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

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 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.

• Authors: 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 Nault, Paulette Bioulac-Sage, Michael R Stratton, Josep M Llovet, Jessica Zucman-Rossi
• Journal: Nature genetics (Nat Genet) Vol. 47 Issue 5 Pg. 505-511 (May 2015) ISSN: 1546-1718 [Electronic] United States
• PMID: 25822088 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Benzoquinones
• HSP90 Heat-Shock Proteins
• Lactams, Macrocyclic
• 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin
• tanespimycin
• NAD(P)H Dehydrogenase (Quinone)
• NQO1 protein, human

Topics

• Aged
• Antineoplastic Agents (pharmacology)
• Benzoquinones (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, genetics)
• Cell Line, Tumor
• DNA Mutational Analysis
• Exome
• Female
• Genetic Association Studies
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Humans
• Lactams, Macrocyclic (pharmacology)
• Liver Neoplasms (drug therapy, genetics)
• Male
• Molecular Targeted Therapy
• NAD(P)H Dehydrogenase (Quinone) (genetics, metabolism)
• Risk Factors
• Sequence Deletion