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Background  Prostate cancer (PC) is a multifocal disease. DNA methylation alterations are not restricted to the immediate peritumor environment, but spatially widespread in the adjacent and distant histologically normal prostate tissues. In the current study, we utilized high-throughput methylation arrays to identify epigenetic changes in the urine from men with and without cancer.    Design, setting, and participants  DNA urine samples were enriched for methylated fragments using MBD methyl-binding antibodies and applied to high density CytoScanHD arrays. Significant loci were validated using quantitative pyrosequencing and binary logistic regression modeling applied to urine sample analyses in a training (n = 83) and validation approach (n = 84). Methylation alterations in prostate tissues using pyrosequencing at the  PLA2G16  locus were examined in 38 histologically normal specimens from men with (TA, n = 26) and without (NTA, n = 12) cancer and correlated to gene expression.    Results  Methylation microarrays identified 3,986 loci showing significantly altered methylation in the urine samples from patients with PC compared to those without (TA vs NTA; p<0.01). These loci were then compared against subjects with their prostates removed to exclude non-prostate cell markers yielding 196 significant regions. Multiple CpGs adjacent to  PLA2G16  CpG island showed increased methylation in TA compared to NTA (p<0.01) in a large validation study of urine samples. The predictive accuracy of  PLA2G16  methylation at CG2 showed the highest predictive value at 0.8 (odds ratio, 1.37; 95% confidence interval, 1.16–1.62; p<0.001). Using a probability cutoff of 0.065, the sensitivity and specificity of the multivariate model was 92% and 35%. When histologically normal prostate tissues/biopsies from patients with PC (TA) were compared to subjects without cancer, significant hypermethylation of  PLA2G16  was noted (odds ratio, 1.35; 95% confidence interval, 1.07–1.71; p = 0.01).    Conclusion   PLA2G16  methylation defines an extensive field defect in histologically normal prostate tissue associated with PC.  PLA2G16  methylation in urine and prostate tissues can detect the presence of PC.

Screening of urine identifies PLA2G16 as a field defect methylation biomarker for prostate cancer detection