Predisposition to Rat Liver Carcinogenesis Chromosome Mapping of Multiple Loci Affecting the Genetic

Previous studies on (BNxF344)F1 (BFF1) rat model of genetic predisposition to hepatocarcinogenesis led to the identification, in BFF1xF344 backcross progeny, of two hepatocarcinogenesis susceptibility (Hcs) and three resistance (Hcr) loci affecting the progression of neoplastic liver nodules. To evaluate the presence of other hepatocarcinogenesis-related loci in the BFF1 genome, nodule induction by resistant hepatocyte model in 116 male BFF2 rats 32 weeks after initiation with diethylnitrosamine was subjected to quantitative trait loci analysis. The rats were typed with 179 genetic markers, and linkage analysis identified three loci on chromosomes 1, 16, and 6, in significant linkage with nodule mean volume (V), volume fraction, and number, respectively, and two loci on chromosomes 4 and 8 in suggestive linkage with V. These loci were differently positioned with respect to Hcs and Hcr loci mapped previously in backcross rats. On the basis of phenotypic and allele distribution patterns of BFF2 rats, loci on chromosomes 1 and 16 were identified as Hcs3 and Hcs4, and loci on chromosomes 4, 8, and 6 as Hcr4, Hcr5, and Hcr6. Additive interactions occurred between Hcs3 and Hcs4, and Hcr4 and a locus on chromosome 3 with less than suggestive linkage with V. All of the loci were in chromosomal regions syntenic to mouse and/or human chromosomal segments showing allelic gain or loss in hepatocellular carcinomas. These data indicate that inheritance of predisposition to rat liver tumor is characterized by the interplay of several genetic factors and suggest some possible mechanisms of polygenic control of human liver cancer.