Abstract C139: Race-specific hypermethylation of breast cancer driver genes concentrates in estrogen receptor-negative tumors

Abstract

Non-Hispanic Black (NHB) women experience disproportionately higher rates of aggressive, estrogen receptor-negative (ER−) and triple-negative breast cancer, yet the molecular basis of these differences remains poorly understood. DNA methylation can link biological outcomes to social and environmental exposures, but it is unknown whether race-associated methylation changes target known cancer driver genes, or whether these alterations preferentially occur in tumor subtypes that drive disparities in breast cancer outcomes. We investigated whether race-associated DNA methylation preferentially targets known breast cancer driver genes and whether these alterations are concentrated in ER− tumors. We studied 85 NHB and non-Hispanic White (NHW) women diagnosed with a first primary breast cancer at Emory University Hospitals from 2001–2019. Tumor tissue DNA methylation was measured genome-wide using the Twist next-generation sequencing (NGS) Methylation Detection System (covering approximately 3.2 million loci). We identified differentially methylated regions (DMRs) by race, overall, and within ER-status subgroups, adjusting for age, smoking, obesity, and stage. DMRs were tested for overlap with Catalogue Of Somatic Mutations In Cancer (COSMIC) cancer driver genes (all drivers, Tier 1, and breast-specific), and each subgroup was analyzed for directional methylation (hyper- vs. hypomethylation). Race-associated DMRs were 2.6-fold more frequent in ER− than ER+ tumors (687 vs. 264). At the site level, ER− tumors showed more than three times the total methylation and a significantly higher per-gene density (Mann-Whitney p = 6.0×10-5). Hypermethylation in NHB women predominated (68% of DMRs) and was almost entirely confined to ER− disease: 97.8% of race-associated DMRs in ER− tumors were hypermethylated in NHB women, whereas ER+ tumors showed no directional skew by race. Race-associated DMRs were significantly enriched for COSMIC cancer drivers, including a 4.8-fold enrichment for breast-specific drivers, whereas ER-status DMRs showed no such enrichment. Four breast cancer driver genes were hypermethylated in NHB women: GATA3 (mean Δβ = 0.055 across 3 DMRs), PLEC (Δβ = 0.124), ARID1B (Δβ = 0.089), and NTRK3 (Δβ = 0.068). Rather than being diffusely distributed across the genome, race-associated methylation is characterized by consistent hypermethylation that disproportionately targets known breast cancer driver genes and is concentrated in ER− tumors, the subtype most strongly associated with breast cancer incidence disparities in NHB women. These findings suggest hypermethylation of cancer driver genes may contribute to aggressive tumor biology. Additionally, because hypermethylation is observed in NHB women and race is a social construct, further investigation is needed to understand the relationship between social exposures and this epigenetic mechanism. Generative AI was used to assist in drafting and editing the text of this abstract. Bayan M. Toloubadei, Lindsay Collin, Tasmiah T. Aziz, Lauren E. McCullough, Jasmine M. Miller-Kleinhenz. Race-specific hypermethylation of breast cancer driver genes concentrates in estrogen receptor-negative tumors [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 C139.