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      Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

      research-article
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      Nature genetics

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          Abstract

          Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, and aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV), and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF3, FGF4, FGF19/CCND1 amplification, TP53 and CDKN2A alterations, appeared at more advanced stages in aggressive tumors. In 28% of the tumors we identified genetic alterations potentially targetable by 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.

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          Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.

          Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.
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            Focal gains of VEGFA and molecular classification of hepatocellular carcinoma.

            Hepatocellular carcinomas represent the third leading cause of cancer-related deaths worldwide. The vast majority of cases arise in the context of chronic liver injury due to hepatitis B virus or hepatitis C virus infection. To identify genetic mechanisms of hepatocarcinogenesis, we characterized copy number alterations and gene expression profiles from the same set of tumors associated with hepatitis C virus. Most tumors harbored 1q gain, 8q gain, or 8p loss, with occasional alterations in 13 additional chromosome arms. In addition to amplifications at 11q13 in 6 of 103 tumors, 4 tumors harbored focal gains at 6p21 incorporating vascular endothelial growth factor A (VEGFA). Fluorescence in situ hybridization on an independent validation set of 210 tumors found 6p21 high-level gains in 14 tumors, as well as 2 tumors with 6p21 amplifications. Strikingly, this locus overlapped with copy gains in 4 of 371 lung adenocarcinomas. Overexpression of VEGFA via 6p21 gain in hepatocellular carcinomas suggested a novel, non-cell-autonomous mechanism of oncogene activation. Hierarchical clustering of gene expression among 91 of these tumors identified five classes, including "CTNNB1", "proliferation", "IFN-related", a novel class defined by polysomy of chromosome 7, and an unannotated class. These class labels were further supported by molecular data; mutations in CTNNB1 were enriched in the "CTNNB1" class, whereas insulin-like growth factor I receptor and RPS6 phosphorylation were enriched in the "proliferation" class. The enrichment of signaling pathway alterations in gene expression classes provides insights on hepatocellular carcinoma pathogenesis. Furthermore, the prevalence of VEGFA high-level gains in multiple tumor types suggests indications for clinical trials of antiangiogenic therapies.
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              Whole-genome sequencing identifies recurrent mutations in hepatocellular carcinoma

              Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole-genome sequencing (WGS) study of 88 matched HCC tumor/normal pairs, 81 of which are Hepatitis B virus (HBV) positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find beta-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumor suppressor (35.2%). The Wnt/beta-catenin and JAK/STAT pathways, altered in 62.5% and 45.5% of cases, respectively, are likely to act as two major oncogenic drivers in HCC. This study also identifies several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 ( JAK1 ), in 9.1% of patients and provides a path toward therapeutic intervention of the disease.
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                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                1 April 2015
                30 March 2015
                May 2015
                01 November 2015
                : 47
                : 5
                : 505-511
                Affiliations
                [1 ]Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d’Hematologie, Paris, F-75010 France
                [2 ]Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
                [3 ]Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Medecine, Biologie humaine, F-93000 Bobigny, France
                [4 ]Université Paris Diderot, F-75013 Paris
                [5 ]Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK
                [6 ]Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America
                [7 ]Assistance Publique-Hôpitaux de Paris, Department of Pathology, Centre hospitalier universitaire Henri Mondor, F-94000 Créteil, France
                [8 ]Hepatocellular Carcinoma Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Liver Unit. Centro de Investigación Biomédica en Red: Enfermedades Hépaticas y Digestivas; Hospital Clínic, Barcelona, Catalonia, Spain
                [9 ]Inserm, UMR-1053; Université de Bordeaux, Bordeaux, F-33076, France
                [10 ]Assistance Publique-Hôpitaux de Paris, Department of Digestive and Hepatobiliary Surgery, Centre hospitalier universitaire Henri Mondor, F-94000 Créteil, France
                [11 ]Inserm, UMR-955, F-94000 Créteil, France
                [12 ]Centre hospitalier universitaire de Bordeaux, Department of Hepatology, Hôpital Saint-André, Bordeaux, F-33076, France
                [13 ]Department of Liver Surgery and Transplant, Fondazione Istituto Tumori, via Venezian 1, 20133 Milan, Italy
                [14 ]Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris – Seine Saint-Denis, Site Jean Verdier, Pôle d’Activité Cancérologique Spécialisée, Service d’Hépatologie, F-93143 Bondy, France
                [15 ]Centre hospitalier universitaire de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, F-33076, France
                [16 ]Mount Sinai Liver Cancer Program (Division of Liver Diseases), Mount Sinai School of Medicine, New York, USA
                [17 ]Institució Catalana de Recerca i Estudis Avançats, Barcelona. Catalonia, Spain
                [18 ]Assistance Publique-Hôpitaux de Paris, Hopital Europeen Georges Pompidou, F-75015 Paris, France
                Author notes
                Correspondence should be addressed to: Jessica Zucman-Rossi; MD, PhD, INSERM U 1162, Génomique fonctionnelle des tumeurs solides, 27 Rue Juliette Dodu, 75010 Paris, France, TEL: +33 1 53 72 51 66, FAX: +33 1 53 72 51 92, jessica.zucman-rossi@ 123456inserm.fr

                Authors Contributions:

                Study concept and design: KS, SI, EL, LBA, MRS, JML, JZR

                Acquisition of data: JC, SR, GC,CM, FS, ALC, RP, LP, CB, AL, JFB, VM, AV, JCN, PBS

                Analysis and interpretation of data: KS, SI, EL, LBA, JC, SR, GC, CM, JS, FS, ALC, RP LP, AV, JCN, JZR

                Drafting the manuscript: KS, SI, EL, SR, JZR

                Critical revision of the manuscript: KS, SI, EL, LBA, JC, SR, RP, CB, JFB, JCN, PBS, JML, JZR

                Statistical analysis: KS, SI, EL

                Obtained funding: FC, JML, JZR

                Article
                EMS62359
                10.1038/ng.3252
                4587544
                25822088
                838966c1-55e2-4d21-b18e-628bea8a6459
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                Genetics
                Genetics

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