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Nat Genet. 2015 May;47(5):505-511. doi: 10.1038/ng.3252. Epub 2015 Mar 30.

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

Schulze K#1,2,3,4, Imbeaud S#1,2,3,4, Letouzé E#1,2,3,4, Alexandrov LB5,6, Calderaro J1,2,3,4,7, Rebouissou S1,2,3,4, Couchy G1,2,3,4, Meiller C1,2,3,4, Shinde J1,2,3,4, Soysouvanh F1,2,3,4, Calatayud AL1,2,3,4, Pinyol R8, Pelletier L1,2,3,4, Balabaud C9, Laurent A10,11, Blanc JF9,12, Mazzaferro V13, Calvo F1,2,3,4, Villanueva A8,14, Nault JC1,2,3,4,15, Bioulac-Sage P9,16, Stratton MR5, Llovet JM8,14,17, Zucman-Rossi J1,2,3,4,18.

Author information

1
Inserm, UMR-1162, Génomique fonctionnelle des Tumeurs solides, Equipe Labellisée Ligue Contre le Cancer, Institut Universitaire d'Hematologie, Paris, F-75010 France.
2
Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
3
Université Paris 13, Sorbonne Paris Cité, Unité de Formation et de Recherche Santé, Medecine, Biologie humaine, F-93000 Bobigny, France.
4
Université Paris Diderot, F-75013 Paris.
5
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
6
Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
7
Assistance Publique-Hôpitaux de Paris, Department of Pathology, Centre hospitalier universitaire Henri Mondor, F-94000 Créteil, France.
8
Hepatocellular Carcinoma Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Liver Unit. Centro de Investigación Biomédica en Red: Enfermedades Hépaticas y Digestivas; Hospital Clínic, Barcelona, Catalonia, Spain.
9
Inserm, UMR-1053; Université de Bordeaux, Bordeaux, F-33076, France.
10
Assistance Publique-Hôpitaux de Paris, Department of Digestive and Hepatobiliary Surgery, Centre hospitalier universitaire Henri Mondor, F-94000 Créteil, France.
11
Inserm, UMR-955, F-94000 Créteil, France.
12
Centre hospitalier universitaire de Bordeaux, Department of Hepatology, Hôpital Saint-André, Bordeaux, F-33076, France.
13
Department of Liver Surgery and Transplant, Fondazione Istituto Tumori, via Venezian 1, 20133 Milan, Italy.
14
Mount Sinai Liver Cancer Program (Division of Liver Diseases), Mount Sinai School of Medicine, New York, USA.
15
Assistance Publique Hôpitaux de Paris, Hôpitaux Universitaires Paris - Seine Saint-Denis, Site Jean Verdier, Pôle d'Activité Cancérologique Spécialisée, Service d'Hépatologie, F-93143 Bondy, France.
16
Centre hospitalier universitaire de Bordeaux, Pellegrin Hospital, Department of Pathology, Bordeaux, F-33076, France.
17
Institució Catalana de Recerca i Estudis Avançats, Barcelona. Catalonia, Spain.
18
Assistance Publique-Hôpitaux de Paris, Hopital Europeen Georges Pompidou, F-75015 Paris, France.
#
Contributed equally

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.

PMID:
25822088
PMCID:
PMC4587544
DOI:
10.1038/ng.3252
[Indexed for MEDLINE]
Free PMC Article
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