Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets

Genomic analyses promise to improve tumor characterization in order to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors revealed mutational signatures associated with specific risk factors, mainly combined alcohol/tobacco consumption, aflatoxin B1 and HBV infection. We identified 161 putative driver genes associated with 11 recurrent pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (HBV) and AXIN1. Analyses according to tumor stage progression revealed TERT promoter mutation as an early event whereas FGF/CCND1 amplification, TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 24% of the tumors, we identified genetic alterations potentially targetable by FDA-approved drugs. In conclusion, we identified risk factor–specific mutational signatures and defined the extensive landscape of altered genes and pathways in HCC, which will be useful to design clinical trials for targeted therapy.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 5 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001001096	None	Illumina HiSeq 2000	419

Publications	Citations
Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Schulze K, Imbeaud S, Letouzé E, Alexandrov LB, Calderaro J, Rebouissou S, Couchy G, Meiller C, Shinde J, Soysouvanh F, Calatayud AL, Pinyol R, Pelletier L, Balabaud C, Laurent A, Blanc JF, Mazzaferro V, Calvo F, Villanueva A, Nault JC, Bioulac-Sage P, Stratton MR, Llovet JM, Zucman-Rossi J. Nat Genet 47: 2015 505-511	959
Mutational landscape of a chemically-induced mouse model of liver cancer. Connor F, Rayner TF, Aitken SJ, Feig C, Lukk M, Santoyo-Lopez J, Odom DT. J Hepatol 69: 2018 840-850	66
Cyclin A2/E1 activation defines a hepatocellular carcinoma subclass with a rearrangement signature of replication stress. Bayard Q, Meunier L, Peneau C, Renault V, Shinde J, Nault JC, Mami I, Couchy G, Amaddeo G, Tubacher E, Bacq D, Meyer V, La Bella T, Debaillon-Vesque A, Bioulac-Sage P, Seror O, Blanc JF, Calderaro J, Deleuze JF, Imbeaud S, Zucman-Rossi J, Letouzé E. Nat Commun 9: 2018 5235	78
Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials. Montal R, Andreu-Oller C, Bassaganyas L, Esteban-Fabró R, Moran S, Montironi C, Moeini A, Pinyol R, Peix J, Cabellos L, Villanueva A, Sia D, Mazzaferro V, Esteller M, Llovet JM. Br J Cancer 121: 2019 340-343	45
Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Péneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro J, Paradis V, Blanc JF, Letouzé E, Nault JC, Amaddeo G, Zucman-Rossi J. Gut 71: 2022 616-626	79