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

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:
 [1] ;  [1] ;  [1] ;  [2] ;  [3] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [4] ;  [1] ;  [5] ;  [6] ;  [7] ;  [8] ;  [1] ;  [9] ;  [10] more »;  [7] ;  [11] ;  [12] ;  [3] « less
  1. INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France)
  2. Wellcome Trust Sanger Inst., Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France); Public Assistance Hospital of Paris (France)
  4. Hepatocellular Carcinoma Translational Research Laboratory, Barcelona (Spain)
  5. INSERM, Bordeaux (France)
  6. Public Assistance Hospital of Paris (France); INSERM, Creteil (France)
  7. INSERM, Bordeaux (France); Bordeaux Univ. Hospital (France)
  8. Fondazione Inst., Milan (Italy)
  9. Hepatocellular Carcinoma Translational Research Laboratory, Barcelona (Spain); Mount Sinai School of Medicine, New York, NY (United States)
  10. INSERM, Paris (France); Paris Descartes Univ., (France); Paris 13 Univ. (France); Paris Diderot Univ. (France); Univ. Hospital of Paris (France)
  11. Wellcome Trust Sanger Inst., Hinxton (United Kingdom)
  12. 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:
OSTI Identifier:
1235730
Report Number(s):
LA-UR--14-28199
Journal ID: ISSN 1061-4036; ng.3252
Grant/Contract Number:
AC52-06NA25396
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
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES DNA sequencing; liver cancer