Abstract 5999: Comparative and integrative analysis of transcriptomic and epigenome wide DNA methylation changes in African American prostate cancer

Abstract

Abstract African American (AA) men have the highest incidence and mortality rate from Prostate cancer (PCa) than any other racial/ethnic group. To understand this racial disparity, molecular features of different types, including gene expression, DNA methylation and other genomic alterations, must be carried out in tumor samples from these 2 populations. To date, PCa genomic studies have largely under-represented tumor samples from AA men due to lack of inclusion of significant numbers in such studies. In this study we carried out genome-wide DNA methylation analysis in 63 clinically annotated fresh-frozen PCa and 50 normal prostate tissues from AA men using the Illumina Infunium 850K Human Methylation EPIC BeadChip array. mRNA expression database from a sub-set of the AA biospecimen were used to assess correlation of transcriptome and epigenomic datasets. Using bioinformatic analysis to integrate a comprehensive set of genomic datasets we identified probesets that were significant (p<0.01) and differentially methylated in AA PCa compared to normal prostate tissues and were significant (p<0.01) and inversely correlated with AA mRNA expression. GO analysis in this AA cohort showed significant differential methylation that were mostly hypermethylated genes with corresponding down-regulated mRNA expression for top genes associated with biological pathways in hemidesmosome assembly, mammary gland development, epidermis development, hormone biosynthetic process and cell communication. On the other hand, few significant differential top hypomethylated genes and corresponding up-regulated mRNA expression were identified in biological pathways of negative regulation of macrophage differentiation, cAMP-dependent protein kinase inhibitor activity, protein destabilization, transcription corepressor activity and fatty acid biosynthetic process. Furthermore, we identified significant and differential methylated genes in our AA PCa cohort that were associated with PCa progression when compared to the TCGA EA and AA dataset. These genes were AMIGO3, IER3, UPB1, GRM7, TFAP2C, TOX2, PLSCR2, ZNF292, ESR2, MIXL1, BOLL and FGF6. Overall, IPA of differential methylated promoter region are genes enriched for network involved in sex-steroid hormonal signals and tumor microenvironment signaling pathways. Our integrative analysis provides new candidate genes associated with prostate cancer progression in AA men as potential targets for improving prostate cancer treatment and addressing the racial disparity problem. Citation Format: Bernard Kwabi-Addo, Somiranjan Ghosh, Chad Creighton, Michael Ittmann. Comparative and integrative analysis of transcriptomic and epigenome wide DNA methylation changes in African American prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5999.