Abstract
To assess differentially methylated "landscapes" according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression. Genomic DNA from 39 prostate cancer specimens was hybridized to CpG island microarrays through differential methylation hybridization. We compared methylation profiles between Gleason score and ERG expression status as well as Gleason score stratified by ERG expression status. In addition, we compared results from our dataset to publicly available datasets of histone modifications in benign prostate cells. We discovered hundreds of distinct differentially methylated regions (DMR) associated with increasing Gleason score and ERG. Furthermore, the number of DMRs associated with Gleason score was greatly expanded by stratifying samples into ERG-positive versus ERG-negative, with ERG-positive/GS-associated DMRs being primarily hypermethylated as opposed to hypomethylated. Finally, we found that there was a significant overlap between either Gleason score-related or ERG-hypermethylated DMRs and distinct regions in benign epithelial cells that have PcG signatures (H3K27me3, SUZ12) and lack active gene expression signatures (H3K4me3, RNA pol II). This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses. Moreover, CpG islands with silent chromatin signatures in benign cells are particularly susceptible to prostate cancer-related hypermethylation.
Highlights
Prostate cancer remains a significant health burden for men and represents a challenge for physicians and patients in deciding optimal treatment course as overdiagnosis has become more prevalent [1]
This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses
CpG islands with silent chromatin signatures in benign cells are susceptible to prostate cancer–related hypermethylation
Summary
Prostate cancer remains a significant health burden for men and represents a challenge for physicians and patients in deciding optimal treatment course as overdiagnosis has become more prevalent [1]. Attributed to the large number of indolent tumors identified in recent years due to widespread prostate-specific antigen (PSA) testing [2, 3] To address this challenge, a great deal of effort is focused on searching the genome for biomarkers that may better inform of prostate cancer prognosis [4]. A great deal of effort is focused on searching the genome for biomarkers that may better inform of prostate cancer prognosis [4] Despite this effort, there has been a general deficiency of clinically useful biomarkers that can be applied pre- and posttreatment, as most do not offer significant additional information beyond classic pathologic parameters such as grade [as indicated by Gleason score (GS)] and stage. If only one pattern is present, this is doubled to give the Gleason score [5, 6]
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