 'Phenotype', 'HP:0001952', (68, 87))	('mice', 'Species', '10090', (21, 25))	('Insm2', 'Gene', '56856', (12, 17))	('reduced insulin secretion and glucose intolerance', 'Disease', 'MESH:D054971', (38, 87))	('Deletion', 'Var', (0, 8))
36379	32511227	Thus, the increased proliferation rate seen in the MYO5B mutants might be driven through altered energy metabolisms.	('altered', 'Reg', (89, 96))	('MYO5B', 'Gene', (51, 56))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (34, 37))	('mutants', 'Var', (57, 64))	('proliferation rate', 'CPA', (20, 38))	('increased', 'PosReg', (10, 19))	('energy', 'MPA', (97, 103))
36383	32511227	Provocative tests using glucagon has previously been performed in patients with undiscovered PPGLs, and these tests have been reported to lead to multi-organ failure or hypertensive emergency in some cases.	('hypertensive emergency', 'Phenotype', 'HP:0100735', (169, 191))	('glucagon', 'Gene', '2641', (24, 32))	('multi-organ failure', 'Disease', 'MESH:D009102', (146, 165))	('tests', 'Var', (110, 115))	('patients', 'Species', '9606', (66, 74))	('hypertensive', 'Disease', 'MESH:D006973', (169, 181))	('multi-organ failure', 'Disease', (146, 165))	('PPGLs', 'Chemical', '-', (93, 98))	('glucagon', 'Gene', (24, 32))	('lead to', 'Reg', (138, 145))	('hypertensive', 'Disease', (169, 181))	('PPGLs', 'Gene', (93, 98))
36386	32511227	An increasing number of studies show dysregulation of the MYO5-pathway in tumorigenesis and malignancy.	('dysregulation', 'Var', (37, 50))	('MYO5', 'Gene', '4644', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MYO5', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('malignancy', 'Disease', 'MESH:D009369', (92, 102))	('tumor', 'Disease', (74, 79))	('malignancy', 'Disease', (92, 102))
36387	32511227	In the present study we have functionally verified the tumorigenic role of three novel MYO5B mutations through their impact on proliferation and migration.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('proliferation', 'CPA', (127, 140))	('mutations', 'Var', (93, 102))	('rat', 'Species', '10116', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('MYO5B', 'Gene', (87, 92))	('tumor', 'Disease', (55, 60))	('impact', 'Reg', (117, 123))	('rat', 'Species', '10116', (134, 137))
36403	32511227	The 22 new cases were sequenced by SureSelect v3/v5 (Agilent Technologies, CA) with paired-end (2*75-100bp) on a HiScanSQ (CPN10-15) or by SureSelect Clinical Research Exome v2 (CREv2; CPN16-CPN123), paired-end (2*100bp) on a NextSeq500 illumina sequencer.	('CPN1', 'Gene', (191, 195))	('CPN1', 'Gene', '1369', (123, 127))	('CPN1', 'Gene', (123, 127))	('CPN1', 'Gene', '1369', (185, 189))	('CPN1', 'Gene', (185, 189))	('CPN1', 'Gene', '1369', (191, 195))	('2*75-100bp', 'Var', (96, 106))
36404	32511227	Only variants predicted to be damaging by functional prediction algorithms and/or previously reported in ClinVar (www.ncbi.nlm.nih.gov/clinvar/) or HGMD (portal.biobase-international.com) databases were included in the final mutation list (S2 Table).	('HGMD', 'Disease', 'None', (148, 152))	('variants', 'Var', (5, 13))	('HGMD', 'Disease', (148, 152))
36405	32511227	Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001001601 (8 previous PPGL samples) and EGAS00001003991 (22 new PPGL samples).	('EGAS00001003991', 'Var', (188, 203))	('EGAS00001001601', 'Var', (142, 157))	('PPGL', 'Chemical', '-', (170, 174))	('EBI', 'Gene', (102, 105))	('CRG', 'Gene', (114, 117))	('CRG', 'Gene', '55636', (114, 117))	('EBI', 'Gene', '6907', (102, 105))	('PPGL', 'Chemical', '-', (212, 216))
36407	32511227	Nine cases with no apparent disease-associated pathogenic mutation by sequencing where further analyzed for exon/gene deletions or duplications by MLPA in 6 genes; SDHA, SDHB, SDHC, SDHD, NF1, and VHL.	('SDHB', 'Gene', '6390', (170, 174))	('SDHD', 'Gene', '6392', (182, 186))	('VHL', 'Gene', (197, 200))	('SDHA', 'Gene', (164, 168))	('MLPA', 'Gene', (147, 151))	('SDHB', 'Gene', (170, 174))	('VHL', 'Gene', '7428', (197, 200))	('NF1', 'Gene', (188, 191))	('SDHC', 'Gene', (176, 180))	('NF1', 'Gene', '4763', (188, 191))	('SDHC', 'Gene', '6391', (176, 180))	('SDHA', 'Gene', '6389', (164, 168))	('duplications', 'Var', (131, 143))	('SDHD', 'Gene', (182, 186))
36408	32511227	MLPA was performed on tumor DNA using the following four SALSA MLPA kits; P081-D1 & P082-C2 (NF1), P226-D1 (SDHx), and P016-C2 (VHL) (MRC-Holland www.mrcholland.com).	('SDH', 'Gene', '6390', (108, 111))	('NF1', 'Gene', '4763', (93, 96))	('VHL', 'Gene', '7428', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('and P016-C2', 'Var', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('SDH', 'Gene', (108, 111))	('tumor', 'Disease', (22, 27))	('VHL', 'Gene', (128, 131))	('P081-D1 &', 'Var', (74, 83))	('NF1', 'Gene', (93, 96))
36410	32511227	The full coding sequence of MYO5B wild type (NM_001080467) and MYO5B sequences harboring the three point mutations c.1760T>C (p.L597P), c.4831G>A (p.G1611S) and c.4921C>T (p.R1641C) were synthesized and cloned into the pCMV6 vector, and tagged with Myc-DKK tag by Invitrogen GeneART (Thermo Fisher Scientific).	('p.G1611S', 'Mutation', 'rs748242455', (147, 155))	('c.4831G>A', 'Mutation', 'rs748242455', (136, 145))	('c.4921C>T', 'Var', (161, 170))	('c.4831G>A', 'Var', (136, 145))	('p.L597P', 'Mutation', 'rs750054708', (126, 133))	('p.R1641C', 'Mutation', 'rs780999931', (172, 180))	('c.4921C>T', 'Mutation', 'rs780999931', (161, 170))	('c.1760T>C', 'Mutation', 'rs750054708', (115, 124))	('c.1760T>C', 'Var', (115, 124))	('Myc', 'Gene', '4609', (249, 252))	('Myc', 'Gene', (249, 252))
36411	32511227	Five vector constructs; pCMV6-Myc-DDK (empty vector), pCMV6-MYO5B-Myc-DDK (MYO5BWT), pCMV6-MYO5B_L587P-Myc-DDK (p.L587P), pCMV6-MYO5B_G1611S-Myc-DDK (p.G1611S), and pCMV6-MYO5B_R1646C-Myc-DDK (p.R1641C) were sub-cloned and verified by DNA Sanger sequencing (GeneArt Gene Synthesis, Invitrogen, ThemoFisher Scientific).	('p.G1611S', 'Mutation', 'rs748242455', (150, 158))	('Myc', 'Gene', (30, 33))	('R1646C', 'Mutation', 'p.R1646C', (177, 183))	('p.L587P', 'Mutation', 'rs750054708', (112, 119))	('Myc', 'Gene', '4609', (141, 144))	('L587P', 'Mutation', 'rs750054708', (97, 102))	('L587P', 'Mutation', 'rs750054708', (114, 119))	('Myc', 'Gene', (66, 69))	('Myc', 'Gene', '4609', (66, 69))	('Myc', 'Gene', '4609', (103, 106))	('Myc', 'Gene', (141, 144))	('p.R1641C', 'Mutation', 'rs780999931', (193, 201))	('Myc', 'Gene', (103, 106))	('Myc', 'Gene', '4609', (184, 187))	('Myc', 'Gene', '4609', (30, 33))	('p.G1611S', 'Var', (150, 158))	('Myc', 'Gene', (184, 187))
36414	32511227	Five constructs per cell line were made; MYO5BWT, p.L587P, p.G1611S, p.R1641C, and empty vector.	('p.R1641C', 'Var', (69, 77))	('p.G1611S', 'Var', (59, 67))	('p.L587P', 'Mutation', 'rs750054708', (50, 57))	('p.G1611S', 'Mutation', 'rs748242455', (59, 67))	('p.R1641C', 'Mutation', 'rs780999931', (69, 77))	('p.L587P', 'Var', (50, 57))
36417	32511227	Western blot was performed using antibodies with ECL-detection (Supersignal West Maximum Fempto, Thermo Fisher Scientific) as follows: FLAG-DDK M2 mouse mAb (1:750, #F3165, Sigma Aldrich), GAPDH rabbit Ab (1:500, sc-25778, Santa Cruz Biotechnology), MYO5B Rabbit mAb (1:250, HPA040902, Atlas Antibodies), transferrin receptor (CD71) rabbit mAb (1:500, #13208, Cell Signaling Technology).	('1:750', 'Var', (158, 163))	('mouse', 'Species', '10090', (147, 152))	('CD71', 'Gene', (327, 331))	('CD71', 'Gene', '22042', (327, 331))
36429	32511227	Cells were subsequently incubated for 15 minutes in 20 mug/ml Alexa fluor conjugated 555 human transferrin (T35352, Thermo Fisher) and thereafter fixed for 15 minutes in 4% paraformaldehyde solution (HistoLab).	('T35352', 'Var', (108, 114))	('human', 'Species', '9606', (89, 94))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (173, 189))	('Alexa fluor', 'Chemical', '-', (62, 73))	('transferrin', 'Gene', '7018', (95, 106))	('transferrin', 'Gene', (95, 106))
36433	32511227	Expression analysis was performed with Clariom S arrays for five constructs (empty vector, MYO5BWT, p.L587P, p.G1611S, and p.R1641C) at three time points of proliferation (24h, 48h, 72h) in duplicates by Eurofins Genomics (www.eurofinsgenomics.eu).	('p.R1641C', 'Mutation', 'rs780999931', (123, 131))	('p.L587P', 'Var', (100, 107))	('p.G1611S', 'Var', (109, 117))	('p.G1611S', 'Mutation', 'rs748242455', (109, 117))	('rat', 'Species', '10116', (164, 167))	('p.R1641C', 'Var', (123, 131))	('p.L587P', 'Mutation', 'rs750054708', (100, 107))
36455	32435750	This makes it hard to come to the correct diagnosis prior to surgery, which may result in an unexpected intraoperative hypertensive crisis because of possible catecholamine excess produced by these lesions.	('result in', 'Reg', (80, 89))	('lesions', 'Var', (198, 205))	('catecholamine', 'Chemical', 'MESH:D002395', (159, 172))	('catecholamine excess', 'MPA', (159, 179))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (119, 138))	('hypertensive', 'Disease', 'MESH:D006973', (119, 131))	('catecholamine excess', 'Phenotype', 'HP:0003334', (159, 179))	('hypertensive', 'Disease', (119, 131))
36510	30997073	Paraganglioma of the tongue with SDHB gene mutation in a patient with Graves' disease We report a case of an apparently sporadic paraganglioma of the tongue with a germ-line mutation in a female patient with asymptomatic Graves' disease.	("Graves' disease", 'Disease', (221, 236))	('SDHB', 'Gene', (33, 37))	("Graves' disease", 'Phenotype', 'HP:0100647', (70, 85))	("Graves' disease", 'Phenotype', 'HP:0100647', (221, 236))	('patient', 'Species', '9606', (57, 64))	('mutation', 'Var', (43, 51))	('paraganglioma', 'Disease', (129, 142))	('paraganglioma', 'Disease', 'MESH:D010235', (129, 142))	('Paraganglioma of the tongue', 'Phenotype', 'HP:0100648', (0, 27))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('mutation', 'Var', (174, 182))	('Paraganglioma of the tongue', 'Disease', (0, 27))	('paraganglioma of the tongue', 'Phenotype', 'HP:0100648', (129, 156))	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	("Graves' disease", 'Disease', 'MESH:D006111', (70, 85))	('SDHB', 'Gene', '6390', (33, 37))	('patient', 'Species', '9606', (195, 202))	("Graves' disease", 'Disease', 'MESH:D006111', (221, 236))	("Graves' disease", 'Disease', (70, 85))
36520	30997073	In addition, hereditary susceptibility also includes five familial PGLs syndromes caused by mutation in the succinate dehydrogenase genes (collectively SDHx) that can be screened by immunohistochemistry and identified by sequencing analysis.9, 10 SDHx mutations represent almost 30% of mutated PGLs.	('familial PGLs syndromes', 'Disease', (58, 81))	('PGLs', 'Phenotype', 'HP:0002668', (67, 71))	('succinate', 'Chemical', 'MESH:D019802', (108, 117))	('PGLs', 'Phenotype', 'HP:0002668', (294, 298))	('SDHx', 'Chemical', '-', (247, 251))	('SDHx', 'Gene', (247, 251))	('mutations', 'Var', (252, 261))	('familial PGLs syndromes', 'Disease', 'MESH:D009386', (58, 81))	('PGLs', 'Disease', (294, 298))	('SDHx', 'Chemical', '-', (152, 156))
36533	30997073	Immunohistochemistry and sequencing analysis for SDHx mutations were performed in another center using anti SDH B rabbit polyclonal antibody (Sigma-Aldrich Corp).	('SDH', 'Gene', '6390', (49, 52))	('SDH', 'Gene', '6390', (108, 111))	('rabbit', 'Species', '9986', (114, 120))	('Sigma-Aldrich Corp', 'Disease', 'MESH:D014923', (142, 160))	('mutations', 'Var', (54, 63))	('Sigma-Aldrich Corp', 'Disease', (142, 160))	('SDH', 'Gene', (49, 52))	('SDHx', 'Chemical', '-', (49, 53))	('SDH', 'Gene', (108, 111))
36542	30997073	This result suggested the presence of a mutation in any of the SDHx genes but SDHA.	('mutation', 'Var', (40, 48))	('presence', 'Reg', (26, 34))	('SDHA', 'Gene', '6389', (78, 82))	('SDHx', 'Gene', (63, 67))	('SDHx', 'Chemical', '-', (63, 67))	('SDHA', 'Gene', (78, 82))
36543	30997073	Mutational analysis confirmed a c.689G>A/p.Arg230His mutation in SDHB gene.	('c.689G>A/p.Arg230His', 'Var', (32, 52))	('confirmed', 'Reg', (20, 29))	('SDHB', 'Gene', '6390', (65, 69))	('c.689G>A', 'Mutation', 'rs587782604', (32, 40))	('p.Arg230His', 'Mutation', 'rs587782604', (41, 52))	('SDHB', 'Gene', (65, 69))
36550	30997073	It was identified a germline mutation in SDHB gene that has been described in Mediterranean population carrying a 45% of malignancy risk.19 Germline mutations in SDHx are inherited in an autosomal dominant manner with an age-related penetrance.1, 7, 8 Genetic testing should be performed in all PGLs.	('mutations', 'Var', (149, 158))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('SDHB', 'Gene', (41, 45))	('PGLs', 'Phenotype', 'HP:0002668', (295, 299))	('malignancy', 'Disease', (121, 131))	('SDHB', 'Gene', '6390', (41, 45))	('SDHx', 'Chemical', '-', (162, 166))	('SDHx', 'Gene', (162, 166))
36560	30997073	A potential link between mutated PGL (especially those of the head and neck) and thyroid gland dysfunction requires further investigation.	('thyroid gland dysfunction', 'Disease', 'MESH:D013959', (81, 106))	('mutated', 'Var', (25, 32))	('PGL', 'Protein', (33, 36))	('thyroid gland dysfunction', 'Disease', (81, 106))
36566	30997073	Our case illustrates, to the best of our knowledge, the first reported primary PGL of the tongue with a documented mutation in SDHB gene, in a patient with asymptomatic Graves' disease.	("Graves' disease", 'Disease', (169, 184))	('patient', 'Species', '9606', (143, 150))	('SDHB', 'Gene', '6390', (127, 131))	("Graves' disease", 'Disease', 'MESH:D006111', (169, 184))	('SDHB', 'Gene', (127, 131))	('primary PGL of the tongue', 'Disease', (71, 96))	('mutation', 'Var', (115, 123))	("Graves' disease", 'Phenotype', 'HP:0100647', (169, 184))
36571	30655972	In many of these tumors, several mutations are reported to occur in the genes of germline and/or somatic cells.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('man', 'Species', '9606', (3, 6))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
36577	30655972	Next-generation sequencing revealed several gene mutations and copy number variations, including of fumarate hydratase (FH), neurofibromatosis type-1 (NF1) and RET.	('copy number variations', 'Var', (63, 85))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (125, 142))	('mutations', 'Var', (49, 58))	('neurofibromatosis type-1', 'Gene', (125, 149))	('NF1', 'Gene', (151, 154))	('RET', 'Gene', '5979', (160, 163))	('fumarate hydratase', 'Gene', '2271', (100, 118))	('FH', 'Gene', '2271', (120, 122))	('NF1', 'Gene', '4763', (151, 154))	('fumarate hydratase', 'Gene', (100, 118))	('neurofibromatosis type-1', 'Gene', '4763', (125, 149))	('RET', 'Gene', (160, 163))
36582	30655972	In nonfamilial PCC/PGL tumors, 41% harbored mutations and one-fifth were in germline genes, including multiple mutations.	('PGL', 'Phenotype', 'HP:0002668', (19, 22))	('PGL tumors', 'Disease', 'MESH:D010235', (19, 29))	('harbored', 'Reg', (35, 43))	('PCC', 'Gene', '1421', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (44, 53))	('PGL tumors', 'Disease', (19, 29))	('PCC', 'Gene', (15, 18))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
36586	30655972	The pathogenesis of most GISTs is a mutation in one of two receptor tyrosine kinase genes, kit and platelet-derived growth factor receptor alpha (PDGFRalpha).	('PDGFRalpha', 'Gene', '5156', (146, 156))	('GISTs', 'Disease', (25, 30))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (99, 144))	('GIST', 'Phenotype', 'HP:0100723', (25, 29))	('platelet-derived growth factor receptor alpha', 'Gene', (99, 144))	('PDGFRalpha', 'Gene', (146, 156))	('mutation', 'Var', (36, 44))
36594	30655972	Somatic mutations (single nucleotide mutations, insertions, and deletions) and copy number variations (CNVs) were detected using statistical approaches in tumor and normal samples from the Ion Reporter software 5.0 tumor-normal workflow (Thermo Fisher Scientific).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('deletions', 'Var', (64, 73))	('insertions', 'Var', (48, 58))	('tumor', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))
36595	30655972	Recurrent genomic regions with CNVs were identified using copy numbers greater than 3 and less than 1 for gains and losses, respectively.	('gains', 'Disease', (106, 111))	('copy numbers', 'Var', (58, 70))	('losses', 'NegReg', (116, 122))	('gains', 'Disease', 'MESH:D015430', (106, 111))
36600	30655972	The laboratory findings on admission showed leukocytosis (1,380x106/l) with granulocytosis (1,303x106/l) and hypoalbuminemia (3.6 mg/dl).	('hypoalbuminemia', 'Phenotype', 'HP:0003073', (109, 124))	('granulocytosis', 'Phenotype', 'HP:0032310', (76, 90))	('hypoalbuminemia', 'Disease', (109, 124))	('1,380x106/l', 'Var', (58, 69))	('leukocytosis', 'Disease', 'MESH:D007964', (44, 56))	('leukocytosis', 'Phenotype', 'HP:0001974', (44, 56))	('1,303x106/l', 'Var', (92, 103))	('granulocytosis', 'Disease', (76, 90))	('leukocytosis', 'Disease', (44, 56))	('hypoalbuminemia', 'Disease', 'MESH:D034141', (109, 124))
36614	30655972	Immunohistochemical examination showed that the tumor cells were positive for Ki67 and p53 (Fig.	('tumor', 'Disease', (48, 53))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('positive', 'Reg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Ki67', 'Var', (78, 82))
36620	30655972	Semiconductor-based next-generation sequencing of 409 cancer-related genes showed both germline and somatic mutations and CNVs of genes.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('CNVs of', 'Var', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (54, 60))
36621	30655972	Table II shows that germline heterozygous variants in NF1 (p.Gln27His; c.81G>T) and RET (p.Asn437Lys: c.1311C>G) were found.	('p.Gln27His; c.81G>T', 'Var', (59, 78))	('RET', 'Gene', (84, 87))	('c.81G>T', 'Mutation', 'c.81G>T', (71, 78))	('c.81G>T', 'Var', (71, 78))	('p.Asn437Lys: c.1311C>G', 'Var', (89, 111))	('NF1', 'Gene', (54, 57))	('NF1', 'Gene', '4763', (54, 57))	('p.Gln27His', 'Mutation', 'p.Q27H', (59, 69))	('RET', 'Gene', '5979', (84, 87))	('c.1311C>G', 'Mutation', 'rs1344280904', (102, 111))	('p.Asn437Lys', 'Mutation', 'rs1344280904', (89, 100))
36622	30655972	Moreover, somatic mutations in NF1 (p.Arg1306Gln; c.3917G>A) and FH (p.Ala104Thr; c.310G>A) were identified with frequencies of 29.4 and 28.6%, respectively.	('FH', 'Gene', '2271', (65, 67))	('p.Arg1306Gln', 'Mutation', 'rs1306237220', (36, 48))	('c.3917G>A', 'Mutation', 'rs1306237220', (50, 59))	('p.Ala104Thr', 'Mutation', 'rs1303488878', (69, 80))	('p.Ala104Thr; c.310G>A', 'Var', (69, 90))	('c.3917G>A', 'Var', (50, 59))	('NF1', 'Gene', (31, 34))	('p.Arg1306Gln; c.3917G>A', 'Var', (36, 59))	('NF1', 'Gene', '4763', (31, 34))	('c.310G>A', 'Mutation', 'rs1303488878', (82, 90))
36625	30655972	Genetic mutation profiling of this tumor demonstrated that the tumor had either germline or somatic mutations of NF1, RET, and FH, but not of SDHs, kit or PDGFRa, suggesting the tumor to be PGL, but not of GIST.	('PDGFRa', 'Gene', '5156', (155, 161))	('PGL', 'Phenotype', 'HP:0002668', (190, 193))	('tumor', 'Disease', (178, 183))	('PDGFRa', 'Gene', (155, 161))	('SDH', 'Gene', '6390', (142, 145))	('RET', 'Gene', '5979', (118, 121))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (63, 68))	('NF1', 'Gene', '4763', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SDH', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('RET', 'Gene', (118, 121))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NF1', 'Gene', (113, 116))	('GIST', 'Phenotype', 'HP:0100723', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('FH', 'Gene', '2271', (127, 129))
36640	30655972	In order to identify causal gene mutations for PCC/PGL without a syndromic presentation, next-generation sequencing might be a promising strategy.	('syndromic', 'Disease', (65, 74))	('PCC', 'Gene', (47, 50))	('syndromic', 'Disease', 'MESH:D013577', (65, 74))	('mutations', 'Var', (33, 42))	('PGL', 'Phenotype', 'HP:0002668', (51, 54))	('PCC', 'Gene', '1421', (47, 50))
36641	30655972	Among mutated driver genes for the induction of PGL in the present case, one must consider the possible role of the receptor tyrosine-kinase RET, which showed germline mutation and copy number gain in the tumor cells.	('receptor tyrosine-kinase', 'Gene', '5979', (116, 140))	('RET', 'Gene', '5979', (141, 144))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('receptor tyrosine-kinase', 'Gene', (116, 140))	('gain', 'PosReg', (193, 197))	('copy number', 'Var', (181, 192))	('germline', 'Var', (159, 167))	('tumor', 'Disease', (205, 210))	('RET', 'Gene', (141, 144))	('PGL', 'Phenotype', 'HP:0002668', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))
36648	30655972	Accumulation of multiple gene alterations including NF1, RET, and FH might be responsible for the malignant transformation of PGL in this case.	('NF1', 'Gene', (52, 55))	('FH', 'Gene', '2271', (66, 68))	('NF1', 'Gene', '4763', (52, 55))	('responsible', 'Reg', (78, 89))	('RET', 'Gene', (57, 60))	('PGL', 'Phenotype', 'HP:0002668', (126, 129))	('alterations', 'Var', (30, 41))	('RET', 'Gene', '5979', (57, 60))
36649	30655972	This might be supported by a report that metastatic phenotype and multiple tumors were significantly more frequent in PGL with FH mutations than in those without.	('PGL', 'Disease', (118, 121))	('multiple tumors', 'Disease', (66, 81))	('multiple tumors', 'Disease', 'MESH:D009369', (66, 81))	('frequent', 'Reg', (106, 114))	('mutations', 'Var', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('more', 'PosReg', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('PGL', 'Phenotype', 'HP:0002668', (118, 121))	('FH', 'Gene', '2271', (127, 129))	('metastatic phenotype', 'CPA', (41, 61))
36703	29578356	Stimulation of these receptors causes vasoconstriction and an increase in blood pressure, which may predispose the patient to bleeding from a vascular anomaly as in the present case.	('blood pressure', 'MPA', (74, 88))	('vasoconstriction', 'MPA', (38, 54))	('increase in blood pressure', 'Phenotype', 'HP:0032263', (62, 88))	('Stimulation', 'Var', (0, 11))	('vascular anomaly', 'Disease', 'MESH:D000783', (142, 158))	('increase', 'PosReg', (62, 70))	('patient', 'Species', '9606', (115, 122))	('vascular anomaly', 'Disease', (142, 158))
36711	29628290	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TP53', 'Gene', '7157', (89, 93))	('IDH1', 'Gene', '3417', (66, 70))	('CTNNB1', 'Gene', '1499', (49, 55))	('lower', 'NegReg', (42, 47))	('NRAS', 'Gene', (57, 61))	('mutations', 'Var', (16, 25))	('leukocyte levels', 'MPA', (105, 121))	('higher', 'PosReg', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('CTNNB1', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (83, 87))	('CASP8', 'Gene', '841', (98, 103))	('TP53', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (57, 61))	('IDH1', 'Gene', (66, 70))	('CASP8', 'Gene', (98, 103))
36712	29628290	Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('copy', 'Var', (103, 107))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
36720	29628290	Antibodies against CTLA-4, PD-1, and PD-L1 are effective in treating a variety of malignancies.	('Antibodies', 'Var', (0, 10))	('PD-L1', 'Gene', (37, 42))	('CTLA-4', 'Gene', '1493', (19, 25))	('malignancies', 'Disease', (82, 94))	('PD-1', 'Gene', (27, 31))	('effective', 'Reg', (47, 56))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('CTLA-4', 'Gene', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
36735	29628290	The six resulting clusters "Immune Subtypes", C1-C6 (with 2416, 2591, 2397, 1157, 385 and 180 cases, respectively) were characterized by a distinct distribution of scores over the five representative signatures (Figure 1A, bottom panel), and showed distinct immune signatures based on the dominant sample characteristics of their tumor samples (Figure 1B-C).	('C1-C6', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
36745	29628290	IDH mutations were enriched in C5 over C4 (80% of IDH mutations, p<2x10-16, Fisher's exact test), suggesting an association of IDH-mutations with favorable immune composition.	('association', 'Interaction', (112, 123))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (50, 53))
36758	29628290	The spatial fraction of tumor regions with tumor infiltrating lymphocytes (TILs), estimated by analysis of digitized TCGA H&E stained slides, varied by immune subtype, with C2 the highest (p<10-16, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('with', 'Var', (168, 172))	('H&E', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
36771	29628290	The immune infiltrate was related to measures of DNA damage, including copy number variation (CNV) burden (both in terms of number of segments and fraction of genome alterations), aneuploidy, loss of heterozygosity (LOH), homologous recombination deficiency (HRD), and intratumor heterogeneity (ITH) (Figure 4A).	('aneuploidy', 'Disease', (180, 190))	('loss of heterozygosity', 'Var', (192, 214))	('copy number variation', 'MPA', (71, 92))	('homologous recombination deficiency', 'Disease', (222, 257))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('HRD', 'Disease', (259, 262))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HRD', 'Disease', 'None', (259, 262))	('men', 'Species', '9606', (137, 140))
36772	29628290	LF correlated negatively with CNV segment burden, with strongest correlation in C6 and C2, and positively with aneuploidy, LOH, HRD, and mutation load, particularly in C3.	('HRD', 'Disease', (128, 131))	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('negatively', 'NegReg', (14, 24))	('men', 'Species', '9606', (37, 40))	('HRD', 'Disease', 'None', (128, 131))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('CNV segment burden', 'MPA', (30, 48))	('mutation load', 'Var', (137, 150))
36773	29628290	Chromosome 1p (including TNFRS9 and VTCN1) amplification associated with higher LF, while its deletion did the opposite.	('VTCN1', 'Gene', '79679', (36, 41))	('TNFRS9', 'Gene', (25, 31))	('amplification', 'Var', (43, 56))	('VTCN1', 'Gene', (36, 41))	('higher', 'PosReg', (73, 79))
36775	29628290	Amplification of chr2, 20q, and 22q (including CTLA4, CD40, and ADORA2 respectively), and deletions of 5q, 9p, and chr19 (including IL13 and IL4, IFNA1 and IFNA2, and ICAM1 respectively) associated with changes in macrophage polarity (Figure S4A).	('macrophage polarity', 'CPA', (214, 233))	('IFNA1', 'Gene', '3439', (146, 151))	('ADORA2', 'Gene', (64, 70))	('chr19', 'Gene', (115, 120))	('CTLA4', 'Gene', (47, 52))	('chr2', 'Gene', (17, 21))	('IL13', 'Gene', (132, 136))	('ICAM1', 'Gene', (167, 172))	('deletions', 'Var', (90, 99))	('ICAM1', 'Gene', '3383', (167, 172))	('IFNA2', 'Gene', (156, 161))	('CD40', 'Gene', (54, 58))	('IFNA2', 'Gene', '3440', (156, 161))	('associated', 'Reg', (187, 197))	('changes', 'Reg', (203, 210))	('ADORA2', 'Gene', '135', (64, 70))	('IFNA1', 'Gene', (146, 151))	('CD40', 'Gene', '958', (54, 58))	('IL4', 'Gene', '3565', (141, 144))	('IL4', 'Gene', (141, 144))	('IL13', 'Gene', '3596', (132, 136))	('CTLA4', 'Gene', '1493', (47, 52))
36776	29628290	IL-13 influences macrophage polarization, implying a possible basis for our observation that IL13 deletions associated with altered M0 macrophage fractions.	('IL-13', 'Gene', '3596', (0, 5))	('influences', 'Reg', (6, 16))	('IL13', 'Gene', (93, 97))	('IL13', 'Gene', '3596', (93, 97))	('macrophage polarization', 'CPA', (17, 40))	('IL-13', 'Gene', (0, 5))	('deletions', 'Var', (98, 107))
36779	29628290	We correlated mutations in 299 cancer driver genes with immune subtypes, and found 33 significant associations (q<0.1) (Figure 4C, Table S2).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('associations', 'Interaction', (98, 110))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (14, 23))
36780	29628290	C1 was enriched in mutations in driver genes, such as TP53, PIK3CA, PTEN or KRAS.	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', (54, 58))
36782	29628290	C3 was enriched in BRAF, CDH1 and PBRM1 mutations, a finding of note since patients with PBRM1 mutations respond particularly well to IM therapy.	('BRAF', 'Gene', '673', (19, 23))	('CDH1', 'Gene', '999', (25, 29))	('BRAF', 'Gene', (19, 23))	('PBRM1', 'Gene', (89, 94))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (89, 94))	('PBRM1', 'Gene', '55193', (34, 39))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (25, 29))
36783	29628290	C4 was enriched in CTNNB1, EGFR, and IDH1 mutations.	('CTNNB1', 'Gene', (19, 25))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('IDH1', 'Gene', (37, 41))	('CTNNB1', 'Gene', '1499', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (42, 51))
36785	29628290	C6 only showed an enrichment in KRAS G12 mutations.	('mutations', 'Var', (41, 50))	('men', 'Species', '9606', (24, 27))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
36786	29628290	Mutations in 23 driver genes associated with increased LF either in specific tumor types or across them, including TP53, HLA-B, BRAF, PTEN, NF1, APC and CASP8.	('BRAF', 'Gene', '673', (128, 132))	('HLA-B', 'Gene', '3106', (121, 126))	('HLA-B', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', '5728', (134, 138))	('tumor type', 'Disease', (77, 87))	('NF1', 'Gene', (140, 143))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (115, 119))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('tumor type', 'Disease', 'MESH:D009369', (77, 87))	('NF1', 'Gene', '4763', (140, 143))	('CASP8', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CASP8', 'Gene', '841', (153, 158))	('APC', 'Disease', (145, 148))	('PTEN', 'Gene', (134, 138))	('BRAF', 'Gene', (128, 132))
36787	29628290	Twelve other events were associated with lower LF, including the IDH1 R132H mutation, GATA3, KRAS, NRAS, CTNNB1 and NOTCH1 (Figure 4D).	('IDH1', 'Gene', '3417', (65, 69))	('GATA3', 'Gene', (86, 91))	('R132H', 'Var', (70, 75))	('KRAS', 'Gene', (93, 97))	('NOTCH1', 'Gene', '4851', (116, 122))	('NOTCH1', 'Gene', (116, 122))	('R132H', 'Mutation', 'rs121913500', (70, 75))	('GATA3', 'Gene', '2625', (86, 91))	('lower', 'NegReg', (41, 46))	('KRAS', 'Gene', '3845', (93, 97))	('CTNNB1', 'Gene', '1499', (105, 111))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))	('IDH1', 'Gene', (65, 69))	('CTNNB1', 'Gene', (105, 111))
36789	29628290	PI3K, NOTCH and RTK/RAS pathway disruptions showed variable, tumor type specific effects on immune factors, while TGF-beta pathway disruptions more consistently associated with lower LF (most prominently in C2 and C6; Figure S4C), higher eosinophils (C2), and increased macrophages.	('lower', 'NegReg', (177, 182))	('TGF-beta', 'Gene', '7040', (114, 122))	('disruptions', 'Var', (131, 142))	('disruptions', 'Var', (32, 43))	('RTK/RAS pathway', 'Gene', (16, 31))	('increased', 'PosReg', (260, 269))	('eosinophils', 'MPA', (238, 249))	('higher', 'PosReg', (231, 237))	('TGF-beta', 'Gene', (114, 122))	('tumor type', 'Disease', (61, 71))	('eosin', 'Chemical', 'MESH:D004801', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor type', 'Disease', 'MESH:D009369', (61, 71))	('macrophages', 'CPA', (270, 281))
36791	29628290	Thus, TGF-beta pathway disruption has context-dependent effects on LF, but may promote increased macrophages, particularly M1.	('TGF-beta', 'Gene', (6, 14))	('disruption', 'Var', (23, 33))	('macrophages', 'CPA', (97, 108))	('promote increased', 'PosReg', (79, 96))	('TGF-beta', 'Gene', '7040', (6, 14))
36797	29628290	No single cis-eQTL significantly correlated with PD-L1 expression, although the SNP rs822337, approximately 1KB upstream of CD274 transcription start, correlated weakly (p=0.074;1.3x10-4 unadjusted; Figure S4G).	('CD274', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (49, 54))	('CD274', 'Gene', '29126', (124, 129))	('rs822337', 'Var', (84, 92))	('PD-L1', 'Gene', (49, 54))	('rs822337', 'Mutation', 'rs822337', (84, 92))
36798	29628290	Lymphocyte fractions tended to be lower in people of Asian ancestry, particularly in UCEC and BLCA (Figure S4H).	('BLCA', 'Disease', (94, 98))	('lower', 'NegReg', (34, 39))	('Asian ancestry', 'Var', (53, 67))	('Lymphocyte fractions', 'CPA', (0, 20))	('UCEC', 'Disease', (85, 89))	('people', 'Species', '9606', (43, 49))	('BLCA', 'Chemical', '-', (94, 98))
36799	29628290	Peptides predicted to bind with MHC proteins (pMHCs) and induce antitumor adaptive immunity were identified from SNV and indel mutations.	('tumor', 'Disease', (68, 73))	('MHC proteins', 'Protein', (32, 44))	('indel mutations', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bind', 'Interaction', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induce', 'PosReg', (57, 63))
36801	29628290	Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Tregs, mast, dendritic, and memory B cells in multiple tumor types (Figure S4K).	('content', 'MPA', (44, 51))	('CD8', 'Gene', '925', (55, 58))	('higher', 'PosReg', (37, 43))	('CD4 memory T cells', 'CPA', (88, 106))	('tumor type', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor type', 'Disease', 'MESH:D009369', (173, 183))	('CD8', 'Gene', (55, 58))	('Neoantigen load', 'Var', (0, 15))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('multiple tumor', 'Disease', (164, 178))	('Tregs', 'CPA', (118, 123))	('lower', 'NegReg', (112, 117))
36809	29628290	In a regression model of all tumors, high load of each virus type associated with immune features (Figure S5C, cancer-type adjusted).	('tumors', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('immune', 'Disease', (82, 88))	('associated', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high load', 'Var', (37, 46))
36828	29628290	CD40 (Figure 6C), IL10 and IDO1, inversely correlated with gene expression, suggesting epigenetic silencing.	('CD40', 'Gene', (0, 4))	('IDO1', 'Gene', (27, 31))	('IL10', 'Gene', (18, 22))	('IL10', 'Gene', '3586', (18, 22))	('correlated', 'Reg', (43, 53))	('gene expression', 'MPA', (59, 74))	('epigenetic silencing', 'Var', (87, 107))	('IDO1', 'Gene', '3620', (27, 31))	('CD40', 'Gene', '958', (0, 4))
36831	29628290	In particular, IMs SLAMF7, SELP, TNFSF4 (OX40L), IL10, and CD40 were amplified less frequently in C5 relative to all samples, while TGFB1, KIR2DL1, and KIR2DL3 deletions were enriched in C5 (Figure 6D), consistent with our observation of lower immune infiltration with TGFB1 deletion (Figure S4A).	('CD40', 'Gene', (59, 63))	('IL10', 'Gene', '3586', (49, 53))	('TGFB1', 'Gene', '7040', (269, 274))	('TGFB1', 'Gene', (269, 274))	('SELP', 'Gene', '6403', (27, 31))	('CD40', 'Gene', '958', (59, 63))	('TNFSF4', 'Gene', '7292', (33, 39))	('SELP', 'Gene', (27, 31))	('TGFB1', 'Gene', '7040', (132, 137))	('deletion', 'Var', (275, 283))	('KIR2DL1', 'Gene', '3802', (139, 146))	('TGFB1', 'Gene', (132, 137))	('OX40L', 'Gene', (41, 46))	('KIR2DL3', 'Gene', (152, 159))	('TNFSF4', 'Gene', (33, 39))	('KIR2DL3', 'Gene', '3804', (152, 159))	('lower', 'NegReg', (238, 243))	('IL10', 'Gene', (49, 53))	('SLAMF7', 'Gene', '57823', (19, 25))	('KIR2DL1', 'Gene', (139, 146))	('OX40L', 'Gene', '7292', (41, 46))	('SLAMF7', 'Gene', (19, 25))
36845	29628290	Some T cell associated ligands were subtype specific, such as CD276 (C2, C6), IL1B (C6), and VEGFB (C4).	('VEGFB', 'Gene', '7423', (93, 98))	('IL1B', 'Gene', (78, 82))	('VEGFB', 'Gene', (93, 98))	('IL1B', 'Gene', '3553', (78, 82))	('CD276', 'Var', (62, 67))
36850	29628290	Somatic alterations in AKAP9, HRAS, KRAS and PREX2 were inferred to modulate the activity of IMs according to both the MR- and SYGNAL-PanImmune, a significant overlap (p=1.6x10-7, Fisher's exact test).	('HRAS', 'Gene', (30, 34))	('PREX2', 'Gene', (45, 50))	('alterations', 'Var', (8, 19))	('KRAS', 'Gene', (36, 40))	('modulate', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (36, 40))	('AKAP9', 'Gene', '10142', (23, 28))	('activity', 'MPA', (81, 89))	('AKAP9', 'Gene', (23, 28))	('HRAS', 'Gene', '3265', (30, 34))	('PREX2', 'Gene', '80243', (45, 50))
36855	29628290	Conversely, causal mutations shared across tumor types may associate with different tumor-specific downstream regulators.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor type', 'Disease', (43, 53))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor type', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', (43, 48))	('associate', 'Reg', (59, 68))
36860	29628290	C3 was regulated by KLF15 and miR-141-3p.	('KLF15', 'Gene', (20, 25))	('miR-141-3p', 'Var', (30, 40))	('KLF15', 'Gene', '28999', (20, 25))
36880	29628290	For example, KRAS mutations were enriched in C1 and but infrequent in C5, suggesting that mutations in driver oncogenes alter pathways that affect immune cells.	('mutations', 'Var', (90, 99))	('alter', 'Reg', (120, 125))	('pathways', 'Pathway', (126, 134))	('affect', 'Reg', (140, 146))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
36881	29628290	Driver mutations such as TP53, by inducing genomic instability, may alter the immune landscape via the generation of neoantigens.	('inducing', 'Reg', (34, 42))	('TP53', 'Gene', (25, 29))	('alter', 'Reg', (68, 73))	('genomic instability', 'MPA', (43, 62))	('immune landscape', 'MPA', (78, 94))	('TP53', 'Gene', '7157', (25, 29))	('neoantigens', 'MPA', (117, 128))	('mutations', 'Var', (7, 16))
36882	29628290	Our findings confirmed previous work showing that mutations in BRAF enhance the immune infiltrate while those in IDH1 diminish it.	('diminish', 'NegReg', (118, 126))	('immune infiltrate', 'CPA', (80, 97))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('enhance', 'PosReg', (68, 75))
36890	29628290	Predicted intracellular networks implied that seven immune related TFs(including interferon and STAT-family transcription factors) may play an active role in transcriptional events related to leukocyte infiltration, and that mutations in six genes (including Ras-family proteins) may influence immune infiltration.	('influence', 'Reg', (284, 293))	('STAT', 'Disease', (96, 100))	('mutations', 'Var', (225, 234))	('immune infiltration', 'CPA', (294, 313))	('STAT', 'Disease', 'None', (96, 100))
36958	29628290	Comparing functional annotations of these clusters, we found that overlap to be reflected in the concordant distribution of mean scores of IFN-gamma, TGF-beta, mutation load and overall leukocyte infiltrate among the overlapping clusters.	('IFN-gamma', 'Gene', '3458', (139, 148))	('IFN-gamma', 'Gene', (139, 148))	('TGF-beta', 'Gene', '7040', (150, 158))	('mutation load', 'Var', (160, 173))	('TGF-beta', 'Gene', (150, 158))
36988	29628290	All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
36990	29628290	Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived.	('aneuploidy', 'Disease', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (31, 41))	('HRD', 'Disease', 'None', (108, 111))	('copy number burden', 'Var', (11, 29))	('loss of heterozygosity', 'Var', (43, 65))	('HRD', 'Disease', (108, 111))
36991	29628290	Copy number burden scores frac_altered and n_segs ("fraction altered", and "number of segments", respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below - 0.1 in log2 relative copy number (CN) space), and the total number of segments in each sample's copy number profile, respectively.	('men', 'Species', '9606', (89, 92))	('deviating', 'NegReg', (143, 152))	('frac_altered', 'Var', (26, 38))	('men', 'Species', '9606', (280, 283))
36992	29628290	LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively.	('LOH_n_seg', 'Var', (0, 9))	('men', 'Species', '9606', (52, 55))	('LOH_frac_altered', 'Var', (14, 30))
36993	29628290	HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (282, 291))	('HRD', 'Disease', 'None', (0, 3))	('scarring', 'Phenotype', 'HP:0100699', (111, 119))	('defects', 'Var', (35, 42))	('HRD', 'Disease', (0, 3))	('LOH', 'NegReg', (163, 166))	('men', 'Species', '9606', (226, 229))
36994	29628290	Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively "altered") arms.	('deleted', 'Var', (67, 74))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
36995	29628290	To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (12, 23))	('tumor type', 'Disease', 'MESH:D009369', (80, 90))	('tumor type', 'Disease', (80, 90))	('deletion', 'Var', (142, 150))
37001	29628290	Furthermore, for each gene, we similarly computed significances of differences of CIBERSORT-estimated relative immune cell subtype levels from their expected levels first in "amplified" and then in "deleted" samples in order to identify the effects of copy number amplification and deletion respectively on immune infiltrate composition while controlling for cancer disease type.	('cancer disease', 'Disease', 'MESH:D009369', (359, 373))	('deletion', 'Var', (282, 290))	('effects', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer disease', 'Disease', (359, 373))	('copy number amplification', 'Var', (252, 277))
37002	29628290	Contributors: Galen Gao, Andrew Cherniack We focused our analysis on genes identified as drivers by the TCGA PanCancer Atlas Driver Mutation Working Group (the CGAT list; TCGA Research Network, "Comprehensive Discovery and Characterization of Driver Genes and Mutations in Human Cancers", unpublished data) that were identified as 1) having 10 or more mutations overall and 2) mutated in two or more tissues.	('CGAT', 'Gene', (160, 164))	('Human', 'Species', '9606', (273, 278))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (352, 361))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancers', 'Disease', (279, 286))	('Cancer', 'Disease', (279, 285))	('Cancers', 'Disease', 'MESH:D009369', (279, 286))	('Cancers', 'Phenotype', 'HP:0002664', (279, 286))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('CGAT', 'Gene', '6570', (160, 164))
37005	29628290	Contributor: Eduard Porta Pardo We used domainXplorer to identify driver genes and mutations that correlate with the leukocyte fraction of the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
37006	29628290	The algorithm uses a linear model that takes into account potential biases caused by differences in the immune responses between the tissues of origin of the tumors, the gender of the patient, the total number of missense mutations in the sample or the patient's age as covariates.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patient', 'Species', '9606', (253, 260))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('missense mutations', 'Var', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (184, 191))
37010	29628290	For each pathway, samples from each of 30 tumor types were divided into two groups of altered and intact cases based on acquisition of non-silent or frameshift mutations, heterozygous or homozygous deletions, or amplifications, in at least one member of the pathway.	('tumor type', 'Disease', (42, 52))	('amplifications', 'Var', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor type', 'Disease', 'MESH:D009369', (42, 52))
37020	29628290	To perform association analyses with single nucleotide polymorphisms (SNPs) at the PDL1 locus, we imputed the genotype data using the Haplotype Reference Consortium as a reference.	('PDL1', 'Gene', '29126', (83, 87))	('single nucleotide polymorphisms', 'Var', (37, 68))	('PDL1', 'Gene', (83, 87))
37029	29628290	Variation in sequencing coverage and tumor purity require careful consideration in order to mitigate the risk of impacting mutation calls and on pMHC, and prior to pMHC calling, sequencing data was subjected to rigorous harmonization efforts, performed by the PanCancer MC3 Consortium.	('Cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impacting', 'Reg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation calls', 'Var', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
37056	29628290	Using output from a PanCan GISTIC2.0 run on ISAR-corrected Affymetrix genome-wide human SNP6.0 array data, deep amplifications, shallow amplifications, non-alterations, shallow deletions, and deep deletions of each immunomodulator gene were called as described in "Genomic Correlations with Immune Phenotype" above for 8461 tumors that both were immune subtyped and had ABSOLUTE purity and ploidy calls.	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('non-alterations', 'Var', (152, 167))	('human', 'Species', '9606', (82, 87))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('shallow deletions', 'Var', (169, 186))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('deep deletions', 'Var', (192, 206))	('shallow amplifications', 'Var', (128, 150))
37072	29628290	Mutation or copy-number events identified by the domainXplorer algorithm were tested for statistical association with the 32 cMRs identified, using the DIGGIT algorithm (above), and retained if associated with one or more of the 32 cMRs in at least one tumor-specific context.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('copy-number', 'Var', (12, 23))
37124	29644036	Our patient and his father were found to have a mutation in the SDHA gene.	('SDHA', 'Gene', (64, 68))	('mutation', 'Var', (48, 56))	('patient', 'Species', '9606', (4, 11))	('SDHA', 'Gene', '6389', (64, 68))
37181	29108378	As shown in Table 4, relative to the controls, there was increased risk of massive intraoperative blood loss in patients with tumors that were either proximally located to vessels or other organs (odds ratio (OR): 4.227) or >= 5 cm in size (OR: 7.321), or in patients who had preoperative preparation time of <= 14 days (OR: 17.747).	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('patients', 'Species', '9606', (259, 267))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (112, 120))	('intraoperative blood loss', 'Disease', (83, 108))	('>= 5 cm', 'Var', (224, 231))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (83, 108))
37193	29108378	Injury to such vascular structures and organs may also occur during the tumor resection, with lacerations capable of inducing intraoperative massive bleeding.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('intraoperative massive bleeding', 'Disease', 'MESH:D016063', (126, 157))	('inducing', 'Reg', (117, 125))	('intraoperative massive bleeding', 'Disease', (126, 157))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('lacerations', 'Var', (94, 105))
37223	28781534	A malignant pheochromocytoma in a child with von Hippel-Lindau mutation Pheochromocytoma is a rare neuroendocrine tumor that arises from the chromaffin cells of the sympathetic nervous system.	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (2, 28))	('malignant pheochromocytoma', 'Disease', (2, 28))	('von Hippel-Lindau', 'Gene', (45, 62))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('neuroendocrine tumor', 'Disease', (99, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (12, 28))	('Pheochromocytoma', 'Disease', (72, 88))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (72, 88))	('mutation', 'Var', (63, 71))	('von Hippel-Lindau', 'Gene', '7428', (45, 62))	('chromaffin', 'Chemical', '-', (141, 151))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (72, 88))	('child', 'Species', '9606', (34, 39))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (99, 119))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (99, 119))
37224	28781534	Over one third of pheochromocytomas are associated with germline mutations.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('pheochromocytomas', 'Disease', (18, 35))	('pheochromocytomas', 'Disease', 'MESH:D010673', (18, 35))	('associated', 'Reg', (40, 50))	('germline mutations', 'Var', (56, 74))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (18, 35))
37226	28781534	Genetic tests revealed the presence of the VHL c 244 C>G (p. Arg 82 Gly) heterozygote mutation in the mother, as well as in the child.	('Arg 82 Gly', 'Var', (61, 71))	('VHL', 'Disease', (43, 46))	('244 C>G', 'Mutation', 'c.244C>G', (49, 56))	('child', 'Species', '9606', (128, 133))	('Arg 82 Gly', 'SUBSTITUTION', 'None', (61, 71))	('VHL', 'Disease', 'MESH:D006623', (43, 46))
37228	28781534	Lifelong complex follow-up is needed, as it is known that at a later age VHL mutation may cause retinal angiomas, cerebellar and spinal hemangioblastomas, relapsed pheocromocytoma, pancreatic and renal cysts, clear cell renal cell carcinoma and endolymphatic sac tumors.	('pancreatic and renal cysts', 'Disease', 'MESH:D010181', (181, 207))	('mutation', 'Var', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('renal cysts', 'Phenotype', 'HP:0000107', (196, 207))	('endolymphatic sac tumors', 'Disease', 'MESH:D036821', (245, 269))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 240))	('retinal angiomas', 'Disease', (96, 112))	('pheocromocytoma', 'Disease', 'None', (164, 179))	('cerebellar and spinal hemangioblastomas', 'Phenotype', 'HP:0006880', (114, 153))	('retinal angiomas', 'Disease', 'MESH:D012173', (96, 112))	('VHL', 'Disease', (73, 76))	('spinal hemangioblastomas', 'Phenotype', 'HP:0009713', (129, 153))	('pheocromocytoma', 'Disease', (164, 179))	('endolymphatic sac tumors', 'Phenotype', 'HP:0030393', (245, 269))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 240))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('spinal hemangioblastomas', 'Disease', (129, 153))	('spinal hemangioblastomas', 'Disease', 'MESH:D018325', (129, 153))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('VHL', 'Disease', 'MESH:D006623', (73, 76))	('clear cell renal cell carcinoma', 'Disease', (209, 240))	('cause', 'Reg', (90, 95))	('endolymphatic sac tumors', 'Disease', (245, 269))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))
37232	28781534	Over one third of the pheochromocytomas are associated with germline mutations of known susceptibility genes belonging to the succcinate dehydrogenase complex (SDHA, SDHB, SDHC, SDHD) or well characterized tumor syndromes: von Hippel-Lindau (VHL), Neurofibromatosis type 1 (NF1) and Multiple endocrine neoplasia type 2 (RET).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (248, 265))	('von Hippel-Lindau', 'Gene', '7428', (223, 240))	('RET', 'Gene', (320, 323))	('SDHD', 'Gene', (178, 182))	('Multiple endocrine neoplasia type 2', 'Disease', (283, 318))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('SDHB', 'Gene', (166, 170))	('SDHC', 'Gene', (172, 176))	('NF1', 'Gene', '4763', (274, 277))	('pheochromocytomas', 'Disease', (22, 39))	('VHL', 'Disease', 'MESH:D006623', (242, 245))	('pheochromocytomas', 'Disease', 'MESH:D010673', (22, 39))	('mutations', 'Var', (69, 78))	('NF1', 'Gene', (274, 277))	('neoplasia', 'Phenotype', 'HP:0002664', (302, 311))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (292, 311))	('Neurofibromatosis type 1', 'Gene', '4763', (248, 272))	('associated', 'Reg', (44, 54))	('RET', 'Gene', '5979', (320, 323))	('tumor', 'Disease', (206, 211))	('von Hippel-Lindau', 'Gene', (223, 240))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (22, 39))	('Multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (283, 318))	('SDHC', 'Gene', '6391', (172, 176))	('SDHD', 'Gene', '6392', (178, 182))	('VHL', 'Disease', (242, 245))	('Neurofibromatosis type 1', 'Gene', (248, 272))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('SDHB', 'Gene', '6390', (166, 170))
37239	28781534	Genetic testing revealed the presence of the VHL c 244 C>G (p. Arg 82 Gly) heterozygote mutation, while the tests for RET, SDHB, SDHC and SDHD were negative.	('SDHC', 'Gene', '6391', (129, 133))	('244 C>G', 'Mutation', 'c.244C>G', (51, 58))	('SDHD', 'Gene', '6392', (138, 142))	('RET', 'Gene', '5979', (118, 121))	('Arg 82 Gly', 'SUBSTITUTION', 'None', (63, 73))	('VHL', 'Disease', (45, 48))	('SDHB', 'Gene', '6390', (123, 127))	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('SDHB', 'Gene', (123, 127))	('Arg 82 Gly', 'Var', (63, 73))	('SDHC', 'Gene', (129, 133))	('SDHD', 'Gene', (138, 142))	('RET', 'Gene', (118, 121))
37244	28781534	Genetic examination: VHL c 244 C>G (p. Arg 82 Gly) heterozygotic mutation.	('244 C>G', 'Mutation', 'c.244C>G', (27, 34))	('Arg 82 Gly', 'Var', (39, 49))	('VHL', 'Disease', 'MESH:D006623', (21, 24))	('VHL', 'Disease', (21, 24))	('Arg 82 Gly', 'SUBSTITUTION', 'None', (39, 49))
37255	28781534	Von Hippel-Lindau disease is an autosomal dominant inherited neoplastic disorder, occurring in about 50% of patients with an isolated familial pheochromocytoma caused by germline mutations in the VHL tumor suppressor gene that demonstrates marked phenotypic variability.	('caused by', 'Reg', (160, 169))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (0, 25))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('autosomal dominant inherited neoplastic disorder', 'Disease', 'MESH:D009386', (32, 80))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (134, 159))	('VHL tumor', 'Disease', (196, 205))	('Von Hippel-Lindau disease', 'Disease', (0, 25))	('neoplastic disorder', 'Phenotype', 'HP:0002664', (61, 80))	('familial pheochromocytoma', 'Disease', (134, 159))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('patients', 'Species', '9606', (108, 116))	('autosomal dominant inherited neoplastic disorder', 'Disease', (32, 80))	('germline mutations', 'Var', (170, 188))	('VHL tumor', 'Disease', 'MESH:D006623', (196, 205))
37260	26273102	Each syndrome is associated with mutation in a gene encoding a particular subunit (or assembly factor) of succinate dehydrogenase (SDHx).	('SDHx', 'Gene', (131, 135))	('succinate dehydrogenase', 'Gene', '6390', (106, 129))	('mutation', 'Var', (33, 41))	('associated', 'Reg', (17, 27))	('succinate dehydrogenase', 'Gene', (106, 129))	('syndrome', 'Disease', (5, 13))	('SDHx', 'Chemical', '-', (131, 135))
37270	26273102	The genetic basis for hereditary PGL syndrome type 1 (PGL1) was discovered by by combining knowledge that hypoxia increases the risk of carotid body PGLs with the presence of a hypoxia-responsive gene encoding succinate dehydrogenase subunit D (SDHD) within a region at chromosome 11q23 linked in family studies to hereditary head and neck PGLs (HNPGLs).	('hereditary PGL syndrome type 1', 'Disease', (22, 52))	('SDHD', 'Gene', (245, 249))	('SDHD', 'Gene', '6392', (245, 249))	('presence', 'Var', (163, 171))	('hypoxia', 'Disease', (106, 113))	('succinate dehydrogenase subunit D', 'Gene', '6392', (210, 243))	('HNPGLs', 'Chemical', '-', (346, 352))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (177, 184))	('succinate dehydrogenase subunit D', 'Gene', (210, 243))	('hereditary PGL syndrome type 1', 'Disease', 'MESH:D010235', (22, 52))	('carotid body PGLs', 'Disease', (136, 153))	('hypoxia', 'Disease', (177, 184))
37271	26273102	The phenotype of germline SDHD mutations was quickly extended to include thoracoabdominal PGLs (TAPGLs) and PCs.	('mutations', 'Var', (31, 40))	('PCs', 'Disease', (108, 111))	('abdominal PGL', 'Disease', 'MESH:D010235', (80, 93))	('SDHD', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (26, 30))	('abdominal PGL', 'Disease', (80, 93))
37272	26273102	Soon thereafter, the SDHC gene was found to be mutated in familial HNPGLs (PGL3) and SDHB mutations were discovered in familial PPGLs (PGL4).	('PGL4', 'Gene', (135, 139))	('PPGLs', 'Chemical', '-', (128, 133))	('PGL4', 'Gene', '6390', (135, 139))	('mutations', 'Var', (90, 99))	('SDHC', 'Gene', (21, 25))	('familial HNPGLs', 'Disease', 'MESH:D009394', (58, 73))	('PGL3', 'Gene', '6391', (75, 79))	('SDHC', 'Gene', '6391', (21, 25))	('PGL3', 'Gene', (75, 79))	('familial HNPGLs', 'Disease', (58, 73))	('familial PPGLs', 'Disease', (119, 133))	('SDHB', 'Gene', (85, 89))	('SDHB', 'Gene', '6390', (85, 89))
37273	26273102	SDHAF2, required for flavination of SDHA, is mutated in the rare PGL2, and PGL5 is associated with mutations in SDHA.	('PGL5', 'Gene', '6389', (75, 79))	('SDHAF2', 'Gene', '54949', (0, 6))	('SDHA', 'Gene', (0, 4))	('PGL5', 'Gene', (75, 79))	('SDHAF2', 'Gene', (0, 6))	('SDHA', 'Gene', '6389', (36, 40))	('PGL2', 'Gene', '54949', (65, 69))	('SDHA', 'Gene', '6389', (112, 116))	('mutations', 'Var', (99, 108))	('SDHA', 'Gene', (36, 40))	('PGL2', 'Gene', (65, 69))	('associated', 'Reg', (83, 93))	('SDHA', 'Gene', '6389', (0, 4))	('SDHA', 'Gene', (112, 116))
37274	26273102	Germline mutations in predisposition genes are now found in 25-30% of PPGLs overall.	('Germline mutations', 'Var', (0, 18))	('PPGLs', 'Disease', (70, 75))	('PPGLs', 'Chemical', '-', (70, 75))	('found', 'Reg', (51, 56))
37275	26273102	Germline mutations in SDHx genes are the commonest genetic cause of PPGLs, occurring in up to 25% cases.	('Germline mutations', 'Var', (0, 18))	('SDHx', 'Gene', (22, 26))	('SDHx', 'Chemical', '-', (22, 26))	('cause', 'Reg', (59, 64))	('PPGLs', 'Chemical', '-', (68, 73))	('PPGLs', 'Disease', (68, 73))
37280	26273102	Therefore, two predictable consequences of SDH inactivation are succinate accumulation and increased production of reactive oxygen species.	('inactivation', 'Var', (47, 59))	('SDH', 'Gene', (43, 46))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (115, 138))	('succinate accumulation', 'MPA', (64, 86))	('SDH', 'Gene', '6390', (43, 46))	('increased', 'PosReg', (91, 100))	('succinate', 'Chemical', 'MESH:D019802', (64, 73))	('increased production of reactive oxygen species', 'Phenotype', 'HP:0025464', (91, 138))	('production of reactive oxygen species', 'MPA', (101, 138))
37282	26273102	Notably, this gene expression signature is shared by PPGLs associated with mutations in VHL.	('PPGLs', 'Chemical', '-', (53, 58))	('associated', 'Reg', (59, 69))	('mutations', 'Var', (75, 84))	('VHL', 'Disease', (88, 91))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
37292	26273102	PGL of the urinary bladder is associated with catcholaminergic symptoms that are provoked by micturition, and may also be associated with painless haematuria.	('associated', 'Reg', (122, 132))	('associated', 'Reg', (30, 40))	('pain', 'Phenotype', 'HP:0012531', (138, 142))	('painless haematuria', 'Disease', 'MESH:D006417', (138, 157))	('PGL', 'Var', (0, 3))	('painless haematuria', 'Disease', (138, 157))	('catcholaminergic', 'Disease', (46, 62))
37301	26273102	Some general points can be made about these syndromes: i) they are autosomal dominant disorders, with maternal imprinting effects for SDHD and SDHAF2; ii) the penetrance of tumour development in subjects carrying SDHx mutations is highly variable, in particular for PGL3-5 - highlighted by the occasional finding that a child or young adult is the index case in a family where the parent (and sometimes grandparent) carrying the pathogenic allele has not developed tumours and iii) tumour development does not clearly follow a predetermined pattern - PPGLs, renal cancer, GISTs and/or pituitary tumours occur in a seemingly random fashion in affected subjects.	('tumour', 'Disease', (173, 179))	('child', 'Species', '9606', (320, 325))	('tumour', 'Disease', 'MESH:D009369', (482, 488))	('tumours', 'Phenotype', 'HP:0002664', (465, 472))	('tumours', 'Disease', 'MESH:D009369', (465, 472))	('tumour', 'Disease', (482, 488))	('SDHx', 'Chemical', '-', (213, 217))	('autosomal dominant disorders', 'Disease', (67, 95))	('pituitary tumours', 'Disease', 'MESH:D010911', (585, 602))	('GISTs', 'Disease', (572, 577))	('tumour', 'Phenotype', 'HP:0002664', (465, 471))	('tumour', 'Disease', 'MESH:D009369', (465, 471))	('tumour', 'Disease', (465, 471))	('cancer', 'Phenotype', 'HP:0002664', (564, 570))	('SDHD', 'Gene', '6392', (134, 138))	('pituitary tumours', 'Disease', (585, 602))	('SDHAF2', 'Gene', '54949', (143, 149))	('SDHAF2', 'Gene', (143, 149))	('PPGLs', 'Disease', (551, 556))	('autosomal dominant disorders', 'Disease', 'MESH:D030342', (67, 95))	('tumours', 'Disease', (595, 602))	('tumour', 'Phenotype', 'HP:0002664', (595, 601))	('SDHD', 'Gene', (134, 138))	('renal cancer', 'Disease', (558, 570))	('tumour', 'Disease', 'MESH:D009369', (595, 601))	('renal cancer', 'Phenotype', 'HP:0009726', (558, 570))	('tumour', 'Disease', (595, 601))	('PGL3', 'Gene', (266, 270))	('tumours', 'Phenotype', 'HP:0002664', (595, 602))	('tumours', 'Disease', 'MESH:D009369', (595, 602))	('mutations', 'Var', (218, 227))	('renal cancer', 'Disease', 'MESH:D007680', (558, 570))	('tumours', 'Disease', (465, 472))	('SDHx', 'Gene', (213, 217))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (482, 488))	('PPGLs', 'Chemical', '-', (551, 556))	('PGL3', 'Gene', '6391', (266, 270))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
37302	26273102	SDHD is maternally imprinted, with the result that the disease almost only ever occurs with paternally inherited mutations and as such, to the uninitiated, may appear to 'skip' generations.	('SDHD', 'Gene', (0, 4))	('mutations', 'Var', (113, 122))	('SDHD', 'Gene', '6392', (0, 4))
37303	26273102	When paternally inherited, SDHD mutations are associated with frequent development of HNPGL and less commonly TAPGLs or phaechromocytomas.	('HNPGL', 'Disease', (86, 91))	('TAPGLs', 'Disease', (110, 116))	('SDHD', 'Gene', '6392', (27, 31))	('mutations', 'Var', (32, 41))	('phaechromocytomas', 'Disease', (120, 137))	('associated with', 'Reg', (46, 61))	('SDHD', 'Gene', (27, 31))
37307	26273102	Prematurely truncating mutations (by frameshift or nonsense variants) are particularly common in SDHD, and one study found that these mutations were associated with a significantly increased risk of phaeochromocytoma or sympathetic PGL compared to missense mutations that were not predicted to impair protein stability.	('SDHD', 'Gene', (97, 101))	('nonsense variants', 'Var', (51, 68))	('common', 'Reg', (87, 93))	('frameshift', 'Var', (37, 47))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (199, 216))	('associated', 'Reg', (149, 159))	('sympathetic PGL', 'Disease', (220, 235))	('mutations', 'Var', (134, 143))	('phaeochromocytoma', 'Disease', (199, 216))	('Prematurely', 'MPA', (0, 11))	('SDHD', 'Gene', '6392', (97, 101))
37309	26273102	SDHAF2 mutations are a rare cause of PPGLs: only four PGL2 families have been described.	('PGL2', 'Gene', (54, 58))	('PGL2', 'Gene', '54949', (54, 58))	('PPGLs', 'Chemical', '-', (37, 42))	('SDHAF2', 'Gene', '54949', (0, 6))	('SDHAF2', 'Gene', (0, 6))	('cause', 'Reg', (28, 33))	('PPGLs', 'Disease', (37, 42))	('mutations', 'Var', (7, 16))
37311	26273102	HNPGLs occur in 75% carriers of paternally inherited mutations, starting from relatively young age (earliest affected aged 22 years) and often multifocal but are not malignant.	('HNPGLs', 'Chemical', '-', (0, 6))	('HNPGLs', 'Disease', (0, 6))	('mutations', 'Var', (53, 62))
37313	26273102	Mutations in SDHC have been identified in patients with HNPGL and, rarely, TAPGLs and PCs.	('identified', 'Reg', (28, 38))	('SDHC', 'Gene', (13, 17))	('SDHC', 'Gene', '6391', (13, 17))	('Mutations', 'Var', (0, 9))	('HNPGL', 'Disease', (56, 61))	('patients', 'Species', '9606', (42, 50))
37315	26273102	Overall, germline SDHC mutations are found in around 4% of HNPGL but very few functioning PPGLs.	('HNPGL', 'Disease', (59, 64))	('SDHC', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('SDHC', 'Gene', '6391', (18, 22))	('PPGLs', 'Chemical', '-', (90, 95))
37316	26273102	Patients with SDHC mutations are more likely to develop carotid body tumours, less likely to have multiple tumours than in SDHD mutated PGL, and have low malignant potential compared to SDHB-mutated PGL.	('multiple tumours', 'Disease', (98, 114))	('carotid body tumours', 'Disease', (56, 76))	('SDHB', 'Gene', (186, 190))	('SDHC', 'Gene', (14, 18))	('develop', 'PosReg', (48, 55))	('multiple tumours', 'Disease', 'MESH:D009369', (98, 114))	('SDHD', 'Gene', (123, 127))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (123, 127))	('SDHC', 'Gene', '6391', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('carotid body tumours', 'Disease', 'MESH:D002345', (56, 76))	('SDHB', 'Gene', '6390', (186, 190))	('malignant potential', 'CPA', (154, 173))
37317	26273102	Nearly 50 unique SDHC mutations have been described in PGL3 to date, and these are evenly distributed between the six coding exons (Fig.	('SDHC', 'Gene', (17, 21))	('SDHC', 'Gene', '6391', (17, 21))	('mutations', 'Var', (22, 31))	('PGL3', 'Gene', '6391', (55, 59))	('PGL3', 'Gene', (55, 59))
37318	26273102	SDHB mutations were first found to be associated with PPGL in 2001.	('associated', 'Reg', (38, 48))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('PPGL', 'Disease', (54, 58))
37319	26273102	In comparison to PGL1, patients with SDHB mutations have lower penetrance for disease and may present with unifocal disease at a later age, with perhaps only about 40% of carriers manifesting the disease by age 40.	('patients', 'Species', '9606', (23, 31))	('SDHB', 'Gene', '6390', (37, 41))	('present with', 'Reg', (94, 106))	('mutations', 'Var', (42, 51))	('penetrance for disease', 'MPA', (63, 85))	('SDHB', 'Gene', (37, 41))	('unifocal disease', 'Disease', (107, 123))	('lower', 'NegReg', (57, 62))
37321	26273102	HNPGL occurs in 20-30%, renal cell cancer in about 14% and GISTs in 2% of carriers of pathogenic SDHB mutations.	('SDHB', 'Gene', (97, 101))	('SDHB', 'Gene', '6390', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('HNPGL', 'Disease', (0, 5))	('mutations', 'Var', (102, 111))	('occurs', 'Reg', (6, 12))	('renal cell cancer', 'Disease', 'MESH:C538614', (24, 41))	('renal cell cancer', 'Disease', (24, 41))
37322	26273102	More than 200 unique SDHB mutations occurring in all its eight coding exons have been described in PGL4; there are interesting clusters of mutations at the junction of exons 3/4 and in exons 6 and 7 that appear to occur within iron-sulfur cluster domains of SDHB (Fig.	('SDHB', 'Gene', (258, 262))	('sulfur', 'Chemical', 'MESH:D013455', (232, 238))	('mutations', 'Var', (139, 148))	('iron', 'Chemical', 'MESH:D007501', (227, 231))	('PGL4', 'Gene', (99, 103))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (26, 35))	('PGL4', 'Gene', '6390', (99, 103))	('SDHB', 'Gene', '6390', (258, 262))	('SDHB', 'Gene', (21, 25))
37323	26273102	Mutations in SDHA were originally described as a cause of autosomal recessive juvenile encephalopathy (Leigh syndrome).	('encephalopathy', 'Phenotype', 'HP:0001298', (87, 101))	('autosomal recessive juvenile encephalopathy', 'Disease', 'MESH:D001927', (58, 101))	('Leigh syndrome', 'Disease', 'MESH:D007888', (103, 117))	('Mutations', 'Var', (0, 9))	('SDHA', 'Gene', '6389', (13, 17))	('autosomal recessive juvenile encephalopathy', 'Disease', (58, 101))	('juvenile encephalopathy', 'Phenotype', 'HP:0005681', (78, 101))	('cause', 'Reg', (49, 54))	('SDHA', 'Gene', (13, 17))	('Leigh syndrome', 'Disease', (103, 117))
37325	26273102	SDHA mutations remain a rare cause of PPGL, accounting for about 3% of cases and with low penetrance such that familial disease is uncommon.	('SDHA', 'Gene', (0, 4))	('familial disease', 'Disease', (111, 127))	('PPGL', 'Disease', (38, 42))	('mutations', 'Var', (5, 14))	('familial disease', 'Disease', 'MESH:D030342', (111, 127))	('SDHA', 'Gene', '6389', (0, 4))	('cause', 'Reg', (29, 34))
37327	26273102	Genetic testing for SDHA mutations is complicated by the presence of three pseudogenes - SDHAP1 (localized to 3q29), SDHAP2 (3q29) and SDHAP3 (5p15.33) - which are highly homologous to not only the coding regions of SDHA but also the intronic regions of the gene.	('SDHAP3', 'Gene', (135, 141))	('mutations', 'Var', (25, 34))	('SDHA', 'Gene', '6389', (117, 121))	('SDHA', 'Gene', (216, 220))	('SDHA', 'Gene', '6389', (135, 139))	('SDHAP2', 'Gene', '727956', (117, 123))	('SDHA', 'Gene', (89, 93))	('SDHA', 'Gene', (20, 24))	('SDHAP1', 'Gene', (89, 95))	('SDHAP3', 'Gene', '728609', (135, 141))	('SDHA', 'Gene', (117, 121))	('SDHAP1', 'Gene', '255812', (89, 95))	('SDHA', 'Gene', '6389', (216, 220))	('SDHAP2', 'Gene', (117, 123))	('SDHA', 'Gene', '6389', (20, 24))	('SDHA', 'Gene', (135, 139))	('SDHA', 'Gene', '6389', (89, 93))
37329	26273102	Fortunately, SDHA immunohistochemistry has proved useful in identifying tumours that are likely to contain SDHA mutations.	('SDHA', 'Gene', '6389', (107, 111))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('mutations', 'Var', (112, 121))	('SDHA', 'Gene', (107, 111))	('SDHA', 'Gene', '6389', (13, 17))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('SDHA', 'Gene', (13, 17))
37332	26273102	Approximately 40% of all PGLs are associated with SDH deficiency, and those associated with SDHB mutations (PGL4) are at higher risk of malignancy.	('mutations', 'Var', (97, 106))	('malignancy', 'Disease', (136, 146))	('associated', 'Reg', (34, 44))	('SDHB', 'Gene', '6390', (92, 96))	('SDH deficiency', 'Disease', (50, 64))	('PGLs', 'Disease', (25, 29))	('SDH deficiency', 'Disease', 'MESH:D007153', (50, 64))	('SDHB', 'Gene', (92, 96))	('malignancy', 'Disease', 'MESH:D009369', (136, 146))	('PGL4', 'Gene', (108, 112))	('PGL4', 'Gene', '6390', (108, 112))
37348	26273102	PCs associated with SDHB mutations (PGL4) show a higher risk of malignancy.	('mutations', 'Var', (25, 34))	('malignancy', 'Disease', (64, 74))	('PGL4', 'Gene', (36, 40))	('PGL4', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', '6390', (20, 24))	('malignancy', 'Disease', 'MESH:D009369', (64, 74))	('SDHB', 'Gene', (20, 24))
37351	26273102	Standard 18F-FDG-PET imaging was reported to have 88% sensitivity in diagnosis of non-metastatic PC/PGL, although this series included a relatively large number of tumors containing SDHB mutations (which are more likely to be positive due to altered glucose transport).	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('glucose', 'Chemical', 'MESH:D005947', (250, 257))	('mutations', 'Var', (187, 196))	('SDHB', 'Gene', '6390', (182, 186))	('FDG', 'Chemical', 'MESH:D019788', (13, 16))	('non-metastatic PC/PGL', 'Disease', (82, 103))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('SDHB', 'Gene', (182, 186))
37357	26273102	Although only 0.05-0.2% of all renal cancers are associated with SDHx mutations, they can be recognised by distinct pathological features including solid or focally cystic growth, uniform cytology with eosinophilic flocculent cytoplasm, intracytoplasmic vacuolations and inclusions and round-to-oval low-grade nuclei.	('eosinophilic', 'Disease', 'MESH:D004802', (202, 214))	('mutations', 'Var', (70, 79))	('renal cancers', 'Disease', (31, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('associated', 'Reg', (49, 59))	('renal cancer', 'Phenotype', 'HP:0009726', (31, 43))	('SDHx', 'Chemical', '-', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('SDHx', 'Gene', (65, 69))	('eosinophilic', 'Disease', (202, 214))	('renal cancers', 'Disease', 'MESH:D007680', (31, 44))
37358	26273102	In SDHB mutated renal cancers, immunohistochemistry for SDHB is negative.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('mutated', 'Var', (8, 15))	('renal cancers', 'Disease', 'MESH:D007680', (16, 29))	('SDHB', 'Gene', '6390', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('renal cancers', 'Disease', (16, 29))	('renal cancer', 'Phenotype', 'HP:0009726', (16, 28))	('SDHB', 'Gene', (3, 7))
37359	26273102	Although no clear-cut genotype-phenotype correlations have been defined, it is interesting to note that four unrelated subjects who developed renal cancer all harboured the same SDHB splice site mutation (c.423+1G>A), and that two of these subjects developed multifocal disease.	('c.423+1G>A', 'Mutation', 'rs398122805', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('renal cancer', 'Disease', (142, 154))	('renal cancer', 'Disease', 'MESH:D007680', (142, 154))	('renal cancer', 'Phenotype', 'HP:0009726', (142, 154))	('multifocal disease', 'Disease', (259, 277))	('multifocal disease', 'Disease', 'None', (259, 277))	('SDHB', 'Gene', '6390', (178, 182))	('c.423+1G>A', 'Var', (205, 215))	('SDHB', 'Gene', (178, 182))
37363	26273102	However, only 50% of such SDH-deficient GISTs are found to be associated with germline mutations in an SDHx gene: 30% due to SDHA mutations, and 10-20% due to mutations in SDHB, SDHC or SDHD.	('SDHD', 'Gene', (186, 190))	('SDH', 'Gene', (178, 181))	('SDHC', 'Gene', '6391', (178, 182))	('SDH', 'Gene', (186, 189))	('mutations', 'Var', (87, 96))	('due', 'Reg', (118, 121))	('SDH', 'Gene', (26, 29))	('SDH', 'Gene', '6390', (103, 106))	('SDHB', 'Gene', '6390', (172, 176))	('SDH', 'Gene', '6390', (172, 175))	('SDHC', 'Gene', (178, 182))	('SDH', 'Gene', '6390', (125, 128))	('SDHA', 'Gene', (125, 129))	('SDH', 'Gene', (103, 106))	('SDH', 'Gene', '6390', (178, 181))	('SDHA', 'Gene', '6389', (125, 129))	('SDHB', 'Gene', (172, 176))	('SDHD', 'Gene', '6392', (186, 190))	('SDH', 'Gene', (172, 175))	('SDH', 'Gene', '6390', (186, 189))	('mutations', 'Var', (130, 139))	('SDH', 'Gene', '6390', (26, 29))	('SDHx', 'Chemical', '-', (103, 107))	('SDH', 'Gene', (125, 128))
37365	26273102	GISTs associated with hereditary PGL due to germline mutations of SDHA, SDHB, SDHC or SDHD are known as the Carney-Stratakis syndrome.	('SDHC', 'Gene', '6391', (78, 82))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (108, 133))	('SDHD', 'Gene', (86, 90))	('associated', 'Reg', (6, 16))	('SDHB', 'Gene', (72, 76))	('SDHA', 'Gene', (66, 70))	('SDHD', 'Gene', '6392', (86, 90))	('Carney-Stratakis syndrome', 'Disease', (108, 133))	('germline mutations', 'Var', (44, 62))	('SDHB', 'Gene', '6390', (72, 76))	('SDHC', 'Gene', (78, 82))	('hereditary PGL', 'Disease', (22, 36))	('SDHA', 'Gene', '6389', (66, 70))
37366	26273102	GISTs also occur as part of the Carney triad: the syndromic but non-hereditary association of SDH-deficient GISTs now known to be associated with hypermethylation of the SDHC promoter.	('SDH', 'Gene', '6390', (94, 97))	('hypermethylation', 'Var', (146, 162))	('SDH', 'Gene', '6390', (170, 173))	('GISTs', 'Disease', (108, 113))	('SDH', 'Gene', (94, 97))	('SDHC', 'Gene', (170, 174))	('SDHC', 'Gene', '6391', (170, 174))	('SDH', 'Gene', (170, 173))	('associated', 'Reg', (130, 140))
37367	26273102	An aetiopathological link between SDHx mutations and pituitary tumours is strongly suggested by case reports of pituitary tumours that demonstrate loss of SDHB immunostaining, occurring in patients who carry germline mutations in SDHA, SDHB, SDHC and SDHD.	('SDHC', 'Gene', '6391', (242, 246))	('pituitary tumours', 'Disease', (112, 129))	('loss', 'NegReg', (147, 151))	('patients', 'Species', '9606', (189, 197))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('pituitary tumours', 'Disease', 'MESH:D010911', (53, 70))	('SDHA', 'Gene', (230, 234))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('SDHB', 'Gene', '6390', (236, 240))	('SDHx', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))	('SDHD', 'Gene', '6392', (251, 255))	('SDHA', 'Gene', '6389', (230, 234))	('SDHC', 'Gene', (242, 246))	('SDHB', 'Gene', '6390', (155, 159))	('pituitary tumours', 'Disease', (53, 70))	('SDHx', 'Chemical', '-', (34, 38))	('SDHD', 'Gene', (251, 255))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('SDHB', 'Gene', (236, 240))	('SDHB', 'Gene', (155, 159))	('pituitary tumours', 'Disease', 'MESH:D010911', (112, 129))	('immunostaining', 'MPA', (160, 174))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))
37370	26273102	A few individuals with an SDHB or an SDHD pathogenic variant have had thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (70, 87))	('thyroid carcinoma', 'Disease', (70, 87))	('SDHD', 'Gene', '6392', (37, 41))	('variant', 'Var', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('SDHD', 'Gene', (37, 41))	('SDHB', 'Gene', '6390', (26, 30))	('SDHB', 'Gene', (26, 30))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (70, 87))
37372	26273102	SDHx are tumour suppressor genes: inheritance of a pathogenic mutation on one allele in the germline is typically accompanied by loss of the normal allele in tumours.	('pathogenic', 'Reg', (51, 61))	('tumour', 'Disease', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('SDHx', 'Chemical', '-', (0, 4))	('mutation', 'Var', (62, 70))	('tumours', 'Disease', (158, 165))	('tumour', 'Disease', (158, 164))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))
37373	26273102	Loss of SDHB immunostaining has proved to be an important tool for recognising tumours associated with mutations in any of the SDHx genes, and indeed is a robust assay in all the multiple tumour types described above.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (103, 112))	('tumour type', 'Disease', (188, 199))	('SDHB', 'Gene', '6390', (8, 12))	('SDHx', 'Chemical', '-', (127, 131))	('SDHx', 'Gene', (127, 131))	('tumour type', 'Disease', 'MESH:D009369', (188, 199))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('SDHB', 'Gene', (8, 12))	('Loss', 'NegReg', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('tumours', 'Disease', 'MESH:D009369', (79, 86))	('tumours', 'Disease', (79, 86))
37374	26273102	In a large multicenter study, 62 of 69 PPGLs associated with mutations in SDHB/C/D/AF2 were negative for SDHB immunohistochemistry, whereas two SDHD-mutated tumours were scored as immunopositive.	('PPGLs', 'Chemical', '-', (39, 44))	('negative', 'NegReg', (92, 100))	('SDHB', 'Gene', '6390', (105, 109))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('SDHB', 'Gene', '6390', (74, 78))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('SDHB', 'Gene', (74, 78))	('mutations', 'Var', (61, 70))	('associated', 'Reg', (45, 55))	('SDHB', 'Gene', (105, 109))	('SDHD', 'Gene', '6392', (144, 148))	('tumours', 'Disease', 'MESH:D009369', (157, 164))	('SDHD', 'Gene', (144, 148))	('tumours', 'Disease', (157, 164))
37376	26273102	Tumors associated with mutations in RET or NF1, on the other hand, usually show positive granular SDHB cytoplasmic staining (consistent with normal mitochondrial location of SDH).	('RET', 'Gene', (36, 39))	('SDH', 'Gene', (98, 101))	('SDH', 'Gene', (174, 177))	('NF1', 'Gene', (43, 46))	('RET', 'Gene', '5979', (36, 39))	('SDHB', 'Gene', '6390', (98, 102))	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (23, 32))	('SDHB', 'Gene', (98, 102))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('NF1', 'Gene', '4763', (43, 46))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SDH', 'Gene', '6390', (98, 101))	('SDH', 'Gene', '6390', (174, 177))
37377	26273102	Immunohistochemistry for SDHA has also been used to identify tumors associated with germline mutations in that gene.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (93, 102))	('SDHA', 'Gene', (25, 29))	('SDHA', 'Gene', '6389', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
37382	26273102	In contrast, PCs are rarely the index event in other forms of hereditary PC because their syndromic features are more highly penetrant: MEN2 (associated with RET mutations) will almost always present with medullary thyroid cancer, Von Recklinhausen's disease (NF1) will be apparent from cutaneous stigmata of that disease and a diagnosis of VHL syndrome is known in about 50-70% cases before PPGLs develop.	('VHL syndrome', 'Disease', (341, 353))	("Von Recklinhausen's disease", 'Disease', (231, 258))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('RET', 'Gene', (158, 161))	('NF1', 'Gene', (260, 263))	("Von Recklinhausen's disease", 'Disease', 'MESH:D014842', (231, 258))	('NF1', 'Gene', '4763', (260, 263))	('thyroid cancer', 'Disease', (215, 229))	('RET', 'Gene', '5979', (158, 161))	('MEN2', 'Var', (136, 140))	('VHL syndrome', 'Disease', 'MESH:D006623', (341, 353))	('thyroid cancer', 'Phenotype', 'HP:0002890', (215, 229))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (205, 229))	('PPGLs', 'Chemical', '-', (392, 397))	('present with', 'Reg', (192, 204))	('thyroid cancer', 'Disease', 'MESH:D013964', (215, 229))
37384	26273102	Consistent with autosomal dominant pattern of inheritance, each child of an individual with a hereditary PGL syndrome has a 50% chance of inheriting the pathogenic variant.	('hereditary PGL syndrome', 'Disease', 'MESH:D010235', (94, 117))	('hereditary PGL syndrome', 'Disease', (94, 117))	('inheriting', 'Reg', (138, 148))	('variant', 'Var', (164, 171))	('child', 'Species', '9606', (64, 69))
37388	26273102	phenoxybenzamine or doxazosin); treatment options for non-secreting HNPGLs include surgery, radiosurgery, radiofrequency ablation or cryoablation; histopathology should include careful assessment of SDHB and SDHA immunohistochemistry; negative SDHB immunohistochemistry should prompt consideration of genetic testing for mutations in SDHA, SDHB, SDHC or SDHD after appropriate genetic counseling; negative SDHA immunohistochemistry should prompt consideration of genetic testing for mutations in SDHA; genetic testing is performed on DNA extracted from peripheral blood leucoytes and should include validated methods for detecting point mutations, insertions and deletions as well as large deletions in SDHx genes; a positive result from genetic testing should lead to cascade testing of first-degree relatives after appropriate counseling and individuals discovered to carry a pathogenic mutation in SDHx genes should undergo lifelong biochemical and clinical surveillance for PPGLs.	('SDHx', 'Gene', (901, 905))	('SDHA', 'Gene', (334, 338))	('SDHA', 'Gene', (406, 410))	('SDHB', 'Gene', '6390', (340, 344))	('HNPGLs', 'Chemical', '-', (68, 74))	('SDHB', 'Gene', '6390', (244, 248))	('SDHA', 'Gene', (208, 212))	('SDHB', 'Gene', (199, 203))	('SDHA', 'Gene', '6389', (334, 338))	('SDHC', 'Gene', (346, 350))	('SDHx', 'Chemical', '-', (901, 905))	('SDHA', 'Gene', '6389', (406, 410))	('SDHx', 'Chemical', '-', (703, 707))	('SDHA', 'Gene', '6389', (208, 212))	('PPGLs', 'Chemical', '-', (978, 983))	('SDHB', 'Gene', (340, 344))	('SDHD', 'Gene', '6392', (354, 358))	('SDHB', 'Gene', (244, 248))	('doxazosin', 'Chemical', 'MESH:D017292', (20, 29))	('mutation', 'Var', (889, 897))	('SDHA', 'Gene', (496, 500))	('SDHD', 'Gene', (354, 358))	('SDHA', 'Gene', '6389', (496, 500))	('SDHC', 'Gene', '6391', (346, 350))	('SDHB', 'Gene', '6390', (199, 203))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (0, 16))
37391	26273102	Elucidating the genetic basis of the hereditary paraganglioma syndromes has stimulated great advances in clinical care for these patients, providing opportunities for early detection and treatment of component tumours, but not without costs: both in terms of resources required for genetic testing and then lifetime screening of SDHx mutation carriers to detect tumour development anywhere from base of skull to pelvis; and also from the psychological burden these patients bear from not knowing if, when, where and in what manner (benign or malignant) these tumours will develop.	('tumours', 'Phenotype', 'HP:0002664', (559, 566))	('component tumours', 'Disease', (200, 217))	('tumours', 'Disease', 'MESH:D009369', (559, 566))	('paraganglioma', 'Phenotype', 'HP:0002668', (48, 61))	('component tumours', 'Disease', 'MESH:D009369', (200, 217))	('tumours', 'Phenotype', 'HP:0002664', (210, 217))	('hereditary paraganglioma syndromes', 'Disease', 'MESH:D010235', (37, 71))	('tumours', 'Disease', 'MESH:D009369', (210, 217))	('tumour', 'Phenotype', 'HP:0002664', (362, 368))	('tumour', 'Disease', 'MESH:D009369', (362, 368))	('tumour', 'Phenotype', 'HP:0002664', (559, 565))	('patients', 'Species', '9606', (465, 473))	('tumour', 'Disease', 'MESH:D009369', (559, 565))	('tumour', 'Disease', (362, 368))	('SDHx', 'Gene', (329, 333))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', (559, 565))	('mutation', 'Var', (334, 342))	('hereditary paraganglioma syndromes', 'Disease', (37, 71))	('tumour', 'Disease', (210, 216))	('patients', 'Species', '9606', (129, 137))	('SDHx', 'Chemical', '-', (329, 333))	('tumours', 'Disease', (559, 566))	('tumours', 'Disease', (210, 217))
37475	24138700	Therapy with radionucleotides may be used for tumors exhibiting uptake on diagnostic scans, with I131-MIBG radiotherapy being the treatment of choice.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('radionucleotides', 'Chemical', '-', (13, 29))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('I131-MIBG', 'Var', (97, 106))	('tumors', 'Disease', (46, 52))	('MIBG', 'Chemical', 'MESH:D019797', (102, 106))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
37484	21997692	This occurs via germline mutations of the SDH subunit genes and hitherto unknown mechanisms.	('germline mutations', 'Var', (16, 34))	('SDH', 'Gene', (42, 45))	('SDH', 'Gene', '6390', (42, 45))	('occurs', 'Reg', (5, 11))
37489	21997692	Two patients each had either pulmonary chondroma or paraganglioma (CT), but none of the examined cases had SDH germline mutations (CSS) or somatic KIT/PDGFRA or BRAF mutations.	('PDGFRA', 'Gene', '5156', (151, 157))	('mutations', 'Var', (166, 175))	('PDGFRA', 'Gene', (151, 157))	('SDH', 'Gene', '6390', (107, 110))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('pulmonary chondroma or paraganglioma', 'Disease', (29, 65))	('pulmonary chondroma', 'Phenotype', 'HP:0031474', (29, 48))	('patients', 'Species', '9606', (4, 12))	('SDH', 'Gene', (107, 110))	('pulmonary chondroma or paraganglioma', 'Disease', 'MESH:D002812', (29, 65))
37500	21997692	Rare examples of wild-type GISTs, mostly intestinal ones, have been reported to harbor BRAF mutations.	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))	('mutations', 'Var', (92, 101))
37502	21997692	In Carney-Stratakis syndrome (GIST and paraganglioma) and familial paraganglioma syndromes, loss-of-function SDHB, C, or D germline mutations are associated with a somatic loss of function alteration causing bi-allelic inactivation of SDH in tumor cells typical of classic tumor suppressor genes.	('Carney-Stratakis syndrome', 'Disease', (3, 28))	('SDHB', 'Gene', '6390', (109, 113))	('bi-allelic inactivation', 'Var', (208, 231))	('loss of function', 'NegReg', (172, 188))	('alteration', 'Var', (189, 199))	('tumor', 'Disease', (242, 247))	('tumor', 'Disease', (273, 278))	('paraganglioma', 'Phenotype', 'HP:0002668', (39, 52))	('paraganglioma', 'Disease', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('SDHB', 'Gene', (109, 113))	('paraganglioma', 'Disease', 'MESH:D010235', (67, 80))	('SDH', 'Gene', '6390', (109, 112))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (3, 28))	('familial paraganglioma syndromes', 'Disease', (58, 90))	('loss-of-function', 'NegReg', (92, 108))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('germline mutations', 'Var', (123, 141))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (58, 90))	('SDH', 'Gene', '6390', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('SDH', 'Gene', (109, 112))	('paraganglioma', 'Disease', (39, 52))	('paraganglioma', 'Disease', 'MESH:D010235', (39, 52))	('SDH', 'Gene', (235, 238))
37505	21997692	It has also been shown that silencing of SDHB expression induces tumor-like phenotypic traits in cell cultures.	('induces', 'Reg', (57, 64))	('tumor', 'Disease', (65, 70))	('SDHB', 'Gene', '6390', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('silencing', 'Var', (28, 37))	('SDHB', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
37513	21997692	Many of them are also SDHB-negative generally reflecting loss-of-function germline mutations in one of the SDH-genes, which in combination with somatic loss-of-function of the other allele lead to silencing of one of the SDH-genes and functional loss of the SDH-complex.	('mutations', 'Var', (83, 92))	('loss-of-function', 'NegReg', (57, 73))	('SDH', 'Gene', '6390', (258, 261))	('SDH', 'Gene', '6390', (107, 110))	('SDHB', 'Gene', '6390', (22, 26))	('SDH', 'Gene', '6390', (221, 224))	('SDHB', 'Gene', (22, 26))	('SDH', 'Gene', '6390', (22, 25))	('loss', 'NegReg', (246, 250))	('SDH', 'Gene', (258, 261))	('loss-of-function', 'NegReg', (152, 168))	('SDH', 'Gene', (107, 110))	('silencing', 'MPA', (197, 206))	('SDH', 'Gene', (22, 25))	('SDH', 'Gene', (221, 224))
37533	21997692	BRAF mutation analysis was performed to detect the previously reported exon 15 mutant.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('exon', 'Var', (71, 75))
37595	21997692	Based on knowledge of the impact of loss of any SDH - subunits inactivation of the entire SDH complex in other tumors associated with SDH-deficiency, especially paragangliomas  - it is appropriate to designate this group as SDH-deficient GISTs.	('SDH', 'Gene', '6390', (224, 227))	('paragangliomas', 'Disease', 'MESH:D010235', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('paragangliomas', 'Phenotype', 'HP:0002668', (161, 175))	('tumors', 'Disease', (111, 117))	('SDH', 'Gene', (90, 93))	('SDH', 'Gene', '6390', (48, 51))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('SDH', 'Gene', (224, 227))	('SDH', 'Gene', '6390', (134, 137))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (224, 242))	('paragangliomas', 'Disease', (161, 175))	('SDH-deficient GIST', 'Disease', (224, 242))	('SDH', 'Gene', (48, 51))	('SDH-deficiency', 'Disease', 'MESH:D007153', (134, 148))	('paraganglioma', 'Phenotype', 'HP:0002668', (161, 174))	('SDH', 'Gene', '6390', (90, 93))	('SDH', 'Gene', (134, 137))	('inactivation', 'Var', (63, 75))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('SDH-deficiency', 'Disease', (134, 148))
37607	21997692	A molecular genetic clue to SDH-deficient GIST is lack of KIT and PDGFRA mutations (wild type), found here in all analyzed SDH-deficient GISTS, similar to previous observations on a smaller number of cases.	('SDH-deficient GIST', 'Disease', (28, 46))	('PDGFRA', 'Gene', '5156', (66, 72))	('PDGFRA', 'Gene', (66, 72))	('KIT', 'Gene', (58, 61))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (123, 141))	('SDH-deficient GIST', 'Disease', (123, 141))	('mutations', 'Var', (73, 82))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (28, 46))
37608	21997692	Also, these tumors seem to be unrelated to the rare KIT/PDGFRA-wild type GISTs carrying BRAF mutations found in adult patients, more often with intestinal GISTs.	('mutations', 'Var', (93, 102))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('PDGFRA', 'Gene', '5156', (56, 62))	('PDGFRA', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('patients', 'Species', '9606', (118, 126))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
37624	21997692	Carney triad patients do not have SDH germline mutations, but SDH-deficiency may be mediated by allelic losses in SDH, and losses in chromosome 1p36, the locus of SDHB, may be the alternative mechanism for loss of function of the SDH complex.	('SDH', 'Gene', '6390', (62, 65))	('SDHB', 'Gene', '6390', (163, 167))	('SDH', 'Gene', '6390', (114, 117))	('SDHB', 'Gene', (163, 167))	('SDH', 'Gene', '6390', (34, 37))	('SDH', 'Gene', '6390', (163, 166))	('SDH', 'Gene', (34, 37))	('SDH', 'Gene', (62, 65))	('patients', 'Species', '9606', (13, 21))	('SDH', 'Gene', (230, 233))	('SDH-deficiency', 'Disease', 'MESH:D007153', (62, 76))	('SDH', 'Gene', (163, 166))	('SDH', 'Gene', (114, 117))	('losses', 'Var', (123, 129))	('SDH', 'Gene', '6390', (230, 233))	('losses', 'NegReg', (104, 110))	('SDH-deficiency', 'Disease', (62, 76))
37626	21997692	The pathogenesis is based on a loss-of-function germline mutation in SDH subunits B, C, or D, and functional loss of the other allele based on currently poorly understood mechanisms.	('SDH', 'Gene', '6390', (69, 72))	('loss', 'NegReg', (109, 113))	('loss-of-function', 'NegReg', (31, 47))	('SDH', 'Gene', (69, 72))	('germline mutation', 'Var', (48, 65))
37629	21997692	However, 54% of patients with paragangliomas, commonly SDH-deficient tumors, were found to have germline SDH mutations in one study.	('SDH-deficient tumors', 'Disease', 'MESH:D009369', (55, 75))	('SDH', 'Gene', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SDH', 'Gene', '6390', (55, 58))	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('paragangliomas', 'Disease', 'MESH:D010235', (30, 44))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('SDH', 'Gene', '6390', (105, 108))	('SDH', 'Gene', (55, 58))	('mutations', 'Var', (109, 118))	('SDH-deficient tumors', 'Disease', (55, 75))	('paragangliomas', 'Disease', (30, 44))	('paragangliomas', 'Phenotype', 'HP:0002668', (30, 44))
37632	21997692	SDHA mutations have been previously found in one patient with a cathecholamine-secreting adrenal paraganglioma.	('cathecholamine', 'Chemical', '-', (64, 78))	('SDHA', 'Gene', (0, 4))	('adrenal paraganglioma', 'Disease', (89, 110))	('patient', 'Species', '9606', (49, 56))	('mutations', 'Var', (5, 14))	('found', 'Reg', (36, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (97, 110))	('secreting adrenal paraganglioma', 'Phenotype', 'HP:0011746', (79, 110))	('SDHA', 'Gene', '6389', (0, 4))	('adrenal paraganglioma', 'Disease', 'MESH:D010236', (89, 110))
37633	21997692	Previously SDHA loss-of function mutation was reported in Leigh syndrome featuring a severe neurodegenerative disorder.	('neurodegenerative disorder', 'Disease', (92, 118))	('SDHA', 'Gene', '6389', (11, 15))	('mutation', 'Var', (33, 41))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (92, 118))	('Leigh syndrome', 'Disease', 'MESH:D007888', (58, 72))	('SDHA', 'Gene', (11, 15))	('loss-of function', 'NegReg', (16, 32))	('Leigh syndrome', 'Disease', (58, 72))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (92, 118))
37695	20672008	123I-MIBG is preferred over 131I-MIBG because of higher sensitivity, lower radiation exposure, and improved imaging quality.	('123I-MIBG', 'Var', (0, 9))	('improved', 'PosReg', (99, 107))	('123I-MIBG', 'Chemical', 'MESH:D019797', (0, 9))	('131I-MIBG', 'Chemical', 'MESH:D019797', (28, 37))	('higher', 'PosReg', (49, 55))
37701	20672008	Germline mutations in NF1, ret, VHL, SHDB, SDHC, and SDHD had been associated with paraganglioma.	('Germline mutations', 'Var', (0, 18))	('NF1', 'Gene', (22, 25))	('SDHC', 'Gene', '6391', (43, 47))	('NF1', 'Gene', '4763', (22, 25))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('SDHD', 'Gene', (53, 57))	('SDHD', 'Gene', '6392', (53, 57))	('paraganglioma', 'Disease', (83, 96))	('ret', 'Gene', (27, 30))	('SHDB', 'Gene', (37, 41))	('associated', 'Reg', (67, 77))	('ret', 'Gene', '5979', (27, 30))	('VHL', 'Disease', 'MESH:D006623', (32, 35))	('paraganglioma', 'Disease', 'MESH:D010235', (83, 96))	('VHL', 'Disease', (32, 35))	('SDHC', 'Gene', (43, 47))
37722	33491666	The longevity gene mIndy (I'm Not Dead, Yet) affects blood pressure through sympathoadrenal mechanisms Reduced expression of the plasma membrane citrate transporter INDY (acronym I'm Not Dead, Yet) extends life span in lower organisms.	('expression', 'Var', (111, 121))	('citrate', 'Chemical', 'MESH:D019343', (145, 152))	('INDY', 'Gene', (165, 169))	('blood pressure', 'MPA', (53, 67))	('INDY', 'Gene', '40049', (165, 169))	('mIndy', 'Gene', '237831', (19, 24))	('extends', 'PosReg', (198, 205))	('affects', 'Reg', (45, 52))	('life span', 'CPA', (206, 215))	('mIndy', 'Gene', (19, 24))
37723	33491666	Deletion of the mammalian Indy (mIndy) gene in rodents improves metabolism via mechanisms akin to caloric restriction, known to lower blood pressure (BP) by sympathoadrenal inhibition.	('lower blood pressure', 'Phenotype', 'HP:0002615', (128, 148))	('Indy', 'Gene', '40049', (33, 37))	('Indy', 'Gene', (33, 37))	('mammalian', 'Species', '9606', (16, 25))	('mIndy', 'Gene', '237831', (32, 37))	('lower', 'NegReg', (128, 133))	('Indy', 'Gene', (26, 30))	('BP', 'Gene', '14563', (150, 152))	('mIndy', 'Gene', (32, 37))	('metabolism', 'MPA', (64, 74))	('Indy', 'Gene', '40049', (26, 30))	('improves', 'PosReg', (55, 63))	('Deletion', 'Var', (0, 8))
37724	33491666	We hypothesized that mIndy deletion attenuates sympathoadrenal support of BP.	('mIndy', 'Gene', '237831', (21, 26))	('mIndy', 'Gene', (21, 26))	('deletion', 'Var', (27, 35))	('attenuates', 'NegReg', (36, 46))	('BP', 'Gene', '14563', (74, 76))
37729	33491666	Our data suggest that deletion of mIndy reduces sympathoadrenal support of BP and HR by attenuating catecholamine biosynthesis.	('mIndy', 'Gene', '237831', (34, 39))	('deletion', 'Var', (22, 30))	('mIndy', 'Gene', (34, 39))	('attenuating', 'NegReg', (88, 99))	('catecholamine', 'Chemical', 'MESH:D002395', (100, 113))	('BP', 'Gene', '14563', (75, 77))	('reduces', 'NegReg', (40, 47))	('catecholamine biosynthesis', 'MPA', (100, 126))
37730	33491666	Deletion of mIndy recapitulates beneficial cardiovascular and metabolic responses to caloric restriction, making it an attractive therapeutic target.	('mIndy', 'Gene', (12, 17))	('mIndy', 'Gene', '237831', (12, 17))	('Deletion', 'Var', (0, 8))
37731	33491666	Deletion of mIndy reduces blood pressure and heart rate by attenuating catecholamine biosynthesis and recapitulates beneficial cardiovascular and metabolic responses to caloric restriction.	('catecholamine biosynthesis', 'MPA', (71, 97))	('blood pressure', 'MPA', (26, 40))	('reduces', 'NegReg', (18, 25))	('reduces blood pressure', 'Phenotype', 'HP:0002615', (18, 40))	('mIndy', 'Gene', (12, 17))	('catecholamine', 'Chemical', 'MESH:D002395', (71, 84))	('heart rate', 'MPA', (45, 55))	('mIndy', 'Gene', '237831', (12, 17))	('attenuating', 'NegReg', (59, 70))	('Deletion', 'Var', (0, 8))
37740	33491666	Deletion of mIndy protected mice from many characteristics of the cardiometabolic syndrome that develop with high-calorie feeding and aging, including adiposity, nonalcoholic fatty liver, insulin resistance, and mitochondrial dysfunction.	('mitochondrial dysfunction', 'Disease', (212, 237))	('cardiometabolic syndrome', 'Disease', 'MESH:D061325', (66, 90))	('nonalcoholic', 'Disease', (162, 174))	('insulin', 'Gene', (188, 195))	('mice', 'Species', '10090', (28, 32))	('cardiometabolic syndrome', 'Disease', (66, 90))	('insulin', 'Gene', '3630', (188, 195))	('adiposity', 'Disease', (151, 160))	('fatty liver', 'Phenotype', 'HP:0001397', (175, 186))	('insulin resistance', 'Phenotype', 'HP:0000855', (188, 206))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (212, 237))	('mIndy', 'Gene', (12, 17))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (212, 237))	('mIndy', 'Gene', '237831', (12, 17))	('Deletion', 'Var', (0, 8))
37741	33491666	Similarly, knockdown of mIndy in rats and mice improved glucose and lipid homeostasis.	('improved', 'PosReg', (47, 55))	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('mIndy', 'Gene', (24, 29))	('mice', 'Species', '10090', (42, 46))	('mIndy', 'Gene', '237831', (24, 29))	('rats', 'Species', '10116', (33, 37))	('knockdown', 'Var', (11, 20))
37744	33491666	We tested the hypothesis that similar to caloric restriction, loss of mIndy reduces arterial BP and heart rate (HR) by decreasing the sympathoadrenal support in mice independently of body composition.	('mice', 'Species', '10090', (161, 165))	('loss', 'Var', (62, 66))	('reduces arterial BP', 'Phenotype', 'HP:0002615', (76, 95))	('decreasing', 'NegReg', (119, 129))	('BP', 'Gene', '14563', (93, 95))	('mIndy', 'Gene', '237831', (70, 75))	('reduces', 'NegReg', (76, 83))	('mIndy', 'Gene', (70, 75))	('heart rate', 'MPA', (100, 110))	('sympathoadrenal support', 'MPA', (134, 157))
37745	33491666	Radiotelemetry was used to evaluate the effect of mIndy deletion on BP and HR in young, age-matched, male mINDY-KO and WT mice fed a normal chow diet, without differences in body composition.	('deletion', 'Var', (56, 64))	('mIndy', 'Gene', '237831', (50, 55))	('mice', 'Species', '10090', (122, 126))	('mINDY', 'Gene', '237831', (106, 111))	('mINDY', 'Gene', (106, 111))	('BP', 'Gene', '14563', (68, 70))	('mIndy', 'Gene', (50, 55))
37746	33491666	Moreover, we assessed autonomic cardiovascular control using state-of-the-art physiological, biochemical, and pharmacological profiling and studied the effect of the deletion of mINDY in adrenal glands, ex vivo and in cellular culture in vitro.	('deletion', 'Var', (166, 174))	('mINDY', 'Gene', '237831', (178, 183))	('mINDY', 'Gene', (178, 183))
37758	33491666	Systolic BP variability in the low-frequency band was reduced by 50% with mINDY deletion (LFsys; WT = 4.8 +- 0.6 mmHg2; mINDY-KO = 2.4 +- 0.4 mmHg2; Figure 3A; P < 0.05).	('mINDY', 'Gene', (74, 79))	('deletion', 'Var', (80, 88))	('mINDY', 'Gene', '237831', (120, 125))	('mINDY', 'Gene', (120, 125))	('BP', 'Gene', '14563', (9, 11))	('reduced', 'NegReg', (54, 61))	('mINDY', 'Gene', '237831', (74, 79))
37762	33491666	These findings strongly support the idea that mINDY deletion is associated with a shift of cardiovascular sympathetic and parasympathetic modulation toward parasympathetic predominance.	('cardiovascular sympathetic', 'Disease', 'MESH:D002318', (91, 117))	('shift', 'Reg', (82, 87))	('cardiovascular sympathetic', 'Disease', (91, 117))	('mINDY', 'Gene', '237831', (46, 51))	('mINDY', 'Gene', (46, 51))	('deletion', 'Var', (52, 60))
37763	33491666	We further investigated the sympathoadrenal system as a mediator of the beneficial cardiovascular effect of mINDY deletion.	('mINDY', 'Gene', '237831', (108, 113))	('mINDY', 'Gene', (108, 113))	('deletion', 'Var', (114, 122))
37782	33491666	This small molecule inhibitor reduces mINDY-mediated citrate uptake in mouse hepatocytes with an IC50 of 0.21 muM and lowers fasting glucose levels and urinary citrate excretion in high-fat diet-induced obese mice.	('urinary citrate excretion', 'MPA', (152, 177))	('mice', 'Species', '10090', (209, 213))	('urinary citrate', 'Phenotype', 'HP:0012406', (152, 167))	('inhibitor', 'Var', (20, 29))	('mINDY', 'Gene', '237831', (38, 43))	('citrate', 'Chemical', 'MESH:D019343', (53, 60))	('obese', 'Disease', 'MESH:D009765', (203, 208))	('citrate', 'Chemical', 'MESH:D019343', (160, 167))	('lowers', 'NegReg', (118, 124))	('mINDY', 'Gene', (38, 43))	('glucose', 'Chemical', 'MESH:D005947', (133, 140))	('mouse', 'Species', '10090', (71, 76))	('reduces', 'NegReg', (30, 37))	('obese', 'Disease', (203, 208))
37783	33491666	We first assessed citrate uptake in MPCs with and without 1 muM of PF-06761281 and found a significant approximately 35% reduction in the presence of the mINDY inhibitor (P < 0.001, Figure 6A).	('PF-06761281', 'Var', (67, 78))	('PF-06761281', 'Chemical', 'MESH:C000609014', (67, 78))	('mINDY', 'Gene', '237831', (154, 159))	('mINDY', 'Gene', (154, 159))	('citrate uptake', 'MPA', (18, 32))	('citrate', 'Chemical', 'MESH:D019343', (18, 25))	('reduction', 'NegReg', (121, 130))
37785	33491666	Previous report showed that PF-06761281 dose-dependently lowers citrate uptake in the liver, kidney, and testis with IC50 values of 1.4, 1.0, and 1.0 muM, respectively, while IC50 values in human hepatocytes are 0.74 muM and in mouse hepatocytes 0.21 muM.	('PF-06761281', 'Chemical', 'MESH:C000609014', (28, 39))	('citrate', 'Chemical', 'MESH:D019343', (64, 71))	('human', 'Species', '9606', (190, 195))	('mouse', 'Species', '10090', (228, 233))	('lowers', 'NegReg', (57, 63))	('PF-06761281', 'Var', (28, 39))	('citrate uptake', 'MPA', (64, 78))
37790	33491666	Next, we assessed whether mIndy deletion can reduce steroid hormone levels and synthesis.	('deletion', 'Var', (32, 40))	('mIndy', 'Gene', '237831', (26, 31))	('synthesis', 'MPA', (79, 88))	('steroid hormone levels', 'MPA', (52, 74))	('steroid', 'Chemical', 'MESH:D013256', (52, 59))	('reduce', 'NegReg', (45, 51))	('mIndy', 'Gene', (26, 31))
37800	33491666	In this setting, ejection fraction (Supplemental Figure 5C), stroke volume (Supplemental Figure 5D) and strain (Supplemental Figure 5, E and F), as well as fractional shortening, cardiac output, end-diastolic- and end-systolic volume, and end-diastolic and end-systolic left ventricle mass (Supplemental Figure 6, A-F) were similar between mINDY-KO and weight-matched WT control mice, used as the correct control group instead of WT littermates, indicating that there were no cardiac structural abnormalities associated with the deletion of mIndy and that no morphological changes accounted for the observed phenotype.	('stroke', 'Disease', (61, 67))	('cardiac structural abnormalities', 'Disease', 'MESH:D006331', (476, 508))	('mIndy', 'Gene', '237831', (541, 546))	('mIndy', 'Gene', (541, 546))	('mINDY', 'Gene', '237831', (340, 345))	('mINDY', 'Gene', (340, 345))	('stroke', 'Disease', 'MESH:D020521', (61, 67))	('cardiac structural abnormalities', 'Phenotype', 'HP:0001627', (476, 508))	('mice', 'Species', '10090', (379, 383))	('deletion', 'Var', (529, 537))	('cardiac structural abnormalities', 'Disease', (476, 508))	('stroke', 'Phenotype', 'HP:0001297', (61, 67))
37802	33491666	In this study, deletion of the longevity gene mIndy (Slc13a5) lowered BP and HR as measured by radiotelemetry.	('Slc13a5', 'Gene', (53, 60))	('BP', 'Gene', '14563', (70, 72))	('deletion', 'Var', (15, 23))	('lowered', 'NegReg', (62, 69))	('mIndy', 'Gene', (46, 51))	('mIndy', 'Gene', '237831', (46, 51))	('Slc13a5', 'Gene', '237831', (53, 60))
37819	33491666	Moreover, inhibition of citrate uptake by mIndy deletion results in AMPK activation and increased mitochondrial activity.	('citrate uptake', 'MPA', (24, 38))	('AMPK activation', 'MPA', (68, 83))	('inhibition', 'NegReg', (10, 20))	('mitochondrial activity', 'MPA', (98, 120))	('citrate', 'Chemical', 'MESH:D019343', (24, 31))	('mIndy', 'Gene', '237831', (42, 47))	('mIndy', 'Gene', (42, 47))	('increased', 'PosReg', (88, 97))	('deletion', 'Var', (48, 56))
37821	33491666	Overall, we hypothesize that the interaction between transcriptional epigenetic regulation and a change in cellular energy levels contributes to the effect of citrate on catecholamine synthesis and secretion.	('effect', 'MPA', (149, 155))	('citrate', 'Chemical', 'MESH:D019343', (159, 166))	('cellular energy levels', 'MPA', (107, 129))	('catecholamine synthesis', 'MPA', (170, 193))	('transcriptional epigenetic regulation', 'Var', (53, 90))	('citrate', 'MPA', (159, 166))	('catecholamine', 'Chemical', 'MESH:D002395', (170, 183))	('change', 'Reg', (97, 103))	('secretion', 'MPA', (198, 207))
37833	33491666	Deletion of mIndy has previously been shown to improve metabolic disease, such as diet-induced obesity, insulin resistance, and nonalcoholic fatty liver disease in mice.	('nonalcoholic fatty liver disease', 'Disease', (128, 160))	('insulin resistance', 'Phenotype', 'HP:0000855', (104, 122))	('obesity', 'Disease', 'MESH:D009765', (95, 102))	('improve', 'PosReg', (47, 54))	('mice', 'Species', '10090', (164, 168))	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (128, 160))	('obesity', 'Disease', (95, 102))	('metabolic disease', 'Disease', (55, 72))	('liver disease', 'Phenotype', 'HP:0001392', (147, 160))	('insulin', 'Gene', (104, 111))	('obesity', 'Phenotype', 'HP:0001513', (95, 102))	('diet-induced obesity', 'Phenotype', 'HP:0012743', (82, 102))	('mIndy', 'Gene', (12, 17))	('fatty liver', 'Phenotype', 'HP:0001397', (141, 152))	('insulin', 'Gene', '3630', (104, 111))	('mIndy', 'Gene', '237831', (12, 17))	('metabolic disease', 'Disease', 'MESH:D008659', (55, 72))	('Deletion', 'Var', (0, 8))
37843	33491666	These data indicate that deletion of mIndy is not associated with structural and/or functional abnormalities in the heart.	('mIndy', 'Gene', (37, 42))	('deletion', 'Var', (25, 33))	('mIndy', 'Gene', '237831', (37, 42))	('abnormalities in the heart', 'Phenotype', 'HP:0001627', (95, 121))
37857	33491666	Deletion or reduction of mIndy/mINDY has been shown to be protective against diet-induced metabolic disorders, including obesity, insulin resistance, and nonalcoholic fatty liver disease.	('liver disease', 'Phenotype', 'HP:0001392', (173, 186))	('obesity', 'Phenotype', 'HP:0001513', (121, 128))	('mINDY', 'Gene', (31, 36))	('metabolic disorders', 'Disease', 'MESH:D008659', (90, 109))	('metabolic disorders', 'Disease', (90, 109))	('insulin', 'Gene', (130, 137))	('nonalcoholic fatty liver disease', 'Disease', (154, 186))	('reduction', 'NegReg', (12, 21))	('mIndy', 'Gene', (25, 30))	('insulin resistance', 'Phenotype', 'HP:0000855', (130, 148))	('mINDY', 'Gene', '237831', (31, 36))	('Deletion', 'Var', (0, 8))	('obesity', 'Disease', (121, 128))	('diet-induced', 'Disease', (77, 89))	('mIndy', 'Gene', '237831', (25, 30))	('fatty liver', 'Phenotype', 'HP:0001397', (167, 178))	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (154, 186))	('obesity', 'Disease', 'MESH:D009765', (121, 128))	('insulin', 'Gene', '3630', (130, 137))
37858	33491666	Here, we added potentially novel pieces to generate a more complete picture of the benefits of decreasing mINDY activity by showing that deletion of mIndy also affects arterial BP and HR by reducing sympathoadrenal activity.	('affects', 'Reg', (160, 167))	('mIndy', 'Gene', (149, 154))	('decreasing', 'NegReg', (95, 105))	('mINDY', 'Gene', '237831', (106, 111))	('mINDY', 'Gene', (106, 111))	('sympathoadrenal activity', 'MPA', (199, 223))	('deletion', 'Var', (137, 145))	('BP', 'Gene', '14563', (177, 179))	('mIndy', 'Gene', '237831', (149, 154))	('activity', 'MPA', (112, 120))	('reducing', 'NegReg', (190, 198))
37859	33491666	Remarkably, recent genome-wide association studies suggested that the Slc13a5 polymorphism rs16956192 contributes to variability in arterial BP.	('BP', 'Gene', '14563', (141, 143))	('rs16956192', 'Var', (91, 101))	('Slc13a5', 'Gene', '237831', (70, 77))	('rs16956192', 'Mutation', 'rs16956192', (91, 101))	('Slc13a5', 'Gene', (70, 77))
37907	33491666	The specific mINDY-mediated citric acid uptake was obtained by subtracting off the nonspecific uptake measured in the presence of PF-06761281.	('PF-06761281', 'Var', (130, 141))	('PF-06761281', 'Chemical', 'MESH:C000609014', (130, 141))	('mINDY', 'Gene', '237831', (13, 18))	('mINDY', 'Gene', (13, 18))	('citric acid', 'Chemical', 'MESH:D019343', (28, 39))
37936	27165774	According to current molecular biology and genetics-based taxonomy, PPGL can be divided into three different clusters characterized by: Krebs cycle reprogramming with oncometabolite accumulation or depletion (group 1a); activation of the (pseudo) hypoxia signalling pathway with increased tumour cell proliferation, invasiveness and migration (group 1b); and aberrant kinase signalling causing a pro-mitogenic and anti-apoptotic state (group 2).	('tumour', 'Disease', (289, 295))	('invasiveness', 'CPA', (316, 328))	('Krebs', 'Chemical', '-', (136, 141))	('increased', 'PosReg', (279, 288))	('hypoxia', 'Disease', 'MESH:D000860', (247, 254))	('kinase', 'CPA', (368, 374))	('activation', 'PosReg', (220, 230))	('depletion', 'MPA', (198, 207))	('PPGL', 'Chemical', '-', (68, 72))	('tumour', 'Phenotype', 'HP:0002664', (289, 295))	('hypoxia', 'Disease', (247, 254))	('causing', 'Reg', (386, 393))	('aberrant', 'Var', (359, 367))	('tumour', 'Disease', 'MESH:D009369', (289, 295))	('pro-mitogenic', 'PosReg', (396, 409))	('anti-apoptotic', 'CPA', (414, 428))	('migration', 'CPA', (333, 342))
37960	27165774	According to a recent study, the 1-year progression-free survival of those with metastatic PPGL was 46% at diagnosis for therapy-naive patients with metastases.	('patients', 'Species', '9606', (135, 143))	('metastases', 'Disease', (149, 159))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('PPGL', 'Chemical', '-', (91, 95))	('PPGL', 'Gene', (91, 95))	('metastatic', 'Var', (80, 90))
37976	27165774	Truncating mutations in proteins constituting the Krebs cycle cause familial PGL syndromes types 1-5, as well as fumarate hydratase-associated PPGL (Fig.	('Truncating mutations', 'Var', (0, 20))	('Krebs', 'Chemical', '-', (50, 55))	('fumarate hydratase', 'Gene', '2271', (113, 131))	('PPGL', 'Chemical', '-', (143, 147))	('fumarate hydratase', 'Gene', (113, 131))	('cause', 'Reg', (62, 67))	('familial PGL syndromes types 1-5', 'Disease', (68, 100))
37980	27165774	It was previously shown that inactivating mutations in the FH gene cause dominant hereditary leiomyomatosis and renal cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cause', 'Reg', (67, 72))	('renal cell cancer', 'Phenotype', 'HP:0005584', (112, 129))	('FH', 'Gene', '2271', (59, 61))	('inactivating mutations', 'Var', (29, 51))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (82, 129))
37981	27165774	Such mutations were recently associated with PPGL with an increased frequency of metastatic disease.	('metastatic disease', 'Disease', (81, 99))	('mutations', 'Var', (5, 14))	('PPGL', 'Disease', (45, 49))	('associated', 'Reg', (29, 39))	('PPGL', 'Chemical', '-', (45, 49))
37982	27165774	It was recently suggested that constitutional mutations in MDH2, which encodes a third enzyme involved in the Krebs cycle, may be involved in PPGL tumourigenesis.	('MDH2', 'Gene', '4191', (59, 63))	('mutations', 'Var', (46, 55))	('MDH2', 'Gene', (59, 63))	('involved', 'Reg', (130, 138))	('PPGL tumour', 'Disease', 'MESH:D009369', (142, 153))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('Krebs', 'Chemical', '-', (110, 115))	('PPGL tumour', 'Disease', (142, 153))
37983	27165774	Familial PGL type 1 is caused by loss of function mutations in the SDHD gene and shows near complete penetrance for parasympathetic PGL tumours that are most commonly located in the head and neck region.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('mutations', 'Var', (50, 59))	('Familial PGL type 1', 'Disease', (0, 19))	('SDHD', 'Gene', (67, 71))	('SDHD', 'Gene', '6392', (67, 71))	('parasympathetic PGL tumours', 'Disease', 'MESH:D010235', (116, 143))	('parasympathetic PGL tumours', 'Disease', (116, 143))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('loss of function', 'NegReg', (33, 49))
37988	27165774	It was recently suggested that mortality is not increased in carriers of SDHD mutations compared to a normal population.	('mortality', 'Disease', (31, 40))	('mutations', 'Var', (78, 87))	('mortality', 'Disease', 'MESH:D003643', (31, 40))	('SDHD', 'Gene', (73, 77))	('SDHD', 'Gene', '6392', (73, 77))
37989	27165774	Familial PGL type 2 is caused by loss of function mutations in the SDHAF2 gene and has so far been detected in a limited number of families.	('mutations', 'Var', (50, 59))	('Familial PGL type 2', 'Disease', (0, 19))	('SDHAF2', 'Gene', '54949', (67, 73))	('SDHAF2', 'Gene', (67, 73))	('loss of function', 'NegReg', (33, 49))
37990	27165774	Familial PGL type 3 is caused by loss of function mutations in the SDHC gene and is mainly characterized by parasympathetic PGLs located in the head and neck region with a low risk of metastases.	('metastases', 'Disease', (184, 194))	('SDHC', 'Gene', '6391', (67, 71))	('mutations', 'Var', (50, 59))	('metastases', 'Disease', 'MESH:D009362', (184, 194))	('Familial PGL type 3', 'Disease', (0, 19))	('SDHC', 'Gene', (67, 71))	('loss of function', 'NegReg', (33, 49))
37991	27165774	Familial PGL type 4 is caused by loss of function mutations in SDHB and is associated with sympathetic PGL with an increased risk of malignancy.	('SDHB', 'Gene', (63, 67))	('malignancy', 'Disease', (133, 143))	('sympathetic PGL', 'Disease', (91, 106))	('mutations', 'Var', (50, 59))	('Familial PGL type 4', 'Disease', (0, 19))	('SDHB', 'Gene', '6390', (63, 67))	('malignancy', 'Disease', 'MESH:D009369', (133, 143))	('loss of function', 'NegReg', (33, 49))
37995	27165774	Mutations in SDHx genes have also been associated with pituitary adenomas.	('pituitary adenomas', 'Disease', 'MESH:D010911', (55, 73))	('SDHx', 'Gene', (13, 17))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (55, 73))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (39, 49))	('pituitary adenomas', 'Disease', (55, 73))
37996	27165774	Familial PGL type 5 is caused by truncating mutations in the SDHA gene.	('SDHA', 'Gene', (61, 65))	('Familial PGL type 5', 'Disease', (0, 19))	('truncating mutations', 'Var', (33, 53))	('caused by', 'Reg', (23, 32))	('SDHA', 'Gene', '6389', (61, 65))
37997	27165774	It is thought that carriers of SDHA mutations have a low penetrance for the development of PPGL tumours, and concomitant presentation with GIST is infrequently observed.	('SDHA', 'Gene', '6389', (31, 35))	('PPGL tumours', 'Disease', 'MESH:D009369', (91, 103))	('PPGL tumours', 'Disease', (91, 103))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('mutations', 'Var', (36, 45))	('SDHA', 'Gene', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))
37998	27165774	Constitutional loss of function mutations in the fumarate hydratase (FH) gene were recently described in patients with PPGL.	('patients', 'Species', '9606', (105, 113))	('PPGL', 'Disease', (119, 123))	('FH', 'Gene', '2271', (69, 71))	('PPGL', 'Chemical', '-', (119, 123))	('mutations', 'Var', (32, 41))	('fumarate hydratase', 'Gene', '2271', (49, 67))	('loss of function', 'NegReg', (15, 31))	('fumarate hydratase', 'Gene', (49, 67))
38000	27165774	It was previously demonstrated that germline FH mutations cause autosomal dominant hereditary leiomyomatosis and renal cell cancer.	('renal cell cancer', 'Phenotype', 'HP:0005584', (113, 130))	('FH', 'Gene', '2271', (45, 47))	('autosomal dominant hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (64, 130))	('cause', 'Reg', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (48, 57))
38002	27165774	Loss of function mutations in these genes causes an accumulation of succinate that inhibits EGLN1-3 enzyme activity (Fig.	('EGLN1-3', 'Gene', '54583;112398;112399', (92, 99))	('EGLN1-3', 'Gene', (92, 99))	('activity', 'MPA', (107, 115))	('inhibits', 'NegReg', (83, 91))	('succinate', 'MPA', (68, 77))	('accumulation', 'PosReg', (52, 64))	('Loss of function', 'NegReg', (0, 16))	('succinate', 'Chemical', 'MESH:D019802', (68, 77))	('mutations', 'Var', (17, 26))
38003	27165774	Inhibition of this enzyme family causes decreased hydroxylation and subsequent ubiqutination of hypoxia-inducible factor (HIF) transcription factors, resulting in a pseudohypoxic state similar to that seen in VHL- and EPAS1-mutated tumours.	('ubiqutination', 'MPA', (79, 92))	('tumours', 'Disease', 'MESH:D009369', (232, 239))	('EPAS1', 'Gene', (218, 223))	('tumours', 'Disease', (232, 239))	('VHL', 'Gene', (209, 212))	('pseudohypoxic state', 'MPA', (165, 184))	('hypoxia', 'Disease', (96, 103))	('decreased hydroxylation', 'Disease', (40, 63))	('VHL', 'Gene', '7428', (209, 212))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('Inhibition', 'Var', (0, 10))	('EPAS1', 'Gene', '2034', (218, 223))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('decreased hydroxylation', 'Disease', 'MESH:C565044', (40, 63))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))
38005	27165774	Tumours with FH mutations have increased levels of fumarate, and similar molecular consequences to those of SDHx-mutated tumours.	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('increased', 'PosReg', (31, 40))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (16, 25))	('fumarate', 'Chemical', 'MESH:D005650', (51, 59))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))	('levels of fumarate', 'MPA', (41, 59))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('FH', 'Gene', '2271', (13, 15))
38006	27165774	Mutations in genes associated with regulation of cellular oxygen sensation and response to hypoxia have been shown to give rise to PPGL (Fig.	('hypoxia', 'Disease', (91, 98))	('PPGL', 'Chemical', '-', (131, 135))	('give rise', 'Reg', (118, 127))	('oxygen', 'Chemical', 'MESH:D010100', (58, 64))	('Mutations', 'Var', (0, 9))	('PPGL', 'Disease', (131, 135))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
38008	27165774	Gain of function mutations in the EPAS1 gene causes PGL-somatostatinoma-polycythemia syndrome.	('EPAS1', 'Gene', '2034', (34, 39))	('EPAS1', 'Gene', (34, 39))	('PGL-somatostatinoma-polycythemia syndrome', 'Disease', (52, 93))	('polycythemia', 'Phenotype', 'HP:0001901', (72, 84))	('PGL-somatostatinoma-polycythemia syndrome', 'Disease', 'MESH:D010235', (52, 93))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
38009	27165774	VHL syndrome is caused by loss of function mutations in the tumour suppressor gene VHL with an incidence of 1/36 000.	('VHL', 'Gene', '7428', (83, 86))	('VHL syndrome', 'Disease', 'MESH:D006623', (0, 12))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('mutations', 'Var', (43, 52))	('VHL syndrome', 'Disease', (0, 12))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('loss of function', 'NegReg', (26, 42))	('VHL', 'Gene', (83, 86))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
38012	27165774	Patients with C598T mutation present with Chuvash polycythemia.	('Chuvash polycythemia', 'Disease', 'MESH:C563918', (42, 62))	('C598T', 'Var', (14, 19))	('C598T', 'Mutation', 'rs28940298', (14, 19))	('polycythemia', 'Phenotype', 'HP:0001901', (50, 62))	('Patients', 'Species', '9606', (0, 8))	('Chuvash polycythemia', 'Disease', (42, 62))
38015	27165774	Gain of function mutations within the EPAS1 gene that encodes the hypoxia-inducible factor-2alpha (HIF2A) protein is associated with autosomal dominant polycythemia.	('polycythemia', 'Phenotype', 'HP:0001901', (152, 164))	('hypoxia-inducible factor-2alpha', 'Gene', '2034', (66, 97))	('HIF2A', 'Gene', '2034', (99, 104))	('EPAS1', 'Gene', '2034', (38, 43))	('hypoxia-inducible factor-2alpha', 'Gene', (66, 97))	('EPAS1', 'Gene', (38, 43))	('HIF2A', 'Gene', (99, 104))	('autosomal dominant polycythemia', 'Disease', (133, 164))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))	('autosomal dominant polycythemia', 'Disease', 'MESH:D011086', (133, 164))
38016	27165774	Activating amino acid transitions at HIF2A hydroxylation sites was recently described as a cause of PPGL, polycythemia and somatostatinoma.	('cause', 'Reg', (91, 96))	('Activating amino acid transitions', 'Var', (0, 33))	('HIF2A', 'Gene', (37, 42))	('PPGL', 'Disease', (100, 104))	('polycythemia', 'Phenotype', 'HP:0001901', (106, 118))	('polycythemia and somatostatinoma', 'Disease', 'MESH:D013005', (106, 138))	('HIF2A', 'Gene', '2034', (37, 42))	('PPGL', 'Chemical', '-', (100, 104))
38018	27165774	To determine the tissue distribution of somatic EPAS1 mutations, deep sequencing of peripheral blood and/or buccal swabs should be performed.	('EPAS1', 'Gene', (48, 53))	('EPAS1', 'Gene', '2034', (48, 53))	('mutations', 'Var', (54, 63))
38020	27165774	Mutations in VHL and EPAS1 cause a cellular pseudohypoxic state through the stabilization of HIF transcription factor proteins (Fig.	('EPAS1', 'Gene', '2034', (21, 26))	('VHL', 'Gene', (13, 16))	('cause', 'Reg', (27, 32))	('EPAS1', 'Gene', (21, 26))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', '7428', (13, 16))	('stabilization', 'MPA', (76, 89))	('cellular pseudohypoxic state', 'MPA', (35, 63))
38021	27165774	Loss of function mutations in the VHL gene results in reduced ubiqutination of HIF transcription factors with subsequent reduction of degradation by the proteasome.	('ubiqutination of HIF transcription factors', 'MPA', (62, 104))	('Loss of function', 'NegReg', (0, 16))	('degradation by the proteasome', 'MPA', (134, 163))	('reduced', 'NegReg', (54, 61))	('VHL', 'Gene', (34, 37))	('reduced ubiqutination', 'Phenotype', 'HP:0000742', (54, 75))	('VHL', 'Gene', '7428', (34, 37))	('mutations', 'Var', (17, 26))	('reduction', 'NegReg', (121, 130))
38023	27165774	Gain of function mutations at EPAS1 hydroxylation sites causes reduced VHL protein binding that diminishes HIF2A ubiqutination enabling HIF escape from degradation.	('EPAS1', 'Gene', '2034', (30, 35))	('diminishes', 'NegReg', (96, 106))	('EPAS1', 'Gene', (30, 35))	('VHL', 'Gene', (71, 74))	('reduced', 'NegReg', (63, 70))	('binding', 'Interaction', (83, 90))	('HIF2A', 'Gene', '2034', (107, 112))	('VHL', 'Gene', '7428', (71, 74))	('HIF2A', 'Gene', (107, 112))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
38025	27165774	Mutations in EGLN1 and EGLN2, genes that encode the proteins responsible for prolyl hydroxylation targeting HIF for degradation, may also confer susceptibility to PPGL.	('PPGL', 'Chemical', '-', (163, 167))	('EGLN2', 'Gene', '112398', (23, 28))	('EGLN1', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('susceptibility', 'Reg', (145, 159))	('prolyl', 'Chemical', '-', (77, 83))	('EGLN2', 'Gene', (23, 28))	('EGLN1', 'Gene', '54583', (13, 18))	('PPGL', 'Disease', (163, 167))
38026	27165774	These tumours predominantly secrete norepinephrine, due to low expression of phenylethanolamine N-methyltransferase (PNMT), and have been linked to hypermethylation of the PNMT gene promoter.	('PNMT', 'Gene', '5409', (172, 176))	('PNMT', 'Gene', '5409', (117, 121))	('secrete norepinephrine', 'MPA', (28, 50))	('norepinephrine', 'Chemical', 'MESH:D009638', (36, 50))	('hypermethylation', 'Var', (148, 164))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('expression', 'MPA', (63, 73))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('low', 'NegReg', (59, 62))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('phenylethanolamine N-methyltransferase', 'Gene', (77, 115))	('phenylethanolamine N-methyltransferase', 'Gene', '5409', (77, 115))	('PNMT', 'Gene', (172, 176))	('tumours', 'Disease', (6, 13))	('PNMT', 'Gene', (117, 121))
38028	27165774	Mutated genes classified as cluster 2 PPGL are tightly linked to regulation of signalling in either RAS/RAF/MAPK or (mTOR) pathways (Fig.	('mTOR', 'Gene', (117, 121))	('mTOR', 'Gene', '2475', (117, 121))	('Mutated genes', 'Var', (0, 13))	('linked', 'Reg', (55, 61))	('RAS/RAF/MAPK', 'Pathway', (100, 112))	('PPGL', 'Chemical', '-', (38, 42))	('PPGL', 'Gene', (38, 42))
38031	27165774	Somatic HRAS mutations are common in PPGL, but no cases with constitutional HRAS mutation and PPGL have been presented.	('PPGL', 'Disease', (37, 41))	('PPGL', 'Chemical', '-', (94, 98))	('HRAS', 'Gene', '3265', (76, 80))	('PPGL', 'Chemical', '-', (37, 41))	('HRAS', 'Gene', '3265', (8, 12))	('HRAS', 'Gene', (76, 80))	('HRAS', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('common', 'Reg', (27, 33))
38032	27165774	NF1, also known as von Recklinghausen's disease, is caused by loss of function mutations in the neurofibromin 1 (NF1) gene with an incidence of 1 : 2500-3000.	("von Recklinghausen's disease", 'Disease', (19, 47))	('neurofibromin 1', 'Gene', (96, 111))	("von Recklinghausen's disease", 'Disease', 'MESH:C537392', (19, 47))	('NF1', 'Gene', (113, 116))	('NF1', 'Gene', '4763', (113, 116))	('loss of function', 'NegReg', (62, 78))	('NF1', 'Gene', (0, 3))	('neurofibromin 1', 'Gene', '4763', (96, 111))	('NF1', 'Gene', '4763', (0, 3))	('mutations', 'Var', (79, 88))
38035	27165774	MEN2 is caused by gain of function mutations within the RET (rearranged during transfection) gene that encodes a tyrosine kinase receptor.	('MEN2', 'Disease', (0, 4))	('rearranged during transfection', 'Gene', '5979', (61, 91))	('RET', 'Gene', '5979', (56, 59))	('MEN', 'Species', '9606', (0, 3))	('rearranged during transfection', 'Gene', (61, 91))	('gain of function', 'PosReg', (18, 34))	('RET', 'Gene', (56, 59))	('mutations', 'Var', (35, 44))
38036	27165774	MEN2 is characterized by susceptibility to multiple endocrine neoplasms: medullary thyroid carcinoma, PCC and parathyroid adenomas.	('thyroid carcinoma', 'Disease', (83, 100))	('parathyroid adenomas', 'Disease', 'MESH:D010282', (110, 130))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (73, 100))	('endocrine neoplasms', 'Phenotype', 'HP:0100568', (52, 71))	('MEN', 'Species', '9606', (0, 3))	('PCC', 'Disease', (102, 105))	('susceptibility', 'Reg', (25, 39))	('parathyroid adenomas', 'Disease', (110, 130))	('parathyroid adenomas', 'Phenotype', 'HP:0002897', (110, 130))	('endocrine neoplasms', 'Disease', (52, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('PCC', 'Phenotype', 'HP:0002666', (102, 105))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (83, 100))	('MEN2', 'Var', (0, 4))	('neoplasms', 'Phenotype', 'HP:0002664', (62, 71))	('endocrine neoplasms', 'Disease', 'MESH:D004701', (52, 71))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (83, 100))
38038	27165774	Mutations in the cysteine-rich extracellular domains located in exons 10-11 underlie a majority of MEN2 cases.	('MEN', 'Species', '9606', (99, 102))	('underlie', 'Reg', (76, 84))	('MEN2 cases', 'Disease', (99, 109))	('Mutations', 'Var', (0, 9))	('cysteine', 'Chemical', 'MESH:D003545', (17, 25))
38039	27165774	Disease-causing variants within noncysteine regions located in exons 13-16 are less common and characterized by pronounced interpatient phenotypic heterogeneity.	('noncysteine', 'Chemical', '-', (32, 43))	('variants', 'Var', (16, 24))	('Disease-causing', 'Reg', (0, 15))	('patient', 'Species', '9606', (128, 135))
38040	27165774	Among carriers of noncysteine mutations, only a minority develops PCC.	('noncysteine', 'Chemical', '-', (18, 29))	('PCC', 'Phenotype', 'HP:0002666', (66, 69))	('noncysteine mutations', 'Var', (18, 39))	('PCC', 'Disease', (66, 69))
38042	27165774	Loss of function mutations in the TMEM127 (transmembrane protein 127) gene causes susceptibility to PCC, and less frequently abdominal PGL.	('transmembrane protein 127', 'Gene', '55654', (43, 68))	('PCC', 'Phenotype', 'HP:0002666', (100, 103))	('Loss of function', 'NegReg', (0, 16))	('abdominal PGL', 'Disease', (125, 138))	('TMEM127', 'Gene', '55654', (34, 41))	('transmembrane protein 127', 'Gene', (43, 68))	('PCC', 'Disease', (100, 103))	('mutations', 'Var', (17, 26))	('TMEM127', 'Gene', (34, 41))
38047	27165774	Loss of function mutations in the MAX (myc-associated factor X) gene has been shown to cause hereditary PCC and less commonly PGL.	('MAX', 'Gene', '4149', (34, 37))	('MAX', 'Gene', (34, 37))	('myc-associated factor X', 'Gene', (39, 62))	('Loss of function', 'NegReg', (0, 16))	('PGL', 'Disease', (126, 129))	('myc-associated factor X', 'Gene', '4149', (39, 62))	('mutations', 'Var', (17, 26))	('PCC', 'Phenotype', 'HP:0002666', (104, 107))
38052	27165774	It has been suggested that tumours with mutations in NF1, RET and HRAS overlap with regard to their mechanisms of tumourigenesis, that diverge on RAS-mediated signalling.	('RET', 'Gene', '5979', (58, 61))	('tumour', 'Disease', (114, 120))	('NF1', 'Gene', (53, 56))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('RET', 'Gene', (58, 61))	('HRAS', 'Gene', (66, 70))	('NF1', 'Gene', '4763', (53, 56))	('mutations', 'Var', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumour', 'Disease', (27, 33))	('tumours', 'Disease', (27, 34))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('HRAS', 'Gene', '3265', (66, 70))
38053	27165774	Mutations in NF1 GTPas domain result in reduced inhibition of RAS intrinsic activity, whilst ligand or mutant-dependent activation of RET results in activation of RAS through downstream signalling.	('activation', 'PosReg', (149, 159))	('RAS intrinsic activity', 'MPA', (62, 84))	('RET', 'Gene', (134, 137))	('NF1', 'Gene', (13, 16))	('activation', 'PosReg', (120, 130))	('Mutations', 'Var', (0, 9))	('reduced inhibition', 'NegReg', (40, 58))	('NF1', 'Gene', '4763', (13, 16))	('RAS', 'Protein', (163, 166))	('RET', 'Gene', '5979', (134, 137))	('GTPas', 'Gene', (17, 22))
38055	27165774	Somatic gain of function mutations in H-RAS has been described in a significant proportion of PPGLs.	('mutations', 'Var', (25, 34))	('PPGLs', 'Chemical', '-', (94, 99))	('PPGLs', 'Disease', (94, 99))	('H-RAS', 'Gene', '3265', (38, 43))	('gain of function', 'PosReg', (8, 24))	('H-RAS', 'Gene', (38, 43))
38056	27165774	Activating mutations in RET occurs at phosphorylation sites causing intrinsic activation resulting in downstream activation of RAS/RAF/MAPK and PI3K/AKT signalling pathways.	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('RET', 'Gene', '5979', (24, 27))	('AKT', 'Gene', (149, 152))	('activation', 'PosReg', (113, 123))	('RET', 'Gene', (24, 27))	('activation', 'PosReg', (78, 88))	('intrinsic', 'MPA', (68, 77))	('AKT', 'Gene', '207', (149, 152))
38057	27165774	Loss of function mutations in TMEM127 results in reduced inhibition of the mTOR pathway in an RAS/RAF/MAPK- and PI3K/AKT-independent manner.	('AKT', 'Gene', '207', (117, 120))	('reduced', 'NegReg', (49, 56))	('AKT', 'Gene', (117, 120))	('TMEM127', 'Gene', (30, 37))	('TMEM127', 'Gene', '55654', (30, 37))	('Loss of function', 'NegReg', (0, 16))	('mutations', 'Var', (17, 26))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('inhibition', 'MPA', (57, 67))
38059	27165774	Mutated MAX causes deregulation of the MYC-MAX-MXD1 pathway that leads to altered transcription and signalling in the NRAS-PIK3CA-AKT1-mTOR pathway.	('MYC', 'Gene', '4609', (39, 42))	('MAX', 'Gene', (43, 46))	('PIK3CA', 'Gene', (123, 129))	('MAX', 'Gene', (8, 11))	('deregulation', 'MPA', (19, 31))	('NRAS', 'Gene', '4893', (118, 122))	('AKT1', 'Gene', '207', (130, 134))	('MXD1', 'Gene', '4084', (47, 51))	('mTOR', 'Gene', (135, 139))	('MYC', 'Gene', (39, 42))	('Mutated', 'Var', (0, 7))	('MAX', 'Gene', '4149', (43, 46))	('AKT1', 'Gene', (130, 134))	('mTOR', 'Gene', '2475', (135, 139))	('NRAS', 'Gene', (118, 122))	('MAX', 'Gene', '4149', (8, 11))	('PIK3CA', 'Gene', '5290', (123, 129))	('altered', 'Reg', (74, 81))	('MXD1', 'Gene', (47, 51))
38061	27165774	The fact that MAX-mutated tumours are distinct from those with NF1/RET/HRAS mutations is also supported by their intermediate expression of PNMT, and subsequent lower production of epinephrine.	('lower', 'NegReg', (161, 166))	('production of epinephrine', 'MPA', (167, 192))	('mutations', 'Var', (76, 85))	('MAX', 'Gene', '4149', (14, 17))	('MAX', 'Gene', (14, 17))	('tumours', 'Disease', (26, 33))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('RET', 'Gene', '5979', (67, 70))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('HRAS', 'Gene', '3265', (71, 75))	('PNMT', 'Gene', (140, 144))	('epinephrine', 'Chemical', 'MESH:D004837', (181, 192))	('HRAS', 'Gene', (71, 75))	('NF1', 'Gene', (63, 66))	('RET', 'Gene', (67, 70))	('PNMT', 'Gene', '5409', (140, 144))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('NF1', 'Gene', '4763', (63, 66))
38066	27165774	VHL-mutated PPGLs show loss of 3p and 11p, whereas those with NF1 mutations show loss of 17q.	('mutations', 'Var', (66, 75))	('PPGLs', 'Chemical', '-', (12, 17))	('PPGLs', 'Gene', (12, 17))	('NF1', 'Gene', (62, 65))	('VHL', 'Gene', (0, 3))	('loss', 'NegReg', (23, 27))	('NF1', 'Gene', '4763', (62, 65))	('VHL', 'Gene', '7428', (0, 3))	('11p', 'MPA', (38, 41))
38070	27165774	Novel findings indicate that somatic ATRX mutations occur in a subset of PPGLs that display a high frequency of metastatic disease.	('PPGLs', 'Gene', (73, 78))	('metastatic disease', 'Disease', (112, 130))	('ATRX', 'Gene', '546', (37, 41))	('ATRX', 'Gene', (37, 41))	('PPGLs', 'Chemical', '-', (73, 78))	('mutations', 'Var', (42, 51))
38071	27165774	Extrapolating findings from other neuroendocrine tumours, inactivation of ATRX is most probably a secondary event that promotes malignancy through establishing the alternative lengthening of telomeres phenotype.	('neuroendocrine tumours', 'Disease', (34, 56))	('promotes', 'PosReg', (119, 127))	('malignancy', 'Disease', 'MESH:D009369', (128, 138))	('ATRX', 'Gene', '546', (74, 78))	('inactivation', 'Var', (58, 70))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('malignancy', 'Disease', (128, 138))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (34, 56))	('ATRX', 'Gene', (74, 78))
38072	27165774	Somatic mutations in the TERT promoter (SDHx-deficient PPGL), as well as in the chromatin modifier KMT2D, have also been identified but remain to be validated by independent observers.	('TERT', 'Gene', (25, 29))	('SDHx-deficient PPGL', 'Disease', 'MESH:D007153', (40, 59))	('mutations', 'Var', (8, 17))	('KMT2D', 'Gene', '8085', (99, 104))	('SDHx-deficient PPGL', 'Disease', (40, 59))	('KMT2D', 'Gene', (99, 104))	('TERT', 'Gene', '7015', (25, 29))
38073	27165774	It has also been demonstrated that metastases accumulate chromosomal aberrations compared to the paired primary tumours.	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('metastases', 'Disease', 'MESH:D009362', (35, 45))	('tumours', 'Disease', 'MESH:D009369', (112, 119))	('tumours', 'Disease', (112, 119))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('chromosomal aberrations', 'Var', (57, 80))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (57, 80))	('metastases', 'Disease', (35, 45))
38075	27165774	ATRX, KMT2D and TERT promoter have also been identified with recurrent mutations but their contribution to the disease remains to be identified.	('TERT', 'Gene', (16, 20))	('ATRX', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (16, 20))	('mutations', 'Var', (71, 80))	('ATRX', 'Gene', '546', (0, 4))	('KMT2D', 'Gene', (6, 11))	('KMT2D', 'Gene', '8085', (6, 11))
38077	27165774	Recurrent copy number alterations as well as miRNA and methylation patterns have been identified, but the particular mechanisms in which these events are involved in PPGL tumourigenesis remain to be clarified.	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('PPGL tumour', 'Disease', 'MESH:D009369', (166, 177))	('miRNA', 'MPA', (45, 50))	('copy number', 'Var', (10, 21))	('PPGL tumour', 'Disease', (166, 177))
38081	27165774	Whether specific epimutations can be directly linked to tumour formation or malignancy remains to be determined.	('malignancy', 'Disease', 'MESH:D009369', (76, 86))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('malignancy', 'Disease', (76, 86))	('linked', 'Reg', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))	('epimutations', 'Var', (17, 29))
38082	27165774	Of particular interest for PPGLs was the recent identification of epimutated SDHC as a cause of GIST.	('SDHC', 'Gene', (77, 81))	('SDHC', 'Gene', '6391', (77, 81))	('GIST', 'Disease', (96, 100))	('cause', 'Reg', (87, 92))	('PPGLs', 'Chemical', '-', (27, 32))	('epimutated', 'Var', (66, 76))
38085	27165774	This includes poor cost effectiveness and long analysis times especially for extensive analyses such as genes of interest in PPGL.	('genes', 'Var', (104, 109))	('PPGL', 'Chemical', '-', (125, 129))	('PPGL', 'Gene', (125, 129))
38090	27165774	A similar approach might soon be used for familial PGL syndromes where patients with SDHB mutations have been most commonly studied.	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (71, 79))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('familial PGL syndromes', 'Disease', (42, 64))
38091	27165774	SDHB carriers have a substantially increased risk of malignant tumours as well as higher mortality, which motivates extensive follow-up.	('mortality', 'Disease', 'MESH:D003643', (89, 98))	('malignant tumours', 'Disease', 'MESH:D009369', (53, 70))	('malignant tumours', 'Disease', (53, 70))	('carriers', 'Var', (5, 13))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('mortality', 'Disease', (89, 98))	('SDHB', 'Gene', '6390', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('SDHB', 'Gene', (0, 4))
38095	27165774	Tumours with mutations in FH, VHL, EPAS1 and succinate dehydrogenase complex genes predominantly produce norepinephrine with low levels of epinephrine.	('succinate', 'Chemical', 'MESH:D019802', (45, 54))	('norepinephrine', 'Chemical', 'MESH:D009638', (105, 119))	('VHL', 'Gene', (30, 33))	('produce norepinephrine', 'MPA', (97, 119))	('VHL', 'Gene', '7428', (30, 33))	('EPAS1', 'Gene', '2034', (35, 40))	('FH', 'Gene', '2271', (26, 28))	('epinephrine', 'Chemical', 'MESH:D004837', (108, 119))	('mutations', 'Var', (13, 22))	('EPAS1', 'Gene', (35, 40))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('epinephrine', 'Chemical', 'MESH:D004837', (139, 150))
38096	27165774	Tumours with RET, NF1, TMEM127, MAX and HRAS mutations show increased levels of both epinephrine and norepinephrine.	('epinephrine', 'Chemical', 'MESH:D004837', (85, 96))	('norepinephrine', 'Chemical', 'MESH:D009638', (101, 115))	('mutations', 'Var', (45, 54))	('RET', 'Gene', (13, 16))	('NF1', 'Gene', (18, 21))	('RET', 'Gene', '5979', (13, 16))	('HRAS', 'Gene', '3265', (40, 44))	('TMEM127', 'Gene', (23, 30))	('MAX', 'Gene', (32, 35))	('norepinephrine', 'MPA', (101, 115))	('TMEM127', 'Gene', '55654', (23, 30))	('MAX', 'Gene', '4149', (32, 35))	('levels of', 'MPA', (70, 79))	('epinephrine', 'Chemical', 'MESH:D004837', (104, 115))	('HRAS', 'Gene', (40, 44))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('increased', 'PosReg', (60, 69))	('NF1', 'Gene', '4763', (18, 21))
38106	27165774	The identification of deregulated telomere maintenance, especially in the alternative lengthening of telomeres (ALT) context, may have therapeutic implications as such tumours have been shown to respond to ATR inhibition.	('deregulated', 'Var', (22, 33))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumours', 'Phenotype', 'HP:0002664', (168, 175))	('ATR', 'Gene', '545', (206, 209))	('ATR', 'Gene', (206, 209))	('tumours', 'Disease', 'MESH:D009369', (168, 175))	('tumours', 'Disease', (168, 175))	('telomere', 'Protein', (34, 42))
38107	27165774	It has been demonstrated that succinate dehydrogenase-deficient PPGLs exhibit a hypermethylator phenotype, and related tumours (GIST) have shown epimutations in SDHC.	('SDHC', 'Gene', (161, 165))	('exhibit', 'Reg', (70, 77))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('hypermethylator phenotype', 'MPA', (80, 105))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('PPGLs', 'Chemical', '-', (64, 69))	('SDHC', 'Gene', '6391', (161, 165))	('epimutations', 'Var', (145, 157))	('tumours', 'Disease', (119, 126))	('PPGLs', 'Gene', (64, 69))	('succinate', 'Chemical', 'MESH:D019802', (30, 39))
38165	31288201	There have been 10 identified gene sites where mutation has led to the development of these tumors.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('led to', 'Reg', (60, 66))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
38309	29386252	Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD Germline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas.	('SDHC', 'Gene', (181, 185))	('SDHD', 'Gene', (186, 190))	('SDHD', 'Gene', (139, 143))	('SDHB', 'Gene', (176, 180))	('SDHC', 'Gene', '6391', (130, 134))	('variants', 'Var', (164, 172))	('SDH', 'Gene', '6390', (176, 179))	('succinate dehydrogenase', 'Gene', '6390', (86, 109))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (233, 251))	('variants', 'Var', (74, 82))	('SDH', 'Gene', (186, 189))	('SDHB', 'Gene', '6390', (124, 128))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (233, 266))	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', (130, 133))	('frequent causes', 'Reg', (204, 219))	('SDH', 'Gene', (176, 179))	('phaeochromocytoma', 'Disease', (233, 250))	('SDH', 'Gene', '6390', (181, 184))	('SDHC', 'Gene', (130, 134))	('SDHB', 'Gene', (124, 128))	('paragangliomas', 'Phenotype', 'HP:0002668', (252, 266))	('paraganglioma', 'Phenotype', 'HP:0002668', (252, 265))	('succinate', 'Chemical', 'MESH:D019802', (86, 95))	('SDH', 'Gene', '6390', (124, 127))	('succinate dehydrogenase', 'Gene', (86, 109))	('phaeochromocytomas', 'Disease', (233, 251))	('SDHC', 'Gene', '6391', (181, 185))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (233, 250))	('SDHB', 'Gene', '6390', (176, 180))	('SDHD', 'Gene', '6392', (186, 190))	('SDHD', 'Gene', '6392', (139, 143))	('phaeochromocytomas/paragangliomas', 'Disease', (233, 266))	('SDH', 'Gene', (181, 184))	('SDH', 'Gene', '6390', (186, 189))	('SDH', 'Gene', '6390', (139, 142))	('SDH', 'Gene', (124, 127))	('SDH', 'Gene', '6390', (130, 133))
38311	29386252	We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.	('SDHB/SDHC/SDHD', 'Gene', (114, 128))	('tumours', 'Phenotype', 'HP:0002664', (39, 46))	('mutation', 'Var', (129, 137))	('tumour', 'Disease', (39, 45))	('tumours', 'Disease', 'MESH:D009369', (39, 46))	('tumours', 'Disease', (39, 46))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))
38313	29386252	876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160).	('germline mutation', 'Var', (45, 62))	('SDHB/SDHC/SDHD', 'Gene', (66, 80))	('patient', 'Species', '9606', (4, 11))	('patients', 'Species', '9606', (4, 12))
38314	29386252	In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations.	('tumour type', 'Disease', (15, 26))	('missense mutations', 'Var', (229, 247))	('tumour type', 'Disease', 'MESH:D009369', (15, 26))	('increased', 'PosReg', (163, 172))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('SDHD:p.Pro81Leu', 'SUBSTITUTION', 'None', (98, 113))	('SDHD:p.Pro81Leu', 'Var', (98, 113))	('SDHB', 'Gene', (224, 228))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
38315	29386252	Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%).	('malignant disease', 'Disease', (8, 25))	('to 7', 'Species', '1214577', (101, 105))	('mutation', 'Var', (62, 70))	('SDHB', 'Gene', (57, 61))	('malignant disease', 'Disease', 'MESH:D009369', (8, 25))
38319	29386252	SDHB mutations are associated with a higher risk of malignancy and renal carcinoma than mutations in other subunits.	('malignancy and renal carcinoma', 'Disease', 'MESH:C538614', (52, 82))	('renal carcinoma', 'Phenotype', 'HP:0005584', (67, 82))	('malignancy', 'Disease', 'MESH:D009369', (52, 62))	('malignancy', 'Disease', (52, 62))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
38320	29386252	We provide more accurate estimates of tumour-specific risks, confirm the mutation-specific phenotype of the SDHD p.Pro81Leu mutation and identify a novel candidate genotype-phenotype association of SDHB missense mutations with effects on SDHB protein stability.	('effects', 'Reg', (227, 234))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('missense mutations', 'Var', (203, 221))	('SDHB', 'Gene', (198, 202))	('p.Pro81Leu', 'Var', (113, 123))	('protein stability', 'MPA', (243, 260))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (113, 123))
38321	29386252	The study sample consisted of men and women referred for SDHB/SDHC/SDHD mutation analysis in National Health Service diagnostic laboratories for a personal or family history of PPGL/HNPGL.	('PPGL/HNPGL', 'Disease', (177, 187))	('women', 'Species', '9606', (38, 43))	('SDHB/SDHC/SDHD', 'Gene', (57, 71))	('mutation', 'Var', (72, 80))
38325	29386252	The DUET and mCSM-PPI scoring systems were used to predict the structural consequences of missense mutations on protein stability and protein-protein affinity, respectively, using the models of SDHB, SDHD and the succinate complex (see supplementary information).	('protein-protein affinity', 'MPA', (134, 158))	('SDHB', 'Gene', (194, 198))	('DUET', 'Gene', (4, 8))	('missense mutations', 'Var', (90, 108))	('DUET', 'Gene', '8997', (4, 8))	('protein stability', 'MPA', (112, 129))
38326	29386252	There were a number of recurrent mutations, for example, SDHB splice-site c.72+1G>T and SDHD missense c.242C>T (p.Pro81Leu) mutations accounted for 20% of probands, and the 10 most common mutations accounted for 48% (see online supplementary figure 3).	('c.72+1G>T', 'Var', (74, 83))	('SDHD', 'Gene', (88, 92))	('p.Pro81Leu', 'Var', (112, 122))	('c.72+1G>T', 'Mutation', 'rs587782703', (74, 83))	('c.242C>T', 'Mutation', 'rs80338844', (102, 110))	('SDHB', 'Gene', (57, 61))	('missense c.242C>T', 'Var', (93, 110))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (112, 122))
38328	29386252	No further thyroid tumours were found beyond the three described previously in SDHB mutation carriers, giving an estimated penetrance of thyroid tumours by age 60 years of 1.5% (95% CI 0.0% to 3.1%) (calculated by Kaplan-Meier analysis of all SDHB mutation carriers).	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('mutation', 'Var', (84, 92))	('thyroid tumours', 'Disease', 'MESH:D013964', (11, 26))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('SDHB', 'Gene', (243, 247))	('thyroid tumours', 'Disease', 'MESH:D013964', (137, 152))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('thyroid tumours', 'Disease', (11, 26))	('thyroid tumours', 'Disease', (137, 152))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('SDHB', 'Gene', (79, 83))
38330	29386252	Of the 21 disease-associated SDHB missense mutations, 20 are predicted to be destabilising, 16 are predicted to destabilise the complex and 4 (p.Cys98Arg, p.Cys101Tyr, p.Cys113Tyr and p.Cys196Tyr) are in metal coordinating cysteines.	('p.Cys113Tyr', 'Var', (168, 179))	('p.Cys98Arg', 'Mutation', 'p.C98R', (143, 153))	('cysteines', 'Chemical', 'MESH:D003545', (223, 232))	('destabilise', 'NegReg', (112, 123))	('disease-associated', 'Reg', (10, 28))	('p.Cys101Tyr', 'Var', (155, 166))	('p.Cys196Tyr', 'Mutation', 'rs876658367', (184, 195))	('missense mutations', 'Var', (34, 52))	('SDHB', 'Gene', (29, 33))	('p.Cys113Tyr', 'Mutation', 'p.C113Y', (168, 179))	('metal', 'Chemical', 'MESH:D008670', (204, 209))	('complex', 'MPA', (128, 135))	('p.Cys98Arg', 'Var', (143, 153))	('p.Cys101Tyr', 'Mutation', 'rs74315371', (155, 166))	('p.Cys196Tyr', 'Var', (184, 195))
38331	29386252	The most destabilising SDHB missense mutation, p.Ile127Ser, affected an isoleucine residue buried deep in the protein with a strong network of intramolecular hydrophobic interactions (figure 3A).	('isoleucine residue buried', 'MPA', (72, 97))	('affected', 'Reg', (60, 68))	('isoleucine', 'Chemical', 'MESH:D007532', (72, 82))	('p.Ile127Ser', 'Var', (47, 58))	('p.Ile127Ser', 'Mutation', 'rs786201095', (47, 58))	('SDHB', 'Gene', (23, 27))
38332	29386252	The three SDHB mutations not predicted to alter protein stability were all predicted to affect the coordination of an iron-sulphur cluster, either directly or by affecting neighbourhood residues (figure 3B).	('affect', 'Reg', (88, 94))	('neighbourhood residues', 'MPA', (172, 194))	('mutations', 'Var', (15, 24))	('affecting', 'Reg', (162, 171))	('iron', 'Chemical', 'MESH:D007501', (118, 122))	('coordination of an iron-sulphur cluster', 'MPA', (99, 138))	('SDHB', 'Gene', (10, 14))
38334	29386252	The p.Pro81Leu mutation is predicted to have a very mild effect on protein stability.	('protein stability', 'MPA', (67, 84))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (4, 14))	('p.Pro81Leu', 'Var', (4, 14))
38335	29386252	Excluding the cases originally analysed by Ricketts et al  to create a replication cohort confirmed the lower risk of PPGL in SDHD p.Pro81Leu mutation carriers versus other SDHD mutation carriers (P=0.031, data not shown).	('p.Pro81Leu', 'SUBSTITUTION', 'None', (131, 141))	('lower', 'NegReg', (104, 109))	('SDHD', 'Gene', (126, 130))	('p.Pro81Leu', 'Var', (131, 141))	('PPGL', 'Disease', (118, 122))
38336	29386252	However, there was a higher overall penetrance for clinical disease (all tumour risk) (P=0.0047) and PPGL risk (P=0.00024) in p.Ile127Ser mutation carriers (the missense mutation with the highest DUET score for predicted protein instability) compared with other missense mutations.	('PPGL', 'Gene', (101, 105))	('p.Ile127Ser', 'Var', (126, 137))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('higher', 'PosReg', (21, 27))	('clinical disease', 'Disease', (51, 67))	('p.Ile127Ser', 'SUBSTITUTION', 'None', (126, 137))
38338	29386252	Bickmann et al  and Bourdeau et al  both describe SDHC p.Arg133X mutation carriers (a mutation that is also common in our cohort) presenting with extra-adrenal paragangliomas and HNPGLs, both benign and malignant.	('HNPGLs', 'Disease', (179, 185))	('p.Arg133X', 'Mutation', 'rs764575966', (55, 64))	('paraganglioma', 'Phenotype', 'HP:0002668', (160, 173))	('p.Arg133X mutation', 'Var', (55, 73))	('extra-adrenal paragangliomas', 'Disease', (146, 174))	('SDHC', 'Gene', (50, 54))	('paragangliomas', 'Phenotype', 'HP:0002668', (160, 174))
38339	29386252	Our findings of SDHC mutation carriers with extra-adrenal paragangliomas, pheochromocytoma and a case of HNPGL with malignant features are consistent with similar tumour risks with SDHC and paternally inherited SDHD mutations (Lefebvre and Foulkes recommend similar tumour screening for SDHC and SDHD mutation carriers).	('SDHC', 'Gene', (16, 20))	('SDHC', 'Gene', (181, 185))	('paraganglioma', 'Phenotype', 'HP:0002668', (58, 71))	('paragangliomas', 'Phenotype', 'HP:0002668', (58, 72))	('SDHD', 'Gene', (211, 215))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('mutation', 'Var', (21, 29))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('mutations', 'Var', (216, 225))	('extra-adrenal paragangliomas, pheochromocytoma', 'Disease', 'MESH:D010673', (44, 90))
38340	29386252	We replicated our previous finding that SDHD p.Pro81Leu mutation carriers manifest almost exclusively with HNPGL, while other SDHD mutation types predispose to both HNPGLs and PPGLs.	('HNPGLs', 'Disease', (165, 171))	('SDHD', 'Gene', (40, 44))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (45, 55))	('HNPGL', 'Disease', (107, 112))	('p.Pro81Leu', 'Var', (45, 55))
38343	29386252	SDHD has a key role in anchoring the SDH complex to the inner mitochondrial membrane, and a truncating SDHD mutation would inactivate the function of the entire SDH complex and be predicted to lead to disordered signalling in the hypoxic gene response pathway and to epigenetic abnormalities resulting from inhibition of enzymes such as prolyl-hydroxylases and ten-eleven translocation enzymes.	('truncating', 'Var', (92, 102))	('hypoxic', 'Disease', 'MESH:D000860', (230, 237))	('disordered', 'Disease', 'MESH:D030342', (201, 211))	('SDHD', 'Gene', (103, 107))	('inhibition', 'NegReg', (307, 317))	('hypoxic', 'Disease', (230, 237))	('disordered', 'Disease', (201, 211))	('ten-eleven translocation enzymes', 'Enzyme', (361, 393))	('function', 'MPA', (138, 146))	('inactivate', 'NegReg', (123, 133))	('epigenetic abnormalities', 'MPA', (267, 291))	('mutation', 'Var', (108, 116))	('lead to', 'Reg', (193, 200))
38344	29386252	The SDHD p.Pro81Leu mutation is predicted not to cause protein instability but to interfere with ubiquinone metabolism/electron transport by changing the folding of helix 1S and by destroying a ubiquinone binding site.	('changing', 'Reg', (141, 149))	('interfere', 'NegReg', (82, 91))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (9, 19))	('ubiquinone', 'Chemical', 'MESH:D014451', (194, 204))	('destroying', 'NegReg', (181, 191))	('folding of', 'MPA', (154, 164))	('ubiquinone binding site', 'MPA', (194, 217))	('SDHD', 'Gene', (4, 8))	('ubiquinone metabolism/electron transport', 'MPA', (97, 137))	('ubiquinone', 'Chemical', 'MESH:D014451', (97, 107))	('p.Pro81Leu', 'Var', (9, 19))
38345	29386252	The small risk of PPGL with the p.Pro81Leu mutations suggests that PPGL and HNPGL result from impairment of different aspects of the function of the SDH complex.	('PPGL', 'Disease', (67, 71))	('function', 'MPA', (133, 141))	('p.Pro81Leu', 'Var', (32, 42))	('impairment', 'NegReg', (94, 104))	('PPGL', 'Disease', (18, 22))	('p.Pro81Leu', 'SUBSTITUTION', 'None', (32, 42))	('SDH', 'Protein', (149, 152))
38347	29386252	We also found a variety of rarer tumour types in individuals with SDHB/SDHC/SDHD mutations, including renal cell carcinoma (RCC), GIST, thyroid and pituitary tumours.	('RCC', 'Disease', (124, 127))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('RCC', 'Disease', 'MESH:C538614', (124, 127))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (102, 122))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('renal cell carcinoma', 'Disease', (102, 122))	('pituitary tumour', 'Phenotype', 'HP:0002893', (148, 164))	('pituitary tumours', 'Disease', (148, 165))	('mutations', 'Var', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('thyroid', 'Disease', (136, 143))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (102, 122))	('SDHB/SDHC/SDHD', 'Gene', (66, 80))	('GIST', 'Disease', (130, 134))	('pituitary tumours', 'Disease', 'MESH:D010911', (148, 165))
38349	29386252	Thus, in a study of 30 SDHx mutation carriers, a tumour was detected in one patient after 1 year follow-up from normal baseline imaging.	('SDHx', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('SDHx', 'Chemical', '-', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))
38409	26874200	There was no significant correlation between the MN, NMN, and 3-MT concentrations in saliva and plasma in the seated position (T1), rhos= .08 (P=0.81), rhos=0.33 (P= 0.32) and rhos=-0.32 (P=0.37) respectively (Figure 1).	('rhos=0.33', 'Var', (152, 161))	('NMN', 'Chemical', 'MESH:D009647', (53, 56))	('rhos= .08', 'Var', (132, 141))	('rhos=-0.32', 'Var', (176, 186))
38410	26874200	There was also no significant relationship between MN, NMN, and 3-MT concentration in saliva and plasma in supine position (T3), rhos=0.31 (P=0.36), rhos=0.57 (P=0.07) and rhos=-0.33 (P=0.36) (Figure 1).	('3-MT', 'MPA', (64, 68))	('rhos=0.57', 'Var', (149, 158))	('NMN', 'Chemical', 'MESH:D009647', (55, 58))
38550	26992356	Among patients with surgically or biochemically confirmed MTC and Bethesda III/IV cytology, one of the 17 (5.9%) RET proto-oncogene tested patients was newly found to harbor a germline DNA mutation (Supplementary Table S1).	('MTC', 'Phenotype', 'HP:0002865', (58, 61))	('patients', 'Species', '9606', (139, 147))	('RET', 'Gene', (113, 116))	('men', 'Species', '9606', (205, 208))	('germline DNA mutation', 'Var', (176, 197))	('patients', 'Species', '9606', (6, 14))	('RET', 'Gene', '5979', (113, 116))
38573	26992356	Clinical utility is established when a test improves the net health benefit for the patients and/or population in which it is used.	('patients', 'Species', '9606', (84, 92))	('net health benefit', 'MPA', (57, 75))	('test', 'Var', (39, 43))	('improves', 'PosReg', (44, 52))
38578	26992356	Contrary to guideline recommendations, only 30/43 MTC patients identified in this series underwent RET proto-oncogene mutation testing.	('RET', 'Gene', (99, 102))	('patients', 'Species', '9606', (54, 62))	('mutation', 'Var', (118, 126))	('MTC', 'Phenotype', 'HP:0002865', (50, 53))	('RET', 'Gene', '5979', (99, 102))	('men', 'Species', '9606', (27, 30))
38579	26992356	Of the 30 tested MTC patients, three (10% [CI 3-28%]) were found to harbor a germline RET mutation, which carries significant implications for the patient's family (Supplementary Table S1).	('RET', 'Gene', '5979', (86, 89))	('germline', 'Var', (77, 85))	('patient', 'Species', '9606', (21, 28))	('patient', 'Species', '9606', (147, 154))	('patients', 'Species', '9606', (21, 29))	('RET', 'Gene', (86, 89))	('men', 'Species', '9606', (171, 174))	('MTC', 'Phenotype', 'HP:0002865', (17, 20))
38613	26971069	After consultation with a tumor specialist, the patient underwent amputation of the distal phalanx of the right thumb (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('patient', 'Species', '9606', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('amputation', 'Var', (66, 76))
38630	26971069	Positivity of protein S-100, chromogranin A, and synaptophysin are considered confirmatory for the diagnosis.	('chromogranin A', 'Gene', '1113', (29, 43))	('synaptophysin', 'Gene', '6855', (49, 62))	('chromogranin A', 'Gene', (29, 43))	('S-100', 'Gene', '6271', (22, 27))	('Positivity', 'Var', (0, 10))	('synaptophysin', 'Gene', (49, 62))	('S-100', 'Gene', (22, 27))
38637	21074512	This review describes mutations in mtDNA and reduced mtDNA copy number, which contribute to OXPHOS defects in cancer cells.	('cancer', 'Disease', (110, 116))	('reduced', 'NegReg', (45, 52))	('mtDNA', 'Gene', (35, 40))	('mtDNA', 'Gene', (53, 58))	('contribute', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('OXPHOS defects', 'MPA', (92, 106))	('mutations', 'Var', (22, 31))	('copy number', 'MPA', (59, 70))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
38638	21074512	Maternally inherited mtDNA renders susceptibility to cancer, and mutation in the nuclear encoded genes causes defects in mtOXPHOS system.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('defects', 'MPA', (110, 117))	('susceptibility', 'Reg', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (65, 73))	('mtOXPHOS system', 'MPA', (121, 136))
38640	21074512	These epigenetic and genetic changes underlie the Warburg phenotype, which contributes to the development of cancer.	('contributes', 'Reg', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('underlie', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Warburg phenotype', 'Disease', (50, 67))	('epigenetic', 'Var', (6, 16))
38643	21074512	Indeed, defect in OXPHOS is described as one of the most common and profound phenotypes of most cancers.	('defect', 'Var', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('OXPHOS', 'MPA', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancers', 'Disease', (96, 103))
38659	21074512	For example mtOXPHOS enzyme succinate dehydrogenase (SDHD, Complex II) is shown to be mutated in hereditary paragangliomas and phaeochromocytomas.	('succinate dehydrogenase', 'Gene', '6389', (28, 51))	('mutated', 'Var', (86, 93))	('SDHD', 'Gene', '6392', (53, 57))	('SDHD', 'Gene', (53, 57))	('paragangliomas', 'Phenotype', 'HP:0002668', (108, 122))	('succinate dehydrogenase', 'Gene', (28, 51))	('paraganglioma', 'Phenotype', 'HP:0002668', (108, 121))	('hereditary paragangliomas and phaeochromocytomas', 'Disease', 'MESH:D010235', (97, 145))
38661	21074512	Mutations in three of the four subunits of succinate dehydrogenase, namely, SDHB, SDHC, and SDHD, have been involved in tumorigenesis.	('SDHB', 'Gene', '6390', (76, 80))	('SDHB', 'Gene', (76, 80))	('succinate dehydrogenase', 'Gene', (43, 66))	('SDHD', 'Gene', '6392', (92, 96))	('SDHC', 'Gene', '6391', (82, 86))	('SDHD', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('succinate dehydrogenase', 'Gene', '6389', (43, 66))	('Mutations', 'Var', (0, 9))	('involved', 'Reg', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))	('SDHC', 'Gene', (82, 86))
38662	21074512	Recently, mutations in SDHD5 gene encoding proteins involved in assembly of SDHD complex contribute to hereditary paragangliomas have been described.	('SDHD', 'Gene', '6392', (76, 80))	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (23, 27))	('SDHD', 'Gene', (23, 27))	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (103, 128))	('hereditary paragangliomas', 'Disease', (103, 128))	('paraganglioma', 'Phenotype', 'HP:0002668', (114, 127))	('paragangliomas', 'Phenotype', 'HP:0002668', (114, 128))	('mutations', 'Var', (10, 19))
38663	21074512	Interestingly, hereditary mutation in SDHA leads to typical mitochondrial disease such as Leigh syndrome characterized by severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity.	('psychomotor retardation', 'Disease', (186, 209))	('Leigh syndrome', 'Disease', (90, 104))	('progressive neurodegenerative disorder', 'Phenotype', 'HP:0002180', (129, 167))	('SDHA', 'Gene', (38, 42))	('mutation', 'Var', (26, 34))	('epilepsy', 'Disease', 'MESH:D004827', (176, 184))	('psychomotor retardation', 'Phenotype', 'HP:0025356', (186, 209))	('mitochondrial disease', 'Disease', (60, 81))	('psychomotor retardation', 'Disease', 'MESH:D011596', (186, 209))	('SDHA', 'Gene', '6389', (38, 42))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (141, 167))	('epilepsy', 'Phenotype', 'HP:0001250', (176, 184))	('mitochondrial disease', 'Disease', 'MESH:D028361', (60, 81))	('Leigh syndrome', 'Disease', 'MESH:D007888', (90, 104))	('neurodegenerative disorder', 'Disease', (141, 167))	('epilepsy', 'Disease', (176, 184))	('leads to', 'Reg', (43, 51))
38665	21074512	Mutation in SDHA gene causes paraganglioma and pheochromocytoma.	('paraganglioma', 'Disease', (29, 42))	('SDHA', 'Gene', '6389', (12, 16))	('Mutation', 'Var', (0, 8))	('paraganglioma', 'Disease', 'MESH:D010235', (29, 42))	('pheochromocytoma', 'Disease', (47, 63))	('pheochromocytoma', 'Disease', 'MESH:D010673', (47, 63))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (47, 63))	('SDHA', 'Gene', (12, 16))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('causes', 'Reg', (22, 28))
38668	21074512	Mutation in SDH genes led to tumorigenesis, and thus, should be considered as tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Mutation', 'Var', (0, 8))	('SDH', 'Gene', '6390', (12, 15))	('led to', 'Reg', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (78, 83))	('SDH', 'Gene', (12, 15))
38669	21074512	In addition, hereditary mutations in the Krebs's cycle enzyme fumarate hydratase (FH) leads to leiomyomas, uterine fibroids, and renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (129, 149))	('uterine fibroids', 'Phenotype', 'HP:0000131', (107, 123))	('leiomyomas', 'Disease', 'MESH:D007889', (95, 105))	('renal cell carcinoma', 'Disease', (129, 149))	('fumarate hydratase', 'Gene', '2271', (62, 80))	('Krebs', 'Chemical', '-', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('fumarate hydratase', 'Gene', (62, 80))	('leads to', 'Reg', (86, 94))	('uterine fibroids', 'Disease', (107, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (129, 149))	('leiomyomas', 'Disease', (95, 105))	('mutations', 'Var', (24, 33))	('FH', 'Gene', '2271', (82, 84))
38670	21074512	Inhibition of FH activity stabilizes hypoxia-inducing factor, which induces angiogenesis in cancer, and thus, promotes tumorigenesis.	('tumor', 'Disease', (119, 124))	('angiogenesis', 'CPA', (76, 88))	('cancer', 'Disease', (92, 98))	('FH', 'Gene', '2271', (14, 16))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('promotes', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('induces', 'PosReg', (68, 75))
38671	21074512	Indeed both germline and somatic mutations in NDUFA13/GRIM-19, a subunit of Complex I involved in mtOXPHOS is linked to Hurthle cell tumors of the thyroid.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Hurthle cell tumors of the thyroid', 'Disease', (120, 154))	('Hurthle cell tumors of the thyroid', 'Disease', 'MESH:C536913', (120, 154))	('GRIM-19', 'Gene', (54, 61))	('linked to', 'Reg', (110, 119))	('Hurthle cell tumors of the thyroid', 'Phenotype', 'HP:0006781', (120, 154))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('mutations', 'Var', (33, 42))	('tumors of the thyroid', 'Phenotype', 'HP:0100031', (133, 154))	('GRIM-19', 'Gene', '51079', (54, 61))
38675	21074512	Somatic mutations affecting isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), which catalyse the conversion of isocitrate to the Krebs cycle-intermediate -ketoglutarate, have been identified in brain tumors.	('brain tumors', 'Disease', 'MESH:D001932', (194, 206))	('Krebs', 'Chemical', '-', (129, 134))	('brain tumors', 'Phenotype', 'HP:0030692', (194, 206))	('ketoglutarate', 'Chemical', '-', (155, 168))	('IDH1', 'Gene', '3417', (62, 66))	('isocitrate', 'Chemical', 'MESH:C034219', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('identified', 'Reg', (180, 190))	('IDH2', 'Gene', (71, 75))	('brain tumors', 'Disease', (194, 206))	('isocitrate', 'Chemical', 'MESH:C034219', (111, 121))	('mutations', 'Var', (8, 17))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('IDH2', 'Gene', '3418', (71, 75))	('IDH1', 'Gene', (62, 66))
38676	21074512	Recent studies also indicate the presence of IDH1 and IDH2 mutations in other type of cancers such as prostate and B-acute lymphoblastic leukemias.	('IDH1', 'Gene', '3417', (45, 49))	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('IDH2', 'Gene', (54, 58))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (123, 146))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lymphoblastic leukemias', 'Disease', (123, 146))	('prostate', 'Disease', (102, 110))	('IDH2', 'Gene', '3418', (54, 58))	('lymphoblastic leukemias', 'Disease', 'MESH:D054198', (123, 146))	('leukemias', 'Phenotype', 'HP:0001909', (137, 146))	('B-acute lymphoblastic leukemias', 'Phenotype', 'HP:0004812', (115, 146))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (117, 146))	('mutations', 'Var', (59, 68))	('cancers', 'Disease', (86, 93))	('IDH1', 'Gene', (45, 49))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('presence', 'Reg', (33, 41))
38677	21074512	Mutation in IDH1 genes impairs its affinity for substrate and dominantly inhibits wild-type IDH1 activity through the formation of catalytically inactive heterodimers, which leads to the expression of hypoxia-inducing factor with subsequent promotion of tumorigenesis.	('impairs', 'NegReg', (23, 30))	('hypoxia', 'Disease', (201, 208))	('promotion', 'PosReg', (241, 250))	('activity', 'MPA', (97, 105))	('IDH1', 'Gene', '3417', (12, 16))	('hypoxia', 'Disease', 'MESH:D000860', (201, 208))	('catalytically', 'MPA', (131, 144))	('leads to', 'Reg', (174, 182))	('heterodimers', 'MPA', (154, 166))	('tumor', 'Disease', (254, 259))	('IDH1', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('formation', 'MPA', (118, 127))	('affinity for substrate', 'MPA', (35, 57))	('IDH1', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))	('inhibits', 'NegReg', (73, 81))	('IDH1', 'Gene', '3417', (92, 96))	('expression', 'MPA', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
38684	21074512	POLG gene was mutated in 63% of breast tumors.	('breast tumors', 'Phenotype', 'HP:0100013', (32, 45))	('mutated', 'Var', (14, 21))	('breast tumors', 'Disease', 'MESH:D001943', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('breast tumors', 'Disease', (32, 45))	('POLG', 'Gene', (0, 4))	('POLG', 'Gene', '5428', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
38685	21074512	Mutations were found in all three domains of the POLG protein, including T251I (the exonuclease domain), P587L (the linker region) and E1143G (the polymerase domain).	('P587L', 'Mutation', 'rs113994096', (105, 110))	('T251I', 'Var', (73, 78))	('POLG', 'Gene', '5428', (49, 53))	('P587L', 'Var', (105, 110))	('E1143G', 'Mutation', 'rs2307441', (135, 141))	('E1143G', 'Var', (135, 141))	('POLG', 'Gene', (49, 53))	('T251I', 'Mutation', 'rs113994094', (73, 78))
38686	21074512	We identified two novel mutations that include one silent (A703A) and one missense (R628Q) mutation in the evolutionarily conserved POLG linker region.	('POLG', 'Gene', '5428', (132, 136))	('R628Q', 'Var', (84, 89))	('R628Q', 'Mutation', 'rs201871736', (84, 89))	('POLG', 'Gene', (132, 136))	('A703A', 'Var', (59, 64))
38687	21074512	Mutant POLG, when expressed in cancer cells, induced a depletion of mtDNA, decreased mitochondrial activity, decreased mitochondrial membrane potential, increased levels of reactive oxygen species and increased matrigel invasion.	('mitochondrial membrane potential', 'MPA', (119, 151))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (109, 151))	('increased', 'PosReg', (201, 210))	('mtDNA', 'MPA', (68, 73))	('cancer', 'Disease', (31, 37))	('levels of reactive oxygen species', 'MPA', (163, 196))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (173, 196))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('matrigel invasion', 'CPA', (211, 228))	('decreased mitochondrial activity', 'Phenotype', 'HP:0040013', (75, 107))	('increased', 'PosReg', (153, 162))	('mitochondrial activity', 'MPA', (85, 107))	('Mutant', 'Var', (0, 6))	('POLG', 'Gene', '5428', (7, 11))	('decreased', 'NegReg', (109, 118))	('depletion', 'MPA', (55, 64))	('increased levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (153, 196))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('POLG', 'Gene', (7, 11))	('decreased', 'NegReg', (75, 84))
38689	21074512	Mitochondrial DNA mutations have been increasingly identified in various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('identified', 'Reg', (51, 61))	('Mitochondrial DNA', 'Gene', (0, 17))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (18, 27))
38690	21074512	A number of mtDNA rearrangements and amplifications have been reported in acute myeloid leukemia.	('acute myeloid leukemia', 'Disease', (74, 96))	('reported', 'Reg', (62, 70))	('mtDNA', 'Gene', (12, 17))	('rearrangements', 'Var', (18, 32))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (74, 96))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (74, 96))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (80, 96))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('amplifications', 'Var', (37, 51))
38691	21074512	Point mutations in mtDNA mutation have been reported in human colorectal cancer cells, esophageal, ovarian, thyroid, head, neck, lung, bladder, renal, and breast cancer cells.	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('bladder', 'Disease', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('esophageal', 'Disease', (87, 97))	('ovarian', 'Disease', (99, 106))	('ovarian', 'Disease', 'MESH:D010051', (99, 106))	('renal', 'Disease', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('human', 'Species', '9606', (56, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('Point mutations', 'Var', (0, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('mtDNA', 'Gene', (19, 24))	('thyroid', 'Disease', (108, 115))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('colorectal cancer', 'Disease', (62, 79))	('breast cancer', 'Disease', (155, 168))	('reported', 'Reg', (44, 52))	('lung', 'Disease', (129, 133))	('head', 'Disease', (117, 121))
38692	21074512	These reports led to a suggestion that mutations in mtDNA D-loop can function as an independent prognostic marker for breast cancer.	('mtDNA D-loop', 'Gene', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (39, 48))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
38693	21074512	For example lack of protective histones, limited DNA repair capability, lack of introns, and continuous exposure to ROS are associated with increased rate of mutations in mtDNA.	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('introns', 'Protein', (80, 87))	('limited', 'NegReg', (41, 48))	('protective histones', 'Protein', (20, 39))	('mtDNA', 'Gene', (171, 176))	('DNA repair', 'MPA', (49, 59))	('lack', 'NegReg', (12, 16))	('mutations', 'Var', (158, 167))
38696	21074512	Mutation in the D-loop region is an important feature and has been reported in variety of tumors examined to date.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('Mutation', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('reported', 'Reg', (67, 75))
38704	21074512	Notably, mtDNA copy number was inversely proportional to several important endogenous antioxidant entities such as total glutathione, Cu-Zn SOD, and catalase.	('copy', 'Var', (15, 19))	('mtDNA', 'Gene', (9, 14))	('glutathione', 'Chemical', 'MESH:D005978', (121, 132))	('catalase', 'Gene', (149, 157))	('catalase', 'Gene', '847', (149, 157))	('total glutathione', 'MPA', (115, 132))
38709	21074512	Subjects with the haplogroup M7b2 showed an increased risk for hematopoietic cancer.	('M7b2', 'Var', (29, 33))	('hematopoietic cancer', 'Disease', 'MESH:D019337', (63, 83))	('hematopoietic cancer', 'Disease', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
38710	21074512	Results also indicated that haplogroup M7b2 is a risk factor for leukemia.	('risk factor', 'Reg', (49, 60))	('leukemia', 'Phenotype', 'HP:0001909', (65, 73))	('leukemia', 'Disease', 'MESH:D007938', (65, 73))	('leukemia', 'Disease', (65, 73))	('haplogroup M7b2', 'Var', (28, 43))
38713	21074512	Bai and colleagues analyzed mtDNA polymorphism in European-American females and reported that A10398G and T16519C increase breast cancer risk.	('increase breast cancer', 'Disease', (114, 136))	('increase breast cancer', 'Disease', 'MESH:D001943', (114, 136))	('T16519C', 'Mutation', 'g.16519T>C', (106, 113))	('T16519C', 'Var', (106, 113))	('A10398G', 'Mutation', 'g.10398A>G', (94, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('A10398G', 'Var', (94, 101))
38714	21074512	In contrast, T3197C and G13708A were found to decrease breast cancer risk.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('T3197C', 'Var', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('G13708A', 'Var', (24, 31))	('G13708A', 'Mutation', 'g.13708G>A', (24, 31))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('T3197C', 'SUBSTITUTION', 'None', (13, 19))	('decrease', 'NegReg', (46, 54))
38715	21074512	Wang's group evaluated polymorphisms in mtDNA associated with increased risk of pancreatic cancer.	('polymorphisms', 'Var', (23, 36))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 97))	('pancreatic cancer', 'Disease', (80, 97))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('mtDNA', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (46, 56))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))
38717	21074512	The 10398A allele localized in NADH dehydrogenase-3 locus (ND3) of mtDNA is associated with increased risk for invasive breast cancer in African-American women.	('ND3', 'Gene', (59, 62))	('invasive breast cancer', 'Disease', 'MESH:D001943', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('invasive breast cancer', 'Disease', (111, 133))	('NADH', 'Chemical', 'MESH:D009243', (31, 35))	('associated', 'Reg', (76, 86))	('women', 'Species', '9606', (154, 159))	('mtDNA', 'Gene', (67, 72))	('10398A', 'Var', (4, 10))
38718	21074512	Similarly, 10398A mutation is also associated with breast and esophageal cancer in Indian women, whereas 10398G had been shown to increase the risk of breast cancer in European-American women.	('women', 'Species', '9606', (186, 191))	('associated', 'Reg', (35, 45))	('breast and esophageal cancer', 'Disease', 'MESH:D004938', (51, 79))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('10398A mutation', 'Var', (11, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('10398G', 'Var', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('women', 'Species', '9606', (90, 95))
38719	21074512	G10398A along with other germline mutation such as G9055GA, T16519C, G13708A, T3197C, and A10398G also result in increased susceptibility to breast cancer in women.	('T16519C', 'Mutation', 'g.16519T>C', (60, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('susceptibility', 'Reg', (123, 137))	('G10398A', 'Mutation', 'g.10398G>A', (0, 7))	('G13708A', 'Var', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('T3197C', 'SUBSTITUTION', 'None', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('A10398G', 'Mutation', 'g.10398A>G', (90, 97))	('G13708A', 'Mutation', 'g.13708G>A', (69, 76))	('women', 'Species', '9606', (158, 163))	('breast cancer', 'Disease', (141, 154))	('G10398A', 'Var', (0, 7))	('G9055GA', 'Var', (51, 58))	('G9055GA', 'Mutation', 'c.9055G>GA', (51, 58))	('A10398G', 'Var', (90, 97))	('T16519C', 'Var', (60, 67))	('T3197C', 'Var', (78, 84))
38720	21074512	Using cybrid approach, Singh's group analyzed tumorigenic potential of 10398A found in African-American woman and found that 10398A induces complex I activity resulting in increased ROS production.	('woman', 'Species', '9606', (104, 109))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('increased', 'PosReg', (172, 181))	('increased ROS production', 'Phenotype', 'HP:0025464', (172, 196))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('ROS production', 'MPA', (182, 196))	('tumor', 'Disease', (46, 51))	('induces', 'Reg', (132, 139))	('10398A', 'Var', (125, 131))	('complex I activity', 'MPA', (140, 158))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
38721	21074512	The 10398A also conferred resistance to apoptosis mediated by Akt activation.	('apoptosis', 'CPA', (40, 49))	('Akt', 'Gene', '207', (62, 65))	('10398A', 'Var', (4, 10))	('Akt', 'Gene', (62, 65))	('activation', 'PosReg', (66, 76))
38722	21074512	Additionally, Kulawiec and colleagues demonstrated that the G10398A leads to an increased tumorigenesis and metastases in mice.	('metastases', 'Disease', (108, 118))	('mice', 'Species', '10090', (122, 126))	('G10398A', 'Var', (60, 67))	('increased', 'PosReg', (80, 89))	('tumor', 'Disease', (90, 95))	('metastases', 'Disease', 'MESH:D009362', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('G10398A', 'Mutation', 'g.10398G>A', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
38723	21074512	Studies suggest that retrograde cross talk involves epigenetic and genetic changes, which play a key role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('epigenetic', 'Var', (52, 62))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
38724	21074512	Epigenetic modification in the nuclear genome plays a key role in human tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Epigenetic modification', 'Var', (0, 23))
38725	21074512	al., performed Restriction Landmark Genome Scanning (RLGS) with the methylation-sensitive enzyme NotI, which recognizes the sequence GCGGCCGC, and showed that 64 sites were hypomethylated and 50 sites were hypermethylated when mtDNA was depleted from four different cell lines.	('hypomethylated', 'Var', (173, 187))	('RLGS', 'Disease', 'None', (53, 57))	('RLGS', 'Disease', (53, 57))
38727	21074512	These data suggest that OXPHOS impairment plays an important role in the aberrant methylation of CpG islands found in nearly all cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('aberrant', 'Var', (73, 81))	('CpG islands', 'Protein', (97, 108))	('methylation', 'MPA', (82, 93))
38728	21074512	Since OXPHOS defect leads to changes in redox status, membrane potential and the level of ATP, it is plausible that either a single intracellular change or a combination of these changes signal epigenetic changes.	('membrane potential', 'MPA', (54, 72))	('changes', 'Reg', (29, 36))	('redox status', 'MPA', (40, 52))	('OXPHOS', 'Var', (6, 12))	('ATP', 'Chemical', 'MESH:D000255', (90, 93))	('level of ATP', 'MPA', (81, 93))
38731	21074512	Accumulated nuclear genome instability can help cells acquire new functions such as resistance to apoptosis, migration, and invasive characteristics, which in turn, can induce tumorigenesis (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('migration', 'CPA', (109, 118))	('resistance', 'CPA', (84, 94))	('induce', 'PosReg', (169, 175))	('nuclear genome instability', 'Var', (12, 38))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('invasive characteristics', 'CPA', (124, 148))
38736	21074512	When mitochondria are 1) injured severely or 2) damage is persistent (for example, mutation in mtDNA), mitocheckpoint can trigger cellular senescence.	('cellular senescence', 'CPA', (130, 149))	('are 1', 'Gene', '6293', (18, 23))	('trigger', 'Reg', (122, 129))	('mutation', 'Var', (83, 91))	('mtDNA', 'Gene', (95, 100))	('are 1', 'Gene', (18, 23))
38737	21074512	Accumulation of mutations in mitochondrial and/or nuclear genome of cells containing severely damaged mitochondria may bypass cellular senescence leading to resistance against apoptosis and development of tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('cellular senescence', 'CPA', (126, 145))	('mutations', 'Var', (16, 25))	('resistance against apoptosis', 'CPA', (157, 185))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))
38753	25879199	This suggests that blockade of HSD10 may halt and/or prevent cancer growth, thus providing a promising novel target for cancer patients as a screening or therapeutic option.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('blockade', 'Var', (19, 27))	('HSD10', 'Gene', (31, 36))	('halt', 'NegReg', (41, 45))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prevent', 'NegReg', (53, 60))
38759	25879199	It is well known that constant reactive oxygen species (ROS) exposure induces mutations in mitochondrial DNA, which lead to cancer initiation and metastasis.	('cancer initiation', 'Disease', (124, 141))	('metastasis', 'CPA', (146, 156))	('induces', 'Reg', (70, 77))	('lead to', 'Reg', (116, 123))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer initiation', 'Disease', 'MESH:D009369', (124, 141))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (31, 54))	('mitochondrial DNA', 'Gene', (91, 108))
38763	25879199	Modification of the mitochondrial permeability transition pore (MPTP) in malignant cells has been shown to render cells more resistant to anticancer therapies, however, the mechanism underlying this resistance is not fully understood.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('resistant', 'CPA', (125, 134))	('Modification', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('more', 'PosReg', (120, 124))	('mitochondrial permeability transition pore', 'MPA', (20, 62))	('cancer', 'Disease', (142, 148))
38769	25879199	Furthermore, HSD10 may promote tumorigenesis and aggressiveness, as elevated HSD10 levels were observed in prostate-to-bone metastases compared to non-malignant prostate and primary prostate tumor tissue.	('metastases', 'Disease', (124, 134))	('HSD10', 'Var', (13, 18))	('elevated', 'PosReg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('aggressiveness', 'Disease', (49, 63))	('prostate tumor', 'Disease', (182, 196))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))	('promote', 'PosReg', (23, 30))	('prostate tumor', 'Disease', 'MESH:D011471', (182, 196))	('aggressiveness', 'Disease', 'MESH:D001523', (49, 63))	('tumor', 'Disease', (191, 196))	('prostate tumor', 'Phenotype', 'HP:0100787', (182, 196))	('levels', 'MPA', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('tumor', 'Disease', (31, 36))	('HSD10', 'Gene', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
38770	25879199	While HSD10 remains underexplored in all cancer types, the current data in bone and prostate cancers strongly suggest that HSD10 may be utilized in cancer cells for protection against cell death and enhancement of unrestricted growth.	('cancer', 'Disease', (148, 154))	('enhancement', 'PosReg', (199, 210))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('bone and prostate cancers', 'Disease', 'MESH:D001859', (75, 100))	('prostate cancers', 'Phenotype', 'HP:0012125', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HSD10', 'Var', (123, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('unrestricted growth', 'CPA', (214, 233))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
38771	25879199	Based on these observations, we postulate that HSD10 overexpression enhances cancer cell growth and resistance to cell death.	('resistance to cell death', 'CPA', (100, 124))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('enhances', 'PosReg', (68, 76))	('HSD10', 'Gene', (47, 52))	('overexpression', 'Var', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
38840	25879199	HSD10 protein expression was increased by 3-fold in HSD10 ov cells compared to EV cells (Figure 1A).	('EV', 'Chemical', '-', (79, 81))	('protein', 'Protein', (6, 13))	('increased', 'PosReg', (29, 38))	('HSD10 ov cells', 'Var', (52, 66))	('HSD10', 'Gene', (0, 5))
38841	25879199	The intensity of HSD10 staining was significantly enhanced in HSD10 ov cells in comparison with EV cells (Figure 1C).	('enhanced', 'PosReg', (50, 58))	('intensity', 'MPA', (4, 13))	('EV', 'Chemical', '-', (96, 98))	('HSD10', 'Var', (62, 67))
38843	25879199	To thoroughly examine the effect of HSD10 in cancer, we used lentiviral transfection to knockdown HSD10 in PC-12 cells.	('PC-12 cells', 'CellLine', 'CVCL:0481', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('knockdown', 'Var', (88, 97))	('HSD10', 'Gene', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
38848	25879199	This reduction in all of the complexes indicates that HSD10 is important for cancer cell functionality, and would likely have a substantial impact on subsequent mitochondrial processes.	('HSD10', 'Var', (54, 59))	('reduction', 'NegReg', (5, 14))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('impact', 'Reg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mitochondrial processes', 'MPA', (161, 184))
38852	25879199	In conjunction with the complex IV data observed in Figure 2D, the level of ATP was significantly elevated in HSD10 ov cells compared to EV cells (Figure 2F), demonstrating a possible increase in energy generation in HSD10-overexpressing PC-12 cells.	('HSD10 ov', 'Var', (110, 118))	('PC-12 cells', 'CellLine', 'CVCL:0481', (238, 249))	('rat', 'Species', '10116', (207, 210))	('rat', 'Species', '10116', (166, 169))	('increase', 'PosReg', (184, 192))	('elevated', 'PosReg', (98, 106))	('energy generation', 'MPA', (196, 213))	('EV', 'Chemical', '-', (137, 139))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('level of ATP', 'MPA', (67, 79))
38853	25879199	On the other hand, citrate synthase enzyme activity, which serves as a measurement of mitochondrial fitness, was reduced in HSD10 shRNA cells (Figure 2E).	('mitochondrial fitness', 'Disease', 'MESH:D028361', (86, 107))	('citrate synthase', 'Gene', (19, 35))	('mitochondrial fitness', 'Disease', (86, 107))	('HSD10', 'Var', (124, 129))	('reduced', 'NegReg', (113, 120))	('citrate synthase', 'Gene', '170587', (19, 35))
38854	25879199	Similarly, ATP production was diminished in HSD10 shRNA cells compared to control shRNA cells (Figure 2F), which was expected in view of the decreased activity observed in all of the ETC.	('ATP', 'Chemical', 'MESH:D000255', (11, 14))	('ATP production', 'MPA', (11, 25))	('HSD10 shRNA', 'Var', (44, 55))	('diminished', 'NegReg', (30, 40))
38864	25879199	Taken together, these results suggest that HSD10 promotes pheochromocytoma cell growth in cell culture and that knockdown of HSD10 has a reverse effect on cancer cell growth.	('HSD10', 'Gene', (125, 130))	('pheochromocytoma', 'Disease', 'MESH:D010673', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('promotes', 'PosReg', (49, 57))	('knockdown', 'Var', (112, 121))	('HSD10', 'Gene', (43, 48))	('pheochromocytoma', 'Disease', (58, 74))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))
38866	25879199	SCID mice inoculated with HSD10 ov cells exhibited drastically larger tumors compared to mice with EV tumor xenografts which displayed very minimal growth (Figure 4C-D).	('larger', 'PosReg', (63, 69))	('EV tumor', 'Disease', 'MESH:D004819', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (89, 93))	('HSD10', 'Var', (26, 31))	('SCID', 'Disease', 'MESH:D053632', (0, 4))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('SCID', 'Disease', (0, 4))	('EV tumor', 'Disease', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('mice', 'Species', '10090', (5, 9))
38869	25879199	While cell viability steadily decreased for both cell groups as the chemical dosage increased, HSD10 ov cells demonstrated significantly higher reduction of MTT at 0.75 and 1 mM concentrations of H2O2 compared to EV cells (Figure 5A).	('rat', 'Species', '10116', (117, 120))	('MTT', 'Chemical', 'MESH:C070243', (157, 160))	('EV', 'Chemical', '-', (213, 215))	('H2O2', 'Chemical', 'MESH:D006861', (196, 200))	('H2O2', 'Var', (196, 200))	('reduction', 'NegReg', (144, 153))	('MTT', 'MPA', (157, 160))	('rat', 'Species', '10116', (185, 188))
38875	25879199	As speculated, complex IV enzyme activity was significantly increased in HSD10 ov cells compared to EV cells after just one hour of H2O2 treatment (Figure 5D).	('H2O2', 'Chemical', 'MESH:D006861', (132, 136))	('activity', 'MPA', (33, 41))	('increased', 'PosReg', (60, 69))	('EV', 'Chemical', '-', (100, 102))	('HSD10 ov', 'Var', (73, 81))
38879	25879199	As expected, both EV and HSD10 ov cells treated with H2O2 exhibited higher percentages of cells undergoing apoptosis (Figure 5F), compared with the untreated matched control groups.	('H2O2', 'Var', (53, 57))	('EV', 'Chemical', '-', (18, 20))	('H2O2', 'Chemical', 'MESH:D006861', (53, 57))	('cells', 'CPA', (90, 95))
38881	25879199	The data presented here support the concept that HSD10 overexpression increases pheochromocytoma cell resistance to cell death induced by oxidative stress.	('increases pheochromocytoma', 'Disease', 'MESH:D010673', (70, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('overexpression', 'Var', (55, 69))	('oxidative stress', 'Phenotype', 'HP:0025464', (138, 154))	('increases pheochromocytoma', 'Disease', (70, 96))	('HSD10', 'Gene', (49, 54))
38887	25879199	Interestingly, CypD protein expression was significantly reduced in HSD10 shRNA cells compared with control shRNA cells (Figure 6B).	('reduced', 'NegReg', (57, 64))	('HSD10 shRNA', 'Var', (68, 79))	('CypD', 'Gene', '282819', (15, 19))	('CypD', 'Gene', (15, 19))
38889	25879199	We suggest that, due to the reductions in both HSD10 and CypD, cancer cells become more susceptible to cell death induction.	('HSD10', 'Var', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CypD', 'Gene', '282819', (57, 61))	('CypD', 'Gene', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('reductions', 'NegReg', (28, 38))	('cancer', 'Disease', (63, 69))
38891	25879199	As shown in Figure 6C, there is an enhanced interaction between HSD10 and CypD in HSD10 ov cells compared to EV cells, which was confirmed using both proteins as pull-down antibodies.	('HSD10', 'Var', (82, 87))	('CypD', 'Gene', '282819', (74, 78))	('enhanced', 'PosReg', (35, 43))	('CypD', 'Gene', (74, 78))	('EV', 'Chemical', '-', (109, 111))	('interaction', 'Interaction', (44, 55))
38895	25879199	As expected, HSD10 levels where increased in HSD10 ov cells compared to EV cells (Figure 6G), consistent with the results in Figure 1A-C. Co-staining of HSD10 and CypD with the mitochondrial markers SODII and Hsp60, respectively, confirms mitochondrial localization of the proteins (Figure 6E-F).	('mitochondrial localization', 'MPA', (239, 265))	('Hsp60', 'Gene', '63868', (209, 214))	('CypD', 'Gene', '282819', (163, 167))	('CypD', 'Gene', (163, 167))	('HSD10', 'Var', (45, 50))	('increased', 'PosReg', (32, 41))	('Hsp60', 'Gene', (209, 214))	('EV', 'Chemical', '-', (72, 74))	('HSD10 levels', 'MPA', (13, 25))
38910	25879199	Suppression of MPTP-induced cell death observed in tumor cells is thought to occur due to CypD molecular interactions which prevent IMM translocation, as inhibition of CypD protects malignant cells from necrosis.	('CypD', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CypD', 'Gene', '282819', (90, 94))	('CypD', 'Gene', (90, 94))	('inhibition', 'Var', (154, 164))	('tumor', 'Disease', (51, 56))	('CypD', 'Gene', '282819', (168, 172))	('necrosis', 'Disease', 'MESH:D009336', (203, 211))	('cell', 'CPA', (28, 32))	('IMM translocation', 'MPA', (132, 149))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('necrosis', 'Disease', (203, 211))
38927	25879199	Most often, cancer cells have disrupted cell death pathways due to mutations that either inhibit pro-apoptotic proteins or elevate anti-apoptotic proteins.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('elevate', 'PosReg', (123, 130))	('cancer', 'Disease', (12, 18))	('cell death', 'CPA', (40, 50))	('pro-apoptotic', 'MPA', (97, 110))	('mutations', 'Var', (67, 76))	('disrupted', 'NegReg', (30, 39))	('inhibit', 'NegReg', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('anti-apoptotic proteins', 'MPA', (131, 154))
38937	25879199	As HSD10 overexpression grants pheochromocytoma cells enhanced cellular proliferative and cell death resistant capabilities, targeted inhibition of HSD10 in cancer cells may provide a novel treatment method.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('overexpression', 'PosReg', (9, 23))	('HSD10', 'Gene', (148, 153))	('inhibition', 'Var', (134, 144))	('rat', 'Species', '10116', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cell death resistant capabilities', 'CPA', (90, 123))	('pheochromocytoma', 'Disease', (31, 47))	('pheochromocytoma', 'Disease', 'MESH:D010673', (31, 47))	('cellular proliferative', 'CPA', (63, 85))	('enhanced', 'PosReg', (54, 62))	('HSD10', 'Gene', (3, 8))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (31, 47))
38942	25879199	In summary, we have provided substantial evidence demonstrating that HSD10 overexpression significantly increased pheochromocytoma cell growth in cell culture and in vivo.	('HSD10', 'Gene', (69, 74))	('pheochromocytoma', 'Disease', 'MESH:D010673', (114, 130))	('increased', 'PosReg', (104, 113))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (114, 130))	('rat', 'Species', '10116', (57, 60))	('overexpression', 'Var', (75, 89))	('pheochromocytoma', 'Disease', (114, 130))
38950	23532898	Single-nucleotide polymorphism (SNP) array analysis of pheochromocytoma tissue demonstrated mosaic deletions of 8p12pter, 21q21.1qter, 22q11.23qter; commonly seen in pheochromocytomas.	('pheochromocytoma', 'Disease', (166, 182))	('pheochromocytoma', 'Disease', 'MESH:D010673', (55, 71))	('deletions', 'Var', (99, 108))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (166, 183))	('pheochromocytoma', 'Disease', 'MESH:D010673', (166, 182))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (166, 182))	('pheochromocytomas', 'Disease', 'MESH:D010673', (166, 183))	('pheochromocytomas', 'Disease', (166, 183))	('8p12pter', 'Gene', (112, 120))	('21q21.1qter', 'Var', (122, 133))	('pheochromocytoma', 'Disease', (55, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (55, 71))
38953	23532898	Subsequent SNP array analysis of skin fibroblasts from the hyperplastic side demonstrated 5% mosaic paternal UPD for 11p15.	('p15', 'Gene', (119, 122))	('p15', 'Gene', '1030', (119, 122))	('mosaic paternal UPD', 'Var', (93, 112))
38954	23532898	We have subsequently used SNP array analysis to identify four patients with subtle hemihyperplasia with low-level mosaic UPD that was not detected by methylation analysis.	('patients', 'Species', '9606', (62, 70))	('subtle hemihyperplasia', 'Disease', (76, 98))	('subtle hemihyperplasia', 'Disease', 'MESH:C565524', (76, 98))	('low-level mosaic UPD', 'Var', (104, 124))
38964	23532898	The three most common epigenotypes found in BWS are loss of methylation of KvDMR, uniparental isodisomy (UPD) 11p15, and hypermethylation of H19DMR.	('loss', 'NegReg', (52, 56))	('p15', 'Gene', (112, 115))	('p15', 'Gene', '1030', (112, 115))	('H19', 'Gene', '283120', (141, 144))	('hypermethylation', 'Var', (121, 137))	('H19', 'Gene', (141, 144))	('KvDMR', 'Gene', (75, 80))	('uniparental isodisomy', 'Disease', (82, 103))	('methylation', 'MPA', (60, 71))	('uniparental isodisomy', 'Disease', 'MESH:D024182', (82, 103))
38973	23532898	However, between 40% and 59% of pheochromocytomas in children <18 years of age are due to known genetic mutations, with the percentage of hereditary disease as high as 70% in children <10 years of age.	('mutations', 'Var', (104, 113))	('pheochromocytomas', 'Disease', 'MESH:D010673', (32, 49))	('hereditary disease', 'Disease', (138, 156))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (32, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (32, 49))	('hereditary disease', 'Disease', 'MESH:D030342', (138, 156))	('children', 'Species', '9606', (53, 61))	('children', 'Species', '9606', (175, 183))	('due', 'Reg', (83, 86))	('pheochromocytomas', 'Disease', (32, 49))
38982	23532898	We have found that strict adherence to reagent lots in generating reference data sets and development of in-house analytics has led to an improved detection of both mosaic copy number abnormalities as well as mosaic homozygosity (Conlin, unpublished data).	('copy number abnormalities', 'Disease', 'MESH:D007674', (172, 197))	('improved', 'PosReg', (138, 146))	('mosaic homozygosity', 'Var', (209, 228))	('copy number abnormalities', 'Disease', (172, 197))
38986	23532898	Slides labeled with antibodies to p57Kip2 were scanned using the Aperio ScanScope   CS slide scanner (Aperio Technologies, Vista, CA).	('p57Kip2', 'Gene', '1028', (34, 41))	('antibodies', 'Var', (20, 30))	('p57Kip2', 'Gene', (34, 41))
39008	23532898	Given the high prevalence of germline mutations in early onset pheochromocytoma that would predispose to future disease, we screened for germline mutations in genes associated with pheochromocytomas including VHL, SDHB, SDHD, and RET, all of which were negative in blood.	('SDHB', 'Gene', '6390', (214, 218))	('VHL', 'Disease', (209, 212))	('pheochromocytoma', 'Disease', (181, 197))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (181, 197))	('RET', 'Gene', '5979', (230, 233))	('pheochromocytomas', 'Disease', 'MESH:D010673', (181, 198))	('pheochromocytomas', 'Disease', (181, 198))	('SDHB', 'Gene', (214, 218))	('SDHD', 'Gene', '6392', (220, 224))	('mutations', 'Var', (38, 47))	('VHL', 'Disease', 'MESH:D006623', (209, 212))	('RET', 'Gene', (230, 233))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (181, 198))	('SDHD', 'Gene', (220, 224))	('pheochromocytoma', 'Disease', 'MESH:D010673', (63, 79))	('mutations', 'Var', (146, 155))	('pheochromocytoma', 'Disease', (63, 79))	('pheochromocytoma', 'Disease', 'MESH:D010673', (181, 197))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (63, 79))
39009	23532898	SNP array analysis, using an Illumina Human Quad 610 BeadChip SNP Array, in the tumor showed mosaic heterozygous deletions in 8p12pter, 21q21.1qter, 22q11.23qter, each consistent with pheochromocytoma as well as an 11.75 Mb region of homozygosity of 11p15.3pter, detected in 70% of cells.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('pheochromocytoma', 'Disease', (184, 200))	('pheochromocytoma', 'Disease', 'MESH:D010673', (184, 200))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (184, 200))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Human', 'Species', '9606', (38, 43))	('tumor', 'Disease', (80, 85))	('21q21.1qter', 'Var', (136, 147))	('p15', 'Gene', (252, 255))	('8p12pter', 'Gene', (126, 134))	('p15', 'Gene', '1030', (252, 255))
39010	23532898	To support the model that 11p homozygosity was likely the predisposing factor for her pheochromocytoma, which would carry a very low adult cancer or recurrence risk, a skin biopsy of the larger leg was performed and subsequently demonstrated homozygosity of 11p15.3pter in 5% of cells (Fig.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('pheochromocytoma', 'Disease', 'MESH:D010673', (86, 102))	('p15', 'Gene', '1030', (260, 263))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (86, 102))	('larger leg', 'Phenotype', 'HP:0001833', (187, 197))	('p15', 'Gene', (260, 263))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('homozygosity', 'Var', (242, 254))	('pheochromocytoma', 'Disease', (86, 102))	('cancer', 'Disease', (139, 145))
39011	23532898	Prompted by the detection of low-level mosaic paternal UPD of 11p15 in this patient, we subsequently tested several additional 11p15 methylation testing-negative patients by SNP array and identified four patients with low-level mosaic 11p UPD (Fig.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (204, 212))	('p15', 'Gene', (64, 67))	('p15', 'Gene', (129, 132))	('p15', 'Gene', '1030', (64, 67))	('p15', 'Gene', '1030', (129, 132))	('mosaic paternal', 'Var', (39, 54))	('patient', 'Species', '9606', (162, 169))	('patient', 'Species', '9606', (76, 83))	('patient', 'Species', '9606', (204, 211))
39024	23532898	Here, we describe low-level mosaic paternal UPD in an 18-monthold girl resulting in IH and bilateral pheochromocytomas.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (101, 118))	('IH', 'Phenotype', 'HP:0001528', (84, 86))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (101, 117))	('mosaic paternal UPD', 'Var', (28, 47))	('bilateral pheochromocytomas', 'Disease', (91, 118))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (91, 118))	('girl', 'Species', '9606', (66, 70))
39028	23532898	Of these, detailed molecular testing was reported for only one case and revealed a normal karyotype, no detectable mutations in RET or NF in the blood or VHL or RET in the tumor, and a normal methylation pattern of KvDMR and H19DMR.	('RET', 'Gene', '5979', (161, 164))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('VHL', 'Disease', (154, 157))	('methylation', 'MPA', (192, 203))	('RET', 'Gene', '5979', (128, 131))	('KvDMR', 'Var', (215, 220))	('tumor', 'Disease', (172, 177))	('RET', 'Gene', (161, 164))	('H19', 'Gene', '283120', (225, 228))	('H19', 'Gene', (225, 228))	('RET', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('VHL', 'Disease', 'MESH:D006623', (154, 157))
39030	23532898	Molecular testing in this patient showed loss of methylation at KvDMR, hypermethylation at H19DMR, and microsatellite genotyping showed paternal UPD for chromosome 11.	('patient', 'Species', '9606', (26, 33))	('methylation', 'MPA', (49, 60))	('H19', 'Gene', (91, 94))	('H19', 'Gene', '283120', (91, 94))	('paternal UPD for chromosome 11', 'CPA', (136, 166))	('hypermethylation', 'Var', (71, 87))	('loss', 'NegReg', (41, 45))
39031	23532898	This patient had biparental inheritance in skin fibroblasts although genetic analysis of the pheochromocytomas was not reported.	('patient', 'Species', '9606', (5, 12))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('biparental', 'Var', (17, 27))	('pheochromocytomas', 'Disease', 'MESH:D010673', (93, 110))	('pheochromocytomas', 'Disease', (93, 110))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (93, 110))
39033	23532898	Although pheochromocytomas are uncommon in BWS, alterations of chromosome 11 have been associated with malignant pheochromocytomas.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (9, 26))	('alterations', 'Var', (48, 59))	('malignant pheochromocytomas', 'Disease', (103, 130))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (9, 25))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (113, 130))	('associated', 'Reg', (87, 97))	('malignant pheochromocytomas', 'Disease', 'MESH:D010673', (103, 130))	('pheochromocytomas', 'Disease', 'MESH:D010673', (9, 26))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (113, 129))	('pheochromocytomas', 'Disease', (9, 26))	('pheochromocytomas', 'Disease', 'MESH:D010673', (113, 130))	('pheochromocytomas', 'Disease', (113, 130))
39036	23532898	CDKN1C encodes p57, a cell cycle inhibitor/tumor suppressor gene and epigenetic dysregulation of p57 has been proposed to have a role in the pathogenesis of several embryonal tumors including hepatoblastomas and rhabdomyosarcomas.	('hepatoblastoma', 'Phenotype', 'HP:0002884', (192, 206))	('p57', 'Gene', (97, 100))	('tumor', 'Disease', (43, 48))	('CDKN1C', 'Gene', '1028', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('epigenetic dysregulation', 'Var', (69, 93))	('p57', 'Gene', (15, 18))	('tumor', 'Disease', (175, 180))	('role', 'Reg', (129, 133))	('rhabdomyosarcomas', 'Phenotype', 'HP:0002859', (212, 229))	('p57', 'Gene', '1028', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CDKN1C', 'Gene', (0, 6))	('embryonal tumors', 'Disease', (165, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('hepatoblastomas and rhabdomyosarcomas', 'Disease', 'MESH:D018197', (192, 229))	('embryonal tumors', 'Phenotype', 'HP:0002898', (165, 181))	('embryonal tumors', 'Disease', 'MESH:D009373', (165, 181))	('p57', 'Gene', '1028', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
39047	23532898	The detection of both hypomethylation at KvDMR and hypermethylation at H19DMR has been used as a surrogate marker for paternal UPD 11p15.	('p15', 'Gene', (133, 136))	('p15', 'Gene', '1030', (133, 136))	('hypermethylation', 'Var', (51, 67))	('KvDMR', 'Var', (41, 46))	('H19', 'Gene', '283120', (71, 74))	('hypomethylation', 'Var', (22, 37))	('H19', 'Gene', (71, 74))
39050	23532898	As noted above, this led us to consider that patients with previously undetected methylation abnormalities could be assayed for low-level mosaic UPD using this SNP array analysis, as we subsequently noted in Patients 2-4 with low-level mosaic paternal UPD at 11p15 in blood previously undetected by methylation analysis.	('Patients', 'Species', '9606', (208, 216))	('p15', 'Gene', (261, 264))	('p15', 'Gene', '1030', (261, 264))	('patients', 'Species', '9606', (45, 53))	('mosaic paternal UPD at', 'Var', (236, 258))
39055	23532898	The overall rate of paternal UPD detection is lower than we expected (23%) but consistent with the published molecular diagnosis rate for patients with isolated hemihyperplasia of <30%.	('isolated hemihyperplasia', 'Phenotype', 'HP:0001528', (152, 176))	('isolated hemihyperplasia', 'Disease', (152, 176))	('isolated hemihyperplasia', 'Disease', 'MESH:C565524', (152, 176))	('patients', 'Species', '9606', (138, 146))	('paternal', 'Var', (20, 28))
39056	23532898	Accordingly, we feel the use of SNP array analysis affords a notable increase in the sensitivity of mosaic paternal UPD 11p15 diagnosis for patients with IH and BWS over MS-RFA, MS-PCR, or MS-MLPA analysis alone.	('increase', 'PosReg', (69, 77))	('p15', 'Gene', (122, 125))	('p15', 'Gene', '1030', (122, 125))	('mosaic paternal UPD', 'Var', (100, 119))	('IH', 'Phenotype', 'HP:0001528', (154, 156))	('patients', 'Species', '9606', (140, 148))
39062	23532898	Given our experience, we now perform sensitive SNP array analysis with a focus on low-level mosaic paternal UPD 11p15 in the assessment of all patients with IH or BWS, even those with subtle asymmetry.	('BWS', 'Disease', (163, 166))	('patients', 'Species', '9606', (143, 151))	('mosaic paternal', 'Var', (92, 107))	('IH', 'Phenotype', 'HP:0001528', (157, 159))	('p15', 'Gene', (114, 117))	('p15', 'Gene', '1030', (114, 117))
39069	23532898	We suggest thatSNP array analysisto detect low-level mosaic paternal UPD is a sensitive adjunct to identify and stratify patients at higher risk for malignancy.	('malignancy', 'Disease', (149, 159))	('mosaic paternal', 'Var', (53, 68))	('patients', 'Species', '9606', (121, 129))	('malignancy', 'Disease', 'MESH:D009369', (149, 159))
39070	23532898	The lower level of detection afforded by SNP array analysis with our methodology can be used to detect patients with low-level mosaic pUPD 11 and further longitudinal study of these patients will help elicit their tumor risk and allow modification of screening recommendations to lead to improved clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Disease', (214, 219))	('patients', 'Species', '9606', (103, 111))	('mosaic pUPD', 'Var', (127, 138))
39119	23448279	Due to a large intra-operative blood loss because of the tumor's extremely high vascularization our patient received high volume replacement in the form of crystalloids (7500mL), colloids (2000mL), and multiple blood transfusions (red blood cells (RBC) 1400mL and fresh frozen plasma (FFP) 1000mL).	('intra-operative blood loss', 'Disease', (15, 41))	('intra-operative blood loss', 'Disease', 'MESH:D006473', (15, 41))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('7500mL', 'Var', (170, 176))	('patient', 'Species', '9606', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('2000mL', 'Var', (189, 195))
39261	21599949	Incidentally, we previously tried to establish the immunohistochemical prognostic indicators of GP using bcl-2, p53, and Ki-67, which are acceptable prognostic indicators in several kinds of neuroendocrine tumors.	('bcl-2', 'Gene', (105, 110))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (191, 212))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('neuroendocrine tumors', 'Disease', (191, 212))	('bcl-2', 'Gene', '596', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('Ki-67', 'Var', (121, 126))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (191, 211))	('p53', 'Gene', (112, 115))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (191, 212))	('p53', 'Gene', '7157', (112, 115))
39409	33882857	Clinical diagnoses were established by classic CA-related paroxysmal complaints (headache, palpitations, and/or profuse sweating) in combination with adrenal tumors with features suggestive of PPGLs on computed tomography (CT) or magnetic resonance imaging (MRI) and elevated plasma CA or metanephrine (MN)/normetanephrine (NMN) levels at least two times the upper limit of normal (ULN).	('adrenal tumors', 'Disease', 'MESH:D000310', (150, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('palpitations', 'Phenotype', 'HP:0001962', (91, 103))	('palpitation', 'Phenotype', 'HP:0001962', (91, 102))	('elevated', 'PosReg', (267, 275))	('sweating', 'Phenotype', 'HP:0000975', (120, 128))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PPGLs', 'Var', (193, 198))	('profuse sweating', 'Phenotype', 'HP:0000975', (112, 128))	('elevated plasma CA', 'Phenotype', 'HP:0003072', (267, 285))	('PPGLs', 'Chemical', '-', (193, 198))	('headache', 'Phenotype', 'HP:0002315', (81, 89))	('adrenal tumors', 'Disease', (150, 164))	('metanephrine', 'Chemical', 'MESH:D008676', (310, 322))	('headache', 'Disease', (81, 89))	('paroxysmal complaints', 'Disease', (58, 79))	('CA-related', 'Disease', (47, 57))	('NMN', 'Chemical', 'MESH:D009647', (324, 327))	('metanephrine', 'Chemical', 'MESH:D008676', (289, 301))	('headache', 'Disease', 'MESH:D006261', (81, 89))	('normetanephrine', 'Chemical', 'MESH:D009647', (307, 322))
39482	33882857	The main impairment pattern in patients with TTS on strain analysis was the apical sparing pattern, which is a distinct result from previous studies.	('patients', 'Species', '9606', (31, 39))	('apical sparing', 'Phenotype', 'HP:0032176', (76, 90))	('apical sparing pattern', 'CPA', (76, 98))	('apical sparing pattern', 'Phenotype', 'HP:0032176', (76, 98))	('TTS', 'Var', (45, 48))
39489	30008476	Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed.	('pheochromocytoma', 'Disease', (157, 173))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (157, 173))	('pheochromocytoma', 'Disease', 'MESH:D010673', (35, 51))	('malate dehydrogenase 2', 'Gene', (85, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (174, 187))	('MDH2', 'Gene', '4191', (79, 83))	('variant', 'Var', (24, 31))	('pheochromocytoma', 'Disease', (35, 51))	('MDH2', 'Gene', '4191', (8, 12))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (35, 51))	('malate dehydrogenase 2', 'Gene', '4191', (85, 107))	('PPGL', 'Chemical', '-', (189, 193))	('paraganglioma', 'Disease', (56, 69))	('paraganglioma', 'Disease', 'MESH:D010235', (56, 69))	('MDH2', 'Gene', (79, 83))	('paraganglioma', 'Disease', (174, 187))	('pheochromocytoma', 'Disease', 'MESH:D010673', (157, 173))	('MDH2', 'Gene', (8, 12))	('paraganglioma', 'Disease', 'MESH:D010235', (174, 187))
39490	30008476	This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype.	('patients', 'Species', '9606', (84, 92))	('MDH2', 'Gene', '4191', (48, 52))	('MDH2', 'Gene', (48, 52))	('pathogenic', 'Reg', (53, 63))	('PPGL', 'Chemical', '-', (79, 83))	('variants', 'Var', (64, 72))
39492	30008476	Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T).	('p.Lys314del', 'Var', (157, 168))	('c.429+1G>T', 'Var', (198, 208))	('involvement', 'Reg', (29, 40))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (91, 102))	('p.Lys314del', 'Mutation', 'p.314del', (157, 168))	('p.Arg104Gly', 'Var', (91, 102))	('p.Ala256Thr', 'Var', (120, 131))	('p.Val160Met', 'Mutation', 'rs138541865', (104, 115))	('c.429+1G>T', 'Mutation', 'rs782251807', (198, 208))	('p.Ala256Thr', 'Mutation', 'rs147655350', (120, 131))	('p.Val160Met', 'Var', (104, 115))
39494	30008476	This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes.	('PPGLs', 'Disease', (144, 149))	('variants', 'Var', (41, 49))	('PPGL', 'Chemical', '-', (205, 209))	('susceptibility', 'Reg', (74, 88))	('MDH2', 'Gene', '4191', (25, 29))	('MDH2', 'Gene', (25, 29))	('patients', 'Species', '9606', (153, 161))	('PGLs', 'Phenotype', 'HP:0002668', (145, 149))	('play', 'Reg', (54, 58))	('PPGL', 'Chemical', '-', (144, 148))	('role', 'Reg', (61, 65))	('PPGL', 'Gene', (69, 73))	('PPGL', 'Chemical', '-', (285, 289))	('PPGL', 'Chemical', '-', (69, 73))
39498	30008476	Among PPGL-associated genes, seven have been found almost exclusively mutated in the germline (SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, and TMEM127), four either in the germline or somatically (RET, VHL, NF1, and MAX), one postzygotically or somatically (EPAS1), and the last one only somatically (HRAS).	('SDHD', 'Gene', (113, 117))	('NF1', 'Gene', (199, 202))	('SDHB', 'Gene', '6390', (101, 105))	('SDHA', 'Gene', (119, 123))	('NF1', 'Gene', '4763', (199, 202))	('EPAS1', 'Gene', (250, 255))	('TMEM127', 'Gene', (135, 142))	('SDHC', 'Gene', (107, 111))	('SDHA', 'Gene', '6389', (119, 123))	('SDHAF2', 'Gene', '54949', (119, 125))	('SDHAF2', 'Gene', (119, 125))	('SDHA', 'Gene', (95, 99))	('RET', 'Gene', '5979', (189, 192))	('SDHB', 'Gene', (101, 105))	('VHL', 'Gene', (194, 197))	('TMEM127', 'Gene', '55654', (135, 142))	('SDHA', 'Gene', '6389', (95, 99))	('PPGL-associated genes', 'Gene', (6, 27))	('PPGL', 'Chemical', '-', (6, 10))	('EPAS1', 'Gene', '2034', (250, 255))	('FH', 'Disease', 'MESH:D006938', (127, 129))	('HRAS', 'Gene', '3265', (293, 297))	('SDHD', 'Gene', '6392', (113, 117))	('VHL', 'Gene', '7428', (194, 197))	('HRAS', 'Gene', (293, 297))	('RET', 'Gene', (189, 192))	('SDHC', 'Gene', '6391', (107, 111))	('mutated', 'Var', (70, 77))
39500	30008476	In addition, other mechanisms such as point variants in the promoter region of TERT, SDHC promoter epimutations, or rearrangements involving MAML3, BRAF, NGFR, and NF1 have been also described.	('NGFR', 'Gene', (154, 158))	('SDHC', 'Gene', (85, 89))	('SDHC', 'Gene', '6391', (85, 89))	('point variants', 'Var', (38, 52))	('NF1', 'Gene', (164, 167))	('TERT', 'Gene', (79, 83))	('NGFR', 'Gene', '4804', (154, 158))	('MAML3', 'Gene', '55534', (141, 146))	('TERT', 'Gene', '7015', (79, 83))	('NF1', 'Gene', '4763', (164, 167))	('MAML3', 'Gene', (141, 146))	('BRAF', 'Gene', '673', (148, 152))	('epimutations', 'Var', (99, 111))	('rearrangements', 'Var', (116, 130))	('BRAF', 'Gene', (148, 152))
39503	30008476	A single MDH2 PV affecting a donor splice-site (c.429+1G>A) was identified in a 55-year-old man with multiple noradrenergic PGLs associated with bone metastasis, and in one apparently unaffected relative with a positive biochemical diagnosis of the disease.	('c.429+1G>A', 'Var', (48, 58))	('associated with', 'Reg', (129, 144))	('PGLs', 'Phenotype', 'HP:0002668', (124, 128))	('bone metastasis', 'CPA', (145, 160))	('MDH2', 'Gene', '4191', (9, 13))	('MDH2', 'Gene', (9, 13))	('c.429+1G>A', 'Mutation', 'c.429+1G>A', (48, 58))
39505	30008476	As alterations in Krebs cycle genes have been associated with a higher metastatic risk of the disease, an early genetic diagnosis of unaffected carriers in these families seems to be crucial.	('Krebs', 'Chemical', '-', (18, 23))	('metastatic', 'CPA', (71, 81))	('associated', 'Reg', (46, 56))	('alterations', 'Var', (3, 14))	('Krebs cycle genes', 'Gene', (18, 35))
39509	30008476	All MDH2 genetic changes, except one in-frame deletion and one variant affecting a donor splice-site, consisted of single-nucleotide substitutions leading to missense, synonymous, or intronic changes, for which we assessed their functional impact.	('synonymous', 'MPA', (168, 178))	('intronic changes', 'MPA', (183, 199))	('consisted of', 'Reg', (102, 114))	('MDH2', 'Gene', '4191', (4, 8))	('MDH2', 'Gene', (4, 8))	('changes', 'Var', (17, 24))	('missense', 'MPA', (158, 166))
39524	30008476	MDH2 gross deletions were tested in 216 cases with good germline DNA quality using a semiquantitative multiplex polymerase chain reaction (PCR) method with labeled primers, as previously described for other genes.	('gross deletions', 'Var', (5, 20))	('MDH2', 'Gene', '4191', (0, 4))	('MDH2', 'Gene', (0, 4))
39526	30008476	The frequency of MDH2 variants was investigated in public databases: dbSNP (https://www.ncbi.nlm.nih.gov/SNP), COSMIC (http://cancer.sanger.ac.uk/cosmic), and gnomAD (http://gnomad.broadinstitute.org/).	('MDH2', 'Gene', '4191', (17, 21))	('MDH2', 'Gene', (17, 21))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('variants', 'Var', (22, 30))
39527	30008476	MDH2 variants identified in <0.1% of the population and without homozygotes described were included in the study and used for further analyses.	('variants', 'Var', (5, 13))	('MDH2', 'Gene', '4191', (0, 4))	('MDH2', 'Gene', (0, 4))
39528	30008476	LOH of the MDH2 variants in tumor DNA was assessed by direct sequencing (if material was available).	('tumor', 'Disease', (28, 33))	('MDH2', 'Gene', '4191', (11, 15))	('MDH2', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('variants', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
39529	30008476	Three distinct in silico approaches were used to assess the functional and three-dimensional (3D) structural effect of the missense variants: (1) measure of the evolutionary conservation in the genome of vertebrate and mammalian species (i.e., phyloP, phastCons, GERP++), (2) prediction of the impact of amino acid substitutions in protein function (i.e., SIFT, Polyphen2, LRT, MutationAssessor, fathmm-MKL, PROVEAN, MetaSVM, MetaLR, MutationTaster), and (3) prediction of protein 3D destabilization (i.e., PoPMu-SiCv3.1, CUPSAT, I-Mutant v3.0, MAESTRO, INPS-3D).	('protein', 'Protein', (332, 339))	('destabilization', 'NegReg', (484, 499))	('amino acid substitutions', 'Var', (304, 328))	('GERP', 'Gene', (263, 267))	('GERP', 'Gene', '81603', (263, 267))	('protein', 'Protein', (473, 480))	('mammalian', 'Species', '9606', (219, 228))
39533	30008476	QuickChange Lightning Site-Directed Mutagenesis Kit (Agilent) was used to generate missense variants in pCMV6-AC-MDH2 (Origene), a plasmid containing the full complementary DNA (cDNA) sequence (NM_005918) of the human MDH2 gene.	('human', 'Species', '9606', (212, 217))	('-AC', 'Chemical', 'MESH:D000186', (109, 112))	('missense variants', 'Var', (83, 100))	('MDH2', 'Gene', '4191', (218, 222))	('MDH2', 'Gene', '4191', (113, 117))	('MDH2', 'Gene', (218, 222))	('MDH2', 'Gene', (113, 117))
39534	30008476	We generated a polymorphism with a minor allele frequency (MAF) = 0.037 in gnomAD (rs10256: p.Lys301Arg), to be used as control.	('p.Lys301Arg', 'Mutation', 'rs10256', (92, 103))	('rs10256', 'Mutation', 'rs10256', (83, 90))	('p.Lys301Arg', 'Var', (92, 103))	('rs10256: p.Lys301Arg', 'Var', (83, 103))	('gnomAD', 'Gene', (75, 81))
39544	30008476	Twelve MDH2 heterozygous variants (Fig.	('variants', 'Var', (25, 33))	('MDH2', 'Gene', '4191', (7, 11))	('MDH2', 'Gene', (7, 11))
39546	30008476	Clinical data of the MDH2 carriers are detailed in Table S3.	('carriers', 'Var', (26, 34))	('MDH2', 'Gene', '4191', (21, 25))	('MDH2', 'Gene', (21, 25))
39550	30008476	Similarly, the splicing for three of the four intronic variants (c.320-26A>C, c.733 +47G>A, and c.734-5C>A) was not predicted affected, while it was anticipated as altered in the remaining intronic variant (c.319+37G>A) identified in a 48-year-old patient with a noradrenergic PCC.	('c.320-26A>C', 'Mutation', 'c.320-26A>C', (65, 76))	('+47G>A', 'Var', (84, 90))	('PCC', 'Gene', (277, 280))	('+47G>A', 'SUBSTITUTION', 'None', (84, 90))	('c.319+37G>A', 'Var', (207, 218))	('c.320-26A>C', 'Var', (65, 76))	('c.734-5C>A', 'Mutation', 'c.734-5C>A', (96, 106))	('patient', 'Species', '9606', (248, 255))	('altered', 'Reg', (164, 171))	('PCC', 'Gene', '1421', (277, 280))	('c.319+37G>A', 'Mutation', 'c.319+37G>A', (207, 218))
39552	30008476	Of the five MDH2 missense variants identified (Table 2), only one (p.Ser3Phe) was outside the functional domains in the transit peptide to mitochondria.	('MDH2', 'Gene', '4191', (12, 16))	('p.Ser3Phe', 'Mutation', 'p.S3F', (67, 76))	('MDH2', 'Gene', (12, 16))	('missense variants', 'Var', (17, 34))
39553	30008476	The variants p.Arg104Gly, p.Gln130Arg, and p.Val160Met were positioned in the lactate/malate dehydrogenase, NAD-binding domain; and p.Ala256Thr in the lactate/malate dehydrogenase, alpha/beta C-terminal domain.	('p.Ala256Thr', 'Mutation', 'rs147655350', (132, 143))	('NAD', 'Chemical', 'MESH:D009243', (108, 111))	('malate dehydrogenase', 'Gene', (86, 106))	('p.Val160Met', 'Mutation', 'rs138541865', (43, 54))	('p.Val160Met', 'Var', (43, 54))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (13, 24))	('p.Arg104Gly', 'Var', (13, 24))	('malate dehydrogenase', 'Gene', (159, 179))	('p.Gln130Arg', 'Mutation', 'p.Q130R', (26, 37))	('malate dehydrogenase', 'Gene', '4200', (86, 106))	('p.Gln130Arg', 'Var', (26, 37))	('malate dehydrogenase', 'Gene', '4200', (159, 179))	('p.Ala256Thr', 'Var', (132, 143))
39556	30008476	Three of the missense variants (p.Arg104Gly, p.Val160Met, and p.Ala256Thr) were predicted to have a damaging effect (impaired functional predictions and destabilization of the 3D structure) (Table 2; Table S4).	('functional', 'MPA', (126, 136))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (32, 43))	('p.Arg104Gly', 'Var', (32, 43))	('p.Ala256Thr', 'Var', (62, 73))	('destabilization', 'NegReg', (153, 168))	('p.Val160Met', 'Mutation', 'rs138541865', (45, 56))	('p.Ala256Thr', 'Mutation', 'rs147655350', (62, 73))	('p.Val160Met', 'Var', (45, 56))	('impaired', 'NegReg', (117, 125))
39561	30008476	The variants p.Arg104Gly and p.Ala256Thr were found in two young patients (25 and 29 years old, respectively) with norepinephrine-producing PCC both diagnosed during pregnancy.	('p.Ala256Thr', 'Var', (29, 40))	('PCC', 'Gene', (140, 143))	('p.Ala256Thr', 'Mutation', 'rs147655350', (29, 40))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (13, 24))	('p.Arg104Gly', 'Var', (13, 24))	('patients', 'Species', '9606', (65, 73))	('norepinephrine', 'Chemical', 'MESH:D009638', (115, 129))	('PCC', 'Gene', '1421', (140, 143))
39563	30008476	The p.Val160Met was identified in a PCC patient without biochemical data.	('PCC', 'Gene', (36, 39))	('patient', 'Species', '9606', (40, 47))	('PCC', 'Gene', '1421', (36, 39))	('p.Val160Met', 'Mutation', 'rs138541865', (4, 15))	('p.Val160Met', 'Var', (4, 15))
39564	30008476	The remaining two missense variants (p.Ser3Phe and p.Gln130Arg) were found in patients older than 45 years, diagnosed with PCC; the former involving an adrenergic tumor and the latter without evidence of excess in catecholamine production (Table S3).	('p.Ser3Phe', 'Mutation', 'p.S3F', (37, 46))	('p.Gln130Arg', 'Mutation', 'p.Q130R', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('PCC', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('p.Gln130Arg', 'Var', (51, 62))	('patients', 'Species', '9606', (78, 86))	('catecholamine', 'Chemical', 'MESH:D002395', (214, 227))	('tumor', 'Disease', (163, 168))	('p.Ser3Phe', 'Var', (37, 46))	('PCC', 'Gene', '1421', (123, 126))	('involving', 'Reg', (139, 148))
39568	30008476	Furthermore, the c.429+1G>T variant, previously described, was found in a 57-year-old patient diagnosed with a PCC and liver metastases.	('c.429+1G>T', 'Mutation', 'rs782251807', (17, 27))	('liver metastases', 'Disease', 'MESH:D009362', (119, 135))	('PCC', 'Gene', '1421', (111, 114))	('patient', 'Species', '9606', (86, 93))	('c.429+1G>T', 'Var', (17, 27))	('PCC', 'Gene', (111, 114))	('liver metastases', 'Disease', (119, 135))
39570	30008476	RBP1 measurement was performed in four available tumors (p.Ser3Phe, p.Arg104Gly, p.Val160Met, and p.Lys314del-tumor), observing a reduced RBP1 expression in three tumors compared with controls: 93.86 +- 1.83% (p = 0.007), 83.18 +- 0.65% (p = 0.007), and 82.44 +- 19.72% (p = 0.030) for p.Lys314del-, p.Arg104Gly-, and p.Val160Met-tumor, respectively (Fig.	('p.Val160Met', 'Mutation', 'rs138541865', (318, 329))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('RBP1', 'Gene', (138, 142))	('tumor', 'Disease', (330, 335))	('p.Lys314del-', 'Var', (286, 298))	('p.Arg104Gly-', 'Var', (300, 312))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (68, 79))	('RBP1', 'Gene', '5947', (138, 142))	('tumors', 'Disease', (49, 55))	('tumor', 'Disease', (163, 168))	('p.Lys314del', 'Mutation', 'p.314del', (286, 297))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('RBP1', 'Gene', (0, 4))	('p.Ser3Phe', 'Mutation', 'p.S3F', (57, 66))	('RBP1', 'Gene', '5947', (0, 4))	('expression', 'MPA', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (163, 169))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (300, 311))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('p.Lys314del', 'Mutation', 'p.314del', (98, 109))	('p.Val160Met', 'Mutation', 'rs138541865', (81, 92))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (110, 115))	('p.Arg104Gly', 'Var', (68, 79))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('reduced', 'NegReg', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
39571	30008476	None of the variants was associated with an altered MDH2 localization, or mitochondrial quantity and morphology (see Supplemental Results).	('MDH2', 'Gene', '4191', (52, 56))	('mitochondrial', 'MPA', (74, 87))	('MDH2', 'Gene', (52, 56))	('variants', 'Var', (12, 20))	('localization', 'MPA', (57, 69))
39572	30008476	Only variant p.Arg104Gly displayed a significant lower MDH2 enzymatic activity at saturating concentration of substrates (p < 0.0001) compared with WT, comparable with the activity detected in the KD cells not expressing MDH2 (Fig.	('MDH2', 'Gene', '4191', (55, 59))	('MDH2', 'Gene', (55, 59))	('MDH2', 'Gene', '4191', (221, 225))	('p.Arg104Gly', 'Var', (13, 24))	('MDH2', 'Gene', (221, 225))	('lower', 'NegReg', (49, 54))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (13, 24))	('enzymatic activity', 'MPA', (60, 78))
39573	30008476	On the other hand, citrate synthase activity, present exclusively in the mitochondria, was similar for all variants (Table S2), suggesting that none of them produced an increased mitochondrial biogenesis to compensate the possible aberrant MDH2 variant.	('citrate synthase', 'Gene', '1431', (19, 35))	('mitochondrial biogenesis', 'MPA', (179, 203))	('variant', 'Var', (245, 252))	('MDH2', 'Gene', '4191', (240, 244))	('MDH2', 'Gene', (240, 244))	('citrate synthase', 'Gene', (19, 35))
39575	30008476	LOH was not detected in any of the tumors carrying the missense variants.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('missense variants', 'Var', (55, 72))
39576	30008476	To evaluate if MDH2 variants could exert a dominant-negative effect on MDH2 WT, we took as a model the p.Arg104Gly variant.	('p.Arg104Gly', 'Mutation', 'rs1474905443', (103, 114))	('p.Arg104Gly', 'Var', (103, 114))	('variants', 'Var', (20, 28))	('MDH2', 'Gene', (15, 19))	('MDH2', 'Gene', '4191', (15, 19))	('MDH2', 'Gene', (71, 75))	('MDH2', 'Gene', '4191', (71, 75))
39579	30008476	Cells cotransfected with both WT and p.Arg104Gly plasmids exhibited lower enzymatic activity in comparison with those cotransfected with WT and EV ones (27.8% +- 22.6; p = 0.0002) (Fig.	('lower', 'NegReg', (68, 73))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (37, 48))	('p.Arg104Gly', 'Var', (37, 48))	('enzymatic activity', 'MPA', (74, 92))	('EV', 'Chemical', '-', (144, 146))
39580	30008476	Another assay was designed to evaluate if p.Val160Met and p.Ala256Thr variants affected the affinity of the enzyme for the substrates, instead of the maximal activity.	('affinity', 'MPA', (92, 100))	('p.Ala256Thr', 'Var', (58, 69))	('p.Val160Met', 'Mutation', 'rs138541865', (42, 53))	('affected', 'Reg', (79, 87))	('p.Ala256Thr', 'Mutation', 'rs147655350', (58, 69))	('p.Val160Met', 'Var', (42, 53))	('maximal activity', 'MPA', (150, 166))
39582	30008476	A tendency of reduced enzymatic activity when decreasing malate concentration was observed for p.Val160Met, significant at 5 mM (5-fold reduction to malate saturating concentration, p = 0.0256) (Fig.	('reduced', 'NegReg', (14, 21))	('p.Val160Met', 'Mutation', 'rs138541865', (95, 106))	('malate', 'Chemical', 'MESH:C030298', (57, 63))	('p.Val160Met', 'Var', (95, 106))	('reduction', 'NegReg', (136, 145))	('enzymatic', 'MPA', (22, 31))	('malate', 'Chemical', 'MESH:C030298', (149, 155))	('malate concentration', 'MPA', (57, 77))	('malate saturating concentration', 'MPA', (149, 180))
39584	30008476	Furthermore, a subtle decrease in the activity was observed for p.Ala256Thr when diminishing concentration of NAD+ (Fig.	('activity', 'MPA', (38, 46))	('decrease', 'NegReg', (22, 30))	('p.Ala256Thr', 'Var', (64, 75))	('NAD+', 'Chemical', 'MESH:D009243', (110, 114))	('p.Ala256Thr', 'Mutation', 'rs147655350', (64, 75))	('diminishing', 'NegReg', (81, 92))
39587	30008476	Simulations of the dimers of the WT apoenzyme, and the p.Ala256Thr and p.Val160Met variants revealed differences in their principal motions.	('p.Val160Met', 'Mutation', 'rs138541865', (71, 82))	('p.Val160Met', 'Var', (71, 82))	('p.Ala256Thr', 'Mutation', 'rs147655350', (55, 66))	('principal motions', 'MPA', (122, 139))	('p.Ala256Thr', 'Var', (55, 66))	('differences', 'Reg', (101, 112))
39588	30008476	In the p.Ala256Thr mutant, the character of the main motions was conserved (Fig.	('p.Ala256Thr', 'Var', (7, 18))	('p.Ala256Thr', 'Mutation', 'rs147655350', (7, 18))	('main motions', 'MPA', (48, 60))
39589	30008476	S5B), whereas in the p.Val160Met mutant the relative movement of the monomers was strongly reduced (Fig.	('S5B', 'Gene', '5711', (0, 3))	('S5B', 'Gene', (0, 3))	('relative movement of the monomers', 'MPA', (44, 77))	('reduced', 'NegReg', (91, 98))	('p.Val160Met', 'Mutation', 'rs138541865', (21, 32))	('p.Val160Met', 'Var', (21, 32))
39590	30008476	Although the dynamics of the p.Ala256Thr variant were similar to that of the WT, closer inspection revealed conformational changes.	('conformational', 'MPA', (108, 122))	('p.Ala256Thr', 'Var', (29, 40))	('p.Ala256Thr', 'Mutation', 'rs147655350', (29, 40))
39591	30008476	In the WT and p.Val160Met variant, the side chain of Phe260, neighboring Ala/Thr256, switches between two orientations, while in the p.Ala256Thr mutant it remains immobile (Fig.	('p.Val160Met', 'Var', (14, 25))	('p.Val160Met', 'Mutation', 'rs138541865', (14, 25))	('Phe260', 'Chemical', '-', (53, 59))	('switches', 'Reg', (85, 93))	('Ala/Thr256', 'Var', (73, 83))	('side chain', 'MPA', (39, 49))	('Phe260', 'Var', (53, 59))	('p.Ala256Thr', 'Mutation', 'rs147655350', (133, 144))	('immobile', 'MPA', (163, 171))	('Ala/Thr256', 'SUBSTITUTION', 'None', (73, 83))
39592	30008476	The results suggest that the p.Ala256Thr variant affects the conformation of the neighboring residues, which contribute to the dimeric interface.	('conformation', 'MPA', (61, 73))	('p.Ala256Thr', 'Var', (29, 40))	('affects', 'Reg', (49, 56))	('p.Ala256Thr', 'Mutation', 'rs147655350', (29, 40))
39593	30008476	This implies that the p.Ala256Thr variant may affect dimerization of MDH2.	('p.Ala256Thr', 'Var', (22, 33))	('MDH2', 'Gene', (69, 73))	('dimerization', 'MPA', (53, 65))	('p.Ala256Thr', 'Mutation', 'rs147655350', (22, 33))	('MDH2', 'Gene', '4191', (69, 73))	('affect', 'Reg', (46, 52))
39594	30008476	In the p.Val160Met variant, changes in the dynamics of the substrate-binding site may affect substrate affinity.	('affect', 'Reg', (86, 92))	('substrate affinity', 'MPA', (93, 111))	('p.Val160Met', 'Mutation', 'rs138541865', (7, 18))	('changes', 'Reg', (28, 35))	('p.Val160Met', 'Var', (7, 18))	('dynamics of the substrate-binding site', 'MPA', (43, 81))
39595	30008476	After the identification of major susceptibility PPGL genes, the list of other genes with modest contributions to the disease has kept growing and it is likely that this number will continue to increase over the near future.	('genes', 'Var', (54, 59))	('PPGL', 'Gene', (49, 53))	('PPGL', 'Chemical', '-', (49, 53))	('susceptibility', 'Reg', (34, 48))
39598	30008476	We were able to classify 2 MDH2 variants as pathogenic and provide evidence that suggests an altered molecular function of MDH2 in 2 others (which have been designated as likely PV), following the criteria established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines.	('MDH2', 'Gene', (123, 127))	('molecular function', 'MPA', (101, 119))	('MDH2', 'Gene', '4191', (27, 31))	('altered', 'Reg', (93, 100))	('MDH2', 'Gene', (27, 31))	('variants', 'Var', (32, 40))	('MDH2', 'Gene', '4191', (123, 127))
39599	30008476	Furthermore, a new patient, carrying the already reported c.429+1G>T MDH2 variant, was identified.	('patient', 'Species', '9606', (19, 26))	('c.429+1G>T', 'Mutation', 'rs782251807', (58, 68))	('MDH2', 'Gene', (69, 73))	('MDH2', 'Gene', '4191', (69, 73))	('c.429+1G>T', 'Var', (58, 68))
39600	30008476	RBP1 expression in the tumor, bioinformatics predictions, and functional assays suggested that p.Arg104Gly is a PV located in the highly conserved NAD-binding site and significantly impairing MDH2 activity.	('MDH2', 'Gene', '4191', (192, 196))	('NAD', 'Chemical', 'MESH:D009243', (147, 150))	('MDH2', 'Gene', (192, 196))	('RBP1', 'Gene', '5947', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (95, 106))	('p.Arg104Gly', 'Var', (95, 106))	('activity', 'MPA', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('impairing', 'NegReg', (182, 191))	('RBP1', 'Gene', (0, 4))
39604	30008476	Enzymatic assays performed by cotransfection of WT and p.Arg104Gly plasmids resembling the heterozygous character of this PV suggested a dominant-negative effect of the p.Arg104Gly-mutant.	('p.Arg104Gly', 'Var', (55, 66))	('p.Arg104Gly-mutant', 'Var', (169, 187))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (169, 180))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (55, 66))
39605	30008476	The two other missense variants, p.Ala256Thr and p.Val160Met, reported as rare SNPs and located in conserved residues, were predicted to produce protein 3D structure destabilization and impaired the MDH2 molecular function.	('molecular function', 'MPA', (204, 222))	('p.Val160Met', 'Var', (49, 60))	('impaired', 'NegReg', (186, 194))	('MDH2', 'Gene', '4191', (199, 203))	('protein', 'Protein', (145, 152))	('MDH2', 'Gene', (199, 203))	('p.Ala256Thr', 'Mutation', 'rs147655350', (33, 44))	('p.Val160Met', 'Mutation', 'rs138541865', (49, 60))	('p.Ala256Thr', 'Var', (33, 44))
39606	30008476	The p.Val160Met was detected in a 54-year-old PCC patient, whose tumor showed low RBP1 expression.	('patient', 'Species', '9606', (50, 57))	('RBP1', 'Gene', '5947', (82, 86))	('tumor', 'Disease', (65, 70))	('low', 'NegReg', (78, 81))	('PCC', 'Gene', '1421', (46, 49))	('expression', 'MPA', (87, 97))	('p.Val160Met', 'Mutation', 'rs138541865', (4, 15))	('p.Val160Met', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('RBP1', 'Gene', (82, 86))	('PCC', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
39609	30008476	The substitutions at residues Val160 and Ala256 could also affect the substrate binding affinity and protein 3D stability, and therefore, neither the enzymatic assay nor the immunofluorescence experiments are able to evaluate the effect.	('affect', 'Reg', (59, 65))	('Ala256', 'Chemical', '-', (41, 47))	('Val160', 'Var', (30, 36))	('Ala256', 'Var', (41, 47))	('substrate binding', 'Interaction', (70, 87))	('protein', 'Protein', (101, 108))	('Val160', 'Chemical', '-', (30, 36))	('substitutions', 'Var', (4, 17))
39610	30008476	Because of that, we conducted MD simulations only with these variants, which suggested that p.Val160Met could be modifying malate binding to the catalytic site, and consequently affecting MDH2 affinity for its substrate.	('MDH2', 'Gene', (188, 192))	('affecting', 'Reg', (178, 187))	('malate', 'MPA', (123, 129))	('p.Val160Met', 'Mutation', 'rs138541865', (92, 103))	('p.Val160Met', 'Var', (92, 103))	('malate', 'Chemical', 'MESH:C030298', (123, 129))	('modifying', 'Reg', (113, 122))	('affinity', 'MPA', (193, 201))	('binding', 'Interaction', (130, 137))	('MDH2', 'Gene', '4191', (188, 192))
39612	30008476	For variant p.Ala256Thr, MD simulations predicted that it could be affecting enzyme dimerization.	('p.Ala256Thr', 'Var', (12, 23))	('p.Ala256Thr', 'Mutation', 'rs147655350', (12, 23))	('affecting', 'Reg', (67, 76))	('enzyme dimerization', 'MPA', (77, 96))
39614	30008476	A second somatic hit was not observed in the tumor of p.Val160Met-related patient and p.Ala256Thr-related tumor was not available.	('patient', 'Species', '9606', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('p.Val160Met', 'Mutation', 'rs138541865', (54, 65))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p.Val160Met-related', 'Var', (54, 73))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', (106, 111))	('p.Ala256Thr', 'Mutation', 'rs147655350', (86, 97))
39615	30008476	A dominant-negative effect for p.Val160Met and p.Ala256Thr variants might be the underlying mechanism as occurs with the p. Arg104Gly variant, although this has not been tested in this study.	('p.Ala256Thr', 'Var', (47, 58))	('Arg104Gly', 'Var', (124, 133))	('p.Ala256Thr', 'Mutation', 'rs147655350', (47, 58))	('p.Val160Met', 'Mutation', 'rs138541865', (31, 42))	('Arg104Gly', 'SUBSTITUTION', 'None', (124, 133))	('p.Val160Met', 'Var', (31, 42))
39617	30008476	Regarding the p.Val160Met variant, although most of our analyses suggested a potential pathogenic role as well, it was also classified as likely pathogenic due to the high number of alleles found (46/277206) in the general population.	('pathogenic', 'Reg', (145, 155))	('pathogenic', 'Reg', (87, 97))	('p.Val160Met', 'Mutation', 'rs138541865', (14, 25))	('p.Val160Met', 'Var', (14, 25))
39618	30008476	For the two other novel missense variants (p.Ser3Phe and p.Gln130Arg) identified, computational analyses did not reach a consensus.	('p.Ser3Phe', 'Var', (43, 52))	('p.Gln130Arg', 'Mutation', 'p.Q130R', (57, 68))	('p.Gln130Arg', 'Var', (57, 68))	('p.Ser3Phe', 'Mutation', 'p.S3F', (43, 52))
39619	30008476	In addition, patients carrying these variants had predominant adrenaline production or nonfunctional tumors, which is in discordance with MDH2-mutated patient and other Krebs cycle genes.	('Krebs', 'Chemical', '-', (169, 174))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('patient', 'Species', '9606', (13, 20))	('patients', 'Species', '9606', (13, 21))	('adrenaline', 'Chemical', 'MESH:D004837', (62, 72))	('patient', 'Species', '9606', (151, 158))	('MDH2', 'Gene', '4191', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('MDH2', 'Gene', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('variants', 'Var', (37, 45))	('adrenaline', 'CPA', (62, 72))	('tumors', 'Disease', (101, 107))
39622	30008476	The p.Lys314del, identified in a patient with multiple noradrenergic PGLs, was classified as pathogenic, as it affects a conserved amino acid, and LOH and low RBP1 expression in the tumor sample were found.	('patient', 'Species', '9606', (33, 40))	('tumor', 'Disease', (182, 187))	('expression', 'MPA', (164, 174))	('p.Lys314del', 'Var', (4, 15))	('p.Lys314del', 'Mutation', 'p.314del', (4, 15))	('RBP1', 'Gene', '5947', (159, 163))	('conserved amino acid', 'MPA', (121, 141))	('low', 'NegReg', (155, 158))	('RBP1', 'Gene', (159, 163))	('PGLs', 'Phenotype', 'HP:0002668', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('affects', 'Reg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
39623	30008476	Finally, a 57-year-old patient with a metastatic pheochromocytoma, clinical phenotype similar to the patient reported, was identified to carry the same variant affecting a donor splice-site (c.429+1G>A).	('pheochromocytoma', 'Disease', 'MESH:D010673', (49, 65))	('c.429+1G>A', 'Var', (191, 201))	('c.429+1G>A', 'Mutation', 'c.429+1G>A', (191, 201))	('patient', 'Species', '9606', (101, 108))	('pheochromocytoma', 'Disease', (49, 65))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (49, 65))	('patient', 'Species', '9606', (23, 30))
39624	30008476	In summary, taking into account only those MDH2 variants identified that display characteristics supportive of a pathogenicity potential, we provide more evidence that suggests the potential role of MDH2 in PPGL predisposition, and indicates that MDH2 germline PV could be responsible for 0.6% of PPGL cases, prevalence comparable with that reported for other recently described PPGL genes.	('PPGL', 'Chemical', '-', (207, 211))	('MDH2', 'Gene', '4191', (247, 251))	('MDH2', 'Gene', (43, 47))	('MDH2', 'Gene', (247, 251))	('PPGL', 'Chemical', '-', (379, 383))	('MDH2', 'Gene', '4191', (199, 203))	('MDH2', 'Gene', (199, 203))	('PPGL', 'Chemical', '-', (297, 301))	('responsible', 'Reg', (273, 284))	('variants', 'Var', (48, 56))	('PPGL', 'Disease', (207, 211))	('PPGL', 'Disease', (297, 301))	('MDH2', 'Gene', '4191', (43, 47))
39628	30008476	On the other hand, it is worthy to note that MDH2 variants were found in metastatic cases, as two of five patients (three of six, if we include the reported MDH2 patient) developed metastases.	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('MDH2', 'Gene', '4191', (45, 49))	('MDH2', 'Gene', '4191', (157, 161))	('MDH2', 'Gene', (45, 49))	('MDH2', 'Gene', (157, 161))	('patient', 'Species', '9606', (106, 113))	('patients', 'Species', '9606', (106, 114))	('metastases', 'Disease', (181, 191))	('found', 'Reg', (64, 69))	('variants', 'Var', (50, 58))	('patient', 'Species', '9606', (162, 169))
39631	30008476	In this study, we were able to demonstrate a functional impact for two variants (p.Arg104Gly and p.Lys314del) and suggested an altered molecular function for other two (p.Val160Met and p.Ala256Thr), but there was insufficient evidence to consider them pathogenic even after applying up to five approaches to classify them.	('p.Ala256Thr', 'Mutation', 'rs147655350', (185, 196))	('p.Arg104Gly', 'Mutation', 'rs1474905443', (81, 92))	('p.Arg104Gly', 'Var', (81, 92))	('p.Lys314del', 'Var', (97, 108))	('p.Lys314del', 'Mutation', 'p.314del', (97, 108))	('p.Ala256Thr', 'Var', (185, 196))	('p.Val160Met', 'Mutation', 'rs138541865', (169, 180))	('molecular function', 'MPA', (135, 153))	('altered', 'Reg', (127, 134))	('p.Val160Met', 'Var', (169, 180))
39632	30008476	Although, it is likely that this rationale is unapproachable in the clinical setting when tumor tissue is unavailable, we demonstrated that MDH2 variants could be classified by a multidisciplinary approach.	('MDH2', 'Gene', '4191', (140, 144))	('MDH2', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('variants', 'Var', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
39696	32569235	For genetic study, ectopic pheochromocytoma is currently associated with germline and/or somatic mutations in more than 20 genes.	('mutations', 'Var', (97, 106))	('ectopic pheochromocytoma', 'Disease', (19, 43))	('ectopic pheochromocytoma', 'Disease', 'MESH:D010673', (19, 43))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (27, 43))	('associated', 'Reg', (57, 67))
39697	32569235	These mutations are divided into three main clusters (Pseudohypoxic signaling cluster, Kinase signaling cluster and Wnt signaling cluster) based on the activation of a particular signaling pathway and each cluster is associated with unique clinical characteristics of patients with these tumors.	('activation', 'PosReg', (152, 162))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('signaling pathway', 'Pathway', (179, 196))	('patients', 'Species', '9606', (268, 276))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', (288, 294))
39749	30694796	Here we focus on succinate dehydrogenase subunit B (SDHB) gene mutation carriers as these tumours carry a high risk of malignant transformation.	('SDHB', 'Gene', (52, 56))	('succinate dehydrogenase subunit B', 'Gene', (17, 50))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('mutation', 'Var', (63, 71))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('SDHB', 'Gene', '6390', (52, 56))	('succinate dehydrogenase subunit B', 'Gene', '6390', (17, 50))	('tumours', 'Disease', (90, 97))
39751	30694796	We undertook a retrospective analysis of longitudinal clinical data of all children and adolescents with SDHB mutations followed up in a single UK tertiary referral centre.	('children', 'Species', '9606', (75, 83))	('SDHB', 'Gene', '6390', (105, 109))	('mutations', 'Var', (110, 119))	('SDHB', 'Gene', (105, 109))
39752	30694796	We also conducted a literature review to inform a suggested surveillance protocol for children and adolescents harbouring SDHB mutations.	('mutations', 'Var', (127, 136))	('SDHB', 'Gene', '6390', (122, 126))	('SDHB', 'Gene', (122, 126))	('children', 'Species', '9606', (86, 94))
39757	30694796	Almost 40-50% of all phaeochromocytomas (PCC) and paragangliomas (PGL) (together known as PPGLs) are now thought to be associated with germline mutations, but within the paediatric population this figure is higher (70-80%).	('germline mutations', 'Var', (135, 153))	('paragangliomas', 'Disease', 'MESH:D010235', (50, 64))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (21, 39))	('phaeochromocytomas', 'Disease', (21, 39))	('PGL', 'Phenotype', 'HP:0002668', (66, 69))	('PGL', 'Phenotype', 'HP:0002668', (91, 94))	('paragangliomas', 'Disease', (50, 64))	('PPGLs', 'Chemical', '-', (90, 95))	('paragangliomas', 'Phenotype', 'HP:0002668', (50, 64))	('associated', 'Reg', (119, 129))
39761	30694796	SDHB mutations are inherited in an autosomal dominant manner and have a lifetime penetrance of 30-40%.	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
39762	30694796	Individuals carrying SDHB mutations command special attention as they contribute a high proportion of the PPGLs occurring in paediatric patients and have a high rate (up to 30%) of malignant transformation.	('PPGLs', 'Chemical', '-', (106, 111))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (136, 144))	('PGL', 'Phenotype', 'HP:0002668', (107, 110))	('SDHB', 'Gene', (21, 25))	('PPGLs', 'Disease', (106, 111))
39763	30694796	Approximately 72% of metastatic PPGLs in childhood are associated with SDHB mutations.	('mutations', 'Var', (76, 85))	('PPGLs', 'Chemical', '-', (32, 37))	('PGL', 'Phenotype', 'HP:0002668', (33, 36))	('SDHB', 'Gene', '6390', (71, 75))	('associated', 'Reg', (55, 65))	('SDHB', 'Gene', (71, 75))	('child', 'Species', '9606', (41, 46))	('metastatic PPGLs', 'Disease', (21, 37))
39764	30694796	This emphasises the importance of lifelong, regular surveillance for all children carrying SDHB mutations in an experienced centre as, although hard to prove, it is generally accepted that early detection and timely resection of SDHB-associated tumours will reduce the risk of metastatic disease.	('SDHB', 'Gene', '6390', (229, 233))	('children', 'Species', '9606', (73, 81))	('tumours', 'Phenotype', 'HP:0002664', (245, 252))	('tumours', 'Disease', 'MESH:D009369', (245, 252))	('metastatic disease', 'CPA', (277, 295))	('SDHB', 'Gene', '6390', (91, 95))	('SDHB', 'Gene', (229, 233))	('tumours', 'Disease', (245, 252))	('reduce', 'NegReg', (258, 264))	('SDHB', 'Gene', (91, 95))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('mutations', 'Var', (96, 105))
39765	30694796	Despite widespread acceptance that individuals who carry SDHB mutations should undergo regular surveillance imaging, there is no clear consensus regarding the optimal modality or frequency.	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
39767	30694796	Since the discovery of SDHB mutations as a cause for PPGL syndromes, increasing numbers of genetically affected young family members are being identified and referred to specialist paediatric services.	('PGL', 'Phenotype', 'HP:0002668', (54, 57))	('cause', 'Reg', (43, 48))	('PPGL syndromes', 'Disease', (53, 67))	('SDHB', 'Gene', '6390', (23, 27))	('SDHB', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
39770	30694796	Based on these combined data, we propose a regular surveillance protocol for screening children with SDHB mutations.	('children', 'Species', '9606', (87, 95))	('SDHB', 'Gene', '6390', (101, 105))	('SDHB', 'Gene', (101, 105))	('mutations', 'Var', (106, 115))
39771	30694796	We undertook a retrospective review of paediatric SDHB mutation-positive index cases and asymptomatic carriers managed in our UK tertiary referral centre.	('SDHB', 'Gene', (50, 54))	('mutation-positive', 'Var', (55, 72))	('SDHB', 'Gene', '6390', (50, 54))
39777	30694796	This included index cases that presented with symptomatic PPGL or individuals with relatives known to carry SDHB mutations.	('SDHB', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('PPGL', 'Disease', (58, 62))	('PGL', 'Phenotype', 'HP:0002668', (59, 62))	('SDHB', 'Gene', '6390', (108, 112))
39779	30694796	However, 20 children were diagnosed genetically between the ages of 5 and 18 years when their individual risk was established, following the identification of an SDHB gene mutation in a family member.	('mutation', 'Var', (172, 180))	('children', 'Species', '9606', (12, 20))	('SDHB', 'Gene', '6390', (162, 166))	('SDHB', 'Gene', (162, 166))
39782	30694796	The median time from diagnosis of the first PPGL to the confirmation of the SDHB mutation was 15 years (range 0-34 years) in the index cases.	('SDHB', 'Gene', '6390', (76, 80))	('mutation', 'Var', (81, 89))	('SDHB', 'Gene', (76, 80))	('PGL', 'Phenotype', 'HP:0002668', (45, 48))
39792	30694796	Data includes 175 patient years of follow-up initiated at either diagnosis (index cases) or the time of identification of SDHB mutation carrier status.	('mutation', 'Var', (127, 135))	('SDHB', 'Gene', '6390', (122, 126))	('patient', 'Species', '9606', (18, 25))	('SDHB', 'Gene', (122, 126))
39798	30694796	Thirty children were found to have SDHB mutations on cascade genetic testing (Table 2).	('mutations', 'Var', (40, 49))	('children', 'Species', '9606', (7, 15))	('SDHB', 'Gene', '6390', (35, 39))	('SDHB', 'Gene', (35, 39))
39805	30694796	The aim of the surveillance screening in SDHB mutation carriers is to detect and manage the clinical manifestations early, thereby reducing potentially serious complications and enhance cure rates.	('enhance', 'PosReg', (178, 185))	('cure rates', 'CPA', (186, 196))	('SDHB', 'Gene', (41, 45))	('SDHB', 'Gene', '6390', (41, 45))	('reducing', 'NegReg', (131, 139))	('mutation', 'Var', (46, 54))
39806	30694796	This is especially pertinent in young patients with SDHB mutations who have much higher reported rates of tumour metastasis.	('SDHB', 'Gene', (52, 56))	('tumour metastasis', 'Disease', (106, 123))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (38, 46))	('mutations', 'Var', (57, 66))	('tumour metastasis', 'Disease', 'MESH:D009362', (106, 123))	('SDHB', 'Gene', '6390', (52, 56))
39807	30694796	The risk of a child with an SDHB mutation developing disease during childhood is very low, but if tumours arise they are potentially more aggressive than adult-onset lesions, although the reason for this is unknown.	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('mutation', 'Var', (33, 41))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('tumours', 'Disease', (98, 105))	('child', 'Species', '9606', (68, 73))	('child', 'Species', '9606', (14, 19))	('SDHB', 'Gene', '6390', (28, 32))	('SDHB', 'Gene', (28, 32))
39812	30694796	The mean age for developing PPGLs in patients with SDHB mutations is 29 years.	('PGL', 'Phenotype', 'HP:0002668', (29, 32))	('mutations', 'Var', (56, 65))	('patients', 'Species', '9606', (37, 45))	('PPGLs', 'Chemical', '-', (28, 33))	('SDHB', 'Gene', '6390', (51, 55))	('SDHB', 'Gene', (51, 55))
39818	30694796	Survival rates in children and young adults with SDHB mutations who develop tumours at 5, 10 and 20 years are 95.8, 95.8 and 71%, respectively.	('SDHB', 'Gene', (49, 53))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('children', 'Species', '9606', (18, 26))	('mutations', 'Var', (54, 63))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('SDHB', 'Gene', '6390', (49, 53))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
39821	30694796	We reviewed the suggested published surveillance protocols for patients with SDHB mutations.	('SDHB', 'Gene', '6390', (77, 81))	('mutations', 'Var', (82, 91))	('SDHB', 'Gene', (77, 81))	('patients', 'Species', '9606', (63, 71))
39839	30694796	Based on our data and the available published literature, we suggest a comprehensive surveillance protocol for paediatric asymptomatic SDHB mutation carriers (Fig.	('SDHB', 'Gene', '6390', (135, 139))	('mutation', 'Var', (140, 148))	('SDHB', 'Gene', (135, 139))
39852	30694796	The authors believe that all children that are identified as SDHB carriers should be entered into prospective surveillance programmes.	('carriers', 'Var', (66, 74))	('children', 'Species', '9606', (29, 37))	('SDHB', 'Gene', '6390', (61, 65))	('SDHB', 'Gene', (61, 65))
39856	30694796	The surveillance programme for SDHB mutation carriers should begin before the risk of tumour formation.	('SDHB', 'Gene', '6390', (31, 35))	('SDHB', 'Gene', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (86, 92))	('mutation', 'Var', (36, 44))
39870	29755524	Besides the three classical PHEO-associated cancer syndromes, namely, multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, and neurofibromatosis type 1 (NF1), new entities have been associated with PHEO: the PGL syndrome types 1 to 5 [(PGL1-5) caused by mutations in succinate dehydrogenase (SDH) subunits D/AF2/C/B/A genes (SDHx), resp.	('multiple endocrine neoplasia type 2', 'Disease', (70, 105))	('PGL1-5', 'Gene', (260, 266))	('SDH', 'Gene', '6390', (349, 352))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (114, 145))	('succinate dehydrogenase', 'Gene', '6390', (291, 314))	('mutations', 'Var', (278, 287))	('SDH', 'Gene', '6390', (316, 319))	('PHEO', 'Phenotype', 'HP:0002666', (28, 32))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (151, 168))	('neurofibromatosis type 1', 'Gene', '4763', (151, 175))	('PGL1-5', 'Gene', '54949;6391;6390;6389', (260, 266))	('PGL syndrome', 'Disease', 'MESH:D010235', (232, 244))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (70, 105))	('neoplasia', 'Phenotype', 'HP:0002664', (89, 98))	('SDH', 'Gene', (349, 352))	('NF1', 'Gene', '4763', (177, 180))	('SDH', 'Gene', (316, 319))	('caused by', 'Reg', (268, 277))	('cancer syndromes', 'Disease', (44, 60))	('NF1', 'Gene', (177, 180))	('succinate dehydrogenase', 'Gene', (291, 314))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (79, 98))	('SDHx', 'Chemical', '-', (349, 353))	('neurofibromatosis type 1', 'Gene', (151, 175))	('PGL syndrome', 'Disease', (232, 244))	('MEN', 'Species', '9606', (107, 110))	('cancer syndromes', 'Disease', 'MESH:D009369', (44, 60))	('PHEO', 'Phenotype', 'HP:0002666', (222, 226))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
39871	29755524	], familial PHEO [caused by mutations in Myc-associated protein X (MAX) and transmembrane protein 127 (TMEM127) genes], and several new susceptibility genes.	('TMEM127', 'Gene', (103, 110))	('TMEM127', 'Gene', '55654', (103, 110))	('Myc', 'Gene', '4609', (41, 44))	('familial PHEO', 'Disease', (3, 16))	('Myc', 'Gene', (41, 44))	('PHEO', 'Phenotype', 'HP:0002666', (12, 16))	('caused by', 'Reg', (18, 27))	('mutations', 'Var', (28, 37))
39877	29755524	Furthermore, two other reasons should be taken into account while considering genetic testing: (1) the high rate of metastatic PHEO associated with some mutations, which may aid in tailoring the appropriate follow-up, and (2) the finding of a mutation in the index case and their relatives, which allows for an individualized surveillance program to timely detect and treat chromaffin and other nonchromaffin cell tumors or disorders.	('chromaffin', 'Chemical', '-', (374, 384))	('rat', 'Species', '10116', (108, 111))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (398, 420))	('chromaffin', 'Chemical', '-', (398, 408))	('mutation', 'Var', (243, 251))	('mutations', 'Var', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (414, 419))	('tumors or disorders', 'Disease', (414, 433))	('chromaffin', 'Disease', (374, 384))	('tumors', 'Phenotype', 'HP:0002664', (414, 420))	('associated', 'Reg', (132, 142))	('metastatic PHEO', 'Disease', (116, 131))	('PHEO', 'Phenotype', 'HP:0002666', (127, 131))	('tumors or disorders', 'Disease', 'MESH:D009369', (414, 433))
39878	29755524	Additionally, when a genetic mutation is suspected to be linked to PHEO, other parameters may aid in the selection of the molecular analysis, namely, the type of catecholamine production and/or the pattern of SDHA/B immunostaining in pathology specimens and a specific imaging phenotype.	('SDHA', 'Gene', (209, 213))	('mutation', 'Var', (29, 37))	('aid', 'Reg', (94, 97))	('catecholamine', 'Chemical', 'MESH:D002395', (162, 175))	('SDHA', 'Gene', '6389', (209, 213))	('PHEO', 'Phenotype', 'HP:0002666', (67, 71))
39879	29755524	Here, we review the clinical phenotypes of pediatric patients with PHEO and associated mutations in susceptibility genes reported in the literature, in an attempt to contribute to a comprehensive genetic screening of PHEO in pediatric age.	('PHEO', 'Phenotype', 'HP:0002666', (217, 221))	('patients', 'Species', '9606', (53, 61))	('PHEO', 'Disease', (67, 71))	('PHEO', 'Phenotype', 'HP:0002666', (67, 71))	('rat', 'Species', '10116', (141, 144))	('mutations', 'Var', (87, 96))
39882	29755524	The susceptibility genes involved in the development of pediatric PHEO may be grouped according to three primary mechanisms of oncogenesis: a pseudohypoxic cluster [mutations in VHL, HIF2A (or EPAS1), PHD1, PHD2, FH, SDHx, and MDH2], a cluster composed of kinase receptor signaling and protein translation pathways (mutations in RET, NF1, and MAX), and a Wnt-altered pathway cluster.	('RET', 'Gene', (329, 332))	('pseudohypoxic', 'Disease', (142, 155))	('MDH2', 'Gene', (227, 231))	('VHL', 'Gene', (178, 181))	('SDHx', 'Gene', (217, 221))	('mutations', 'Var', (165, 174))	('EPAS1', 'Gene', (193, 198))	('PHEO', 'Phenotype', 'HP:0002666', (66, 70))	('SDHx', 'Chemical', '-', (217, 221))	('RET', 'Gene', '5979', (329, 332))	('VHL', 'Gene', '7428', (178, 181))	('PHD1', 'Gene', (201, 205))	('protein translation pathways', 'Pathway', (286, 314))	('PHD2', 'Gene', (207, 211))	('NF1', 'Gene', '4763', (334, 337))	('HIF2A', 'Gene', (183, 188))	('MDH2', 'Gene', '4191', (227, 231))	('NF1', 'Gene', (334, 337))	('EPAS1', 'Gene', '2034', (193, 198))
39886	29755524	However, a long-standing process of hypoxia (or pseudohypoxia) causes HIF-alpha excess, which promotes a nuclear overexpression of these genes, ultimately leading to cancer development, migration, invasion, and metastasis.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('pseudohypoxia', 'Disease', 'None', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('excess', 'Var', (80, 86))	('rat', 'Species', '10116', (189, 192))	('hypoxia', 'Disease', (54, 61))	('cancer', 'Disease', (166, 172))	('migration', 'CPA', (186, 195))	('overexpression', 'PosReg', (113, 127))	('metastasis', 'CPA', (211, 221))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('leading to', 'Reg', (155, 165))	('nuclear', 'MPA', (105, 112))	('invasion', 'CPA', (197, 205))	('hypoxia', 'Disease', 'MESH:D000860', (54, 61))	('hypoxia', 'Disease', (36, 43))	('long-standing', 'Phenotype', 'HP:0003698', (11, 24))	('pseudohypoxia', 'Disease', (48, 61))	('HIF-alpha', 'Protein', (70, 79))
39888	29755524	Loss-of-function mutations in SDHx or FH lead to succinate and fumarate accumulation, respectively, and to a subsequent inhibition of HIF-alpha hydroxylation, a necessary signal recognition step for its degradation by the VHL protein.	('Loss-of-function', 'NegReg', (0, 16))	('succinate', 'Chemical', 'MESH:D019802', (49, 58))	('VHL', 'Gene', (222, 225))	('SDHx', 'Gene', (30, 34))	('fumarate', 'Chemical', 'MESH:D005650', (63, 71))	('HIF-alpha hydroxylation', 'MPA', (134, 157))	('SDHx', 'Chemical', '-', (30, 34))	('VHL', 'Gene', '7428', (222, 225))	('inhibition', 'NegReg', (120, 130))	('mutations', 'Var', (17, 26))	('fumarate accumulation', 'MPA', (63, 84))	('succinate', 'MPA', (49, 58))
39889	29755524	Mutations in HIF-alpha promote electrostatic changes in the protein isoforms, which impair hydroxylation by PHD molecules, preventing the signaling for degradation by the VHL protein.	('promote', 'Reg', (23, 30))	('HIF-alpha', 'Gene', (13, 22))	('VHL', 'Gene', (171, 174))	('Mutations', 'Var', (0, 9))	('electrostatic changes in the protein isoforms', 'MPA', (31, 76))	('hydroxylation', 'MPA', (91, 104))	('VHL', 'Gene', '7428', (171, 174))	('signaling for degradation', 'MPA', (138, 163))	('impair', 'NegReg', (84, 90))	('preventing', 'NegReg', (123, 133))
39890	29755524	Finally, VHL mutations originate defective proteins that do not recognize hydroxylated HIF-alpha isoforms for degradation.	('mutations', 'Var', (13, 22))	('proteins', 'Protein', (43, 51))	('VHL', 'Gene', '7428', (9, 12))	('VHL', 'Gene', (9, 12))
39893	29755524	Germline mutations in specific exons of the RET may lead to constitutive activation of its protein tyrosine kinase domain and subsequent downstream activation of Ras/mitogen-activated protein kinase and PI3 kinase/AKT pathways, promoting tumorigenesis through cell proliferation and reduced apoptosis.	('RET', 'Gene', (44, 47))	('cell proliferation', 'CPA', (260, 278))	('activation', 'PosReg', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('apoptosis', 'CPA', (291, 300))	('activation', 'PosReg', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('AKT', 'Gene', '207', (214, 217))	('Germline', 'Var', (0, 8))	('promoting', 'PosReg', (228, 237))	('tumor', 'Disease', (238, 243))	('reduced', 'NegReg', (283, 290))	('RET', 'Gene', '5979', (44, 47))	('AKT', 'Gene', (214, 217))	('rat', 'Species', '10116', (272, 275))	('protein tyrosine kinase domain', 'MPA', (91, 121))
39896	29755524	Loss-of-function mutations in NF1 result in an enhanced cell proliferation through impaired Ras signaling inhibition.	('Loss-of-function', 'NegReg', (0, 16))	('Ras signaling', 'Pathway', (92, 105))	('enhanced', 'PosReg', (47, 55))	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('rat', 'Species', '10116', (68, 71))	('cell proliferation', 'CPA', (56, 74))	('inhibition', 'NegReg', (106, 116))	('mutations', 'Var', (17, 26))	('impaired', 'NegReg', (83, 91))
39898	29755524	Loss-of-function mutations in MAX generate a protein incapable of binding to Myc in the nucleus, leading to proliferation, angiogenesis, and repression of cell differentiation.	('Loss-of-function', 'NegReg', (0, 16))	('Myc', 'Gene', (77, 80))	('rat', 'Species', '10116', (115, 118))	('incapable', 'NegReg', (53, 62))	('repression of cell differentiation', 'CPA', (141, 175))	('angiogenesis', 'CPA', (123, 135))	('proliferation', 'CPA', (108, 121))	('MAX', 'Gene', (30, 33))	('Myc', 'Gene', '4609', (77, 80))	('rat', 'Species', '10116', (38, 41))	('mutations', 'Var', (17, 26))
39900	29755524	To our knowledge, 10 genes have been described in association with PHEO at a pediatric age: VHL (MIM *608537), rearranged during transfection (RET; MIM +164761), NF1 (MIM *613113), SDHD (MIM *602690), SDHB (MIM *185470), SDHA (MIM *600857), MAX (MIM *154950), HIF2A (MIM *603349), FH (MIM *136850), and PHD1 (MIM *606424).	('MIM *602690', 'Var', (187, 198))	('MIM *136850', 'Var', (285, 296))	('RET', 'Gene', '5979', (143, 146))	('MIM *613113', 'Var', (167, 178))	('MIM *185470', 'Var', (207, 218))	('VHL', 'Gene', (92, 95))	('SDHA', 'Gene', (221, 225))	('SDHD', 'Gene', '6392', (181, 185))	('PHEO', 'Phenotype', 'HP:0002666', (67, 71))	('MIM *606424', 'Var', (309, 320))	('SDHB', 'Gene', '6390', (201, 205))	('SDHA', 'Gene', '6389', (221, 225))	('NF1', 'Gene', '4763', (162, 165))	('RET', 'Gene', (143, 146))	('MIM *608537', 'Var', (97, 108))	('SDHD', 'Gene', (181, 185))	('VHL', 'Gene', '7428', (92, 95))	('NF1', 'Gene', (162, 165))	('SDHB', 'Gene', (201, 205))	('MIM *154950', 'Var', (246, 257))	('MIM *603349', 'Var', (267, 278))	('MIM *600857', 'Var', (227, 238))
39901	29755524	These genes are TMEM127 (MIM *613403), PHD2 (MIM *606425), SDHAF2 (MIM *613019), SDHC (MIM *602413), HRAS (MIM *190020), KIF1B (MIM *605995), and ATRX (MIM *300032).	('SDHC', 'Gene', (81, 85))	('MIM *190020', 'Var', (107, 118))	('MIM *602413', 'Var', (87, 98))	('MIM *613019', 'Var', (67, 78))	('SDHAF2', 'Gene', '54949', (59, 65))	('TMEM127', 'Gene', (16, 23))	('SDHAF2', 'Gene', (59, 65))	('SDHC', 'Gene', '6391', (81, 85))	('PHD2', 'Gene', (39, 43))	('MIM *605995', 'Var', (128, 139))	('TMEM127', 'Gene', '55654', (16, 23))	('MIM *613403', 'Var', (25, 36))	('MIM *606425', 'Var', (45, 56))	('MIM *300032', 'Var', (152, 163))
39902	29755524	A pediatric PHEO can be included in one of the following five cancer syndromes: VHL, MEN2, NF1, and those associated with PHD1/2 and HIF2A mutations.	('VHL', 'Gene', (80, 83))	('MEN', 'Species', '9606', (85, 88))	('NF1', 'Gene', (91, 94))	('mutations', 'Var', (139, 148))	('cancer syndromes', 'Disease', 'MESH:D009369', (62, 78))	('VHL', 'Gene', '7428', (80, 83))	('PHD1/2', 'Gene', '112398;54583', (122, 128))	('HIF2A', 'Gene', (133, 138))	('NF1', 'Gene', '4763', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer syndromes', 'Disease', (62, 78))	('PHEO', 'Phenotype', 'HP:0002666', (12, 16))	('PHD1/2', 'Gene', (122, 128))	('MEN2', 'Disease', (85, 89))
39906	29755524	Pediatric PHEO tends to present earlier when VHL is mutated, compared with other PHEO-associated germline mutations: The mean age of diagnosis of PHEO is 12 years, and the youngest age reported to date is 4 years.	('VHL', 'Gene', '7428', (45, 48))	('mutated', 'Var', (52, 59))	('PHEO', 'Phenotype', 'HP:0002666', (146, 150))	('VHL', 'Gene', (45, 48))	('PHEO', 'Phenotype', 'HP:0002666', (81, 85))	('PHEO', 'Phenotype', 'HP:0002666', (10, 14))
39907	29755524	Large deletions and truncating mutations of VHL predispose to hemangiomas of central nervous system (including retina) and RCC, but not to PHEO (VHL disease type 1).	('VHL', 'Gene', '7428', (145, 148))	('hemangiomas', 'Phenotype', 'HP:0001028', (62, 73))	('VHL disease', 'Disease', (145, 156))	('VHL', 'Gene', (44, 47))	('truncating mutations', 'Var', (20, 40))	('PHEO', 'Phenotype', 'HP:0002666', (139, 143))	('RCC', 'Disease', (123, 126))	('VHL', 'Gene', '7428', (44, 47))	('hemangiomas of central nervous system', 'Disease', (62, 99))	('RCC', 'Disease', 'MESH:C538614', (123, 126))	('VHL disease', 'Disease', 'MESH:D006623', (145, 156))	('hemangiomas of central nervous system', 'Disease', 'MESH:D020786', (62, 99))	('VHL', 'Gene', (145, 148))	('Large deletions', 'Var', (0, 15))	('predispose', 'Reg', (48, 58))
39908	29755524	Missense mutations predispose to PHEO (VHL disease type 2), which may be associated with hemangioblastomas (VHL disease type 2A), hemangioblastomas and RCC (VHL disease type 2B), or only PHEO (VHL disease type 2C).	('VHL disease type 2', 'Disease', 'MESH:D006623', (157, 175))	('PHEO', 'Phenotype', 'HP:0002666', (187, 191))	('VHL disease type 2', 'Disease', 'MESH:D006623', (108, 126))	('VHL disease type 2B', 'Disease', 'MESH:D006623', (157, 176))	('associated', 'Reg', (73, 83))	('VHL disease type 2', 'Disease', (39, 57))	('hemangioblastomas', 'Disease', 'MESH:D018325', (89, 106))	('predispose', 'Reg', (19, 29))	('VHL disease type 2', 'Disease', 'MESH:D006623', (193, 211))	('hemangioblastomas', 'Disease', (130, 147))	('RCC', 'Disease', (152, 155))	('PHEO', 'Disease', (33, 37))	('VHL disease type 2B', 'Disease', (157, 176))	('VHL disease type 2', 'Disease', (108, 126))	('VHL disease type 2', 'Disease', 'MESH:D006623', (39, 57))	('PHEO', 'Phenotype', 'HP:0002666', (33, 37))	('hemangioblastomas', 'Disease', (89, 106))	('RCC', 'Disease', 'MESH:C538614', (152, 155))	('hemangioblastomas', 'Disease', 'MESH:D018325', (130, 147))	('VHL disease type 2', 'Disease', (193, 211))	('Missense mutations', 'Var', (0, 18))
39909	29755524	VHL mutations are the most prevalent in pediatric patients with PHEO, ranging from 28.0% to 49.0% of cases.	('patients', 'Species', '9606', (50, 58))	('PHEO', 'Disease', (64, 68))	('VHL', 'Gene', (0, 3))	('PHEO', 'Phenotype', 'HP:0002666', (64, 68))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))	('prevalent', 'Reg', (27, 36))
39910	29755524	However, although syndromic features that raise suspicion for VHL disease have a high penetrance across the age spectrum, pediatric patients with PHEO-associated VHL mutations often present without other syndromic features of the disease.	('VHL', 'Gene', (162, 165))	('syndromic', 'Disease', (18, 27))	('syndromic features of the disease', 'Disease', 'MESH:D000013', (204, 237))	('mutations', 'Var', (166, 175))	('VHL', 'Gene', '7428', (162, 165))	('syndromic features of the disease', 'Disease', (204, 237))	('syndromic', 'Disease', 'MESH:D013577', (18, 27))	('PHEO', 'Phenotype', 'HP:0002666', (146, 150))	('syndromic', 'Disease', (204, 213))	('VHL disease', 'Disease', 'MESH:D006623', (62, 73))	('PHEO-associated', 'Disease', (146, 161))	('VHL', 'Gene', (62, 65))	('syndromic', 'Disease', 'MESH:D013577', (204, 213))	('VHL', 'Gene', '7428', (62, 65))	('patients', 'Species', '9606', (132, 140))	('VHL disease', 'Disease', (62, 73))
39912	29755524	Additionally, more than half of patients with VHL disease have de novo mutations; that is, the family history is unremarkable in these cases.	('mutations', 'Var', (71, 80))	('VHL disease', 'Disease', (46, 57))	('patients', 'Species', '9606', (32, 40))	('VHL disease', 'Disease', 'MESH:D006623', (46, 57))
39915	29755524	It may be subdivided into two clinical subtypes: MEN2A (MIM #171400) and MEN2B (MIM #162300).	('MEN2A', 'Gene', (49, 54))	('MEN2A', 'Gene', '5979', (49, 54))	('MEN2B', 'Gene', (73, 78))	('MIM #162300', 'Var', (80, 91))	('MEN2B', 'Gene', '5979', (73, 78))	('MIM #171400', 'Var', (56, 67))
39918	29755524	MEN2A patients with specific mutations in RET codons 631 and 634 have the highest incidence of PHEO.	('RET', 'Gene', '5979', (42, 45))	('MEN2A', 'Gene', '5979', (0, 5))	('MEN2A', 'Gene', (0, 5))	('mutations', 'Var', (29, 38))	('PHEO', 'Disease', (95, 99))	('patients', 'Species', '9606', (6, 14))	('RET', 'Gene', (42, 45))	('PHEO', 'Phenotype', 'HP:0002666', (95, 99))
39929	29755524	The syndrome of PHEO/PGL and somatostatinoma associated with polycythemia, caused by HIF2A mutations, is a new PHEO-associated cancer syndrome described initially in 2012.	('polycythemia', 'Phenotype', 'HP:0001901', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('polycythemia', 'Disease', (61, 73))	('PHEO', 'Phenotype', 'HP:0002666', (111, 115))	('somatostatinoma', 'Disease', 'MESH:D013005', (29, 44))	('associated', 'Reg', (45, 55))	('somatostatinoma', 'Disease', (29, 44))	('HIF2A', 'Gene', (85, 90))	('syndrome of PHEO/PGL', 'Disease', (4, 24))	('mutations', 'Var', (91, 100))	('caused', 'Reg', (75, 81))	('polycythemia', 'Disease', 'MESH:D011086', (61, 73))	('PHEO', 'Phenotype', 'HP:0002666', (16, 20))	('cancer syndrome', 'Disease', 'MESH:D009369', (127, 142))	('cancer syndrome', 'Disease', (127, 142))
39932	29755524	Overall clinical manifestations and their frequency in the 62 published cases with HIF2A mutations are as follows: isolated polycythemia in 29 patients (45.0%); polycythemia and PHEO/PGL in nine patients (14.5%); polycythemia, PHEO/PGL, and somatostatinoma in six patients (9.6%); isolated PHEO/PGL in 14 patients (22.6%); brain hemangiomas in three patients (4.8%, one with a concomitant PGL); and duodenal gangliocytic PGL in two patients (3.2%).	('brain hemangiomas', 'Disease', (323, 340))	('polycythemia', 'Phenotype', 'HP:0001901', (161, 173))	('polycythemia', 'Disease', (213, 225))	('polycythemia', 'Disease', (124, 136))	('mutations', 'Var', (89, 98))	('PHEO', 'Phenotype', 'HP:0002666', (290, 294))	('HIF2A', 'Gene', (83, 88))	('polycythemia', 'Disease', 'MESH:D011086', (213, 225))	('polycythemia', 'Disease', 'MESH:D011086', (124, 136))	('PHEO', 'Phenotype', 'HP:0002666', (227, 231))	('duodenal gangliocytic PGL', 'Disease', (399, 424))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (432, 440))	('somatostatinoma', 'Disease', 'MESH:D013005', (241, 256))	('brain hemangiomas', 'Disease', 'MESH:D006391', (323, 340))	('somatostatinoma', 'Disease', (241, 256))	('PHEO', 'Phenotype', 'HP:0002666', (178, 182))	('polycythemia', 'Disease', (161, 173))	('patients', 'Species', '9606', (305, 313))	('polycythemia', 'Phenotype', 'HP:0001901', (213, 225))	('polycythemia', 'Disease', 'MESH:D011086', (161, 173))	('patients', 'Species', '9606', (264, 272))	('polycythemia', 'Phenotype', 'HP:0001901', (124, 136))	('isolated PHEO/PGL', 'Disease', (281, 298))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (350, 358))	('hemangiomas', 'Phenotype', 'HP:0001028', (329, 340))
39937	29755524	However, some patients have somatic mosaicism, where the mutation is found in tumor cells and in a fraction of normal tissues (e.g., leukocytes and buccal cells).	('mutation', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('patients', 'Species', '9606', (14, 22))
39938	29755524	Thus, there may be a possibility of transmission of a HIF2A mutation to the next generation by an affected member who has mosaicism that includes the gametes; however, such cases have never been described until now.	('HIF2A', 'Gene', (54, 59))	('mutation', 'Var', (60, 68))	('rat', 'Species', '10116', (85, 88))	('transmission', 'Reg', (36, 48))
39939	29755524	Additionally, there are seven familial cases of HIF2A mutations, but the majority had only polycythemia, and two nonrelated cases of germline mutations in adult patients with isolated PHEO.	('polycythemia', 'Phenotype', 'HP:0001901', (91, 103))	('polycythemia', 'Disease', 'MESH:D011086', (91, 103))	('mutations', 'Var', (54, 63))	('PHEO', 'Phenotype', 'HP:0002666', (184, 188))	('patients', 'Species', '9606', (161, 169))	('HIF2A', 'Gene', (48, 53))	('polycythemia', 'Disease', (91, 103))
39940	29755524	This evidence has led experts to develop recommendations regarding the genetic testing and counseling, as well as to the clinical follow-up of patients with HIF2A mutations.	('HIF2A', 'Gene', (157, 162))	('mutations', 'Var', (163, 172))	('patients', 'Species', '9606', (143, 151))
39941	29755524	Germline mutations in PHD1/2 were reported in patients with polycythemia and PHEO/PGL.	('Germline mutations', 'Var', (0, 18))	('patients', 'Species', '9606', (46, 54))	('reported', 'Reg', (34, 42))	('polycythemia', 'Phenotype', 'HP:0001901', (60, 72))	('PHD1/2', 'Gene', '112398;54583', (22, 28))	('polycythemia', 'Disease', 'MESH:D011086', (60, 72))	('PHD1/2', 'Gene', (22, 28))	('PHEO/PGL', 'Disease', (77, 85))	('PHEO', 'Phenotype', 'HP:0002666', (77, 81))	('polycythemia', 'Disease', (60, 72))
39942	29755524	In this syndrome, patients develop polycythemia at a later age relative to HIF2A mutation carriers, but they appear to have a similar high risk of recurrent chromaffin cell tumors, especially PGL.	('chromaffin', 'Chemical', '-', (157, 167))	('develop', 'PosReg', (27, 34))	('mutation', 'Var', (81, 89))	('HIF2A', 'Gene', (75, 80))	('PGL', 'Disease', (192, 195))	('polycythemia', 'Disease', (35, 47))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('polycythemia', 'Phenotype', 'HP:0001901', (35, 47))	('polycythemia', 'Disease', 'MESH:D011086', (35, 47))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (157, 179))
39944	29755524	Pediatric patients with PHEO and PGL usually have germline mutations in the SDHB, SDHD, or VHL.	('SDHB', 'Gene', '6390', (76, 80))	('SDHB', 'Gene', (76, 80))	('germline mutations', 'Var', (50, 68))	('VHL', 'Gene', (91, 94))	('SDHD', 'Gene', (82, 86))	('VHL', 'Gene', '7428', (91, 94))	('SDHD', 'Gene', '6392', (82, 86))	('patients', 'Species', '9606', (10, 18))	('PHEO', 'Phenotype', 'HP:0002666', (24, 28))
39945	29755524	SDHB mutations cause PGL4 (MIM #115310), an autosomal dominant disorder characterized mainly by the development of sympathetic abdominal (67.0%) and thoracic PGL (17.6%), parasympathetic head and neck (HN) PGL (27.5%), and/or PHEO (11.4%).	('cause', 'Reg', (15, 20))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (44, 71))	('mutations', 'Var', (5, 14))	('PHEO', 'Disease', (226, 230))	('PGL4', 'Gene', '6390', (21, 25))	('SDHB', 'Gene', '6390', (0, 4))	('PGL4', 'Gene', (21, 25))	('autosomal dominant disorder', 'Disease', (44, 71))	('PHEO', 'Phenotype', 'HP:0002666', (226, 230))	('SDHB', 'Gene', (0, 4))
39946	29755524	Pediatric patients with PHEO harbor an SDHB mutation in 13.6% of cases, and the majority develop this tumor at >=8 yo.	('mutation', 'Var', (44, 52))	('SDHB', 'Gene', '6390', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('SDHB', 'Gene', (39, 43))	('PHEO', 'Disease', (24, 28))	('patients', 'Species', '9606', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('PHEO', 'Phenotype', 'HP:0002666', (24, 28))
39947	29755524	PGL4 is associated with the highest incidence of PHEO (96.0%) of all the PGL syndromes in this age range; an SDHB mutation is most likely present when a pediatric PHEO occurs concomitantly with an abdominal PGL (68.0%) but is less likely than other SDHx mutations when it occurs in association with thoracic (8.0%) and HN PGL (4.0%).	('SDHx', 'Chemical', '-', (249, 253))	('HN PGL', 'Disease', (319, 325))	('PHEO', 'Phenotype', 'HP:0002666', (49, 53))	('SDHB', 'Gene', '6390', (109, 113))	('mutation', 'Var', (114, 122))	('SDHB', 'Gene', (109, 113))	('PGL syndrome', 'Disease', 'MESH:D010235', (73, 85))	('PHEO', 'Phenotype', 'HP:0002666', (163, 167))	('HN PGL', 'Disease', 'MESH:D010235', (319, 325))	('PGL4', 'Gene', '6390', (0, 4))	('PGL4', 'Gene', (0, 4))	('PGL syndrome', 'Disease', (73, 85))	('abdominal PGL', 'Disease', (197, 210))
39948	29755524	SDHB mutations are also associated with the development of RCC (14%), gastrointestinal stromal tumors [GIST; 2%; isolated or associated with PGL (Carney dyad or Carney-Stratakis syndrome) or PGL and chondroma (Carney triad)] and pituitary adenomas (rare).	('PGL', 'Disease', (191, 194))	('pituitary adenomas', 'Disease', 'MESH:D010911', (229, 247))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PGL', 'Disease', (141, 144))	('SDHB', 'Gene', (0, 4))	('RCC', 'Disease', (59, 62))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (229, 247))	('pituitary adenomas', 'Disease', (229, 247))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (161, 186))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (70, 101))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (70, 101))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('chondroma', 'Disease', (199, 208))	('mutations', 'Var', (5, 14))	('associated with', 'Reg', (24, 39))	('chondroma', 'Disease', 'MESH:D002812', (199, 208))	('gastrointestinal stromal tumors', 'Disease', (70, 101))	('SDHB', 'Gene', '6390', (0, 4))	('Carney-Stratakis syndrome', 'Disease', (161, 186))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
39949	29755524	Germline SDHD mutations predispose carriers to PGL1 (MIM #168000).	('predispose carriers', 'Reg', (24, 43))	('SDHD', 'Gene', '6392', (9, 13))	('SDHD', 'Gene', (9, 13))	('PGL1', 'Gene', (47, 51))	('mutations', 'Var', (14, 23))
39951	29755524	Pediatric PHEO is associated with SDHD mutations in 6.7% of cases.	('Pediatric PHEO', 'Disease', (0, 14))	('mutations', 'Var', (39, 48))	('associated', 'Reg', (18, 28))	('SDHD', 'Gene', '6392', (34, 38))	('SDHD', 'Gene', (34, 38))	('PHEO', 'Phenotype', 'HP:0002666', (10, 14))
39953	29755524	Nonchromaffin cell tumors may also occur in patients with SDHD mutations (RCC, 8%; GIST rare, isolated, or part of Carney dyad/Carney-Stratakis syndrome/or triad; and pituitary adenomas, rare).	('Carney-Stratakis syndrome', 'Disease', (127, 152))	('mutations', 'Var', (63, 72))	('Nonchromaffin cell tumors', 'Disease', (0, 25))	('patients', 'Species', '9606', (44, 52))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (3, 25))	('occur', 'Reg', (35, 40))	('RCC', 'Disease', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (127, 152))	('pituitary adenomas', 'Disease', 'MESH:D010911', (167, 185))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (167, 185))	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('SDHD', 'Gene', '6392', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Nonchromaffin cell tumors', 'Disease', 'MESH:D010236', (0, 25))	('SDHD', 'Gene', (58, 62))	('pituitary adenomas', 'Disease', (167, 185))
39954	29755524	PGL1 almost always manifests when the SDHD mutation is paternally inherited, due to a selective somatic loss of the maternal chromosome 11.	('loss', 'NegReg', (104, 108))	('mutation', 'Var', (43, 51))	('manifests', 'Reg', (19, 28))	('SDHD', 'Gene', (38, 42))	('SDHD', 'Gene', '6392', (38, 42))	('PGL1', 'Gene', (0, 4))
39957	29755524	Very rarely, loss of the paternal 11q (where SDHD allele is located) and a mitotic recombination of the maternal 11q (carrying an SDHD mutation) with the paternal 11p15 imprinted oncosuppressor region may lead to the phenotypic expression of the disease, inherited from the mother.	('lead to', 'Reg', (205, 212))	('SDHD', 'Gene', (130, 134))	('SDHD', 'Gene', '6392', (130, 134))	('loss', 'Var', (13, 17))	('SDHD', 'Gene', '6392', (45, 49))	('mitotic recombination', 'CPA', (75, 96))	('SDHD', 'Gene', (45, 49))	('mutation', 'Var', (135, 143))
39959	29755524	Indeed, recent case series reveal that pediatric PHEO harboring VHL mutations can occur in association with abdominal (20.0%) and/or thoracic (3.0%) PGL, with a small study reporting this phenotype in 38.0% of cases.	('PHEO', 'Phenotype', 'HP:0002666', (49, 53))	('VHL', 'Gene', (64, 67))	('VHL', 'Gene', '7428', (64, 67))	('abdominal', 'Disease', (108, 117))	('mutations', 'Var', (68, 77))
39960	29755524	Additionally, pediatric patients with PHEO-associated VHL mutations have a significantly higher likelihood of new contralateral adrenal and extraadrenal tumors than have mutations in other genes.	('mutations', 'Var', (58, 67))	('PHEO', 'Phenotype', 'HP:0002666', (38, 42))	('adrenal and extraadrenal tumors', 'Phenotype', 'HP:0100631', (128, 159))	('PHEO-associated', 'Disease', (38, 53))	('VHL', 'Gene', (54, 57))	('VHL', 'Gene', '7428', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('extraadrenal tumors', 'Disease', (140, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('patients', 'Species', '9606', (24, 32))	('extraadrenal tumors', 'Disease', 'MESH:C565335', (140, 159))
39961	29755524	The youngest age reported to date is 8 years, and although the age of diagnosis of PGL is younger than that of PHEO, PGL may occur simultaneously (33.3%) or develop after PHEO (33.3%) in patients with HIF2A mutations.	('patients', 'Species', '9606', (187, 195))	('PHEO', 'Phenotype', 'HP:0002666', (111, 115))	('HIF2A', 'Gene', (201, 206))	('mutations', 'Var', (207, 216))	('PHEO', 'Phenotype', 'HP:0002666', (171, 175))
39964	29755524	As previously stated, PHD1 mutations may cause a phenotype (pediatric penetrance, multifocal, and recurrent PGL) similar to that of HIF2A mutations, as proteins coded by both genes are partners in the PHD/HIF-alpha/VHL pathway.	('mutations', 'Var', (27, 36))	('VHL', 'Gene', (215, 218))	('VHL', 'Gene', '7428', (215, 218))	('PHD1', 'Gene', (22, 26))	('cause', 'Reg', (41, 46))
39965	29755524	Patients with PHD1/PHD2/HIF2A mutations should be closely followed up with functional imaging techniques for recurrence, with 18F-fluorodihydroxyphenylalanine (18F-FDOPA) position emission tomography (PET)/computed tomography (CT) being the most accurate among all the available techniques.	('18F-fluorodihydroxyphenylalanine', 'Chemical', 'MESH:C043437', (126, 158))	('rat', 'Species', '10116', (250, 253))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (160, 169))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (30, 39))	('PHD1/PHD2/HIF2A', 'Gene', (14, 29))
39967	29755524	FH mutations are among the rare genetic etiologies of PHEO, with an estimated prevalence of 1.05% in two cohorts of PHEO/PGL patients (totalizing 670 cases).	('PHEO', 'Disease', (54, 58))	('PHEO', 'Phenotype', 'HP:0002666', (54, 58))	('PHEO', 'Phenotype', 'HP:0002666', (116, 120))	('mutations', 'Var', (3, 12))	('patients', 'Species', '9606', (125, 133))
39969	29755524	FH mutations have shown to predispose patients to PHEO and multifocal PGL (mainly abdominal) with a significantly higher rate than mutations in other PHEO susceptibility genes.	('PHEO', 'Disease', (50, 54))	('predispose', 'Reg', (27, 37))	('PHEO', 'Phenotype', 'HP:0002666', (50, 54))	('patients', 'Species', '9606', (38, 46))	('PHEO', 'Phenotype', 'HP:0002666', (150, 154))	('mutations', 'Var', (3, 12))	('multifocal PGL', 'Disease', (59, 73))	('rat', 'Species', '10116', (121, 124))
39970	29755524	The familial PHEO syndrome caused by MAX mutations has a prevalence of <2.0% among the genetic etiologies of PHEO.	('mutations', 'Var', (41, 50))	('caused', 'Reg', (27, 33))	('familial PHEO syndrome', 'Disease', (4, 26))	('PHEO', 'Phenotype', 'HP:0002666', (109, 113))	('familial PHEO syndrome', 'Disease', 'MESH:D009386', (4, 26))	('MAX', 'Gene', (37, 40))	('PHEO', 'Phenotype', 'HP:0002666', (13, 17))
39972	29755524	MAX mutations may predispose patients with PHEO to thoracic and abdominal PGL (18.5%), including at a pediatric age (14.3%).	('patients', 'Species', '9606', (29, 37))	('MAX', 'Gene', (0, 3))	('PHEO', 'Phenotype', 'HP:0002666', (43, 47))	('predispose', 'Reg', (18, 28))	('PHEO', 'Disease', (43, 47))	('mutations', 'Var', (4, 13))
39978	29755524	The high frequency of high risk RET mutations [in particular, the NM_020975.4(RET):c.1900T>C (p.Cys634Arg)] for bPHEO in published cohorts could be an explanation, although sample bias (small sample sizes) should also be considered.	('4(RET):c.1900T>C', 'Var', (76, 92))	('RET', 'Gene', (78, 81))	('RET', 'Gene', '5979', (32, 35))	('bPHEO', 'Disease', (112, 117))	('PHEO', 'Phenotype', 'HP:0002666', (113, 117))	('4(RET):c.1900T>C', 'SUBSTITUTION', 'None', (76, 92))	('p.Cys634Arg', 'Mutation', 'rs75076352', (94, 105))	('RET', 'Gene', '5979', (78, 81))	('RET', 'Gene', (32, 35))
39979	29755524	However, pediatric patients with bPHEO may harbor an SDHD mutation in 6.9-12.5% of cases, and its presence might thus be considered in these cases.	('PHEO', 'Phenotype', 'HP:0002666', (34, 38))	('patients', 'Species', '9606', (19, 27))	('bPHEO', 'Disease', (33, 38))	('SDHD', 'Gene', '6392', (53, 57))	('SDHD', 'Gene', (53, 57))	('mutation', 'Var', (58, 66))
39980	29755524	MAX mutations predispose carriers to a high risk of bPHEO or multifocal synchronous unilateral tumors (68.4%), including at a pediatric age (41.0%).	('bPHEO', 'Disease', (52, 57))	('MAX', 'Gene', (0, 3))	('predispose', 'Reg', (14, 24))	('multifocal synchronous unilateral tumors', 'Disease', 'None', (61, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('PHEO', 'Phenotype', 'HP:0002666', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutations', 'Var', (4, 13))	('multifocal synchronous unilateral tumors', 'Disease', (61, 101))
