Mapping of genetic modifiers of thymic lymphoma development in p53-knockout mice

The strain dependency of the spectrum and latency of tumors has been reported in p53 -deficient (KO) mice, suggesting the presence of modifiers for the outcome of the p53 deficiency. The modifiers provide clues to the oncogenic pathway in cells lacking p53 , the most frequently mutated gene in a wide variety of human cancers. To search the modifiers, we induced 160 lymphomas and 69 skin tumors by γ-irradiation of p53 (KO/+) backcross mice between BALB/c and MSM strains and performed genome scan. 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 development ( P values in Mantel–Cox test were 0.0007, 0.0007 and 0.0003, respectively). Mp53D3 also increased the latency of skin tumors ( P value, 0.0008). The linkage of Mp53D2 was confirmed by the experiment using 94 p53 -KO mice consomic for chromosome 19, providing a significant linkage. However, the linkage was not confirmed for Mp53D1 or Mp53D3 , suggesting epistasis of genes involved in the tumorigenesis.