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Exome-sequencing identifies new oncogenes and tumor suppressor genes recurrently altered in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. High-resolution copy number analysis of 125 tumors of which 24 were subjected to whole-exome sequencing identified 135 homozygous deletions and 994 somatic gene mutations with predicted functional consequences. We identified new recurrent alterations in 4 genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses demonstrated tumor suppressor properties for IRF2 whose inactivation, exclusively found in hepatitis B virus related tumors, leads to impaired TP53 function. Alternatively, inactivation of proteins involved in chromatin remodeling was frequent and predominant in alcohol related tumors. Moreover, activation of the oxidative stress metabolism and inactivation of RPS6KA3 were new pathways associated with WNT/beta-catenin activation, thereby suggesting a cooperative effect in tumorigenesis. This study shows the dramatic somatic genetic diversity in HCC, it reveals interactions between oncogene and tumor suppressor gene mutations markedly related to specific risk factors.

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Dataset ID Description Technology Samples
EGAD00001000131 Illumina HiSeq 2000 48
Publications Citations
Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
Nat Genet 44: 2012 694-698
Next-generation sequencing identified new oncogenes and tumor suppressor genes in human hepatic tumors.
Oncoimmunology 1: 2012 1612-1613
Signatures of mutational processes in human cancer.
Nature 500: 2013 415-421
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets.
Nat Genet 47: 2015 505-511
Mutational landscape of a chemically-induced mouse model of liver cancer.
J Hepatol 69: 2018 840-850
Advances in genomic hepatocellular carcinoma research.
Gigascience 7: 2018 None
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress.
Nat Commun 9: 2018 5235
Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials.
Br J Cancer 121: 2019 340-343
Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma.
Gut 71: 2022 616-626