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World J Gastroenterol. May 28, 2014; 20(20): 6236-6243
Published online May 28, 2014. doi: 10.3748/wjg.v20.i20.6236
Role of hepatitis B virus DNA integration in human hepatocarcinogenesis
Hoang Hai, Akihiro Tamori, Norifumi Kawada
Hoang Hai, Akihiro Tamori, Norifumi Kawada, Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
Author contributions: Hai H wrote the manuscript; Tamori A and Kawada N revised the manuscript.
Correspondence to: Akihiro Tamori, MD, PhD, Associate Professor, Department of Hepatology, Osaka City University Graduate School of Medicine, 1-4-3, Asahimachi, Abeno-ku, Osaka 5458585, Japan.
Telephone: +81-6-66453811 Fax: +81-6-66461433
Received: November 2, 2013
Revised: December 14, 2013
Accepted: January 14, 2014
Published online: May 28, 2014

Liver cancer ranks sixth in cancer incidence, and is the third leading cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, which arises from hepatocytes and accounts for approximately 70%-85% of cases. Hepatitis B virus (HBV) frequently causes liver inflammation, hepatic damage and subsequent cirrhosis. Integrated viral DNA is found in 85%-90% of HBV-related HCCs. Its presence in tumors from non-cirrhotic livers of children or young adults further supports the role of viral DNA integration in hepatocarcinogenesis. Integration of subgenomic HBV DNA fragments into different locations within the host DNA is a significant feature of chronic HBV infection. Integration has two potential consequences: (1) the host genome becomes altered (“cis” effect); and (2) the HBV genome becomes altered (“trans” effect). The cis effect includes insertional mutagenesis, which can potentially disrupt host gene function or alter host gene regulation. Tumor progression is frequently associated with rearrangement and partial gain or loss of both viral and host sequences. However, the role of integrated HBV DNA in hepatocarcinogenesis remains controversial. Modern technology has provided a new paradigm to further our understanding of disease mechanisms. This review summarizes the role of HBV DNA integration in human carcinogenesis.

Keywords: Hepatitis B virus, Integration, Hepatocarcinogenesis, Cis effect, Trans effect, Whole genome sequencing

Core tip: A high viral load is associated with an elevated risk of hepatocellular carcinoma (HCC), and the risk remains increased in hepatitis B surface antigen-negative hepatitis B virus (HBV) and occult infections. The ability of HBV to integrate into the infected host’s hepatocyte genome is one of the most important direct pro-oncogenic properties. The recent development of efficient tools for genome-wide analysis of gene expression and genetic defects has allowed a comprehensive overview of the changes occurring with HCC. Specific HBV features, including the integration of viral DNA into host chromosomes, may trigger increased genetic instability.