{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"study_type":["Other"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001001601"],"host":["EGA"],"description":["EGA study EGAS00001001601"],"dataset_title":["Exome sequencing of nine PCC/PGL tumors"],"repository":["EGA"],"category":["restricted"],"pubmed_abstract":["One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p < 0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. In conclusion, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed MYO5B to be recurrently mutated in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis."],"pubmed_title":["Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes."],"pubmed_authors":["Wilzén Annica A, Rehammar Anna A, Muth Andreas A, Nilsson Ola O, Tešan Tomić Tajana T, Wängberg Bo B, Kristiansson Erik E, Abel Frida F"],"name_synonyms":["Mutations, Gangliocytic Paragangliomas, chemodectoma, Adhesions, Materials, Paraganglioma, Genetic, single-organism transport, Material, Paragangliomatas, Adhesion, cell adhesion molecule activity, Genetic Materials, Cistron, Gene, Gangliocytic Paraganglioma, Cell Adhesions, single organism cell adhesion, Genetic Material., Paragangliomata, Cistrons, Paragangliomas, Cell, Gangliocytic"],"description_synonyms":["Rac GTPase, PRKBA, dlmo, Akt/PKB, Materials, DLMO, ectodin, BAA88244, D-Rac1, D-Rac2, DAKT1/PKB, Physical, vif, rac, SDH, CMH15, Tumor, AKT1, Diagnosis, Long Term, Mutation Frequency, Mutations, Motor, dLmo, dLMO, DmelCG8556, pheochromocytoma, Rac-2, Rac-1, Method, symptoms, Whole Transcriptome, Transcriptome Sequencing, Mutation Frequencies, AAF01186, average, A, Dmrho, 9430097D22, Motor Activities, Q, DMRHO, Nmyc1, procedures, QPs3, RacPK, SDH4., DmelCG8416, Bd, Rab-5, Dlmo, CCA3, Homo sapiens disease, fliH, HRB, Hrb, PAL, CXXC finger protein 9, Diagnose, Tumors, 0610006G05Rik, chemodectoma, screening, dRac1, Rho-1, Exome, CG3664, familial, Longterm Effect, CG1004, Paragangliomata, Procedure, Diagnoses, dRab5, AKT/PKB, GTPase Rac1, Benign, Postmortem, AW545629, PCC, p-Akt, RHOHP1, xN-myc1, Complete Transcriptome, vif Genes, Q Genes, DmRAC2, DmRAC1, D-Rho1, AI326383, signs, 2248, Benign Neoplasms, INSDC_feature:gene, Methodological, RHO, Rho, dAKT/dPKB, PKB/dAKT, Malignant Neoplasms, Activities, rhomboid/veinlet, Material, Wise, Whole Exome Sequencing, ARHD, Myr6, RIP, Rip, Dmrac1, rho, other neoplasm, AAF51265, DmRab5, DmelCG3283, RAC-ALPHA, DmelCG4006, Effects, Dehydrogenase, Nmyc, Neoplasms, ODED, DRac, number, Arhd, Fumarate Reductase, sor Gene, AI661750, CACA, Aim, AIM, Rate, IP, NMYC, disease or disorder, Screening, PGL, CG6500, single organism cell adhesion, Antemortem, D-Rac, nmyc, Technique, dRac, DNMT1, HGAD, dRhoA, Complete, Ip, Exome Sequencings, beadex/dLMO, DNMT1_HUMAN, Longterm, 0710008N11Rik, Long-Term, Diagnoses and Examinations, Nmuc1, DmRAC, Sequencing, RAB5a, Study, Neoplasias, API6, Whole Exome, AKT, RhoHP1, Akt, Whole, Drac, dRho1, bHLHe37, constitutitional genetic, XNmyc, CG2248, Cancer, DNA (cytosine-5)-methyltransferase 1, DmelCG6500, Antemortem Diagnoses, Pheochromocytoma, Rho kinase, findings, Malignant Neoplasm, Complete Exome Sequencings, akt, l(2)52Fa, disorders, DAkt1, sor, DAKT1, MCMT, Cell, Exome Sequencing, PKB, MT, CWS6, MV, CWS3, CG3283, CWS2, Long Term Effects, chemical analysis, Mutation Rates, PKB-ALPHA, Neoplasm, AI462105, condition, CG4006, PGL1, Q Gene, PGL4, Mutation, dnRho, Reductase, CXXC9, Dakt1, CT-2, DmelCG2248, Locomotor Activities, E3.10/J3.8, Cancers, CXXC-type zinc finger protein 