Project 1: Diagnose high-grade ovarian serous carcinoma precursors and occult tumors

Abstract (Project 1) The objective is to streamline the detection of incidental occult ovarian carcinoma and its precursor lesions in fallopian tubes, which are the site of origin of “ovarian” high-grade serous carcinoma (HGSC). The updated paradigm in the genesis of ovarian HGSC posits that tumor initiation occurs in the fallopian tube epithelium through a precursor stage, serous tubal intraepithelial carcinoma (STIC). Women at high risk for ovarian cancer are up to 20-35 times more likely to develop HGSC in their lifetime. The current recommendation for these women is to undergo risk-reduction salpingo-oophorectomy (RRSO) after their childbearing age. This procedure reduces but does not eliminate HGSC risk entirely because STIC or occult HGSC cells may have spread to the peritoneum prior to surgery, portending a recurrence of an advanced stage disease. The current standard-of- care diagnosis is based on examining surgically removed fallopian tubes. Since the lesions are grossly inconspicuous, pathologists randomly section tubes and review only limited representative tissue sections, precluding an accurate diagnosis and often failing to predict clinical outcome. Project 1 aims to apply Real-SeqS and DREAMing in assessing STIC/HGSC specific aneuploidy patterns and methylation markers, respectively, to sensitively diagnose STICs and incipient HGSC in RRSO specimens after brushing the surface of tubes and ovaries to collect epithelial cells for Real-SeqS and DREAMing analyses. We propose the following two specific aims. Aim 1. Assess the performance of Real-SeqS and DREAMing using tubal brushing specimens from prospective RRSO specimens. Aim 2. Using several cutting-edge methods, assess the prioritized amplified cancer genes including CCNE1 and RSF1 for their cancer-spreading phenotypes including proliferation, motility, invasion, and tumor-forming ability in peritoneal tissues. This project springboards from several recent studies published by current SPORE.