High-resolution characterization of a hepatocellular carcinoma genome

Hepatocellular carcinoma, one of the most common virus-associated cancers, is the third most frequent cause of cancer-related death worldwide(1). By massively parallel sequencing(2) of a primary hepatitis C virus-positive hepatocellular carcinoma (36x coverage) and matched lymphocytes (> 28x 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(3) 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(4,5) at a higher sequence depth (> 76x 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.