Abstract
Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. Here by conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. We show that HBV is prone to integrate into rare fragile sites and functional genomic regions including CpG islands. We observe a distinct pattern in the preferential sites of HBV integration between tumour and non-tumour tissues. HBV insertional sites are significantly enriched in the proximity of telomeres in tumours. Recurrent HBV target genes are identified with few that overlap. The overall HBV integration frequency is much higher in tumour genomes of males than in females, with a significant enrichment of integration into chromosome 17. Furthermore, a cirrhosis-dependent HBV integration pattern is observed, affecting distinct targeted genes. Our data suggest that HBV integration has a high potential to drive oncogenic transformation.
Highlights
Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis
Previous isolation of HBV integration sites using PCR-based methods[7] and more recent use of deep sequencing in a small size cohort of Hepatocellular carcinoma (HCC) patients suggests that the HBV insertional sites occurred randomly throughout the genome, leading to the presumption that there were no preferential sites of integration
To search for HBV integration sites across the HCC genome and decode viral–host interactions, we conducted high-throughput viral integration detection (HIVID) analysis on tumour and adjacent non-tumour liver genomes extracted in a cohort including 426 clinically and pathologically well-characterized HBV-associated HCC cases: 298 with cirrhosis and 128 without cirrhosis; 360 males and 66 females (Supplementary Figs 1–3 and Supplementary Table 1)
Summary
Hepatitis B virus (HBV) can integrate into the human genome, contributing to genomic instability and hepatocarcinogenesis. By conducting high-throughput viral integration detection and RNA sequencing, we identify 4,225 HBV integration events in tumour and adjacent non-tumour samples from 426 patients with HCC. Chronic infection with hepatitis B or C virus (HBV or HCV) represents the major risk factors for the development of HCC2,3. Recurrent HBV integrations have recently been identified in a large cohort of HCC patients through the application of high-throughput nextgeneration sequencing[8,9,10,11]. We conducted high-throughput viral integration detection (HIVID), a highly sensitive method for assaying viral insertion compared with the whole-genome sequencing, and analysed 426 HBV-associated HCC patients with or without cirrhosis[17]. Our results revealed an excessive HBV integration across the host genome with particular genomic pattern in a gender or cirrhosis-dependent manner
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