The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities

Abstract

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therap y -induced genoto xicity. Neoplastic cells also deplo y man y mis-e xpressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and surviv al. Here, w e present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to con v entional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC y et ha v e distinct characteristics based on con v entional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therap y -resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and re v eals ne w vulnerabilities of aggressiv e endometrial cancer where none currently exist.