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

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.

miR-30a inhibits the osteogenic differentiation of the tibia-derived MSCs in congenital pseudarthrosis via targeting HOXD8

“…HOXD8 is a crucial mediator in cellular processes, especially tumor progression [ 29 , 30 ]. Additionally, HOXD8 has been reported to act as a promoter in the osteogenic differentiation of MSCs [ 18 ].…”

The role of zinc finger proteins in malignant tumors

“…97 Similarly, Xu and colleagues perform genome-wide DNA methylation profiling in leukocyte DNA from 280 African American prostate cancer patients and find ZNF-471 and ZNF-577 are differentially methylated. 98 Besides, the up-regulation of ZNF143 by cisplatin may be directly involved in the cisplatin inducible expression of mitochondrial ribosome protein S11(MRPS11). 99 Moreover, ZNF93 is overexpressed in cisplatin-resistant ovarian cancer cell lines and shows enhanced drug sensitivity.…”

“…In reproductive system‐related cancers, Li and colleagues analyze whole‐genome, whole‐transcriptome, and DNA methylation data for 208 pairs of tumor tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer and find 18% each have deletions in ZNF292 and CHD1 97 . Similarly, Xu and colleagues perform genome‐wide DNA methylation profiling in leukocyte DNA from 280 African American prostate cancer patients and find ZNF‐471 and ZNF‐577 are differentially methylated 98 . Besides, the up‐regulation of ZNF143 by cisplatin may be directly involved in the cisplatin inducible expression of mitochondrial ribosome protein S11(MRPS11) 99 .…”

Prostate cancer in omics era

“…Xu and colleagues discovered a modest increase in overall methylation levels with increasing Gleason score after genome-wide DNA methylation profiling in leukocyte DNA from 280 African American PCa patients. They also discovered 77 differentially methylated regions/genes, including 10 homeobox genes and six zinc finger protein genes, which may be valuable biomarkers for aggressive PCa [ 63 ].…”