Journal of the National Cancer Institute Advance Access published online on July 2, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp180
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ARTICLE |
Associations Between Hepatitis B Virus Mutations and the Risk of Hepatocellular Carcinoma: A Meta-Analysis
Affiliation of authors: Department of Epidemiology, Second Military Medical University, Shanghai, China
Correspondence to: Guangwen Cao, MD, PhD, Department of Epidemiology, Second Military Medical University, 800 Xiang-yin Rd, Shanghai 200433, China (e-mail: gcao{at}smmu.edu.cn).
Background: The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC).
Methods: We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided.
Results: Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype.
Conclusions: HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.
| CONTEXT AND CAVEATS Prior knowledge There are conflicting data on the association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis. Study design A meta-analysis of pooled results from case–control and cohort studies that examined associations between mutation in the PreS, enhancer II, basal core promoter, and precore regions of HBV, and the risk of hepatocellular carcinoma (HCC). Contribution PreS mutations, C1653T, T1753V, and A1762T/G1764A were each associated with an increased risk of HCC and were increasingly more prevalent as chronic HBV infection progressed from the asymptomatic hepatitis B surface antigen carrier state to liver cirrhosis or HCC. Most of these mutations, alone and in combination, were more than 80% specific for the prediction of HCC. Implications Frequent examination of patients with chronic HBV infections for the presence of PreS mutations, C1653T, T1753V, and A1762T/G1764A may be useful for identifying which patients require preventive antiviral treatment and for the prediction of HCC. Limitations HBV mutation data were not available for all participants. The findings may not be generalizable to populations that are infected with HBV genotypes other than C or B. Only studies published in English or Chinese were included. From the Editors
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Manuscript received October 8, 2008; revised April 28, 2009; accepted May 22, 2009.
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J Natl Cancer Inst 2009 101: 1033.