• Finding: Mutations, gene fusions, and genetic susceptibility factors are identified in HCV-induced hepatocellular carcinoma.

  • Approach: Massively parallel, genome-wide strategy is used to characterize hepatocellular carcinoma.

  • Impact: Genome-wide studies can characterize individual cancer genomes and intra-tumoral heterogeneity.

Hepatocellular carcinoma (HCC) remains the third most common cause of cancer-related deaths across the world, and persistent infection with hepatitis C virus (HCV), known as chronic hepatitis C (CHC), is often the underlying cause. In two recent articles, authors performed molecular analysis of either the HCC tumor genome or DNA from HCC-affected patients to explore the genetic basis of HCV-induced HCC. Totoki and colleagues sequenced short-insert genomic libraries from a primary HCV-positive HCC tumor and lymphocytes. High-resolution characterization of this hepatocellular carcinoma genome identified more than 11,000 somatically acquired mutations. In addition to these mutations, the authors also found 22 chromosomal rearrangements generating 4 somatic fusion transcripts, including BCORL1-ELF4, which was shown to have reduced transcriptional repression activity when compared to wild-type BCORL1. Lastly, whole-exome sequencing identified a nonsense mutation in TSC1, a known tumor suppressor gene, in a minority of tumor cells. In a related article, Kumar and colleagues used genome-wide analysis to identify genetic susceptibility factors associated with HCV-induced HCC. The most highly associated single nucleotide polymorphism, rs2596542, was found to be located within the class I major histocompatibility complex (MHC) region, in the 5′ flanking region of MICA, the MHC class I polypeptide-related sequence A gene. Upon further genotyping, the authors discovered rs2596542 to be associated specifically with progression from CHC to HCC, rather than to susceptibility to CHC. Importantly, individuals with rs2596542 expressed lower levels of soluble MICA, lending support to the conclusion that the development of HCV-induced HCC is influenced by genetic variations in the host immune system. In both articles, molecular analysis of HCV-induced HCC uncovered unique genes that may provide future therapeutic targets for the treatment of this disease.

Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F, Ishikawa S, et al. High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet 2011 Apr 17. [Epub ahead of print]

Kumar V, Kato N, Urabe Y, Takahashi A, Muroyama R, Hosono N, et al. Genome-wide association study identifies a susceptibility locus for HCV-induced hepatocellular carcinoma. Nat Genet 2011 Apr 17. [Epub ahead of print]

Note:Research Watch is written by Cancer Discovery Editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.