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

Kornelius Schulze, Sandrine Imbeaud, Eric Letouzé, Ludmil B. Alexandrov, Julien Calderaro, Sandra Rebouissou, Gabrielle Couchy, Clément Meiller, Jayendra Shinde, Frederic Soysouvanh, Anna Line Calatayud, Roser Pinyol, Laura Pelletier, Charles Balabaud, Alexis Laurent, Jean Frederic Blanc, Vincenzo Mazzaferro, Fabien Calvo, Augusto Villanueva, Jean Charles NaultPaulette Bioulac-Sage, Michael R. Stratton, Josep M. Llovet, Jessica Zucman-Rossi

Research output: Contribution to journalArticlepeer-review

Abstract

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 B 1. 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.

Original languageEnglish
Pages (from-to)505-511
Number of pages7
JournalNature Genetics
Volume47
Issue number5
DOIs
Publication statusPublished - May 30 2015

ASJC Scopus subject areas

  • Genetics
  • Medicine(all)

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