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

Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tum...

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Published in:	Nature genetics Vol. 47; no. 5; pp. 505 - 511
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01.05.2015 Nature Publishing Group
Subjects:	13 13/106 45 45/23 45/61 631/208/514/1948 692/699/67/1504/1610 Aflatoxins Aged Agriculture Animal Genetics and Genomics Antineoplastic Agents - pharmacology BASIC BIOLOGICAL SCIENCES Benzoquinones - pharmacology Biomedical and Life Sciences Biomedicine Cancer Cancer Research Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - genetics Cell Line, Tumor Development and progression DNA Mutational Analysis DNA sequencing Exome Exome sequencing Female Gene Function Gene mutations Genetic aspects Genetic Association Studies Genetics Genomes Health aspects Hepatoma HSP90 Heat-Shock Proteins - antagonists & inhibitors Human Genetics Human health and pathology Humans Hépatology and Gastroenterology Identification and classification Infections Lactams, Macrocyclic - pharmacology letter Life Sciences liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - genetics Male Medical research Metabolism Methods Molecular Targeted Therapy Mutation NAD(P)H Dehydrogenase (Quinone) - genetics NAD(P)H Dehydrogenase (Quinone) - metabolism Patients Quantitative Methods Risk Factors Sequence Deletion Tobacco Tumors
ISSN:	1061-4036, 1546-1718
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Summary:	Jessica Zucman-Rossi and colleagues report exome sequences of 243 hepatocellular carcinomas. They identify mutational signatures associated with specific risk factors such as alcohol, tobacco and aflatoxin B1 and find genetic alterations potentially targetable by FDA-approved drugs in 28% of the tumors. 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.
Bibliography:	SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 PMCID: PMC4587544 USDOE AC52-06NA25396 LA-UR-14-28199 Authors Contributions Analysis and interpretation of data: KS, SI, EL, LBA, JC, SR, GC, CM, JS, FS, ALC, RP LP, AV, JCN, JZR Acquisition of data: JC, SR, GC,CM, FS, ALC, RP, LP, CB, AL, JFB, VM, AV, JCN, PBS Critical revision of the manuscript: KS, SI, EL, LBA, JC, SR, RP, CB, JFB, JCN, PBS, JML, JZR Statistical analysis: KS, SI, EL Study concept and design: KS, SI, EL, LBA, MRS, JML, JZR Obtained funding: FC, JML, JZR Drafting the manuscript: KS, SI, EL, SR, JZR
ISSN:	1061-4036 1546-1718
DOI:	10.1038/ng.3252