Trans-ancestry mutational landscape of hepatocellular carcinoma genomes

Nat Genet. 2014 Dec;46(12):1267-73. doi: 10.1038/ng.3126. Epub 2014 Nov 2.

Abstract

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Asian Continental Ancestry Group
  • Carcinoma, Hepatocellular / epidemiology
  • Carcinoma, Hepatocellular / ethnology*
  • Carcinoma, Hepatocellular / genetics*
  • CpG Islands
  • DNA Mutational Analysis
  • European Continental Ancestry Group
  • Exome
  • Gene Expression Regulation, Neoplastic
  • Genome, Human*
  • Genome, Viral
  • Hepacivirus / genetics
  • Hepatitis B virus / genetics
  • Humans
  • Japan
  • Liver Neoplasms / epidemiology
  • Liver Neoplasms / ethnology*
  • Liver Neoplasms / genetics*
  • Models, Statistical
  • Mutation*
  • Principal Component Analysis
  • TOR Serine-Threonine Kinases / genetics
  • Telomerase / genetics
  • United States

Substances

  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • TERT protein, human
  • Telomerase