39986	29755524	At a pediatric age, metastatic PHEO occurs in the context of SDHB mutations in 57.0% of cases.	('mutations', 'Var', (66, 75))	('PHEO', 'Phenotype', 'HP:0002666', (31, 35))	('SDHB', 'Gene', '6390', (61, 65))	('SDHB', 'Gene', (61, 65))	('metastatic PHEO', 'Disease', (20, 35))
39987	29755524	Additionally, considering the largest case series of pediatric PHEO, the metastatic rate of PHEO and/or PGL associated with SDHB mutations (18.2-26.0%) was significantly higher when compared with that of carriers of mutations in other susceptibility genes; a lower lifetime expectancy of carriers of SHDB mutations was also recognized.	('SDHB', 'Gene', (124, 128))	('higher', 'PosReg', (170, 176))	('PHEO', 'Phenotype', 'HP:0002666', (63, 67))	('mutations', 'Var', (129, 138))	('rat', 'Species', '10116', (84, 87))	('metastatic rate', 'CPA', (73, 88))	('PHEO', 'Phenotype', 'HP:0002666', (92, 96))	('SDHB', 'Gene', '6390', (124, 128))
39989	29755524	When comparing all the available functional imaging techniques for this purpose, the most accurate for patients with SDHx mutations is [68Ga]-DOTA(0)-Tyr(3)-octreotate ([68Ga]-DOTATATE) PET/CT, followed by [18F]-fluoro-2-deoxy-d-glucose PET/CT.	(']-DOTATATE', 'Chemical', '-', (174, 184))	('DOTA(0)-Tyr(3)-octreotate', 'Chemical', '-', (142, 167))	('rat', 'Species', '10116', (94, 97))	('mutations', 'Var', (122, 131))	('SDHx', 'Chemical', '-', (117, 121))	('patients', 'Species', '9606', (103, 111))	('SDHx', 'Gene', (117, 121))	('fluoro-2-deoxy-d-glucose', 'Chemical', '-', (212, 236))
39993	29755524	While the metastatic risk does not appear to be high, it may be worth to consider the analysis of VHL in a pediatric patient with a metastatic PHEO, due to the high prevalence of VHL mutations at this age range.	('PHEO', 'Phenotype', 'HP:0002666', (143, 147))	('mutations', 'Var', (183, 192))	('VHL', 'Gene', (98, 101))	('VHL', 'Gene', '7428', (98, 101))	('VHL', 'Gene', (179, 182))	('patient', 'Species', '9606', (117, 124))	('VHL', 'Gene', '7428', (179, 182))
39997	29755524	The familial PHEO syndrome caused by MAX mutations is associated with metastatic PHEO in 10.5% of cases, considering all ages.	('mutations', 'Var', (41, 50))	('metastatic PHEO', 'Disease', (70, 85))	('caused', 'Reg', (27, 33))	('familial PHEO syndrome', 'Disease', (4, 26))	('familial PHEO syndrome', 'Disease', 'MESH:D009386', (4, 26))	('MAX', 'Gene', (37, 40))	('PHEO', 'Phenotype', 'HP:0002666', (13, 17))	('PHEO', 'Phenotype', 'HP:0002666', (81, 85))	('associated', 'Reg', (54, 64))
39999	29755524	However, in a study of patients with PHEO-associated MAX mutations, five patients were <=18 yo, of which one had a metastatic tumor.	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (57, 66))	('MAX', 'Gene', (53, 56))	('PHEO', 'Phenotype', 'HP:0002666', (37, 41))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Disease', (126, 131))
40000	29755524	PGL5 (MIM #614165) is caused by mutations in the subunit A of the SDH complex, which are found in 3.0% of all PHEO/PGL patients.	('SDH', 'Gene', '6390', (66, 69))	('PHEO', 'Phenotype', 'HP:0002666', (110, 114))	('PHEO/PGL', 'Disease', (110, 118))	('patients', 'Species', '9606', (119, 127))	('PGL5', 'Gene', '6389', (0, 4))	('SDH', 'Gene', (66, 69))	('PGL5', 'Gene', (0, 4))	('caused by', 'Reg', (22, 31))	('mutations', 'Var', (32, 41))	('found', 'Reg', (89, 94))
40001	29755524	SDHA mutations predispose patients to HN PGL (38.9%), abdominal PGL (27.8%), and unilateral PHEO (24.0%).	('HN PGL', 'Disease', (38, 44))	('unilateral PHEO', 'Disease', (81, 96))	('SDHA', 'Gene', (0, 4))	('predispose', 'Reg', (15, 25))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (26, 34))	('HN PGL', 'Disease', 'MESH:D010235', (38, 44))	('SDHA', 'Gene', '6389', (0, 4))	('abdominal PGL', 'Disease', (54, 67))	('PHEO', 'Phenotype', 'HP:0002666', (92, 96))
40002	29755524	SDHA mutations also confer susceptibility to GIST (30% of SDHx deficient GIST) and pituitary adenomas (rare).	('GIST', 'Disease', (45, 49))	('SDHA', 'Gene', (0, 4))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (83, 101))	('pituitary adenomas', 'Disease', (83, 101))	('mutations', 'Var', (5, 14))	('susceptibility', 'Reg', (27, 41))	('SDHA', 'Gene', '6389', (0, 4))	('SDHx deficient GIST', 'Disease', 'MESH:D046152', (58, 77))	('SDHx deficient GIST', 'Disease', (58, 77))	('pituitary adenomas', 'Disease', 'MESH:D010911', (83, 101))
40004	29755524	In the largest case series (totalizing 38 patients) of PHEO/PGL-associated SDHA mutations, the reported prevalence of metastatic PHEO/PGL in general was 11%.	('SDHA', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))	('PHEO', 'Phenotype', 'HP:0002666', (55, 59))	('PHEO', 'Phenotype', 'HP:0002666', (129, 133))	('SDHA', 'Gene', '6389', (75, 79))	('patients', 'Species', '9606', (42, 50))
40005	29755524	FH mutations are associated with a high rate of metastatic PHEO.	('metastatic PHEO', 'Disease', (48, 63))	('PHEO', 'Phenotype', 'HP:0002666', (59, 63))	('mutations', 'Var', (3, 12))	('rat', 'Species', '10116', (40, 43))
40006	29755524	In the largest collaborative cohort study of PHEO/PGL where the main susceptibility genes were analyzed, PHEO/PGL caused by FH mutations had a significantly higher rate of malignancy than had tumors associated with other gene mutations.	('malignancy', 'Disease', 'MESH:D009369', (172, 182))	('malignancy', 'Disease', (172, 182))	('tumors', 'Disease', (192, 198))	('rat', 'Species', '10116', (22, 25))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('caused', 'Reg', (114, 120))	('PHEO/PGL', 'Disease', (105, 113))	('higher', 'PosReg', (157, 163))	('PHEO', 'Phenotype', 'HP:0002666', (105, 109))	('rat', 'Species', '10116', (164, 167))	('mutations', 'Var', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PHEO', 'Phenotype', 'HP:0002666', (45, 49))
40007	29755524	Thus, similar to NF1 and MAX mutations, where small samples have been shown a propensity for malignant PHEO, it may be important to maintain a higher index of suspicion for the presence of malignancy when following up pediatric patients with PHEO-associated SDHA and FH mutations.	('malignancy', 'Disease', 'MESH:D009369', (189, 199))	('PHEO', 'Phenotype', 'HP:0002666', (103, 107))	('SDHA', 'Gene', (258, 262))	('patients', 'Species', '9606', (228, 236))	('mutations', 'Var', (270, 279))	('malignancy', 'Disease', (189, 199))	('NF1', 'Gene', (17, 20))	('PHEO', 'Phenotype', 'HP:0002666', (242, 246))	('NF1', 'Gene', '4763', (17, 20))	('PHEO-associated', 'Disease', (242, 257))	('SDHA', 'Gene', '6389', (258, 262))
40010	29755524	Considering 84 patients with a solitary and apparently nonsyndromic PHEO (the largest case series at a pediatric age), mutations in VHL, SDHB, and SDHD were found in 62, 8, and 3 cases, respectively.	('VHL', 'Gene', (132, 135))	('patients', 'Species', '9606', (15, 23))	('syndromic', 'Disease', (58, 67))	('VHL', 'Gene', '7428', (132, 135))	('PHEO', 'Phenotype', 'HP:0002666', (68, 72))	('syndromic', 'Disease', 'MESH:D013577', (58, 67))	('SDHB', 'Gene', '6390', (137, 141))	('SDHB', 'Gene', (137, 141))	('found', 'Reg', (157, 162))	('SDHD', 'Gene', '6392', (147, 151))	('SDHD', 'Gene', (147, 151))	('mutations', 'Var', (119, 128))
40014	29755524	Similar to VHL disease, tumors associated with SDHx, HIF2A, and FH mutations produce and/or secrete noradrenaline/normetanephrine but rarely adrenaline/metanephrine.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('VHL disease', 'Disease', (11, 22))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('adrenaline', 'Chemical', 'MESH:D004837', (103, 113))	('metanephrine', 'Chemical', 'MESH:D008676', (117, 129))	('SDHx', 'Chemical', '-', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (67, 76))	('VHL disease', 'Disease', 'MESH:D006623', (11, 22))	('metanephrine', 'Chemical', 'MESH:D008676', (152, 164))	('secrete noradrenaline/normetanephrine', 'MPA', (92, 129))	('adrenaline', 'Chemical', 'MESH:D004837', (141, 151))
40015	29755524	However, PHEO associated with SDHx mutations also produce and/or secrete dopamine/methoxytyramine, which is rarely detected in VHL disease.	('PHEO', 'Disease', (9, 13))	('secrete dopamine/methoxytyramine', 'MPA', (65, 97))	('methoxytyramine', 'Chemical', 'MESH:C001746', (82, 97))	('VHL disease', 'Disease', 'MESH:D006623', (127, 138))	('dopamine', 'Chemical', 'MESH:D004298', (73, 81))	('SDHx', 'Gene', (30, 34))	('SDHx', 'Chemical', '-', (30, 34))	('PHEO', 'Phenotype', 'HP:0002666', (9, 13))	('VHL disease', 'Disease', (127, 138))	('mutations', 'Var', (35, 44))
40020	29755524	Lack of staining for SDHB in PHEO is highly suggestive of germline mutations in SDHx genes (90.0%), whereas immunonegative staining for SDHA (75.0%) is indicative of SDHA mutations.	('SDHA', 'Gene', '6389', (166, 170))	('SDHA', 'Gene', (136, 140))	('mutations', 'Var', (67, 76))	('SDHB', 'Gene', '6390', (21, 25))	('SDHA', 'Gene', (166, 170))	('PHEO', 'Phenotype', 'HP:0002666', (29, 33))	('SDHA', 'Gene', '6389', (136, 140))	('SDHB', 'Gene', (21, 25))	('SDHx', 'Chemical', '-', (80, 84))	('SDHx', 'Gene', (80, 84))
40021	29755524	False negatives (positive or weakly positive staining) may occur in SDHD-related lesions for SDHB staining, and SDHD immunohistochemistry may aid in these cases (positive staining predicts SDHx mutations).	('SDHB', 'Gene', (93, 97))	('SDHD', 'Gene', '6392', (68, 72))	('mutations', 'Var', (194, 203))	('SDHD', 'Gene', (112, 116))	('SDHD', 'Gene', (68, 72))	('SDHD', 'Gene', '6392', (112, 116))	('SDHx', 'Gene', (189, 193))	('SDHx', 'Chemical', '-', (189, 193))	('SDHB', 'Gene', '6390', (93, 97))
40025	29755524	These missed lesions on 18F-FDOPA PET/CT are often associated with SDHB and SDHD mutations, and it is worth to consider focused genetic screening for SDHx mutations in 18F-FDOPA PET/CT-negative PHEO/PGL.	('18F-FDOPA', 'Chemical', 'MESH:C043437', (168, 177))	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (76, 80))	('18F-FDOPA', 'Chemical', 'MESH:C043437', (24, 33))	('SDHB', 'Gene', '6390', (67, 71))	('SDHx', 'Gene', (150, 154))	('associated', 'Reg', (51, 61))	('SDHB', 'Gene', (67, 71))	('SDHx', 'Chemical', '-', (150, 154))	('PHEO', 'Phenotype', 'HP:0002666', (194, 198))	('mutations', 'Var', (81, 90))
40029	29755524	Genetic testing is of paramount importance in pediatric patients with an apparently sporadic PHEO, because (1) the rate of mutations found in this clinical setting is close to 80.0%; (2) 10 PHEO-associated genes have been reported in pediatric patients, each gene conferring distinct profiles of propensity for the development of chromaffin and nonchromaffin cell tumors and for biological behaviors; and (3) it allows for tailoring specific diagnostic, treatment, and surveillance programs to these patients, taking into account the germline mutation founded and its genotype-phenotype correlation.	('patients', 'Species', '9606', (56, 64))	('rat', 'Species', '10116', (115, 118))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumors', 'Disease', (364, 370))	('chromaffin', 'Chemical', '-', (330, 340))	('patients', 'Species', '9606', (500, 508))	('PHEO', 'Phenotype', 'HP:0002666', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('PHEO', 'Phenotype', 'HP:0002666', (190, 194))	('chromaffin', 'Chemical', '-', (348, 358))	('chromaffin and nonchromaffin cell tumors', 'Phenotype', 'HP:0002666', (330, 370))	('patients', 'Species', '9606', (244, 252))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (348, 370))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('mutations', 'Var', (123, 132))
40031	29755524	VHL, SDHB, and SDHD are the most frequently mutated, whereas other genes are rarely found in pediatric patients.	('SDHB', 'Gene', '6390', (5, 9))	('SDHD', 'Gene', (15, 19))	('SDHD', 'Gene', '6392', (15, 19))	('SDHB', 'Gene', (5, 9))	('mutated', 'Var', (44, 51))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('patients', 'Species', '9606', (103, 111))
40032	29755524	The high rate of malignancy with SDHB mutations demands extensive initial diagnostic surveys and a close surveillance program.	('rat', 'Species', '10116', (9, 12))	('SDHB', 'Gene', '6390', (33, 37))	('malignancy', 'Disease', (17, 27))	('SDHB', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('malignancy', 'Disease', 'MESH:D009369', (17, 27))
40033	29755524	Similarly, the greater likelihood of recurrent tumors in pediatric patients with VHL and SDHD mutations needs a proactive long-term follow-up.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('patients', 'Species', '9606', (67, 75))	('VHL', 'Gene', (81, 84))	('mutations', 'Var', (94, 103))	('VHL', 'Gene', '7428', (81, 84))	('SDHD', 'Gene', '6392', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SDHD', 'Gene', (89, 93))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
40034	29755524	Also, pediatric carriers of PHEO-associated mutations may differ in the clinical phenotype when compared to adult carriers (e.g., the higher rate of bPHEO and PGL in pediatric VHL disease), findings that may change the clinical attitude regarding the extent of diagnostic and follow-up strategies.	('differ', 'Reg', (58, 64))	('PHEO', 'Phenotype', 'HP:0002666', (28, 32))	('bPHEO', 'Disease', (149, 154))	('rat', 'Species', '10116', (288, 291))	('mutations', 'Var', (44, 53))	('pediatric VHL disease', 'Disease', 'MESH:D006623', (166, 187))	('PHEO', 'Phenotype', 'HP:0002666', (150, 154))	('change', 'Reg', (208, 214))	('rat', 'Species', '10116', (141, 144))	('PGL', 'Disease', (159, 162))	('pediatric VHL disease', 'Disease', (166, 187))
40035	29755524	Due to the rarity of PHEO-associated mutations in other susceptibility genes, data retrieved from the published literature may hinder the establishment of genotype-phenotype correlations for some of these genes.	('hinder', 'NegReg', (127, 133))	('PHEO-associated', 'Disease', (21, 36))	('mutations', 'Var', (37, 46))	('rat', 'Species', '10116', (116, 119))	('PHEO', 'Phenotype', 'HP:0002666', (21, 25))
40036	29755524	Nevertheless, new mutations have been described at a pediatric age that correlate with specific phenotypes (e.g., HIF2A mutations and "Pacak-Zhuang" syndrome), opening new options for sequential genetic testing approach and for individualized strategies regarding diagnosis, treatment, long-term follow-up, and genetic counseling.	('HIF2A', 'Gene', (114, 119))	('rat', 'Species', '10116', (245, 248))	('mutations', 'Var', (120, 129))
40066	26559265	Routine noncontrast CT can be used as a screening tool for pheochromocytoma by combining 3 imaging phenotypes: size <=3 cm, unenhanced attenuation values <=10 HU, and absence of suspicious morphology, and may substitute for biochemical testing in the preoperative setting.	('unenhanced attenuation values', 'MPA', (124, 153))	('<=3', 'Var', (116, 119))	('pheochromocytoma', 'Disease', (59, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('pheochromocytoma', 'Disease', 'MESH:D010673', (59, 75))
40072	26559265	Delaying operation causes many troubles and burdens to patients and hospital, and is a dilemma because most AIs are nonfunctioning adenomas.	('patients', 'Species', '9606', (55, 63))	('adenomas', 'Disease', 'MESH:D000236', (131, 139))	('Delaying', 'Var', (0, 8))	('adenomas', 'Disease', (131, 139))
40121	26559265	A combination of tumor size <=3 cm, UA <=10 HU, and absence of suspicious morphology had 100% specificity for the exclusion of pheochromocytomas and malignancies (Table 3).	('tumor', 'Disease', (17, 22))	('pheochromocytomas and malignancies', 'Disease', 'MESH:D010673', (127, 161))	('<=3', 'Var', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (127, 143))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
40175	25563310	Clinical and Genetic Investigation of a Multi-generational Chinese Family Afflicted with Von Hippel-Lindau Disease Von Hippel-Lindau (VHL) disease is a hereditary tumor disorder caused by mutations or deletions of the VHL gene.	('Von Hippel-Lindau Disease', 'Disease', 'MESH:D006623', (89, 114))	('VHL', 'Gene', '7428', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('hereditary tumor disorder', 'Disease', (152, 177))	('VHL', 'Gene', (218, 221))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (115, 146))	('VHL', 'Gene', (134, 137))	('Von Hippel-Lindau Disease', 'Disease', (89, 114))	('VHL', 'Gene', '7428', (218, 221))	('caused by', 'Reg', (178, 187))	('hereditary tumor disorder', 'Disease', 'MESH:D030342', (152, 177))	('mutations', 'Var', (188, 197))	('deletions', 'Var', (201, 210))
40181	25563310	At last, we summarized the VHL gene mutation in China by the literature review.	('VHL', 'Gene', '7428', (27, 30))	('mutation', 'Var', (36, 44))	('VHL', 'Gene', (27, 30))
40184	25563310	A linkage analysis resulted in a high maximal LOD score of 8.26 (theta = 0.0) for the marker D3S1263, which is in the same chromosome region as VHL.	('D3S1263', 'Var', (93, 100))	('VHL', 'Gene', '7428', (144, 147))	('VHL', 'Gene', (144, 147))
40185	25563310	Sequence analysis resulted in the identification of a functional C>T transition mutation (c. 499 C>T, p.R167W) located in exon 3 of the 167th codon of VHL.	('p.R167W', 'Mutation', 'rs5030820', (102, 109))	('499 C>T', 'Var', (93, 100))	('VHL', 'Gene', (151, 154))	('VHL', 'Gene', '7428', (151, 154))	('499 C>T', 'SUBSTITUTION', 'None', (93, 100))
40186	25563310	The most frequent VHL mutations in China are p.S65 W, p.N78 S, p.R161Q and p.R167 W. The results supported the notion that the genomic sequence that corresponds to the 167th residue of VHL is a mutational hotspot.	('VHL', 'Gene', '7428', (18, 21))	('p.R167 W', 'Mutation', 'rs5030820', (75, 83))	('p.N78 S', 'Mutation', 'rs5030804', (54, 61))	('p.R161Q', 'Var', (63, 70))	('p.S65 W', 'Mutation', 'rs5030826', (45, 52))	('p.R161Q', 'Mutation', 'rs730882035', (63, 70))	('mutations', 'Var', (22, 31))	('VHL', 'Gene', (185, 188))	('p.N78 S', 'Var', (54, 61))	('VHL', 'Gene', '7428', (185, 188))	('VHL', 'Gene', (18, 21))	('p.S65 W', 'Var', (45, 52))	('p.R167 W.', 'Var', (75, 84))
40189	25563310	The syndrome is caused by mutations or deletions of the VHL gene located on human chromosome 3p25, and is characterized by multi-organ tumors involvement, which include hemangioblastomas (HBs) in the central nervous system, retinal angiomas, renal clear cell carcinomas (RCCs) and cysts, pheochromocytomas, pancreatic cysts, and pancreatic endocrine tumors (PETs).	('VHL', 'Gene', (56, 59))	('PETs', 'Phenotype', 'HP:0030405', (358, 362))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (169, 185))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('renal clear cell carcinomas', 'Disease', (242, 269))	('hemangioblastomas', 'Disease', 'MESH:D018325', (169, 186))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (288, 305))	('mutations', 'Var', (26, 35))	('pancreatic endocrine tumors', 'Disease', (329, 356))	('retinal angiomas', 'Disease', (224, 240))	('pancreatic cysts', 'Disease', 'MESH:D010181', (307, 323))	('VHL', 'Gene', '7428', (56, 59))	('retinal angiomas', 'Disease', 'MESH:D012173', (224, 240))	('pancreatic endocrine tumors', 'Disease', 'MESH:D010190', (329, 356))	('pancreatic endocrine tumors', 'Phenotype', 'HP:0030405', (329, 356))	('renal clear cell carcinomas', 'Disease', 'MESH:C538614', (242, 269))	('RCC', 'Disease', (271, 274))	('multi-organ tumors involvement', 'Disease', 'MESH:C564969', (123, 153))	('multi-organ tumors involvement', 'Disease', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('hemangioblastomas', 'Disease', (169, 186))	('caused by', 'Reg', (16, 25))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (288, 304))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('pancreatic cysts', 'Disease', (307, 323))	('pheochromocytomas', 'Disease', 'MESH:D010673', (288, 305))	('cysts', 'Disease', (281, 286))	('pheochromocytomas', 'Disease', (288, 305))	('tumors', 'Phenotype', 'HP:0002664', (350, 356))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (307, 323))	('deletions', 'Var', (39, 48))	('human', 'Species', '9606', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (350, 355))
40191	25563310	The mutated p.VHL is thought to disrupt tumor-suppression through hypoxia-inducible factor (HIF)-1alpha-mediated effects that result in the degradation of HIF.	('mutated', 'Var', (4, 11))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (66, 103))	('HIF', 'MPA', (155, 158))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('disrupt', 'NegReg', (32, 39))	('tumor', 'Disease', (40, 45))	('degradation', 'MPA', (140, 151))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('VHL', 'Gene', (14, 17))	('VHL', 'Gene', '7428', (14, 17))
40196	25563310	Faulty genes within the network can act synergistically to induce tumors and the network can result in a cascade effect that affects tumor suppression by activating and inhibiting downstream genes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('induce', 'PosReg', (59, 65))	('tumor', 'Disease', (133, 138))	('inhibiting', 'NegReg', (169, 179))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Faulty genes', 'Var', (0, 12))	('activating', 'PosReg', (154, 164))	('result in', 'Reg', (93, 102))
40202	25563310	Currently, based on the analysis of more than 300 families afflicted with VHL disease, more than 823 distinct mutations have been detected and registered in the Universal VHL-Mutation Database.	('mutations', 'Var', (110, 119))	('VHL disease', 'Disease', 'MESH:D006623', (74, 85))	('VHL', 'Gene', (74, 77))	('VHL', 'Gene', (171, 174))	('VHL', 'Gene', '7428', (74, 77))	('VHL', 'Gene', '7428', (171, 174))	('VHL disease', 'Disease', (74, 85))
40210	25563310	We genotyped three polymorphic microsatellite markers that flanked VHL on chromosome 3p25 (D3S3691, D3S1597 and D3S1263).	('VHL', 'Gene', '7428', (67, 70))	('D3S3691', 'Var', (91, 98))	('D3S1597', 'Var', (100, 107))	('D3S1263', 'Var', (112, 119))	('VHL', 'Gene', (67, 70))
40222	25563310	A functional C>T transition mutation located within exon 3 of VHL (c. 499 C>T, p.R167W) was identified by mutation screening.	('499 C>T', 'Var', (70, 77))	('p.R167W', 'Mutation', 'rs5030820', (79, 86))	('VHL', 'Gene', (62, 65))	('499 C>T', 'SUBSTITUTION', 'None', (70, 77))	('VHL', 'Gene', '7428', (62, 65))
40224	25563310	Currently, nine studies including the present study have been conducted on 77 Chinese families and have described 49 mutations of VHL.	('VHL', 'Gene', (130, 133))	('mutations', 'Var', (117, 126))	('VHL', 'Gene', '7428', (130, 133))
40226	25563310	Independent of phenotype, the most frequent mutations were p.S65W, p.N78S, p.R161Q and p.R167W.	('p.N78S', 'Mutation', 'rs5030804', (67, 73))	('p.S65W', 'Var', (59, 65))	('p.R161Q', 'Mutation', 'rs730882035', (75, 82))	('p.S65W', 'Mutation', 'rs5030826', (59, 65))	('p.N78S', 'Var', (67, 73))	('p.R167W', 'Mutation', 'rs5030820', (87, 94))	('p.R167W', 'Var', (87, 94))	('frequent', 'Reg', (35, 43))	('p.R161Q', 'Var', (75, 82))
40227	25563310	The majority of the mutations (40) were associated with phenotype I. Mutation p.R167W was associated with phenotypes IIA, IIB, and IIC.	('p.R167W', 'Var', (78, 85))	('IIB', 'Disease', (122, 125))	('p.R167W', 'Mutation', 'rs5030820', (78, 85))
40228	25563310	Mutation p.Y98C was associated with phenotype IIA.	('p.Y98C', 'Var', (9, 15))	('p.Y98C', 'Mutation', 'rs864321643', (9, 15))	('associated', 'Reg', (20, 30))
40229	25563310	p.N78S, p.S80I, p.P86S, p.V130F, and intron 1 splice mutation c. 340 + 5G>C were associated with phenotype IIB, and p.H125P and p.R161Q were associated with phenotype IIC.	('p.P86S', 'Var', (16, 22))	('p.N78S', 'Var', (0, 6))	('p.R161Q', 'Mutation', 'rs730882035', (128, 135))	('340 + 5G>C', 'Var', (65, 75))	('340 + 5G>C', 'SUBSTITUTION', 'None', (65, 75))	('p.P86S', 'Mutation', 'rs398123481', (16, 22))	('p.V130F', 'Var', (24, 31))	('p.H125P', 'Mutation', 'rs869025643', (116, 123))	('p.H125P', 'Var', (116, 123))	('associated', 'Reg', (141, 151))	('p.S80I', 'Mutation', 'rs5030805', (8, 14))	('p.N78S', 'Mutation', 'rs5030804', (0, 6))	('p.S80I', 'Var', (8, 14))	('p.R161Q', 'Var', (128, 135))	('p.V130F', 'Mutation', 'rs104893830', (24, 31))	('associated', 'Reg', (81, 91))
40230	25563310	VHL disease is an autosomal dominant familial neoplasm syndrome caused by mutations in VHL that can lead to the development of tumors and cysts in multiple organs.	('autosomal dominant familial neoplasm syndrome', 'Disease', (18, 63))	('VHL', 'Gene', '7428', (87, 90))	('VHL disease', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('autosomal dominant familial neoplasm syndrome', 'Disease', 'MESH:D030342', (18, 63))	('mutations', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('caused by', 'Reg', (64, 73))	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('VHL', 'Gene', (0, 3))	('neoplasm', 'Phenotype', 'HP:0002664', (46, 54))	('lead to', 'Reg', (100, 107))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (87, 90))
40231	25563310	In our study, we identified a functional C>T transition mutation (c. 499 C>T, p.R167 W) in the VHL gene in a North-western Chinese family suffering from VHL disease by linkage and sequencing analyses.	('499 C>T', 'SUBSTITUTION', 'None', (69, 76))	('VHL', 'Gene', (153, 156))	('VHL', 'Gene', (95, 98))	('p.R167 W', 'Mutation', 'rs5030820', (78, 86))	('VHL disease', 'Disease', (153, 164))	('VHL', 'Gene', '7428', (153, 156))	('VHL', 'Gene', '7428', (95, 98))	('499 C>T', 'Var', (69, 76))	('VHL disease', 'Disease', 'MESH:D006623', (153, 164))
40232	25563310	The p.R167W mutation resulted in the substitution of arginine at position 167 with a tryptophan residue that co-segregated only in affected individuals.	('arginine at position 167 with a tryptophan', 'Mutation', 'rs5030820', (53, 95))	('substitution', 'Reg', (37, 49))	('arginine', 'MPA', (53, 61))	('p.R167W', 'Mutation', 'rs5030820', (4, 11))	('resulted in', 'Reg', (21, 32))	('p.R167W', 'Var', (4, 11))
40234	25563310	The results of this research firmly indicated that the p.R167W mutation of VHL caused the disease in this family.	('disease', 'Disease', (90, 97))	('VHL', 'Gene', (75, 78))	('caused', 'Reg', (79, 85))	('VHL', 'Gene', '7428', (75, 78))	('p.R167W', 'Mutation', 'rs5030820', (55, 62))	('p.R167W', 'Var', (55, 62))
40236	25563310	Mutations in VHL that result in amino acid changes between codons 157-189 tend to be associated with increases in the severity of tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('amino acid changes', 'Var', (32, 50))	('severity', 'MPA', (118, 126))	('increases', 'PosReg', (101, 110))	('VHL', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('VHL', 'Gene', '7428', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
40238	25563310	Notably, the p.R167W mutation was found in four VHL phenotypes.	('VHL', 'Gene', '7428', (48, 51))	('p.R167W', 'Mutation', 'rs5030820', (13, 20))	('p.R167W', 'Var', (13, 20))	('found', 'Reg', (34, 39))	('VHL', 'Gene', (48, 51))
40240	25563310	reported that germline mutations of codon 167 convey a high risk for the development of pheochromocytoma.	('codon 167', 'Gene', (36, 45))	('pheochromocytoma', 'Disease', (88, 104))	('pheochromocytoma', 'Disease', 'MESH:D010673', (88, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (88, 104))	('germline mutations', 'Var', (14, 32))
40241	25563310	Moreover, the codon 167 mutation is correlated with the pheochromocytoma coalition with PETs.	('pheochromocytoma coalition', 'Disease', 'MESH:D010673', (56, 82))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('codon 167 mutation', 'Var', (14, 32))	('PETs', 'Phenotype', 'HP:0030405', (88, 92))	('pheochromocytoma coalition', 'Disease', (56, 82))	('correlated with', 'Reg', (36, 51))
40242	25563310	found the mutant VHL alleles that are associated with the subtypes that are characterized by pheochromocytoma with (p.R167Q and p.Rl67W) or without renal carcinoma (p.Y98H and p.Y112H).	('p.R167Q', 'Var', (116, 123))	('p.Y112H', 'Var', (176, 183))	('p.Y112H', 'Mutation', 'rs104893824', (176, 183))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('associated', 'Reg', (38, 48))	('renal carcinoma', 'Phenotype', 'HP:0005584', (148, 163))	('p.Y98H', 'Var', (165, 171))	('pheochromocytoma', 'Disease', 'MESH:D010673', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('p.Rl67W', 'Var', (128, 135))	('VHL', 'Gene', (17, 20))	('p.Y98H', 'Mutation', 'rs5030809', (165, 171))	('renal carcinoma', 'Disease', 'MESH:C538614', (148, 163))	('p.R167Q', 'Mutation', 'rs5030821', (116, 123))	('VHL', 'Gene', '7428', (17, 20))	('renal carcinoma', 'Disease', (148, 163))	('pheochromocytoma', 'Disease', (93, 109))
40243	25563310	However, in the family we studied, the p.Rl67W mutation was connected to the pheochromocytoma without renal carcinoma phenotype.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal carcinoma', 'Disease', 'MESH:C538614', (102, 117))	('connected', 'Reg', (60, 69))	('pheochromocytoma', 'Disease', (77, 93))	('renal carcinoma', 'Disease', (102, 117))	('pheochromocytoma', 'Disease', 'MESH:D010673', (77, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (102, 117))	('p.Rl67W', 'Var', (39, 46))
40244	25563310	In China, there were reports of associations of p.Rl67W with each subtype of VHL.	('VHL', 'Gene', '7428', (77, 80))	('VHL', 'Gene', (77, 80))	('associations', 'Interaction', (32, 44))	('p.Rl67W', 'Var', (48, 55))
40245	25563310	To the best of our knowledge, the first reported the association of p.R167W with Type II VHL in a family of Chinese origin.	('p.R167W', 'Mutation', 'rs5030820', (68, 75))	('Type II VHL', 'Disease', 'MESH:D006623', (81, 92))	('Type II VHL', 'Disease', (81, 92))	('p.R167W', 'Var', (68, 75))	('association', 'Interaction', (53, 64))
40246	25563310	The p.Rl67W mutation resulted in a change from arginine to tryptophan at position 167.	('arginine to tryptophan at position 167', 'Mutation', 'rs5030820', (47, 85))	('change', 'Reg', (35, 41))	('arginine to tryptophan at position 167', 'MPA', (47, 85))	('p.Rl67W', 'Var', (4, 11))
40248	25563310	Moreover, the benzene ring structure of tryptophan can affect the secondary and three-dimensional structure of proteins, and indeed, replacement of residues by tryptophan in other polypeptides has been associated with various diseases.	('replacement', 'Var', (133, 144))	('affect', 'Reg', (55, 61))	('associated', 'Reg', (202, 212))	('residues', 'Var', (148, 156))	('benzene', 'Chemical', 'MESH:D001554', (14, 21))	('tryptophan', 'Chemical', 'MESH:D014364', (160, 170))	('tryptophan', 'Chemical', 'MESH:D014364', (40, 50))	('benzene ring structure', 'MPA', (14, 36))
40250	25563310	Our summary of the numbers of VHL mutations that have been reported in various Chinese families revealed that these numbers are substantially lower than the numbers of mutations that have been reported in populations of European origin.	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (30, 33))	('mutations', 'Var', (34, 43))
40251	25563310	The most frequent mutations in China are p.S65W, p.N78S, p.R161Q and p.R167W, and the most frequent mutations in Western countries are p.F76del, p.N78S, p.Rl61Stop, p.R167Q, p.R167W and p.L178P.	('p.R167W', 'Mutation', 'rs5030820', (174, 181))	('p.S65W', 'Var', (41, 47))	('p.N78S', 'Var', (49, 55))	('p.R167W', 'Var', (174, 181))	('p.S65W', 'Mutation', 'rs5030826', (41, 47))	('p.R161Q', 'Mutation', 'rs730882035', (57, 64))	('p.N78S', 'Mutation', 'rs5030804', (145, 151))	('p.L178P', 'Mutation', 'rs5030822', (186, 193))	('p.R161Q', 'Var', (57, 64))	('p.F76del', 'Mutation', 'p.76delF', (135, 143))	('p.N78S', 'Mutation', 'rs5030804', (49, 55))	('p.R167W', 'Mutation', 'rs5030820', (69, 76))	('p.L178P', 'Var', (186, 193))	('p.R167W', 'Var', (69, 76))	('p.R167Q', 'Mutation', 'rs5030821', (165, 172))	('p.R167Q', 'Var', (165, 172))	('p.Rl61Stop', 'Var', (153, 163))	('p.N78S', 'Var', (145, 151))	('p.F76del', 'Var', (135, 143))
40255	25563310	In summary, the present study identified a functional C>T transition mutation (c. 499 C>T, p.R167W) located within exon 3 of VHL that is likely the cause of VHL disease in this family.	('VHL', 'Gene', (125, 128))	('VHL', 'Gene', '7428', (125, 128))	('VHL disease', 'Disease', 'MESH:D006623', (157, 168))	('VHL', 'Gene', (157, 160))	('499 C>T', 'SUBSTITUTION', 'None', (82, 89))	('VHL', 'Gene', '7428', (157, 160))	('cause', 'Reg', (148, 153))	('p.R167W', 'Mutation', 'rs5030820', (91, 98))	('VHL disease', 'Disease', (157, 168))	('499 C>T', 'Var', (82, 89))
40256	25563310	VHL mutations suggest that the function of VHL might be similar to other check-point proteins in that when mutations are present, uncontrolled cell proliferation (or more precisely, neoplasias) arise in various tissues.	('neoplasias', 'Phenotype', 'HP:0002664', (182, 192))	('mutations', 'Var', (107, 116))	('VHL', 'Gene', (43, 46))	('neoplasias', 'Disease', 'MESH:D009369', (182, 192))	('neoplasias', 'Disease', (182, 192))	('VHL', 'Gene', '7428', (43, 46))	('VHL', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('VHL', 'Gene', '7428', (0, 3))
40319	24675699	The hereditary PHEO appears as a component of multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF1) or familial paraganglioma syndromes (caused by mutations of SDHD and SDHB genes).	('SDHD', 'Gene', '6392', (215, 219))	('multiple endocrine neoplasia type 2', 'Disease', (46, 81))	('NF1', 'Gene', (150, 153))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (158, 190))	('neurofibromatosis type 1', 'Gene', (124, 148))	('VHL', 'Disease', 'MESH:D006623', (118, 121))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (91, 116))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (124, 141))	('SDHD', 'Gene', (215, 219))	('neoplasia', 'Phenotype', 'HP:0002664', (65, 74))	('caused by', 'Reg', (192, 201))	('von Hippel-Lindau disease', 'Disease', (91, 116))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (46, 81))	('neurofibromatosis type 1', 'Gene', '4763', (124, 148))	('VHL', 'Disease', (118, 121))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (55, 74))	('NF1', 'Gene', '4763', (150, 153))	('PHEO', 'Phenotype', 'HP:0002666', (15, 19))	('MEN', 'Species', '9606', (83, 86))	('familial paraganglioma syndromes', 'Disease', (158, 190))	('SDHB', 'Gene', (224, 228))	('paraganglioma', 'Phenotype', 'HP:0002668', (167, 180))	('mutations', 'Var', (202, 211))
40346	24675699	The identified RET germline mutations in MEN2-associated PHEO patients were as follows: 7 (50%) C634Y, 1 (7.1%) C634R, 3 (21.4%) C634W, 1 (7.1%) C618R and 2 (14.3%) M918T.	('C634Y', 'Var', (96, 101))	('PHEO', 'Phenotype', 'HP:0002666', (57, 61))	('MEN2-associated', 'Disease', (41, 56))	('C634W', 'Var', (129, 134))	('C634R', 'Var', (112, 117))	('C618R', 'Mutation', 'rs76262710', (145, 150))	('C634Y', 'Mutation', 'rs75996173', (96, 101))	('C634W', 'SUBSTITUTION', 'None', (129, 134))	('RET', 'Gene', '5979', (15, 18))	('MEN', 'Species', '9606', (41, 44))	('M918T', 'Mutation', 'rs74799832', (165, 170))	('C634R', 'Mutation', 'rs75076352', (112, 117))	('C618R', 'Var', (145, 150))	('patients', 'Species', '9606', (62, 70))	('RET', 'Gene', (15, 18))	('M918T', 'Var', (165, 170))
40379	24675699	It was observed that PHEOs associated with SDHx mutations and VHL disease had a markedly increase in the expression of major angiogenic molecules than those associated with NF1 disease, MEN2 syndrome or sporadic tumors.	('SDHx', 'Chemical', '-', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('SDHx', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('NF1 disease', 'Disease', 'MESH:C537392', (173, 184))	('PHEOs', 'Chemical', '-', (21, 26))	('MEN2 syndrome', 'Disease', 'MESH:D013577', (186, 199))	('sporadic tumors', 'Disease', 'MESH:D009369', (203, 218))	('VHL disease', 'Disease', 'MESH:D006623', (62, 73))	('MEN2 syndrome', 'Disease', (186, 199))	('expression of major angiogenic molecules', 'MPA', (105, 145))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('sporadic tumors', 'Disease', (203, 218))	('NF1 disease', 'Disease', (173, 184))	('VHL disease', 'Disease', (62, 73))	('increase', 'PosReg', (89, 97))	('PHEO', 'Phenotype', 'HP:0002666', (21, 25))
40380	24675699	The expression level of VEGF-A in hereditary paraganglioma associated with inactivation of the SDHD gene was higher than those observed in sporadic tumors.	('inactivation', 'Var', (75, 87))	('expression level', 'MPA', (4, 20))	('VEGF-A', 'Gene', '7422', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('VEGF-A', 'Gene', (24, 30))	('higher', 'PosReg', (109, 115))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (34, 58))	('sporadic tumors', 'Disease', (139, 154))	('SDHD', 'Gene', '6392', (95, 99))	('paraganglioma', 'Phenotype', 'HP:0002668', (45, 58))	('hereditary paraganglioma', 'Disease', (34, 58))	('SDHD', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('sporadic tumors', 'Disease', 'MESH:D009369', (139, 154))
40398	24675699	Sections representing PHEO were submitted to routine immunohistochemical technique, which comprises deparaffination and rehydration, antigenic recovery, inactivation of endogenous peroxidase, and blockage of unspecific reactions.	('PHEO', 'Phenotype', 'HP:0002666', (22, 26))	('inactivation', 'Var', (153, 165))	('paraffin', 'Chemical', 'MESH:D010232', (102, 110))	('endogenous peroxidase', 'Enzyme', (169, 190))
40399	24675699	Primary antibodies were incubated overnight at a temperature of 4  C, at dilutions of 1:100 (VEGF-A), 1:100 (VEGFR-1), and 1:200 (VEGFR-2), followed by application of streptavidin horseradish peroxidase conjugate (LSAB; DakoCytomation, Via Real Carpinteria, CA, USA), and diaminobenzidinetetrahydrochloride (Kit DAB; DakoCytomation).	('VEGFR-2', 'Gene', (130, 137))	('VEGFR-1', 'Gene', (109, 116))	('horseradish', 'Species', '3704', (180, 191))	('DAB', 'Chemical', 'MESH:C000469', (312, 315))	('VEGFR-1', 'Gene', '2321', (109, 116))	('diaminobenzidinetetrahydrochloride', 'Chemical', '-', (272, 306))	('1:100', 'Var', (102, 107))	('1:200', 'Var', (123, 128))	('VEGF-A', 'Gene', '7422', (93, 99))	('VEGFR-2', 'Gene', '3791', (130, 137))	('VEGF-A', 'Gene', (93, 99))
40412	20223020	Genetic predisposition can occur within the familial tumour syndromes multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) and neurofibromatosis type 1 (NF-1), or be due to mutations in genes specific to the development of paraganglioma only.	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('paraganglioma', 'Disease', (239, 252))	('VHL', 'Disease', (134, 137))	('neurofibromatosis type 1', 'Gene', (143, 167))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('neurofibromatosis type 1', 'Gene', '4763', (143, 167))	('paraganglioma', 'Disease', 'MESH:D010235', (239, 252))	('NF-1', 'Gene', '4763', (169, 173))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (79, 98))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (143, 160))	('von Hippel-Lindau', 'Gene', (115, 132))	('MEN', 'Species', '9606', (107, 110))	('NF-1', 'Gene', (169, 173))	('mutations', 'Var', (189, 198))	('von Hippel-Lindau', 'Gene', '7428', (115, 132))	('paraganglioma', 'Phenotype', 'HP:0002668', (239, 252))	('neoplasia', 'Phenotype', 'HP:0002664', (89, 98))	('familial tumour syndromes multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (44, 105))
40458	20223020	The genetic defect of paragangliomas is an inactivating mutation in one of the paraganglioma genes, the so-called PGL genes.	('paraganglioma', 'Disease', 'MESH:D010235', (79, 92))	('inactivating mutation', 'Var', (43, 64))	('genetic defect of paragangliomas', 'Disease', 'MESH:D030342', (4, 36))	('paraganglioma', 'Disease', (22, 35))	('genetic defect of paragangliomas', 'Disease', (4, 36))	('PGL', 'Gene', (114, 117))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('paraganglioma', 'Disease', 'MESH:D010235', (22, 35))	('paraganglioma', 'Disease', (79, 92))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))
40459	20223020	Somatic, inactivating mutations result in sporadic, mostly solitary tumours.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('inactivating mutations', 'Var', (9, 31))	('result in', 'Reg', (32, 41))	('mostly solitary tumours', 'Disease', (52, 75))	('sporadic', 'Disease', (42, 50))	('mostly solitary tumours', 'Disease', 'MESH:D054705', (52, 75))
40466	20223020	Mutations in DNA of genes encoding enzymes called succinate dehydrogenase (SDH) are associated with development of paragangliomas.	('succinate dehydrogenase', 'Gene', '6390', (50, 73))	('paragangliomas', 'Disease', (115, 129))	('paragangliomas', 'Disease', 'MESH:D010235', (115, 129))	('SDH', 'Gene', '6390', (75, 78))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Phenotype', 'HP:0002668', (115, 128))	('paragangliomas', 'Phenotype', 'HP:0002668', (115, 129))	('associated', 'Reg', (84, 94))	('succinate dehydrogenase', 'Gene', (50, 73))	('SDH', 'Gene', (75, 78))	('DNA of', 'Gene', (13, 19))
40473	20223020	If in a cell of a paraganglioma a mutation is present in one of the SDH genes, insufficient ATP will be available in relation to the need for energy.	('paraganglioma', 'Disease', 'MESH:D010235', (18, 31))	('ATP', 'Chemical', 'MESH:D000255', (92, 95))	('SDH', 'Gene', (68, 71))	('mutation', 'Var', (34, 42))	('insufficient', 'Disease', (79, 91))	('insufficient', 'Disease', 'MESH:D000309', (79, 91))	('paraganglioma', 'Phenotype', 'HP:0002668', (18, 31))	('paraganglioma', 'Disease', (18, 31))	('SDH', 'Gene', '6390', (68, 71))
40483	20223020	Mutations in the SDHB gene give a higher risk for malignant, especially extra-adrenal abdominal, paragangliomas than SDHD mutations do.	('paragangliomas', 'Phenotype', 'HP:0002668', (97, 111))	('extra-adrenal abdominal', 'Disease', (72, 95))	('SDHD', 'Gene', '6392', (117, 121))	('SDHB', 'Gene', '6390', (17, 21))	('paraganglioma', 'Phenotype', 'HP:0002668', (97, 110))	('Mutations', 'Var', (0, 9))	('paragangliomas', 'Disease', (97, 111))	('paragangliomas', 'Disease', 'MESH:D010235', (97, 111))	('SDHB', 'Gene', (17, 21))	('malignant', 'Disease', (50, 59))	('SDHD', 'Gene', (117, 121))
40485	20223020	Also mutations in this gene may cause hereditary paragangliomas; however, these mutations occur less frequently than SDHD mutations.	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (38, 63))	('hereditary paragangliomas', 'Disease', (38, 63))	('mutations', 'Var', (5, 14))	('paragangliomas', 'Phenotype', 'HP:0002668', (49, 63))	('paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('SDHD', 'Gene', (117, 121))	('cause', 'Reg', (32, 37))	('SDHD', 'Gene', '6392', (117, 121))
40487	20223020	Mutations in this gene cause a disease involving a combination of atrophy of the optical nerve, myopathy and ataxia, although without paragangliomas.	('ataxia', 'Disease', (109, 115))	('paraganglioma', 'Phenotype', 'HP:0002668', (134, 147))	('myopathy', 'Phenotype', 'HP:0003198', (96, 104))	('myopathy', 'Disease', (96, 104))	('paragangliomas', 'Phenotype', 'HP:0002668', (134, 148))	('Mutations', 'Var', (0, 9))	('ataxia', 'Phenotype', 'HP:0001251', (109, 115))	('ataxia', 'Disease', 'MESH:D001259', (109, 115))	('paragangliomas', 'Disease', 'MESH:D010235', (134, 148))	('atrophy of the optical nerve', 'Disease', 'MESH:D009896', (66, 94))	('cause', 'Reg', (23, 28))	('paragangliomas', 'Disease', (134, 148))	('myopathy', 'Disease', 'MESH:D009135', (96, 104))	('atrophy of the optical nerve', 'Disease', (66, 94))
40492	20223020	If a child inherits a mutated paraganglioma gene from one of its parents, it becomes a disease-gene carrier.	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('child', 'Species', '9606', (5, 10))	('paraganglioma', 'Disease', (30, 43))	('mutated', 'Var', (22, 29))	('paraganglioma', 'Disease', 'MESH:D010235', (30, 43))
40496	20223020	Exclusive transmission of the disease via the father may be explained by a hereditary mutation of the SDHD gene from the father combined with imprinting of the homologous allele from the mother, together with the loss of 11p15, 5.	('SDHD', 'Gene', (102, 106))	('SDHD', 'Gene', '6392', (102, 106))	('mutation', 'Var', (86, 94))
40518	20223020	especially children of fathers with a SDHD mutation have to be investigated periodically   early diagnosis is indicated, because morbidity is related to the diameter of the tumour   if possible, resection of a paraganglioma has to be performed at an early stage   preferably, the surgical procedure should be performed by surgeons with experience in the head and neck region and in techniques of vascular reconstruction   DNA analysis of children from families with a known SDH mutation has to be performed before the age of 5 years	('paraganglioma', 'Disease', 'MESH:D010235', (210, 223))	('children', 'Species', '9606', (11, 19))	('tumour', 'Disease', (173, 179))	('SDH', 'Gene', '6390', (38, 41))	('SDH', 'Gene', '6390', (474, 477))	('mutation', 'Var', (43, 51))	('paraganglioma', 'Phenotype', 'HP:0002668', (210, 223))	('children', 'Species', '9606', (438, 446))	('SDH', 'Gene', (474, 477))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('SDH', 'Gene', (38, 41))	('paraganglioma', 'Disease', (210, 223))	('mutation', 'Var', (478, 486))	('SDHD', 'Gene', (38, 42))	('SDHD', 'Gene', '6392', (38, 42))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
40520	33810219	Around 40% of pheochromocytomas/paragangliomas (PPGL) harbor germline mutations, representing the highest heritability among human tumors.	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('germline mutations', 'Var', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('human', 'Species', '9606', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('pheochromocytomas/paragangliomas', 'Disease', (14, 46))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('PPGL', 'Chemical', '-', (48, 52))	('paragangliomas', 'Phenotype', 'HP:0002668', (32, 46))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (14, 31))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (14, 46))
40522	33810219	In this review, we present the potential relevance of non-coding RNA molecules including microRNAs, long non-coding RNAs and circular RNAs in PPGL pathogenesis and diagnosis.	('long non-coding RNAs', 'Var', (100, 120))	('PPGL', 'Disease', (142, 146))	('PPGL', 'Chemical', '-', (142, 146))
40527	33810219	Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic, prognostic factors, and even potential treatment targets.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('implicated', 'Reg', (99, 109))	('long non-coding RNAs', 'Var', (49, 69))
40529	33810219	Non-coding RNA molecules encompassing microRNAs, long non-coding RNAs, and circular RNAs have been implicated in the pathogenesis of various tumors, and were also proposed as valuable diagnostic and prognostic factors, and even potential therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('implicated', 'Reg', (99, 109))	('long non-coding RNAs', 'Var', (49, 69))
40530	33810219	Given the fact that the pathogenesis of tumors including pheochromocytomas/paragangliomas (PPGL) is partly linked to epigenetic dysregulation, it is reasonable to investigate their epigenetic expression profiles.	('pheochromocytomas/paragangliomas', 'Disease', (57, 89))	('epigenetic', 'Var', (117, 127))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('linked', 'Reg', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (57, 89))	('PPGL', 'Chemical', '-', (91, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (57, 74))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
40535	33810219	This proportion of germline mutations has the highest degree of heritability among human tumors.	('germline mutations', 'Var', (19, 37))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
40540	33810219	On the other side up to 50% of patients with metastatic PPGL have specific germline mutations.	('PPGL', 'Gene', (56, 60))	('patients', 'Species', '9606', (31, 39))	('germline', 'Var', (75, 83))	('PPGL', 'Chemical', '-', (56, 60))
40541	33810219	The risk of metastasis is particularly high in individuals harboring germline SDHB mutations.	('mutations', 'Var', (83, 92))	('SDHB', 'Gene', '6390', (78, 82))	('metastasis', 'CPA', (12, 22))	('SDHB', 'Gene', (78, 82))	('germline', 'Var', (69, 77))	('high', 'Reg', (39, 43))
40542	33810219	PPGL susceptibility can be associated with mutations either in tumor suppressor genes (e.g., VHL, NF1, SDHB) or in proto-oncogenes (e.g., RET, HRAS).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('SDHB', 'Gene', (103, 107))	('RET', 'Gene', '5979', (138, 141))	('susceptibility', 'Reg', (5, 19))	('VHL', 'Gene', '7428', (93, 96))	('NF1', 'Gene', (98, 101))	('mutations', 'Var', (43, 52))	('PPGL', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SDHB', 'Gene', '6390', (103, 107))	('NF1', 'Gene', '4763', (98, 101))	('HRAS', 'Gene', '3265', (143, 147))	('PPGL', 'Chemical', '-', (0, 4))	('RET', 'Gene', (138, 141))	('VHL', 'Gene', (93, 96))	('HRAS', 'Gene', (143, 147))
40547	33810219	The cortical admixture type was found to be correlated with MAX (MYC associated factor X) mutations, which is also included as one of the susceptibility genes for hereditary PPGL.	('mutations', 'Var', (90, 99))	('correlated', 'Reg', (44, 54))	('PPGL', 'Chemical', '-', (174, 178))	('MYC associated factor X', 'Gene', '4149', (65, 88))	('MAX', 'Gene', '4149', (60, 63))	('MAX', 'Gene', (60, 63))	('MYC associated factor X', 'Gene', (65, 88))
40573	33810219	Novel treatment options including VEGF (vascular endothelial growth factor) and tyrosine kinase inhibitors (e.g., axitinib, dovitinib, lenvatinib, sunitinib) exist for patients with SDHA, SDHB, SDHD, RET, VHL, and FH mutations in renal cell carcinoma and PPGL; furthermore, immunotherapies targeting PD-L1 (programmed death-ligand 1) checkpoint protein (e.g., pembrolizumab, ipilimumab, nivolumab) are currently under clinical investigation.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('VHL', 'Gene', (205, 208))	('vascular endothelial growth factor', 'Gene', '7422', (40, 74))	('SDHB', 'Gene', '6390', (188, 192))	('SDHD', 'Gene', (194, 198))	('RET', 'Gene', '5979', (200, 203))	('PPGL', 'Chemical', '-', (255, 259))	('PPGL', 'Gene', (255, 259))	('vascular endothelial growth factor', 'Gene', (40, 74))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (230, 250))	('VHL', 'Gene', '7428', (205, 208))	('VEGF', 'Gene', '7422', (34, 38))	('SDHB', 'Gene', (188, 192))	('PD-L1', 'Gene', (300, 305))	('VEGF', 'Gene', (34, 38))	('RET', 'Gene', (200, 203))	('PD-L1', 'Gene', '29126', (300, 305))	('programmed death-ligand 1', 'Gene', (307, 332))	('SDHA', 'Gene', (182, 186))	('renal cell carcinoma', 'Disease', (230, 250))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (230, 250))	('SDHA', 'Gene', '6389', (182, 186))	('SDHD', 'Gene', '6392', (194, 198))	('programmed death-ligand 1', 'Gene', '29126', (307, 332))	('patients', 'Species', '9606', (168, 176))	('mutations', 'Var', (217, 226))
40574	33810219	Poly ADP-ribose polymerase (PARP) inhibitors (e.g., olaparib) represent another perspective in patients harboring SDHx mutations due to elevated levels of succinate and NAD+ inhibiting homologous recombination-based DNA repair mechanism which is known to be corrected by PARP, thus keeping aberrant cells alive.	('Poly ADP-ribose polymerase', 'Gene', '142', (0, 26))	('elevated levels of succinate', 'Phenotype', 'HP:0020149', (136, 164))	('SDH', 'Gene', (114, 117))	('NAD+', 'Chemical', 'MESH:D009243', (169, 173))	('PARP', 'Gene', '142', (28, 32))	('homologous', 'MPA', (185, 195))	('PARP', 'Gene', (28, 32))	('NAD+', 'MPA', (169, 173))	('PARP', 'Gene', '142', (271, 275))	('mutations', 'Var', (119, 128))	('PARP', 'Gene', (271, 275))	('elevated', 'PosReg', (136, 144))	('Poly ADP-ribose polymerase', 'Gene', (0, 26))	('SDH', 'Gene', '6390', (114, 117))	('succinate', 'Chemical', 'MESH:D019802', (155, 164))	('inhibiting', 'NegReg', (174, 184))	('levels', 'MPA', (145, 151))	('patients', 'Species', '9606', (95, 103))	('olaparib', 'Chemical', 'MESH:C531550', (52, 60))
40575	33810219	Furthermore, there are two kinase signaling pathways (PI3K-Akt-mTOR and Ras-Raf-Erk) affected by mutations of RET, MAX, NF1, and TMEM127, which can be inhibited by kinase signaling inhibitors (e.g., the mTOR inhibitor everolimus).	('mutations', 'Var', (97, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (218, 228))	('NF1', 'Gene', (120, 123))	('MAX', 'Gene', (115, 118))	('TMEM127', 'Gene', '55654', (129, 136))	('mTOR', 'Gene', '2475', (203, 207))	('RET', 'Gene', '5979', (110, 113))	('mTOR', 'Gene', (63, 67))	('Akt', 'Gene', (59, 62))	('Erk', 'Gene', (80, 83))	('affected', 'Reg', (85, 93))	('MAX', 'Gene', '4149', (115, 118))	('Akt', 'Gene', '207', (59, 62))	('Erk', 'Gene', '5594', (80, 83))	('RET', 'Gene', (110, 113))	('mTOR', 'Gene', '2475', (63, 67))	('Raf', 'Gene', '114486', (76, 79))	('TMEM127', 'Gene', (129, 136))	('NF1', 'Gene', '4763', (120, 123))	('mTOR', 'Gene', (203, 207))	('Raf', 'Gene', (76, 79))
40582	33810219	Non-coding RNA molecules have been shown to be implicated in the pathogenesis of tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('Non-coding', 'Var', (0, 10))	('RNA molecules', 'Protein', (11, 24))	('implicated', 'Reg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
40602	33810219	Epigenetic alterations can precede tumor formation (hence the prognostic value) and play major role in cell-to-cell communication (hence the therapeutic value) and by analyzing differential expression profiles, protein-protein interactions, gene set enrichment, dimensionality reduction, and tissue composition, it was elucidated that normal tissues adjacent to the tumor represent a unique in-between state concerning the molecular landscape.	('tumor', 'Disease', (366, 371))	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))
40607	33810219	LncRNA BSN-AS2 and C9orf147 are future candidates to investigate their roles in tumorigenesis as their overexpression was associated with poor prognosis; moreover, the underexpression of C9orf147 was associated with good prognosis (Table 1).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('BSN-AS2', 'Gene', (7, 14))	('C9orf147', 'Gene', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('underexpression', 'Var', (168, 183))	('tumor', 'Disease', (80, 85))	('C9orf147', 'Gene', (19, 27))	('BSN-AS2', 'Gene', '100132677', (7, 14))	('C9orf147', 'Gene', '100133204', (187, 195))	('overexpression', 'PosReg', (103, 117))	('C9orf147', 'Gene', '100133204', (19, 27))
40610	33810219	PTPRJ underexpression was found to be correlated with good prognosis.	('PTPRJ', 'Gene', (0, 5))	('PTPRJ', 'Gene', '5795', (0, 5))	('underexpression', 'Var', (6, 21))
40614	33810219	In the SDHx subtype, a putative lncRNA BC063866 was found to be able to distinguish between metastatic tumors and tumors that remain indolent.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SDH', 'Gene', (7, 10))	('tumors', 'Disease', (103, 109))	('BC063866', 'Var', (39, 47))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('SDH', 'Gene', '6390', (7, 10))
40616	33810219	Furthermore, lncRNA BC063866 was found to be an independent risk factor for poor outcome in SDHx mutants, although this marker should be replicated in large prospective cohorts, as well.	('SDH', 'Gene', '6390', (92, 95))	('SDH', 'Gene', (92, 95))	('mutants', 'Var', (97, 104))
40620	33810219	In contrast to the previous study, this bioinformatical approach revealed underexpressed PTPRJ to be related to unfavorable prognosis.	('PTPRJ', 'Gene', (89, 94))	('PTPRJ', 'Gene', '5795', (89, 94))	('underexpressed', 'Var', (74, 88))	('related', 'Reg', (101, 108))
40624	33810219	It is also noteworthy that miR-483-5p, miR-195, and miR-34a were shown to be differentially expressed in adrenocortical cancer, as well.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('miR-483-5p', 'Chemical', '-', (27, 37))	('miR-34a', 'Gene', '407040', (52, 59))	('miR-34a', 'Gene', (52, 59))	('adrenocortical cancer', 'Disease', (105, 126))	('miR-483-5p', 'Var', (27, 37))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (105, 126))	('miR-195', 'Gene', (39, 46))	('miR-195', 'Gene', '406971', (39, 46))
40629	33810219	Upregulated expression of miR-1225-3p has been found in sporadic recurrent pheochromocytomas in comparison to benign pheochromocytomas that raised its potential as a marker of PPGL recurrence.	('miR-1225-3p', 'Var', (26, 37))	('pheochromocytomas', 'Disease', (75, 92))	('benign pheochromocytomas', 'Disease', 'MESH:D010673', (110, 134))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (117, 133))	('pheochromocytomas', 'Disease', 'MESH:D010673', (117, 134))	('pheochromocytomas', 'Disease', (117, 134))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (75, 92))	('benign pheochromocytomas', 'Disease', (110, 134))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (75, 91))	('expression', 'MPA', (12, 22))	('Upregulated', 'PosReg', (0, 11))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (117, 134))	('pheochromocytomas', 'Disease', 'MESH:D010673', (75, 92))	('PPGL', 'Chemical', '-', (176, 180))
40632	33810219	The aforementioned recent ceRNA study also shed light on miR-148b-3p and miR-338-3p in respect of favorable prognosis and overall survival in PPGL.	('PPGL', 'Chemical', '-', (142, 146))	('miR-338-3p', 'Var', (73, 83))	('PPGL', 'Disease', (142, 146))	('miR-148b-3p', 'Var', (57, 68))
40635	33810219	Significantly altered expression of miR-101, miR-183, and miR-483-5p was revealed in metastatic pheochromocytoma tissues versus benign ones and validated by RT-qPCR.	('miR-483-5p', 'Chemical', '-', (58, 68))	('miR-483-5p', 'Var', (58, 68))	('altered', 'Reg', (14, 21))	('pheochromocytoma', 'Disease', 'MESH:D010673', (96, 112))	('miR-101', 'Chemical', '-', (36, 43))	('pheochromocytoma', 'Disease', (96, 112))	('expression', 'MPA', (22, 32))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (96, 112))	('miR-183', 'Gene', '406959', (45, 52))	('miR-183', 'Gene', (45, 52))	('miR-101', 'Gene', (36, 43))
40636	33810219	Among them, miR-101 and miR-183 significantly differed in SDHB mutant vs. wild type samples and interestingly, miR-483-5p had significantly lower expression in SDHB mutant malignant pheochromocytoma compared to all other malignant pheochromocytomas.	('SDHB', 'Gene', (58, 62))	('lower', 'NegReg', (140, 145))	('SDHB', 'Gene', (160, 164))	('miR-101', 'Chemical', '-', (12, 19))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (172, 198))	('malignant pheochromocytomas', 'Disease', 'MESH:D010673', (221, 248))	('expression', 'MPA', (146, 156))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (231, 248))	('miR-483-5p', 'Chemical', '-', (111, 121))	('malignant pheochromocytoma', 'Disease', (172, 198))	('differed', 'Reg', (46, 54))	('miR-183', 'Gene', '406959', (24, 31))	('mutant', 'Var', (63, 69))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (221, 247))	('SDHB', 'Gene', '6390', (58, 62))	('malignant pheochromocytomas', 'Disease', (221, 248))	('miR-183', 'Gene', (24, 31))	('SDHB', 'Gene', '6390', (160, 164))	('mutant', 'Var', (165, 171))	('miR-483-5p', 'Var', (111, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (231, 247))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (182, 198))
40637	33810219	Furthermore, miR-101, miR-183, and miR-483-5p were measurable from serum samples, as well.	('miR-483-5p', 'Chemical', '-', (35, 45))	('miR-183', 'Gene', '406959', (22, 29))	('miR-183', 'Gene', (22, 29))	('miR-483-5p', 'Var', (35, 45))	('miR-101', 'Chemical', '-', (13, 20))	('miR-101', 'Var', (13, 20))
40638	33810219	In practice, this might raise the possibility that a patient without SDHB mutation might be screened for miR expression profile changes to assess the risk of malignancy.	('mutation', 'Var', (74, 82))	('SDHB', 'Gene', (69, 73))	('miR expression profile', 'MPA', (105, 127))	('malignancy', 'Disease', (158, 168))	('SDHB', 'Gene', '6390', (69, 73))	('malignancy', 'Disease', 'MESH:D009369', (158, 168))	('changes', 'Reg', (128, 135))	('patient', 'Species', '9606', (53, 60))
40639	33810219	In another study investigating snap-frozen samples, significantly higher expression of miR-483-5p in metastatic PPGL was found, as well, validated by RT-qPCR.	('PPGL', 'Chemical', '-', (112, 116))	('miR-483-5p', 'Chemical', '-', (87, 97))	('expression', 'MPA', (73, 83))	('higher', 'PosReg', (66, 72))	('miR-483-5p', 'Var', (87, 97))
40645	33810219	Moreover, miR-483-5p is a marker of worse disease-free survival in metastatic pheochromocytoma.	('pheochromocytoma', 'Disease', (78, 94))	('miR-483-5p', 'Chemical', '-', (10, 20))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('miR-483-5p', 'Var', (10, 20))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))
40647	33810219	When PPGL was compared with normal adrenal medullary tissues, overexpressed miR-210 was significantly associated with SDHx or VHL mutant genotypes known to exhibit the pseudohypoxia phenotype.	('VHL', 'Gene', '7428', (126, 129))	('miR-210', 'Gene', (76, 83))	('overexpressed', 'PosReg', (62, 75))	('hypoxia', 'Disease', (174, 181))	('PPGL', 'Chemical', '-', (5, 9))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('miR-210', 'Gene', '406992', (76, 83))	('SDH', 'Gene', '6390', (118, 121))	('associated', 'Interaction', (102, 112))	('VHL', 'Gene', (126, 129))	('SDH', 'Gene', (118, 121))	('mutant', 'Var', (130, 136))
40648	33810219	The aforementioned miR-96 and miR-183 were described to contribute to the differentiation block of cells of SDHB mutated tumors.	('SDHB', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-183', 'Gene', '406959', (30, 37))	('miR-183', 'Gene', (30, 37))	('tumors', 'Disease', (121, 127))	('miR-96', 'Gene', '407053', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('miR-96', 'Gene', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('differentiation block of', 'CPA', (74, 98))	('mutated', 'Var', (113, 120))	('SDHB', 'Gene', '6390', (108, 112))	('contribute', 'Reg', (56, 66))
40654	33810219	Robust upregulation was identified with miR-96 especially in SDHB mutants.	('upregulation', 'PosReg', (7, 19))	('mutants', 'Var', (66, 73))	('SDHB', 'Gene', '6390', (61, 65))	('miR-96', 'Gene', '407053', (40, 46))	('miR-96', 'Gene', (40, 46))	('SDHB', 'Gene', (61, 65))
40661	33810219	Similar to UCA1, SOX6 also acts as a provoking factor in hypoxic injuries and inhibition of SOX6 leads to an ease of hypoxic injury (Figure 3).	('SOX6', 'Gene', (92, 96))	('inhibition', 'Var', (78, 88))	('hypoxic injuries', 'Disease', 'MESH:D002534', (57, 73))	('hypoxic injury', 'Disease', (117, 131))	('SOX6', 'Gene', '55553', (92, 96))	('hypoxic injury', 'Disease', 'MESH:D002534', (117, 131))	('SOX6', 'Gene', (17, 21))	('SOX6', 'Gene', '55553', (17, 21))	('ease', 'PosReg', (109, 113))	('UCA1', 'Gene', '652995', (11, 15))	('UCA1', 'Gene', (11, 15))	('hypoxic injuries', 'Disease', (57, 73))
40665	33810219	These include miR-483-5p, miR-195, and miR-34a.	('miR-34a', 'Gene', '407040', (39, 46))	('miR-483-5p', 'Var', (14, 24))	('miR-483-5p', 'Chemical', '-', (14, 24))	('miR-34a', 'Gene', (39, 46))	('miR-195', 'Gene', (26, 33))	('miR-195', 'Gene', '406971', (26, 33))
40674	33810219	The emerging role of non-coding RNA in the setting of clinical evaluation and therapeutic approaches of clinically challenging tumors is an attractive candidate for precision medicine.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('non-coding RNA', 'Var', (21, 35))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
40680	33320109	Diagnosis was based on typical symptoms and signs in 58 patients, genetic testing in 12 and work-up of an adrenal incidentaloma in 9.	('patients', 'Species', '9606', (56, 64))	('adrenal incidentaloma', 'Disease', (106, 127))	('genetic testing', 'Var', (66, 81))	('adrenal incidentaloma', 'Disease', 'MESH:C538238', (106, 127))
40685	33320109	The occurrence of haemodynamic complications during surgery was not significantly affected by the secretory phenotype in our study, but noradrenergic tumours show a worse post-surgical outcome.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('noradrenergic', 'Var', (136, 149))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('tumours', 'Disease', (150, 157))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
40691	33320109	Over the last years, however, pheochromocytomas have been increasingly diagnosed during the work-up of an incidentally discovered adrenal mass or as a result of genetic case detection testing, as these tumours carry a very high rate of germline mutations, up to 35-40% in recent series.	('pheochromocytomas', 'Disease', 'MESH:D010673', (30, 47))	('germline mutations', 'Var', (236, 254))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (30, 47))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('tumours', 'Disease', (202, 209))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (30, 46))	('pheochromocytomas', 'Disease', (30, 47))
40757	33320109	Patients with a noradrenergic PC showed less often normalisation of their blood pressure after surgery as opposed to patients with an adrenergic phenotype (P < 0.05; Table 2).	('normalisation', 'MPA', (51, 64))	('noradrenergic', 'Var', (16, 29))	('blood pressure', 'MPA', (74, 88))	('PC', 'Phenotype', 'HP:0002666', (30, 32))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (117, 125))	('PC', 'Gene', '5091', (30, 32))
40773	33320109	In total, we found a pathogenic germline mutation in one-third of all index patients, a proportion similar to those reported by previous genetic studies on PPGL, ranging from 25 to 40% of patients.	('patients', 'Species', '9606', (76, 84))	('PPGL', 'Chemical', '-', (156, 160))	('germline mutation', 'Var', (32, 49))	('patients', 'Species', '9606', (188, 196))	('pathogenic', 'Reg', (21, 31))
40881	33081307	When a mutation is detected in a susceptibility gene such as VHL, SDH, or the recently discovered MDH2, a search for common co-occurring tumors is indicated.	('MDH2', 'Gene', (98, 102))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('SDH', 'Gene', '6390', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('SDH', 'Gene', (66, 69))	('VHL', 'Gene', (61, 64))	('mutation', 'Var', (7, 15))	('VHL', 'Gene', '7428', (61, 64))	('MDH2', 'Gene', '4191', (98, 102))
40882	33081307	Mutation in the SDHB subunit is also associated with the risk for malignancy and worse prognosis.	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('SDHB', 'Gene', '6390', (16, 20))	('Mutation', 'Var', (0, 8))	('SDHB', 'Gene', (16, 20))	('malignancy', 'Disease', (66, 76))	('associated', 'Reg', (37, 47))
40883	33081307	In 50% of patients with metastatic disease, a mutation in the SDHB gene was found.	('found', 'Reg', (76, 81))	('SDHB', 'Gene', '6390', (62, 66))	('metastatic disease', 'Disease', (24, 42))	('patients', 'Species', '9606', (10, 18))	('mutation', 'Var', (46, 54))	('SDHB', 'Gene', (62, 66))
40891	33081307	PGLs are classified into three clusters by the Cancer Genome Atlas (TCGA) on the basis of molecular, cytogenetic abnormalities, and specific single-nucleotide causative mutations, which led to the development of PPGLs.	('Cancer', 'Disease', (47, 53))	('led to', 'Reg', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('PGL', 'Phenotype', 'HP:0002668', (213, 216))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('PGL', 'Phenotype', 'HP:0002668', (0, 3))	('PPGLs', 'Chemical', '-', (212, 217))	('single-nucleotide', 'Var', (141, 158))	('PPGLs', 'Disease', (212, 217))
40896	33081307	This group includes germline mutations in succinate dehydrogenase subunits SDHA, SDHB, SDHC, SDHD or SDHAF2 (SDHx):succinate dehydrogenase complex assembly factor 2, and FH (a second enzyme in the TCA cycle).	('SDHA', 'Gene', (75, 79))	('succinate dehydrogenase', 'Gene', (42, 65))	('succinate dehydrogenase complex assembly factor 2', 'Gene', (115, 164))	('SDHA', 'Gene', '6389', (75, 79))	('SDHB', 'Gene', (81, 85))	('SDH', 'Gene', (81, 84))	('SDH', 'Gene', '6390', (87, 90))	('SDHC', 'Gene', '6391', (87, 91))	('SDH', 'Gene', '6390', (109, 112))	('FH', 'Disease', 'MESH:D006938', (170, 172))	('SDHD', 'Gene', '6392', (93, 97))	('SDH', 'Gene', '6390', (93, 96))	('succinate dehydrogenase', 'Gene', '6390', (42, 65))	('mutations', 'Var', (29, 38))	('SDH', 'Gene', '6390', (101, 104))	('SDHA', 'Gene', (101, 105))	('SDH', 'Gene', '6390', (75, 78))	('TCA', 'Chemical', '-', (197, 200))	('SDH', 'Gene', (87, 90))	('succinate dehydrogenase', 'Gene', '6390', (115, 138))	('SDHD', 'Gene', (93, 97))	('SDHA', 'Gene', '6389', (101, 105))	('SDH', 'Gene', (109, 112))	('succinate dehydrogenase complex assembly factor 2', 'Gene', '54949', (115, 164))	('SDHC', 'Gene', (87, 91))	('SDHB', 'Gene', '6390', (81, 85))	('SDH', 'Gene', '6390', (81, 84))	('SDHAF2', 'Gene', '54949', (101, 107))	('SDHAF2', 'Gene', (101, 107))	('SDH', 'Gene', (101, 104))	('SDH', 'Gene', (93, 96))	('SDH', 'Gene', (75, 78))
40900	33081307	A pseudo-hypoxic state is caused by the presence of abnormal, mutated VHL, SDH, EGLN1, and HIF2A genes.	('VHL', 'Gene', (70, 73))	('pseudo-hypoxic state', 'Disease', (2, 22))	('VHL', 'Gene', '7428', (70, 73))	('presence', 'Reg', (40, 48))	('EGLN1', 'Gene', '54583', (80, 85))	('HIF2A', 'Gene', (91, 96))	('caused by', 'Reg', (26, 35))	('abnormal', 'Var', (52, 60))	('SDH', 'Gene', '6390', (75, 78))	('EGLN1', 'Gene', (80, 85))	('SDH', 'Gene', (75, 78))	('HIF2A', 'Gene', '2034', (91, 96))	('mutated', 'Var', (62, 69))
40903	33081307	The Wnt signaling cluster is another group that are, in particular, triggered by somatic mutations in the CSDE1 gene or somatic gene fusions which affect the MAML3 gene.	('CSDE1', 'Gene', '7812', (106, 111))	('triggered', 'Reg', (68, 77))	('MAML3', 'Gene', '55534', (158, 163))	('MAML3', 'Gene', (158, 163))	('fusions', 'Var', (133, 140))	('mutations', 'Var', (89, 98))	('CSDE1', 'Gene', (106, 111))
40906	33081307	The kinase signaling cluster (50-60% of PPGLs) includes germline or somatic mutations in RET, NF1, MAX, HRAS, and TMEM127 genes.	('NF1', 'Gene', '4763', (94, 97))	('mutations', 'Var', (76, 85))	('RET', 'Gene', (89, 92))	('TMEM127', 'Gene', (114, 121))	('PPGLs', 'Chemical', '-', (40, 45))	('HRAS', 'Gene', (104, 108))	('TMEM127', 'Gene', '55654', (114, 121))	('PGL', 'Phenotype', 'HP:0002668', (41, 44))	('RET', 'Gene', '5979', (89, 92))	('MAX', 'Gene', (99, 102))	('NF1', 'Gene', (94, 97))	('HRAS', 'Gene', '3265', (104, 108))
40907	33081307	The RAS/MAPK and PI3/AKT signaling pathways are enabled due to RET proto-oncogene activation or NF1 tumor suppressor inactivation, resulting in tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (144, 149))	('enabled', 'PosReg', (48, 55))	('RET', 'Gene', '5979', (63, 66))	('tumor', 'Disease', (100, 105))	('inactivation', 'Var', (117, 129))	('PI3', 'Gene', '5266', (17, 20))	('AKT', 'Gene', '207', (21, 24))	('RET', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('PI3', 'Gene', (17, 20))	('NF1', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('AKT', 'Gene', (21, 24))	('NF1', 'Gene', '4763', (96, 99))
40908	33081307	In contrast, TMEM127 mutations trigger the mTOR pathways.	('TMEM127', 'Gene', '55654', (13, 20))	('mTOR', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (43, 47))	('trigger', 'Reg', (31, 38))	('TMEM127', 'Gene', (13, 20))	('mutations', 'Var', (21, 30))
40909	33081307	Another mechanism includes deactivation of the MAX suppressor gene, causing an abnormally elevated expression of cofactor MYC (proto-oncogene), resulting in the formation of PPGLs.	('expression', 'MPA', (99, 109))	('elevated', 'PosReg', (90, 98))	('formation', 'MPA', (161, 170))	('PPGLs', 'MPA', (174, 179))	('PGL', 'Phenotype', 'HP:0002668', (175, 178))	('PPGLs', 'Chemical', '-', (174, 179))	('deactivation', 'Var', (27, 39))	('MAX suppressor gene', 'Gene', (47, 66))
40914	33081307	They are caused by mutations in the succinate dehydrogenase (SDH) complex, which is necessary for the mitochondrial electron transport chain and ATP generation.	('caused by', 'Reg', (9, 18))	('SDH', 'Gene', (61, 64))	('mutations', 'Var', (19, 28))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('SDH', 'Gene', '6390', (61, 64))	('succinate dehydrogenase', 'Gene', (36, 59))	('succinate dehydrogenase', 'Gene', '6390', (36, 59))
40918	33081307	It is correlated with inactivating mutations of the SDHD gene localized on chromosome 11q23.	('SDHD', 'Gene', '6392', (52, 56))	('SDHD', 'Gene', (52, 56))	('inactivating mutations', 'Var', (22, 44))
40921	33081307	SDHD mutations are also associated with maternal genomic imprinting.	('associated', 'Reg', (24, 34))	('mutations', 'Var', (5, 14))	('SDHD', 'Gene', '6392', (0, 4))	('maternal genomic imprinting', 'CPA', (40, 67))	('SDHD', 'Gene', (0, 4))
40922	33081307	Tumors are more likely to develop in children if the father is affected or a mutation carrier himself.	('mutation', 'Var', (77, 85))	('children', 'Species', '9606', (37, 45))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))
40926	33081307	PGLs typically produce catecholamines such as dopamine and norepinephrine, and only 10% of SDHB mutated tumors are biochemically silent; however, the clinical consequences are generally the result of significant mass effect rather than catecholamine excess.	('mutated', 'Var', (96, 103))	('catecholamines', 'Chemical', 'MESH:D002395', (23, 37))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('catecholamine excess', 'Phenotype', 'HP:0003334', (236, 256))	('dopamine', 'MPA', (46, 54))	('SDHB', 'Gene', '6390', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('produce catecholamines', 'MPA', (15, 37))	('norepinephrine', 'MPA', (59, 73))	('PGL', 'Phenotype', 'HP:0002668', (0, 3))	('tumors', 'Disease', (104, 110))	('dopamine', 'Chemical', 'MESH:D004298', (46, 54))	('norepinephrine', 'Chemical', 'MESH:D009638', (59, 73))	('SDHB', 'Gene', (91, 95))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('catecholamine', 'Chemical', 'MESH:D002395', (23, 36))	('catecholamine', 'Chemical', 'MESH:D002395', (236, 249))
40928	33081307	The SDHB gene mutation increases the risk of renal cell carcinoma, gastrointestinal stromal tumor (GIST), and breast and papillary thyroid carcinoma, and while patients with metastatic disease should be routinely tested for the presence of the predisposing SDHB mutation, there are no guidelines regarding the screening of asymptomatic SDHx gene mutation carriers.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (67, 97))	('SDH', 'Gene', (257, 260))	('SDH', 'Gene', (4, 7))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (67, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('SDH', 'Gene', (336, 339))	('gastrointestinal stromal tumor', 'Disease', (67, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SDHB', 'Gene', '6390', (257, 261))	('SDHB', 'Gene', '6390', (4, 8))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (45, 65))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (131, 148))	('GIST', 'Phenotype', 'HP:0100723', (99, 103))	('SDHB', 'Gene', (257, 261))	('SDHB', 'Gene', (4, 8))	('increases', 'PosReg', (23, 32))	('SDH', 'Gene', '6390', (257, 260))	('SDH', 'Gene', '6390', (4, 7))	('patients', 'Species', '9606', (160, 168))	('breast and papillary thyroid carcinoma', 'Disease', 'MESH:D001943', (110, 148))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (121, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('mutation', 'Var', (14, 22))	('renal cell carcinoma', 'Disease', (45, 65))	('SDH', 'Gene', '6390', (336, 339))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (45, 65))
40930	33081307	PGL3 syndrome is caused by an SDHC gene mutation located on 1q21-q23 and is inherited in an autosomal dominant pattern.	('SDHC', 'Gene', (30, 34))	('mutation', 'Var', (40, 48))	('PGL3', 'Gene', '6391', (0, 4))	('PGL', 'Phenotype', 'HP:0002668', (0, 3))	('SDHC', 'Gene', '6391', (30, 34))	('PGL3', 'Gene', (0, 4))	('caused by', 'Reg', (17, 26))
40933	33081307	Mutations in the SDHAF2 gene have also been recently reported.	('SDHAF2', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('SDHAF2', 'Gene', '54949', (17, 23))
40934	33081307	SDHAF2 mutation results in a rare type of familial paraganglioma syndrome that leads to HNPGL, but only in the children of a father who is a carrier of the defective gene.	('familial paraganglioma syndrome', 'Disease', (42, 73))	('HNPGL', 'Disease', (88, 93))	('SDHAF2', 'Gene', '54949', (0, 6))	('leads', 'Reg', (79, 84))	('results in', 'Reg', (16, 26))	('SDHAF2', 'Gene', (0, 6))	('children', 'Species', '9606', (111, 119))	('familial paraganglioma syndrome', 'Disease', 'MESH:D010235', (42, 73))	('HNPGL', 'Phenotype', 'HP:0002864', (88, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (51, 64))	('mutation', 'Var', (7, 15))	('PGL', 'Phenotype', 'HP:0002668', (90, 93))
40935	33081307	Genetic screening of SDHAF2 mutation is crucial in patients with HNPGL with suspicious family history, young age of onset, or multiple tumors and have already tested negative for SDHB, SDHC, and SDHD mutations.	('SDHAF2', 'Gene', '54949', (21, 27))	('PGL', 'Phenotype', 'HP:0002668', (67, 70))	('HNPGL', 'Phenotype', 'HP:0002864', (65, 70))	('SDHAF2', 'Gene', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SDHC', 'Gene', (185, 189))	('HNPGL', 'Disease', (65, 70))	('SDHB', 'Gene', '6390', (179, 183))	('mutation', 'Var', (28, 36))	('tumors', 'Disease', (135, 141))	('SDHD', 'Gene', (195, 199))	('patients', 'Species', '9606', (51, 59))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('SDHD', 'Gene', '6392', (195, 199))	('SDHB', 'Gene', (179, 183))	('SDHC', 'Gene', '6391', (185, 189))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
40938	33081307	Inactivation of tumor-suppressor genes (TSGs) is caused by overall DNA hypomethylation and hypermethylation of CpG islands located in the closest vicinity of the promoter.	('tumor-suppressor', 'Gene', '7248', (16, 32))	('tumor-suppressor', 'Gene', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('hypermethylation', 'Var', (91, 107))	('Inactivation', 'NegReg', (0, 12))	('hypomethylation', 'Var', (71, 86))
40939	33081307	In a study by Chen et al., the methylation status of a panel of TSGs (p16, HIC1, DcR1, DcR2, DR4, DR5, CASP8, HSP47, MGMT, and RASSF1A) has been determined and compared in HNPGLs with and without SDH mutations.	('HSP47', 'Gene', (110, 115))	('HIC1', 'Gene', (75, 79))	('HNPGL', 'Phenotype', 'HP:0002864', (172, 177))	('MGMT', 'Gene', (117, 121))	('mutations', 'Var', (200, 209))	('p16', 'Gene', '1029', (70, 73))	('PGL', 'Phenotype', 'HP:0002668', (174, 177))	('CASP8', 'Gene', '841', (103, 108))	('DR5', 'Gene', (98, 101))	('DR4', 'Gene', (93, 96))	('HIC1', 'Gene', '3090', (75, 79))	('HSP47', 'Gene', '871', (110, 115))	('CASP8', 'Gene', (103, 108))	('DcR2', 'Gene', '8793', (87, 91))	('HNPGLs', 'Disease', (172, 178))	('SDH', 'Gene', '6390', (196, 199))	('DcR1', 'Gene', '23405', (81, 85))	('MGMT', 'Gene', '4255', (117, 121))	('DcR2', 'Gene', (87, 91))	('DR4', 'Gene', '3126', (93, 96))	('RASSF1A', 'Gene', '11186', (127, 134))	('RASSF1A', 'Gene', (127, 134))	('methylation', 'MPA', (31, 42))	('SDH', 'Gene', (196, 199))	('p16', 'Gene', (70, 73))	('DR5', 'Gene', '8795', (98, 101))	('DcR1', 'Gene', (81, 85))
40940	33081307	Six out of 10 TSGs showed frequent methylation: HIC1 and those involved in the apoptosis pathway DcR1, DcR2, DR4, DR5, and CASPS8.	('DR5', 'Gene', (114, 117))	('DcR1', 'Gene', (97, 101))	('DcR2', 'Gene', (103, 107))	('DR5', 'Gene', '8795', (114, 117))	('DR4', 'Gene', (109, 112))	('HIC1', 'Gene', '3090', (48, 52))	('HIC1', 'Gene', (48, 52))	('DcR1', 'Gene', '23405', (97, 101))	('methylation', 'Var', (35, 46))	('DR4', 'Gene', '3126', (109, 112))	('DcR2', 'Gene', '8793', (103, 107))
40943	33081307	It may provide a better understanding of the crucial role of the mutations acquired on various level of disease development, as well as those underlying the carcinogenesis of HNPGLs.	('carcinogenesis of HNPGLs', 'Disease', 'MESH:D063646', (157, 181))	('carcinogenesis of HNPGLs', 'Disease', (157, 181))	('PGL', 'Phenotype', 'HP:0002668', (177, 180))	('mutations', 'Var', (65, 74))	('HNPGL', 'Phenotype', 'HP:0002864', (175, 180))
40944	33081307	analyzed 50 "mutation hotspot" variants in PCC and PGL using NGS in 20 patients with HNPGL and 85 patients with PPGL.	('PCC', 'Gene', (43, 46))	('PGL', 'Gene', (51, 54))	('variants', 'Var', (31, 39))	('PGL', 'Phenotype', 'HP:0002668', (113, 116))	('patients', 'Species', '9606', (71, 79))	('PPGL', 'Chemical', '-', (112, 116))	('patients', 'Species', '9606', (98, 106))	('PCC', 'Phenotype', 'HP:0002666', (43, 46))	('PGL', 'Phenotype', 'HP:0002668', (87, 90))	('PGL', 'Phenotype', 'HP:0002668', (51, 54))	('HNPGL', 'Phenotype', 'HP:0002864', (85, 90))
40945	33081307	The authors identified mutations in HRAS (7.1%), and BRAF (1.2%) as well as for TP53 in 2.35% of cases.	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('TP53', 'Gene', '7157', (80, 84))	('HRAS', 'Gene', '3265', (36, 40))	('TP53', 'Gene', (80, 84))	('mutations', 'Var', (23, 32))	('HRAS', 'Gene', (36, 40))
40946	33081307	In the group of PPGL tumors with identified hereditary mutations (21 cases), HRAS, BRAF, and TP53 genes were not mutated.	('mutations', 'Var', (55, 64))	('PPGL tumors', 'Disease', (16, 27))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('PGL', 'Phenotype', 'HP:0002668', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('HRAS', 'Gene', '3265', (77, 81))	('BRAF', 'Gene', '673', (83, 87))	('PPGL tumors', 'Disease', 'MESH:D009369', (16, 27))	('HRAS', 'Gene', (77, 81))	('BRAF', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
40947	33081307	It was concluded that the occurrence of HRAS/BRAF mutations predominates in sporadic PPGL (8.9%) but is inconsequential for inherited PPGL.	('mutations', 'Var', (50, 59))	('HRAS', 'Gene', '3265', (40, 44))	('PPGL', 'Disease', (85, 89))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))	('PPGL', 'Chemical', '-', (134, 138))	('PPGL', 'Chemical', '-', (85, 89))	('PGL', 'Phenotype', 'HP:0002668', (86, 89))	('HRAS', 'Gene', (40, 44))	('PGL', 'Phenotype', 'HP:0002668', (135, 138))
40955	33081307	An agreement in the literature on the selection of mutations in HNPGL has been drawn, and encompasses the following genes: SDHA, SDHB, SDHD, SDHAF2, SDHC, SDHB, VHL, FH, RET.	('mutations', 'Var', (51, 60))	('SDHC', 'Gene', (149, 153))	('SDHD', 'Gene', '6392', (135, 139))	('RET', 'Gene', (170, 173))	('HNPGL', 'Gene', (64, 69))	('SDHB', 'Gene', '6390', (155, 159))	('SDHB', 'Gene', '6390', (129, 133))	('SDHD', 'Gene', (135, 139))	('SDHAF2', 'Gene', '54949', (141, 147))	('SDHAF2', 'Gene', (141, 147))	('SDHA', 'Gene', (141, 145))	('VHL', 'Gene', (161, 164))	('PGL', 'Phenotype', 'HP:0002668', (66, 69))	('HNPGL', 'Phenotype', 'HP:0002864', (64, 69))	('SDHA', 'Gene', (123, 127))	('SDHA', 'Gene', '6389', (141, 145))	('SDHC', 'Gene', '6391', (149, 153))	('SDHB', 'Gene', (155, 159))	('SDHB', 'Gene', (129, 133))	('RET', 'Gene', '5979', (170, 173))	('SDHA', 'Gene', '6389', (123, 127))	('FH', 'Disease', 'MESH:D006938', (166, 168))	('VHL', 'Gene', '7428', (161, 164))
41051	32793409	Similar to other types of spinal metastases, the location of the spinal cord injury in MSP cases determines the type of neurological deficit, while lesions in the thoracolumbar regions are often manifested as low back pain, lower extremity sensory abnormality, weakness, and dysuria.	('dysuria', 'Disease', 'MESH:D053159', (275, 282))	('dysuria', 'Phenotype', 'HP:0100518', (275, 282))	('pain', 'Phenotype', 'HP:0012531', (218, 222))	('low back pain', 'Phenotype', 'HP:0003419', (209, 222))	('back pain', 'Disease', (213, 222))	('spinal metastases', 'Disease', (26, 43))	('neurological deficit', 'Disease', 'MESH:D009461', (120, 140))	('weakness', 'Disease', 'MESH:D018908', (261, 269))	('extremity sensory abnormality', 'Disease', (230, 259))	('extremity sensory abnormality', 'Disease', 'MESH:D012678', (230, 259))	('dysuria', 'Disease', (275, 282))	('lower extremity', 'Phenotype', 'HP:0006385', (224, 239))	('spinal metastases', 'Disease', 'MESH:D009362', (26, 43))	('weakness', 'Disease', (261, 269))	('neurological deficit', 'Disease', (120, 140))	('back pain', 'Phenotype', 'HP:0003418', (213, 222))	('back pain', 'Disease', 'MESH:D001416', (213, 222))	('spinal cord injury', 'Disease', (65, 83))	('lesions', 'Var', (148, 155))	('neurological deficit', 'Phenotype', 'HP:0000707', (120, 140))	('spinal cord injury', 'Disease', 'MESH:D013119', (65, 83))
41056	32793409	In addition, genetic analysis can further assist in the diagnosis of pheochromocytoma.	('genetic analysis', 'Var', (13, 29))	('pheochromocytoma', 'Disease', (69, 85))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (69, 85))	('pheochromocytoma', 'Disease', 'MESH:D010673', (69, 85))
41122	31750236	On the other hand, lithium can also cause damage to the thyroid cell with consequent signs and symptoms of thyroiditis.	('thyroiditis', 'Disease', 'MESH:D013959', (107, 118))	('cause', 'Reg', (36, 41))	('lithium', 'Var', (19, 26))	('lithium', 'Chemical', 'MESH:D008094', (19, 26))	('damage', 'MPA', (42, 48))	('thyroiditis', 'Disease', (107, 118))	('thyroiditis', 'Phenotype', 'HP:0100646', (107, 118))
41124	31750236	Lithium was found to increase the intrathyroidal iodine content as well as to inhibit release of thyroid hormones from the thyroid into the circulation due to altered tubulin polymerization in thyrocytes.	('Lithium', 'Chemical', 'MESH:D008094', (0, 7))	('tubulin polymerization', 'MPA', (167, 189))	('increase the intrathyroidal iodine content', 'Phenotype', 'HP:0031220', (21, 63))	('inhibit release of thyroid hormones', 'Phenotype', 'HP:0002930', (78, 113))	('altered', 'Reg', (159, 166))	('rat', 'Species', '10116', (37, 40))	('iodine', 'Chemical', 'MESH:D007455', (49, 55))	('inhibit', 'NegReg', (78, 85))	('intrathyroidal iodine content', 'MPA', (34, 63))	('Lithium', 'Var', (0, 7))	('increase', 'PosReg', (21, 29))
41130	31750236	Functional in vitro models revealed that Wnt/beta-catenin signaling may be important in lithium-associated goiter, as lithium significantly increased human thyrocyte proliferation mediated by Wnt/beta-catenin pathway.	('human', 'Species', '9606', (150, 155))	('lithium', 'Var', (118, 125))	('beta-catenin', 'Gene', '1499', (196, 208))	('rat', 'Species', '10116', (173, 176))	('lithium', 'Chemical', 'MESH:D008094', (118, 125))	('goiter', 'Disease', (107, 113))	('beta-catenin', 'Gene', '1499', (45, 57))	('goiter', 'Disease', 'MESH:D006042', (107, 113))	('goiter', 'Phenotype', 'HP:0000853', (107, 113))	('human thyrocyte proliferation', 'CPA', (150, 179))	('lithium', 'Chemical', 'MESH:D008094', (88, 95))	('lithium-associated', 'Disease', (88, 106))	('increased', 'PosReg', (140, 149))	('beta-catenin', 'Gene', (45, 57))	('beta-catenin', 'Gene', (196, 208))
41154	31750236	analyzed the role of lithium in a rat follicular cell line intrinsically expressing NIS (FRTL5), and a follicular thyroid cancer cell line FTC133 stably transfected with NIS.	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (103, 128))	('thyroid cancer', 'Phenotype', 'HP:0002890', (114, 128))	('FTC', 'Disease', 'MESH:C572845', (139, 142))	('NIS', 'Var', (84, 87))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (103, 128))	('FTC', 'Disease', (139, 142))	('FTC', 'Phenotype', 'HP:0006731', (139, 142))	('rat', 'Species', '10116', (34, 37))	('lithium', 'Chemical', 'MESH:D008094', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('follicular thyroid cancer', 'Disease', (103, 128))	('TC', 'Phenotype', 'HP:0002890', (140, 142))
41192	31750236	The overall survival was significantly better in lithium-aided RAI treated patients, but the analysis was not adjusted by other factors affecting the outcome such as age, number, and location of metastatic foci.	('RAI', 'Chemical', 'MESH:D007455', (63, 66))	('lithium-aided', 'Var', (49, 62))	('patients', 'Species', '9606', (75, 83))	('lithium', 'Chemical', 'MESH:D008094', (49, 56))	('better', 'PosReg', (39, 45))
41218	31750236	TBX1 deficiency may potentially contribute to the low proliferative index of parathyroid tumors.	('TBX1', 'Gene', '6899', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('low', 'NegReg', (50, 53))	('TBX1', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('parathyroid tumors', 'Disease', 'MESH:D010282', (77, 95))	('rat', 'Species', '10116', (61, 64))	('parathyroid tumors', 'Disease', (77, 95))	('proliferative index', 'MPA', (54, 73))	('rat', 'Species', '10116', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
41221	31750236	To summarize, pre-clinical in vitro studies consistently show that lithium induces proliferation and PTH secretion in parathyroid cells (Table 1).	('PTH', 'Gene', '5741', (101, 104))	('proliferation', 'CPA', (83, 96))	('lithium', 'Var', (67, 74))	('lithium', 'Chemical', 'MESH:D008094', (67, 74))	('rat', 'Species', '10116', (120, 123))	('PTH', 'Gene', (101, 104))	('rat', 'Species', '10116', (90, 93))
41291	30112225	We report the case of a 65-year-old man known for hypertension, cholelithiasis, and panic disorder with no personal or family history of pheochromocytoma, paraganglioma, Multiple Endocrine Neoplasia Type 2 syndrome, Von Hippel Lindau syndrome, Neurofibromatosis Type 1, or Succinyl Dehydrogenase mutations.	('Multiple Endocrine Neoplasia Type 2 syndrome', 'Disease', 'MESH:D018813', (170, 214))	('panic disorder', 'Phenotype', 'HP:0025269', (84, 98))	('cholelithiasis', 'Disease', (64, 78))	('hypertension', 'Disease', 'MESH:D006973', (50, 62))	('Von Hippel Lindau syndrome', 'Disease', 'MESH:D006623', (216, 242))	('paraganglioma', 'Disease', (155, 168))	('hypertension', 'Disease', (50, 62))	('paraganglioma', 'Disease', 'MESH:D010235', (155, 168))	('panic disorder', 'Disease', (84, 98))	('pheochromocytoma', 'Disease', 'MESH:D010673', (137, 153))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (179, 198))	('hypertension', 'Phenotype', 'HP:0000822', (50, 62))	('panic disorder', 'Disease', 'MESH:D016584', (84, 98))	('cholelithiasis', 'Phenotype', 'HP:0001081', (64, 78))	('Multiple Endocrine Neoplasia Type 2 syndrome', 'Disease', (170, 214))	('pheochromocytoma', 'Disease', (137, 153))	('paraganglioma', 'Phenotype', 'HP:0002668', (155, 168))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (137, 153))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (244, 261))	('cholelithiasis', 'Disease', 'MESH:D002769', (64, 78))	('Von Hippel Lindau syndrome', 'Disease', (216, 242))	('man', 'Species', '9606', (36, 39))	('person', 'Species', '9606', (107, 113))	('Neurofibromatosis Type 1', 'Gene', '4763', (244, 268))	('Neurofibromatosis Type 1', 'Gene', (244, 268))	('Neoplasia', 'Phenotype', 'HP:0002664', (189, 198))	('mutations', 'Var', (296, 305))
41429	27709415	Although mouse models, rodent pheochromocytoma cell lines and other cell lines have yielded important information, there is no model representing both the genotype and the fully developed phenotypes of actual tumors that are most likely to metastasize or cause local morbidity, particularly tumors that occur in patients with germline mutations of the SDHB gene, which encodes a subunit of succinate dehydrogenase.	('metastasize', 'CPA', (240, 251))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('SDHB', 'Gene', (352, 356))	('cause', 'Reg', (255, 260))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('pheochromocytoma cell lines', 'Disease', 'MESH:D010673', (30, 57))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (30, 46))	('tumors', 'Disease', (291, 297))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('patients', 'Species', '9606', (312, 320))	('actual tumors', 'Disease', (202, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', 'MESH:D009369', (291, 297))	('tumors', 'Disease', (209, 215))	('pheochromocytoma cell lines', 'Disease', (30, 57))	('germline mutations', 'Var', (326, 344))	('mouse', 'Species', '10090', (9, 14))	('actual tumors', 'Disease', 'MESH:D009369', (202, 215))
41445	27709415	For comparison to sections of the intact tumor tissue, sections were stained immunohistochemically with antibodies directed against chromogranin A (CgA) (# LK2H10, Ventana, pre-diluted), S100 (# 4C4.9, Ventana, pre-diluted), Ki 67 (# 30.9, Ventana, pre-diluted), tyrosine hydroxylase (TH) (#22941, Immunostar, 1:4000), and succinate dehydrogenase B (SDHB)(#HP0028668, Sigma).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('chromogranin A', 'Gene', '1113', (132, 146))	('CgA', 'Gene', (148, 151))	('tumor', 'Disease', (41, 46))	('chromogranin A', 'Gene', (132, 146))	('tyrosine hydroxylase', 'Gene', '7054', (263, 283))	('succinate dehydrogenase B', 'Gene', (323, 348))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('CgA', 'Gene', '1113', (148, 151))	('TH', 'Gene', '7054', (285, 287))	('succinate dehydrogenase B', 'Gene', '6390', (323, 348))	('#22941', 'Var', (290, 296))	('SDHB', 'Gene', (350, 354))	('tyrosine hydroxylase', 'Gene', (263, 283))
41488	26170485	Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour.	('VHL', 'Disease', (75, 78))	('patients', 'Species', '9606', (6, 14))	('bladder tumour', 'Disease', (257, 271))	('patient', 'Species', '9606', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (265, 271))	('adrenal tumour', 'Disease', 'MESH:D000310', (175, 189))	('tumour', 'Disease', 'MESH:D009369', (265, 271))	('SDHB', 'Gene', '6390', (219, 223))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('VHL', 'Disease', 'MESH:D006623', (75, 78))	('tumour', 'Disease', (265, 271))	('tumour', 'Disease', (33, 39))	('bladder tumour', 'Phenotype', 'HP:0009725', (257, 271))	('patient', 'Species', '9606', (6, 13))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('SDHB', 'Gene', (219, 223))	('patient', 'Species', '9606', (204, 211))	('mutation', 'Var', (229, 237))	('adrenal tumour', 'Disease', (175, 189))	('tumour', 'Disease', (183, 189))	('bladder tumour', 'Disease', 'MESH:D001749', (257, 271))
41520	26170485	Contralateral adrenal tumour developed in one patient with VHL, in another with presumed sporadic phaeochromocytoma local tumour was present (in this patient a regional lymph node was inaccessible on initial surgery), the third patient with an SDHB mutation developed tumour growth in an adrenal gland, the original site of which was the bladder.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Disease', (22, 28))	('VHL', 'Disease', (59, 62))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('SDHB', 'Gene', '6390', (244, 248))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('mutation', 'Var', (249, 257))	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('tumour', 'Disease', (268, 274))	('patient', 'Species', '9606', (150, 157))	('tumour', 'Disease', (122, 128))	('developed', 'Reg', (258, 267))	('SDHB', 'Gene', (244, 248))	('patient', 'Species', '9606', (228, 235))	('Contralateral adrenal tumour', 'Disease', 'MESH:D000310', (0, 28))	('patient', 'Species', '9606', (46, 53))	('phaeochromocytoma local tumour', 'Disease', (98, 128))	('VHL', 'Disease', 'MESH:D006623', (59, 62))	('phaeochromocytoma local tumour', 'Disease', 'MESH:D009364', (98, 128))	('Contralateral adrenal tumour', 'Disease', (0, 28))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))
41528	26170485	In our own previous series of adrenalectomies (8 of 50 for phaeochromocytoma) and in keeping with other similar studies, laparoscopic adrenalectomy in comparison to open adrenalectomy resulted in a significantly shorter hospital stay and less post-operative morbidity, although operating time was longer.	('shorter', 'NegReg', (212, 219))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (59, 76))	('laparoscopic', 'Var', (121, 133))	('phaeochromocytoma', 'Disease', (59, 76))	('hospital stay', 'MPA', (220, 233))
41530	26170485	In the current study we have demonstrated tumour development in 6% in patients in whom phaeochromocytoma and abdominal parganglioma had been surgically removed, it is arguable that genuine local recurrence in our study occurred in only one patient, in the remaining two patients who had tumour development after initial surgery; one with VHL and the other with an SDHB mutation, could possibly be explained by the increased clinical incidence of bilateral phaeochromocytomas (around 40-60%) in patients with VHL, and that patients with SDHB mutations have an increased risk of the development of multi-focal phaeochromocytomas.	('patient', 'Species', '9606', (494, 501))	('VHL', 'Disease', 'MESH:D006623', (508, 511))	('patient', 'Species', '9606', (240, 247))	('SDHB', 'Gene', '6390', (364, 368))	('phaeochromocytoma', 'Disease', (608, 625))	('mutations', 'Var', (541, 550))	('phaeochromocytoma', 'Disease', (456, 473))	('multi-focal phaeochromocytomas', 'Disease', (596, 626))	('abdominal parganglioma', 'Disease', 'MESH:D015746', (109, 131))	('patients', 'Species', '9606', (522, 530))	('patient', 'Species', '9606', (270, 277))	('bilateral phaeochromocytomas', 'Disease', 'MESH:D006312', (446, 474))	('patients', 'Species', '9606', (70, 78))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('patient', 'Species', '9606', (70, 77))	('patient', 'Species', '9606', (522, 529))	('abdominal parganglioma', 'Disease', (109, 131))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (608, 625))	('VHL', 'Disease', 'MESH:D006623', (338, 341))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (456, 473))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('bilateral phaeochromocytomas', 'Disease', (446, 474))	('SDHB', 'Gene', (364, 368))	('SDHB', 'Gene', '6390', (536, 540))	('tumour', 'Disease', 'MESH:D009369', (287, 293))	('tumour', 'Disease', (287, 293))	('VHL', 'Disease', (508, 511))	('multi-focal phaeochromocytomas', 'Disease', 'MESH:D015140', (596, 626))	('phaeochromocytoma', 'Disease', (87, 104))	('SDHB', 'Gene', (536, 540))	('patients', 'Species', '9606', (270, 278))	('VHL', 'Disease', (338, 341))	('patients', 'Species', '9606', (494, 502))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (87, 104))
41549	24693229	More recently, the development of SST-analogues radiolabeled with 68Ga for positron emission tomography (PET) imaging such as [68Ga-DOTA0-Tyr3]octreotide (68Ga-DOTATOC, 68Ga-edotreotide), [68Ga-DOTA0-1NaI3]octreotide (68Ga-DOTANOC), and [68Ga-DOTA0-Tyr3]octreotate (68Ga-DOTATATE) has brought clear advantages compared to radiolabeled SST-analogues scintigraphy offering a higher spatial resolution and improving pharmacokinetics.	('advantages', 'PosReg', (299, 309))	('68Ga-DOTATATE', 'Chemical', '-', (266, 279))	('[68Ga-DOTA0-Tyr3', 'Var', (126, 142))	('[68Ga-DOTA0-Tyr3]', 'Var', (237, 254))	('improving', 'PosReg', (403, 412))	('pharmacokinetics', 'MPA', (413, 429))	('octreotide', 'Chemical', 'MESH:D015282', (143, 153))	('octreotide', 'Chemical', 'MESH:D015282', (206, 216))	('[68Ga-DOTA0-1NaI3', 'Var', (188, 205))
41551	24693229	In particular, 68Ga-DOTANOC also shows a good affinity for SSTR subtypes 3 and 5, 68Ga-DOTATOC also binds to SSTR5 (although with lower affinity than DOTANOC), while 68Ga-DOTATATE has a predominant affinity for SSTR2.	('SSTR2', 'Gene', '6752', (211, 216))	('binds', 'Interaction', (100, 105))	('68Ga-DOTATOC', 'Var', (82, 94))	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', (109, 114))	('SSTR2', 'Gene', (211, 216))	('68Ga-DOTATATE', 'Chemical', '-', (166, 179))
41563	24693229	All paragangliomas were detected with 68Ga-DOTANOC and were strongly positive.	('detected', 'Reg', (24, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (4, 17))	('paragangliomas', 'Disease', 'MESH:D010235', (4, 18))	('paragangliomas', 'Disease', (4, 18))	('paragangliomas', 'Phenotype', 'HP:0002668', (4, 18))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('68Ga-DOTANOC', 'Var', (38, 50))	('gliomas', 'Phenotype', 'HP:0009733', (11, 18))
41567	24693229	reported a higher sensitivity for lesion detection of 68Ga-DOTATOC PET/CT in metastatic phaeochromocytoma patients (n = 6) compared to 123I-MIBG scan (92% and 63%, resp.).	('phaeochromocytoma', 'Disease', 'MESH:D010673', (88, 105))	('68Ga-DOTATOC PET/CT', 'Var', (54, 73))	('phaeochromocytoma', 'Disease', (88, 105))	('patients', 'Species', '9606', (106, 114))	('123I-MIBG', 'Chemical', 'MESH:D019797', (135, 144))
41626	24693229	Additionally, in a subgroup of patients with multiple meningiomas, 68Ga-DOTATOC PET/CT was able to identify more lesions compared to CT or MRI (19 versus 10, resp.).	('meningiomas', 'Phenotype', 'HP:0002858', (54, 65))	('meningioma', 'Phenotype', 'HP:0002858', (54, 64))	('68Ga-DOTATOC', 'Var', (67, 79))	('multiple meningiomas', 'Disease', 'MESH:D008577', (45, 65))	('multiple meningiomas', 'Disease', (45, 65))	('patients', 'Species', '9606', (31, 39))
41638	24693229	Although the overall detection rate for both procedures was comparable (positive results in 72% and 77% of the cases for 68Ga-DOTATATE and [18F]FDG, resp.	('68Ga-DOTATATE', 'Var', (121, 134))	('68Ga-DOTATATE', 'Chemical', '-', (121, 134))	('[18F]FDG', 'Var', (139, 147))
41640	24693229	retrospectively compared PET/CT with 68Ga-DOTATATE, [18F]FDG, and [18F]DOPA in 18 patients with residual/recurrent MTC suspected on the basis of elevated serum calcitonin levels.	('68Ga-DOTATATE', 'Chemical', '-', (37, 50))	('elevated', 'PosReg', (145, 153))	('[18F]', 'Var', (66, 71))	('serum calcitonin levels', 'MPA', (154, 177))	('patients', 'Species', '9606', (82, 90))	('DOPA', 'Chemical', 'MESH:D004295', (71, 75))	('elevated serum calcitonin', 'Phenotype', 'HP:0003528', (145, 170))	('MTC', 'Phenotype', 'HP:0002865', (115, 118))	('[18F]FDG', 'Var', (52, 60))
41641	24693229	Results showed statistically different sensitivity values between [18F]DOPA and [18F]FDG-PET/CT (72% and 17%, resp.)	('[18F]', 'Var', (80, 85))	('[18F]', 'Var', (66, 71))	('DOPA', 'Chemical', 'MESH:D004295', (71, 75))
41662	24693229	We reported a series of 39 patients with metastatic thymic malignancies evaluated by 68Ga-SST-analogues PET/CT and [18F]FDG-PET/CT.	('[18F]FDG-PET/CT', 'Var', (115, 130))	('patients', 'Species', '9606', (27, 35))	('thymic malignancies', 'Disease', (52, 71))	('thymic malignancies', 'Disease', 'MESH:D013953', (52, 71))
41680	24693229	68Ga-DOTATOC PET/CT was positive in 61% of the investigated patients; however, on a lesion-by-lesion basis, only 22% of [18F]FDG-positive metastases were seen with 68Ga-DOTATOC PET/CT.	('68Ga-DOTATOC PET/CT', 'Var', (164, 183))	('patients', 'Species', '9606', (60, 68))	('metastases', 'Disease', (138, 148))	('metastases', 'Disease', 'MESH:D009362', (138, 148))
41684	24693229	On a side-by-side analysis only 30% of bone scintigraphy-positive metastases were seen with 68Ga-DOTATOC PET/CT.	('metastases', 'Disease', (66, 76))	('68Ga-DOTATOC PET/CT', 'Var', (92, 111))	('metastases', 'Disease', 'MESH:D009362', (66, 76))
41710	22347965	Clinicoradiological manifestations of paraganglioma syndromes associated with succinyl dehydrogenase enzyme mutation Paragangliomas are rare tumours derived from the autonomic nervous system that have increasingly been recognised to have a genetic predisposition.	('tumours', 'Disease', (141, 148))	('paraganglioma syndromes', 'Disease', (38, 61))	('associated', 'Reg', (62, 72))	('Paragangliomas', 'Disease', (117, 131))	('paraganglioma', 'Phenotype', 'HP:0002668', (38, 51))	('Paragangliomas', 'Phenotype', 'HP:0002668', (117, 131))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('Paragangliomas', 'Disease', 'MESH:D010235', (117, 131))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('mutation', 'Var', (108, 116))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (38, 61))
41711	22347965	Mutations of the enzyme succinyl dehydrogenase (SDH) have proven to result in paraganglioma formation.	('SDH', 'Gene', '6390', (48, 51))	('paraganglioma', 'Disease', (78, 91))	('SDH', 'Gene', (48, 51))	('result in', 'Reg', (68, 77))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Disease', 'MESH:D010235', (78, 91))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))
41712	22347965	SDHB and SDHD mutations are more common, whereas SDHA and SDHC mutations are rare.	('SDHD', 'Disease', 'None', (9, 13))	('SDHA', 'Gene', (49, 53))	('common', 'Reg', (33, 39))	('SDHC', 'Gene', (58, 62))	('SDHD', 'Disease', (9, 13))	('SDHC', 'Gene', '6391', (58, 62))	('SDHB', 'Gene', '6390', (0, 4))	('mutations', 'Var', (14, 23))	('SDHB', 'Gene', (0, 4))	('SDHA', 'Gene', '6389', (49, 53))
41713	22347965	Patients with SDHB mutations are prone to extra-adrenal pheochromocytomas, malignant disease and extra-paraganglial neoplasia, whereas SDHD mutations have a greater propensity for multiple, benign head and neck paragangliomas.	('neck paragangliomas', 'Disease', 'MESH:D010235', (206, 225))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('SDHB', 'Gene', '6390', (14, 18))	('extra-paraganglial neoplasia', 'Disease', 'MESH:D009369', (97, 125))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (206, 225))	('malignant disease', 'Disease', 'MESH:D009369', (75, 92))	('extra-adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (42, 73))	('malignant disease', 'Disease', (75, 92))	('SDHD', 'Disease', (135, 139))	('Patients', 'Species', '9606', (0, 8))	('paraganglioma', 'Phenotype', 'HP:0002668', (211, 224))	('SDHB', 'Gene', (14, 18))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (56, 73))	('neck paragangliomas', 'Disease', (206, 225))	('prone', 'Reg', (33, 38))	('extra-paraganglial neoplasia', 'Disease', (97, 125))	('paragangliomas', 'Phenotype', 'HP:0002668', (211, 225))	('extra-adrenal pheochromocytomas', 'Phenotype', 'HP:0006737', (42, 73))	('SDHD', 'Disease', 'None', (135, 139))	('mutations', 'Var', (19, 28))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (48, 73))	('extra-adrenal pheochromocytomas', 'Disease', (42, 73))	('neoplasia', 'Phenotype', 'HP:0002664', (116, 125))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (197, 225))
41714	22347965	Diagnosis of a sporadic paraganglioma or pheochromocytoma should lead to a full genetic workup of the patient and family if SDH mutations are found.	('mutations', 'Var', (128, 137))	('patient', 'Species', '9606', (102, 109))	('SDH', 'Gene', '6390', (124, 127))	('paraganglioma', 'Phenotype', 'HP:0002668', (24, 37))	('paraganglioma or pheochromocytoma', 'Disease', 'MESH:D010673', (24, 57))	('sporadic paraganglioma', 'Disease', 'MESH:D010235', (15, 37))	('SDH', 'Gene', (124, 127))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (41, 57))	('sporadic paraganglioma', 'Disease', (15, 37))	('paraganglioma or pheochromocytoma', 'Disease', (24, 57))
41715	22347965	We present our imaging experience with a series of patients with proven SDH mutations resulting in paragangliomas with a review of the literature.	('paragangliomas', 'Disease', (99, 113))	('paragangliomas', 'Disease', 'MESH:D010235', (99, 113))	('paragangliomas', 'Phenotype', 'HP:0002668', (99, 113))	('mutations', 'Var', (76, 85))	('paraganglioma', 'Phenotype', 'HP:0002668', (99, 112))	('SDH', 'Gene', '6390', (72, 75))	('resulting in', 'Reg', (86, 98))	('SDH', 'Gene', (72, 75))	('patients', 'Species', '9606', (51, 59))
41719	22347965	One recently recognised genetic predisposition relates to mutations of the enzyme succinyl dehydrogenase (SDH).	('mutations', 'Var', (58, 67))	('SDH', 'Gene', (106, 109))	('SDH', 'Gene', '6390', (106, 109))
41721	22347965	Recently discovered mutations of the SDH enzyme have proven to result directly in paraganglioma formation, and tumours previously thought to be sporadic may, therefore, be hereditary.	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('SDH', 'Gene', (37, 40))	('tumours', 'Disease', (111, 118))	('paraganglioma', 'Disease', (82, 95))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('SDH', 'Gene', '6390', (37, 40))	('paraganglioma', 'Disease', 'MESH:D010235', (82, 95))	('result', 'Reg', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('mutations', 'Var', (20, 29))	('tumours', 'Disease', 'MESH:D009369', (111, 118))
41725	22347965	This functional division relates to the various SDH subunit mutation clinical presentations.	('SDH', 'Gene', (48, 51))	('mutation', 'Var', (60, 68))	('SDH', 'Gene', '6390', (48, 51))
41732	22347965	The exact pathogenetic mechanism whereby the subunit mutations result in paraganglioma formation is not known.	('paraganglioma', 'Disease', 'MESH:D010235', (73, 86))	('mutations', 'Var', (53, 62))	('paraganglioma', 'Phenotype', 'HP:0002668', (73, 86))	('result in', 'Reg', (63, 72))	('paraganglioma', 'Disease', (73, 86))
41739	22347965	Subsequent studies confirmed that SDHB and SDHC mutations also resulted in familial paragangliomas.	('familial paragangliomas', 'Disease', 'MESH:D010235', (75, 98))	('SDHC', 'Gene', '6391', (43, 47))	('familial paragangliomas', 'Disease', (75, 98))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', (34, 38))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('paragangliomas', 'Phenotype', 'HP:0002668', (84, 98))	('resulted in', 'Reg', (63, 74))	('mutations', 'Var', (48, 57))	('SDHC', 'Gene', (43, 47))
41740	22347965	SDHA mutation, however, has at present only been associated with metabolic neurodegenerative disorders.	('SDHA', 'Gene', (0, 4))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (75, 101))	('associated', 'Reg', (49, 59))	('SDHA', 'Gene', '6389', (0, 4))	('metabolic neurodegenerative disorders', 'Disease', (65, 102))	('metabolic neurodegenerative disorders', 'Disease', 'MESH:D019636', (65, 102))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (75, 102))	('mutation', 'Var', (5, 13))
41741	22347965	The incidence of underlying SDH mutations in patients with apparently sporadic parasympathetic paragangliomas of the head and neck has been reported as high as 28% (7% due to SDHB, 4% SDHC and 17% SDHD).	('SDHD', 'Disease', 'None', (197, 201))	('SDH', 'Gene', (28, 31))	('SDH', 'Gene', '6390', (184, 187))	('patients', 'Species', '9606', (45, 53))	('SDHB', 'Gene', (175, 179))	('SDHC', 'Gene', '6391', (184, 188))	('SDH', 'Gene', '6390', (175, 178))	('paragangliomas', 'Disease', 'MESH:D010235', (95, 109))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('SDH', 'Gene', '6390', (197, 200))	('mutations', 'Var', (32, 41))	('SDH', 'Gene', (184, 187))	('paragangliomas of the head and neck', 'Phenotype', 'HP:0002864', (95, 130))	('SDH', 'Gene', (175, 178))	('SDHC', 'Gene', (184, 188))	('SDHD', 'Disease', (197, 201))	('SDH', 'Gene', (197, 200))	('paragangliomas', 'Disease', (95, 109))	('SDH', 'Gene', '6390', (28, 31))	('SDHB', 'Gene', '6390', (175, 179))
41743	22347965	SDH mutations follow an autosomal dominant inheritance pattern.	('mutations', 'Var', (4, 13))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', '6390', (0, 3))
41744	22347965	SDHD mutations are also subject to genomic imprinting of the maternal allele.	('mutations', 'Var', (5, 14))	('SDHD', 'Disease', 'None', (0, 4))	('SDHD', 'Disease', (0, 4))
41754	22347965	The precise incidence rate of SDH mutations is unknown.	('SDH', 'Gene', (30, 33))	('mutations', 'Var', (34, 43))	('SDH', 'Gene', '6390', (30, 33))
41755	22347965	SDHB and SDHD mutations have similar prevalence and are more common compared to SDHC, which is rare.	('SDHD', 'Disease', 'None', (9, 13))	('SDHD', 'Disease', (9, 13))	('SDHC', 'Gene', (80, 84))	('common', 'Reg', (61, 67))	('SDHB', 'Gene', '6390', (0, 4))	('SDHC', 'Gene', '6391', (80, 84))	('mutations', 'Var', (14, 23))	('SDHB', 'Gene', (0, 4))
41756	22347965	SDHB mutation more commonly results in the formation of paragangliomas associated with the sympathetic system.	('paragangliomas', 'Disease', (56, 70))	('paragangliomas', 'Disease', 'MESH:D010235', (56, 70))	('paragangliomas', 'Phenotype', 'HP:0002668', (56, 70))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('SDHB', 'Gene', '6390', (0, 4))	('results in', 'Reg', (28, 38))	('SDHB', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
41759	22347965	There is an increased risk of malignant paragangliomas and metastatic disease with SDHB mutation (Fig.	('paraganglioma', 'Phenotype', 'HP:0002668', (40, 53))	('paragangliomas', 'Phenotype', 'HP:0002668', (40, 54))	('mutation', 'Var', (88, 96))	('SDHB', 'Gene', (83, 87))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (30, 54))	('malignant paragangliomas', 'Disease', (30, 54))	('metastatic disease', 'Disease', (59, 77))	('SDHB', 'Gene', '6390', (83, 87))
41763	22347965	SDHD mutations are associated with parasympathetic extra-adrenal paragangliomas.	('associated', 'Reg', (19, 29))	('parasympathetic extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (35, 79))	('paragangliomas', 'Phenotype', 'HP:0002668', (65, 79))	('mutations', 'Var', (5, 14))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHD', 'Disease', 'None', (0, 4))	('parasympathetic extra-adrenal paragangliomas', 'Disease', (35, 79))	('SDHD', 'Disease', (0, 4))
41766	22347965	As with SDHB mutations, pheochromocytomas are less common.	('SDHB', 'Gene', '6390', (8, 12))	('pheochromocytomas', 'Disease', 'MESH:D010673', (24, 41))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (24, 41))	('pheochromocytomas', 'Disease', (24, 41))	('SDHB', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (24, 40))
41769	22347965	SDHB mutuations can result in head and neck paraganglioma formation, and SDHD mutations can develop thoracic and abdominal extra-adrenal paragangliomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (44, 57))	('abdominal extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (113, 151))	('mutuations', 'Var', (5, 15))	('paraganglioma', 'Disease', (137, 150))	('SDHD', 'Disease', (73, 77))	('paragangliomas', 'Phenotype', 'HP:0002668', (137, 151))	('paraganglioma', 'Disease', (44, 57))	('mutations', 'Var', (78, 87))	('abdominal extra-adrenal paragangliomas', 'Disease', (113, 151))	('paraganglioma', 'Disease', 'MESH:D010235', (137, 150))	('SDHB', 'Gene', '6390', (0, 4))	('SDHD', 'Disease', 'None', (73, 77))	('result in', 'Reg', (20, 29))	('paraganglioma', 'Disease', 'MESH:D010235', (44, 57))	('develop', 'PosReg', (92, 99))	('SDHB', 'Gene', (0, 4))	('paraganglioma', 'Phenotype', 'HP:0002668', (137, 150))
41770	22347965	Both mutations can result in pheochromocytoma formation.	('pheochromocytoma', 'Disease', (29, 45))	('result in', 'Reg', (19, 28))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (29, 45))	('mutations', 'Var', (5, 14))	('pheochromocytoma', 'Disease', 'MESH:D010673', (29, 45))
41772	22347965	SDHA mutations have been described in Leigh syndrome, a metabolic neurodegenerative disorder, and are not currently recognised to result in paraganglioma formation.	('described', 'Reg', (25, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('SDHA', 'Gene', (0, 4))	('Leigh syndrome', 'Disease', 'MESH:D007888', (38, 52))	('metabolic neurodegenerative disorder', 'Disease', (56, 92))	('paraganglioma', 'Disease', (140, 153))	('mutations', 'Var', (5, 14))	('metabolic neurodegenerative disorder', 'Disease', 'MESH:D019636', (56, 92))	('SDHA', 'Gene', '6389', (0, 4))	('paraganglioma', 'Disease', 'MESH:D010235', (140, 153))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (66, 92))	('Leigh syndrome', 'Disease', (38, 52))
41773	22347965	SDHC mutations are rare and result in head and neck paraganglioma formation.	('paraganglioma', 'Disease', 'MESH:D010235', (52, 65))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('result in', 'Reg', (28, 37))	('paraganglioma', 'Disease', (52, 65))
41775	22347965	Very rarely do SDHC mutations result in pheochromocytoma formation.	('pheochromocytoma', 'Disease', (40, 56))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (40, 56))	('pheochromocytoma', 'Disease', 'MESH:D010673', (40, 56))	('result in', 'Reg', (30, 39))	('SDHC', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('SDHC', 'Gene', '6391', (15, 19))
41776	22347965	The recent advances in genetics with regards to SDH mutations have implications for radiology.	('mutations', 'Var', (52, 61))	('SDH', 'Gene', (48, 51))	('SDH', 'Gene', '6390', (48, 51))
41779	22347965	SDH mutation-positive patients need ongoing screening as they are at high risk for developing paragangliomas, pheochromocytomas and further multifocal extraganglial tumours.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (110, 127))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('SDH', 'Gene', (0, 3))	('patients', 'Species', '9606', (22, 30))	('mutation-positive', 'Var', (4, 21))	('paragangliomas', 'Disease', (94, 108))	('paragangliomas', 'Disease', 'MESH:D010235', (94, 108))	('paragangliomas', 'Phenotype', 'HP:0002668', (94, 108))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('SDH', 'Gene', '6390', (0, 3))	('pheochromocytomas', 'Disease', 'MESH:D010673', (110, 127))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('pheochromocytomas', 'Disease', (110, 127))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (110, 126))	('tumours', 'Disease', (165, 172))
41782	22347965	In cases of SDHB mutation screening as early as 10 years of age is recommended.	('SDHB', 'Gene', '6390', (12, 16))	('SDHB', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))
41784	22347965	SDHB and SDHD mutations result in paraganglioma formation.	('SDHD', 'Disease', 'None', (9, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('paraganglioma', 'Disease', (34, 47))	('result in', 'Reg', (24, 33))	('SDHD', 'Disease', (9, 13))	('SDHB', 'Gene', '6390', (0, 4))	('paraganglioma', 'Disease', 'MESH:D010235', (34, 47))	('mutations', 'Var', (14, 23))	('SDHB', 'Gene', (0, 4))
41785	22347965	Whereas SDHB patients are prone to extra-adrenal pheochromocytomas, malignant disease and extra-paraganglial neoplasia, SDHD mutations have a greater propensity for multiple, benign head and neck paragangliomas.	('malignant disease', 'Disease', 'MESH:D009369', (68, 85))	('extra-adrenal pheochromocytomas', 'Disease', (35, 66))	('SDHB', 'Gene', '6390', (8, 12))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (191, 210))	('malignant disease', 'Disease', (68, 85))	('patients', 'Species', '9606', (13, 21))	('SDHD', 'Disease', (120, 124))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (49, 66))	('SDHB', 'Gene', (8, 12))	('extra-paraganglial neoplasia', 'Disease', (90, 118))	('extra-adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (35, 66))	('neck paragangliomas', 'Disease', (191, 210))	('mutations', 'Var', (125, 134))	('paragangliomas', 'Phenotype', 'HP:0002668', (196, 210))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('SDHD', 'Disease', 'None', (120, 124))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (41, 66))	('prone', 'Reg', (26, 31))	('multiple', 'Disease', (165, 173))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (49, 65))	('extra-adrenal pheochromocytomas', 'Phenotype', 'HP:0006737', (35, 66))	('extra-paraganglial neoplasia', 'Disease', 'MESH:D009369', (90, 118))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (182, 210))	('neck paragangliomas', 'Disease', 'MESH:D010235', (191, 210))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))
41843	16990424	Regular control solutions were Bio-Rad Urine Standard and Lyphocheck Urine controls (catalogue numbers C-390-10 and C-395-10).	('Rad', 'Gene', (35, 38))	('C-395-10', 'Var', (116, 124))	('Rad', 'Gene', '6236', (35, 38))
41845	16990424	For all specimens in which either normetanephrine, metanephrine or 3-methoxytyramine were above the age- and sex- specific references ranges, and where the patient was seen at the John Radcliffe or a general practice within the referral area, a review of all biochemistry, hematology, immunology and online radiology results was carried out (including an assessment of clinical information provided at the time of the request).	('Rad', 'Gene', (185, 188))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (67, 84))	('metanephrine', 'Chemical', 'MESH:D008676', (51, 63))	('normetanephrine', 'Chemical', 'MESH:D009647', (34, 49))	('metanephrine', 'Chemical', 'MESH:D008676', (37, 49))	('normetanephrine', 'Var', (34, 49))	('Rad', 'Gene', '6236', (185, 188))	('patient', 'Species', '9606', (156, 163))
41910	33884914	The resulting metabolites directly damage cardiomyocytes and cause changes in cardiac structure and function; this phenomenon is known as catecholamine cardiomyopathy.	('damage cardiomyocytes', 'Disease', 'MESH:D009422', (35, 56))	('changes', 'Reg', (67, 74))	('cardiomyopathy', 'Disease', 'MESH:D009202', (152, 166))	('function', 'MPA', (100, 108))	('catecholamine', 'Chemical', 'MESH:D002395', (138, 151))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (152, 166))	('damage cardiomyocytes', 'Disease', (35, 56))	('cardiac structure', 'MPA', (78, 95))	('metabolites', 'Var', (14, 25))	('cardiomyopathy', 'Disease', (152, 166))
41939	33884914	Moreover, echocardiography revealed a lesion occupying the left ventricle, with no blood perfusion, combined with decreased left ventricular systolic and diastolic function (ejection fraction [EF]: 49%; early to late diastolic transmitral flow velocity [E/A]: 2.4).	('decreased left ventricular systolic', 'Disease', (114, 149))	('decreased left ventricular systolic', 'Disease', 'MESH:D002303', (114, 149))	('lesion', 'Var', (38, 44))
42018	32554825	Well-differentiated grade 3 GI NENs with a Ki-67 <55% should be treated as for grade 1 and 2 GI NENs unless there is evidence of rapid tumour growth, in which case they should be treated as for poorly differentiated NECs.	('NENs', 'Phenotype', 'HP:0100634', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('NENs', 'Phenotype', 'HP:0100634', (31, 35))	('Ki-67', 'Var', (43, 48))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))
42046	32554825	Hydroxychloroquine as a treatment for Covid-19 can cause hypoglycaemia, which should be differentiated from hyperinsulinaemic hypoglycemia.	('hypoglycaemia', 'Phenotype', 'HP:0001943', (57, 70))	('hyperinsulinaemic hypoglycemia', 'Disease', 'MESH:D007003', (108, 138))	('Hydroxychloroquine', 'Var', (0, 18))	('Hydroxychloroquine', 'Chemical', 'MESH:D006886', (0, 18))	('Covid-19', 'Disease', (38, 46))	('hypoglycemia', 'Phenotype', 'HP:0001943', (126, 138))	('hyperinsulinaemic hypoglycemia', 'Disease', (108, 138))	('cause', 'Reg', (51, 56))	('hypoglycaemia', 'Disease', 'None', (57, 70))	('hyperinsulinaemic hypoglycemia', 'Phenotype', 'HP:0000825', (108, 138))	('Covid-19', 'Disease', 'MESH:C000657245', (38, 46))	('hypoglycaemia', 'Disease', (57, 70))
42090	32554825	Patients may develop treatment-related fevers, leucopenia and lymphopenia post-PRRT and 131I-MIBG therapy.	('develop', 'PosReg', (13, 20))	('lymphopenia', 'Disease', 'MESH:D008231', (62, 73))	('lymphopenia', 'Phenotype', 'HP:0001888', (62, 73))	('131I-MIBG', 'Var', (88, 97))	('fevers', 'Phenotype', 'HP:0001945', (39, 45))	('leucopenia', 'Disease', (47, 57))	('Patients', 'Species', '9606', (0, 8))	('lymphopenia', 'Disease', (62, 73))	('treatment-related fevers', 'Disease', (21, 45))	('leucopenia', 'Disease', 'MESH:C536227', (47, 57))	('131I-MIBG', 'Chemical', 'MESH:D019797', (88, 97))
42114	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
42118	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('expression', 'MPA', (134, 144))	('levels', 'MPA', (118, 124))	('protein degradation', 'MPA', (65, 84))	('contribute', 'Reg', (91, 101))	('elevated', 'PosReg', (109, 117))	('AURKA', 'Gene', '6790', (128, 133))	('activation', 'PosReg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))
42120	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
42121	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (129, 134))	('AURKA', 'Gene', '6790', (12, 17))	('AKIs suppresses cancer', 'Disease', (138, 160))	('AURKA', 'Gene', (129, 134))	('AURKA', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
42140	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('overexpression', 'PosReg', (34, 48))	('AURKA', 'Gene', '6790', (75, 80))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
42141	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('AURKA', 'Gene', '6790', (30, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('gene amplification', 'Var', (67, 85))	('AURKA', 'Gene', (30, 35))
42168	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (86, 91))	('AURKA', 'Gene', '6790', (111, 116))	('stabilize', 'PosReg', (101, 110))	('cdh', 'Protein', (164, 167))	('autophosphorylation', 'MPA', (44, 63))	('PUM2', 'Gene', (20, 24))	('AURKA', 'Gene', (86, 91))	('AURKA', 'Gene', (111, 116))	('stimulate', 'PosReg', (34, 43))	('autoactivation', 'MPA', (68, 82))	('expression', 'MPA', (125, 135))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
42171	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
42179	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (25, 30))	('AURKA', 'Gene', '6790', (142, 147))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', '6790', (50, 55))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))
42187	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('AURKA', 'Gene', (124, 129))	('AURKA', 'Gene', (19, 24))	('mitotic progression', 'CPA', (176, 195))	('IKK2', 'Gene', '3551', (28, 32))	('bipolar spindle assembly', 'CPA', (147, 171))
42193	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
42204	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
42211	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
42213	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('TPX2', 'Gene', '22974', (20, 24))
42223	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Chemical', '-', (66, 72))	('Thr148', 'Var', (66, 72))	('promotion', 'PosReg', (111, 120))	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('Ser184', 'Var', (77, 83))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('Ser184', 'Chemical', '-', (77, 83))	('AURKA', 'Gene', '6790', (24, 29))	('facilitates', 'PosReg', (84, 95))	('pancreatic cancer', 'Disease', (151, 168))
42232	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('glycolysis', 'MPA', (114, 124))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Phosphorylation', 'MPA', (0, 15))	('Ser162', 'Var', (36, 42))	('Ser162', 'Chemical', '-', (36, 42))	('LDHB', 'Gene', (19, 23))	('tumor', 'Disease', (156, 161))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('LDHB', 'Gene', '3945', (19, 23))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))
42233	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('AURKA', 'Gene', (105, 110))
42236	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('enhanced', 'PosReg', (56, 64))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
42240	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('AURKA', 'Gene', (0, 5))	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('Ser283', 'Var', (120, 126))	('regulates', 'Reg', (6, 15))	('LIMK2', 'Gene', (16, 21))	('Thr494', 'Var', (128, 134))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('Ser283', 'Chemical', '-', (120, 126))	('AURKA', 'Gene', '6790', (0, 5))	('Thr505', 'Chemical', '-', (139, 145))	('subcellular localization', 'MPA', (39, 63))
42241	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('anchorage-independent growth', 'CPA', (111, 139))	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('RalA', 'Gene', '5898', (68, 72))	('enhances', 'PosReg', (83, 91))	('AURKA', 'Gene', '6790', (42, 47))	('cell migration', 'CPA', (92, 106))	('RalA', 'Gene', '5898', (17, 21))	('phosphorylation', 'Var', (49, 64))
42242	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('enhancing', 'PosReg', (134, 143))	('Thr267', 'Chemical', '-', (71, 77))	('Thr493', 'Var', (90, 96))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (107, 114))	('protein stability', 'MPA', (115, 132))	('ALDH1A1', 'Gene', '216', (107, 114))	('Thr493', 'Chemical', '-', (90, 96))	('regulates', 'Reg', (97, 106))	('ALDH1A1', 'Gene', (0, 7))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))
42245	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', '6790', (43, 48))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
42247	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
42250	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (80, 87))	('RASSF1A', 'Gene', '11186', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('RASSF1A', 'Gene', (80, 87))	('arrest', 'Disease', (148, 154))	('AURKA', 'Gene', (30, 35))	('Ser203', 'Chemical', '-', (39, 45))	('induce', 'Reg', (122, 128))	('Thr202', 'Chemical', '-', (50, 56))	('ability', 'MPA', (69, 76))	('RASSF1A', 'Gene', (19, 26))	('AURKA', 'Gene', '6790', (30, 35))	('microtubules', 'Protein', (105, 117))
42254	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'Var', (0, 15))	('facilitating', 'PosReg', (129, 141))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('NSCLC', 'Disease', (170, 175))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))
42261	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('Ser365', 'Var', (39, 45))	('transcriptional activity', 'MPA', (76, 100))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('AURKA', 'Gene', (30, 35))
42264	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))
42266	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('AURKA', 'Gene', '6790', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('KCTD12', 'Gene', (83, 89))	('cancer', 'Disease', (55, 61))
42276	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('AURKA', 'Gene', (65, 70))	('BPR1K0609S1', 'Var', (161, 172))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
42278	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('toxicity', 'Disease', (25, 33))	('somnolence', 'Disease', (102, 112))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('neutropenia', 'Disease', (89, 100))	('MLN8237', 'Var', (62, 69))
42279	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
42280	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
42281	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('cell proliferation', 'CPA', (34, 52))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('senescence', 'CPA', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MLN8237', 'Var', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('accelerating', 'PosReg', (121, 133))	('inducing', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'CPA', (106, 115))	('arrest', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
42282	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('EMT process', 'CPA', (4, 15))	('MLN8237 treatment', 'Var', (35, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))
42283	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
42284	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
42285	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
42286	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
42287	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
42291	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
42292	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
42293	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
42294	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('N-myc', 'Gene', (86, 91))	('benefit', 'PosReg', (132, 139))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
42295	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
42296	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
42297	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
42298	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
42299	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
42300	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
42302	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
42304	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('affecting', 'Reg', (56, 65))	('NF-kB pathway', 'Pathway', (70, 83))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
42305	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('decreases', 'NegReg', (13, 22))	('tumor', 'Disease', (68, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('leiomyosarcoma', 'Disease', (97, 111))
42308	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'CPA', (104, 119))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
42309	33451333	AT9283 exhibits strong activity against several kinases.	('kinases', 'Pathway', (48, 55))	('AT9283', 'Var', (0, 6))	('activity', 'MPA', (23, 31))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
42310	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('tumor', 'Disease', (60, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))	('BCR-ABL', 'Gene', (138, 145))
42313	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
42316	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('MK-0457', 'Var', (0, 7))	('apoptosis', 'CPA', (106, 115))	('cell cycle progression', 'CPA', (71, 93))	('accumulation', 'PosReg', (16, 28))
42318	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
42320	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', (57, 64))	('BCR-ABL', 'Gene', '25', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
42321	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
42322	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('suppresses', 'NegReg', (71, 81))	('apoptosis', 'CPA', (43, 52))	('PHA-739358', 'Var', (0, 10))	('arrest', 'Disease', (35, 41))	('EMT process', 'CPA', (86, 97))	('induces', 'Reg', (16, 23))	('autophagy', 'CPA', (57, 66))
42323	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
42324	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
42325	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
42326	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Var', (30, 38))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
42334	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
42337	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
42341	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('Myc', 'Gene', '17869', (14, 17))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
42344	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('metastases', 'Disease', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Akt', 'Gene', '207', (183, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('increase', 'PosReg', (68, 76))	('LC3B', 'Gene', '81631', (165, 169))	('MLN8237', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))
42345	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
42348	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
42349	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('MLN8054', 'Var', (25, 32))
42350	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
42355	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('lymphoma', 'Disease', (78, 86))	('hTERT', 'Gene', (126, 131))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('reductions', 'NegReg', (105, 115))	('microRNA levels', 'MPA', (137, 152))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
42359	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', '1956', (0, 4))
42363	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
42364	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
42367	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('senescence', 'CPA', (127, 137))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))
42368	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('mitochondrial apoptosis', 'CPA', (178, 201))	('AML', 'Disease', (205, 208))	('p53', 'Gene', (160, 163))	('activated', 'PosReg', (68, 77))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
42371	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('p53', 'Gene', (188, 191))	('increases', 'PosReg', (38, 47))	('PHLDA1', 'Gene', (177, 183))	('reduction', 'NegReg', (128, 137))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))
42372	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
42373	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('tumor', 'Disease', (88, 93))
42391	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
42400	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
42404	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('increased', 'PosReg', (92, 101))	('p53', 'Gene', (75, 78))	('mutation', 'Var', (79, 87))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
42530	31307198	The functions of MYC-associated factor X (MAX) and prolyl hydroxylase 2 (PHD2) mutations in the contribution to the pathogenesis of paragangliomas still remain unclear.	('MYC-associated factor X', 'Gene', '4149', (17, 40))	('MYC-associated factor X', 'Gene', (17, 40))	('prolyl', 'Chemical', 'MESH:C065612', (51, 57))	('MAX', 'Gene', '4149', (42, 45))	('MAX', 'Gene', (42, 45))	('paragangliomas', 'Disease', (132, 146))	('paragangliomas', 'Disease', 'MESH:D010235', (132, 146))	('paragangliomas', 'Phenotype', 'HP:0002668', (132, 146))	('PHD2', 'Gene', (73, 77))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('PHD2', 'Gene', '54583', (73, 77))	('mutations', 'Var', (79, 88))
42549	31307198	Until recently, only 10% of PPCs were associated with hereditary syndromes namely von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis type 1, resulting from a germline mutation in the tumor suppressor gene Von Hippel Lindau (VHL), proto-oncogene RET, and tumor suppressor gene Neurofibromatosis 1 (NF1) respectively.	('hereditary syndromes', 'Disease', 'MESH:D061325', (54, 74))	('multiple endocrine neoplasia type 2', 'Disease', (109, 144))	('germline mutation', 'Var', (193, 210))	('NF1', 'Gene', '4763', (332, 335))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (150, 167))	('Von Hippel Lindau', 'Disease', 'MESH:D006623', (240, 257))	('tumor', 'Disease', (218, 223))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (82, 107))	('neurofibromatosis type 1', 'Gene', '4763', (150, 174))	('RET', 'Gene', (280, 283))	('Neurofibromatosis 1', 'Gene', (311, 330))	('VHL', 'Gene', (259, 262))	('associated', 'Reg', (38, 48))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (311, 328))	('PPCs', 'Disease', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (289, 294))	('NF1', 'Gene', (332, 335))	('von Hippel-Lindau disease', 'Disease', (82, 107))	('PPCs', 'Disease', 'MESH:D010673', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (109, 144))	('Neurofibromatosis 1', 'Gene', '4763', (311, 330))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('VHL', 'Gene', '7428', (259, 262))	('neoplasia', 'Phenotype', 'HP:0002664', (128, 137))	('hereditary syndromes', 'Disease', (54, 74))	('neurofibromatosis type 1', 'Gene', (150, 174))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('Von Hippel Lindau', 'Disease', (240, 257))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (118, 137))	('RET', 'Gene', '5979', (280, 283))
42551	31307198	Since the beginning of the 21st century, it has become apparent that about 35% of sporadic PPCs are due to a germline mutation in one of susceptible genes.	('due to', 'Reg', (100, 106))	('PPCs', 'Disease', (91, 95))	('germline mutation', 'Var', (109, 126))	('PPCs', 'Disease', 'MESH:D010673', (91, 95))
42557	31307198	In C1A, DNA and histone hypermethylation is observed in SDHx, fumarate hydratase (FH) and malate dehydrogenase 2 (MDH2) gene linked tumors.	('linked tumors', 'Disease', (125, 138))	('linked tumors', 'Disease', 'MESH:D009369', (125, 138))	('malate dehydrogenase 2', 'Gene', (90, 112))	('MDH2', 'Gene', (114, 118))	('malate dehydrogenase 2', 'Gene', '4191', (90, 112))	('SDH', 'Gene', '6390', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('histone hypermethylation', 'Var', (16, 40))	('fumarate hydratase', 'Gene', '2271', (62, 80))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('fumarate hydratase', 'Gene', (62, 80))	('MDH2', 'Gene', '4191', (114, 118))	('SDH', 'Gene', (56, 59))	('C1A', 'Disease', (3, 6))	('FH', 'Gene', '2271', (82, 84))
42564	31307198	The latter also happens in VHL mutations.	('mutations', 'Var', (31, 40))	('VHL', 'Gene', '7428', (27, 30))	('VHL', 'Gene', (27, 30))
42565	31307198	have recently described a hypermethylator phenotype in SDH-related paragangliomas.	('SDH', 'Gene', '6390', (55, 58))	('SDH', 'Gene', (55, 58))	('paragangliomas', 'Disease', 'MESH:D010235', (67, 81))	('hypermethylator', 'Var', (26, 41))	('paragangliomas', 'Disease', (67, 81))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('paragangliomas', 'Phenotype', 'HP:0002668', (67, 81))
42569	31307198	The discovery of SDHD mutations in families with paraganglioma syndrome type 1 (PGL1) was in 2000.	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (49, 71))	('SDHD', 'Gene', '6392', (17, 21))	('SDHD', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('paraganglioma', 'Phenotype', 'HP:0002668', (49, 62))	('paraganglioma syndrome', 'Disease', (49, 71))
42572	31307198	Later in 2009, Pasini and Stratakis extensively reviewed 95 international manuscripts on SDHx mutations comprising a total of 395 SDHD mutation carriers.	('SDH', 'Gene', (89, 92))	('SDH', 'Gene', (130, 133))	('mutations', 'Var', (94, 103))	('SDHD', 'Gene', (130, 134))	('SDHD', 'Gene', '6392', (130, 134))	('SDH', 'Gene', '6390', (89, 92))	('SDH', 'Gene', '6390', (130, 133))
42573	31307198	Since then, several other large patient case series have also been reported, describing the genotype-phenotype correlation of SDHD mutations.	('mutations', 'Var', (131, 140))	('patient', 'Species', '9606', (32, 39))	('SDHD', 'Gene', (126, 130))	('SDHD', 'Gene', '6392', (126, 130))
42577	31307198	SDHD mutations are common in HNPGLs, which are vastly biochemically silent, that is, with the exception of 20%, that secrete dopamine and/or its metabolite methoxytyramine.	('metabolite methoxytyramine', 'MPA', (145, 171))	('HNPGLs', 'Disease', (29, 35))	('mutations', 'Var', (5, 14))	('dopamine', 'Chemical', 'MESH:D004298', (125, 133))	('SDHD', 'Gene', '6392', (0, 4))	('methoxytyramine', 'Chemical', 'MESH:C001746', (156, 171))	('SDHD', 'Gene', (0, 4))	('secrete dopamine', 'MPA', (117, 133))	('HNPGLs', 'Phenotype', 'HP:0002864', (29, 35))
42579	31307198	Although SDHD mutations can be inherited both via the maternal and paternal lines, paragangliomas almost never develop after maternal transmission of the mutation.	('SDHD', 'Gene', '6392', (9, 13))	('paragangliomas', 'Disease', (83, 97))	('paragangliomas', 'Disease', 'MESH:D010235', (83, 97))	('SDHD', 'Gene', (9, 13))	('paragangliomas', 'Phenotype', 'HP:0002668', (83, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('mutations', 'Var', (14, 23))
42580	31307198	As maternally derived SDHD mutation carriers will still pass the mutation to their offspring in 50% of cases, PGL1 can skip generations.	('mutation', 'Var', (27, 35))	('SDHD', 'Gene', (22, 26))	('SDHD', 'Gene', '6392', (22, 26))	('mutation', 'Var', (65, 73))
42581	31307198	This may in part explain the occurrence of SDHD germline mutations in apparently nonfamilial cases.	('germline mutations', 'Var', (48, 66))	('SDHD', 'Gene', '6392', (43, 47))	('SDHD', 'Gene', (43, 47))
42582	31307198	Furthermore, an individual who inherits an SDHD pathogenic variant from his/her father is at high risk of manifesting paragangliomas and, to a lesser extent, pheochromocytomas.	('pheochromocytomas', 'Disease', (158, 175))	('SDHD', 'Gene', '6392', (43, 47))	('pheochromocytomas', 'Disease', 'MESH:D010673', (158, 175))	('SDHD', 'Gene', (43, 47))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (158, 175))	('paragangliomas', 'Disease', (118, 132))	('paragangliomas', 'Disease', 'MESH:D010235', (118, 132))	('variant', 'Var', (59, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('paraganglioma', 'Phenotype', 'HP:0002668', (118, 131))	('paragangliomas', 'Phenotype', 'HP:0002668', (118, 132))
42584	31307198	Neumann et al first published data on age-related penetrance in SDHD mutation carriers in 2004.	('mutation', 'Var', (69, 77))	('SDHD', 'Gene', (64, 68))	('SDHD', 'Gene', '6392', (64, 68))
42585	31307198	SDHD mutations showed 50% penetrance by age 31 rising to 86% by the age of 50.	('SDHD', 'Gene', (0, 4))	('SDHD', 'Gene', '6392', (0, 4))	('mutations', 'Var', (5, 14))
42590	31307198	van Hulsteijn et al presented a systematic literature review and meta-analysis in 2012 on the risk of malignant paragangliomas in SDHD mutation carriers.	('malignant paragangliomas', 'Disease', 'MESH:D010235', (102, 126))	('SDHD', 'Gene', (130, 134))	('SDHD', 'Gene', '6392', (130, 134))	('carriers', 'Reg', (144, 152))	('paragangliomas', 'Phenotype', 'HP:0002668', (112, 126))	('malignant paragangliomas', 'Disease', (102, 126))	('mutation', 'Var', (135, 143))	('paraganglioma', 'Phenotype', 'HP:0002668', (112, 125))
42592	31307198	The pooled incidence for malignant paragangliomas was 8% in SDHD mutation carriers.	('malignant paragangliomas', 'Disease', (25, 49))	('SDHD', 'Gene', '6392', (60, 64))	('SDHD', 'Gene', (60, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (35, 49))	('malignant paragangliomas', 'Disease', 'MESH:D010235', (25, 49))	('mutation', 'Var', (65, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (35, 48))
42593	31307198	Paraganglioma syndrome type 3 (PGL3) is associated with mutations of SDHC, located on chromosome 1q21.	('mutations', 'Var', (56, 65))	('Paraganglioma syndrome', 'Disease', 'MESH:D010235', (0, 22))	('SDHC', 'Gene', (69, 73))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('SDHC', 'Gene', '6391', (69, 73))	('PGL3', 'Gene', '6391', (31, 35))	('Paraganglioma syndrome', 'Disease', (0, 22))	('associated', 'Reg', (40, 50))	('PGL3', 'Gene', (31, 35))
42594	31307198	In contrast to patients with PGL1 and PGL4, SDHC mutation carriers mostly present with single HNPGLs.	('SDHC', 'Gene', '6391', (44, 48))	('patients', 'Species', '9606', (15, 23))	('HNPGLs', 'Phenotype', 'HP:0002864', (94, 100))	('mutation', 'Var', (49, 57))	('PGL4', 'Gene', (38, 42))	('PGL4', 'Gene', '6390', (38, 42))	('SDHC', 'Gene', (44, 48))
42598	31307198	Two large series of patients consisting of 598 and 445 patients with HNPGLs presented by Neumann et al and Burnichon et al have shown similar prevalence of 3.6% and 4.3% for SDHC mutations respectively.	('SDHC', 'Gene', (174, 178))	('SDHC', 'Gene', '6391', (174, 178))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (179, 188))	('patients', 'Species', '9606', (55, 63))	('HNPGLs', 'Phenotype', 'HP:0002864', (69, 75))
42600	31307198	Family history is positive in the minority of patients with SDHC mutations (12% to 25%), suggesting a low tumor penetrance.	('patients', 'Species', '9606', (46, 54))	('SDHC', 'Gene', '6391', (60, 64))	('mutations', 'Var', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('SDHC', 'Gene', (60, 64))	('tumor', 'Disease', (106, 111))
42601	31307198	Syndrome associated with mutations of SDHB gene, located on chromosome 1p36.13, was designated as paraganglioma syndrome type 4 (PGL4).	('mutations', 'Var', (25, 34))	('PGL4', 'Gene', (129, 133))	('PGL4', 'Gene', '6390', (129, 133))	('paraganglioma syndrome type 4', 'Disease', (98, 127))	('associated', 'Reg', (9, 19))	('paraganglioma syndrome type 4', 'Disease', 'OMIM:115310', (98, 127))	('Syndrome', 'Disease', (0, 8))	('SDHB', 'Gene', '6390', (38, 42))	('SDHB', 'Gene', (38, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))
42602	31307198	Patients with SDHB mutations frequently develop sPGLs (52% to 84%) and PHEOs (18% to 28%).	('PHEOs', 'Disease', 'MESH:D010673', (71, 76))	('PHEOs', 'Phenotype', 'HP:0002666', (71, 76))	('PHEOs', 'Disease', (71, 76))	('sPGLs', 'Disease', (48, 53))	('mutations', 'Var', (19, 28))	('sPGLs', 'Disease', 'MESH:D010235', (48, 53))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', '6390', (14, 18))	('develop', 'PosReg', (40, 47))	('SDHB', 'Gene', (14, 18))
42605	31307198	The estimated age-related tumor penetrance in SDHB mutation carriers is 29% at age 30 rising to 45% at age 40.	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutation', 'Var', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
42607	31307198	Mutations of SDHB were associated with malignant PHEOs and HNPGLs in 20.6-41% cases.	('PHEOs', 'Phenotype', 'HP:0002666', (49, 54))	('HNPGLs', 'Disease', (59, 65))	('malignant PHEOs', 'Disease', 'MESH:D010673', (39, 54))	('SDHB', 'Gene', '6390', (13, 17))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('HNPGLs', 'Phenotype', 'HP:0002864', (59, 65))	('malignant PHEOs', 'Disease', (39, 54))	('associated', 'Reg', (23, 33))
42608	31307198	It has also been shown that patients with a germline SDHB pathogenic variant can develop malignant PPCs at any site.	('PPCs', 'Disease', (99, 103))	('variant', 'Var', (69, 76))	('SDHB', 'Gene', '6390', (53, 57))	('SDHB', 'Gene', (53, 57))	('PPCs', 'Disease', 'MESH:D010673', (99, 103))	('patients', 'Species', '9606', (28, 36))	('develop', 'PosReg', (81, 88))
42609	31307198	The systematic literature review and meta-analysis done by van Hulsteijn et al on the risk of malignant tumors in SDHB and SDHD mutation carriers, revealed a pooled incidence of 17% in the SDHB group.	('malignant tumors', 'Disease', 'MESH:D009369', (94, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('SDHD', 'Gene', (123, 127))	('SDHD', 'Gene', '6392', (123, 127))	('mutation', 'Var', (128, 136))	('SDHB', 'Gene', '6390', (189, 193))	('malignant tumors', 'Disease', (94, 110))	('SDHB', 'Gene', (189, 193))
42611	31307198	Furthermore, multivariate analysis of a series of 54 patients done in France for malignant PPCs demonstrated that identification of SDHB mutation was the only risk factor for mortality.	('PPCs', 'Disease', (91, 95))	('SDHB', 'Gene', (132, 136))	('mutation', 'Var', (137, 145))	('patients', 'Species', '9606', (53, 61))	('PPCs', 'Disease', 'MESH:D010673', (91, 95))	('SDHB', 'Gene', '6390', (132, 136))
42612	31307198	The 5-year survival probability was 36% for patients with SDHB mutation versus 67% for patients without SDHB mutation.	('SDHB', 'Gene', (58, 62))	('patients', 'Species', '9606', (44, 52))	('mutation', 'Var', (63, 71))	('SDHB', 'Gene', '6390', (104, 108))	('SDHB', 'Gene', '6390', (58, 62))	('patients', 'Species', '9606', (87, 95))	('SDHB', 'Gene', (104, 108))
42615	31307198	A follow-up multicenter study was undertaken in Spain and the Netherlands with the joint aims of identifying new mutation carriers and assessing the frequency of SDHAF2 mutations amongst 443 sporadic PPCs.	('mutations', 'Var', (169, 178))	('PPCs', 'Disease', 'MESH:D010673', (200, 204))	('SDHAF2', 'Gene', '54949', (162, 168))	('PPCs', 'Disease', (200, 204))	('SDHAF2', 'Gene', (162, 168))
42616	31307198	Only one additional SDHAF2-related family was identified in Spanish patients, which interestingly carried the exact mutation, p.Gly78Arg, previously discovered in the Netherlands.	('SDHAF2', 'Gene', '54949', (20, 26))	('SDHAF2', 'Gene', (20, 26))	('p.Gly78Arg', 'Mutation', 'p.G78R', (126, 136))	('p.Gly78Arg', 'Var', (126, 136))	('patients', 'Species', '9606', (68, 76))
42617	31307198	The same study also concluded SDHAF2 mutation analysis is justified in very young patients with isolated HNPGL without mutations in SDHD, SDHC, or SDHB, and in individuals with familial antecedents who are negative for mutations in all other risk genes.	('SDHD', 'Gene', (132, 136))	('mutation', 'Var', (37, 45))	('patients', 'Species', '9606', (82, 90))	('SDHC', 'Gene', (138, 142))	('isolated HNPGL', 'Disease', (96, 110))	('SDHB', 'Gene', '6390', (147, 151))	('SDHC', 'Gene', '6391', (138, 142))	('SDHB', 'Gene', (147, 151))	('mutations', 'Var', (119, 128))	('SDHAF2', 'Gene', (30, 36))	('SDHD', 'Gene', '6392', (132, 136))	('SDHAF2', 'Gene', '54949', (30, 36))
42619	31307198	The findings associated with the same mutation were age at diagnosis below 40 years, 100% affected at age 50, 100% with HNPGLs and 91% with multifocal tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('multifocal tumors', 'Disease', 'None', (140, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('HNPGLs', 'Phenotype', 'HP:0002864', (120, 126))	('mutation', 'Var', (38, 46))	('HNPGLs', 'Disease', (120, 126))	('multifocal tumors', 'Disease', (140, 157))
42621	31307198	In 2010, the mutation in the gene of the final subunit in the mitochondrial complex, SDHA, located on chromosome 5p15 was linked to PPCs.	('SDHA', 'Gene', (85, 89))	('PPCs', 'Disease', 'MESH:D010673', (132, 136))	('mutation', 'Var', (13, 21))	('PPCs', 'Disease', (132, 136))	('SDHA', 'Gene', '6389', (85, 89))	('linked', 'Reg', (122, 128))
42622	31307198	Although HNPGLs have been detected with mutations in SDHA the risk of developing such tumors remains unknown.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HNPGLs', 'Disease', (9, 15))	('tumors', 'Disease', (86, 92))	('SDHA', 'Gene', '6389', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('mutations', 'Var', (40, 49))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SDHA', 'Gene', (53, 57))	('HNPGLs', 'Phenotype', 'HP:0002864', (9, 15))
42624	31307198	The incidence of FH mutation in PPCs is estimated at about 1%.	('FH', 'Gene', '2271', (17, 19))	('PPCs', 'Disease', (32, 36))	('mutation', 'Var', (20, 28))	('PPCs', 'Disease', 'MESH:D010673', (32, 36))
42625	31307198	Mutations in FH predispose to hereditary leiomyomatosis and renal cell carcinoma.	('hereditary leiomyomatosis and renal cell carcinoma', 'Disease', 'MESH:C535516', (30, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (60, 80))	('predispose', 'Reg', (16, 26))	('Mutations', 'Var', (0, 9))	('FH', 'Gene', '2271', (13, 15))
42626	31307198	Interestingly, about 40% of cases carrying germline FH mutation presented a metastatic paragangliomas.	('germline', 'Var', (43, 51))	('FH', 'Gene', '2271', (52, 54))	('paragangliomas', 'Disease', 'MESH:D010235', (87, 101))	('paragangliomas', 'Disease', (87, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (87, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (87, 100))
42628	31307198	von Hippel-Lindau syndrome is caused by inactivation of the tumor suppressor gene VHL located on chromosome 3p25-p26.	('p26', 'Gene', '23423', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('caused by', 'Reg', (30, 39))	('VHL', 'Gene', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('von Hippel-Lindau syndrome', 'Disease', (0, 26))	('VHL', 'Gene', '7428', (82, 85))	('tumor', 'Disease', (60, 65))	('p26', 'Gene', (113, 116))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (0, 26))	('inactivation', 'Var', (40, 52))
42636	31307198	The prevalence of hereditary HNPGLs in patients with VHL mutation is reported to be 0.5%.	('mutation', 'Var', (57, 65))	('patients', 'Species', '9606', (39, 47))	('VHL', 'Gene', (53, 56))	('hereditary HNPGLs', 'Disease', (18, 35))	('VHL', 'Gene', '7428', (53, 56))	('HNPGLs', 'Phenotype', 'HP:0002864', (29, 35))
42642	31307198	HIF-2alpha mutations were found to disrupt prolyl hydroxylation.	('mutations', 'Var', (11, 20))	('prolyl hydroxylation', 'MPA', (43, 63))	('disrupt', 'NegReg', (35, 42))	('HIF-2alpha', 'Gene', '2034', (0, 10))	('prolyl', 'Chemical', 'MESH:C065612', (43, 49))	('HIF-2alpha', 'Gene', (0, 10))
42644	31307198	Thus, the longer half-life of the mutant protein results in the upregulation of downstream targets (endothelin-1, erythropoietin, glucose transporter 1, or vascular endothelial growth factor).	('erythropoietin', 'Gene', (114, 128))	('protein', 'Protein', (41, 48))	('endothelin-1', 'Gene', '1906', (100, 112))	('endothelin-1', 'Gene', (100, 112))	('glucose', 'Chemical', 'MESH:D005947', (130, 137))	('glucose transporter 1', 'MPA', (130, 151))	('erythropoietin', 'Gene', '2056', (114, 128))	('upregulation', 'PosReg', (64, 76))	('vascular endothelial growth factor', 'Gene', (156, 190))	('vascular endothelial growth factor', 'Gene', '7422', (156, 190))	('mutant', 'Var', (34, 40))
42648	31307198	So far only one study described a patient with erythrocytosis and abdominal paragangliomas who was found to harbor a mutation in the PHD2 gene.	('PHD2', 'Gene', '54583', (133, 137))	('PHD2', 'Gene', (133, 137))	('erythrocytosis', 'Phenotype', 'HP:0001901', (47, 61))	('patient', 'Species', '9606', (34, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (76, 89))	('paragangliomas', 'Phenotype', 'HP:0002668', (76, 90))	('erythrocytosis', 'Disease', (47, 61))	('mutation', 'Var', (117, 125))	('erythrocytosis', 'Disease', 'MESH:D011086', (47, 61))	('abdominal paragangliomas', 'Disease', 'MESH:D010235', (66, 90))	('abdominal paragangliomas', 'Disease', (66, 90))
42650	31307198	RET mutations have been associated with increased activation of PI3K/v-Akt signals and RAS/RAF/MAPK signaling pathways.	('Akt', 'Gene', '207', (71, 74))	('RET', 'Gene', '5979', (0, 3))	('Akt', 'Gene', (71, 74))	('activation', 'PosReg', (50, 60))	('RET', 'Gene', (0, 3))	('RAF', 'Gene', '22882', (91, 94))	('RAF', 'Gene', (91, 94))	('mutations', 'Var', (4, 13))
42657	31307198	Patients with FMTC do not have a risk of developing PHEOs.	('FMTC', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('PHEOs', 'Phenotype', 'HP:0002666', (52, 57))	('MTC', 'Phenotype', 'HP:0002865', (15, 18))	('PHEOs', 'Disease', 'MESH:D010673', (52, 57))	('PHEOs', 'Disease', (52, 57))
42663	31307198	Mutations of the gene lead to the neurofibromatosis type 1 syndrome (NF1).	('NF1', 'Gene', '4763', (69, 72))	('lead to', 'Reg', (22, 29))	('neurofibromatosis type 1 syndrome', 'Disease', (34, 67))	('Mutations', 'Var', (0, 9))	('neurofibromatosis type 1 syndrome', 'Disease', 'MESH:D009456', (34, 67))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (34, 51))	('NF1', 'Gene', (69, 72))
42667	31307198	Recently, somatic NF1 mutations have been linked to the pathogenesis of apparently sporadic PPCs.	('linked', 'Reg', (42, 48))	('PPCs', 'Disease', (92, 96))	('PPCs', 'Disease', 'MESH:D010673', (92, 96))	('mutations', 'Var', (22, 31))	('NF1', 'Gene', (18, 21))	('NF1', 'Gene', '4763', (18, 21))
42670	31307198	Mutations of TMEM127 have been related to PHEOs.	('TMEM127', 'Gene', '55654', (13, 20))	('PHEOs', 'Disease', 'MESH:D010673', (42, 47))	('PHEOs', 'Phenotype', 'HP:0002666', (42, 47))	('Mutations', 'Var', (0, 9))	('related', 'Reg', (31, 38))	('PHEOs', 'Disease', (42, 47))	('TMEM127', 'Gene', (13, 20))
42673	31307198	It has been shown that the mammalian target of rapamycin complex 1 (mTORC1) is specifically affected by TMEM127 knockdown, leading to increased phosphorylation of targets of mTORC1.	('phosphorylation', 'MPA', (144, 159))	('mammalian', 'Species', '9606', (27, 36))	('TMEM127', 'Gene', '55654', (104, 111))	('mTORC1', 'Gene', '382056', (68, 74))	('rapamycin', 'Chemical', 'MESH:D020123', (47, 56))	('mTORC1', 'Gene', (174, 180))	('knockdown', 'Var', (112, 121))	('mTORC1', 'Gene', '382056', (174, 180))	('mTORC1', 'Gene', (68, 74))	('increased', 'PosReg', (134, 143))	('TMEM127', 'Gene', (104, 111))
42674	31307198	Genetic studies of PPC patients indicate a low prevalence of TMEM127 mutations (approximately 2%).	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (23, 31))	('TMEM127', 'Gene', '55654', (61, 68))	('TMEM127', 'Gene', (61, 68))	('PPC', 'Disease', (19, 22))
42676	31307198	In most cases, mutation carriers suffered from PHEOs only (unilateral as well as bilateral tumors) and secreted a high level of metanephrines.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutation', 'Var', (15, 23))	('bilateral tumors', 'Disease', 'MESH:D009396', (81, 97))	('PHEOs', 'Disease', 'MESH:D010673', (47, 52))	('PHEOs', 'Phenotype', 'HP:0002666', (47, 52))	('secreted', 'MPA', (103, 111))	('suffered', 'Reg', (33, 41))	('PHEOs', 'Disease', (47, 52))	('metanephrines', 'Chemical', 'MESH:D008676', (128, 141))	('bilateral tumors', 'Disease', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('high level of metanephrines', 'MPA', (114, 141))
42680	31307198	MAX mutations are associated with bilateral PHEOs and show apparent paternal transmission of the disease.	('MAX', 'Gene', (0, 3))	('PHEOs', 'Disease', 'MESH:D010673', (44, 49))	('PHEOs', 'Phenotype', 'HP:0002666', (44, 49))	('MAX', 'Gene', '4149', (0, 3))	('associated', 'Reg', (18, 28))	('PHEOs', 'Disease', (44, 49))	('mutations', 'Var', (4, 13))
42684	31307198	Genetic mutations of NF1 and RET are known to affect RAS signaling and are associated with the formation of PPCs.	('PPCs', 'Disease', 'MESH:D010673', (108, 112))	('RET', 'Gene', (29, 32))	('RAS signaling', 'MPA', (53, 66))	('mutations', 'Var', (8, 17))	('affect', 'Reg', (46, 52))	('PPCs', 'Disease', (108, 112))	('NF1', 'Gene', (21, 24))	('RET', 'Gene', '5979', (29, 32))	('NF1', 'Gene', '4763', (21, 24))	('associated', 'Reg', (75, 85))
42685	31307198	However association of RAS mutation itself with PPCs was reported in a series of 4 male patients (3 presenting with PHEOs and 1 with sPGL) in 2013.	('PPCs', 'Disease', 'MESH:D010673', (48, 52))	('association', 'Reg', (8, 19))	('PHEOs', 'Phenotype', 'HP:0002666', (116, 121))	('patients', 'Species', '9606', (88, 96))	('PPCs', 'Disease', (48, 52))	('PHEOs', 'Disease', 'MESH:D010673', (116, 121))	('PHEOs', 'Disease', (116, 121))	('mutation', 'Var', (27, 35))	('RAS', 'Gene', (23, 26))
42687	31307198	Before 2000, only one genetically determined form of the disease was thought to exist, but it has now been shown that about 30% of paragangliomas are genetically determined due to the presence of mutation in one of the 15 susceptibility genes identified to date.	('mutation', 'Var', (196, 204))	('paragangliomas', 'Disease', (131, 145))	('paragangliomas', 'Disease', 'MESH:D010235', (131, 145))	('paragangliomas', 'Phenotype', 'HP:0002668', (131, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (131, 144))	('presence', 'Reg', (184, 192))
42692	31307198	Germline mutations in SDHA and SDHC are associated with HNPGLs and sympathetic paragangliomas.	('Germline mutations', 'Var', (0, 18))	('SDHA', 'Gene', (22, 26))	('sympathetic paragangliomas', 'Disease', 'MESH:D010235', (67, 93))	('HNPGLs', 'Disease', (56, 62))	('SDHA', 'Gene', '6389', (22, 26))	('paragangliomas', 'Phenotype', 'HP:0002668', (79, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('SDHC', 'Gene', (31, 35))	('SDHC', 'Gene', '6391', (31, 35))	('HNPGLs', 'Phenotype', 'HP:0002864', (56, 62))	('associated', 'Reg', (40, 50))	('sympathetic paragangliomas', 'Disease', (67, 93))
42693	31307198	SDHAF2 mutations are associated with HNPGLs.	('SDHAF2', 'Gene', '54949', (0, 6))	('HNPGLs', 'Phenotype', 'HP:0002864', (37, 43))	('SDHAF2', 'Gene', (0, 6))	('associated', 'Reg', (21, 31))	('HNPGLs', 'Disease', (37, 43))	('mutations', 'Var', (7, 16))
42694	31307198	SDHD and SDHB mutations are associated with HNPGLs, sPGLs and PHEOs, whilst TMEM127 and MAX with PHEOs.	('SDHB', 'Gene', (9, 13))	('TMEM127', 'Gene', '55654', (76, 83))	('SDHD', 'Gene', '6392', (0, 4))	('PHEOs', 'Phenotype', 'HP:0002666', (62, 67))	('sPGLs', 'Disease', (52, 57))	('SDHD', 'Gene', (0, 4))	('MAX', 'Gene', (88, 91))	('PHEOs', 'Disease', (62, 67))	('PHEOs', 'Disease', 'MESH:D010673', (97, 102))	('mutations', 'Var', (14, 23))	('associated', 'Reg', (28, 38))	('HNPGLs', 'Phenotype', 'HP:0002864', (44, 50))	('HNPGLs', 'Disease', (44, 50))	('sPGLs', 'Disease', 'MESH:D010235', (52, 57))	('PHEOs', 'Phenotype', 'HP:0002666', (97, 102))	('SDHB', 'Gene', '6390', (9, 13))	('TMEM127', 'Gene', (76, 83))	('PHEOs', 'Disease', 'MESH:D010673', (62, 67))	('MAX', 'Gene', '4149', (88, 91))	('PHEOs', 'Disease', (97, 102))
42695	31307198	SDHB mutations are generally associated with a higher incidence of malignant tumors compared to mutations in other SDHx genes.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('malignant tumors', 'Disease', 'MESH:D009369', (67, 83))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', '6390', (115, 118))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SDH', 'Gene', (115, 118))	('malignant tumors', 'Disease', (67, 83))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))
42696	31307198	Furthermore, germline mutations in SDHx also occur in around 30% of HNPGLs that are regarded sporadic due to the absence of a family history, suggesting that these HNPGLs may be "occult familial" cases.	('SDH', 'Gene', '6390', (35, 38))	('HNPGLs', 'Phenotype', 'HP:0002864', (68, 74))	('HNPGLs', 'Phenotype', 'HP:0002864', (164, 170))	('occur', 'Reg', (45, 50))	('germline mutations', 'Var', (13, 31))	('SDH', 'Gene', (35, 38))	('HNPGLs', 'Disease', (68, 74))
42698	31307198	If PPCs are found without any syndromic or familial presentation, metastatic tumors should be tested for SDHB mutations.	('tumors', 'Disease', (77, 83))	('tested', 'Reg', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('SDHB', 'Gene', '6390', (105, 109))	('mutations', 'Var', (110, 119))	('syndromic', 'Disease', 'MESH:D061325', (30, 39))	('PPCs', 'Disease', (3, 7))	('SDHB', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('syndromic', 'Disease', (30, 39))	('PPCs', 'Disease', 'MESH:D010673', (3, 7))
42699	31307198	Multiple abdominal paragangliomas should be first tested for the presence of SDHB mutations and female patients with multiple paragangliomas associated with somatostatinomas, should be first tested for HIF2alpha mutations.	('paragangliomas', 'Phenotype', 'HP:0002668', (126, 140))	('multiple paragangliomas', 'Disease', (117, 140))	('paraganglioma', 'Phenotype', 'HP:0002668', (19, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (126, 139))	('SDHB', 'Gene', '6390', (77, 81))	('Multiple abdominal paragangliomas', 'Disease', 'MESH:D010235', (0, 33))	('multiple paragangliomas', 'Disease', 'MESH:D010235', (117, 140))	('somatostatinomas', 'Disease', 'MESH:D013005', (157, 173))	('mutations', 'Var', (82, 91))	('HIF2alpha', 'Gene', '2034', (202, 211))	('SDHB', 'Gene', (77, 81))	('paragangliomas', 'Phenotype', 'HP:0002668', (19, 33))	('patients', 'Species', '9606', (103, 111))	('somatostatinomas', 'Disease', (157, 173))	('HIF2alpha', 'Gene', (202, 211))	('Multiple abdominal paragangliomas', 'Disease', (0, 33))
42701	31307198	Various recommendations have been suggested regarding early detection of mutations depending on family history, tumor site, character and location, multiplicity and presence of metastasis.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (73, 82))
42705	28977863	SFTA1P, LINC01272, GATA6-AS1 and MIR3945HG were closely related to the survival time of LUSC.	('GATA6-AS1', 'Var', (19, 28))	('SFTA1P', 'Gene', '207107', (0, 6))	('MIR3945HG', 'Gene', (33, 42))	('SFTA1P', 'Gene', (0, 6))	('LUSC', 'Phenotype', 'HP:0030359', (88, 92))	('MIR3945HG', 'Gene', '731424', (33, 42))	('LINC01272', 'Gene', (8, 17))	('LINC01272', 'Gene', '100506115', (8, 17))	('survival time of LUSC', 'CPA', (71, 92))	('related', 'Reg', (56, 63))
42716	28977863	The Cancer Genome Atlas (TCGA) database of LUSC has facilitated the analysis on the high throughput data of various genomic alterations, including non-coding RNAs.	('non-coding', 'Var', (147, 157))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))
42722	28977863	Survival analyses showed that SFTA1P, LINC01272, GATA6-AS1 and MIR3945HG were significantly related to the survival time of LUSC (Figure 4).	('GATA6-AS1', 'Var', (49, 58))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('LINC01272', 'Gene', '100506115', (38, 47))	('MIR3945HG', 'Gene', '731424', (63, 72))	('related', 'Reg', (92, 99))	('LINC01272', 'Gene', (38, 47))	('survival time of LUSC', 'CPA', (107, 128))	('SFTA1P', 'Gene', '207107', (30, 36))	('MIR3945HG', 'Gene', (63, 72))	('SFTA1P', 'Gene', (30, 36))
42730	28977863	The OncoPrint from cBioPortal showed that 14% (69/501) cases with genetic alterations could be obtained (Figure 8A), except RP1-78O14.1, whose data were not available in cBioPortal.	('RP1', 'Gene', '6101', (124, 127))	('genetic alterations', 'Var', (66, 85))	('RP1', 'Gene', (124, 127))
42731	28977863	And only SFTA1P, LINC00968, LINC00961, and FENDRR had genetic alterations, including amplification, deep deletion and mRNA upregulation.	('deep deletion', 'Var', (100, 113))	('LINC00968', 'Gene', (17, 26))	('LINC00968', 'Gene', '100507632', (17, 26))	('mRNA', 'MPA', (118, 122))	('LINC00961', 'Gene', '158376', (28, 37))	('SFTA1P', 'Gene', '207107', (9, 15))	('LINC00961', 'Gene', (28, 37))	('upregulation', 'PosReg', (123, 135))	('amplification', 'Var', (85, 98))	('SFTA1P', 'Gene', (9, 15))
42737	28977863	In these patients, the mean expression level of LINC00968 was notably lower in LUSC tissues (0.3343+-0.08582) than that of non-cancerous lung tissues (0.8258+-0.1469; P=0.0085, Figure 10A).	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('LINC00968', 'Gene', (48, 57))	('patients', 'Species', '9606', (9, 17))	('non-cancerous lung', 'Disease', 'MESH:D002289', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('LUSC', 'Disease', (79, 83))	('LINC00968', 'Gene', '100507632', (48, 57))	('non-cancerous lung', 'Disease', (123, 141))	('lower', 'NegReg', (70, 75))	('0.3343+-0.08582', 'Var', (93, 108))	('expression level', 'MPA', (28, 44))
42749	28977863	In the support of the result, GATA6-AS1 might act as a tumor suppressor in the several cancers including BLCA, CESC, ESCA, LUAD, pheochromocytoma and paraganglioma (PCPG) and UCEC.	('CESC', 'Disease', (111, 115))	('cancers', 'Disease', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('paraganglioma', 'Phenotype', 'HP:0002668', (150, 163))	('BLCA', 'Disease', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (129, 163))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('GATA6-AS1', 'Var', (30, 39))	('ESCA', 'Disease', (117, 121))	('tumor', 'Disease', (55, 60))	('UCEC', 'Disease', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (129, 145))	('LUAD', 'Phenotype', 'HP:0030078', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('LUAD', 'Disease', (123, 127))
42753	28977863	In LUAD patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify the sensitivity (namely exon 21 L858R, exon 19 deletion) or resistance (namely exon 20 T790M and/or insertion) to tyrosine kinase inhibitor (TKI) mediated targeted therapeutic strategies.	('modify', 'Reg', (73, 79))	('exon 19 deletion', 'Var', (119, 135))	('L858R', 'Mutation', 'rs121434568', (112, 117))	('EGFR', 'Gene', '1956', (18, 22))	('T790M', 'Mutation', 'rs121434569', (167, 172))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('T790M', 'Var', (167, 172))	('EGFR', 'Gene', (18, 22))	('resistance', 'MPA', (140, 150))	('deletion', 'Var', (127, 135))	('L858R', 'Var', (112, 117))	('sensitivity', 'MPA', (84, 95))	('insertion', 'Var', (180, 189))	('patients', 'Species', '9606', (8, 16))
42755	28977863	Ten lncRNAs with the highest diagnostic value (SFTA1P, LINC00968, LINC00961, LINC01572, RP1-78O14.1, FENDRR, LINC01314, LINC01272, GATA6-AS1, and MIR3945HG) were selected for further investigation of their clinical roles in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('MIR3945HG', 'Gene', '731424', (146, 155))	('LINC01572', 'Gene', (77, 86))	('LINC01572', 'Gene', '101927957', (77, 86))	('LINC00968', 'Gene', '100507632', (55, 64))	('clinical', 'Species', '191496', (206, 214))	('SFTA1P', 'Gene', (47, 53))	('LINC01272', 'Gene', '100506115', (120, 129))	('LINC00961', 'Gene', '158376', (66, 75))	('LINC01314', 'Gene', (109, 118))	('LINC01272', 'Gene', (120, 129))	('FENDRR', 'Var', (101, 107))	('LINC00961', 'Gene', (66, 75))	('RP1', 'Gene', (88, 91))	('MIR3945HG', 'Gene', (146, 155))	('LINC00968', 'Gene', (55, 64))	('RP1', 'Gene', '6101', (88, 91))	('SFTA1P', 'Gene', '207107', (47, 53))	('LINC01314', 'Gene', '100996492', (109, 118))
42756	28977863	EGFR mutations are extremely rare (<5%) in LUSC; nonetheless, other genetic alterations, like overexpression and gene amplification are much common in LUSC, which play pivotal roles in the biological process and disease development of LUSC.	('LUSC', 'Disease', (151, 155))	('gene amplification', 'Var', (113, 131))	('EGFR', 'Gene', (0, 4))	('common', 'Reg', (141, 147))	('LUSC', 'Phenotype', 'HP:0030359', (235, 239))	('mutations', 'Var', (5, 14))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('LUSC', 'Phenotype', 'HP:0030359', (151, 155))	('EGFR', 'Gene', '1956', (0, 4))
42761	28977863	The top 10 lncRNAs (SFTA1P, LINC00968, LINC00961, LINC01572, RP1-78O14.1, FENDRR, LINC01314, LINC01272, GATA6-AS1, and MIR3945HG) had extremely high diagnostic values for LUSC, since the AUCs were all over 0.99.	('LINC00968', 'Gene', (28, 37))	('LINC00961', 'Gene', (39, 48))	('LINC01314', 'Gene', '100996492', (82, 91))	('SFTA1P', 'Gene', '207107', (20, 26))	('RP1', 'Gene', (61, 64))	('LINC01572', 'Gene', (50, 59))	('LINC00968', 'Gene', '100507632', (28, 37))	('LINC01572', 'Gene', '101927957', (50, 59))	('RP1', 'Gene', '6101', (61, 64))	('LUSC', 'Disease', (171, 175))	('MIR3945HG', 'Gene', (119, 128))	('SFTA1P', 'Gene', (20, 26))	('LINC01272', 'Gene', '100506115', (93, 102))	('LINC01314', 'Gene', (82, 91))	('LUSC', 'Phenotype', 'HP:0030359', (171, 175))	('LINC00961', 'Gene', '158376', (39, 48))	('MIR3945HG', 'Gene', '731424', (119, 128))	('LINC01272', 'Gene', (93, 102))	('FENDRR', 'Var', (74, 80))
42769	28977863	Down-regulation of FENDRR was found in gastric cancer and moreover, FENDRR was closely related to the poor prognosis in gastric cancer.	('FENDRR', 'Var', (68, 74))	('gastric cancer', 'Disease', (39, 53))	('FENDRR', 'Gene', (19, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('Down-regulation', 'NegReg', (0, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
42774	28977863	SNP rs11256676 in Phenotypes DMFS5mand of Chr.	('Chr', 'Disease', (42, 45))	('rs11256676', 'Mutation', 'rs11256676', (4, 14))	('DMFS5mand', 'Var', (29, 38))
42781	28977863	Furthermore, the genetic alterations can also regulate the function of certain lncRNA, and thus influence the clinical outcome.	('regulate', 'Reg', (46, 54))	('clinical', 'Species', '191496', (110, 118))	('function', 'MPA', (59, 67))	('genetic alterations', 'Var', (17, 36))	('influence', 'Reg', (96, 105))
42782	28977863	Only several studies explored single lncRNAs and their genetic variants in lung cancer.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('variants', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
42783	28977863	For instance, among the advanced lung cancer patients, cases with rs3200401 CT and CT + TT genotypes in MALAT1 had clearly better prognosis than those with the MALAT1 rs3200401 CC genotype.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('rs3200401', 'Mutation', 'rs3200401', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('better', 'PosReg', (123, 129))	('rs3200401', 'Var', (66, 75))	('MALAT1', 'Gene', '378938', (104, 110))	('MALAT1', 'Gene', '378938', (160, 166))	('MALAT1', 'Gene', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('patients', 'Species', '9606', (45, 53))	('rs3200401', 'Mutation', 'rs3200401', (167, 176))	('MALAT1', 'Gene', (160, 166))	('lung cancer', 'Disease', (33, 44))
42784	28977863	SNP rs114020893 of NEXN-AS1 at 1p31.1 might also contribute to lung cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('NEXN-AS1', 'Gene', '374987', (19, 27))	('NEXN-AS1', 'Gene', (19, 27))	('rs114020893', 'Mutation', 'rs114020893', (4, 15))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('contribute', 'Reg', (49, 59))	('SNP', 'Var', (0, 3))
42785	28977863	In the current study, gene amplification, deep deletion and mRNA upregulation were detected in SFTA1P, LINC00968, LINC00961 and FENDRR and these genetic alterations of the lncRNAs showed a close correlation with survival of LUSC.	('SFTA1P', 'Gene', (95, 101))	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('LINC00968', 'Gene', (103, 112))	('LINC00968', 'Gene', '100507632', (103, 112))	('mRNA', 'MPA', (60, 64))	('LINC00961', 'Gene', '158376', (114, 123))	('gene amplification', 'Var', (22, 40))	('SFTA1P', 'Gene', '207107', (95, 101))	('upregulation', 'PosReg', (65, 77))	('deep deletion', 'Var', (42, 55))	('LINC00961', 'Gene', (114, 123))
42787	28977863	Overall, we show a signature of aberrantly expressed lncRNAs in LUSC tissues and the top 10 of them have great clinical value to act as diagnostic biomarkers, and indicators to evaluate the survival and progression of LUSC.	('aberrantly expressed', 'Var', (32, 52))	('clinical', 'Species', '191496', (111, 119))	('lncRNAs', 'Gene', (53, 60))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('LUSC', 'Phenotype', 'HP:0030359', (218, 222))
42803	27989324	Mutations in MDH2, Encoding a Krebs Cycle Enzyme, Cause Early-Onset Severe Encephalopathy MDH2 encodes mitochondrial malate dehydrogenase (MDH), which is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle.	('MDH2', 'Gene', (13, 17))	('Krebs', 'Chemical', '-', (30, 35))	('MDH', 'Gene', (13, 16))	('Encephalopathy', 'Phenotype', 'HP:0001298', (75, 89))	('MDH2', 'Gene', '4191', (90, 94))	('malate', 'Chemical', 'MESH:C030298', (186, 192))	('Krebs', 'Chemical', '-', (250, 255))	('MDH', 'Gene', '4191', (13, 16))	('Cause', 'Reg', (50, 55))	('Mutations', 'Var', (0, 9))	('MDH', 'Gene', (90, 93))	('Encephalopathy', 'Disease', (75, 89))	('MDH2', 'Gene', '4191', (13, 17))	('MDH', 'Gene', (139, 142))	('MDH2', 'Gene', (90, 94))	('oxaloacetate', 'Chemical', 'MESH:D062907', (196, 208))	('MDH', 'Gene', '4191', (90, 93))	('MDH', 'Gene', '4191', (139, 142))	('malate', 'Chemical', 'MESH:C030298', (117, 123))	('Encephalopathy', 'Disease', 'MESH:D001927', (75, 89))
42804	27989324	We report bi-allelic pathogenic mutations in MDH2 in three unrelated subjects presenting with early-onset generalized hypotonia, psychomotor delay, refractory epilepsy, and elevated lactate in the blood and cerebrospinal fluid.	('psychomotor delay', 'Disease', (129, 146))	('elevated lactate in the blood', 'Phenotype', 'HP:0002151', (173, 202))	('MDH2', 'Gene', (45, 49))	('elevated lactate in the blood and cerebrospinal fluid', 'Phenotype', 'HP:0002490', (173, 226))	('elevated', 'PosReg', (173, 181))	('psychomotor delay', 'Disease', 'MESH:D011596', (129, 146))	('epilepsy', 'Phenotype', 'HP:0001250', (159, 167))	('refractory epilepsy', 'Disease', (148, 167))	('refractory epilepsy', 'Disease', 'MESH:D000069279', (148, 167))	('psychomotor delay', 'Phenotype', 'HP:0001263', (129, 146))	('generalized hypotonia', 'Disease', (106, 127))	('mutations', 'Var', (32, 41))	('lactate', 'MPA', (182, 189))	('lactate', 'Chemical', 'MESH:D019344', (182, 189))	('hypotonia', 'Phenotype', 'HP:0001290', (118, 127))	('generalized hypotonia', 'Phenotype', 'HP:0001290', (106, 127))	('generalized hypotonia', 'Disease', 'MESH:D009123', (106, 127))	('pathogenic', 'Reg', (21, 31))
42809	27989324	We show that loss-of-function mutations in MDH2 are also associated with severe neurological clinical presentations in children.	('MDH2', 'Gene', (43, 47))	('loss-of-function', 'NegReg', (13, 29))	('children', 'Species', '9606', (119, 127))	('mutations', 'Var', (30, 39))	('severe neurological clinical presentations', 'Disease', (73, 115))
42814	27989324	The Krebs cycle is intimately linked to the RC, and Krebs cycle defects are among the diseases that mimic or cause RC deficiencies.	('cause', 'Reg', (109, 114))	('Krebs', 'Chemical', '-', (4, 9))	('RC deficiencies', 'Disease', (115, 130))	('Krebs', 'Chemical', '-', (52, 57))	('defects', 'Var', (64, 71))	('RC deficiencies', 'Disease', 'MESH:D007153', (115, 130))
42816	27989324	Here, we show that mutations in MDH2 (MIM: 154100), encoding the Krebs cycle enzyme mitochondrial malate dehydrogenase (MDH), are responsible for severe neurological manifestations in children.	('MDH', 'Gene', '4191', (32, 35))	('MDH', 'Gene', (32, 35))	('responsible', 'Reg', (130, 141))	('mutations', 'Var', (19, 28))	('Krebs', 'Chemical', '-', (65, 70))	('children', 'Species', '9606', (184, 192))	('MDH', 'Gene', '4191', (120, 123))	('malate', 'Chemical', 'MESH:C030298', (98, 104))	('MDH', 'Gene', (120, 123))
42817	27989324	We report bi-allelic MDH2 variants in three unrelated subjects presenting with an early-onset mitochondrial phenotype comprising generalized hypotonia, psychomotor delay, and refractory epilepsy.	('hypotonia', 'Phenotype', 'HP:0001290', (141, 150))	('with', 'Reg', (74, 78))	('MDH2', 'Gene', (21, 25))	('psychomotor delay', 'Phenotype', 'HP:0001263', (152, 169))	('generalized hypotonia', 'Disease', (129, 150))	('epilepsy', 'Phenotype', 'HP:0001250', (186, 194))	('generalized hypotonia', 'Phenotype', 'HP:0001290', (129, 150))	('generalized hypotonia', 'Disease', 'MESH:D009123', (129, 150))	('refractory epilepsy', 'Disease', 'MESH:D000069279', (175, 194))	('psychomotor delay', 'Disease', (152, 169))	('MDH2 variant', 'CellLine', 'CVCL:7204', (21, 33))	('refractory epilepsy', 'Disease', (175, 194))	('psychomotor delay', 'Disease', 'MESH:D011596', (152, 169))	('variants', 'Var', (26, 34))
42827	27989324	WES via previously described methodologies and bioinformatic filtering pipelines identified compound-heterozygous missense variants in MDH2 (GenBank: NM_005918.3): c.398C>T (p.Pro133Leu) and c.620C>T (p.Pro207Leu).	('p.Pro133Leu', 'Mutation', 'rs375002796', (174, 185))	('c.620C>T', 'Var', (191, 199))	('p.Pro207Leu', 'Mutation', 'rs1057519566', (201, 212))	('c.620C>T', 'Mutation', 'rs1057519566', (191, 199))	('c.398C>T', 'Var', (164, 172))	('MDH2', 'Gene', (135, 139))	('c.398C>T', 'Mutation', 'rs375002796', (164, 172))
42828	27989324	Familial segregation studies showed that the c.398C>T variant was inherited from the father (F1:I.1) and the c.620C>T variant was inherited from the mother (F1:I.2), whereas a healthy sister (F1:II.1) was a heterozygous carrier of the paternal (c.398C>T) variant only (Figure 1A).	('c.620C>T', 'Var', (109, 117))	('c.398C>T', 'Mutation', 'rs375002796', (245, 253))	('c.620C>T', 'Mutation', 'rs1057519566', (109, 117))	('c.398C>T', 'Var', (45, 53))	('c.398C>T', 'Mutation', 'rs375002796', (45, 53))
42840	27989324	WES identified two heterozygous MDH2 variants: a paternally inherited c.398C>T (p.Pro133Leu) missense variant, which was also found in S1, and a maternally inherited c.596delG (p.Gly199Alafs*10) nonsense variant (Figure 1A).	('p.Gly199Alafs*10', 'Var', (177, 193))	('c.398C>T', 'Mutation', 'rs375002796', (70, 78))	('MDH2 variant', 'CellLine', 'CVCL:7204', (32, 44))	('p.Pro133Leu', 'Mutation', 'rs375002796', (80, 91))	('c.398C>T', 'Var', (70, 78))	('MDH2', 'Gene', (32, 36))	('p.Gly199Alafs*10', 'FRAMESHIFT', 'None', (177, 193))	('c.596delG', 'Mutation', 'rs1057519567', (166, 175))
42841	27989324	GenePROF ranked MDH2 as the most likely disease-causing gene for an unrelated affected subject (S3, F3:II.1) who also carries a maternally inherited c.398C>T (p.Pro133Leu) MDH2 variant (Figure 1A).	('MDH2 variant', 'CellLine', 'CVCL:7204', (172, 184))	('c.398C>T', 'Mutation', 'rs375002796', (149, 157))	('MDH2', 'Gene', (172, 176))	('p.Pro133Leu', 'Mutation', 'rs375002796', (159, 170))	('c.398C>T', 'Var', (149, 157))
42847	27989324	The c.620C>T variant detected in S1 was absent from public databases, whereas the c.109G>A variant detected in S3 was found two times, and the c.398C>T variant, present in all subjects, was listed seven times only in a heterozygous state in ~120,000 alleles from the Exome Aggregation Consortium (ExAC) Browser.	('c.398C>T', 'Var', (143, 151))	('c.109G>A', 'Mutation', 'rs782308462', (82, 90))	('c.109G>A', 'Var', (82, 90))	('c.398C>T', 'Mutation', 'rs375002796', (143, 151))	('c.620C>T', 'Var', (4, 12))	('c.620C>T', 'Mutation', 'rs1057519566', (4, 12))
42848	27989324	The dimeric protein was co-crystallized with malate ion and nicotinamide-adenine-dinucleotide (NAD) for visualization of the structure and analysis of the structural consequences of MDH2 variants (Figure 1C).	('nicotinamide-adenine-dinucleotide', 'Chemical', 'MESH:D009243', (60, 93))	('MDH2 variant', 'CellLine', 'CVCL:7204', (182, 194))	('MDH2', 'Gene', (182, 186))	('variants', 'Var', (187, 195))	('NAD', 'Chemical', 'MESH:D009243', (95, 98))	('malate', 'Chemical', 'MESH:C030298', (45, 51))
42849	27989324	Gly37 is located in the NAD binding pocket; the mutation from this residue to arginine is likely to alter the binding of the coenzyme as a result of steric hindrance.	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('NAD', 'Chemical', 'MESH:D009243', (24, 27))	('Gly37', 'Var', (0, 5))	('binding', 'Interaction', (110, 117))	('mutation', 'Var', (48, 56))	('alter', 'Reg', (100, 105))	('Gly37', 'Chemical', '-', (0, 5))
42855	27989324	Thus, Pro133 and Pro207 are predicted to have structural roles by contributing to the overall architecture of MDH2.	('architecture', 'MPA', (94, 106))	('Pro207', 'Chemical', '-', (17, 23))	('Pro133', 'Var', (6, 12))	('contributing', 'Reg', (66, 78))	('MDH2', 'Gene', (110, 114))	('Pro207', 'Var', (17, 23))	('Pro133', 'Chemical', '-', (6, 12))
42856	27989324	Consequently, the p.Pro133Leu and p.Pro207Leu variants might result in destabilization of protein regions necessary for functional protein folding.	('result', 'Reg', (61, 67))	('protein', 'Protein', (90, 97))	('destabilization', 'MPA', (71, 86))	('p.Pro207Leu', 'Var', (34, 45))	('p.Pro133Leu', 'Var', (18, 29))	('p.Pro207Leu', 'Mutation', 'rs1057519566', (34, 45))	('p.Pro133Leu', 'Mutation', 'rs375002796', (18, 29))
42857	27989324	We used primary fibroblast cultures established from S1 and S3 to confirm the role of MDH2 variants in disease.	('MDH2 variant', 'CellLine', 'CVCL:7204', (86, 98))	('MDH2', 'Gene', (86, 90))	('variants', 'Var', (91, 99))
42858	27989324	Western blotting showed that MDH2 levels were not detectable in either S1 or S3 fibroblasts, supporting the notion that corresponding MDH2 variants adversely affect the stability of the protein (Figure 2A).	('MDH2', 'Gene', (134, 138))	('MDH2 variant', 'CellLine', 'CVCL:7204', (134, 146))	('affect', 'Reg', (158, 164))	('stability', 'MPA', (169, 178))	('variants', 'Var', (139, 147))
42860	27989324	The activity was notably lower in cells obtained from the parents of S1 (F1: I.1 and I.2, heterozygous for the c.398C>T and c.620C>T variants, respectively) than in control fibroblasts.	('c.398C>T', 'Mutation', 'rs375002796', (111, 119))	('c.620C>T', 'Mutation', 'rs1057519566', (124, 132))	('lower', 'NegReg', (25, 30))	('c.398C>T', 'Var', (111, 119))	('activity', 'MPA', (4, 12))	('c.620C>T', 'Var', (124, 132))
42864	27989324	To definitively substantiate that the disease-segregating missense MDH2 variants indeed cause MDH2 deficiency, we used the yeast Saccharomyces cerevisiae as a proven system for modeling mitochondrial-disease-causing mutations.	('missense', 'Var', (58, 66))	('mitochondrial-disease', 'Disease', 'MESH:D028361', (186, 207))	('MDH2 deficiency', 'Disease', (94, 109))	('mitochondrial-disease', 'Disease', (186, 207))	('variants', 'Var', (72, 80))	('yeast', 'Species', '4932', (123, 128))	('Saccharomyces cerevisiae', 'Species', '4932', (129, 153))	('MDH2 variant', 'CellLine', 'CVCL:7204', (67, 79))	('MDH2 deficiency', 'Disease', 'MESH:D007153', (94, 109))	('cause', 'Reg', (88, 93))	('MDH2', 'Gene', (67, 71))
42867	27989324	The human Gly37, Pro133, and Pro207 residues (corresponding to Gly30, Pro128, and Pro202, respectively, in yeast MDH1) are all conserved between the two species (Figure 1B).	('human', 'Species', '9606', (4, 9))	('MDH1', 'Gene', '853777', (113, 117))	('MDH1', 'Gene', (113, 117))	('Pro202', 'Var', (82, 88))	('Pro207', 'Chemical', '-', (29, 35))	('Pro133', 'Chemical', '-', (17, 23))	('Pro128', 'Chemical', '-', (70, 76))	('Pro202', 'Chemical', '-', (82, 88))	('yeast', 'Species', '4932', (107, 112))	('Pro128', 'Var', (70, 76))	('Gly37', 'Chemical', '-', (10, 15))	('Gly30', 'Var', (63, 68))	('Pro207', 'Var', (29, 35))	('Gly30', 'Chemical', '-', (63, 68))
42884	27989324	Enzyme deficiencies in the Krebs cycle have been rarely reported as the cause of metabolic disease presentations on the assumption that loss-of-function mutations affecting these key enzymes appear to be typically incompatible with life.	('metabolic disease', 'Disease', (81, 98))	('mutations', 'Var', (153, 162))	('metabolic disease', 'Disease', 'MESH:D008659', (81, 98))	('Krebs', 'Chemical', '-', (27, 32))	('Enzyme deficiencies', 'Disease', 'MESH:D008661', (0, 19))	('Enzyme deficiencies', 'Disease', (0, 19))
42885	27989324	To date, only recessively inherited variants in SDH (succinate dehydrogenase), FH (fumarate hydratase [MIM: 136850]), and ACO2 (aconitase 2 [MIM: 100850]) have been associated with human disease.	('human', 'Species', '9606', (181, 186))	('SDH', 'Gene', '6390', (48, 51))	('aconitase 2', 'Gene', (128, 139))	('associated', 'Reg', (165, 175))	('FH', 'Gene', '2271', (79, 81))	('fumarate hydratase', 'Gene', '2271', (83, 101))	('fumarate hydratase', 'Gene', (83, 101))	('SDH', 'Gene', (48, 51))	('ACO2', 'Gene', (122, 126))	('variants', 'Var', (36, 44))	('succinate dehydrogenase', 'Gene', '6390', (53, 76))	('ACO2', 'Gene', '50', (122, 126))	('aconitase 2', 'Gene', '50', (128, 139))	('succinate dehydrogenase', 'Gene', (53, 76))
42887	27989324	Recessively inherited SDHA variants are mainly associated with Leigh syndrome (MIM: 256000), and mutations in SDHB (MIM: 185470), SDHD (MIM: 602690), and SDHAF1 (MIM: 612848) are involved in severe infantile neurological presentations or cardiomyopathy associated with significant complex II deficiency.	('mutations', 'Var', (97, 106))	('SDHA', 'Gene', (154, 158))	('variants', 'Var', (27, 35))	('Leigh syndrome', 'Disease', (63, 77))	('SDHD', 'Gene', (130, 134))	('SDHA', 'Gene', '6389', (154, 158))	('associated', 'Reg', (47, 57))	('SDHB', 'Gene', (110, 114))	('cardiomyopathy', 'Disease', (238, 252))	('complex II deficiency', 'Disease', 'MESH:C565375', (281, 302))	('SDHAF1', 'Gene', '644096', (154, 160))	('SDHA', 'Gene', (22, 26))	('cardiomyopathy', 'Disease', 'MESH:D009202', (238, 252))	('involved', 'Reg', (179, 187))	('complex II deficiency', 'Disease', (281, 302))	('SDHA', 'Gene', '6389', (22, 26))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (238, 252))	('SDHAF1', 'Gene', (154, 160))	('SDHD', 'Gene', '6392', (130, 134))	('SDHB', 'Gene', '6390', (110, 114))	('Leigh syndrome', 'Disease', 'MESH:D007888', (63, 77))
42888	27989324	Fumarase deficiency, associated with recessively inherited FH variants, is a metabolic disorder characterized by neurological impairment in early childhood accompanied by encephalopathy and seizures, often leading to death in the first years of life (for a review, see Ottolenghi et al.).	('neurological impairment', 'Phenotype', 'HP:0000707', (113, 136))	('Fumarase deficiency', 'Disease', (0, 19))	('neurological impairment', 'Disease', (113, 136))	('encephalopathy', 'Disease', 'MESH:D001927', (171, 185))	('neurological impairment', 'Disease', 'MESH:D009422', (113, 136))	('death', 'Disease', 'MESH:D003643', (217, 222))	('encephalopathy', 'Phenotype', 'HP:0001298', (171, 185))	('leading to', 'Reg', (206, 216))	('metabolic disorder', 'Disease', 'MESH:D008659', (77, 95))	('seizures', 'Disease', (190, 198))	('FH', 'Gene', '2271', (59, 61))	('metabolic disorder', 'Disease', (77, 95))	('Fumarase deficiency', 'Phenotype', 'HP:0003536', (0, 19))	('seizures', 'Disease', 'MESH:D012640', (190, 198))	('encephalopathy', 'Disease', (171, 185))	('metabolic disorder', 'Phenotype', 'HP:0001939', (77, 95))	('child', 'Species', '9606', (146, 151))	('seizures', 'Phenotype', 'HP:0001250', (190, 198))	('Fumarase deficiency', 'Disease', 'MESH:C538191', (0, 19))	('variants', 'Var', (62, 70))	('death', 'Disease', (217, 222))
42889	27989324	Finally, mutations in ACO2, encoding mitochondrial aconitase, are responsible for cerebellar-retinal degeneration in childhood.	('cerebellar-retinal degeneration', 'Disease', 'MESH:D012162', (82, 113))	('mitochondrial aconitase', 'Gene', (37, 60))	('mitochondrial aconitase', 'Gene', '50', (37, 60))	('mutations', 'Var', (9, 18))	('cerebellar-retinal degeneration', 'Disease', (82, 113))	('ACO2', 'Gene', (22, 26))	('responsible', 'Reg', (66, 77))	('retinal degeneration', 'Phenotype', 'HP:0000546', (93, 113))	('ACO2', 'Gene', '50', (22, 26))	('child', 'Species', '9606', (117, 122))
42890	27989324	Our report documents that loss-of-function mutations in MDH2 are compatible with life and are associated with early-onset severe neurological disease, and the deleterious nature of the identified MDH2 variants has been confirmed by functional assessment in both human cells and a yeast model.	('MDH2', 'Gene', (196, 200))	('yeast', 'Species', '4932', (280, 285))	('human', 'Species', '9606', (262, 267))	('neurological disease', 'Disease', 'MESH:D020271', (129, 149))	('neurological disease', 'Disease', (129, 149))	('variants', 'Var', (201, 209))	('mutations', 'Var', (43, 52))	('MDH2', 'Gene', (56, 60))	('MDH2 variant', 'CellLine', 'CVCL:7204', (196, 208))	('loss-of-function', 'NegReg', (26, 42))	('neurological disease', 'Phenotype', 'HP:0000707', (129, 149))
42902	27989324	However, targeted knockdown of MDH2 expression in HeLa cells by small hairpin RNA did lead to the accumulation of both malate and fumarate.	('knockdown', 'Var', (18, 27))	('HeLa', 'CellLine', 'CVCL:0030', (50, 54))	('fumarate', 'Chemical', 'MESH:D005650', (130, 138))	('accumulation of', 'MPA', (98, 113))	('fumarate', 'MPA', (130, 138))	('malate', 'Chemical', 'MESH:C030298', (119, 125))	('MDH2', 'Gene', (31, 35))	('lead to', 'Reg', (86, 93))
42905	27989324	Impairment of the PDH complex leads to a decrease in the production of NADH and FADH2, which donate electrons to the RC to complete the OXPHOS by generating ATP.	('production', 'MPA', (57, 67))	('NADH', 'Gene', (71, 75))	('ATP', 'Chemical', 'MESH:D000255', (157, 160))	('decrease', 'NegReg', (41, 49))	('ATP', 'MPA', (157, 160))	('Impairment', 'Var', (0, 10))	('NADH', 'Chemical', 'MESH:D009243', (71, 75))	('FADH2', 'Gene', (80, 85))
42908	27989324	Although the recessive MDH2 variants identified in the affected subjects described in this study lead to a severe neurological presentation, the fact that their parents are heterozygous carriers could place them at an elevated risk of tumorigenesis.	('MDH2', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('variants', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('MDH2 variant', 'CellLine', 'CVCL:7204', (23, 35))	('tumor', 'Disease', (235, 240))	('lead to', 'Reg', (97, 104))
42910	27989324	For heterozygous carriers of mutations in the different SDH genes associated with infantile neurological presentations, the situation is unclear.	('infantile neurological presentations', 'Disease', (82, 118))	('mutations', 'Var', (29, 38))	('associated', 'Reg', (66, 76))	('SDH', 'Gene', '6390', (56, 59))	('SDH', 'Gene', (56, 59))
42911	27989324	Although there is no indication of cancer susceptibility in either family with MDH2 mutations, we are recommending ongoing surveillance and screening.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('MDH2', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
42912	27989324	In conclusion, we have shown that bi-allelic variants in MDH2, encoding a mitochondrially targeted Krebs cycle enzyme, are responsible for a severe infantile neurological phenotype.	('bi-allelic variants', 'Var', (34, 53))	('MDH2', 'Gene', (57, 61))	('Krebs', 'Chemical', '-', (99, 104))	('responsible for', 'Reg', (123, 138))
42914	27989324	The data reported in this paper have been deposited in ClinVar (as three independent submissions corresponding to each subject or organization) under accession numbers ClinVar: SCV000321300 and SCV000321301for c.398C>T and c.620C>T, respectively; SCV000322707 and SCV000322708 for c.398C>T and c.596delG, respectively; and SCV000299301 for c.109G>A and c.398C>T.	('SCV000299301', 'Var', (323, 335))	('SCV000321301for', 'Var', (194, 209))	('c.398C>T', 'Var', (353, 361))	('SCV000322708', 'Var', (264, 276))	('c.596delG', 'Mutation', 'rs1057519567', (294, 303))	('c.398C>T', 'Mutation', 'rs375002796', (353, 361))	('SCV000322707', 'Var', (247, 259))	('c.398C>T', 'Mutation', 'rs375002796', (281, 289))	('c.398C>T', 'Var', (210, 218))	('c.109G>A', 'Var', (340, 348))	('c.109G>A', 'Mutation', 'rs782308462', (340, 348))	('SCV000321300', 'Var', (177, 189))	('c.398C>T', 'Mutation', 'rs375002796', (210, 218))	('c.620C>T', 'Var', (223, 231))	('c.620C>T', 'Mutation', 'rs1057519566', (223, 231))
42988	21692797	These tumors typically occur in a benign form but may present in a malignant form and reach up to 36 % or even higher in subjects with extra-adrenal tumors, in particular when associated with the mutation of the gene encoding the B subunit of the mitochondrial complex II enzyme succinate dehydrogenase enzyme (SDHB).	('mutation', 'Var', (196, 204))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('extra-adrenal tumors', 'Disease', 'MESH:D010236', (135, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('extra-adrenal tumors', 'Disease', (135, 155))	('associated', 'Reg', (176, 186))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (149, 155))	('SDHB', 'Gene', '6390', (311, 315))	('SDHB', 'Gene', (311, 315))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('adrenal tumor', 'Phenotype', 'HP:0100631', (141, 154))
42991	21692797	From several clinical studies, the highest predictive value might include the extra-adrenal tumor location, presence of SDHB mutations, and tumor size.	('mutations', 'Var', (125, 134))	('extra-adrenal tumor', 'Disease', (78, 97))	('adrenal tumor', 'Phenotype', 'HP:0100631', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (92, 97))	('SDHB', 'Gene', '6390', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SDHB', 'Gene', (120, 124))	('extra-adrenal tumor', 'Disease', 'MESH:D010236', (78, 97))	('tumor', 'Disease', (140, 145))
43008	21692797	Genetic testing for mutations in pheochromocytoma susceptible genes [RET (rearranged during transfection), VHL (von Hippel-Lindau gene), SDHB, and SDHD (succinate dehydrogenase subunit D gene) was performed at NIH, at Mayo Medical Laboratories, Rochester, MN or at Division of Molecular Diagnostics at the University of Pittsburgh Medical Center Department of Genetics of the Children's Hospital of Philadelphia, PA as described elsewhere or at Institute of Biology and Medical Genetics of the First Faculty of Medicine, Charles University in Prague.	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (112, 129))	('VHL', 'Gene', '7428', (107, 110))	('RET', 'Gene', '5979', (69, 72))	('pheochromocytoma', 'Disease', (33, 49))	('pheochromocytoma', 'Disease', 'MESH:D010673', (33, 49))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (33, 49))	('SDHB', 'Gene', '6390', (137, 141))	('Children', 'Species', '9606', (376, 384))	('SDHB', 'Gene', (137, 141))	('SDHD', 'Gene', '6392', (147, 151))	('Mayo', 'Species', '162683', (218, 222))	('RET', 'Gene', (69, 72))	('von Hippel-Lindau', 'Disease', (112, 129))	('MN', 'CellLine', 'CVCL:U508', (256, 258))	('SDHD', 'Gene', (147, 151))	('VHL', 'Gene', (107, 110))	('mutations', 'Var', (20, 29))
43019	21692797	Genetic testing for germ-line mutations or clinical assessment revealed 9 (25.7 %) carriers of germ-line mutations in patients with malignant pheochromocytoma (2x SDHB, 4x RET, and 3x VHL), compared to 11 (14.7 %) carriers in subjects with benign pheochromocytoma (2x RET, 5x VHL, and 4x neurofibromatosis type I) (Table 1).	('pheochromocytoma', 'Phenotype', 'HP:0002666', (142, 158))	('VHL', 'Gene', (276, 279))	('VHL', 'Gene', '7428', (184, 187))	('mutations', 'Var', (105, 114))	('benign pheochromocytoma', 'Disease', (240, 263))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (132, 158))	('VHL', 'Gene', '7428', (276, 279))	('RET', 'Gene', '5979', (172, 175))	('malignant pheochromocytoma', 'Disease', (132, 158))	('benign pheochromocytoma', 'Disease', 'MESH:D010673', (240, 263))	('SDHB', 'Gene', '6390', (163, 167))	('RET', 'Gene', '5979', (268, 271))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (288, 305))	('neurofibromatosis type I', 'Disease', (288, 312))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (247, 263))	('VHL', 'Gene', (184, 187))	('SDHB', 'Gene', (163, 167))	('neurofibromatosis type I', 'Disease', 'MESH:C537392', (288, 312))	('RET', 'Gene', (172, 175))	('RET', 'Gene', (268, 271))	('patients', 'Species', '9606', (118, 126))
43054	21692797	The strongest predictors are extra-adrenal locations and the presence of mutation of the SDHB gene.	('presence of mutation', 'Var', (61, 81))	('mutation', 'Var', (73, 81))	('SDHB', 'Gene', '6390', (89, 93))	('SDHB', 'Gene', (89, 93))
43069	21692797	This could be explained by the relatively low number of subjects who have been tested positive for mutations in the SDHB-gene which has been found to be strongly associated not only with malignant disease but also with either dopamine secreting tumors or no catecholamine production at all.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('malignant disease', 'Disease', (187, 204))	('dopamine', 'Chemical', 'MESH:D004298', (226, 234))	('catecholamine', 'Chemical', 'MESH:D002395', (258, 271))	('SDHB', 'Gene', '6390', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('associated', 'Reg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mutations', 'Var', (99, 108))	('SDHB', 'Gene', (116, 120))	('malignant disease', 'Disease', 'MESH:D009369', (187, 204))	('tumors', 'Disease', (245, 251))
43071	21692797	However, only two patients with mutation of the SDHB-gene, which is strongly associated with a malignant behavior of extra-adrenal pheochromocytoma, were included in the present study.	('SDHB', 'Gene', (48, 52))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (123, 147))	('extra-adrenal pheochromocytoma', 'Disease', (117, 147))	('SDHB', 'Gene', '6390', (48, 52))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (131, 147))	('extra-adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (117, 147))	('patients', 'Species', '9606', (18, 26))	('extra-adrenal pheochromocytoma', 'Phenotype', 'HP:0006737', (117, 147))	('mutation', 'Var', (32, 40))	('associated with', 'Reg', (77, 92))
43104	17683569	Additionally, positive staining for [Leu5]-enkephalin, [Met5]-enkephalin, somatostatin, pancreatic polypeptide, and vasoactive intestinal polypeptide (VIP) was identified.	('VIP', 'Gene', '7432', (151, 154))	('somatostatin', 'Gene', '6750', (74, 86))	('VIP', 'Gene', (151, 154))	('vasoactive intestinal polypeptide', 'Gene', (116, 149))	('[Leu5]-enkephalin', 'Var', (36, 53))	('pancreatic polypeptide', 'Gene', '5539', (88, 110))	('somatostatin', 'Gene', (74, 86))	('pancreatic polypeptide', 'Gene', (88, 110))	('vasoactive intestinal polypeptide', 'Gene', '7432', (116, 149))	('[Met5]-enkephalin', 'Var', (55, 72))
43108	17683569	Due to histopathologic diagnosis, genetic testing for familial paraganglioma, neurofibromatosis type 1, von Hippel-Lindau disease, the Carney triad, multiple endocrine neoplasia type 2, and mutations of the succinate dehydrogenase genes (SDHB, SDHC, and SDHD) was performed that was negative.	('multiple endocrine neoplasia type 2', 'Disease', (149, 184))	('SDHB', 'Gene', '6390', (238, 242))	('SDHC', 'Gene', (244, 248))	('neoplasia', 'Phenotype', 'HP:0002664', (168, 177))	('paraganglioma', 'Phenotype', 'HP:0002668', (63, 76))	('mutations', 'Var', (190, 199))	('neurofibromatosis type 1, von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (78, 129))	('SDHB', 'Gene', (238, 242))	('familial paraganglioma', 'Disease', (54, 76))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (149, 184))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (78, 95))	('Carney triad', 'Disease', (135, 147))	('SDHD', 'Gene', '6392', (254, 258))	('SDHC', 'Gene', '6391', (244, 248))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (158, 177))	('familial paraganglioma', 'Disease', 'MESH:D010235', (54, 76))	('SDHD', 'Gene', (254, 258))
43120	17683569	Paragangliomas may be hereditary and can be associated with familial paraganglioma, neurofibromatosis type 1, von Hippel-Lindau disease, the Carney triad, multiple endocrine neoplasia type 2, and mutations of the succinate dehydrogenase genes (SDHB, SDHC, and SDHD).	('SDHC', 'Gene', '6391', (250, 254))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('SDHB', 'Gene', '6390', (244, 248))	('multiple endocrine neoplasia type 2', 'Disease', (155, 190))	('paraganglioma', 'Phenotype', 'HP:0002668', (69, 82))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (84, 101))	('familial paraganglioma', 'Disease', 'MESH:D010235', (60, 82))	('SDHB', 'Gene', (244, 248))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('SDHC', 'Gene', (250, 254))	('SDHD', 'Gene', '6392', (260, 264))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (155, 190))	('Paragangliomas', 'Disease', (0, 14))	('mutations', 'Var', (196, 205))	('associated', 'Reg', (44, 54))	('neoplasia', 'Phenotype', 'HP:0002664', (174, 183))	('neurofibromatosis type 1, von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (84, 135))	('familial paraganglioma', 'Disease', (60, 82))	('Carney triad', 'Disease', (141, 153))	('SDHD', 'Gene', (260, 264))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (164, 183))
43152	32608378	Advanced pharmacological therapies for neurofibromatosis type 1-related tumors Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin.	('loss of function', 'NegReg', (198, 214))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Neurofibromatosis Type 1', 'Gene', '4763', (79, 103))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('variant', 'Var', (215, 222))	('Neurofibromatosis Type 1', 'Gene', (79, 103))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('neurofibromatosis type 1-related tumors', 'Disease', (39, 78))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (39, 56))	('tumor-predisposition disorder', 'Disease', (135, 164))	('NF1', 'Gene', (230, 233))	('tumor-predisposition disorder', 'Disease', 'OMIM:614327', (135, 164))	('neurofibroma', 'Phenotype', 'HP:0001067', (39, 51))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (79, 96))	('neurofibromatosis type 1-related tumors', 'Disease', 'MESH:C537392', (39, 78))
43153	32608378	The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation.	('sarcoma', 'Disease', (66, 73))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('increased', 'PosReg', (128, 137))	('activity', 'MPA', (46, 54))	('increased', 'PosReg', (36, 45))	('neurofibromin', 'Protein', (15, 28))	('sarcoma', 'Disease', 'MESH:D012509', (66, 73))	('absence', 'Var', (4, 11))
43159	32608378	Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the tumor suppressor gene NF1.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NF1', 'Gene', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('tumor', 'Disease', (56, 61))	('Neurofibromatosis Type 1', 'Gene', (0, 24))	('tumor', 'Disease', (151, 156))	('variant', 'Var', (136, 143))	('tumor-predisposition disorder', 'Disease', (56, 85))	('tumor-predisposition disorder', 'Disease', 'OMIM:614327', (56, 85))	('Neurofibromatosis Type 1', 'Gene', '4763', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
43162	32608378	Risk of cancer in NF1 patients is 2 to 5 times higher than in the general population (6,7).	('cancer', 'Disease', (8, 14))	('higher', 'PosReg', (47, 53))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NF1', 'Var', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
43170	32608378	The germline mutation rate of NF1 is some 10-fold higher than that observed for most other inherited disease genes.	('higher', 'PosReg', (50, 56))	('NF1', 'Gene', (30, 33))	('inherited disease', 'Disease', 'MESH:D030342', (91, 108))	('germline mutation', 'Var', (4, 21))	('inherited disease', 'Disease', (91, 108))
43171	32608378	Currently, over 2600 different inherited mutations in NF1 have been reported in the Human Gene Mutation Database (HGMD ) as a cause of NF1 (11-16).	('mutations', 'Var', (41, 50))	('cause', 'Reg', (126, 131))	('NF1', 'Gene', (54, 57))	('Human', 'Species', '9606', (84, 89))	('NF1', 'Disease', (135, 138))
43178	32608378	Other clinical features require an additional somatic mutation, resulting in biallelic NF1 inactivation, as seen in the development of cafe-au-lait macules (CALMs), neurofibromas, GIST, glomus tumors, juvenile myelomonocytic leukemia (JMML), bone dysplasia and pheochromocytoma (25).	('juvenile myelomonocytic leukemia', 'Disease', (201, 233))	('glomus tumors', 'Disease', 'MESH:D005918', (186, 199))	('neurofibromas', 'Phenotype', 'HP:0001067', (165, 178))	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (201, 233))	('bone dysplasia', 'Phenotype', 'HP:0002652', (242, 256))	('neurofibromas', 'Disease', 'MESH:D009455', (165, 178))	('GIST', 'Phenotype', 'HP:0100723', (180, 184))	('NF1', 'Gene', (87, 90))	('JMML', 'Phenotype', 'HP:0012209', (235, 239))	('bone dysplasia', 'Disease', 'MESH:D001848', (242, 256))	('CALMs', 'Phenotype', 'HP:0000957', (157, 162))	('neurofibroma', 'Phenotype', 'HP:0001067', (165, 177))	('glomus tumors', 'Disease', (186, 199))	('biallelic', 'Var', (77, 86))	('neurofibromas', 'Disease', (165, 178))	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (201, 233))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('pheochromocytoma', 'Disease', 'MESH:D010673', (261, 277))	('cafe-au-lait macules', 'Phenotype', 'HP:0000957', (135, 155))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('bone dysplasia', 'Disease', (242, 256))	('pheochromocytoma', 'Disease', (261, 277))	('inactivation', 'NegReg', (91, 103))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (261, 277))	('macules', 'Phenotype', 'HP:0012733', (148, 155))
43179	32608378	Furthermore, mouse models of MPNST have shown that biallelic inactivation of the NF1 gene may not be sufficient for tumour formation and that additional genetic alterations such as mutation of TP53, CDKN2A or SUZ12, are required for the progression of MPNST (7,29,30).	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('SUZ12', 'Gene', '52615', (209, 214))	('mouse', 'Species', '10090', (13, 18))	('MPNST', 'Phenotype', 'HP:0100697', (29, 34))	('SUZ12', 'Gene', (209, 214))	('biallelic inactivation', 'Var', (51, 73))	('NF1', 'Gene', (81, 84))	('TP53', 'Gene', '22059', (193, 197))	('tumour', 'Disease', (116, 122))	('MPNST', 'Phenotype', 'HP:0100697', (252, 257))	('CDKN2A', 'Gene', '12578', (199, 205))	('mutation', 'Var', (181, 189))	('TP53', 'Gene', (193, 197))	('CDKN2A', 'Gene', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
43187	32608378	Cognitive dysfunction has a high impact on NF1 children, since school-age children with NF1 have higher rates of developmental delay and cognitive impairment than their pairs, and many of them carry a concurrent diagnosis of attention deficit/hyperactivity disorder.	('cognitive impairment', 'Disease', (137, 157))	('developmental delay', 'Disease', 'MESH:D002658', (113, 132))	('attention deficit/hyperactivity disorder', 'Disease', 'MESH:D001289', (225, 265))	('hyperactivity', 'Phenotype', 'HP:0000752', (243, 256))	('NF1', 'Var', (88, 91))	('Cognitive dysfunction', 'Disease', (0, 21))	('developmental delay', 'Disease', (113, 132))	('cognitive impairment', 'Disease', 'MESH:D003072', (137, 157))	('children', 'Species', '9606', (74, 82))	('children', 'Species', '9606', (47, 55))	('developmental delay', 'Phenotype', 'HP:0001263', (113, 132))	('Cognitive dysfunction', 'Disease', 'MESH:D003072', (0, 21))	('attention deficit/hyperactivity disorder', 'Disease', (225, 265))	('attention deficit', 'Phenotype', 'HP:0007018', (225, 242))	('cognitive impairment', 'Phenotype', 'HP:0100543', (137, 157))
43193	32608378	Patients with NF1 are also at risk to develop other malignancies in adulthood, like gastrointestinal stromal tumors, pheochromocytoma, duodenal carcinoid, high grade glioma and breast cancer.	('pheochromocytoma', 'Disease', 'MESH:D010673', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('glioma', 'Phenotype', 'HP:0009733', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('pheochromocytoma', 'Disease', (117, 133))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (117, 133))	('carcinoid', 'Disease', 'MESH:D002276', (144, 153))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (84, 115))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (84, 115))	('malignancies', 'Disease', (52, 64))	('NF1', 'Var', (14, 17))	('carcinoid', 'Phenotype', 'HP:0100570', (144, 153))	('develop', 'PosReg', (38, 45))	('carcinoid', 'Disease', (144, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('glioma and breast cancer', 'Disease', 'MESH:D001943', (166, 190))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (84, 114))	('gastrointestinal stromal tumors', 'Disease', (84, 115))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('duodenal carcinoid', 'Phenotype', 'HP:0006771', (135, 153))
43201	32608378	Although the 5-year overall survival for patients with low grade glioma is 85%, progression-free survival for those with unresectable/residual disease requiring treatment is significantly lower (40%) (41).	('glioma', 'Disease', (65, 71))	('lower', 'NegReg', (188, 193))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('patients', 'Species', '9606', (41, 49))	('low grade', 'Var', (55, 64))
43231	32608378	Although rare in patients with NF-1, few studies have shown that women with NF1 are at a higher risk of developing early onset breast cancer with aggressive behaviour and a poorer prognosis, compared to the general population.	('aggressive behaviour', 'Phenotype', 'HP:0000718', (146, 166))	('NF1', 'Var', (76, 79))	('aggressive behaviour', 'Disease', (146, 166))	('NF-1', 'Gene', '4763', (31, 35))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('patients', 'Species', '9606', (17, 25))	('NF-1', 'Gene', (31, 35))	('aggressive behaviour', 'Disease', 'MESH:D001523', (146, 166))	('women', 'Species', '9606', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
43292	32608378	Finally, there are several ongoing trials with selective tyrosine kinase inhibitors like Nilotinib (NCT01275586), Trametinib (NCT03363217) (123), or Cabozantinib (NCT02101736), and mTOR pathway inhibitors like Everolimus (NCT01365468).	('Everolimus', 'Chemical', 'MESH:D000068338', (210, 220))	('Cabozantinib', 'Chemical', 'MESH:C558660', (149, 161))	('NCT02101736', 'Var', (163, 174))	('Trametinib', 'Chemical', 'MESH:C560077', (114, 124))	('Nilotinib', 'Chemical', 'MESH:C498826', (89, 98))	('NCT01275586', 'Var', (100, 111))	('mTOR', 'Gene', '2475', (181, 185))	('mTOR', 'Gene', (181, 185))
43295	32608378	These include the use of small molecules, like PLX3397 (an inhibitor of CSF1 and KIT) used in combination with mTor pathway inhibitors (NCT02584647) (125), or modified BET inhibitors to overcome resistance in MPNST (126).	('CSF1', 'Gene', '1435', (72, 76))	('KIT', 'Gene', '3815', (81, 84))	('mTor', 'Gene', (111, 115))	('MPNST', 'Phenotype', 'HP:0100697', (209, 214))	('KIT', 'Gene', (81, 84))	('mTor', 'Gene', '2475', (111, 115))	('BET', 'Gene', '92737', (168, 171))	('modified', 'Var', (159, 167))	('CSF1', 'Gene', (72, 76))	('BET', 'Gene', (168, 171))
43299	32608378	GTP-RAS activates a multitude of effectors protein, including the RAF and the MEK/ERK signalling cascades, which promote proliferation, and the PI3K/mTOR pathway, which promotes growth and cell survival.	('growth', 'CPA', (178, 184))	('promotes', 'PosReg', (169, 177))	('RAF', 'Gene', (66, 69))	('cell survival', 'CPA', (189, 202))	('proliferation', 'CPA', (121, 134))	('promote', 'PosReg', (113, 120))	('mTOR', 'Gene', '2475', (149, 153))	('activates', 'PosReg', (8, 17))	('mTOR', 'Gene', (149, 153))	('ERK', 'Gene', '5594', (82, 85))	('GTP-RAS', 'Var', (0, 7))	('GTP', 'Chemical', '-', (0, 3))	('ERK', 'Gene', (82, 85))	('RAF', 'Gene', '22882', (66, 69))
43300	33182397	Novel DNMT3A Germline Variant in a Patient with Multiple Paragangliomas and Papillary Thyroid Carcinoma The use of next generation technologies has helped to unravel the genetics of rare inherited diseases, facilitating the discovery of new susceptibility genes.	('inherited diseases', 'Disease', 'MESH:D030342', (187, 205))	('Patient', 'Species', '9606', (35, 42))	('Paragangliomas and Papillary Thyroid Carcinoma', 'Disease', 'MESH:D000077273', (57, 103))	('Thyroid Carcinoma', 'Phenotype', 'HP:0002890', (86, 103))	('Papillary Thyroid Carcinoma', 'Phenotype', 'HP:0002895', (76, 103))	('Carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('Paragangliomas', 'Phenotype', 'HP:0002668', (57, 71))	('inherited diseases', 'Disease', (187, 205))	('Variant', 'Var', (22, 29))	('DNMT3A', 'Gene', (6, 12))	('DNMT3A', 'Gene', '1788', (6, 12))
43302	33182397	Here we describe a novel DNMT3A germline variant identified by whole-exome sequencing in a patient with multiple paragangliomas and papillary thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (142, 159))	('paragangliomas', 'Phenotype', 'HP:0002668', (113, 127))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('DNMT3A', 'Gene', (25, 31))	('multiple paragangliomas and papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (104, 159))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (132, 159))	('variant', 'Var', (41, 48))	('patient', 'Species', '9606', (91, 98))
43303	33182397	The increased methylation of DNMT3A target genes observed in the proband's sample points towards a gain-of-function effect of the variant, contrasting with the inactivation caused by loss-of-function alterations commonly seen in other neoplasia and in patients with Tatton-Brown-Rahman syndrome.	('gain-of-function', 'PosReg', (99, 115))	('Tatton-Brown-Rahman syndrome', 'Disease', (266, 294))	('neoplasia', 'Disease', (235, 244))	('methylation', 'MPA', (14, 25))	('Tatton-Brown-Rahman syndrome', 'Disease', 'OMIM:615879', (266, 294))	('patients', 'Species', '9606', (252, 260))	('variant', 'Var', (130, 137))	('neoplasia', 'Disease', 'MESH:D009369', (235, 244))	('neoplasia', 'Phenotype', 'HP:0002664', (235, 244))	('increased', 'PosReg', (4, 13))
43305	33182397	We recently found germline DNMT3A gain-of-function variants in two patients with head and neck paragangliomas causing a characteristic hypermethylated DNA profile.	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('patients', 'Species', '9606', (67, 75))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (81, 109))	('neck paragangliomas', 'Disease', 'MESH:D010235', (90, 109))	('variants', 'Var', (51, 59))	('gain-of-function', 'PosReg', (34, 50))	('hypermethylated DNA profile', 'MPA', (135, 162))	('DNMT3A', 'Gene', (27, 33))	('neck paragangliomas', 'Disease', (90, 109))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))
43306	33182397	Here, whole-exome sequencing identifies a novel germline DNMT3A variant (p.Gly332Arg) in a patient with bilateral carotid paragangliomas, papillary thyroid carcinoma and idiopathic intellectual disability.	('papillary thyroid carcinoma', 'Disease', (138, 165))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (138, 165))	('DNMT3A', 'Gene', (57, 63))	('paragangliomas', 'Phenotype', 'HP:0002668', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('paraganglioma', 'Phenotype', 'HP:0002668', (122, 135))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (148, 165))	('bilateral carotid paragangliomas', 'Disease', (104, 136))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (138, 165))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (114, 136))	('patient', 'Species', '9606', (91, 98))	('p.Gly332Arg', 'Var', (73, 84))	('p.Gly332Arg', 'Mutation', 'rs760854242', (73, 84))	('bilateral carotid paragangliomas', 'Disease', 'MESH:D002345', (104, 136))	('intellectual disability', 'Phenotype', 'HP:0001249', (181, 204))
43307	33182397	The variant, located in the Pro-Trp-Trp-Pro (PWWP) domain of the protein involved in chromatin targeting, affects a residue mutated in papillary thyroid tumors and located between the two residues found mutated in microcephalic dwarfism patients.	('Trp', 'Chemical', 'MESH:D014364', (36, 39))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (135, 159))	('Pro', 'Chemical', 'MESH:D011392', (40, 43))	('mutated', 'Var', (124, 131))	('papillary thyroid tumors', 'Disease', 'MESH:D000077273', (135, 159))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (214, 236))	('affects', 'Reg', (106, 113))	('microcephalic dwarfism', 'Disease', (214, 236))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (214, 236))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('Pro', 'Chemical', 'MESH:D011392', (28, 31))	('patients', 'Species', '9606', (237, 245))	('papillary thyroid tumors', 'Disease', (135, 159))	('Trp', 'Chemical', 'MESH:D014364', (32, 35))	('dwarfism', 'Phenotype', 'HP:0003510', (228, 236))	('Pro-Trp', 'Chemical', '-', (28, 35))
43308	33182397	An increased methylation of DNMT3A target genes, compatible with a gain-of-function effect of the alteration, was observed in saliva DNA from the proband and in one independent acute myeloid leukemia sample carrying the same p.Gly332Arg variant.	('methylation', 'MPA', (13, 24))	('increased', 'PosReg', (3, 12))	('acute myeloid leukemia', 'Disease', (177, 199))	('p.Gly332Arg', 'Mutation', 'rs760854242', (225, 236))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (177, 199))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (177, 199))	('leukemia', 'Phenotype', 'HP:0001909', (191, 199))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (183, 199))	('p.Gly332Arg', 'Var', (225, 236))
43309	33182397	Although further studies are needed to support a causal role of DNMT3A variants in paraganglioma, the description of a new DNMT3A alteration in a patient with multiple clinical features suggests a heterogeneous phenotypic spectrum related to DNMT3A germline variants.	('variants', 'Var', (71, 79))	('alteration', 'Var', (130, 140))	('DNMT3A', 'Gene', (64, 70))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('DNMT3A', 'Gene', (123, 129))	('paraganglioma', 'Disease', (83, 96))	('patient', 'Species', '9606', (146, 153))	('paraganglioma', 'Disease', 'MESH:D010235', (83, 96))
43310	33182397	The drip of new susceptibility genes involved in the development of pheochromocytoma (PCC) and paraganglioma (PGL), altogether PPGLs, has not ceased since the discovery of pathogenic variants in the succinate dehydrogenase (SDH) genes in the early 2000s.	('SDH', 'Gene', '6390', (224, 227))	('succinate dehydrogenase', 'Gene', (199, 222))	('paraganglioma', 'Disease', (95, 108))	('succinate dehydrogenase', 'Gene', '6390', (199, 222))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('pheochromocytoma', 'Disease', (68, 84))	('variants', 'Var', (183, 191))	('PPGL', 'Chemical', '-', (127, 131))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('SDH', 'Gene', (224, 227))	('PGL', 'Phenotype', 'HP:0002668', (110, 113))	('pheochromocytoma', 'Disease', 'MESH:D010673', (68, 84))	('paraganglioma', 'Disease', 'MESH:D010235', (95, 108))	('PGL', 'Phenotype', 'HP:0002668', (128, 131))	('PCC', 'Phenotype', 'HP:0002666', (86, 89))
43311	33182397	Thus, up to 35-40% of PPGL patients carry a germline variant in one of the almost twenty high:or low:penetrant susceptibility genes related to the disease described so far.	('PGL', 'Phenotype', 'HP:0002668', (23, 26))	('PPGL', 'Disease', (22, 26))	('germline variant', 'Var', (44, 60))	('PPGL', 'Chemical', '-', (22, 26))	('patients', 'Species', '9606', (27, 35))
43316	33182397	On the one hand, germline de novo loss-of-function variants in DNMT3A cause Tatton-Brown-Rahman syndrome (TBRS), an autosomal dominant condition characterized by overgrowth, intellectual disability and distinctive facial appearance.	('distinctive facial appearance', 'Phenotype', 'HP:0001999', (202, 231))	('Tatton-Brown-Rahman syndrome', 'Disease', (76, 104))	('Tatton-Brown-Rahman syndrome', 'Disease', 'OMIM:615879', (76, 104))	('variants', 'Var', (51, 59))	('loss-of-function', 'NegReg', (34, 50))	('overgrowth', 'Phenotype', 'HP:0001548', (162, 172))	('DNMT3A', 'Gene', (63, 69))	('intellectual disability', 'Phenotype', 'HP:0001249', (174, 197))
43317	33182397	On the other hand and despite not being identified until 2010, somatic variants in DNMT3A are one of the most recurrent events across blood cancers of the myeloid lineage.	('variants', 'Var', (71, 79))	('blood cancers', 'Disease', (134, 147))	('blood cancers', 'Phenotype', 'HP:0001909', (134, 147))	('age', 'Gene', (167, 170))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('blood cancers', 'Disease', 'MESH:D007022', (134, 147))	('age', 'Gene', '5973', (167, 170))	('DNMT3A', 'Gene', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
43318	33182397	Up to 22% of acute myeloid leukemia (AML) patients carry a somatic variant in DNMT3A and these alterations have been associated with poor prognosis and adverse survival outcomes for AML patients.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (13, 35))	('leukemia', 'Phenotype', 'HP:0001909', (27, 35))	('associated', 'Reg', (117, 127))	('DNMT3A', 'Gene', (78, 84))	('variant', 'Var', (67, 74))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('AML', 'Disease', 'MESH:D015470', (182, 185))	('AML', 'Phenotype', 'HP:0004808', (37, 40))	('acute myeloid leukemia', 'Disease', (13, 35))	('AML', 'Disease', (37, 40))	('AML', 'Phenotype', 'HP:0004808', (182, 185))	('patients', 'Species', '9606', (42, 50))	('AML', 'Disease', (182, 185))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (13, 35))	('patients', 'Species', '9606', (186, 194))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (19, 35))
43319	33182397	Interestingly, there is overlap of the spectrum of DNMT3A variants in TBRS and hematological malignancies, with some examples of both diseases occurring in the same patient.	('variants', 'Var', (58, 66))	('hematological malignancies', 'Disease', (79, 105))	('patient', 'Species', '9606', (165, 172))	('hematological malignancies', 'Disease', 'MESH:D019337', (79, 105))	('TBRS', 'Disease', (70, 74))	('DNMT3A', 'Gene', (51, 57))	('hematological malignancies', 'Phenotype', 'HP:0004377', (79, 105))
43320	33182397	Moreover, a germline DNMT3A loss-of-function variant has been found causing familial AML, in this case in the absence of TBRS symptoms.	('loss-of-function', 'NegReg', (28, 44))	('DNMT3A', 'Gene', (21, 27))	('familial AML', 'Disease', 'MESH:D015470', (76, 88))	('familial AML', 'Disease', (76, 88))	('AML', 'Phenotype', 'HP:0004808', (85, 88))	('variant', 'Var', (45, 52))
43321	33182397	We recently identified missense germline variants in DNMT3A in two patients with multiple head and neck PGLs.	('DNMT3A', 'Gene', (53, 59))	('patients', 'Species', '9606', (67, 75))	('missense germline variants', 'Var', (23, 49))	('PGL', 'Phenotype', 'HP:0002668', (104, 107))
43322	33182397	Unlike what happens in patients with TBRS and in AML and other neoplasia, in which the gene is usually inactivated by loss-of-function alterations, we demonstrated that DNMT3A-mutated PGLs exhibited a significant overall methylation, indicating an activating role of the variants.	('PGL', 'Phenotype', 'HP:0002668', (184, 187))	('AML', 'Disease', (49, 52))	('neoplasia', 'Phenotype', 'HP:0002664', (63, 72))	('PGLs', 'Gene', (184, 188))	('DNMT3A-mutated', 'Var', (169, 183))	('patients', 'Species', '9606', (23, 31))	('neoplasia', 'Disease', 'MESH:D009369', (63, 72))	('activating', 'PosReg', (248, 258))	('methylation', 'MPA', (221, 232))	('neoplasia', 'Disease', (63, 72))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
43324	33182397	This duality has been also reported for the histone methyltransferase EZH2, in which somatic gain-of-function variants are frequently found in lymphoma, while inactivating germline alterations cause the Weaver overgrowth syndrome.	('lymphoma', 'Disease', (143, 151))	('lymphoma', 'Disease', 'MESH:D008223', (143, 151))	('overgrowth syndrome', 'Disease', 'MESH:D001765', (210, 229))	('variants', 'Var', (110, 118))	('histone methyltransferase', 'Gene', '56979', (44, 69))	('overgrowth', 'Phenotype', 'HP:0001548', (210, 220))	('overgrowth syndrome', 'Disease', (210, 229))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('histone methyltransferase', 'Gene', (44, 69))	('EZH2', 'Gene', '2146', (70, 74))	('EZH2', 'Gene', (70, 74))	('gain-of-function', 'PosReg', (93, 109))
43326	33182397	The filtering process resulted in 541 variants, six of which were found in the public archive ClinVar  (Table S1) and only one was found in a gene previously associated to PPGLs, DNMT3A (c.994G > A, p.Gly332Arg; VAF = 0.48).	('AF', 'Disease', 'MESH:D001281', (213, 215))	('resulted in', 'Reg', (22, 33))	('variants', 'Var', (38, 46))	('p.Gly332Arg', 'Var', (199, 210))	('c.994G > A', 'Var', (187, 197))	('c.994G > A', 'Mutation', 'rs760854242', (187, 197))	('p.Gly332Arg', 'Mutation', 'rs760854242', (199, 210))	('PGL', 'Phenotype', 'HP:0002668', (173, 176))	('PPGL', 'Chemical', '-', (172, 176))
43328	33182397	This frequency is below the frequency found for pathogenic variants in SDHB, a gene whose alterations have the lowest penetrance amongst those found in the known PPGL susceptibility genes.	('SDHB', 'Gene', '6390', (71, 75))	('variants', 'Var', (59, 67))	('SDHB', 'Gene', (71, 75))	('PGL', 'Phenotype', 'HP:0002668', (163, 166))	('PPGL', 'Chemical', '-', (162, 166))
43329	33182397	The Gly332 residue is located within the Pro-Trp-Trp-Pro (PWWP) domain of DNMT3A, described to function as a chromatin methylation reader by recognizing both DNA and histone methylated lysines.	('lysines', 'Chemical', 'MESH:D008239', (185, 192))	('Gly332', 'Var', (4, 10))	('DNA', 'MPA', (158, 161))	('Pro', 'Chemical', 'MESH:D011392', (53, 56))	('DNMT3A', 'Gene', (74, 80))	('Pro', 'Chemical', 'MESH:D011392', (41, 44))	('Trp', 'Chemical', 'MESH:D014364', (45, 48))	('Pro-Trp', 'Chemical', '-', (41, 48))	('Trp', 'Chemical', 'MESH:D014364', (49, 52))	('Gly332', 'Chemical', '-', (4, 10))	('histone', 'Protein', (166, 173))	('recognizing', 'Reg', (141, 152))
43330	33182397	There are 31 missense variants in gnomAD, including p.Gly332Arg, located within the PWWP domain of DNMT3A, all of them with frequencies bellow 6.4 x 10-5 (Table S2).	('gnomAD', 'Gene', (34, 40))	('p.Gly332Arg', 'Mutation', 'rs760854242', (52, 63))	('p.Gly332Arg', 'Var', (52, 63))
43332	33182397	Three different missense somatic variants have been reported in five independent samples in COSMIC  or cBioPortal  databases affecting the Gly332 residue (Figure 1a): p.Gly332Glu (n = 1; found in one clear cell renal cell carcinoma), p.Gly332Arg (n = 3; found in PTC, AML and essential thrombocythemia) and p.Gly332Val (n = 1; found in one PTC); although the causality of these variants has not been assessed.	('clear cell renal cell carcinoma', 'Disease', (200, 231))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (211, 231))	('p.Gly332Glu', 'Var', (167, 178))	('p.Gly332Arg', 'Var', (234, 245))	('affecting', 'Reg', (125, 134))	('essential thrombocythemia', 'Disease', (276, 301))	('Gly332', 'Chemical', '-', (309, 315))	('p.Gly332Val', 'Var', (307, 318))	('Gly332', 'Chemical', '-', (236, 242))	('essential thrombocythemia', 'Disease', 'MESH:D013920', (276, 301))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (200, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('PTC', 'Phenotype', 'HP:0002895', (263, 266))	('Gly332', 'Chemical', '-', (139, 145))	('p.Gly332Val', 'Mutation', 'p.G332V', (307, 318))	('thrombocythemia', 'Phenotype', 'HP:0001894', (286, 301))	('p.Gly332Glu', 'Mutation', 'rs751360082', (167, 178))	('PTC', 'Phenotype', 'HP:0002895', (340, 343))	('AML', 'Disease', 'MESH:D015470', (268, 271))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (200, 231))	('AML', 'Disease', (268, 271))	('Gly332', 'Chemical', '-', (169, 175))	('AML', 'Phenotype', 'HP:0004808', (268, 271))	('p.Gly332Arg', 'Mutation', 'rs760854242', (234, 245))
43335	33182397	In the predicted structure of the PWWP domain of the DNMT3A Gly332Arg mutant, the position of the Arg lies opposite to the Phe303 residue and could form an additional side to the conserved aromatic cage formed by the amino acids Phe303, Trp306, Trp330 and Asp333.	('DNMT3A', 'Gene', (53, 59))	('Trp306', 'Var', (237, 243))	('Phe303', 'Chemical', '-', (229, 235))	('age', 'Gene', (199, 202))	('Gly332Arg', 'SUBSTITUTION', 'None', (60, 69))	('Gly332Arg', 'Var', (60, 69))	('Phe303', 'Var', (229, 235))	('Asp333', 'Chemical', '-', (256, 262))	('Trp330', 'Chemical', '-', (245, 251))	('Phe303', 'Chemical', '-', (123, 129))	('Arg', 'Chemical', 'MESH:D001120', (98, 101))	('Trp306', 'Chemical', '-', (237, 243))	('age', 'Gene', '5973', (199, 202))	('Arg', 'Chemical', 'MESH:D001120', (66, 69))
43336	33182397	Thus, it is possible that an Arg residue in the 332 position could promote the stabilization of the binding to the trimethyl lysine present in histone H3.	('trimethyl lysine', 'Chemical', 'MESH:C003712', (115, 131))	('binding', 'Interaction', (100, 107))	('Arg residue', 'Var', (29, 40))	('Arg', 'Chemical', 'MESH:D001120', (29, 32))	('stabilization', 'MPA', (79, 92))	('trimethyl lysine', 'MPA', (115, 131))	('promote', 'PosReg', (67, 74))
43338	33182397	Hierarchical clustering grouped all the controls together and separated from the proband's sample that showed a recognizable methylated profile (Figure 3a), suggesting that the p.Gly332Arg DNMT3A variant produces a similar alteration in germline global methylation than the observed for the previously reported PPGL patients.	('p.Gly332Arg', 'Mutation', 'rs760854242', (177, 188))	('PPGL', 'Disease', (311, 315))	('PGL', 'Phenotype', 'HP:0002668', (312, 315))	('PPGL', 'Chemical', '-', (311, 315))	('germline global methylation', 'MPA', (237, 264))	('DNMT3A', 'Gene', (189, 195))	('patients', 'Species', '9606', (316, 324))	('p.Gly332Arg', 'Var', (177, 188))	('alteration', 'Reg', (223, 233))
43339	33182397	We also speculated that the methylated profile observed upon alteration of DNMT3A in PPGL patients could be similar to the one described for patients with microcephalic dwarfism harboring germline gain-of-function DNMT3A variants.	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (155, 177))	('alteration', 'Var', (61, 71))	('DNMT3A', 'Gene', (75, 81))	('microcephalic dwarfism', 'Disease', (155, 177))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (155, 177))	('methylated profile', 'MPA', (28, 46))	('PPGL', 'Gene', (85, 89))	('variants', 'Var', (221, 229))	('PGL', 'Phenotype', 'HP:0002668', (86, 89))	('PPGL', 'Chemical', '-', (85, 89))	('dwarfism', 'Phenotype', 'HP:0003510', (169, 177))	('patients', 'Species', '9606', (90, 98))	('patients', 'Species', '9606', (141, 149))	('gain-of-function', 'PosReg', (197, 213))
43340	33182397	To explore this, we investigated the methylation status of the 307 differentially methylated probes in lymphocyte DNAs from the previously reported PGL DNMT3A variant carriers and in blood samples from patients with either overgrowth or dwarfism due to DNMT3A germline variants.	('investigated', 'Reg', (20, 32))	('PGL DNMT3A', 'Gene', (148, 158))	('overgrowth', 'CPA', (223, 233))	('overgrowth', 'Phenotype', 'HP:0001548', (223, 233))	('dwarfism', 'Phenotype', 'HP:0003510', (237, 245))	('patients', 'Species', '9606', (202, 210))	('PGL', 'Phenotype', 'HP:0002668', (148, 151))	('dwarfism', 'CPA', (237, 245))	('variant', 'Var', (159, 166))
43344	33182397	In addition, we were able to collect an AML sample carrying the p.Gly332Arg DNMT3A variant and investigated whether this somatic substitution could also be causing a gain-of-function in AML.	('AML', 'Disease', 'MESH:D015470', (40, 43))	('p.Gly332Arg', 'Var', (64, 75))	('AML', 'Disease', 'MESH:D015470', (186, 189))	('p.Gly332Arg', 'Mutation', 'rs760854242', (64, 75))	('AML', 'Phenotype', 'HP:0004808', (186, 189))	('AML', 'Disease', (186, 189))	('AML', 'Phenotype', 'HP:0004808', (40, 43))	('AML', 'Disease', (40, 43))	('DNMT3A', 'Gene', (76, 82))	('gain-of-function', 'PosReg', (166, 182))
43345	33182397	To explore this, we profiled one AML sample carrying the p.Gly332Arg DNMT3A variant (this sample also carries another DNMT3A variant and two frameshift variants in TET2), with AML samples extracted from TCGA and carriers of DNMT3A somatic variants known to cause global methylation alterations (i.e., the bona fide p.Arg882 DNMT3A loss-of-function alteration).	('Arg882', 'Chemical', '-', (317, 323))	('p.Gly332Arg', 'Mutation', 'rs760854242', (57, 68))	('AML', 'Disease', 'MESH:D015470', (33, 36))	('AML', 'Phenotype', 'HP:0004808', (176, 179))	('AML', 'Disease', (176, 179))	('AML', 'Disease', (33, 36))	('p.Arg882', 'Var', (315, 323))	('TET2', 'Gene', '54790', (164, 168))	('AML', 'Phenotype', 'HP:0004808', (33, 36))	('loss-of-function', 'NegReg', (331, 347))	('DNMT3A', 'Gene', (69, 75))	('AML', 'Disease', 'MESH:D015470', (176, 179))	('p.Gly332Arg', 'Var', (57, 68))	('methylation alterations', 'MPA', (270, 293))	('TET2', 'Gene', (164, 168))
43346	33182397	We also included three samples carrying additional frameshift TET2 variants.	('TET2', 'Gene', (62, 66))	('frameshift', 'Var', (51, 61))	('TET2', 'Gene', '54790', (62, 66))
43347	33182397	The unsupervised clustering, using the aforementioned methylation signature, revealed that the p.Gly332Arg mutated AML showed a completely different profile to the one observed for the samples carrying the recurrent p.Arg882 DNMT3A inactivating variant (Figure S1).	('AML', 'Disease', 'MESH:D015470', (115, 118))	('p.Gly332Arg', 'Var', (95, 106))	('p.Gly332Arg', 'Mutation', 'rs760854242', (95, 106))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('AML', 'Disease', (115, 118))	('p.Arg882', 'Var', (216, 224))	('Arg882', 'Chemical', '-', (218, 224))
43349	33182397	Overall, these results suggest that the p.Gly332Arg DNMT3A variant led, in germline and also in AML, to a characteristic methylation profile, distinct to the profile caused by well-known DNMT3A inactivating variants.	('AML', 'Disease', (96, 99))	('p.Gly332Arg', 'Var', (40, 51))	('p.Gly332Arg', 'Mutation', 'rs760854242', (40, 51))	('methylation profile', 'MPA', (121, 140))	('DNMT3A', 'Gene', (52, 58))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('AML', 'Phenotype', 'HP:0004808', (96, 99))
43350	33182397	Although the sample carrying the p.Gly332Arg variant harbors an additional variant in the MTase domain of DNMT3A (p.Arg720Cys), its low allele frequency together with the fact that variants in this domain likely disrupt the catalytic activity of the enzyme, supports that the observed methylated profile is caused by the PWWP variant.	('disrupt', 'NegReg', (212, 219))	('p.Gly332Arg', 'Var', (33, 44))	('p.Gly332Arg', 'Mutation', 'rs760854242', (33, 44))	('p.Arg720Cys', 'Mutation', 'rs1197133406', (114, 125))	('catalytic activity', 'MPA', (224, 242))
43353	33182397	Later it was demonstrated that this was a consequence of oncometabolite accumulation, caused by pathogenic variants in Krebs cycle genes.	('Krebs', 'Chemical', '-', (119, 124))	('Krebs', 'Gene', (119, 124))	('variants', 'Var', (107, 115))	('oncometabolite accumulation', 'MPA', (57, 84))
43354	33182397	More recently, disrupting variants in ATRX and in other chromatin-remodeling genes, including post-zygotic H3F3A gain-of-function alterations, have also been found recurrently in PPGLs.	('gain-of-function', 'PosReg', (113, 129))	('ATRX', 'Gene', (38, 42))	('H3F3A', 'Gene', '3020', (107, 112))	('alterations', 'Var', (130, 141))	('PPGL', 'Chemical', '-', (179, 183))	('PGL', 'Phenotype', 'HP:0002668', (180, 183))	('ATRX', 'Gene', '546', (38, 42))	('H3F3A', 'Gene', (107, 112))	('PPGLs', 'Disease', (179, 184))	('variants', 'Var', (26, 34))
43355	33182397	The identification of DNMT3A activating variants leading to a specific CIMP further supported the association between epigenetic modifications and PPGL development.	('association', 'Interaction', (98, 109))	('leading to', 'Reg', (49, 59))	('DNMT3A', 'Gene', (22, 28))	('PPGL', 'Chemical', '-', (147, 151))	('variants', 'Var', (40, 48))	('PGL', 'Phenotype', 'HP:0002668', (148, 151))	('CIMP', 'Disease', (71, 75))
43356	33182397	In addition to the variants reported in patients with PGLs, germline gain-of-function DNMT3A variants located in the PWWP domain which cause widespread DNA hypermethylation at polycomb-regulated regions (with the H3K27me3 mark) have been found in patients with microcephalic dwarfism, an extreme growth disorder.	('growth disorder', 'Disease', (296, 311))	('PGL', 'Phenotype', 'HP:0002668', (54, 57))	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (261, 283))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (261, 283))	('patients', 'Species', '9606', (40, 48))	('dwarfism', 'Phenotype', 'HP:0003510', (275, 283))	('microcephalic dwarfism', 'Disease', (261, 283))	('variants', 'Var', (93, 101))	('patients', 'Species', '9606', (247, 255))	('growth disorder', 'Phenotype', 'HP:0001507', (296, 311))	('gain-of-function', 'PosReg', (69, 85))	('DNMT3A', 'Gene', (86, 92))	('growth disorder', 'Disease', 'MESH:D006130', (296, 311))
43357	33182397	A similar growth deficiency has been observed in mice carrying a DNMT3A PWWP germline variant in the Asp329 residue (corresponding to the human Asp333).	('variant in', 'Var', (86, 96))	('human', 'Species', '9606', (138, 143))	('growth deficiency', 'Phenotype', 'HP:0001510', (10, 27))	('mice', 'Species', '10090', (49, 53))	('growth deficiency', 'Disease', 'MESH:D006130', (10, 27))	('Asp333', 'Chemical', '-', (144, 150))	('Asp329', 'Chemical', '-', (101, 107))	('growth deficiency', 'Disease', (10, 27))
43358	33182397	This results in DNA hypermethylation and de-repression of developmental regulatory genes that manifests phenotypically as dominant postnatal growth retardation.	('growth retardation', 'Phenotype', 'HP:0001510', (141, 159))	('postnatal growth retardation', 'Disease', (131, 159))	('hypermethylation', 'Var', (20, 36))	('de-repression', 'NegReg', (41, 54))	('postnatal growth retardation', 'Phenotype', 'HP:0008897', (131, 159))	('postnatal growth retardation', 'Disease', 'MESH:D006130', (131, 159))	('developmental regulatory genes', 'Gene', (58, 88))	('results in DNA', 'Reg', (5, 19))
43359	33182397	In the same way, the murine equivalent to the human Lys299Ile found in patients with PGL, disrupts both DNA and H3K36me2/3 binding by altering the aromatic cage conformation of the PWWP domain of DNMT3A, finally leading to disruption of the sub-nuclear localization of DNMT3A.	('binding', 'Interaction', (123, 130))	('altering', 'Reg', (134, 142))	('H3K36me2/3', 'Protein', (112, 122))	('PGL', 'Phenotype', 'HP:0002668', (85, 88))	('Lys299Ile', 'Var', (52, 61))	('patients', 'Species', '9606', (71, 79))	('DNA', 'Protein', (104, 107))	('age', 'Gene', (157, 160))	('DNMT3A', 'Gene', (196, 202))	('human', 'Species', '9606', (46, 51))	('age', 'Gene', '5973', (157, 160))	('Lys299Ile', 'SUBSTITUTION', 'None', (52, 61))	('disrupts', 'NegReg', (90, 98))	('sub-nuclear localization', 'MPA', (241, 265))	('DNMT3A', 'Gene', (269, 275))	('murine', 'Species', '10090', (21, 27))	('disruption', 'Reg', (223, 233))
43360	33182397	In PGL patients, we demonstrated that germline DNMT3A variants in residues within the PWWP domain caused significant hypermethylation of homeobox-containing genes involved in early embryonic development.	('hypermethylation', 'MPA', (117, 133))	('DNMT3A', 'Gene', (47, 53))	('homeobox-containing', 'Gene', (137, 156))	('PGL', 'Phenotype', 'HP:0002668', (3, 6))	('variants', 'Var', (54, 62))	('patients', 'Species', '9606', (7, 15))
43361	33182397	This contrasts with the widespread hypomethylation observed in TBRS patients carrying germline DNMT3A variants, especially enriched at genes involved in morphogenesis, development and malignancy predisposition pathways.	('variants', 'Var', (102, 110))	('DNMT3A', 'Gene', (95, 101))	('malignancy', 'Disease', 'MESH:D009369', (184, 194))	('patients', 'Species', '9606', (68, 76))	('malignancy', 'Disease', (184, 194))
43363	33182397	The conservation of Gly332 within the PWWP domain and its location between Trp330 and Asp333, the two residues altered in patients with microcephalic dwarfism, highly suggest a disruptive role of the variant.	('Asp333', 'Chemical', '-', (86, 92))	('dwarfism', 'Phenotype', 'HP:0003510', (150, 158))	('patients', 'Species', '9606', (122, 130))	('Trp330', 'Chemical', '-', (75, 81))	('Gly332', 'Chemical', '-', (20, 26))	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (136, 158))	('microcephalic dwarfism', 'Disease', (136, 158))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (136, 158))	('Gly332', 'Var', (20, 26))
43364	33182397	The substitution of the wild-type Gly332 by an Arg could stabilize the link with trimethylated histone H3 causing, as occurred with the previously reported variants found in PGL patients, a gain of alternative activities by DNMT3A.	('trimethylated histone', 'Chemical', '-', (81, 102))	('stabilize', 'Reg', (57, 66))	('PGL', 'Phenotype', 'HP:0002668', (174, 177))	('link', 'Interaction', (71, 75))	('alternative activities', 'MPA', (198, 220))	('patients', 'Species', '9606', (178, 186))	('DNMT3A', 'Enzyme', (224, 230))	('Gly332 by an Arg', 'Mutation', 'rs760854242', (34, 50))	('gain', 'PosReg', (190, 194))	('PGL', 'Disease', (174, 177))	('Gly332', 'Var', (34, 40))
43366	33182397	Moreover, overall alterations of DNA methylation have been also observed in blood cells from TET2 (hypermethylation) or EZH2 (hypomethylation) germline pathogenic loss-of-function variant carriers.	('alterations', 'Reg', (18, 29))	('EZH2', 'Gene', (120, 124))	('variant', 'Var', (180, 187))	('TET2', 'Gene', (93, 97))	('loss-of-function', 'NegReg', (163, 179))	('DNA', 'Gene', (33, 36))	('TET2', 'Gene', '54790', (93, 97))	('EZH2', 'Gene', '2146', (120, 124))
43369	33182397	Interestingly, an AML pedigree carrying a germline DNMT3A loss-of-function mutation has no symptoms of TBRS and only three patients with TBRS have been reported to develop AML.	('AML', 'Disease', (18, 21))	('AML', 'Phenotype', 'HP:0004808', (172, 175))	('AML', 'Phenotype', 'HP:0004808', (18, 21))	('mutation', 'Var', (75, 83))	('patients', 'Species', '9606', (123, 131))	('loss-of-function', 'NegReg', (58, 74))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('DNMT3A', 'Gene', (51, 57))	('AML', 'Disease', 'MESH:D015470', (18, 21))	('AML', 'Disease', (172, 175))
43370	33182397	Somatic alterations in the epigenetic regulators TET2 and DNMT3A represent a frequent cause of clonal hematopoiesis, an aging-related mechanism in which somatic variants in early blood cell progenitors confer an advantage to mutated clones.	('variants', 'Var', (161, 169))	('age', 'Gene', (218, 221))	('TET2', 'Gene', (49, 53))	('alterations', 'Var', (8, 19))	('hematopoiesis', 'Disease', 'MESH:C536227', (102, 115))	('age', 'Gene', '5973', (218, 221))	('cause', 'Reg', (86, 91))	('DNMT3A', 'Gene', (58, 64))	('TET2', 'Gene', '54790', (49, 53))	('hematopoiesis', 'Disease', (102, 115))
43372	33182397	Interestingly, several variants affecting the Gly332 residue (including p.Gly332Arg and p.Gly332Glu) have been found in healthy individuals with clonal hematopoietic mutations.	('found', 'Reg', (111, 116))	('Gly332', 'Chemical', '-', (90, 96))	('p.Gly332Glu', 'Var', (88, 99))	('Gly332', 'Chemical', '-', (46, 52))	('Gly332', 'Chemical', '-', (74, 80))	('p.Gly332Arg', 'Var', (72, 83))	('p.Gly332Glu', 'Mutation', 'rs751360082', (88, 99))	('p.Gly332Arg', 'Mutation', 'rs760854242', (72, 83))
43373	33182397	In fact, the Gly332Arg variant is included in a list of leukemogenic driver mutations affecting genes known to promote clonal expansion of hematopoietic stem cells (Table S2).	('mutations', 'Var', (76, 85))	('leukemogenic', 'Disease', (56, 68))	('Gly332Arg', 'SUBSTITUTION', 'None', (13, 22))	('Gly332Arg', 'Var', (13, 22))	('promote', 'PosReg', (111, 118))
43374	33182397	It has been suggested that the presence of some pathogenic TBRS variants amongst the general population is due to age-related clonal hematopoiesis, questioning the utility of databases such as gnomAD in DNMT3A variant pathogenicity stratification.	('age', 'Gene', '5973', (114, 117))	('hematopoiesis', 'Disease', 'MESH:C536227', (133, 146))	('TBRS', 'Gene', (59, 63))	('hematopoiesis', 'Disease', (133, 146))	('age', 'Gene', (114, 117))	('pathogenic', 'Reg', (48, 58))	('variants', 'Var', (64, 72))
43375	33182397	The methylated profile observed in the AML sample carrying the p.Gly332Arg variant further suggests that alteration of specific residues within the PWWP domain of DNMT3A leading to activation of its methylation capacities, may have oncogenic potential to both endocrine malignancies (PPGL) and AML.	('DNMT3A', 'Gene', (163, 169))	('methylation capacities', 'MPA', (199, 221))	('alteration', 'Var', (105, 115))	('AML', 'Disease', 'MESH:D015470', (39, 42))	('p.Gly332Arg', 'Mutation', 'rs760854242', (63, 74))	('endocrine malignancies', 'Disease', (260, 282))	('AML', 'Disease', 'MESH:D015470', (294, 297))	('endocrine malignancies', 'Disease', 'MESH:D004701', (260, 282))	('PPGL', 'Chemical', '-', (284, 288))	('endocrine malignancies', 'Phenotype', 'HP:0100568', (260, 282))	('AML', 'Disease', (39, 42))	('activation', 'PosReg', (181, 191))	('AML', 'Disease', (294, 297))	('PGL', 'Phenotype', 'HP:0002668', (285, 288))	('p.Gly332Arg', 'Var', (63, 74))	('AML', 'Phenotype', 'HP:0004808', (39, 42))	('AML', 'Phenotype', 'HP:0004808', (294, 297))	('oncogenic potential', 'CPA', (232, 251))
43379	33182397	Moreover, COSMIC reports only one DNMT3A variant affecting the microcephalic dwarfism-mutated residue Asp333 and it affects an anaplastic thyroid carcinoma, further supporting the relevance of the PWWP domain in thyroid cancer.	('dwarfism', 'Phenotype', 'HP:0003510', (77, 85))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (127, 155))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (138, 155))	('variant', 'Var', (41, 48))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (63, 85))	('thyroid carcinoma', 'Disease', (138, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (212, 226))	('affects', 'Reg', (116, 123))	('DNMT3A', 'Gene', (34, 40))	('thyroid cancer', 'Phenotype', 'HP:0002890', (212, 226))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (138, 155))	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (63, 85))	('Asp333', 'MPA', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('microcephalic dwarfism', 'Disease', (63, 85))	('Asp333', 'Chemical', '-', (102, 108))	('affecting', 'Reg', (49, 58))	('thyroid cancer', 'Disease', (212, 226))
43381	33182397	In summary, we describe and perform methylome analysis for a novel DNMT3A activating variant in a patient with multiple clinical features.	('DNMT3A', 'Gene', (67, 73))	('variant', 'Var', (85, 92))	('patient', 'Species', '9606', (98, 105))	('activating', 'PosReg', (74, 84))
43382	33182397	Although the causal role of DNMT3A variants in PPGL has not been demonstrated, our results stress the heterogeneous phenotypic spectrum related to DNMT3A germline variants and support a dual nature of this gene in disease.	('variants', 'Var', (35, 43))	('PPGL', 'Chemical', '-', (47, 51))	('PPGL', 'Gene', (47, 51))	('DNMT3A', 'Gene', (147, 153))	('PGL', 'Phenotype', 'HP:0002668', (48, 51))
43388	33182397	Tumor DNA from a patient with AML and carrying two somatic variants in DNMT3A (p.Gly332Arg and p.Arg720Cys) and two in TET2 (p.Arg1216Ter and p.Arg544Ter) was used for methylation profiling.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DNMT3A', 'Gene', (71, 77))	('p.Arg720Cys', 'Var', (95, 106))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('p.Arg544Ter', 'Mutation', 'rs1440692352', (142, 153))	('TET2', 'Gene', '54790', (119, 123))	('patient', 'Species', '9606', (17, 24))	('AML', 'Disease', (30, 33))	('p.Arg544Ter', 'Var', (142, 153))	('p.Gly332Arg', 'Mutation', 'rs760854242', (79, 90))	('AML', 'Phenotype', 'HP:0004808', (30, 33))	('p.Arg1216Ter', 'Var', (125, 137))	('p.Gly332Arg', 'Var', (79, 90))	('p.Arg720Cys', 'Mutation', 'rs1197133406', (95, 106))	('TET2', 'Gene', (119, 123))	('p.Arg1216Ter', 'Mutation', 'rs1009194427', (125, 137))
43391	33182397	Filtering was applied to exclude variants present in gnomAD with AF > 0.00005, variants present in internal exomes or in the CIBERER Spanish Variant Server , noncoding substitutions and variants in genomic regions with low mappability, with low depth readings or quality or with the alternative allele present in < 20% of reads.	('substitutions', 'Var', (168, 181))	('mappability', 'MPA', (223, 234))	('variants', 'Var', (79, 87))	('AF', 'Disease', 'MESH:D001281', (65, 67))	('variants', 'Var', (186, 194))
43392	33182397	The PredictSNP1 consensus classifier was used to predict the effect of the only nucleotide substitution affecting a gene previously associated with PPGL and that passed all filtering steps.	('PredictSNP1', 'Gene', '6625', (4, 15))	('nucleotide substitution', 'Var', (80, 103))	('PredictSNP1', 'Gene', (4, 15))	('PGL', 'Phenotype', 'HP:0002668', (149, 152))	('PPGL', 'Chemical', '-', (148, 152))
43396	33182397	The H3K36me3 peptide was modelled into the DNMT3A PWWP Gly332Arg mutant structure obtained using the DNMT3B PWWP domain structure bound to H3K36me3 peptide (PDB code 5CIU) as a reference to ensure no clashes with the methylated lysine.	('Gly332Arg', 'SUBSTITUTION', 'None', (55, 64))	('Gly332Arg', 'Var', (55, 64))	('DNMT3B', 'Gene', '1789', (101, 107))	('DNMT3B', 'Gene', (101, 107))	('lysine', 'Chemical', 'MESH:D008239', (228, 234))
43400	33182397	In a subsequent analysis, we used the same list of 307 probes to profile methylation data from blood of patients with microcephalic dwarfism (n = 1) or overgrowth syndrome (n = 2) (GSE120428) and compare them to controls (n = 2) and to PGLs carrying DNMT3A variants (n = 2).	('variants', 'Var', (257, 265))	('methylation', 'MPA', (73, 84))	('microcephalic dwarfism', 'Phenotype', 'HP:0008873', (118, 140))	('microcephalic dwarfism', 'Disease', (118, 140))	('microcephalic dwarfism', 'Disease', 'MESH:C537533', (118, 140))	('overgrowth syndrome', 'Disease', 'MESH:D001765', (152, 171))	('dwarfism', 'Phenotype', 'HP:0003510', (132, 140))	('overgrowth syndrome', 'Disease', (152, 171))	('overgrowth', 'Phenotype', 'HP:0001548', (152, 162))	('patients', 'Species', '9606', (104, 112))	('PGL', 'Phenotype', 'HP:0002668', (236, 239))
43401	33182397	Finally, we extracted methylation data from 12 AML samples available from The Cancer Genome Atlas (TCGA), corresponding to 213 out of the 307 probes aforementioned for hierarchical clustering with one additional AML sample carrying the p.Gly332Arg variant, another DNMT3A variant (p.Arg720Cys) and two frameshift TET2 mutations.	('p.Gly332Arg', 'Mutation', 'rs760854242', (236, 247))	('TET2', 'Gene', (313, 317))	('Cancer', 'Disease', (78, 84))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('AML', 'Disease', 'MESH:D015470', (212, 215))	('TET2', 'Gene', '54790', (313, 317))	('AML', 'Disease', (47, 50))	('p.Arg720Cys', 'Mutation', 'rs1197133406', (281, 292))	('AML', 'Phenotype', 'HP:0004808', (47, 50))	('AML', 'Phenotype', 'HP:0004808', (212, 215))	('p.Gly332Arg', 'Var', (236, 247))	('AML', 'Disease', (212, 215))
43402	33182397	The TCGA samples were all carriers of mutations in DNMT3A known to cause global methylation alterations (i.e., p.Arg882Cys/His) and three of them also harbored TET2 frameshift mutations.	('cause', 'Reg', (67, 72))	('His', 'Chemical', 'MESH:D006639', (123, 126))	('TET2', 'Gene', '54790', (160, 164))	('TET2', 'Gene', (160, 164))	('p.Arg882Cys', 'Var', (111, 122))	('mutations', 'Var', (38, 47))	('DNMT3A', 'Gene', (51, 57))	('global methylation alterations', 'MPA', (73, 103))	('p.Arg882Cys', 'SUBSTITUTION', 'None', (111, 122))
43403	33182397	We describe a novel germline DNMT3A variant (p.Gly332Arg) identified by whole-exome sequencing in a patient with multiple clinical features: bilateral carotid PGLs, PTC and idiopathic intellectual disability.	('intellectual disability', 'Phenotype', 'HP:0001249', (184, 207))	('p.Gly332Arg', 'Var', (45, 56))	('patient', 'Species', '9606', (100, 107))	('PGL', 'Phenotype', 'HP:0002668', (159, 162))	('p.Gly332Arg', 'Mutation', 'rs760854242', (45, 56))	('PTC', 'Phenotype', 'HP:0002895', (165, 168))	('DNMT3A', 'Gene', (29, 35))	('PTC', 'Disease', (165, 168))
43404	33182397	The variant affects a residue found mutated in papillary thyroid tumors and the structural modelling of the PWWP domain predicts the substitution to alter the interaction of DNMT3A with H3K36me3.	('alter', 'Reg', (149, 154))	('papillary thyroid tumors', 'Disease', (47, 71))	('substitution', 'Var', (133, 145))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (47, 71))	('interaction', 'Interaction', (159, 170))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('DNMT3A', 'Protein', (174, 180))	('variant', 'Var', (4, 11))	('papillary thyroid tumors', 'Disease', 'MESH:D000077273', (47, 71))	('H3K36me3', 'Protein', (186, 194))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
43405	33182397	Moreover, we observed an increased methylation of DNMT3A target genes in saliva DNA from the proband and in one independent AML sample carrying the same p.Gly332Arg variant, compatible with a gain-of-function effect of the alteration.	('DNMT3A', 'Gene', (50, 56))	('AML', 'Phenotype', 'HP:0004808', (124, 127))	('increased', 'PosReg', (25, 34))	('AML', 'Disease', (124, 127))	('methylation', 'MPA', (35, 46))	('gain-of-function', 'PosReg', (192, 208))	('AML', 'Disease', 'MESH:D015470', (124, 127))	('p.Gly332Arg', 'Var', (153, 164))	('p.Gly332Arg', 'Mutation', 'rs760854242', (153, 164))
43406	33182397	Although the causal role of DNMT3A variants in PPGL has not been demonstrated, our finding stresses the heterogeneous phenotypic spectrum related to DNMT3A germline variants.	('PGL', 'Phenotype', 'HP:0002668', (48, 51))	('PPGL', 'Chemical', '-', (47, 51))	('PPGL', 'Gene', (47, 51))	('variants', 'Var', (35, 43))
43407	33182397	The following are available online at , Figure S1: Hierarchical clustering performed with one AML sample carrying the p.Gly332Arg DNMT3A mutation (black circle) and 12 AML samples from TCGA carrying mutations known to cause global methylation alterations: loss-of-function p.Arg882Cys/His DNMT3A mutations (blue boxes) and TET2 frameshift mutations (purple boxes).	('AML', 'Disease', (94, 97))	('TET2', 'Gene', (323, 327))	('AML', 'Phenotype', 'HP:0004808', (94, 97))	('p.Arg882Cys', 'SUBSTITUTION', 'None', (273, 284))	('p.Arg882Cys', 'Var', (273, 284))	('His', 'Chemical', 'MESH:D006639', (285, 288))	('AML', 'Disease', 'MESH:D015470', (168, 171))	('AML', 'Phenotype', 'HP:0004808', (168, 171))	('loss-of-function', 'NegReg', (256, 272))	('DNMT3A', 'Gene', (289, 295))	('AML', 'Disease', (168, 171))	('AML', 'Disease', 'MESH:D015470', (94, 97))	('p.Gly332Arg', 'Var', (118, 129))	('TET2', 'Gene', '54790', (323, 327))	('p.Gly332Arg', 'Mutation', 'rs760854242', (118, 129))
43408	33182397	Profiling was based on methylation data from the 213 probes, out of the 307 significantly differentially methylated between DNMT3A-mutated and non-mutated tissues in patients with PPGL, contained in the Infinium HumanMethylation450 BeadChip, Figure S2: Schematic representation of the methylation analysis pipeline, Table S1: Filtered exome variants found in ClinVar, Table S2: Variants affecting the PWWP domain found in gnomAD, Table S3: List of differentially methylated CpGs between DNMT3A-mutated and non-mutated samples.	('PPGL', 'Chemical', '-', (180, 184))	('Variants', 'Var', (378, 386))	('PGL', 'Phenotype', 'HP:0002668', (181, 184))	('variants', 'Var', (341, 349))	('Pro', 'Chemical', 'MESH:D011392', (0, 3))	('patients', 'Species', '9606', (166, 174))
43446	32481723	In this regard, a correlation between 131I-MIBG treatment dose per body weight and hematological toxicity has been reported in a dose-escalation study conducted by Matthay et al.	('hematological toxicity', 'Disease', 'MESH:D006402', (83, 105))	('MIBG', 'Chemical', 'MESH:D019797', (43, 47))	('131I-MIBG', 'Var', (38, 47))	('hematological toxicity', 'Disease', (83, 105))
43450	32481723	evaluated the efficacy and safety of the combined therapy with 131I-MIBG and chemotherapy in a 10-day course in 16 children with resistant and relapsed neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (152, 165))	('neuroblastoma', 'Disease', (152, 165))	('children', 'Species', '9606', (115, 123))	('neuroblastoma', 'Phenotype', 'HP:0003006', (152, 165))	('131I-MIBG', 'Var', (63, 72))	('MIBG', 'Chemical', 'MESH:D019797', (68, 72))
43452	32481723	The same authors showed the efficacy and the feasibility of 131I-MIBG chemotherapy combination treatment in 13 pediatric patients with newly diagnosed neuroblastoma as well.	('MIBG', 'Chemical', 'MESH:D019797', (65, 69))	('neuroblastoma', 'Phenotype', 'HP:0003006', (151, 164))	('131I-MIBG', 'Var', (60, 69))	('neuroblastoma', 'Disease', 'MESH:D009447', (151, 164))	('patients', 'Species', '9606', (121, 129))	('neuroblastoma', 'Disease', (151, 164))
43468	32481723	However, the utilization of 131I-MIBG has been reported in case of ineffective surgery due to difficult anatomical access (i.e., retroperitoneal localization) or in patients with diffuse metastases of the rare malignant forms.	('metastases', 'Disease', (187, 197))	('metastases', 'Disease', 'MESH:D009362', (187, 197))	('131I-MIBG', 'Var', (28, 37))	('patients', 'Species', '9606', (165, 173))	('MIBG', 'Chemical', 'MESH:D019797', (33, 37))
43475	32481723	Therefore, a theragnostic treatment based on the somatostatin analogs has been developed using 177Lu, 111In, and 90Y.	('177Lu', 'Var', (95, 100))	('90Y', 'Var', (113, 116))	('111In', 'Var', (102, 107))	('somatostatin', 'Gene', '6750', (49, 61))	('177Lu', 'Chemical', 'MESH:C000615061', (95, 100))	('111In', 'Chemical', 'MESH:C000615551', (102, 107))	('somatostatin', 'Gene', (49, 61))
43484	32481723	It is worth mentioning that while 90Y is an almost pure beta- emitter, with a maximum energy of 2.3 MeV and tissue penetration of 11 mm, 177Lu presents lower energy (0.5 MeV) and a range of penetration of 2 mm.	('177Lu', 'Var', (137, 142))	('energy', 'MPA', (158, 164))	('177Lu', 'Chemical', 'MESH:C000615061', (137, 142))
43485	32481723	Furthermore, 177Lu is also characterized by a gamma co-emission that can be utilized for the in vivo imaging.	('177Lu', 'Chemical', 'MESH:C000615061', (13, 18))	('gamma co-emission', 'MPA', (46, 63))	('177Lu', 'Var', (13, 18))
43530	32481723	Pre-therapeutic and therapeutic assessment authors evaluated the efficacy, toxicity, and dosimetry of compartmental radioimmunotherapy and suggested that 131I-labelled3F8 may have clinical utility in maintaining remission in high-risk or recurrent medulloblastoma, with favorable dosimetry.	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('toxicity', 'Disease', (75, 83))	('remission', 'MPA', (212, 221))	('131I-labelled3F8', 'Var', (154, 170))	('medulloblastoma', 'Disease', 'MESH:D008527', (248, 263))	('medulloblastoma', 'Phenotype', 'HP:0002885', (248, 263))	('medulloblastoma', 'Disease', (248, 263))
43531	32481723	131I-8H9, binding the membrane protein B7-H3, may present another attractive radiolabeled antibody for targeted radioimmunotherapy in children with brain tumors.	('brain tumors', 'Disease', (148, 160))	('B7-H3', 'Gene', (39, 44))	('H9', 'CellLine', 'CVCL:1240', (6, 8))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('B7-H3', 'Gene', '80381', (39, 44))	('brain tumors', 'Phenotype', 'HP:0030692', (148, 160))	('131I-8H9', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('children', 'Species', '9606', (134, 142))	('brain tumors', 'Disease', 'MESH:D001932', (148, 160))
43532	32481723	In three pediatric patients with embryonal tumors, radioimmunotherapy with 131I- 8H9 seemed to be safe, and SPECT-based dosimetry showed an advantageous therapeutic index.	('embryonal tumors', 'Disease', 'MESH:D009373', (33, 49))	('patients', 'Species', '9606', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('embryonal tumors', 'Phenotype', 'HP:0002898', (33, 49))	('131I- 8H9', 'Var', (75, 84))	('embryonal tumors', 'Disease', (33, 49))	('H9', 'CellLine', 'CVCL:1240', (82, 84))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))
43533	32481723	Moreover, it has demonstrated a minimal risk of radionecrosis in children treated with intraventricular radioimmunotherapy with radiolabeled antibodies 131I-8H9 and 131I-3F8.	('children', 'Species', '9606', (65, 73))	('131I-8H9', 'Var', (152, 160))	('H9', 'CellLine', 'CVCL:1240', (158, 160))	('131I-3F8', 'Var', (165, 173))
43543	32481723	A previous multicentric study aimed to determine the response rate, survival, and toxicity of tandem infusions of high activity 131I MIBG in children with relapsed/refractory neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (175, 188))	('toxicity', 'Disease', (82, 90))	('children', 'Species', '9606', (141, 149))	('MIBG', 'Gene', (133, 137))	('refractory neuroblastoma', 'Disease', 'MESH:D009447', (164, 188))	('131I', 'Var', (128, 132))	('refractory neuroblastoma', 'Disease', (164, 188))	('MIBG', 'Chemical', 'MESH:D019797', (133, 137))	('toxicity', 'Disease', 'MESH:D064420', (82, 90))
43564	32481723	New data for the potential use of the theragnostic couple 64Cu/67Cu-SARTATE in neuroblastoma will be provided by an ongoing clinical trial .	('neuroblastoma', 'Phenotype', 'HP:0003006', (79, 92))	('64Cu', 'Chemical', 'MESH:C000615411', (58, 62))	('64Cu/67Cu-SARTATE', 'Var', (58, 75))	('67Cu', 'Chemical', 'MESH:C000615412', (63, 67))	('neuroblastoma', 'Disease', 'MESH:D009447', (79, 92))	('neuroblastoma', 'Disease', (79, 92))	('SARTATE', 'Chemical', '-', (68, 75))
43567	32481723	131I-CLR1404 has the potential to become a tumor-targeted radiotherapeutic drug with broad applicability in pediatric oncology.	('131I-CLR1404', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('oncology', 'Phenotype', 'HP:0002664', (118, 126))	('CLR1404', 'Chemical', 'MESH:C000599353', (5, 12))	('tumor', 'Disease', (43, 48))
43573	32481723	Regarding intraventricular radioimmunotherapy in patients with medulloblastoma, groundbreaking radiolabeled antibodies such as 131I-8HD, and 131I-3F8 may be effective.	('131I-8HD', 'Var', (127, 135))	('medulloblastoma', 'Disease', 'MESH:D008527', (63, 78))	('medulloblastoma', 'Phenotype', 'HP:0002885', (63, 78))	('patients', 'Species', '9606', (49, 57))	('medulloblastoma', 'Disease', (63, 78))	('131I-3F8', 'Var', (141, 149))
43578	32481723	124I/131I-8HD radioimmunotherapy with CED infusion, bypassing the BBB, maybe promising in the treatment of these patients as well.	('CED', 'Disease', 'MESH:D003966', (38, 41))	('patients', 'Species', '9606', (113, 121))	('CED', 'Disease', (38, 41))	('124I/131I-8HD', 'Var', (0, 13))
43586	32023584	Head and Neck Paraganglioma Atypically Carrying a Succinate Dehydrogenase Subunit B Mutation (L157X) A 53-year-old woman was admitted to a hospital for gradual left-ear hearing loss over 2 years.	('Head and Neck Paraganglioma', 'Phenotype', 'HP:0002864', (0, 27))	('left-ear hearing loss', 'Disease', 'MESH:D004427', (160, 181))	('Paraganglioma', 'Phenotype', 'HP:0002668', (14, 27))	('left-ear hearing loss', 'Disease', (160, 181))	('L157X', 'Var', (94, 99))	('Paraganglioma', 'Disease', (14, 27))	('Paraganglioma', 'Disease', 'MESH:D010235', (14, 27))	('woman', 'Species', '9606', (115, 120))	('hearing loss', 'Phenotype', 'HP:0000365', (169, 181))	('L157X', 'Mutation', 'p.L157X', (94, 99))
43588	32023584	Mutations of succinate dehydrogenase (SDH) were suspected, but SDHB staining remained in the tumor.	('succinate dehydrogenase', 'Gene', '6390', (13, 36))	('SDHB', 'Gene', (63, 67))	('SDH', 'Gene', '6390', (63, 66))	('SDH', 'Gene', '6390', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('succinate dehydrogenase', 'Gene', (13, 36))	('SDH', 'Gene', (63, 66))	('tumor', 'Disease', (93, 98))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (38, 41))	('SDHB', 'Gene', '6390', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
43589	32023584	Genetic testing identified a known SDHB mutation (L157X).	('L157X', 'Mutation', 'p.L157X', (50, 55))	('L157X', 'Var', (50, 55))	('SDHB', 'Gene', '6390', (35, 39))	('SDHB', 'Gene', (35, 39))
43590	32023584	The patient had head and neck paraganglioma with an SDHB mutation (L157X) more typical of an SDHD mutation.	('SDHB', 'Gene', (52, 56))	('SDHD', 'Gene', (93, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (30, 43))	('L157X', 'Mutation', 'p.L157X', (67, 72))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (16, 43))	('patient', 'Species', '9606', (4, 11))	('SDHB', 'Gene', '6390', (52, 56))	('neck paraganglioma', 'Disease', (25, 43))	('L157X', 'Var', (67, 72))	('SDHD', 'Gene', '6392', (93, 97))	('neck paraganglioma', 'Disease', 'MESH:D010235', (25, 43))
43591	32023584	SDHB immunohistochemistry is useful for detecting SDHx mutations, but careful interpretation is needed.	('mutations', 'Var', (55, 64))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', '6390', (50, 53))	('SDHB', 'Gene', '6390', (0, 4))	('SDH', 'Gene', (50, 53))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))
43593	32023584	Genetic testing shows that over 30% of patients with PPGL carry germline mutations.	('germline mutations', 'Var', (64, 82))	('PPGL', 'Chemical', '-', (53, 57))	('PPGL', 'Gene', (53, 57))	('patients', 'Species', '9606', (39, 47))
43596	32023584	Immunohistochemistry for SDHB is reportedly a valuable tool for detecting patients with PPGL carrying SDHA, SDHB, SDHC, or SDHD mutations.	('SDHB', 'Gene', (108, 112))	('mutations', 'Var', (128, 137))	('PPGL', 'Chemical', '-', (88, 92))	('PPGL', 'Gene', (88, 92))	('patients', 'Species', '9606', (74, 82))	('SDHD', 'Gene', (123, 127))	('SDHD', 'Gene', '6392', (123, 127))	('SDHA', 'Gene', '6389', (102, 106))	('SDHB', 'Gene', '6390', (25, 29))	('SDHC', 'Gene', (114, 118))	('SDHB', 'Gene', (25, 29))	('SDHB', 'Gene', '6390', (108, 112))	('SDHC', 'Gene', '6391', (114, 118))	('SDHA', 'Gene', (102, 106))
43598	32023584	In the present case, an SDHB germline mutation (L157X) carrier presented with HNPGL, which is generally typical of patients harboring SDHD mutations.	('L157X', 'Var', (48, 53))	('patients', 'Species', '9606', (115, 123))	('HNPGL', 'Disease', (78, 83))	('presented with', 'Reg', (63, 77))	('SDHD', 'Gene', (134, 138))	('SDHD', 'Gene', '6392', (134, 138))	('L157X', 'Mutation', 'p.L157X', (48, 53))	('SDHB', 'Gene', '6390', (24, 28))	('SDHB', 'Gene', (24, 28))
43619	32023584	Based on the tumor locations and pathological diagnosis of carotid paraganglioma, an SDHD mutation was suspected.	('tumor', 'Disease', (13, 18))	('SDHD', 'Gene', '6392', (85, 89))	('carotid paraganglioma', 'Disease', (59, 80))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('SDHD', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutation', 'Var', (90, 98))	('carotid paraganglioma', 'Disease', 'MESH:D002345', (59, 80))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))	('carotid paraganglioma', 'Phenotype', 'HP:0100635', (59, 80))
43620	32023584	SDHB immunostaining of the tumor was performed to detect the absence of SDHB staining due to SDHx mutations, but SDHB was actually immunopositive with a weak-diffuse pattern (Fig.	('SDH', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('SDHB', 'Gene', '6390', (113, 117))	('SDH', 'Gene', '6390', (93, 96))	('tumor', 'Disease', (27, 32))	('SDH', 'Gene', (0, 3))	('SDHB', 'Gene', (72, 76))	('SDH', 'Gene', '6390', (72, 75))	('SDHB', 'Gene', (113, 117))	('mutations', 'Var', (98, 107))	('SDHB', 'Gene', '6390', (0, 4))	('SDH', 'Gene', (72, 75))	('SDH', 'Gene', '6390', (113, 116))	('SDH', 'Gene', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))	('SDHB', 'Gene', '6390', (72, 76))
43621	32023584	We performed further genetic testing to confirm the presence of an SDHx mutation and to assess the risk of metastasis.	('SDH', 'Gene', '6390', (67, 70))	('SDH', 'Gene', (67, 70))	('mutation', 'Var', (72, 80))
43624	32023584	Surprisingly, genetic testing from a peripheral blood sample identified a known SDHB germline mutation (L157X) (Fig.	('SDHB', 'Gene', (80, 84))	('L157X', 'Mutation', 'p.L157X', (104, 109))	('SDHB', 'Gene', '6390', (80, 84))	('L157X', 'Var', (104, 109))
43627	32023584	According to recent reports, over 30% of patients with PPGL carry germline mutations, which is more frequent than the rates described in older reports.	('patients', 'Species', '9606', (41, 49))	('germline mutations', 'Var', (66, 84))	('PPGL', 'Gene', (55, 59))	('carry', 'Reg', (60, 65))	('PPGL', 'Chemical', '-', (55, 59))
43629	32023584	Mutations of SDHs promote hypoxic signal transduction, which leads to tumorigenesis.	('leads to', 'Reg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SDH', 'Gene', (13, 16))	('tumor', 'Disease', (70, 75))	('hypoxic signal transduction', 'MPA', (26, 53))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', '6390', (13, 16))	('promote', 'PosReg', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
43630	32023584	Genotype-phenotype correlations associated with SDH mutations have been previously reported.	('mutations', 'Var', (52, 61))	('SDH', 'Gene', (48, 51))	('SDH', 'Gene', '6390', (48, 51))
43631	32023584	The SDHB mutation is associated with abdominal extra-adrenal lesions and metastatic disease, while the SDHD mutation is associated with head and neck lesions that are unlikely to cause metastatic disease.	('mutation', 'Var', (9, 17))	('associated', 'Reg', (120, 130))	('associated', 'Reg', (21, 31))	('adrenal lesions and metastatic disease', 'Disease', 'MESH:D018223', (53, 91))	('SDHB', 'Gene', '6390', (4, 8))	('SDHD', 'Gene', '6392', (103, 107))	('SDHB', 'Gene', (4, 8))	('SDHD', 'Gene', (103, 107))
43632	32023584	The present patient initially had manifestation of head and neck tumors but was carrying an SDHB mutation.	('SDHB', 'Gene', '6390', (92, 96))	('neck tumors', 'Disease', 'MESH:D006258', (60, 71))	('SDHB', 'Gene', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('head and neck tumors', 'Phenotype', 'HP:0012288', (51, 71))	('neck tumors', 'Disease', (60, 71))	('mutation', 'Var', (97, 105))	('patient', 'Species', '9606', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
43633	32023584	Genetic testing showed c.470delT in exon 5 of SDHB, resulting in a change from a leucine to a stop codon at position 157 (L157X).	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('L157X', 'Mutation', 'p.L157X', (122, 127))	('c.470delT', 'Mutation', 'c.470delT', (23, 32))	('c.470delT', 'Var', (23, 32))	('change', 'Reg', (67, 73))	('leucine', 'Chemical', 'MESH:D007930', (81, 88))	('L157X', 'Var', (122, 127))
43635	32023584	According to the reports, all of these patients harboring the SDHB (L157X) mutation had manifestations of paraaortic tumors, in contrast to our patient, who had head and neck tumors.	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('L157X', 'Var', (68, 73))	('patient', 'Species', '9606', (39, 46))	('neck tumors', 'Disease', 'MESH:D006258', (170, 181))	('patients', 'Species', '9606', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('paraaortic tumors', 'Disease', (106, 123))	('neck tumors', 'Disease', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patient', 'Species', '9606', (144, 151))	('L157X', 'Mutation', 'p.L157X', (68, 73))	('head and neck tumors', 'Phenotype', 'HP:0012288', (161, 181))	('paraaortic tumors', 'Disease', 'MESH:D009369', (106, 123))	('SDHB', 'Gene', '6390', (62, 66))	('SDHB', 'Gene', (62, 66))
43636	32023584	One of the previous patients showed multiple metastases to the lungs, a typical malignant feature of SDHB mutation.	('SDHB', 'Gene', (101, 105))	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('mutation', 'Var', (106, 114))	('patients', 'Species', '9606', (20, 28))	('SDHB', 'Gene', '6390', (101, 105))	('metastases', 'Disease', (45, 55))
43637	32023584	Our patient, on the other hand, was characterized by manifestations mimicking PPGL with an SDHD mutation rather than SDHB mutations.	('PPGL', 'Disease', (78, 82))	('SDHB', 'Gene', (117, 121))	('PPGL', 'Chemical', '-', (78, 82))	('patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (96, 104))	('SDHD', 'Gene', (91, 95))	('SDHD', 'Gene', '6392', (91, 95))	('SDHB', 'Gene', '6390', (117, 121))
43639	32023584	In association with SDH mutations, approximately 80-98% of SDHD mutation carriers have head and neck lesions, while 15-31% of SDHB mutation carriers also have HNPGL.	('SDH', 'Gene', '6390', (126, 129))	('mutation', 'Var', (64, 72))	('SDHB', 'Gene', (126, 130))	('SDH', 'Gene', (20, 23))	('SDH', 'Gene', (126, 129))	('SDH', 'Gene', '6390', (20, 23))	('SDH', 'Gene', (59, 62))	('SDHD', 'Gene', '6392', (59, 63))	('SDHB', 'Gene', '6390', (126, 130))	('HNPGL', 'Disease', (159, 164))	('SDHD', 'Gene', (59, 63))	('SDH', 'Gene', '6390', (59, 62))
43640	32023584	HNPGL patients carrying SDHB germline mutations were recently evaluated, and the metastatic rate was found to be only 6%.	('SDHB', 'Gene', (24, 28))	('germline', 'Var', (29, 37))	('patients', 'Species', '9606', (6, 14))	('SDHB', 'Gene', '6390', (24, 28))
43641	32023584	This clinical feature differed from the findings of a previous report on SDHB mutation carriers without head and neck lesions.	('SDHB', 'Gene', '6390', (73, 77))	('mutation', 'Var', (78, 86))	('SDHB', 'Gene', (73, 77))
43646	32023584	SDHB immunostaining is useful for detecting the presence of an SDHx mutation in HPPS.	('SDH', 'Gene', '6390', (63, 66))	('mutation', 'Var', (68, 76))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', (63, 66))	('HPPS', 'Disease', 'None', (80, 84))	('SDHB', 'Gene', '6390', (0, 4))	('HPPS', 'Disease', (80, 84))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))
43648	32023584	Loss of SDH enzymatic activity suggests the biallelic inactivation of SDH genes.	('SDH', 'Gene', '6390', (8, 11))	('SDH', 'Gene', '6390', (70, 73))	('Loss', 'NegReg', (0, 4))	('SDH', 'Gene', (8, 11))	('SDH', 'Gene', (70, 73))	('biallelic inactivation', 'Var', (44, 66))
43651	32023584	The weak-diffuse pattern is more frequent in tumors with SDHD mutations than in those with SDHB mutations.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SDHD', 'Gene', '6392', (57, 61))	('tumors', 'Disease', (45, 51))	('SDHB', 'Gene', '6390', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('weak-diffuse pattern', 'MPA', (4, 24))	('SDHD', 'Gene', (57, 61))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('SDHB', 'Gene', (91, 95))	('mutations', 'Var', (62, 71))
43653	32023584	The present case demonstrated a weak-diffuse pattern on SDHB immunostaining, and genetic testing ultimately identified a known SDHB mutation.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('SDHB', 'Gene', '6390', (127, 131))	('SDHB', 'Gene', (127, 131))	('mutation', 'Var', (132, 140))
43654	32023584	SDHB immunostaining was not confirmed in the two previously reported cases with SDHB mutations (L157X).	('SDHB', 'Gene', (80, 84))	('L157X', 'Var', (96, 101))	('mutations (L157X', 'Var', (85, 101))	('SDHB', 'Gene', '6390', (0, 4))	('L157X', 'Mutation', 'p.L157X', (96, 101))	('SDHB', 'Gene', (0, 4))	('SDHB', 'Gene', '6390', (80, 84))
43658	32023584	We herein report rare case of HNPGL with an SDHB mutation (L157X), which are typical phenotypes of an SDHD mutation.	('L157X', 'Var', (59, 64))	('SDHB', 'Gene', '6390', (44, 48))	('SDHB', 'Gene', (44, 48))	('SDHD', 'Gene', (102, 106))	('SDHD', 'Gene', '6392', (102, 106))	('L157X', 'Mutation', 'p.L157X', (59, 64))
43659	32023584	SDHB immunohistochemistry is a valuable tool for detecting SDHx mutations, but careful interpretation is needed.	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', (59, 62))	('SDHB', 'Gene', '6390', (0, 4))	('mutations', 'Var', (64, 73))	('SDHB', 'Gene', (0, 4))	('SDH', 'Gene', '6390', (0, 3))	('SDH', 'Gene', '6390', (59, 62))
43674	30991354	PPGL frequently produces catecholamines and can manifest with several cardiovascular syndromes, including stress cardiomyopathy and myocardial infarction.	('manifest', 'Reg', (48, 56))	('stress cardiomyopathy', 'Disease', 'MESH:D054549', (106, 127))	('myocardial infarction', 'Disease', (132, 153))	('myocardial infarction', 'Disease', 'MESH:D009203', (132, 153))	('catecholamines', 'MPA', (25, 39))	('cardiovascular syndromes', 'Disease', 'MESH:D002318', (70, 94))	('man', 'Species', '9606', (48, 51))	('stress cardiomyopathy', 'Disease', (106, 127))	('PPGL', 'Var', (0, 4))	('myocardial infarction', 'Phenotype', 'HP:0001658', (132, 153))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (113, 127))	('PPGL', 'Chemical', '-', (0, 4))	('cardiovascular syndromes', 'Disease', (70, 94))	('catecholamines', 'Chemical', 'MESH:D002395', (25, 39))	('produces', 'Reg', (16, 24))
43793	30740044	Thus, we chose to analyze the progenitors of the sympathetic and chromaffin lineages at the level of the ZO at E10.5 and E11.5.	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('E11.5', 'Var', (121, 126))	('chromaffin', 'Chemical', '-', (65, 75))	('E10.5', 'Var', (111, 116))
43796	30740044	By injecting tamoxifen (TAM) at E10.5 or E11.5 and analyzing the ZO with the mesenteric/para-aortic sympathetic ganglia around it, we found that the two components are of different origin, with RetTOM+ cells traced from either E10.5 or E11.5 giving rise only to the sympathetic mesenteric and para-aortic ganglia and not chromaffin cells of the ZO (Figures 1B,C).	('TAM', 'Chemical', 'MESH:D013629', (24, 27))	('Ret', 'Gene', '19713', (194, 197))	('para-aortic ganglia', 'Disease', 'MESH:D001018', (293, 312))	('para-aortic sympathetic ganglia', 'Disease', (88, 119))	('tamoxifen', 'Chemical', 'MESH:D013629', (13, 22))	('E11.5', 'Var', (236, 241))	('para-aortic ganglia', 'Disease', (293, 312))	('para-aortic sympathetic ganglia', 'Disease', 'MESH:D001018', (88, 119))	('chromaffin', 'Chemical', '-', (321, 331))	('E10.5', 'Var', (227, 232))	('Ret', 'Gene', (194, 197))
43806	30740044	As mentioned above, cells of the Ret+ lineage traced from E10.5 and E11.5 delineated specifically the sympathetic mesenteric and para-aortic ganglia and not the chromaffin cells of ZO, indicating that the neuroendocrine chromaffin cells of the ZO are not derived from Ret+ precursors.	('para-aortic ganglia', 'Disease', (129, 148))	('chromaffin', 'Chemical', '-', (161, 171))	('Ret', 'Gene', '19713', (33, 36))	('chromaffin', 'Chemical', '-', (220, 230))	('Ret', 'Gene', (268, 271))	('E10.5', 'Var', (58, 63))	('para-aortic ganglia', 'Disease', 'MESH:D001018', (129, 148))	('Ret', 'Gene', '19713', (268, 271))	('E11.5', 'Var', (68, 73))	('Ret', 'Gene', (33, 36))
43808	30740044	Thus, given the absence of RetTOM+ cells traced from E10.5 and E11.5 in the chromaffin cells of the ZO, we reasoned that the organ could be derived from nerve-associated SCPs, similarly to the chromaffin cells of the adrenal gland.	('E10.5', 'Var', (53, 58))	('Ret', 'Gene', (27, 30))	('chromaffin', 'Chemical', '-', (76, 86))	('Ret', 'Gene', '19713', (27, 30))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('E11.5', 'Var', (63, 68))	('chromaffin', 'Chemical', '-', (193, 203))
43810	30740044	It was previously shown that neural crest migration is complete by E11.5 and at this stage there are no neural crest cells at the embryo trunk which are multipotent and can give rise directly to sympathetic neurons.	('rat', 'Species', '10116', (45, 48))	('give rise', 'Reg', (173, 182))	('E11.5', 'Var', (67, 72))
43812	30740044	This resulted in tracing of SCPs along the nerves exiting the spinal cord and at the vicinity of the SA primordium by E12.5 (Figure 2A).	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('resulted in', 'Reg', (5, 16))	('E12.5', 'Var', (118, 123))	('SA', 'Chemical', '-', (101, 103))
43828	30740044	To induce a significant decrease in SCPs (all of which are SOX10+), we injected TAM both at E11.5 and E12.5 (Figure 4K).	('SOX10', 'Gene', '20665', (59, 64))	('E12.5', 'Var', (102, 107))	('TAM', 'Chemical', 'MESH:D013629', (80, 83))	('SCPs', 'MPA', (36, 40))	('decrease', 'NegReg', (24, 32))	('SOX10', 'Gene', (59, 64))
43830	30740044	Upon SCP-ablation, ZO was significantly affected, as shown by a 32.45% decrease in total TH+ cell numbers.	('decrease', 'NegReg', (71, 79))	('SCP-ablation', 'Var', (5, 17))	('TH+', 'Chemical', 'MESH:D013910', (89, 92))
43834	30740044	Firstly, upon TAM injection at E11.5 in Plp1YFP mice, we find a 5-10% tracing of the sympathetic neurons of the para-aortic ganglia.	('E11.5', 'Var', (31, 36))	('Plp1', 'Gene', (40, 44))	('mice', 'Species', '10090', (48, 52))	('Plp1', 'Gene', '18823', (40, 44))	('para-aortic ganglia', 'Disease', 'MESH:D001018', (112, 131))	('para-aortic ganglia', 'Disease', (112, 131))	('TAM', 'Chemical', 'MESH:D013629', (14, 17))
43835	30740044	Secondly, we observe a noticeable reduction in the size of the para-aortic ganglia upon ablation of the visceral motorneurons, which are responsible for the delivery of SCPs to the SA anlage.	('ablation', 'Var', (88, 96))	('para-aortic ganglia', 'Disease', (63, 82))	('para-aortic ganglia', 'Disease', 'MESH:D001018', (63, 82))	('reduction', 'NegReg', (34, 43))	('size', 'MPA', (51, 55))	('SA', 'Chemical', '-', (181, 183))
43836	30740044	However, glial ablation by TAM injection at E11.5 and E12.5 does not seem to significantly affect these ganglia, which could be due to the non-extensive expression of the transgene in this population.	('E12.5', 'Var', (54, 59))	('E11.5', 'Var', (44, 49))	('TAM', 'Chemical', 'MESH:D013629', (27, 30))
43838	30740044	The lineage tracing experiments proved that Ascl1+ progenitors contribute to the development of ZO (Figure 1D), and suggested that the absence of Ascl1 should inhibit the differentiation of SCPs toward chromaffin cells in ZO.	('Ascl1', 'Gene', (44, 49))	('development', 'CPA', (81, 92))	('absence', 'Var', (135, 142))	('Ascl1', 'Gene', '17172', (146, 151))	('chromaffin', 'Chemical', '-', (202, 212))	('Ascl1', 'Gene', (146, 151))	('differentiation of SCPs toward chromaffin cells', 'CPA', (171, 218))	('Ascl1', 'Gene', '17172', (44, 49))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('inhibit', 'NegReg', (159, 166))
43842	30740044	Contrary to this, homozygous mutant embryos (Ascl1CreERT/CreERT2;R26TOM/+) lacked the mesenteric ganglion and para-aortic sympathetic ganglia located above the dorsal aorta and featured an obvious decrease of TH+ chromaffin cells in ZO (Figures 5A,B).	('TH+ chromaffin cells', 'CPA', (209, 229))	('lacked', 'NegReg', (75, 81))	('Ascl1', 'Gene', '17172', (45, 50))	('para-aortic sympathetic ganglia', 'Disease', (110, 141))	('TH+ chromaffin', 'Chemical', '-', (209, 223))	('para-aortic sympathetic ganglia', 'Disease', 'MESH:D001018', (110, 141))	('Ascl1', 'Gene', (45, 50))	('mesenteric ganglion and', 'CPA', (86, 109))	('decrease', 'NegReg', (197, 205))	('R26TOM/+', 'Var', (65, 73))
43843	30740044	Furthermore, in the location of the mutant ZO, we observed TH+/CARThigh/Ascl1TOM+ and TH-/CARThigh/Ascl1TOM+ cells almost uniquely in mutant embryos, which might mean that Ascl1 is also involved in the downregulation of sympathetic-like markers such as CART in immature progenitors in order for them to differentiate into mature TH+/CART- cells, or that a very small portion of the mesenteric ganglion was formed but did not separate from the future ZO.	('Ascl1', 'Gene', '17172', (72, 77))	('CART', 'Gene', '27220', (253, 257))	('CART', 'Gene', '27220', (333, 337))	('rat', 'Species', '10116', (429, 432))	('TH+', 'Chemical', 'MESH:D013910', (329, 332))	('Th', 'Chemical', 'MESH:D013910', (93, 95))	('TH+', 'Chemical', 'MESH:D013910', (59, 62))	('CART', 'Gene', (90, 94))	('Ascl1', 'Gene', (72, 77))	('Th', 'Chemical', 'MESH:D013910', (66, 68))	('mutant', 'Var', (134, 140))	('CART', 'Gene', (63, 67))	('Ascl1', 'Gene', '17172', (172, 177))	('CART', 'Gene', (253, 257))	('CART', 'Gene', '27220', (90, 94))	('downregulation', 'NegReg', (202, 216))	('Ascl1', 'Gene', '17172', (99, 104))	('CART', 'Gene', (333, 337))	('Ascl1', 'Gene', (172, 177))	('CART', 'Gene', '27220', (63, 67))	('mutant', 'Var', (36, 42))	('Ascl1', 'Gene', (99, 104))
43845	30740044	Furthermore, analysis of E15.5 embryos using the SCP (glial) markers S100B and SOX10 revealed an accumulation of S100B+/SOX10+/Ascl1TOM+ SCPs in mutant embryos, which were almost absent in control embryos (Figure 5C).	('Ascl1', 'Gene', '17172', (127, 132))	('Ascl1', 'Gene', (127, 132))	('SOX10', 'Gene', '20665', (79, 84))	('mutant', 'Var', (145, 151))	('S100B', 'Gene', '20203', (113, 118))	('S100B', 'Gene', (113, 118))	('SOX10', 'Gene', (120, 125))	('accumulation', 'PosReg', (97, 109))	('S100B', 'Gene', (69, 74))	('SOX10', 'Gene', (79, 84))	('S100B', 'Gene', '20203', (69, 74))	('SOX10', 'Gene', '20665', (120, 125))
43846	30740044	These results suggest that in the absence of Ascl1, the SCPs that serve as progenitors of the future chromaffin cells are not able to differentiate and are abnormally accumulating either in the SCP stage (as shown by the presence of S100B+/SOX10+/Ascl1TOM+ cells in the mutant) or in the transition from an immature neuroblast-like cell to a mature chromaffin cell (as seen by the numerous CART+/Ascl1TOM+ cells in the mutant within the abnormal ZO) (Figures 5D,E).	('chromaffin', 'Chemical', '-', (349, 359))	('Ascl1', 'Gene', '17172', (247, 252))	('mutant', 'Var', (419, 425))	('Ascl1', 'Gene', (247, 252))	('CART', 'Gene', (390, 394))	('SOX10', 'Gene', '20665', (240, 245))	('Ascl1', 'Gene', '17172', (396, 401))	('Ascl1', 'Gene', '17172', (45, 50))	('CART', 'Gene', '27220', (390, 394))	('Ascl1', 'Gene', (396, 401))	('Ascl1', 'Gene', (45, 50))	('S100B', 'Gene', '20203', (233, 238))	('S100B', 'Gene', (233, 238))	('chromaffin', 'Chemical', '-', (101, 111))	('SOX10', 'Gene', (240, 245))	('Th', 'Chemical', 'MESH:D013910', (0, 2))
