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p53 Mutations, Chronic Hepatitis B Virus Infection, and Alfatoxin Exposure in Hepatocellular Carcinoma in Taiwan¹

Division of Environmental Health Sciences [R. M. L. Y-J. Z. R. M. S.] and Division of Biostatistics [W-Y.T.], Columbia University School of Public Health, New York, New York 10032; Graduate Institute of Epidemiology, College of Public Health [L-Y. W., C-J. C.] and Department of Surgery, College of Medicine [P-H. L. C-S. L.], National Taiwan University, Taipei, Taiwan

Recent studies have implicated aflatoxin B₁ (AFB₁) exposure as an etiological agent in hepatocellular carcinoma (HCC) and suggested an interaction with chronic hepatitis B virus (HBV) infection. Worldwide AFB₁ exposure correlates with a specific mutation at codon 249 in the p53 tumor suppressor gene in liver tumors. This study investigated the roles of HBV and AFB₁ in the HCC carcinogenic pathway involving p53 mutations. In cases and controls, chronic HBV infection was assessed by serum hepatitis B surface antigen (HBsAg) and AFB₁ exposure by immunohistochemical detection of AFB₁-DNA adduct in liver tissue. p53 protein mutations in tumor tissues of HCC cases were identified by immunohistochemistry and DNA mutations by single-stranded conformational polymorphism and sequencing analysis. Both chronic HBsAg carrier status and liver AFB₁-DNA adducts were significantly higher in cases than in controls with odds ratios (OR) of 8.4 and 3.9, respectively (P < 0.01). Moreover, HCC risk was greatest in individuals with both AFB₁-DNA adducts and HBsAg, suggesting a viral-chemical interaction. Mutant p53 protein, mutations in the p53 gene, and specific codon 249 mutations were detected in 37, 29, and 13%, respectively, of the HCC cases. Most of the DNA mutations were transversions, and the only major clustering site for mutations was codon 249. AFB₁-DNA adducts were associated with p53 protein (OR = 2.9, P = 0.054) and DNA mutations (OR = 2.9, P = 0.082) but with borderline significance. All of the codon 249 mutations (n = 12) occurred in HBsAg-seropositive carriers, resulting in an OR of 10.0 (P < 0.05), suggesting that HBV may be involved in the selection of these mutations. The ORs between HBsAg and p53 DNA and protein mutations were 2.6 (P = 0.077) and 1.8 (P > 0.05), respectively. Both p53 DNA and protein mutations were related to tumor stage, suggesting that they are late events. These studies provided further support for the role of aflatoxin exposure in HCC in Taiwan and insight into viral-chemical interactions and molecular pathogenesis.

¹ This work was supported by NIH Grants ES05116 and CA13696 and Department of Health, Executive Yuan, Taipei, Taiwan.

² Deceased.

³ To whom requests for reprints should be addressed, at Division of Environmental Health Sciences, School of Public Health, Columbia University, 701 West 168th Street. New York, NY 10032. Phone: (212) 305-1996; Fax: (212) 305-5328; E-mail: rps1@columbia.edu.

Received 2/27/97. Accepted 6/16/97.

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