International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

G25. Genetic Mapping of a Tumor Susceptibility Locus that Influences N-methyl-N-nitrosourea Induction of Thymic Lymphomas in Mice to Chromosome 4

Joe M. Angel, and Ellen R. Richie
The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX U.S.A.

Tumor susceptibility genes modify the response of individuals to carcinogen exposure. Multiple genes are involved and each gene contributes to, but is not solely responsible for predisposition to developing a particular type of cancer. The overall susceptibility of an individual to carcinogen exposure is determined by the combined effects of both susceptibility and resistance genes. N-methyl-N-nitrosourea (MNU) is a direct acting carcinogen that induces T-cell lymphomas in mice. AKR/J mice have a higher incidence and shorter latency than most other inbred mouse strains that have been tested. Results from studies of genetic crosses of AKR/J with resistant C57L/J mice suggest that MNU susceptibility is a multigenic trait. We have previously reported that the tumor susceptibility locus (Tlag1) mapping to central mouse chromosome 7 between Tyr and Hbb influences susceptibility to MNU. Mice inheriting a copy of Tlag1 from C57L are more resistant to MNU than mice inheriting two copies from AKR suggesting that Tlag1 is a resistance locus dominantly inherited from the C57L parent. Treatment of AKXL recombinant inbred (RI) mice that are homozygous for the AKR allele of Tlag1 with MNU revealed three distinct phenotypes of MNU susceptibility, a highly susceptible phenotype similar to AKR, a resistant phenotype similar to C57L, and a moderate susceptible phenotype. These results suggest that at least two additional MNU susceptibility loci, not linked to Tlag1 segregate in crosses of AKR with C57L mice. We have now mapped a locus that influences MNU susceptibility to the central region of mouse chromosome 4 in AKR (AKR C57L)F1 mice. Unlike Tlag1, inheritance of a copy of the chromosome 4 locus from the C57L parent results in an increased susceptibility to MNU compared to mice inheriting two copies from the AKR parent, indicating that it is a susceptibility locus with the dominant allele being inherited from the resistant parent. The association of MNU susceptibility with inheritance of the central region of chromosome 4 was confirmed using (AKR C57L)F3 mice genetically selected to be homozygous for the AKR allele of Tlag1 and either homozygous for AKR alleles or C57L alleles of the central region of chromosome 4. Mice homozygous for C57L alleles of central chromosome 4 had a significantly higher incidence of MNU-induced lymphomas than mice homozygous for AKR alleles.

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