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Temporal relationship between hepatitis B virus enhancer II/basal core promoter sequence variation and risk of hepatocellular carcinoma
  1. Y-C Chou1,
  2. M-W Yu1,
  3. C-F Wu1,
  4. S-Y Yang1,
  5. C-L Lin2,
  6. C-J Liu3,
  7. W-L Shih1,
  8. P-J Chen3,
  9. Y-F Liaw4,
  10. C-J Chen5
  1. 1
    Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
  2. 2
    Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
  3. 3
    Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
  4. 4
    Liver Research Unit, Chang Gung University, Taoyuan, Taiwan
  5. 5
    Genomics Research Center, Academia Sinica, Taipei, Taiwan
  1. Professor M-W Yu, Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road Zhongzheng District, Taipei City 10055, Taiwan; yumw{at}


Background and aims: To investigate the temporal relationship between sequence variation in the enhancer II (EnhII), basal core promoter (BCP), and precore regions of hepatitis B virus (HBV) and the risk of hepatocellular carcinoma (HCC), we conducted a nested case–control study within a cohort of 4841 male HBV carriers who were recruited during the period 1988–1992.

Methods: The HBV DNA sequence was determined in baseline blood samples taken from 132 incident cases and 204 controls. Base exchanges during follow-up in 71 cases were compared with 81 controls with samples taken during a similar length of follow-up.

Results: Nine single nucleotide polymorphisms in the EnhII/BCP regions (six of which were genotype C HBV related) were associated with subsequent risk of HCC. The strength of these associations decreased as the lag time between baseline measurement and diagnosis increased over 3 years. However, an increased disease risk in subjects with BCP double variants (mostly T1762/A1764) or genotype C HBV-related variants was evident 9 years or more before diagnosis. The BCP double variants (odds ratio, 1.92 (95% confidence interval, 1.14 to 3.25)) were statistically significantly associated with HCC risk even after adjusting for alanine aminotransferase levels, antibodies against HBV e antigen, HBV genotype, HBV viral load, and other sequence variants. Longitudinal analysis indicated that the increased HCC risks for at-risk sequence variants were attributable to the persistence of these variants.

Conclusions: HCC risk is associated with sequence variation in the EnhII/BCP regions of HBV, and persistence of at-risk sequence variants is critical for HCC development.

  • Hepatocellular carcinoma
  • hepatitis B virus
  • enhancer II
  • basal core promoter
  • precore

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  • Funding: This study was financially supported by grants NSC 93-2320-B-002-013 and NSC 94-3112-B-002-017 from the National Science Council, Taiwan.

  • Competing interests: None.

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