P53 GENE-MUTATIONS AND PROTEIN ACCUMULATION IN HUMAN OVARIAN-CANCER

Mutations of the p53 gene on chromosome 17p are a common genetic chang e in the malignant progression of many cancers. We have analyzed 38 ma lignant tumors of ovarian or peritoneal mullerian type for evidence of p53 variations at either the DNA or protein levels. Genetic studies w ere based on single-strand conformation polymorphism analysis and DNA sequencing of exons 2 through 11 of the p53 gene; mutations were detec ted in 79% of the tumors. These data show a statistically significant association between mutations at C.G pairs and a history of estrogen t herapy. Two of 20 patients whose normal tissue could be studied carrie d germ-line mutations of p53. Immunohistochemical analysis of the p53 protein was carried out using monoclonal antibody PAb180l. Ninety-six percent of the missense mutations were associated with abnormal accumu lation of p53 protein, but nonsense mutations, a splicing mutation, an d most deletions did not result in p53 protein accumulation. A statist ically significant association between p53 protein accumulation in poo rly differentiated stage III serous carcinomas and small primary tumor size at diagnosis was found, perhaps suggesting that p53 protein accu mulation accelerates the metastatic spread from a primary tumor. Overa ll, our findings indicate that alterations of p53 play a major role in ovarian cancer, including predisposition to the disease in some patie nts, and suggest a possible mechanism for somatic mutations leading to this cancer.