GENETIC BACKGROUND ALTERS THE SPECTRUM OF TUMORS THAT DEVELOP IN P53-DEFICIENT MICE

Using gene targeting in embryonic stem cells, we have generated mice w ith one or two null p53 germ line alleles. Mice with both p53 alleles inactivated are developmentally normal but highly susceptible to the e arly development of spontaneous tumors. Initial studies were performed in mice with a mixed inbred genetic background (75% C57BL/6 and 25% 1 29/Sv) (Donehower et al., Nature (London) 356, 215-221, 1992). To stud y the effect of genetic background on tumorigenesis in p53-deficient m ice, 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 de veloped tumors sooner than the mixed genetic background p53-deficient animals. The most frequently observed tumor in p53 null mice of both g enetic 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 b ackground. In addition to malignant lymphomas, the 129/Sv p53-deficien t 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 ac celerate a prior tumor predisposition and that genetic background can play a role in mediating both the rate and spectrum of tumor developme nt in these mice.