Disparity landscapes of viral-induced structural variations in hepatocellular carcinoma: Mechanistic characterization and functional implications

Abstract

Oncoviruses can integrate into the host genome and cause tumorigenesis. In particular, hepatitis B virus (HBV) infection accounts for more than 50% of hepatocellular carcinoma (HCC) worldwide. We revealed the global geographical disparity of HBV integration that the landscape of HBV integration between HCC tumor and non-tumorous liver varied in regional cohorts, suggesting the different degrees of clonal enrichment. Most HBV integrations were positionally enriched at telomeres and centromeres (T&C) and they highlighted the novel co-involvement of HBV integration, which likely introduces genomic instability in HCC development. This was confirmed by phospho-H2AX staining. We constructed a large meta-cohort of multiple ethnicities to refine the landscape of HBV integration. This enables the gene set/family level exploration. As TERT is the most frequently integrated gene, we further investigated the underlying mechanistic modulation of TERT transcription activation and revealed the concurrent influence by the orientation and relative distance of HBV integration. Additionally, clonal disparity of HBV integration was observed among patients and the higher level of clonal disparity score can indicate poor patients’ prognostication. Taken together, our study uncovered the different levels of clonal enrichment of HBV integration, mechanistic insights, and prognostic biomarker signature, to strengthen our understanding in HBV-associated hepatocarcinogenesis.