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Susceptibility to Aflatoxin B₁-related Primary Hepatocellular Carcinoma in Mice and Humans

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892 [K. A. M.]; Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland 20892 [K. H., J. R., P. W., K. H. B.]; Population Science Division, Fox Chase Cancer Center, Philadelphia, Pennsylvania 70119 [T. L., R. A. M., A. A. E., W. T. L.]; and Fudan Medical University, Shanghai, China [F-M. S.]

The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B₁ (AFB₁)-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB₁ is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB₁, AFB₁-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB₁ detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13–3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB₁-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB₁-induced HCC and significantly more sensitive to AFB₁ acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB₁-susceptible mouse model may provide new insights into hepatocarcinogenesis.

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