43872	30740044	All tracing experiments using inducible CreERT2 lines (Plp1, Sox10, Ret and Ascl1-driven) were performed using heterozygotes for both the CreERT2 and the reporter R26RYFP or R26RTOMATO.	('R26RTOMATO', 'Var', (174, 184))	('Ret', 'Gene', (68, 71))	('R26RYFP', 'Var', (163, 170))	('Plp1', 'Gene', '18823', (55, 59))	('Ret', 'Gene', '19713', (68, 71))	('Ascl1', 'Gene', '17172', (76, 81))	('Ascl1', 'Gene', (76, 81))	('Sox10', 'Gene', '20665', (61, 66))	('Sox10', 'Gene', (61, 66))	('Plp1', 'Gene', (55, 59))
43909	30740044	In accordance to these observations, by using the RetCreERT2;R26TOM strain and injecting TAM at E10.5 and E11.5, 24- and 48-h prior to the detection for the first chromaffin cells in the SA primordium, we showed that at E15.5 RetTOM was expressed specifically in the sympathetic ganglia and was almost absent in the ZO chromaffin cells, suggesting a lineage split of SA progenitors as early as E10.5.	('Ret', 'Gene', '19713', (50, 53))	('chromaffin', 'Chemical', '-', (319, 329))	('Ret', 'Gene', (226, 229))	('ZO chromaffin', 'Chemical', '-', (316, 329))	('SA', 'Chemical', '-', (187, 189))	('Ret', 'Gene', '19713', (226, 229))	('chromaffin', 'Chemical', '-', (163, 173))	('E15.5', 'Var', (220, 225))	('TAM', 'Chemical', 'MESH:D013629', (89, 92))	('SA', 'Chemical', '-', (367, 369))	('Ret', 'Gene', (50, 53))
43912	30740044	Next, using the inducible Ascl1CreERT2;R26TOM strain, we observed that recombination at E11.5 resulted in Ascl1TOM+ cells found only in the ZO.	('Ascl1', 'Gene', (106, 111))	('E11.5', 'Var', (88, 93))	('Ascl1', 'Gene', '17172', (106, 111))	('Ascl1', 'Gene', '17172', (26, 31))	('Ascl1', 'Gene', (26, 31))
43913	30740044	Thus, our results showed an established lineage separation between sympathetic and chromaffin progenitors at around E10.5 and E11.5, a time point at which only SOX10+ cells are detected at the adrenal gland anlage but no TH+ cells.	('rat', 'Species', '10116', (52, 55))	('SOX10', 'Gene', (160, 165))	('chromaffin', 'Chemical', '-', (83, 93))	('TH+', 'Chemical', 'MESH:D013910', (221, 224))	('E11.5', 'Var', (126, 131))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('SOX10', 'Gene', '20665', (160, 165))
43917	30740044	Lineage tracing induced in Plp1CreERT2;R26YFP embryos at E11.5, a time when no neural crest cells are found anymore except at the tip of the tail, revealed recombination of roughly half the chromaffin cells of the ZO, while no tracing was observed in most sympathetic structures such as the suprarenal ganglion, the mesenteric ganglion and anterior part of the sympathetic chain.	('Plp1', 'Gene', (27, 31))	('recombination', 'Var', (156, 169))	('chromaffin', 'Chemical', '-', (190, 200))	('Plp1', 'Gene', '18823', (27, 31))
43919	30740044	To obtain further confirmation of the SCP involvement in ZO development, we injected TAM at E11.5 and E12.5 in mice of the Sox10CreERT2;R26DTA strain and analyzed them at a much later developmental stage (E17.5).	('Sox10', 'Gene', '20665', (123, 128))	('Sox10', 'Gene', (123, 128))	('E12.5', 'Var', (102, 107))	('mice', 'Species', '10090', (111, 115))	('TAM', 'Chemical', 'MESH:D013629', (85, 88))
43920	30740044	This genetic manipulation allowed for almost total glial ablation, as seen by the numbers of SOX10+ cells and resulted in a significant decrease in the total chromaffin cell numbers of the ZO, but left all sympathetic ganglia unaffected.	('genetic manipulation', 'Var', (5, 25))	('chromaffin cell numbers', 'CPA', (158, 181))	('chromaffin', 'Chemical', '-', (158, 168))	('decrease', 'NegReg', (136, 144))	('SOX10', 'Gene', '20665', (93, 98))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('glial', 'CPA', (51, 56))	('SOX10', 'Gene', (93, 98))
43922	30740044	Targeted SCP-ablation might be compensated in the sympathetic component through increased proliferation of the remaining neuroblasts during development.	('rat', 'Species', '10116', (97, 100))	('increased', 'PosReg', (80, 89))	('SCP-ablation', 'Var', (9, 21))
43925	30740044	Taken together, these studies suggest that Ascl1 ablation should lead to the accumulation of defective progenitors of the SA fates that are not able to differentiate into Th-expressing cells.	('accumulation', 'PosReg', (77, 89))	('SA', 'Chemical', '-', (122, 124))	('Th', 'Chemical', 'MESH:D013910', (171, 173))	('Ascl1', 'Gene', '17172', (43, 48))	('ablation', 'Var', (49, 57))	('Ascl1', 'Gene', (43, 48))
43928	30740044	Indeed, in Ascl1CreERT2/CreERT2;R26TOM/+ mutant embryos at E15.5, following TAM injection at E10.5, we observed a plethora of glial-marker-expressing Ascl1TOM+ cells that were in much fewer numbers in the control Ascl1CreERT2/+;R26TOM/+ embryos, accompanied by a significant decrease in TH+ cell numbers.	('Ascl1', 'Gene', (150, 155))	('Ascl1', 'Gene', (213, 218))	('TAM', 'Chemical', 'MESH:D013629', (76, 79))	('mutant', 'Var', (41, 47))	('Ascl1', 'Gene', (11, 16))	('Ascl1', 'Gene', '17172', (11, 16))	('decrease', 'NegReg', (275, 283))	('TH+ cell numbers', 'CPA', (287, 303))	('Ascl1', 'Gene', '17172', (150, 155))	('plethora', 'Phenotype', 'HP:0001050', (114, 122))	('TH+', 'Chemical', 'MESH:D013910', (287, 290))	('Ascl1', 'Gene', '17172', (213, 218))
43934	30740044	Nerve ablation resulted in significant chromaffin cell loss in the ZO and a mild phenotype in the posterior sympathetic ganglia, indicating that at least some component of the ZO must also be neural-crest derived or that some of the SCPs reached the forming ZO just before the nerve underwent apoptosis.	('loss', 'NegReg', (55, 59))	('Nerve ablation', 'Var', (0, 14))	('ablation', 'Var', (6, 14))	('chromaffin', 'Chemical', '-', (39, 49))	('chromaffin cell', 'CPA', (39, 54))
43935	30740044	Moreover, we observed that the ZO was composed from CART-/TH+ cells and CART+/TH+ cells, and that both subtypes were significantly reduced upon the visceral nerve ablation.	('ablation', 'Var', (163, 171))	('CART', 'Gene', (52, 56))	('CART', 'Gene', (72, 76))	('CART', 'Gene', '27220', (52, 56))	('reduced', 'NegReg', (131, 138))	('CART', 'Gene', '27220', (72, 76))	('TH+', 'Chemical', 'MESH:D013910', (78, 81))	('TH+', 'Chemical', 'MESH:D013910', (58, 61))
43942	30740044	In an attempt to examine their organization in space, we performed an array of experiments on whole embryo trunks during early stages of SA development, ranging from E12.5 to E13.5.	('E13.5', 'Var', (175, 180))	('E12.5', 'Var', (166, 171))	('SA', 'Chemical', '-', (137, 139))
43974	30150569	In addition, mutation of succinate dehydrogenase gene subunits SDHB and SDHD are strongly correlated with extra-adrenal location, younger age, multiple tumors, metastasis and poor prognosis.	('extra-adrenal location', 'Disease', (106, 128))	('multiple tumors', 'Disease', (143, 158))	('SDHB', 'Gene', (63, 67))	('multiple tumors', 'Disease', 'MESH:D009369', (143, 158))	('SDHD', 'Disease', 'None', (72, 76))	('correlated', 'Reg', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (13, 21))	('SDHD', 'Disease', (72, 76))	('metastasis', 'Disease', (160, 170))	('SDHB', 'Gene', '6390', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
44015	30150569	There are 20 susceptibility genes for PPGLs at present: SDHA, SDHAF2, SDHC, KIF1B, TMEM127, FH, NF1, RET, VHL, SDHD, SDHB, MAX, HRAS, ATRX, EPAS1/HIF2A, MEN1, EGLN1/PDH2, EGLN2/PDH1, MDH2 and IDH1 in various types of mutations including germline only, germline and somatic, somatic only, somatic and somatic mosaicism and single patients or families.	('TMEM127', 'Gene', '55654', (83, 90))	('ATRX', 'Gene', (134, 138))	('EPAS1', 'Gene', (140, 145))	('MDH2', 'Gene', '4191', (183, 187))	('ATRX', 'Gene', '546', (134, 138))	('SDHC', 'Gene', (70, 74))	('HIF2A', 'Gene', '2034', (146, 151))	('MEN1', 'Gene', (153, 157))	('EGLN2', 'Gene', '112398', (171, 176))	('IDH1', 'Gene', '3417', (192, 196))	('SDHB', 'Gene', '6390', (117, 121))	('HIF2A', 'Gene', (146, 151))	('FH', 'Disease', 'MESH:D006938', (92, 94))	('EGLN2', 'Gene', (171, 176))	('EGLN1', 'Gene', '54583', (159, 164))	('PGL', 'Phenotype', 'HP:0002668', (39, 42))	('SDHD', 'Disease', (111, 115))	('SDHA', 'Gene', (56, 60))	('KIF1B', 'Gene', '23095', (76, 81))	('PPGLs', 'Gene', (38, 43))	('EGLN1', 'Gene', (159, 164))	('HRAS', 'Gene', '3265', (128, 132))	('SDHA', 'Gene', '6389', (56, 60))	('SDHAF2', 'Gene', (62, 68))	('SDHB', 'Gene', (117, 121))	('EPAS1', 'Gene', '2034', (140, 145))	('SDHAF2', 'Gene', '54949', (62, 68))	('SDHA', 'Gene', (62, 66))	('VHL', 'Gene', '7428', (106, 109))	('HRAS', 'Gene', (128, 132))	('MDH2', 'Gene', (183, 187))	('PPGLs', 'Chemical', '-', (38, 43))	('VHL', 'Gene', (106, 109))	('RET', 'Gene', '5979', (101, 104))	('patients', 'Species', '9606', (329, 337))	('SDHC', 'Gene', '6391', (70, 74))	('SDHD', 'Disease', 'None', (111, 115))	('SDHA', 'Gene', '6389', (62, 66))	('NF1', 'Gene', '4763', (96, 99))	('TMEM127', 'Gene', (83, 90))	('KIF1B', 'Gene', (76, 81))	('IDH1', 'Gene', (192, 196))	('MEN1', 'Gene', '4221', (153, 157))	('NF1', 'Gene', (96, 99))	('mutations', 'Var', (217, 226))	('RET', 'Gene', (101, 104))
44016	30150569	Germline mutations in predisposition genes are found in 25-30% of PPGLs overall.	('Germline mutations', 'Var', (0, 18))	('PGL', 'Phenotype', 'HP:0002668', (67, 70))	('PPGLs', 'Disease', (66, 71))	('found', 'Reg', (47, 52))	('PPGLs', 'Chemical', '-', (66, 71))
44017	30150569	Germline mutations in succinate dehydrogenase subunit x (SDHx) including SDHA, SDHB, SDHC, SDHD and SDHAF2 are the most common genetic cause of PPGLs, occurring in up to 25% of cases.	('Germline mutations', 'Var', (0, 18))	('PPGLs', 'Disease', (144, 149))	('SDHA', 'Gene', (73, 77))	('cause', 'Reg', (135, 140))	('SDHA', 'Gene', '6389', (73, 77))	('SDHB', 'Gene', (79, 83))	('SDHC', 'Gene', (85, 89))	('SDHD', 'Disease', 'None', (91, 95))	('PPGLs', 'Chemical', '-', (144, 149))	('SDHA', 'Gene', (100, 104))	('SDHx', 'Gene', (57, 61))	('PGL', 'Phenotype', 'HP:0002668', (145, 148))	('SDHA', 'Gene', '6389', (100, 104))	('SDHAF2', 'Gene', (100, 106))	('SDHx', 'Chemical', '-', (57, 61))	('SDHAF2', 'Gene', '54949', (100, 106))	('SDHC', 'Gene', '6391', (85, 89))	('SDHB', 'Gene', '6390', (79, 83))	('SDHD', 'Disease', (91, 95))
44023	30150569	Loss of SDHB protein immunoreactivity in tumors with SDHx mutation is reported with 100% sensitivity and 84% specificity.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SDHx', 'Chemical', '-', (53, 57))	('SDHB', 'Gene', '6390', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('SDHx', 'Gene', (53, 57))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('SDHB', 'Gene', (8, 12))	('Loss', 'NegReg', (0, 4))	('mutation', 'Var', (58, 66))	('immunoreactivity', 'MPA', (21, 37))	('protein', 'Protein', (13, 20))
44025	30150569	The SDHB mutation is the only established factor that indicates future metastasis.	('mutation', 'Var', (9, 17))	('SDHB', 'Gene', (4, 8))	('SDHB', 'Gene', '6390', (4, 8))
44051	30150569	Non-functioning PPGLs including SDHB mutation in part but not all are interested in the view point of cell maturation and function of catecholamine synthesis and secretion.	('catecholamine', 'Chemical', 'MESH:D002395', (134, 147))	('SDHB', 'Gene', '6390', (32, 36))	('PPGLs', 'Chemical', '-', (16, 21))	('mutation', 'Var', (37, 45))	('SDHB', 'Gene', (32, 36))	('PGL', 'Phenotype', 'HP:0002668', (17, 20))
44106	30148191	MIBG negativity was also reported to be associates with its malignant character and SDHB mutation.	('MIBG', 'Chemical', 'MESH:D019797', (0, 4))	('SDHB', 'Gene', '6390', (84, 88))	('mutation', 'Var', (89, 97))	('SDHB', 'Gene', (84, 88))	('MIBG', 'Gene', (0, 4))
44109	30148191	Another study, tumors with an intense accumulation of FDG tended to have SDH mutation.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('SDH', 'Gene', '6390', (73, 76))	('mutation', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('FDG', 'Chemical', 'MESH:D019788', (54, 57))	('SDH', 'Gene', (73, 76))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
44132	29350258	In addition, the mice treated with 0.28, 0.56 and 1.11 MBq of 211At-MABG showed only a temporary weight reduction, with recovery in weight by day 10.	('211At', 'Chemical', '-', (62, 67))	('weight', 'MPA', (132, 138))	('mice', 'Species', '10090', (17, 21))	('211At-MABG', 'Gene', (62, 72))	('0.56', 'Var', (41, 45))	('weight reduction', 'Disease', 'MESH:D015431', (97, 113))	('weight reduction', 'Disease', (97, 113))
44133	29350258	211At-MABG exhibited a strong tumor volume-reducing effect in a mouse model of pheochromocytoma without weight reduction.	('pheochromocytoma', 'Disease', 'MESH:D010673', (79, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (79, 95))	('211At-MABG', 'Var', (0, 10))	('weight reduction', 'Disease', 'MESH:D015431', (104, 120))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('weight reduction', 'Disease', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('pheochromocytoma', 'Disease', (79, 95))	('211At', 'Chemical', '-', (0, 5))	('tumor', 'Disease', (30, 35))	('mouse', 'Species', '10090', (64, 69))
44134	29350258	Therefore, 211At-MABG might be an effective therapeutic agent for the treatment of malignant pheochromocytoma.	('211At', 'Chemical', '-', (11, 16))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('211At-MABG', 'Var', (11, 21))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (83, 109))	('malignant pheochromocytoma', 'Disease', (83, 109))
44139	29350258	Of these treatments, 131I-MIBG has been shown to prolong survival.	('131I-MIBG', 'Chemical', '-', (21, 30))	('131I-MIBG', 'Var', (21, 30))	('prolong', 'PosReg', (49, 56))	('survival', 'CPA', (57, 65))
44140	29350258	131I-MIBG is a false analog of norepinephrine and is therefore taken into the pheochromocytoma cell via the uptake-1 mechanism.	('pheochromocytoma', 'Disease', (78, 94))	('131I-MIBG', 'Var', (0, 9))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('norepinephrine', 'Chemical', 'MESH:D009638', (31, 45))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))	('131I-MIBG', 'Chemical', '-', (0, 9))
44141	29350258	131I-MIBG, because of the cytotoxic effects of beta-radiation, can improve survival in patients with malignant pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('131I-MIBG', 'Var', (0, 9))	('beta-', 'Chemical', '-', (47, 52))	('survival', 'MPA', (75, 83))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (101, 127))	('malignant pheochromocytoma', 'Disease', (101, 127))	('patients', 'Species', '9606', (87, 95))	('improve', 'PosReg', (67, 74))	('131I-MIBG', 'Chemical', '-', (0, 9))
44146	29350258	The therapeutic applications of alpha-emitters have mainly focused on 211At, 233Ra, 213Bi and 225Ac.	('233Ra', 'Var', (77, 82))	('213Bi', 'Var', (84, 89))	('211At', 'Var', (70, 75))	('211At', 'Chemical', '-', (70, 75))
44152	29350258	The purpose of the present study was to investigate the therapeutic effects of 211At-MABG in a pheochromocytoma model both in vitro and in vivo.	('211At-MABG', 'Var', (79, 89))	('pheochromocytoma', 'Disease', (95, 111))	('pheochromocytoma', 'Disease', 'MESH:D010673', (95, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (95, 111))	('211At', 'Chemical', '-', (79, 84))
44168	29350258	When the PC12 tumor volumes had reached approximately 50 mm3, the mice (body weight 20.89 +- 1.30 g) were injected intravenously with 211At-MABG (0.28, 0.56, 1.11, 1.85, 3.70 and 5.55 MBq; five mice per dose) or PBS (ten mice).	('PC12', 'CellLine', 'CVCL:0481', (9, 13))	('tumor', 'Disease', (14, 19))	('mice', 'Species', '10090', (66, 70))	('0.28', 'Var', (146, 150))	('mice', 'Species', '10090', (221, 225))	('211At', 'Chemical', '-', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PBS', 'Chemical', '-', (212, 215))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
44187	29350258	The inhibition assay showed that desipramine (DMI), a selective inhibitor of the norepinephrine transporter, and dl-norepinephrine significantly inhibited cell uptake of the product (p < 0.01, Supplementary Fig.	('dl-norepinephrine', 'Var', (113, 130))	('desipramine', 'Chemical', 'MESH:D003891', (33, 44))	('dl-norepinephrine', 'Chemical', 'MESH:D009638', (113, 130))	('DMI', 'Chemical', 'MESH:D003891', (46, 49))	('cell uptake', 'CPA', (155, 166))	('inhibited', 'NegReg', (145, 154))
44190	29350258	211At-MABG treatment dose-dependently increased the proportion of cells with DNA DSB and the percentages of cells with DNA DSB treated with 2.0 and 6.0 kBq/mL 211At-MABG were significantly higher than that in the control group (p < 0.05 for 2.0 kBq/mL, p < 0.01 for 6.0 kBq/mL; Fig.	('211At', 'Chemical', '-', (159, 164))	('211At-MABG', 'Var', (159, 169))	('higher', 'PosReg', (189, 195))	('211At', 'Chemical', '-', (0, 5))	('increased', 'PosReg', (38, 47))
44191	29350258	Table 1 shows the biodistribution of 211At-MABG in PC12-tumor bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('211At', 'Chemical', '-', (37, 42))	('mice', 'Species', '10090', (70, 74))	('PC12-tumor', 'Disease', (51, 61))	('PC12-tumor', 'Disease', 'MESH:D009369', (51, 61))	('211At-MABG', 'Var', (37, 47))
44192	29350258	The uptake of 211At-MABG in tumors was higher than that in other organs and tissues at all time points (Table 1).	('higher', 'PosReg', (39, 45))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('211At-MABG', 'Var', (14, 24))	('uptake', 'MPA', (4, 10))	('211At', 'Chemical', '-', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
44193	29350258	211At-MABG rapidly accumulated in tumors, and tumor uptake at 1 h after injection reached approximately 30% ID/g.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('211At-MABG', 'Var', (0, 10))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('211At', 'Chemical', '-', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
44204	29350258	In two of the five mice injected with 1.11 MBq 211At-MABG, the tumor disappeared until around day 28.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('211At', 'Chemical', '-', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mice', 'Species', '10090', (19, 23))	('211At-MABG', 'Var', (47, 57))
44210	29350258	On day 3 after injection, all the mice injected with 0.28 and 0.56 MBq of 211At-MABG showed a decrease in body weight of less than 5% (p <= 0.05 for 0.28 MBq, p <= 0.01 for 0.56 MBq).	('211At-MABG', 'Gene', (74, 84))	('0.28', 'Var', (53, 57))	('mice', 'Species', '10090', (34, 38))	('body weight', 'CPA', (106, 117))	('211At', 'Chemical', '-', (74, 79))	('decrease', 'NegReg', (94, 102))
44211	29350258	Also, mice injected with 1.11 MBq of 211At-MABG showed a decrease in body weight of 10-20% (p <= 0.01), and a decrease in body weight of 20% was observed in one of the five mice 3 days after injection.	('decrease', 'NegReg', (57, 65))	('mice', 'Species', '10090', (6, 10))	('211At', 'Chemical', '-', (37, 42))	('body weight', 'CPA', (69, 80))	('211At-MABG', 'Var', (37, 47))	('mice', 'Species', '10090', (173, 177))
44214	29350258	In contrast, all mice treated with 1.85, 3.70 and 5.55 MBq 211At-MABG showed decreases in body weight of more than 20% on day 3 or 4 after 211At-MABG administration, and were therefore killed humanely at that time.	('mice', 'Species', '10090', (17, 21))	('body weight', 'CPA', (90, 101))	('211At', 'Chemical', '-', (139, 144))	('211At-MABG', 'Var', (59, 69))	('rat', 'Species', '10116', (158, 161))	('decreases', 'NegReg', (77, 86))	('211At', 'Chemical', '-', (59, 64))
44217	29350258	Since 1.11 MBq of 211At-MABG was the MTD, we analyzed the temporal histological changes in the PC12 tumors on days 1, 3 and 7 after administration of 1.11 MBq 211At-MABG.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('211At', 'Chemical', '-', (159, 164))	('PC12 tumors', 'Disease', (95, 106))	('PC12 tumors', 'Disease', 'MESH:D009369', (95, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('211At-MABG', 'Var', (159, 169))	('rat', 'Species', '10116', (140, 143))	('211At', 'Chemical', '-', (18, 23))
44220	29350258	In sections of tumors from mice treated with 211At-MABG, there were no nests of tumor cells, whereas hemorrhage and lymphocyte infiltration were observed (Fig.	('211At', 'Chemical', '-', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', (80, 85))	('211At-MABG', 'Var', (45, 55))	('hemorrhage', 'Disease', (101, 111))	('tumor', 'Disease', (15, 20))	('hemorrhage', 'Disease', 'MESH:D006470', (101, 111))	('tumors', 'Disease', (15, 21))
44222	29350258	In Ki-67-stained sections of tumors from mice treated with 211At-MABG, proliferating (Ki-67-positive) tumor cells tended to decrease in a time-dependent manner (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Ki-67', 'Gene', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('decrease', 'NegReg', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Ki-67', 'Gene', '17345', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('rat', 'Species', '10116', (78, 81))	('tumors', 'Disease', (29, 35))	('211At', 'Chemical', '-', (59, 64))	('mice', 'Species', '10090', (41, 45))	('Ki-67', 'Gene', (86, 91))	('211At-MABG', 'Var', (59, 69))	('Ki-67', 'Gene', '17345', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('proliferating', 'CPA', (71, 84))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (29, 34))
44223	29350258	Sections of tumors from mice treated with 1.85 MBq 211At-MABG showed larger hemorrhage and necrotic areas than following treatment with 1.11 MBq 211At-MABG (Fig.	('larger', 'PosReg', (69, 75))	('211At', 'Chemical', '-', (51, 56))	('hemorrhage', 'Disease', (76, 86))	('1.85', 'Var', (42, 46))	('211At', 'Chemical', '-', (145, 150))	('mice', 'Species', '10090', (24, 28))	('necrotic', 'Disease', (91, 99))	('hemorrhage', 'Disease', 'MESH:D006470', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('necrotic', 'Disease', 'MESH:D009336', (91, 99))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
44225	29350258	The area of fibrous tissue was larger following treatment with 5.55 MBq 211At-MABG (Fig.	('5.55 MBq 211At-MABG', 'Var', (63, 82))	('larger', 'PosReg', (31, 37))	('211At', 'Chemical', '-', (72, 77))
44234	29350258	Treatment with 211At-MABG reduced the tumor volumes in PC12 tumor-bearing mice in a dose-dependent manner.	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('211At', 'Chemical', '-', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PC12', 'CellLine', 'CVCL:0481', (55, 59))	('reduced', 'NegReg', (26, 33))	('211At-MABG', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
44235	29350258	In mice treated with 211At-MABG, reductions in body weight and in the number of myeloid cells in the bone marrow were not severe.	('body weight', 'CPA', (47, 58))	('mice', 'Species', '10090', (3, 7))	('reductions', 'NegReg', (33, 43))	('211At-MABG', 'Var', (21, 31))	('211At', 'Chemical', '-', (21, 26))
44236	29350258	This may indicate that 211At-MABG has tumor-reducing effects without severe radiation-induced side effects.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('211At', 'Chemical', '-', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('211At-MABG', 'Var', (23, 33))
44242	29350258	In this study, 211At-MABG reduced the PC12 cell survival ratio in a dose-dependent manner.	('211At', 'Chemical', '-', (15, 20))	('PC12', 'CellLine', 'CVCL:0481', (38, 42))	('reduced', 'NegReg', (26, 33))	('211At-MABG', 'Var', (15, 25))	('rat', 'Species', '10116', (57, 60))	('PC12 cell survival ratio', 'CPA', (38, 62))
44246	29350258	This cell death mechanism, as confirmed in this study, supports the hypothesis of cell injury by alpha-particles and is most likely the main mechanism by which 211At-MABG causes cell death in pheochromocytoma.	('211At-MABG', 'Var', (160, 170))	('pheochromocytoma', 'Disease', (192, 208))	('211At', 'Chemical', '-', (160, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (192, 208))	('pheochromocytoma', 'Disease', 'MESH:D010673', (192, 208))
44247	29350258	Similar to the findings of a previous study using a neuroblastoma model, biodistribution studies showed that 211At-MABG accumulated more in the adrenal gland and heart than in other organs.	('neuroblastoma', 'Disease', (52, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (52, 65))	('211At-MABG', 'Var', (109, 119))	('211At', 'Chemical', '-', (109, 114))	('accumulated', 'PosReg', (120, 131))	('neuroblastoma', 'Disease', 'MESH:D009447', (52, 65))
44251	29350258	Although we did not directly compare the therapeutic effects of 211At-MABG in the neuroblastoma model to those in pheochromocytoma models (because we have not yet been able to establish a neuroblastoma mouse model), the current data suggest that 211At-MABG may be more effective in pheochromocytoma than in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (82, 95))	('211At', 'Chemical', '-', (246, 251))	('211At', 'Chemical', '-', (64, 69))	('pheochromocytoma', 'Disease', 'MESH:D010673', (282, 298))	('pheochromocytoma', 'Disease', 'MESH:D010673', (114, 130))	('neuroblastoma', 'Disease', (188, 201))	('pheochromocytoma', 'Disease', (114, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (188, 201))	('pheochromocytoma', 'Disease', (282, 298))	('neuroblastoma', 'Disease', (307, 320))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (282, 298))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (114, 130))	('neuroblastoma', 'Phenotype', 'HP:0003006', (307, 320))	('neuroblastoma', 'Disease', 'MESH:D009447', (188, 201))	('neuroblastoma', 'Disease', 'MESH:D009447', (307, 320))	('mouse', 'Species', '10090', (202, 207))	('neuroblastoma', 'Disease', (82, 95))	('neuroblastoma', 'Phenotype', 'HP:0003006', (82, 95))	('211At-MABG', 'Var', (246, 256))
44252	29350258	Some previous studies investigating neuroblastoma and pheochromocytoma cells in vitro have shown the possible therapeutic effects of 211At-MABG.	('211At-MABG', 'Var', (133, 143))	('pheochromocytoma', 'Disease', (54, 70))	('neuroblastoma', 'Disease', 'MESH:D009447', (36, 49))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (54, 70))	('neuroblastoma', 'Disease', (36, 49))	('pheochromocytoma', 'Disease', 'MESH:D010673', (54, 70))	('211At', 'Chemical', '-', (133, 138))	('neuroblastoma', 'Phenotype', 'HP:0003006', (36, 49))
44254	29350258	In this regard, this study showed that 211At-MABG has therapeutic effects in vivo, and thus provides further insight into the therapeutic potential of 211At-MABG.	('therapeutic effects', 'CPA', (54, 73))	('211At', 'Chemical', '-', (151, 156))	('211At', 'Chemical', '-', (39, 44))	('211At-MABG', 'Var', (39, 49))
44255	29350258	In PC12 tumor-bearing mice, 211At-MABG treatment at doses of 0.56 MBq and higher reduced tumor volumes compared with those in control mice.	('mice', 'Species', '10090', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('211At-MABG', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PC12', 'CellLine', 'CVCL:0481', (3, 7))	('tumor', 'Disease', (8, 13))	('reduced', 'NegReg', (81, 88))	('211At', 'Chemical', '-', (28, 33))	('mice', 'Species', '10090', (22, 26))	('tumor', 'Disease', (89, 94))
44256	29350258	The present study once again provides new insights into the therapeutic effects of 211At-MABG in a pheochromocytoma mouse model.	('pheochromocytoma', 'Disease', (99, 115))	('pheochromocytoma', 'Disease', 'MESH:D010673', (99, 115))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (99, 115))	('211At-MABG', 'Var', (83, 93))	('mouse', 'Species', '10090', (116, 121))	('211At', 'Chemical', '-', (83, 88))
44262	29350258	The histological findings of this study confirmed the effectiveness of 211At-MABG in reducing tumor volumes.	('211At-MABG', 'Var', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('reducing', 'NegReg', (85, 93))	('tumor', 'Disease', (94, 99))	('211At', 'Chemical', '-', (71, 76))
44271	29350258	using the same pheochromocytoma mouse model, administration of 57 MBq of 131I-MIBG maximally reduced tumor volume to approximately 30% of the volume on day 0, while in this study tumors treated with 1.11 MBq 211At-MABG were reduced to approximately 3.3% of the volume on day 0.	('pheochromocytoma', 'Disease', (15, 31))	('131I-MIBG', 'Chemical', '-', (73, 82))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (15, 31))	('tumors', 'Disease', (179, 185))	('211At', 'Chemical', '-', (208, 213))	('reduced', 'NegReg', (93, 100))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('pheochromocytoma', 'Disease', 'MESH:D010673', (15, 31))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('rat', 'Species', '10116', (53, 56))	('mouse', 'Species', '10090', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('131I-MIBG', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', (179, 184))
44272	29350258	Therefore, the MTD of 211At-MABG, while being a fraction of the MTD for 131I-MIBG, would have a significantly greater tumor-reducing effect (approximately nine times) in pheochromocytoma therapy than 131I-MIBG.	('pheochromocytoma', 'Disease', (170, 186))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (170, 186))	('131I-MIBG', 'Chemical', '-', (200, 209))	('131I-MIBG', 'Chemical', '-', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('greater', 'PosReg', (110, 117))	('211At', 'Chemical', '-', (22, 27))	('pheochromocytoma', 'Disease', 'MESH:D010673', (170, 186))	('tumor', 'Disease', (118, 123))	('211At-MABG', 'Var', (22, 32))
44273	29350258	A systematic review and meta-analysis of the effect of 131I-MIBG on tumor volume found a complete remission rate after 131I-MIBG therapy of 3%, a partial remission rate of 27% and a stable disease rate of 52%.	('tumor', 'Disease', (68, 73))	('rat', 'Species', '10116', (108, 111))	('rat', 'Species', '10116', (197, 200))	('131I-MIBG', 'Chemical', '-', (55, 64))	('131I-MIBG', 'Var', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('rat', 'Species', '10116', (164, 167))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('131I-MIBG', 'Chemical', '-', (119, 128))
44274	29350258	In this study, all five mice treated with the MTD of 211At-MABG (1.11 MBq) showed a reduction in tumor volume, and in two of them the tumor disappeared until day 28 after 211At-MABG administration.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (24, 28))	('reduction', 'NegReg', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('rat', 'Species', '10116', (190, 193))	('211At', 'Chemical', '-', (53, 58))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('211At', 'Chemical', '-', (171, 176))	('211At-MABG', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
44275	29350258	Moreover, based on the percentage tumor volume reduction, in mice receiving 1.11 MBq 211At-MABG, tumor volumes were reduced by 96.7% compared to the volumes at baseline.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('211At', 'Chemical', '-', (85, 90))	('1.11 MBq 211At-MABG', 'Var', (76, 95))	('reduced', 'NegReg', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (34, 39))
44283	29350258	Mice receiving a dose of 211At-MABG lower than or equal to the MTD showed temporary weight reduction after administration but then a gradual recovery in body weight.	('211At', 'Chemical', '-', (25, 30))	('weight reduction', 'Disease', (84, 100))	('rat', 'Species', '10116', (115, 118))	('211At-MABG', 'Var', (25, 35))	('Mice', 'Species', '10090', (0, 4))	('weight reduction', 'Disease', 'MESH:D015431', (84, 100))
44284	29350258	Thus, there was no significant weight reduction at 10 days after 211At-MABG administration compared with the body weight of control mice.	('rat', 'Species', '10116', (84, 87))	('weight reduction', 'Disease', 'MESH:D015431', (31, 47))	('weight reduction', 'Disease', (31, 47))	('mice', 'Species', '10090', (132, 136))	('211At-MABG', 'Var', (65, 75))	('211At', 'Chemical', '-', (65, 70))
44288	29350258	The treatment with 211At-MABG at the MTD (1.11 MBq) caused no marked change in bone marrow cellularity compared with the bone marrow of the control group.	('bone marrow cellularity', 'CPA', (79, 102))	('marrow cellularity', 'Phenotype', 'HP:0005561', (84, 102))	('211At-MABG', 'Var', (19, 29))	('211At', 'Chemical', '-', (19, 24))
44290	29350258	There were no marked histological changes in any organs treated with the MTD of 211At-MABG, whereas some vacuolated medullary cells were detected in adrenal gland treated with 3.70 and 5.55 MBq of 211At-MABG.	('211At', 'Chemical', '-', (80, 85))	('vacuolated medullary cells', 'Phenotype', 'HP:0008659', (105, 131))	('211At', 'Chemical', '-', (197, 202))	('211At-MABG', 'Var', (80, 90))	('211At-MABG', 'Var', (197, 207))
44296	29350258	211At-MABG showed a strong tumor volume-reducing effect in a pheochromocytoma mouse model without severe adverse effects such as weight reduction and reductions in the numbers of myeloid cells in the bone marrow.	('weight reduction', 'Disease', 'MESH:D015431', (129, 145))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('211At', 'Chemical', '-', (0, 5))	('weight reduction', 'Disease', (129, 145))	('tumor', 'Disease', (27, 32))	('211At-MABG', 'Var', (0, 10))	('pheochromocytoma', 'Disease', (61, 77))	('reductions', 'NegReg', (150, 160))	('pheochromocytoma', 'Disease', 'MESH:D010673', (61, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (61, 77))	('mouse', 'Species', '10090', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
44300	27594983	She had a germline 1132delG frameshift mutation in MEN1, no mutation in CDKN1B (p27) and no RET mutation, but had both RET polymorphisms Gly691Ser and Arg982Cys.	('Gly691Ser', 'Var', (137, 146))	('MEN1', 'Gene', (51, 55))	('CDKN1B', 'Gene', '1027', (72, 78))	('MEN1', 'Gene', '4221', (51, 55))	('RET', 'Gene', (119, 122))	('Arg982Cys', 'Var', (151, 160))	('RET', 'Gene', (92, 95))	('CDKN1B', 'Gene', (72, 78))	('1132delG', 'Mutation', 'c.1132delG', (19, 27))	('Arg982Cys', 'SUBSTITUTION', 'None', (151, 160))	('RET', 'Gene', '5979', (119, 122))	('Gly691Ser', 'SUBSTITUTION', 'None', (137, 146))	('RET', 'Gene', '5979', (92, 95))
44301	27594983	This is the first case report of a combination of typical clinical findings of MEN1 harboring a germline MEN1 mutation and the MEN2-like phenotype with negative full RET gene analysis of pathogenic variants.	('MEN1', 'Gene', '4221', (79, 83))	('MEN', 'Species', '9606', (127, 130))	('MEN1', 'Gene', (79, 83))	('RET', 'Gene', '5979', (166, 169))	('MEN1', 'Gene', (105, 109))	('MEN', 'Species', '9606', (79, 82))	('MEN1', 'Gene', '4221', (105, 109))	('mutation', 'Var', (110, 118))	('RET', 'Gene', (166, 169))	('MEN', 'Species', '9606', (105, 108))
44302	27594983	Possible explanations include a previously unrecognized phenotype-genotype association or the influence of potential phenotypic modifying RET variants.	('RET', 'Gene', (138, 141))	('variants', 'Var', (142, 150))	('RET', 'Gene', '5979', (138, 141))
44304	27594983	Multiple endocrine neoplasia type 1 (MEN1) is a syndrome with autosomal dominant (AD) transmission; it is defined as the presence of endocrine tumors in two out of three of its main affected tissues (parathyroid, anterior pituitary and enter-opancreatic neuroendocrine tissues); it results usually from germline inactivation of the MEN1 tumor suppressor gene.	('germline inactivation', 'Var', (303, 324))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (337, 342))	('AD', 'Disease', 'MESH:D000544', (82, 84))	('Multiple endocrine neoplasia type 1', 'Gene', '4221', (0, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('MEN1', 'Gene', '4221', (332, 336))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('enter-opancreatic neuroendocrine', 'Disease', 'MESH:D004751', (236, 268))	('MEN1', 'Gene', '4221', (37, 41))	('MEN1', 'Gene', (332, 336))	('enter-opancreatic neuroendocrine', 'Disease', (236, 268))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('autosomal dominant', 'Disease', (62, 80))	('Multiple endocrine neoplasia type 1', 'Gene', (0, 35))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('endocrine tumors', 'Disease', 'MESH:D004701', (133, 149))	('MEN1', 'Gene', (37, 41))	('rat', 'Species', '10116', (202, 205))	('endocrine tumors', 'Disease', (133, 149))	('tumor', 'Disease', (143, 148))	('AD', 'Disease', (82, 84))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('autosomal dominant', 'Disease', 'MESH:D017827', (62, 80))
44305	27594983	Multiple endocrine neoplasia type 2 (MEN2) is defined as one of two clinical syndromes (MEN2A and MEN2B) of an AD disorder with medullary thyroid cancer, each due to germline activating mutation of the RET proto-oncogene.	('MEN', 'Species', '9606', (98, 101))	('Multiple endocrine neoplasia type 2', 'Disease', (0, 35))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('RET', 'Gene', (202, 205))	('due to', 'Reg', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('MEN2B', 'Gene', (98, 103))	('MEN2B', 'Gene', '5979', (98, 103))	('MEN', 'Species', '9606', (88, 91))	('thyroid cancer', 'Disease', (138, 152))	('thyroid cancer', 'Disease', 'MESH:D013964', (138, 152))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('germline activating mutation', 'Var', (166, 194))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (128, 152))	('MEN2A', 'Gene', '5979', (88, 93))	('MEN2A', 'Gene', (88, 93))	('RET', 'Gene', '5979', (202, 205))	('Multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (0, 35))	('AD disorder', 'Disease', (111, 122))	('MEN', 'Species', '9606', (37, 40))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('AD disorder', 'Disease', 'MESH:D000544', (111, 122))
44309	27594983	reported that combined knockout of p27 and p18 CDKI genes in mice caused neoplasia with the tissue specificity simultaneously of MEN1 plus MEN2.	('MEN', 'Species', '9606', (139, 142))	('mice', 'Species', '10090', (61, 65))	('MEN', 'Species', '9606', (129, 132))	('caused', 'Reg', (66, 72))	('neoplasia', 'Disease', 'MESH:D009369', (73, 82))	('CDKI', 'Gene', (47, 51))	('CDKI', 'Gene', '1033', (47, 51))	('knockout', 'Var', (23, 31))	('neoplasia', 'Phenotype', 'HP:0002664', (73, 82))	('p18', 'Gene', '100689229', (43, 46))	('p27', 'Gene', (35, 38))	('MEN1', 'Gene', (129, 133))	('MEN1', 'Gene', '4221', (129, 133))	('p18', 'Gene', (43, 46))	('neoplasia', 'Disease', (73, 82))
44310	27594983	reported homozygous inactivation of p27 in a rat strain manifesting tumors of both MEN1 and MEN2; they also reported a human kindred with a MEN1-like syndrome and a p27 germline mutation.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('man', 'Species', '9606', (121, 124))	('MEN1-like syndrome', 'Disease', (140, 158))	('man', 'Species', '9606', (56, 59))	('p27', 'Gene', (36, 39))	('p27 germline mutation', 'Var', (165, 186))	('rat', 'Species', '10116', (45, 48))	('human', 'Species', '9606', (119, 124))	('MEN1', 'Gene', '4221', (140, 144))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('MEN1', 'Gene', '4221', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MEN1-like syndrome', 'Disease', 'MESH:D018761', (140, 158))	('MEN1', 'Gene', (140, 144))	('MEN', 'Species', '9606', (92, 95))	('MEN1', 'Gene', (83, 87))	('tumors', 'Disease', (68, 74))	('MEN', 'Species', '9606', (140, 143))	('MEN', 'Species', '9606', (83, 86))
44311	27594983	reported rare MEN1-like families with mutation of p27 or other CDKI genes (p21, p18, p15) but no MEN1 mutation.	('p15', 'Gene', (85, 88))	('p27', 'Gene', (50, 53))	('MEN1', 'Gene', '4221', (14, 18))	('p15', 'Gene', '1030', (85, 88))	('MEN1', 'Gene', (14, 18))	('MEN1', 'Gene', (97, 101))	('p18', 'Gene', '100689229', (80, 83))	('MEN1', 'Gene', '4221', (97, 101))	('p18', 'Gene', (80, 83))	('CDKI', 'Gene', (63, 67))	('mutation', 'Var', (38, 46))	('p21', 'Gene', (75, 78))	('CDKI', 'Gene', '1033', (63, 67))	('p21', 'Gene', '644914', (75, 78))
44312	27594983	The MEN1-like syndrome attributed to these mutations was later named MENX (in rats) or MEN4 (in humans).	('rats', 'Species', '10116', (78, 82))	('MEN1-like syndrome', 'Disease', (4, 22))	('MEN', 'Species', '9606', (4, 7))	('MEN4', 'Gene', '1027', (87, 91))	('mutations', 'Var', (43, 52))	('MEN', 'Species', '9606', (69, 72))	('MEN1-like syndrome', 'Disease', 'MESH:D018761', (4, 22))	('MEN', 'Species', '9606', (87, 90))	('MEN4', 'Gene', (87, 91))	('humans', 'Species', '9606', (96, 102))
44313	27594983	Unlike in rodents, none of the reported human families with MEN1 syndrome and CDKI mutations has shown features of MEN2.	('mutations', 'Var', (83, 92))	('MEN1 syndrome', 'Disease', (60, 73))	('human', 'Species', '9606', (40, 45))	('CDKI', 'Gene', '1033', (78, 82))	('CDKI', 'Gene', (78, 82))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (60, 73))	('MEN2', 'Disease', (115, 119))	('MEN', 'Species', '9606', (115, 118))	('MEN', 'Species', '9606', (60, 63))
44314	27594983	Here we report a patient with a germline mutation in the MEN1 gene and features of MEN1 and MEN2.	('MEN1', 'Gene', '4221', (57, 61))	('MEN', 'Species', '9606', (92, 95))	('MEN1', 'Gene', (83, 87))	('MEN', 'Species', '9606', (57, 60))	('MEN1', 'Gene', '4221', (83, 87))	('patient', 'Species', '9606', (17, 24))	('MEN', 'Species', '9606', (83, 86))	('MEN1', 'Gene', (57, 61))	('germline mutation in', 'Var', (32, 52))	('MEN2', 'Disease', (92, 96))
44322	27594983	Genetic testing revealed a germline frameshift mutation 1132delG (NM_130799.2) in MEN1 (also called c.1039delG (NM_000244.3) and described at the protein level as p.Ala347Argfs*26).	('1132delG', 'Mutation', 'c.1132delG', (56, 64))	('c.1039delG', 'Mutation', 'c.1039delG', (100, 110))	('p.Ala347Argfs*26', 'Var', (163, 179))	('p.Ala347Argfs*26', 'Mutation', 'p.A347RfsX26', (163, 179))	('MEN1', 'Gene', (82, 86))	('MEN1', 'Gene', '4221', (82, 86))
44324	27594983	She was found to be heterozygous for the Gly691Ser polymorphism in RET exon 11 and the Arg982Cys polymorphism in exon 18, as well as several more common synonymous polymorphisms in the gene.	('Arg982Cys', 'Var', (87, 96))	('Gly691Ser', 'SUBSTITUTION', 'None', (41, 50))	('RET', 'Gene', '5979', (67, 70))	('Gly691Ser', 'Var', (41, 50))	('Arg982Cys', 'SUBSTITUTION', 'None', (87, 96))	('RET', 'Gene', (67, 70))
44326	27594983	The patient's son and daughter also tested positive for the MEN1 mutation 1132delG, and full RET sequencing showed that they carry the same both RET polymorphisms (Gly691Ser and Arg982Cys) as their mother.	('Gly691Ser', 'SUBSTITUTION', 'None', (164, 173))	('RET', 'Gene', '5979', (145, 148))	('RET', 'Gene', '5979', (93, 96))	('Gly691Ser', 'Var', (164, 173))	('Arg982Cys', 'SUBSTITUTION', 'None', (178, 187))	('patient', 'Species', '9606', (4, 11))	('1132delG', 'Mutation', 'c.1132delG', (74, 82))	('MEN1', 'Gene', (60, 64))	('RET', 'Gene', (145, 148))	('RET', 'Gene', (93, 96))	('MEN1', 'Gene', '4221', (60, 64))	('Arg982Cys', 'Var', (178, 187))
44335	27594983	As this tumor was initially misdiagnosed as a neurofibroma, loss of heterozygosity (LOH) analysis at the site of the frameshift mutation was attempted but unsuccessful.	('frameshift mutation', 'Var', (117, 136))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('neurofibroma', 'Disease', (46, 58))	('neurofibroma', 'Phenotype', 'HP:0001067', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('neurofibroma', 'Disease', 'MESH:D009455', (46, 58))	('tumor', 'Disease', (8, 13))
44341	27594983	Although the patient carries a germline MEN1 mutation, yet she manifests MEN2-like features, including pheochromocytoma and thickened corneal nerves.	('pheochromocytoma', 'Disease', 'MESH:D010673', (103, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('thickened corneal nerves', 'Phenotype', 'HP:0010726', (124, 148))	('patient', 'Species', '9606', (13, 20))	('MEN1', 'Gene', (40, 44))	('man', 'Species', '9606', (63, 66))	('MEN1', 'Gene', '4221', (40, 44))	('mutation', 'Var', (45, 53))	('MEN', 'Species', '9606', (73, 76))	('pheochromocytoma', 'Disease', (103, 119))	('MEN', 'Species', '9606', (40, 43))
44343	27594983	LOH at 11q13 was found in two tumors, thus reinforcing the likelihood that most of these rare tumors result from biallelic MEN1 gene inactivation.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('MEN1', 'Gene', '4221', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('biallelic', 'Var', (113, 122))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('MEN1', 'Gene', (123, 127))	('result from', 'Reg', (101, 112))
44349	27594983	To our knowledge, this is the first report in the literature of a patient showing classical MEN1 features harboring a germline MEN1 mutation, in addition to MEN2-like features with negative RET mutation analysis.	('MEN', 'Species', '9606', (92, 95))	('RET', 'Gene', (190, 193))	('MEN', 'Species', '9606', (127, 130))	('MEN', 'Species', '9606', (157, 160))	('rat', 'Species', '10116', (54, 57))	('patient', 'Species', '9606', (66, 73))	('RET', 'Gene', '5979', (190, 193))	('MEN1', 'Gene', '4221', (92, 96))	('MEN1', 'Gene', '4221', (127, 131))	('MEN1', 'Gene', (92, 96))	('mutation', 'Var', (132, 140))	('MEN1', 'Gene', (127, 131))
44351	27594983	Testing revealed widespread expression of the RET mutation, Lys666Met; and clinical manifestations included medullary thyroid cancer (MTC) in two members and CCH in three members, out of the eight total members carrying RET mutation.	('RET', 'Gene', '5979', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CCH', 'Chemical', '-', (158, 161))	('thyroid cancer', 'Disease', (118, 132))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (108, 132))	('thyroid cancer', 'Phenotype', 'HP:0002890', (118, 132))	('RET', 'Gene', (220, 223))	('CCH', 'Disease', (158, 161))	('Lys666Met', 'Var', (60, 69))	('RET', 'Gene', '5979', (46, 49))	('thyroid cancer', 'Disease', 'MESH:D013964', (118, 132))	('man', 'Species', '9606', (84, 87))	('Lys666Met', 'SUBSTITUTION', 'None', (60, 69))	('MTC', 'Phenotype', 'HP:0002865', (134, 137))	('RET', 'Gene', (46, 49))
44352	27594983	Twelve members of this family also carried a mutation in IVS4 + 1G > A of the MEN1 gene, with a total of four patients carrying both MEN1 and RET mutations.	('RET', 'Gene', '5979', (142, 145))	('IVS4 + 1G > A', 'Mutation', 'c.IVS4+1G>A', (57, 70))	('1G > A', 'SUBSTITUTION', 'None', (64, 70))	('1G > A', 'Var', (64, 70))	('RET', 'Gene', (142, 145))	('MEN1', 'Gene', '4221', (78, 82))	('MEN1', 'Gene', (133, 137))	('MEN1', 'Gene', (78, 82))	('MEN1', 'Gene', '4221', (133, 137))	('patients', 'Species', '9606', (110, 118))	('carried', 'Reg', (35, 42))
44353	27594983	In this family, the co-existence of MEN1 and RET mutations did not seem to alter the onset or course of any one tumor type, tumor behavior, or typical phenotype as compared with patients with the same MEN1 or RET mutations separately.	('tumor behavior', 'Disease', 'MESH:D001523', (124, 138))	('RET', 'Gene', (209, 212))	('alter', 'Reg', (75, 80))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (178, 186))	('MEN1', 'Gene', '4221', (36, 40))	('tumor', 'Disease', (112, 117))	('RET', 'Gene', '5979', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor behavior', 'Disease', (124, 138))	('MEN1', 'Gene', '4221', (201, 205))	('MEN1', 'Gene', (36, 40))	('RET', 'Gene', '5979', (209, 212))	('rat', 'Species', '10116', (227, 230))	('MEN1', 'Gene', (201, 205))	('RET', 'Gene', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))
44356	27594983	In addition to a MEN1 mutation IVS5 + 1G > A, RET analysis revealed the polymorphism Tyr791Phe (Table 1).	('Tyr791Phe', 'Var', (85, 94))	('IVS5 + 1G > A', 'Mutation', 'c.IVS5+1G>A', (31, 44))	('1G > A', 'SUBSTITUTION', 'None', (38, 44))	('Tyr791Phe', 'SUBSTITUTION', 'None', (85, 94))	('RET', 'Gene', '5979', (46, 49))	('1G > A', 'Var', (38, 44))	('MEN1', 'Gene', (17, 21))	('MEN1', 'Gene', '4221', (17, 21))	('RET', 'Gene', (46, 49))
44359	27594983	Therefore, it is possible, but not proven, that CCH in this family occurred as a result of phenotypic modifying effect of Tyr791Phe in combination to chronic hypercalcemia.	('Tyr791Phe', 'SUBSTITUTION', 'None', (122, 131))	('hypercalcemia', 'Disease', (158, 171))	('hypercalcemia', 'Phenotype', 'HP:0003072', (158, 171))	('hypercalcemia', 'Disease', 'MESH:D006934', (158, 171))	('CCH', 'Chemical', '-', (48, 51))	('CCH', 'Disease', (48, 51))	('Tyr791Phe', 'Var', (122, 131))
44360	27594983	The prevalence of the RET polymorphism Gly691Ser is common, occurring in about 40% of Europeans and 37% in Latino populations, whereas Arg982Cys is present in about 2.4% of Europeans and about 5% of Asian populations.	('RET', 'Gene', (22, 25))	('RET', 'Gene', '5979', (22, 25))	('Arg982Cys', 'Var', (135, 144))	('Gly691Ser', 'SUBSTITUTION', 'None', (39, 48))	('Arg982Cys', 'SUBSTITUTION', 'None', (135, 144))	('Gly691Ser', 'Var', (39, 48))
44361	27594983	It is notable that the RET polymorphism Gly691Ser, while not believed to be a pathogenic mutation on its own, has been suggested to modulate the effect of RET mutations.	('Gly691Ser', 'Var', (40, 49))	('RET', 'Gene', (23, 26))	('modulate', 'Reg', (132, 140))	('RET', 'Gene', '5979', (155, 158))	('RET', 'Gene', (155, 158))	('RET', 'Gene', '5979', (23, 26))	('Gly691Ser', 'SUBSTITUTION', 'None', (40, 49))
44362	27594983	Even when present along with the RET polymorphism Arg982Cys as in our patient, it may modulate the effect of a mutation in a separate gene.	('modulate', 'Reg', (86, 94))	('RET', 'Gene', (33, 36))	('Arg982Cys', 'Var', (50, 59))	('rat', 'Species', '10116', (129, 132))	('effect', 'MPA', (99, 105))	('patient', 'Species', '9606', (70, 77))	('RET', 'Gene', '5979', (33, 36))	('Arg982Cys', 'SUBSTITUTION', 'None', (50, 59))
44363	27594983	The allelic frequency of Gly691Ser has been found to be significantly higher in patients with sporadic MTC as compared with normal controls (28 vs 19%).	('patients', 'Species', '9606', (80, 88))	('MTC', 'Phenotype', 'HP:0002865', (103, 106))	('Gly691Ser', 'SUBSTITUTION', 'None', (25, 34))	('Gly691Ser', 'Var', (25, 34))	('sporadic MTC', 'Disease', (94, 106))	('higher', 'PosReg', (70, 76))
44365	27594983	In a case series report of four unrelated patients having neurofibromas and thickened corneal nerves, testing in one patient was negative for NF1 and RET analysis, however, revealed the presence of RET Gly691Ser polymorphism.	('NF1', 'Gene', '4763', (142, 145))	('RET', 'Gene', (198, 201))	('RET', 'Gene', (150, 153))	('Gly691Ser', 'SUBSTITUTION', 'None', (202, 211))	('thickened corneal nerves', 'Phenotype', 'HP:0010726', (76, 100))	('Gly691Ser', 'Var', (202, 211))	('patient', 'Species', '9606', (42, 49))	('neurofibromas', 'Disease', (58, 71))	('RET', 'Gene', '5979', (150, 153))	('RET', 'Gene', '5979', (198, 201))	('patient', 'Species', '9606', (117, 124))	('neurofibromas', 'Phenotype', 'HP:0001067', (58, 71))	('neurofibromas', 'Disease', 'MESH:D009455', (58, 71))	('patients', 'Species', '9606', (42, 50))	('NF1', 'Gene', (142, 145))	('neurofibroma', 'Phenotype', 'HP:0001067', (58, 70))
44367	27594983	A study researching congenital anomalies of the kidney or urinary tract found that when the Gly691Ser polymorphism is combined with the rarer Arg982Cys RET polymorphism in vitro, this resulted in almost complete loss of MAPK phosphorylation that is critical for kidney formation, which neither polymorphism individually had any effect on.	('RET', 'Gene', (152, 155))	('Arg982Cys', 'Var', (142, 151))	('Gly691Ser', 'SUBSTITUTION', 'None', (92, 101))	('MAPK phosphorylation', 'MPA', (220, 240))	('anomalies of the kidney', 'Phenotype', 'HP:0000077', (31, 54))	('RET', 'Gene', '5979', (152, 155))	('congenital anomalies of the kidney', 'Disease', 'MESH:D000013', (20, 54))	('Arg982Cys', 'SUBSTITUTION', 'None', (142, 151))	('congenital anomalies of the kidney', 'Disease', (20, 54))	('loss', 'NegReg', (212, 216))	('Gly691Ser', 'Var', (92, 101))
44368	27594983	This raises the question of whether in our patient the RET polymorphisms Gly691Ser and Arg982Cys, either individually or in combination, are working in synergy with the MEN1 mutation 1132delG or with another gene to produce features of MEN2.	('Arg982Cys', 'Var', (87, 96))	('1132delG', 'Mutation', 'c.1132delG', (183, 191))	('1132delG', 'Var', (183, 191))	('RET', 'Gene', '5979', (55, 58))	('synergy', 'Disease', 'None', (152, 159))	('patient', 'Species', '9606', (43, 50))	('Gly691Ser', 'SUBSTITUTION', 'None', (73, 82))	('synergy', 'Disease', (152, 159))	('Gly691Ser', 'Var', (73, 82))	('MEN1', 'Gene', (169, 173))	('MEN1', 'Gene', '4221', (169, 173))	('RET', 'Gene', (55, 58))	('Arg982Cys', 'SUBSTITUTION', 'None', (87, 96))	('MEN', 'Species', '9606', (236, 239))	('MEN', 'Species', '9606', (169, 172))
44370	27594983	The presence of the RET polymorphisms Gly691Ser or Arg982Cys could in part explain some of the MEN2-like features of this patient.	('RET', 'Gene', '5979', (20, 23))	('Gly691Ser', 'SUBSTITUTION', 'None', (38, 47))	('Arg982Cys', 'Var', (51, 60))	('Gly691Ser', 'Var', (38, 47))	('patient', 'Species', '9606', (122, 129))	('RET', 'Gene', (20, 23))	('Arg982Cys', 'SUBSTITUTION', 'None', (51, 60))	('MEN', 'Species', '9606', (95, 98))	('MEN2-like', 'Disease', (95, 104))
44371	27594983	Other possible explanations of the MEN2-like features include a previously unrecognized phenotype-genotype association with the 1132delG frameshift mutation in MEN1, the presence of an occult RET mutation in the patient undetected by full gene sequencing, association with an unknown MEN2-like syndrome, or the influence of potential phenotypic modifying RET variants.	('MEN2-like syndrome', 'Disease', 'MESH:C537419', (284, 302))	('MEN', 'Species', '9606', (284, 287))	('1132delG', 'Mutation', 'c.1132delG', (128, 136))	('RET', 'Gene', (192, 195))	('RET', 'Gene', '5979', (355, 358))	('MEN', 'Species', '9606', (160, 163))	('1132delG frameshift mutation', 'Var', (128, 156))	('MEN2-like', 'Disease', (35, 44))	('patient', 'Species', '9606', (212, 219))	('MEN1', 'Gene', (160, 164))	('MEN', 'Species', '9606', (35, 38))	('MEN1', 'Gene', '4221', (160, 164))	('RET', 'Gene', '5979', (192, 195))	('MEN2-like syndrome', 'Disease', (284, 302))	('RET', 'Gene', (355, 358))
44374	27594983	Germline MEN1 mutation can rarely be associated with some of the classic expressions of both MEN1 and MEN2-like features together.	('MEN', 'Species', '9606', (102, 105))	('MEN1', 'Gene', (93, 97))	('MEN1', 'Gene', '4221', (93, 97))	('MEN1', 'Gene', '4221', (9, 13))	('mutation', 'Var', (14, 22))	('MEN1', 'Gene', (9, 13))	('associated', 'Reg', (37, 47))	('MEN', 'Species', '9606', (93, 96))	('MEN', 'Species', '9606', (9, 12))
44376	27594983	The presence of potential phenotypic modifying RET variants, could, at least in part, explain the MEN2-like phenotype in this MEN1 patient.	('MEN1', 'Gene', (126, 130))	('MEN', 'Species', '9606', (98, 101))	('MEN1', 'Gene', '4221', (126, 130))	('RET', 'Gene', (47, 50))	('MEN', 'Species', '9606', (126, 129))	('variants', 'Var', (51, 59))	('MEN2-like', 'Disease', (98, 107))	('RET', 'Gene', '5979', (47, 50))	('patient', 'Species', '9606', (131, 138))
44377	27594983	The combination observed in this patient may point to a single molecular pathway, and supports the possibility of as yet unrecognized connections between the molecular pathways for MEN1 (menin protein) and MEN2 (RET protein).	('MEN1', 'Gene', '4221', (181, 185))	('patient', 'Species', '9606', (33, 40))	('RET', 'Gene', '5979', (212, 215))	('menin', 'Gene', '4221', (187, 192))	('molecular pathway', 'Pathway', (63, 80))	('point to', 'Reg', (45, 53))	('MEN', 'Species', '9606', (181, 184))	('MEN', 'Species', '9606', (206, 209))	('RET', 'Gene', (212, 215))	('menin', 'Gene', (187, 192))	('MEN2', 'Var', (206, 210))	('MEN1', 'Gene', (181, 185))
44382	27594983	Furthermore, the presence of certain polymorphisms, may influence the disease course, or result in the manifestation of a new phenotype.	('polymorphisms', 'Var', (37, 50))	('disease course', 'CPA', (70, 84))	('result in', 'Reg', (89, 98))	('influence', 'Reg', (56, 65))	('presence', 'Var', (17, 25))	('man', 'Species', '9606', (103, 106))
44385	27594983	Papers of special note have been highlighted as:   of interest;    of considerable interest MEN1 and MEN2 are rare autosomal dominant disorders, that result from germline mutations in the MEN1 and RET genes, respectively.	('RET', 'Gene', (197, 200))	('autosomal dominant', 'Disease', 'MESH:D017827', (115, 133))	('MEN', 'Species', '9606', (92, 95))	('MEN', 'Species', '9606', (188, 191))	('dominant disorders', 'Disease', 'MESH:D004194', (125, 143))	('autosomal dominant', 'Disease', (115, 133))	('result from', 'Reg', (150, 161))	('MEN2', 'Disease', (101, 105))	('dominant disorders', 'Disease', (125, 143))	('RET', 'Gene', '5979', (197, 200))	('MEN1', 'Gene', (188, 192))	('MEN1', 'Gene', '4221', (92, 96))	('germline mutations', 'Var', (162, 180))	('MEN1', 'Gene', '4221', (188, 192))	('MEN1', 'Gene', (92, 96))	('MEN', 'Species', '9606', (101, 104))
44386	27594983	Mutations in other genes, like CDKI, result in a MEN1-like syndrome in man, but in mice result in manifestation of tumors of MEN1 and MEN2.	('MEN1', 'Gene', (49, 53))	('man', 'Species', '9606', (98, 101))	('result in', 'Reg', (37, 46))	('MEN', 'Species', '9606', (49, 52))	('man', 'Species', '9606', (71, 74))	('MEN1-like syndrome', 'Disease', 'MESH:D018761', (49, 67))	('MEN1', 'Gene', '4221', (125, 129))	('mice', 'Species', '10090', (83, 87))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('Mutations', 'Var', (0, 9))	('CDKI', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('MEN', 'Species', '9606', (134, 137))	('MEN1', 'Gene', (125, 129))	('tumors', 'Disease', (115, 121))	('MEN', 'Species', '9606', (125, 128))	('CDKI', 'Gene', '1033', (31, 35))	('MEN1', 'Gene', '4221', (49, 53))	('MEN1-like syndrome', 'Disease', (49, 67))	('tumors', 'Disease', 'MESH:D009369', (115, 121))
44389	27594983	She had both RET polymorphisms Gly691Ser and Arg982Cys.	('RET', 'Gene', (13, 16))	('Arg982Cys', 'Var', (45, 54))	('Gly691Ser', 'SUBSTITUTION', 'None', (31, 40))	('Gly691Ser', 'Var', (31, 40))	('Arg982Cys', 'SUBSTITUTION', 'None', (45, 54))	('RET', 'Gene', '5979', (13, 16))
44391	27594983	Thickened corneal nerves is typically a feature of MEN2B, or NF1, and has been reported in MEN2A as well, but not in MEN1.	('Thickened', 'Var', (0, 9))	('Thickened corneal nerves', 'Phenotype', 'HP:0010726', (0, 24))	('MEN1', 'Gene', '4221', (117, 121))	('MEN1', 'Gene', (117, 121))	('MEN2B', 'Gene', (51, 56))	('NF1', 'Gene', (61, 64))	('MEN2B', 'Gene', '5979', (51, 56))	('NF1', 'Gene', '4763', (61, 64))	('corneal nerves', 'CPA', (10, 24))	('MEN2A', 'Gene', (91, 96))	('MEN2A', 'Gene', '5979', (91, 96))
44393	27594983	The presence of the RET polymorphisms Gly691Ser or Arg982Cys may account for the MEN2-like features of this patient.	('MEN', 'Species', '9606', (81, 84))	('Gly691Ser', 'SUBSTITUTION', 'None', (38, 47))	('RET', 'Gene', '5979', (20, 23))	('Arg982Cys', 'Var', (51, 60))	('Gly691Ser', 'Var', (38, 47))	('RET', 'Gene', (20, 23))	('Arg982Cys', 'SUBSTITUTION', 'None', (51, 60))	('patient', 'Species', '9606', (108, 115))	('MEN2-like', 'Disease', (81, 90))
44415	27052084	At mean BP 45 mmHg and mean PAP 29 mm of Hg, patient was connected to cardiopulmonary bypass (CPB) with 4 L/min flows without cardioplegia on emergency basis after 3 min following IV injection of 225 mg of heparin.	('cardioplegia', 'Disease', (126, 138))	('cardioplegia', 'Disease', 'None', (126, 138))	('heparin', 'Chemical', 'MESH:D006493', (206, 213))	('patient', 'Species', '9606', (45, 52))	('PAP', 'Var', (28, 31))
44429	27052084	CPB can precipitate hypertensive crisis and tachyarrhythmias in these patients.	('patients', 'Species', '9606', (70, 78))	('hypertensive crisis', 'Phenotype', 'HP:0100735', (20, 39))	('hypertensive', 'Disease', (20, 32))	('CPB', 'Var', (0, 3))	('tachyarrhythmias', 'Disease', (44, 60))	('precipitate', 'Reg', (8, 19))	('arrhythmia', 'Phenotype', 'HP:0011675', (49, 59))	('tachyarrhythmias', 'Disease', 'MESH:D013610', (44, 60))	('hypertensive', 'Disease', 'MESH:D006973', (20, 32))
44538	26322453	Within the paraganglioma group, resection of glomus vagale led to worse outcomes and, in general, tumors located at the cranial base have poorer outcomes, as would be expected.	('tumors', 'Disease', (98, 104))	('paraganglioma', 'Disease', 'MESH:D010235', (11, 24))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('paraganglioma', 'Phenotype', 'HP:0002668', (11, 24))	('resection', 'Var', (32, 41))	('paraganglioma', 'Disease', (11, 24))	('resection of glomus vagale', 'Phenotype', 'HP:0002886', (32, 58))	('glomus vagale', 'Phenotype', 'HP:0002886', (45, 58))
44553	19190077	Mutations of nuclear genes encoding subunits B, C, and D of the mitochondrial enzyme succinate dehydrogenase (SDHB 1p35-p36.1, SDHC 1q21, SDHD 11q23) give rise to hereditary PGL syndromes PGL4, PGL3, and PGL1 respectively.	('SDHC', 'Gene', (127, 131))	('SDHB', 'Gene', (110, 114))	('succinate dehydrogenase', 'Gene', '6390', (85, 108))	('PGL3', 'Gene', '6391', (194, 198))	('give rise to', 'Reg', (150, 162))	('SDHC', 'Gene', '6391', (127, 131))	('PGL3', 'Gene', (194, 198))	('PGL1', 'Disease', (204, 208))	('PGL4', 'Gene', '6390', (188, 192))	('SDHD', 'Gene', '6392', (138, 142))	('PGL4', 'Gene', (188, 192))	('hereditary PGL syndromes', 'Disease', (163, 187))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', '6390', (110, 114))	('SDHD', 'Gene', (138, 142))	('hereditary PGL syndromes', 'Disease', 'MESH:D010235', (163, 187))	('succinate dehydrogenase', 'Gene', (85, 108))
44555	19190077	Mitochondrial dysfunction due to SDHx mutations have been linked to tumorigenesis by upregulation of hypoxic and angiogenesis pathways, apoptosis resistance and developmental culling of neuronal precursor cells.	('tumor', 'Disease', (68, 73))	('linked', 'Reg', (58, 64))	('SDHx', 'Chemical', '-', (33, 37))	('apoptosis resistance', 'CPA', (136, 156))	('developmental culling of neuronal precursor cells', 'CPA', (161, 210))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutations', 'Var', (38, 47))	('upregulation', 'PosReg', (85, 97))	('SDHx', 'Gene', (33, 37))
44557	19190077	SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal PGLs, with a high malignant potential, but also head and neck paragangliomas (HNPGL).	('neck paragangliomas', 'Disease', (140, 159))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (131, 159))	('adrenal PGLs', 'Disease', (75, 87))	('extra-adrenal', 'Disease', (36, 49))	('HNPGL', 'Phenotype', 'HP:0002864', (161, 166))	('mutations', 'Var', (5, 14))	('predispose', 'Reg', (22, 32))	('paragangliomas', 'Phenotype', 'HP:0002668', (145, 159))	('SDHB', 'Gene', '6390', (0, 4))	('PGLs', 'Phenotype', 'HP:0002668', (83, 87))	('neck paragangliomas', 'Disease', 'MESH:D010235', (140, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (145, 158))	('SDHB', 'Gene', (0, 4))
44558	19190077	SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal PGLs.	('HNPGL', 'Phenotype', 'HP:0002864', (56, 61))	('multifocal', 'Disease', (45, 55))	('mutations', 'Var', (5, 14))	('SDHD', 'Gene', '6392', (0, 4))	('PGLs', 'Phenotype', 'HP:0002668', (107, 111))	('associated', 'Reg', (29, 39))	('SDHD', 'Gene', (0, 4))
44559	19190077	SDHC mutations are a rare cause of mainly HNPGL.	('HNPGL', 'Phenotype', 'HP:0002864', (42, 47))	('cause', 'Reg', (26, 31))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('mainly HNPGL', 'Disease', (35, 47))
44564	19190077	The identification of SDHx mutations in patients with PGL is warranted for a tailor-made approach to the biochemical diagnosis, imaging, treatment, follow-up, and family screening.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (40, 48))	('SDHx', 'Chemical', '-', (22, 26))	('SDHx', 'Gene', (22, 26))
44575	19190077	An up-to-date overview of all reported SDHx allelic variants that give rise to familial PGL syndromes is available online at http://chromium.liacs.nl/lovd_sdh/.	('SDHx', 'Chemical', '-', (39, 43))	('SDHx', 'Gene', (39, 43))	('familial PGL syndromes', 'Disease', 'MESH:D010235', (79, 101))	('variants', 'Var', (52, 60))	('sdh', 'Gene', (155, 158))	('familial PGL syndromes', 'Disease', (79, 101))	('sdh', 'Gene', '6390', (155, 158))	('give rise', 'Reg', (66, 75))
44577	19190077	Within a European-American registry of patients with PGL, the prevalence of underlying SDHx mutations was 10% among 371 patients with apparently sporadic sPGL (6% SDHB, 4% SDHD) and 28% among 121 patients with HNPGL (7% SDHB, 4% SDHC, and 17% SDHD).	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (196, 204))	('SDHB', 'Gene', '6390', (220, 224))	('HNPGL', 'Phenotype', 'HP:0002864', (210, 215))	('SDHC', 'Gene', '6391', (229, 233))	('SDHB', 'Gene', (220, 224))	('SDHB', 'Gene', '6390', (163, 167))	('SDHD', 'Gene', '6392', (243, 247))	('mutations', 'Var', (92, 101))	('SDHx', 'Gene', (87, 91))	('SDHD', 'Gene', '6392', (172, 176))	('sPGL', 'Chemical', '-', (154, 158))	('SDHB', 'Gene', (163, 167))	('SDHD', 'Gene', (243, 247))	('sPGL', 'Disease', (154, 158))	('patients', 'Species', '9606', (120, 128))	('SDHC', 'Gene', (229, 233))	('SDHx', 'Chemical', '-', (87, 91))	('SDHD', 'Gene', (172, 176))
44579	19190077	SDHB mutations mainly predispose to extra-adrenal, and to a lesser extent, adrenal sPGLs, with a high malignant potential.	('PGLs', 'Phenotype', 'HP:0002668', (84, 88))	('adrenal sPGLs', 'Disease', (75, 88))	('extra-adrenal', 'Disease', (36, 49))	('sPGL', 'Chemical', '-', (83, 87))	('mutations', 'Var', (5, 14))	('predispose', 'Reg', (22, 32))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))
44580	19190077	SDHD mutations are typically associated with multifocal HNPGL and usually benign adrenal and extra-adrenal sPGL.	('HNPGL', 'Phenotype', 'HP:0002864', (56, 61))	('multifocal', 'Disease', (45, 55))	('mutations', 'Var', (5, 14))	('sPGL', 'Chemical', '-', (107, 111))	('SDHD', 'Gene', '6392', (0, 4))	('associated', 'Reg', (29, 39))	('SDHD', 'Gene', (0, 4))
44581	19190077	SDHC mutations appear to be a rare cause of mainly HNPGL and sPGL.	('HNPGL', 'Phenotype', 'HP:0002864', (51, 56))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('sPGL', 'Disease', (61, 65))	('cause', 'Reg', (35, 40))	('HNPGL', 'Disease', (51, 56))	('sPGL', 'Chemical', '-', (61, 65))
44582	19190077	More recently, germ line SDHB, SDHC, and SDHD mutations have implicated in a new clinical syndrome, the Stratakis-Carney dyad associating gastrointestinal stromal tumor and PGL.	('gastrointestinal stromal tumor', 'Disease', (138, 168))	('PGL', 'Disease', (173, 176))	('mutations', 'Var', (46, 55))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (138, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('SDHC', 'Gene', (31, 35))	('implicated in', 'Reg', (61, 74))	('SDHD', 'Gene', '6392', (41, 45))	('SDHB', 'Gene', '6390', (25, 29))	('SDHB', 'Gene', (25, 29))	('SDHD', 'Gene', (41, 45))	('SDHC', 'Gene', '6391', (31, 35))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (138, 168))
44583	19190077	In this review, distinct clinical expressions associated with mutations in different subunits of the SDHx gene will be discussed, as well as present insights in to optimal strategies for establishing the biochemical diagnosis, tumor localization, and therapy of PGL.	('tumor', 'Disease', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('SDHx', 'Gene', (101, 105))	('mutations', 'Var', (62, 71))	('SDHx', 'Chemical', '-', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
44587	19190077	Abnormal SDH function due to mutations of nuclear DNA encoding for one of its subunits results in two completely different phenotypes.	('Abnormal SDH function', 'Disease', 'MESH:D056486', (0, 21))	('Abnormal SDH function', 'Disease', (0, 21))	('mutations', 'Var', (29, 38))	('nuclear DNA', 'Gene', (42, 53))
44588	19190077	Defects in SDHA cause metabolic neurodenerative disorders like congenital Leigh syndrome and late-onset optic atrophy, ataxia and myopathy, whereas SDHB, SDHC, and SDHD mutations predispose to familial PGL.	('mutations', 'Var', (169, 178))	('ataxia', 'Disease', (119, 125))	('ataxia', 'Disease', 'MESH:D001259', (119, 125))	('SDHC', 'Gene', '6391', (154, 158))	('SDHA', 'Gene', (11, 15))	('SDHB', 'Gene', '6390', (148, 152))	('cause', 'Reg', (16, 21))	('SDHA', 'Gene', '6389', (11, 15))	('congenital Leigh syndrome', 'Disease', 'MESH:D007888', (63, 88))	('optic atrophy', 'Disease', (104, 117))	('myopathy', 'Disease', 'MESH:D009135', (130, 138))	('optic atrophy', 'Phenotype', 'HP:0000648', (104, 117))	('metabolic neurodenerative disorders', 'Disease', (22, 57))	('SDHB', 'Gene', (148, 152))	('SDHC', 'Gene', (154, 158))	('Defects', 'Var', (0, 7))	('SDHD', 'Gene', '6392', (164, 168))	('predispose', 'Reg', (179, 189))	('metabolic neurodenerative disorders', 'Disease', 'MESH:D008659', (22, 57))	('congenital Leigh syndrome', 'Disease', (63, 88))	('myopathy', 'Phenotype', 'HP:0003198', (130, 138))	('ataxia', 'Phenotype', 'HP:0001251', (119, 125))	('myopathy', 'Disease', (130, 138))	('SDHD', 'Gene', (164, 168))	('familial PGL', 'Disease', (193, 205))	('optic atrophy', 'Disease', 'MESH:D009896', (104, 117))
44589	19190077	The molecular and cellular mechanisms linking these latter SDHx mutations and tumorigenesis have not been fully elucidated.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('SDHx', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SDHx', 'Chemical', '-', (59, 63))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', (78, 83))
44590	19190077	Also, the pathophysiology of distinct clinical phenotypes associated with abnormalities in different SDH subunits remains to be unraveled.	('SDH', 'Gene', (101, 104))	('abnormalities', 'Var', (74, 87))	('SDH', 'Gene', '6390', (101, 104))
44591	19190077	Consistent with Knudson's two-hit hypothesis for tumorigenesis involving in a tumor suppressor gene, a heterozygous germ line mutation in an SDHx gene is usually associated with somatic loss of the non-mutant allele in the tumor, i.e., loss of heterozygosity.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('loss', 'NegReg', (186, 190))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (78, 83))	('SDHx', 'Chemical', '-', (141, 145))	('SDHx', 'Gene', (141, 145))
44593	19190077	Actually, the abnormal SDH function induces an accumulation of succinate.	('SDH', 'Gene', (23, 26))	('abnormal', 'Var', (14, 22))	('SDH', 'Gene', '6390', (23, 26))	('succinate', 'MPA', (63, 72))	('succinate', 'Chemical', 'MESH:D019802', (63, 72))	('accumulation', 'PosReg', (47, 59))
44598	19190077	Apart from a role in the pathogenesis of PGL in patients with germ line mutations, somatic SDHx mutation may also be rarely involved in the development of sporadic PGL.	('SDHx', 'Chemical', '-', (91, 95))	('SDHx', 'Gene', (91, 95))	('mutation', 'Var', (96, 104))	('involved', 'Reg', (124, 132))	('PGL', 'Disease', (41, 44))	('patients', 'Species', '9606', (48, 56))
44601	19190077	Among 84 patients with an apparently sporadic sPGL, eight had an SDHB mutation, 62.5% of them had an extra-adrenal tumor, and 84% had a malignant disease.	('patients', 'Species', '9606', (9, 17))	('malignant disease', 'Disease', 'MESH:D009369', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('malignant disease', 'Disease', (136, 153))	('extra-adrenal tumor', 'Disease', 'MESH:D010236', (101, 120))	('sPGL', 'Chemical', '-', (46, 50))	('extra-adrenal tumor', 'Disease', (101, 120))	('SDHB', 'Gene', '6390', (65, 69))	('mutation', 'Var', (70, 78))	('adrenal tumor', 'Phenotype', 'HP:0100631', (107, 120))	('SDHB', 'Gene', (65, 69))
44602	19190077	In this series, in the presence of an SDHB mutation, the odd ratio for an extra-adrenal tumor as primary site was calculated to 19.8 and for a malignant to 19.	('mutation', 'Var', (43, 51))	('adrenal tumor', 'Phenotype', 'HP:0100631', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('SDHB', 'Gene', '6390', (38, 42))	('SDHB', 'Gene', (38, 42))	('extra-adrenal tumor', 'Disease', (74, 93))	('extra-adrenal tumor', 'Disease', 'MESH:D010236', (74, 93))
44607	19190077	The mean age at diagnosis of PGL in SDHB mutation carriers in previous series was ~ 30 years.	('mutation', 'Var', (41, 49))	('SDHB', 'Gene', (36, 40))	('SDHB', 'Gene', '6390', (36, 40))
44609	19190077	In the International SDH Consortium population, age-related penetrance (the proportion of gene carriers manifesting the signs or symptoms of the disease by a given age) among SDHB mutation carriers was 29% by age 30 and 45% by age 40.	('SDH', 'Gene', (175, 178))	('SDH', 'Gene', (21, 24))	('SDH', 'Gene', '6390', (175, 178))	('SDHB', 'Gene', '6390', (175, 179))	('SDHB', 'Gene', (175, 179))	('SDH', 'Gene', '6390', (21, 24))	('mutation', 'Var', (180, 188))	('carriers', 'Reg', (189, 197))
44612	19190077	Reversely, the prevalence of deleterious SDHB mutations among patients with malignant sPGL is 30%, and even higher (48%) if the tumor originates from an extra-adrenal location.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('patients', 'Species', '9606', (62, 70))	('SDHB', 'Gene', '6390', (41, 45))	('sPGL', 'Chemical', '-', (86, 90))	('tumor', 'Disease', (128, 133))	('SDHB', 'Gene', (41, 45))
44615	19190077	An underlying SDHB mutation was shown to be an independent predictor of mortality: in 54 patients with malignant sPGL, the 5-year probability of survival was 36% in SDHB mutation carriers and 67% in the absence of SDHB mutation.	('SDHB', 'Gene', '6390', (214, 218))	('SDHB', 'Gene', '6390', (165, 169))	('SDHB', 'Gene', (214, 218))	('SDHB', 'Gene', '6390', (14, 18))	('patients', 'Species', '9606', (89, 97))	('sPGL', 'Chemical', '-', (113, 117))	('SDHB', 'Gene', (165, 169))	('SDHB', 'Gene', (14, 18))	('mutation', 'Var', (170, 178))
44616	19190077	Median survival after the diagnosis of the first metastasis was 42 months for the SDHB mutation carriers and 244 months for patients with no SDHB mutation.	('patients', 'Species', '9606', (124, 132))	('SDHB', 'Gene', (141, 145))	('SDHB', 'Gene', '6390', (82, 86))	('SDHB', 'Gene', (82, 86))	('mutation', 'Var', (87, 95))	('SDHB', 'Gene', '6390', (141, 145))
44617	19190077	Finally, in multivariate analysis, only the presence of SDHB mutations was significantly and independently associated with survival: the presence of SDHB mutations was associated with an excess mortality (relative risk 2.7).	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', '6390', (149, 153))	('SDHB', 'Gene', (56, 60))	('SDHB', 'Gene', (149, 153))	('associated', 'Reg', (107, 117))	('presence', 'Var', (137, 145))	('mutations', 'Var', (154, 163))
44620	19190077	Apart from malignant sPGL, SDHB mutations have been suggested to be associated with renal cell carcinomas of early onset.	('sPGL', 'Chemical', '-', (21, 25))	('associated', 'Reg', (68, 78))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (84, 105))	('renal cell carcinomas', 'Disease', (84, 105))	('SDHB', 'Gene', '6390', (27, 31))	('mutations', 'Var', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('SDHB', 'Gene', (27, 31))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (84, 105))
44622	19190077	In addition, clinical phenotypes may largely differ between family members with the same SDHB mutation.	('SDHB', 'Gene', (89, 93))	('SDHB', 'Gene', '6390', (89, 93))	('mutation', 'Var', (94, 102))	('differ', 'Reg', (45, 51))
44623	19190077	In our recent study, features that are associated with aggressive tumor behavior, including young age at presentation, large tumor size, metastatic disease at presentation, and hypersecretion of dopamine were equally distributed among patients with missense versus truncating mutations and were independent of exon locations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('hypersecretion of dopamine', 'MPA', (177, 203))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('dopamine', 'Chemical', 'MESH:D004298', (195, 203))	('hypersecretion of dopamine', 'Phenotype', 'HP:0011979', (177, 203))	('tumor', 'Disease', (66, 71))	('patients', 'Species', '9606', (235, 243))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('metastatic disease', 'Disease', (137, 155))	('tumor', 'Disease', (125, 130))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (55, 80))	('missense', 'Var', (249, 257))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('aggressive tumor behavior', 'Disease', (55, 80))
44624	19190077	Identical mutations may result in SDHB-related tumors of variable location and severity.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('result in', 'Reg', (24, 33))	('SDHB', 'Gene', '6390', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SDHB', 'Gene', (34, 38))	('mutations', 'Var', (10, 19))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
44625	19190077	SDHC mutations are mainly associated with the development of HNPGL.	('HNPGL', 'Disease', (61, 66))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('HNPGL', 'Phenotype', 'HP:0002864', (61, 66))	('associated with', 'Reg', (26, 41))
44626	19190077	A limited number of SDHC mutation carriers have been identified worldwide.	('SDHC', 'Gene', '6391', (20, 24))	('SDHC', 'Gene', (20, 24))	('mutation', 'Var', (25, 33))
44627	19190077	Within large population-based international registries, the prevalence of SDHC mutations varied between 0% for patients with sPGL and 4% for patients with HNPGL.	('patients', 'Species', '9606', (141, 149))	('HNPGL', 'Phenotype', 'HP:0002864', (155, 160))	('patients', 'Species', '9606', (111, 119))	('sPGL', 'Chemical', '-', (125, 129))	('SDHC', 'Gene', (74, 78))	('sPGL', 'Disease', (125, 129))	('mutations', 'Var', (79, 88))	('SDHC', 'Gene', '6391', (74, 78))
44629	19190077	However, a malignant catecholamine-producing PGL at the carotid bifurcation has been reported in a patient with a IVS5 + 1G > T SDHC mutation.	('patient', 'Species', '9606', (99, 106))	('1G > T', 'Var', (121, 127))	('catecholamine', 'Chemical', 'MESH:D002395', (21, 34))	('IVS5 + 1G > T', 'Mutation', 'c.IVS5+1G>T', (114, 127))	('SDHC', 'Gene', (128, 132))	('SDHC', 'Gene', '6391', (128, 132))	('1G > T', 'SUBSTITUTION', 'None', (121, 127))
44630	19190077	SDHC mutations were originally believed to be associated only with HNPGL, but recently, adrenal and extra-adrenal sPGL were reported.	('HNPGL', 'Disease', (67, 72))	('SDHC', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('HNPGL', 'Phenotype', 'HP:0002864', (67, 72))	('associated', 'Reg', (46, 56))	('sPGL', 'Chemical', '-', (114, 118))
44631	19190077	SDHD mutations are mainly associated with multifocal HNPGL and benign PGL.	('multifocal HNPGL', 'Disease', (42, 58))	('benign PGL', 'Disease', (63, 73))	('mutations', 'Var', (5, 14))	('SDHD', 'Gene', '6392', (0, 4))	('HNPGL', 'Phenotype', 'HP:0002864', (53, 58))	('SDHD', 'Gene', (0, 4))	('associated', 'Reg', (26, 36))
44634	19190077	ages at tumor diagnosis were 30.6 years (14.3) in SDHD mutation carriers.	('SDHD', 'Gene', '6392', (50, 54))	('SDHD', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('mutation', 'Var', (55, 63))
44635	19190077	The study by the International SDH Consortium showed that by age 40, an estimated 69% of SDHD mutation carriers are diagnosed with HNPGL, whereas by age 60, 35% are diagnosed with sPGL.	('SDH', 'Gene', (89, 92))	('SDH', 'Gene', '6390', (31, 34))	('SDH', 'Gene', '6390', (89, 92))	('diagnosed', 'Reg', (116, 125))	('HNPGL', 'Phenotype', 'HP:0002864', (131, 136))	('sPGL', 'Chemical', '-', (180, 184))	('SDH', 'Gene', (31, 34))	('SDHD', 'Gene', '6392', (89, 93))	('HNPGL', 'Disease', (131, 136))	('SDHD', 'Gene', (89, 93))	('mutation', 'Var', (94, 102))
44637	19190077	Among 200 carriers of the well-known Dutch founder SDHD mutation D92Y, there were three patients with metastatic HNPGL and two with metastatic sPGL.	('sPGL', 'Chemical', '-', (143, 147))	('D92Y', 'Var', (65, 69))	('patients', 'Species', '9606', (88, 96))	('D92Y', 'Mutation', 'rs80338845', (65, 69))	('SDHD', 'Gene', '6392', (51, 55))	('metastatic HNPGL', 'Disease', (102, 118))	('SDHD', 'Gene', (51, 55))	('HNPGL', 'Phenotype', 'HP:0002864', (113, 118))
44638	19190077	It was argued that SDHD-associated malignancy might be specifically linked to the D92Y mutation and/or gene-environment interactions in the Netherlands.	('linked', 'Reg', (68, 74))	('SDHD', 'Gene', '6392', (19, 23))	('D92Y', 'Mutation', 'rs80338845', (82, 86))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('SDHD', 'Gene', (19, 23))	('malignancy', 'Disease', (35, 45))	('D92Y', 'Var', (82, 86))
44640	19190077	In general, however, both parasympathetic and sPGL in SDHD mutation carriers are rarely malignant.	('SDHD', 'Gene', (54, 58))	('mutation', 'Var', (59, 67))	('sPGL', 'Chemical', '-', (46, 50))	('SDHD', 'Gene', '6392', (54, 58))
44641	19190077	With respect to genotype-phenotype correlations in SDHD-related tumors, carriers of an nonsense and/or splicing mutation were suggested to develop symptoms at an earlier age than missense-mutation carriers, possibly due to the formation of a truncated protein and failure of the normal function of mitochondrial complex II.	('nonsense and/or', 'Var', (87, 102))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('symptoms', 'Disease', (147, 155))	('SDHD', 'Gene', '6392', (51, 55))	('develop', 'PosReg', (139, 146))	('SDHD', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
44642	19190077	Also there is a tendency for SDHD mutation carriers of truncating mutations to develop phaeochromocytoma in addition to HNPGL.	('SDHD', 'Gene', '6392', (29, 33))	('SDHD', 'Gene', (29, 33))	('develop', 'PosReg', (79, 86))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (87, 104))	('truncating mutations', 'Var', (55, 75))	('HNPGL', 'Phenotype', 'HP:0002864', (120, 125))	('phaeochromocytoma', 'Disease', (87, 104))
44659	19190077	Furthermore, 111In-pentetreotide scintigraphy, another less specific technique was found to have an excellent sensitivity (> 90%) for HNPGL and may be useful for screening for these tumors in carriers of SDHx gene mutations.	('SDHx', 'Gene', (204, 208))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('HNPGL', 'Disease', (134, 139))	('mutations', 'Var', (214, 223))	('HNPGL', 'Phenotype', 'HP:0002864', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('SDHx', 'Chemical', '-', (204, 208))
44663	19190077	The authors prefer to combine an alpha-adrenoceptor blocking agent (phenoxybenzamine, doxazosin), a beta-adrenoceptor blocking agent (propranolol, atenolol), and alpha-methyl-paratyrosine, an inhibitor of catecholamine synthesis.	('atenolol', 'Chemical', 'MESH:D001262', (147, 155))	('alpha-methyl-paratyrosine', 'Chemical', 'MESH:D019805', (162, 187))	('alpha-adrenoceptor', 'MPA', (33, 51))	('doxazosin', 'Chemical', 'MESH:D017292', (86, 95))	('phenoxybenzamine', 'Var', (68, 84))	('propranolol', 'Chemical', 'MESH:D011433', (134, 145))	('catecholamine', 'Chemical', 'MESH:D002395', (205, 218))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (68, 84))
44669	19190077	Treatment with therapeutic doses of 131I-MIBG or combination chemotherapy (cyclophosphamide, vincristine, and darcabazine) may induce (partial) responses.	('induce', 'Reg', (127, 133))	('131I-MIBG', 'Var', (36, 45))	('darcabazine', 'Chemical', '-', (110, 121))	('vincristine', 'Chemical', 'MESH:D014750', (93, 104))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (75, 91))	('131I-MIBG', 'Chemical', '-', (36, 45))
44671	19190077	Symptomatic treatment by decreasing catecholamine burden can be obtained with alpha-adrenergic blockers and alpha-methyl-paratyrosine.	('decreasing catecholamine burden', 'Phenotype', 'HP:0045012', (25, 56))	('catecholamine burden', 'MPA', (36, 56))	('alpha-methyl-paratyrosine', 'Chemical', 'MESH:D019805', (108, 133))	('alpha-methyl-paratyrosine', 'Var', (108, 133))	('decreasing', 'NegReg', (25, 35))	('catecholamine', 'Chemical', 'MESH:D002395', (36, 49))
44676	19190077	Furthermore, SDHD-related disease is characterized by maternal genomic imprinting: individuals who inherit a mutation from mother remain free of PGL, but may still pass on the mutation to their offspring.	('SDHD', 'Gene', (13, 17))	('SDHD', 'Gene', '6392', (13, 17))	('mutation', 'Var', (109, 117))
44679	19190077	These observations indicate that a negative family history by no means rules out an underlying SDH mutation.	('SDH', 'Gene', '6390', (95, 98))	('SDH', 'Gene', (95, 98))	('mutation', 'Var', (99, 107))
44680	19190077	Reversely, among patients with apparently sporadic sPGL, the prevalences of SDHB and SDHD mutations are 4-7% and 1-4% respectively.	('SDHB', 'Gene', '6390', (76, 80))	('mutations', 'Var', (90, 99))	('SDHB', 'Gene', (76, 80))	('sPGL', 'Chemical', '-', (51, 55))	('SDHD', 'Gene', '6392', (85, 89))	('patients', 'Species', '9606', (17, 25))	('SDHD', 'Gene', (85, 89))
44686	19190077	Asymptomatic carriers of an SDHx-mutation among the relatives of affected patients may benefit from tumor screening for early detection of PGL, because the chances of post-operative morbidity and metastatic spread rise with increasing tumor size.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('SDHx-mutation', 'Var', (28, 41))	('tumor', 'Disease', (100, 105))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('SDHx-mutation', 'Gene', (28, 41))	('metastatic spread', 'CPA', (196, 213))	('SDHx', 'Chemical', '-', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
44691	19190077	The only exceptions are the children of female SDHD mutation carriers, who do not require clinical surveillance because of maternal imprinting.	('children', 'Species', '9606', (28, 36))	('SDHD', 'Gene', (47, 51))	('SDHD', 'Gene', '6392', (47, 51))	('mutation', 'Var', (52, 60))
44693	19190077	In case of SDHB mutation carriership, we recommend to commence investigations as early as before the age of 10.	('SDHB', 'Gene', (11, 15))	('carriership', 'Reg', (25, 36))	('mutation', 'Var', (16, 24))	('SDHB', 'Gene', '6390', (11, 15))
44707	23404627	Fostamatinib (R935788; NSC 745942) is a potent, oral prodrug that is rapidly and extensively converted to the active moiety R406 by alkaline phosphatases in the intestinal mucosa.	('alkaline phosphatase', 'Gene', '250', (132, 152))	('R935788;', 'Var', (14, 22))	('Fostamatinib', 'Chemical', 'MESH:C523665', (0, 12))	('alkaline phosphatases', 'Phenotype', 'HP:0003155', (132, 153))	('alkaline phosphatase', 'Gene', (132, 152))
44708	23404627	R406 (NSC 742317) is a kinase inhibitor with relative selectivity for spleen tyrosine kinase (Syk) but also inhibits other kinases of particular interest as therapeutic targets in oncology including Flt3, aurora A kinase, and RET.	('Flt3', 'Gene', (199, 203))	('Syk', 'Gene', '6850', (94, 97))	('aurora A kinase', 'Enzyme', (205, 220))	('inhibits', 'NegReg', (108, 116))	('Syk', 'Gene', (94, 97))	('Flt3', 'Gene', '2322', (199, 203))	('RET', 'Gene', (226, 229))	('R406', 'Var', (0, 4))	('RET', 'Gene', '5979', (226, 229))	('oncology', 'Phenotype', 'HP:0002664', (180, 188))
44709	23404627	Fostamatinib and R406 have also been shown to decrease vascular endothelial growth factor (VEGF) expression and angiogenesis.	('VEGF', 'Gene', '7422', (91, 95))	('angiogenesis', 'CPA', (112, 124))	('R406', 'Var', (17, 21))	('Fostamatinib', 'Chemical', 'MESH:C523665', (0, 12))	('VEGF', 'Gene', (91, 95))	('vascular endothelial growth factor', 'Gene', (55, 89))	('decrease', 'NegReg', (46, 54))	('expression', 'MPA', (97, 107))	('vascular endothelial growth factor', 'Gene', '7422', (55, 89))
44710	23404627	R406 showed selective sensitivity in the National Cancer Institute (NCI) 60-cell line screen, with highest sensitivity against the renal carcinoma cell lines with EC50 equivalent to 0.15 muM, and reduced tumor burden in renal tumor xenografts at doses not associated with appreciable toxicities.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('renal carcinoma', 'Disease', 'MESH:C538614', (131, 146))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('R406', 'Var', (0, 4))	('renal carcinoma', 'Phenotype', 'HP:0005584', (131, 146))	('renal carcinoma', 'Disease', (131, 146))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('Cancer', 'Disease', (50, 56))	('renal tumor', 'Disease', 'MESH:D007674', (220, 231))	('renal tumor', 'Phenotype', 'HP:0009726', (220, 231))	('renal tumor', 'Disease', (220, 231))	('toxicities', 'Disease', 'MESH:D064420', (284, 294))	('reduced', 'NegReg', (196, 203))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('toxicities', 'Disease', (284, 294))	('tumor', 'Disease', (204, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('tumor', 'Disease', (226, 231))
44711	23404627	R406 also showed activity against some colon and non-small cell lung cancer (NSCLC) lines.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('R406', 'Var', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('activity', 'MPA', (17, 25))	('NSCLC', 'Disease', (77, 82))	('colon', 'Disease', (39, 44))	('non-small cell lung cancer', 'Disease', (49, 75))
44720	23404627	Other inclusion criteria included: measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.0); Eastern Cooperative Oncology Group (ECOG) performance status <= 2; life expectancy >= 3 months; adequate marrow, hepatic and renal function defined as absolute neutrophil count >= 1.5 x 109/L, platelets >= 100 x 109/L, total bilirubin <= 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 x ULN and creatinine < 1.5 x ULN or a creatinine clearance >= 60 mL/min/1.73 m2 for patients with creatinine levels >= 1.5 x ULN.	('creatinine clearance', 'MPA', (503, 523))	('alanine aminotransferase', 'Gene', '2875', (427, 451))	('creatinine', 'MPA', (475, 485))	('bilirubin', 'Chemical', 'MESH:D001663', (342, 351))	('AST', 'Gene', '26503', (418, 421))	('Oncology', 'Phenotype', 'HP:0002664', (137, 145))	('aspartate aminotransferase', 'Gene', '26503', (390, 416))	('>= 100 x 109/L', 'Var', (320, 334))	('aspartate aminotransferase', 'Gene', (390, 416))	('patients', 'Species', '9606', (549, 557))	('Tumors', 'Phenotype', 'HP:0002664', (96, 102))	('AST', 'Gene', (418, 421))	('Solid Tumors', 'Disease', 'MESH:D009369', (90, 102))	('alanine aminotransferase', 'Gene', (427, 451))	('Solid Tumors', 'Disease', (90, 102))
44948	24628963	Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset.	('proteinuria', 'Disease', (42, 53))	('VEGF', 'Gene', '7422', (95, 99))	('progression-free', 'Disease', (129, 145))	('proteinuria', 'Phenotype', 'HP:0000093', (237, 248))	('proteinuria', 'Disease', 'MESH:D011507', (237, 248))	('proteinuria', 'Phenotype', 'HP:0000093', (42, 53))	('vascular endothelial growth factor', 'Gene', (59, 93))	('hypertension', 'Disease', 'MESH:D006973', (28, 40))	('proteinuria', 'Disease', 'MESH:D011507', (42, 53))	('vitamin D', 'Chemical', 'MESH:D014807', (194, 203))	('hypertension', 'Disease', (28, 40))	('vascular endothelial growth factor', 'Gene', '7422', (59, 93))	('VEGF', 'Gene', (95, 99))	('hypertension', 'Phenotype', 'HP:0000822', (28, 40))	('polymorphisms', 'Var', (101, 114))	('proteinuria', 'Disease', (237, 248))
44956	24628963	VEGF polymorphisms were not associated with patient outcome.	('VEGF', 'Gene', '7422', (0, 4))	('patient', 'Species', '9606', (44, 51))	('VEGF', 'Gene', (0, 4))	('polymorphisms', 'Var', (5, 18))
44969	24628963	In addition, VEGF polymorphisms have been found to be predictive of hypertension and associated with time to progression in advanced breast cancer treated with bevacizumab.	('VEGF', 'Gene', '7422', (13, 17))	('hypertension', 'Disease', 'MESH:D006973', (68, 80))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('bevacizumab', 'Chemical', 'MESH:D000068258', (160, 171))	('hypertension', 'Disease', (68, 80))	('hypertension', 'Phenotype', 'HP:0000822', (68, 80))	('VEGF', 'Gene', (13, 17))	('polymorphisms', 'Var', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('associated', 'Reg', (85, 95))
44980	24628963	In predefined ancillary studies we also explored the role of circulating VEGF, VEGF polymorphisms, vitamin D status, and vitamin D metabolism-related polymorphism in predicting toxicities and treatment efficacy.	('vitamin D', 'Chemical', 'MESH:D014807', (121, 130))	('vitamin D', 'Chemical', 'MESH:D014807', (99, 108))	('toxicities', 'Disease', 'MESH:D064420', (177, 187))	('VEGF', 'Gene', '7422', (79, 83))	('toxicities', 'Disease', (177, 187))	('VEGF', 'Gene', '7422', (73, 77))	('polymorphism', 'Var', (150, 162))	('VEGF', 'Gene', (73, 77))	('VEGF', 'Gene', (79, 83))	('polymorphisms', 'Var', (84, 97))
44981	24628963	Eligibility criteria for inclusion in this trial were: histologically or cytologically proven diagnosis of WMD-NEN; metastatic or inoperable disease not previously treated with chemotherapy; age >=18 years; progressive disease as documented by Response Evaluation Criteria in Solid Tumors (RECIST); Eastern Cooperative Oncology Group (ECOG) performance status 0-2; life expectancy of at least 12 weeks; measurable and/or evaluable lesions according to RECIST; adequate bone marrow reserve (neutrophils >=1500/mm3 and platelets >=80,000/mm3); hemoglobin >=9.0 g/dl; total bilirubin <=1.5 times the upper limit of normal; prothrombin time-international normalized ratio/partial thromboplastin time (PT-INR/PTT) <1.5 times the upper limit of normal; serum creatinine <=1.5 times the upper limit of normal; potential; ability to comply with the protocol procedures.	('Solid Tumors', 'Disease', 'MESH:D009369', (276, 288))	('Solid Tumors', 'Disease', (276, 288))	('bone marrow reserve', 'CPA', (469, 488))	('Tumor', 'Phenotype', 'HP:0002664', (282, 287))	('Tumors', 'Phenotype', 'HP:0002664', (282, 288))	('serum creatinine', 'MPA', (747, 763))	('partial thromboplastin time', 'Phenotype', 'HP:0003645', (668, 695))	('Oncology', 'Phenotype', 'HP:0002664', (319, 327))	('<=1.5', 'Var', (581, 586))
44988	24628963	Plasma samples were obtained from patients who consented to having optional blood draws for analysis of VEGF (kit) and VEGF polymorphisms, circulating vitamin D (25-OH colecalcipherol) and vitamin D polymorphism.	('VEGF', 'Gene', '7422', (119, 123))	('vitamin D', 'Chemical', 'MESH:D014807', (189, 198))	('vitamin D', 'Chemical', 'MESH:D014807', (151, 160))	('25-OH colecalcipherol', 'Chemical', '-', (162, 183))	('VEGF', 'Gene', '7422', (104, 108))	('VEGF', 'Gene', (119, 123))	('polymorphisms', 'Var', (124, 137))	('patients', 'Species', '9606', (34, 42))	('VEGF', 'Gene', (104, 108))
44989	24628963	Vitamin D polymorphism (rs4646536) and VEGF polymorphisms (rs699947 and rs1570360) were assessed using the ABI TaqMan allelic discrimination kit by real-time PCR with standard methodology.	('rs1570360', 'Var', (72, 81))	('rs1570360', 'Mutation', 'rs1570360', (72, 81))	('rs4646536', 'Var', (24, 33))	('rs699947', 'Var', (59, 67))	('VEGF', 'Gene', (39, 43))	('rs4646536', 'Mutation', 'rs4646536', (24, 33))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('VEGF', 'Gene', '7422', (39, 43))	('rs699947', 'Mutation', 'rs699947', (59, 67))
44999	24628963	The capecitabine dose was modified as follows: delayed for 1 week if granulocyte counts were <1.5 x 109/L and/or platelet counts were <100 x 109/L; interrupted until improvement to grade 0-1 in the event of hand and foot syndrome or severe palmar-plantar erythema with blistering and desquamation; discontinued for 1 week in case of persistent diarrhea, otherwise antidiarrheal agents were prescribed for grade 1 or 2 diarrhea; stopped for 1 week in case of grade 2 mucositis; interrupted until recovery in the event of grade 3 or 4 mucositis, then restarted at a 25% reduction in dosage.	('diarrhea', 'Disease', (418, 426))	('palmar-plantar erythema', 'Phenotype', 'HP:0025493', (240, 263))	('diarrhea', 'Phenotype', 'HP:0002014', (344, 352))	('diarrhea', 'Phenotype', 'HP:0002014', (368, 376))	('mucositis', 'Disease', 'MESH:D052016', (466, 475))	('foot syndrome', 'Disease', (216, 229))	('diarrhea', 'Disease', 'MESH:D003967', (418, 426))	('mucositis', 'Disease', (466, 475))	('diarrhea', 'Disease', (344, 352))	('diarrhea', 'Disease', (368, 376))	('palmar-plantar erythema', 'Disease', 'MESH:C565041', (240, 263))	('mucositis', 'Disease', 'MESH:D052016', (533, 542))	('blistering and desquamation', 'Phenotype', 'HP:0008066', (269, 296))	('diarrhea', 'Disease', 'MESH:D003967', (368, 376))	('erythema', 'Phenotype', 'HP:0010783', (255, 263))	('diarrhea', 'Disease', 'MESH:D003967', (344, 352))	('desquamation', 'Phenotype', 'HP:0040189', (284, 296))	('palmar-plantar erythema', 'Disease', (240, 263))	('mucositis', 'Disease', (533, 542))	('diarrhea', 'Phenotype', 'HP:0002014', (418, 426))	('capecitabine', 'Chemical', 'MESH:D000069287', (4, 16))	('foot syndrome', 'Disease', 'MESH:D005534', (216, 229))	('<100 x 109/L', 'Var', (134, 146))	('persistent diarrhea', 'Phenotype', 'HP:0002028', (333, 352))
45000	24628963	Pretreatment and on-study evaluations included: history; physical examination; laboratory tests; and analysis of tumor markers (chromogranin A), serum VEGF, VEGF polymorphism, vitamin D, vitamin D polymorphism.	('tumor', 'Disease', (113, 118))	('VEGF', 'Gene', '7422', (151, 155))	('VEGF', 'Gene', '7422', (157, 161))	('vitamin D', 'Chemical', 'MESH:D014807', (176, 185))	('chromogranin A', 'Gene', (128, 142))	('polymorphism', 'Var', (162, 174))	('vitamin D', 'Chemical', 'MESH:D014807', (187, 196))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('VEGF', 'Gene', (151, 155))	('VEGF', 'Gene', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('chromogranin A', 'Gene', '1113', (128, 142))
45041	24628963	There was a non significant association between rs699947 polymorphism and hypertension: hypertension was present in7/10 patients (70.0%) with CC genotype and in 7/18 patients (38.9%) with CA/AA genotype (p = 0.11).	('hypertension', 'Disease', (74, 86))	('rs699947', 'Var', (48, 56))	('hypertension', 'Disease', (88, 100))	('hypertension', 'Phenotype', 'HP:0000822', (88, 100))	('hypertension', 'Phenotype', 'HP:0000822', (74, 86))	('patients', 'Species', '9606', (166, 174))	('patients', 'Species', '9606', (120, 128))	('hypertension', 'Disease', 'MESH:D006973', (74, 86))	('hypertension', 'Disease', 'MESH:D006973', (88, 100))	('rs699947', 'Mutation', 'rs699947', (48, 56))
45042	24628963	No association was found between rs699947 polymorphism and proteinuria.	('proteinuria', 'Phenotype', 'HP:0000093', (59, 70))	('proteinuria', 'Disease', (59, 70))	('proteinuria', 'Disease', 'MESH:D011507', (59, 70))	('rs699947', 'Mutation', 'rs699947', (33, 41))	('rs699947', 'Var', (33, 41))
45043	24628963	No association between rs1570360 polymorphism and either hypertension or proteinuria was observed.	('hypertension', 'Disease', 'MESH:D006973', (57, 69))	('proteinuria', 'Disease', (73, 84))	('hypertension', 'Disease', (57, 69))	('proteinuria', 'Phenotype', 'HP:0000093', (73, 84))	('rs1570360', 'Mutation', 'rs1570360', (23, 32))	('hypertension', 'Phenotype', 'HP:0000822', (57, 69))	('proteinuria', 'Disease', 'MESH:D011507', (73, 84))	('rs1570360', 'Var', (23, 32))
45044	24628963	Rs699947 and rs1570360 polymorphisms both failed to be associated with progression-free survival (data not shown).	('Rs699947', 'Var', (0, 8))	('Rs699947', 'Mutation', 'Rs699947', (0, 8))	('rs1570360', 'Mutation', 'rs1570360', (13, 22))	('rs1570360', 'Var', (13, 22))
45048	24628963	Vitamin D polymorphism failed to be associated with hypertension, proteinuria, and PFS (data not shown).	('proteinuria', 'Disease', (66, 77))	('proteinuria', 'Phenotype', 'HP:0000093', (66, 77))	('PFS', 'Disease', (83, 86))	('polymorphism', 'Var', (10, 22))	('Vitamin D', 'Gene', (0, 9))	('proteinuria', 'Disease', 'MESH:D011507', (66, 77))	('hypertension', 'Disease', 'MESH:D006973', (52, 64))	('hypertension', 'Disease', (52, 64))	('associated', 'Reg', (36, 46))	('hypertension', 'Phenotype', 'HP:0000822', (52, 64))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
45057	24628963	Hypertension, a common side effect of bevacizumab linked to VEGF inhibition, is associated with a greater efficacy of this monoclonal antibody, and VEGF polymorphisms, which are predictive of bevacizumab-induced hypertension, are also correlated with the drug's efficacy.	('VEGF', 'Gene', '7422', (60, 64))	('inhibition', 'NegReg', (65, 75))	('VEGF', 'Gene', (148, 152))	('hypertension', 'Disease', 'MESH:D006973', (212, 224))	('VEGF', 'Gene', (60, 64))	('hypertension', 'Disease', (212, 224))	('Hypertension', 'Phenotype', 'HP:0000822', (0, 12))	('VEGF', 'Gene', '7422', (148, 152))	('hypertension', 'Phenotype', 'HP:0000822', (212, 224))	('Hypertension', 'Disease', 'MESH:D006973', (0, 12))	('efficacy', 'MPA', (106, 114))	('bevacizumab', 'Chemical', 'MESH:D000068258', (38, 49))	('bevacizumab', 'Chemical', 'MESH:D000068258', (192, 203))	('greater', 'PosReg', (98, 105))	('Hypertension', 'Disease', (0, 12))	('polymorphisms', 'Var', (153, 166))
45078	23355199	Only 2.7% of 1,140 carcinomas from various sites exhibited cathepsin K labeling, thus suggesting that among carcinomas, cathepsin K labeling is highly specific for translocation RCC.	('cathepsin K', 'Gene', (120, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('translocation', 'Var', (164, 177))	('cathepsin K', 'Gene', (59, 70))	('cathepsin K', 'Gene', '1513', (59, 70))	('cathepsin K', 'Gene', '1513', (120, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('carcinomas', 'Disease', (108, 118))	('carcinomas', 'Disease', 'MESH:D002277', (108, 118))	('RCC', 'Disease', 'MESH:C538614', (178, 181))	('RCC', 'Disease', (178, 181))	('RCC', 'Phenotype', 'HP:0005584', (178, 181))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('carcinomas', 'Disease', (19, 29))	('carcinomas', 'Disease', 'MESH:D002277', (19, 29))
45081	23355199	Germline mutations in the cathepsin K gene underlie the sclerosing bone disorder pycnodysostosis.	('Germline mutations', 'Var', (0, 18))	('bone disorder pycnodysostosis', 'Disease', 'MESH:D058631', (67, 96))	('bone disorder pycnodysostosis', 'Disease', (67, 96))	('underlie', 'Reg', (43, 51))	('cathepsin K', 'Gene', (26, 37))	('cathepsin K', 'Gene', '1513', (26, 37))
45086	23355199	Among them, TFE3 and TFEB are implicated in gene fusions resulting from chromosome translocations in a subset of renal cell carcinoma (RCC), including the Xp11 translocation RCC and the t(6;11)(p21;q12) RCC.	('p11', 'Gene', '6281', (156, 159))	('TFE3', 'Gene', (12, 16))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('t(6;11)(p21;q12)', 'STRUCTURAL_ABNORMALITY', 'None', (186, 202))	('TFEB', 'Gene', (21, 25))	('TFE3', 'Gene', '7030', (12, 16))	('p11', 'Gene', (156, 159))	('RCC', 'Disease', (203, 206))	('RCC', 'Phenotype', 'HP:0005584', (203, 206))	('renal cell carcinoma', 'Disease', (113, 133))	('TFEB', 'Gene', '7942', (21, 25))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (113, 133))	('RCC', 'Disease', 'MESH:C538614', (203, 206))	('t(6;11)(p21;q12', 'Var', (186, 201))	('resulting', 'Reg', (57, 66))	('RCC', 'Disease', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (174, 177))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('RCC', 'Disease', (135, 138))	('implicated', 'Reg', (30, 40))	('RCC', 'Disease', 'MESH:C538614', (174, 177))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (113, 133))
45119	23355199	This suggests that cathepsin K can be helpful in distinguishing translocation RCCs from other carcinomas, and that positive labeling for cathepsin K in an epithelial neoplasm is highly suggestive of an MiTF family- related carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (94, 103))	('carcinomas', 'Disease', (94, 104))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Disease', (223, 232))	('epithelial neoplasm', 'Disease', (155, 174))	('RCCs', 'Phenotype', 'HP:0005584', (78, 82))	('epithelial neoplasm', 'Phenotype', 'HP:0031492', (155, 174))	('epithelial neoplasm', 'Disease', 'MESH:D002277', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('carcinomas', 'Disease', 'MESH:D002277', (94, 104))	('carcinoma', 'Disease', (94, 103))	('MiTF', 'Gene', '4286', (202, 206))	('cathepsin K', 'Gene', (19, 30))	('translocation', 'Var', (64, 77))	('carcinoma', 'Disease', 'MESH:D002277', (223, 232))	('cathepsin K', 'Gene', '1513', (19, 30))	('cathepsin K', 'Gene', (137, 148))	('cathepsin K', 'Gene', '1513', (137, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (166, 174))	('MiTF', 'Gene', (202, 206))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))
45127	23355199	For example, the ASPL-TFE3 gene fusion is present in both ASPS and a subset of translocation RCCs; however, in contrast to consistent diffuse cathepsin K positivity of ASPS, ASPL-TFE3 translocation RCCs are almost always negative for cathepsin K. Along these lines, clear cell sarcoma harbors a unique chromosome translocation t(12;22)(q13;q13), causing fusion of the Ewing sarcoma- associated gene (EWS) to the activity transcription factor 1 (ATF1) gene.	('ASPS', 'Gene', (168, 172))	('RCC', 'Phenotype', 'HP:0005584', (93, 96))	('activity transcription factor 1', 'Gene', '466', (412, 443))	('RCC', 'Disease', (93, 96))	('ASPL', 'Gene', '79058', (174, 178))	('cathepsin K', 'Gene', (142, 153))	('RCC', 'Disease', 'MESH:C538614', (198, 201))	('EWS', 'Gene', (400, 403))	('ASPS', 'Gene', '79058', (58, 62))	('ASPL', 'Gene', (17, 21))	('cathepsin K', 'Gene', '1513', (142, 153))	('fusion', 'Var', (354, 360))	('ASPS', 'Phenotype', 'HP:0012218', (58, 62))	('ATF1', 'Gene', '466', (445, 449))	('RCC', 'Disease', 'MESH:C538614', (93, 96))	('clear cell sarcoma', 'Disease', (266, 284))	('Ewing sarcoma- associated gene', 'Gene', '2130', (368, 398))	('sarcoma', 'Phenotype', 'HP:0100242', (374, 381))	('t(12;22)(q13;q13)', 'STRUCTURAL_ABNORMALITY', 'None', (327, 344))	('ASPS', 'Gene', '79058', (168, 172))	('RCCs', 'Phenotype', 'HP:0005584', (198, 202))	('activity transcription factor 1', 'Gene', (412, 443))	('ASPS', 'Phenotype', 'HP:0012218', (168, 172))	('sarcoma', 'Phenotype', 'HP:0100242', (277, 284))	('Ewing sarcoma- associated gene', 'Gene', (368, 398))	('causing', 'Reg', (346, 353))	('ASPL', 'Gene', '79058', (17, 21))	('cathepsin K', 'Gene', (234, 245))	('RCCs', 'Phenotype', 'HP:0005584', (93, 97))	('cathepsin K', 'Gene', '1513', (234, 245))	('EWS', 'Gene', '2130', (400, 403))	('ASPL', 'Gene', (174, 178))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (368, 381))	('ASPS', 'Gene', (58, 62))	('TFE3', 'Gene', (22, 26))	('TFE3', 'Gene', (179, 183))	('RCC', 'Disease', (198, 201))	('RCC', 'Phenotype', 'HP:0005584', (198, 201))	('ATF1', 'Gene', (445, 449))	('clear cell sarcoma', 'Disease', 'MESH:D018227', (266, 284))	('TFE3', 'Gene', '7030', (22, 26))	('TFE3', 'Gene', '7030', (179, 183))
45210	22270996	Prevalence of Germline Mutations in Patients with Pheochromocytoma or Abdominal Paraganglioma and Sporadic Presentation: A Population-Based Study in Western Sweden Germline mutations in the susceptibility genes RET, SDHB, SDHD, and VHL have been reported in 7.5-24% of patients with pheochromocytoma (Pheo) or paraganglioma (PGL) and sporadic presentation.	('RET', 'Gene', (211, 214))	('PGL', 'Phenotype', 'HP:0002668', (325, 328))	('pheochromocytoma', 'Disease', 'MESH:D010673', (283, 299))	('paraganglioma', 'Phenotype', 'HP:0002668', (310, 323))	('VHL', 'Disease', (232, 235))	('patients', 'Species', '9606', (269, 277))	('SDHD', 'Gene', '6392', (222, 226))	('pheochromocytoma', 'Disease', (283, 299))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (50, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (283, 299))	('Pheo', 'Phenotype', 'HP:0002666', (50, 54))	('Paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('Pheochromocytoma or Abdominal Paraganglioma', 'Disease', (50, 93))	('mutations', 'Var', (173, 182))	('SDHD', 'Gene', (222, 226))	('SDHB', 'Gene', '6390', (216, 220))	('RET', 'Gene', '5979', (211, 214))	('VHL', 'Disease', 'MESH:D006623', (232, 235))	('paraganglioma', 'Disease', (310, 323))	('Patients', 'Species', '9606', (36, 44))	('paraganglioma', 'Disease', 'MESH:D010235', (310, 323))	('Pheochromocytoma or Abdominal Paraganglioma', 'Disease', 'MESH:D010673', (50, 93))	('Pheo', 'Phenotype', 'HP:0002666', (301, 305))	('SDHB', 'Gene', (216, 220))
45215	22270996	Germline mutations were investigated by using direct sequencing for point mutations in RET, SDHB, SDHD, and VHL, and multiplex ligation-dependent probe amplification for gross deletions in SDHB, SDHC, SDHD, and VHL.	('SDHD', 'Gene', (201, 205))	('SDHD', 'Gene', '6392', (201, 205))	('SDHC', 'Gene', (195, 199))	('point mutations', 'Var', (68, 83))	('SDHB', 'Gene', '6390', (92, 96))	('SDHC', 'Gene', '6391', (195, 199))	('RET', 'Gene', '5979', (87, 90))	('SDHD', 'Gene', '6392', (98, 102))	('SDHB', 'Gene', (92, 96))	('VHL', 'Disease', (108, 111))	('SDHD', 'Gene', (98, 102))	('VHL', 'Disease', 'MESH:D006623', (108, 111))	('RET', 'Gene', (87, 90))	('SDHB', 'Gene', '6390', (189, 193))	('VHL', 'Disease', 'MESH:D006623', (211, 214))	('SDHB', 'Gene', (189, 193))	('VHL', 'Disease', (211, 214))
45217	22270996	Mutations were only seen in RET (n = 1) and SDHB (n = 3).	('SDHB', 'Gene', '6390', (44, 48))	('RET', 'Gene', '5979', (28, 31))	('SDHB', 'Gene', (44, 48))	('Mutations', 'Var', (0, 9))	('RET', 'Gene', (28, 31))
45218	22270996	Notably, in the patients with SDHB mutations, no malignant phenotype was observed during a mean follow-up of 23.3 years.	('SDHB', 'Gene', '6390', (30, 34))	('patients', 'Species', '9606', (16, 24))	('SDHB', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
45219	22270996	The frequency of germline mutations in patients with apparently sporadic Pheo and abdominal PGL in Western Sweden was lower than in previous studies.	('PGL', 'Phenotype', 'HP:0002668', (92, 95))	('patients', 'Species', '9606', (39, 47))	('Pheo', 'Phenotype', 'HP:0002666', (73, 77))	('germline mutations', 'Var', (17, 35))	('Pheo', 'Disease', (73, 77))	('abdominal PGL', 'Disease', (82, 95))
45222	22270996	Recently mutations in PHD2, SDHA, TMEM127, Kif-1Bbeta, and MAX have been described in association with Pheo/PGL.	('described', 'Reg', (73, 82))	('mutations', 'Var', (9, 18))	('PHD2', 'Gene', '54583', (22, 26))	('Pheo', 'Phenotype', 'HP:0002666', (103, 107))	('SDHA', 'Gene', (28, 32))	('PHD2', 'Gene', (22, 26))	('TMEM127', 'Gene', '55654', (34, 41))	('Kif-1Bbeta', 'Gene', (43, 53))	('PGL', 'Phenotype', 'HP:0002668', (108, 111))	('SDHA', 'Gene', '6389', (28, 32))	('Pheo/PGL', 'Disease', (103, 111))	('association', 'Reg', (86, 97))	('TMEM127', 'Gene', (34, 41))
45224	22270996	in 2002 reported 24% germline mutations in SDHB, SDHD, RET, and VHL in patients with clinically nonsyndromic Pheo/PGL, genetic screening in these patients has attracted considerable interest.	('VHL', 'Disease', 'MESH:D006623', (64, 67))	('RET', 'Gene', '5979', (55, 58))	('VHL', 'Disease', (64, 67))	('SDHB', 'Gene', '6390', (43, 47))	('patients', 'Species', '9606', (71, 79))	('germline mutations', 'Var', (21, 39))	('SDHB', 'Gene', (43, 47))	('RET', 'Gene', (55, 58))	('SDHD', 'Gene', '6392', (49, 53))	('PGL', 'Phenotype', 'HP:0002668', (114, 117))	('Pheo', 'Phenotype', 'HP:0002666', (109, 113))	('patients', 'Species', '9606', (146, 154))	('SDHD', 'Gene', (49, 53))
45238	22270996	Based on the presumed frequency of findings stepwise genetic testing was performed in the following order: (1) Sanger sequencing for point mutations in SDHB (exon 1-8), SDHD (exon 1-4) and VHL (exon 1-3); (2) In patients with negative sequencing results in SDHB, SDHD, and VHL sequencing of RET (exons 10, 11, 14, and 16); (3) In patients negative after testing for RET-mutation the presence of deletions in SDHB, SDHC, SDHD, and VHL was investigated by using multiplex ligation-dependent probe amplification (MLPA).	('SDHB', 'Gene', (408, 412))	('SDHD', 'Gene', '6392', (169, 173))	('SDHB', 'Gene', (152, 156))	('SDHD', 'Gene', '6392', (263, 267))	('RET', 'Gene', (291, 294))	('patients', 'Species', '9606', (212, 220))	('patients', 'Species', '9606', (330, 338))	('SDHC', 'Gene', '6391', (414, 418))	('RET', 'Gene', '5979', (366, 369))	('VHL', 'Disease', (273, 276))	('SDHD', 'Gene', '6392', (420, 424))	('VHL', 'Disease', (430, 433))	('SDHD', 'Gene', (169, 173))	('VHL', 'Disease', 'MESH:D006623', (189, 192))	('SDHD', 'Gene', (263, 267))	('SDHB', 'Gene', '6390', (257, 261))	('RET', 'Gene', (366, 369))	('SDHD', 'Gene', (420, 424))	('SDHC', 'Gene', (414, 418))	('SDHB', 'Gene', '6390', (408, 412))	('RET', 'Gene', '5979', (291, 294))	('SDHB', 'Gene', (257, 261))	('SDHB', 'Gene', '6390', (152, 156))	('VHL', 'Disease', 'MESH:D006623', (273, 276))	('deletions', 'Var', (395, 404))	('VHL', 'Disease', 'MESH:D006623', (430, 433))	('VHL', 'Disease', (189, 192))
45243	22270996	DNA sequencing:SDHB, SDHD, and VHL section) was analyzed for exon deletions by MLPA for SDHB, SDHC, and SDHD (SALSA P226, MRC Holland, Amsterdam, The Netherlands) and VHL (SALSA P016-B2) and run according to the manufacturer's recommendations.	('exon deletions', 'Var', (61, 75))	('SDHB', 'Gene', '6390', (15, 19))	('VHL', 'Disease', (167, 170))	('VHL', 'Disease', 'MESH:D006623', (167, 170))	('SDHB', 'Gene', '6390', (88, 92))	('SDHB', 'Gene', (15, 19))	('SDHB', 'Gene', (88, 92))	('VHL', 'Disease', (31, 34))	('man', 'Species', '9606', (212, 215))	('SDHD', 'Gene', '6392', (21, 25))	('VHL', 'Disease', 'MESH:D006623', (31, 34))	('MLPA', 'Gene', (79, 83))	('SDHC', 'Gene', (94, 98))	('SDHD', 'Gene', '6392', (104, 108))	('SDHD', 'Gene', (21, 25))	('SDHC', 'Gene', '6391', (94, 98))	('SDHD', 'Gene', (104, 108))
45252	22270996	Sequencing revealed one case with a missense mutation in the RET-gene, two cases with missense, and one case with a splice-site mutation in SDHB (Table 1).	('RET', 'Gene', (61, 64))	('SDHB', 'Gene', '6390', (140, 144))	('SDHB', 'Gene', (140, 144))	('RET', 'Gene', '5979', (61, 64))	('missense mutation', 'Var', (36, 53))
45253	22270996	Six patients had single nucleotide polymorphisms in SDHB: c.18A>C (p.Ala6Ala) n = 4; c.24C>T (p.Ser8Ser) n = 1; c.487T>C (p.Ser163Pro) n = 1, Leiden Open Variants Database (LOVD) ID SDHB_00008, SDHB_00011, and SDHB_00038, respectively (http://chromium.liacs.nl/lovd_sdh/home.php?select_db=SDHB).	('p.Ala6Ala', 'SUBSTITUTION', 'None', (67, 76))	('sdh', 'Gene', '6390', (266, 269))	('p.Ala6Ala', 'Var', (67, 76))	('p.Ser8Ser', 'Mutation', 'rs148738139', (94, 103))	('SDHB', 'Gene', '6390', (182, 186))	('c.24C>T', 'Var', (85, 92))	('c.24C>T', 'Mutation', 'rs148738139', (85, 92))	('c.487T>C', 'Mutation', 'rs33927012', (112, 120))	('c.18A>C', 'Mutation', 'rs2746462', (58, 65))	('patients', 'Species', '9606', (4, 12))	('SDHB', 'Gene', '6390', (210, 214))	('SDHB', 'Gene', '6390', (289, 293))	('SDHB', 'Gene', '6390', (52, 56))	('SDHB', 'Gene', (182, 186))	('c.487T>C', 'Var', (112, 120))	('SDHB', 'Gene', '6390', (194, 198))	('c.18A>C', 'Var', (58, 65))	('SDHB', 'Gene', (210, 214))	('p.Ser163Pro', 'Mutation', 'rs33927012', (122, 133))	('sdh', 'Gene', (266, 269))	('SDHB', 'Gene', (52, 56))	('SDHB', 'Gene', (289, 293))	('SDHB', 'Gene', (194, 198))
45255	22270996	The patient with a previously unrecognized RET p.Cys609Tyr mutation underwent a prophylactic thyroidectomy at age 40 years, 13 years after surgery for Pheo.	('p.Cys609Tyr', 'Var', (47, 58))	('RET', 'Gene', (43, 46))	('Pheo', 'Phenotype', 'HP:0002666', (151, 155))	('p.Cys609Tyr', 'Mutation', 'rs77939446', (47, 58))	('patient', 'Species', '9606', (4, 11))	('RET', 'Gene', '5979', (43, 46))
45257	22270996	All three patients with SDHB mutations are alive without evidence of tumor recurrence or malignant development at 15.7, 26.0, and 28.1 years of follow-up, respectively (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('mutations', 'Var', (29, 38))	('SDHB', 'Gene', '6390', (24, 28))	('patients', 'Species', '9606', (10, 18))	('SDHB', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
45259	22270996	Mutations were only seen in RET and SDHB.	('SDHB', 'Gene', '6390', (36, 40))	('RET', 'Gene', '5979', (28, 31))	('SDHB', 'Gene', (36, 40))	('Mutations', 'Var', (0, 9))	('RET', 'Gene', (28, 31))
45260	22270996	Notably, in the patients with SDHB mutations no evidence of malignancy was observed during a mean follow up of 23.3 years.	('malignancy', 'Disease', (60, 70))	('patients', 'Species', '9606', (16, 24))	('SDHB', 'Gene', '6390', (30, 34))	('SDHB', 'Gene', (30, 34))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('mutations', 'Var', (35, 44))
45265	22270996	Considering established risk factors for hereditary disease, tested patients were more likely to have germline mutations than patients who did not consent to the study and patients who had died before the study started, because tested patients were younger and more frequently had malignant disease.	('malignant disease', 'Disease', 'MESH:D009369', (281, 298))	('hereditary disease', 'Disease', (41, 59))	('germline mutations', 'Var', (102, 120))	('patients', 'Species', '9606', (235, 243))	('hereditary disease', 'Disease', 'MESH:D030342', (41, 59))	('malignant disease', 'Disease', (281, 298))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (172, 180))
45268	22270996	However, a 39-year-old son of one deceased man with a malignant PGL has been diagnosed with an SDHB mutation (418 G>T, p.Val140Phe, LOVD ID SDHB_00095).	('PGL', 'Phenotype', 'HP:0002668', (64, 67))	('man', 'Species', '9606', (43, 46))	('418 G>T', 'Mutation', 'rs267607032', (110, 117))	('p.Val140Phe', 'Mutation', 'rs267607032', (119, 130))	('SDHB', 'Gene', '6390', (95, 99))	('418 G>T', 'Var', (110, 117))	('SDHB', 'Gene', '6390', (140, 144))	('SDHB', 'Gene', (95, 99))	('SDHB', 'Gene', (140, 144))	('p.Val140Phe', 'Var', (119, 130))
45274	22270996	SDHB carriers develop a malignant phenotype in 34.3-37.5% of the cases.	('malignant', 'CPA', (24, 33))	('develop', 'Reg', (14, 21))	('carriers', 'Var', (5, 13))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))
45275	22270996	In the present study, no patient with SDHB mutation had developed malignancy at presentation or during long-time follow-up (mean 23.3 years).	('malignancy', 'Disease', 'MESH:D009369', (66, 76))	('mutation', 'Var', (43, 51))	('malignancy', 'Disease', (66, 76))	('patient', 'Species', '9606', (25, 32))	('SDHB', 'Gene', '6390', (38, 42))	('SDHB', 'Gene', (38, 42))
45276	22270996	Hypermethylation of the P16INK4A promotor has been associated with malignant phenotype in SDHB carriers, indicating stepwise genetic changes during the malignant transformation.	('malignant phenotype', 'Disease', (67, 86))	('SDHB', 'Gene', '6390', (90, 94))	('SDHB', 'Gene', (90, 94))	('Hypermethylation', 'Var', (0, 16))	('associated', 'Reg', (51, 61))	('P16INK4A', 'Gene', (24, 32))	('P16INK4A', 'Gene', '1029', (24, 32))
45280	22270996	In this registry-based study, we found a frequency of germline mutations in patients with apparently sporadic pheochromocytoma and abdominal paraganglioma in Western Sweden of 5.6%.	('patients', 'Species', '9606', (76, 84))	('pheochromocytoma', 'Disease', 'MESH:D010673', (110, 126))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (131, 154))	('abdominal paraganglioma', 'Disease', (131, 154))	('germline mutations', 'Var', (54, 72))	('paraganglioma', 'Phenotype', 'HP:0002668', (141, 154))	('pheochromocytoma', 'Disease', (110, 126))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (110, 126))
45284	22277577	We report the uneventful cumulative administration of 111 GBq (= 3 Ci) 131I-MIBG in a patient with metastatic paraganglioma.	('GBq', 'Chemical', '-', (58, 61))	('paraganglioma', 'Disease', 'MESH:D010235', (110, 123))	('131I-MIBG', 'Var', (71, 80))	('metastatic', 'Disease', (99, 109))	('patient', 'Species', '9606', (86, 93))	('131I-MIBG', 'Chemical', '-', (71, 80))	('paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('paraganglioma', 'Disease', (110, 123))
45285	22277577	Ten courses of 131I-MIBG therapy were given within six years, accomplishing symptomatic, hormonal and tumour responses with no serious adverse effects.	('131I-MIBG', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('131I-MIBG', 'Chemical', '-', (15, 24))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))
45287	22277577	The observed cumulative activity of 131I-MIBG represents the highest value reported to our knowledge, and even though 12.6 GBq of 90Y-DOTATOC were added intermediately, no associated relevant bone marrow, hepatic or other toxicity were observed.	('GBq', 'Chemical', '-', (123, 126))	('toxicity', 'Disease', 'MESH:D064420', (222, 230))	('toxicity', 'Disease', (222, 230))	('131I-MIBG', 'Var', (36, 45))	('131I-MIBG', 'Chemical', '-', (36, 45))
45295	22277577	One patient with metastatic pheochromocytoma was noted to receive as much as 85.9 GBq (2321 mCi) 131I-MIBG.	('pheochromocytoma', 'Disease', 'MESH:D010673', (28, 44))	('131I-MIBG', 'Chemical', '-', (97, 106))	('patient', 'Species', '9606', (4, 11))	('metastatic', 'Disease', (17, 27))	('pheochromocytoma', 'Disease', (28, 44))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (28, 44))	('GBq', 'Chemical', '-', (82, 85))	('131I-MIBG', 'Var', (97, 106))
45334	22277577	We report the uncomplicated administration of 111 GBq (= 3 Ci) cumulative activity of 131I-MIBG without serious toxicity.	('toxicity', 'Disease', (112, 120))	('131I-MIBG', 'Chemical', '-', (86, 95))	('GBq', 'Chemical', '-', (50, 53))	('131I-MIBG', 'Var', (86, 95))	('toxicity', 'Disease', 'MESH:D064420', (112, 120))
45335	22277577	This case underscores the therapeutic potential of 131I-MIBG therapy in metastatic disease as well as inter-individual dose-tolerance variability.	('131I-MIBG', 'Chemical', '-', (51, 60))	('131I-MIBG', 'Var', (51, 60))	('metastatic disease', 'Disease', (72, 90))
45493	32462735	Metabolomics, machine learning and immunohistochemistry to predict succinate dehydrogenase mutational status in phaeochromocytomas and paragangliomas Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours with a hereditary background in over one-third of patients.	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('PPGLs', 'Chemical', '-', (189, 194))	('tumours', 'Phenotype', 'HP:0002664', (220, 227))	('mutational', 'Var', (91, 101))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (205, 227))	('paragangliomas', 'Phenotype', 'HP:0002668', (135, 149))	('neuroendocrine tumours', 'Disease', (205, 227))	('succinate dehydrogenase', 'Gene', '6390', (67, 90))	('patients', 'Species', '9606', (278, 286))	('paragangliomas', 'Phenotype', 'HP:0002668', (173, 187))	('succinate dehydrogenase', 'Gene', (67, 90))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (112, 149))	('Phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (150, 187))
45494	32462735	Mutations in succinate dehydrogenase (SDH) genes increase the risk for PPGLs and several other tumours.	('succinate dehydrogenase', 'Gene', '6390', (13, 36))	('SDH', 'Gene', '6390', (38, 41))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('PPGLs', 'Chemical', '-', (71, 76))	('succinate dehydrogenase', 'Gene', (13, 36))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumours', 'Disease', (95, 102))	('increase', 'Reg', (49, 57))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (38, 41))	('PPGLs', 'Disease', (71, 76))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
45495	32462735	Mutations in subunit B (SDHB) in particular are a risk factor for metastatic disease, further highlighting the importance of identifying SDHx mutations for patient management.	('SDH', 'Gene', '6390', (24, 27))	('SDH', 'Gene', (137, 140))	('risk factor', 'Reg', (50, 61))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (24, 27))	('metastatic disease', 'Disease', (66, 84))	('SDHB', 'Gene', '6390', (24, 28))	('SDH', 'Gene', '6390', (137, 140))	('SDHB', 'Gene', (24, 28))	('patient', 'Species', '9606', (156, 163))
45503	32462735	From 186 tumours with confirmed status of SDHx variant pathogenicity, the combination of the two methods resulted in 185 correct predictions, highlighting the benefits of both strategies for patient management.	('tumours', 'Disease', 'MESH:D009369', (9, 16))	('SDH', 'Gene', '6390', (42, 45))	('tumours', 'Disease', (9, 16))	('variant', 'Var', (47, 54))	('SDH', 'Gene', (42, 45))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('patient', 'Species', '9606', (191, 198))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))
45506	32462735	Mutations of genes encoding these proteins can result in phaeochromocytomas and paragangliomas (PPGLs), gastrointestinal stromal tumours, renal cell carcinomas, and pituitary adenomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (80, 94))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('renal cell carcinomas', 'Disease', (138, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (165, 183))	('pituitary adenomas', 'Disease', (165, 183))	('result in', 'Reg', (47, 56))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (104, 136))	('Mutations', 'Var', (0, 9))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (138, 159))	('gastrointestinal stromal tumours', 'Disease', (104, 136))	('PPGLs', 'Chemical', '-', (96, 101))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (57, 94))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (138, 159))	('pituitary adenomas', 'Disease', 'MESH:D010911', (165, 183))
45507	32462735	The mutations occur almost exclusively in the germline, leaving the patient and potentially family members at lifelong risk for disease.	('mutations', 'Var', (4, 13))	('leaving', 'Reg', (56, 63))	('patient', 'Species', '9606', (68, 75))
45508	32462735	Mutations in SDHB in particular predispose to metastatic PPGL and are associated with increased mortality.	('predispose to', 'Reg', (32, 45))	('SDHB', 'Gene', '6390', (13, 17))	('metastatic PPGL', 'Disease', (46, 61))	('mortality', 'Disease', 'MESH:D003643', (96, 105))	('associated', 'Reg', (70, 80))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('mortality', 'Disease', (96, 105))
45510	32462735	For gene variants affecting SDH, the routinely applied method is immunohistochemistry for SDHB (SDHB-IHC), where staining intensity of tumoural cells is compared with that of non-tumoural cells as internal control.	('SDH', 'Gene', '6390', (96, 99))	('SDHB-IHC', 'Gene', (96, 104))	('SDHB', 'Gene', (90, 94))	('SDHB-IHC', 'Gene', '6390', (96, 104))	('tumoural', 'Disease', (135, 143))	('SDH', 'Gene', (28, 31))	('SDH', 'Gene', (90, 93))	('tumoural', 'Disease', 'MESH:D009369', (179, 187))	('SDH', 'Gene', (96, 99))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('variants', 'Var', (9, 17))	('tumoural', 'Disease', (179, 187))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('SDHB', 'Gene', '6390', (96, 100))	('SDHB', 'Gene', '6390', (90, 94))	('SDH', 'Gene', '6390', (28, 31))	('SDH', 'Gene', '6390', (90, 93))	('tumoural', 'Disease', 'MESH:D009369', (135, 143))	('SDHB', 'Gene', (96, 100))
45514	32462735	The ratio of these two metabolites, the tissue succinate to fumarate ratio (SFR), can predict SDHx mutations with a high sensitivity and specificity in PPGL and is also now being applied to other tumours.	('fumarate', 'Chemical', 'MESH:D005650', (60, 68))	('SDH', 'Gene', '6390', (94, 97))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('mutations', 'Var', (99, 108))	('succinate', 'Chemical', 'MESH:D019802', (47, 56))	('SDH', 'Gene', (94, 97))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('tumours', 'Disease', (196, 203))
45515	32462735	So far, there has been no formal comparison of the two methods for predicting SDHx mutational status.	('SDH', 'Gene', '6390', (78, 81))	('mutational status', 'Var', (83, 100))	('SDH', 'Gene', (78, 81))
45523	32462735	Genetic testing, accomplished as previously described, yielded findings of germline or somatic variants in 18 genes in 49.1% (195/397) of patients (for simplicity, only 11 are displayed in Table 1).	('findings', 'Reg', (63, 71))	('patients', 'Species', '9606', (138, 146))	('germline', 'Var', (75, 83))
45524	32462735	Eleven patients had variants of unknown significance in SDH genes, classified as variants of unknown significance according to the standards and guidelines of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.	('variants', 'Var', (20, 28))	('patients', 'Species', '9606', (7, 15))	('SDH', 'Gene', '6390', (56, 59))	('SDH', 'Gene', (56, 59))
45535	32462735	Patients from cohort 2 (excluding SDHx variants of unknown significance and FFPE only tissue) were used to develop the models and were randomly divided into training and internal validation sets in ratios ranging from 50/50 to 90/10 in steps of 10%.	('Patients', 'Species', '9606', (0, 8))	('SDH', 'Gene', (34, 37))	('variants', 'Var', (39, 47))	('SDH', 'Gene', '6390', (34, 37))
45536	32462735	The predictive models were applied to the PPGLs of cohort 1 to calculate the likelihood of SDHx mutations (external validation).	('SDH', 'Gene', (91, 94))	('SDH', 'Gene', '6390', (91, 94))	('mutations', 'Var', (96, 105))	('PPGLs', 'Chemical', '-', (42, 47))
45553	32462735	The LDA models calculate probabilities for the likelihood of an SDHx mutation based on the metabolite inputs; for the samples differently rated in LDA A and LDA B, the probabilities were 57% and 99% for LDA A, and 42% and 32% for LDA B, respectively (supplementary material, Table S5).	('SDH', 'Gene', (64, 67))	('LDA B', 'Chemical', '-', (157, 162))	('LDA B', 'Chemical', '-', (230, 235))	('mutation', 'Var', (69, 77))	('SDH', 'Gene', '6390', (64, 67))
45560	32462735	Metabolite profiling complemented SDHB-IHC by correctly predicting the SDHx mutational status of all but one case where SDHB-IHC incorrectly predicted the mutational status.	('SDH', 'Gene', (71, 74))	('predicting', 'Reg', (56, 66))	('SDHB-IHC', 'Gene', (120, 128))	('SDHB-IHC', 'Gene', (34, 42))	('mutational', 'Var', (76, 86))	('SDH', 'Gene', '6390', (120, 123))	('SDHB-IHC', 'Gene', '6390', (34, 42))	('SDHB-IHC', 'Gene', '6390', (120, 128))	('SDH', 'Gene', (34, 37))	('SDH', 'Gene', (120, 123))	('SDH', 'Gene', '6390', (71, 74))	('SDH', 'Gene', '6390', (34, 37))
45565	32462735	Accuracy of predictions of SDHx mutations according to SDHB-IHC indicated no significant differences between local pathologists and experts, suggesting that SDHB-IHC does not require specialised training (Table 5).	('SDHB-IHC', 'Gene', '6390', (157, 165))	('SDHB-IHC', 'Gene', (157, 165))	('SDH', 'Gene', '6390', (55, 58))	('SDHB-IHC', 'Gene', '6390', (55, 63))	('SDH', 'Gene', (157, 160))	('SDHB-IHC', 'Gene', (55, 63))	('SDH', 'Gene', (27, 30))	('mutations', 'Var', (32, 41))	('SDH', 'Gene', (55, 58))	('SDH', 'Gene', '6390', (157, 160))	('SDH', 'Gene', '6390', (27, 30))
45567	32462735	These six cases comprised five head and neck paragangliomas with SDHx mutations and one adrenal PPGL without an SDHx mutation, indicating again that head and neck paragangliomas are the most challenging specimens to interpret (supplementary material, Table S5).	('SDH', 'Gene', '6390', (65, 68))	('mutations', 'Var', (70, 79))	('neck paragangliomas', 'Disease', (40, 59))	('SDH', 'Gene', (112, 115))	('neck paragangliomas', 'Disease', (158, 177))	('paragangliomas', 'Phenotype', 'HP:0002668', (45, 59))	('SDH', 'Gene', (65, 68))	('SDH', 'Gene', '6390', (112, 115))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (31, 59))	('paragangliomas', 'Phenotype', 'HP:0002668', (163, 177))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (149, 177))	('neck paragangliomas', 'Disease', 'MESH:D010235', (40, 59))	('neck paragangliomas', 'Disease', 'MESH:D010235', (158, 177))
45568	32462735	Amongst the tumours evaluated, there were 11 patients (three in cohort 1 and eight in cohort 2) with a variant of unknown significance in one of the SDHx genes.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('SDH', 'Gene', '6390', (149, 152))	('tumours', 'Disease', (12, 19))	('SDH', 'Gene', (149, 152))	('patients', 'Species', '9606', (45, 53))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('variant', 'Var', (103, 110))
45571	32462735	LDA Model B predicted SDH impairment in two further PPGLs, a splice site variant in SDHA (NM_004168.3:c.457-1G>A) and an indel variant in SDHC (NM_003001.3:c.256_257insTTT, p. (Gly86delinsValCys).	('NM_003001.3:c.256_257insTTT', 'Mutation', 'c.256_257insTTT', (144, 171))	('NM_003001.3:c.256_257insTTT', 'Var', (144, 171))	('SDH', 'Gene', '6390', (138, 141))	('SDH impairment', 'Disease', (22, 36))	('NM_004168.3', 'Var', (90, 101))	('SDHC', 'Gene', (138, 142))	('NM_004168.3:c.457-1G>A', 'Mutation', 'c.457-1G>A', (90, 112))	('SDH', 'Gene', '6390', (22, 25))	('SDH', 'Gene', '6390', (84, 87))	('SDH', 'Gene', (138, 141))	('SDH impairment', 'Disease', 'MESH:D060825', (22, 36))	('SDHC', 'Gene', '6391', (138, 142))	('PPGLs', 'Chemical', '-', (52, 57))	('SDH', 'Gene', (22, 25))	('SDH', 'Gene', (84, 87))
45573	32462735	The missense variant of SDHA, NM_004168.3:c.1772C>T, p.(Ala591Val), was predicted to have no functional impact based on metabolite profiling and SDHB-IHC as interpreted by a local pathologist.	('NM_004168.3:c.1772C>T', 'Mutation', 'rs367621815', (30, 51))	('SDH', 'Gene', '6390', (24, 27))	('c.1772C>T', 'Var', (42, 51))	('SDH', 'Gene', '6390', (145, 148))	('SDH', 'Gene', (145, 148))	('SDHB-IHC', 'Gene', '6390', (145, 153))	('SDH', 'Gene', (24, 27))	('SDHB-IHC', 'Gene', (145, 153))	('p.(Ala591Val)', 'Mutation', 'rs367621815', (53, 66))
45577	32462735	We therefore propose an approach that combines metabolite profiling and SDHB-IHC to better facilitate identifying or excluding SDH impairment when tumour material is available, particularly for selected patients in whom there is a suspicion of the presence of SDH mutation and where genetic testing yields equivocal or negative results or is unavailable.	('SDH', 'Gene', (127, 130))	('SDH', 'Gene', '6390', (72, 75))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('SDHB-IHC', 'Gene', (72, 80))	('SDH impairment when tumour', 'Disease', (127, 153))	('patients', 'Species', '9606', (203, 211))	('SDHB-IHC', 'Gene', '6390', (72, 80))	('SDH', 'Gene', '6390', (260, 263))	('SDH', 'Gene', (72, 75))	('mutation', 'Var', (264, 272))	('SDH impairment when tumour', 'Disease', 'MESH:D009369', (127, 153))	('SDH', 'Gene', '6390', (127, 130))	('SDH', 'Gene', (260, 263))
45578	32462735	First, the high specificity of metabolite profiling (99%) translates to high positive predictive value of a positive result, strongly indicating a mutation in an SDHx gene.	('mutation', 'Var', (147, 155))	('SDH', 'Gene', '6390', (162, 165))	('indicating', 'Reg', (134, 144))	('SDH', 'Gene', (162, 165))
45594	32462735	While the predictive models generated in this study were targeted towards identifying SDHx mutations, other models could be generated based on measurements of metabolites in the same panel to predict mutations and functional deficiencies impacting other enzymes.	('SDH', 'Gene', '6390', (86, 89))	('functional deficiencies', 'Disease', 'MESH:D015499', (214, 237))	('functional deficiencies', 'Disease', (214, 237))	('SDH', 'Gene', (86, 89))	('mutations', 'Var', (91, 100))
45595	32462735	Results are provided as per cent probabilities of the tumour harbouring an SDHx mutation.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('SDH', 'Gene', '6390', (75, 78))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('SDH', 'Gene', (75, 78))	('mutation', 'Var', (80, 88))
45598	32462735	In our combined cohorts, a total of 11 variants of unknown significance in SDHx genes were identified.	('SDH', 'Gene', '6390', (75, 78))	('SDH', 'Gene', (75, 78))	('variants', 'Var', (39, 47))
45602	32462735	At least in one of these cases, SDHA NM_004168.3: c.457-1G>A, evidence suggests a true mutation.	('SDH', 'Gene', (32, 35))	('c.457-1G>A', 'Var', (50, 60))	('c.457-1G>A', 'SUBSTITUTION', 'None', (50, 60))	('SDH', 'Gene', '6390', (32, 35))
45609	32545894	Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers.	('roles', 'Reg', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('HOX gene', 'Gene', (51, 59))	('mis-regulation', 'Var', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
45616	32545894	Multiple reports have demonstrated that mis-regulation of HOX genes expression plays key roles in the development of cancers.	('mis-regulation', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('roles', 'Reg', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('HOX genes', 'Gene', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
45671	32545894	The expression correlation observed between HOXB5, HOXB6, and HOXB7 in ESCA, is in line with a previous report that showed that expression changes in the three "midcluster" HOXB genes, namely HOXB5, HOXB6, and HOXB7, can trigger changes in the transcriptional program of adult esophageal cells, with implications to the early stages of esophageal carcinogenesis.	('HOXB', 'Gene', (62, 66))	('HOXB7', 'Gene', '3217', (210, 215))	('HOXB7', 'Gene', (210, 215))	('HOXB', 'Gene', (44, 48))	('HOXB', 'Gene', (173, 177))	('HOXB', 'Gene', '3210', (199, 203))	('HOXB', 'Gene', (51, 55))	('HOXB', 'Gene', (210, 214))	('HOXB6', 'Gene', '3216', (51, 56))	('HOXB6', 'Gene', (51, 56))	('HOXB5', 'Gene', (44, 49))	('HOXB', 'Gene', (192, 196))	('HOXB6', 'Gene', '3216', (199, 204))	('HOXB7', 'Gene', '3217', (62, 67))	('trigger changes', 'Reg', (221, 236))	('esophageal carcinogenesis', 'Disease', (336, 361))	('HOXB7', 'Gene', (62, 67))	('HOXB', 'Gene', '3210', (62, 66))	('changes', 'Var', (139, 146))	('HOXB6', 'Gene', (199, 204))	('HOXB', 'Gene', '3210', (44, 48))	('HOXB', 'Gene', '3210', (173, 177))	('transcriptional program', 'MPA', (244, 267))	('HOXB5', 'Gene', '3215', (44, 49))	('HOXB5', 'Gene', (192, 197))	('HOXB', 'Gene', '3210', (51, 55))	('HOXB', 'Gene', '3210', (210, 214))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (336, 361))	('HOXB', 'Gene', (199, 203))	('HOXB', 'Gene', '3210', (192, 196))	('ESCA', 'Phenotype', 'HP:0011459', (71, 75))	('HOXB5', 'Gene', '3215', (192, 197))
45812	29264546	We identified in this family germline mutation of the RET protooncogene.	('RET', 'Gene', '5979', (54, 57))	('RET', 'Gene', (54, 57))	('germline mutation', 'Var', (29, 46))
45880	29082061	Dopamine levels were severely elevated, >25x normal range at 6988 mug/day (0-250).	('6988 mug/day', 'Var', (61, 73))	('elevated', 'PosReg', (30, 38))	('Dopamine levels', 'MPA', (0, 15))	('Dopamine', 'Chemical', 'MESH:D004298', (0, 8))
45923	28675758	Metformin Suppresses Proliferation and Viability of Rat Pheochromocytoma Cells Previous studies have clearly demonstrated that metformin inhibits cell proliferation and cell growth in many types of human cancers.	('cell growth', 'CPA', (169, 180))	('rat', 'Species', '10116', (158, 161))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('cell proliferation', 'CPA', (146, 164))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('human', 'Species', '9606', (198, 203))	('Proliferation', 'CPA', (21, 34))	('Viability', 'CPA', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rat', 'Species', '10116', (116, 119))	('inhibits', 'NegReg', (137, 145))	('rat', 'Species', '10116', (28, 31))	('Suppresses', 'NegReg', (10, 20))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('metformin', 'Var', (127, 136))	('Rat Pheochromocytoma', 'CellLine', 'CVCL:0492', (52, 72))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (56, 72))	('metformin', 'Chemical', 'MESH:D008687', (127, 136))
45933	28675758	Genetic studies have demonstrated that mutations of several genes could increase the risk of pheochromocytoma, such as multiple endocrine neoplasia 2A, 2B (MEN2A and MEN2B), and von Hippel-Lindau (VHL).	('increase', 'PosReg', (72, 80))	('von Hippel-Lindau', 'Gene', (178, 195))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('multiple endocrine neoplasia', 'Disease', (119, 147))	('pheochromocytoma', 'Disease', (93, 109))	('pheochromocytoma', 'Disease', 'MESH:D010673', (93, 109))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (128, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (138, 147))	('mutations', 'Var', (39, 48))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (119, 147))	('von Hippel-Lindau', 'Gene', '24874', (178, 195))	('VHL', 'Disease', 'MESH:D006623', (197, 200))	('rat', 'Species', '10116', (28, 31))	('VHL', 'Disease', (197, 200))
45937	28675758	In addition, several retrospective reports showed that metformin is also associated with a decreased risk of developing cancer and cancer-related mortality.	('cancer', 'Disease', (131, 137))	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('metformin', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('decreased', 'NegReg', (91, 100))
45973	28675758	Among them, Ccna2, Ccnb2, and PCNA were significantly downregulated by metformin treatment (Figure 5A), whereas other cell-cycle regulators, including Cdkn1b, Cdkn1c, Ccnd1, and Ccnd3, remained unaffected (Figure 5B).	('metformin', 'Var', (71, 80))	('Cdkn1c', 'Gene', '246060', (159, 165))	('Ccnd3', 'Gene', (178, 183))	('metformin', 'Chemical', 'MESH:D008687', (71, 80))	('PCNA', 'Gene', '25737', (30, 34))	('Cdkn1b', 'Gene', (151, 157))	('PCNA', 'Gene', (30, 34))	('Cdkn1b', 'Gene', '83571', (151, 157))	('Ccnd3', 'Gene', '25193', (178, 183))	('Ccna2', 'Gene', (12, 17))	('Ccnb2', 'Gene', '363088', (19, 24))	('Ccnb2', 'Gene', (19, 24))	('Ccnd1', 'Gene', (167, 172))	('Ccnd1', 'Gene', '58919', (167, 172))	('downregulated', 'NegReg', (54, 67))	('Cdkn1c', 'Gene', (159, 165))	('Ccna2', 'Gene', '114494', (12, 17))
45977	28675758	Moreover, phosphorylated ACC, a downstream target of AMPK, was also induced by metformin (Figure 6A, 6B).	('ACC', 'Gene', (25, 28))	('AMPK', 'Gene', (53, 57))	('phosphorylated', 'MPA', (10, 24))	('induced', 'Reg', (68, 75))	('metformin', 'Var', (79, 88))	('metformin', 'Chemical', 'MESH:D008687', (79, 88))	('AMPK', 'Gene', '78975', (53, 57))
45986	28675758	At the molecular level, our results indicate that Ccna2 and Ccnb2, which are 2 critical regulators of cell-cycle progression, are downregulated by metformin and may be intracellular targets of its antiproliferative activities.	('downregulated', 'NegReg', (130, 143))	('Ccna2', 'Gene', '114494', (50, 55))	('rat', 'Species', '10116', (208, 211))	('metformin', 'Var', (147, 156))	('Ccnb2', 'Gene', '363088', (60, 65))	('metformin', 'Chemical', 'MESH:D008687', (147, 156))	('Ccna2', 'Gene', (50, 55))	('Ccnb2', 'Gene', (60, 65))
45990	28675758	Previous studies have shown that metformin exerts an antitumor effect in breast and prostate cancer cells through a decrease of cyclin D1 level.	('metformin', 'Chemical', 'MESH:D008687', (33, 42))	('cyclin D1', 'Gene', '58919', (128, 137))	('decrease', 'NegReg', (116, 124))	('cyclin D1', 'Gene', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (73, 99))	('tumor', 'Disease', (57, 62))	('metformin', 'Var', (33, 42))
45993	28675758	Mechanistically, initial studies found that metformin activates the AMPK pathway, which is essential for the antiproliferative effects of metformin.	('AMPK', 'Gene', '78975', (68, 72))	('metformin', 'Var', (44, 53))	('activates', 'PosReg', (54, 63))	('AMPK', 'Gene', (68, 72))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('rat', 'Species', '10116', (120, 123))	('metformin', 'Chemical', 'MESH:D008687', (138, 147))
45994	28675758	However, subsequent studies showed that genetic inhibition of the AMPK pathway did not inhibit the effect of metformin, suggesting that additional mechanisms are involved.	('metformin', 'Chemical', 'MESH:D008687', (109, 118))	('AMPK', 'Gene', (66, 70))	('genetic', 'Var', (40, 47))	('AMPK', 'Gene', '78975', (66, 70))
45996	28675758	Here, we found that metformin also activates phosphorylated AMPK, whereas it inhibits phosphorylated mTOR and ERK1/2.	('activates', 'PosReg', (35, 44))	('mTOR', 'Gene', (101, 105))	('AMPK', 'Gene', (60, 64))	('ERK1/2', 'Gene', (110, 116))	('ERK1/2', 'Gene', '50689;116590', (110, 116))	('metformin', 'Var', (20, 29))	('metformin', 'Chemical', 'MESH:D008687', (20, 29))	('AMPK', 'Gene', '78975', (60, 64))	('inhibits', 'NegReg', (77, 85))	('mTOR', 'Gene', '56718', (101, 105))
46002	28675758	At the molecular level, AMPK, mTOR, and ERK1/2 signaling pathways were regulated by metformin.	('metformin', 'Chemical', 'MESH:D008687', (84, 93))	('AMPK', 'Gene', '78975', (24, 28))	('regulated', 'Reg', (71, 80))	('AMPK', 'Gene', (24, 28))	('ERK1/2', 'Gene', (40, 46))	('ERK1/2', 'Gene', '50689;116590', (40, 46))	('mTOR', 'Gene', '56718', (30, 34))	('mTOR', 'Gene', (30, 34))	('metformin', 'Var', (84, 93))
46161	25589844	The immunohistochemical staining for chromogranin A was positive (x200) (Fig.	('x200', 'Var', (66, 70))	('chromogranin A', 'Gene', (37, 51))	('chromogranin A', 'Gene', '1113', (37, 51))
46171	25589844	Such unusual cases should lead us to evaluate the pheochromocytoma further, such as for gene mutations and MEN, if the patient is young.	('patient', 'Species', '9606', (119, 126))	('pheochromocytoma', 'Disease', (50, 66))	('pheochromocytoma', 'Disease', 'MESH:D010673', (50, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (50, 66))	('gene mutations', 'Var', (88, 102))	('MEN', 'Species', '9606', (107, 110))
46182	24516563	Unexpectedly, luciferase expression, bioluminescence and GFP expression were paradoxically increased by both camptothecin and SN38, the active metabolite of irinotecan, thereby masking cell death.	('GFP', 'Gene', (57, 60))	('camptothecin', 'Chemical', 'MESH:D002166', (109, 121))	('SN38', 'Var', (126, 130))	('camptothecin', 'Var', (109, 121))	('expression', 'MPA', (25, 35))	('irinotecan', 'Chemical', 'MESH:D000077146', (157, 167))	('increased', 'PosReg', (91, 100))	('bioluminescence', 'MPA', (37, 52))	('luciferase', 'Enzyme', (14, 24))
46226	24516563	Aside from expression of its two marker proteins, MPC G-L9 is similar to its parent tumor.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('MPC G-L9', 'Var', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('MPC', 'Chemical', '-', (50, 53))	('tumor', 'Disease', (84, 89))
46259	24516563	With MPC GL-9, the results of cytotoxicity testing by XTT assay were comparable to those with the parent tumor.	('MPC GL-9', 'Var', (5, 13))	('GL-9', 'CellLine', 'CVCL:0045', (9, 13))	('cytotoxicity', 'Disease', (30, 42))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('MPC', 'Chemical', '-', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('tumor', 'Disease', (105, 110))
46265	24516563	Because CgA is a marker for neuroendocrine secretory granules, this finding indicates that the drug effects on levels of luciferase and GFP are specific to the GFP-luciferase construct rather than increased granule content or other generalized cellular responses.	('CgA', 'Gene', '1113', (8, 11))	('GFP-luciferase', 'Var', (160, 174))	('GFP', 'Gene', (136, 139))	('CgA', 'Gene', (8, 11))
46269	24516563	On a molar basis the most potent drug was SN38, which was approximately 10 times as potent as camptothecin, with 100 ng/mL SN38 (0.26 uM) or 1 ug/mL camptothecin (2.7 uM) each causing ~90% cell death (Fig.	('camptothecin', 'Chemical', 'MESH:D002166', (94, 106))	('cell death', 'CPA', (189, 199))	('camptothecin', 'Chemical', 'MESH:D002166', (149, 161))	('SN38', 'Var', (123, 127))
46273	24516563	8, SN38 killed human PCC cells similarly to camptothecin, although both drugs were less effective against human PCC than against MPC cells.	('human', 'Species', '9606', (106, 111))	('human', 'Species', '9606', (15, 20))	('PCC', 'Gene', (112, 115))	('PCC', 'Gene', (21, 24))	('SN38', 'Var', (3, 7))	('PCC', 'Phenotype', 'HP:0002666', (112, 115))	('MPC', 'Chemical', '-', (129, 132))	('camptothecin', 'Chemical', 'MESH:D002166', (44, 56))	('PCC', 'Phenotype', 'HP:0002666', (21, 24))	('PCC', 'Gene', '1421', (112, 115))	('PCC', 'Gene', '1421', (21, 24))
46277	24516563	Importantly, the representative tumors tested included three from patients with germline SDHB mutations, which are the most likely to metastasize.	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('SDHB', 'Gene', '6390', (89, 93))	('tumors', 'Disease', (32, 38))	('SDHB', 'Gene', (89, 93))	('patients', 'Species', '9606', (66, 74))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
46305	24516563	In addition, cytostasis induced by pre-treatment with high concentrations of 5-aza might cause MPC and MTT cells to more closely resemble primary human PCC/PGL cultures, in which no tumor cells proliferate, thereby possibly increasing the relevance of both models.	('5-aza', 'Var', (77, 82))	('tumor', 'Disease', (182, 187))	('PCC/PGL', 'Gene', '1421', (152, 159))	('PCC', 'Phenotype', 'HP:0002666', (152, 155))	('MTT', 'Chemical', '-', (103, 106))	('cytostasis', 'MPA', (13, 23))	('MPC', 'Chemical', '-', (95, 98))	('human', 'Species', '9606', (146, 151))	('5-aza', 'Chemical', 'MESH:D001374', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('PGL', 'Phenotype', 'HP:0002668', (156, 159))	('PCC/PGL', 'Gene', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
46310	24516563	Tumors with SDHB mutations have a distinct pseudo-hypoxic signature.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SDHB', 'Gene', '6390', (12, 16))	('SDHB', 'Gene', (12, 16))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('pseudo-hypoxic signature', 'MPA', (43, 67))	('mutations', 'Var', (17, 26))
46312	24516563	However, a wide range of responsiveness among the three tested tumors from patients with SDHB mutations suggests that characteristics of individual tumors will be more important than genetic background.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('SDHB', 'Gene', '6390', (89, 93))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('SDHB', 'Gene', (89, 93))
46318	24516563	This can occur either in response to a methylation inhibitor such as 5-azacytidine or to a histone deacetylase inhibitor, which would facilitate chromatin remodeling and removal of methylated DNA.	('5-azacytidine', 'Chemical', 'MESH:D001374', (69, 82))	('5-azacytidine', 'Var', (69, 82))	('chromatin remodeling', 'CPA', (145, 165))	('facilitate', 'PosReg', (134, 144))
46321	24516563	It should be borne in mind that TOP1 inhibitors and other drugs can cause anomalous increases in CMV reporter-controlled expression of luciferase and GFP, potentially confounding the interpretation of tumor imaging studies and pre-clinical drug testing.	('luciferase', 'Enzyme', (135, 145))	('inhibitors', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('anomalous increases', 'Disease', 'MESH:D003805', (74, 93))	('TOP1', 'Gene', (32, 36))	('anomalous increases', 'Disease', (74, 93))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('CMV reporter-controlled expression', 'MPA', (97, 131))	('tumor', 'Disease', (201, 206))	('GFP', 'Gene', (150, 153))
46325	23267837	We further demonstrated significant anti-tumor effects mediated by cytotoxic somatostatin analogs, AN-162 and AN-238, by LHRH antagonist, Cetrorelix, by the cytotoxic LHRH analog, AN-152, and by recently developed GHRH antagonist, MIA-602, on MPC and for AN-152 and MIA-602 on MTT cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('AN', 'Chemical', 'MESH:D000431', (99, 101))	('tumor', 'Disease', (41, 46))	('somatostatin', 'Gene', '20604', (77, 89))	('GHRH', 'Gene', (214, 218))	('somatostatin', 'Gene', (77, 89))	('MPC', 'Chemical', '-', (243, 246))	('AN-162', 'Var', (99, 105))	('AN', 'Chemical', 'MESH:D000431', (180, 182))	('AN', 'Chemical', 'MESH:D000431', (110, 112))	('AN-238', 'Var', (110, 116))	('AN', 'Chemical', 'MESH:D000431', (255, 257))	('MTT', 'Chemical', '-', (277, 280))	('GHRH', 'Gene', '14601', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
46337	23267837	Recently, a new class of GHRH antagonists (MIA-313, MIA-602, MIA-604, and MIA-610) was generated by Schally and co-workers and shown to be effective anti-neoplastic agents, as for example demonstrated on ovarian cancer.	('MIA-604', 'Var', (61, 68))	('GHRH', 'Gene', '14601', (25, 29))	('ovarian cancer', 'Disease', (204, 218))	('MIA-313', 'Var', (43, 50))	('GHRH', 'Gene', (25, 29))	('MIA-602', 'Var', (52, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('MIA-610', 'Var', (74, 81))	('MIA-604', 'CellLine', 'CVCL:0816', (61, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
46343	23267837	Aberrantly expressed neuropeptide hormone receptors are frequently found in a subgroup of adrenocortical tumors, especially in ACTH-independent macronodular adrenal hyperplasia.	('ACTH', 'Gene', '18976', (127, 131))	('Aberrantly expressed', 'Var', (0, 20))	('hormone receptor', 'Gene', (34, 50))	('adrenocortical tumors', 'Disease', (90, 111))	('adrenal hyperplasia', 'Phenotype', 'HP:0008221', (157, 176))	('hormone receptor', 'Gene', '15370', (34, 50))	('ACTH', 'Gene', (127, 131))	('found', 'Reg', (67, 72))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (90, 111))	('macronodular adrenal hyperplasia', 'Disease', 'MESH:C565662', (144, 176))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('macronodular adrenal hyperplasia', 'Disease', (144, 176))	('macronodular adrenal hyperplasia', 'Phenotype', 'HP:0008231', (144, 176))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
46358	23267837	In our current investigation we employed somatostatin octapeptide analog RC-160, targeted cytotoxic somatostatin analogs AN-162 and AN-238, LHRH antagonist Cetrorelix, cytotoxic LHRH analog AN-152 as well as GHRH antagonist MIA-602.	('GHRH', 'Gene', (208, 212))	('somatostatin', 'Gene', '20604', (41, 53))	('somatostatin', 'Gene', '20604', (100, 112))	('AN', 'Chemical', 'MESH:D000431', (121, 123))	('AN', 'Chemical', 'MESH:D000431', (190, 192))	('AN-238', 'Var', (132, 138))	('AN', 'Chemical', 'MESH:D000431', (132, 134))	('somatostatin', 'Gene', (100, 112))	('GHRH', 'Gene', '14601', (208, 212))	('somatostatin', 'Gene', (41, 53))
46370	23267837	Furthermore, mediated by activation of caspases 3 and 7, AN-152 (10-7-10-8 mol/l) directed MPC into programmed cell death (24h-72h) (Fig.	('programmed cell', 'CPA', (100, 115))	('AN-152', 'Var', (57, 63))	('MPC', 'Chemical', '-', (91, 94))	('AN', 'Chemical', 'MESH:D000431', (57, 59))
46375	23267837	Finally, since also the GHRH receptor was abundantly expressed on MTT cells we were interested to studied possible anti-tumor effects mediated by the GHRH antagonist MIA-602 and could show that MIA-602 decreased MTT cell survival only at a rather high concentration of 10-5 mol/l after 2-3 days (Fig.	('MIA-602', 'Var', (194, 201))	('GHRH receptor', 'Gene', (24, 37))	('MTT', 'Chemical', '-', (66, 69))	('GHRH receptor', 'Gene', '14602', (24, 37))	('GHRH', 'Gene', '14601', (24, 28))	('MTT', 'Chemical', '-', (212, 215))	('decreased', 'NegReg', (202, 211))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('GHRH', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('GHRH', 'Gene', (24, 28))	('MTT cell survival', 'CPA', (212, 229))	('tumor', 'Disease', (120, 125))	('GHRH', 'Gene', '14601', (150, 154))
46376	23267837	Studies on the possible effects of the targeted cytotoxic somatostatin analogs AN-162 and AN-238 on MTT cells are still ongoing.	('MTT', 'Chemical', '-', (100, 103))	('AN-162', 'Var', (79, 85))	('AN', 'Chemical', 'MESH:D000431', (79, 81))	('AN-238', 'Var', (90, 96))	('AN', 'Chemical', 'MESH:D000431', (90, 92))	('somatostatin', 'Gene', '20604', (58, 70))	('somatostatin', 'Gene', (58, 70))
46384	23267837	Also our present study adds further evidence for significant anti-tumor effects mediated by the cytotoxic somatostatin analogs AN-162 and AN-238 on pheochromocytoma cells in vitro.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('AN-162', 'Var', (127, 133))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (148, 164))	('tumor', 'Disease', (66, 71))	('pheochromocytoma', 'Disease', 'MESH:D010673', (148, 164))	('somatostatin', 'Gene', '20604', (106, 118))	('AN', 'Chemical', 'MESH:D000431', (127, 129))	('AN-238', 'Var', (138, 144))	('AN', 'Chemical', 'MESH:D000431', (138, 140))	('somatostatin', 'Gene', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('pheochromocytoma', 'Disease', (148, 164))
46387	23267837	Additionally, in experimental models, analogs of LHRH have been shown to exert direct effects on human breast and bladder cancers through specific LHRH receptors, while non targeted doxorubicin was not as effective and more toxic.	('effects', 'Reg', (86, 93))	('LHRH receptors', 'Protein', (147, 161))	('LHRH', 'Gene', (49, 53))	('breast', 'Disease', (103, 109))	('bladder cancers', 'Phenotype', 'HP:0009725', (114, 129))	('human', 'Species', '9606', (97, 102))	('doxorubicin', 'Chemical', 'MESH:D004317', (182, 193))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('analogs', 'Var', (38, 45))	('bladder cancers', 'Disease', 'MESH:D001749', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancers', 'Disease', (114, 129))
46392	23267837	In our study, we especially focused on MIA-602 and found significant reductions in cell viability on both MPC and MTT cells.	('MIA-602', 'Var', (39, 46))	('MTT', 'Chemical', '-', (114, 117))	('cell viability', 'CPA', (83, 97))	('reductions', 'NegReg', (69, 79))	('MPC', 'Chemical', '-', (106, 109))
46393	23267837	Furthermore, just recently, MIA-602 has been shown to significantly decrease cell viability and well known parameters of tumor spreading on three different human cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('decrease', 'NegReg', (68, 76))	('tumor', 'Disease', (121, 126))	('MIA-602', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('human', 'Species', '9606', (156, 161))	('cell viability', 'CPA', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
46412	19124817	We report the effect of intravenous administration of low-osmolar contrast during CT on plasma catecholamine release, blood pressure, and heart rate in patients with and without pheochromocytoma, to determine whether it induces catecholamine release that increases blood pressure or heart rate.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (178, 194))	('heart rate', 'MPA', (283, 293))	('blood pressure', 'MPA', (118, 132))	('plasma catecholamine release', 'MPA', (88, 116))	('catecholamine release', 'MPA', (228, 249))	('increases', 'PosReg', (255, 264))	('induces', 'Reg', (220, 227))	('pheochromocytoma', 'Disease', (178, 194))	('increases blood pressure', 'Phenotype', 'HP:0032263', (255, 279))	('catecholamine', 'Chemical', 'MESH:D002395', (228, 241))	('pheochromocytoma', 'Disease', 'MESH:D010673', (178, 194))	('low-osmolar', 'Var', (54, 65))	('blood pressure', 'MPA', (265, 279))	('catecholamine', 'Chemical', 'MESH:D002395', (95, 108))	('patients', 'Species', '9606', (152, 160))
46453	22584711	Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome To evaluate whether germline variants of the succinate dehydrogenase genes might be phenotypic modifiers in patients with multiple endocrine neoplasia type 2.	('SDHD', 'Gene', '6392', (52, 56))	('G12S', 'Var', (27, 31))	('MEN2A', 'Gene', (79, 84))	('MEN2A', 'Gene', '5979', (79, 84))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (216, 251))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (225, 244))	('patients', 'Species', '9606', (202, 210))	('neoplasia', 'Phenotype', 'HP:0002664', (235, 244))	('multiple endocrine neoplasia type 2', 'Disease', (216, 251))	('patients', 'Species', '9606', (65, 73))	('G12S', 'Mutation', 'rs34677591', (27, 31))	('SDHD', 'Gene', (52, 56))
46454	22584711	Mutations of genes encoding subunits of the succinate dehydrogenase are associated with hereditary paraganglioma/pheochromocytoma syndrome.	('hereditary paraganglioma', 'Disease', (88, 112))	('hereditary paraganglioma', 'Disease', 'MESH:D010235', (88, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (99, 112))	('associated', 'Reg', (72, 82))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (113, 129))	('Mutations', 'Var', (0, 9))	('pheochromocytoma syndrome', 'Disease', 'MESH:D010673', (113, 138))	('pheochromocytoma syndrome', 'Disease', (113, 138))
46455	22584711	Pheochromocytoma is one of the main manifestations of multiple endocrine neoplasia type 2 caused by germline mutation of the rearranged during transfection proto-oncogene.	('Pheochromocytoma', 'Disease', (0, 16))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (63, 82))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (54, 89))	('neoplasia', 'Phenotype', 'HP:0002664', (73, 82))	('multiple endocrine neoplasia type 2', 'Disease', (54, 89))	('rearranged during transfection', 'Gene', '5979', (125, 155))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('germline mutation', 'Var', (100, 117))	('rearranged during transfection', 'Gene', (125, 155))	('caused by', 'Reg', (90, 99))
46456	22584711	Polymorphisms of the succinate dehydrogenase genes were analyzed in 77 rearranged during transfection mutation carriers, 47 patients with sporadic medullary thyroid cancer, 48 patients with sporadic Pheo, and 100 healthy individuals.	('patients', 'Species', '9606', (176, 184))	('thyroid cancer', 'Disease', 'MESH:D013964', (157, 171))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (147, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('mutation', 'Var', (102, 110))	('rearranged during transfection', 'Gene', (71, 101))	('thyroid cancer', 'Phenotype', 'HP:0002890', (157, 171))	('thyroid cancer', 'Disease', (157, 171))	('rearranged during transfection', 'Gene', '5979', (71, 101))	('patients', 'Species', '9606', (124, 132))
46461	22584711	No associations between G12S and age of manifestation, incidence of pheochromocytoma or hyperparathyroidism, or level of serum calcitonin were observed.	('pheochromocytoma or hyperparathyroidism', 'Disease', (68, 107))	('pheochromocytoma or hyperparathyroidism', 'Disease', 'MESH:D010673', (68, 107))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (88, 107))	('G12S', 'Var', (24, 28))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('G12S', 'Mutation', 'rs34677591', (24, 28))
46462	22584711	The high prevalence of the G12S variant in patients with multiple endocrine neoplasia type 2A raises questions about its role as a genetic modifier, but this proposal remains to be established.	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (57, 92))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (66, 85))	('G12S', 'Var', (27, 31))	('multiple endocrine neoplasia type 2', 'Disease', (57, 92))	('patients', 'Species', '9606', (43, 51))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('G12S', 'Mutation', 'rs34677591', (27, 31))
46464	22584711	Germline gain-of-function mutations of the RET proto-oncogene cause multiple endocrine neoplasia type 2 (MEN2), an autosomal dominantly inherited disease with an approximate prevalence of 2.5 per 100.000 in the general population.	('gain-of-function', 'PosReg', (9, 25))	('RET', 'Gene', (43, 46))	('neoplasia', 'Phenotype', 'HP:0002664', (87, 96))	('autosomal dominantly inherited disease', 'Disease', (115, 153))	('multiple endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (68, 103))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (77, 96))	('mutations', 'Var', (26, 35))	('multiple endocrine neoplasia type 2', 'Disease', (68, 103))	('autosomal dominantly inherited disease', 'Disease', 'MESH:D030342', (115, 153))	('MEN', 'Species', '9606', (105, 108))
46466	22584711	Several important genotype-phenotype associations have been determined; the most commonly affected codon, 634 (nearly 85% of MEN2A cases), frequently associates with Pheo and hyperparathyroidism, whereas mutations of codons 609, 611, 618, and 620 (accounting for 10-15% of MEN2A) usually associate with the milder form of MEN2 -.	('MEN2A', 'Gene', (273, 278))	('MEN', 'Species', '9606', (273, 276))	('associates with', 'Reg', (150, 165))	('MEN2 -', 'Disease', (322, 328))	('MEN', 'Species', '9606', (322, 325))	('mutations', 'Var', (204, 213))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (175, 194))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (175, 194))	('MEN2A', 'Gene', (125, 130))	('MEN2A', 'Gene', '5979', (125, 130))	('associate', 'Reg', (288, 297))	('hyperparathyroidism', 'Disease', (175, 194))	('MEN', 'Species', '9606', (125, 128))	('MEN2A', 'Gene', '5979', (273, 278))
46467	22584711	Hereditary paraganglioma/pheochromocytoma (PGL) syndrome is caused by the germline heterozygous mutations of the SDHx genes (SDHB, SDHC, SDHD, encoding subunits B, C and D, respectively) - and the newly identified SDH5 gene and TMEM127.	('SDHx', 'Chemical', '-', (113, 117))	('SDHB', 'Gene', (125, 129))	('SDHx', 'Gene', (113, 117))	('SDH5', 'Gene', (214, 218))	('Hereditary paraganglioma/pheochromocytoma (PGL) syndrome', 'Disease', 'MESH:D010235', (0, 56))	('TMEM127', 'Gene', (228, 235))	('TMEM127', 'Gene', '55654', (228, 235))	('SDHD', 'Gene', (137, 141))	('SDHD', 'Gene', '6392', (137, 141))	('SDH5', 'Gene', '54949', (214, 218))	('paraganglioma', 'Phenotype', 'HP:0002668', (11, 24))	('SDHC', 'Gene', (131, 135))	('caused', 'Reg', (60, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (25, 41))	('SDHC', 'Gene', '6391', (131, 135))	('mutations', 'Var', (96, 105))	('SDHB', 'Gene', '6390', (125, 129))
46470	22584711	Accumulation of amino-acid coding polymorphisms (S163P in SDHB, G12S, and H50R in SDHD) has been found among patients with MTC, especially in those with familial tumors.	('H50R', 'Mutation', 'rs11214077', (74, 78))	('G12S', 'Var', (64, 68))	('SDHB', 'Gene', (58, 62))	('MTC', 'Disease', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('familial tumors', 'Disease', 'MESH:D009386', (153, 168))	('patients', 'Species', '9606', (109, 117))	('S163P', 'Var', (49, 54))	('familial tumors', 'Disease', (153, 168))	('S163P', 'Mutation', 'rs33927012', (49, 54))	('G12S', 'Mutation', 'rs34677591', (64, 68))	('SDHD', 'Gene', (82, 86))	('SDHD', 'Gene', '6392', (82, 86))	('H50R', 'Var', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('SDHB', 'Gene', '6390', (58, 62))
46472	22584711	These previous data may suggest a possible connection between SDHx polymorphisms and familial MTC and/or C-cell hyperplasia/hypercalcitoninemia; however, the occurrence of the SDHx variants among patients harboring germline RET mutations has not been previously examined.	('C-cell hyperplasia', 'Disease', 'MESH:C537418', (105, 123))	('hyperplasia/hypercalcitoninemia', 'Disease', 'MESH:D006965', (112, 143))	('variants', 'Var', (181, 189))	('C-cell hyperplasia', 'Disease', (105, 123))	('SDHx', 'Chemical', '-', (176, 180))	('patients', 'Species', '9606', (196, 204))	('SDHx', 'Gene', (62, 66))	('hyperplasia/hypercalcitoninemia', 'Disease', (112, 143))	('SDHx', 'Chemical', '-', (62, 66))	('SDHx', 'Gene', (176, 180))	('familial MTC', 'Disease', (85, 97))
46473	22584711	Therefore, the aim of the present study was to investigate whether polymorphisms of the SDHx genes could influence clinical manifestations of the disease in a cohort of subjects harboring RET mutations.	('SDHx', 'Chemical', '-', (88, 92))	('SDHx', 'Gene', (88, 92))	('polymorphisms', 'Var', (67, 80))	('influence', 'Reg', (105, 114))
46474	22584711	In addition, we wanted to determine whether the prevalence of SDHx polymorphisms in patients with sporadic MTC, sporadic Pheo and healthy subjects might be different from that found in RET mutation carriers.	('SDHx', 'Chemical', '-', (62, 66))	('SDHx', 'Gene', (62, 66))	('polymorphisms', 'Var', (67, 80))	('patients', 'Species', '9606', (84, 92))
46477	22584711	In total, 77 patients with germline RET proto-oncogene mutations who were members of 21 unrelated families with MEN2 syndrome were identified by genetic screening at our center.	('MEN2 syndrome', 'Disease', 'MESH:D013577', (112, 125))	('patients', 'Species', '9606', (13, 21))	('MEN2 syndrome', 'Disease', (112, 125))	('mutations', 'Var', (55, 64))
46480	22584711	Total thyroidectomy was performed in all patients with germline RET mutation in the symptomatic group and was also offered to all individuals from the asymptomatic group.	('patients', 'Species', '9606', (41, 49))	('germline', 'Var', (55, 63))	('RET', 'Gene', (64, 67))
46483	22584711	Pre-operative evaluation included medical history, physical examination, thyroid and abdominal ultrasonography, CT or magnetic resonance imaging (MRI), MIBG-scintigraphy, routine biochemical testing, serum calcitonin measurements, and mutation analysis of exons 10-14 of the RET gene.	('men', 'Species', '9606', (224, 227))	('mutation analysis', 'Var', (235, 252))	('RET', 'Gene', (275, 278))	('MIBG', 'Chemical', '-', (152, 156))
46487	22584711	The mutation analysis of RET exons 10-14 and the entire VHL, SDHB, and SDHD genes revealed no disease-causing mutations.	('VHL', 'Gene', (56, 59))	('VHL', 'Gene', '7428', (56, 59))	('SDHD', 'Gene', '6392', (71, 75))	('SDHB', 'Gene', '6390', (61, 65))	('mutation', 'Var', (4, 12))	('SDHD', 'Gene', (71, 75))	('SDHB', 'Gene', (61, 65))
46488	22584711	Patients with confirmed VHL (five patients), SDHB (one patient), or SDHD (one patient) mutations were excluded from the study.	('VHL', 'Gene', '7428', (24, 27))	('patient', 'Species', '9606', (78, 85))	('SDHD', 'Gene', '6392', (68, 72))	('SDHD', 'Gene', (68, 72))	('Patients', 'Species', '9606', (0, 8))	('patient', 'Species', '9606', (34, 41))	('SDHB', 'Gene', '6390', (45, 49))	('patients', 'Species', '9606', (34, 42))	('VHL', 'Gene', (24, 27))	('SDHB', 'Gene', (45, 49))	('patient', 'Species', '9606', (55, 62))	('mutations', 'Var', (87, 96))
46489	22584711	Five patients were initially thought to have sporadic pheochromocytoma, but were later identified as having a disease-causing RET mutation and were included in the study as RET mutation carriers.	('patients', 'Species', '9606', (5, 13))	('sporadic pheochromocytoma', 'Disease', 'MESH:D010673', (45, 70))	('mutation', 'Var', (130, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (54, 70))	('sporadic pheochromocytoma', 'Disease', (45, 70))	('RET', 'Gene', (126, 129))
46491	22584711	Mutation analysis of the VHL, SDHB, and SDHD genes in cases of apparently sporadic Pheo were performed by direct sequencing of the entire coding region of the VHL, SDHB, and SDHD genes, as previously reported,, and large deletion analysis of the VHL, SDHB, SDHC, and SDHD genes performed using multiplex ligation probe amplification.	('SDHD', 'Gene', '6392', (40, 44))	('VHL', 'Gene', '7428', (246, 249))	('SDHB', 'Gene', '6390', (251, 255))	('deletion', 'Var', (221, 229))	('SDHC', 'Gene', (257, 261))	('SDHD', 'Gene', (40, 44))	('SDHB', 'Gene', '6390', (30, 34))	('SDHB', 'Gene', '6390', (164, 168))	('SDHD', 'Gene', '6392', (174, 178))	('SDHB', 'Gene', (251, 255))	('SDHD', 'Gene', '6392', (267, 271))	('VHL', 'Gene', (25, 28))	('SDHB', 'Gene', (30, 34))	('SDHD', 'Gene', (174, 178))	('VHL', 'Gene', (159, 162))	('SDHB', 'Gene', (164, 168))	('VHL', 'Gene', (246, 249))	('SDHC', 'Gene', '6391', (257, 261))	('SDHD', 'Gene', (267, 271))	('VHL', 'Gene', '7428', (25, 28))	('VHL', 'Gene', '7428', (159, 162))
46492	22584711	The nucleotide change of G to A, which corresponds to the G12S polymorphism, results in the preservation of the BanI restriction cleavage site.	('BanI restriction cleavage site', 'MPA', (112, 142))	('G12S', 'Var', (58, 62))	('nucleotide change', 'Var', (4, 21))	('G to A', 'Gene', (25, 31))	('G12S', 'Mutation', 'rs34677591', (58, 62))
46493	22584711	Therefore, digestion with the BanI restriction enzyme (New England BioLabs Inc., Ipswich, MA, USA) for 90 min at 37 C was performed after polymerase chain reaction (PCR) amplification of exon 1 of the SDHD gene for genotyping of RET mutation carriers, sporadic MTC patients, and 100 controls (Figure 1).	('SDHD', 'Gene', (201, 205))	('SDHD', 'Gene', '6392', (201, 205))	('RET', 'Disease', (229, 232))	('mutation', 'Var', (233, 241))	('patients', 'Species', '9606', (265, 273))
46495	22584711	Eight of the 55 patients with MEN2A (15.5%) had the G12S variant, whereas it was absent in the MEN2B and FMTC groups.	('MEN2A', 'Gene', '5979', (30, 35))	('MEN2B', 'Gene', '5979', (95, 100))	('G12S', 'Mutation', 'rs34677591', (52, 56))	('patients', 'Species', '9606', (16, 24))	('G12S', 'Var', (52, 56))	('MEN2A', 'Gene', (30, 35))	('MEN2B', 'Gene', (95, 100))
46497	22584711	No association between the G12S polymorphism of the SDHD gene and the incidence of Pheo or hyperparathyroidism in RET mutation carriers was observed, and the age of disease manifestation was similar in G12S carriers and in non-carriers (43+-9 versus 40+-3 years in probands and 29.6+-19.3 versus 32.5+-20.5 years in non-carriers).	('G12S', 'Mutation', 'rs34677591', (27, 31))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (91, 110))	('SDHD', 'Gene', '6392', (52, 56))	('G12S', 'Var', (202, 206))	('G12S', 'Var', (27, 31))	('hyperparathyroidism', 'Disease', (91, 110))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (91, 110))	('G12S', 'Mutation', 'rs34677591', (202, 206))	('Pheo', 'Disease', (83, 87))	('SDHD', 'Gene', (52, 56))
46498	22584711	Among probands with RET mutations, carriers of the G12S had higher serum calcitonin levels compared with those who did not carry the SDHD G12S variant (6,864+-11,111 versus 1,250+-932 pg/ml), but the difference was not significant.	('G12S', 'Mutation', 'rs34677591', (138, 142))	('higher', 'PosReg', (60, 66))	('G12S', 'Var', (51, 55))	('SDHD', 'Gene', '6392', (133, 137))	('higher serum calcitonin levels', 'Phenotype', 'HP:0003528', (60, 90))	('SDHD', 'Gene', (133, 137))	('mutations', 'Var', (24, 33))	('serum calcitonin levels', 'MPA', (67, 90))	('G12S', 'Mutation', 'rs34677591', (51, 55))
46499	22584711	Among family members with RET mutations, serum calcitonin levels were similar in G12S carriers and non-carriers 436+-876 versus 393+-556 pg/ml) (Table 2).	('G12S', 'Mutation', 'rs34677591', (81, 85))	('G12S', 'Var', (81, 85))	('mutations', 'Var', (30, 39))	('serum calcitonin levels', 'MPA', (41, 64))
46501	22584711	showed that two RET variants (G691S and S904S) may modify the age of onset of MTC in family members; and Tamanaha et al.	('modify', 'Reg', (51, 57))	('G691S', 'Mutation', 'rs1799939', (30, 35))	('G691S', 'Var', (30, 35))	('S904S', 'Var', (40, 45))	('S904S', 'Mutation', 'rs1800863', (40, 45))
46502	22584711	reported that two intronic polymorphisms of RET may modify the phenotype in a large family with G533C RET mutation, while Baumgartner-Parzer found that the L769L and the IVS14-24 may act as modifiers in some forms of hereditary and sporadic MTC.	('L769L', 'Mutation', 'rs1800861', (156, 161))	('RET', 'Gene', (102, 105))	('L769L', 'Var', (156, 161))	('G533C', 'Var', (96, 101))	('mutation', 'Var', (106, 114))	('G533C', 'Mutation', 'rs75873440', (96, 101))	('modify', 'Reg', (52, 58))	('phenotype', 'MPA', (63, 72))
46504	22584711	This latter study showed that of the several polymorphisms of genes encoding the RET protein, its co-receptors and ligands, only the synonymous polymorphism A432A of the RET gene associated weakly with tumor spectra in patients with MEN2A.	('RET', 'Gene', (170, 173))	('A432A', 'Var', (157, 162))	('tumor', 'Disease', (202, 207))	('MEN2A', 'Gene', (233, 238))	('MEN2A', 'Gene', '5979', (233, 238))	('weakly', 'NegReg', (190, 196))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
46505	22584711	MEN2-related MTC RET variants have been analyzed as genetic susceptibility factors for the development of sporadic MTC: polymorphisms located in coding regions of RET, G691S, L769L, S836S, and S904S have been shown to be over-represented in patients with sporadic MTC - compared with the general population, but others were unable to confirm these associations,.	('S836S', 'Mutation', 'rs1800862', (182, 187))	('over-represented', 'PosReg', (221, 237))	('G691S', 'Mutation', 'rs1799939', (168, 173))	('polymorphisms', 'Var', (120, 133))	('L769L', 'Var', (175, 180))	('MEN', 'Species', '9606', (0, 3))	('patients', 'Species', '9606', (241, 249))	('L769L', 'Mutation', 'rs1800861', (175, 180))	('S904S', 'Var', (193, 198))	('men', 'Species', '9606', (98, 101))	('G691S', 'Var', (168, 173))	('S904S', 'Mutation', 'rs1800863', (193, 198))	('S836S', 'Var', (182, 187))
46506	22584711	Germline mutations of SDHx genes encoding subunits of the mitochondrial complex II represent a genetic susceptibility for Pheo/PGL.	('Germline mutations', 'Var', (0, 18))	('SDHx', 'Gene', (22, 26))	('SDHx', 'Chemical', '-', (22, 26))	('susceptibility', 'Reg', (103, 117))	('Pheo/PGL', 'Disease', (122, 130))
46508	22584711	reported a family with C-cell hyperplasia, a pre-cancerous state of MTC, who were proved to have the H50R variant of the SDHD gene.	('SDHD', 'Gene', (121, 125))	('H50R', 'Var', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('C-cell hyperplasia', 'Disease', (23, 41))	('H50R', 'Mutation', 'rs11214077', (101, 105))	('SDHD', 'Gene', '6392', (121, 125))	('C-cell hyperplasia', 'Disease', 'MESH:C537418', (23, 41))
46509	22584711	demonstrated an increased frequency of amino acid-coding SDHx polymorphisms in patients with sporadic and familial MTC.	('SDHx', 'Chemical', '-', (57, 61))	('SDHx', 'Gene', (57, 61))	('polymorphisms', 'Var', (62, 75))	('patients', 'Species', '9606', (79, 87))	('sporadic', 'Disease', (93, 101))	('familial MTC', 'Disease', (106, 118))
46510	22584711	In addition, a systemic evaluation of genetic variants of the SDHx genes among patients with sporadic MTC showed a significant association between the H50R variant and sporadic MTC in Spanish patients, although this observation was absent in an English cohort.	('sporadic MTC', 'Disease', (168, 180))	('variant', 'Var', (156, 163))	('H50R', 'Mutation', 'rs11214077', (151, 155))	('patients', 'Species', '9606', (192, 200))	('variants', 'Var', (46, 54))	('SDHx', 'Gene', (62, 66))	('H50R', 'Gene', (151, 155))	('patients', 'Species', '9606', (79, 87))	('SDHx', 'Chemical', '-', (62, 66))
46511	22584711	Variants of the SDHx genes have been implicated in the pathogenesis of various endocrine and non-endocrine tumors, such as Merkel cell carcinoma, carcinoid, papillary thyroid cancer, and renal cell cancer found in patients with Cowden-like syndrome.	('Variants', 'Var', (0, 8))	('patients', 'Species', '9606', (214, 222))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (157, 181))	('SDHx', 'Chemical', '-', (16, 20))	('Cowden-like syndrome', 'Disease', 'MESH:C567337', (228, 248))	('carcinoid', 'Phenotype', 'HP:0100570', (146, 155))	('carcinoid', 'Disease', (146, 155))	('Merkel cell carcinoma', 'Disease', (123, 144))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('endocrine', 'Disease', (79, 88))	('non-endocrine tumors', 'Disease', (93, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('papillary thyroid cancer', 'Disease', (157, 181))	('Cowden-like syndrome', 'Disease', (228, 248))	('SDHx', 'Gene', (16, 20))	('implicated', 'Reg', (37, 47))	('renal cell cancer', 'Disease', 'MESH:C538614', (187, 204))	('renal cell cancer', 'Disease', (187, 204))	('thyroid cancer', 'Phenotype', 'HP:0002890', (167, 181))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (123, 144))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (157, 181))	('carcinoid', 'Disease', 'MESH:D002276', (146, 155))	('renal cell cancer', 'Phenotype', 'HP:0005584', (187, 204))	('non-endocrine tumors', 'Disease', 'MESH:C536126', (93, 113))
46512	22584711	In the present study, we found that the G12S variant was significantly over-represented among RET mutation carriers compared with sporadic MTC, sporadic Pheo, or control individuals.	('over-represented', 'PosReg', (71, 87))	('RET', 'Gene', (94, 97))	('G12S', 'Mutation', 'rs34677591', (40, 44))	('G12S', 'Var', (40, 44))
46514	22584711	detected G12S in a patient with MEN2B harboring the M918T mutation of the RET gene.	('patient', 'Species', '9606', (19, 26))	('RET', 'Gene', (74, 77))	('M918T', 'Var', (52, 57))	('G12S', 'Mutation', 'rs34677591', (9, 13))	('G12S', 'Var', (9, 13))	('MEN2B', 'Gene', (32, 37))	('M918T', 'Mutation', 'rs74799832', (52, 57))	('MEN2B', 'Gene', '5979', (32, 37))
46515	22584711	Interestingly, the prevalence of alterations of the SDHx genes in patients with RET mutations was similar in our study and the study of Montani et al..	('mutations', 'Var', (84, 93))	('SDHx genes', 'Gene', (52, 62))	('patients', 'Species', '9606', (66, 74))	('SDHx', 'Chemical', '-', (52, 56))
46520	22584711	More importantly, in our study, the high incidence of the G12S variant among RET carriers, especially in those with the MEN2A phenotype, raised the possibility that this variant may have a role in the phenotypic modulation of the disease.	('MEN2A', 'Gene', (120, 125))	('MEN2A', 'Gene', '5979', (120, 125))	('G12S', 'Var', (58, 62))	('role', 'Reg', (189, 193))	('G12S', 'Mutation', 'rs34677591', (58, 62))
46523	22584711	reported an increased prevalence of intronic SDHB polymorphisms among patients with malignant Pheo compared with patients with benign tumors.	('patients', 'Species', '9606', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('benign tumors', 'Disease', (127, 140))	('patients', 'Species', '9606', (113, 121))	('polymorphisms', 'Var', (50, 63))	('malignant Pheo', 'Disease', (84, 98))	('SDHB', 'Gene', '6390', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('SDHB', 'Gene', (45, 49))	('benign tumors', 'Disease', 'MESH:D009369', (127, 140))	('intronic', 'Protein', (36, 44))
46524	22584711	In conclusion, we found a significantly higher prevalence of the G12S variant of the SDHD gene among germline RET mutation carriers presenting with MEN2A compared with the control group.	('higher', 'PosReg', (40, 46))	('MEN2A', 'Gene', (148, 153))	('MEN2A', 'Gene', '5979', (148, 153))	('SDHD', 'Gene', '6392', (85, 89))	('G12S', 'Var', (65, 69))	('SDHD', 'Gene', (85, 89))	('G12S', 'Mutation', 'rs34677591', (65, 69))
46527	32117073	Catecholamine excess can lead to a kind of cardiomyopathy similar to that seen in tako-tsubo syndrome (TTS).	('cardiomyopathy', 'Disease', (43, 57))	('Catecholamine', 'Chemical', 'MESH:D002395', (0, 13))	('Catecholamine excess', 'Phenotype', 'HP:0003334', (0, 20))	('tako-tsubo syndrome', 'Disease', (82, 101))	('Catecholamine', 'Var', (0, 13))	('cardiomyopathy', 'Disease', 'MESH:D009202', (43, 57))	('lead to', 'Reg', (25, 32))	('tsubo syndrome', 'Phenotype', 'HP:0030824', (87, 101))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (43, 57))	('TTS', 'Disease', 'MESH:D054549', (103, 106))	('TTS', 'Disease', (103, 106))	('tako-tsubo syndrome', 'Disease', 'MESH:D054549', (82, 101))
46552	32117073	The initial laboratory work-up showed: CK-MB 58.13 mug/L (normal <2.88), high-sensitivity Troponin I 1754 ng/L (normal <14), BNP 2623 pg/mL (normal <100), corroborating the diagnosis of acute myocardial infarction.	('acute myocardial infarction', 'Disease', 'MESH:D009203', (186, 213))	('high-sensitivity Troponin I', 'MPA', (73, 100))	('BNP', 'Gene', (125, 128))	('CK-MB', 'Var', (39, 44))	('myocardial infarction', 'Phenotype', 'HP:0001658', (192, 213))	('acute myocardial infarction', 'Disease', (186, 213))	('BNP', 'Gene', '4879', (125, 128))
46559	32117073	A 24 h urine collection was performed and revealed high metanephrine (3795 mug/24 h, normal <350) and normetanephrine (2172 mug/24 h, normal <600) levels.	('normetanephrine', 'MPA', (102, 117))	('metanephrine', 'MPA', (56, 68))	('metanephrine', 'Chemical', 'MESH:D008676', (56, 68))	('normetanephrine', 'Chemical', 'MESH:D009647', (102, 117))	('2172', 'Var', (119, 123))	('metanephrine', 'Chemical', 'MESH:D008676', (105, 117))
46587	32117073	The most common germline mutations associated with familial pheochromocytoma are: REarranged during Transfection (RET) proto-oncogene, von Hippel-Lindau gene (VHL), neurofibromatosis type 1 gene (NF1), genes encoding four succinate dehydrogenase complex subunits (SDHx; i.e., SDHA, SDHB, SDHC, and SDHD genes), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), transmembrane protein 127 gene (TMEM 127), and myc-associated factor (MAX).	('SDHC', 'Gene', '6391', (288, 292))	('transmembrane protein 127 gene', 'Gene', (376, 406))	('SDHA', 'Gene', '6389', (367, 371))	('neurofibromatosis type 1', 'Gene', (165, 189))	('succinate dehydrogenase complex assembly factor 2', 'Gene', (311, 360))	('RET', 'Gene', (114, 117))	('NF1', 'Gene', '4763', (196, 199))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (165, 182))	('familial pheochromocytoma', 'Disease', (51, 76))	('SDHAF2', 'Gene', '54949', (367, 373))	('SDHAF2', 'Gene', (367, 373))	('mutations', 'Var', (25, 34))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('NF1', 'Gene', (196, 199))	('SDHA', 'Gene', (276, 280))	('SDHC', 'Gene', (288, 292))	('SDHB', 'Gene', '6390', (282, 286))	('VHL', 'Gene', '7428', (159, 162))	('neurofibromatosis type 1', 'Gene', '4763', (165, 189))	('SDHA', 'Gene', '6389', (276, 280))	('von Hippel-Lindau', 'Disease', (135, 152))	('REarranged during Transfection', 'Gene', '5979', (82, 112))	('SDHD', 'Gene', '6392', (298, 302))	('VHL', 'Gene', (159, 162))	('TMEM 127', 'Gene', '55654', (408, 416))	('REarranged during Transfection', 'Gene', (82, 112))	('SDHB', 'Gene', (282, 286))	('RET', 'Gene', '5979', (114, 117))	('transmembrane protein 127 gene', 'Gene', '55654', (376, 406))	('succinate dehydrogenase complex assembly factor 2', 'Gene', '54949', (311, 360))	('associated', 'Reg', (35, 45))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (51, 76))	('SDHD', 'Gene', (298, 302))	('TMEM 127', 'Gene', (408, 416))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (135, 152))	('SDHA', 'Gene', (367, 371))
46588	32117073	Furthermore, cases of biochemically silent abdominal pheochromocytomas/PPGLs in individuals harboring the SDHB gene mutations have been reported.	('abdominal pheochromocytomas', 'Disease', (43, 70))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (53, 70))	('abdominal pheochromocytomas', 'Disease', 'MESH:D010673', (43, 70))	('SDHB', 'Gene', '6390', (106, 110))	('mutations', 'Var', (116, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('SDHB', 'Gene', (106, 110))
46620	32090084	In recent years, genetic changes in PCPG have received increasing attention, and mutations or loss of genes encoding succinate dehydrogenase (SDH) are clinically important genetic changes, which are associated with the increased metastatic rate of human PCPG.	('associated', 'Reg', (199, 209))	('SDH', 'Gene', '6390', (142, 145))	('human', 'Species', '9606', (248, 253))	('succinate dehydrogenase', 'Gene', '6390', (117, 140))	('loss', 'NegReg', (94, 98))	('succinate dehydrogenase', 'Gene', (117, 140))	('metastatic rate', 'CPA', (229, 244))	('SDH', 'Gene', (142, 145))	('mutations', 'Var', (81, 90))
46621	32090084	It has been proved that the pathogenesis of nonfamilial PCPG involves SDHB mutation-associated PCPG pro-cadherin gamma-C3 (PCDHGC3) gene promoter methylation as well as EPAS1 mutations encoding HIF2alpha.	('EPAS1', 'Gene', (169, 174))	('SDHB', 'Gene', '6390', (70, 74))	('nonfamilial PCPG', 'Disease', (44, 60))	('SDHB', 'Gene', (70, 74))	('mutation-associated', 'Reg', (75, 94))	('HIF2alpha', 'Gene', (194, 203))	('mutations', 'Var', (175, 184))	('PCDHGC3', 'Gene', (123, 130))	('EPAS1', 'Gene', '2034', (169, 174))	('PCDHGC3', 'Gene', '5098', (123, 130))	('HIF2alpha', 'Gene', '2034', (194, 203))
46625	32090084	As depicted in Figure 5, the survival analysis of these hub genes by using Starbase database revealed that PCPG patients with a high expression of BUB1, BUB1B, TTK, CENPA, or NDC80 had shorter survival time and higher risk of death (P < 0.05 and hazard ratio >1).	('NDC80', 'Gene', (175, 180))	('shorter', 'NegReg', (185, 192))	('death', 'Disease', 'MESH:D003643', (226, 231))	('death', 'Disease', (226, 231))	('TTK', 'Gene', (160, 163))	('BUB1B', 'Gene', (153, 158))	('high', 'Var', (128, 132))	('CENPA', 'Gene', (165, 170))	('survival time', 'CPA', (193, 206))	('BUB1', 'Gene', (147, 151))
46627	32090084	We further showed that the patients with a high expression of genes in the salmon module had an earlier onset age, and the eigengene of the salmon module was highly correlated with the metastasis as well as malignancy of tumors.	('high', 'Var', (43, 47))	('malignancy of tumors', 'Disease', 'MESH:D009369', (207, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('malignancy of tumors', 'Disease', (207, 227))	('metastasis', 'CPA', (185, 195))	('correlated', 'Reg', (165, 175))
46693	30352425	In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%).	('detected', 'Reg', (58, 66))	('iPPGL', 'Chemical', '-', (12, 17))	('mutations', 'Var', (19, 28))	('iPPGL', 'Disease', (12, 17))	('fPPGL', 'Chemical', '-', (116, 121))
46696	30352425	Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.	('Pheochromocytoma/paraganglioma', 'Disease', (0, 30))	('paraganglioma', 'Phenotype', 'HP:0002668', (17, 30))	('germline mutations', 'Var', (113, 131))	('Pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (0, 30))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))
46708	30352425	To date, at least 16 genes have been identified to be responsible for hereditary PPGLs and exome sequencing approaches have defined the occurrence of somatic mutations in candidate genes that partly overlap with those found as germline variants.	('PPGLs', 'Chemical', '-', (81, 86))	('mutations', 'Var', (158, 167))	('PPGLs', 'Disease', (81, 86))
46742	30352425	Tumor volume (median, range) in iPPGL patients was 35.9 mL (0.9-904.3 mL), which was significantly larger in comparison to the fPPGL group (12.1 mL, 0.3-296.7 mL; P = 0.003, Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('iPPGL', 'Var', (32, 37))	('fPPGL', 'Chemical', '-', (127, 132))	('iPPGL', 'Chemical', '-', (32, 37))	('larger', 'PosReg', (99, 105))	('patients', 'Species', '9606', (38, 46))
46750	30352425	All five of the NF1 patients had syndromic clinical features and one of the patients with SDHB mutation had a history of clear cell renal carcinoma so first suspicion had been a VHL mutation.	('NF1', 'Gene', (16, 19))	('patients', 'Species', '9606', (76, 84))	('SDHB', 'Gene', '6390', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('SDHB', 'Gene', (90, 94))	('NF1', 'Gene', '4763', (16, 19))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (121, 147))	('renal carcinoma', 'Phenotype', 'HP:0005584', (132, 147))	('syndromic', 'Disease', (33, 42))	('clear cell renal carcinoma', 'Disease', (121, 147))	('VHL', 'Gene', (178, 181))	('patients', 'Species', '9606', (20, 28))	('syndromic', 'Disease', 'MESH:D013577', (33, 42))	('VHL', 'Gene', '7428', (178, 181))	('mutation', 'Var', (95, 103))
46782	30352425	Specifically, patients with NF1 mutations were recommended until very recently, to undergo screening for PPGLs only when additional symptoms raised the suspicion of catecholamine excess.	('NF1', 'Gene', '4763', (28, 31))	('catecholamine', 'Chemical', 'MESH:D002395', (165, 178))	('PPGLs', 'Chemical', '-', (105, 110))	('catecholamine excess', 'MPA', (165, 185))	('PPGLs', 'Gene', (105, 110))	('catecholamine excess', 'Phenotype', 'HP:0003334', (165, 185))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (14, 22))	('NF1', 'Gene', (28, 31))
46786	30352425	Within the surveillance group, the prevalence of malignancy was the highest, which likely reflects the large proportion of patients with SDHB mutations.	('mutations', 'Var', (142, 151))	('malignancy', 'Disease', 'MESH:D009369', (49, 59))	('malignancy', 'Disease', (49, 59))	('patients', 'Species', '9606', (123, 131))	('SDHB', 'Gene', '6390', (137, 141))	('SDHB', 'Gene', (137, 141))
46800	29779047	PASS and GAPP were applied on 41 PCCs; 13 PCCs were diagnosed in ten multiple endocrine neoplasia type 2A (MEN 2A) patients carrying established germline RET proto-oncogene mutations, as well as 28 assumed sporadic PCCs.	('RET', 'Gene', (154, 157))	('multiple endocrine neoplasia type 2A', 'Gene', (69, 105))	('multiple endocrine neoplasia type 2A', 'Gene', '5979', (69, 105))	('MEN 2A', 'Gene', (107, 113))	('PCCs', 'Phenotype', 'HP:0002666', (42, 46))	('PCCs', 'Phenotype', 'HP:0002666', (33, 37))	('GAPP', 'Chemical', '-', (9, 13))	('PCCs', 'Phenotype', 'HP:0002666', (215, 219))	('PCC', 'Gene', (42, 45))	('neoplasia', 'Phenotype', 'HP:0002664', (88, 97))	('PCC', 'Gene', (215, 218))	('patients', 'Species', '9606', (115, 123))	('PCC', 'Gene', (33, 36))	('PCC', 'Gene', '1421', (42, 45))	('PCC', 'Gene', '1421', (215, 218))	('mutations', 'Var', (173, 182))	('PCC', 'Gene', '1421', (33, 36))	('RET', 'Gene', '5979', (154, 157))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (78, 97))	('MEN 2A', 'Gene', '5979', (107, 113))
46802	29779047	In addition, 7/13 tumors (54%) exhibited GAPP scores >= 3, indicative of a "moderately differentiated type" with risk of future recurrence.	('GAPP', 'Chemical', '-', (41, 45))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('GAPP scores', 'Var', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
46816	29779047	We therefore sought to determine the PASS and GAPP score ranges and the follow-up for PCCs with established constitutional RET mutations at our institution, to investigate whether these classification systems can predict patients at risk for malignancy in MEN 2A patients.	('MEN 2A', 'Gene', (256, 262))	('patients', 'Species', '9606', (221, 229))	('MEN 2A', 'Gene', '5979', (256, 262))	('patients', 'Species', '9606', (263, 271))	('RET', 'Gene', (123, 126))	('malignancy', 'Disease', 'MESH:D009369', (242, 252))	('PCC', 'Gene', (86, 89))	('RET', 'Gene', '5979', (123, 126))	('PCCs', 'Phenotype', 'HP:0002666', (86, 90))	('mutations', 'Var', (127, 136))	('GAPP', 'Chemical', '-', (46, 50))	('malignancy', 'Disease', (242, 252))	('PCC', 'Gene', '1421', (86, 89))
46817	29779047	We screened our clinical databases and identified 10 patients with 13 resected PCCs during the period 1987-2017, all patients harboring RET constitutional mutations (c.1900T>C in two, c.1858T>C in one, and c.1900T>G in the remaining seven patients) (Table 1).	('RET', 'Gene', '5979', (136, 139))	('PCC', 'Gene', '1421', (79, 82))	('c.1858T>C', 'Var', (184, 193))	('patients', 'Species', '9606', (53, 61))	('c.1900T>G', 'Mutation', 'rs75076352', (206, 215))	('patients', 'Species', '9606', (239, 247))	('c.1900T>C', 'Var', (166, 175))	('c.1900T>G', 'Var', (206, 215))	('RET', 'Gene', (136, 139))	('PCC', 'Gene', (79, 82))	('PCCs', 'Phenotype', 'HP:0002666', (79, 83))	('c.1900T>C', 'Mutation', 'rs75076352', (166, 175))	('patients', 'Species', '9606', (117, 125))	('c.1858T>C', 'Mutation', 'rs77316810', (184, 193))
46836	29779047	Using the GAPP algorithm, seven out of 13 (54%) MEN 2A PCCs displayed GAPP scores >= 3, thereby establishing them as "moderately differentiated" with a significant risk of future relapse or metastatic disease (Table 1, Fig.	('PCC', 'Gene', '1421', (55, 58))	('GAPP', 'Chemical', '-', (10, 14))	('MEN 2A', 'Gene', '5979', (48, 54))	('MEN 2A', 'Gene', (48, 54))	('PCC', 'Gene', (55, 58))	('PCCs', 'Phenotype', 'HP:0002666', (55, 59))	('GAPP', 'Chemical', '-', (70, 74))	('metastatic disease', 'CPA', (190, 208))	('GAPP scores', 'Var', (70, 81))
46858	29779047	Since MEN 2A PCCs harbor RET proto-oncogene mutations and express a specific hypoxia gene expression signature, this common genetic profile might in theory result in distinct histological patterns for subsets of cases.	('result', 'Reg', (156, 162))	('RET', 'Gene', '5979', (25, 28))	('hypoxia', 'Disease', (77, 84))	('PCCs', 'Phenotype', 'HP:0002666', (13, 17))	('PCC', 'Gene', (13, 16))	('RET', 'Gene', (25, 28))	('mutations', 'Var', (44, 53))	('proto-oncogene', 'Gene', (29, 43))	('MEN 2A', 'Gene', '5979', (6, 12))	('MEN 2A', 'Gene', (6, 12))	('PCC', 'Gene', '1421', (13, 16))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
46860	29779047	The significant association between high PASS scores and MEN 2A PCCs was further substantiated when a similar connotation was seen when applying the GAPP algorithm.	('high PASS scores', 'Var', (36, 52))	('MEN 2A', 'Gene', '5979', (57, 63))	('PCC', 'Gene', (64, 67))	('PCCs', 'Phenotype', 'HP:0002666', (64, 68))	('PCC', 'Gene', '1421', (64, 67))	('GAPP', 'Chemical', '-', (149, 153))	('MEN 2A', 'Gene', (57, 63))
46867	29779047	The majority (9/13) of MEN 2A-related PCCs in our cohort have been previously screened for somatic SDHB mutations, and all nine cases demonstrated wild-type sequences.	('mutations', 'Var', (104, 113))	('PCC', 'Gene', '1421', (38, 41))	('MEN 2A', 'Gene', '5979', (23, 29))	('MEN 2A', 'Gene', (23, 29))	('SDHB', 'Gene', '6390', (99, 103))	('PCC', 'Gene', (38, 41))	('PCCs', 'Phenotype', 'HP:0002666', (38, 42))	('SDHB', 'Gene', (99, 103))
46868	29779047	This would suggest that SDHB mutations are uncommonly found among MEN 2A PCCs and could therefore support the notion that the vast majority of these lesions are indeed benign:although endowed with high PASS and GAPP scores.	('PCC', 'Gene', '1421', (73, 76))	('mutations', 'Var', (29, 38))	('MEN 2A', 'Gene', '5979', (66, 72))	('MEN 2A', 'Gene', (66, 72))	('PCC', 'Gene', (73, 76))	('PCCs', 'Phenotype', 'HP:0002666', (73, 77))	('SDHB', 'Gene', '6390', (24, 28))	('SDHB', 'Gene', (24, 28))	('GAPP', 'Chemical', '-', (211, 215))
46870	29779047	Patients harboring a mutation known to be accountable for development of PCC must be followed up lifelong regarding PCC, with biochemical evaluation at least yearly and adrenal imaging either based on positive biochemistry, or at individualized intervals.	('PCC', 'Gene', '1421', (73, 76))	('PCC', 'Gene', (116, 119))	('mutation', 'Var', (21, 29))	('Patients', 'Species', '9606', (0, 8))	('PCC', 'Gene', (73, 76))	('PCC', 'Gene', '1421', (116, 119))
46917	29423169	Chemotherapy and I131-MIBG have also been used therapeutically in malignant paraganglioma.	('malignant paraganglioma', 'Disease', 'MESH:C565335', (66, 89))	('I131-MIBG', 'Var', (17, 26))	('paraganglioma', 'Phenotype', 'HP:0002668', (76, 89))	('malignant paraganglioma', 'Disease', (66, 89))
47003	28724929	As a result, non-selective alpha blockade can lead to persistent intraoperative hypotension requiring fluid therapy and continuous catecholamine infusion, although it works better to control hypertensive crises.	('lead to', 'Reg', (46, 53))	('intraoperative hypotension', 'Disease', (65, 91))	('hypotension', 'Phenotype', 'HP:0002615', (80, 91))	('intraoperative hypotension', 'Disease', 'MESH:D007022', (65, 91))	('hypertensive crises', 'Phenotype', 'HP:0100735', (191, 210))	('hypertensive', 'Disease', 'MESH:D006973', (191, 203))	('catecholamine', 'Chemical', 'MESH:D002395', (131, 144))	('hypertensive', 'Disease', (191, 203))	('non-selective', 'Var', (13, 26))
47004	28724929	So far, several studies have confirmed the relationship between phenoxybenzamine and perioperative hypotension in patients with pheochromocytoma.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (64, 80))	('pheochromocytoma', 'Disease', 'MESH:D010673', (128, 144))	('hypotension', 'Disease', 'MESH:D007022', (99, 110))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (128, 144))	('phenoxybenzamine', 'Var', (64, 80))	('hypotension', 'Disease', (99, 110))	('patients', 'Species', '9606', (114, 122))	('hypotension', 'Phenotype', 'HP:0002615', (99, 110))	('pheochromocytoma', 'Disease', (128, 144))
47052	28476870	Measurements of plasma methoxytyramine have been introduced for identifying patients with metastatic PPGLs, HNPGLs and tumors due to mutations of genes encoding succinate dehydrogenase subunits.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (76, 84))	('metastatic PPGLs', 'Disease', (90, 106))	('HNPGLs', 'Phenotype', 'HP:0002864', (108, 114))	('HNPGL', 'Phenotype', 'HP:0002864', (108, 113))	('mutations', 'Var', (133, 142))	('HNPGLs and tumors', 'Disease', 'MESH:D009369', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('men', 'Species', '9606', (7, 10))	('methoxytyramine', 'Chemical', 'MESH:C001746', (23, 38))	('PPGLs', 'Chemical', '-', (101, 106))
47092	28476870	Plasma concentrations of methoxytyramine and metanephrine were respectively increased above UCs in 45.5% and 53.5% of patients with PPGLs and 31.6% and none of the patients with HNPGLs, compared to 1.1% and 0.4% of patients without tumors (Fig.	('patients', 'Species', '9606', (215, 223))	('PPGLs', 'Var', (132, 137))	('Plasma concentrations of methoxytyramine', 'MPA', (0, 40))	('metanephrine', 'MPA', (45, 57))	('increased', 'PosReg', (76, 85))	('methoxytyramine', 'Chemical', 'MESH:C001746', (25, 40))	('metanephrine', 'Chemical', 'MESH:D008676', (45, 57))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('HNPGLs', 'Phenotype', 'HP:0002864', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('HNPGLs', 'Chemical', '-', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (118, 126))	('PPGLs', 'Chemical', '-', (132, 137))	('tumors', 'Disease', (232, 238))	('HNPGL', 'Phenotype', 'HP:0002864', (178, 183))
47095	28476870	With the addition of methoxytyramine, diagnostic specificity decreased to 95.1%, while sensitivity increased to 98.6% for the detection of PPGLs and to 50.0% for the detection of HNPGLs.	('PPGLs', 'Chemical', '-', (139, 144))	('methoxytyramine', 'Chemical', 'MESH:C001746', (21, 36))	('HNPGL', 'Phenotype', 'HP:0002864', (179, 184))	('diagnostic specificity', 'MPA', (38, 60))	('methoxytyramine', 'Var', (21, 36))	('PPGLs', 'Disease', (139, 144))	('HNPGLs', 'Phenotype', 'HP:0002864', (179, 185))	('decreased', 'NegReg', (61, 70))	('HNPGLs', 'Chemical', '-', (179, 185))
47097	28476870	All the three patients with PPGLs and solitary increases in plasma methoxytyramine had mutations of the gene for succinate dehydrogenase subunit D and all presented with extra-adrenal paragangliomas, including one patient who also had a HNPGL.	('HNPGL', 'Phenotype', 'HP:0002864', (237, 242))	('PPGLs', 'Disease', (28, 33))	('patient', 'Species', '9606', (214, 221))	('HNPGL', 'Chemical', '-', (237, 242))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (170, 198))	('presented with', 'Reg', (155, 169))	('patient', 'Species', '9606', (14, 21))	('paragangliomas', 'Phenotype', 'HP:0002668', (184, 198))	('paraganglioma', 'Phenotype', 'HP:0002668', (184, 197))	('methoxytyramine', 'Chemical', 'MESH:C001746', (67, 82))	('plasma methoxytyramine', 'MPA', (60, 82))	('PPGLs', 'Chemical', '-', (28, 33))	('increases', 'PosReg', (47, 56))	('extra-adrenal paragangliomas', 'Disease', (170, 198))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (87, 96))
47102	28476870	One patient with an SDHB mutation had an 11.3 x 7.6 x 9.3 cm pelvic paraganglioma with extensive metastases that remained biochemically negative on repeated testing.	('metastases', 'Disease', (97, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (68, 81))	('mutation', 'Var', (25, 33))	('patient', 'Species', '9606', (4, 11))	('paraganglioma', 'Disease', (68, 81))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('SDHB', 'Gene', '6390', (20, 24))	('paraganglioma', 'Disease', 'MESH:D010235', (68, 81))	('SDHB', 'Gene', (20, 24))
47110	28476870	Among the patients with PPGLs, 45.5% had increases of both normetanephrine and methoxytyramine above UCs and 49.3% had increases of both normetanephrine and metanephrine above UCs compared to less than 0.3% of patients without tumors (Fig.	('methoxytyramine', 'MPA', (79, 94))	('normetanephrine', 'Chemical', 'MESH:D009647', (59, 74))	('metanephrine', 'MPA', (157, 169))	('PPGLs', 'Var', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('normetanephrine', 'Chemical', 'MESH:D009647', (137, 152))	('PPGLs', 'Chemical', '-', (24, 29))	('patients', 'Species', '9606', (210, 218))	('metanephrine', 'Chemical', 'MESH:D008676', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('metanephrine', 'Chemical', 'MESH:D008676', (62, 74))	('increases', 'PosReg', (41, 50))	('tumors', 'Disease', (227, 233))	('normetanephrine', 'MPA', (59, 74))	('patients', 'Species', '9606', (10, 18))	('metanephrine', 'Chemical', 'MESH:D008676', (140, 152))	('increases', 'PosReg', (119, 128))	('methoxytyramine', 'Chemical', 'MESH:C001746', (79, 94))	('tumors', 'Disease', 'MESH:D009369', (227, 233))
47117	28476870	Of the patients with PPGLs, 185 (86.9%) had increases of one or more of the metabolites in the triplet panel of more than 2-fold above UCs compared with only 3 patients without tumors (Fig.	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (160, 168))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('PPGLs', 'Var', (21, 26))	('metabolites in', 'MPA', (76, 90))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('PPGLs', 'Chemical', '-', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('increases', 'PosReg', (44, 53))
47121	28476870	More importantly, we show that the addition of methoxytyramine to the standard test panel improves diagnostic utility by increasing the proportion of patients with highly positive predictive test results who may benefit by a decision to immediately locate and manage the tumors rather than be subject to further follow-up biochemical testing to confirm or exclude disease.	('methoxytyramine', 'Chemical', 'MESH:C001746', (47, 62))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('methoxytyramine', 'Var', (47, 62))	('tumors', 'Disease', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('diagnostic utility', 'MPA', (99, 117))	('patients', 'Species', '9606', (150, 158))	('increasing', 'PosReg', (121, 131))	('improves', 'PosReg', (90, 98))
47122	28476870	Our study also extends previous observations that measurements of methoxytyramine can be useful for identifying dopamine-producing HNPGLs, by significantly increasing test performance beyond that of the standard test panel.	('test performance', 'MPA', (167, 183))	('HNPGLs', 'Chemical', '-', (131, 137))	('HNPGLs', 'Disease', (131, 137))	('HNPGLs', 'Phenotype', 'HP:0002864', (131, 137))	('methoxytyramine', 'Chemical', 'MESH:C001746', (66, 81))	('HNPGL', 'Phenotype', 'HP:0002864', (131, 136))	('dopamine-producing HNPGLs', 'Disease', (112, 137))	('methoxytyramine', 'Var', (66, 81))	('men', 'Species', '9606', (57, 60))	('dopamine', 'Chemical', 'MESH:D004298', (112, 120))	('increasing', 'PosReg', (156, 166))
47136	28476870	As we now outline here, the addition of methoxytyramine to the test panel increases to over 70% the proportion of patients with highly predictive positive results for multiple metabolites.	('methoxytyramine', 'Var', (40, 55))	('patients', 'Species', '9606', (114, 122))	('methoxytyramine', 'Chemical', 'MESH:C001746', (40, 55))	('increases', 'PosReg', (74, 83))
47139	28476870	Addition of methoxytyramine to standard tests of normetanephrine and metanephrine has already established utility, beyond screening for PPGLs, by pointing to possible metastatic disease or the presence of mutations in genes for succinate dehydrogenase.	('metastatic disease', 'Disease', (167, 185))	('pointing', 'Reg', (146, 154))	('metanephrine', 'Chemical', 'MESH:D008676', (52, 64))	('mutations', 'Var', (205, 214))	('PPGLs', 'Chemical', '-', (136, 141))	('metanephrine', 'Chemical', 'MESH:D008676', (69, 81))	('presence', 'Reg', (193, 201))	('methoxytyramine', 'Chemical', 'MESH:C001746', (12, 27))	('normetanephrine', 'Chemical', 'MESH:D009647', (49, 64))
47340	24642075	Pheochromocytomas tend to occur in specific families and genotype-phenotype correlations have demonstrated that missense mutations in VHL predispose to pheochromocytoma, referred to as type 2 VHL.	('pheochromocytoma', 'Disease', (152, 168))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('missense mutations', 'Var', (112, 130))	('pheochromocytoma', 'Disease', 'MESH:D010673', (152, 168))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (152, 168))	('VHL', 'Gene', (192, 195))	('Pheochromocytomas', 'Disease', (0, 17))	('VHL', 'Gene', (134, 137))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('predispose to', 'Reg', (138, 151))	('VHL', 'Gene', '7428', (134, 137))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('VHL', 'Gene', '7428', (192, 195))
47341	24642075	Type I VHL, often characterized by germline deletions, insertions, and nonsense mutations of the VHL gene, uncommonly is associated with the development of pheochromocytoma.	('pheochromocytoma', 'Disease', (156, 172))	('VHL', 'Gene', '7428', (97, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (156, 172))	('associated with', 'Reg', (121, 136))	('pheochromocytoma', 'Disease', 'MESH:D010673', (156, 172))	('insertions', 'Var', (55, 65))	('nonsense mutations', 'Var', (71, 89))	('Type I VHL', 'Disease', (0, 10))	('VHL', 'Gene', (7, 10))	('Type I VHL', 'Disease', 'MESH:D006623', (0, 10))	('VHL', 'Gene', '7428', (7, 10))	('VHL', 'Gene', (97, 100))
47362	24642075	NF1 is a critical negative regulator of TSC2 and mTOR, and loss of function actives downstream effectors such as S6K.	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('S6K', 'MPA', (113, 116))	('TSC2', 'Gene', '7249', (40, 44))	('TSC2', 'Gene', (40, 44))	('NF1', 'Gene', (0, 3))	('actives', 'Reg', (76, 83))	('NF1', 'Gene', '4763', (0, 3))	('loss', 'Var', (59, 63))
47369	24642075	Over the past decade the genetics of this syndrome have been elucidated with identification of mutations of the genes encoding the succinate dehydrogenase (SDH) subunits.	('SDH', 'Gene', '6390', (156, 159))	('succinate dehydrogenase', 'Gene', (131, 154))	('succinate dehydrogenase', 'Gene', '6390', (131, 154))	('mutations', 'Var', (95, 104))	('SDH', 'Gene', (156, 159))
47372	24642075	Mutations in specific subunits of this enzyme complex are a common cause of the hereditary paraganglioma/pheochromocytoma syndromes.	('cause', 'Reg', (67, 72))	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (105, 121))	('Mutations', 'Var', (0, 9))	('hereditary paraganglioma/pheochromocytoma syndromes', 'Disease', 'MESH:D010673', (80, 131))
47373	24642075	Mutations in the SDHB and SDHD genes have been the most well characterized of the SDH deficiencies.	('SDHB', 'Gene', '6390', (17, 21))	('SDHD', 'Gene', (26, 30))	('SDH deficiencies', 'Disease', (82, 98))	('SDHD', 'Gene', '6392', (26, 30))	('Mutations', 'Var', (0, 9))	('SDH deficiencies', 'Disease', 'MESH:D007153', (82, 98))	('SDHB', 'Gene', (17, 21))
47376	24642075	Subsequently it was found that patients with germline succinate dehydrogenase B/C/D mutations are also at risk for the development of an aggressive form of kidney cancer (SDH-RCC).	('kidney cancer', 'Disease', 'MESH:D007680', (156, 169))	('risk', 'Reg', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (84, 93))	('kidney cancer', 'Phenotype', 'HP:0009726', (156, 169))	('SDH-RCC', 'Disease', (171, 178))	('patients', 'Species', '9606', (31, 39))	('SDH-RCC', 'Disease', 'MESH:C538614', (171, 178))	('kidney cancer', 'Disease', (156, 169))	('succinate dehydrogenase', 'Gene', (54, 77))	('succinate dehydrogenase', 'Gene', '6390', (54, 77))
47377	24642075	The majority of patients with germline SDHD mutations are at risk for the development of multiple chromafin tumors, with the most common site being head and neck paraganglioma (>79%).	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (148, 175))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (16, 24))	('SDHD', 'Gene', (39, 43))	('SDHD', 'Gene', '6392', (39, 43))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('neck paraganglioma', 'Disease', (157, 175))	('neck paraganglioma', 'Disease', 'MESH:D010235', (157, 175))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
47378	24642075	Patients with germline SDHB gene mutations less commonly are found to develop multiple tumors, however they can be distributed in all locations, most commonly in the abdomen.	('develop', 'PosReg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SDHB', 'Gene', '6390', (23, 27))	('mutations', 'Var', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', (23, 27))	('multiple', 'Disease', (78, 86))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
47384	24642075	SDHA gene mutation can be associated with Leigh's disease, a severe, early onset encephalopathy.	("Leigh's disease", 'Disease', (42, 57))	('SDHA', 'Gene', (0, 4))	('mutation', 'Var', (10, 18))	('encephalopathy', 'Disease', 'MESH:D001927', (81, 95))	('SDHA', 'Gene', '6389', (0, 4))	('encephalopathy', 'Phenotype', 'HP:0001298', (81, 95))	("Leigh's disease", 'Disease', 'MESH:D007888', (42, 57))	('associated', 'Reg', (26, 36))	('encephalopathy', 'Disease', (81, 95))
47385	24642075	Recently, several reports have identified SDHA mutations in patients with functional paraganglioma and pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('functional paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (74, 119))	('paraganglioma', 'Phenotype', 'HP:0002668', (85, 98))	('SDHA', 'Gene', (42, 46))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (47, 56))	('SDHA', 'Gene', '6389', (42, 46))
47391	24642075	A PHD2 mutation has been recently reported in a patient with recurrent abdominal paraganglioma and polycythemia.	('polycythemia', 'Disease', (99, 111))	('reported', 'Reg', (34, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (81, 94))	('PHD2', 'Gene', '54583', (2, 6))	('polycythemia', 'Phenotype', 'HP:0001901', (99, 111))	('polycythemia', 'Disease', 'MESH:D011086', (99, 111))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (71, 94))	('PHD2', 'Gene', (2, 6))	('patient', 'Species', '9606', (48, 55))	('mutation', 'Var', (7, 15))	('abdominal paraganglioma', 'Disease', (71, 94))
47393	24642075	Germline mutation in KIF1Bbeta has been described in a large family with neural crest tumors and non-neural tumors including several bilateral pheochromocytomas.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (133, 160))	('non-neural tumors', 'Disease', 'MESH:C536408', (97, 114))	('neural crest tumors', 'Disease', (73, 92))	('non-neural tumors', 'Disease', (97, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('neural crest tumors', 'Disease', 'MESH:C536408', (73, 92))	('KIF1Bbeta', 'Gene', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (143, 160))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('bilateral pheochromocytomas', 'Disease', (133, 160))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('described', 'Reg', (40, 49))	('Germline mutation', 'Var', (0, 17))
47396	24642075	Whole genome sequencing identified germline mutations in MAX to be responsible for several familial cases of pheochromocytoma.	('MAX', 'Gene', (57, 60))	('responsible', 'Reg', (67, 78))	('pheochromocytoma', 'Disease', (109, 125))	('pheochromocytoma', 'Disease', 'MESH:D010673', (109, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (109, 125))	('germline mutations', 'Var', (35, 53))	('MAX', 'Gene', '4149', (57, 60))
47397	24642075	In patients with suspected familial cases but no identifiable mutations in known genes, MAX mutations were found in 8.5% of cases.	('familial', 'Disease', (27, 35))	('mutations', 'Var', (92, 101))	('patients', 'Species', '9606', (3, 11))	('MAX', 'Gene', '4149', (88, 91))	('MAX', 'Gene', (88, 91))	('found', 'Reg', (107, 112))
47399	24642075	Exon sequencing of this region demonstrated a germline mutation at a gene known as TMEM127.	('germline mutation', 'Var', (46, 63))	('TMEM127', 'Gene', (83, 90))	('TMEM127', 'Gene', '55654', (83, 90))
47400	24642075	Germline mutations were found in 30% of familial and about 3% of sporadic pheochromocytomas.	('Germline mutations', 'Var', (0, 18))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (74, 91))	('pheochromocytomas', 'Disease', 'MESH:D010673', (74, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('pheochromocytomas', 'Disease', (74, 91))	('found', 'Reg', (24, 29))	('familial', 'Disease', (40, 48))
47402	24642075	Studies indicate that TMEM127 may be a negative regulator of mTORC1 and loss of protein function activates downstream pathways such as S6K and 4EBP1.	('activates', 'PosReg', (97, 106))	('mTORC1', 'Gene', (61, 67))	('loss', 'Var', (72, 76))	('TMEM127', 'Gene', (22, 29))	('EBP1', 'Gene', (144, 148))	('TMEM127', 'Gene', '55654', (22, 29))	('protein', 'Protein', (80, 87))	('EBP1', 'Gene', '4790', (144, 148))	('S6K', 'Disease', (135, 138))	('mTORC1', 'Gene', '382056', (61, 67))
47404	24642075	Recently 2 patients at the National Institutes of Health with paraganglioma were found to have somatic gain of function mutation in HIF2a.	('mutation', 'Var', (120, 128))	('paraganglioma', 'Phenotype', 'HP:0002668', (62, 75))	('HIF2a', 'Gene', '2034', (132, 137))	('paraganglioma', 'Disease', (62, 75))	('patients', 'Species', '9606', (11, 19))	('gain of function', 'PosReg', (103, 119))	('HIF2a', 'Gene', (132, 137))	('paraganglioma', 'Disease', 'MESH:D010235', (62, 75))
47412	24642075	As mentioned above the NF1 is an extremely large gene and sequencing can be very costly; therefore a clinical diagnosis and the findings of elevated epinephrine or metanephrine often suffices, as de novo NF1 mutations are common.	('NF1', 'Gene', (204, 207))	('metanephrine', 'Chemical', 'MESH:D008676', (164, 176))	('NF1', 'Gene', '4763', (204, 207))	('NF1', 'Gene', (23, 26))	('mutations', 'Var', (208, 217))	('NF1', 'Gene', '4763', (23, 26))	('epinephrine', 'Chemical', 'MESH:D004837', (149, 160))	('elevated epinephrine', 'Phenotype', 'HP:0003639', (140, 160))	('elevated', 'PosReg', (140, 148))	('epinephrine', 'MPA', (149, 160))
47414	24642075	The incidence of malignancy is much higher with SDHB mutations, therefore, if a pheochromocytoma appears to be invasive or associated with metastatic disease, this gene should be considered for testing.	('pheochromocytoma', 'Disease', (80, 96))	('associated', 'Reg', (123, 133))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('malignancy', 'Disease', (17, 27))	('pheochromocytoma', 'Disease', 'MESH:D010673', (80, 96))	('mutations', 'Var', (53, 62))	('malignancy', 'Disease', 'MESH:D009369', (17, 27))	('SDHB', 'Gene', '6390', (48, 52))	('SDHB', 'Gene', (48, 52))
47426	24642075	In patients without a prior diagnosis of a hereditary syndrome, genetic testing prior to surgery may be usefjul.	('hereditary syndrome', 'Disease', (43, 62))	('patients', 'Species', '9606', (3, 11))	('hereditary syndrome', 'Disease', 'MESH:D009386', (43, 62))	('genetic', 'Var', (64, 71))
47428	24642075	However, findings such as germline SDHB mutation could lead recommendation of total adrenalectomy due to the higher incidence of malignancy.	('mutation', 'Var', (40, 48))	('malignancy', 'Disease', (129, 139))	('SDHB', 'Gene', (35, 39))	('germline', 'Var', (26, 34))	('lead', 'Reg', (55, 59))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('SDHB', 'Gene', '6390', (35, 39))
47459	26405465	Left-sided paroidectomy was performed due to the lesion within the left parietal salivary gland (later shown to be a basal cell adenoma in a histopathological examination) while no specimen collection or resection of the right-sided tumor were attempted due to the size and macroscopic presentation of the lesion.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('basal cell adenoma', 'Phenotype', 'HP:0002671', (117, 135))	('Left-sided', 'Disease', (0, 10))	('tumor', 'Disease', (233, 238))	('basal cell adenoma', 'Disease', (117, 135))	('lesion', 'Var', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('basal cell adenoma', 'Disease', 'MESH:D000236', (117, 135))
47462	26405465	The examination showed a well-encapsulated tumor on the left, sized 84x65x50 mm - no regression observed following radiation therapy.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('84x65x50 mm -', 'Var', (68, 81))
47482	26405465	Mutations within the succinate dehydrogenase genes were reported as causes of paraganglioma syndrome (PGL).	('causes', 'Reg', (68, 74))	('paraganglioma syndrome', 'Disease', (78, 100))	('PGL', 'Disease', (102, 105))	('Mutations', 'Var', (0, 9))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (78, 100))	('PGL', 'Disease', 'MESH:D010235', (102, 105))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))
47483	26405465	Such mutations contribute to the occurrence of multiple locations of glomus tumors in 100% of cases.	('glomus tumors', 'Disease', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('glomus tumors', 'Disease', 'MESH:D005918', (69, 82))
47484	26405465	Tumors originating from paraganglial tissue may develop in various genetic diseases such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (von Recklinghausen disease, NF1), multiple endocrine neoplasias of type 2 (MEN2 - mutation within the RET protooncogene), TMEM127, and MAX.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('VHL', 'Disease', 'MESH:D006623', (120, 123))	('neurofibromatosis type 1', 'Gene', (126, 150))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('develop', 'Reg', (48, 55))	('MEN2 - mutation', 'Var', (227, 242))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (126, 143))	('endocrine neoplasias', 'Phenotype', 'HP:0100568', (195, 215))	('von Recklinghausen disease', 'Disease', 'MESH:C537392', (152, 178))	('RET', 'Gene', '5979', (254, 257))	('NF1', 'Gene', '4763', (180, 183))	('multiple endocrine neoplasias of type 2', 'Disease', (186, 225))	('genetic diseases', 'Disease', 'MESH:D030342', (67, 83))	('von Hippel-Lindau syndrome', 'Disease', (92, 118))	('Tumors', 'Disease', (0, 6))	('von Hippel-Lindau syndrome', 'Disease', 'MESH:D006623', (92, 118))	('multiple endocrine neoplasias of type 2', 'Disease', 'MESH:D018813', (186, 225))	('NF1', 'Gene', (180, 183))	('neurofibromatosis type 1', 'Gene', '4763', (126, 150))	('VHL', 'Disease', (120, 123))	('von Recklinghausen disease', 'Disease', (152, 178))	('genetic diseases', 'Disease', (67, 83))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TMEM127', 'Gene', (274, 281))	('RET', 'Gene', (254, 257))	('TMEM127', 'Gene', '55654', (274, 281))	('neoplasias', 'Phenotype', 'HP:0002664', (205, 215))
47627	24018082	123I-MIBG scintigraphy is highly specific and seems to be superior to CT scan and ultrasonography in identifying neoplastic and hyperplastic adrenomedullary lesions.	('hyperplastic adrenomedullary lesions', 'Disease', (128, 164))	('123I-MIBG', 'Var', (0, 9))	('hyperplastic adrenomedullary lesions', 'Disease', 'MESH:D051437', (128, 164))	('123I-MIBG', 'Chemical', '-', (0, 9))	('neoplastic', 'Disease', (113, 123))
47633	24018082	In patients with Rearranged during Transfection (RET) mutations, responsible for type 2 MEN syndrome, and with other mutations such as succinate dehydrogenase subunit B, bilateral AMH has been identified.	('RET', 'Gene', '5979', (49, 52))	('type 2 MEN syndrome', 'Disease', (81, 100))	('mutations', 'Var', (54, 63))	('RET', 'Gene', (49, 52))	('Rearranged during Transfection', 'Gene', (17, 47))	('patients', 'Species', '9606', (3, 11))	('AMH', 'Chemical', '-', (180, 183))	('Rearranged during Transfection', 'Gene', '5979', (17, 47))	('type 2 MEN syndrome', 'Disease', 'MESH:D018813', (81, 100))
47650	24018082	Laparoscopic adrenalectomies have smaller incisions; less intraoperative blood loss; and reduced postoperative wound complications, pain, and infections.	('pain', 'Phenotype', 'HP:0012531', (132, 136))	('pain', 'Disease', 'MESH:D010146', (132, 136))	('pain', 'Disease', (132, 136))	('adrenalectomies', 'Disease', (13, 28))	('less', 'NegReg', (53, 57))	('infections', 'Disease', (142, 152))	('Laparoscopic', 'Var', (0, 12))	('reduced', 'NegReg', (89, 96))	('intraoperative blood loss', 'Disease', (58, 83))	('smaller incisions', 'Phenotype', 'HP:0005486', (34, 51))	('intraoperative blood loss', 'Disease', 'MESH:D016063', (58, 83))	('infections', 'Disease', 'MESH:D007239', (142, 152))
47682	18210106	Since the year 2000, patients with somatostatin receptor-positive metastatic, inoperable GEPNETs and malignant pheochromocytomas have been treated with the radiolabeled somatostatin analogue [177Lu-DOTA0, Tyr3]octreotate (177Lu-octreotate) in our institution.	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (222, 238))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (111, 128))	('177Lu-DOTA0,', 'Chemical', '-', (192, 204))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('somatostatin', 'Gene', (169, 181))	('patients', 'Species', '9606', (21, 29))	('somatostatin', 'Gene', '6750', (35, 47))	('Tyr3]octreotate', 'Chemical', 'MESH:C470036', (205, 220))	('[177Lu-DOTA0', 'Var', (191, 203))	('malignant pheochromocytomas', 'Disease', (101, 128))	('malignant pheochromocytomas', 'Disease', 'MESH:D010673', (101, 128))	('somatostatin', 'Gene', (35, 47))	('somatostatin', 'Gene', '6750', (169, 181))
47684	18210106	Although infrequent, hormonal release-induced crises can occur after 177Lu-octreotate treatment.	('hormonal release-induced', 'MPA', (21, 45))	('177Lu-octreotate', 'Var', (69, 85))	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (69, 85))	('men', 'Species', '9606', (91, 94))
47731	18210106	After 131I-MIBG therapy, excessive catecholamine secretion with the above-mentioned severe symptomatology has been reported.	('131I-MIBG', 'Chemical', 'MESH:D019797', (6, 15))	('catecholamine secretion', 'MPA', (35, 58))	('catecholamine', 'Chemical', 'MESH:D002395', (35, 48))	('131I-MIBG', 'Var', (6, 15))	('men', 'Species', '9606', (74, 77))	('excessive catecholamine', 'Phenotype', 'HP:0003334', (25, 48))
47742	18210106	When possible, we stop somatostatin analogues before 177Lu-octreotate therapy to prevent competitive binding to the somatostatin receptors with 177Lu-octreotate.	('somatostatin', 'Gene', '6750', (23, 35))	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (144, 160))	('somatostatin', 'Gene', '6750', (116, 128))	('somatostatin', 'Gene', (23, 35))	('177Lu-octreotate', 'Var', (144, 160))	('binding', 'Interaction', (101, 108))	('somatostatin', 'Gene', (116, 128))	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (53, 69))
47759	18210106	Other less serious side effects shortly after 177Lu-octreotate, such as nausea, vomiting, and abdominal pain, are more common and can be controlled by supportive measures.	('vomiting', 'Disease', (80, 88))	('vomiting', 'Disease', 'MESH:D014839', (80, 88))	('abdominal pain', 'Phenotype', 'HP:0002027', (94, 108))	('nausea', 'Disease', (72, 78))	('abdominal pain', 'Disease', (94, 108))	('nausea', 'Phenotype', 'HP:0002018', (72, 78))	('nausea', 'Disease', 'MESH:D009325', (72, 78))	('177Lu-octreotate', 'Chemical', 'MESH:C554548', (46, 62))	('pain', 'Phenotype', 'HP:0012531', (104, 108))	('vomiting', 'Phenotype', 'HP:0002013', (80, 88))	('abdominal pain', 'Disease', 'MESH:D015746', (94, 108))	('177Lu-octreotate', 'Var', (46, 62))
47766	33768452	Genetic events underlying the development of these lesions are noted in several different signaling pathways, of which mutations in genes regulating the tricarboxylic acid (TCA) cycle are particularly associated to metastatic disease.	('metastatic disease', 'Disease', (215, 233))	('associated', 'Reg', (201, 211))	('TCA', 'Chemical', 'MESH:D014233', (173, 176))	('mutations', 'Var', (119, 128))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (153, 171))
47791	33768452	Germline mutations are most commonly detected in the Succinate dehydrogenase complex flavoprotein subunit B (SDHB), RET, VHL and NF1 genes, while somatic mutations are most commonly observed in Harvey rat sarcoma viral oncogene homolog (HRAS), NF1, Endothelial PAS domain-containing protein 1 (EPAS1) and RET.	('Endothelial PAS domain-containing protein 1', 'Gene', '29452', (249, 292))	('rat', 'Species', '10116', (201, 204))	('sarcoma', 'Disease', 'MESH:D012509', (205, 212))	('Endothelial PAS domain-containing protein 1', 'Gene', (249, 292))	('SDHB', 'Gene', (109, 113))	('mutations', 'Var', (9, 18))	('sarcoma', 'Disease', (205, 212))	('EPAS1', 'Gene', (294, 299))	('RET', 'Gene', (116, 119))	('NF1', 'Gene', (129, 132))	('Succinate dehydrogenase', 'Gene', '6390', (53, 76))	('sarcoma', 'Phenotype', 'HP:0100242', (205, 212))	('detected', 'Reg', (37, 45))	('VHL', 'Gene', (121, 124))	('Succinate dehydrogenase', 'Gene', (53, 76))
47795	33768452	Tumors adhering to the kinase cluster (approximately 50% of all PPGLs) are often pheochromocytomas with low metastatic potential, and this cluster contains tumors with either germline or somatic mutations in NF1, RET, Myc-associated factor X (MAX), Transmembrane Protein 127 (TMEM127), Kinesin Family Member 1B (KIF1B-beta), and HRAS.	('pheochromocytomas', 'Disease', (81, 98))	('NF1', 'Gene', (208, 211))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Myc-associated factor X', 'Gene', '4149', (218, 241))	('TMEM127', 'Gene', (276, 283))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (81, 98))	('Tumors', 'Disease', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('MAX', 'Gene', '4149', (243, 246))	('Myc-associated factor X', 'Gene', (218, 241))	('PPGLs', 'Chemical', '-', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('KIF1B-beta', 'Gene', (312, 322))	('TMEM127', 'Gene', '55654', (276, 283))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (195, 204))	('Transmembrane Protein 127', 'Gene', (249, 274))	('tumors', 'Disease', (156, 162))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (81, 97))	('Transmembrane Protein 127', 'Gene', '55654', (249, 274))	('MAX', 'Gene', (243, 246))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('pheochromocytomas', 'Disease', 'MESH:D010673', (81, 98))
47799	33768452	TCA cycle aberrant PPGLs in general exhibit the highest risk of metastatic dissemination, which is due to the fact that the accumulation of onco-metabolites will inhibit the cellular effects of dioxygenases, a group of enzymes that catalyze the oxidation of various substrates via the conversion of alpha-ketoglutarate to succinate (Fig.	('PPGLs', 'Chemical', '-', (19, 24))	('TCA', 'Gene', (0, 3))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (299, 318))	('inhibit', 'NegReg', (162, 169))	('rat', 'Species', '10116', (314, 317))	('TCA', 'Chemical', 'MESH:D014233', (0, 3))	('aberrant', 'Var', (10, 18))	('dioxygenases', 'Enzyme', (194, 206))	('oxidation', 'MPA', (245, 254))	('succinate', 'Chemical', 'MESH:D019802', (322, 331))	('cellular effects', 'MPA', (174, 190))	('rat', 'Species', '10116', (271, 274))	('metastatic dissemination', 'CPA', (64, 88))
47802	33768452	On the other hand, pseudo-hypoxia-driven PPGLs without TCA cycle mutations are generally driven by mutations in the signaling networks that regulate hypoxia-inducible factor (HIF)-mediated transcription of target gene programs (Fig.	('hypoxia', 'Disease', (26, 33))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('PPGLs', 'Disease', (41, 46))	('driven by', 'Reg', (89, 98))	('TCA', 'Chemical', 'MESH:D014233', (55, 58))	('TCA cycle', 'Gene', (55, 64))	('mutations', 'Var', (99, 108))	('hypoxia', 'Disease', 'MESH:D000860', (149, 156))	('PPGLs', 'Chemical', '-', (41, 46))	('hypoxia', 'Disease', (149, 156))
47803	33768452	These events include inactivating mutations of the VHL, Egl-9 Family Hypoxia Inducible Factor 2 (EGLN2; encoding prolyl hydroxylase 1, PHD1) and EGLN1 (encoding PHD2) genes, as well as activating EPAS1/HIF2-alpha mutations.	('HIF2-alpha', 'Gene', (202, 212))	('inactivating mutations', 'Var', (21, 43))	('EGLN2', 'Gene', '112398', (97, 102))	('Egl-9 Family Hypoxia Inducible Factor 2', 'Gene', (56, 95))	('EGLN1', 'Gene', '54583', (145, 150))	('PHD1', 'Gene', (135, 139))	('activating', 'PosReg', (185, 195))	('HIF2-alpha', 'Gene', '2034', (202, 212))	('Egl-9 Family Hypoxia Inducible Factor 2', 'Gene', '112398', (56, 95))	('PHD2', 'Gene', (161, 165))	('EGLN2', 'Gene', (97, 102))	('PHD2', 'Gene', '54583', (161, 165))	('mutations', 'Var', (213, 222))	('VHL', 'Gene', (51, 54))	('EGLN1', 'Gene', (145, 150))	('PHD1', 'Gene', '112398', (135, 139))
47806	33768452	Given these molecular differences, TCA cycle-driven tumors are even more prone to metastatic spread than other PPGLs within the pseudo-hypoxia cluster, and there is probably a need to distinguish TCA cycle aberrant from TCA cycle non-aberrant PPGLs in terms of risk stratification.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('hypoxia', 'Disease', (135, 142))	('hypoxia', 'Disease', 'MESH:D000860', (135, 142))	('rat', 'Species', '10116', (268, 271))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('aberrant', 'Var', (206, 214))	('TCA', 'Chemical', 'MESH:D014233', (220, 223))	('prone', 'Reg', (73, 78))	('TCA', 'Chemical', 'MESH:D014233', (196, 199))	('TCA', 'Chemical', 'MESH:D014233', (35, 38))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('PPGLs', 'Chemical', '-', (243, 248))	('metastatic spread', 'CPA', (82, 99))	('PPGLs', 'Chemical', '-', (111, 116))
47807	33768452	This is furthermore mirrored by syndromic manifestations, in which SDHx mutated PPGLs display a significant increased risk of disseminated disease, while VHL associated tumors rarely exhibit metastatic potential:although adhering to the same transcriptional cluster.	('PPGLs', 'Gene', (80, 85))	('mutated', 'Var', (72, 79))	('SDH', 'Gene', '6390', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('disseminated disease', 'Disease', (126, 146))	('PPGLs', 'Chemical', '-', (80, 85))	('tumors', 'Disease', (169, 175))	('SDH', 'Gene', (67, 70))
47808	33768452	The Wnt cluster contains mostly pheochromocytomas with somatic fusions involving the Mastermind Like Transcriptional Coactivator 3 (MAML3) gene as well as Cold Shock Domain Containing E1 (CDSE1) mutations.	('Mastermind Like Transcriptional Coactivator 3', 'Gene', '55534', (85, 130))	('MAML3', 'Gene', '55534', (132, 137))	('Shock', 'Phenotype', 'HP:0031273', (160, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (32, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (32, 49))	('mutations', 'Var', (195, 204))	('CDSE1', 'Gene', (188, 193))	('pheochromocytomas', 'Disease', 'MESH:D010673', (32, 49))	('Mastermind Like Transcriptional Coactivator 3', 'Gene', (85, 130))	('MAML3', 'Gene', (132, 137))	('pheochromocytomas', 'Disease', (32, 49))	('fusions', 'Var', (63, 70))
47809	33768452	The MAML3 protein acts as a transcriptional coactivator of NOTCH pathway associated genes, and MAML3 fusions and MAML3 overexpression are recurrent features in various tumor types.	('fusions', 'Var', (101, 108))	('MAML3', 'Gene', '55534', (95, 100))	('MAML3', 'Gene', '55534', (4, 9))	('tumor', 'Disease', (168, 173))	('MAML3', 'Gene', (95, 100))	('MAML3', 'Gene', (4, 9))	('MAML3', 'Gene', (113, 118))	('MAML3', 'Gene', '55534', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
47811	33768452	In PPGL, CDSE1 mutations are found on the somatic level and are expected to exhibit loss-of-function properties.	('loss-of-function', 'NegReg', (84, 100))	('PPGL', 'Chemical', '-', (3, 7))	('CDSE1', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))
47830	33768452	As of this, PPGL patients with germline RET mutations may exhibit alarming histological features, although these patients very rarely present with metastatic disease in the clinical setting.	('RET', 'Gene', (40, 43))	('PPGL', 'Chemical', '-', (12, 16))	('patients', 'Species', '9606', (113, 121))	('germline', 'Var', (31, 39))	('patients', 'Species', '9606', (17, 25))
47845	33768452	The advent of modern next-generation analyses have revolutionized the ability to classify PPGLs, not only in terms of transcriptome clustering but also as a way to detect germline alterations in patients in need of genetic counselling and to pinpoint high-risk mutations in TCA cycle/pseudo-hypoxia-related PPGLs indicating higher risk of metastatic events.	('mutations', 'Var', (261, 270))	('PPGLs', 'Gene', (307, 312))	('hypoxia', 'Disease', (291, 298))	('rat', 'Species', '10116', (184, 187))	('hypoxia', 'Disease', 'MESH:D000860', (291, 298))	('rat', 'Species', '10116', (30, 33))	('patients', 'Species', '9606', (195, 203))	('PPGLs', 'Chemical', '-', (307, 312))	('PPGLs', 'Chemical', '-', (90, 95))	('TCA', 'Chemical', 'MESH:D014233', (274, 277))
47846	33768452	Following the detection of absent SDHB expression in hereditary PPGLs in patients with germline SDHB or SDHD mutations, several independent groups have verified the value of SDHB immunohistochemistry to pinpoint SDHx gene mutations occurring either on the somatic or germline level in PPGL.	('SDH', 'Gene', '6390', (96, 99))	('SDH', 'Gene', '6390', (104, 107))	('SDH', 'Gene', '6390', (174, 177))	('SDHD', 'Gene', (104, 108))	('SDH', 'Gene', (34, 37))	('PPGL', 'Chemical', '-', (64, 68))	('SDH', 'Gene', (96, 99))	('SDH', 'Gene', (104, 107))	('mutations', 'Var', (222, 231))	('expression', 'MPA', (39, 49))	('PPGL', 'Chemical', '-', (285, 289))	('SDH', 'Gene', '6390', (212, 215))	('absent', 'NegReg', (27, 33))	('SDH', 'Gene', (174, 177))	('PPGLs', 'Chemical', '-', (64, 69))	('patients', 'Species', '9606', (73, 81))	('SDH', 'Gene', (212, 215))	('SDHD', 'Gene', '6392', (104, 108))	('SDH', 'Gene', '6390', (34, 37))
47847	33768452	The reason behind the ability of SDHB staining to pinpoint cases with either SDHB, C, or D subunit mutations stems from the fact that the succinate dehydrogenase enzyme complex is anchored to the mitochondrial inner membrane via the C and D subunits.	('mutations', 'Var', (99, 108))	('succinate dehydrogenase', 'Gene', (138, 161))	('SDHB', 'Gene', (77, 81))	('succinate dehydrogenase', 'Gene', '6390', (138, 161))
47848	33768452	The scoring and interpretation of SDHB immunohistochemistry has been proved highly reproducible between pathologists and also a reliable tool in terms of detecting underlying SDHx gene mutations.	('SDH', 'Gene', (175, 178))	('SDH', 'Gene', (34, 37))	('mutations', 'Var', (185, 194))	('SDH', 'Gene', '6390', (175, 178))	('SDH', 'Gene', '6390', (34, 37))
47850	33768452	In contrast, SDHA mutated PPGLs lose both SDHA and B immunoreactivity, and therefore, SDHA immunohistochemistry could complement the screening panel to detect rare PPGLs with SDHA mutations.	('SDHA', 'Gene', '6389', (86, 90))	('mutated', 'Var', (18, 25))	('lose', 'NegReg', (32, 36))	('B immunoreactivity', 'MPA', (51, 69))	('SDHA', 'Gene', (42, 46))	('PPGLs', 'Chemical', '-', (26, 31))	('PPGLs', 'Chemical', '-', (164, 169))	('SDHA', 'Gene', '6389', (13, 17))	('SDHA', 'Gene', (86, 90))	('SDHA', 'Gene', '6389', (175, 179))	('SDHA', 'Gene', '6389', (42, 46))	('SDHA', 'Gene', (13, 17))	('SDHA', 'Gene', (175, 179))
47851	33768452	SDHD immunostaining has also been assessed in PPGLs, in which positive immunoreactivity was observed in SDHx gene mutated cases:while wild-type cases stained negative.	('SDH', 'Gene', '6390', (104, 107))	('SDH', 'Gene', (0, 3))	('mutated', 'Var', (114, 121))	('SDH', 'Gene', (104, 107))	('SDHD', 'Gene', '6392', (0, 4))	('SDH', 'Gene', '6390', (0, 3))	('SDHD', 'Gene', (0, 4))	('PPGLs', 'Chemical', '-', (46, 51))
47852	33768452	The reason for this paradoxal and inverted finding could be the potential de-masking of the SDHD epitope upon mutation-mediated disruption of the SDH complex.	('mutation-mediated disruption', 'Var', (110, 138))	('SDH', 'Gene', (92, 95))	('SDHD', 'Gene', '6392', (92, 96))	('SDHD', 'Gene', (92, 96))	('SDH', 'Gene', '6390', (146, 149))	('de-masking', 'NegReg', (74, 84))	('SDH', 'Gene', '6390', (92, 95))	('SDH', 'Gene', (146, 149))	('disruption', 'Var', (128, 138))
47853	33768452	Moreover, immunohistochemistry targeting fumarate hydratase (FH) has been proven as an efficient method to pinpoint rare FH gene germline mutations in PPGL, in turn coupled to the hereditary leiomatosis and renal cell carcinoma (HLRCC) syndrome.	('FH', 'Gene', '2271', (121, 123))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (207, 227))	('fumarate hydratase', 'Gene', '2271', (41, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('FH', 'Gene', '2271', (61, 63))	('PPGL', 'Chemical', '-', (151, 155))	('PPGL', 'Gene', (151, 155))	('fumarate hydratase', 'Gene', (41, 59))	('coupled to', 'Reg', (165, 175))	('hereditary leiomatosis and renal cell carcinoma (HLRCC) syndrome', 'Disease', 'MESH:C538614', (180, 244))	('mutations', 'Var', (138, 147))
47855	33768452	CAIX is frequently found up-regulated in PPGL with underlying VHL gene mutations, and the identification of strong immunoreactivity in a PPGL might therefore be a way to identify VHL driven tumors with a lower (but not unneglectable) risk of aggressive behavior than TCA cycle aberrant PPGLs.	('CAIX', 'Gene', '768', (0, 4))	('TCA', 'Chemical', 'MESH:D014233', (267, 270))	('up-regulated', 'PosReg', (25, 37))	('aggressive behavior', 'Disease', (242, 261))	('PPGL', 'Chemical', '-', (286, 290))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('aggressive behavior', 'Phenotype', 'HP:0000718', (242, 261))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PPGL', 'Chemical', '-', (137, 141))	('VHL gene', 'Gene', (62, 70))	('mutations', 'Var', (71, 80))	('CAIX', 'Gene', (0, 4))	('tumors', 'Disease', (190, 196))	('PPGL', 'Chemical', '-', (41, 45))	('PPGLs', 'Chemical', '-', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('aggressive behavior', 'Disease', 'MESH:D001523', (242, 261))
47856	33768452	Similarly, rare cases of MAX mutated or gene rearranged PPGLs usually exhibit loss of MAX protein expression:adding yet another potential tool to the diagnostic workup of these lesions.	('MAX', 'Gene', '4149', (25, 28))	('MAX', 'Gene', (25, 28))	('MAX', 'Gene', '4149', (86, 89))	('MAX', 'Gene', (86, 89))	('gene rearranged', 'Var', (40, 55))	('loss', 'NegReg', (78, 82))	('PPGLs', 'Chemical', '-', (56, 61))	('PPGLs', 'Gene', (56, 61))
47857	33768452	Besides immunohistochemical analyses aiding in the context of underlying mutations, an additional marker of prognostic significance include chromogranin B (CHGB), which was the top downregulated gene in an expressional study when stratifying for metastatic PPGLs.	('chromogranin B', 'Gene', '1114', (140, 154))	('rat', 'Species', '10116', (232, 235))	('metastatic PPGLs', 'Disease', (246, 262))	('chromogranin B', 'Gene', (140, 154))	('CHGB', 'Gene', '1114', (156, 160))	('PPGLs', 'Chemical', '-', (257, 262))	('CHGB', 'Gene', (156, 160))	('mutations', 'Var', (73, 82))
47864	33768452	As previously discussed, gene fusions involving MAML3 and CDSE1 mutations are overrepresented in PPGL associated to the Wnt transcriptome cluster, and these tumors have a significantly higher metastatic rate than PPGL associated to the kinase cluster.	('overrepresented', 'PosReg', (78, 93))	('metastatic rate', 'CPA', (192, 207))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('MAML3', 'Gene', '55534', (48, 53))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('MAML3', 'Gene', (48, 53))	('higher', 'PosReg', (185, 191))	('PPGL', 'Chemical', '-', (213, 217))	('mutations', 'Var', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CDSE1', 'Gene', (58, 63))	('rat', 'Species', '10116', (203, 206))	('PPGL', 'Chemical', '-', (97, 101))	('PPGL', 'Gene', (97, 101))
47865	33768452	Moreover, metastatic PPGLs also harbor somatic gene alterations of potential value for further investigations, such as mutations in transport and cell adhesion genes, recurrent Transcriptional regulator ATRX (ATRX) mutations as well as upregulated Telomerase reverse transcriptase (TERT) gene expression and TERT gene rearrangements.	('upregulated', 'PosReg', (236, 247))	('rat', 'Species', '10116', (56, 59))	('ATRX', 'Gene', (209, 213))	('TERT', 'Gene', '7015', (308, 312))	('Transcriptional regulator ATRX', 'Gene', (177, 207))	('TERT', 'Gene', '7015', (282, 286))	('ATRX', 'Gene', (203, 207))	('TERT', 'Gene', (282, 286))	('mutations', 'Var', (215, 224))	('PPGLs', 'Chemical', '-', (21, 26))	('Transcriptional regulator ATRX', 'Gene', '546', (177, 207))	('Telomerase reverse transcriptase', 'Gene', (248, 280))	('ATRX', 'Gene', '546', (209, 213))	('ATRX', 'Gene', '546', (203, 207))	('Telomerase reverse transcriptase', 'Gene', '7015', (248, 280))	('expression', 'MPA', (293, 303))	('mutations', 'Var', (119, 128))	('TERT', 'Gene', (308, 312))
47866	33768452	TERT gene aberrancies are common in various cancers and usually confer an increased TERT mRNA gene output, which is thought to confer immortalization through the elongation of telomeric DNA for these tumor types.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('TERT', 'Gene', (0, 4))	('increased', 'PosReg', (74, 83))	('tumor', 'Disease', (200, 205))	('TERT', 'Gene', '7015', (0, 4))	('aberrancies', 'Var', (10, 21))
47867	33768452	ATRX encodes a chromatin remodeling protein, and mutations in this gene were intimately coupled to an alternative lengthening of telomeres, furthermore suggesting that the regulation of telomeric regions is crucial for metastatic PPGLs.	('mutations', 'Var', (49, 58))	('ATRX', 'Gene', (0, 4))	('PPGLs', 'Chemical', '-', (230, 235))	('ATRX', 'Gene', '546', (0, 4))	('coupled', 'Reg', (88, 95))	('PPGLs', 'Disease', (230, 235))
47868	33768452	To add to the association between epigenetic regulators and metastatic potential, somatic mutations in SET domain containing 2 histone lysine methyltransferase (SETD2) have also been found overrepresented in PPGLs with disseminated disease.	('mutations', 'Var', (90, 99))	('SETD2', 'Gene', '29072', (161, 166))	('overrepresented', 'PosReg', (189, 204))	('SETD2', 'Gene', (161, 166))	('disseminated disease', 'Disease', (219, 239))	('PPGLs', 'Chemical', '-', (208, 213))
47870	33768452	In contrast, mutations in other components of the epigenetic machinery that governs chromatin remodeling are mostly found in metastatic-free PPGLs.	('PPGLs', 'Chemical', '-', (141, 146))	('mutations', 'Var', (13, 22))	('found', 'Reg', (116, 121))
47872	33768452	In terms of epigenetic modifications, we know that especially TCA cycle aberrant PPGLs display unique methylation profiles on both global and gene-specific levels.	('PPGLs', 'Chemical', '-', (81, 86))	('TCA', 'Chemical', 'MESH:D014233', (62, 65))	('methylation profiles', 'MPA', (102, 122))	('PPGLs', 'Gene', (81, 86))	('aberrant', 'Var', (72, 80))
47873	33768452	Although no clear-cut methylation panel for clinical usage in terms of prognostication exists, the association between hypermethylation, TCA cycle defects and metastatic PPGLs could have clinical implications in terms of treatment.	('TCA', 'Chemical', 'MESH:D014233', (137, 140))	('metastatic', 'CPA', (159, 169))	('TCA cycle', 'Gene', (137, 146))	('defects', 'Var', (147, 154))	('hypermethylation', 'Var', (119, 135))	('association', 'Interaction', (99, 110))	('PPGLs', 'Chemical', '-', (170, 175))
47874	33768452	For example, as O(6)-methylguanine-DNA methyltransferase (MGMT) constitutes an epigenetically silenced gene in SDHx mutated PPGLs, this could probably explain the partial effect of temozolomide in these cases.	('MGMT', 'Gene', '4255', (58, 62))	('O(6)-methylguanine-DNA methyltransferase', 'Gene', '4255', (16, 56))	('MGMT', 'Gene', (58, 62))	('PPGLs', 'Gene', (124, 129))	('SDH', 'Gene', '6390', (111, 114))	('temozolomide', 'Chemical', 'MESH:D000077204', (181, 193))	('mutated', 'Var', (116, 123))	('SDH', 'Gene', (111, 114))	('PPGLs', 'Chemical', '-', (124, 129))
47965	33734413	Of the GISTs, none carried c-kit or PDGFRA mutations, 13 tumors (65.0%) were located in the jejunum or ileum, and 6 tumors (30.0%) were located in the duodenum.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('GISTs', 'Phenotype', 'HP:0100723', (7, 12))	('c-kit', 'Gene', '3815', (27, 32))	('c-kit', 'Gene', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('PDGFRA', 'Gene', '5156', (36, 42))	('PDGFRA', 'Gene', (36, 42))	('tumors', 'Disease', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
47993	33734413	Inactivating mutations in NF1 is associated with downstream activation of mitogen-activated protein kinase, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling, and uncontrolled cellular growth, differentiation, and survival, which is associated with the disease origin of NF1, including NF1-associated neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (340, 348))	('uncontrolled cellular growth', 'CPA', (202, 230))	('NF1', 'Gene', (325, 328))	('NF1', 'Gene', '4763', (310, 313))	('activation', 'PosReg', (60, 70))	('neoplasms', 'Disease', 'MESH:D009369', (340, 349))	('survival', 'CPA', (253, 261))	('NF1', 'Gene', (310, 313))	('Inactivating mutations', 'Var', (0, 22))	('differentiation', 'CPA', (232, 247))	('protein kinase B', 'Gene', '2185', (138, 154))	('mechanistic target of rapamycin', 'Gene', (155, 186))	('mechanistic target of rapamycin', 'Gene', '2475', (155, 186))	('mitogen-activated', 'MPA', (74, 91))	('neoplasms', 'Disease', (340, 349))	('protein kinase B', 'Gene', (138, 154))	('NF1', 'Gene', '4763', (26, 29))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (325, 328))	('neoplasms', 'Phenotype', 'HP:0002664', (340, 349))
48002	33734413	A 2000 review found that NF1-associated LGGs undergo malignant transformation more frequently than comparable sporadic LGGs; thus, malignant transformation of NF1-associated LGGs may be associated with the increased prevalence and younger age of diagnosis for HGG among patients with NF1 in our study compared with the general population.	('NF1', 'Gene', '4763', (159, 162))	('patients', 'Species', '9606', (270, 278))	('malignant transformation', 'Var', (131, 155))	('NF1', 'Gene', (284, 287))	('HGG', 'Disease', (260, 263))	('NF1', 'Gene', '4763', (284, 287))	('NF1', 'Gene', (25, 28))	('NF1', 'Gene', '4763', (25, 28))	('NF1', 'Gene', (159, 162))
48056	22889334	A cryptic BAP1 splice mutation in a family with uveal and cutaneous melanoma, and paraganglioma Inactivating germ line BRCA1-associated protein-1 (BAP1) mutations have recently been reported in families with uveal or cutaneous malignant melanoma (UMM, CMM), mesothelioma, and meningioma.	('mutations', 'Var', (153, 162))	('BAP1', 'Gene', (10, 14))	('mesothelioma', 'Disease', (258, 270))	('meningioma', 'Disease', 'MESH:D008577', (276, 286))	('mesothelioma', 'Disease', 'MESH:D008654', (258, 270))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (217, 245))	('paraganglioma', 'Disease', (82, 95))	('paraganglioma', 'Disease', 'MESH:D010235', (82, 95))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (217, 245))	('BAP1', 'Gene', '8314', (147, 151))	('BRCA1-associated protein-1', 'Gene', '8314', (119, 145))	('uveal or cutaneous malignant melanoma', 'Phenotype', 'HP:0007716', (208, 245))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('BRCA1-associated protein-1', 'Gene', (119, 145))	('Inactivating', 'NegReg', (96, 108))	('BAP1', 'Gene', '8314', (10, 14))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('BAP1', 'Gene', (147, 151))	('cutaneous melanoma', 'Disease', (58, 76))	('meningioma', 'Disease', (276, 286))	('cutaneous malignant melanoma', 'Disease', (217, 245))	('reported', 'Reg', (182, 190))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (58, 76))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (58, 76))	('meningioma', 'Phenotype', 'HP:0002858', (276, 286))	('malignant melanoma', 'Phenotype', 'HP:0002861', (227, 245))
48057	22889334	Although apparently predisposing to a wide range of tumors, the exact tumor spectrum associated with germ line BAP1 mutations has yet to be established.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BAP1', 'Gene', '8314', (111, 115))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BAP1', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
48058	22889334	Here, we report a novel germ line BAP1 splice mutation, c.1708C>G (p.Leu570fs*40), in a multiple-case Danish UMM family with a spectrum of other tumors.	('c.1708C>G', 'Var', (56, 65))	('BAP1', 'Gene', (34, 38))	('p.Leu570fs*40', 'Mutation', 'p.L570fsX40', (67, 80))	('c.1708C>G', 'Mutation', 'c.1708C>G', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('BAP1', 'Gene', '8314', (34, 38))
48059	22889334	Whole-exome sequencing identified an apparent missense mutation of BAP1 in UMM, CMM, as well as paraganglioma, breast cancer, and suspected mesothelioma cases in the family.	('paraganglioma', 'Disease', 'MESH:D010235', (96, 109))	('mesothelioma', 'Disease', (140, 152))	('mesothelioma', 'Disease', 'MESH:D008654', (140, 152))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutation', 'Var', (46, 63))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('BAP1', 'Gene', '8314', (67, 71))	('paraganglioma', 'Disease', (96, 109))	('breast cancer', 'Disease', (111, 124))	('BAP1', 'Gene', (67, 71))
48060	22889334	Bioinformatic analysis and splicing assays demonstrated that this mutation creates a strong cryptic splice donor, resulting in aberrant splicing and a truncating frameshift of the BAP1 transcript.	('BAP1', 'Gene', '8314', (180, 184))	('splicing', 'MPA', (136, 144))	('mutation', 'Var', (66, 74))	('BAP1', 'Gene', (180, 184))	('truncating', 'MPA', (151, 161))
48063	22889334	The report of a germ line inactivating mutation of the BRCA1-associated protein-1 (BAP1) in a patient with uveal malignant melanoma (UMM) as a part of the initial discovery of frequent somatic BAP1 mutations in UMM suggested a role for BAP1 in cancer predisposition.	('inactivating mutation', 'Var', (26, 47))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('malignant melanoma', 'Phenotype', 'HP:0002861', (113, 131))	('uveal malignant melanoma', 'Disease', (107, 131))	('mutations', 'Var', (198, 207))	('BAP1', 'Gene', '8314', (236, 240))	('patient', 'Species', '9606', (94, 101))	('BAP1', 'Gene', '8314', (83, 87))	('BAP1', 'Gene', '8314', (193, 197))	('uveal malignant melanoma', 'Disease', 'MESH:C536494', (107, 131))	('BRCA1-associated protein-1', 'Gene', '8314', (55, 81))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('BRCA1-associated protein-1', 'Gene', (55, 81))	('BAP1', 'Gene', (236, 240))	('cancer', 'Disease', (244, 250))	('uveal malignant melanoma', 'Phenotype', 'HP:0007716', (107, 131))	('BAP1', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('BAP1', 'Gene', (193, 197))
48064	22889334	Consistent with this finding, recently identified germ line BAP1 mutations in two families with a syndrome characterized by multiple skin-colored elevated melanocytic tumors, with some individuals also developing UMM or cutaneous malignant melanoma (CMM).	('cutaneous malignant melanoma', 'Disease', (220, 248))	('UMM', 'Disease', (213, 216))	('developing', 'Reg', (202, 212))	('cutaneous malignant melanoma', 'Disease', 'MESH:C562393', (220, 248))	('BAP1', 'Gene', '8314', (60, 64))	('melanocytic tumors', 'Disease', (155, 173))	('melanocytic tumors', 'Disease', 'MESH:D009508', (155, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('BAP1', 'Gene', (60, 64))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (220, 248))	('mutations', 'Var', (65, 74))	('malignant melanoma', 'Phenotype', 'HP:0002861', (230, 248))
48065	22889334	At the same time, reported germ line BAP1 mutations in two families with at least five patients with mesothelioma, as well as individuals diagnosed with other cancers including UMM.	('cancers', 'Disease', (159, 166))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('BAP1', 'Gene', '8314', (37, 41))	('mesothelioma', 'Disease', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('BAP1', 'Gene', (37, 41))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('mutations', 'Var', (42, 51))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
48066	22889334	More recently, described a UMM family with cases of CMM, meningioma, and lung adenocarcinoma carrying a BAP1 mutation.	('BAP1', 'Gene', '8314', (104, 108))	('lung adenocarcinoma', 'Disease', (73, 92))	('meningioma', 'Disease', (57, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('meningioma', 'Phenotype', 'HP:0002858', (57, 67))	('BAP1', 'Gene', (104, 108))	('meningioma', 'Disease', 'MESH:D008577', (57, 67))	('CMM', 'Disease', (52, 55))	('mutation', 'Var', (109, 117))
48067	22889334	Similarly, reported two families with BAP1 mutations co-segregating with both UMM and CMM, as well as four other mutations in sporadic UMM and/or CMM cases.	('BAP1', 'Gene', (38, 42))	('UMM', 'Disease', (78, 81))	('CMM', 'Disease', (86, 89))	('mutations', 'Var', (43, 52))	('BAP1', 'Gene', '8314', (38, 42))
48068	22889334	All 14 of the germ line BAP1 mutations reported to date are predicted to result in protein truncation via nonsense mutation, frameshift caused by insertions/deletions, or alteration of a canonical dinucleotide splice donor/acceptor sequences.	('frameshift', 'Var', (125, 135))	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('nonsense mutation', 'Var', (106, 123))	('insertions/deletions', 'Var', (146, 166))	('alteration', 'Reg', (171, 181))	('result', 'Reg', (73, 79))	('protein truncation', 'MPA', (83, 101))	('BAP1', 'Gene', '8314', (24, 28))
48069	22889334	Among them, two families described by report skin-colored melanocytic tumors in all mutation carriers, while carriers from one family and another sporadic case described by Njauw display a similar but distinct nevoid melanoma-like melanocytic proliferations.	('skin-colored melanocytic tumors', 'Disease', (45, 76))	('melanoma', 'Disease', 'MESH:D008545', (217, 225))	('mutation', 'Var', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('skin-colored melanocytic tumors', 'Disease', 'MESH:D012878', (45, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('melanoma', 'Phenotype', 'HP:0002861', (217, 225))	('melanoma', 'Disease', (217, 225))
48071	22889334	Here, we report a Danish family with multiple UMM and suspected mesothelioma cases, as well as several other cancers including CMM, breast cancer, and paraganglioma, carrying an apparent missense mutation of BAP1 resulting in the creation of a strong cryptic splice donor, aberrant splicing, and a truncating frameshift of the BAP1 transcript.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('missense mutation', 'Var', (187, 204))	('BAP1', 'Gene', (327, 331))	('splicing', 'MPA', (282, 290))	('BAP1', 'Gene', (208, 212))	('paraganglioma', 'Phenotype', 'HP:0002668', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('mesothelioma', 'Disease', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('mesothelioma', 'Disease', 'MESH:D008654', (64, 76))	('cancers', 'Disease', (109, 116))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', (132, 145))	('aberrant', 'MPA', (273, 281))	('BAP1', 'Gene', '8314', (327, 331))	('BAP1', 'Gene', '8314', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('paraganglioma', 'Disease', (151, 164))	('truncating', 'MPA', (298, 308))	('paraganglioma', 'Disease', 'MESH:D010235', (151, 164))
48080	22889334	Among these was a single non-synonymous variant in BAP1 (c.1708C>G, p.Leu570Val), which was also not listed in the sequence derived from approximately 6000 additional human chromosomes annotated by the NHLBI exome project (http://evs.gs.washington.edu/EVS/) or Kaviar (http://db.systemsbiology.net/kaviar/cgi-pub/Kaviar.pl).	('BAP1', 'Gene', (51, 55))	('p.Leu570Val', 'Mutation', 'p.L570V', (68, 79))	('c.1708C>G', 'Var', (57, 66))	('c.1708C>G', 'Mutation', 'c.1708C>G', (57, 66))	('human', 'Species', '9606', (167, 172))	('BAP1', 'Gene', '8314', (51, 55))
48081	22889334	While a conservative leucine to valine change is not consistent with previously reported germ line BAP1 mutations, which were all predicted to result in truncated protein, analysis of the potential effects of the nucleotide change on splicing using the information theory methodology of; https://splice.uwo.ca/) suggested that the variant creates a strong cryptic splice donor site.	('variant', 'Var', (331, 338))	('BAP1', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('leucine', 'Chemical', 'MESH:D007930', (21, 28))	('cryptic splice donor site', 'MPA', (356, 381))	('valine', 'Chemical', 'MESH:D014633', (32, 38))	('leucine', 'Var', (21, 28))	('BAP1', 'Gene', '8314', (99, 103))
48082	22889334	The predicted incorrectly spliced mRNA would be missing 22 bp from the end of exon 13 and would result in a frameshift and truncation 121 amino acids in advance of the normal stop codon (p.Leu570fs*40).	('p.Leu570fs*40', 'Mutation', 'p.L570fsX40', (187, 200))	('frameshift', 'Var', (108, 118))	('truncation', 'MPA', (123, 133))	('p.Leu570fs*40', 'Var', (187, 200))	('result in', 'Reg', (96, 105))
48083	22889334	The c.1708C>G mutation was present in all UMM (III-1, IV-2, and III-8) and CMM (IV-3) cases, the patient with paraganglioma (III-3), the case with both breast cancer and unconfirmed mesothelioma (II-4), the individual with both MFH and a suspected mesothelioma diagnosis (III-12), the case with pulmonary adenocarcinoma (II-1), the unaffected members who volunteered for presymptomatic testing (II-6, III-5, and IV-5), but not in the patient with prolactinoma (IV-4).	('paraganglioma', 'Disease', 'MESH:D010235', (110, 123))	('patient', 'Species', '9606', (97, 104))	('prolactinoma', 'Phenotype', 'HP:0040278', (447, 459))	('c.1708C>G', 'Var', (4, 13))	('mesothelioma', 'Disease', (248, 260))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('mesothelioma', 'Disease', 'MESH:D008654', (248, 260))	('prolactinoma', 'Disease', (447, 459))	('mesothelioma', 'Disease', (182, 194))	('mesothelioma', 'Disease', 'MESH:D008654', (182, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('prolactinoma', 'Disease', 'MESH:D015175', (447, 459))	('patient', 'Species', '9606', (434, 441))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (295, 319))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (295, 319))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('pulmonary adenocarcinoma', 'Disease', (295, 319))	('paraganglioma', 'Disease', (110, 123))	('c.1708C>G', 'Mutation', 'c.1708C>G', (4, 13))
48084	22889334	We next performed RT-PCR analysis to evaluate whether aberrant splicing of the BAP1 transcript occurs precisely as predicted in carriers of the c.1708C>G mutation.	('c.1708C>G', 'Var', (144, 153))	('BAP1', 'Gene', '8314', (79, 83))	('BAP1', 'Gene', (79, 83))	('c.1708C>G', 'Mutation', 'c.1708C>G', (144, 153))
48087	22889334	As predicted, blood from individuals harboring the c.1708C>G variant yields both the 124-bp product as well as a second band 22 bp shorter, suggesting that the cryptic splice donor causes aberrant splicing.	('c.1708C>G', 'Mutation', 'c.1708C>G', (51, 60))	('causes', 'Reg', (181, 187))	('c.1708C>G', 'Var', (51, 60))	('splicing', 'MPA', (197, 205))
48088	22889334	Sequencing of the correctly spliced 124-bp product from c.1708C>G heterozygous individuals indicated no detectable trace of the c.1708C>G allele, suggesting that the majority of transcript from the mutant allele is improperly spliced (Fig.	('c.1708C>G', 'Var', (128, 137))	('c.1708C>G', 'Mutation', 'c.1708C>G', (56, 65))	('c.1708C>G', 'Var', (56, 65))	('c.1708C>G', 'Mutation', 'c.1708C>G', (128, 137))
48091	22889334	Another UMM case (III-1) displayed monosomy of chromosome 3, but the DNA was of insufficient quantity to genotype c.1708C>G.	('c.1708C>G', 'Var', (114, 123))	('monosomy', 'MPA', (35, 43))	('c.1708C>G', 'Mutation', 'c.1708C>G', (114, 123))
48092	22889334	BAP1 immunohistochemistry was performed on available archival tumor tissues from carriers of this germ line BAP1 mutation but was not successful.	('mutation', 'Var', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BAP1', 'Gene', (0, 4))	('BAP1', 'Gene', '8314', (108, 112))	('tumor', 'Disease', (62, 67))	('BAP1', 'Gene', (108, 112))	('BAP1', 'Gene', '8314', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
48094	22889334	Of the eight reported multi-cancer families harboring germ line inactivating BAP1 mutations, including the family reported here, three have both UMM and mesothelioma (or suspected mesothelioma).	('mesothelioma', 'Disease', 'MESH:D008654', (180, 192))	('mesothelioma', 'Disease', 'MESH:D008654', (153, 165))	('multi-cancer', 'Disease', (22, 34))	('multi-cancer', 'Disease', 'MESH:D009369', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('BAP1', 'Gene', '8314', (77, 81))	('mutations', 'Var', (82, 91))	('mesothelioma', 'Disease', (180, 192))	('mesothelioma', 'Disease', (153, 165))	('BAP1', 'Gene', (77, 81))	('UMM', 'Disease', (145, 148))
48096	22889334	Notably, we identified a patient with paraganglioma carrying a germ line BAP1 mutation and showed that the WT BAP1 allele was lost somatically.	('BAP1', 'Gene', '8314', (73, 77))	('BAP1', 'Gene', '8314', (110, 114))	('mutation', 'Var', (78, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (38, 51))	('BAP1', 'Gene', (73, 77))	('BAP1', 'Gene', (110, 114))	('paraganglioma', 'Disease', (38, 51))	('patient', 'Species', '9606', (25, 32))	('paraganglioma', 'Disease', 'MESH:D010235', (38, 51))
48098	22889334	We suggest that BAP1 is truly a broad-spectrum tumor suppressor gene and that multi-cancer families and cases of apparently sporadic paragangliomas warrant screening for germ line BAP1 mutations.	('paragangliomas', 'Disease', (133, 147))	('paragangliomas', 'Disease', 'MESH:D010235', (133, 147))	('tumor', 'Disease', (47, 52))	('multi-cancer', 'Disease', (78, 90))	('paragangliomas', 'Phenotype', 'HP:0002668', (133, 147))	('BAP1', 'Gene', '8314', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('BAP1', 'Gene', '8314', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BAP1', 'Gene', (180, 184))	('mutations', 'Var', (185, 194))	('paraganglioma', 'Phenotype', 'HP:0002668', (133, 146))	('BAP1', 'Gene', (16, 20))	('multi-cancer', 'Disease', 'MESH:D009369', (78, 90))
48101	22889334	Germ line BAP1 mutations have recently been identified in a few families with melanoma and mesothelioma.	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma and mesothelioma', 'Disease', 'MESH:D008654', (78, 103))	('identified', 'Reg', (44, 54))	('BAP1', 'Gene', '8314', (10, 14))
48102	22889334	We report an apparent missense mutation of BAP1 resulting in aberrant splicing and a truncating frameshift in a family with melanoma, suspected mesothelioma, and paraganglioma.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('BAP1', 'Gene', (43, 47))	('melanoma', 'Disease', (124, 132))	('paraganglioma', 'Disease', 'MESH:D010235', (162, 175))	('mesothelioma', 'Disease', (144, 156))	('resulting in', 'Reg', (48, 60))	('BAP1', 'Gene', '8314', (43, 47))	('aberrant splicing', 'MPA', (61, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('truncating', 'MPA', (85, 95))	('mesothelioma', 'Disease', 'MESH:D008654', (144, 156))	('missense mutation', 'Var', (22, 39))	('paraganglioma', 'Disease', (162, 175))
48243	32026115	Some reports suggest the use of nonselective alpha blockers, such as phentolamine or phenoxybenzamine, for the treatment of gastrointestinal complications of pheochromocytoma.	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (85, 101))	('gastrointestinal complications of pheochromocytoma', 'Disease', (124, 174))	('phentolamine', 'Chemical', 'MESH:D010646', (69, 81))	('phenoxybenzamine', 'Var', (85, 101))	('gastrointestinal complications', 'Phenotype', 'HP:0004798', (124, 154))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (158, 174))	('gastrointestinal complications of pheochromocytoma', 'Disease', 'MESH:D010673', (124, 174))
48251	32026115	Another possibility can be maldistribution of adrenergic receptors, which should be affected by over-secreted catecholamines due to pheochromocytoma and would recover gradually postoperatively, which might be consistent with our patient's recovery time course.	('over-secreted', 'PosReg', (96, 109))	('pheochromocytoma', 'Disease', 'MESH:D010673', (132, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (132, 148))	('affected', 'Reg', (84, 92))	('maldistribution', 'Var', (27, 42))	('catecholamines', 'Chemical', 'MESH:D002395', (110, 124))	('adrenergic receptors', 'Protein', (46, 66))	('patient', 'Species', '9606', (229, 236))	('pheochromocytoma', 'Disease', (132, 148))
48254	32026115	MIBG 123I-metaiodobenzylguanidine NR Normal range SVI Stroke volume index SVV Stroke volume variation SO conducted the anesthetic management.	('Stroke', 'Disease', (78, 84))	('Stroke', 'Disease', 'MESH:D020521', (78, 84))	('Stroke', 'Phenotype', 'HP:0001297', (54, 60))	('MIBG', 'Chemical', 'MESH:C492712', (0, 4))	('Stroke', 'Disease', 'MESH:D020521', (54, 60))	('123I-metaiodobenzylguanidine', 'Chemical', 'MESH:C492712', (5, 33))	('Stroke', 'Phenotype', 'HP:0001297', (78, 84))	('123I-metaiodobenzylguanidine', 'Var', (5, 33))	('Stroke volume variation', 'Disease', (78, 101))	('Stroke volume variation', 'Disease', 'MESH:D020521', (78, 101))	('SO', 'Chemical', 'MESH:C443440', (102, 104))	('Stroke', 'Disease', (54, 60))
48274	31778356	RET oncogene mutations in neural crest tissue in thyroid can lead to MTC development.	('RET', 'Gene', '5979', (0, 3))	('lead to', 'Reg', (61, 68))	('MTC', 'Phenotype', 'HP:0002865', (69, 72))	('RET', 'Gene', (0, 3))	('men', 'Species', '9606', (80, 83))	('MTC development', 'CPA', (69, 84))	('mutations', 'Var', (13, 22))
48301	31778356	According to TNM Staging System of American Joint Committee on Cancer (AJCC) seventh edition (in use at time of thyroidectomy), tumor staging was pT2 N0 Mx - Stage II for medullary thyroid carcinoma and pT3 N0 MX - Stage III for papillary thyroid cancer.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('pT2 N0 Mx -', 'Var', (146, 157))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (171, 198))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (229, 253))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (181, 198))	('TNM', 'Gene', (13, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (181, 198))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (229, 253))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('thyroid cancer', 'Phenotype', 'HP:0002890', (239, 253))	('tumor', 'Disease', (128, 133))	('TNM', 'Gene', '10178', (13, 16))	('thyroid carcinoma', 'Disease', (181, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('papillary thyroid cancer', 'Disease', (229, 253))
48343	31778356	The hypotheses of a common genetic drive was excluded because of different mutations in the two histological types: mutation of RET gene for MTC and mainly BRAF gene for PTC.	('PTC', 'Disease', 'MESH:C536915', (170, 173))	('BRAF', 'Gene', (156, 160))	('RET', 'Gene', '5979', (128, 131))	('MTC', 'Phenotype', 'HP:0002865', (141, 144))	('mutation', 'Var', (116, 124))	('PTC', 'Phenotype', 'HP:0002895', (170, 173))	('PTC', 'Disease', (170, 173))	('RET', 'Gene', (128, 131))	('BRAF', 'Gene', '673', (156, 160))
48455	31234811	Master regulator analysis of paragangliomas carrying SDHx, VHL, or MAML3 genetic alterations Succinate dehydrogenase (SDH) loss and mastermind-like 3 (MAML3) translocation are two clinically important genetic alterations that correlate with increased rates of metastasis in subtypes of human paraganglioma and pheochromocytoma (PPGL) neuroendocrine tumors.	('SDH', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (310, 326))	('Succinate dehydrogenase', 'Gene', '6390', (93, 116))	('loss', 'NegReg', (123, 127))	('MAML3', 'Gene', (151, 156))	('mastermind-like 3', 'Gene', '55534', (132, 149))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('neuroendocrine tumors', 'Disease', (334, 355))	('paraganglioma', 'Phenotype', 'HP:0002668', (292, 305))	('human', 'Species', '9606', (286, 291))	('SDH', 'Gene', '6390', (118, 121))	('MAML3', 'Gene', '55534', (151, 156))	('paragangliomas', 'Disease', 'MESH:D010235', (29, 43))	('alterations', 'Var', (81, 92))	('metastasis', 'CPA', (260, 270))	('VHL', 'Gene', (59, 62))	('mastermind-like 3', 'Gene', (132, 149))	('paragangliomas', 'Phenotype', 'HP:0002668', (29, 43))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('MAML3', 'Gene', (67, 72))	('increased', 'PosReg', (241, 250))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (334, 355))	('SDH', 'Gene', '6390', (53, 56))	('SDH', 'Gene', (118, 121))	('MAML3', 'Gene', '55534', (67, 72))	('paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (292, 326))	('VHL', 'Gene', '7428', (59, 62))	('paragangliomas', 'Disease', (29, 43))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (334, 355))	('Succinate dehydrogenase', 'Gene', (93, 116))
48458	31234811	We hypothesize that a key to understanding tumorigenesis driven by these genetic alterations is identification of the transcription factors responsible for the observed oncogenic transcriptional changes.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('alterations', 'Var', (81, 92))
48469	31234811	Over the last two decades more than 20 potentially causative genetic alterations have been elucidated for PPGL, including mutations in genes involved in kinase signalling, hypoxic response, and tricarboxylic acid (TCA) cycle metabolism.	('TCA', 'Chemical', 'MESH:D014233', (214, 217))	('hypoxic', 'Disease', (172, 179))	('hypoxic', 'Disease', 'MESH:D000860', (172, 179))	('PPGL', 'Gene', (106, 110))	('causative', 'Reg', (51, 60))	('mutations', 'Var', (122, 131))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (194, 212))
48471	31234811	In particular, patients with mutations in genes encoding components of the succinate dehydrogenase (SDH) complex of the TCA cycle, tend toward shorter metastasis-free survival and shorter overall survival.	('succinate dehydrogenase', 'Gene', (75, 98))	('patients', 'Species', '9606', (15, 23))	('SDH', 'Gene', '6390', (100, 103))	('shorter', 'NegReg', (143, 150))	('TCA', 'Chemical', 'MESH:D014233', (120, 123))	('metastasis-free survival', 'CPA', (151, 175))	('mutations', 'Var', (29, 38))	('SDH', 'Gene', (100, 103))	('shorter', 'NegReg', (180, 187))	('overall survival', 'CPA', (188, 204))	('succinate dehydrogenase', 'Gene', '6390', (75, 98))
48472	31234811	Recently, a large-scale integrative genomic analysis of PPGL through The Cancer Genome Atlas (TCGA) Project described another important genetic alteration in PPGL: a translocation involving the MAML3 gene.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (73, 92))	('PPGL', 'Gene', (56, 60))	('PPGL', 'Gene', (158, 162))	('translocation', 'Var', (166, 179))	('MAML3', 'Gene', '55534', (194, 199))	('Cancer Genome Atlas', 'Disease', (73, 92))	('MAML3', 'Gene', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))
48474	31234811	Collectively, this study estimated that ~ 11% of PPGL patients carry germline mutations in the four genes (SDHA, SDHB, SDHC, SDHD; SDHx) encoding SDH subunits, and ~ 5% of PPGL patients have tumor DNA carrying the novel MAML3 translocation.	('SDHA', 'Gene', '6389', (107, 111))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('SDH', 'Gene', '6390', (119, 122))	('SDH', 'Gene', (107, 110))	('SDH', 'Gene', (146, 149))	('SDH', 'Gene', (131, 134))	('SDH', 'Gene', (113, 116))	('SDHC', 'Gene', '6391', (119, 123))	('mutations', 'Var', (78, 87))	('MAML3', 'Gene', (220, 225))	('SDHx', 'Chemical', '-', (131, 135))	('SDHD', 'Gene', '6392', (125, 129))	('SDH', 'Gene', (119, 122))	('SDHB', 'Gene', '6390', (113, 117))	('SDH', 'Gene', '6390', (125, 128))	('MAML3', 'Gene', '55534', (220, 225))	('tumor', 'Disease', (191, 196))	('SDHD', 'Gene', (125, 129))	('SDHC', 'Gene', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('SDH', 'Gene', '6390', (107, 110))	('patients', 'Species', '9606', (177, 185))	('SDH', 'Gene', '6390', (131, 134))	('SDHB', 'Gene', (113, 117))	('SDH', 'Gene', '6390', (146, 149))	('SDHA', 'Gene', (107, 111))	('SDH', 'Gene', '6390', (113, 116))	('SDH', 'Gene', (125, 128))
48482	31234811	In the latter case, hypoxic signalling is thought to be constitutively activated due to a defect in VHL, the E3 ubiquitin ligase responsible for ubiquitination of hydroxylated HIF-alpha subunits, normally targeting them for proteasomal degradation.	('defect', 'Var', (90, 96))	('activated', 'PosReg', (71, 80))	('hypoxic', 'Disease', (20, 27))	('hypoxic', 'Disease', 'MESH:D000860', (20, 27))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (100, 103))
48485	31234811	We are ultimately interested in understanding the mechanistic linkage between specific gene defects and PPGL tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('defects', 'Var', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('PPGL', 'Gene', (104, 108))	('tumor', 'Disease', (109, 114))
48513	31234811	Stable SDHC-loss and hemizygous control cell lines were plated into 96-well plates at a density of approximately 20,000 cells per well in 100 muL of DMEM medium containing 10% FBS, penicillin (100 units/mL), streptomycin (100 mug/mL), 1 mM pyruvate, 1X MEM NEAA, and 10 mM HEPES buffer (pH 7.2-7.5) and cultured at 21% O2 and 5% CO2.	('HEPES', 'Chemical', 'MESH:D006531', (273, 278))	('penicillin', 'Chemical', 'MESH:D010406', (181, 191))	('pyruvate', 'Chemical', 'MESH:D019289', (240, 248))	('DMEM medium', 'Chemical', '-', (149, 160))	('CO2', 'Chemical', '-', (329, 332))	('streptomycin', 'Chemical', 'MESH:D013307', (208, 220))	('100', 'Var', (222, 225))	('O2', 'Chemical', '-', (319, 321))	('O2', 'Chemical', '-', (330, 332))	('SDHC-loss', 'Disease', 'MESH:D015431', (7, 16))	('NEAA', 'Chemical', '-', (257, 261))	('SDHC-loss', 'Disease', (7, 16))
48548	31234811	Importantly, this suggests that HIF-related transcriptional dysregulation is detectible, but that it inadequately accounts for the majority of transcriptional perturbations observed in these "pseudohypoxic" tumor subtypes, and that dysregulation of other transcription factors may play a much more important role in driving oncogenic transcriptomic patterns than previously appreciated.	('dysregulation', 'Var', (232, 245))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('hypoxic', 'Disease', 'MESH:D000860', (198, 205))	('tumor', 'Disease', (207, 212))	('hypoxic', 'Disease', (198, 205))
48550	31234811	This is particularly intriguing because the reported MAML3 translocations involve chr18~chr4 fusion (TCF4~MAML3 gene fusion) or chr17~chr4 fusion (UBTF-MAML3 gene fusion), with the IRX4 locus on chromosome 5 being unaffected in either case.	('MAML3', 'Gene', '55534', (106, 111))	('IRX4', 'Gene', '50805', (181, 185))	('chr17~chr4', 'Var', (128, 138))	('MAML3', 'Gene', (106, 111))	('UBTF', 'Gene', (147, 151))	('chr18~chr4', 'Gene', (82, 92))	('TCF4', 'Gene', (101, 105))	('TCF4', 'Gene', '6925', (101, 105))	('MAML3', 'Gene', '55534', (152, 157))	('MAML3', 'Gene', (152, 157))	('IRX4', 'Gene', (181, 185))	('UBTF', 'Gene', '7343', (147, 151))	('MAML3', 'Gene', '55534', (53, 58))	('MAML3', 'Gene', (53, 58))
48554	31234811	These data support the notion that subnetwork #2 is likely important for cell survival, and additionally, that modulation of subnetwork #1 may be a mechanism by which tumor cells acquire an invasive phenotype.	('modulation', 'Var', (111, 121))	('subnetwork #1', 'Gene', (125, 138))	('invasive phenotype', 'CPA', (190, 208))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('acquire', 'PosReg', (179, 186))	('tumor', 'Disease', (167, 172))
48573	31234811	We then specifically considered EPAS1, a transcription factor of much interest to the field, testing the hypothesis that tumors originating from different SDH subunit mutations have variable EPAS1 activity.	('EPAS1', 'Gene', (191, 196))	('SDH', 'Gene', '6390', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (167, 176))	('activity', 'MPA', (197, 205))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('SDH', 'Gene', (155, 158))	('EPAS1', 'Gene', '2034', (32, 37))	('EPAS1', 'Gene', '2034', (191, 196))	('EPAS1', 'Gene', (32, 37))
48574	31234811	3e, revealed similarly elevated levels of EPAS1 activity in SDHB-null, SDHC-null, and SDHD-null PPGL tumors compared to those attributable to RET of NF1 gain-of-function mutations.	('gain-of-function', 'PosReg', (153, 169))	('SDHD-null PPGL tumors', 'Disease', 'MESH:C564833', (86, 107))	('SDHC', 'Gene', '6391', (71, 75))	('activity', 'MPA', (48, 56))	('RET', 'Gene', '5979', (142, 145))	('mutations', 'Var', (170, 179))	('elevated', 'PosReg', (23, 31))	('SDHB', 'Gene', '6390', (60, 64))	('SDHD-null PPGL tumors', 'Disease', (86, 107))	('SDHB', 'Gene', (60, 64))	('EPAS1', 'Gene', '2034', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('EPAS1', 'Gene', (42, 47))	('RET', 'Gene', (142, 145))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NF1', 'Gene', (149, 152))	('NF1', 'Gene', '4763', (149, 152))	('SDHC', 'Gene', (71, 75))
48593	31234811	This analysis revealed five potentially conserved MRs, a number that is higher than would be predicted by random chance, suggesting that perturbation of these MRs represents a conserved biological response to SDH loss (Fig.	('SDH loss', 'Disease', (209, 217))	('perturbation', 'Var', (137, 149))	('SDH loss', 'Disease', 'MESH:D015431', (209, 217))
48603	31234811	A second subset of synergistic partners (FOS, HMX2, HOXA11, ARNTL, RXRG, ZIC2, POU3F2, TAL1, EHF, POU3F1, KLF15, NR1H3, NFE2L3, AR, and BCL6B) was inferred for which ZFP423 binding attenuates the general transcription-activating activity of these TFs.	('RXRG', 'Gene', '6258', (67, 71))	('FOS', 'Gene', (41, 44))	('NFE2L3', 'Gene', (120, 126))	('TAL1', 'Gene', (87, 91))	('EHF', 'Gene', '26298', (93, 96))	('FOS', 'Gene', '2353', (41, 44))	('NR1H3', 'Gene', (113, 118))	('KLF15', 'Gene', '28999', (106, 111))	('RXRG', 'Gene', (67, 71))	('ZFP423', 'Var', (166, 172))	('HOXA11', 'Gene', (52, 58))	('POU3F2', 'Gene', '5454', (79, 85))	('BCL6B', 'Gene', '255877', (136, 141))	('HMX2', 'Gene', '3167', (46, 50))	('POU3F2', 'Gene', (79, 85))	('HMX2', 'Gene', (46, 50))	('NFE2L3', 'Gene', '9603', (120, 126))	('general transcription-activating activity', 'MPA', (196, 237))	('TAL1', 'Gene', '6886', (87, 91))	('BCL6B', 'Gene', (136, 141))	('POU3F1', 'Gene', (98, 104))	('ZIC2', 'Gene', (73, 77))	('HOXA11', 'Gene', '3207', (52, 58))	('attenuates', 'NegReg', (181, 191))	('ZIC2', 'Gene', '7546', (73, 77))	('KLF15', 'Gene', (106, 111))	('NR1H3', 'Gene', '10062', (113, 118))	('binding', 'Interaction', (173, 180))	('ARNTL', 'Gene', '406', (60, 65))	('ARNTL', 'Gene', (60, 65))	('POU3F1', 'Gene', '5453', (98, 104))	('EHF', 'Gene', (93, 96))
48629	31234811	The differentiation responses of SH-SY5Y to retinoic acid have been previously well-characterized, with resultant phenotypic changes in neurite outgrowth that are readily apparent through morphological image analysis that has been broadly used to probe the pathways involved in neuronal differentiation.	('retinoic acid', 'Chemical', 'MESH:D014212', (44, 57))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (33, 40))	('changes', 'Reg', (125, 132))	('SH-SY5Y', 'Var', (33, 40))
48636	31234811	This, in turn, suggests that perturbation of TF activities plays a larger role in modulating oncogenic gene expression in these tumors than previously appreciated.	('modulating', 'Reg', (82, 92))	('oncogenic gene expression', 'MPA', (93, 118))	('perturbation', 'Var', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
48638	31234811	Since the molecular defect in VHL-loss tumors is mutation of the VHL E3 ubiquitin ligase downstream of the prolylhydroxylases believed to be poisoned by succinate accumulation, one potential hypothesis is that these conserved MRs are previously unappreciated direct or indirect clients of both prolylhydroxylases and VHL E3 ubiquitin ligase.	('VHL', 'Gene', '7428', (65, 68))	('VHL-loss tumors', 'Disease', (30, 45))	('VHL', 'Gene', '7428', (317, 320))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('succinate', 'Chemical', 'MESH:D019802', (153, 162))	('VHL', 'Gene', (30, 33))	('mutation', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('VHL', 'Gene', '7428', (30, 33))	('VHL', 'Gene', (65, 68))	('VHL-loss tumors', 'Disease', 'MESH:D006623', (30, 45))	('VHL', 'Gene', (317, 320))
48649	31234811	Categories of other potential mechanisms include dysregulation of other TFs, classical epigenomic derangement via dioxygenase poisoning of TET DNA demethylases and Jumonji domain-containing histone demethylases, as well as dysregulation of cellular acylation patterns, as recently described.	('poisoning', 'Disease', 'MESH:D011041', (126, 135))	('cellular acylation patterns', 'MPA', (240, 267))	('dysregulation', 'Var', (223, 236))	('dysregulation', 'Var', (49, 62))	('poisoning', 'Disease', (126, 135))
48684	30540124	However, a much higher incidence of adrenal tumors (>15 times) has been demonstrated in the pediatric population in south and southeastern Brazil, and these tumors are associated with a specific germline mutation in TP53 .	('TP53', 'Gene', (216, 220))	('tumors', 'Disease', (44, 50))	('associated', 'Reg', (168, 178))	('adrenal tumors', 'Disease', 'MESH:D000310', (36, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('adrenal tumors', 'Disease', (36, 50))	('germline mutation', 'Var', (195, 212))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TP53', 'Gene', '7157', (216, 220))
48689	30540124	In south and southeastern Brazil, approximately 78% of children and 13% of adults with adrenal tumors harbor a specific germline mutation (p.R337H) of the p53 tumor suppressor.	('p.R337H', 'Mutation', 'rs121912664', (139, 146))	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('adrenal tumors', 'Disease', 'MESH:D000310', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('adrenal tumors', 'Disease', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p.R337H', 'Var', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (95, 100))	('children', 'Species', '9606', (55, 63))
48690	30540124	A founder effect has been demonstrated in the great majority of pediatric Brazilian patients with adrenocortical tumors caused by this p53 mutation.	('mutation', 'Var', (139, 147))	('patients', 'Species', '9606', (84, 92))	('p53', 'Gene', (135, 138))	('caused by', 'Reg', (120, 129))	('adrenocortical tumors', 'Disease', (98, 119))	('p53', 'Gene', '7157', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (98, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
48696	30540124	LFS is a cancer predisposition syndrome usually caused by an inherited TP53 gene mutation and is characterized by a high occurrence of sarcomas, early onset breast cancer, brain cancer and leukemia.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('sarcomas', 'Disease', 'MESH:D012509', (135, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('sarcomas', 'Phenotype', 'HP:0100242', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('brain cancer', 'Phenotype', 'HP:0030692', (172, 184))	('sarcomas', 'Disease', (135, 143))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('LFS', 'Disease', (0, 3))	('breast cancer', 'Disease', (157, 170))	('leukemia', 'Phenotype', 'HP:0001909', (189, 197))	('brain cancer', 'Disease', 'MESH:D001932', (172, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TP53', 'Gene', '7157', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('caused by', 'Reg', (48, 57))	('leukemia', 'Disease', (189, 197))	('mutation', 'Var', (81, 89))	('leukemia', 'Disease', 'MESH:D007938', (189, 197))	('cancer', 'Disease', (164, 170))	('brain cancer', 'Disease', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (178, 184))	('TP53', 'Gene', (71, 75))
48698	30540124	Somatic TP53 mutations have been identified in 25-35% of sporadic ACCs.	('mutations', 'Var', (13, 22))	('identified', 'Reg', (33, 43))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))
48699	30540124	Nevertheless, these mutations represent a late event during carcinogenesis and have been associated with larger tumors and more advanced disease.	('associated', 'Reg', (89, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
48700	30540124	Somatic mutations in the TP53 gene are a predictor of poor overall survival in adults with ACC.	('Somatic mutations', 'Var', (0, 17))	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', (25, 29))
48704	30540124	Genetic or epigenetic alterations in the 11p15 region may alter the expression of the CDKN1C, IGF2 and H19 genes, which are structurally organized in a cluster, increasing IGF2 expression and inactivating the CDKN1C and H19 genes, which are a negative cell cycle regulator and a transcriptional repressor of IGF2, respectively.	('expression', 'MPA', (68, 78))	('IGF2', 'Gene', (94, 98))	('alter', 'Reg', (58, 63))	('CDKN1C', 'Gene', (209, 215))	('expression', 'MPA', (177, 187))	('IGF2', 'Gene', (172, 176))	('IGF2', 'Gene', '3481', (308, 312))	('CDKN1C', 'Gene', '1028', (86, 92))	('H19', 'Gene', (103, 106))	('epigenetic alterations', 'Var', (11, 33))	('IGF2', 'Gene', '3481', (94, 98))	('H19', 'Gene', (220, 223))	('H19', 'Gene', '283120', (103, 106))	('IGF2', 'Gene', '3481', (172, 176))	('CDKN1C', 'Gene', (86, 92))	('CDKN1C', 'Gene', '1028', (209, 215))	('H19', 'Gene', '283120', (220, 223))	('inactivating', 'NegReg', (192, 204))	('increasing', 'PosReg', (161, 171))	('IGF2', 'Gene', (308, 312))
48708	30540124	Furthermore, the difference between BUB1B and PINK1 gene expression was a significant predictor of OS in adults.	('expression', 'MPA', (57, 67))	('PINK1', 'Gene', '65018', (46, 51))	('PINK1', 'Gene', (46, 51))	('predictor', 'Reg', (86, 95))	('BUB1B', 'Gene', '701', (36, 41))	('BUB1B', 'Gene', (36, 41))	('difference', 'Var', (17, 27))
48725	30540124	High levels of Ki67 have also been associated with worse OS in patients with advanced disease and can help in decision-making regarding treatment.	('men', 'Species', '9606', (141, 144))	('worse OS', 'Disease', (51, 59))	('associated', 'Reg', (35, 45))	('help', 'Reg', (102, 106))	('patients', 'Species', '9606', (63, 71))	('Ki67', 'Var', (15, 19))
48757	30540124	In addition to its use in the adjuvant setting, mitotane is associated with a 30% objective response rate among patients with metastatic disease in retrospective studies.	('mitotane', 'Chemical', 'MESH:D008939', (48, 56))	('metastatic disease', 'Disease', (126, 144))	('patients', 'Species', '9606', (112, 120))	('mitotane', 'Var', (48, 56))
