THE MOLECULAR GENETICS OF GYNECOLOGIC CANCERS

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Gynecologic cancers remains a major health problem for women in this country with approximately 25,000 deaths annually attributed to these cancers. The purpose of this project is to characterize the molecular genetics of this group of tumors and ultimately use that information for clinical application in designing therapeutic and prevention trials. We have characterized 63 ovarian tumors which span the histologic spectrum from benign cystadenomas through tumors of "low malignant potential" to ovarian carcinomas for mutations in the ras , P53, and Rb oncogenes. Results from this study revealed that activated ras genes are found in 10% of benign cystadenomas and 30% of "LMP" tumors but not in ovarian carcinomas. In addition, mutations in the tumor suppressor genes P53 and Rb occur in ovarian carcinomas (48 and 14% respectively) but are not present in LMP tumors. This suggested that these tumors are discrete biologic entities. Of further interest, the incidence of activated ras genes in LMP tumors is higher in more advanced tumors suggesting it is a negative prognostic factor for these tumors. Future projects will examine the value of p53 mutations as a prognostic or an early detection marker in ovarian cancers by examining large numbers of early and advanced stage ovarian cancers. We are also examining endometrial specimens which span the histologic spectrum from benign to malignant for mutations in the ras and p53 genes. Activated ras genes are found in the atypical hyperplasias (14%) and endometrial carcinomas (5%). P53 mutations rare found in approximately 15% of hyperplasia and carcinomas. These studies will help to identify the molecular genetic events which are important in the genesis of these tumors. In addition, it will characterize the temporal relationship among these events enabling one to determine if any of these molecular lesions can be used as markers of early disease.