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Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional 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 yet have distinct characteristics based on conventional 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 therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.<\/jats:p>","DOI":"10.1093\/narcan\/zcae015","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T20:25:24Z","timestamp":1712175924000},"source":"Crossref","is-referenced-by-count":13,"title":["The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities"],"prefix":"10.1093","volume":"6","author":[{"given":"Xingyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill,\u00a0School of Medicine , Chapel Hill , NC - 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2583-7080","authenticated-orcid":false,"given":"Sayali","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill,\u00a0School of Medicine , Chapel Hill , NC - 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8331-2357","authenticated-orcid":false,"given":"Di","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, University of North Carolina at Chapel Hill, School of Dentistry , Chapel Hill , NC - 27599 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L","family":"Bowser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill,\u00a0School of Medicine , Chapel Hill , NC - 27599 , USA"},{"name":"UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC - 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus","family":"Vaziri","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill,\u00a0School of Medicine , Chapel Hill , NC - 27599 , USA"},{"name":"UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC - 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,4,8]]},"reference":[{"key":"2024040811104018500_B1","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.1158\/1055-9965.EPI-22-0590","article-title":"RNA-based classification of homologous recombination deficiency in racially diverse patients with breast cancer","volume":"31","author":"Walens","year":"2022","journal-title":"Cancer Epidemiol. 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