GENOMIC AND EPIGENETIC SIGNATURES OF HEPATITIS VIRUSES IN LIVER CANCER

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 a 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). This provides a unique opportunity to test whether different etiological agents (HBV and HCV) dictate distinct mutational landscapes across the genome and a unique epigenetic signature which reprogram gene expression pattern.

The HCC-specific genomic mutations were studied in 80 HCC biopsy samples from three etiology groups – HBV-infected, HCV-infected, or other. To explore the mutational signature we performed high-resolution sequencing that enables the detection of low-frequency passenger mutations, by using SureSelect™ Target Enrichment system. Bioinformatical analysis revealed significant etiology-dependent regional mutations-rate in specific genes and etiology specific pathways that are mutated in HCC. These observations suggest that viral infection modulate somatic mutations causing HCC. We also studied the epigenetic changes of HCV-infected HCC cells in a genome wide histone modifications and DNA methylation. Epigenetic analysis unraveled known and novel pathways that are controlled by the virus such as Hepatic lipid metabolism, which plays an essential role in the viral life cycle, transcription factors that are involved in oncogenesis and EMT, cell cycle and immunity.

Our novel approach link between etiology and cancer genome, and provides a perspective into the mechanisms that shape mutational signature development in cancer. The findings may enhance rational administrations of targeted drugs according to etiology, and unravel etiology-dependent diagnostic markers for HCC.