48765	30540124	Mitotane also increases the concentrations of cortisol-binding globulin hormone (CBG), steroid-binding globulin (SHBG), and thyroxine-binding globulin (TBG).	('CBG', 'Gene', '866', (81, 84))	('Mitotane', 'Var', (0, 8))	('cortisol-binding globulin hormone', 'MPA', (46, 79))	('increases', 'PosReg', (14, 23))	('SHBG', 'Gene', '6462', (113, 117))	('steroid-binding globulin', 'MPA', (87, 111))	('CBG', 'Gene', (81, 84))	('thyroxine-binding globulin', 'Gene', '6906', (124, 150))	('Mitotane', 'Chemical', 'MESH:D008939', (0, 8))	('TBG', 'Gene', (152, 155))	('thyroxine-binding globulin', 'Gene', (124, 150))	('steroid', 'Chemical', 'MESH:D013256', (87, 94))	('SHBG', 'Gene', (113, 117))	('TBG', 'Gene', '6906', (152, 155))	('concentrations', 'MPA', (28, 42))
48766	30540124	Furthermore, mitotane may impair pituitary gland function by reducing TSH secretion with consequent hypothyroidism and gonadal function causing hypergonadotropic hypogonadism.	('reducing', 'NegReg', (61, 69))	('hypogonadism', 'Phenotype', 'HP:0000135', (162, 174))	('reducing TSH secretion with consequent hypothyroidism', 'Phenotype', 'HP:0008245', (61, 114))	('reducing TSH', 'Phenotype', 'HP:0031098', (61, 73))	('hypothyroidism', 'Disease', 'MESH:D007037', (100, 114))	('mitotane', 'Chemical', 'MESH:D008939', (13, 21))	('hypothyroidism', 'Disease', (100, 114))	('gonadal function', 'CPA', (119, 135))	('TSH', 'Chemical', '-', (70, 73))	('hypothyroidism', 'Phenotype', 'HP:0000821', (100, 114))	('TSH secretion', 'MPA', (70, 83))	('hypergonadotropic hypogonadism', 'Phenotype', 'HP:0000815', (144, 174))	('mitotane', 'Var', (13, 21))	('impair', 'NegReg', (26, 32))	('hypogonadism', 'Disease', (162, 174))	('pituitary', 'CPA', (33, 42))	('hypogonadism', 'Disease', 'MESH:D007006', (162, 174))
48770	30540124	Notably, mitotane induces adrenal insufficiency due to the inhibition of steroidogenesis enzymes.	('inhibition', 'NegReg', (59, 69))	('steroidogenesis enzymes', 'Enzyme', (73, 96))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (26, 47))	('steroid', 'Chemical', 'MESH:D013256', (73, 80))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (26, 47))	('mitotane', 'Var', (9, 17))	('induces', 'Reg', (18, 25))	('adrenal insufficiency', 'Disease', (26, 47))	('mitotane', 'Chemical', 'MESH:D008939', (9, 17))
48789	30540124	These susceptibility genes can be divided into two clusters: cluster 1 tumors include those with mutations of genes encoding the von Hippel-Lindau (VHL) suppressor, the four subunits of the succinate dehydrogenase complex (SDHA, SDHB, SDHC, and SDHD), and less commonly, the enzyme responsible for flavination of the SDHA subunit (SDHAF2), fumarate hydratase, malate dehydrogenase 2, and prolyl hydroxylases 1 and 2.	('mutations', 'Var', (97, 106))	('SDHB', 'Gene', '6390', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('SDHC', 'Gene', (235, 239))	('SDHD', 'Gene', '6392', (245, 249))	('fumarate hydratase', 'Gene', '2271', (340, 358))	('SDHB', 'Gene', (229, 233))	('VHL', 'Disease', 'MESH:D006623', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('von Hippel-Lindau', 'Gene', (129, 146))	('malate dehydrogenase 2', 'Gene', (360, 382))	('SDHD', 'Gene', (245, 249))	('SDHC', 'Gene', '6391', (235, 239))	('malate dehydrogenase 2', 'Gene', '4191', (360, 382))	('von Hippel-Lindau', 'Gene', '7428', (129, 146))	('fumarate hydratase', 'Gene', (340, 358))	('SDHAF2', 'Gene', (331, 337))	('SDHAF2', 'Gene', '54949', (331, 337))	('VHL', 'Disease', (148, 151))
48790	30540124	These genetic alterations result in stabilization of hypoxia-inducible factors and activation of the hypoxia signaling pathways.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('hypoxia', 'Disease', (101, 108))	('stabilization', 'MPA', (36, 49))	('hypoxia', 'Disease', 'MESH:D000860', (101, 108))	('genetic alterations', 'Var', (6, 25))	('activation', 'PosReg', (83, 93))
48791	30540124	Cluster 2 includes tumors with mutations of the neurofibromatosis type 1 (NF1) tumor suppressor gene, the rearranged during transfection (RET) proto-oncogene, genes encoding transmembrane protein 127 (TMEM127) and MYC-associated factor X (MAX) (Table 3).	('tumors', 'Disease', (19, 25))	('transmembrane protein 127', 'Gene', (174, 199))	('mutations', 'Var', (31, 40))	('neurofibromatosis type 1 (NF1) tumor', 'Disease', 'MESH:C537392', (48, 84))	('RET', 'Gene', '5979', (138, 141))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('transmembrane protein 127', 'Gene', '55654', (174, 199))	('TMEM127', 'Gene', (201, 208))	('TMEM127', 'Gene', '55654', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MYC-associated factor X', 'Gene', '4149', (214, 237))	('MYC-associated factor X', 'Gene', (214, 237))	('RET', 'Gene', (138, 141))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('MAX', 'Gene', '4149', (239, 242))	('MAX', 'Gene', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (48, 65))
48794	30540124	Most PPGLs hypersecrete catecholamines and are associated with increased cardiovascular morbidity and mortality.	('PPGLs', 'Chemical', '-', (5, 10))	('PPGLs', 'Var', (5, 10))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (73, 97))	('increased', 'PosReg', (63, 72))	('associated with', 'Reg', (47, 62))	('cardiovascular', 'Disease', (73, 87))	('hypersecrete catecholamines', 'MPA', (11, 38))	('catecholamines', 'Chemical', 'MESH:D002395', (24, 38))
48795	30540124	Additionally, PPGLs may cause mass-effect symptoms and have malignant potential.	('cause', 'Reg', (24, 29))	('PPGLs', 'Var', (14, 19))	('PPGLs', 'Chemical', '-', (14, 19))	('malignant potential', 'CPA', (60, 79))	('mass-effect symptoms', 'Disease', (30, 50))
48800	30540124	Patients who are young and those with larger tumors (>6 cm), positive genetic testing (especially SDHB) or paragangliomas have an increased risk of metastasis and require long-term follow-up.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('paragangliomas', 'Disease', (107, 121))	('metastasis', 'CPA', (148, 158))	('SDHB', 'Gene', '6390', (98, 102))	('paragangliomas', 'Disease', 'MESH:D010235', (107, 121))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('SDHB', 'Gene', (98, 102))	('Patients', 'Species', '9606', (0, 8))	('paragangliomas', 'Phenotype', 'HP:0002668', (107, 121))	('paraganglioma', 'Phenotype', 'HP:0002668', (107, 120))	('positive genetic testing', 'Var', (61, 85))
48802	30540124	In a recent study, 76% of patients with malignant PPGLs had germline mutations in susceptibility genes for PPGL (SDHB, 44%; SDHD, 8%; VHL, 12%; NF1, 12%; and RET, 0%).	('mutations', 'Var', (69, 78))	('SDHB', 'Gene', '6390', (113, 117))	('PPGL', 'Gene', (107, 111))	('RET', 'Gene', (158, 161))	('VHL', 'Disease', (134, 137))	('PPGLs', 'Chemical', '-', (50, 55))	('VHL', 'Disease', 'MESH:D006623', (134, 137))	('SDHD', 'Gene', '6392', (124, 128))	('SDHB', 'Gene', (113, 117))	('patients', 'Species', '9606', (26, 34))	('RET', 'Gene', '5979', (158, 161))	('NF1', 'Gene', '4763', (144, 147))	('NF1', 'Gene', (144, 147))	('SDHD', 'Gene', (124, 128))
48803	30540124	TMEM127 and MAX mutations have also been described in patients with malignant PPGLs.	('described', 'Reg', (41, 50))	('PPGLs', 'Chemical', '-', (78, 83))	('patients', 'Species', '9606', (54, 62))	('TMEM127', 'Gene', '55654', (0, 7))	('mutations', 'Var', (16, 25))	('MAX', 'Gene', '4149', (12, 15))	('MAX', 'Gene', (12, 15))	('PPGLs', 'Disease', (78, 83))	('TMEM127', 'Gene', (0, 7))
48812	30540124	123I-MIBG is inferior to 18F-FDG-PET or somatostatin receptor imaging for paragangliomas or metastatic disease associated with SDHx-related tumors.	('paragangliomas', 'Disease', (74, 88))	('paragangliomas', 'Disease', 'MESH:D010235', (74, 88))	('paragangliomas', 'Phenotype', 'HP:0002668', (74, 88))	('123I-MIBG', 'Var', (0, 9))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('SDHx', 'Chemical', '-', (127, 131))	('123I-MIBG', 'Chemical', '-', (0, 9))	('18F-FDG', 'Chemical', '-', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))	('metastatic disease', 'CPA', (92, 110))
48824	30540124	Patients with pheochromocytomas larger than 6 cm or paragangliomas of any size and/or those who are carriers of SDHB mutations need imaging studies to localize metastatic disease.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('mutations', 'Var', (117, 126))	('pheochromocytomas', 'Disease', (14, 31))	('paragangliomas', 'Disease', (52, 66))	('paragangliomas', 'Disease', 'MESH:D010235', (52, 66))	('pheochromocytomas', 'Disease', 'MESH:D010673', (14, 31))	('SDHB', 'Gene', '6390', (112, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('paragangliomas', 'Phenotype', 'HP:0002668', (52, 66))	('SDHB', 'Gene', (112, 116))	('Patients', 'Species', '9606', (0, 8))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (14, 31))	('carriers', 'Reg', (100, 108))
48843	30540124	Two small studies of 90Y-DOTATOC and 177Lu-DOTATOC showed tumor response rates of 8% and 17%, respectively.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('90Y-DOTATOC', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('177Lu-DOTATOC', 'Var', (37, 50))
48849	30540124	In this study, most of the patients who exhibited a positive response to sunitinib therapy had SDHB germline mutations.	('sunitinib', 'Chemical', 'MESH:D000077210', (73, 82))	('SDHB', 'Gene', '6390', (95, 99))	('patients', 'Species', '9606', (27, 35))	('SDHB', 'Gene', (95, 99))	('germline mutations', 'Var', (100, 118))
48852	30540124	Among PPGL patients, SDHB and SDHD mutation carriers have a significant risk of recurrence.	('SDHB', 'Gene', '6390', (21, 25))	('SDHD', 'Gene', '6392', (30, 34))	('SDHD', 'Gene', (30, 34))	('PPGL', 'Gene', (6, 10))	('mutation', 'Var', (35, 43))	('patients', 'Species', '9606', (11, 19))	('SDHB', 'Gene', (21, 25))
48859	29618619	Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('disease-free survival time', 'CPA', (94, 120))	('shortened', 'NegReg', (73, 82))	('interferon', 'Gene', (37, 47))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (136, 142))	('deletion', 'Var', (25, 33))	('patients', 'Species', '9606', (158, 166))	('interferon', 'Gene', '3439', (37, 47))
48861	29618619	Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy.	('interferon', 'Gene', (107, 117))	('CTLA-4', 'Gene', '1493', (236, 242))	('deletion', 'Var', (95, 103))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('CTLA-4', 'Gene', (236, 242))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', '1493', (244, 287))	('interferon', 'Gene', '3439', (107, 117))	('associated with', 'Reg', (201, 216))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', (244, 287))	('defensin', 'Gene', (146, 154))	('resistance to', 'CPA', (217, 230))
48864	29618619	Previous studies estimate that 25% of the cancer genome is affected by arm-level SCNAs and 10% by focal SCNAs with 2% overlap.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('SCNAs', 'Var', (81, 86))	('cancer', 'Disease', (42, 48))
48867	29618619	Another study exploring the copy number profiles of 3131 tumor genomes across 26 cancer types identified 158 recurrent focal SCNAs including 76 amplification affecting 1566 genes and 82 deletions affecting 2001 genes.	('amplification affecting', 'Var', (144, 167))	('focal SCNAs', 'Disease', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (186, 195))
48873	29618619	Survival analyses of different tumor types indicated that patients with homozygous deletion of interferon or defensin genes exhibit much worse overall or disease-free survival.	('worse', 'NegReg', (137, 142))	('interferon', 'Gene', '3439', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('disease-free survival', 'CPA', (154, 175))	('tumor', 'Disease', (31, 36))	('overall', 'CPA', (143, 150))	('homozygous deletion', 'Var', (72, 91))	('interferon', 'Gene', (95, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('defensin genes', 'Gene', (109, 123))
48874	29618619	RNA-seq gene expression analyses between patients with and without IFN/DEF deletion in 19 cancer types indicate that homozygous deletions of IFN and DEF activate oncogenic and cell cycle pathways but repress immune response pathways.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IFN', 'Gene', '3439', (141, 144))	('repress immune response', 'Phenotype', 'HP:0002721', (200, 223))	('IFN', 'Gene', (141, 144))	('patients', 'Species', '9606', (41, 49))	('immune response pathways', 'Pathway', (208, 232))	('IFN', 'Gene', '3439', (67, 70))	('activate', 'PosReg', (153, 161))	('repress', 'NegReg', (200, 207))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('DEF', 'Gene', (149, 152))	('deletions', 'Var', (128, 137))	('IFN', 'Gene', (67, 70))
48876	29618619	Since a large body of evidence suggest that interferons and defensins play major roles in tumor immunity by recognizing tumor cells and serve as a bridge to spontaneous adaptive T cell response, our findings suggest a common molecular mechanism mediated by the deletion of interferon and defensin genes, through which tumor cells escape immune detection and destruction.	('defensin genes', 'Gene', (288, 302))	('interferon', 'Gene', '3439', (273, 283))	('interferon', 'Gene', '3439', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (261, 269))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (120, 125))
48889	29618619	beta = 0.2), the minimum number of required events (K) is calculated as: where Zalpha/2 = 1.96, Zbeta = 0.84, pi1 and pi2 are the proportions to be allocated into two groups and were determined by the HDI/HDD frequencies in each cancer type.	('cancer', 'Disease', (229, 235))	('pi1', 'Var', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Zalpha/2 = 1.96', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pi2', 'Var', (118, 121))	('HDD', 'Disease', (205, 208))	('pi2', 'Species', '1214577', (118, 121))	('HDD', 'Disease', 'None', (205, 208))
48921	29618619	Since both interferons and defensins are involved in innate immune response and play important roles in recognizing tumor cells and inducing an anti-tumor immune response, the widespread, homozygous deletion of these genes suggests a common molecular mechanism through which tumor cells escape immune destruction.	('interferon', 'Gene', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('interferon', 'Gene', '3439', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (116, 121))
48946	29618619	We asked the question whether homozygous deletions of interferon genes are passive hitchhiking events due to the nearby CDKN2A deletion, or they play an active role in tumorigenesis and affect the patient survival.	('play', 'Reg', (145, 149))	('affect', 'Reg', (186, 192))	('interferon', 'Gene', '3439', (54, 64))	('tumor', 'Disease', (168, 173))	('CDKN2A', 'Gene', (120, 126))	('deletion', 'Var', (127, 135))	('interferon', 'Gene', (54, 64))	('CDKN2A', 'Gene', '1029', (120, 126))	('patient survival', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
48948	29618619	We performed the survival analyses on three patient groups: (I) patients only have CDKN2A deletion (CDKN2A-/IFN+); (II) patients have CDKN2A deletion and additional IFN gene deletions (CDKN2A-/IFN-); and (III) patients have neither CDKN2A nor IFN gene deletions (CDKN2A+/IFN+).	('deletion', 'Var', (90, 98))	('IFN', 'Gene', '3439', (271, 274))	('IFN', 'Gene', (243, 246))	('CDKN2A nor IFN', 'Gene', '1029;3439', (232, 246))	('CDKN2A', 'Gene', (83, 89))	('CDKN2A', 'Gene', '1029', (100, 106))	('CDKN2A', 'Gene', (263, 269))	('IFN', 'Gene', (193, 196))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', (232, 238))	('patient', 'Species', '9606', (120, 127))	('CDKN2A-/IFN+);', 'Gene', '1029;3439', (100, 114))	('IFN', 'Gene', (271, 274))	('patients', 'Species', '9606', (210, 218))	('CDKN2A', 'Gene', (185, 191))	('deletion', 'Var', (141, 149))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', (134, 140))	('IFN', 'Gene', '3439', (165, 168))	('CDKN2A', 'Gene', '1029', (232, 238))	('IFN', 'Gene', '3439', (108, 111))	('CDKN2A-/IFN-', 'Gene', (185, 197))	('CDKN2A nor IFN', 'Gene', (232, 246))	('CDKN2A+/IFN+', 'Gene', '3439', (263, 275))	('IFN', 'Gene', '3439', (243, 246))	('CDKN2A', 'Gene', '1029', (185, 191))	('CDKN2A-/IFN+)', 'Gene', (100, 113))	('patient', 'Species', '9606', (44, 51))	('CDKN2A-/IFN-)', 'Gene', '1029;3439', (185, 198))	('patients', 'Species', '9606', (64, 72))	('CDKN2A+/IFN+', 'Gene', (263, 275))	('CDKN2A', 'Gene', '1029', (134, 140))	('IFN', 'Gene', (165, 168))	('patients', 'Species', '9606', (120, 128))	('CDKN2A', 'Gene', (100, 106))	('patient', 'Species', '9606', (210, 217))	('IFN', 'Gene', '3439', (193, 196))	('IFN', 'Gene', (108, 111))
48955	29618619	It could be also due to other confounding factors such as PTEN and RB1 deletions, which tend to be mutually exclusive with HDIs and HDDs (Supplementary Figure 7).	('deletions', 'Var', (71, 80))	('PTEN', 'Gene', '5728', (58, 62))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))	('HDIs and HDDs', 'Disease', 'None', (123, 136))	('PTEN', 'Gene', (58, 62))
48956	29618619	To identify gene expression signatures associated with the deletion of IFN and DEF genes, we performed gene expression analysis on each of the 19 cancer types (or 17 cancer types when COAD and READ are combined as colorectal cancer, LUSC and LUAD are combined as lung cancer) having high frequencies of HDI and HDD.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (225, 231))	('COAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('IFN', 'Gene', '3439', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('HDD', 'Disease', 'None', (311, 314))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('colorectal cancer', 'Disease', (214, 231))	('HDD', 'Disease', (311, 314))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('IFN', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deletion', 'Var', (59, 67))	('cancer', 'Disease', (268, 274))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))
48970	29618619	In a recent report, copy loss of type I interferon genes are found in 6 out of 12 melanoma patients that resist to anti-CTLA-4 treatment, but in none of the 4 responders (P = 0.23, two-tailed Fisher exact test).	('copy loss', 'Var', (20, 29))	('patients', 'Species', '9606', (91, 99))	('interferon', 'Gene', '3439', (40, 50))	('CTLA-4', 'Gene', '1493', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('interferon', 'Gene', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CTLA-4', 'Gene', (120, 126))
48975	29618619	As a comparison, deletions of two tumor suppressor genes CDKN2A (P = 0.63) and PTEN (P = 0.55) are not associated with responders or non-responders (Fig.	('tumor', 'Disease', (34, 39))	('CDKN2A', 'Gene', (57, 63))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PTEN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', '5728', (79, 83))
48976	29618619	Taken together, our meta-analyses of two independent melanoma cohorts suggest the deletion of interferon and defensin genes is significantly associated anti-CTLA-4 treatment resistance, and might be a potential prognostic biomarker to predict resistance to other immunotherapies.	('CTLA-4', 'Gene', (157, 163))	('interferon', 'Gene', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('CTLA-4', 'Gene', '1493', (157, 163))	('deletion', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('associated', 'Reg', (141, 151))	('interferon', 'Gene', '3439', (94, 104))
48978	29618619	In this study, we analyzed the copy number profiles of 10,759 primary cancer tissues and found the homozygous deletions of type I interferon and defensin genes are pervasive in 19 TCGA cancer types, and the alteration frequency is much higher than those of well-known tumor suppressors PTEN and RB1 in the same cancer type (Supplementary Figure 7).	('interferon', 'Gene', '3439', (130, 140))	('PTEN', 'Gene', '5728', (286, 290))	('cancer', 'Disease', (311, 317))	('defensin', 'Gene', (145, 153))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('RB1', 'Gene', '5925', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PTEN', 'Gene', (286, 290))	('tumor', 'Disease', (268, 273))	('interferon', 'Gene', (130, 140))	('RB1', 'Gene', (295, 298))	('deletions', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
48979	29618619	More importantly, homozygous deletions of interferon and defensin genes associate with worse overall or disease-free survival, and the resistance to anti-CTLA4 treatment in melanoma patients.	('CTLA4', 'Gene', (154, 159))	('defensin', 'Gene', (57, 65))	('worse', 'NegReg', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('interferon', 'Gene', '3439', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('disease-free survival', 'CPA', (104, 125))	('resistance', 'CPA', (135, 145))	('patients', 'Species', '9606', (182, 190))	('overall', 'CPA', (93, 100))	('interferon', 'Gene', (42, 52))	('CTLA4', 'Gene', '1493', (154, 159))	('homozygous deletions', 'Var', (18, 38))
48980	29618619	Defects in the type I interferon signaling pathway have been proposed as a potential mechanism of cancer escape (insensitivity) to immunotherapy in mice and prostate cancer cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interferon', 'Gene', '3439', (22, 32))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('Defects', 'Var', (0, 7))	('interferon', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', (98, 104))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
48985	29618619	By analyzing the genomes of 10,759 cancer patients across 31 cancer types, we found interferon and defensin genes are homozygously deleted with high frequencies in 19 cancer types, and the surviving time of patients with these deletions are significantly reduced.	('reduced', 'NegReg', (255, 262))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('interferon', 'Gene', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('surviving time', 'CPA', (189, 203))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('interferon', 'Gene', '3439', (84, 94))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('defensin genes', 'Gene', (99, 113))	('cancer', 'Disease', (35, 41))
48989	28753846	Little is known, however, about how the level of genetic alteration across an entire cancer genome affects tumor grade or stage or survival.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('affects', 'Reg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('genetic alteration', 'Var', (49, 67))	('stage', 'CPA', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('survival', 'CPA', (131, 139))
48999	28753846	Cancers with higher levels of genomic alterations are associated with worse pathologic features and survival.	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('genomic alterations', 'Var', (30, 49))
49003	28753846	Much less is known about how the level of genetic alteration across an entire cancer genome affects the natural history of an individual malignancy.	('malignancy', 'Disease', (137, 147))	('affects', 'Reg', (92, 99))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('genetic alteration', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('malignancy', 'Disease', 'MESH:D009369', (137, 147))
49005	28753846	While some studies have shown clustering of mutations that are associated with grade and stage, the effect that genomic alterations have on tumor grade and stage on histopathologic analysis has not been fully elucidated.	('associated', 'Reg', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
49006	28753846	With the publication of whole cancer genomes as part of The Cancer Genome Atlas (TCGA) and International Cancer Genome consortium, the association of whole-genome alterations such as mutation count (MC) and copy number variation (CNV) can now be correlated with clinicopathologic characteristics, survival outcomes, and therapeutic response.	('Cancer', 'Disease', (105, 111))	('Cancer Genome Atlas', 'Disease', (60, 79))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (60, 79))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (30, 36))	('correlated', 'Reg', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('MC', 'Chemical', '-', (199, 201))	('copy number variation', 'Var', (207, 228))	('mutation count', 'Disease', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
49016	28753846	For tumors types with substaging (eg, T2a and T2b in BLCA), substages were combined for analysis.	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('T2b', 'Var', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
49037	28753846	There was no association with Fuhrman grade and MC for a four-tier (p = 0.27) or a two-tier system; however, CNV was associated with higher Fuhrman grade in both four-tier (p = 0.0006) and two-tier (p = 0.0001) systems.	('Fuhrman grade', 'CPA', (140, 153))	('CNV', 'Var', (109, 112))	('MC', 'Chemical', '-', (48, 50))	('higher', 'PosReg', (133, 139))
49045	28753846	PRAD had the third lowest MC and the lowest CNV.	('lowest', 'NegReg', (37, 43))	('lowest', 'NegReg', (19, 25))	('MC', 'Chemical', '-', (26, 28))	('CNV', 'MPA', (44, 47))	('PRAD', 'Var', (0, 4))
49058	28753846	Genetic instability has largely been studied in terms of microsatellite instability and chromosomal instability, and has been linked to adverse pathology and survival in colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('colon cancer', 'Disease', 'MESH:D015179', (170, 182))	('colon cancer', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('microsatellite', 'Var', (57, 71))	('linked', 'Reg', (126, 132))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
49059	28753846	One theory, described by Kinzler and Vogelstein, is that mutations in "caretaker" genes that maintain the integrity of the genome is an early event in cancer development that accelerates the accumulation of additional mutations that eventually lead to neoplasia.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (218, 227))	('accelerates', 'PosReg', (175, 186))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))	('neoplasia', 'Disease', (252, 261))	('mutations', 'Var', (57, 66))	('lead to', 'Reg', (244, 251))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('neoplasia', 'Disease', 'MESH:D009369', (252, 261))
49060	28753846	Our data support the role of genetic instability in the progression to higher grade and/or higher stage cancer for some genitourinary malignancies.	('cancer for some genitourinary malignancies', 'Phenotype', 'HP:0007379', (104, 146))	('genetic instability', 'Var', (29, 48))	('higher grade', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('genitourinary malignancies', 'Disease', 'MESH:D014564', (120, 146))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genitourinary malignancies', 'Disease', (120, 146))
49061	28753846	High MC has previously been associated with greater response to checkpoint inhibitors in melanoma, non-small cell lung cancer, and renal cell carcinoma.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('renal cell carcinoma', 'Disease', (131, 151))	('MC', 'Chemical', '-', (5, 7))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (99, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('non-small cell lung cancer', 'Disease', (99, 125))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (131, 151))	('High MC', 'Var', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('response', 'MPA', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
49145	26314582	Thompson has suggested that tumours with a PASS >= 6 were biologically more aggressive than tumours with a PASS <4.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('PASS >= 6', 'Var', (43, 52))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('aggressive', 'CPA', (76, 86))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumours', 'Disease', 'MESH:D009369', (28, 35))	('tumours', 'Disease', (28, 35))
49205	25019060	These include multiple endocrine neoplasia type 2 arising from mutations in the rearranged during transfection (RET) proto-oncogene; von Hippel-Lindau (VHL) syndrome caused by mutations of the VHL gene; and von Recklinghausen's disease due to mutations of the neurofibromatosis type 1 (NF1) gene.	('neurofibromatosis type 1', 'Gene', (260, 284))	('mutations', 'Var', (176, 185))	('NF1', 'Gene', '4763', (286, 289))	("von Recklinghausen's disease", 'Disease', 'MESH:C537392', (207, 235))	('VHL', 'Disease', (193, 196))	('RET', 'Gene', '5979', (112, 115))	('mutations', 'Var', (63, 72))	("von Recklinghausen's disease", 'Disease', (207, 235))	('NF1', 'Gene', (286, 289))	('neoplasia', 'Phenotype', 'HP:0002664', (33, 42))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (23, 49))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (260, 277))	('VHL', 'Disease', (152, 155))	('neurofibromatosis type 1', 'Gene', '4763', (260, 284))	('caused by', 'Reg', (166, 175))	('endocrine neoplasia type 2', 'Disease', (23, 49))	('RET', 'Gene', (112, 115))	('mutations', 'Var', (243, 252))	('VHL', 'Disease', 'MESH:D006623', (193, 196))	('von Hippel-Lindau (VHL) syndrome', 'Disease', 'MESH:D006623', (133, 165))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (23, 42))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
49206	25019060	In addition, mutations in genes encoding succinate dehydrogenase subunits (SDHD, SDHC, and SDHB) are associated with familial PGL syndromes (PGL1, PGL3, and PGL4), respectively.	('SDHC', 'Gene', (81, 85))	('mutations', 'Var', (13, 22))	('SDHC', 'Gene', '6391', (81, 85))	('SDHB', 'Gene', '6390', (91, 95))	('SDHD', 'Gene', '6392', (75, 79))	('PGL3', 'Gene', '6391', (147, 151))	('PGL', 'Phenotype', 'HP:0002668', (147, 150))	('PGL', 'Phenotype', 'HP:0002668', (126, 129))	('PGL3', 'Gene', (147, 151))	('familial PGL syndromes', 'Disease', 'MESH:D010235', (117, 139))	('PGL4', 'Gene', '6390', (157, 161))	('SDHD', 'Gene', (75, 79))	('PGL', 'Phenotype', 'HP:0002668', (141, 144))	('PGL4', 'Gene', (157, 161))	('SDHB', 'Gene', (91, 95))	('associated', 'Reg', (101, 111))	('PGL', 'Phenotype', 'HP:0002668', (157, 160))	('familial PGL syndromes', 'Disease', (117, 139))
49209	25019060	However, rates of malignancy have been reported as high as 50% in patients with SDHB mutation.	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('SDHB', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('patients', 'Species', '9606', (66, 74))	('malignancy', 'Disease', (18, 28))	('SDHB', 'Gene', '6390', (80, 84))
49220	25019060	However, all of these reports are based on limited numbers of patients and lesions with the exception of a recent study on the role of EBRT and 131I-MIBG in non-head-and-neck PCC or PGL (Table 1).	('EBRT', 'Chemical', '-', (135, 139))	('PGL', 'Phenotype', 'HP:0002668', (182, 185))	('131I-MIBG', 'Chemical', 'MESH:D019797', (144, 153))	('PCC', 'Gene', (175, 178))	('131I-MIBG', 'Var', (144, 153))	('patients', 'Species', '9606', (62, 70))	('PCC', 'Gene', '1421', (175, 178))
49363	23941827	1B shows that cells that had been treated with the polyclonal anti-CPE IgGs exhibited 2-fold more cyto-toxicity than cells that were treated with non-specific IgGs.	('toxicity', 'Disease', (103, 111))	('anti-CPE', 'Gene', (62, 70))	('anti-CPE', 'Var', (62, 70))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))
49370	23941827	2 shows that cells treated with recombinant mCPE exhibited significantly less cytotoxicity under metabolic stress than the untreated controls, further supporting our hypothesis that CPE serves as a survival factor.	('less', 'NegReg', (73, 77))	('mCPE', 'Var', (44, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (78, 90))	('cytotoxicity', 'Disease', (78, 90))
49375	23941827	Using qRT-PCR to assay for BCL-2 mRNA, it was shown that HCC cells treated with CPE exhibited a ~2.4-fold increase in BCL-2 mRNA expression (t-test p < 0.05) (Fig.	('BCL-2', 'Gene', '596', (27, 32))	('BCL-2', 'Gene', (27, 32))	('BCL-2', 'Gene', '596', (118, 123))	('HCC', 'Phenotype', 'HP:0001402', (57, 60))	('increase', 'PosReg', (106, 114))	('CPE', 'Var', (80, 83))	('BCL-2', 'Gene', (118, 123))
49386	23941827	To determine if CPE plays a role in Wnt/beta-catenin signaling in HCC cells, we carried out Western blot analysis for active-beta-catenin, phospho-GSK3beta (Ser9), (Tyr216), phos-pho-GSK3alpha (Ser21) and phosphor-AKT and PKC (Fig.	('Tyr216', 'Var', (165, 171))	('beta-catenin', 'Gene', (125, 137))	('GSK3alpha', 'Gene', '2931', (183, 192))	('Ser9', 'Chemical', '-', (157, 161))	('AKT', 'Gene', '207', (214, 217))	('AKT', 'Gene', (214, 217))	('beta-catenin', 'Gene', (40, 52))	('beta-catenin', 'Gene', '1499', (125, 137))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('Ser21', 'Chemical', '-', (194, 199))	('beta-catenin', 'Gene', '1499', (40, 52))	('GSK3beta', 'Gene', (147, 155))	('Tyr216', 'Chemical', '-', (165, 171))	('GSK3beta', 'Gene', '2932', (147, 155))	('GSK3alpha', 'Gene', (183, 192))
49387	23941827	There was a 40% increase in active-beta-catenin (t-test p < 0.03) and 17% increasing in phospho-GSK3beta (Ser9) (t-test p < 0.02), however no changes were found in the expression of phospho-GSK3beta (Tyr216), phospho -GSK3alpha (Ser21), phospho-AKT or phospho-PKC.	('beta-catenin', 'Gene', (35, 47))	('GSK3beta', 'Gene', '2932', (96, 104))	('Tyr216', 'Chemical', '-', (200, 206))	('AKT', 'Gene', '207', (245, 248))	('GSK3beta', 'Gene', (190, 198))	('Tyr216', 'Var', (200, 206))	('GSK3alpha', 'Gene', (218, 227))	('beta-catenin', 'Gene', '1499', (35, 47))	('increase', 'PosReg', (16, 24))	('GSK3alpha', 'Gene', '2931', (218, 227))	('AKT', 'Gene', (245, 248))	('GSK3beta', 'Gene', '2932', (190, 198))	('Ser9', 'Chemical', '-', (106, 110))	('Ser21', 'Chemical', '-', (229, 234))	('GSK3beta', 'Gene', (96, 104))
49398	23941827	7 C shows that ~22% fewer HT1080 cells migrated through the BME barrier when treated with CPE compared to that of untreated cells (control).	('HT1080', 'Gene', (26, 32))	('HT1080', 'Gene', '8872', (26, 32))	('CPE', 'Var', (90, 93))	('fewer', 'NegReg', (20, 25))	('rat', 'Species', '10116', (42, 45))
49450	23941827	On the other hand, our studies on CPE- N in PHEOs showed that high copy numbers of CPE- N mRNA indicated a metastatic tumor, or future recurrence or metastasis with poor prognosis.	('PHEOs', 'Chemical', '-', (44, 49))	('metastasis', 'CPA', (149, 159))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('CPE- N', 'Gene', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('indicated', 'Reg', (95, 104))	('tumor', 'Disease', (118, 123))	('high copy numbers', 'Var', (62, 79))
49492	21565667	Distinction of the two major subtypes is important because removal of an APA may lead to cure of hypertension with attendant reduction in health risks and improvement in quality of life, whereas patients with IHA require lifelong treatment with antihypertensive drugs; However, targeted therapy using a mineralocorticoid receptor blocker may lead to improved blood pressure control with the need for fewer medications in some patients.	('improvement', 'PosReg', (155, 166))	('blood pressure control', 'MPA', (359, 381))	('hypertension', 'Disease', (97, 109))	('reduction', 'NegReg', (125, 134))	('removal', 'Var', (59, 66))	('hypertension', 'Phenotype', 'HP:0000822', (97, 109))	('mineralocorticoid receptor', 'Gene', '4306', (303, 329))	('hypertension', 'Disease', 'MESH:D006973', (97, 109))	('hypertensive', 'Disease', 'MESH:D006973', (249, 261))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (426, 434))	('PA', 'Phenotype', 'HP:0011736', (74, 76))	('hypertensive', 'Disease', (249, 261))	('mineralocorticoid receptor', 'Gene', (303, 329))	('mineralocorticoid receptor blocker', 'Phenotype', 'HP:0004319', (303, 337))	('improved', 'PosReg', (350, 358))
49536	21565667	Overall, the sensitivity of an increased ARR to identify combinations of PRA and aldosterone compatible with PA was 66% (80% in blacks versus 56% in whites).	('combinations', 'Var', (57, 69))	('aldosterone', 'Chemical', 'MESH:D000450', (81, 92))	('PA', 'Phenotype', 'HP:0011736', (109, 111))	('PRA', 'Gene', (73, 76))	('aldosterone', 'MPA', (81, 92))	('PRA', 'Gene', '6277', (73, 76))
49564	21565667	Among the catecholamine metabolites, vanillymandelic acid has been shown to have poor diagnostic sensitivity and, thus, measurement of the fractionated catecholamine metabolites-metanephrine and normetanephrine in the plasma or urine- are the preferred screening tests for pheochromocytoma.	('metanephrine', 'Chemical', 'MESH:D008676', (178, 190))	('catecholamine', 'Chemical', 'MESH:D002395', (10, 23))	('pheochromocytoma', 'Disease', (273, 289))	('vanillymandelic acid', 'Chemical', '-', (37, 57))	('catecholamine', 'Chemical', 'MESH:D002395', (152, 165))	('vanillymandelic acid', 'Var', (37, 57))	('pheochromocytoma', 'Disease', 'MESH:D010673', (273, 289))	('normetanephrine', 'Chemical', 'MESH:D009647', (195, 210))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (273, 289))	('metanephrine', 'Chemical', 'MESH:D008676', (198, 210))
49578	21565667	These include concomitant use of drugs, especially phenoxybenzamine, tricyclic antidepressants, buspirone, and drugs containing catecholamines such as decongestants and weight loss aids.	('catecholamines', 'Chemical', 'MESH:D002395', (128, 142))	('weight loss aids', 'Disease', 'MESH:D015431', (169, 185))	('weight loss aids', 'Disease', (169, 185))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (51, 67))	('buspirone', 'Chemical', 'MESH:D002065', (96, 105))	('phenoxybenzamine', 'Var', (51, 67))	('weight loss', 'Phenotype', 'HP:0001824', (169, 180))
49591	21565667	In general serial testing will increase specificity at the expense of lower sensitivity and this must be kept in mind when employing such strategies for identification of a potentially fatal disorder.	('fatal disorder', 'Disease', (185, 199))	('serial testing', 'Var', (11, 25))	('fatal disorder', 'Disease', 'MESH:D034062', (185, 199))	('specificity', 'MPA', (40, 51))	('increase', 'PosReg', (31, 39))
49594	21384277	A case of carotid body paraganglioma and haemangioblastoma of the spinal cord in a patient with the N131K missense mutation in the VHL gene The article describes paraganglioma case in woman with von Hippel-Lindau disease.	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (195, 220))	('carotid body paraganglioma', 'Disease', 'MESH:D002345', (10, 36))	('carotid body paraganglioma', 'Disease', (10, 36))	('haemangioblastoma of the spinal cord', 'Disease', 'MESH:D013118', (41, 77))	('VHL', 'Disease', (131, 134))	('paraganglioma', 'Disease', (162, 175))	('von Hippel-Lindau disease', 'Disease', (195, 220))	('paraganglioma', 'Phenotype', 'HP:0002668', (23, 36))	('paraganglioma', 'Disease', 'MESH:D010235', (162, 175))	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (10, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('VHL', 'Disease', 'MESH:D006623', (131, 134))	('woman', 'Species', '9606', (184, 189))	('paraganglioma', 'Disease', (23, 36))	('haemangioblastoma of the spinal cord', 'Disease', (41, 77))	('haemangioblastoma', 'Phenotype', 'HP:0010797', (41, 58))	('N131K missense mutation', 'Var', (100, 123))	('paraganglioma', 'Disease', 'MESH:D010235', (23, 36))	('patient', 'Species', '9606', (83, 90))	('N131K', 'Mutation', 'rs1064794272', (100, 105))
49595	21384277	She was found to be a carrier of a rare germline mutation in the VHL gene (393C>A; N131K).	('VHL', 'Disease', (65, 68))	('393C>A; N131K', 'Var', (75, 88))	('VHL', 'Disease', 'MESH:D006623', (65, 68))	('393C>A', 'Mutation', 'rs1064794272', (75, 81))	('N131K', 'Mutation', 'rs1064794272', (83, 88))
49604	21384277	The condition is caused by carrying germline mutations of the VHL gene.	('VHL', 'Disease', (62, 65))	('germline mutations', 'Var', (36, 54))	('VHL', 'Disease', 'MESH:D006623', (62, 65))	('caused by', 'Reg', (17, 26))
49605	21384277	The diagnosis of VHL disease is established based on genealogical/clinical criteria and an analysis of carrying mutations of the VHL gene.	('VHL', 'Disease', (129, 132))	('VHL', 'Disease', (17, 20))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('VHL disease', 'Disease', 'MESH:D006623', (17, 28))	('mutations', 'Var', (112, 121))	('VHL disease', 'Disease', (17, 28))	('VHL', 'Disease', 'MESH:D006623', (129, 132))
49655	21384277	Herein we describe a rare case of carotid body paraganglioma in a woman with von Hippel-Lindau disease, caused by the N131K mutation in the VHL gene.	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (34, 60))	('carotid body paraganglioma', 'Disease', 'MESH:D002345', (34, 60))	('carotid body paraganglioma', 'Disease', (34, 60))	('N131K', 'Var', (118, 123))	('paraganglioma', 'Phenotype', 'HP:0002668', (47, 60))	('VHL', 'Disease', (140, 143))	('N131K', 'Mutation', 'rs1064794272', (118, 123))	('VHL', 'Disease', 'MESH:D006623', (140, 143))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (77, 102))	('woman', 'Species', '9606', (66, 71))	('von Hippel-Lindau disease', 'Disease', (77, 102))	('caused by', 'Reg', (104, 113))
49656	21384277	The N131K is a rare missense mutation of the VHL gene.	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('N131K', 'Mutation', 'rs1064794272', (4, 9))	('N131K', 'Var', (4, 9))	('VHL', 'Disease', (45, 48))
49658	21384277	VHL type 2 disease is typically caused by missense mutations.	('caused', 'Reg', (32, 38))	('missense mutations', 'Var', (42, 60))	('VHL type 2 disease', 'Disease', (0, 18))	('VHL type 2 disease', 'Disease', 'MESH:D006623', (0, 18))
49659	21384277	However, only specific missense mutations are associated with pheochromocytoma:those mutations which map to protein binding sites of pVHL and which are predicted to cause local protein defects.	('pheochromocytoma', 'Disease', 'MESH:D010673', (62, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('protein defects', 'Disease', 'MESH:D011488', (177, 192))	('cause', 'Reg', (165, 170))	('protein defects', 'Disease', (177, 192))	('missense', 'Var', (23, 31))	('mutations', 'Var', (85, 94))	('associated', 'Reg', (46, 56))	('pVHL', 'Gene', '7428', (133, 137))	('pVHL', 'Gene', (133, 137))	('pheochromocytoma', 'Disease', (62, 78))
49661	21384277	VHL kindreds with pheochromocytoma-associated missense mutations require careful surveillance for pheochromocytoma as this is frequently the first manifestation.	('missense mutations', 'Var', (46, 64))	('pheochromocytoma', 'Disease', 'MESH:D010673', (18, 34))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('VHL', 'Disease', 'MESH:D006623', (0, 3))	('VHL', 'Disease', (0, 3))	('pheochromocytoma', 'Disease', (98, 114))	('pheochromocytoma', 'Disease', 'MESH:D010673', (98, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (98, 114))	('pheochromocytoma', 'Disease', (18, 34))
49662	21384277	Therefore, the correlation between the 393C>A (N131K) missense mutation and VHL type 2 may be useful in genetic counselling.	('N131K', 'Mutation', 'rs1064794272', (47, 52))	('393C>A', 'Mutation', 'rs1064794272', (39, 45))	('VHL', 'Disease', (76, 79))	('VHL', 'Disease', 'MESH:D006623', (76, 79))	('393C>A (N131K', 'Var', (39, 52))
49694	21384277	Therefore, a correlation between the 393C>A (N131K) missense mutation and VHL type 2 may be useful in genetic counselling.	('N131K', 'Mutation', 'rs1064794272', (45, 50))	('393C>A', 'Mutation', 'rs1064794272', (37, 43))	('393C>A (N131K', 'Var', (37, 50))	('VHL', 'Disease', (74, 77))	('VHL', 'Disease', 'MESH:D006623', (74, 77))
49697	20833333	Four distinct syndromes - PGL1-4 - are related to mutations in the succinate dehydrogenase gene - mitochondrial complex involved in electron transfer and Krebs cycle.	('Krebs', 'Chemical', '-', (154, 159))	('mutations', 'Var', (50, 59))	('related', 'Reg', (39, 46))	('succinate', 'Chemical', 'MESH:D019802', (67, 76))	('hydrogen', 'Chemical', 'MESH:D006859', (79, 87))
49699	20833333	We also describe recent discoveries in HIF-related pathway of tumorigenesis and mutations in new SDH-related genes that have improved our understanding of this disease.	('HIF-related', 'Pathway', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (80, 89))	('SDH', 'Gene', '6390', (97, 100))	('tumor', 'Disease', (62, 67))	('SDH', 'Gene', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
49707	20833333	The two most recent additions to this group include mutations in SDH5 and propyl hydroxylase domain 2 (PDH2) genes that, although extremely rare, are also associated with PHEOs/PGLs.	('mutations', 'Var', (52, 61))	('PDH', 'Gene', '54704', (103, 106))	('associated', 'Reg', (155, 165))	('PHEOs/PGLs', 'Disease', (171, 181))	('SDH5', 'Gene', (65, 69))	('PDH', 'Gene', (103, 106))
49709	20833333	Despite the fact that different SDH mutations occur in single multi-unit enzyme, they express significant phenotype heterogeneity.	('SDH', 'Gene', (32, 35))	('SDH', 'Gene', '6390', (32, 35))	('mutations', 'Var', (36, 45))
49714	20833333	Further testing revealed PGL1 to be related to mutation in the SDHD gene on 11q23 (Table 1), PGL2 to SDH5 on 11q13.1, PGL3 to mutation in SDHC on 1q21 and PGL4 to SDHB on 1p35-p36.1.	('PGL3', 'Gene', '6391', (118, 122))	('related', 'Reg', (36, 43))	('SDHB', 'Gene', '6390', (163, 167))	('SDHB', 'Gene', (163, 167))	('PGL3', 'Gene', (118, 122))	('PGL4', 'Gene', '6390', (155, 159))	('mutation', 'Var', (47, 55))	('SDHC', 'Gene', (138, 142))	('mutation', 'Var', (126, 134))	('PGL2', 'Gene', '54949', (93, 97))	('SDHC', 'Gene', '6391', (138, 142))	('SDHD', 'Gene', '6392', (63, 67))	('PGL2', 'Gene', (93, 97))	('PGL4', 'Gene', (155, 159))	('SDHD', 'Gene', (63, 67))
49721	20833333	To not underestimate the need for apparently secondary importance of the SDH-related part of the chain, one should remember that inactivating mutation in SDHA causes the same necrotizing encephalopathy (Leigh syndrome) as mutation in any other complex of the ETC.	('SDHA', 'Gene', (154, 158))	('SDH', 'Gene', (154, 157))	('SDH', 'Gene', '6390', (73, 76))	('encephalopathy', 'Disease', 'MESH:D001927', (187, 201))	('Leigh syndrome', 'Disease', 'MESH:D007888', (203, 217))	('necrotizing encephalopathy', 'Phenotype', 'HP:0006976', (175, 201))	('encephalopathy', 'Phenotype', 'HP:0001298', (187, 201))	('encephalopathy', 'Disease', (187, 201))	('causes', 'Reg', (159, 165))	('SDH', 'Gene', '6390', (154, 157))	('SDHA', 'Gene', '6389', (154, 158))	('SDH', 'Gene', (73, 76))	('inactivating mutation', 'Var', (129, 150))	('Leigh syndrome', 'Disease', (203, 217))
49723	20833333	It is the only non transmembrane complex, the only non-proton pump, and while the main goal of electron transfer is to generate enough H+-driven gradient for ATP synthesis, the hydroxylation of succinate to fumarate actually generates intra-matrix H+ that can actually diminish that gradient.	('gradient', 'MPA', (283, 291))	('H+-driven gradient', 'MPA', (135, 153))	('ATP', 'Chemical', 'MESH:D000255', (158, 161))	('diminish', 'NegReg', (269, 277))	('succinate', 'Chemical', 'MESH:D019802', (194, 203))	('fumarate', 'Chemical', 'MESH:D005650', (207, 215))	('hydroxylation', 'Var', (177, 190))
49731	20833333	In contrast, mutation in the catalytic subunit SDHA causes necrotizing encephalopathy, which is caused by other mutations in genes involved in energy metabolism, such as the rest of the members of electron transfer chain and components of pyruvate dehydrogenase complex.	('SDHA', 'Gene', (47, 51))	('caused', 'Reg', (96, 102))	('hydrogen', 'Chemical', 'MESH:D006859', (250, 258))	('mutation', 'Var', (13, 21))	('encephalopathy', 'Disease', 'MESH:D001927', (71, 85))	('SDHA', 'Gene', '6389', (47, 51))	('necrotizing encephalopathy', 'Phenotype', 'HP:0006976', (59, 85))	('encephalopathy', 'Phenotype', 'HP:0001298', (71, 85))	('causes', 'Reg', (52, 58))	('encephalopathy', 'Disease', (71, 85))
49732	20833333	Genes for SDHC, B, and D are nuclear and the mode of inheritance is autosomal dominant with maternal imprinting for SDHD and inactivating germline mutations result in loss of function of SDH.	('SDH', 'Gene', '6390', (10, 13))	('loss of function', 'NegReg', (167, 183))	('SDHC', 'Gene', (10, 14))	('SDH', 'Gene', (116, 119))	('inactivating', 'Var', (125, 137))	('SDH', 'Gene', '6390', (187, 190))	('SDH', 'Gene', (10, 13))	('SDHC', 'Gene', '6391', (10, 14))	('SDHD', 'Gene', (116, 120))	('SDHD', 'Gene', '6392', (116, 120))	('SDH', 'Gene', (187, 190))	('SDH', 'Gene', '6390', (116, 119))
49735	20833333	Apart from classic VHL and SDH-mutation associated PHEO/PGL, tumorigenesis pathway includes recently discovered mutations along this pathway like PDH2 and possibly KIF1B.	('KIF1B', 'Gene', (164, 169))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('PDH', 'Gene', '54704', (146, 149))	('KIF1B', 'Gene', '23095', (164, 169))	('SDH', 'Gene', '6390', (27, 30))	('SDH', 'Gene', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PDH', 'Gene', (146, 149))	('tumor', 'Disease', (61, 66))	('VHL', 'Disease', (19, 22))
49736	20833333	Thus, for SDH-related mutations, decrease in fumarate production and accumulation of succinate would be expected with a significant decrease in the amount of SDH subunits.	('SDH', 'Gene', '6390', (10, 13))	('decrease', 'NegReg', (33, 41))	('SDH', 'Gene', (158, 161))	('SDH', 'Gene', (10, 13))	('amount of', 'MPA', (148, 157))	('accumulation', 'PosReg', (69, 81))	('fumarate production', 'MPA', (45, 64))	('fumarate', 'Chemical', 'MESH:D005650', (45, 53))	('mutations', 'Var', (22, 31))	('SDH', 'Gene', '6390', (158, 161))	('succinate', 'Chemical', 'MESH:D019802', (85, 94))	('decrease', 'NegReg', (132, 140))
49741	20833333	Another interesting observations on genotype-phenotype correlation show significant differences in clinical presentation among mutations in different SDH subunits.	('mutations', 'Var', (127, 136))	('SDH', 'Gene', (150, 153))	('differences', 'Reg', (84, 95))	('SDH', 'Gene', '6390', (150, 153))
49742	20833333	While all SDH-related mutations result in near abolished SDH complex activity, SDHB related tumors have a significant malignant potential and are commonly found in the abdomen compared to SDHD and SDHC tumors that are almost always benign and commonly found in the head and neck areas.	('SDH', 'Gene', '6390', (10, 13))	('SDHC tumors', 'Disease', 'MESH:D009369', (197, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('SDH', 'Gene', '6390', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('SDHB', 'Gene', (79, 83))	('SDH', 'Gene', '6390', (79, 82))	('SDHD', 'Gene', '6392', (188, 192))	('SDH', 'Gene', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SDH', 'Gene', '6390', (197, 200))	('SDH', 'Gene', '6390', (188, 191))	('tumors', 'Disease', (92, 98))	('abolished', 'NegReg', (47, 56))	('activity', 'MPA', (69, 77))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('SDH', 'Gene', (57, 60))	('SDHD', 'Gene', (188, 192))	('SDH', 'Gene', (79, 82))	('mutations', 'Var', (22, 31))	('SDH', 'Gene', (197, 200))	('SDHC tumors', 'Disease', (197, 208))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('SDH', 'Gene', (188, 191))	('tumors', 'Disease', (202, 208))	('malignant potential', 'CPA', (118, 137))	('SDHB', 'Gene', '6390', (79, 83))
49745	20833333	On the other hand, Dahia showed in an animal model of heterozygous SDHD mutation that there is an early upregulation of glycolytic enzymes that differ from classic late Warburg effect.	('upregulation', 'PosReg', (104, 116))	('glycolytic', 'Enzyme', (120, 130))	('SDHD', 'Gene', (67, 71))	('SDHD', 'Gene', '6392', (67, 71))	('Dahia', 'Chemical', '-', (19, 24))	('mutation', 'Var', (72, 80))
49748	20833333	supported previous findings of the high frequency of SDHD and SDHC mutations in head and neck paragangliomas, as well as higher frequency of abdominal and pelvic disease and overall malignancy in SDHB mutations.	('malignancy', 'Disease', 'MESH:D009369', (182, 192))	('mutations', 'Var', (201, 210))	('malignancy', 'Disease', (182, 192))	('neck paragangliomas', 'Disease', (89, 108))	('SDHC', 'Gene', (62, 66))	('SDHD', 'Gene', (53, 57))	('SDHD', 'Gene', '6392', (53, 57))	('mutations', 'Var', (67, 76))	('SDHB', 'Gene', '6390', (196, 200))	('SDHC', 'Gene', '6391', (62, 66))	('paragangliomas', 'Phenotype', 'HP:0002668', (94, 108))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (89, 108))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))	('abdominal and pelvic disease', 'Disease', 'MESH:D017699', (141, 169))	('SDHB', 'Gene', (196, 200))	('higher', 'PosReg', (121, 127))	('neck paragangliomas', 'Disease', 'MESH:D010235', (89, 108))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (80, 108))
49749	20833333	Both mediastinal PGLs and PGLs of the large para-aortic paraganglion, described by Emil Zuckerkandl, usually associate with SDHB or SDHD mutations.	('SDHB', 'Gene', (124, 128))	('SDHD', 'Gene', (132, 136))	('mutations', 'Var', (137, 146))	('associate', 'Reg', (109, 118))	('SDHD', 'Gene', '6392', (132, 136))	('SDHB', 'Gene', '6390', (124, 128))
49750	20833333	Pediatric PHEOs/PGLs seem to be familial to greater degree than tumors in adults, mostly related to SDHB mutation and manifest with more aggressive course - higher rate of malignancy and more metastatic disease on presentation (Pacak et al.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('mutation', 'Var', (105, 113))	('malignancy', 'Disease', 'MESH:D009369', (172, 182))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('malignancy', 'Disease', (172, 182))	('related', 'Reg', (89, 96))	('metastatic disease', 'CPA', (192, 210))	('SDHB', 'Gene', '6390', (100, 104))	('SDHB', 'Gene', (100, 104))	('PHEOs/PGLs', 'Disease', (10, 20))
49751	20833333	SDHB mutations predispose to mainly extra-adrenal PHEOs with a high malignant potential and, less frequently, to benign parasympathetic head and neck PGLs.	('extra-adrenal PHEOs', 'Disease', (36, 55))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('predispose to', 'Reg', (15, 28))
49755	20833333	By age 40, 45% of SDHB mutation carriers show clinical signs of the disease.	('SDHB', 'Gene', (18, 22))	('SDHB', 'Gene', '6390', (18, 22))	('mutation', 'Var', (23, 31))
49757	20833333	If malignant sympathetic PGL arises from an extra-adrenal primary tumor, the prevalence of SDHB mutation can reach close to 50%.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('malignant sympathetic PGL', 'Disease', (3, 28))	('tumor', 'Disease', (66, 71))	('SDHB', 'Gene', '6390', (91, 95))	('mutation', 'Var', (96, 104))	('SDHB', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
49760	20833333	Younger age or metastatic disease at presentation, larger tumor size, and, to lesser extend, dopaminergic secretory profile and misssense mutation seem to associate with more aggressive tumor behavior, but there is no clear phenotype/genotype correlation.	('metastatic', 'Disease', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('associate with', 'Reg', (155, 169))	('dopamine', 'Chemical', 'MESH:D004298', (93, 101))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (175, 200))	('tumor', 'Disease', (186, 191))	('dopaminergic secretory profile', 'MPA', (93, 123))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('aggressive tumor behavior', 'Disease', (175, 200))	('misssense mutation', 'Var', (128, 146))	('more', 'PosReg', (170, 174))
49762	20833333	SDHD mutations are typically associated with multifocal parasympathetic head and neck PGLs and usually benign extra-adrenal and adrenal PHEOs.	('SDHD', 'Gene', (0, 4))	('SDHD', 'Gene', '6392', (0, 4))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (29, 39))
49763	20833333	A German-Polish cohort of 34 patients with SDHD mutation showed that 53% of carriers had adrenal PHEO, while 79% had head and neck PGLs.	('patients', 'Species', '9606', (29, 37))	('adrenal PHEO', 'Disease', (89, 101))	('SDHD', 'Gene', '6392', (43, 47))	('SDHD', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))
49764	20833333	Metastatic pheochromocytoma is rare in SDHD mutation carriers for both sympathetic and parasympathetic disease, but can occur.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (11, 27))	('mutation', 'Var', (44, 52))	('Metastatic pheochromocytoma', 'Disease', (0, 27))	('SDHD', 'Gene', (39, 43))	('parasympathetic disease', 'Disease', (87, 110))	('SDHD', 'Gene', '6392', (39, 43))	('Metastatic pheochromocytoma', 'Disease', 'MESH:D010673', (0, 27))	('parasympathetic disease', 'Disease', 'MESH:D001342', (87, 110))
49765	20833333	For example, the D92Y cofounder mutation was described to be associated with malignant course of the disease, but additional mutations with malignant potential have been described.	('D92Y', 'Mutation', 'rs80338845', (17, 21))	('associated', 'Reg', (61, 71))	('malignant', 'CPA', (77, 86))	('D92Y', 'Var', (17, 21))
49767	20833333	SDHC mutations are rare, and are almost exclusively associated with parasympathetic head and neck PGL, although rare cases of SDHC-associated extra-adrenal PHEO have been reported.	('SDHC', 'Gene', (126, 130))	('SDHC', 'Gene', (0, 4))	('SDHC', 'Gene', '6391', (126, 130))	('associated', 'Reg', (52, 62))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))
49771	20833333	It was clearly familial and initially mapped to chromosome 11, but as other PGL syndromes were successfully found to be related to specific gene mutations, one thing seem to hold in relation to PGL2: it was not related to mutation in SDHA subunit - the only subunit left without mutation causing PHEO/PGL.	('PGL syndrome', 'Disease', (76, 88))	('PGL2', 'Gene', (194, 198))	('mutation', 'Var', (222, 230))	('SDHA', 'Gene', (234, 238))	('PGL syndrome', 'Disease', 'MESH:D010235', (76, 88))	('PGL2', 'Gene', '54949', (194, 198))	('SDHA', 'Gene', '6389', (234, 238))
49773	20833333	Low and behold, when they decided to test the PGL2 kindred, mutation in SHD5 at G78R was found in 45 members of this lineage with disease haplotype and none in controls or lineage members without disease and without disease-specific haplotype.	('G78R', 'Var', (80, 84))	('G78R', 'Mutation', 'rs113560320', (80, 84))	('found', 'Reg', (89, 94))	('PGL2', 'Gene', '54949', (46, 50))	('PGL2', 'Gene', (46, 50))	('SHD5', 'Gene', (72, 76))
49774	20833333	Furthemore, mutation in SDH5 gene results in about 95% decrease in flavination (attachment of FAD) of the SDHA and significant decrease in the overall SDH activity.	('SDH', 'Gene', '6390', (151, 154))	('SDHA', 'Gene', (106, 110))	('SDH', 'Gene', '6390', (24, 27))	('SDH', 'Gene', (106, 109))	('SDH', 'Gene', (151, 154))	('decrease', 'NegReg', (127, 135))	('decrease', 'NegReg', (55, 63))	('SDH', 'Gene', (24, 27))	('SDHA', 'Gene', '6389', (106, 110))	('mutation', 'Var', (12, 20))	('SDH', 'Gene', '6390', (106, 109))
49776	20833333	Despite excitement following this discovery and the fact that it advanced further our understanding of the SDH complex, overall SDH5 mutation are very rare, with only one additional family described thus far.	('mutation', 'Var', (133, 141))	('SDH', 'Gene', '6390', (128, 131))	('SDH', 'Gene', '6390', (107, 110))	('SDH', 'Gene', (128, 131))	('SDH', 'Gene', (107, 110))
44669	20833333	Treatment with therapeutic doses of 131I-MIBG or combination chemotherapy (cyclophosphamide, vincristine, and darcabazine) may induce (partial) responses.	('induce', 'Reg', (127, 133))	('131I-MIBG', 'Var', (36, 45))	('darcabazine', 'Chemical', '-', (110, 121))	('vincristine', 'Chemical', 'MESH:D014750', (93, 104))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (75, 91))	('131I-MIBG', 'Chemical', '-', (36, 45))
44671	20833333	Symptomatic treatment by decreasing catecholamine burden can be obtained with alpha-adrenergic blockers and alpha-methyl-paratyrosine.	('decreasing catecholamine burden', 'Phenotype', 'HP:0045012', (25, 56))	('catecholamine burden', 'MPA', (36, 56))	('alpha-methyl-paratyrosine', 'Chemical', 'MESH:D019805', (108, 133))	('alpha-methyl-paratyrosine', 'Var', (108, 133))	('decreasing', 'NegReg', (25, 35))	('catecholamine', 'Chemical', 'MESH:D002395', (36, 49))
49798	20833333	SDH-related PHEO/PGL are rare, but potentially lethal conditions SDH is a mitochondrial complex participating in both electron transfer and the Krebs cycle There are 4 PGL syndromes, related to mutations of different succinate dehydrogenase subunits Biochemically these tumors can be secretory or silent Some of these tumors - especially SDHB-related tumors - carry significant malignant potential	('SDH', 'Gene', '6390', (65, 68))	('hydrogen', 'Chemical', 'MESH:D006859', (229, 237))	('tumors', 'Disease', 'MESH:D009369', (351, 357))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Disease', 'MESH:D009369', (318, 324))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))	('SDHB', 'Gene', '6390', (338, 342))	('SDH', 'Gene', '6390', (0, 3))	('tumors', 'Disease', (270, 276))	('SDH', 'Gene', (65, 68))	('SDHB', 'Gene', (338, 342))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('PGL syndrome', 'Disease', 'MESH:D010235', (168, 180))	('SDH', 'Gene', '6390', (338, 341))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('SDH', 'Gene', (0, 3))	('Krebs', 'Chemical', '-', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('mutations', 'Var', (194, 203))	('tumors', 'Disease', (351, 357))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('SDH', 'Gene', (338, 341))	('tumors', 'Disease', (318, 324))	('succinate', 'Chemical', 'MESH:D019802', (217, 226))	('PGL syndrome', 'Disease', (168, 180))
49814	31883060	After careful consideration, the LVT was treated with the low molecular weight heparin dalteparine (5000E mane 7500E nocte sc daily) for 3 weeks followed by enoxaparine (10,000E sc daily) for another 7 weeks.	('dalteparine', 'Chemical', '-', (87, 98))	('LVT', 'Disease', 'MESH:D013927', (33, 36))	('heparin', 'Chemical', 'MESH:D006493', (79, 86))	('LVT', 'Disease', (33, 36))	('enoxaparine', 'Chemical', 'MESH:D017984', (157, 168))	('5000E mane', 'Var', (100, 110))
49855	31367219	Paragangliomas can be sporadic or familial and associated with various syndromes such as VHL disease, Carney triad, neurofibromatosis type 1, MEN 2A and 2B, and hereditary pheochromocytoma/paraganglioma syndrome associated with SDH gene mutations.	('hereditary pheochromocytoma', 'Disease', 'MESH:D010673', (161, 188))	('Paragangliomas', 'Phenotype', 'HP:0002668', (0, 14))	('hereditary pheochromocytoma', 'Disease', (161, 188))	('paraganglioma syndrome', 'Disease', (189, 211))	('associated', 'Reg', (47, 57))	('MEN 2A and 2B', 'Gene', '5979', (142, 155))	('neurofibromatosis type 1', 'Gene', (116, 140))	('SDH', 'Gene', '6390', (228, 231))	('paraganglioma', 'Phenotype', 'HP:0002668', (189, 202))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (116, 133))	('mutations', 'Var', (237, 246))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (189, 211))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (172, 188))	('associated', 'Reg', (212, 222))	('VHL disease', 'Disease', 'MESH:D006623', (89, 100))	('SDH', 'Gene', (228, 231))	('Paragangliomas', 'Disease', (0, 14))	('VHL disease', 'Disease', (89, 100))	('Carney triad', 'Disease', (102, 114))	('Paragangliomas', 'Disease', 'MESH:D010235', (0, 14))	('neurofibromatosis type 1', 'Gene', '4763', (116, 140))
49857	31367219	It is currently thought, according to some studies, that 65%-80% of all pheochromocytomas/paragangliomas are associated with somatic or germline mutations and some can further be associated with one of the above syndromes.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (72, 89))	('associated', 'Reg', (109, 119))	('associated', 'Reg', (179, 189))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (72, 88))	('germline mutations', 'Var', (136, 154))	('paragangliomas', 'Disease', (90, 104))	('pheochromocytomas', 'Disease', (72, 89))	('paragangliomas', 'Disease', 'MESH:D010235', (90, 104))	('pheochromocytomas', 'Disease', 'MESH:D010673', (72, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (90, 103))	('paragangliomas', 'Phenotype', 'HP:0002668', (90, 104))
49858	31367219	The American Society of Clinical Oncology recommends offering genetic screening for all patients with a risk of at least 10% of carrying a genetic mutation, especially when the results aid in diagnosis or influence the management of the patient or family members at hereditary risk of cancer.	('influence', 'Reg', (205, 214))	('aid', 'Reg', (185, 188))	('patient', 'Species', '9606', (88, 95))	('Oncology', 'Phenotype', 'HP:0002664', (33, 41))	('patients', 'Species', '9606', (88, 96))	('genetic mutation', 'Var', (139, 155))	('patient', 'Species', '9606', (237, 244))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
49860	31367219	Pheochromocytoma/paraganglioma syndrome is associated with a mutation in one SDH subunit that plays a critical role in mitochondria.	('SDH', 'Gene', (77, 80))	('Pheochromocytoma', 'Disease', (0, 16))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (17, 39))	('mutation', 'Var', (61, 69))	('paraganglioma', 'Phenotype', 'HP:0002668', (17, 30))	('SDH', 'Gene', '6390', (77, 80))	('associated', 'Reg', (43, 53))	('paraganglioma syndrome', 'Disease', (17, 39))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))
49861	31367219	Immunohistochemistry for SDHB has been shown to be an excellent screening tool for a mutation in SDH genes.	('SDH', 'Gene', (25, 28))	('SDH', 'Gene', '6390', (97, 100))	('mutation', 'Var', (85, 93))	('SDHB', 'Gene', '6390', (25, 29))	('SDH', 'Gene', (97, 100))	('SDHB', 'Gene', (25, 29))	('SDH', 'Gene', '6390', (25, 28))
49863	31367219	As a result, loss of tumoral immunohistochemical staining for SDHB occurs when there is germline mutation of SDHA, SDHB, SDHC, or SDHD accompanied by inactivation of the normal allele.	('SDHB', 'Gene', '6390', (115, 119))	('SDHB', 'Gene', '6390', (62, 66))	('SDHA', 'Gene', '6389', (109, 113))	('tumoral', 'Disease', (21, 28))	('SDHB', 'Gene', (115, 119))	('tumoral', 'Disease', 'MESH:D009369', (21, 28))	('SDHD', 'Gene', (130, 134))	('SDHD', 'Gene', '6392', (130, 134))	('SDHC', 'Gene', (121, 125))	('loss', 'NegReg', (13, 17))	('mutation', 'Var', (97, 105))	('SDHC', 'Gene', '6391', (121, 125))	('SDHA', 'Gene', (109, 113))	('SDHB', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
49864	31367219	This makes loss of staining for SDHB a sensitive marker, suggestive of germline pathogenic variants of any of the SDH subunits.	('SDHB', 'Gene', '6390', (32, 36))	('SDH', 'Gene', '6390', (114, 117))	('SDHB', 'Gene', (32, 36))	('SDH', 'Gene', '6390', (32, 35))	('variants', 'Var', (91, 99))	('SDH', 'Gene', (114, 117))	('SDH', 'Gene', (32, 35))
49865	31367219	Germline pathogenic variants in SDHA show loss of staining for SDHA, in addition to loss of staining for SDHB.	('staining', 'MPA', (50, 58))	('variants', 'Var', (20, 28))	('SDHA', 'Gene', '6389', (32, 36))	('SDHB', 'Gene', '6390', (105, 109))	('staining', 'MPA', (92, 100))	('SDHA', 'Gene', (63, 67))	('SDHB', 'Gene', (105, 109))	('SDHA', 'Gene', (32, 36))	('SDHA', 'Gene', '6389', (63, 67))	('loss', 'NegReg', (42, 46))
49909	30101131	Thus, patients with LNM had significantly larger tumors than those without LNM (Mann-Whitney U-test, P = 0.035).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('LNM', 'Var', (20, 23))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('patients', 'Species', '9606', (6, 14))	('larger', 'PosReg', (42, 48))
49932	30101131	Paraganglioma has similar morphological, immunohistochemical, and genetic features to GP (hypoxia-inducible factor-2alpha gain-of-function mutations have been detected in both GP and paraganglioma).	('paraganglioma', 'Disease', (183, 196))	('Paraganglioma', 'Disease', (0, 13))	('mutations', 'Var', (139, 148))	('hypoxia-inducible factor-2alpha', 'Gene', '2034', (90, 121))	('hypoxia-inducible factor-2alpha', 'Gene', (90, 121))	('gain-of-function', 'PosReg', (122, 138))	('paraganglioma', 'Disease', 'MESH:D010235', (183, 196))	('paraganglioma', 'Phenotype', 'HP:0002668', (183, 196))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))
49941	23065809	DNAs extracted from 17 different cancer cell lines and 31 primary pheochromocytoma tumors were analyzed for deletion and mutation of RD using qPCR and direct DNA sequencing.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (66, 82))	('pheochromocytoma tumors', 'Disease', (66, 89))	('pheochromocytoma tumors', 'Disease', 'MESH:D010673', (66, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutation', 'Var', (121, 129))	('deletion', 'Var', (108, 116))
49943	23065809	While some of these RD deletion events occurred along with deletions of the entire INK4/ARF locus, other RD deletion events were independent of genetic alterations in p15, p14ARF, and p16.	('ARF', 'Disease', 'MESH:D058186', (88, 91))	('p15', 'Gene', (167, 170))	('p14ARF', 'Gene', (172, 178))	('INK4', 'Gene', (83, 87))	('deletions', 'Var', (59, 68))	('occurred', 'Reg', (39, 47))	('ARF', 'Disease', (88, 91))	('p15', 'Gene', '1030', (167, 170))	('ARF', 'Disease', 'MESH:D058186', (175, 178))	('INK4', 'Gene', '1029', (83, 87))	('p16', 'Gene', '1029', (184, 187))	('ARF', 'Disease', (175, 178))	('p14ARF', 'Gene', '1029', (172, 178))	('p16', 'Gene', (184, 187))
49945	23065809	This study demonstrates for the first time that deletion of the RD enhancer is a prevalent event in human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('human', 'Species', '9606', (100, 105))	('RD enhancer', 'Gene', (64, 75))	('cancer', 'Disease', (106, 112))	('deletion', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
49956	23065809	The RD/CDC6 interaction provides a novel mechanism that is important in cell cycle control and carcinogenesis since its perturbation by RD alterations and/or increased expression of CDC6 may down-regulate both the Rb and P53 pathways.	('P53', 'Gene', (221, 224))	('P53', 'Gene', '7157', (221, 224))	('expression', 'MPA', (168, 178))	('carcinogenesis', 'Disease', 'MESH:D063646', (95, 109))	('alterations', 'Var', (139, 150))	('carcinogenesis', 'Disease', (95, 109))	('down-regulate', 'NegReg', (191, 204))	('CDC6', 'Gene', '990', (182, 186))	('CDC6', 'Gene', '990', (7, 11))	('CDC6', 'Gene', (182, 186))	('CDC6', 'Gene', (7, 11))	('increased', 'PosReg', (158, 167))
49962	23065809	Deletion, methylation, and point mutations of p16, p15, and p14ARF were evaluated as previously reported with primers and probes listed in Table 2.	('p14ARF', 'Gene', (60, 66))	('p16', 'Gene', '1029', (46, 49))	('point mutations', 'Var', (27, 42))	('p15', 'Gene', (51, 54))	('p14ARF', 'Gene', '1029', (60, 66))	('p15', 'Gene', '1030', (51, 54))	('p16', 'Gene', (46, 49))
49968	23065809	Subsequently, the gene dosage of RD in different cancer cell lines and tumors was determined and the results were interpreted as follows: dosage <25%, homozygous deletion (RD-/-); dosage between 25% and 75%, hemizygous deletion (RD+/-); and dosage >75%, RD wild type (RD+/+).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('dosage between 25%', 'Var', (180, 198))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (71, 77))	('dosage <25%', 'Var', (138, 149))	('cancer', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
49979	23065809	We first extracted genomic DNAs from 18 human cell lines (one normal oral epithelial cell line, 17 neoplastic cell lines) and investigated potential genetic abnormalities of RD including homozygous/hemizygous deletions and point mutations.	('point mutations', 'Var', (223, 238))	('genetic abnormalities', 'Disease', 'MESH:D030342', (149, 170))	('human', 'Species', '9606', (40, 45))	('genetic abnormalities', 'Disease', (149, 170))
49982	23065809	While four cell lines, SCC-9, UM-SCC-22A, PANC-1, and MIA PaCa-2, harbored homozygous deletions of RD, hemizygous deletions of RD were found in SCC-15, SCC-4, and SCC-25 cells.	('SCC-4', 'Gene', (152, 157))	('SCC', 'Gene', '6317', (33, 36))	('SCC', 'Gene', '6317', (23, 26))	('SCC-9', 'CellLine', 'CVCL:1685', (23, 28))	('SCC', 'Gene', (144, 147))	('SCC-4', 'Gene', '23383', (152, 157))	('SCC', 'Gene', (152, 155))	('SCC', 'Gene', (163, 166))	('SCC', 'Gene', '6317', (144, 147))	('SCC', 'Gene', (33, 36))	('deletions', 'Var', (86, 95))	('SCC', 'Gene', '6317', (152, 155))	('SCC', 'Gene', (23, 26))	('PANC-1', 'CellLine', 'CVCL:0480', (42, 48))	('SCC', 'Gene', '6317', (163, 166))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (54, 64))
49983	23065809	Interestingly, no point mutations of RD were identified in any of these 17 tumor cell lines, demonstrating that hemizygous (3/17) and homozygous (4/17) deletions are the major mechanisms to inactivate RD at the DNA level.	('inactivate', 'NegReg', (190, 200))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('deletions', 'Var', (152, 161))	('tumor', 'Disease', (75, 80))
49984	23065809	Of the four RD-/- cell lines, UM-SCC-22A, PANC-1, and MIA PaCa-2 also harbored homozygous deletions of p15, p14ARF, and p16, indicating that the entire INK4/ARF locus was deleted in these cell lines.	('ARF', 'Disease', 'MESH:D058186', (111, 114))	('SCC', 'Gene', '6317', (33, 36))	('ARF', 'Disease', (111, 114))	('p16', 'Gene', '1029', (120, 123))	('p14ARF', 'Gene', '1029', (108, 114))	('p16', 'Gene', (120, 123))	('INK4', 'Gene', (152, 156))	('ARF', 'Disease', 'MESH:D058186', (157, 160))	('SCC', 'Gene', (33, 36))	('p14ARF', 'Gene', (108, 114))	('ARF', 'Disease', (157, 160))	('p15', 'Gene', (103, 106))	('deletions', 'Var', (90, 99))	('INK4', 'Gene', '1029', (152, 156))	('p15', 'Gene', '1030', (103, 106))	('PANC-1', 'CellLine', 'CVCL:0480', (42, 48))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (54, 64))
49985	23065809	In contrast, SCC-9 harbored homozygous deletions of RD, p15, and p14ARF, but retained intact p16, suggesting that the deletion event in SCC-9 occurs at the upstream of the p16 gene.	('deletions', 'Var', (39, 48))	('p14ARF', 'Gene', '1029', (65, 71))	('p16', 'Gene', '1029', (93, 96))	('SCC-9', 'Gene', (136, 141))	('p16', 'Gene', (172, 175))	('SCC-9', 'CellLine', 'CVCL:1685', (13, 18))	('SCC-9', 'CellLine', 'CVCL:1685', (136, 141))	('p16', 'Gene', (93, 96))	('p14ARF', 'Gene', (65, 71))	('p15', 'Gene', (56, 59))	('p15', 'Gene', '1030', (56, 59))	('p16', 'Gene', '1029', (172, 175))
49986	23065809	Out of the three RD+/- cell lines, SCC-4 had intact p15, p14ARF, and p16 genes, indicative of RD-specific genetic alterations in this cell line; SCC-15 and SCC-25 had methylated p16 and homozygous deletion of p16, respectively, whereas their p15 and p14ARF genes remained intact, suggesting that there are two independent inactivating events targeting RD and p16, respectively, in SCC-15 and SCC-25.	('methylated', 'Var', (167, 177))	('p16', 'Gene', (209, 212))	('p16', 'Gene', (178, 181))	('p14ARF', 'Gene', '1029', (250, 256))	('SCC', 'Gene', (156, 159))	('SCC', 'Gene', '6317', (35, 38))	('p16', 'Gene', '1029', (209, 212))	('SCC', 'Gene', '6317', (145, 148))	('p15', 'Gene', '1030', (52, 55))	('SCC-4', 'Gene', '23383', (35, 40))	('SCC', 'Gene', '6317', (392, 395))	('p16', 'Gene', '1029', (178, 181))	('deletion', 'Var', (197, 205))	('SCC', 'Gene', (35, 38))	('SCC', 'Gene', (145, 148))	('p14ARF', 'Gene', '1029', (57, 63))	('SCC', 'Gene', (392, 395))	('p14ARF', 'Gene', (250, 256))	('p16', 'Gene', (359, 362))	('p16', 'Gene', '1029', (359, 362))	('SCC', 'Gene', '6317', (381, 384))	('p15', 'Gene', (242, 245))	('SCC-4', 'Gene', (35, 40))	('p14ARF', 'Gene', (57, 63))	('SCC', 'Gene', (381, 384))	('p16', 'Gene', (69, 72))	('p15', 'Gene', (52, 55))	('SCC', 'Gene', '6317', (156, 159))	('p16', 'Gene', '1029', (69, 72))	('p15', 'Gene', '1030', (242, 245))
49988	23065809	For example, CAL-27 and PC3 (both RD+/+) had promoter hypermethylation in p15 and p16, respectively, whereas DU145 had a point mutation (G   T) in exon 2 of p16, which leads to mutated P16 (Asp74Tyr) and P14ARF (Arg88Leu) proteins.	('p15', 'Gene', (74, 77))	('P16', 'Gene', (185, 188))	('DU145', 'CellLine', 'CVCL:0105', (109, 114))	('p15', 'Gene', '1030', (74, 77))	('Arg88Leu', 'SUBSTITUTION', 'None', (212, 220))	('mutated', 'MPA', (177, 184))	('p16', 'Gene', (82, 85))	('Arg88Leu', 'Var', (212, 220))	('PC3', 'Gene', (24, 27))	('p16', 'Gene', '1029', (82, 85))	('Asp74Tyr', 'SUBSTITUTION', 'None', (190, 198))	('P14ARF', 'Gene', '1029', (204, 210))	('PC3', 'Gene', '3853', (24, 27))	('Asp74Tyr', 'Var', (190, 198))	('p16', 'Gene', (157, 160))	('P14ARF', 'Gene', (204, 210))	('point mutation', 'Var', (121, 135))	('P16', 'Gene', '1029', (185, 188))	('p16', 'Gene', '1029', (157, 160))
49992	23065809	As expected, no expression of p15, p14ARF, and p16 was detected in cell lines with homozygous deletions of the entire INK4/ARF locus (UM-SCC-22A, PANC-1, and MIA PaCa-2).	('ARF', 'Disease', (38, 41))	('p15', 'Gene', (30, 33))	('p15', 'Gene', '1030', (30, 33))	('PANC-1', 'CellLine', 'CVCL:0480', (146, 152))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (158, 168))	('SCC', 'Gene', '6317', (137, 140))	('p16', 'Gene', (47, 50))	('ARF', 'Disease', 'MESH:D058186', (123, 126))	('p14ARF', 'Gene', '1029', (35, 41))	('ARF', 'Disease', (123, 126))	('deletions', 'Var', (94, 103))	('p14ARF', 'Gene', (35, 41))	('ARF', 'Disease', 'MESH:D058186', (38, 41))	('p16', 'Gene', '1029', (47, 50))	('INK4', 'Gene', '1029', (118, 122))	('INK4', 'Gene', (118, 122))	('SCC', 'Gene', (137, 140))
49993	23065809	Similar results were observed with SCC-9, which has homozygous deletions of RD, p15, and p14ARF but intact p16, suggesting that the transcription of p16 in this cell line is silenced through yet-to-be identified mechanisms.	('p16', 'Gene', '1029', (149, 152))	('p14ARF', 'Gene', (89, 95))	('p16', 'Gene', '1029', (107, 110))	('deletions', 'Var', (63, 72))	('p16', 'Gene', (107, 110))	('silenced', 'NegReg', (174, 182))	('transcription', 'MPA', (132, 145))	('p16', 'Gene', (149, 152))	('p14ARF', 'Gene', '1029', (89, 95))	('p15', 'Gene', (80, 83))	('SCC-9', 'CellLine', 'CVCL:1685', (35, 40))	('p15', 'Gene', '1030', (80, 83))
50002	23065809	Interestingly, both p16 and p14ARF were over-expressed in DU145, a cell line harboring mutated P16 and P14ARF proteins.	('P14ARF', 'Gene', (103, 109))	('mutated', 'Var', (87, 94))	('p14ARF', 'Gene', '1029', (28, 34))	('P16', 'Gene', '1029', (95, 98))	('p16', 'Gene', (20, 23))	('p14ARF', 'Gene', (28, 34))	('DU145', 'CellLine', 'CVCL:0105', (58, 63))	('over-expressed', 'PosReg', (40, 54))	('p16', 'Gene', '1029', (20, 23))	('P14ARF', 'Gene', '1029', (103, 109))	('P16', 'Gene', (95, 98))
50014	23065809	While the p16 gene is homozygously deleted in UM-SCC-22A, it is transcriptionally silenced in SCC-15 (through methylation) and SCC-9 (through unknown mechanisms).	('SCC', 'Gene', (127, 130))	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', (94, 97))	('SCC', 'Gene', '6317', (127, 130))	('p16', 'Gene', (10, 13))	('SCC', 'Gene', '6317', (49, 52))	('SCC', 'Gene', '6317', (94, 97))	('methylation', 'Var', (110, 121))	('SCC-9', 'CellLine', 'CVCL:1685', (127, 132))	('p16', 'Gene', '1029', (10, 13))
50020	23065809	As listed in Table 3, homozygous and hemizygous deletions of RD were identified in one and three tumors, respectively, while no "normal" specimens harbored RD alterations.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('deletions', 'Var', (48, 57))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
50021	23065809	The overall frequency of RD alterations in this cohort of pheochromocytomas is 13.0% (4/31).	('alterations', 'Var', (28, 39))	('pheochromocytomas', 'Disease', 'MESH:D010673', (58, 75))	('pheochromocytomas', 'Disease', (58, 75))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (58, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))
50022	23065809	In comparison, deletions (hemizygous and homozygous), point mutation, and aberrant CpG methylation of p16 were found in 9, 1, and 11 tumors with an overall frequency of 67.7% (21/31).	('aberrant CpG methylation', 'Var', (74, 98))	('found', 'Reg', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', (133, 139))	('p16', 'Gene', (102, 105))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('p16', 'Gene', '1029', (102, 105))	('point mutation', 'Var', (54, 68))	('deletions', 'Var', (15, 24))
50023	23065809	In the group of four pheochromocytomas with RD alterations, one tumor (T21) harbored homozygous deletions of both RD and p16, and another tumor (T5) had hemizygous deletions of both RD and p16, indicating that alterations of RD and p16 in these two tumors may result from a single molecular event in the INK4/ARF locus.	('tumor', 'Disease', (138, 143))	('deletions', 'Var', (164, 173))	('tumor', 'Disease', (249, 254))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (21, 37))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('p16', 'Gene', (232, 235))	('ARF', 'Disease', (309, 312))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('alterations', 'Var', (210, 221))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('p16', 'Gene', '1029', (232, 235))	('p16', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('p16', 'Gene', '1029', (121, 124))	('result from', 'Reg', (260, 271))	('pheochromocytomas', 'Disease', (21, 38))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('pheochromocytomas', 'Disease', 'MESH:D010673', (21, 38))	('ARF', 'Disease', 'MESH:D058186', (309, 312))	('deletions', 'Var', (96, 105))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('INK4', 'Gene', '1029', (304, 308))	('tumor', 'Disease', (64, 69))	('p16', 'Gene', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (21, 38))	('alterations', 'Var', (47, 58))	('INK4', 'Gene', (304, 308))	('tumors', 'Disease', (249, 255))	('p16', 'Gene', '1029', (189, 192))
50024	23065809	The remaining pheochromocytomas with RD alterations, T1 and T18L, harbored hemizygously deleted RD; however, the status of p16 in these two tumors were different: p16 was methylated in T18L, but remained intact in T1.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (14, 30))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (14, 31))	('p16', 'Gene', '1029', (163, 166))	('methylated', 'Var', (171, 181))	('tumors', 'Disease', (140, 146))	('p16', 'Gene', (123, 126))	('pheochromocytomas', 'Disease', (14, 31))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('T18L', 'Mutation', 'p.T18L', (185, 189))	('pheochromocytomas', 'Disease', 'MESH:D010673', (14, 31))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('p16', 'Gene', (163, 166))	('p16', 'Gene', '1029', (123, 126))	('T18L', 'Mutation', 'p.T18L', (60, 64))	('T18L', 'Var', (185, 189))
50028	23065809	Importantly, the only tumor (T16L) exhibiting highly expressed P16 had an intact RD, but a point mutation in p16 leading to a partial loss of P16 function.	('p16', 'Gene', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('P16', 'Gene', '1029', (142, 145))	('P16', 'Gene', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('P16', 'Gene', (142, 145))	('function', 'MPA', (146, 154))	('p16', 'Gene', '1029', (109, 112))	('tumor', 'Disease', (22, 27))	('P16', 'Gene', '1029', (63, 66))	('loss', 'NegReg', (134, 138))	('point mutation', 'Var', (91, 105))	('T16L', 'Mutation', 'p.T16L', (29, 33))
50031	23065809	In a panel of 17 human cell lines derived from different types of cancers, up to 41.2% (7/17) demonstrated homozygous (4/17) or hemizygous (3/17) RD deletions.	('human', 'Species', '9606', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('RD deletions', 'Var', (146, 158))
50032	23065809	We also showed that in a cohort of 31 human pheochromocytoma tumors, three tumors harbored hemizygous deletions of RD and one tumor had homozygous deletions of RD.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (61, 67))	('human', 'Species', '9606', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('pheochromocytoma tumors', 'Disease', 'MESH:D010673', (44, 67))	('tumor', 'Disease', (126, 131))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('pheochromocytoma tumors', 'Disease', (44, 67))	('deletions', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (61, 66))
50033	23065809	These results reveal that deletion of RD occurs in human cancer cells and tumor tissues with a considerable incidence (11/48, 22.9%).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('cancer', 'Disease', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('deletion', 'Var', (26, 34))	('human', 'Species', '9606', (51, 56))	('tumor', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
50035	23065809	Moreover, some cancer cell lines and tumors had intact RD, but harbored genetic alterations (i.e., deletion, methylation, and point mutations) in one or more of the p15, p14ARF, and p16 genes.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('methylation', 'Var', (109, 120))	('p16', 'Gene', (182, 185))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('p15', 'Gene', (165, 168))	('p15', 'Gene', '1030', (165, 168))	('point mutations', 'Var', (126, 141))	('p14ARF', 'Gene', (170, 176))	('p14ARF', 'Gene', '1029', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('p16', 'Gene', '1029', (182, 185))	('deletion', 'Var', (99, 107))	('tumors', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('alterations', 'Reg', (80, 91))
50037	23065809	However, hemizygous and homozygous deletions of RD were identified both in diverse human cancer cell lines and pheochromocytoma tumor tissues, but not in non-malignant cells in vitro or non-tumor human tissue samples.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (111, 127))	('human', 'Species', '9606', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('pheochromocytoma tumor', 'Disease', 'MESH:D010673', (111, 133))	('tumor', 'Disease', (190, 195))	('cancer', 'Disease', (89, 95))	('deletions', 'Var', (35, 44))	('tumor', 'Disease', (128, 133))	('pheochromocytoma tumor', 'Disease', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
50038	23065809	In contrast, a spectrum of genetic alterations of p15, p14ARF, and p16 were present in these cell lines and tumor specimens, including not only deletion, but also methylation and point mutations.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('p14ARF', 'Gene', (55, 61))	('p16', 'Gene', '1029', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p14ARF', 'Gene', '1029', (55, 61))	('tumor', 'Disease', (108, 113))	('deletion', 'Var', (144, 152))	('point mutations', 'Var', (179, 194))	('methylation', 'Var', (163, 174))	('p16', 'Gene', (67, 70))	('p15', 'Gene', (50, 53))	('p15', 'Gene', '1030', (50, 53))
50039	23065809	Specifically, both methylation and deletion are major mechanisms to inactive p16 in pheochromocytomas as evidenced by their incidences of 29.0% (10/31) and 35.5% (11/31), respectively.	('p16', 'Gene', (77, 80))	('methylation', 'Var', (19, 30))	('inactive', 'NegReg', (68, 76))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (84, 101))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (84, 100))	('p16', 'Gene', '1029', (77, 80))	('pheochromocytomas', 'Disease', (84, 101))	('deletion', 'Var', (35, 43))	('pheochromocytomas', 'Disease', 'MESH:D010673', (84, 101))
50042	23065809	However, it is important to note that how genetic alterations of RD contribute to the regulation of tumor suppressors P15, P14ARF, and P16 as well as carcinogenesis remains to be further investigated.	('regulation', 'MPA', (86, 96))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('P16', 'Gene', '1029', (135, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('P15', 'Gene', (118, 121))	('tumor', 'Disease', (100, 105))	('P15', 'Gene', '1030', (118, 121))	('carcinogenesis', 'Disease', (150, 164))	('contribute', 'Reg', (68, 78))	('P14ARF', 'Gene', '1029', (123, 129))	('genetic alterations', 'Var', (42, 61))	('P16', 'Gene', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('P14ARF', 'Gene', (123, 129))
50048	28738844	Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma Germline mutations in genes encoding subunits of succinate dehydrogenase (SDH) are associated with the development of pheochromocytoma (PC) and/or paraganglioma (PGL).	('pheochromocytoma', 'Disease', (197, 213))	('mutations', 'Var', (88, 97))	('paraganglioma', 'Disease', (226, 239))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (197, 213))	('SDH', 'Gene', '6390', (153, 156))	('pheochromocytoma', 'Disease', 'MESH:D010673', (44, 60))	('associated with', 'Reg', (162, 177))	('paraganglioma', 'Disease', 'MESH:D010235', (226, 239))	('succinate', 'Chemical', 'MESH:D019802', (128, 137))	('pheochromocytoma', 'Disease', (44, 60))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('paraganglioma', 'Disease', (65, 78))	('SDH', 'Gene', (153, 156))	('paraganglioma', 'Disease', 'MESH:D010235', (65, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (226, 239))	('SDH', 'Gene', '6390', (12, 15))	('SDHAF3', 'Gene', '57001', (12, 18))	('pheochromocytoma', 'Disease', 'MESH:D010673', (197, 213))	('paraganglioma', 'Phenotype', 'HP:0002668', (65, 78))	('SDHAF3', 'Gene', (12, 18))	('SDH', 'Gene', (12, 15))
50049	28738844	As assembly factors have been identified as playing a role in maturation of individual SDH subunits and assembly of the functioning SDH complex, we hypothesized that SDHAF3 variants may be associated with PC/PGL and functionality of SDH.	('SDH', 'Gene', '6390', (87, 90))	('SDH', 'Gene', (233, 236))	('SDH', 'Gene', '6390', (166, 169))	('SDHAF3', 'Gene', (166, 172))	('associated', 'Reg', (189, 199))	('SDH', 'Gene', '6390', (132, 135))	('SDHAF3', 'Gene', '57001', (166, 172))	('variants', 'Var', (173, 181))	('SDH', 'Gene', (87, 90))	('SDH', 'Gene', (132, 135))	('SDH', 'Gene', (166, 169))	('SDH', 'Gene', '6390', (233, 236))	('PC/PGL', 'Disease', (205, 211))
50050	28738844	DNA was extracted from the blood of 37 individuals (from 23 families) with germline SDH mutations and 18 PC/PGL (15 sporadic, 3 familial) and screened for mutations using a custom gene panel, containing SDHAF3 (SDH assembly factor 3) as well as eight known PC/PGL susceptibility genes.	('SDH', 'Gene', '6390', (203, 206))	('mutations', 'Var', (155, 164))	('SDHAF3', 'Gene', '57001', (203, 209))	('SDH assembly factor 3', 'Gene', (211, 232))	('mutations', 'Var', (88, 97))	('SDH assembly factor 3', 'Gene', '57001', (211, 232))	('SDH', 'Gene', (203, 206))	('SDH', 'Gene', '6390', (211, 214))	('SDH', 'Gene', '6390', (84, 87))	('SDHAF3', 'Gene', (203, 209))	('SDH', 'Gene', (211, 214))	('SDH', 'Gene', (84, 87))
50052	28738844	Using massively parallel sequencing, we identified a variant in SDHAF3, c.157 T > C (p.Phe53Leu), associated with increased prevalence in familial and sporadic PC/PGL (6.6%) when compared to normal populations (1.2% [1000 Genomes], p = 0.003; 2.1% [Exome Aggregation Consortium], p = 0.0063).	('SDHAF3', 'Gene', '57001', (64, 70))	('p.Phe53Leu', 'Mutation', 'rs62624461', (85, 95))	('c.157 T > C', 'Var', (72, 83))	('SDHAF3', 'Gene', (64, 70))	('c.157 T > C', 'Mutation', 'rs62624461', (72, 83))
50053	28738844	In silico prediction tools suggest this variant is probably damaging to protein function, hence we assessed molecular and functional consequences of the resulting amino acid change (p.Phe53Leu) in yeast and human cells.	('yeast', 'Species', '4932', (197, 202))	('variant', 'Var', (40, 47))	('p.Phe53Leu', 'Mutation', 'rs62624461', (182, 192))	('amino acid change', 'Var', (163, 180))	('human', 'Species', '9606', (207, 212))	('protein function', 'MPA', (72, 88))
50054	28738844	We showed that introduction of SDHAF3 p.Phe53Leu into Sdh7 (ortholog of SDHAF3 in humans) null yeast resulted in impaired function, as observed by its failure to restore SDH activity when expressed in Sdh7 null yeast relative to WT SDHAF3.	('SDHAF3', 'Gene', '57001', (232, 238))	('function', 'MPA', (122, 130))	('SDHAF3', 'Gene', (232, 238))	('SDHAF3', 'Gene', '57001', (72, 78))	('p.Phe53Leu', 'Var', (38, 48))	('activity', 'MPA', (174, 182))	('SDH', 'Gene', (170, 173))	('SDH', 'Gene', (232, 235))	('SDHAF3', 'Gene', (72, 78))	('SDH', 'Gene', '6390', (31, 34))	('yeast', 'Species', '4932', (95, 100))	('SDH', 'Gene', '6390', (72, 75))	('SDHAF3', 'Gene', '57001', (31, 37))	('p.Phe53Leu', 'Mutation', 'rs62624461', (38, 48))	('Sdh7', 'Gene', (201, 205))	('SDHAF3', 'Gene', (31, 37))	('SDH', 'Gene', (31, 34))	('SDH', 'Gene', (72, 75))	('yeast', 'Species', '4932', (211, 216))	('SDH', 'Gene', '6390', (232, 235))	('SDH', 'Gene', '6390', (170, 173))	('humans', 'Species', '9606', (82, 88))	('Sdh7', 'Gene', (54, 58))
50055	28738844	As SDHAF3 is involved in maturation of SDHB, we tested the functional impact of SDHAF3 c.157 T > C and various clinically relevant SDHB mutations on this interaction.	('SDHB', 'Gene', '6390', (131, 135))	('c.157 T > C', 'Mutation', 'rs62624461', (87, 98))	('SDHB', 'Gene', '6390', (39, 43))	('SDHAF3', 'Gene', (80, 86))	('SDHAF3', 'Gene', '57001', (3, 9))	('SDHB', 'Gene', (131, 135))	('c.157 T > C', 'Var', (87, 98))	('SDHB', 'Gene', (39, 43))	('SDHAF3', 'Gene', '57001', (80, 86))	('mutations', 'Var', (136, 145))	('tested', 'Reg', (48, 54))	('SDHAF3', 'Gene', (3, 9))
50056	28738844	Our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), with impaired interaction observed in the presence of the SDHAF3 c.157 T > C variant.	('SDHAF3', 'Gene', '57001', (154, 160))	('c.157 T > C', 'Var', (161, 172))	('human', 'Species', '9606', (24, 29))	('SDHB', 'Gene', '6390', (68, 72))	('interacts', 'Interaction', (53, 62))	('SDHAF3', 'Gene', (46, 52))	('SDHB', 'Gene', (68, 72))	('SDHAF3', 'Gene', (154, 160))	('c.157 T > C', 'Mutation', 'rs62624461', (161, 172))	('SDHAF3', 'Gene', '57001', (46, 52))
50058	28738844	We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) may be more prevalent in individuals with PC/PGL, and is hypomorphic via impaired interaction with SDHB.	('SDHAF3', 'Gene', '57001', (122, 128))	('SDHAF3', 'Gene', '57001', (19, 25))	('hypomorphic via impaired', 'Disease', (213, 237))	('hypomorphic via impaired', 'Disease', 'MESH:D009422', (213, 237))	('SDHB', 'Gene', (50, 54))	('c.157 T > C', 'Mutation', 'rs62624461', (130, 141))	('interacts', 'Interaction', (26, 35))	('PC/PGL', 'Disease', (198, 204))	('p.Phe53Leu', 'Mutation', 'rs62624461', (143, 153))	('interaction', 'Interaction', (238, 249))	('SDHB', 'Gene', '6390', (255, 259))	('SDHAF3', 'Gene', (122, 128))	('SDHAF3', 'Gene', (19, 25))	('c.157 T > C', 'Var', (130, 141))	('SDHB', 'Gene', (255, 259))	('prevalent', 'Reg', (168, 177))	('SDHB', 'Gene', '6390', (50, 54))
50060	28738844	SDH is comprised of four nuclear encoded subunits (SDHA, B, C and D), and germline mutation in any of these SDH subunits is associated with a variable risk of developing neoplasia.	('neoplasia', 'Disease', (170, 179))	('SDH', 'Gene', '6390', (51, 54))	('SDH', 'Gene', '6390', (108, 111))	('SDHA, B, C and D', 'Gene', '6389', (51, 67))	('germline mutation', 'Var', (74, 91))	('SDH', 'Gene', (0, 3))	('neoplasia', 'Phenotype', 'HP:0002664', (170, 179))	('SDH', 'Gene', (51, 54))	('neoplasia', 'Disease', 'MESH:D009369', (170, 179))	('SDH', 'Gene', (108, 111))	('SDH', 'Gene', '6390', (0, 3))
50061	28738844	Nevertheless, discordant phenotypes are observed both within and between families carrying the same SDH mutation, suggesting that other environmental, genetic or epigenetic factors influence the clinical phenotype.	('SDH', 'Gene', '6390', (100, 103))	('SDH', 'Gene', (100, 103))	('influence', 'Reg', (181, 190))	('iron', 'Chemical', 'MESH:D007501', (139, 143))	('mutation', 'Var', (104, 112))
50062	28738844	SDH genes (SDHA, SDHB, SDHC, SDHD) act as classical tumor suppressors, such that germline heterozygous inactivating mutations coupled with somatic loss of the remaining wild-type allele leads to complete loss of enzyme function and development of associated tumors.	('tumor', 'Disease', (258, 263))	('SDH', 'Gene', (11, 14))	('tumor', 'Disease', (52, 57))	('SDHA', 'Gene', (11, 15))	('loss', 'NegReg', (204, 208))	('loss', 'NegReg', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('SDH', 'Gene', '6390', (0, 3))	('SDHA', 'Gene', '6389', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('SDH', 'Gene', (17, 20))	('SDH', 'Gene', '6390', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SDHD', 'Gene', '6392', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('inactivating mutations', 'Var', (103, 125))	('SDHC', 'Gene', '6391', (23, 27))	('tumors', 'Disease', (258, 264))	('SDH', 'Gene', (0, 3))	('SDHB', 'Gene', '6390', (17, 21))	('SDH', 'Gene', '6390', (29, 32))	('SDH', 'Gene', '6390', (17, 20))	('SDH', 'Gene', '6390', (11, 14))	('SDH', 'Gene', (23, 26))	('SDHD', 'Gene', (29, 33))	('function', 'MPA', (219, 227))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('enzyme', 'Enzyme', (212, 218))	('SDHB', 'Gene', (17, 21))	('SDHC', 'Gene', (23, 27))	('SDH', 'Gene', (29, 32))
50063	28738844	SDHx mutations have been linked to tumorigenesis as a result of a number of downstream consequences.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('linked', 'Reg', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (35, 40))	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))
50066	28738844	Inhibition of the alpha-ketoglutarate-dependent dioxygenase, prolyl hydroxylase (PHD), leads to HIF stabilization, increased expression of HIF targets, and ultimately induction of a hypoxic response under normoxic conditions (pseudo-hypoxia).	('PHD', 'Disease', (81, 84))	('hypoxic response', 'MPA', (182, 198))	('increased', 'PosReg', (115, 124))	('hypoxia', 'Disease', 'MESH:D000860', (233, 240))	('expression', 'MPA', (125, 135))	('hypoxia', 'Disease', (233, 240))	('HIF', 'CPA', (96, 99))	('Inhibition', 'Var', (0, 10))	('PHD', 'Disease', 'MESH:D011547', (81, 84))	('induction', 'Reg', (167, 176))
50067	28738844	In line with this proposed mechanism of action, both increased stability of HIF and increased expression of HIF targets have been identified in SDHx-mutated paragangliomas and pheochromocytomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (157, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (176, 192))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (176, 193))	('paragangliomas', 'Disease', (157, 171))	('paragangliomas', 'Disease', 'MESH:D010235', (157, 171))	('paragangliomas', 'Phenotype', 'HP:0002668', (157, 171))	('stability', 'MPA', (63, 72))	('pheochromocytomas', 'Disease', (176, 193))	('SDHx', 'Chemical', '-', (144, 148))	('SDHx-mutated', 'Var', (144, 156))	('pheochromocytomas', 'Disease', 'MESH:D010673', (176, 193))	('increased', 'PosReg', (53, 62))	('increased', 'PosReg', (84, 93))	('expression', 'MPA', (94, 104))	('SDHx-mutated', 'Gene', (144, 156))
50071	28738844	To date, mutations affecting SDHAF1 (involved in maturation of SDHB) and SDHAF2 (required for covalent attachment of FAD to SDHA) have been associated with human diseases.	('SDHB', 'Gene', (63, 67))	('associated', 'Reg', (140, 150))	('SDHAF1', 'Gene', (29, 35))	('SDHA', 'Gene', (73, 77))	('SDHA', 'Gene', (124, 128))	('mutations', 'Var', (9, 18))	('SDHA', 'Gene', '6389', (29, 33))	('SDHAF2', 'Gene', '54949', (73, 79))	('SDHAF2', 'Gene', (73, 79))	('SDHA', 'Gene', (29, 33))	('SDHB', 'Gene', '6390', (63, 67))	('human', 'Species', '9606', (156, 161))	('SDHA', 'Gene', '6389', (73, 77))	('SDHAF1', 'Gene', '644096', (29, 35))	('SDHA', 'Gene', '6389', (124, 128))
50072	28738844	SDHAF1 mutations have been identified in individuals with leukoencephalopathy, but not yet in subjects with paragangliomas or pheochromocytomas.	('pheochromocytomas', 'Disease', (126, 143))	('identified', 'Reg', (27, 37))	('pheochromocytomas', 'Disease', 'MESH:D010673', (126, 143))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (58, 77))	('paragangliomas', 'Disease', (108, 122))	('paragangliomas', 'Disease', 'MESH:D010235', (108, 122))	('paragangliomas', 'Phenotype', 'HP:0002668', (108, 122))	('SDHAF1', 'Gene', '644096', (0, 6))	('paraganglioma', 'Phenotype', 'HP:0002668', (108, 121))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (126, 143))	('SDHAF1', 'Gene', (0, 6))	('leukoencephalopathy', 'Disease', (58, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (126, 142))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (58, 77))	('mutations', 'Var', (7, 16))
50073	28738844	A SDHAF2 loss-of-function mutation (p.Gly78Arg) has been reported in two unrelated families with head and neck paragangliomas.	('p.Gly78Arg', 'Var', (36, 46))	('neck paragangliomas', 'Disease', (106, 125))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (106, 125))	('p.Gly78Arg', 'Mutation', 'rs113560320', (36, 46))	('paragangliomas', 'Phenotype', 'HP:0002668', (111, 125))	('paraganglioma', 'Phenotype', 'HP:0002668', (111, 124))	('SDHAF2', 'Gene', (2, 8))	('SDHAF2', 'Gene', '54949', (2, 8))	('loss-of-function', 'NegReg', (9, 25))	('neck paragangliomas', 'Disease', 'MESH:D010235', (106, 125))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (97, 125))
50074	28738844	In the tumors of affected individuals, this mutation was shown to impair flavinylation of SDHA.	('flavinylation', 'MPA', (73, 86))	('mutation', 'Var', (44, 52))	('SDHA', 'Gene', '6389', (90, 94))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('SDHA', 'Gene', (90, 94))	('impair', 'NegReg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
50075	28738844	Additionally, in vitro experiments showed that the p.Gly78Arg mutant leads to complete loss of SDH activity, through impaired covalent flavinylation of SDHA and destabilization of the SDHAF2 protein.	('loss', 'NegReg', (87, 91))	('destabilization', 'NegReg', (161, 176))	('impaired covalent flavinylation of SDHA', 'Disease', 'MESH:D009422', (117, 156))	('impaired covalent flavinylation of SDHA', 'Disease', (117, 156))	('SDHAF2', 'Gene', '54949', (184, 190))	('SDHAF2', 'Gene', (184, 190))	('SDH', 'Gene', (184, 187))	('SDH', 'Gene', '6390', (152, 155))	('protein', 'Protein', (191, 198))	('SDH', 'Gene', '6390', (95, 98))	('p.Gly78Arg', 'Var', (51, 61))	('SDH', 'Gene', '6390', (184, 187))	('SDH', 'Gene', (152, 155))	('activity', 'MPA', (99, 107))	('SDH', 'Gene', (95, 98))	('p.Gly78Arg', 'Mutation', 'rs113560320', (51, 61))
50076	28738844	Subsequent studies in large cohorts of apparently sporadic paragangliomas and pheochromocytomas have failed to identify germline or somatic SDHAF2 mutations, suggesting that mutations within SDHAF2 may be rare.	('mutations', 'Var', (147, 156))	('paragangliomas', 'Disease', (59, 73))	('paragangliomas', 'Disease', 'MESH:D010235', (59, 73))	('paragangliomas', 'Phenotype', 'HP:0002668', (59, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (59, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('SDHAF2', 'Gene', '54949', (191, 197))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (78, 95))	('SDHAF2', 'Gene', '54949', (140, 146))	('SDHAF2', 'Gene', (191, 197))	('pheochromocytomas', 'Disease', 'MESH:D010673', (78, 95))	('pheochromocytomas', 'Disease', (78, 95))	('SDHAF2', 'Gene', (140, 146))
50078	28738844	Mutations in the LYR motif of human SDHAF1 were shown to attenuate interaction with iron-sulfur biogenesis components supporting a role for SDHAF1 in maturation of the holo-SDHB complex.	('human', 'Species', '9606', (30, 35))	('SDHAF1', 'Gene', '644096', (36, 42))	('SDHAF1', 'Gene', (36, 42))	('SDHB', 'Gene', '6390', (173, 177))	('SDHAF1', 'Gene', '644096', (140, 146))	('SDHAF1', 'Gene', (140, 146))	('SDHB', 'Gene', (173, 177))	('Mutations', 'Var', (0, 9))	('sulfur', 'Chemical', 'MESH:D013455', (89, 95))	('iron', 'Chemical', 'MESH:D007501', (84, 88))	('interaction', 'Interaction', (67, 78))	('attenuate', 'NegReg', (57, 66))
50081	28738844	We therefore hypothesized that mutations within the newly identified SDH assembly factor, SDHAF3, may be associated with the pathogenesis of pheochromocytoma and/or paraganglioma syndromes.	('pheochromocytoma', 'Disease', (141, 157))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (165, 188))	('mutations', 'Var', (31, 40))	('SDHAF3', 'Gene', (90, 96))	('SDH', 'Gene', '6390', (69, 72))	('pheochromocytoma', 'Disease', 'MESH:D010673', (141, 157))	('SDH', 'Gene', '6390', (90, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('paraganglioma syndromes', 'Disease', (165, 188))	('SDH', 'Gene', (69, 72))	('SDHAF3', 'Gene', '57001', (90, 96))	('SDH', 'Gene', (90, 93))	('associated', 'Reg', (105, 115))
50082	28738844	Furthermore, given SDHAF3 is involved in the maturation of SDHB, we hypothesized that mutations within either of these genes may impair this process.	('impair', 'NegReg', (129, 135))	('mutations', 'Var', (86, 95))	('SDHAF3', 'Gene', '57001', (19, 25))	('SDHAF3', 'Gene', (19, 25))	('SDHB', 'Gene', '6390', (59, 63))	('SDHB', 'Gene', (59, 63))
50083	28738844	DNA was extracted from peripheral blood leukocytes of 37 individuals (from 23 families) with germline SDH mutations (16 SDHB, 1 SDHC and 6 SDHD families) and 100 individuals with no known disease (ie.	('SDH', 'Gene', (139, 142))	('SDH', 'Gene', '6390', (128, 131))	('SDHD', 'Gene', (139, 143))	('SDHD', 'Gene', '6392', (139, 143))	('SDH', 'Gene', (102, 105))	('SDH', 'Gene', (120, 123))	('SDHB', 'Gene', '6390', (120, 124))	('SDHC', 'Gene', (128, 132))	('SDH', 'Gene', '6390', (139, 142))	('SDHC', 'Gene', '6391', (128, 132))	('mutations', 'Var', (106, 115))	('SDHB', 'Gene', (120, 124))	('SDH', 'Gene', (128, 131))	('SDH', 'Gene', '6390', (102, 105))	('SDH', 'Gene', '6390', (120, 123))
50087	28738844	A custom gene panel (TruSeq  Custom Amplicon Assay, Illumina) was developed, encompassing our candidate gene - SDHAF3 (NM_020186); as well as eight known pheochromocytoma/paraganglioma suseptibility genes (MAX [NM_002382], SDHB [NM_003000], SDHC [NM_003001], SDHD [NM_003002], SDHAF2 [NM_017841], RET [NM_020975], TMEM127 [NM_017849] and VHL [NM_000551]).	('paraganglioma', 'Disease', (171, 184))	('TMEM127', 'Gene', '55654', (314, 321))	('SDHC', 'Gene', '6391', (241, 245))	('paraganglioma', 'Disease', 'MESH:D010235', (171, 184))	('SDHAF3', 'Gene', '57001', (111, 117))	('VHL', 'Gene', (338, 341))	('SDHB', 'Gene', (223, 227))	('SDHAF3', 'Gene', (111, 117))	('SDHAF2', 'Gene', (277, 283))	('SDHAF2', 'Gene', '54949', (277, 283))	('pheochromocytoma', 'Disease', 'MESH:D010673', (154, 170))	('paraganglioma', 'Phenotype', 'HP:0002668', (171, 184))	('VHL', 'Gene', '7428', (338, 341))	('SDHD', 'Gene', '6392', (259, 263))	('RET', 'Gene', '5979', (297, 300))	('SDHC', 'Gene', (241, 245))	('pheochromocytoma', 'Disease', (154, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (154, 170))	('SDHD', 'Gene', (259, 263))	('TMEM127', 'Gene', (314, 321))	('[NM_020975]', 'Var', (301, 312))	('SDHB', 'Gene', '6390', (223, 227))	('RET', 'Gene', (297, 300))
50089	28738844	Annotation of functional consequences to variant calls was performed using ANNOVAR (version 2013Jul), which incorporates various in silico tools, including (but not limited to) PolyPhen-2, SIFT, MutationTaster.	('SIFT', 'Disease', (189, 193))	('variant', 'Var', (41, 48))	('SIFT', 'Disease', 'None', (189, 193))
50091	28738844	SDHAF3 variants identified by massively parallel sequencing were confirmed by Sanger sequencing.	('SDHAF3', 'Gene', (0, 6))	('variants', 'Var', (7, 15))	('SDHAF3', 'Gene', '57001', (0, 6))
50097	28738844	For SDHAF3 and SDH2 sequence variants, site-directed mutagenesis was carried out using Phusion high-fidelity DNA polymerase (Thermo Fisher Scientific).	('SDH2', 'Gene', (15, 19))	('variants', 'Var', (29, 37))	('SDHAF3', 'Gene', '57001', (4, 10))	('SDHAF3', 'Gene', (4, 10))
50106	28738844	Anti-Sdh1, Sdh2 and Sdh3 were from a previous study.	('Sdh3', 'Gene', '6391', (20, 24))	('Sdh2', 'Gene', (11, 15))	('Sdh3', 'Gene', (20, 24))	('Anti-Sdh1', 'Var', (0, 9))
50108	28738844	Site-directed mutagenesis (QuikChange Lightning Site-Directed Mutagenesis Kit, Agilent) was used to produce the SDHAF3 variant (p.Phe53Leu [c.157 T > C, NM_020186]) and SDHB mutants (p.Ala43Pro [c.127G > C, NM_003000], p.Arg46Gly [c.136C > G], p.Arg46Gln [c.137G > A], p.Cys101Tyr [c.302G > A], p.Ile127Ser [c.380 T > G], p.Pro197Arg [c.590C > G], p.Arg242His [c.725G > A]).	('SDHAF3', 'Gene', '57001', (112, 118))	('c.590C > G', 'Mutation', 'rs74315367', (335, 345))	('p.Cys101Tyr [c.302G > A]', 'Var', (269, 293))	('SDHB', 'Gene', (169, 173))	('p.Pro197Arg [c.590C > G]', 'Var', (322, 346))	('c.302G > A', 'Mutation', 'rs74315371', (282, 292))	('p.Ala43Pro', 'Mutation', 'rs745559875', (183, 193))	('c.157 T > C', 'Mutation', 'rs62624461', (140, 151))	('SDHAF3', 'Gene', (112, 118))	('p.Ile127Ser [c.380 T > G]', 'Var', (295, 320))	('p.Arg242His [c.725G > A]', 'Var', (348, 372))	('p.Phe53Leu', 'Mutation', 'rs62624461', (128, 138))	('p.Arg46Gln [c.137G > A]', 'Var', (244, 267))	('p.Arg46Gly [c.136C > G]', 'Var', (219, 242))	('c.127G > C', 'Mutation', 'c.127G>C', (195, 205))	('p.Ala43Pro [c.127G > C', 'Var', (183, 205))	('p.Arg46Gly', 'Mutation', 'rs74315370', (219, 229))	('Q', 'Chemical', '-', (27, 28))	('c.136C > G', 'Mutation', 'rs74315370', (231, 241))	('c.380 T > G', 'Mutation', 'rs786201095', (308, 319))	('p.Arg242His', 'Mutation', 'rs74315368', (348, 359))	('p.Pro197Arg', 'Mutation', 'rs74315367', (322, 333))	('SDHB', 'Gene', '6390', (169, 173))	('c.137G > A', 'Mutation', 'rs772551056', (256, 266))	('p.Ile127Ser', 'Mutation', 'rs786201095', (295, 306))	('c.725G > A', 'Mutation', 'rs74315368', (361, 371))	('p.Arg46Gln', 'Mutation', 'rs772551056', (244, 254))	('p.Cys101Tyr', 'Mutation', 'rs74315371', (269, 280))
50109	28738844	The SDHAF3 variant was generated in a commercially available plasmid, pCMV6-SDHAF3-Myc-DDK (RC204626, Origene); while the SDHB mutants were generated in a plasmid (pEGFP-N1; 6085-1, Clonetech) containing wild-type SDHB.	('SDHAF3', 'Gene', (76, 82))	('SDHB', 'Gene', '6390', (214, 218))	('SDHB', 'Gene', '6390', (122, 126))	('Myc', 'Gene', '4609', (83, 86))	('SDHB', 'Gene', (214, 218))	('SDHAF3', 'Gene', '57001', (4, 10))	('SDHB', 'Gene', (122, 126))	('Myc', 'Gene', (83, 86))	('SDHAF3', 'Gene', '57001', (76, 82))	('variant', 'Var', (11, 18))	('SDHAF3', 'Gene', (4, 10))
50130	28738844	Citrate synthase: Approximately 20 mug of protein was added to 470 muL of reaction mixture consisting (in final concentrations) 5 mM of KH2PO4, 45 mM of K2HPO4, 100 muM 5, 5'-dithio-bis-(2-nitrobenzoic acid) (DTNB) in distilled water at pH 7.4.	('KH2PO4', 'Chemical', '-', (136, 142))	('water', 'Chemical', 'MESH:D014867', (228, 233))	('DTNB', 'Chemical', '-', (209, 213))	('KH2PO4', 'Var', (136, 142))	("5, 5'-dithio-bis-(2-nitrobenzoic acid)", 'Chemical', 'MESH:D004228', (169, 207))	('Citrate synthase', 'Gene', '1431', (0, 16))	('K2HPO4', 'Chemical', 'MESH:C013216', (153, 159))	('Citrate synthase', 'Gene', (0, 16))
50135	28738844	During validation of our targeted PC/PGL gene panel (MiSeq platform), we noted that one individual (S11_1) with a previously identified germline SDHB splice-site mutation (within intron 3 [IVS3]) also harbored a germline SDHAF3 c.157 T > C (p.Phe53Leu) variant (rs62624461).	('SDHB', 'Gene', '6390', (145, 149))	('c.157 T > C', 'Mutation', 'rs62624461', (228, 239))	('SDHB', 'Gene', (145, 149))	('SDHAF3', 'Gene', (221, 227))	('p.Phe53Leu', 'Mutation', 'rs62624461', (241, 251))	('c.157 T > C', 'Var', (228, 239))	('rs62624461', 'Var', (262, 272))	('SDHAF3', 'Gene', '57001', (221, 227))	('rs62624461', 'Mutation', 'rs62624461', (262, 272))
50137	28738844	Although this SDHAF3 variant has been identified in population studies (minor allele frequency [MAF] 0.0118 [1000 Genomes_Phase 3_ALL] and 0.0209 [Exome Aggregation Consortium, ExAC]), it is predicted to be damaging by several in silico tools (score of 0.777 [PolyPhen-2 v2.2.2r398], score of 0 [SIFT]).	('SIFT', 'Disease', (296, 300))	('SDHAF3', 'Gene', (14, 20))	('SIFT', 'Disease', 'None', (296, 300))	('variant', 'Var', (21, 28))	('SDHAF3', 'Gene', '57001', (14, 20))
50138	28738844	Since SDHAF3 was recently shown to be involved in mediating SDHB maturation, we determined the prevalence of the SDHAF3 c.157 T > C variant among other subjects either with SDH-related PC/PGL or apparently sporadic PC/PGL, in comparison with normal controls.	('SDH', 'Gene', (113, 116))	('SDH', 'Gene', (60, 63))	('SDHAF3', 'Gene', (6, 12))	('SDHAF3', 'Gene', '57001', (113, 119))	('SDH', 'Gene', (6, 9))	('SDHB', 'Gene', '6390', (60, 64))	('SDH', 'Gene', '6390', (173, 176))	('SDHB', 'Gene', (60, 64))	('SDH', 'Gene', '6390', (6, 9))	('SDHAF3', 'Gene', '57001', (6, 12))	('PC/PGL', 'Disease', (185, 191))	('c.157 T > C', 'Mutation', 'rs62624461', (120, 131))	('SDH', 'Gene', '6390', (60, 63))	('SDH', 'Gene', '6390', (113, 116))	('SDH', 'Gene', (173, 176))	('SDHAF3', 'Gene', (113, 119))	('c.157 T > C', 'Var', (120, 131))
50139	28738844	The frequency of SDHAF3 c.157 T > C in our Australian population was determined by direct sequencing of 100 healthy controls (48% males) with no known familial association to SDH-related disease.	('SDH', 'Gene', (175, 178))	('c.157 T > C', 'Var', (24, 35))	('SDH', 'Gene', (17, 20))	('SDHAF3', 'Gene', '57001', (17, 23))	('SDH', 'Gene', '6390', (175, 178))	('SDHAF3', 'Gene', (17, 23))	('c.157 T > C', 'Mutation', 'rs62624461', (24, 35))	('SDH', 'Gene', '6390', (17, 20))
50140	28738844	Of 200 alleles assessed, 6 were found to exhibit the minor allele (c.157C [NM_020186], p.Phe53Leu, rs62624461), resulting in a minor allele frequency (MAF) of 0.0300, which is consistent with the MAF reported in ExAC (0.0209; p = 0.452) (Table 1).	('p.Phe53Leu', 'Var', (87, 97))	('c.157C [NM_020186]', 'Var', (67, 85))	('rs62624461', 'Mutation', 'rs62624461', (99, 109))	('rs62624461', 'Var', (99, 109))	('p.Phe53Leu', 'Mutation', 'rs62624461', (87, 97))
50141	28738844	When looking at all disease-affected individuals (familial and sporadic, n = 38; Table 1), there is an increased prevalence (6.6% [MAF 0.0658]) of the SDHAF3 c.157 T > C variant when compared to the larger populations of disease-free individuals, specifically 1000 Genomes (Phase 3_ALL) and ExAC populations (1.2% [MAF 0.0118, p = 0.003] and 2.1% [MAF 0.0209, p = 0.022], respectively).	('SDHAF3', 'Gene', '57001', (151, 157))	('c.157 T > C', 'Mutation', 'rs62624461', (158, 169))	('SDHAF3', 'Gene', (151, 157))	('c.157 T > C', 'Var', (158, 169))
50142	28738844	However, no statistically significant difference was observed when comparing the prevalence of the SDHAF3 c.157 T > C variant in disease-affected individuals (familial and sporadic) to a smaller disesase-free population (Australian, 3.0% [MAF 0.0300, p = 0.300]; Table 1).	('SDHAF3', 'Gene', (99, 105))	('c.157 T > C', 'Mutation', 'rs62624461', (106, 117))	('SDHAF3', 'Gene', '57001', (99, 105))	('c.157 T > C', 'Var', (106, 117))
50143	28738844	To further assess the potential role of SDHAF3 in pheochromoctyomas and/or paragangliomas, 15 tumors of apparently sporadic origin were assessed for the presence of the SDHAF3 c.157 T > C (Additional file 1: Table S2).	('15 tumors', 'Disease', (91, 100))	('SDHAF3', 'Gene', '57001', (40, 46))	('15 tumors', 'Disease', 'MESH:C567447', (91, 100))	('paragangliomas', 'Disease', 'MESH:D010235', (75, 89))	('c.157 T > C', 'Mutation', 'rs62624461', (176, 187))	('pheochromoctyomas', 'Disease', 'None', (50, 67))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SDHAF3', 'Gene', (169, 175))	('pheochromoctyomas', 'Disease', (50, 67))	('SDHAF3', 'Gene', (40, 46))	('c.157 T > C', 'Var', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('SDHAF3', 'Gene', '57001', (169, 175))	('paragangliomas', 'Disease', (75, 89))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))
50144	28738844	SDHB immunohistochemical assessment was performed in those cases where formalin-fixed paraffin embedded tissue was available (n = 9; Table S2), only one of which harbors the SDHAF3 c.157 T > C variant (#9).	('SDHAF3', 'Gene', '57001', (174, 180))	('c.157 T > C', 'Var', (181, 192))	('paraffin', 'Chemical', 'MESH:D010232', (86, 94))	('formalin', 'Chemical', 'MESH:D005557', (71, 79))	('SDHB', 'Gene', '6390', (0, 4))	('SDHAF3', 'Gene', (174, 180))	('c.157 T > C', 'Mutation', 'rs62624461', (181, 192))	('SDHB', 'Gene', (0, 4))
50145	28738844	SDHB immunohistochemistry was positive in all cases, with no apparent difference in staining intensity or pattern observed between the SDHAF3 c.157 T > C variant case and the wild-type cases (Additional file 1: Table S2).	('SDHAF3', 'Gene', (135, 141))	('c.157 T > C', 'Var', (142, 153))	('SDHB', 'Gene', '6390', (0, 4))	('SDHAF3', 'Gene', '57001', (135, 141))	('SDHB', 'Gene', (0, 4))	('c.157 T > C', 'Mutation', 'rs62624461', (142, 153))
50147	28738844	presence of pheochromocytoma and/or paraganglioma) were assessed for the presence of SDHAF3 c.157 T > C (Additional file 2: Table S1).	('SDHAF3', 'Gene', '57001', (85, 91))	('paraganglioma', 'Disease', (36, 49))	('pheochromocytoma', 'Disease', 'MESH:D010673', (12, 28))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (12, 28))	('c.157 T > C', 'Mutation', 'rs62624461', (92, 103))	('paraganglioma', 'Disease', 'MESH:D010235', (36, 49))	('SDHAF3', 'Gene', (85, 91))	('c.157 T > C', 'Var', (92, 103))	('paraganglioma', 'Phenotype', 'HP:0002668', (36, 49))	('pheochromocytoma', 'Disease', (12, 28))
50150	28738844	Taken together, of 23 individuals with SDH-related familial pheochromocytoma and/or paraganglioma, two were heterozygous for SDHAF3 c.157 T > C, giving a MAF of 0.0435 (Table 1) which was not significantly different from our Australian population of healthy controls (p = 0.646) nor from the 1000 Genomes (Phase 3_ALL) (p = 0.106) or ExAC (p = 0.251) populations (Table 1).	('paraganglioma', 'Disease', (84, 97))	('SDHAF3', 'Gene', (125, 131))	('c.157 T > C', 'Mutation', 'rs62624461', (132, 143))	('SDH', 'Gene', (39, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('SDH', 'Gene', '6390', (125, 128))	('paraganglioma', 'Disease', 'MESH:D010235', (84, 97))	('c.157 T > C', 'Var', (132, 143))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (51, 76))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('SDHAF3', 'Gene', '57001', (125, 131))	('SDH', 'Gene', '6390', (39, 42))	('SDH', 'Gene', (125, 128))	('familial pheochromocytoma', 'Disease', (51, 76))
50151	28738844	When only SDHB-mutated individuals from our cohort are considered, then co-carriage of SDHAF3 c.157 T > C (MAF 0.0625) does not differ from the Australian (p = 0.603), 1000 Genomes (Phase 3_ALL) (p = 0.057) or ExAC (p = 0.144) populations (Table 1).	('SDHAF3', 'Gene', (87, 93))	('c.157 T > C', 'Var', (94, 105))	('SDHAF3', 'Gene', '57001', (87, 93))	('SDHB', 'Gene', '6390', (10, 14))	('SDHB', 'Gene', (10, 14))	('c.157 T > C', 'Mutation', 'rs62624461', (94, 105))
50152	28738844	In addition to individual S11_1, an additional 14 SDHB mutation carrying members of this family (S11) were assessed (Additional file 3: Table S3).	('SDHB', 'Gene', (50, 54))	('SDHB', 'Gene', '6390', (50, 54))	('mutation', 'Var', (55, 63))
50153	28738844	The SDHAF3 c.157 T > C variant was identified in an additional seven SDHB mutation carrying family members.	('SDHB', 'Gene', (69, 73))	('c.157 T > C', 'Var', (11, 22))	('SDHAF3', 'Gene', '57001', (4, 10))	('SDHB', 'Gene', '6390', (69, 73))	('c.157 T > C', 'Mutation', 'rs62624461', (11, 22))	('SDHAF3', 'Gene', (4, 10))
50154	28738844	Five individuals in this family have (to date) presented with pheochromocytoma and/or paraganglioma (S11_1, S11_2, S11_3, S11_4 and S11_5).	('pheochromocytoma', 'Disease', 'MESH:D010673', (62, 78))	('paraganglioma', 'Disease', 'MESH:D010235', (86, 99))	('S11_1', 'Var', (101, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('S11_3', 'Var', (115, 120))	('paraganglioma', 'Disease', (86, 99))	('S11_4 and S11_5', 'Var', (122, 137))	('presented with', 'Reg', (47, 61))	('pheochromocytoma', 'Disease', (62, 78))
50155	28738844	Of those with germline SDHB mutation and SDHAF3 variant (n = 7), three (43%) have developed pheochromocytomas or paragangliomas (S11_1, S11_2 and S11_3); while two (25%) of those with germline SDHB mutation and wild-type SDHAF3 (n = 8) have developed paragangliomas (p = 0.47, Chi-squared test).	('paragangliomas', 'Disease', 'MESH:D010235', (113, 127))	('paragangliomas', 'Phenotype', 'HP:0002668', (113, 127))	('paragangliomas', 'Disease', (251, 265))	('SDHB', 'Gene', '6390', (23, 27))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('SDHAF3', 'Gene', '57001', (41, 47))	('mutation', 'Var', (28, 36))	('SDHAF3', 'Gene', (41, 47))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (92, 108))	('SDHB', 'Gene', (23, 27))	('SDHAF3', 'Gene', '57001', (221, 227))	('pheochromocytomas or paragangliomas', 'Disease', (92, 127))	('variant', 'Var', (48, 55))	('paragangliomas', 'Disease', (113, 127))	('pheochromocytomas or paragangliomas', 'Disease', 'MESH:D010673', (92, 127))	('SDHB', 'Gene', '6390', (193, 197))	('paragangliomas', 'Disease', 'MESH:D010235', (251, 265))	('SDHAF3', 'Gene', (221, 227))	('paraganglioma', 'Phenotype', 'HP:0002668', (251, 264))	('paragangliomas', 'Phenotype', 'HP:0002668', (251, 265))	('developed', 'PosReg', (82, 91))	('SDHB', 'Gene', (193, 197))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (92, 109))
50156	28738844	Of note, the tumors of individuals S11_1, S11_2 and S11_4 all exhibited loss of the normal SDHB allele and retention of the mutated allele (SDHB IVS3 splice-site mutation).	('loss', 'NegReg', (72, 76))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('SDHB', 'Gene', '6390', (91, 95))	('S11_2', 'Var', (42, 47))	('SDHB', 'Gene', (91, 95))	('SDHB', 'Gene', '6390', (140, 144))	('S11_4', 'Var', (52, 57))	('SDHB', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('S11_1', 'Var', (35, 40))
50157	28738844	Additionally, immunohistochemical assessment demonstrated loss of SDHB staining in all three tumors from individuals S11_1, S11_2 and S11_4.	('SDHB', 'Gene', (66, 70))	('loss', 'NegReg', (58, 62))	('S11_4', 'Var', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('staining', 'MPA', (71, 79))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SDHB', 'Gene', '6390', (66, 70))	('tumors', 'Disease', (93, 99))
50159	28738844	The expression of wild-type (WT) SDHAF3 in yeast cells lacking Sdh7, a yeast ortholog of SDHAF3, enhanced respiratory growth of mutant cells; however, the SDHAF3 p.Phe53Leu variant failed to fully rescue the respiratory growth defect (Fig.	('yeast', 'Species', '4932', (71, 76))	('yeast', 'Species', '4932', (43, 48))	('SDHAF3', 'Gene', (155, 161))	('SDHAF3', 'Gene', '57001', (89, 95))	('Sdh7', 'Gene', (63, 67))	('SDHAF3', 'Gene', (33, 39))	('mutant', 'Var', (128, 134))	('respiratory growth defect', 'Disease', (208, 233))	('enhanced', 'PosReg', (97, 105))	('SDHAF3', 'Gene', '57001', (155, 161))	('p.Phe53Leu', 'Mutation', 'rs62624461', (162, 172))	('SDHAF3', 'Gene', (89, 95))	('respiratory growth defect', 'Disease', 'MESH:D012131', (208, 233))	('respiratory', 'MPA', (106, 117))	('SDHAF3', 'Gene', '57001', (33, 39))	('p.Phe53Leu variant', 'Var', (162, 180))
50161	28738844	Interestingly, the SDHAF3 p.Phe53Leu variant did not restore SQR activity in sdh7  cells, in contrast to the effect of WT SDHAF3 (Fig.	('SDHAF3', 'Gene', '57001', (122, 128))	('SDHAF3', 'Gene', '57001', (19, 25))	('p.Phe53Leu', 'Mutation', 'rs62624461', (26, 36))	('p.Phe53Leu variant', 'Var', (26, 44))	('SQR activity', 'CPA', (61, 73))	('SDHAF3', 'Gene', (122, 128))	('SDHAF3', 'Gene', (19, 25))	('Q', 'Chemical', '-', (62, 63))
50162	28738844	1b), suggesting that the p.Phe53Leu substitution in SDHAF3 is a hypomorphic mutation that contributes to SDH deficiency.	('SDHAF3', 'Gene', (52, 58))	('SDH deficiency', 'Disease', (105, 119))	('SDHAF3', 'Gene', '57001', (52, 58))	('contributes', 'Reg', (90, 101))	('p.Phe53Leu', 'Mutation', 'rs62624461', (25, 35))	('p.Phe53Leu substitution', 'Var', (25, 48))	('SDH deficiency', 'Disease', 'MESH:D007153', (105, 119))
50164	28738844	We found that steady-state levels of SDHAF3 p.Phe53Leu were equal to those of WT SDHAF3 in sdh7  cells, consistent with stable expression of SDHAF3 p.Phe53Leu (Fig.	('p.Phe53Leu', 'Mutation', 'rs62624461', (148, 158))	('SDHAF3', 'Gene', '57001', (81, 87))	('p.Phe53Leu', 'Mutation', 'rs62624461', (44, 54))	('p.Phe53Leu', 'Var', (148, 158))	('SDHAF3', 'Gene', (37, 43))	('SDHAF3', 'Gene', '57001', (141, 147))	('SDHAF3', 'Gene', (81, 87))	('SDHAF3', 'Gene', '57001', (37, 43))	('SDHAF3', 'Gene', (141, 147))
50165	28738844	Meanwhile, substitution of residues in the LYR motif (p.Tyr13Ala and p.Arg14Ala) dramatically decreased SDHAF3 levels (Fig.	('SDHAF3', 'Gene', (104, 110))	('p.Tyr13Ala', 'Mutation', 'p.Y13A', (54, 64))	('p.Arg14Ala', 'Var', (69, 79))	('p.Arg14Ala', 'Mutation', 'p.R14A', (69, 79))	('SDHAF3', 'Gene', '57001', (104, 110))	('decreased', 'NegReg', (94, 103))	('p.Tyr13Ala', 'Var', (54, 64))
50170	28738844	Lane 2 and 4), suggesting that SDHAF3 p.Phe53Leu may be capable of interacting with Sdh2.	('SDHAF3', 'Gene', (31, 37))	('interacting', 'Interaction', (67, 78))	('Sdh2', 'Gene', (84, 88))	('SDHAF3', 'Gene', '57001', (31, 37))	('p.Phe53Leu', 'Mutation', 'rs62624461', (38, 48))	('p.Phe53Leu', 'Var', (38, 48))
50173	28738844	We exploited this phenotype to further confirm the physical interaction between SDHAF3 p.Phe53Leu and Sdh2.	('p.Phe53Leu', 'Var', (87, 97))	('SDHAF3', 'Gene', (80, 86))	('Sdh2', 'Gene', (102, 106))	('SDHAF3', 'Gene', '57001', (80, 86))	('interaction', 'Interaction', (60, 71))	('p.Phe53Leu', 'Mutation', 'rs62624461', (87, 97))
50174	28738844	We performed immunoprecipitation of SDHAF3 p.Phe53Leu with mitochondrial lysates from sdh7  cells wherein Sdh2-His6Myc2 is exogenously expressed.	('SDHAF3', 'Gene', '57001', (36, 42))	('p.Phe53Leu', 'Mutation', 'rs62624461', (43, 53))	('p.Phe53Leu', 'Var', (43, 53))	('SDHAF3', 'Gene', (36, 42))	('Myc', 'Gene', '4609', (115, 118))	('Myc', 'Gene', (115, 118))
50176	28738844	To assess the effect of the SDHAF3 p.Phe53Leu variant in mammalian cells, SDHAF3 was knocked down in HEK293 cells using siRNA, and the effects on SDH (succinate dehydrogenase activity) measured.	('SDH', 'Gene', (74, 77))	('HEK293', 'CellLine', 'CVCL:0045', (101, 107))	('succinate', 'Chemical', 'MESH:D019802', (151, 160))	('SDH', 'Gene', '6390', (28, 31))	('SDHAF3', 'Gene', '57001', (74, 80))	('mammalian', 'Species', '9606', (57, 66))	('SDH', 'Gene', '6390', (146, 149))	('SDH', 'Gene', (28, 31))	('293 cells', 'CellLine', 'CVCL:0045', (104, 113))	('SDHAF3', 'Gene', (74, 80))	('knocked down', 'NegReg', (85, 97))	('SDHAF3', 'Gene', '57001', (28, 34))	('SDH', 'Gene', '6390', (74, 77))	('p.Phe53Leu', 'Mutation', 'rs62624461', (35, 45))	('SDH', 'Gene', (146, 149))	('SDHAF3', 'Gene', (28, 34))	('p.Phe53Leu', 'Var', (35, 45))
50177	28738844	A reduction in SDH activity was observed in SDHAF3 knockdown cells compared to WT cells (p = 0.0132; Fig.	('SDH', 'Gene', (44, 47))	('SDHAF3', 'Gene', '57001', (44, 50))	('reduction', 'NegReg', (2, 11))	('SDH', 'Gene', '6390', (15, 18))	('SDH', 'Gene', '6390', (44, 47))	('SDHAF3', 'Gene', (44, 50))	('SDH', 'Gene', (15, 18))	('knockdown', 'Var', (51, 60))
50178	28738844	Following SDHAF3 knockdown, re-introduction of WT SDHAF3 lead to restored SDH activity (Fig.	('SDH', 'Gene', (74, 77))	('SDHAF3', 'Gene', '57001', (50, 56))	('SDH', 'Gene', '6390', (10, 13))	('SDH', 'Gene', (10, 13))	('SDHAF3', 'Gene', (50, 56))	('SDH', 'Gene', '6390', (50, 53))	('SDHAF3', 'Gene', '57001', (10, 16))	('SDH', 'Gene', '6390', (74, 77))	('knockdown', 'Var', (17, 26))	('SDH', 'Gene', (50, 53))	('SDHAF3', 'Gene', (10, 16))
50179	28738844	Further to this, the p.Phe53Leu variant was also able to restore SDH activity to the same extent as the WT SDHAF3 (p = 0.1486; Fig.	('SDH', 'Gene', '6390', (65, 68))	('restore', 'PosReg', (57, 64))	('SDHAF3', 'Gene', (107, 113))	('SDH', 'Gene', '6390', (107, 110))	('p.Phe53Leu', 'Mutation', 'rs62624461', (21, 31))	('SDHAF3', 'Gene', '57001', (107, 113))	('SDH', 'Gene', (65, 68))	('p.Phe53Leu', 'Var', (21, 31))	('SDH', 'Gene', (107, 110))
50180	28738844	Western blotting of SDHB failed to show any significant differences in expression on re-introduction of the WT SDHAF3 and p.Phe53Leu variant, demonstrating that the observed effects on SDH activity were SDHAF3 dependent (data not shown).	('SDHAF3', 'Gene', (111, 117))	('SDH', 'Gene', '6390', (185, 188))	('activity', 'MPA', (189, 197))	('SDH', 'Gene', '6390', (203, 206))	('SDHAF3', 'Gene', '57001', (203, 209))	('SDH', 'Gene', (20, 23))	('SDH', 'Gene', '6390', (111, 114))	('SDH', 'Gene', (185, 188))	('p.Phe53Leu', 'Mutation', 'rs62624461', (122, 132))	('SDH', 'Gene', (203, 206))	('p.Phe53Leu', 'Var', (122, 132))	('SDHB', 'Gene', '6390', (20, 24))	('SDHAF3', 'Gene', '57001', (111, 117))	('SDHAF3', 'Gene', (203, 209))	('SDH', 'Gene', (111, 114))	('SDHB', 'Gene', (20, 24))	('SDH', 'Gene', '6390', (20, 23))
50183	28738844	This interaction was impaired with the introduction of the SDHAF3 p.Phe53Leu variant (Fig.	('SDHAF3', 'Gene', (59, 65))	('impaired', 'NegReg', (21, 29))	('SDHAF3', 'Gene', '57001', (59, 65))	('p.Phe53Leu', 'Mutation', 'rs62624461', (66, 76))	('interaction', 'Interaction', (5, 16))	('p.Phe53Leu', 'Var', (66, 76))
50184	28738844	Further assessment of the interaction between SDHB and SDHAF3 was carried out using clinically relevant SDHB mutants.	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('SDHAF3', 'Gene', (55, 61))	('interaction', 'Interaction', (26, 37))	('SDHAF3', 'Gene', '57001', (55, 61))	('SDHB', 'Gene', '6390', (104, 108))	('mutants', 'Var', (109, 116))	('SDHB', 'Gene', (104, 108))
50185	28738844	Introduction of SDHB mutants with WT SDHAF3 impaired normal SDHB-SDHAF3 interaction to varying degrees (Fig.	('mutants', 'Var', (21, 28))	('SDHAF3', 'Gene', (65, 71))	('interaction', 'Interaction', (72, 83))	('impaired', 'NegReg', (44, 52))	('SDHB', 'Gene', '6390', (60, 64))	('SDHB', 'Gene', '6390', (16, 20))	('SDHB', 'Gene', (60, 64))	('SDHB', 'Gene', (16, 20))	('SDHAF3', 'Gene', (37, 43))	('SDHAF3', 'Gene', '57001', (65, 71))	('SDHAF3', 'Gene', '57001', (37, 43))
50186	28738844	Interestingly, complete abrogation of the SDHB-SDHAF3 interaction was seen with the SDHB p.Arg242His mutant; reduced interaction was observed for all other mutants, with the exception of the SDHB p.Ile127Ser mutant that appeared to be unaffected.	('abrogation', 'NegReg', (24, 34))	('SDHAF3', 'Gene', '57001', (47, 53))	('SDHB', 'Gene', (191, 195))	('interaction', 'Interaction', (117, 128))	('p.Ile127Ser', 'Var', (196, 207))	('SDHB', 'Gene', '6390', (84, 88))	('SDHB', 'Gene', '6390', (191, 195))	('p.Ile127Ser', 'Mutation', 'rs786201095', (196, 207))	('p.Arg242His', 'Mutation', 'rs74315368', (89, 100))	('p.Arg242His', 'Var', (89, 100))	('SDHB', 'Gene', (84, 88))	('SDHAF3', 'Gene', (47, 53))	('interaction', 'Interaction', (54, 65))	('SDHB', 'Gene', '6390', (42, 46))	('SDHB', 'Gene', (42, 46))
50188	28738844	2b), the complete loss of interaction observed on introduction of the SDHB p.Arg242His mutant is highly suggestive of p.Arg242 being a putative interaction site for SDHAF3.	('interaction', 'Interaction', (144, 155))	('Arg242', 'Chemical', '-', (120, 126))	('loss', 'NegReg', (18, 22))	('SDHB', 'Gene', '6390', (70, 74))	('SDHB', 'Gene', (70, 74))	('p.Arg242', 'Var', (118, 126))	('p.Arg242His', 'Mutation', 'rs74315368', (75, 86))	('p.Arg242His', 'Var', (75, 86))	('SDHAF3', 'Gene', '57001', (165, 171))	('interaction', 'Interaction', (26, 37))	('SDHAF3', 'Gene', (165, 171))	('Arg242', 'Chemical', '-', (77, 83))
50189	28738844	The interaction observed between WT SDHB and SDHAF3 p.Phe53Leu was also impaired, to varying degrees, with the introduction of SDHB mutants (Fig.	('SDHAF3', 'Gene', (45, 51))	('introduction', 'Reg', (111, 123))	('impaired', 'NegReg', (72, 80))	('interaction', 'Interaction', (4, 15))	('SDHB', 'Gene', '6390', (36, 40))	('SDHB', 'Gene', (36, 40))	('SDHB', 'Gene', '6390', (127, 131))	('mutants', 'Var', (132, 139))	('SDHAF3', 'Gene', '57001', (45, 51))	('SDHB', 'Gene', (127, 131))	('p.Phe53Leu', 'Mutation', 'rs62624461', (52, 62))
50190	28738844	Complete loss of interaction was not only observed with the SDHB p.Arg242His mutant but also with mutants affecting residue 46 (p.Arg46Gly and p.Arg46Gln).	('p.Arg46Gly', 'Mutation', 'rs74315370', (128, 138))	('p.Arg46Gln', 'Var', (143, 153))	('interaction', 'Interaction', (17, 28))	('SDHB', 'Gene', '6390', (60, 64))	('p.Arg46Gln', 'Mutation', 'rs772551056', (143, 153))	('p.Arg46Gly', 'Var', (128, 138))	('loss', 'NegReg', (9, 13))	('SDHB', 'Gene', (60, 64))	('p.Arg242His', 'Mutation', 'rs74315368', (65, 76))	('p.Arg242His', 'Var', (65, 76))
50191	28738844	Interestingly, enhanced binding was observed with SDHB p.Ile127Ser and p.Cys101Tyr mutants; whereas no effect on interaction was evident with SDHB p.Ala43Pro and p.Pro197Arg mutants.	('p.Ala43Pro', 'Mutation', 'rs745559875', (147, 157))	('SDHB', 'Gene', (142, 146))	('p.Pro197Arg', 'Var', (162, 173))	('p.Cys101Tyr', 'Mutation', 'rs74315371', (71, 82))	('SDHB', 'Gene', (50, 54))	('binding', 'Interaction', (24, 31))	('p.Pro197Arg', 'Mutation', 'rs74315367', (162, 173))	('p.Ile127Ser', 'Var', (55, 66))	('p.Cys101Tyr', 'Var', (71, 82))	('p.Ile127Ser', 'Mutation', 'rs786201095', (55, 66))	('SDHB', 'Gene', '6390', (142, 146))	('enhanced', 'PosReg', (15, 23))	('SDHB', 'Gene', '6390', (50, 54))
50194	28738844	Complete abrogation of SDHB-SDHAF3 interaction, following introduction of SDHB p.Arg46Gly and p.Arg46Gln mutants with SDHAF3 p.Phe53Leu (Fig.	('p.Arg46Gly', 'Var', (79, 89))	('SDHB', 'Gene', '6390', (23, 27))	('SDHB', 'Gene', '6390', (74, 78))	('p.Arg46Gln', 'Var', (94, 104))	('SDHAF3', 'Gene', (118, 124))	('interaction', 'Interaction', (35, 46))	('SDHB', 'Gene', (74, 78))	('abrogation', 'NegReg', (9, 19))	('SDHAF3', 'Gene', '57001', (28, 34))	('SDHB', 'Gene', (23, 27))	('p.Arg46Gly', 'Mutation', 'rs74315370', (79, 89))	('SDHAF3', 'Gene', '57001', (118, 124))	('p.Phe53Leu', 'Mutation', 'rs62624461', (125, 135))	('p.Arg46Gln', 'Mutation', 'rs772551056', (94, 104))	('SDHAF3', 'Gene', (28, 34))
50196	28738844	Additional studies in yeast revealed that Sdh2 p.Arg235His, which corresponds to the SDHB p.Arg242His mutation, resulted in impairment of SDH function.	('impairment of SDH function', 'Disease', 'MESH:D003072', (124, 150))	('impairment of SDH function', 'Disease', (124, 150))	('yeast', 'Species', '4932', (22, 27))	('p.Arg235His', 'Var', (47, 58))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('p.Arg242His', 'Mutation', 'rs74315368', (90, 101))	('p.Arg242His', 'Var', (90, 101))	('Sdh2', 'Gene', (42, 46))	('p.Arg235His', 'Mutation', 'p.R235H', (47, 58))
50197	28738844	Compared to WT Sdh2, sdh2  cells expressing Sdh2 p.Arg235His exhibited reduced SQR activity (Fig.	('Q', 'Chemical', '-', (80, 81))	('Sdh2', 'Gene', (44, 48))	('p.Arg235His', 'Mutation', 'p.R235H', (49, 60))	('sdh2', 'Gene', '6390', (21, 25))	('sdh2', 'Gene', (21, 25))	('reduced', 'NegReg', (71, 78))	('SQR activity', 'CPA', (79, 91))	('p.Arg235His', 'Var', (49, 60))
50198	28738844	Interestingly, the substitution of p.Arg235 with His did not affect SDH activity (Fig.	('p.Arg235', 'Var', (35, 43))	('p.Arg235 with His', 'Mutation', 'p.R235H', (35, 52))	('SDH', 'Gene', '6390', (68, 71))	('SDH', 'Gene', (68, 71))
50200	28738844	The 3Fe-4S cluster in SDHB is in close juxtaposition to p.Arg242 (Fig.	('p.Arg242', 'Var', (56, 64))	('SDHB', 'Gene', '6390', (22, 26))	('Arg242', 'Chemical', '-', (58, 64))	('SDHB', 'Gene', (22, 26))
50203	28738844	Given that p.Arg242 in SDHB (p.Arg235 in Sdh2) is critical for the interaction between SDHB and SDHAF3 (Fig.	('p.Arg242', 'Var', (11, 19))	('SDHAF3', 'Gene', (96, 102))	('SDHB', 'Gene', '6390', (23, 27))	('Sdh2', 'Gene', (41, 45))	('SDHB', 'Gene', (23, 27))	('p.Arg242 in SDHB', 'Mutation', 'rs74315368', (11, 27))	('SDHAF3', 'Gene', '57001', (96, 102))	('interaction', 'Interaction', (67, 78))	('Arg235', 'Chemical', '-', (31, 37))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))
50204	28738844	2b, lane 9), it is possible that the 3Fe-4S cluster may become more susceptible to ROS-related damage in SDHB p.Arg242His mutants.	('SDHB', 'Gene', '6390', (105, 109))	('SDHB', 'Gene', (105, 109))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('p.Arg242His', 'Mutation', 'rs74315368', (110, 121))	('p.Arg242His', 'Var', (110, 121))
50205	28738844	However, we cannot completely rule out the possibility that the Q binding site is altered in cells harboring SDHB p.Arg242His.	('p.Arg242His', 'Mutation', 'rs74315368', (114, 125))	('SDHB', 'Gene', '6390', (109, 113))	('SDHB', 'Gene', (109, 113))	('Q', 'Chemical', '-', (64, 65))	('p.Arg242His', 'Var', (114, 125))
50206	28738844	In this study, we have identified a variant in the SDH assembly factor 3 (SDHAF3, c.157 T > C [p.Phe53Leu]) that may be associated with increased prevalence of pheochromocytoma and/or paraganglioma (PC/PGL).	('associated', 'Reg', (120, 130))	('c.157 T > C [', 'Var', (82, 95))	('paraganglioma', 'Disease', 'MESH:D010235', (184, 197))	('pheochromocytoma', 'Disease', (160, 176))	('SDH assembly factor 3', 'Gene', '57001', (51, 72))	('SDHAF3', 'Gene', '57001', (74, 80))	('p.Phe53Leu', 'Mutation', 'rs62624461', (95, 105))	('pheochromocytoma', 'Disease', 'MESH:D010673', (160, 176))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (160, 176))	('c.157 T > C', 'Mutation', 'rs62624461', (82, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (184, 197))	('SDHAF3', 'Gene', (74, 80))	('paraganglioma', 'Disease', (184, 197))	('SDH assembly factor 3', 'Gene', (51, 72))
50208	28738844	Furthermore, our in vitro studies in human cells show that SDHAF3 interacts with SDHB (residues 46 and 242), and that interaction between SDHAF3 p.Phe53Leu and SDHB is impaired.	('p.Phe53Leu', 'Var', (145, 155))	('SDHAF3', 'Gene', (59, 65))	('SDHB', 'Gene', '6390', (160, 164))	('SDHAF3', 'Gene', (138, 144))	('SDHB', 'Gene', (160, 164))	('residues 46', 'Var', (87, 98))	('SDHB', 'Gene', '6390', (81, 85))	('interaction', 'Interaction', (118, 129))	('SDHAF3', 'Gene', '57001', (59, 65))	('SDHB', 'Gene', (81, 85))	('SDHAF3', 'Gene', '57001', (138, 144))	('p.Phe53Leu', 'Mutation', 'rs62624461', (145, 155))	('impaired', 'NegReg', (168, 176))	('human', 'Species', '9606', (37, 42))	('interacts', 'Interaction', (66, 75))
50210	28738844	Germline mutations within any of its four subunits (SDHA, B, C and D) have been associated with development of a number of tumors, including pheochromocytoma and/or paraganglioma, gastrointestinal stromal tumors, renal cancer, and pituitary adenomas.	('Germline mutations', 'Var', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('pheochromocytoma', 'Disease', 'MESH:D010673', (141, 157))	('renal cancer', 'Disease', (213, 225))	('renal cancer', 'Phenotype', 'HP:0009726', (213, 225))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('pheochromocytoma', 'Disease', (141, 157))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('paraganglioma', 'Phenotype', 'HP:0002668', (165, 178))	('renal cancer', 'Disease', 'MESH:D007680', (213, 225))	('associated with', 'Reg', (80, 95))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (180, 211))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (180, 211))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumors', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastrointestinal stromal tumors', 'Disease', (180, 211))	('paraganglioma', 'Disease', (165, 178))	('SDHA, B, C and D', 'Gene', '6389', (52, 68))	('pituitary adenomas', 'Disease', 'MESH:D010911', (231, 249))	('paraganglioma', 'Disease', 'MESH:D010235', (165, 178))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (231, 249))	('pituitary adenomas', 'Disease', (231, 249))
50212	28738844	To date, loss-of-function mutations in SDHAF1 (biallelic) and SDHAF2 have been associated with infantile leukoencephalopathy and head and neck paragangliomas, respectively.	('SDHAF1', 'Gene', '644096', (39, 45))	('SDHAF2', 'Gene', (62, 68))	('neck paragangliomas', 'Disease', 'MESH:D010235', (138, 157))	('SDHAF1', 'Gene', (39, 45))	('SDHAF2', 'Gene', '54949', (62, 68))	('paragangliomas', 'Phenotype', 'HP:0002668', (143, 157))	('paraganglioma', 'Phenotype', 'HP:0002668', (143, 156))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (129, 157))	('leukoencephalopathy', 'Disease', (105, 124))	('infantile leukoencephalopathy', 'Phenotype', 'HP:0007105', (95, 124))	('mutations', 'Var', (26, 35))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (105, 124))	('neck paragangliomas', 'Disease', (138, 157))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (138, 157))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (105, 124))	('loss-of-function', 'NegReg', (9, 25))
50215	28738844	Taken together, we hypothesized that mutations within the newly identified SDH assembly factor, SDHAF3, may be associated with the pathogenesis of pheochromocytoma and/or paraganglioma syndromes.	('paraganglioma', 'Phenotype', 'HP:0002668', (171, 184))	('SDH', 'Gene', '6390', (96, 99))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (171, 194))	('SDHAF3', 'Gene', (96, 102))	('paraganglioma syndromes', 'Disease', (171, 194))	('SDH', 'Gene', (96, 99))	('associated', 'Reg', (111, 121))	('mutations', 'Var', (37, 46))	('SDH', 'Gene', '6390', (75, 78))	('SDHAF3', 'Gene', '57001', (96, 102))	('pheochromocytoma', 'Disease', (147, 163))	('pheochromocytoma', 'Disease', 'MESH:D010673', (147, 163))	('SDH', 'Gene', (75, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (147, 163))
50216	28738844	In this study, we identified a SDHAF3 c.157 T > C (p.Phe53Leu) variant in familial and sporadic cases of PC/PGL, observing a minor allele frequency (MAF) of 0.0658.	('SDHAF3', 'Gene', (31, 37))	('SDHAF3', 'Gene', '57001', (31, 37))	('c.157 T > C', 'Mutation', 'rs62624461', (38, 49))	('p.Phe53Leu', 'Mutation', 'rs62624461', (51, 61))	('c.157 T > C', 'Var', (38, 49))	('PC/PGL', 'Disease', (105, 111))
50218	28738844	This prompted us to perform additional studies, to clarify the role that the SDHAF3 p.Phe53Leu variant may play in the pathogenesis of PC/PGL.	('p.Phe53Leu', 'Mutation', 'rs62624461', (84, 94))	('SDHAF3', 'Gene', '57001', (77, 83))	('p.Phe53Leu', 'Var', (84, 94))	('SDHAF3', 'Gene', (77, 83))	('PC/PGL', 'Disease', (135, 141))
50219	28738844	Through yeast studies we were able to show that introduction of the SDHAF3 p.Phe53Leu variant, into Sdh7 null yeast (ortholog of SDHAF3 in humans) resulted in impaired function, observed by its failure to fully restore SDH activity when expressed in Sdh7 null yeast relative to wild-type (WT) SDHAF3.	('SDH', 'Gene', (68, 71))	('SDHAF3', 'Gene', '57001', (129, 135))	('Sdh7', 'Gene', (100, 104))	('p.Phe53Leu variant', 'Var', (75, 93))	('SDH', 'Gene', (219, 222))	('SDHAF3', 'Gene', (129, 135))	('yeast', 'Species', '4932', (8, 13))	('SDH', 'Gene', (129, 132))	('activity', 'MPA', (223, 231))	('SDH', 'Gene', '6390', (293, 296))	('function', 'MPA', (168, 176))	('SDHAF3', 'Gene', '57001', (293, 299))	('yeast', 'Species', '4932', (110, 115))	('humans', 'Species', '9606', (139, 145))	('impaired', 'NegReg', (159, 167))	('SDHAF3', 'Gene', (293, 299))	('yeast', 'Species', '4932', (260, 265))	('SDH', 'Gene', (293, 296))	('SDH', 'Gene', '6390', (68, 71))	('SDH', 'Gene', '6390', (219, 222))	('p.Phe53Leu', 'Mutation', 'rs62624461', (75, 85))	('SDHAF3', 'Gene', '57001', (68, 74))	('SDH', 'Gene', '6390', (129, 132))	('SDHAF3', 'Gene', (68, 74))
50220	28738844	Taken together, these findings indicate that although SDHAF3 p.Phe53Leu is at best a very low penetrance allele for PC/PGL per se, it may play a modifying role as observed by its hypomorphic activity.	('SDHAF3', 'Gene', '57001', (54, 60))	('p.Phe53Leu', 'Mutation', 'rs62624461', (61, 71))	('modifying', 'Reg', (145, 154))	('p.Phe53Leu', 'Var', (61, 71))	('SDHAF3', 'Gene', (54, 60))
50222	28738844	In this study, two PC/PGL tumors from patients harboring germline SDHB (IVS3 splice-site) mutation and SDHAF3 (c.157 T > C) variant showed loss of SDHB staining by immunohistochemistry.	('staining', 'MPA', (152, 160))	('SDHB', 'Gene', (66, 70))	('SDHAF3', 'Gene', (103, 109))	('PGL tumors', 'Disease', 'MESH:D010235', (22, 32))	('c.157 T > C', 'Mutation', 'rs62624461', (111, 122))	('SDHB', 'Gene', '6390', (66, 70))	('loss', 'NegReg', (139, 143))	('SDHAF3', 'Gene', '57001', (103, 109))	('PGL tumors', 'Disease', (22, 32))	('c.157 T > C', 'Var', (111, 122))	('SDHB', 'Gene', '6390', (147, 151))	('SDHB', 'Gene', (147, 151))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutation', 'Var', (90, 98))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
50223	28738844	This raises the question of how SDHAF3 c.157 T > C can play a role in PC/PGL tumorigenesis, in SDH-deficient tumors.	('SDH-deficient tumors', 'Disease', (95, 115))	('SDHAF3', 'Gene', '57001', (32, 38))	('c.157 T > C', 'Mutation', 'rs62624461', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('SDH-deficient tumors', 'Disease', 'MESH:D009369', (95, 115))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('SDHAF3', 'Gene', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PC/PGL', 'Disease', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('play', 'Reg', (55, 59))	('tumor', 'Disease', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (109, 114))	('c.157 T > C', 'Var', (39, 50))
50224	28738844	Clearly, by the time that inactivation of both SDHB alleles has occurred in the tumor, SDHAF3 c.157 T > C presumably has no additional role, as SDHAF3 appears to interact specifically with SDHB.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SDHAF3', 'Gene', '57001', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('interact', 'Interaction', (162, 170))	('SDHAF3', 'Gene', (87, 93))	('c.157 T > C', 'Var', (94, 105))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('tumor', 'Disease', (80, 85))	('SDHAF3', 'Gene', '57001', (87, 93))	('SDHB', 'Gene', '6390', (189, 193))	('SDHAF3', 'Gene', (144, 150))	('SDHB', 'Gene', (189, 193))	('c.157 T > C', 'Mutation', 'rs62624461', (94, 105))
50225	28738844	Nevertheless, we conjecture that the germline presence of this hypomorphic SDHAF3 c.157 T > C allele may over time lead to instability of SDH.	('SDHAF3', 'Gene', '57001', (75, 81))	('c.157 T > C', 'Var', (82, 93))	('SDH', 'Gene', '6390', (138, 141))	('c.157 T > C', 'Mutation', 'rs62624461', (82, 93))	('SDH', 'Gene', '6390', (75, 78))	('SDH', 'Gene', (138, 141))	('SDHAF3', 'Gene', (75, 81))	('instability', 'MPA', (123, 134))	('SDH', 'Gene', (75, 78))	('lead to', 'Reg', (115, 122))
50226	28738844	Further, as SDHB is a known tumor suppressor and hence requires inactivation of both alleles for tumorigenesis, the timeframe between SDHB germline (first hit) and somatic loss of the normal SDHB allele (second hit) provides a means by which the SDHAF3 c.157 T > C allele could act.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (28, 33))	('SDHAF3', 'Gene', '57001', (246, 252))	('SDHB', 'Gene', (191, 195))	('loss', 'Var', (172, 176))	('SDHB', 'Gene', '6390', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SDHB', 'Gene', (12, 16))	('c.157 T > C', 'Mutation', 'rs62624461', (253, 264))	('tumor', 'Disease', (97, 102))	('SDHAF3', 'Gene', (246, 252))	('SDHB', 'Gene', '6390', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SDHB', 'Gene', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SDHB', 'Gene', '6390', (191, 195))	('c.157 T > C', 'Var', (253, 264))
50227	28738844	To further understand the role of SDHAF3, and the impact of p.Phe53Leu in greater detail, we assessed its ability to interact with SDHB.	('SDHB', 'Gene', '6390', (131, 135))	('interact', 'Interaction', (117, 125))	('SDHAF3', 'Gene', '57001', (34, 40))	('SDHB', 'Gene', (131, 135))	('p.Phe53Leu', 'Mutation', 'rs62624461', (60, 70))	('p.Phe53Leu', 'Var', (60, 70))	('SDHAF3', 'Gene', (34, 40))
50230	28738844	We wanted to assess SDHAF3-SDHB interaction further by introducing clinically relevant SDHB mutations.	('SDHAF3', 'Gene', '57001', (20, 26))	('SDHB', 'Gene', '6390', (87, 91))	('mutations', 'Var', (92, 101))	('SDHB', 'Gene', '6390', (27, 31))	('SDHAF3', 'Gene', (20, 26))	('SDHB', 'Gene', (27, 31))	('SDHB', 'Gene', (87, 91))
50231	28738844	Interaction between wild-type SDHAF3 and SDHB p.Arg242His mutant was not observed, implicating this region of SDHB as a direct binding site for SDHAF3.	('SDHB', 'Gene', (110, 114))	('binding', 'Interaction', (127, 134))	('p.Arg242His', 'Var', (46, 57))	('SDHAF3', 'Gene', '57001', (144, 150))	('SDHAF3', 'Gene', '57001', (30, 36))	('p.Arg242His', 'Mutation', 'rs74315368', (46, 57))	('SDHB', 'Gene', '6390', (41, 45))	('SDHAF3', 'Gene', (30, 36))	('SDHB', 'Gene', '6390', (110, 114))	('SDHAF3', 'Gene', (144, 150))	('SDHB', 'Gene', (41, 45))
50232	28738844	(2015) recently demonstrated that SDHAF1 interacts with SDHB with contacts between SDHB residues 146-153, 183-185 and 198-202.	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (83, 87))	('SDHB', 'Gene', (56, 60))	('residues 146-153', 'Var', (88, 104))	('SDHAF1', 'Gene', '644096', (34, 40))	('contacts', 'Interaction', (66, 74))	('SDHAF1', 'Gene', (34, 40))	('SDHB', 'Gene', '6390', (83, 87))	('interacts', 'Interaction', (41, 50))
50235	28738844	Our study shows that SDHAF3, in fact, is a direct binding partner for the LYR motif of SDHB (p.240-242).	('SDHAF3', 'Gene', '57001', (21, 27))	('p.240-242', 'Var', (93, 102))	('binding', 'Interaction', (50, 57))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))	('SDHAF3', 'Gene', (21, 27))
50237	28738844	On introduction of the SDHAF3 p.Phe53Leu variant, SDHAF3-SDHB interaction was completely lost for SDHB p.Arg46Gln and p.Arg46Gly mutants, implicating residue 46 (contained within an IYR binding site [p.44-46]) as another region of SDHB that may interact with SDHAF3.	('SDHAF3', 'Gene', '57001', (50, 56))	('interaction', 'Interaction', (62, 73))	('lost', 'NegReg', (89, 93))	('SDHB', 'Gene', (231, 235))	('SDHAF3', 'Gene', (50, 56))	('SDHB', 'Gene', (57, 61))	('p.Phe53Leu', 'Var', (30, 40))	('p.Arg46Gln', 'Mutation', 'rs772551056', (103, 113))	('SDHAF3', 'Gene', '57001', (259, 265))	('SDHAF3', 'Gene', '57001', (23, 29))	('p.Phe53Leu', 'Mutation', 'rs62624461', (30, 40))	('SDHAF3', 'Gene', (259, 265))	('p.Arg46Gly', 'Mutation', 'rs74315370', (118, 128))	('SDHB', 'Gene', '6390', (98, 102))	('p.Arg46Gly', 'Var', (118, 128))	('SDHAF3', 'Gene', (23, 29))	('p.Arg46Gln', 'Var', (103, 113))	('SDHB', 'Gene', '6390', (231, 235))	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (98, 102))
50239	28738844	Alternatively, the impaired binding may arise from secondary consequences of the p.Arg46 mutation.	('p.Arg46', 'Var', (81, 88))	('impaired', 'NegReg', (19, 27))	('binding', 'Interaction', (28, 35))	('Arg46', 'Chemical', '-', (83, 88))
50240	28738844	Interestingly, our previous structural modeling of these SDHB mutations had not identified the functional impact on SDHB, as both glycine and glutamine are capable of fitting within the space left by arginine, and the electron path is not nearby.	('glutamine', 'Chemical', 'MESH:D005973', (142, 151))	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', '6390', (116, 120))	('SDHB', 'Gene', (57, 61))	('SDHB', 'Gene', (116, 120))	('glycine', 'Chemical', 'MESH:D005998', (130, 137))	('arginine', 'Chemical', 'MESH:D001120', (200, 208))	('mutations', 'Var', (62, 71))
50241	28738844	The findings of our current study suggest that mutations affecting residue 46 of SDHB are pathogenic via preventing maturation of SDHB.	('SDHB', 'Gene', '6390', (130, 134))	('SDHB', 'Gene', '6390', (81, 85))	('maturation', 'MPA', (116, 126))	('preventing', 'NegReg', (105, 115))	('SDHB', 'Gene', (130, 134))	('SDHB', 'Gene', (81, 85))	('mutations affecting residue 46', 'Var', (47, 77))
50242	28738844	(2014), whereby the SDHB p.Arg46Gln mutation did not impair SDHB interaction with HSC20, although reduced binding to the HSC20 complex and SDHA were noted, suggestive of an effect on formation of a mature SDH complex.	('SDH', 'Gene', (60, 63))	('SDHA', 'Gene', '6389', (139, 143))	('SDH', 'Gene', (20, 23))	('HSC20', 'Gene', (82, 87))	('reduced', 'NegReg', (98, 105))	('SDH', 'Gene', (139, 142))	('HSC20', 'Gene', (121, 126))	('SDHB', 'Gene', '6390', (60, 64))	('p.Arg46Gln', 'Mutation', 'rs772551056', (25, 35))	('SDH', 'Gene', '6390', (205, 208))	('SDHB', 'Gene', '6390', (20, 24))	('binding', 'Interaction', (106, 113))	('SDHB', 'Gene', (60, 64))	('SDH', 'Gene', '6390', (60, 63))	('SDH', 'Gene', (205, 208))	('SDHB', 'Gene', (20, 24))	('SDH', 'Gene', '6390', (20, 23))	('p.Arg46Gln', 'Var', (25, 35))	('interaction', 'Interaction', (65, 76))	('HSC20', 'Gene', '150274', (82, 87))	('SDH', 'Gene', '6390', (139, 142))	('SDHA', 'Gene', (139, 143))	('HSC20', 'Gene', '150274', (121, 126))
50243	28738844	Interestingly, introduction of the SDHAF3 p.Phe53Leu variant resulted in a stronger SDHAF3-SDHB interaction in the presence of the SDHB p.Cys101Tyr mutant.	('SDHB', 'Gene', '6390', (131, 135))	('SDHAF3', 'Gene', (35, 41))	('stronger', 'PosReg', (75, 83))	('SDHAF3', 'Gene', (84, 90))	('SDHB', 'Gene', (131, 135))	('interaction', 'Interaction', (96, 107))	('p.Phe53Leu', 'Mutation', 'rs62624461', (42, 52))	('p.Cys101Tyr', 'Mutation', 'rs74315371', (136, 147))	('SDHB', 'Gene', '6390', (91, 95))	('SDHAF3', 'Gene', '57001', (35, 41))	('SDHB', 'Gene', (91, 95))	('p.Phe53Leu', 'Var', (42, 52))	('p.Cys101Tyr', 'Var', (136, 147))	('SDHAF3', 'Gene', '57001', (84, 90))
50244	28738844	Since Cys101 is a ligand to the 2Fe-2S center in the N-terminal domain of SDHB, the enhanced interaction is suggestive that SDHAF3 interacts with apo-SDHB.	('SDHAF3', 'Gene', (124, 130))	('SDHB', 'Gene', '6390', (74, 78))	('SDHB', 'Gene', (74, 78))	('interaction', 'Interaction', (93, 104))	('SDHB', 'Gene', '6390', (150, 154))	('Cys101', 'Var', (6, 12))	('SDHB', 'Gene', (150, 154))	('SDHAF3', 'Gene', '57001', (124, 130))	('enhanced', 'PosReg', (84, 92))	('Cys101', 'Chemical', '-', (6, 12))	('interacts', 'Interaction', (131, 140))
50248	28738844	We have shown that SDHAF3 interacts directly with SDHB (residue 242 being key to this interaction), and that a variant in SDHAF3 (c.157 T > C [p.Phe53Leu]) appears to be more prevalent in individuals with pheochromocytomas and/or paragangliomas, and is hypomorphic via impaired interaction with SDHB.	('SDHAF3', 'Gene', '57001', (19, 25))	('paragangliomas', 'Disease', 'MESH:D010235', (230, 244))	('paragangliomas', 'Phenotype', 'HP:0002668', (230, 244))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (205, 221))	('paraganglioma', 'Phenotype', 'HP:0002668', (230, 243))	('pheochromocytomas', 'Disease', (205, 222))	('SDHAF3', 'Gene', (19, 25))	('pheochromocytomas', 'Disease', 'MESH:D010673', (205, 222))	('SDHB', 'Gene', (295, 299))	('prevalent', 'Reg', (175, 184))	('c.157 T > C', 'Mutation', 'rs62624461', (130, 141))	('hypomorphic via impaired', 'Disease', 'MESH:D009422', (253, 277))	('interacts', 'Interaction', (26, 35))	('p.Phe53Leu', 'Mutation', 'rs62624461', (143, 153))	('c.157 T > C', 'Var', (130, 141))	('SDHB', 'Gene', '6390', (50, 54))	('paragangliomas', 'Disease', (230, 244))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (205, 222))	('SDHAF3', 'Gene', '57001', (122, 128))	('SDHB', 'Gene', (50, 54))	('SDHB', 'Gene', '6390', (295, 299))	('SDHAF3', 'Gene', (122, 128))	('hypomorphic via impaired', 'Disease', (253, 277))
50249	28738844	Further studies of larger numbers of PC/PGL will, however, be required to fully clarify the role of SDHAF3 (c.157 T > C [p.Phe53Leu]) in the pathogenesis of PC/PGL.	('SDHAF3', 'Gene', (100, 106))	('PC/PGL', 'Disease', (157, 163))	('c.157 T > C', 'Var', (108, 119))	('SDHAF3', 'Gene', '57001', (100, 106))	('p.Phe53Leu', 'Mutation', 'rs62624461', (121, 131))	('c.157 T > C', 'Mutation', 'rs62624461', (108, 119))
50281	28325651	In the bladder, paraganglioma was most commonly treated with partial cystectomy (40%), followed by transurethral resection of the bladder (20%), complete cystectomy with reconstruction (13.3%), radical cystectomy plus ileal conduit (6.7%), radical cystectomy plus continent diversion (6.7%), and radical cystectomy plus orthotopic diversion (6.7%).	('paraganglioma', 'Disease', (16, 29))	('partial', 'Var', (61, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (16, 29))	('paraganglioma', 'Disease', 'MESH:D010235', (16, 29))
50298	28325651	The patients in this study were followed closely due to inherited conditions associated with mutations of genes including von Hippel-Lindau and succinate dehydrogenase.	('mutations', 'Var', (93, 102))	('succinate dehydrogenase', 'Gene', (144, 167))	('von Hippel-Lindau', 'Disease', 'MESH:D006623', (122, 139))	('patients', 'Species', '9606', (4, 12))	('von Hippel-Lindau', 'Disease', (122, 139))
50494	24466223	Integrative Genetic Characterization and Phenotype Correlations in Pheochromocytoma and Paraganglioma Tumours About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS.	('SDHB', 'Gene', '6390', (276, 280))	('VHL', 'Gene', (302, 305))	('Paraganglioma', 'Disease', 'MESH:D010235', (88, 101))	('SDHD', 'Gene', (288, 292))	('Pheochromocytoma', 'Disease', (67, 83))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (67, 83))	('SDHA', 'Gene', (270, 274))	('Pheochromocytoma and Paraganglioma Tumours', 'Disease', 'MESH:D010673', (67, 109))	('Tumours', 'Phenotype', 'HP:0002664', (102, 109))	('Pheochromocytoma', 'Disease', (123, 139))	('germline', 'Var', (191, 199))	('EPAS1', 'Gene', (307, 312))	('SDHA', 'Gene', (294, 298))	('TMEM127', 'Gene', (324, 331))	('RET', 'Gene', (314, 317))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (123, 139))	('SDHA', 'Gene', '6389', (270, 274))	('VHL', 'Gene', '7428', (302, 305))	('SDHB', 'Gene', (276, 280))	('SDHC', 'Gene', (282, 286))	('SDHA', 'Gene', '6389', (294, 298))	('Paraganglioma', 'Disease', 'MESH:D010235', (150, 163))	('PGL', 'Phenotype', 'HP:0002668', (165, 168))	('Tumour', 'Phenotype', 'HP:0002664', (102, 108))	('Paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('MAX', 'Gene', (333, 336))	('SDHAF2', 'Gene', '54949', (294, 300))	('Paraganglioma', 'Disease', (88, 101))	('SDHAF2', 'Gene', (294, 300))	('patients', 'Species', '9606', (170, 178))	('PCC', 'Phenotype', 'HP:0002666', (141, 144))	('TMEM127', 'Gene', '55654', (324, 331))	('NF1', 'Gene', '4763', (319, 322))	('EPAS1', 'Gene', '2034', (307, 312))	('Paraganglioma', 'Phenotype', 'HP:0002668', (150, 163))	('Paraganglioma', 'Disease', (150, 163))	('H-RAS', 'Gene', (341, 346))	('SDHD', 'Gene', '6392', (288, 292))	('NF1', 'Gene', (319, 322))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (67, 83))	('RET', 'Gene', '5979', (314, 317))	('SDHC', 'Gene', '6391', (282, 286))	('H-RAS', 'Gene', '3265', (341, 346))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (123, 139))
50506	24466223	Translational studies show that approximately 60% of PCC and PGL cases have either germline or somatic mutations in one of 13 suggested disease causing loci; SDH subunits A, B, C and D, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS .	('EPAS1', 'Gene', '2034', (199, 204))	('MAX', 'Gene', (225, 228))	('TMEM127', 'Gene', '55654', (216, 223))	('RET', 'Gene', '5979', (206, 209))	('mutations', 'Var', (103, 112))	('NF1', 'Gene', '4763', (211, 214))	('H-RAS', 'Gene', (233, 238))	('PGL', 'Phenotype', 'HP:0002668', (61, 64))	('NF1', 'Gene', (211, 214))	('VHL', 'Gene', (194, 197))	('EPAS1', 'Gene', (199, 204))	('RET', 'Gene', (206, 209))	('H-RAS', 'Gene', '3265', (233, 238))	('SDH subunits', 'Gene', (158, 170))	('SDHAF2', 'Gene', '54949', (186, 192))	('PCC', 'Disease', (53, 56))	('SDHAF2', 'Gene', (186, 192))	('VHL', 'Gene', '7428', (194, 197))	('PCC', 'Phenotype', 'HP:0002666', (53, 56))	('TMEM127', 'Gene', (216, 223))
50507	24466223	In the clinical setting, genetic screening of these genes by fragment prioritization of germline DNA is regarded as golden standard of care, and may have a substantial impact on patient management.	('patient', 'Species', '9606', (178, 185))	('genetic', 'Var', (25, 32))	('impact', 'Reg', (168, 174))
50512	24466223	Selected patients were previously screened for mutations in H-RAS describing somatic genetic variants (n = 4) and MAX describing no pathogenic genetic variant.	('patients', 'Species', '9606', (9, 17))	('H-RAS', 'Gene', '3265', (60, 65))	('variants', 'Var', (93, 101))	('mutations', 'Var', (47, 56))	('H-RAS', 'Gene', (60, 65))
50523	24466223	Using a phenotype guided fragment prioritization approach, exons and intron-exon boundaries of SDHB (NM_003000.2), SDHC (NM_003001.3), SDHD (NM_003002.2), SDHAF2 (NM_017841.2), VHL (NM_000551.3), EPAS1 (exons 9 and 12, NM_001430.4), RET (exons 10-11 and 13-16, NM_020975.4), TMEM127 (NM_017849.3), MAX (NM_002382.3) and H-RAS (exons 2 and 3, NM_176795.3) were amplified by PCR and sequenced using automated Sanger sequencing (Beckman Coulter Genomics, Takeley, UK).	('RET', 'Gene', (233, 236))	('SDHB', 'Gene', '6390', (95, 99))	('EPAS1', 'Gene', (196, 201))	('SDHD', 'Gene', '6392', (135, 139))	('NM_002382.3', 'Var', (303, 314))	('SDHB', 'Gene', (95, 99))	('SDHC', 'Gene', (115, 119))	('TMEM127', 'Gene', (275, 282))	('VHL', 'Gene', (177, 180))	('H-RAS', 'Gene', (320, 325))	('SDHD', 'Gene', (135, 139))	('EPAS1', 'Gene', '2034', (196, 201))	('H-RAS', 'Gene', '3265', (320, 325))	('RET', 'Gene', '5979', (233, 236))	('TMEM127', 'Gene', '55654', (275, 282))	('VHL', 'Gene', '7428', (177, 180))	('SDHAF2', 'Gene', '54949', (155, 161))	('SDHAF2', 'Gene', (155, 161))	('SDHC', 'Gene', '6391', (115, 119))
50531	24466223	Inclusion criteria were presence of pathogenic or unknown variants in SDHB, SDHC, VHL or clinical criteria of NF1.	('NF1', 'Gene', (110, 113))	('SDHB', 'Gene', '6390', (70, 74))	('SDHB', 'Gene', (70, 74))	('NF1', 'Gene', '4763', (110, 113))	('variants', 'Var', (58, 66))	('VHL', 'Gene', (82, 85))	('SDHC', 'Gene', (76, 80))	('VHL', 'Gene', '7428', (82, 85))	('SDHC', 'Gene', '6391', (76, 80))
50546	24466223	Re-sequencing revealed a pathogenic nonsense mutation in SDHB; c.268C>T, p.Arg90* that was present in DNA from blood.	('SDHB', 'Gene', '6390', (57, 61))	('p.Arg90*', 'Var', (73, 81))	('p.Arg90*', 'Mutation', 'p.R90*', (73, 81))	('SDHB', 'Gene', (57, 61))	('pathogenic', 'Reg', (25, 35))	('c.268C>T', 'Mutation', 'rs74315366', (63, 71))
50547	24466223	There were 12 cases with pathogenic mutations in the VHL gene.	('VHL', 'Gene', '7428', (53, 56))	('VHL', 'Gene', (53, 56))	('mutations', 'Var', (36, 45))
50548	24466223	Patient number 9 with bilateral PCC (index case) had a pathogenic germline missense mutation in VHL; c.482G>A p.Arg161Gln.	('c.482G>A p.Arg161Gln', 'Var', (101, 121))	('pathogenic', 'Reg', (55, 65))	('PCC', 'Phenotype', 'HP:0002666', (32, 35))	('p.Arg161Gln', 'Mutation', 'rs730882035', (110, 121))	('c.482G>A', 'Mutation', 'rs730882035', (101, 109))	('VHL', 'Gene', (96, 99))	('VHL', 'Gene', '7428', (96, 99))	('Patient', 'Species', '9606', (0, 7))
50549	24466223	A family comprising of three siblings with bilateral or unilateral PCC had pathogenic germline missense mutation in VHL; c.499C>T, p.Arg167Trp.	('c.499C>T', 'Mutation', 'rs5030820', (121, 129))	('PCC', 'Phenotype', 'HP:0002666', (67, 70))	('pathogenic', 'Reg', (75, 85))	('VHL', 'Gene', (116, 119))	('VHL', 'Gene', '7428', (116, 119))	('p.Arg167Trp', 'Mutation', 'rs5030820', (131, 142))	('p.Arg167Trp', 'Var', (131, 142))	('c.499C>T', 'Var', (121, 129))
50550	24466223	Both p.Arg161Gln and p.Arg167Trp had previously been reported as pathogenic.	('pathogenic', 'Reg', (65, 75))	('p.Arg161Gln', 'Var', (5, 16))	('p.Arg167Trp', 'Mutation', 'rs5030820', (21, 32))	('p.Arg167Trp', 'Var', (21, 32))	('p.Arg161Gln', 'Mutation', 'rs730882035', (5, 16))
50552	24466223	There were six unique SNVs; c.193T>G, p.Ser65Ala; c.193T>A, p.Ser65Thr; c.238A>G, p.Ser80Gly; c.458T>A, p.Leu153Gln; c.475A>G, p.Lys159Glu and c.551T>A, p.Leu184His in one patient each.	('p.Lys159Glu', 'Mutation', 'p.K159E', (127, 138))	('c.458T>A', 'Var', (94, 102))	('p.Leu153Gln; c.475A>G', 'Var', (104, 125))	('p.Leu153Gln', 'Mutation', 'rs193922611', (104, 115))	('c.551T>A', 'Var', (143, 151))	('c.458T>A', 'Mutation', 'rs193922611', (94, 102))	('c.551T>A', 'Mutation', 'rs1200051286', (143, 151))	('p.Ser65Ala; c.193T>A', 'Var', (38, 58))	('p.Lys159Glu', 'Var', (127, 138))	('p.Ser65Thr', 'Mutation', 'rs786202513', (60, 70))	('c.238A>G', 'Var', (72, 80))	('c.193T>A', 'Var', (50, 58))	('patient', 'Species', '9606', (172, 179))	('c.475A>G', 'Mutation', 'rs755022508', (117, 125))	('p.Ser65Ala', 'Mutation', 'rs869025616', (38, 48))	('p.Leu184His', 'Var', (153, 164))	('c.193T>G', 'Var', (28, 36))	('p.Ser80Gly', 'Mutation', 'rs786202787', (82, 92))	('c.193T>G', 'Mutation', 'rs869025616', (28, 36))	('c.193T>A', 'Mutation', 'rs760678574', (50, 58))	('c.475A>G', 'Var', (117, 125))	('p.Leu184His', 'Mutation', 'p.L184H', (153, 164))	('c.238A>G', 'Mutation', 'rs786202787', (72, 80))
50553	24466223	Patient number 4 had a 30 base pair deletion c.163_192del, p.Glu55_Arg64del that was absent in DNA from peripheral blood.	('c.163_192del', 'Var', (45, 57))	('p.Glu55_Arg64del', 'Var', (59, 75))	('c.163_192del', 'Mutation', 'c.163_192del', (45, 57))	('p.Glu55_Arg64del', 'DELETION', 'None', (59, 75))	('Patient', 'Species', '9606', (0, 7))
50554	24466223	All carriers of somatic VHL mutations had unilateral PCC, sporadic disease presentation and there were no apparent signs or symptoms of VHL syndrome.	('VHL', 'Gene', '7428', (24, 27))	('VHL syndrome', 'Disease', 'MESH:D006623', (136, 148))	('PCC', 'Phenotype', 'HP:0002666', (53, 56))	('VHL', 'Gene', (136, 139))	('VHL syndrome', 'Disease', (136, 148))	('VHL', 'Gene', (24, 27))	('VHL', 'Gene', '7428', (136, 139))	('mutations', 'Var', (28, 37))
50555	24466223	Two patients had mutations in EPAS1 which were absent in DNA from their blood; one c.1586T>C, p.Leu529Pro and one c.1589C>T, p.Ala530Val.	('EPAS1', 'Gene', '2034', (30, 35))	('EPAS1', 'Gene', (30, 35))	('c.1586T>C', 'Var', (83, 92))	('p.Leu529Pro', 'Var', (94, 105))	('p.Ala530Val', 'Mutation', 'p.A530V', (125, 136))	('p.Ala530Val', 'Var', (125, 136))	('c.1586T>C', 'Mutation', 'rs199474737', (83, 92))	('c.1589C>T', 'Var', (114, 123))	('patients', 'Species', '9606', (4, 12))	('p.Leu529Pro', 'Mutation', 'rs199474737', (94, 105))	('c.1589C>T', 'Mutation', 'rs1349207461', (114, 123))
50558	24466223	There were 13 patients with pathogenic mutations in RET.	('RET', 'Gene', (52, 55))	('RET', 'Gene', '5979', (52, 55))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (39, 48))
50559	24466223	Eight had germline pathogenic mutations and clinical characteristics of MEN2 syndrome; c.1826G>C, p.Cys609Ser; c.1832G>A, p.Cys611Tyr; c.1900T>C, p.Cys634Arg; c.1900T>G, p.Cys634Gly; c.1901G>A, p. Cys634Tyr; c.2410G>A, p.Val804Met in one patient each and c.2753T>C, p.Met918Thr in tow different patients.	('p.Cys611Tyr', 'Mutation', 'rs377767397', (122, 133))	('p.Cys634Gly', 'Mutation', 'rs75076352', (170, 181))	('c.1901G>A', 'Mutation', 'rs75996173', (183, 192))	('MEN2 syndrome', 'Disease', 'MESH:D013577', (72, 85))	('patient', 'Species', '9606', (238, 245))	('c.1832G>A', 'Mutation', 'rs377767397', (111, 120))	('c.1826G>C', 'Var', (87, 96))	('patient', 'Species', '9606', (295, 302))	('c.1900T>C', 'Var', (135, 144))	('MEN2 syndrome', 'Disease', (72, 85))	('c.2753T>C', 'Var', (255, 264))	('c.1901G>A', 'Var', (183, 192))	('p.Cys634Arg', 'Mutation', 'rs75076352', (146, 157))	('Cys634Tyr', 'SUBSTITUTION', 'None', (197, 206))	('p.Met918Thr', 'Mutation', 'rs74799832', (266, 277))	('c.1826G>C', 'Mutation', 'rs77939446', (87, 96))	('c.2410G>A', 'Var', (208, 217))	('c.1900T>G', 'Mutation', 'rs75076352', (159, 168))	('c.2410G>A', 'Mutation', 'rs79658334', (208, 217))	('p.Met918Thr', 'Var', (266, 277))	('p.Val804Met', 'Mutation', 'rs79658334', (219, 230))	('p.Cys609Ser', 'Mutation', 'rs77939446', (98, 109))	('c.2753T>C', 'Mutation', 'rs74799832', (255, 264))	('p.Val804Met', 'Var', (219, 230))	('c.1832G>A', 'Var', (111, 120))	('patients', 'Species', '9606', (295, 303))	('Cys634Tyr', 'Var', (197, 206))	('p.Cys611Tyr; c.1900T>C', 'Var', (122, 144))	('c.1900T>C', 'Mutation', 'rs75076352', (135, 144))
50560	24466223	Two patients with unilateral PCC and sporadic disease presentation had somatic mutation in RET; c.1900T>G, p.Cys634Gly and c.1900T>C, p.Cys634Arg.	('RET', 'Gene', (91, 94))	('c.1900T>G', 'Mutation', 'rs75076352', (96, 105))	('p.Cys634Gly', 'Mutation', 'rs75076352', (107, 118))	('c.1900T>G', 'Var', (96, 105))	('p.Cys634Arg', 'Mutation', 'rs75076352', (134, 145))	('PCC', 'Phenotype', 'HP:0002666', (29, 32))	('c.1900T>C', 'Mutation', 'rs75076352', (123, 132))	('PCC', 'Disease', (29, 32))	('RET', 'Gene', '5979', (91, 94))	('patients', 'Species', '9606', (4, 12))	('p.Cys634Arg', 'Var', (134, 145))	('c.1900T>C', 'Var', (123, 132))	('p.Cys634Gly', 'Var', (107, 118))
50561	24466223	For three of the patients with SNVs in RET there were no constitutional DNA available; c.1891G>T, p.Asp631Tyr in one patient and c.2753T>C, p.Met918Thr in two patients.	('p.Asp631Tyr', 'Mutation', 'rs377767406', (98, 109))	('RET', 'Gene', (39, 42))	('c.2753T>C', 'Var', (129, 138))	('p.Met918Thr', 'Mutation', 'rs74799832', (140, 151))	('c.1891G>T', 'Var', (87, 96))	('c.1891G>T', 'Mutation', 'rs377767406', (87, 96))	('c.2753T>C', 'Mutation', 'rs74799832', (129, 138))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (117, 124))	('p.Asp631Tyr', 'Var', (98, 109))	('patients', 'Species', '9606', (17, 25))	('RET', 'Gene', '5979', (39, 42))	('p.Met918Thr', 'Var', (140, 151))	('patient', 'Species', '9606', (159, 166))	('patients', 'Species', '9606', (159, 167))
50563	24466223	All these RET mutations are described as pathogenic in the literature.	('RET', 'Gene', (10, 13))	('mutations', 'Var', (14, 23))	('RET', 'Gene', '5979', (10, 13))
50564	24466223	Four patients had previously been described with somatic H-RAS mutations.	('mutations', 'Var', (63, 72))	('patients', 'Species', '9606', (5, 13))	('H-RAS', 'Gene', (57, 62))	('H-RAS', 'Gene', '3265', (57, 62))
50565	24466223	One additional somatic mutation in H-RAS; c.181C>A, p.Gln61Lys; was detected in a male patient that had sporadic disease presentation.	('c.181C>A', 'Var', (42, 50))	('H-RAS', 'Gene', (35, 40))	('patient', 'Species', '9606', (87, 94))	('c.181C>A', 'Mutation', 'rs28933406', (42, 50))	('p.Gln61Lys', 'Var', (52, 62))	('H-RAS', 'Gene', '3265', (35, 40))	('p.Gln61Lys', 'Mutation', 'rs28933406', (52, 62))
50567	24466223	There were two VUS in SDHC; c.328C>T, Pro110Ser and c.490A>T, Met164Leu in two different patients with unilateral PCC and sporadic disease presentation.	('SDHC', 'Gene', (22, 26))	('PCC', 'Phenotype', 'HP:0002666', (114, 117))	('c.490A>T', 'Mutation', 'rs200375156', (52, 60))	('SDHC', 'Gene', '6391', (22, 26))	('c.328C>T', 'Var', (28, 36))	('Met164Leu', 'Var', (62, 71))	('c.490A>T', 'Var', (52, 60))	('Pro110Ser', 'Mutation', 'rs1368606697', (38, 47))	('Pro110Ser', 'Var', (38, 47))	('Met164Leu', 'SUBSTITUTION', 'None', (62, 71))	('c.328C>T', 'Mutation', 'rs1368606697', (28, 36))	('patients', 'Species', '9606', (89, 97))	('PCC', 'Disease', (114, 117))
50568	24466223	Succinate dehydrogenase subunit C Met164Leu has been reported to have impact in functional models but was classified as benign in vivo.	('impact', 'Reg', (70, 76))	('Met164Leu', 'Var', (34, 43))	('Met164Leu', 'SUBSTITUTION', 'None', (34, 43))
50576	24466223	Sanger sequencing revealed a single nucleotide polymorphism in VHL; c.548C>T, p.Ser183Leu.	('c.548C>T', 'Mutation', 'rs5030823', (68, 76))	('VHL', 'Gene', '7428', (63, 66))	('VHL', 'Gene', (63, 66))	('c.548C>T', 'Var', (68, 76))	('p.Ser183Leu', 'Mutation', 'rs5030823', (78, 89))	('p.Ser183Leu', 'Var', (78, 89))
50577	24466223	In tumour tissue, loss of heterozogosity and copy number loss was observed on the whole arm of chromosome 3p by Omni-1-quad SNP array (Illumina, CA, USA).VHL; c.548C>T, p.Ser183Leu has been classified as pathogenic in a functional model but the individual contribution of the allele to patient phenotype is not fully described.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('p.Ser183Leu', 'Mutation', 'rs5030823', (169, 180))	('VHL', 'Gene', (154, 157))	('p.Ser183Leu', 'Var', (169, 180))	('c.548C>T', 'Mutation', 'rs5030823', (159, 167))	('tumour', 'Disease', (3, 9))	('patient', 'Species', '9606', (286, 293))	('VHL', 'Gene', '7428', (154, 157))
50578	24466223	Codon 183 is conserved among mammalian orthologs and in silico analysis determined the variant as probably pathogenic: SIFT (0,18) and Polyphen2 (1,0).	('SIFT', 'Disease', 'None', (119, 123))	('Polyphen2', 'Var', (135, 144))	('mammalian', 'Species', '9606', (29, 38))	('SIFT', 'Disease', (119, 123))	('pathogenic', 'Reg', (107, 117))
50580	24466223	Re-sequencing revealed a RET mutation c.2372A>T, p.Tyr791Phe that was found in constitutional DNA.	('RET', 'Gene', '5979', (25, 28))	('p.Tyr791Phe', 'Mutation', 'rs77724903', (49, 60))	('c.2372A>T', 'Var', (38, 47))	('RET', 'Gene', (25, 28))	('c.2372A>T', 'Mutation', 'rs77724903', (38, 47))
50581	24466223	The pathogenicity of RET p.Tyr791Phe is disputed.	('p.Tyr791Phe', 'Var', (25, 36))	('RET', 'Gene', (21, 24))	('p.Tyr791Phe', 'Mutation', 'rs77724903', (25, 36))	('RET', 'Gene', '5979', (21, 24))
50582	24466223	There were no pathogenic variants discovered in SDHAF2, TMEM127 and MAX.	('SDHAF2', 'Gene', (48, 54))	('variants', 'Var', (25, 33))	('TMEM127', 'Gene', (56, 63))	('SDHAF2', 'Gene', '54949', (48, 54))	('TMEM127', 'Gene', '55654', (56, 63))
50584	24466223	There were no LOH at coordinates corresponding to SDHC loci in tumours from patients with germline SDHC Pro110Ser and Met164Leu variants.	('tumours', 'Disease', (63, 70))	('patients', 'Species', '9606', (76, 84))	('SDHC', 'Gene', '6391', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('Met164Leu', 'Var', (118, 127))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('SDHC', 'Gene', (50, 54))	('Pro110Ser', 'Var', (104, 113))	('Met164Leu', 'SUBSTITUTION', 'None', (118, 127))	('SDHC', 'Gene', '6391', (50, 54))	('Pro110Ser', 'Mutation', 'rs1368606697', (104, 113))	('tumours', 'Disease', 'MESH:D009369', (63, 70))	('SDHC', 'Gene', (99, 103))
50585	24466223	Patient 36 with a germline VHL p.Ser183Leu had LOH at the VHL loci.	('VHL', 'Gene', (27, 30))	('p.Ser183Leu', 'Mutation', 'rs5030823', (31, 42))	('p.Ser183Leu', 'Var', (31, 42))	('VHL', 'Gene', (58, 61))	('VHL', 'Gene', '7428', (58, 61))	('Patient', 'Species', '9606', (0, 7))	('VHL', 'Gene', '7428', (27, 30))
50588	24466223	The frequency of mutifocal tumours were also different in germline carriers (53%) compared to patients with somatic carrier status (0%, P<0.001) as well as those without known mutations (2%, P<0.001).	('patients', 'Species', '9606', (94, 102))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('tumours', 'Disease', (27, 34))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('germline carriers', 'Var', (58, 75))
50590	24466223	Preoperative levels of urine norepinephrine were lower in patients with germline carrier status compared to somatic carriers and those without mutation (P = 0.049 and P = 0.033 respectively).	('norepinephrine', 'Chemical', 'MESH:D009638', (29, 43))	('urine norepinephrine', 'Phenotype', 'HP:0003345', (23, 43))	('lower', 'NegReg', (49, 54))	('patients', 'Species', '9606', (58, 66))	('germline carrier status', 'Var', (72, 95))
50592	24466223	Stratification according to genotype into cluster 1; SDHx/VHL/EPAS1 mutants and cluster 2; RET/NF1/H-RAS mutants, resulted in a difference in age at diagnosis between cluster 2 carriers (median 45) and patients without mutations (median 53, P = 0.036).	('RET', 'Gene', (91, 94))	('SDHx', 'Chemical', '-', (53, 57))	('NF1', 'Gene', (95, 98))	('H-RAS', 'Gene', '3265', (99, 104))	('NF1', 'Gene', '4763', (95, 98))	('patients', 'Species', '9606', (202, 210))	('VHL', 'Gene', (58, 61))	('EPAS1', 'Gene', (62, 67))	('difference', 'Reg', (128, 138))	('EPAS1', 'Gene', '2034', (62, 67))	('H-RAS', 'Gene', (99, 104))	('RET', 'Gene', '5979', (91, 94))	('VHL', 'Gene', '7428', (58, 61))	('mutants', 'Var', (68, 75))
50600	24466223	A total of 33 patients (37%) had pathogenic variants in SDHB, VHL, EPAS1, RET and H-RAS.	('SDHB', 'Gene', '6390', (56, 60))	('EPAS1', 'Gene', (67, 72))	('SDHB', 'Gene', (56, 60))	('RET', 'Gene', (74, 77))	('H-RAS', 'Gene', '3265', (82, 87))	('EPAS1', 'Gene', '2034', (67, 72))	('pathogenic', 'Reg', (33, 43))	('RET', 'Gene', '5979', (74, 77))	('VHL', 'Gene', (62, 65))	('H-RAS', 'Gene', (82, 87))	('patients', 'Species', '9606', (14, 22))	('VHL', 'Gene', '7428', (62, 65))	('variants', 'Var', (44, 52))
50601	24466223	Including patients with clinical criteria of Neurofibromatosis type 1 and loss of heterozygosity at the NF1 locus, 41% of the cohort could be associated with genetic aberrations in known genes.	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (45, 62))	('loss', 'Var', (74, 78))	('associated', 'Reg', (142, 152))	('patients', 'Species', '9606', (10, 18))	('genetic aberrations', 'Var', (158, 177))	('Neurofibromatosis type 1', 'Gene', (45, 69))	('NF1', 'Gene', '4763', (104, 107))	('Neurofibromatosis type 1', 'Gene', '4763', (45, 69))	('NF1', 'Gene', (104, 107))
50604	24466223	Loss of heterozygosity could be detected in tumour DNA from 11/12 patients having somatic or germline mutations in the SDHB or VHL genes.	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('SDHB', 'Gene', '6390', (119, 123))	('tumour', 'Disease', (44, 50))	('VHL', 'Gene', (127, 130))	('mutations', 'Var', (102, 111))	('SDHB', 'Gene', (119, 123))	('VHL', 'Gene', '7428', (127, 130))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('patients', 'Species', '9606', (66, 74))
50605	24466223	SNParray analysis of tumour DNA from patient 10 (VHL p.Arg161Gln) did not show LOH at any locus.	('p.Arg161Gln', 'Var', (53, 64))	('patient', 'Species', '9606', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('p.Arg161Gln', 'Mutation', 'rs730882035', (53, 64))	('VHL', 'Gene', (49, 52))	('tumour', 'Disease', (21, 27))	('VHL', 'Gene', '7428', (49, 52))
50609	24466223	This strongly suggest that these patients do have a germline mutation in NF1 .	('NF1', 'Gene', '4763', (73, 76))	('germline mutation', 'Var', (52, 69))	('patients', 'Species', '9606', (33, 41))	('NF1', 'Gene', (73, 76))
50611	24466223	For SDHC Pro110Ser and Met164Leu, clinical presentation and family history did not indicate familial paraganglioma type 3.	('familial paraganglioma type', 'Disease', 'MESH:D010235', (92, 119))	('Pro110Ser', 'Mutation', 'rs1368606697', (9, 18))	('SDHC', 'Gene', (4, 8))	('familial paraganglioma type', 'Disease', (92, 119))	('SDHC', 'Gene', '6391', (4, 8))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('Met164Leu', 'Var', (23, 32))	('Pro110Ser', 'Var', (9, 18))	('Met164Leu', 'SUBSTITUTION', 'None', (23, 32))
50612	24466223	Analysis of the biochemical phenotype revealed a high norepinephrine to epinephrine ratio, pointing to a disease causing mutation in the SDHx or VHL loci.	('epinephrine', 'Chemical', 'MESH:D004837', (57, 68))	('VHL', 'Gene', '7428', (145, 148))	('SDHx', 'Gene', (137, 141))	('disease causing', 'Reg', (105, 120))	('norepinephrine', 'Chemical', 'MESH:D009638', (54, 68))	('SDHx', 'Chemical', '-', (137, 141))	('mutation', 'Var', (121, 129))	('epinephrine', 'Chemical', 'MESH:D004837', (72, 83))	('VHL', 'Gene', (145, 148))	('high', 'PosReg', (49, 53))	('high norepinephrine', 'Phenotype', 'HP:0003345', (49, 68))	('norepinephrine to epinephrine ratio', 'MPA', (54, 89))
50613	24466223	Available literature did not support neither classification of pathogenic nor benign status of SDHC Pro110Ser and Met164Leu.	('SDHC', 'Gene', (95, 99))	('SDHC', 'Gene', '6391', (95, 99))	('Met164Leu', 'Var', (114, 123))	('Pro110Ser', 'Mutation', 'rs1368606697', (100, 109))	('Pro110Ser', 'Var', (100, 109))	('Met164Leu', 'SUBSTITUTION', 'None', (114, 123))
50614	24466223	In patient 37 with the germline VHL p.Ser183Leu variant there was no family history suggesting VHL syndrome.	('VHL', 'Gene', (32, 35))	('VHL', 'Gene', (95, 98))	('VHL', 'Gene', '7428', (32, 35))	('patient', 'Species', '9606', (3, 10))	('VHL', 'Gene', '7428', (95, 98))	('VHL syndrome', 'Disease', (95, 107))	('p.Ser183Leu', 'Mutation', 'rs5030823', (36, 47))	('VHL syndrome', 'Disease', 'MESH:D006623', (95, 107))	('p.Ser183Leu', 'Var', (36, 47))
50616	24466223	The ratio of norepinephrine to epinephrine was high indicating a mutation in SDHx or VHL genes.	('ratio', 'MPA', (4, 9))	('SDHx', 'Chemical', '-', (77, 81))	('VHL', 'Gene', (85, 88))	('SDHx', 'Gene', (77, 81))	('norepinephrine', 'Chemical', 'MESH:D009638', (13, 27))	('epinephrine', 'Chemical', 'MESH:D004837', (31, 42))	('mutation', 'Var', (65, 73))	('VHL', 'Gene', '7428', (85, 88))	('epinephrine', 'Chemical', 'MESH:D004837', (16, 27))
50618	24466223	However, several indicators point out this variant as potentially pathogenic and as most variants in the VHL gene are pathogenic, this variant should influence the clinical management of the proband.	('VHL', 'Gene', (105, 108))	('variants', 'Var', (89, 97))	('influence', 'Reg', (150, 159))	('pathogenic', 'Reg', (118, 128))	('VHL', 'Gene', '7428', (105, 108))	('variant', 'Var', (43, 50))	('pathogenic', 'Reg', (66, 76))
50619	24466223	The molecular phenotype of EPAS1 mutated tumours has been disputed.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('EPAS1', 'Gene', '2034', (27, 32))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('mutated', 'Var', (33, 40))	('EPAS1', 'Gene', (27, 32))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
50621	24466223	Catecholamine production detected in EPAS1 carriers in this study suggested cluster 1 differentiation.	('Catecholamine', 'Chemical', 'MESH:D002395', (0, 13))	('carriers', 'Var', (43, 51))	('EPAS1', 'Gene', '2034', (37, 42))	('Catecholamine production', 'MPA', (0, 24))	('EPAS1', 'Gene', (37, 42))
50623	24466223	Additionally, the catecholamine output observed in H-RAS mutated tumours resemble that of RET and NF1 .	('H-RAS', 'Gene', '3265', (51, 56))	('H-RAS', 'Gene', (51, 56))	('RET', 'Gene', '5979', (90, 93))	('catecholamine', 'Chemical', 'MESH:D002395', (18, 31))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('NF1', 'Gene', (98, 101))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('NF1', 'Gene', '4763', (98, 101))	('RET', 'Gene', (90, 93))	('catecholamine output', 'MPA', (18, 38))	('mutated', 'Var', (57, 64))	('tumours', 'Disease', (65, 72))
50625	24466223	As previously described, germline carriers were significantly younger at time of diagnosis, and had a higher frequency of multifocal disease.	('multifocal disease', 'Disease', 'None', (122, 140))	('multifocal disease', 'Disease', (122, 140))	('germline carriers', 'Var', (25, 42))
50627	24466223	Five of 13 patients with recurrent disease were carriers of germline mutations in SDHB or RET, the remaining eight patients had sporadic disease presentation.	('patients', 'Species', '9606', (115, 123))	('SDHB', 'Gene', '6390', (82, 86))	('RET', 'Gene', '5979', (90, 93))	('germline mutations', 'Var', (60, 78))	('SDHB', 'Gene', (82, 86))	('RET', 'Gene', (90, 93))	('patients', 'Species', '9606', (11, 19))
50630	24466223	There is a growing rationale for analysing somatic events in PCC and PGL tumours as a diagnostic test: (1) EPAS1 mutations may occur early in embryogenesis and these mosaic carriers are not found by analysis of DNA in peripheral blood; (2) Translational studies have suggested using genotype as predictive markers for sensitivity to targeted therapy; SDHx/VHL mutations might benefit from antiangiogenic treatment whereas RET/NF1/TMEM127/MAX driven tumours could benefit from inhibitions of kinase pathways.	('tumours', 'Phenotype', 'HP:0002664', (449, 456))	('tumours', 'Disease', 'MESH:D009369', (449, 456))	('VHL', 'Gene', (356, 359))	('EPAS1', 'Gene', (107, 112))	('TMEM127', 'Gene', '55654', (430, 437))	('NF1', 'Gene', '4763', (426, 429))	('tumour', 'Phenotype', 'HP:0002664', (449, 455))	('tumours', 'Disease', (73, 80))	('RET', 'Gene', (422, 425))	('PGL', 'Phenotype', 'HP:0002668', (69, 72))	('NF1', 'Gene', (426, 429))	('VHL', 'Gene', '7428', (356, 359))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('EPAS1', 'Gene', '2034', (107, 112))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('kinase pathways', 'Pathway', (491, 506))	('PGL tumours', 'Disease', 'MESH:D010235', (69, 80))	('SDHx', 'Chemical', '-', (351, 355))	('mutations', 'Var', (360, 369))	('PGL tumours', 'Disease', (69, 80))	('tumours', 'Disease', (449, 456))	('PCC', 'Phenotype', 'HP:0002666', (61, 64))	('RET', 'Gene', '5979', (422, 425))	('TMEM127', 'Gene', (430, 437))
50669	23424694	Genetic mutation within the succinate dehydrogenase B unit (SDHB) and succinate dehydrogenase D unit (SDHD) are associated with increased risk for extra-adrenal paragangliomas.	('Genetic mutation', 'Var', (0, 16))	('paraganglioma', 'Phenotype', 'HP:0002668', (161, 174))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (147, 175))	('extra-adrenal paragangliomas', 'Disease', (147, 175))	('SDHB', 'Gene', '6390', (60, 64))	('paragangliomas', 'Phenotype', 'HP:0002668', (161, 175))	('SDHB', 'Gene', (60, 64))	('SDHD', 'Gene', (102, 106))	('SDHD', 'Gene', '6392', (102, 106))	('associated', 'Reg', (112, 122))
50670	23424694	It has also been reported that incidence and prevalence of malignant paragangliomas are higher in patients with SDHB mutation.	('higher', 'PosReg', (88, 94))	('malignant paragangliomas', 'Disease', (59, 83))	('paraganglioma', 'Phenotype', 'HP:0002668', (69, 82))	('patients', 'Species', '9606', (98, 106))	('SDHB', 'Gene', '6390', (112, 116))	('SDHB', 'Gene', (112, 116))	('paragangliomas', 'Phenotype', 'HP:0002668', (69, 83))	('malignant paragangliomas', 'Disease', 'MESH:C565335', (59, 83))	('mutation', 'Var', (117, 125))
50755	33795528	High expression CCL18 was tightly related to poor prognosis in various tumor, including ovarian cancer, pancreatic ductal adenocarcinoma gallbladder carcinoma and gastric cancer etc.	('gastric cancer', 'Phenotype', 'HP:0012126', (163, 177))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CCL18', 'Gene', (16, 21))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (104, 136))	('ovarian cancer', 'Disease', 'MESH:D010051', (88, 102))	('High expression', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CCL18', 'Gene', '6362', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('gastric cancer', 'Disease', (163, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('ovarian cancer', 'Disease', (88, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))	('related', 'Reg', (34, 41))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('gastric cancer', 'Disease', 'MESH:D013274', (163, 177))	('pancreatic ductal adenocarcinoma gallbladder carcinoma', 'Disease', 'MESH:D021441', (104, 158))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
50760	33795528	This study revealed that the high expression of CCL18 was associated with poor prognosis and might be a promising candidate gene affecting the occurrence and development of PCPG.	('high', 'Var', (29, 33))	('expression', 'MPA', (34, 44))	('associated', 'Reg', (58, 68))	('PCPG', 'Chemical', '-', (173, 177))	('PCPG', 'Disease', (173, 177))	('CCL18', 'Gene', (48, 53))	('CCL18', 'Gene', '6362', (48, 53))
50805	33551992	We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland.	('changes', 'Reg', (200, 207))	('TFTs', 'MPA', (211, 215))	('patient', 'Species', '9606', (33, 40))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (67, 82))	('hypothyroidism', 'Disease', (125, 139))	('primary hypothyroidism', 'Phenotype', 'HP:0000832', (117, 139))	('hypothyroidism', 'Phenotype', 'HP:0000821', (125, 139))	('primary hyperthyroidism', 'Disease', (59, 82))	('177Lu-DOTATATE', 'Var', (154, 168))	('primary hyperthyroidism', 'Disease', 'MESH:D006980', (59, 82))	('177Lu-DOTATATE', 'Chemical', '-', (304, 318))	('177Lu-DOTATATE', 'Chemical', '-', (154, 168))	('hypothyroidism', 'Disease', 'MESH:D007037', (125, 139))	('primary hyperthyroidism', 'Phenotype', 'HP:0000832', (59, 82))
50817	33551992	177Lu-DOTATATE therapy has also been associated with the disruption of endocrine function, although these effects are extremely rare and is often transient.	('177Lu-DOTATATE', 'Chemical', '-', (0, 14))	('associated', 'Reg', (37, 47))	('disruption of endocrine function', 'MPA', (57, 89))	('177Lu-DOTATATE', 'Var', (0, 14))
50820	33551992	A 29-year-old male with metastatic paraganglioma with succinate dehydrogenase subunit B (SDHB) germline pathogenic variant was enrolled in the 177Lu-DOTATATE trial (ClinicalTrials.gov identifier: NCT03206060) for the treatment of inoperable, metastatic PPGL at our center.	('variant', 'Var', (115, 122))	('paraganglioma', 'Disease', 'MESH:D010235', (35, 48))	('PPGL', 'Chemical', '-', (253, 257))	('paraganglioma', 'Disease', (35, 48))	('succinate dehydrogenase subunit B', 'Gene', '6390', (54, 87))	('SDHB', 'Gene', '6390', (89, 93))	('metastatic', 'Disease', (24, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (35, 48))	('177Lu-DOTATATE', 'Chemical', '-', (143, 157))	('succinate dehydrogenase subunit B', 'Gene', (54, 87))	('SDHB', 'Gene', (89, 93))
50849	33551992	However, the temporal association of marked changes in TFTs as well as a significant increase of anti-thyroid antibody titers associated with 177Lu-DOTATATE therapy, along with evidence of increased 177Lu-DOTATATE uptake on the SPECT imaging likely suggests a contribution of PRRT to thyroid disruption.	('changes', 'Reg', (44, 51))	('177Lu-DOTATATE', 'Var', (142, 156))	('177Lu-DOTATATE', 'Chemical', '-', (142, 156))	('anti-thyroid antibody titers', 'MPA', (97, 125))	('increase', 'PosReg', (85, 93))	('177Lu-DOTATATE', 'Chemical', '-', (199, 213))	('TFTs', 'MPA', (55, 59))
50850	33551992	Moreover, development of autoimmune thyroiditis has in fact been reported following 177Lu-DOTATATE therapy.	('autoimmune thyroiditis', 'Disease', 'MESH:D013967', (25, 47))	('thyroiditis', 'Phenotype', 'HP:0100646', (36, 47))	('177Lu-DOTATATE', 'Var', (84, 98))	('autoimmune thyroiditis', 'Disease', (25, 47))	('177Lu-DOTATATE', 'Chemical', '-', (84, 98))
50858	33551992	177Lu-DOTATATE therapy may have caused further damage to the thyroid follicles leading to increased exposure of thyroid parenchymal antigens (TPO, Tg), which in turn may have enhanced autoimmune-mediated destruction facilitating rapid progression toward overt hypothyroidism.	('autoimmune-mediated', 'CPA', (184, 203))	('overt hypothyroidism', 'Phenotype', 'HP:0008223', (254, 274))	('enhanced', 'PosReg', (175, 183))	('increased', 'PosReg', (90, 99))	('TPO', 'Gene', '7173', (142, 145))	('hypothyroidism', 'Disease', 'MESH:D007037', (260, 274))	('TPO', 'Gene', (142, 145))	('hypothyroidism', 'Phenotype', 'HP:0000821', (260, 274))	('exposure', 'MPA', (100, 108))	('177Lu-DOTATATE', 'Var', (0, 14))	('177Lu-DOTATATE', 'Chemical', '-', (0, 14))	('hypothyroidism', 'Disease', (260, 274))
50861	33551992	The exact mechanism of 177Lu-DOTATATE-associated thyroid disruption has not been elucidated.	('177Lu-DOTATATE-associated', 'Var', (23, 48))	('177Lu-DOTATATE', 'Chemical', '-', (23, 37))	('thyroid disruption', 'Disease', (49, 67))
50866	33551992	68Ga-DOTATOC, a somatostatin analog that predominantly targets SSTR-2 and SSTR-5 has demonstrated increased uptake in five of eight cases of Hashimoto's thyroiditis.	("Hashimoto's thyroiditis", 'Disease', (141, 164))	('uptake', 'MPA', (108, 114))	('SSTR-5', 'Gene', '6755', (74, 80))	("Hashimoto's thyroiditis", 'Disease', 'MESH:D050031', (141, 164))	('SSTR-5', 'Gene', (74, 80))	('68Ga-DOTATOC', 'Var', (0, 12))	('increased', 'PosReg', (98, 107))	('SSTR-2', 'Gene', (63, 69))	("Hashimoto's thyroiditis", 'Phenotype', 'HP:0000872', (141, 164))	('SSTR-2', 'Gene', '6752', (63, 69))	('thyroiditis', 'Phenotype', 'HP:0100646', (153, 164))
50878	33551992	Apart from pituitary-thyroid axis, endocrine disruption associated with 177Lu-DOTATATE therapy has also been noted to affect pituitary-adrenal and pituitary-gonadal axes, albeit most of these effects are transient.	('endocrine disruption', 'MPA', (35, 55))	('177Lu-DOTATATE', 'Chemical', '-', (72, 86))	('affect', 'Reg', (118, 124))	('pituitary-adrenal', 'MPA', (125, 142))	('177Lu-DOTATATE', 'Var', (72, 86))	('pituitary-gonadal', 'CPA', (147, 164))
50880	33551992	In conclusion, 177Lu-DOTATATE therapy can be associated with transient or permanent disruption of thyroid function.	('disruption of thyroid function', 'Phenotype', 'HP:0002926', (84, 114))	('177Lu-DOTATATE', 'Chemical', '-', (15, 29))	('177Lu-DOTATATE', 'Var', (15, 29))	('thyroid function', 'Disease', (98, 114))
50897	33128872	Consequently, catecholamine excess states such as PPGL can cause substantial dysregulation of physiological systems, and lead to pronounced changes in pulmonary (vasoplegia), coronary (myocardial infarction), cerebrovascular (stroke), and remaining systemic vascular tone (hypertension), as well as myocardial disease (cardiomyopathies), tachyarrhythmias (benign and fatal), hypercoagulability (thromboembolism), immune dysregulation (cytokine storm), and diabetogenic states; these outcomes are the same as the risk factors that lead to adverse outcomes from COVID-19.	('myocardial infarction', 'Disease', (185, 206))	('stroke', 'Phenotype', 'HP:0001297', (226, 232))	('PPGL', 'Chemical', '-', (50, 54))	('PPGL', 'Var', (50, 54))	('catecholamine', 'Chemical', 'MESH:D002395', (14, 27))	('vasoplegia', 'Disease', 'MESH:D056987', (162, 172))	('arrhythmias', 'Phenotype', 'HP:0011675', (343, 354))	('myocardial infarction', 'Phenotype', 'HP:0001658', (185, 206))	('stroke', 'Disease', 'MESH:D020521', (226, 232))	('catecholamine excess', 'Phenotype', 'HP:0003334', (14, 34))	('thromboembolism', 'Disease', 'MESH:D013923', (395, 410))	('hypertension', 'Disease', 'MESH:D006973', (273, 285))	('myocardial infarction', 'Disease', 'MESH:D009203', (185, 206))	('thromboembolism', 'Phenotype', 'HP:0001907', (395, 410))	('hypertension', 'Disease', (273, 285))	('stroke', 'Disease', (226, 232))	('hypercoagulability', 'Disease', 'MESH:D019851', (375, 393))	('cardiomyopathies', 'Phenotype', 'HP:0001638', (319, 335))	('tachyarrhythmias', 'Disease', 'MESH:D013610', (338, 354))	('hypercoagulability', 'Disease', (375, 393))	('hypertension', 'Phenotype', 'HP:0000822', (273, 285))	('hypercoagulability', 'Phenotype', 'HP:0100724', (375, 393))	('changes', 'Reg', (140, 147))	('myocardial disease', 'Disease', 'MESH:D009202', (299, 317))	('vasoplegia', 'Disease', (162, 172))	('cardiomyopathies', 'Disease', 'MESH:D009202', (319, 335))	('tachyarrhythmias', 'Disease', (338, 354))	('thromboembolism', 'Disease', (395, 410))	('myocardial disease', 'Disease', (299, 317))	('cardiomyopathies', 'Disease', (319, 335))	('COVID-19', 'Disease', 'MESH:C000657245', (560, 568))	('immune dysregulation', 'Phenotype', 'HP:0002958', (413, 433))	('COVID-19', 'Disease', (560, 568))
50901	33128872	Further, these systems or axes are interconnected; eg, catecholamines can lead to the release of cytokines and vice versa.	('release of cytokines', 'MPA', (86, 106))	('catecholamines', 'Chemical', 'MESH:D002395', (55, 69))	('catecholamines', 'Var', (55, 69))	('lead to', 'Reg', (74, 81))
50904	33128872	Furthermore, such patients with coexisting PPGL and COVID-19 would require appropriate and early intervention to avoid catastrophic outcomes such as stroke, myocardial infarction, circulatory collapse, and death from superimposed risk (figure ).	('myocardial infarction', 'Disease', (157, 178))	('circulatory', 'Disease', (180, 191))	('COVID-19', 'Disease', (52, 60))	('stroke', 'Disease', 'MESH:D020521', (149, 155))	('coexisting', 'Var', (32, 42))	('PPGL', 'Gene', (43, 47))	('myocardial infarction', 'Phenotype', 'HP:0001658', (157, 178))	('PPGL', 'Chemical', '-', (43, 47))	('stroke', 'Phenotype', 'HP:0001297', (149, 155))	('death', 'Disease', 'MESH:D003643', (206, 211))	('death', 'Disease', (206, 211))	('patients', 'Species', '9606', (18, 26))	('COVID-19', 'Disease', 'MESH:C000657245', (52, 60))	('stroke', 'Disease', (149, 155))	('myocardial infarction', 'Disease', 'MESH:D009203', (157, 178))
50916	33128872	In general, catecholamines seem to inhibit the T-helper type 1 cell-mediated cytokine response (including IL-1, IL-2, IL-12, interferon-gamma, and TNFalpha), and augment the T-helper type 2 cell-mediated cytokine response (including IL-6 and IL-10; key players in cytokine storm syndrome or multisystem inflammatory syndrome in children).	('IL-1', 'Gene', '3552', (118, 122))	('children', 'Species', '9606', (328, 336))	('augment', 'NegReg', (162, 169))	('interferon-gamma', 'Gene', (125, 141))	('catecholamines', 'Chemical', 'MESH:D002395', (12, 26))	('TNFalpha', 'Gene', '7124', (147, 155))	('T-helper type 1', 'MPA', (47, 62))	('multisystem inflammatory syndrome', 'Disease', 'MESH:D056587', (291, 324))	('IL-1', 'Gene', (118, 122))	('IL-1', 'Gene', '3552', (242, 246))	('multisystem inflammatory syndrome', 'Disease', (291, 324))	('catecholamines', 'Var', (12, 26))	('interferon-gamma', 'Gene', '3458', (125, 141))	('IL-1', 'Gene', '3552', (106, 110))	('IL-2', 'Gene', (112, 116))	('IL-6', 'Gene', '3569', (233, 237))	('cytokine', 'Disease', (264, 272))	('IL-1', 'Gene', (242, 246))	('IL-6', 'Gene', (233, 237))	('IL-10', 'Gene', '3586', (242, 247))	('inhibit', 'NegReg', (35, 42))	('T-helper type 2 cell-mediated cytokine response', 'MPA', (174, 221))	('TNFalpha', 'Gene', (147, 155))	('IL-1', 'Gene', (106, 110))	('IL-10', 'Gene', (242, 247))	('IL-2', 'Gene', '3558', (112, 116))
50922	33128872	Severe COVID-19 is also associated with a reduction in the number of natural killer cells.	('COVID-19', 'Disease', (7, 15))	('reduction', 'NegReg', (42, 51))	('Severe', 'Var', (0, 6))	('COVID-19', 'Disease', 'MESH:C000657245', (7, 15))
50937	33128872	The superimposed angiotensin II-mediated vasoconstriction and the catecholamine excess from PPGL can lead to profound cardiovascular effects through several mechanisms.	('PPGL', 'Chemical', '-', (92, 96))	('angiotensin II', 'Gene', '183', (17, 31))	('catecholamine', 'Chemical', 'MESH:D002395', (66, 79))	('PPGL', 'Var', (92, 96))	('catecholamine excess', 'MPA', (66, 86))	('catecholamine excess', 'Phenotype', 'HP:0003334', (66, 86))	('angiotensin II', 'Gene', (17, 31))	('cardiovascular effects', 'MPA', (118, 140))	('lead to', 'Reg', (101, 108))
50949	33128872	Conversely, we believe that catecholamines might predispose to or precipitate life-threatening decompensations, especially in the setting of COVID-19.	('catecholamines', 'Var', (28, 42))	('precipitate', 'Reg', (66, 77))	('COVID-19', 'Disease', (141, 149))	('predispose', 'Reg', (49, 59))	('catecholamines', 'Chemical', 'MESH:D002395', (28, 42))	('COVID-19', 'Disease', 'MESH:C000657245', (141, 149))
50950	33128872	Up to 71% of patients with PPGL die of cardiovascular causes, with 19 3% experiencing acute, sometimes fatal, cardiovascular complications.	('cardiovascular complications', 'Phenotype', 'HP:0001626', (110, 138))	('cardiovascular complications', 'Disease', 'MESH:D002318', (110, 138))	('cardiovascular complications', 'Disease', (110, 138))	('patients', 'Species', '9606', (13, 21))	('cardiovascular', 'Disease', (39, 53))	('PPGL', 'Chemical', '-', (27, 31))	('PPGL', 'Var', (27, 31))
50964	33128872	Catecholamine excess can also cause beta2-adrenoceptor-mediated vaso-dilation, which can reverse the compensatory hypoxic vasoconstriction in the vasculature that surrounds poorly ventilated alveoli.	('Catecholamine', 'Chemical', 'MESH:D002395', (0, 13))	('beta2-adrenoceptor', 'Gene', (36, 54))	('Catecholamine excess', 'Phenotype', 'HP:0003334', (0, 20))	('beta2-adrenoceptor', 'Gene', '154', (36, 54))	('Catecholamine', 'Var', (0, 13))
50965	33128872	These effects might cause a mismatch between ventilation and perfusion, leading to intrapulmonary shunting that could potentially worsen the already present hypoxaemia in patients with COVID-19.	('leading to', 'Reg', (72, 82))	('cause', 'Reg', (20, 25))	('intrapulmonary shunting', 'MPA', (83, 106))	('COVID-19', 'Disease', 'MESH:C000657245', (185, 193))	('patients', 'Species', '9606', (171, 179))	('hypoxaemia', 'Disease', 'None', (157, 167))	('effects', 'Var', (6, 13))	('mismatch', 'MPA', (28, 36))	('hypoxaemia', 'Disease', (157, 167))	('intrapulmonary shunting', 'Phenotype', 'HP:0031225', (83, 106))	('COVID-19', 'Disease', (185, 193))
50971	33128872	51-75% of patients with PPGL have fasting hyperglycaemia as a result of beta-cell alpha2-adrenoceptor-mediated inhibition of insulin secretion.	('beta-cell alpha2-adrenoceptor-mediated', 'Protein', (72, 110))	('insulin', 'Gene', '3630', (125, 132))	('hyperglycaemia', 'Disease', 'None', (42, 56))	('fasting hyperglycaemia', 'Phenotype', 'HP:0003162', (34, 56))	('PPGL', 'Chemical', '-', (24, 28))	('hyperglycaemia', 'Disease', (42, 56))	('patients', 'Species', '9606', (10, 18))	('PPGL', 'Var', (24, 28))	('insulin', 'Gene', (125, 132))
50981	33128872	These risk factors include hypertension, diabetes, and cardiovascular disease; and in patients with PPGL, there is a potential for the additional burden of malignancy, which in itself was shown to be an important risk factor for COVID-19-related death even after multivariate analysis.	('COVID-19', 'Disease', 'MESH:C000657245', (229, 237))	('death', 'Disease', 'MESH:D003643', (246, 251))	('hypertension', 'Disease', 'MESH:D006973', (27, 39))	('death', 'Disease', (246, 251))	('cardiovascular disease', 'Disease', (55, 77))	('diabetes', 'Disease', 'MESH:D003920', (41, 49))	('COVID-19', 'Disease', (229, 237))	('malignancy', 'Disease', 'MESH:D009369', (156, 166))	('hypertension', 'Disease', (27, 39))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (55, 77))	('hypertension', 'Phenotype', 'HP:0000822', (27, 39))	('malignancy', 'Disease', (156, 166))	('PPGL', 'Chemical', '-', (100, 104))	('cardiovascular disease', 'Disease', 'MESH:D002318', (55, 77))	('PPGL', 'Var', (100, 104))	('diabetes', 'Disease', (41, 49))	('patients', 'Species', '9606', (86, 94))
50983	33128872	Interfering with the influence of catecholamines on the pulmonary and cardiovascular system (table) in such a balanced compensatory state might lead to cardiovascular and respiratory failure.	('respiratory failure', 'Phenotype', 'HP:0002878', (171, 190))	('Interfering', 'Var', (0, 11))	('cardiovascular and respiratory failure', 'Disease', 'MESH:D012131', (152, 190))	('catecholamines', 'Chemical', 'MESH:D002395', (34, 48))	('lead to', 'Reg', (144, 151))
50988	33128872	Metyrosine might offer additional benefits, as treatment will not only dampen catecholamine synthesis and action on various organs via adrenoceptors, but could also attenuate the hyperinflammatory response, cytokine storm syndrome, or multisystem inflammatory syndrome in children.	('cytokine storm syndrome', 'MPA', (207, 230))	('attenuate', 'NegReg', (165, 174))	('multisystem inflammatory syndrome', 'Disease', 'MESH:D056587', (235, 268))	('children', 'Species', '9606', (272, 280))	('hyperinflammatory response', 'Phenotype', 'HP:0012649', (179, 205))	('dampen', 'NegReg', (71, 77))	('action on various organs via adrenoceptors', 'MPA', (106, 148))	('catecholamine synthesis', 'MPA', (78, 101))	('multisystem inflammatory syndrome', 'Disease', (235, 268))	('catecholamine', 'Chemical', 'MESH:D002395', (78, 91))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))	('hyperinflammatory response', 'MPA', (179, 205))
50989	33128872	In a well designed experiment by Staedtke and colleagues, inhibition of tyrosine hydroxylase with metyrosine decreased excess cytokine release in response to bacterial infections, T-cell targeting antibodies, and chimeric antigen receptor T cells in mice.	('decreased', 'NegReg', (109, 118))	('bacterial infections', 'Disease', 'MESH:D001424', (158, 178))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('inhibition', 'Var', (58, 68))	('metyrosine decreased', 'Phenotype', 'HP:0500133', (98, 118))	('bacterial infections', 'Phenotype', 'HP:0002718', (158, 178))	('excess cytokine release', 'MPA', (119, 142))	('metyrosine', 'Chemical', 'MESH:D019805', (98, 108))	('bacterial infections', 'Disease', (158, 178))	('mice', 'Species', '10090', (250, 254))	('tyrosine', 'Chemical', 'MESH:D014443', (100, 108))
50994	33128872	Furthermore, the use of metyrosine can be very beneficial in patients with PPGL and COVID-19 because of its well known effect on catecholamine synthesis.	('COVID-19', 'Disease', 'MESH:C000657245', (84, 92))	('metyrosine', 'Chemical', 'MESH:D019805', (24, 34))	('COVID-19', 'Disease', (84, 92))	('patients', 'Species', '9606', (61, 69))	('PPGL', 'Chemical', '-', (75, 79))	('catecholamine synthesis', 'MPA', (129, 152))	('PPGL', 'Gene', (75, 79))	('catecholamine', 'Chemical', 'MESH:D002395', (129, 142))	('metyrosine', 'Var', (24, 34))
51012	33128872	A subset of patients who develop severe COVID-19 and require intensive care unit admission could be at risk for developing post-intensive care unit syndrome, characterised by new or persistent physical, psychological, and cognitive impairments after hospital discharge.	('patients', 'Species', '9606', (12, 20))	('COVID-19', 'Disease', 'MESH:C000657245', (40, 48))	('post-intensive care unit syndrome', 'Disease', (123, 156))	('COVID-19', 'Disease', (40, 48))	('cognitive impairments', 'Phenotype', 'HP:0100543', (222, 243))	('severe', 'Var', (33, 39))	('cognitive impairments', 'Disease', 'MESH:D003072', (222, 243))	('cognitive impairments', 'Disease', (222, 243))
51014	33128872	In our opinion, patients with PPGL and mild COVID-19 infection or suspected COVID-19 infection not requiring hospitalisation, who are already on adrenoceptor blockers or other anti-hypertensives, can continue with these medications, and these anti-hypertensive regimens should not be interrupted as long as the blood pressure and heart rate remain stable.	('infection', 'Disease', (85, 94))	('infection', 'Disease', 'MESH:D007239', (53, 62))	('hypertensive', 'Disease', 'MESH:D006973', (181, 193))	('infection', 'Disease', 'MESH:D007239', (85, 94))	('COVID-19', 'Disease', 'MESH:C000657245', (44, 52))	('hypertensive', 'Disease', 'MESH:D006973', (248, 260))	('COVID-19', 'Disease', (76, 84))	('hypertensive', 'Disease', (248, 260))	('hypertensive', 'Disease', (181, 193))	('patients', 'Species', '9606', (16, 24))	('PPGL', 'Chemical', '-', (30, 34))	('COVID-19', 'Disease', (44, 52))	('PPGL', 'Var', (30, 34))	('hypertensives', 'Disease', 'MESH:D006973', (181, 194))	('anti-hypertensives', 'Phenotype', 'HP:0000822', (176, 194))	('hypertensives', 'Disease', (181, 194))	('COVID-19', 'Disease', 'MESH:C000657245', (76, 84))	('infection', 'Disease', (53, 62))
51016	33128872	Because patients with coexistent PPGL and COVID-19 are at risk for hyperglycaemia, optimal glycaemic control might be necessary for better outcomes.	('coexistent', 'Var', (22, 32))	('PPGL', 'Gene', (33, 37))	('hyperglycaemia', 'Disease', (67, 81))	('hyperglycaemia', 'Disease', 'None', (67, 81))	('PPGL', 'Chemical', '-', (33, 37))	('COVID-19', 'Disease', 'MESH:C000657245', (42, 50))	('COVID-19', 'Disease', (42, 50))	('patients', 'Species', '9606', (8, 16))
51021	33128872	However, if a patient remains stable on adrenoceptor blockade or there is no previously detected rapid tumour growth (regardless of secretory status), it is not unreasonable to actively monitor and defer surgery in a patient with COVID-19 and PPGL until the resolution of the infection or the patient tests negative for SARS-CoV-2 on a nasopharyngeal swab.	('infection', 'Disease', 'MESH:D007239', (276, 285))	('SARS-CoV-2', 'Species', '2697049', (320, 330))	('patient', 'Species', '9606', (217, 224))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('PPGL', 'Chemical', '-', (243, 247))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('PPGL', 'Var', (243, 247))	('infection', 'Disease', (276, 285))	('patient', 'Species', '9606', (14, 21))	('patient', 'Species', '9606', (293, 300))	('COVID-19', 'Disease', 'MESH:C000657245', (230, 238))	('tumour', 'Disease', (103, 109))	('COVID-19', 'Disease', (230, 238))
51038	32948195	Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas.	('variants', 'Var', (68, 76))	('paragangliomas/pheochromocytomas', 'Disease', (118, 150))	('pathogenic/likely', 'Reg', (39, 56))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (133, 150))	('SDH', 'Gene', '6390', (84, 87))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (133, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (118, 131))	('paragangliomas', 'Phenotype', 'HP:0002668', (118, 132))	('SDH', 'Gene', (84, 87))	('paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (118, 150))
51039	32948195	SDHB variants were found in three patients, whereas SDHD was mutated in two cases.	('SDHD', 'Gene', '6392', (52, 56))	('found', 'Reg', (19, 24))	('SDHB', 'Gene', '6390', (0, 4))	('patients', 'Species', '9606', (34, 42))	('variants', 'Var', (5, 13))	('SDHB', 'Gene', (0, 4))	('SDHD', 'Gene', (52, 56))
51040	32948195	Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex.	('succinate dehydrogenase', 'Gene', (130, 153))	('SDH', 'Gene', '6390', (79, 82))	('SDH', 'Gene', '6390', (155, 158))	('SDHAF4', 'Gene', (79, 85))	('SDH', 'Gene', (68, 71))	('SDHAF3', 'Gene', '57001', (68, 74))	('succinate dehydrogenase', 'Gene', '6390', (130, 153))	('SDH', 'Gene', (79, 82))	('SDH', 'Gene', (155, 158))	('SDHAF4', 'Gene', '135154', (79, 85))	('missense variants', 'Var', (28, 45))	('SDHAF3', 'Gene', (68, 74))	('pathogenic', 'Reg', (17, 27))	('SDH', 'Gene', '6390', (68, 71))
51041	32948195	In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT).	('patient', 'Species', '9606', (5, 12))	('IDH2', 'Gene', (46, 50))	('IDH2', 'Gene', '3418', (46, 50))	('MutationTaster', 'Var', (154, 168))	('variant', 'Var', (31, 38))
51042	32948195	Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors.	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (147, 157))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('tumors', 'Disease', (182, 188))	('variants', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
51043	32948195	Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.	('SDH', 'Gene', '6390', (219, 222))	('SDH', 'Gene', (139, 142))	('VPGL', 'Phenotype', 'HP:0002886', (44, 48))	('SDH', 'Gene', (154, 157))	('lead to', 'Reg', (192, 199))	('SDH', 'Gene', (219, 222))	('SDH', 'Gene', '6390', (139, 142))	('SDH', 'Gene', '6390', (154, 157))	('mutations', 'Var', (122, 131))	('VPGL', 'Chemical', '-', (44, 48))	('disruptions', 'Var', (200, 211))
51053	32948195	A familial form of HNPGLs predominantly occurs as paraganglioma syndromes and results from mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2 genes, encoding for succinate dehydrogenase (SDH; mitochondrial complex II) components.	('SDH', 'Gene', (116, 119))	('SDH', 'Gene', '6390', (104, 107))	('SDHA', 'Gene', (104, 108))	('SDHD', 'Gene', (122, 126))	('SDH', 'Gene', '6390', (184, 187))	('SDHA', 'Gene', '6389', (104, 108))	('SDHC', 'Gene', (116, 120))	('SDHB', 'Gene', (110, 114))	('occurs', 'Reg', (40, 46))	('SDH', 'Gene', (122, 125))	('SDH', 'Gene', '6390', (110, 113))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (50, 73))	('SDH', 'Gene', (104, 107))	('succinate dehydrogenase', 'Gene', (159, 182))	('paraganglioma syndromes', 'Disease', (50, 73))	('SDH', 'Gene', (184, 187))	('results from', 'Reg', (78, 90))	('SDH', 'Gene', '6390', (132, 135))	('SDHA', 'Gene', (132, 136))	('SDH', 'Gene', (110, 113))	('paraganglioma', 'Phenotype', 'HP:0002668', (50, 63))	('SDH', 'Gene', '6390', (116, 119))	('SDHA', 'Gene', '6389', (132, 136))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('SDHC', 'Gene', '6391', (116, 120))	('HNPGLs', 'Phenotype', 'HP:0002864', (19, 25))	('SDHAF2', 'Gene', '54949', (132, 138))	('HNPGLs', 'Disease', (19, 25))	('SDHAF2', 'Gene', (132, 138))	('SDHD', 'Gene', '6392', (122, 126))	('mutations', 'Var', (91, 100))	('succinate dehydrogenase', 'Gene', '6390', (159, 182))	('SDHB', 'Gene', '6390', (110, 114))	('SDH', 'Gene', (132, 135))	('SDH', 'Gene', '6390', (122, 125))
51054	32948195	Mutations in the SDHD gene are the most frequently found in HNPGLs, followed by SDHB and SDHC mutations.	('SDHB', 'Gene', (80, 84))	('SDHC', 'Gene', (89, 93))	('SDHD', 'Gene', '6392', (17, 21))	('HNPGLs', 'Phenotype', 'HP:0002864', (60, 66))	('SDHC', 'Gene', '6391', (89, 93))	('Mutations', 'Var', (0, 9))	('SDHD', 'Gene', (17, 21))	('HNPGLs', 'Disease', (60, 66))	('found', 'Reg', (51, 56))	('SDHB', 'Gene', '6390', (80, 84))
51056	32948195	SDHAF2 variants rarely present in paragangliomas/pheochromocytomas (PGLs/PCCs).	('SDHAF2', 'Gene', '54949', (0, 6))	('paragangliomas', 'Phenotype', 'HP:0002668', (34, 48))	('paraganglioma', 'Phenotype', 'HP:0002668', (34, 47))	('SDHAF2', 'Gene', (0, 6))	('PCC', 'Gene', '1421', (73, 76))	('paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (34, 66))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('variants', 'Var', (7, 15))	('paragangliomas/pheochromocytomas', 'Disease', (34, 66))	('PCC', 'Gene', (73, 76))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (49, 66))	('gliomas', 'Phenotype', 'HP:0009733', (41, 48))	('present', 'Reg', (23, 30))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (49, 65))
51057	32948195	Familial mutations in SDHA have been reported for Leigh syndrome and, most recently, a few have been identified for HNPGLs.	('SDHA', 'Gene', (22, 26))	('HNPGLs', 'Phenotype', 'HP:0002864', (116, 122))	('SDHA', 'Gene', '6389', (22, 26))	('Leigh syndrome', 'Disease', (50, 64))	('reported', 'Reg', (37, 45))	('Familial mutations', 'Var', (0, 18))	('Leigh syndrome', 'Disease', 'MESH:D007888', (50, 64))
51058	32948195	Mutations in the VHL, TMEM127, RET, NF1, and MAX genes also harbor the risk for HNPGL development.	('risk', 'Reg', (71, 75))	('NF1', 'Gene', (36, 39))	('RET', 'Gene', '5979', (31, 34))	('MAX', 'Gene', (45, 48))	('NF1', 'Gene', '4763', (36, 39))	('RET', 'Gene', (31, 34))	('TMEM127', 'Gene', (22, 29))	('Mutations', 'Var', (0, 9))	('VHL', 'Gene', (17, 20))	('TMEM127', 'Gene', '55654', (22, 29))	('VHL', 'Gene', '7428', (17, 20))	('HNPGL', 'Disease', (80, 85))
51059	32948195	Additionally, potentially driver somatic/germline variants were identified in several other genes, such as ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, JAG1, PRDM2, PRDM8, SETD2, ASPM, ZIC, and GRIK1.	('CSDE1', 'Gene', (147, 152))	('PRDM8', 'Gene', '56978', (205, 210))	('BRAF', 'Gene', '673', (119, 123))	('BRAF', 'Gene', (119, 123))	('variants', 'Var', (50, 58))	('BRCA2', 'Gene', '675', (132, 137))	('JAG1', 'Gene', '182', (192, 196))	('KIF1B', 'Gene', (167, 172))	('ASPM', 'Gene', (219, 223))	('IDH1', 'Gene', '3417', (161, 165))	('ZIC', 'Gene', (225, 228))	('PRDM8', 'Gene', (205, 210))	('MEN1', 'Gene', '4221', (181, 185))	('CSDE1', 'Gene', '7812', (147, 152))	('CDKN2A', 'Gene', '1029', (139, 145))	('ASPM', 'Gene', '259266', (219, 223))	('RET', 'Gene', (187, 190))	('GRIK1', 'Gene', (234, 239))	('KMT2D', 'Gene', (174, 179))	('GRIK1', 'Gene', '2897', (234, 239))	('MEN1', 'Gene', (181, 185))	('ARNT', 'Gene', '405', (107, 111))	('FGFR3', 'Gene', (154, 159))	('RET', 'Gene', '5979', (187, 190))	('BAP1', 'Gene', '8314', (113, 117))	('ARNT', 'Gene', (107, 111))	('SETD2', 'Gene', (212, 217))	('ZIC', 'Gene', '7545', (225, 228))	('FGFR3', 'Gene', '2261', (154, 159))	('KIF1B', 'Gene', '23095', (167, 172))	('PRDM2', 'Gene', (198, 203))	('PRDM2', 'Gene', '7799', (198, 203))	('JAG1', 'Gene', (192, 196))	('BRCA2', 'Gene', (132, 137))	('SETD2', 'Gene', '29072', (212, 217))	('BRCA1', 'Gene', '672', (125, 130))	('IDH1', 'Gene', (161, 165))	('BRCA1', 'Gene', (125, 130))	('KMT2D', 'Gene', '8085', (174, 179))	('BAP1', 'Gene', (113, 117))	('CDKN2A', 'Gene', (139, 145))
51075	32948195	In VPGLs, we identified pathogenic/likely pathogenic variants of genes that were previously shown to be associated with PGLs/PCCs: VHL, SDHx, NF1, RET, HRAS, KRAS, EPAS1 (HIF2A), ATRX, CSDE1, BRAF, FGFR1, FGFR2, FGFR3, FGFR4, FGFRL1, SETD2, ARNT, TP53, TP53BP1, TP53BP2, TP53I13, KMT2D, BAP1, IDH1, IDH2, SDHAF1, SDHAP2, FH, EGLN1, MDH2, TMEM127, MAX, KIF1B, MEN1, GDNF, GNAS, CDKN2A, BRCA1, and BRCA2 as well as in other groups of genes (Additional file 1).	('SDH', 'Gene', (305, 308))	('MDH2', 'Gene', (332, 336))	('KMT2D', 'Gene', (280, 285))	('SETD2', 'Gene', '29072', (234, 239))	('RET', 'Gene', (147, 150))	('SDH', 'Gene', (313, 316))	('FH', 'Disease', 'MESH:D006938', (321, 323))	('IDH1', 'Gene', (293, 297))	('FGFR1', 'Gene', (198, 203))	('FGFR3', 'Gene', '2261', (212, 217))	('ATRX', 'Gene', '546', (179, 183))	('TP53I13', 'Gene', (271, 278))	('EGLN1', 'Gene', '54583', (325, 330))	('SDHAP2', 'Gene', (313, 319))	('GNAS', 'Gene', '2778', (371, 375))	('TMEM127', 'Gene', (338, 345))	('SDHAF1', 'Gene', '644096', (305, 311))	('GDNF', 'Gene', (365, 369))	('BRAF', 'Gene', '673', (192, 196))	('BAP1', 'Gene', '8314', (287, 291))	('KRAS', 'Gene', (158, 162))	('FGFRL1', 'Gene', '53834', (226, 232))	('CSDE1', 'Gene', (185, 190))	('FGFR3', 'Gene', (212, 217))	('EPAS1', 'Gene', (164, 169))	('IDH2', 'Gene', (299, 303))	('KIF1B', 'Gene', (352, 357))	('NF1', 'Gene', (142, 145))	('BAP1', 'Gene', (287, 291))	('IDH2', 'Gene', '3418', (299, 303))	('ATRX', 'Gene', (179, 183))	('GNAS', 'Gene', (371, 375))	('TP53BP1', 'Gene', '7158', (253, 260))	('TP53BP2', 'Gene', (262, 269))	('MDH2', 'Gene', '4191', (332, 336))	('TP53', 'Gene', (247, 251))	('VHL', 'Gene', (131, 134))	('IDH1', 'Gene', '3417', (293, 297))	('KMT2D', 'Gene', '8085', (280, 285))	('SDH', 'Gene', '6390', (305, 308))	('VPGL', 'Chemical', '-', (3, 7))	('FGFR4', 'Gene', '2264', (219, 224))	('TP53BP2', 'Gene', '7159', (262, 269))	('ARNT', 'Gene', (241, 245))	('VHL', 'Gene', '7428', (131, 134))	('SDHAP2', 'Gene', '727956', (313, 319))	('MEN1', 'Gene', '4221', (359, 363))	('FGFR2', 'Gene', (205, 210))	('BRAF', 'Gene', (192, 196))	('TP53', 'Gene', '7157', (247, 251))	('TP53', 'Gene', (253, 257))	('NF1', 'Gene', '4763', (142, 145))	('MEN1', 'Gene', (359, 363))	('VPGL', 'Phenotype', 'HP:0002886', (3, 7))	('SDH', 'Gene', '6390', (136, 139))	('CSDE1', 'Gene', '7812', (185, 190))	('BRCA2', 'Gene', (396, 401))	('BRCA1', 'Gene', '672', (385, 390))	('TP53', 'Gene', '7157', (253, 257))	('TP53', 'Gene', (271, 275))	('BRCA2', 'Gene', '675', (396, 401))	('HRAS', 'Gene', (152, 156))	('ARNT', 'Gene', '405', (241, 245))	('TP53I13', 'Gene', '90313', (271, 278))	('KRAS', 'Gene', '3845', (158, 162))	('SDH', 'Gene', '6390', (313, 316))	('FGFR1', 'Gene', '2260', (198, 203))	('TP53', 'Gene', (262, 266))	('HIF2A', 'Gene', '2034', (171, 176))	('TP53', 'Gene', '7157', (271, 275))	('FGFR4', 'Gene', (219, 224))	('PCC', 'Gene', '1421', (125, 128))	('HIF2A', 'Gene', (171, 176))	('FGFR2', 'Gene', '2263', (205, 210))	('CDKN2A', 'Gene', (377, 383))	('TP53', 'Gene', '7157', (262, 266))	('BRCA1', 'Gene', (385, 390))	('CDKN2A', 'Gene', '1029', (377, 383))	('SDH', 'Gene', (136, 139))	('EPAS1', 'Gene', '2034', (164, 169))	('TP53BP1', 'Gene', (253, 260))	('HRAS', 'Gene', '3265', (152, 156))	('EGLN1', 'Gene', (325, 330))	('KIF1B', 'Gene', '23095', (352, 357))	('FGFRL1', 'Gene', (226, 232))	('RET', 'Gene', '5979', (147, 150))	('TMEM127', 'Gene', '55654', (338, 345))	('SDHAF1', 'Gene', (305, 311))	('SETD2', 'Gene', (234, 239))	('GDNF', 'Gene', '2668', (365, 369))	('PCC', 'Gene', (125, 128))	('variants', 'Var', (53, 61))
51082	32948195	Exome analysis of the tumor revealed no variants in the potentially causative genes for PGLs/PCCs.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('PCC', 'Gene', '1421', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('PCC', 'Gene', (93, 96))	('variants', 'Var', (40, 48))
51083	32948195	However, we found likely pathogenic variants characterized by high "pathogenicity scores" as well as by frameshift mutations in several tumor-associated genes, such as CYSLTR2, GPX2, ENPP7, CD34, UBA7, and others (Additional file 1).	('CYSLTR2', 'Gene', '57105', (168, 175))	('frameshift mutations', 'Var', (104, 124))	('CD34', 'Gene', (190, 194))	('CD34', 'Gene', '947', (190, 194))	('UBA7', 'Gene', '7318', (196, 200))	('CYSLTR2', 'Gene', (168, 175))	('GPX2', 'Gene', '2877', (177, 181))	('ENPP7', 'Gene', '339221', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ENPP7', 'Gene', (183, 188))	('GPX2', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('variants', 'Var', (36, 44))	('UBA7', 'Gene', (196, 200))	('pathogenic', 'Reg', (25, 35))	('tumor', 'Disease', (136, 141))
51084	32948195	For the UTS2R gene, we identified a likely pathogenic variant, NM_018949: c.C313A, p.P105T (chr17: 80332513, rs140576840), that had not been reported in the ClinVar or COSMIC databases before.	('pathogenic', 'Reg', (43, 53))	('c.C313A', 'Var', (74, 81))	('p.P105T', 'Var', (83, 90))	('p.P105T', 'Mutation', 'rs140576840', (83, 90))	('rs140576840', 'Mutation', 'rs140576840', (109, 120))	('UTS2R', 'Gene', '2837', (8, 13))	('NM_018949: c.C313A', 'Mutation', 'rs140576840', (63, 81))	('UTS2R', 'Gene', (8, 13))
51088	32948195	A likely pathogenic variant, NM_004804: c.C296T, p.T99I (chr2: 96933370, rs780418079), was also determined for the CIAO1 gene.	('pathogenic', 'Reg', (9, 19))	('c.C296T', 'Var', (40, 47))	('CIAO1', 'Gene', '9391', (115, 120))	('NM_004804: c.C296T', 'Mutation', 'rs780418079', (29, 47))	('rs780418079', 'Mutation', 'rs780418079', (73, 84))	('CIAO1', 'Gene', (115, 120))	('p.T99I', 'Mutation', 'rs780418079', (49, 55))	('rs780418079', 'Var', (73, 84))
51090	32948195	Alterations in CIAO1 are associated with hereditary PGL/PCC syndromes according to the MalaCards database (https://www.malacards.org/).	('associated', 'Reg', (25, 35))	('hereditary PGL/PCC syndromes', 'Disease', (41, 69))	('Alterations', 'Var', (0, 11))	('CIAO1', 'Gene', '9391', (15, 20))	('CIAO1', 'Gene', (15, 20))	('hereditary PGL/PCC syndromes', 'Disease', 'MESH:D010235', (41, 69))
51091	32948195	The likely pathogenic missense variant NM_017558: c.G1352C, p.R451P (chr16: 71127814, rs7200485) of the HYDIN gene was also identified in this VPGL.	('HYDIN', 'Gene', (104, 109))	('rs7200485', 'Mutation', 'rs7200485', (86, 95))	('NM_017558: c.G1352C', 'Mutation', 'rs7200485', (39, 58))	('p.R451P', 'Mutation', 'rs7200485', (60, 67))	('VPGL', 'Phenotype', 'HP:0002886', (143, 147))	('pathogenic', 'Reg', (11, 21))	('c.G1352C', 'Var', (50, 58))	('rs7200485', 'Var', (86, 95))	('HYDIN', 'Gene', '54768', (104, 109))	('VPGL', 'Chemical', '-', (143, 147))
51093	32948195	Additionally, we found several likely pathogenic variants reported in the COSMIC database for the following genes: CD109 (COSM1621920; liver and lung cancer), CYSLTR2 (COSM1367341; colon cancer), DENND6B (COSM1035425; endometrial cancer), and OR9I1 (COSM385271; lung cancer).	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('COSM1621920;', 'Var', (122, 134))	('lung cancer', 'Disease', (262, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('OR9I1', 'Gene', (243, 248))	('colon cancer', 'Disease', (181, 193))	('OR9I1', 'Gene', '219954', (243, 248))	('liver and lung cancer', 'Disease', 'MESH:D008175', (135, 156))	('DENND6B', 'Gene', (196, 203))	('endometrial cancer', 'Phenotype', 'HP:0012114', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('COSM385271;', 'Var', (250, 261))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('CYSLTR2', 'Gene', '57105', (159, 166))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('endometrial cancer', 'Disease', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancer', 'Disease', (145, 156))	('COSM1367341;', 'Var', (168, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('CD109', 'Gene', (115, 120))	('DENND6B', 'Gene', '414918', (196, 203))	('endometrial cancer', 'Disease', 'MESH:D016889', (218, 236))	('CD109', 'Gene', '135228', (115, 120))	('CYSLTR2', 'Gene', (159, 166))	('colon cancer', 'Disease', 'MESH:D015179', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pathogenic', 'Reg', (38, 48))	('COSM1035425;', 'Var', (205, 217))
51106	32948195	We detected a likely pathogenic missense variant in the SDHB gene, NM_003000: c.A307G, p.M103V (chr1: 17355211, rs140178341).	('NM_003000: c.A307G', 'Mutation', 'rs140178341', (67, 85))	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('p.M103V', 'Var', (87, 94))	('rs140178341', 'Mutation', 'rs140178341', (112, 123))	('c.A307G', 'Var', (78, 85))	('pathogenic', 'Reg', (21, 31))	('p.M103V', 'Mutation', 'rs140178341', (87, 94))
51108	32948195	Additionally, two novel frameshift mutations were found in SDHB, NM_003000: c.308_309insTAAG, p.M103fs (chr1: 17355209) and NM_003000: c.304_305insATGAT, p.A102fs (chr1: 17355213).	('p.A102fs', 'Mutation', 'p.A102fsX', (154, 162))	('p.M103fs', 'Mutation', 'p.M103fsX', (94, 102))	('c.304_305insATGAT', 'Var', (135, 152))	('p.A102fs', 'Var', (154, 162))	('p.M103fs', 'Var', (94, 102))	('SDHB', 'Gene', '6390', (59, 63))	('SDHB', 'Gene', (59, 63))	('c.308_309insTAAG', 'Var', (76, 92))	('c.304_305insATGAT', 'INSERTION', 'None', (135, 152))	('c.308_309insTAAG', 'INSERTION', 'None', (76, 92))
51109	32948195	A likely pathogenic missense variant was also observed in ARNT, NM_001197325: c.C1834T, p.R612C (chr1: 150788806, rs778430234); a variant that had not been previously reported, neither in the ClinVar nor in the COSMIC databases.	('ARNT', 'Gene', '405', (58, 62))	('pathogenic', 'Reg', (9, 19))	('ARNT', 'Gene', (58, 62))	('c.C1834T', 'Var', (78, 86))	('p.R612C', 'Mutation', 'rs778430234', (88, 95))	('rs778430234', 'Mutation', 'rs778430234', (114, 125))	('p.R612C', 'Var', (88, 95))	('NM_001197325: c.C1834T', 'Mutation', 'rs778430234', (64, 86))
51110	32948195	However, likely pathogenic variants in the ARNT gene were earlier determined in CPGLs.	('CPGL', 'Phenotype', 'HP:0100635', (80, 84))	('variants', 'Var', (27, 35))	('ARNT', 'Gene', '405', (43, 47))	('ARNT', 'Gene', (43, 47))
51111	32948195	One of these distinctive genes is a novel likely pathogenic variant for RXFP1, NM_021634: c.G172A, p.D58N (chr4: 159493972).	('p.D58N', 'Mutation', 'rs1351663425', (99, 105))	('RXFP1', 'Gene', (72, 77))	('NM_021634: c.G172A', 'Mutation', 'rs1351663425', (79, 97))	('RXFP1', 'Gene', '59350', (72, 77))	('c.G172A', 'Var', (90, 97))	('pathogenic', 'Reg', (49, 59))	('p.D58N', 'Var', (99, 105))
51115	32948195	A likely pathogenic variant NM_024776: c.C2908T, p.R970C (crh15: 77471361, rs117879553) in the PEAK1 gene was also revealed in this patient's VPGL.	('pathogenic', 'Reg', (9, 19))	('NM_024776: c.C2908T', 'Mutation', 'rs117879553', (28, 47))	('rs117879553', 'Mutation', 'rs117879553', (75, 86))	('VPGL', 'Chemical', '-', (142, 146))	('c.C2908T', 'Var', (39, 47))	('p.R970C', 'Mutation', 'rs117879553', (49, 56))	('PEAK1', 'Gene', (95, 100))	('VPGL', 'Phenotype', 'HP:0002886', (142, 146))	('rs117879553', 'Var', (75, 86))	('patient', 'Species', '9606', (132, 139))	('PEAK1', 'Gene', '79834', (95, 100))	('p.R970C', 'Var', (49, 56))
51119	32948195	We determined a likely pathogenic variant NM_004787: c.A934G, p.I312V (chr4: 20512137, rs139850475) for this gene.	('NM_004787: c.A934G', 'Mutation', 'rs139850475', (42, 60))	('p.I312V', 'Var', (62, 69))	('c.A934G', 'Var', (53, 60))	('rs139850475', 'Mutation', 'rs139850475', (87, 98))	('pathogenic', 'Reg', (23, 33))	('rs139850475', 'Var', (87, 98))	('p.I312V', 'Mutation', 'rs139850475', (62, 69))
51122	32948195	On the other hand, it has been reported that SLIT2 is frequently inactivated in gliomas by hypermethylation at the CpG island within its promoter region and can act as a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('gliomas', 'Phenotype', 'HP:0009733', (80, 87))	('gliomas', 'Disease', (80, 87))	('inactivated', 'NegReg', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SLIT2', 'Gene', (45, 50))	('gliomas', 'Disease', 'MESH:D005910', (80, 87))	('SLIT2', 'Gene', '9353', (45, 50))	('tumor', 'Disease', (170, 175))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('hypermethylation', 'Var', (91, 107))
51123	32948195	A likely pathogenic variant was also found in the AMPH gene, NM_001635: c.A2024G, p.Q675R (chr7: 38424483, rs147019216T).	('pathogenic', 'Reg', (9, 19))	('AMPH', 'Gene', (50, 54))	('p.Q675R', 'Var', (82, 89))	('c.A2024G', 'Var', (72, 80))	('p.Q675R', 'Mutation', 'rs147019216', (82, 89))	('AMPH', 'Gene', '273', (50, 54))	('rs147019216T', 'Var', (107, 119))	('NM_001635: c.A2024G', 'Mutation', 'rs147019216', (61, 80))
51126	32948195	Additionally, AMPH knockdown reduces apoptosis and promotes cell cycle progression and migration of breast cancer cells.	('migration', 'CPA', (87, 96))	('AMPH', 'Gene', '273', (14, 18))	('apoptosis', 'CPA', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('knockdown', 'Var', (19, 28))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('promotes', 'PosReg', (51, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('reduces', 'NegReg', (29, 36))	('AMPH', 'Gene', (14, 18))	('cell cycle progression', 'CPA', (60, 82))
51127	32948195	In the HAPLN3 gene, we also identified a likely pathogenic variant, NM_178232: c.G316A, p.G106R (chr15: 89424765, rs140982817), described in the COSMIC database as associated with lung and caecum cancer (COSM1375297).	('rs140982817', 'Var', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('NM_178232: c.G316A', 'Mutation', 'rs140982817', (68, 86))	('associated', 'Reg', (164, 174))	('HAPLN3', 'Gene', '145864', (7, 13))	('HAPLN3', 'Gene', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('p.G106R', 'Mutation', 'rs140982817', (88, 95))	('cancer', 'Disease', (196, 202))	('p.G106R', 'Var', (88, 95))	('c.G316A', 'Var', (79, 86))	('rs140982817', 'Mutation', 'rs140982817', (114, 125))
51134	32948195	Exome analysis of the VPGL revealed the existence of likely pathogenic missense variants of both the SDHAF3 and SDHAF4 genes: NM_020186: c.T157C, p.F53L (chr7: 96747192, rs62624461) and NM_145267: c.C223T, p.P75S (chr6: 71298323, rs146446063), respectively (Additional file 1).	('p.P75S', 'Var', (206, 212))	('SDHAF4', 'Gene', (112, 118))	('c.T157C', 'Var', (137, 144))	('NM_145267: c.C223T', 'Mutation', 'rs146446063', (186, 204))	('SDHAF4', 'Gene', '135154', (112, 118))	('p.P75S', 'Mutation', 'rs146446063', (206, 212))	('pathogenic', 'Reg', (60, 70))	('rs62624461', 'Mutation', 'rs62624461', (170, 180))	('VPGL', 'Chemical', '-', (22, 26))	('p.F53L', 'Mutation', 'rs62624461', (146, 152))	('rs146446063', 'Var', (230, 241))	('NM_145267: c.C223T', 'Var', (186, 204))	('NM_020186: c.T157C', 'Mutation', 'rs62624461', (126, 144))	('p.F53L', 'Var', (146, 152))	('rs146446063', 'Mutation', 'rs146446063', (230, 241))	('SDHAF3', 'Gene', '57001', (101, 107))	('NM_020186: c.T157C', 'Var', (126, 144))	('VPGL', 'Phenotype', 'HP:0002886', (22, 26))	('rs62624461', 'Var', (170, 180))	('SDHAF3', 'Gene', (101, 107))
51136	32948195	Previously, we found a likely pathogenic missense variant of SDHAF3 from CPGL (not published).	('SDHAF3', 'Gene', '57001', (61, 67))	('missense variant', 'Var', (41, 57))	('pathogenic', 'Reg', (30, 40))	('SDHAF3', 'Gene', (61, 67))	('CPGL', 'Phenotype', 'HP:0100635', (73, 77))
51137	32948195	A variant of this gene, which may probably damage the protein function (according to the in silico tools used for analysis), was determined in familial and sporadic PGLs/PCCs.	('protein function', 'MPA', (54, 70))	('PCC', 'Gene', (170, 173))	('variant', 'Var', (2, 9))	('determined', 'Reg', (129, 139))	('PCC', 'Gene', '1421', (170, 173))	('damage', 'Reg', (43, 49))
51138	32948195	For VPGL, we revealed several likely pathogenic variants of the COL19A1 (COSM1235991; related to plasma cell myeloma and lung cancer), SEC31B (COSM913945; involved in endometrial and colorectal cancer), THSD7B (COSM247830; associated with prostate cancer), and TIAM1 (COSM1566097, COSM1566096; related to rectum cancer) genes, which have been previously described in the COSMIC database.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('myeloma', 'Disease', (109, 116))	('pathogenic', 'Reg', (37, 47))	('COL19A1', 'Gene', (64, 71))	('rectum cancer', 'Phenotype', 'HP:0100743', (305, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('colorectal cancer', 'Disease', 'MESH:D015179', (183, 200))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('TIAM1', 'Gene', (261, 266))	('endometrial', 'Disease', (167, 178))	('prostate cancer', 'Disease', 'MESH:D011471', (239, 254))	('prostate cancer', 'Phenotype', 'HP:0012125', (239, 254))	('colorectal cancer', 'Disease', (183, 200))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('VPGL', 'Chemical', '-', (4, 8))	('rectum cancer', 'Disease', 'MESH:D012004', (305, 318))	('prostate cancer', 'Disease', (239, 254))	('variants', 'Var', (48, 56))	('lung cancer', 'Disease', (121, 132))	('SEC31B', 'Gene', (135, 141))	('myeloma', 'Disease', 'MESH:D009101', (109, 116))	('TIAM1', 'Gene', '7074', (261, 266))	('THSD7B', 'Gene', (203, 209))	('rectum cancer', 'Disease', (305, 318))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (183, 200))	('VPGL', 'Phenotype', 'HP:0002886', (4, 8))	('plasma cell myeloma', 'Phenotype', 'HP:0006775', (97, 116))
51139	32948195	Additionally, we identified likely pathogenic variants of CRNN, CYP4B1, ELL, ENPP7, FAT2, NCOR2, SART1, TIAM1, VIM, and other genes involved in tumorigenesis according to literature data.	('ELL', 'Gene', '8178', (72, 75))	('ELL', 'Gene', (72, 75))	('TIAM1', 'Gene', (104, 109))	('FAT2', 'Gene', (84, 88))	('TIAM1', 'Gene', '7074', (104, 109))	('tumor', 'Disease', (144, 149))	('pathogenic', 'Reg', (35, 45))	('variants', 'Var', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CRNN', 'Gene', '49860', (58, 62))	('NCOR2', 'Gene', (90, 95))	('VIM', 'Gene', '7431', (111, 114))	('SART1', 'Gene', '9092', (97, 102))	('ENPP7', 'Gene', (77, 82))	('NCOR2', 'Gene', '9612', (90, 95))	('VIM', 'Gene', (111, 114))	('SART1', 'Gene', (97, 102))	('CYP4B1', 'Gene', '1580', (64, 70))	('ENPP7', 'Gene', '339221', (77, 82))	('CRNN', 'Gene', (58, 62))	('FAT2', 'Gene', '2196', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CYP4B1', 'Gene', (64, 70))
51149	32948195	In the VPGL of this patient, we found no pathogenic/likely pathogenic variants for any of the PGL/PCC potentially causative genes, including SDHx (Additional file 1).	('SDH', 'Gene', '6390', (141, 144))	('VPGL', 'Chemical', '-', (7, 11))	('PCC', 'Gene', (98, 101))	('variants', 'Var', (70, 78))	('patient', 'Species', '9606', (20, 27))	('SDH', 'Gene', (141, 144))	('VPGL', 'Phenotype', 'HP:0002886', (7, 11))	('PCC', 'Gene', '1421', (98, 101))
51150	32948195	Nevertheless, for several genes, we identified likely pathogenic variants reported in the COSMIC database and associated with different types of cancer: ACAD11 (COSM3695823; colon cancer), MTNR1B (COSM1561913; rectum, lung, liver, and colorectal cancer), NTF4 (COSM3404440; glioma and rhabdomyosarcoma), PATZ1 (COSM273076; acute lymphoblastic leukaemia and colon cancer), SAMD9L (COSM3784101; prostate cancer), and TRIM16 (COSM401683; lung cancer).	('cancer', 'Disease', (145, 151))	('MTNR1B', 'Gene', (189, 195))	('ACAD11', 'Gene', (153, 159))	('PATZ1', 'Gene', '23598', (304, 309))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('acute lymphoblastic leukaemia and colon cancer', 'Disease', 'MESH:D015179', (323, 369))	('COSM3695823;', 'Var', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('glioma', 'Disease', (274, 280))	('COSM1561913;', 'Var', (197, 209))	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (323, 352))	('cancer', 'Disease', 'MESH:D009369', (402, 408))	('COSM401683;', 'Var', (423, 434))	('colorectal cancer', 'Phenotype', 'HP:0003003', (235, 252))	('NTF4', 'Gene', '4909', (255, 259))	('PATZ1', 'Gene', (304, 309))	('sarcoma', 'Phenotype', 'HP:0100242', (294, 301))	('glioma', 'Disease', 'MESH:D005910', (274, 280))	('lung cancer', 'Disease', (435, 446))	('colon cancer', 'Phenotype', 'HP:0003003', (357, 369))	('cancer', 'Disease', (246, 252))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('variants', 'Var', (65, 73))	('lung', 'Disease', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('rhabdomyosarcoma', 'Disease', (285, 301))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (180, 186))	('MTNR1B', 'Gene', '4544', (189, 195))	('TRIM16', 'Gene', (415, 421))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (235, 252))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('lung cancer', 'Disease', 'MESH:D008175', (435, 446))	('cancer', 'Disease', (363, 369))	('colon cancer', 'Disease', 'MESH:D015179', (357, 369))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('SAMD9L', 'Gene', (372, 378))	('cancer', 'Disease', (402, 408))	('COSM273076;', 'Var', (311, 322))	('TRIM16', 'Gene', '10626', (415, 421))	('lung cancer', 'Phenotype', 'HP:0100526', (435, 446))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (285, 301))	('cancer', 'Phenotype', 'HP:0002664', (402, 408))	('colorectal cancer', 'Disease', (235, 252))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('SAMD9L', 'Gene', '219285', (372, 378))	('prostate cancer', 'Disease', 'MESH:D011471', (393, 408))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (285, 301))	('prostate cancer', 'Phenotype', 'HP:0012125', (393, 408))	('COSM3404440;', 'Var', (261, 273))	('NTF4', 'Gene', (255, 259))	('colon cancer', 'Disease', (174, 186))	('ACAD11', 'Gene', '84129', (153, 159))	('liver', 'Disease', (224, 229))	('COSM3784101;', 'Var', (380, 392))	('cancer', 'Disease', (440, 446))	('colon cancer', 'Disease', (357, 369))	('prostate cancer', 'Disease', (393, 408))
51151	32948195	A likely pathogenic variant was also revealed for the AMBRA1 gene, involved in cancer development and chemotherapy resistance.	('pathogenic', 'Reg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('AMBRA1', 'Gene', (54, 60))	('AMBRA1', 'Gene', '55626', (54, 60))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('variant', 'Var', (20, 27))
51152	32948195	Several other genes with likely pathogenic variants that were previously shown to participate in tumorigenesis were also found within this patient's exome.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('variants', 'Var', (43, 51))	('patient', 'Species', '9606', (139, 146))
51153	32948195	For example, the CHST4 gene, which is associated with colon mucinous adenocarcinoma (MalaCards database); CLCA4, a tumor suppressor gene encoding for the calcium-activated chloride channel A4 that can inhibit tumor cell proliferation, migration, and invasion; ESR1, characterized by mutations responsible for the resistance to endocrine therapy in breast cancer; P2RY1, involved in the regulation of multidrug chemoresistance of bladder cancer cells; and PATZ1, which acts as a tumor suppressor gene in thyroid cancer and is associated with the development of testicular tumors, sarcoma, and lung cancer.	('CHST4', 'Gene', '10164', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (571, 576))	('tumor', 'Disease', (115, 120))	('thyroid cancer', 'Disease', (503, 517))	('ESR1', 'Gene', '2099', (260, 264))	('PATZ1', 'Gene', '23598', (455, 460))	('PATZ1', 'Gene', (455, 460))	('bladder cancer', 'Disease', (429, 443))	('bladder cancer', 'Disease', 'MESH:D001749', (429, 443))	('breast cancer', 'Phenotype', 'HP:0003002', (348, 361))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('sarcoma', 'Phenotype', 'HP:0100242', (579, 586))	('cancer', 'Phenotype', 'HP:0002664', (597, 603))	('tumor', 'Disease', (209, 214))	('associated', 'Reg', (38, 48))	('ESR1', 'Gene', (260, 264))	('invasion', 'CPA', (250, 258))	('tumor', 'Disease', (478, 483))	('bladder cancer', 'Phenotype', 'HP:0009725', (429, 443))	('testicular tumors', 'Disease', (560, 577))	('cancer', 'Phenotype', 'HP:0002664', (437, 443))	('colon mucinous adenocarcinoma', 'Disease', (54, 83))	('P2RY1', 'Gene', '5028', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('lung cancer', 'Disease', (592, 603))	('breast cancer', 'Disease', 'MESH:D001943', (348, 361))	('thyroid cancer', 'Disease', 'MESH:D013964', (503, 517))	('tumor', 'Disease', 'MESH:D009369', (478, 483))	('breast cancer', 'Disease', (348, 361))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('colon mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (54, 83))	('tumor', 'Disease', (571, 576))	('mutations', 'Var', (283, 292))	('thyroid cancer', 'Phenotype', 'HP:0002890', (503, 517))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('CHST4', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (571, 576))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('testicular tumors', 'Disease', 'MESH:D013736', (560, 577))	('tumor', 'Phenotype', 'HP:0002664', (478, 483))	('testicular tumors', 'Phenotype', 'HP:0010788', (560, 577))	('inhibit', 'NegReg', (201, 208))	('lung cancer', 'Disease', 'MESH:D008175', (592, 603))	('CLCA4', 'Gene', '22802', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('sarcoma', 'Disease', 'MESH:D012509', (579, 586))	('P2RY1', 'Gene', (363, 368))	('tumors', 'Phenotype', 'HP:0002664', (571, 577))	('CLCA4', 'Gene', (106, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (592, 603))	('sarcoma', 'Disease', (579, 586))	('cancer', 'Phenotype', 'HP:0002664', (511, 517))	('associated', 'Reg', (525, 535))
51154	32948195	Furthermore, we found alterations in the PRKCI gene related to many tumors and WIF1 hypermethylation, frequently observed in cancer cells.	('tumors', 'Disease', (68, 74))	('WIF1', 'Gene', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('WIF1', 'Gene', '11197', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('alterations', 'Var', (22, 33))	('PRKCI', 'Gene', '5584', (41, 46))	('related', 'Reg', (52, 59))	('hypermethylation', 'Var', (84, 100))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('PRKCI', 'Gene', (41, 46))
51164	32948195	Exome analysis of the VPGL revealed likely pathogenic variants in several PGL/PCC potentially causative genes: SDHB, SDHAF4, FGFRL1, and IDH2 (Additional file 1).	('SDHAF4', 'Gene', (117, 123))	('SDHB', 'Gene', (111, 115))	('FGFRL1', 'Gene', (125, 131))	('PCC', 'Gene', (78, 81))	('IDH2', 'Gene', (137, 141))	('pathogenic', 'Reg', (43, 53))	('FGFRL1', 'Gene', '53834', (125, 131))	('VPGL', 'Phenotype', 'HP:0002886', (22, 26))	('IDH2', 'Gene', '3418', (137, 141))	('SDHAF4', 'Gene', '135154', (117, 123))	('PCC', 'Gene', '1421', (78, 81))	('variants', 'Var', (54, 62))	('VPGL', 'Chemical', '-', (22, 26))	('SDHB', 'Gene', '6390', (111, 115))
51165	32948195	A splice acceptor mutation identified in the SDHB gene (chr1: 17350571, rs786201161) was described as a germline pathogenic variant in the ClinVar database.	('rs786201161', 'Mutation', 'rs786201161', (72, 83))	('rs786201161', 'Var', (72, 83))	('SDHB', 'Gene', '6390', (45, 49))	('SDHB', 'Gene', (45, 49))
51166	32948195	This variant has been previously reported in association with an SDHB-related disorder, hereditary cancer-predisposing syndrome, gastrointestinal stromal tumor, and hereditary PGL/PCC syndromes.	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (129, 159))	('hereditary PGL/PCC syndromes', 'Disease', (165, 193))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('gastrointestinal stromal tumor', 'Disease', (129, 159))	('variant', 'Var', (5, 12))	('hereditary cancer', 'Disease', 'MESH:D009369', (88, 105))	('hereditary PGL/PCC syndromes', 'Disease', 'MESH:D010235', (165, 193))	('SDHB', 'Gene', '6390', (65, 69))	('reported', 'Reg', (33, 41))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (129, 159))	('association', 'Reg', (45, 56))	('hereditary cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('SDHB', 'Gene', (65, 69))
51167	32948195	The mutation destroys the canonical splice acceptor site within intron 5 of the SDHB gene and is expected to cause abnormal gene splicing, likely resulting in an absent or disrupted protein product.	('cause', 'Reg', (109, 114))	('SDHB', 'Gene', (80, 84))	('gene splicing', 'MPA', (124, 137))	('mutation', 'Var', (4, 12))	('absent', 'NegReg', (162, 168))	('disrupted', 'NegReg', (172, 181))	('destroys', 'NegReg', (13, 21))	('canonical splice acceptor site', 'MPA', (26, 56))	('protein product', 'MPA', (182, 197))	('SDHB', 'Gene', '6390', (80, 84))
51168	32948195	For SDHAF4, we found a novel likely pathogenic missense mutation NM_145267: c.C223T, p.P75S (chr6: 71298323, rs146446063).	('rs146446063', 'Mutation', 'rs146446063', (109, 120))	('SDHAF4', 'Gene', '135154', (4, 10))	('c.C223T', 'Var', (76, 83))	('pathogenic', 'Reg', (36, 46))	('p.P75S', 'Var', (85, 91))	('rs146446063', 'Var', (109, 120))	('NM_145267: c.C223T', 'Mutation', 'rs146446063', (65, 83))	('SDHAF4', 'Gene', (4, 10))	('p.P75S', 'Mutation', 'rs146446063', (85, 91))
51169	32948195	The likely pathogenic missense mutation identified in the FGFRL1 gene, NM_001004356: c.C442T, p.R148C (chr4: 1017613, rs201696860), has not been previously reported in the ClinVar database; however, it was detected in lung adenocarcinoma and described in the COSMIC database (COSM119740).	('p.R148C', 'Mutation', 'rs201696860', (94, 101))	('FGFRL1', 'Gene', '53834', (58, 64))	('FGFRL1', 'Gene', (58, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('lung adenocarcinoma', 'Disease', (218, 237))	('rs201696860', 'Mutation', 'rs201696860', (118, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (218, 237))	('c.C442T', 'Var', (85, 92))	('NM_001004356: c.C442T', 'Mutation', 'rs201696860', (71, 92))	('pathogenic', 'Reg', (11, 21))	('p.R148C', 'Var', (94, 101))
51170	32948195	Finally, in the IDH2 gene, we found a novel mutation NM_001289910: c.T998C, p.L333P (chr15: 90628257) that was predicted as a likely pathogenic variant according to all the prediction algorithms used.	('IDH2', 'Gene', (16, 20))	('pathogenic', 'Reg', (133, 143))	('p.L333P', 'Var', (76, 83))	('IDH2', 'Gene', '3418', (16, 20))	('p.L333P', 'Mutation', 'p.L333P', (76, 83))	('NM_001289910: c.T998C', 'Mutation', 'c.998T>C', (53, 74))
51171	32948195	For this VPGL, we also determined likely pathogenic variants in a few genes that were reported in the COSMIC database and associated with different types of cancer: ATP2A1 (COSM1184049; colon cancer), ACAD11 (COSM3695823; colon cancer), ERCC4 (COSM967199; endometrial, colorectal, and papillary thyroid cancer), and VPS13B (COSM3698729, COSM3698730; colon cancer and lung bronchioloalveolar adenocarcinoma).	('VPS13B', 'Gene', '157680', (316, 322))	('ACAD11', 'Gene', (201, 207))	('variants', 'Var', (52, 60))	('ERCC4', 'Gene', '2072', (237, 242))	('colon cancer', 'Disease', (222, 234))	('endometrial', 'Disease', (256, 267))	('ERCC4', 'Gene', (237, 242))	('cancer', 'Disease', (192, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (391, 405))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('COSM967199;', 'Var', (244, 255))	('colon cancer', 'Disease', 'MESH:D015179', (186, 198))	('VPGL', 'Phenotype', 'HP:0002886', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', (303, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('colon cancer', 'Phenotype', 'HP:0003003', (350, 362))	('VPS13B', 'Gene', (316, 322))	('cancer', 'Disease', (356, 362))	('papillary thyroid cancer', 'Disease', (285, 309))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('COSM3698730', 'Var', (337, 348))	('COSM1184049', 'Var', (173, 184))	('colorectal', 'Disease', (269, 279))	('colon cancer', 'Phenotype', 'HP:0003003', (222, 234))	('cancer', 'Disease', (228, 234))	('colon cancer', 'Disease', (186, 198))	('colon cancer', 'Disease', 'MESH:D015179', (350, 362))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', (157, 163))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (285, 309))	('cancer', 'Disease', 'MESH:D009369', (303, 309))	('associated', 'Reg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('COSM3695823', 'Var', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('colon cancer', 'Disease', 'MESH:D015179', (222, 234))	('adenocarcinoma', 'Disease', (391, 405))	('ACAD11', 'Gene', '84129', (201, 207))	('ATP2A1', 'Gene', '487', (165, 171))	('VPGL', 'Chemical', '-', (9, 13))	('colorectal', 'Disease', 'MESH:D015179', (269, 279))	('COSM3698729', 'Var', (324, 335))	('ATP2A1', 'Gene', (165, 171))	('colon cancer', 'Disease', (350, 362))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (285, 309))	('thyroid cancer', 'Phenotype', 'HP:0002890', (295, 309))	('colon cancer', 'Phenotype', 'HP:0003003', (186, 198))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
51172	32948195	Moreover, likely pathogenic variants were identified in genes reported as tumor-associated ones according to the literature; for example, in CD248, LGR5, LRP1B, PBRM1, and PTPA.	('CD248', 'Gene', '57124', (141, 146))	('PBRM1', 'Gene', (161, 166))	('PTPA', 'Gene', '5524', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('LGR5', 'Gene', '8549', (148, 152))	('LRP1B', 'Gene', (154, 159))	('variants', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PBRM1', 'Gene', '55193', (161, 166))	('LRP1B', 'Gene', '53353', (154, 159))	('tumor', 'Disease', (74, 79))	('PTPA', 'Gene', (172, 176))	('CD248', 'Gene', (141, 146))	('LGR5', 'Gene', (148, 152))	('pathogenic', 'Reg', (17, 27))
51180	32948195	Using whole-exome sequencing, we found a pathogenic germline mutation in the SDHD gene, NM_003002: c.A305G, p.H102R (chr11: 111959726, rs104894302) (Additional file 1).	('rs104894302', 'Var', (135, 146))	('p.H102R', 'Mutation', 'rs104894302', (108, 115))	('rs104894302', 'Mutation', 'rs104894302', (135, 146))	('SDHD', 'Gene', '6392', (77, 81))	('SDHD', 'Gene', (77, 81))	('c.A305G', 'Var', (99, 106))	('p.H102R', 'Var', (108, 115))	('pathogenic', 'Reg', (41, 51))	('NM_003002: c.A305G', 'Mutation', 'rs104894302', (88, 106))
51181	32948195	This variant is described in the ClinVar database as a likely pathogenic germline one and has been found in malignant paraganglioma.	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('malignant paraganglioma', 'Disease', (108, 131))	('variant', 'Var', (5, 12))	('malignant paraganglioma', 'Disease', 'MESH:C565335', (108, 131))	('paraganglioma', 'Phenotype', 'HP:0002668', (118, 131))	('pathogenic', 'Reg', (62, 72))
51182	32948195	At the same position in the SDHD gene (codon 102), a sequence change leading to an amino acid substitution of a histidine for either a leucine, a proline, or a tyrosine was also observed in individuals with paragangliomas.	('SDHD', 'Gene', (28, 32))	('leucine', 'Chemical', 'MESH:D007930', (135, 142))	('substitution', 'Var', (94, 106))	('tyrosine', 'Chemical', 'MESH:D014443', (160, 168))	('histidine', 'Chemical', 'MESH:D006639', (112, 121))	('glioma', 'Phenotype', 'HP:0009733', (214, 220))	('gliomas', 'Phenotype', 'HP:0009733', (214, 221))	('paraganglioma', 'Phenotype', 'HP:0002668', (207, 220))	('proline', 'Chemical', 'MESH:D011392', (146, 153))	('paragangliomas', 'Disease', 'MESH:D010235', (207, 221))	('SDHD', 'Gene', '6392', (28, 32))	('paragangliomas', 'Phenotype', 'HP:0002668', (207, 221))	('paragangliomas', 'Disease', (207, 221))
51184	32948195	In VPGL, we also identified likely pathogenic variants reported in the COSMIC database for the following genes: ABCB4 (COSM1092579; endometrial and colorectal cancer), LHX8 (COSM1560500; rectum and stomach cancer), DAPK2 (COSM1678527; clear cell renal cell carcinoma), STARD10 (COSM1475880; breast cancer), and ZNF599 (COSM328007; pancreas cancer).	('pancreas cancer', 'Disease', (331, 346))	('LHX8', 'Gene', '431707', (168, 172))	('rectum and stomach cancer', 'Disease', 'MESH:D012004', (187, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('stomach cancer', 'Phenotype', 'HP:0012126', (198, 212))	('COSM1475880;', 'Var', (278, 290))	('VPGL', 'Phenotype', 'HP:0002886', (3, 7))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (235, 266))	('STARD10', 'Gene', (269, 276))	('COSM1560500;', 'Var', (174, 186))	('DAPK2', 'Gene', (215, 220))	('ABCB4', 'Gene', '5244', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ZNF599', 'Gene', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('breast cancer', 'Disease', 'MESH:D001943', (291, 304))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('breast cancer', 'Disease', (291, 304))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (246, 266))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (235, 266))	('variants', 'Var', (46, 54))	('colorectal cancer', 'Disease', (148, 165))	('DAPK2', 'Gene', '23604', (215, 220))	('VPGL', 'Chemical', '-', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('LHX8', 'Gene', (168, 172))	('pancreas cancer', 'Disease', 'MESH:D010190', (331, 346))	('ZNF599', 'Gene', '148103', (311, 317))	('COSM1678527;', 'Var', (222, 234))	('clear cell renal cell carcinoma', 'Disease', (235, 266))	('ABCB4', 'Gene', (112, 117))	('pancreas cancer', 'Phenotype', 'HP:0002894', (331, 346))	('STARD10', 'Gene', '10809', (269, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
51187	32948195	The proto-oncogene ROS1 belongs to the subfamily of tyrosine kinase insulin receptor genes; ROS1 fusions were found in a variety of tumors.	('ROS1', 'Gene', (92, 96))	('found', 'Reg', (110, 115))	('fusions', 'Var', (97, 104))	('ROS1', 'Gene', '6098', (92, 96))	('tyrosine kinase', 'Gene', '7294', (52, 67))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('ROS1', 'Gene', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('ROS1', 'Gene', '6098', (19, 23))	('tyrosine kinase', 'Gene', (52, 67))
51188	32948195	The protein product of the SETD3 gene participates in lysine degradation and chromatin organization; alterations in this gene are associated with renal cell carcinoma according to the MalaCards database.	('renal cell carcinoma', 'Disease', (146, 166))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (146, 166))	('SETD3', 'Gene', '84193', (27, 32))	('alterations', 'Var', (101, 112))	('chromatin organization', 'MPA', (77, 99))	('lysine degradation', 'MPA', (54, 72))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (146, 166))	('SETD3', 'Gene', (27, 32))	('lysine', 'Chemical', 'MESH:D008239', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('participates', 'Reg', (38, 50))	('associated', 'Reg', (130, 140))
51194	32948195	A Matas test made to the outpatient was positive: Clamping the CCA caused retrograde blood flow in the supratrochlear artery.	('retrograde blood flow', 'MPA', (74, 95))	('outpatient', 'Species', '9606', (25, 35))	('Clamping', 'Var', (50, 58))
51198	32948195	In this patient, we found a pathogenic stop-gain mutation NM_003000: c.C79T, p.R27X (chr1: 17371377, rs74315369) in the SDHB gene.	('p.R27X', 'Mutation', 'rs74315369', (77, 83))	('rs74315369', 'Mutation', 'rs74315369', (101, 111))	('SDHB', 'Gene', '6390', (120, 124))	('c.C79T', 'Var', (69, 75))	('NM_003000: c.C79T', 'Mutation', 'rs74315369', (58, 75))	('rs74315369', 'Var', (101, 111))	('p.R27X', 'Var', (77, 83))	('patient', 'Species', '9606', (8, 15))	('SDHB', 'Gene', (120, 124))	('pathogenic', 'Reg', (28, 38))
51201	32948195	In this patient's VPGL, we first identified likely pathogenic variants in a number of genes that have previously been found in other tumors according to the COSMIC database: VSIG10 (COSM935687; endometrial cancer), MRGPRX1 (COSM3687222; colon and lung cancer), DUSP27 (COSM144660; diffuse large B cell lymphoma), and C10orf88 (COSM3686556; colon cancer).	('DUSP27', 'Gene', (261, 267))	('MRGPRX1', 'Gene', '259249', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('C10orf88', 'Gene', '80007', (317, 325))	('patient', 'Species', '9606', (8, 15))	('colon cancer', 'Disease', (340, 352))	('VPGL', 'Phenotype', 'HP:0002886', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (295, 310))	('colon and lung cancer', 'Disease', 'MESH:D008175', (237, 258))	('DUSP27', 'Gene', '92235', (261, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('endometrial cancer', 'Phenotype', 'HP:0012114', (194, 212))	('lymphoma', 'Phenotype', 'HP:0002665', (302, 310))	('large B cell', 'Phenotype', 'HP:0005404', (289, 301))	('B cell lymphoma', 'Disease', 'MESH:D016393', (295, 310))	('B cell lymphoma', 'Disease', (295, 310))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', (133, 139))	('VSIG10', 'Gene', '54621', (174, 180))	('endometrial cancer', 'Disease', (194, 212))	('colon cancer', 'Phenotype', 'HP:0003003', (340, 352))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('COSM3687222', 'Var', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('C10orf88', 'Gene', (317, 325))	('endometrial cancer', 'Disease', 'MESH:D016889', (194, 212))	('COSM3686556;', 'Var', (327, 339))	('COSM144660;', 'Var', (269, 280))	('VPGL', 'Chemical', '-', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('variants', 'Var', (62, 70))	('colon cancer', 'Disease', 'MESH:D015179', (340, 352))	('MRGPRX1', 'Gene', (215, 222))	('VSIG10', 'Gene', (174, 180))
51209	32948195	Using the whole exome-sequencing, a missense mutation in the SDHD gene, NM_003002: c.A305G, p.H102R (chr11: 111959726, rs104894302), was determined in the VPGL (Additional file 1).	('p.H102R', 'Var', (92, 99))	('SDHD', 'Gene', '6392', (61, 65))	('VPGL', 'Chemical', '-', (155, 159))	('rs104894302', 'Mutation', 'rs104894302', (119, 130))	('SDHD', 'Gene', (61, 65))	('p.H102R', 'Mutation', 'rs104894302', (92, 99))	('NM_003002: c.A305G', 'Mutation', 'rs104894302', (72, 90))	('VPGL', 'Phenotype', 'HP:0002886', (155, 159))	('c.A305G', 'Var', (83, 90))
51211	32948195	According to the COSMIC database, we found likely pathogenic variants that were earlier detected in other malignancies: TLL1 (COSM1671424; colorectal cancer), CDH8 (COSM972084; endometrial, pancreatic, and skin cancer), ANAPC5 (COSM936016; endometrial cancer), ACAN (COSM3690591, COSM3690590; colon cancer), C7orf72 (COSM3698459; colon cancer), and ZNF599 (COSM328007; pancreatic cancer).	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (369, 386))	('C7orf72', 'Gene', '100130988', (308, 315))	('colon cancer', 'Disease', (293, 305))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('TLL1', 'Gene', (120, 124))	('malignancies', 'Disease', (106, 118))	('COSM3690591', 'Var', (267, 278))	('ZNF599', 'Gene', '148103', (349, 355))	('skin cancer', 'Disease', 'MESH:D012878', (206, 217))	('ACAN', 'Gene', '176', (261, 265))	('ANAPC5', 'Gene', '51433', (220, 226))	('ANAPC5', 'Gene', (220, 226))	('colon cancer', 'Disease', (330, 342))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('TLL1', 'Gene', '7092', (120, 124))	('CDH8', 'Gene', (159, 163))	('colon cancer', 'Phenotype', 'HP:0003003', (293, 305))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('ACAN', 'Gene', (261, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (369, 386))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('C7orf72', 'Gene', (308, 315))	('endometrial cancer', 'Phenotype', 'HP:0012114', (240, 258))	('CDH8', 'Gene', '1006', (159, 163))	('COSM3698459;', 'Var', (317, 329))	('COSM3690590', 'Var', (280, 291))	('skin cancer', 'Disease', (206, 217))	('pancreatic cancer', 'Disease', (369, 386))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('colon cancer', 'Phenotype', 'HP:0003003', (330, 342))	('endometrial cancer', 'Disease', (240, 258))	('colon cancer', 'Disease', 'MESH:D015179', (293, 305))	('ZNF599', 'Gene', (349, 355))	('endometrial cancer', 'Disease', 'MESH:D016889', (240, 258))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('skin cancer', 'Phenotype', 'HP:0008069', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('colon cancer', 'Disease', 'MESH:D015179', (330, 342))	('variants', 'Var', (61, 69))	('colorectal cancer', 'Disease', (139, 156))
51212	32948195	Additionally, likely pathogenic variants were revealed in well-known tumor-associated genes.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('variants', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('pathogenic', 'Reg', (21, 31))
51213	32948195	For example, variant NM_004996: c.C3901T, p.R1301C (chr16: 16225727, rs201533167) was detected in the ABCC1 gene; this variant seems to be pathogenic according to all the prediction tools used for analysis.	('ABCC1', 'Gene', (102, 107))	('rs201533167', 'Var', (69, 80))	('p.R1301C', 'Var', (42, 50))	('pathogenic', 'Reg', (139, 149))	('p.R1301C', 'Mutation', 'rs201533167', (42, 50))	('c.C3901T', 'Var', (32, 40))	('NM_004996: c.C3901T', 'Mutation', 'rs201533167', (21, 40))	('ABCC1', 'Gene', '4363', (102, 107))	('rs201533167', 'Mutation', 'rs201533167', (69, 80))
51215	32948195	The ALDH1L1 gene, in which we found the likely pathogenic variant NM_012190: c.G68A, p.G23D (chr3: 125879755, rs143122118), is a potential tumor suppressor gene, encoding for a protein involved in folate metabolism.	('p.G23D', 'Mutation', 'rs143122118', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('folate', 'Chemical', 'MESH:D005492', (197, 203))	('ALDH1L1', 'Gene', (4, 11))	('NM_012190: c.G68A', 'Mutation', 'rs143122118', (66, 83))	('NM_012190', 'Gene', (66, 75))	('ALDH1L1', 'Gene', '10840', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('pathogenic', 'Reg', (47, 57))	('p.G23D', 'Var', (85, 91))	('rs143122118', 'Mutation', 'rs143122118', (110, 121))	('c.G68A', 'Var', (77, 83))
51216	32948195	A likely pathogenic variant NM_007194: c.T1091C, p.I364T (chr22: 29092893, rs774179198) was revealed in the CHEK2 gene, which is commonly mutated in hereditary cancer.	('rs774179198', 'Mutation', 'rs774179198', (75, 86))	('pathogenic', 'Reg', (9, 19))	('NM_007194: c.T1091C', 'Mutation', 'rs774179198', (28, 47))	('CHEK2', 'Gene', '11200', (108, 113))	('hereditary cancer', 'Disease', 'MESH:D009369', (149, 166))	('p.I364T', 'Var', (49, 56))	('CHEK2', 'Gene', (108, 113))	('p.I364T', 'Mutation', 'rs774179198', (49, 56))	('hereditary cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('c.T1091C', 'Var', (39, 47))	('rs774179198', 'Var', (75, 86))
51217	32948195	In COL4A1, a variant NM_001845: c.G4442A, p.R1481Q (chr13: 110814597, rs376607450) was observed.	('NM_001845: c.G4442A', 'Mutation', 'rs376607450', (21, 40))	('p.R1481Q', 'Mutation', 'rs376607450', (42, 50))	('rs376607450', 'Mutation', 'rs376607450', (70, 81))	('COL4A1', 'Gene', (3, 9))	('c.G4442A', 'Var', (32, 40))	('rs376607450', 'Var', (70, 81))	('NM_001845: c.G4442A', 'Var', (21, 40))	('COL4A1', 'Gene', '1282', (3, 9))
51219	32948195	In the MADD gene, a novel stop-gain variant NM_003682: c.C2077T, p.Q693X (chr11: 47306036) was found.	('NM_003682: c.C2077T', 'Var', (44, 63))	('p.Q693X', 'Var', (65, 72))	('MADD', 'Gene', '8567', (7, 11))	('MADD', 'Gene', (7, 11))	('p.Q693X', 'Mutation', 'p.Q693X', (65, 72))	('NM_003682: c.C2077T', 'Mutation', 'c.2077C>T', (44, 63))
51221	32948195	In this patient's VPGL, we also observed a variant NM_015641: c.G1123A, p.V375M (chr7: 115897393, rs202205760) in TES, a tumor suppressor gene involved in the regulation of tumorigenesis, angiogenesis, and metastasis.	('TES', 'Gene', (114, 117))	('NM_015641: c.G1123A', 'Var', (51, 70))	('VPGL', 'Chemical', '-', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('c.G1123A', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('TES', 'Chemical', 'MESH:C004551', (114, 117))	('tumor', 'Disease', (121, 126))	('p.V375M', 'Mutation', 'rs202205760', (72, 79))	('rs202205760', 'Var', (98, 109))	('tumor', 'Disease', (173, 178))	('rs202205760', 'Mutation', 'rs202205760', (98, 109))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('patient', 'Species', '9606', (8, 15))	('NM_015641: c.G1123A', 'Mutation', 'rs202205760', (51, 70))	('p.V375M', 'Var', (72, 79))	('VPGL', 'Phenotype', 'HP:0002886', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
51222	32948195	Additionally, a likely pathogenic variant NM_017672: c.C1337G, p.A446G (chr15: 50916466) in the TRPM7 gene was found.	('TRPM7', 'Gene', (96, 101))	('p.A446G', 'Mutation', 'p.A446G', (63, 70))	('p.A446G', 'Var', (63, 70))	('TRPM7', 'Gene', '54822', (96, 101))	('NM_017672: c.C1337G', 'Mutation', 'c.1337C>G', (42, 61))	('pathogenic', 'Reg', (23, 33))
51226	32948195	In 6 of them, we revealed the existence of pathogenic/likely pathogenic variants of genes encoding for components of the SDH complex (SDHB, SDHD, SDHAF3, and SDHAF4), confirming their high mutation frequency not only in paragangliomas and pheochromocytomas but also in VPGLs as distinct tumor types.	('SDH', 'Gene', '6390', (121, 124))	('SDHAF3', 'Gene', (146, 152))	('SDH', 'Gene', (140, 143))	('SDHB', 'Gene', '6390', (134, 138))	('SDH', 'Gene', '6390', (158, 161))	('pathogenic', 'CPA', (61, 71))	('SDH', 'Gene', (146, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (220, 233))	('glioma', 'Phenotype', 'HP:0009733', (227, 233))	('VPGL', 'Chemical', '-', (269, 273))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (239, 256))	('SDH', 'Gene', (121, 124))	('SDHAF4', 'Gene', (158, 164))	('SDHB', 'Gene', (134, 138))	('tumor', 'Disease', (287, 292))	('SDH', 'Gene', '6390', (134, 137))	('SDH', 'Gene', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('SDHAF4', 'Gene', '135154', (158, 164))	('variants', 'Var', (72, 80))	('paragangliomas', 'Phenotype', 'HP:0002668', (220, 234))	('SDHD', 'Gene', '6392', (140, 144))	('VPGL', 'Phenotype', 'HP:0002886', (269, 273))	('SDH', 'Gene', '6390', (140, 143))	('gliomas', 'Phenotype', 'HP:0009733', (227, 234))	('pathogenic/likely', 'Reg', (43, 60))	('SDH', 'Gene', (134, 137))	('SDH', 'Gene', '6390', (146, 149))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (239, 255))	('SDHD', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (220, 256))	('SDHAF3', 'Gene', '57001', (146, 152))
51227	32948195	Moreover, likely pathogenic variants were identified in different tumor-associated genes as well as variants that have previously been found in common tumors, such as lung, colorectal, endometrial, and renal cancers.	('variants', 'Var', (28, 36))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung', 'Disease', (167, 171))	('endometrial', 'Disease', (185, 196))	('renal cancers', 'Disease', (202, 215))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('colorectal', 'Disease', (173, 183))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('pathogenic', 'Reg', (17, 27))	('renal cancers', 'Disease', 'MESH:D007680', (202, 215))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('variants', 'Var', (100, 108))	('tumor', 'Disease', (151, 156))	('colorectal', 'Disease', 'MESH:D015179', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
51228	32948195	Our results indicate a high heterogeneity among VPGLs that is supported by a wide number of identified pathogenic/likely pathogenic variants in different genes (besides mutations in SDHx/SDHAF1-4 genes) in each patient.	('SDHAF1', 'Gene', (187, 193))	('SDHAF1', 'Gene', '644096', (187, 193))	('SDH', 'Gene', (182, 185))	('pathogenic', 'CPA', (121, 131))	('VPGL', 'Chemical', '-', (48, 52))	('SDH', 'Gene', '6390', (187, 190))	('VPGL', 'Phenotype', 'HP:0002886', (48, 52))	('variants', 'Var', (132, 140))	('pathogenic/likely', 'Reg', (103, 120))	('SDH', 'Gene', (187, 190))	('SDH', 'Gene', '6390', (182, 185))	('patient', 'Species', '9606', (211, 218))
51248	31146085	Up to one-third of patients with PPGLs have germline DNA mutations, including mutations in succinate dehydrogenase complex subunit B or D (SDHB or SDHD) associated with the hereditary paraganglioma syndrome 4 and 1, respectively, RET mutations leading to multiple endocrine neoplasia 2 (MEN2), germline VHL gene mutation causing von Hippel-Lindau (VHL) disease, NF1 mutation causing neurofibromatosis type 1, and others.	('VHL', 'Gene', '7428', (303, 306))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (329, 360))	('neoplasia', 'Phenotype', 'HP:0002664', (274, 283))	('neurofibromatosis type 1', 'Gene', '4763', (383, 407))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (264, 283))	('RET', 'Gene', '5979', (230, 233))	('PPGLs', 'Chemical', '-', (33, 38))	('VHL', 'Gene', '7428', (348, 351))	('NF1', 'Gene', '4763', (362, 365))	('hereditary paraganglioma syndrome', 'Disease', (173, 206))	('mutations', 'Var', (78, 87))	('succinate dehydrogenase complex subunit B', 'Gene', (91, 132))	('succinate dehydrogenase complex subunit B', 'Gene', '6390', (91, 132))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (264, 283))	('NF1', 'Gene', (362, 365))	('patients', 'Species', '9606', (19, 27))	('SDHB', 'Gene', '6390', (139, 143))	('RET', 'Gene', (230, 233))	('SDHD', 'Gene', '6392', (147, 151))	('mutations', 'Var', (234, 243))	('neurofibromatosis type 1', 'Gene', (383, 407))	('leading to', 'Reg', (244, 254))	('VHL', 'Gene', (303, 306))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D061325', (173, 206))	('endocrine neoplasia', 'Disease', (264, 283))	('SDHB', 'Gene', (139, 143))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (383, 400))	('paraganglioma', 'Phenotype', 'HP:0002668', (184, 197))	('associated', 'Reg', (153, 163))	('SDHD', 'Gene', (147, 151))	('VHL', 'Gene', (348, 351))
51252	31146085	In fact, there are currently no reliable clinical or laboratory tests to predict malignancy, although some positive associations have been shown with germline SDHB mutation, extra-adrenal site of disease, persistent postoperative hypertension, and tumor diameter greater than 5 cm.	('SDHB', 'Gene', '6390', (159, 163))	('tumor', 'Disease', (248, 253))	('hypertension', 'Disease', 'MESH:D006973', (230, 242))	('SDHB', 'Gene', (159, 163))	('extra-adrenal site', 'Disease', (174, 192))	('hypertension', 'Disease', (230, 242))	('mutation', 'Var', (164, 172))	('hypertension', 'Phenotype', 'HP:0000822', (230, 242))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('malignancy', 'Disease', (81, 91))
51255	31146085	Because multiple studies have demonstrated a link between alteration in miRNAs and the development of cancer, miRNA profiling has been investigated as a potential diagnostic, prognostic, and therapeutic tool in a wide range of cancers (e.g., thyroid, lung, breast, cervical, soft tissue sarcoma, and adrenocortical tumors).	('cervical', 'Disease', (265, 273))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('adrenocortical tumors', 'Disease', 'MESH:D018268', (300, 321))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('alteration', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('adrenocortical tumors', 'Disease', (300, 321))	('lung', 'Disease', (251, 255))	('breast', 'Disease', (257, 263))	('cancer', 'Disease', (102, 108))	('thyroid', 'Disease', (242, 249))	('cancer', 'Disease', (227, 233))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (275, 294))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('sarcoma', 'Disease', 'MESH:D012509', (287, 294))	('sarcoma', 'Disease', (287, 294))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))
51256	31146085	A comprehensive miRNA analysis of benign and malignant pheochromocytoma tumors by Patterson et al demonstrated statistically significant higher expression of miR-483-5p, miR-183, and miR-101 in malignant samples, suggesting that these markers can serve as a diagnostic tool.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR-183', 'Gene', '406959', (170, 177))	('miR-183', 'Gene', (170, 177))	('miR-101', 'Var', (183, 190))	('expression', 'MPA', (144, 154))	('malignant pheochromocytoma tumors', 'Disease', 'MESH:D010673', (45, 78))	('higher', 'PosReg', (137, 143))	('miR-483', 'Gene', '619552', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('malignant pheochromocytoma tumors', 'Disease', (45, 78))	('miR-483', 'Gene', (158, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (55, 71))
51289	31146085	Germline mutation status was compared as individual mutations compared to no germline mutation and as SDHB mutation versus all other germline mutations versus no germline mutation.	('SDHB', 'Gene', '6390', (102, 106))	('mutation', 'Var', (107, 115))	('SDHB', 'Gene', (102, 106))
51295	31146085	MicroRNA-210 has been associated with PPGLs, SDHB mutation, and hypoxia.	('hypoxia', 'Disease', (64, 71))	('hypoxia', 'Disease', 'MESH:D000860', (64, 71))	('MicroRNA-210', 'Gene', '406992', (0, 12))	('PPGLs', 'Chemical', '-', (38, 43))	('SDHB', 'Gene', '6390', (45, 49))	('SDHB', 'Gene', (45, 49))	('MicroRNA-210', 'Gene', (0, 12))	('associated', 'Reg', (22, 32))	('mutation', 'Var', (50, 58))	('PPGLs', 'Disease', (38, 43))
51299	31146085	Although there is currently no reliable method to predict malignancy, a few positive associations have been shown with increased age at time of diagnosis, SDHB mutation, extra-adrenal site of disease, persistent postoperative hypertension, and a tumor size greater than 5 cm.	('mutation', 'Var', (160, 168))	('malignancy', 'Disease', 'MESH:D009369', (58, 68))	('hypertension', 'Disease', 'MESH:D006973', (226, 238))	('SDHB', 'Gene', (155, 159))	('malignancy', 'Disease', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('hypertension', 'Disease', (226, 238))	('hypertension', 'Phenotype', 'HP:0000822', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))	('SDHB', 'Gene', '6390', (155, 159))
51304	31146085	MicroRNAs have been found to facilitate tumor growth, invasion, angiogenesis, and immune evasion through the posttranscriptional regulation of various proteins.	('MicroRNAs', 'Var', (0, 9))	('proteins', 'Protein', (151, 159))	('invasion', 'CPA', (54, 62))	('immune evasion', 'MPA', (82, 96))	('angiogenesis', 'CPA', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('facilitate', 'PosReg', (29, 39))	('posttranscriptional', 'MPA', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
51306	31146085	Some studies have profiled miRNA expression in patients with PPGLs, including miR-15a, miR-16, miR-483-5p, miR-183, miR-101, miR-139, miR-541, and miR-765.	('miR-183', 'Gene', '406959', (107, 114))	('patients', 'Species', '9606', (47, 55))	('miR-16', 'Gene', (87, 93))	('miRNA expression', 'MPA', (27, 43))	('miR-139', 'Gene', (125, 132))	('miR-101', 'Var', (116, 123))	('miR-183', 'Gene', (107, 114))	('miR-541', 'Gene', (134, 141))	('miR-483', 'Gene', (95, 102))	('miR-15a', 'Gene', '406948', (78, 85))	('miR-16', 'Gene', '51573', (87, 93))	('miR-541', 'Gene', '100126308', (134, 141))	('miR-483', 'Gene', '619552', (95, 102))	('profiled', 'Reg', (18, 26))	('miR-765', 'Gene', (147, 154))	('PPGLs', 'Chemical', '-', (61, 66))	('miR-765', 'Gene', '768220', (147, 154))	('miR-15a', 'Gene', (78, 85))	('miR-139', 'Gene', '406931', (125, 132))
51312	31146085	Finally, using The Cancer Genome Atlas, Fishbein et al found that overexpression of miR-210 in primary PPGL tissue was associated with SDHB and VHL germline mutations and more aggressive disease.	('aggressive disease', 'Disease', (176, 194))	('Cancer', 'Disease', (19, 25))	('SDHB', 'Gene', '6390', (135, 139))	('germline mutations', 'Var', (148, 166))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Disease', 'MESH:D009369', (19, 25))	('miR-210', 'Gene', (84, 91))	('miR-210', 'Gene', '406992', (84, 91))	('SDHB', 'Gene', (135, 139))	('VHL', 'Gene', (144, 147))	('aggressive disease', 'Disease', 'MESH:D001523', (176, 194))	('overexpression', 'PosReg', (66, 80))	('VHL', 'Gene', '7428', (144, 147))	('associated', 'Reg', (119, 129))
51339	32125009	PPGL-induced TS was characterized by more global ballooning's pattern (22/104, 21.2% vs 3/49, 6.1%, P = 0.02), and lower left ventricular ejection fraction (25.54 +- 11.3 vs 31.82 +- 9.93, P = 0.0072) compared to exogenous catecholamine-induced TS.	('catecholamine', 'Chemical', 'MESH:D002395', (223, 236))	('left ventricular ejection fraction', 'MPA', (121, 155))	('PPGL-', 'Chemical', '-', (0, 5))	('lower left ventricular ejection', 'Phenotype', 'HP:0005162', (115, 146))	('PPGL-induced', 'Var', (0, 12))	('lower', 'NegReg', (115, 120))	('TS', 'Phenotype', 'HP:0011665', (245, 247))	('TS', 'Phenotype', 'HP:0011665', (13, 15))
51381	32125009	Death occurred in 3.7% (n = 4) of the patients with PPGL-, 4% (n = 2) with exogenous catecholamine-induced TS.	('TS', 'Phenotype', 'HP:0011665', (107, 109))	('Death', 'Disease', 'MESH:D003643', (0, 5))	('Death', 'Disease', (0, 5))	('PPGL-', 'Var', (52, 57))	('PPGL-', 'Chemical', '-', (52, 57))	('patients', 'Species', '9606', (38, 46))	('catecholamine', 'Chemical', 'MESH:D002395', (85, 98))
51390	32125009	Complication rates were higher in PPGL-induced TS, but this did not reach significant levels.	('Complication', 'CPA', (0, 12))	('higher', 'PosReg', (24, 30))	('PPGL-induced', 'Var', (34, 46))	('PPGL-', 'Chemical', '-', (34, 39))	('TS', 'Phenotype', 'HP:0011665', (47, 49))
51421	28405881	Simultaneous measurement of the 3-O-methylated metabolite of dopamine, methoxytyramine (MTY), has been advocated in particular for the diagnosis of P/PGL due to an underlying mutation of the succinate dehydrogenase B (SDHB) gene which is associated with an increased rate of metastatic disease.	('succinate dehydrogenase B', 'Gene', '6390', (191, 216))	('PGL', 'Phenotype', 'HP:0002668', (150, 153))	('methoxytyramine', 'Chemical', 'MESH:C001746', (71, 86))	('MTY', 'Chemical', 'MESH:C001746', (88, 91))	('SDHB', 'Gene', '6390', (218, 222))	('mutation', 'Var', (175, 183))	('SDHB', 'Gene', (218, 222))	('P/PGL', 'Disease', (148, 153))	('dopamine', 'Chemical', 'MESH:D004298', (61, 69))	('3-O', 'Chemical', '-', (32, 35))	('metastatic disease', 'Disease', (275, 293))	('associated', 'Reg', (238, 248))	('succinate dehydrogenase B', 'Gene', (191, 216))
51431	28405881	P/PGL occur with an extremely low annual incidence rate of less than 10 cases per million population, and the symptomatology of these tumors is protean and often nonspecific.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('P/PGL', 'Var', (0, 5))	('PGL', 'Phenotype', 'HP:0002668', (2, 5))
51444	28837712	While the vast majority of GISTs in adults are driven by mutations in the genes encoding the KIT or PDGFRA receptor tyrosine kinases, about 85% of GISTs in children and 10-15% of GISTs in adults lack those mutations (WT GISTs).	('driven by', 'Reg', (47, 56))	('lack', 'NegReg', (195, 199))	('KIT', 'Gene', (93, 96))	('WT GIST', 'Disease', (217, 224))	('WT GIST', 'Disease', 'MESH:D046152', (217, 224))	('children', 'Species', '9606', (156, 164))	('PDGFRA', 'Gene', '5156', (100, 106))	('GIST', 'Phenotype', 'HP:0100723', (179, 183))	('PDGFRA', 'Gene', (100, 106))	('GIST', 'Phenotype', 'HP:0100723', (27, 31))	('GISTs', 'Disease', (27, 32))	('GIST', 'Phenotype', 'HP:0100723', (220, 224))	('GIST', 'Phenotype', 'HP:0100723', (147, 151))	('mutations', 'Var', (57, 66))
51449	28837712	In one multicenter report, SDH germline mutations were detected in 12% (4/34) of patients with WT GISTs who had no personal or family history of paraganglioma.	('paraganglioma', 'Disease', (145, 158))	('detected', 'Reg', (55, 63))	('GIST', 'Phenotype', 'HP:0100723', (98, 102))	('paraganglioma', 'Disease', 'MESH:D010235', (145, 158))	('patients', 'Species', '9606', (81, 89))	('SDH', 'Gene', (27, 30))	('germline mutations', 'Var', (31, 49))	('paraganglioma', 'Phenotype', 'HP:0002668', (145, 158))	('WT GIST', 'Disease', 'MESH:D046152', (95, 102))	('SDH', 'Gene', '6390', (27, 30))	('WT GIST', 'Disease', (95, 102))
51451	28837712	The penetration of the clinical phenotype associated with SDH gene mutations is also unknown, since germline testing results for the first-degree relatives of patients with newly identified, SDH-mutated GISTs have not been reported.	('SDH', 'Gene', (58, 61))	('patients', 'Species', '9606', (159, 167))	('mutations', 'Var', (67, 76))	('SDH', 'Gene', '6390', (191, 194))	('GIST', 'Phenotype', 'HP:0100723', (203, 207))	('SDH', 'Gene', (191, 194))	('SDH', 'Gene', '6390', (58, 61))
51452	28837712	However, on the basis of available evidence, the National Comprehensive Cancer Network (NCCN) recommends testing gastric WT GISTs for SDHB expression by immunohistochemistry and for germline mutations in the SDH genes.	('SDH', 'Gene', (208, 211))	('SDH', 'Gene', (134, 137))	('WT GIST', 'Disease', 'MESH:D046152', (121, 128))	('SDH', 'Gene', '6390', (208, 211))	('germline mutations', 'Var', (182, 200))	('WT GIST', 'Disease', (121, 128))	('SDHB', 'Gene', '6390', (134, 138))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))	('SDHB', 'Gene', (134, 138))	('GIST', 'Phenotype', 'HP:0100723', (124, 128))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))	('SDH', 'Gene', '6390', (134, 137))
51454	28837712	Identifying a germline mutation could alert treating physicians to a presumed increased risk of GIST recurrence and paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (116, 129))	('paraganglioma', 'Disease', (116, 129))	('GIST recurrence', 'Disease', (96, 111))	('GIST', 'Phenotype', 'HP:0100723', (96, 100))	('paraganglioma', 'Disease', 'MESH:D010235', (116, 129))	('germline mutation', 'Var', (14, 31))
51461	26584481	A 22-year-old woman with type IIb VHL presented with signs and symptoms of acute decompensated heart failure.	('heart failure', 'Disease', (95, 108))	('VHL', 'Disease', 'MESH:D006623', (34, 37))	('VHL', 'Disease', (34, 37))	('heart failure', 'Phenotype', 'HP:0001635', (95, 108))	('woman', 'Species', '9606', (14, 19))	('heart failure', 'Disease', 'MESH:D006333', (95, 108))	('type IIb', 'Var', (25, 33))
51464	26584481	Genetic analysis revealed a germline mutation (exon 3 deletion of VHL).	('VHL', 'Disease', (66, 69))	('revealed', 'Reg', (17, 25))	('exon 3 deletion', 'Var', (47, 62))	('VHL', 'Disease', 'MESH:D006623', (66, 69))
51473	26584481	We present the case of a 22-year-old woman who was diagnosed in childhood with type IIb VHL, with known multiple retinal angiomas, pancreatic cysts, and spinal and cerebellar hemangioblastomas.	('pancreatic cysts', 'Disease', 'MESH:D010181', (131, 147))	('cerebellar hemangioblastomas', 'Disease', (164, 192))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (131, 147))	('woman', 'Species', '9606', (37, 42))	('retinal angiomas', 'Disease', 'MESH:D012173', (113, 129))	('cerebellar hemangioblastomas', 'Disease', 'MESH:D018325', (164, 192))	('cerebellar hemangioblastomas', 'Phenotype', 'HP:0006880', (164, 192))	('retinal angiomas', 'Disease', (113, 129))	('type IIb', 'Var', (79, 87))	('pancreatic cysts', 'Disease', (131, 147))	('spinal', 'Disease', (153, 159))	('VHL', 'Disease', (88, 91))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
51485	26584481	Genetic analysis revealed a germline mutation (exon 3 deletion) of the VHL tumor suppressor gene on the short arm of chromosome 3.	('VHL tumor', 'Disease', (71, 80))	('revealed', 'Reg', (17, 25))	('VHL tumor', 'Disease', 'MESH:D006623', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('exon', 'Var', (47, 51))	('short arm', 'Phenotype', 'HP:0009824', (104, 113))
51593	27746437	reported that a 50-g glucose-tolerance test showed the pattern of diabetes mellitus and the level of measured somatostatin in their case of somatostatin-secreting pheochromocytoma, other such cases predominantly reported immunostaining of somatostatin and not about diabetes.	('pheochromocytoma', 'Disease', 'MESH:D010673', (163, 179))	('diabetes mellitus', 'Disease', (66, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (163, 179))	('diabetes', 'Disease', (66, 74))	('diabetes mellitus', 'Disease', 'MESH:D003920', (66, 83))	('diabetes', 'Disease', (266, 274))	('diabetes', 'Disease', 'MESH:D003920', (66, 74))	('diabetes', 'Disease', 'MESH:D003920', (266, 274))	('pheochromocytoma', 'Disease', (163, 179))	('glucose', 'Chemical', 'MESH:D005947', (21, 28))	('immunostaining', 'Var', (221, 235))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (66, 83))
51601	27746437	The reasons are as follows: 1) at least one-third of all patients with PPGLs have disease-causing germline mutations; 2) mutations of succinate dehydrogenase complex subunit B (SDHB) lead to metastatic disease in 40% or more of affected patients; and 3) establishing a hereditary syndrome in the proband may result in an earlier diagnosis and treatment of PPGLs and other syndromic manifestations among relatives.	('mutations', 'Var', (121, 130))	('succinate dehydrogenase complex subunit B', 'Gene', '6390', (134, 175))	('hereditary syndrome', 'Disease', (269, 288))	('metastatic', 'Disease', (191, 201))	('patients', 'Species', '9606', (57, 65))	('SDHB', 'Gene', '6390', (177, 181))	('SDHB', 'Gene', (177, 181))	('disease-causing', 'Reg', (82, 97))	('hereditary syndrome', 'Disease', 'MESH:D009386', (269, 288))	('PPGLs', 'Disease', (356, 361))	('lead to', 'Reg', (183, 190))	('succinate dehydrogenase complex subunit B', 'Gene', (134, 175))	('patients', 'Species', '9606', (237, 245))
51631	26413481	The remaining rare categories of aldosterone producers (1%) are adrenocortical carcinoma, or ectopic production of aldosterone such as ovarian or renal source.	('aldosterone', 'Chemical', 'MESH:D000450', (115, 126))	('aldosterone', 'Chemical', 'MESH:D000450', (33, 44))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (64, 88))	('adrenocortical carcinoma', 'Disease', (64, 88))	('renal source', 'Disease', (146, 158))	('ovarian', 'Disease', (135, 142))	('ovarian', 'Disease', 'MESH:D010051', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('ectopic', 'Var', (93, 100))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (64, 88))
51737	26413481	Further, surgery for APA has been shown to normalize hypokalemia and improve if not normalize blood pressure.	('hypokalemia', 'Disease', 'MESH:D007008', (53, 64))	('APA', 'Gene', (21, 24))	('hypokalemia', 'Phenotype', 'HP:0002900', (53, 64))	('surgery', 'Var', (9, 16))	('improve', 'PosReg', (69, 76))	('blood pressure', 'MPA', (94, 108))	('hypokalemia', 'Disease', (53, 64))
51759	26413481	Type III familial hyperaldosteronism involves a germline mutation in the gene coding for ion channel KCNJ5.	('KCNJ5', 'Gene', (101, 106))	('hyperaldosteronism', 'Phenotype', 'HP:0000859', (18, 36))	('involves', 'Reg', (37, 45))	('Type III familial hyperaldosteronism', 'Disease', (0, 36))	('Type III familial hyperaldosteronism', 'Disease', 'MESH:D003480', (0, 36))	('KCNJ5', 'Gene', '3762', (101, 106))	('germline mutation', 'Var', (48, 65))
51822	26413481	Selective, competitive, short-acting alpha-blockers like doxazosin (Cardura), prazosin (Minipress) and terazosin (Hytrin) are preferred in some institutions as they are associated with less reflex tachycardia and a lower incidence of postoperative hypotension as compared to phenoxybenzamine.	('hypotension', 'Disease', (248, 259))	('prazosin', 'Chemical', 'MESH:D011224', (78, 86))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (275, 291))	('terazosin', 'Var', (103, 112))	('Cardura', 'Chemical', 'MESH:D017292', (68, 75))	('hypotension', 'Phenotype', 'HP:0002615', (248, 259))	('tachycardia', 'Disease', 'MESH:D013610', (197, 208))	('less', 'NegReg', (185, 189))	('tachycardia', 'Phenotype', 'HP:0001649', (197, 208))	('hypotension', 'Disease', 'MESH:D007022', (248, 259))	('Hytrin', 'Chemical', 'MESH:C041226', (114, 120))	('tachycardia', 'Disease', (197, 208))	('terazosin', 'Chemical', 'MESH:C041226', (103, 112))	('doxazosin', 'Chemical', 'MESH:D017292', (57, 66))
51823	26413481	In a study, comparing the use of these different classes of alpha blockers in the preoperative management of laparoscopic resection of pheochromocytoma, phenoxybenzamine use was associated with better decrease in intra-operative hypertension at the expense of prolonged post-operative hypotension requiring the use of vasopressors.	('hypertension', 'Disease', (229, 241))	('hypotension', 'Disease', (285, 296))	('hypertension', 'Disease', 'MESH:D006973', (229, 241))	('hypertension', 'Phenotype', 'HP:0000822', (229, 241))	('pheochromocytoma', 'Disease', (135, 151))	('phenoxybenzamine', 'Var', (153, 169))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('men', 'Species', '9606', (101, 104))	('hypotension', 'Phenotype', 'HP:0002615', (285, 296))	('-operative hypotension', 'Phenotype', 'HP:0001278', (274, 296))	('hypotension', 'Disease', 'MESH:D007022', (285, 296))	('decrease', 'NegReg', (201, 209))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (153, 169))
51836	26413481	Metyrosine helps to control blood pressure during induction of anesthesia and surgical manipulation of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('control blood pressure', 'MPA', (20, 42))	('Metyrosine', 'Chemical', 'MESH:D019805', (0, 10))	('Metyrosine', 'Var', (0, 10))
51935	24274233	Preperitoneal carbondioxide inflation caused the blood pressure to increase by another 30% systolically and diastolically and manipulation of the paraganglioma resulted in a systolic and diastolic blood pressure above 230 and 100 mmHg, respectively.	('carbondioxide', 'Chemical', 'MESH:D002245', (14, 27))	('paraganglioma', 'Disease', 'MESH:D010235', (146, 159))	('man', 'Species', '9606', (126, 129))	('increase', 'PosReg', (67, 75))	('manipulation', 'Var', (126, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (146, 159))	('blood pressure', 'MPA', (49, 63))	('paraganglioma', 'Disease', (146, 159))
