title: Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
abstract: 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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)-674, Génomique Fonctionnelle des Tumeurs Solides, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Guichard
authors.forename: Giuliana
authors.initials: G
authors.lastname: Amaddeo
authors.forename: Sandrine
authors.initials: S
authors.lastname: Imbeaud
authors.forename: Yannick
authors.initials: Y
authors.lastname: Ladeiro
authors.forename: Laura
authors.initials: L
authors.lastname: Pelletier
authors.forename: Ichrafe Ben
authors.initials: IB
authors.lastname: Maad
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Mélanie
authors.initials: M
authors.lastname: Letexier
authors.forename: Françoise
authors.initials: F
authors.lastname: Degos
authors.forename: Bruno
authors.initials: B
authors.lastname: Clément
authors.forename: Charles
authors.initials: C
authors.lastname: Balabaud
authors.forename: Eric
authors.initials: E
authors.lastname: Chevet
authors.forename: Alexis
authors.initials: A
authors.lastname: Laurent
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Couchy
authors.forename: Eric
authors.initials: E
authors.lastname: Letouzé
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D056915:DNA Copy Number Variations; D006801:Humans; D050836:Interferon Regulatory Factor-2 / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics
chemical_list: C494229:IRF2 protein, human; D050836:Interferon Regulatory Factor-2