International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


M Rosemann
GSF Natl. Research Center for Environment and Health

1) Kuosaite V, 1) Schneider R, 2) Richter T, 1) Favor J, 1) Atkinson MJ
1) GSF Natl. Research Center for Environment and Health, Neuherberg, 2) Technical University  Munich

Individual cancer risk can vary considerably depending on inherited genetic conditions. We used a mouse model of  Thorium227 induced osteosarcoma to map susceptibility loci and analyse candidate modifier genes. Backcross studies from strains Balb/c, CBA/CA, C3H and 102 revealed genetic linkage to loci on distinct chromosomes. A locus on chromosome 14 (about 5cM including the Rb1 gene) exhibited the most significant linkage and was thus considered the major susceptibility locus. Comparative sequencing of the Rb1 gene revealed a hexanucleotide duplication in the promoter of the Balb/c strain, which is associated with osteosarcoma resistance with and shows enhanced transcriptional activity (CAT reporter assays, mRNA quantification). The most significant effects upon osteosarcoma-predisposition were found if multilocus inheritance was taken into account. In C3H/102 testcrossed mice, tumor incidence was 22% for RR genotype compared to 75% for SS genotype with indications for epistatic locus interaction. About 20% of the variance can be explained by these two factors.The phenotypic effect was even more striking in Balb/c and CBA/CA mice, where 4 additional modifier loci where detected. Interestingly, susceptibility alleles at 3 loci were derived from the more sensitive Balb/c strain and at 2 loci from the resistant CBA/CA strain. Mice with  susceptible genotypes at all five loci developed 100% early tumors, whereas only 1 of 11 mice with resistance genotypes at all 5 loci developed a tumor at all. These compound genotypes derived from paternal and maternal alleles confer a much stronger phenotypic effect than observed in the parental inbred strains.

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