Chambwe, Nyasha, Frimer, Marina, Goldstein, Zoe, Barbi, Mali, Hooper, William, Founta, Kyriaki, Belleau, Pascal, Chu, Timothy, Deschenes, Astrid, Kramer, Melissa, Oku, Ali, Winterkorn, Lara, Vaksman, Zalman, Yueh, Brian, Ozler, Kadir, Nizam, Aaron, Balogun, Onyinye D, Mccombie, W Richard, Krasnitz, Alexander, Robine, Nicolas, Beyaz, Semir (September 2025) Comprehensive molecular characterization of high-grade endometrial cancer in an ancestrally diverse cohort. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities, 2025 Sep 18-21, Baltimore, MD.
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.
| Item Type: | Conference or Workshop Item (Paper) |
|---|---|
| Subjects: | diseases & disorders > cancer diseases & disorders diseases & disorders > cancer > cancer types > endometrial cancer diseases & disorders > cancer > cancer types |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab CSHL labs > Krasnitz lab CSHL labs > McCombie lab CSHL labs > Tuveson lab |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 18 September 2025 |
| Date Deposited: | 07 Oct 2025 12:40 |
| Last Modified: | 07 Oct 2025 12:40 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/41979 |
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