Abstract A098: Allostatic load and tumor biology in uterine carcinosarcoma: A potential driver of endometrial cancer disparities

Abstract

Black patients experience disproportionately higher endometrial cancer (EC) mortality than White patients, and uterine carcinosarcoma, an aggressive high-risk histology, is diagnosed more frequently and portends worse outcomes among Black patients. Allostatic load (AL), a composite biomarker of cumulative physiologic stress, is disproportionately elevated among Black patients and independently associated with worse EC survival, offering a candidate biological pathway linking structural inequity to tumor behavior. Whether AL leaves a distinct molecular imprint on carcinosarcoma tumors has not been described. Patients with EC treated at a single institution (2014-2023) with archival tumor tissue underwent RNA and DNA sequencing. AL was calculated from 10 cardiovascular, metabolic, and inflammatory biomarkers dichotomized into low (0-2) and high (3-8) groups. Within the carcinosarcoma subset, differential gene expression (DESeq2, FDR<0.05) and gene set enrichment analysis comparing high- versus low-AL tumors were performed. Of 92 patients (38% Black, 53.3% White), high-AL patients were significantly more likely to identify as Black (49.0%) than low-AL patients (24.4%, p=0.048). Carcinosarcoma comprised 19 patients (20.7%; 8 low-AL, 11 high-AL). Unsupervised clustering of differentially expressed genes on heatmap analysis distinctly separated high- and low-AL carcinosarcoma tumors. On volcano plot analysis, high-AL tumors showed predominantly downregulated genes, most significantly myogenic/cytoskeletal transcripts (RYR1, TTN, ACTN2, MYH3, KLHL41), while the top upregulated genes were neuroectodermal/stem-associated (SOX2-OT, PAX6, PTPRZ1, CRB1, SLITRK2), suggesting a shift in heterologous differentiation phenotype. GSEA revealed the greatest number of significantly enriched Hallmark pathways in carcinosarcoma (31 gene sets, FDR<0.05) compared with the overall cohort (16), endometrioid (18), and serous (15) histologies. Positively enriched pathways in high-AL tumors included cell proliferation and cell cycle (EF2 targets, MYC targets, DNA repair and G2/M checkpoint) suggesting increased proliferative activity. Additionally, high-AL tumors were characterized by immune-suppressed biology. Negatively enriched pathways included inflammatory and immune signaling (TNF-alpha, IL6-JAK-STAT3 signaling complement and inflammatory response). Uterine carcinosarcoma, a histology that disproportionately affects Black patients, showed the greatest AL-associated transcriptional and pathway differences of any EC histology. These findings are hypothesis-generating and warrant further study as a mechanism underlying racial disparities in EC outcomes and immunotherapy response. Miller Singleton, Stephen Crockett, David Corcoran, Victoria Bae-Jump, Olivia Lara. Allostatic load and tumor biology in uterine carcinosarcoma: A potential driver of endometrial cancer disparities [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 A098.