Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets
Abstract
Our 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. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, 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. Finally, 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:
-
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- INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France)
- Wellcome Trust Sanger Inst., Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
- INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France); Public Assistance Hospital of Paris (France)
- Hepatocellular Carcinoma Translational Research Laboratory, Barcelona (Spain)
- INSERM, Bordeaux (France)
- Public Assistance Hospital of Paris (France); INSERM, Creteil (France)
- INSERM, Bordeaux (France); Bordeaux Univ. Hospital (France)
- Fondazione Inst., Milan (Italy)
- Hepatocellular Carcinoma Translational Research Laboratory, Barcelona (Spain); Mount Sinai School of Medicine, New York, NY (United States)
- INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France); Univ. Hospital of Paris (France)
- Wellcome Trust Sanger Inst., Hinxton (United Kingdom)
- Hepatocellular Carcinoma Translational Research Laboratory, Barcelona (Spain); Mount Sinai School of Medicine, New York, NY (United States); Catalan Inst. for Research Studies, Barcelona (Spain)
- Publication Date:
- Research Org.:
- Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1235730
- Report Number(s):
- LA-UR-14-28199
Journal ID: ISSN 1061-4036; ng.3252
- Grant/Contract Number:
- AC52-06NA25396
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Genetics
- Additional Journal Information:
- Journal Volume: 47; Journal Issue: 5; Journal ID: ISSN 1061-4036
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; DNA sequencing; liver cancer
Citation Formats
Schulze, Kornelius, Imbeaud, Sandrine, Letouzé, Eric, Alexandrov, Ludmil B., Calderaro, Julien, Rebouissou, Sandra, Couchy, Gabrielle, Meiller, Clément, Shinde, Jayendra, Soysouvanh, Frederic, Calatayud, Anna-Line, Pinyol, Roser, Pelletier, Laura, Balabaud, Charles, Laurent, Alexis, Blanc, Jean-Frederic, Mazzaferro, Vincenzo, Calvo, Fabien, Villanueva, Augusto, Nault, Jean-Charles, Bioulac-Sage, Paulette, Stratton, Michael R., Llovet, Josep M., and Zucman-Rossi, Jessica. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. United States: N. p., 2015.
Web. doi:10.1038/ng.3252.
Schulze, Kornelius, Imbeaud, Sandrine, Letouzé, Eric, Alexandrov, Ludmil B., Calderaro, Julien, Rebouissou, Sandra, Couchy, Gabrielle, Meiller, Clément, Shinde, Jayendra, Soysouvanh, Frederic, Calatayud, Anna-Line, Pinyol, Roser, Pelletier, Laura, Balabaud, Charles, Laurent, Alexis, Blanc, Jean-Frederic, Mazzaferro, Vincenzo, Calvo, Fabien, Villanueva, Augusto, Nault, Jean-Charles, Bioulac-Sage, Paulette, Stratton, Michael R., Llovet, Josep M., & Zucman-Rossi, Jessica. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. United States. https://doi.org/10.1038/ng.3252
Schulze, Kornelius, Imbeaud, Sandrine, Letouzé, Eric, Alexandrov, Ludmil B., Calderaro, Julien, Rebouissou, Sandra, Couchy, Gabrielle, Meiller, Clément, Shinde, Jayendra, Soysouvanh, Frederic, Calatayud, Anna-Line, Pinyol, Roser, Pelletier, Laura, Balabaud, Charles, Laurent, Alexis, Blanc, Jean-Frederic, Mazzaferro, Vincenzo, Calvo, Fabien, Villanueva, Augusto, Nault, Jean-Charles, Bioulac-Sage, Paulette, Stratton, Michael R., Llovet, Josep M., and Zucman-Rossi, Jessica. Mon .
"Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets". United States. https://doi.org/10.1038/ng.3252. https://www.osti.gov/servlets/purl/1235730.
@article{osti_1235730,
title = {Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets},
author = {Schulze, Kornelius and Imbeaud, Sandrine and Letouzé, Eric and Alexandrov, Ludmil B. and Calderaro, Julien and Rebouissou, Sandra and Couchy, Gabrielle and Meiller, Clément and Shinde, Jayendra and Soysouvanh, Frederic and Calatayud, Anna-Line and Pinyol, Roser and Pelletier, Laura and Balabaud, Charles and Laurent, Alexis and Blanc, Jean-Frederic and Mazzaferro, Vincenzo and Calvo, Fabien and Villanueva, Augusto and Nault, Jean-Charles and Bioulac-Sage, Paulette and Stratton, Michael R. and Llovet, Josep M. and Zucman-Rossi, Jessica},
abstractNote = {Our 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. These analyses according to tumor stage progression identified TERT promoter mutation as an early event, whereasFGF3, 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. Finally, 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.},
doi = {10.1038/ng.3252},
journal = {Nature Genetics},
number = 5,
volume = 47,
place = {United States},
year = {Mon Mar 30 00:00:00 EDT 2015},
month = {Mon Mar 30 00:00:00 EDT 2015}
}
Web of Science
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