Increased mutation frequency and altered spectrum in one of four thymic lymphomas derived from tumor prone p53/Big...

p53 (-/-), lacI (+/-) double transgenic (p53/Big Blue3) mice provide an opportunity to examine the relationship in vivo between somatic mutation and tumorigenesis. Previously, the frequency and spectra of lacI mutations were found to be similar in normal tissues of 6 week old p53 (-/-) lacI (+/-) and p53 (+/+) lacI (+/-) mice. Herein, p53 (-/-), lacI (+/-) mice were used to examine the frequency and spectrum of spontaneous mutation in thymic lymphomas. Four mice with thymic lymphomas were sacrificed at 2.5, 3, 4 and 4.5 months of age. Normal thymus harvested from two p53 (+/+) lacI (+/-) mice and two p53 (-/-) lacI (+/-) mice served as controls. The mutation frequency in tumor 108 (6.8 x 10(-5)) was elevated 2.3-fold relative to the p53 (-/-) control (P<0.0001; chi2 test). The mutation spectra were also different (P=0.0009; Fisher exact test); in particular, A:T-->G:C transitions were prominently overrepresented in tumor 108. In addition, there were two examples of unusual deletions with inversions. In tumors 44 and 115, but not 110, there were trends toward increased mutation frequencies and altered spectra, but, within the constraints of present sample sizes, the results are not statistically significant. In conclusion, these findings suggest that altered frequencies and spectra exist in a subset of thymic lymphomas, perhaps due to somatic mutation in one or more DNA repair genes.