GENETIC CONTROL OF MURINE HEPATOCARCINOGENESIS

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The primary focus of this research project is the identification and characterization of specific genes that control the susceptibility of inbred mice to hepatocarcinogenesis. This project will aid in elucidating general mechanisms of cancer susceptibility that will be of value in understanding genetic variation in human populations in risk for cancer development. Previous studies resulted in the identification of the Hcs locus, which is responsible for the high susceptibility of C3H mice to liver tumor induction, and the demonstration that this gene regulates the proliferation of preneoplastic and normal hepatocytes. The first two aims of the present application are directed toward the molecular characterization of the Hcs gene using a reverse genetic approach. The chromosomal location of the Hcs gene will be determined by analysis of animals from crosses between C3H/HeJ mice and resistant inbred mice for cosegregation between carcinogen sensitivity and DNA- based genetic markers, including endogenous nonectropic murine leukemia viruses, restriction fragment length polymorphisms, and microsatellites. A physical map of the chromosomal region containing the Hcs locus will be constructed by analysis of a mouse genomic library of yeast artificial chromosomes. Candidate sequences from the region that are expressed at the RNA level in mouse liver will be evaluated in order to identify a cDNA encoding the Hcs gene. The third aim is to investigate the interaction between mouse liver cancer susceptibility genes and the initiation of hepatocarcinogenesis by mutations induced in the c-Ha-ras proto-oncogene. tumors induced by treatment with vinyl carbamate in 10 inbred strains of varying susceptibilities to hepatocarcinogenesis will be analyzed for the presence of mutant c-Ha-ras alleles. Fourth, the biological and genetic basis for the high susceptibility of DBA/2J male mice will be investigated by studying the development of preneoplastic hepatic lesions in carcinogen-treated animals, and by attempting to genetically map the major gene responsible for the sensitivity of this strain to liver tumor induction by using methods similar to those used in Aim 1. Finally, the hormonal regulation of liver tumor induction will be investigated by directly studying the inhibitory effects of estrogen on hepatocarcinogenesis in C57BL/6J, C3H/HeJ, and C57BR/cdJ mice and by genetic studies of the basis for the unusually high susceptibility of female C57BR/cdJ mice to liver tumor induction.