P53 STATUS IN SPONTANEOUS AND DIMETHYLNITROSAMINE-INDUCED RENAL-CELL TUMORS FROM RATS

Rats carrying the Eker tumor-susceptibility mutation (Eker rats) are p redisposed to developing renal cell carcinoma. Rats heterozygous for t he Eker mutation develop spontaneous multiple bilateral renal cell tum ors by the age of 1 yr. In a previous study, Eker-mutation carrier and noncarrier rats were exposed to the renal carcinogen dimethylnitrosam ine (DMN), and male rats carrying the Eker mutation exhibited a 70-fol d increase in the induction of renal adenomas and carcinomas when comp ared with noncarrier rats. In this study, spontaneous and DMN-induced rat renal cell tumors (adenomas and carcinomas) were analyzed for muta tions of the p53 gene by direct sequencing of cDNA polymerase chain re action products, There were no mutations in p53 cDNA derived from rena l tumors from six untreated rats. Mutations were found in one of 15 of the DMN-induced tumors: a transition at codon 140, CCT --> CTT, in a renal adenoma. Additionally, seven cell lines derived from spontaneous renal cell tumors did not contain mutations in p53. The low frequency of p53 mutations (one of 21 renal cell tumors and none of seven cell lines derived from renal cell tumors) indicates that the development o f both spontaneous and carcinogen-induced renal tumors involved a non- p53-dependent pathway. As p53 is infrequently mutated in human renal c ell carcinomas and in rat renal mesenchymal tumors, it is likely that a tumor suppressor gene or genes other than p53 are involved in the de velopment of renal cancer. (C) 1995 Wiley-Liss, Inc.