Abstract 1012: Investigating genetic and transcriptomic drivers of endometrial cancer disparities in Black/African American women

Abstract Endometrial cancer (EC) is the sixth most common gynecological malignancy globally, with an increasing incidence over the last two decades. Black/African American (BAA) women are disproportionately affected, experiencing higher rates of high-grade EC and associated mortality compared to Non-Hispanic White (NHW) women. These disparities likely result from complex interactions between social determinants and biological factors. Notably, BAA women are 2-3 times more likely to be diagnosed with aggressive, high-grade EC and have significantly higher mortality rates, underscoring an urgent need to address this disparity. Uterine EC disparities arise from intricate tumor microenvironments characterized by cellular niches with distinct genotypes, phenotypes, and spatial transcriptomic landscapes. In estrogen-dependent EC tumorigenesis, the endometrium undergoes unregulated proliferation, progressing from normal tissue to atypical hyperplasia and ultimately carcinoma. The heterogeneity of EC tumors presents challenges for therapeutic targeting, contributing to poor outcomes. This study investigates the genetic and transcriptomic features within the tumor microenvironment of BAA EC patients to uncover drivers of these disparities. Our cohort includes primary, metastatic, and normal uterine tissues classified as uterine endometrial adenocarcinoma, along with two serous papillary carcinoma cases of varying tumor grades. RNA-sequencing analysis revealed differential gene expression enriched in pathways related to cell proliferation, epithelial-to-mesenchymal transition (EMT), DNA damage response, and immune modulation. Preliminary whole-exome sequencing (WES) data implicate both established and potentially novel mutations in genes associated with cell cycle regulation, angiogenesis, chromatin remodeling, and cell signaling. Paired WES analysis identified somatic variants and copy number alterations in key genes, correlating with known EC-driven genetic alterations documented in the literature. Spatial transcriptomics is being applied to characterize gene signatures across cellular neighborhoods within the tumor microenvironment. This approach elucidates the spatial architecture and cellular niches driving immune modulation and tumor progression. By integrating genomic and spatial transcriptomic data, we aim to provide a comprehensive understanding of the tumor microenvironment in BAA EC patients. This study represents a significant step toward identifying genetic and transcriptomic drivers of EC disparities in BAA women, with the goal of informing the development of improved diagnostic and therapeutic strategies to reduce these inequities. Citation Format: Danyelle Paine, Yuxin Jin, Javier Arias-Stella III, David Craig, John Carpten. Investigating genetic and transcriptomic drivers of endometrial cancer disparities in Black/African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1012.