Abstract LB238: Spatial transcriptomics identifies distinct molecular and immune pathways in endometrial cancer in African American women

Abstract Endometrial cancer (EC) mortality continues to rise in the United States, with African American (AA) women experiencing more than double the mortality rate of non-Hispanic White (NHW) women and a higher prevalence of aggressive histologic subtypes. While socioeconomic and access-related factors contribute to these disparities, growing evidence suggests that molecular features and tumor microenvironment (TME) states may also influence disease behavior and outcomes. We hypothesized that EC tumors from AA patients may harbor distinct combinations of somatic alterations, germline risk variants, and cellular states that contribute to aggressive disease biology. Formalin-fixed paraffin-embedded archival tissues were obtained from 37 EC cases, including 25 AA and 12 NHW tumors, with matched normal tissue available for 12 cases. Molecular subtyping was performed using immunohistochemistry (IHC) and whole-exome sequencing (WES) to identify somatic and germline alterations. Tumors were classified into POLE-like, microsatellite instable MMR-deficient (MMRD/MSI), copy number high p53-abnormal (CNH), and copy number low no specific molecular profile (NSMP) subgroups. Spatial transcriptomics (ST; 10X Visium) was performed to resolve tumor, stromal, and immune programs, followed by pathway enrichment and copy number inference analyses. MMRD/MSI tumors, defined by loss of mismatch repair protein expression, exhibited recurrent PTEN mutations, activating PIK3CA and CTNNB1 alterations, and frequent disruption of chromatin remodeling genes including ARID1A/B and KMT2 family members. NSMP tumors were characterized by canonical exon 3 CTNNB1 mutations, co-occurring PIK3CA hotspots, and alterations in epigenetic regulators and transcription factors. CNH tumors, associated with the poorest clinical outcomes, demonstrated TP53 inactivating events, PIK3CA activation, elevated aneuploidy burden, and genomic features consistent with increased proliferative capacity. Spatial transcriptomic analyses revealed distinct TME states across molecular subtypes. MMRD/MSI tumors displayed an immune-inflamed phenotype with elevated IFN-γ signaling, CD8⁺ T-cell infiltration, active antigen-presentation programs, and partial epithelial-mesenchymal transition features. Within this subgroup, AA tumors showed stronger inflammatory signaling and antigen-presentation gene variation. NSMP tumors exhibited a predominantly immune-excluded TME, characterized by reduced chemokine expression and limited dendritic cell recruitment, largely consistent across race groups. In contrast, CNH tumors demonstrated an immune-desert phenotype with minimal adaptive immune infiltration and pronounced chromosomal instability, most evident in AA tumors. Our preliminary conclusions suggest that, across molecular subtypes, tumors from AA and NHW patients exhibit largely shared global features and architectures. Despite largely shared global transcriptomic architectures across race groups, subtype-specific pathway and tumor microenvironment differences were evident, suggesting that endometrial cancer disparities are driven by subtle biological variation and supporting integrative, context-aware precision oncology approaches. Citation Format: Danyelle Hill, Yuxin Jin, Javier Arias-Stella, Joseph Carlson, David Craig, Rania Bassiouni, John Carpten. Spatial transcriptomics identifies distinct molecular and immune pathways in endometrial cancer in African American women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB238.