Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Multiplicative effects of risk factors in hepatocarcinogenesis in prevalent area of china

Z Sun MD, L Ming PhD

Cancer Institute, Chinese Academy of Medicial Sciences, Beijing, China,

AIM: The importance of HBV in hepatocarcinogenesis was well known, especially in area of prevalence. Many studies had shown that serum HBsAg, the generally used marker of HBV infection, might under-estimated the etiological role of HBV infection in liver cancer. METHODS: Our recent studies on a large series of pathologically diagnosed HCC from a high incidence area of China, Qidong city, had demonstrated that 86% of these patients were HBsAg sero-positive. The remaining sero-negative HCC were all shown to have other HBV markers, either having high titer anti-HBc in serum and/or having HBV x gene sequence in HCC DNA which was detected by PCR and confirmed by its unique structural features. Therefore, this study demonstrated that HBV was a general causative agent of HCC in this area, meanwhile, it also suggested that other risk factors had played limited role as an independent hepatic carcinogen. RESULTS: Serum assays showed that 2.9% (3/106) of the HCC cases had anti-HCV antibodies, whereas parallel detection of anti-HBc showed 100% positivity (106/106). The three HCV infected HCC patients were all co-infected by HBV. The prevalence rate of anti-HCV in the local population was found to be 1.1% (3/282). Although it had been shown in previous prospective study on HBsAg positive chronic hepatitis men that HCV infection significantly increased the risk of HBV carriers after adjustment for other factors through multivariate analysis, however, the rarity of HCV infection in this population means that HCV is of little absolute importance as a cause of HCC. Recent epidemiological data had shown that the HBsAg positive, middle aged males in Qidong, the persons having peak incidence, were 3 times more risky to develop HCC than their counterparts in Beijing, suggesting the possible role of co-factor/s. Aflatoxin was considered to be the major candidate on the basis of previous studies which measured its individual exposure. The 249 codon arg/ser missense mutation (249ser) of p53 gene in HCC was demonstrated to be very tightly associated only with pre-exposure to both HBV and aflatoxin, providing a unique molecular epidemiological marker of the genetic damage resulting from their etiological interaction in hepatocarcinogenesis. In Qidong at least, we could not identify even a very small number of HCC to be attributable to aflatoxin as its main causative agent without HBV participation. The age specific 249ser mutation rate of p53 in HCC of Qidong, when analyzed with the relevant HCC incidence data, could demonstrate that the majority of the 3 fold increase of HCC cases in Qidong over their counterparts in Beijing were the clonal growth of 249ser mutants, caused by HBV infection plus aflatoxin exposure. Therefore, although aflatoxin was shown here as a hepatic co-carcinogen, yet this co-factor caused very significant increase of risk to develop liver cancer on the background of chronic HBV infection. Extended prospective study also showed that the level of aflatoxin exposure was relatively low in such situation. CONCLUSIONS: These facts strongly indicated that control of aflatoxin exposure among HBV infected persons, especially among those having chronic hepatitis, through medical advice in diet design with immunological monitoring of its metabolite in urine should constitute a major therapeutic component to significantly reduce the risk of hepatocellular carcinoma at the present time when there is no effective treatment to clear the existing HBV infection. Prospective follow-up of HBV carriers also showed that family history increased the risk to develop HCC in the prevalent area after adjustment for age and aflatoxin exposure. Its genetic background needs further investigation.

KEY WORDS: hepatocarcinogenesis, Aflatoxin, p53 mutation, family history, hepatocellular carcinoma.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on anticancer strategies.