51967	24149047	The VHL gene is epigenetically inactivated in pheochromocytomas and abdominal paragangliomas Pheochromocytoma (PCC) and abdominal paraganglioma (PGL) are neuroendocrine tumors that present with clinical symptoms related to increased catecholamine levels.	('abdominal paragangliomas', 'Disease', 'MESH:D010235', (68, 92))	('Pheochromocytoma', 'Disease', (93, 109))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (46, 62))	('pheochromocytomas', 'Disease', (46, 63))	('abdominal paragangliomas', 'Disease', (68, 92))	('pheochromocytomas', 'Disease', 'MESH:D010673', (46, 63))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (154, 174))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))	('epigenetically', 'Var', (16, 30))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (154, 175))	('VHL', 'Gene', (4, 7))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (68, 91))	('catecholamine', 'Chemical', 'MESH:D002395', (233, 246))	('paragangliomas', 'Phenotype', 'HP:0002668', (78, 92))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (154, 175))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (46, 63))	('PCC', 'Phenotype', 'HP:0002666', (111, 114))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (120, 143))	('PGL', 'Phenotype', 'HP:0002668', (145, 148))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('VHL', 'Gene', '7428', (4, 7))	('catecholamine levels', 'MPA', (233, 253))	('increased', 'PosReg', (223, 232))	('paraganglioma', 'Phenotype', 'HP:0002668', (130, 143))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('neuroendocrine tumors', 'Disease', (154, 175))	('increased catecholamine levels', 'Phenotype', 'HP:0003334', (223, 253))	('abdominal paraganglioma', 'Disease', (120, 143))
51970	24149047	Aberrant RET promoter methylation was observed in two cases only.	('RET', 'Gene', '5979', (9, 12))	('methylation', 'MPA', (22, 33))	('Aberrant', 'Var', (0, 8))	('RET', 'Gene', (9, 12))
51980	24149047	Approximately one third of PCC and PGL patients carry a constitutional mutation in a predisposing gene including EGLN1 (PDH2), EPAS1 (HIF2A), KIF1Bbeta, MAX, NF1, RET, SDHA, SDHAF2 (SDH5), SDHB, SDHC, SDHD, TMEM127, and VHL.	('patients', 'Species', '9606', (39, 47))	('RET,', 'Gene', '5979', (163, 167))	('NF1', 'Gene', (158, 161))	('SDHA', 'Chemical', '-', (168, 172))	('SDHC', 'Gene', (195, 199))	('SDHA', 'Gene', (168, 172))	('SDH5', 'Gene', (182, 186))	('VHL.', 'Gene', '7428', (220, 224))	('VHL.', 'Gene', (220, 224))	('PCC', 'Phenotype', 'HP:0002666', (27, 30))	('EGLN1 (PDH2', 'Gene', (113, 124))	('SDHAF2', 'Gene', (174, 180))	('SDHA', 'Chemical', '-', (174, 178))	(', SDHB,', 'Gene', '6390', (187, 194))	('PGL', 'Phenotype', 'HP:0002668', (35, 38))	('SDH5', 'Gene', '54949', (182, 186))	('mutation', 'Var', (71, 79))	('EPAS1', 'Gene', (127, 132))	('SDHD, TMEM', 'Gene', '6392', (201, 211))	('NF1', 'Gene', '4763', (158, 161))	('SDHAF2', 'Chemical', '-', (174, 180))	('PCC', 'Disease', (27, 30))	('PDH2', 'Gene', (120, 124))
51982	24149047	Studies of DNA methylation have revealed CpG hypermethylator phenotypes in PGLs carrying a SDHB, or SDHx mutation as was also demonstrated in a mouse model.	('mutation', 'Var', (105, 113))	('mouse', 'Species', '10090', (144, 149))	('rat', 'Species', '10116', (133, 136))	('SDHx', 'Gene', (100, 104))	('SDHB', 'Gene', (91, 95))	('SDHx', 'Chemical', '-', (100, 104))	('hypermethylator phenotypes', 'MPA', (45, 71))	('PGL', 'Phenotype', 'HP:0002668', (75, 78))
51998	24149047	No significant correlations were found between MetI values and gender (P = 0.5), age at surgery (P = 0.65), tumor weight or size (P = 0.4), epinephrine levels (P = 0.14), norepinephrine levels (P = 0.53), dopamine levels (P = 0.7), constitutional SDHB mutations (P = 0.1) or clinical MEN 2A syndrome (P = 0.31).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MEN', 'Species', '9606', (284, 287))	('epinephrine levels', 'MPA', (140, 158))	('epinephrine', 'Chemical', 'MESH:D004837', (140, 151))	('epinephrine', 'Chemical', 'MESH:D004837', (174, 185))	('norepinephrine', 'Chemical', 'MESH:D009638', (171, 185))	('SDHB', 'Gene', '6390', (247, 251))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MetI', 'Chemical', '-', (47, 51))	('tumor', 'Disease', (108, 113))	('mutations', 'Var', (252, 261))	('norepinephrine levels', 'MPA', (171, 192))	('SDHB', 'Gene', (247, 251))	('dopamine', 'Chemical', 'MESH:D004298', (205, 213))	('dopamine levels', 'MPA', (205, 220))
52005	24149047	No significant correlations were found between VHL gene expression and gender (P = 0.8 for assay 1, P = 0.5 for assay 2), age at surgery (P = 0.58 for assay 1, P = 0.73 for assay 2), epinephrine levels (P = 0.5 for both assay 1 and 2), dopamine levels (P = 0.9 for assay 1, P = 0.3 for assay 2), constitutional SDHB mutations (P = 0.1), or clinical MEN 2A syndrome (P = 0.8 for assay 1, P = 0.6 for assay 2).	('MEN', 'Species', '9606', (349, 352))	('mutations', 'Var', (316, 325))	('SDHB', 'Gene', '6390', (311, 315))	('VHL', 'Gene', (47, 50))	('SDHB', 'Gene', (311, 315))	('epinephrine levels', 'MPA', (183, 201))	('clinical MEN 2A syndrome', 'Disease', (340, 364))	('dopamine', 'Chemical', 'MESH:D004298', (236, 244))	('dopamine levels', 'MPA', (236, 251))	('epinephrine', 'Chemical', 'MESH:D004837', (183, 194))
52011	24149047	Given that gene silencing by promoter CpG methylation is an important epigenetic mechanism in tumorigenesis, our results indicate that VHL promoter hypermethylation could play a role in the development of PCC and PGL.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('VHL', 'Gene', (135, 138))	('promoter hypermethylation', 'Var', (139, 164))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PCC', 'Phenotype', 'HP:0002666', (205, 208))	('PGL', 'Phenotype', 'HP:0002668', (213, 216))	('PCC', 'Disease', (205, 208))	('hypermethylation', 'Var', (148, 164))	('PGL', 'Disease', (213, 216))	('tumor', 'Disease', (94, 99))	('play', 'Reg', (171, 175))	('role', 'Reg', (178, 182))
52021	24149047	A CpG hypermethylator phenotype has been described for the PGL and SDHB as well as SDHx mutated entity.	('PGL', 'Gene', (59, 62))	('SDHB', 'Gene', '6390', (67, 71))	('SDHB', 'Gene', (67, 71))	('mutated', 'Var', (88, 95))	('PGL', 'Phenotype', 'HP:0002668', (59, 62))	('SDHx', 'Chemical', '-', (83, 87))
52023	24149047	Neither VHL promoter methylation nor VHL gene expression correlated with SDHB mutations and accompanying CpG island methylator phenotype (CIMP).	('CIMP', 'Chemical', '-', (138, 142))	('VHL', 'Gene', (37, 40))	('mutations', 'Var', (78, 87))	('SDHB', 'Gene', '6390', (73, 77))	('SDHB', 'Gene', (73, 77))
52025	24149047	In summary, our results show that the VHL gene promoter is hypermethylated in pheochromocytomas and paragangliomas, accompanied by stunted gene expression, a finding that highlights the importance of VHL inactivation in the etiology of these tumors.	('gene expression', 'MPA', (139, 154))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('paragangliomas', 'Disease', (100, 114))	('paragangliomas', 'Disease', 'MESH:D010235', (100, 114))	('paragangliomas', 'Phenotype', 'HP:0002668', (100, 114))	('VHL gene', 'Gene', (38, 46))	('paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('hypermethylated', 'Var', (59, 74))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('pheochromocytomas', 'Disease', (78, 95))	('tumors', 'Disease', (242, 248))	('pheochromocytomas', 'Disease', 'MESH:D010673', (78, 95))
52032	24149047	In addition, occurrence of constitutional SDHB mutations and clinical VHL, MEN 2A, and NF1 syndrome is given in Table S1.	('MEN', 'Species', '9606', (75, 78))	('NF1 syndrome', 'Disease', 'MESH:C537392', (87, 99))	('mutations', 'Var', (47, 56))	('NF1 syndrome', 'Disease', (87, 99))	('SDHB', 'Gene', '6390', (42, 46))	('SDHB', 'Gene', (42, 46))
52044	24149047	In short, pre-made master mix:including DNA polymerase from QIAGEN:was used to amplify 1 microl of bisulphite-treated DNA in a PCR reaction, using the following conditions: 95  C for 15 min, followed by 45 cycles of: (95  C 30 s, 56  C [all assays except SDHB, SDHC, and SDHD; 53  C] 30 s, 72  C 30 s), and 72  C for 10 min.	('SDHD', 'Gene', '6392', (271, 275))	('SDHD', 'Gene', (271, 275))	('bisulphite', 'Chemical', 'MESH:C042345', (99, 109))	('95  C 30 s', 'Var', (218, 228))
52092	23958171	However, since we were already confronted with two tumorous lesions, we sought an imaging modality with higher resolution and, taking a similar, recently published case report into account, decided to perform a whole-body somatostatine-receptor Positron-Emission-Tomography (PET) scan with [68Ga-DOTA]-TATE.	('tumorous lesions', 'Disease', (51, 67))	('tumorous lesions', 'Disease', 'MESH:D051437', (51, 67))	('[68Ga-DOTA]-TATE', 'Var', (290, 306))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))
52108	23958171	The ectopic ACTH-source was eventually localised by [68Ga-DOTA]-TATE-PET and was surgically removed, which led to complete remission of the hypercortisolaemic syndrome.	('ACTH', 'Chemical', '-', (12, 16))	('hypercortisolaemic syndrome', 'Disease', 'MESH:D013577', (140, 167))	('hypercortisolaemic syndrome', 'Disease', (140, 167))	('[68Ga-DOTA]-TATE-PET', 'Var', (52, 72))
52124	23224622	Important in maintaining physiological homeostasis, EPI also contributes to the etiology of numerous stress-related pathologies, including cardiovascular and neuropsychiatric disorders, immune dysfunction and even cancer.	('contributes', 'Reg', (61, 72))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('immune dysfunction', 'Disease', (186, 204))	('EPI', 'Var', (52, 55))	('EPI', 'Chemical', 'MESH:D004837', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('neuropsychiatric disorders', 'Disease', (158, 184))	('immune dysfunction', 'Disease', 'MESH:D007154', (186, 204))	('neuropsychiatric disorders', 'Disease', 'MESH:D001523', (158, 184))
52135	23224622	Ionization source (ESI) parameters were further optimized by automatic flow injection analyses provided by the Analyst software package (Vers 1.51, AB Sciex) with curtain gas (30 psi), ESI voltage (5500V), temperature (600 C), gas 1 (70 psi) and gas 2 (60 psi).	('5500V', 'Var', (198, 203))	('gas 1', 'Gene', (227, 232))	('gas 2', 'Gene', (246, 251))	('gas 1', 'Gene', '2619', (227, 232))	('Ionization', 'Disease', 'MESH:D004194', (0, 10))	('gas 2', 'Gene', '2620', (246, 251))	('Ionization', 'Disease', (0, 10))
52188	23282968	IMMUNOHISTOCHEMICAL LOSS OF SUCCINATE DEHYDROGENASE SUBUNIT A (SDHA) IN GASTROINTESTINAL STROMAL TUMORS (GISTS) SIGNALS SDHA GERMLINE MUTATION A subset (7-10%) of gastric GISTs is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH-complex consisting of mitochondrial inner membrane proteins.	('SDHB', 'Gene', (265, 269))	('GASTROINTESTINAL STROMAL TUMORS', 'Phenotype', 'HP:0100723', (72, 103))	('SUCCINATE DEHYDROGENASE', 'Gene', (28, 51))	('SDH', 'Gene', (265, 268))	('SDH', 'Gene', (314, 317))	('succinate dehydrogenase', 'Gene', '6389', (224, 247))	('SDH', 'Gene', (249, 252))	('SDH', 'Gene', '6390', (120, 123))	('SDHA', 'Gene', (120, 124))	('SDH', 'Gene', '6390', (63, 66))	('SDHA', 'Gene', (63, 67))	('succinate dehydrogenase', 'Gene', (224, 247))	('loss', 'NegReg', (216, 220))	('SDHA', 'Gene', '6389', (120, 124))	('SDHA', 'Gene', '6389', (63, 67))	('SUCCINATE DEHYDROGENASE', 'Gene', '6389', (28, 51))	('TUMORS', 'Phenotype', 'HP:0002664', (97, 103))	('SDH', 'Gene', (120, 123))	('SDH', 'Gene', (63, 66))	('MUTATION', 'Var', (134, 142))	('SDHB', 'Gene', '6390', (265, 269))	('SDH', 'Gene', '6390', (265, 268))	('SDH', 'Gene', '6390', (314, 317))	('gastric', 'Disease', (163, 170))	('SDH', 'Gene', '6390', (249, 252))
52190	23282968	Some of these patients have germline mutations of SDH-subunits B, C, or D, known as Carney-Stratakis syndrome when combined with paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (84, 109))	('paraganglioma', 'Disease', (129, 142))	('SDH', 'Gene', '6390', (50, 53))	('paraganglioma', 'Disease', 'MESH:D010235', (129, 142))	('Carney-Stratakis syndrome', 'Disease', (84, 109))	('germline mutations', 'Var', (28, 46))	('patients', 'Species', '9606', (14, 22))	('SDH', 'Gene', (50, 53))
52191	23282968	More recently, germline mutations in SDH-subunit A (SDHA) have been also reported in few patients with KIT/PDGFRA wild type GISTs.	('SDH', 'Gene', (37, 40))	('PDGFRA', 'Gene', (107, 113))	('SDH', 'Gene', '6390', (52, 55))	('SDHA', 'Gene', (52, 56))	('reported', 'Reg', (73, 81))	('PDGFRA', 'Gene', '5156', (107, 113))	('SDH', 'Gene', '6390', (37, 40))	('SDH', 'Gene', (52, 55))	('patients', 'Species', '9606', (89, 97))	('SDHA', 'Gene', '6389', (52, 56))	('germline mutations', 'Var', (15, 33))
52193	23282968	Cases with available DNA were tested for SDHA, B, C, and D gene mutations using a hybridization-based custom capture next-generation sequencing assay.	('SDHA, B', 'Gene', '6389', (41, 48))	('D gene', 'Gene', (57, 63))	('mutations', 'Var', (64, 73))
52196	23282968	Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('SDHA', 'Gene', '6389', (8, 12))	('SDHA', 'Gene', (8, 12))	('SDHA', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutants', 'Var', (57, 64))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))	('SDHA', 'Gene', '6389', (52, 56))
52199	23282968	Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (one germline), and 11 SDHB, SDHC or SDHD mutations (mostly germline), and 11 patients with no SDH mutations.	('SDHA', 'Gene', '6389', (74, 78))	('SDH', 'Gene', (28, 31))	('SDHB', 'Gene', (112, 116))	('SDH', 'Gene', '6390', (184, 187))	('SDHC', 'Gene', (118, 122))	('SDH', 'Gene', '6390', (112, 115))	('mutations', 'Var', (79, 88))	('SDH', 'Gene', (74, 77))	('SDH', 'Gene', '6390', (118, 121))	('SDHD', 'Gene', '6392', (126, 130))	('SDH', 'Gene', '6390', (13, 16))	('SDHB', 'Gene', '6390', (28, 32))	('SDH', 'Gene', (184, 187))	('SDHA', 'Gene', (13, 17))	('SDH', 'Gene', '6390', (126, 129))	('SDH', 'Gene', (112, 115))	('SDHA', 'Gene', '6389', (13, 17))	('SDHD', 'Gene', (126, 130))	('SDH', 'Gene', (118, 121))	('SDHB', 'Gene', (28, 32))	('SDHC', 'Gene', '6391', (118, 122))	('SDH', 'Gene', '6390', (28, 31))	('SDH', 'Gene', (13, 16))	('SDH', 'Gene', (126, 129))	('patients', 'Species', '9606', (167, 175))	('SDHB', 'Gene', '6390', (112, 116))	('SDH', 'Gene', '6390', (74, 77))	('SDHA', 'Gene', (74, 78))
52201	23282968	SDHA-negative GISTs comprise approximately 30% of SDHB-negative/SDH-deficient GISTs, and SDHA loss generally correlates with SDHA mutations.	('SDHA', 'Gene', '6389', (125, 129))	('SDH-deficient', 'Disease', 'MESH:D007153', (64, 77))	('SDHA', 'Gene', (0, 4))	('SDHA', 'Gene', (89, 93))	('SDHB', 'Gene', (50, 54))	('loss', 'NegReg', (94, 98))	('SDHA', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))	('SDHA', 'Gene', '6389', (0, 4))	('SDH-deficient', 'Disease', (64, 77))	('SDHA', 'Gene', '6389', (89, 93))	('SDHB', 'Gene', '6390', (50, 54))
52208	23282968	A minority of patients with SDH-deficient GISTs have found to harbor germline mutations of SDHB, SDHC, or SDHD, known as the Carney-Stratakis syndrome when combined with paraganglioma.	('paraganglioma', 'Disease', 'MESH:D010235', (170, 183))	('SDH-deficient', 'Disease', (28, 41))	('Carney-Stratakis syndrome', 'Disease', (125, 150))	('SDHB', 'Gene', '6390', (91, 95))	('SDHD', 'Gene', '6392', (106, 110))	('SDHC', 'Gene', (97, 101))	('mutations', 'Var', (78, 87))	('SDH-deficient', 'Disease', 'MESH:D007153', (28, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (170, 183))	('SDHD', 'Gene', (106, 110))	('SDHB', 'Gene', (91, 95))	('paraganglioma', 'Disease', (170, 183))	('patients', 'Species', '9606', (14, 22))	('SDHC', 'Gene', '6391', (97, 101))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (125, 150))
52210	23282968	Recently, a small number of GISTs have been found associated with germline loss-of-function mutations of SDHA gene encoding the key catalytic component of the SDH-complex.	('SDH', 'Gene', (105, 108))	('loss-of-function', 'NegReg', (75, 91))	('SDH', 'Gene', '6390', (159, 162))	('SDHA', 'Gene', '6389', (105, 109))	('mutations', 'Var', (92, 101))	('SDH', 'Gene', (159, 162))	('SDH', 'Gene', '6390', (105, 108))	('SDHA', 'Gene', (105, 109))
52211	23282968	Such mutations have been previously detected in an abdominal catecholamine secreting paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (85, 98))	('paraganglioma', 'Disease', (85, 98))	('detected', 'Reg', (36, 44))	('mutations', 'Var', (5, 14))	('paraganglioma', 'Disease', 'MESH:D010235', (85, 98))	('catecholamine', 'Chemical', 'MESH:D002395', (61, 74))
52213	23282968	A significant portion of paraganglioma patients has mutations in the other SDH subunits, SDHB, SDHC, and SDHD.	('SDHC', 'Gene', (95, 99))	('patients', 'Species', '9606', (39, 47))	('SDHD', 'Gene', (105, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (25, 38))	('SDH', 'Gene', '6390', (95, 98))	('SDHB', 'Gene', (89, 93))	('SDH', 'Gene', (105, 108))	('SDH', 'Gene', (89, 92))	('SDH', 'Gene', (95, 98))	('SDHC', 'Gene', '6391', (95, 99))	('SDH', 'Gene', '6390', (75, 78))	('paraganglioma', 'Disease', (25, 38))	('mutations', 'Var', (52, 61))	('SDHD', 'Gene', '6392', (105, 109))	('paraganglioma', 'Disease', 'MESH:D010235', (25, 38))	('SDH', 'Gene', '6390', (105, 108))	('SDHB', 'Gene', '6390', (89, 93))	('SDH', 'Gene', '6390', (89, 92))	('SDH', 'Gene', (75, 78))
52214	23282968	In this study, we report 36 SDHA-negative gastric GISTs among 127 SDHB-negative/SDH-deficient GISTs and examine SDHA and other SDH-subunit mutations, and pathology and prognosis of these tumors.	('SDHB', 'Gene', (66, 70))	('SDH', 'Gene', (66, 69))	('SDH', 'Gene', (28, 31))	('SDH', 'Gene', '6390', (112, 115))	('SDHA', 'Gene', (112, 116))	('SDH', 'Gene', '6390', (127, 130))	('SDHA', 'Gene', '6389', (112, 116))	('SDH', 'Gene', '6390', (80, 83))	('SDH-deficient', 'Disease', (80, 93))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('SDH-deficient', 'Disease', 'MESH:D007153', (80, 93))	('SDH', 'Gene', (112, 115))	('SDH', 'Gene', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', (187, 193))	('SDHB', 'Gene', '6390', (66, 70))	('SDH', 'Gene', (80, 83))	('SDH', 'Gene', '6390', (66, 69))	('gastric GISTs', 'Disease', (42, 55))	('SDH', 'Gene', '6390', (28, 31))	('mutations', 'Var', (139, 148))	('SDHA', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('SDHA', 'Gene', '6389', (28, 32))
52224	23282968	SDH-subunit genes SDHA, SDHB, SDHC, and SDHD were evaluated for mutations using a hybridization-based custom capture reagent (Agilent, Inc., Santa Clara, CA) followed by sequencing on the GAIIx instrument (Illumina, Inc., San Diego, CA) according to manufacturer's protocols.	('SDHD', 'Gene', '6392', (40, 44))	('SDH', 'Gene', '6390', (18, 21))	('SDHA', 'Gene', (18, 22))	('SDH', 'Gene', '6390', (40, 43))	('SDHB', 'Gene', (24, 28))	('SDHA', 'Gene', '6389', (18, 22))	('SDH', 'Gene', '6390', (0, 3))	('SDHC', 'Gene', (30, 34))	('SDH', 'Gene', '6390', (24, 27))	('SDHD', 'Gene', (40, 44))	('men', 'Species', '9606', (200, 203))	('SDH', 'Gene', (18, 21))	('mutations', 'Var', (64, 73))	('SDH', 'Gene', '6390', (30, 33))	('SDH', 'Gene', (40, 43))	('SDH', 'Gene', (0, 3))	('SDH', 'Gene', (24, 27))	('SDH', 'Gene', (30, 33))	('SDHC', 'Gene', '6391', (30, 34))	('SDHB', 'Gene', '6390', (24, 28))
52226	23282968	The reference sequence for SDHA was NM_004168; SDHB: NM_003000; SDHC: NM_003001; and SDHD: NM_003002.	('SDHC', 'Gene', '6391', (64, 68))	('SDHA', 'Gene', (27, 31))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('SDHD', 'Gene', '6392', (85, 89))	('NM_003000', 'Var', (53, 62))	('SDHD', 'Gene', (85, 89))	('SDHA', 'Gene', '6389', (27, 31))	('NM_003001', 'Var', (70, 79))	('NM_004168', 'Var', (36, 45))	('SDHC', 'Gene', (64, 68))
52227	23282968	A subset of SDHA mutations was further validated by TaqMan assay (Invitrogen/Life Technologies, Carlsbad, CA).	('SDHA', 'Gene', '6389', (12, 16))	('mutations', 'Var', (17, 26))	('SDHA', 'Gene', (12, 16))
52232	23282968	SDHA mutations were detected in all 7 SDHA-negative tumors with available sequencing data, and 6 of them were germline mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SDHA', 'Gene', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SDHA', 'Gene', (0, 4))	('tumors', 'Disease', (52, 58))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SDHA', 'Gene', '6389', (0, 4))	('SDHA', 'Gene', '6389', (38, 42))
52264	23282968	There was a strong correlation between immunohistochemically observed loss of SDHA and SDHA mutations, which were detected in all 7 patients analyzed, while only present in 3 of 25 patients with SDHA-positive, SDHB-negative GISTs.	('SDHA', 'Gene', (195, 199))	('loss', 'NegReg', (70, 74))	('SDHA', 'Gene', (87, 91))	('SDHA', 'Gene', '6389', (78, 82))	('mutations', 'Var', (92, 101))	('patients', 'Species', '9606', (181, 189))	('SDHA', 'Gene', '6389', (195, 199))	('SDHB', 'Gene', '6390', (210, 214))	('SDHB', 'Gene', (210, 214))	('SDHA', 'Gene', (78, 82))	('SDHA', 'Gene', '6389', (87, 91))	('patients', 'Species', '9606', (132, 140))
52265	23282968	On the other hand, none of these patients with SDHA-negative GISTs had SDHB, SDHC, or SDHD mutations.	('SDHA', 'Gene', (47, 51))	('SDHC', 'Gene', (77, 81))	('SDHD', 'Gene', (86, 90))	('SDHC', 'Gene', '6391', (77, 81))	('patients', 'Species', '9606', (33, 41))	('SDHB', 'Gene', '6390', (71, 75))	('SDHA', 'Gene', '6389', (47, 51))	('SDHB', 'Gene', (71, 75))	('mutations', 'Var', (91, 100))	('SDHD', 'Gene', '6392', (86, 90))
52266	23282968	Therefore, SDHA mutations (mostly verified as germline here) are the apparent cause for SDHA loss and destabilization of the SDH-complex, especially because bi-allelic changes with losses or somatic mutations in SDHA-locus were common and detected in most cases in this study.	('SDH', 'Gene', (88, 91))	('SDHA', 'Gene', (212, 216))	('SDHA', 'Gene', '6389', (11, 15))	('loss', 'NegReg', (93, 97))	('SDH', 'Gene', (11, 14))	('SDH', 'Gene', (212, 215))	('SDH', 'Gene', '6390', (125, 128))	('SDHA', 'Gene', '6389', (88, 92))	('mutations', 'Var', (16, 25))	('SDHA', 'Gene', (11, 15))	('SDH', 'Gene', '6390', (88, 91))	('SDHA', 'Gene', '6389', (212, 216))	('SDHA', 'Gene', (88, 92))	('losses', 'NegReg', (181, 187))	('SDH', 'Gene', (125, 128))	('SDH', 'Gene', '6390', (11, 14))	('SDH', 'Gene', '6390', (212, 215))
52267	23282968	A previous study also showed SDHA germline mutations coupled with somatic SDHA mutations in the tumor in some cases.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SDHA', 'Gene', '6389', (29, 33))	('SDHA', 'Gene', '6389', (74, 78))	('tumor', 'Disease', (96, 101))	('germline mutations', 'Var', (34, 52))	('SDHA', 'Gene', (29, 33))	('SDHA', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mutations', 'Var', (79, 88))
52268	23282968	Therefore, these SDHA alterations seem to follow a classic two hit hypothesis of tumor suppressor genes, as has been previously found for other SDH-subunit gene mutations in paragangliomas.	('SDHA', 'Gene', (17, 21))	('SDH', 'Gene', '6390', (144, 147))	('paraganglioma', 'Phenotype', 'HP:0002668', (174, 187))	('paragangliomas', 'Phenotype', 'HP:0002668', (174, 188))	('SDH', 'Gene', (17, 20))	('SDH', 'Gene', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('alterations', 'Var', (22, 33))	('mutations', 'Var', (161, 170))	('SDHA', 'Gene', '6389', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SDH', 'Gene', '6390', (17, 20))	('paragangliomas', 'Disease', 'MESH:D010235', (174, 188))	('tumor', 'Disease', (81, 86))	('paragangliomas', 'Disease', (174, 188))
52269	23282968	Both truncating and missense SDHA germline mutations were associated with the loss of protein expression.	('missense', 'Var', (20, 28))	('SDHA', 'Gene', '6389', (29, 33))	('protein expression', 'MPA', (86, 104))	('loss', 'NegReg', (78, 82))	('SDHA', 'Gene', (29, 33))
52270	23282968	This is not surprising in view of most SDH-subunit loss-of-function mutations in SDHB-negative paragangliomas also being missense mutations.	('paragangliomas', 'Disease', (95, 109))	('SDH', 'Gene', (39, 42))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('SDH', 'Gene', '6390', (39, 42))	('missense', 'Var', (121, 129))	('SDHB', 'Gene', '6390', (81, 85))	('loss-of-function', 'NegReg', (51, 67))	('SDH', 'Gene', '6390', (81, 84))	('paragangliomas', 'Disease', 'MESH:D010235', (95, 109))	('SDHB', 'Gene', (81, 85))	('mutations', 'Var', (68, 77))	('SDH', 'Gene', (81, 84))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))
52271	23282968	Loss of function has also been resulting from missense mutations in other tumor suppressor proteins, such as merlin, the NF2 gene product in schwannoma, and TSC1 in transitional cell carcinoma.	('missense mutations', 'Var', (46, 64))	('merlin', 'Gene', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('carcinoma', 'Disease', 'MESH:D002277', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('TSC1', 'Gene', '7248', (157, 161))	('NF2', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('carcinoma', 'Disease', (183, 192))	('schwannoma', 'Disease', (141, 151))	('TSC1', 'Gene', (157, 161))	('Loss of function', 'NegReg', (0, 16))	('tumor', 'Disease', (74, 79))	('schwannoma', 'Disease', 'MESH:D009442', (141, 151))	('merlin', 'Gene', '4771', (109, 115))	('NF2', 'Gene', '4771', (121, 124))	('schwannoma', 'Phenotype', 'HP:0100008', (141, 151))
52278	23282968	According to our observations, SDHA mutations in SDHB-negative (SDH-deficient) GISTs seem to be as common as other SDH-subunit mutations together.	('SDHB', 'Gene', (49, 53))	('SDHA', 'Gene', '6389', (31, 35))	('SDH', 'Gene', (64, 67))	('SDH', 'Gene', '6390', (49, 52))	('SDH', 'Gene', '6390', (64, 67))	('SDH', 'Gene', '6390', (31, 34))	('SDH-deficient', 'Disease', 'MESH:D007153', (64, 77))	('SDH', 'Gene', (49, 52))	('mutations', 'Var', (36, 45))	('SDHA', 'Gene', (31, 35))	('SDH', 'Gene', '6390', (115, 118))	('SDH', 'Gene', (31, 34))	('SDHB', 'Gene', '6390', (49, 53))	('SDH', 'Gene', (115, 118))	('SDH-deficient', 'Disease', (64, 77))
52280	23282968	A caveat in the comparison of the relative frequencies of SDH-subunit gene mutations is that large deletions can escape detection in our custom capture mutation search.	('SDH', 'Gene', (58, 61))	('mutations', 'Var', (75, 84))	('SDH', 'Gene', '6390', (58, 61))
52298	21663639	Both, pediatric and CT-GISTs, metastasize frequently to regional lymph nodes (29%) and are usually wild type (WT) for common KIT-/PDGFRA mutations.	('mutations', 'Var', (137, 146))	('metastasize', 'CPA', (30, 41))	('PDGFRA', 'Gene', (130, 136))	('GISTs', 'Phenotype', 'HP:0100723', (23, 28))	('PDGFRA', 'Gene', '5156', (130, 136))
52301	21663639	The two cases of pediatric/young adult GIST without the other components of CT showed all the features of the triad: female gender, young age, multifocal antral-based gastric GIST with biphasic histological growth pattern, lymph node metastases, hypercellularity and WT status for common KIT-, PDGFRA- and B-RAF mutations.	('KIT-', 'Gene', (288, 292))	('PDGFRA-', 'Gene', '5156', (294, 301))	('B-RAF', 'Gene', '673', (306, 311))	('PDGFRA-', 'Gene', (294, 301))	('mutations', 'Var', (312, 321))	('lymph node metastases', 'Disease', (223, 244))	('lymph node metastases', 'Disease', 'MESH:D009362', (223, 244))	('B-RAF', 'Gene', (306, 311))
52313	21663639	The gastric GISTs in CT are usually multifocal, antral based and show a wild type (WT) for common mutations in receptor tyrosine kinase gene KIT and for homologue oncogene platelet-derived growth factor receptor alpha gene (PDGFRA) and they present with typical biphasic growth pattern.	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (172, 217))	('PDGFRA', 'Gene', (224, 230))	('platelet-derived growth factor receptor alpha', 'Gene', (172, 217))	('PDGFRA', 'Gene', '5156', (224, 230))	('mutations', 'Var', (98, 107))	('GISTs', 'Phenotype', 'HP:0100723', (12, 17))
52329	21663639	Mutational analysis showed a WT for KIT (exons 9, 11, 13, 17) and PDGFRA (exons 12, 14, 18) as well as for B-RAF exon 15 V600E mutations.	('V600E', 'Mutation', 'rs113488022', (121, 126))	('PDGFRA', 'Gene', '5156', (66, 72))	('V600E', 'Var', (121, 126))	('PDGFRA', 'Gene', (66, 72))	('B-RAF', 'Gene', '673', (107, 112))	('B-RAF', 'Gene', (107, 112))
52330	21663639	However, further examination disclosed a rare PDGFRA exon 10 polymorphism (c. 1432 T > C; p. S478P) that is present on the DNA level but does not lead to alterations on the protein level.	('S478P', 'SUBSTITUTION', 'None', (93, 98))	('1432 T > C', 'Var', (78, 88))	('S478P', 'Var', (93, 98))	('PDGFRA', 'Gene', (46, 52))	('PDGFRA', 'Gene', '5156', (46, 52))	('1432 T > C', 'SUBSTITUTION', 'None', (78, 88))
52342	21663639	The tumor was WT for KIT exons 9, 11, 13 and 17, PDGFRA exons 10, 12, 14 and 18 as well as for B-RAF exon 15 mutations.	('tumor', 'Disease', (4, 9))	('B-RAF', 'Gene', '673', (95, 100))	('PDGFRA', 'Gene', (49, 55))	('PDGFRA', 'Gene', '5156', (49, 55))	('B-RAF', 'Gene', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
52348	21663639	The patients young age, female gender, tumor localisation, mutational status (WT for KIT, PDGFRA and B-RAF mutations), (histo)morphological growth pattern (multilobular gastric tumor, biphasic growth pattern, hypercellularity, plasmacytoid cell morphology), immunohistochemistry findings and the pattern of metastasis (lymph node and liver metastases) are consistent with the previous two cases (figure 3).	('mutations', 'Var', (107, 116))	('multilobular gastric tumor', 'Disease', (156, 182))	('liver metastases', 'Disease', (334, 350))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PDGFRA', 'Gene', '5156', (90, 96))	('PDGFRA', 'Gene', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('liver metastases', 'Disease', 'MESH:D009362', (334, 350))	('gastric tumor', 'Phenotype', 'HP:0006753', (169, 182))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (39, 44))	('B-RAF', 'Gene', '673', (101, 106))	('multilobular gastric tumor', 'Disease', 'None', (156, 182))	('tumor', 'Disease', (177, 182))	('B-RAF', 'Gene', (101, 106))
52351	21663639	In contrast to most of the sporadic GISTs of the adults, both CT-GISTs and pediatric GISTs are WT for common mutations of the receptor tyrosine kinase genes KIT and PDGFRA.	('GISTs', 'Phenotype', 'HP:0100723', (85, 90))	('PDGFRA', 'Gene', '5156', (165, 171))	('PDGFRA', 'Gene', (165, 171))	('GISTs', 'Phenotype', 'HP:0100723', (65, 70))	('mutations', 'Var', (109, 118))	('KIT', 'Gene', (157, 160))	('GISTs', 'Phenotype', 'HP:0100723', (36, 41))
52353	21663639	Similarly, our two cases of pediatric/young adult GIST without other components of CT (case 2 and 3) showed all the features of the CT-GISTs: young age, female gender, antral-based gastric GIST, multifocal tumor growth, biphasic histological growth pattern, hypercellularity, WT status for common KIT-, PDGFRA- and B-RAF mutations and presence of lymph node metastases (table 1).	('B-RAF', 'Gene', '673', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('lymph node metastases', 'Disease', (347, 368))	('PDGFRA-', 'Gene', (303, 310))	('KIT-', 'Gene', (297, 301))	('hypercellularity', 'CPA', (258, 274))	('B-RAF', 'Gene', (315, 320))	('mutations', 'Var', (321, 330))	('GISTs', 'Phenotype', 'HP:0100723', (135, 140))	('multifocal tumor', 'Disease', (195, 211))	('multifocal tumor', 'Disease', 'None', (195, 211))	('PDGFRA-', 'Gene', '5156', (303, 310))	('lymph node metastases', 'Disease', 'MESH:D009362', (347, 368))
52358	33947839	Currently, about 70% of PPGLs can be explained by germline or somatic mutations in several broadly expressed susceptibility genes including RET, VHL, and SDHB, while for the remaining, mainly sporadic cases, the pathogenesis is still unclear.	('VHL', 'Gene', '7428', (145, 148))	('mutations', 'Var', (70, 79))	('explained', 'Reg', (37, 46))	('RET', 'Gene', (140, 143))	('PPGLs', 'Chemical', '-', (24, 29))	('SDHB', 'Gene', (154, 158))	('VHL', 'Gene', (145, 148))	('PPGLs', 'Disease', (24, 29))
52359	33947839	Even for known susceptible genes, how mutations in these mostly ubiquitous genes result in tissue-specific pathogenesis remains unanswered, and why RET-mutated tumors almost always occur in the adrenal while SDHB-mutated tumors mostly occur extra-adrenal remains a mystery.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', (221, 227))	('result', 'Reg', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (160, 166))	('mutations', 'Var', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
52361	33947839	Copy number deletion and GIPC2 promoter hypermethylation but not GIPC2 mutation, accompanied with reduced GIPC2 expression, were observed in 39 of 55 PPGLs in our cohort.	('mutation', 'Var', (71, 79))	('GIPC2', 'Gene', (65, 70))	('PPGLs', 'Chemical', '-', (150, 155))	('GIPC2', 'Gene', (25, 30))	('Copy number deletion', 'Var', (0, 20))	('hypermethylation', 'Var', (40, 56))	('reduced', 'NegReg', (98, 105))	('GIPC2 expression', 'MPA', (106, 122))
52364	33947839	Overexpressing GIPC2 in PC12 cells inhibited tumor growth in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('nude mice', 'Species', '10090', (61, 70))	('PC12', 'CellLine', 'CVCL:0481', (24, 28))	('Overexpressing', 'Var', (0, 14))	('inhibited', 'NegReg', (35, 44))	('GIPC2', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
52366	33947839	We found that PPGL-causing mutations in RET and in SDHB could lead to primary rat adrenal chromaffin cell proliferation, ERK activation, and p27 downregulation, all requiring downregulating GIPC2.	('mutations', 'Var', (27, 36))	('activation', 'PosReg', (125, 135))	('RET', 'Gene', (40, 43))	('PPGL-causing', 'Reg', (14, 26))	('downregulation', 'NegReg', (145, 159))	('ERK', 'Protein', (121, 124))	('rat', 'Species', '10116', (113, 116))	('chromaffin', 'Chemical', '-', (90, 100))	('rat', 'Species', '10116', (78, 81))	('p27', 'Gene', (141, 144))	('lead to', 'Reg', (62, 69))	('PPGL', 'Chemical', '-', (14, 18))	('SDHB', 'Gene', (51, 55))	('downregulating', 'NegReg', (175, 189))
52368	33947839	In contrast, the PPGL-predisposing VHL mutations had no effect on proliferation and GIPC2 expression but caused p53 downregulation and reduced apoptosis in chromaffin cells compared with wild-type VHL.	('PPGL-predisposing', 'Gene', (17, 34))	('VHL', 'Gene', (197, 200))	('downregulation', 'NegReg', (116, 130))	('VHL', 'Gene', '7428', (197, 200))	('mutations', 'Var', (39, 48))	('PPGL', 'Chemical', '-', (17, 21))	('apoptosis', 'CPA', (143, 152))	('reduced', 'NegReg', (135, 142))	('p53', 'Gene', (112, 115))	('VHL', 'Gene', (35, 38))	('GIPC2', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('chromaffin', 'Chemical', '-', (156, 166))	('VHL', 'Gene', '7428', (35, 38))	('rat', 'Species', '10116', (73, 76))
52373	33947839	The application of next-generation sequencing accelerated the discovery of driver susceptibility gene mutations.	('accelerated', 'PosReg', (46, 57))	('rat', 'Species', '10116', (52, 55))	('mutations', 'Var', (102, 111))	('rat', 'Species', '10116', (28, 31))
52376	33947839	Few studies addressed how susceptibility gene mutations lead to PPGL pathogenesis in chromaffin cells.	('PPGL', 'Chemical', '-', (64, 68))	('mutations', 'Var', (46, 55))	('PPGL', 'Gene', (64, 68))	('chromaffin', 'Chemical', '-', (85, 95))
52377	33947839	For example, when PPGL-predisposing RET C634R mutation was introduced to PC12 rat pheochromocytoma cells, the cells underwent neuronal differentiation rather than proliferation.	('neuronal differentiation', 'Disease', (126, 150))	('rat', 'Species', '10116', (170, 173))	('pheochromocytoma', 'Disease', (82, 98))	('C634R', 'Var', (40, 45))	('C634R', 'SUBSTITUTION', 'None', (40, 45))	('rat', 'Species', '10116', (78, 81))	('underwent', 'Reg', (116, 125))	('PC12', 'CellLine', 'CVCL:0481', (73, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('pheochromocytoma', 'Disease', 'MESH:D010673', (82, 98))	('rat', 'Species', '10116', (151, 154))	('neuronal differentiation', 'Disease', 'MESH:D009410', (126, 150))	('PPGL', 'Chemical', '-', (18, 22))
52378	33947839	On the other hand, for MEN 2A syndrome patients with the common RET C634R mutation, only about 50% develop pheochromocytoma, suggesting the tumorigenesis may require additional genetic events.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (107, 123))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pheochromocytoma', 'Disease', 'MESH:D010673', (107, 123))	('MEN 2A', 'Gene', (23, 29))	('MEN 2A', 'Gene', '5979', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('C634R', 'Var', (68, 73))	('C634R', 'SUBSTITUTION', 'None', (68, 73))	('pheochromocytoma', 'Disease', (107, 123))
52379	33947839	Whole-genome scanning of PPGLs by array CGH (Comparative Genomic Hybridization) revealed that hereditary and sporadic PPGLs often harbor high-frequency deletions of 1p, 3pq, 11pq, 17p, 21q, especially 1p.	('PPGLs', 'Gene', (118, 123))	('PPGLs', 'Chemical', '-', (118, 123))	('rat', 'Species', '10116', (50, 53))	('3pq', 'Var', (169, 172))	('PPGLs', 'Chemical', '-', (25, 30))	('deletions', 'Var', (152, 161))	('11pq', 'Gene', (174, 178))	('17p', 'Gene', (180, 183))
52385	33947839	p27 mutation in rat results in MENX syndrome similar in phenotype and gene expression pattern to human pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (103, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('rat', 'Species', '10116', (16, 19))	('MENX syndrome', 'Disease', (31, 44))	('human', 'Species', '9606', (97, 102))	('mutation', 'Var', (4, 12))	('p27', 'Gene', (0, 3))	('results in', 'Reg', (20, 30))	('pheochromocytoma', 'Disease', (103, 119))
52388	33947839	In this study, using high-resolution microarrays and selecting for genes with preferential expression in adrenal, we identified a novel tumor suppressor gene GIPC2, that was inactivated in a majority of sporadic PPGL tumors due to copy number deletion and promoter hypermethylation.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('GIPC2', 'Gene', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('promoter hypermethylation', 'Var', (256, 281))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('PPGL tumors', 'Disease', (212, 223))	('tumor', 'Disease', (136, 141))	('copy number deletion', 'Var', (231, 251))	('PPGL tumors', 'Disease', 'MESH:D009369', (212, 223))
52395	33947839	1B), and 39 tumors had copy number deletion from our cohort of 55 PPGL samples by qPCR, including all 7 RET-mutated PPGL (Fig.	('copy number deletion', 'Var', (23, 43))	('PPGL', 'Chemical', '-', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('PPGL', 'Chemical', '-', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
52397	33947839	The expression level of GIPC2 decreased significantly in copy number deleted tumors compared with copy number normal tumors (Fig.	('tumors', 'Disease', (77, 83))	('expression level', 'MPA', (4, 20))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('GIPC2', 'Gene', (24, 29))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('copy number deleted', 'Var', (57, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('decreased', 'NegReg', (30, 39))
52398	33947839	IHC staining of adrenal tissue sections demonstrated a moderate to high expression of GIPC2 in the nuclei and cytoplasm of normal medulla cells, low expression in tumors without GIPC2 deletion, and no expression of GIPC2 in GIPC2 deletion tumors (Fig.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('GIPC2', 'Gene', (86, 91))	('expression', 'MPA', (72, 82))	('rat', 'Species', '10116', (47, 50))	('tumors', 'Disease', (163, 169))	('GIPC2', 'Gene', (224, 229))	('expression', 'MPA', (149, 159))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('deletion', 'Var', (230, 238))	('rat', 'Species', '10116', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))
52401	33947839	Since aberrant promoter methylation was a well-recognized epigenetic mechanism involved in tumor suppressor gene silencing in cancers, we determined the methylation levels of GIPC2 promoter in PPGL samples by MALDI-TOF mass spectrometry (Sequenom EpiTYPER) and found significantly higher levels of methylation in the PPGL samples than normal tissues (Fig.	('PPGL', 'Chemical', '-', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('aberrant', 'Var', (6, 14))	('higher', 'PosReg', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('methylation', 'MPA', (153, 164))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancers', 'Disease', (126, 133))	('levels', 'MPA', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('tumor', 'Disease', (91, 96))	('methylation', 'MPA', (298, 309))	('PPGL', 'Chemical', '-', (317, 321))
52408	33947839	The EdU staining assay indicated GIPC2 knockdown increased the cell proliferation in ACC cells (Fig.	('rat', 'Species', '10116', (75, 78))	('increased', 'PosReg', (49, 58))	('knockdown', 'Var', (39, 48))	('cell proliferation in ACC cells', 'CPA', (63, 94))	('GIPC2', 'Gene', (33, 38))
52411	33947839	Significant downregulation of phospho-ERK1/2 and phospho-MEK was found in GIPC2 overexpressing cells while the upregulation of them was obtained in GIPC2-knockdown cells (Fig.	('downregulation', 'NegReg', (12, 26))	('overexpressing', 'Var', (80, 94))	('ERK1/2', 'Gene', '5595;5594', (38, 44))	('MEK', 'Gene', '5609', (57, 60))	('GIPC2', 'Gene', (74, 79))	('ERK1/2', 'Gene', (38, 44))	('MEK', 'Gene', (57, 60))
52413	33947839	HIF-1A was also upregulated by GIPC2 knockdown and this was independent of the MAPK/ERK pathway, as it was not blocked by MAPK/ERK inhibitor PD98059 (Fig.	('upregulated', 'PosReg', (16, 27))	('HIF-1A', 'Gene', (0, 6))	('knockdown', 'Var', (37, 46))	('GIPC2', 'Gene', (31, 36))	('PD98059', 'Chemical', 'MESH:C093973', (141, 148))	('HIF-1A', 'Gene', '3091', (0, 6))
52420	33947839	Western blot confirmed that p27 was significantly increased after overexpression of GIPC2 in PC12, 293T, and hPheo1 cells, while decreased when knocking down GIPC2 in HEK293 cells (Fig.	('293T', 'CellLine', 'CVCL:0063', (99, 103))	('knocking', 'Var', (144, 152))	('increased', 'PosReg', (50, 59))	('GIPC2', 'Gene', (84, 89))	('p27', 'MPA', (28, 31))	('overexpression', 'PosReg', (66, 80))	('decreased', 'NegReg', (129, 138))	('HEK293', 'CellLine', 'CVCL:0045', (167, 173))	('PC12', 'CellLine', 'CVCL:0481', (93, 97))
52434	33947839	We demonstrated that in the presence of dexamethasone (Dex), an analog of the adrenal cortical glucocorticoid to which adrenal chromaffin cells are chronically exposed, ACC underwent proliferation instead of differentiation when transfected with either a MEN 2A-causing RET634 mutant or a MEN 2B-causing RET918 mutant (Fig.	('RET918', 'Gene', (304, 310))	('Dex', 'Chemical', 'MESH:D003907', (55, 58))	('MEN 2B', 'Gene', '5979', (289, 295))	('chromaffin', 'Chemical', '-', (127, 137))	('dexamethasone', 'Chemical', 'MESH:D003907', (40, 53))	('rat', 'Species', '10116', (190, 193))	('differentiation', 'CPA', (208, 223))	('rat', 'Species', '10116', (10, 13))	('MEN 2A', 'Gene', '5979', (255, 261))	('MEN 2A', 'Gene', (255, 261))	('mutant', 'Var', (277, 283))	('MEN 2B', 'Gene', (289, 295))	('mutant', 'Var', (311, 317))	('RET634', 'Gene', (270, 276))
52436	33947839	A similar proliferative effect of RET mutant but not wild type can be observed in several cell lines in the presence of Dex (Supplementary Fig.	('RET', 'Gene', (34, 37))	('rat', 'Species', '10116', (17, 20))	('Dex', 'Chemical', 'MESH:D003907', (120, 123))	('mutant', 'Var', (38, 44))
52437	33947839	In the absence of Dex, transfection of RET mutant but not wild type RET resulted in apoptosis in ACC (Fig.	('Dex', 'Chemical', 'MESH:D003907', (18, 21))	('RET', 'Gene', (39, 42))	('apoptosis', 'CPA', (84, 93))	('mutant', 'Var', (43, 49))
52442	33947839	The proliferation accelerated in RET634/RET918-transfected cells when GIPC2 was knocked down (Fig.	('proliferation', 'CPA', (4, 17))	('GIPC2', 'Gene', (70, 75))	('rat', 'Species', '10116', (11, 14))	('rat', 'Species', '10116', (24, 27))	('accelerated', 'PosReg', (18, 29))	('knocked down', 'Var', (80, 92))
52443	33947839	5B), indicating opposing effects of GIPC2 and PPGL-causing RET mutations on proliferation.	('mutations', 'Var', (63, 72))	('PPGL-causing', 'Gene', (46, 58))	('rat', 'Species', '10116', (83, 86))	('PPGL', 'Chemical', '-', (46, 50))	('RET', 'Disease', (59, 62))
52444	33947839	We found the level of GIPC2 and p27/p18 downregulated but phospho-ERK1/2 and phospho-RB significantly increased in RET634/RET918-transfected ACCs, while p53 level remained unchanged (Fig.	('p18', 'Gene', '1031', (36, 39))	('ERK1/2', 'Gene', (66, 72))	('phospho-RB', 'MPA', (77, 87))	('level', 'MPA', (13, 18))	('downregulated', 'NegReg', (40, 53))	('ERK1/2', 'Gene', '5595;5594', (66, 72))	('RET634/RET918-transfected', 'Var', (115, 140))	('p18', 'Gene', (36, 39))	('GIPC2', 'MPA', (22, 27))	('increased', 'PosReg', (102, 111))
52446	33947839	Together, these results suggest that the PPGL-causing RET mutation leads to chromaffin cell proliferation primarily via downregulating GIPC2.	('RET', 'Gene', (54, 57))	('rat', 'Species', '10116', (99, 102))	('PPGL-causing RET', 'Gene', (41, 57))	('chromaffin', 'Chemical', '-', (76, 86))	('chromaffin cell proliferation', 'CPA', (76, 105))	('mutation', 'Var', (58, 66))	('GIPC2', 'Gene', (135, 140))	('PPGL', 'Chemical', '-', (41, 45))	('leads to', 'Reg', (67, 75))	('downregulating', 'NegReg', (120, 134))
52447	33947839	We next asked whether GIPC2 had a similar role in mediating the oncogenic effects of SDHx mutations in SDHx-related hereditary PPGL, since SDHx-related hereditary tumors also significantly downregulated GIPC2 and p27 (Fig.	('hereditary tumors', 'Disease', 'MESH:D030342', (152, 169))	('SDH', 'Gene', (139, 142))	('mutations', 'Var', (90, 99))	('SDH', 'Gene', '6390', (103, 106))	('SDH', 'Gene', (85, 88))	('GIPC2', 'Protein', (203, 208))	('downregulated', 'NegReg', (189, 202))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('hereditary tumors', 'Disease', (152, 169))	('PPGL', 'Chemical', '-', (127, 131))	('SDH', 'Gene', '6390', (139, 142))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('SDH', 'Gene', '6390', (85, 88))	('SDH', 'Gene', (103, 106))
52448	33947839	Mutations of the genes encoding succinate dehydrogenase subunits B (SDHB) and D (SDHD) are the most well-known causes of hereditary paraganglia.	('hereditary paraganglia', 'Disease', (121, 143))	('SDHD', 'Gene', '6392', (81, 85))	('causes', 'Reg', (111, 117))	('SDHD', 'Gene', (81, 85))	('SDHB', 'Gene', (68, 72))	('Mutations', 'Var', (0, 9))	('hereditary paraganglia', 'Disease', 'MESH:D030342', (121, 143))	('succinate dehydrogenase subunits B', 'Gene', (32, 66))	('succinate dehydrogenase subunits B', 'Gene', '6390', (32, 66))
52449	33947839	The overexpression of a PPGL-causing SDHB mutation or the knockdown of wild type SDHD protein (both resulted in the increased intracellular concentration of oncometabolite succinate) led to ACC proliferation and corresponding changes of the downstream genes including GIPC2, p27, p18, phosphor-pRb, and phospho-ERK, similar to the RET mutant (Fig.	('SDHD', 'Gene', '6392', (81, 85))	('GIPC2', 'Gene', (268, 273))	('increased', 'PosReg', (116, 125))	('ACC', 'PosReg', (190, 193))	('p27', 'Gene', (275, 278))	('PPGL-causing SDHB', 'Gene', (24, 41))	('mutation', 'Var', (42, 50))	('SDHD', 'Gene', (81, 85))	('increased intracellular concentration', 'Phenotype', 'HP:0003575', (116, 153))	('PPGL', 'Chemical', '-', (24, 28))	('overexpression', 'PosReg', (4, 18))	('p18', 'Gene', '1031', (280, 283))	('changes', 'Reg', (226, 233))	('SDHB', 'Gene', (37, 41))	('pRb', 'Gene', (294, 297))	('rat', 'Species', '10116', (147, 150))	('succinate', 'Chemical', 'MESH:D019802', (172, 181))	('rat', 'Species', '10116', (201, 204))	('pRb', 'Gene', '5925', (294, 297))	('p18', 'Gene', (280, 283))
52452	33947839	Thus, the oncogenic effect of PPGL-causing SDHB-mutation is also mediated by downregulating GIPC2.	('SDHB-mutation', 'Gene', (43, 56))	('SDHB-mutation', 'Var', (43, 56))	('downregulating', 'NegReg', (77, 91))	('PPGL', 'Chemical', '-', (30, 34))	('GIPC2', 'Gene', (92, 97))
52454	33947839	We observed drastically increased GIPC2 promoter methylation in chromaffin cells when transfected with SDHB mutant, but not RET mutants (Fig.	('chromaffin', 'Chemical', '-', (64, 74))	('SDHB', 'Gene', (103, 107))	('GIPC2', 'Gene', (34, 39))	('mutant', 'Var', (108, 114))	('increased', 'PosReg', (24, 33))
52456	33947839	In cell lines, the addition of DMS can also induce GIPC2 methylation as well as proliferation, while octyl-alpha-ketoglutarate, a membrane-permeating 2-KG analog, had opposite effects (Supplementary Fig.	('induce', 'PosReg', (44, 50))	('DMS', 'Chemical', 'MESH:C056451', (31, 34))	('proliferation', 'CPA', (80, 93))	('octyl-alpha-ketoglutarate', 'Chemical', '-', (101, 126))	('methylation', 'MPA', (57, 68))	('GIPC2', 'Gene', (51, 56))	('rat', 'Species', '10116', (122, 125))	('rat', 'Species', '10116', (87, 90))	('DMS', 'Var', (31, 34))
52457	33947839	GIPC2 and p27 were not as significantly decreased in VHL-mutated tumors (Cluster 1B) as in Clusters A and 2A (Fig.	('p27', 'Var', (10, 13))	('VHL', 'Gene', (53, 56))	('tumors', 'Disease', (65, 71))	('VHL', 'Gene', '7428', (53, 56))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('decreased', 'NegReg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
52459	33947839	The VHL-type 1 mutation is not associated with PPGL and VHL-type 2C mutation is associated only with PPGL, while type 2A and 2B are associated with PPGL and other syndrome diseases.	('VHL', 'Gene', (56, 59))	('PPGL', 'Chemical', '-', (101, 105))	('associated', 'Reg', (132, 142))	('syndrome diseases', 'Disease', (163, 180))	('VHL', 'Gene', '7428', (56, 59))	('mutation', 'Var', (68, 76))	('PPGL', 'Chemical', '-', (47, 51))	('associated', 'Reg', (80, 90))	('PPGL', 'Disease', (148, 152))	('VHL', 'Gene', (4, 7))	('PPGL', 'Disease', (101, 105))	('syndrome diseases', 'Disease', 'MESH:D003141', (163, 180))	('VHL', 'Gene', '7428', (4, 7))	('PPGL', 'Chemical', '-', (148, 152))
52460	33947839	Overexpression of VHL wild type and mutants did not induce proliferation (Fig.	('VHL', 'Gene', '7428', (18, 21))	('rat', 'Species', '10116', (66, 69))	('VHL', 'Gene', (18, 21))	('mutants', 'Var', (36, 43))
52461	33947839	To reduce the effects of basal VHL activity, we first knocked down wild-type VHL in ACC before introducing various VHL constructs.	('VHL', 'Gene', '7428', (31, 34))	('knocked down', 'Var', (54, 66))	('VHL', 'Gene', (115, 118))	('VHL', 'Gene', '7428', (115, 118))	('VHL', 'Gene', (77, 80))	('VHL', 'Gene', '7428', (77, 80))	('VHL', 'Gene', (31, 34))
52463	33947839	In fact, wild type and type I VHL mutant could stabilize p53 and induce apoptosis in ACC, but all type 2 VHL mutants failed to stabilize p53, and reduce the apoptosis of ACC (Fig.	('p53', 'MPA', (57, 60))	('VHL', 'Gene', (105, 108))	('apoptosis', 'CPA', (157, 166))	('VHL', 'Gene', (30, 33))	('induce', 'Reg', (65, 71))	('VHL', 'Gene', '7428', (105, 108))	('VHL', 'Gene', '7428', (30, 33))	('apoptosis', 'CPA', (72, 81))	('mutants', 'Var', (109, 116))	('reduce', 'NegReg', (146, 152))	('mutant', 'Var', (34, 40))
52464	33947839	In addition, In PC12 cells, all type 2 mutants reduced the p53 activity compared with wild type and type 1 mutant, regardless of whether GIPC2 was overexpressed (Fig.	('mutants', 'Var', (39, 46))	('PC12', 'CellLine', 'CVCL:0481', (16, 20))	('reduced', 'NegReg', (47, 54))	('p53', 'Enzyme', (59, 62))
52465	33947839	The results indicate that p53 but not GIPC2 may be involved in the tumorigenesis of VHL-related PPGL.	('VHL', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('p53', 'Var', (26, 29))	('VHL', 'Gene', '7428', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('involved', 'Reg', (51, 59))	('tumor', 'Disease', (67, 72))	('PPGL', 'Chemical', '-', (96, 100))
52466	33947839	We report the identification of a tumor suppressor gene, GIPC2 on chromosome 1p31.1, whose inactivation was associated with promoter hypermethylation and LOH in a majority of the sporadic PPGLs.	('GIPC2', 'Gene', (57, 62))	('LOH', 'Var', (154, 157))	('tumor', 'Disease', (34, 39))	('promoter', 'MPA', (124, 132))	('inactivation', 'MPA', (91, 103))	('PPGLs', 'Chemical', '-', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PPGLs', 'Disease', (188, 193))
52467	33947839	We also provide evidence that the oncogenic effects on chromaffin cells by common RET- and SDH- mutations found in hereditary PPGL are mediated by downregulating GIPC2.	('downregulating', 'NegReg', (147, 161))	('SDH', 'Gene', (91, 94))	('chromaffin', 'Chemical', '-', (55, 65))	('SDH', 'Gene', '6390', (91, 94))	('GIPC2', 'Gene', (162, 167))	('PPGL', 'Chemical', '-', (126, 130))	('PPGL', 'Gene', (126, 130))	('RET-', 'Gene', (82, 86))	('mutations', 'Var', (96, 105))
52471	33947839	Germline mutations of RET and SDHB predispose the carrier to PPGL by downregulating GIPC2.	('Germline mutations', 'Var', (0, 18))	('RET', 'Gene', (22, 25))	('PPGL', 'Disease', (61, 65))	('predispose', 'Reg', (35, 45))	('downregulating', 'NegReg', (69, 83))	('GIPC2', 'MPA', (84, 89))	('PPGL', 'Chemical', '-', (61, 65))	('SDHB', 'Gene', (30, 34))
52472	33947839	Loss of GIPC2 resulted in p27 repression, activation of HIF-1alpha as well as the pERK pathways, proliferation of chromaffin cells, and possibly with the help of other 1p genes, oncogenic transformations leading to PPGL.	('pERK', 'Gene', '9451', (82, 86))	('PPGL', 'Chemical', '-', (215, 219))	('HIF-1alpha', 'Gene', (56, 66))	('rat', 'Species', '10116', (104, 107))	('oncogenic transformations', 'CPA', (178, 203))	('proliferation', 'CPA', (97, 110))	('p27 repression', 'Protein', (26, 40))	('chromaffin', 'Chemical', '-', (114, 124))	('activation', 'PosReg', (42, 52))	('HIF-1alpha', 'Gene', '3091', (56, 66))	('Loss', 'Var', (0, 4))	('GIPC2', 'Gene', (8, 13))	('pERK', 'Gene', (82, 86))
52484	33947839	Based on GIPC2's role and expression level, the Cluster 1B (VHL-related) was distinct from Cluster 2A and 1A (RET- and SDHx-related respectively), a classification that was consistent with the cytogenetics observations of large numbers of PPGLs, which showed the VHL-related tumors with chromosomal deletion patterns (mostly 3pq and 11p) that are distinct from those of RET- and SDHx-related tumors (mostly 1p and 3q).	('PPGLs', 'Chemical', '-', (239, 244))	('SDH', 'Gene', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('VHL', 'Gene', (263, 266))	('VHL', 'Gene', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (392, 398))	('SDH', 'Gene', '6390', (379, 382))	('tumors', 'Disease', (275, 281))	('VHL', 'Gene', '7428', (263, 266))	('VHL', 'Gene', '7428', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('3pq', 'Var', (325, 328))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('tumors', 'Phenotype', 'HP:0002664', (392, 398))	('SDH', 'Gene', '6390', (119, 122))	('SDH', 'Gene', (379, 382))	('tumors', 'Disease', (392, 398))
52487	33947839	It is well-known that type 2C VHL mutants, which predispose only to PPGL, are normal with respect to HIF regulation, suggesting that a VHL target other than HIF is responsible for VHL-associated PPGL.	('VHL', 'Gene', (135, 138))	('VHL', 'Gene', (180, 183))	('PPGL', 'Disease', (68, 72))	('mutants', 'Var', (34, 41))	('PPGL', 'Disease', (195, 199))	('VHL', 'Gene', '7428', (135, 138))	('VHL', 'Gene', '7428', (180, 183))	('VHL', 'Gene', (30, 33))	('PPGL', 'Chemical', '-', (68, 72))	('VHL', 'Gene', '7428', (30, 33))	('PPGL', 'Chemical', '-', (195, 199))
52489	33947839	We found the ability of a VHL mutation to predispose to PPGL is reflected by its ability to destabilize p53 and to reduce apoptosis (Fig.	('destabilize', 'NegReg', (92, 103))	('apoptosis', 'CPA', (122, 131))	('VHL', 'Gene', (26, 29))	('mutation', 'Var', (30, 38))	('VHL', 'Gene', '7428', (26, 29))	('PPGL', 'Disease', (56, 60))	('reduce', 'NegReg', (115, 121))	('p53', 'Protein', (104, 107))	('predispose', 'Reg', (42, 52))	('PPGL', 'Chemical', '-', (56, 60))
52495	33947839	To detect copy number variation (CNV) in sporadic PPGL, Affymetrix genome-wide human SNP array 6.0 was used.	('human', 'Species', '9606', (79, 84))	('PPGL', 'Chemical', '-', (50, 54))	('PPGL', 'Gene', (50, 54))	('copy number variation', 'Var', (10, 31))
52519	29878124	A Unique Case of Metastatic, Functional, Hereditary Paraganglioma Associated With anSDHC Germline Mutation Mutations in genes encoding for the succinate dehydrogenase (SDH) complex are linked to hereditary paraganglioma syndromes.	('Paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('succinate dehydrogenase', 'Gene', (143, 166))	('succinate dehydrogenase', 'Gene', '6390', (143, 166))	('hereditary paraganglioma syndromes', 'Disease', (195, 229))	('Associated', 'Reg', (66, 76))	('SDH', 'Gene', (168, 171))	('SDH', 'Gene', '6390', (168, 171))	('Hereditary Paraganglioma', 'Disease', 'MESH:D010235', (41, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (206, 219))	('SDH', 'Gene', '6390', (84, 87))	('hereditary paraganglioma syndromes', 'Disease', 'MESH:D061325', (195, 229))	('linked to', 'Reg', (185, 194))	('Hereditary Paraganglioma', 'Disease', (41, 65))	('Mutations', 'Var', (107, 116))	('SDH', 'Gene', (84, 87))
52525	29878124	Genetic testing revealed a heterozygousSDHC c.43C>T, p.Arg15X mutation, which was also detected in her daughter and her grandson, both of whom have no biochemical or imaging evidence of paraganglioma syndrome yet.	('SDHC', 'Gene', '6391', (39, 43))	('paraganglioma syndrome', 'Disease', (186, 208))	('paraganglioma syndrome', 'Disease', 'MESH:D010235', (186, 208))	('c.43C>T', 'Mutation', 'rs201286421', (44, 51))	('p.Arg15X', 'Mutation', 'rs201286421', (53, 61))	('p.Arg15X', 'Var', (53, 61))	('paraganglioma', 'Phenotype', 'HP:0002668', (186, 199))	('SDHC', 'Gene', (39, 43))
52531	29878124	Mutations in the genes encoding different subunits of the succinate dehydrogenase (SDH) enzyme complexes, which are responsible for oxidative metabolism and electron transfer, have been linked to hereditary paragangliomas.	('linked to', 'Reg', (186, 195))	('succinate dehydrogenase', 'Gene', '6390', (58, 81))	('hereditary paragangliomas', 'Disease', (196, 221))	('SDH', 'Gene', '6390', (83, 86))	('succinate dehydrogenase', 'Gene', (58, 81))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Phenotype', 'HP:0002668', (207, 220))	('SDH', 'Gene', (83, 86))	('paragangliomas', 'Phenotype', 'HP:0002668', (207, 221))	('hereditary paragangliomas', 'Disease', 'MESH:D010235', (196, 221))
52533	29878124	Mutations in theSDHC locus are rare and usually manifest with isolated, benign, nonfunctional (parasympathetic), and asymptomatic head and neck paragangliomas.	('SDHC', 'Gene', (16, 20))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (139, 158))	('paragangliomas', 'Phenotype', 'HP:0002668', (144, 158))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (130, 158))	('SDHC', 'Gene', '6391', (16, 20))	('manifest', 'Reg', (48, 56))	('paraganglioma', 'Phenotype', 'HP:0002668', (144, 157))	('neck paragangliomas', 'Disease', 'MESH:D010235', (139, 158))	('Mutations', 'Var', (0, 9))	('neck paragangliomas', 'Disease', (139, 158))	('nonfunctional', 'Disease', (80, 93))
52534	29878124	Our case exemplifies a distinctive variant:functional, metastatic, abdominal paraganglioma associated with anSDHC mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('SDHC', 'Gene', '6391', (109, 113))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (67, 90))	('abdominal paraganglioma', 'Disease', (67, 90))	('SDHC', 'Gene', (109, 113))	('mutation', 'Var', (114, 122))	('associated', 'Reg', (91, 101))
52547	29878124	She also received everolimus that was later switched into sunitinib and then temozolomide, which did not prevent disease progression, and she expired in 2012. , The germline mutation screen was negative for SDHB and SDHD gene mutations but was positive for a heterozygous SDHC c.43C>T (p. Arg15X) mutation.	('SDHB', 'Gene', '6390', (207, 211))	('sunitinib', 'Chemical', 'MESH:D000077210', (58, 67))	('SDHB', 'Gene', (207, 211))	('Arg15X', 'SUBSTITUTION', 'None', (289, 295))	('everolimus', 'Chemical', 'MESH:D000068338', (18, 28))	('temozolomide', 'Chemical', 'MESH:D000077204', (77, 89))	('SDHC', 'Gene', (272, 276))	('SDHD', 'Gene', '6392', (216, 220))	('SDHC', 'Gene', '6391', (272, 276))	('SDHD', 'Gene', (216, 220))	('c.43C>T', 'Mutation', 'rs201286421', (277, 284))	('negative', 'NegReg', (194, 202))	('Arg15X', 'Var', (289, 295))
52554	29878124	The sameSDHC mutation was detected in germline DNA of her 36-year-old daughter and 9-year-old grandson, who remain clinically, biochemically, and radiologically free of paraganglioma.	('SDHC', 'Gene', '6391', (8, 12))	('paraganglioma', 'Disease', (169, 182))	('mutation', 'Var', (13, 21))	('paraganglioma', 'Disease', 'MESH:D010235', (169, 182))	('SDHC', 'Gene', (8, 12))	('detected', 'Reg', (26, 34))	('paraganglioma', 'Phenotype', 'HP:0002668', (169, 182))
52556	29878124	We herein report a case of functional, metastatic abdominal paraganglioma associated with SDHC germline mutation.	('germline', 'Var', (95, 103))	('SDHC', 'Gene', (90, 94))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (50, 73))	('SDHC', 'Gene', '6391', (90, 94))	('abdominal paraganglioma', 'Disease', (50, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (60, 73))	('associated', 'Reg', (74, 84))
52557	29878124	Paraganglioma syndrome 3 is associated with SDHC mutations and classically presents with isolated, asymptomatic, benign, nonfunctional head and neck paragangliomas.	('SDHC', 'Gene', '6391', (44, 48))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (135, 163))	('Paraganglioma syndrome', 'Disease', 'MESH:D010235', (0, 22))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (28, 38))	('neck paragangliomas', 'Disease', (144, 163))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (144, 163))	('Paraganglioma', 'Phenotype', 'HP:0002668', (0, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (149, 162))	('paragangliomas', 'Phenotype', 'HP:0002668', (149, 163))	('neck paragangliomas', 'Disease', 'MESH:D010235', (144, 163))	('SDHC', 'Gene', (44, 48))	('Paraganglioma syndrome', 'Disease', (0, 22))
52560	29878124	reported a case of malignant sympathetic paraganglioma in a patient with a deletion of the SDHC gene.	('SDHC', 'Gene', (91, 95))	('patient', 'Species', '9606', (60, 67))	('SDHC', 'Gene', '6391', (91, 95))	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('deletion', 'Var', (75, 83))	('malignant sympathetic paraganglioma', 'Phenotype', 'HP:0100697', (19, 54))	('malignant sympathetic paraganglioma', 'Disease', 'MESH:C565335', (19, 54))	('malignant sympathetic paraganglioma', 'Disease', (19, 54))
52561	29878124	reported a case of the SDHC mutation manifesting as a locally aggressive, catecholamine-producing, temporal bone paraganglioma associated with increased hypoxia-inducible factor 2alpha expression.	('bone paraganglioma', 'Disease', 'MESH:D010235', (108, 126))	('bone paraganglioma', 'Disease', (108, 126))	('increased', 'PosReg', (143, 152))	('SDHC', 'Gene', '6391', (23, 27))	('expression', 'MPA', (185, 195))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('hypoxia-inducible factor 2alpha', 'Gene', '2034', (153, 184))	('mutation', 'Var', (28, 36))	('catecholamine', 'Chemical', 'MESH:D002395', (74, 87))	('hypoxia-inducible factor 2alpha', 'Gene', (153, 184))	('SDHC', 'Gene', (23, 27))
52563	29878124	A high false-negative rate (29% to 44%) of123I-MIBG imaging is frequently observed in metastatic tumors with unfavorable prognosis, as seen in hereditary paraganglioma syndrome, as a result of the SDHB mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (154, 167))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D061325', (143, 176))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SDHB', 'Gene', '6390', (197, 201))	('observed', 'Reg', (74, 82))	('SDHB', 'Gene', (197, 201))	('mutation', 'Var', (202, 210))	('123I-MIBG', 'Chemical', 'MESH:D019797', (42, 51))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('hereditary paraganglioma syndrome', 'Disease', (143, 176))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('result', 'Reg', (183, 189))
52567	29878124	The SDHC Arg15X mutation has been previously reported in patients with paraganglioma and is predicted to be pathogenic.	('Arg15X', 'Var', (9, 15))	('paraganglioma', 'Disease', (71, 84))	('reported', 'Reg', (45, 53))	('SDHC', 'Gene', (4, 8))	('patients', 'Species', '9606', (57, 65))	('Arg15X', 'Mutation', 'rs201286421', (9, 15))	('SDHC', 'Gene', '6391', (4, 8))	('paraganglioma', 'Disease', 'MESH:D010235', (71, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))
52570	29878124	This patient's tumor had a predominant, weakly diffuse cytoplasmic staining, which has been reported in some tumors with SDH mutations, especiallySDHD, and is compatible with deficient SDH function, expected to occur after an early SDHC truncation.	('SDH', 'Gene', '6390', (185, 188))	('SDH', 'Gene', '6390', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('SDH', 'Gene', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('SDH', 'Gene', (232, 235))	('SDHC', 'Gene', '6391', (232, 236))	('SDH', 'Gene', (185, 188))	('SDH', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('mutations', 'Var', (125, 134))	('especiallySDHD', 'Disease', 'None', (136, 150))	('especiallySDHD', 'Disease', (136, 150))	('tumor', 'Disease', (15, 20))	('deficient SDH function', 'Disease', (175, 197))	('SDHC', 'Gene', (232, 236))	('patient', 'Species', '9606', (5, 12))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('deficient SDH function', 'Disease', 'MESH:D015499', (175, 197))	('SDH', 'Gene', '6390', (232, 235))	('SDH', 'Gene', '6390', (146, 149))	('tumor', 'Disease', (109, 114))
52572	29878124	Loss of heterozygosity detection could have been further confounded by admixed nontumor cells (e.g., from extensive vascularity).	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Loss', 'NegReg', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('heterozygosity', 'Var', (8, 22))
52573	29878124	Although the germline SDHC mutation is likely the primary cause of the paraganglioma in this patient, this tumor may have acquired additional changes that contributed to its unusually aggressive behavior and poor outcome.	('SDHC', 'Gene', (22, 26))	('paraganglioma', 'Disease', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('aggressive behavior', 'Phenotype', 'HP:0000718', (184, 203))	('SDHC', 'Gene', '6391', (22, 26))	('cause', 'Reg', (58, 63))	('paraganglioma', 'Disease', 'MESH:D010235', (71, 84))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))
52576	29878124	However, when an SDHx mutation (including SDHC) is identified in a relative of a proband, periodic biochemical and whole-body imaging studies are indicated.	('mutation', 'Var', (22, 30))	('SDH', 'Gene', '6390', (42, 45))	('SDHC', 'Gene', (42, 46))	('SDH', 'Gene', (17, 20))	('SDH', 'Gene', (42, 45))	('SDHC', 'Gene', '6391', (42, 46))	('SDH', 'Gene', '6390', (17, 20))
52578	29878124	Our case is unique in that our patient had a pathogenicSDHC germline mutation with a metastatic abdominal paraganglioma that was functional (sympathetic).	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (96, 119))	('abdominal paraganglioma', 'Disease', (96, 119))	('germline mutation', 'Var', (60, 77))	('SDHC', 'Gene', (55, 59))	('patient', 'Species', '9606', (31, 38))	('SDHC', 'Gene', '6391', (55, 59))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))
52581	29172408	A novel neurofibromatosis type 1 (NF1) mutation in a patient with NF1 and pheochromocytoma To the Editor, Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant inherent disorders with an incidence of one in 3,000 individuals.	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (106, 123))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (8, 25))	('autosomal dominant inherent disorders', 'Disease', 'MESH:D030342', (163, 200))	('neurofibromatosis type 1', 'Gene', '4763', (8, 32))	('NF1', 'Gene', '4763', (132, 135))	('pheochromocytoma', 'Disease', 'MESH:D010673', (74, 90))	('NF1', 'Gene', '4763', (66, 69))	('patient', 'Species', '9606', (53, 60))	('NF1', 'Gene', (132, 135))	('pheochromocytoma', 'Disease', (74, 90))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('NF1', 'Gene', (66, 69))	('Neurofibromatosis type 1', 'Gene', '4763', (106, 130))	('neurofibromatosis type 1', 'Gene', (8, 32))	('NF1', 'Gene', '4763', (34, 37))	('mutation', 'Var', (39, 47))	('Neurofibromatosis type 1', 'Gene', (106, 130))	('autosomal dominant inherent disorders', 'Disease', (163, 200))	('NF1', 'Gene', (34, 37))
52585	29172408	Here, we report a novel germline mutation in the NF1 gene in a patient with NF1 and pheochromocytoma.	('NF1', 'Gene', '4763', (76, 79))	('pheochromocytoma', 'Disease', (84, 100))	('pheochromocytoma', 'Disease', 'MESH:D010673', (84, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (84, 100))	('germline mutation', 'Var', (24, 41))	('patient', 'Species', '9606', (63, 70))	('NF1', 'Gene', (49, 52))	('NF1', 'Gene', (76, 79))	('NF1', 'Gene', '4763', (49, 52))
52610	29172408	Genetic analysis of the index patient detected a novel germline NF1c.6533delT in exon 43 of the NF1 gene, and the identical germline mutation was found in both sisters (other family members refused genetic analysis) (Fig.	('patient', 'Species', '9606', (30, 37))	('c.6533delT', 'DELETION', 'None', (67, 77))	('NF1', 'Gene', (64, 67))	('NF1', 'Gene', '4763', (64, 67))	('NF1', 'Gene', '4763', (96, 99))	('NF1', 'Gene', (96, 99))	('c.6533delT', 'Var', (67, 77))
52614	29172408	This is caused by a mutation in the NF1 gene and results in a predisposition to cancer with rates of malignancy 5% to 15% higher than the general population; primarily due to markedly increased risks of malignant peripheral nerve sheath tumors and central nervous system tumors including optic glioma.	('malignant peripheral nerve sheath tumors', 'Disease', 'MESH:D018319', (203, 243))	('glioma', 'Phenotype', 'HP:0009733', (294, 300))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('mutation', 'Var', (20, 28))	('central nervous system tumors', 'Disease', 'MESH:D016543', (248, 277))	('malignant peripheral nerve sheath tumors', 'Disease', (203, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('optic glioma', 'Phenotype', 'HP:0009734', (288, 300))	('cancer', 'Disease', (80, 86))	('NF1', 'Gene', '4763', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('malignancy', 'Disease', 'MESH:D009369', (101, 111))	('NF1', 'Gene', (36, 39))	('caused by', 'Reg', (8, 17))	('higher', 'PosReg', (122, 128))	('increased', 'PosReg', (184, 193))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('malignancy', 'Disease', (101, 111))	('central nervous system tumors', 'Disease', (248, 277))	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (203, 243))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('optic glioma', 'Disease', (288, 300))	('nervous system tumors', 'Phenotype', 'HP:0004375', (256, 277))	('optic glioma', 'Disease', 'MESH:D020339', (288, 300))
52623	29172408	Until now, there has been limited information regarding a genetic-clinical association except that the deletion of a whole NF1 gene (manifesting early, large numbers of cutaneous neurofibromas, severe cognitive abnormalities, somatic overgrowth, and facial dysmorphism) and 3-bp in-frame deletion of Exon 17, c.2970-2972 delAAT (manifesting typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas).	('severe cognitive abnormalities', 'Phenotype', 'HP:0010864', (194, 224))	('cognitive abnormalities', 'Disease', 'MESH:D003072', (201, 224))	('NF1', 'Gene', '4763', (372, 375))	('c.2970-2972 delAAT', 'Var', (309, 327))	('cutaneous neurofibromas', 'Disease', (169, 192))	('neurofibromas', 'Disease', (415, 428))	('pigmentary', 'Disease', 'MESH:D005902', (349, 359))	('pigmentary', 'Disease', (349, 359))	('NF1', 'Gene', (372, 375))	('cutaneous neurofibromas', 'Phenotype', 'HP:0100698', (169, 192))	('NF1', 'Gene', '4763', (123, 126))	('neurofibromas', 'Phenotype', 'HP:0001067', (179, 192))	('cognitive abnormalities', 'Phenotype', 'HP:0100543', (201, 224))	('neurofibromas', 'Disease', 'MESH:D009455', (179, 192))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (405, 428))	('NF1', 'Gene', (123, 126))	('facial dysmorphism', 'Disease', 'None', (250, 268))	('overgrowth', 'Phenotype', 'HP:0001548', (234, 244))	('neurofibromas', 'Phenotype', 'HP:0001067', (415, 428))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (250, 268))	('cognitive abnormalities', 'Disease', (201, 224))	('neurofibromas', 'Disease', 'MESH:D009455', (415, 428))	('facial dysmorphism', 'Disease', (250, 268))	('somatic overgrowth', 'Disease', (226, 244))	('neurofibromas', 'Disease', (179, 192))	('somatic overgrowth', 'Disease', 'MESH:D013001', (226, 244))	('pigmentary features', 'Phenotype', 'HP:0001000', (349, 368))	('cutaneous neurofibromas', 'Disease', 'MESH:D009455', (169, 192))	('c.2970-2972 delAAT', 'Mutation', 'rs267606606', (309, 327))
52625	29172408	In the case presented here, we were unable to determine whether the present novel mutation in the NF1 correlates with pheochromocytoma as the sisters of the patient showed no signs of pheochromocytoma and refused further evaluation.	('pheochromocytoma', 'Disease', (184, 200))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (118, 134))	('patient', 'Species', '9606', (157, 164))	('pheochromocytoma', 'Disease', 'MESH:D010673', (184, 200))	('mutation', 'Var', (82, 90))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (184, 200))	('pheochromocytoma', 'Disease', 'MESH:D010673', (118, 134))	('NF1', 'Gene', (98, 101))	('NF1', 'Gene', '4763', (98, 101))	('pheochromocytoma', 'Disease', (118, 134))
52627	29172408	In conclusion, we identified a novel NF1c.6533delT mutation in a Korean patient with NF1 and pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('c.6533delT', 'Var', (40, 50))	('pheochromocytoma', 'Disease', 'MESH:D010673', (93, 109))	('NF1', 'Gene', (37, 40))	('NF1', 'Gene', (85, 88))	('patient', 'Species', '9606', (72, 79))	('NF1', 'Gene', '4763', (37, 40))	('NF1', 'Gene', '4763', (85, 88))	('c.6533delT', 'DELETION', 'None', (40, 50))	('pheochromocytoma', 'Disease', (93, 109))
52637	28986400	Our results confirmed that non-selective alpha-blockade produced a more significant anti-hypertensive effect than selective alpha-blockade.	('hypertensive', 'Disease', (89, 101))	('non-selective', 'Var', (27, 40))	('hypertensive', 'Disease', 'MESH:D006973', (89, 101))
52648	28986400	Because new receptors are constantly being made, the effects of non-selective alpha-blockade do not last its half-life (24 h); therefore, patients must take the medication every 8-12 h. Also, non-selective alpha-blockade may cause side effects such as orthostatic hypotension, reflex tachycardia and nasal congestion because of the inhibition of alpha2 receptors.	('tachycardia', 'Disease', (284, 295))	('orthostatic hypotension', 'Disease', 'MESH:D007024', (252, 275))	('nasal congestion', 'Disease', (300, 316))	('tachycardia', 'Disease', 'MESH:D013610', (284, 295))	('nasal congestion', 'Phenotype', 'HP:0001742', (300, 316))	('hypotension', 'Phenotype', 'HP:0002615', (264, 275))	('orthostatic hypotension', 'Disease', (252, 275))	('non-selective alpha-blockade', 'Var', (192, 220))	('inhibition', 'NegReg', (332, 342))	('cause', 'Reg', (225, 230))	('tachycardia', 'Phenotype', 'HP:0001649', (284, 295))	('patients', 'Species', '9606', (138, 146))	('orthostatic hypotension', 'Phenotype', 'HP:0001278', (252, 275))	('alpha2 receptors', 'Protein', (346, 362))
52721	28986400	As stated, non-selective alpha-blockade provides more obvious preventive effects by irreversible receptor binding, more immediate effects and a significant anti-hypertensive effect.	('hypertensive', 'Disease', (161, 173))	('hypertensive', 'Disease', 'MESH:D006973', (161, 173))	('non-selective', 'Var', (11, 24))	('alpha-blockade', 'Protein', (25, 39))
52725	28986400	Our results confirmed that non-selective alpha-blockade produced a more significant anti-hypertensive effect compared with selective alpha-blockade, for both systolic and diastolic blood pressure.	('hypertensive', 'Disease', (89, 101))	('non-selective', 'Var', (27, 40))	('hypertensive', 'Disease', 'MESH:D006973', (89, 101))	('systolic and', 'MPA', (158, 170))
52745	28986400	Multiple endocrine neoplasia II can be associated with mutation in the RET gene.	('Multiple endocrine neoplasia II', 'Disease', 'MESH:D009377', (0, 31))	('Multiple endocrine neoplasia II', 'Disease', (0, 31))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('RET', 'Gene', '5979', (71, 74))	('associated', 'Reg', (39, 49))	('mutation', 'Var', (55, 63))	('RET', 'Gene', (71, 74))
52752	28986400	Our study of selective vs non-selective alpha-blockade for preoperative preparation of 526 patients undergoing open adrenalectomy for PPGL confirmed that non-selective alpha-blockade resulted in a more significant anti-hypertensive effect than selective alpha-blockade.	('patients', 'Species', '9606', (91, 99))	('hypertensive', 'Disease', 'MESH:D006973', (219, 231))	('hypertensive', 'Disease', (219, 231))	('PPGL', 'Chemical', '-', (134, 138))	('non-selective', 'Var', (154, 167))
52797	25428406	Conversely, the use of beta-blockade before sufficient alpha-blockade would precipitate or worsen a pheochromocytoma crisis.	('pheochromocytoma', 'Disease', 'MESH:D010673', (100, 116))	('use', 'Var', (16, 19))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (100, 116))	('beta-blockade', 'Var', (23, 36))	('worsen', 'NegReg', (91, 97))	('precipitate', 'Reg', (76, 87))	('pheochromocytoma', 'Disease', (100, 116))
52801	25428406	A catecholaminesurge in these patients may also lead to myocardial hibernation or myocardial stunning.	('myocardial stunning', 'Disease', (82, 101))	('catecholamines', 'Chemical', 'MESH:D002395', (2, 16))	('myocardial', 'Disease', (56, 66))	('patients', 'Species', '9606', (30, 38))	('lead to', 'Reg', (48, 55))	('catecholaminesurge', 'Var', (2, 20))
52843	28900474	The presence of a malignant paraganglioma in the paediatric age group makes it necessary to define the biochemical phenotype and family history, since it may be part of a syndromic condition, as in the case of mutations in the gene that codes for the enzyme succinate dehydrogenase B subunit SDHB), C (SDHC) or D (SDHD).	('syndromic condition', 'Disease', 'MESH:D009135', (171, 190))	('SDHB', 'Gene', (292, 296))	('SDHD', 'Gene', '6392', (314, 318))	('mutations', 'Var', (210, 219))	('SDHC', 'Gene', '6391', (302, 306))	('malignant paraganglioma', 'Disease', (18, 41))	('SDHD', 'Gene', (314, 318))	('paraganglioma', 'Phenotype', 'HP:0002668', (28, 41))	('SDHC', 'Gene', (302, 306))	('malignant paraganglioma', 'Disease', 'MESH:C565335', (18, 41))	('SDHB', 'Gene', '6390', (292, 296))	('syndromic condition', 'Disease', (171, 190))
52847	28099363	Different RET gene mutation-induced multiple endocrine neoplasia type 2A in 3 Chinese families Multiple endocrine neoplasia type 2A (MEN2A) is a condition with inherited autosomal dominant mutations in RET (rearranged during transfection) gene that predisposes the carrier to extremely high risk of medullary thyroid cancer (MTC) and other MEN2A-associated tumors such as parathyroid cancer and/or pheochromocytoma.	('MEN2A', 'Gene', (340, 345))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (398, 414))	('MEN2A', 'Gene', '5979', (340, 345))	('predisposes', 'Reg', (249, 260))	('Multiple endocrine neoplasia type 2A', 'Gene', (95, 131))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('rearranged during transfection', 'Gene', (207, 237))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (299, 323))	('parathyroid cancer', 'Disease', 'MESH:D010282', (372, 390))	('RET', 'Gene', (202, 205))	('parathyroid cancer', 'Disease', (372, 390))	('rearranged during transfection', 'Gene', '5979', (207, 237))	('multiple endocrine neoplasia type 2A', 'Gene', (36, 72))	('multiple endocrine neoplasia type 2A', 'Gene', '5979', (36, 72))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('tumors', 'Disease', (357, 363))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))	('neoplasia', 'Phenotype', 'HP:0002664', (114, 123))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (372, 390))	('RET', 'Gene', (10, 13))	('mutations', 'Var', (189, 198))	('thyroid cancer', 'Disease', (309, 323))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (45, 64))	('Multiple endocrine neoplasia type 2A', 'Gene', '5979', (95, 131))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (104, 123))	('mutation-induced', 'Var', (19, 35))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('RET', 'Gene', '5979', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('thyroid cancer', 'Disease', 'MESH:D013964', (376, 390))	('thyroid cancer', 'Phenotype', 'HP:0002890', (309, 323))	('RET', 'Gene', '5979', (202, 205))	('pheochromocytoma', 'Disease', 'MESH:D010673', (398, 414))	('thyroid cancer', 'Disease', 'MESH:D013964', (309, 323))	('thyroid cancer', 'Phenotype', 'HP:0002890', (376, 390))	('neoplasia', 'Phenotype', 'HP:0002664', (55, 64))	('MTC', 'Phenotype', 'HP:0002865', (325, 328))	('MEN2A', 'Gene', '5979', (133, 138))	('pheochromocytoma', 'Disease', (398, 414))	('MEN2A', 'Gene', (133, 138))
52850	28099363	Different mutations in the RET gene were identified: C634S in Family 1, C611Y in Family 2, and C634Y in Family 3.	('C634S', 'Mutation', 'rs75076352', (53, 58))	('RET', 'Gene', (27, 30))	('C634Y', 'Mutation', 'rs75996173', (95, 100))	('C611Y', 'Var', (72, 77))	('C634Y', 'Var', (95, 100))	('C634S', 'Var', (53, 58))	('C611Y', 'Mutation', 'rs377767397', (72, 77))
52857	28099363	FMTC is associated with simple medullary thyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('FMTC', 'Var', (0, 4))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('associated', 'Reg', (8, 18))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (31, 58))	('MTC', 'Phenotype', 'HP:0002865', (1, 4))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
52859	28099363	Of these, more than 95% of MEN2A cases present a single point mutation in the RET gene.	('RET', 'Gene', (78, 81))	('MEN2A', 'Gene', (27, 32))	('single point mutation', 'Var', (49, 70))	('MEN2A', 'Gene', '5979', (27, 32))
52863	28099363	In the wild-type RET, phosphorylation of its tyrosine kinase domain stimulates the receptor and consequently the downstream signaling pathways.	('tyrosine', 'Chemical', 'MESH:D014443', (45, 53))	('receptor', 'Pathway', (83, 91))	('downstream signaling pathways', 'Pathway', (113, 142))	('stimulates', 'PosReg', (68, 78))	('phosphorylation', 'Var', (22, 37))
52864	28099363	However, nucleotide mutations in 7 exons (exons 8, 10, 11, 13, 14, 15, or 16) of the RET gene resulting in Cys to Tyr in the RET protein have been found.	('Cys to Tyr in the RET protein', 'MPA', (107, 136))	('RET', 'Gene', (85, 88))	('Tyr', 'Chemical', 'MESH:D014443', (114, 117))	('nucleotide mutations', 'Var', (9, 29))	('Cys', 'Chemical', 'MESH:D003545', (107, 110))
52865	28099363	All these gain-of-function mutations lead to a constitutive activation of RET, which consequently causes hyperplasia and cancerization of the affected cells.	('mutations', 'Var', (27, 36))	('RET', 'Protein', (74, 77))	('causes', 'Reg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hyperplasia', 'Disease', (105, 116))	('activation', 'PosReg', (60, 70))	('gain-of-function', 'PosReg', (10, 26))	('cancerization', 'CPA', (121, 134))	('hyperplasia', 'Disease', 'MESH:D006965', (105, 116))
52868	28099363	Any 1 of the 5 cysteine residues (609, 611, 618, 620, and 634) in the cysteine-rich region of the RET extracellular domain can cause MEN2A and FMTC.	('cysteine', 'Chemical', 'MESH:D003545', (70, 78))	('618', 'Var', (44, 47))	('MTC', 'Phenotype', 'HP:0002865', (144, 147))	('cause', 'Reg', (127, 132))	('cysteine', 'Chemical', 'MESH:D003545', (15, 23))	('FMTC', 'Disease', (143, 147))	('MEN2A', 'Gene', '5979', (133, 138))	('609', 'Var', (34, 37))	('MEN2A', 'Gene', (133, 138))
52869	28099363	Herein, we present the findings of different RET gene mutation-induced MEN2A in 3 Chinese families with diverse medical histories, as well as clinical, laboratory, and genetic characteristics.	('MEN2A', 'Gene', (71, 76))	('mutation-induced', 'Var', (54, 70))	('RET gene', 'Gene', (45, 53))	('MEN2A', 'Gene', '5979', (71, 76))
52887	28099363	Total DNA isolated from the peripheral blood of all the probands was used for screening the potential mutations in the following genes: SDHAF2 (succinate dehydrogenase complex assembly factor 2), SDHB (succinate dehydrogenase subunit B), SDHC (succinate dehydrogenase subunit C), SDHD (succinate dehydrogenase subunit D), MAX (MYC associated factor X), NF1 (neurofibromin 1), RET, and VHL (Von Hippel-Lindau) using Target Capture-Based Deep Sequencing (BGI Health, Shenzhen, Guangdong, China).	('SDHD', 'Gene', (280, 284))	('SDHB', 'Gene', '6390', (196, 200))	('succinate dehydrogenase complex assembly factor 2', 'Gene', '54949', (144, 193))	('SDHAF2', 'Gene', (136, 142))	('SDHAF2', 'Gene', '54949', (136, 142))	('succinate dehydrogenase subunit B', 'Gene', '6390', (202, 235))	('succinate dehydrogenase subunit C', 'Gene', (244, 277))	('mutations', 'Var', (102, 111))	('VHL', 'Gene', (385, 388))	('succinate dehydrogenase subunit D', 'Gene', '6392', (286, 319))	('NF1', 'Gene', '4763', (353, 356))	('SDHB', 'Gene', (196, 200))	('SDHC', 'Gene', '6391', (238, 242))	('Von Hippel-Lindau', 'Gene', '7428', (390, 407))	('MAX', 'Gene', '4149', (322, 325))	('succinate dehydrogenase complex assembly factor 2', 'Gene', (144, 193))	('Von Hippel-Lindau', 'Gene', (390, 407))	('MYC associated factor X', 'Gene', (327, 350))	('succinate dehydrogenase subunit B', 'Gene', (202, 235))	('NF1', 'Gene', (353, 356))	('VHL', 'Gene', '7428', (385, 388))	('neurofibromin 1', 'Gene', '4763', (358, 373))	('MYC associated factor X', 'Gene', '4149', (327, 350))	('SDHD', 'Gene', '6392', (280, 284))	('succinate dehydrogenase subunit C', 'Gene', '6391', (244, 277))	('neurofibromin 1', 'Gene', (358, 373))	('SDHC', 'Gene', (238, 242))	('MAX', 'Gene', (322, 325))	('succinate dehydrogenase subunit D', 'Gene', (286, 319))
52892	28099363	The mutation in the RET gene in proband 1 was Cys634Ser (Fig.	('RET', 'Gene', (20, 23))	('Cys634Ser', 'SUBSTITUTION', 'None', (46, 55))	('Cys634Ser', 'Var', (46, 55))
52903	28099363	Proband 1 (Cys634Ser) mainly showed pheochromocytoma with MTC being indicated, proband 2 (Cys611Tyr) presented MTC and pheochromocytoma, whereas the only symptom of proband 3 (Cys634Tyr) was MTC.	('Cys634Ser', 'Var', (11, 20))	('Cys611Tyr', 'Var', (90, 99))	('Cys634Tyr', 'Var', (176, 185))	('MTC', 'Phenotype', 'HP:0002865', (58, 61))	('pheochromocytoma', 'Disease', (36, 52))	('Cys634Tyr', 'SUBSTITUTION', 'None', (176, 185))	('pheochromocytoma', 'Disease', (119, 135))	('Cys611Tyr', 'SUBSTITUTION', 'None', (90, 99))	('pheochromocytoma', 'Disease', 'MESH:D010673', (36, 52))	('Cys634Ser', 'SUBSTITUTION', 'None', (11, 20))	('MTC', 'Phenotype', 'HP:0002865', (111, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('MTC', 'Phenotype', 'HP:0002865', (191, 194))	('pheochromocytoma', 'Disease', 'MESH:D010673', (119, 135))	('MTC', 'Disease', (111, 114))
52905	28099363	Therefore, we concluded that the cysteine substitution by tyrosine was predisposed to induce MTC, which metastasized easily while the cysteine substitution by serine was inclined to induce pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (189, 205))	('cysteine substitution by tyrosine', 'Var', (33, 66))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (189, 205))	('tyrosine', 'Chemical', 'MESH:D014443', (58, 66))	('MTC', 'Phenotype', 'HP:0002865', (93, 96))	('cysteine', 'Chemical', 'MESH:D003545', (33, 41))	('induce MTC', 'Disease', (86, 96))	('serine', 'Chemical', 'MESH:D012694', (159, 165))	('cysteine', 'Chemical', 'MESH:D003545', (134, 142))	('MTC', 'Disease', (93, 96))	('pheochromocytoma', 'Disease', (189, 205))
52907	28099363	In this case report, we presented the clinical, laboratory, and genetic characteristics of 3 Chinese families with different RET gene mutation-induced MEN2A.	('RET gene', 'Gene', (125, 133))	('MEN2A', 'Gene', '5979', (151, 156))	('MEN2A', 'Gene', (151, 156))	('mutation-induced', 'Var', (134, 150))
52908	28099363	The 3 probands harbor Cys634Ser, Cys611Tyr, and Cys634Tyr mutations in the gene, respectively.	('Cys634Ser', 'SUBSTITUTION', 'None', (22, 31))	('Cys634Tyr', 'Var', (48, 57))	('Cys611Tyr', 'Var', (33, 42))	('Cys634Ser', 'Var', (22, 31))	('Cys634Tyr', 'SUBSTITUTION', 'None', (48, 57))	('Cys611Tyr', 'SUBSTITUTION', 'None', (33, 42))
52912	28099363	Of the 3 RET gene mutation-induced MEN2A syndromes reported in this study, 2 included the mutation on residue 634 and the third on residue 611; however, they showed diverse phenotypes.	('MEN2A', 'Gene', (35, 40))	('mutation on residue 634', 'Var', (90, 113))	('RET gene', 'Gene', (9, 17))	('MEN2A', 'Gene', '5979', (35, 40))
52913	28099363	Carlomagno et al found that different phenotypes of MEN2A and FMTC resulting from Cys-634 mutation of MEN2A could lead to higher activity of RET as compared to Cys-620 mutation of FMTC.	('RET', 'Enzyme', (141, 144))	('MEN2A', 'Gene', (102, 107))	('MTC', 'Phenotype', 'HP:0002865', (181, 184))	('Cys-634 mutation', 'Var', (82, 98))	('higher', 'PosReg', (122, 128))	('MTC', 'Phenotype', 'HP:0002865', (63, 66))	('MEN2A', 'Gene', '5979', (52, 57))	('Cys', 'Chemical', 'MESH:D003545', (160, 163))	('MEN2A', 'Gene', (52, 57))	('Cys', 'Chemical', 'MESH:D003545', (82, 85))	('activity', 'MPA', (129, 137))	('MEN2A', 'Gene', '5979', (102, 107))
52914	28099363	Conversely, the alteration of only certain amino acids (634 in MEN2A and 918 in MEN2B) effectuates a sufficiently high RET stimulation to cause a neoplastic transformation of adrenal chromaffin cells, indicating that even in the MEN2A phenotype, pheochromocytomas have been observed less frequently than MTCs.	('MEN2A', 'Gene', '5979', (63, 68))	('neoplastic transformation', 'CPA', (146, 171))	('MTC', 'Phenotype', 'HP:0002865', (304, 307))	('MEN2A', 'Gene', (63, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (246, 262))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (246, 263))	('MEN2B', 'Gene', (80, 85))	('cause', 'Reg', (138, 143))	('chromaffin', 'Chemical', '-', (183, 193))	('MEN2B', 'Gene', '5979', (80, 85))	('MEN2A', 'Gene', '5979', (229, 234))	('pheochromocytomas', 'Disease', 'MESH:D010673', (246, 263))	('634', 'Var', (56, 59))	('MEN2A', 'Gene', (229, 234))	('pheochromocytomas', 'Disease', (246, 263))	('alteration', 'Var', (16, 26))
52916	28099363	This exhibition of phenotype at different ages could be attributed to the proband and her sister showing increased sensitivity to the Cys611Tyr mutation than their mother.	('Cys611Tyr', 'SUBSTITUTION', 'None', (134, 143))	('Cys611Tyr', 'Var', (134, 143))	('sensitivity', 'MPA', (115, 126))	('increased', 'PosReg', (105, 114))
52918	28099363	Moreover, the expression of dominant-negative forms of AKT has been recently reported to inhibit RET-MEN2A oncogenic activity, indicating that the second family members could harbor different AKT activities.	('AKT', 'Gene', (192, 195))	('AKT', 'Gene', (55, 58))	('dominant-negative', 'Var', (28, 45))	('AKT', 'Gene', '207', (192, 195))	('MEN2A', 'Gene', '5979', (101, 106))	('inhibit', 'NegReg', (89, 96))	('MEN2A', 'Gene', (101, 106))	('AKT', 'Gene', '207', (55, 58))
52922	28099363	For the same reason, screening of RET mutation and prediction of MEN2 with high-risk of pheochromocytoma should be carried out at the earliest.	('pheochromocytoma', 'Disease', (88, 104))	('MEN', 'Species', '9606', (65, 68))	('pheochromocytoma', 'Disease', 'MESH:D010673', (88, 104))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (88, 104))	('mutation', 'Var', (38, 46))
52924	28099363	In the case of MEN2A patients with early manifestation of pheochromocytoma, screening and confirming the RET mutation followed by a timely treatment at an early stage is suggested to prevent the development of MTC.	('RET', 'Gene', (105, 108))	('pheochromocytoma', 'Disease', 'MESH:D010673', (58, 74))	('MTC', 'Phenotype', 'HP:0002865', (210, 213))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (58, 74))	('patients', 'Species', '9606', (21, 29))	('MEN2A', 'Gene', (15, 20))	('MEN2A', 'Gene', '5979', (15, 20))	('pheochromocytoma', 'Disease', (58, 74))	('mutation', 'Var', (109, 117))
52926	28099363	In order to improve prognosis, thyroidectomy should be conducted by 5 to 10 years of age in children carrying the RET gene mutations at codons 609, 630, 768, 790, 791, 804, and 891 (referred as level 1).	('RET gene', 'Gene', (114, 122))	('children', 'Species', '9606', (92, 100))	('mutations', 'Var', (123, 132))
52931	28099363	Therefore, transgenic mice carrying each of these 3 mutations could be established and used for studying the underlying mechanisms in RET gene mutation-induced MEN2A.	('mutation-induced', 'Var', (143, 159))	('transgenic mice', 'Species', '10090', (11, 26))	('MEN2A', 'Gene', (160, 165))	('RET gene', 'Gene', (134, 142))	('MEN2A', 'Gene', '5979', (160, 165))
52932	28099363	We might also aspire to explore the diverse functions and phenotypes by transfecting thyroid or chromaffin cell lines with plasmids expressing different RET mutations.	('chromaffin', 'Chemical', '-', (96, 106))	('mutations', 'Var', (157, 166))	('RET', 'Gene', (153, 156))
52978	26649218	Deep biopsy may cause uncontrolled bleeding and require tracheotomy.	('bleeding', 'Disease', (35, 43))	('bleeding', 'Disease', 'MESH:D006470', (35, 43))	('Deep biopsy', 'Var', (0, 11))	('cause', 'Reg', (16, 21))
52993	26649218	Apart from characterizing a lesion as neuroendocrine tumor, 68Ga-DOTA-peptide PET/CT can reveal extension of disease and exclude synchronous and metastatic lesions.	('68Ga-DOTA-peptide', 'Var', (60, 77))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (38, 58))	('extension', 'Disease', (96, 105))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (38, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('neuroendocrine tumor', 'Disease', (38, 58))	('exclude', 'NegReg', (121, 128))
53013	26543766	Hereditary HNPGLs are mostly caused by mutations of the SDHD gene, but SDHB and SDHC mutations are not uncommon in such patients.	('SDHD', 'Gene', (56, 60))	('SDHD', 'Gene', '6392', (56, 60))	('caused by', 'Reg', (29, 38))	('PGLs', 'Phenotype', 'HP:0002668', (13, 17))	('SDHB', 'Gene', '6390', (71, 75))	('mutations', 'Var', (39, 48))	('SDHB', 'Gene', (71, 75))	('SDHC', 'Gene', (80, 84))	('patients', 'Species', '9606', (120, 128))	('HNPGLs', 'Phenotype', 'HP:0002864', (11, 17))	('SDHC', 'Gene', '6391', (80, 84))	('Hereditary HNPGLs', 'Disease', (0, 17))
53014	26543766	Multiple head and neck paragangliomas are common in patients with SDHD mutations, while malignant head and neck paraganglioma is mostly seen in patients with SDHB mutations (Burnichon et al.	('SDHB', 'Gene', '6390', (158, 162))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (98, 125))	('paragangliomas', 'Phenotype', 'HP:0002668', (23, 37))	('SDHD', 'Gene', (66, 70))	('paraganglioma', 'Phenotype', 'HP:0002668', (23, 36))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (9, 36))	('mutations', 'Var', (71, 80))	('neck paragangliomas', 'Disease', (18, 37))	('SDHB', 'Gene', (158, 162))	('common', 'Reg', (42, 48))	('patients', 'Species', '9606', (52, 60))	('neck paraganglioma', 'Disease', 'MESH:D010235', (18, 36))	('neck paraganglioma', 'Disease', (107, 125))	('neck paraganglioma', 'Disease', 'MESH:D010235', (107, 125))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (9, 37))	('neck paragangliomas', 'Disease', 'MESH:D010235', (18, 37))	('patients', 'Species', '9606', (144, 152))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (18, 37))	('SDHD', 'Gene', '6392', (66, 70))	('paraganglioma', 'Phenotype', 'HP:0002668', (112, 125))
53077	26543766	Recurrent genetic alterations have so far been reported for thymomas as well as for thymic squamous cell carcinoma.	('genetic alterations', 'Var', (10, 29))	('thymoma', 'Phenotype', 'HP:0100522', (60, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('thymomas', 'Disease', (60, 68))	('squamous cell carcinoma', 'Disease', (91, 114))	('thymomas', 'Disease', 'MESH:D013945', (60, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))	('reported', 'Reg', (47, 55))
53078	26543766	Deletions of chromosome 6p are reported with type A thymoma and gains of chromosome 1q and losses of chromosomes 6 and 13q are reported with type B3 thymomas (Zettl et al.).	('thymoma', 'Phenotype', 'HP:0100522', (149, 156))	('thymoma', 'Phenotype', 'HP:0100522', (52, 59))	('type B3 thymomas', 'Disease', 'MESH:D013945', (141, 157))	('type A thymoma', 'Disease', (45, 59))	('losses', 'NegReg', (91, 97))	('type A thymoma', 'Disease', 'MESH:D013945', (45, 59))	('gains', 'PosReg', (64, 69))	('type B3 thymomas', 'Disease', (141, 157))	('Deletions', 'Var', (0, 9))
53082	26543766	Only 2 % of PGLs are found in the mediastinum and are associated with germ line mutations in either SDHB or SDHD.	('SDHD', 'Gene', '6392', (108, 112))	('PGLs', 'Phenotype', 'HP:0002668', (12, 16))	('mutations', 'Var', (80, 89))	('SDHB', 'Gene', '6390', (100, 104))	('SDHB', 'Gene', (100, 104))	('associated', 'Reg', (54, 64))	('SDHD', 'Gene', (108, 112))
53086	26543766	Mutations in the genes encoding succinate dehydrogenase (SDH) subunits B, C, and D cause extra-adrenal PGLs.	('SDH', 'Gene', (57, 60))	('extra-adrenal PGLs', 'Disease', (89, 107))	('Mutations', 'Var', (0, 9))	('cause', 'Reg', (83, 88))	('PGLs', 'Phenotype', 'HP:0002668', (103, 107))	('succinate dehydrogenase', 'Gene', '6390', (32, 55))	('SDH', 'Gene', '6390', (57, 60))	('succinate dehydrogenase', 'Gene', (32, 55))
53110	23853620	Cocaine can block the reuptake of noradrenaline, leading to increasing its concentration and consequently its effects as well, and induce local or diffuse coronary vasoconstriction in normal coronary artery segments per se, cocaine can also trigger pheochromocytoma crisis, and therefore, cardiac complications such as myocardial infarction due to these additive effects are intended to occur.	('concentration', 'MPA', (75, 88))	('myocardial infarction', 'Disease', (319, 340))	('cardiac complications', 'Disease', (289, 310))	('cocaine', 'Var', (224, 231))	('reuptake', 'MPA', (22, 30))	('myocardial infarction', 'Phenotype', 'HP:0001658', (319, 340))	('pheochromocytoma', 'Disease', 'MESH:D010673', (249, 265))	('trigger', 'Reg', (241, 248))	('local', 'MPA', (138, 143))	('myocardial infarction', 'Disease', 'MESH:D009203', (319, 340))	('pheochromocytoma', 'Disease', (249, 265))	('increasing', 'PosReg', (60, 70))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (249, 265))	('Cocaine', 'Chemical', 'MESH:D003042', (0, 7))	('noradrenaline', 'Chemical', 'MESH:D009638', (34, 47))	('induce', 'Reg', (131, 137))	('cardiac complications', 'Disease', 'MESH:D005117', (289, 310))	('effects', 'MPA', (110, 117))	('cocaine', 'Chemical', 'MESH:D003042', (224, 231))
53142	23853620	Similarly, many conditions such as tricyclic antidepressant consumption, drugs stimulating adrenergic receptors, dopamine antagonists, many drugs prescribed for obesity and other over the counter medications such as nasal decongestants containing ephedrine, pseudoephedrine, or phenylproanolamine can also precipitate myocardial infarction in individuals with underlying pheochromocytomas.	('pheochromocytomas', 'Disease', (371, 388))	('obesity', 'Phenotype', 'HP:0001513', (161, 168))	('myocardial infarction', 'Phenotype', 'HP:0001658', (318, 339))	('phenylproanolamine', 'Var', (278, 296))	('precipitate', 'Reg', (306, 317))	('pheochromocytomas', 'Disease', 'MESH:D010673', (371, 388))	('obesity', 'Disease', (161, 168))	('pseudoephedrine', 'Chemical', 'MESH:D054199', (258, 273))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (371, 388))	('obesity', 'Disease', 'MESH:D009765', (161, 168))	('phenylproanolamine', 'Chemical', '-', (278, 296))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (371, 387))	('ephedrine', 'Chemical', 'MESH:D004809', (247, 256))	('myocardial infarction', 'Disease', (318, 339))	('dopamine', 'Chemical', 'MESH:D004298', (113, 121))	('myocardial infarction', 'Disease', 'MESH:D009203', (318, 339))	('drugs', 'Var', (73, 78))	('ephedrine', 'Chemical', 'MESH:D004809', (264, 273))
53200	22974104	SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function.	('PDGFRA', 'Gene', (117, 123))	('PDGFRA', 'Gene', '5156', (117, 123))	('gastrointestinal stromal tumors', 'Disease', (69, 100))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (134, 165))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (134, 165))	('SDHA', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SDHA', 'Gene', '6389', (0, 4))	('GIST', 'Phenotype', 'HP:0100723', (170, 174))	('gastrointestinal stromal tumors', 'Disease', (134, 165))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (69, 100))	('mutations', 'Var', (22, 31))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (69, 100))	('succinate dehydrogenase', 'Gene', '6389', (220, 243))	('SDH', 'Gene', (245, 248))	('succinate dehydrogenase', 'Gene', (220, 243))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('loss of function', 'NegReg', (5, 21))
53201	22974104	A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II.	('SDHA', 'Gene', '6389', (125, 129))	('GIST', 'Phenotype', 'HP:0100723', (61, 65))	('PDGFRA WT GIST', 'Gene', '5156', (51, 65))	('PDGFRA WT GIST', 'Gene', (51, 65))	('SDHA', 'Gene', (125, 129))	('mutations', 'Var', (112, 121))
53202	22974104	A germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform.	('SDHA', 'Gene', '6389', (29, 33))	('p.Arg31X', 'Var', (11, 19))	('p.Arg31X', 'Mutation', 'rs142441643', (11, 19))	('SDHA', 'Gene', (29, 33))
53203	22974104	An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort.	('p.D38V missense', 'Var', (14, 29))	('SDHA', 'Gene', (42, 46))	('p.D38V', 'Mutation', 'rs34635677', (14, 20))	('GIST', 'Phenotype', 'HP:0100723', (120, 124))	('PDGFRA WT GIST', 'Gene', '5156', (110, 124))	('PDGFRA WT GIST', 'Gene', (110, 124))	('SDHA', 'Gene', '6389', (42, 46))	('patients', 'Species', '9606', (125, 133))
53204	22974104	Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors.	('SDHA', 'Gene', (75, 79))	('GIST', 'Phenotype', 'HP:0100723', (139, 143))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('SDHA', 'Gene', '6389', (32, 36))	('WT GIST tumors', 'Disease', (136, 150))	('mutations', 'Var', (80, 89))	('WT GIST tumors', 'Disease', 'MESH:D046152', (136, 150))	('SDHA', 'Gene', '6389', (75, 79))	('SDHA', 'Gene', (32, 36))	('expression', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('loss', 'NegReg', (24, 28))
53207	22974104	Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults.	('PDGFRA WT GIST', 'Gene', (74, 88))	('SDH complex', 'Gene', (17, 28))	('GIST', 'Phenotype', 'HP:0100723', (84, 88))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (54, 64))	('PDGFRA WT GIST', 'Gene', '5156', (74, 88))
53209	22974104	The majority of gastrointestinal stromal tumors (GIST) harbor gain-of-function mutations in KIT or PDGFRA, resulting in the activation of the downstream pathways PI3K/AKT, Ras/MAPK, and JAK/STAT3, and playing a crucial role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('activation', 'PosReg', (124, 134))	('tumor', 'Disease', (227, 232))	('STAT3', 'Gene', (190, 195))	('gain-of-function', 'PosReg', (62, 78))	('KIT', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (16, 47))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (16, 47))	('mutations', 'Var', (79, 88))	('PI3K/AKT', 'Pathway', (162, 170))	('STAT3', 'Gene', '6774', (190, 195))	('PDGFRA', 'Gene', '5156', (99, 105))	('PDGFRA', 'Gene', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('tumor', 'Disease', (41, 46))	('gastrointestinal stromal tumors', 'Disease', (16, 47))	('GIST', 'Phenotype', 'HP:0100723', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('Ras/MAPK', 'Pathway', (172, 180))
53210	22974104	A subset of GIST lack specific KIT or PDGFRA mutations and form a heterogeneous group, including NF1, Carney Triad (CT), Carney-Stratakis Syndrome (CSS), pediatric and young adult GIST, and a small proportion (<10%) of sporadic adult GIST.	('Carney-Stratakis Syndrome', 'Disease', 'MESH:C564650', (121, 146))	('NF1', 'Gene', (97, 100))	('mutations', 'Var', (45, 54))	('KIT', 'Gene', (31, 34))	('CSS', 'Disease', (148, 151))	('PDGFRA', 'Gene', (38, 44))	('NF1', 'Gene', '4763', (97, 100))	('PDGFRA', 'Gene', '5156', (38, 44))	('Carney Triad', 'Disease', (102, 114))	('CSS', 'Disease', 'MESH:C536436', (148, 151))	('GIST', 'Phenotype', 'HP:0100723', (12, 16))	('GIST', 'Phenotype', 'HP:0100723', (234, 238))	('Carney-Stratakis Syndrome', 'Disease', (121, 146))	('GIST', 'Phenotype', 'HP:0100723', (180, 184))
53211	22974104	The mechanisms involved in the tumorigenesis of GIST lacking KIT or PDGFRA mutations are still poorly understood.	('PDGFRA', 'Gene', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('mutations', 'Var', (75, 84))	('GIST', 'Phenotype', 'HP:0100723', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('PDGFRA', 'Gene', '5156', (68, 74))
53219	22974104	Loss of SDHB is also seen in WT GIST occuring in the context of CSS with genlius mutation of SDHB or SDHC (II).	('SDHB', 'Gene', '6390', (8, 12))	('SDHB', 'Gene', (93, 97))	('mutation', 'Var', (81, 89))	('SDHB', 'Gene', (8, 12))	('CSS', 'Disease', (64, 67))	('SDHC', 'Gene', (101, 105))	('CSS', 'Disease', 'MESH:C536436', (64, 67))	('SDHC', 'Gene', '6391', (101, 105))	('SDHB', 'Gene', '6390', (93, 97))	('GIST', 'Phenotype', 'HP:0100723', (32, 36))
53222	22974104	One possible explanation is loss of function mutations in the SDHA gene, which have been recently identified in four patients (one pediatric and 3 young adult) with sporadic GIST lacking KIT or PDGFRA mutations.	('mutations', 'Var', (45, 54))	('SDHA', 'Gene', (62, 66))	('GIST', 'Phenotype', 'HP:0100723', (174, 178))	('PDGFRA', 'Gene', (194, 200))	('PDGFRA', 'Gene', '5156', (194, 200))	('patients', 'Species', '9606', (117, 125))	('SDHA', 'Gene', '6389', (62, 66))
53223	22974104	The aim of this study was to assess globally by next generation sequencing mutations in the SDH-pathway, as well as determine the mutational and expression status of SDHA in a series of syndromic and sporadic GIST without mutations in KIT or PDGFRA.	('SDHA', 'Gene', '6389', (166, 170))	('GIST', 'Phenotype', 'HP:0100723', (209, 213))	('SDHA', 'Gene', (166, 170))	('KIT', 'Gene', (235, 238))	('SDH-pathway', 'Gene', (92, 103))	('mutations', 'Var', (75, 84))	('PDGFRA', 'Gene', '5156', (242, 248))	('PDGFRA', 'Gene', (242, 248))
53235	22974104	Western blotting was performed to assess the expression of SDHA in WT GIST with and without SDHA mutation.	('SDHA', 'Gene', (59, 63))	('SDHA', 'Gene', '6389', (92, 96))	('SDHA', 'Gene', '6389', (59, 63))	('mutation', 'Var', (97, 105))	('SDHA', 'Gene', (92, 96))	('GIST', 'Phenotype', 'HP:0100723', (70, 74))
53236	22974104	Frozen tissue from seven WT GIST (two with SDHA mutation and five without SDHA mutation) were homogenized in RIPA buffer supplemented with protease and phosphatase inhibitors.	('RIPA buffer', 'Chemical', '-', (109, 120))	('SDHA', 'Gene', '6389', (74, 78))	('SDHA', 'Gene', '6389', (43, 47))	('mutation', 'Var', (48, 56))	('GIST', 'Phenotype', 'HP:0100723', (28, 32))	('SDHA', 'Gene', (74, 78))	('SDHA', 'Gene', (43, 47))
53245	22974104	Massive parallel next-generation sequencing of six cases of WT GIST (five pediatric and one young adult) revealed that the GIST from the young adult patient (22 year-old man, with multinodular gastric lesions and multiple liver metastases) carried a C to T transition at nucleotide 206 in SDHA exon 2, a nonsense mutation resulting in the replacement of arginine with a stop codon at residue 31 of SDHA, causing truncation of the peptide chain at residue 30 (p.Arg31X) (Figure 1).	('SDHA', 'Gene', '6389', (289, 293))	('replacement', 'Var', (339, 350))	('multinodular gastric lesions', 'Disease', 'MESH:D013272', (180, 208))	('multinodular gastric lesions', 'Disease', (180, 208))	('SDHA', 'Gene', (398, 402))	('metastases', 'Disease', (228, 238))	('GIST', 'Phenotype', 'HP:0100723', (123, 127))	('p.Arg31X', 'Mutation', 'rs142441643', (459, 467))	('SDHA', 'Gene', (289, 293))	('causing', 'Reg', (404, 411))	('truncation', 'MPA', (412, 422))	('arginine', 'Chemical', 'MESH:D001120', (354, 362))	('metastases', 'Disease', 'MESH:D009362', (228, 238))	('patient', 'Species', '9606', (149, 156))	('GIST', 'Phenotype', 'HP:0100723', (63, 67))	('C to T transition at nucleotide 206', 'Mutation', 'rs886043564', (250, 285))	('SDHA', 'Gene', '6389', (398, 402))	('man', 'Species', '9606', (170, 173))
53249	22974104	Since two prior reports also identified mutations in SDHA exons 9 and 13 in WT GIST, we performed targeted SDHA exons 2, 9 and 13 sequencing in 11 additional cases of pediatric and young adult WT GIST.	('SDHA', 'Gene', '6389', (107, 111))	('GIST', 'Phenotype', 'HP:0100723', (196, 200))	('SDHA', 'Gene', '6389', (53, 57))	('SDHA', 'Gene', (107, 111))	('mutations', 'Var', (40, 49))	('GIST', 'Phenotype', 'HP:0100723', (79, 83))	('SDHA', 'Gene', (53, 57))
53250	22974104	By this method, another young adult WT GIST (26 year-old woman with bulky intra-peritoneal and liver metastatic disease) was identified to harbor a missense mutation in SDHA exon 2 (p. D38V)(Figure 2).	('liver metastatic disease', 'Disease', 'MESH:D008107', (95, 119))	('GIST', 'Phenotype', 'HP:0100723', (39, 43))	('SDHA', 'Gene', '6389', (169, 173))	('woman', 'Species', '9606', (57, 62))	('missense', 'Var', (148, 156))	('liver metastatic disease', 'Disease', (95, 119))	('D38V', 'SUBSTITUTION', 'None', (185, 189))	('D38V', 'Var', (185, 189))	('SDHA', 'Gene', (169, 173))
53254	22974104	To confirm the functional impact of SDHA mutation, we assessed SDHA protein expression by western blotting in seven WT GISTs, including three samples from the two patients with SDHA mutation and four without SDHA mutation (Figure 3).	('patients', 'Species', '9606', (163, 171))	('GIST', 'Phenotype', 'HP:0100723', (119, 123))	('SDHA', 'Gene', '6389', (36, 40))	('SDHA', 'Gene', '6389', (63, 67))	('SDHA', 'Gene', (63, 67))	('SDHA', 'Gene', '6389', (208, 212))	('SDHA', 'Gene', '6389', (177, 181))	('SDHA', 'Gene', (36, 40))	('mutation', 'Var', (182, 190))	('SDHA', 'Gene', (177, 181))	('SDHA', 'Gene', (208, 212))
53255	22974104	We found that SDHA expression was absent in the two cases harboring a mutation of SDHA and present in the other cases.	('SDHA', 'Gene', (14, 18))	('SDHA', 'Gene', '6389', (82, 86))	('mutation', 'Var', (70, 78))	('absent', 'NegReg', (34, 40))	('SDHA', 'Gene', '6389', (14, 18))	('SDHA', 'Gene', (82, 86))
53257	22974104	The WT GIST associated with a germline SDHA mutation showed complete loss of both SDHA and SDHB protein (Figure 4 A,B), while the tumor with a somatic, heterozygous SDHA mutation showed significant decreased in SDHA immuno-expression, as well as complete loss of SDHB (Figure 4 C,D).	('protein', 'Protein', (96, 103))	('loss', 'NegReg', (69, 73))	('mutation', 'Var', (44, 52))	('SDHB', 'Gene', (263, 267))	('SDHA', 'Gene', '6389', (82, 86))	('GIST', 'Phenotype', 'HP:0100723', (7, 11))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('decreased', 'NegReg', (198, 207))	('SDHA', 'Gene', (39, 43))	('loss', 'NegReg', (255, 259))	('SDHA', 'Gene', (165, 169))	('SDHB', 'Gene', '6390', (91, 95))	('SDHA', 'Gene', '6389', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SDHA', 'Gene', '6389', (165, 169))	('SDHA', 'Gene', (211, 215))	('SDHA', 'Gene', '6389', (211, 215))	('SDHB', 'Gene', '6390', (263, 267))	('SDHB', 'Gene', (91, 95))	('SDHA', 'Gene', (82, 86))
53259	22974104	Furthermore, both SDHA and SDHB expression was preserved in a control case of a young adult GIST carrying a KIT exon 11 deletion (Figure 4 G,H).	('GIST', 'Phenotype', 'HP:0100723', (92, 96))	('SDHA', 'Gene', (18, 22))	('KIT exon 11', 'Gene', (108, 119))	('SDHB', 'Gene', '6390', (27, 31))	('deletion', 'Var', (120, 128))	('SDHB', 'Gene', (27, 31))	('SDHA', 'Gene', '6389', (18, 22))
53266	22974104	Mutations of one of the gene encoding these subunits impair the activity of this complex and lead to the stabilization and activation of HIF-1a, which in turn activates cell proliferation and angiogenesis.	('HIF-1a', 'Gene', '3091', (137, 143))	('HIF-1a', 'Gene', (137, 143))	('stabilization', 'MPA', (105, 118))	('activates', 'PosReg', (159, 168))	('angiogenesis', 'CPA', (192, 204))	('Mutations', 'Var', (0, 9))	('activity', 'MPA', (64, 72))	('activation', 'PosReg', (123, 133))	('cell proliferation', 'CPA', (169, 187))	('impair', 'NegReg', (53, 59))
53267	22974104	In addition to paragangliomas and pheochromocytomas, a number of other solid tumors have been associated with mutations in genes encoding the succinate dehydrogenase complex (SDH) complex II.	('succinate dehydrogenase', 'Gene', '6389', (142, 165))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('solid tumors', 'Disease', (71, 83))	('mutations', 'Var', (110, 119))	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (15, 51))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (34, 50))	('associated', 'Reg', (94, 104))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('succinate dehydrogenase', 'Gene', (142, 165))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('paraganglioma', 'Phenotype', 'HP:0002668', (15, 28))	('paragangliomas', 'Phenotype', 'HP:0002668', (15, 29))
53270	22974104	This syndrome is associated with germline point mutations or large deletions of the genes encoding the SDHB, SDHC or SDHD subunits.	('SDHB', 'Gene', (103, 107))	('SDHC', 'Gene', '6391', (109, 113))	('associated', 'Reg', (17, 27))	('SDHD', 'Gene', '6392', (117, 121))	('large deletions', 'Var', (61, 76))	('SDHC', 'Gene', (109, 113))	('SDHB', 'Gene', '6390', (103, 107))	('SDHD', 'Gene', (117, 121))
53271	22974104	Strikingly, inactivating germline mutations in SDHB or SDHC genes have been also identified in sporadic WT GISTs occurring in patients without a personal or family history of paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (175, 188))	('paraganglioma', 'Disease', (175, 188))	('SDHB', 'Gene', '6390', (47, 51))	('SDHC', 'Gene', (55, 59))	('SDHB', 'Gene', (47, 51))	('SDHC', 'Gene', '6391', (55, 59))	('patients', 'Species', '9606', (126, 134))	('paraganglioma', 'Disease', 'MESH:D010235', (175, 188))	('GIST', 'Phenotype', 'HP:0100723', (107, 111))	('identified', 'Reg', (81, 91))	('inactivating germline mutations', 'Var', (12, 43))
53273	22974104	Germline mutations in SDHA are associated with neurodegenerative diseases such as an early-onset encephalopathy, known as Leigh syndrome and a late-onset optic atrophy, ataxia and myopathy.	('Germline mutations', 'Var', (0, 18))	('myopathy', 'Disease', 'MESH:D009135', (180, 188))	('optic atrophy', 'Disease', (154, 167))	('encephalopathy', 'Phenotype', 'HP:0001298', (97, 111))	('optic atrophy', 'Phenotype', 'HP:0000648', (154, 167))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (47, 73))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (47, 73))	('Leigh syndrome', 'Disease', 'MESH:D007888', (122, 136))	('associated', 'Reg', (31, 41))	('encephalopathy', 'Disease', (97, 111))	('Leigh syndrome', 'Disease', (122, 136))	('myopathy', 'Phenotype', 'HP:0003198', (180, 188))	('myopathy', 'Disease', (180, 188))	('ataxia', 'Phenotype', 'HP:0001251', (169, 175))	('optic atrophy', 'Disease', 'MESH:D009896', (154, 167))	('neurodegenerative diseases', 'Disease', (47, 73))	('ataxia', 'Disease', (169, 175))	('ataxia', 'Disease', 'MESH:D001259', (169, 175))	('SDHA', 'Gene', (22, 26))	('encephalopathy', 'Disease', 'MESH:D001927', (97, 111))	('SDHA', 'Gene', '6389', (22, 26))
53275	22974104	However, two recent studies allowed the identification of SDHA germline mutations in at least 3% patients with apparently sporadic cases of paraganglioma or pheochromocytoma.	('SDHA', 'Gene', '6389', (58, 62))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('SDHA', 'Gene', (58, 62))	('paraganglioma or pheochromocytoma', 'Disease', 'MESH:D010673', (140, 173))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (157, 173))	('germline mutations', 'Var', (63, 81))	('paraganglioma or pheochromocytoma', 'Disease', (140, 173))	('patients', 'Species', '9606', (97, 105))
53276	22974104	Interestingly, four cases of sporadic KIT and PDGFRA WT GIST occurring in one pediatric and three young adult patients have also been associated with germline mutation of SDHA.	('associated', 'Reg', (134, 144))	('SDHA', 'Gene', (171, 175))	('germline', 'Var', (150, 158))	('PDGFRA WT GIST', 'Gene', '5156', (46, 60))	('SDHA', 'Gene', '6389', (171, 175))	('PDGFRA WT GIST', 'Gene', (46, 60))	('GIST', 'Phenotype', 'HP:0100723', (56, 60))	('patients', 'Species', '9606', (110, 118))
53277	22974104	In the present study, we investigated a series of 17 apparently sporadic and Carney's triad-related KIT and PDGFRA WT GIST for SDHA mutations and found an additional two cases with mutations in this gene.	('mutations', 'Var', (132, 141))	('PDGFRA WT GIST', 'Gene', '5156', (108, 122))	('PDGFRA WT GIST', 'Gene', (108, 122))	('SDHA', 'Gene', '6389', (127, 131))	('Carney', 'Disease', (77, 83))	('GIST', 'Phenotype', 'HP:0100723', (118, 122))	('SDHA', 'Gene', (127, 131))
53278	22974104	The p.Arg31X SDHA germline mutation identified in our study leads to a truncated protein.	('truncated', 'MPA', (71, 80))	('p.Arg31X', 'Var', (4, 12))	('SDHA', 'Gene', '6389', (13, 17))	('leads to', 'Reg', (60, 68))	('p.Arg31X', 'Mutation', 'rs142441643', (4, 12))	('SDHA', 'Gene', (13, 17))
53280	22974104	The second SDHA mutation identified in our study (p.D38V) has been reported as a single nucleotide polymorphism.	('SDHA', 'Gene', '6389', (11, 15))	('p.D38V', 'Var', (50, 56))	('p.D38V', 'Mutation', 'rs34635677', (50, 56))	('SDHA', 'Gene', (11, 15))
53285	22974104	By performing western blotting, we identified a loss of SDHA protein expression in the two mutated cases whereas expression was retained in the non-mutated cases.	('loss', 'NegReg', (48, 52))	('SDHA', 'Gene', '6389', (56, 60))	('SDHA', 'Gene', (56, 60))	('mutated', 'Var', (91, 98))	('expression', 'MPA', (69, 79))
53286	22974104	This result was expected in the tumor with the p.Arg31X mutation because this mutation leads to a truncated SDHA protein.	('SDHA', 'Gene', '6389', (108, 112))	('p.Arg31X', 'Var', (47, 55))	('SDHA', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('leads to', 'Reg', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('p.Arg31X', 'Mutation', 'rs142441643', (47, 55))	('tumor', 'Disease', (32, 37))	('truncated', 'MPA', (98, 107))
53287	22974104	Although the p.D38V missense mutation does not lead to a truncated protein, the SDHA expression was significantly decreased by IHC and not detected by Western blot.	('expression', 'MPA', (85, 95))	('SDHA', 'Gene', '6389', (80, 84))	('SDHA', 'Gene', (80, 84))	('decreased', 'NegReg', (114, 123))	('p.D38V', 'Mutation', 'rs34635677', (13, 19))	('p.D38V missense', 'Var', (13, 28))
53288	22974104	This result can be explained by a conformational change of the mutated SDHA protein compromising the antigenic epitope for the antibody.	('mutated', 'Var', (63, 70))	('compromising', 'NegReg', (84, 96))	('conformational', 'MPA', (34, 48))	('SDHA', 'Gene', '6389', (71, 75))	('protein', 'Protein', (76, 83))	('antigenic epitope', 'MPA', (101, 118))	('SDHA', 'Gene', (71, 75))
53289	22974104	Another explanation is that the p.D38V mutation leads to SDHA protein instability.	('p.D38V', 'Var', (32, 38))	('leads to', 'Reg', (48, 56))	('p.D38V', 'Mutation', 'rs34635677', (32, 38))	('SDHA', 'Gene', '6389', (57, 61))	('SDHA', 'Gene', (57, 61))
53296	22974104	In contrast, whereas SDHB expression was not detected in all WT GIST included in our series, all these tumors (except the two with a mutation of the SDHA gene) displayed expression of SDHA.	('SDHA', 'Gene', '6389', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (133, 141))	('SDHA', 'Gene', '6389', (149, 153))	('GIST', 'Phenotype', 'HP:0100723', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', (103, 109))	('SDHB', 'Gene', '6390', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('SDHA', 'Gene', (184, 188))	('SDHA', 'Gene', (149, 153))	('SDHB', 'Gene', (21, 25))	('expression', 'MPA', (170, 180))
53298	22974104	By pooling our results with those of previous studies, it appears that the majority of mutations of genes encoding subunits of the SDH complex II identified in apparently sporadic KIT and PDGFRA WT GIST occurred in young adults (9 out of 13 patients).	('GIST', 'Phenotype', 'HP:0100723', (198, 202))	('mutations', 'Var', (87, 96))	('PDGFRA WT GIST', 'Gene', '5156', (188, 202))	('patients', 'Species', '9606', (241, 249))	('PDGFRA WT GIST', 'Gene', (188, 202))
53301	22974104	Although the number of identified mutation carriers is still low, current observations suggest that mutations of the succinate dehydrogenase complex II are more particularly associated with KIT and PDGFRA WT GIST occurring in young adults, outside the Carney's triad trait.	('mutations', 'Var', (100, 109))	('associated', 'Reg', (174, 184))	('succinate dehydrogenase', 'Gene', (117, 140))	('PDGFRA WT GIST', 'Gene', '5156', (198, 212))	('PDGFRA WT GIST', 'Gene', (198, 212))	('succinate dehydrogenase', 'Gene', '6389', (117, 140))	('GIST', 'Phenotype', 'HP:0100723', (208, 212))
53303	22974104	Genetic screening for SDHB, C and D germline mutations is recommended for patients with paraganglioma/pheochromocytoma and SDH deficient GISTs.	('germline mutations', 'Var', (36, 54))	('patients', 'Species', '9606', (74, 82))	('GIST', 'Phenotype', 'HP:0100723', (137, 141))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('paraganglioma/pheochromocytoma and SDH deficient GISTs', 'Disease', 'MESH:D010673', (88, 142))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (102, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))
53304	22974104	At the time of this writing, it remains uncertain whether patients with SDHA-deficient GIST are also at increased risk for the tumors associated with SDHx germline mutation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('SDHx', 'Gene', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('SDHx', 'Chemical', '-', (150, 154))	('GIST', 'Phenotype', 'HP:0100723', (87, 91))	('SDHA-deficient GIST', 'Disease', (72, 91))	('patients', 'Species', '9606', (58, 66))	('germline mutation', 'Var', (155, 172))	('SDHA-deficient GIST', 'Disease', 'MESH:D046152', (72, 91))
53342	21333207	Recent advances in genetic analysis have demonstrated hereditary causes of paragangliomas as well, such as mutations in the enzyme succinate dehydrogenase.	('mutations', 'Var', (107, 116))	('paragangliomas', 'Disease', 'MESH:D010235', (75, 89))	('causes', 'Reg', (65, 71))	('paragangliomas', 'Disease', (75, 89))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))
53366	32870176	In a retrospective cohort study on 205,750 hypertensive patients, cardiovascular event rates were higher in patients with RHT.	('hypertensive', 'Disease', (43, 55))	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (108, 116))	('hypertensive', 'Disease', 'MESH:D006973', (43, 55))	('higher', 'PosReg', (98, 104))	('RHT', 'Var', (122, 125))	('cardiovascular', 'CPA', (66, 80))	('cardiovascular event', 'Phenotype', 'HP:0001626', (66, 86))
53369	32870176	Although, RHT and controlled HT have the same risk factors such as older age, high body mass index, chronic kidney disease (CKD), and diabetes, which lead to endothelial dysfunction, arterial stiffness, and vascular damage; the exact pathophysiology responsible for resistance is unclear.	('diabetes', 'Disease', (134, 142))	('endothelial dysfunction', 'Disease', (158, 181))	('high body', 'Var', (78, 87))	('lead to', 'Reg', (150, 157))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (100, 122))	('diabetes', 'Disease', 'MESH:D003920', (134, 142))	('vascular damage', 'Disease', (207, 222))	('high body mass index', 'Phenotype', 'HP:0031418', (78, 98))	('chronic kidney disease', 'Disease', 'MESH:D051436', (100, 122))	('CKD', 'Phenotype', 'HP:0012622', (124, 127))	('kidney disease', 'Phenotype', 'HP:0000112', (108, 122))	('endothelial dysfunction', 'Disease', 'MESH:C536439', (158, 181))	('arterial stiffness', 'MPA', (183, 201))	('chronic kidney disease', 'Disease', (100, 122))	('vascular damage', 'Disease', 'MESH:D000783', (207, 222))
53376	32870176	Factors associated with volume overload are excess aldosterone, obesity, high dietary salt intake, and CKD (19, 27, 28).	('high dietary salt intake', 'Phenotype', 'HP:0000127', (73, 97))	('CKD', 'Var', (103, 106))	('excess aldosterone', 'Phenotype', 'HP:0000859', (44, 62))	('obesity', 'Disease', 'MESH:D009765', (64, 71))	('excess', 'PosReg', (44, 50))	('volume overload', 'Phenotype', 'HP:0011105', (24, 39))	('obesity', 'Disease', (64, 71))	('aldosterone', 'MPA', (51, 62))	('volume', 'MPA', (24, 30))	('CKD', 'Phenotype', 'HP:0012622', (103, 106))	('aldosterone', 'Chemical', 'MESH:D000450', (51, 62))	('dietary salt', 'Chemical', 'MESH:D017673', (78, 90))	('obesity', 'Phenotype', 'HP:0001513', (64, 71))
53381	32870176	A substudy of the PATHWAY-2 trial concluded that the antihypertensive effect of spironolactone was related to a significant reduction in thoracic fluid content.	('hypertensive', 'Disease', (57, 69))	('reduction', 'NegReg', (124, 133))	('spironolactone', 'Chemical', 'MESH:D013148', (80, 94))	('PA', 'Phenotype', 'HP:0011736', (18, 20))	('spironolactone', 'Var', (80, 94))	('thoracic fluid content', 'MPA', (137, 159))	('hypertensive', 'Disease', 'MESH:D006973', (57, 69))
53388	32870176	Inaccurate measurement of BP may lead to an incorrect diagnosis of RHT.	('lead', 'Reg', (33, 37))	('men', 'Species', '9606', (18, 21))	('Inaccurate measurement of BP', 'Phenotype', 'HP:0032263', (0, 28))	('RHT', 'Disease', (67, 70))	('Inaccurate', 'Var', (0, 10))
53424	32870176	Moreover, CKD may obstruct the response to antihypertensive treatment and promote resistance, which causes further damage to the kidneys, resulting in a vicious cycle.	('hypertensive', 'Disease', (47, 59))	('kidneys', 'MPA', (129, 136))	('men', 'Species', '9606', (65, 68))	('promote', 'PosReg', (74, 81))	('damage to the kidneys', 'Phenotype', 'HP:0000112', (115, 136))	('CKD', 'Phenotype', 'HP:0012622', (10, 13))	('resistance', 'MPA', (82, 92))	('vicious cycle', 'MPA', (153, 166))	('damage', 'MPA', (115, 121))	('CKD', 'Var', (10, 13))	('hypertensive', 'Disease', 'MESH:D006973', (47, 59))	('obstruct', 'NegReg', (18, 26))
53432	32870176	Sudden onset or worsening hypertension under the age of 30 or over the age of 55, presence of murmur over renal artery locations, unexplained asymmetry in kidney sizes, increased serum creatinine levels by more than 30% with the use of RAAS blockers, or recurrent pulmonary edema associated with hypertensive fluctuations could be used for RVH screening.	('hypertension', 'Disease', 'MESH:D006973', (26, 38))	('creatinine', 'Chemical', 'MESH:D003404', (185, 195))	('pulmonary edema', 'Phenotype', 'HP:0100598', (264, 279))	('asymmetry in kidney sizes', 'Phenotype', 'HP:0012210', (142, 167))	('increased', 'PosReg', (169, 178))	('serum creatinine levels', 'MPA', (179, 202))	('hypertensive', 'Disease', 'MESH:D006973', (296, 308))	('recurrent', 'Disease', (254, 263))	('hypertension', 'Disease', (26, 38))	('hypertensive', 'Disease', (296, 308))	('presence', 'Var', (82, 90))	('pulmonary edema', 'Disease', 'MESH:D011654', (264, 279))	('increased serum creatinine', 'Phenotype', 'HP:0003259', (169, 195))	('edema', 'Phenotype', 'HP:0000969', (274, 279))	('hypertension', 'Phenotype', 'HP:0000822', (26, 38))	('pulmonary edema', 'Disease', (264, 279))
53474	32870176	Also, antineoplastic agents such as tyrosine kinase inhibitors and antidepressants can exacerbate hypertension.	('hypertension', 'Disease', (98, 110))	('hypertension', 'Phenotype', 'HP:0000822', (98, 110))	('exacerbate', 'PosReg', (87, 97))	('tyrosine', 'Var', (36, 44))	('hypertension', 'Disease', 'MESH:D006973', (98, 110))
53476	32870176	Vitamin D deficiency is known to be related to hypertension.	('related', 'Reg', (36, 43))	('Vitamin D', 'Gene', (0, 9))	('hypertension', 'Disease', (47, 59))	('hypertension', 'Phenotype', 'HP:0000822', (47, 59))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('deficiency', 'Var', (10, 20))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('hypertension', 'Disease', 'MESH:D006973', (47, 59))
53477	32870176	Moreover, in a study evaluating 101 patients with RHT treated with renal denervation, those with significant vitamin D deficiency showed a blunted decrease in SBP in response to treatment.	('deficiency', 'Var', (119, 129))	('patients', 'Species', '9606', (36, 44))	('SBP', 'Gene', (159, 162))	('men', 'Species', '9606', (183, 186))	('decrease', 'NegReg', (147, 155))	('vitamin D', 'Chemical', 'MESH:D014807', (109, 118))	('vitamin', 'Gene', (109, 116))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (109, 129))	('SBP', 'Gene', '8991', (159, 162))
53478	32870176	Vitamin D deficiency is very common in Turkey with a reported prevalence of almost 75%.	('Vitamin D', 'Gene', (0, 9))	('Turkey', 'Species', '9103', (39, 45))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('deficiency', 'Var', (10, 20))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
53502	32870176	Adhering to healthy lifestyle behaviors was found to be related to a significant reduction in cardiovascular events in patients with RHT.	('cardiovascular', 'Disease', (94, 108))	('cardiovascular events', 'Phenotype', 'HP:0001626', (94, 115))	('patients', 'Species', '9606', (119, 127))	('reduction', 'NegReg', (81, 90))	('cardiovascular event', 'Phenotype', 'HP:0001626', (94, 114))	('Adhering', 'Var', (0, 8))
53511	32870176	Vitamin D deficiency is significantly common in our country and patients with RHT should be encouraged to sunbath properly in natural sunshine.	('patients', 'Species', '9606', (64, 72))	('Vitamin', 'Gene', (0, 7))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('deficiency', 'Var', (10, 20))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))
53543	32870176	It should be noted that hydralazine can cause increased sympathetic tone and sodium retention, and minoxidil induces hirsutism.	('minoxidil', 'Chemical', 'MESH:D008914', (99, 108))	('hirsutism', 'Disease', (117, 126))	('increased', 'PosReg', (46, 55))	('sodium', 'Chemical', 'MESH:D012964', (77, 83))	('hirsutism', 'Disease', 'MESH:D006628', (117, 126))	('sodium retention', 'MPA', (77, 93))	('hydralazine', 'Chemical', 'MESH:D006830', (24, 35))	('sympathetic tone', 'MPA', (56, 72))	('hydralazine', 'Var', (24, 35))	('hirsutism', 'Phenotype', 'HP:0001007', (117, 126))	('induces', 'Reg', (109, 116))
53548	32870176	Vitamin D deficiency is highly prevalent in Turkey and is shown to be related to RHT.	('RHT', 'Disease', (81, 84))	('Vitamin', 'Gene', (0, 7))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('deficiency', 'Var', (10, 20))	('related', 'Reg', (70, 77))	('Vitamin D', 'Chemical', 'MESH:D014807', (0, 9))	('Turkey', 'Species', '9103', (44, 50))
53554	32870176	Inhibition of aminopeptidase A down-regulates the brain renin-angiotensin system and decreases sympathetic outflow.	('decreases', 'NegReg', (85, 94))	('aminopeptidase A', 'Gene', '2028', (14, 30))	('sympathetic outflow', 'MPA', (95, 114))	('renin', 'Gene', (56, 61))	('down-regulates', 'NegReg', (31, 45))	('Inhibition', 'Var', (0, 10))	('aminopeptidase A', 'Gene', (14, 30))	('renin', 'Gene', '5972', (56, 61))
53590	32971818	Immunohistochemistry and Mutation Analysis of SDHx Genes in Carotid Paragangliomas Carotid paragangliomas (CPGLs) are rare neuroendocrine tumors often associated with mutations in SDHx genes.	('mutations', 'Var', (167, 176))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (123, 143))	('Carotid paraganglioma', 'Phenotype', 'HP:0100635', (83, 104))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (123, 144))	('associated', 'Reg', (151, 161))	('SDH', 'Gene', '6390', (46, 49))	('Carotid paragangliomas', 'Disease', 'MESH:D002345', (83, 105))	('CPGLs', 'Chemical', '-', (107, 112))	('PGLs', 'Phenotype', 'HP:0002668', (108, 112))	('Carotid Paragangliomas', 'Phenotype', 'HP:0100635', (60, 82))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('Paragangliomas', 'Disease', (68, 82))	('Paragangliomas', 'Disease', 'MESH:D010235', (68, 82))	('SDH', 'Gene', '6390', (180, 183))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (123, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('SDH', 'Gene', (46, 49))	('paragangliomas', 'Phenotype', 'HP:0002668', (91, 105))	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('Carotid paragangliomas', 'Disease', (83, 105))	('neuroendocrine tumors', 'Disease', (123, 144))	('Paragangliomas', 'Phenotype', 'HP:0002668', (68, 82))	('CPGL', 'Phenotype', 'HP:0100635', (107, 111))	('SDH', 'Gene', (180, 183))
53591	32971818	The immunohistochemistry of succinate dehydrogenase (SDH) subunits has been considered a useful instrument for the prediction of SDHx mutations in paragangliomas/pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('SDH', 'Gene', (53, 56))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('SDH', 'Gene', (129, 132))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (162, 179))	('paragangliomas', 'Phenotype', 'HP:0002668', (147, 161))	('paragangliomas/pheochromocytomas', 'Disease', (147, 179))	('paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (147, 179))	('succinate dehydrogenase', 'Gene', '6390', (28, 51))	('SDH', 'Gene', '6390', (53, 56))	('SDH', 'Gene', '6390', (129, 132))	('succinate dehydrogenase', 'Gene', (28, 51))	('mutations', 'Var', (134, 143))
53593	32971818	To identify pathogenic/likely pathogenic variants in SDHx genes, exome sequencing data analysis among 42 CPGL patients was performed.	('CPGL', 'Phenotype', 'HP:0100635', (105, 109))	('variants', 'Var', (41, 49))	('SDH', 'Gene', (53, 56))	('SDH', 'Gene', '6390', (53, 56))	('patients', 'Species', '9606', (110, 118))	('pathogenic/likely', 'Reg', (12, 29))
53595	32971818	We encountered SDHx variants in 38% (16/42) of the cases in SDHx genes.	('SDH', 'Gene', (60, 63))	('variants', 'Var', (20, 28))	('SDH', 'Gene', '6390', (15, 18))	('SDH', 'Gene', '6390', (60, 63))	('SDH', 'Gene', (15, 18))
53596	32971818	IHC showed negative (5/15) or weak diffuse (10/15) SDHB staining in most tumors with variants in any of SDHx (94%, 15/16).	('SDH', 'Gene', '6390', (51, 54))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('variants', 'Var', (85, 93))	('SDH', 'Gene', '6390', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SDH', 'Gene', (104, 107))	('SDH', 'Gene', (51, 54))	('SDHB', 'Gene', '6390', (51, 55))	('tumors', 'Disease', (73, 79))	('SDHB', 'Gene', (51, 55))
53598	32971818	Positive immunoreactivity for all SDH subunits was found in one case with a variant in SDHD.	('variant', 'Var', (76, 83))	('SDH', 'Gene', '6390', (87, 90))	('SDH', 'Gene', (34, 37))	('SDH', 'Gene', (87, 90))	('SDHD', 'Gene', (87, 91))	('SDHD', 'Gene', '6392', (87, 91))	('found', 'Reg', (51, 56))	('SDH', 'Gene', '6390', (34, 37))
53599	32971818	Notably, CPGL samples without variants in SDHx also demonstrated negative (2/11) or weak diffuse (9/11) SDHB staining (42%, 11/26).	('variants', 'Var', (30, 38))	('SDH', 'Gene', '6390', (42, 45))	('SDH', 'Gene', '6390', (104, 107))	('SDH', 'Gene', (42, 45))	('SDH', 'Gene', (104, 107))	('SDHB', 'Gene', '6390', (104, 108))	('CPGL', 'Phenotype', 'HP:0100635', (9, 13))	('SDHB', 'Gene', (104, 108))
53601	32971818	However, given the high sensitivity of SDHB immunohistochemistry, it could be used for initial identifications of patients potentially carrying SDHx mutations for recommendation of genetic testing.	('SDH', 'Gene', (39, 42))	('SDH', 'Gene', '6390', (144, 147))	('mutations', 'Var', (149, 158))	('SDHB', 'Gene', '6390', (39, 43))	('SDH', 'Gene', (144, 147))	('SDHB', 'Gene', (39, 43))	('SDH', 'Gene', '6390', (39, 42))	('patients', 'Species', '9606', (114, 122))
53611	32971818	Germline pathogenic variants in these genes are mainly associated with PCCs but have also been seen in CPGLs.	('variants', 'Var', (20, 28))	('PCCs', 'Disease', (71, 75))	('associated', 'Reg', (55, 65))	('PGLs', 'Phenotype', 'HP:0002668', (104, 108))	('CPGL', 'Phenotype', 'HP:0100635', (103, 107))	('CPGLs', 'Chemical', '-', (103, 108))	('CPGLs', 'Disease', (103, 108))
53612	32971818	Apparently sporadic cases of CPGLs have been reported as being associated with germline mutations in SDHA, SDHB, SDHD, and VHL, as well as somatic mutations in VHL, RET, IDH1, and IDH2.	('mutations', 'Var', (147, 156))	('SDHD', 'Gene', (113, 117))	('mutations', 'Var', (88, 97))	('IDH1', 'Gene', '3417', (170, 174))	('VHL', 'Gene', '7428', (160, 163))	('IDH2', 'Gene', (180, 184))	('CPGLs', 'Chemical', '-', (29, 34))	('IDH2', 'Gene', '3418', (180, 184))	('associated', 'Reg', (63, 73))	('VHL', 'Gene', (123, 126))	('SDHB', 'Gene', '6390', (107, 111))	('RET', 'Gene', '5979', (165, 168))	('PGLs', 'Phenotype', 'HP:0002668', (30, 34))	('SDHA', 'Gene', (101, 105))	('VHL', 'Gene', '7428', (123, 126))	('CPGL', 'Phenotype', 'HP:0100635', (29, 33))	('SDHA', 'Gene', '6389', (101, 105))	('IDH1', 'Gene', (170, 174))	('SDHB', 'Gene', (107, 111))	('CPGLs', 'Disease', (29, 34))	('VHL', 'Gene', (160, 163))	('SDHD', 'Gene', '6392', (113, 117))	('RET', 'Gene', (165, 168))
53614	32971818	The immunohistochemistry (IHC) of SDHB and SDHA subunits has been proposed as a useful method to predict underlying SDHx mutations in first-line diagnostics of hereditary PCCs/PGLs.	('hereditary PCCs', 'Disease', 'MESH:D030342', (160, 175))	('mutations', 'Var', (121, 130))	('SDH', 'Gene', (43, 46))	('SDH', 'Gene', (116, 119))	('SDH', 'Gene', (34, 37))	('hereditary PCCs', 'Disease', (160, 175))	('SDHA', 'Gene', '6389', (43, 47))	('PGLs', 'Phenotype', 'HP:0002668', (176, 180))	('SDHB', 'Gene', '6390', (34, 38))	('SDH', 'Gene', '6390', (43, 46))	('SDHB', 'Gene', (34, 38))	('SDH', 'Gene', '6390', (116, 119))	('SDHA', 'Gene', (43, 47))	('SDH', 'Gene', '6390', (34, 37))
53615	32971818	All PGLs carrying SDHA mutations showed negative SDHA staining, while SDHA-positive immunoreactivity was observed in tumors with mutations in other SDHx genes.	('SDH', 'Gene', '6390', (49, 52))	('SDH', 'Gene', (70, 73))	('SDH', 'Gene', '6390', (18, 21))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('SDHA', 'Gene', (18, 22))	('SDHA', 'Gene', (49, 53))	('SDHA', 'Gene', '6389', (18, 22))	('SDHA', 'Gene', '6389', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SDH', 'Gene', (49, 52))	('tumors', 'Disease', (117, 123))	('mutations', 'Var', (23, 32))	('SDH', 'Gene', (18, 21))	('SDH', 'Gene', '6390', (148, 151))	('SDH', 'Gene', '6390', (70, 73))	('SDHA', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('PGLs', 'Phenotype', 'HP:0002668', (4, 8))	('negative', 'NegReg', (40, 48))	('SDHA', 'Gene', '6389', (70, 74))	('SDH', 'Gene', (148, 151))
53616	32971818	Loss of cytoplasmic SDHB staining or a weak diffuse cytoplasmic blush instead of a normal granular staining pattern was revealed in PGLs with mutations in SDHB, SDHC, or SDHD.	('SDHC', 'Gene', (161, 165))	('mutations', 'Var', (142, 151))	('SDHD', 'Gene', (170, 174))	('SDHB', 'Gene', (155, 159))	('SDHC', 'Gene', '6391', (161, 165))	('Loss', 'NegReg', (0, 4))	('SDHB', 'Gene', '6390', (20, 24))	('PGLs', 'Phenotype', 'HP:0002668', (132, 136))	('SDHB', 'Gene', '6390', (155, 159))	('SDHB', 'Gene', (20, 24))	('SDHD', 'Gene', '6392', (170, 174))
53617	32971818	Additionally, several cases of PGLs/PCCs with SDHA mutations showed a loss of SDHB protein expression coupled with negative SDHA staining.	('PGLs', 'Phenotype', 'HP:0002668', (31, 35))	('expression', 'MPA', (91, 101))	('mutations', 'Var', (51, 60))	('SDHA', 'Gene', '6389', (46, 50))	('loss', 'NegReg', (70, 74))	('SDHB', 'Gene', '6390', (78, 82))	('SDHA', 'Gene', (124, 128))	('protein', 'Protein', (83, 90))	('SDHB', 'Gene', (78, 82))	('SDHA', 'Gene', (46, 50))	('SDHA', 'Gene', '6389', (124, 128))
53620	32971818	About 90% of PGLs/PCCs with mutations in SDHB, SDHC, SDHD, and SDHAF2 were SDHB immunonegative and SDHA immunopositive.	('SDHA', 'Gene', (99, 103))	('SDHC', 'Gene', (47, 51))	('SDHC', 'Gene', '6391', (47, 51))	('SDHAF2', 'Gene', '54949', (63, 69))	('PGLs', 'Phenotype', 'HP:0002668', (13, 17))	('SDHA', 'Gene', (63, 67))	('SDHD', 'Gene', (53, 57))	('SDHAF2', 'Gene', (63, 69))	('SDHD', 'Gene', '6392', (53, 57))	('SDHB', 'Gene', '6390', (75, 79))	('SDHB', 'Gene', '6390', (41, 45))	('SDHA', 'Gene', '6389', (99, 103))	('SDHB', 'Gene', (75, 79))	('SDHA', 'Gene', '6389', (63, 67))	('SDHB', 'Gene', (41, 45))	('mutations', 'Var', (28, 37))
53621	32971818	Loss of SDHA/SDHB staining was detected in 75% of tumors with SDHA mutations.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('SDHA', 'Gene', '6389', (8, 12))	('SDHA', 'Gene', (62, 66))	('SDHB', 'Gene', '6390', (13, 17))	('mutations', 'Var', (67, 76))	('Loss', 'NegReg', (0, 4))	('SDHB', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SDHA', 'Gene', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('SDHA', 'Gene', '6389', (62, 66))
53623	32971818	These results established the usability of SDHA/SDHB immunohistochemistry to identify SDHx mutations in PGLs/PCCs.	('SDH', 'Gene', '6390', (86, 89))	('SDH', 'Gene', (43, 46))	('SDH', 'Gene', '6390', (48, 51))	('SDH', 'Gene', (86, 89))	('PGLs/PCCs', 'Gene', (104, 113))	('SDH', 'Gene', (48, 51))	('mutations', 'Var', (91, 100))	('SDHA', 'Gene', '6389', (43, 47))	('SDH', 'Gene', '6390', (43, 46))	('PGLs', 'Phenotype', 'HP:0002668', (104, 108))	('SDHB', 'Gene', '6390', (48, 52))	('SDHA', 'Gene', (43, 47))	('SDHB', 'Gene', (48, 52))
53624	32971818	For example, changed SDHB immunostaining can be caused by not only exonic mutations in the SDHx genes but also by the epigenetic alterations (epimutations), mutations in regulatory regions, changes in the expression and functionality of transcription factors, or other components of energy metabolism.	('SDH', 'Gene', (91, 94))	('caused', 'Reg', (48, 54))	('changes', 'Reg', (190, 197))	('epigenetic alterations', 'Var', (118, 140))	('SDH', 'Gene', (21, 24))	('SDH', 'Gene', '6390', (21, 24))	('exonic mutations', 'Var', (67, 83))	('SDHB', 'Gene', '6390', (21, 25))	('mutations', 'Var', (157, 166))	('SDH', 'Gene', '6390', (91, 94))	('immunostaining', 'MPA', (26, 40))	('SDHB', 'Gene', (21, 25))	('changed', 'Reg', (13, 20))
53625	32971818	Another method for prediction of SDHx mutation status bases on evaluating the succinate-to-fumarate ratio (SFR) using liquid chromatography-mass spectrometry.	('fumarate', 'Chemical', 'MESH:D005650', (91, 99))	('SDH', 'Gene', (33, 36))	('succinate-to-fumarate ratio', 'MPA', (78, 105))	('succinate', 'Chemical', 'MESH:D019802', (78, 87))	('SDH', 'Gene', '6390', (33, 36))	('mutation', 'Var', (38, 46))
53628	32971818	In this work, we first performed a correlation analysis between variants in the SDHx genes and their expression at the protein level in a representative set of CPGLs.	('CPGLs', 'Chemical', '-', (160, 165))	('PGLs', 'Phenotype', 'HP:0002668', (161, 165))	('SDH', 'Gene', '6390', (80, 83))	('expression', 'MPA', (101, 111))	('SDH', 'Gene', (80, 83))	('variants', 'Var', (64, 72))	('CPGL', 'Phenotype', 'HP:0100635', (160, 164))
53630	32971818	We also evaluated the possibility of SDHA/SDHB immunostaining use to predict variants in any of the SDHx genes in CPGLs.	('variants', 'Var', (77, 85))	('CPGL', 'Phenotype', 'HP:0100635', (114, 118))	('SDH', 'Gene', '6390', (100, 103))	('SDH', 'Gene', (37, 40))	('SDH', 'Gene', '6390', (42, 45))	('SDH', 'Gene', (100, 103))	('SDH', 'Gene', (42, 45))	('SDHA', 'Gene', '6389', (37, 41))	('SDH', 'Gene', '6390', (37, 40))	('SDHB', 'Gene', '6390', (42, 46))	('SDHA', 'Gene', (37, 41))	('SDHB', 'Gene', (42, 46))	('CPGLs', 'Chemical', '-', (114, 119))	('PGLs', 'Phenotype', 'HP:0002668', (115, 119))
53631	32971818	We have found that SDHB staining does not always correlate with SDHx variants, while several studies proposed the immunohistochemistry of the SDHB subunit as a useful instrument for the prediction of SDHx mutation status.	('SDH', 'Gene', (19, 22))	('SDHB', 'Gene', (142, 146))	('SDH', 'Gene', (64, 67))	('SDHB', 'Gene', '6390', (19, 23))	('SDH', 'Gene', '6390', (142, 145))	('variants', 'Var', (69, 77))	('SDHB', 'Gene', (19, 23))	('SDH', 'Gene', '6390', (200, 203))	('SDH', 'Gene', (142, 145))	('SDH', 'Gene', '6390', (19, 22))	('SDH', 'Gene', '6390', (64, 67))	('SDHB', 'Gene', '6390', (142, 146))	('SDH', 'Gene', (200, 203))
53632	32971818	These important results indicate the necessity of genetic testing of SDHx variants along with IHC study in CPGLs.	('SDH', 'Gene', '6390', (69, 72))	('SDH', 'Gene', (69, 72))	('CPGLs', 'Chemical', '-', (107, 112))	('PGLs', 'Phenotype', 'HP:0002668', (108, 112))	('CPGL', 'Phenotype', 'HP:0100635', (107, 111))	('variants', 'Var', (74, 82))
53634	32971818	Pathogenic/likely pathogenic variants in the SDHx genes were found in 16 out of 42 (38%) patients with CPGLs (Table 1, Figure 1).	('found', 'Reg', (61, 66))	('SDH', 'Gene', (45, 48))	('variants', 'Var', (29, 37))	('patients', 'Species', '9606', (89, 97))	('PGLs', 'Phenotype', 'HP:0002668', (104, 108))	('CPGL', 'Phenotype', 'HP:0100635', (103, 107))	('Pathogenic/likely', 'Reg', (0, 17))	('CPGLs', 'Chemical', '-', (103, 108))	('CPGLs', 'Disease', (103, 108))	('SDH', 'Gene', '6390', (45, 48))
53635	32971818	Among the 42 studied patients, ten had variants in the SDHD gene (24%), two were characterized with variants in SDHB (5%), three had variants in SDHC (7%), and one carried a variant in SDHA (2%).	('variants', 'Var', (100, 108))	('SDHA', 'Gene', (185, 189))	('SDHB', 'Gene', '6390', (112, 116))	('patients', 'Species', '9606', (21, 29))	('SDHB', 'Gene', (112, 116))	('SDHD', 'Gene', '6392', (55, 59))	('SDHC', 'Gene', (145, 149))	('SDHA', 'Gene', '6389', (185, 189))	('SDHC', 'Gene', '6391', (145, 149))	('variants', 'Var', (39, 47))	('SDHD', 'Gene', (55, 59))
53637	32971818	Pathogenic/likely pathogenic variants were found in RET and IDH1; no variants in VHL, TMEM127, MAX, IDH2, FH, SLC25A11, and SDHAF1-4 genes were identified.	('SDHAF1-4', 'Gene', (124, 132))	('SLC25A11', 'Gene', (110, 118))	('TMEM127', 'Gene', '55654', (86, 93))	('VHL', 'Gene', (81, 84))	('IDH1', 'Gene', (60, 64))	('RET', 'Gene', '5979', (52, 55))	('VHL', 'Gene', '7428', (81, 84))	('variants', 'Var', (29, 37))	('IDH2', 'Gene', (100, 104))	('Pathogenic/likely', 'Reg', (0, 17))	('IDH1', 'Gene', '3417', (60, 64))	('RET', 'Gene', (52, 55))	('SLC25A11', 'Gene', '8402', (110, 118))	('TMEM127', 'Gene', (86, 93))	('IDH2', 'Gene', '3418', (100, 104))	('SDHAF1-4', 'Gene', '644096;54949;57001;135154', (124, 132))
53638	32971818	Pathogenic variants in RET were observed in three (7%) patients with CPGLs.	('RET', 'Gene', (23, 26))	('observed', 'Reg', (32, 40))	('variants', 'Var', (11, 19))	('Pathogenic', 'Reg', (0, 10))	('CPGL', 'Phenotype', 'HP:0100635', (69, 73))	('RET', 'Gene', '5979', (23, 26))	('CPGLs', 'Chemical', '-', (69, 74))	('patients', 'Species', '9606', (55, 63))	('PGLs', 'Phenotype', 'HP:0002668', (70, 74))
53639	32971818	A pathogenic variant in RET NM_020975: c.2372A > T, p.(Tyr791Phe) (chr10: 43613908, rs77724903;13936) was revealed in two patients who also carried pathogenic/likely pathogenic variants in SDHA (Pat16) and SDHD (Pat35).	('RET', 'Gene', '5979', (24, 27))	('SDHA', 'Gene', (189, 193))	('p.(Tyr791Phe', 'Var', (52, 64))	('p.(Tyr791Phe)', 'SUBSTITUTION', 'None', (52, 65))	('rs77724903', 'DBSNP_MENTION', 'None', (84, 94))	('pathogenic', 'Reg', (2, 12))	('rs77724903', 'Var', (84, 94))	('SDHD', 'Gene', '6392', (206, 210))	('RET', 'Gene', (24, 27))	('patients', 'Species', '9606', (122, 130))	('c.2372A > T', 'Var', (39, 50))	('pathogenic/likely', 'Reg', (148, 165))	('SDHD', 'Gene', (206, 210))	('SDHA', 'Gene', '6389', (189, 193))
53640	32971818	In Pat27, we found a pathogenic variant in RET NM_020975: c.2944C > T, p.(Arg982Cys) (chr10: 43620335, rs17158558) that was corepresented with a likely pathogenic frameshift variant in the SDHC gene.	('p.(Arg982Cys)', 'SUBSTITUTION', 'None', (71, 84))	('RET', 'Gene', (43, 46))	('frameshift', 'Var', (163, 173))	('rs17158558', 'Var', (103, 113))	('SDHC', 'Gene', (189, 193))	('c.2944C > T', 'Var', (58, 69))	('pathogenic', 'Reg', (152, 162))	('rs17158558', 'DBSNP_MENTION', 'None', (103, 113))	('SDHC', 'Gene', '6391', (189, 193))	('p.(Arg982Cys', 'Var', (71, 83))	('RET', 'Gene', '5979', (43, 46))	('pathogenic', 'Reg', (21, 31))
53641	32971818	A likely pathogenic variant in IDH1 NM_005896: c.394C > T, p.(Arg132Cys) (chr2: 209113113, rs121913499) has been observed in one (2%) patient (Pat31) together with no mutations in the SDHx genes.	('p.(Arg132Cys', 'Var', (59, 71))	('pathogenic', 'Reg', (9, 19))	('IDH1', 'Gene', '3417', (31, 35))	('rs121913499', 'DBSNP_MENTION', 'None', (91, 102))	('SDH', 'Gene', '6390', (184, 187))	('rs121913499', 'Var', (91, 102))	('c.394C > T', 'Var', (47, 57))	('p.(Arg132Cys)', 'SUBSTITUTION', 'None', (59, 72))	('SDH', 'Gene', (184, 187))	('patient', 'Species', '9606', (134, 141))	('IDH1', 'Gene', (31, 35))
53646	32971818	The Spearman's rank correlation coefficient (rs) between the presence of mutations in any SDHx genes and negative or weak diffuse SDHB staining was 0.51, p <= 0.05.	('SDH', 'Gene', (130, 133))	('SDH', 'Gene', '6390', (90, 93))	('SDHB', 'Gene', '6390', (130, 134))	('SDH', 'Gene', (90, 93))	('SDHB', 'Gene', (130, 134))	('SDH', 'Gene', '6390', (130, 133))	('mutations', 'Var', (73, 82))
53647	32971818	Negative or weak diffuse SDHB staining was found in nine out of ten cases with pathogenic/likely pathogenic SDHD variants; one SDHD-mutated tumor showed positive staining of all SDH subunits.	('SDHD', 'Gene', '6392', (108, 112))	('SDH', 'Gene', '6390', (108, 111))	('SDH', 'Gene', '6390', (25, 28))	('SDH', 'Gene', (127, 130))	('SDH', 'Gene', (178, 181))	('SDH', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('SDHD', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('SDHD', 'Gene', '6392', (127, 131))	('SDHB', 'Gene', '6390', (25, 29))	('SDH', 'Gene', (108, 111))	('SDHB', 'Gene', (25, 29))	('SDH', 'Gene', '6390', (178, 181))	('variants', 'Var', (113, 121))	('SDH', 'Gene', '6390', (127, 130))	('SDHD', 'Gene', (108, 112))	('tumor', 'Disease', (140, 145))
53649	32971818	In two out of three samples with pathogenic/likely pathogenic variants in the SDHC gene, we identified weak diffuse SDHB staining and simultaneous positive SDHC expression.	('SDHC', 'Gene', '6391', (78, 82))	('expression', 'MPA', (161, 171))	('SDHB', 'Gene', '6390', (116, 120))	('variants', 'Var', (62, 70))	('SDHB', 'Gene', (116, 120))	('SDHC', 'Gene', (156, 160))	('SDHC', 'Gene', (78, 82))	('SDHC', 'Gene', '6391', (156, 160))
53651	32971818	All samples with pathogenic/likely pathogenic variants in the SDHB gene showed negative SDHB staining.	('SDHB', 'Gene', '6390', (88, 92))	('negative', 'NegReg', (79, 87))	('SDHB', 'Gene', (88, 92))	('variants', 'Var', (46, 54))	('SDHB', 'Gene', '6390', (62, 66))	('SDHB', 'Gene', (62, 66))
53652	32971818	A pathogenic/likely pathogenic variant in the SDHA gene was identified only in one patient.	('pathogenic/likely', 'Reg', (2, 19))	('SDHA', 'Gene', '6389', (46, 50))	('patient', 'Species', '9606', (83, 90))	('SDHA', 'Gene', (46, 50))	('variant', 'Var', (31, 38))
53654	32971818	Among twenty-six CPGLs with no pathogenic/likely pathogenic variants in the SDHx genes, negative or weak diffuse SDHB staining was observed in eleven cases (42%).	('SDH', 'Gene', (113, 116))	('SDHB', 'Gene', '6390', (113, 117))	('CPGL', 'Phenotype', 'HP:0100635', (17, 21))	('SDHB', 'Gene', (113, 117))	('SDH', 'Gene', '6390', (76, 79))	('CPGLs', 'Chemical', '-', (17, 22))	('PGLs', 'Phenotype', 'HP:0002668', (18, 22))	('SDH', 'Gene', '6390', (113, 116))	('SDH', 'Gene', (76, 79))	('variants', 'Var', (60, 68))
53656	32971818	Three tumors with pathogenic variants of the RET gene, which were corepresented with SDHA, SDHC, and SDHD variants, have been characterized by negative or weak diffuse SDHB staining.	('SDHC', 'Gene', (91, 95))	('SDHD', 'Gene', (101, 105))	('SDHD', 'Gene', '6392', (101, 105))	('pathogenic', 'Reg', (18, 28))	('SDHA', 'Gene', (85, 89))	('RET', 'Gene', '5979', (45, 48))	('SDHC', 'Gene', '6391', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('RET', 'Gene', (45, 48))	('variants', 'Var', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('SDHA', 'Gene', '6389', (85, 89))	('SDHB', 'Gene', '6390', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('SDHB', 'Gene', (168, 172))
53657	32971818	Positive immunoreactivity was found in one patient with a likely pathogenic variant in the IDH1 gene occurring with no variant in SDHx.	('pathogenic', 'Reg', (65, 75))	('variant', 'Var', (76, 83))	('patient', 'Species', '9606', (43, 50))	('SDH', 'Gene', (130, 133))	('IDH1', 'Gene', (91, 95))	('IDH1', 'Gene', '3417', (91, 95))	('SDH', 'Gene', '6390', (130, 133))
53661	32971818	SDH has a critical role in mitochondrial metabolism; disruption of the SDH complex leads to abnormal accumulation of succinate in the cytosol, reprogramming of the energy metabolism, increased ROS production, stabilization of hypoxia-inducible factors (HIFs), and altered gene expression (in particular, for HIF targets).	('altered', 'Reg', (264, 271))	('increased ROS production', 'Phenotype', 'HP:0025464', (183, 207))	('SDH', 'Gene', '6390', (71, 74))	('hypoxia', 'Disease', 'MESH:D000860', (226, 233))	('SDH', 'Gene', '6390', (0, 3))	('disruption', 'Var', (53, 63))	('SDH', 'Gene', (71, 74))	('succinate', 'Chemical', 'MESH:D019802', (117, 126))	('SDH', 'Gene', (0, 3))	('ROS', 'Chemical', '-', (193, 196))	('gene expression', 'MPA', (272, 287))	('accumulation of succinate', 'MPA', (101, 126))	('HIFs', 'Disease', (253, 257))	('ROS production', 'MPA', (193, 207))	('reprogramming', 'MPA', (143, 156))	('increased', 'PosReg', (183, 192))	('HIFs', 'Disease', 'None', (253, 257))	('hypoxia', 'Disease', (226, 233))	('stabilization', 'MPA', (209, 222))
53664	32971818	Variants in SDHD are more frequently observed in HNPGLs, followed by SDHB and SDHC mutations.	('HNPGLs', 'Disease', (49, 55))	('Variants', 'Var', (0, 8))	('SDHB', 'Gene', (69, 73))	('SDHC', 'Gene', '6391', (78, 82))	('SDHD', 'Gene', (12, 16))	('SDHD', 'Gene', '6392', (12, 16))	('observed', 'Reg', (37, 45))	('PGLs', 'Phenotype', 'HP:0002668', (51, 55))	('SDHB', 'Gene', '6390', (69, 73))	('SDHC', 'Gene', (78, 82))
53665	32971818	SDHA variants show extremely low penetrance in HNPGLs.	('SDHA', 'Gene', (0, 4))	('HNPGLs', 'Disease', (47, 53))	('PGLs', 'Phenotype', 'HP:0002668', (49, 53))	('SDHA', 'Gene', '6389', (0, 4))	('variants', 'Var', (5, 13))
53666	32971818	We obtained similar results; however, SDHC variants were found more often than SDHB variants.	('SDHC', 'Gene', (38, 42))	('SDHC', 'Gene', '6391', (38, 42))	('SDHB', 'Gene', '6390', (79, 83))	('variants', 'Var', (43, 51))	('SDHB', 'Gene', (79, 83))
53667	32971818	Previously, it has been reported that SDHC mutations are mainly associated with the development of CPGLs, explaining this difference.	('associated with', 'Reg', (64, 79))	('SDHC', 'Gene', (38, 42))	('SDHC', 'Gene', '6391', (38, 42))	('CPGL', 'Phenotype', 'HP:0100635', (99, 103))	('CPGLs', 'Chemical', '-', (99, 104))	('PGLs', 'Phenotype', 'HP:0002668', (100, 104))	('mutations', 'Var', (43, 52))	('CPGLs', 'Disease', (99, 104))
53668	32971818	Mutations in any of the SDHx genes can cause a destabilization of the SDH complex, loss of its enzymatic activity, and a disruption in the electron transport function.	('disruption', 'Reg', (121, 131))	('SDH', 'Gene', '6390', (24, 27))	('destabilization', 'MPA', (47, 62))	('SDH', 'Gene', '6390', (70, 73))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (24, 27))	('SDH', 'Gene', (70, 73))	('electron transport function', 'MPA', (139, 166))	('enzymatic activity', 'MPA', (95, 113))	('loss', 'NegReg', (83, 87))
53669	32971818	Numerous studies have reported a changed expression pattern of SDHB presented as negative or weak diffuse immunostaining in tumors with SDHA-, SDHB-, SDHC-, and SDHD mutations.	('SDHC', 'Gene', (150, 154))	('SDHD', 'Gene', (161, 165))	('SDHB', 'Gene', (143, 147))	('SDHA', 'Gene', (136, 140))	('SDHB', 'Gene', (63, 67))	('mutations', 'Var', (166, 175))	('expression', 'MPA', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('SDHA', 'Gene', '6389', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SDHC', 'Gene', '6391', (150, 154))	('changed', 'Reg', (33, 40))	('tumors', 'Disease', (124, 130))	('negative', 'NegReg', (81, 89))	('weak', 'NegReg', (93, 97))	('SDHB', 'Gene', '6390', (143, 147))	('SDHD', 'Gene', '6392', (161, 165))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('SDHB', 'Gene', '6390', (63, 67))
53670	32971818	It was shown that negative SDHB staining is more commonly associated with mutations in SDHB, whereas weak diffuse staining often occurs in SDHD-mutated tumors.	('SDHD', 'Gene', (139, 143))	('associated', 'Reg', (58, 68))	('SDHD', 'Gene', '6392', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('SDHB', 'Gene', '6390', (87, 91))	('mutations', 'Var', (74, 83))	('negative', 'NegReg', (18, 26))	('SDHB', 'Gene', '6390', (27, 31))	('tumors', 'Disease', (152, 158))	('SDHB', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('SDHB', 'Gene', (87, 91))
53671	32971818	We also detected loss of SDHB expression in all patients with SDHB variants and weak diffuse SDHB staining in the majority of SDHD mutation carriers that support this finding.	('expression', 'MPA', (30, 40))	('SDHB', 'Gene', '6390', (62, 66))	('SDHB', 'Gene', (93, 97))	('SDHB', 'Gene', '6390', (25, 29))	('SDHD', 'Gene', (126, 130))	('SDHD', 'Gene', '6392', (126, 130))	('SDHB', 'Gene', (25, 29))	('loss', 'NegReg', (17, 21))	('patients', 'Species', '9606', (48, 56))	('SDHB', 'Gene', '6390', (93, 97))	('variants', 'Var', (67, 75))	('SDHB', 'Gene', (62, 66))	('mutation', 'Var', (131, 139))
53672	32971818	Studied patients carrying variants in SDHC showed both negative and weak diffuse SDHB staining.	('SDHC', 'Gene', (38, 42))	('SDHC', 'Gene', '6391', (38, 42))	('SDHB', 'Gene', '6390', (81, 85))	('variants', 'Var', (26, 34))	('SDHB', 'Gene', (81, 85))	('patients', 'Species', '9606', (8, 16))
53674	32971818	Generally, both patterns indicate SDH deficiency, which is a surrogate marker for SDHx germline mutations almost always causing the gene biallelic inactivation.	('SDH', 'Gene', (82, 85))	('SDH', 'Gene', (34, 37))	('SDH deficiency', 'Disease', (34, 48))	('SDH deficiency', 'Disease', 'MESH:D007153', (34, 48))	('SDH', 'Gene', '6390', (82, 85))	('causing', 'Reg', (120, 127))	('mutations', 'Var', (96, 105))	('SDH', 'Gene', '6390', (34, 37))
53675	32971818	Somatic events leading to biallelic inactivation have been rarely reported for the SDHx genes.	('SDH', 'Gene', '6390', (83, 86))	('SDH', 'Gene', (83, 86))	('biallelic', 'Var', (26, 35))
53677	32971818	However, based on this conception, we can suppose that in the majority of studied patients with SDH deficiency, the mutations of SDHx genes are germline.	('SDH', 'Gene', '6390', (96, 99))	('SDH', 'Gene', (129, 132))	('patients', 'Species', '9606', (82, 90))	('SDH', 'Gene', (96, 99))	('mutations', 'Var', (116, 125))	('SDH', 'Gene', '6390', (129, 132))	('SDH deficiency', 'Disease', (96, 110))	('SDH deficiency', 'Disease', 'MESH:D007153', (96, 110))
53678	32971818	In one patient with a novel likely pathogenic frameshift SDHD variant, we found retention of SDHB expression.	('pathogenic', 'Reg', (35, 45))	('SDHB', 'Gene', (93, 97))	('patient', 'Species', '9606', (7, 14))	('SDHD', 'Gene', '6392', (57, 61))	('frameshift', 'Var', (46, 56))	('SDHD', 'Gene', (57, 61))	('SDHB', 'Gene', '6390', (93, 97))
53679	32971818	In a patient with a pathogenic SDHA variant, we have seen completely absent SDHA expression and weak diffuse SDHB immunostaining that is in accordance with the literature.	('SDHA', 'Gene', '6389', (31, 35))	('SDHA', 'Gene', '6389', (76, 80))	('patient', 'Species', '9606', (5, 12))	('SDHB', 'Gene', '6390', (109, 113))	('variant', 'Var', (36, 43))	('SDHB', 'Gene', (109, 113))	('absent', 'NegReg', (69, 75))	('SDHA', 'Gene', (31, 35))	('SDHA', 'Gene', (76, 80))	('pathogenic', 'Reg', (20, 30))	('expression', 'MPA', (81, 91))
53681	32971818	Negative SDHA expression is defined both when mutation leads to the truncated protein and owing to missense mutation.	('SDHA', 'Gene', '6389', (9, 13))	('leads', 'Reg', (55, 60))	('truncated protein', 'MPA', (68, 85))	('SDHA', 'Gene', (9, 13))	('mutation', 'Var', (46, 54))	('missense mutation', 'Var', (99, 116))
53683	32971818	Moreover, SDHA mutation is a rare event in PGLs; therefore, the use of SDHB immunohistochemistry seems to be more expedient than SDHA/SDHB immunohistochemistry for prediction of mutations in any SDHx genes.	('SDH', 'Gene', '6390', (10, 13))	('SDHA', 'Gene', (10, 14))	('SDHB', 'Gene', '6390', (71, 75))	('SDHA', 'Gene', '6389', (129, 133))	('SDH', 'Gene', '6390', (71, 74))	('SDH', 'Gene', (195, 198))	('SDHB', 'Gene', '6390', (134, 138))	('SDHA', 'Gene', '6389', (10, 14))	('SDH', 'Gene', (129, 132))	('SDH', 'Gene', (10, 13))	('SDHB', 'Gene', (71, 75))	('SDHB', 'Gene', (134, 138))	('SDH', 'Gene', '6390', (134, 137))	('SDH', 'Gene', (71, 74))	('SDH', 'Gene', '6390', (195, 198))	('PGLs', 'Phenotype', 'HP:0002668', (43, 47))	('SDH', 'Gene', (134, 137))	('SDH', 'Gene', '6390', (129, 132))	('mutations', 'Var', (178, 187))	('SDHA', 'Gene', (129, 133))
53684	32971818	The loss of SDHC expression was revealed in one out of three patients with variants in the SDHC gene.	('SDHC', 'Gene', (91, 95))	('SDHC', 'Gene', '6391', (91, 95))	('expression', 'MPA', (17, 27))	('patients', 'Species', '9606', (61, 69))	('SDHC', 'Gene', (12, 16))	('loss', 'NegReg', (4, 8))	('variants', 'Var', (75, 83))	('SDHC', 'Gene', '6391', (12, 16))
53685	32971818	This variant, NM_003001.3: c.224G > A, p.(Gly75Asp) (chr1: 161310428b rs786205147;189841), was described in the ClinVar database as a germline likely pathogenic variant associated with the hereditary cancer-predisposing syndrome and Carney triad with no experimental evidence of its pathogenicity to date.	('hereditary cancer', 'Disease', (189, 206))	('Carney triad', 'Disease', (233, 245))	('c.224G > A', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('p.(Gly75Asp)', 'SUBSTITUTION', 'None', (39, 51))	('associated', 'Reg', (169, 179))	('pathogenic', 'Reg', (150, 160))	('p.(Gly75Asp', 'Var', (39, 50))	('rs786205147', 'DBSNP_MENTION', 'None', (70, 81))	('hereditary cancer', 'Disease', 'MESH:D009369', (189, 206))	('rs786205147', 'Var', (70, 81))
53687	32971818	Therefore, we can suggest that, except for SDHA, no evident correlations have been found between negative SDHC and SDHD immunohistochemistry and the presence of pathogenic variants in the corresponding genes.	('SDHD', 'Gene', '6392', (115, 119))	('SDHC', 'Gene', (106, 110))	('variants', 'Var', (172, 180))	('SDHD', 'Gene', (115, 119))	('SDHC', 'Gene', '6391', (106, 110))	('SDHA', 'Gene', '6389', (43, 47))	('SDHA', 'Gene', (43, 47))
53688	32971818	Among 42 patients with CPGLs, we revealed pathogenic RET variants in three cases and a likely pathogenic IDH1 variant in one patient.	('CPGLs', 'Chemical', '-', (23, 28))	('patients', 'Species', '9606', (9, 17))	('RET', 'Gene', (53, 56))	('CPGL', 'Phenotype', 'HP:0100635', (23, 27))	('IDH1', 'Gene', (105, 109))	('PGLs', 'Phenotype', 'HP:0002668', (24, 28))	('IDH1', 'Gene', '3417', (105, 109))	('RET', 'Gene', '5979', (53, 56))	('patient', 'Species', '9606', (125, 132))	('patient', 'Species', '9606', (9, 16))	('variants', 'Var', (57, 65))	('pathogenic', 'Reg', (42, 52))
53692	32971818	However, more cases are needed to assess the impact of IDHx mutations on the stability of the SDH complex.	('mutations', 'Var', (60, 69))	('IDHx', 'Gene', (55, 59))	('SDH', 'Gene', '6390', (94, 97))	('SDH', 'Gene', (94, 97))
53693	32971818	Despite the great results showing a high correlation of SDHB immunohistochemistry with the presence of SDHx variants (94%), negative or weak diffuse SDHB staining has also been found in 42% of tumors without pathogenic/likely pathogenic variants in any SDHx genes.	('SDHB', 'Gene', '6390', (56, 60))	('SDH', 'Gene', (253, 256))	('SDHB', 'Gene', '6390', (149, 153))	('SDHB', 'Gene', (56, 60))	('SDH', 'Gene', '6390', (103, 106))	('SDHB', 'Gene', (149, 153))	('SDH', 'Gene', '6390', (149, 152))	('tumors', 'Disease', (193, 199))	('SDH', 'Gene', '6390', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('variants', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('SDH', 'Gene', (149, 152))	('SDH', 'Gene', (103, 106))	('SDH', 'Gene', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('SDH', 'Gene', '6390', (253, 256))
53694	32971818	In this case, SDH deficiency can be caused by mutations in the DNA regions, which have not been screened, or epimutations.	('SDH deficiency', 'Disease', 'MESH:D007153', (14, 28))	('mutations', 'Var', (46, 55))	('DNA regions', 'Gene', (63, 74))	('caused by', 'Reg', (36, 45))	('epimutations', 'Var', (109, 121))	('SDH deficiency', 'Disease', (14, 28))
53695	32971818	Given these data, we presumed that SDHB immunohistochemistry could be used for the initial assessment of SDHx variants in CPGLs with genetic testing in parallel.	('SDH', 'Gene', (105, 108))	('SDH', 'Gene', '6390', (35, 38))	('PGLs', 'Phenotype', 'HP:0002668', (123, 127))	('SDHB', 'Gene', (35, 39))	('CPGLs', 'Chemical', '-', (122, 127))	('variants', 'Var', (110, 118))	('CPGL', 'Phenotype', 'HP:0100635', (122, 126))	('SDH', 'Gene', '6390', (105, 108))	('SDH', 'Gene', (35, 38))	('SDHB', 'Gene', '6390', (35, 39))
53696	32971818	Additional SDHA staining increases the cost of the IHC analysis, but among PGLs/PCCs, SDHA mutation frequency is extremely low, and in the majority of such cases, negative or weak diffuse SDHB staining is also observed.	('SDHA', 'Gene', '6389', (86, 90))	('SDHA', 'Gene', '6389', (11, 15))	('mutation', 'Var', (91, 99))	('SDHB', 'Gene', '6390', (188, 192))	('PGLs', 'Phenotype', 'HP:0002668', (75, 79))	('low', 'NegReg', (123, 126))	('SDHA', 'Gene', (11, 15))	('SDHA', 'Gene', (86, 90))	('SDHB', 'Gene', (188, 192))
53709	32971818	VCF files included data on allele frequency (1000 Genomes Project, ExAC, gnomAD, Kaviar, and ESP-6500 ), variant annotation (ClinVar, dbSNP, and COSMIC), position region conservation score (PhastCons and PhyloP [both PHAST v. 1.5, Siepel Lab, Cold Spring Harbor, NY, USA]), localization of variants in protein domains (InterPro [v. 81.0, Wellcome Genome Campus, Hinxton, Cambridgeshire, UK]), as well as on pathogenicity prediction (SIFT [v. 6.2.1, Fred Hutchinson Cancer Research Center, Seattle, WA, USA], PolyPhen2 [v. 2.2.2, Harvard Medical School, Boston, MA, USA], MutationTaster [v. 2013-03-20, "Charite-Universitatsmedizin Berlin", Berlin, Germany], and LRT [v. 0.2, Tel-Aviv University, Tel Aviv, Israel]).	('Cancer', 'Phenotype', 'HP:0002664', (465, 471))	('Cancer', 'Disease', (465, 471))	('2.1', 'Gene', (444, 447))	('2.1', 'Gene', '6700', (444, 447))	('Hutchinson Cancer', 'Phenotype', 'HP:0012413', (454, 471))	('Cancer', 'Disease', 'MESH:D009369', (465, 471))	('Cold Spring Harbor', 'Disease', (243, 261))	('Cold Spring Harbor', 'Disease', 'MESH:C537062', (243, 261))	('Tel', 'Gene', '2120', (696, 699))	('Tel', 'Gene', (675, 678))	('variants', 'Var', (290, 298))	('Tel', 'Gene', '2120', (675, 678))	('Tel', 'Gene', (696, 699))
53717	32971818	Correlation analysis between SDHB staining and the presence of mutations in any SDHx genes was performed using the Spearman's rank correlation test with STATISTICA 10 (StatSoft Inc., Tulsa, OK, USA).	('mutations', 'Var', (63, 72))	('SDHB', 'Gene', '6390', (29, 33))	('SDHB', 'Gene', (29, 33))	('SDH', 'Gene', '6390', (80, 83))	('SDH', 'Gene', '6390', (29, 32))	('SDH', 'Gene', (80, 83))	('SDH', 'Gene', (29, 32))
53718	32971818	This is the first study on the correlation between SDHx mutation status and their protein expression, respectively estimated with exome sequencing and IHC in a representative set of CPGLs.	('SDH', 'Gene', '6390', (51, 54))	('protein expression', 'MPA', (82, 100))	('CPGL', 'Phenotype', 'HP:0100635', (182, 186))	('SDH', 'Gene', (51, 54))	('CPGLs', 'Chemical', '-', (182, 187))	('PGLs', 'Phenotype', 'HP:0002668', (183, 187))	('mutation', 'Var', (56, 64))
53719	32971818	It has previously been reported that negative or weak diffuse SDHB staining has high sensitivity and specificity for the prediction of mutations of SDHx in PGLs/PCCs.	('SDH', 'Gene', '6390', (62, 65))	('SDH', 'Gene', (62, 65))	('SDH', 'Gene', '6390', (148, 151))	('mutations', 'Var', (135, 144))	('SDH', 'Gene', (148, 151))	('SDHB', 'Gene', '6390', (62, 66))	('PGLs', 'Phenotype', 'HP:0002668', (156, 160))	('SDHB', 'Gene', (62, 66))
53722	32971818	Based on the collected data, we believe that SDHB immunohistochemistry could be used for primary identifications of patients potentially carrying SDHx variants who should be further referred for genetic testing.	('variants', 'Var', (151, 159))	('patients', 'Species', '9606', (116, 124))	('SDH', 'Gene', '6390', (146, 149))	('SDH', 'Gene', (45, 48))	('SDHB', 'Gene', '6390', (45, 49))	('SDHB', 'Gene', (45, 49))	('SDH', 'Gene', (146, 149))	('SDH', 'Gene', '6390', (45, 48))
53731	32732920	The AUCs for differentiating paragangliomas and UCDs were 0.920, 0.888, 0.909, and 0.765 for SUVmax, SUVmean, SUVpeak, and TLG, respectively.	('0.765', 'Var', (83, 88))	('TLG', 'Chemical', '-', (123, 126))	('paragangliomas', 'Disease', 'MESH:D010235', (29, 43))	('paragangliomas', 'Disease', (29, 43))	('CDs', 'Chemical', 'MESH:D002104', (49, 52))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('paragangliomas', 'Phenotype', 'HP:0002668', (29, 43))
53807	32732920	Some paragangliomas are caused by a germline mutation in SDH (SDHB, SDHC, and SDHD) or VHL tumor suppressor genes.	('SDH', 'Gene', (68, 71))	('VHL tumor', 'Disease', (87, 96))	('SDHB', 'Gene', '6390', (62, 66))	('SDH', 'Gene', '6390', (57, 60))	('paragangliomas', 'Disease', (5, 19))	('SDHC', 'Gene', (68, 72))	('SDH', 'Gene', '6390', (62, 65))	('VHL tumor', 'Disease', 'MESH:D006623', (87, 96))	('SDHD', 'Gene', '6392', (78, 82))	('caused by', 'Reg', (24, 33))	('paraganglioma', 'Phenotype', 'HP:0002668', (5, 18))	('SDH', 'Gene', '6390', (78, 81))	('SDHB', 'Gene', (62, 66))	('SDH', 'Gene', (57, 60))	('SDH', 'Gene', (62, 65))	('SDHD', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('paragangliomas', 'Disease', 'MESH:D010235', (5, 19))	('SDH', 'Gene', '6390', (68, 71))	('SDH', 'Gene', (78, 81))	('paragangliomas', 'Phenotype', 'HP:0002668', (5, 19))	('SDHC', 'Gene', '6391', (68, 72))	('germline mutation', 'Var', (36, 53))
53808	32732920	Mutations in these genes are associated with the induction of a hypoxic response under normal oxygen conditions, a response mediated by the oxygen-regulated transcription factor hypoxia-inducible factor 1a.	('oxygen', 'Chemical', 'MESH:D010100', (140, 146))	('hypoxia-inducible factor 1a', 'Gene', '3091', (178, 205))	('Mutations', 'Var', (0, 9))	('oxygen', 'Chemical', 'MESH:D010100', (94, 100))	('associated', 'Reg', (29, 39))	('hypoxia-inducible factor 1a', 'Gene', (178, 205))	('hypoxic response', 'MPA', (64, 80))
53809	32732920	SDH and VHL mutations could result in the stabilization of hypoxia-inducible factor 1a leading to inhibition of the tricarboxylic acid cycle and increased glycolysis, which could in turn cause increased glucose demand and high FDG uptake (Warburg effect).	('VHL', 'Gene', '7428', (8, 11))	('high FDG uptake', 'MPA', (222, 237))	('tricarboxylic acid cycle', 'MPA', (116, 140))	('SDH', 'Gene', '6390', (0, 3))	('increased glucose', 'Phenotype', 'HP:0003074', (193, 210))	('glycolysis', 'MPA', (155, 165))	('glucose', 'Chemical', 'MESH:D005947', (203, 210))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (116, 134))	('SDH', 'Gene', (0, 3))	('glucose demand', 'MPA', (203, 217))	('inhibition', 'NegReg', (98, 108))	('increased', 'PosReg', (145, 154))	('increased', 'PosReg', (193, 202))	('cause', 'Reg', (187, 192))	('VHL', 'Gene', (8, 11))	('hypoxia-inducible factor 1a', 'Gene', (59, 86))	('FDG', 'Chemical', 'MESH:D019788', (227, 230))	('mutations', 'Var', (12, 21))	('stabilization', 'MPA', (42, 55))	('hypoxia-inducible factor 1a', 'Gene', '3091', (59, 86))
53844	32207268	Additionally, in this study, metastatic PPGLs at diagnosis or during the follow-up period were associated with a 2.40-fold higher risk of mortality than non-metastatic PPGLs, adjusted for age, sex, cerebrovascular diseases, cardiovascular disease, diabetes mellitus, and fractures.	('fractures', 'Disease', 'MESH:D050723', (271, 280))	('diabetes mellitus', 'Disease', (248, 265))	('cerebrovascular diseases', 'Disease', (198, 222))	('metastatic PPGLs', 'Var', (29, 45))	('PGL', 'Phenotype', 'HP:0002668', (169, 172))	('cardiovascular disease', 'Disease', (224, 246))	('diabetes mellitus', 'Disease', 'MESH:D003920', (248, 265))	('cerebrovascular diseases', 'Disease', 'MESH:D002561', (198, 222))	('PPGLs', 'Chemical', '-', (40, 45))	('PGL', 'Phenotype', 'HP:0002668', (41, 44))	('mortality', 'Disease', 'MESH:D003643', (138, 147))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (224, 246))	('PPGLs', 'Chemical', '-', (168, 173))	('fractures', 'Disease', (271, 280))	('cardiovascular disease', 'Disease', 'MESH:D002318', (224, 246))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (248, 265))	('mortality', 'Disease', (138, 147))
53848	31185588	Chiari Malformation Type 1 in EPAS1-Associated Syndrome A syndrome of multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia due to somatic mosaic gain-of-function mutation of EPAS1, encoding HIF-2alpha, was previously described.	('polycythemia', 'Disease', (134, 146))	('EPAS1', 'Gene', (30, 35))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('paragangliomas', 'Phenotype', 'HP:0002668', (79, 93))	('polycythemia', 'Disease', 'MESH:D011086', (134, 146))	('EPAS1', 'Gene', '2034', (198, 203))	('mutation', 'Var', (186, 194))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (94, 110))	('Malformation Type', 'Disease', (7, 24))	('Chiari Malformation', 'Phenotype', 'HP:0002308', (0, 19))	('gain-of-function', 'PosReg', (169, 185))	('HIF-2alpha', 'Gene', '2034', (214, 224))	('EPAS1', 'Gene', '2034', (30, 35))	('polycythemia', 'Phenotype', 'HP:0001901', (134, 146))	('somatostatinoma', 'Disease', 'MESH:D013005', (113, 128))	('A syndrome of multiple paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (56, 111))	('somatostatinoma', 'Disease', (113, 128))	('EPAS1', 'Gene', (198, 203))	('Malformation Type', 'Disease', 'MESH:D000014', (7, 24))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (94, 111))	('HIF-2alpha', 'Gene', (214, 224))	('Chiari Malformation Type 1', 'Phenotype', 'HP:0007099', (0, 26))
53850	31185588	Abnormal bone growth of the skull base may lead to Chiari malformation type I.	('Chiari malformation', 'Phenotype', 'HP:0002308', (51, 70))	('Chiari malformation type I.', 'Phenotype', 'HP:0007099', (51, 78))	('Chiari malformation type I', 'Phenotype', 'HP:0007099', (51, 77))	('lead to', 'Reg', (43, 50))	('bone growth of the skull', 'Phenotype', 'HP:0004437', (9, 33))	('Abnormal', 'Var', (0, 8))	('Chiari malformation type I', 'Disease', (51, 77))	('Abnormal bone growth', 'Phenotype', 'HP:0011849', (0, 20))	('Chiari malformation type I', 'Disease', 'MESH:D001139', (51, 77))
53851	31185588	We report two cases of EPAS1 gain-of-function mutation syndrome with Chiari malformation and developmental skull base anomalies.	('gain-of-function', 'PosReg', (29, 45))	('Chiari malformation', 'Phenotype', 'HP:0002308', (69, 88))	('Chiari malformation', 'Disease', (69, 88))	('EPAS1', 'Gene', '2034', (23, 28))	('mutation', 'Var', (46, 54))	('skull base anomalies', 'Phenotype', 'HP:0002693', (107, 127))	('EPAS1', 'Gene', (23, 28))	('Chiari malformation', 'Disease', 'MESH:D001139', (69, 88))
53853	31185588	The syndrome was confirmed genetically by identification of the functional EPAS1 gain-of-function mutation in the resected tumors and circulating leukocytes.	('EPAS1', 'Gene', (75, 80))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (98, 106))	('gain-of-function', 'PosReg', (81, 97))	('EPAS1', 'Gene', '2034', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
53854	31185588	Both patients were confirmed for characteristics of EPAS1 gain-of-function mutation syndrome by complete blood count (CBC), plasma biochemistry, and computed tomography (CT) of the abdomen and pelvis.	('patients', 'Species', '9606', (5, 13))	('mutation', 'Var', (75, 83))	('EPAS1', 'Gene', '2034', (52, 57))	('EPAS1', 'Gene', (52, 57))	('gain-of-function', 'PosReg', (58, 74))
53856	31185588	The present study implicates EPAS1 mutations in abnormal posterior fossa development resulting in Chiari malformation type I.  Chiari malformation type I is characterized by caudal displacement of the cerebellar tonsils through the foramen magnum of at least 5 mm in adults.	('Chiari malformation', 'Phenotype', 'HP:0002308', (127, 146))	('Chiari malformation type I', 'Phenotype', 'HP:0007099', (127, 153))	('Chiari malformation type I', 'Disease', (98, 124))	('Chiari malformation type I', 'Disease', 'MESH:D001139', (98, 124))	('Chiari malformation type I', 'Disease', (127, 153))	('Chiari malformation type I', 'Phenotype', 'HP:0007099', (98, 124))	('mutations', 'Var', (35, 44))	('Chiari malformation', 'Phenotype', 'HP:0002308', (98, 117))	('Chiari malformation type I.', 'Phenotype', 'HP:0007099', (98, 125))	('EPAS1', 'Gene', '2034', (29, 34))	('Chiari malformation type I', 'Disease', 'MESH:D001139', (127, 153))	('abnormal posterior fossa', 'Phenotype', 'HP:0000932', (48, 72))	('EPAS1', 'Gene', (29, 34))
53861	31185588	Mosaic gain-of-function EPAS1 mutations have been found to cause a syndrome encompassing multiple paragangliomas/pheochromocytomas, somatostatinoma, and polycythemia, also called Pacak-Zhuang syndrome.	('multiple paragangliomas/pheochromocytomas', 'Disease', (89, 130))	('paragangliomas', 'Phenotype', 'HP:0002668', (98, 112))	('somatostatinoma', 'Disease', 'MESH:D013005', (132, 147))	('EPAS1', 'Gene', '2034', (24, 29))	('polycythemia', 'Phenotype', 'HP:0001901', (153, 165))	('somatostatinoma', 'Disease', (132, 147))	('gain-of-function', 'PosReg', (7, 23))	('polycythemia', 'Disease', 'MESH:D011086', (153, 165))	('EPAS1', 'Gene', (24, 29))	('Pacak-Zhuang syndrome', 'Disease', (179, 200))	('multiple paragangliomas/pheochromocytomas', 'Disease', 'MESH:D010673', (89, 130))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (113, 129))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (113, 130))	('mutations', 'Var', (30, 39))	('syndrome', 'Disease', (67, 75))	('polycythemia', 'Disease', (153, 165))
53862	31185588	Herein, we report two patients with EPAS1 gain-of-function mutation syndrome, Chiari malformation type I and other developmental anomalies of the posterior fossa and spine.	('EPAS1', 'Gene', '2034', (36, 41))	('Chiari malformation type I', 'Disease', (78, 104))	('anomalies of the posterior fossa', 'Phenotype', 'HP:0000932', (129, 161))	('EPAS1', 'Gene', (36, 41))	('Chiari malformation type I', 'Disease', 'MESH:D001139', (78, 104))	('patients', 'Species', '9606', (22, 30))	('Chiari malformation type I', 'Phenotype', 'HP:0007099', (78, 104))	('mutation', 'Var', (59, 67))	('gain-of-function', 'PosReg', (42, 58))	('Chiari malformation', 'Phenotype', 'HP:0002308', (78, 97))
53870	31185588	Identification of the EPAS1 gain-of-function mutation in the resected tumor tissues and circulating leukocytes confirmed the underlying syndrome.	('EPAS1', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('mutation', 'Var', (45, 53))	('gain-of-function', 'PosReg', (28, 44))	('EPAS1', 'Gene', '2034', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
53901	31185588	Thus, this suggests that the gain-of-function mutation in HIF-2alpha leads to the persistence of cartilaginous structures due to delayed closure of the dorsal mesoderm or lack of endochondral ossification in bony growth centers of the sacral spinous processes and lamina.	('gain-of-function', 'PosReg', (29, 45))	('HIF-2alpha', 'Gene', '2034', (58, 68))	('lack', 'NegReg', (171, 175))	('cartilaginous', 'Disease', 'MESH:D015831', (97, 110))	('delayed closure', 'Phenotype', 'HP:0000270', (129, 144))	('endochondral ossification', 'CPA', (179, 204))	('cartilaginous', 'Disease', (97, 110))	('mutation', 'Var', (46, 54))	('HIF-2alpha', 'Gene', (58, 68))	('delayed closure of the dorsal mesoderm', 'CPA', (129, 167))
53910	31185588	The appearance of incidental Chiari malformation and reduced bony development of the spine and skull base in our patients with gain-of-function EPAS1 mutation suggests that persistent hypoxic signaling resulted in incomplete mesenchymal development that manifested as 1) reduced ossification of posterior fossa bones and, secondarily, Chiari I malformation, 2) impaired development of the sacrum leading to spina bifida occulta of S1 and segmentation anomalies of the sacral ala, and 3) impaired development of other brain structures resulting in asymptomatic brain vascular anomalies.	('EPAS1', 'Gene', '2034', (144, 149))	('vascular anomalies', 'Phenotype', 'HP:0002597', (566, 584))	('segmentation anomalies of the sacral ala', 'Phenotype', 'HP:0008455', (438, 478))	('impaired', 'NegReg', (361, 369))	('Chiari malformation', 'Disease', 'MESH:D001139', (29, 48))	('hypoxic', 'Disease', 'MESH:D000860', (184, 191))	('reduced', 'NegReg', (271, 278))	('impaired', 'NegReg', (487, 495))	('Chiari malformation', 'Phenotype', 'HP:0002308', (29, 48))	('development of other brain structures', 'CPA', (496, 533))	('hypoxic', 'Disease', (184, 191))	('impaired development of the sacrum', 'Phenotype', 'HP:0008455', (361, 395))	('segmentation anomalies of the sacral ala', 'Disease', 'MESH:C537538', (438, 478))	('development of the sacrum', 'CPA', (370, 395))	('segmentation anomalies of the sacral ala', 'Disease', (438, 478))	('ossification', 'CPA', (279, 291))	('patients', 'Species', '9606', (113, 121))	('EPAS1', 'Gene', (144, 149))	('brain vascular anomalies', 'Disease', (560, 584))	('brain vascular anomalies', 'Disease', 'MESH:D002561', (560, 584))	('spina bifida occulta of S1', 'CPA', (407, 433))	('mutation', 'Var', (150, 158))	('gain-of-function', 'PosReg', (127, 143))	('Chiari I malformation', 'Phenotype', 'HP:0007099', (335, 356))	('spina bifida', 'Phenotype', 'HP:0002414', (407, 419))	('reduced ossification', 'Phenotype', 'HP:0002750', (271, 291))	('Chiari malformation', 'Disease', (29, 48))	('spina bifida occulta', 'Phenotype', 'HP:0003298', (407, 427))	('spina bifida occulta of S1', 'Phenotype', 'HP:0004614', (407, 433))
53919	31185588	Herein, we describe two patients with EPAS1-gain-of-function (Pacak-Zhuang) syndrome and features of incidental Chiari I malformation, i.e., greater than 5 mm tonsillar herniation below the foramen magnum.	('EPAS1', 'Gene', '2034', (38, 43))	('greater', 'Var', (141, 148))	('EPAS1', 'Gene', (38, 43))	('Chiari I malformation', 'Phenotype', 'HP:0007099', (112, 133))	('patients', 'Species', '9606', (24, 32))
53921	31185588	The reduced boney development of the spine and skull base in these patients with gain-of-function mutation in EPAS1 suggests that persistent hypoxic signaling results in incomplete mesenchymal development.	('reduced', 'NegReg', (4, 11))	('mutation', 'Var', (98, 106))	('hypoxic', 'Disease', (141, 148))	('incomplete', 'NegReg', (170, 180))	('patients', 'Species', '9606', (67, 75))	('hypoxic', 'Disease', 'MESH:D000860', (141, 148))	('gain-of-function', 'PosReg', (81, 97))	('EPAS1', 'Gene', '2034', (110, 115))	('reduced boney development', 'Phenotype', 'HP:0002750', (4, 29))	('EPAS1', 'Gene', (110, 115))
53922	31185588	This report implicates mutations in EPAS1, encoding HIF-2alpha, in the development of Chiari malformation type I. Conceptualization:identified malformation: J.S.R., Z.Z., K.P., J.D.H.	('K.P.', 'Var', (171, 175))	('Chiari malformation', 'Phenotype', 'HP:0002308', (86, 105))	('HIF-2alpha', 'Gene', (52, 62))	('EPAS1', 'Gene', '2034', (36, 41))	('Chiari malformation type I.', 'Phenotype', 'HP:0007099', (86, 113))	('Chiari malformation type I', 'Phenotype', 'HP:0007099', (86, 112))	('EPAS1', 'Gene', (36, 41))	('HIF-2alpha', 'Gene', '2034', (52, 62))	('J.S.R.', 'Var', (157, 163))	('Z.Z.', 'Var', (165, 169))	('Chiari malformation type I', 'Disease', (86, 112))	('Chiari malformation type I', 'Disease', 'MESH:D001139', (86, 112))
54008	28400922	Catecholamines cause myocardial toxicity by enhancing lipid mobility, calcium overloading, oxygen derived free radical production, increased sarcolemmal permeability as well as by provoking a state of oxygen supply-demand mismatch.	('calcium overloading', 'MPA', (70, 89))	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('provoking', 'Reg', (180, 189))	('enhancing', 'PosReg', (44, 53))	('increased', 'PosReg', (131, 140))	('sarcolemmal permeability', 'MPA', (141, 165))	('oxygen', 'Chemical', 'MESH:D010100', (201, 207))	('oxygen derived free radical production', 'MPA', (91, 129))	('Catecholamines', 'Chemical', 'MESH:D002395', (0, 14))	('myocardial toxicity', 'Disease', 'MESH:D009202', (21, 40))	('calcium', 'Chemical', 'MESH:D002118', (70, 77))	('man', 'Species', '9606', (217, 220))	('oxygen derived free radical', 'Chemical', '-', (91, 118))	('myocardial toxicity', 'Disease', (21, 40))	('Catecholamines', 'Var', (0, 14))	('lipid mobility', 'MPA', (54, 68))	('oxygen', 'Chemical', 'MESH:D010100', (91, 97))
54011	28400922	In 2 of 3 patients that developed acute LV dysfunction in our study such events followed acute stress, suggesting that increases in catecholamine levels over and above the background elevation precipitated by "stress" may provoke acute LV dysfunction in pheo patients in a manner similar to TC.	('TC', 'Phenotype', 'HP:0011665', (291, 293))	('LV dysfunction', 'Disease', 'MESH:C535509', (236, 250))	('LV dysfunction', 'Disease', 'MESH:C535509', (40, 54))	('patients', 'Species', '9606', (259, 267))	('man', 'Species', '9606', (273, 276))	('increases', 'Var', (119, 128))	('catecholamine', 'Chemical', 'MESH:D002395', (132, 145))	('catecholamine levels', 'MPA', (132, 152))	('provoke', 'Reg', (222, 229))	('LV dysfunction', 'Disease', (40, 54))	('increases in catecholamine levels', 'Phenotype', 'HP:0003334', (119, 152))	('pheo', 'Phenotype', 'HP:0002666', (254, 258))	('LV dysfunction', 'Disease', (236, 250))	('patients', 'Species', '9606', (10, 18))
54051	27818820	IHC was performed with the following panel of antibodies: Pancytokeratin (PanCK) (clone AE1/AE3, Dako), vimentin (clone V-9, Dako), EMA (clone E29, Dako), CD99 (clone 12E7, Dako), calretinin (5A5, LabIndia), inhibin (AMY82, LabIndia), S-100 (Leica), neuron-specific enolase (NSE) (Dako), chromogranin-A (clone 5H7, Leica), synaptophysin (clone 27G12, Leica), desmin (clone 33, Dako), smooth muscle actin (SMA) (clone 1A4, Novocastra), and S-100 (Leica).	('SMA', 'Gene', '6606', (405, 408))	('CD99', 'Gene', '4267', (155, 159))	('S-100', 'Gene', '6271', (235, 240))	('calretinin', 'Gene', '794', (180, 190))	('AE3', 'Gene', (92, 95))	('vimentin', 'Gene', '7431', (104, 112))	('S-100', 'Gene', (439, 444))	('vimentin', 'Gene', (104, 112))	('NSE', 'Gene', '2026', (275, 278))	('NSE', 'Gene', (275, 278))	('chromogranin-A', 'Gene', (288, 302))	('AE1', 'Gene', '6521', (88, 91))	('S-100', 'Gene', '6271', (439, 444))	('synaptophysin', 'Gene', (323, 336))	('SMA', 'Gene', (405, 408))	('AE3', 'Gene', '6508', (92, 95))	('chromogranin-A', 'Gene', '1113', (288, 302))	('desmin', 'Gene', (359, 365))	('clone', 'Var', (338, 343))	('neuron-specific enolase', 'Gene', (250, 273))	('AE1', 'Gene', (88, 91))	('synaptophysin', 'Gene', '6855', (323, 336))	('calretinin', 'Gene', (180, 190))	('neuron-specific enolase', 'Gene', '2026', (250, 273))	('CD99', 'Gene', (155, 159))	('desmin', 'Gene', '1674', (359, 365))	('S-100', 'Gene', (235, 240))
54083	27818820	Luteinized granulosa cell tumor shows varying presence of nuclear grooves with vimentin, inhibin, calretinin, CD99, and SMA positivity with variable immunoreactivity for desmin and PanCK and negativity with EMA.	('granulosa cell tumor', 'Disease', 'MESH:D006106', (11, 31))	('vimentin', 'Gene', (79, 87))	('calretinin', 'Gene', '794', (98, 108))	('SMA', 'Gene', '6606', (120, 123))	('granulosa cell tumor', 'Disease', (11, 31))	('CD99', 'Gene', '4267', (110, 114))	('immunoreactivity', 'MPA', (149, 165))	('inhibin', 'Protein', (89, 96))	('CD99', 'Gene', (110, 114))	('Luteinized granulosa cell tumor', 'Phenotype', 'HP:0031919', (0, 31))	('positivity', 'Var', (124, 134))	('calretinin', 'Gene', (98, 108))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('desmin', 'Gene', (170, 176))	('PanCK', 'Protein', (181, 186))	('vimentin', 'Gene', '7431', (79, 87))	('SMA', 'Gene', (120, 123))	('desmin', 'Gene', '1674', (170, 176))
54127	26299943	Because of a 50% stenosis in the left circumflex artery, patient PC-4 was initially treated as having an AMI and weaned off ECMO support after 48 h under stable hemodynamic conditions.	('stenosis', 'Var', (17, 25))	('PC-4', 'Gene', '3475', (65, 69))	('patient', 'Species', '9606', (57, 64))	('PC-4', 'Gene', (65, 69))
54145	26299943	Patients DK-1 and DK-2 were admitted to the emergency department with out-of-hospital cardiac arrest.	('cardiac arrest', 'Disease', 'MESH:D006323', (86, 100))	('DK-2', 'Var', (18, 22))	('cardiac arrest', 'Disease', (86, 100))	('cardiac arrest', 'Phenotype', 'HP:0001695', (86, 100))	('Patients', 'Species', '9606', (0, 8))	('DK-1', 'Gene', '28491', (9, 13))	('DK-1', 'Gene', (9, 13))
54246	22584712	On the other hand, human disease susceptibility can be seen as the result of either rare germline genetic variations of high penetrance or as common genomic variants of low penetrance.	('variations', 'Var', (106, 116))	('human', 'Species', '9606', (19, 24))	('human disease susceptibility', 'Disease', (19, 47))
54247	22584712	In this way, a vast variety of allelic alterations have been identified that correlate with the risk of cancer, other common diseases (e.g., diabetes, hypertension, autism, obesity, etc.)	('obesity', 'Disease', (173, 180))	('allelic alterations', 'Var', (31, 50))	('hypertension', 'Disease', 'MESH:D006973', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('correlate', 'Reg', (77, 86))	('autism', 'Disease', (165, 171))	('diabetes', 'Disease', (141, 149))	('obesity', 'Phenotype', 'HP:0001513', (173, 180))	('hypertension', 'Phenotype', 'HP:0000822', (151, 163))	('hypertension', 'Disease', (151, 163))	('diabetes', 'Disease', 'MESH:D003920', (141, 149))	('obesity', 'Disease', 'MESH:D009765', (173, 180))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('autism', 'Phenotype', 'HP:0000717', (165, 171))	('autism', 'Disease', 'MESH:D001321', (165, 171))
54254	22584712	For instance the HCP5 single nucleotide polymorphism serves as a predictor for a hypersensitivity to antiviral drug medications, and the CYP2C19 variant is associated with a diminished clopidogrel response,.	('single nucleotide polymorphism', 'Var', (22, 52))	('hypersensitivity', 'Disease', 'MESH:D004342', (81, 97))	('HCP5', 'Gene', '10866', (17, 21))	('diminished', 'NegReg', (174, 184))	('CYP2C19', 'Gene', (137, 144))	('clopidogrel response', 'MPA', (185, 205))	('HCP5', 'Gene', (17, 21))	('CYP2C19', 'Gene', '1557', (137, 144))	('clopidogrel', 'Chemical', 'MESH:D000077144', (185, 196))	('hypersensitivity', 'Disease', (81, 97))
54260	22584712	MEN 2 is an autosomal-dominant, transmitted tumor syndrome caused by germline mutation in the RET (REarrangend during Transfection) proto-oncogene and is comprised of the key endocrine neoplasia components of pheochromocytoma, hyperparathyroidism, and, importantly, medullary thyroid carcinoma (MTC) as the life-limiting alteration,.	('endocrine neoplasia', 'Disease', (175, 194))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (266, 293))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (276, 293))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (227, 246))	('neoplasia', 'Phenotype', 'HP:0002664', (185, 194))	('RET', 'Gene', '5979', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('MEN', 'Species', '9606', (0, 3))	('germline mutation', 'Var', (69, 86))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (175, 194))	('pheochromocytoma', 'Disease', 'MESH:D010673', (209, 225))	('tumor syndrome', 'Disease', (44, 58))	('tumor syndrome', 'Disease', 'MESH:D009369', (44, 58))	('RET', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('pheochromocytoma', 'Disease', (209, 225))	('hyperparathyroidism', 'Disease', (227, 246))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (276, 293))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (209, 225))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (175, 194))	('thyroid carcinoma', 'Disease', (276, 293))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (227, 246))	('caused by', 'Reg', (59, 68))	('MTC', 'Phenotype', 'HP:0002865', (295, 298))
54263	22584712	Furthermore, family members not harboring family-specific disease-associated mutations can be definitively advised that they only have the same risk as the general population of developing the component neoplasias of MEN 2, so could be excluded from lifelong clinical surveillance and prophylactic surgeries.	('neoplasia', 'Phenotype', 'HP:0002664', (203, 212))	('neoplasias', 'Phenotype', 'HP:0002664', (203, 213))	('neoplasias', 'Disease', 'MESH:D009369', (203, 213))	('neoplasias', 'Disease', (203, 213))	('mutations', 'Var', (77, 86))	('MEN', 'Species', '9606', (217, 220))
54266	22584712	MEN 2B is the most aggressive form caused by germline mutations in codon 918 (98%) or codon 883 (2%) and is associated with an age of onset for MTC in the first year of life.	('MTC', 'Phenotype', 'HP:0002865', (144, 147))	('caused', 'Reg', (35, 41))	('codon 883', 'Var', (86, 95))	('codon', 'Gene', (67, 72))	('MEN 2B', 'Gene', (0, 6))	('germline mutations in', 'Var', (45, 66))	('MEN 2B', 'Gene', '5979', (0, 6))
54276	22584712	For instance, the variant IVS1-126G > T in a large family with the G533C mutation was associated with an early onset of disease.	('IVS1-126G > T', 'Mutation', 'c.IVS1-126G>T', (26, 39))	('associated with', 'Reg', (86, 101))	('IVS1-126G > T', 'Var', (26, 39))	('G533C', 'Var', (67, 72))	('G533C', 'Mutation', 'rs75873440', (67, 72))
54288	22584712	Today, there is growing evidence that about 25-30% of all patients with pheochromocytoma and paraganglioma harbor a germline mutation.	('pheochromocytoma', 'Disease', (72, 88))	('pheochromocytoma', 'Disease', 'MESH:D010673', (72, 88))	('paraganglioma', 'Disease', 'MESH:D010235', (93, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (72, 88))	('germline mutation', 'Var', (116, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('paraganglioma', 'Disease', (93, 106))	('patients', 'Species', '9606', (58, 66))
54292	22584712	In patients with NF1 and pheochromocytoma there are no mutation hot spots, instead the alterations are spread all over the gene and include large deletions or rearrangements in about 10% of patients.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (25, 41))	('patients', 'Species', '9606', (190, 198))	('NF1', 'Gene', (17, 20))	('rearrangements', 'Var', (159, 173))	('patients', 'Species', '9606', (3, 11))	('NF1', 'Gene', '4763', (17, 20))	('pheochromocytoma', 'Disease', (25, 41))	('pheochromocytoma', 'Disease', 'MESH:D010673', (25, 41))
54309	22584712	Cowden syndrome is caused by germline mutations of the PTEN tumor suppressor gene.	('PTEN', 'Gene', '5728', (55, 59))	('caused by', 'Reg', (19, 28))	('PTEN', 'Gene', (55, 59))	('Cowden syndrome', 'Disease', 'MESH:D006223', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Cowden syndrome', 'Disease', (0, 15))	('tumor', 'Disease', (60, 65))	('germline mutations', 'Var', (29, 47))
54313	22584712	Gardner syndrome is caused by germline mutations in the APC gene and is characterized by gastrointestinal adenomatous polyps and a high risk of developing gastrointestinal and other cancers.	('gastrointestinal', 'Disease', 'MESH:D005767', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Gardner syndrome', 'Disease', (0, 16))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('gastrointestinal adenomatous polyps', 'Disease', (89, 124))	('adenomatous polyps', 'Phenotype', 'HP:0005227', (106, 124))	('gastrointestinal', 'Disease', 'MESH:D005767', (155, 171))	('germline mutations', 'Var', (30, 48))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('gastrointestinal adenomatous polyps', 'Disease', 'MESH:D018256', (89, 124))	('gastrointestinal', 'Disease', (89, 105))	('Gardner syndrome', 'Disease', 'MESH:D005736', (0, 16))	('APC', 'Gene', (56, 59))	('cancers', 'Disease', (182, 189))	('gastrointestinal', 'Disease', (155, 171))	('caused by', 'Reg', (20, 29))	('APC', 'Gene', '324', (56, 59))
54334	22584712	Therefore, for NMTC, it has been argued that heritability is most likely the main contributor to the high standardized incidence ratios and that familial aggregations of NMTC are most likely the result of germline mutations in susceptibility genes.	('MTC', 'Phenotype', 'HP:0002865', (171, 174))	('result', 'Reg', (195, 201))	('germline mutations', 'Var', (205, 223))	('familial aggregation', 'Disease', 'MESH:D020914', (145, 165))	('familial aggregation', 'Disease', (145, 165))	('MTC', 'Phenotype', 'HP:0002865', (16, 19))
54418	32376047	The importance of genetic changes in human tumors is well documented in publicly available resources such as The Cancer Genome Atlas database, where numerous genetic alterations, both germline and somatic, have been linked to prognosis, treatment response, and/or survival.	('linked', 'Reg', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Cancer', 'Disease', (113, 119))	('alterations', 'Var', (166, 177))	('Cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('genetic alterations', 'Var', (158, 177))	('human', 'Species', '9606', (37, 42))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
54419	32376047	In this review, we focus on genetic testing for germline mutations in patients with endocrine surgical disorders.	('germline mutations', 'Var', (48, 66))	('patients', 'Species', '9606', (70, 78))	('endocrine surgical disorders', 'Disease', (84, 112))	('endocrine surgical disorders', 'Disease', 'MESH:D004700', (84, 112))
54420	32376047	Importantly, germline mutation testing has the potential to benefit (1) affected individuals by providing prognostic, risk of malignancy, and additional disease risk information and (2) at-risk family members through identification and exoneration of affected and unaffected individuals, respectively.	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('germline mutation testing', 'Var', (13, 38))	('malignancy', 'Disease', (126, 136))
54421	32376047	Importantly, genetic testing allows for early diagnosis through screening and surveillance and gene-based treatments that are likely to reduce patient morbidity and mortality.	('genetic', 'Var', (13, 20))	('mortality', 'Disease', 'MESH:D003643', (165, 174))	('patient', 'Species', '9606', (143, 150))	('gene-based treatments', 'Var', (95, 116))	('mortality', 'Disease', (165, 174))
54423	32376047	Here, we provide an up-to-date overview of genetic testing in endocrine diseases encountered by the endocrine surgeon and its impact on surgical management.	('endocrine diseases', 'Disease', (62, 80))	('endocrine diseases', 'Disease', 'MESH:D004700', (62, 80))	('genetic testing', 'Var', (43, 58))
54433	32376047	For example, patients with HPT-JT syndrome owing to a germline CDC73 gene mutation have a high-risk of parathyroid cancer and multigland disease causing their PHPT.	('PHPT', 'Disease', (159, 163))	('mutation', 'Var', (74, 82))	('HPT-JT syndrome', 'Disease', 'MESH:C563273', (27, 42))	('PHPT', 'Phenotype', 'HP:0008200', (159, 163))	('thyroid cancer', 'Phenotype', 'HP:0002890', (107, 121))	('parathyroid cancer', 'Disease', 'MESH:D010282', (103, 121))	('parathyroid cancer', 'Disease', (103, 121))	('patients', 'Species', '9606', (13, 21))	('multigland disease', 'Disease', 'MESH:D003141', (126, 144))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HPT-JT syndrome', 'Disease', (27, 42))	('multigland disease', 'Disease', (126, 144))	('CDC73', 'Gene', (63, 68))	('CDC73', 'Gene', '79577', (63, 68))
54436	32376047	In patients with MEN1 mutation, a bilateral neck exploration with subtotal versus total parathyroidectomy (with autograft) and cervical thymectomy should be performed, because these patients may have parathyroid rests in the thymus that can cause recurrence, and they are at risk of thymic carcinoid.	('carcinoid', 'Phenotype', 'HP:0100570', (290, 299))	('mutation', 'Var', (22, 30))	('thymic carcinoid', 'Disease', (283, 299))	('rests in the thymus', 'Phenotype', 'HP:0100521', (212, 231))	('thymic carcinoid', 'Disease', 'MESH:D002276', (283, 299))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (182, 190))	('subtotal versus total parathyroidectomy', 'Disease', 'MESH:C567307', (66, 105))	('MEN1', 'Gene', (17, 21))	('subtotal versus total parathyroidectomy', 'Disease', (66, 105))	('MEN1', 'Gene', '4221', (17, 21))
54437	32376047	Patients with familial isolated PHPT owing to GCM2 mutations should also have a bilateral neck exploration and removal of all enlarged parathyroid glands, and, if all 4 parathyroid glands are involved, a subtotal parathyroidectomy should be performed.	('GCM2', 'Gene', '9247', (46, 50))	('mutations', 'Var', (51, 60))	('PHPT', 'Phenotype', 'HP:0008200', (32, 36))	('enlarged parathyroid glands', 'Phenotype', 'HP:0008208', (126, 153))	('GCM2', 'Gene', (46, 50))	('Patients', 'Species', '9606', (0, 8))	('familial isolated PHPT', 'Disease', (14, 36))
54451	32376047	Owing to the high-risk of thyroid cancer in these patients, screening ultrasound for thyroid cancer should be performed in all at-risk individuals with a germline mutation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (50, 58))	('germline', 'Var', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (26, 40))	('thyroid cancer', 'Disease', (26, 40))	('thyroid cancer', 'Disease', (85, 99))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('thyroid cancer', 'Disease', 'MESH:D013964', (26, 40))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
54457	32376047	The MEN2 syndrome has an autosomal dominant pattern of inheritance and is owing to germline mutations in the RET proto-oncogene.	('RET', 'Gene', (109, 112))	('MEN2 syndrome', 'Disease', (4, 17))	('RET', 'Gene', '5979', (109, 112))	('mutations', 'Var', (92, 101))
54462	32376047	Prophylactic and/or early thyroidectomy is the only curative option for patients with MTC who test positive for a RET mutation, but who have no clinical evidence of disease (normal calcitonin and thyroid ultrasound).	('MTC', 'Phenotype', 'HP:0002865', (86, 89))	('RET', 'Gene', '5979', (114, 117))	('mutation', 'Var', (118, 126))	('RET', 'Gene', (114, 117))	('patients', 'Species', '9606', (72, 80))
54463	32376047	Due to the high risk of developing MTC over their lifetime (>90%), prophylactic thyroidectomy is recommended for all patients who are carriers of the RET mutation.	('RET', 'Gene', (150, 153))	('MTC', 'Phenotype', 'HP:0002865', (35, 38))	('mutation', 'Var', (154, 162))	('RET', 'Gene', '5979', (150, 153))	('carriers', 'Reg', (134, 142))	('patients', 'Species', '9606', (117, 125))
54467	32376047	Furthermore, because of the high risk of tumor multifocality in patients harboring the RET mutation, total thyroidectomy is recommended.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutation', 'Var', (91, 99))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', (41, 46))	('RET', 'Gene', '5979', (87, 90))	('RET', 'Gene', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
54471	32376047	PPGL represents the most heritable tumor in humans, with up to 50% of PPGL occurring as a result of germline mutation in a susceptibility gene.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('result of', 'Reg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('humans', 'Species', '9606', (44, 50))	('tumor', 'Disease', (35, 40))	('PPGL', 'Disease', (0, 4))	('PPGL', 'Disease', (70, 74))	('germline mutation', 'Var', (100, 117))
54472	32376047	Furthermore, prior studies have shown that up to 27% of patients with apparently sporadic disease harbor a PPGL-related germline mutation.	('patients', 'Species', '9606', (56, 64))	('sporadic disease', 'Disease', 'MESH:D003141', (81, 97))	('PPGL-related', 'Gene', (107, 119))	('germline', 'Var', (120, 128))	('sporadic disease', 'Disease', (81, 97))
54475	32376047	For example, patients with PPGL and a mutation in NF1, RET, or VHL have a low risk of metastatic disease, and as such may be good candidates for laparoscopic and/or partial adrenalectomy, especially if the tumor is small (<2-3 cm), and there is no family history of metastatic disease.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('PPGL', 'Gene', (27, 31))	('RET', 'Gene', '5979', (55, 58))	('NF1', 'Gene', (50, 53))	('tumor', 'Disease', (206, 211))	('patients', 'Species', '9606', (13, 21))	('NF1', 'Gene', '4763', (50, 53))	('RET', 'Gene', (55, 58))	('VHL', 'Gene', '7428', (63, 66))	('VHL', 'Gene', (63, 66))	('mutation', 'Var', (38, 46))	('metastatic disease', 'CPA', (86, 104))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
54476	32376047	Conversely, patients with a mutation in SDHB, FH, or MAX and a large primary tumor have a higher risk of metastatic disease and may require open and total adrenalectomy.	('SDHB', 'Gene', '6390', (40, 44))	('metastatic disease', 'CPA', (105, 123))	('patients', 'Species', '9606', (12, 20))	('SDHB', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutation', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('FH', 'Disease', 'MESH:D006938', (46, 48))
54482	32376047	However, the risk of metastatic/malignant disease in inherited PNETs as compared with sporadic PNETs by tumor size is different.	('malignant disease', 'Disease', 'MESH:D009369', (32, 49))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NETs', 'Phenotype', 'HP:0100634', (64, 68))	('malignant disease', 'Disease', (32, 49))	('tumor', 'Disease', (104, 109))	('inherited', 'Var', (53, 62))	('NETs', 'Phenotype', 'HP:0100634', (96, 100))	('PNETs', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
54484	32376047	Recently, Tirosh et al demonstrated that patients with VHL-associated PNETs who had a missense mutation or any mutation type of the VHL gene in exon 3 were more likely to undergo surgical intervention (had tumor growth or developed metastatic disease) at a higher rate compared with patients with other mutation types.	('VHL', 'Gene', (132, 135))	('PNETs', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('undergo', 'Reg', (171, 178))	('surgical intervention', 'CPA', (179, 200))	('VHL', 'Gene', '7428', (132, 135))	('patients', 'Species', '9606', (283, 291))	('missense mutation', 'Var', (86, 103))	('NETs', 'Phenotype', 'HP:0100634', (71, 75))	('patients', 'Species', '9606', (41, 49))	('VHL', 'Gene', (55, 58))	('tumor growth', 'Disease', (206, 218))	('VHL', 'Gene', '7428', (55, 58))	('tumor growth', 'Disease', 'MESH:D006130', (206, 218))
54485	32376047	Furthermore, in silico computational analysis of the germline missense VHL mutations showed those that had >80% prediction for disease-causing mutations had aggressive tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('VHL', 'Gene', (71, 74))	('aggressive tumors', 'Disease', 'MESH:D001523', (157, 174))	('VHL', 'Gene', '7428', (71, 74))	('mutations', 'Var', (75, 84))	('aggressive tumors', 'Disease', (157, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
54487	32376047	Christakis et al observed that patients with MEN1 mutations in exon 2 had a higher rate of PNETs and distant metastasis as compared with patients with MEN1 mutations in exons 3-10.	('MEN1', 'Gene', (45, 49))	('MEN1', 'Gene', (151, 155))	('MEN1', 'Gene', '4221', (45, 49))	('MEN1', 'Gene', '4221', (151, 155))	('NETs', 'Phenotype', 'HP:0100634', (92, 96))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (31, 39))
54488	32376047	MEN1 missense germline mutations have also been associated with PNET progression as compared with nonsense and frameshift mutations.	('MEN1', 'Gene', '4221', (0, 4))	('missense germline', 'Var', (5, 22))	('associated', 'Reg', (48, 58))	('PNET progression', 'Disease', (64, 80))	('MEN1', 'Gene', (0, 4))
54491	32376047	In fact, genetic testing in patients with MEN1 has been shown to identify patients with the mutation on an average of 10 years earlier, before development of any clinical symptoms of the disease.	('mutation', 'Var', (92, 100))	('MEN1', 'Gene', (42, 46))	('MEN1', 'Gene', '4221', (42, 46))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (28, 36))
54566	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
54572	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
54641	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('LAG3', 'Gene', '3902', (128, 132))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
54645	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
54714	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
54715	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
54753	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))
54792	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
54806	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
54816	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
54869	26113602	In humans, PCC is a rare tumor of which ~25% of cases are associated with germline mutations, commonly in subunits of succinate dehydrogenase (SDH), which is part of mitochondrial complex II.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', (25, 30))	('x', 'Chemical', 'MESH:D000082', (186, 187))	('succinate dehydrogenase', 'Gene', '6390', (118, 141))	('humans', 'Species', '9606', (3, 9))	('PCC', 'Phenotype', 'HP:0002666', (11, 14))	('succinate dehydrogenase', 'Gene', (118, 141))	('PCC', 'Disease', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
54939	26113602	Mutations in VHL and SDH result in accumulation of succinate which directly inhibits prolyl hydroxylase (PHD), thereby inducing Hif-1alpha accumulation; Hif-1alpha causes PCC tumorogenesis by increasing angiogenesis, proliferation, invasion and metastasis.	('succinate', 'Chemical', 'MESH:D019802', (51, 60))	('PCC tumorogenesis', 'Disease', (171, 188))	('inducing', 'Reg', (119, 127))	('PHD', 'Disease', (105, 108))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('x', 'Chemical', 'MESH:D000082', (97, 98))	('Mutations', 'Var', (0, 9))	('Hif-1alpha', 'Gene', '15251', (153, 163))	('PCC tumorogenesis', 'Disease', 'OMIM:115700', (171, 188))	('Hif-1alpha', 'Gene', (153, 163))	('PHD', 'Disease', 'MESH:D011547', (105, 108))	('causes', 'Reg', (164, 170))	('inhibits', 'NegReg', (76, 84))	('Hif-1alpha', 'Gene', '15251', (128, 138))	('Hif-1alpha', 'Gene', (128, 138))	('VHL', 'Disease', (13, 16))	('increasing', 'PosReg', (192, 202))	('SDH', 'Gene', (21, 24))	('PCC', 'Phenotype', 'HP:0002666', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('angiogenesis', 'CPA', (203, 215))
54940	26113602	Mutations in the RET proto-oncogene and in NF1 activate RAS/RAF/MAPK and PI3K/Akt/mTOR signaling pathways, which play critical roles in tumorogenesis.	('activate', 'PosReg', (47, 55))	('NF1', 'Gene', (43, 46))	('Akt', 'Gene', '11651', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Mutations', 'Var', (0, 9))	('mTOR', 'Gene', (82, 86))	('RAF', 'Gene', (60, 63))	('Akt', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('RAF', 'Gene', '387609', (60, 63))	('mTOR', 'Gene', '56717', (82, 86))	('tumor', 'Disease', (136, 141))
54945	26113602	For instance, C16-ceramide and sphinganine both directly inhibit complex IV activity in the liver, which results in oxidative stress.	('C16-ceramide', 'Var', (14, 26))	('oxidative stress', 'Phenotype', 'HP:0025464', (116, 132))	('complex IV activity', 'MPA', (65, 84))	('x', 'Chemical', 'MESH:D000082', (117, 118))	('inhibit', 'NegReg', (57, 64))	('results in', 'Reg', (105, 115))	('C16-ceramide', 'Chemical', 'MESH:C097760', (14, 26))	('oxidative stress', 'MPA', (116, 132))	('sphinganine', 'Chemical', 'MESH:C005682', (31, 42))	('x', 'Chemical', 'MESH:D000082', (71, 72))
54949	26113602	Thus, the CerS2 null mouse provides additional indications that oxidative stress is a key player in PCC formation, although the mechanism of oxidative stress is somewhat different inasmuch as SDH function was normal, the Hif-1alpha protein was not upregulated, and Akt and mTOR phosphorylation was not detected in the PCC (data not shown); moreover, ceroid accumulation is not observed in PCC caused by SDH mutations, suggesting that the mechanism of PCC formation differs between SDH mutations and that observed in the CerS null mouse.	('oxidative stress', 'Phenotype', 'HP:0025464', (64, 80))	('mTOR', 'Gene', (273, 277))	('PCC', 'Phenotype', 'HP:0002666', (389, 392))	('mutations', 'Var', (485, 494))	('mouse', 'Species', '10090', (530, 535))	('PCC', 'Phenotype', 'HP:0002666', (318, 321))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('ceroid', 'Chemical', 'MESH:D002566', (350, 356))	('Akt', 'Gene', (265, 268))	('mouse', 'Species', '10090', (21, 26))	('PCC', 'Phenotype', 'HP:0002666', (451, 454))	('x', 'Chemical', 'MESH:D000082', (142, 143))	('x', 'Chemical', 'MESH:D000082', (65, 66))	('Akt', 'Gene', '11651', (265, 268))	('mTOR', 'Gene', '56717', (273, 277))	('PCC', 'Phenotype', 'HP:0002666', (100, 103))	('SDH', 'Gene', (481, 484))	('Hif-1alpha', 'Gene', '15251', (221, 231))	('Hif-1alpha', 'Gene', (221, 231))
54952	26113602	There is one report of a human patient with a mutation in CerS2, in which a 27 kb de novo deletion in one allele of chromosome 1q21 was detected, although there is no evidence that this patient displays either mitochondrial dysfunction or PCC.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (210, 235))	('deletion', 'Var', (90, 98))	('CerS2', 'Gene', (58, 63))	('mitochondrial dysfunction', 'Disease', (210, 235))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (210, 235))	('human', 'Species', '9606', (25, 30))	('PCC', 'Phenotype', 'HP:0002666', (239, 242))	('patient', 'Species', '9606', (31, 38))	('mutation', 'Var', (46, 54))	('patient', 'Species', '9606', (186, 193))
54953	26113602	There is, however, a relationship between altered CerS expression and cancer.	('altered', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('x', 'Chemical', 'MESH:D000082', (56, 57))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('CerS', 'Protein', (50, 54))
55036	28641581	Beta blockade before alpha blockade is definitely contraindicated in the setting of pheochromocytoma, and will itself lead to challenges in the cardiovascular management because of unopposed alpha stimulation.	('lead to', 'Reg', (118, 125))	('Beta', 'Var', (0, 4))	('pheochromocytoma', 'Disease', (84, 100))	('pheochromocytoma', 'Disease', 'MESH:D010673', (84, 100))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (84, 100))	('man', 'Species', '9606', (159, 162))	('alpha stimulation', 'MPA', (191, 208))
55071	22566196	External Beam Radiation Therapy (EBRT) for Patients with Malignant Pheochromocytoma and Non-Head and Neck Paraganglioma: Combination with 131I-MIBG In patients with malignant pheochromocytoma and paraganglioma, 131I-MIBG radiotherapy can achieve an objective response rate of 30-50% with the dose limiting toxicity being hematologic.	('paraganglioma', 'Disease', 'MESH:D010235', (196, 209))	('131I-MIBG', 'Var', (211, 220))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (165, 191))	('malignant pheochromocytoma', 'Disease', (165, 191))	('Patients', 'Species', '9606', (43, 51))	('131I-MIBG', 'Chemical', 'MESH:D019797', (138, 147))	('patients', 'Species', '9606', (151, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (196, 209))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (67, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (175, 191))	('paraganglioma', 'Disease', (196, 209))	('toxicity', 'Disease', 'MESH:D064420', (306, 314))	('toxicity', 'Disease', (306, 314))	('Malignant Pheochromocytoma and Non-Head and Neck Paraganglioma', 'Disease', 'MESH:D010673', (57, 119))	('Paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))	('Head and Neck Paraganglioma', 'Phenotype', 'HP:0002864', (92, 119))	('131I-MIBG', 'Chemical', 'MESH:D019797', (211, 220))
55076	22566196	Due to widespread systemic metastases with areas of bulky, symptomatic tumor, five of the 17 patients were treated with sequential 131I-MIBG (2 mCi/kg per treatment) and external beam radiotherapy to nine sites.	('metastases', 'Disease', 'MESH:D009362', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('131I-MIBG', 'Chemical', 'MESH:D019797', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('metastases', 'Disease', (27, 37))	('tumor', 'Disease', (71, 76))	('patients', 'Species', '9606', (93, 101))	('131I-MIBG', 'Var', (131, 140))
55081	22566196	PCC/PGL are often benign, but are associated with high morbidity secondary to mass effect and increased levels of circulating catecholamines which can lead to severe hypertension, stroke, and even death.	('hypertension', 'Phenotype', 'HP:0000822', (166, 178))	('death', 'Disease', 'MESH:D003643', (197, 202))	('PCC/PGL', 'Var', (0, 7))	('death', 'Disease', (197, 202))	('catecholamines', 'Chemical', 'MESH:D002395', (126, 140))	('increased', 'PosReg', (94, 103))	('stroke', 'Phenotype', 'HP:0001297', (180, 186))	('PGL', 'Phenotype', 'HP:0002668', (4, 7))	('increased levels of circulating catecholamines', 'Phenotype', 'HP:0003334', (94, 140))	('lead to', 'Reg', (151, 158))	('levels of circulating catecholamines', 'MPA', (104, 140))	('hypertension', 'Disease', 'MESH:D006973', (166, 178))	('PCC', 'Phenotype', 'HP:0002666', (0, 3))	('stroke', 'Disease', (180, 186))	('hypertension', 'Disease', (166, 178))	('stroke', 'Disease', 'MESH:D020521', (180, 186))
55106	22566196	Response evaluation criteria in solid tumors (RECIST) v1.1 was used to define disease progression or stability in the subset of five patients treated with combined 131I-MIBG and EBRT.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('solid tumors', 'Disease', 'MESH:D009369', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (133, 141))	('131I-MIBG', 'Chemical', 'MESH:D019797', (164, 173))	('131I-MIBG', 'Var', (164, 173))	('EBRT', 'Chemical', '-', (178, 182))	('solid tumors', 'Disease', (32, 44))
55112	22566196	Three of the five patients had genetic testing for mutations in one of the known PCC/PGL susceptibility genes, which was performed in a CLIA approved laboratory as part of routine clinical care.	('PGL', 'Phenotype', 'HP:0002668', (85, 88))	('mutations', 'Var', (51, 60))	('PCC/PGL', 'Gene', (81, 88))	('PCC', 'Phenotype', 'HP:0002666', (81, 84))	('patients', 'Species', '9606', (18, 26))
55139	22566196	Since the dose limiting toxicity of 131I-MIBG is bone marrow suppression and the dose limiting toxicity of EBRT is peri-tumoral normal tissue damage, these non-overlapping toxicities can allow a higher dose of radiation to tumor tissue with a lower level of toxicity.	('toxicities', 'Disease', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (95, 103))	('higher', 'PosReg', (195, 201))	('toxicity', 'Disease', (24, 32))	('EBRT', 'Chemical', '-', (107, 111))	('tumor', 'Disease', (120, 125))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (49, 72))	('tumor', 'Disease', (223, 228))	('toxicity', 'Disease', 'MESH:D064420', (258, 266))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('bone marrow suppression', 'CPA', (49, 72))	('131I-MIBG', 'Chemical', 'MESH:D019797', (36, 45))	('131I-MIBG', 'Var', (36, 45))	('toxicity', 'Disease', (258, 266))	('toxicities', 'Disease', 'MESH:D064420', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))
55146	22566196	In addition, while this is the first study to our knowledge that uses the RECIST v1.1 criteria to assess tumor control, we only were able to apply these criteria to the subset of five patients treated with combined EBRT and 131I-MIBG based on availability of follow up imaging in our retrospective review.	('patients', 'Species', '9606', (184, 192))	('131I-MIBG', 'Chemical', 'MESH:D019797', (224, 233))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('131I-MIBG', 'Var', (224, 233))	('EBRT', 'Var', (215, 219))	('tumor', 'Disease', (105, 110))	('EBRT', 'Chemical', '-', (215, 219))
55151	22566196	The high rate of local control for bulky metastases that was achieved in our current patient cohort, despite eventual systemic progression, suggests that combining 131I-MIBG with EBRT can be safely performed due to non-overlapping toxicities and can achieve excellent control of locally bulky tumors.	('patient', 'Species', '9606', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('EBRT', 'Chemical', '-', (179, 183))	('131I-MIBG', 'Chemical', 'MESH:D019797', (164, 173))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('131I-MIBG', 'Var', (164, 173))	('toxicities', 'Disease', (231, 241))	('tumors', 'Disease', (293, 299))	('metastases', 'Disease', (41, 51))	('toxicities', 'Disease', 'MESH:D064420', (231, 241))
55152	22566196	These data are being used to develop a prospective protocol for multi-modality management of malignant PCC/PGL that includes combined 131I-MIBG with EBRT.	('EBRT', 'Chemical', '-', (149, 153))	('PCC', 'Phenotype', 'HP:0002666', (103, 106))	('131I-MIBG', 'Var', (134, 143))	('malignant PCC/PGL', 'Disease', (93, 110))	('PGL', 'Phenotype', 'HP:0002668', (107, 110))	('131I-MIBG', 'Chemical', 'MESH:D019797', (134, 143))
55175	24939623	However, some studies suggest that selective blockade with its improved side effect profile and wider availability can control blood pressure perioperatively as effectively as PXB and avoid prolonged postoperative hypotension.	('hypotension', 'Disease', 'MESH:D007022', (214, 225))	('avoid prolonged postoperative hypotension', 'Phenotype', 'HP:0001278', (184, 225))	('PXB', 'Chemical', 'MESH:D010643', (176, 179))	('hypotension', 'Disease', (214, 225))	('control blood pressure', 'MPA', (119, 141))	('hypotension', 'Phenotype', 'HP:0002615', (214, 225))	('selective', 'Var', (35, 44))
55302	23087853	In many patients with pheochromocytoma, especially in those with extra-adrenal pheochromocytoma, adrenal pheochromocytoma larger than 5 cm, or mutations of genes encoding mainly subunits B and D of the mitochondrial enzyme succinate dehydrogenase [SDHB and SDHD], the possibility of metastatic disease or multiple tumors should be considered.	('SDHB', 'Gene', (248, 252))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (97, 121))	('pheochromocytoma', 'Disease', (22, 38))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (71, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (97, 121))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (71, 95))	('adrenal pheochromocytoma', 'Disease', (97, 121))	('pheochromocytoma', 'Disease', 'MESH:D010673', (105, 121))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('multiple tumors', 'Disease', 'MESH:D009369', (305, 320))	('mutations', 'Var', (143, 152))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (79, 95))	('pheochromocytoma', 'Disease', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('extra-adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (65, 95))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (105, 121))	('SDHD', 'Gene', '6392', (257, 261))	('SDHB', 'Gene', '6390', (248, 252))	('patients', 'Species', '9606', (8, 16))	('extra-adrenal pheochromocytoma', 'Disease', (65, 95))	('pheochromocytoma', 'Disease', 'MESH:D010673', (79, 95))	('pheochromocytoma', 'Disease', 'MESH:D010673', (22, 38))	('SDHD', 'Gene', (257, 261))	('extra-adrenal pheochromocytoma', 'Phenotype', 'HP:0006737', (65, 95))	('pheochromocytoma', 'Disease', (79, 95))	('multiple tumors', 'Disease', (305, 320))
55310	23087853	Scintigraphy imaging with I-123 MIBG, compared with I-131 MIBG, is advantageous because of its optimal delta-emissions and lack of ss-particles that result in a lower absorbed dose.	('delta-emissions', 'MPA', (103, 118))	('absorbed dose', 'MPA', (167, 180))	('MIBG', 'Var', (32, 36))	('I-131 MIBG', 'Chemical', 'MESH:D019797', (52, 62))	('I-123 MIBG', 'Var', (26, 36))	('I-123 MIBG', 'Chemical', '-', (26, 36))
55311	23087853	Importantly, the normal adrenal medullary may show physiological uptake of both I-131and I-123 MIBG.	('I-131and', 'Chemical', '-', (80, 88))	('I-131and', 'Var', (80, 88))	('I-123', 'Var', (89, 94))	('I-123 MIBG', 'Chemical', '-', (89, 99))
55315	23087853	SPECT with I-123MIBG improves the identification of lesions in case of lesions with limited uptake or those with central necrosis.	('I-123MIBG', 'Chemical', '-', (11, 20))	('necrosis', 'Disease', (121, 129))	('improves', 'PosReg', (21, 29))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('I-123MIBG', 'Var', (11, 20))
55398	23087853	I123/I131-MIBG with or without SPECT-CT is routinely employed for imaging pheochromocytomas.	('MIBG', 'Chemical', 'MESH:D019797', (10, 14))	('I123/I131-MIBG', 'Var', (0, 14))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (74, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (74, 90))	('pheochromocytomas', 'Disease', (74, 91))	('pheochromocytomas', 'Disease', 'MESH:D010673', (74, 91))
55507	33822312	1 Robert Graves Institute, Tallaght University Hospital, D24.2 Department of Chemical Pathology, Tallaght University Hospital, D24.3 Diabetes Complications Research Centre, School of Medicine, UCD, D4.	('D24.3', 'Var', (127, 132))	('Diabetes', 'Disease', 'MESH:D003920', (133, 141))	('men', 'Species', '9606', (69, 72))	('Diabetes', 'Disease', (133, 141))
55544	33822312	Conclusion: Using comprehensive in-vivo techniques we have demonstrated significant abnormalities in glucocorticoid metabolism in patients with AI driven by dysregulation in the pre-receptor enzyme activity controlling tissue-specific GC availability, which can be improved following treatment with DR-HC.	('DR-HC', 'Chemical', '-', (299, 304))	('met', 'Gene', (116, 119))	('abnormalities', 'Reg', (84, 97))	('dysregulation', 'Var', (157, 170))	('men', 'Species', '9606', (289, 292))	('patients', 'Species', '9606', (130, 138))	('met', 'Gene', '79811', (116, 119))
55661	33822312	More severe atherosclerosis in T1DM is associated with a phenotype of central adiposity, higher VLDL, chylomicron and LDL particles, hypertrigyceridaemia and low HDL-C.	('VLDL', 'MPA', (96, 100))	('central adiposity', 'MPA', (70, 87))	('atherosclerosis', 'Disease', (12, 27))	('low HDL', 'Phenotype', 'HP:0003233', (158, 165))	('higher', 'PosReg', (89, 95))	('chylomicron', 'MPA', (102, 113))	('low', 'Var', (158, 161))	('DM', 'Disease', 'MESH:D009223', (33, 35))	('hypertrigyceridaemia', 'Disease', (133, 153))	('atherosclerosis', 'Disease', 'MESH:D050197', (12, 27))	('atherosclerosis', 'Phenotype', 'HP:0002621', (12, 27))
55683	33822312	A diagnosis of Graves' hyperthyroidism was made (TSH < 0.004 mIU/L (0.4-4.5), FT4 60 pmol/L (9-23), FT3 > 46.1 pmol/L (2.3-5.5), TSH receptor antibody 19.0 IU/L (< 1.8)).	('TSH', 'Chemical', 'MESH:D013972', (49, 52))	('< 0.004 mIU/L', 'Var', (53, 66))	('hyperthyroidism', 'Disease', 'MESH:D006980', (23, 38))	('TSH', 'Chemical', 'MESH:D013972', (129, 132))	('TSH receptor', 'Gene', '7253', (129, 141))	('FT4', 'Chemical', '-', (78, 81))	('TSH receptor', 'Gene', (129, 141))	('FT3 >', 'Var', (100, 105))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (23, 38))	('T3', 'Chemical', 'MESH:D014284', (101, 103))	('hyperthyroidism', 'Disease', (23, 38))
55726	33822312	ALB gene sequencing revealed a heterozygous Arg242His mutation confirming a diagnosis of FDH.	('FD', 'Disease', 'MESH:D004402', (89, 91))	('Arg242His', 'Var', (44, 53))	('ALB', 'Gene', (0, 3))	('ALB', 'Gene', '213', (0, 3))
55727	33822312	Familial Dysalbuminaemic Hyperthyroxinaemia (FDH) is an autosomal dominant condition, characterized by abnormal circulating albumin with increased T4 affinity, causing artefactual elevation of FT4 concentrations in euthyroid individuals.	('FT4 concentrations', 'MPA', (193, 211))	('T4 affinity', 'Protein', (147, 158))	('Dysalbuminaemic Hyperthyroxinaemia', 'Phenotype', 'HP:0008247', (9, 43))	('FD', 'Disease', 'MESH:D004402', (45, 47))	('Familial Dysalbuminaemic Hyperthyroxinaemia', 'Disease', 'MESH:D020936', (0, 43))	('abnormal', 'Var', (103, 111))	('Familial Dysalbuminaemic Hyperthyroxinaemia', 'Disease', (0, 43))	('increased', 'PosReg', (137, 146))	('elevation', 'PosReg', (180, 189))	('FT4', 'Chemical', '-', (193, 196))
55818	33822312	Mean pre-operative inpatient duration was 6 days during which alpha-blockade was achieved with Phenoxybenzamine (mean-daily-dose 1.5mg/kg/day), and volume expansion with intravenous fluids (mean-daily-volume 3L).	('alpha-blockade', 'MPA', (62, 76))	('Phenoxybenzamine', 'Var', (95, 111))	('Phenoxybenzamine', 'Chemical', 'MESH:D010643', (95, 111))	('patient', 'Species', '9606', (21, 28))
55837	33822312	IGF-1 levels >ULN were newly identified in 3(3.8%) patients on treatment, one of whom had normal baseline levels.	('IGF-1', 'Gene', '3479', (0, 5))	('levels >ULN', 'Var', (6, 17))	('IGF-1', 'Gene', (0, 5))	('patients', 'Species', '9606', (51, 59))	('men', 'Species', '9606', (68, 71))
55869	33822312	High Iodine content/pharmacological properties can result in thyroid dysfunction.	('High', 'Var', (0, 4))	('thyroid dysfunction', 'Disease', (61, 80))	('thyroid dysfunction', 'Disease', 'MESH:D013959', (61, 80))	('Iodine', 'Chemical', 'MESH:D007455', (5, 11))	('result in', 'Reg', (51, 60))
55892	33822312	Our study highlights the possibility of achieving higher treatment success rate with single calculate131I activity compared to a fixed activity and potential reducing radiation exposure.	('men', 'Species', '9606', (62, 65))	('single calculate131I activity', 'Var', (85, 114))	('higher', 'PosReg', (50, 56))	('treatment success', 'CPA', (57, 74))
55932	33822312	54% (n = 19) of the patients had mild hyponatraemia (Na 130-134), 26% (n = 9) had moderate hyponatraemia (Na 125-129), and 20% (n = 7) had severe hyponatraemia (Na < 125).	('Na 130-134', 'Var', (53, 63))	('hyponatraemia', 'Disease', (91, 104))	('hyponatraemia', 'Disease', 'None', (38, 51))	('hyponatraemia', 'Disease', (38, 51))	('hyponatraemia', 'Disease', 'None', (146, 159))	('patients', 'Species', '9606', (20, 28))	('moderate hyponatraemia', 'Phenotype', 'HP:0002902', (82, 104))	('hyponatraemia', 'Disease', (146, 159))	('hyponatraemia', 'Disease', 'None', (91, 104))	('Na 125-129', 'Var', (106, 116))
56028	33822312	Apart from common gastrointestinal side effects, long term Metformin use leads to vitamin B12 malabsorption and to a lesser extent, folate and iron malabsorption.	('iron malabsorption', 'Disease', (143, 161))	('folate', 'MPA', (132, 138))	('malabsorption', 'Phenotype', 'HP:0002024', (94, 107))	('malabsorption', 'Disease', (148, 161))	('B12 malabsorption', 'Phenotype', 'HP:0200118', (90, 107))	('malabsorption', 'Disease', 'MESH:D008286', (148, 161))	('iron malabsorption', 'Disease', 'MESH:D008286', (143, 161))	('malabsorption', 'Disease', (94, 107))	('folate', 'Chemical', 'MESH:D005492', (132, 138))	('malabsorption', 'Disease', 'MESH:D008286', (94, 107))	('Metformin', 'Chemical', 'MESH:D008687', (59, 68))	('Metformin', 'Var', (59, 68))	('malabsorption', 'Phenotype', 'HP:0002024', (148, 161))	('vitamin B12', 'Chemical', 'MESH:D014805', (82, 93))
56039	33822312	M. McDermott1, P. Twomey2, S. Van der Kamp2 and RK.	('S. Van der', 'Var', (27, 37))	('RK', 'Gene', '64080', (48, 50))	('P. Twomey2', 'Var', (15, 25))
56069	33822312	1School of Biomedical Sciences, Ulster University, Coleraine, BT52 1SA, UK Benefits of PYY(1-36) on pancreatic beta-cell mass, through NPY1R activation, are well-established, with obvious potential exploitation for diabetes therapy.	('pancreatic', 'MPA', (100, 110))	('NPY1R', 'Gene', (135, 140))	('PYY', 'Var', (87, 90))	('diabetes', 'Disease', (215, 223))	('diabetes', 'Disease', 'MESH:D003920', (215, 223))	('activation', 'PosReg', (141, 151))
56076	33822312	Characteristic STZ reductions (P < 0.05-P < 0.001) in islet number, beta-cell and islet areas, and increase overall alpha-area as well as central islet invasion of alpha-cells were apparent in GluCreERT2;ROSA26-eYFP transgenic mice.	('ROSA26', 'Gene', (204, 210))	('central islet invasion', 'CPA', (138, 160))	('GluCreERT2', 'Var', (193, 203))	('reductions', 'NegReg', (19, 29))	('ROSA26', 'Gene', '14910', (204, 210))	('STZ', 'Chemical', 'MESH:D013311', (15, 18))	('islet number', 'CPA', (54, 66))	('increase', 'PosReg', (99, 107))	('alpha-area', 'CPA', (116, 126))	('transgenic mice', 'Species', '10090', (216, 231))
56078	33822312	In addition, whilst STZ decreased (P < 0.001) alpha- to beta-cell transition, this transdifferentaition process was significantly (P < 0.001) up-regulated by SL-PYY(1-36).	('decreased', 'NegReg', (24, 33))	('SL-PYY', 'Chemical', '-', (158, 164))	('up-regulated', 'PosReg', (142, 154))	('SL-PYY(1-36', 'Var', (158, 169))	('alpha- to beta-cell transition', 'CPA', (46, 76))	('STZ', 'Chemical', 'MESH:D013311', (20, 23))
56104	33822312	This showed markedly elevated pituitary hormone levels of ACTH (1399 pg/ml), prolactin (353,084 mIU/L), TSH (217 IU/L), FSH (> 200 mIU/ml) and GH (519 ng/ml) consistent with a multifunctional pituitary cyst.	('ACTH', 'Gene', '5443', (58, 62))	('prolactin', 'Gene', '5617', (77, 86))	('TSH', 'Chemical', 'MESH:D013972', (104, 107))	('prolactin', 'Gene', (77, 86))	('pituitary hormone levels', 'MPA', (30, 54))	('pituitary cyst', 'Phenotype', 'HP:0410278', (192, 206))	('elevated', 'PosReg', (21, 29))	('GH', 'Gene', '8836', (143, 145))	('ACTH', 'Gene', (58, 62))	('217 IU/L', 'Var', (109, 117))	('353,084', 'Var', (88, 95))
56134	33822312	Acidophilic stem cell adenomas represent 0.2% of pituitary adenomas and are potentially aggressive.	('Acidophilic', 'Var', (0, 11))	('pituitary adenomas', 'Disease', 'MESH:D010911', (49, 67))	('adenoma', 'Disease', (22, 29))	('adenoma', 'Disease', 'MESH:D000236', (59, 66))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (49, 67))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (49, 66))	('adenoma', 'Disease', (59, 66))	('pituitary adenomas', 'Disease', (49, 67))	('adenoma', 'Disease', 'MESH:D000236', (22, 29))
56168	33822312	Gel filtration chromatography was performed and confirmed the presence of high molecular weight TSH variant alongside normal TSH.	('TSH', 'Chemical', 'MESH:D013972', (125, 128))	('high', 'MPA', (74, 78))	('TSH', 'Gene', (96, 99))	('variant', 'Var', (100, 107))	('TSH', 'Chemical', 'MESH:D013972', (96, 99))
56207	33822312	Admission thyroid function showed TSH 9.04 mIU/L despite the inhibitory effect of severe acute illness on TSH secretion and a normal T4 of 16.3 pmol/L.	('TSH', 'Var', (34, 37))	('TSH', 'Chemical', 'MESH:D013972', (34, 37))	('TSH', 'Chemical', 'MESH:D013972', (106, 109))	('TSH secretion', 'MPA', (106, 119))
56258	33822312	Basal measurements of LH 1.3I U/L, FSH 4.5 IU/L, TSH 0.72 mIU/L, T4 16.8 pmol/L and IGF1 63 ug/L were consistent with ongoing panhypopituitarism.	('TSH', 'Var', (49, 52))	('hypopituitarism', 'Phenotype', 'HP:0040075', (129, 144))	('hypopituitarism', 'Disease', 'MESH:D007018', (129, 144))	('TSH', 'Chemical', 'MESH:D013972', (49, 52))	('LH 1', 'Gene', (22, 26))	('IGF1', 'Gene', '3479', (84, 88))	('hypopituitarism', 'Disease', (129, 144))	('LH 1', 'Gene', '5351', (22, 26))	('panhypopituitarism', 'Phenotype', 'HP:0000871', (126, 144))	('men', 'Species', '9606', (13, 16))	('IGF1', 'Gene', (84, 88))
56268	33822312	Laboratory investigations revealed; hyponatremia, serum sodium 127 (135-145) mmol/L; central hypothyroidism, TSH 0.20 (0.3-4.2) mU/L and FT4 4.6 (12-22) pmol/L.	('hypothyroidism', 'Disease', 'MESH:D007037', (93, 107))	('central hypothyroidism', 'Phenotype', 'HP:0011787', (85, 107))	('hyponatremia', 'Phenotype', 'HP:0002902', (36, 48))	('hypothyroidism', 'Phenotype', 'HP:0000821', (93, 107))	('hyponatremia', 'Disease', 'MESH:D007010', (36, 48))	('hypothyroidism', 'Disease', (93, 107))	('TSH', 'Chemical', 'MESH:D013972', (109, 112))	('hyponatremia', 'Disease', (36, 48))	('FT4', 'Chemical', '-', (137, 140))	('TSH', 'Var', (109, 112))	('serum sodium 127', 'MPA', (50, 66))	('sodium', 'Chemical', 'MESH:D012964', (56, 62))
56271	33822312	Urine volume increased (7 L in 24 hours) following commencement of Hydrocortisone replacement; she was diagnosed with central diabetes insipidus; serum osmolality 302 (285-295) mOsm/Kg and urine osmolality 127 mOsm/Kg and commenced on Desmopressin.	('285-295) mOsm/Kg', 'Var', (168, 184))	('serum osmolality', 'MPA', (146, 162))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (126, 144))	('men', 'Species', '9606', (225, 228))	('urine osmolality', 'MPA', (189, 205))	('Hydrocortisone', 'Chemical', 'MESH:D006854', (67, 81))	('Urine volume', 'MPA', (0, 12))	('men', 'Species', '9606', (54, 57))	('central diabetes insipidus', 'Disease', (118, 144))	('men', 'Species', '9606', (89, 92))	('central diabetes insipidus', 'Phenotype', 'HP:0000863', (118, 144))	('increased', 'PosReg', (13, 22))	('central diabetes insipidus', 'Disease', 'MESH:D020790', (118, 144))	('men', 'Species', '9606', (59, 62))
56274	33822312	She was commenced on Prednisolone 30 mg daily with resolution of some components of pituitary function over 3 months; oestradiol 634 pmol/L, TSH 0.48 (0.3-4.2) mU/L and FT4 20.6 (12-22) pmol/L.	('oestradiol', 'Chemical', 'MESH:D004958', (118, 128))	('TSH', 'Var', (141, 144))	('FT4', 'Chemical', '-', (169, 172))	('men', 'Species', '9606', (11, 14))	('oestradiol', 'MPA', (118, 128))	('Prednisolone', 'Chemical', 'MESH:D011239', (21, 33))	('TSH', 'Chemical', 'MESH:D013972', (141, 144))
56291	33822312	We await repeat antibody testing to confirm that switching of insulin reduced insulin antibody levels.	('switching', 'Var', (49, 58))	('insulin reduced insulin', 'Disease', (62, 85))	('insulin reduced insulin', 'Disease', 'MESH:D007333', (62, 85))
56351	33822312	Ten years later, genetic testing revealed a pathogenic variant in the gene encoding the carboxy terminal part of the HIST1H1E protein which confirmed her diagnosis of HIST1H1E syndrome.	('variant', 'Var', (55, 62))	('HIST1H1E', 'Gene', (167, 175))	('HIST1H1E', 'Gene', '3008', (167, 175))	('pathogenic', 'Reg', (44, 54))	('HIST1H1E', 'Gene', (117, 125))	('HIST1H1E', 'Gene', '3008', (117, 125))
56384	33822312	Intravenous (IV) metoprolol and phentolamine led to profound hypotension and pulseless electrical activity cardiac arrest.	('cardiac arrest', 'Disease', 'MESH:D006323', (107, 121))	('hypotension', 'Disease', 'MESH:D007022', (61, 72))	('metoprolol', 'Var', (17, 27))	('cardiac arrest', 'Disease', (107, 121))	('hypotension', 'Disease', (61, 72))	('cardiac arrest', 'Phenotype', 'HP:0001695', (107, 121))	('phentolamine', 'Chemical', 'MESH:D010646', (32, 44))	('hypotension', 'Phenotype', 'HP:0002615', (61, 72))	('metoprolol', 'Chemical', 'MESH:D008790', (17, 27))	('phentolamine', 'Var', (32, 44))
56451	33822312	Emerging evidence suggests 22q11 deletions are associated with hypogonadism and developmental abnormalities involving cardiac, neurological and genitourinary systems.	('developmental abnormalities', 'Disease', 'MESH:D006130', (80, 107))	('22q11', 'Gene', (27, 32))	('hypogonadism', 'Disease', 'MESH:D007006', (63, 75))	('hypogonadism', 'Phenotype', 'HP:0000135', (63, 75))	('associated', 'Reg', (47, 57))	('hypogonadism', 'Disease', (63, 75))	('developmental abnormalities', 'Disease', (80, 107))	('deletions', 'Var', (33, 42))
56452	33822312	48XXXY karyotype is a well-recognized condition of high aneuploidy known to be associated with intellectual disability.	('aneuploidy', 'Disease', (56, 66))	('associated', 'Reg', (79, 89))	('intellectual disability', 'Disease', (95, 118))	('48XXXY karyotype', 'Var', (0, 16))	('aneuploidy', 'Disease', 'MESH:D000782', (56, 66))	('intellectual disability', 'Phenotype', 'HP:0001249', (95, 118))
56455	33822312	Persistent ovulatory function at 30 years in Turner's Syndrome Monosomy 45:X C Miller1, N Phelan1 1Department of Endocrinology, St James's Hospital, Dublin Turner syndrome is the most common chromosomal abnormality in females occurring in 1/2000-1/2500 live births with short stature and ovarian insufficiency the most common manifestations.	('Monosomy', 'Var', (63, 71))	('short stature and ovarian insufficiency', 'Disease', 'MESH:D016649', (270, 309))	("Turner's Syndrome", 'Disease', (45, 62))	('men', 'Species', '9606', (105, 108))	('short stature', 'Phenotype', 'HP:0004322', (270, 283))	("Turner's Syndrome", 'Disease', 'MESH:D014424', (45, 62))
56513	33822312	Androgen receptor analysis confirmed a hemizygous pathogenic androgen receptor gene variant, c.2612C>T (p.Ala871Val), which is compatible with a of diagnosis partial androgen insensitivity syndrome.	('androgen receptor', 'Gene', '367', (61, 78))	('c.2612C>T', 'Var', (93, 102))	('Ala871Val', 'Chemical', '-', (106, 115))	('pathogenic', 'Reg', (50, 60))	('partial androgen insensitivity syndrome', 'Disease', (158, 197))	('Androgen receptor', 'Gene', '367', (0, 17))	('Androgen receptor', 'Gene', (0, 17))	('androgen receptor', 'Gene', (61, 78))
56515	33822312	We highlight a case of co-existent partial androgen insensitivity and pituitary adenoma within a single family which has not been described in the literature to date.	('pituitary adenoma', 'Disease', (70, 87))	('partial', 'Var', (35, 42))	('pituitary adenoma', 'Disease', 'MESH:D010911', (70, 87))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (70, 87))
56551	33822312	A family history of diabetes was noted but not of FPLD, however, specific mutation scanning of LMNA and PPARG identified heterozygosity for the pathogenic variant p.R582C in LMNA, confirming a diagnosis of 'atypical' FLPD 2.	('diabetes', 'Disease', (20, 28))	('PPARG', 'Gene', '5468', (104, 109))	('p.R582C', 'Mutation', 'rs918645468', (163, 170))	('PPARG', 'Gene', (104, 109))	('diabetes', 'Disease', 'MESH:D003920', (20, 28))	("'atypical' FLPD 2", 'Disease', (206, 223))	('LMNA', 'Gene', (95, 99))	('LMNA', 'Gene', (174, 178))	('LMNA', 'Gene', '4000', (95, 99))	('pathogenic', 'Reg', (144, 154))	('p.R582C', 'Var', (163, 170))	('LMNA', 'Gene', '4000', (174, 178))
56554	33822312	Typical FPLD has been associated with more severe metabolic phenotypes and the presence of AN, whereas 'atypical' FPLD is associated with a milder phenotype, including the absence of AN with lipodystrophy being more evident in lower limbs, again observed in our patient.	('lower limb', 'Phenotype', 'HP:0006385', (227, 237))	('lipodystrophy', 'Phenotype', 'HP:0009125', (191, 204))	('met', 'Gene', '79811', (50, 53))	('met', 'Gene', (50, 53))	('patient', 'Species', '9606', (262, 269))	('lipodystrophy', 'Disease', (191, 204))	('presence', 'Var', (79, 87))
56568	33822312	A recent Cochrane review has suggested that supplementation with Vitamin D during pregnancy may reduce the risk of gestational diabetes and its related complications such as preeclampsia.	('eclampsia', 'Disease', 'MESH:D004461', (177, 186))	('eclampsia', 'Disease', (177, 186))	('diabetes', 'Disease', 'MESH:D003920', (127, 135))	('Vitamin D', 'Chemical', 'MESH:D014807', (65, 74))	('supplementation', 'Var', (44, 59))	('preeclampsia', 'Phenotype', 'HP:0100602', (174, 186))	('men', 'Species', '9606', (50, 53))	('gestational diabetes', 'Phenotype', 'HP:0009800', (115, 135))	('reduce', 'NegReg', (96, 102))	('eclampsia', 'Phenotype', 'HP:0100601', (177, 186))	('diabetes', 'Disease', (127, 135))
56648	33822312	A review of genetic databases and published literature T Cronin1, E Rasheed1, M Mac Aogain1, S Savage1, E Walsh1, VEF Crowley1 1Department of Biochemistry, St James's Hospital, Dublin Familial partial lipodystrophy type 2 (FPLP2) is a rare condition associated with allelic variants on the LMNA gene.	('LMNA', 'Gene', (290, 294))	('lipodystrophy', 'Phenotype', 'HP:0009125', (201, 214))	('LMNA', 'Gene', '4000', (290, 294))	('allelic variants', 'Var', (266, 282))	('associated', 'Reg', (250, 260))	('Familial partial lipodystrophy type 2', 'Disease', (184, 221))	('men', 'Species', '9606', (134, 137))
56649	33822312	The "typical' FPLD2 phenotype is associated with a variant 'hotspot' affecting codon 482, while 'atypical' sub-types constitute all other allelic variants associated with FPLD2 phenotypic expression.	('FPLD2', 'Gene', (171, 176))	('FPLD2', 'Gene', '4000', (171, 176))	('codon 482', 'Var', (79, 88))	('FPLD2', 'Gene', (14, 19))	('FPLD2', 'Gene', '4000', (14, 19))
56653	33822312	Literature searches were subsequently performed to find peer-reviewed phenotypic data associated with FPLD2 variants.	('FPLD2', 'Gene', (102, 107))	('FPLD2', 'Gene', '4000', (102, 107))	('variants', 'Var', (108, 116))
56654	33822312	Twenty-nine missense variants were identified with supported FPLD2 phenotypic associations, of which three were related to 'typical' forms.	('FPLD2', 'Gene', '4000', (61, 66))	('related', 'Reg', (112, 119))	('missense variants', 'Var', (12, 29))	('FPLD2', 'Gene', (61, 66))
56676	33822312	Male Pituitary-Gonadal Axis Function in Obstructive Sleep Apnoea Syndrome: The Effect of Continuous Positive Airway Pressure R Leigh1, SM Hamon2, M McWeeney3, P O' Shea4, A O' Loughlin5.	('Sleep Apnoea', 'Phenotype', 'HP:0010535', (52, 64))	('Obstructive Sleep Apnoea Syndrome', 'Disease', 'MESH:D012893', (40, 73))	('Apnoea', 'Phenotype', 'HP:0002104', (58, 64))	('Obstructive Sleep Apnoea Syndrome', 'Disease', (40, 73))	("P O' Shea4", 'Var', (159, 169))	('Obstructive Sleep Apnoea', 'Phenotype', 'HP:0002870', (40, 64))	('M McWeeney3', 'Var', (146, 157))
56734	33822312	Inpatient Glycaemic Control is Poor in Patients Receiving Insulin Therapy N Reidy1, MC O' Donovan1, MJ Hannon1.	('Patients', 'Species', '9606', (39, 47))	('MJ', 'Disease', 'MESH:D009207', (100, 102))	('Insulin', 'Gene', '3630', (58, 65))	('N Reidy1', 'Var', (74, 82))	('Insulin', 'Gene', (58, 65))	('patient', 'Species', '9606', (2, 9))
56774	33822312	More recently, novel in vitro approaches have facilitated the functional assessment of multiple potential protein variants coded by specific genes, including in PPARG, where genetic variants are associated with autosomal dominant Familial Partial Lipodystrophy Type 3 (FPLD3).	('men', 'Species', '9606', (79, 82))	('associated', 'Reg', (195, 205))	('variants', 'Var', (182, 190))	('variants', 'Var', (114, 122))	('autosomal dominant Familial Partial Lipodystrophy Type', 'Disease', 'MESH:D052496', (211, 265))	('PPARG', 'Gene', '5468', (161, 166))	('PPARG', 'Gene', (161, 166))	('Lipodystrophy', 'Phenotype', 'HP:0009125', (247, 260))
56775	33822312	Methods: Logistic Regression and Random Forest Machine Learning analysis were applied to determine the performance of REVEL (and other in-silico tools) relative to MITER a classifier programme derived from a pooled functional assay for PPARG variants.	('PPARG', 'Gene', '5468', (236, 241))	('PPARG', 'Gene', (236, 241))	('variants', 'Var', (242, 250))
56929	33822312	J Kim1, N Ng1, M Zamuner1, N Siddique1, M Byrne1 1Department of Endocrinology, Mater Misericordiae University Hospital, Dublin 7, Ireland Mutations in the HNF1-beta gene can result in pancreatic agenesis leading to insufficient insulin secretion and a diagnosis of diabetes.	('insufficient insulin secretion', 'Disease', 'MESH:D000309', (215, 245))	('diabetes', 'Disease', (265, 273))	('men', 'Species', '9606', (56, 59))	('diabetes', 'Disease', 'MESH:D003920', (265, 273))	('insufficient insulin secretion', 'Disease', (215, 245))	('Kim1', 'Gene', (2, 6))	('result in', 'Reg', (174, 183))	('HNF1-beta', 'Gene', '6927', (155, 164))	('pancreatic agenesis', 'Disease', 'MESH:C564908', (184, 203))	('Kim1', 'Gene', '26762', (2, 6))	('HNF1-beta', 'Gene', (155, 164))	('Mutations', 'Var', (138, 147))	('pancreatic agenesis', 'Disease', (184, 203))
56933	33822312	12 participants with HNF1-beta gene mutations were phenotyped.	('HNF1-beta', 'Gene', (21, 30))	('participants', 'Species', '9606', (3, 15))	('mutations', 'Var', (36, 45))	('HNF1-beta', 'Gene', '6927', (21, 30))
56956	33494435	HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models Low oxygen levels (hypoxia) as well as genetic defects activating hypoxia signaling pathways (pseudohypoxia) are known to contribute to tumorigenesis and therapy resistance in various cancers.	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('genetic defects', 'Var', (144, 159))	('contribute', 'Reg', (227, 237))	('activating', 'PosReg', (160, 170))	('oxygen', 'Chemical', 'MESH:D010100', (109, 115))	('HIF2alpha', 'Gene', '13819', (0, 9))	('tumor', 'Disease', (241, 246))	('therapy resistance', 'CPA', (259, 277))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('Low oxygen levels', 'Phenotype', 'HP:0012418', (105, 122))	('hypoxia', 'Disease', (205, 212))	('cancers', 'Disease', 'MESH:D009369', (289, 296))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (63, 79))	('Radioresistance', 'CPA', (44, 59))	('HIF2alpha', 'Gene', (0, 9))	('hypoxia', 'Disease', (124, 131))	('hypoxia', 'Disease', 'MESH:D000860', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Pheochromocytoma', 'Disease', (63, 79))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (63, 79))	('hypoxia', 'Disease', (171, 178))	('hypoxia', 'Disease', (27, 34))	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('cancers', 'Disease', (289, 296))
56973	33494435	[177Lu]Lu-DOTA-TATE is one such therapy, and has shown encouraging treatment responses, including in PCCs/PGLs.	('PCCs/PGLs', 'Disease', (101, 110))	('PCCs', 'Chemical', '-', (101, 105))	('Lu-DOTA-TATE', 'Chemical', 'MESH:C447941', (7, 19))	('[177Lu]Lu-DOTA-TATE', 'Var', (0, 19))
56980	33494435	In a subgroup of PCCs/PGLs, mutations of germline and somatic origin associated with the dysregulation of hypoxia signaling pathways have been described to result in the oxygen-independent stabilization of HIFalpha:a metabolic state that is referred to as pseudohypoxia.	('hypoxia', 'Disease', 'MESH:D000860', (262, 269))	('HIFalpha', 'Gene', '15251;13819', (206, 214))	('hypoxia', 'Disease', (106, 113))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('HIFalpha', 'Gene', (206, 214))	('oxygen-independent stabilization', 'MPA', (170, 202))	('oxygen', 'Chemical', 'MESH:D010100', (170, 176))	('hypoxia', 'Disease', (262, 269))	('mutations', 'Var', (28, 37))	('PCCs', 'Chemical', '-', (17, 21))
56983	33494435	Since the stabilization of HIF2alpha is often associated with treatment resistance in various cancers, we hypothesized that it may also contribute to the radiation resistance of PCCs/PGLs.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('PCCs/PGLs', 'Disease', (178, 187))	('radiation resistance', 'CPA', (154, 174))	('contribute', 'Reg', (136, 146))	('cancers', 'Disease', (94, 101))	('PCCs', 'Chemical', '-', (178, 182))	('HIF2alpha', 'Gene', '13819', (27, 36))	('stabilization', 'Var', (10, 23))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('associated', 'Reg', (46, 56))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('HIF2alpha', 'Gene', (27, 36))
56994	33494435	Genetically modified MPC +HIF2alpha spheroids showed increases in growth rates, maximum diameters, and resistance to external irradiation compared to MPC +EV spheroids, resembling a Hif2alpha-deficient "empty vector" control (Figure 2A).	('MPC', 'Var', (21, 24))	('Hif2alpha', 'Gene', (182, 191))	('resistance', 'CPA', (103, 113))	('growth rates', 'CPA', (66, 78))	('spheroids', 'Chemical', '-', (36, 45))	('HIF2alpha', 'Gene', (26, 35))	('maximum diameters', 'CPA', (80, 97))	('spheroids', 'Chemical', '-', (158, 167))	('MPC +EV', 'Chemical', '-', (150, 157))	('increases', 'PosReg', (53, 62))	('Hif2alpha', 'Gene', '13819', (182, 191))	('HIF2alpha', 'Gene', '13819', (26, 35))
56997	33494435	A significantly (p < 0.001) higher irradiation dose was necessary to achieve the growth arrest of MPC +HIF2alpha (GAD = 16 +- 1 Gy) compared to MPC +EV spheroids (GAD = 5.0 +- 0.3 Gy) (Figure 2B).	('MPC +EV', 'Chemical', '-', (144, 151))	('growth arrest', 'Disease', (81, 94))	('growth arrest', 'Disease', 'MESH:D006323', (81, 94))	('MPC +HIF2alpha', 'Var', (98, 112))	('growth arrest', 'Phenotype', 'HP:0001510', (81, 94))	('GAD', 'Phenotype', 'HP:0031164', (114, 117))	('GAD', 'Phenotype', 'HP:0031164', (163, 166))
56998	33494435	At the highest irradiation dose of 40 Gy, the reduction in the relative growth of MPC +HIF2alpha spheroids (%SG = -19 +- 3%) was significantly (p < 0.001) lower compared to MPC +EV spheroids (%SG = -75 +- 4%).	('spheroids', 'Chemical', '-', (97, 106))	('reduction', 'NegReg', (46, 55))	('MPC +EV', 'Chemical', '-', (173, 180))	('lower', 'NegReg', (155, 160))	('spheroids', 'Chemical', '-', (181, 190))	('MPC +HIF2alpha', 'Var', (82, 96))
57001	33494435	Additional investigations on the supplementation of nutritional medium with frequently used cell culture additives showed that G418 (250 microg/mL) and DMSO (0.5%) significantly (p < 0.001) altered the treatment outcome after the external irradiation of both MPC +HIF2alpha and MPC +EV spheroids (for details see Supplementary Data, Table S3 and Figure S2).	('DMSO', 'Chemical', 'MESH:D004121', (152, 156))	('G418', 'Chemical', 'MESH:C010680', (127, 131))	('MPC +EV', 'Chemical', '-', (278, 285))	('G418', 'Var', (127, 131))	('HIF2alpha', 'Gene', '13819', (264, 273))	('altered', 'Reg', (190, 197))	('treatment', 'MPA', (202, 211))	('HIF2alpha', 'Gene', (264, 273))
57002	33494435	In brief, the radiosensitizing properties of G418 decreased the doses required for the long-term control of spheroids, whereas the radioprotective properties of DMSO increased the doses required for achieving both short-term growth arrest and long-term spheroid control.	('spheroids', 'Chemical', '-', (108, 117))	('doses', 'MPA', (64, 69))	('growth arrest', 'Disease', 'MESH:D006323', (225, 238))	('G418', 'Chemical', 'MESH:C010680', (45, 49))	('growth arrest', 'Phenotype', 'HP:0001510', (225, 238))	('DMSO', 'Chemical', 'MESH:D004121', (161, 165))	('decreased', 'NegReg', (50, 59))	('G418', 'Var', (45, 49))	('growth arrest', 'Disease', (225, 238))
57004	33494435	After exposure to initial activity, concentrations between 0 and 1.25 MBq/mL, which approximately correspond to absorbed doses between 0 and 10 Gy, both MPC +HIF2alpha and MPC +EV spheroids showed three response scenarios, similar to what has been observed after external irradiation (Figure 3A).	('MPC +EV', 'Chemical', '-', (172, 179))	('HIF2alpha', 'Gene', '13819', (158, 167))	('MPC', 'Var', (153, 156))	('HIF2alpha', 'Gene', (158, 167))	('EV spheroids', 'Chemical', '-', (177, 189))
57006	33494435	Short-term growth arrest was reached at significantly (p < 0.05) higher initial activity concentrations administered to MPC +HIF2alpha spheroids (GAD = 1.7 +- 0.7 MBq/mL,  14 +- 6 Gy) compared to MPC +EV (GAD = 0.3 +- 0.02 MBq/mL,  2.2 +- 0.2 Gy) (Figure 3B).	('MPC +EV', 'Chemical', '-', (196, 203))	('GAD', 'Phenotype', 'HP:0031164', (205, 208))	('spheroids', 'Chemical', '-', (135, 144))	('MPC +HIF2alpha', 'Var', (120, 134))	('activity', 'MPA', (80, 88))	('growth arrest', 'Disease', (11, 24))	('growth arrest', 'Disease', 'MESH:D006323', (11, 24))	('higher', 'PosReg', (65, 71))	('GAD', 'Phenotype', 'HP:0031164', (146, 149))	('growth arrest', 'Phenotype', 'HP:0001510', (11, 24))
57008	33494435	The long-term control of MPC +HIF2alpha spheroids required higher initial activity concentrations (SCD50 = 0.6 +- 0.02 MBq/mL,  4.6 +- 0.2 Gy) compared to MPC +EV (SCD50 = 0.3 +- 0.02 MBq/mL,  2.7 +- 0.1 Gy), (Figure 3C).	('MPC', 'Var', (25, 28))	('MPC +EV', 'Chemical', '-', (155, 162))	('HIF2alpha', 'Gene', '13819', (30, 39))	('activity concentrations', 'MPA', (74, 97))	('spheroids', 'Chemical', '-', (40, 49))	('HIF2alpha', 'Gene', (30, 39))	('higher', 'PosReg', (59, 65))
57015	33494435	Our investigations provide the first experimental evidence that the expression of HIF2a contributes to a radiation-resistant phenotype of PCCs/PGLs.	('HIF2a', 'Gene', (82, 87))	('HIF2a', 'Gene', '13819', (82, 87))	('PCCs/PGLs', 'Disease', (138, 147))	('PCCs', 'Chemical', '-', (138, 142))	('expression', 'Var', (68, 78))	('contributes to', 'Reg', (88, 102))	('radiation-resistant phenotype', 'CPA', (105, 134))
57016	33494435	PCCs/PGLs of the pseudohypoxic cluster are characterized by higher HIF2alpha expression and HIF2alpha protein stabilization through multiple mechanisms, including mutations in VHL, FH or succinate dehydrogenase genes preventing HIF degradation or mutations sparing the protein from proteasomal degradation.	('VHL', 'Gene', '22346', (176, 179))	('sparing', 'NegReg', (257, 264))	('FH', 'Disease', 'MESH:D006938', (181, 183))	('protein stabilization', 'MPA', (102, 123))	('HIF2alpha', 'Gene', (92, 101))	('mutations', 'Var', (247, 256))	('PCCs', 'Chemical', '-', (0, 4))	('protein', 'Protein', (269, 276))	('HIF2alpha', 'Gene', (67, 76))	('preventing', 'NegReg', (217, 227))	('higher', 'PosReg', (60, 66))	('proteasomal degradation', 'MPA', (282, 305))	('HIF2alpha', 'Gene', '13819', (92, 101))	('HIF degradation', 'Disease', 'MESH:D055959', (228, 243))	('VHL', 'Gene', (176, 179))	('expression', 'MPA', (77, 87))	('mutations', 'Var', (163, 172))	('HIF degradation', 'Disease', (228, 243))	('HIF2alpha', 'Gene', '13819', (67, 76))
57051	33494435	When G418 remained in the medium during treatment experiments instead of penicillin and streptomycin, MPC spheroids showed elevated radiosensitivity characterized by significantly decreased SCD50.	('penicillin', 'Chemical', 'MESH:D010406', (73, 83))	('G418', 'Var', (5, 9))	('radiosensitivity', 'CPA', (132, 148))	('elevated', 'PosReg', (123, 131))	('decreased', 'NegReg', (180, 189))	('streptomycin', 'Chemical', 'MESH:D013307', (88, 100))	('spheroids', 'Chemical', '-', (106, 115))	('SCD50', 'MPA', (190, 195))	('MPC', 'Chemical', '-', (102, 105))	('elevated radiosensitivity', 'Phenotype', 'HP:0010997', (123, 148))	('G418', 'Chemical', 'MESH:C010680', (5, 9))
57057	33494435	The effect most likely results from prolonged radiation exposure during [177Lu]LuCl3 incubation, where spheroids re-oxygenate after initial radiation-induced tissue damage, leading to the enhanced radiosensitivity of previously radioresistant tumor cells.	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (188, 213))	('enhanced', 'PosReg', (188, 196))	('spheroids', 'Chemical', '-', (103, 112))	('radiosensitivity', 'CPA', (197, 213))	('[177Lu', 'Var', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('prolonged radiation exposure', 'Phenotype', 'HP:0011133', (36, 64))	('LuCl3', 'Chemical', '-', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('oxygen', 'Chemical', 'MESH:D010100', (116, 122))	('tumor', 'Disease', (243, 248))
57060	33494435	By using [177Lu]LuCl3 instead of, e.g., [177Lu]Lu-DOTA-TATE for the incubation of MPC spheroids, we excluded all aspects of SSTR2-specific targeting from interfering with the experimental outcome of radionuclide treatment.	('spheroids', 'Chemical', '-', (86, 95))	('LuCl3', 'Chemical', '-', (16, 21))	('SSTR2', 'Gene', (124, 129))	('MPC', 'Chemical', '-', (82, 85))	('[177Lu]Lu-DOTA-TATE', 'Var', (40, 59))	('Lu-DOTA-TATE', 'Chemical', 'MESH:C447941', (47, 59))	('SSTR2', 'Gene', '20606', (124, 129))
57194	33256692	Positron emission tomography (PET) with 18F-fluorodihydroxyphenylalanine, 18F-fluorodeoxyglucose, 18F-fluorodopamine, 11C-hydroxyephedrine or 68Ga-labelled somatostatin analogues have lower radiation exposure and superior image quality but a higher cost than MIBG However, these PET approaches can be used as alternatives to 123I-MIBG or as additional procedures if 123I-MIBG scanning is negative.	('age', 'Gene', '5973', (224, 227))	('MIBG', 'Chemical', '-', (371, 375))	('somatostatin', 'Gene', '6750', (156, 168))	('123I-MIBG', 'Chemical', '-', (325, 334))	('MIBG', 'Chemical', '-', (330, 334))	('123I-MIBG', 'Chemical', '-', (366, 375))	('somatostatin', 'Gene', (156, 168))	('18F-fluorodihydroxyphenylalanine', 'Var', (40, 72))	('age', 'Gene', (224, 227))	('18F-fluorodopamine', 'Chemical', '-', (98, 116))	('68Ga', 'Chemical', 'MESH:C000615430', (142, 146))	('11C-hydroxyephedrine', 'Chemical', '-', (118, 138))	('MIBG', 'Chemical', '-', (259, 263))	('18F-fluorodopamine', 'Var', (98, 116))	('18F-fluorodihydroxyphenylalanine', 'Chemical', 'MESH:C043437', (40, 72))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (74, 96))	('18F-fluorodeoxyglucose', 'Var', (74, 96))
57332	32604789	Germline mutations contributes to the tumor growth and progression.	('Germline mutations', 'Var', (0, 18))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('progression', 'CPA', (55, 66))
57335	32604789	Cluster 1 genes that are associated with hypoxic response (von Hippel-Lindau (VHL), succinate dehydrogenase A (SDHA), succinate dehydrogenase B (SDHB), succinate dehydrogenase C (SDHC), succinate dehydrogenase D (SDHD) and succinate dehydrogenase AF2 (SDHAF2) and hypoxia-inducible transcription factors (2A HIF2A)) while cluster 2 tumors (rearranged during transfection (RET), neurofibromatosis 1 (NF1), transmembrane protein 127 (TMEM127) and MYC-associated factor X (MAX)) mutations that activates kinase signaling and protein translation.	('kinase signaling', 'MPA', (501, 517))	('SDHB', 'Gene', (145, 149))	('VHL', 'Gene', (78, 81))	('neurofibromatosis 1', 'Gene', '4763', (378, 397))	('succinate dehydrogenase A', 'Gene', (84, 109))	('MYC-associated factor X', 'Gene', '4149', (445, 468))	('hypoxia', 'Disease', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('activates', 'PosReg', (491, 500))	('SDHC', 'Gene', (179, 183))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('von Hippel-Lindau', 'Gene', (59, 76))	('RET', 'Gene', '5979', (372, 375))	('succinate dehydrogenase A', 'Gene', '6389', (84, 109))	('mutations', 'Var', (476, 485))	('VHL', 'Gene', '7428', (78, 81))	('SDHA', 'Gene', (111, 115))	('SDHD', 'Gene', '6392', (213, 217))	('neurofibromatosis 1', 'Gene', (378, 397))	('succinate dehydrogenase B', 'Gene', (118, 143))	('succinate dehydrogenase D', 'Gene', '6392', (186, 211))	('hypoxia', 'Disease', 'MESH:D000860', (264, 271))	('succinate dehydrogenase C', 'Gene', '6391', (152, 177))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (378, 395))	('succinate dehydrogenase D', 'Gene', (186, 211))	('SDHA', 'Gene', '6389', (111, 115))	('tumors', 'Disease', (332, 338))	('NF1', 'Gene', '4763', (399, 402))	('succinate dehydrogenase C', 'Gene', (152, 177))	('succinate dehydrogenase AF2', 'Gene', (223, 250))	('von Hippel-Lindau', 'Gene', '7428', (59, 76))	('protein translation', 'MPA', (522, 541))	('SDHAF2', 'Gene', '54949', (252, 258))	('SDHAF2', 'Gene', (252, 258))	('RET', 'Gene', (372, 375))	('succinate dehydrogenase B', 'Gene', '6390', (118, 143))	('SDHD', 'Gene', (213, 217))	('SDHA', 'Gene', (252, 256))	('NF1', 'Gene', (399, 402))	('TMEM127', 'Gene', (432, 439))	('SDHB', 'Gene', '6390', (145, 149))	('HIF2A', 'Gene', '2034', (308, 313))	('hypoxic', 'Disease', (41, 48))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('HIF2A', 'Gene', (308, 313))	('SDHC', 'Gene', '6391', (179, 183))	('hypoxic', 'Disease', 'MESH:D000860', (41, 48))	('SDHA', 'Gene', '6389', (252, 256))	('succinate dehydrogenase AF2', 'Gene', '54949', (223, 250))	('MYC-associated factor X', 'Gene', (445, 468))	('TMEM127', 'Gene', '55654', (432, 439))	('succinate dehydrogenase A', 'Gene', '6389', (223, 248))
57348	32604789	The 131I-MIBG therapy adverse events include leukopenia, thrombocytopenia and bone marrow toxicity.	('thrombocytopenia', 'Disease', (57, 73))	('leukopenia', 'Disease', 'MESH:D007970', (45, 55))	('leukopenia', 'Disease', (45, 55))	('bone marrow toxicity', 'Disease', (78, 98))	('MIBG', 'Chemical', 'MESH:D019797', (9, 13))	('131I-MIBG', 'Var', (4, 13))	('thrombocytopenia', 'Disease', 'MESH:D013921', (57, 73))	('leukopenia', 'Phenotype', 'HP:0001882', (45, 55))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (57, 73))	('bone marrow toxicity', 'Disease', 'MESH:D001855', (78, 98))
57373	31988909	Genetic mutations in the succinate dehydrogenase genes have been described in paraganglioma patients, and those with early onset should be evaluated when genetic testing is available.	('paraganglioma', 'Disease', (78, 91))	('described', 'Reg', (65, 74))	('succinate dehydrogenase', 'Gene', '6390', (25, 48))	('patients', 'Species', '9606', (92, 100))	('succinate dehydrogenase', 'Gene', (25, 48))	('paraganglioma', 'Disease', 'MESH:D010235', (78, 91))	('Genetic mutations', 'Var', (0, 17))	('paraganglioma', 'Phenotype', 'HP:0002668', (78, 91))
57402	31988909	Genetic analyses disclosed the role of mutations in the succinate dehydrogenase (SDH) genes in familial and nonfamilial paragangliomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('succinate dehydrogenase', 'Gene', '6390', (56, 79))	('familial paragangliomas', 'Disease', (111, 134))	('mutations', 'Var', (39, 48))	('succinate dehydrogenase', 'Gene', (56, 79))	('SDH', 'Gene', '6390', (81, 84))	('gliomas', 'Phenotype', 'HP:0009733', (127, 134))	('familial paragangliomas', 'Disease', 'MESH:D010235', (111, 134))	('SDH', 'Gene', (81, 84))	('paragangliomas', 'Phenotype', 'HP:0002668', (120, 134))
57403	31988909	Succinate dehydrogenase enzymatic activity is lost partially or completely in the tumor, despite the typo of gene mutation 8.	('Succinate dehydrogenase', 'Gene', (0, 23))	('gene mutation', 'Var', (109, 122))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lost', 'NegReg', (46, 50))	('tumor', 'Disease', (82, 87))	('Succinate dehydrogenase', 'Gene', '6390', (0, 23))
57411	31988909	Nuclear imaging may also be required, especially in genetic cases, to delineate the extent of the tumor and detect possible synchronous lesions in mutation carries or those at risk (positive family history and young age).	('synchronous lesions', 'Disease', (124, 143))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('synchronous lesions', 'Disease', 'MESH:D009378', (124, 143))	('tumor', 'Disease', (98, 103))	('mutation carries', 'Var', (147, 163))
57418	31988909	Catecholamine and 24-h urinary metanephrine concentrations were normal, and screening for germline mutations in PGL-1, PGL-2, PGL-3, PGL4, and PGL-5 were negative.	('PGL-5', 'Gene', (143, 148))	('PGL-2', 'Gene', '54949', (119, 124))	('Catecholamine', 'Chemical', 'MESH:D002395', (0, 13))	('metanephrine', 'Chemical', 'MESH:D008676', (31, 43))	('PGL-1', 'Gene', (112, 117))	('PGL4', 'Gene', (133, 137))	('PGL4', 'Gene', '6390', (133, 137))	('PGL-3', 'Gene', '6391', (126, 131))	('PGL-2', 'Gene', (119, 124))	('mutations', 'Var', (99, 108))	('PGL-3', 'Gene', (126, 131))	('PGL-5', 'Gene', '6389', (143, 148))
57431	31988909	PGL2 relates to mutation in the SDHAF2 gene and presents as head and neck paraganglioma without other known lesions.	('neck paraganglioma', 'Disease', 'MESH:D010235', (69, 87))	('mutation', 'Var', (16, 24))	('PGL2', 'Gene', '54949', (0, 4))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (60, 87))	('presents', 'Reg', (48, 56))	('PGL2', 'Gene', (0, 4))	('SDHAF2', 'Gene', '54949', (32, 38))	('SDHAF2', 'Gene', (32, 38))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))	('neck paraganglioma', 'Disease', (69, 87))
57432	31988909	PGL3 is related to mutation in the SDHC gene and is associated with head and neck paragangliomas and gastrointestinal stromal tumors.	('neck paragangliomas and gastrointestinal stromal tumors', 'Disease', 'MESH:C564650', (77, 132))	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('mutation', 'Var', (19, 27))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (68, 96))	('PGL3', 'Gene', '6391', (0, 4))	('associated', 'Reg', (52, 62))	('PGL3', 'Gene', (0, 4))	('gliomas', 'Phenotype', 'HP:0009733', (89, 96))	('SDHC', 'Gene', (35, 39))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (68, 96))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (68, 95))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('SDHC', 'Gene', '6391', (35, 39))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (101, 132))
57433	31988909	PGL4 relates to mutation in the SDHB gene and the disease could present as pheochromocytoma or head and neck paraganglioma, gastrointestinal stromal tumors, and renal cell carcinoma.	('gastrointestinal stromal tumors', 'Disease', (124, 155))	('SDHB', 'Gene', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('PGL4', 'Gene', '6390', (0, 4))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (161, 181))	('PGL4', 'Gene', (0, 4))	('present', 'Reg', (64, 71))	('neck paraganglioma', 'Disease', (104, 122))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (95, 122))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('renal cell carcinoma', 'Disease', (161, 181))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (161, 181))	('pheochromocytoma', 'Disease', 'MESH:D010673', (75, 91))	('paraganglioma', 'Phenotype', 'HP:0002668', (109, 122))	('neck paraganglioma', 'Disease', 'MESH:D010235', (104, 122))	('pheochromocytoma', 'Disease', (75, 91))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (124, 155))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (124, 155))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (75, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('mutation', 'Var', (16, 24))	('SDHB', 'Gene', '6390', (32, 36))
57434	31988909	PGL5 correlates with mutation in the SDHD gene and could present with paraganglioma and gastrointestinal stromal tumors.	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (88, 119))	('paraganglioma and gastrointestinal stromal tumors', 'Disease', 'MESH:C564650', (70, 119))	('SDHD', 'Gene', '6392', (37, 41))	('PGL5', 'Gene', '6389', (0, 4))	('SDHD', 'Gene', (37, 41))	('mutation', 'Var', (21, 29))	('PGL5', 'Gene', (0, 4))	('paraganglioma', 'Phenotype', 'HP:0002668', (70, 83))	('present with', 'Reg', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
57435	31988909	Carney-Stratakis syndrome, or Carney dyad, is autosomal dominant and associated with mutations in the SDHB, SDHC, and SDHD genes.	('Carney-Stratakis syndrome', 'Disease', (0, 25))	('SDHD', 'Gene', (118, 122))	('SDHD', 'Gene', '6392', (118, 122))	('SDHB', 'Gene', '6390', (102, 106))	('associated', 'Reg', (69, 79))	('SDHC', 'Gene', (108, 112))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (0, 25))	('mutations', 'Var', (85, 94))	('SDHB', 'Gene', (102, 106))	('Carney dyad', 'Disease', 'MESH:D056733', (30, 41))	('SDHC', 'Gene', '6391', (108, 112))	('Carney dyad', 'Disease', (30, 41))
57509	31988909	Genetic mutations have been described in paraganglioma patients, and those with early onset should be evaluated when genetic testing is available.	('paraganglioma', 'Phenotype', 'HP:0002668', (41, 54))	('patients', 'Species', '9606', (55, 63))	('paraganglioma', 'Disease', (41, 54))	('Genetic mutations', 'Var', (0, 17))	('paraganglioma', 'Disease', 'MESH:D010235', (41, 54))	('described', 'Reg', (28, 37))
57566	31747934	She was tested for genetic variants of lactate dehydrogenase, succinate dehydrogenase and for mutations associated with multiple endocrine neoplasia, type 2; results were negative.	('tested', 'Reg', (8, 14))	('variants', 'Var', (27, 35))	('mutations', 'Var', (94, 103))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (129, 148))	('neoplasia', 'Phenotype', 'HP:0002664', (139, 148))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (129, 148))	('endocrine neoplasia', 'Disease', (129, 148))	('lactate', 'Enzyme', (39, 46))
57580	31747934	However, hypotension should be expected to be as likely in VL as in open surgery, since it is initially associated with renal vein ligature and interruption of catecholamine incretion, followed by relative adrenal insufficiency later on.	('adrenal insufficiency', 'Disease', (206, 227))	('hypotension', 'Disease', 'MESH:D007022', (9, 20))	('interruption', 'Var', (144, 156))	('hypotension', 'Disease', (9, 20))	('associated', 'Reg', (104, 114))	('catecholamine', 'Chemical', 'MESH:D002395', (160, 173))	('hypotension', 'Phenotype', 'HP:0002615', (9, 20))	('adrenal insufficiency', 'Phenotype', 'HP:0000846', (206, 227))	('adrenal insufficiency', 'Disease', 'MESH:D000309', (206, 227))
57622	27376430	Genetic testing for RET proto-oncogene mutation revealed a common polymorphism in exon (c.2071 G>A/p.G691S) and a synonymous variation in exon 15 (c.2712 C>G/p.S904S).	('c.2712 C>G/p.S904S', 'Var', (147, 165))	('RET', 'Gene', '5979', (20, 23))	('c.2071 G>A/p.G691S', 'Var', (88, 106))	('RET', 'Gene', (20, 23))	('p.S904S', 'Mutation', 'rs1800863', (158, 165))	('p.G691S', 'Mutation', 'rs1799939', (99, 106))	('c.2071 G>A', 'Mutation', 'rs1799939', (88, 98))	('c.2712 C>G', 'Mutation', 'rs1800863', (147, 157))
57642	27376430	Genetic test for BRAF gene V600E mutation was negative.	('BRAF', 'Gene', (17, 21))	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Var', (27, 32))	('V600E', 'Mutation', 'rs113488022', (27, 32))
57693	27376430	However, I131 MIBG has a 77-90% sensitivity and 95-100% specificity in detecting such tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('I131 MIBG', 'Var', (9, 18))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('I131 MIBG', 'Chemical', 'MESH:D019797', (9, 18))
57700	27376430	Recent studies in the clinical trials of BRAF inhibitors in patients with malignant melanoma are promising for the treatment of this highly lethal disease.Notably, genetic test for BRAF (V600E) activating mutation was negative in our patient.	('patient', 'Species', '9606', (60, 67))	('malignant melanoma', 'Disease', 'MESH:D008545', (74, 92))	('malignant melanoma', 'Disease', (74, 92))	('V600E', 'Mutation', 'rs113488022', (187, 192))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('BRAF', 'Gene', '673', (41, 45))	('BRAF', 'Gene', (181, 185))	('V600E', 'Var', (187, 192))	('patient', 'Species', '9606', (234, 241))	('BRAF', 'Gene', '673', (181, 185))	('BRAF', 'Gene', (41, 45))	('malignant melanoma', 'Phenotype', 'HP:0002861', (74, 92))
57711	30080879	UBTOR depletion activates mTOR signaling and promotes cell growth, whilst UBTOR overexpression suppresses colony formation in cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('suppresses', 'NegReg', (95, 105))	('cancer', 'Disease', (126, 132))	('UBTOR', 'Chemical', '-', (74, 79))	('cell growth', 'CPA', (54, 65))	('promotes', 'PosReg', (45, 53))	('depletion', 'Var', (6, 15))	('activates', 'PosReg', (16, 25))	('colony formation in', 'CPA', (106, 125))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('UBTOR', 'Chemical', '-', (0, 5))	('mTOR signaling', 'Pathway', (26, 40))
57712	30080879	Studies in cultured cells and zebrafish model show that UBTOR inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption result in higher mTOR activity and aggravate HRAS(G12V) induced neoplasia in the zebrafish.	('UBTOR', 'Chemical', '-', (56, 61))	('inhibits', 'NegReg', (62, 70))	('neoplasia', 'Phenotype', 'HP:0002664', (226, 235))	('mTOR activity', 'MPA', (179, 192))	('gene disruption', 'Var', (146, 161))	('ubtor', 'Gene', (140, 145))	('higher', 'PosReg', (172, 178))	('neoplasia', 'Disease', (226, 235))	('mTOR signaling', 'MPA', (71, 85))	('zebrafish', 'Species', '7955', (30, 39))	('ubtor', 'Chemical', '-', (140, 145))	('aggravate', 'PosReg', (197, 206))	('G12V', 'Mutation', 'rs104894230', (212, 216))	('HRAS', 'CPA', (207, 211))	('zebrafish', 'Species', '7955', (243, 252))	('stabilizing', 'MPA', (89, 100))	('mTOR complex component DEPTOR', 'MPA', (105, 134))	('neoplasia', 'Disease', 'MESH:D009369', (226, 235))
57713	30080879	Lastly, UBTOR depletion promotes tumor growth and mTOR signaling in a xenograft mouse model.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('UBTOR', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mouse', 'Species', '10090', (80, 85))	('depletion', 'Var', (14, 23))	('mTOR signaling', 'MPA', (50, 64))	('UBTOR', 'Chemical', '-', (8, 13))	('promotes', 'PosReg', (24, 32))	('tumor', 'Disease', (33, 38))
57715	30080879	The mTOR signaling pathways are essential for cell growth and clinically mis-regulation of the mTOR pathways are implicated in human diseases including tumor formation, obesity, epilepsy, autism and neurodegeneration.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mTOR pathways', 'Pathway', (95, 108))	('obesity', 'Disease', (169, 176))	('human', 'Species', '9606', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('epilepsy', 'Disease', (178, 186))	('autism and neurodegeneration', 'Disease', 'MESH:D001321', (188, 216))	('tumor', 'Disease', (152, 157))	('obesity', 'Phenotype', 'HP:0001513', (169, 176))	('implicated', 'Reg', (113, 123))	('mis-regulation', 'Var', (73, 87))	('neurodegeneration', 'Phenotype', 'HP:0002180', (199, 216))	('autism', 'Phenotype', 'HP:0000717', (188, 194))	('epilepsy', 'Disease', 'MESH:D004827', (178, 186))	('epilepsy', 'Phenotype', 'HP:0001250', (178, 186))	('obesity', 'Disease', 'MESH:D009765', (169, 176))
57717	30080879	Inhibiting Ubtor function promotes cell growth in neurons and cancer cells.	('Inhibiting', 'Var', (0, 10))	('promotes', 'PosReg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cell growth in neurons', 'CPA', (35, 57))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Ubtor function', 'Gene', (11, 25))	('Ubtor', 'Chemical', '-', (11, 16))
57719	30080879	Functional analyses in human cells and the zebrafish model indicate Ubtor inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, and ubtor gene disruption resulted in higher mTOR activity and aggravated cancer formation in the zebrafish.	('zebrafish', 'Species', '7955', (246, 255))	('mTOR signaling', 'MPA', (83, 97))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('stabilizing', 'MPA', (101, 112))	('cancer', 'Disease', (222, 228))	('aggravated', 'PosReg', (211, 221))	('ubtor', 'Chemical', '-', (152, 157))	('Ubtor', 'Chemical', '-', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mTOR complex component DEPTOR', 'MPA', (117, 146))	('gene disruption', 'Var', (158, 173))	('inhibits', 'NegReg', (74, 82))	('human', 'Species', '9606', (23, 28))	('zebrafish', 'Species', '7955', (43, 52))	('ubtor', 'Gene', (152, 157))	('higher', 'PosReg', (186, 192))	('mTOR activity', 'MPA', (193, 206))
57720	30080879	UBTOR depletion promotes tumor growth and mTOR signaling in xenograft-bearing mice.	('promotes', 'PosReg', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('depletion', 'Var', (6, 15))	('UBTOR', 'Gene', (0, 5))	('UBTOR', 'Chemical', '-', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('mice', 'Species', '10090', (78, 82))	('mTOR signaling', 'MPA', (42, 56))
57721	30080879	Thus our study provide evidence that Ubtor constitutes a novel negative feedback mechanism to control mTOR signaling and cell growth, and manipulations of Ubtor function may potentially be utilized to optimize mTOR signaling activities for treatments of cancers and other diseases.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('manipulations', 'Var', (138, 151))	('Ubtor', 'Chemical', '-', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('mTOR signaling', 'MPA', (102, 116))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('cell growth', 'CPA', (121, 132))	('Ubtor', 'Chemical', '-', (155, 160))
57736	30080879	In parallel, Ubtor depletion promotes tumor growth and mTOR signaling in xenograft-bearing mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mice', 'Species', '10090', (91, 95))	('depletion', 'Var', (19, 28))	('mTOR signaling', 'MPA', (55, 69))	('Ubtor', 'Gene', (13, 18))	('Ubtor', 'Chemical', '-', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('promotes', 'PosReg', (29, 37))
57744	30080879	Fluorescence dye Cy3 labeled small interference RNA (Cy3-siRNA) was transfected into the dissociated hippocampal neurons to knock down Ubtor expression levels (Fig 1C), and the outgrowth of the neurites were revealed by acetylated tubulin stain and measured at 36 hours post in vitro culture (HIV) and 56 HIV (Fig 1A and S2A Fig).	('Ubtor', 'MPA', (135, 140))	('Cy3', 'Chemical', '-', (53, 56))	('Cy3', 'Chemical', '-', (17, 20))	('Ubtor', 'Chemical', '-', (135, 140))	('knock', 'Var', (124, 129))
57745	30080879	The results showed the neurite outgrowth length was almost twice long in Ubtor knock-down hippocampal neurons compared with neurons transfected with control siRNA at 36 HIV (Fig 1B).	('knock-down', 'Var', (79, 89))	('Ubtor', 'Chemical', '-', (73, 78))	('neurite outgrowth length', 'CPA', (23, 47))	('Ubtor', 'Gene', (73, 78))
57746	30080879	Longer neurite outgrowth length was also observed in Ubtor knock-down hippocampal neurons at 56 HIV (S2A Fig).	('Longer', 'PosReg', (0, 6))	('knock-down', 'Var', (59, 69))	('Ubtor', 'Chemical', '-', (53, 58))
57750	30080879	Small interference RNA (siRNA) was transfected into the ld-PC12 cells to knock down Ubtor expression levels (Fig 1G).	('PC12', 'CellLine', 'CVCL:0481', (59, 63))	('knock', 'Var', (73, 78))	('Ubtor expression levels', 'MPA', (84, 107))	('Ubtor', 'Chemical', '-', (84, 89))
57751	30080879	After the transfected cells were treated with NGF for 48 hours, the neurite outgrowth length doubled in Ubtor knock-down cells compared with cells transfected with control siRNA (Fig 1D and 1E).	('neurite outgrowth length', 'CPA', (68, 92))	('doubled', 'PosReg', (93, 100))	('Ubtor', 'Gene', (104, 109))	('knock-down', 'Var', (110, 120))	('Ubtor', 'Chemical', '-', (104, 109))
57753	30080879	UBTOR was listed as a downregulated or mutated gene in tumor tissues in previous studies.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutated', 'Var', (39, 46))	('UBTOR', 'Gene', (0, 5))	('UBTOR', 'Chemical', '-', (0, 5))
57755	30080879	Thus we examined effects of UBTOR reduction in cultured human cells by lentivirus mediated shRNA knockdowns (Fig 2B).	('knockdowns', 'Var', (97, 107))	('human', 'Species', '9606', (56, 61))	('reduction', 'NegReg', (34, 43))	('UBTOR', 'Gene', (28, 33))	('shRNA', 'Gene', (91, 96))	('UBTOR', 'Chemical', '-', (28, 33))
57756	30080879	The results showed UBTOR knock-down promoted proliferation in human HEK293T cells and human glioblastoma U87MG cells (Fig 2A).	('rat', 'Species', '10116', (52, 55))	('glioblastoma', 'Disease', (92, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (92, 104))	('proliferation', 'CPA', (45, 58))	('human', 'Species', '9606', (62, 67))	('HEK293T', 'CellLine', 'CVCL:0063', (68, 75))	('UBTOR', 'Gene', (19, 24))	('knock-down', 'Var', (25, 35))	('human', 'Species', '9606', (86, 91))	('U87MG', 'CellLine', 'CVCL:0022', (105, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('UBTOR', 'Chemical', '-', (19, 24))	('promoted', 'PosReg', (36, 44))
57757	30080879	In addition, UBTOR knock-down also promoted colony formation in HEK293T cells (Fig 2C).	('colony formation', 'CPA', (44, 60))	('HEK293T', 'CellLine', 'CVCL:0063', (64, 71))	('promoted', 'PosReg', (35, 43))	('UBTOR', 'Gene', (13, 18))	('UBTOR', 'Chemical', '-', (13, 18))	('knock-down', 'Var', (19, 29))
57761	30080879	We found no difference in the phosphorylation levels of ERK1/2, a crucial kinase of the Ras-MAPK signaling pathway, between the Ubtor knock-down and control PC12 cells (S4B Fig).	('knock-down', 'Var', (134, 144))	('phosphorylation', 'MPA', (30, 45))	('MAPK', 'Gene', '50689;116590;50689', (92, 96))	('Ubtor', 'Chemical', '-', (128, 133))	('ERK1/2', 'Gene', (56, 62))	('ERK1/2', 'Gene', '50689;116590', (56, 62))	('PC12', 'CellLine', 'CVCL:0481', (157, 161))	('MAPK', 'Gene', (92, 96))
57762	30080879	Phosphorylation level of RPS6 (p-S6), a read-out of mTORC1 activity, was marked higher in the Ubtor knock-down ld-PC12 cells before NGF treatment (Fig 3A).	('p-S6', 'Gene', (31, 35))	('mTORC1', 'Gene', '382056', (52, 58))	('RPS6', 'Gene', (25, 29))	('knock-down', 'Var', (100, 110))	('RPS6', 'Gene', '6194', (25, 29))	('mTORC1', 'Gene', (52, 58))	('Phosphorylation level', 'MPA', (0, 21))	('p-S6', 'Gene', '338413', (31, 35))	('higher', 'PosReg', (80, 86))	('PC12', 'CellLine', 'CVCL:0481', (114, 118))	('Ubtor', 'Chemical', '-', (94, 99))
57786	30080879	In the PC12 cells, the expression level of DEPTOR was reduced by 40% after 6 hours treatment of NGF (Fig 6A), consistent with degradation of DEPTOR caused by mTOR activation.	('expression level', 'MPA', (23, 39))	('NGF', 'Var', (96, 99))	('reduced', 'NegReg', (54, 61))	('PC12', 'CellLine', 'CVCL:0481', (7, 11))
57790	30080879	In agreement with UBTOR's stabilization effect on DEPTOR, knockdown of UBTOR in HEK293T cells caused significant reduction of DEPTOR under basal growth condition (Fig 6B).	('UBTOR', 'Chemical', '-', (18, 23))	('UBTOR', 'Gene', (71, 76))	('reduction', 'NegReg', (113, 122))	('UBTOR', 'Chemical', '-', (71, 76))	('DEPTOR', 'MPA', (126, 132))	('knockdown', 'Var', (58, 67))	('HEK293T', 'CellLine', 'CVCL:0063', (80, 87))
57792	30080879	The transmembrane domain of UBTOR (Delta896-916) was dispensable for the stabilization effect on DEPTOR, whilst further deletion into the C terminal region of UBTOR protein (Delta852-916) abrogated this stabilization effect (Fig 6C).	('UBTOR', 'Chemical', '-', (159, 164))	('Delta852-916', 'Var', (174, 186))	('stabilization', 'MPA', (203, 216))	('Delta852', 'Mutation', 'c.del852', (174, 182))	('abrogated', 'NegReg', (188, 197))	('stabilization', 'MPA', (73, 86))	('Delta896', 'Mutation', 'c.del896', (35, 43))	('Delta896-916', 'Var', (35, 47))	('UBTOR', 'Chemical', '-', (28, 33))
57793	30080879	As expected, the UBTOR1-467 N terminal region was required for the full stabilization effects of DEPTOR (Fig 6D), because UBTOR1-467 interacted with DEPTOR (Fig 5).	('UBTOR', 'Chemical', '-', (17, 22))	('interacted', 'Interaction', (133, 143))	('UBTOR1-467', 'Var', (122, 132))	('UBTOR', 'Chemical', '-', (122, 127))
57797	30080879	To investigate Ubtor's functions in intact animals, ubtor gene was disrupted in zebrafish by TALEN and CRISPR/Cas9 mediated mutagenesis (see Materials and Methods).	('Ubtor', 'Chemical', '-', (15, 20))	('disrupted', 'NegReg', (67, 76))	('ubtor', 'Chemical', '-', (52, 57))	('mutagenesis', 'Var', (124, 135))	('ubtor gene', 'Gene', (52, 62))	('zebrafish', 'Species', '7955', (80, 89))
57798	30080879	The targeted gene disruption resulted in frame-shift and multiple stop codons in the Ubtor coding sequence.	('resulted in', 'Reg', (29, 40))	('Ubtor', 'Chemical', '-', (85, 90))	('stop codons', 'MPA', (66, 77))	('frame-shift', 'Var', (41, 52))	('disruption', 'Var', (18, 28))
57800	30080879	The homozygous ubtor mutant had no gross developmental abnormalities.	('mutant', 'Var', (21, 27))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (41, 68))	('ubtor', 'Chemical', '-', (15, 20))	('developmental abnormalities', 'Disease', (41, 68))	('developmental abnormalities', 'Disease', 'MESH:D006130', (41, 68))
57801	30080879	Results from behavior tests showed ubtor mutant had enhanced fear-evoked freezing and compromised C-start responses (S7 Fig), suggesting ubtor mutation had subtle but significant effects on neurodevelopment and animal physiology.	('ubtor', 'Chemical', '-', (137, 142))	('mutant', 'Var', (41, 47))	('ubtor', 'Chemical', '-', (35, 40))	('compromised', 'NegReg', (86, 97))	('fear-evoked freezing', 'CPA', (61, 81))	('enhanced', 'PosReg', (52, 60))	('C-start responses', 'MPA', (98, 115))	('ubtor', 'Gene', (35, 40))
57802	30080879	To determine if UBTOR's regulation of mTOR signaling also occur in intact animals, we examined p-S6K levels in ubtor mutant and control larvae at 5 dpf, and found p-S6K was increased approximately 4-fold in the brains of ubtor mutant compared with the controls (Fig 7A).	('p-S6K', 'Gene', (163, 168))	('mutant', 'Var', (227, 233))	('mutant', 'Var', (117, 123))	('p-S6K', 'Gene', (95, 100))	('ubtor', 'Chemical', '-', (111, 116))	('UBTOR', 'Chemical', '-', (16, 21))	('p-S6K', 'Gene', '6198', (163, 168))	('ubtor', 'Chemical', '-', (221, 226))	('increased', 'PosReg', (173, 182))	('ubtor', 'Gene', (111, 116))	('ubtor', 'Gene', (221, 226))	('p-S6K', 'Gene', '6198', (95, 100))
57803	30080879	To further examine the effects of ubtor mutation on the mTOR signaling, zebrafish of 13.5 dpf were fasted for 12 hours to down-regulate, then refed with ample food for 12 hours to activate the mTOR activities.	('mutation', 'Var', (40, 48))	('ubtor', 'Chemical', '-', (34, 39))	('down-regulate', 'NegReg', (122, 135))	('zebrafish', 'Species', '7955', (72, 81))	('activate', 'PosReg', (180, 188))
57806	30080879	The ubtor mutation caused significantly higher levels of p-S6K and p-S6 in the fasted animals, and significantly higher p-S6 levels in the refed animals (Fig 7B).	('higher', 'PosReg', (40, 46))	('p-S6', 'Gene', '338413', (67, 71))	('p-S6K', 'Gene', (57, 62))	('p-S6', 'Gene', '338413', (57, 61))	('ubtor', 'Gene', (4, 9))	('higher', 'PosReg', (113, 119))	('p-S6', 'Gene', (67, 71))	('mutation', 'Var', (10, 18))	('p-S6', 'Gene', '338413', (120, 124))	('p-S6', 'Gene', (57, 61))	('p-S6', 'Gene', (120, 124))	('p-S6K', 'Gene', '6198', (57, 62))	('ubtor', 'Chemical', '-', (4, 9))
57807	30080879	Thus, ubtor mutation caused significant upregulation of the mTOR signaling in the intact animals.	('ubtor', 'Gene', (6, 11))	('upregulation', 'PosReg', (40, 52))	('mutation', 'Var', (12, 20))	('mTOR signaling', 'MPA', (60, 74))	('ubtor', 'Chemical', '-', (6, 11))
