Abstract B145: African ancestry is associated with dysregulation of MYC target genes in high-grade endometrial cancer

Abstract

Non-endometrioid endometrial cancer (EC) represents a minority of EC incidence but is disproportionately responsible for EC mortality. Women of African ancestry have a higher risk of being diagnosed with high-grade, primarily non-endometrioid subtypes of EC, contributing to EC survival disparities. The molecular basis of this higher risk is poorly understood. In this study, we characterize genomic and proteomic alterations associated with African ancestry in a cohort of 276 women with high-grade EC from the Detroit Metropolitan area. In this cohort, 60% of the women were of a non-endometrioid histology (42% serous, 11% mixed cell, 7% clear cell). We inferred genetic ancestry using ADMIXTURE from whole exome sequencing data. Using a threshold of 80% to assign categorical ancestral group labels, we identified 108 women of primarily African, 90 of European, 77 Admixed, and 1 of American Admixed ancestry. We compared differences in somatic SNP, insertion and deletion, copy number, and driver mutation rates between ancestries. Using mass spectrometry-based proteomic expression, we performed ancestry-based differential protein expression and gene set enrichment analysis. We developed Fine-Gray survival models to understand how differentially expressed gene sets influence endometrial cancer-specific survival. Gene set variation analysis revealed cancer hallmark gene sets associated with increasing proportions of African ancestry (adjusted p < 0.05) that included MYC targets, E2F targets, and genes involved in the G2M checkpoint. While African ancestry was associated with MYC amplifications in univariate analysis (OR = 2.2, p < 0.05), this association was attenuated in multivariate analyses controlling for histology, TP53 mutation status, and molecular subtype (p = 0.47). However, the MYC target gene set remained positively associated with African ancestry after controlling for MYC copy number (adjusted p < 0.05). African ancestry was positively correlated with the expression of MYC-associated genes such as BRD4 and PAX8 (R2 = 0.12, 0.14; p value < 0.05). In multivariate linear regression analyses adjusting for patient age, histology, molecular subtype, and stage, both African ancestry (β = -191.34, p value <0.05) and PAX8 expression (β = -113.75, p value < 0.05) were independently correlated with decreased immune infiltration. In multivariate analyses, the MYC targets gene set enrichment scores were associated with poorer five-year endometrial cancer specific survival after controlling for age, histology, neighborhood socioeconomic status, ancestry, race, body mass index, stage, and molecular subtype (HR 2.11, 95%CI 1.06-4.21, p < 0.05). These results suggest that African ancestry is associated with dysregulation of MYC target genes implicating this mechanism as a survival determinant independent of histological or molecular subtype in high-grade EC. Targeting MYC or its downstream effectors may improve survival outcomes, particularly in the more aggressive EC subtypes that are more prevalent in women of African ancestry. Devin Gee, Abdulfatai Tijjani, Kassidy Lundy-Perez, Emma Saart, Michele L. Cote, Nyasha Chambwe. African ancestry is associated with dysregulation of MYC target genes in high-grade endometrial cancer [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 B145.