High-resolution genomic profiling of liver cancer links etiology with mutation and epigenetic signatures.

BACKGROUND: Hepatocellular carcinoma (HCC) is a model of diverse spectrum of cancers, since it is induced by well-known etiologies, mainly Hepatitis C virus (HCV) and Hepatitis B virus (HBV). Here we aimed to identify HCV-specific mutational signature and explored the link between the HCV-related regional variation in mutations rates and HCV-induced alterations in genome-wide chromatin organization.

METHODS: To identify an HCV-specific mutational signature in HCC, we performed high-resolution targeted sequencing to detect passenger mutations on 64 HCC samples from three etiology groups - HBV, HCV, or other. To explore the link between genomic signature and genome-wide chromatin organization we performed ChIP-seq for the transcriptionally permissive H3K4me3, H3K9ac and suppressive H3K9me3 modifications following HCV infection.

RESULTS: Regional variation in mutations rates analysis revealed significant etiology-dependent regional mutations-rate in 12 genes: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4 and ARSD. We found an enrichment of C->T transversion mutations in the HCV-associated HCC cases. Furthermore, these cases exhibited regional variation in mutations rates associated with genomic intervals where HCV infection dictates epigenetic alterations. This signature may be related to the HCV-induced decreased expression of genes encoding key enzymes in the base excision repair pathway.

CONCLUSIONS: We identified novel distinct HCV etiology-dependent mutation signatures in HCC associated with HCV-induced alterations in histone modification. This study presents a link between cancer-causing mutagenesis, and the increased predisposition to liver cancer in chronic HCV-infected individuals, and unveils novel etiology-specific mechanisms leading to HCC and cancer in general.