HUMAN LIVER CARCINOGENESIS

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We and others have previously shown that the frequency of 249ser p53 mutation in human hepatocellular carcinoma is positively correlated with dietary aflatoxin B1 exposure in the high cancer risk areas of Asia and Africa. This dose-response relationship between aflatoxin B1 exposure and 249ser p53 mutations has been extended to North America, i.e., Mexico. In addition, 249ser p53 mutant cells have been detected in nontumorous liver tissue and the frequency of these mutant cells is positively correlated with estimated dose of dietary aflatoxin B1 exposure. We have previously reported a high frequency of p53 mutations at A:T base pairs in hepatic angiosarcoma associated with vinyl chloride exposure. These data are consistent with the epoxide metabolite of vinyl chloride binding to deoxyadenosine in DNA. These studies have been extended to examine the p53 tumor suppressor gene in angiosarcoma that is not associated with vinyl chloride exposure. The p53 mutational spectrum did not include mutations at A:T base pairs. In addition, p53 mutations were rare in hepatocellular carcinoma associated with oral contraceptive use. Hepatitis B and C viruses also contribute to human liver carcinogenesis. The hepatitis B viral X gene (HBx) is frequently integrated in human hepatocellular carcinomas (HCC) from high risk geographic regions. Therefore, we have investigated the interaction of HBx and p53 proteins. Hbx binds to p53 and inhibits p53-dependent apoptosis, which could increase the survival and clonal expansion of Hbx-expressing cells during liver carcinogenesis. Since about 80% of HCC produce alpha-fetoprotein and about 50% of HCC in Qidong, China contain a 249ser mutant p53, we have initiated a collaborative study with the Cancer Institute, C.A.M.S., Beijing, to develop gene therapy (p53 driven by alpha-fetoprotein promoter) of HCC.