Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis

Abstract

Growing evidence demonstrates that hepatitis B virus (HBV) integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in hepatocellular carcinomas (HCCs). To determine if HBV integration occurs and affects cellular genes at such a stage of infection, we analysed viral-host junctions in chronic hepatitis tissues without HCC using PCR amplification with primers specific to human Alu-repeat and HBV. We obtained 42 independent viral-host junctions from six patients examined and identified chromosomal locations for 20 of the 42 junctions. In six clones, each integration apparently affected a single gene. These six candidate genes included one known tumor suppressor gene, three human homologs of drosophila genes that are critical for organ development, one putative oncogene and one recently found chemokine. Our data, together with previously reported HBV integrants in HCCs, suggested preferential HBV integration into chromosome 3 (P ¼ 0.022). Our virus-tagging approach provided (a) firm evidence of HBV integration in hepatocytes at an early stage of chronic infection and (b) revealed cellular genes possibly affected by HBV integration and potentially involved in early steps of the process leading to carcinogenesis.

Hepatitis B virus-related hepatocellular carcinoma: paradigms for viral-related human carcinogenesis

“…hepatitis Minami et al, 2005); moreover, ancient observations based on Southern blotting have been recently confirmed by PCR-based approaches, demonstrating that, at least in some cases, integration of the viral DNA may occur during the acute stage of infection (Lugassy et al, 1987;Murakami et al, 2004). Integration therefore precedes development of the tumor, and comparative analyses of the various restriction profiles at different times during the course of HBV infection suggest progressive clonal expansion of certain infected cells.…”

Hepatitis B virus X gene and hepatocarcinogenesis

“…Some of the mechanisms that have been suggested for HBV-mediated hepatocarcinogenesis include: persistent inflammation [8,9] and viral integration resulting in chromosomal instability and insertional mutagenesis [10][11][12][13][14][15][16][17]; as well as the expression of certain viral proteins such as HBV X protein (HBx) and HBV surface antigens, which may exert their effects on cell cycle, cell growth, and apoptosis by interfering with cell signaling and transcription [14,[18][19][20][21][22][23][24][25][26][27].…”

DNA double-strand breaks, potential targets for HBV integration

“…Integrated HBV sequences have been seen in most (about 80%) HBV-related HCCs. Growing evidence demonstrates that HBV integration and resulting insertional mutagenesis play an important role in cell growth or maintenance in HCC [3] . Viral integration events often show preferential or common sites, for example, HPV integration in cervical carcinoma frequently occurs near the c-Myc locus [4] , so we may be able to investigate the HBV preferred integration sites and the exact molecular mechanisms.…”