SUSCEPTIBILITY TO HEPATOCELLULAR-CARCINOMA IS ASSOCIATED WITH GENETIC-VARIATION IN THE ENZYMATIC DETOXIFICATION OF AFLATOXIN B-1

Aflatoxin B-1 (AFB(1)) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB(1) is met abolized via the phase I and II detoxification pathways; hence, geneti c variation at those loci may predict susceptibility to the effects of AFB(1). To test this hypothesis, genetic variation in two AFB(1) deto xification genes, epoxide hydrolase (EPHX) and glutathione S-transfera se M1 (GSTM1), was contrasted with the presence of serum AFB(1)-albumi n adducts, the presence of hepatocellular carcinoma (HCC), and with p5 3 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB(1)-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overr epresented in persons with HCC, also in a case-control study. The rela tionship of EPHX to HCC varied by hepatitis B surface antigen status a nd indicated that a synergistic effect may exist. p53 codon 249 mutati ons were observed only among HCC patients with one or both high-risk g enotypes. These results indicate that individuals with mutant genotype s at EPHX and GSTM1 may be at greater risk of developing AFB(1) adduct s, p53 mutations, and HCC when exposed to AFB(1). Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carrier s with low-risk genotypes. These findings support the existence of gen etic susceptibility in humans to the environmental carcinogen AFB(1) a nd indicate that there is a synergistic increase in risk of HCC with t he combination of hepatitis B virus infection and susceptible genotype .