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.