Genetic background alters the spectrum of tumors that develop in p53-deficient mice.

Using gene targeting in embryonic stem cells, we have generated mice with one or two null p53 germ line alleles. Mice with both p53 alleles inactivated are developmentally normal but highly susceptible to the early development of spontaneous tumors. Initial studies were performed in mice with a mixed inbred genetic background (75% C57BL/6 and 25% 129/Sv) (Donehower et al., Nature (London) 356, 215-221, 1992). To study the effect of genetic background on tumorigenesis in p53-deficient mice, we have put the p53 null allele into a pure 129/Sv background and monitored tumor development. 129/Sv mice with two p53 null alleles developed tumors sooner than the mixed genetic background p53-deficient animals. The most frequently observed tumor in p53 null mice of both genetic backgrounds was a malignant lymphoma. Because the 129/Sv strain has a low incidence of lymphoma, the frequent occurrence of lymphomas in all p53 null mice suggests that this particular tumor type may be a direct result of p53 loss and not a result of a particular genetic background. In addition to malignant lymphomas, the 129/Sv p53-deficient mice showed an increased incidence of aggressive teratocarcinomas (8 of 18 tumor-bearing males), a tumor type rare in virtually all inbred mice except for 129 strains. Thus, it appears that loss of p53 may accelerate a prior tumor predisposition and that genetic background can play a role in mediating both the rate and spectrum of tumor development in these mice.