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

被引：1153

作者：

Guichard, Cecile ^{[1
,2
]}

Amaddeo, Giuliana ^{[1
,2
]}

Imbeaud, Sandrine ^{[1
,2
]}

Ladeiro, Yannick ^{[1
,2
]}

Pelletier, Laura ^{[1
,2
]}

Ben Maad, Ichrafe ^{[1
,2
]}

Calderaro, Julien ^{[1
,2
,3
]}

Bioulac-Sage, Paulette ^{[4
,5
]}

Letexier, Melanie ^{[6
]}

Degos, Francoise ^{[7
]}

Clement, Bruno ^{[8
]}

Balabaud, Charles ^{[4
,5
]}

Chevet, Eric ^{[4
]}

Laurent, Alexis ^{[9
,10
]}

Couchy, Gabrielle ^{[1
,2
]}

Letouze, Eric ^{[11
]}

Calvo, Fabien ^{[12
]}

Zucman-Rossi, Jessica ^{[1
,2
,13
]}

机构：

[1] Inst Univ Hematol IUH, Unite Mixte Rech UMR 674, Inst Natl Sante & Rech Med INSERM, Paris, France

[2] Univ Paris 05, Fac Med, Paris, France

[3] Ctr Hosp Univ CHU Henri Mondor, AP HP, Dept Pathol, Creteil, France

[4] Univ Bordeaux 2, INSERM, UMR 1053, F-33076 Bordeaux, France

[5] Pellegrin Hosp, CHU Bordeaux, Dept Pathol, Bordeaux, France

[6] IntegraGen, Evry, France

[7] Univ Paris Diderot, Beaujon Hosp, AP HP, Dept Hepatol, Clichy, France

[8] Univ Rennes 1, INSERM, UMR 991, Rennes, France

[9] CHU Henri Mondor, AP HP, F-94010 Creteil, France

[10] Hop Henri Mondor, INSERM, U955, F-94010 Creteil, France

[11] Programme Cartes Identite Tumeurs, Paris, France

[12] Inst Natl Canc INCa, Boulogne, France

[13] Hop Europeen Georges Pompidou, AP HP, Paris, France

来源：

NATURE GENETICS | 2012年 / 44卷 / 06期

关键词：

P53; GENE; ARID1A; CANCER; INACTIVATION; RECOGNITION; PATTERNS;

D O I：

10.1038/ng.2256

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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/beta-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.

引用

页码：694 / U120

页数：7

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