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

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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.

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Figure 1: Profiles of verified mutations with functional consequences in HCC.
Figure 2: Overview of mutations and major associated clinical features.
Figure 3: Major pathways commonly altered by somatic mutations or homozygous gene deletions.
Figure 4: IRF2 is a new tumor suppressor gene in HCC that controls the p53 pathway.

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Acknowledgements

We warmly thank T. Burguiere, G. Thomas, R. Fahraeus and C. Mlynarczyk for their helpful participation in this work. We also thank J. Saric, C. Laurent, B. Le Bail, A. Rullier, A. Sa Cunha, J.T. Van Nhieu, D. Cherqui and D. Azoulay for contributing to tissue collection. This work was supported by INCa with the ICGC project, the Ligue Nationale Contre le Cancer (Cartes d'Identité des Tumeurs program), the PAIR-CHC project NoFLIC (funded by INCa and the Association pour la Recherche Contre le Cancer, ARC), the Réseau National Centre de Recherches Biocosmétiques (CRB) Foie, HEPTROMIC (Framework Programme 7, FP7) and BioIntelligence (OSEO). G.A. is supported by a fellowship from the Agence Nationale de Recherches sur le Sida et les Hepatites Virales (ANRS).

Author information

C.G., S.I., M.L. and I.B.M. designed, analyzed and verified the whole-exome sequencing data. G.A. and Y.L. designed and performed the IRF2 analyses. S.I. performed statistical analyses. C.G., G.A., Y.L., L.P., I.B.M. and G.C. performed the sequencing validation. J.C. and P.B.-S. provided samples and pathological reviewing. F.D., B.C., C.B. and A.L. provided samples and clinical information. S.I., C.G. and E.C. contributed to pathway analyses. E.L. and S.I. analyzed copy-number variant data. F.C. organized the project through the ICGC and participated in the achievement of the study. J.Z.-R. designed and coordinated the overall study. All authors contributed to writing the manuscript.

Correspondence to Jessica Zucman-Rossi.

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Guichard, C., Amaddeo, G., Imbeaud, S. et al. Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44, 694–698 (2012) doi:10.1038/ng.2256

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