Genomic analyses promise to improve tumor characterization to optimize personalized treatment for patients with hepatocellular carcinoma (HCC). Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors, mainly combined alcohol and tobacco consumption and exposure to aflatoxin B1. We identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors and centered on CTNNB1 (alcohol), TP53 (hepatitis B virus, HBV) and AXIN1. Analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereas FGF3, FGF4, FGF19 or CCND1 amplification and TP53 and CDKN2A alterations appeared at more advanced stages in aggressive tumors. In 28% of the tumors, we identified genetic alterations potentially targetable by US Food and Drug Administration (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.
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Gene Expression Omnibus
We warmly thank A. Boulais, C. Guichard, I. Ben Maad and C. Pilati for helpful participation in this work. We thank L. de Koning, C. Baldeyron, A. Barbet and C. Lecerf from the Institut Curie for the reverse-phase protein array experiments. We also thank J. Saric, C. Laurent, L. Chiche, B. Le Bail and C. Castain (Centre Hospitalier Universitaire Bordeaux) and D. Cherqui and J. Tran Van Nhieu (Centre Hospitalier Universitaire Henri Mondor, Créteil) for contributing to the tissue collection. This work was supported by Institut National du Cancer (INCa) with the ICGC project, the PAIR-CHC project NoFLIC (funded by INCa and Association pour la Recherche contre le Cancer, ARC), HEPTROMIC (Framework Programme 7), Cancéropole Ile de France, Centres de Ressources Biologiques (CRB) Liver Tumors, Tumorotheque Centre Hospitalier Universitaire Bordeaux and Centre Hospitalier Universitaire Henri Mondor, BioIntelligence (OSEO) and INSERM. J.-C.N. was supported by a fellowship from INCa. K.S. is supported by the Deutsche Forschungsgemeinschaft (DFG grant SCHU 2893/2-1). Research performed at Los Alamos National Laboratory was carried out under the auspices of the National Nuclear Security Administration of the US Department of Energy. V.M. is supported by a grant from AIRC (Italian Association for Cancer Research). J.M.L. is supported by grants from the European Comission Framework Programme 7 (HEPTROMIC, proposal 259744), The Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF-2010-16055 and SAF-2013-41027) and the Asociación Española Contra el Cáncer (AECC).
Integrated supplementary information
List of mutations identified by exome sequencing (hypermutated CHC892T excluded).
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Genes, Chromosomes and Cancer (2019)