Hepatitis B Virus DNA Integration Drives Carcinogenesis and Provides a New Biomarker for HBV-related HCC

Mechanistic studies of HBV integration-induced insertional mutagenesis help develop precise HCC therapy. HBV inte-gration provides a unique junctional DNA biomarker valu-able for monitoring residual HCC after therapy or the development of de novo recurrence.Hepatitis B virus (HBV) DNA integration is an incidental event in the virus replication cycle and occurs in less than 1% of infected hepatocytes during viral infection. However, HBV DNA is present in the genome of approximately 90% of HBV-related HCCs and is the most common somatic muta-tion. Whole genome sequencing of liver tissues from chronic hepatitis B patients showed integration occurring at random positions in human chromosomes; however, in the genomes of HBV-related HCC patients, there are integration hotspots. Both the enrichment of the HBV-integration pro-portion in HCC and the emergence of integration hotspots suggested a strong positive selection of HBV-integrated he-patocytes to progress to HCC. The activation of HBV inte-gration hotspot genes, such as telomerase (TERT) or histone methyltransferase (MLL4/KMT2B), resembles insertional mutagenesis by oncogenic animal retroviruses. These candidate oncogenic genes might shed new light on HBV-related HCC biology and become targets for new cancer therapies. Finally, the HBV integrations in individual HCC contain unique sequences at the junctions, such as virus-host chimera DNA (vh-DNA) presumably being a signature mole -cule for individual HCC. HBV integration may thus provide a new cell-free tumor DNA biomarker to monitor residual HCC after curative therapies or to track the development of de novo HCC. (Cell Mol Gastroenterol Hepatol 2023;15:921-929; https://doi.org/10.1016/j.jcmgh.2023.01.001)