The genome of the BALB/c mouse strain provides alleles that dominantly inhibit hepatocellular tumor development in F1 crosses with the highly hepatocarcinogenesis-susceptible C3H/He strain. Genome-wide linkage analysis using a 1536 -single-nucleotide polymorphism array in a (C3H/He ؋ BALB/c)F2 intercross population treated with urethane to induce hepatocellular tumor development revealed a locus with a major role in the resistance to hepatocarcinogenesis. This locus, designated hepatocarcinogen resistance 3 (Hpcr3) and mapping to central chromosome 15, showed a linkage at LOD score ؍ 16.52 and accounted for 40% of the phenotypical variance. The BALB/c-derived allele at Hpcr3 reduced tumoroccupied area of the liver up to 25-fold, in a semidominant way. Additional minor loci were mapped to chromosomes 1, 10, and 18. A gene expression profile of normal adult mouse liver showed a significant association with susceptibility of BALB/c, C3H/He, and F1 mice to hepatocarcinogenesis and identified the genes expressed in the Hpcr3 locus region; moreover, this analysis implicated the E2F1 pathway in the modulation of the phenotype susceptibility to hepatocarcinogenesis. Conclusion: These findings, indicating the complex genetics of dominant resistance to hepatocarcinogenesis, represent a step toward the identification of the genes underlying this phenotype. (HEPATOLOGY 2008;48:617-623.) I nbred strains of laboratory mice constitute disease models that have allowed characterization of the genetic determinants of inherited susceptibility to different types of tumorigenesis, because they display a wide range of spontaneous and chemically induced tumor incidence. 1 In particular, the mouse hepatocellular tumor model provided the first formal demonstration of the polygenic nature of inherited cancer predisposition. 2 C3H/He mice represent one of the strains most susceptible to hepatocarcinogenesis. In this strain, genetic susceptibility to hepatocarcinogenesis is associated with the size but not with the number of liver neoplastic lesions, suggesting that tumor growth/progression but not tumor initiation is genetically controlled. 3 Crosses between C3H/He mice and the resistant C57BL/6J or A/J strain produce F1 hybrids in which the susceptibility trait is dominant, 4 whereas the same trait is recessive in crosses with the resistant BALB/c strain, which therefore carries dominant tumor resistance alleles. 5 Seven hepatocarcinogenesis susceptibility loci (Hcs1-7) have been mapped in crosses between C3H/He and either C57BL/6J or A/J mice, 2,6 whereas BALB/c-derived alleles have not yet been characterized.
We carried out a genetic linkage study to map the BALB/c-derived hepatocarcinogen resistance loci and to identify putative genetic targets of these loci by analysis of the gene expression profile of normal mouse liver.
Materials and Methods
Mice, Phenotypes, and Tissues. The intercross population consisted of (BALB/cJ ϫ C3H/HeJ)F2 mice (n ϭ 182 males) treated with urethane (300 mg/kg body weight