Abstract 1481: Disparity landscapes of HBV integration in hepatocellular carcinoma: Mechanistic characterization and functional implications

Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a common malignancy worldwide. About half of all new liver cancers worldwide each year occur in China due to a high prevalence of hepatitis B virus (HBV) infection. HBV DNA integrates into the human genome, disrupting the endogenous tumor suppressors/regulatory genes or enhancing the activity of proto-oncogenes. It would be useful to examine the different NGS-based databases to provide a more unbiased and comprehensive survey of HBV integration. We aimed to take advantage of publicly available datasets of different regional cohorts to determine the disparity landscapes of integration events among sample cohorts, tissue types, chromosomal positions, individual host and viral genes, and genic locations. By comparing HCC tumor with non-tumorous liver, landscape of HBV integration was delineated at gene-independent and gene-dependent manners. Moreover, we performed mechanistic investigations on how HBV-TERT integration led to TERT activation and derived a score to predict patients’ prognostication according to their clonal disparity landscape of HBV integration. We revealed a global geographical disparity of HBV integration that the landscape of HBV integration between HCC and non-tumorous liver varied in regional cohorts, suggesting the different degrees of clonal enrichment. In the Mainland China, Hong Kong and Mongolia cohorts, HCC tumors had higher numbers of events than the non-tumorous livers, whereas in the French and US cohorts, the reverse was true. Moreover, most HBV integrations were positionally enriched at the telomeres and centromeres, and this highlighted the novel co-involvement of HBV integration at these regions, which likely introduces greater genomic instability. Furthermore, we constructed a large meta-cohort of multiple ethnicities to refine the landscape of HBV integration. This enabled the identification of events at key HCC-related genes (e.g., TERT, KMT2B, and CCNA2) and gene families (e.g., cyclin, cadherin, and contactin). As TERT is the most frequently integrated gene by HBV, we further investigated the mechanistic modulation of TERT transcription activation by combining and analyzing our in-house sample cohort with a previous report and luciferase reporter assays. This revealed the positive concurrent influence by both the orientation and relative distance of HBV integration (closer to transcription start site) from the TERT gene. Additionally, we observed clonal disparity of HBV integration among patients and the higher level of the clonal disparity score correlated with poor prognostication of HCC patients. Our study uncovered the different levels of clonal enrichment of HBV integration and identified mechanistic insights and prognostic biomarker. This strengthens our understanding of HBV-associated hepatocarcinogenesis. Citation Format: Xueying Lyu, Karen Man-Fong Sze, Joyce Man-Fong Lee, Abdullah Husain, Irene Oi-Lin Ng, Daniel Wai-Hung Ho. Disparity landscapes of HBV integration in hepatocellular carcinoma: Mechanistic characterization and functional implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1481.