Search for novel genomic regions related to liver carcinogenesis by using a hepatitis B virus integration site as a genetic probe

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Human genomic regions flanking integrated hepatitis B virus (HBV) were investigated from liver tissues of chronic hepatitis, liver cancers and non-cancerous tissues surrounding liver cancers. We developed an HBV-Alu PCR method to efficiently amplify the viral-host junctions. From 26 cases with chronic hepatitis and 10 with liver cancer, 75 viral-host junctions were cloned and genomic sequences were determined. Together with genomic database search and our results, we could identify a human telomerase reverse transcriptase (hTERT) gene and MLL4 gene as common integration sites. These two genes were found integrated exclusively in liver cancer tissues. HBV integration into an hTERT gene was found in about 5 % of liver cancer cases where HBV integration sites were investigated.To investigate when the integration into hTERT occur during chronic HBV infection, we searched for HBV-hTERT chimeric sequences in chronic hepatitis tissues by PCR with several primer sets, but no HBV-hTERT chimeras were detected. Thus it is suggested that HBV integration into the hTERT gene occurs in more advanced stages of HBV infection than chronic hepatitis.