Abstract IA14: Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice

Abstract

Abstract Robust preclinical models of ovarian high-grade serous carcinoma (HGSC) are needed to advance our understanding of HGSC pathogenesis and to test novel strategies aimed at improving clinical outcomes for women with the disease. Genetically engineered mouse models of HGSC have been developed that recapitulate the likely cell of origin (fallopian tube epithelium), underlying genetic defects, histology, and biologic behavior of human HGSCs, but the degree to which the mouse tumors acquire the somatic genomic changes, gene expression profiles, and immune microenvironment that characterize human HGSCs remains unclear. We used integrative molecular characterization of oviductal HGSCs arising in the context of Brca1, Trp53, Rb1, and Nf1 (BPRN) inactivation to determine whether the mouse tumors recapitulate human HGSCs across multiple domains of molecular features. Targeted DNA sequencing showed that the mouse BPRN tumors, but not endometrioid carcinoma-like tumors based on different genetic defects (e.g., Apc, Pten, Arid1a), acquire somatic mutations and widespread copy number alterations similar to those observed in human HGSCs. RNA sequencing showed that the mouse HGSCs most closely model the immunoreactive and mesenchymal subsets of human HGSCs. A combined immunogenomic analysis showed that the immune microenvironment of BPRN tumors models key aspects of tumor-immune dynamics in human HGSC, with enrichment of immunosuppressive cell subsets (myeloid-derived suppressor cells and regulatory T cells) as observed in the immunoreactive and mesenchymal subsets of human tumors. These findings, as well as early proof-of-principle studies, support the BPRN model as a robust preclinical experimental platform to help overcome barriers to clinical success in preventing, diagnosing, and treating this lethal cancer. Citation Format: Kathleen R. Cho. Integrated molecular characterization of the genome, transcriptome, and immune microenvironment in oviductal high-grade serous carcinomas arising in genetically engineered mice [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA14.