THE INTERPLAY BETWEEN EPIGENETIC AND GENOMIC SIGNATURES OF HEPATITIS C VIRUS IN HEPATOCELLULAR CARCINOMA
2Cancer Personalized Medicine and Diagnostic Genomics Lab, Faculty of Medicine in the Galilee, Bar-Ilan University, Zefat
3Systems Computational Biology, Faculty of Engineering, Bar-Ilan University, Ramat-Gan
4Epigenetics in Human Health and Disease Laboratory, Baker IDI Heart & Diabetes Institute, Melbourne
5Davidoff Center, Rabin Medical Center, Beilinson Campus, Tel Aviv University, Petach-Tikva
6West Galilee Medical Center, Internal Department, Naharya
7Department of Surgery, Ziv Medical Center, Zefat
The evolutionary theory assumes that occurrence of mutations in cancer is random. However, recent studies suggest that passenger mutations are not randomly scattered in cancer genomes and that chromatin organization dictate mutations profiles. Hepatocellular carcinoma (HCC) serves as a model of diverse spectrum of cancers, since it is induced by a number of well-known etiological agents, mainly Hepatitis C virus (HCV) and Hepatitis B virus (HBV). Thus, it provides a unique opportunity to test the hypothesis that different etiological agents induce differential epigenetic profiles, and correspondingly differential rates of oncogenic mutations. We explored the link between genome wide chromatin organization alterations induced by HCV and HCV-specific genomic signature. Epigenetic analysis unraveled known and novel pathways that are misregulated by the virus such as Hepatic lipid metabolism, cell motility and cell cycle. These epigenetic alternations influence host gene expression and are essential for the HCV life cycle. Moreover, we demonstrate that HCV leaves an "epigenetic signature" on the host chromatin that is not fully recovered following virus eradication but can be reverted by epigenetic modifier drugs. These mechanisms are implicated in HCV "hit and run" scenario following HCV eradication that may elucidate the cause for the residual risk for HCC following HCV eradication. To explore the mutational signature we performed high-resolution target sequencing that enables the detection of low-frequency passenger mutations in 64 HCC biopsies from three etiology groups – HBV, HCV, or other. We identified novel distinct etiology-dependent regional mutations signatures. Significant correlation between high mutation rate and enrichment of chromatin modifications associated with closed transcription provides a link between etiology and cancer genome. Our study unveils novel etiology-specific mechanisms leading to cancer.
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