2026 年 5 巻 1 号 p. 3-19
The molecular mechanisms by which hepatitis B virus (HBV) contributes to hepatocellular carcinoma (HCC) have been investigated since the late 1970s. This review follows advances in molecular biology and sequencing, particularly since the mid-2000s, which have enabled detailed analysis of HBV DNA integrations into the human genomes.
Molecular cloning and Sanger sequencing have identified that HBV integrates into several gene regions and non-genic regions, mainly repetitive sequences. Chromosomal rearrangements have also been observed. Our group first reported HBV integration into centromeric alpha satellite DNA (αSat) of HCC cells associated with genomic rearrangements. Second- generation (short-read) sequencing has found that many gene regions are involved in HBV integration with TERT promoter the most. Approximately 30 HCC-driver genes including TERT, CTNNB1 and TP53 have been identified. Third-generation (long-read) sequencing has revealed that driver genes are located not only close to HBV integration sites but also distant from HBV integration sites through structural variations (SVs). Also, 10-50% of HBV integrations have been confirmed to occur in centromeric or other repetitive regions, key loci for initiating SVs. Computational methods have emphasized that αSat may be the preferential locus for HBV integration. Recent completion of the full αSat sequence, the “real” goal of the Human Genome Project, allows better exploration of this underappreciated genome. Together, findings in this article refine current views of HBV-related hepatocarcinogenesis.
Ongoing advances in sequencing and centromeric biology are expected to deepen our understanding of virus-induced genomic instability and guide future strategies for early detection, prevention, and treatment of HBV-related HCC.
