International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)


RK Kominami
Graduate School of Medical and Dental Sciences, Niigata University

1) Ochiai Y, 1) Tamura Y, 1) Saito Y, 1) Matsuki A, 1) Wakabayashi Y, 2) Niwa O
1) Department of Gene Regulation, Graduate School of Medical and Dental Sciences, Niigata University, 2) Radiation Biology Center, Kyoto University

Individuals inheriting the same mutation predisposing to cancer often express different phenotypes with respect to spectrum of tumors and age of onset. Li-Fraumeni patients with p53 gene mutations are susceptible to sarcomas and carcinoma of the breast and their outcomes range from early aggressive cancer to disease-free survival. This may reflect the presence of low penetrance genes in the human population as well as environmental factors that can modify the impact of p53 mutation. Identification of the p53 modifiers is important for its public health implications and also gives clues to signaling pathways in cells lacking p53, the most frequently mutated gene in human cancers. p53-KO mice develop tumors at a very young age and heterozygotes are extremely susceptible to radiation-induced thymic lymphomas. To search the modifiers, we have performed genome scan for 160 lymphomas and 69 skin tumors induced by ?-ray irradiation of p53(KO/+) backcross mice between BALB/c and MSM strains. BALB/c-derived alleles at three loci on chromosome 19, Mp53D1 (modifier of p53-deficiency) at D19Mit5, Mp53D2 at D19Mit90 and Mp53D3 at D19Mit123, extended the latency of thymic lymphoma (P value in Mantel-Cox test was 0.0007, 0.0007 and 0.0003, respectively), and Mp53D3 also increased the latency of skin tumors (P value, 0.0008). The linkage of Mp53D2 was confirmed by the experiment of using 94 p53-KO mice consomic for chromosome 19, providing a significant linkage. However, Mp53D1 or Mp53D3 was not confirmed of the linkage, suggesting epistasis of genes involved in the tumorigenesis.

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