57808	30080879	HRAS(G12V), a dominant-active form of human oncogene HRAS, can promote tumor formation when overexpressed in zebrafish embryos.	('HRAS(G12V', 'Var', (0, 9))	('zebrafish', 'Species', '7955', (109, 118))	('human', 'Species', '9606', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('G12V', 'Mutation', 'rs104894230', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promote', 'PosReg', (63, 70))	('tumor', 'Disease', (71, 76))
57809	30080879	Consistent with the in vitro effects of UBTOR knockdowns on cell growth and colony formation in the cultured cells, microinjection of the HRAS(G12V) construct into zebrafish ubtor mutant embryos increased neoplasia rate to over 70% compared with about 30% for the injection into the wild type controls (Fig 7C).	('zebrafish', 'Species', '7955', (164, 173))	('neoplasia', 'Disease', (205, 214))	('rat', 'Species', '10116', (215, 218))	('mutant', 'Var', (180, 186))	('G12V', 'Mutation', 'rs104894230', (143, 147))	('UBTOR', 'Chemical', '-', (40, 45))	('neoplasia', 'Disease', 'MESH:D009369', (205, 214))	('neoplasia', 'Phenotype', 'HP:0002664', (205, 214))	('HRAS(G12V', 'Gene', (138, 147))	('increased', 'PosReg', (195, 204))	('ubtor', 'Chemical', '-', (174, 179))
57810	30080879	In total, 19 out of the 59 wild type control zebrafish developed tumors, whilst 26 out of the 37 ubtor mutants had tumors (chi12 = 13.23, P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutants', 'Var', (103, 110))	('zebrafish', 'Species', '7955', (45, 54))	('ubtor', 'Chemical', '-', (97, 102))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
57817	30080879	Thus, UBTOR depletion promoted tumor growth and mTOR signaling in the xenograft mouse model.	('mTOR signaling', 'MPA', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('promoted', 'PosReg', (22, 30))	('tumor', 'Disease', (31, 36))	('mouse', 'Species', '10090', (80, 85))	('UBTOR', 'Gene', (6, 11))	('UBTOR', 'Chemical', '-', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('depletion', 'Var', (12, 21))
57818	30080879	In this study, UBTOR depletion promotes neurite and cellular growth, whilst UBTOR overexpression suppresses colony formation in cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('suppresses', 'NegReg', (97, 107))	('UBTOR', 'Chemical', '-', (76, 81))	('promotes', 'PosReg', (31, 39))	('neurite', 'CPA', (40, 47))	('UBTOR', 'Chemical', '-', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('depletion', 'Var', (21, 30))	('cellular growth', 'CPA', (52, 67))	('colony formation', 'CPA', (108, 124))	('cancer', 'Disease', (128, 134))
57820	30080879	Investigations in the zebrafish model further showed disruption of ubtor gene upregulated the mTOR signaling and promoted HRAS(G12V) mediated tumor formation in intact animals.	('disruption', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('promoted', 'PosReg', (113, 121))	('upregulated', 'PosReg', (78, 89))	('mTOR signaling', 'MPA', (94, 108))	('tumor', 'Disease', (142, 147))	('ubtor gene', 'Gene', (67, 77))	('G12V', 'Mutation', 'rs104894230', (127, 131))	('ubtor', 'Chemical', '-', (67, 72))	('zebrafish', 'Species', '7955', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
57821	30080879	Similarly, UBTOR depletion promoted tumor growth and mTOR signaling in a xenograft mouse model.	('UBTOR', 'Gene', (11, 16))	('mouse', 'Species', '10090', (83, 88))	('promoted', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('depletion', 'Var', (17, 26))	('mTOR signaling', 'MPA', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('UBTOR', 'Chemical', '-', (11, 16))
57829	30080879	Abnormal activation of the mTOR signaling may provide explanation why UBTOR is downregulated or mutated in tumor tissues.	('mutated', 'Var', (96, 103))	('activation', 'PosReg', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('UBTOR', 'Chemical', '-', (70, 75))	('mTOR signaling', 'Pathway', (27, 41))	('downregulated', 'NegReg', (79, 92))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
57830	30080879	Consistent with this view, our results show UBTOR knock-down promote growth in HEK293T and U87MG cells, and overexpression of UBTOR reduced colony formation in both the HEK293T cells and the carcinoma T24 cells.	('knock-down', 'Var', (50, 60))	('promote', 'PosReg', (61, 68))	('growth', 'CPA', (69, 75))	('reduced', 'NegReg', (132, 139))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('U87MG', 'CellLine', 'CVCL:0022', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('UBTOR', 'Gene', (44, 49))	('colony formation', 'CPA', (140, 156))	('carcinoma', 'Disease', (191, 200))	('UBTOR', 'Chemical', '-', (44, 49))	('UBTOR', 'Chemical', '-', (126, 131))	('HEK293T', 'CellLine', 'CVCL:0063', (79, 86))	('HEK293T', 'CellLine', 'CVCL:0063', (169, 176))
57831	30080879	Enhancement of HRASG12V mediated tumor formation in the homozygous ubtor zebrafish mutant and larger xenograft tumor growth of UBOTR-depleted U87MG cells in the nude mice further support involvement of Ubtor in neoplasia.	('mutant', 'Var', (83, 89))	('zebrafish', 'Species', '7955', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('neoplasia', 'Phenotype', 'HP:0002664', (211, 220))	('tumor', 'Disease', (33, 38))	('ubtor', 'Chemical', '-', (67, 72))	('U87MG', 'CellLine', 'CVCL:0022', (142, 147))	('xenograft tumor', 'Disease', (101, 116))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('HRASG12V mediated', 'Gene', (15, 32))	('xenograft tumor', 'Disease', 'MESH:D009369', (101, 116))	('tumor', 'Disease', (111, 116))	('neoplasia', 'Disease', 'MESH:D009369', (211, 220))	('Ubtor', 'Chemical', '-', (202, 207))	('HRASG12V', 'CellLine', 'CVCL:M676', (15, 23))	('Enhancement', 'PosReg', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('neoplasia', 'Disease', (211, 220))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('nude mice', 'Species', '10090', (161, 170))
57840	30080879	Manipulations of Ubtor function may potentially be utilized to optimize mTOR signaling activities for treatments of cancers and other diseases.	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('Ubtor', 'Chemical', '-', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('Manipulations', 'Var', (0, 13))
57854	30080879	To disrupt the ubtor gene in the zebrafish, three lesions were introduced into the zebrafish genome via the TALEN and CRSPR/Cas9 mediated targeted gene modifications (see S1 Table for target site sequences and lesion information).	('zebrafish', 'Species', '7955', (83, 92))	('gene modifications', 'Var', (147, 165))	('modifications', 'Var', (152, 165))	('ubtor gene', 'Gene', (15, 25))	('zebrafish', 'Species', '7955', (33, 42))	('ubtor', 'Chemical', '-', (15, 20))
57868	30080879	Preliminary tests showed ubtor mutant fish exhibited reduced C-start after repetitive stimulations.	('reduced', 'NegReg', (53, 60))	('ubtor', 'Chemical', '-', (25, 30))	('C-start', 'MPA', (61, 68))	('ubtor mutant', 'Var', (25, 37))
57935	27867439	Evaluation of Head and Neck Paragangliomas by Computed Tomography in Patients with Pheochromocytoma-Paraganglioma Syndromes Hereditary head and neck paragangliomas (HNP) are very often associated with pheochromocytoma-paraganglioma syndromes, which are caused by mutations in genes encoding subunits of succinate dehydrogenase (SDHx) complex.	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (135, 163))	('Paraganglioma', 'Phenotype', 'HP:0002668', (28, 41))	('Paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('mutations', 'Var', (263, 272))	('pheochromocytoma-paraganglioma syndromes', 'Disease', (201, 241))	('succinate dehydrogenase', 'Gene', '6389', (303, 326))	('Neck Paragangliomas', 'Disease', 'MESH:D010235', (23, 42))	('Pheochromocytoma-Paraganglioma', 'Disease', (83, 113))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))	('neck paragangliomas', 'Disease', (144, 163))	('SDHx', 'Gene', (328, 332))	('succinate dehydrogenase', 'Gene', (303, 326))	('paragangliomas', 'Phenotype', 'HP:0002668', (149, 163))	('paraganglioma', 'Phenotype', 'HP:0002668', (149, 162))	('HNP', 'Chemical', '-', (165, 168))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (201, 217))	('SDHx', 'Chemical', '-', (328, 332))	('Head and Neck Paragangliomas', 'Phenotype', 'HP:0002864', (14, 42))	('Paragangliomas', 'Phenotype', 'HP:0002668', (28, 42))	('neck paragangliomas', 'Disease', 'MESH:D010235', (144, 163))	('Neck Paragangliomas', 'Disease', (23, 42))	('pheochromocytoma-paraganglioma syndromes', 'Disease', 'MESH:D010673', (201, 241))	('Patients', 'Species', '9606', (69, 77))	('paraganglioma', 'Phenotype', 'HP:0002668', (218, 231))	('associated', 'Reg', (185, 195))	('HNP', 'Phenotype', 'HP:0002864', (165, 168))	('Pheochromocytoma-Paraganglioma', 'Disease', 'MESH:D010673', (83, 113))
57937	27867439	A total of 72 patients with SDHx mutations underwent computed tomography examinations of the head and neck.	('SDHx', 'Chemical', '-', (28, 32))	('patients', 'Species', '9606', (14, 22))	('SDHx', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
57939	27867439	The HNP were statistically more frequent in carriers of SDHD mutations compared to carriers of SDHB mutations (72.1% vs. 43.5%, p=0.033).	('SDHD', 'Gene', (56, 60))	('SDHD', 'Gene', '6392', (56, 60))	('SDHB', 'Gene', '6390', (95, 99))	('mutations', 'Var', (61, 70))	('HNP', 'Disease', (4, 7))	('SDHB', 'Gene', (95, 99))	('HNP', 'Phenotype', 'HP:0002864', (4, 7))	('HNP', 'Chemical', '-', (4, 7))	('frequent', 'Reg', (32, 40))
57940	27867439	Multiple tumors more often occurred in patients with SDHD mutations 26/31 (83.9%) than in patients with SDHB mutations 6/11 (54.5%) p=0.05.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('SDHD', 'Gene', (53, 57))	('SDHD', 'Gene', '6392', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('SDHB', 'Gene', '6390', (104, 108))	('occurred', 'Reg', (27, 35))	('Multiple tumors', 'Disease', (0, 15))	('Multiple tumors', 'Disease', 'MESH:D009369', (0, 15))	('SDHB', 'Gene', (104, 108))
57941	27867439	There was a significant difference in the prevalence of carotid paragangliomas between patients with SDHB and SDHD mutations (7/11 [63.6%] vs. 30/31 [96.8%], respectively, p=0.004).	('carotid paragangliomas', 'Disease', 'MESH:D002345', (56, 78))	('mutations', 'Var', (115, 124))	('SDHB', 'Gene', (101, 105))	('SDHB', 'Gene', '6390', (101, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (64, 78))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (56, 78))	('carotid paragangliomas', 'Disease', (56, 78))	('SDHD', 'Gene', '6392', (110, 114))	('patients', 'Species', '9606', (87, 95))	('SDHD', 'Gene', (110, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (64, 77))
57942	27867439	Patients with SDHD mutations more often had carotid paragangliomas located on the left side than on the right side, as compared to SDHB mutations 25/31 (80.6%) vs. 4/11 (36.4%), p=0.006.	('SDHB', 'Gene', '6390', (131, 135))	('carotid paragangliomas', 'Disease', (44, 66))	('SDHB', 'Gene', (131, 135))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))	('paragangliomas', 'Phenotype', 'HP:0002668', (52, 66))	('Patients', 'Species', '9606', (0, 8))	('carotid paragangliomas', 'Disease', 'MESH:D002345', (44, 66))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('SDHD', 'Gene', (14, 18))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (44, 66))
57943	27867439	SDHx mutations predispose to multifocal and bilateral HNP.	('HNP', 'Phenotype', 'HP:0002864', (54, 57))	('mutations', 'Var', (5, 14))	('HNP', 'Chemical', '-', (54, 57))	('SDHx', 'Chemical', '-', (0, 4))	('SDHx', 'Gene', (0, 4))	('predispose to', 'Reg', (15, 28))
57945	27867439	Patients with SDHD mutations are characterized by higher frequency of HNP than patients with SDHB mutations, which is mainly driven by higher frequency of carotid body tumors in patients with SDHD mutations.	('carotid body tumors', 'Disease', 'MESH:D002345', (155, 174))	('HNP', 'Phenotype', 'HP:0002864', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('SDHB', 'Gene', (93, 97))	('carotid body tumors', 'Disease', (155, 174))	('HNP', 'Chemical', '-', (70, 73))	('SDHB', 'Gene', '6390', (93, 97))	('carotid body tumors', 'Phenotype', 'HP:0002668', (155, 174))	('patients', 'Species', '9606', (178, 186))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('SDHD', 'Gene', (192, 196))	('SDHD', 'Gene', '6392', (192, 196))	('patients', 'Species', '9606', (79, 87))	('SDHD', 'Gene', (14, 18))	('HNP', 'Disease', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
57953	27867439	Mutations in ten different genes connected with hereditary HNP were found.	('hereditary HNP', 'Disease', (48, 62))	('Mutations', 'Var', (0, 9))	('HNP', 'Chemical', '-', (59, 62))	('HNP', 'Phenotype', 'HP:0002864', (59, 62))
57954	27867439	Pheochromocytoma-paraganglioma (PGL) syndromes are associated with SDHx gene mutations, encoding the subunits of the succinate dehydrogenase enzyme complex, subunit D (SDHD), B (SDHB) and C (SDHC), (PGL type 1,4, and 3, respectively).	('SDHx', 'Chemical', '-', (67, 71))	('SDHD', 'Gene', '6392', (168, 172))	('SDHx', 'Gene', (67, 71))	('paraganglioma', 'Phenotype', 'HP:0002668', (17, 30))	('PGL', 'Phenotype', 'HP:0002668', (32, 35))	('SDHD', 'Gene', (168, 172))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('succinate dehydrogenase', 'Gene', (117, 140))	('associated', 'Reg', (51, 61))	('PGL', 'Phenotype', 'HP:0002668', (199, 202))	('mutations', 'Var', (77, 86))	('SDHC', 'Gene', (191, 195))	('SDHC', 'Gene', '6391', (191, 195))	('Pheochromocytoma-paraganglioma', 'Disease', 'MESH:D010673', (0, 30))	('SDHB', 'Gene', '6390', (178, 182))	('succinate dehydrogenase', 'Gene', '6389', (117, 140))	('Pheochromocytoma-paraganglioma', 'Disease', (0, 30))	('SDHB', 'Gene', (178, 182))
57955	27867439	Recently, germline mutations in two consecutive subunits of succinate dehydrogenase (SDHA, SDHAF2) have been found in patients with pheochromocytoma-paraganglioma syndrome.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (132, 148))	('SDHA', 'Gene', (85, 89))	('succinate dehydrogenase', 'Gene', (60, 83))	('pheochromocytoma-paraganglioma syndrome', 'Disease', (132, 171))	('found', 'Reg', (109, 114))	('SDHA', 'Gene', '6389', (85, 89))	('SDHA', 'Gene', '6389', (91, 95))	('succinate dehydrogenase', 'Gene', '6389', (60, 83))	('germline mutations', 'Var', (10, 28))	('paraganglioma', 'Phenotype', 'HP:0002668', (149, 162))	('SDHAF2', 'Gene', '54949', (91, 97))	('SDHAF2', 'Gene', (91, 97))	('pheochromocytoma-paraganglioma syndrome', 'Disease', 'MESH:D010673', (132, 171))	('patients', 'Species', '9606', (118, 126))	('SDHA', 'Gene', (91, 95))
57959	27867439	The patients with confirmed SDHx mutations by genetic testing entered the study.	('SDHx', 'Chemical', '-', (28, 32))	('patients', 'Species', '9606', (4, 12))	('SDHx', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
57960	27867439	This study consisted of 72 patients with SDXs mutations (36 men, 36 women, mean age 44+-14.26 y, age range 13-74 yrs, 44 index cases, 28 relatives), 23 (31.9%) patients with SDHB mutations, 5 (6.9%) with SDHC mutations, and 44 (61.1%) with SDHD mutations.	('patients', 'Species', '9606', (160, 168))	('SDXs', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('men', 'Species', '9606', (70, 73))	('SDHB', 'Gene', '6390', (174, 178))	('patients', 'Species', '9606', (27, 35))	('women', 'Species', '9606', (68, 73))	('SDHD', 'Gene', '6392', (240, 244))	('SDXs', 'Chemical', '-', (41, 45))	('men', 'Species', '9606', (60, 63))	('mutations', 'Var', (179, 188))	('SDHC', 'Gene', (204, 208))	('SDHB', 'Gene', (174, 178))	('SDHD', 'Gene', (240, 244))	('SDHC', 'Gene', '6391', (204, 208))
57980	27867439	Table 2 shows the number and locations of paragangliomas in patients with SDHx mutations.	('paragangliomas', 'Disease', (42, 56))	('SDHx', 'Gene', (74, 78))	('paragangliomas', 'Disease', 'MESH:D010235', (42, 56))	('paragangliomas', 'Phenotype', 'HP:0002668', (42, 56))	('SDHx', 'Chemical', '-', (74, 78))	('patients', 'Species', '9606', (60, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (42, 55))	('mutations', 'Var', (79, 88))
57987	27867439	We compared HNP of patients with SDHB and SDHD mutations.	('SDHB', 'Gene', '6390', (33, 37))	('patients', 'Species', '9606', (19, 27))	('HNP', 'Phenotype', 'HP:0002864', (12, 15))	('HNP', 'Chemical', '-', (12, 15))	('SDHD', 'Gene', '6392', (42, 46))	('mutations', 'Var', (47, 56))	('SDHB', 'Gene', (33, 37))	('SDHD', 'Gene', (42, 46))	('HNP', 'Disease', (12, 15))
57989	27867439	Patients with SDHD mutations more often had carotid paragangliomas located on the left side than on the right side as compared with SDHB mutations (25/31 vs. 4/11, p=0.006), but in both groups the prevalence of bilateral localization of carotid paragangliomas was similar (15/30 [50.0%] vs. 3/7 [42.9%], respectively, p=NS).	('carotid paragangliomas', 'Disease', (44, 66))	('SDHB', 'Gene', (132, 136))	('carotid paragangliomas', 'Disease', (237, 259))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (237, 259))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))	('paragangliomas', 'Phenotype', 'HP:0002668', (52, 66))	('carotid paragangliomas', 'Disease', 'MESH:D002345', (44, 66))	('Patients', 'Species', '9606', (0, 8))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('carotid paragangliomas', 'Disease', 'MESH:D002345', (237, 259))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (44, 66))	('paraganglioma', 'Phenotype', 'HP:0002668', (245, 258))	('paragangliomas', 'Phenotype', 'HP:0002668', (245, 259))	('SDHD', 'Gene', (14, 18))	('SDHB', 'Gene', '6390', (132, 136))
57990	27867439	No statistical difference between both groups of SDHx mutations in the Shamblin classification was found (Figure 3).	('SDHx', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('SDHx', 'Chemical', '-', (49, 53))	('Shamblin classification', 'Disease', (71, 94))
57991	27867439	No marked differences between the prevalence of vagal, jugular and tympanic paragangliomas in terms of SDHB and SDHD mutations were found.	('mutations', 'Var', (117, 126))	('SDHB', 'Gene', (103, 107))	('tympanic paraganglioma', 'Phenotype', 'HP:0006715', (67, 89))	('jugular', 'Disease', (55, 62))	('tympanic paragangliomas', 'Disease', (67, 90))	('SDHD', 'Gene', (112, 116))	('SDHD', 'Gene', '6392', (112, 116))	('tympanic paragangliomas', 'Disease', 'MESH:D010235', (67, 90))	('paraganglioma', 'Phenotype', 'HP:0002668', (76, 89))	('paragangliomas', 'Phenotype', 'HP:0002668', (76, 90))	('SDHB', 'Gene', '6390', (103, 107))
57992	27867439	The comparison of patients with SDHB and SDHD mutations is shown in Table 3.	('SDHB', 'Gene', '6390', (32, 36))	('mutations', 'Var', (46, 55))	('SDHB', 'Gene', (32, 36))	('SDHD', 'Gene', '6392', (41, 45))	('patients', 'Species', '9606', (18, 26))	('SDHD', 'Gene', (41, 45))
57994	27867439	Patients with SDHD mutations statistically more often revealed bilateral localization of HNP, 25/31 (80.6%) vs. 5/11 (45.5%) with SDHB, p=0.03.	('revealed', 'Reg', (54, 62))	('HNP', 'Disease', (89, 92))	('SDHB', 'Gene', '6390', (130, 134))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))	('HNP', 'Phenotype', 'HP:0002864', (89, 92))	('Patients', 'Species', '9606', (0, 8))	('HNP', 'Chemical', '-', (89, 92))	('SDHB', 'Gene', (130, 134))	('SDHD', 'Gene', (14, 18))
57995	27867439	Out of 72 patients with SDHx mutations, 7 patients (4 with SDHB and 3 with SDHD gene mutations) had a malignant disease with distant metastases to bones, liver, lungs and lymph nodes, and 6 of them had head and neck paragangliomas (Figure 4A-4D).	('malignant disease', 'Disease', 'MESH:D009369', (102, 119))	('paragangliomas', 'Phenotype', 'HP:0002668', (216, 230))	('paraganglioma', 'Phenotype', 'HP:0002668', (216, 229))	('metastases', 'Disease', 'MESH:D009362', (133, 143))	('mutations', 'Var', (29, 38))	('malignant disease', 'Disease', (102, 119))	('SDHD', 'Gene', '6392', (75, 79))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (202, 230))	('SDHx', 'Gene', (24, 28))	('SDHD', 'Gene', (75, 79))	('metastases', 'Disease', (133, 143))	('neck paragangliomas', 'Disease', 'MESH:D010235', (211, 230))	('SDHx', 'Chemical', '-', (24, 28))	('SDHB and 3', 'Gene', '6390', (59, 69))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (42, 50))	('neck paragangliomas', 'Disease', (211, 230))
57997	27867439	Among 72 patients with confirmed SDHx mutations we found HNP in 44 (61.1%) patients.	('patients', 'Species', '9606', (9, 17))	('SDHx', 'Chemical', '-', (33, 37))	('HNP', 'Disease', (57, 60))	('patients', 'Species', '9606', (75, 83))	('HNP', 'Phenotype', 'HP:0002864', (57, 60))	('HNP', 'Chemical', '-', (57, 60))	('mutations', 'Var', (38, 47))	('SDHx', 'Gene', (33, 37))
58005	27867439	The average age of patients in all group was 44+-14.26 yrs, in groups of SDHB and SDHD mutations the mean age was similar.	('patients', 'Species', '9606', (19, 27))	('SDHD', 'Gene', '6392', (82, 86))	('SDHD', 'Gene', (82, 86))	('SDHB', 'Gene', '6390', (73, 77))	('mutations', 'Var', (87, 96))	('SDHB', 'Gene', (73, 77))
58006	27867439	Head and neck paragangliomas were statistically more prevalent among SDHD mutation carriers (72.1%) compared with SDHB mutation carriers (43.5%), like in other studies.	('mutation', 'Var', (74, 82))	('SDHB', 'Gene', '6390', (114, 118))	('Head and neck paragangliomas', 'Phenotype', 'HP:0002864', (0, 28))	('SDHB', 'Gene', (114, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (14, 27))	('prevalent', 'Reg', (53, 62))	('neck paragangliomas', 'Disease', 'MESH:D010235', (9, 28))	('paragangliomas', 'Phenotype', 'HP:0002668', (14, 28))	('SDHD', 'Gene', '6392', (69, 73))	('neck paragangliomas', 'Disease', (9, 28))	('SDHD', 'Gene', (69, 73))
58008	27867439	In our study, carotid paragangliomas significantly more commonly occurred in patients with SDHD mutations and were more often located on the left side.	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))	('carotid paragangliomas', 'Disease', (14, 36))	('carotid paragangliomas', 'Phenotype', 'HP:0100635', (14, 36))	('more', 'PosReg', (51, 55))	('SDHD', 'Gene', (91, 95))	('SDHD', 'Gene', '6392', (91, 95))	('patients', 'Species', '9606', (77, 85))	('carotid paragangliomas', 'Disease', 'MESH:D002345', (14, 36))	('occurred', 'Reg', (65, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))	('mutations', 'Var', (96, 105))
58010	27867439	Morbidity related to surgical resection (postoperative neurovascular complications) for Shamblin type III carotid body tumors is higher than for type I and II.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('type III carotid body tumors', 'Disease', 'MESH:D002345', (97, 125))	('postoperative neurovascular complications', 'Disease', (41, 82))	('Shamblin', 'Var', (88, 96))	('type III carotid body tumors', 'Disease', (97, 125))	('postoperative neurovascular complications', 'Disease', 'MESH:D011183', (41, 82))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('carotid body tumors', 'Phenotype', 'HP:0002668', (106, 125))
58019	27867439	In our study, patients with SDHD mutation significantly more commonly had multifocal paragangliomas than patients with SDHB mutations, as in the study by Neumann, 26 patients out of 31 with SDHD mutations in the present study had multifocal paragangliomas compared with 6 out of 11 patients with SDHB mutations.	('SDHD', 'Gene', (28, 32))	('multifocal paragangliomas', 'Disease', (230, 255))	('SDHB', 'Gene', (119, 123))	('multifocal paragangliomas', 'Disease', 'None', (230, 255))	('patients', 'Species', '9606', (14, 22))	('SDHD', 'Gene', '6392', (190, 194))	('patients', 'Species', '9606', (282, 290))	('paraganglioma', 'Phenotype', 'HP:0002668', (85, 98))	('paragangliomas', 'Phenotype', 'HP:0002668', (85, 99))	('mutation', 'Var', (33, 41))	('patients', 'Species', '9606', (105, 113))	('SDHD', 'Gene', (190, 194))	('mutations', 'Var', (195, 204))	('SDHD', 'Gene', '6392', (28, 32))	('SDHB', 'Gene', '6390', (296, 300))	('multifocal paragangliomas', 'Disease', (74, 99))	('multifocal paragangliomas', 'Disease', 'None', (74, 99))	('SDHB', 'Gene', '6390', (119, 123))	('paraganglioma', 'Phenotype', 'HP:0002668', (241, 254))	('paragangliomas', 'Phenotype', 'HP:0002668', (241, 255))	('patients', 'Species', '9606', (166, 174))	('SDHB', 'Gene', (296, 300))
58028	27867439	Patients with SDHD mutations are characterized by higher frequency of head and neck paragangliomas than patients with SDHB mutations which is mainly caused by a higher frequency of carotid body tumors in patients with SDHD mutations.	('neck paragangliomas', 'Disease', 'MESH:D010235', (79, 98))	('SDHD', 'Gene', (218, 222))	('patients', 'Species', '9606', (204, 212))	('SDHB', 'Gene', '6390', (118, 122))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('SDHD', 'Gene', '6392', (14, 18))	('paragangliomas', 'Phenotype', 'HP:0002668', (84, 98))	('carotid body tumors', 'Disease', 'MESH:D002345', (181, 200))	('carotid body tumors', 'Disease', (181, 200))	('SDHB', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('neck paragangliomas', 'Disease', (79, 98))	('higher frequency of head', 'Phenotype', 'HP:0000256', (50, 74))	('SDHD', 'Gene', (14, 18))	('patients', 'Species', '9606', (104, 112))	('carotid body tumors', 'Phenotype', 'HP:0002668', (181, 200))	('SDHD', 'Gene', '6392', (218, 222))	('mutations', 'Var', (19, 28))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (70, 98))
58046	27316501	During the hospital admissions, she was found to have polymorphic VT requiring DC version three times in a span of 2 months.	('VT', 'Disease', 'MESH:D017180', (66, 68))	('DC version', 'MPA', (79, 89))	('polymorphic', 'Var', (54, 65))
58070	27316501	The mechanism of QT prolongation is not clear; however, alpha-adrenergic stimulation can prolong the QT by prolonging the action potential duration.	('prolonging', 'PosReg', (107, 117))	('alpha-adrenergic stimulation', 'Var', (56, 84))	('prolong', 'PosReg', (89, 96))	('QT prolongation', 'Disease', 'MESH:D008133', (17, 32))	('QT prolongation', 'Disease', (17, 32))	('action potential duration', 'MPA', (122, 147))
58131	21614574	Remarkably, the presence of a carotid body tumor was an independent predictor of increased daytime sleepiness (beta = 0.287, P = 0.029).	('daytime sleepiness', 'Disease', 'MESH:D012893', (91, 109))	('increased daytime sleepiness', 'Phenotype', 'HP:0002189', (81, 109))	('carotid body tumor', 'Disease', (30, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('daytime sleepiness', 'Disease', (91, 109))	('carotid body tumor', 'Disease', 'MESH:D002345', (30, 48))	('presence', 'Var', (16, 24))	('carotid body tumor', 'Phenotype', 'HP:0002668', (30, 48))	('increased', 'PosReg', (81, 90))	('daytime sleepiness', 'Phenotype', 'HP:0002189', (91, 109))
58138	21614574	Familial paraganglioma syndromes are associated with germline mutations in the genes encoding the B, C, and D subunits of mitochondrial complex II succinate dehydrogenase (SDH).	('germline mutations', 'Var', (53, 71))	('Familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (0, 32))	('SDH', 'Gene', (172, 175))	('associated', 'Reg', (37, 47))	('Familial paraganglioma syndromes', 'Disease', (0, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (9, 22))	('SDH', 'Gene', '6390', (172, 175))
58140	21614574	Among these three genes, mutations in SDH-D subunit are the most prominent cause of HNP.	('cause', 'Reg', (75, 80))	('SDH', 'Gene', '6390', (38, 41))	('HNP', 'Disease', (84, 87))	('mutations', 'Var', (25, 34))	('HNP', 'Phenotype', 'HP:0002864', (84, 87))	('SDH', 'Gene', (38, 41))
58262	33381322	Through genetic testing, the endocrinologist diagnosed the patient with hereditary paraganglioma-pheochromocytoma associated with mutation in SDHD gene.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (97, 113))	('mutation', 'Var', (130, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (83, 96))	('patient', 'Species', '9606', (59, 66))	('hereditary paraganglioma-pheochromocytoma', 'Disease', 'MESH:D010673', (72, 113))	('hereditary paraganglioma-pheochromocytoma', 'Disease', (72, 113))	('associated', 'Reg', (114, 124))	('SDHD', 'Gene', '6392', (142, 146))	('SDHD', 'Gene', (142, 146))
58277	33381322	Presurgery hospital medications included PO phenoxybenzamine 30 mg BID prior to surgery, metoprolol 75 mg BID, IV fluids 200 ml/hr, oxycodone 5 mg/10 mg, and lorazepam 2 mg PO once as needed.	('PO phenoxybenzamine', 'Var', (41, 60))	('BID', 'Gene', '637', (67, 70))	('BID', 'Gene', (67, 70))	('BID', 'Gene', '637', (106, 109))	('metoprolol', 'Chemical', 'MESH:D008790', (89, 99))	('oxycodone', 'Chemical', 'MESH:D010098', (132, 141))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (44, 60))	('lorazepam', 'Chemical', 'MESH:D008140', (158, 167))	('BID', 'Gene', (106, 109))
58278	33381322	Twenty-four hours prior to surgery the patient's blood pressure and heart rate ranges were (113-148)/(68-94) mmHg and (65-98) bpm, respectively.	('heart', 'MPA', (68, 73))	('patient', 'Species', '9606', (39, 46))	('113-148', 'Var', (92, 99))
58323	31362359	Such tumors also have a relationship with various other tumors, such as neuroblastomas, that also originate from the adrenal medulla and extra-adrenal sympathetic tissues as well as tumors co-occurring in various hereditary tumor syndromes, for instance, medullary thyroid carcinoma in MEN2, renal cell carcinoma in VHL disease, and gastrointestinal stromal tumors (GIST) in the context of succinate dehydrogenase subunit gene (collectively called SDHx) mutations.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (292, 312))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('VHL disease', 'Disease', (316, 327))	('neuroblastomas', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('tumors', 'Disease', (56, 62))	('hereditary tumor', 'Disease', (213, 229))	('tumors', 'Disease', (358, 364))	('neuroblastomas', 'Disease', 'MESH:D009447', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (333, 364))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (333, 364))	('hereditary tumor', 'Disease', 'MESH:D009386', (213, 229))	('tumors', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (358, 364))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (255, 282))	('MEN', 'Species', '9606', (286, 289))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (265, 282))	('succinate dehydrogenase', 'Gene', (390, 413))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (292, 312))	('thyroid carcinoma', 'Disease', (265, 282))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('SDHx', 'Chemical', '-', (448, 452))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('gastrointestinal stromal tumors', 'Disease', (333, 364))	('tumors', 'Disease', (5, 11))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (265, 282))	('GIST', 'Phenotype', 'HP:0100723', (366, 370))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('tumors', 'Phenotype', 'HP:0002664', (358, 364))	('VHL disease', 'Disease', 'MESH:D006623', (316, 327))	('succinate dehydrogenase', 'Gene', '6390', (390, 413))	('neuroblastomas', 'Phenotype', 'HP:0003006', (72, 86))	('mutations', 'Var', (454, 463))	('renal cell carcinoma', 'Disease', (292, 312))
58339	31362359	Cluster 1 is characterized by the pseudohypoxia pathway and includes, among others, PCC/PGL with VHL and SDHx mutations.	('SDHx', 'Chemical', '-', (105, 109))	('PGL', 'Phenotype', 'HP:0002668', (88, 91))	('VHL', 'Gene', '7428', (97, 100))	('mutations', 'Var', (110, 119))	('SDHx', 'Gene', (105, 109))	('PCC', 'Phenotype', 'HP:0002666', (84, 87))	('pseudohypoxia pathway', 'Pathway', (34, 55))	('VHL', 'Gene', (97, 100))
58340	31362359	Cluster 2 is characterized by activation of kinase signaling pathways and includes, among others, PCC/PGL with RET and NF1 gene mutations.	('mutations', 'Var', (128, 137))	('kinase signaling pathways', 'Pathway', (44, 69))	('PGL', 'Phenotype', 'HP:0002668', (102, 105))	('activation', 'PosReg', (30, 40))	('NF1', 'Gene', (119, 122))	('PCC', 'Phenotype', 'HP:0002666', (98, 101))	('NF1', 'Gene', '4763', (119, 122))	('RET', 'Gene', (111, 114))
58341	31362359	With the identification of new somatic drivers, including gene fusions, a new cluster 3 has been recognized, representing tumors with Wnt signaling activation.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('gene fusions', 'Var', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
58345	31362359	Furthermore, "disease modifying genes" have been recognized, including somatic mutations in ATRX, which mostly co-exist with mutations in SDHB or IDH1/2, with a suggested synergistic effect on tumorigenesis and tumor progression.	('SDHB', 'Gene', (138, 142))	('mutations', 'Var', (125, 134))	('ATRX', 'Gene', (92, 96))	('IDH1/2', 'Gene', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('ATRX', 'Gene', '546', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('IDH1/2', 'Gene', '3417;3418', (146, 152))	('tumor', 'Disease', (193, 198))	('SDHB', 'Gene', '6390', (138, 142))	('mutations', 'Var', (79, 88))
58346	31362359	We will focus on the driver mutations in Clusters 1 and 2, discuss the most common members with special attention to the SDHx family, and highlight some recently identified gene mutations, as seen in Table 1.	('SDHx', 'Chemical', '-', (121, 125))	('mutations', 'Var', (178, 187))	('mutations', 'Var', (28, 37))
58347	31362359	This cluster represents germline or somatic gene mutations resulting in a dysfunctional hypoxic (pseudo-hypoxic) response with a central role for hypoxia inducible factor (HIF)1 alpha and HIF2 alpha, which are the main components of the response to low oxygen levels.	('mutations', 'Var', (49, 58))	('HIF2 alpha', 'Gene', '2034', (188, 198))	('resulting in', 'Reg', (59, 71))	('oxygen', 'Chemical', 'MESH:D010100', (253, 259))	('dysfunctional hypoxic', 'Disease', (74, 95))	('HIF2 alpha', 'Gene', (188, 198))	('dysfunctional hypoxic', 'Disease', 'MESH:D000860', (74, 95))	('hypoxia inducible factor (HIF)1 alpha', 'Gene', '3091', (146, 183))	('low oxygen levels', 'Phenotype', 'HP:0012418', (249, 266))
58350	31362359	The VHL/EPAS1-related subgroup includes mutations in genes directly involved in activation of the HIF signaling pathway such as VHL germline (g), somatic (s), EPAS1/HIF2 alpha (g,s) and EGLN1/2 (g).	('EPAS1', 'Gene', (8, 13))	('VHL', 'Gene', '7428', (128, 131))	('EGLN1/2', 'Gene', '54583;112398', (186, 193))	('VHL', 'Gene', '7428', (4, 7))	('EGLN1/2', 'Gene', (186, 193))	('HIF signaling pathway', 'Pathway', (98, 119))	('EPAS1', 'Gene', '2034', (159, 164))	('mutations', 'Var', (40, 49))	('HIF2 alpha', 'Gene', '2034', (165, 175))	('VHL', 'Gene', (4, 7))	('EPAS1', 'Gene', (159, 164))	('HIF2 alpha', 'Gene', (165, 175))	('EPAS1', 'Gene', '2034', (8, 13))	('VHL', 'Gene', (128, 131))
58351	31362359	The TCA-cycle-related subgroup includes mutations in genes encoding energy metabolism enzymes such as SDHx (g), FH (g), MDH2 (g) and IDH1/2 (s).	('MDH2', 'Gene', '4191', (120, 124))	('MDH2', 'Gene', (120, 124))	('SDHx', 'Chemical', '-', (102, 106))	('SDHx', 'Gene', (102, 106))	('TCA', 'Chemical', 'MESH:D014238', (4, 7))	('mutations', 'Var', (40, 49))	('IDH1/2', 'Gene', (133, 139))	('TCA-cycle-related', 'Disease', (4, 21))	('IDH1/2', 'Gene', '3417;3418', (133, 139))
58352	31362359	Inactivating mutations lead to an accumulation of TCA metabolites causing epigenetic changes in HIF stability and are associated with a hypermethylated phenotype.	('epigenetic changes', 'MPA', (74, 92))	('accumulation', 'PosReg', (34, 46))	('Inactivating mutations', 'Var', (0, 22))	('associated', 'Reg', (118, 128))	('TCA metabolites', 'MPA', (50, 65))	('TCA', 'Chemical', 'MESH:D014238', (50, 53))
58355	31362359	The VHL gene is known to cause von Hippel-Lindau (VHL) disease, an autosomal dominant familial tumor syndrome characterized by multiple benign and malignant tumors including retinal and central nervous system hemangioblastomas, renal cysts, clear cell renal cell carcinomas (RCC), pancreatic cysts, pancreatic neuroendocrine tumors, endolymphatic sac tumors, and epididymal cystadenomas.	('endolymphatic sac tumors', 'Disease', 'MESH:D036821', (333, 357))	('renal cysts', 'Phenotype', 'HP:0000107', (228, 239))	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (241, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('pancreatic cysts', 'Disease', (281, 297))	('carcinomas', 'Phenotype', 'HP:0030731', (263, 273))	('renal cysts', 'Disease', 'MESH:D007674', (228, 239))	('clear cell renal cell carcinomas', 'Disease', (241, 273))	('epididymal cystadenomas', 'Disease', (363, 386))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (281, 297))	('cause', 'Reg', (25, 30))	('malignant tumors', 'Disease', 'MESH:D018198', (147, 163))	('retinal and central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (174, 226))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('RCC', 'Disease', 'MESH:C538614', (275, 278))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('autosomal dominant familial tumor syndrome', 'Disease', (67, 109))	('epididymal cystadenomas', 'Disease', 'MESH:D003537', (363, 386))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (252, 273))	('malignant tumors', 'Disease', (147, 163))	('VHL', 'Gene', (4, 7))	('endolymphatic sac tumors', 'Phenotype', 'HP:0030393', (333, 357))	('epididymal cystadenomas', 'Phenotype', 'HP:0030424', (363, 386))	('VHL', 'Gene', (50, 53))	('autosomal dominant familial tumor syndrome', 'Disease', 'MESH:D030342', (67, 109))	('tumors', 'Phenotype', 'HP:0002664', (351, 357))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (299, 331))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (241, 273))	('von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (31, 62))	('pancreatic cysts', 'Disease', 'MESH:D010181', (281, 297))	('gene', 'Var', (8, 12))	('VHL', 'Gene', '7428', (4, 7))	('endolymphatic sac tumors', 'Disease', (333, 357))	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (194, 226))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('pancreatic neuroendocrine tumors', 'Disease', (299, 331))	('VHL', 'Gene', '7428', (50, 53))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (252, 272))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (310, 331))	('renal cysts', 'Disease', (228, 239))	('RCC', 'Disease', (275, 278))	('RCC', 'Phenotype', 'HP:0005584', (275, 278))	('endocrine tumor', 'Phenotype', 'HP:0100568', (315, 330))
58356	31362359	VHL disease shows a genotype-phenotype correlation; VHL type 2 is characterized by missense mutations and is linked to PCC, which is observed in 10-26% of VHL patients.	('VHL disease', 'Disease', (0, 11))	('VHL', 'Gene', '7428', (52, 55))	('VHL', 'Gene', '7428', (155, 158))	('PCC', 'Phenotype', 'HP:0002666', (119, 122))	('missense mutations', 'Var', (83, 101))	('PCC', 'Disease', (119, 122))	('VHL', 'Gene', (0, 3))	('VHL disease', 'Disease', 'MESH:D006623', (0, 11))	('VHL', 'Gene', (52, 55))	('linked', 'Reg', (109, 115))	('VHL', 'Gene', '7428', (0, 3))	('patients', 'Species', '9606', (159, 167))	('VHL', 'Gene', (155, 158))
58357	31362359	Germline mutations in VHL account for 5-10% of hereditary PCC/PGL, and somatic VHL mutations have been found in about 10% of sporadic PCC/PGL.	('Germline mutations', 'Var', (0, 18))	('VHL', 'Gene', '7428', (79, 82))	('VHL', 'Gene', (22, 25))	('VHL', 'Gene', '7428', (22, 25))	('PGL', 'Phenotype', 'HP:0002668', (62, 65))	('PCC', 'Phenotype', 'HP:0002666', (58, 61))	('PGL', 'Phenotype', 'HP:0002668', (138, 141))	('PCC/PGL', 'Disease', (58, 65))	('PCC', 'Phenotype', 'HP:0002666', (134, 137))	('VHL', 'Gene', (79, 82))
58358	31362359	The EPAS1/HIF2 alpha gene encodes for HIF2 alpha and mutations lead to its reduced degradation and stabilization.	('degradation', 'MPA', (83, 94))	('EPAS1', 'Gene', '2034', (4, 9))	('HIF2 alpha', 'Gene', '2034', (38, 48))	('EPAS1', 'Gene', (4, 9))	('stabilization', 'MPA', (99, 112))	('mutations', 'Var', (53, 62))	('reduced', 'NegReg', (75, 82))	('HIF2 alpha', 'Gene', '2034', (10, 20))	('HIF2 alpha', 'Gene', (38, 48))	('HIF2 alpha', 'Gene', (10, 20))
58359	31362359	Somatic EPAS1/HIF2 alpha mutations have been found in 5-10% of PCC/PGL.	('HIF2 alpha', 'Gene', (14, 24))	('mutations', 'Var', (25, 34))	('EPAS1', 'Gene', (8, 13))	('HIF2 alpha', 'Gene', '2034', (14, 24))	('PCC/PGL', 'Disease', (63, 70))	('PGL', 'Phenotype', 'HP:0002668', (67, 70))	('PCC', 'Phenotype', 'HP:0002666', (63, 66))	('EPAS1', 'Gene', '2034', (8, 13))	('found', 'Reg', (45, 50))
58360	31362359	EPAS1/HIF2 alpha mutations are also linked to polycythemia and somatostinoma.	('EPAS1', 'Gene', '2034', (0, 5))	('EPAS1', 'Gene', (0, 5))	('HIF2 alpha', 'Gene', '2034', (6, 16))	('linked', 'Reg', (36, 42))	('HIF2 alpha', 'Gene', (6, 16))	('mutations', 'Var', (17, 26))	('polycythemia and somatostinoma', 'Disease', 'MESH:D011086', (46, 76))	('polycythemia', 'Phenotype', 'HP:0001901', (46, 58))
58364	31362359	Mutations in the SDHx family are currently the most common germline mutations found in hereditary PCC/PGL and account for about 20-30% of hereditary cases.	('PGL', 'Phenotype', 'HP:0002668', (102, 105))	('SDHx', 'Chemical', '-', (17, 21))	('SDHx', 'Gene', (17, 21))	('PCC', 'Phenotype', 'HP:0002666', (98, 101))	('Mutations', 'Var', (0, 9))	('PCC/PGL', 'Disease', (98, 105))
58365	31362359	SDHx-related PCC/PGL are caused by mutations in five genes of the SDHx family, SDHA, SDHB, SDHC, SDHD, and SDHAF2, which encode the corresponding proteins.	('SDHA', 'Gene', '6389', (107, 111))	('SDHx-related PCC/PGL', 'Disease', (0, 20))	('SDHC', 'Gene', '6391', (91, 95))	('PCC/PGL', 'Disease', (13, 20))	('SDHD', 'Gene', (97, 101))	('SDHA', 'Gene', (79, 83))	('SDHB', 'Gene', '6390', (85, 89))	('SDHx', 'Gene', (66, 70))	('SDHA', 'Gene', '6389', (79, 83))	('caused by', 'Reg', (25, 34))	('SDHC', 'Gene', (91, 95))	('SDHB', 'Gene', (85, 89))	('PCC', 'Phenotype', 'HP:0002666', (13, 16))	('SDHx', 'Chemical', '-', (66, 70))	('SDHAF2', 'Gene', '54949', (107, 113))	('SDHAF2', 'Gene', (107, 113))	('PGL', 'Phenotype', 'HP:0002668', (17, 20))	('SDHA', 'Gene', (107, 111))	('SDHx', 'Chemical', '-', (0, 4))	('SDHD', 'Gene', '6392', (97, 101))	('mutations', 'Var', (35, 44))
58370	31362359	Mutations in the SDHx family are predominantly linked to extra-adrenal PGLs.	('extra-adrenal PGLs', 'Disease', (57, 75))	('SDHx', 'Chemical', '-', (17, 21))	('SDHx', 'Gene', (17, 21))	('Mutations', 'Var', (0, 9))	('linked', 'Reg', (47, 53))	('PGL', 'Phenotype', 'HP:0002668', (71, 74))
58371	31362359	SDHB mutations are associated with abdominal and thoracic PGL and show a 30-70% risk of metastasis.	('associated', 'Reg', (19, 29))	('metastasis', 'CPA', (88, 98))	('PGL', 'Phenotype', 'HP:0002668', (58, 61))	('mutations', 'Var', (5, 14))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))
58372	31362359	SDHD and SDHA mutations are mostly found in abdominal, thoracic, head, and neck PGLs.	('abdominal', 'Disease', (44, 53))	('SDHA', 'Gene', '6389', (9, 13))	('SDHD', 'Gene', '6392', (0, 4))	('SDHA', 'Gene', (9, 13))	('head', 'Disease', (65, 69))	('SDHD', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('PGL', 'Phenotype', 'HP:0002668', (80, 83))
58373	31362359	SDHC and SDHAF2 mutations are associated with head and neck PGLs.	('associated', 'Reg', (30, 40))	('PGL', 'Phenotype', 'HP:0002668', (60, 63))	('SDHC', 'Gene', (0, 4))	('SDHAF2', 'Gene', '54949', (9, 15))	('mutations', 'Var', (16, 25))	('SDHC', 'Gene', '6391', (0, 4))	('SDHAF2', 'Gene', (9, 15))
58374	31362359	Mutations in the SDHD and SDHAF2 genes, both located on chromosome 11, show a parent-of-origin-dependent inheritance effect in which mutations almost exclusively cause disease after paternal transmission.	('SDHD', 'Gene', '6392', (17, 21))	('Mutations', 'Var', (0, 9))	('SDHD', 'Gene', (17, 21))	('mutations', 'Var', (133, 142))	('cause', 'Reg', (162, 167))	('SDHAF2', 'Gene', '54949', (26, 32))	('SDHAF2', 'Gene', (26, 32))	('disease', 'Disease', (168, 175))
58375	31362359	Mutations in the SDHx family have also been associated with other tumors such as SDH-deficient GIST, SDH-deficient RCC, and SDH-deficient pituitary adenoma.	('associated', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('GIST', 'Phenotype', 'HP:0100723', (95, 99))	('SDHx', 'Chemical', '-', (17, 21))	('deficient pituitary adenoma', 'Phenotype', 'HP:0010627', (128, 155))	('tumors', 'Disease', (66, 72))	('SDHx', 'Gene', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('SDH-deficient GIST, SDH-deficient RCC', 'Disease', 'MESH:C538614', (81, 118))	('Mutations', 'Var', (0, 9))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (138, 155))	('SDH-deficient pituitary adenoma', 'Disease', (124, 155))	('SDH-deficient pituitary adenoma', 'Disease', 'MESH:D010911', (124, 155))
58376	31362359	If the SDH complex becomes instable by dysfunction of any of the components, the SDHB subunit is degraded in the cytoplasm.	('degraded', 'NegReg', (97, 105))	('SDH', 'Gene', (7, 10))	('SDHB', 'Gene', '6390', (81, 85))	('SDH', 'Gene', '6390', (81, 84))	('SDHB', 'Gene', (81, 85))	('SDH', 'Gene', '6390', (7, 10))	('dysfunction', 'Var', (39, 50))	('SDH', 'Gene', (81, 84))
58377	31362359	The loss of SDHB expression can be detected by SDHB protein immunohistochemistry (IHC); this can be used to detect tumors with mutations in one of the five genes.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SDHB', 'Gene', '6390', (12, 16))	('expression', 'MPA', (17, 27))	('SDHB', 'Gene', (12, 16))	('SDHB', 'Gene', '6390', (47, 51))	('SDHB', 'Gene', (47, 51))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (127, 136))	('loss', 'NegReg', (4, 8))
58378	31362359	In addition, loss of SDHA IHC can detect tumors with SDHA germline mutations.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SDHA', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('SDHA', 'Gene', '6389', (53, 57))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('loss', 'Var', (13, 17))	('SDHA', 'Gene', '6389', (21, 25))	('SDHA', 'Gene', (53, 57))
58381	31362359	SDHB IHC positivity comprises granular cytoplasmatic staining with the same intensity as the internal positive control cells (non-tumoral cells, e.g., lymphocytes, endothelial cells, fibroblasts).	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('granular cytoplasmatic staining', 'MPA', (30, 61))	('positivity', 'Var', (9, 19))	('SDHB', 'Gene', '6390', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('SDHB', 'Gene', (0, 4))
58387	31362359	Mutant FH results in accumulation of fumarate leading to PHD inactivation and HIF stabilization.	('accumulation', 'PosReg', (21, 33))	('PHD', 'Disease', 'MESH:D011547', (57, 60))	('fumarate', 'Chemical', 'MESH:D005650', (37, 45))	('PHD', 'Disease', (57, 60))	('fumarate', 'MPA', (37, 45))	('HIF stabilization', 'CPA', (78, 95))	('Mutant', 'Var', (0, 6))	('inactivation', 'NegReg', (61, 73))
58388	31362359	Mutations in this gene have classically been associated with hereditary cutaneous and uterine leiomyomatosis and a specific variant of RCC, which is regarded as a separate entity by the WHO.	('leiomyomatosis', 'Disease', (94, 108))	('uterine leiomyomatosis', 'Phenotype', 'HP:0000131', (86, 108))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('RCC', 'Disease', 'MESH:C538614', (135, 138))	('RCC', 'Disease', (135, 138))	('associated', 'Reg', (45, 55))	('Mutations', 'Var', (0, 9))	('leiomyomatosis', 'Disease', 'MESH:D018231', (94, 108))	('cutaneous and uterine leiomyomatosis', 'Phenotype', 'HP:0007620', (72, 108))
58389	31362359	In addition, low tumor levels of 5-hmC (resembling those in SDHB-deficient tumors) and positive 2SC staining have been detected in tumors with FH mutations, suggestive of altered DNA methylation and protein succination, respectively.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('SDHB-deficient tumors', 'Disease', (60, 81))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('low tumor', 'Disease', (13, 22))	('mutations', 'Var', (146, 155))	('SDHB-deficient tumors', 'Disease', 'MESH:D009369', (60, 81))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('altered', 'Reg', (171, 178))	('low tumor', 'Disease', 'MESH:D009800', (13, 22))
58393	31362359	Mutations result in the production of 2-hydroxyglutarate instead of alpha-ketoglutarate, and its accumulation activates the hypoxic pathway.	('2-hydroxyglutarate', 'MPA', (38, 56))	('accumulation activates', 'PosReg', (97, 119))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (68, 87))	('Mutations', 'Var', (0, 9))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (38, 56))	('hypoxic pathway', 'Pathway', (124, 139))
58394	31362359	Somatic IDH1 and IDH2 mutations are typically present in low-grade and secondary high-grade gliomas and have rarely been found in PGLs.	('IDH1', 'Gene', (8, 12))	('low-grade', 'Disease', (57, 66))	('IDH2', 'Gene', '3418', (17, 21))	('PGL', 'Phenotype', 'HP:0002668', (130, 133))	('IDH2', 'Gene', (17, 21))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Disease', (92, 99))	('IDH1', 'Gene', '3417', (8, 12))	('mutations', 'Var', (22, 31))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('present', 'Reg', (46, 53))
58396	31362359	The SLC25A11 gene encodes the mitochondrial 2-oxoglutarate/malate carrier and germline mutations have been identified in abdominal as well as head and neck PGLs and may be associated with metastases.	('2-oxoglutarate', 'Chemical', 'MESH:D007656', (44, 58))	('identified', 'Reg', (107, 117))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('associated', 'Reg', (172, 182))	('PGL', 'Phenotype', 'HP:0002668', (156, 159))	('abdominal', 'Disease', (121, 130))	('SLC25A11', 'Gene', '8402', (4, 12))	('metastases', 'Disease', (188, 198))	('malate', 'Chemical', 'MESH:C030298', (59, 65))	('SLC25A11', 'Gene', (4, 12))	('mutations', 'Var', (87, 96))
58401	31362359	In addition, positive DLST immunostaining was detected in tumors with TCA-cycle or EPAS1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TCA-cycle', 'Gene', (70, 79))	('DLST', 'Gene', (22, 26))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('EPAS1', 'Gene', '2034', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('EPAS1', 'Gene', (83, 88))	('mutations', 'Var', (89, 98))	('TCA', 'Chemical', 'MESH:D014238', (70, 73))	('DLST', 'Gene', '1743', (22, 26))
58402	31362359	It encompasses germline or somatic mutations in RET (g/s), NF1 (g/s), MAX (g/s), MEN1 (g), TMEM127 (g), H-RAS (s), and KIF1B (g/s).	('KIF1B', 'Gene', (119, 124))	('RET', 'Gene', (48, 51))	('KIF1B', 'Gene', '23095', (119, 124))	('H-RAS', 'Gene', (104, 109))	('TMEM127', 'Gene', (91, 98))	('TMEM127', 'Gene', '55654', (91, 98))	('H-RAS', 'Gene', '3265', (104, 109))	('NF1', 'Gene', (59, 62))	('MEN1', 'Gene', '4221', (81, 85))	('MEN1', 'Gene', (81, 85))	('NF1', 'Gene', '4763', (59, 62))	('mutations', 'Var', (35, 44))
58403	31362359	These mutations are associated with the activation of the RAS-RAF-ERK, PI3K-AKT-mTOR (RET, HRAS, NF1, TMEM127, KIF1B), and MYC-MAX (MAX) kinase signaling pathways.	('RAF', 'Gene', (62, 65))	('HRAS', 'Gene', (91, 95))	('NF1', 'Gene', (97, 100))	('NF1', 'Gene', '4763', (97, 100))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('KIF1B', 'Gene', (111, 116))	('TMEM127', 'Gene', '55654', (102, 109))	('activation', 'PosReg', (40, 50))	('KIF1B', 'Gene', '23095', (111, 116))	('ERK', 'Gene', '2048', (66, 69))	('HRAS', 'Gene', '3265', (91, 95))	('TMEM127', 'Gene', (102, 109))	('RAF', 'Gene', '22882', (62, 65))	('mutations', 'Var', (6, 15))	('ERK', 'Gene', (66, 69))
58404	31362359	Activating germline mutations in the RET gene cause the multiple endocrine neoplasia type 2 (MEN2) syndrome characterized by the development of PCC and medullary thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (162, 179))	('Activating', 'PosReg', (0, 10))	('RET', 'Gene', (37, 40))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (152, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('multiple endocrine neoplasia type 2 (MEN2) syndrome', 'Disease', 'MESH:D018813', (56, 107))	('thyroid carcinoma', 'Disease', (162, 179))	('neoplasia', 'Phenotype', 'HP:0002664', (75, 84))	('PCC', 'Phenotype', 'HP:0002666', (144, 147))	('germline mutations', 'Var', (11, 29))	('cause', 'Reg', (46, 51))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (162, 179))	('PCC', 'Disease', (144, 147))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (65, 84))
58405	31362359	PCC occur in 40-50% of patients with MEN2 and the risk of PCC is associated with specific RET mutations.	('MEN', 'Species', '9606', (37, 40))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (23, 31))	('PCC', 'Phenotype', 'HP:0002666', (58, 61))	('PCC', 'Phenotype', 'HP:0002666', (0, 3))	('PCC', 'Disease', (58, 61))	('PCC', 'Disease', (0, 3))
58407	31362359	Germline RET mutations have been detected in 5% of hereditary PCC/PGL and somatic mutations in about 5% of sporadic tumors.	('sporadic tumors', 'Disease', (107, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('detected', 'Reg', (33, 41))	('PGL', 'Phenotype', 'HP:0002668', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('sporadic tumors', 'Disease', 'MESH:D009369', (107, 122))	('PCC', 'Phenotype', 'HP:0002666', (62, 65))	('mutations', 'Var', (13, 22))	('PCC/PGL', 'Disease', (62, 69))
58409	31362359	Inactivating mutations in the NF1 gene disrupt this inhibitory effect.	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('Inactivating mutations', 'Var', (0, 22))	('disrupt', 'NegReg', (39, 46))	('inhibitory effect', 'MPA', (52, 69))
58411	31362359	However, only approximately 6% of patients with the autosomal dominant NF1 syndrome, characterized by germline NF1 mutations, develop PCC, and germline mutations account for <5% of all PCC/PGL.	('NF1', 'Gene', (111, 114))	('mutations', 'Var', (115, 124))	('autosomal dominant NF1 syndrome', 'Disease', (52, 83))	('NF1', 'Gene', (71, 74))	('NF1', 'Gene', '4763', (111, 114))	('develop', 'Reg', (126, 133))	('NF1', 'Gene', '4763', (71, 74))	('autosomal dominant NF1 syndrome', 'Disease', 'MESH:C537392', (52, 83))	('PGL', 'Phenotype', 'HP:0002668', (189, 192))	('PCC', 'Disease', (134, 137))	('patients', 'Species', '9606', (34, 42))	('PCC', 'Phenotype', 'HP:0002666', (134, 137))	('PCC', 'Phenotype', 'HP:0002666', (185, 188))	('PCC/PGL', 'Disease', (185, 192))
58416	31362359	Truncated MAX mutations can cause dysregulation of the mTOR pathway.	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('MAX', 'Gene', (10, 13))	('cause', 'Reg', (28, 33))	('dysregulation', 'MPA', (34, 47))	('Truncated', 'Var', (0, 9))	('mutations', 'Var', (14, 23))
58417	31362359	Although MAX IHC has been described in the literature, with the potential to detect MAX mutations in patients in case of absent immunostaining, comparable to negative SDHB staining, this has not found widespread application.	('patients', 'Species', '9606', (101, 109))	('SDHB', 'Gene', '6390', (167, 171))	('mutations', 'Var', (88, 97))	('SDHB', 'Gene', (167, 171))	('MAX', 'Gene', (84, 87))
58421	31362359	In addition to its transport function, KIF1B beta plays a role in apoptosis and dysfunctional KIF1B beta due to mutations in the KIF1B gene and can lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('dysfunctional', 'Disease', (80, 93))	('dysfunctional', 'Disease', 'MESH:D006331', (80, 93))	('KIF1B', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', (156, 161))	('KIF1B', 'Gene', '23095', (94, 99))	('KIF1B', 'Gene', (39, 44))	('KIF1B', 'Gene', (129, 134))	('KIF1B', 'Gene', '23095', (39, 44))	('KIF1B', 'Gene', '23095', (129, 134))	('lead to', 'Reg', (148, 155))
58423	31362359	KIF1B mutant PCC/PGL shows a similar transcription profile as RET and NF1 mutant PCC/PGL.	('KIF1B', 'Gene', (0, 5))	('mutant', 'Var', (6, 12))	('NF1', 'Gene', '4763', (70, 73))	('PGL', 'Phenotype', 'HP:0002668', (85, 88))	('KIF1B', 'Gene', '23095', (0, 5))	('PCC', 'Phenotype', 'HP:0002666', (81, 84))	('PGL', 'Phenotype', 'HP:0002668', (17, 20))	('PCC', 'Phenotype', 'HP:0002666', (13, 16))	('mutant', 'Var', (74, 80))	('NF1', 'Gene', (70, 73))
58427	31362359	Germline mutations in the MEN1 gene lead to MEN1 syndrome, characterized by various types of endocrine and non-endocrine tumors, including pituitary adenomas, hyperplastic parathyroids, and neuroendocrine pancreatic tumors, with a high penetrance of disease but PCC/PGL are rare and account for <1% of PCC/PGL.	('Germline mutations', 'Var', (0, 18))	('MEN1 syndrome', 'Disease', 'MESH:D018761', (44, 57))	('neuroendocrine pancreatic tumors', 'Disease', 'MESH:D018358', (190, 222))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (205, 222))	('MEN1', 'Gene', (26, 30))	('non-endocrine tumors', 'Disease', 'MESH:C536126', (107, 127))	('hyperplastic parathyroids', 'Phenotype', 'HP:0008208', (159, 184))	('lead to', 'Reg', (36, 43))	('pituitary adenomas', 'Disease', 'MESH:D010911', (139, 157))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (139, 157))	('neuroendocrine pancreatic tumors', 'Disease', (190, 222))	('MEN1', 'Gene', '4221', (44, 48))	('pituitary adenomas', 'Disease', (139, 157))	('PCC', 'Phenotype', 'HP:0002666', (262, 265))	('PGL', 'Phenotype', 'HP:0002668', (266, 269))	('PCC', 'Phenotype', 'HP:0002666', (302, 305))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('PGL', 'Phenotype', 'HP:0002668', (306, 309))	('MEN1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (139, 156))	('non-endocrine tumors', 'Disease', (107, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MEN1 syndrome', 'Disease', (44, 57))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('endocrine tumor', 'Phenotype', 'HP:0100568', (111, 126))	('MEN1', 'Gene', '4221', (26, 30))
58438	31362359	However, significant interobserver and intraobserver variability is described in scoring the presence or absence of high cellularity, nuclear pleomorphism, and hyperchromasia.	('high', 'Protein', (116, 120))	('nuclear pleomorphism', 'Var', (134, 154))	('hyperchromasia', 'Disease', (160, 174))	('hyperchromasia', 'Disease', 'None', (160, 174))
58453	31362359	Recurrence and metastases are strongly associated with SDHB mutations; the presence of SDHB mutations should be considered a risk factor for metastases or recurrence.	('SDHB', 'Gene', (55, 59))	('metastases', 'Disease', (15, 25))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('mutations', 'Var', (92, 101))	('Recurrence', 'CPA', (0, 10))	('metastases', 'Disease', 'MESH:D009362', (15, 25))	('associated', 'Reg', (39, 49))	('SDHB', 'Gene', '6390', (55, 59))	('mutations', 'Var', (60, 69))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))	('metastases', 'Disease', (141, 151))
58454	31362359	As described above, SDHB IHC is a strong indication for tumors with SDHx mutations.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SDHx', 'Chemical', '-', (68, 72))	('SDHx', 'Gene', (68, 72))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SDHB', 'Gene', '6390', (20, 24))	('mutations', 'Var', (73, 82))	('SDHB', 'Gene', (20, 24))
58455	31362359	Loss of SDHB staining is not seen either in prognostically unfavorable SDHB-mutated tumors or in all tumors with SDHx mutations; however, SDHB IHC negativity by itself has also been correlated with metastases.	('SDHB', 'Gene', '6390', (8, 12))	('SDHB', 'Gene', '6390', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('SDHx', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SDHB', 'Gene', (8, 12))	('SDHB', 'Gene', (71, 75))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('SDHB', 'Gene', '6390', (138, 142))	('SDHx', 'Chemical', '-', (113, 117))	('metastases', 'Disease', (198, 208))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('correlated', 'Reg', (182, 192))	('tumors', 'Disease', (101, 107))	('SDHB', 'Gene', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
58458	31362359	Additionally, MAML3 fusion gene variants, leading to Wnt signaling upregulation, as seen in Cluster 3, described above, are associated with metastases.	('MAML3', 'Gene', '55534', (14, 19))	('MAML3', 'Gene', (14, 19))	('metastases', 'Disease', (140, 150))	('associated', 'Reg', (124, 134))	('upregulation', 'PosReg', (67, 79))	('variants', 'Var', (32, 40))	('Wnt signaling', 'MPA', (53, 66))	('metastases', 'Disease', 'MESH:D009362', (140, 150))
58459	31362359	In the same study, Ki67 was found to be correlated with metastatic disease.	('metastatic', 'Disease', (56, 66))	('Ki67', 'Chemical', '-', (19, 23))	('correlated', 'Reg', (40, 50))	('Ki67', 'Var', (19, 23))
58460	31362359	Interestingly, the tumor with the highest Ki67 expression was MAML3 fusion-positive.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Ki67', 'Var', (42, 46))	('Ki67', 'Chemical', '-', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MAML3', 'Gene', '55534', (62, 67))	('MAML3', 'Gene', (62, 67))	('tumor', 'Disease', (19, 24))	('expression', 'MPA', (47, 57))
58462	31362359	Fourteen PGL, six metastatic and eight non-metastatic, as well as two distant metastases were significantly methylated at one or more of the following gene promoters, RASSF1A, NORE1A, p16INK4A, RARB, DCR2, CDH1, and APC.	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('RASSF1A', 'Gene', (167, 174))	('p16INK4A', 'Gene', (184, 192))	('NORE1A', 'Gene', '83593', (176, 182))	('PGL', 'Phenotype', 'HP:0002668', (9, 12))	('p16INK4A', 'Gene', '1029', (184, 192))	('DCR2', 'Gene', (200, 204))	('CDH1', 'Gene', '999', (206, 210))	('RASSF1A', 'Gene', '11186', (167, 174))	('RARB', 'Gene', (194, 198))	('APC', 'Disease', 'MESH:D011125', (216, 219))	('APC', 'Disease', (216, 219))	('methylated', 'Var', (108, 118))	('NORE1A', 'Gene', (176, 182))	('metastases', 'Disease', (78, 88))	('RARB', 'Gene', '5915', (194, 198))	('DCR2', 'Gene', '8793', (200, 204))	('CDH1', 'Gene', (206, 210))
58466	31362359	Whole exome sequencing is expected to become the standard of genetic analysis in the next 5-10 years, allowing rapid detection of mutations in PCC and PGL patients and families.	('PCC', 'Gene', (143, 146))	('PGL', 'Phenotype', 'HP:0002668', (151, 154))	('mutations', 'Var', (130, 139))	('patients', 'Species', '9606', (155, 163))	('PCC', 'Phenotype', 'HP:0002666', (143, 146))	('PGL', 'Gene', (151, 154))
58469	31362359	In addition, a modified GAPP (M-GAPP) has been proposed, incorporating loss of SDHB staining as a criterion, which seems logical in light of the increased metastatic risk related to SDHB mutations.	('SDHB', 'Gene', (182, 186))	('GAPP', 'Chemical', '-', (24, 28))	('mutations', 'Var', (187, 196))	('SDHB', 'Gene', '6390', (79, 83))	('SDHB', 'Gene', '6390', (182, 186))	('GAPP', 'Chemical', '-', (32, 36))	('SDHB', 'Gene', (79, 83))
58470	31362359	However, the loss of SDHB staining occurs with all SDHx mutations, and increased risk has not been noted for SDHA, SDHC, and SDHD mutations.	('mutations', 'Var', (56, 65))	('SDHA', 'Gene', '6389', (109, 113))	('SDHC', 'Gene', '6391', (115, 119))	('SDHx', 'Gene', (51, 55))	('SDHB', 'Gene', '6390', (21, 25))	('SDHD', 'Gene', '6392', (125, 129))	('SDHx', 'Chemical', '-', (51, 55))	('loss', 'NegReg', (13, 17))	('SDHC', 'Gene', (115, 119))	('SDHB', 'Gene', (21, 25))	('SDHA', 'Gene', (109, 113))	('SDHD', 'Gene', (125, 129))
58538	31078058	To evaluate the acute radiation-related toxicity of 211At-MABG, we conducted biodistribution and dosimetry studies of 211At-MABG in ICR mice to estimate the doses absorbed by organs.	('mice', 'Species', '10090', (136, 140))	('toxicity', 'Disease', (40, 48))	('211At-MABG', 'Var', (118, 128))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))
58541	31078058	The administration of 1.1, 2.2, and 3.3 MBq of 211At-MABG induced transient body weight loss, and 4.4 MBq of 211At-MABG induced unrecoverable body weight loss; thus, the MTD was 3.3 MBq for ICR mice.	('weight loss', 'Phenotype', 'HP:0001824', (81, 92))	('weight loss', 'Phenotype', 'HP:0001824', (147, 158))	('body weight loss', 'Disease', 'MESH:D015431', (142, 158))	('body weight loss', 'Disease', 'MESH:D015431', (76, 92))	('body weight loss', 'Disease', (142, 158))	('mice', 'Species', '10090', (194, 198))	('body weight loss', 'Disease', (76, 92))	('211At-MABG', 'Var', (47, 57))
58549	31078058	Chemotherapy with cyclophosphamide, vincristine, and dacarbazine has a limited duration of effects and confers no survival benefits, whereas 131I-MIBG prolongs survival.	('dacarbazine', 'Chemical', 'MESH:D003606', (53, 64))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (18, 34))	('131I-MIBG', 'Chemical', '-', (141, 150))	('prolongs', 'PosReg', (151, 159))	('131I-MIBG', 'Var', (141, 150))	('vincristine', 'Chemical', 'MESH:D014750', (36, 47))
58554	31078058	We previously demonstrated strong antitumor effects of 211At-MABG in nude mice bearing pheochromocytoma xenograft tumors, suggesting potential efficacy of 211At-MABG as a new therapeutic option for malignant pheochromocytoma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (87, 103))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (198, 224))	('malignant pheochromocytoma', 'Disease', (198, 224))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (208, 224))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('211At-MABG', 'Var', (155, 165))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('pheochromocytoma xenograft tumors', 'Disease', 'MESH:D010673', (87, 120))	('nude mice', 'Species', '10090', (69, 78))	('pheochromocytoma xenograft tumors', 'Disease', (87, 120))
58559	31078058	Therefore, surrogate imaging probes such as 123I-MIBG and 131I-MIBG would be appropriate for dosimetry in patients.	('131I-MIBG', 'Chemical', '-', (58, 67))	('123I-MIBG', 'Var', (44, 53))	('123I-MIBG', 'Chemical', '-', (44, 53))	('patients', 'Species', '9606', (106, 114))	('131I-MIBG', 'Var', (58, 67))
58563	31078058	Therefore, it is important to evaluate whether 211At-MABG induces unexpected radiation-related toxicity before performing first-in-human studies.	('human', 'Species', '9606', (131, 136))	('211At-MABG', 'Var', (47, 57))	('toxicity', 'Disease', 'MESH:D064420', (95, 103))	('toxicity', 'Disease', (95, 103))
58565	31078058	We additionally determined the maximum tolerated dose (MTD) of 211At-MABG for ICR mice on the basis of body weight loss and assessed the acute radiotoxicity induced by MTD on the basis of organ weights, histologic features, hematologic indices, and biochemical indices.	('mice', 'Species', '10090', (82, 86))	('acute radiotoxicity', 'Disease', (137, 156))	('body weight loss', 'Disease', 'MESH:D015431', (103, 119))	('211At-MABG', 'Var', (63, 73))	('body weight loss', 'Disease', (103, 119))	('weight loss', 'Phenotype', 'HP:0001824', (108, 119))	('acute radiotoxicity', 'Disease', 'MESH:D059787', (137, 156))
58590	31078058	Although the plasma T3 concentration in the 211At-MABG treatment group was higher than that in the control group at day 5 after administration (P < .01), there was no significant difference at day 28 (Figure 5).	('plasma T3 concentration', 'MPA', (13, 36))	('higher', 'PosReg', (75, 81))	('211At-MABG', 'Var', (44, 54))	('T3', 'Chemical', 'MESH:D014284', (20, 22))
58591	31078058	Similarly, the norepinephrine levels in the 211At-MABG group were significantly higher than those in the control group at day 5 (P < .05), whereas there was no significant difference at day 28 (Figure 5).	('norepinephrine', 'Chemical', 'MESH:D009638', (15, 29))	('211At-MABG', 'Var', (44, 54))	('higher', 'PosReg', (80, 86))	('norepinephrine levels', 'MPA', (15, 36))
58593	31078058	The alpha-emitting radiopharmaceutical 211At-MABG is expected to achieve better outcomes in metastatic pheochromocytoma than the beta--emitting radiopharmaceutical 131I-MIBG.	('pheochromocytoma', 'Disease', 'MESH:D010673', (103, 119))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('beta-', 'Chemical', '-', (129, 134))	('pheochromocytoma', 'Disease', (103, 119))	('131I-MIBG', 'Chemical', '-', (164, 173))	('211At-MABG', 'Var', (39, 49))
58597	31078058	We therefore considered it necessary to evaluate whether 211At-MABG induces unexpected acute radiotoxicity in mice before the first-in-human study is performed.	('211At-MABG', 'Var', (57, 67))	('acute radiotoxicity', 'Disease', 'MESH:D059787', (87, 106))	('mice', 'Species', '10090', (110, 114))	('human', 'Species', '9606', (135, 140))	('acute radiotoxicity', 'Disease', (87, 106))
58599	31078058	Because tumor uptake of 211At-MABG would affect the biodistribution in the whole body, the present study employed non-tumor-bearing ICR mice and included a comprehensive evaluation of acute radiotoxicity.	('biodistribution in the whole body', 'MPA', (52, 85))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('211At-MABG', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (8, 13))	('acute radiotoxicity', 'Disease', 'MESH:D059787', (184, 203))	('acute radiotoxicity', 'Disease', (184, 203))	('affect', 'Reg', (41, 47))
58605	31078058	These findings suggest that administration of high doses of 211At-MABG may provide information on radiotoxicity induced by 211At-MABG.	('radiotoxicity', 'Disease', 'None', (98, 111))	('radiotoxicity', 'Disease', (98, 111))	('211At-MABG', 'Var', (123, 133))
58620	31078058	Although the present study showed that high doses of 211At-MABG were well tolerated in mice and unexpected radiation-induced toxicity was not observed under our conditions, the study has several limitations.	('toxicity', 'Disease', (125, 133))	('mice', 'Species', '10090', (87, 91))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('211At-MABG', 'Var', (53, 63))
58622	31078058	Second, the present examination in male mice cannot address the possibility that some toxicity might be present only in females, although to our knowledge, no female-specific toxicity has been reported in patients treated with 131I-MIBG.	('toxicity', 'Disease', 'MESH:D064420', (175, 183))	('patients', 'Species', '9606', (205, 213))	('131I-MIBG', 'Chemical', '-', (227, 236))	('toxicity', 'Disease', (175, 183))	('toxicity', 'Disease', 'MESH:D064420', (86, 94))	('toxicity', 'Disease', (86, 94))	('mice', 'Species', '10090', (40, 44))	('131I-MIBG', 'Var', (227, 236))
58630	31078058	Unexpected severe toxicity was not observed in the present study, although high radiation doses were absorbed by most organs, especially the thyroid, heart, stomach, and adrenal glands, after injection of 3.3 MBq of 211At-MABG.	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('211At-MABG', 'Var', (216, 226))	('toxicity', 'Disease', (18, 26))
58632	30087776	A patient with a germline SDHB mutation presenting with an isolated pituitary macroprolactinoma Symptomatic pituitary adenomas occur with a prevalence of approximately 0.1% in the general population.	('prolactinoma', 'Phenotype', 'HP:0040278', (83, 95))	('pituitary adenomas', 'Disease', 'MESH:D010911', (108, 126))	('macroprolactinoma', 'Phenotype', 'HP:0012342', (78, 95))	('mutation', 'Var', (31, 39))	('SDHB', 'Gene', '6390', (26, 30))	('SDHB', 'Gene', (26, 30))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (108, 126))	('pituitary macroprolactinoma', 'Disease', 'MESH:D015175', (68, 95))	('pituitary adenomas', 'Disease', (108, 126))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (108, 125))	('patient', 'Species', '9606', (2, 9))	('isolated pituitary macroprolactinoma Symptomatic pituitary adenomas', 'Phenotype', 'HP:0011761', (59, 126))	('pituitary macroprolactinoma', 'Disease', (68, 95))
58634	30087776	Recently, loss-of-function mutations in genes encoding succinate dehydrogenase subunits (SDHx) or MYC-associated factor X (MAX) have been found to predispose to pituitary adenomas in co-existence with paragangliomas or phaeochromocytomas.	('mutations', 'Var', (27, 36))	('MYC-associated factor X', 'Gene', '4149', (98, 121))	('MYC-associated factor X', 'Gene', (98, 121))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (161, 179))	('paragangliomas or phaeochromocytomas', 'Disease', 'MESH:D010235', (201, 237))	('loss-of-function', 'NegReg', (10, 26))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (161, 178))	('pituitary adenomas', 'Disease', (161, 179))	('succinate dehydrogenase', 'Gene', '6390', (55, 78))	('SDHx', 'Chemical', '-', (89, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (201, 214))	('succinate dehydrogenase', 'Gene', (55, 78))	('paragangliomas', 'Phenotype', 'HP:0002668', (201, 215))	('paragangliomas or phaeochromocytomas', 'Disease', (201, 237))	('pituitary adenomas', 'Disease', 'MESH:D010911', (161, 179))	('MAX', 'Gene', '4149', (123, 126))	('MAX', 'Gene', (123, 126))
58635	30087776	It is rare, however, for a familial SDHx mutation to manifest as an isolated pituitary adenoma.	('SDHx', 'Chemical', '-', (36, 40))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (68, 94))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (77, 94))	('mutation', 'Var', (41, 49))	('pituitary adenoma', 'Disease', (77, 94))	('pituitary adenoma', 'Disease', 'MESH:D010911', (77, 94))
58636	30087776	We present the case of a pituitary lactotroph adenoma in a patient with a heterozygous germline SDHB mutation, in the absence of concomitant neoplasms.	('neoplasms', 'Disease', 'MESH:D009369', (141, 150))	('neoplasms', 'Disease', (141, 150))	('patient', 'Species', '9606', (59, 66))	('pituitary lactotroph adenoma', 'Disease', 'MESH:D015175', (25, 53))	('SDHB', 'Gene', '6390', (96, 100))	('pituitary lactotroph adenoma', 'Disease', (25, 53))	('SDHB', 'Gene', (96, 100))	('mutation', 'Var', (101, 109))	('neoplasms', 'Phenotype', 'HP:0002664', (141, 150))
58640	30087776	Our patient's SDHB mutation was identified when we realised that her father had a metastatic paraganglioma, prompting genetic testing.	('mutation', 'Var', (19, 27))	('paraganglioma', 'Disease', 'MESH:D010235', (93, 106))	('patient', 'Species', '9606', (4, 11))	('SDHB', 'Gene', '6390', (14, 18))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('paraganglioma', 'Disease', (93, 106))	('SDHB', 'Gene', (14, 18))
58642	30087776	This histological feature is suggestive of an SDHx mutation and should prompt further screening for mutations by immunohistochemistry and/or genetic testing.	('SDHx', 'Chemical', '-', (46, 50))	('mutation', 'Var', (51, 59))	('SDHx', 'Gene', (46, 50))
58645	30087776	SDHx mutated pituitary adenomas may display clinically aggressive behaviour and demonstrate variable response to medical treatment.	('pituitary adenomas', 'Phenotype', 'HP:0002893', (13, 31))	('pituitary adenomas', 'Disease', (13, 31))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (13, 30))	('SDHx', 'Chemical', '-', (0, 4))	('mutated pituitary adenomas', 'Phenotype', 'HP:0011761', (5, 31))	('SDHx', 'Gene', (0, 4))	('mutated', 'Var', (5, 12))	('pituitary adenomas', 'Disease', 'MESH:D010911', (13, 31))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (55, 75))
58646	30087776	Histological evidence of intracytoplasmic vacuoles in a pituitary adenoma might suggest an SDH-deficient tumour and should prompt further screening for SDHx mutations.	('pituitary adenoma', 'Disease', (56, 73))	('pituitary adenoma', 'Disease', 'MESH:D010911', (56, 73))	('SDH-deficient tumour', 'Disease', 'MESH:D009369', (91, 111))	('mutations', 'Var', (157, 166))	('SDH-deficient tumour', 'Disease', (91, 111))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (56, 73))	('SDHx', 'Chemical', '-', (152, 156))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('SDHx', 'Gene', (152, 156))
58647	30087776	Immunohistochemistry may not always predict the presence of SDHx mutations.	('SDHx', 'Chemical', '-', (60, 64))	('SDHx', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
58651	30087776	More recently, loss-of-function mutations in genes encoding succinate dehydrogenase (SDH) subunits have been implicated in the development of the rare but increasingly recognised co-existence of paraganglioma/phaeochromocytoma and pituitary adenoma.	('succinate dehydrogenase', 'Gene', '6390', (60, 83))	('succinate dehydrogenase', 'Gene', (60, 83))	('SDH', 'Gene', (85, 88))	('paraganglioma', 'Phenotype', 'HP:0002668', (195, 208))	('pituitary adenoma', 'Disease', (231, 248))	('paraganglioma/phaeochromocytoma', 'Disease', (195, 226))	('pituitary adenoma', 'Disease', 'MESH:D010911', (231, 248))	('mutations', 'Var', (32, 41))	('paraganglioma/phaeochromocytoma', 'Disease', 'MESH:D010235', (195, 226))	('SDH', 'Gene', '6390', (85, 88))	('loss-of-function', 'NegReg', (15, 31))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (231, 248))
58654	30087776	Loss-of-function mutations in genes encoding the SDH subunits (SDHx: SDHA, SDHB, SDHC, SDHD) or its assembly factor (SDHAF2) have long been associated with various tumours, including paragangliomas and phaeochromocytomas, gastrointestinal stromal tumours (GISTs), renal carcinomas and pituitary adenomas.	('SDH', 'Gene', '6390', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('pituitary adenomas', 'Disease', 'MESH:D010911', (285, 303))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (285, 303))	('pituitary adenomas', 'Disease', (285, 303))	('renal carcinomas', 'Disease', 'MESH:C538614', (264, 280))	('paragangliomas', 'Phenotype', 'HP:0002668', (183, 197))	('tumours', 'Disease', (247, 254))	('SDHD', 'Gene', '6392', (87, 91))	('mutations', 'Var', (17, 26))	('SDH', 'Gene', (81, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (183, 196))	('SDH', 'Gene', '6390', (63, 66))	('SDH', 'Gene', '6390', (87, 90))	('SDHC', 'Gene', '6391', (81, 85))	('SDH', 'Gene', (49, 52))	('tumours', 'Phenotype', 'HP:0002664', (247, 254))	('tumours', 'Disease', 'MESH:D009369', (247, 254))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (285, 302))	('paragangliomas and phaeochromocytomas, gastrointestinal stromal tumours', 'Disease', 'MESH:C564650', (183, 254))	('SDHD', 'Gene', (87, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (270, 280))	('renal carcinomas', 'Disease', (264, 280))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('SDH', 'Gene', '6390', (69, 72))	('SDH', 'Gene', '6390', (117, 120))	('SDHAF2', 'Gene', '54949', (117, 123))	('renal carcinomas', 'Phenotype', 'HP:0005584', (264, 280))	('SDHAF2', 'Gene', (117, 123))	('SDHA', 'Gene', (69, 73))	('SDHA', 'Gene', (117, 121))	('SDH', 'Gene', (63, 66))	('SDHB', 'Gene', '6390', (75, 79))	('SDH', 'Gene', '6390', (75, 78))	('tumours', 'Disease', (164, 171))	('SDH', 'Gene', (87, 90))	('SDHA', 'Gene', '6389', (69, 73))	('Loss-of-function', 'NegReg', (0, 16))	('SDHA', 'Gene', '6389', (117, 121))	('SDHC', 'Gene', (81, 85))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('SDH', 'Gene', (69, 72))	('SDH', 'Gene', '6390', (81, 84))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('SDHx', 'Chemical', '-', (63, 67))	('SDH', 'Gene', (117, 120))	('SDHB', 'Gene', (75, 79))	('SDH', 'Gene', (75, 78))
58655	30087776	Previously, there have been three reported cases of pituitary adenoma occurring in association with familial SDHB mutation, in the absence of a personal history of paraganglioma.	('pituitary adenoma', 'Disease', (52, 69))	('SDHB', 'Gene', '6390', (109, 113))	('pituitary adenoma', 'Disease', 'MESH:D010911', (52, 69))	('SDHB', 'Gene', (109, 113))	('paraganglioma', 'Phenotype', 'HP:0002668', (164, 177))	('paraganglioma', 'Disease', (164, 177))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (52, 69))	('mutation', 'Var', (114, 122))	('paraganglioma', 'Disease', 'MESH:D010235', (164, 177))
58656	30087776	We describe a patient with SDHB mutation who developed a lactotroph adenoma without any other tumour manifestation.	('tumour', 'Disease', (94, 100))	('developed', 'PosReg', (45, 54))	('adenoma', 'Disease', (68, 75))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('mutation', 'Var', (32, 40))	('SDHB', 'Gene', '6390', (27, 31))	('patient', 'Species', '9606', (14, 21))	('SDHB', 'Gene', (27, 31))	('adenoma', 'Disease', 'MESH:D000236', (68, 75))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
58682	30087776	He was a carrier of a germline missense SDHB mutation (c.298T>C, p.Ser100Pro).	('SDHB', 'Gene', '6390', (40, 44))	('SDHB', 'Gene', (40, 44))	('p.Ser100Pro', 'Mutation', 'p.S100P', (65, 76))	('p.Ser100Pro', 'Var', (65, 76))	('c.298T>C', 'Mutation', 'c.298T>C', (55, 63))	('c.298T>C', 'Var', (55, 63))
58689	30087776	It is highly unusual for a patient with a germline SDHB mutation to present as an isolated pituitary adenoma.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (91, 108))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (82, 108))	('patient', 'Species', '9606', (27, 34))	('pituitary adenoma', 'Disease', (91, 108))	('SDHB', 'Gene', '6390', (51, 55))	('SDHB', 'Gene', (51, 55))	('mutation', 'Var', (56, 64))	('pituitary adenoma', 'Disease', 'MESH:D010911', (91, 108))	('present', 'Reg', (68, 75))
58690	30087776	Certainly, germline mutations in SDHx, and more recently MAX, are recognised as an infrequent syndromic cause of pituitary adenomas.	('MAX', 'Gene', (57, 60))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (113, 130))	('SDHx', 'Chemical', '-', (33, 37))	('pituitary adenomas', 'Disease', (113, 131))	('MAX', 'Gene', '4149', (57, 60))	('pituitary adenomas', 'Disease', 'MESH:D010911', (113, 131))	('cause', 'Reg', (104, 109))	('germline mutations', 'Var', (11, 29))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (113, 131))	('SDHx', 'Gene', (33, 37))
58692	30087776	Although the mean age of diagnosis of paraganglioma/phaeochromocytoma in SDHB mutation carriers is reported to be in the third decade, recent systematic screening of large families identified numerous patients with newly recognised disease at older ages.	('patients', 'Species', '9606', (201, 209))	('mutation', 'Var', (78, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (38, 51))	('paraganglioma/phaeochromocytoma', 'Disease', (38, 69))	('paraganglioma/phaeochromocytoma', 'Disease', 'MESH:D010235', (38, 69))	('SDHB', 'Gene', '6390', (73, 77))	('SDHB', 'Gene', (73, 77))
58693	30087776	Our case adds to the three previous reports of isolated pituitary adenoma in the setting of an inherited SDHB mutation and familial paraganglioma.	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (47, 73))	('SDHB', 'Gene', '6390', (105, 109))	('pituitary adenoma', 'Disease', (56, 73))	('pituitary adenoma', 'Disease', 'MESH:D010911', (56, 73))	('SDHB', 'Gene', (105, 109))	('familial paraganglioma', 'Disease', (123, 145))	('mutation', 'Var', (110, 118))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (56, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (132, 145))	('familial paraganglioma', 'Disease', 'MESH:D010235', (123, 145))
58700	30087776	The limited literature available suggests that pituitary adenomas associated with SDHx mutations exhibit clinically aggressive behaviour, but further data are needed for detailed characterisation of the response to medical treatment SDHx-related pituitary adenomas.	('pituitary adenomas', 'Disease', (246, 264))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (47, 64))	('SDHx', 'Chemical', '-', (82, 86))	('SDHx', 'Gene', (82, 86))	('associated', 'Reg', (66, 76))	('pituitary adenomas', 'Disease', 'MESH:D010911', (246, 264))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (116, 136))	('pituitary adenomas', 'Disease', 'MESH:D010911', (47, 65))	('SDHx', 'Chemical', '-', (233, 237))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (246, 264))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (47, 65))	('mutations', 'Var', (87, 96))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (246, 263))	('pituitary adenomas', 'Disease', (47, 65))
58706	30087776	The presence of prominent intracytoplasmic vacuoles should prompt the examining histopathologist to perform SDHB and SDHA immunostaining to screen for a possible SDHx mutation.	('SDHA', 'Gene', '6389', (117, 121))	('SDHB', 'Gene', (108, 112))	('mutation', 'Var', (167, 175))	('SDHA', 'Gene', (117, 121))	('screen', 'Reg', (140, 146))	('SDHx', 'Chemical', '-', (162, 166))	('SDHB', 'Gene', '6390', (108, 112))	('SDHx', 'Gene', (162, 166))
58707	30087776	A recent multicentre interobserver variation analysis on the use of SDHB/SHDA immunohistochemistry in paragangliomas and phaeochromocytomas and a study on pituitary adenomas confirmed its use as a cheap and reliable tool to identify patients with SDHx mutations, prior to genetic testing.	('pituitary adenomas', 'Disease', 'MESH:D010911', (155, 173))	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('paragangliomas', 'Phenotype', 'HP:0002668', (102, 116))	('SDHx', 'Chemical', '-', (247, 251))	('SDHB', 'Gene', '6390', (68, 72))	('SDHx', 'Gene', (247, 251))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (155, 173))	('pituitary adenomas', 'Disease', (155, 173))	('mutations', 'Var', (252, 261))	('SDHB', 'Gene', (68, 72))	('paragangliomas and phaeochromocytomas', 'Disease', 'MESH:D010235', (102, 139))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (155, 172))	('patients', 'Species', '9606', (233, 241))
58708	30087776	In our specific case, the substitution p.Ser100Pro might have resulted in impaired SDHB binding to iron-sulphur clusters and possibly in impaired interactions between the protein and the other subunits.	('SDHB', 'Gene', (83, 87))	('impaired', 'NegReg', (74, 82))	('impaired', 'NegReg', (137, 145))	('p.Ser100Pro', 'Var', (39, 50))	('interactions', 'Interaction', (146, 158))	('SDHB', 'Gene', '6390', (83, 87))	('binding', 'Interaction', (88, 95))	('iron-sulphur', 'Protein', (99, 111))	('p.Ser100Pro', 'Mutation', 'p.S100P', (39, 50))
58709	30087776	In in vitro studies, the p.Ser100Pro substitution did not show elevated succinate level, but had an increased succinate/fumarate ratio.	('succinate', 'Chemical', 'MESH:D019802', (110, 119))	('increased', 'PosReg', (100, 109))	('elevated succinate', 'Phenotype', 'HP:0020149', (63, 81))	('succinate/fumarate ratio', 'MPA', (110, 134))	('fumarate', 'Chemical', 'MESH:D005650', (120, 128))	('p.Ser100Pro', 'Mutation', 'p.S100P', (25, 36))	('p.Ser100Pro', 'Var', (25, 36))	('increased succinate', 'Phenotype', 'HP:0020149', (100, 119))	('succinate level', 'MPA', (72, 87))	('succinate', 'Chemical', 'MESH:D019802', (72, 81))
58712	30087776	It is possible that mutated SDHB becomes less stable and degraded at a higher rate than the WT protein in the paraganglioma tissue but not in the pituitary adenoma.	('pituitary adenoma', 'Disease', (146, 163))	('pituitary adenoma', 'Disease', 'MESH:D010911', (146, 163))	('paraganglioma', 'Disease', 'MESH:D010235', (110, 123))	('stable', 'MPA', (46, 52))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (146, 163))	('degraded', 'NegReg', (57, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (110, 123))	('less', 'NegReg', (41, 45))	('SDHB', 'Gene', '6390', (28, 32))	('paraganglioma', 'Disease', (110, 123))	('SDHB', 'Gene', (28, 32))	('mutated', 'Var', (20, 27))
58715	30087776	Furthermore, this case demonstrates that immunohistochemistry is not always predictive of SDHx mutations and therefore cannot replace genetic analysis.	('SDHx', 'Chemical', '-', (90, 94))	('SDHx', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))
58777	29850871	These abnormalities appear to induce an interstitial mononuclear inflammatory response and occasionally contraction band necrosis.	('necrosis', 'Disease', (121, 129))	('interstitial mononuclear inflammatory response', 'CPA', (40, 86))	('necrosis', 'Disease', 'MESH:D009336', (121, 129))	('abnormalities', 'Var', (6, 19))	('induce', 'Reg', (30, 36))
58801	29850871	In the acute phase, intravenous administration of adenosine has been shown to transiently improve myocardial perfusion, wall motion score index, and left ventricular ejection fraction (LVEF) in TTS, suggesting that intense microvascular constriction plays a major role in the pathophysiology.	('TTS', 'Phenotype', 'HP:0011665', (194, 197))	('wall motion score index', 'MPA', (120, 143))	('adenosine', 'Var', (50, 59))	('myocardial perfusion', 'MPA', (98, 118))	('adenosine', 'Chemical', 'MESH:D000241', (50, 59))	('rat', 'Species', '10116', (40, 43))	('left ventricular ejection fraction', 'MPA', (149, 183))	('improve', 'PosReg', (90, 97))
58813	29850871	In rodent heart failure models, administration of isoproterenol yields apical fibrosis, and abnormalities of apical contraction and metabolism, features known to occur in dysfunctional apical segments during the acute phase in TTS using fludeoxyglucose-positron emission tomographic studies.	('isoproterenol', 'Chemical', 'MESH:D007545', (50, 63))	('fibrosis', 'Disease', 'MESH:D005355', (78, 86))	('fibrosis', 'Disease', (78, 86))	('heart failure', 'Phenotype', 'HP:0001635', (10, 23))	('metabolism', 'MPA', (132, 142))	('men', 'Species', '9606', (195, 198))	('heart failure', 'Disease', (10, 23))	('rat', 'Species', '10116', (40, 43))	('fludeoxyglucose', 'Chemical', 'MESH:D019788', (237, 252))	('apical fibrosis', 'Phenotype', 'HP:0032176', (71, 86))	('abnormalities', 'Var', (92, 105))	('dysfunctional', 'Disease', 'MESH:D006331', (171, 184))	('apical contraction', 'CPA', (109, 127))	('TTS', 'Phenotype', 'HP:0011665', (227, 230))	('dysfunctional', 'Disease', (171, 184))	('heart failure', 'Disease', 'MESH:D006333', (10, 23))
58821	29850871	A polymorphism of the G-protein receptor kinase 5 (GRK5) gene L41Q that blunts beta2-Gi trafficking appears common in TTS.	('L41Q', 'Var', (62, 66))	('G-protein receptor kinase 5', 'Gene', '2869', (22, 49))	('TTS', 'Phenotype', 'HP:0011665', (118, 121))	('GRK5', 'Gene', '2869', (51, 55))	('beta2', 'Gene', (79, 84))	('blunts', 'NegReg', (72, 78))	('G-protein receptor kinase 5', 'Gene', (22, 49))	('beta2', 'Gene', '10242', (79, 84))	('GRK5', 'Gene', (51, 55))	('polymorphism', 'Var', (2, 14))	('L41Q', 'Mutation', 'rs2230345', (62, 66))
58828	29850871	Cell survival is achieved through various mechanisms: (i) direct inhibition of apoptosis, (ii) inhibition of proapoptotic transcriptional factors, (iii) enhancement of anti-apoptotic transcriptional factors, and (iv) enhancement of cell metabolism by inhibition of the GSK3.	('inhibition', 'NegReg', (65, 75))	('men', 'Species', '9606', (224, 227))	('enhancement', 'PosReg', (153, 164))	('GSK3', 'Gene', (269, 273))	('cell metabolism', 'CPA', (232, 247))	('inhibition', 'NegReg', (95, 105))	('proapoptotic transcriptional factors', 'MPA', (109, 145))	('inhibition', 'Var', (251, 261))	('apoptosis', 'CPA', (79, 88))	('men', 'Species', '9606', (160, 163))	('enhancement', 'PosReg', (217, 228))	('anti-apoptotic transcriptional factors', 'MPA', (168, 206))
58835	29850871	In women with subarachnoid haemorrhage, low levels of oestradiol have been associated with an increased risk of LV wall motion abnormalities.	('subarachnoid haemorrhage', 'Phenotype', 'HP:0002138', (14, 38))	('oestradiol', 'Protein', (54, 64))	('oestradiol', 'Chemical', 'MESH:D004958', (54, 64))	('subarachnoid haemorrhage', 'Disease', 'MESH:D013345', (14, 38))	('low', 'Var', (40, 43))	('low levels of oestradiol', 'Phenotype', 'HP:0008214', (40, 64))	('women', 'Species', '9606', (3, 8))	('motion abnormalities', 'Disease', 'MESH:D009041', (120, 140))	('subarachnoid haemorrhage', 'Disease', (14, 38))	('motion abnormalities', 'Disease', (120, 140))	('LV wall motion abnormalities', 'Phenotype', 'HP:0012667', (112, 140))
58840	29850871	Polymorphisms in adrenergic genes indeed affect receptor function and downstream signalling, and this raises the possibility that their distribution may differ in TTS patients.	('downstream signalling', 'MPA', (70, 91))	('Polymorphisms', 'Var', (0, 13))	('receptor function', 'MPA', (48, 65))	('patients', 'Species', '9606', (167, 175))	('TTS', 'Phenotype', 'HP:0011665', (163, 166))	('TTS', 'Disease', (163, 166))	('adrenergic genes', 'Gene', (17, 33))	('affect', 'Reg', (41, 47))
58841	29850871	Indeed, functional variants of adrenergic receptor genes have been associated with the magnitude of cardiac dysfunction in patients with subarachnoid haemorrhage and pheochromocytoma, conditions which can trigger TTS.	('cardiac dysfunction', 'Disease', (100, 119))	('pheochromocytoma', 'Disease', (166, 182))	('adrenergic receptor genes', 'Gene', (31, 56))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (100, 119))	('pheochromocytoma', 'Disease', 'MESH:D010673', (166, 182))	('subarachnoid haemorrhage', 'Disease', (137, 161))	('TTS', 'Phenotype', 'HP:0011665', (213, 216))	('patients', 'Species', '9606', (123, 131))	('subarachnoid haemorrhage', 'Phenotype', 'HP:0002138', (137, 161))	('subarachnoid haemorrhage', 'Disease', 'MESH:D013345', (137, 161))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (166, 182))	('associated', 'Reg', (67, 77))	('variants', 'Var', (19, 27))
58842	29850871	beta1-adrenergic receptor (amino acid position 389) and beta2-adrenergic receptor (amino acid position 27) variants were associated with a greater release of troponin I and alpha2-adrenergic receptor deletion (del322-325) with reduced LVEF.	('beta2-adrenergic receptor', 'Gene', (56, 81))	('reduced', 'NegReg', (227, 234))	('beta1-adrenergic receptor', 'Gene', (0, 25))	('beta2-adrenergic receptor', 'Gene', '154', (56, 81))	('variants', 'Var', (107, 115))	('alpha2-adrenergic receptor', 'Protein', (173, 199))	('del322-325', 'Mutation', 'c.322_325del', (210, 220))	('release of troponin I', 'MPA', (147, 168))	('greater', 'PosReg', (139, 146))	('beta1-adrenergic receptor', 'Gene', '153', (0, 25))	('LVEF', 'Disease', (235, 239))	('del322-325', 'Var', (210, 220))
58844	29850871	In contrast, a different distribution of beta1-receptor polymorphisms Arg389Gly [homozygous arginine (Arg)/Arg] is more frequently found in TTS, while beta2-receptor polymorphisms Gln27Glu [homozygous glutamine (Gln)/Gln] were found more frequently in healthy controls, and no difference was observed in the beta2-receptor Arg16Gly variant between groups.	('found', 'Reg', (131, 136))	('glutamine', 'Chemical', 'MESH:D005973', (201, 210))	('beta2', 'Gene', (308, 313))	('arginine', 'Chemical', 'MESH:D001120', (92, 100))	('Gln', 'Chemical', 'MESH:D005973', (217, 220))	('Arg', 'Chemical', 'MESH:D001120', (107, 110))	('TTS', 'Disease', (140, 143))	('beta2', 'Gene', (151, 156))	('Arg389Gly', 'SUBSTITUTION', 'None', (70, 79))	('Arg16Gly', 'SUBSTITUTION', 'None', (323, 331))	('beta1', 'Gene', '10678', (41, 46))	('Arg389Gly', 'Var', (70, 79))	('Gln', 'Chemical', 'MESH:D005973', (212, 215))	('Gln', 'Chemical', 'MESH:D005973', (180, 183))	('beta2', 'Gene', '10242', (308, 313))	('Gln27Glu', 'SUBSTITUTION', 'None', (180, 188))	('Gln27Glu', 'Var', (180, 188))	('TTS', 'Phenotype', 'HP:0011665', (140, 143))	('Arg', 'Chemical', 'MESH:D001120', (102, 105))	('beta2', 'Gene', '10242', (151, 156))	('Arg16Gly', 'Var', (323, 331))	('Arg', 'Chemical', 'MESH:D001120', (323, 326))	('Arg', 'Chemical', 'MESH:D001120', (70, 73))	('beta1', 'Gene', (41, 46))
58845	29850871	Furthermore, similar genetic polymorphisms in the beta1-adrenergic receptor and the beta2-adrenergic receptor were noted in TTS and controls, while a higher frequency of rs17098707 polymorphism in the GRK5 gene was found in TTS patients.	('beta1-adrenergic receptor', 'Gene', '153', (50, 75))	('GRK5', 'Gene', (201, 205))	('rs17098707', 'Mutation', 'rs17098707', (170, 180))	('beta2-adrenergic receptor', 'Gene', (84, 109))	('beta2-adrenergic receptor', 'Gene', '154', (84, 109))	('patients', 'Species', '9606', (228, 236))	('TTS', 'Phenotype', 'HP:0011665', (224, 227))	('GRK5', 'Gene', '2869', (201, 205))	('beta1-adrenergic receptor', 'Gene', (50, 75))	('TTS', 'Disease', (124, 127))	('rs17098707 polymorphism', 'Var', (170, 193))	('TTS', 'Phenotype', 'HP:0011665', (124, 127))	('TTS', 'Disease', (224, 227))
58932	29785166	Pheochromocytoma and renal cell carcinoma can occur as a part of complex syndromes, such as type 2 multiple endocrine neoplasia (as a consequence of RET proto-oncogene mutations), Von Hippel-Lindau disease (mutations of the VHL gene), or pheochromocytoma-paraganglioma syndromes (heterozygous germline mutations of succinate dehydrogenase subunits B, C, and D).	('VHL', 'Gene', '7428', (224, 227))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (108, 127))	('paraganglioma', 'Phenotype', 'HP:0002668', (255, 268))	('mutations', 'Var', (168, 177))	('RET', 'Gene', '5979', (149, 152))	('type 2', 'Disease', (92, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('endocrine neoplasia', 'Disease', (108, 127))	('occur', 'Reg', (46, 51))	('pheochromocytoma-paraganglioma syndromes', 'Disease', (238, 278))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (21, 41))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (0, 16))	('RET', 'Gene', (149, 152))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('endocrine neoplasia', 'Disease', 'MESH:D009377', (108, 127))	('Von Hippel-Lindau disease', 'Disease', (180, 205))	('VHL', 'Gene', (224, 227))	('Pheochromocytoma', 'Disease', (0, 16))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (238, 254))	('neoplasia', 'Phenotype', 'HP:0002664', (118, 127))	('renal cell carcinoma', 'Disease', (21, 41))	('Von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (180, 205))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (21, 41))	('pheochromocytoma-paraganglioma syndromes', 'Disease', 'MESH:D010673', (238, 278))
58937	28944243	About 30% of PPGLs are attributed to germline mutations.	('germline mutations', 'Var', (37, 55))	('PPGLs', 'Chemical', '-', (13, 18))	('attributed', 'Reg', (23, 33))	('PGL', 'Phenotype', 'HP:0002668', (14, 17))	('PPGLs', 'Disease', (13, 18))
58949	28944243	Additionally, postoperative PPGLs have a 15% relapse risk, with most being metastatic recurrence that can occur decades after surgery, implying a need for effective screening and cheap long-term follow-up management (Amar et al.	('PGL', 'Phenotype', 'HP:0002668', (29, 32))	('metastatic recurrence', 'Disease', (75, 96))	('postoperative', 'Var', (14, 27))	('PPGLs', 'Chemical', '-', (28, 33))	('PPGLs', 'Gene', (28, 33))	('relapse', 'CPA', (45, 52))
58984	28944243	This progressively decreased to 32.1% (9/28), 10.6% (5/47), and 12.8% (5/39) patients from diagnosis age groups >=20-<40, >=40-<60, and >=60 years old, respectively.	('patients', 'Species', '9606', (77, 85))	('>=40-<60', 'Var', (122, 130))	('>=20-<40', 'Var', (112, 120))
58988	28944243	Three SDHB missense mutations were found; twice in codon 136 of exon 1 and a frameshift mutation in codon 620 of exon 6.	('SDHB', 'Gene', (6, 10))	('SDHB', 'Gene', '6390', (6, 10))	('frameshift mutation in codon', 'Var', (77, 105))
58990	28944243	Two SDHD mutations were also found; these consisted of frameshifts at codon 10 of exon 1 and codon 242 of exon 3, respectively.	('SDHD', 'Disease', (4, 8))	('SDHD', 'Disease', 'None', (4, 8))	('frameshifts at codon 10', 'Var', (55, 78))	('codon 242', 'Var', (93, 102))
58991	28944243	Two VHL mutations were found with both having a missense at codon 191 of exon 1 and codon 499 of exon 3, respectively.	('VHL', 'Disease', (4, 7))	('missense at codon 191', 'Var', (48, 69))	('VHL', 'Disease', 'MESH:D006623', (4, 7))	('codon 499', 'Var', (84, 93))
58995	28944243	2014) However, only three-quarter of patients with malignant PPGLs and a quarter of patients in the study cohort had any functional imaging done, displaying the lack of uptake of the available imaging modality and variable practice among clinicians in the absence of genetic analysis to guide specific surveillance and postoperative management.	('malignant', 'Var', (51, 60))	('PPGLs', 'Chemical', '-', (61, 66))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (84, 92))	('PPGLs', 'Gene', (61, 66))	('PGL', 'Phenotype', 'HP:0002668', (62, 65))
58997	28944243	While most PPGLs have a low risk of malignancy, patients with SDHB mutations have higher risks of malignancy, and conversely patients with RET germline mutations have a much lower risk of malignancy (Amar et al.	('RET', 'Gene', (139, 142))	('SDHB', 'Gene', '6390', (62, 66))	('malignancy', 'Disease', (188, 198))	('malignancy', 'Disease', (98, 108))	('mutations', 'Var', (67, 76))	('malignancy', 'Disease', 'MESH:D009369', (98, 108))	('PPGLs', 'Chemical', '-', (11, 16))	('RET', 'Gene', '5979', (139, 142))	('PGL', 'Phenotype', 'HP:0002668', (12, 15))	('malignancy', 'Disease', 'MESH:D009369', (36, 46))	('malignancy', 'Disease', 'MESH:D009369', (188, 198))	('patients', 'Species', '9606', (48, 56))	('malignancy', 'Disease', (36, 46))	('SDHB', 'Gene', (62, 66))	('patients', 'Species', '9606', (125, 133))
59000	28944243	This is particularly seen in SDH mutations, where family history may be absent (Welander et al.	('SDH', 'Gene', '6390', (29, 32))	('mutations', 'Var', (33, 42))	('SDH', 'Gene', (29, 32))
59010	28944243	reported finding germline mutations for one fifth of those falling in this age group with sporadic PPGLs (Neumann et al.	('falling', 'Phenotype', 'HP:0002527', (59, 66))	('PPGLs', 'Chemical', '-', (99, 104))	('germline mutations', 'Var', (17, 35))	('PGL', 'Phenotype', 'HP:0002668', (100, 103))	('PPGLs', 'Disease', (99, 104))
59056	26487970	The results showed p.C634R mutation in exon 11 and polymorphisms in p.A432A, p.G691S, and p.S904S.	('p.C634R', 'Mutation', 'rs75076352', (19, 26))	('p.C634R', 'Var', (19, 26))	('p.S904S', 'Mutation', 'rs1800863', (90, 97))	('p.G691S', 'Var', (77, 84))	('p.A432A', 'Var', (68, 75))	('p.G691S', 'Mutation', 'rs1799939', (77, 84))	('p.S904S', 'Var', (90, 97))	('p.A432A', 'SUBSTITUTION', 'None', (68, 75))
59059	26487970	Germline RET mutations are generally observed in 98% of patients with MEN2A.	('patients', 'Species', '9606', (56, 64))	('observed', 'Reg', (37, 45))	('MEN2A', 'Gene', (70, 75))	('RET', 'Gene', '5979', (9, 12))	('MEN2A', 'Gene', '5979', (70, 75))	('mutations', 'Var', (13, 22))	('RET', 'Gene', (9, 12))
59061	26487970	RET mutations are mostly missense and located in the extracellular domain of RET (exons 10 and 11) and are correlated with high frequency of pheochromocytoma (more than 50%).	('RET', 'Gene', (77, 80))	('pheochromocytoma', 'Disease', (141, 157))	('missense', 'Var', (25, 33))	('RET', 'Gene', '5979', (0, 3))	('pheochromocytoma', 'Disease', 'MESH:D010673', (141, 157))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('RET', 'Gene', (0, 3))	('RET', 'Gene', '5979', (77, 80))	('correlated with', 'Reg', (107, 122))	('mutations', 'Var', (4, 13))
59064	26487970	Mutations at codon 634 of the RET gene correspond to a C classification, which is associated with high risk of aggressive MTC.	('RET', 'Gene', (30, 33))	('MTC', 'Phenotype', 'HP:0002865', (122, 125))	('associated', 'Reg', (82, 92))	('C classification', 'Disease', (55, 71))	('aggressive MTC', 'Disease', (111, 125))	('RET', 'Gene', '5979', (30, 33))	('Mutations at codon 634', 'Var', (0, 22))
59091	9735667	The serum norepinephrine and epinephrine levels were 4791 pg/ml (normal value; 100~410 pg/ml) and 1657 pg/ml (normal value; a120 pg/ml), respectively.	('serum norepinephrine', 'MPA', (4, 24))	('epinephrine', 'Chemical', 'MESH:D004837', (29, 40))	('epinephrine', 'Chemical', 'MESH:D004837', (13, 24))	('1657 pg/ml', 'Var', (98, 108))	('epinephrine levels', 'MPA', (29, 47))	('norepinephrine', 'Chemical', 'MESH:D009638', (10, 24))
59164	26104921	Despite the relatively high rate of Ki67 positivity, complete tumor resection resulted in favorable clinical outcomes.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('positivity', 'Var', (41, 51))	('tumor', 'Disease', (62, 67))	('Ki67', 'Protein', (36, 40))	('Ki67', 'Chemical', '-', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
59213	26104921	suggested that routine analysis for mutations of the RET, VHL, SDHD, and SDHB genes in patients with apparently sporadic presentation of pheochromocytoma should be considered as the clinical standard of care.	('RET', 'Gene', (53, 56))	('mutations', 'Var', (36, 45))	('SDHB', 'Gene', '6390', (73, 77))	('pheochromocytoma', 'Disease', (137, 153))	('VHL', 'Gene', (58, 61))	('RET', 'Gene', '5979', (53, 56))	('pheochromocytoma', 'Disease', 'MESH:D010673', (137, 153))	('SDHD', 'Gene', '6392', (63, 67))	('VHL', 'Gene', '7428', (58, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (137, 153))	('patients', 'Species', '9606', (87, 95))	('SDHD', 'Gene', (63, 67))	('SDHB', 'Gene', (73, 77))
59214	26104921	However, whether these genetic alterations are also associated with composite pheochromocytoma remains unclear.	('pheochromocytoma', 'Disease', (78, 94))	('associated', 'Reg', (52, 62))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('genetic alterations', 'Var', (23, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))
59230	26104921	In the present cases, the rate of Ki67-positive cells was 6.2, 4.3, and 1.0%, respectively, and all patients remained free of tumor recurrence for up to 6 years postsurgery without adjuvant chemotherapy or radiation.	('Ki67-positive cells', 'Var', (34, 53))	('Ki67', 'Chemical', '-', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patients', 'Species', '9606', (100, 108))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
59334	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))	('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))	('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))
59340	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.	('tuberin', 'Gene', (144, 151))	('disease-causing', 'Reg', (2, 17))	('hamartin', 'Gene', (82, 90))	('TSC1', 'Gene', '7248', (37, 41))	('TSC', 'Gene', (98, 101))	('TSC', 'Gene', (37, 40))	('TSC1', 'Gene', (37, 41))	('TSC', 'Gene', '7248;7249', (193, 196))	('tuberin', 'Gene', '7249', (144, 151))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (179, 187))	('TSC', 'Gene', '7248;7249', (37, 40))	('TSC', 'Gene', (193, 196))	('TSC2', 'Gene', '7249', (98, 102))	('TSC2', 'Gene', (98, 102))	('TSC', 'Gene', '7248;7249', (98, 101))	('hamartin', 'Gene', '7248', (82, 90))
59350	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))
59459	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))	('CD117', 'Gene', '3815', (47, 52))	('tumors', 'Disease', (16, 22))	('PAX8', 'Gene', '7849', (41, 45))	('CD117', 'Gene', (47, 52))
59496	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))
59500	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))
59502	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))
59504	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', 'Protein', (26, 33))	('carcinoma', 'Disease', 'MESH:D009369', (108, 117))
59507	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))
59528	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))	('patients', 'Species', '9606', (23, 31))	('SDH', 'Gene', (41, 44))	('SDH', 'Gene', '6390', (41, 44))
59530	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))	('SDHB', 'Gene', '6390', (36, 40))	('SDHD', 'Gene', '6392', (114, 118))	('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))
59531	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))	('SDH B', 'Gene', '6390', (91, 96))	('PHEO', 'Chemical', '-', (118, 122))	('SDHB', 'Gene', '6390', (22, 26))	('SDHB', 'Gene', (22, 26))	('germline mutation', 'Var', (66, 83))
59534	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))
59536	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))	('Renal tumors', 'Disease', (0, 12))	('associated', 'Reg', (13, 23))	('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))
59540	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))	('activity', 'MPA', (36, 44))	('lack', 'Var', (17, 21))	('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))
59543	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))	('CA-IX', 'Gene', (167, 172))	('loss', 'NegReg', (109, 113))	('mutation', 'Var', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('VHL', 'Gene', (79, 82))	('CA-IX', 'Gene', '768', (167, 172))	('tumors', 'Disease', (54, 60))
59545	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))
59546	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))
59549	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.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TSC', 'Gene', '7248;7249', (124, 127))	('SDH', 'Gene', (116, 119))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutation', 'Var', (17, 25))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SDH', 'Gene', '6390', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TSC', 'Gene', (124, 127))	('tumor', 'Disease', (92, 97))	('SDH', 'Gene', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('SDH', 'Gene', '6390', (116, 119))	('contribute', 'Reg', (142, 152))
59555	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.	('TSC', 'Gene', (72, 75))	('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))	('mTOR', 'Gene', (192, 196))	('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))
59558	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))
59583	19672813	For instance, only 3-5% of PCC, related to a MEN2 and a mutation of the RET oncogene, show a malignant transformation.	('PCC', 'Phenotype', 'HP:0002666', (27, 30))	('malignant transformation', 'CPA', (93, 117))	('RET', 'Gene', '5979', (72, 75))	('PCC', 'Disease', (27, 30))	('mutation', 'Var', (56, 64))	('RET', 'Gene', (72, 75))
59585	19672813	This high risk of malignancy in patients with PGL4 is caused by a mutation of the gene encoding succinate dehydrogenase, subunit B (SDHB).	('PGL4', 'Gene', (46, 50))	('patients', 'Species', '9606', (32, 40))	('PGL4', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (132, 136))	('caused by', 'Reg', (54, 63))	('succinate dehydrogenase, subunit B', 'Gene', '6390', (96, 130))	('malignancy', 'Disease', 'MESH:D009369', (18, 28))	('malignancy', 'Disease', (18, 28))	('mutation', 'Var', (66, 74))	('SDHB', 'Gene', '6390', (132, 136))
59639	19672813	Since 1983, several studies have investigated the therapeutic option of radiolabeled MIBG in the treatment of malignant neuroendocrine tumors using either single or cumulative doses of 131I-MIBG, with a variable total dosage.	('131I-MIBG', 'Chemical', '-', (185, 194))	('MIBG', 'Chemical', '-', (85, 89))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (120, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('131I-MIBG', 'Var', (185, 194))	('malignant neuroendocrine tumors', 'Disease', 'MESH:D018358', (110, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MIBG', 'Chemical', '-', (190, 194))	('malignant neuroendocrine tumors', 'Disease', (110, 141))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (120, 140))
59640	19672813	A retrospective analysis of 19 patients with malignant PCC or paraganglioma revealed an objective tumor response in 47% after treatment with 131I-MIBG with a median initial dose of 7.4 GBq (200 mCi) and a median cumulative dose of 22.2 GBq (600 mCi).	('131I-MIBG', 'Chemical', '-', (141, 150))	('GBq', 'Chemical', '-', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PCC', 'Phenotype', 'HP:0002666', (55, 58))	('paraganglioma', 'Phenotype', 'HP:0002668', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GBq', 'Chemical', '-', (236, 239))	('paraganglioma', 'Disease', (62, 75))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Disease', (98, 103))	('131I-MIBG', 'Var', (141, 150))	('paraganglioma', 'Disease', 'MESH:D010235', (62, 75))
59643	19672813	Despite a lack of complete tumor response, a palliative treatment effect of 131I-MIBG therapy has been noted.	('131I-MIBG', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('131I-MIBG', 'Chemical', '-', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
59644	19672813	published data from 28 patients treated with 131I-MIBG and showed a partial remission of tumor size in 8 patients and a biochemical PR in 12 patients.	('patients', 'Species', '9606', (105, 113))	('131I-MIBG', 'Chemical', '-', (45, 54))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('131I-MIBG', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('patients', 'Species', '9606', (141, 149))
59648	19672813	Treatment with high-dose 131I-MIBG in a number of patients resulted in an objective tumor response in 30% of patients, stabilization of disease in 57% of patients, and progression of disease in 13% of patients.	('patients', 'Species', '9606', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('131I-MIBG', 'Chemical', '-', (25, 34))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patients', 'Species', '9606', (154, 162))	('stabilization', 'MPA', (119, 132))	('tumor', 'Disease', (84, 89))	('131I-MIBG', 'Var', (25, 34))
59662	19672813	According to this study, treatment with high-dose of 131I-MIBG produced a sustained CR, PR, or SD in 67% of patients, with tolerable toxicity.	('131I-MIBG', 'Chemical', '-', (53, 62))	('toxicity', 'Disease', 'MESH:D064420', (133, 141))	('toxicity', 'Disease', (133, 141))	('131I-MIBG', 'Var', (53, 62))	('patients', 'Species', '9606', (108, 116))	('SD', 'Disease', 'MESH:D029461', (95, 97))
59664	19672813	Combination of 131I-MIBG therapy with chemotherapy did not show any convincing results, but an increased toxicity, and cannot be recommended.	('131I-MIBG', 'Var', (15, 24))	('toxicity', 'Disease', 'MESH:D064420', (105, 113))	('toxicity', 'Disease', (105, 113))	('131I-MIBG', 'Chemical', '-', (15, 24))
59676	19672813	Although the uptake intensity and number of tumor sites of MIBG-scan was superior to 111In-octreotide, seven foci were only found by octreotide scintigraphy.	('MIBG-scan', 'Var', (59, 68))	('MIBG', 'Chemical', '-', (59, 63))	('uptake intensity', 'MPA', (13, 29))	('octreotide', 'Chemical', 'MESH:D015282', (133, 143))	('octreotide', 'Chemical', 'MESH:D015282', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('111In-octreotide', 'Chemical', 'MESH:C094279', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
59693	19672813	A comparative analysis showed superior effects of treatment with SOM230 versus octreotide (OCT) in primary PCC cell cultures, concerning the reduction of catecholamine levels, modulation of cell growth, and apoptosis.	('catecholamine levels', 'MPA', (154, 174))	('catecholamine', 'Chemical', 'MESH:D002395', (154, 167))	('apoptosis', 'CPA', (207, 216))	('cell growth', 'CPA', (190, 201))	('SOM230', 'Var', (65, 71))	('octreotide', 'Chemical', 'MESH:D015282', (79, 89))	('OCT', 'Chemical', 'MESH:D015282', (91, 94))	('reduction', 'NegReg', (141, 150))	('PCC', 'Phenotype', 'HP:0002666', (107, 110))
59716	19672813	However, CVD has been shown to produce partial remissions and in single cases complete remissions, to improve symptoms and rarely, to lead to tumor shrinkage that made surgical resection possible.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('improve', 'PosReg', (102, 109))	('CVD', 'Var', (9, 12))	('tumor', 'Disease', (142, 147))	('symptoms', 'MPA', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
59737	19672813	This was confirmed by a small series study of 3 patients with malignant paraganglioma reporting one very good partial remission and 2 PR induced by a therapy with sunitinib at a standard dose (50 mg daily, 4 weeks on, 2 weeks off).	('malignant paraganglioma', 'Disease', (62, 85))	('malignant paraganglioma', 'Disease', 'MESH:C565335', (62, 85))	('sunitinib', 'Chemical', 'MESH:D000077210', (163, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('50', 'Var', (193, 195))	('patients', 'Species', '9606', (48, 56))
59763	19672813	Featuring a moderate progression, these patients may benefit from a 131I-MIBG therapy, which can achieve substantial tumor responses and possibly an elimination of micrometastases.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('metastases', 'Disease', (169, 179))	('patients', 'Species', '9606', (40, 48))	('tumor', 'Disease', (117, 122))	('131I-MIBG', 'Var', (68, 77))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('131I-MIBG', 'Chemical', '-', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
59766	19672813	Combination of 131I-MIBG therapy with chemotherapy did not show any benefit, but as it is accompanied by increased toxicity, it may not be recommended.	('131I-MIBG', 'Var', (15, 24))	('toxicity', 'Disease', (115, 123))	('toxicity', 'Disease', 'MESH:D064420', (115, 123))	('131I-MIBG', 'Chemical', '-', (15, 24))
59835	33805450	Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune-Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association.	('GH-secreting pituitary adenoma', 'Disease', (11, 41))	('neoplasia', 'Phenotype', 'HP:0002664', (275, 284))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (24, 41))	('PA', 'Phenotype', 'HP:0002893', (120, 122))	('glioma', 'Phenotype', 'HP:0009733', (372, 378))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (256, 284))	('paraganglioma', 'Phenotype', 'HP:0002668', (365, 378))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (90, 116))	('tumours', 'Disease', (72, 79))	('AIP', 'Gene', '9049', (145, 148))	('multiple endocrine neoplasia', 'Disease', (256, 284))	('familial isolated pituitary adenoma', 'Disease', 'MESH:C566321', (81, 116))	('phaeochromocytoma/paraganglioma-pituitary adenoma', 'Disease', 'MESH:D010911', (347, 396))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (265, 284))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('Carney complex', 'Disease', (329, 343))	('systemic diseases', 'Disease', (233, 250))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('systemic diseases', 'Disease', 'MESH:D034721', (233, 250))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (379, 396))	('AIP', 'Gene', (145, 148))	('endocrine neoplasia type', 'Disease', 'MESH:D018761', (265, 289))	('McCune-Albright syndrome', 'Disease', 'MESH:D005357', (303, 327))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('GH-secreting pituitary adenoma', 'Disease', 'MESH:D049912', (11, 41))	('GPR101', 'Gene', '83550', (162, 168))	('endocrine neoplasia type', 'Disease', (265, 289))	('phaeochromocytoma/paraganglioma-pituitary adenoma', 'Disease', (347, 396))	('familial isolated pituitary adenoma', 'Disease', (81, 116))	('GPR101', 'Gene', (162, 168))	('duplications', 'Var', (169, 181))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (99, 116))	('McCune-Albright syndrome', 'Disease', (303, 327))	('XLAG', 'Chemical', '-', (207, 211))	('PA', 'Phenotype', 'HP:0002893', (43, 45))
59836	33805450	This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.	('acromegaly', 'Phenotype', 'HP:0000845', (70, 80))	('gigantism', 'Disease', (85, 94))	('acromegaly', 'Disease', (70, 80))	('acromegaly', 'Disease', 'MESH:D000172', (70, 80))	('mutations', 'Var', (44, 53))
59848	33805450	Additionally, deficiency in the immunoglobulin superfamily member 1 (IGSF1), may result in somatotroph neurosecretory hyperfunction in adults.	('IGSF1', 'Gene', '3547', (69, 74))	('IGSF1', 'Gene', (69, 74))	('immunoglobulin superfamily member 1', 'Gene', (32, 67))	('somatotroph neurosecretory hyperfunction', 'Disease', 'MESH:D049912', (91, 131))	('immunoglobulin superfamily member 1', 'Gene', '3547', (32, 67))	('result in', 'Reg', (81, 90))	('deficiency', 'Var', (14, 24))	('somatotroph neurosecretory hyperfunction', 'Disease', (91, 131))
59849	33805450	Hereditary GH-secreting pituitary tumours can manifest as an isolated manifestation, called familial isolated pituitary adenoma (FIPA), due to either loss-of-function mutations in aryl hydrocarbon receptor interacting protein (AIP) or due to gain-of-function gene duplication in GPR101, causing XLAG.	('Hereditary GH-secreting pituitary tumours', 'Disease', 'MESH:D049912', (0, 41))	('XLAG', 'Disease', (295, 299))	('aryl hydrocarbon receptor interacting protein', 'Gene', (180, 225))	('mutations', 'Var', (167, 176))	('familial isolated pituitary adenoma', 'Disease', (92, 127))	('gain-of-function', 'PosReg', (242, 258))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('AIP', 'Gene', '9049', (227, 230))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('Hereditary GH-secreting pituitary tumours', 'Disease', (0, 41))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (110, 127))	('loss-of-function', 'NegReg', (150, 166))	('AIP', 'Gene', (227, 230))	('gene duplication', 'Var', (259, 275))	('aryl hydrocarbon receptor interacting protein', 'Gene', '9049', (180, 225))	('isolated pituitary adenoma', 'Phenotype', 'HP:0011761', (101, 127))	('familial isolated pituitary adenoma', 'Disease', 'MESH:C566321', (92, 127))	('PA', 'Phenotype', 'HP:0002893', (131, 133))	('GPR101', 'Gene', '83550', (279, 285))	('pituitary tumour', 'Phenotype', 'HP:0002893', (24, 40))	('GPR101', 'Gene', (279, 285))	('XLAG', 'Chemical', '-', (295, 299))
59853	33805450	However, due to de novo mutations or lack of known family history, often as a result of low disease penetrance, FIPA can also be present in apparently sporadic:so called simplex:patients or in patients with mosaicism.	('patients', 'Species', '9606', (193, 201))	('PA', 'Phenotype', 'HP:0002893', (114, 116))	('FIPA', 'Disease', (112, 116))	('patients', 'Species', '9606', (178, 186))	('low disease', 'Disease', 'MESH:D009800', (88, 99))	('low disease', 'Disease', (88, 99))	('mutations', 'Var', (24, 33))	('simplex', 'Disease', (170, 177))
59857	33805450	Depending on genetic background, FIPA can be divided into three subgroups: (i) AIP mutation-positive patients; (ii) families with duplication of GPR101 (all XLAG cases have GH excess, with the vast majority combined with prolactin excess); (iii) families with no identifiable genetic cause.	('duplication', 'Var', (130, 141))	('patients', 'Species', '9606', (101, 109))	('GH', 'Gene', '2688', (173, 175))	('mutation-positive', 'Reg', (83, 100))	('AIP', 'Gene', '9049', (79, 82))	('GPR101', 'Gene', '83550', (145, 151))	('PA', 'Phenotype', 'HP:0002893', (35, 37))	('GPR101', 'Gene', (145, 151))	('AIP', 'Gene', (79, 82))	('XLAG', 'Chemical', '-', (157, 161))	('prolactin excess', 'Phenotype', 'HP:0000870', (221, 237))
59858	33805450	In our cohort of 318 AIP (and GPR101) mutation-negative FIPA families, 21% have homogenous acromegaly (representing 46% of the 147 homogeneous AIP negative families) and 32% has heterogenous FIPA with at least member with acromegaly (59% of the 171 heterogenous FIPA kindreds).	('acromegaly', 'Disease', 'MESH:D000172', (91, 101))	('GPR101', 'Gene', '83550', (30, 36))	('acromegaly', 'Disease', 'MESH:D000172', (222, 232))	('mutation-negative', 'Var', (38, 55))	('PA', 'Phenotype', 'HP:0002893', (264, 266))	('GPR101', 'Gene', (30, 36))	('PA', 'Phenotype', 'HP:0002893', (193, 195))	('acromegaly', 'Disease', (222, 232))	('AIP', 'Gene', (143, 146))	('AIP', 'Gene', (21, 24))	('acromegaly', 'Phenotype', 'HP:0000845', (91, 101))	('AIP', 'Gene', '9049', (143, 146))	('AIP', 'Gene', '9049', (21, 24))	('acromegaly', 'Disease', (91, 101))	('acromegaly', 'Phenotype', 'HP:0000845', (222, 232))	('PA', 'Phenotype', 'HP:0002893', (58, 60))
59862	33805450	Overview: AIP mutations can be identified in up to 40% of familial acromegaly and gigantism.	('gigantism', 'Disease', (82, 91))	('familial acromegaly', 'Disease', (58, 77))	('familial acromegaly', 'Disease', 'MESH:D000172', (58, 77))	('acromegaly', 'Phenotype', 'HP:0000845', (67, 77))	('AIP', 'Gene', '9049', (10, 13))	('mutations', 'Var', (14, 23))	('AIP', 'Gene', (10, 13))
59863	33805450	However, AIP mutations are also identified in apparently sporadic (simplex) cases of PitNETs, mostly among young-onset patients.	('AIP', 'Gene', (9, 12))	('AIP', 'Gene', '9049', (9, 12))	('patients', 'Species', '9606', (119, 127))	('PitNETs', 'Disease', (85, 92))	('identified', 'Reg', (32, 42))	('mutations', 'Var', (13, 22))
59864	33805450	This phenomenon is observed due to low penetrance (12.5-30%) of the disease in AIP mutation carriers, rather than de novo mutations.	('mutation', 'Var', (83, 91))	('AIP', 'Gene', (79, 82))	('AIP', 'Gene', '9049', (79, 82))
59866	33805450	In acromegaly/gigantism patients associated with AIP mutations, a higher GH level has been observed, with no difference in insulin growth factor 1 (IGF-1) level and prolactin co-secretion.	('acromegaly', 'Disease', (3, 13))	('acromegaly', 'Phenotype', 'HP:0000845', (3, 13))	('insulin growth factor 1', 'Gene', (123, 146))	('GH', 'Gene', '2688', (73, 75))	('mutations', 'Var', (53, 62))	('acromegaly', 'Disease', 'MESH:D000172', (3, 13))	('higher', 'PosReg', (66, 72))	('patients', 'Species', '9606', (24, 32))	('AIP', 'Gene', '9049', (49, 52))	('insulin growth factor 1', 'Gene', '3479', (123, 146))	('IGF-1', 'Gene', '3479', (148, 153))	('AIP', 'Gene', (49, 52))	('IGF-1', 'Gene', (148, 153))
59876	33805450	These results highlight the clinical value of genetic testing for AIP mutations among acromegalic patients and their family members.	('mutations', 'Var', (70, 79))	('acromegalic', 'Disease', 'MESH:D000172', (86, 97))	('acromegalic', 'Disease', (86, 97))	('patients', 'Species', '9606', (98, 106))	('AIP', 'Gene', '9049', (66, 69))	('AIP', 'Gene', (66, 69))
59877	33805450	On the other hand, with the identification of small, non-functioning lesions, probably representing incidentalomas, screening can lead to increased anxiety and health care spending.	('increased', 'PosReg', (138, 147))	('lead', 'Reg', (130, 134))	('anxiety', 'Disease', (148, 155))	('anxiety', 'Phenotype', 'HP:0000739', (148, 155))	('lesions', 'Var', (69, 76))	('anxiety', 'Disease', 'MESH:D001007', (148, 155))	('non-functioning', 'NegReg', (53, 68))
59882	33805450	The association between AIP mutations and pituitary tumours was found ten years later in 2006 in North-Finnish and Italian kindreds.	('AIP', 'Gene', '9049', (24, 27))	('association', 'Interaction', (4, 15))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('pituitary tumours', 'Disease', (42, 59))	('pituitary tumour', 'Phenotype', 'HP:0002893', (42, 58))	('pituitary tumours', 'Disease', 'MESH:D010911', (42, 59))	('mutations', 'Var', (28, 37))	('AIP', 'Gene', (24, 27))
59883	33805450	Subsequently, mutation in the AIP gene was noted as the most common genetic cause of FIPA, including familial acromegaly and gigantism cases.	('PA', 'Phenotype', 'HP:0002893', (87, 89))	('AIP', 'Gene', '9049', (30, 33))	('acromegaly', 'Phenotype', 'HP:0000845', (110, 120))	('familial acromegaly', 'Disease', (101, 120))	('AIP', 'Gene', (30, 33))	('mutation', 'Var', (14, 22))	('FIPA', 'Disease', (85, 89))	('cause', 'Reg', (76, 81))	('gigantism', 'Disease', (125, 134))	('familial acromegaly', 'Disease', 'MESH:D000172', (101, 120))
59884	33805450	Several sets of founder mutations have been identified, such as the original cohort of Finnish patients (Q14* mutation), but also Italian (R304*), English (a small duplication mutation) and Northern Irish (R304* independent from the Italian) cohorts, the latter providing a genetic background to the historical and folklore Irish giant legends.	('Q14*', 'SUBSTITUTION', 'None', (105, 109))	('patients', 'Species', '9606', (95, 103))	('R304*', 'SUBSTITUTION', 'None', (206, 211))	('R304*', 'Var', (139, 144))	('R304*', 'SUBSTITUTION', 'None', (139, 144))	('Q14*', 'Var', (105, 109))	('R304*', 'Var', (206, 211))
59888	33805450	AIP mutation results in elevated concentrations of cAMP.	('concentrations', 'MPA', (33, 47))	('mutation', 'Var', (4, 12))	('cAMP', 'Chemical', '-', (51, 55))	('AIP', 'Gene', '9049', (0, 3))	('elevated', 'PosReg', (24, 32))	('AIP', 'Gene', (0, 3))
59889	33805450	Disrupting the cAMP pathway is an important factor contributing to pituitary tumourigenesis observed in CNC, MAS and XLAG.	('pituitary tumour', 'Disease', 'MESH:D010911', (67, 83))	('cAMP', 'Chemical', '-', (15, 19))	('XLAG', 'Chemical', '-', (117, 121))	('cAMP pathway', 'Pathway', (15, 27))	('Disrupting', 'Var', (0, 10))	('CNC', 'Disease', (104, 107))	('MAS', 'Disease', (109, 112))	('pituitary tumour', 'Phenotype', 'HP:0002893', (67, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('pituitary tumour', 'Disease', (67, 83))
59890	33805450	Dysfunction of AIP protein leads to reduced Galphai-2 and Galphai-3 protein expression, which is responsible for inhibition of cAMP synthesis.	('Dysfunction', 'Var', (0, 11))	('Galphai-3 protein', 'Protein', (58, 75))	('AIP', 'Gene', (15, 18))	('AIP', 'Gene', '9049', (15, 18))	('cAMP', 'Chemical', '-', (127, 131))	('expression', 'MPA', (76, 86))	('Galphai-2', 'Protein', (44, 53))	('reduced', 'NegReg', (36, 43))
59893	33805450	While truncating mutations in AIP are obviously disease-causing, it is a challenge to predict pathogenicity of missense variants.	('disease-causing', 'Reg', (48, 63))	('AIP', 'Gene', (30, 33))	('truncating mutations', 'Var', (6, 26))	('AIP', 'Gene', '9049', (30, 33))
59894	33805450	Diagnosis: Genetic testing includes sequencing in tumour suppressor genes.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (50, 56))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('sequencing', 'Var', (36, 46))
59896	33805450	As most cases develop symptoms before the age of 30 years, in asymptomatic AIP mutation carriers, follow-up is suggested to be performed until this age.	('symptoms', 'MPA', (22, 30))	('AIP', 'Gene', '9049', (75, 78))	('AIP', 'Gene', (75, 78))	('develop', 'Reg', (14, 21))	('mutation', 'Var', (79, 87))
59899	33805450	Patients with AIP mutation require more often multimodal approaches including radiotherapy and reoperation.	('AIP', 'Gene', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('AIP', 'Gene', '9049', (14, 17))	('mutation', 'Var', (18, 26))
59924	33805450	To date, all females have been shown to have de novo germline GPR101 duplication, while mosaic mutations have been described in males except for a few familial cases with mother-to-son inheritance.	('GPR101', 'Gene', '83550', (62, 68))	('GPR101', 'Gene', (62, 68))	('duplication', 'Var', (69, 80))
59925	33805450	The phenotype of patients with somatic and germline GPR101 duplication remains the same.	('duplication', 'Var', (59, 70))	('patients', 'Species', '9606', (17, 25))	('GPR101', 'Gene', '83550', (52, 58))	('GPR101', 'Gene', (52, 58))
59926	33805450	Diagnosis: Genetic testing should be performed using array comparative genomic hybridisation (aCGH) array, but in negative cases with a suggestive phenotype, alternative methods such as copy number variation digital droplet polymerase chain reaction (PCR) for GPR101 to detect smaller duplications or high-density aCGH should be considered.	('GPR101', 'Gene', (260, 266))	('GH', 'Gene', '2688', (96, 98))	('duplications', 'Var', (285, 297))	('GH', 'Gene', '2688', (316, 318))	('copy', 'Var', (186, 190))	('GPR101', 'Gene', '83550', (260, 266))
59927	33805450	On suspicion of a mosaic XLAG mutation, analysis of affected tissue should be performed.	('mosaic', 'Var', (18, 24))	('mutation', 'Var', (30, 38))	('XLAG', 'Chemical', '-', (25, 29))	('XLAG', 'Gene', (25, 29))
59935	33805450	Conversely, MEN1 mutations have been described in 1.2% of sporadic acromegaly patients younger than 30 years The prevalence of patients with acromegaly and MEN1 phenotype (defined as occurrence of at least one other MEN1-associated tumour) has been noted in 6.6% of 414 patients with acromegaly, but the prevalence of MEN1 mutations in this group is much lower.	('patients', 'Species', '9606', (78, 86))	('acromegaly', 'Disease', (67, 77))	('acromegaly', 'Phenotype', 'HP:0000845', (67, 77))	('MEN1', 'Gene', (318, 322))	('mutations', 'Var', (17, 26))	('sporadic acromegaly', 'Disease', (58, 77))	('MEN1', 'Gene', '4221', (156, 160))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('MEN1', 'Gene', (216, 220))	('tumour', 'Disease', (232, 238))	('MEN1', 'Gene', (156, 160))	('acromegaly', 'Disease', 'MESH:D000172', (141, 151))	('MEN1', 'Gene', '4221', (12, 16))	('MEN1', 'Gene', '4221', (216, 220))	('acromegaly', 'Disease', 'MESH:D000172', (284, 294))	('patients', 'Species', '9606', (270, 278))	('acromegaly', 'Phenotype', 'HP:0000845', (141, 151))	('acromegaly', 'Disease', (141, 151))	('patients', 'Species', '9606', (127, 135))	('MEN1', 'Gene', (12, 16))	('acromegaly', 'Disease', (284, 294))	('MEN1', 'Gene', '4221', (318, 322))	('acromegaly', 'Phenotype', 'HP:0000845', (284, 294))	('acromegaly', 'Disease', 'MESH:D000172', (67, 77))	('sporadic acromegaly', 'Disease', 'MESH:D000172', (58, 77))
59945	33805450	Ectopic GHRH and GH production due to lung neuroendocrine tumour related to MEN1 mutation has been found only in one patient.	('GHRH', 'Gene', '2691', (8, 12))	('GH', 'Gene', '2688', (8, 10))	('GHRH', 'Gene', (8, 12))	('lung neuroendocrine tumour', 'Disease', (38, 64))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('mutation', 'Var', (81, 89))	('MEN1', 'Gene', (76, 80))	('GH', 'Gene', '2688', (17, 19))	('MEN1', 'Gene', '4221', (76, 80))	('Ectopic', 'MPA', (0, 7))	('lung neuroendocrine tumour', 'Disease', 'MESH:D008175', (38, 64))	('patient', 'Species', '9606', (117, 124))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (43, 64))
59946	33805450	Gigantism associated with MEN1 mutation occurs in approximately 1% of cases, this could be due to a pituitary tumour or, rarely, due to a GHRH-secreting pancreas tumour.	('due', 'Reg', (91, 94))	('pancreas tumour', 'Disease', (153, 168))	('pancreas tumour', 'Disease', 'MESH:D010190', (153, 168))	('mutation', 'Var', (31, 39))	('pituitary tumour', 'Phenotype', 'HP:0002893', (100, 116))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('pituitary tumour', 'Disease', (100, 116))	('GHRH', 'Gene', '2691', (138, 142))	('Gigantism', 'Disease', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('pancreas tumour', 'Phenotype', 'HP:0002894', (153, 168))	('pituitary tumour', 'Disease', 'MESH:D010911', (100, 116))	('MEN1', 'Gene', (26, 30))	('GHRH', 'Gene', (138, 142))	('MEN1', 'Gene', '4221', (26, 30))
59952	33805450	MEN1 mutated PAs manifest predominantly in the 4th decade of life, but various ages of onset have been noted (from 5 years to 90 years).	('MEN1', 'Gene', '4221', (0, 4))	('PAs', 'Disease', (13, 16))	('PAs', 'Chemical', 'MESH:D011478', (13, 16))	('mutated', 'Var', (5, 12))	('PA', 'Phenotype', 'HP:0002893', (13, 15))	('MEN1', 'Gene', (0, 4))
59956	33805450	Genetics: Inactivating mutation of the MEN1 gene, located on chromosome 11q13, was first reported in 1997, but the phenotype of MEN1 syndrome was first noted in a patient with acromegaly and enlarged parathyroid glands by Erdheim in 1903.	('enlarged parathyroid glands', 'Phenotype', 'HP:0008208', (191, 218))	('acromegaly', 'Phenotype', 'HP:0000845', (176, 186))	('MEN1', 'Gene', '4221', (128, 132))	('acromegaly', 'Disease', (176, 186))	('MEN1', 'Gene', (128, 132))	('acromegaly', 'Disease', 'MESH:D000172', (176, 186))	('Inactivating mutation', 'Var', (10, 31))	('patient', 'Species', '9606', (163, 170))	('MEN1', 'Gene', (39, 43))	('MEN1', 'Gene', '4221', (39, 43))
59958	33805450	More recently, MEN1 mosaic mutations have also been reported.	('MEN1', 'Gene', '4221', (15, 19))	('MEN1', 'Gene', (15, 19))	('mosaic mutations', 'Var', (20, 36))
59959	33805450	Most pathogenic germline MEN1 variants are frameshift mutations (42%), followed by nonsense mutations (14%), missense mutations, splice site mutations and large deletions.	('variants', 'Var', (30, 38))	('MEN1', 'Gene', '4221', (25, 29))	('missense mutations', 'Var', (109, 127))	('pathogenic', 'Reg', (5, 15))	('frameshift mutations', 'Var', (43, 63))	('MEN1', 'Gene', (25, 29))
59960	33805450	Inactivating mutations of MEN1 lead to premature menin truncation and its impaired activity.	('activity', 'MPA', (83, 91))	('menin', 'Gene', (49, 54))	('impaired', 'NegReg', (74, 82))	('Inactivating mutations', 'Var', (0, 22))	('lead to', 'Reg', (31, 38))	('menin', 'Gene', '4221', (49, 54))	('MEN1', 'Gene', (26, 30))	('premature', 'MPA', (39, 48))	('MEN1', 'Gene', '4221', (26, 30))
59964	33805450	Diagnosis: Diagnosis of MEN1 could be (i) clinically established if a patient develops two or more MEN1 associated tumours (pituitary and parathyroid adenoma, pancreatic neuroendocrine tumour); (ii) by the presence of one characteristic MEN1 tumour and one first-degree relative with confirmed MEN1 mutation or (iii) due to family cascade genetic screening in asymptomatic carriers.	('tumours', 'Disease', (115, 122))	('MEN1', 'Gene', '4221', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('MEN1', 'Gene', (294, 298))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('tumour', 'Disease', (115, 121))	('pancreatic neuroendocrine tumour', 'Phenotype', 'HP:0030405', (159, 191))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('MEN1', 'Gene', (24, 28))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('tumour', 'Disease', (242, 248))	('MEN1', 'Gene', '4221', (237, 241))	('patient', 'Species', '9606', (70, 77))	('parathyroid adenoma', 'Phenotype', 'HP:0002897', (138, 157))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (170, 191))	('parathyroid adenoma', 'Disease', (138, 157))	('pancreatic neuroendocrine tumour', 'Disease', 'MESH:D010190', (159, 191))	('MEN1', 'Gene', (237, 241))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('parathyroid adenoma', 'Disease', 'MESH:D010282', (138, 157))	('tumour', 'Disease', (185, 191))	('MEN1', 'Gene', '4221', (99, 103))	('pancreatic neuroendocrine tumour', 'Disease', (159, 191))	('mutation', 'Var', (299, 307))	('MEN1', 'Gene', '4221', (294, 298))	('MEN1', 'Gene', (99, 103))
59966	33805450	MEN1 mutation carriers should undergo periodic clinical screening.	('MEN1', 'Gene', '4221', (0, 4))	('mutation', 'Var', (5, 13))	('MEN1', 'Gene', (0, 4))
59970	33805450	It has been suggested that MEN1 gene replacement, by the use of adenoviral vectors, would decrease pituitary tumour proliferation.	('MEN1', 'Gene', '4221', (27, 31))	('pituitary tumour', 'Disease', (99, 115))	('MEN1', 'Gene', (27, 31))	('gene replacement', 'Var', (32, 48))	('pituitary tumour', 'Disease', 'MESH:D010911', (99, 115))	('decrease', 'NegReg', (90, 98))	('pituitary tumour', 'Phenotype', 'HP:0002893', (99, 115))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
59971	33805450	Another option is the potential use of a monoclonal antibody to the vascular endothelial growth factor (VEGF-A), which inhibits angiogenic pathways.	('angiogenic pathways', 'Pathway', (128, 147))	('vascular endothelial growth factor', 'Gene', (68, 102))	('vascular endothelial growth factor', 'Gene', '7422', (68, 102))	('VEGF-A', 'Gene', (104, 110))	('monoclonal antibody', 'Var', (41, 60))	('inhibits', 'NegReg', (119, 127))
59972	33805450	In a study of MEN1 mouse models with prolactinoma, the implementation of VEGF-A resulted in lowering of the prolactin concentration in treated animals but not controls.	('MEN1', 'Gene', '4221', (14, 18))	('prolactinoma', 'Disease', (37, 49))	('MEN1', 'Gene', (14, 18))	('lowering', 'NegReg', (92, 100))	('prolactin concentration', 'MPA', (108, 131))	('lowering of the prolactin concentration', 'Phenotype', 'HP:0008202', (92, 131))	('prolactinoma', 'Disease', 'MESH:D015175', (37, 49))	('prolactinoma', 'Phenotype', 'HP:0040278', (37, 49))	('implementation', 'Var', (55, 69))	('mouse', 'Species', '10090', (19, 24))	('VEGF-A', 'Gene', (73, 79))
59974	33805450	MEN4: About 10-20% of patients presenting a MEN1-like phenotype have no identifiable MEN1 mutations.	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (22, 30))	('MEN1', 'Gene', '4221', (44, 48))	('MEN1', 'Gene', (44, 48))	('MEN1', 'Gene', (85, 89))	('MEN1', 'Gene', '4221', (85, 89))
59975	33805450	Further genetic investigations have revealed a small number of patients harbouring loss of function mutation in the CDKN1B gene (up to 3% of cases with negative MEN1 results).	('MEN1', 'Gene', '4221', (161, 165))	('CDKN1B', 'Gene', (116, 122))	('CDKN1B', 'Gene', '1027', (116, 122))	('loss of function', 'NegReg', (83, 99))	('mutation', 'Var', (100, 108))	('patients', 'Species', '9606', (63, 71))	('MEN1', 'Gene', (161, 165))
59976	33805450	The syndrome of association between MEN1 phenotype and CDKN1B mutations has been termed MEN4.	('CDKN1B', 'Gene', '1027', (55, 61))	('CDKN1B', 'Gene', (55, 61))	('MEN1', 'Gene', (36, 40))	('MEN1', 'Gene', '4221', (36, 40))	('mutations', 'Var', (62, 71))
59978	33805450	To date, less than 50 cases with CDKN1B mutations (the majority of patients presenting with hyperparathyroidism) have been noted, one-third of those conjoined with pituitary tumours.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('patients', 'Species', '9606', (67, 75))	('CDKN1B', 'Gene', '1027', (33, 39))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (92, 111))	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (92, 111))	('pituitary tumour', 'Phenotype', 'HP:0002893', (164, 180))	('hyperparathyroidism', 'Disease', (92, 111))	('mutations', 'Var', (40, 49))	('CDKN1B', 'Gene', (33, 39))	('pituitary tumours', 'Disease', (164, 181))	('pituitary tumours', 'Disease', 'MESH:D010911', (164, 181))
59980	33805450	In a large cohort of 190 patients with Cushing's disease, 2.6% had CDKN1B variants.	("Cushing's disease", 'Disease', (39, 56))	('CDKN1B', 'Gene', '1027', (67, 73))	('CDKN1B', 'Gene', (67, 73))	('patients', 'Species', '9606', (25, 33))	('variants', 'Var', (74, 82))	("Cushing's disease", 'Disease', 'MESH:D003480', (39, 56))
59992	33805450	Genetics: MAS is caused by mosaicism for mutations in GNAS gene, located at chromosome 20q13.3.	('mutations', 'Var', (41, 50))	('MAS', 'Disease', (10, 13))	('GNAS', 'Gene', (54, 58))	('GNAS', 'Gene', '2778', (54, 58))	('caused by', 'Reg', (17, 26))
59994	33805450	A gain-of-function mutation in the GNAS gene, affecting codons Arg201 and Gln227, results in a constitutively activated cAMP pathway and leads to persistent GH hypersecretion and cell proliferation..	('Gln227', 'Chemical', '-', (74, 80))	('gain-of-function', 'PosReg', (2, 18))	('cAMP', 'Chemical', '-', (120, 124))	('GNAS', 'Gene', '2778', (35, 39))	('GH', 'Gene', '2688', (157, 159))	('Arg201', 'Chemical', '-', (63, 69))	('cAMP pathway', 'Pathway', (120, 132))	('GNAS', 'Gene', (35, 39))	('Gln227', 'Var', (74, 80))	('cell proliferation..', 'CPA', (179, 199))	('codons', 'Var', (56, 62))
60014	33805450	The analysis of archive tissue revealed a PRKAR1A mutation.	('PRKAR1A', 'Gene', '5573', (42, 49))	('PRKAR1A', 'Gene', (42, 49))	('mutation', 'Var', (50, 58))
60016	33805450	Most are caused by a germline-inactivating mutation mainly in the PRKAR1A gene (CNC1), located on the 17q22-24 locus, but recently other protein kinase A regulatory subunit 1alpha (PKA) mutations, including PRKACB, have also been described.	('caused by', 'Reg', (9, 18))	('mutations', 'Var', (186, 195))	('CNC1', 'Gene', (80, 84))	('PKA', 'Gene', (181, 184))	('PRKAR1A', 'Gene', (66, 73))	('PRKACB', 'Gene', '5567', (207, 213))	('PRKAR1A', 'Gene', '5573', (66, 73))	('CNC1', 'Gene', '5573', (80, 84))	('PRKACB', 'Gene', (207, 213))
60018	33805450	Patients with large deletions of PRKAR1A develop the diseases earlier with a more severe phenotype, including metastatic psammomatous melanotic schwannoma.	('PRKAR1A', 'Gene', (33, 40))	('develop', 'PosReg', (41, 48))	('large deletions', 'Var', (14, 29))	('psammomatous melanotic schwannoma', 'Disease', (121, 154))	('PRKAR1A', 'Gene', '5573', (33, 40))	('psammomatous melanotic schwannoma', 'Disease', 'MESH:D008577', (121, 154))	('Patients', 'Species', '9606', (0, 8))	('schwannoma', 'Phenotype', 'HP:0100008', (144, 154))
60020	33805450	Inactivating mutations of PRKAR1A lead to uncontrolled activation of cAMP-dependent kinase activity in affected tissues.	('PRKAR1A', 'Gene', (26, 33))	('uncontrolled', 'MPA', (42, 54))	('Inactivating mutations', 'Var', (0, 22))	('PRKAR1A', 'Gene', '5573', (26, 33))	('cAMP', 'Chemical', '-', (69, 73))	('cAMP-dependent', 'Enzyme', (69, 83))	('activation', 'PosReg', (55, 65))
60024	33805450	Another way to confirm CNC diagnosis is the occurrence of one major criterion and an affected first-degree relative or a known inactivating PRKAR1A mutation.	('CNC', 'Disease', (23, 26))	('PRKAR1A', 'Gene', (140, 147))	('inactivating', 'Var', (127, 139))	('PRKAR1A', 'Gene', '5573', (140, 147))	('mutation', 'Var', (148, 156))
60033	33805450	Genetic predisposition of this rare condition has been relatively recently found in 2009 in a familial case of prolactinoma with paraganglioma and SDHB mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('prolactinoma', 'Disease', 'MESH:D015175', (111, 123))	('prolactinoma', 'Phenotype', 'HP:0040278', (111, 123))	('paraganglioma', 'Disease', (129, 142))	('SDHB', 'Gene', '6390', (147, 151))	('paraganglioma', 'Disease', 'MESH:D010235', (129, 142))	('SDHB', 'Gene', (147, 151))	('prolactinoma', 'Disease', (111, 123))	('mutation', 'Var', (152, 160))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
60034	33805450	Subsequently, in 2012, a patient with aggressive GH-secreting PitNETs with bilateral phaeochromocytomas and a pathogenic variant of SDHD mutation was described.	('SDHD', 'Gene', (132, 136))	('variant', 'Var', (121, 128))	('mutation', 'Var', (137, 145))	('patient', 'Species', '9606', (25, 32))	('bilateral phaeochromocytomas', 'Disease', (75, 103))	('bilateral phaeochromocytomas', 'Disease', 'MESH:D006312', (75, 103))	('GH', 'Gene', '2688', (49, 51))	('SDHD', 'Gene', '6392', (132, 136))
60036	33805450	Acromegaly with SDHx mutation: The most common genetic cause of 3Pa is a germline loss of function mutation of the succinate dehydrogenase (SDH)x gene.	('SDH', 'Gene', '6390', (140, 143))	('loss of function', 'NegReg', (82, 98))	('SDH', 'Gene', (140, 143))	('mutation', 'Var', (99, 107))	('SDH', 'Gene', '6390', (16, 19))	('Acromegaly', 'Phenotype', 'HP:0000845', (0, 10))	('Acromegaly', 'Disease', 'MESH:D000172', (0, 10))	('3Pa', 'Disease', (64, 67))	('SDH', 'Gene', (16, 19))	('Acromegaly', 'Disease', (0, 10))
60037	33805450	GH-secreting PAs associated with SDHx mutations tend to be aggressive macroadenomas.	('SDH', 'Gene', (33, 36))	('PA', 'Phenotype', 'HP:0002893', (13, 15))	('SDH', 'Gene', '6390', (33, 36))	('PAs', 'Chemical', 'MESH:D011478', (13, 16))	('GH', 'Gene', '2688', (0, 2))	('aggressive macroadenomas', 'Disease', (59, 83))	('mutations', 'Var', (38, 47))	('aggressive macroadenomas', 'Disease', 'MESH:D001523', (59, 83))
60038	33805450	To date, 4 GH-PitNETs with an SDHx mutation have been described (SDHD and SDHB mutations).	('SDH', 'Gene', (74, 77))	('SDH', 'Gene', '6390', (65, 68))	('SDH', 'Gene', (30, 33))	('SDHB', 'Gene', '6390', (74, 78))	('SDHB', 'Gene', (74, 78))	('SDH', 'Gene', (65, 68))	('SDH', 'Gene', '6390', (74, 77))	('mutation', 'Var', (35, 43))	('GH', 'Gene', '2688', (11, 13))	('SDH', 'Gene', '6390', (30, 33))	('SDHD', 'Gene', '6392', (65, 69))	('SDHD', 'Gene', (65, 69))
60039	33805450	Gigantism related to SDHx mutation has not been reported yet.	('SDH', 'Gene', '6390', (21, 24))	('Gigantism', 'Disease', (0, 9))	('SDH', 'Gene', (21, 24))	('mutation', 'Var', (26, 34))
60042	33805450	A unique histopathological feature of pituitary adenoma with SDHx mutations is intracytoplasmic vacuoles, which can correspond to the presence of autophagic bodies.	('mutations', 'Var', (66, 75))	('pituitary adenoma', 'Disease', 'MESH:D010911', (38, 55))	('SDH', 'Gene', (61, 64))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (38, 55))	('SDH', 'Gene', '6390', (61, 64))	('pituitary adenoma', 'Disease', (38, 55))
60043	33805450	More recently, SDHx mutations have been observed in patients with an isolated pituitary tumour and without personal or familial history of PPGL, but none of them had somatotropinoma (3 prolactinomas out of 263 patients with PAs).	('somatotropinoma', 'Disease', 'MESH:D049912', (166, 181))	('pituitary tumour', 'Phenotype', 'HP:0002893', (78, 94))	('PA', 'Phenotype', 'HP:0002893', (224, 226))	('PPGL', 'Chemical', '-', (139, 143))	('pituitary tumour', 'Disease', (78, 94))	('prolactinomas', 'Disease', 'MESH:D015175', (185, 198))	('somatotropinoma', 'Disease', (166, 181))	('observed', 'Reg', (40, 48))	('pituitary tumour', 'Disease', 'MESH:D010911', (78, 94))	('SDH', 'Gene', '6390', (15, 18))	('prolactinomas', 'Disease', (185, 198))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (210, 218))	('PAs', 'Chemical', 'MESH:D011478', (224, 227))	('prolactinoma', 'Phenotype', 'HP:0040278', (185, 197))	('mutations', 'Var', (20, 29))	('patients', 'Species', '9606', (52, 60))	('SDH', 'Gene', (15, 18))
60046	33805450	Germline mutation of SDH results in the accumulation of oncometabolites that inhibit degradation of hypoxia transcription factor (HIFalpha).	('inhibit', 'NegReg', (77, 84))	('SDH', 'Gene', (21, 24))	('SDH', 'Gene', '6390', (21, 24))	('Germline mutation', 'Var', (0, 17))	('oncometabolites', 'MPA', (56, 71))	('hypoxia', 'Disease', 'MESH:D000860', (100, 107))	('hypoxia', 'Disease', (100, 107))	('accumulation', 'PosReg', (40, 52))
60047	33805450	The penetrance of pituitary tumours in SDHx mutation-positive patients is very low (1% of cases).	('SDH', 'Gene', (39, 42))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('mutation-positive', 'Var', (44, 61))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('pituitary tumour', 'Phenotype', 'HP:0002893', (18, 34))	('pituitary tumours', 'Disease', 'MESH:D010911', (18, 35))	('low', 'NegReg', (79, 82))	('pituitary tumours', 'Disease', (18, 35))	('SDH', 'Gene', '6390', (39, 42))	('patients', 'Species', '9606', (62, 70))
60052	33805450	Patients with germline MAX mutation may also develop other systemic manifestations like renal oncocytoma or lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('renal oncocytoma', 'Disease', 'MESH:C537750', (88, 104))	('renal oncocytoma', 'Disease', (88, 104))	('develop', 'Reg', (45, 52))	('Patients', 'Species', '9606', (0, 8))	('lung cancer', 'Disease', (108, 119))	('germline', 'Var', (14, 22))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (88, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
60053	33805450	Germline MAX mutations are associated with tumourigenesis involving neuroendocrine cells, renal tumours or small cell lung cancer.	('small cell lung cancer', 'Disease', 'MESH:D055752', (107, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('renal tumours', 'Disease', (90, 103))	('tumour', 'Disease', (43, 49))	('associated', 'Reg', (27, 37))	('small cell lung cancer', 'Disease', (107, 129))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('MAX', 'Gene', (9, 12))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('mutations', 'Var', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('renal tumours', 'Disease', 'MESH:D007680', (90, 103))	('tumour', 'Disease', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
60054	33805450	Point mutations and small exonic and intronic deletions of MAX have been linked to PAs.	('PA', 'Phenotype', 'HP:0002893', (83, 85))	('MAX', 'Gene', (59, 62))	('linked', 'Reg', (73, 79))	('PAs', 'Disease', (83, 86))	('small exonic', 'Var', (20, 32))	('Point mutations', 'Var', (0, 15))	('PAs', 'Chemical', 'MESH:D011478', (83, 86))
60055	33805450	The association of pituitary tumours and PPGL may also appear due to MEN1 mutation (to date, one mixed GH/PRL macroadenoma out of four PitNETs).	('pituitary tumours', 'Disease', 'MESH:D010911', (19, 36))	('mutation', 'Var', (74, 82))	('adenoma', 'Disease', (115, 122))	('MEN1', 'Gene', (69, 73))	('PRL', 'Gene', (106, 109))	('pituitary tumours', 'Disease', (19, 36))	('MEN1', 'Gene', '4221', (69, 73))	('association', 'Interaction', (4, 15))	('PPGL', 'Disease', (41, 45))	('PRL', 'Gene', '5617', (106, 109))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('GH', 'Gene', '2688', (103, 105))	('PPGL', 'Chemical', '-', (41, 45))	('adenoma', 'Disease', 'MESH:D000236', (115, 122))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))	('pituitary tumour', 'Phenotype', 'HP:0002893', (19, 35))
60060	33805450	The specific mechanism of NF1 mutations leading to GH excess has not been identified yet.	('NF1', 'Gene', (26, 29))	('leading', 'Reg', (40, 47))	('NF1', 'Gene', '4763', (26, 29))	('mutations', 'Var', (30, 39))	('GH', 'Gene', '2688', (51, 53))
60066	33805450	Genetic testing confirmed NF1 mutation and excluded MEN1 mutation.	('confirmed', 'Reg', (16, 25))	('MEN1', 'Gene', '4221', (52, 56))	('MEN1', 'Gene', (52, 56))	('mutation', 'Var', (30, 38))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (26, 29))
60067	33805450	The PA tissue showed no loss of the wild type allele of the NF1 gene, but harboured a somatic GNAS p.R201C mutation, not supporting NF1 being causative in pituitary adenoma development.	('pituitary adenoma', 'Disease', (155, 172))	('p.R201C', 'Var', (99, 106))	('NF1', 'Gene', '4763', (132, 135))	('pituitary adenoma', 'Disease', 'MESH:D010911', (155, 172))	('GNAS', 'Gene', '2778', (94, 98))	('NF1', 'Gene', '4763', (60, 63))	('p.R201C', 'Mutation', 'rs11554273', (99, 106))	('NF1', 'Gene', (60, 63))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (155, 172))	('GNAS', 'Gene', (94, 98))	('PA', 'Phenotype', 'HP:0002893', (4, 6))	('NF1', 'Gene', (132, 135))
60068	33805450	In the other published case with NF1 mutation and somatotroph PA, somatic changes were not assessed.	('NF1', 'Gene', (33, 36))	('PA', 'Phenotype', 'HP:0002893', (62, 64))	('NF1', 'Gene', '4763', (33, 36))	('mutation', 'Var', (37, 45))
60070	33805450	This autosomal-dominant syndrome is caused by an inactivating mutation of the NF1 gene, located on chromosome 17q11.2.	('autosomal-dominant syndrome', 'Disease', (5, 32))	('inactivating mutation', 'Var', (49, 70))	('caused by', 'Reg', (36, 45))	('NF1', 'Gene', (78, 81))	('autosomal-dominant syndrome', 'Disease', 'MESH:D030342', (5, 32))	('NF1', 'Gene', '4763', (78, 81))
60074	33805450	Recent data revealed that IGSF1 deficiency results in somatotroph neurosecretory hyperfunction.	('IGSF1', 'Gene', (26, 31))	('somatotroph neurosecretory hyperfunction', 'Disease', (54, 94))	('results in', 'Reg', (43, 53))	('somatotroph neurosecretory hyperfunction', 'Disease', 'MESH:D049912', (54, 94))	('IGSF1', 'Gene', '3547', (26, 31))	('deficiency', 'Var', (32, 42))
60076	33805450	Its loss-of-function mutations cause central hypothyroidism, hypoprolactinaemia and macroorchidism.	('hypothyroidism', 'Phenotype', 'HP:0000821', (45, 59))	('hypothyroidism', 'Disease', (45, 59))	('loss-of-function', 'NegReg', (4, 20))	('macroorchidism', 'Phenotype', 'HP:0000053', (84, 98))	('hypoprolactinaemia and macroorchidism', 'Disease', 'MESH:D005600', (61, 98))	('hypothyroidism', 'Disease', 'MESH:D007037', (45, 59))	('central hypothyroidism', 'Phenotype', 'HP:0011787', (37, 59))	('mutations', 'Var', (21, 30))
60077	33805450	Additionally, 52.4% of adult patients with germline IGSF1 mutation present acromegalic facial features as well as organ changes due to GH excess.	('GH', 'Gene', '2688', (135, 137))	('patients', 'Species', '9606', (29, 37))	('IGSF1', 'Gene', '3547', (52, 57))	('IGSF1', 'Gene', (52, 57))	('acromegalic', 'Disease', 'MESH:D000172', (75, 86))	('mutation', 'Var', (58, 66))	('organ changes', 'CPA', (114, 127))	('acromegalic', 'Disease', (75, 86))
60080	33805450	A germline IGSF1 variant has been identified in three family members with XLAG-related gigantism, but the reported variant has up to 0.01 minor allele frequency and has been reported as benign by ClinVar, and is therefore unlikely to be related to the phenotype.	('IGSF1', 'Gene', '3547', (11, 16))	('variant', 'Var', (115, 122))	('IGSF1', 'Gene', (11, 16))	('XLAG-related gigantism', 'Disease', (74, 96))	('XLAG', 'Chemical', '-', (74, 78))	('variant', 'Var', (17, 24))
60082	33805450	Tuberous Sclerosis Complex is an autosomal-dominant genetic disorder caused by loss-of-function mutation in either the TSC1 gene on chromosome 9q34.13 or the TSC2 gene on chromosome 16p13.3.	('autosomal-dominant genetic disorder', 'Disease', (33, 68))	('TSC2', 'Gene', (158, 162))	('TSC1', 'Gene', '7248', (119, 123))	('Tuberous Sclerosis', 'Disease', (0, 18))	('loss-of-function', 'NegReg', (79, 95))	('TSC1', 'Gene', (119, 123))	('mutation', 'Var', (96, 104))	('Tuberous Sclerosis', 'Disease', 'MESH:D014402', (0, 18))	('autosomal-dominant genetic disorder', 'Disease', 'MESH:D030342', (33, 68))	('TSC2', 'Gene', '7249', (158, 162))
60084	33805450	To date, four patients with the TSC mutation and pituitary tumour have been described, including only one somatotropinoma.	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('somatotropinoma', 'Disease', 'MESH:D049912', (106, 121))	('pituitary tumour', 'Phenotype', 'HP:0002893', (49, 65))	('TSC', 'Gene', '7248;7249', (32, 35))	('pituitary tumour', 'Disease', (49, 65))	('pituitary tumour', 'Disease', 'MESH:D010911', (49, 65))	('somatotropinoma', 'Disease', (106, 121))	('patients', 'Species', '9606', (14, 22))	('TSC', 'Gene', (32, 35))	('mutation', 'Var', (36, 44))
60091	33805450	However, in a study of genome-wide sequencing, GNAS mutation has been found in 5 out of 8 plurihormonal PAs secreting GH and prolactin and in 9 out of 23 pure GH somatotropinomas.	('GH somatotropinomas', 'Phenotype', 'HP:0011760', (159, 178))	('GH somatotropinomas', 'Disease', (159, 178))	('PA', 'Phenotype', 'HP:0002893', (104, 106))	('GH somatotropinomas', 'Disease', 'MESH:D049912', (159, 178))	('GNAS', 'Gene', (47, 51))	('plurihormonal PAs secreting GH', 'Disease', 'MESH:D049912', (90, 120))	('plurihormonal PAs secreting GH', 'Disease', (90, 120))	('mutation', 'Var', (52, 60))	('GNAS', 'Gene', '2778', (47, 51))	('found', 'Reg', (70, 75))
60092	33805450	Alterations of DNA methylation have also been linked with GNAS mutation.	('GNAS', 'Gene', '2778', (58, 62))	('Alterations', 'Var', (0, 11))	('DNA', 'Protein', (15, 18))	('GNAS', 'Gene', (58, 62))	('linked', 'Reg', (46, 52))
60093	33805450	In a recent study, PIT1 lineage tumours showed global hypomethylation, chromosome alterations and transposable element overexpression.	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('chromosome alterations', 'CPA', (71, 93))	('global', 'MPA', (47, 53))	('transposable element', 'CPA', (98, 118))	('PIT1', 'Gene', (19, 23))	('overexpression', 'PosReg', (119, 133))	('PIT1', 'Gene', '5449', (19, 23))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('hypomethylation', 'Var', (54, 69))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))
60094	33805450	However, in GNAS mutated tumours, DNA hypomethylation and limited chromosomal alterations have been noted.	('GNAS', 'Gene', (12, 16))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('GNAS', 'Gene', '2778', (12, 16))	('tumours', 'Disease', (25, 32))	('mutated', 'Var', (17, 24))
60096	33805450	To date, no association has been observed between GNAS mutation and granulation patterns in histopathology results.	('GNAS', 'Gene', '2778', (50, 54))	('GNAS', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))
60098	33805450	In GNAS positive patients, mutations are almost always located on the maternal allele due to paternal imprinting.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (17, 25))	('GNAS', 'Gene', '2778', (3, 7))	('GNAS', 'Gene', (3, 7))
60100	33805450	In around 30% of GH-secreting PAs with negative GNAS mutation, GIPR is expressed at a significantly higher level than in the normal pituitary gland.	('GNAS', 'Gene', '2778', (48, 52))	('higher level', 'PosReg', (100, 112))	('GIPR', 'Gene', '2696', (63, 67))	('PAs', 'Chemical', 'MESH:D011478', (30, 33))	('PA', 'Phenotype', 'HP:0002893', (30, 32))	('GH', 'Gene', '2688', (17, 19))	('GNAS', 'Gene', (48, 52))	('negative', 'Var', (39, 47))	('GIPR', 'Gene', (63, 67))
60107	33805450	However, several somatic variants associated with the cAMP pathway, calcium signalling and ATP signalling have been observed (Table 2), which may suggest the important role of these pathways in the pathogenesis of GH-secreting PAs.	('associated', 'Reg', (34, 44))	('variants', 'Var', (25, 33))	('GH', 'Gene', '2688', (214, 216))	('cAMP', 'Chemical', '-', (54, 58))	('cAMP pathway', 'Pathway', (54, 66))	('calcium', 'Chemical', 'MESH:D002118', (68, 75))	('ATP', 'Chemical', 'MESH:D000255', (91, 94))	('PAs', 'Chemical', 'MESH:D011478', (227, 230))	('PA', 'Phenotype', 'HP:0002893', (227, 229))
60108	33805450	In patients with DICER1 mutations and pituitary blastoma, immunohistochemistry for GH was positive in 10 out of 14 studied tumours.	('pituitary blastoma', 'Disease', 'MESH:D018202', (38, 56))	('pituitary blastoma', 'Disease', (38, 56))	('DICER1', 'Gene', '23405', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('died', 'Disease', 'MESH:D003643', (118, 122))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('died', 'Disease', (118, 122))	('patients', 'Species', '9606', (3, 11))	('tumours', 'Disease', (123, 130))	('mutations', 'Var', (24, 33))	('GH', 'Gene', '2688', (83, 85))	('DICER1', 'Gene', (17, 23))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
60112	33805450	Further studies found a relationship between epigenetic modifications and pituitary tumourigenesis.	('pituitary tumour', 'Disease', (74, 90))	('pituitary tumour', 'Phenotype', 'HP:0002893', (74, 90))	('pituitary tumour', 'Disease', 'MESH:D010911', (74, 90))	('epigenetic modifications', 'Var', (45, 69))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))
60116	33805450	If blood-derived GPR101 duplication testing is negative using a CGH array, analysis of affected tissue or alternative tissue DNA and gene-specific methods (ddPCR) should follow before ruling out this diagnosis.	('GH', 'Gene', '2688', (65, 67))	('GPR101', 'Gene', '83550', (17, 23))	('GPR101', 'Gene', (17, 23))	('duplication', 'Var', (24, 35))
60122	33805450	We should consider the disadvantages: (i) psychological burden of increasing anxiety, guilt and depression due to carrying a genetic alteration and transmitting it to offspring, (ii) identifying variants with uncertain significance leading to uncertainty and (iii) costs.	('guilt', 'Disease', (86, 91))	('variants', 'Var', (195, 203))	('anxiety', 'Disease', 'MESH:D001007', (77, 84))	('depression', 'Disease', 'MESH:D000275', (96, 106))	('depression', 'Phenotype', 'HP:0000716', (96, 106))	('depression', 'Disease', (96, 106))	('anxiety', 'Disease', (77, 84))	('anxiety', 'Phenotype', 'HP:0000739', (77, 84))	('genetic alteration', 'Var', (125, 143))	('increasing', 'PosReg', (66, 76))
60255	30352407	Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively.	('PCC/PGL', 'Gene', '1421', (117, 124))	('paraganglioma', 'Disease', 'MESH:D010235', (101, 114))	('SDHB', 'Gene', (9, 13))	('pheochromocytoma', 'Disease', 'MESH:D010673', (36, 52))	('Pheochromocytoma and paragangliomas', 'Disease', 'MESH:D010673', (80, 115))	('SDHD', 'Gene', (18, 22))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (130, 151))	('pheochromocytoma', 'Disease', (36, 52))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('mutations', 'Var', (23, 32))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('PCC/PGL', 'Gene', (117, 124))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (130, 150))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (130, 151))	('paraganglioma', 'Disease', (57, 70))	('chromaffin', 'Chemical', '-', (168, 178))	('paraganglioma', 'Disease', 'MESH:D010235', (57, 70))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('paragangliomas', 'Phenotype', 'HP:0002668', (101, 115))	('SDHB', 'Gene', '6390', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('neuroendocrine tumors', 'Disease', (130, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (57, 70))	('paraganglioma', 'Disease', (101, 114))	('SDHD', 'Gene', '6392', (18, 22))
60259	30352407	Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing.	('patient', 'Species', '9606', (46, 53))	('succinate dehydrogenase complex subunit D', 'Gene', '6392', (177, 218))	('succinate dehydrogenase complex subunit D', 'Gene', (177, 218))	('iron-sulfur subunit B) and SDHD', 'Gene', '6392', (144, 175))	('SDHB', 'Gene', '6390', (106, 110))	('succinate dehydrogenase', 'Gene', '6390', (177, 200))	('mutations', 'Var', (89, 98))	('SDHB', 'Gene', (106, 110))	('succinate dehydrogenase', 'Gene', (112, 135))	('succinate dehydrogenase', 'Gene', '6390', (112, 135))
60260	30352407	Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation.	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('SDHD', 'Gene', (73, 77))	('mutation', 'Var', (51, 59))	('patients', 'Species', '9606', (11, 19))	('SDHD', 'Gene', '6392', (73, 77))
60261	30352407	The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene.	('SDH', 'Gene', (88, 91))	('SDH', 'Gene', '6390', (126, 129))	('c.334-337delACTG', 'Mutation', 'c.334_337delACTG', (102, 118))	('c343C>T', 'Mutation', 'rs751000085', (56, 63))	('c343C>T', 'Var', (56, 63))	('SDHB', 'Gene', '6390', (88, 92))	('SDH', 'Gene', (126, 129))	('SDHB', 'Gene', (88, 92))	('SDH', 'Gene', (41, 44))	('c.541-542A>G', 'Var', (68, 80))	('c.541-542A>G', 'Mutation', 'c.541_542A>G', (68, 80))	('SDHD', 'Gene', (126, 130))	('SDHD', 'Gene', '6392', (126, 130))	('SDH', 'Gene', '6390', (88, 91))	('c.334-337delACTG', 'Var', (102, 118))	('SDH', 'Gene', '6390', (41, 44))
60262	30352407	IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB.	('c.541-2A>G', 'Mutation', 'rs786201161', (45, 55))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('c.343C>T', 'Mutation', 'rs751000085', (32, 40))	('SDHB', 'Gene', '6390', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('c.343C>T', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('c.541-2A>G', 'Var', (45, 55))	('positive', 'PosReg', (72, 80))	('SDHB', 'Gene', (95, 99))	('tumors', 'Disease', (16, 22))	('expression', 'MPA', (81, 91))
60263	30352407	Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB.	('SDHB', 'Gene', (111, 115))	('c.334-337delACTG', 'Var', (16, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('expression', 'MPA', (51, 61))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('c.334-337delACTG', 'Mutation', 'c.334_337delACTG', (16, 32))	('SDHD', 'Gene', '6392', (65, 69))	('SDHD', 'Gene', (65, 69))	('SDHB', 'Gene', '6390', (111, 115))
60265	30352407	Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.	('PCC/PGL', 'Gene', (135, 142))	('SDHB', 'Gene', (83, 87))	('PCC/PGL', 'Gene', '1421', (135, 142))	('SDHD', 'Gene', '6392', (95, 99))	('mutation', 'Var', (100, 108))	('SDHD', 'Gene', (95, 99))	('patient', 'Species', '9606', (56, 63))	('SDHB', 'Gene', '6390', (83, 87))
60276	30352407	Loss of SDHB by immunohistochemistry (IHC) in PCC/PGL is strongly correlated with SDH subunit gene mutation.	('PCC/PGL', 'Gene', (46, 53))	('SDHB', 'Gene', '6390', (8, 12))	('SDH', 'Gene', (82, 85))	('SDH', 'Gene', '6390', (8, 11))	('PCC/PGL', 'Gene', '1421', (46, 53))	('mutation', 'Var', (99, 107))	('Loss', 'NegReg', (0, 4))	('SDHB', 'Gene', (8, 12))	('SDH', 'Gene', (8, 11))	('SDH', 'Gene', '6390', (82, 85))
60279	30352407	The tricarboxylic acid (TCA) cycle-related subgroup contains germline mutations in succinate dehydrogenase subunits SDHA, SDHB, SDHC, SDHD as well as SDHAF2 (succinate dehydrogenase complex assembly factor 2), FH (fumarate hydratase), MDH2 (malate dehydrogenase 2) and GOT2 (glutamic-oxaloacetic transaminase 2).	('succinate dehydrogenase', 'Gene', '6390', (158, 181))	('GOT2', 'Gene', (269, 273))	('glutamic-oxaloacetic transaminase 2', 'Gene', '2806', (275, 310))	('succinate dehydrogenase complex assembly factor 2', 'Gene', '54949', (158, 207))	('succinate dehydrogenase', 'Gene', (83, 106))	('SDHC', 'Gene', '6391', (128, 132))	('fumarate hydratase', 'Gene', '2271', (214, 232))	('MDH2', 'Gene', (235, 239))	('SDHD', 'Gene', '6392', (134, 138))	('succinate dehydrogenase complex assembly factor 2', 'Gene', (158, 207))	('SDHAF2', 'Gene', (150, 156))	('SDHAF2', 'Gene', '54949', (150, 156))	('mutations', 'Var', (70, 79))	('FH', 'Gene', '2271', (210, 212))	('malate dehydrogenase 2', 'Gene', (241, 263))	('SDHA', 'Gene', (150, 154))	('glutamic-oxaloacetic transaminase 2', 'Gene', (275, 310))	('SDHB', 'Gene', '6390', (122, 126))	('TCA', 'Chemical', 'MESH:D014233', (24, 27))	('succinate dehydrogenase', 'Gene', '6390', (83, 106))	('SDHC', 'Gene', (128, 132))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (4, 22))	('SDHD', 'Gene', (134, 138))	('SDHA', 'Gene', '6389', (150, 154))	('MDH2', 'Gene', '4191', (235, 239))	('GOT2', 'Gene', '2806', (269, 273))	('SDHA', 'Gene', (116, 120))	('fumarate hydratase', 'Gene', (214, 232))	('malate dehydrogenase 2', 'Gene', '4191', (241, 263))	('SDHA', 'Gene', '6389', (116, 120))	('SDHB', 'Gene', (122, 126))
60281	30352407	Germline mutations in SDH gene are responsible for 6-9% of sporadic PCC/PGLs, 29% of pediatric cases, 38% of malignant tumors and more than 80% of familial aggregations of PGL and PCC.	('Germline mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('malignant tumors', 'Disease', (109, 125))	('PCC/PGL', 'Gene', (68, 75))	('malignant tumors', 'Disease', 'MESH:D018198', (109, 125))	('PCC', 'Gene', (68, 71))	('PCC', 'Gene', '1421', (180, 183))	('SDH', 'Gene', '6390', (22, 25))	('PCC/PGL', 'Gene', '1421', (68, 75))	('PCC', 'Gene', '1421', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('responsible', 'Reg', (35, 46))	('SDH', 'Gene', (22, 25))	('PCC', 'Gene', (180, 183))
60282	30352407	Germline mutations in the SDHB gene are associated with hereditary paraganglioma syndrome type 4 (PGL4), while germline mutations of SDHD are present in hereditary paraganglioma syndrome type 1 (PGL1).	('Germline mutations', 'Var', (0, 18))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D010235', (56, 89))	('hereditary paraganglioma syndrome', 'Disease', (56, 89))	('hereditary paraganglioma syndrome', 'Disease', 'MESH:D010235', (153, 186))	('SDHD', 'Gene', '6392', (133, 137))	('paraganglioma', 'Phenotype', 'HP:0002668', (164, 177))	('PGL4', 'Gene', (98, 102))	('PGL4', 'Gene', '6390', (98, 102))	('SDHB', 'Gene', '6390', (26, 30))	('SDHD', 'Gene', (133, 137))	('SDHB', 'Gene', (26, 30))	('hereditary paraganglioma syndrome type 1', 'Disease', (153, 193))	('hereditary paraganglioma syndrome type 1', 'Disease', 'MESH:D010235', (153, 193))	('associated', 'Reg', (40, 50))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))
60287	30352407	Here, we report the identification of a nonsense mutation and a splice site mutation in the SDHB gene and an SDHD frameshift mutation by genetic screening and immunohistochemistry.	('SDHB', 'Gene', '6390', (92, 96))	('SDHD', 'Gene', '6392', (109, 113))	('nonsense mutation', 'Var', (40, 57))	('SDHD', 'Gene', (109, 113))	('SDHB', 'Gene', (92, 96))	('splice site mutation', 'Var', (64, 84))
60293	30352407	To conduct Target Capture-Based Deep Sequencing (BGI Health, Shenzhen, Guangdong, China), total DNA isolated from peripheral blood cells of the patients was used to screen for potential mutations in the following genes: SDHAF2, SDHB, SDHC, SDHD, MAX (MYC associated factor X), NF1 (neurofibromin 1), RET (Ret proto-oncogene), VHL (von Hippel-Lindau) and TMEM127 (transmembrane protein 127).	('transmembrane protein 127', 'Gene', '55654', (363, 388))	('VHL', 'Disease', 'MESH:D006623', (326, 329))	('von Hippel-Lindau', 'Gene', (331, 348))	('NF1', 'Gene', '4763', (277, 280))	('MYC associated factor X', 'Gene', '4149', (251, 274))	('transmembrane protein 127', 'Gene', (363, 388))	('SDHD', 'Gene', (240, 244))	('SDHB', 'Gene', '6390', (228, 232))	('SDHC', 'Gene', (234, 238))	('MAX', 'Gene', (246, 249))	('NF1', 'Gene', (277, 280))	('von Hippel-Lindau', 'Gene', '7428', (331, 348))	('neurofibromin 1', 'Gene', '4763', (282, 297))	('TMEM127', 'Gene', (354, 361))	('VHL', 'Disease', (326, 329))	('RET', 'Gene', '5979', (300, 303))	('SDHB', 'Gene', (228, 232))	('neurofibromin 1', 'Gene', (282, 297))	('Ret', 'Gene', (305, 308))	('TMEM127', 'Gene', '55654', (354, 361))	('SDHAF2', 'Gene', '54949', (220, 226))	('mutations', 'Var', (186, 195))	('SDHAF2', 'Gene', (220, 226))	('SDHC', 'Gene', '6391', (234, 238))	('patients', 'Species', '9606', (144, 152))	('SDHD', 'Gene', '6392', (240, 244))	('MYC associated factor X', 'Gene', (251, 274))	('MAX', 'Gene', '4149', (246, 249))	('RET', 'Gene', (300, 303))	('Ret', 'Gene', '5979', (305, 308))
60294	30352407	Of these patients, 3 with SDHB or SDHD mutations; 21 in 5 families with VHL mutations; 10 in 4 families with RET mutations and 1 with somatic HIF2A, which has been described in our previous study.	('patients', 'Species', '9606', (9, 17))	('RET', 'Gene', (109, 112))	('mutations', 'Var', (76, 85))	('HIF2A', 'Gene', '2034', (142, 147))	('mutations', 'Var', (39, 48))	('SDHD', 'Gene', (34, 38))	('SDHB', 'Gene', '6390', (26, 30))	('SDHB', 'Gene', (26, 30))	('SDHD', 'Gene', '6392', (34, 38))	('VHL', 'Disease', 'MESH:D006623', (72, 75))	('RET', 'Gene', '5979', (109, 112))	('VHL', 'Disease', (72, 75))	('HIF2A', 'Gene', (142, 147))
60303	30352407	Among all the patients, three were identified with SDHx mutations.	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (56, 65))	('SDHx', 'Chemical', '-', (51, 55))	('SDHx', 'Gene', (51, 55))
60323	30352407	We identified two heterozygous germline mutations in the SDHB gene: c.343C>T in proband 1 (Fig.	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (57, 61))	('c.343C>T', 'Var', (68, 76))	('c.343C>T', 'Mutation', 'rs751000085', (68, 76))
60325	30352407	In addition, a frame-shift variant (c.334_337delACTG, p.Asp113Metfs*21) in exon 4 of the SDHD gene was detected in proband 3 (Fig.	('c.334_337delACTG', 'Var', (36, 52))	('p.Asp113Metfs*21', 'Var', (54, 70))	('c.334_337delACTG', 'Mutation', 'c.334_337delACTG', (36, 52))	('SDHD', 'Gene', '6392', (89, 93))	('SDHD', 'Gene', (89, 93))	('p.Asp113Metfs*21', 'Mutation', 'rs587776648', (54, 70))
60326	30352407	In addition, we identified a somatic point mutation in the SRD5A2 gene (c.578A>G) in proband 2.	('c.578A>G', 'Var', (72, 80))	('SRD5A2', 'Gene', (59, 65))	('c.578A>G', 'Mutation', 'rs763296857', (72, 80))	('SRD5A2', 'Gene', '6716', (59, 65))
60327	30352407	Since multiple lines of evidence indicate that IHC staining of SDHB is a robust and reliable surrogate marker for SDH gene mutations, we conducted IHC of SDHB on all the tumor tissues.	('SDHB', 'Gene', (63, 67))	('SDH', 'Gene', '6390', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('SDH', 'Gene', '6390', (114, 117))	('SDH', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SDH', 'Gene', (63, 66))	('SDHB', 'Gene', '6390', (154, 158))	('tumor', 'Disease', (170, 175))	('SDH', 'Gene', '6390', (154, 157))	('SDH', 'Gene', (114, 117))	('SDHB', 'Gene', '6390', (63, 67))	('SDHB', 'Gene', (154, 158))	('mutations', 'Var', (123, 132))
60328	30352407	Positive expression of SDHB was observed using IHC staining in proband 1-derived tumor tissues that harbor the c.343C>T SDHB gene mutation (Fig.	('c.343C>T', 'Mutation', 'rs751000085', (111, 119))	('SDHB', 'Gene', '6390', (23, 27))	('c.343C>T', 'Var', (111, 119))	('SDHB', 'Gene', '6390', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('SDHB', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SDHB', 'Gene', (120, 124))	('tumor', 'Disease', (81, 86))
60329	30352407	Expression of the c.541_2A>G SDHB mutant allele (proband 2) in PGL cells and surrounding endothelial and inflammatory cells revealed a distinct cytoplasmic granular staining pattern (Fig.	('c.541_2A>G', 'Var', (18, 28))	('c.541_2A>G', 'Mutation', 'c.541_2A>G', (18, 28))	('SDHB', 'Gene', (29, 33))	('SDHB', 'Gene', '6390', (29, 33))
60330	30352407	Tissue samples of proband 3 (c.334_337delACTG mutation) were negative for SDHD (Fig.	('SDHD', 'Gene', (74, 78))	('c.334_337delACTG mutation', 'Var', (29, 54))	('c.334_337delACTG', 'Mutation', 'c.334_337delACTG', (29, 45))	('SDHD', 'Gene', '6392', (74, 78))
60333	30352407	Of which, Ivana Jochmanova reported the c.343C>T as a function affected mutation; van Hulsteijn et al.	('van Hulsteijn', 'Disease', 'MESH:C536530', (82, 95))	('c.343C>T', 'Mutation', 'rs751000085', (40, 48))	('c.343C>T', 'Var', (40, 48))	('van Hulsteijn', 'Disease', (82, 95))
60334	30352407	reported the c.343C>T as a pathologic mutation, which leads to malignant PGL with bone metastasis.	('bone metastasis', 'Disease', (82, 97))	('leads to', 'Reg', (54, 62))	('c.343C>T', 'Mutation', 'rs751000085', (13, 21))	('bone metastasis', 'Disease', 'MESH:D009362', (82, 97))	('c.343C>T', 'Var', (13, 21))	('malignant PGL', 'Disease', (63, 76))
60335	30352407	Although the c.343C>T mutation results in the replacement of an arginine by a termination codon (p.Arg115Ter), IHC staining the showed positive SDHB in the tumor from the 14-year-old boy (Fig.	('c.343C>T', 'Var', (13, 21))	('arginine', 'Chemical', 'MESH:D001120', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('replacement', 'MPA', (46, 57))	('c.343C>T', 'Mutation', 'rs751000085', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('SDHB', 'Gene', '6390', (144, 148))	('p.Arg115Ter', 'Mutation', 'rs6256', (97, 108))	('tumor', 'Disease', (156, 161))	('boy', 'Species', '9606', (183, 186))	('SDHB', 'Gene', (144, 148))	('results in', 'Reg', (31, 41))
60336	30352407	A recent nationwide study of 194 SDHB mutation carriers found the prevalence of c.343C>T mutation is about 1.5% (3/194; 1 with PCC and 2 with PGLs), suggesting that this mutation is likely to be underestimated.	('SDHB', 'Gene', '6390', (33, 37))	('c.343C>T', 'Mutation', 'rs751000085', (80, 88))	('PCC', 'Gene', (127, 130))	('SDHB', 'Gene', (33, 37))	('c.343C>T', 'Var', (80, 88))	('PCC', 'Gene', '1421', (127, 130))
60343	30352407	It seems that the c.541-2A>G carriers had a higher penetrance, early onset, more severe and complicated phenotypes, which warrants further investigation.	('higher', 'PosReg', (44, 50))	('c.541-2A>G', 'Mutation', 'rs786201161', (18, 28))	('c.541-2A>G', 'Var', (18, 28))
60344	30352407	Though more than 130 unique SDHD gene mutations have been reported in hereditary PGL1, only two studies listed the c.334_337delACTG variant as we report here.	('SDHD', 'Gene', (28, 32))	('mutations', 'Var', (38, 47))	('c.334_337delACTG', 'Mutation', 'c.334_337delACTG', (115, 131))	('SDHD', 'Gene', '6392', (28, 32))
60345	30352407	reported the c.334_337delACTG mutant in a sporadic carrier and a syndromic or familial carrier, while Benn et al.	('c.334_337delACTG', 'Mutation', 'c.334_337delACTG', (13, 29))	('syndromic', 'Disease', (65, 74))	('c.334_337delACTG', 'Var', (13, 29))	('syndromic', 'Disease', 'MESH:D013577', (65, 74))
60347	30352407	Since none of these groups investigated the expression of this mutated gene, we are the first to study the expression of SDHD and SDHB in the c.334-337delATCG carrier.	('SDHD', 'Gene', (121, 125))	('c.334-337delATCG', 'Var', (142, 158))	('SDHB', 'Gene', '6390', (130, 134))	('c.334-337delATCG', 'Mutation', 'c.334_337delATCG', (142, 158))	('SDHB', 'Gene', (130, 134))	('SDHD', 'Gene', '6392', (121, 125))
60349	30352407	A previous study suggests that a weak-diffused pattern of SDHB may have a stronger correlation with mutations in SDHD rather than SDHB.	('mutations', 'Var', (100, 109))	('SDHB', 'Gene', (58, 62))	('SDHD', 'Gene', (113, 117))	('SDHD', 'Gene', '6392', (113, 117))	('SDHB', 'Gene', '6390', (130, 134))	('SDHB', 'Gene', (130, 134))	('SDHB', 'Gene', '6390', (58, 62))
60350	30352407	Based on the findings in our study, c.334_337delATCG in the SDHD gene appeared to affect SDHB expression and thus linked to a more grievous phenotype (simultaneous PCC and PGL lesions).	('linked to', 'Reg', (114, 123))	('c.334_337delATCG', 'Var', (36, 52))	('SDHD', 'Gene', (60, 64))	('SDHD', 'Gene', '6392', (60, 64))	('more', 'PosReg', (126, 130))	('PCC', 'Gene', (164, 167))	('c.334_337delATCG', 'Mutation', 'c.334_337delATCG', (36, 52))	('PGL lesions', 'Disease', (172, 183))	('SDHB', 'Gene', '6390', (89, 93))	('expression', 'MPA', (94, 104))	('PCC', 'Gene', '1421', (164, 167))	('affect', 'Reg', (82, 88))	('SDHB', 'Gene', (89, 93))
60353	30352407	SDHB mutations mainly predispose to extra-adrenal PGLs and to a lesser extent to adrenal PCCs and HNPGLs, while SDHD mutations are typically associated with multifocal HNPGLs and less frequently with adrenal PCCs and extra-adrenal PGLs.	('mutations', 'Var', (117, 126))	('PCC', 'Gene', (89, 92))	('extra-adrenal PGLs', 'Disease', (36, 54))	('SDHD', 'Gene', (112, 116))	('mutations', 'Var', (5, 14))	('SDHD', 'Gene', '6392', (112, 116))	('predispose', 'Reg', (22, 32))	('associated with', 'Reg', (141, 156))	('PCC', 'Gene', '1421', (208, 211))	('SDHB', 'Gene', '6390', (0, 4))	('PCC', 'Gene', '1421', (89, 92))	('SDHB', 'Gene', (0, 4))	('PCC', 'Gene', (208, 211))
60355	30352407	Notably, the c.334_337delACTG carrier in this study showed HNPGL in the right jugular foramen five years before entry into our study.	('c.334_337delACTG', 'Mutation', 'c.334_337delACTG', (13, 29))	('c.334_337delACTG', 'Var', (13, 29))	('HNPGL', 'Gene', (59, 64))
60364	30352407	The two SDHB germline mutation carriers did not present with metastases, but a literature review suggests that patients with such mutations may present with metastases in the neck, lung, mediastinum, abdomen and pelvic region.	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('SDHB', 'Gene', '6390', (8, 12))	('present', 'Reg', (144, 151))	('metastases', 'Disease', (61, 71))	('SDHB', 'Gene', (8, 12))	('mutations', 'Var', (130, 139))	('metastases', 'Disease', (157, 167))	('metastases', 'Disease', 'MESH:D009362', (61, 71))	('patients', 'Species', '9606', (111, 119))
60365	30352407	Rare cases of metastatic HNPGLs have been described within SDHD mutation carriers and their estimated prevalence is 0-10%.	('SDHD', 'Gene', (59, 63))	('SDHD', 'Gene', '6392', (59, 63))	('mutation', 'Var', (64, 72))	('metastatic HNPGLs', 'Disease', (14, 31))
60368	30352407	Though it is likely that not all SDHB IHC-negative tumors will carry SDH mutations, IHC remains a phenotypic test as well as an indirect genotypic test.	('SDH', 'Gene', (33, 36))	('SDH', 'Gene', '6390', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SDHB', 'Gene', '6390', (33, 37))	('SDH', 'Gene', (69, 72))	('SDHB', 'Gene', (33, 37))	('SDH', 'Gene', '6390', (33, 36))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (73, 82))
60371	30352407	In conclusion, we presented three gene-specific germline mutations in SDH genes and their relevant phenotypes.	('germline mutations', 'Var', (48, 66))	('SDH', 'Gene', '6390', (70, 73))	('SDH', 'Gene', (70, 73))
60372	30352407	Findings of our study suggest that the incidence of c.343C>T mutations is likely underestimated in PCC/PGL patients.	('c.343C>T', 'Mutation', 'rs751000085', (52, 60))	('PCC/PGL', 'Gene', (99, 106))	('c.343C>T', 'Var', (52, 60))	('PCC/PGL', 'Gene', '1421', (99, 106))	('patients', 'Species', '9606', (107, 115))
60373	30352407	Patients with the SDHB mutation, c.541-2A>G, had severe and complicated phenotypes.	('SDHB', 'Gene', (18, 22))	('c.541-2A>G', 'Mutation', 'rs786201161', (33, 43))	('Patients', 'Species', '9606', (0, 8))	('c.541-2A>G', 'Var', (33, 43))	('SDHB', 'Gene', '6390', (18, 22))
60374	30352407	The c.334_337delATCG SDHD mutation appears to influence SDHB expression and associates with a more aggressive phenotype.	('influence', 'Reg', (46, 55))	('SDHB', 'Gene', '6390', (56, 60))	('SDHB', 'Gene', (56, 60))	('SDHD', 'Gene', '6392', (21, 25))	('SDHD', 'Gene', (21, 25))	('c.334_337delATCG', 'Mutation', 'c.334_337delATCG', (4, 20))	('c.334_337delATCG', 'Var', (4, 20))	('aggressive', 'CPA', (99, 109))	('expression', 'MPA', (61, 71))
60381	30199552	EFS (4 to 16 Hz) induced frequency-dependent aortic contractions in both Crotalus and Bothrops.	('Bothrops', 'Species', '8724', (86, 94))	('Crotalus', 'Species', '8732', (73, 81))	('EFS', 'Var', (0, 3))	('aortic contractions', 'MPA', (45, 64))
60382	30199552	The EFS-induced contractions were significantly reduced in the presence of either guanethidine or phentolamine in both snakes (p<0.05), whereas tetrodotoxin had no effect in either.	('phentolamine', 'Var', (98, 110))	('guanethidine', 'Var', (82, 94))	('reduced', 'NegReg', (48, 55))	('tetrodotoxin', 'Chemical', 'MESH:D013779', (144, 156))	('guanethidine', 'Chemical', 'MESH:D006145', (82, 94))	('phentolamine', 'Chemical', 'MESH:D010646', (98, 110))
60388	30199552	These findings indicate that the endothelium as the potential source for the catecholamines in response to EFS.	('catecholamines', 'MPA', (77, 91))	('catecholamines', 'Chemical', 'MESH:D002395', (77, 91))	('EFS', 'Var', (107, 110))
60462	29623675	Surgical modifications of the procedure along with advances in postoperative management led to prolonged patient survival, frequently into adulthood.	('patient survival', 'CPA', (105, 121))	('patient', 'Species', '9606', (105, 112))	('modifications', 'Var', (9, 22))	('prolonged', 'PosReg', (95, 104))
60654	27366943	Nonetheless, the extension and relevance of the MYC-PVT1 deregulation in tumorigenesis has not yet been systematically addressed.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MYC-PVT1', 'Gene', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('MYC-PVT1', 'Gene', '4609;5820', (48, 56))	('deregulation', 'Var', (57, 69))
60657	27366943	PVT1 misregulation in KIRC is mostly associated to promoter hypomethylation rather than locus amplification.	('promoter hypomethylation', 'Var', (51, 75))	('PVT1', 'Gene', (0, 4))	('misregulation', 'Var', (5, 18))	('associated', 'Reg', (37, 47))	('PVT1', 'Gene', '5820', (0, 4))
60668	27366943	However, the extension and relevance of MYC and PVT1 alterations in tumorigenesis has not yet been thoroughly addressed.	('tumor', 'Disease', (68, 73))	('alterations', 'Var', (53, 64))	('PVT1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MYC', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PVT1', 'Gene', '5820', (48, 52))
60672	27366943	Moreover, we found that PVT1 up-regulation in KIRC is the result of promoter hypomethylation rather than copy number amplification.	('PVT1', 'Gene', (24, 28))	('up-regulation', 'PosReg', (29, 42))	('promoter hypomethylation', 'Var', (68, 92))	('PVT1', 'Gene', '5820', (24, 28))
60674	27366943	We set out to investigate the impact of MYC-PVT1 deregulation in several cancers using multi-omics data for approximately 7000 patients from the TCGA (Table S1).	('cancers', 'Disease', (73, 80))	('MYC-PVT1', 'Gene', '4609;5820', (40, 48))	('deregulation', 'Var', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (127, 135))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('MYC-PVT1', 'Gene', (40, 48))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
60676	27366943	MYC-PVT1 locus amplification was widespread and present in over half of the patients for most tumor types (Figure S1A).	('MYC-PVT1', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patients', 'Species', '9606', (76, 84))	('amplification', 'Var', (15, 28))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('MYC-PVT1', 'Gene', '4609;5820', (0, 8))
60687	27366943	Furthermore, supporting the impact of PVT1 in the clinical outcome of KIRC patients, we observed that high expression levels were significantly associated with neoplasm status after surgery and advanced clinical stage or metastasis (Fisher's Exact -test p-value < 0.05) (Figure 2D).	('associated with', 'Reg', (144, 159))	('high', 'Var', (102, 106))	('PVT1', 'Gene', (38, 42))	('patients', 'Species', '9606', (75, 83))	('metastasis', 'CPA', (221, 231))	('neoplasm', 'Disease', (160, 168))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('PVT1', 'Gene', '5820', (38, 42))	('neoplasm', 'Disease', 'MESH:D009369', (160, 168))
60696	27366943	Further analysis revealed that most KIRC patients with PVT1 up-regulation also presented PVT1 promoter hypomethylation (Fisher's Exact -test p-value < 0.005, Figure 3C).	('up-regulation', 'PosReg', (60, 73))	('promoter', 'MPA', (94, 102))	('PVT1', 'Gene', (89, 93))	('hypomethylation', 'Var', (103, 118))	('patients', 'Species', '9606', (41, 49))	('PVT1', 'Gene', (55, 59))	('PVT1', 'Gene', '5820', (89, 93))	('PVT1', 'Gene', '5820', (55, 59))
60700	27366943	In general, PVT1 locus amplification contributed significantly for PVT1 misregulation in most cancer types (Figure 3F and S3E).	('PVT1', 'Gene', (67, 71))	('PVT1', 'Gene', '5820', (12, 16))	('PVT1', 'Gene', '5820', (67, 71))	('misregulation', 'Var', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('contributed', 'Reg', (37, 48))	('PVT1', 'Gene', (12, 16))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
60702	27366943	Overall, our results suggest that PVT1 misregulation in KIRC is the result of promoter hypomethylation.	('PVT1', 'Gene', (34, 38))	('PVT1', 'Gene', '5820', (34, 38))	('misregulation', 'Var', (39, 52))
60704	27366943	We found that patients with high PVT1 expression levels also showed a significant increase of MYC protein concentration for five cancers, including KIRC (Figure 4A).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('PVT1', 'Gene', '5820', (33, 37))	('cancers', 'Disease', (129, 136))	('expression levels', 'Var', (38, 55))	('increase', 'PosReg', (82, 90))	('high', 'Var', (28, 32))	('MYC protein concentration', 'MPA', (94, 119))	('PVT1', 'Gene', (33, 37))	('KIRC', 'Disease', (148, 152))	('patients', 'Species', '9606', (14, 22))
60705	27366943	Because MYC is an oncogenic transcription-factor we then explored whether MYC-PVT1 deregulation would impact genes responsive to MYC.	('MYC-PVT1', 'Gene', '4609;5820', (74, 82))	('deregulation', 'Var', (83, 95))	('genes responsive', 'MPA', (109, 125))	('impact', 'Reg', (102, 108))	('MYC-PVT1', 'Gene', (74, 82))
60708	27366943	Collectively, our results show that MYC-PVT1 misregulation appears to be an important predictor of poor prognosis in renal carcinoma.	('MYC-PVT1', 'Gene', '4609;5820', (36, 44))	('misregulation', 'Var', (45, 58))	('renal carcinoma', 'Disease', 'MESH:C538614', (117, 132))	('MYC-PVT1', 'Gene', (36, 44))	('renal carcinoma', 'Disease', (117, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('renal carcinoma', 'Phenotype', 'HP:0005584', (117, 132))
60710	27366943	Our pan-cancer analysis using diverse multi-omics data revealed that KIRC is the malignancy for which MYC-PVT1 misregulation is most strongly associated with a poor overall survival.	('poor', 'NegReg', (160, 164))	('cancer', 'Disease', (8, 14))	('misregulation', 'Var', (111, 124))	('MYC-PVT1', 'Gene', '4609;5820', (102, 110))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('KIRC', 'Disease', (69, 73))	('associated', 'Reg', (142, 152))	('overall survival', 'MPA', (165, 181))	('malignancy', 'Disease', (81, 91))	('MYC-PVT1', 'Gene', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
60713	27366943	Hence, our results suggest that promoter hypomethylation is an important cause of PVT1 up-regulation in tumor patients lacking 8q24 locus amplification.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('PVT1', 'Gene', (82, 86))	('up-regulation', 'PosReg', (87, 100))	('tumor', 'Disease', (104, 109))	('PVT1', 'Gene', '5820', (82, 86))	('promoter hypomethylation', 'Var', (32, 56))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
60722	27366943	Inhibition of MYC is an attractive pharmacological approach for cancer treatment.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MYC', 'Protein', (14, 17))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
60725	27366943	Since loss of PVT1 RNA in colon cancer cell line reduces MYC protein to more normal levels, inhibiting PVT1 could be a more accessible and feasible therapeutic strategy for renal cancer.	('MYC protein', 'Protein', (57, 68))	('renal cancer', 'Disease', 'MESH:D007680', (173, 185))	('loss', 'Var', (6, 10))	('reduces', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('PVT1', 'Gene', (103, 107))	('PVT1', 'Gene', (14, 18))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('colon cancer', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('renal cancer', 'Disease', (173, 185))	('PVT1', 'Gene', '5820', (14, 18))	('renal cancer', 'Phenotype', 'HP:0009726', (173, 185))	('PVT1', 'Gene', '5820', (103, 107))
60726	27366943	Modulation of lncRNAs functions have showed promising anticancer effects and expanded the development of lncRNA-based cancer therapies involving small interfering RNAs, antisense oligonucleotides, ribozymes and aptamers.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('oligonucleotides', 'Chemical', 'MESH:D009841', (179, 195))	('antisense oligonucleotides', 'Var', (169, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('RNAs', 'Protein', (163, 167))	('small interfering', 'Var', (145, 162))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
60732	27366943	RNA-seq and BS-seq data for HEK293 and KIRC cell lines were obtained from the GEO (http://www.ncbi.nlm.nih.gov/geo/, GSE68938, GSE51867, GSE64451, GSE44866).	('HEK293', 'CellLine', 'CVCL:0045', (28, 34))	('GSE64451', 'Var', (137, 145))	('GSE44866', 'Var', (147, 155))	('GSE51867', 'Var', (127, 135))	('GSE68938', 'Var', (117, 125))
60750	27366943	The statistical significance of differences in MYC protein levels between patients with low and high PVT1 expression was assessed using Student's T-test.	('PVT1', 'Gene', '5820', (101, 105))	('low', 'NegReg', (88, 91))	('patients', 'Species', '9606', (74, 82))	('expression', 'MPA', (106, 116))	('high', 'Var', (96, 100))	('PVT1', 'Gene', (101, 105))	('MYC protein levels', 'MPA', (47, 65))
60873	25007069	ELISA results revealed a significant increase in the levels of met-enkephalin and norepinephrine in the CSF of rats that received micro-HPC injection compared to the empty capsule group (p < 0.05; Table 2).	('micro-HPC', 'Var', (130, 139))	('norepinephrine', 'MPA', (82, 96))	('norepinephrine', 'Chemical', 'MESH:D009638', (82, 96))	('rats', 'Species', '10116', (111, 115))	('increase', 'PosReg', (37, 45))	('met-enkephalin', 'Gene', '5443', (63, 77))	('met-enkephalin', 'Gene', (63, 77))
60875	25007069	The behavioral results showed that micro-HPC administration significantly increased the withdrawal threshold to the mechanical stimulus in the contralateral and ipsilateral paws compared with the Walker 256 group on days 18, 21 and 25 (p < 0.05, Figure 2C).	('increased', 'PosReg', (74, 83))	('withdrawal threshold to the mechanical stimulus', 'MPA', (88, 135))	('micro-HPC', 'Var', (35, 44))	('rat', 'Species', '10116', (53, 56))
60877	25007069	These results indicate that intrathecal injection of micro-HPC could reduce the mechanical allodynia induced by Walker 256 inoculation.	('mechanical allodynia', 'Disease', 'MESH:D006930', (80, 100))	('mechanical allodynia', 'Disease', (80, 100))	('allodynia', 'Phenotype', 'HP:0012533', (91, 100))	('reduce', 'NegReg', (69, 75))	('micro-HPC', 'Var', (53, 62))	('rat', 'Species', '10116', (31, 34))
60880	25007069	Moreover, coadministration with naloxone and rauwolscine provided significant incremental reductions on PWT (2.89 +- 1.39 vs. 15.09 +- 1.16 g, p < 0.05, Figure 3).	('reductions', 'NegReg', (90, 100))	('rauwolscine', 'Var', (45, 56))	('rat', 'Species', '10116', (20, 23))	('naloxone', 'Chemical', 'MESH:D009270', (32, 40))	('rauwolscine', 'Chemical', 'MESH:D015016', (45, 56))
60881	25007069	These data indicate that the met-enkephalin and norepinephrine secreted by spinal implanted micro-HPC might mediate the anti-allodynia effect.	('met-enkephalin', 'Gene', (29, 43))	('norepinephrine', 'Chemical', 'MESH:D009638', (48, 62))	('allodynia', 'Phenotype', 'HP:0012533', (125, 134))	('allodynia', 'Disease', (125, 134))	('micro-HPC', 'Var', (92, 101))	('met-enkephalin', 'Gene', '5443', (29, 43))	('allodynia', 'Disease', 'MESH:D006930', (125, 134))
60897	25007069	In terminal cancer patients, implantation of adrenal medullary tissue has been shown to produce pain relief, which is associated with increased level of met-enkephalin and norepinephrine.	('met-enkephalin', 'Gene', (153, 167))	('pain', 'Disease', 'MESH:D010146', (96, 100))	('pain', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('patients', 'Species', '9606', (19, 27))	('implantation', 'Var', (29, 41))	('cancer', 'Disease', (12, 18))	('norepinephrine', 'MPA', (172, 186))	('norepinephrine', 'Chemical', 'MESH:D009638', (172, 186))	('pain', 'Phenotype', 'HP:0012531', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('increased', 'PosReg', (134, 143))	('met-enkephalin', 'Gene', '5443', (153, 167))
60967	24699253	Of particular concern are patients carrying mutations in the SDHB gene, as these patients are more prone than other patients to develop more aggressive and metastatic disease.	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (26, 34))	('develop', 'PosReg', (128, 135))	('mutations', 'Var', (44, 53))	('SDHB', 'Gene', (61, 65))	('prone', 'Reg', (99, 104))
60972	24699253	The rat PHEO cell line PC12, developed in 1976, has a MAX gene deletion that has been recently discovered in a human PHEO kindred.	('PC12', 'CellLine', 'CVCL:0481', (23, 27))	('human', 'Species', '9606', (111, 116))	('MAX gene', 'Gene', (54, 62))	('deletion', 'Var', (63, 71))	('rat', 'Species', '10116', (4, 7))
61010	24699253	A subset of patient data that was previously published (GSE 39716) containing SDHB mutation samples was used for comparison with MTT cell line expression.	('MTT', 'Chemical', 'MESH:C070243', (129, 132))	('GSE', 'Chemical', '-', (56, 59))	('mutation', 'Var', (83, 91))	('SDHB', 'Gene', (78, 82))	('patient', 'Species', '9606', (12, 19))
61046	24699253	Moreover, our combined analysis of the drug screening and the microarray data sets suggested possible drug combinations that are supported by sporadic, but useful, reports in the literature on similar drugs or drug categories in the treatment of metastatic PHEO/PGL patients.	('combinations', 'Var', (107, 119))	('patients', 'Species', '9606', (266, 274))	('metastatic PHEO/PGL', 'Disease', (246, 265))	('rat', 'Species', '10116', (183, 186))
61058	24699253	For example, the recent discovery of mutations in the MAX gene (which is part of the Myc-Max-Mxd1 network) highlights the value of the rat PHEO cell line PC12, which lacks a functional MAX gene, as previously described.	('rat', 'Species', '10116', (135, 138))	('Myc', 'Gene', (85, 88))	('PC12', 'CellLine', 'CVCL:0481', (154, 158))	('mutations', 'Var', (37, 46))	('MAX gene', 'Gene', (54, 62))	('Myc', 'Gene', '24577', (85, 88))
61071	24699253	In addition, HDAC inhibitors may influence the level of acetylation of other non-histone effector molecules, including Hsp90 and NF-kB, two other important molecular targets in PHEO.	('Hsp90', 'Gene', '3320', (119, 124))	('influence', 'Reg', (33, 42))	('NF-kB', 'Protein', (129, 134))	('level of acetylation', 'MPA', (47, 67))	('Hsp90', 'Gene', (119, 124))	('inhibitors', 'Var', (18, 28))
61074	24699253	Recent evidence points to a role of DNA methylation in the pathogenesis of SDH mutant PHEOs, opening the opportunity to use drugs such as the DNA methyltransferase inhibitor decitabine (5-aza-2'deoxycytabine), which was one of the hits in our screening.	('SDH', 'Gene', '6390', (75, 78))	('mutant', 'Var', (79, 85))	('SDH', 'Gene', (75, 78))	('PHEOs', 'Disease', (86, 91))
61089	22812497	The high potassium content (1345.7 mg/100 g) may be responsible for promoting neurite extension, too.	('neurite extension', 'CPA', (78, 95))	('1345.7 mg/100', 'Var', (28, 41))	('promoting', 'PosReg', (68, 77))	('potassium', 'Chemical', 'MESH:D011188', (9, 18))	('high potassium content', 'Phenotype', 'HP:0002153', (4, 26))
61124	22812497	[3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide] (MTT), phosphate buffered saline (PBS), dimethyl sulfoxide (DMSO), F-12 K medium (Kaighn's Modification of Ham's F-12 Medium), NGF-7 S from murine submaxillary gland, MEK inhibitor (U0126, PD98059), and PI3K inhibitor (LY294002) were obtained from Sigma Co. (St. Louis, MO, USA).	('[3-[4,5-dimethythiazol-2-yl]-2,5-diphenyltetrazolium bromide]', 'Chemical', '-', (0, 61))	('U0126', 'Chemical', 'MESH:C113580', (244, 249))	('MEK', 'Gene', '17242', (229, 232))	('LY294002', 'Chemical', 'MESH:C085911', (281, 289))	('PD98059', 'Chemical', 'MESH:C093973', (251, 258))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (102, 120))	('DMSO', 'Chemical', 'MESH:D004121', (122, 126))	('U0126', 'Var', (244, 249))	('MTT', 'Chemical', 'MESH:C070243', (63, 66))	('phosphate buffered saline', 'Chemical', '-', (69, 94))	('MEK', 'Gene', (229, 232))	('murine', 'Species', '10090', (202, 208))	('LY294002', 'Var', (281, 289))	('PBS', 'Chemical', '-', (96, 99))
61152	22812497	Stock solution (10 mM) of MEK inhibitor (U0126, PD98059) and PI3K inhibitor (LY294002) were prepared in DMSO and stored in -20  C in the dark.	('U0126', 'Chemical', 'MESH:C113580', (41, 46))	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('PD98059', 'Var', (48, 55))	('MEK', 'Gene', '17242', (26, 29))	('DMSO', 'Chemical', 'MESH:D004121', (104, 108))	('LY294002', 'Var', (77, 85))	('U0126', 'Var', (41, 46))	('PD98059', 'Chemical', 'MESH:C093973', (48, 55))	('MEK', 'Gene', (26, 29))
61153	22812497	10 muM for U0126, 10-50 muM of LY294002; and 40 muM for PD98059 was then prepared by diluting in medium just before use.	('LY294002', 'Var', (31, 39))	('U0126', 'Chemical', 'MESH:C113580', (11, 16))	('LY294002', 'Chemical', 'MESH:C085911', (31, 39))	('U0126', 'Var', (11, 16))	('PD98059', 'Chemical', 'MESH:C093973', (56, 63))
61176	22812497	It was shown that neurite outgrowth induced by NGF and aqueous extract of P. giganteus was markedly inhibited (p < 0.05) by MEK inhibitors U0126 and PD98059 (Figure 4a and 4b).	('MEK', 'Gene', '17242', (124, 127))	('U0126', 'Var', (139, 144))	('U0126', 'Chemical', 'MESH:C113580', (139, 144))	('neurite outgrowth', 'CPA', (18, 35))	('P. giganteus', 'Species', '143291', (74, 86))	('MEK', 'Gene', (124, 127))	('PD98059', 'Var', (149, 156))	('inhibited', 'NegReg', (100, 109))	('PD98059', 'Chemical', 'MESH:C093973', (149, 156))
61177	22812497	In fact, in PC12 cell treated with aqueous extract combined with either 10 muM of U0126 or 40 muM of PD98059, the decrease in the number of neuritic processes was significant (p < 0.05).	('PD98059', 'Chemical', 'MESH:C093973', (101, 108))	('decrease', 'NegReg', (114, 122))	('U0126', 'Var', (82, 87))	('U0126', 'Chemical', 'MESH:C113580', (82, 87))
61178	22812497	On the contrary, an inhibitor of PI3K/Akt pathway, LY294002, did not inhibit aqueous extract- and NGF-induced neurite outgrowth at the concentration of 10 muM and 20 muM (p > 0.05).	('LY294002', 'Var', (51, 59))	('inhibit', 'NegReg', (69, 76))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))	('Akt', 'Gene', '24185', (38, 41))	('rat', 'Species', '10116', (142, 145))	('Akt', 'Gene', (38, 41))
61179	22812497	LY294002 at the concentration of 30 muM started to cause inhibition effects on PC12 in a concentration-dependent manner.	('LY294002', 'Var', (0, 8))	('rat', 'Species', '10116', (23, 26))	('PC12', 'Gene', (79, 83))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('inhibition', 'NegReg', (57, 67))	('rat', 'Species', '10116', (96, 99))
61180	22812497	At 30 muM of LY294002, the number of elongated PC12 cells with neurites doubled the cell diameter decreased significantly, by 49.6% and 63.5%, for NGF- and aqueous extract-treated cells; respectively (Figure 4c).	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('decreased', 'NegReg', (98, 107))	('cell diameter', 'CPA', (84, 97))	('LY294002', 'Var', (13, 21))
61213	22812497	Besides, lysophosphatidylethanolamine from Grifola frondosa induced activation of ERK1/2 of PC12 cells thus stimulated neurite outgrowth and inhibited serum withdrawal-induced apoptosis.	('stimulated', 'PosReg', (108, 118))	('serum withdrawal-induced apoptosis', 'CPA', (151, 185))	('Grifola frondosa', 'Species', '5627', (43, 59))	('neurite outgrowth', 'CPA', (119, 136))	('lysophosphatidylethanolamine', 'Var', (9, 37))	('activation', 'PosReg', (68, 78))	('ERK1/2', 'Protein', (82, 88))	('inhibited', 'NegReg', (141, 150))	('lysophosphatidylethanolamine', 'Chemical', 'MESH:C008301', (9, 37))
61216	22812497	Similarly, alpha-Phenyl-N-tert-butylnitron was also found to induce neurite outgrowth in PC12 independent of TrkA.	('neurite outgrowth', 'CPA', (68, 85))	('induce', 'PosReg', (61, 67))	('TrkA', 'Gene', '59109', (109, 113))	('TrkA', 'Gene', (109, 113))	('alpha-Phenyl-N-tert-butylnitron', 'Chemical', '-', (11, 42))	('alpha-Phenyl-N-tert-butylnitron', 'Var', (11, 42))
61220	22812497	In the present study, upon inhibition by MEK-selective inhibitor U0126 and PD98059, the percentage of neurite outgrowth decreased significantly.	('decreased', 'NegReg', (120, 129))	('PD98059', 'Chemical', 'MESH:C093973', (75, 82))	('U0126', 'Chemical', 'MESH:C113580', (65, 70))	('MEK', 'Gene', (41, 44))	('PD98059', 'Var', (75, 82))	('MEK', 'Gene', '17242', (41, 44))	('inhibition', 'NegReg', (27, 37))
61222	22812497	Inhibition of PI3K/Akt signalling by LY294002 also negatively affected neurite outgrowth of PC12.	('neurite outgrowth', 'CPA', (71, 88))	('Akt', 'Gene', '24185', (19, 22))	('negatively', 'NegReg', (51, 61))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('Akt', 'Gene', (19, 22))	('LY294002', 'Var', (37, 45))
61223	22812497	This finding suggested that neurite outgrowth potentiated by P. giganteus in PC12 cells is also regulated by PI3K/Akt signaling pathway.	('P. giganteus', 'Var', (61, 73))	('potentiated', 'PosReg', (46, 57))	('Akt', 'Gene', (114, 117))	('neurite outgrowth', 'CPA', (28, 45))	('P. giganteus', 'Species', '143291', (61, 73))	('Akt', 'Gene', '24185', (114, 117))
61224	22812497	However, it was noted that PI3K/Akt inhibitor did not markedly affect the activities of ERK, therefore neurite extension of PC12 still could be observed at lower concentrations of LY294002.	('rat', 'Species', '10116', (169, 172))	('Akt', 'Gene', '24185', (32, 35))	('LY294002', 'Var', (180, 188))	('Akt', 'Gene', (32, 35))	('ERK', 'Gene', (88, 91))	('ERK', 'Gene', '24338', (88, 91))	('neurite extension', 'CPA', (103, 120))	('LY294002', 'Chemical', 'MESH:C085911', (180, 188))
61313	20398431	Alterations in genes encoding nfs-1, frataxin and isd-11 that could lead to a diminished SDH activity have not been detected in NB.	('SDH', 'Gene', (89, 92))	('nfs-1', 'Gene', (30, 35))	('diminished', 'NegReg', (78, 88))	('Alterations', 'Var', (0, 11))	('isd-11', 'Gene', '57128', (50, 56))	('SDH', 'Gene', '6390', (89, 92))	('nfs-1', 'Gene', '9054', (30, 35))	('isd-11', 'Gene', (50, 56))
61318	20398431	Pheochromocytomas and paragangliomas frequently exhibit mutations in the succinate dehydrogenase (SDH) subunits SDHB, SDHC, SDHD indicating that these SDH subunits act as tumor suppressors in neuroendocrine tissues.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('SDHB', 'Gene', (112, 116))	('SDH', 'Gene', '6390', (98, 101))	('SDHC', 'Gene', (118, 122))	('SDH', 'Gene', '6390', (112, 115))	('SDH', 'Gene', '6390', (151, 154))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('mutations', 'Var', (56, 65))	('SDH', 'Gene', (98, 101))	('SDH', 'Gene', '6390', (118, 121))	('succinate dehydrogenase', 'Gene', (73, 96))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('paragangliomas', 'Disease', 'MESH:D010235', (22, 36))	('SDHD', 'Gene', '6392', (124, 128))	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (22, 35))	('SDH', 'Gene', (112, 115))	('SDH', 'Gene', '6390', (124, 127))	('SDH', 'Gene', (151, 154))	('Pheochromocytomas', 'Disease', (0, 17))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('SDH', 'Gene', (118, 121))	('SDHD', 'Gene', (124, 128))	('SDHC', 'Gene', '6391', (118, 122))	('exhibit', 'Reg', (48, 55))	('SDHB', 'Gene', '6390', (112, 116))	('succinate dehydrogenase', 'Gene', '6390', (73, 96))	('SDH', 'Gene', (124, 127))	('tumor', 'Disease', (171, 176))	('paragangliomas', 'Disease', (22, 36))
61323	20398431	Pathogenic mutations in SDH5 have been identified in paragangliomas.	('mutations', 'Var', (11, 20))	('Pathogenic', 'Reg', (0, 10))	('SDH5', 'Gene', (24, 28))	('identified', 'Reg', (39, 49))	('paragangliomas', 'Disease', (53, 67))	('paragangliomas', 'Disease', 'MESH:D010235', (53, 67))	('SDH5', 'Gene', '54949', (24, 28))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))	('paragangliomas', 'Phenotype', 'HP:0002668', (53, 67))
61324	20398431	Mutations in the PHOX2B and anaplastic lymphoma kinase (ALK) genes are linked to a predisposition for neuroblastoma.	('PHOX2B', 'Gene', (17, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('anaplastic lymphoma kinase', 'Gene', '238', (28, 54))	('PHOX2B', 'Gene', '8929', (17, 23))	('linked to', 'Reg', (71, 80))	('ALK', 'Gene', '238', (56, 59))	('neuroblastoma', 'Disease', 'MESH:D009447', (102, 115))	('Mutations', 'Var', (0, 9))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (28, 47))	('neuroblastoma', 'Disease', (102, 115))	('anaplastic lymphoma kinase', 'Gene', (28, 54))	('neuroblastoma', 'Phenotype', 'HP:0003006', (102, 115))	('ALK', 'Gene', (56, 59))
61325	20398431	Mutations in PHOX2B have been found in a minority of familial neuroblastoma cases.	('PHOX2B', 'Gene', (13, 19))	('familial neuroblastoma', 'Disease', 'MESH:D009447', (53, 75))	('PHOX2B', 'Gene', '8929', (13, 19))	('neuroblastoma', 'Phenotype', 'HP:0003006', (62, 75))	('found', 'Reg', (30, 35))	('Mutations', 'Var', (0, 9))	('familial neuroblastoma', 'Disease', (53, 75))	('familial neuroblastoma', 'Phenotype', 'HP:0006742', (53, 75))
61326	20398431	Mutations in the VHL gene cause von Hippel-Lindau disease, a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, including clear cell renal carcinoma and pheochromocytoma.	('cause', 'Reg', (26, 31))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (178, 204))	('renal carcinoma', 'Phenotype', 'HP:0005584', (189, 204))	('familial cancer syndrome', 'Disease', (82, 106))	('Mutations', 'Var', (0, 9))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (32, 57))	('pheochromocytoma', 'Disease', 'MESH:D010673', (209, 225))	('cell renal carcinoma', 'Disease', 'MESH:C538614', (184, 204))	('cell renal carcinoma', 'Disease', (184, 204))	('von Hippel-Lindau disease', 'Disease', (32, 57))	('VHL', 'Gene', (17, 20))	('pheochromocytoma', 'Disease', (209, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (209, 225))	('familial cancer syndrome', 'Disease', 'MESH:D009386', (82, 106))	('neoplasms', 'Phenotype', 'HP:0002664', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('VHL', 'Gene', '7428', (17, 20))	('benign neoplasms', 'Disease', (150, 166))	('benign neoplasms', 'Disease', 'MESH:D009369', (150, 166))
61329	20398431	Accordingly, not only is SDHB protein suppressed in tumors with mutations in SDHB and SDHD, but also in a subset of tumors with VHL mutations which act through HIF1alpha.	('VHL', 'Gene', '7428', (128, 131))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('HIF1alpha', 'Gene', '3091', (160, 169))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SDHB', 'Gene', '6390', (77, 81))	('suppressed', 'NegReg', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (64, 73))	('HIF1alpha', 'Gene', (160, 169))	('protein', 'Protein', (30, 37))	('SDHD', 'Gene', '6392', (86, 90))	('tumors', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', (52, 58))	('SDHB', 'Gene', '6390', (25, 29))	('SDHB', 'Gene', (77, 81))	('VHL', 'Gene', (128, 131))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('SDHD', 'Gene', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('SDHB', 'Gene', (25, 29))
61330	20398431	In addition, alterations of proteins involved in Fe-S cluster biogenesis, including Nitrogen fixation-1 homolog (nfs-1), LYR motif containing 4 (LYRM4; isd11), and frataxin, can lead to a reduction of SDH activity.	('nfs-1', 'Gene', (113, 118))	('nfs-1', 'Gene', '9054', (113, 118))	('isd11', 'Gene', '57128', (152, 157))	('SDH', 'Gene', (201, 204))	('LYRM4', 'Gene', (145, 150))	('Fe-S', 'Chemical', 'MESH:D007501', (49, 53))	('reduction', 'NegReg', (188, 197))	('SDH', 'Gene', '6390', (201, 204))	('isd11', 'Gene', (152, 157))	('LYR motif containing 4', 'Gene', (121, 143))	('activity', 'MPA', (205, 213))	('LYR motif containing 4', 'Gene', '57128', (121, 143))	('LYRM4', 'Gene', '57128', (145, 150))	('Nitrogen', 'Chemical', 'MESH:D009584', (84, 92))	('alterations', 'Var', (13, 24))
61331	20398431	For example, disrupted expression of frataxin in murine hepatocytes causes decreased oxidative phosphorylation (OXPHOS) paralleled by reduced activity of iron-sulfur cluster-containing proteins.	('iron', 'Chemical', 'MESH:D007501', (154, 158))	('activity', 'MPA', (142, 150))	('iron-sulfur', 'Protein', (154, 165))	('sulfur', 'Chemical', 'MESH:D013455', (159, 165))	('decreased', 'NegReg', (75, 84))	('oxidative phosphorylation', 'MPA', (85, 110))	('reduced', 'NegReg', (134, 141))	('disrupted', 'Var', (13, 22))	('frataxin', 'Gene', (37, 45))	('murine', 'Species', '10090', (49, 55))	('expression', 'MPA', (23, 33))
61343	20398431	Besides the association of SDH and tumor development, loss of NADH: ubiquinone oxidoreductase (complex I) of the respiratory chain has also been shown in oxiphilic tumors.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Disease', (164, 169))	('oxidoreductase', 'Gene', (79, 93))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NADH', 'Chemical', 'MESH:D009243', (62, 66))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('oxiphilic tumors', 'Disease', (154, 170))	('tumor', 'Disease', (35, 40))	('SDH', 'Gene', (27, 30))	('oxidoreductase', 'Gene', '8630', (79, 93))	('loss', 'Var', (54, 58))	('oxiphilic tumors', 'Disease', 'MESH:D009369', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('SDH', 'Gene', '6390', (27, 30))
61389	20398431	As pheochromocytomas and NB originate from neural crest and pheochromocytomas frequently show reduced SDH activity caused by pathogenic SDH mutations, we measured the enzymatic activity of SDH in NB.	('SDH', 'Gene', '6390', (189, 192))	('SDH', 'Gene', (102, 105))	('SDH', 'Gene', (136, 139))	('reduced', 'NegReg', (94, 101))	('pheochromocytomas', 'Disease', (3, 20))	('pheochromocytomas', 'Disease', 'MESH:D010673', (3, 20))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (60, 77))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (3, 20))	('SDH', 'Gene', (189, 192))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('mutations', 'Var', (140, 149))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (3, 19))	('pheochromocytomas', 'Disease', (60, 77))	('activity', 'MPA', (106, 114))	('pheochromocytomas', 'Disease', 'MESH:D010673', (60, 77))	('SDH', 'Gene', '6390', (102, 105))	('SDH', 'Gene', '6390', (136, 139))
61392	20398431	To evaluate if this massive downregulation of SDH in NB is due to a mutation in one of the four nuclear-encoded SDH subunits, we sequenced the SDH genes.	('SDH', 'Gene', (112, 115))	('mutation', 'Var', (68, 76))	('SDH', 'Gene', (143, 146))	('SDH', 'Gene', '6390', (46, 49))	('downregulation', 'NegReg', (28, 42))	('SDH', 'Gene', '6390', (112, 115))	('SDH', 'Gene', (46, 49))	('SDH', 'Gene', '6390', (143, 146))
61396	20398431	In addition, a new nucleotide substitution, c.1948A>G p.Asn650Asp, was detected in three NB samples in SDHA.	('c.1948A>G p.Asn650Asp', 'Var', (44, 65))	('p.Asn650Asp', 'Mutation', 'p.N650D', (54, 65))	('p.Asn650Asp', 'Var', (54, 65))	('c.1948A>G', 'Mutation', 'c.1948A>G', (44, 53))
61398	20398431	Because low SDH activity can be caused by downregulation of iron-sulfur subunits we also sequenced nfs-1, LYRM4, frataxin (n = 7) for pathogenic mutations.	('nfs-1', 'Gene', (99, 104))	('nfs-1', 'Gene', '9054', (99, 104))	('mutations', 'Var', (145, 154))	('iron', 'Chemical', 'MESH:D007501', (60, 64))	('iron-sulfur subunits', 'Protein', (60, 80))	('SDH', 'Gene', '6390', (12, 15))	('downregulation', 'NegReg', (42, 56))	('LYRM4', 'Gene', (106, 111))	('activity', 'MPA', (16, 24))	('SDH', 'Gene', (12, 15))	('sulfur', 'Chemical', 'MESH:D013455', (65, 71))	('LYRM4', 'Gene', '57128', (106, 111))	('low', 'NegReg', (8, 11))
61402	20398431	Because the investigated NBs had no pathogenic SDH mutations and the amount of the VHL protein was unaffected, we evaluated the enzymatic activities of the other OXPHOS complexes in comparison to normal kidney tissue.	('NBs', 'Chemical', 'MESH:D009556', (25, 28))	('VHL', 'Gene', '7428', (83, 86))	('mutations', 'Var', (51, 60))	('SDH', 'Gene', (47, 50))	('SDH', 'Gene', '6390', (47, 50))	('VHL', 'Gene', (83, 86))
61413	20398431	Mutations in the assembly factors SDHAF1 and SDH5 could also be excluded to be the cause of the observed phenotype.	('SDHAF1', 'Gene', '644096', (34, 40))	('SDH5', 'Gene', (45, 49))	('SDHAF1', 'Gene', (34, 40))	('Mutations', 'Var', (0, 9))	('SDH5', 'Gene', '54949', (45, 49))
61415	20398431	Although NBs and pheochromocytomas share a common origin, carcinogenesis in NBs is not linked to pathogenic VHL mutations, as in a subset of pheochromocytomas.	('VHL', 'Gene', '7428', (108, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (141, 158))	('pheochromocytomas', 'Disease', (17, 34))	('NBs', 'Chemical', 'MESH:D009556', (76, 79))	('pheochromocytomas', 'Disease', 'MESH:D010673', (17, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('NBs', 'Chemical', 'MESH:D009556', (9, 12))	('mutations', 'Var', (112, 121))	('pheochromocytomas', 'Disease', (141, 158))	('carcinogenesis', 'Disease', (58, 72))	('pheochromocytomas', 'Disease', 'MESH:D010673', (141, 158))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (17, 33))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (17, 34))	('VHL', 'Gene', (108, 111))
61416	20398431	Deletions of the short arm of chromosome 3 are often observed in a specific subset of aggressive NBs.	('NBs', 'Chemical', 'MESH:D009556', (97, 100))	('observed', 'Reg', (53, 61))	('aggressive NBs', 'Disease', (86, 100))	('short arm', 'Phenotype', 'HP:0009824', (17, 26))	('Deletions', 'Var', (0, 9))
61423	20398431	Since frataxin, nfs-1 and isd11 are only three proteins of the ISC (iron sulfur cluster) machinery, it can not be excluded that a mutation in one of the other proteins involved in ISC biogenesis is responsible for the massive impairment of the SDH activity in NB.	('isd11', 'Gene', (26, 31))	('SDH', 'Gene', '6390', (244, 247))	('activity', 'MPA', (248, 256))	('mutation', 'Var', (130, 138))	('isd11', 'Gene', '57128', (26, 31))	('nfs-1', 'Gene', '9054', (16, 21))	('SDH', 'Gene', (244, 247))	('iron sulfur', 'Chemical', '-', (68, 79))	('nfs-1', 'Gene', (16, 21))
61491	32575796	Alterations in either result in mitochondrial defects, which makes their treatment particularly challenging.	('rat', 'Species', '10116', (4, 7))	('Alterations', 'Var', (0, 11))	('mitochondrial defects', 'CPA', (32, 53))	('result in', 'Reg', (22, 31))
61496	32575796	Mitochondrial disorders play a pivotal role in tumorigenesis by orchestrating metabolic reprogramming, apoptosis, and ROS signaling at virtually all stages, from tumor initiation to metastasis, and mtDNA mutations have been proposed as drivers/modifiers of tumorigenesis in many cancers.	('rat', 'Species', '10116', (71, 74))	('tumor', 'Disease', (162, 167))	('mtDNA', 'Gene', (198, 203))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancers', 'Disease', (279, 286))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (204, 213))	('Mitochondrial disorders', 'Disease', 'MESH:D028361', (0, 23))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (47, 52))	('Mitochondrial disorders', 'Disease', (0, 23))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
61498	32575796	These large-scale studies identified intrinsic replicative errors, characterized by an asymmetric bias towards C > T and T > C transitions on the mtDNA heavy and light strands respectively, as the most prominent source of mtDNA mutations, overpowering the 4% caused by ROS exposure.	('C > T', 'Var', (111, 116))	('overpowering', 'PosReg', (239, 251))	('ROS', 'Chemical', 'MESH:D017382', (269, 272))	('T > C', 'Var', (121, 126))	('mutations', 'Var', (228, 237))
61499	32575796	While neutral missense mutations were found to gradually drift towards homoplasmy, deleterious frameshift or nonsense mutations, often resulting in truncated proteins, were almost exclusively heteroplasmic, thus highlighting a selective pressure in cancer cells to retain residual mitochondrial functionality.	('proteins', 'Protein', (158, 166))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('resulting', 'Reg', (135, 144))	('cancer', 'Disease', (249, 255))	('frameshift', 'Var', (95, 105))	('missense mutations', 'Var', (14, 32))	('truncated', 'MPA', (148, 157))	('nonsense mutations', 'Var', (109, 127))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
61505	32575796	Transmitochondrial cybrid studies thus showed that complex I mutants can exhibit both pro- and anti-tumorigenic effects in cancer, in an OXPHOS- and ROS-dependent fashion, as detailed below.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('cancer', 'Disease', (123, 129))	('pro-', 'CPA', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutants', 'Var', (61, 68))
61506	32575796	The ND5 m.12418insA frameshift mutation, found in colorectal cancers, leads to a truncated ND5 protein, which destabilizes the assembly of the membrane-embedded arm of complex I.	('colorectal cancers', 'Disease', (50, 68))	('truncated', 'MPA', (81, 90))	('destabilizes', 'NegReg', (110, 122))	('assembly', 'MPA', (127, 135))	('leads', 'Reg', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('ND5 m.12418insA frameshift', 'Var', (4, 30))	('colorectal cancers', 'Disease', 'MESH:D015179', (50, 68))	('frameshift', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('m.12418insA', 'Mutation', 'c.M.12418insA', (8, 19))	('ND5', 'Gene', (91, 94))
61511	32575796	Osteosarcoma cybrids harboring a heteroplasmic ND5 mutation were thus endowed with resistance to oxidative stress and, subsequently, enhanced tumorigenicity upon subcutaneous injection in nude mice.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('ND5', 'Gene', (47, 50))	('tumor', 'Disease', (142, 147))	('nude mice', 'Species', '10090', (188, 197))	('Osteosarcoma', 'Disease', (0, 12))	('mutation', 'Var', (51, 59))	('Osteosarcoma', 'Phenotype', 'HP:0002669', (0, 12))	('Osteosarcoma', 'Disease', 'MESH:D012516', (0, 12))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('enhanced', 'PosReg', (133, 141))
61512	32575796	ND5-mutant homoplasmic cybrids, however, showed increased levels in both mitochondrial and intracellular ROS, which led to apoptosis and prevented tumor formation in vivo.	('prevented', 'NegReg', (137, 146))	('tumor', 'Disease', (147, 152))	('ND5-mutant', 'Var', (0, 10))	('increased', 'PosReg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('levels in', 'MPA', (58, 67))	('ND5-mutant', 'Gene', (0, 10))	('apoptosis', 'CPA', (123, 132))	('led to', 'Reg', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))
61513	32575796	The ND1m.3571insC frameshift mutation, observed in thyroid oncocytic carcinoma, also generates a truncated ND1 protein, which leads to complex I disassembly.	('leads to', 'Reg', (126, 134))	('frameshift mutation', 'Var', (18, 37))	('ND1', 'Gene', (107, 110))	('ND1', 'Gene', '4535', (107, 110))	('3571insC', 'Mutation', 'c.3571insC', (9, 17))	('thyroid oncocytic carcinoma', 'Disease', (51, 78))	('thyroid oncocytic carcinoma', 'Disease', 'MESH:C535584', (51, 78))	('rat', 'Species', '10116', (89, 92))	('truncated', 'MPA', (97, 106))	('ND1', 'Gene', '4535', (4, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('ND1', 'Gene', (4, 7))
61514	32575796	Transmitochondrial osteosarcoma cybrids expressing this ND1 mutant totally lost their complex I activity and their basal oxygen consumption, revealing a dramatic OXPHOS deficit.	('lost', 'NegReg', (75, 79))	('basal oxygen consumption', 'MPA', (115, 139))	('ND1', 'Gene', '4535', (56, 59))	('complex I activity', 'MPA', (86, 104))	('ND1', 'Gene', (56, 59))	('OXPHOS', 'MPA', (162, 168))	('oxygen', 'Chemical', 'MESH:D010100', (121, 127))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('mutant', 'Var', (60, 66))	('osteosarcoma', 'Disease', (19, 31))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))
61517	32575796	Another ND1mutation (missense m.3460G>A, A52T) showed a weaker phenotype as homoplasmic osteosarcoma cybrids retained 50% of complex I activity, with only a partial reduction in basal oxygen consumption.	('osteosarcoma', 'Disease', 'MESH:D012516', (88, 100))	('ND1', 'Gene', '4535', (8, 11))	('A52T', 'Mutation', 'rs199476118', (41, 45))	('ND1', 'Gene', (8, 11))	('complex I', 'Enzyme', (125, 134))	('m.3460G>A', 'Mutation', 'rs199476118', (30, 39))	('activity', 'MPA', (135, 143))	('basal oxygen consumption', 'MPA', (178, 202))	('oxygen', 'Chemical', 'MESH:D010100', (184, 190))	('osteosarcoma', 'Phenotype', 'HP:0002669', (88, 100))	('missense m.3460G>A', 'Var', (21, 39))	('osteosarcoma', 'Disease', (88, 100))
61519	32575796	A third type of mutation (m.4776G>A; A103T), found in the ND2 subunit of complex I in head and neck squamous cell carcinoma, also illustrates the role of ROS accumulation and HIF1alpha stabilization in tumorigenesis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('m.4776G>A', 'Mutation', 'm.4776G>A', (26, 35))	('tumor', 'Disease', (202, 207))	('A103T', 'Mutation', 'c.103A>T', (37, 42))	('ND2', 'Gene', (58, 61))	('ND2', 'Gene', '4536', (58, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('rat', 'Species', '10116', (136, 139))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('m.4776G>A; A103T', 'Var', (26, 42))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
61520	32575796	This mutation, which impaired cell respiration and increased ROS production, led to a feedback metabolic signaling involving pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase 2 (PDK2).	('pyruvate dehydrogenase', 'Gene', '54704', (125, 147))	('increased ROS production', 'Phenotype', 'HP:0025464', (51, 75))	('PDH', 'Gene', '54704', (149, 152))	('pyruvate dehydrogenase kinase 2', 'Gene', (158, 189))	('ROS production', 'MPA', (61, 75))	('pyruvate dehydrogenase', 'Gene', (125, 147))	('increased', 'PosReg', (51, 60))	('pyruvate dehydrogenase kinase 2', 'Gene', '5164', (158, 189))	('rat', 'Species', '10116', (40, 43))	('cell respiration', 'MPA', (30, 46))	('led to', 'Reg', (77, 83))	('impaired', 'NegReg', (21, 29))	('PDH', 'Gene', (149, 152))	('pyruvate dehydrogenase', 'Gene', '54704', (158, 180))	('feedback metabolic signaling', 'MPA', (86, 114))	('PDK2', 'Gene', (191, 195))	('mutation', 'Var', (5, 13))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
61522	32575796	Finally, the highly-metastatic capacities of murine Lewis lung carcinoma and fibrosarcoma were attributed to the missense m.13997G>A (P25L) and frameshift m.13885insC mutations, respectively, in the mtDNA ND6-encoding gene, as further confirmed in cybrids.	('frameshift m.13885insC', 'Var', (144, 166))	('P25L', 'Mutation', 'rs35460768', (134, 138))	('fibrosarcoma', 'Disease', (77, 89))	('m.13885insC', 'Mutation', 'c.M.13885insC', (155, 166))	('lung carcinoma', 'Disease', 'MESH:D008175', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('m.13997G>A', 'Mutation', 'rs35460768', (122, 132))	('mtDNA ND6-encoding', 'Gene', (199, 217))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (77, 89))	('fibrosarcoma', 'Disease', 'MESH:D005354', (77, 89))	('missense m.13997G>A', 'Var', (113, 132))	('lung carcinoma', 'Disease', (58, 72))	('murine', 'Species', '10090', (45, 51))	('highly-metastatic capacities', 'CPA', (13, 41))
61523	32575796	The increased metastatic capacity of these complex I mutants was also associated with a higher ROS production, which led to high levels of HIF1alpha, of the anti-apoptotic MCL-1 protein, and of the vascular endothelial growth factor (VEGF), thus nurturing neoangiogenesis.	('higher', 'PosReg', (88, 94))	('MCL-1', 'Gene', (172, 177))	('ROS production', 'MPA', (95, 109))	('MCL-1', 'Gene', '4170', (172, 177))	('vascular endothelial growth factor', 'Gene', '7422', (198, 232))	('HIF1alpha', 'MPA', (139, 148))	('mutants', 'Var', (53, 60))	('metastatic capacity', 'CPA', (14, 33))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('increased', 'PosReg', (4, 13))	('vascular endothelial growth factor', 'Gene', (198, 232))
61525	32575796	NADPH-oxidase 1 (NOX1) activity was also shown to contribute to tumorigenesis, together with increased mitochondrial ROS, as a result of complex I dysfunction.	('tumor', 'Disease', (64, 69))	('NADPH-oxidase 1', 'Gene', (0, 15))	('dysfunction', 'Var', (147, 158))	('increased', 'PosReg', (93, 102))	('NADPH-oxidase 1', 'Gene', '27035', (0, 15))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('activity', 'MPA', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mitochondrial ROS', 'MPA', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
61526	32575796	The various osteosarcoma cybrids analyzed, carrying the m.3460G>A/MT-ND1 (A52T), m.11778G>A/MT-ND4 (R340H), and m.14484T>C/MT-ND6 (M64V) point mutations, respectively, exhibited decreased OXPHOS and ATP production.	('MT-ND1', 'Gene', '4535', (66, 72))	('decreased', 'NegReg', (178, 187))	('m.3460G>A', 'Mutation', 'rs199476118', (56, 65))	('osteosarcoma', 'Disease', (12, 24))	('osteosarcoma', 'Disease', 'MESH:D012516', (12, 24))	('ATP production', 'MPA', (199, 213))	('R340H', 'Mutation', 'rs199476112', (100, 105))	('M64V', 'Mutation', 'rs199476104', (131, 135))	('m.11778G>A', 'SUBSTITUTION', 'None', (81, 91))	('m.11778G>A', 'Var', (81, 91))	('A52T', 'Mutation', 'rs199476118', (74, 78))	('MT-ND4', 'Gene', (92, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (12, 24))	('m.14484T>C', 'Var', (112, 122))	('MT-ND6', 'Gene', '4541', (123, 129))	('MT-ND6', 'Gene', (123, 129))	('ATP', 'Chemical', 'MESH:D000255', (199, 202))	('MT-ND1', 'Gene', (66, 72))	('MT-ND4', 'Gene', '4538', (92, 98))	('m.14484T>C', 'SUBSTITUTION', 'None', (112, 122))	('OXPHOS', 'MPA', (188, 194))
61528	32575796	Overall, mutations in complex I appear to exert anti-tumorigenic effects only upon complete abolishment of complex I function, which prevents ROS production.	('abolishment of complex I function', 'Phenotype', 'HP:0011923', (92, 125))	('abolishment', 'NegReg', (92, 103))	('prevents', 'NegReg', (133, 141))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ROS', 'Chemical', 'MESH:D017382', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('function', 'MPA', (117, 125))	('ROS production', 'MPA', (142, 156))	('tumor', 'Disease', (53, 58))	('complex I', 'Gene', (22, 31))	('complex', 'Protein', (107, 114))
61530	32575796	Several studies reported that OXPHOS dysfunction, as a consequence of complex I impairment, leads to a metabolic shift towards glycolysis, which enables cells to maintain cell growth and ATP production.	('OXPHOS dysfunction', 'Disease', (30, 48))	('metabolic shift towards glycolysis', 'MPA', (103, 137))	('enables', 'PosReg', (145, 152))	('OXPHOS dysfunction', 'Disease', 'MESH:C535470', (30, 48))	('impairment', 'Var', (80, 90))	('cell growth', 'CPA', (171, 182))	('ATP', 'Chemical', 'MESH:D000255', (187, 190))	('leads to', 'Reg', (92, 100))
61532	32575796	Increasing the mutational load from 72% of mutant ND5 in heteroplasmic cybrids to 96% in homoplasmic cybrids gradually decreased respiration (from 53% to 17% of wild type (WT)) and OXPHOS-linked ATP production (from 21% to 2% of WT), while it concomitantly increased glucose uptake and lactate production (from 28% to 56% of WT).	('lactate', 'Chemical', 'MESH:D019344', (286, 293))	('decreased', 'NegReg', (119, 128))	('glucose uptake', 'MPA', (267, 281))	('lactate production', 'MPA', (286, 304))	('OXPHOS-linked ATP production', 'MPA', (181, 209))	('increased', 'PosReg', (257, 266))	('mutational', 'Var', (15, 25))	('ATP', 'Chemical', 'MESH:D000255', (195, 198))	('rat', 'Species', '10116', (134, 137))	('mutant', 'Var', (43, 49))	('glucose', 'Chemical', 'MESH:D005947', (267, 274))	('respiration', 'MPA', (129, 140))	('increased glucose', 'Phenotype', 'HP:0003074', (257, 274))	('ND5', 'Gene', (50, 53))
61535	32575796	HIF1alpha stimulated the expression of the glucose transporters 1 (SLC2A1) and 3 (SLC2A3) as well as a series of glycolytic enzymes, including phosphofructokinase (PFKP), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase (PGK1), and lactate dehydrogenase (LDHA).	('PDH', 'Gene', (215, 218))	('SLC2A3', 'Gene', (82, 88))	('SLC2A1', 'Gene', '6513', (67, 73))	('expression', 'MPA', (25, 35))	('lactate dehydrogenase', 'Gene', '3939', (257, 278))	('SLC2A3', 'Gene', '6515', (82, 88))	('PGK1', 'Gene', '5230', (246, 250))	('LDHA', 'Gene', '3939', (280, 284))	('PFKP', 'Gene', (164, 168))	('HIF1alpha', 'Var', (0, 9))	('PDH', 'Gene', '54704', (215, 218))	('PGK1', 'Gene', (246, 250))	('SLC2A1', 'Gene', (67, 73))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('lactate dehydrogenase', 'Gene', (257, 278))	('rat', 'Species', '10116', (233, 236))	('PFKP', 'Gene', '5214', (164, 168))	('stimulated', 'PosReg', (10, 20))	('LDHA', 'Gene', (280, 284))
61536	32575796	Taken together, these data indicate that complex I mutations could induce a Warburg-like effect in cancer cells, fostering tumor growth.	('Warburg-like effect', 'CPA', (76, 95))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('fostering', 'PosReg', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('induce', 'PosReg', (67, 73))
61537	32575796	Beyond the Warburg effect, a metabolic shift towards complex II-dependent succinate oxidation was recently described as an adaptive mechanism to compensate for OXPHOS dysfunction in high-grade prostate cancers, mutant for the ND1 subunit of complex I.	('prostate cancers', 'Phenotype', 'HP:0012125', (193, 209))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('prostate cancers', 'Disease', (193, 209))	('OXPHOS dysfunction', 'Disease', 'MESH:C535470', (160, 178))	('succinate', 'Chemical', 'MESH:D019802', (74, 83))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('prostate cancers', 'Disease', 'MESH:D011471', (193, 209))	('mutant', 'Var', (211, 217))	('ND1', 'Gene', '4535', (226, 229))	('OXPHOS dysfunction', 'Disease', (160, 178))	('ND1', 'Gene', (226, 229))
61540	32575796	The catabolism of serine, a precursor for nucleic acids, proteins, and fatty acids, was also shown to maintain OXPHOS activity in colon cancer cells with mutant complex I, by producing NADH and feeding it to the ETC.	('catabolism', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('OXPHOS activity', 'MPA', (111, 126))	('NADH', 'Chemical', 'MESH:D009243', (185, 189))	('maintain', 'PosReg', (102, 110))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('fatty acids', 'Chemical', 'MESH:D005227', (71, 82))	('serine', 'Chemical', 'MESH:D012694', (18, 24))	('NADH', 'MPA', (185, 189))	('colon cancer', 'Disease', (130, 142))	('mutant', 'Var', (154, 160))
61543	32575796	By applying a genome-wide CRISPR screening on human K562 chronic myeloid leukemia cells concomitantly treated with oligomycin, an inhibitor of complex V, Mootha and colleagues identified a series of both synthetic lethal mutants and suppressors showing that complex I mutations can alleviate complex V dysfunction.	('mutations', 'Var', (268, 277))	('complex V dysfunction', 'MPA', (292, 313))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (57, 81))	('myeloid leukemia', 'Disease', (65, 81))	('RISP', 'Gene', (27, 31))	('RISP', 'Gene', '66694', (27, 31))	('K562', 'CellLine', 'CVCL:0004', (52, 56))	('human', 'Species', '9606', (46, 51))	('mutants', 'Var', (221, 228))	('leukemia', 'Phenotype', 'HP:0001909', (73, 81))	('myeloid leukemia', 'Disease', 'MESH:D007951', (65, 81))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (65, 81))	('alleviate', 'NegReg', (282, 291))	('oligomycin', 'Chemical', 'MESH:D009840', (115, 125))
61545	32575796	Experimental depletion of cytosolic NADPH, known to drive reductive pathways, suppressed the protective effect of complex I loss against complex V inactivation, thus supporting the role of reductive metabolism in these effects.	('NADPH', 'Gene', (36, 41))	('NADPH', 'Gene', '1666', (36, 41))	('complex V inactivation', 'MPA', (137, 159))	('suppressed', 'NegReg', (78, 88))	('depletion', 'Var', (13, 22))	('protective', 'MPA', (93, 103))
61550	32575796	Deleterious mutations in any of the four subunits of complex II decrease SDH activity and result in abnormal accumulation of succinate, as observed in complex II-mutated cells in vitro and in the extracellular fluids (plasma, urine, saliva, and feces) of complex II-deficient patients.	('patients', 'Species', '9606', (276, 284))	('decrease', 'NegReg', (64, 72))	('succinate', 'Chemical', 'MESH:D019802', (125, 134))	('SDH', 'Gene', '6390', (73, 76))	('mutations', 'Var', (12, 21))	('subunits of complex II decrease', 'Phenotype', 'HP:0008314', (41, 72))	('activity', 'MPA', (77, 85))	('SDH', 'Gene', (73, 76))	('accumulation', 'PosReg', (109, 121))
61551	32575796	Complex II mutations, principally affecting SDHB and SDHD subunits, have been associated with various cancers including hereditary paraganglioma and pheochromocytoma (i.e., neuroendocrine tumors of the paraganglionic tissue), gastrointestinal stromal tumors, and renal cell carcinoma.	('mutations', 'Var', (11, 20))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (263, 283))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (173, 194))	('gastrointestinal stromal tumors', 'Disease', (226, 257))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumors of the paraganglionic tissue', 'Phenotype', 'HP:0002668', (188, 223))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('associated', 'Reg', (78, 88))	('neuroendocrine tumors', 'Disease', (173, 194))	('renal cell carcinoma', 'Disease', (263, 283))	('SDHD', 'Gene', '6392', (53, 57))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (263, 283))	('SDHB', 'Gene', (44, 48))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (226, 257))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (226, 257))	('SDHD', 'Gene', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('hereditary paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (120, 165))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (173, 194))
61553	32575796	The R22X nonsense SDHD mutation found in hereditary paraganglioma and pheochromocytoma generates a truncated SDHD protein of 21 amino acids (instead of 159), resulting in the loss of complex II electron transfer and enzymatic activities and in the activation of the HIF1alpha signaling pathway.	('activation', 'PosReg', (248, 258))	('R22X', 'Var', (4, 8))	('HIF1alpha signaling pathway', 'Pathway', (266, 293))	('SDHD', 'Gene', '6392', (109, 113))	('rat', 'Species', '10116', (91, 94))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (70, 86))	('SDHD', 'Gene', (109, 113))	('complex II electron transfer', 'MPA', (183, 211))	('R22X', 'Mutation', 'rs104894306', (4, 8))	('SDHD', 'Gene', '6392', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('enzymatic activities', 'MPA', (216, 236))	('loss', 'NegReg', (175, 179))	('SDHD', 'Gene', (18, 22))	('hereditary paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (41, 86))
61554	32575796	The R22X nonsense SDHD mutation leads to succinate accumulation, which inhibits the activity of prolyl hydroxylase (PHD) and, consequently, induces HIF1alpha stabilization.	('R22X', 'Var', (4, 8))	('PHD', 'Disease', 'MESH:D011547', (116, 119))	('induces', 'Reg', (140, 147))	('PHD', 'Disease', (116, 119))	('R22X', 'Mutation', 'rs104894306', (4, 8))	('SDHD', 'Gene', '6392', (18, 22))	('activity', 'MPA', (84, 92))	('succinate accumulation', 'MPA', (41, 63))	('leads to', 'Reg', (32, 40))	('SDHD', 'Gene', (18, 22))	('inhibits', 'NegReg', (71, 79))	('succinate', 'Chemical', 'MESH:D019802', (41, 50))	('HIF1alpha stabilization', 'MPA', (148, 171))
61558	32575796	Succinate accumulation resulting from complex II mutations was shown to inhibit other 2-OG-dependent dioxygenases, including the Jumonji C (JmjC)-domain containing histone lysine demethylases (KDMs) and the ten-eleven translocation (TET) family of DNA hydroxylases (Figure 3).	('Succinate accumulation', 'MPA', (0, 22))	('mutations', 'Var', (49, 58))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('TET', 'Chemical', '-', (233, 236))	('oxygen', 'Chemical', 'MESH:D010100', (103, 109))	('inhibit', 'NegReg', (72, 79))	('2-OG-dependent dioxygenases', 'Enzyme', (86, 113))	('complex II', 'Gene', (38, 48))
61560	32575796	Succinate accumulation was shown to reduce TET-induced levels of 5hmC in human embryonic kidney cells (HEK293T) with SDHA/B knockdown as well as in mice livers with transient SDHA knockdown.	('Succinate accumulation', 'MPA', (0, 22))	('knockdown', 'Var', (124, 133))	('SDHA/B', 'Gene', (117, 123))	('TET', 'Chemical', '-', (43, 46))	('reduce', 'NegReg', (36, 42))	('TET-induced levels of 5hmC', 'MPA', (43, 69))	('embryonic kidney', 'Disease', (79, 95))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('human', 'Species', '9606', (73, 78))	('mice', 'Species', '10090', (148, 152))	('embryonic kidney', 'Disease', 'MESH:D007674', (79, 95))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))	('5hmC', 'Chemical', 'MESH:C011865', (65, 69))
61562	32575796	As mentioned above, SDH mutations can promote tumorigenesis by a succinate-mediated genome-wide epigenetic remodeling.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SDH', 'Gene', (20, 23))	('tumor', 'Disease', (46, 51))	('promote', 'PosReg', (38, 45))	('mutations', 'Var', (24, 33))	('succinate', 'Chemical', 'MESH:D019802', (65, 74))	('SDH', 'Gene', '6390', (20, 23))
61563	32575796	As shown in mouse SDHB-knockout chromaffin cells, increased succinate levels were associated with CpG island hypermethylation in the promoters of genes encoding proteins such as the matrix-metalloprotease inhibitor SPOCK2, the metastasis suppressor DNAJA4, and the cell adhesion marker KRT19, thus resulting in a derepression of epithelial-to-mesenchymal transition (EMT).	('SPOCK2', 'Gene', '94214', (215, 221))	('epithelial-to-mesenchymal transition', 'CPA', (329, 365))	('derepression', 'PosReg', (313, 325))	('succinate', 'Chemical', 'MESH:D019802', (60, 69))	('increased', 'PosReg', (50, 59))	('KRT19', 'Gene', (286, 291))	('succinate levels', 'MPA', (60, 76))	('mouse', 'Species', '10090', (12, 17))	('KRT19', 'Gene', '16669', (286, 291))	('chromaffin', 'Chemical', '-', (32, 42))	('hypermethylation', 'Var', (109, 125))	('increased succinate levels', 'Phenotype', 'HP:0020149', (50, 76))	('SPOCK2', 'Gene', (215, 221))
61570	32575796	Taken together, these studies indicate that the succinate-induced hypermethylator phenotype acts as a double-edged sword in the physiopathology of cancers harboring SDH mutations, as it can either promote or inhibit cancer progression, depending on the genes targeted for methylation.	('SDH', 'Gene', '6390', (165, 168))	('succinate', 'Chemical', 'MESH:D019802', (48, 57))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (169, 178))	('inhibit', 'NegReg', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('SDH', 'Gene', (165, 168))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancers', 'Disease', (147, 154))	('promote', 'PosReg', (197, 204))
61571	32575796	As complex II links the ETC to the TCA cycle, alterations of its functions expectedly result in important metabolic rewiring, found to support the bioenergetic needs of tumors.	('result in', 'Reg', (86, 95))	('rat', 'Species', '10116', (50, 53))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('TCA', 'Chemical', 'MESH:D014233', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('alterations', 'Var', (46, 57))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('metabolic', 'MPA', (106, 115))	('tumors', 'Disease', (169, 175))
61587	32575796	Chandel and collaborators recently showed that the activity of complex III (ubiquinol-cytochrome c reductase) of the ETC is needed for the immune suppressive function of Treg cells and that its ablation leads to fatal inflammatory disease in treated mice, through modified metabolite production.	('inflammatory disease', 'Disease', (218, 238))	('modified', 'Reg', (264, 272))	('cytochrome c', 'Gene', (86, 98))	('leads to', 'Reg', (203, 211))	('ablation', 'Var', (194, 202))	('ubiquinol', 'Chemical', 'MESH:C003741', (76, 85))	('inflammatory disease', 'Disease', 'MESH:D007249', (218, 238))	('cytochrome c', 'Gene', '54205', (86, 98))	('rat', 'Species', '10116', (19, 22))	('metabolite production', 'MPA', (273, 294))	('mice', 'Species', '10090', (250, 254))
61588	32575796	Mice whose Treg cells are deficient in complex III were generated, by deleting the gene encoding the Rieske iron-sulfur protein (RISP), one of its essential subunits.	('RISP', 'Gene', '66694', (129, 133))	('RISP', 'Gene', (129, 133))	('deficient in complex III', 'Phenotype', 'HP:0011924', (26, 50))	('rat', 'Species', '10116', (60, 63))	('Rieske iron-sulfur protein', 'Gene', (101, 127))	('Rieske iron-sulfur protein', 'Gene', '66694', (101, 127))	('Mice', 'Species', '10090', (0, 4))	('deleting', 'Var', (70, 78))
61593	32575796	However, HSC impaired respiration was accompanied by a decreased NAD+/NADH ratio and, as observed for RISP-null Treg cells, levels of the metabolites 2-hydroxyglutarate and succinate were increased, as that of fumarate.	('HSC', 'Var', (9, 12))	('RISP', 'Gene', '66694', (102, 106))	('RISP', 'Gene', (102, 106))	('rat', 'Species', '10116', (75, 78))	('fumarate', 'Chemical', 'MESH:D005650', (210, 218))	('respiration', 'MPA', (22, 33))	('impaired', 'NegReg', (13, 21))	('NAD+/NADH ratio', 'MPA', (65, 80))	('decreased', 'NegReg', (55, 64))	('NADH', 'Chemical', 'MESH:D009243', (70, 74))	('NAD+', 'Chemical', 'MESH:D009243', (65, 69))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (214, 217))	('succinate', 'Chemical', 'MESH:D019802', (173, 182))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (150, 168))	('rat', 'Species', '10116', (164, 167))	('increased', 'PosReg', (188, 197))
61598	32575796	These effects of a dysfunctional complex III in reducing NAD+/NADH ratios, proliferation, and angiogenesis were confirmed in vivo in mice harboring a deletion of the Uqcrq gene, encoding the ubiquinol-binding protein QPC, a critical subunit of complex III.	('QPC', 'Gene', (217, 220))	('angiogenesis', 'CPA', (94, 106))	('Uqcrq', 'Gene', (166, 171))	('mice', 'Species', '10090', (133, 137))	('rat', 'Species', '10116', (67, 70))	('NAD+', 'Chemical', 'MESH:D009243', (57, 61))	('dysfunctional', 'Disease', 'MESH:D009461', (19, 32))	('NADH', 'Chemical', 'MESH:D009243', (62, 66))	('ubiquinol', 'Chemical', 'MESH:C003741', (191, 200))	('NAD+/NADH ratios', 'MPA', (57, 73))	('reducing', 'NegReg', (48, 56))	('QPC', 'Gene', '22272', (217, 220))	('deletion', 'Var', (150, 158))	('rat', 'Species', '10116', (82, 85))	('proliferation', 'CPA', (75, 88))	('Uqcrq', 'Gene', '22272', (166, 171))	('dysfunctional', 'Disease', (19, 32))
61620	32575796	Instead of the etomoxir-dependent pharmacological inhibition of CPT1, CPT1 knock downs were performed.	('CPT1', 'Gene', (70, 74))	('CPT1', 'Gene', '1374', (64, 68))	('etomoxir', 'Chemical', 'MESH:C054207', (15, 23))	('knock downs', 'Var', (75, 86))	('CPT1', 'Gene', (64, 68))	('CPT1', 'Gene', '1374', (70, 74))
61622	32575796	CPT1 knock down in the BT549 breast cancer cell line demonstrated the role of CPT1 for cell proliferation, independently of FAO.	('CPT1', 'Gene', '1374', (78, 82))	('rat', 'Species', '10116', (99, 102))	('cell proliferation', 'CPA', (87, 105))	('rat', 'Species', '10116', (60, 63))	('CPT1', 'Gene', (78, 82))	('knock down', 'Var', (5, 15))	('BT549', 'CellLine', 'CVCL:1092', (23, 28))	('CPT1', 'Gene', '1374', (0, 4))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('CPT1', 'Gene', (0, 4))
61636	32575796	The outcome of these transfers can be beneficial, for instance, in tissue healing; on the other hand, they can also enhance tumor progression.	('transfers', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('enhance', 'PosReg', (116, 123))	('tumor', 'Disease', (124, 129))	('tissue healing', 'CPA', (67, 81))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
61639	32575796	Mitochondria donation from MSCs to damaged or cancer cells has invariably been shown to improve recipient cell survival (see reviews).	('recipient cell survival', 'CPA', (96, 119))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('improve', 'PosReg', (88, 95))	('cancer', 'Disease', (46, 52))	('Mitochondria', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
61642	32575796	On the contrary, the transfer to T cells of mitochondria originating from myeloid cells was shown to exacerbate inflammation and to lead to asthma aggravation.	('asthma', 'Phenotype', 'HP:0002099', (140, 146))	('aggravation', 'PosReg', (147, 158))	('transfer', 'Var', (21, 29))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('inflammation', 'Disease', (112, 124))	('exacerbate', 'PosReg', (101, 111))	('lead to', 'Reg', (132, 139))	('asthma', 'Disease', (140, 146))	('asthma', 'Disease', 'MESH:D001249', (140, 146))
61665	32575796	In particular, OXPHOS restoration in rho0 cells was found to re-activate the enzymatic activity of dihydroorotate dehydrogenase (DHODH), which is the ubiquinone-oxidoreductase responsible for orotate formation through dihydroorotate oxidation (Figure 1).	('ubiquinone', 'Chemical', 'MESH:D014451', (150, 160))	('rho0', 'Var', (37, 41))	('orotate', 'Chemical', 'MESH:D009963', (192, 199))	('dihydroorotate', 'Chemical', 'MESH:C004768', (218, 232))	('orotate', 'Chemical', 'MESH:D009963', (106, 113))	('re-activate', 'PosReg', (61, 72))	('dihydroorotate dehydrogenase', 'Gene', '1723', (99, 127))	('enzymatic activity', 'MPA', (77, 95))	('OXPHOS restoration', 'Var', (15, 33))	('dihydroorotate', 'Chemical', 'MESH:C004768', (99, 113))	('rat', 'Species', '10116', (27, 30))	('DHODH', 'Gene', (129, 134))	('DHODH', 'Gene', '1723', (129, 134))	('orotate', 'Chemical', 'MESH:D009963', (225, 232))	('dihydroorotate dehydrogenase', 'Gene', (99, 127))
61694	32575796	In NSCLC and RCC patients, the presence of Akkermansia muciniphila in their gut microbiota was associated to a better response to PD-1 blockade.	('NSCLC', 'Disease', (3, 8))	('Akkermansia muciniphila', 'Gene', (43, 66))	('Akkermansia muciniphila', 'Species', '239935', (43, 66))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('better', 'PosReg', (111, 117))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('RCC', 'Disease', (13, 16))	('patients', 'Species', '9606', (17, 25))	('RCC', 'Phenotype', 'HP:0005584', (13, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('response', 'MPA', (118, 126))	('presence', 'Var', (31, 39))
61723	32575796	One example of transient gene therapy is the expression of the wild-type and functional subunit 4 of NADH dehydrogenase (ND4), via adeno-associated virus (AAV) vectors and by intravitreal injection, in patients suffering from LHON disease in connection with the point mutation G11778A in their mitochondrial ND4 encoding gene.	('ND4', 'Gene', (121, 124))	('NADH dehydrogenase', 'Gene', 'None', (101, 119))	('LHON disease', 'Phenotype', 'HP:0030831', (226, 238))	('LHON disease', 'Disease', (226, 238))	('G11778A', 'Var', (277, 284))	('patients', 'Species', '9606', (202, 210))	('adeno-associated virus', 'Species', '272636', (131, 153))	('NADH dehydrogenase', 'Gene', (101, 119))	('AAV', 'Species', '272636', (155, 158))	('G11778A', 'Mutation', 'g.11778G>A', (277, 284))
61726	32575796	This is notably owing to the non-functional ubiquitin ligase Parkin and PTEN-induced putative kinase 1 (PINK1) in connection with the numerous mutations found in the corresponding PARK2 and PINK1 genes in patients with Parkinson's disease.	('patients', 'Species', '9606', (205, 213))	('PARK2', 'Gene', (180, 185))	("Parkinson's disease", 'Disease', (219, 238))	('PINK1', 'Gene', (104, 109))	('PINK1', 'Gene', (190, 195))	("Parkinson's disease", 'Disease', 'MESH:D010300', (219, 238))	('mutations', 'Var', (143, 152))
61730	32575796	Mitochondrial dysfunction, leading to decreased ATP production, increased oxidative stress, apoptosis, and loss of tissue function, is the hallmark of aging and of numerous pathologies, including those caused by ischemia injury, mtDNA mutations, and metabolic disorders.	('tissue', 'MPA', (115, 121))	('metabolic disorders', 'Disease', 'MESH:D008659', (250, 269))	('decreased', 'NegReg', (38, 47))	('apoptosis', 'CPA', (92, 101))	('ischemia injury', 'Disease', (212, 227))	('ATP production', 'MPA', (48, 62))	('increased oxidative stress', 'Phenotype', 'HP:0025464', (64, 90))	('mutations', 'Var', (235, 244))	('Mitochondrial dysfunction', 'Disease', (0, 25))	('metabolic disorders', 'Disease', (250, 269))	('mtDNA', 'Gene', (229, 234))	('Mitochondrial dysfunction', 'Disease', 'MESH:D028361', (0, 25))	('oxidative stress', 'MPA', (74, 90))	('Mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (0, 25))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))	('ATP', 'Chemical', 'MESH:D000255', (48, 51))	('increased', 'PosReg', (64, 73))	('ischemia injury', 'Disease', 'MESH:D007511', (212, 227))
61742	32575796	The Q-SYMBIO latest trial and longer (two-year end-point) to date suggested that the supplementation with CoQ10 reduced cardiovascular death, but will definitely need to be confirmed owing to the small number of patients tested.	('CoQ10', 'Chemical', 'MESH:C024989', (106, 111))	('cardiovascular death', 'Disease', (120, 140))	('supplementation', 'Var', (85, 100))	('cardiovascular death', 'Disease', 'MESH:D002318', (120, 140))	('patients', 'Species', '9606', (212, 220))	('reduced', 'NegReg', (112, 119))	('CoQ10', 'Gene', (106, 111))
61753	31528828	New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene.	('Pheochromocytoma Surveillance', 'Disease', (18, 47))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('caused by', 'Reg', (160, 169))	('VHL', 'Gene', (113, 116))	('VHL', 'Gene', (71, 74))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (132, 159))	('Missense Mutations', 'Var', (75, 93))	('autosomal dominant syndrome', 'Disease', (132, 159))	('Patients', 'Species', '9606', (57, 65))	('VHL', 'Gene', '7428', (71, 74))	('VHL', 'Gene', '7428', (113, 116))	('Von Hippel-Lindau (VHL) disease', 'Disease', 'MESH:D006623', (94, 125))	('VHL', 'Gene', (196, 199))	('Pheochromocytoma Surveillance', 'Disease', 'MESH:D010673', (18, 47))	('VHL', 'Gene', '7428', (196, 199))	('germline mutations', 'Var', (170, 188))
61759	31528828	VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%).	('large gene deletion', 'Var', (167, 186))	('frameshift mutations', 'Var', (67, 87))	('missense mutations', 'Var', (4, 22))	('VHL', 'Gene', (0, 3))	('stop', 'MPA', (105, 109))	('VHL', 'Gene', '7428', (0, 3))	('splicing site', 'Var', (134, 147))
61760	31528828	The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007).	('mutations', 'Var', (45, 54))	('codon 167', 'Var', (4, 13))	('PHEO', 'Disease', (93, 97))	('VHL', 'Gene', (41, 44))	('VHL', 'Gene', '7428', (41, 44))	('associated', 'Reg', (77, 87))
61761	31528828	PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively).	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (21, 41))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (10, 42))	('VHL', 'Gene', (81, 84))	('pancreatic neuroendocrine tumors', 'Disease', (10, 42))	('missense mutations', 'Var', (85, 103))	('VHL', 'Gene', '7428', (81, 84))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (21, 42))	('associated', 'Reg', (65, 75))	('PHEOs', 'Disease', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (10, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
61762	31528828	In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations.	('pancreatic cysts', 'Disease', (13, 29))	('renal cysts', 'Phenotype', 'HP:0000107', (61, 72))	('pancreatic cyst', 'Phenotype', 'HP:0001737', (13, 28))	('nonmissense mutations', 'Var', (208, 229))	('VHL', 'Gene', '7428', (199, 202))	('central nervous system hemangioblastomas', 'Disease', 'MESH:D018325', (107, 147))	('pancreatic cysts', 'Disease', 'MESH:D010181', (13, 29))	('pancreatic cysts', 'Phenotype', 'HP:0001737', (13, 29))	('VHL', 'Gene', (199, 202))	('central nervous system hemangioblastomas', 'Disease', (107, 147))	('renal cysts', 'Disease', 'MESH:D007674', (61, 72))	('nervous system hemangioblastomas', 'Phenotype', 'HP:0006880', (115, 147))	('hemangioblastoma', 'Phenotype', 'HP:0010797', (130, 146))	('renal cysts', 'Disease', (61, 72))
61763	31528828	VHL missense mutations were highly associated with PHEO and PNETs.	('associated', 'Reg', (35, 45))	('missense mutations', 'Var', (4, 22))	('PNETs', 'Disease', (60, 65))	('VHL', 'Gene', (0, 3))	('PHEO', 'Disease', (51, 55))	('VHL', 'Gene', '7428', (0, 3))
61764	31528828	Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.	('children', 'Species', '9606', (25, 33))	('VHL', 'Gene', '7428', (39, 42))	('VHL', 'Gene', (39, 42))	('missense mutations', 'Var', (53, 71))
61770	31528828	VHL is primarily caused by inactivation of the VHL tumor-suppressor protein, which plays a key role in cellular oxygen sensing by targeting hypoxia-inducible factors (HIFs) for ubiquitination and proteasomal degradation.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inactivation', 'Var', (27, 39))	('VHL tumor', 'Disease', (47, 56))	('targeting', 'Reg', (130, 139))	('hypoxia', 'Disease', (140, 147))	('hypoxia', 'Disease', 'MESH:D000860', (140, 147))	('VHL', 'Gene', (47, 50))	('VHL', 'Gene', (0, 3))	('ubiquitination', 'Disease', 'MESH:C563003', (177, 191))	('VHL tumor', 'Disease', 'MESH:D006623', (47, 56))	('caused by', 'Reg', (17, 26))	('VHL', 'Gene', '7428', (47, 50))	('VHL', 'Gene', '7428', (0, 3))	('ubiquitination', 'Disease', (177, 191))	('oxygen', 'Chemical', 'MESH:D010100', (112, 118))	('proteasomal', 'MPA', (196, 207))
61771	31528828	Approximately 95% to 100% of individuals with a clinical diagnosis of VHL have a disease-causing mutation.	('VHL', 'Gene', (70, 73))	('disease-causing', 'Reg', (81, 96))	('VHL', 'Gene', '7428', (70, 73))	('mutation', 'Var', (97, 105))
61777	31528828	VHL genetic diagnosis is also essential for family counseling before disease onset in individuals harboring VHL mutations.	('VHL', 'Gene', '7428', (108, 111))	('mutations', 'Var', (112, 121))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (108, 111))
61780	31528828	Type 1 VHL is characterized by truncating or large deletion mutations that confer a low risk for PHEOs, whereas type 2 VHL is characterized by missense mutations and an increased risk for PHEOs.	('large deletion mutations', 'Var', (45, 69))	('VHL', 'Gene', (119, 122))	('missense mutations', 'Var', (143, 161))	('VHL', 'Gene', '7428', (119, 122))	('truncating', 'Var', (31, 41))	('VHL', 'Gene', (7, 10))	('VHL', 'Gene', '7428', (7, 10))	('PHEOs', 'Disease', (97, 102))
61781	31528828	In addition, PNETs are more often diagnosed in patients with VHL disease with exon 3 intragenic mutations, compared with patients with VHL disease with large deletions.	('VHL disease', 'Disease', 'MESH:D006623', (135, 146))	('VHL disease', 'Disease', 'MESH:D006623', (61, 72))	('diagnosed', 'Reg', (34, 43))	('patients', 'Species', '9606', (47, 55))	('VHL disease', 'Disease', (135, 146))	('exon 3', 'Var', (78, 84))	('VHL disease', 'Disease', (61, 72))	('PNETs', 'Disease', (13, 18))	('patients', 'Species', '9606', (121, 129))
61810	31528828	Two of the three young patients with PNETs had missense VHL mutations.	('VHL', 'Gene', (56, 59))	('missense', 'Var', (47, 55))	('VHL', 'Gene', '7428', (56, 59))	('patients', 'Species', '9606', (23, 31))	('PNETs', 'Disease', (37, 42))
61812	31528828	VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%; Table 2).	('large gene deletion', 'Var', (167, 186))	('frameshift mutations', 'Var', (67, 87))	('missense mutations', 'Var', (4, 22))	('VHL', 'Gene', (0, 3))	('stop', 'MPA', (105, 109))	('splicing', 'Var', (134, 142))	('VHL', 'Gene', '7428', (0, 3))
61813	31528828	Codon 167 was a hotspot for VHL mutations, identified in 10 cases from 5 of 22 kindreds (22.7%).	('VHL', 'Gene', (28, 31))	('mutations', 'Var', (32, 41))	('VHL', 'Gene', '7428', (28, 31))
61814	31528828	Among those 10 patients with codon 167 mutations, PNETs developed in six, CNS HBs in five, PCs in three, and RCCs in two.	('CNS HBs', 'Disease', (74, 81))	('codon 167', 'Gene', (29, 38))	('patients', 'Species', '9606', (15, 23))	('PNETs', 'Disease', (50, 55))	('mutations', 'Var', (39, 48))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('PCs', 'Disease', (91, 94))
61815	31528828	Among the 22 families, intragenic VHL mutations (81.8%) were located in exon 1 (six families; 27.3%), exon 2 (two families; 22, 9.1%), and exon 3 (10 families; 45.5%).	('mutations', 'Var', (38, 47))	('VHL', 'Gene', (34, 37))	('VHL', 'Gene', '7428', (34, 37))
61816	31528828	Large VHL deletions (two families; 9.1%) and splicing sites (two families; 9,1%) were less frequent among the 22 families.	('VHL', 'Gene', '7428', (6, 9))	('VHL', 'Gene', (6, 9))	('deletions', 'Var', (10, 19))
61817	31528828	All mutations but one have been previously reported in VHL disease.	('mutations', 'Var', (4, 13))	('reported', 'Reg', (43, 51))	('VHL disease', 'Disease', 'MESH:D006623', (55, 66))	('VHL disease', 'Disease', (55, 66))
61818	31528828	The germline VHL frameshift mutation c.309_322del14 (p.G104fs*23), leading to a premature stop codon, was previously described as a somatic event in RCCs in the Catalogue of Somatic Mutations in Cancer.	('RCC', 'Disease', (149, 152))	('premature stop codon', 'MPA', (80, 100))	('c.309_322del14', 'Mutation', 'rs869025628', (37, 51))	('Cancer', 'Phenotype', 'HP:0002664', (195, 201))	('VHL', 'Gene', (13, 16))	('p.G104fs*23', 'Mutation', 'rs869025628', (53, 64))	('VHL', 'Gene', '7428', (13, 16))	('RCC', 'Disease', 'MESH:C538614', (149, 152))	('c.309_322del14', 'Var', (37, 51))
61819	31528828	Two large VHL deletions were identified in two families of patients with VHL disease: an exon 1 and a complete VHL deletion (Fig.	('deletion', 'Var', (115, 123))	('VHL', 'Gene', (73, 76))	('VHL', 'Gene', (111, 114))	('VHL', 'Gene', '7428', (73, 76))	('VHL disease', 'Disease', (73, 84))	('VHL', 'Gene', '7428', (111, 114))	('patients', 'Species', '9606', (59, 67))	('VHL', 'Gene', (10, 13))	('VHL disease', 'Disease', 'MESH:D006623', (73, 84))	('VHL', 'Gene', '7428', (10, 13))
61820	31528828	VHL missense mutations were highly associated with PHEO when compared with other mutations (89.5% vs. 0%; P = 0.0001; chi2= 23.54; Table 5).	('associated', 'Reg', (35, 45))	('missense mutations', 'Var', (4, 22))	('VHL', 'Gene', (0, 3))	('PHEO', 'Disease', (51, 55))	('VHL', 'Gene', '7428', (0, 3))
61821	31528828	In addition, PNETs were significantly more frequent in patients with VHL disease with missense mutations when compared with nonmissense defects (73.7% vs. 16.7%; P = 0.002; chi2= 9.57).	('VHL disease', 'Disease', (69, 80))	('patients', 'Species', '9606', (55, 63))	('VHL disease', 'Disease', 'MESH:D006623', (69, 80))	('missense mutations', 'Var', (86, 104))	('PNETs', 'Disease', (13, 18))
61822	31528828	In contrast, PCs (91.7% vs. 26.3%; P = 0.0001; chi2= 12,58), renal cysts (66.7% vs. 26.3%; P = 0.027; chi2= 4.92), and CNS HBs (91.7% vs. 47.3%; P = 0.027; chi2= 6.30) were more frequent in patients with nonmissense variants (truncating or large deletion) when compared with missense mutations (Table 5).	('large deletion', 'Var', (240, 254))	('PCs', 'Disease', (13, 16))	('renal cysts', 'Phenotype', 'HP:0000107', (61, 72))	('patients', 'Species', '9606', (190, 198))	('CNS', 'Disease', (119, 122))	('truncating', 'Var', (226, 236))	('renal cysts', 'Disease', 'MESH:D007674', (61, 72))	('renal cysts', 'Disease', (61, 72))
61824	31528828	We found that missense mutations conferred an increased risk of PHEO and PNET development but a decreased risk of CNS HBs, PCs, and renal cysts.	('PNET', 'Disease', (73, 77))	('decreased', 'NegReg', (96, 105))	('PHEO', 'Disease', (64, 68))	('CNS HBs', 'Disease', (114, 121))	('renal cysts', 'Disease', 'MESH:D007674', (132, 143))	('renal cysts', 'Disease', (132, 143))	('missense mutations', 'Var', (14, 32))	('PCs', 'Disease', (123, 126))	('renal cysts', 'Phenotype', 'HP:0000107', (132, 143))
61825	31528828	In our cohort, the majority of VHL mutations detected were missense, as previously described.	('VHL', 'Gene', '7428', (31, 34))	('missense', 'Var', (59, 67))	('VHL', 'Gene', (31, 34))	('mutations', 'Var', (35, 44))
61828	31528828	We also reported here a 5-cm PHEO in a 4-year-old boy with VHL harboring the p.Gly114Ser mutation.	('boy', 'Species', '9606', (50, 53))	('VHL', 'Gene', '7428', (59, 62))	('p.Gly114Ser', 'Mutation', 'rs869025636', (77, 88))	('p.Gly114Ser', 'Var', (77, 88))	('VHL', 'Gene', (59, 62))
61830	31528828	In both cases, patients carried VHL missense mutations (Val84Leu and Gln164Arg).	('VHL', 'Gene', (32, 35))	('patients', 'Species', '9606', (15, 23))	('VHL', 'Gene', '7428', (32, 35))	('Gln164Arg', 'SUBSTITUTION', 'None', (69, 78))	('Gln164Arg', 'Var', (69, 78))	('Val84Leu', 'SUBSTITUTION', 'None', (56, 64))	('Val84Leu', 'Var', (56, 64))
61834	31528828	Similarly, we think PHEO surveillance should initiate before 5 years of age, but only in children with VHL missense mutations and by measuring annually plasma metanephrine levels, without imaging.	('plasma metanephrine levels', 'MPA', (152, 178))	('VHL', 'Gene', '7428', (103, 106))	('metanephrine', 'Chemical', 'MESH:D008676', (159, 171))	('missense mutations', 'Var', (107, 125))	('children', 'Species', '9606', (89, 97))	('VHL', 'Gene', (103, 106))
61835	31528828	Although PHEOs in VHL disease are rarely malignant, starting annual screening of plasma metanephrine levels before 5 years of age only in a subset of children with VHL disease (those harboring VHL missense mutations) is cost-effective and will allow an earlier diagnosis of a tumor associated with hypertension and increased cardiovascular morbidity.	('VHL', 'Gene', '7428', (18, 21))	('hypertension', 'Disease', (298, 310))	('VHL disease', 'Disease', 'MESH:D006623', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('cardiovascular morbidity', 'Phenotype', 'HP:0001626', (325, 349))	('VHL', 'Gene', (164, 167))	('metanephrine', 'Chemical', 'MESH:D008676', (88, 100))	('VHL disease', 'Disease', (164, 175))	('hypertension', 'Phenotype', 'HP:0000822', (298, 310))	('VHL', 'Gene', '7428', (164, 167))	('missense mutations', 'Var', (197, 215))	('VHL', 'Gene', (193, 196))	('tumor', 'Disease', (276, 281))	('children', 'Species', '9606', (150, 158))	('VHL disease', 'Disease', 'MESH:D006623', (18, 29))	('VHL', 'Gene', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('VHL', 'Gene', '7428', (193, 196))	('VHL disease', 'Disease', (18, 29))	('hypertension', 'Disease', 'MESH:D006973', (298, 310))
61837	31528828	Codon 167 was a hotspot for VHL mutations in our cohort.	('VHL', 'Gene', (28, 31))	('mutations', 'Var', (32, 41))	('VHL', 'Gene', '7428', (28, 31))
61838	31528828	Mutations in this codon represent approximately 43% of mutations in American and Canadian families with type 2 VHL disease.	('VHL disease', 'Disease', 'MESH:D006623', (111, 122))	('Mutations in', 'Var', (0, 12))	('VHL disease', 'Disease', (111, 122))
61839	31528828	Codon 167 mutations have been associated with an increased risk of PHEO, PNET and RCC development.	('associated', 'Reg', (30, 40))	('PNET', 'Disease', (73, 77))	('PHEO', 'Disease', (67, 71))	('Codon 167 mutations', 'Var', (0, 19))	('RCC', 'Disease', 'MESH:C538614', (82, 85))	('RCC', 'Disease', (82, 85))
61845	31528828	Here, we demonstrated a higher frequency of PNETs in patients with VHL disease with missense mutations (VHL type 2).	('patients', 'Species', '9606', (53, 61))	('VHL type 2', 'Disease', 'MESH:D006623', (104, 114))	('VHL disease', 'Disease', (67, 78))	('PNETs', 'Disease', (44, 49))	('VHL type 2', 'Disease', (104, 114))	('VHL disease', 'Disease', 'MESH:D006623', (67, 78))	('missense mutations', 'Var', (84, 102))
61848	31528828	showed that PNETs occurred significantly more frequently in patients with VHL disease with intragenic mutations compared with large deletions.	('VHL disease', 'Disease', 'MESH:D006623', (74, 85))	('PNETs', 'Disease', (12, 17))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (102, 111))	('VHL disease', 'Disease', (74, 85))
61849	31528828	In addition, PNETs in VHL disease were significantly associated with mutations affecting exon 3 with hotspots in codons 161 and 167.	('VHL disease', 'Disease', 'MESH:D006623', (22, 33))	('mutations affecting', 'Var', (69, 88))	('associated', 'Reg', (53, 63))	('VHL disease', 'Disease', (22, 33))	('PNETs', 'Disease', (13, 18))
61856	31528828	In our cohort, the two cases of malignant PNETs in VHL disease carried the missense mutation p.Arg167Trp at codon 167 in exon 3.	('p.Arg167Trp', 'Mutation', 'rs5030820', (93, 104))	('p.Arg167Trp', 'Var', (93, 104))	('VHL disease', 'Disease', 'MESH:D006623', (51, 62))	('VHL disease', 'Disease', (51, 62))
61857	31528828	Early age at onset, truncating VHL mutations, and CNS HB as the first presenting tumor were related to a decreased survival in a Chinese cohort of patients with VHL disease.	('VHL', 'Gene', '7428', (31, 34))	('VHL disease', 'Disease', (161, 172))	('survival', 'MPA', (115, 123))	('truncating', 'Var', (20, 30))	('VHL disease', 'Disease', 'MESH:D006623', (161, 172))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('VHL', 'Gene', (161, 164))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('VHL', 'Gene', '7428', (161, 164))	('VHL', 'Gene', (31, 34))	('CNS HB', 'Gene', (50, 56))	('decreased', 'NegReg', (105, 114))	('tumor', 'Disease', (81, 86))	('mutations', 'Var', (35, 44))
61858	31528828	CNS HBs were associated with nonmissense VHL mutations in our study when compared with missense mutations, as previously reported.	('VHL', 'Gene', '7428', (41, 44))	('CNS', 'Var', (0, 3))	('associated', 'Reg', (13, 23))	('VHL', 'Gene', (41, 44))
61860	31528828	In conclusion, VHL missense mutations were highly associated with PHEOs, whereas CNS HBs were more often diagnosed in patients with VHL truncating mutations, as previously described.	('VHL', 'Gene', (132, 135))	('VHL', 'Gene', (15, 18))	('VHL', 'Gene', '7428', (132, 135))	('VHL', 'Gene', '7428', (15, 18))	('missense mutations', 'Var', (19, 37))	('associated', 'Reg', (50, 60))	('patients', 'Species', '9606', (118, 126))	('PHEOs', 'Disease', (66, 71))
61861	31528828	Interestingly, PNETs were significantly more associated with VHL missense mutations in our cohort.	('VHL', 'Gene', (61, 64))	('PNETs', 'Disease', (15, 20))	('missense mutations', 'Var', (65, 83))	('VHL', 'Gene', '7428', (61, 64))
61862	31528828	Therefore, patients with VHL missense mutations should be closely monitored for PNET development, particularly those with exon 3 missense mutations who carry a higher risk of malignancy.	('malignancy', 'Disease', (175, 185))	('VHL', 'Gene', (25, 28))	('malignancy', 'Disease', 'MESH:D009369', (175, 185))	('VHL', 'Gene', '7428', (25, 28))	('patients', 'Species', '9606', (11, 19))	('missense mutations', 'Var', (29, 47))
61863	31528828	In addition, our data support that biochemical screening for PHEO should be initiated at birth for patients with VHL disease harboring missense mutations.	('patients', 'Species', '9606', (99, 107))	('VHL disease', 'Disease', (113, 124))	('missense mutations', 'Var', (135, 153))	('VHL disease', 'Disease', 'MESH:D006623', (113, 124))
61892	31211058	Presence of S100, specifically expressed by sustentacular cells, allows for the ruling in of paragangliomas and pheochromocytomas, although it may be sometimes absent.	('paragangliomas and pheochromocytomas', 'Disease', 'MESH:D010673', (93, 129))	('S100', 'Gene', '6271', (12, 16))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (112, 129))	('paragangliomas', 'Phenotype', 'HP:0002668', (93, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (112, 128))	('S100', 'Gene', (12, 16))	('Presence', 'Var', (0, 8))
61932	31019814	The abdominal magnetic resonance imaging revealed a left adrenal tumor with 4.3cm length, hyperintense in T2-weighted images and hypointense in T1, with peripheral contrast enhancement and increased washout, possibly indicating a pheochromocytoma.	('hypointense', 'Var', (129, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('adrenal tumor', 'Phenotype', 'HP:0100631', (57, 70))	('enhancement', 'PosReg', (173, 184))	('left adrenal tumor', 'Disease', (52, 70))	('washout', 'MPA', (199, 206))	('left adrenal tumor', 'Disease', 'MESH:D000310', (52, 70))	('pheochromocytoma', 'Disease', (230, 246))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (230, 246))	('T2-weighted images', 'MPA', (106, 124))	('pheochromocytoma', 'Disease', 'MESH:D010673', (230, 246))	('increased', 'PosReg', (189, 198))
61934	31019814	At biochemical evaluation, she presented elevation of plasma and urinary normetanephrine [3503 pg/mL (<120) and 5505 ug/24h (50-650) resp.]	('5505 ug/24h', 'Var', (112, 123))	('urinary normetanephrine', 'Phenotype', 'HP:0003345', (65, 88))	('elevation', 'PosReg', (41, 50))	('normetanephrine', 'Chemical', 'MESH:D009647', (73, 88))
61943	31019814	Histological examination showed a well-delimitated pheochromocytoma with 3.0x2.5x1.8cm and potential malignant biological behavior with PASS score = 11 (Table 2) (potential malignant biological behavior if PASS score >= 6).	('pheochromocytoma', 'Disease', (51, 67))	('PASS score =', 'Var', (136, 148))	('pheochromocytoma', 'Disease', 'MESH:D010673', (51, 67))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (51, 67))
61964	31019814	Germline mutations in genes associated with malignant behavior were absent, lessening the malignancy potential.	('Germline mutations', 'Var', (0, 18))	('malignancy', 'Disease', (90, 100))	('malignancy', 'Disease', 'MESH:D009369', (90, 100))	('lessening', 'NegReg', (76, 85))
61980	30288966	Commonly recommended treatment options for metastatic PPGLs include surgery for removing the tumor bulk, different combinations of chemotherapy, endoradiotherapy using [131I]metaiodobenzylguanidine, external radiation therapy to areas such as bone where metastases are not accessible for surgery, embolization to block tumor blood supply and sometimes also cryo- or radiofrequency ablation.	('tumor', 'Disease', (319, 324))	('metastases', 'Disease', 'MESH:D009362', (254, 264))	('embolization', 'Var', (297, 309))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PPGLs', 'Chemical', '-', (54, 59))	('tumor', 'Disease', (93, 98))	('block tumor', 'Disease', (313, 324))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('metastases', 'Disease', (254, 264))	('block tumor', 'Disease', 'MESH:D006327', (313, 324))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
62012	30288966	Tumor-bearing SCID/beige mice (n = 2) and SKH1 mice (n = 2) received 15 MBq of [68Ga]Ga-DOTA-(Tyr3)octreotide (TOC) or [68Ga]Ga-DOTA-(Tyr3)octreotate (TATE) at a molar activity of 25 GBq/micromol, respectively.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (25, 29))	('Ga-DOTA-(Tyr3)octreotide', 'Chemical', '-', (85, 109))	('Ga-DOTA-(Tyr3)octreotate', 'Chemical', '-', (125, 149))	('[68Ga]Ga-DOTA-', 'Var', (119, 133))	('[68Ga]Ga-DOTA-', 'Var', (79, 93))	('SCID', 'Gene', '19090', (14, 18))	('mice', 'Species', '10090', (47, 51))	('SCID', 'Gene', (14, 18))
62032	30288966	Liver metastases in SKH1 mice were detected 19 days after intravenous cell injection and showed a significantly higher exponential growth rate (40%/day) compared to the other metastases models (between 17 and 27%/day).	('mice', 'Species', '10090', (25, 29))	('higher', 'PosReg', (112, 118))	('SKH1', 'Var', (20, 24))	('exponential growth rate', 'CPA', (119, 142))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('Liver metastases', 'Disease', 'MESH:D009362', (0, 16))	('Liver metastases', 'Disease', (0, 16))	('metastases', 'Disease', (175, 185))	('metastases', 'Disease', 'MESH:D009362', (175, 185))	('metastases', 'Disease', (6, 16))
62039	30288966	Of note, significant linear relationships with luminescence intensities of tumors were more frequently observed among O-methylated catecholamine metabolites compared to free catecholamines.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('O-methylated', 'Var', (118, 130))	('catecholamine', 'Chemical', 'MESH:D002395', (174, 187))	('luminescence intensities', 'MPA', (47, 71))	('catecholamine', 'Chemical', 'MESH:D002395', (131, 144))	('catecholamines', 'Chemical', 'MESH:D002395', (174, 188))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('observed', 'Reg', (103, 111))
62062	30288966	Since combined T and B cell deficiency in SHO mice carrying a homozygous Prkdcscid mutation did not improve the engraftment of circulating MPCLUC/GZ cells, we suspect innate immune responses to be responsible.	('engraftment', 'MPA', (112, 123))	('B cell deficiency', 'Disease', 'MESH:D016393', (21, 38))	('B cell deficiency', 'Disease', (21, 38))	('mutation', 'Var', (83, 91))	('mice', 'Species', '10090', (46, 50))	('Prkdcscid', 'Gene', (73, 82))
62066	30288966	Additional interactions of anti-Asialo GM1 serum with murine monocytes, fetal thymocytes and basophils might have also contributed.	('anti-Asialo', 'Var', (27, 38))	('GM1', 'Chemical', 'MESH:D005677', (39, 42))	('interactions', 'Interaction', (11, 23))	('murine', 'Species', '10090', (54, 60))
62067	30288966	In SCID/beige mice, impaired NK cell function due to the Lystbg-J mutation in addition to T and B cell deficiency was associated with highly efficient engraftment of circulating MPCLUC/GZ cells and almost immediate tumor formation.	('engraftment', 'CPA', (151, 162))	('mice', 'Species', '10090', (14, 18))	('B cell deficiency', 'Disease', 'MESH:D016393', (96, 113))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('B cell deficiency', 'Disease', (96, 113))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('impaired NK cell', 'Phenotype', 'HP:0012176', (20, 36))	('impaired NK', 'Disease', (20, 31))	('Lystbg-J', 'Gene', (57, 65))	('mutation', 'Var', (66, 74))	('SCID', 'Gene', '19090', (3, 7))	('tumor', 'Disease', (215, 220))	('impaired NK', 'Disease', 'MESH:D009422', (20, 31))	('SCID', 'Gene', (3, 7))
62084	30288966	These findings are in agreement with clinical findings of high SSTR2 densities in metastatic human PPGLs, especially in those due to mutations in succinate dehydrogenase subunit 2 (SDHB).	('succinate dehydrogenase subunit 2', 'Gene', (146, 179))	('human', 'Species', '9606', (93, 98))	('PPGLs', 'Chemical', '-', (99, 104))	('due', 'Reg', (126, 129))	('mutations', 'Var', (133, 142))	('SDHB', 'Gene', (181, 185))	('succinate dehydrogenase subunit 2', 'Gene', '6390', (146, 179))	('densities', 'MPA', (69, 78))
62107	30094312	Elevation of catecholamine levels was not observed upon endocrinological examination, but 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy revealed abnormal accumulation of 123I-MIBG, consistent with the site of abnormal FDG accumulation.	('123I-MIBG', 'Chemical', 'MESH:D019797', (120, 129))	('catecholamine', 'Chemical', 'MESH:D002395', (13, 26))	('123I-MIBG', 'Var', (178, 187))	('123I-MIBG', 'Chemical', 'MESH:D019797', (178, 187))	('accumulation', 'PosReg', (162, 174))	('123I-metaiodobenzylguanidine', 'Chemical', 'MESH:D019797', (90, 118))	('Elevation of catecholamine', 'Phenotype', 'HP:0003334', (0, 26))
62116	30094312	Surgery was performed without any complications, and the pathological tumor diagnosis was T1aN0M0 grade 2 endometrial adenocarcinoma (myometrial invasion was close to 50%) and paraganglioma.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('paraganglioma', 'Disease', 'MESH:D010235', (176, 189))	('tumor', 'Disease', (70, 75))	('T1aN0M0', 'Var', (90, 97))	('endometrial adenocarcinoma', 'Disease', (106, 132))	('paraganglioma', 'Phenotype', 'HP:0002668', (176, 189))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (106, 132))	('paraganglioma', 'Disease', (176, 189))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (106, 132))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
62141	29909963	Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes Multiple primary tumors (MPTs) affect a substantial proportion of cancer survivors and can result from various causes, including inherited predisposition.	('Multiple primary tumors', 'Disease', 'MESH:D009378', (165, 188))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('Variants', 'Var', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Multiple primary tumors', 'Disease', (165, 188))	('P', 'Chemical', 'MESH:D010758', (154, 155))	('cancer', 'Disease', (231, 237))	('P', 'Chemical', 'MESH:D010758', (21, 22))	('Tumor', 'Phenotype', 'HP:0002664', (148, 153))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('affect', 'Reg', (196, 202))	('Tumor', 'Phenotype', 'HP:0002664', (78, 83))	('P', 'Chemical', 'MESH:D010758', (191, 192))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('result', 'Reg', (256, 262))
62142	29909963	Currently, germline genetic testing of MPT-affected individuals for variants in cancer-predisposition genes (CPGs) is mostly targeted by tumor type.	('variants', 'Var', (68, 76))	('P', 'Chemical', 'MESH:D010758', (40, 41))	('tumor', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('P', 'Chemical', 'MESH:D010758', (110, 111))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Disease', (80, 86))
62144	29909963	Despite previous negative genetic assessment and molecular investigations, pathogenic variants in moderate- and high-risk CPGs were detected in 67/440 (15.2%) probands.	('P', 'Chemical', 'MESH:D010758', (123, 124))	('CPGs', 'Disease', (122, 126))	('variants', 'Var', (86, 94))
62145	29909963	In most individuals with a germline variant assessed as pathogenic or likely pathogenic (P/LP), at least one of their tumor types was characteristic of variants in the relevant CPG.	('P', 'Chemical', 'MESH:D010758', (92, 93))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('P', 'Chemical', 'MESH:D010758', (89, 90))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('P', 'Chemical', 'MESH:D010758', (178, 179))	('tumor', 'Disease', (118, 123))	('variants', 'Var', (152, 160))	('LP', 'Chemical', 'MESH:D008070', (91, 93))
62146	29909963	However, in 29 probands (42.2% of those with a P/LP variant), the tumor phenotype appeared discordant.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('P', 'Chemical', 'MESH:D010758', (47, 48))	('P/LP', 'Var', (47, 51))	('LP', 'Chemical', 'MESH:D008070', (49, 51))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('P', 'Chemical', 'MESH:D010758', (50, 51))
62147	29909963	The frequency of individuals with truncating or splice-site CPG variants and at least one discordant tumor type was significantly higher than in a control population (chi2 = 43.642; p <= 0.0001).	('higher', 'PosReg', (130, 136))	('CPG', 'Gene', (60, 63))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('truncating', 'MPA', (34, 44))	('variants', 'Var', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('P', 'Chemical', 'MESH:D010758', (61, 62))
62148	29909963	2/67 (3%) probands with P/LP variants had evidence of multiple inherited neoplasia allele syndrome (MINAS) with deleterious variants in two CPGs.	('neoplasia', 'Phenotype', 'HP:0002664', (73, 82))	('P', 'Chemical', 'MESH:D010758', (24, 25))	('multiple inherited neoplasia allele syndrome', 'Disease', (54, 98))	('P', 'Chemical', 'MESH:D010758', (27, 28))	('variants', 'Var', (29, 37))	('multiple inherited neoplasia allele syndrome', 'Disease', 'MESH:D030342', (54, 98))	('LP', 'Chemical', 'MESH:D008070', (26, 28))	('P', 'Chemical', 'MESH:D010758', (141, 142))
62149	29909963	Together with variant detection rates from a previous series of similarly ascertained MPT-affected individuals, the present results suggest that first-line comprehensive CPG analysis in an MPT cohort referred to clinical genetics services would detect a deleterious variant in about a third of individuals.	('P', 'Chemical', 'MESH:D010758', (171, 172))	('variant', 'Var', (266, 273))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('detect', 'Reg', (245, 251))	('P', 'Chemical', 'MESH:D010758', (190, 191))
62153	29909963	To date, the major factors prompting investigation for germline CPG variants have been family history and features of specific familial cancer syndromes.	('variants', 'Var', (68, 76))	('CPG', 'Gene', (64, 67))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (127, 152))	('P', 'Chemical', 'MESH:D010758', (65, 66))	('familial cancer syndromes', 'Disease', (127, 152))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
62170	29909963	Variants were extracted from VCF files if they were within a gene specified in a comprehensive list of 83 CPGs (Table 1) and had a predicted Sequence Ontology (SO) consequence indicating a deleterious effect on protein function.	('Variants', 'Var', (0, 8))	('protein function', 'MPA', (211, 227))	('effect', 'Reg', (201, 207))	('P', 'Chemical', 'MESH:D010758', (107, 108))
62174	29909963	Genes were included if deleterious variants affecting them were associated with adult-onset tumors and if neoplastic lesions were likely to be a primary presenting feature.	('associated', 'Reg', (64, 74))	('variants', 'Var', (35, 43))	('neoplastic lesions', 'Disease', (106, 124))	('neoplastic lesions', 'Disease', 'MESH:D051437', (106, 124))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (106, 124))	('tumors', 'Disease', 'MESH:D009369', (92, 98))
62178	29909963	Third, variants were retained for further review if the predicted consequence was among a list of SO terms indicating protein truncation, if there was evidence of pathogenicity in ClinVar (at least two-star evidence of pathogenic or likely pathogenic [P/LP] effect corresponding to multiple submissions with no conflicts as to the assertion of clinical significance), or if the variant was assigned a disease mutation (DM) status in the Human Gene Mutation Database (HGMD).	('LP', 'Chemical', 'MESH:D008070', (254, 256))	('disease mutation', 'Disease', (401, 417))	('Human', 'Species', '9606', (437, 442))	('P', 'Chemical', 'MESH:D010758', (255, 256))	('DM', 'Disease', 'MESH:D009223', (419, 421))	('variant', 'Var', (378, 385))	('P', 'Chemical', 'MESH:D010758', (252, 253))
62181	29909963	Retained variants were subsequently excluded if their putative pathogenicity could be refuted by one of the following criteria: (1) a predicted protein-truncating variant for which there was at least two-star evidence of a benign or uncertain effect in ClinVar; (2) a predicted protein-truncating variant in a proto-oncogene in a list compiled on the basis of a literature review (constitutional cancer-predisposing variants in proto-oncogenes are associated with gain-of-function variants, so truncation of the protein product is unlikely to increase tumor risk), (3) a predicted protein-truncating variant affecting <5% of the canonical transcript (according to the LOFTEE VEP plugin), (4) a variant affecting a gene associated with only recessive tumor predisposition (as defined by a literature review) unless an individual appeared to harbor two filtered variants in the same gene, and (5) a variant with HGMD DM status or that exceeded the CADD score threshold and had at least two-star evidence of a benign or uncertain clinical effect or one-star evidence if there were multiple submissions without a P/LP assertion.	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('tumor', 'Disease', (750, 755))	('tumor', 'Disease', 'MESH:D009369', (552, 557))	('HGMD DM', 'Disease', (910, 917))	('tumor', 'Disease', 'MESH:D009369', (750, 755))	('P', 'Chemical', 'MESH:D010758', (677, 678))	('tumor', 'Phenotype', 'HP:0002664', (552, 557))	('recessive tumor', 'Disease', 'MESH:D009369', (740, 755))	('variant', 'Var', (897, 904))	('tumor', 'Phenotype', 'HP:0002664', (750, 755))	('cancer', 'Disease', (396, 402))	('recessive tumor', 'Disease', (740, 755))	('P', 'Chemical', 'MESH:D010758', (1112, 1113))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('HGMD DM', 'Disease', 'MESH:D009223', (910, 917))	('P', 'Chemical', 'MESH:D010758', (1109, 1110))	('LP', 'Chemical', 'MESH:D008070', (1111, 1113))	('variant', 'Var', (694, 701))	('tumor', 'Disease', (552, 557))
62183	29909963	Additionally, for each variant, it was noted whether the corresponding individual had previously been diagnosed with a tumor typically associated with pathogenic variants in that gene (according to Rahman, the Familial Cancer Database, or the original paper reporting the gene as a CPG).	('Familial Cancer', 'Disease', 'MESH:D009369', (210, 225))	('tumor', 'Disease', (119, 124))	('Cancer', 'Phenotype', 'HP:0002664', (219, 225))	('variants', 'Var', (162, 170))	('associated', 'Reg', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Familial Cancer', 'Disease', (210, 225))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('P', 'Chemical', 'MESH:D010758', (283, 284))
62186	29909963	Structural variant (SV) calls that were predicted to affect a gene on the gene list (n = 83) were filtered and assessed according to the quality of the call, rarity of the variant, and biological plausibility of tumor predisposition caused by the variant (Figure S2).	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('variant', 'Var', (247, 254))	('tumor', 'Disease', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
