Abstract LB376: Historical redlining and DNA methylation in prostate tumors

Abstract Introduction. Growing literature demonstrates a role of neighborhood disadvantage (ND), which disproportionately affects African American (AA) men, in prostate cancer (PC) disparities by race. One component of ND is historical redlining, which involved the systematic denial of mortgages in certain urban neighborhoods, often based on race. Redlining led to disinvestment and subsequent ND over time, and has been linked with poorer health outcomes in the present day. Epigenetic perturbations related to chronic stress may play a role in these associations. We hypothesized that residing in a formerly redlined neighborhood would be associated with prostate tumor DNA methylation (DNAm) alterations. Methods. This cross-sectional study leveraged prostate tumor DNAm data for AA men with PC who received radical prostatectomy at the University of Maryland Medical Center between 1992-2021. Historical redlining status was determined by intersecting participants' address at diagnosis with the 1930s Home Owners’ Loan Corporation redlining map of the Baltimore metropolitan area. DNAm was measured using Illumina’s EPIC v2 array. After quality control steps, there were 683,765 CpG sites for analysis. Linear regression models were used to estimate associations between historical redlining and DNAm levels (beta values, ranging from 0-1), adjusting for age at surgery and year of surgery. Differentially methylated regions (DMRs) were identified using the bumphunter R package. Results. We included 92 AA men with a median (interquartile range, IQR) age of 60 (54-63) years at surgery. Eight men (9%) lived in a historically redlined neighborhood. Residence in a redlined neighborhood was significantly associated with DNAm at 12 CpG sites after adjustment for multiple comparisons [False Discovery Rate (FDR)-adjusted p<0.05], 10 of which exhibited hypomethylation [IQR for difference: (-0.14, -0.07)]. These sites annotated to nine genes: PLEKHG5, KDR, ZDHHC19, ZNF316, ZFYVE21, CDH26, HPCA, FAM228B, PTPRN2. The most significant CpG site (cg11384525) was in ZDHHC19, which plays a role in tumor progression via S-palmitoylation activity (mean DNAm for men in redlined vs. non-redlined neighborhoods: 0.76 vs. 0.92; p=6.4x10-9; FDR-adjusted p=2.2x10-3). We identified one significant DMR involving hypomethylation of TNXB, which encodes an extracellular matrix glycoprotein that is associated with tumor progression for several cancers, including PC. Discussion. In this study of AA men with PC, tumor DNAm levels at 12 CpG sites were significantly different among men who resided in historically redlined neighborhoods. This study is one of the first to suggest associations of historical redlining with prostate tumor DNAm. Additional research is needed to replicate these findings and further investigate the relationships between the neighborhood environment, epigenetic tumor modifications, and PC disparities to elucidate mechanisms and inform interventions. Citation Format: Joseph Boyle, Camryn Cohen, Derrick Butts, Jimmie L. Slade, Yuji Zhang, Teklu B. Legesse, Ashley Johnson, Kimberly Clark, Jessica Wimbush, Nicholas Ambulos, Jing Yin, Jong Y. Park, Eberechukwu Onukwugha, Arif Hussain, Cheryl L. Knott, Kathryn H. Barry. Historical redlining and DNA methylation in prostate tumors [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 LB376.