Abstract
Infection with the Hepatitis B Virus (HBV) is one of the strongest risk-factors for liver cancer (hepatocellular carcinoma, HCC). One of the reported drivers of HCC is the integration of HBV DNA into the host cell genome, which may induce pro-carcinogenic pathways. These reported pathways include: induction of chromosomal instability; generation of insertional mutagenesis in key cancer-associated genes; transcription of downstream cancer-associated cellular genes; and/or formation of a persistent source of viral protein expression (particularly HBV surface and X proteins). The contribution of each of these specific mechanisms towards carcinogenesis is currently unclear. Here, we review the current knowledge of specific sites of HBV DNA integration into the host genome, which sheds light on these mechanisms. We give an overview of previously-used methods to detect HBV DNA integration and the enrichment of integration events in specific functional and structural cellular genomic sites. Finally, we posit a theoretical model of HBV DNA integration during disease progression and highlight open questions in the field.
Highlights
Chronic infection by Hepatitis B Virus (HBV) is one of the major causes of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide
Hepatitis B virus DNA integration is observed in all known hepadnaviruses, including the woodchuck and duck models of HBV infection [26,27,28], as well as chimpanzees [29,30] and humans [31,32,33] chronically infected with HBV
The Sleeping Beauty (SB) transposon mutagenesis system generates many more integrations than HBV infection (~350 SB integrations compared to 1–10 HBV integrations per tumour) and the SB system requires additional stimuli for carcinogenesis, suggesting that these pathways may not reflect those driven by HBV DNA integration
Summary
Chronic infection by Hepatitis B Virus (HBV) is one of the major causes of liver cirrhosis and hepatocellular carcinoma (HCC) worldwide. The risk of HBV-associated HCC (though highly associated with chronic antiviral inflammation [8,9]) can persist after functional clearance of the virus infection [10], suggesting that other factors can drive hepatocarcinogenesis. These include chromosomal instability from past genotoxic injury, residual expression of oncogenic viral proteins, or the presence of pre-neoplastic genetic changes, all of which may be driven by integrated HBV DNA
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