62188	29909963	Remaining variants were regarded as potentially pathogenic if they affected a gene associated with tumor predisposition in the heterozygous state (unless there was evidence of homozygosity or compound heterozygosity) and fell into one of the following categories: (1) copy-number loss of coding regions of a tumor-suppressor gene, (2) copy-number gain of coding regions of a proto-oncogene, and (3) any SV type with a predicted breakpoint disrupting the gene.	('tumor', 'Disease', (99, 104))	('affected', 'Reg', (67, 75))	('variants', 'Var', (10, 18))	('disrupting', 'NegReg', (439, 449))	('loss', 'NegReg', (280, 284))	('gain', 'PosReg', (347, 351))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('copy-number', 'Var', (268, 279))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('SV type', 'Disease', 'MESH:D017827', (403, 410))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (308, 313))	('copy-number', 'Var', (335, 346))	('SV type', 'Disease', (403, 410))
62190	29909963	The occurrence of tumors associated with disruption of particular genes in individuals harboring suspected SVs was noted in the same manner as for single-nucleotide variants (SNVs) and indels.	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('disruption', 'Var', (41, 51))	('tumors', 'Disease', (18, 24))	('single-nucleotide variants', 'Var', (147, 173))	('genes', 'Gene', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
62191	29909963	Inversions, translocations, and tandem duplications were confirmed by sequencing across breakpoints, whereas deletions were confirmed by fragment size resulting from long-range PCR if sequencing across the breakpoint was not possible.	('P', 'Chemical', 'MESH:D010758', (177, 178))	('tandem duplications', 'Var', (32, 51))	('translocations', 'Var', (12, 26))
62195	29909963	Only truncating or splice-site variants were considered for comparison purposes because these are less likely to be false positives and made up 52/63 (82.5%) (see Results) of the P/LP variants in our cohort.	('P/LP variants', 'Var', (179, 192))	('P', 'Chemical', 'MESH:D010758', (182, 183))	('P', 'Chemical', 'MESH:D010758', (179, 180))	('LP', 'Chemical', 'MESH:D008070', (181, 183))	('variants', 'Var', (184, 192))	('made', 'Reg', (136, 140))
62214	29909963	Six occurrences of P/LP variants occurred in two members of the same family, and only three of these contributed to the detection rates quoted below.	('variants', 'Var', (24, 32))	('LP', 'Chemical', 'MESH:D008070', (21, 23))	('occurred', 'Reg', (33, 41))	('P', 'Chemical', 'MESH:D010758', (19, 20))	('P/LP', 'Gene', (19, 23))	('P', 'Chemical', 'MESH:D010758', (22, 23))
62215	29909963	Overall, 63 variants in 17 genes in 61 (13.9%) probands were assessed as P/LP (summary in Table 3; full description with phenotype and previous testing in Table S6).	('LP', 'Chemical', 'MESH:D008070', (75, 77))	('variants', 'Var', (12, 20))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('P/LP', 'Disease', (73, 77))	('P', 'Chemical', 'MESH:D010758', (73, 74))	('assessed', 'Reg', (61, 69))
62216	29909963	Individuals with variants in moderate-risk CPGs CHEK2 (MIM: 604373; n = 14) and ATM (MIM: 607585; n = 10) were the most frequent; one homozygote was detected for CHEK2: c.1100delC (p.Thr367Metfs) (Ensembl: ENST00000328354; GenBank: NM_007194.3]; annotated in our data as c.1229delC [p.Thr410fs] [Ensembl: ENST00000382580; GenBank: NM_001005735.1]).	('CHEK2', 'Gene', '11200', (48, 53))	('p.Thr367Met', 'Var', (181, 192))	('variants', 'Var', (17, 25))	('ATM', 'Gene', (80, 83))	('c.1100delC', 'Mutation', 'rs555607708', (169, 179))	('CHEK2', 'Gene', '11200', (162, 167))	('CHEK2', 'Gene', (48, 53))	('P', 'Chemical', 'MESH:D010758', (44, 45))	('p.Thr367Met', 'SUBSTITUTION', 'None', (181, 192))	('c.1229delC', 'Mutation', 'rs555607708', (271, 281))	('CHEK2', 'Gene', (162, 167))	('ATM', 'Gene', '472', (80, 83))	('c.1229delC [p.Thr410fs]', 'Var', (271, 294))	('p.Thr410fs', 'Mutation', 'rs555607708', (283, 293))
62217	29909963	Individuals with variants in BRCA2 (MIM: 600185; n = 6), PALB2 (MIM: 610355; n = 6), FH (MIM: 136850; n = 5), NF1 (MIM: 613113; n = 4), NTHL1 (MIM: 602656; homozygous, n = 3), MAX (MIM: 154950; n = 2), PTEN (MIM: 601728; n = 2), SDHB (MIM: 185470; n = 2), BMPR1A (MIM: 601299; n = 1), BRCA1 (MIM: 113705; n = 1), CDKN1B (MIM: 600778; n = 1), EXT2 (MIM: 608210; n = 1), MLH1 (MIM: 120436; n = 1), MSH2 (MIM: 609309; n = 1), and PMS2 (MIM: 600259; n = 1) were also noted.	('SDHB', 'Gene', '6390', (229, 233))	('NF1', 'Gene', '4763', (110, 113))	('EXT2', 'Gene', (342, 346))	('NTHL1', 'Gene', (136, 141))	('PALB2', 'Gene', '79728', (57, 62))	('EXT2', 'Gene', '2132', (342, 346))	('MSH2', 'Gene', (396, 400))	('PTEN', 'Gene', (202, 206))	('PMS2', 'Gene', (427, 431))	('NF1', 'Gene', (110, 113))	('variants', 'Var', (17, 25))	('NTHL1', 'Gene', '4913', (136, 141))	('SDHB', 'Gene', (229, 233))	('CDKN1B', 'Gene', (313, 319))	('MSH2', 'Gene', '4436', (396, 400))	('PTEN', 'Gene', '5728', (202, 206))	('MLH1', 'Gene', (369, 373))	('BMPR1A', 'Gene', '657', (256, 262))	('BRCA2', 'Gene', (29, 34))	('MLH1', 'Gene', '4292', (369, 373))	('PMS2', 'Gene', '5395', (427, 431))	('CDKN1B', 'Gene', '1027', (313, 319))	('BRCA1', 'Gene', '672', (285, 290))	('PALB2', 'Gene', (57, 62))	('BRCA1', 'Gene', (285, 290))	('BMPR1A', 'Gene', (256, 262))	('BRCA2', 'Gene', '675', (29, 34))
62219	29909963	Pre-testing information was available for 57/63 P/LP variants, 41/57 (71.9%) of which occurred in an individual who had at least one previous genetic test and 7/57 (12.3%) of which were eventually detected by clinical services.	('P', 'Chemical', 'MESH:D010758', (0, 1))	('occurred', 'Reg', (86, 94))	('P/LP', 'Gene', (48, 52))	('P', 'Chemical', 'MESH:D010758', (48, 49))	('P', 'Chemical', 'MESH:D010758', (51, 52))	('variants', 'Var', (53, 61))	('LP', 'Chemical', 'MESH:D008070', (50, 52))
62222	29909963	Of the 61 probands identified with a P/LP variant, 36 (59%; 8.2% of all probands) had previously been diagnosed with a tumor typically associated with the relevant CPG.	('P', 'Chemical', 'MESH:D010758', (165, 166))	('tumor', 'Disease', (119, 124))	('P', 'Chemical', 'MESH:D010758', (40, 41))	('P/LP', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('LP', 'Chemical', 'MESH:D008070', (39, 41))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('P', 'Chemical', 'MESH:D010758', (37, 38))
62224	29909963	Two probands harbored two P/LP variants in multiple CPGs.	('P', 'Chemical', 'MESH:D010758', (26, 27))	('variants', 'Var', (31, 39))	('LP', 'Chemical', 'MESH:D008070', (28, 30))	('P', 'Chemical', 'MESH:D010758', (29, 30))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('P/LP variants', 'Var', (26, 39))
62225	29909963	One individual with colorectal adenocarcinoma at age 50 years and breast cancer at 57 years carried a PMS2 frameshift variant (c.741-742insTGAAG [p.Pro247_Ser248fs] [Ensembl: ENST00000265849; GenBank: NM_000535.6]) and a BMPR1A nonsense variant (c.730C>T [p.Arg244*] [Ensembl: ENST00000372037; GenBank: NM_004329.2]).	('PMS2', 'Gene', (102, 106))	('BMPR1A', 'Gene', '657', (221, 227))	('colorectal adenocarcinoma', 'Disease', (20, 45))	('PMS2', 'Gene', '5395', (102, 106))	('c.741-742insTGAAG', 'Var', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (20, 45))	('BMPR1A', 'Gene', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('c.741-742insTGAAG', 'Mutation', 'c.741_742insTGAAG', (127, 144))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('c.730C>T', 'Mutation', 'rs766462610', (246, 254))	('p.Arg244*', 'Mutation', 'rs766462610', (256, 265))	('p.Pro247_Ser248fs', 'Mutation', 'p.P,S247,248fsX', (146, 163))	('c.730C>T [p.Arg244*] [', 'Var', (246, 268))
62226	29909963	Immunohistochemistry of the bowel tumor showed loss of PMS2; MSI was also demonstrated, leading to diagnostic sequencing of PMS2, although there was no family history of neoplasia other than an ovarian cancer in a second-degree relative after age 70 years.	('neoplasia', 'Disease', (170, 179))	('MSI', 'Disease', 'None', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('ovarian cancer', 'Disease', (194, 208))	('sequencing', 'Var', (110, 120))	('PMS2', 'Gene', (55, 59))	('MSI', 'Disease', (61, 64))	('neoplasia', 'Phenotype', 'HP:0002664', (170, 179))	('PMS2', 'Gene', (124, 128))	('bowel tumor', 'Disease', (28, 39))	('bowel tumor', 'Disease', 'MESH:D015212', (28, 39))	('loss', 'NegReg', (47, 51))	('neoplasia', 'Disease', 'MESH:D009369', (170, 179))	('PMS2', 'Gene', '5395', (124, 128))	('PMS2', 'Gene', '5395', (55, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (194, 208))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('ovarian cancer', 'Disease', 'MESH:D010051', (194, 208))
62228	29909963	Additionally, an individual with bilateral pheochromocytoma at ages 16 and 35 years and no reported family history of neoplasia was identified with variants in FH (c.521C>G [p.Pro174Arg] [Ensembl: ENST00000366560; GenBank: NM_000143.3]) and MAX (c.1A>G [p.Met1Val] [Ensembl: ENST00000358664; GenBank: NM_002382.4]).	('c.1A>G [', 'Var', (246, 254))	('neoplasia', 'Disease', (118, 127))	('c.521C>G [p.Pro174Arg] [', 'Var', (164, 188))	('c.1A>G', 'Mutation', 'rs587778967', (246, 252))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (43, 59))	('variants', 'Var', (148, 156))	('neoplasia', 'Disease', 'MESH:D009369', (118, 127))	('neoplasia', 'Phenotype', 'HP:0002664', (118, 127))	('p.Pro174Arg', 'Mutation', 'rs587778720', (174, 185))	('bilateral pheochromocytoma', 'Disease', 'MESH:D010673', (33, 59))	('c.521C>G', 'Mutation', 'rs552816150', (164, 172))	('p.Met1Val', 'Mutation', 'rs587778967', (254, 263))	('bilateral pheochromocytoma', 'Disease', (33, 59))
62229	29909963	The latter variant is predicted to abolish the MAX initiation codon, and previous analysis of tumor tissue from an individual carrying it demonstrated loss of the wild-type allele and a lack of full-length MAX protein product.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('MAX initiation codon', 'MPA', (47, 67))	('abolish', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('lack', 'NegReg', (186, 190))	('loss', 'NegReg', (151, 155))	('variant', 'Var', (11, 18))
62234	29909963	Five undetected variants:including one P/LP PMS2 variant (c.741-742insTGAAG [p.Pro247_Ser248fs] [Ensembl: ENST00000265849; GenBank: NM_000535.6]), where 58/202 (20.6%) reads contained the insertion:were indels for which IGV review showed a VAF below the threshold for filtering.	('P', 'Chemical', 'MESH:D010758', (39, 40))	('PMS2', 'Gene', '5395', (44, 48))	('P', 'Chemical', 'MESH:D010758', (44, 45))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('LP', 'Chemical', 'MESH:D008070', (41, 43))	('p.Pro247_Ser248fs', 'Mutation', 'p.P,S247,248fsX', (77, 94))	('P', 'Chemical', 'MESH:D010758', (42, 43))	('c.741-742insTGAAG', 'Var', (58, 75))	('c.741-742insTGAAG', 'Mutation', 'c.741_742insTGAAG', (58, 75))	('PMS2', 'Gene', (44, 48))
62235	29909963	One undetected variant in TMEM127 (MIM: 613403) (c.665C>T [p.Ala222Val] [Ensembl: ENST00000258439; GenBank: NM_017849.3]) was covered by only two reads.	('TMEM127', 'Gene', (26, 33))	('c.665C>T', 'Mutation', 'rs373951977', (49, 57))	('p.Ala222Val', 'Mutation', 'rs373951977', (59, 70))	('TMEM127', 'Gene', '55654', (26, 33))	('c.665C>T [', 'Var', (49, 59))
62238	29909963	This was because the VAF was marginally below the filtering threshold of 33% for ATM (c.2426C>A [p.Ser809*] [Ensembl: ENST00000278616; GenBank: NM_000051]) (7/22 [32%] reads) and MAX (c.97C>T [p.Arg33*] [Ensembl: ENST00000358664; GenBank: NM_002382]) (9/29 [31%] reads).	('c.2426C>A [p.Ser809*] [', 'Var', (86, 109))	('c.2426C>A', 'Mutation', 'rs730881348', (86, 95))	('p.Ser809*', 'Mutation', 'rs730881348', (97, 106))	('c.97C', 'Var', (184, 189))	('ATM', 'Gene', (81, 84))	('p.Arg33*', 'Var', (193, 201))	('p.Arg33*', 'SUBSTITUTION', 'None', (193, 201))	('ATM', 'Gene', '472', (81, 84))	('c.97C>T', 'Mutation', 'rs1057522542', (184, 191))
62239	29909963	In our dataset, 52 truncating or splice-site variants were observed in 440 MPT probands, whereas 298 were observed in 8,992 gnomAD genomes; the latter is based on observed variant frequency estimates adjusted to reflect sex distribution of the MPT series (13.6% for the MPT dataset versus 3.3% for the gnomAD dataset; chi2 = 84.903, p = < 0.0001).	('variants', 'Var', (45, 53))	('truncating', 'MPA', (19, 29))	('P', 'Chemical', 'MESH:D010758', (271, 272))	('P', 'Chemical', 'MESH:D010758', (76, 77))	('P', 'Chemical', 'MESH:D010758', (245, 246))
62240	29909963	41 truncating or splice-site CPG variants occurred in a proband with at least one tumor type uncharacteristic of the relevant CPG, and the frequency of such variants in these individuals was also compared with that in gnomAD.	('occurred', 'Reg', (42, 50))	('P', 'Chemical', 'MESH:D010758', (30, 31))	('CPG', 'Gene', (29, 32))	('P', 'Chemical', 'MESH:D010758', (127, 128))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('variants', 'Var', (33, 41))
62242	29909963	SV analysis revealed six potentially pathogenic variants in 440 (1.4%) probands (Table 4), two of whom had previously been diagnosed with tumors typically associated with variants in the relevant gene.	('pathogenic', 'Reg', (37, 47))	('associated', 'Reg', (155, 165))	('variants', 'Var', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('variants', 'Var', (171, 179))
62243	29909963	An additional two had no associated tumor but a family history of such tumors in a first-degree relative (colorectal cancer at age 56 years for the individual with a SMAD4 translocation and renal cell carcinoma at age 69 for the individual with the TSC1 duplication).	('colorectal cancer', 'Disease', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('tumor', 'Disease', (36, 41))	('translocation', 'Var', (172, 185))	('TSC1', 'Gene', (249, 253))	('SMAD4', 'Gene', '4089', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (190, 210))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('TSC1', 'Gene', '7248', (249, 253))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('renal cell carcinoma', 'Disease', (190, 210))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (190, 210))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('SMAD4', 'Gene', (166, 171))
62244	29909963	One individual with an inversion of PTEN exon 7 had been diagnosed with breast cancer at age 45 years and had a strong family history of this tumor, which had occurred in her sister (age 57 years), mother (age 57 years), and maternal cousin (age 49 years).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', (142, 147))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('inversion', 'Var', (23, 32))
62247	29909963	After combining SVs passing our filters and ACMG-assessed P/LP SNVs and indels, we observed a P/LP variant in 67 (15.2%) probands tested.	('LP', 'Chemical', 'MESH:D008070', (60, 62))	('LP', 'Chemical', 'MESH:D008070', (96, 98))	('P/LP variant', 'Var', (94, 106))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('variant', 'Var', (99, 106))	('P', 'Chemical', 'MESH:D010758', (97, 98))	('P', 'Chemical', 'MESH:D010758', (94, 95))	('P', 'Chemical', 'MESH:D010758', (61, 62))
62248	29909963	38 probands (8.6% of total) had such a variant and a typically associated tumor.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('variant', 'Var', (39, 46))
62251	29909963	Of the 69 P/LP variants (including SVs) of interest detected in probands, the relevant locus was sequenced in a family member on seven occasions.	('P/LP variants', 'Var', (10, 23))	('P', 'Chemical', 'MESH:D010758', (10, 11))	('P', 'Chemical', 'MESH:D010758', (13, 14))	('variants', 'Var', (15, 23))	('LP', 'Chemical', 'MESH:D008070', (12, 14))
62252	29909963	The relevant variant was detected in four of seven family members, two of whom had been diagnosed with a typically associated tumor (breast cancer in PALB2 and BRCA1 variants).	('BRCA1', 'Gene', (160, 165))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('PALB2', 'Gene', '79728', (150, 155))	('PALB2', 'Gene', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('variants', 'Var', (166, 174))	('BRCA1', 'Gene', '672', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('tumor', 'Disease', (126, 131))
62255	29909963	Thus, we analyzed 460 MPT-affected individuals who had previously undergone routine genetic assessment and/or molecular testing (but without a molecular diagnosis) by using WGS for variants in 83 CPGs and identified a P/LP variant in 67/440 (15.2%) probands (incorporating SNVs, indels, and SVs), including those affected by moderate- and high-risk CPGs.	('P', 'Chemical', 'MESH:D010758', (23, 24))	('P', 'Chemical', 'MESH:D010758', (350, 351))	('variants', 'Var', (181, 189))	('LP', 'Chemical', 'MESH:D008070', (220, 222))	('P/LP variant', 'Var', (218, 230))	('P', 'Chemical', 'MESH:D010758', (221, 222))	('P', 'Chemical', 'MESH:D010758', (218, 219))	('variant', 'Var', (223, 230))	('P', 'Chemical', 'MESH:D010758', (197, 198))
62256	29909963	Because the MPT cohort reported here was mostly ascertained from UK genetics centers (and was similar to the previous retrospective cohort that did not have a known genetic cause), we estimate (by assuming that WGS would detect variants identified by routine targeted sequencing approaches) that comprehensive genetic analysis in a genetics-center-referred series of individuals with MPTs (and no prior genetic testing) would detect a P/LP variant in around a third of individuals (20.7% + 12.1% [estimated under the assumption of a diagnostic yield of 15.2% in the 79.3% of individuals without a variant in routine testing] = 32.8%).	('P', 'Chemical', 'MESH:D010758', (435, 436))	('detect', 'Reg', (426, 432))	('P', 'Chemical', 'MESH:D010758', (13, 14))	('P/LP variant', 'Var', (435, 447))	('P', 'Chemical', 'MESH:D010758', (385, 386))	('LP', 'Chemical', 'MESH:D008070', (437, 439))	('P', 'Chemical', 'MESH:D010758', (438, 439))	('variant', 'Var', (440, 447))
62257	29909963	The estimated proportion of individuals with a P/LP variant and a typical tumor would be ~27.5% (20.7% [all of those with variants detected by targeted analysis had a typical tumor] + [79.3% x 8.6% = 6.8%]).	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('LP', 'Chemical', 'MESH:D008070', (49, 51))	('P/LP variant', 'Var', (47, 59))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('P', 'Chemical', 'MESH:D010758', (47, 48))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('P', 'Chemical', 'MESH:D010758', (50, 51))
62259	29909963	The estimates for diagnostic yield are approximate and would be influenced by ascertainment processes but do suggest that a comprehensive testing for CPG variants significantly increases the detection of P/LP variants over the targeted testing that has been routinely employed in most genetics centers.	('variants', 'Var', (209, 217))	('variants', 'Var', (154, 162))	('P', 'Chemical', 'MESH:D010758', (204, 205))	('P', 'Chemical', 'MESH:D010758', (207, 208))	('LP', 'Chemical', 'MESH:D008070', (206, 208))	('CPG', 'Gene', (150, 153))	('P', 'Chemical', 'MESH:D010758', (151, 152))	('increases', 'PosReg', (177, 186))	('P/LP', 'Gene', (204, 208))	('detection', 'MPA', (191, 200))
62260	29909963	Most MPT-affected individuals (38/67 [56.7%] and 38/440 [8.6%] of all pre-assessed probands tested in the current study) with a P/LP variant had been diagnosed with a tumor type characteristically associated with variants in the relevant CPG, findings that have the greatest clinical utility.	('MPT-affected', 'Disease', (5, 17))	('P/LP variant', 'Var', (128, 140))	('variants', 'Var', (213, 221))	('P', 'Chemical', 'MESH:D010758', (239, 240))	('P', 'Chemical', 'MESH:D010758', (6, 7))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('P', 'Chemical', 'MESH:D010758', (131, 132))	('variant', 'Var', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('P', 'Chemical', 'MESH:D010758', (128, 129))	('LP', 'Chemical', 'MESH:D008070', (130, 132))	('tumor', 'Disease', (167, 172))
62267	29909963	Some combination types making up >1% of MPT combinations, e.g., breast-thyroid (3.6% in MPT data), are not observed frequently (<1%) in the population-based cohort used here, which could be accounted for by referral prompted by suspicion of germline PTEN variants.	('P', 'Chemical', 'MESH:D010758', (89, 90))	('variants', 'Var', (255, 263))	('breast-thyroid', 'Disease', 'MESH:D013959', (64, 78))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('PTEN', 'Gene', (250, 254))	('breast-thyroid', 'Disease', (64, 78))	('PTEN', 'Gene', '5728', (250, 254))	('P', 'Chemical', 'MESH:D010758', (250, 251))
62268	29909963	Breast cancer accounted for almost a quarter of tumors in our series, and most genes in which deleterious variants were detected are breast CPGs, many of which are not routinely tested in the UK.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('variants', 'Var', (106, 114))	('breast CPGs', 'Disease', (133, 144))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('P', 'Chemical', 'MESH:D010758', (141, 142))	('Breast cancer', 'Disease', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
62269	29909963	Pathogenic variants in ATM and CHEK2 are associated with moderate risks, and these genes had not been tested by the referring center in any of the individuals with P/LP variants.	('ATM', 'Gene', (23, 26))	('CHEK2', 'Gene', '11200', (31, 36))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('variants', 'Var', (11, 19))	('P', 'Chemical', 'MESH:D010758', (164, 165))	('CHEK2', 'Gene', (31, 36))	('ATM', 'Gene', '472', (23, 26))	('LP', 'Chemical', 'MESH:D008070', (166, 168))	('P', 'Chemical', 'MESH:D010758', (167, 168))
62270	29909963	Six probands had pathogenic variants in PALB2, a gene initially thought to confer moderate risk but subsequently reported to have a penetrance somewhere between that of moderate- and high-risk genes such as BRCA1 and BRCA2.	('BRCA2', 'Gene', '675', (217, 222))	('PALB2', 'Gene', '79728', (40, 45))	('variants', 'Var', (28, 36))	('PALB2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (207, 212))	('pathogenic', 'Reg', (17, 27))	('BRCA2', 'Gene', (217, 222))	('BRCA1', 'Gene', (207, 212))
62271	29909963	A number of CPGs in which variants were identified, such as MAX and FH, have been relatively recently described as causing pheochromocytoma and paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (144, 157))	('P', 'Chemical', 'MESH:D010758', (13, 14))	('paraganglioma', 'Disease', (144, 157))	('causing', 'Reg', (115, 122))	('pheochromocytoma', 'Disease', (123, 139))	('pheochromocytoma', 'Disease', 'MESH:D010673', (123, 139))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (123, 139))	('paraganglioma', 'Disease', 'MESH:D010235', (144, 157))	('variants', 'Var', (26, 34))
62275	29909963	Consistent with this are mutation detection rates of ~4% in individuals with earlier-onset (<=30 years) breast cancer and ~17% in MPT-affected individuals who were referred for germline TP53 testing and who generally fulfilled criteria for that investigation, had tumors characteristic of Li Fraumeni syndrome, and had an average age at diagnosis (of a first primary tumor) before 30 years.	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('tumors', 'Disease', (264, 270))	('P', 'Chemical', 'MESH:D010758', (131, 132))	('P', 'Chemical', 'MESH:D010758', (187, 188))	('Li Fraumeni syndrome', 'Disease', 'MESH:D016864', (289, 309))	('Li Fraumeni syndrome', 'Disease', (289, 309))	('tumor', 'Disease', (264, 269))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('TP53', 'Gene', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', (367, 372))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('TP53', 'Gene', '7157', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))
62277	29909963	The application of a 76-gene panel to ~1,000 cancer-affected adults referred for germline genetic testing and ACMG-guideline-based assessment of the resulting variants showed a 17.5% rate, whereas tumor-normal sequencing of a similarly sized series with advanced cancer from the same center (regardless of genetic testing referral) reported an equivalent figure of 12.6%.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', (263, 269))	('variants', 'Var', (159, 167))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Disease', (45, 51))	('tumor', 'Disease', (197, 202))
62278	29909963	The genes containing the most frequent pathogenic variants in both studies were similar to those in the current study (BRCA1, BRCA2, CHEK2, and ATM), but the detection rates were lower than our estimate of around a third of newly referred MPT-affected individuals, most likely reflecting a greater likelihood of a germline pathogenic variant in both genetics referrals and in MPT-affected individuals.	('ATM', 'Gene', '472', (144, 147))	('lower', 'NegReg', (179, 184))	('MPT-affected', 'Disease', (239, 251))	('P', 'Chemical', 'MESH:D010758', (240, 241))	('BRCA1', 'Gene', (119, 124))	('P', 'Chemical', 'MESH:D010758', (377, 378))	('BRCA2', 'Gene', (126, 131))	('CHEK2', 'Gene', '11200', (133, 138))	('ATM', 'Gene', (144, 147))	('variants', 'Var', (50, 58))	('CHEK2', 'Gene', (133, 138))	('BRCA2', 'Gene', '675', (126, 131))	('BRCA1', 'Gene', '672', (119, 124))
62281	29909963	Strikingly, this resulted in the identification of a large number of probands (29/67 [43.2%]) who harbored a P/LP CPG variant but whose tumor phenotypes were not entirely typical for the relevant CPG.	('P', 'Chemical', 'MESH:D010758', (109, 110))	('CPG', 'Gene', (114, 117))	('P', 'Chemical', 'MESH:D010758', (112, 113))	('P/LP', 'Var', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('P', 'Chemical', 'MESH:D010758', (115, 116))	('LP', 'Chemical', 'MESH:D008070', (111, 113))	('tumor', 'Disease', (136, 141))	('P', 'Chemical', 'MESH:D010758', (197, 198))
62282	29909963	This situation has been frequently reported by other studies of extensive NGS testing of cancer cohorts and represents a challenge for clinicians because the relevance of the variant to cancer risk in the consultand (including unaffected family members) is less clear.	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('variant', 'Var', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
62283	29909963	Specific atypical associations observed in this analysis were heterogeneous, and numbers were small, but some patterns were noted; for example, 5/16 (31.2%) carriers of CHEK2 variants had been previously diagnosed with renal cell carcinoma (RCC) (breast cancer occurred in 8/16 [50%]).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('variants', 'Var', (175, 183))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 239))	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('breast cancer', 'Disease', (247, 260))	('CHEK2', 'Gene', '11200', (169, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('RCC', 'Disease', 'MESH:C538614', (241, 244))	('renal cell carcinoma', 'Disease', (219, 239))	('CHEK2', 'Gene', (169, 174))	('RCC', 'Disease', (241, 244))	('RCC', 'Phenotype', 'HP:0005584', (241, 244))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (219, 239))
62284	29909963	An odds ratio of 2.1 for RCC has previously been observed in CHEK2-variant carriers but only in association with the c.470T>C (p.Ile157Thr) founder variant in a Polish population.	('CHEK2-variant', 'CellLine', 'CVCL:7204', (61, 74))	('P', 'Chemical', 'MESH:D010758', (161, 162))	('CHEK2-variant', 'Var', (61, 74))	('p.Ile157Thr', 'Mutation', 'rs17879961', (127, 138))	('c.470T>C', 'Mutation', 'rs17879961', (117, 125))	('RCC', 'Phenotype', 'HP:0005584', (25, 28))	('RCC', 'Disease', 'MESH:C538614', (25, 28))	('CHEK2-variant', 'Gene', (61, 74))	('RCC', 'Disease', (25, 28))	('c.470T>C', 'Var', (117, 125))
62285	29909963	2/6 (33.3%) carriers of PALB2 variants had cutaneous melanoma before the age of 40 years, and 2/10 (20%) individuals with ATM variants had thyroid cancer before that age, but an analysis of 182 melanoma families demonstrated only one pathogenic PALB2 variant, and thyroid malignancies have not been reported at increased frequency in carriers of homozygous or heterozygous ATM variants.	('variants', 'Var', (30, 38))	('PALB2', 'Gene', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('thyroid cancer', 'Disease', (139, 153))	('ATM', 'Gene', (122, 125))	('PALB2', 'Gene', '79728', (24, 29))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('PALB2', 'Gene', '79728', (245, 250))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('ATM', 'Gene', (373, 376))	('thyroid cancer', 'Disease', 'MESH:D013964', (139, 153))	('thyroid malignancies', 'Disease', (264, 284))	('thyroid malignancies', 'Disease', 'MESH:D013959', (264, 284))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('thyroid cancer', 'Phenotype', 'HP:0002890', (139, 153))	('melanoma', 'Disease', (53, 61))	('cutaneous melanoma', 'Disease', (43, 61))	('variant', 'Var', (251, 258))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (43, 61))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (43, 61))	('ATM', 'Gene', '472', (122, 125))	('thyroid malignancies', 'Phenotype', 'HP:0100031', (264, 284))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('PALB2', 'Gene', (24, 29))	('ATM', 'Gene', '472', (373, 376))
62287	29909963	For example, although FH variants were demonstrated to predispose to RCC in 2002, they were shown to predispose to pheochromocytoma and paraganglioma 12 years later.	('RCC', 'Disease', 'MESH:C538614', (69, 72))	('RCC', 'Disease', (69, 72))	('variants', 'Var', (25, 33))	('paraganglioma', 'Phenotype', 'HP:0002668', (136, 149))	('predispose', 'Reg', (55, 65))	('pheochromocytoma', 'Disease', 'MESH:D010673', (115, 131))	('paraganglioma', 'Disease', (136, 149))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (115, 131))	('predispose', 'Reg', (101, 111))	('paraganglioma', 'Disease', 'MESH:D010235', (136, 149))	('RCC', 'Phenotype', 'HP:0005584', (69, 72))	('pheochromocytoma', 'Disease', (115, 131))
62289	29909963	Our observation of a significantly higher rate of loss-of-function variants associated with non-characteristic tumors in our cohort than in the gnomAD dataset suggests that at least some variants identified in individuals with atypical phenotypes are relevant.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('loss-of-function', 'NegReg', (50, 66))	('variants', 'Var', (67, 75))
62290	29909963	We would, however, urge caution in automatically linking a pathogenic CPG variant to the observed tumor phenotype without further evidence, such as larger studies of variant carriers or tumor studies that demonstrate a variant's causative effect.	('pathogenic', 'Reg', (59, 69))	('CPG', 'Gene', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('P', 'Chemical', 'MESH:D010758', (71, 72))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('variant', 'Var', (74, 81))	('tumor', 'Disease', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
62291	29909963	Another possibility is that tumors can occur coincidentally in the presence of a pathogenic constitutional CPG variant.	('variant', 'Var', (111, 118))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('P', 'Chemical', 'MESH:D010758', (108, 109))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
62292	29909963	For example, an in-frame FH insertion (c.1433-1434insAAA [p.Lys477_Asn478insLys] [Ensembl: ENST00000366560; GenBank: NM_000143.3]) was identified in three individuals, none of whom had been diagnosed with typical hereditary leiomyoma or RCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('hereditary leiomyoma or RCC tumors', 'Disease', 'MESH:C538614', (213, 247))	('c.1433-1434insAAA', 'Var', (39, 56))	('hereditary leiomyoma or RCC tumors', 'Disease', (213, 247))	('RCC', 'Phenotype', 'HP:0005584', (237, 240))	('p.Lys477_Asn478insLys', 'Mutation', 'p.K477_,478N,K', (58, 79))	('c.1433-1434insAAA', 'Mutation', 'c.1433_1434insAAA', (39, 56))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
62293	29909963	This variant causes recessively inherited fumarate hydratase deficiency (MIM: 606812) and has been demonstrated to disrupt enzyme activity.	('causes', 'Reg', (13, 19))	('inherited fumarate hydratase deficiency', 'Disease', (32, 71))	('variant', 'Var', (5, 12))	('disrupt', 'NegReg', (115, 122))	('enzyme activity', 'MPA', (123, 138))	('fumarate hydratase deficiency', 'Phenotype', 'HP:0003536', (42, 71))	('inherited fumarate hydratase deficiency', 'Disease', 'MESH:C538191', (32, 71))
62295	29909963	Unusual MPT-CPG associations can occur when an individual harbors variants in multiple CPGs, either because (at least) one of the variants remains unidentified through diagnostic testing or because an interactive effect exists between them.	('interactive', 'Interaction', (201, 212))	('P', 'Chemical', 'MESH:D010758', (13, 14))	('associations', 'Interaction', (16, 28))	('variants', 'Var', (66, 74))	('P', 'Chemical', 'MESH:D010758', (9, 10))	('MPT-CPG', 'Gene', (8, 15))	('P', 'Chemical', 'MESH:D010758', (88, 89))
62297	29909963	In the case of PMS2 and BMPR1A variants, the former appears to be penetrant on the basis of tumor studies, whereas the significance of the latter is unclear.	('variants', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BMPR1A', 'Gene', '657', (24, 30))	('tumor', 'Disease', (92, 97))	('PMS2', 'Gene', (15, 19))	('PMS2', 'Gene', '5395', (15, 19))	('BMPR1A', 'Gene', (24, 30))
62298	29909963	For the individual with FH and MAX variants, it is easier to attribute the diagnosed pheochromocytomas to the truncating MAX variant, but evidence for the role of FH in this tumor type is accumulating, and this variant could have contributed to tumorigenesis.	('tumor', 'Disease', (174, 179))	('pheochromocytomas', 'Disease', 'MESH:D010673', (85, 102))	('contributed', 'Reg', (230, 241))	('pheochromocytomas', 'Disease', (85, 102))	('variants', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (85, 102))	('tumor', 'Disease', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
62299	29909963	Although WGS could arguably offer the most sensitive and comprehensive strategy for detecting germline CPG variants, it is resource intensive in terms of sequencing, data storage, and analytical capacity.	('CPG', 'Gene', (103, 106))	('variants', 'Var', (107, 115))	('P', 'Chemical', 'MESH:D010758', (104, 105))
62305	29909963	This illustrates the broader scope of WGS, but our results do not suggest that WGS offers enhanced CPG SNV or indel detection at present.	('indel', 'Var', (110, 115))	('P', 'Chemical', 'MESH:D010758', (100, 101))	('CPG', 'Var', (99, 102))
62306	29909963	WGS identified six SVs predicted to affect a gene of interest, and two of these occurred in an individual whose personal or family history included tumors consistent with variants in that gene.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('affect', 'Reg', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumors', 'Disease', (148, 154))	('variants', 'Var', (171, 179))
62307	29909963	The medical record showed no evidence that the individual with the PTEN inversion exhibited other features of constitutional variants in this gene, such as macrocephaly, as well as no record of an examination in a consultation where only BRCA1 and BRCA2 testing was anticipated.	('macrocephaly', 'Disease', (156, 168))	('BRCA2', 'Gene', '675', (248, 253))	('macrocephaly', 'Phenotype', 'HP:0000256', (156, 168))	('BRCA1', 'Gene', '672', (238, 243))	('PTEN', 'Gene', (67, 71))	('inversion', 'Var', (72, 81))	('PTEN', 'Gene', '5728', (67, 71))	('BRCA1', 'Gene', (238, 243))	('BRCA2', 'Gene', (248, 253))	('macrocephaly', 'Disease', 'MESH:D058627', (156, 168))
62310	29909963	Furthermore, WGS can detect inversions and translocations that are not characterized by MLPA.	('LP', 'Chemical', 'MESH:D008070', (89, 91))	('inversions', 'Var', (28, 38))	('translocations', 'Var', (43, 57))
62311	29909963	A note of caution, however, arises from a deletion involving BRCA2 exons 14-16; we were made aware of this deletion by the referring clinician, but it was not detected through our analyses.	('deletion', 'Var', (42, 50))	('BRCA2', 'Gene', '675', (61, 66))	('BRCA2', 'Gene', (61, 66))
62312	29909963	This includes novel CPGs (many of the P/LP variants in this analysis were detected because the gene or region was not available for testing at the time of consultation).	('P', 'Chemical', 'MESH:D010758', (38, 39))	('CPGs', 'Disease', (20, 24))	('P', 'Chemical', 'MESH:D010758', (21, 22))	('P', 'Chemical', 'MESH:D010758', (41, 42))	('variants', 'Var', (43, 51))	('LP', 'Chemical', 'MESH:D008070', (40, 42))
62313	29909963	However, evidence of regulatory elements that influence the expression of any given gene is accumulating, and high-throughput functional assays for studying them provide the opportunity to define diagnostically significant variants affecting CPGs.	('P', 'Chemical', 'MESH:D010758', (243, 244))	('variants', 'Var', (223, 231))	('CPGs', 'Disease', (242, 246))
62314	29909963	In summary, we have demonstrated that the application of comprehensive CPG testing to a cohort of previously investigated MPT-affected individuals resulted in the detection of multiple pathogenic variants with relevance to the management of those individuals and their relatives.	('MPT-affected', 'Gene', (122, 134))	('P', 'Chemical', 'MESH:D010758', (123, 124))	('P', 'Chemical', 'MESH:D010758', (72, 73))	('pathogenic', 'Reg', (185, 195))	('variants', 'Var', (196, 204))
62315	29909963	The finding that comprehensive genetic analysis of MPT-affected individuals can frequently result in the identification of pathogenic CPG variants that cannot automatically be attributed as causative for the observed MPT clinical phenotype has important implications both for clinical practice and for future research into the phenotypic consequences of germline CPG variants.	('P', 'Chemical', 'MESH:D010758', (364, 365))	('result in', 'Reg', (91, 100))	('variants', 'Var', (138, 146))	('P', 'Chemical', 'MESH:D010758', (52, 53))	('pathogenic', 'Reg', (123, 133))	('CPG', 'Gene', (134, 137))	('P', 'Chemical', 'MESH:D010758', (135, 136))	('P', 'Chemical', 'MESH:D010758', (218, 219))
62316	29909963	Summing together variant detection rates from a previous series of MPT-affected individuals ascertained in a similar manner and the present results suggests that first-line application of WGS (or other strategies for comprehensive CPG variant detection) to a clinical-genetics-referral-based cohort of MPT-affected individuals would detect a deleterious mutation in about a third of individuals, a large proportion of whom would not have a family history of cancer in a first-degree relative.	('cancer', 'Disease', 'MESH:D009369', (458, 464))	('cancer', 'Disease', (458, 464))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('MPT-affected', 'Gene', (302, 314))	('detect', 'Reg', (333, 339))	('deleterious', 'Reg', (342, 353))	('cancer', 'Phenotype', 'HP:0002664', (458, 464))	('P', 'Chemical', 'MESH:D010758', (303, 304))	('mutation', 'Var', (354, 362))	('P', 'Chemical', 'MESH:D010758', (232, 233))
62382	26855794	123I- MIBG causes low radiation dose, superior image quality, and high sensitivity in comparison to 131I-MIBG.	('131I-MIBG', 'Chemical', 'MESH:D019797', (100, 109))	('123I- MIBG', 'Chemical', 'MESH:D019797', (0, 10))	('123I- MIBG', 'Var', (0, 10))	('image', 'MPA', (47, 52))	('sensitivity', 'MPA', (71, 82))
62462	26215714	The lymph node was negative for malignant neoplasm; the diagnosis was small leiomyoma (+ s100-actin).	('small leiomyoma', 'Disease', (70, 85))	('+ s100-actin', 'Var', (87, 99))	('neoplasm', 'Phenotype', 'HP:0002664', (42, 50))	('small leiomyoma', 'Disease', 'MESH:D007889', (70, 85))	('malignant neoplasm', 'Disease', (32, 50))	('malignant neoplasm', 'Disease', 'MESH:D009369', (32, 50))
62499	25520578	Mutations within genes PGL1, PGL3, PGL4 (responsible for coding of 3 subtypes of succinate dehydrogenase) predispose to paraganglioma occurrence.	('PGL3', 'Gene', '6391', (29, 33))	('PGL4', 'Gene', (35, 39))	('PGL4', 'Gene', '6390', (35, 39))	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('PGL3', 'Gene', (29, 33))	('predispose to', 'Reg', (106, 119))	('paraganglioma', 'Disease', (120, 133))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Disease', 'MESH:D010235', (120, 133))	('PGL1', 'Gene', (23, 27))
62530	25520578	Patients who underwent microscopically incomplete surgery had a higher rate of overall survival (100%), as compared to the patients in whom the surgery was grossly incomplete (84%), however this difference was not statistically significant.	('higher', 'PosReg', (64, 70))	('patients', 'Species', '9606', (123, 131))	('Patients', 'Species', '9606', (0, 8))	('microscopically', 'Var', (23, 38))	('overall survival', 'MPA', (79, 95))
62563	24688789	Twenty-five percent of pheochromocytoma and paraganglioma occur in the setting of familial syndromes (SDH gene mutations; MEN 2A/B; von Hipple-Lindau; Neurofibromatosis I; Carney triad).	('mutations', 'Var', (111, 120))	('paraganglioma', 'Phenotype', 'HP:0002668', (44, 57))	('SDH', 'Gene', (102, 105))	('occur', 'Reg', (58, 63))	('2A/B', 'SUBSTITUTION', 'None', (126, 130))	('paraganglioma', 'Disease', (44, 57))	('2A/B', 'Var', (126, 130))	('pheochromocytoma', 'Disease', (23, 39))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (151, 168))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (23, 39))	('familial syndromes', 'Disease', (82, 100))	('pheochromocytoma', 'Disease', 'MESH:D010673', (23, 39))	('von Hipple-Lindau; Neurofibromatosis I', 'Disease', 'MESH:D006623', (132, 170))	('paraganglioma', 'Disease', 'MESH:D010235', (44, 57))	('von Hipple-Lindau; Neurofibromatosis I', 'Disease', (132, 170))	('SDH', 'Gene', '6390', (102, 105))
62594	24688789	Typically in Tako-Tsubo disease, the decreased ejection fraction caused by myocardial alterations undergoes spontaneous recovery.	('Tako-Tsubo disease', 'Disease', (13, 31))	('Tako-Tsubo disease', 'Disease', 'MESH:D054549', (13, 31))	('ejection fraction', 'MPA', (47, 64))	('decreased ejection fraction', 'Phenotype', 'HP:0012664', (37, 64))	('decreased', 'NegReg', (37, 46))	('alterations', 'Var', (86, 97))
62601	24688789	Normalization of blood volume reduces the risk of prolonged hypotension after tumour removal.	('hypotension', 'Disease', 'MESH:D007022', (60, 71))	('tumour removal', 'Disease', (78, 92))	('Normalization', 'Var', (0, 13))	('reduces the risk of prolonged hypotension', 'Phenotype', 'HP:0001278', (30, 71))	('hypotension', 'Disease', (60, 71))	('blood volume reduces', 'Phenotype', 'HP:0011106', (17, 37))	('hypotension', 'Phenotype', 'HP:0002615', (60, 71))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('tumour removal', 'Disease', 'MESH:D009369', (78, 92))
62611	24688789	Phentolamine is alpha-adrenergic antagonist that can be given intravenously as continuous infusion or as boluses of 1 to 2 mg; it can cause tachycardia if the patient is not receiving beta-blockers.	('tachycardia', 'Disease', (140, 151))	('Phentolamine', 'Var', (0, 12))	('tachycardia', 'Disease', 'MESH:D013610', (140, 151))	('cause', 'Reg', (134, 139))	('Phentolamine', 'Chemical', 'MESH:D010646', (0, 12))	('patient', 'Species', '9606', (159, 166))	('tachycardia', 'Phenotype', 'HP:0001649', (140, 151))
62625	24688789	Alpha-adrenergic blockade (phenoxybenzamine or phentolamine) is usually started at the time of diagnosis and it is carried on preoperatively under close blood pressure monitoring, to prevent cardiovascular complications that may occur during surgery due to excess catecholamine secretion.	('phentolamine', 'Var', (47, 59))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (27, 43))	('catecholamine', 'Chemical', 'MESH:D002395', (264, 277))	('cardiovascular complications', 'Disease', 'MESH:D002318', (191, 219))	('cardiovascular complications', 'Disease', (191, 219))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (191, 219))	('excess catecholamine', 'Phenotype', 'HP:0003334', (257, 277))	('close blood pressure', 'Phenotype', 'HP:0002615', (147, 167))	('phenoxybenzamine', 'Var', (27, 43))	('phentolamine', 'Chemical', 'MESH:D010646', (47, 59))
62640	22403753	Bilateral adrenal pheochromocytoma with a germline L790F mutation in the RET oncogene About ten percent of pheochromocytomas are associated with familial syndrome.	('associated', 'Reg', (129, 139))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (107, 123))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (18, 34))	('familial syndrome', 'Disease', (145, 162))	('RET', 'Gene', '5979', (73, 76))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (10, 34))	('pheochromocytomas', 'Disease', 'MESH:D010673', (107, 124))	('L790F', 'Mutation', 'rs75030001', (51, 56))	('pheochromocytomas', 'Disease', (107, 124))	('familial syndrome', 'Disease', 'MESH:D009386', (145, 162))	('Bilateral adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (0, 34))	('Bilateral adrenal pheochromocytoma', 'Disease', (0, 34))	('L790F', 'Var', (51, 56))	('RET', 'Gene', (73, 76))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (107, 124))
62643	22403753	Genetic test detected a L790F germline mutation of RET oncogene.	('RET', 'Gene', '5979', (51, 54))	('L790F', 'Mutation', 'rs75030001', (24, 29))	('L790F', 'Var', (24, 29))	('RET', 'Gene', (51, 54))	('detected', 'Reg', (13, 21))
62647	22403753	However, it is now recognized that the frequency of germline mutations in apparently sporadic pheochromocytoma is as high as 24%.	('pheochromocytoma', 'Disease', (94, 110))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (94, 110))	('germline mutations', 'Var', (52, 70))	('pheochromocytoma', 'Disease', 'MESH:D010673', (94, 110))
62652	22403753	We report a case of a 44-year-old man with bilateral pheochromocytomas whose genetic study shows a rare germline L790F mutation of RET oncogene.	('L790F', 'Mutation', 'rs75030001', (113, 118))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (53, 70))	('man', 'Species', '9606', (34, 37))	('bilateral pheochromocytomas', 'Disease', (43, 70))	('L790F', 'Var', (113, 118))	('RET', 'Gene', '5979', (131, 134))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (43, 70))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('RET', 'Gene', (131, 134))
62662	22403753	We tested germline mutation of RET oncogene with patient's informed consent.	('RET', 'Gene', '5979', (31, 34))	('patient', 'Species', '9606', (49, 56))	('tested', 'Reg', (3, 9))	('RET', 'Gene', (31, 34))	('germline mutation', 'Var', (10, 27))
62666	22403753	After the result of germline mutation of RET oncogene, we diagnosed the patient as multiple endocrine neoplasia type 2A, and searched an evidence of medullary thyroid cancer in the patient and his family members.	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (83, 111))	('thyroid cancer', 'Disease', (159, 173))	('patient', 'Species', '9606', (181, 188))	('thyroid cancer', 'Phenotype', 'HP:0002890', (159, 173))	('RET', 'Gene', (41, 44))	('thyroid cancer', 'Disease', 'MESH:D013964', (159, 173))	('patient', 'Species', '9606', (72, 79))	('germline mutation', 'Var', (20, 37))	('multiple endocrine neoplasia', 'Disease', (83, 111))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (149, 173))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('neoplasia', 'Phenotype', 'HP:0002664', (102, 111))	('RET', 'Gene', '5979', (41, 44))
62671	22403753	According to the European Network for the Study of Adrenal Tumors Pheochromocytoma Working Group, germline mutation rate was 25.9% from 642 pheochromocytoma and paraganglioma patients.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (140, 156))	('paraganglioma', 'Phenotype', 'HP:0002668', (161, 174))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (66, 82))	('paraganglioma', 'Disease', (161, 174))	('germline mutation', 'Var', (98, 115))	('Adrenal Tumors Pheochromocytoma Working', 'Disease', (51, 90))	('Adrenal Tumors Pheochromocytoma Working', 'Disease', 'MESH:D010673', (51, 90))	('pheochromocytoma', 'Disease', (140, 156))	('patients', 'Species', '9606', (175, 183))	('Tumors', 'Phenotype', 'HP:0002664', (59, 65))	('paraganglioma', 'Disease', 'MESH:D010235', (161, 174))	('Adrenal Tumors Pheochromocytoma', 'Phenotype', 'HP:0006748', (51, 82))	('pheochromocytoma', 'Disease', 'MESH:D010673', (140, 156))
62672	22403753	In the other study, 24.3% of the 271 sporadic pheochromocytoma patients had germline mutations.	('pheochromocytoma', 'Disease', (46, 62))	('pheochromocytoma', 'Disease', 'MESH:D010673', (46, 62))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (46, 62))	('patients', 'Species', '9606', (63, 71))	('germline mutations', 'Var', (76, 94))
62681	22403753	In this case we can exclude NF1 mutation based on the clinical features.	('NF1', 'Gene', '4763', (28, 31))	('mutation', 'Var', (32, 40))	('NF1', 'Gene', (28, 31))
62690	22403753	Germline mutation of RET oncogene is associated with MEN type 2 which has typical character of genotype-phenotype correlation and mutation hot spots.	('MEN type 2', 'Disease', (53, 63))	('MEN', 'Species', '9606', (53, 56))	('RET', 'Gene', (21, 24))	('associated', 'Reg', (37, 47))	('Germline mutation', 'Var', (0, 17))	('RET', 'Gene', '5979', (21, 24))
62694	22403753	Patients with level 1 mutations (codons 609, 768, 790, 791, 804 and 891) have the lowest risk for medullary thyroid cancer, patients with level 2 mutations (codons 611, 618, 620 and 634) are intermediate risk, and patient with level 3 mutations (codons 883 and 918) have the highest risk for medullary thyroid cancer.	('thyroid cancer', 'Disease', (302, 316))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (98, 122))	('thyroid cancer', 'Disease', (108, 122))	('patient', 'Species', '9606', (214, 221))	('thyroid cancer', 'Phenotype', 'HP:0002890', (108, 122))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (292, 316))	('lowest', 'NegReg', (82, 88))	('thyroid cancer', 'Disease', 'MESH:D013964', (302, 316))	('thyroid cancer', 'Disease', 'MESH:D013964', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('codons 609', 'Var', (33, 43))	('Patients', 'Species', '9606', (0, 8))	('codons 883', 'Var', (246, 256))	('patient', 'Species', '9606', (124, 131))	('codons', 'Var', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (124, 132))	('thyroid cancer', 'Phenotype', 'HP:0002890', (302, 316))
62695	22403753	Medullary thyroid cancer was developed in 100% of level 3, 73% of level 2 and only 45% of level 1 RET gene mutation.	('thyroid cancer', 'Phenotype', 'HP:0002890', (10, 24))	('thyroid cancer', 'Disease', (10, 24))	('Medullary thyroid cancer', 'Phenotype', 'HP:0002865', (0, 24))	('RET', 'Gene', (98, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutation', 'Var', (107, 115))	('RET', 'Gene', '5979', (98, 101))
62696	22403753	In this case, L790F mutation was found in RET oncogene, which was not reported before in Korea.	('L790F', 'Var', (14, 19))	('RET', 'Gene', '5979', (42, 45))	('L790F', 'Mutation', 'rs75030001', (14, 19))	('RET', 'Gene', (42, 45))
62697	22403753	first described a new hot spot for mutations affecting codon 790 of RET oncogene.	('mutations affecting codon 790', 'Var', (35, 64))	('RET', 'Gene', (68, 71))	('RET', 'Gene', '5979', (68, 71))
62698	22403753	They reported that nine (69%) of 13 carriers with L790F mutation had developed medullary thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (89, 103))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (79, 103))	('L790F', 'Var', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('thyroid cancer', 'Phenotype', 'HP:0002890', (89, 103))	('thyroid cancer', 'Disease', (89, 103))	('L790F', 'Mutation', 'rs75030001', (50, 55))
62699	22403753	Initially, L790F mutation was reported to be associated with pheochromocytoma, but in the following study, L790F mutation rarely associated with pheochromocytoma.	('associated', 'Reg', (129, 139))	('pheochromocytoma', 'Disease', (145, 161))	('L790F mutation', 'Var', (11, 25))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('L790F', 'Mutation', 'rs75030001', (11, 16))	('L790F', 'Mutation', 'rs75030001', (107, 112))	('pheochromocytoma', 'Disease', 'MESH:D010673', (145, 161))	('associated', 'Reg', (45, 55))	('pheochromocytoma', 'Disease', (61, 77))	('L790F', 'Var', (107, 112))	('pheochromocytoma', 'Disease', 'MESH:D010673', (61, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (61, 77))
62700	22403753	Interestingly, this case shows bilateral pheochromocytomas which was rare phenotype of L790F and does not show medullary thyroid cancer which was common phenotype of L790F.	('thyroid cancer', 'Disease', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('thyroid cancer', 'Disease', 'MESH:D013964', (121, 135))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (31, 58))	('L790F', 'Mutation', 'rs75030001', (87, 92))	('L790F', 'Mutation', 'rs75030001', (166, 171))	('L790F', 'Var', (87, 92))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (111, 135))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (41, 58))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (41, 57))	('bilateral pheochromocytomas', 'Disease', (31, 58))	('thyroid cancer', 'Phenotype', 'HP:0002890', (121, 135))
62704	22403753	The highest-risk category of pheochromocytoma includes SDHB, SDHD and the level 3 risk of RET; the high-risk category includes VHL missense mutation and the level 2 risk of RET; the least-high risk category includes VHL truncating mutations and level 1 risk of RET.	('SDHB', 'Gene', (55, 59))	('SDHB', 'Gene', '6390', (55, 59))	('pheochromocytoma', 'Disease', (29, 45))	('RET', 'Gene', '5979', (261, 264))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('RET', 'Gene', '5979', (173, 176))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (29, 45))	('VHL', 'Disease', (216, 219))	('VHL', 'Disease', (127, 130))	('missense mutation', 'Var', (131, 148))	('RET', 'Gene', '5979', (90, 93))	('SDHD', 'Gene', '6392', (61, 65))	('VHL', 'Disease', 'MESH:D006623', (216, 219))	('pheochromocytoma', 'Disease', 'MESH:D010673', (29, 45))	('SDHD', 'Gene', (61, 65))	('RET', 'Gene', (261, 264))	('RET', 'Gene', (90, 93))	('RET', 'Gene', (173, 176))
62705	22403753	The incidence of germline mutation of multifocal or bilateral pheochromocytomas was much higher than that of unilateral pheochromocytoma.	('bilateral pheochromocytomas', 'Disease', (52, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (52, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))	('higher', 'Reg', (89, 95))	('germline mutation', 'Var', (17, 34))	('unilateral pheochromocytoma', 'Disease', 'MESH:D010673', (109, 136))	('unilateral pheochromocytoma', 'Disease', (109, 136))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (62, 79))
62708	22403753	They recommended sequential mutational analysis of RET, followed by VHL and SDHD in bilateral pheochromocytoma.	('SDHD', 'Gene', (76, 80))	('SDHD', 'Gene', '6392', (76, 80))	('VHL', 'Disease', (68, 71))	('RET', 'Gene', '5979', (51, 54))	('VHL', 'Disease', 'MESH:D006623', (68, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (94, 110))	('mutational analysis', 'Var', (28, 47))	('RET', 'Gene', (51, 54))	('bilateral pheochromocytoma', 'Disease', (84, 110))	('bilateral pheochromocytoma', 'Disease', 'MESH:D010673', (84, 110))
62709	22403753	This case is the first report of L790F RET germline mutation in Korea.	('RET', 'Gene', (39, 42))	('L790F', 'Var', (33, 38))	('RET', 'Gene', '5979', (39, 42))	('L790F', 'Mutation', 'rs75030001', (33, 38))
62743	20642819	With the advances in imaging technology, ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) may be useful in localizing the tumor, while I131-methyliodobenzylguanidine (I131-MIBG) and positron emission tomography (PET)-CT help to evaluate its function.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('I131-methyliodobenzylguanidine', 'Var', (160, 190))	('I131-methyliodobenzylguanidine', 'Chemical', '-', (160, 190))	('I131', 'Chemical', 'MESH:C000614965', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('MIBG', 'Chemical', 'MESH:D019797', (197, 201))	('I131', 'Chemical', 'MESH:C000614965', (192, 196))
62744	20642819	The significance of cystoscopy is limited and biopsy is not recommended since the tumor is usually located in the submucosa with an intact surface, and biopsy may provoke a hypertensive episode in patients who have not had proper medical treatment.	('patients', 'Species', '9606', (197, 205))	('provoke', 'Reg', (163, 170))	('biopsy', 'Var', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('hypertensive', 'Disease', 'MESH:D006973', (173, 185))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('hypertensive', 'Disease', (173, 185))	('tumor', 'Disease', (82, 87))
62760	19605896	In the many cases, especially those in man, pheochromocytoma is associated with familial tumor syndromes due to inherited mutations in a variety of proto-oncogenes and tumor suppressor genes.	('associated', 'Reg', (64, 74))	('man', 'Species', '9606', (39, 42))	('tumor', 'Disease', (168, 173))	('familial tumor syndromes', 'Disease', 'MESH:D009386', (80, 104))	('pheochromocytoma', 'Disease', (44, 60))	('familial tumor syndromes', 'Disease', (80, 104))	('man', 'Species', '9606', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pheochromocytoma', 'Disease', 'MESH:D010673', (44, 60))	('mutations', 'Var', (122, 131))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (44, 60))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
62852	19605896	Pheochromocytomas are present in roughly half of the cases of MEN2 and result from a mutation in the RET proto-oncogene.	('result from', 'Reg', (71, 82))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('MEN', 'Species', '9606', (62, 65))	('mutation', 'Var', (85, 93))	('RET', 'Gene', '5979', (101, 104))	('Pheochromocytomas', 'Disease', (0, 17))	('MEN2', 'Gene', (62, 66))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('RET', 'Gene', (101, 104))
62853	19605896	In fact, bilateral pheochromocytomas are a strong factor in screening for RET mutations in affected human patients.	('RET', 'Gene', (74, 77))	('bilateral pheochromocytomas', 'Disease', (9, 36))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (19, 35))	('human', 'Species', '9606', (100, 105))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (19, 36))	('mutations', 'Var', (78, 87))	('RET', 'Gene', '5979', (74, 77))	('patients', 'Species', '9606', (106, 114))	('bilateral pheochromocytomas', 'Disease', 'MESH:D010673', (9, 36))
62854	19605896	In cases of VHL syndrome, the absence of the VHL protein leads to stabilization of hypoxia inducible factor 1alpha thereby potentiating cell growth and angiogenesis.	('angiogenesis', 'CPA', (152, 164))	('VHL', 'Disease', (12, 15))	('VHL syndrome', 'Disease', (12, 24))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('absence', 'Var', (30, 37))	('cell growth', 'CPA', (136, 147))	('VHL', 'Disease', (45, 48))	('VHL', 'Disease', 'MESH:D006623', (45, 48))	('VHL syndrome', 'Disease', 'MESH:D006623', (12, 24))	('potentiating', 'PosReg', (123, 135))	('VHL', 'Disease', 'MESH:D006623', (12, 15))	('hypoxia', 'Disease', (83, 90))	('stabilization', 'MPA', (66, 79))
62875	16405730	Mutation analysis of SDHB and SDHC: novel germline mutations in sporadic head and neck paraganglioma and familial paraganglioma and/or pheochromocytoma Germline mutations of the SDHD, SDHB and SDHC genes, encoding three of the four subunits of succinate dehydrogenase, are a major cause of hereditary paraganglioma and pheochromocytoma, and demonstrate that these genes are classic tumor suppressors.	('mutations', 'Var', (51, 60))	('pheochromocytoma', 'Disease', (135, 151))	('familial paraganglioma', 'Disease', (105, 127))	('SDHB', 'Gene', (184, 188))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('paraganglioma', 'Phenotype', 'HP:0002668', (87, 100))	('neck paraganglioma', 'Disease', (82, 100))	('SDHB', 'Gene', '6390', (21, 25))	('SDHD', 'Gene', (178, 182))	('paraganglioma', 'Phenotype', 'HP:0002668', (301, 314))	('succinate dehydrogenase', 'Gene', '6392', (244, 267))	('SDHC', 'Gene', (30, 34))	('classic tumor', 'Disease', 'MESH:D005693', (374, 387))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (73, 100))	('SDHC', 'Gene', (193, 197))	('classic tumor', 'Disease', (374, 387))	('hereditary paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (290, 335))	('neck paraganglioma', 'Disease', 'MESH:D010235', (82, 100))	('SDHB', 'Gene', (21, 25))	('familial paraganglioma', 'Disease', 'MESH:D010235', (105, 127))	('pheochromocytoma', 'Disease', 'MESH:D010673', (319, 335))	('paraganglioma', 'Phenotype', 'HP:0002668', (114, 127))	('SDHB', 'Gene', '6390', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('cause', 'Reg', (281, 286))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('SDHC', 'Gene', '6391', (30, 34))	('pheochromocytoma', 'Disease', (319, 335))	('succinate dehydrogenase', 'Gene', (244, 267))	('mutations', 'Var', (161, 170))	('SDHC', 'Gene', '6391', (193, 197))	('SDHD', 'Gene', '6392', (178, 182))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (319, 335))
62877	16405730	Using conformation sensitive gel electrophoresis (CSGE) and direct DNA sequencing to analyse genomic DNA from peripheral blood lymphocytes, here we describe the mutation analysis of the SDHB and SDHC genes in 37 patients with sporadic (i.e.	('SDHC', 'Gene', (195, 199))	('SDHB', 'Gene', (186, 190))	('SDHC', 'Gene', '6391', (195, 199))	('mutation analysis', 'Var', (161, 178))	('patients', 'Species', '9606', (212, 220))	('SDHB', 'Gene', '6390', (186, 190))
62879	16405730	Two sporadic patients were found to have a SDHB splice site mutation in intron 4, c.423+1G>A, which produces a mis-spliced transcript with a 54 nucleotide deletion, resulting in an 18 amino acid in-frame deletion.	('c.423+1G>A', 'Mutation', 'rs398122805', (82, 92))	('SDHB', 'Gene', '6390', (43, 47))	('patients', 'Species', '9606', (13, 21))	('SDHB', 'Gene', (43, 47))	('c.423+1G>A', 'Var', (82, 92))
62880	16405730	A third patient was found to carry the c.214C>T (p.Arg72Cys) missense mutation in exon 4 of SDHC, which is situated in a highly conserved protein motif that constitutes the quinone-binding site of the succinate: ubiquinone oxidoreductase (SQR) complex in E. coli.	('succinate', 'Chemical', 'MESH:D019802', (201, 210))	('SDHC', 'Gene', '6391', (92, 96))	('quinone', 'Chemical', 'MESH:C004532', (215, 222))	('c.214C>T', 'Var', (39, 47))	('p.Arg72Cys', 'Mutation', 'rs756676111', (49, 59))	('patient', 'Species', '9606', (8, 15))	('c.214C>T', 'Mutation', 'rs756676111', (39, 47))	('quinone', 'Chemical', 'MESH:C004532', (173, 180))	('SDHC', 'Gene', (92, 96))	('E. coli', 'Species', '562', (255, 262))
62881	16405730	Together with our previous results, we found 27 germline mutations of SDH genes in 95 cases (28%) of sporadic head and neck paraganglioma.	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (110, 137))	('SDH', 'Gene', '6390', (70, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (124, 137))	('neck paraganglioma', 'Disease', (119, 137))	('neck paraganglioma', 'Disease', 'MESH:D010235', (119, 137))	('SDH', 'Gene', (70, 73))	('germline mutations', 'Var', (48, 66))
62882	16405730	In addition all index patients of five families showing hereditary pheochromocytoma-paraganglioma were found to carry germline mutations of SDHB: four of which were novel, c.343C>T (p.Arg115X), c.141G>A (p.Trp47X), c.281G>A (p.Arg94Lys), and c.653G>C (p.Trp218Ser), and one reported previously, c.136C>T, p.Arg46X.	('hereditary pheochromocytoma', 'Disease', 'MESH:D010673', (56, 83))	('pheochromocytoma-paraganglioma', 'Disease', (67, 97))	('hereditary pheochromocytoma', 'Disease', (56, 83))	('c.136C>T', 'Var', (295, 303))	('c.343C>T', 'Mutation', 'rs751000085', (172, 180))	('c.343C>T', 'Var', (172, 180))	('p.Arg94Lys', 'Mutation', 'rs761381025', (225, 235))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (67, 83))	('c.136C>T', 'Mutation', 'rs74315370', (295, 303))	('patients', 'Species', '9606', (22, 30))	('p.Trp218Ser', 'Mutation', 'p.W218S', (252, 263))	('SDHB', 'Gene', '6390', (140, 144))	('paraganglioma', 'Phenotype', 'HP:0002668', (84, 97))	('c.141G>A', 'Var', (194, 202))	('c.141G>A', 'Mutation', 'rs1060503762', (194, 202))	('c.281G>A', 'Mutation', 'rs761381025', (215, 223))	('c.653G>C', 'Mutation', 'c.653G>C', (242, 250))	('c.653G>C', 'Var', (242, 250))	('SDHB', 'Gene', (140, 144))	('p.Arg46X', 'Mutation', 'rs74315370', (305, 313))	('pheochromocytoma-paraganglioma', 'Disease', 'MESH:D010673', (67, 97))	('p.Arg115X', 'Mutation', 'rs751000085', (182, 191))	('p.Trp47X', 'Mutation', 'rs1060503762', (204, 212))
62883	16405730	In conclusion, these data indicate that germline mutations of SDHB and SDHC play a minor role in sporadic head and neck paraganglioma and further underline the importance of germline SDHB mutations in cases of familial pheochromocytoma-paraganglioma.	('SDHB', 'Gene', (183, 187))	('SDHB', 'Gene', '6390', (62, 66))	('neck paraganglioma', 'Disease', 'MESH:D010235', (115, 133))	('SDHC', 'Gene', '6391', (71, 75))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (106, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (219, 235))	('SDHB', 'Gene', '6390', (183, 187))	('neck paraganglioma', 'Disease', (115, 133))	('sporadic', 'Disease', (97, 105))	('mutations', 'Var', (188, 197))	('familial pheochromocytoma-paraganglioma', 'Disease', 'MESH:C531777', (210, 249))	('familial pheochromocytoma-paraganglioma', 'Disease', (210, 249))	('paraganglioma', 'Phenotype', 'HP:0002668', (236, 249))	('SDHB', 'Gene', (62, 66))	('SDHC', 'Gene', (71, 75))
62888	16405730	no known family history), clustering in families has long been recognized, and the search for susceptibility loci led to the mapping of two putative loci: PGL1-11q23 and PGL2-11q13.	('PGL', 'Phenotype', 'HP:0002668', (170, 173))	('PGL', 'Phenotype', 'HP:0002668', (155, 158))	('PGL1-11q23', 'Var', (155, 165))	('PGL2', 'Gene', '54949', (170, 174))	('PGL2', 'Gene', (170, 174))
62889	16405730	The identification of PGL1 followed in 2000, when Baysal et al  reported germline mutations in SDHD (succinate dehydrogenase, subunit D) in PGL1-linked families.	('succinate dehydrogenase', 'Gene', '6392', (101, 124))	('SDHD', 'Gene', '6392', (95, 99))	('PGL', 'Phenotype', 'HP:0002668', (140, 143))	('mutations', 'Var', (82, 91))	('SDHD', 'Gene', (95, 99))	('succinate dehydrogenase', 'Gene', (101, 124))	('PGL', 'Phenotype', 'HP:0002668', (22, 25))
62890	16405730	Subsequently, germline mutations in SDHC (PGL3-1q21) and SDHB (PGL4-1p36) were identified using a candidate gene approach, and both Astuti et al  and others have reported that germline mutations of SDHB are involved in familial pheochromocytoma.	('SDHB', 'Gene', '6390', (198, 202))	('SDHB', 'Gene', '6390', (57, 61))	('SDHB', 'Gene', (198, 202))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (228, 244))	('mutations', 'Var', (185, 194))	('PGL', 'Phenotype', 'HP:0002668', (63, 66))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (219, 244))	('SDHB', 'Gene', (57, 61))	('PGL', 'Phenotype', 'HP:0002668', (42, 45))	('SDHC', 'Gene', (36, 40))	('involved', 'Reg', (207, 215))	('familial pheochromocytoma', 'Disease', (219, 244))	('SDHC', 'Gene', '6391', (36, 40))
62894	16405730	Previously we reported the frequency of SDHD mutations in familial and sporadic head and neck paraganglioma in the Netherlands.	('SDHD', 'Gene', '6392', (40, 44))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (80, 107))	('mutations', 'Var', (45, 54))	('SDHD', 'Gene', (40, 44))	('neck paraganglioma', 'Disease', (89, 107))	('neck paraganglioma', 'Disease', 'MESH:D010235', (89, 107))	('paraganglioma', 'Phenotype', 'HP:0002668', (94, 107))
62895	16405730	Nearly all clearly familial paraganglioma is accounted for by the Dutch founder mutations Asp92Tyr and Leu139Pro.	('familial paraganglioma', 'Disease', (19, 41))	('paraganglioma', 'Phenotype', 'HP:0002668', (28, 41))	('familial paraganglioma', 'Disease', 'MESH:D010235', (19, 41))	('Asp92Tyr', 'SUBSTITUTION', 'None', (90, 98))	('Asp92Tyr', 'Var', (90, 98))	('Leu139Pro', 'Var', (103, 112))	('Leu139Pro', 'SUBSTITUTION', 'None', (103, 112))
62896	16405730	However, a group of 37 sporadic patients tested negative for SDHD mutations.	('mutations', 'Var', (66, 75))	('SDHD', 'Gene', (61, 65))	('SDHD', 'Gene', '6392', (61, 65))	('patients', 'Species', '9606', (32, 40))
62908	16405730	All the patients ascertained in Leiden had previously been investigated for the presence of SDHD mutations using SSCP and restriction digestion analysis and found to be negative.	('mutations', 'Var', (97, 106))	('SDHD', 'Gene', (92, 96))	('SDHD', 'Gene', '6392', (92, 96))	('patients', 'Species', '9606', (8, 16))
62909	16405730	Mutations in three of the familial pheochromocytoma-paraganglioma cases were detected using CSGE analysis and confirmed by direct sequencing, while the remaining two were identified by direct sequencing of the SDHB gene, indicated by a suspicious clinical history.	('familial pheochromocytoma-paraganglioma', 'Disease', (26, 65))	('familial pheochromocytoma-paraganglioma', 'Disease', 'MESH:C531777', (26, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (52, 65))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', '6390', (210, 214))	('SDHB', 'Gene', (210, 214))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (35, 51))
62912	16405730	To detect SDHB variants, mismatch PCR primers were designed and appropriate restriction enzymes were selected using the PIRA PCR software (Table 1).	('variants', 'Var', (15, 23))	('SDHB', 'Gene', (10, 14))	('SDHB', 'Gene', '6390', (10, 14))
62922	16405730	This patient was described briefly in a previous report that examined SDH activity in paraganglioma, using the former mutation nomenclature of IVS4+1G>A.	('paraganglioma', 'Disease', 'MESH:D010235', (86, 99))	('patient', 'Species', '9606', (5, 12))	('IVS4+1G>A', 'Var', (143, 152))	('SDH', 'Gene', '6390', (70, 73))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('SDH', 'Gene', (70, 73))	('paraganglioma', 'Disease', (86, 99))	('IVS4+1G>A', 'Mutation', 'c.IVS4+1G>A', (143, 152))
62924	16405730	The splice site mutation in intron 4 abolishes the consensus splice donor sequence and thus may result in splicing abnormalities.	('mutation', 'Var', (16, 24))	('abolishes', 'NegReg', (37, 46))	('splicing abnormalities', 'MPA', (106, 128))	('consensus splice donor sequence', 'MPA', (51, 82))	('donor', 'Species', '9606', (68, 73))	('result in', 'Reg', (96, 105))
62927	16405730	As these patients are all of ethnic Dutch origin and are apparently unrelated, this mutation may represent a SDHB founder mutation in The Netherlands.	('patients', 'Species', '9606', (9, 17))	('SDHB', 'Gene', (109, 113))	('SDHB', 'Gene', '6390', (109, 113))	('mutation', 'Var', (84, 92))
62928	16405730	All sporadic patients were also analyzed for mutations in the six exons of SDHC.	('SDHC', 'Gene', '6391', (75, 79))	('SDHC', 'Gene', (75, 79))	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (13, 21))
62931	16405730	A transition of C to T at base pair 214 in exon 4, resulted in the missense mutation of a highly conserved arginine residue (p.Arg72Cys), located in the putative quinone-binding site of complex II.	('p.Arg72Cys', 'Mutation', 'rs756676111', (125, 135))	('p.Arg72Cys', 'Var', (125, 135))	('C to T at base pair 214', 'Mutation', 'rs756676111', (16, 39))	('missense mutation', 'Var', (67, 84))	('arginine', 'Chemical', 'MESH:D001120', (107, 115))	('quinone', 'Chemical', 'MESH:C004532', (162, 169))	('resulted in', 'Reg', (51, 62))
62934	16405730	The functionality of all missense mutations should be interpreted cautiously, and particularly in a case such as this as this is only the second report of a missense mutation of SDHC and the patient presented without a family history.	('SDHC', 'Gene', (178, 182))	('missense mutation', 'Var', (157, 174))	('SDHC', 'Gene', '6391', (178, 182))	('patient', 'Species', '9606', (191, 198))
62941	16405730	Both patients were found to carry a germline nonsense mutation of SDHB, c.343C>T (p.Arg115X) which leads to a truncation of the protein at under half its normal length of 280 amino acids.	('SDHB', 'Gene', (66, 70))	('c.343C>T', 'Mutation', 'rs751000085', (72, 80))	('leads to', 'Reg', (99, 107))	('patients', 'Species', '9606', (5, 13))	('c.343C>T', 'Var', (72, 80))	('protein', 'Protein', (128, 135))	('p.Arg115X', 'Mutation', 'rs751000085', (82, 91))	('SDHB', 'Gene', '6390', (66, 70))	('truncation', 'MPA', (110, 120))
62946	16405730	Analysis of DNA from the index patient revealed a missense mutation c. 653G>C (p.Trp218Ser) in exon 7 of SDHB.	('653G>C', 'SUBSTITUTION', 'None', (71, 77))	('SDHB', 'Gene', '6390', (105, 109))	('p.Trp218Ser', 'Mutation', 'p.W218S', (79, 90))	('SDHB', 'Gene', (105, 109))	('653G>C', 'Var', (71, 77))	('patient', 'Species', '9606', (31, 38))
62947	16405730	This missense change affects an amino acid that is conserved in both mammals and in D. melanogaster, C. elegans, S. cerevisiae and A. thaliana.	('D. melanogaster', 'Species', '7227', (84, 99))	('affects', 'Reg', (21, 28))	('missense change', 'Var', (5, 20))	('C. elegans', 'Species', '6239', (101, 111))	('A. thaliana', 'Species', '3702', (131, 142))	('S. cerevisiae', 'Species', '4932', (113, 126))
62961	16405730	The index patient was found to carry a c.141G>A germline variant of SDHB resulting in a stop codon at codon 47 (p.Trp47X).	('c.141G>A', 'Mutation', 'rs1060503762', (39, 47))	('c.141G>A', 'Var', (39, 47))	('p.Trp47X', 'Mutation', 'rs1060503762', (112, 120))	('SDHB', 'Gene', '6390', (68, 72))	('patient', 'Species', '9606', (10, 17))	('SDHB', 'Gene', (68, 72))
62964	16405730	FGT57.6, a male of Pakistani descent, presented with a retroperitoneal paraganglioma, and had three male relatives (from a large extended family) with similar clinical profiles.	('retroperitoneal paraganglioma', 'Disease', (55, 84))	('retroperitoneal paraganglioma', 'Phenotype', 'HP:0006729', (55, 84))	('FGT57.6', 'Var', (0, 7))	('retroperitoneal paraganglioma', 'Disease', 'MESH:D012186', (55, 84))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))
62974	16405730	The index case and his nephew were available for testing and both were found to be carrying a missense variant of SDHB, c.281G>A, resulting in the substitution of arginine for lysine at codon 94 (p.Arg94Lys).	('arginine for lysine at codon 94', 'Mutation', 'p.K94R', (163, 194))	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('substitution', 'Reg', (147, 159))	('c.281G>A', 'Var', (120, 128))	('p.Arg94Lys', 'Mutation', 'rs761381025', (196, 206))	('c.281G>A', 'Mutation', 'rs761381025', (120, 128))	('p.Arg94Lys', 'Var', (196, 206))
62975	16405730	Arginine 94 is highly conserved and adjacent to a cysteine that constitutes one of the highly conserved cysteine regions that are the putative non-heme iron-sulfur clusters of SDHB.	('SDHB', 'Gene', '6390', (176, 180))	('SDHB', 'Gene', (176, 180))	('cysteine', 'Chemical', 'MESH:D003545', (104, 112))	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('cysteine', 'Chemical', 'MESH:D003545', (50, 58))	('heme', 'Chemical', 'MESH:D006418', (147, 151))	('iron-sulfur', 'Chemical', '-', (152, 163))	('Arginine 94', 'Var', (0, 11))
62982	16405730	The index patient was found to carry a previously described mutation in exon 2 of SDHB, c.136C>T, p.Arg46X.	('SDHB', 'Gene', '6390', (82, 86))	('patient', 'Species', '9606', (10, 17))	('p.Arg46X', 'Var', (98, 106))	('SDHB', 'Gene', (82, 86))	('c.136C>T', 'Var', (88, 96))	('p.Arg46X', 'Mutation', 'rs74315370', (98, 106))	('c.136C>T', 'Mutation', 'rs74315370', (88, 96))
62984	16405730	Including our previous results, we have screened a total of 95 sporadic head and neck paraganglioma cases for germline mutations of SDH genes and found 24 (25%) in SDHD, 2 (2%) in SDHB and 1 (1%) in SDHC (total = 28%).	('neck paraganglioma', 'Disease', (81, 99))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (72, 99))	('SDHB', 'Gene', '6390', (180, 184))	('SDH', 'Gene', '6390', (199, 202))	('neck paraganglioma', 'Disease', 'MESH:D010235', (81, 99))	('paraganglioma', 'Phenotype', 'HP:0002668', (86, 99))	('SDHC', 'Gene', '6391', (199, 203))	('SDH', 'Gene', '6390', (164, 167))	('mutations', 'Var', (119, 128))	('SDHB', 'Gene', (180, 184))	('SDH', 'Gene', '6390', (180, 183))	('SDH', 'Gene', (199, 202))	('SDH', 'Gene', '6390', (132, 135))	('SDHD', 'Gene', '6392', (164, 168))	('SDH', 'Gene', (164, 167))	('SDHC', 'Gene', (199, 203))	('SDHD', 'Gene', (164, 168))	('SDH', 'Gene', (132, 135))	('SDH', 'Gene', (180, 183))
62985	16405730	Further studies will be required to discern whether the remaining cases can be explained by mutations of SDH genes not currently detectable with the techniques used or whether these are true sporadic cases, not attributable to germline mutations of one of the SDH genes.	('SDH', 'Gene', (105, 108))	('SDH', 'Gene', '6390', (105, 108))	('mutations', 'Var', (92, 101))	('SDH', 'Gene', '6390', (260, 263))	('SDH', 'Gene', (260, 263))
62987	16405730	This seems particularly likely in the case of the very common SDHD mutation Asp92Tyr (D92Y) which accounts for 19 of the 24 sporadic SDHD cases, but may also explain the prevalence of the c.423+1G>A SDHB mutation.	('c.423+1G>A', 'Var', (188, 198))	('c.423+1G>A', 'Mutation', 'rs398122805', (188, 198))	('SDHD', 'Gene', '6392', (133, 137))	('SDHD', 'Gene', (133, 137))	('Asp92Tyr', 'Var', (76, 84))	('Asp92Tyr', 'SUBSTITUTION', 'None', (76, 84))	('SDHD', 'Gene', '6392', (62, 66))	('SDHB', 'Gene', '6390', (199, 203))	('SDHB', 'Gene', (199, 203))	('SDHD', 'Gene', (62, 66))	('D92Y', 'Mutation', 'rs80338845', (86, 90))
62988	16405730	Previous studies of mutations of SDH genes related to sporadic head and neck paraganglioma have examined SDHB, C, and D together or SDHD only.	('SDH', 'Gene', (105, 108))	('SDH', 'Gene', (33, 36))	('SDHD', 'Gene', (132, 136))	('SDHB', 'Gene', '6390', (105, 109))	('neck paraganglioma', 'Disease', 'MESH:D010235', (72, 90))	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('related', 'Reg', (43, 50))	('SDHB', 'Gene', (105, 109))	('SDH', 'Gene', '6390', (132, 135))	('SDH', 'Gene', '6390', (105, 108))	('SDH', 'Gene', '6390', (33, 36))	('neck paraganglioma', 'Disease', (72, 90))	('SDH', 'Gene', (132, 135))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (63, 90))	('SDHD', 'Gene', '6392', (132, 136))	('mutations', 'Var', (20, 29))
62989	16405730	The four studies examining all three genes included 103 cases and found 3 mutations of SDHB, 0 mutations of SDHC and 7 mutations of SDHD.	('SDHD', 'Gene', (132, 136))	('SDHB', 'Gene', '6390', (87, 91))	('mutations', 'Var', (74, 83))	('SDHC', 'Gene', (108, 112))	('SDHC', 'Gene', '6391', (108, 112))	('SDHD', 'Gene', '6392', (132, 136))	('SDHB', 'Gene', (87, 91))
62990	16405730	Including the current study, a total of 5 mutations of SDHB have been found in 141 cases (3.5%), and 1 of SDHC (0.7%).	('SDHB', 'Gene', (55, 59))	('SDHC', 'Gene', (106, 110))	('SDHC', 'Gene', '6391', (106, 110))	('SDHB', 'Gene', '6390', (55, 59))	('found', 'Reg', (70, 75))	('mutations', 'Var', (42, 51))
62991	16405730	The two studies that looked only at SDHD were both conducted in The Netherlands and found 33 mutations in 93 Dutch cases (35%).	('SDHD', 'Gene', '6392', (36, 40))	('mutations', 'Var', (93, 102))	('SDHD', 'Gene', (36, 40))	('Dutch', 'Disease', (109, 114))
62992	16405730	The higher incidence in The Netherlands is largely attributable to the common Dutch mutations Asp92Tyr (D92Y), Leu95Pro (L95P) and Leu139Pro (L139P).	('Leu139Pro', 'Var', (131, 140))	('Leu139Pro', 'SUBSTITUTION', 'None', (131, 140))	('L95P', 'Mutation', 'rs80338846', (121, 125))	('D92Y', 'Mutation', 'rs80338845', (104, 108))	('Asp92Tyr', 'SUBSTITUTION', 'None', (94, 102))	('Leu95Pro', 'SUBSTITUTION', 'None', (111, 119))	('L139P', 'Mutation', 'rs80338847', (142, 147))	('Asp92Tyr', 'Var', (94, 102))	('Leu95Pro', 'Var', (111, 119))
62993	16405730	While this study was conducted with the aim of identifying the incidence of germline mutations of SDHB and SDHC in paraganglioma/pheochromocytoma, it is worth remembering that we did not examine DNA from tumors, so no conclusion can be drawn on the incidence of somatic mutations of SDHB and SDHC in paraganglioma.	('paraganglioma', 'Disease', 'MESH:D010235', (300, 313))	('SDHC', 'Gene', (292, 296))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('paraganglioma', 'Disease', (115, 128))	('paraganglioma', 'Disease', 'MESH:D010235', (115, 128))	('SDHB', 'Gene', '6390', (283, 287))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('paraganglioma', 'Phenotype', 'HP:0002668', (300, 313))	('SDHC', 'Gene', (107, 111))	('tumors', 'Disease', (204, 210))	('SDHB', 'Gene', (283, 287))	('SDHB', 'Gene', '6390', (98, 102))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (129, 145))	('mutations', 'Var', (85, 94))	('paraganglioma', 'Phenotype', 'HP:0002668', (115, 128))	('SDHC', 'Gene', '6391', (292, 296))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('paraganglioma/pheochromocytoma', 'Disease', (115, 145))	('SDHB', 'Gene', (98, 102))	('paraganglioma', 'Disease', (300, 313))	('SDHC', 'Gene', '6391', (107, 111))	('paraganglioma/pheochromocytoma', 'Disease', 'MESH:D010673', (115, 145))
62994	16405730	Previous studies that did address this question, including SDHD, found no evidence of somatic SDH mutations playing a role in paraganglioma, with the exception of Gimm et al  who reported a single case with a somatic mutation of SDHD, Pro81Leu.	('SDH', 'Gene', '6390', (94, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (126, 139))	('SDHD', 'Gene', (229, 233))	('SDHD', 'Gene', '6392', (229, 233))	('Pro81Leu', 'Mutation', 'rs80338844', (235, 243))	('SDH', 'Gene', '6390', (229, 232))	('paraganglioma', 'Disease', (126, 139))	('mutations', 'Var', (98, 107))	('SDH', 'Gene', (59, 62))	('SDHD', 'Gene', '6392', (59, 63))	('SDH', 'Gene', (94, 97))	('paraganglioma', 'Disease', 'MESH:D010235', (126, 139))	('SDHD', 'Gene', (59, 63))	('SDH', 'Gene', (229, 232))	('SDH', 'Gene', '6390', (59, 62))
62996	16405730	The five novel SDHB mutations described here further underline the importance of germline mutations of this gene in cases of paraganglioma and pheochromocytoma.	('SDHB', 'Gene', '6390', (15, 19))	('paraganglioma and pheochromocytoma', 'Disease', 'MESH:D010673', (125, 159))	('SDHB', 'Gene', (15, 19))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (143, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (125, 138))	('mutations', 'Var', (20, 29))
62997	16405730	The striking variability in the penetrance and phenotype of SDHB mutations in several the families described illustrates the difficulty in ascertaining the family history of patients.	('patients', 'Species', '9606', (174, 182))	('SDHB', 'Gene', '6390', (60, 64))	('SDHB', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
62998	16405730	Similarly, McDonnell et al  recently described a remarkable pedigree in which a single case, a young boy, led to the detection of a further 17 SDHB mutation carriers, 4 of whom were phenotypically affected.	('mutation', 'Var', (148, 156))	('SDHB', 'Gene', (143, 147))	('boy', 'Species', '9606', (101, 104))	('SDHB', 'Gene', '6390', (143, 147))
63001	16405730	Much of this increase is attributable to the recent availability of genetic testing of SDH genes.	('SDH', 'Gene', (87, 90))	('genetic', 'Var', (68, 75))	('SDH', 'Gene', '6390', (87, 90))
63007	16405730	The patient carrying a SDHC mutation described in this report joins the small number of individuals with SDHC mutations reported to date, which include a family showing five cases of non-chromaffin paraganglioma and carrying a mutation that ablates the start codon ATG, (c.3G>A).	('paraganglioma', 'Disease', (198, 211))	('SDHC', 'Gene', '6391', (105, 109))	('SDHC', 'Gene', '6391', (23, 27))	('mutations', 'Var', (110, 119))	('paraganglioma', 'Disease', 'MESH:D010235', (198, 211))	('c.3G>A', 'Mutation', 'rs587776652', (271, 277))	('patient', 'Species', '9606', (4, 11))	('chromaffin paraganglioma', 'Phenotype', 'HP:0002666', (187, 211))	('mutation', 'Var', (28, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('ablates', 'NegReg', (241, 248))	('c.3G>A', 'Var', (271, 277))	('SDHC', 'Gene', (105, 109))	('SDHC', 'Gene', (23, 27))
63009	16405730	A splice donor site mutation (IVS5+1G>A) was identified in this patient, resulting in the skipping of exon 5.	('patient', 'Species', '9606', (64, 71))	('donor', 'Species', '9606', (9, 14))	('skipping', 'MPA', (90, 98))	('IVS5+1G>A', 'Mutation', 'c.IVS5+1G>A', (30, 39))	('IVS5+1G>A', 'Var', (30, 39))
63010	16405730	More recently Bauters et al  identified a missense mutation (c.473T>C; Leu158Pro) in a case of carotid body paraganglioma, and Baysal et al  described a family with head and neck paraganglioma with an 8 kb Alu-mediated SDHC deletion.	('carotid body paraganglioma', 'Phenotype', 'HP:0100635', (95, 121))	('carotid body paraganglioma', 'Disease', (95, 121))	('SDHC', 'Gene', (219, 223))	('paraganglioma', 'Phenotype', 'HP:0002668', (179, 192))	('neck paraganglioma', 'Disease', (174, 192))	('Leu158Pro', 'Var', (71, 80))	('neck paraganglioma', 'Disease', 'MESH:D010235', (174, 192))	('SDHC', 'Gene', '6391', (219, 223))	('paraganglioma', 'Phenotype', 'HP:0002668', (108, 121))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (165, 192))	('c.473T>C', 'Mutation', 'c.473T>C', (61, 69))	('carotid body paraganglioma', 'Disease', 'MESH:D002345', (95, 121))	('Leu158Pro', 'SUBSTITUTION', 'None', (71, 80))
63012	16405730	The c.214C>T change in SDHC results in the substitution of arginine for cysteine.	('c.214C>T', 'Mutation', 'rs756676111', (4, 12))	('SDHC', 'Gene', '6391', (23, 27))	('cysteine', 'Chemical', 'MESH:D003545', (72, 80))	('substitution', 'Var', (43, 55))	('c.214C>T', 'Var', (4, 12))	('arginine', 'Chemical', 'MESH:D001120', (59, 67))	('results in', 'Reg', (28, 38))	('SDHC', 'Gene', (23, 27))
63014	16405730	Mutants of E. coli carrying a substitution of arginine 31 are unable to grow aerobically on succinate as a carbon source.	('unable', 'NegReg', (62, 68))	('carbon', 'Chemical', 'MESH:D002244', (107, 113))	('succinate', 'Chemical', 'MESH:D019802', (92, 101))	('substitution', 'Var', (30, 42))	('arginine 31', 'Var', (46, 57))	('E. coli', 'Species', '562', (11, 18))	('arginine', 'Chemical', 'MESH:D001120', (46, 54))
63015	16405730	In addition, mutation of the histidine adjacent to Arginine 47 caused a marked reduction in the catalytic efficiency of quinone reduction in S. cerevisiae .	('histidine', 'Chemical', 'MESH:D006639', (29, 38))	('catalytic efficiency', 'MPA', (96, 116))	('mutation', 'Var', (13, 21))	('S. cerevisiae', 'Species', '4932', (141, 154))	('Arginine', 'Chemical', 'MESH:D001120', (51, 59))	('Arginine 47', 'Var', (51, 62))	('quinone', 'Chemical', 'MESH:C004532', (120, 127))	('reduction', 'NegReg', (79, 88))
63016	16405730	Although relatively few SDHC mutations carriers are known, totaling 15 individuals, including 4 with no other known affected family members, all affected individuals had head and neck paragangliomas, including one case of a metastatic, catecholamine-secreting carotid body tumor.	('neck paragangliomas', 'Disease', 'MESH:D010235', (179, 198))	('SDHC', 'Gene', (24, 28))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (170, 197))	('mutations', 'Var', (29, 38))	('SDHC', 'Gene', '6391', (24, 28))	('neck paragangliomas', 'Disease', (179, 198))	('carotid body tumor', 'Phenotype', 'HP:0002668', (260, 278))	('carotid body tumor', 'Disease', (260, 278))	('paragangliomas', 'Phenotype', 'HP:0002668', (184, 198))	('paraganglioma', 'Phenotype', 'HP:0002668', (184, 197))	('catecholamine', 'Chemical', 'MESH:D002395', (236, 249))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('carotid body tumor', 'Disease', 'MESH:D002345', (260, 278))	('had', 'Reg', (166, 169))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (170, 198))
63018	16405730	In this study we detected germline mutations of SDHB in 5% and of SDHC in 2.5% of sporadic head and neck paraganglioma cases.	('neck paraganglioma', 'Disease', 'MESH:D010235', (100, 118))	('germline mutations', 'Var', (26, 44))	('SDHC', 'Gene', (66, 70))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (91, 118))	('SDHC', 'Gene', '6391', (66, 70))	('neck paraganglioma', 'Disease', (100, 118))	('detected', 'Reg', (17, 25))	('SDHB', 'Gene', '6390', (48, 52))	('paraganglioma', 'Phenotype', 'HP:0002668', (105, 118))	('SDHB', 'Gene', (48, 52))
63019	16405730	Including data from published studies, a total of 5 mutations of SDHB (3.5%) and 1 of SDHC (0.7%) have been reported in 141 cases.	('mutations', 'Var', (52, 61))	('reported', 'Reg', (108, 116))	('SDHB', 'Gene', '6390', (65, 69))	('SDHC', 'Gene', (86, 90))	('SDHC', 'Gene', '6391', (86, 90))	('SDHB', 'Gene', (65, 69))
63020	16405730	Together with our previous study of SDHD mutations we have now found 27 SDH germline mutations in 95 cases (28%) of sporadic head and neck paraganglioma, the majority of these being Dutch founder mutations of SDHD.	('SDH', 'Gene', (209, 212))	('SDHD', 'Gene', (36, 40))	('SDHD', 'Gene', '6392', (36, 40))	('head and neck paraganglioma', 'Phenotype', 'HP:0002864', (125, 152))	('paraganglioma', 'Phenotype', 'HP:0002668', (139, 152))	('SDH', 'Gene', '6390', (72, 75))	('neck paraganglioma', 'Disease', (134, 152))	('SDH', 'Gene', '6390', (36, 39))	('mutations', 'Var', (85, 94))	('SDHD', 'Gene', (209, 213))	('SDHD', 'Gene', '6392', (209, 213))	('SDH', 'Gene', (72, 75))	('neck paraganglioma', 'Disease', 'MESH:D010235', (134, 152))	('SDH', 'Gene', '6390', (209, 212))	('SDH', 'Gene', (36, 39))
63022	16405730	In contrast, germline mutations of SDHB were found in all cases of familial pheochromocytoma and/or paraganglioma.	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (67, 92))	('paraganglioma', 'Disease', 'MESH:D010235', (100, 113))	('SDHB', 'Gene', (35, 39))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (76, 92))	('familial pheochromocytoma', 'Disease', (67, 92))	('paraganglioma', 'Phenotype', 'HP:0002668', (100, 113))	('germline mutations', 'Var', (13, 31))	('paraganglioma', 'Disease', (100, 113))	('found', 'Reg', (45, 50))	('SDHB', 'Gene', '6390', (35, 39))
63023	16405730	The clinical data presented illustrates the striking variability in phenotype related to SDHB mutations, even within a single family.	('SDHB', 'Gene', '6390', (89, 93))	('SDHB', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
63024	16405730	The mutation of SDHC reported here is only the fifth to be described, extending our knowledge of the phenotype related to mutations of this gene The author(s) declare that they have no competing interests JPB collected, edited and analysed the data, co-designed the study, and wrote the manuscript.	('SDHC', 'Gene', (16, 20))	('mutations', 'Var', (122, 131))	('mutation', 'Var', (4, 12))	('SDHC', 'Gene', '6391', (16, 20))
63077	32759464	2), which resulted in SDH subunits B (SDHB) mutation in one patient.	('patient', 'Species', '9606', (60, 67))	('mutation', 'Var', (44, 52))	('SDHB', 'Gene', '6390', (38, 42))	('SDH subunits B', 'Gene', '6390', (22, 36))	('resulted in', 'Reg', (10, 21))	('SDHB', 'Gene', (38, 42))	('SDH subunits B', 'Gene', (22, 36))
63090	32759464	For the treatment of metastatic paraganglioma of the younger patient, targeted radiation therapy with 131I-MIBG (metaiodobenzylguanidine) was performed twice.	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('paraganglioma', 'Disease', (32, 45))	('metaiodobenzylguanidine', 'Chemical', 'MESH:D019797', (113, 136))	('patient', 'Species', '9606', (61, 68))	('131I-MIBG', 'Var', (102, 111))	('MIBG', 'Chemical', 'MESH:D019797', (107, 111))	('paraganglioma', 'Disease', 'MESH:D010235', (32, 45))
63097	32759464	Her gene study revealed SDHB mutation, thus familial evaluation was recommended.	('revealed', 'Reg', (15, 23))	('mutation', 'Var', (29, 37))	('SDHB', 'Gene', (24, 28))	('SDHB', 'Gene', '6390', (24, 28))
63101	32759464	An etiology of paraganglioma has not been well known, however, exposure to chronic hypoxia or germ line mutation of SDH subunits are accepted as one of the etiology.	('paraganglioma', 'Disease', (15, 28))	('hypoxia', 'Disease', 'MESH:D000860', (83, 90))	('SDH', 'Gene', (116, 119))	('paraganglioma', 'Disease', 'MESH:D010235', (15, 28))	('mutation', 'Var', (104, 112))	('hypoxia', 'Disease', (83, 90))	('paraganglioma', 'Phenotype', 'HP:0002668', (15, 28))	('SDH', 'Gene', '6390', (116, 119))
63102	32759464	The mutation of SDH is known to activate chronic hypoxia pathways in the cells then induces paraganglioma from the carotid body.	('paraganglioma', 'Disease', (92, 105))	('mutation', 'Var', (4, 12))	('SDH', 'Gene', '6390', (16, 19))	('hypoxia', 'Disease', 'MESH:D000860', (49, 56))	('paraganglioma', 'Disease', 'MESH:D010235', (92, 105))	('activate', 'PosReg', (32, 40))	('hypoxia', 'Disease', (49, 56))	('SDH', 'Gene', (16, 19))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))	('induces', 'Reg', (84, 91))
63143	32759464	Genetic component also has been known as an important risk factor for malignant paraganglioma; SDHB mutation is associated with metastatic disease at an early age.	('associated with', 'Reg', (112, 127))	('malignant paraganglioma', 'Disease', (70, 93))	('SDHB', 'Gene', '6390', (95, 99))	('mutation', 'Var', (100, 108))	('malignant paraganglioma', 'Disease', 'MESH:C565335', (70, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('SDHB', 'Gene', (95, 99))	('metastatic disease', 'Disease', (128, 146))
63159	31597347	They can be separated into three different molecular clusters depending on their underlying gene mutations in any of the at least 20 known susceptibility genes: The pseudohypoxia-associated cluster 1, the kinase signaling-associated cluster 2, and the Wnt signaling-associated cluster 3.	('hypoxia', 'Disease', (171, 178))	('mutations', 'Var', (97, 106))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))
63167	31597347	Patients with known mutations in susceptibility genes tend to develop PCC/PGL at a younger age, compared with patients with sporadic tumors, in part because of biochemical and/or anatomic surveillance.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('sporadic tumors', 'Disease', (124, 139))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Patients', 'Species', '9606', (0, 8))	('PCC/PGL', 'Disease', 'MESH:D010673', (70, 77))	('sporadic tumors', 'Disease', 'MESH:D020821', (124, 139))	('PCC/PGL', 'Disease', (70, 77))	('mutations', 'Var', (20, 29))
63177	31597347	About 10% of PCCs and a significantly higher proportion:35-40%:of PGLs are metastatic, especially those due to mutations of the succinate dehydrogenase A/B (SDHA/B) gene.	('mutations', 'Var', (111, 120))	('SDHA', 'Gene', (157, 161))	('PGLs', 'Disease', (66, 70))	('PCC', 'Gene', (13, 16))	('succinate', 'Chemical', 'MESH:D013386', (128, 137))	('due to', 'Reg', (104, 110))	('metastatic', 'CPA', (75, 85))	('SDHA', 'Gene', '6389', (157, 161))	('PCC', 'Gene', '1421', (13, 16))
63183	31597347	In the most recent American Joint Committee of Cancer Staging (AJCC) guidelines a novel TNM staging for PCC/PGL was introduced, and clinical relevance has recently been validated retrospectively with PCCs and sympathetic PGLs in stage III-IV (regional lymph node metastases or invasion into surrounding tissue or distant metastases) being associated with increased PASS/GAPP scores and increased mortality, as well as aberrations in the pseudo-hypoxia pathway cluster.	('increased', 'PosReg', (355, 364))	('increased', 'PosReg', (386, 395))	('metastases', 'Disease', (321, 331))	('metastases', 'Disease', 'MESH:D009362', (263, 273))	('PCC/PGL', 'Disease', 'MESH:D010673', (104, 111))	('metastases', 'Disease', (263, 273))	('PCC', 'Gene', (104, 107))	('PASS/GAPP scores', 'MPA', (365, 381))	('aberrations', 'Var', (418, 429))	('PCC', 'Gene', (200, 203))	('PCC', 'Gene', '1421', (104, 107))	('hypoxia', 'Disease', (444, 451))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('PCC', 'Gene', '1421', (200, 203))	('TNM', 'Gene', '10178', (88, 91))	('PCC/PGL', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (444, 451))	('mortality', 'MPA', (396, 405))	('TNM', 'Gene', (88, 91))	('metastases', 'Disease', 'MESH:D009362', (321, 331))
63184	31597347	These include size (>=5-6 cm), extra-adrenal location of the primary tumor, noradrenergic/dopaminergic biochemical phenotype, mutations of the succinate dehydrogenase A and B (SDHA/B) genes, tumor multiplicity/recurrence, and age at first presentation (<20 years).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('SDHA', 'Gene', '6389', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (69, 74))	('dopamine', 'Chemical', 'MESH:D004298', (90, 98))	('tumor multiplicity', 'Disease', 'MESH:D009369', (191, 209))	('noradrenergic/dopaminergic', 'MPA', (76, 102))	('SDHA', 'Gene', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('mutations', 'Var', (126, 135))	('tumor multiplicity', 'Disease', (191, 209))	('succinate', 'Chemical', 'MESH:D013386', (143, 152))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
63189	31597347	Cluster 1 is called pseudohypoxic since it mimics cellular hypoxia: The Krebs cycle is disrupted due to mutations in several genes (SDHA[AF2]/B/C/D, FH, MDH2, and IDH) and, therefore, the Krebs cycle and oxidative phosphorylation are impaired resulting in increased cellular glycolysis.	('cellular glycolysis', 'MPA', (266, 285))	('mutations', 'Var', (104, 113))	('Krebs', 'Enzyme', (72, 77))	('Krebs cycle', 'MPA', (188, 199))	('disrupted', 'NegReg', (87, 96))	('FH', 'Gene', '2271', (149, 151))	('IDH', 'Gene', (163, 166))	('oxidative phosphorylation', 'MPA', (204, 229))	('SDHA', 'Gene', (132, 136))	('impaired', 'NegReg', (234, 242))	('IDH', 'Gene', '3417', (163, 166))	('hypoxia', 'Disease', (59, 66))	('MDH2', 'Gene', '4191', (153, 157))	('hypoxia', 'Disease', 'MESH:D000860', (59, 66))	('MDH2', 'Gene', (153, 157))	('increased', 'PosReg', (256, 265))	('SDHA', 'Gene', '6389', (132, 136))
63191	31597347	Inactivation of PHD1/2 results in less HIF-alpha hydroxylation and less HIF-alpha ubiquitination/degradation (HIF-alpha is stabilized), which is also VHL-dependent; thus, VHL mutations also lead to HIF-alpha stabilization and accumulation.	('accumulation', 'PosReg', (226, 238))	('PHD1', 'Gene', '112398', (16, 20))	('HIF-alpha stabilization', 'MPA', (198, 221))	('HIF-alpha hydroxylation', 'MPA', (39, 62))	('HIF-alpha ubiquitination/degradation', 'MPA', (72, 108))	('less', 'NegReg', (67, 71))	('VHL', 'Gene', (150, 153))	('VHL', 'Gene', (171, 174))	('PHD1', 'Gene', (16, 20))	('lead', 'Reg', (190, 194))	('VHL', 'Gene', '7428', (150, 153))	('less', 'NegReg', (34, 38))	('mutations', 'Var', (175, 184))	('VHL', 'Gene', '7428', (171, 174))	('Inactivation', 'Var', (0, 12))
63192	31597347	Via HIF-alpha stabilization and accumulation, cluster 1 mutations promote angiogenesis (VEGF/PDGF transcription amongst others), tumor invasion, metastasis and other cellular processes.	('mutations', 'Var', (56, 65))	('tumor invasion', 'Disease', 'MESH:D009361', (129, 143))	('metastasis', 'CPA', (145, 155))	('VEGF', 'Gene', (88, 92))	('angiogenesis', 'CPA', (74, 86))	('promote', 'PosReg', (66, 73))	('HIF-alpha', 'Protein', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cluster 1', 'Gene', (46, 55))	('tumor invasion', 'Disease', (129, 143))	('VEGF', 'Gene', '7422', (88, 92))
63193	31597347	PCCs/PGLs resulting especially from mutations in Krebs cycle enzyme SDHx subunits are often multiple, aggressive, metastatic, and have a poorer prognosis, compared to PCCs/PGLs bearing other susceptibility gene mutations, especially those related to cluster 2.	('PCCs/PGLs', 'Disease', 'MESH:D010673', (0, 9))	('PCCs/PGLs', 'Disease', (0, 9))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (167, 176))	('SDHx', 'Gene', (68, 72))	('mutations', 'Var', (36, 45))	('PCCs/PGLs', 'Disease', (167, 176))
63194	31597347	Cluster 1 mutations can be subdivided in pseudohypoxic Krebs cycle-related and pseudohypoxia VHL/EPAS1-related PCCs/PGLs (see above).	('pseudohypoxia VHL', 'Disease', (79, 96))	('PCCs/PGLs', 'Disease', (111, 120))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (111, 120))	('pseudohypoxia VHL', 'Disease', 'MESH:D006623', (79, 96))	('EPAS1', 'Gene', '2034', (97, 102))	('mutations', 'Var', (10, 19))	('EPAS1', 'Gene', (97, 102))	('pseudohypoxic Krebs cycle-related', 'Disease', (41, 74))
63197	31597347	These mutations lead to activation of the phosphatidylinositol-3-kinase (PI3K)/AKT, mammalian target of rapamycin (mTORC1)/p70S6 kinase (p70S6K), and RAS/RAF/ERK signaling pathway and promote cell proliferation, survival, cancer development, and angiogenesis.	('mTORC1', 'Gene', (115, 121))	('AKT', 'Gene', (79, 82))	('p70S6K', 'Gene', (137, 143))	('mTORC1', 'Gene', '382056', (115, 121))	('promote', 'PosReg', (184, 191))	('mammalian target of rapamycin', 'Gene', '2475', (84, 113))	('cell proliferation', 'CPA', (192, 210))	('angiogenesis', 'CPA', (246, 258))	('survival', 'CPA', (212, 220))	('cancer', 'Disease', (222, 228))	('AKT', 'Gene', '207', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('activation', 'PosReg', (24, 34))	('mutations', 'Var', (6, 15))	('mammalian target of rapamycin', 'Gene', (84, 113))	('p70S6K', 'Gene', '6198', (137, 143))	('RAF', 'Gene', '22882', (154, 157))	('ERK', 'Gene', (158, 161))	('phosphatidylinositol-3-kinase', 'Gene', '5295', (42, 71))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('ERK', 'Gene', '2048', (158, 161))	('RAF', 'Gene', (154, 157))	('phosphatidylinositol-3-kinase', 'Gene', (42, 71))
63198	31597347	Most of the cluster 2 mutations lead to an adrenergic biochemical phenotype with production of adrenalin (measured metabolite: metanephrine) +/- noradrenalin (measured metabolite: normetanephrine).	('lead to', 'Reg', (32, 39))	('normetanephrine', 'Chemical', 'MESH:D009647', (180, 195))	('adrenergic biochemical phenotype', 'MPA', (43, 75))	('adrenalin', 'MPA', (95, 104))	('metanephrine', 'Chemical', 'MESH:D008676', (183, 195))	('cluster 2', 'Gene', (12, 21))	('mutations', 'Var', (22, 31))	('noradrenalin', 'Chemical', 'None', (145, 157))	('metanephrine', 'Chemical', 'MESH:D008676', (127, 139))
63199	31597347	Max mutations are most likely to show an intermediate biochemical phenotype.	('mutations', 'Var', (4, 13))	('Max', 'Gene', '4149', (0, 3))	('Max', 'Gene', (0, 3))
63201	31597347	MAML3 mutations lead to overactivation of Wnt and Hedgehog signaling.	('overactivation', 'PosReg', (24, 38))	('MAML3', 'Gene', '55534', (0, 5))	('MAML3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
63202	31597347	These tumors strongly express chromogranin A. CSDE1 mutations lead to over-activation of beta-catenin, a target of Wnt signaling, and favor tumor proliferation, invasion, and metastases.	('over-activation', 'PosReg', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('favor', 'PosReg', (134, 139))	('chromogranin A', 'Gene', (30, 44))	('metastases', 'Disease', 'MESH:D009362', (175, 185))	('beta-catenin', 'Gene', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('CSDE1', 'Gene', (46, 51))	('beta-catenin', 'Gene', '1499', (89, 101))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('chromogranin A', 'Gene', '1113', (30, 44))	('metastases', 'Disease', (175, 185))	('invasion', 'CPA', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CSDE1', 'Gene', '7812', (46, 51))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', (6, 11))	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Disease', (140, 145))
63207	31597347	Somatic tumor mutations may indeed also influence prognosis, since different somatic mutations correlate with different metastatic risks in a similar manner as germline mutations do (Table 1), although, of course, this is still the subject of ongoing research.	('prognosis', 'CPA', (50, 59))	('influence', 'Reg', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('metastatic', 'CPA', (120, 130))	('tumor', 'Disease', (8, 13))	('mutations', 'Var', (14, 23))
63208	31597347	Moreover, a personalized molecular-targeted therapy approach could result from somatic mutations such as RET, NF1, HRAS, MAX, TMEM127, or those of defective pseudohypoxia signaling, much as it does from the molecular testing in other cancer entities such as differentiated thyroid carcinoma, bronchial carcinoma, or breast cancer.	('NF1', 'Gene', '4763', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('bronchial carcinoma', 'Disease', 'MESH:D002283', (292, 311))	('defective pseudohypoxia signaling', 'Disease', 'MESH:C566796', (147, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (316, 329))	('mutations', 'Var', (87, 96))	('RET', 'Gene', (105, 108))	('NF1', 'Gene', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (273, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('HRAS', 'Gene', '3265', (115, 119))	('MAX', 'Gene', (121, 124))	('breast cancer', 'Disease', 'MESH:D001943', (316, 329))	('HRAS', 'Gene', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('breast cancer', 'Disease', (316, 329))	('defective pseudohypoxia signaling', 'Disease', (147, 180))	('thyroid carcinoma', 'Disease', (273, 290))	('TMEM127', 'Gene', (126, 133))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (273, 290))	('result from', 'Reg', (67, 78))	('TMEM127', 'Gene', '55654', (126, 133))	('cancer', 'Disease', (323, 329))	('bronchial carcinoma', 'Disease', (292, 311))	('MAX', 'Gene', '4149', (121, 124))	('RET', 'Gene', '5979', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('cancer', 'Disease', (234, 240))
63218	31597347	Moreover, a substantial proportion of PCCs/PGLs in SDHx mutation carriers also appear to show some additional deficiency in the enzyme dopamine-beta-hydroxylase, which catalyzes the final step in catecholamine synthesis:the conversion of dopamine to noradrenalin; patients with such tumors show increased production of the dopamine metabolite 3-methoxytyramine.	('dopamine-beta-hydroxylase', 'Gene', (135, 160))	('SDHx', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('catecholamine', 'Chemical', 'MESH:D002395', (196, 209))	('dopamine', 'Chemical', 'MESH:D004298', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumors', 'Disease', (283, 289))	('conversion', 'MPA', (224, 234))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (343, 360))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (38, 47))	('dopamine-beta-hydroxylase', 'Gene', '1621', (135, 160))	('dopamine', 'Chemical', 'MESH:D004298', (135, 143))	('patients', 'Species', '9606', (264, 272))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('mutation', 'Var', (56, 64))	('increased', 'PosReg', (295, 304))	('PCCs/PGLs', 'Disease', (38, 47))	('deficiency', 'NegReg', (110, 120))	('noradrenalin', 'Chemical', 'None', (250, 262))	('dopamine', 'Chemical', 'MESH:D004298', (323, 331))
63221	31597347	Moreover, SDHx mutation carriers often show reduced synthesis and secretion of normetanephrine and in rare cases lack the initial rate-limiting enzyme of catecholamine synthesis (tyrosine hydroxylase); such cases may be termed non-functional or biochemically silent.	('mutation', 'Var', (15, 23))	('catecholamine', 'Chemical', 'MESH:D002395', (154, 167))	('secretion of normetanephrine', 'MPA', (66, 94))	('synthesis', 'MPA', (52, 61))	('tyrosine', 'Chemical', 'None', (179, 187))	('SDHx', 'Gene', (10, 14))	('reduced', 'NegReg', (44, 51))	('normetanephrine', 'Chemical', 'MESH:D009647', (79, 94))	('lack', 'NegReg', (113, 117))
63222	31597347	SDHx mutation carriers can therefore be diagnosed preferentially by normetanephrine and 3-methoxytyramine while, in cases of silent phenotypes, circulating chromogranin A may be a useful marker.	('chromogranin A', 'Gene', '1113', (156, 170))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (88, 105))	('normetanephrine', 'MPA', (68, 83))	('3-methoxytyramine', 'MPA', (88, 105))	('normetanephrine', 'Chemical', 'MESH:D009647', (68, 83))	('chromogranin A', 'Gene', (156, 170))	('SDHx', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
63227	31597347	Patients with chromaffin cell tumors due to cluster 2 mutations are usually diagnosed by elevations in both normetanephrine and metanephrine or only metanephrine.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('chromaffin cell tumors', 'Phenotype', 'HP:0002666', (14, 36))	('elevations', 'PosReg', (89, 99))	('mutations', 'Var', (54, 63))	('metanephrine', 'Chemical', 'MESH:D008676', (111, 123))	('metanephrine', 'Chemical', 'MESH:D008676', (128, 140))	('metanephrine', 'Chemical', 'MESH:D008676', (149, 161))	('Patients', 'Species', '9606', (0, 8))	('metanephrine', 'MPA', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('normetanephrine', 'MPA', (108, 123))	('cluster 2', 'Gene', (44, 53))	('normetanephrine', 'Chemical', 'MESH:D009647', (108, 123))
63229	31597347	Especially in the case of a history/suspicion of PGLs, metastatic disease or in SDHx mutation carriers, additional assessments of plasma 3-methoxytyramine (but not urinary 3-methoxytyramine) are useful since highly elevated 3-methoxytyramine levels may suggest the presence of metastatic tumors.	('3-methoxytyramine levels', 'MPA', (224, 248))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('carriers', 'Reg', (94, 102))	('elevated', 'PosReg', (215, 223))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (137, 154))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (224, 241))	('3-methoxytyramine', 'Chemical', 'MESH:C001746', (172, 189))	('highly elevated 3-methoxytyramine', 'Phenotype', 'HP:0030234', (208, 241))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('tumors', 'Disease', (288, 294))	('SDHx', 'Gene', (80, 84))
63233	31597347	However, for SDHx mutated PGLs, HN PGLs, metastatic disease, and small, multiple PCCs/PGLs, both CT/MRI and meta-[123I]iodobenzylguanidine ([123I]MIBG) single-photon emission computed tomography (SPECT) suffer from significantly lower sensitivity compared to more recent radionuclide imaging.	('PCCs/PGLs', 'Disease', 'MESH:D010673', (81, 90))	('[123I]MIBG', 'Chemical', 'MESH:D019797', (140, 150))	('mutated', 'Var', (18, 25))	('sensitivity', 'MPA', (235, 246))	('SDHx', 'Gene', (13, 17))	('meta-[123I]iodobenzylguanidine', 'Chemical', 'MESH:D019797', (108, 138))	('metastatic disease', 'Disease', (41, 59))	('lower', 'NegReg', (229, 234))	('PCCs/PGLs', 'Disease', (81, 90))
63234	31597347	A recent meta-analysis of pooled PCC/PGL detection by radionuclide imaging showed the highest sensitivity (93%) for 68Gallium-labeled somatostatin receptor analogs (SSAs) positron emission tomography/computed tomography ([68Ga]Ga-DOTA-SSA PET/CT), the second highest sensitivity for dihydroxy-[18F]fluorophenylalanine ([18F]FDOPA) PET/CT (80%), and the lowest sensitivity for [18F]fluorodeoxyglucose ([18F]FDG) PET/CT (74%).	('[18F]fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (376, 399))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (319, 329))	('[68Ga]Ga-DOTA-SSA', 'Var', (221, 238))	('PCC/PGL', 'Disease', 'MESH:D010673', (33, 40))	('dihydroxy-[18F]fluorophenylalanine', 'MPA', (283, 317))	('PCC/PGL', 'Disease', (33, 40))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (221, 238))	('somatostatin', 'Chemical', 'MESH:D013004', (134, 146))	('68Gallium', 'Chemical', 'MESH:D005708', (116, 125))	('dihydroxy-[18F]fluorophenylalanine', 'Chemical', 'MESH:C054651', (283, 317))	('[18F]FDG', 'Chemical', 'MESH:D019788', (401, 409))
63235	31597347	However, in order to choose the imaging modality with the highest sensitivity, it is important to consider that different sub-groups of PCC/PGL patients show different sensitivities to [68Ga]Ga-DOTA-SSAs, [18F]FDOPA, and [18F]FDG PET/CT, respectively.	('[18F', 'Var', (205, 209))	('PCC/PGL', 'Disease', (136, 143))	('PCC/PGL', 'Disease', 'MESH:D010673', (136, 143))	('[18F]FDG', 'Chemical', 'MESH:D019788', (221, 229))	('[68Ga]Ga-DOTA-SSAs', 'Var', (185, 203))	('patients', 'Species', '9606', (144, 152))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (205, 215))	('[18F]FDG', 'Var', (221, 229))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (185, 202))
63236	31597347	The sensitivities to the different imaging modalities depend on the presence of PGL versus PCC, HN PGLs, sporadic metastatic, or non-metastatic disease, cluster 1 Krebs cycle-related SDHx mutations and VHL/EPAS1 pseudohypoxia-related mutations or cluster 2 kinase signaling-associated mutations (Table 2).	('mutations', 'Var', (188, 197))	('PGL', 'Disease', (80, 83))	('hypoxia', 'Disease', (218, 225))	('hypoxia', 'Disease', 'MESH:D000860', (218, 225))	('EPAS1', 'Gene', '2034', (206, 211))	('PCC', 'Gene', '1421', (91, 94))	('VHL', 'Gene', (202, 205))	('EPAS1', 'Gene', (206, 211))	('SDHx', 'Gene', (183, 187))	('non-metastatic disease', 'Disease', (129, 151))	('VHL', 'Gene', '7428', (202, 205))	('PCC', 'Gene', (91, 94))
63237	31597347	Metastatic SDHB-related PCCs/PGLs ([68Ga]Ga-DOTA-SSA 99% vs. [18F]FDOPA 61% vs. [18F]FDG PET/CT 86%); SDHA-related PCCs/PGLs (highest lesion detection sensitivity: [68Ga]Ga-DOTA-SSA > [18F]FDG > [18F]FDOPA PET/CT); SDHD-related PCCs/PGLs ([68Ga]Ga-DOTA-SSA 99% vs. [18F]FDOPA 87% vs. [18F]FDG PET/CT 62%); Pediatric SDHx-related PGLs/PCCs ([68Ga]Ga-DOTA-SSA 94% vs. [18F]FDG PET/CT 79%); HN PGLs (frequently SDHD-related) ([68Ga]Ga-DOTA-SSA 100% vs. [18F]FDOPA 97% vs. [18F]FDG PET/CT 71%); PGLs [pooled lesion-based sensitivity of [68Ga]Ga-DOTA-SSA PET/CT was higher, compared to [18F]FDOPA PET/CT in two different studies ([68Ga]Ga-DOTA-SSA 99% and 100% vs. [18F]FDOPA PET/CT 68% and 71%, respectively)]; Sporadic metastatic PCCs/PGLs ([68Ga]Ga-DOTA-SSA 98% vs. [18F]FDOPA 75% vs. [18F]FDG PET/CT 49%).	('PCC', 'Gene', (727, 730))	('SDHB', 'Gene', (11, 15))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (660, 670))	('SDHD', 'Gene', '6392', (215, 219))	('PCCs/PGLs', 'Disease', (115, 124))	('[18F]FDG', 'Chemical', 'MESH:D019788', (80, 88))	('[18F]FDG', 'Chemical', 'MESH:D019788', (284, 292))	('PCC', 'Gene', '1421', (727, 730))	('PCC', 'Gene', (115, 118))	('SDHD', 'Gene', (408, 412))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (164, 181))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (24, 33))	('SDHD', 'Gene', (215, 219))	('CT 68', 'Gene', '166863', (675, 680))	('[18F]FDG', 'Chemical', 'MESH:D019788', (366, 374))	('PCC', 'Gene', '1421', (115, 118))	('PCC', 'Gene', (334, 337))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (61, 71))	('[18F]FDG', 'Chemical', 'MESH:D019788', (783, 791))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (195, 205))	('SDHA', 'Gene', (102, 106))	('PCCs/PGLs', 'Disease', (24, 33))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (423, 440))	('CT 68', 'Gene', (675, 680))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (35, 52))	('PCC', 'Gene', '1421', (334, 337))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (450, 460))	('PCC', 'Gene', (24, 27))	('SDHA', 'Gene', '6389', (102, 106))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (239, 256))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (532, 549))	('SDHB', 'Gene', '6390', (11, 15))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (228, 237))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (727, 736))	('PCC', 'Gene', (228, 231))	('PCC', 'Gene', '1421', (24, 27))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (581, 591))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (265, 275))	('PCC', 'Gene', '1421', (228, 231))	('[18F]FDOPA', 'Chemical', 'MESH:C043437', (764, 774))	('[18F]FDG', 'Chemical', 'MESH:D019788', (184, 192))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (115, 124))	('[18F]FDG', 'Chemical', 'MESH:D019788', (469, 477))	('[68Ga]Ga-DOTA-SSA', 'Var', (738, 755))	('PCCs/PGLs', 'Disease', (228, 237))	('PCCs/PGLs', 'Disease', (727, 736))	('SDHD', 'Gene', '6392', (408, 412))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (738, 755))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (340, 357))	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (625, 642))
63241	31597347	For HN PGLs, sporadic sympathetic PGLs, metastatic tumors, and SDHx-related PCCs/PGLs, [68Ga]Ga-DOTA-SSA PET/CT should be the first choice radionuclide imaging for diagnosis, staging, and follow-up (Table 1 and Table 2).	('[68Ga]Ga-DOTA-SSA', 'Chemical', 'MESH:C043055', (87, 104))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HN PGLs', 'Disease', (4, 11))	('PCCs/PGLs', 'Disease', (76, 85))	('SDHx-related', 'Disease', (63, 75))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (76, 85))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('[68Ga]Ga-DOTA-SSA', 'Var', (87, 104))
63256	31597347	Moreover, extra-adrenal location, a noradrenergic or dopaminergic biochemical phenotype, high chromogranin A levels, young age <20 years, multiplicity, and, most importantly, pseudohypoxic cluster 1-related germline mutations (especially SDHA/B), are associated with a higher metastatic risk and an adverse prognosis once metastasis is found.	('chromogranin A', 'Gene', (94, 108))	('SDHA', 'Gene', '6389', (238, 242))	('metastatic', 'CPA', (276, 286))	('dopamine', 'Chemical', 'MESH:D004298', (53, 61))	('SDHA', 'Gene', (238, 242))	('noradrenergic', 'MPA', (36, 49))	('mutations', 'Var', (216, 225))	('chromogranin A', 'Gene', '1113', (94, 108))
63265	31597347	We suggest especially radionuclide imaging three-four months after presumed complete resection of a metastatic/multiple PCC, any PGL, or high-risk (SDHA/B) mutation carrier in the case of post-operative abnormal biochemistry or non-functional tumor (Table 3).	('SDHA', 'Gene', '6389', (148, 152))	('mutation', 'Var', (156, 164))	('PCC', 'Gene', (120, 123))	('SDHA', 'Gene', (148, 152))	('metastatic/multiple', 'Disease', (100, 119))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('PGL', 'Gene', (129, 132))	('PCC', 'Gene', '1421', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
63268	31597347	For patients with high-risk mutations (especially SDHA/B), we suggest clinical/biochemical control every six months and MRI every one-two years (consider CT for suspected lung involvement or use an alternate approach using CT and MRI).	('SDHA', 'Gene', '6389', (50, 54))	('lung involvement', 'Disease', (171, 187))	('SDHA', 'Gene', (50, 54))	('patients', 'Species', '9606', (4, 12))	('lung involvement', 'Disease', 'MESH:D008171', (171, 187))	('mutations', 'Var', (28, 37))
63273	31597347	The international multicenter prospective cohort study PROSPHEO including patients with a history of PCC/PGL, newly-diagnosed PCC/PGL, or mutations in PCC/PGL susceptibility genes from different centers in Germany and Switzerland over 18 years may eventually be able to answer questions concerning benefits of follow-up surveillance as well as the optimal follow-up procedures.	('PCC/PGL', 'Disease', 'MESH:D010673', (101, 108))	('PCC/PGL', 'Disease', (101, 108))	('patients', 'Species', '9606', (74, 82))	('PCC/PGL', 'Disease', (126, 133))	('PCC/PGL', 'Disease', 'MESH:D010673', (126, 133))	('PCC/PGL', 'Disease', 'MESH:D010673', (151, 158))	('PCC/PGL', 'Disease', (151, 158))	('mutations', 'Var', (138, 147))
63279	31597347	Watchful waiting with frequent follow-up may be the optimal initial approach in patients with non-functioning HN PGL, especially without evidence of significant tumor growth and/or compression of surrounding structures.	('patients', 'Species', '9606', (80, 88))	('non-functioning', 'Var', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HN PGL', 'Gene', (110, 116))	('tumor', 'Disease', (161, 166))
63287	31597347	Nevertheless, perioperative hypertension seems to be slightly better controlled with phenoxybenzamine (especially in those patients with high catecholamine or metanephrine levels), although with more pronounced postoperative hypotension.	('hypotension', 'Disease', 'MESH:D007022', (225, 236))	('perioperative', 'Disease', (14, 27))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (85, 101))	('metanephrine', 'Chemical', 'MESH:D008676', (159, 171))	('catecholamine', 'Chemical', 'MESH:D002395', (142, 155))	('better', 'PosReg', (62, 68))	('hypotension', 'Disease', (225, 236))	('hypertension', 'Disease', 'MESH:D006973', (28, 40))	('patients', 'Species', '9606', (123, 131))	('phenoxybenzamine', 'Var', (85, 101))	('high catecholamine', 'Phenotype', 'HP:0003334', (137, 155))	('hypertension', 'Disease', (28, 40))	('hypotension', 'Phenotype', 'HP:0002615', (225, 236))	('hypertension', 'Phenotype', 'HP:0000822', (28, 40))
63294	31597347	In two of these studies, the mean progression-free survival (PFS) of [131I]MIBG treated patients was 23.1 and 28.5 months, respectively.	('[131I]', 'Var', (69, 75))	('patients', 'Species', '9606', (88, 96))	('MIBG', 'Gene', (75, 79))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (69, 79))
63303	31597347	Of the 68 patients who received at least one therapeutic dose of HSA [131I]MIBG, 17 (25%) had a durable reduction in baseline anti-hypertensive medication use.	('reduction', 'NegReg', (104, 113))	('anti-hypertensive medication', 'Phenotype', 'HP:0000822', (126, 154))	('hypertensive', 'Disease', 'MESH:D006973', (131, 143))	('HSA [131I]MIBG', 'Var', (65, 79))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (69, 79))	('patients', 'Species', '9606', (10, 18))	('hypertensive', 'Disease', (131, 143))
63310	31597347	Although most studies consist of small numbers and limited follow-up, in one direct comparison study the percentage of patients with tumors showing disease stabilization was significantly greater after PRRT using [177Lu]Lu-DOTA(Tyr3)octreotate (TATE) (100%) compared to [131I]MIBG (62.5%), with a longer PFS/OS of 38.5/60.8 months in the [177Lu]Lu-DOTATATE group versus 20.6/41.2 months in the [131I]MIBG group.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (270, 280))	('[177Lu]Lu-DOTA(Tyr3)octreotate', 'Chemical', 'MESH:C554548', (213, 243))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('[177Lu]Lu-DOTATATE', 'Var', (338, 356))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (394, 404))	('[177Lu]Lu-DOTATATE', 'Chemical', 'MESH:C447941', (338, 356))	('[177Lu]Lu-DOTA', 'Var', (213, 227))	('TATE', 'Chemical', 'MESH:C554548', (245, 249))	('disease stabilization', 'CPA', (148, 169))	('TATE', 'Chemical', 'MESH:C554548', (352, 356))	('greater', 'PosReg', (188, 195))
63311	31597347	The benefit of [177Lu]Lu-DOTATATE, compared to [131I]MIBG, regarding PFS and OS was even stronger in the subgroup of PGLs (PFS/OS [177Lu]Lu-DOTATATE: 22.8/60.8, PFS/OS [131I]MIBG: 14.4/38.5).	('PFS', 'Disease', (69, 72))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (47, 57))	('PFS/OS [177Lu]Lu-DOTATATE', 'Var', (123, 148))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (168, 178))	('[177Lu]Lu-DOTATATE', 'Var', (15, 33))	('[177Lu]Lu-DOTATATE', 'Chemical', 'MESH:C447941', (15, 33))	('[177Lu]Lu-DOTATATE', 'Chemical', 'MESH:C447941', (130, 148))
63312	31597347	Further clinically controlled studies (e.g., NCT04029428, NCT03923257, NCT03206060) should be awaited with regard to recommendations and guidelines, including the selection of the radionuclide (90Y, 177Lu; another potential future option is the use of alpha-emitting radionuclides), doses and dose regimens, but also the consideration of specific risk constellations (nephrotoxicity, patient age, co-medication with SSA).	('patient', 'Species', '9606', (384, 391))	('NCT03206060', 'Var', (71, 82))	('nephrotoxicity', 'Disease', (368, 382))	('nephrotoxicity', 'Disease', 'MESH:D007674', (368, 382))	('NCT04029428', 'Var', (45, 56))	('177Lu', 'Chemical', 'MESH:C575017', (199, 204))	('NCT03923257', 'Chemical', 'MESH:C079985', (58, 69))
63319	31597347	Very recently, HSA [131I]MIBG (Azedra) has been FDA-approved in the United States for the treatment of metastatic PCC/PGL.	('HSA [131I]MIBG', 'Var', (15, 29))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (19, 29))	('PCC/PGL', 'Disease', (114, 121))	('PCC/PGL', 'Disease', 'MESH:D010673', (114, 121))
63320	31597347	However, HSA [131I]MIBG was associated with a higher rate of hematologic toxicity although it can result in long-lasting disease stabilization and it may be preferable in patients with good bone marrow reserve.	('hematologic toxicity', 'Disease', (61, 81))	('[131I]MIBG', 'Chemical', 'MESH:D019797', (13, 23))	('patients', 'Species', '9606', (171, 179))	('HSA [131I]MIBG', 'Var', (9, 23))	('hematologic toxicity', 'Disease', 'MESH:D006402', (61, 81))	('good bone marrow', 'Phenotype', 'HP:0005528', (185, 201))
63328	31597347	Prolonged CVD chemotherapy (median of 20.5 cycles) in 12 patients with SDHB mutations led to a total response in 83% of patients [partial response 8/12 (66.7%) patients, complete response 2/12 (16.7%) patients, assessed by Response Evaluation Criteria in Solid Tumors (RECIST)] and a PFS/OS of 930 and 1190 days, respectively.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (160, 168))	('mutations', 'Var', (76, 85))	('SDHB', 'Gene', '6390', (71, 75))	('patients', 'Species', '9606', (57, 65))	('Tumors', 'Phenotype', 'HP:0002664', (261, 267))	('Solid Tumors', 'Disease', 'MESH:D009369', (255, 267))	('SDHB', 'Gene', (71, 75))	('Solid Tumors', 'Disease', (255, 267))	('patients', 'Species', '9606', (120, 128))
63330	31597347	Monotherapy with the DNA-alkylating chemotherapeutic temozolomide, an oral metabolite of dacarbazine, showed a partial response (33%) or stable disease (47%) in a total of 80% of patients with SDHB mutations, and thus may be used as a single agent treatment, or alternatively could be considered as a maintenance regime for tumor stabilization subsequent to six-nine cycles of CVD chemotherapy (150 mg/m2 on days 1-5, at 28 day intervals).	('SDHB', 'Gene', '6390', (193, 197))	('SDHB', 'Gene', (193, 197))	('temozolomide', 'Chemical', 'MESH:C047246', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('tumor', 'Disease', (324, 329))	('dacarbazine', 'Chemical', 'MESH:D003606', (89, 100))	('mutations', 'Var', (198, 207))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
63331	31597347	Down-regulation of the DNA repairing enzyme O-6-methylguanine-DNA methyltransferase (MGMT) via hypermethylation in SDHB mutated tumors appears to lead to increased susceptibility of SDHB-related PCCs/PGLs to temozolomide.	('PCCs/PGLs', 'Disease', 'MESH:D010673', (195, 204))	('SDHB', 'Gene', '6390', (115, 119))	('O-6-methylguanine-DNA methyltransferase', 'Gene', (44, 83))	('temozolomide', 'Chemical', 'MESH:C047246', (208, 220))	('SDHB', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Down-regulation', 'NegReg', (0, 15))	('tumors', 'Disease', (128, 134))	('MGMT', 'Gene', (85, 89))	('hypermethylation', 'Var', (95, 111))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('O-6-methylguanine-DNA methyltransferase', 'Gene', '4255', (44, 83))	('MGMT', 'Gene', '4255', (85, 89))	('SDHB', 'Gene', '6390', (182, 186))	('PCCs/PGLs', 'Disease', (195, 204))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutated', 'Var', (120, 127))	('SDHB', 'Gene', (182, 186))
63335	31597347	On a case-by-case decision, prolonged treatment with CVD chemotherapy with 20 cycles of CVD is suggested, especially in the case of patients with SDHB mutations.	('patients', 'Species', '9606', (132, 140))	('SDHB', 'Gene', '6390', (146, 150))	('mutations', 'Var', (151, 160))	('SDHB', 'Gene', (146, 150))
63338	31597347	They all have anti-angiogenic effects and may be interesting therapy options for cluster 1 and cluster 2 mutated PCCs/PGLs.	('PCCs/PGLs', 'Disease', (113, 122))	('mutated', 'Var', (105, 112))	('anti-angiogenic effects', 'CPA', (14, 37))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (113, 122))
63345	31597347	A total of 6/8 (75%) of the patients with stable disease or partial responses in this study were SDHB mutation carriers, indicating clinical benefit especially for SDHB-related PCCs/PGLs.	('SDHB', 'Gene', (97, 101))	('mutation', 'Var', (102, 110))	('benefit', 'PosReg', (141, 148))	('SDHB', 'Gene', '6390', (164, 168))	('PCCs/PGLs', 'Disease', (177, 186))	('PCCs/PGLs', 'Disease', 'MESH:D010673', (177, 186))	('patients', 'Species', '9606', (28, 36))	('SDHB', 'Gene', (164, 168))	('SDHB', 'Gene', '6390', (97, 101))
63348	31597347	The RET-mutated patient with MEN2A was still on sunitinib therapy by the time the study was published (after 64 cycles) which may implicate that RET and SDHx mutation carriers as benefiting the most.	('SDHx', 'Gene', (153, 157))	('RET', 'Gene', '5979', (145, 148))	('MEN2A', 'Gene', '5979', (29, 34))	('mutation', 'Var', (158, 166))	('RET', 'Gene', (4, 7))	('MEN2A', 'Gene', (29, 34))	('RET', 'Gene', (145, 148))	('sunitinib', 'Chemical', 'MESH:C473478', (48, 57))	('patient', 'Species', '9606', (16, 23))	('RET', 'Gene', '5979', (4, 7))
63374	31610522	MRI showed a 30 mm tumor on the interaortocaval region and 123I-MIBG concentrated in this area.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('123I-MIBG', 'Chemical', 'MESH:D019797', (59, 68))	('123I-MIBG', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
63383	31610522	All are caused by mutations in the rearranged duringtransfection (RET) gene and are inherited in an autosomal dominant fashion.	('caused by', 'Reg', (8, 17))	('RET', 'Gene', '5979', (66, 69))	('RET', 'Gene', (66, 69))	('mutations', 'Var', (18, 27))
63397	31610522	123I-MIBG was concentrated in bilateral adrenal tumors and the patient was diagnosed with bilateral PCCs.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('123I-MIBG', 'Var', (0, 9))	('123I-MIBG', 'Chemical', 'MESH:D019797', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('adrenal tumors', 'Disease', (40, 54))	('PCCs', 'Disease', 'MESH:D010673', (100, 104))	('PCCs', 'Phenotype', 'HP:0002666', (100, 104))	('patient', 'Species', '9606', (63, 70))	('PCCs', 'Disease', (100, 104))	('PCC', 'Phenotype', 'HP:0002666', (100, 103))	('adrenal tumors', 'Disease', 'MESH:D000310', (40, 54))
63404	31610522	Additionally, 123I-MIBG newly concentrated in the tumor (Fig.	('123I-MIBG', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('123I-MIBG', 'Chemical', 'MESH:D019797', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
63426	31610522	Multiple endocrine neoplasia type 2A is a multiple endocrine neoplasia syndrome caused by germ-line activating RET proto-oncogene mutations and characterized by medullary thyroid cancer and PCC.	('multiple endocrine neoplasia syndrome', 'Disease', (42, 79))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('neoplasia', 'Phenotype', 'HP:0002664', (19, 28))	('Multiple endocrine neoplasia type 2A', 'Gene', (0, 36))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (51, 70))	('PCC', 'Disease', 'MESH:D010673', (190, 193))	('RET', 'Gene', '5979', (111, 114))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('caused by', 'Reg', (80, 89))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (161, 185))	('PCC', 'Disease', (190, 193))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (9, 28))	('PCC', 'Phenotype', 'HP:0002666', (190, 193))	('Multiple endocrine neoplasia type 2A', 'Gene', '5979', (0, 36))	('RET', 'Gene', (111, 114))	('thyroid cancer', 'Disease', (171, 185))	('mutations', 'Var', (130, 139))	('multiple endocrine neoplasia syndrome', 'Disease', 'MESH:D009377', (42, 79))	('neoplasia', 'Phenotype', 'HP:0002664', (61, 70))
63427	31610522	Approximately 50% of patients with the RET mutation develop PCC.	('RET', 'Gene', (39, 42))	('mutation', 'Var', (43, 51))	('PCC', 'Disease', 'MESH:D010673', (60, 63))	('PCC', 'Phenotype', 'HP:0002666', (60, 63))	('PCC', 'Disease', (60, 63))	('patients', 'Species', '9606', (21, 29))	('RET', 'Gene', '5979', (39, 42))
63560	29113559	To date, 17 studies from the NTP have reported xenobiotic-induced mesotheliomas in F344 rats; the F344 rat is particularly sensitive to developing this tumor type and is the only rodent strain reported to develop mesothelioma following xenobiotic exposure by a route other than peritoneal injection.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('rat', 'Species', '10116', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mesothelioma', 'Disease', (213, 225))	('mesotheliomas', 'Disease', 'MESH:D008654', (66, 79))	('rat', 'Species', '10116', (88, 91))	('mesotheliomas', 'Disease', (66, 79))	('mesothelioma', 'Disease', (66, 78))	('tumor', 'Disease', (152, 157))	('xenobiotic-', 'Phenotype', 'HP:0031838', (47, 58))	('develop', 'PosReg', (205, 212))	('mesothelioma', 'Disease', 'MESH:D008654', (213, 225))	('NTP', 'Chemical', '-', (29, 32))	('F344', 'Var', (98, 102))	('mesothelioma', 'Disease', 'MESH:D008654', (66, 78))	('rats', 'Species', '10116', (88, 92))
63586	29113559	The causative frame-disrupting mutations of the DMD gene precludes the full translation of its protein product, dystrophin, causing progressive muscle disease.	('mutations', 'Var', (31, 40))	('causing', 'Reg', (124, 131))	('frame-disrupting', 'Reg', (14, 30))	('full translation', 'MPA', (71, 87))	('precludes', 'NegReg', (57, 66))	('muscle disease', 'Disease', (144, 158))	('muscle disease', 'Disease', 'MESH:D009135', (144, 158))	('DMD gene', 'Gene', (48, 56))
63662	29113559	A classic seminoma would be positive for OCT4 and D2-40 whereas a spermatocytic tumor would be negative for both.	('seminoma', 'Disease', 'MESH:D018239', (10, 18))	('spermatocytic tumor', 'Disease', 'MESH:C563236', (66, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('positive', 'Reg', (28, 36))	('seminoma', 'Disease', (10, 18))	('D2-40', 'Var', (50, 55))	('OCT4', 'Protein', (41, 45))	('spermatocytic tumor', 'Disease', (66, 85))
63952	26460615	Deciphering the molecular basis of invasiveness in Sdhb-deficient cells Metastatic pheochromocytomas and paragangliomas (PPGL) are malignant neuroendocrine tumors frequently associated with germline mutations in the SDHB gene.	('Metastatic pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (72, 119))	('Sdhb', 'Gene', '6390', (51, 55))	('paragangliomas', 'Phenotype', 'HP:0002668', (105, 119))	('associated', 'Reg', (174, 184))	('germline mutations', 'Var', (190, 208))	('malignant neuroendocrine tumors', 'Disease', 'MESH:D018358', (131, 162))	('Sdhb', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('malignant neuroendocrine tumors', 'Disease', (131, 162))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (141, 162))	('PGL', 'Disease', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))	('SDHB', 'Gene', (216, 220))	('PGL', 'Disease', 'MESH:D010235', (122, 125))
63954	26460615	In the present study, we report the characterization of a unique model of Sdhb knockout in mouse chromaffin cells.	('chromaffin', 'Chemical', '-', (97, 107))	('mouse', 'Species', '10090', (91, 96))	('Sdhb', 'Gene', (74, 78))	('knockout', 'Var', (79, 87))
63955	26460615	This phenotype is associated with the modulation of Twist1, Twist2, Tcf3, Snai1, N-cadherin or Krt19 expression, reflecting an EMT-like reprogramming of cells.	('Twist1', 'Gene', (52, 58))	('modulation', 'Var', (38, 48))	('Twist2', 'Gene', (60, 66))	('N-cadherin', 'Gene', '1000', (81, 91))	('Twist2', 'Gene', '117581', (60, 66))	('Krt19', 'Gene', (95, 100))	('Snai1', 'Gene', '6615', (74, 79))	('Tcf3', 'Gene', (68, 72))	('Twist1', 'Gene', '7291', (52, 58))	('Tcf3', 'Gene', '6929', (68, 72))	('Snai1', 'Gene', (74, 79))	('N-cadherin', 'Gene', (81, 91))
63958	26460615	In about 40% of cases, PPGL are inherited, which implies that a germline mutation has been identified in one of the 13 known PPGL predisposition genes: the RET and HIF2A proto-oncogenes and the NF1, VHL, SDHx (SDHA, SDHB, SDHC, SDHD and SDHAF2), MAX, TMEM127, FH and MDH2 tumor suppressor genes.	('SDHC', 'Gene', (222, 226))	('PGL', 'Disease', 'MESH:D010235', (126, 129))	('SDH', 'Gene', '6390', (216, 219))	('FH', 'Disease', 'MESH:D006938', (260, 262))	('HIF2A', 'Gene', '2034', (164, 169))	('VHL', 'Disease', 'MESH:D006623', (199, 202))	('SDH', 'Gene', (210, 213))	('MDH2 tumor', 'Disease', 'MESH:D009369', (267, 277))	('HIF2A', 'Gene', (164, 169))	('PGL', 'Disease', (24, 27))	('SDH', 'Gene', '6390', (237, 240))	('SDH', 'Gene', '6390', (228, 231))	('SDH', 'Gene', (216, 219))	('SDH', 'Gene', '6390', (222, 225))	('TMEM127', 'Gene', (251, 258))	('PGL', 'Disease', (126, 129))	('mutation', 'Var', (73, 81))	('SDHD', 'Gene', '6392', (228, 232))	('SDHAF2', 'Gene', '54949', (237, 243))	('SDHC', 'Gene', '6391', (222, 226))	('SDHAF2', 'Gene', (237, 243))	('SDH', 'Gene', (237, 240))	('NF1', 'Gene', '4763', (194, 197))	('SDHA', 'Gene', (237, 241))	('RET', 'Gene', '5979', (156, 159))	('VHL', 'Disease', (199, 202))	('SDH', 'Gene', '6390', (204, 207))	('SDHA', 'Gene', '6389', (237, 241))	('SDH', 'Gene', (228, 231))	('TMEM127', 'Gene', '55654', (251, 258))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('SDH', 'Gene', (222, 225))	('SDH', 'Gene', '6390', (210, 213))	('PGL', 'Disease', 'MESH:D010235', (24, 27))	('NF1', 'Gene', (194, 197))	('SDHA', 'Gene', (210, 214))	('SDHD', 'Gene', (228, 232))	('MDH2 tumor', 'Disease', (267, 277))	('SDHA', 'Gene', '6389', (210, 214))	('RET', 'Gene', (156, 159))	('SDH', 'Gene', (204, 207))
63961	26460615	Patients carrying an SDHB mutation are more likely to develop a metastatic form of their disease with a median survival substantially reduced, compared to patients without SDHB mutation.	('mutation', 'Var', (26, 34))	('patients', 'Species', '9606', (155, 163))	('Patients', 'Species', '9606', (0, 8))	('reduced', 'NegReg', (134, 141))	('develop', 'PosReg', (54, 61))	('SDHB', 'Gene', (21, 25))	('metastatic', 'CPA', (64, 74))
63969	26460615	KRT19 extinction is due to the methylation of its promoter, as described in uterine leiomyoma, renal cell carcinoma, as well as in neuroblastoma, another neural crest cell derived tumor.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('neuroblastoma', 'Disease', (131, 144))	('KRT19', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('renal cell carcinoma', 'Disease', (95, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (95, 115))	('neuroblastoma', 'Disease', 'MESH:D009447', (131, 144))	('tumor', 'Disease', (180, 185))	('neuroblastoma', 'Phenotype', 'HP:0003006', (131, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('leiomyoma', 'Disease', (84, 93))	('methylation', 'Var', (31, 42))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (76, 93))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (95, 115))	('leiomyoma', 'Disease', 'MESH:D007889', (84, 93))
63971	26460615	We and others, recently demonstrated that mutations in SDHx genes (encoding succinate dehydrogenase subunits) lead to succinate accumulation, which inhibits DNA demethylases (TET enzymes), leading to a global hypermethylation of DNA.	('succinate', 'Chemical', 'MESH:D019802', (76, 85))	('SDH', 'Gene', '6390', (55, 58))	('succinate', 'Chemical', 'MESH:D019802', (118, 127))	('succinate dehydrogenase', 'Gene', '6390', (76, 99))	('inhibits', 'NegReg', (148, 156))	('succinate dehydrogenase', 'Gene', (76, 99))	('SDH', 'Gene', (55, 58))	('mutations', 'Var', (42, 51))	('succinate accumulation', 'MPA', (118, 140))
63972	26460615	In SDHB-mutated PPGL and in Sdhb-/- immortalized mouse chromaffin cells (imCC), we demonstrated that KRT19 was one of the most hypermethylated and down-regulated gene.	('PGL', 'Disease', 'MESH:D010235', (17, 20))	('down-regulated', 'NegReg', (147, 161))	('chromaffin', 'Chemical', '-', (55, 65))	('mouse', 'Species', '10090', (49, 54))	('KRT19', 'Gene', (101, 106))	('PGL', 'Disease', (17, 20))	('SDHB-mutated', 'Var', (3, 15))
63973	26460615	Following these observations, we evaluated here the consequences of SDHB loss and the role of KRT19 in the establishment of a metastatic phenotype following in vitro inactivation of Sdhb in murine chromaffin cells.	('loss', 'NegReg', (73, 77))	('murine', 'Species', '10090', (190, 196))	('Sdhb', 'Gene', (182, 186))	('inactivation', 'Var', (166, 178))	('SDHB', 'Gene', (68, 72))	('chromaffin', 'Chemical', '-', (197, 207))
63978	26460615	Using qRT-PCR, we validated that the expression of the main markers of EMT, Twist1, Twist2, Tcf3 and Snai1 were significantly increased, while N-cadherin and Krt19's expression were significantly decreased in Sdhb-/- imCC (Figure 2B and 3C).	('Twist2', 'Gene', '117581', (84, 90))	('Twist1', 'Gene', (76, 82))	('Snai1', 'Gene', '6615', (101, 106))	('N-cadherin', 'Gene', (143, 153))	('decreased', 'NegReg', (196, 205))	('Tcf3', 'Gene', (92, 96))	('expression', 'MPA', (166, 176))	('N-cadherin', 'Gene', '1000', (143, 153))	('Sdhb-/- imCC', 'Var', (209, 221))	('Snai1', 'Gene', (101, 106))	('Twist2', 'Gene', (84, 90))	('expression', 'MPA', (37, 47))	('increased', 'PosReg', (126, 135))	('Tcf3', 'Gene', '6929', (92, 96))	('Twist1', 'Gene', '7291', (76, 82))
63980	26460615	Interestingly, transcriptome analyses showed a significant overexpression of Cd24a, Muc1, Lgals3, Lgals3bp, Lgals9, Ptk2 and integrins alpha1, alpha8, alpha11, beta3 and beta5 mRNAs in Sdhb-/- imCC compared to WT cells (Supplementary Figure 3), underscoring the high adherent properties of Sdhb-deficient cells.	('Lgals3', 'Gene', (98, 104))	('Muc1', 'Gene', '4582', (84, 88))	('Lgals3', 'Gene', '3958', (90, 96))	('Muc1', 'Gene', (84, 88))	('Cd24a', 'Gene', (77, 82))	('Lgals3bp', 'Gene', (98, 106))	('Sdhb-/- imCC', 'Var', (185, 197))	('Lgals3', 'Gene', (90, 96))	('overexpression', 'PosReg', (59, 73))	('Lgals9', 'Gene', (108, 114))	('Ptk2', 'Gene', (116, 120))	('Lgals3', 'Gene', '3958', (98, 104))	('Lgals3bp', 'Gene', '3959', (98, 106))	('alpha1, alpha8, alpha11, beta3 and beta5', 'Gene', '1934', (135, 175))	('Lgals9', 'Gene', '3965', (108, 114))	('Cd24a', 'Gene', '100133941', (77, 82))	('Ptk2', 'Gene', '5747', (116, 120))
63983	26460615	Altogether, these data established that loss of SDHB promotes a transcriptional reprogramming that is associated with an EMT phenotype in the mouse chromaffin cell line.	('transcriptional reprogramming', 'CPA', (64, 93))	('promotes', 'PosReg', (53, 61))	('mouse', 'Species', '10090', (142, 147))	('loss', 'Var', (40, 44))	('chromaffin', 'Chemical', '-', (148, 158))	('SDHB', 'Gene', (48, 52))
63988	26460615	In the present study, we demonstrate that Sdhb inactivation alone is sufficient to promote the in vitro transformation of mouse chromaffin cells into invasive cells.	('inactivation', 'Var', (47, 59))	('in vitro transformation', 'CPA', (95, 118))	('chromaffin', 'Chemical', '-', (128, 138))	('Sdhb', 'Gene', (42, 46))	('promote', 'PosReg', (83, 90))	('mouse', 'Species', '10090', (122, 127))
63989	26460615	We show that Sdhb knockout leads to a molecular reprogramming compatible with the activation of an EMT-like process, as highlighted by both transcriptional and protein modulations of Twist1/2, Tcf3, Snai1, N-cadherin and Krt19, previously shown to be differentially expressed in SDHB-malignant human PPGL.	('Sdhb', 'Gene', (13, 17))	('human', 'Species', '9606', (294, 299))	('Snai1', 'Gene', (199, 204))	('Tcf3', 'Gene', (193, 197))	('molecular reprogramming', 'CPA', (38, 61))	('PGL', 'Disease', (301, 304))	('N-cadherin', 'Gene', (206, 216))	('Twist1/2', 'Gene', '7291;117581', (183, 191))	('N-cadherin', 'Gene', '1000', (206, 216))	('PGL', 'Disease', 'MESH:D010235', (301, 304))	('Twist1/2', 'Gene', (183, 191))	('Tcf3', 'Gene', '6929', (193, 197))	('knockout', 'Var', (18, 26))	('Snai1', 'Gene', '6615', (199, 204))	('Krt19', 'Gene', (221, 226))
63992	26460615	While mutations in the 4 SDHx genes lead to a complete loss of SDH activity and predispose to PPGL, it is still unclear why SDHB inactivation only is responsible for metastatic forms of the disease.	('SDH', 'Gene', '6390', (63, 66))	('loss', 'NegReg', (55, 59))	('SDH', 'Gene', '6390', (124, 127))	('predispose', 'Reg', (80, 90))	('PGL', 'Disease', (95, 98))	('SDH', 'Gene', (25, 28))	('SDH', 'Gene', (63, 66))	('activity', 'MPA', (67, 75))	('SDH', 'Gene', (124, 127))	('PGL', 'Disease', 'MESH:D010235', (95, 98))	('mutations', 'Var', (6, 15))	('SDH', 'Gene', '6390', (25, 28))
63993	26460615	Our results in the Sdhb knockout cell model are in favor of the second one and suggest that SDHB inactivation is sufficient to induce both PPGL tumorigenesis and the EMT-associated metastatic phenotype.	('PGL', 'Disease', 'MESH:D010235', (140, 143))	('tumor', 'Disease', (144, 149))	('induce', 'PosReg', (127, 133))	('SDHB', 'Gene', (92, 96))	('PGL', 'Disease', (140, 143))	('inactivation', 'Var', (97, 109))	('EMT-associated metastatic phenotype', 'CPA', (166, 201))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
63996	26460615	However, we observed the loss of N-Cadherin after Sdhb inactivation.	('Sdhb', 'Gene', (50, 54))	('inactivation', 'Var', (55, 67))	('loss', 'NegReg', (25, 29))	('N-Cadherin', 'Gene', (33, 43))	('N-Cadherin', 'Gene', '1000', (33, 43))
64001	26460615	By being one of the most significantly hypermethylated, and one of the most significantly down-regulated gene, KRT19 was a pertinent candidate to decipher the still misunderstood link between SDHB deficiency, hypermethylation, EMT and malignancy.	('SDHB deficiency', 'Disease', (192, 207))	('SDHB deficiency', 'Disease', 'MESH:D007153', (192, 207))	('malignancy', 'Disease', 'MESH:D009369', (235, 245))	('hypermethylation', 'Var', (209, 225))	('malignancy', 'Disease', (235, 245))
64003	26460615	We show that SDHB loss alone induces a neuroendoMT phenomenon associated with increased metastatic abilities and likely explaining the bad prognosis caused by SDHB mutations in patients.	('induces', 'Reg', (29, 36))	('loss', 'NegReg', (18, 22))	('metastatic abilities', 'CPA', (88, 108))	('patients', 'Species', '9606', (177, 185))	('increased', 'PosReg', (78, 87))	('SDHB', 'Gene', (13, 17))	('neuroendoMT phenomenon', 'Disease', (39, 61))	('mutations', 'Var', (164, 173))
64023	26460615	The antibodies used were: anti-SDHA (Abcam, Ab14715), anti-SNAI1 (Abcam, Ab85931), anti-KRT19 (Thermo RB9021), anti-N-cadherin (Abcam, Ab12221), and anti alpha-tubulin (Sigma-Aldrich).	('SDHA', 'Gene', '6389', (31, 35))	('N-cadherin', 'Gene', (116, 126))	('anti-KRT19', 'Var', (83, 93))	('alpha-tubulin', 'Gene', '10376', (154, 167))	('N-cadherin', 'Gene', '1000', (116, 126))	('SDHA', 'Gene', (31, 35))	('SNAI1', 'Gene', '6615', (59, 64))	('SNAI1', 'Gene', (59, 64))	('alpha-tubulin', 'Gene', (154, 167))
64117	27298894	Cut section showed grey brown with grey white area The postoperative course was uneventful with complete disappearance of pain and the neurological examination was normal.	('disappearance', 'NegReg', (105, 118))	('grey brown', 'Var', (19, 29))	('pain', 'Phenotype', 'HP:0012531', (122, 126))	('pain', 'Disease', 'MESH:D010146', (122, 126))	('pain', 'Disease', (122, 126))
64129	22241719	The microRNA expression changes associated with malignancy and SDHB mutation in pheochromocytoma Currently, the diagnosis of malignant pheochromocytoma can only be made when there is clinical evidence of metastasis or extensive local invasion.	('SDHB', 'Gene', (63, 67))	('pheochromocytoma', 'Disease', (80, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('pheochromocytoma', 'Disease', (135, 151))	('metastasis', 'CPA', (204, 214))	('mutation', 'Var', (68, 76))	('clinical', 'Species', '191496', (183, 191))	('pheochromocytoma', 'Disease', 'MESH:D010673', (135, 151))	('malignancy', 'Disease', (48, 58))	('pheochromocytoma', 'Disease', 'MESH:D010673', (80, 96))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('changes', 'Reg', (24, 31))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (125, 151))	('SDHB', 'Gene', '6390', (63, 67))	('microRNA expression', 'MPA', (4, 23))	('malignant pheochromocytoma', 'Disease', (125, 151))	('malignancy', 'Disease', 'MESH:D009369', (48, 58))
64137	22241719	Overall our data suggest that misexpression of miR-483-5p, miR-101, and miR-183 is associated with malignant pheochromocytoma.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (99, 125))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (109, 125))	('malignant pheochromocytoma', 'Disease', (99, 125))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('miR-483', 'Gene', '619552', (47, 54))	('associated', 'Reg', (83, 93))	('miR-183', 'Gene', '406959', (72, 79))	('miR-483', 'Gene', (47, 54))	('miR-183', 'Gene', (72, 79))	('miR', 'Gene', '220972', (72, 75))	('misexpression', 'Var', (30, 43))	('miR', 'Gene', (72, 75))
64144	22241719	Although germline mutation in genes including RET, VHL, SDHC, SDHB, SDHD, TMEM127, MAX, or NF1 is associated with developing pheochromocytoma/PGL, the molecular events involved in malignant transformation are poorly understood.	('pheochromocytoma', 'Disease', 'MESH:D010673', (125, 141))	('MAX', 'Gene', (83, 86))	('VHL', 'Disease', (51, 54))	('TMEM127', 'Gene', '55654', (74, 81))	('SDHB', 'Gene', '6390', (62, 66))	('associated with', 'Reg', (98, 113))	('pheochromocytoma', 'Disease', (125, 141))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (125, 141))	('NF1', 'Gene', '4763', (91, 94))	('RET', 'Gene', '5979', (46, 49))	('SDHC', 'Gene', '6391', (56, 60))	('SDHB', 'Gene', (62, 66))	('NF1', 'Gene', (91, 94))	('SDHD', 'Gene', '6392', (68, 72))	('VHL', 'Disease', 'MESH:D006623', (51, 54))	('RET', 'Gene', (46, 49))	('SDHD', 'Gene', (68, 72))	('SDHC', 'Gene', (56, 60))	('TMEM127', 'Gene', (74, 81))	('germline mutation', 'Var', (9, 26))
64148	22241719	Consistent with this prediction, numerous studies have linked altered miRNA expression to cancer, both as diagnostic markers and as functional contributors.	('altered', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
64156	22241719	Patients had genetic testing for mutations or large deletions in RET, VHL, SDHB, SDHC, and SDHD.	('SDHC', 'Gene', (81, 85))	('RET', 'Gene', '5979', (65, 68))	('SDHC', 'Gene', '6391', (81, 85))	('SDHB', 'Gene', '6390', (75, 79))	('mutations', 'Var', (33, 42))	('SDHD', 'Gene', (91, 95))	('RET', 'Gene', (65, 68))	('large deletions', 'Var', (46, 61))	('SDHD', 'Gene', '6392', (91, 95))	('VHL', 'Disease', (70, 73))	('Patients', 'Species', '9606', (0, 8))	('SDHB', 'Gene', (75, 79))	('VHL', 'Disease', 'MESH:D006623', (70, 73))
64161	22241719	Briefly, for each array, 300 ng of total RNA (either tumor or reference) were labeled with Cy3 or Cy5 using the Array Labeling Kit (Exiqon, Vedbaek, Denmark).	('Cy5', 'Var', (98, 101))	('Cy3', 'Chemical', '-', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Cy5', 'Chemical', 'MESH:C085321', (98, 101))	('tumor', 'Disease', (53, 58))	('Cy3', 'Var', (91, 94))
64171	22241719	The following TaqMan MicroRNA Assays used in this study were obtained from Applied Biosystems: hsa-miR-483-5p (ID 2338), hsa-miR-101 (ID 2253), hsa-miR-513a-5p (ID 2090), hsa-miR-183 (ID 2269), has-miR-16 (ID), mmu-miR-710 (ID 1645), and U6 (ID 1973).	('miR', 'Gene', (198, 201))	('miR', 'Gene', '220972', (99, 102))	('miR-483', 'Gene', '619552', (99, 106))	('miR-16', 'Gene', '51573', (198, 204))	('miR', 'Gene', (125, 128))	('miR', 'Gene', (148, 151))	('miR', 'Gene', (99, 102))	('ID 2269', 'Var', (184, 191))	('miR-183', 'Gene', '406959', (175, 182))	('miR', 'Gene', '220972', (215, 218))	('miR', 'Gene', '220972', (175, 178))	('miR-183', 'Gene', (175, 182))	('miR', 'Gene', (215, 218))	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', (175, 178))	('miR-16', 'Gene', (198, 204))	('miR-483', 'Gene', (99, 106))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', '220972', (148, 151))
64198	22241719	In addition, when samples with succinate dehydrogenase subunit B (SDHB) mutations were compared with all non-SDHB mutation samples, we found that miR-101 and miR-183 were significantly different (Fig.	('SDHB', 'Gene', (66, 70))	('mutations', 'Var', (72, 81))	('different', 'Reg', (185, 194))	('succinate dehydrogenase subunit B', 'Gene', '6390', (31, 64))	('miR', 'Gene', '220972', (158, 161))	('SDHB', 'Gene', '6390', (109, 113))	('miR', 'Gene', (158, 161))	('SDHB', 'Gene', (109, 113))	('succinate dehydrogenase subunit B', 'Gene', (31, 64))	('miR-183', 'Gene', '406959', (158, 165))	('miR-183', 'Gene', (158, 165))	('miR', 'Gene', '220972', (146, 149))	('miR', 'Gene', (146, 149))	('SDHB', 'Gene', '6390', (66, 70))
64199	22241719	Interestingly, for this comparison miR-483-5p expression did not differ; however, when only the malignant samples were compared, miR-483-5p expression was significantly lower in SDHB mutation positive tumors vs all other genotypes (Fig.	('miR-483', 'Gene', (35, 42))	('miR-483', 'Gene', '619552', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('miR-483', 'Gene', (129, 136))	('mutation positive', 'Var', (183, 200))	('tumors', 'Disease', (201, 207))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('SDHB', 'Gene', '6390', (178, 182))	('lower', 'NegReg', (169, 174))	('miR-483', 'Gene', '619552', (35, 42))	('SDHB', 'Gene', (178, 182))
64208	22241719	Since carriers of SDHB mutations are likely to have malignant pheochromocytoma, we further assessed the ability of miRNA expression to be a marker of malignancy in non-SDHB tumors.	('SDHB', 'Gene', (18, 22))	('SDHB', 'Gene', '6390', (18, 22))	('malignancy', 'Disease', (150, 160))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (62, 78))	('SDHB', 'Gene', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('mutations', 'Var', (23, 32))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (52, 78))	('SDHB', 'Gene', '6390', (168, 172))	('malignant pheochromocytoma', 'Disease', (52, 78))	('tumors', 'Disease', (173, 179))	('malignancy', 'Disease', 'MESH:D009369', (150, 160))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', (115, 118))
64226	22241719	Several clinical and pathologic factors and germline mutations are associated with malignant pheochromocytoma.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (93, 109))	('clinical', 'Species', '191496', (8, 16))	('germline mutations', 'Var', (44, 62))	('associated', 'Reg', (67, 77))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (83, 109))	('malignant pheochromocytoma', 'Disease', (83, 109))
64230	22241719	SDHB encodes a subunit of the mitochondrial complex II, and mutations in SDHB lead to hereditary PGLs and occur at a high rate in malignant pheochromocytomas.	('malignant pheochromocytomas', 'Disease', 'MESH:D010673', (130, 157))	('lead to', 'Reg', (78, 85))	('hereditary PGLs', 'Disease', (86, 101))	('SDHB', 'Gene', '6390', (0, 4))	('rat', 'Species', '10116', (122, 125))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (140, 157))	('mutations', 'Var', (60, 69))	('malignant pheochromocytomas', 'Disease', (130, 157))	('SDHB', 'Gene', '6390', (73, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (140, 156))	('SDHB', 'Gene', (0, 4))	('SDHB', 'Gene', (73, 77))
64231	22241719	In addition, several studies have shown an association between SDHB mutations and shorter overall survival in patients with malignant pheochromocytoma and PGL.	('SDHB', 'Gene', (63, 67))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (134, 150))	('shorter', 'NegReg', (82, 89))	('SDHB', 'Gene', '6390', (63, 67))	('mutations', 'Var', (68, 77))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (124, 150))	('PGL', 'Disease', (155, 158))	('malignant pheochromocytoma', 'Disease', (124, 150))	('patients', 'Species', '9606', (110, 118))	('overall survival', 'MPA', (90, 106))
64232	22241719	We found significant expression differences in miR-101 and miR-183 when samples with SDHB mutations were compared with all non-SDHB genotypes (RET, VHL, NF1, and sporadic).	('mutations', 'Var', (90, 99))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('NF1', 'Gene', (153, 156))	('RET', 'Gene', (143, 146))	('SDHB', 'Gene', '6390', (127, 131))	('expression', 'MPA', (21, 31))	('miR', 'Gene', '220972', (59, 62))	('SDHB', 'Gene', '6390', (85, 89))	('miR', 'Gene', (59, 62))	('NF1', 'Gene', '4763', (153, 156))	('SDHB', 'Gene', (85, 89))	('SDHB', 'Gene', (127, 131))	('VHL', 'Disease', 'MESH:D006623', (148, 151))	('miR-183', 'Gene', '406959', (59, 66))	('miR-183', 'Gene', (59, 66))	('VHL', 'Disease', (148, 151))	('RET', 'Gene', '5979', (143, 146))
64254	10992729	This was thus a case of Cushing's syndrome resulting from ectopic ACTH production in anterior mediastinal paraganglioma.	('mediastinal paraganglioma', 'Disease', 'MESH:D008480', (94, 119))	("Cushing's syndrome", 'Phenotype', 'HP:0003118', (24, 42))	("Cushing's syndrome", 'Disease', (24, 42))	('ectopic', 'Var', (58, 65))	("Cushing's syndrome", 'Disease', 'MESH:D003480', (24, 42))	('mediastinal paraganglioma', 'Disease', (94, 119))	('ACTH', 'Gene', (66, 70))	('resulting from', 'Reg', (43, 57))	('paraganglioma', 'Phenotype', 'HP:0002668', (106, 119))	('ACTH', 'Gene', '5443', (66, 70))
64314	10992729	However, the presence of bands of connective tissue, nuclear pleomorphism with bizarre forms and absence of festfoons or rosettes are histological features more in favor of paraganglioma.	('paraganglioma', 'Disease', (173, 186))	('rosettes', 'Phenotype', 'HP:0031925', (121, 129))	('paraganglioma', 'Disease', 'MESH:D010235', (173, 186))	('paraganglioma', 'Phenotype', 'HP:0002668', (173, 186))	('bizarre forms', 'CPA', (79, 92))	('nuclear pleomorphism', 'Var', (53, 73))
64450	23152728	Norepinephrine-secreting tumours cause sustained hypertension, while tumours that secrete large amounts of both epinephrine and norepinephrine are associated with episodic hypertension.	('associated with', 'Reg', (147, 162))	('hypertension', 'Disease', 'MESH:D006973', (172, 184))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Norepinephrine-secreting', 'Var', (0, 24))	('hypertension', 'Disease', (172, 184))	('tumours', 'Disease', (25, 32))	('episodic hypertension', 'Disease', 'MESH:D006973', (163, 184))	('hypertension', 'Disease', 'MESH:D006973', (49, 61))	('epinephrine', 'Chemical', 'MESH:D004837', (112, 123))	('episodic hypertension', 'Phenotype', 'HP:0000875', (163, 184))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('hypertension', 'Disease', (49, 61))	('hypertension', 'Phenotype', 'HP:0000822', (172, 184))	('norepinephrine', 'Chemical', 'MESH:D009638', (128, 142))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('hypertension', 'Phenotype', 'HP:0000822', (49, 61))	('Norepinephrine', 'Chemical', 'MESH:D009638', (0, 14))	('tumours', 'Disease', (69, 76))	('epinephrine', 'Chemical', 'MESH:D004837', (3, 14))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('episodic hypertension', 'Disease', (163, 184))	('epinephrine', 'Chemical', 'MESH:D004837', (131, 142))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
64523	19669229	Inhibition of the PI3K Pathway Suppresses Hormonal Secretion and Limits Growth in Pheochromocytoma Cells Operative resection is the only curative treatment for pheochromocytomas.	('PI3K Pathway', 'Pathway', (18, 30))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (160, 177))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (160, 176))	('Hormonal Secretion', 'MPA', (42, 60))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (82, 98))	('pheochromocytomas', 'Disease', 'MESH:D010673', (160, 177))	('Inhibition', 'Var', (0, 10))	('pheochromocytomas', 'Disease', (160, 177))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('Limits', 'NegReg', (65, 71))	('Suppresses', 'NegReg', (31, 41))	('Pheochromocytoma', 'Disease', (82, 98))	('Growth', 'MPA', (72, 78))
64524	19669229	Inhibition of the phosphatidylinositol-3 kinase (PI3K)-Akt pathway has been shown to be an effective treatment of neuroendocrine (NE) tumors in vitro.	('tumors', 'Disease', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
64525	19669229	We hypothesized that inhibition of the PI3K-Akt pathway would be a viable strategy to inhibit growth and hormonal secretion in pheochromocytoma cells.	('pheochromocytoma', 'Disease', (127, 143))	('inhibition', 'Var', (21, 31))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (127, 143))	('inhibit', 'NegReg', (86, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (127, 143))	('PI3K-Akt pathway', 'Pathway', (39, 55))
64530	19669229	LY294002 significantly inhibited the PI3K-Akt pathway.	('LY294002', 'Var', (0, 8))	('PI3K-Akt pathway', 'Pathway', (37, 53))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('inhibited', 'NegReg', (23, 32))
64533	19669229	LY294002 effectively inhibits the PI3K-Akt pathway, suppresses NE tumor markers, and decreases cellular proliferation via apoptosis in vitro.	('LY294002', 'Var', (0, 8))	('decreases', 'NegReg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('inhibits', 'NegReg', (21, 29))	('PI3K-Akt pathway', 'Pathway', (34, 50))	('tumor', 'Disease', (66, 71))	('apoptosis', 'CPA', (122, 131))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('cellular proliferation', 'CPA', (95, 117))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('suppresses', 'NegReg', (52, 62))
64534	19669229	Inhibition of the PI3K pathway may represent a new strategy in the treatment of pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (80, 97))	('pheochromocytomas', 'Disease', (80, 97))	('pheochromocytomas', 'Disease', 'MESH:D010673', (80, 97))	('Inhibition', 'Var', (0, 10))	('PI3K pathway', 'Pathway', (18, 30))
64542	19669229	In turn, PI3K activates Akt (alternaively, protein kinase B) by phosphorylation at the threonine 308 and serine 473 residues.	('phosphorylation', 'MPA', (64, 79))	('threonine', 'Chemical', 'MESH:D013912', (87, 96))	('Akt', 'Pathway', (24, 27))	('protein kinase B', 'Gene', (43, 59))	('serine 473', 'Var', (105, 115))	('PI3K', 'Var', (9, 13))	('activates', 'PosReg', (14, 23))	('protein kinase B', 'Gene', '2185', (43, 59))	('serine', 'Chemical', 'MESH:D012694', (105, 111))
64549	19669229	This led us to hypothesize that inhibition of the PI3K-Akt pathway could lower NE markers, suppress hormonal secretion, and inhibit growth in an in vitro model of pheochromocytoma.	('inhibition', 'Var', (32, 42))	('pheochromocytoma', 'Disease', 'MESH:D010673', (163, 179))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (163, 179))	('NE markers', 'MPA', (79, 89))	('suppress', 'NegReg', (91, 99))	('growth', 'CPA', (132, 138))	('PI3K-Akt pathway', 'Pathway', (50, 66))	('hormonal secretion', 'MPA', (100, 118))	('lower', 'NegReg', (73, 78))	('pheochromocytoma', 'Disease', (163, 179))	('inhibit', 'NegReg', (124, 131))
64554	19669229	Rat pheochromocytoma PC-12 cells were obtained from American Type Culture Collection (ATCC, Manassas, VA) and were maintained in Ham's F12K medium (ATCC) supplemented with 15% horse serum (Sigma Aldrich, St. Louis, MO), 2.5% fetal bovine serum (Sigma Aldrich), and 100 IU/ml penicillin plus 100 microg/ml streptomycin (Invitrogen, Carlsbad, CA), as previously described.	('penicillin', 'Chemical', 'MESH:D010406', (275, 285))	('PC-12', 'CellLine', 'CVCL:0481', (21, 26))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (4, 20))	('horse', 'Species', '9796', (176, 181))	('streptomycin', 'Chemical', 'MESH:D013307', (305, 317))	('F12K', 'SUBSTITUTION', 'None', (135, 139))	('F12K', 'Var', (135, 139))	('pheochromocytoma', 'Disease', (4, 20))	('bovine', 'Species', '9913', (231, 237))	('pheochromocytoma', 'Disease', 'MESH:D010673', (4, 20))
64555	19669229	The cells were maintained in a humidified atmosphere of 5% CO2 at 37 C. The PC-12 pheochromocytoma cells were treated with the PI3K-specific inhibitor LY294002 (Sigma Aldrich) in concentrations from 0 to 100 microM, and whole cell lysates were prepared as previously described.	('LY294002', 'Var', (151, 159))	('PC-12', 'CellLine', 'CVCL:0481', (76, 81))	('pheochromocytoma', 'Disease', (82, 98))	('LY294002', 'Chemical', 'MESH:C085911', (151, 159))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('pheochromocytoma', 'Disease', 'MESH:D010673', (82, 98))	('CO2', 'Chemical', '-', (59, 62))
64562	19669229	SuperSignal West Femto (Pierce Biotechnology) was used for ASCL1, pAkt, and cleaved caspase-3 according to the manufacturer's instructions.	('caspase-3', 'Gene', (84, 93))	('cleaved', 'Var', (76, 83))	('caspase-3', 'Gene', '836', (84, 93))
64572	19669229	The PC-12 pheochromocytoma cells were treated with the Akt inhibitor LY294002 for two days.	('LY294002', 'Var', (69, 77))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (10, 26))	('PC-12', 'CellLine', 'CVCL:0481', (4, 9))	('LY294002', 'Chemical', 'MESH:C085911', (69, 77))	('pheochromocytoma', 'Disease', (10, 26))	('pheochromocytoma', 'Disease', 'MESH:D010673', (10, 26))
64575	19669229	Treatment with LY294002 resulted in a dose-dependent decrease in pAkt, indicating inhibition of the pathway.	('LY294002', 'Chemical', 'MESH:C085911', (15, 23))	('pAkt', 'MPA', (65, 69))	('decrease', 'NegReg', (53, 61))	('LY294002', 'Var', (15, 23))
64576	19669229	There was no change in the total expression of Akt with increasing concentrations of LY294002.	('LY294002', 'Chemical', 'MESH:C085911', (85, 93))	('LY294002', 'Var', (85, 93))	('Akt', 'Pathway', (47, 50))
64578	19669229	Thus, the PI3K-Akt pathway is highly active in pheochromocytoma cells, and it can be inhibited by LY294002.	('PI3K-Akt pathway', 'Pathway', (10, 26))	('inhibited', 'NegReg', (85, 94))	('LY294002', 'Chemical', 'MESH:C085911', (98, 106))	('pheochromocytoma', 'Disease', (47, 63))	('pheochromocytoma', 'Disease', 'MESH:D010673', (47, 63))	('active', 'MPA', (37, 43))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (47, 63))	('LY294002', 'Var', (98, 106))
64579	19669229	Treatment with LY294002 led to a dose-dependent decrease in ASCL1 (Fig.	('LY294002', 'Chemical', 'MESH:C085911', (15, 23))	('ASCL1', 'MPA', (60, 65))	('decrease', 'NegReg', (48, 56))	('LY294002', 'Var', (15, 23))
64582	19669229	We therefore wanted to see if LY294002 was also able to decrease CgA in PC-12 pheochromocytoma cells.	('PC-12', 'CellLine', 'CVCL:0481', (72, 77))	('pheochromocytoma', 'Disease', (78, 94))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('decrease CgA', 'Phenotype', 'HP:0002720', (56, 68))	('CgA', 'MPA', (65, 68))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))	('decrease', 'NegReg', (56, 64))	('LY294002', 'Var', (30, 38))
64583	19669229	3, treatment of PC-12 cells with LY294002 decreased CgA, suggesting an overall decrease in hormonal secretion.	('hormonal secretion', 'MPA', (91, 109))	('decreased', 'NegReg', (42, 51))	('LY294002', 'Chemical', 'MESH:C085911', (33, 41))	('PC-12', 'CellLine', 'CVCL:0481', (16, 21))	('decrease', 'NegReg', (79, 87))	('decreased CgA', 'Phenotype', 'HP:0002720', (42, 55))	('LY294002', 'Var', (33, 41))	('CgA', 'MPA', (52, 55))
64584	19669229	Our group has demonstrated growth suppression associated with PI3K-Akt inhibition in medullary thyroid cancer cells.	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (85, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('PI3K-Akt', 'Var', (62, 70))	('inhibition', 'NegReg', (71, 81))	('growth suppression', 'CPA', (27, 45))	('thyroid cancer', 'Disease', (95, 109))	('thyroid cancer', 'Phenotype', 'HP:0002890', (95, 109))	('thyroid cancer', 'Disease', 'MESH:D013964', (95, 109))
64587	19669229	Growth was inhibited in a dose-dependent manner by LY294002 (Fig.	('inhibited', 'NegReg', (11, 20))	('LY294002', 'Chemical', 'MESH:C085911', (51, 59))	('LY294002', 'Var', (51, 59))	('Growth', 'CPA', (0, 6))
64588	19669229	Moreover, growth was significantly suppressed after only 2 days by the lowest amount of LY294002 used (P < 0.001, one-way ANOVA).	('LY294002', 'Chemical', 'MESH:C085911', (88, 96))	('suppressed', 'NegReg', (35, 45))	('growth', 'MPA', (10, 16))	('LY294002', 'Var', (88, 96))
64590	19669229	Noticing significantly limited cellular proliferation with LY294002 treatment in PC-12 cells, we wanted to study the mechanism of this inhibition.	('LY294002', 'Var', (59, 67))	('PC-12', 'CellLine', 'CVCL:0481', (81, 86))	('LY294002', 'Chemical', 'MESH:C085911', (59, 67))	('limited', 'NegReg', (23, 30))	('cellular proliferation', 'CPA', (31, 53))
64592	19669229	After 2 days of PI3K inhibition by LY294002, increased cleavage in both PARP and caspase-3 (Fig.	('caspase-3', 'Gene', '836', (81, 90))	('LY294002', 'Var', (35, 43))	('increased', 'PosReg', (45, 54))	('PARP', 'Gene', '142', (72, 76))	('caspase-3', 'Gene', (81, 90))	('cleavage', 'MPA', (55, 63))	('PARP', 'Gene', (72, 76))	('LY294002', 'Chemical', 'MESH:C085911', (35, 43))
64593	19669229	These increases were dose dependent and suggest that the cell death observed by MTT was due to apoptosis, which indicates that LY294002 causes growth inhibition via apoptosis.	('LY294002', 'Chemical', 'MESH:C085911', (127, 135))	('apoptosis', 'CPA', (165, 174))	('growth inhibition', 'CPA', (143, 160))	('MTT', 'Chemical', '-', (80, 83))	('LY294002', 'Var', (127, 135))
64612	19669229	As these patients often suffer from symptoms such as sweating, headache, tachycardia, and hypertension, inhibition of the PI3K-Akt pathway could be therapeutically useful if it decreases hormonal secretion.	('patients', 'Species', '9606', (9, 17))	('hypertension', 'Disease', (90, 102))	('headache', 'Disease', (63, 71))	('sweating', 'Disease', (53, 61))	('sweating', 'Phenotype', 'HP:0000975', (53, 61))	('headache', 'Disease', 'MESH:D006261', (63, 71))	('tachycardia', 'Phenotype', 'HP:0001649', (73, 84))	('headache', 'Phenotype', 'HP:0002315', (63, 71))	('suffer', 'Reg', (24, 30))	('decreases', 'NegReg', (177, 186))	('tachycardia', 'Disease', 'MESH:D013610', (73, 84))	('hypertension', 'Disease', 'MESH:D006973', (90, 102))	('tachycardia', 'Disease', (73, 84))	('PI3K-Akt pathway', 'Pathway', (122, 138))	('inhibition', 'Var', (104, 114))	('hormonal secretion', 'MPA', (187, 205))	('hypertension', 'Phenotype', 'HP:0000822', (90, 102))
64620	19669229	Inhibition of the PI3K-Akt pathway with LY294002 in pheochromocytoma cells downregulated the NE phenotype, decreased hormonal secretion, and suppressed growth via apoptosis.	('LY294002', 'Chemical', 'MESH:C085911', (40, 48))	('downregulated', 'NegReg', (75, 88))	('pheochromocytoma', 'Disease', 'MESH:D010673', (52, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (52, 68))	('PI3K-Akt pathway', 'Pathway', (18, 34))	('growth via apoptosis', 'CPA', (152, 172))	('decreased', 'NegReg', (107, 116))	('hormonal secretion', 'MPA', (117, 135))	('NE phenotype', 'MPA', (93, 105))	('decreased hormonal', 'Phenotype', 'HP:0000824', (107, 125))	('suppressed', 'NegReg', (141, 151))	('LY294002', 'Var', (40, 48))	('pheochromocytoma', 'Disease', (52, 68))
64734	21060768	suggested that the combination of 131I-MIBG and cisplatinum or doxorubicin could selectively increase radiation doses delivered to neuroblastoma cells.	('neuroblastoma', 'Disease', (131, 144))	('cisplatinum', 'Chemical', 'MESH:D002945', (48, 59))	('radiation', 'Disease', 'MESH:D004194', (102, 111))	('increase', 'PosReg', (93, 101))	('radiation', 'Disease', (102, 111))	('neuroblastoma', 'Phenotype', 'HP:0003006', (131, 144))	('131I-MIBG', 'Var', (34, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('neuroblastoma', 'Disease', 'MESH:D009447', (131, 144))	('131I-MIBG', 'Chemical', '-', (34, 43))
64750	33114456	Identification of Novel Mutations and Expressions of EPAS1 in Phaeochromocytomas and Paragangliomas Endothelial PAS domain-containing protein 1 (EPAS1) is an oxygen-sensitive component of the hypoxia-inducible factors (HIFs) having reported implications in many cancers by inducing a pseudo-hypoxic microenvironment.	('p', 'Chemical', 'MESH:D010758', (134, 135))	('HIFs', 'Disease', (219, 223))	('c', 'Chemical', 'MESH:D002244', (175, 176))	('EPAS1', 'Gene', (53, 58))	('oxygen', 'Chemical', 'MESH:D010100', (158, 164))	('c', 'Chemical', 'MESH:D002244', (262, 263))	('hypoxia', 'Disease', (192, 199))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('p', 'Chemical', 'MESH:D010758', (293, 294))	('c', 'Chemical', 'MESH:D002244', (73, 74))	('c', 'Chemical', 'MESH:D002244', (246, 247))	('HIFs', 'Disease', 'None', (219, 223))	('men', 'Species', '9606', (311, 314))	('c', 'Chemical', 'MESH:D002244', (301, 302))	('c', 'Chemical', 'MESH:D002244', (277, 278))	('p', 'Chemical', 'MESH:D010758', (284, 285))	('p', 'Chemical', 'MESH:D010758', (234, 235))	('hypoxia', 'Disease', 'MESH:D000860', (192, 199))	('cancers', 'Disease', 'MESH:D009369', (262, 269))	('p', 'Chemical', 'MESH:D010758', (194, 195))	('EPAS1', 'Gene', (145, 150))	('Mutations', 'Var', (24, 33))	('c', 'Chemical', 'MESH:D002244', (204, 205))	('cancers', 'Phenotype', 'HP:0002664', (262, 269))	('EPAS1', 'Gene', '2034', (53, 58))	('cancers', 'Disease', (262, 269))	('p', 'Chemical', 'MESH:D010758', (243, 244))	('implications', 'Reg', (241, 253))	('p', 'Chemical', 'MESH:D010758', (178, 179))	('c', 'Chemical', 'MESH:D002244', (212, 213))	('Phaeochromocytomas and Paragangliomas', 'Disease', 'MESH:D010235', (62, 99))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('Endothelial PAS domain-containing protein 1', 'Gene', '2034', (100, 143))	('Paragangliomas', 'Phenotype', 'HP:0002668', (85, 99))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('pseudo-hypoxic microenvironment', 'MPA', (284, 315))	('c', 'Chemical', 'MESH:D002244', (297, 298))	('Endothelial PAS domain-containing protein 1', 'Gene', (100, 143))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('EPAS1', 'Gene', '2034', (145, 150))	('c', 'Chemical', 'MESH:D002244', (265, 266))	('p', 'Chemical', 'MESH:D010758', (40, 41))	('inducing', 'Reg', (273, 281))
64752	33114456	This study aims to identify EPAS1 mutations and alterations in DNA copy number, mRNA and protein expression in patients with phaeochromocytomas/paragangliomas.	('c', 'Chemical', 'MESH:D002244', (136, 137))	('alterations', 'Reg', (48, 59))	('paragangliomas', 'Phenotype', 'HP:0002668', (144, 158))	('paraganglioma', 'Phenotype', 'HP:0002668', (144, 157))	('p', 'Chemical', 'MESH:D010758', (125, 126))	('EPAS1', 'Gene', (28, 33))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('DNA copy number', 'MPA', (63, 78))	('phaeochromocytomas/paragangliomas', 'Disease', (125, 158))	('p', 'Chemical', 'MESH:D010758', (99, 100))	('protein expression', 'MPA', (89, 107))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('c', 'Chemical', 'MESH:D002244', (130, 131))	('p', 'Chemical', 'MESH:D010758', (144, 145))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (125, 158))	('p', 'Chemical', 'MESH:D010758', (111, 112))	('mutations', 'Var', (34, 43))	('patients', 'Species', '9606', (111, 119))
64754	33114456	High-resolution melt-curve analysis followed by Sanger sequencing was used to detect mutations in EPAS1.	('EPAS1', 'Gene', (98, 103))	('c', 'Chemical', 'MESH:D002244', (21, 22))	('mutations', 'Var', (85, 94))	('c', 'Chemical', 'MESH:D002244', (61, 62))	('c', 'Chemical', 'MESH:D002244', (82, 83))
64757	33114456	In phaeochromocytomas, 12% (n = 7/57) of patients had mutations in the EPAS1 sequence, which includes two novel mutations (c.1091A>T; p.Lys364Met and c.1129A>T; p.Ser377Cys).	('p.Ser377Cys', 'SUBSTITUTION', 'None', (161, 172))	('p.Ser377Cys', 'Var', (161, 172))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('c', 'Chemical', 'MESH:D002244', (95, 96))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (3, 21))	('c', 'Chemical', 'MESH:D002244', (150, 151))	('c', 'Chemical', 'MESH:D002244', (14, 15))	('c.1129A>T', 'SUBSTITUTION', 'None', (150, 159))	('c', 'Chemical', 'MESH:D002244', (83, 84))	('c.1091A>T', 'Var', (123, 132))	('phaeochromocytomas', 'Disease', (3, 21))	('patients', 'Species', '9606', (41, 49))	('c.1129A>T', 'Var', (150, 159))	('p.Lys364Met', 'Var', (134, 145))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('EPAS1', 'Gene', (71, 76))	('p.Lys364Met', 'SUBSTITUTION', 'None', (134, 145))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('c.1091A>T', 'SUBSTITUTION', 'None', (123, 132))
64758	33114456	Contrastingly, in paragangliomas, 7% (n = 1/14) of patients had EPAS1 mutations and only the c.1091A>T; p.Lys364Met mutation was detected.	('mutations', 'Var', (70, 79))	('EPAS1', 'Gene', (64, 69))	('p.Lys364Met', 'Var', (104, 115))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('paraganglioma', 'Phenotype', 'HP:0002668', (18, 31))	('c.1091A>T', 'Var', (93, 102))	('paragangliomas', 'Disease', (18, 32))	('paragangliomas', 'Disease', 'MESH:D010235', (18, 32))	('patients', 'Species', '9606', (51, 59))	('paragangliomas', 'Phenotype', 'HP:0002668', (18, 32))	('p.Lys364Met', 'SUBSTITUTION', 'None', (104, 115))	('c.1091A>T', 'SUBSTITUTION', 'None', (93, 102))	('c', 'Chemical', 'MESH:D002244', (133, 134))
64759	33114456	In silico analysis revealed that the p.Lys364Met mutation has pathological potential based on the functionality of the protein, whereas the p.Ser377Cys mutation was predicted to be neutral or tolerated.	('p.Ser377Cys', 'Var', (140, 151))	('p', 'Chemical', 'MESH:D010758', (140, 141))	('p', 'Chemical', 'MESH:D010758', (165, 166))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (62, 63))	('p.Lys364Met', 'SUBSTITUTION', 'None', (37, 48))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('c', 'Chemical', 'MESH:D002244', (170, 171))	('c', 'Chemical', 'MESH:D002244', (101, 102))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('p.Lys364Met', 'Var', (37, 48))	('p', 'Chemical', 'MESH:D010758', (75, 76))	('p.Ser377Cys', 'SUBSTITUTION', 'None', (140, 151))	('pathological potential', 'CPA', (62, 84))	('c', 'Chemical', 'MESH:D002244', (71, 72))
64761	33114456	Most of the patients with EPAS1 mutations exhibited aberrant DNA changes, mRNA and protein overexpression.	('patients', 'Species', '9606', (12, 20))	('exhibited', 'Reg', (42, 51))	('EPAS1', 'Gene', (26, 31))	('overexpression', 'PosReg', (91, 105))	('p', 'Chemical', 'MESH:D010758', (83, 84))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('DNA changes', 'MPA', (61, 72))	('c', 'Chemical', 'MESH:D002244', (65, 66))	('mutations', 'Var', (32, 41))	('p', 'Chemical', 'MESH:D010758', (12, 13))
64762	33114456	In addition, these alterations of EPAS1 were associated with tumour weight and location.	('tumour weight', 'Disease', 'MESH:D009369', (61, 74))	('c', 'Chemical', 'MESH:D002244', (49, 50))	('associated', 'Reg', (45, 55))	('alterations', 'Var', (19, 30))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('c', 'Chemical', 'MESH:D002244', (81, 82))	('EPAS1', 'Protein', (34, 39))	('tumour weight', 'Disease', (61, 74))
64763	33114456	Thus, the molecular dysregulation of EPAS1 could play crucial roles in the pathogenesis of phaeochromocytomas and paragangliomas.	('p', 'Chemical', 'MESH:D010758', (75, 76))	('p', 'Chemical', 'MESH:D010758', (91, 92))	('c', 'Chemical', 'MESH:D002244', (14, 15))	('paragangliomas', 'Phenotype', 'HP:0002668', (114, 128))	('c', 'Chemical', 'MESH:D002244', (96, 97))	('paraganglioma', 'Phenotype', 'HP:0002668', (114, 127))	('dysregulation', 'Var', (20, 33))	('p', 'Chemical', 'MESH:D010758', (49, 50))	('EPAS1', 'Protein', (37, 42))	('p', 'Chemical', 'MESH:D010758', (114, 115))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (91, 128))	('c', 'Chemical', 'MESH:D002244', (43, 44))	('roles', 'Reg', (62, 67))	('c', 'Chemical', 'MESH:D002244', (57, 58))	('play', 'Reg', (49, 53))	('c', 'Chemical', 'MESH:D002244', (54, 55))	('c', 'Chemical', 'MESH:D002244', (102, 103))
64773	33114456	Cluster 2 involves genetic mutations associated with the abnormal activation of kinase signalling pathway, e.g., NF1, KIF1Bbeta, MAX, RET, TMEM127.	('mutations', 'Var', (27, 36))	('KIF1Bbeta', 'Gene', (118, 127))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('RET', 'Gene', (134, 137))	('abnormal activation of kinase signalling', 'Phenotype', 'HP:0012175', (57, 97))	('c', 'Chemical', 'MESH:D002244', (41, 42))	('NF1', 'Gene', (113, 116))	('TMEM127', 'Gene', (139, 146))	('TMEM127', 'Gene', '55654', (139, 146))	('NF1', 'Gene', '4763', (113, 116))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('kinase signalling pathway', 'Pathway', (80, 105))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('RET', 'Gene', '5979', (134, 137))	('activation', 'PosReg', (66, 76))
64774	33114456	Additionally, activating mutations of Wnt-signalling pathway or its components, including somatic mutations of CSDE1 (cold shock domain containing E1) and MAML3 (mastermind like transcriptional coactivator 3) genes are known as cluster 3 in phaeochromocytomas and paragangliomas.	('c', 'Chemical', 'MESH:D002244', (136, 137))	('cold shock domain containing E1', 'Gene', '7812', (118, 149))	('c', 'Chemical', 'MESH:D002244', (96, 97))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (241, 278))	('c', 'Chemical', 'MESH:D002244', (15, 16))	('c', 'Chemical', 'MESH:D002244', (183, 184))	('c', 'Chemical', 'MESH:D002244', (246, 247))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('cold shock domain containing E1', 'Gene', (118, 149))	('mutations', 'Var', (25, 34))	('c', 'Chemical', 'MESH:D002244', (126, 127))	('CSDE1', 'Gene', (111, 116))	('c', 'Chemical', 'MESH:D002244', (118, 119))	('Wnt-signalling pathway', 'Pathway', (38, 60))	('p', 'Chemical', 'MESH:D010758', (186, 187))	('MAML3', 'Gene', (155, 160))	('mastermind like transcriptional coactivator 3', 'Gene', (162, 207))	('c', 'Chemical', 'MESH:D002244', (252, 253))	('c', 'Chemical', 'MESH:D002244', (197, 198))	('c', 'Chemical', 'MESH:D002244', (228, 229))	('p', 'Chemical', 'MESH:D010758', (264, 265))	('p', 'Chemical', 'MESH:D010758', (241, 242))	('CSDE1', 'Gene', '7812', (111, 116))	('activating', 'PosReg', (14, 24))	('c', 'Chemical', 'MESH:D002244', (194, 195))	('MAML3', 'Gene', '55534', (155, 160))	('c', 'Chemical', 'MESH:D002244', (82, 83))	('c', 'Chemical', 'MESH:D002244', (68, 69))	('mutations', 'Var', (98, 107))	('paragangliomas', 'Phenotype', 'HP:0002668', (264, 278))	('mastermind like transcriptional coactivator 3', 'Gene', '55534', (162, 207))	('paraganglioma', 'Phenotype', 'HP:0002668', (264, 277))	('shock', 'Phenotype', 'HP:0031273', (123, 128))	('p', 'Chemical', 'MESH:D010758', (71, 72))
64776	33114456	Recent studies have demonstrated that mutations in endothelial PAS domain-containing protein 1 (EPAS1) is associated with manifestations of phaeochromocytomas and paragangliomas.	('c', 'Chemical', 'MESH:D002244', (2, 3))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (140, 177))	('associated', 'Reg', (106, 116))	('c', 'Chemical', 'MESH:D002244', (151, 152))	('endothelial PAS domain-containing protein 1', 'Gene', '2034', (51, 94))	('c', 'Chemical', 'MESH:D002244', (145, 146))	('c', 'Chemical', 'MESH:D002244', (110, 111))	('EPAS1', 'Gene', (96, 101))	('paraganglioma', 'Phenotype', 'HP:0002668', (163, 176))	('endothelial PAS domain-containing protein 1', 'Gene', (51, 94))	('paragangliomas', 'Phenotype', 'HP:0002668', (163, 177))	('c', 'Chemical', 'MESH:D002244', (74, 75))	('mutations', 'Var', (38, 47))
64778	33114456	The identification of somatic mutations affecting EPAS1 in phaeochromocytomas and paragangliomas led to the hypothesis that the stabilization of HIF-alpha plays crucial roles in the development of chromaffin tumours through the phenomenon known as pseudo-hypoxia.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('p', 'Chemical', 'MESH:D010758', (151, 152))	('p', 'Chemical', 'MESH:D010758', (110, 111))	('hypoxia', 'Disease', (255, 262))	('p', 'Chemical', 'MESH:D010758', (228, 229))	('stabilization', 'MPA', (128, 141))	('c', 'Chemical', 'MESH:D002244', (64, 65))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('tumours', 'Disease', (208, 215))	('c', 'Chemical', 'MESH:D002244', (70, 71))	('p', 'Chemical', 'MESH:D010758', (155, 156))	('hypoxia', 'Disease', 'MESH:D000860', (255, 262))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('c', 'Chemical', 'MESH:D002244', (197, 198))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('p', 'Chemical', 'MESH:D010758', (248, 249))	('c', 'Chemical', 'MESH:D002244', (164, 165))	('c', 'Chemical', 'MESH:D002244', (28, 29))	('EPAS1', 'Gene', (50, 55))	('p', 'Chemical', 'MESH:D010758', (257, 258))	('tumours', 'Disease', 'MESH:D009369', (208, 215))	('mutations', 'Var', (30, 39))	('c', 'Chemical', 'MESH:D002244', (12, 13))	('c', 'Chemical', 'MESH:D002244', (44, 45))	('c', 'Chemical', 'MESH:D002244', (161, 162))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (59, 96))	('men', 'Species', '9606', (189, 192))	('chromaffin tumours', 'Phenotype', 'HP:0002666', (197, 215))	('chromaffin', 'Chemical', '-', (197, 207))	('men', 'Species', '9606', (233, 236))
64779	33114456	In a pseudo-hypoxic state, abnormal HIF-alpha function enhances cell proliferation and tumour growth.	('abnormal', 'Var', (27, 35))	('c', 'Chemical', 'MESH:D002244', (64, 65))	('p', 'Chemical', 'MESH:D010758', (5, 6))	('cell proliferation', 'CPA', (64, 82))	('HIF-alpha', 'Protein', (36, 45))	('p', 'Chemical', 'MESH:D010758', (14, 15))	('p', 'Chemical', 'MESH:D010758', (42, 43))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('c', 'Chemical', 'MESH:D002244', (18, 19))	('c', 'Chemical', 'MESH:D002244', (49, 50))	('tumour growth', 'Disease', (87, 100))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour growth', 'Disease', 'MESH:D006130', (87, 100))	('enhances', 'PosReg', (55, 63))	('c', 'Chemical', 'MESH:D002244', (60, 61))
64780	33114456	So far, EPAS1 mutations have been reported in a few phaeochromocytomas and paragangliomas.	('EPAS1', 'Gene', (8, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('reported', 'Reg', (34, 42))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (52, 89))	('p', 'Chemical', 'MESH:D010758', (52, 53))	('p', 'Chemical', 'MESH:D010758', (36, 37))	('p', 'Chemical', 'MESH:D010758', (75, 76))	('mutations', 'Var', (14, 23))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))
64781	33114456	Therefore, further research on the effects of EPAS1 mutation on gene expression in a large cohort of patients with phaeochromocytomas and paragangliomas is critical to unveil its roles in the phaeochromocytomas/paragangliomas pathogenesis.	('c', 'Chemical', 'MESH:D002244', (120, 121))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('p', 'Chemical', 'MESH:D010758', (101, 102))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (192, 225))	('mutation', 'Var', (52, 60))	('p', 'Chemical', 'MESH:D010758', (226, 227))	('c', 'Chemical', 'MESH:D002244', (39, 40))	('patients', 'Species', '9606', (101, 109))	('c', 'Chemical', 'MESH:D002244', (126, 127))	('p', 'Chemical', 'MESH:D010758', (138, 139))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('paraganglioma', 'Phenotype', 'HP:0002668', (211, 224))	('p', 'Chemical', 'MESH:D010758', (211, 212))	('c', 'Chemical', 'MESH:D002244', (197, 198))	('c', 'Chemical', 'MESH:D002244', (203, 204))	('paraganglioma', 'Phenotype', 'HP:0002668', (138, 151))	('EPAS1', 'Gene', (46, 51))	('c', 'Chemical', 'MESH:D002244', (156, 157))	('phaeochromocytomas/paragangliomas', 'Disease', (192, 225))	('paragangliomas', 'Phenotype', 'HP:0002668', (211, 225))	('c', 'Chemical', 'MESH:D002244', (91, 92))	('c', 'Chemical', 'MESH:D002244', (161, 162))	('p', 'Chemical', 'MESH:D010758', (192, 193))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (115, 152))	('paragangliomas', 'Phenotype', 'HP:0002668', (138, 152))	('p', 'Chemical', 'MESH:D010758', (71, 72))
64782	33114456	Herein, we investigated mutations in EPAS1 in a cohort of phaeochromocytoma (n = 57) or paraganglioma (n = 14) and have described the clinical, molecular and genetic features of patients carrying somatic EPAS1 mutations.	('mutations', 'Var', (210, 219))	('c', 'Chemical', 'MESH:D002244', (63, 64))	('c', 'Chemical', 'MESH:D002244', (48, 49))	('mutations', 'Var', (24, 33))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('patients', 'Species', '9606', (178, 186))	('phaeochromocytoma', 'Disease', (58, 75))	('paraganglioma', 'Disease', (88, 101))	('c', 'Chemical', 'MESH:D002244', (164, 165))	('c', 'Chemical', 'MESH:D002244', (69, 70))	('paraganglioma', 'Disease', 'MESH:D010235', (88, 101))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (58, 75))	('EPAS1', 'Gene', (37, 42))	('c', 'Chemical', 'MESH:D002244', (139, 140))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('c', 'Chemical', 'MESH:D002244', (187, 188))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('investigated', 'Reg', (11, 23))	('c', 'Chemical', 'MESH:D002244', (202, 203))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('EPAS1', 'Gene', (204, 209))
64798	33114456	Moreover, six patients with phaeochromocytomas harbouring EPAS1 mutation had shown catecholamine secretion.	('c', 'Chemical', 'MESH:D002244', (33, 34))	('mutation', 'Var', (64, 72))	('catecholamine', 'Chemical', 'MESH:D002395', (83, 96))	('c', 'Chemical', 'MESH:D002244', (83, 84))	('c', 'Chemical', 'MESH:D002244', (87, 88))	('EPAS1', 'Gene', (58, 63))	('catecholamine secretion', 'MPA', (83, 106))	('phaeochromocytomas', 'Disease', (28, 46))	('patients', 'Species', '9606', (14, 22))	('c', 'Chemical', 'MESH:D002244', (39, 40))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (28, 46))	('c', 'Chemical', 'MESH:D002244', (99, 100))
64815	33114456	HRM analysis of exon 1 and exon 9 of EPAS1 gene sequence were carried out to screen the possible mutations in genomic DNA extracted from 71 tumours and 10 control tissues.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (97, 106))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('c', 'Chemical', 'MESH:D002244', (62, 63))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('c', 'Chemical', 'MESH:D002244', (155, 156))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('tumours', 'Disease', (140, 147))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('c', 'Chemical', 'MESH:D002244', (78, 79))	('c', 'Chemical', 'MESH:D002244', (54, 55))	('EPAS1', 'Gene', (37, 42))
64842	33114456	In this study, a fold change of more than 2 was considered as DNA amplification or high EPAS1 expression, whereas fold change of less 0.5 was considered as DNA deletion or low EPAS1 expression.	('p', 'Chemical', 'MESH:D010758', (68, 69))	('c', 'Chemical', 'MESH:D002244', (142, 143))	('p', 'Chemical', 'MESH:D010758', (96, 97))	('c', 'Chemical', 'MESH:D002244', (48, 49))	('low', 'NegReg', (172, 175))	('EPAS1', 'Protein', (88, 93))	('p', 'Chemical', 'MESH:D010758', (184, 185))	('expression', 'MPA', (94, 104))	('high', 'Var', (83, 87))	('c', 'Chemical', 'MESH:D002244', (73, 74))	('c', 'Chemical', 'MESH:D002244', (22, 23))	('c', 'Chemical', 'MESH:D002244', (119, 120))
64843	33114456	The possible impact of EPAS1 mutation on protein expression in mutated (n = 8) and non-mutated (n = 8) tissues samples of phaeochromocytomas and paragangliomas was investigated by immunofluorescence analysis.	('mutation', 'Var', (29, 37))	('p', 'Chemical', 'MESH:D010758', (4, 5))	('c', 'Chemical', 'MESH:D002244', (196, 197))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('c', 'Chemical', 'MESH:D002244', (17, 18))	('protein expression', 'MPA', (41, 59))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('p', 'Chemical', 'MESH:D010758', (145, 146))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('p', 'Chemical', 'MESH:D010758', (114, 115))	('paragangliomas', 'Phenotype', 'HP:0002668', (145, 159))	('p', 'Chemical', 'MESH:D010758', (15, 16))	('c', 'Chemical', 'MESH:D002244', (193, 194))	('paraganglioma', 'Phenotype', 'HP:0002668', (145, 158))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (122, 159))	('p', 'Chemical', 'MESH:D010758', (122, 123))	('EPAS1', 'Gene', (23, 28))	('c', 'Chemical', 'MESH:D002244', (133, 134))
64849	33114456	The generated signals from EPAS1 was categorised as "0" (0% to less than 10%), "+" (10% to <30%), "++" (30% to <50%) and "+++" (>50%) according to the percentage and intensity of EPAS1 protein staining.	('c', 'Chemical', 'MESH:D002244', (136, 137))	('p', 'Chemical', 'MESH:D010758', (185, 186))	('c', 'Chemical', 'MESH:D002244', (154, 155))	('p', 'Chemical', 'MESH:D010758', (151, 152))	('+++" (>50%', 'Var', (122, 132))	('c', 'Chemical', 'MESH:D002244', (135, 136))	('EPAS1', 'Gene', (27, 32))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('++" (30% to <50%', 'Var', (99, 115))
64855	33114456	In the present study, genetic alterations in the EPAS1 sequence were noted in 12% (7/57) of phaeochromocytoma tumours (Table 1).	('noted', 'Reg', (69, 74))	('c', 'Chemical', 'MESH:D002244', (28, 29))	('p', 'Chemical', 'MESH:D010758', (7, 8))	('phaeochromocytoma tumours', 'Disease', 'MESH:D009369', (92, 117))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('c', 'Chemical', 'MESH:D002244', (103, 104))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('genetic alterations', 'Var', (22, 41))	('c', 'Chemical', 'MESH:D002244', (61, 62))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('phaeochromocytoma tumours', 'Phenotype', 'HP:0002666', (92, 117))	('phaeochromocytoma tumours', 'Disease', (92, 117))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('EPAS1', 'Gene', (49, 54))
64856	33114456	Two novel mutations c.1091A>T and c.1129A>T were identified in exon 9 (Figure 2).	('c.1091A>T', 'SUBSTITUTION', 'None', (20, 29))	('c.1091A>T', 'Var', (20, 29))	('c.1129A>T', 'Var', (34, 43))	('c.1129A>T', 'SUBSTITUTION', 'None', (34, 43))
64857	33114456	Both mutations were somatic heterozygous missense mutations (p.Lys364Met and P.Ser377Cys).	('Ser377Cys', 'Chemical', '-', (79, 88))	('p.Lys364Met', 'SUBSTITUTION', 'None', (61, 72))	('P.Ser377Cys', 'Var', (77, 88))	('p.Lys364Met', 'Var', (61, 72))	('c', 'Chemical', 'MESH:D002244', (26, 27))
64858	33114456	In paragangliomas, 7% (1/14) of patients had shown EPAS1 mutations.	('paragangliomas', 'Disease', (3, 17))	('paragangliomas', 'Disease', 'MESH:D010235', (3, 17))	('patients', 'Species', '9606', (32, 40))	('paraganglioma', 'Phenotype', 'HP:0002668', (3, 16))	('paragangliomas', 'Phenotype', 'HP:0002668', (3, 17))	('mutations', 'Var', (57, 66))	('EPAS1', 'Gene', (51, 56))
64859	33114456	The only c.1091A>T (p.Lys364Met) was identified tumour tissues in paraganglioma (Table 1).	('paraganglioma', 'Disease', 'MESH:D010235', (66, 79))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('p.Lys364Met', 'Var', (20, 31))	('c.1091A>T', 'Var', (9, 18))	('paraganglioma', 'Phenotype', 'HP:0002668', (66, 79))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('paraganglioma', 'Disease', (66, 79))	('p.Lys364Met', 'SUBSTITUTION', 'None', (20, 31))	('c.1091A>T', 'SUBSTITUTION', 'None', (9, 18))
64861	33114456	In silico analysis predicted that the identified mutation c.1091A>T (p.Lys364Met) was disease causing as it could cause changes in protein structure and function with pathological consequences (Table 1).	('c', 'Chemical', 'MESH:D002244', (120, 121))	('protein structure', 'MPA', (131, 148))	('c', 'Chemical', 'MESH:D002244', (24, 25))	('p.Lys364Met', 'Var', (69, 80))	('p.Lys364Met', 'SUBSTITUTION', 'None', (69, 80))	('function', 'MPA', (153, 161))	('c', 'Chemical', 'MESH:D002244', (189, 190))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('c', 'Chemical', 'MESH:D002244', (143, 144))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('c', 'Chemical', 'MESH:D002244', (180, 181))	('c', 'Chemical', 'MESH:D002244', (94, 95))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('c.1091A>T', 'Var', (58, 67))	('c', 'Chemical', 'MESH:D002244', (108, 109))	('c', 'Chemical', 'MESH:D002244', (156, 157))	('p', 'Chemical', 'MESH:D010758', (167, 168))	('c', 'Chemical', 'MESH:D002244', (58, 59))	('cause changes', 'Reg', (114, 127))	('c', 'Chemical', 'MESH:D002244', (176, 177))	('c', 'Chemical', 'MESH:D002244', (114, 115))	('c.1091A>T', 'SUBSTITUTION', 'None', (58, 67))
64864	33114456	Patients with phaeochromocytomas bearing mutation were four males and four females with a mean age of 41 years (age range 22-58).	('mutation', 'Var', (41, 49))	('phaeochromocytomas', 'Disease', (14, 32))	('phaeochromocytomas', 'Disease', 'MESH:D010673', (14, 32))	('Patients', 'Species', '9606', (0, 8))
64865	33114456	The mutations noted in this study were from functioning tumours.	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('mutations', 'Var', (4, 13))	('c', 'Chemical', 'MESH:D002244', (47, 48))
64866	33114456	Among the seven patients with phaeochromocytoma harbouring mutated EPAS1, two patients had clinical confirmation of neurofibromatosis 1 (case 94 and case 122).	('c', 'Chemical', 'MESH:D002244', (137, 138))	('EPAS1', 'Gene', (67, 72))	('c', 'Chemical', 'MESH:D002244', (96, 97))	('phaeochromocytoma', 'Disease', (30, 47))	('c', 'Chemical', 'MESH:D002244', (41, 42))	('c', 'Chemical', 'MESH:D002244', (35, 36))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (78, 86))	('c', 'Chemical', 'MESH:D002244', (149, 150))	('neurofibromatosis 1', 'Gene', '4763', (116, 135))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (30, 47))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (116, 133))	('neurofibromatosis 1', 'Gene', (116, 135))	('mutated', 'Var', (59, 66))	('c', 'Chemical', 'MESH:D002244', (91, 92))
64867	33114456	Table 2 revealed the associations of identified mutations with the clinical and pathological factors of patients with phaeochromocytomas/paragangliomas (Table 2).	('p', 'Chemical', 'MESH:D010758', (137, 138))	('c', 'Chemical', 'MESH:D002244', (89, 90))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (118, 151))	('c', 'Chemical', 'MESH:D002244', (129, 130))	('paragangliomas', 'Phenotype', 'HP:0002668', (137, 151))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('phaeochromocytomas/paragangliomas', 'Disease', (118, 151))	('c', 'Chemical', 'MESH:D002244', (72, 73))	('p', 'Chemical', 'MESH:D010758', (104, 105))	('paraganglioma', 'Phenotype', 'HP:0002668', (137, 150))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('p', 'Chemical', 'MESH:D010758', (118, 119))	('c', 'Chemical', 'MESH:D002244', (95, 96))	('patients', 'Species', '9606', (104, 112))	('mutations', 'Var', (48, 57))	('associations', 'Interaction', (21, 33))
64868	33114456	EPAS1 mutations occur in tumours with higher tumour weight (>50 gm) (Table 2; p = 0.0001).	('EPAS1', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour weight', 'Disease', (45, 58))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('tumours', 'Disease', 'MESH:D009369', (25, 32))	('tumour weight', 'Disease', 'MESH:D009369', (45, 58))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('tumours', 'Disease', (25, 32))	('mutations', 'Var', (6, 15))
64869	33114456	Moreover, EPAS1 mutations were associated with the large tumour size (>=50 mm).	('tumour', 'Disease', (57, 63))	('c', 'Chemical', 'MESH:D002244', (35, 36))	('mutations', 'Var', (16, 25))	('EPAS1', 'Gene', (10, 15))	('associated', 'Reg', (31, 41))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
64870	33114456	Most of the mutated samples (7 out of 8) had larger tumours (Table 2; p = 0.044).	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('mutated', 'Var', (12, 19))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('larger', 'PosReg', (45, 51))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
64871	33114456	Other than this, there was no association between the mutations in EPAS1 with patients' age, sex, race or the side, location and presence of tumour metastasis in patients with phaeochromocytomas/paragangliomas.	('patients', 'Species', '9606', (78, 86))	('c', 'Chemical', 'MESH:D002244', (135, 136))	('p', 'Chemical', 'MESH:D010758', (195, 196))	('c', 'Chemical', 'MESH:D002244', (181, 182))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (176, 209))	('EPAS1', 'Gene', (67, 72))	('mutations', 'Var', (54, 63))	('p', 'Chemical', 'MESH:D010758', (162, 163))	('c', 'Chemical', 'MESH:D002244', (118, 119))	('tumour metastasis', 'Disease', (141, 158))	('patients', 'Species', '9606', (162, 170))	('paragangliomas', 'Phenotype', 'HP:0002668', (195, 209))	('paraganglioma', 'Phenotype', 'HP:0002668', (195, 208))	('p', 'Chemical', 'MESH:D010758', (176, 177))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('c', 'Chemical', 'MESH:D002244', (187, 188))	('p', 'Chemical', 'MESH:D010758', (129, 130))	('c', 'Chemical', 'MESH:D002244', (34, 35))	('tumour metastasis', 'Disease', 'MESH:D009362', (141, 158))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('phaeochromocytomas/paragangliomas', 'Disease', (176, 209))	('p', 'Chemical', 'MESH:D010758', (78, 79))
64872	33114456	Amongst the phaeochromocytomas and paragangliomas (n = 71), 79% (56/71) showed DNA number amplification, whereas 21% (15/71) had DNA number deletion.	('c', 'Chemical', 'MESH:D002244', (17, 18))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (12, 49))	('DNA number deletion', 'Var', (129, 148))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('paragangliomas', 'Phenotype', 'HP:0002668', (35, 49))	('p', 'Chemical', 'MESH:D010758', (35, 36))	('p', 'Chemical', 'MESH:D010758', (12, 13))	('paraganglioma', 'Phenotype', 'HP:0002668', (35, 48))	('c', 'Chemical', 'MESH:D002244', (23, 24))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('DNA number', 'MPA', (79, 89))
64887	33114456	On the contrary, in EPAS1 mutation-negative tumour tissues (n = 8), 75% of samples showed no change or low expression and 25% of patients had shown high EPAS1 protein expression (Figure 1).	('p', 'Chemical', 'MESH:D010758', (129, 130))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('EPAS1 protein', 'Protein', (153, 166))	('EPAS1', 'Gene', (20, 25))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('p', 'Chemical', 'MESH:D010758', (159, 160))	('expression', 'MPA', (107, 117))	('tumour', 'Disease', (44, 50))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('patients', 'Species', '9606', (129, 137))	('low', 'NegReg', (103, 106))	('p', 'Chemical', 'MESH:D010758', (169, 170))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('p', 'Chemical', 'MESH:D010758', (109, 110))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('mutation-negative', 'Var', (26, 43))
64890	33114456	A statistically significant positive correlation of EPAS1 DNA copy number changes and mRNA expression were noted in the present study (r = +0.538; p = 0.009, Fisher exact test).	('p', 'Chemical', 'MESH:D010758', (120, 121))	('c', 'Chemical', 'MESH:D002244', (168, 169))	('p', 'Chemical', 'MESH:D010758', (147, 148))	('c', 'Chemical', 'MESH:D002244', (10, 11))	('p', 'Chemical', 'MESH:D010758', (28, 29))	('p', 'Chemical', 'MESH:D010758', (93, 94))	('c', 'Chemical', 'MESH:D002244', (62, 63))	('EPAS1', 'Gene', (52, 57))	('mRNA expression', 'MPA', (86, 101))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('c', 'Chemical', 'MESH:D002244', (74, 75))	('c', 'Chemical', 'MESH:D002244', (23, 24))	('copy number changes', 'Var', (62, 81))	('p', 'Chemical', 'MESH:D010758', (64, 65))
64891	33114456	As shown in Figure 5A, 70.2% (40/57) copy number amplified tumour samples had higher EPAS1 mRNA expression, whereas EPAS1 mRNA downregulation was only noted in 71.5% (5/7) of the EPAS1 DNA number deletion tumours (Figure 5A).	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumours', 'Disease', 'MESH:D009369', (205, 212))	('tumour', 'Disease', (205, 211))	('copy', 'Var', (37, 41))	('tumours', 'Disease', (205, 212))	('higher', 'PosReg', (78, 84))	('EPAS1', 'Gene', (179, 184))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('p', 'Chemical', 'MESH:D010758', (39, 40))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('EPAS1', 'Protein', (85, 90))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('tumour', 'Disease', (59, 65))
64892	33114456	The associations of EPAS1 mRNA expressions with copy number variation are presented in Figure 5B.	('c', 'Chemical', 'MESH:D002244', (48, 49))	('EPAS1', 'Gene', (20, 25))	('p', 'Chemical', 'MESH:D010758', (50, 51))	('copy number variation', 'Var', (48, 69))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('p', 'Chemical', 'MESH:D010758', (74, 75))	('p', 'Chemical', 'MESH:D010758', (33, 34))	('associations', 'Interaction', (4, 16))
64893	33114456	Patients with EPAS1 DNA copy number amplification exhibited significantly higher mRNA expression in comparison to no change or deletion groups (Figure 5B).	('p', 'Chemical', 'MESH:D010758', (140, 141))	('copy number amplification', 'Var', (24, 49))	('p', 'Chemical', 'MESH:D010758', (38, 39))	('mRNA expression', 'MPA', (81, 96))	('c', 'Chemical', 'MESH:D002244', (24, 25))	('higher', 'PosReg', (74, 80))	('c', 'Chemical', 'MESH:D002244', (117, 118))	('p', 'Chemical', 'MESH:D010758', (103, 104))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('EPAS1', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('c', 'Chemical', 'MESH:D002244', (43, 44))	('p', 'Chemical', 'MESH:D010758', (26, 27))
64894	33114456	Most of the tumour samples with no changes or deletion of EPAS1 DNA copy number exhibited similar results in mRNA expressions.	('deletion', 'Var', (46, 54))	('c', 'Chemical', 'MESH:D002244', (68, 69))	('tumour', 'Disease', (12, 18))	('c', 'Chemical', 'MESH:D002244', (35, 36))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('EPAS1', 'Gene', (58, 63))	('p', 'Chemical', 'MESH:D010758', (22, 23))	('mRNA expressions', 'MPA', (109, 125))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('p', 'Chemical', 'MESH:D010758', (116, 117))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
64895	33114456	On the other hand, most of the tumour samples with EPAS1 copy number amplifications had increased mRNA and protein expression.	('p', 'Chemical', 'MESH:D010758', (59, 60))	('p', 'Chemical', 'MESH:D010758', (107, 108))	('p', 'Chemical', 'MESH:D010758', (41, 42))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('copy number amplifications', 'Var', (57, 83))	('increased', 'PosReg', (88, 97))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('p', 'Chemical', 'MESH:D010758', (71, 72))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('c', 'Chemical', 'MESH:D002244', (57, 58))	('EPAS1', 'Gene', (51, 56))	('tumour', 'Disease', (31, 37))
64898	33114456	In addition, the majority (5/8) of tumours with EPAS1 mutations showed higher expression of protein when compared with non-neoplastic adrenal gland or mutation-negative tissues (Figure 4).	('higher', 'PosReg', (71, 77))	('tumours', 'Disease', (35, 42))	('p', 'Chemical', 'MESH:D010758', (126, 127))	('mutations', 'Var', (54, 63))	('c', 'Chemical', 'MESH:D002244', (105, 106))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('EPAS1', 'Gene', (48, 53))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('neoplastic adrenal gland', 'Phenotype', 'HP:0100631', (123, 147))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('protein', 'Protein', (92, 99))	('neoplastic adrenal', 'Phenotype', 'HP:0100631', (123, 141))	('expression of', 'MPA', (78, 91))
64899	33114456	This study identified novel mutations and clinicopathological implications of EPAS1 dysregulation in the pathogenesis of phaeochromocytoma/paraganglioma.	('dysregulation', 'Var', (84, 97))	('EPAS1', 'Gene', (78, 83))	('c', 'Chemical', 'MESH:D002244', (126, 127))	('c', 'Chemical', 'MESH:D002244', (58, 59))	('paraganglioma', 'Phenotype', 'HP:0002668', (139, 152))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('c', 'Chemical', 'MESH:D002244', (42, 43))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (121, 152))	('phaeochromocytoma/paraganglioma', 'Disease', (121, 152))	('p', 'Chemical', 'MESH:D010758', (49, 50))	('p', 'Chemical', 'MESH:D010758', (139, 140))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('c', 'Chemical', 'MESH:D002244', (47, 48))	('p', 'Chemical', 'MESH:D010758', (105, 106))	('p', 'Chemical', 'MESH:D010758', (64, 65))
64900	33114456	The mutation analysis of EPAS1 in 71 phaeochromocytomas and paragangliomas resulted in the identification of two heterozygous somatic mutations, which have not been previously reported in phaeochromocytomas and paragangliomas.	('p', 'Chemical', 'MESH:D010758', (165, 166))	('c', 'Chemical', 'MESH:D002244', (199, 200))	('c', 'Chemical', 'MESH:D002244', (48, 49))	('mutation analysis', 'Var', (4, 21))	('p', 'Chemical', 'MESH:D010758', (37, 38))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('paraganglioma', 'Phenotype', 'HP:0002668', (211, 224))	('p', 'Chemical', 'MESH:D010758', (211, 212))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (188, 225))	('paraganglioma', 'Phenotype', 'HP:0002668', (60, 73))	('p', 'Chemical', 'MESH:D010758', (60, 61))	('p', 'Chemical', 'MESH:D010758', (178, 179))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('EPAS1', 'Gene', (25, 30))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (37, 74))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('paragangliomas', 'Phenotype', 'HP:0002668', (211, 225))	('c', 'Chemical', 'MESH:D002244', (99, 100))	('paragangliomas', 'Phenotype', 'HP:0002668', (60, 74))	('c', 'Chemical', 'MESH:D002244', (42, 43))	('c', 'Chemical', 'MESH:D002244', (193, 194))
64901	33114456	The detected mutation p.Lys364Met in exon 9 was predicted to be pathogenic to the functionality of EPAS1 protein in computational analysis.	('p.Lys364Met', 'SUBSTITUTION', 'None', (22, 33))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('p', 'Chemical', 'MESH:D010758', (119, 120))	('p', 'Chemical', 'MESH:D010758', (48, 49))	('EPAS1 protein', 'Protein', (99, 112))	('p.Lys364Met', 'Var', (22, 33))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('c', 'Chemical', 'MESH:D002244', (73, 74))	('p', 'Chemical', 'MESH:D010758', (22, 23))	('c', 'Chemical', 'MESH:D002244', (53, 54))	('p', 'Chemical', 'MESH:D010758', (105, 106))	('c', 'Chemical', 'MESH:D002244', (85, 86))	('p', 'Chemical', 'MESH:D010758', (64, 65))
64903	33114456	Moreover, in the present study, we have noted that the patients with phaeochromocytoma/paraganglioma having EPAS1 mutations had no mutations in phaeochromocytoma/paraganglioma-susceptible gene panels except NF1 in two patients with Neurofibromatosis 1.	('NF1', 'Gene', (207, 210))	('mutations', 'Var', (114, 123))	('paraganglioma', 'Phenotype', 'HP:0002668', (87, 100))	('p', 'Chemical', 'MESH:D010758', (55, 56))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('p', 'Chemical', 'MESH:D010758', (204, 205))	('Neurofibromatosis 1', 'Gene', (232, 251))	('EPAS1', 'Gene', (108, 113))	('phaeochromocytoma/paraganglioma', 'Disease', (144, 175))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (144, 175))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (232, 249))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('p', 'Chemical', 'MESH:D010758', (162, 163))	('c', 'Chemical', 'MESH:D002244', (149, 150))	('p', 'Chemical', 'MESH:D010758', (218, 219))	('Neurofibromatosis 1', 'Gene', '4763', (232, 251))	('c', 'Chemical', 'MESH:D002244', (179, 180))	('patients', 'Species', '9606', (218, 226))	('c', 'Chemical', 'MESH:D002244', (155, 156))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('p', 'Chemical', 'MESH:D010758', (193, 194))	('c', 'Chemical', 'MESH:D002244', (74, 75))	('p', 'Chemical', 'MESH:D010758', (144, 145))	('p', 'Chemical', 'MESH:D010758', (17, 18))	('p', 'Chemical', 'MESH:D010758', (87, 88))	('NF1', 'Gene', '4763', (207, 210))	('c', 'Chemical', 'MESH:D002244', (202, 203))	('phaeochromocytoma/paraganglioma', 'Disease', (69, 100))	('phaeochromocytoma/paraganglioma', 'Disease', 'MESH:D010235', (69, 100))	('patients', 'Species', '9606', (55, 63))	('p', 'Chemical', 'MESH:D010758', (181, 182))
64906	33114456	Furthermore, gain-of-function mutations (p.Phe374Tyr and p.Met368Ile) in exon 9 EPAS1 in phaeochromocytomas/paragangliomas associated with the increased stability of HIF2alpha.	('increased', 'PosReg', (143, 152))	('c', 'Chemical', 'MESH:D002244', (24, 25))	('stability', 'CPA', (153, 162))	('gain-of-function', 'PosReg', (13, 29))	('HIF2alpha', 'Gene', '2034', (166, 175))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('p.Phe374Tyr', 'Var', (41, 52))	('p.Met368Ile', 'SUBSTITUTION', 'None', (57, 68))	('c', 'Chemical', 'MESH:D002244', (94, 95))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (89, 122))	('p.Met368Ile', 'Var', (57, 68))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('p.Phe374Tyr', 'SUBSTITUTION', 'None', (41, 52))	('paragangliomas', 'Phenotype', 'HP:0002668', (108, 122))	('paraganglioma', 'Phenotype', 'HP:0002668', (108, 121))	('EPAS1', 'Gene', (80, 85))	('HIF2alpha', 'Gene', (166, 175))	('c', 'Chemical', 'MESH:D002244', (145, 146))	('phaeochromocytomas/paragangliomas', 'Disease', (89, 122))
64907	33114456	Higher EPAS1 protein expression in mutated samples implied that the results of the current study are consistent with the previous findings.	('EPAS1 protein', 'Protein', (7, 20))	('mutated', 'Var', (35, 42))	('p', 'Chemical', 'MESH:D010758', (13, 14))	('c', 'Chemical', 'MESH:D002244', (83, 84))	('p', 'Chemical', 'MESH:D010758', (121, 122))	('expression', 'MPA', (21, 31))	('c', 'Chemical', 'MESH:D002244', (101, 102))	('Higher', 'PosReg', (0, 6))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('p', 'Chemical', 'MESH:D010758', (46, 47))	('p', 'Chemical', 'MESH:D010758', (53, 54))	('protein', 'Protein', (13, 20))
64909	33114456	EPAS1 mutations have been identified in several pathological conditions in humans, including congenital heart disease, erythrocytosis, Lynch syndrome, polycythaemia and in various tumours, e.g., in paraganglioma, phaeochromocytoma, pancreatic adenocarcinoma.	('p', 'Chemical', 'MESH:D010758', (213, 214))	('congenital heart disease', 'Disease', (93, 117))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('p', 'Chemical', 'MESH:D010758', (151, 152))	('c', 'Chemical', 'MESH:D002244', (224, 225))	('congenital heart disease', 'Phenotype', 'HP:0001627', (93, 117))	('Lynch syndrome', 'Disease', 'MESH:D003123', (135, 149))	('paraganglioma', 'Phenotype', 'HP:0002668', (198, 211))	('identified', 'Reg', (26, 36))	('pancreatic adenocarcinoma', 'Disease', (232, 257))	('polycythaemia', 'Disease', (151, 164))	('c', 'Chemical', 'MESH:D002244', (126, 127))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('c', 'Chemical', 'MESH:D002244', (61, 62))	('mutations', 'Var', (6, 15))	('c', 'Chemical', 'MESH:D002244', (85, 86))	('erythrocytosis', 'Disease', 'MESH:D011086', (119, 133))	('c', 'Chemical', 'MESH:D002244', (251, 252))	('EPAS1', 'Gene', (0, 5))	('c', 'Chemical', 'MESH:D002244', (138, 139))	('humans', 'Species', '9606', (75, 81))	('congenital heart disease', 'Disease', 'MESH:D006331', (93, 117))	('c', 'Chemical', 'MESH:D002244', (155, 156))	('erythrocytosis', 'Phenotype', 'HP:0001901', (119, 133))	('c', 'Chemical', 'MESH:D002244', (218, 219))	('erythrocytosis', 'Disease', (119, 133))	('p', 'Chemical', 'MESH:D010758', (232, 233))	('c', 'Chemical', 'MESH:D002244', (235, 236))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (232, 257))	('paraganglioma, phaeochromocytoma', 'Disease', 'MESH:D010235', (198, 230))	('tumours', 'Disease', (180, 187))	('p', 'Chemical', 'MESH:D010758', (48, 49))	('c', 'Chemical', 'MESH:D002244', (248, 249))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (232, 257))	('Lynch syndrome', 'Disease', (135, 149))	('c', 'Chemical', 'MESH:D002244', (241, 242))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('p', 'Chemical', 'MESH:D010758', (198, 199))	('polycythaemia', 'Disease', 'MESH:C548016', (151, 164))	('c', 'Chemical', 'MESH:D002244', (57, 58))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
64910	33114456	Somatic EPAS1 mutations in different cancers indicate that these mutations may occur in a cell during embryogenesis or later, which in turn predispose the affected tissues or organ to form tumours.	('c', 'Chemical', 'MESH:D002244', (129, 130))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('c', 'Chemical', 'MESH:D002244', (49, 50))	('c', 'Chemical', 'MESH:D002244', (159, 160))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('c', 'Chemical', 'MESH:D002244', (40, 41))	('p', 'Chemical', 'MESH:D010758', (140, 141))	('c', 'Chemical', 'MESH:D002244', (6, 7))	('p', 'Chemical', 'MESH:D010758', (146, 147))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('c', 'Chemical', 'MESH:D002244', (37, 38))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumours', 'Disease', (189, 196))	('EPAS1', 'Gene', (8, 13))	('predispose', 'Reg', (140, 150))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('c', 'Chemical', 'MESH:D002244', (81, 82))	('mutations', 'Var', (65, 74))
64913	33114456	The current study reports EPAS1 mutations in patients with phaeochromocytomas and paragangliomas and their correlation with various clinicopathological factors.	('paragangliomas', 'Phenotype', 'HP:0002668', (82, 96))	('c', 'Chemical', 'MESH:D002244', (137, 138))	('patients', 'Species', '9606', (45, 53))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('c', 'Chemical', 'MESH:D002244', (64, 65))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('p', 'Chemical', 'MESH:D010758', (45, 46))	('c', 'Chemical', 'MESH:D002244', (70, 71))	('mutations', 'Var', (32, 41))	('p', 'Chemical', 'MESH:D010758', (139, 140))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('c', 'Chemical', 'MESH:D002244', (4, 5))	('EPAS1', 'Gene', (26, 31))	('c', 'Chemical', 'MESH:D002244', (107, 108))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('paraganglioma', 'Phenotype', 'HP:0002668', (82, 95))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (59, 96))	('c', 'Chemical', 'MESH:D002244', (154, 155))
64914	33114456	The association of EPAS1 mutations with high tumour weight (p = 0.001) and larger tumour size (p = 0.044) implied that mutations of EPAS1 may contribute to the progression of this group of tumours.	('high tumour weight', 'Disease', 'MESH:D009369', (40, 58))	('c', 'Chemical', 'MESH:D002244', (142, 143))	('high tumour weight', 'Disease', (40, 58))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('tumour', 'Disease', (45, 51))	('EPAS1', 'Gene', (132, 137))	('mutations', 'Var', (25, 34))	('EPAS1', 'Gene', (19, 24))	('p', 'Chemical', 'MESH:D010758', (108, 109))	('mutations', 'Var', (119, 128))	('p', 'Chemical', 'MESH:D010758', (60, 61))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('association', 'Interaction', (4, 15))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Disease', (82, 88))	('p', 'Chemical', 'MESH:D010758', (184, 185))	('tumours', 'Disease', (189, 196))	('tumours', 'Disease', 'MESH:D009369', (189, 196))	('tumours', 'Phenotype', 'HP:0002664', (189, 196))	('p', 'Chemical', 'MESH:D010758', (95, 96))	('p', 'Chemical', 'MESH:D010758', (160, 161))	('contribute', 'Reg', (142, 152))
64916	33114456	Thus, the gain-of-function mutations of EPAS1 can lead to increased expression of VEGF and Flt1 in endothelial cells, which in turn promotes angiogenesis, thereby promoting tumour growth and progression.	('mutations', 'Var', (27, 36))	('tumour growth', 'Disease', 'MESH:D006130', (173, 186))	('expression', 'MPA', (68, 78))	('Flt1', 'Gene', '2321', (91, 95))	('p', 'Chemical', 'MESH:D010758', (70, 71))	('c', 'Chemical', 'MESH:D002244', (111, 112))	('promotes', 'PosReg', (132, 140))	('progression', 'CPA', (191, 202))	('VEGF', 'Gene', '7422', (82, 86))	('promoting', 'PosReg', (163, 172))	('p', 'Chemical', 'MESH:D010758', (163, 164))	('VEGF', 'Gene', (82, 86))	('tumour growth', 'Disease', (173, 186))	('p', 'Chemical', 'MESH:D010758', (132, 133))	('c', 'Chemical', 'MESH:D002244', (46, 47))	('increased', 'PosReg', (58, 67))	('c', 'Chemical', 'MESH:D002244', (21, 22))	('gain-of-function', 'PosReg', (10, 26))	('Flt1', 'Gene', (91, 95))	('c', 'Chemical', 'MESH:D002244', (60, 61))	('angiogenesis', 'CPA', (141, 153))	('EPAS1', 'Gene', (40, 45))	('c', 'Chemical', 'MESH:D002244', (121, 122))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('p', 'Chemical', 'MESH:D010758', (191, 192))
64918	33114456	In addition, mutations in EPAS1 increased the stability of HIF2alpha leading to pseudo-hypoxic response, thus allowing for the activation of target genes and hence contributing to chromaffin cells tumorigenesis.	('HIF2alpha', 'Gene', (59, 68))	('c', 'Chemical', 'MESH:D002244', (128, 129))	('pseudo-hypoxic response', 'MPA', (80, 103))	('c', 'Chemical', 'MESH:D002244', (191, 192))	('chromaffin cells', 'Disease', (180, 196))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('c', 'Chemical', 'MESH:D002244', (180, 181))	('p', 'Chemical', 'MESH:D010758', (98, 99))	('EPAS1', 'Gene', (26, 31))	('c', 'Chemical', 'MESH:D002244', (164, 165))	('HIF2alpha', 'Gene', '2034', (59, 68))	('contributing to', 'Reg', (164, 179))	('stability', 'MPA', (46, 55))	('activation', 'PosReg', (127, 137))	('mutations', 'Var', (13, 22))	('leading to', 'Reg', (69, 79))	('c', 'Chemical', 'MESH:D002244', (161, 162))	('p', 'Chemical', 'MESH:D010758', (89, 90))	('c', 'Chemical', 'MESH:D002244', (34, 35))	('chromaffin', 'Chemical', '-', (180, 190))	('p', 'Chemical', 'MESH:D010758', (65, 66))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('increased', 'PosReg', (32, 41))
64919	33114456	Therefore, mutations of EPAS1 may reduce HIF2alpha breakdown, which in turn could promote carcinogenesis by inducing pseudo-hypoxic conditions and promoting angiogenesis.	('p', 'Chemical', 'MESH:D010758', (126, 127))	('mutations', 'Var', (11, 20))	('promote', 'PosReg', (82, 89))	('p', 'Chemical', 'MESH:D010758', (117, 118))	('c', 'Chemical', 'MESH:D002244', (65, 66))	('HIF2alpha', 'Gene', '2034', (41, 50))	('c', 'Chemical', 'MESH:D002244', (38, 39))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('p', 'Chemical', 'MESH:D010758', (82, 83))	('carcinogenesis', 'Disease', (90, 104))	('promoting', 'PosReg', (147, 156))	('p', 'Chemical', 'MESH:D010758', (147, 148))	('EPAS1', 'Gene', (24, 29))	('reduce', 'NegReg', (34, 40))	('inducing', 'Reg', (108, 116))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('angiogenesis', 'CPA', (157, 169))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('c', 'Chemical', 'MESH:D002244', (130, 131))	('HIF2alpha', 'Gene', (41, 50))	('pseudo-hypoxic conditions', 'MPA', (117, 142))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('c', 'Chemical', 'MESH:D002244', (112, 113))	('p', 'Chemical', 'MESH:D010758', (47, 48))
64920	33114456	DNA copy number aberrations, dysregulated mRNA and protein level expressions in genes are commonly acquired changes in the cancer cells, thus playing a key role in the initiation and progression of cancers.	('p', 'Chemical', 'MESH:D010758', (6, 7))	('copy number aberrations', 'Var', (4, 27))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('dysregulated', 'Var', (29, 41))	('c', 'Chemical', 'MESH:D002244', (198, 199))	('c', 'Chemical', 'MESH:D002244', (126, 127))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('p', 'Chemical', 'MESH:D010758', (67, 68))	('c', 'Chemical', 'MESH:D002244', (4, 5))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('p', 'Chemical', 'MESH:D010758', (51, 52))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('c', 'Chemical', 'MESH:D002244', (108, 109))	('c', 'Chemical', 'MESH:D002244', (130, 131))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('c', 'Chemical', 'MESH:D002244', (123, 124))	('p', 'Chemical', 'MESH:D010758', (142, 143))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('p', 'Chemical', 'MESH:D010758', (183, 184))	('cancer', 'Disease', (123, 129))	('c', 'Chemical', 'MESH:D002244', (201, 202))
64921	33114456	In the current study, the aberrant EPAS1 DNA number in patients with phaeochromocytomas/paragangliomas implied its potential roles in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('c', 'Chemical', 'MESH:D002244', (137, 138))	('p', 'Chemical', 'MESH:D010758', (55, 56))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('aberrant', 'Var', (26, 34))	('EPAS1', 'Protein', (35, 40))	('phaeochromocytomas/paragangliomas', 'Disease', (69, 102))	('p', 'Chemical', 'MESH:D010758', (69, 70))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('p', 'Chemical', 'MESH:D010758', (115, 116))	('p', 'Chemical', 'MESH:D010758', (88, 89))	('c', 'Chemical', 'MESH:D002244', (74, 75))	('roles', 'Reg', (125, 130))	('p', 'Chemical', 'MESH:D010758', (105, 106))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (69, 102))	('carcinogenesis', 'Disease', (134, 148))	('patients', 'Species', '9606', (55, 63))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))
64922	33114456	Similarly, the dysregulated expression of EPAS1 mRNA in tumour samples indicated the tumour-associated functionality of EPAS1 in phaeochromocytomas and paragangliomas.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('c', 'Chemical', 'MESH:D002244', (96, 97))	('tumour', 'Disease', (85, 91))	('paragangliomas', 'Phenotype', 'HP:0002668', (152, 166))	('p', 'Chemical', 'MESH:D010758', (30, 31))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('EPAS1', 'Gene', (42, 47))	('c', 'Chemical', 'MESH:D002244', (140, 141))	('EPAS1', 'Gene', (120, 125))	('p', 'Chemical', 'MESH:D010758', (66, 67))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('c', 'Chemical', 'MESH:D002244', (75, 76))	('tumour', 'Disease', (56, 62))	('p', 'Chemical', 'MESH:D010758', (129, 130))	('c', 'Chemical', 'MESH:D002244', (106, 107))	('expression', 'MPA', (28, 38))	('dysregulated', 'Var', (15, 27))	('p', 'Chemical', 'MESH:D010758', (152, 153))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (129, 166))	('paraganglioma', 'Phenotype', 'HP:0002668', (152, 165))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
64924	33114456	The differential EPAS1 DNA number and mRNA expression in phaeochromocytomas and paragangliomas implied that the aberration of EPAS1 could affect these tumours in a different manner.	('c', 'Chemical', 'MESH:D002244', (142, 143))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('paragangliomas', 'Phenotype', 'HP:0002668', (80, 94))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (57, 94))	('c', 'Chemical', 'MESH:D002244', (62, 63))	('p', 'Chemical', 'MESH:D010758', (45, 46))	('tumours', 'Disease', (151, 158))	('affect', 'Reg', (138, 144))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('mRNA expression', 'MPA', (38, 53))	('EPAS1', 'Gene', (17, 22))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('p', 'Chemical', 'MESH:D010758', (57, 58))	('tumours', 'Disease', 'MESH:D009369', (151, 158))	('c', 'Chemical', 'MESH:D002244', (132, 133))	('c', 'Chemical', 'MESH:D002244', (68, 69))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('EPAS1', 'Gene', (126, 131))	('p', 'Chemical', 'MESH:D010758', (80, 81))	('aberration', 'Var', (112, 122))
64929	33114456	Moreover, the DNA amplification and mRNA overexpression in patients with phaeochromocytomas/paragangliomas bearing EPAS1 mutations is indicative of the concerted aberration of EPAS1 in the pathogenesis for this group of tumours.	('mutations', 'Var', (121, 130))	('p', 'Chemical', 'MESH:D010758', (189, 190))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('DNA amplification', 'MPA', (14, 31))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('tumours', 'Disease', 'MESH:D009369', (220, 227))	('EPAS1', 'Gene', (115, 120))	('p', 'Chemical', 'MESH:D010758', (92, 93))	('c', 'Chemical', 'MESH:D002244', (152, 153))	('c', 'Chemical', 'MESH:D002244', (78, 79))	('p', 'Chemical', 'MESH:D010758', (20, 21))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (73, 106))	('p', 'Chemical', 'MESH:D010758', (59, 60))	('patients', 'Species', '9606', (59, 67))	('c', 'Chemical', 'MESH:D002244', (84, 85))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (92, 106))	('c', 'Chemical', 'MESH:D002244', (138, 139))	('c', 'Chemical', 'MESH:D002244', (155, 156))	('overexpression', 'PosReg', (41, 55))	('tumours', 'Disease', (220, 227))	('mRNA', 'MPA', (36, 40))	('phaeochromocytomas/paragangliomas', 'Disease', (73, 106))	('tumours', 'Phenotype', 'HP:0002664', (220, 227))	('p', 'Chemical', 'MESH:D010758', (73, 74))	('p', 'Chemical', 'MESH:D010758', (215, 216))	('p', 'Chemical', 'MESH:D010758', (47, 48))
64931	33114456	Previous studies reported that dysregulation and gain-of-function mutation of EPAS1 associated with neuroendocrine tumours such as paraganglioma and phaeochromocytomas by inducing pseudo-hypoxic tumour microenvironment.	('c', 'Chemical', 'MESH:D002244', (175, 176))	('p', 'Chemical', 'MESH:D010758', (189, 190))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('p', 'Chemical', 'MESH:D010758', (149, 150))	('p', 'Chemical', 'MESH:D010758', (180, 181))	('paraganglioma and phaeochromocytomas', 'Disease', 'MESH:D010235', (131, 167))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))	('c', 'Chemical', 'MESH:D002244', (160, 161))	('p', 'Chemical', 'MESH:D010758', (131, 132))	('c', 'Chemical', 'MESH:D002244', (125, 126))	('hypoxic tumour', 'Disease', 'MESH:D009369', (187, 201))	('mutation', 'Var', (66, 74))	('c', 'Chemical', 'MESH:D002244', (204, 205))	('p', 'Chemical', 'MESH:D010758', (19, 20))	('c', 'Chemical', 'MESH:D002244', (109, 110))	('men', 'Species', '9606', (214, 217))	('gain-of-function', 'PosReg', (49, 65))	('paraganglioma', 'Phenotype', 'HP:0002668', (131, 144))	('c', 'Chemical', 'MESH:D002244', (60, 61))	('dysregulation', 'MPA', (31, 44))	('EPAS1', 'Gene', (78, 83))	('neuroendocrine tumours', 'Disease', (100, 122))	('c', 'Chemical', 'MESH:D002244', (154, 155))	('neuroendocrine tumours', 'Disease', 'MESH:D018358', (100, 122))	('hypoxic tumour', 'Disease', (187, 201))	('c', 'Chemical', 'MESH:D002244', (193, 194))	('c', 'Chemical', 'MESH:D002244', (88, 89))	('inducing', 'PosReg', (171, 179))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
64933	33114456	This study has reported multiple novel EPAS1 mutations in patients with phaeochromocytomas/paragangliomas.	('paraganglioma', 'Phenotype', 'HP:0002668', (91, 104))	('EPAS1', 'Gene', (39, 44))	('p', 'Chemical', 'MESH:D010758', (58, 59))	('mutations', 'Var', (45, 54))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (72, 105))	('p', 'Chemical', 'MESH:D010758', (17, 18))	('phaeochromocytomas/paragangliomas', 'Disease', (72, 105))	('p', 'Chemical', 'MESH:D010758', (72, 73))	('p', 'Chemical', 'MESH:D010758', (29, 30))	('patients', 'Species', '9606', (58, 66))	('paragangliomas', 'Phenotype', 'HP:0002668', (91, 105))	('p', 'Chemical', 'MESH:D010758', (91, 92))
64934	33114456	These mutations were noted to be related with altered expression and/or structural and functional changes in EPAS1, which in turn could play an important role in the pathogenesis of phaeochromocytomas and paragangliomas.	('p', 'Chemical', 'MESH:D010758', (182, 183))	('EPAS1', 'Gene', (109, 114))	('play', 'Reg', (136, 140))	('paraganglioma', 'Phenotype', 'HP:0002668', (205, 218))	('p', 'Chemical', 'MESH:D010758', (205, 206))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (182, 219))	('c', 'Chemical', 'MESH:D002244', (119, 120))	('p', 'Chemical', 'MESH:D010758', (146, 147))	('altered', 'Reg', (46, 53))	('paragangliomas', 'Phenotype', 'HP:0002668', (205, 219))	('mutations', 'Var', (6, 15))	('structural', 'MPA', (72, 82))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('functional', 'MPA', (87, 97))	('c', 'Chemical', 'MESH:D002244', (187, 188))	('c', 'Chemical', 'MESH:D002244', (130, 131))	('role', 'Reg', (154, 158))	('c', 'Chemical', 'MESH:D002244', (98, 99))	('p', 'Chemical', 'MESH:D010758', (136, 137))	('expression', 'MPA', (54, 64))	('p', 'Chemical', 'MESH:D010758', (56, 57))	('p', 'Chemical', 'MESH:D010758', (166, 167))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('c', 'Chemical', 'MESH:D002244', (193, 194))
64981	30483454	It has also been linked to mutations in the gene for succinate dehydrogenase (SDHD) subunits, rearranged during transfection (RET), and many other genes, which are autosomal dominant in nature.	('mutations', 'Var', (27, 36))	('rearranged during transfection', 'Gene', (94, 124))	('SDHD', 'Gene', (78, 82))	('SDHD', 'Gene', '6392', (78, 82))	('RET', 'Gene', '5979', (126, 129))	('rearranged during transfection', 'Gene', '5979', (94, 124))	('succinate dehydrogenase', 'Gene', '6392', (53, 76))	('RET', 'Gene', (126, 129))	('succinate dehydrogenase', 'Gene', (53, 76))	('linked', 'Reg', (17, 23))
65072	30345003	Establishment of the fact that mutations in multiple components of the PHD-VHL-HIF-2alpha pathway associate with pseudohypoxia-driven tumorigenesis allowed us not only to better understand the effect of this phenomenon but also to more deeply appreciate the value of functional abnormalities in the physiologic tissue oxygen-sensing mechanism.	('mutations', 'Var', (31, 40))	('PHD-VHL-HIF-2alpha', 'Disease', (71, 89))	('associate', 'Reg', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('pseudohypoxia', 'Disease', (113, 126))	('PHD-VHL-HIF-2alpha', 'Disease', 'MESH:D006623', (71, 89))	('functional abnormalities', 'Disease', (267, 291))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('pseudohypoxia', 'Disease', 'None', (113, 126))	('functional abnormalities', 'Disease', 'MESH:D000014', (267, 291))	('oxygen', 'Chemical', 'MESH:D010100', (318, 324))	('tumor', 'Disease', (134, 139))
65073	30345003	Mutations in the tricarboxylic acid cycle-related genes opened an additional window into understanding the physiology of one of the basic cellular metabolic pathways and consequences of its disruption.	('Mutations', 'Var', (0, 9))	('tricarboxylic acid cycle-related genes', 'Gene', (17, 55))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (17, 35))
65074	30345003	New pathophysiologically distinct groups of mutations will widen and deepen our understanding of additional pathways in PPGL tumorigenesis and hopefully introduce additional diagnostic and therapeutic approaches.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PPGL', 'Gene', (120, 124))	('tumor', 'Disease', (125, 130))	('mutations', 'Var', (44, 53))
65087	30345003	We now know that PPGLs represent the highest hereditary-driven endocrine condition:up to 40% of cases are related to mutations in 15 well-established driver genes and a growing number of disease-modifying genes and these numbers are expected to grow - .	('mutations', 'Var', (117, 126))	('endocrine condition', 'Phenotype', 'HP:0000818', (63, 82))	('related', 'Reg', (106, 113))	('PGLs', 'Phenotype', 'HP:0002668', (18, 22))	('PPGLs', 'Gene', (17, 22))	('PPGLs', 'Chemical', '-', (17, 22))
65093	30345003	It represents 15 to 20% of PPGLs, which are hereditary in 25% of cases, and includes tumors associated with mutations in von Hippel-Lindau tumor suppressor gene ( VHL), Elegans homologs ( EGLN1-3), and endothelial PAS domain protein 1 ( EPAS1) gene.	('von Hippel-Lindau tumor', 'Disease', 'MESH:D006623', (121, 144))	('PPGLs', 'Chemical', '-', (27, 32))	('VHL', 'Gene', (163, 166))	('endothelial PAS domain protein 1', 'Gene', (202, 234))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('EPAS1', 'Gene', '2034', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('associated', 'Reg', (92, 102))	('tumors', 'Disease', (85, 91))	('VHL', 'Gene', '7428', (163, 166))	('von Hippel-Lindau tumor', 'Disease', (121, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('PGLs', 'Phenotype', 'HP:0002668', (28, 32))	('EGLN1', 'Gene', '54583', (188, 193))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('mutations', 'Var', (108, 117))	('EGLN1', 'Gene', (188, 193))	('EPAS1', 'Gene', (237, 242))	('endothelial PAS domain protein 1', 'Gene', '2034', (202, 234))
65094	30345003	VHL, expressing both germline and somatic mutation patterns, shows mutation in up to 100% of patients with VHL-related PPGL.	('VHL', 'Gene', '7428', (107, 110))	('mutation', 'Var', (67, 75))	('PPGL', 'Disease', (119, 123))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (107, 110))	('patients', 'Species', '9606', (93, 101))
65101	30345003	Whereas the first will be self-limited and seldom provide enough time for efficient tumorigenesis, pseudohypoxia can definitely extend to the significant length of time; in the case of VHL mutation, it will associate with a lack of recognition and degradation of the HIFalpha and beta heterodimer (in the case of PPGL, it is mostly HIF-2alpha), which will bind to the core DNA RCTCG sequence at the hypoxia-responsive elements (HREs) to activate transcription of multiple genes that could associate with tumor formation, including glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF), and many others.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('HIFalpha', 'Gene', (267, 275))	('hypoxia', 'Disease', (105, 112))	('vascular endothelial growth factor', 'Gene', '7422', (562, 596))	('glucose transporter 1', 'Gene', '6513', (531, 552))	('VEGF', 'Gene', '7422', (598, 602))	('HIF-2alpha', 'Gene', (332, 342))	('hypoxia', 'Disease', 'MESH:D000860', (399, 406))	('tumor', 'Disease', (504, 509))	('vascular endothelial growth factor', 'Gene', (562, 596))	('glucose transporter 1', 'Gene', (531, 552))	('hypoxia', 'Disease', 'MESH:D000860', (105, 112))	('VEGF', 'Gene', (598, 602))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (504, 509))	('GLUT1', 'Gene', '6513', (554, 559))	('pseudohypoxia', 'Disease', (99, 112))	('VHL', 'Gene', (185, 188))	('HIFalpha', 'Gene', '3091;2034', (267, 275))	('activate', 'PosReg', (437, 445))	('pseudohypoxia', 'Disease', 'None', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (504, 509))	('HIF-2alpha', 'Gene', '2034', (332, 342))	('transcription', 'MPA', (446, 459))	('tumor', 'Disease', (84, 89))	('mutation', 'Var', (189, 197))	('GLUT1', 'Gene', (554, 559))	('VHL', 'Gene', '7428', (185, 188))	('hypoxia', 'Disease', (399, 406))
65102	30345003	The importance of the PHD-VHL-HIF-2alpha pathway in the pathogenesis of PPGL was also shown through the association of mutations in every component of this pathway (reviewed in ).	('association', 'Reg', (104, 115))	('PPGL', 'Disease', (72, 76))	('PHD-VHL-HIF-2alpha', 'Disease', (22, 40))	('PHD-VHL-HIF-2alpha', 'Disease', 'MESH:D006623', (22, 40))	('mutations', 'Var', (119, 128))
65103	30345003	Mutations in EGLN 1 and 2, which encode PDH 2 and 1, respectively, were also shown to associate with the development of PPGLs.	('PPGLs', 'Chemical', '-', (120, 125))	('EGLN 1 and 2', 'Gene', '54583;112398', (13, 25))	('associate with', 'Reg', (86, 100))	('Mutations', 'Var', (0, 9))	('PGLs', 'Phenotype', 'HP:0002668', (121, 125))	('PPGLs', 'Disease', (120, 125))
65104	30345003	Germline, mosaic, or constitutional gain-of-function mutations in EPAS1 also associate with an increase in the transcriptional activity of HIF-2alpha target genes , , although the actual transcriptional signature seems to differ somewhat from the one associated with VHL and is associated with a distinct clinical constellation, including PPGL, polycythemia, and somatostatinomas, and is referred to as Zhuang-Pacak syndrome.	('gain-of-function', 'PosReg', (36, 52))	('polycythemia', 'Phenotype', 'HP:0001901', (345, 357))	('polycythemia', 'Disease', 'MESH:D011086', (345, 357))	('Zhuang-Pacak syndrome', 'Disease', (403, 424))	('HIF-2alpha', 'Gene', (139, 149))	('increase', 'PosReg', (95, 103))	('VHL', 'Gene', (267, 270))	('PPGL', 'Disease', (339, 343))	('EPAS1', 'Gene', '2034', (66, 71))	('mutations', 'Var', (53, 62))	('VHL', 'Gene', '7428', (267, 270))	('somatostatinomas', 'Disease', 'MESH:D013005', (363, 379))	('HIF-2alpha', 'Gene', '2034', (139, 149))	('EPAS1', 'Gene', (66, 71))	('transcriptional activity', 'MPA', (111, 135))	('polycythemia', 'Disease', (345, 357))	('somatostatinomas', 'Disease', (363, 379))
65109	30345003	There are recently described constitutional mutations of the malate dehydrogenase ( MH2):the enzyme that converts malate to oxaloacetate further down the TCA:that associate with PGL in a single family .	('TCA', 'MPA', (154, 157))	('TCA', 'Chemical', 'MESH:D014233', (154, 157))	('malate dehydrogenase', 'Gene', (61, 81))	(' MH2):', 'Gene', (83, 89))	('malate', 'Chemical', 'MESH:C030298', (61, 67))	('malate dehydrogenase', 'Gene', '4199', (61, 81))	('mutations', 'Var', (44, 53))	('malate', 'Chemical', 'MESH:C030298', (114, 120))	('oxaloacetate', 'Chemical', 'MESH:D062907', (124, 136))
65115	30345003	These mutations are associated with the activation of kinase signaling pathways: RAS-RAF-MEK and PI3K-AKT-mTOR for RET, HRAS, NF1, and TMEM127 and MYC-MAX for MAX.	('MYC', 'Gene', (147, 150))	('MAX', 'Gene', '4149', (151, 154))	('NF1', 'Gene', '4763', (126, 129))	('mTOR', 'Gene', (106, 110))	('RET', 'Gene', (115, 118))	('MAX', 'Gene', (159, 162))	('TMEM127', 'Gene', (135, 142))	('MYC', 'Gene', '4609', (147, 150))	('NF1', 'Gene', (126, 129))	('RAF', 'Gene', '22882', (85, 88))	('mTOR', 'Gene', '2475', (106, 110))	('mutations', 'Var', (6, 15))	('MEK', 'Gene', '5609', (89, 92))	('MAX', 'Gene', (151, 154))	('TMEM127', 'Gene', '55654', (135, 142))	('activation', 'PosReg', (40, 50))	('HRAS', 'Gene', '3265', (120, 124))	('RAF', 'Gene', (85, 88))	('HRAS', 'Gene', (120, 124))	('MEK', 'Gene', (89, 92))	('kinase signaling pathways', 'Pathway', (54, 79))	('MAX', 'Gene', '4149', (159, 162))	('RET', 'Gene', '5979', (115, 118))
65123	30345003	A small proportion of PPGLs show additional kinase signaling pathway-associated mutations in FGFR1, KIF1B, and MET but these still need to be validated.	('PGLs', 'Phenotype', 'HP:0002668', (23, 27))	('mutations', 'Var', (80, 89))	('PPGLs', 'Gene', (22, 27))	('PPGLs', 'Chemical', '-', (22, 27))	('KIF1B', 'Gene', '23095', (100, 105))	('KIF1B', 'Gene', (100, 105))	('kinase signaling pathway-associated', 'Pathway', (44, 79))	('FGFR1', 'Gene', (93, 98))	('MET', 'Gene', (111, 114))	('FGFR1', 'Gene', '2260', (93, 98))
65125	30345003	Tumors in this group occur in 5 to 10% of PPGLs and in most cases are related to somatic mutations in tumor suppressor cold shock domain-containing E1 ( CSDE1) and oncogene mastermind-like transcriptional coactivator 3 ( MAML3).	('mastermind-like transcriptional coactivator 3', 'Gene', (173, 218))	('tumor', 'Disease', (102, 107))	('mastermind-like transcriptional coactivator 3', 'Gene', '55534', (173, 218))	('PGLs', 'Phenotype', 'HP:0002668', (43, 47))	('shock', 'Phenotype', 'HP:0031273', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PPGLs', 'Chemical', '-', (42, 47))	('Tumors', 'Disease', (0, 6))	('CSDE1', 'Gene', (153, 158))	('CSDE1', 'Gene', '7812', (153, 158))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (89, 98))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('related', 'Reg', (70, 77))	('MAML3', 'Gene', '55534', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MAML3', 'Gene', (221, 226))
65126	30345003	Somatic mutations in five genes: ATRX, KMT2D, SETD2, TERT, and TP53:have a synergistic effect on PPGL tumorigenesis and raise the possibility of association with an excessively aggressive course of the disease.	('SETD2', 'Gene', (46, 51))	('TERT', 'Gene', (53, 57))	('TERT', 'Gene', '7015', (53, 57))	('excessively aggressive', 'Phenotype', 'HP:0000718', (165, 187))	('KMT2D', 'Gene', (39, 44))	('KMT2D', 'Gene', '8085', (39, 44))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))	('ATRX', 'Gene', '546', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mutations', 'Var', (8, 17))	('SETD2', 'Gene', '29072', (46, 51))	('association', 'Interaction', (145, 156))	('ATRX', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('PPGL', 'Gene', (97, 101))
65129	30345003	Pathogenesis-based knowledge had also allowed us to design new therapeutic approaches; the best example would be the use of specific HIF-2alpha antagonists (PT2399) and prolyl hydroxylase activators (R59949 and KRH102053) that promote HIF hydroxylation, thus restoring VHL-driven recognition and rapid degradation.	('HIF hydroxylation', 'MPA', (235, 252))	('VHL', 'Gene', '7428', (269, 272))	('HIF-2alpha', 'Gene', '2034', (133, 143))	('R59949', 'Var', (200, 206))	('KRH102053', 'Var', (211, 220))	('restoring', 'PosReg', (259, 268))	('HIF-2alpha', 'Gene', (133, 143))	('VHL', 'Gene', (269, 272))	('promote', 'PosReg', (227, 234))	('rapid degradation', 'MPA', (296, 313))
65133	29617662	Driver Fusions and Their Implications in the Development and Treatment of Human Cancers Gene fusions represent an important class of somatic alterations in cancer.	('Gene fusions', 'Var', (88, 100))	('Human Cancers', 'Disease', (74, 87))	('Human Cancers', 'Disease', 'MESH:D009369', (74, 87))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))
65135	29617662	Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect.	('oncogenes', 'Gene', (104, 113))	('tumor', 'Disease', (178, 183))	('expression', 'MPA', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('increased', 'PosReg', (130, 139))	('fusions', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
65141	29617662	To date, many studies have focused on determining the landscape of SNPs, insertions, deletions, and copy number alterations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (85, 94))	('SNPs', 'Var', (67, 71))	('copy number alterations', 'Var', (100, 123))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('insertions', 'Var', (73, 83))	('cancer', 'Disease', (127, 133))
65142	29617662	Although such genomic alterations make up a large fraction of the typical tumor mutation burden, gene fusions also play a critical role in oncogenesis.	('alterations', 'Var', (22, 33))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
65144	29617662	Gene fusions function as diagnostic markers for specific cancer types.	('Gene fusions', 'Var', (0, 12))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
65145	29617662	For example, a frequent translocation between chromosomes 11 and 22 creates a fusion between EWSR1 and FLI1 in Ewing's sarcoma.	('fusion', 'Var', (78, 84))	('translocation', 'Var', (24, 37))	('FLI1', 'Gene', (103, 107))	('EWSR1', 'Gene', (93, 98))	('FLI1', 'Gene', '2313', (103, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('EWSR1', 'Gene', '2130', (93, 98))	("Ewing's sarcoma", 'Disease', (111, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))
65152	29617662	performed breakpoint analysis on exon microarrays across 974 cancer samples and identified 198 candidate fusions in annotated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('fusions', 'Var', (105, 112))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
65154	29617662	Some studies focus on important classes of genes, such as kinase fusions, which may have particular structural properties that are selected for during oncogenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('kinase fusions', 'Var', (58, 72))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
65168	29617662	Fusion events may be associated with altered expression of one or both of the fusion gene partners, a well-known example being multiple myeloma tumors in which translocation t(4;14) fuses the highly expressed IGH locus with the tyrosine protein kinase FGFR3.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('FGFR3', 'Gene', (252, 257))	('myeloma tumors', 'Disease', 'MESH:D009101', (136, 150))	('IGH', 'Gene', '3492', (209, 212))	('IGH', 'Gene', (209, 212))	('myeloma tumors', 'Disease', (136, 150))	('multiple myeloma', 'Phenotype', 'HP:0006775', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FGFR3', 'Gene', '2261', (252, 257))	('translocation t', 'Var', (160, 175))
65170	29617662	Figure 2A shows that between 6% (mesothelioma [MESO]) and 28% (KIRP) of kinase fusions displayed outlier overexpression of the kinase partner.	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('fusions', 'Var', (79, 86))	('mesothelioma', 'Disease', (33, 45))	('overexpression', 'PosReg', (105, 119))
65171	29617662	Oncogenes tended to show higher likelihoods of overexpression, whereas TSGs displayed lower likelihoods.	('Oncogenes', 'Var', (0, 9))	('TSG', 'Gene', '57045', (71, 74))	('overexpression', 'MPA', (47, 61))	('TSG', 'Gene', (71, 74))
65172	29617662	Between 3% (breast invasive carcinoma [BRCA]) and 38% (PCPG) of TSG fusions showed outlier underexpression, generally higher than both oncogenes and kinases.	('BRCA', 'Gene', (39, 43))	('fusions', 'Var', (68, 75))	('TSG', 'Gene', (64, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (12, 37))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (12, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('breast invasive carcinoma', 'Disease', (12, 37))	('BRCA', 'Gene', '672', (39, 43))	('underexpression', 'NegReg', (91, 106))	('TSG', 'Gene', '57045', (64, 67))
65174	29617662	Samples with fusions involving oncogenes, such as EGFR, ERBB2, and RET, showed increased expression of those genes relative to samples without fusions across cancer types.	('increased', 'PosReg', (79, 88))	('expression', 'MPA', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('RET', 'Gene', '5979', (67, 70))	('EGFR', 'Gene', '1956', (50, 54))	('fusions', 'Var', (13, 20))	('cancer', 'Disease', (158, 164))	('ERBB2', 'Gene', '2064', (56, 61))	('EGFR', 'Gene', (50, 54))	('ERBB2', 'Gene', (56, 61))	('RET', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
65178	29617662	For example, TP53 is affected by mutations rather than fusions in most cancer types.	('TP53', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (13, 17))
65179	29617662	However, in sarcoma (SARC), both fusions and mutations affecting TP53 were detected.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (65, 69))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('TP53', 'Gene', (65, 69))	('sarcoma', 'Disease', (12, 19))	('fusions', 'Var', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('detected', 'Reg', (75, 83))
65180	29617662	In acute myeloid leukemia (LAML), several CBFB fusions but no mutations were observed, yet other cancer types also exhibited CBFB mutations (Table S3; Figure S2).	('CBFB', 'Gene', '865', (125, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('cancer', 'Disease', (97, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('CBFB', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('exhibited', 'Reg', (115, 124))	('CBFB', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (130, 139))	('fusions', 'Var', (47, 54))	('acute myeloid leukemia', 'Disease', (3, 25))	('CBFB', 'Gene', '865', (42, 46))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
65184	29617662	Recurrent CBFB-MYH11 fusions in LAML are significantly associated with decreased expression of the tumor suppressor CBFB, which functions as a transcriptional regulator (Figure 2D).	('tumor', 'Disease', (99, 104))	('CBFB', 'Gene', (10, 14))	('MYH11', 'Gene', '4629', (15, 20))	('MYH11', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CBFB', 'Gene', '865', (116, 120))	('fusions', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CBFB', 'Gene', '865', (10, 14))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (81, 91))	('CBFB', 'Gene', (116, 120))
65185	29617662	In breast cancer, copy number amplification is a well-known mechanism of ERBB2 overexpression, and treatment of these HER2+ patients with trastuzumab is an established and effective targeted therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('copy number amplification', 'Var', (18, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HER2', 'Gene', (118, 122))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('trastuzumab', 'Chemical', 'MESH:D000068878', (138, 149))	('HER2', 'Gene', '2064', (118, 122))	('overexpression', 'PosReg', (79, 93))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('patients', 'Species', '9606', (124, 132))
65186	29617662	Interestingly, three of four samples with ERBB2 fusions and two samples without a called fusion showed HPV integration within 1 Mb of ERBB2.	('fusions', 'Var', (48, 55))	('ERBB2', 'Gene', '2064', (134, 139))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('HPV integration', 'CPA', (103, 118))
65189	29617662	Comparison of kinase fusions across different cancer types indicated that kinase fusions are significantly enriched in THCA (35.6%, Fisher's exact test, p < 2.2e-16) (Figure 3B).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('THCA', 'Disease', (119, 123))	('kinase fusions', 'Var', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
65193	29617662	For example, there are more TK fusions in THCA and GBM, more CK1 fusions in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and esophageal carcinoma (ESCA) and more AGC fusions in liver hepatocellular carcinoma (LIHC).	('colon adenocarcinoma', 'Disease', (121, 141))	('TK fusions', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('COAD', 'Disease', (143, 147))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 236))	('CK1', 'Gene', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('esophageal carcinoma', 'Disease', (154, 174))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('LIHC', 'Disease', (238, 242))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (121, 141))	('corpus endometrial carcinoma', 'Disease', (84, 112))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (84, 112))	('fusions', 'Var', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('CK1', 'Species', '2498238', (61, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('liver hepatocellular carcinoma', 'Disease', (206, 236))	('LIHC', 'Disease', 'None', (238, 242))	('COAD', 'Disease', 'MESH:D029424', (143, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))
65194	29617662	Across different cancer types, we found an enrichment of TK and TKL kinase fusions for 3'-kinases but no strong preference for 5'-kinases (Figure S3).	('TKL', 'Gene', (64, 67))	('fusions', 'Var', (75, 82))	("3'-kinases", 'MPA', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TKL', 'Gene', '7294', (64, 67))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
65196	29617662	As expected, fusions in the FGFR kinase family (FGFR2 and FGFR3) are the most frequent 5'-kinase fusions, given their high recurrence in individual cancer types (Figure 3C).	('cancer', 'Disease', (148, 154))	('FGFR2', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('FGFR3', 'Gene', (58, 63))	('fusions', 'Var', (13, 20))
65206	29617662	For example, we found a TRABD-DDR2 fusion in one head and neck squamous cell carcinoma (HNSC) sample, which fused the stronger TRABD promoter with DDR2, resulting in its overexpression (Figure 4D).	('neck squamous cell carcinoma', 'Disease', (58, 86))	('DDR2', 'Gene', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('DDR2', 'Gene', '4921', (30, 34))	('DDR2', 'Gene', '4921', (147, 151))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('fusion', 'Var', (35, 41))	('DDR2', 'Gene', (147, 151))	('overexpression', 'PosReg', (170, 184))
65208	29617662	DDR2 fusions were also detected in another nine samples from five different cancer types, which could be treated similarly given sufficient DDR2 overexpression (Table S1).	('fusions', 'Var', (5, 12))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DDR2', 'Gene', '4921', (140, 144))	('DDR2', 'Gene', (140, 144))	('cancer', 'Disease', (76, 82))	('DDR2', 'Gene', (0, 4))	('overexpression', 'PosReg', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
65209	29617662	Although mutations in oncogenes or TSGs may lead to tumorigenesis, fusions involving those genes are also an important class of cancer driver events.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lead to', 'Reg', (44, 51))	('tumor', 'Disease', (52, 57))	('TSG', 'Gene', '57045', (35, 38))	('mutations', 'Var', (9, 18))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TSG', 'Gene', (35, 38))	('cancer', 'Disease', (128, 134))
65211	29617662	We characterized patients as having a driver mutation, a mutation in a driver gene, and/or a driver fusion (fusion involving a driver gene).	('mutation', 'Var', (57, 65))	('driver fusion', 'Disease', (93, 106))	('driver gene', 'Gene', (71, 82))	('driver', 'Disease', (38, 44))	('patients', 'Species', '9606', (17, 25))
65212	29617662	Although the majority of cancer cases have known driver mutations (48.6%, mean 6.8 mutations) or mutations in driver genes (28.1%, mean 4.2 mutations), we found that 8.3% have both driver mutations and driver fusion events (mean 5.5 mutations and 1.2 fusions), 6.4% have both mutations and fusions in driver genes (mean 4.2 mutations and 1.3 fusions), and 1.8% have driver fusions only (mean 1.1 fusions) (Figure 5A).	('mutations', 'Var', (97, 106))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (324, 333))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (276, 285))	('fusions', 'Var', (290, 297))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
65214	29617662	The significant decrease in the numbers of mutations (Mann-Whitney U test, p < 2.2e-16) reflects the functionality of fusions across multiple cancer types.	('multiple cancer', 'Disease', (133, 148))	('decrease', 'NegReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (43, 52))	('multiple cancer', 'Disease', 'MESH:D009369', (133, 148))
65215	29617662	Moreover, within cancer types, we observed a range of 0.2% (HNSC) to 14.0% (LAML) of tumors with fusions but no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('fusions', 'Var', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
65224	29617662	Several Food and Drug Administration (FDA)-approved drugs exist to target ALK fusions in lung and other cancer types.	('ALK', 'Gene', (74, 77))	('lung', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (78, 85))	('ALK', 'Gene', '238', (74, 77))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
65226	29617662	In most cases, fusion status corresponded to copy number neutral overexpression of ALK (Figure 6D).	('ALK', 'Gene', '238', (83, 86))	('copy number neutral', 'Var', (45, 64))	('corresponded', 'Reg', (29, 41))	('overexpression', 'PosReg', (65, 79))	('ALK', 'Gene', (83, 86))
65229	29617662	We detected ESR1 fusions in 16 samples from five different cancer types (9 samples from BRCA).	('ESR1', 'Gene', '2099', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('fusions', 'Var', (17, 24))	('BRCA', 'Gene', '672', (88, 92))	('ESR1', 'Gene', (12, 16))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('BRCA', 'Gene', (88, 92))	('detected', 'Reg', (3, 11))
65231	29617662	We observed strict mutual exclusivity between ESR1 mutations and fusions (Figure 5C).	('ESR1', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', '2099', (46, 50))
65236	29617662	Similarly, ESR1 expression is higher when ESR1 is mutated in BRCA, CESC, and UCEC, which are all hormone receptor-related cancer types.	('ESR1', 'Gene', '2099', (11, 15))	('higher', 'PosReg', (30, 36))	('UCEC', 'Disease', (77, 81))	('cancer', 'Disease', (122, 128))	('ESR1', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CESC', 'Disease', (67, 71))	('hormone receptor', 'Gene', (97, 113))	('mutated', 'Var', (50, 57))	('ESR1', 'Gene', (11, 15))	('ESR1', 'Gene', '2099', (42, 46))	('hormone receptor', 'Gene', '3164', (97, 113))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA', 'Gene', '672', (61, 65))	('expression', 'MPA', (16, 26))	('BRCA', 'Gene', (61, 65))
65237	29617662	Further functional study to determine the mechanism of ESR1 fusions could suggest drug development directions.	('ESR1', 'Gene', (55, 59))	('ESR1', 'Gene', '2099', (55, 59))	('fusions', 'Var', (60, 67))
65240	29617662	However, patients with known driver fusions may be poor candidates for immunotherapy because of their reduced mutational burden, especially without clear evidence of immune cell infiltration and overall immunogenicity.	('patients', 'Species', '9606', (9, 17))	('reduced', 'NegReg', (102, 109))	('mutational burden', 'MPA', (110, 127))	('fusions', 'Var', (36, 43))
65248	29617662	When comparing fusion events with the remainder of the cancer cohort, fusions involving oncogenes such as EGFR, ERBB2, and RET had increased expression.	('ERBB2', 'Gene', '2064', (112, 117))	('increased', 'PosReg', (131, 140))	('ERBB2', 'Gene', (112, 117))	('RET', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (141, 151))	('EGFR', 'Gene', '1956', (106, 110))	('RET', 'Gene', '5979', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('fusions', 'Var', (70, 77))	('cancer', 'Disease', (55, 61))	('EGFR', 'Gene', (106, 110))
65250	29617662	In addition to well-known recurrent fusions such as FGFR3-TACC3, we also detected 245 kinases with recurrent fusions to different partner genes, which may ultimately prove to be successful drug targets.	('TACC3', 'Gene', '10460', (58, 63))	('FGFR3', 'Gene', '2261', (52, 57))	('TACC3', 'Gene', (58, 63))	('fusions', 'Var', (109, 116))	('FGFR3', 'Gene', (52, 57))
65251	29617662	We showed that a meaningful percentage of patients (1.8%) harbor fusions involving cancer driver genes but have no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (42, 50))	('fusions', 'Var', (65, 72))	('cancer', 'Disease', (83, 89))
65254	29617662	The significant decrease in mutational burden observed in patients with fusions in driver genes points toward a reduced efficacy of immunotherapy in these patients, despite fusion peptides themselves potentially being good immunogenic targets.	('decrease', 'NegReg', (16, 24))	('efficacy of immunotherapy', 'CPA', (120, 145))	('patients', 'Species', '9606', (155, 163))	('mutational burden', 'MPA', (28, 45))	('reduced', 'NegReg', (112, 119))	('patients', 'Species', '9606', (58, 66))	('fusions', 'Var', (72, 79))
65256	29617662	We sought to prioritize fusions relevant to cancer by highlighting their associations with gene expression, potential for targeted therapy, and roles in cancer hallmark pathways.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gene expression', 'MPA', (91, 106))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associations', 'Interaction', (73, 85))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('fusions', 'Var', (24, 31))
65258	29617662	Fusions play an increasingly appreciated role in tumorigenesis and progression and represent an important source of improved treatment options.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('progression', 'CPA', (67, 78))	('Fusions', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
65273	29617662	The percentage of kinase genes in each group across different cancer types was defined as the number of kinase genes with fusions in each group divided by their sum, denoted as pg.	('fusions', 'Var', (122, 129))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
65278	29617662	For TCGA tumor samples where both MC3 (Key Resources Table) mutation calls and gene fusion calls were available, we obtained the genetic alteration events, including fusion, inframe deletion, inframe insertion, missense mutation, nonsense mutation, nonstop mutation, splice site mutation, and translation start site mutation in 299 driver genes.	('nonstop', 'Disease', (249, 256))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('nonsense mutation', 'Var', (230, 247))	('missense mutation', 'Var', (211, 228))	('tumor', 'Disease', (9, 14))	('inframe insertion', 'Var', (192, 209))	('splice', 'MPA', (267, 273))	('MC3', 'Gene', (34, 37))	('fusion', 'Var', (166, 172))	('MC3', 'Gene', '4159', (34, 37))
65280	29617662	Highly recurrent fusions were found in prostate, bladder, breast, and lung cancers Expression increased in oncogene fusions but decreased in tumor suppressor genes Thyroid carcinoma showed significantly higher rates of kinase fusions Tumors with fusion events tend to have lower mutational burden	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('increased', 'PosReg', (94, 103))	('Tumors', 'Disease', 'MESH:D009369', (234, 240))	('Expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('prostate', 'Disease', (39, 47))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (164, 181))	('fusions', 'Var', (116, 123))	('decreased', 'NegReg', (128, 137))	('breast', 'Disease', (58, 64))	('oncogene', 'Gene', (107, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Tumors', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('bladder', 'Disease', (49, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('tumor', 'Disease', (141, 146))	('Tumors', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (164, 181))	('Thyroid carcinoma', 'Disease', (164, 181))
65328	11580870	CO2 pneumo peritoneum has been claimed to produce hypercapnia, respiratory acidosis, increase in the systemic vascular resistance, decreased cardiac index and increased mean arterial pressure.	('respiratory acidosis', 'Phenotype', 'HP:0005972', (63, 83))	('hypercapnia', 'Phenotype', 'HP:0012416', (50, 61))	('hypercapnia', 'Disease', (50, 61))	('decreased', 'NegReg', (131, 140))	('increased', 'PosReg', (159, 168))	('hypercapnia', 'Disease', 'MESH:D006935', (50, 61))	('respiratory acidosis', 'Disease', (63, 83))	('mean arterial pressure', 'MPA', (169, 191))	('cardiac index', 'MPA', (141, 154))	('systemic vascular resistance', 'MPA', (101, 129))	('respiratory acidosis', 'Disease', 'MESH:D000142', (63, 83))	('CO2', 'Chemical', 'MESH:D002245', (0, 3))	('increased mean arterial pressure', 'Phenotype', 'HP:0004972', (159, 191))	('acidosis', 'Phenotype', 'HP:0001941', (75, 83))	('CO2', 'Var', (0, 3))	('increase', 'PosReg', (85, 93))
65357	28924583	This situation is further compounded by the lack of assay standardisation and the use of different reporting units for both aldosterone (ng/dL, ng/L, pg/mL and pmol/L) and renin (PRA: ng/mL/h, nmol/L/h and pmol/L/min; DRC: muIU/mL, mIU/L and ng/L).	('ng/L', 'Var', (242, 246))	('mIU', 'Chemical', '-', (232, 235))	('mIU/L', 'Var', (232, 237))	('renin', 'Gene', (172, 177))	('nmol/L/h', 'Var', (193, 201))	('PRA', 'Var', (179, 182))	('renin', 'Gene', '5972', (172, 177))	('aldosterone', 'Chemical', 'MESH:D000450', (124, 135))	('pmol/L/min', 'Var', (206, 216))
65373	28924583	In brief, the inclusion criteria for healthy volunteers were; age >=18years, BMI <=30 kg/m2, non-pregnant, BP<140/90 mm Hg, normal electrolytes and kidney function (MDRD equation eGFR>=60 mL/min/1.73 m2), non-smoker, Irish Caucasian, and not taking prescribed/Over The Counter (OTC) medications for a minimum of 3 months.	('min/1', 'Gene', '966', (191, 196))	('MDRD', 'Disease', (165, 169))	('BP<140/90', 'Var', (107, 116))	('kidney function', 'MPA', (148, 163))	('min/1', 'Gene', (191, 196))	('MDRD', 'Disease', 'None', (165, 169))
65407	28924583	When stratified according to gender, a cut-off of <=4.5 mIU/L in women and <=14.2 mIU/L in men resulted in a diagnostic sensitivity of 100% in both sexes and specificity of 98% and 89%, respectively.	('<=4.5', 'Var', (50, 55))	('mIU', 'Chemical', '-', (82, 85))	('men', 'Species', '9606', (67, 70))	('men', 'Species', '9606', (91, 94))	('<=14.2', 'Var', (75, 81))	('women', 'Species', '9606', (65, 70))	('mIU', 'Chemical', '-', (56, 59))
65433	28924583	In men and women, the DRC ROC curve analyses (AUC=0.97) demonstrated the high predictive power of this biochemical marker to select out those patients without PA. A cut-off for DRC <=14.2 mIU/L resulted in a diagnostic sensitivity and specificity of 100% and 84%, respectively and likelihood ratio of 6.2:1.	('<=14.2', 'Var', (181, 187))	('PA', 'Phenotype', 'HP:0011736', (159, 161))	('mIU', 'Chemical', '-', (188, 191))	('women', 'Species', '9606', (11, 16))	('patients', 'Species', '9606', (142, 150))	('DRC', 'MPA', (177, 180))	('men', 'Species', '9606', (13, 16))	('men', 'Species', '9606', (3, 6))
65554	28685135	For larger tumors, suspicious lymph nodes, infiltrative margins upon local resection, nuclear pleomorphism, or high mitotic activity, they suggested pancreaticoduodenectomy with lymph node dissection.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('pancreatic', 'Disease', (149, 159))	('nuclear pleomorphism', 'Var', (86, 106))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('pancreatic', 'Disease', 'MESH:D010195', (149, 159))	('high', 'Var', (111, 115))
65623	28078330	Meanwhile, malignancy is reported in up to 70% among those with extra-adrenal tumors, and up to 50% of those with SDHB mutations.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('reported', 'Reg', (25, 33))	('malignancy', 'Disease', 'MESH:D009369', (11, 21))	('SDHB', 'Gene', '6390', (114, 118))	('malignancy', 'Disease', (11, 21))	('SDHB', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('extra-adrenal tumors', 'Disease', 'MESH:D010236', (64, 84))	('extra-adrenal tumors', 'Disease', (64, 84))	('mutations', 'Var', (119, 128))
65720	28078330	Because metyrosine takes 3 days to reach its full effect, and because it results in incomplete blockade, institutions that advocate use of catecholamine synthesis blockade use this in tandem with alpha- or calcium-channel blockade.	('catecholamine synthesis blockade', 'Phenotype', 'HP:0003334', (139, 171))	('blockade', 'MPA', (95, 103))	('metyrosine', 'Var', (8, 18))	('catecholamine', 'Chemical', 'MESH:D002395', (139, 152))	('metyrosine', 'Chemical', 'MESH:D019805', (8, 18))	('calcium', 'Chemical', 'MESH:D002118', (206, 213))
65738	28078330	In patients who received phenoxybenzamine, the irreversible alpha blockade can contribute to hypotension in the first 24 hours or longer (half-life is 10 days) after tumor removal, and thus, fluid resuscitation becomes paramount.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('hypotension', 'Disease', (93, 104))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (25, 41))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('hypotension', 'Phenotype', 'HP:0002615', (93, 104))	('tumor', 'Disease', (166, 171))	('phenoxybenzamine', 'Var', (25, 41))	('contribute to', 'Reg', (79, 92))	('patients', 'Species', '9606', (3, 11))	('hypotension', 'Disease', 'MESH:D007022', (93, 104))
65740	28078330	Pheo-induced stimulation of the alpha-2 receptor can inhibit insulin release leading to hyperglycemia.	('Pheo-induced', 'Var', (0, 12))	('inhibit', 'NegReg', (53, 60))	('hyperglycemia', 'Disease', (88, 101))	('stimulation', 'PosReg', (13, 24))	('insulin release', 'MPA', (61, 76))	('alpha-2 receptor', 'Protein', (32, 48))	('hyperglycemia', 'Phenotype', 'HP:0003074', (88, 101))	('hyperglycemia', 'Disease', 'MESH:D006943', (88, 101))	('Pheo', 'Chemical', '-', (0, 4))
65741	28078330	Discontinuation of this stimulus can result in hyperinsulinemia and hypoglycemia.	('hypoglycemia', 'Phenotype', 'HP:0001943', (68, 80))	('result in', 'Reg', (37, 46))	('hyperinsulinemia and hypoglycemia', 'Disease', 'MESH:D044903', (47, 80))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (47, 63))	('Discontinuation', 'Var', (0, 15))
65746	28078330	Larger tumor size, sympathetic paragangliomas (rather than pheochromocytomas stemming from adrenal gland), and succinate dehydrogenase B (SDHB) mutations are associated with decreased overall survival as these clinical characteristics are associated with a higher risk of metastases.	('metastases', 'Disease', 'MESH:D009362', (272, 282))	('overall survival', 'MPA', (184, 200))	('succinate dehydrogenase B', 'Gene', (111, 136))	('metastases', 'Disease', (272, 282))	('mutations', 'Var', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('paragangliomas', 'Disease', 'MESH:D010235', (31, 45))	('paragangliomas', 'Phenotype', 'HP:0002668', (31, 45))	('pheochromocytomas stemming from adrenal', 'Phenotype', 'HP:0006748', (59, 98))	('paraganglioma', 'Phenotype', 'HP:0002668', (31, 44))	('succinate dehydrogenase B', 'Gene', '6390', (111, 136))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('SDHB', 'Gene', '6390', (138, 142))	('pheochromocytomas stemming', 'Phenotype', 'HP:0002666', (59, 85))	('decreased', 'NegReg', (174, 183))	('pheochromocytomas', 'Disease', 'MESH:D010673', (59, 76))	('pheochromocytomas', 'Disease', (59, 76))	('SDHB', 'Gene', (138, 142))	('tumor', 'Disease', (7, 12))	('paragangliomas', 'Disease', (31, 45))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
65767	28078330	As mentioned previously, those patients with mutations of the SDHB gene carry a significantly higher risk of malignant disease.	('mutations', 'Var', (45, 54))	('malignant disease', 'Disease', (109, 126))	('patients', 'Species', '9606', (31, 39))	('SDHB', 'Gene', '6390', (62, 66))	('SDHB', 'Gene', (62, 66))	('malignant disease', 'Disease', 'MESH:D009369', (109, 126))
65809	24520306	I131-methyliodobenzylguanidine (MIBG) is an analog of norepinephrine and is absorbed by the paraganglioma tissue.	('paraganglioma', 'Disease', (92, 105))	('norepinephrine', 'Chemical', 'MESH:D009638', (54, 68))	('paraganglioma', 'Disease', 'MESH:D010235', (92, 105))	('I131-methyliodobenzylguanidine', 'Var', (0, 30))	('MIBG', 'Chemical', '-', (32, 36))	('I131-methyliodobenzylguanidine', 'Chemical', '-', (0, 30))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))
65810	24520306	I131-MIBG has been used in diagnosing and localizing extra-adrenal paraganglioma with a specificity close to 100% and a sensitivity approaching 90%.	('I131-MIBG', 'Var', (0, 9))	('extra-adrenal paraganglioma', 'Disease', (53, 80))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (53, 80))	('MIBG', 'Chemical', '-', (5, 9))	('paraganglioma', 'Phenotype', 'HP:0002668', (67, 80))
65840	23933153	We have moved from the "10% tumor" to the "10 gene tumor" to our current understanding of 13 susceptibility genes: the von Hippel-Lindau (VHL) gene; the RET gene in multiple endocrine neoplasia type 2 (MEN2); the neurofibromatosis type 1 (NF-1) gene associated with von Recklinghausen's disease; mutations of the A, B, C, and D subunits of the mitochondrial succinate dehydrogenase complex (SDH); the SDHAF2 gene; TMEM127 gene mutations; MAX gene mutations; PHD2; and the recently described: H-RAS and gain-of-function HIF2alpha mutations.	('NF-1', 'Gene', (239, 243))	('von Hippel-Lindau', 'Gene', (119, 136))	('tumor', 'Disease', (28, 33))	('TMEM127', 'Gene', (414, 421))	('neurofibromatosis type 1', 'Gene', (213, 237))	('RET', 'Gene', '5979', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (213, 230))	('SDH', 'Chemical', '-', (401, 404))	('PHD2', 'Gene', (458, 462))	('succinate', 'Chemical', 'MESH:D019802', (358, 367))	('von Hippel-Lindau', 'Gene', '7428', (119, 136))	('tumor', 'Disease', (51, 56))	('neoplasia', 'Phenotype', 'HP:0002664', (184, 193))	('TMEM127', 'Gene', '55654', (414, 421))	('MAX gene', 'Gene', (438, 446))	('mutations', 'Var', (529, 538))	('VHL', 'Gene', (138, 141))	('neurofibroma', 'Phenotype', 'HP:0001067', (213, 225))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (174, 200))	('SDH', 'Chemical', '-', (391, 394))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('HIF2alpha', 'Gene', (519, 528))	('RET', 'Gene', (153, 156))	('neurofibromatosis type 1', 'Gene', '4763', (213, 237))	('PHD2', 'Gene', '54583', (458, 462))	("von Recklinghausen's disease", 'Disease', 'MESH:C537392', (266, 294))	('endocrine neoplasia type 2', 'Disease', (174, 200))	('mutations', 'Var', (427, 436))	('SDHAF2', 'Gene', '54949', (401, 407))	('associated', 'Reg', (250, 260))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (174, 193))	('SDHAF2', 'Gene', (401, 407))	('gain-of-function', 'PosReg', (502, 518))	("von Recklinghausen's disease", 'Disease', (266, 294))	('H-RAS', 'Gene', (492, 497))	('VHL', 'Gene', '7428', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MEN', 'Species', '9606', (202, 205))	('HIF2alpha', 'Gene', '2034', (519, 528))	('H-RAS', 'Gene', '3265', (492, 497))	('mutations', 'Var', (447, 456))	('NF-1', 'Gene', '4763', (239, 243))	('mutations', 'Var', (296, 305))
65841	23933153	Approximately 35% of pheochromocytomas/paragangliomas are associated with an inherited mutation and, as recently reported, approximately 14% of sporadic tumors demonstrate somatic mutations.	('pheochromocytomas', 'Phenotype', 'HP:0002666', (21, 38))	('sporadic tumors', 'Disease', 'MESH:D009369', (144, 159))	('associated', 'Reg', (58, 68))	('pheochromocytomas/paragangliomas', 'Disease', (21, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('sporadic tumors', 'Disease', (144, 159))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (21, 53))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (21, 37))	('paragangliomas', 'Phenotype', 'HP:0002668', (39, 53))	('mutation', 'Var', (87, 95))	('paraganglioma', 'Phenotype', 'HP:0002668', (39, 52))
65845	23933153	Currently, pheochromocytoma/paraganglioma predisposing genetic mutations are most commonly clustered based on transcriptomes: Cluster 1 = hypoxic transcriptional signature (SDH genes = 1A and VHL gene = 1B), HIF2alpha; Cluster 2 = kinase receptor signaling and protein translation (RET, NF1, TMEM127, MAX).	('mutations', 'Var', (63, 72))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (11, 27))	('HIF2alpha', 'Gene', '2034', (208, 217))	('pheochromocytoma/paraganglioma', 'Disease', (11, 41))	('RET', 'Gene', '5979', (282, 285))	('HIF2alpha', 'Gene', (208, 217))	('SDH', 'Chemical', '-', (173, 176))	('paraganglioma', 'Phenotype', 'HP:0002668', (28, 41))	('hypoxic', 'Disease', (138, 145))	('hypoxic', 'Disease', 'MESH:D000860', (138, 145))	('VHL', 'Gene', (192, 195))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (11, 41))	('RET', 'Gene', (282, 285))	('VHL', 'Gene', '7428', (192, 195))	('TMEM127', 'Gene', (292, 299))	('TMEM127', 'Gene', '55654', (292, 299))
65851	23933153	Loss of function mutations in the VHL gene results in stabilization of HIFalpha leading to downstream transcription of cellular proliferation genes and to von Hippel-Lindau disease.	('stabilization', 'MPA', (54, 67))	('HIFalpha', 'MPA', (71, 79))	('von Hippel-Lindau disease', 'Disease', (155, 180))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (155, 180))	('Loss of function', 'NegReg', (0, 16))	('VHL', 'Gene', (34, 37))	('downstream transcription', 'MPA', (91, 115))	('cellular proliferation genes', 'Gene', (119, 147))	('VHL', 'Gene', '7428', (34, 37))	('mutations', 'Var', (17, 26))
65862	23933153	Activating mutations of this proto-oncogene lead to the autosomal dominant syndrome known as multiple endocrine neoplasia type 2 (MEN 2).	('lead to', 'Reg', (44, 51))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (56, 83))	('MEN', 'Species', '9606', (130, 133))	('Activating mutations', 'Var', (0, 20))	('endocrine neoplasia type 2', 'Disease', (102, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (112, 121))	('endocrine neoplasia type 2', 'Disease', 'MESH:D018813', (102, 128))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (102, 121))	('autosomal dominant syndrome', 'Disease', (56, 83))
65864	23933153	MEN2A mutations are associated with a disulfide bond disruption causing active homodimers to increase tyrosine kinase activity.	('MEN2A', 'Gene', '5979', (0, 5))	('active homodimers', 'MPA', (72, 89))	('disulfide', 'Chemical', 'MESH:D004220', (38, 47))	('MEN2A', 'Gene', (0, 5))	('increase', 'PosReg', (93, 101))	('disulfide bond disruption', 'MPA', (38, 63))	('tyrosine kinase activity', 'MPA', (102, 126))	('mutations', 'Var', (6, 15))	('increase tyrosine kinase', 'Phenotype', 'HP:0003231', (93, 117))
65865	23933153	MEN2B mutations are known to alter the substrate specificity of RET.	('substrate specificity', 'MPA', (39, 60))	('MEN2B', 'Gene', '5979', (0, 5))	('RET', 'Gene', (64, 67))	('RET', 'Gene', '5979', (64, 67))	('mutations', 'Var', (6, 15))	('MEN2B', 'Gene', (0, 5))	('alter', 'Reg', (29, 34))
65873	23933153	Inactivating mutations of NF1 lead to the autosomal dominant disorder von Recklinghausen's disease or neurofibromatosis type 1 (NF1).	('lead to', 'Reg', (30, 37))	('neurofibromatosis type 1', 'Gene', (102, 126))	('neurofibromatosis type 1', 'Gene', '4763', (102, 126))	("autosomal dominant disorder von Recklinghausen's disease", 'Disease', 'MESH:C537392', (42, 98))	('NF1', 'Gene', (26, 29))	('Inactivating mutations', 'Var', (0, 22))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (102, 119))	('neurofibroma', 'Phenotype', 'HP:0001067', (102, 114))
65875	23933153	Patients with NF1 are at risk for the development of various tumors including neurofibromas, medullary thyroid carcinoma, carcinoid tumors, parathyroid tumors, peripheral nerve sheath tumors, and pheochromocytomas.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (103, 120))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (93, 120))	('neurofibromas', 'Phenotype', 'HP:0001067', (78, 91))	('neurofibromas', 'Disease', 'MESH:D009455', (78, 91))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('carcinoid tumors', 'Disease', (122, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (196, 212))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('peripheral nerve sheath tumors', 'Disease', (160, 190))	('carcinoid', 'Phenotype', 'HP:0100570', (122, 131))	('pheochromocytomas', 'Disease', (196, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('pheochromocytomas', 'Disease', 'MESH:D010673', (196, 213))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('neurofibroma', 'Phenotype', 'HP:0001067', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('NF1', 'Var', (14, 17))	('tumors', 'Disease', (61, 67))	('neurofibromas', 'Disease', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (196, 213))	('tumors', 'Disease', (132, 138))	('peripheral nerve sheath tumors', 'Disease', 'MESH:D010524', (160, 190))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (103, 120))	('thyroid carcinoma', 'Disease', (103, 120))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('parathyroid tumors', 'Disease', 'MESH:D010282', (140, 158))	('parathyroid tumors', 'Disease', (140, 158))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('carcinoid tumors', 'Disease', 'MESH:D002276', (122, 138))
65882	23933153	Inactivating mutations of SDHx genes results in an accumulation of succinate and reactive oxygen free radicals, which can stabilize HIFalpha and thus activate the hypoxia dependent pathways.	('activate', 'PosReg', (150, 158))	('succinate', 'MPA', (67, 76))	('reactive oxygen free radicals', 'Chemical', '-', (81, 110))	('SDHx', 'Gene', (26, 30))	('SDHx', 'Chemical', '-', (26, 30))	('Inactivating mutations', 'Var', (0, 22))	('accumulation', 'PosReg', (51, 63))	('succinate', 'Chemical', 'MESH:D019802', (67, 76))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('stabilize HIFalpha', 'MPA', (122, 140))	('hypoxia', 'Disease', (163, 170))
65892	23933153	Mutations in all four genes of the SDHx complex are now known to be associated with the development of pheochromocytoma/paraganglioma though the clinical presentation varies significantly depending on which gene is mutated.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (103, 119))	('associated with', 'Reg', (68, 83))	('paraganglioma', 'Phenotype', 'HP:0002668', (120, 133))	('SDHx complex', 'Gene', (35, 47))	('pheochromocytoma/paraganglioma', 'Disease', (103, 133))	('Mutations', 'Var', (0, 9))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (103, 133))	('SDHx', 'Chemical', '-', (35, 39))
65893	23933153	The link between SDHA mutations and pheochromocytoma/paragangliomas was long hypothesized but not proven until 2011.	('SDHA', 'Gene', (17, 21))	('pheochromocytoma/paragangliomas', 'Disease', (36, 67))	('pheochromocytoma/paragangliomas', 'Disease', 'MESH:D010673', (36, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (36, 52))	('mutations', 'Var', (22, 31))	('SDHA', 'Gene', '6389', (17, 21))	('paraganglioma', 'Phenotype', 'HP:0002668', (53, 66))	('paragangliomas', 'Phenotype', 'HP:0002668', (53, 67))
65897	23933153	later described 6 patients with SDHA mutations whose ages at presentation ranged from 27-77 years and who presented with an adrenal pheochromocytoma (1 patient), extra adrenal paragangliomas (3 patients), or head and neck paragangliomas (2 patients).	('extra adrenal paragangliomas', 'Phenotype', 'HP:0006737', (162, 190))	('patient', 'Species', '9606', (194, 201))	('gliomas', 'Phenotype', 'HP:0009733', (183, 190))	('patient', 'Species', '9606', (240, 247))	('patient', 'Species', '9606', (18, 25))	('SDHA', 'Gene', (32, 36))	('patient', 'Species', '9606', (152, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (222, 235))	('paragangliomas', 'Phenotype', 'HP:0002668', (222, 236))	('extra adrenal paragangliomas', 'Disease', 'MESH:D010236', (162, 190))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (132, 148))	('SDHA', 'Gene', '6389', (32, 36))	('gliomas', 'Phenotype', 'HP:0009733', (229, 236))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (124, 148))	('patients', 'Species', '9606', (194, 202))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (124, 148))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (217, 236))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (208, 236))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (240, 248))	('patients', 'Species', '9606', (18, 26))	('adrenal pheochromocytoma', 'Disease', (124, 148))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (208, 236))	('paragangliomas', 'Phenotype', 'HP:0002668', (176, 190))	('paraganglioma', 'Phenotype', 'HP:0002668', (176, 189))	('extra adrenal paragangliomas', 'Disease', (162, 190))	('presented with', 'Reg', (106, 120))
65898	23933153	described a 30-year-old male patient with a SDHA mutation who presented with a non-secretory pituitary adenoma that demonstrated loss of SDHA protein expression, similar to that of the patients' mother who presented with an SDHA-related paraganglioma.	('patient', 'Species', '9606', (29, 36))	('pituitary adenoma', 'Disease', (93, 110))	('pituitary adenoma', 'Disease', 'MESH:D010911', (93, 110))	('SDHA', 'Gene', (224, 228))	('paraganglioma', 'Phenotype', 'HP:0002668', (237, 250))	('loss', 'NegReg', (129, 133))	('patient', 'Species', '9606', (185, 192))	('mutation', 'Var', (49, 57))	('SDHA', 'Gene', '6389', (44, 48))	('SDHA', 'Gene', '6389', (137, 141))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (93, 110))	('paraganglioma', 'Disease', (237, 250))	('patients', 'Species', '9606', (185, 193))	('SDHA', 'Gene', '6389', (224, 228))	('SDHA', 'Gene', (44, 48))	('SDHA', 'Gene', (137, 141))	('paraganglioma', 'Disease', 'MESH:D010235', (237, 250))
65899	23933153	This study suggests a potential role of SDHA mutations in the development of other tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutations', 'Var', (45, 54))	('SDHA', 'Gene', '6389', (40, 44))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SDHA', 'Gene', (40, 44))
65908	23933153	SDHB mutations are also known to be associated with an increased risk for development of other tumors such as renal cell carcinoma, gastrointestinal stromal tumors, breast cancer, and papillary thyroid cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('gastrointestinal stromal tumors', 'Disease', (132, 163))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', (95, 101))	('SDHB', 'Gene', (0, 4))	('papillary thyroid cancer', 'Disease', (184, 208))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', (165, 178))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (184, 208))	('tumors', 'Disease', (157, 163))	('mutations', 'Var', (5, 14))	('thyroid cancer', 'Phenotype', 'HP:0002890', (194, 208))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (132, 163))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (132, 163))	('associated', 'Reg', (36, 46))	('renal cell carcinoma', 'Disease', (110, 130))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (184, 208))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('SDHB', 'Gene', '6390', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
65909	23933153	With the associations of these tumors, SDHx related mutations may eventually be considered a metabolic syndrome of sorts.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SDHx', 'Chemical', '-', (39, 43))	('SDHx related', 'Gene', (39, 51))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('associations', 'Interaction', (9, 21))	('tumors', 'Disease', 'MESH:D009369', (31, 37))
65912	23933153	SDHC gene mutations are associated with head and neck paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (54, 68))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (40, 68))	('associated', 'Reg', (24, 34))	('SDHC', 'Gene', (0, 4))	('SDHC', 'Gene', '6391', (0, 4))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (40, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('mutations', 'Var', (10, 19))	('paraganglioma', 'Phenotype', 'HP:0002668', (54, 67))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (49, 68))
65916	23933153	SDHD gene mutations predispose patients to development of head and neck paragangliomas.	('neck paragangliomas', 'Phenotype', 'HP:0002864', (67, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (72, 85))	('paragangliomas', 'Phenotype', 'HP:0002668', (72, 86))	('SDHD', 'Gene', '6392', (0, 4))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (58, 86))	('patients', 'Species', '9606', (31, 39))	('predispose', 'Reg', (20, 30))	('mutations', 'Var', (10, 19))	('SDHD', 'Gene', (0, 4))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (58, 86))	('gliomas', 'Phenotype', 'HP:0009733', (79, 86))
65920	23933153	Interestingly, SDHD mutations exhibit maternal imprinting resulting in disease only with paternal transmission.	('SDHD', 'Gene', (15, 19))	('SDHD', 'Gene', '6392', (15, 19))	('resulting in', 'Reg', (58, 70))	('disease', 'Disease', (71, 78))	('mutations', 'Var', (20, 29))
65922	23933153	Mutations in the SDHAF2 gene result in the rare autosomal dominant syndrome know as familial paraganglioma syndrome 2.	('autosomal dominant syndrome', 'Disease', (48, 75))	('SDHAF2', 'Gene', (17, 23))	('result in', 'Reg', (29, 38))	('familial paraganglioma syndrome', 'Disease', (84, 115))	('Mutations', 'Var', (0, 9))	('paraganglioma', 'Phenotype', 'HP:0002668', (93, 106))	('familial paraganglioma syndrome', 'Disease', 'MESH:D010235', (84, 115))	('autosomal dominant syndrome', 'Disease', 'MESH:D030342', (48, 75))	('SDHAF2', 'Gene', '54949', (17, 23))
