Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma

Nat Genet. 2012 May 27;44(7):765-9. doi: 10.1038/ng.2295.

Abstract

To survey hepatitis B virus (HBV) integration in liver cancer genomes, we conducted massively parallel sequencing of 81 HBV-positive and 7 HBV-negative hepatocellular carcinomas (HCCs) and adjacent normal tissues. We found that HBV integration is observed more frequently in the tumors (86.4%) than in adjacent liver tissues (30.7%). Copy-number variations (CNVs) were significantly increased at HBV breakpoint locations where chromosomal instability was likely induced. Approximately 40% of HBV breakpoints within the HBV genome were located within a 1,800-bp region where the viral enhancer, X gene and core gene are located. We also identified recurrent HBV integration events (in ≥ 4 HCCs) that were validated by RNA sequencing (RNA-seq) and Sanger sequencing at the known and putative cancer-related TERT, MLL4 and CCNE1 genes, which showed upregulated gene expression in tumor versus normal tissue. We also report evidence that suggests that the number of HBV integrations is associated with patient survival.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / virology*
  • Chromosomal Instability / genetics
  • Cyclin E / genetics
  • DNA Copy Number Variations / genetics
  • DNA, Viral / genetics
  • DNA-Binding Proteins / genetics
  • Female
  • Hepatitis B virus / genetics*
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / virology*
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Oncogene Proteins / genetics
  • RNA, Viral / genetics
  • Survival Rate
  • Telomerase / genetics
  • Virus Integration / genetics*

Substances

  • CCNE1 protein, human
  • Cyclin E
  • DNA, Viral
  • DNA-Binding Proteins
  • Oncogene Proteins
  • RNA, Viral
  • MLL4 protein, human
  • TERT protein, human
  • Telomerase

Associated data

  • GEO/GSE25097