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World J Hepatol. Jan 27, 2015; 7(1): 113-120
Published online Jan 27, 2015. doi: 10.4254/wjh.v7.i1.113
Clinical utility of complex mutations in the core promoter and proximal precore regions of the hepatitis B virus genome
Young Min Park
Young Min Park, Hepatology Center, Department of Internal Medicine, Bundang Jesaeng General Hospital, Seongnam-si, Kyungki-do 463-774, South Korea
Young Min Park, Biomedical Research Center, Bundang Jesaeng General Hospital, Seongnam-si, Kyungki-do 463-774, South Korea
Author contributions: Park YM solely contributed to this paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Young Min Park, MD, PhD, Hepatology Center, Department of Internal Medicine, Bundang Jesaeng General Hospital, 255-2, Seohyun-dong, Bundang-gu, Seongnam-si, Kyungki-do 463-774, South Korea. ymp1@outlook.com
Telephone: +82-31-7790676 Fax: +82-31-7790164
Received: August 28, 2014
Peer-review started: August 28, 2014
First decision: September 28, 2014
Revised: October 12, 2014
Accepted: October 28, 2014
Article in press: October 29, 2014
Published online: January 27, 2015
Abstract

The core promoter and proximal precore regions are the most complex portions of the hepatitis B virus (HBV) genome. These regions cooperatively regulate viral replication and differentially regulate the synthesis of the viral proteins E, core, and X. Multiple mutations in these regions are associated with the persistency of viral infection and the development of cirrhosis and hepatocellular carcinoma (HCC). In South Korea, nearly all HBVs are classified as HBV genotype C2; the majority of these viruses have the basal core promoter double mutation, a precore stop mutation, or both. These mutations may play a role in the alteration of viral and clinical features, and abundant and complex mutations are particularly prevalent in the core promoter and proximal precore regions. We previously demonstrated that the accumulation of ≥ 6 mutations at eight key nucleotides located in these regions (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A, and G1899A) is a useful marker to predict the development of HCC regardless of advanced liver disease. In addition, certain mutation combinations were predominant in cases with ≥ 4 mutations. In cases with ≤ 5 mutations, a low Hepatitis B e antigen titer (< 35 signal to noise ratio) was indicative of HCC risk. Viral mutation data of the single HBV genotype C2 suggest that the combined effect of the number and pattern of mutations in the core promoter and proximal precore regions is helpful in predicting HCC risk.

Keywords: Hepatitis B virus, Point mutation, Hepatitis B virus X protein, Hepatocellular carcinoma, Cancer screening

Core tip: Multiple mutations in the core promoter and proximal precore regions of the hepatitis B virus (HBV) genome are associated with hepatocellular carcinoma (HCC), but mutations predictive of outcome in chronic HBV carriers have not been distinguished. In the Korean HBV genotype C2, the number of mutations at eight key nucleotides located in these regions (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A, and G1899A) is positively correlated with HCC. In addition, some selected mutation combinations among individuals with ≥ 4 mutations are predominant in the HCC group.