65923	23933153	These mutations are very rare but when they do occur they predispose individuals to the development of head and neck paragangliomas.	('gliomas', 'Phenotype', 'HP:0009733', (124, 131))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (112, 131))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (103, 131))	('paragangliomas', 'Phenotype', 'HP:0002668', (117, 131))	('paraganglioma', 'Phenotype', 'HP:0002668', (117, 130))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (103, 131))	('predispose', 'Reg', (58, 68))	('mutations', 'Var', (6, 15))
65925	23933153	There currently is no indication that SDHAF2 mutations predispose metastatic disease.	('SDHAF2', 'Gene', '54949', (38, 44))	('mutations', 'Var', (45, 54))	('SDHAF2', 'Gene', (38, 44))	('predispose', 'Reg', (55, 65))	('metastatic disease', 'Disease', (66, 84))
65930	23933153	Given the recent discovery of TMEM127 mutations predisposing to the development of pheochromocytomas/paragangliomas more large studies are needed to elucidate the clinical presentation of pheochromocytoma/paraganglioma associated TMEM127 mutations.	('gliomas', 'Phenotype', 'HP:0009733', (108, 115))	('TMEM127', 'Gene', '55654', (230, 237))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (188, 218))	('pheochromocytomas/paragangliomas', 'Disease', (83, 115))	('TMEM127', 'Gene', (30, 37))	('TMEM127', 'Gene', '55654', (30, 37))	('paragangliomas', 'Phenotype', 'HP:0002668', (101, 115))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (83, 99))	('paraganglioma', 'Phenotype', 'HP:0002668', (205, 218))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (188, 204))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (83, 100))	('mutations', 'Var', (38, 47))	('TMEM127', 'Gene', (230, 237))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (83, 115))	('pheochromocytoma/paraganglioma', 'Disease', (188, 218))
65931	23933153	The current literature suggests TMEM127 mutations predispose to metanephrine producing adrenal pheochromocytomas in middle-aged individuals (around 40 years of life).	('adrenal pheochromocytomas', 'Disease', (87, 112))	('TMEM127', 'Gene', (32, 39))	('TMEM127', 'Gene', '55654', (32, 39))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (87, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (95, 111))	('mutations', 'Var', (40, 49))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (95, 112))	('metanephrine', 'Disease', (64, 76))	('predispose', 'Reg', (50, 60))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (87, 112))	('metanephrine', 'Chemical', 'MESH:D008676', (64, 76))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (87, 112))
65933	23933153	reported mutations in the TMEM-127 gene in seven families, 16 patients, with pheochromocytoma.	('TMEM-127', 'Gene', '55654', (26, 34))	('mutations', 'Var', (9, 18))	('pheochromocytoma', 'Disease', (77, 93))	('patients', 'Species', '9606', (62, 70))	('pheochromocytoma', 'Disease', 'MESH:D010673', (77, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('TMEM-127', 'Gene', (26, 34))
65935	23933153	Following the discovery of a link between TMEM127 mutations and pheochromocytoma several other investigators reported the presence TMEM127 mutations in pheochromocytoma patients.	('pheochromocytoma', 'Disease', (152, 168))	('patients', 'Species', '9606', (169, 177))	('TMEM127', 'Gene', '55654', (42, 49))	('mutations', 'Var', (50, 59))	('pheochromocytoma', 'Disease', (64, 80))	('TMEM127', 'Gene', (131, 138))	('mutations', 'Var', (139, 148))	('pheochromocytoma', 'Disease', 'MESH:D010673', (152, 168))	('TMEM127', 'Gene', '55654', (131, 138))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (152, 168))	('pheochromocytoma', 'Disease', 'MESH:D010673', (64, 80))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (64, 80))	('TMEM127', 'Gene', (42, 49))
65937	23933153	A study by Neumann et al., however, reported the presence of TMEM127 mutations in a patient with head and neck paragangliomas and another patient with an adrenal pheochromocytoma and an extra-adrenal paraganglioma.	('presence', 'Reg', (49, 57))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (186, 213))	('paraganglioma', 'Phenotype', 'HP:0002668', (111, 124))	('paragangliomas', 'Phenotype', 'HP:0002668', (111, 125))	('gliomas', 'Phenotype', 'HP:0009733', (118, 125))	('mutations', 'Var', (69, 78))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('extra-adrenal paraganglioma', 'Disease', (186, 213))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (97, 125))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (154, 178))	('TMEM127', 'Gene', (61, 68))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (154, 178))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (97, 125))	('patient', 'Species', '9606', (84, 91))	('adrenal pheochromocytoma', 'Disease', (154, 178))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (106, 125))	('patient', 'Species', '9606', (138, 145))	('TMEM127', 'Gene', '55654', (61, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (200, 213))
65938	23933153	Very little malignancy with TMEM127 mutations has been reported.	('TMEM127', 'Gene', '55654', (28, 35))	('mutations', 'Var', (36, 45))	('malignancy', 'Disease', 'MESH:D009369', (12, 22))	('malignancy', 'Disease', (12, 22))	('TMEM127', 'Gene', (28, 35))
65941	23933153	Mutation of MAX results in increased cellular proliferation and has been associated with development of pheochromocytomas.	('increased', 'PosReg', (27, 36))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (104, 121))	('cellular proliferation', 'CPA', (37, 59))	('Mutation', 'Var', (0, 8))	('MAX', 'Gene', (12, 15))	('pheochromocytomas', 'Disease', 'MESH:D010673', (104, 121))	('associated with', 'Reg', (73, 88))	('pheochromocytomas', 'Disease', (104, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (104, 120))
65943	23933153	Clinically, MAX mutations appear to be most commonly associated with adrenal pheochromocytomas and paternal transmission of MAX mutations has been suggested.	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (69, 93))	('mutations', 'Var', (16, 25))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('MAX', 'Gene', (12, 15))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (77, 94))	('associated', 'Reg', (53, 63))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (69, 94))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (69, 94))	('adrenal pheochromocytomas', 'Disease', (69, 94))
65944	23933153	study, that presented the link between MAX mutations and pheochromocytoma for the first time, reported the presence of MAX mutations in 12 patients with adrenal pheochromocytomas (8 bilateral).	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (153, 178))	('patients', 'Species', '9606', (139, 147))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (153, 178))	('pheochromocytoma', 'Disease', (57, 73))	('adrenal pheochromocytomas', 'Disease', (153, 178))	('presence', 'Reg', (107, 115))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (57, 73))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (161, 178))	('pheochromocytoma', 'Disease', (161, 177))	('pheochromocytoma', 'Disease', 'MESH:D010673', (57, 73))	('pheochromocytoma', 'Disease', 'MESH:D010673', (161, 177))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (153, 177))	('MAX', 'Gene', (119, 122))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (161, 177))	('mutations', 'Var', (123, 132))
65945	23933153	presented clinical data for 19 patients found to have MAX mutations and reported all presented with adrenal pheochromocytomas at a mean age of 34 years; 13 had bilateral or multiple adrenal tumors, 3 patients had an additional extra-adrenal sympathetic paraganglioma, and 2 patients eventually developed metastatic disease.	('mutations', 'Var', (58, 67))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (108, 125))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (100, 125))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (100, 125))	('paraganglioma', 'Phenotype', 'HP:0002668', (253, 266))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (108, 124))	('patients', 'Species', '9606', (274, 282))	('multiple adrenal tumors', 'Disease', 'MESH:D000310', (173, 196))	('multiple adrenal tumors', 'Disease', (173, 196))	('extra-adrenal sympathetic paraganglioma', 'Disease', (227, 266))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (100, 124))	('extra-adrenal sympathetic paraganglioma', 'Disease', 'MESH:D010236', (227, 266))	('MAX', 'Gene', (54, 57))	('adrenal pheochromocytomas', 'Disease', (100, 125))	('presented with', 'Reg', (85, 99))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (31, 39))	('adrenal tumor', 'Phenotype', 'HP:0100631', (182, 195))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
65946	23933153	Overall these tumors may be more frequently metastatic than other hereditary pheochromocytomas/paragangliomas, except those with SDHB/SDHD mutations.	('hereditary pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (66, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (95, 108))	('mutations', 'Var', (139, 148))	('SDHB', 'Gene', '6390', (129, 133))	('SDHB', 'Gene', (129, 133))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (77, 93))	('metastatic', 'CPA', (44, 54))	('hereditary pheochromocytomas/paragangliomas', 'Disease', (66, 109))	('SDHD', 'Gene', (134, 138))	('SDHD', 'Gene', '6392', (134, 138))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (77, 94))	('gliomas', 'Phenotype', 'HP:0009733', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('paragangliomas', 'Phenotype', 'HP:0002668', (95, 109))
65949	23933153	Based on these studies, MAX mutations appear to predispose to development of adrenal pheochromocytomas between 30 and 40 years of age with a mixed noradrenergic and adrenergic biochemical phenotype.	('MAX', 'Gene', (24, 27))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (77, 102))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (77, 102))	('adrenal pheochromocytomas', 'Disease', (77, 102))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (85, 102))	('predispose to', 'Reg', (48, 61))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (77, 101))	('mutations', 'Var', (28, 37))
65950	23933153	The association between PHD2 and HRAS mutations with pheochromocytoma/paraganglioma have only been described in a limited number of patients thus far.	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (53, 83))	('PHD2', 'Gene', '54583', (24, 28))	('HRAS', 'Gene', '3265', (33, 37))	('paraganglioma', 'Phenotype', 'HP:0002668', (70, 83))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('HRAS', 'Gene', (33, 37))	('PHD2', 'Gene', (24, 28))	('pheochromocytoma/paraganglioma', 'Disease', (53, 83))	('mutations', 'Var', (38, 47))	('patients', 'Species', '9606', (132, 140))
65952	23933153	described a patient with erythrocytosis and abdominal paragangliomas who was found to harbor a mutation in the PHD2 gene.	('PHD2', 'Gene', '54583', (111, 115))	('paragangliomas', 'Phenotype', 'HP:0002668', (54, 68))	('abdominal paragangliomas', 'Disease', 'MESH:D010235', (44, 68))	('erythrocytosis', 'Phenotype', 'HP:0001901', (25, 39))	('erythrocytosis', 'Disease', 'MESH:D011086', (25, 39))	('erythrocytosis', 'Disease', (25, 39))	('abdominal paragangliomas', 'Disease', (44, 68))	('gliomas', 'Phenotype', 'HP:0009733', (61, 68))	('patient', 'Species', '9606', (12, 19))	('paraganglioma', 'Phenotype', 'HP:0002668', (54, 67))	('PHD2', 'Gene', (111, 115))	('mutation', 'Var', (95, 103))
65955	23933153	Genetic mutations of NF1 and RET are known to affect RAS signaling and are associated with the development of pheochromocytoma/paraganglioma but a mutation to RAS itself predisposing to the development of these tumors was only recently described.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('RET', 'Gene', (29, 32))	('RAS signaling', 'MPA', (53, 66))	('pheochromocytoma/paraganglioma', 'Disease', (110, 140))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (8, 17))	('affect', 'Reg', (46, 52))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (110, 140))	('associated', 'Reg', (75, 85))	('paraganglioma', 'Phenotype', 'HP:0002668', (127, 140))	('NF1', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('RET', 'Gene', '5979', (29, 32))	('tumors', 'Disease', (211, 217))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (110, 126))
65956	23933153	very recently described the presence of H-RAS mutations in a series of 4 male patients, 3 presenting with pheochromocytoma and 1 with an abdominal paraganglioma.	('abdominal paraganglioma', 'Disease', (137, 160))	('paraganglioma', 'Phenotype', 'HP:0002668', (147, 160))	('mutations', 'Var', (46, 55))	('H-RAS', 'Gene', '3265', (40, 45))	('presence', 'Reg', (28, 36))	('patients', 'Species', '9606', (78, 86))	('pheochromocytoma', 'Disease', (106, 122))	('H-RAS', 'Gene', (40, 45))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (106, 122))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (137, 160))	('pheochromocytoma', 'Disease', 'MESH:D010673', (106, 122))
65958	23933153	The discovery of this mutation presents a further link between RAS proteins and the development of pheochromocytoma/paraganglioma.	('paraganglioma', 'Phenotype', 'HP:0002668', (116, 129))	('link', 'Reg', (50, 54))	('mutation', 'Var', (22, 30))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (99, 129))	('RAS proteins', 'Protein', (63, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (99, 115))	('pheochromocytoma/paraganglioma', 'Disease', (99, 129))
65964	23933153	demonstrated that HIF1alpha deficiency stimulates cellular proliferation as opposed to hypoxic growth arrest.	('stimulates', 'PosReg', (39, 49))	('hypoxic growth arrest', 'Disease', 'MESH:D006323', (87, 108))	('deficiency', 'Var', (28, 38))	('cellular proliferation', 'CPA', (50, 72))	('HIF1alpha', 'Gene', (18, 27))	('growth arrest', 'Phenotype', 'HP:0001510', (95, 108))	('HIF1alpha', 'Gene', '3091', (18, 27))	('hypoxic growth arrest', 'Disease', (87, 108))
65965	23933153	Recently, gain-of-function HIF2alpha mutations were discovered in several patients with paraganglioma and associated polycythemia and in vivo and in vitro studies have been performed to support the oncogenic role HIF2alpha in pheochromocytoma/paraganglioma.	('paraganglioma', 'Disease', (243, 256))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (226, 256))	('polycythemia', 'Disease', (117, 129))	('paraganglioma', 'Disease', 'MESH:D010235', (243, 256))	('polycythemia', 'Disease', 'MESH:D011086', (117, 129))	('HIF2alpha', 'Gene', '2034', (213, 222))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (226, 242))	('HIF2alpha', 'Gene', (27, 36))	('paraganglioma', 'Phenotype', 'HP:0002668', (243, 256))	('paraganglioma', 'Disease', (88, 101))	('patients', 'Species', '9606', (74, 82))	('paraganglioma', 'Disease', 'MESH:D010235', (88, 101))	('mutations', 'Var', (37, 46))	('gain-of-function', 'PosReg', (10, 26))	('polycythemia', 'Phenotype', 'HP:0001901', (117, 129))	('pheochromocytoma/paraganglioma', 'Disease', (226, 256))	('HIF2alpha', 'Gene', '2034', (27, 36))	('HIF2alpha', 'Gene', (213, 222))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))
65966	23933153	Several studies have recently been published describing the clinical presentation of paragangliomas developed in the setting of gain-of-function HIF2alpha mutations.	('paragangliomas', 'Disease', (85, 99))	('paragangliomas', 'Disease', 'MESH:D010235', (85, 99))	('paragangliomas', 'Phenotype', 'HP:0002668', (85, 99))	('paraganglioma', 'Phenotype', 'HP:0002668', (85, 98))	('mutations', 'Var', (155, 164))	('HIF2alpha', 'Gene', (145, 154))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gain-of-function', 'PosReg', (128, 144))	('HIF2alpha', 'Gene', '2034', (145, 154))
65969	23933153	described a case of a 24-year-old female who presented with an adrenal pheochromocytoma and was found to have a somatic HIF2alpha mutation.	('HIF2alpha', 'Gene', '2034', (120, 129))	('mutation', 'Var', (130, 138))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (63, 87))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (71, 87))	('HIF2alpha', 'Gene', (120, 129))	('adrenal pheochromocytoma', 'Disease', (63, 87))	('adrenal pheochromocytoma', 'Disease', 'MESH:D010673', (63, 87))
65970	23933153	recently described a case of a 25-year-old female with polycythemia who presented with adrenal and extra-adrenal paragangliomas and was found to have a gain-of-function HIF2alpha mutation.	('gliomas', 'Phenotype', 'HP:0009733', (120, 127))	('paragangliomas', 'Phenotype', 'HP:0002668', (113, 127))	('HIF2alpha', 'Gene', (169, 178))	('paraganglioma', 'Phenotype', 'HP:0002668', (113, 126))	('mutation', 'Var', (179, 187))	('extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (99, 127))	('polycythemia', 'Disease', (55, 67))	('polycythemia', 'Phenotype', 'HP:0001901', (55, 67))	('HIF2alpha', 'Gene', '2034', (169, 178))	('extra-adrenal paragangliomas', 'Disease', (99, 127))	('polycythemia', 'Disease', 'MESH:D011086', (55, 67))	('gain-of-function', 'PosReg', (152, 168))
65971	23933153	recently described a case of a 35-year-old male with polycythemia who presented with an extra-adrenal paraganglioma progressing to metastatic disease with an associated HIF2alpha mutation.	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('HIF2alpha', 'Gene', (169, 178))	('extra-adrenal paraganglioma', 'Disease', (88, 115))	('polycythemia', 'Disease', 'MESH:D011086', (53, 65))	('polycythemia', 'Phenotype', 'HP:0001901', (53, 65))	('mutation', 'Var', (179, 187))	('extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (88, 115))	('HIF2alpha', 'Gene', '2034', (169, 178))	('metastatic disease', 'Disease', (131, 149))	('polycythemia', 'Disease', (53, 65))
65972	23933153	recently described 7 patients with HIF2alpha mutations, 3 of whom presented with multiple paragangliomas and polycythemia, 1 of whom presented with multiple paragangliomas, 2 of whom presented with solitary pheochromocytomas, and 1 of whom presented with a solitary paraganglioma.	('polycythemia', 'Disease', (109, 121))	('multiple paragangliomas', 'Disease', 'MESH:D010235', (148, 171))	('presented with', 'Reg', (66, 80))	('gliomas', 'Phenotype', 'HP:0009733', (97, 104))	('polycythemia', 'Disease', 'MESH:D011086', (109, 121))	('patients', 'Species', '9606', (21, 29))	('paraganglioma', 'Phenotype', 'HP:0002668', (157, 170))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (207, 224))	('paraganglioma', 'Disease', (266, 279))	('multiple paragangliomas', 'Disease', 'MESH:D010235', (81, 104))	('multiple paragangliomas', 'Disease', (148, 171))	('paraganglioma', 'Disease', 'MESH:D010235', (266, 279))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('paraganglioma', 'Disease', (90, 103))	('HIF2alpha', 'Gene', (35, 44))	('paraganglioma', 'Disease', 'MESH:D010235', (90, 103))	('paragangliomas', 'Phenotype', 'HP:0002668', (157, 171))	('polycythemia', 'Phenotype', 'HP:0001901', (109, 121))	('multiple paragangliomas', 'Disease', (81, 104))	('paraganglioma', 'Phenotype', 'HP:0002668', (266, 279))	('mutations', 'Var', (45, 54))	('paraganglioma', 'Disease', (157, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (207, 223))	('HIF2alpha', 'Gene', '2034', (35, 44))	('pheochromocytomas', 'Disease', 'MESH:D010673', (207, 224))	('paraganglioma', 'Disease', 'MESH:D010235', (157, 170))	('paragangliomas', 'Phenotype', 'HP:0002668', (90, 104))	('paraganglioma', 'Phenotype', 'HP:0002668', (90, 103))	('pheochromocytomas', 'Disease', (207, 224))
65973	23933153	These findings indicate that HIF2alpha mutations may be present in the absence of polycythemia.	('polycythemia', 'Disease', (82, 94))	('HIF2alpha', 'Gene', (29, 38))	('polycythemia', 'Phenotype', 'HP:0001901', (82, 94))	('polycythemia', 'Disease', 'MESH:D011086', (82, 94))	('mutations', 'Var', (39, 48))	('HIF2alpha', 'Gene', '2034', (29, 38))
65974	23933153	Based on the current findings presented in the literature HIF2alpha gain-of-function mutations appear to predispose to development of multiple extra-adrenal paragangliomas (multiple pheochromocytomas are much less common) and multiple duodenal somatostatinomas in females with polycythemia development either at birth or in early childhood.	('paraganglioma', 'Phenotype', 'HP:0002668', (157, 170))	('somatostatinomas', 'Disease', (244, 260))	('polycythemia', 'Disease', (277, 289))	('multiple extra-adrenal paragangliomas', 'Disease', (134, 171))	('multiple extra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (134, 171))	('pheochromocytomas', 'Disease', 'MESH:D010673', (182, 199))	('paragangliomas', 'Phenotype', 'HP:0002668', (157, 171))	('pheochromocytomas', 'Disease', (182, 199))	('gain-of-function', 'PosReg', (68, 84))	('HIF2alpha', 'Gene', '2034', (58, 67))	('polycythemia', 'Phenotype', 'HP:0001901', (277, 289))	('mutations', 'Var', (85, 94))	('polycythemia', 'Disease', 'MESH:D011086', (277, 289))	('gliomas', 'Phenotype', 'HP:0009733', (164, 171))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (182, 198))	('somatostatinomas', 'Disease', 'MESH:D013005', (244, 260))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (182, 199))	('HIF2alpha', 'Gene', (58, 67))
65975	23933153	The link between (pseudo) hypoxia and pheochromocytoma/paraganglioma has been long hypothesized but it was not until the discovery of the VHL mutation that a true association was made.	('pheochromocytoma/paraganglioma', 'Disease', (38, 68))	('VHL', 'Gene', '7428', (138, 141))	('hypoxia', 'Disease', 'MESH:D000860', (26, 33))	('hypoxia', 'Disease', (26, 33))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (38, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (55, 68))	('mutation', 'Var', (142, 150))	('VHL', 'Gene', (138, 141))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (38, 54))
65983	23933153	Adrenal pheochromocytomas are more commonly associated with VHL, RET, NF1, TMEM127, or MAX gene mutations than with SDHx or HIF2alpha gene mutations.	('associated', 'Reg', (44, 54))	('HIF2alpha', 'Gene', (124, 133))	('RET', 'Gene', '5979', (65, 68))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (8, 24))	('SDHx', 'Chemical', '-', (116, 120))	('VHL', 'Gene', (60, 63))	('Adrenal pheochromocytomas', 'Disease', (0, 25))	('MAX', 'Gene', (87, 90))	('Adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (0, 25))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (8, 25))	('VHL', 'Gene', '7428', (60, 63))	('TMEM127', 'Gene', (75, 82))	('RET', 'Gene', (65, 68))	('TMEM127', 'Gene', '55654', (75, 82))	('Adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (0, 25))	('HIF2alpha', 'Gene', '2034', (124, 133))	('NF1', 'Gene', (70, 73))	('mutations', 'Var', (96, 105))
65984	23933153	Extra-adrenal sympathetic paragangliomas are most commonly associated with SDHB mutations.	('paraganglioma', 'Phenotype', 'HP:0002668', (26, 39))	('paragangliomas', 'Phenotype', 'HP:0002668', (26, 40))	('Extra-adrenal sympathetic paragangliomas', 'Disease', 'MESH:D010236', (0, 40))	('mutations', 'Var', (80, 89))	('SDHB', 'Gene', '6390', (75, 79))	('associated', 'Reg', (59, 69))	('gliomas', 'Phenotype', 'HP:0009733', (33, 40))	('SDHB', 'Gene', (75, 79))	('Extra-adrenal sympathetic paragangliomas', 'Disease', (0, 40))
65985	23933153	Head and neck paragangliomas are associated with SDHD (often multiple), SDHC, SDHAF2, and SDHB gene mutations.	('mutations', 'Var', (100, 109))	('SDHB', 'Gene', '6390', (90, 94))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (9, 28))	('SDHB', 'Gene', (90, 94))	('SDHC', 'Gene', '6391', (72, 76))	('paraganglioma', 'Phenotype', 'HP:0002668', (14, 27))	('neck paragangliomas', 'Disease', 'MESH:D010235', (9, 28))	('SDHAF2', 'Gene', (78, 84))	('associated', 'Reg', (33, 43))	('paragangliomas', 'Phenotype', 'HP:0002668', (14, 28))	('SDHC', 'Gene', (72, 76))	('SDHD', 'Gene', '6392', (49, 53))	('SDHAF2', 'Gene', '54949', (78, 84))	('gliomas', 'Phenotype', 'HP:0009733', (21, 28))	('neck paragangliomas', 'Disease', (9, 28))	('SDHD', 'Gene', (49, 53))
65986	23933153	SDHAF2 mutations should be considered in patients with head and neck paragangliomas, who have a strong family history of head and neck tumors or present at a young age and are negative for other SDHx mutations.	('head and neck tumors', 'Phenotype', 'HP:0012288', (121, 141))	('head and neck paragangliomas', 'Disease', 'MESH:D006258', (55, 83))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (55, 83))	('SDHAF2', 'Gene', '54949', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SDHAF2', 'Gene', (0, 6))	('neck tumors', 'Disease', 'MESH:D006258', (130, 141))	('paraganglioma', 'Phenotype', 'HP:0002668', (69, 82))	('gliomas', 'Phenotype', 'HP:0009733', (76, 83))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (64, 83))	('neck tumors', 'Disease', (130, 141))	('patients', 'Species', '9606', (41, 49))	('SDHx', 'Chemical', '-', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('paragangliomas', 'Phenotype', 'HP:0002668', (69, 83))	('head and neck tumor', 'Phenotype', 'HP:0012288', (121, 140))	('mutations', 'Var', (7, 16))
65989	23933153	To date, there is no large-scale study on biochemical phenotypes that includes TMEM127, MAX, and HIF2alpha mutations or SDHB-related adrenal pheochromocytomas.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (141, 157))	('mutations', 'Var', (107, 116))	('TMEM127', 'Gene', '55654', (79, 86))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (141, 158))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (133, 158))	('SDHB-', 'Gene', (120, 125))	('adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (133, 158))	('adrenal pheochromocytomas', 'Disease', (133, 158))	('HIF2alpha', 'Gene', '2034', (97, 106))	('SDHB-', 'Gene', '6390', (120, 125))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (133, 157))	('TMEM127', 'Gene', (79, 86))	('HIF2alpha', 'Gene', (97, 106))
65991	23933153	If these tumors are found without any syndromic or familial presentation we recommend that: metastatic tumors to be tested for SDHB mutations; multiple abdominal paragangliomas should be first tested for the presence of SDHD mutations; multiple/bilateral adrenal pheochromocytomas should be tested for TMEM127 mutations; and multiple paragangliomas associated with other neuroendocrine tumors, currently with somatostatinoma, should first be tested for HIF2alpha mutations.	('TMEM127', 'Gene', (302, 309))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (255, 279))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (371, 392))	('HIF2alpha', 'Gene', '2034', (453, 462))	('bilateral adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (245, 280))	('tumors', 'Disease', (103, 109))	('paragangliomas', 'Phenotype', 'HP:0002668', (334, 348))	('SDHB', 'Gene', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('paraganglioma', 'Phenotype', 'HP:0002668', (334, 347))	('syndromic', 'Disease', (38, 47))	('TMEM127', 'Gene', '55654', (302, 309))	('mutations', 'Var', (310, 319))	('bilateral adrenal pheochromocytomas', 'Disease', (245, 280))	('gliomas', 'Phenotype', 'HP:0009733', (341, 348))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (263, 280))	('neuroendocrine tumors', 'Disease', (371, 392))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('SDHD', 'Gene', '6392', (220, 224))	('somatostatinoma', 'Disease', 'MESH:D013005', (409, 424))	('tumors', 'Phenotype', 'HP:0002664', (386, 392))	('abdominal paragangliomas', 'Disease', 'MESH:D010235', (152, 176))	('somatostatinoma', 'Disease', (409, 424))	('abdominal paragangliomas', 'Disease', (152, 176))	('multiple paragangliomas', 'Disease', 'MESH:D010235', (325, 348))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('paraganglioma', 'Phenotype', 'HP:0002668', (162, 175))	('paragangliomas', 'Phenotype', 'HP:0002668', (162, 176))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('HIF2alpha', 'Gene', (453, 462))	('SDHD', 'Gene', (220, 224))	('tumors', 'Disease', (386, 392))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (371, 392))	('syndromic', 'Disease', 'MESH:D013577', (38, 47))	('mutations', 'Var', (225, 234))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('gliomas', 'Phenotype', 'HP:0009733', (169, 176))	('SDHB', 'Gene', '6390', (127, 131))	('mutations', 'Var', (132, 141))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (263, 279))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (255, 280))	('multiple paragangliomas', 'Disease', (325, 348))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (386, 392))	('mutations', 'Var', (463, 472))
65993	23933153	RET, NF1, and VHL-related pheochromocytomas/paragangliomas are associated with positive SDHB IHC while SDHx-related pheochromocytomas/paragangliomas are associated with negative SDHB staining (SDHD-related tumors can be weakly positive).	('SDHD', 'Gene', (193, 197))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (26, 58))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('SDHB', 'Gene', (88, 92))	('VHL', 'Gene', (14, 17))	('paragangliomas', 'Phenotype', 'HP:0002668', (134, 148))	('RET', 'Gene', '5979', (0, 3))	('gliomas', 'Phenotype', 'HP:0009733', (141, 148))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('paraganglioma', 'Phenotype', 'HP:0002668', (134, 147))	('positive', 'Var', (79, 87))	('tumors', 'Disease', (206, 212))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (26, 43))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (116, 132))	('VHL', 'Gene', '7428', (14, 17))	('pheochromocytomas/paragangliomas', 'Disease', (116, 148))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (26, 42))	('RET', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('SDHB', 'Gene', '6390', (178, 182))	('gliomas', 'Phenotype', 'HP:0009733', (51, 58))	('pheochromocytomas/paragangliomas', 'Disease', (26, 58))	('SDHD', 'Gene', '6392', (193, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (44, 57))	('paragangliomas', 'Phenotype', 'HP:0002668', (44, 58))	('SDHB', 'Gene', '6390', (88, 92))	('pheochromocytomas/paragangliomas', 'Disease', 'MESH:D010673', (116, 148))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (116, 133))	('SDHx', 'Chemical', '-', (103, 107))	('SDHB', 'Gene', (178, 182))
65994	23933153	Negative IHC for SDHA has been correlated with the presence of an SDHA mutation.	('SDHA', 'Gene', (17, 21))	('mutation', 'Var', (71, 79))	('SDHA', 'Gene', (66, 70))	('SDHA', 'Gene', '6389', (17, 21))	('SDHA', 'Gene', '6389', (66, 70))
65996	23933153	As previously mentioned, many of the genetic mutations discussed are associated with tumors and findings other than pheochromocytoma/paraganglioma that need to be followed.	('paraganglioma', 'Phenotype', 'HP:0002668', (133, 146))	('mutations', 'Var', (45, 54))	('pheochromocytoma/paraganglioma', 'Disease', 'MESH:D010673', (116, 146))	('genetic mutations', 'Var', (37, 54))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('associated', 'Reg', (69, 79))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (116, 132))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('pheochromocytoma/paraganglioma', 'Disease', (116, 146))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
65997	23933153	Prophylactic thyroidectomy, for example, is recommended for patients with specific RET mutations.	('patients', 'Species', '9606', (60, 68))	('RET', 'Gene', (83, 86))	('mutations', 'Var', (87, 96))	('RET', 'Gene', '5979', (83, 86))
65998	23933153	Patients with SDHB mutations should be followed closely by both biochemistry and serial imaging for development of metastatic disease, especially those who presented with their primary tumor at a young age.	('primary tumor', 'Disease', 'MESH:D009369', (177, 190))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('primary tumor', 'Disease', (177, 190))	('SDHB', 'Gene', '6390', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('metastatic disease', 'Disease', (115, 133))	('SDHB', 'Gene', (14, 18))
66129	22154086	For retroviral delivery and expression of luciferase in MTT cells, we first generated the construct pLLuc via replacement of EGFP with a luciferase gene between the BamH-1 and Not-1 sites of the retroviral vector pLEGFP.	('EGFP', 'Gene', (125, 129))	('MTT', 'Chemical', 'MESH:C070243', (56, 59))	('replacement', 'Var', (110, 121))	('luciferase', 'Gene', (137, 147))
66176	22154086	This was somewhat unexpected because the primary tumor from which MPC and MTT are derived arose in a Nf1 knockout mouse generated by insertion of a neomycin resistance gene in reverse orientation into the Nf1 gene and the original MPC line was intrinsically G418-resistant (JF Powers, unpublished).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('insertion', 'Var', (133, 142))	('Nf1', 'Gene', '18015', (101, 104))	('MTT', 'Chemical', 'MESH:C070243', (74, 77))	('Nf1', 'Gene', '18015', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('G418', 'Chemical', 'MESH:C010680', (258, 262))	('tumor', 'Disease', (49, 54))	('mouse', 'Species', '10090', (114, 119))	('neomycin', 'Chemical', 'MESH:D009355', (148, 156))	('Nf1', 'Gene', (101, 104))	('Nf1', 'Gene', (205, 208))
66284	33743242	In the present case, we succeeded in safely transecting the adrenal feeder arteries and dissecting the dorsal side of the tumor via a retroperitoneal laparoscopic approach.	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', (122, 127))	('transecting', 'Var', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))
66287	33743242	During surgery for large PPGLs producing a lot of catecholamines, direct manipulation of the tumor frequently precipitates a hypertensive crisis despite preoperative treatment with an alpha blocker.	('hypertensive crisis', 'Phenotype', 'HP:0100735', (125, 144))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('catecholamines', 'Chemical', 'MESH:D002395', (50, 64))	('tumor', 'Disease', (93, 98))	('hypertensive', 'Disease', 'MESH:D006973', (125, 137))	('precipitates', 'Reg', (110, 122))	('PPGLs', 'Var', (25, 30))	('hypertensive', 'Disease', (125, 137))	('PPGLs', 'Chemical', '-', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
66305	33670168	For instance, alterations of VHL first identified in families with von Hippel-Lindau are present in >90% of cases of sporadic clear cell RCC.	('alterations', 'Var', (14, 25))	('von Hippel-Lindau', 'Gene', '7428', (67, 84))	('VHL', 'Gene', (29, 32))	('VHL', 'Gene', '7428', (29, 32))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('RCC', 'Disease', (137, 140))	('present', 'Reg', (89, 96))	('von Hippel-Lindau', 'Gene', (67, 84))
66306	33670168	Similarly, alterations in MET which were identified in patients with hereditary papillary renal carcinoma (HPRC) are also present in 17% of sporadic type 1 papillary RCCs, and 81% of these cases have altered MET status.	('alterations', 'Var', (11, 22))	('renal carcinoma', 'Phenotype', 'HP:0005584', (90, 105))	('MET', 'Gene', (26, 29))	('MET', 'Gene', (208, 211))	('hereditary papillary renal carcinoma', 'Disease', 'MESH:C538614', (69, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (80, 105))	('RCC', 'Phenotype', 'HP:0005584', (166, 169))	('papillary RCCs', 'Disease', 'MESH:D002291', (156, 170))	('hereditary papillary renal carcinoma', 'Disease', (69, 105))	('altered', 'Reg', (200, 207))	('MET', 'Gene', '79811', (208, 211))	('MET', 'Gene', '79811', (26, 29))	('patients', 'Species', '9606', (55, 63))	('papillary RCCs', 'Disease', (156, 170))
66316	33670168	Patients with a germline VHL mutation have over 90% disease penetrance by the age of 65.	('mutation', 'Var', (29, 37))	('age', 'Gene', (78, 81))	('germline', 'Var', (16, 24))	('age', 'Gene', '5973', (78, 81))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', (25, 28))	('disease penetrance', 'CPA', (52, 70))	('VHL', 'Gene', '7428', (25, 28))
66319	33670168	Deletion and frameshift alterations have a higher propensity for development of clear cell RCC but low risk for pheochromocytoma.	('men', 'Species', '9606', (72, 75))	('RCC', 'Disease', 'MESH:C538614', (91, 94))	('RCC', 'Disease', (91, 94))	('RCC', 'Phenotype', 'HP:0005584', (91, 94))	('pheochromocytoma', 'Disease', (112, 128))	('frameshift alterations', 'Var', (13, 35))	('pheochromocytoma', 'Disease', 'MESH:D010673', (112, 128))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (112, 128))	('Deletion', 'Var', (0, 8))
66320	33670168	In contrast, missense alterations have a higher propensity for development of pheochromocytoma.	('pheochromocytoma', 'Disease', (78, 94))	('men', 'Species', '9606', (70, 73))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (78, 94))	('pheochromocytoma', 'Disease', 'MESH:D010673', (78, 94))	('missense alterations', 'Var', (13, 33))
66331	33670168	Alteration of the MET gene (located on chromosome 7q31) was ultimately identified as the cause of this condition initially based on the study of families with high prevalence of papillary RCC without any identifiable changes on chromosome 3p.	('cause', 'Reg', (89, 94))	('papillary RCC', 'Disease', 'MESH:C538614', (178, 191))	('Alteration', 'Var', (0, 10))	('papillary RCC', 'Disease', (178, 191))	('MET', 'Gene', '79811', (18, 21))	('MET', 'Gene', (18, 21))	('RCC', 'Phenotype', 'HP:0005584', (188, 191))
66332	33670168	Missense mutations are specific to the tyrosine kinase domain of the MET gene and act as a proto-oncogene.	('MET', 'Gene', (69, 72))	('MET', 'Gene', '79811', (69, 72))	('Missense mutations', 'Var', (0, 18))
66334	33670168	In affected individuals, the activating mutation allows inappropriate upregulation of the numerous downstream regulators by the MET kinase without its interaction with HGF.	('mutation', 'Var', (40, 48))	('HGF', 'Gene', (168, 171))	('upregulation', 'PosReg', (70, 82))	('MET', 'Gene', '79811', (128, 131))	('activating', 'Reg', (29, 39))	('MET', 'Gene', (128, 131))	('HGF', 'Gene', '3082', (168, 171))
66346	33670168	Just recently added to the World Health Organization classification of RCC, Succinate dehydrogenase (SDH)-deficient RCC is associated with a germline mutation in the genes encoding any of the SDH subunits (SDHA, SDHB, SDHC, SDHD).	('SDH', 'Gene', '6390', (224, 227))	('SDHC', 'Gene', '6391', (218, 222))	('Succinate dehydrogenase', 'Gene', '6390', (76, 99))	('SDHB', 'Gene', '6390', (212, 216))	('SDHD', 'Gene', (224, 228))	('RCC', 'Phenotype', 'HP:0005584', (116, 119))	('RCC', 'Disease', (116, 119))	('SDH', 'Gene', '6390', (206, 209))	('SDH', 'Gene', (218, 221))	('SDHA', 'Gene', (206, 210))	('SDH', 'Gene', (192, 195))	('SDH', 'Gene', (224, 227))	('SDHB', 'Gene', (212, 216))	('RCC', 'Disease', 'MESH:C538614', (116, 119))	('SDHA', 'Gene', '6389', (206, 210))	('SDHC', 'Gene', (218, 222))	('SDH', 'Gene', '6390', (212, 215))	('deficient RCC', 'Disease', (106, 119))	('RCC', 'Disease', (71, 74))	('SDH', 'Gene', '6390', (101, 104))	('RCC', 'Phenotype', 'HP:0005584', (71, 74))	('SDH', 'Gene', (206, 209))	('deficient RCC', 'Disease', 'MESH:C538614', (106, 119))	('associated', 'Reg', (123, 133))	('SDH', 'Gene', (212, 215))	('mutation in', 'Var', (150, 161))	('RCC', 'Disease', 'MESH:C538614', (71, 74))	('Succinate dehydrogenase', 'Gene', (76, 99))	('SDH', 'Gene', '6390', (218, 221))	('SDHD', 'Gene', '6392', (224, 228))	('SDH', 'Gene', '6390', (192, 195))	('SDH', 'Gene', (101, 104))
66349	33670168	Originally described in 2004, mutations in the SDHB subunit are the most frequently seen in SDH-deficient RCC.	('SDHB', 'Gene', '6390', (47, 51))	('SDH-deficient RCC', 'Disease', (92, 109))	('SDHB', 'Gene', (47, 51))	('SDH-deficient RCC', 'Disease', 'MESH:C538614', (92, 109))	('seen', 'Reg', (84, 88))	('mutations', 'Var', (30, 39))	('RCC', 'Phenotype', 'HP:0005584', (106, 109))
66352	33670168	First implicated in the development of malignant mesothelioma and uveal melanoma, germline BRCA1-associated protein-1 (BAP1) mutations are a relatively recently discovered tumor predisposition syndrome.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('mutations', 'Var', (125, 134))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('men', 'Species', '9606', (31, 34))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (39, 61))	('BRCA1-associated protein-1', 'Gene', (91, 117))	('tumor', 'Disease', (172, 177))	('malignant mesothelioma', 'Disease', (39, 61))	('BAP1', 'Gene', '8314', (119, 123))	('BRCA1-associated protein-1', 'Gene', '8314', (91, 117))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (39, 61))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('BAP1', 'Gene', (119, 123))
66357	33670168	Examination of families with a BAP1 mutation and RCC showed the development of early onset tumors, many of which were fast growing and with higher Fuhrman grade on pathologic analysis.	('tumors', 'Disease', (91, 97))	('RCC', 'Disease', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('BAP1', 'Gene', '8314', (31, 35))	('men', 'Species', '9606', (71, 74))	('BAP1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RCC', 'Phenotype', 'HP:0005584', (49, 52))	('mutation', 'Var', (36, 44))	('RCC', 'Disease', 'MESH:C538614', (49, 52))
66362	33670168	It is inherited in an autosomal dominant fashion with mutations mapped in the 1990s to the TSC1 and TSC2 genes located on chromosome 9q34 and 16p13, respectively.	('TSC1', 'Gene', '7248', (91, 95))	('TSC2', 'Gene', (100, 104))	('mutations', 'Var', (54, 63))	('TSC1', 'Gene', (91, 95))	('TSC2', 'Gene', '7249', (100, 104))
66363	33670168	TSC1 and TSC2 are tumor suppressor genes that follows Knudson's two-hit model with development of the manifestations occurring with loss of the 2nd hit mutation/inactivation.	('tumor', 'Disease', (18, 23))	('men', 'Species', '9606', (90, 93))	('loss', 'Var', (132, 136))	('TSC2', 'Gene', '7249', (9, 13))	('TSC1', 'Gene', '7248', (0, 4))	('mutation/inactivation', 'Var', (152, 173))	('TSC1', 'Gene', (0, 4))	('TSC2', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
66379	33670168	For localized disease, decades of experience managing these patients have made it possible to tailor the approach based on the specific germline mutation as a direct result of the biological nature of the renal tumors.	('renal tumors', 'Disease', 'MESH:D007674', (205, 217))	('localized disease', 'Disease', (4, 21))	('renal tumors', 'Disease', (205, 217))	('localized disease', 'Disease', 'MESH:D012594', (4, 21))	('patients', 'Species', '9606', (60, 68))	('germline mutation', 'Var', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('renal tumors', 'Phenotype', 'HP:0009726', (205, 217))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))
66380	33670168	Biologic aggressiveness is associated with each specific germline mutation.	('aggressiveness', 'Phenotype', 'HP:0000718', (9, 23))	('germline', 'Var', (57, 65))	('associated', 'Reg', (27, 37))	('aggressiveness', 'Disease', 'MESH:D001523', (9, 23))	('aggressiveness', 'Disease', (9, 23))
66410	33670168	Given the aggressiveness of the tumors seen in certain germline mutations (specifically HLRCC and SDH-deficient tumors), we routinely perform a local regional lymph node dissection at time of surgery in these settings for larger or more complex solid tumors, even in the setting of preoperatively normal lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('germline mutations', 'Var', (55, 73))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('RCC', 'Disease', (90, 93))	('RCC', 'Phenotype', 'HP:0005584', (90, 93))	('aggressiveness of the tumors', 'Disease', 'MESH:D001523', (10, 38))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('SDH-deficient tumors', 'Disease', 'MESH:D009369', (98, 118))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('aggressiveness', 'Phenotype', 'HP:0000718', (10, 24))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('RCC', 'Disease', 'MESH:C538614', (90, 93))	('tumors', 'Disease', (251, 257))	('aggressiveness of the tumors', 'Disease', (10, 38))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('SDH-deficient tumors', 'Disease', (98, 118))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', (112, 118))
66610	33194923	Finally, clevidipine is an ultrashort-acting IV CCB with a rapid onset, which causes arteriolar vasodilation and has an added advantage of a simplified dose titration due to rapid inactivation by tissue and blood esterase but is absolutely contraindicated in patients with egg and soy allergies as well as in those with lipid disorders.	('clevidipine', 'Var', (9, 20))	('patients', 'Species', '9606', (259, 267))	('soy allergies', 'Phenotype', 'HP:0003193', (281, 294))	('arteriolar vasodilation', 'MPA', (85, 108))	('clevidipine', 'Chemical', 'MESH:C118563', (9, 20))	('egg', 'Disease', (273, 276))	('lipid disorders', 'Disease', (320, 335))	('lipid disorders', 'Disease', 'MESH:D052439', (320, 335))	('egg and soy allergies', 'Phenotype', 'HP:0410328', (273, 294))	('allergies', 'Phenotype', 'HP:0012393', (285, 294))
66616	33194923	Hydralazine lacks the negative inotropic effect and causes reflex tachycardia by activation of the RAAS pathway, which can negate its antihypertensive effects.	('Hydralazine', 'Var', (0, 11))	('RAAS pathway', 'Pathway', (99, 111))	('Hydralazine', 'Chemical', 'MESH:D006830', (0, 11))	('hypertensive', 'Disease', 'MESH:D006973', (138, 150))	('reflex tachycardia', 'Disease', (59, 77))	('tachycardia', 'Phenotype', 'HP:0001649', (66, 77))	('reflex tachycardia', 'Disease', 'MESH:D013610', (59, 77))	('hypertensive', 'Disease', (138, 150))	('negative inotropic', 'MPA', (22, 40))	('causes', 'Reg', (52, 58))	('lacks', 'NegReg', (12, 17))
66618	33194923	With activity at the dopamine 1 receptor and alpha-adrenoreceptors, fenoldopam causes increases in renal blood flow and urinary flow, in addition to natriuresis.	('fenoldopam', 'Chemical', 'MESH:D018818', (68, 78))	('natriuresis', 'MPA', (149, 160))	('increases', 'PosReg', (86, 95))	('urinary flow', 'MPA', (120, 132))	('renal blood flow', 'MPA', (99, 115))	('dopamine 1 receptor', 'Protein', (21, 40))	('fenoldopam', 'Var', (68, 78))	('alpha-adrenoreceptors', 'Protein', (45, 66))	('dopamine', 'Chemical', 'MESH:D004298', (21, 29))
66623	33194923	Similarly, alpha adrenergic blockers such as phenoxybenzamine and doxazosin are specifically used in catecholamine-induced hypertension such as paragangliomas and pheochromocytoma.	('paragangliomas', 'Phenotype', 'HP:0002668', (144, 158))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (163, 179))	('doxazosin', 'Chemical', 'MESH:D017292', (66, 75))	('phenoxybenzamine', 'Chemical', 'MESH:D010643', (45, 61))	('paragangliomas and pheochromocytoma', 'Disease', 'MESH:D010673', (144, 179))	('paraganglioma', 'Phenotype', 'HP:0002668', (144, 157))	('hypertension', 'Disease', (123, 135))	('catecholamine', 'Chemical', 'MESH:D002395', (101, 114))	('hypertension', 'Phenotype', 'HP:0000822', (123, 135))	('phenoxybenzamine', 'Var', (45, 61))	('hypertension', 'Disease', 'MESH:D006973', (123, 135))
66630	33194923	In addition, clonidine is another orally used antihypertensive drug that activates alpha 2-adrenergic receptors and decreases central sympathetic tone, thereby causing vasodilation.	('central sympathetic tone', 'MPA', (126, 150))	('alpha 2-adrenergic receptors', 'Protein', (83, 111))	('vasodilation', 'MPA', (168, 180))	('hypertensive', 'Disease', 'MESH:D006973', (50, 62))	('causing', 'Reg', (160, 167))	('hypertensive', 'Disease', (50, 62))	('clonidine', 'Var', (13, 22))	('clonidine', 'Chemical', 'MESH:D003000', (13, 22))	('decreases', 'NegReg', (116, 125))	('activates', 'PosReg', (73, 82))
66657	33194923	Additionally, it is important to evaluate for the presence of Von-Hippel Lindau disease (VHL), neurofibromatosis-1(NF-1), and rearranged during transfection (RET) in cases of suspected pheochromocytomas and succinate dehydrogenase complex subunits (SDHD, SDHB, SDHC) gene mutations in paragangliomas.	('mutations', 'Var', (272, 281))	('SDHD', 'Gene', (249, 253))	('Von-Hippel Lindau disease', 'Disease', (62, 87))	('SDHC', 'Gene', (261, 265))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (95, 112))	('neurofibromatosis-1(NF-1)', 'Disease', 'MESH:C537392', (95, 120))	('RET', 'Gene', '5979', (158, 161))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (185, 202))	('VHL', 'Disease', (89, 92))	('paragangliomas', 'Disease', 'MESH:D010235', (285, 299))	('paraganglioma', 'Phenotype', 'HP:0002668', (285, 298))	('paragangliomas', 'Phenotype', 'HP:0002668', (285, 299))	('RET', 'Gene', (158, 161))	('SDHB', 'Gene', '6390', (255, 259))	('SDHC', 'Gene', '6391', (261, 265))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (185, 201))	('VHL', 'Disease', 'MESH:D006623', (89, 92))	('pheochromocytomas', 'Disease', 'MESH:D010673', (185, 202))	('SDHD', 'Gene', '6392', (249, 253))	('pheochromocytomas', 'Disease', (185, 202))	('paragangliomas', 'Disease', (285, 299))	('SDHB', 'Gene', (255, 259))	('Von-Hippel Lindau disease', 'Disease', 'MESH:D006623', (62, 87))
66670	33194923	Liddle syndrome is a consequence of gain-of-function mutation of the gene encoding the three subunit channel proteins (alpha, beta, and gamma) of aldosterone-dependent epithelial sodium channel (ENaC) in the collecting ducts.	('gain-of-function', 'PosReg', (36, 52))	('Liddle syndrome', 'Disease', 'MESH:D056929', (0, 15))	('mutation', 'Var', (53, 61))	('sodium', 'Chemical', 'MESH:D012964', (179, 185))	('Liddle syndrome', 'Disease', (0, 15))	('aldosterone', 'Chemical', 'MESH:D000450', (146, 157))
66671	33194923	These mutations inhibit degradation of ENaC and excessive sodium absorption culminating to hypertension, hypokalemia, metabolic alkalosis, and a low plasma renin and aldosterone.	('inhibit', 'NegReg', (16, 23))	('hypokalemia', 'Disease', (105, 116))	('hypertension', 'Disease', (91, 103))	('renin', 'Gene', '5972', (156, 161))	('metabolic alkalosis', 'Disease', (118, 137))	('aldosterone', 'Chemical', 'MESH:D000450', (166, 177))	('hypertension', 'Phenotype', 'HP:0000822', (91, 103))	('sodium', 'Chemical', 'MESH:D012964', (58, 64))	('hypokalemia', 'Phenotype', 'HP:0002900', (105, 116))	('mutations', 'Var', (6, 15))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (118, 137))	('excessive', 'PosReg', (48, 57))	('hypokalemia', 'Disease', 'MESH:D007008', (105, 116))	('excessive sodium', 'Phenotype', 'HP:0003228', (48, 64))	('alkalosis', 'Phenotype', 'HP:0001948', (128, 137))	('sodium absorption', 'MPA', (58, 75))	('low plasma renin', 'Phenotype', 'HP:0003351', (145, 161))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (118, 137))	('hypertension', 'Disease', 'MESH:D006973', (91, 103))	('ENaC', 'Protein', (39, 43))	('low', 'NegReg', (145, 148))	('renin', 'Gene', (156, 161))	('degradation', 'MPA', (24, 35))
66734	32109495	Germline alterations in at least 15 genes are implicated in pheochromocytoma and are found in upwards of 40% of cases.	('implicated', 'Reg', (46, 56))	('pheochromocytoma', 'Disease', (60, 76))	('pheochromocytoma', 'Disease', 'MESH:D010673', (60, 76))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (60, 76))	('Germline alterations', 'Var', (0, 20))
66735	32109495	Even among patients without clinical evidence of a hereditable pheochromocytoma syndrome, 25% are found to be positive for an associated germline mutation.	('pheochromocytoma syndrome', 'Disease', 'MESH:D010673', (63, 88))	('pheochromocytoma syndrome', 'Disease', (63, 88))	('germline mutation', 'Var', (137, 154))	('positive', 'Reg', (110, 118))	('patients', 'Species', '9606', (11, 19))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (63, 79))
66864	32435362	As expected, GW7647 robustly stimulated CPT1A expression (Figure 3), whereas compounds 3a-e, 10e, and 13e induced only a weak CPT1A mRNA expression.	('GW7647', 'Chemical', 'MESH:C453899', (13, 19))	('stimulated', 'PosReg', (29, 39))	('GW7647', 'Var', (13, 19))	('CPT1A', 'Gene', '1374', (126, 131))	('CPT1A', 'Gene', '1374', (40, 45))	('13e', 'Chemical', '-', (102, 105))	('expression', 'MPA', (46, 56))	('CPT1A', 'Gene', (126, 131))	('CPT1A', 'Gene', (40, 45))
66865	32435362	Notably, the combinations of GW7647 with 3a-e, 10e, or 13e were able to significantly repress CPT1A expression, supporting the antagonistic behavior of the novel compounds on PPARalpha (Figure 3).	('combinations', 'Interaction', (13, 25))	('repress', 'NegReg', (86, 93))	('PPARalpha', 'Gene', '5465', (175, 184))	('CPT1A', 'Gene', (94, 99))	('expression', 'MPA', (100, 110))	('PPARalpha', 'Gene', (175, 184))	('GW7647', 'Var', (29, 35))	('GW7647', 'Chemical', 'MESH:C453899', (29, 35))	('13e', 'Chemical', '-', (55, 58))	('CPT1A', 'Gene', '1374', (94, 99))
66875	32435362	In particular, 3c, 3d, and 10e drastically and significantly decreased paraganglioma cell line viability, as shown by concentration-response curves (Figure 5, panels A, B, C) and cytotoxic concentration (CC50) values in the low micromolar range (Figure 5, panel D).	('10e', 'Var', (27, 30))	('paraganglioma', 'Phenotype', 'HP:0002668', (71, 84))	('decreased paraganglioma', 'Disease', 'MESH:D010235', (61, 84))	('decreased paraganglioma', 'Disease', (61, 84))
66880	32435362	In this structure GW6471, bearing an amide headgroup, does not interact with Y464 and pushes the H12 to assume an inactive and less structured conformation.	('inactive', 'MPA', (114, 122))	('Y464', 'Chemical', '-', (77, 81))	('amide', 'Chemical', 'MESH:D000577', (37, 42))	('GW6471', 'Var', (18, 24))	('GW6471', 'Chemical', 'MESH:C449302', (18, 24))	('H12', 'Protein', (97, 100))
66887	32435362	The phenyldiazenyl group was surrounded by sulfur-containing residues such as C275, C276, M355, and M330, forming profitable sulfur-arene interactions.	('C275', 'Var', (78, 82))	('sulfur', 'Chemical', 'MESH:D013455', (43, 49))	('M330', 'Var', (100, 104))	('arene', 'Chemical', '-', (132, 137))	('interactions', 'Interaction', (138, 150))	('C276', 'Var', (84, 88))	('sulfur', 'Chemical', 'MESH:D013455', (125, 131))	('M355', 'Var', (90, 94))	('phenyldiazenyl', 'Chemical', '-', (4, 18))
66888	32435362	By looking at the binding mode of compound 10e (Figures 6B and S3, Supporting Information), it was observed that an H-bond was also formed, through its carbonyl oxygen, with the OH group of the Y314 side chain, whereas the aromatic ring of the benzenesulfonamide moiety made hydrophobic interactions with V444 and F273.	('F273', 'Var', (314, 318))	('oxygen', 'Chemical', 'MESH:D010100', (161, 167))	('V444', 'Chemical', '-', (305, 309))	('benzenesulfonamide', 'Chemical', 'MESH:C038198', (244, 262))	('F273', 'Chemical', '-', (314, 318))	('Y314', 'Chemical', '-', (194, 198))	('V444', 'Var', (305, 309))
66890	32435362	The phenylbenzamide moiety, besides the hydrophobic contacts observed for 3a, formed two additional H-bonds with the T279 OH group and the NH backbone of A333 on the beta-sheet.	('T279 OH', 'Var', (117, 124))	('phenylbenzamide', 'Chemical', '-', (4, 19))	('H-bonds', 'Interaction', (100, 107))
66892	32435362	Noteworthy, the benzenesulfonamide headgroup of 3a and 10e projected into an area that is usually occupied by the side chain of Y464 in PPARalpha LBD bound to agonist ligands, such as GW409544 (Supporting Information, Figure S4B).	('GW409544', 'Chemical', 'MESH:C442829', (184, 192))	('benzenesulfonamide', 'Chemical', 'MESH:C038198', (16, 34))	('PPARalpha', 'Gene', '5465', (136, 145))	('Y464', 'Var', (128, 132))	('PPARalpha', 'Gene', (136, 145))	('Y464', 'Chemical', '-', (128, 132))	('GW409544', 'Var', (184, 192))	('bound', 'Interaction', (150, 155))
66897	32435362	In fact, the insertion of the more hydrophilic nitro group (3d), or the bulkier methylamide group (3e), caused a slight decrease in potency; for derivatives 3f and 3g, a further drop in PPARalpha antagonistic activity was observed, produced by the impaired accommodation of an additional aromatic ring into arm I of PPARalpha.	('PPARalpha', 'Gene', (316, 325))	('PPARalpha', 'Gene', (186, 195))	('drop', 'NegReg', (178, 182))	('antagonistic activity', 'MPA', (196, 217))	('impaired accommodation', 'Phenotype', 'HP:0030801', (248, 270))	('methylamide', 'Chemical', '-', (80, 91))	('decrease', 'NegReg', (120, 128))	('insertion', 'Var', (13, 22))	('accommodation of an additional aromatic ring', 'MPA', (257, 301))	('PPARalpha', 'Gene', '5465', (316, 325))	('PPARalpha', 'Gene', '5465', (186, 195))	('potency', 'MPA', (132, 139))	('nitro', 'Chemical', '-', (47, 52))	('impaired', 'NegReg', (248, 256))
66899	32435362	Derivatives 4a-d, bearing the amide headgroup and phenyldiazenyl tail group, turned out to be less active because of the loss of profitable H-bonds and pi-pi stacking interactions with Y314 observed in docking experiments.	('Y314', 'Chemical', '-', (185, 189))	('loss', 'NegReg', (121, 125))	('H-bonds', 'Protein', (140, 147))	('phenyldiazenyl', 'Chemical', '-', (50, 64))	('Y314', 'Var', (185, 189))	('amide', 'Chemical', 'MESH:D000577', (30, 35))	('pi-pi stacking interactions', 'CPA', (152, 179))	('-d', 'Chemical', 'MESH:D003903', (14, 16))
66900	32435362	On comparing the docked pose of 3a and 4c (Figure S5B, Supporting Information), it is clear that, despite a similar positioning of the phenyldiazenyl tail, the amide moiety was not properly oriented to engage an H bond with Y314.	('Y314', 'Chemical', '-', (224, 228))	('phenyldiazenyl', 'Chemical', '-', (135, 149))	('engage', 'Interaction', (202, 208))	('H bond', 'Interaction', (212, 218))	('amide', 'Chemical', 'MESH:D000577', (160, 165))	('Y314', 'Var', (224, 228))
66902	32435362	From the docked pose of 10e, it can be argued that the primary amide (10a) was no longer able to form the hydrophobic interactions with residues V444 and F273, whereas both aliphatic (10b) and aromatic groups (10c and 10d) could not be placed at an optimal distance to favorably interact with such residues.	('V444', 'Chemical', '-', (145, 149))	('F273', 'Var', (154, 158))	('V444', 'Var', (145, 149))	('amide', 'Chemical', 'MESH:D000577', (63, 68))	('F273', 'Chemical', '-', (154, 158))	('hydrophobic interactions', 'MPA', (106, 130))
66903	32435362	As shown in Figure S5C, the phenylbenzamide tails of both 10e and 10b displayed the same orientation; however, the butyl amide headgroup of 10b could not properly interact with Y314, but instead was oriented toward Q277.	('Y314', 'Var', (177, 181))	('butyl amide', 'Chemical', '-', (115, 126))	('phenylbenzamide', 'Chemical', '-', (28, 43))	('Y314', 'Chemical', '-', (177, 181))	('Q277', 'Var', (215, 219))
66905	32435362	However, introduction of phenyl and benzyl substituents (13c and 13d) on the amide headgroup introduced steric restrictions, making it more difficult for the ligands to interact with Y314 and with the hydrophobic residues A441, V444, and F273.	('F273', 'Var', (238, 242))	('A441', 'Var', (222, 226))	('Y314', 'Chemical', '-', (183, 187))	('A441', 'Chemical', '-', (222, 226))	('V444', 'Chemical', '-', (228, 232))	('amide', 'Chemical', 'MESH:D000577', (77, 82))	('F273', 'Chemical', '-', (238, 242))	('interact', 'Interaction', (169, 177))	('V444', 'Var', (228, 232))	('Y314', 'Var', (183, 187))
66946	30808127	Echocardiography was performed in 46 patients (41.8%) due to cardiovascular symptoms such as chest pain or dyspnea (n = 8), abnormal ECG (n = 14) or cardiovascular risk factors (n = 8), and for preoperative screening (n = 16).	('dyspnea', 'Disease', (107, 114))	('chest pain', 'Disease', 'MESH:D002637', (93, 103))	('chest pain', 'Disease', (93, 103))	('patients', 'Species', '9606', (37, 45))	('dyspnea', 'Disease', 'MESH:D004417', (107, 114))	('abnormal', 'Var', (124, 132))	('abnormal ECG', 'Phenotype', 'HP:0003115', (124, 136))	('chest pain', 'Phenotype', 'HP:0100749', (93, 103))	('pain', 'Phenotype', 'HP:0012531', (99, 103))	('cardiovascular symptoms', 'Phenotype', 'HP:0001626', (61, 84))	('dyspnea', 'Phenotype', 'HP:0002094', (107, 114))	('cardiovascular symptoms', 'Disease', 'MESH:D020821', (61, 84))	('ECG', 'Chemical', '-', (133, 136))	('cardiovascular symptoms', 'Disease', (61, 84))
66980	30808127	Out of 54 patients with a medical history of hypertension, 34 (63.0%) discontinued antihypertensive medication after the resection of the PPGLs (eight in the Group 1 and 20 in the Group 2).	('discontinued', 'NegReg', (70, 82))	('hypertensive', 'Disease', 'MESH:D006973', (87, 99))	('antihypertensive medication', 'Phenotype', 'HP:0000822', (83, 110))	('resection', 'Var', (121, 130))	('hypertension', 'Phenotype', 'HP:0000822', (45, 57))	('hypertensive', 'Disease', (87, 99))	('hypertension', 'Disease', 'MESH:D006973', (45, 57))	('PPGLs', 'Chemical', '-', (138, 143))	('hypertension', 'Disease', (45, 57))	('patients', 'Species', '9606', (10, 18))	('PPGLs', 'Gene', (138, 143))
66986	30808127	Catecholamines can induce myocardial damage by microvascular dysfunction of the coronary arteries, multivessel epicardial spasm, impaired fatty acid metabolism, myocarditis and catecholamine-mediated myocardial dysfunction.	('myocardial damage', 'Disease', 'MESH:D009202', (26, 43))	('fatty acid', 'Chemical', 'MESH:D005227', (138, 148))	('catecholamine', 'Chemical', 'MESH:D002395', (177, 190))	('myocarditis', 'Disease', (161, 172))	('impaired', 'Var', (129, 137))	('myocarditis', 'Phenotype', 'HP:0012819', (161, 172))	('microvascular', 'CPA', (47, 60))	('Catecholamines', 'Chemical', 'MESH:D002395', (0, 14))	('myocardial dysfunction', 'Disease', 'MESH:D009202', (200, 222))	('myocardial damage', 'Disease', (26, 43))	('myocardial dysfunction', 'Disease', (200, 222))	('induce', 'Reg', (19, 25))	('epicardial spasm', 'Disease', 'MESH:D013035', (111, 127))	('myocarditis', 'Disease', 'MESH:D009205', (161, 172))	('epicardial spasm', 'Disease', (111, 127))
67121	31511074	They are characterised by germline mutations of genes that lead to the early onset of distinctive tumour subtypes in specific organs.	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (35, 44))
67142	31511074	In the American NLST trial, annual low-dose chest CT in long-term smokers reduced lung cancer mortality by 20% compared to annual chest radiography.	('low-dose', 'Var', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('reduced', 'NegReg', (74, 81))
67328	31511074	These tumours also show amplification of MDM2 and CDK4 positivity on FISH testing, whereas lipomas do not.	('lipomas', 'Disease', (91, 98))	('CDK4', 'Gene', (50, 54))	('lipomas', 'Disease', 'MESH:D008067', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('positivity', 'Var', (55, 65))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('MDM', 'Disease', (41, 44))	('lipomas', 'Phenotype', 'HP:0012032', (91, 98))	('amplification', 'Var', (24, 37))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('lipomas', 'Phenotype', 'HP:0001012', (91, 98))	('MDM', 'Disease', 'MESH:D007645', (41, 44))	('lipoma', 'Phenotype', 'HP:0012032', (91, 97))	('tumours', 'Disease', (6, 13))
67380	31511074	Advance DWI and PWI may further improve accuracy of MRI in discriminating various subtype of kidney cancers and has shown potential in discriminating chromophobe RCC from other subtypes.	('chromophobe RCC', 'Disease', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('kidney cancer', 'Phenotype', 'HP:0009726', (93, 106))	('PWI', 'Var', (16, 19))	('kidney cancers', 'Phenotype', 'HP:0009726', (93, 107))	('kidney cancers', 'Disease', 'MESH:D007680', (93, 107))	('chromophobe RCC', 'Disease', 'MESH:D002292', (150, 165))	('kidney cancers', 'Disease', (93, 107))	('improve', 'PosReg', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
67446	31511074	More than 66% of the responders indicated that the benefits of AI and machine learning are much bigger or slightly bigger than the risks for cancer imaging.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('machine learning', 'Var', (70, 86))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
67695	31511074	2000;20(6):1585-603 High-quality evidence shows that MRI in biopsy-naive men can reduce the number of men who need prostate biopsy and can reduce the number of diagnoses of clinically insignificant cancers that are unlikely to cause harm.	('men', 'Species', '9606', (73, 76))	('reduce', 'NegReg', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('reduce', 'NegReg', (139, 145))	('men', 'Species', '9606', (102, 105))	('MRI', 'Var', (53, 56))
67719	31511074	The detection of bone metastases in patients with high-risk prostate cancer: 99mTc-MDP Planar bone scintigraphy, single- and multi-field-of-view SPECT, 18F-fluoride PET, and 18F-fluoride PET/CT.	('prostate cancer', 'Phenotype', 'HP:0012125', (60, 75))	('MDP', 'Chemical', 'MESH:D000119', (83, 86))	('patients', 'Species', '9606', (36, 44))	('prostate cancer', 'Disease', (60, 75))	('bone metastases', 'Disease', (17, 32))	('bone metastases', 'Disease', 'MESH:D009362', (17, 32))	('18F-fluoride', 'Chemical', '-', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('18F-fluoride PET/CT', 'Var', (174, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (60, 75))	('18F-fluoride', 'Chemical', '-', (174, 186))	('Tc', 'Chemical', 'MESH:D013667', (80, 82))
67795	31511074	131I-MIBG--a new agent in diagnosis and treatment of pheochromocytoma.	('men', 'Species', '9606', (45, 48))	('131I-MIBG--', 'Var', (0, 11))	('pheochromocytoma', 'Disease', (53, 69))	('pheochromocytoma', 'Disease', 'MESH:D010673', (53, 69))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (53, 69))	('131I-MIBG', 'Chemical', '-', (0, 9))
67807	31511074	PET imaging with a [68Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions.	('prostate cancer', 'Disease', (75, 90))	('PSMA', 'Gene', '2346', (42, 46))	('[68Ga', 'Var', (19, 24))	('gallium', 'Chemical', 'MESH:D005708', (25, 32))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Ga', 'Chemical', 'MESH:D005708', (22, 24))	('PSMA', 'Gene', (42, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('tumour lesions', 'Disease', (142, 156))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('tumour lesions', 'Disease', 'MESH:D001932', (142, 156))	('humans', 'Species', '9606', (111, 117))
67823	31511074	For both metastatic and myeloma bone disease, deficiencies in the ability of serum biomarkers to reflect disease status particularly in later stages of the disease strengthens the need for quantitative whole body imaging.	('myeloma bone disease', 'Disease', 'MESH:D009101', (24, 44))	('deficiencies', 'Var', (46, 58))	('myeloma bone disease', 'Disease', (24, 44))	('metastatic', 'Disease', (9, 19))
67932	31511074	Probing molecular changes will aid not only cancer diagnosis, but also provide tumour grading, based on gene-expression analysis and imaging measurements of cell proliferation and changes in metabolism; staging, based on imaging of metastatic spread and elevation of protein biomarkers; and the detection of therapeutic response, using serial molecular imaging measurements or monitoring of serum markers.	('changes', 'Var', (18, 25))	('changes', 'Reg', (180, 187))	('men', 'Species', '9606', (368, 371))	('cell proliferation', 'CPA', (157, 175))	('metastatic spread', 'CPA', (232, 249))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('men', 'Species', '9606', (148, 151))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('metabolism', 'MPA', (191, 201))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('protein biomarkers', 'MPA', (267, 285))	('tumour', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
68085	31511074	Methods: Retrospective analysis of 388 prostate cancer patients enrolled in five prospective studies (NCT02940262, NCT03368547, NCT03042312, UCLA IRB#17-001336, NCT03515577).	('NCT02940262', 'Var', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('prostate cancer', 'Disease', (39, 54))	('NCT03368547', 'Var', (115, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (39, 54))	('patients', 'Species', '9606', (55, 63))	('NCT03042312', 'Var', (128, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))
68152	31511074	In this study, we aim to study the value of b800/b0 in addition to ADC values.	('AD', 'Disease', 'MESH:D000544', (67, 69))	('AD', 'Disease', (67, 69))	('b800/b0', 'Var', (44, 51))
68158	31511074	Conclusion The b800/b0 ratio in diffusion weighted imaging could help to differentiate benign from malignant gallbladder lesions, and it may be more reliable than the ADC values in the quantitative assessment of the DWI.	('AD', 'Disease', 'MESH:D000544', (167, 169))	('AD', 'Disease', (167, 169))	('gallbladder lesions', 'Disease', (109, 128))	('b800/b0', 'Var', (15, 22))	('men', 'Species', '9606', (204, 207))	('gallbladder lesions', 'Disease', 'MESH:D005705', (109, 128))
68280	31511074	More recently, F18 FDG-PET/CT, imaging which has various oncological applications, has been recommended as an important complementary tool in the detection of bone metastases and evaluation of therapy response.	('men', 'Species', '9606', (126, 129))	('men', 'Species', '9606', (97, 100))	('bone metastases', 'Disease', 'MESH:D009362', (159, 174))	('bone metastases', 'Disease', (159, 174))	('FDG', 'Chemical', 'MESH:D019788', (19, 22))	('F18', 'Var', (15, 18))
68305	31511074	While diagnostic certainty was comparable, ratings for lesion conspicuity were significantly higher for the combination of CI/IO (4(3-5)) compared to CI only (3(3-4);p<0.05).	('higher', 'PosReg', (93, 99))	('CI/IO', 'Var', (123, 128))	('IO', 'Chemical', '-', (126, 128))
68355	31511074	The study was performed in 404 patients with NPC who had undergone MR imaging with a standard protocol which included T1W, T2W- fat-suppressed (FS), contrast-enhanced-T1W (CE-T1W) and CE-T1W-FS sequences.	('NPC', 'Disease', 'MESH:D052556', (45, 48))	('T2W-', 'Var', (123, 127))	('NPC', 'Disease', (45, 48))	('T1W', 'Var', (118, 121))	('patients', 'Species', '9606', (31, 39))
68407	31511074	Distant metastases free survival was significantly better in patients with ypT0-2 (versus ypT3-4, P=0.0028) and ypN0 (versus ypN1-2, P=0.0040).	('metastases', 'Disease', (8, 18))	('ypT0-2', 'Var', (75, 81))	('patients', 'Species', '9606', (61, 69))	('metastases', 'Disease', 'MESH:D009362', (8, 18))	('ypN0', 'Var', (112, 116))	('better', 'PosReg', (51, 57))
68415	31511074	The values of ADCbm were significantly higher (p<0.01) in women, 477.3+-17.7 mum/s (95% IC), than in men, 426.3+-14.0 mum/s (95% IC).	('higher', 'PosReg', (39, 45))	('men', 'Species', '9606', (101, 104))	('477.3+-17.7', 'Var', (65, 76))	('women', 'Species', '9606', (58, 63))	('men', 'Species', '9606', (60, 63))	('AD', 'Disease', 'MESH:D000544', (14, 16))	('AD', 'Disease', (14, 16))
68431	31511074	Methods: Single-site retrospective analysis of histologically confirmed FH-deficient renal cancer, or patients with renal cancer and Germline FH mutation.	('renal cancer', 'Disease', (116, 128))	('FH-deficient renal cancer', 'Disease', (72, 97))	('renal cancer', 'Phenotype', 'HP:0009726', (85, 97))	('FH', 'Gene', '2271', (72, 74))	('renal cancer', 'Phenotype', 'HP:0009726', (116, 128))	('FH-deficient renal cancer', 'Disease', 'MESH:D007680', (72, 97))	('Germline', 'Var', (133, 141))	('patients', 'Species', '9606', (102, 110))	('renal cancer', 'Disease', 'MESH:D007680', (85, 97))	('renal cancer', 'Disease', 'MESH:D007680', (116, 128))	('FH', 'Gene', '2271', (142, 144))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
68443	30893643	Driver mutations were used to categorize patients accordingly to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown).	('kinase signaling', 'MPA', (175, 191))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (228, 246))	('VHL', 'Gene', '7428', (254, 257))	('SDHB', 'Gene', '6390', (115, 119))	('EPAS1', 'Gene', '2034', (258, 263))	('tricarboxylic acid cycle', 'MPA', (228, 252))	('kinase signaling', 'MPA', (265, 281))	('SDHB', 'Gene', (115, 119))	('EPAS1', 'Gene', (258, 263))	('patients', 'Species', '9606', (41, 49))	('VHL', 'Gene', (254, 257))	('mutated', 'Var', (120, 127))
68445	30893643	Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 [95% CI 1.79-18.06]) as well as norepinephrine (OR 3.01 [95% CI 1.02-8.79]) and dopamine (OR 6.39 [95% CI 1.62-25.24]) but not to PPGL location.	('SDHB', 'Gene', '6390', (76, 80))	('dopamine', 'Chemical', 'MESH:D004298', (179, 187))	('SDHB', 'Gene', (76, 80))	('PPGL', 'Chemical', '-', (229, 233))	('correlation', 'Interaction', (59, 70))	('mutation', 'Var', (81, 89))	('norepinephrine', 'MPA', (131, 145))	('norepinephrine', 'Chemical', 'MESH:D009638', (131, 145))	('dopamine', 'MPA', (179, 187))	('metastasis', 'CPA', (41, 51))
68455	30893643	It has also been proposed that PPGL with somatic abberations in genes releated to telomere maintenance (inactivation of ATRX or transcriptional activation of TERT) as well as chromatin maintenance (SETD2) could have more aggressive features and may thus be disease modifiers.	('ATRX', 'Gene', (120, 124))	('transcriptional', 'MPA', (128, 143))	('SETD2', 'Gene', (198, 203))	('SETD2', 'Gene', '29072', (198, 203))	('TERT', 'Gene', (158, 162))	('ATRX', 'Gene', '546', (120, 124))	('abberations', 'Var', (49, 60))	('aggressive features', 'CPA', (221, 240))	('TERT', 'Gene', '7015', (158, 162))	('activation', 'PosReg', (144, 154))	('PPGL', 'Chemical', '-', (31, 35))
68457	30893643	Tumor location (PGL versus PCC), germline SDHB mutations (SDHB mutated versus SDHB wild type), ATRX mutation, TERT overexpression, catecholamine secretion (noradrenergic or dopaminergic versus adrenergic) and large size of the primary tumor have all been independently associated with metastasis.	('ATRX', 'Gene', (95, 99))	('SDHB', 'Gene', (58, 62))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('SDHB', 'Gene', '6390', (78, 82))	('PCC', 'Gene', (27, 30))	('ATRX', 'Gene', '546', (95, 99))	('PCC', 'Gene', '1421', (27, 30))	('associated', 'Reg', (269, 279))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('mutations', 'Var', (47, 56))	('catecholamine', 'Chemical', 'MESH:D002395', (131, 144))	('SDHB', 'Gene', (78, 82))	('SDHB', 'Gene', '6390', (58, 62))	('SDHB', 'Gene', '6390', (42, 46))	('metastasis', 'Disease', (285, 295))	('catecholamine secretion', 'MPA', (131, 154))	('mutation', 'Var', (100, 108))	('TERT', 'Gene', (110, 114))	('tumor', 'Disease', (235, 240))	('TERT', 'Gene', '7015', (110, 114))	('dopamine', 'Chemical', 'MESH:D004298', (173, 181))	('SDHB', 'Gene', (42, 46))
68459	30893643	Size of the primary tumor, gender, SDHB mutation, catecholamine profile, ATRX mutation and TERT overexpression are suggested to be prognostic factors for survival.	('mutation', 'Var', (40, 48))	('catecholamine profile', 'MPA', (50, 71))	('mutation', 'Var', (78, 86))	('TERT', 'Gene', (91, 95))	('SDHB', 'Gene', (35, 39))	('catecholamine profile', 'Phenotype', 'HP:0003334', (50, 71))	('ATRX', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('TERT', 'Gene', '7015', (91, 95))	('catecholamine', 'Chemical', 'MESH:D002395', (50, 63))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ATRX', 'Gene', '546', (73, 77))	('SDHB', 'Gene', '6390', (35, 39))	('tumor', 'Disease', (20, 25))
68461	30893643	We and others have proposed that the improved characterization of PPGL driver mutations provide additional information beyond the dichotomous categorization based on SDHB.	('SDHB', 'Gene', (166, 170))	('mutations', 'Var', (78, 87))	('PPGL', 'Chemical', '-', (66, 70))	('SDHB', 'Gene', '6390', (166, 170))	('PPGL', 'Gene', (66, 70))
68470	30893643	With the TCGA publication as a starting point and taking into account the available literature, we selected three different systems for driver gene categorization: A 2-molecular subgroup system accordingly to SDHB mutation status: SDHB mutated or SDHB wild type.	('mutation', 'Var', (214, 222))	('SDHB', 'Gene', '6390', (231, 235))	('SDHB', 'Gene', (231, 235))	('SDHB', 'Gene', '6390', (247, 251))	('mutated', 'Var', (236, 243))	('SDHB', 'Gene', '6390', (209, 213))	('SDHB', 'Gene', (247, 251))	('SDHB', 'Gene', (209, 213))
68472	30893643	PPGL with driver mutations associated with different molecular subgroups as well as those without a driver mutation was classified as Wnt/unknown.	('associated', 'Reg', (27, 37))	('PPGL', 'Gene', (0, 4))	('mutations', 'Var', (17, 26))	('PPGL', 'Chemical', '-', (0, 4))
68482	30893643	PPGL-related driver mutations were detected in 437 patients (62.6%, 95% CI 58.5-65.7, Supplementary Figure 3, Supplementary Table 1) that were confirmed as germline in 178 (25.3%, 95% CI 22.3-28.7) and somatic in 237 (33.7%, 95% CI 30.3-37.3).	('PPGL', 'Chemical', '-', (0, 4))	('PPGL-related', 'Gene', (0, 12))	('patients', 'Species', '9606', (51, 59))	('mutations', 'Var', (20, 29))
68484	30893643	Two-molecular subgroups: SDHB mutated 58 patients (8.3%, 95% CI 6.4-10.5, Table 2) and SDHB wild type 645 patients (91.8% 95% CI 89.5-93.6).	('mutated', 'Var', (30, 37))	('patients', 'Species', '9606', (41, 49))	('SDHB', 'Gene', '6390', (25, 29))	('patients', 'Species', '9606', (106, 114))	('SDHB', 'Gene', (25, 29))	('SDHB', 'Gene', '6390', (87, 91))	('SDHB', 'Gene', (87, 91))
68489	30893643	Categorization accordingly to the 2-,3- and 4-molecular subgroup systems as well as catecholamine profile, WHO classification and ATRX mutation status correlated with metastatic disease in univariate Cox regression analyses (Figure 1, Table 3): Those with SDHB mutated PPGLs had metastatic disease in 46.6% (27/58 patients, OR 8.81 [95% CI 4.92-15.78]; P<0.001) that was higher compared to SDHB wild type 8.9% (58/645 patients) PPGLs.	('SDHB', 'Gene', '6390', (390, 394))	('mutated', 'Var', (261, 268))	('PPGL', 'Chemical', '-', (269, 273))	('ATRX', 'Gene', (130, 134))	('PPGLs', 'Gene', (269, 274))	('patients', 'Species', '9606', (314, 322))	('PPGL', 'Chemical', '-', (428, 432))	('SDHB', 'Gene', (390, 394))	('ATRX', 'Gene', '546', (130, 134))	('SDHB', 'Gene', '6390', (256, 260))	('patients', 'Species', '9606', (418, 426))	('catecholamine profile', 'Phenotype', 'HP:0003334', (84, 105))	('catecholamine', 'Chemical', 'MESH:D002395', (84, 97))	('SDHB', 'Gene', (256, 260))	('metastatic disease', 'CPA', (279, 297))
68493	30893643	While ATRX mutated PPGL showed a positive correlation with metastases in the univariate analysis, information on ATRX mutation status was only available in a subset of patients (467/703) that also lacked complete clinical annotations.	('ATRX', 'Gene', '546', (113, 117))	('PPGL', 'Gene', (19, 23))	('ATRX', 'Gene', (6, 10))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('PPGL', 'Chemical', '-', (19, 23))	('ATRX', 'Gene', '546', (6, 10))	('patients', 'Species', '9606', (168, 176))	('metastases', 'Disease', (59, 69))	('mutated', 'Var', (11, 18))	('ATRX', 'Gene', (113, 117))	('positive', 'Reg', (33, 41))
68495	30893643	In model 1 (exploring the role of 2-molecular subtype; Table 3, Column B), SDHB mutation (OR 5.68 [95% CI 1.79-18.06]; P=0.003) as well as norepinephrine (OR 3.01 [95% CI 1.02-8.79]; P=0.045) and dopamine (OR 6.39 [95% CI 1.62-25.24]; P=0.008) secretion but not WHO classification were associated with metastatic disease.	('SDHB', 'Gene', '6390', (75, 79))	('norepinephrine', 'MPA', (139, 153))	('dopamine', 'MPA', (196, 204))	('SDHB', 'Gene', (75, 79))	('mutation', 'Var', (80, 88))	('dopamine', 'Chemical', 'MESH:D004298', (196, 204))	('norepinephrine', 'Chemical', 'MESH:D009638', (139, 153))
68498	30893643	Thus, in the context of clinical characteristics the only relevant molecular biomarker for predicting metastasis was categorization accordingly to SDHB mutation status.	('SDHB', 'Gene', '6390', (147, 151))	('mutation', 'Var', (152, 160))	('SDHB', 'Gene', (147, 151))
68499	30893643	Age at diagnosis (Hazard ratio [HR] 1.04 [95% CI 1.01-1.05]; P=0.019), metastatic stage (HR 6.63 [95% CI 3.46-12.7]; p<0.001), PGL (HR 2.6 [95% CI 1.32-5.15]; P=0.006), SDHB mutation (HR [95% CI 1.32-5.94]; P=0.007), pseudohypoxia TCA-cycle (HR 2.28 [95% CI 1.03-5.08]; p=0.043) and ATRX mutation (HR 9.44 [95% CI 3.29-27.15]; P<0.001) correlated with worse survival in univariate cox regression analyses (Table 4, Supplementary Figure 4).	('mutation', 'Var', (288, 296))	('SDHB', 'Gene', '6390', (169, 173))	('SDHB', 'Gene', (169, 173))	('mutation', 'Var', (174, 182))	('ATRX', 'Gene', '546', (283, 287))	('worse', 'NegReg', (352, 357))	('TCA', 'Chemical', 'MESH:D014233', (231, 234))	('ATRX', 'Gene', (283, 287))
68506	30893643	While tumor location, biochemical phenotype and the driver gene classifications all showed different frequencies of metastatic disease in the univariate analyses, the only categorization accordingly to a driver gene that remained significant in the multivariate models was SDHB mutation status.	('metastatic disease', 'Disease', (116, 134))	('SDHB', 'Gene', '6390', (273, 277))	('SDHB', 'Gene', (273, 277))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('mutation', 'Var', (278, 286))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
68508	30893643	Major driver genes in the reviewed studies were NF1, VHL, RET, SDHB, and HRAS that were mutated in 45.2% in of PPGL.	('RET', 'Gene', '5979', (58, 61))	('SDHB', 'Gene', (63, 67))	('NF1', 'Gene', '4763', (48, 51))	('HRAS', 'Gene', '3265', (73, 77))	('HRAS', 'Gene', (73, 77))	('VHL', 'Gene', (53, 56))	('RET', 'Gene', (58, 61))	('VHL', 'Gene', '7428', (53, 56))	('mutated', 'Var', (88, 95))	('SDHB', 'Gene', '6390', (63, 67))	('PPGL', 'Chemical', '-', (111, 115))	('NF1', 'Gene', (48, 51))
68517	30893643	reviewed the frequency of metastatic disease in patients with hereditary PPGL: RET, 2.9%; VHL, 3.4%; SDHD, 3.5%; and SDHB, 30.7%.	('SDHD', 'Gene', (101, 105))	('SDHD', 'Gene', '6392', (101, 105))	('SDHB', 'Gene', (117, 121))	('RET', 'Gene', '5979', (79, 82))	('VHL', 'Gene', '7428', (90, 93))	('metastatic disease', 'Disease', (26, 44))	('SDHB', 'Gene', '6390', (117, 121))	('hereditary', 'Var', (62, 72))	('RET', 'Gene', (79, 82))	('patients', 'Species', '9606', (48, 56))	('PPGL', 'Chemical', '-', (73, 77))	('VHL', 'Gene', (90, 93))	('PPGL', 'Gene', (73, 77))
68521	30893643	However, only molecular categorization accordingly to SDHB mutation status, but not other molecular systems or mutations, was associated with metastasis in the multivariate models.	('associated', 'Reg', (126, 136))	('SDHB', 'Gene', '6390', (54, 58))	('metastasis', 'CPA', (142, 152))	('SDHB', 'Gene', (54, 58))	('mutation', 'Var', (59, 67))
68525	30893643	Lack of data on ATRX inactivation or TERT expression is also a relevant limitation as it has been associated with higher frequency of metastasis as well as poor survival.	('inactivation', 'Var', (21, 33))	('TERT', 'Gene', (37, 41))	('TERT', 'Gene', '7015', (37, 41))	('ATRX', 'Gene', '546', (16, 20))	('metastasis', 'CPA', (134, 144))	('ATRX', 'Gene', (16, 20))
68532	30893643	However, only SDHB mutation status remained significant in the multivariate model.	('SDHB', 'Gene', '6390', (14, 18))	('mutation', 'Var', (19, 27))	('SDHB', 'Gene', (14, 18))
68605	30052223	An immediate urinary normetadrenaline/creatinine ratio was high at 5.40umol/mmol creat (normal range 0.00-0.350 umol/mmol creat), considered highly suspicious of pheochromocytoma.	('creat', 'Chemical', '-', (38, 43))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (162, 178))	('creatinine', 'Chemical', 'MESH:D003404', (38, 48))	('pheochromocytoma', 'Disease', 'MESH:D010673', (162, 178))	('5.40umol/mmol creat', 'Var', (67, 86))	('creat', 'Chemical', '-', (81, 86))	('normetadrenaline', 'Chemical', 'MESH:D009647', (21, 37))	('creat', 'Chemical', '-', (122, 127))	('urinary normetadrenaline/creatinine ratio', 'MPA', (13, 54))	('pheochromocytoma', 'Disease', (162, 178))
68647	26998444	Classic triad of headache, palpitation and diaphoresis in hypertensive patients had the LR+ 6.312 (95 % CI 0.217-183.217) and LR-0.139 (95 % CI 0.059-0.331).	('hypertensive', 'Disease', 'MESH:D006973', (58, 70))	('palpitation', 'Disease', (27, 38))	('headache', 'Disease', (17, 25))	('hypertensive', 'Disease', (58, 70))	('patients', 'Species', '9606', (71, 79))	('headache', 'Phenotype', 'HP:0002315', (17, 25))	('headache', 'Disease', 'MESH:D006261', (17, 25))	('diaphoresis', 'Phenotype', 'HP:0000975', (43, 54))	('palpitation', 'Phenotype', 'HP:0001962', (27, 38))	('LR+', 'Var', (88, 91))	('LR-0.139', 'Var', (126, 134))	('diaphoresis', 'Disease', (43, 54))
68659	26998444	Clinical awareness of this tumor should be stressed because 1) Surgical removal is curative in more than 90 % of patients (The 5-year patient survival after removal of benign pheochromocytoma has been ranged from 84 to 96 %), 2) Tumor excision has significant effect on hypertension, the most important cause of pheochromocytoma related mortality and morbidity.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patient', 'Species', '9606', (113, 120))	('hypertension', 'Disease', (270, 282))	('tumor', 'Disease', (27, 32))	('patients', 'Species', '9606', (113, 121))	('hypertension', 'Phenotype', 'HP:0000822', (270, 282))	('pheochromocytoma', 'Disease', (312, 328))	('Tumor', 'Phenotype', 'HP:0002664', (229, 234))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (175, 191))	('pheochromocytoma', 'Disease', 'MESH:D010673', (312, 328))	('pheochromocytoma', 'Disease', (175, 191))	('hypertension', 'Disease', 'MESH:D006973', (270, 282))	('Tumor excision', 'Var', (229, 243))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (312, 328))	('pheochromocytoma', 'Disease', 'MESH:D010673', (175, 191))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patient', 'Species', '9606', (134, 141))
68771	25494863	Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas.	('LOH', 'Var', (33, 36))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (64, 81))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (64, 82))	('SDHB', 'Gene', '6390', (44, 48))	('pituitary adenomas', 'Disease', (64, 82))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (135, 152))	('MEN1', 'Gene', '4221', (117, 121))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (135, 151))	('MEN1', 'Gene', (117, 121))	('SDHB', 'Gene', (44, 48))	('pheochromocytomas', 'Disease', (135, 152))	('pheochromocytomas', 'Disease', 'MESH:D010673', (135, 152))	('pituitary adenomas', 'Disease', 'MESH:D010911', (64, 82))
68772	25494863	All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (8, 25))	('alterations', 'Var', (56, 67))	('pituitary adenomas', 'Disease', 'MESH:D010911', (8, 26))	('patients', 'Species', '9606', (30, 38))	('SDHX', 'Chemical', '-', (51, 55))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (8, 26))	('pituitary adenomas', 'Disease', (8, 26))	('SDHX', 'Gene', (51, 55))
68773	25494863	Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL.	('mutation', 'Var', (105, 113))	('pituitary adenomas', 'Disease', (77, 95))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (77, 94))	('pituitary adenomas', 'Disease', (140, 158))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (140, 157))	('pituitary adenomas', 'Disease', 'MESH:D010911', (77, 95))	('MEN1', 'Gene', (160, 164))	('pheo/PGL', 'Disease', (189, 197))	('Mutations', 'Var', (0, 9))	('pituitary adenomas', 'Disease', 'MESH:D010911', (140, 158))	('MEN1', 'Gene', '4221', (160, 164))	('associated', 'Reg', (173, 183))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (77, 95))	('pheo', 'Chemical', '-', (38, 42))	('associated', 'Reg', (61, 71))	('pheo', 'Chemical', '-', (189, 193))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (140, 158))
68778	25494863	The simultaneous occurrence of these two tumor types might be explained by the following: 1) a pheo/PGL-related gene mutation, which, in addition to the pheo/PGL, also causes PA, as suggested for the SDHX mutation being involved in PA formation; 2) a mutation in a familial PA gene that also causes pheo/PGL; 3) a digenic disease, ie, two gene abnormalities are present in the same patient or family causing the two diseases; 4) a single, possibly novel, gene causing both diseases; 5) ectopic hypothalamic hormone-secreting adrenal tumors causing pituitary enlargement mimicking PA; or 6) the development of a pituitary adenoma and a pheo/PGL in the same patient or same family due to pure coincidence.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('pituitary adenoma', 'Disease', 'MESH:D010911', (611, 628))	('renal tumor', 'Phenotype', 'HP:0009726', (527, 538))	('tumor', 'Phenotype', 'HP:0002664', (533, 538))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (611, 628))	('adrenal tumors', 'Disease', (525, 539))	('patient', 'Species', '9606', (382, 389))	('PGL; 3', 'Gene', (304, 310))	('pituitary adenoma', 'Disease', (611, 628))	('pituitary enlargement', 'Disease', 'MESH:D006529', (548, 569))	('SDHX', 'Chemical', '-', (200, 204))	('pheo', 'Chemical', '-', (153, 157))	('pheo', 'Chemical', '-', (635, 639))	('pituitary enlargement', 'Phenotype', 'HP:0012505', (548, 569))	('pituitary enlargement', 'Disease', (548, 569))	('patient', 'Species', '9606', (656, 663))	('tumor', 'Disease', (41, 46))	('PGL; 3', 'Gene', '6391', (304, 310))	('tumor', 'Disease', (533, 538))	('pheo', 'Chemical', '-', (95, 99))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('adrenal tumors', 'Disease', 'MESH:D000310', (525, 539))	('pheo', 'Chemical', '-', (299, 303))	('tumor', 'Disease', 'MESH:D009369', (533, 538))	('mutation', 'Var', (251, 259))	('tumors', 'Phenotype', 'HP:0002664', (533, 539))	('mutation', 'Var', (117, 125))	('PA', 'Disease', (580, 582))
68781	25494863	Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and LOH at the MEN1 locus in two pheochromocytomas.	('LOH', 'Var', (33, 36))	('pheochromocytomas', 'Disease', 'MESH:D010673', (116, 133))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (64, 81))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (64, 82))	('SDHB', 'Gene', '6390', (44, 48))	('pituitary adenomas', 'Disease', (64, 82))	('SDHB', 'Gene', (44, 48))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (116, 133))	('pituitary adenomas', 'Disease', 'MESH:D010911', (64, 82))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (116, 132))	('MEN1', 'Gene', (98, 102))	('MEN1', 'Gene', '4221', (98, 102))	('pheochromocytomas', 'Disease', (116, 133))
68784	25494863	Probands from 23 aryl hydrocarbon receptor interacting protein (AIP) mutation negative familial isolated PA (FIPA) families (defined as two or more subjects with pituitary adenomas but no syndromic features of other diseases such as multiple endocrine neoplasia (MEN)-1 or Carney complex) served as controls.	('endocrine neoplasia (MEN)-1', 'Gene', (242, 269))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (242, 261))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (162, 180))	('familial isolated PA', 'Disease', (87, 107))	('AIP', 'Gene', '9049', (64, 67))	('mutation', 'Var', (69, 77))	('Carney complex', 'Disease', (273, 287))	('AIP', 'Gene', (64, 67))	('pituitary adenomas', 'Disease', (162, 180))	('endocrine neoplasia (MEN)-1', 'Gene', '4221', (242, 269))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (162, 179))	('neoplasia', 'Phenotype', 'HP:0002664', (252, 261))	('pituitary adenomas', 'Disease', 'MESH:D010911', (162, 180))
68792	25494863	Microsatellites D1S170 and D1S3669 for the SDHB locus were identified on the National Center for Biotechnology Information website (http://www.ncbi.nlm.nih.gov/) and the University of California, Santa Cruz Genome Browser website (http://genome.ucsc.edu/).	('D1S3669', 'Var', (27, 34))	('SDHB', 'Gene', '6390', (43, 47))	('SDHB', 'Gene', (43, 47))	('D1S170', 'Var', (16, 22))
68793	25494863	Details of the microsatellites at the 11q13 locus (for MEN1) were previously described.	('microsatellites', 'Var', (15, 30))	('MEN1', 'Gene', (55, 59))	('MEN1', 'Gene', '4221', (55, 59))
68796	25494863	Pheochromocytomas of patients with the MEN1 mutation were stained for menin using a rabbit polyclonal antimenin antibody (Abcam; ab2605, dilution 1:500), as previously described.	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('menin', 'Gene', (70, 75))	('mutation', 'Var', (44, 52))	('rabbit', 'Species', '9986', (84, 90))	('menin', 'Gene', '4221', (106, 111))	('patients', 'Species', '9606', (21, 29))	('Pheochromocytomas', 'Disease', (0, 17))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('menin', 'Gene', (106, 111))	('menin', 'Gene', '4221', (70, 75))	('MEN1', 'Gene', (39, 43))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (0, 16))	('MEN1', 'Gene', '4221', (39, 43))
68809	25494863	One patient with a VHL mutation and a family history of clear-cell renal tumor and multiple hemangioblastomas had a PA presenting at 15 years (no typical VHL manifestations at this stage).	('mutation', 'Var', (23, 31))	('clear-cell renal tumor', 'Phenotype', 'HP:0006770', (56, 78))	('VHL', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patient', 'Species', '9606', (4, 11))	('VHL', 'Gene', (154, 157))	('multiple hemangioblastomas', 'Disease', 'MESH:D018325', (83, 109))	('VHL', 'Gene', '7428', (19, 22))	('VHL', 'Gene', '7428', (154, 157))	('clear-cell renal tumor', 'Disease', 'MESH:C538614', (56, 78))	('renal tumor', 'Phenotype', 'HP:0009726', (67, 78))	('multiple hemangioblastomas', 'Disease', (83, 109))	('multiple hemangioblastomas', 'Phenotype', 'HP:0012329', (83, 109))	('clear-cell renal tumor', 'Disease', (56, 78))
68810	25494863	Two patients with MEN1 mutations had a pheochromocytoma.	('MEN1', 'Gene', (18, 22))	('pheochromocytoma', 'Disease', (39, 55))	('MEN1', 'Gene', '4221', (18, 22))	('mutations', 'Var', (23, 32))	('pheochromocytoma', 'Disease', 'MESH:D010673', (39, 55))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (39, 55))	('patients', 'Species', '9606', (4, 12))
68821	25494863	All patients harbored one gene mutation except one patient, who had a VHL mutation and an SDHA variant of unknown significance.	('VHL', 'Gene', (70, 73))	('harbored', 'Reg', (13, 21))	('mutation', 'Var', (74, 82))	('SDHA', 'Gene', '6389', (90, 94))	('VHL', 'Gene', '7428', (70, 73))	('mutation', 'Var', (31, 39))	('patient', 'Species', '9606', (4, 11))	('SDHA', 'Gene', (90, 94))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (4, 12))
68823	25494863	None of the patients in our cohort had AIP or CDKN1B mutations.	('patients', 'Species', '9606', (12, 20))	('CDKN1B', 'Gene', '1027', (46, 52))	('AIP', 'Gene', '9049', (39, 42))	('mutations', 'Var', (53, 62))	('AIP', 'Gene', (39, 42))	('CDKN1B', 'Gene', (46, 52))
68824	25494863	We identified 11 kindreds (including 16 patients) with germline SDHX variants (Supplemental Table 6).	('variants', 'Var', (69, 77))	('SDHX', 'Chemical', '-', (64, 68))	('SDHX', 'Gene', (64, 68))	('patients', 'Species', '9606', (40, 48))
68825	25494863	Seven families had a pathogenic SDH mutation, whereas four had a variant of unknown significance.	('SDH', 'Gene', (32, 35))	('SDH', 'Gene', '6390', (32, 35))	('pathogenic', 'Reg', (21, 31))	('mutation', 'Var', (36, 44))
68826	25494863	All patients with SDHX mutations/variants had a pituitary macroadenoma.	('SDHX', 'Chemical', '-', (18, 22))	('pituitary macroadenoma', 'Disease', (48, 70))	('patients', 'Species', '9606', (4, 12))	('mutations/variants', 'Var', (23, 41))	('SDHX', 'Gene', (18, 22))	('pituitary macroadenoma', 'Disease', 'MESH:D010900', (48, 70))
68828	25494863	In particular, patient 5 was interesting in whom the germline mutation was a large deletion affecting exons 6-8 of the SDHB gene, whereas in the tumor sample the whole gene was deleted with no detectable exons 6-8 and a reduced amount of the other exons.	('patient', 'Species', '9606', (15, 22))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SDHB', 'Gene', '6390', (119, 123))	('tumor', 'Disease', (145, 150))	('SDHB', 'Gene', (119, 123))	('deletion', 'Var', (83, 91))
68830	25494863	One of these (c.969C>T, p.Gly323Gly) was identified in a patient (patient 15) with a Wilms tumor (at the age of 1 y), retroperitoneal liposarcomas (32 and 40 y), a PGL in the retroperitoneum (50 y), a renal oncocytoma (50 y), and a nonfunctioning pituitary adenoma (NFPA; 53 y).	('pituitary adenoma', 'Disease', 'MESH:D010911', (247, 264))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (247, 264))	('Wilms tumor', 'Disease', (85, 96))	('liposarcomas', 'Phenotype', 'HP:0012034', (134, 146))	('c.969C>T', 'Var', (14, 22))	('pituitary adenoma', 'Disease', (247, 264))	('renal oncocytoma', 'Disease', (201, 217))	('patient', 'Species', '9606', (57, 64))	('nonfunctioning pituitary adenoma', 'Phenotype', 'HP:0011761', (232, 264))	('retroperitoneal liposarcomas', 'Phenotype', 'HP:0006729', (118, 146))	('retroperitoneal liposarcomas', 'Disease', (118, 146))	('p.Gly323Gly', 'Var', (24, 35))	('Wilms tumor', 'Disease', 'MESH:D009396', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p.Gly323Gly', 'SUBSTITUTION', 'None', (24, 35))	('renal oncocytoma', 'Disease', 'MESH:C537750', (201, 217))	('Wilms tumor', 'Phenotype', 'HP:0002667', (85, 96))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (201, 217))	('retroperitoneal liposarcomas', 'Disease', 'MESH:C538370', (118, 146))	('patient', 'Species', '9606', (66, 73))	('c.969C>T', 'Mutation', 'rs142849100', (14, 22))
68831	25494863	His mother (no known tumors) carried the c.969C<T variant.	('c.969C<T', 'Var', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', (21, 27))	('c.969C<T', 'Mutation', 'rs142849100', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
68832	25494863	The other SDHA variant was identified in a patient with a VHL mutation and PA (patient 21).	('SDHA', 'Gene', (10, 14))	('patient', 'Species', '9606', (43, 50))	('VHL', 'Gene', (58, 61))	('mutation', 'Var', (62, 70))	('patient', 'Species', '9606', (79, 86))	('VHL', 'Gene', '7428', (58, 61))	('SDHA', 'Gene', '6389', (10, 14))
68833	25494863	We have also identified an SDHB variant (c.80G>A p.Arg27Gln, patient 17) of unknown significance.	('patient', 'Species', '9606', (61, 68))	('c.80G>A p.Arg27Gln', 'Var', (41, 59))	('SDHB', 'Gene', '6390', (27, 31))	('p.Arg27Gln', 'Mutation', 'rs373976827', (49, 59))	('SDHB', 'Gene', (27, 31))	('c.80G>A', 'Mutation', 'rs200671534', (41, 48))
68835	25494863	An SDHAF2 variant c.-52T>C was identified in a patient with somatotroph macroadenoma and head and neck PGL.	('SDHAF2', 'Gene', (3, 9))	('c.-52T>C', 'Var', (18, 26))	('patient', 'Species', '9606', (47, 54))	('c.-52T>C', 'Mutation', 'rs964335433', (18, 26))	('variant c.-52T>C', 'Var', (10, 26))	('somatotroph macroadenoma', 'Disease', (60, 84))	('somatotroph macroadenoma', 'Disease', 'MESH:D049912', (60, 84))	('SDHAF2', 'Gene', '54949', (3, 9))
68837	25494863	We identified two families with SDH mutations in which a family member with a PA did not carry the germline SDHX mutation: family 6 with two SDHC mutation-positive siblings had PA and/or PGL, whereas a first cousin had an NFPA but no SDHC mutation; and family 7 in whom the parent and child both had SDHD mutation-positive PGL and another child had a microprolactinoma but no SDHD mutation (Supplemental Figure 1).	('SDHD', 'Gene', (376, 380))	('SDH', 'Gene', (234, 237))	('SDH', 'Gene', '6390', (32, 35))	('SDHC', 'Gene', (141, 145))	('microprolactinoma', 'Phenotype', 'HP:0012341', (351, 368))	('SDH', 'Gene', (376, 379))	('SDH', 'Gene', '6390', (141, 144))	('SDHC', 'Gene', (234, 238))	('SDH', 'Gene', (32, 35))	('SDHD', 'Gene', '6392', (300, 304))	('child', 'Species', '9606', (285, 290))	('SDH', 'Gene', '6390', (108, 111))	('microprolactinoma', 'Disease', (351, 368))	('SDH', 'Gene', '6390', (300, 303))	('SDH', 'Gene', (141, 144))	('child', 'Species', '9606', (339, 344))	('prolactinoma', 'Phenotype', 'HP:0040278', (356, 368))	('SDHC', 'Gene', '6391', (141, 145))	('SDHX', 'Chemical', '-', (108, 112))	('SDH', 'Gene', '6390', (234, 237))	('SDHD', 'Gene', '6392', (376, 380))	('SDHD', 'Gene', (300, 304))	('microprolactinoma', 'Disease', 'MESH:D015175', (351, 368))	('SDH', 'Gene', '6390', (376, 379))	('mutations', 'Var', (36, 45))	('SDHC', 'Gene', '6391', (234, 238))	('SDH', 'Gene', (300, 303))	('SDH', 'Gene', (108, 111))
68838	25494863	An 18-year-old patient with a pathogenic VHL mutation [c.340G>C, a missense mutation affecting a surface amino-acid ], had an invasive GH- and prolactin (PRL)-positive PA as shown in Supplemental Table 6 and Supplemental Figure 2.	('PRL', 'Gene', (154, 157))	('patient', 'Species', '9606', (15, 22))	('[c.340G>C', 'Var', (54, 63))	('prolactin', 'Gene', '5617', (143, 152))	('PRL', 'Gene', '5617', (154, 157))	('pathogenic', 'Reg', (30, 40))	('prolactin', 'Gene', (143, 152))	('c.340G>C', 'Mutation', 'rs869025636', (55, 63))	('VHL', 'Gene', (41, 44))	('VHL', 'Gene', '7428', (41, 44))
68839	25494863	We identified two patients (patients 22 and 23) with a germline MEN1 mutation and pheochromocytoma, whereas all the other tested genes were normal (Supplemental Table 6).	('pheochromocytoma', 'Disease', (82, 98))	('mutation', 'Var', (69, 77))	('MEN1', 'Gene', '4221', (64, 68))	('patients', 'Species', '9606', (18, 26))	('pheochromocytoma', 'Disease', 'MESH:D010673', (82, 98))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (82, 98))	('MEN1', 'Gene', (64, 68))	('patients', 'Species', '9606', (28, 36))
68840	25494863	Both pheochromocytomas showed LOH in the MEN1 gene, supporting, although not proving, the pathogenic role of MEN1 in these tumors (see Figure 4, A and B).	('LOH', 'Var', (30, 33))	('MEN1', 'Gene', '4221', (41, 45))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (5, 21))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (5, 22))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('MEN1', 'Gene', (109, 113))	('MEN1', 'Gene', '4221', (109, 113))	('pheochromocytomas', 'Disease', (5, 22))	('pheochromocytomas', 'Disease', 'MESH:D010673', (5, 22))	('MEN1', 'Gene', (41, 45))
68845	25494863	The PAs of patients with SDHX mutations (patients 1 and 2 from family 1, patient 4, and patient 5) were characterized by intracytoplasmic vacuoles.	('patient', 'Species', '9606', (88, 95))	('patient', 'Species', '9606', (41, 48))	('PAs', 'Disease', (4, 7))	('patient', 'Species', '9606', (11, 18))	('SDHX', 'Chemical', '-', (25, 29))	('PAs', 'Disease', 'MESH:D011471', (4, 7))	('mutations', 'Var', (30, 39))	('patient', 'Species', '9606', (73, 80))	('patients', 'Species', '9606', (41, 49))	('SDHX', 'Gene', (25, 29))	('patients', 'Species', '9606', (11, 19))
68850	25494863	Vacuoles were not seen in the PA of the patient with the germline VHL mutation (without SDH mutation) (Supplemental Figure 2).	('SDH', 'Gene', (88, 91))	('patient', 'Species', '9606', (40, 47))	('SDH', 'Gene', '6390', (88, 91))	('VHL', 'Gene', (66, 69))	('mutation', 'Var', (70, 78))	('VHL', 'Gene', '7428', (66, 69))
68851	25494863	The SDHB staining of PAs with the SDHB mutation showed either a loss of expression of SDHB or a faint expression (Figures 2D and 3E).	('SDHB', 'Gene', (86, 90))	('mutation', 'Var', (39, 47))	('expression', 'MPA', (102, 112))	('PAs', 'Disease', (21, 24))	('expression', 'MPA', (72, 82))	('loss', 'NegReg', (64, 68))	('PAs', 'Disease', 'MESH:D011471', (21, 24))	('SDHB', 'Gene', '6390', (34, 38))	('SDHB', 'Gene', '6390', (4, 8))	('SDHB', 'Gene', (34, 38))	('SDHB', 'Gene', (4, 8))	('SDHB', 'Gene', '6390', (86, 90))
68852	25494863	Because SDHX mutations are known to alter mitochondrial function, immunostaining was performed for a mitochondrial membrane protein with the anti-113-1 antibody.	('alter', 'Reg', (36, 41))	('SDHX', 'Gene', (8, 12))	('SDHX', 'Chemical', '-', (8, 12))	('mitochondrial function', 'MPA', (42, 64))	('mutations', 'Var', (13, 22))
68856	25494863	Menin staining of the pheochromocytoma samples of the patients with MEN1 mutations showed either no menin-positive cells or weakly positive staining nuclei (Figure 4).	('menin', 'Gene', (100, 105))	('Menin', 'Gene', (0, 5))	('pheochromocytoma', 'Disease', (22, 38))	('patients', 'Species', '9606', (54, 62))	('menin', 'Gene', '4221', (100, 105))	('pheochromocytoma', 'Disease', 'MESH:D010673', (22, 38))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('MEN1', 'Gene', (68, 72))	('Menin', 'Gene', '4221', (0, 5))	('MEN1', 'Gene', '4221', (68, 72))	('mutations', 'Var', (73, 82))
68859	25494863	Systematic testing of this population for alterations of the known pituitary and pheo/PGL-related genes suggest that SDH mutations play a pathogenic role in the development of PAs in some of these patients.	('PAs', 'Disease', 'MESH:D011471', (176, 179))	('SDH', 'Gene', '6390', (117, 120))	('mutations', 'Var', (121, 130))	('patients', 'Species', '9606', (197, 205))	('SDH', 'Gene', (117, 120))	('pathogenic role', 'Reg', (138, 153))	('pheo', 'Chemical', '-', (81, 85))	('PAs', 'Disease', (176, 179))
68861	25494863	On the other hand, the MEN1 mutations can sometimes lead to pheo/PGLs, as suggested previously, and here we present supporting LOH and immunostaining findings.	('MEN1', 'Gene', '4221', (23, 27))	('pheo', 'Chemical', '-', (60, 64))	('MEN1', 'Gene', (23, 27))	('pheo/PGLs', 'Disease', (60, 69))	('lead to', 'Reg', (52, 59))	('mutations', 'Var', (28, 37))
68870	25494863	Of the six suggested explanations for the coexistence of PA and pheo/PGL that we outlined in the introductory text, we could confirm the following options: 1) a pheo/PGL-related gene causes PA, 2) a pituitary gene causes pheo/PGL, 5) ectopic hypothalamic hormone synthesis in a pheochromocytoma, and probably one or more families in our cohort match option, and 6) representing pure coincidence.	('pheo', 'Chemical', '-', (278, 282))	('pheo', 'Chemical', '-', (221, 225))	('pheochromocytoma', 'Disease', 'MESH:D010673', (278, 294))	('gene', 'Var', (178, 182))	('pheo', 'Chemical', '-', (64, 68))	('ectopic', 'Var', (234, 241))	('pheo', 'Chemical', '-', (161, 165))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (278, 294))	('pheochromocytoma', 'Disease', (278, 294))	('causes', 'Reg', (183, 189))	('causes', 'Reg', (214, 220))
68873	25494863	In our cohort 19 patients (48%) had a germline alteration, among them 17 (43%) with a genetic variant in the pheo/PGL genes.	('pheo', 'Chemical', '-', (109, 113))	('pheo/PGL', 'Gene', (109, 117))	('patients', 'Species', '9606', (17, 25))	('genetic variant', 'Var', (86, 101))
68876	25494863	One of them screened a group of patients (26 PGL patients and eight carriers) with a particular SDHD mutation due to a founder effect for the presence of a PA. One GH-secreting macroadenoma and three nonfunctioning microadenomas (suggested to be incidentalomas) were diagnosed in this patient cohort.	('microadenomas', 'Disease', (215, 228))	('patients', 'Species', '9606', (32, 40))	('patient', 'Species', '9606', (32, 39))	('GH-secreting macroadenoma', 'Disease', 'MESH:D049912', (164, 189))	('patient', 'Species', '9606', (49, 56))	('patient', 'Species', '9606', (285, 292))	('incidentalomas', 'Disease', (246, 260))	('microadenomas', 'Disease', 'None', (215, 228))	('SDHD', 'Gene', '6392', (96, 100))	('patients', 'Species', '9606', (49, 57))	('incidentalomas', 'Disease', 'MESH:C538238', (246, 260))	('mutation', 'Var', (101, 109))	('SDHD', 'Gene', (96, 100))	('GH-secreting macroadenoma', 'Disease', (164, 189))
68878	25494863	In the second study, 309 PAs were screened for SDH mutations and a macroprolactinoma with two different somatic SDHA mutations with normal sequence in the germline was found.	('macroprolactinoma', 'Phenotype', 'HP:0012342', (67, 84))	('prolactinoma', 'Phenotype', 'HP:0040278', (72, 84))	('SDH', 'Gene', (112, 115))	('mutations', 'Var', (51, 60))	('macroprolactinoma', 'Disease', 'MESH:D015175', (67, 84))	('SDH', 'Gene', (47, 50))	('PAs', 'Disease', (25, 28))	('macroprolactinoma', 'Disease', (67, 84))	('SDHA', 'Gene', '6389', (112, 116))	('PAs', 'Disease', 'MESH:D011471', (25, 28))	('SDH', 'Gene', '6390', (47, 50))	('SDH', 'Gene', '6390', (112, 115))	('SDHA', 'Gene', (112, 116))
68880	25494863	Two patients with SDHD mutations were found to have a PA, and in one of these cases, LOH at the SDHD locus was shown in the macroprolactinoma.	('prolactinoma', 'Phenotype', 'HP:0040278', (129, 141))	('SDHD', 'Gene', '6392', (18, 22))	('mutations', 'Var', (23, 32))	('macroprolactinoma', 'Phenotype', 'HP:0012342', (124, 141))	('SDHD', 'Gene', '6392', (96, 100))	('patients', 'Species', '9606', (4, 12))	('macroprolactinoma', 'Disease', 'MESH:D015175', (124, 141))	('SDHD', 'Gene', (18, 22))	('SDHD', 'Gene', (96, 100))	('macroprolactinoma', 'Disease', (124, 141))
68882	25494863	Summarizing our cases combined with the cases available in the literature (altogether 109 cases since 1952), we have tried to identify any particular features for each gene alteration for the tumor not classically associated with that gene.	('alteration', 'Var', (173, 183))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
68883	25494863	Twenty cases have a confirmed SDHX mutation with pituitary adenoma [(two SDHA, eight SDHB, two SDHC, and eight SDHD ].	('pituitary adenoma', 'Disease', 'MESH:D010911', (49, 66))	('SDHC', 'Gene', (95, 99))	('SDHA', 'Gene', (73, 77))	('SDHC', 'Gene', '6391', (95, 99))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (49, 66))	('SDHX', 'Chemical', '-', (30, 34))	('SDHA', 'Gene', '6389', (73, 77))	('SDHB', 'Gene', '6390', (85, 89))	('SDHB', 'Gene', (85, 89))	('SDHD', 'Gene', '6392', (111, 115))	('mutation', 'Var', (35, 43))	('SDHX', 'Gene', (30, 34))	('SDHD', 'Gene', (111, 115))	('pituitary adenoma', 'Disease', (49, 66))
68884	25494863	The patients with an SDH mutation had various PA types (Supplemental Tables 3 and 6): nine macroprolactinomas, three somatotroph adenomas, and five NFPAs have been described.	('PAs', 'Disease', (150, 153))	('PAs', 'Disease', 'MESH:D011471', (150, 153))	('macroprolactinoma', 'Phenotype', 'HP:0012342', (91, 108))	('adenomas', 'Disease', 'MESH:D000236', (129, 137))	('mutation', 'Var', (25, 33))	('macroprolactinoma', 'Disease', 'MESH:D015175', (91, 108))	('SDH', 'Gene', (21, 24))	('adenomas', 'Disease', (129, 137))	('macroprolactinoma', 'Disease', (91, 108))	('patients', 'Species', '9606', (4, 12))	('prolactinoma', 'Phenotype', 'HP:0040278', (96, 108))	('SDH', 'Gene', '6390', (21, 24))
68890	25494863	Two patients had a VHL mutation, one with a PRL and one with a GH- and PRL-secreting adenoma.	('mutation', 'Var', (23, 31))	('PRL', 'Gene', '5617', (71, 74))	('adenoma', 'Disease', (85, 92))	('VHL', 'Gene', (19, 22))	('PRL', 'Gene', '5617', (44, 47))	('VHL', 'Gene', '7428', (19, 22))	('patients', 'Species', '9606', (4, 12))	('PRL', 'Gene', (71, 74))	('PRL', 'Gene', (44, 47))	('adenoma', 'Disease', 'MESH:D000236', (85, 92))
68891	25494863	Six patients had a confirmed MEN1 mutation and pheo/PGL: five patients with pheochromocytoma and one head and neck PGL.	('pheo', 'Chemical', '-', (76, 80))	('pheochromocytoma', 'Disease', (76, 92))	('pheochromocytoma', 'Disease', 'MESH:D010673', (76, 92))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (76, 92))	('mutation', 'Var', (34, 42))	('pheo', 'Chemical', '-', (47, 51))	('MEN1', 'Gene', '4221', (29, 33))	('MEN1', 'Gene', (29, 33))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (62, 70))
68892	25494863	We have identified a novel feature of the PAs of patients harboring SDHX variants.	('variants', 'Var', (73, 81))	('SDHX', 'Gene', (68, 72))	('SDHX', 'Chemical', '-', (68, 72))	('PAs', 'Disease', (42, 45))	('patients', 'Species', '9606', (49, 57))	('PAs', 'Disease', 'MESH:D011471', (42, 45))
68899	25494863	Oncocytic PAs have recently been identified to contain somatic mutations affecting mitochondrial respiratory chain complex I, but these tumors do not show the vacuolar changes we have identified in the SDH-related samples.	('mutations', 'Var', (63, 72))	('tumors', 'Disease', (136, 142))	('mitochondrial respiratory chain complex I', 'Enzyme', (83, 124))	('SDH', 'Gene', '6390', (202, 205))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('vacuolar changes', 'Phenotype', 'HP:0001922', (159, 175))	('Oncocytic PAs', 'Disease', 'MESH:C535584', (0, 13))	('SDH', 'Gene', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Oncocytic PAs', 'Disease', (0, 13))
68900	25494863	Inactivation of succinate dehydrogenase or VHL can lead to activation of the hypoxia inducible factor pathway and a pseudohypoxic state.	('hypoxia', 'Disease', (77, 84))	('VHL', 'Gene', (43, 46))	('VHL', 'Gene', '7428', (43, 46))	('succinate dehydrogenase', 'Gene', '6390', (16, 39))	('succinate dehydrogenase', 'Gene', (16, 39))	('activation', 'PosReg', (59, 69))	('Inactivation', 'Var', (0, 12))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
68902	25494863	It is not known whether the vacuoles seen in the SDH-related tumors are due to the pseudohypoxic state, but we did not observe this phenomenon in the VHL mutation-related PA (Supplemental Figure 2).	('SDH', 'Gene', '6390', (49, 52))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('VHL', 'Gene', (150, 153))	('SDH', 'Gene', (49, 52))	('VHL', 'Gene', '7428', (150, 153))	('mutation-related', 'Var', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
68904	25494863	These vacuoles were not specifically described in the studies of recently published SDHX mutations associated with PAs, but based on the available histological pictures, the presence of vacuoles cannot be ruled out.	('PAs', 'Disease', 'MESH:D011471', (115, 118))	('SDHX', 'Chemical', '-', (84, 88))	('SDHX', 'Gene', (84, 88))	('mutations', 'Var', (89, 98))	('PAs', 'Disease', (115, 118))	('associated', 'Reg', (99, 109))
68905	25494863	Vacuoles have been described in SDHB mutation-related renal carcinoma and were attributed to giant mitochondria, but the clear cytoplasm observed in these tumors can also represent glycogen or fat.	('SDHB', 'Gene', '6390', (32, 36))	('glycogen', 'Chemical', 'MESH:D006003', (181, 189))	('renal carcinoma', 'Disease', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutation-related', 'Var', (37, 53))	('SDHB', 'Gene', (32, 36))	('renal carcinoma', 'Phenotype', 'HP:0005584', (54, 69))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('tumors', 'Disease', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('renal carcinoma', 'Disease', 'MESH:C538614', (54, 69))
68909	25494863	Taking into account that succinate dehydrogenase enzymes, being part of the mitochondrial complex II, play an important role in mitochondrial function, mutations that affect the activity of these enzymes might have a role in mitochondria dysfunction.	('mutations', 'Var', (152, 161))	('succinate dehydrogenase', 'Gene', '6390', (25, 48))	('succinate dehydrogenase', 'Gene', (25, 48))	('mitochondria dysfunction', 'Disease', 'MESH:C564925', (225, 249))	('mitochondria dysfunction', 'Disease', (225, 249))	('activity', 'MPA', (178, 186))
68910	25494863	We believe that the vacuoles represent a hallmark of PA in patients with the SDHX variant, but their nature remains to be further investigated.	('variant', 'Var', (82, 89))	('SDHX', 'Chemical', '-', (77, 81))	('patients', 'Species', '9606', (59, 67))	('SDHX', 'Gene', (77, 81))
68916	25494863	In addition, we noted intracytoplasmic vacuoles in PAs of patients affected by SDH mutations.	('SDH', 'Gene', '6390', (79, 82))	('mutations', 'Var', (83, 92))	('affected', 'Reg', (67, 75))	('PAs', 'Disease', (51, 54))	('noted', 'Reg', (16, 21))	('SDH', 'Gene', (79, 82))	('PAs', 'Disease', 'MESH:D011471', (51, 54))	('patients', 'Species', '9606', (58, 66))
68917	25494863	Together with the single case reports available in the literature, this large cohort supports the hypothesis that in some families SDH mutations may have a role in PA formation and MEN1 mutations may have a role in the development of pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (234, 250))	('MEN1', 'Gene', '4221', (181, 185))	('role', 'Reg', (207, 211))	('mutations', 'Var', (186, 195))	('role', 'Reg', (156, 160))	('mutations', 'Var', (135, 144))	('SDH', 'Gene', '6390', (131, 134))	('PA formation', 'Disease', (164, 176))	('pheochromocytoma', 'Disease', (234, 250))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (234, 250))	('SDH', 'Gene', (131, 134))	('MEN1', 'Gene', (181, 185))
68949	25028617	Extra-adrenal paraganglioma rate of malignancy is more than intra-adrenal paragangliomas, especially if related to succinate dehydrogenase B mutations (SDHB).	('paragangliomas', 'Phenotype', 'HP:0002668', (74, 88))	('mutations', 'Var', (141, 150))	('SDHB', 'Gene', (152, 156))	('paraganglioma', 'Phenotype', 'HP:0002668', (14, 27))	('intra-adrenal paragangliomas', 'Disease', (60, 88))	('Extra-adrenal paraganglioma', 'Disease', 'MESH:D010236', (0, 27))	('malignancy', 'Disease', 'MESH:D009369', (36, 46))	('intra-adrenal paragangliomas', 'Disease', 'MESH:D010236', (60, 88))	('Extra-adrenal paraganglioma', 'Disease', (0, 27))	('related', 'Reg', (104, 111))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))	('malignancy', 'Disease', (36, 46))	('SDHB', 'Gene', '6390', (152, 156))
68950	25028617	One study showed that 55% of paragangliomas are malignant, and 83.3% of them had genetic mutation.	('paragangliomas', 'Disease', 'MESH:D010235', (29, 43))	('genetic mutation', 'Var', (81, 97))	('paragangliomas', 'Disease', (29, 43))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('paragangliomas', 'Phenotype', 'HP:0002668', (29, 43))
68992	24946328	A 24h-urine test was performed and it revealed elevated norepinephrine (3011 nmol/d [N: <600nmol/d), creatinine (107 ummol/L [N: 44-106]), and a norepinephrine/creatinine ratio (292.3 umol/mmol [N <70 umol/mmol]), thus confirming biochemical catecholamine activity, suggesting a presumptive diagnosis of a biochemically active glomus vagale.	('glomus vagale', 'Phenotype', 'HP:0002886', (327, 340))	('292.3', 'Var', (178, 183))	('norepinephrine', 'MPA', (56, 70))	('elevated', 'PosReg', (47, 55))	('creatinine', 'MPA', (101, 111))	('catecholamine', 'Chemical', 'MESH:D002395', (242, 255))	('norepinephrine/creatinine ratio', 'MPA', (145, 176))	('norepinephrine', 'Chemical', 'MESH:D009638', (56, 70))	('elevated norepinephrine', 'Phenotype', 'HP:0003345', (47, 70))	('norepinephrine', 'Chemical', 'MESH:D009638', (145, 159))	('creatinine', 'Chemical', 'MESH:D003404', (101, 111))	('creatinine', 'Chemical', 'MESH:D003404', (160, 170))	('24h', 'Chemical', '-', (2, 5))
69026	21615192	In addition to differences in catecholamine enzyme expression, the presence of either constitutive or regulated secretory pathways contributes further to the very unique mutation-dependent catecholamine production and release, resulting in various clinical presentations.	('catecholamine', 'Chemical', 'MESH:D002395', (30, 43))	('mutation-dependent', 'Var', (170, 188))	('catecholamine', 'Chemical', 'MESH:D002395', (189, 202))	('release', 'MPA', (218, 225))	('resulting in', 'Reg', (227, 239))	('catecholamine production', 'MPA', (189, 213))
69028	21615192	Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development.	('oxidative stress', 'MPA', (110, 126))	('mitochondrial impairment', 'Var', (69, 93))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('impairment', 'Var', (83, 93))	('leads to', 'Reg', (94, 102))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('tumor', 'Disease', (156, 161))	('mitochondrial impairment', 'Phenotype', 'HP:0003287', (69, 93))
69029	21615192	In terms of cancer pathogenesis, pheochromocytomas and paragangliomas represent tumors where the oxidative phosphorylation defect due to the mutation of succinate dehydrogenase is the cause, not a consequence, of tumor development.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('succinate dehydrogenase', 'Gene', (153, 176))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (33, 50))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('paraganglioma', 'Phenotype', 'HP:0002668', (55, 68))	('paragangliomas', 'Phenotype', 'HP:0002668', (55, 69))	('tumor', 'Disease', (80, 85))	('succinate dehydrogenase', 'Gene', '6390', (153, 176))	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (33, 69))	('cancer', 'Disease', (12, 18))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (33, 49))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('oxidative phosphorylation defect', 'MPA', (97, 129))	('mutation', 'Var', (141, 149))
69030	21615192	Any succinate dehydrogenase pathogenic mutation results in the shift from oxidative phosphorylation to aerobic glycolysis in the cytoplasm (also called anaerobic glycolysis if hypoxia is the main cause of such a shift).	('mutation', 'Var', (39, 47))	('hypoxia', 'Disease', 'MESH:D000860', (176, 183))	('succinate dehydrogenase', 'Gene', (4, 27))	('succinate dehydrogenase', 'Gene', '6390', (4, 27))	('oxidative phosphorylation', 'MPA', (74, 99))	('shift', 'Reg', (63, 68))	('results in', 'Reg', (48, 58))	('aerobic glycolysis', 'MPA', (103, 121))	('pathogenic', 'Reg', (28, 38))	('hypoxia', 'Disease', (176, 183))
69033	21615192	Soon oxidative stress will be tightly linked to a multistep cancer process in which the mutation of various genes (perhaps in a logistic way) ultimately results in uncontrolled growth, proliferation, and metastatic potential of practically any cell.	('oxidative stress', 'Phenotype', 'HP:0025464', (5, 21))	('mutation', 'Var', (88, 96))	('results in', 'Reg', (153, 163))	('proliferation', 'CPA', (185, 198))	('linked', 'Reg', (38, 44))	('uncontrolled', 'MPA', (164, 176))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('metastatic potential', 'CPA', (204, 224))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
69052	21615192	In 1957 Axelrod and co-workers described O-methylation as the important pathways in catecholamine metabolism and LaBrosse and co-workers for the first time demonstrated elevated urine excretion of normetanephrine (O-methylated metabolite of NE) in patients with pheochromocytoma.	('pheochromocytoma', 'Disease', 'MESH:D010673', (262, 278))	('elevated urine excretion of normetanephrine', 'Phenotype', 'HP:0003345', (169, 212))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (262, 278))	('normetanephrine', 'Chemical', 'MESH:D009647', (197, 212))	('elevate', 'Disease', 'MESH:D006973', (169, 176))	('catecholamine metabolism', 'MPA', (84, 108))	('urine excretion of normetanephrine', 'MPA', (178, 212))	('catecholamine', 'Chemical', 'MESH:D002395', (84, 97))	('elevate', 'Disease', (169, 176))	('patients', 'Species', '9606', (248, 256))	('O-methylation', 'Var', (41, 54))	('pheochromocytoma', 'Disease', (262, 278))
69099	21615192	Catecholamines also tend to decrease intestinal motility and tone and to inhibit intestinal secretion.	('Catecholamines', 'Chemical', 'MESH:D002395', (0, 14))	('tone', 'CPA', (61, 65))	('intestinal motility', 'CPA', (37, 56))	('decrease', 'NegReg', (28, 36))	('intestinal secretion', 'MPA', (81, 101))	('Catecholamines', 'Var', (0, 14))	('inhibit', 'NegReg', (73, 80))
69117	21615192	Among different pheochromocytomas, activities of tyrosine hydroxylase are high in tumors from patients with MEN2 and low in those from von Hippel-Lindau (VHL) patients or patients with non-functional tumors.	('tumors', 'Disease', (82, 88))	('high', 'PosReg', (74, 78))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('pheochromocytomas', 'Disease', (16, 33))	('pheochromocytomas', 'Disease', 'MESH:D010673', (16, 33))	('von Hippel-Lindau', 'Gene', '7428', (135, 152))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('patients', 'Species', '9606', (94, 102))	('activities', 'MPA', (35, 45))	('VHL', 'Gene', (154, 157))	('patients', 'Species', '9606', (171, 179))	('MEN2', 'Var', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('VHL', 'Gene', '7428', (154, 157))	('low', 'NegReg', (117, 120))	('patients', 'Species', '9606', (159, 167))	('tyrosine hydroxylase', 'Gene', '7054', (49, 69))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (16, 32))	('tyrosine hydroxylase', 'Gene', (49, 69))	('tumors', 'Disease', (200, 206))	('von Hippel-Lindau', 'Gene', (135, 152))
69122	21615192	Translating these findings into clinical practice, patients with MEN2 pheochromocytoma present more often with paroxysmal hypertension, tachyarrhythmia, sweating, or other catecholamine-related symptoms or signs than patients with VHL tumors.	('sweating', 'Phenotype', 'HP:0000975', (153, 161))	('pheochromocytoma', 'Disease', 'MESH:D010673', (70, 86))	('tachyarrhythmia', 'Disease', 'MESH:D013610', (136, 151))	('pheochromocytoma', 'Disease', (70, 86))	('catecholamine', 'Chemical', 'MESH:D002395', (172, 185))	('paroxysmal hypertension', 'Disease', 'MESH:D006973', (111, 134))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('patients', 'Species', '9606', (51, 59))	('paroxysmal hypertension', 'Phenotype', 'HP:0000875', (111, 134))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('paroxysmal hypertension', 'Disease', (111, 134))	('tachyarrhythmia', 'Disease', (136, 151))	('sweating', 'Disease', (153, 161))	('hypertension', 'Phenotype', 'HP:0000822', (122, 134))	('VHL tumors', 'Disease', (231, 241))	('patients', 'Species', '9606', (217, 225))	('VHL tumors', 'Disease', 'MESH:D006623', (231, 241))	('MEN2', 'Var', (65, 69))
69125	21615192	One hundred seventy three patients with pheochromocytoma, including 38 with MEN2, 10 with NF1, 66 with VHL syndrome and 59 with mutations of genes for SDH type B or D were included.	('VHL syndrome', 'Disease', (103, 115))	('SDH', 'Gene', '6390', (151, 154))	('NF1', 'Gene', '4763', (90, 93))	('pheochromocytoma', 'Disease', (40, 56))	('mutations', 'Var', (128, 137))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (40, 56))	('VHL syndrome', 'Disease', 'MESH:D006623', (103, 115))	('SDH', 'Gene', (151, 154))	('patients', 'Species', '9606', (26, 34))	('pheochromocytoma', 'Disease', 'MESH:D010673', (40, 56))	('NF1', 'Gene', (90, 93))
69127	21615192	VHL patients usually showed solitary increases in normetanephrine, whereas additional or solitary increases in methoxytyramine characterized 70% of patients with SDH mutations.	('patients', 'Species', '9606', (148, 156))	('normetanephrine', 'MPA', (50, 65))	('mutations', 'Var', (166, 175))	('normetanephrine', 'Chemical', 'MESH:D009647', (50, 65))	('SDH', 'Gene', '6390', (162, 165))	('methoxytyramine', 'MPA', (111, 126))	('VHL', 'Gene', (0, 3))	('increases', 'PosReg', (37, 46))	('methoxytyramine', 'Chemical', 'MESH:C001746', (111, 126))	('patients', 'Species', '9606', (4, 12))	('SDH', 'Gene', (162, 165))	('VHL', 'Gene', '7428', (0, 3))
69128	21615192	Patients with NF1 and MEN2 could be discriminated from those with VHL and SDH mutations in 99% of cases by the combination of normetanephrine and metanephrine (Table 2).	('SDH', 'Gene', (74, 77))	('NF1', 'Gene', '4763', (14, 17))	('mutations', 'Var', (78, 87))	('metanephrine', 'Chemical', 'MESH:D008676', (146, 158))	('normetanephrine', 'Chemical', 'MESH:D009647', (126, 141))	('Patients', 'Species', '9606', (0, 8))	('metanephrine', 'Chemical', 'MESH:D008676', (129, 141))	('SDH', 'Gene', '6390', (74, 77))	('VHL', 'Gene', (66, 69))	('VHL', 'Gene', '7428', (66, 69))	('NF1', 'Gene', (14, 17))
69129	21615192	Measurement of plasma methoxytyramine discriminated patients with SDH mutations from those with VHL mutations in a further 78% of cases.	('mutations', 'Var', (70, 79))	('SDH', 'Gene', '6390', (66, 69))	('SDH', 'Gene', (66, 69))	('VHL', 'Gene', (96, 99))	('discriminated', 'Reg', (38, 51))	('methoxytyramine', 'Chemical', 'MESH:C001746', (22, 37))	('VHL', 'Gene', '7428', (96, 99))	('patients', 'Species', '9606', (52, 60))
69137	21615192	However, elevations in plasma or urinary DOPA and DA are not sensitive or specific markers of benign or metastatic pheochromocytoma since they can also be found in patients with pheochromocytoma related to SDHB mutations.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (178, 194))	('pheochromocytoma', 'Disease', 'MESH:D010673', (115, 131))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (115, 131))	('mutations', 'Var', (211, 220))	('urinary DOPA', 'Phenotype', 'HP:0011979', (33, 45))	('pheochromocytoma', 'Disease', (178, 194))	('SDHB', 'Gene', '6390', (206, 210))	('DOPA', 'Chemical', 'MESH:D004295', (41, 45))	('DA', 'Chemical', 'MESH:D004298', (50, 52))	('urinary DOPA', 'MPA', (33, 45))	('patients', 'Species', '9606', (164, 172))	('pheochromocytoma', 'Disease', 'MESH:D010673', (178, 194))	('found', 'Reg', (155, 160))	('SDHB', 'Gene', (206, 210))	('pheochromocytoma', 'Disease', (115, 131))	('elevations', 'PosReg', (9, 19))
69207	21615192	Since the mitochondria serves as the main source of prooxidants, any mitochondrial impairment leads to severe oxidative stress, a major outcome of which is tumor development (Figure 6).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('impairment', 'Var', (83, 93))	('leads to', 'Reg', (94, 102))	('oxidative stress', 'Phenotype', 'HP:0025464', (110, 126))	('tumor', 'Disease', (156, 161))	('mitochondrial impairment', 'Phenotype', 'HP:0003287', (69, 93))
44587	21615192	Abnormal SDH function due to mutations of nuclear DNA encoding for one of its subunits results in two completely different phenotypes.	('Abnormal SDH function', 'Disease', 'MESH:D056486', (0, 21))	('Abnormal SDH function', 'Disease', (0, 21))	('mutations', 'Var', (29, 38))	('nuclear DNA', 'Gene', (42, 53))
69216	21615192	Defects in SDHA cause a metabolic neurodegenerative disorder called Leigh syndrome, whereas SDHB, SDHC and SDHD mutations predispose to familial pheochromocytoma via different mechanisms (Figure 7).	('SDHD', 'Gene', (107, 111))	('SDHC', 'Gene', '6391', (98, 102))	('SDHA', 'Gene', (11, 15))	('mutations', 'Var', (112, 121))	('predispose', 'Reg', (122, 132))	('cause', 'Reg', (16, 21))	('SDHA', 'Gene', '6389', (11, 15))	('SDHB', 'Gene', '6390', (92, 96))	('Leigh syndrome', 'Disease', 'MESH:D007888', (68, 82))	('familial pheochromocytoma', 'Disease', 'MESH:C531777', (136, 161))	('Leigh syndrome', 'Disease', (68, 82))	('SDHC', 'Gene', (98, 102))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (34, 60))	('Defects', 'Var', (0, 7))	('neurodegenerative disorder', 'Disease', (34, 60))	('SDHB', 'Gene', (92, 96))	('familial pheochromocytoma', 'Disease', (136, 161))	('SDHD', 'Gene', '6392', (107, 111))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (145, 161))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (34, 60))
69219	21615192	Thus, when the complex II is disrupted at SDHA, the succinate dehydrogenase activity is impaired, if entirely, a severe neurodegenerative changes in various organs occur.	('neurodegenerative changes', 'Phenotype', 'HP:0002180', (120, 145))	('disrupted', 'Var', (29, 38))	('SDHA', 'Gene', (42, 46))	('impaired', 'NegReg', (88, 96))	('activity', 'MPA', (76, 84))	('succinate dehydrogenase', 'Gene', '6390', (52, 75))	('succinate dehydrogenase', 'Gene', (52, 75))	('SDHA', 'Gene', '6389', (42, 46))
69220	21615192	If the complex II is disrupted at other subunits, electron transfer is impaired (it is unknown whether various mutations may cause a different electron transfer via SDHB/C/D subunits) including the abnormal removal of electrons from the flavin group of SDHA.	('mutations', 'Var', (111, 120))	('removal of electrons from the flavin group', 'MPA', (207, 249))	('electron transfer', 'MPA', (50, 67))	('impaired', 'NegReg', (71, 79))	('SDHB', 'Gene', '6390', (165, 169))	('SDHA', 'Gene', '6389', (253, 257))	('cause', 'Reg', (125, 130))	('flavin', 'Chemical', 'MESH:C024132', (237, 243))	('SDHB', 'Gene', (165, 169))	('SDHA', 'Gene', (253, 257))	('electron transfer', 'MPA', (143, 160))
69224	21615192	Any pathogenic mutation of SDH subunits results in the abolition of SDH enzymatic activity and activation of the angiogenic, hypoxic, and apoptotic pathways by various mechanisms, including increased transcription of vascular endothelial growth factor, glycolytic enzymes, and histone demethylation (Figure 7).	('mutation', 'Var', (15, 23))	('SDH', 'Gene', (68, 71))	('SDH', 'Gene', '6390', (27, 30))	('angiogenic', 'Pathway', (113, 123))	('vascular endothelial growth factor', 'Gene', (217, 251))	('increased', 'PosReg', (190, 199))	('glycolytic enzymes', 'Enzyme', (253, 271))	('activation', 'PosReg', (95, 105))	('SDH', 'Gene', (27, 30))	('vascular endothelial growth factor', 'Gene', '7422', (217, 251))	('transcription', 'MPA', (200, 213))	('apoptotic pathways', 'Pathway', (138, 156))	('SDH', 'Gene', '6390', (68, 71))	('histone demethylation', 'MPA', (277, 298))	('hypoxic', 'Pathway', (125, 132))	('abolition', 'NegReg', (55, 64))
69225	21615192	Disruptions in SDH activity also results in the accumulation of succinate, causing chronic oxidative stress, as first reported by Ishii et al.	('oxidative stress', 'Phenotype', 'HP:0025464', (91, 107))	('Disruptions', 'Var', (0, 11))	('results in', 'Reg', (33, 43))	('succinate', 'MPA', (64, 73))	('SDH', 'Gene', '6390', (15, 18))	('activity', 'MPA', (19, 27))	('accumulation', 'MPA', (48, 60))	('succinate', 'Chemical', 'MESH:D019802', (64, 73))	('SDH', 'Gene', (15, 18))
69231	21615192	In patients with the VHL gene mutation, VHL protein cannot be degraded (there is incorrect binding of VHL protein-elongin-cullin complex) and HIF-1alpha accumulates.	('accumulates', 'PosReg', (153, 164))	('VHL', 'Gene', (40, 43))	('mutation', 'Var', (30, 38))	('VHL', 'Gene', '7428', (21, 24))	('HIF-1alpha', 'Gene', (142, 152))	('VHL', 'Gene', '7428', (40, 43))	('VHL', 'Gene', (102, 105))	('patients', 'Species', '9606', (3, 11))	('VHL', 'Gene', (21, 24))	('binding', 'Interaction', (91, 98))	('VHL', 'Gene', '7428', (102, 105))	('HIF-1alpha', 'Gene', '3091', (142, 152))
69232	21615192	Overaccumulation of HIF-1alpha results in the overexpression of various genes (e.g.	('Overaccumulation', 'Var', (0, 16))	('HIF-1alpha', 'Gene', (20, 30))	('HIF-1alpha', 'Gene', '3091', (20, 30))	('overexpression', 'MPA', (46, 60))
69241	21615192	also demonstrated the presence of giant mitochondria in renal cell carcinoma related to SDHB gene mutation.	('renal cell carcinoma', 'Disease', (56, 76))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (56, 76))	('mutation', 'Var', (98, 106))	('related', 'Reg', (77, 84))	('SDHB', 'Gene', '6390', (88, 92))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (56, 76))	('SDHB', 'Gene', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('presence', 'Reg', (22, 30))
69249	21615192	The mean age at diagnosis of paraganglioma in SDHB mutation carriers in previous series was approximately 30 years.	('paraganglioma', 'Disease', (29, 42))	('SDHB', 'Gene', '6390', (46, 50))	('SDHB', 'Gene', (46, 50))	('paraganglioma', 'Disease', 'MESH:D010235', (29, 42))	('mutation', 'Var', (51, 59))	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))
69251	21615192	In the International SDH Consortium population, age-related penetrance (the proportion of gene carriers manifesting the signs or symptoms of the disease by a given age) among SDHB mutation carriers is estimated to be around 45% by age 40.	('SDH', 'Gene', (175, 178))	('SDH', 'Gene', (21, 24))	('SDH', 'Gene', '6390', (175, 178))	('SDHB', 'Gene', '6390', (175, 179))	('SDHB', 'Gene', (175, 179))	('SDH', 'Gene', '6390', (21, 24))	('mutation', 'Var', (180, 188))	('carriers', 'Reg', (189, 197))
69253	21615192	In patients in whom a primary tumor originates in abdominal location with subsequent development of metastatic disease, there is a 40-50% chance that the disease is related to a SDHB gene mutation.	('mutation', 'Var', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('related', 'Reg', (165, 172))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SDHB', 'Gene', (178, 182))	('SDHB', 'Gene', '6390', (178, 182))	('tumor', 'Disease', (30, 35))
69257	21615192	Furthermore, there are excellent studies showing that SDHB mutations are associated with the presence of clear cell carcinoma and perhaps papillary thyroid carcinoma.	('papillary thyroid carcinoma', 'Disease', (138, 165))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (138, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (148, 165))	('SDHB', 'Gene', '6390', (54, 58))	('SDHB', 'Gene', (54, 58))	('associated', 'Reg', (73, 83))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (138, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('mutations', 'Var', (59, 68))	('clear cell carcinoma', 'Disease', (105, 125))
69259	21615192	In addition, clinical phenotypes may differ largely between family members with the same SDHB mutation.	('differ', 'Reg', (37, 43))	('SDHB', 'Gene', (89, 93))	('SDHB', 'Gene', '6390', (89, 93))	('mutation', 'Var', (94, 102))
69260	21615192	However, recent studies show that patients with metastatic disease who developed their primary tumor before age 20 have disease most commonly related to a SDHB mutation (Pacak et al., unpublished data).	('mutation', 'Var', (160, 168))	('SDHB', 'Gene', (155, 159))	('SDHB', 'Gene', '6390', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('metastatic disease', 'Disease', (48, 66))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('disease', 'Disease', (120, 127))	('related', 'Reg', (142, 149))	('tumor', 'Disease', (95, 100))
69261	21615192	SDHD mutations are mainly associated with head and neck paragangliomas, most often multiple, or multiple extra-adrenal pheochromocytomas.	('neck paragangliomas', 'Disease', 'MESH:D010235', (51, 70))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (51, 70))	('associated', 'Reg', (26, 36))	('paragangliomas', 'Phenotype', 'HP:0002668', (56, 70))	('mutations', 'Var', (5, 14))	('extra-adrenal pheochromocytomas', 'Disease', (105, 136))	('SDHD', 'Gene', '6392', (0, 4))	('adrenal pheochromocytoma', 'Phenotype', 'HP:0006748', (111, 135))	('extra-adrenal pheochromocytomas', 'Phenotype', 'HP:0006737', (105, 136))	('neck paragangliomas', 'Disease', (51, 70))	('adrenal pheochromocytomas', 'Phenotype', 'HP:0006748', (111, 136))	('paraganglioma', 'Phenotype', 'HP:0002668', (56, 69))	('SDHD', 'Gene', (0, 4))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (119, 136))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (119, 135))	('multiple', 'Disease', (83, 91))	('extra-adrenal pheochromocytomas', 'Disease', 'MESH:D010673', (105, 136))
69269	21615192	In contrast to SDHB gene mutation carriers where clear cell carcinoma of kidney is found in up to about 14% of patients, in SDHD carriers this number does not exceed 6%.	('SDHB', 'Gene', '6390', (15, 19))	('clear cell carcinoma of kidney', 'Disease', (49, 79))	('clear cell carcinoma of kidney', 'Disease', 'MESH:C538614', (49, 79))	('SDHD', 'Gene', '6392', (124, 128))	('mutation', 'Var', (25, 33))	('SDHB', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma of kidney', 'Phenotype', 'HP:0005584', (60, 79))	('found', 'Reg', (83, 88))	('SDHD', 'Gene', (124, 128))	('patients', 'Species', '9606', (111, 119))
69271	21615192	SDHC mutations are mainly associated with the development of head and neck paragangliomas.	('neck paragangliomas', 'Disease', 'MESH:D010235', (70, 89))	('paraganglioma', 'Phenotype', 'HP:0002668', (75, 88))	('SDHC', 'Gene', (0, 4))	('neck paragangliomas', 'Disease', (70, 89))	('mutations', 'Var', (5, 14))	('SDHC', 'Gene', '6391', (0, 4))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (70, 89))	('associated with', 'Reg', (26, 41))	('paragangliomas', 'Phenotype', 'HP:0002668', (75, 89))
69273	21615192	Within a population-based international registry of patients with head and neck paragangliomas, the prevalence of SDHC mutations was 4%, versus 7% and 17% for SDHB, and SDHD, respectively.	('neck paragangliomas', 'Disease', (75, 94))	('SDHB', 'Gene', '6390', (159, 163))	('SDHD', 'Gene', '6392', (169, 173))	('neck paragangliomas', 'Phenotype', 'HP:0002864', (75, 94))	('SDHB', 'Gene', (159, 163))	('SDHD', 'Gene', (169, 173))	('neck paragangliomas', 'Disease', 'MESH:D010235', (75, 94))	('SDHC', 'Gene', (114, 118))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('paragangliomas', 'Phenotype', 'HP:0002668', (80, 94))	('mutations', 'Var', (119, 128))	('SDHC', 'Gene', '6391', (114, 118))	('patients', 'Species', '9606', (52, 60))
69277	21615192	During the past two decades more evidence for an important role of ATP synthase dysregulation in cancer has been presented.	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ATP', 'Chemical', 'MESH:D000255', (67, 70))	('dysregulation', 'Var', (80, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
69290	21615192	Thus, due to the acidic microenvironment surrounding tumors, cell surface ATP synthase inhibition holds a new avenue to specifically kill tumor cells, either directly or by killing endothelial cells of the microvessels that nourish a tumor.	('ATP', 'Chemical', 'MESH:D000255', (74, 77))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('iron', 'Chemical', 'MESH:D007501', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('inhibition', 'Var', (87, 97))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
69298	21615192	This also applies to pheochromocytoma patients, especially those with SDHB mutations.	('SDHB', 'Gene', '6390', (70, 74))	('SDHB', 'Gene', (70, 74))	('pheochromocytoma', 'Disease', (21, 37))	('mutations', 'Var', (75, 84))	('patients', 'Species', '9606', (38, 46))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (21, 37))	('pheochromocytoma', 'Disease', 'MESH:D010673', (21, 37))
69299	21615192	first observed that in patients with SDHB mutation [18F]-fluorodeoxyglycose positron emission tomography is far superior to other functional imaging studies, even to the most specific radiopharmaceutical, [18F]-fluorodopamine.	('[18F]-fluorodopamine', 'Chemical', '-', (205, 225))	('SDHB', 'Gene', '6390', (37, 41))	('patients', 'Species', '9606', (23, 31))	('mutation', 'Var', (42, 50))	('SDHB', 'Gene', (37, 41))	('[18F]-fluorodeoxyglycose', 'Chemical', '-', (51, 75))
69318	21615192	This approach may be used clinically to augment the therapeutic efficacy of [131I]-MIBG in patients with advanced malignant pheochromocytoma and other related tumors such as neuroblastoma.	('patients', 'Species', '9606', (91, 99))	('neuroblastoma', 'Phenotype', 'HP:0003006', (174, 187))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('malignant pheochromocytoma', 'Disease', 'MESH:D010673', (114, 140))	('MIBG', 'Chemical', 'MESH:D019797', (83, 87))	('tumors', 'Disease', (159, 165))	('therapeutic', 'MPA', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('-MIBG', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (174, 187))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('[131I]-MIBG', 'Var', (76, 87))	('neuroblastoma', 'Disease', (174, 187))	('augment', 'PosReg', (40, 47))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (124, 140))	('malignant pheochromocytoma', 'Disease', (114, 140))
69320	21615192	In summary, various pheochromocytomas, especially those related to SDH gene mutations, can be viewed as an "oxidative stress disease" and could be successfully treated in the future by targeting oxidative phosphorylation, glycolysis, glucose sensing and its cell entry as well as microenvironment acidification and ATP handling.	('stress disease', 'Disease', (118, 132))	('mutations', 'Var', (76, 85))	('pheochromocytomas', 'Disease', 'MESH:D010673', (20, 37))	('glycolysis', 'MPA', (222, 232))	('ATP', 'Chemical', 'MESH:D000255', (315, 318))	('pheochromocytomas', 'Disease', (20, 37))	('SDH', 'Gene', '6390', (67, 70))	('targeting', 'Reg', (185, 194))	('stress disease', 'Disease', 'MESH:D000079225', (118, 132))	('oxidative stress', 'Phenotype', 'HP:0025464', (108, 124))	('iron', 'Chemical', 'MESH:D007501', (288, 292))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (20, 37))	('oxidative phosphorylation', 'MPA', (195, 220))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (20, 36))	('SDH', 'Gene', (67, 70))	('glucose', 'Chemical', 'MESH:D005947', (234, 241))
69393	22855666	An aggressive behavior may also be suggested by the presence of nuclear pleomorphism, mitotic activity and infiltrative margin.	('aggressive behavior', 'Disease', (3, 22))	('aggressive behavior', 'Disease', 'MESH:D001523', (3, 22))	('aggressive behavior', 'Phenotype', 'HP:0000718', (3, 22))	('mitotic activity', 'CPA', (86, 102))	('nuclear pleomorphism', 'Var', (64, 84))
69406	22429592	Mutations in three genes causing well characterized tumor syndromes are associated with an increased risk of developing pheochromocytomas and paragangliomas including VHL (von Hippel-Lindau disease), NF1 (Neurofibromatosis Type 1), and RET (Multiple Endocrine Neoplasia Type 2).	('NF1', 'Gene', (200, 203))	('tumor', 'Disease', (52, 57))	('von Hippel-Lindau disease', 'Disease', 'MESH:D006623', (172, 197))	('Neoplasia', 'Phenotype', 'HP:0002664', (260, 269))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('paraganglioma', 'Phenotype', 'HP:0002668', (142, 155))	('VHL', 'Gene', '7428', (167, 170))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('von Hippel-Lindau disease', 'Disease', (172, 197))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (250, 269))	('RET', 'Gene', '5979', (236, 239))	('Mutations', 'Var', (0, 9))	('Multiple Endocrine Neoplasia Type 2', 'Disease', 'MESH:D018813', (241, 276))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (120, 137))	('paragangliomas', 'Phenotype', 'HP:0002668', (142, 156))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (205, 222))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Neurofibromatosis Type 1', 'Gene', '4763', (205, 229))	('Neurofibromatosis Type 1', 'Gene', (205, 229))	('RET', 'Gene', (236, 239))	('Multiple Endocrine Neoplasia Type 2', 'Disease', (241, 276))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (120, 156))	('NF1', 'Gene', '4763', (200, 203))	('VHL', 'Gene', (167, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (120, 136))
69407	22429592	Mutations in any of the succinate dehydrogenase (SDH) complex subunit genes (SDHA, SDHB, SDHC, SDHD) can lead to pheochromocytomas and paragangliomas with variable penetrance, as can mutations in the subunit cofactor, SDHAF2.	('SDH', 'Gene', '6390', (49, 52))	('SDHA', 'Gene', '6389', (218, 222))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (113, 130))	('SDH', 'Gene', '6390', (95, 98))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('paraganglioma', 'Phenotype', 'HP:0002668', (135, 148))	('SDH', 'Gene', (83, 86))	('paragangliomas', 'Phenotype', 'HP:0002668', (135, 149))	('SDH', 'Gene', (89, 92))	('SDH', 'Gene', (218, 221))	('mutations', 'Var', (183, 192))	('SDHD', 'Gene', '6392', (95, 99))	('SDH', 'Gene', (49, 52))	('SDHC', 'Gene', '6391', (89, 93))	('SDH', 'Gene', '6390', (77, 80))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', '6390', (83, 87))	('SDH', 'Gene', (95, 98))	('succinate dehydrogenase', 'Gene', '6389', (24, 47))	('pheochromocytomas and paragangliomas', 'Disease', 'MESH:D010673', (113, 149))	('lead to', 'Reg', (105, 112))	('succinate dehydrogenase', 'Gene', (24, 47))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (113, 129))	('SDHD', 'Gene', (95, 99))	('SDHA', 'Gene', (77, 81))	('SDH', 'Gene', (77, 80))	('SDHB', 'Gene', (83, 87))	('SDHC', 'Gene', (89, 93))	('SDH', 'Gene', '6390', (83, 86))	('SDHA', 'Gene', '6389', (77, 81))	('SDH', 'Gene', '6390', (218, 221))	('SDHAF2', 'Gene', '54949', (218, 224))	('SDHAF2', 'Gene', (218, 224))	('SDH', 'Gene', '6390', (89, 92))	('SDHA', 'Gene', (218, 222))
69409	22429592	Although these tumors are rare in the general population, occurring in 2-8 per million people, they are more commonly associated with an inherited mutation than any other cancer type.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('people', 'Species', '9606', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('mutation', 'Var', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', (171, 177))	('associated', 'Reg', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', (15, 21))
69410	22429592	This review summarizes the known germline and somatic mutations leading to pheochromocytoma and paraganglioma development, as well as biochemical profiling for PCC/PGL and screening of mutation carriers.	('paraganglioma', 'Disease', 'MESH:D010235', (96, 109))	('mutations', 'Var', (54, 63))	('PCC/PGL', 'Gene', '1421', (160, 167))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('pheochromocytoma', 'Disease', (75, 91))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (75, 91))	('leading to', 'Reg', (64, 74))	('paraganglioma', 'Disease', (96, 109))	('pheochromocytoma', 'Disease', 'MESH:D010673', (75, 91))	('PCC/PGL', 'Gene', (160, 167))
69424	22429592	However, currently the only reliable predictor of malignancy is a germline mutation in Succinate dehydrogenase subunit B (SDHB), one of the known susceptibility genes (discussed further below).	('malignancy', 'Disease', (50, 60))	('Succinate dehydrogenase subunit B', 'Gene', '6390', (87, 120))	('SDHB', 'Gene', '6390', (122, 126))	('SDHB', 'Gene', (122, 126))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))	('Succinate dehydrogenase subunit B', 'Gene', (87, 120))	('germline mutation', 'Var', (66, 83))
69425	22429592	Population-based studies have found approximately one-third of patients with apparently sporadic PCC/PGL have a germline mutation in a known susceptibility gene.	('PCC/PGL', 'Gene', '1421', (97, 104))	('patients', 'Species', '9606', (63, 71))	('germline mutation', 'Var', (112, 129))	('PCC/PGL', 'Gene', (97, 104))
69428	22429592	Therefore, although PCC/PGLs are infrequent, they are more commonly associated with an inherited mutation than any other cancer type.	('associated', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PGLs', 'Gene', '25796', (24, 28))	('PCC/PGL', 'Gene', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('mutation', 'Var', (97, 105))	('cancer', 'Disease', (121, 127))	('PCC/PGL', 'Gene', '1421', (20, 27))	('PGLs', 'Gene', (24, 28))
69441	22429592	Under hypoxic conditions, or if there is a mutation in VHL, this interaction cannot take place, resulting in the loss of ubiquitation of HIFalpha, and thus allowing it to bind to the HIFbeta subunit and target transcription of hypoxia inducible genes.	('hypoxia', 'Disease', 'MESH:D000860', (227, 234))	('hypoxic conditions', 'Disease', (6, 24))	('HIFbeta', 'Protein', (183, 190))	('HIFalpha', 'Gene', (137, 145))	('mutation', 'Var', (43, 51))	('hypoxic conditions', 'Disease', 'MESH:D009135', (6, 24))	('transcription', 'MPA', (210, 223))	('loss', 'NegReg', (113, 117))	('target', 'Reg', (203, 209))	('VHL', 'Gene', (55, 58))	('bind', 'Interaction', (171, 175))	('ubiquitation', 'MPA', (121, 133))	('VHL', 'Gene', '7428', (55, 58))	('hypoxia', 'Disease', (227, 234))
69442	22429592	VHL is a tumor suppressor gene and most vHL-associated PCCs show loss of heterozygosity (LOH) of the wild type allele as the second hit according to Knudson's two hit hypothesis.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('loss', 'Var', (65, 69))	('PCC', 'Gene', '1421', (55, 58))	('vHL', 'Gene', '7428', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('vHL', 'Gene', (40, 43))	('PCC', 'Gene', (55, 58))	('VHL', 'Gene', (0, 3))	('tumor', 'Disease', (9, 14))	('VHL', 'Gene', '7428', (0, 3))
69444	22429592	Patients with Type 1 vHL disease have truncating mutations or exon deletions with a lower penetrance for PCC and a higher penetrance for RCC.	('exon deletions', 'Var', (62, 76))	('PCC', 'Gene', '1421', (105, 108))	('Patients', 'Species', '9606', (0, 8))	('RCC', 'Phenotype', 'HP:0005584', (137, 140))	('Type 1 vHL disease', 'Disease', (14, 32))	('RCC', 'Disease', 'MESH:C538614', (137, 140))	('truncating mutations', 'Var', (38, 58))	('RCC', 'Disease', (137, 140))	('PCC', 'Gene', (105, 108))	('Type 1 vHL disease', 'Disease', 'MESH:D005776', (14, 32))
69445	22429592	Patients with Type 2 vHL disease have missense mutations in the VHL gene, which are associated with development of RCC or PCC depending on the location of the missense mutation.	('associated with', 'Reg', (84, 99))	('RCC', 'Phenotype', 'HP:0005584', (115, 118))	('missense mutations', 'Var', (38, 56))	('RCC', 'Disease', 'MESH:C538614', (115, 118))	('PCC', 'Gene', (122, 125))	('RCC', 'Disease', (115, 118))	('VHL', 'Gene', (64, 67))	('Patients', 'Species', '9606', (0, 8))	('VHL', 'Gene', '7428', (64, 67))	('Type 2 vHL disease', 'Disease', (14, 32))	('Type 2 vHL disease', 'Disease', 'MESH:D005776', (14, 32))	('PCC', 'Gene', '1421', (122, 125))
69446	22429592	Specifically, mutations which disrupt the VHL-HIF protein interaction tend to lead to RCC development, whereas mutations in other parts of the VHL protein tend to lead to PCC development.	('RCC', 'Phenotype', 'HP:0005584', (86, 89))	('mutations', 'Var', (111, 120))	('mutations', 'Var', (14, 23))	('VHL', 'Gene', '7428', (143, 146))	('interaction', 'Interaction', (58, 69))	('PCC', 'Gene', (171, 174))	('lead to', 'Reg', (78, 85))	('VHL-HIF', 'Disease', (42, 49))	('RCC', 'Disease', 'MESH:C538614', (86, 89))	('VHL', 'Gene', (143, 146))	('VHL', 'Gene', (42, 45))	('lead to', 'Reg', (163, 170))	('VHL', 'Gene', '7428', (42, 45))	('RCC', 'Disease', (86, 89))	('PCC', 'Gene', '1421', (171, 174))	('VHL-HIF', 'Disease', 'MESH:D006623', (42, 49))
69448	22429592	Furthermore, missense mutations which affect the surface of the folded protein have a higher risk of PCC development than missense mutations which affect the deeper protein core.	('PCC', 'Gene', (101, 104))	('PCC', 'Gene', '1421', (101, 104))	('missense mutations', 'Var', (13, 31))
69449	22429592	Neurofibromatosis Type 1 (NF1), also called von Recklinghausen's disease, is an autosomal dominant genetic disorder caused by inactivating mutations in the tumor suppressor gene, NF1.	('autosomal dominant genetic disorder', 'Disease', 'MESH:D030342', (80, 115))	('autosomal dominant genetic disorder', 'Disease', (80, 115))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	("von Recklinghausen's disease", 'Disease', (44, 72))	('Neurofibromatosis Type 1', 'Gene', (0, 24))	('NF1', 'Gene', (26, 29))	('caused by', 'Reg', (116, 125))	("von Recklinghausen's disease", 'Disease', 'MESH:C537392', (44, 72))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NF1', 'Gene', '4763', (26, 29))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('tumor', 'Disease', (156, 161))	('NF1', 'Gene', (179, 182))	('Neurofibromatosis Type 1', 'Gene', '4763', (0, 24))	('NF1', 'Gene', '4763', (179, 182))	('inactivating mutations', 'Var', (126, 148))
69452	22429592	When NF1 is mutated, there is constitutive activation of Ras and hence, the downstream MAPK, PI3K and mTOR pathways, leading to uncontrolled cellular growth and differentiation.	('differentiation', 'CPA', (161, 176))	('MAPK', 'Pathway', (87, 91))	('NF1', 'Gene', (5, 8))	('activation', 'PosReg', (43, 53))	('mutated', 'Var', (12, 19))	('Ras', 'Pathway', (57, 60))	('uncontrolled', 'MPA', (128, 140))	('NF1', 'Gene', '4763', (5, 8))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('PI3K', 'Pathway', (93, 97))
69453	22429592	Up to 50% of NF1 patients have a de novo mutation, and there is variable penetrance and expressivity of the disease even in patients with the same mutation.	('NF1', 'Gene', (13, 16))	('mutation', 'Var', (41, 49))	('NF1', 'Gene', '4763', (13, 16))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (124, 132))
69461	22429592	When ligand binds to the RET receptor, or there is an activating mutation, a cell signaling cascade is triggered through the PI3 kinase pathway to regulate cell proliferation and apoptosis.	('activating', 'PosReg', (54, 64))	('RET', 'Gene', '5979', (25, 28))	('apoptosis', 'CPA', (179, 188))	('RET', 'Gene', (25, 28))	('PI3 kinase pathway', 'Pathway', (125, 143))	('regulate', 'Reg', (147, 155))	('binds', 'Interaction', (12, 17))	('mutation', 'Var', (65, 73))	('cell proliferation', 'CPA', (156, 174))
69466	22429592	Almost all cases of MEN 2B are caused by a single missense mutation in codon 918 in exon 16 of RET (p.Met918Thr).	('RET', 'Gene', (95, 98))	('p.Met918Thr', 'Var', (100, 111))	('MEN 2B', 'Gene', (20, 26))	('p.Met918Thr', 'Mutation', 'rs74799832', (100, 111))	('RET', 'Gene', '5979', (95, 98))	('MEN 2B', 'Gene', '5979', (20, 26))	('caused by', 'Reg', (31, 40))
69468	22429592	The diagnosis of FMTC is based on the absence of PCC and hyperparathyroidism in two or more generations within a family or by providing evidence of a RET mutation in a codon associated with susceptibility to only medullary thyroid cancer, including codons 768, 790, 804 and 891.	('hyperparathyroidism', 'Phenotype', 'HP:0000843', (57, 76))	('associated', 'Reg', (174, 184))	('PCC', 'Gene', '1421', (49, 52))	('RET', 'Gene', (150, 153))	('thyroid cancer', 'Disease', 'MESH:D013964', (223, 237))	('hyperparathyroidism', 'Disease', (57, 76))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (213, 237))	('mutation in', 'Var', (154, 165))	('PCC', 'Gene', (49, 52))	('RET', 'Gene', '5979', (150, 153))	('susceptibility', 'Reg', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('hyperparathyroidism', 'Disease', 'MESH:D006961', (57, 76))	('thyroid cancer', 'Phenotype', 'HP:0002890', (223, 237))	('thyroid cancer', 'Disease', (223, 237))
69470	22429592	The risk of PCC in MEN 2 is associated with specific RET mutations, with the highest risk associated with mutations codons 634, 883, 918, and double mutations in codons 804 plus 805 or 806.	('MEN', 'Species', '9606', (19, 22))	('RET', 'Gene', (53, 56))	('mutations codons 634', 'Var', (106, 126))	('PCC', 'Gene', '1421', (12, 15))	('double mutations', 'Var', (142, 158))	('RET', 'Gene', '5979', (53, 56))	('883', 'Var', (128, 131))	('918', 'Var', (133, 136))	('PCC', 'Gene', (12, 15))
69473	22429592	The age to begin screening with annual biochemistries is suggested based on risk of PCC by mutation as discussed above.	('PCC', 'Gene', (84, 87))	('mutation', 'Var', (91, 99))	('PCC', 'Gene', '1421', (84, 87))
69474	22429592	Screening begins as early as age 8 for all MEN 2B patients and for MEN 2A patients with mutations in codons 630 or 634, and screening begins at age 20 for all other MEN 2A associated mutations.	('MEN 2A', 'Gene', '5979', (67, 73))	('MEN 2A', 'Gene', (67, 73))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (74, 82))	('MEN 2B', 'Gene', '5979', (43, 49))	('MEN 2A', 'Gene', '5979', (165, 171))	('MEN 2A', 'Gene', (165, 171))	('mutations in codons 630', 'Var', (88, 111))	('MEN 2B', 'Gene', (43, 49))
69475	22429592	Mutations in any one of the Succinate dehydrogenase (SDH) complex subunits can lead to PCC/PGL formation.	('SDH', 'Gene', (53, 56))	('PCC/PGL', 'Gene', '1421', (87, 94))	('Succinate dehydrogenase', 'Gene', '6390', (28, 51))	('SDH', 'Gene', '6390', (53, 56))	('Mutations', 'Var', (0, 9))	('PCC/PGL', 'Gene', (87, 94))	('Succinate dehydrogenase', 'Gene', (28, 51))	('lead to', 'Reg', (79, 86))
69479	22429592	Mutations in SDHD lead to PGL1.	('SDHD', 'Gene', (13, 17))	('SDHD', 'Gene', '6392', (13, 17))	('Mutations', 'Var', (0, 9))	('lead', 'Reg', (18, 22))	('PGL1', 'Gene', (26, 30))
69482	22429592	Mutations in SDHD are inherited in an autosomal dominant fashion with a parent of origin effect.	('SDHD', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('SDHD', 'Gene', '6392', (13, 17))
69486	22429592	Complicating the issue further, there have been a few reported cases of a maternally transmitted SDHD mutant allele.	('mutant', 'Var', (102, 108))	('SDHD', 'Gene', (97, 101))	('SDHD', 'Gene', '6392', (97, 101))
69489	22429592	described a three generation kindred with PCC/PGL who share a maternally transmitted SDHD mutation found in both germline and tumor DNA analysis.	('SDHD', 'Gene', '6392', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PCC/PGL', 'Gene', (42, 49))	('SDHD', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutation', 'Var', (90, 98))	('PCC/PGL', 'Gene', '1421', (42, 49))	('tumor', 'Disease', (126, 131))
69491	22429592	The penetrance for PCC/PGL in SDHD mutation carriers reaches 90% or higher by age 70.	('PCC/PGL', 'Gene', (19, 26))	('penetrance', 'MPA', (4, 14))	('PCC/PGL', 'Gene', '1421', (19, 26))	('SDHD', 'Gene', '6392', (30, 34))	('SDHD', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
69493	22429592	SDHD mutation carriers can develop adrenal based PCC, but usually this is one of multiple PCC/PGL tumors throughout the body.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('PCC', 'Gene', '1421', (49, 52))	('develop', 'PosReg', (27, 34))	('PGL tumors', 'Disease', (94, 104))	('PCC', 'Gene', '1421', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PCC', 'Gene', (49, 52))	('SDHD', 'Gene', '6392', (0, 4))	('PCC/PGL', 'Gene', (90, 97))	('PCC', 'Gene', (90, 93))	('PGL tumors', 'Disease', 'MESH:D010235', (94, 104))	('SDHD', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('PCC/PGL', 'Gene', '1421', (90, 97))
69494	22429592	The associated risk of malignancy is less than 5% for SDHD mutation carriers.	('SDHD', 'Gene', (54, 58))	('SDHD', 'Gene', '6392', (54, 58))	('mutation', 'Var', (59, 67))	('malignancy', 'Disease', 'MESH:D009369', (23, 33))	('malignancy', 'Disease', (23, 33))
69497	22429592	One common mutation, c.232G>A; p.Gly78Arg, was identified in two distinct families with head and neck PGL (one family with Dutch decent and one with Spanish decent).	('c.232G>A', 'Mutation', 'rs113560320', (21, 29))	('p.Gly78Arg', 'Var', (31, 41))	('c.232G>A; p.Gly78Arg', 'Var', (21, 41))	('p.Gly78Arg', 'Mutation', 'rs113560320', (31, 41))
69500	22429592	Out of 57 family members, 24 had an SDHAF2 mutation; and 91% of affected individuals had more than one head and neck PGL.	('mutation', 'Var', (43, 51))	('SDHAF2', 'Gene', (36, 42))	('SDHAF2', 'Gene', '54949', (36, 42))	('more than one head', 'Phenotype', 'HP:0000256', (89, 107))
69502	22429592	These data are based on small numbers of patients but suggest that individuals with multiple head and neck PGL who are negative for other SDH gene mutations, should be tested for SDHAF2 mutations.	('SDH', 'Gene', '6390', (179, 182))	('mutations', 'Var', (186, 195))	('SDHAF2', 'Gene', '54949', (179, 185))	('SDH', 'Gene', '6390', (138, 141))	('SDHAF2', 'Gene', (179, 185))	('SDH', 'Gene', (179, 182))	('tested', 'Reg', (168, 174))	('patients', 'Species', '9606', (41, 49))	('SDH', 'Gene', (138, 141))
69503	22429592	However, even in this subset, mutations in SDHAF2 are quite rare as one study found no mutations in 201 patients with head and neck PGL who had already been screened, and were negative, for mutations in SDHD, SDHC, or SDHB.	('SDHC', 'Gene', (209, 213))	('SDHD', 'Gene', (203, 207))	('SDHB', 'Gene', '6390', (218, 222))	('SDHC', 'Gene', '6391', (209, 213))	('mutations', 'Var', (190, 199))	('SDHB', 'Gene', (218, 222))	('mutations', 'Var', (30, 39))	('SDHAF2', 'Gene', '54949', (43, 49))	('SDHAF2', 'Gene', (43, 49))	('SDHD', 'Gene', '6392', (203, 207))	('patients', 'Species', '9606', (104, 112))
69504	22429592	Mutations in SDHC are responsible for PGL3 syndrome, which is inherited in an autosomal dominant manner with no parent of origin effect.	('SDHC', 'Gene', (13, 17))	('responsible', 'Reg', (22, 33))	('PGL3 syndrome', 'Disease', 'MESH:C565335', (38, 51))	('SDHC', 'Gene', '6391', (13, 17))	('Mutations', 'Var', (0, 9))	('PGL3 syndrome', 'Disease', (38, 51))
69506	22429592	Mutations in SDHC are less common compared to those in SDHD and SDHB, and occur in only 0-6.6% of PCC/PGL patients.	('SDHC', 'Gene', (13, 17))	('PCC/PGL', 'Gene', (98, 105))	('SDHB', 'Gene', '6390', (64, 68))	('SDHC', 'Gene', '6391', (13, 17))	('SDHB', 'Gene', (64, 68))	('PCC/PGL', 'Gene', '1421', (98, 105))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (106, 114))	('SDHD', 'Gene', '6392', (55, 59))	('SDHD', 'Gene', (55, 59))
69507	22429592	Patients with SDHC mutations tend to have solitary head and neck PGL, but rare extra adrenal PGLs and even PCC have been described.	('PGLs', 'Gene', (93, 97))	('PCC', 'Gene', '1421', (107, 110))	('SDHC', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('SDHC', 'Gene', '6391', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('PCC', 'Gene', (107, 110))	('PGLs', 'Gene', '25796', (93, 97))
69508	22429592	Mutations in SDHB are responsible for PGL4 syndrome, conferring tumor susceptibility with an autosomal dominant inheritance.	('responsible', 'Reg', (22, 33))	('SDHB', 'Gene', '6390', (13, 17))	('PGL4 syndrome', 'Disease', (38, 51))	('PGL4 syndrome', 'Disease', 'MESH:D010235', (38, 51))	('conferring tumor', 'Disease', 'MESH:D009369', (53, 69))	('Mutations', 'Var', (0, 9))	('SDHB', 'Gene', (13, 17))	('conferring tumor', 'Disease', (53, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
69511	22429592	Although the precise mechanism for tumorigenesis is unknown, mutations in SDHB are associated with dysregulation of the hypoxia pathway including over-expression of HIFalpha and hypoxia inducible gene products such as VEGF.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('dysregulation of the hypoxia', 'Disease', 'MESH:D000860', (99, 127))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('HIFalpha', 'Protein', (165, 173))	('SDHB', 'Gene', '6390', (74, 78))	('SDHB', 'Gene', (74, 78))	('hypoxia', 'Disease', (178, 185))	('hypoxia', 'Disease', (120, 127))	('mutations', 'Var', (61, 70))	('VEGF', 'Gene', (218, 222))	('over-expression', 'PosReg', (146, 161))	('associated', 'Reg', (83, 93))	('tumor', 'Disease', (35, 40))	('hypoxia', 'Disease', 'MESH:D000860', (178, 185))	('dysregulation of the hypoxia', 'Disease', (99, 127))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('VEGF', 'Gene', '7422', (218, 222))
69512	22429592	Mutations range from point mutations and small insertions and deletions to large deletions or duplications of the SDHB gene loci (reviewed in).	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('point mutations', 'Var', (21, 36))	('deletions', 'Var', (62, 71))	('insertions', 'Var', (47, 57))	('duplications', 'Var', (94, 106))
69514	22429592	The largest study to date, including 295 patients with SDHB mutations, found that the lifetime risk by age 60 of a SDHB mutation carrier developing a non-head and neck PGL was 52% with a mean age of diagnosis of 27 years old; the risk of developing a head and neck PGL was 29% with a mean age of diagnosis of 42 years old.	('SDHB', 'Gene', (55, 59))	('SDHB', 'Gene', '6390', (115, 119))	('SDHB', 'Gene', (115, 119))	('mutation', 'Var', (120, 128))	('patients', 'Species', '9606', (41, 49))	('SDHB', 'Gene', '6390', (55, 59))	('mutations', 'Var', (60, 69))
69515	22429592	SDHB mutation associated tumors carry a substantial risk of malignancy which has been estimated to range from 31-71%.	('malignancy', 'Disease', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('SDHB', 'Gene', '6390', (0, 4))	('SDHB', 'Gene', (0, 4))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('mutation', 'Var', (5, 13))
69519	22429592	Interestingly, mutations in SDHB may confer susceptibility to other cancers, as carriers of SDHB mutations have an increased incidence of gastrointestinal stromal tumors (GIST), papillary thyroid cancer, neuroblastoma and various types of renal cell carcinoma, including clear cell and papillary RCC.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (178, 202))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (239, 259))	('RCC', 'Phenotype', 'HP:0005584', (296, 299))	('RCC', 'Disease', (296, 299))	('GIST', 'Disease', (171, 175))	('SDHB', 'Gene', '6390', (92, 96))	('gastrointestinal stromal tumors', 'Disease', (138, 169))	('GIST', 'Phenotype', 'HP:0100723', (171, 175))	('mutations', 'Var', (15, 24))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (178, 202))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('thyroid cancer', 'Phenotype', 'HP:0002890', (188, 202))	('SDHB', 'Gene', '6390', (28, 32))	('RCC', 'Disease', 'MESH:C538614', (296, 299))	('GIST', 'Disease', 'MESH:D046152', (171, 175))	('neuroblastoma', 'Disease', (204, 217))	('renal cell carcinoma', 'Disease', (239, 259))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (239, 259))	('SDHB', 'Gene', (92, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (204, 217))	('clear cell', 'Disease', (271, 281))	('SDHB', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('neuroblastoma', 'Disease', 'MESH:D009447', (204, 217))	('papillary thyroid cancer', 'Disease', (178, 202))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (138, 169))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (138, 169))
69520	22429592	A similar phenomenon was noted with BRCA1 and BRCA2 mutations, which were initially identified as associated with breast and ovarian cancers, but are now known to confer increased risks for multiple cancer types.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('BRCA1', 'Gene', (36, 41))	('BRCA2', 'Gene', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('BRCA2', 'Gene', '675', (46, 51))	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (114, 140))	('cancer', 'Disease', (199, 205))	('BRCA1', 'Gene', '672', (36, 41))	('ovarian cancers', 'Phenotype', 'HP:0100615', (125, 140))	('associated', 'Reg', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
69521	22429592	The risk of associated RCC is reported as high as 14% in one large study of 295 SDHB mutation carriers compared to the 1.49% lifetime risk in the general population.	('SDHB', 'Gene', (80, 84))	('RCC', 'Phenotype', 'HP:0005584', (23, 26))	('mutation', 'Var', (85, 93))	('RCC', 'Disease', 'MESH:C538614', (23, 26))	('RCC', 'Disease', (23, 26))	('SDHB', 'Gene', '6390', (80, 84))
69522	22429592	Of note, mutations in SDHB (and also in SDHD and SDHC) have been associated with Carney-Stratakis syndrome (GIST and PGL), but have not yet been found in Carney triad (extra adrenal PGL, GIST and pulmonary chondroma), suggesting the triad syndrome may be the result of a yet unidentified genetic cause.	('SDHD', 'Gene', '6392', (40, 44))	('pulmonary chondroma', 'Phenotype', 'HP:0031474', (196, 215))	('GIST', 'Disease', (108, 112))	('mutations', 'Var', (9, 18))	('associated', 'Reg', (65, 75))	('GIST', 'Disease', (187, 191))	('SDHC', 'Gene', '6391', (49, 53))	('GIST', 'Phenotype', 'HP:0100723', (108, 112))	('Carney-Stratakis syndrome', 'Disease', (81, 106))	('GIST', 'Phenotype', 'HP:0100723', (187, 191))	('Carney triad', 'Disease', (154, 166))	('GIST', 'Disease', 'MESH:D046152', (108, 112))	('SDHD', 'Gene', (40, 44))	('triad syndrome', 'Disease', (233, 247))	('SDHB', 'Gene', '6390', (22, 26))	('GIST', 'Disease', 'MESH:D046152', (187, 191))	('pulmonary chondroma', 'Disease', 'MESH:D002812', (196, 215))	('pulmonary chondroma', 'Disease', (196, 215))	('triad syndrome', 'Disease', 'MESH:C565803', (233, 247))	('Carney-Stratakis syndrome', 'Disease', 'MESH:C564650', (81, 106))	('SDHC', 'Gene', (49, 53))	('SDHB', 'Gene', (22, 26))
69523	22429592	More research is needed to define the risk of other cancers associated with SDHB mutations.	('SDHB', 'Gene', '6390', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('SDHB', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
69525	22429592	Bilallelic mutations in SDHA lead to Leigh's syndrome, characterized by an early onset neurodegenerative disorder, and mutations can also cause a form of cardiomyopathy.	('SDHA', 'Gene', (24, 28))	('lead to', 'Reg', (29, 36))	('cardiomyopathy', 'Disease', (154, 168))	('Bilallelic mutations', 'Var', (0, 20))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (87, 113))	('neurodegenerative disorder', 'Disease', (87, 113))	('cause', 'Reg', (138, 143))	("Leigh's syndrome", 'Disease', (37, 53))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (154, 168))	('SDHA', 'Gene', '6389', (24, 28))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (87, 113))	('mutations', 'Var', (119, 128))	('cardiomyopathy', 'Disease', 'MESH:D009202', (154, 168))	("Leigh's syndrome", 'Disease', 'MESH:D007888', (37, 53))
69526	22429592	Mutations in this subunit of complex II were not identified in patients with PCC/PGL until recently.	('Mutations', 'Var', (0, 9))	('PCC/PGL', 'Gene', (77, 84))	('PCC/PGL', 'Gene', '1421', (77, 84))	('patients', 'Species', '9606', (63, 71))
69527	22429592	Subsequently, the same group published a series demonstrating that SDHA mutations represented approximately three percent of germline mutations in apparently sporadic PCC/PGL.	('mutations', 'Var', (72, 81))	('PCC/PGL', 'Gene', (167, 174))	('SDHA', 'Gene', '6389', (67, 71))	('PCC/PGL', 'Gene', '1421', (167, 174))	('SDHA', 'Gene', (67, 71))
69529	22429592	Genetic testing for SDHA mutations is complicated by the existence of two known pseudogenes on chromosomes 3 and 5; and therefore, it currently is not offered by clinical genetic testing laboratories.	('SDHA', 'Gene', (20, 24))	('mutations', 'Var', (25, 34))	('SDHA', 'Gene', '6389', (20, 24))
69534	22429592	The penetrance of mutations in TMEM127 is still not well defined.	('TMEM127', 'Gene', '55654', (31, 38))	('TMEM127', 'Gene', (31, 38))	('mutations', 'Var', (18, 27))
69535	22429592	Mutations confer disease susceptibility in an autosomal dominant fashion with LOH being a common second hit in tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('Mutations', 'Var', (0, 9))
69536	22429592	Initial studies suggested that all mutations led to adrenal based PCC, typically unilateral and in patients with no prior family history.	('led to', 'Reg', (45, 51))	('PCC', 'Gene', '1421', (66, 69))	('patients', 'Species', '9606', (99, 107))	('PCC', 'Gene', (66, 69))	('mutations', 'Var', (35, 44))
69537	22429592	However, more recently, bilateral adrenal PCC, extra adrenal and head and neck PGL have been described in patients with germline mutations in TMEM127, so more data are needed to define the associated clinical syndrome.	('TMEM127', 'Gene', (142, 149))	('described', 'Reg', (93, 102))	('PCC', 'Gene', '1421', (42, 45))	('TMEM127', 'Gene', '55654', (142, 149))	('germline mutations', 'Var', (120, 138))	('extra', 'Disease', (47, 52))	('PCC', 'Gene', (42, 45))	('patients', 'Species', '9606', (106, 114))
69539	22429592	Most recently inherited mutations in MAX were identified as associated with PCC/PGL susceptibility.	('PCC/PGL', 'Gene', '1421', (76, 83))	('MAX', 'Gene', (37, 40))	('mutations', 'Var', (24, 33))	('PCC/PGL', 'Gene', (76, 83))	('associated', 'Reg', (60, 70))
69541	22429592	Tumors from these patients clustered on expression array analysis with tumors having known mutations in RET, NF1 and TMEM127.	('TMEM127', 'Gene', (117, 124))	('RET', 'Gene', '5979', (104, 107))	('TMEM127', 'Gene', '55654', (117, 124))	('NF1', 'Gene', (109, 112))	('NF1', 'Gene', '4763', (109, 112))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', (71, 77))	('mutations', 'Var', (91, 100))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (18, 26))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('RET', 'Gene', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
69545	22429592	found bilateral adrenal PCC in eight of twelve cases studied with MAX mutations; moreover, three of eight probands had malignant PCC.	('PCC', 'Gene', (129, 132))	('mutations', 'Var', (70, 79))	('PCC', 'Gene', '1421', (24, 27))	('PCC', 'Gene', (24, 27))	('PCC', 'Gene', '1421', (129, 132))
69546	22429592	Future research is needed to define the penetrance of disease associated with this mutation and the true risk of malignancy.	('mutation', 'Var', (83, 91))	('malignancy', 'Disease', (113, 123))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))
69553	22429592	Biochemical profile for SDHB mutated tumors is similar to that of vHL patients with a normetanephrine predominance, but they can also have high methoxytyramine excretion (the o-methylated metabolite of dopamine) in addition to, or as the only elevated biochemical marker.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('patients', 'Species', '9606', (70, 78))	('high', 'PosReg', (139, 143))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('methoxytyramine', 'Chemical', 'MESH:C001746', (144, 159))	('SDHB', 'Gene', '6390', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutated', 'Var', (29, 36))	('normetanephrine', 'Chemical', 'MESH:D009647', (86, 101))	('tumors', 'Disease', (37, 43))	('SDHB', 'Gene', (24, 28))	('vHL', 'Gene', (66, 69))	('vHL', 'Gene', '7428', (66, 69))	('methoxytyramine excretion', 'MPA', (144, 169))	('dopamine', 'Chemical', 'MESH:D004298', (202, 210))
69554	22429592	Tumors associated with SDHC, SDHD, and SDHAF2 mutations, often located in the head and neck, are derived from parasympathetic ganglia which usually do not secrete catecholamines.	('SDHD', 'Gene', '6392', (29, 33))	('SDHC', 'Gene', '6391', (23, 27))	('mutations', 'Var', (46, 55))	('SDHD', 'Gene', (29, 33))	('Tumors', 'Disease', (0, 6))	('SDHAF2', 'Gene', '54949', (39, 45))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SDHAF2', 'Gene', (39, 45))	('SDHC', 'Gene', (23, 27))	('catecholamines', 'Chemical', 'MESH:D002395', (163, 177))
69556	22429592	Finally, the biochemical profiles of tumors associated with mutations in TMEM127, SDHA, and MAX have not been well established.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('TMEM127', 'Gene', (73, 80))	('TMEM127', 'Gene', '55654', (73, 80))	('SDHA', 'Gene', '6389', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('mutations', 'Var', (60, 69))	('SDHA', 'Gene', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
69565	22429592	showed that methoxytyramine also is highly correlated with the presence of metastases in patients with or without SDHB mutations, and therefore, has high utility in monitoring disease.	('SDHB', 'Gene', '6390', (114, 118))	('SDHB', 'Gene', (114, 118))	('correlated', 'Reg', (43, 53))	('metastases', 'Disease', (75, 85))	('methoxytyramine', 'MPA', (12, 27))	('patients', 'Species', '9606', (89, 97))	('methoxytyramine', 'Chemical', 'MESH:C001746', (12, 27))	('mutations', 'Var', (119, 128))	('metastases', 'Disease', 'MESH:D009362', (75, 85))
69567	22429592	Unaffected carriers of SDHB, SDHC, SDHD, and SDHAF2 mutations who have normal plasma metanephrines and catecholamine results, should have screening imaging with MRI (or CT scan) of the thorax, abdomen and pelvis and head and neck every two years.	('mutations', 'Var', (52, 61))	('SDHD', 'Gene', (35, 39))	('SDHD', 'Gene', '6392', (35, 39))	('metanephrines', 'Chemical', 'MESH:D008676', (85, 98))	('SDHAF2', 'Gene', '54949', (45, 51))	('SDHB', 'Gene', '6390', (23, 27))	('SDHAF2', 'Gene', (45, 51))	('catecholamine', 'Chemical', 'MESH:D002395', (103, 116))	('SDHB', 'Gene', (23, 27))	('SDHC', 'Gene', (29, 33))	('SDHC', 'Gene', '6391', (29, 33))
69569	22429592	PCC/PGLs, even malignant and multi-focal tumors, have been reported in children as young as five to eight years old in association with SDHB and SDHD mutations; therefore, screening for unaffected mutation carriers should begin between ages five and ten.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SDHD', 'Gene', (145, 149))	('multi-focal tumors', 'Disease', (29, 47))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('PCC/PGL', 'Gene', (0, 7))	('PGLs', 'Gene', '25796', (4, 8))	('SDHB', 'Gene', '6390', (136, 140))	('mutations', 'Var', (150, 159))	('SDHB', 'Gene', (136, 140))	('children', 'Species', '9606', (71, 79))	('multi-focal tumors', 'Disease', 'MESH:D015140', (29, 47))	('PCC/PGL', 'Gene', '1421', (0, 7))	('PGLs', 'Gene', (4, 8))	('SDHD', 'Gene', '6392', (145, 149))
69571	22429592	As tumors associated with mutations in SDHB have a higher chance of malignant progression, more frequent follow-up after diagnosis of an initial tumor may be warranted.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (3, 8))	('SDHB', 'Gene', '6390', (39, 43))	('tumors', 'Disease', (3, 9))	('malignant progression', 'CPA', (68, 89))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SDHB', 'Gene', (39, 43))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
69574	22429592	Several studies have screened specific candidate genes for somatic mutations in PCC/PGL, but overall, few somatic mutations have been identified.	('PCC/PGL', 'Gene', '1421', (80, 87))	('PCC/PGL', 'Gene', (80, 87))	('mutations', 'Var', (67, 76))
69579	22429592	Interestingly, mice with heterozygous Pten mutations, or conditional knockouts, develop malignant PCC/PGL.	('PCC/PGL', 'Gene', (98, 105))	('PCC/PGL', 'Gene', '1421', (98, 105))	('mutations', 'Var', (43, 52))	('Pten', 'Gene', (38, 42))	('develop', 'PosReg', (80, 87))	('malignant', 'CPA', (88, 97))	('Pten', 'Gene', '19211', (38, 42))	('mice', 'Species', '10090', (15, 19))
69585	22429592	The data have shown expected results of increased expression of hypoxia related genes in tumors with germline mutations in VHL or SDH genes.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (110, 119))	('hypoxia', 'Disease', (64, 71))	('SDH', 'Gene', (130, 133))	('hypoxia', 'Disease', 'MESH:D000860', (64, 71))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('VHL', 'Gene', (123, 126))	('VHL', 'Gene', '7428', (123, 126))	('increased', 'PosReg', (40, 49))	('SDH', 'Gene', '6390', (130, 133))	('expression', 'MPA', (50, 60))
69586	22429592	examined 202 PCC/PGL for expression array analysis and the results were consistent with previous data clustering together the RET/NF1/TMEM127 mutated tumors separately from VHL/SDHx mutated tumors based on upregulation of MAPK signaling and neuroendocrine differentiation gene expression vs. upregulation of genes involved in angiogenesis and hypoxia, respectively.	('VHL', 'Gene', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('hypoxia', 'Disease', (343, 350))	('mutated', 'Var', (142, 149))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TMEM127', 'Gene', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MAPK signaling', 'Pathway', (222, 236))	('upregulation', 'PosReg', (206, 218))	('tumors', 'Disease', (190, 196))	('tumors', 'Disease', (150, 156))	('VHL', 'Gene', '7428', (173, 176))	('hypoxia', 'Disease', 'MESH:D000860', (343, 350))	('PCC/PGL', 'Gene', (13, 20))	('TMEM127', 'Gene', '55654', (134, 141))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('RET', 'Gene', '5979', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('upregulation', 'PosReg', (292, 304))	('NF1', 'Gene', '4763', (130, 133))	('neuroendocrine differentiation gene', 'Gene', (241, 276))	('SDHx', 'Chemical', '-', (177, 181))	('RET', 'Gene', (126, 129))	('NF1', 'Gene', (130, 133))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('PCC/PGL', 'Gene', '1421', (13, 20))
69590	22429592	This suggestion is based on data showing that at least a third of patients with apparently sporadic PCC/PGL and over half of patients with head and neck PGL, have an identified germline mutation in one of the known susceptibility genes.	('PCC/PGL', 'Gene', '1421', (100, 107))	('germline mutation', 'Var', (177, 194))	('PCC/PGL', 'Gene', (100, 107))	('patients', 'Species', '9606', (66, 74))	('patients', 'Species', '9606', (125, 133))
69591	22429592	In addition, patients with only adrenal PCC have up to a 21% mutation detection rate, and the rate can be as high as 59% if diagnosed by 18 years of age.	('PCC', 'Gene', (40, 43))	('mutation', 'Var', (61, 69))	('PCC', 'Gene', '1421', (40, 43))	('patients', 'Species', '9606', (13, 21))
69593	22429592	Ten known susceptibility genes have been identified to date, making PCC/PGL more commonly associated with an inherited mutation than any other cancer type.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutation', 'Var', (119, 127))	('PCC/PGL', 'Gene', (68, 75))	('associated', 'Reg', (90, 100))	('PCC/PGL', 'Gene', '1421', (68, 75))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
69596	21755051	Functional Imaging of Pheochromocytoma with 68Ga-DOTATOC and 68C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%).	('HED', 'Gene', (65, 68))	('pheochromocytoma', 'Disease', (190, 206))	('Rat', 'Species', '10116', (136, 139))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (190, 206))	('develop', 'Reg', (182, 189))	('Endocrine Neoplasia', 'Phenotype', 'HP:0100568', (116, 135))	('Rat', 'Species', '10116', (94, 97))	('Rats', 'Species', '10116', (136, 140))	('HED', 'Gene', '1896', (65, 68))	('68Ga-DOTATOC', 'Var', (44, 56))	('Pheochromocytoma', 'Disease', 'MESH:D010673', (22, 38))	('Multiple Endocrine Neoplasia', 'Disease', (107, 135))	('Neoplasia', 'Phenotype', 'HP:0002664', (126, 135))	('pheochromocytoma', 'Disease', 'MESH:D010673', (190, 206))	('Pheochromocytoma', 'Disease', (22, 38))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (22, 38))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('multitumor syndrome', 'Disease', 'MESH:D013577', (162, 181))	('multitumor syndrome', 'Disease', (162, 181))	('Multiple Endocrine Neoplasia', 'Disease', 'MESH:D009377', (107, 135))
69599	21755051	We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or 11C-Hydroxyephedrine (HED), a norepinephrine analogue.	('pheochromocytoma', 'Phenotype', 'HP:0002666', (73, 89))	('HED', 'Gene', (212, 215))	('68Ga-DOTATOC', 'Chemical', 'MESH:C499142', (150, 162))	('pheochromocytomas', 'Disease', 'MESH:D010673', (73, 90))	('11C-Hydroxyephedrine', 'Chemical', '-', (190, 210))	('pheochromocytomas', 'Disease', (73, 90))	('11C-Hydroxyephedrine', 'Var', (190, 210))	('norepinephrine', 'Chemical', 'MESH:D009638', (220, 234))	('rat', 'Species', '10116', (69, 72))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (73, 90))	('HED', 'Gene', '1896', (212, 215))
69614	21755051	However, although it often achieves successful palliation, 131I-MIBG therapy has limited effect on tumor control and it is generally not curative.	('tumor', 'Disease', (99, 104))	('131I-MIBG', 'Chemical', 'MESH:D019797', (59, 68))	('rat', 'Species', '10116', (139, 142))	('131I-MIBG', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
69626	21755051	Affected rats are homozygous for a germline frameshift mutation in the Cdkn1b gene (p27Kip1) and are hereafter indicated as affected or mut/mut.	('Cdkn1b', 'Gene', (71, 77))	('rats', 'Species', '10116', (9, 13))	('Cdkn1b', 'Gene', '83571', (71, 77))	('p27Kip1', 'Var', (84, 91))
69653	21755051	Comparisons between the two groups of animals showed elevated uptake of 11C-HED in all mutant rats compared to the controls: the adrenal to liver ratios in mutant rats was 1.6 (+-0.5) but was only 0.7 (+-0.1) in normal rats (P = .002) (Table 1).	('rat', 'Species', '10116', (163, 166))	('rat', 'Species', '10116', (94, 97))	('rat', 'Species', '10116', (146, 149))	('elevated', 'PosReg', (53, 61))	('rats', 'Species', '10116', (219, 223))	('adrenal', 'MPA', (129, 136))	('HED', 'Gene', '1896', (76, 79))	('11C', 'Chemical', 'MESH:C000615233', (72, 75))	('HED', 'Gene', (76, 79))	('mutant', 'Var', (87, 93))	('mutant', 'Var', (156, 162))	('rats', 'Species', '10116', (163, 167))	('rats', 'Species', '10116', (94, 98))	('uptake', 'MPA', (62, 68))	('rat', 'Species', '10116', (219, 222))
69654	21755051	Also 68Ga-DOTATOC uptake was elevated in the adrenal glands of mutant rats compared to the normal controls, although to a lesser extent compared to 11C-HED uptake.	('elevated', 'PosReg', (29, 37))	('68Ga-DOTATOC uptake', 'MPA', (5, 24))	('mutant', 'Var', (63, 69))	('HED', 'Gene', '1896', (152, 155))	('HED', 'Gene', (152, 155))	('11C', 'Chemical', 'MESH:C000615233', (148, 151))	('rats', 'Species', '10116', (70, 74))	('68Ga-DOTATOC', 'Chemical', 'MESH:C499142', (5, 17))
69656	21755051	Affected rats have a germline mutation in Cdkn1b that makes the encoded protein highly unstable and as a consequence they have extremely reduced levels, or complete loss, of p27Kip1 in their tissues, as previously reported.	('p27Kip1', 'Var', (174, 181))	('levels', 'MPA', (145, 151))	('Cdkn1b', 'Gene', (42, 48))	('Cdkn1b', 'Gene', '83571', (42, 48))	('unstable', 'MPA', (87, 95))	('loss', 'NegReg', (165, 169))	('rats', 'Species', '10116', (9, 13))	('reduced', 'NegReg', (137, 144))
69657	21755051	The results confirmed the low level of p27Kip1 expression in the adrenal medullary cells of the mutant rats compared to those of wild-type control rats (Figure 1).	('p27Kip1', 'Var', (39, 46))	('rats', 'Species', '10116', (103, 107))	('mutant', 'Var', (96, 102))	('rats', 'Species', '10116', (147, 151))
69658	21755051	In humans, several normal and neoplastic tissues show an inverse relationship between p27Kip1 expression and the proliferation activity of the tumor cells.	('tumor', 'Disease', (143, 148))	('p27Kip1', 'Var', (86, 93))	('inverse', 'NegReg', (57, 64))	('humans', 'Species', '9606', (3, 9))	('expression', 'MPA', (94, 104))	('rat', 'Species', '10116', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
69660	21755051	Therefore, we determined the proliferative index of the rat tumor cells by immunohistochemical staining for the proliferation marker Ki67 (MIB-5 antigen) to determine whether the low p27Kip1 levels had an effect on cell proliferation.	('rat', 'Species', '10116', (227, 230))	('cell proliferation', 'CPA', (215, 233))	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rat', 'Species', '10116', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('p27Kip1', 'Var', (183, 190))	('tumor', 'Disease', (60, 65))	('Ki67', 'Chemical', '-', (133, 137))
69676	21755051	Quantitative RT-PCR showed that the expression of the Slc6a2 gene (norepinephrine transporter) is comparable between mutant and wild-type animals.	('Slc6a2', 'Gene', '83511', (54, 60))	('mutant', 'Var', (117, 123))	('norepinephrine transporter', 'Gene', '83511', (67, 93))	('norepinephrine transporter', 'Gene', (67, 93))	('Slc6a2', 'Gene', (54, 60))
69679	21755051	Of course we cannot exclude that differences might exist between mutant and control rats in the final amount of norepinephrine transporter protein or in its activity.	('mutant', 'Var', (65, 71))	('norepinephrine transporter', 'Gene', '83511', (112, 138))	('norepinephrine transporter', 'Gene', (112, 138))	('rats', 'Species', '10116', (84, 88))	('activity', 'MPA', (157, 165))
69681	21755051	This is in agreement with the increased expression level of the Sstr2 gene in mutant compared to normal rat adrenals.	('Sstr2', 'Gene', (64, 69))	('expression level', 'MPA', (40, 56))	('Sstr2', 'Gene', '54305', (64, 69))	('increased', 'PosReg', (30, 39))	('mutant', 'Var', (78, 84))	('rat', 'Species', '10116', (104, 107))
69683	21755051	Immunohistochemical staining confirmed the low levels of p27Kip1 in the mutant rat adrenals and showed a moderate to elevated proliferation index of the tumors.	('proliferation index', 'CPA', (126, 145))	('mutant', 'Var', (72, 78))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('rat', 'Species', '10116', (109, 112))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('rat', 'Species', '10116', (79, 82))	('elevated', 'PosReg', (117, 125))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('p27Kip1', 'Var', (57, 64))
69685	21755051	Immunoreactivity for Ki67 in the rat lesions was higher than that displayed by human pheochromocytoma, usually lower than 3.5%.	('human', 'Species', '9606', (79, 84))	('Ki67', 'Var', (21, 25))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (85, 101))	('Ki67', 'Chemical', '-', (21, 25))	('rat', 'Species', '10116', (33, 36))	('pheochromocytoma', 'Disease', (85, 101))	('pheochromocytoma', 'Disease', 'MESH:D010673', (85, 101))	('Immunoreactivity', 'MPA', (0, 16))
69688	21755051	No metastatic spread was observed both by histology and by PET in any of the affected animals subjected to imaging, maybe because it had not yet taken place as the mutant rats were relatively young (5 months old) and their average life-span is 10 +- 2 months.	('mutant', 'Var', (164, 170))	('metastatic spread', 'CPA', (3, 20))	('rats', 'Species', '10116', (171, 175))
69700	21755051	Internal radiotherapy of pheochromocytoma with 131I-MIBG has been used with some success in reducing tumor bulk, thereby attenuating the symptoms associated to catecholamines oversecretion and alleviating pain.	('reducing', 'NegReg', (92, 100))	('symptoms', 'MPA', (137, 145))	('catecholamines', 'Chemical', 'MESH:D002395', (160, 174))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (25, 41))	('pain', 'Phenotype', 'HP:0012531', (205, 209))	('alleviating', 'NegReg', (193, 204))	('131I-MIBG', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('pain', 'Disease', 'MESH:D010146', (205, 209))	('pain', 'Disease', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('pheochromocytoma', 'Disease', (25, 41))	('catecholamines oversecretion', 'MPA', (160, 188))	('pheochromocytoma', 'Disease', 'MESH:D010673', (25, 41))	('131I-MIBG', 'Chemical', 'MESH:D019797', (47, 56))	('attenuating', 'NegReg', (121, 132))
69703	21755051	The mutant p27 protein associated with the MENX syndrome is degraded very fast by the proteasome so that its level in the tissues of affected rats is extremely reduced or totally absent.	('mutant', 'Var', (4, 10))	('level', 'MPA', (109, 114))	('absent', 'NegReg', (179, 185))	('p27', 'Gene', (11, 14))	('reduced', 'NegReg', (160, 167))	('MENX syndrome', 'Disease', 'MESH:D013577', (43, 56))	('rats', 'Species', '10116', (142, 146))	('protein', 'Protein', (15, 22))	('degraded', 'NegReg', (60, 68))	('MENX syndrome', 'Disease', (43, 56))	('associated', 'Reg', (23, 33))
69752	18996821	Mutations in protooncogenes have been identified in numerous tumor syndromes.	('identified', 'Reg', (38, 48))	('numerous tumor', 'Disease', (52, 66))	('protooncogenes', 'Gene', (13, 27))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('numerous tumor', 'Disease', 'MESH:D009369', (52, 66))
69753	18996821	Mutations in the RET protooncogene on chromosome 10, encoding a transmembrane receptor tyrosine kinase, has been linked to the development of multiple endocrine neoplasia type 2A (MEN 2A) syndrome.	('multiple endocrine neoplasia type 2A', 'Gene', (142, 178))	('RET', 'Gene', (17, 20))	('multiple endocrine neoplasia type 2A', 'Gene', '5979', (142, 178))	('Mutations', 'Var', (0, 9))	('linked to', 'Reg', (113, 122))	('MEN 2A', 'Gene', '5979', (180, 186))	('MEN 2A', 'Gene', (180, 186))	('RET', 'Gene', '5979', (17, 20))	('neoplasia', 'Phenotype', 'HP:0002664', (161, 170))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (151, 170))
69756	18996821	Like mutations in the RET protooncogene resulting in MEN 2A, mutations in KIT and PDGFRA (platelet-derived growth factor receptor, alpha polypeptide), both transmembrane tyrosine kinase receptors, have been associated with the formation of gastrointestinal stromal tumors (GISTs).	('PDGFRA', 'Gene', (82, 88))	('RET', 'Gene', (22, 25))	('MEN 2A', 'Gene', (53, 59))	('platelet-derived growth factor receptor, alpha polypeptide', 'Gene', '5156', (90, 148))	('MEN 2A', 'Gene', '5979', (53, 59))	('gastrointestinal stromal tumors', 'Disease', (240, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('RET', 'Gene', '5979', (22, 25))	('mutations', 'Var', (61, 70))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (240, 270))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (240, 271))	('KIT', 'Gene', (74, 77))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (240, 271))	('associated with', 'Reg', (207, 222))	('GISTs', 'Phenotype', 'HP:0100723', (273, 278))	('PDGFRA', 'Gene', '5156', (82, 88))
69758	18996821	Most GISTs have a gain-of-function mutation in the KIT protooncogene, while 5% have a constitutive activating mutation in the PDGFRA gene.	('PDGFRA', 'Gene', (126, 132))	('KIT protooncogene', 'Gene', (51, 68))	('mutation', 'Var', (35, 43))	('gain-of-function', 'PosReg', (18, 34))	('GISTs', 'Phenotype', 'HP:0100723', (5, 10))	('PDGFRA', 'Gene', '5156', (126, 132))
69771	18996821	A germline mutation in the RET gene (p.Cys634Ser in exon 11) was identified in the niece.	('p.Cys634Ser', 'Var', (37, 48))	('p.Cys634Ser', 'Mutation', 'rs75076352', (37, 48))	('RET', 'Gene', (27, 30))	('RET', 'Gene', '5979', (27, 30))
69788	18996821	However, tumor tissue from these GISTs often lack both KIT and PDGFRA mutations, and these tumors are distinguished by their unique phenotype of multicentricity, location in the small intestine, morphology, and nonaggressive behavior.	('tumors', 'Disease', (91, 97))	('KIT', 'Gene', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (70, 79))	('lack', 'NegReg', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('PDGFRA', 'Gene', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PDGFRA', 'Gene', '5156', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('GISTs', 'Phenotype', 'HP:0100723', (33, 38))	('tumor', 'Disease', (91, 96))
69793	18996821	In 2006, Perry et al described 3 cases of nonfamilial occurrences of abdominal paraganglioma and GISTs that did not exhibit the germline SDHA, SDHB, SDHC, SDHD, or KIT mutations that are generally associated with familial paraganglioma or GIST syndromes.	('SDHD', 'Gene', (155, 159))	('paraganglioma', 'Phenotype', 'HP:0002668', (79, 92))	('SDHA', 'Gene', '6389', (137, 141))	('SDHC', 'Gene', (149, 153))	('SDHB', 'Gene', (143, 147))	('paraganglioma', 'Phenotype', 'HP:0002668', (222, 235))	('mutations', 'Var', (168, 177))	('abdominal paraganglioma', 'Disease', 'MESH:D010235', (69, 92))	('GIST syndrome', 'Disease', (239, 252))	('familial paraganglioma', 'Disease', (213, 235))	('GIST syndrome', 'Disease', 'MESH:D046152', (239, 252))	('associated', 'Reg', (197, 207))	('abdominal paraganglioma', 'Disease', (69, 92))	('SDHD', 'Gene', '6392', (155, 159))	('SDHC', 'Gene', '6391', (149, 153))	('SDHB', 'Gene', '6390', (143, 147))	('GISTs', 'Phenotype', 'HP:0100723', (97, 102))	('familial paraganglioma', 'Disease', 'MESH:D010235', (213, 235))	('SDHA', 'Gene', (137, 141))
69804	18996821	The presence of a RET mutation in an affected family member raises the possibility that RET mutations may be causal for GIST, although coincidence is also a possibility.	('mutation', 'Var', (22, 30))	('RET', 'Gene', '5979', (18, 21))	('RET', 'Gene', (88, 91))	('RET', 'Gene', '5979', (88, 91))	('RET', 'Gene', (18, 21))
69805	18996821	It would be of interest to look for similar activating RET mutations in other individuals with GISTs, occurring either alone or with paraganglioma syndromes, who do not harbor mutations in KIT, PDGFRA, or other known genes.	('paraganglioma syndromes', 'Disease', (133, 156))	('activating', 'PosReg', (44, 54))	('GISTs', 'Disease', (95, 100))	('RET', 'Gene', '5979', (55, 58))	('PDGFRA', 'Gene', (194, 200))	('RET', 'Gene', (55, 58))	('PDGFRA', 'Gene', '5156', (194, 200))	('mutations', 'Var', (59, 68))	('paraganglioma', 'Phenotype', 'HP:0002668', (133, 146))	('paraganglioma syndromes', 'Disease', 'MESH:D010235', (133, 156))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))
69899	33334087	Embolization of paragangliomas prior to surgery has several advantages over the sole surgical resection approach.	('Embolization', 'Var', (0, 12))	('paragangliomas', 'Disease', 'MESH:D010235', (16, 30))	('paragangliomas', 'Disease', (16, 30))	('paraganglioma', 'Phenotype', 'HP:0002668', (16, 29))	('paragangliomas', 'Phenotype', 'HP:0002668', (16, 30))
69988	30949620	Translating in vivo metabolomic analysis of succinate dehydrogenase deficient tumours into clinical utility Mutations in the mitochondrial enzyme succinate dehydrogenase (SDH) subunit genes are associated with a wide spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), gastrointestinal stromal tumours (GIST), renal cell carcinoma (RCC) and pituitary adenomas.	('succinate dehydrogenase', 'Gene', (44, 67))	('RCC', 'Disease', (354, 357))	('SDH', 'Gene', (171, 174))	('phaeochromocytoma and paraganglioma', 'Disease', 'MESH:D010235', (247, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('dehydrogenase deficient tumours', 'Disease', (54, 85))	('succinate dehydrogenase', 'Gene', (146, 169))	('pituitary adenomas', 'Disease', 'MESH:D010911', (363, 381))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('associated with', 'Reg', (194, 209))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (363, 380))	('RCC', 'Disease', 'MESH:C538614', (354, 357))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (363, 381))	('pituitary adenomas', 'Disease', (363, 381))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (291, 323))	('paraganglioma', 'Phenotype', 'HP:0002668', (269, 282))	('dehydrogenase deficient tumours', 'Disease', 'MESH:D009369', (54, 85))	('succinate dehydrogenase', 'Gene', '6390', (44, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (332, 352))	('tumours', 'Disease', (316, 323))	('tumours', 'Disease', (229, 236))	('tumours', 'Disease', (78, 85))	('succinate dehydrogenase', 'Gene', '6390', (146, 169))	('tumours', 'Phenotype', 'HP:0002664', (316, 323))	('SDH', 'Gene', '6390', (171, 174))	('tumours', 'Disease', 'MESH:D009369', (316, 323))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('renal cell carcinoma', 'Disease', (332, 352))	('gastrointestinal stromal tumours', 'Disease', (291, 323))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (332, 352))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('Mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
69993	30949620	A succinate peak was seen in six patients, all of whom had a germline SDHx mutation or loss of SDHB by immunohistochemistry.	('loss', 'NegReg', (87, 91))	('patients', 'Species', '9606', (33, 41))	('succinate peak', 'MPA', (2, 16))	('mutation', 'Var', (75, 83))	('succinate', 'Chemical', 'MESH:D019802', (2, 11))	('SDHB', 'Gene', '6390', (95, 99))	('SDHB', 'Gene', (95, 99))	('SDHx', 'Gene', (70, 74))	('SDHx', 'Chemical', '-', (70, 74))
69994	30949620	A succinate peak was also detected in two patients with a metastatic wild-type GIST (wtGIST) and no detectable germline SDHx mutation but a somatic epimutation in SDHC.	('epimutation', 'Var', (148, 159))	('succinate peak', 'MPA', (2, 16))	('succinate', 'Chemical', 'MESH:D019802', (2, 11))	('SDHx', 'Chemical', '-', (120, 124))	('SDHx', 'Gene', (120, 124))	('SDHC', 'Gene', (163, 167))	('patients', 'Species', '9606', (42, 50))	('SDHC', 'Gene', '6391', (163, 167))
70002	30949620	SDHx mutations were described initially in association with head and neck paragangliomas (derived from parasympathetic ganglia) and in phaeochromocytomas and paragangliomas (PPGL, derived from sympathetic ganglia and often secreting catecholamines).	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('paragangliomas', 'Phenotype', 'HP:0002668', (74, 88))	('paragangliomas', 'Phenotype', 'HP:0002668', (158, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (158, 171))	('head and neck paragangliomas', 'Phenotype', 'HP:0002864', (60, 88))	('neck paragangliomas', 'Disease', 'MESH:D010235', (69, 88))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('association', 'Reg', (43, 54))	('mutations', 'Var', (5, 14))	('SDHx', 'Chemical', '-', (0, 4))	('phaeochromocytomas and paragangliomas', 'Disease', 'MESH:D010235', (135, 172))	('catecholamines', 'Chemical', 'MESH:D002395', (233, 247))	('SDHx', 'Gene', (0, 4))	('neck paragangliomas', 'Disease', (69, 88))	('paraganglioma', 'Phenotype', 'HP:0002668', (74, 87))
70003	30949620	It is now recognised that approximately 40% of PPGL patients harbour a germline mutation in an inherited PPGL gene and SDHx mutations are the most common cause of PPGL predisposition.	('mutations', 'Var', (124, 133))	('PPGL', 'Disease', (47, 51))	('SDHx', 'Chemical', '-', (119, 123))	('PPGL', 'Gene', (105, 109))	('germline mutation', 'Var', (71, 88))	('patients', 'Species', '9606', (52, 60))
70004	30949620	In addition, germline SDHB mutations are associated with a high risk of malignancy in PPGL.	('mutations', 'Var', (27, 36))	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('associated', 'Reg', (41, 51))	('SDHB', 'Gene', '6390', (22, 26))	('malignancy', 'Disease', (72, 82))	('SDHB', 'Gene', (22, 26))	('PPGL', 'Disease', (86, 90))
70005	30949620	Other tumour types associated with SDHx mutations include gastrointestinal stromal tumours (GISTs) and renal cell carcinomas (RCCs).	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('tumour', 'Disease', (6, 12))	('RCC', 'Disease', 'MESH:C538614', (126, 129))	('gastrointestinal stromal tumours', 'Disease', 'MESH:D046152', (58, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (40, 49))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('SDHx', 'Gene', (35, 39))	('tumour', 'Disease', (83, 89))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (103, 124))	('SDHx', 'Chemical', '-', (35, 39))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('renal cell carcinomas', 'Disease', (103, 124))	('gastrointestinal stromal tumours', 'Disease', (58, 90))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (103, 124))	('RCC', 'Disease', (126, 129))
70007	30949620	However GISTs without KIT and PDGFRA gene mutations, known as wild-type (wtGIST), account for 15% of adult and 85% of paediatric GIST tumours and recent studies suggest that up to 88% of wtGIST are SDH-deficient.	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('GIST tumours', 'Disease', (129, 141))	('KIT', 'Gene', (22, 25))	('SDH-deficient', 'Disease', (198, 211))	('PDGFRA', 'Gene', '5156', (30, 36))	('GIST tumours', 'Disease', 'MESH:D046152', (129, 141))	('mutations', 'Var', (42, 51))	('PDGFRA', 'Gene', (30, 36))	('SDH-deficient', 'Disease', 'MESH:D007153', (198, 211))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
70008	30949620	wtGIST with SDH-deficiency may harbour a germline SDHx mutation (75% of cases) or an SDHC gene epimutation with hypermethylation of the promoter region.	('SDHx', 'Gene', (50, 54))	('SDHC', 'Gene', (85, 89))	('SDH-deficiency', 'Disease', (12, 26))	('epimutation', 'Var', (95, 106))	('SDHC', 'Gene', '6391', (85, 89))	('mutation', 'Var', (55, 63))	('SDH-deficiency', 'Disease', 'MESH:D007153', (12, 26))	('SDHx', 'Chemical', '-', (50, 54))
70011	30949620	Finally germline SDHx mutations have been described in rare patients with pituitary adenomas.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (74, 91))	('pituitary adenomas', 'Disease', (74, 92))	('described', 'Reg', (42, 51))	('patients', 'Species', '9606', (60, 68))	('SDHx', 'Chemical', '-', (17, 21))	('SDHx', 'Gene', (17, 21))	('pituitary adenomas', 'Disease', 'MESH:D010911', (74, 92))	('mutations', 'Var', (22, 31))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (74, 92))
70013	30949620	Succinate has been shown to be elevated by 100-fold in SDHx-mutated PPGL tumours ex-vivo compared with non-SDHx mutated PPGL tumours.	('PPGL tumours', 'Disease', 'MESH:D009369', (68, 80))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('PPGL tumours', 'Disease', (68, 80))	('Succinate', 'Chemical', 'MESH:D019802', (0, 9))	('Succinate', 'MPA', (0, 9))	('PPGL tumours', 'Disease', 'MESH:D009369', (120, 132))	('PPGL tumours', 'Disease', (120, 132))	('SDHx-mutated', 'Var', (55, 67))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('elevated', 'PosReg', (31, 39))	('SDHx', 'Chemical', '-', (55, 59))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('SDHx', 'Chemical', '-', (107, 111))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))
70014	30949620	Recently, in vivo detection of succinate by MR spectroscopy was reported in two patient cohorts with SDH deficient PPGL.	('succinate', 'Chemical', 'MESH:D019802', (31, 40))	('deficient', 'Var', (105, 114))	('SDH', 'Gene', '6390', (101, 104))	('SDH', 'Gene', (101, 104))	('patient', 'Species', '9606', (80, 87))
70015	30949620	Similarly, the non-invasive detection of 2-hydroxyglutarate with 1H-MRS has been demonstrated in glioma in patients with a gain of function mutation in another citric acid cycle enzyme, isocitrate dehydrogenase 1 (IDH1).	('patients', 'Species', '9606', (107, 115))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (41, 59))	('glioma', 'Disease', (97, 103))	('gain of function', 'PosReg', (123, 139))	('citric acid', 'Chemical', 'MESH:D019343', (160, 171))	('IDH1', 'Gene', (214, 218))	('mutation', 'Var', (140, 148))	('1H', 'Chemical', '-', (65, 67))	('IDH1', 'Gene', '3417', (214, 218))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('isocitrate dehydrogenase 1', 'Gene', (186, 212))	('isocitrate dehydrogenase 1', 'Gene', '3417', (186, 212))
70031	30949620	A germline mutation in a SDHx gene was identified in 9/15 (60%) of subjects: 5 in SDHB (4 missense variants and 1 truncating variant) and 4 in SDHA (1 missense and 3 truncating).	('SDHB', 'Gene', '6390', (82, 86))	('SDHx', 'Gene', (25, 29))	('SDHA', 'Gene', '6389', (143, 147))	('SDHx', 'Chemical', '-', (25, 29))	('SDHB', 'Gene', (82, 86))	('SDHA', 'Gene', (143, 147))	('missense variants', 'Var', (90, 107))
70039	30949620	The in vivo detection of succinate on 1H-MRS correlated with tumour SDH deficiency: 4 of the 6 cases had a germline SDHx mutation and loss of SDHB expression on immunohistochemistry and a somatic SDHC epimutation was detected in 2 of the 6 (Figure 1).	('succinate', 'Chemical', 'MESH:D019802', (25, 34))	('tumour SDH deficiency', 'Disease', 'MESH:D009369', (61, 82))	('1H', 'Chemical', '-', (38, 40))	('SDHB', 'Gene', (142, 146))	('tumour SDH deficiency', 'Disease', (61, 82))	('SDHC', 'Gene', (196, 200))	('SDHx', 'Chemical', '-', (116, 120))	('expression', 'MPA', (147, 157))	('SDHx', 'Gene', (116, 120))	('SDHC', 'Gene', '6391', (196, 200))	('SDHB', 'Gene', '6390', (142, 146))	('mutation', 'Var', (121, 129))	('loss', 'NegReg', (134, 138))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
70041	30949620	Patient #8 with a germline SDHB mutation (c.600G>T p.Trp200Cys) and a glomus paraganglioma, demonstrated an SCR of 1.19; however the linewidth (29 Hz) was so broad due to the proximity of metallic dental work that the peak assignments were not reliable (Figure S1).	('paraganglioma', 'Phenotype', 'HP:0002668', (77, 90))	('p.Trp200Cys', 'Var', (51, 62))	('glomus paraganglioma', 'Disease', (70, 90))	('glomus paraganglioma', 'Disease', 'MESH:D010235', (70, 90))	('c.600G>T', 'Var', (42, 50))	('SDHB', 'Gene', '6390', (27, 31))	('p.Trp200Cys', 'SUBSTITUTION', 'None', (51, 62))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('SDHB', 'Gene', (27, 31))	('c.600G>T', 'Mutation', 'rs397516836', (42, 50))	('Patient', 'Species', '9606', (0, 7))
70044	30949620	Patient #4 had a metastatic wtGIST with no detectable germline SDHx mutation and preserved SDHB protein expression in the tumour tissue; choline was confidently fitted on LCModel but no succinate was seen.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('succinate', 'Chemical', 'MESH:D019802', (186, 195))	('choline', 'Chemical', 'MESH:D002794', (137, 144))	('mutation', 'Var', (68, 76))	('SDHB', 'Gene', '6390', (91, 95))	('tumour', 'Disease', (122, 128))	('SDHx', 'Gene', (63, 67))	('expression', 'MPA', (104, 114))	('SDHB', 'Gene', (91, 95))	('SDHx', 'Chemical', '-', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('Patient', 'Species', '9606', (0, 7))
70052	30949620	Subject #2 with a metastatic paraganglioma to the lung, bone and lymph node and a germline SDHB mutation (c.268C>T p.Arg90*) underwent 1H-MRS on a large pelvic nodal metastasis prior to treatment with four cycles of lutetium 177-labelled peptide receptor radionuclide therapy.	('paraganglioma', 'Phenotype', 'HP:0002668', (29, 42))	('paraganglioma to the lung', 'Disease', 'MESH:D010235', (29, 54))	('SDHB', 'Gene', '6390', (91, 95))	('p.Arg90*', 'SUBSTITUTION', 'None', (115, 123))	('p.Arg90*', 'Var', (115, 123))	('paraganglioma to the lung', 'Disease', (29, 54))	('large pelvic', 'Phenotype', 'HP:0010779', (147, 159))	('SDHB', 'Gene', (91, 95))	('1H', 'Chemical', '-', (135, 137))	('radionuclide', 'Chemical', 'MESH:D011868', (255, 267))	('lutetium', 'Chemical', 'MESH:D008187', (216, 224))	('glioma', 'Phenotype', 'HP:0009733', (36, 42))	('c.268C>T', 'Mutation', 'rs74315366', (106, 114))
70061	30949620	All six tumours with a positive succinate peak and elevated SCR were associated with a germline SDHx mutation (n = 4) or an SDHC epimutation (n = 2).	('positive', 'PosReg', (23, 31))	('succinate peak', 'MPA', (32, 46))	('tumours', 'Disease', (8, 15))	('SDHC', 'Gene', (124, 128))	('positive succinate peak', 'Phenotype', 'HP:0020149', (23, 46))	('SCR', 'MPA', (60, 63))	('SDHx', 'Gene', (96, 100))	('succinate', 'Chemical', 'MESH:D019802', (32, 41))	('SDHC', 'Gene', '6391', (124, 128))	('SDHx', 'Chemical', '-', (96, 100))	('epimutation', 'Var', (129, 140))	('elevated', 'PosReg', (51, 59))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mutation', 'Var', (101, 109))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
70063	30949620	Our findings are complementary to a previous study in which 1H-MRS was applied to 9 patients with paraganglioma and a succinate peak was detected in all 5 with an SDHx mutation but not in the 4 patients without a mutation.	('SDHx', 'Chemical', '-', (163, 167))	('1H', 'Chemical', '-', (60, 62))	('patients', 'Species', '9606', (194, 202))	('paraganglioma', 'Disease', (98, 111))	('succinate peak', 'MPA', (118, 132))	('patients', 'Species', '9606', (84, 92))	('succinate', 'Chemical', 'MESH:D019802', (118, 127))	('paraganglioma', 'Disease', 'MESH:D010235', (98, 111))	('mutation', 'Var', (168, 176))	('to 9', 'Species', '1214577', (79, 83))	('SDHx', 'Gene', (163, 167))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))
70064	30949620	We have demonstrated for the first time that 1H-MRS can also be used to determine the SDH status of GISTs and pituitary adenomas and that a succinate peak can be detected in SDH-deficient tumours with epigenetic inactivation of SDHC.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('pituitary adenomas', 'Disease', 'MESH:D010911', (110, 128))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (110, 128))	('pituitary adenomas', 'Disease', (110, 128))	('SDH', 'Gene', '6390', (174, 177))	('SDHC', 'Gene', (228, 232))	('SDH', 'Gene', '6390', (86, 89))	('SDH', 'Gene', '6390', (228, 231))	('SDH-deficient tumours', 'Disease', 'MESH:D009369', (174, 195))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (110, 127))	('epigenetic inactivation', 'Var', (201, 224))	('SDH', 'Gene', (174, 177))	('1H', 'Chemical', '-', (45, 47))	('SDH', 'Gene', (86, 89))	('succinate', 'Chemical', 'MESH:D019802', (140, 149))	('SDH', 'Gene', (228, 231))	('SDHC', 'Gene', '6391', (228, 232))	('tumours', 'Phenotype', 'HP:0002664', (188, 195))	('SDH-deficient tumours', 'Disease', (174, 195))
70066	30949620	Potential diagnostic applications of this new approach include: (a) assessing the pathogenicity of patients with a germline SDHx variants of uncertain significance and a potentially SDH-related tumour; (b) investigating possible metastatic lesions e.g.	('SDH', 'Gene', (182, 185))	('tumour', 'Disease', (194, 200))	('SDH', 'Gene', '6390', (124, 127))	('investigating', 'Reg', (206, 219))	('patients', 'Species', '9606', (99, 107))	('SDH', 'Gene', (124, 127))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('SDH', 'Gene', '6390', (182, 185))	('SDHx', 'Chemical', '-', (124, 128))	('variants', 'Var', (129, 137))
70081	30949620	This important application of 1H-MRS could be expanded to include other tumours with specific metabolic defects including fumarate hydratase deficient tumours, IDH1 mutant tumours and the recently identified malate dehydrogenase 2 (MDH2) deficient tumours.	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('IDH1', 'Gene', (160, 164))	('tumours', 'Disease', (72, 79))	('tumours', 'Disease', (248, 255))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('IDH1', 'Gene', '3417', (160, 164))	('fumarate', 'MPA', (122, 130))	('tumours', 'Phenotype', 'HP:0002664', (248, 255))	('fumarate hydratase deficient', 'Phenotype', 'HP:0003536', (122, 150))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('1H', 'Chemical', '-', (30, 32))	('tumours', 'Disease', (151, 158))	('tumours', 'Disease', 'MESH:D009369', (248, 255))	('hydratase deficient tumours', 'Disease', (131, 158))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('malate dehydrogenase 2 (MDH2) deficient tumours', 'Disease', 'MESH:C564973', (208, 255))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('tumours', 'Disease', 'MESH:D009369', (151, 158))	('hydratase deficient tumours', 'Disease', 'MESH:C538191', (131, 158))	('tumours', 'Disease', (172, 179))	('mutant', 'Var', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumours', 'Phenotype', 'HP:0002664', (172, 179))	('tumours', 'Disease', 'MESH:D009369', (172, 179))
70091	30217226	Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas Cancer susceptibility germline variants generally require somatic alteration of the remaining allele to drive oncogenesis and, in some cases, tumor mutational profiles.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('Cancer', 'Disease', (102, 108))	('tumor', 'Disease', (244, 249))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('oncogenesis', 'CPA', (212, 223))	('drive', 'Reg', (206, 211))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('variants', 'Var', (133, 141))
70092	30217226	Whether combined germline and somatic bi-allelic alterations are universally required for germline variation to influence tumor mutational profile is unclear.	('variation', 'Var', (99, 108))	('influence', 'Reg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
70093	30217226	Here, we performed an exome-wide analysis of the frequency and functional effect of bi-allelic alterations in The Cancer Genome Atlas (TCGA).	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('bi-allelic alterations', 'Var', (84, 106))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer', 'Disease', (114, 120))
70094	30217226	We discovered significant enrichment of bi-allelic alterations in mismatch repair (MMR) genes and identified six bi-allelic carriers with elevated MSI, consistent with Lynch syndrome.	('Lynch syndrome', 'Disease', 'MESH:D003123', (168, 182))	('MMR) genes', 'Gene', (83, 93))	('bi-allelic alterations', 'Var', (40, 62))	('elevated MSI', 'Disease', 'MESH:D006937', (138, 150))	('elevated MSI', 'Disease', (138, 150))	('Lynch syndrome', 'Disease', (168, 182))
70095	30217226	Using MSI burden and bi-allelic alteration status, we reclassify two variants of unknown significance in MSH6 as potentially pathogenic for Lynch syndrome.	('variants', 'Var', (69, 77))	('MSH6', 'Gene', '2956', (105, 109))	('MSH6', 'Gene', (105, 109))	('Lynch syndrome', 'Disease', (140, 154))	('Lynch syndrome', 'Disease', 'MESH:D003123', (140, 154))	('pathogenic', 'Reg', (125, 135))
70096	30217226	Extending our analysis of MSI to a set of 127 DNA damage repair (DDR) genes, we identified a novel association between methylation of SHPRH and MSI burden.	('methylation', 'Var', (119, 130))	('SHPRH', 'Gene', (134, 139))	('MSI burden', 'CPA', (144, 154))	('SHPRH', 'Gene', '257218', (134, 139))
70097	30217226	We find that bi-allelic alterations are infrequent in TCGA but most frequently occur in BRCA1/2 and MMR genes.	('occur', 'Reg', (79, 84))	('TCGA', 'Gene', (54, 58))	('BRCA1/2', 'Gene', (88, 95))	('bi-allelic alterations', 'Var', (13, 35))	('BRCA1/2', 'Gene', '672;675', (88, 95))	('MMR', 'Gene', (100, 103))
70099	30217226	In rare familial cancer, inherited variation can both increase cancer risk and influence the molecular landscape of a tumor.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('increase', 'PosReg', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('influence', 'Reg', (79, 88))	('molecular landscape', 'MPA', (93, 112))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', (17, 23))	('familial cancer', 'Disease', (8, 23))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('inherited variation', 'Var', (25, 44))	('familial cancer', 'Disease', 'MESH:D009369', (8, 23))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
70102	30217226	For example, carriers of pathogenic mutations in BRCA1/2 have both increased cancer risk and molecular evidence of homologous recombination deficiency in their tumors.	('deficiency in their tumors', 'Disease', (140, 166))	('BRCA1/2', 'Gene', '672;675', (49, 56))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (36, 45))	('homologous', 'MPA', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('deficiency in their tumors', 'Disease', 'MESH:D009369', (140, 166))	('BRCA1/2', 'Gene', (49, 56))
70103	30217226	Novel sequencing and analytical methods can be used to reveal a myriad of molecular phenotypes in the tumor, such as mutational signatures, rearrangement signatures, MSI, and infiltrating immune cell content.	('mutational', 'Var', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('rearrangement signatures', 'Var', (140, 164))	('MSI', 'Disease', (166, 169))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
70104	30217226	Rare variants in BRCA1/2 have been associated with mutational signature 3, a novel rearrangement signature, and an overall increased mutational burden.	('rearrangement', 'MPA', (83, 96))	('mutational burden', 'MPA', (133, 150))	('BRCA1/2', 'Gene', '672;675', (17, 24))	('mutational signature 3', 'MPA', (51, 73))	('associated', 'Reg', (35, 45))	('variants', 'Var', (5, 13))	('BRCA1/2', 'Gene', (17, 24))
70105	30217226	Common variants in the APOBEC3 region have been associated with the corresponding APOBEC deficient mutational signature, and a haplotype at the 19p13.3 locus has been associated with somatic mutation of PTEN.	('PTEN', 'Gene', (203, 207))	('PTEN', 'Gene', '5728', (203, 207))	('associated', 'Reg', (48, 58))	('APOBEC3', 'Gene', (23, 30))	('variants', 'Var', (7, 15))	('APOBEC deficient mutational signature', 'MPA', (82, 119))	('associated', 'Reg', (167, 177))
70107	30217226	Taken together, these results demonstrate that both common and rare germline variation can influence the somatic phenotype of sporadic cancers.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('influence', 'Reg', (91, 100))	('germline variation', 'Var', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('sporadic cancers', 'Disease', 'MESH:D009369', (126, 142))	('sporadic cancers', 'Disease', (126, 142))
70108	30217226	Similar to the two-hit mechanism of inactivation of tumor suppressor genes in familial cancer syndromes described by Nordling and then Knudson decades ago, germline and somatic bi-allelic alteration of BRCA1/2 is required to induce somatic mutational signature 3, a single germline "hit" is not sufficient.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('familial cancer syndromes', 'Disease', 'MESH:D009386', (78, 103))	('tumor', 'Disease', (52, 57))	('BRCA1/2', 'Gene', '672;675', (202, 209))	('bi-allelic alteration', 'Var', (177, 198))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('familial cancer syndromes', 'Disease', (78, 103))	('BRCA1/2', 'Gene', (202, 209))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
70111	30217226	In contrast with previous studies of TCGA germline variation that focused on specific cancer types or candidate genes, we performed an exome-wide analysis to identify genes affected by both germline and somatic alterations (referred to as bi-allelic alteration) and study their association with somatic phenotypes.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('alterations', 'Var', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
70112	30217226	Specifically, we conducted an integrated study of all genetic factors that contribute to somatic MSI burden and identified six individuals with characteristics consistent with Lynch syndrome: bi-allelic alteration of a MMR gene, elevated somatic MSI, and an earlier age of cancer diagnosis.	('Lynch syndrome', 'Disease', (176, 190))	('elevated', 'PosReg', (229, 237))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('Lynch syndrome', 'Disease', 'MESH:D003123', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('bi-allelic alteration', 'Var', (192, 213))	('MMR', 'Gene', (219, 222))
70120	30217226	Methylation calls were performed for each gene and each cancer type independently.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('Methylation calls', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
70122	30217226	To determine if methylation calls were associated with reduced somatic gene expression, a linear model of the form log10 (Eij)~Ci + Mij was used, where Eij denotes expression of gene j in tumor i, Ci denotes cancer type of sample i, and Mij denotes binary methylation status of gene j in sample i.	('tumor', 'Disease', (188, 193))	('cancer', 'Disease', (208, 214))	('reduced', 'NegReg', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('methylation calls', 'Var', (16, 33))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
70126	30217226	To identify somatic mutational signatures, counts for each of 96 possible somatic substitutions +- 1 bp context were obtained for all tumor samples.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('substitutions', 'Var', (82, 95))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
70129	30217226	A one-way Fisher's exact test was used to test for an abundance of another alteration of interest in SHPRH methylation positive individuals vs. SHPRH methylation negative individuals.	('SHPRH', 'Gene', '257218', (144, 149))	('SHPRH', 'Gene', (101, 106))	('positive', 'Var', (119, 127))	('methylation positive', 'Var', (107, 127))	('SHPRH', 'Gene', '257218', (101, 106))	('SHPRH', 'Gene', (144, 149))
70133	30217226	Similarly, we repeated the analysis using a less restrictive definition of LOH, referred to as "allelic imbalance" (AI), that accommodates other mechanisms such as copy neutral LOH, subclonal LOH, or intra-tumoral SCNA heterogeneity (see "Methods").	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('imbalance', 'Phenotype', 'HP:0002172', (104, 113))	('intra-tumoral', 'Disease', (200, 213))	('copy neutral', 'Var', (164, 176))	('intra-tumoral', 'Disease', 'MESH:D009369', (200, 213))
70134	30217226	DDR genes were assigned to eight gene sets using pathway information: direct repair, translesion synthesis, mismatch repair, Fanconi anemia, non-homologous end joining, base excision repair, homologous recombination, and nucleotide excision repair.	('Fanconi anemia', 'Disease', (125, 139))	('translesion synthesis', 'MPA', (85, 106))	('non-homologous end joining', 'MPA', (141, 167))	('homologous recombination', 'Var', (191, 215))	('Fanconi anemia', 'Disease', 'MESH:D005199', (125, 139))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (125, 139))	('direct repair', 'MPA', (70, 83))	('base excision repair', 'MPA', (169, 189))	('anemia', 'Phenotype', 'HP:0001903', (133, 139))	('mismatch repair', 'MPA', (108, 123))
70136	30217226	For each gene set and cancer type, we calculated the fraction of individuals with bi-allelic, germline, somatic, or epigenetic alteration of any gene in the gene set (Fig.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('epigenetic alteration', 'Var', (116, 137))	('bi-allelic', 'Var', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
70139	30217226	We discovered associations between breast cancer and germline alteration of the Fanconi anemia and tumor suppressor gene set, which are likely driven by BRCA1/2 germline variants (Additional file 1: Figure S4a).	('tumor', 'Disease', (99, 104))	('associations', 'Interaction', (14, 26))	('Fanconi anemia', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('BRCA1/2', 'Gene', (153, 160))	('Fanconi anemia', 'Disease', 'MESH:D005199', (80, 94))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('variants', 'Var', (170, 178))	('BRCA1/2', 'Gene', '672;675', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('anemia', 'Phenotype', 'HP:0001903', (88, 94))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (80, 94))
70140	30217226	We expanded our analysis to include known pathogenic missense variants from the ClinVar database and discovered additional significant associations between pheochromocytoma and paraganglioma (PCPG) and both the predisposition and oncogene sets (Additional file 1: Figure S4b and Additional file 5: Table S4).	('missense variants', 'Var', (53, 70))	('paraganglioma', 'Disease', (177, 190))	('pheochromocytoma', 'Disease', (156, 172))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (156, 172))	('paraganglioma', 'Disease', 'MESH:D010235', (177, 190))	('pheochromocytoma', 'Disease', 'MESH:D010673', (156, 172))	('paraganglioma', 'Phenotype', 'HP:0002668', (177, 190))
70141	30217226	This association is driven by missense variants in SDHB and RET that predispose to PCPG and have been previously reported in TCGA.	('RET', 'Gene', (60, 63))	('PCPG', 'Disease', (83, 87))	('predispose', 'Reg', (69, 79))	('missense variants', 'Var', (30, 47))	('RET', 'Gene', '5979', (60, 63))	('SDHB', 'Gene', '6390', (51, 55))	('SDHB', 'Gene', (51, 55))
70143	30217226	We conclude that there is no cancer type in TCGA that harbors an excess of damaging germline variants in DDR or cancer-relevant genes, with the exception of the well-described predisposition syndrome genes BRCA1/2, SDHB, and RET.	('RET', 'Gene', (225, 228))	('cancer', 'Disease', (29, 35))	('SDHB', 'Gene', '6390', (215, 219))	('BRCA1/2', 'Gene', '672;675', (206, 213))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SDHB', 'Gene', (215, 219))	('variants', 'Var', (93, 101))	('RET', 'Gene', '5979', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BRCA1/2', 'Gene', (206, 213))	('DDR', 'Gene', (105, 108))
70145	30217226	The remaining individual carried a germline:somatic alteration of MSH5 (Fig.	('MSH5', 'Gene', (66, 70))	('somatic alteration', 'Var', (44, 62))	('MSH5', 'Gene', '4439', (66, 70))
70147	30217226	Four of the germline:somatic alteration carriers have uterine cancer (UCEC) and two have colon cancer (COAD), cancer type characteristic of Lynch syndrome (Fig.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('COAD', 'Disease', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (89, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('uterine cancer', 'Phenotype', 'HP:0010784', (54, 68))	('cancer', 'Disease', (62, 68))	('colon cancer', 'Disease', 'MESH:D015179', (89, 101))	('Lynch syndrome', 'Disease', (140, 154))	('Lynch syndrome', 'Disease', 'MESH:D003123', (140, 154))	('colon cancer', 'Disease', (89, 101))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('alteration', 'Var', (29, 39))
70149	30217226	Using previously published MSI data, we investigated the fraction of microsatellite loci that exhibit instability in the tumor (somatic MSI burden) of individuals carrying alterations in MMR genes.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('MMR', 'Gene', (187, 190))	('tumor', 'Disease', (121, 126))	('alterations', 'Var', (172, 183))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
70150	30217226	Figure 2a shows germline, somatic, and epigenetic alteration status of L-MMR genes for all individuals classified as MSI high (MSI-H) by Hause et al., with bi-allelic mutation carriers grouped to the left.	('epigenetic alteration', 'Var', (39, 60))	('MSI-H', 'Disease', (127, 132))	('MSI-H', 'Disease', 'MESH:D000848', (127, 132))	('L-MMR', 'Gene', (71, 76))
70152	30217226	Using a linear model controlling for cancer type, we found that the 6 individuals with germline:somatic MMR alterations were diagnosed on average 14 years earlier (p = 0.0041) and have 2.8 fold higher somatic MSI (p = 3.95e-15) than individuals with any other type of MMR pathway alteration (Fig.	('higher', 'PosReg', (194, 200))	('MMR', 'Gene', (104, 107))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('somatic MSI', 'CPA', (201, 212))	('alterations', 'Var', (108, 119))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
70153	30217226	Of the five individuals with germline:somatic alteration of a L-MMR gene, four carried a germline LOF variant that is known to be pathogenic for Lynch syndrome, and one carried a LOF variant MSH6 (p.I855fs) not present in ClinVar (Additional file 1: Table S7).	('L-MMR', 'Gene', (62, 67))	('alteration', 'Var', (46, 56))	('Lynch syndrome', 'Disease', (145, 159))	('Lynch syndrome', 'Disease', 'MESH:D003123', (145, 159))	('p.I855fs', 'Var', (197, 205))	('MSH6', 'Gene', (191, 195))	('LOF', 'NegReg', (98, 101))	('variant', 'Var', (102, 109))	('MSH6', 'Gene', '2956', (191, 195))	('p.I855fs', 'Mutation', 'p.I855fsX', (197, 205))
70154	30217226	This frameshift MSH6 VUS is five base pairs upstream of a known pathogenic frameshift variant.	('MSH6', 'Gene', '2956', (16, 20))	('MSH6', 'Gene', (16, 20))	('frameshift', 'Var', (5, 15))	('frameshift variant', 'Var', (75, 93))
70155	30217226	This suggests that disruption of the reading frame in this gene region is pathogenic and the novel MSH6 variant likely also predisposes to Lynch syndrome (Additional file 1: Table S8).	('predisposes', 'Reg', (124, 135))	('disruption', 'Var', (19, 29))	('Lynch syndrome', 'Disease', (139, 153))	('MSH6', 'Gene', '2956', (99, 103))	('Lynch syndrome', 'Disease', 'MESH:D003123', (139, 153))	('MSH6', 'Gene', (99, 103))	('variant', 'Var', (104, 111))
70157	30217226	Interestingly, we observed the identical nonsense mutation in PMS2 (p.R628X) in two individuals, once as an inherited variant and once as an acquired somatic mutation (Additional file 1: Figure S5).	('PMS2', 'Gene', '5395', (62, 66))	('p.R628X', 'Var', (68, 75))	('PMS2', 'Gene', (62, 66))	('p.R628X', 'Mutation', 'rs63750451', (68, 75))
70158	30217226	We expanded our analysis to include missense variants known to be pathogenic for Lynch syndrome from ClinVar.	('missense variants', 'Var', (36, 53))	('Lynch syndrome', 'Disease', 'MESH:D003123', (81, 95))	('Lynch syndrome', 'Disease', (81, 95))
70159	30217226	We identified one individual with bi-allelic alteration of MSH2 involving a pathogenic missense germline variant (p.S554 N) and a somatic LOF mutation (Additional file 1: Table S7).	('pathogenic', 'Reg', (76, 86))	('p.S554 N', 'Var', (114, 122))	('MSH2', 'Gene', (59, 63))	('MSH2', 'Gene', '4436', (59, 63))	('p.S554 N', 'Mutation', 'rs63750597', (114, 122))
70160	30217226	Including missense somatic mutations with a CADD score >= 20 led to the identification of one individual with bi-allelic alteration of PMS2 involving a germline LOF variant (p.R563X) and a secondary somatic missense mutation (Additional file 1: Table S8).	('p.R563X', 'Mutation', 'rs587778618', (174, 181))	('LOF', 'NegReg', (161, 164))	('PMS2', 'Gene', (135, 139))	('p.R563X', 'Var', (174, 181))	('PMS2', 'Gene', '5395', (135, 139))
70161	30217226	We reasoned that the phenotype of elevated somatic MSI and germline:somatic L-MMR mutation could be used to identify germline VUS likely to be pathogenic for Lynch syndrome.	('mutation', 'Var', (82, 90))	('Lynch syndrome', 'Disease', (158, 172))	('Lynch syndrome', 'Disease', 'MESH:D003123', (158, 172))	('L-MMR', 'Gene', (76, 81))
70163	30217226	Three individuals met the criteria of having an MSI-H phenotype and a bi-allelic L-MMR mutation involving a likely damaging missense germline variant.	('missense', 'Var', (124, 132))	('MSI-H', 'Disease', (48, 53))	('L-MMR', 'Gene', (81, 86))	('mutation', 'Var', (87, 95))	('MSI-H', 'Disease', 'MESH:D000848', (48, 53))
70164	30217226	One was the previously identified MSH2 p.S554N variant carrier, the others carried two VUS: MSH2 (p.P616R) and MSH6 (p.F432C) (Additional file 1: Table S8).	('p.S554N variant', 'Var', (39, 54))	('MSH2', 'Gene', (92, 96))	('p.P616R', 'Mutation', 'rs587779965', (98, 105))	('p.S554N', 'Mutation', 'rs63750597', (39, 46))	('MSH2', 'Gene', '4436', (92, 96))	('MSH6', 'Gene', (111, 115))	('MSH2', 'Gene', (34, 38))	('MSH2', 'Gene', '4436', (34, 38))	('p.F432C', 'Var', (117, 124))	('MSH6', 'Gene', '2956', (111, 115))	('p.P616R', 'Var', (98, 105))	('p.F432C', 'Mutation', 'rs750528093', (117, 124))
70165	30217226	Closer investigation of the MSH6 p.F432C variant showed that other amino acid substitutions at the same residue were classified as pathogenic in ClinVar (Additional file 1: Table S8).	('pathogenic', 'Reg', (131, 141))	('ClinVar', 'Disease', (145, 152))	('MSH6', 'Gene', (28, 32))	('p.F432C', 'Var', (33, 40))	('p.F432C', 'Mutation', 'rs750528093', (33, 40))	('MSH6', 'Gene', '2956', (28, 32))
70167	30217226	The individual carrying the MSH6 p.F432C variant was diagnosed earlier than average (Z = - 1.03) while the individual carrying the MSH2 p.P616R variant was diagnosed later (Z = 1.20).	('p.F432C', 'Var', (33, 40))	('MSH6', 'Gene', (28, 32))	('p.F432C', 'Mutation', 'rs750528093', (33, 40))	('p.P616R', 'Mutation', 'rs587779965', (136, 143))	('MSH6', 'Gene', '2956', (28, 32))	('MSH2', 'Gene', (131, 135))	('MSH2', 'Gene', '4436', (131, 135))
70168	30217226	Age of diagnosis cannot be used alone to classify a variant; however, this evidence suggests that MSH2 p.P616R may not be pathogenic.	('MSH2', 'Gene', (98, 102))	('p.P616R', 'Var', (103, 110))	('MSH2', 'Gene', '4436', (98, 102))	('p.P616R', 'Mutation', 'rs587779965', (103, 110))
70169	30217226	While validation is required to confirm pathogenicity of this variant as well as the previously mentioned MSH6 p.I855fs, we offer evidence that these variants may predispose to Lynch syndrome, as well as show evidence suggesting that MSH2 p.P616R may be benign.	('variants', 'Var', (150, 158))	('MSH6', 'Gene', '2956', (106, 110))	('MSH2', 'Gene', (234, 238))	('predispose', 'Reg', (163, 173))	('Lynch syndrome', 'Disease', (177, 191))	('MSH2', 'Gene', '4436', (234, 238))	('Lynch syndrome', 'Disease', 'MESH:D003123', (177, 191))	('MSH6', 'Gene', (106, 110))	('p.I855fs', 'Mutation', 'p.I855fsX', (111, 119))	('p.P616R', 'Var', (239, 246))	('p.P616R', 'Mutation', 'rs587779965', (239, 246))
70170	30217226	Taken together, we have identified ten individuals with germline:somatic MMR alterations, six of which carry a germline variant that is known to be pathogenic for Lynch syndrome (Table 1).	('MMR', 'Gene', (73, 76))	('pathogenic', 'Reg', (148, 158))	('Lynch syndrome', 'Disease', (163, 177))	('alterations', 'Var', (77, 88))	('Lynch syndrome', 'Disease', 'MESH:D003123', (163, 177))	('variant', 'Var', (120, 127))
70171	30217226	We found that both Bi-LOF (p = 2.78e-15) and Bi-Miss (p = 1.01e-10) groups have significantly elevated MSI (Fig.	('Bi-Miss', 'Var', (45, 52))	('elevated MSI', 'Disease', 'MESH:D006937', (94, 106))	('elevated MSI', 'Disease', (94, 106))
70174	30217226	Having shown that combined germline LOF and missense somatic mutations are sufficient to cause elevated MSI, we hypothesized that damaging germline variation in the absence of somatic mutation could also increase somatic MSI.	('LOF', 'NegReg', (36, 39))	('elevated MSI', 'Disease', (95, 107))	('increase', 'PosReg', (204, 212))	('somatic MSI', 'CPA', (213, 224))	('elevated MSI', 'Disease', 'MESH:D006937', (95, 107))	('missense', 'Var', (44, 52))
70175	30217226	There were no significant association between damaging germline variation in the MMR pathway and somatic MSI burden (Additional file 1: Figure S7 and Table S12).	('somatic MSI burden', 'CPA', (97, 115))	('S12', 'Gene', '6268', (156, 159))	('germline variation', 'Var', (55, 73))	('S12', 'Gene', (156, 159))	('MMR pathway', 'Pathway', (81, 92))
70176	30217226	Known variants showed the strongest effect (0.02 fold increase in MSI burden), and this was largely driven by MLH3 p.V741F, a variant with conflicting reports of pathogenicity that is carried by 195 individuals.	('increase', 'PosReg', (54, 62))	('MLH3', 'Gene', '27030', (110, 114))	('MLH3', 'Gene', (110, 114))	('p.V741F', 'Mutation', 'rs28756990', (115, 122))	('p.V741F', 'Var', (115, 122))
70179	30217226	In addition, we discovered a novel association between methylation of SHPRH and elevated somatic MSI (p = 1.19e-16) (Fig.	('elevated', 'PosReg', (80, 88))	('SHPRH', 'Gene', '257218', (70, 75))	('somatic MSI', 'CPA', (89, 100))	('methylation', 'Var', (55, 66))	('SHPRH', 'Gene', (70, 75))
70181	30217226	Methylation of SHPRH was associated with a 16% decrease in gene expression in a pan-cancer analysis (Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('SHPRH', 'Gene', (15, 20))	('Methylation', 'Var', (0, 11))	('decrease', 'NegReg', (47, 55))	('gene expression', 'MPA', (59, 74))	('SHPRH', 'Gene', '257218', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
70182	30217226	We observed that methylation of SHPRH has the strongest effect both on SHPRH expression and somatic MSI burden in uterine cancer (Fig.	('expression', 'MPA', (77, 87))	('SHPRH', 'Gene', (32, 37))	('SHPRH', 'Gene', (71, 76))	('effect', 'Reg', (56, 62))	('cancer', 'Disease', (122, 128))	('methylation', 'Var', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('SHPRH', 'Gene', '257218', (71, 76))	('uterine cancer', 'Phenotype', 'HP:0010784', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SHPRH', 'Gene', '257218', (32, 37))
70184	30217226	Methylation of MLH1 and SHPRH are both associated with mutational signature 6, with a stronger association in uterine cancer (Additional file 1: Figure S11).	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutational', 'Var', (55, 65))	('uterine cancer', 'Phenotype', 'HP:0010784', (110, 124))	('S11', 'Gene', '6267', (152, 155))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('S11', 'Gene', (152, 155))	('associated', 'Reg', (39, 49))	('SHPRH', 'Gene', '257218', (24, 29))	('SHPRH', 'Gene', (24, 29))	('MLH1', 'Gene', '4292', (15, 19))	('MLH1', 'Gene', (15, 19))
70187	30217226	Furthermore, we found a significant, albeit weaker, association between somatic expression of SHPRH and MSI burden, indicating that SHPRH methylation likely affects MSI burden via silencing of SHPRH (Additional file 1: Table S15).	('silencing', 'NegReg', (180, 189))	('SHPRH', 'Gene', (94, 99))	('SHPRH', 'Gene', '257218', (193, 198))	('SHPRH', 'Gene', (193, 198))	('SHPRH', 'Gene', (132, 137))	('S15', 'Gene', (225, 228))	('affects', 'Reg', (157, 164))	('SHPRH', 'Gene', '257218', (94, 99))	('MSI burden', 'MPA', (165, 175))	('SHPRH', 'Gene', '257218', (132, 137))	('methylation', 'Var', (138, 149))	('S15', 'Gene', '6209', (225, 228))
70188	30217226	We hypothesized that mono- or bi-allelic alterations in other DDR pathways may also be associated with known mutational signatures, as has been demonstrated between bi-allelic alteration of BRCA1/2 and mutational signature 3.	('DDR pathways', 'Pathway', (62, 74))	('bi-allelic alterations', 'Var', (30, 52))	('associated', 'Reg', (87, 97))	('BRCA1/2', 'Gene', (190, 197))	('mono-', 'Var', (21, 26))	('BRCA1/2', 'Gene', '672;675', (190, 197))
70189	30217226	We first attempted to replicate the BRCA1/2 association, but surprisingly found high levels of mutational signature 3 in individuals carrying mono-allelic damaging germline BRCA1/2 variation.	('variation', 'Var', (181, 190))	('BRCA1/2', 'Gene', (173, 180))	('BRCA1/2', 'Gene', (36, 43))	('BRCA1/2', 'Gene', '672;675', (173, 180))	('BRCA1/2', 'Gene', '672;675', (36, 43))
70190	30217226	However, when we considered AI events to be bi-allelic alterations, we no longer found a significant association between mono-allelic BRCA1/2 alterations and somatic mutational signature 3 (Additional file 1: Figure S13 and Additional file 6: Table S16).	('alterations', 'Var', (142, 153))	('BRCA1/2', 'Gene', (134, 141))	('S16', 'Gene', (249, 252))	('S16', 'Gene', '6217', (249, 252))	('BRCA1/2', 'Gene', '672;675', (134, 141))
70192	30217226	We next tested for association between 30 somatic mutational signatures from COSMIC and germline bi-allelic alteration in six DDR pathways with more than five individuals carrying bi-allelic alteration (FA, MMR, HR, BER, NHEJ, and TLS) (Additional file 1: Figure S14a).	('tested', 'Reg', (8, 14))	('S14', 'Gene', (263, 266))	('S14', 'Gene', '6208', (263, 266))	('bi-allelic alteration', 'Var', (97, 118))	('TLS', 'Gene', (231, 234))	('TLS', 'Gene', '2521', (231, 234))	('DDR pathways', 'Pathway', (126, 138))
70193	30217226	The only significant association uncovered (FDR < 15%) was between Fanconi anemia and signature 3, which was driven by the known association between BRCA1/2 alterations and signature 3.	('BRCA1/2', 'Gene', (149, 156))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (67, 81))	('Fanconi anemia', 'Disease', (67, 81))	('alterations', 'Var', (157, 168))	('BRCA1/2', 'Gene', '672;675', (149, 156))	('Fanconi anemia', 'Disease', 'MESH:D005199', (67, 81))	('anemia', 'Phenotype', 'HP:0001903', (75, 81))	('signature 3', 'Gene', (86, 97))
70194	30217226	We repeated this analysis expanding to include individuals with mono-allelic germline alteration in DDR pathways and found no significant associations (Additional file 1: Figure S14b).	('germline alteration', 'Var', (77, 96))	('S14', 'Gene', (178, 181))	('DDR pathways', 'Pathway', (100, 112))	('S14', 'Gene', '6208', (178, 181))
70196	30217226	Known pathogenic variation in SDHB/RET, BRCA1/2, and MMR genes is thought to be responsible for a subset of pheochromocytoma and paraganglioma, breast, ovarian, colon, and uterine cancers in TCGA.	('pheochromocytoma', 'Disease', 'MESH:D010673', (108, 124))	('RET', 'Gene', (35, 38))	('pheochromocytoma', 'Disease', (108, 124))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (108, 124))	('BRCA1/2', 'Gene', (40, 47))	('SDHB', 'Gene', '6390', (30, 34))	('MMR', 'Gene', (53, 56))	('paraganglioma, breast, ovarian, colon', 'Disease', 'MESH:D061325', (129, 166))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SDHB', 'Gene', (30, 34))	('BRCA1/2', 'Gene', '672;675', (40, 47))	('responsible', 'Reg', (80, 91))	('paraganglioma', 'Phenotype', 'HP:0002668', (129, 142))	('uterine cancer', 'Phenotype', 'HP:0010784', (172, 186))	('RET', 'Gene', '5979', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', (180, 187))	('variation', 'Var', (17, 26))	('uterine cancers', 'Phenotype', 'HP:0010784', (172, 187))
70197	30217226	Another relatively common cancer syndrome that predisposes to cancer types found in TCGA is Li-Fraumeni syndrome (LFS), which arises due to inherited variation in TP53.	('variation', 'Var', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('TCGA', 'Gene', (84, 88))	('TP53', 'Gene', '7157', (163, 167))	('cancer syndrome', 'Disease', 'MESH:D009369', (26, 41))	('cancer syndrome', 'Disease', (26, 41))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (92, 112))	('TP53', 'Gene', (163, 167))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Li-Fraumeni syndrome', 'Disease', (92, 112))
70198	30217226	Using the IARC-TP53 variant database, we identified 38 individuals carrying a potential LFS variant (Additional file 5: Table S4).	('LFS', 'Gene', (88, 91))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('variant', 'Var', (92, 99))
70199	30217226	Interestingly, aside from bi-allelic MMR alteration, we observed that pathogenic germline variation in cancer predisposition genes was not associated with an earlier age of diagnosis in 8913 individuals with both germline and age of diagnosis data available.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('variation', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
70200	30217226	To explore this further, we divided individuals into two groups: those who developed the cancer type expected given the predisposition gene altered and those with another cancer type.	('altered', 'Var', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
70201	30217226	Using this approach, we found significant associations between germline alteration status and age of diagnosis for the expected cancer type (Fig.	('germline', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (128, 134))
70204	30217226	To determine if damaging germline variation in other predisposition genes was associated with earlier age of diagnosis, we examined 75 cancer predisposition genes not included in the previous analysis.	('associated', 'Reg', (78, 88))	('cancer', 'Disease', (135, 141))	('germline variation', 'Var', (25, 43))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
70208	30217226	However, we believe much of the variation in age of diagnosis due to germline variation lies in genes associated with prevalent cancer predisposition syndromes.	('germline variation', 'Var', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (128, 134))
70210	30217226	To our knowledge, our study is the first exome-wide analysis of the prevalence of bi-allelic alterations across the full spectrum of cancer types represented in TCGA and one of the first to integrate somatic methylation data for a large number of genes.	('TCGA', 'Disease', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('bi-allelic alterations', 'Var', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
70211	30217226	While a diagnosis of Lynch syndrome cannot be made without a family history, we identified ten individuals with bi-allelic alteration in an MMR gene, elevated somatic MSI burden, and, in individuals with bi-allelic LOF mutations, earlier age of cancer diagnosis.	('Lynch syndrome', 'Disease', 'MESH:D003123', (21, 35))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('MMR gene', 'Gene', (140, 148))	('cancer', 'Disease', (245, 251))	('elevated', 'PosReg', (150, 158))	('bi-allelic alteration', 'Var', (112, 133))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('somatic MSI burden', 'CPA', (159, 177))	('Lynch syndrome', 'Disease', (21, 35))
70212	30217226	The genes harboring bi-allelic alterations by our analyses are predominantly those that are less frequently mutated in Lynch syndrome: MSH6 and PMS2.	('Lynch syndrome', 'Disease', 'MESH:D003123', (119, 133))	('PMS2', 'Gene', (144, 148))	('MSH6', 'Gene', (135, 139))	('PMS2', 'Gene', '5395', (144, 148))	('bi-allelic', 'Var', (20, 30))	('Lynch syndrome', 'Disease', (119, 133))	('MSH6', 'Gene', '2956', (135, 139))
70215	30217226	The median age of cancer onset in TCGA is 60; thus, the individuals in TCGA carrying cancer predisposing variants may have genetic modifier mechanisms that delay cancer onset and severity.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('TCGA', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (85, 91))	('delay cancer', 'Disease', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('variants', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('delay cancer', 'Disease', 'MESH:D009369', (156, 168))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
70216	30217226	Interestingly, proposed mechanisms of genetic compensation delaying cancer onset have been described previously both for Lynch syndrome and Li-Fraumeni syndrome.	('genetic compensation', 'Var', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Lynch syndrome', 'Disease', (121, 135))	('Li-Fraumeni syndrome', 'Disease', (140, 160))	('Lynch syndrome', 'Disease', 'MESH:D003123', (121, 135))	('delaying', 'NegReg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (140, 160))
70218	30217226	This observation is consistent with the previously proposed idea that bi-allelic MMR mutation is likely not the tumor-initiating event but instead acts to accelerate tumor growth (Fig.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('MMR', 'Gene', (81, 84))	('tumor', 'Disease', (166, 171))	('mutation', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('accelerate', 'PosReg', (155, 165))	('tumor', 'Disease', (112, 117))	('bi-allelic', 'Var', (70, 80))
70219	30217226	Given our observations, we propose that the less damaging Bi-Miss mutations could lead to slower tumor growth than Bi-LOF mutations.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('Bi-Miss mutations', 'Var', (58, 75))	('slower', 'NegReg', (90, 96))
70220	30217226	demonstrated that somatic mutational signature 3 and BRCA1/2 LOH bi-allelic inactivation could be used to reclassify BRCA1/2 germline variants that were previously considered VUS.	('BRCA1/2', 'Gene', (117, 124))	('variants', 'Var', (134, 142))	('BRCA1/2 LOH', 'Gene', (53, 64))	('BRCA1/2', 'Gene', (53, 60))	('BRCA1/2', 'Gene', '672;675', (117, 124))	('BRCA1/2', 'Gene', '672;675', (53, 60))	('BRCA1/2 LOH', 'Gene', '672', (53, 64))
70221	30217226	We identify two novel potentially damaging Lynch syndrome variants in MSH6.	('variants', 'Var', (58, 66))	('MSH6', 'Gene', (70, 74))	('Lynch syndrome', 'Disease', (43, 57))	('MSH6', 'Gene', '2956', (70, 74))	('damaging', 'Reg', (34, 42))	('Lynch syndrome', 'Disease', 'MESH:D003123', (43, 57))
70222	30217226	Of note, the ClinVar pathogenic Lynch predisposing MSH2 variant was not present in the ANNOVAR ClinVar database despite being reported in ClinVar, highlighting the importance of manual curation of potentially pathogenic variants.	('MSH2', 'Gene', (51, 55))	('variant', 'Var', (56, 63))	('MSH2', 'Gene', '4436', (51, 55))
70223	30217226	Germline MMR variants can be used to guide therapy and monitoring for patients at risk.	('variants', 'Var', (13, 21))	('patients', 'Species', '9606', (70, 78))	('MMR', 'Gene', (9, 12))
70224	30217226	For example, the risk of colorectal cancer can be reduced in individuals carrying pathogenic germline MMR variants using a daily aspirin regimen.	('aspirin', 'Chemical', 'MESH:D001241', (129, 136))	('variants', 'Var', (106, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (25, 42))	('colorectal cancer', 'Disease', (25, 42))	('reduced', 'NegReg', (50, 57))	('MMR', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (25, 42))
70225	30217226	Distinguishing between sporadic cancer and cancer driven by inherited variation is important both for treatment of the individual as well as for informing relatives who may carry the same inherited predisposition.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (32, 38))	('sporadic cancer', 'Disease', 'MESH:D009369', (23, 38))	('variation', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('sporadic cancer', 'Disease', (23, 38))
70226	30217226	The novel variants we discovered could increase the knowledge base of variants that predispose to cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('variants', 'Var', (10, 18))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('variants', 'Var', (70, 78))	('cancer', 'Disease', (98, 104))
70227	30217226	Despite these constraints, we successfully identified a novel association between methylation of SHPRH and somatic MSI burden, with a particularly strong effect in uterine cancer where SHPRH methylated individuals exhibit a 2.4 fold increase in somatic MSI burden.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('methylation', 'Var', (82, 93))	('somatic MSI burden', 'MPA', (107, 125))	('SHPRH', 'Gene', '257218', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('SHPRH', 'Gene', '257218', (185, 190))	('SHPRH', 'Gene', (185, 190))	('somatic', 'CPA', (245, 252))	('cancer', 'Disease', (172, 178))	('increase', 'PosReg', (233, 241))	('uterine cancer', 'Phenotype', 'HP:0010784', (164, 178))	('SHPRH', 'Gene', (97, 102))	('methylated', 'Var', (191, 201))
70229	30217226	Knockdown of SHPRH in yeast has previously been shown to increase DNA breaks and genomic instability.	('Knockdown', 'Var', (0, 9))	('yeast', 'Species', '4932', (22, 27))	('SHPRH', 'Gene', (13, 18))	('genomic instability', 'CPA', (81, 100))	('increase', 'PosReg', (57, 65))	('SHPRH', 'Gene', '257218', (13, 18))	('DNA breaks', 'CPA', (66, 76))
70232	30217226	We illustrate how differences in LOH calling methodology for germline BRCA1/2 variants can lead to conflicting conclusions about the frequency of bi-allelic alteration (Additional file 1: Figure S13).	('BRCA1/2', 'Gene', '672;675', (70, 77))	('lead to', 'Reg', (91, 98))	('BRCA1/2', 'Gene', (70, 77))	('variants', 'Var', (78, 86))
70234	30217226	In addition to individuals with potential Lynch syndrome, we identified individuals who carry germline variants that reportedly predispose to Li-Fraumeni spectrum cancers as well as pheochromocytoma and paraganglioma.	('Lynch syndrome', 'Disease', 'MESH:D003123', (42, 56))	('predispose', 'Reg', (128, 138))	('paraganglioma', 'Phenotype', 'HP:0002668', (203, 216))	('Li-Fraumeni spectrum cancers', 'Disease', (142, 170))	('paraganglioma', 'Disease', 'MESH:D010235', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('variants', 'Var', (103, 111))	('pheochromocytoma', 'Disease', (182, 198))	('paraganglioma', 'Disease', (203, 216))	('Li-Fraumeni spectrum cancers', 'Disease', 'MESH:D016864', (142, 170))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (182, 198))	('Lynch syndrome', 'Disease', (42, 56))	('pheochromocytoma', 'Disease', 'MESH:D010673', (182, 198))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
70237	30217226	This confirms the variable penetrance of some variants associated with predisposition syndromes: a variant can predispose to one cancer type but have no significant effect on the course of disease of another cancer type.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (208, 214))	('predispose', 'Reg', (111, 121))	('variant', 'Var', (99, 106))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
70238	30217226	Some individuals with an inherited predisposition variant will not acquire the cancer type they are predisposed toward, but "bad luck" or environmental exposures will lead them to develop a sporadic cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('variant', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('sporadic cancer', 'Disease', 'MESH:D009369', (190, 205))	('develop', 'PosReg', (180, 187))	('cancer', 'Disease', (199, 205))	('sporadic cancer', 'Disease', (190, 205))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
70239	30217226	We later showed that germline variation in known cancer predisposition genes only led to an earlier age of diagnosis only in a subset of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('germline variation', 'Var', (21, 39))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
70240	30217226	From these observations, we conclude that germline variation has the ability to influence both somatic phenotypes and cancer development, but often, this ability is dependent on other somatic alterations or tissue type-specific processes.	('cancer', 'Disease', (118, 124))	('somatic phenotypes', 'CPA', (95, 113))	('germline variation', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('influence', 'Reg', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
70250	29504908	Exome analysis of 52 CBTs revealed potential driver mutations (PDMs) in 21 genes: ARNT, BAP1, BRAF, BRCA1, BRCA2, CDKN2A, CSDE1, FGFR3, IDH1, KIF1B, KMT2D, MEN1, RET, SDHA, SDHB, SDHC, SDHD, SETD2, TP53BP1, TP53BP2, and TP53I13.	('KMT2D', 'Gene', '8085', (149, 154))	('BRCA1', 'Gene', '672', (100, 105))	('BRCA2', 'Gene', '675', (107, 112))	('BRCA1', 'Gene', (100, 105))	('IDH1', 'Gene', (136, 140))	('TP53BP2', 'Gene', (207, 214))	('SDHD', 'Gene', (185, 189))	('RET', 'Gene', (162, 165))	('BAP1', 'Gene', (88, 92))	('CDKN2A', 'Gene', (114, 120))	('SDHA', 'Gene', (167, 171))	('CSDE1', 'Gene', '7812', (122, 127))	('TP53I13', 'Gene', '90313', (220, 227))	('SDHC', 'Gene', (179, 183))	('SDHB', 'Gene', '6390', (173, 177))	('SDHA', 'Gene', '6389', (167, 171))	('TP53BP1', 'Gene', '7158', (198, 205))	('KIF1B', 'Gene', (142, 147))	('MEN1', 'Gene', '4221', (156, 160))	('IDH1', 'Gene', '3417', (136, 140))	('BRAF', 'Gene', '673', (94, 98))	('CBTs', 'Phenotype', 'HP:0002668', (21, 25))	('FGFR3', 'Gene', (129, 134))	('BRAF', 'Gene', (94, 98))	('KMT2D', 'Gene', (149, 154))	('CDKN2A', 'Gene', '1029', (114, 120))	('TP53BP1', 'Gene', (198, 205))	('SETD2', 'Gene', (191, 196))	('MEN1', 'Gene', (156, 160))	('TP53BP2', 'Gene', '7159', (207, 214))	('SDHB', 'Gene', (173, 177))	('ARNT', 'Gene', '405', (82, 86))	('FGFR3', 'Gene', '2261', (129, 134))	('BRCA2', 'Gene', (107, 112))	('ARNT', 'Gene', (82, 86))	('mutations', 'Var', (52, 61))	('SETD2', 'Gene', '29072', (191, 196))	('SDHC', 'Gene', '6391', (179, 183))	('KIF1B', 'Gene', '23095', (142, 147))	('RET', 'Gene', '5979', (162, 165))	('BAP1', 'Gene', '8314', (88, 92))	('SDHD', 'Gene', '6392', (185, 189))	('TP53I13', 'Gene', (220, 227))	('CSDE1', 'Gene', (122, 127))
70251	29504908	Exome analysis of 52 CBTs for the first time revealed the average mutation load for these tumors and also identified potential driver mutations as well as their frequencies and co-occurrence with the other PDMs.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mutation', 'Var', (66, 74))	('mutations', 'Var', (134, 143))	('CBTs', 'Phenotype', 'HP:0002668', (21, 25))
70261	29504908	The majority of these familial paraganglioma syndromes are due to mutations in genes encoding distinctive subunits of the mitochondrial succinate dehydrogenase (SDH) complex.	('mutations', 'Var', (66, 75))	('succinate dehydrogenase', 'Gene', (136, 159))	('familial paraganglioma syndromes', 'Disease', 'MESH:D010235', (22, 54))	('SDH', 'Gene', (161, 164))	('familial paraganglioma syndromes', 'Disease', (22, 54))	('paraganglioma', 'Phenotype', 'HP:0002668', (31, 44))	('due', 'Reg', (59, 62))	('succinate dehydrogenase', 'Gene', '6390', (136, 159))	('SDH', 'Gene', '6390', (161, 164))
70263	29504908	Besides, somatic mutations in more than 30 causative genes are described as drivers for paragangliomas.	('paragangliomas', 'Disease', (88, 102))	('paraganglioma', 'Phenotype', 'HP:0002668', (88, 101))	('paragangliomas', 'Phenotype', 'HP:0002668', (88, 102))	('paragangliomas', 'Disease', 'MESH:D010235', (88, 102))	('somatic mutations', 'Var', (9, 26))
70269	29504908	In some of them, a part of somatic mutations is generated by exposures such as tobacco smoking in lung cancer and ultraviolet light in cutaneous melanoma, or by abnormalities of DNA maintenance as a defective DNA mismatch repair in some colorectal tumors.	('colorectal tumors', 'Disease', 'MESH:D015179', (237, 254))	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cutaneous melanoma', 'Disease', (135, 153))	('lung cancer', 'Disease', (98, 109))	('colorectal tumors', 'Disease', (237, 254))	('DNA', 'MPA', (209, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (135, 153))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (135, 153))	('tobacco', 'Species', '4097', (79, 86))	('defective', 'NegReg', (199, 208))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('abnormalities', 'Var', (161, 174))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutations', 'Var', (35, 44))
70271	29504908	Variant filtering by frequency in healthy population can be used to exclude potentially germline mutations in absence of non-tumor tissue.	('non-tumor', 'Disease', 'MESH:D009369', (121, 130))	('non-tumor', 'Disease', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Variant', 'Var', (0, 7))
70272	29504908	It was recently observed that the samples with high mutation load among the other samples in the same cancer type are more sensitive to immunotherapy, which can be very promising for tumor treatment.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('sensitive', 'Reg', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Disease', (102, 108))	('high mutation load', 'Var', (47, 65))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', (183, 188))
70279	29504908	Databases dbSNP, dbNSFP, ClinVar, MutationTaster, SIFT, PolyPhen-2, FATHMM, phastCons, PhyloP, 1000 Genomes Project, ExAC, COSMIC, GO, ConsensusPathDB, and OMIM were used as information resources for identified variants.	('SIFT', 'Disease', 'None', (50, 54))	('variants', 'Var', (211, 219))	('SIFT', 'Disease', (50, 54))
70286	29504908	Mutations in genes encoding succinate dehydrogenase (SDH) subunits can cause pseudohypoxic state in PGLs and PCC.	('SDH', 'Gene', (53, 56))	('cause', 'Reg', (71, 76))	('PGLs', 'Phenotype', 'HP:0002668', (100, 104))	('succinate dehydrogenase', 'Gene', '6390', (28, 51))	('SDH', 'Gene', '6390', (53, 56))	('Mutations', 'Var', (0, 9))	('PCC', 'Phenotype', 'HP:0002666', (109, 112))	('succinate dehydrogenase', 'Gene', (28, 51))	('pseudohypoxic state', 'MPA', (77, 96))
70291	29504908	Therefore, a mutation in any of these genes, collectively termed SDHx genes, would impair the structure of the entire complex leading to oncogenesis.	('oncogenesis', 'CPA', (137, 148))	('mutation', 'Var', (13, 21))	('impair', 'NegReg', (83, 89))	('SDHx', 'Chemical', '-', (65, 69))	('structure', 'MPA', (94, 103))
70292	29504908	Generally, germline mutations in the SDHx genes lead to heritable PGLs, PCC, and other tumors.	('PCC', 'Phenotype', 'HP:0002666', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('PCC', 'Disease', (72, 75))	('SDHx', 'Chemical', '-', (37, 41))	('SDHx', 'Gene', (37, 41))	('PGLs', 'Disease', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PGLs', 'Phenotype', 'HP:0002668', (66, 70))	('germline mutations', 'Var', (11, 29))	('tumors', 'Disease', (87, 93))	('lead to', 'Reg', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
70293	29504908	Only one potential driver missense mutation NM_004168: c.792C > A, p.(Phe264Leu) (chr5:231,012) was identified in SDHA gene.	('p.(Phe264Leu)', 'Mutation', 'rs1237513803', (67, 80))	('SDHA', 'Gene', '6389', (114, 118))	('NM_004168: c.792C > A', 'Mutation', 'rs1448872185', (44, 65))	('SDHA', 'Gene', (114, 118))	('c.792C > A', 'Var', (55, 65))
70295	29504908	PDM NM_003000: c.541-2A > G (chr1:17,350,571, rs786201161) is located in splice-site described in ClinVar as germline mutation with pathogenic or probably pathogenic clinical significance.	('rs786201161', 'Mutation', 'rs786201161', (46, 57))	('rs786201161', 'Var', (46, 57))	('c.541-2A > G', 'Var', (15, 27))	('NM_003000: c.541-2A > G', 'Mutation', 'rs786201161', (4, 27))
70297	29504908	A mutation NM_003000: c.724C > T, p.(Arg242Cys) (chr1:17,349,144, rs786203251) is deposited as germline pathogenic one and described as a risk factor for PGLs, PCC, and hereditary gastro-intestinal stromal tumor.	('PGLs', 'Disease', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('rs786203251', 'Mutation', 'rs786203251', (66, 77))	('PCC', 'Disease', (160, 163))	('p.(Arg242Cys)', 'Mutation', 'rs786203251', (34, 47))	('PGLs', 'Phenotype', 'HP:0002668', (154, 158))	('PCC', 'Phenotype', 'HP:0002666', (160, 163))	('NM_003000: c.724C > T', 'Mutation', 'rs786203251', (11, 32))	('intestinal stromal tumor', 'Phenotype', 'HP:0100723', (187, 211))	('hereditary gastro-intestinal stromal tumor', 'Disease', 'MESH:D007414', (169, 211))	('rs786203251', 'Var', (66, 77))	('hereditary gastro-intestinal stromal tumor', 'Disease', (169, 211))
70298	29504908	A mutation NM_003000: c.763A > T, p.(Lys255*) (chr1:17,349,105) is included only in Ensembl database.	('NM_003000: c.763A > T', 'Mutation', 'rs184765949', (11, 32))	('p.(Lys255*', 'Var', (34, 44))	('p.(Lys255*)', 'SUBSTITUTION', 'None', (34, 45))	('c.763A > T', 'Var', (22, 32))
70299	29504908	Two mutations, NM_003000: c.233A > G, p.(Lys78Arg) (chr1:17,359,608, rs774960237) and NM_003000: c.763A > T, p.(Lys255*) (chr1:17,349,105), do not have description of clinical effect in databases.	('c.233A > G', 'Var', (26, 36))	('p.(Lys255*', 'Var', (109, 119))	('p.(Lys78Arg)', 'SUBSTITUTION', 'None', (38, 50))	('NM_003000: c.233A > G', 'Mutation', 'rs774960237', (15, 36))	('rs774960237', 'Mutation', 'rs774960237', (69, 80))	('NM_003000: c.763A > T', 'Mutation', 'rs184765949', (86, 107))	('p.(Lys78Arg', 'Var', (38, 49))	('p.(Lys255*)', 'SUBSTITUTION', 'None', (109, 120))	('rs774960237', 'Var', (69, 80))	('NM_003000: c.763A > T', 'Var', (86, 107))
70300	29504908	4), only the SDHB mutation c.763A > T was identified among selected genes of interest.	('c.763A > T', 'Var', (27, 37))	('SDHB', 'Gene', '6390', (13, 17))	('c.763A > T', 'Mutation', 'rs184765949', (27, 37))	('SDHB', 'Gene', (13, 17))
70304	29504908	In sample "Pat31", it co-occurs with PDMs in IDH1 and TP53I13 genes and probably acts as the initial driver which needs to be activated with other pathogenic influences such as additional somatic mutations.	('IDH1', 'Gene', '3417', (45, 49))	('PDMs', 'Var', (37, 41))	('TP53I13', 'Gene', (54, 61))	('TP53I13', 'Gene', '90313', (54, 61))	('IDH1', 'Gene', (45, 49))
70305	29504908	We identified three samples with SDHC mutations, one of them contained two different PDMs, NM_003001: c.224G > A, p.(Gly75Asp) (chr1: 161,310,428, rs786205147) and NM_003001: c.7G > A, p.(Ala3Thr) (chr1:161,284,202, rs748243732).	('SDHC', 'Gene', '6391', (33, 37))	('NM_003001: c.224G > A', 'Mutation', 'rs786205147', (91, 112))	('NM_003001: c.7G > A', 'Mutation', 'rs748243732', (164, 183))	('NM_003001: c.7G > A', 'Var', (164, 183))	('p.(Ala3Thr)', 'Mutation', 'rs748243732', (185, 196))	('rs786205147', 'Mutation', 'rs786205147', (147, 158))	('rs748243732', 'Mutation', 'rs748243732', (216, 227))	('p.(Gly75Asp)', 'Mutation', 'rs786205147', (114, 126))	('rs786205147', 'Var', (147, 158))	('mutations', 'Var', (38, 47))	('SDHC', 'Gene', (33, 37))	('rs748243732', 'Var', (216, 227))
70306	29504908	PDM c.224G > A is described in dbSNP as germline mutation, and it is indicated in ClinVar as probably pathogenic one, because it was found as a rare single nucleotide variant (SNV) in patient with Karney's triad (it seems to be a sporadic disease).	('c.224G > A', 'Mutation', 'rs786205147', (4, 14))	("Karney's triad", 'Disease', (197, 211))	('patient', 'Species', '9606', (184, 191))	('PDM c.224G > A', 'Var', (0, 14))
70307	29504908	PDM c.7G > A was described as a rare germline mutation with unknown clinical significance in gastro-intestinal stromal tumors and PGLs.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('gastro-intestinal stromal tumors', 'Disease', 'MESH:D046152', (93, 125))	('PGLs', 'Phenotype', 'HP:0002668', (130, 134))	('intestinal stromal tumors', 'Phenotype', 'HP:0100723', (100, 125))	('PDM c.7G > A', 'Var', (0, 12))	('c.7G > A', 'Mutation', 'rs748243732', (4, 12))	('intestinal stromal tumor', 'Phenotype', 'HP:0100723', (100, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gastro-intestinal stromal tumors', 'Disease', (93, 125))	('PGLs', 'Disease', (130, 134))
70309	29504908	Therefore, we can suggest that patient has non-highly pathogenic mutations in both copies of SDHB or in the same copy that caused cumulative effect and became the reason for tumor growth.	('tumor', 'Disease', (174, 179))	('SDHB', 'Gene', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('patient', 'Species', '9606', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('SDHB', 'Gene', '6390', (93, 97))	('mutations', 'Var', (65, 74))
70311	29504908	One deletion undescribed in databases NM_003001: c.409delT, p.(Trp137fs) (chr1:161,332,121) was identified in gene SDHC.	('c.409delT', 'DELETION', 'None', (49, 58))	('c.409delT', 'Var', (49, 58))	('p.(Trp137fs)', 'Mutation', 'p.W137fsX)', (60, 72))	('SDHC', 'Gene', (115, 119))	('SDHC', 'Gene', '6391', (115, 119))
70312	29504908	Moreover, the stop-codon located near the frameshift in codon 133 (p.(Arg133Ter)) is represented in databases and associated with PGLs.	('PGLs', 'Phenotype', 'HP:0002668', (130, 134))	('p.(Arg133Ter', 'Var', (67, 79))	('p.(Arg133Ter)', 'SUBSTITUTION', 'None', (67, 80))	('associated', 'Reg', (114, 124))	('frameshift', 'Var', (42, 52))	('PGLs', 'Disease', (130, 134))
70313	29504908	We identified SDHD mutations in seven CBT samples.	('SDHD', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('SDHD', 'Gene', '6392', (14, 18))
70314	29504908	In two samples, it was a nonsense mutation NM_003002: c.112C > T, p.(Arg38*) (chr11:111,958,640, rs80338843).	('p.(Arg38*)', 'SUBSTITUTION', 'None', (66, 76))	('NM_003002: c.112C > T', 'Mutation', 'rs80338843', (43, 64))	('p.(Arg38*', 'Var', (66, 75))	('rs80338843', 'Var', (97, 107))	('rs80338843', 'Mutation', 'rs80338843', (97, 107))
70318	29504908	Thus, a mutation c.205G > T forming stop-codon also appears to be pathogenic one that is confirmed by data from SIFT, MutationTaster, LRT, and phastCons resources.	('c.205G > T', 'Mutation', 'rs896411432', (17, 27))	('c.205G > T', 'Var', (17, 27))	('SIFT', 'Disease', (112, 116))	('pathogenic', 'Reg', (66, 76))	('SIFT', 'Disease', 'None', (112, 116))
70320	29504908	A similar mutation c209G > A, p.(Arg70Lys) in the same codon is described in ClinVar with unknown clinical significance.	('c209G > A', 'Var', (19, 28))	('p.(Arg70Lys)', 'Mutation', 'rs755047928', (30, 42))	('c209G > A', 'Mutation', 'rs755047928', (19, 28))	('p.(Arg70Lys', 'Var', (30, 41))
70322	29504908	This fact may suggest the pathogenic effect of mutation c210G > C. Three mutations causing frameshift, that usually has a highly pathogenic effect, were evaluated - NM_003002: c.217dupA, p.(Ser73fs) (chr11:111,959,637), NM_003002: c.220_228delGTT TTG CTCinsT, p.(Val74fs) (chr11:111,959,639), and NM_003002: c.13dupT, p.(Trp5fs) (chr.11: 111,957,643).	('c.217dupA', 'Var', (176, 185))	('c.13dupT', 'DUPLICATION', 'None', (308, 316))	('c210G > C', 'Mutation', 'rs1280159816', (56, 65))	('c.220_228delGTT', 'DELETION', 'None', (231, 246))	('p.(Trp5fs)', 'Mutation', 'p.W5fsX)', (318, 328))	('c.217dupA', 'DUPLICATION', 'None', (176, 185))	('p.(Val74fs)', 'Mutation', 'rs869025620', (260, 271))	('c.220_228delGTT', 'Var', (231, 246))	('p.(Ser73fs)', 'Mutation', 'rs876658511', (187, 198))	('NM_003002: c.13dupT', 'Var', (297, 316))	('c210G > C.', 'Var', (56, 66))	('p.(Val74fs', 'Var', (260, 270))
70323	29504908	Germline mutation in the same codon c.14G > A, leading to hereditary PCC, was described earlier.	('c.14G > A', 'Mutation', 'rs375758522', (36, 45))	('leading to', 'Reg', (47, 57))	('hereditary PCC', 'Disease', (58, 72))	('c.14G > A', 'Var', (36, 45))	('PCC', 'Phenotype', 'HP:0002666', (69, 72))
70326	29504908	We found mutation NM_005896: c.548A > G, p.(Tyr183Cys) (chr2:209,108,301, rs34599179) in two samples and mutation NM_005896: c.94 T > G, p.(Phe32Val) (chr2:209,116,182, rs142923780) in one sample.	('p.(Phe32Val', 'Var', (137, 148))	('rs142923780', 'Var', (169, 180))	('p.(Tyr183Cys', 'Var', (41, 53))	('rs142923780', 'Mutation', 'rs142923780', (169, 180))	('NM_005896: c.548A > G', 'Var', (18, 39))	('rs34599179', 'Mutation', 'rs34599179', (74, 84))	('NM_005896: c.94 T > G', 'Mutation', 'rs142923780', (114, 135))	('NM_005896: c.94 T > G', 'Var', (114, 135))	('p.(Tyr183Cys)', 'SUBSTITUTION', 'None', (41, 54))	('NM_005896: c.548A > G', 'Mutation', 'rs34599179', (18, 39))	('p.(Phe32Val)', 'SUBSTITUTION', 'None', (137, 149))
70327	29504908	In one sample, we detected mutation NM_005896: c.394C > T, p.(Arg132Cys) (chr2:209,113,113, rs121913499), which is indicated in ClinVar as a somatic pathogenic/likely pathogenic variant detected in many tumor types.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('NM_005896: c.394C > T', 'Mutation', 'rs121913499', (36, 57))	('rs121913499', 'Mutation', 'rs121913499', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('p.(Arg132Cys)', 'Mutation', 'rs121913499', (59, 72))	('c.394C > T', 'Var', (47, 57))
70328	29504908	The frequency of IDH1 mutations in PCC/PGLs is low.	('PCC', 'Phenotype', 'HP:0002666', (35, 38))	('PGLs', 'Phenotype', 'HP:0002668', (39, 43))	('IDH1', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('IDH1', 'Gene', '3417', (17, 21))
70329	29504908	In paragangliomas, a mutation in IDH1 was first recorded during the analysis of 365 samples.	('paragangliomas', 'Disease', 'MESH:D010235', (3, 17))	('paragangliomas', 'Disease', (3, 17))	('IDH1', 'Gene', (33, 37))	('paraganglioma', 'Phenotype', 'HP:0002668', (3, 16))	('paragangliomas', 'Phenotype', 'HP:0002668', (3, 17))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', '3417', (33, 37))
70334	29504908	Therefore, we can suggest that frequency of IDH1 mutations may be associated with localization of paragangliomas.	('paragangliomas', 'Phenotype', 'HP:0002668', (98, 112))	('mutations', 'Var', (49, 58))	('IDH1', 'Gene', (44, 48))	('associated', 'Reg', (66, 76))	('IDH1', 'Gene', '3417', (44, 48))	('paragangliomas', 'Disease', 'MESH:D010235', (98, 112))	('paragangliomas', 'Disease', (98, 112))	('paraganglioma', 'Phenotype', 'HP:0002668', (98, 111))
70337	29504908	We found a rare (0.0074) variant NM_001668: c.1551 T > G, p.(Asp517Glu) (chr1:150,789,864, rs10305741) of ARNT gene in two samples.	('rs10305741', 'Mutation', 'rs10305741', (91, 101))	('ARNT', 'Gene', (106, 110))	('NM_001668', 'Gene', (33, 42))	('rs10305741', 'Var', (91, 101))	('NM_001668: c.1551 T > G', 'Mutation', 'rs10305741', (33, 56))	('p.(Asp517Glu)', 'Mutation', 'rs10305741', (58, 71))	('c.1551 T > G', 'Var', (44, 56))	('ARNT', 'Gene', '405', (106, 110))	('p.(Asp517Glu', 'Var', (58, 70))
70338	29504908	c.1551 T > G may be non-pathogenic mutation according to SIFT database.	('SIFT', 'Disease', 'None', (57, 61))	('SIFT', 'Disease', (57, 61))	('c.1551 T > G', 'Var', (0, 12))	('c.1551 T > G', 'Mutation', 'rs10305741', (0, 12))
70341	29504908	The Cosmic database describes another mutation in the same codon (c.2335C > T, p. non-pathogenic (Pro779Ser)) in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('c.2335C > T', 'Var', (66, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('c.2335C > T', 'Mutation', 'rs200078254', (66, 77))	('Pro779Ser', 'Mutation', 'rs200078254', (98, 107))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
70342	29504908	However, in the case of Pro779Ser, the charge of the amino acid residue is changing in contrast to Pro779Ala.	('Pro779Ser', 'Var', (24, 33))	('charge of the amino acid residue', 'MPA', (39, 71))	('Pro779Ala', 'Mutation', 'rs200078254', (99, 108))	('changing', 'Reg', (75, 83))	('Pro779Ser', 'Mutation', 'rs200078254', (24, 33))
70349	29504908	In one sample, we found non-pathogenic missense mutation NM_005657: c.5242C > T, p.(Arg1748Cys) (chr15:43,705,365, rs140689367) (SIFT = 0.13), highest population MAF < 0.01 described in Ensembl database.	('SIFT', 'Disease', 'None', (129, 133))	('NM_005657: c.5242C > T', 'Mutation', 'rs140689367', (57, 79))	('rs140689367', 'Var', (115, 126))	('rs140689367', 'Mutation', 'rs140689367', (115, 126))	('p.(Arg1748Cys)', 'SUBSTITUTION', 'None', (81, 95))	('NM_005657: c.5242C > T', 'Var', (57, 79))	('SIFT', 'Disease', (129, 133))	('p.(Arg1748Cys', 'Var', (81, 94))	('MAF', 'Gene', '4094', (162, 165))	('MAF', 'Gene', (162, 165))
70350	29504908	In two samples, we found NM_005657: c.880 T > C, p.(Ser294Pro) (chr15:43,769,851, rs61751060) non-pathogenic missense mutation (SIFT = 0.36) with global MAF of 0.003 described in Ensembl database.	('rs61751060', 'Var', (82, 92))	('SIFT', 'Disease', (128, 132))	('c.880 T > C', 'Var', (36, 47))	('p.(Ser294Pro)', 'SUBSTITUTION', 'None', (49, 62))	('rs61751060', 'Mutation', 'rs61751060', (82, 92))	('SIFT', 'Disease', 'None', (128, 132))	('p.(Ser294Pro', 'Var', (49, 61))	('NM_005657: c.880 T > C', 'Mutation', 'rs61751060', (25, 47))	('MAF', 'Gene', '4094', (153, 156))	('MAF', 'Gene', (153, 156))
70355	29504908	Four single nucleotide polymorphisms in TP53BP2 are significantly correlated with gastric cancer susceptibility.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('correlated', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('TP53BP2', 'Gene', '7159', (40, 47))	('gastric cancer', 'Disease', (82, 96))	('TP53BP2', 'Gene', (40, 47))	('single nucleotide polymorphisms', 'Var', (5, 36))
70359	29504908	In another sample, we found mutation NM_005426: c.179C > T, p.(Ala60Val) (chr1:223,991,959, rs61749337) described in dbSNP and Ensembl databases.	('p.(Ala60Val', 'Var', (60, 71))	('c.179C > T', 'Var', (48, 58))	('rs61749337', 'Var', (92, 102))	('p.(Ala60Val)', 'SUBSTITUTION', 'None', (60, 72))	('NM_005426: c.179C > T', 'Mutation', 'rs61749337', (37, 58))	('rs61749337', 'Mutation', 'rs61749337', (92, 102))
70360	29504908	The mutation is pathogenic one by MutationTaster, LRT, and PolyPhen-2 predictions (MutationTaster score = 1.0, LRT prediction = 'Disease', and PolyPhen-2 score = 0.94), but it has not been described in literature (Global MAF < 0.003).	('MAF', 'Gene', '4094', (221, 224))	('MAF', 'Gene', (221, 224))	('pathogenic', 'Reg', (16, 26))	('mutation', 'Var', (4, 12))
70361	29504908	In one sample, we found mutation NM_005426: c.1515G > C, p.(Gln505His) (chr1:223,985,963, rs61824007) described in dbSNP and Ensembl databases.	('c.1515G > C', 'Var', (44, 55))	('NM_005426: c.1515G > C', 'Mutation', 'rs61824007', (33, 55))	('p.(Gln505His)', 'Mutation', 'rs61824007', (57, 70))	('rs61824007', 'Mutation', 'rs61824007', (90, 100))	('rs61824007', 'Var', (90, 100))	('p.(Gln505His', 'Var', (57, 69))
70365	29504908	In two samples, we found somatic missense mutation NM_138349: c.148C > G, p. (Pro50Ala) (chr17:27,896,342, rs112563021) with allele frequency 0.005810, MAF < 0.01(G).	('rs112563021', 'Mutation', 'rs112563021', (107, 118))	('NM_138349: c.148C > G', 'Mutation', 'rs112563021', (51, 72))	('Pro50Ala', 'Var', (78, 86))	('NM_138349', 'Var', (51, 60))	('c.148C > G', 'Var', (62, 72))	('Pro50Ala', 'SUBSTITUTION', 'None', (78, 86))	('MAF', 'Gene', '4094', (152, 155))	('rs112563021', 'Var', (107, 118))	('MAF', 'Gene', (152, 155))
70368	29504908	We identified two samples with RET mutations.	('RET', 'Gene', (31, 34))	('RET', 'Gene', '5979', (31, 34))	('mutations', 'Var', (35, 44))
70369	29504908	In both cases, it was NM_020630: c.2372A > T, p.(Tyr791Phe) (chr10:43,613,908, rs77724903) located in exon 13 and changing protein structure.	('p.(Tyr791Phe', 'Var', (46, 58))	('p.(Tyr791Phe)', 'SUBSTITUTION', 'None', (46, 59))	('c.2372A > T', 'Var', (33, 44))	('rs77724903', 'Mutation', 'rs77724903', (79, 89))	('NM_020630: c.2372A > T', 'Mutation', 'rs77724903', (22, 44))	('changing', 'Reg', (114, 122))	('rs77724903', 'Var', (79, 89))	('protein structure', 'MPA', (123, 140))
70370	29504908	Some data indicates that RET c.2372A > T is associated with familial medullary thyroid carcinoma (FMTC), hereditary cancer-predisposing syndrome, Hirschsprung disease, multiple endocrine neoplasia (MEN) including types 1, 2a, 2b, and 4, pheochromocytoma, and renal adysplasia.	('RET', 'Gene', '5979', (25, 28))	('renal adysplasia', 'Disease', 'MESH:C563261', (259, 275))	('c.2372A > T', 'Var', (29, 40))	('neoplasia', 'Phenotype', 'HP:0002664', (187, 196))	('multiple endocrine neoplasia', 'Disease', 'MESH:D009377', (168, 196))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('multiple endocrine neoplasia', 'Disease', (168, 196))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (177, 196))	('RET', 'Gene', (25, 28))	('hereditary cancer', 'Disease', (105, 122))	('Hirschsprung disease', 'Disease', (146, 166))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (146, 166))	('MEN', 'Species', '9606', (198, 201))	('c.2372A > T', 'Mutation', 'rs77724903', (29, 40))	('renal adysplasia', 'Phenotype', 'HP:0000110', (259, 275))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (79, 96))	('hereditary cancer', 'Disease', 'MESH:D009369', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pheochromocytoma', 'Disease', 'MESH:D010673', (237, 253))	('thyroid carcinoma', 'Disease', (79, 96))	('associated', 'Reg', (44, 54))	('renal adysplasia', 'Disease', (259, 275))	('pheochromocytoma', 'Disease', (237, 253))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (237, 253))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (69, 96))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (79, 96))
70377	29504908	Missense mutations in the KIF1B gene were found for the first time in two PCC samples in 2008.	('KIF1B', 'Gene', '23095', (26, 31))	('PCC', 'Phenotype', 'HP:0002666', (74, 77))	('found', 'Reg', (42, 47))	('KIF1B', 'Gene', (26, 31))	('Missense mutations', 'Var', (0, 18))
70378	29504908	Later, a group of relatives was found that increased probability of developing not only PCC, but also neuroblastomas, ganglioneuromas, and lung tumors for germline mutations in the KIF1B gene.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('lung tumors', 'Disease', 'MESH:D008175', (139, 150))	('KIF1B', 'Gene', (181, 186))	('KIF1B', 'Gene', '23095', (181, 186))	('lung tumors', 'Disease', (139, 150))	('PCC', 'Disease', (88, 91))	('ganglioneuromas', 'Disease', (118, 133))	('neuroblastomas', 'Disease', 'MESH:D009447', (102, 116))	('lung tumors', 'Phenotype', 'HP:0100526', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PCC', 'Phenotype', 'HP:0002666', (88, 91))	('neuroblastomas', 'Disease', (102, 116))	('germline mutations', 'Var', (155, 173))	('developing', 'PosReg', (68, 78))	('ganglioneuromas', 'Disease', 'MESH:D005729', (118, 133))
70380	29504908	In this work, we identified two KIF1B mutations NM_015074: c.4717C > T, p.(Pro1573Ser) (chr1:10,431,229) and NM_015074: c.1579G > C, p.(Gly527Arg) (chr1:10,355,764).	('NM_015074: c.4717C > T', 'Var', (48, 70))	('p.(Gly527Arg)', 'Mutation', 'rs745444863', (133, 146))	('p.(Pro1573Ser', 'Var', (72, 85))	('NM_015074: c.1579G > C', 'Var', (109, 131))	('p.(Gly527Arg', 'Var', (133, 145))	('NM_015074: c.1579G > C', 'Mutation', 'rs1060499983', (109, 131))	('NM_015074: c.4717C > T', 'Mutation', 'c.4717C>T', (48, 70))	('KIF1B', 'Gene', (32, 37))	('KIF1B', 'Gene', '23095', (32, 37))	('p.(Pro1573Ser)', 'SUBSTITUTION', 'None', (72, 86))
70381	29504908	Both germline and somatic mutations in KIF1B gene have been found in pheochromocytoma, occasionally occurring in combinations with mutations in other genes, such as NF1, RET, VHL, and SDHx.	('RET', 'Gene', (170, 173))	('RET', 'Gene', '5979', (170, 173))	('mutations', 'Var', (26, 35))	('VHL', 'Gene', (175, 178))	('found', 'Reg', (60, 65))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (69, 85))	('KIF1B', 'Gene', (39, 44))	('VHL', 'Gene', '7428', (175, 178))	('NF1', 'Gene', (165, 168))	('KIF1B', 'Gene', '23095', (39, 44))	('pheochromocytoma', 'Disease', (69, 85))	('NF1', 'Gene', '4763', (165, 168))	('SDHx', 'Chemical', '-', (184, 188))	('pheochromocytoma', 'Disease', 'MESH:D010673', (69, 85))
70382	29504908	In our PGL cohort, one of two samples also has additional PDM in BAP1 gene.	('BAP1', 'Gene', '8314', (65, 69))	('PDM', 'Var', (58, 61))	('BAP1', 'Gene', (65, 69))
70389	29504908	In one sample, we identified mutation NM_058197: c.187G > C, p.(Gly63Arg) (chr9:21,974,640, rs45456595).	('p.(Gly63Arg', 'Var', (61, 72))	('p.(Gly63Arg)', 'SUBSTITUTION', 'None', (61, 73))	('c.187G > C', 'Var', (49, 59))	('rs45456595', 'Var', (92, 102))	('NM_058197: c.187G > C', 'Mutation', 'rs45456595', (38, 59))	('rs45456595', 'Mutation', 'rs45456595', (92, 102))
70392	29504908	Mutations in BRAF gene were initially identified in cancer types that are commonly associated with mutations in different isoforms of RAS, such as malignant melanoma and well-differentiated thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (190, 204))	('malignant melanoma', 'Phenotype', 'HP:0002861', (147, 165))	('malignant melanoma', 'Disease', 'MESH:D008545', (147, 165))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (198, 204))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('identified', 'Reg', (38, 48))	('thyroid cancer', 'Disease', (190, 204))	('malignant melanoma', 'Disease', (147, 165))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('thyroid cancer', 'Disease', 'MESH:D013964', (190, 204))	('mutations', 'Var', (99, 108))	('associated', 'Reg', (83, 93))
70393	29504908	We identified only one sample with a non-canonical BRAF mutation NM_00433: c.533G > A, p.(Arg178Gln) (chr7:140,508,767, rs746348396), which changes protein structure.	('p.(Arg178Gln', 'Var', (87, 99))	('protein structure', 'MPA', (148, 165))	('rs746348396', 'Mutation', 'rs746348396', (120, 131))	('rs746348396', 'Var', (120, 131))	('changes', 'Reg', (140, 147))	('c.533G > A', 'Var', (75, 85))	('BRAF', 'Gene', '673', (51, 55))	('NM_00433: c.533G > A', 'Mutation', 'rs746348396', (65, 85))	('p.(Arg178Gln)', 'Mutation', 'rs746348396', (87, 100))	('BRAF', 'Gene', (51, 55))
70397	29504908	Germline mutations in these genes are associated with hereditary breast and ovarian cancers, Fallopian tube, prostate, peritoneal, and pancreatic cancers.	('Germline mutations', 'Var', (0, 18))	('pancreatic cancers', 'Disease', 'MESH:D010190', (135, 153))	('pancreatic cancers', 'Disease', (135, 153))	('prostate', 'Disease', (109, 117))	('peritoneal', 'Disease', (119, 129))	('associated', 'Reg', (38, 48))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (135, 153))	('hereditary breast and ovarian cancers', 'Disease', 'MESH:D061325', (54, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancers', 'Phenotype', 'HP:0100615', (76, 91))	('Fallopian tube', 'Disease', (93, 107))
70399	29504908	PDM NM_003000: c.5019G > A, p.(Met1673Ile) (chr17:41,222,975, rs1799967) was identified in BRCA1 gene.	('BRCA1', 'Gene', (91, 96))	('NM_003000: c.5019G > A', 'Mutation', 'rs1799967', (4, 26))	('rs1799967', 'Mutation', 'rs1799967', (62, 71))	('p.(Met1673Ile)', 'SUBSTITUTION', 'None', (28, 42))	('c.5019G > A', 'Var', (15, 26))	('p.(Met1673Ile', 'Var', (28, 41))	('BRCA1', 'Gene', '672', (91, 96))
70400	29504908	In one sample, a rare mutation NM_000059: c.4585G > A, p.(Gly1529Arg) (chr13:32,913,077, rs28897728) was evaluated in BRCA2 gene.	('c.4585G > A', 'Var', (42, 53))	('BRCA2', 'Gene', (118, 123))	('rs28897728', 'Var', (89, 99))	('NM_000059: c.4585G > A', 'Mutation', 'rs28897728', (31, 53))	('rs28897728', 'Mutation', 'rs28897728', (89, 99))	('BRCA2', 'Gene', '675', (118, 123))	('p.(Gly1529Arg)', 'Mutation', 'rs28897728', (55, 69))
70403	29504908	In this gene, we identified a mutation NM_007158: c.416C > T, p.(Ala139Val) (chr1:115,277,136, rs151170620).	('rs151170620', 'Var', (95, 106))	('NM_007158: c.416C > T', 'Mutation', 'rs151170620', (39, 60))	('rs151170620', 'Mutation', 'rs151170620', (95, 106))	('p.(Ala139Val)', 'Mutation', 'rs151170620', (62, 75))	('c.416C > T', 'Var', (50, 60))
70406	29504908	Germline mutations in the BAP1 are