Genomic and biological characterization of Hepatitis B virus integration sites in the human genome associated with hepatocarcinogenesis

Hepatitis B virus (HBV) gene insertion into the human genome is frequently observed in hepatocellular carcinoma (HCC). The characteristics of the HBV integration site (HBVIS) and its selective oncogenic effects remain unclear. This study aimed to systematically identify the distinctive traits of HBVIS and associate them with potential carcinogenesis. HBVISs curated from published articles and databases were remapped to build a unique dataset of 29,153 HBVISs. A normalized metric was defined to assess the HBVIS distribution in the whole genome. Differentially expressed genes (DEGs) with two or more HBVISs from different contrasts were selected for enrichment analysis to explore the biological processes and pathways of integration hotspots related to HCC. We identified significant enrichment of HBVIS on chr5, chr8, chr17, chr19, and chrY in tumors (P<0.01). Distinct preferential integration patterns were observed in the telomeric regions of some chromosomes, cancer genes, and regulatory regions. Our statistics revealed that HBV integrations are enriched in the proximal promoter (within 1kb), CpG islands, and 3′-untranslated region (UTR) compared with the expected (P<0.05), rather than fragile chromosomal regions and open chromatin regions. DEGs in HBV-infected cases distinguished them from uninfected cases, mainly enriched in abnormal carboxylic acid metabolism and the cytochrome P450 pathway. HBV possesses certain selective integration traits in the human genome. The enrichment of HBVIS for HCC could be a susceptibility profile for hepatocarcinogenesis. The genomic and biological characterization of HBV integration associated with HCC may provide novel evidence to support the carcinogenic risk of HBV.