Abstract C160: Inflammatory, immune and proliferative pathways differentiate the tumors of Black and White Women in the Carolina Endometrial Cancer Study

Abstract

Endometrial cancer (EC) harbors one of the largest survival disparities in US cancers for Black vs White women. Black women are known to have a higher prevalence of histologic (serous) and molecular (TP53 mutant) EC subtypes with more aggressive biology, but this is unlikely to fully explain this survival disparity as Black women have worse outcomes within all the histologic and molecular subtypes of this disease. Thus, we assessed gene expression differences between the tumors from Black and White women enrolled in the Carolina Endometrial Cancer Study (CECS) to identify other potential biological contributors to the significant disparities for Black women. CECS is an ongoing population-based, case-only study of incident EC in North Carolina that integrates tumor biology and clinical/epidemiologic factors. Differential gene expression (Limma/Voom) and gene set enrichment analysis were performed (FDR<0.05), comparing the ECs of Black vs White women within histologic (endometrioid vs serous) and molecular subtypes (MSI-High vs TP53 wild type vs TP53 mutant). Tumor specimens from the first 275 CECS patients have undergone DNA/RNA sequencing, with this analysis limited to endometrioid and serous histologic subtypes and the MSI-High/TP53 wild type/TP53 mutant molecular subtypes (n=197, 114 White, 83 Black). Among endometrioid (n=155) and serous (n=42) ECs, pathways that were downregulated in Black vs White women included inflammatory response, TNF-alpha signaling and the interferon gamma response. Whereas, E2F targets and G2M checkpoint pathways were upregulated in Black vs White women. When stratifying to just endometroid tumors, the MYC targets pathway was also enriched in Black vs White women. In analyses stratified by molecular subtype, oxidative phosphorylation and the WNT/beta-catenin pathways showed enrichment in MSI-High (N=47) ECs of Black vs White women. Specific to TP53 wildtype ECs (n=97), glycolysis, estrogen early and late response pathways were decreased and myogenesis pathways were increased in the tumors of Black vs White women. For TP53 mutant ECs (N=53), pathways downregulated in the tumors of Black vs White women included inflammatory response, TNF-alpha signaling and the interferon gamma response while the E2F and G2M checkpoint pathways were upregulated in Black women. Cell type deconvolution analysis demonstrated greater macrophage infiltration in tumors from White women. However, adjustment for macrophage infiltration only partially attenuated the race-associated inflammatory pathways, while the proliferative E2F and G2M signatures remained significantly enriched in Black women, suggesting that immune composition alone does not explain these transcriptional differences. Inflammatory, immune, and proliferative programs distinguished EC tumors from Black and White women across histologic and molecular subtypes. Further work is needed to investigate whether these pathway differences underlie disparities in EC outcomes for Black women that persist across the spectrum of EC. Caitlin Witt, David Corcoran, Temitope Keku, Adam Pfefferle, Michele C. Hayward, Olivia Lara, Andrew F. Olshan, Hazel B. Nichols, William C. Zamboni, Victoria L. Bae-Jump. Inflammatory, immune and proliferative pathways differentiate the tumors of Black and White Women in the Carolina Endometrial Cancer Study [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C160.