The accumulation of genetic and epigenetic alterations at the sites of tumor suppressor genes and oncogenes has been associated with the progression of human malignancies. The long term goal of this application is the identification of a tumor suppressor gene(s) involved in the early stages of ovarian tumor development. The study of molecular genetic changes in ovarian cancer has been limited by the fact that tumor progression in this malignancy is not well understood. In particular, it is unclear whether a benign tumor or a low malignant potential tumor of the ovary can give rise to tumors of greater malignant potential. Nonetheless, studies of ovarian tumors have implicated at least 3 genes on chromosome 17 in the development of ovarian cancer. The proposed study will test the hypothesis that genetic alterations at 17pl3.3 are associated with low grade tumors and that genetic changes at 17q2l and at the p53 locus (17p13.1) are associated with high grade tumors. Particular attention will be focused on the study of low malignant potential lesions with the retrospective evaluation of allelic deletions in paraffin embedded ovarian tumors of low grade. Moreover, to determine if the accumulation of genetic alterations is correlated with the acquisition of a more malignant cellular phenotype, studies will also be performed at the different histologic areas within the same ovarian tumor. These studies will involve Southern and PCR methodologies. Eventually, chromosomal walking studies will be used to localize the tumor suppressor gene sequence on 17p13.3.
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