Journal of the National Cancer Institute Advance Access originally published online on August 11, 2008
JNCI Journal of the National Cancer Institute 2008 100(16):1134-1143; doi:10.1093/jnci/djn243
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Associations Between Hepatitis B Virus Genotype and Mutants and the Risk of Hepatocellular Carcinoma
Affiliations of authors: Genomics Research Center, Academia Sinica and Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan (HIY, CLJ, SLY, CJC); Department of Microbiology, National Taiwan University College of Medicine, Taipei, Taiwan (SHY); Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan (PJC, DSC); Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Wallingford, CT (UHI, JS); Graduate Institute of Aboriginal Health, Tzu Chi University, Hualien, Taiwan (LYW); Department of Gastroenterology, Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan (SNL); Chang-Gung Memorial Hospital and Chang-Gung University, Taoyuan, Taiwan (YFL)
Correspondence to: Chien-Jen Chen, ScD, Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang, Taipei 11529, Taiwan (e-mail: cjchen{at}ntu.edu.tw).
Background: The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum (viral load). However, it is unclear whether genetic characteristics of HBV, including HBV genotype and specific genetic mutations, contribute to the risk of HCC. We examined the HCC risk associated with HBV genotypes and common variants in the precore and basal core promoter (BCP) regions.
Methods: From January 5, 1991, to December 21, 1992, baseline blood samples were collected from 2762 Taiwanese men and women who were seropositive for HBV surface antigen but had not been diagnosed with HCC; the samples were tested for HBV viral load by real-time polymerase chain reaction and genotyped by melting curve analysis. Participants who had a baseline serum HBV DNA level greater than 104 copies/mL (n = 1526) were tested for the precore G1896A and BCP A1762T/G1764A mutants by direct sequencing. Incident cases of HCC were ascertained through follow-up examinations and computerized linkage to the National Cancer Registry and death certification profiles. A Cox proportional hazards model was used to estimate the risk of HCC associated with HBV genotype and precore and BCP mutants after adjustment for other risk factors. All statistical tests were two-sided.
Results: A total of 153 HCC cases occurred during 33 847 person-years of follow-up. The HCC incidence rates per 100 000 person-years for participants infected with HBV genotype B or C were 305.6 (95% confidence interval [CI] = 236.9 to 388.1) and 785.8 (95% CI = 626.8 to 972.9), respectively. Among participants with a baseline HBV DNA level of at least 104 copies/mL, HCC incidence per 100 000 person-years was higher for those with the precore G1896 (wild-type) variant than for those with the G1896A variant (955.5 [95% CI = 749.0 to 1201.4] vs 269.4 [95% CI = 172.6 to 400.9]) and for those with the BCP A1762T/G1764A double mutant than for those with BCP A1762/G1764 (wild-type) variant (1149.2 [95% CI = 872.6 to 1485.6] vs 358.7 [95% CI = 255.1 to 490.4]). The multivariable-adjusted hazard ratio of developing HCC was 1.76 (95% CI = 1.19 to 2.61) for genotype C vs genotype B, 0.34 (95% CI = 0.21 to 0.57) for precore G1896A vs wild type, and 1.73 (95% CI = 1.13 to 2.67) for BCP A1762T/G1764A vs wild type. Risk was highest among participants infected with genotype C HBV and wild type for the precore 1896 variant and mutant for the BCP 1762/1764 variant (adjusted hazard ratio = 2.99, 95% CI = 1.57 to 5.70, P < .001).
Conclusions: HBV genotype C and specific alleles of BCP and precore were associated with risk of HCC. These associations were independent of serum HBV DNA level.
| CONTEXT AND CAVEATS Prior knowledge The risk of hepatocellular carcinoma (HCC) increases with increasing level of hepatitis B virus (HBV) in serum. However, it is unclear whether HBV genotype and common variants in the precore and basal core promoter (BCP) regions contribute to the risk of HCC. Study design The incidence of HCC in association with HBV genotype and mutants was estimated for participants in a community-based cohort study with long-term follow-up. Contribution HBV genotype C and the BCP A1762T/G1764A mutant were independent risk factors for HCC, and the precore G1896A mutant was associated with a decreased risk of HCC. Implications HBV genotype and precore and BCP mutation status, in addition to other factors, including age, sex, and HBV viral load, may help identify those who are at an increased risk for liver disease progression. Limitations The analysis of HBV genotype and mutants was based on a single blood sample obtained at study entry. Uncommon mutations were detected but not analyzed because of small sample sizes. From the Editors
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Manuscript received January 23, 2008; revised May 23, 2008; accepted June 16, 2008.
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