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Global Hypomethylation (LINE-1) and Gene-Specific Hypermethylation (GSTP1) on Initial Negative Prostate Biopsy as Markers of Prostate Cancer on a Rebiopsy

Purpose: Men at risk of missed prostate cancer on a negative biopsy often undergo a rebiopsy. We evaluated whether global hypomethylation, measured through LINE-1 methylation, and GSTP1 hypermethylation on a negative biopsy are associated with subsequent prostate cancer diagnosis. Experimental Design: We performed a case–control study nested in an unselected series of 737 men who received at least two prostate biopsies at least three months apart at the Molinette Hospital (Turin, Italy). Two pathology wards were included for replication purposes. The study included 67 cases and 62 controls in Ward 1 and 62 cases and 66 controls in Ward 2. We used pyrosequencing to analyze LINE-1 and GSTP1 methylation in the negative biopsies. Odds ratios (OR) of prostate cancer diagnosis were estimated using conditional logistic regression. Results: After mutual adjustment, GSTP1 hypermethylation was associated with an OR of prostate cancer diagnosis of 5.1 (95% confidence interval: 1.7–14.9) in Ward 1 and 2.0 (0.8–5.3) in Ward 2, whereas an association was suggested only for low LINE-1 methylation levels (<70% vs. 70%–74%) with an OR of 2.1 (0.5–9.1) in Ward 1 and 1.6 (0.4–6.1) in Ward 2. When the two wards were combined the association was stronger for tumors with Gleason score ≥4+3 [GSTP1 hypermethylation: 9.2 (2.0–43.1); LINE-1 (<70% vs. 70%–74%): 9.2 (1.4–59.3)]. GSTP-1 alone improved the predictive capability of the model (P = 0.007). Conclusions: GSTP1 hypermethylation on a negative biopsy is associated with the risk of prostate cancer on a rebiopsy, especially of high-grade prostate cancer. Consistent results were found only for extremely low LINE-1 methylation levels. Clin Cancer Res; 22(4); 984–92. ©2015 AACR.