9, Drac1b, Drac1a, Longterm Effects, dAkt/PKB, peptidyl-alpha-hydroxyglycine alpha-amidating lyase activity, Rac1b, 225, Succinic Oxidase, hereditary, Extra Adrenal, Neoplasia, CLEC2C, Antemortem Diagnosis, HEL114, Activity, HSN1E, determination, Paragangliomatas, Motor Activity, Rho A, mycna, mycnb, A Genes, hdp-a, Techniques, Succinate, DmelCG1004, DmelCG3664, diseases, rho-1, motor activity, diseases and disorders, DRho, Extra-Adrenal, Effect, 8416, human disease, AU045498, sor Genes, Complete Exome Sequencing, Whole Transcriptome Sequencing, AA571387, USAG-1, CII-4, N-myc, PKB|Akt, rhoA, RHO1, Rho1, genetic, Adhesions, Methodological Studies, XN-myc, l(2)k08232, rho1, Adhesion, Malignancies, Fumarate, Frequency, Long-Term Effects, RAB5, dakt, DmRHO-A, RHOb, HSC0013, Gangliocytic Paraganglioma, CG8556, l(3)89Bq, RAC1, D-Rac 1, Dm Rho1, D-Rac 2, rhom, PKB/Akt, PKB/AKT, Screenings, RhoN19, Dm Rab5, dAkt, dAKT, rac1, Frequencies, rac2, Examinations and Diagnoses, RhoA, Diseases, ve, Pheochromocytomas, peptidylamidoglycolate peptidylamide-lyase (glyoxylate-forming), Genetic Materials, RHOM, RhoM, rab5, Postmortem Diagnosis, DAkt, Paragangliomas, Genetic Material, Gangliocytic, l(3)04226, Diagnoses and Examination, Ptd, single organism intracellular transport, ADCADN, DPKB, Postmortem Diagnoses, Dm Rac1, Oxidase, UNQ203/PRO229, pAkt, DNA (cytosine-5-)-methyltransferase 1, susceptibility to, Ve, CG8416, SDH4, Methodological Study, SDH1, SDH2, DMRHOa, sdhB, DMRHOb, CBT1, disease, DRac1, Dakt, DRac2, single-organism intracellular transport, Paraganglioma, RacB, Patient, Sostl, mKIAA1119, RacA, dPKB, Lmo, LMO, Cistron, inherited genetic, DRacA, hdp, DRacB, Transcriptome Sequencings, metavinculin, DRab5, DRAC-PK85, DracA, other disease, Dmelrho, cybS, Procedures, DRORHO, Complete Exome, SDHb, vif Gene, Benign Neoplasm, Drac2, Drac1, Gene, Malignant, SDH-IP, Locomotor, Rho GTPase, Dpkb, mycn, DRhoA, dttg, Studies, Mass, CMD1W, Drab5, SDH-Ip, D730048C23Rik, VCL, study, WES, Genetic, Malignancy, cell adhesion molecule activity, CTRCT4, Locomotor Activity, DRho1, DrhoA, non-neoplastic, OPN2, MODED, Clients, Drho1, DRAC-PK, Benign Tumors, disorder, Long-Term Effect, A Gene, DNA MTase HsaI, peptidylamidoglycolate peptidylamide-lyase activity, Succinic Dehydrogenase, iks, DNMT, Extra-Adrenal Pheochromocytoma, medical condition, l(2)k02107b, Cistrons, Client, Examination and Diagnoses, photoreceptor PCC, C130049H11Rik, cry-g-D, Mass Screenings, DNA methyltransferase HsaI, c-nmyc, Succinic, D-Akt, techniques, CRYG4, Gangliocytic Paragangliomas, Rates, Genes, Complete Transcriptome Sequencing, akt1, dAkt1, SDHIP, DRAC-PK66, Extra-Adrenal Pheochromocytomas, C85612, Cell Adhesions, alpha-hydroxyglycine amidating dealkylase activity, Nmyc-1, hld, dakt1, Physical Activities, PKBalpha, cardinality, CCP, RAB, Rab, dAKT1, assay, RAC, Rac, MVCL, n(2)k07236, methodology, m.HsaI"],"pubmed_title_synonyms":["Mutations, Gangliocytic Paragangliomas, chemodectoma, Adhesions, Materials, Paraganglioma, Genetic, single-organism transport, Material, Paragangliomatas, Adhesion, cell adhesion molecule activity, Genetic Materials, Cistron, Gene, Gangliocytic Paraganglioma, Cell Adhesions, single organism cell adhesion, Genetic Material., Paragangliomata, Cistrons, Paragangliomas, Cell, Gangliocytic"],"pubmed_abstract_synonyms":["Rac GTPase, PRKBA, dlmo, Akt/PKB, Materials, DLMO, ectodin, BAA88244, D-Rac1, D-Rac2, DAKT1/PKB, Physical, rac, SDH, CMH15, Tumor, AKT1, Diagnosis, Long Term, Mutation