The prevention of any malignancy inevitably depends on the successful interruption of the transition from a precursor to a malignant state. To accomplish this, the precursor must be known. The precursor to pelvic serous carcinoma has not been previously identified, hampering efforts to study its evolution from benign mucosa. This application summarizes a series of studies that will explore the relationship between a clonal, epithelial-specific alteration in p53 function (""""""""p53 signature"""""""") in the distal fallopian tube and pelvic serous carcinoma. This plan of study is justified by the recent discoveries that 1) the distal fallopian tube is the principal site of early serous carcinoma development in women with germ line BRCA mutations (BRCA+), 2) it is a possible site of origin for over one half of """"""""ovarian"""""""" serous carcinomas, and 3) harbors this candidate precursor. The proposed studies are designed to clarify the link between p53 signatures and pelvic serous carcinoma by attempting to connect them topographically and genetically to early serous carcinomas, identifying biomarkers that are shared between p53 signatures and early serous carcinoma, and establishing an in vitro model from cultures of secretory mucosal cells. These pilot studies are designed to establish the p53 signature as a necessary if not sufficient event in the pathogenesis of pelvic serous carcinoma. If successful, these studies will be followed by more focused applications designed to prospectively test the p53 signature as a surrogate endpoint for serous carcinoma, that if ameliorated, will alter the risk of this lethal form of epithelial ovarian cancer.
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