Genetic control of resistance to hepatocarcinogenesis by the mouseHpcr3locus

Abstract

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 ‫؍‬ 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 MethodsMice, 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) at 7 days of age, kept without any further treat-

Risk of HCC: Genetic heterogeneity and complex genetics

“…Indeed, in three genetic crosses with different mouse strains, 3-4 unlinked loci per cross were mapped, with no overlap among crosses [70][71][72]. Similar observations of strain-combination-specific, non-overlapping sets of loci have been reported in rat hepatocarcinogenesis [73,74].…”

Genetic Predisposition to Hepatocarcinogenesis in Inbred and Outbred Mouse Lines Selected for High or Low Inflammatory Response

“…In mice, the complex nature of HCC genetic control was demonstrated in animal models, and several susceptible QTLs were described: Hcs 1-8 (for HCC susceptibility locus) in chromosomes 1, 2, 5, 7, 8, 12, and 19 and Hcf 1-2 (for HCC female susceptibility locus) in chromosomes 1 and 17. Other QTLs were associated with resistance to HCC: Hcr2 in chromosome 10, Hpcr3 in central chromosome 15, and Hpcr4 in chromosome 1 [33, 34].…”

Experimental Models to Define the Genetic Predisposition to Liver Cancer

“…Further attempts to identify modifier genes, based on the analysis of single nucleotide polymorphisms, were carried out [57]. The genome of the BALB/c mouse strain provides alleles that dominantly inhibit the development of HCC in F1 crosses with the susceptible C3H/He strain.…”

“…The genome of the BALB/c mouse strain provides alleles that dominantly inhibit the development of HCC in F1 crosses with the susceptible C3H/He strain. Genome-wide linkage analysis using a 1536-single-nucleotide polymorphism array in a (C3H/Hex BALB/c)F2 intercrosses, treated with urethane to induce HCC, identified the Hpcr3 resistance locus, which maps to the central part of chromosome 15 and accounts for about 40% of the phenothypical variance [57]. Importantly, this locus is situated in a region homologous to rat Hcs1, which influences the promotion and progression stages of liver carcinogenesis.…”