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Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
Guichard, Cécile; Amaddeo, Giuliana; Imbeaud, Sandrine; Ladeiro, Yannick; Pelletier, Laura; Maad, Ichrafe Ben; Calderaro, Julien; Bioulac-Sage, Paulette; Letexier, Mélanie; Degos, Françoise; Clément, Bruno; Balabaud, Charles; Chevet, Eric; Laurent, Alexis; Couchy, Gabrielle; Letouzé, Eric; Calvo, Fabien; Zucman-Rossi, Jessica.
Afiliação
  • Guichard C; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité Mixte de Recherche (UMR)-674, Génomique Fonctionnelle des Tumeurs Solides, Paris, France.
Nat Genet ; 44(6): 694-8, 2012 May 06.
Article em En | MEDLINE | ID: mdl-22561517
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/ß-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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Variações do Número de Cópias de DNA / Neoplasias Hepáticas / Mutação Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2012 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma Hepatocelular / Variações do Número de Cópias de DNA / Neoplasias Hepáticas / Mutação Tipo de estudo: Prognostic_studies / Risk_factors_studies Limite: Humans Idioma: En Revista: Nat Genet Assunto da revista: GENETICA MEDICA Ano de publicação: 2012 Tipo de documento: Article País de afiliação: França