Ovarian cancer is the leading cause of death due to cancer in the female genital tract, primarily because of the asymptomatic nature of this cancer during the early stages of tumorigenesis and poor prognosis by the time the tumors are detected (Stage III or IV). One of the three types of hereditary ovarian cancer that has been identified is Lynch Syndrome II, a subgroup of hereditary nonpolyposis colorectal cancer (HNPCC). Colon tumors from HNPCC families are associated with inheritance of a mutated mismatch repair gene and exhibit genetic instability, as demonstrated by alterations in tumor DNA at microsatellites. In preliminary studies, we observed that genetic instability occurred in five of ten ovarian cancer cell lines and was an ongoing and dynamic process. In one case, the 2774 cell line and the 2774 tumor (from which the cell line was derived) encoded only a mutant allele for the mismatch repair gene hMSH2, whereas, the normal tissue was heterozygotic for the hMSH2 gene. The goal of this proposal is to (1) assess the incidence of genetic instability in ovarian cancer (2) analyze HNPCC families with incidence of ovarian cancer and identify the gene responsible for inheritance of the disease (3) assess what downstream events occur subsequent to a 'second hit' at a mismatch repair locus. I believe my proposed will contribute to the understanding of initiating and secondary events in ovarian cancer are essential tools needed to combat this evasive and deadly cancer.
