EGAGenomicsIllumina HiSeq 2000Exome Sequencinghttps://ega-archive.org/studies/EGAS00001000217EGAEGA study EGAS00001000217Genetic landscape of hepatocellular carcinomaEGArestrictedGenomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (FDA)-approved drugs. In conclusion, we identified risk factor-specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.Schulze Kornelius K, Imbeaud Sandrine S, Letouzé Eric E, Alexandrov Ludmil B LB, Calderaro Julien J, Rebouissou Sandra S, Couchy Gabrielle G, Meiller Clément C, Shinde Jayendra J, Soysouvanh Frederic F, Calatayud Anna-Line AL, Pinyol Roser R, Pelletier Laura L, Balabaud Charles C, Laurent Alexis A, Blanc Jean-Frederic JF, Mazzaferro Vincenzo V, Calvo Fabien F, Villanueva Augusto A, Nault Jean-Charles JC, Bioulac-Sage Paulette P, Stratton Michael R MR, Llovet Josep M JM, Zucman-Rossi Jessica JCarcinomas, whole exome, Carcinoma, Genes, Liver, Materials, Transforming Gene, Genetic, tumor suppressor, Adult Liver Cancers, Hepatocellular carcinoma, Liver Cancer, Hepatoma, Exomes, adult primary hepatocellular carcinoma, Liver Cancers, Gene, Cell Carcinoma, Liver Cell, Cancers, adult hepatoma, Adult, Hepatomas, Cistrons, Liver Cell Carcinoma, Cell Carcinomas, Transforming Genes, cell cycle regulator, Oncogene, HCC, Material, Liver Cell Carcinomas, Hepatocellular Carcinoma., Hepatocellular, Adult Liver Cancer, Genetic Materials, Cistron, Transforming, Adult Liver, Hepatocellular Carcinomas, Genetic Material, Cancerbiochemical pathways, DNA Oxidative, Dm DWnt3/5, Metabolic Process, RGD1563860, DWnt-5, Materials, DWnt-4, tumor suppressor, determination, Dint-1, DmelCG4889, Particle, Metabolic Concepts, Smarcf1, Nitrative Stress, l(2)wg, adult hepatoma, Risk Factor Score, Tumor, Hepatomas, 1-hydroxyethane, Liver Cell Carcinoma, Damage, Tp53, Catenin, P270, Chromatin Assembly, alcohol, Mutations, BAF250a, wnt-4, cell cycle regulator, Risk Factors, int-1, Oxidative DNA, AI646973, Oxidative, RSK, bbl, Dm-1, Alkohol, Nitro-Oxidative Stress, Dm-2, Dm-3, DmelCG1916, Concepts, Whole Transcriptome, Transcriptome Sequencing, Nitro-Oxidative Stresses, Metabolism Concept, Dm Wg, Catnb, Oxidative Injury, Phenomenon, Wnt-4, DNA Damage, l(2)02657, ATP-dependent chromatin remodeling, Wnt-1, Wnt-3, Correlates, Wnt-2, ISPK-1, Oxidative Injuries, DRCTNNB1A, ctnnb1, I, BCC7, rsk, catabolism, Complete Exome Sequencing, Whole Transcriptome Sequencing, Chromatin Remodeling, Oxidative Cleavage, adult primary hepatocellular carcinoma, iecur, HLD5, Human hepatitis B virus, metabolic process resulting in cell growth, Adult, Aethanol, Oxidative DNA Damages, [CH2Me(OH)], DWnt5, WNT, Wnt, DWnt4, Anti-oxidative, DWnt3, DWnt2, Hepatocellular Carcinoma, Social, Homologous Serum, Dehydrated ethanol, high frequency, Oxidative Stress Injuries, Oxidative Stresses, Dwnt5, Health Correlates, Dwnt4, Br, biotransformation, dWnt2, Malignancies, Catabolism, ELD, wnt, Sp, Tumors, spiritus vini, hOSA1, Carcinoma, Liver, hepatitis B virus, IRF-2, Process, metabolism