Frequency, Mutations, Motor, dLmo, dLMO, DmelCG8556, pheochromocytoma, Rac-2, Rac-1, Method, symptoms, Whole Transcriptome, Transcriptome Sequencing, Mutation Frequencies, AAF01186, average, Dmrho, 9430097D22, Motor Activities, DMRHO, Nmyc1, procedures, QPs3, RacPK, SDH4., DmelCG8416, Bd, Rab-5, Dlmo, CCA3, Homo sapiens disease, fliH, HRB, Hrb, PAL, CXXC finger protein 9, Diagnose, Tumors, 0610006G05Rik, chemodectoma, screening, dRac1, Rho-1, Exome, CG3664, familial, Longterm Effect, CG1004, Paragangliomata, Procedure, Diagnoses, dRab5, AKT/PKB, GTPase Rac1, Benign, Postmortem, AW545629, PCC, p-Akt, Ontology Projects, RHOHP1, xN-myc1, Complete Transcriptome, Ontology, DmRAC2, Projects, DmRAC1, D-Rho1, AI326383, signs, 2248, Benign Neoplasms, INSDC_feature:gene, Methodological, RHO, Rho, dAKT/dPKB, PKB/dAKT, Malignant Neoplasms, Activities, rhomboid/veinlet, Material, Wise, Whole Exome Sequencing, ARHD, Myr6, RIP, Rip, Dmrac1, rho, other neoplasm, AAF51265, DmRab5, DmelCG3283, RAC-ALPHA, DmelCG4006, Effects, Dehydrogenase, Nmyc, Neoplasms, ODED, DRac, number, Arhd, Fumarate Reductase, Gene Ontology Project, Gene Ontology, AI661750, CACA, Aim, AIM, Rate, IP, NMYC, disease or disorder, Screening, PGL, CG6500, single organism cell adhesion, Antemortem, D-Rac, nmyc, Technique, dRac, DNMT1, HGAD, dRhoA, Complete, Ip, Exome Sequencings, beadex/dLMO, DNMT1_HUMAN, Longterm, 0710008N11Rik, Long-Term, Diagnoses and Examinations, Nmuc1, DmRAC, Sequencing, RAB5a, Study, Neoplasias, API6, Whole Exome, AKT, RhoHP1, Akt, Whole, Drac, dRho1, bHLHe37, constitutitional genetic, XNmyc, CG2248, Cancer, DNA (cytosine-5)-methyltransferase 1, DmelCG6500, Antemortem Diagnoses, Pheochromocytoma, Rho kinase, findings, Malignant Neoplasm, Complete Exome Sequencings, akt, l(2)52Fa, disorders, DAkt1, DAKT1, MCMT, Cell, Exome Sequencing, PKB, MT, CWS6, MV, CWS3, CG3283, CWS2, Long Term Effects, chemical analysis, Mutation Rates, PKB-ALPHA, Neoplasm, AI462105, condition, CG4006, PGL1, PGL4, Mutation, dnRho, Reductase, CXXC9, Dakt1, Ontology Project, CT-2, DmelCG2248, Locomotor Activities, E3.10/J3.8, Cancers, CXXC-type zinc finger protein 9, Drac1b, Drac1a, Longterm Effects, dAkt/PKB, peptidyl-alpha-hydroxyglycine alpha-amidating lyase activity, Rac1b, 225, Succinic Oxidase, hereditary, Extra Adrenal, Neoplasia, CLEC2C, Antemortem Diagnosis, Gene Ontology Projects, HEL114, Activity, HSN1E, determination, Paragangliomatas, Motor Activity, Rho A, mycna, mycnb, hdp-a, Techniques, Succinate, DmelCG1004, DmelCG3664, diseases, rho-1, motor activity, Project, diseases and disorders, DRho, Extra-Adrenal, Effect, 8416, human disease, AU045498, Complete Exome Sequencing, Whole Transcriptome Sequencing, AA571387, USAG-1, CII-4, N-myc, PKB|Akt, rhoA, RHO1, Rho1, genetic, Adhesions, Methodological Studies, XN-myc, l(2)k08232, rho1, Adhesion, Malignancies, Fumarate, Frequency, Long-Term Effects, RAB5, dakt, DmRHO-A, RHOb, HSC0013, Gangliocytic Paraganglioma, CG8556, l(3)89Bq, RAC1, D-Rac 1, Dm Rho1, D-Rac 2, rhom, PKB/Akt, PKB/AKT, Screenings, RhoN19, Dm Rab5, dAkt, dAKT, rac1, Frequencies, rac2, Examinations and Diagnoses, RhoA, Diseases, ve, Pheochromocytomas, peptidylamidoglycolate peptidylamide-lyase (glyoxylate-forming), Genetic Materials, RHOM, RhoM, rab5, Postmortem Diagnosis, DAkt, Paragangliomas, Genetic Material, Gangliocytic, l(3)04226, Diagnoses and Examination, Ptd, Gene Ontologies, single organism intracellular transport, ADCADN, DPKB, Postmortem Diagnoses, Dm Rac1, Oxidase, Ontologies, UNQ203/PRO229, pAkt, DNA (cytosine-5-)-methyltransferase 