Pathogenesis of Ovarian Serous Carcinoma as the Basis for Immunologic Directed Diagnosis and Treatment

The purpose of this study is to elucidate the pathogenesis of serous carcinoma by identifying the molecular genetic changes and preferentially expressed genes of different histological types of serous neoplasms. We hypothesize that the development of serous carcinoma proceeds along two main pathways one is rapid progression from ovarian surface epithelium to high-grade serous carcinoma without well-established morphological precursors de novo pathway and the other is a gradual development from borderline tumors, to non-invasive micropapillary serous carcinomas then to low-grade carcinomas stepwise pathway. The first pathway results in a high-grade neoplasm conventional serous carcinoma and the second leads to the development of a lowgrade indolent tumor. Both types of carcinomas and the putative precursor lesions of invasive MPSC are characterized by distinctive molecular genetic alterations and specific gene expression. We identified that mutations in KRAS and BRAF genes characterized the development of low-grade serous carcinomas. Expression of HLA-G, apoE and membralin molecules were confined to high-grade serous carcinomas. This project, designed to test our proposed model of diverse pathways in the pathogenesis of ovarian serous carcinoma, provides an etiologic basis for the other two projects.