γ-ray induced hepatocarcinogenesis in p53-deficient mice

Background: Mutations in the p53 gene are frequent genetic alterations in human hepatocellular carcinoma (HCC), but, little is known of the molecular genetic changes that occur during murine hepatocarcinogenesis. Materials and Methods: To characterize the properties of constitutive p53 deficiency that contribute to fiver tumor development, a total of 168 Fl mice of two different strains (C3H, which are susceptible to hepatocarcinogenesis and MSM [Mus. M. molossinus] with a single null p53 allele) were exposed to a single 3-Gy dose of whole-body gamma-irradiation at 4 weeks of age and observed for a period of 360 days. The genotype of the mice and the p53 spectrum of the tumors were investigated by polymerase chain reaction (PCR) analysis. Results: Thirty-five gamma-ray-induced HCCs were obtained as a result of this experiment. 11 (40%) of the mice with liver tumor were wild-type for p53. All liver tumors examined retained the wild-type p53 allele, indicating that p53 itself may nor be a target for radiation-induced alteration. Only two p53-deficient mice in the liver tumor group developed thymic lymphomas. The p53-deficient mice showed no significant differences in the number, size, or growth rate of HCC or in the apparent development of HCC. Conclusions: These results indicate that p53 deficiency does not enhance the rate of development ol degree of malignancy of radiation-induced HCC in mice but may instead favor the development of multiple primary cancers.