American men of African ancestry (AA) have higher prostate cancer (PCa) incidence and mortality rates compared to American men of European ancestry (EA). Differences in genetic susceptibility mechanisms may contribute to this disparity.
To gain insights into the regulatory mechanisms of PCa susceptibility variants, we tested the association between SNPs and DNA methylation (DNAm) at nearby CpG sites across the genome in benign and cancer prostate tissue from 75 AA and 75 EA men. Genome-wide SNP data (from benign tissue) and DNAm were generated using Illumina arrays.
Among AA men, we identified 6,298 and 2,641 cis-meQTLs (FDR of 0.05) in benign and tumor tissue, respectively, with 6,960 and 1,700 detected in EA men. We leveraged GWAS summary statistics to identify previously reported PCa GWAS signals likely to share a common causal variant with a detected meQTL. We identified 9 GWAS-meQTL pairs with strong evidence of co-localization (4 in EA benign, 3 in EA tumor, 2 in AA benign, and 3 in AA tumor). Among these co-localized GWAS-meQTL pairs, we identified co-localizing eQTLs impacting four eGenes with known roles in tumorigenesis.
These findings highlight epigenetic regulatory mechanisms by which PCa-risk SNPs can modify local DNAm and/or gene expression in prostate tissue.
Overall, our findings showed general consistency in the meQTL landscape of AA and EA men, but meQTLs often differ by tissue type (normal vs. cancer). Ancestry-based LD differences and lack of AA representation in GWAS decrease statistical power to detect co-localization for some regions.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2024 Jan 31 [Epub ahead of print]
Dayana Delgado, Marc Gillard, Lin Tong, Kathryn Demanelis, Meritxell Oliva, Kevin J Gleason, Meytal Chernoff, Lin Chen, Gladell P Paner, Donald Vander Griend, Brandon L Pierce
University of Chicago, Chicago, United States., University of Chicago, United States., University of Pittsburgh, Pittsburgh, PA, United States., University of Chicago, Chicago, IL, United States., AbbVie (United States), United States., University of Illinois at Chicago, Chicago, IL, United States.