Abstract A140: Comprehensive molecular characterization of high-grade endometrial cancer in an ancestrally diverse cohort

Abstract Endometrial cancer (EC) exhibits significant disparities across populations, with Black women disproportionately more likely to present with aggressive high-grade subtypes that have the worst prognostic outcomes. While social determinants such as delayed diagnosis and unequal access to care contribute to these disparities, the molecular drivers of more aggressive EC in women of African descent remain understudied. To address this gap, we assembled a diverse cohort of 81 patients—predominantly with high-grade EC—treated within a major hospital system in the New York metropolitan area. We performed tumor-normal whole-genome and transcriptome sequencing to comprehensively characterize the molecular disease landscape. 65% of our patients were of predominantly African continental genetic ancestry, and 58% of those individuals had copy number high (CN-H) tumors. 13 patients were identified as carriers of germline pathogenic variants. Somatic mutation analysis revealed TP53 (57%), PIK3CA (30%), PTEN (27%), and ARID1A (25%) as the most frequently altered genes. TP53 somatic mutations were most frequent in carcinosarcoma and serous subtypes, while PIK3CA and ARID1A mutation frequencies were higher in endometrioid and clear cell carcinoma. Notably, MECOM amplifications were enriched in patients of African ancestry, while PPP2R1A alterations were absent in carcinosarcoma cases. Copy number analysis revealed that 50% of patients of African ancestry exhibited whole-genome doubling events, along with a diverse array of complex structural variation, including extrachromosomal DNA (ecDNA). We identified 27 ecDNA events across 19 patients, many of which were associated with elevated gene expression. Transcriptomic analysis identified six genes differentially expressed between patients of African ancestry and all the other patients in our cohort, with RPS26 showing the strongest association with African ancestry. Cell type deconvolution further revealed increased CD8 T cell tumor infiltration associated with African ancestry. These findings provide insights into the genomic and molecular landscape of EC in a racially diverse patient cohort, and reveal ancestry-associated genomic features that may contribute to aggressive phenotypes. We anticipate that these studies might shed light into molecular determinants of aggressive EC and potential ancestry-informed therapeutic strategies. Citation Format: Nyasha Chambwe, Marina Frimer, Zoe Goldstein, Mali Barbi, William Hooper, Kyriaki Founta, Pascal Belleau, Timothy Chu, Astrid Deschênes, Melissa Kramer, Ali Oku, Lara Winterkorn, Zalman Vaksman, Brian Yueh, Kadir Ozler, Aaron Nizam, Onyinye D. Balogun, W Richard. McCombie, Alexander Krasnitz, Nicolas Robine, Semir Beyaz. Comprehensive molecular characterization of high-grade endometrial cancer in an ancestrally diverse cohort abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A140.