1, susceptibility to, Ve, CG8416, SDH4, Methodological Study, SDH1, SDH2, DMRHOa, sdhB, DMRHOb, CBT1, disease, DRac1, Dakt, DRac2, single-organism intracellular transport, Paraganglioma, RacB, Patient, Sostl, mKIAA1119, RacA, dPKB, Lmo, LMO, Cistron, inherited genetic, DRacA, hdp, DRacB, Transcriptome Sequencings, metavinculin, DRab5, DRAC-PK85, DracA, other disease, Dmelrho, cybS, Procedures, DRORHO, Complete Exome, SDHb, Benign Neoplasm, Drac2, Drac1, Gene, Malignant, SDH-IP, Locomotor, Rho GTPase, Dpkb, mycn, DRhoA, dttg, Studies, Mass, CMD1W, Drab5, SDH-Ip, D730048C23Rik, VCL, study, WES, Genetic, Malignancy, cell adhesion molecule activity, CTRCT4, Locomotor Activity, DRho1, DrhoA, non-neoplastic, OPN2, MODED, Clients, Drho1, DRAC-PK, Benign Tumors, disorder, Long-Term Effect, DNA MTase HsaI, peptidylamidoglycolate peptidylamide-lyase activity, Succinic Dehydrogenase, iks, DNMT, Extra-Adrenal Pheochromocytoma, medical condition, l(2)k02107b, Cistrons, Client, Examination and Diagnoses, photoreceptor PCC, C130049H11Rik, cry-g-D, Mass Screenings, DNA methyltransferase HsaI, c-nmyc, Succinic, D-Akt, techniques, CRYG4, Gangliocytic Paragangliomas, Rates, Complete Transcriptome Sequencing, akt1, dAkt1, SDHIP, DRAC-PK66, Extra-Adrenal Pheochromocytomas, C85612, Cell Adhesions, alpha-hydroxyglycine amidating dealkylase activity, Nmyc-1, hld, dakt1, Physical Activities, PKBalpha, cardinality, CCP, RAB, Rab, dAKT1, assay, RAC, Rac, MVCL, n(2)k07236, methodology, m.HsaI"],"additional_accession":[]},"is_claimable":false,"name":"Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes","description":"One out of ten patients with pheochromocytoma (PCC) and paraganglioma (PGL) develop malignant disease. Today there are no reliable pathological methods to predict malignancy at the time of diagnosis. Tumors harboring mutations in the succinate dehydrogenase subunit B (SDHB) gene often metastasize but the sequential genetic events resulting in malignant progression are not fully understood. The aim of this study was to identify somatic mutations that contribute to the malignant transformation of PCC/PGL. We performed pair-wise (tumor-normal) whole-exome sequencing to analyze the somatic mutational landscape in five malignant and four benign primary PCC/sympathetic PGL (sPGL), including two biological replicates from each specimen. In total, 225 unique somatic mutations were identified in 215 genes, with an average mutation rate of 0.54 mutations/megabase. Malignant tumors had a significantly higher number of mutations compared to benign tumors (p<0.001). Three novel genes were identified as recurrently mutated; MYCN, MYO5B and VCL, and mutations in these genes were exclusively found in malignant sPGL tumors. Mutations in the MYO5B gene could be verified in two publicly available data sets. A gene ontology analysis of mutated genes showed enrichment of cellular functions related to cytoskeletal protein binding, myosin complex, and motor activity, many of which had functions in Rab and Rac/Rho GTPase pathways. Conclusively, we have identified recurrent mutations in genes related to intracellular transport and cell adhesion, and we have confirmed recurrent mutations of MYO5B in PCC/PGL cases with malignant potential. Our study suggests that deregulated Rab and Rac/Rho pathways may be important in PCC/PGL tumorigenesis.","dates":{"updated":"2017-07-26 15:39:26"},"accession":"EGAS00001001601","cross_references":{"TAXONOMY":["9606"],"pubmed":["26650627"],"EGA":["EGAD00001001854","EGAC00001000411"]}}