Abstract 175: Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma

Abstract

Abstract High grade serous carcinoma (HGSC) is the most common and deadly form of ovarian cancer. Although HGSC can arise from cells in the ovarian surface epithelium (OSE) or fallopian (oviductal) tubal epithelium (TE), the cell state and genetic alterations for HGSC initiation and progression remains unclear. Previous studies with cell type-specific mouse knockouts found inconsistencies in tumorigenesis and chemoresistance. These data can be explained if specific gene signatures in specific cell types have varied tumorigenic potential and chemoresistance. To determine specific gene combinations necessary for OSE and TE malignant transformation, we designed a CRISPR knock out (KO) mini-library against commonly mutated genes of HGSC. Our previous results revealed efficient gene combinations for ex vivo OSE transformation events and a preference for OSE stem cell transformation. To build on our previous studies, we extended our screening methods into TE cells. Our studies utilize an organoid approach to identify the most cancer-prone cell populations. They also test if cell differentiation state determines a specific set of genetic alterations necessary for HGSC initiation. Our screening platform has the potential to determine whether specific genetic alterations in specific cell types are required for malignant transformation. Additionally, our results may improve on previous models of HGSC initiation and progression. Citation Format: Daryl J. Phuong, Amanda P. Armstrong, Andrea Flesken-Nikitin, Alexander Y. Nikitin, John C. Schimenti. Determining the genetic alterations in initiation and progression of high-grade serous ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 175.