Methylation in benign prostate and risk of disease progression in men subsequently diagnosed with prostate cancer

Abstract

In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue—prior to malignant transformation—may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received “definitive” treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23–4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51–8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07–13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease.

Epigenetic analysis identifies factors driving racial disparity in prostate cancer

“…Epigenetic changes are an inherent genomic property that appears early during development or acquired during life due to exposure to certain environmental factors . Variations in methylation have also been reported among AA and CA ethnic groups, with studies suggesting the existence of race‐specific methylation differences at birth . Several studies have reported that hypermethylation of CpG is a predominant event occurring in PCa .…”

“…Incidentally, an increase in odds ratio for this polymorphism was higher in AA compared with CA which further indicates epigenetic variation among races. The availability of only a few gene‐specific studies, investigated through DNA methylation amongst AA and CA men with PCa, has provided only incremental advancement in our understanding of the global epigenetic factors driving racial disparity . Nevertheless, the differential methylation pattern of APC , AR , GSTP1 , NKX2 ‐5, PMEPA1 , RARB , ROBO1 , SPARC , and TIMP3 genes has been identified in AA vs CA patients.…”

“…Nevertheless, the differential methylation pattern of APC , AR , GSTP1 , NKX2 ‐5, PMEPA1 , RARB , ROBO1 , SPARC , and TIMP3 genes has been identified in AA vs CA patients. Rybicki et al (2016) identified hypermethylation of APC and RARB in benign prostate of CA and AA, respectively, which could have a predictive role in determining the risk of biochemical recurrence (BCR) . Importantly, only a few studies have identified global methylation differences among AA and CA PCa patients .…”

“…The availability of only a few gene-specific studies, investigated through DNA methylation amongst AA and CA men with PCa, has provided only incremental advancement in our understanding of the global epigenetic factors driving racial disparity. [22][23][24][25][26][27] Nevertheless, the differential methylation pattern of APC, 24 AR, 23 GSTP1, 22,23 PMEPA1, 25 RARB, 23,24 ROBO1, 26 SPARC, 23 and TIMP3 23 genes has been identified in AA vs CA patients. Rybicki et al (2016) identified hypermethylation of APC and RARB in benign prostate of CA and AA, respectively, which could have a predictive role in determining the risk of biochemical recurrence (BCR).…”

The role of miR-24 as a race related genetic factor in prostate cancer

“…These reports indicate that AfA patients have hyper-methylation of genes in normal or pre-cancerous prostate tissues that may promote malignancy. Thus hyper-methylation of tumor-suppressor genes may be involved in the racial differences between AfA and CaA patients [6, 7]. However, the relationship between these abnormal methylation patterns and prostate carcinogenesis is still unknown.…”