High-resolution Characterization of a Hepatocellular Carcinoma Genome

Nat Genet. 2011 May;43(5):464-9. doi: 10.1038/ng.804. Epub 2011 Apr 17.

Abstract

Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide. By massively parallel sequencing of a primary hepatitis C virus-positive hepatocellular carcinoma (36× coverage) and matched lymphocytes (>28× coverage) from the same individual, we identified more than 11,000 somatic substitutions of the tumor genome that showed predominance of T>C/A>G transition and a decrease of the T>C substitution on the transcribed strand, suggesting preferential DNA repair. Gene annotation enrichment analysis of 63 validated non-synonymous substitutions revealed enrichment of phosphoproteins. We further validated 22 chromosomal rearrangements, generating four fusion transcripts that had altered transcriptional regulation (BCORL1-ELF4) or promoter activity. Whole-exome sequencing at a higher sequence depth (>76× coverage) revealed a TSC1 nonsense substitution in a subpopulation of the tumor cells. This first high-resolution characterization of a virus-associated cancer genome identified previously uncharacterized mutation patterns, intra-chromosomal rearrangements and fusion genes, as well as genetic heterogeneity within the tumor.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / virology
  • Exons
  • Gene Rearrangement
  • Genes, Tumor Suppressor
  • Genetic Variation
  • Genomic Library
  • Genomics
  • Hepacivirus / pathogenicity
  • Humans
  • INDEL Mutation
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / virology
  • Mutation
  • Oncogenes
  • Polymorphism, Single Nucleotide
  • Selection, Genetic