Epigenome-Wide Association Study of Prostate Cancer in African Americans Identifies DNA Methylation Biomarkers for Aggressive Disease.

Yifan Xu,Chia-Wen Tsai,Da-Tian Bau,Wen-Shin Chang,Curtis A Pettaway,Yuyan Han,Jian Gu,Maosheng Huang

doi:10.3390/biom11121826

Abstract

DNA methylation plays important roles in prostate cancer (PCa) development and progression. African American men have higher incidence and mortality rates of PCa than other racial groups in U.S. The goal of this study was to identify differentially methylated CpG sites and genes between clinically defined aggressive and nonaggressive PCa in African Americans. We performed genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients using Illumina MethylationEPIC array that contains about 860K CpG sties. There was a slight increase of overall methylation level (mean β value) with the increasing Gleason scores (GS = 6, GS = 7, GS ≥ 8, P for trend = 0.002). There were 78 differentially methylated CpG sites with P < 10−4 and 9 sites with P < 10−5 in the trend test. We also found 77 differentially methylated regions/genes (DMRs), including 10 homeobox genes and six zinc finger protein genes. A gene ontology (GO) molecular pathway enrichment analysis of these 77 DMRs found that the main enriched pathway was DNA-binding transcriptional factor activity. A few representative DMRs include HOXD8, SOX11, ZNF-471, and ZNF-577. Our study suggests that leukocyte DNA methylation may be valuable biomarkers for aggressive PCa and the identified differentially methylated genes provide biological insights into the modulation of immune response by aggressive PCa.

Highlights

IntroductionProstate cancer (PCa) is the most common cancer and second leading cause of cancer death in American men, with an estimated 248,530 new cases and 34,130 deaths from prostate cancer (PCa) in the U.S in 2021 [1]
UTR, but much higher levels were found in the gene body, 30 UTR, and intergenic region (IGR), consistent with the literature of lower promoter methylation allowing a more open chromatin structure and active transcription [28]
When we compared the overall leukocyte methylation levels of Gleason Score (GS) = 6, GS = 7, and GS ≥ 8 patients, there was a slight increase of methylation level with the increase of Gleason scores

Summary

Introduction

Prostate cancer (PCa) is the most common cancer and second leading cause of cancer death in American men, with an estimated 248,530 new cases and 34,130 deaths from PCa in the U.S in 2021 [1]. African American men have the highest incidence and mortality rates among all the racial/ethnic groups in the U.S [2,3]. Testing has enabled the detection of PCa at early stages and greatly improved the survival of PCa. The majority of PSA screening-detected PCa are localized, indolent, and not life-threatening. Most of the PCa patients opt to receive upfront aggressive therapies (radical proctectomy and radiotherapy) that are often associated with significant morbidity, overdiagnosis and overtreatment for localized PCa patients have become

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