resulting in cell growth, Exome, Diversities, Liver Cell, Irf-2, Ethyl alcohol, HBV, predicted, beta-catenin, Benign, clone 2.4, HCC, Oxidative and Nitrosative Stress, D-wnt-2, Genetic Materials, Score, B120, secretion, bfy, Adult Liver, DNA Oxidative Damages, DWint-1, [OEtH], Genetic Material, activation, CG4889, Carcinomas, DWnt3/5, fg, Complete Transcriptome, S6K-alpha3, Factors, Social Risk Factors, EtOH, Risk, anon-WO03040301.228, Hepatoma, Remodeling, anon-EST:Liang-2.4, WG, Osa1, OSA1, common, Benign Neoplasms, INSDC_feature:gene, MPK-9, MRX19, Genetic Diversity, alcohol etilico, Methylcarbinol, 9830146E22Rik, Malignant Neoplasms, Nitro-Oxidative, Social Risk, CG1916, Health, Material, Whole Exome Sequencing, P53, Wg, p44, bhy, Cistron, Oxidative Stress Injury, DNA, Hepatocellular Carcinomas, Transcriptome Sequencings, Oxidative Damage, HYCC1, Oxidative Stress, Complete Exome, CLS, Antioxidative, Processes, Neoplasms, Disassembly, p53, etanol, Benign Neoplasm, number, Hepatitis, Chromatin Disassemblies, Antioxidative Stress, Cell Carcinoma, Gene, Metabolic Processes, Malignant, LFS1, PRO2286, presence, rsk2, DWnt-3/5, jecur, Stresses, Cell Carcinomas, S6KII, Aethylalkohol, hELD, Oxidative Nitrative, Liver Cell Carcinomas, Stress Injury, Metabolism, Gene Products, Adult Liver Cancer, Oxidative Cleavages, Dane, Chromatin Disassembly, ctnnb, beta-Catenin, B virus, Metabolism Phenomena, Oxidative Damages, Risk Factor, irf-2, study, WES, Complete, Injury, Exome Sequencings, Diversity, Populations at Risk, Genetic, Liver Cancer, Malignancy, DmelCG6407, BAF250, HU-3, Liver Cancers, NRF2, Metabolic Concept, Risk Score, Nrf2, Beta-catenin, dWnt, Wnt/Wg, Sequencing, Wnt1, Population at Risk, Wnt3, wnt4, Neoplasias, wnt3, wnt2, C2H5OH, wnt1, Whole Exome, Trp53, Wnt3/5, DmelCG4698, OK/SW-cl.35, Anti oxidative Stress, Oxidative DNA Damage, Antioxidative Stresses, Whole, RSK2, Rsk2, wnt5, Social Risk Factor, TRP53, Variation, human hepatitis B virus HBV, Cancer, Genetic Variations, Risk Scores., Hepatitis B viruses, p90, SMARCF1, Malignant Neoplasm, Complete Exome Sequencings, Variations, BM029, degradation, l(2)rO727, Proteins, Dane Particle, pp90RSK2, Hepatitis Virus, MAPKAPK1B, function, Factor, p90RSK3, Anti-oxidative Stresses, Cistrons, Risk Factor Scores, wgl, p90-RSK2, Xp53, Concept, Metabolic Phenomena, hepatitis B virus (HBV), viruses, Metabolism Concepts, count in organism, Exome Sequencing, Oxidative Nitrative Stress, spd, CTNNB, MT, MAPKAPK-1b, Oxidative Nitrative Stresses, 1110030E03Rik, chemical analysis, Protein, Phenomena, Genetic Diversities, Neoplasm, alcool ethylique, IRF2, hepatitis B virus HBV, metabolism, Metabolic Phenomenon, MRD14, Chromatin, C1orf4, C130006E23, multicellular organism metabolic process, Complete Transcriptome Sequencing, Anti-oxidative Stress, frequent, Adult Liver Cancers, Hepatocellular carcinoma, biodegradation, DNA Oxidative Damage, Metabolic, Chromatin Modeling, CG4698, Dwnt-2, Dwnt-3, Cancers, Cleavage, Dm