High-resolution liver cancer genomic profiling links etiology, epigenetic and mutation signatures

Hepatocellular carcinoma (HCC) is a model of diverse spectrum of cancers, since it is induced bywell-known etiologies, mainly Hepatitis C virus (HCV) and Hepatitis B virus (HBV). We exploredthe link between HCV-specific genomic signature and HCV-induced genome-wide epigeneticalterations. Using high-resolution sequencing that detected low-frequency passenger mutations inHCC from three etiology groups – HBV, HCV, or other, we identified novel distinct etiology-dependent mutation signatures. We demonstrated that HCV infection induces epigenetic changes thatpersist as "epigenetic signature" following virus eradication and reprogram host gene expression.High mutation rate associated with HCV etiology correlated with HCV-induced changes inepigenetic markers leading to compacted chromatin. Our study unveils a novel etiology-specificmechanisms leading to cancer, linking etiology to cancer genome.