Abstract B018: MYC is sufficient to generate mid-life high-grade serous ovarian and serous endometrial carcinomas in a BRCA wild type p53-R270H mouse model

Abstract

Abstract Genetically engineered mouse models (GEMM) have fundamentally changed how cancer etiology, early detection, and treatment can be understood. Mouse models have been developed that support the fallopian tube as the origin of some ovarian cancers. However, serous endometrial cancer is a much rarer gynecologic cancer with fewer models available. The genetics of serous endometrial cancer are very similar that of high-grade serous ovarian cancer. The most common mutation found in both high-grade serous ovarian cancer and serous uterine cancer is p53 and in humans, MYC is amongst the most amplified genes in both tyeps of cancer. We developed a GEMM of high-grade serous ovarian cancer by using a fallopian tube epithelium specific promoter Ovgp1 to express MYC and dominant negative mutant p53-R270H. Female mice developed lethal cancer at an average of 15.1 months. Histopathological examination of mice revealed HGSOC characteristics including nuclear p53 and nuclear MYC in clusters of cells within the fallopian tube epithelium and ovarian surface epithelium. Unexpectedly, nuclear p53 and MYC clustered cell expression was also identified in the uterine luminal epithelium, possibly from intraepithelial metastasis from the fallopian tube epithelium. Extracted tumor cells exhibited strong loss of heterozygosity at the p53 locus, leaving the mutant allele. Copy number alterations in these cancer cells were prevalent, disrupting a large fraction of genes. Transcriptome profiles most closely matched human HGSOC and serous endometrial cancer. Histological and transcriptomic findings are consistent with the hypothesis that serous uterine cancer may originate from the fallopian tube epithelium. Citation Format: Alexandra Blackman, Amy Rees, Rob Bowers, Christian Jones, Silvia Vaena, Shelby Carter, Evan Villamor, Della Evans, George Fullbright, David Long, Laura Spruill, Martin Romeo, Kristi Helke, Anthony Emanuel, Joe Delaney. MYC is sufficient to generate mid-life high-grade serous ovarian and serous endometrial carcinomas in a BRCA wild type p53-R270H mouse model [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B018.