DWnt2, Dm DWnt4, beta, ATP-dependent chromatin remodelling, Protein Gene Products, AI194320, Livers, Gene Proteins, hydroxyethane, Dwnt-5, cardinality, Stress, Hepatocellular, assay, DWnt-3, Nitro Oxidative Stress, DWnt-2, DWnt-1, Neoplasia, Gla, Hepatitis B, Anabolism, CG6407Carcinomas, Carcinoma, WES, Complete Transcriptome, Complete, Liver, Complete Transcriptome Sequencing, Exome Sequencings, Complete Exome Sequencings, Adult Liver Cancers, Liver Cancer, Complete Exome, Hepatoma, Complete Exome Sequencing, Whole Transcriptome Sequencing, Exome, Liver Cancers, Cell Carcinoma, Liver Cell, Cancers, Adult, Hepatomas, Liver Cell Carcinoma, Sequencing, Cell Carcinomas, Exome Sequencing, Whole Exome, Liver Cell Carcinomas, Hepatocellular Carcinoma., Whole, Whole Exome Sequencing, Hepatocellular, Adult Liver Cancer, Whole Transcriptome, Transcriptome Sequencing, Adult Liver, Hepatocellular Carcinomas, Transcriptome Sequencings, CancerFgf-3, MTS1, NSC 529592, Fgf-4, Materials, p19<ARF>, Product, determination, -)-Isomer, Particle, HST-1, cD1, Pctr1, adult hepatoma, Risk Factor Score, Tumor, Hepatomas, 1-hydroxyethane, Liver Cell Carcinoma, Tp53, hTRT, HBGF-3, alcohol, Mutations, PPP1R49, Aflatoxin B, Risk Factors, Hstf-1, kinky, Associations, Mesc, bbl, Alkohol, hEST2, Pharmaceutical Product, DKCB4, 2, 3, ARF-INK4a, Whole Transcriptome, Transcriptome Sequencing, Arf, ARF, Catnb, 2':4, Fs(3)Hor, p16(INK4a), Correlates, treatment, DRCTNNB1A, DmelCG2684, ctnnb1, BCC7, DKCA2, Complete Exome Sequencing, Whole Transcriptome Sequencing, CycD1, adult primary hepatocellular carcinoma, iecur, HLD5, Human hepatitis B virus, MTS-1, (6aR-cis)-Isomer, Adult, Aethanol, NTef2, [CH2Me(OH)], 2H-Labeled, Hepatocellular Carcinoma, Social, HBGF-4, genetic, INT2, Dehydrated ethanol, Homologous Serum, Health Correlates, medicine, Pharmaceutical, AI316800, disease management, Xfgf4, Therapies, ccnd1a, P14, Malignancies, P16, P19, P16-INK4A, Bfc, TR, Tumors, spiritus vini, Therapy, Carcinoma, Fgf15, 14C-Labeled, Liver, hepatitis B virus, Hst1, MLM, Exome, familial, p16, XFGF-3, Liver Cell, armadillo, Ethyl alcohol, tobacco, HBV, Cyclopenta(c)furo(3', Fs(3)Sz11, beta-catenin, NSC-529592, Aflatoxin B1 Dihydrochloride, Benign, HST, HCC, fgf3-A, Score, Genetic Materials, bfy, Pharmaceutic, Adult Liver, HSDB3453, [OEtH], Genetic Material, bcl-1, Carcinomas, Complete Transcriptome, Factors, 9a-tetrahydro-4-methoxy-, Social Risk Factors, hst, Risk, EtOH, TCS1, Hepatoma, Benign Neoplasms, HSDB-3453, Treatments, alcohol etilico, Methylcarbinol, early, Malignant Neoplasms, Social Risk, Health, Patient, Material, 6a, Horka, common tobacco, Whole Exome Sequencing, P53, Fu, CG2684, p44, Fs(3)Horka, 3H-Labeled, bhy, 6aalpha, Cistron, inherited genetic, Hepatocellular Carcinomas, fused, Aflatoxin B1, other neoplasm, Transcriptome Sequencings, INK4A, CDKN2, HYCC1, knobbly, HSTF1, Complete Exome, FGF(ii), INK4, Neoplasms, p53, etanol, Benign Neoplasm, Hepatitis, Cell Carcinoma, Gene, tumour