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.