Endometrial carcinoma is the most common malignancy of the female genital tract in the United States. However, very little is known about the molecular genetic alterations that underlie the development and progression of this common malignancy. Clues to the molecular pathogenesis of endometrial carcinoma have been provided by studies of colorectal tumorigenesis. Endometrial and colorectal tumors share several features including frequent K-ras and p53 gene mutations, histopathological appearance, and occurrence in a familial cancer syndrome, HNPCC (hereditary non-polyposis colorectal cancer). HNPCC has recently been found to be caused by mutations in DNA mismatch repair genes, hMSH2 or hMLH1, resulting in a molecular phenotype characterized by instability of microsatellite sequences. Microsatellite instability (MI) has been identified in a subset (20%) of presumably sporadic endometrial carcinomas. Molecular genetic studies will be used to address the following specific aims: 1) To evaluate endometrial carcinoma. and its precursor lesions. for chromosomal regions that commonly undergo loss of heterozygosity. All non-acrocentric chromosomal arms will be evaluated for loss of heterozygosity using selected microsatellite loci in order to identify regions of the genome that may harbor genes important in the development and progression of endometrial carcinoma. 2) To assess precursor lesions of endometrial carcinoma for clonality and for microsatellite instability. Endometrial hyperplasias, the precursors of endometrial carcinoma, will be evaluated for clonality and for MI to determine when they are manifest during endometrial tumorigenesis. 3) To analyze MI positive endometrial carcinomas for mutations in known mismatch repair genes. The MI positive endometrial carcinomas will be screened to identify possible mutations in the known DNA mismatch repair genes. If mutations are identified we will determine if they are somatic or germline. 4) To identify novel genes that may be responsible for the MI phenotype associated with endometrial carcinoma. Two approaches will be used to identify novel genes. One will rely on routine searching of dbEST (database of Expressed Sequence Tags) with known mismatch repair genes and the other will involve a genetic screen in S. cerevisiae for dominant negative effects on microsatellite mitotic instability. The proposed studies are directed at contributing an understanding to the molecular pathogenesis of endometrial carcinoma. Understanding the molecular genetic alterations responsible for this disease will provide a basis for the development of more effective diagnostic/treatment strategies for this common malignancy affecting women.