stage, K-FGF, Malignant, PRO2286, LFS1, fgfe-B, jecur, fgf4, Cell Carcinomas, Aethylalkohol, Liver Cell Carcinomas, Xfgf-4, Adult Liver Cancer, cis(+, Dane, DmF2, TP2, ctnnb, B virus, Risk Factor, lod, Drugs, WES, Complete, Exome Sequencings, Populations at Risk, Fgfk, Genetic, Malignancy, Liver Cancer, xfgf3, Cyl-1, Liver Cancers, Risk Score, HSDB 3453, KFGF, Sequencing, Population at Risk, XEFGF, Neoplasias, C2H5OH, Whole Exome, Trp53, drugs, OK/SW-cl.35, Ink4a|Arf, CMM9, (6aR-cis)-, kFGF, Clients, Whole, efgf, fgfe, CMM2, Social Risk Factor, p19ARF, 11-dione, prad1, Aflatoxin B(1), TRP53, FGF19, Preparation, Kb, BCL1, constitutitional genetic, ccnd1, 9aalpha-Tetrahydro-4-methoxycyclopenta(c)furo(3', human hepatitis B virus HBV, Ki, Cancer, Pharmaceuticals, 3-h)(1)benzopyran-1, AXIN, Products, D11S287E, Hepatitis B viruses, TP16, Malignant Neoplasm, Complete Exome Sequencings, P16INK4, Int-2, drug, Dane Particle, Nicotiana tabacum var. Samsun, Hepatitis Virus, Factor, TRT, NSC529592, Medications, Risk Factor Scores, Cistrons, p19-lt-ARF-gt-, Client, p16INK4a, Xp53, PRAD1, hepatitis B virus (HBV), viruses, Axin, Exome Sequencing, disease management., CTNNB, EST2, P14ARF, Nicotania tabacum, chemical analysis, U21B31, Neoplasm, alcool ethylique, Ink4a/Arf, AI327039, American tobacco, Kfgf, hepatitis B virus HBV, Foods, P16INK4A, hst-1, MRD19, Complete Transcriptome Sequencing, Adult Liver Cancers, Hepatocellular carcinoma, KS3, Pharmaceutic Preparations, CDK4I, Cancers, 5)furo(2, Lds, Risk Scores, INK4a-ARF, Drug, fgf-4, Livers, hydroxyethane, Preparations, Therapeutic, PFBMFT1, Int-P, P19ARF, Hepatocellular, Treatment, assay, Pharmaceutical Products, hereditary, Neoplasia, Pharmaceutical Preparation, Hepatitis BfalseExome-sequencing identifies new oncogenes and tumor suppressor genes recurrently altered in hepatocellular carcinomaHepatocellular carcinoma (HCC) is the most common primary liver malignancy. High-resolution copy number analysis of 125 tumors of which 24 were subjected to whole-exome sequencing identified 135 homozygous deletions and 994 somatic gene mutations with predicted functional consequences. We identified new recurrent alterations in 4 genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses demonstrated tumor suppressor properties for IRF2 whose inactivation, exclusively found in hepatitis B virus related tumors, leads to impaired TP53 function. Alternatively, inactivation of proteins involved in chromatin remodeling was frequent and predominant in alcohol related tumors. Moreover, activation of the oxidative stress metabolism and inactivation of RPS6KA3 were new pathways associated with WNT/beta-catenin activation, thereby suggesting a cooperative effect in tumorigenesis. This study shows the dramatic somatic genetic diversity in HCC, it reveals interactions between oncogene and tumor suppressor gene mutations markedly related to specific risk factors.2023-09-26 17:10:02EGAS00001000217960625822088EGAD00001000131EGAC00001002924