The Interplay between Etiology-Dependent Genomic and Epigenetic Signatures: The Paradigm of 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 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 dictate distinct mutational landscapes across the genome through a unique epigenetic signature. The HCC-specific genomic mutations were studied in 80 HCC biopsies from three etiology groups - HBV, HCV, or other. To explore the mutational signature we performed target high-resolution sequencing that enables the detection of low-frequency passenger mutations. By using this strategy we identified novel distinct etiology-dependent regional mutations signature in specific genes and pathways in HCC that was not detected previously by exome sequencing of liver tumors. These observations suggest that viral infection modulate somatic mutations causing HCC. To explore the link between genomic signature and genome wide chromatin organization we studied the epigenetic changes occur following HCV infection. Epigenetic analysis unraveled known and novel pathways that are controlled by the virus such as Hepatic lipid metabolism, cell motility, cell cycle and immunity. Invers correlation between high mutation rate and enrichment of chromatin modifications associated with active transcription provides a link between etiology and cancer genome. Our novel approach offers a perspective into the mechanisms that shape mutational signature development in cancer.