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The incidence and mortality of prostate cancer (PC) is approximately 2-fold higher among African-Americans as compared to Caucasians and very low in Asian. We hypothesize that inactivation ofGSTP1genes through CpG methylation plays a role in the pathogenesis of PC, and its ability to serve as a diagnostic marker that differs among ethnic groups.GSTP1promoter hypermethylation and its correlation with clinico-pathological findings were evaluated in 291 PC (Asian = 170; African-American = 44; Caucasian = 77) and 172 benign prostate hypertrophy samples (BPH) (Asian = 96; African-American = 38; Caucasian = 38) using methylation-specific PCR. In PC cells, 5-aza-dC treatment increased expression of GSTP1 mRNA transcripts. The methylation of all CpG sites was found in 191 of 291 PC (65.6%), but only in 34 of 139 BPH (24.5%). TheGSTP1hypermethylation was significantly higher in PC as compared to BPH in each ethnic group (p< 0.0001). Logistic regression analysis (PCvs. BPH) showed that African-Americans had a higher hazard ratio (HR) (13.361) compared to Caucasians (3.829) and Asian (8.603). Chi-square analysis showed correlation ofGSTP1hypermethylation with pathological findings (pT categories and higher Gleason sum) in Asian PC (p< 0.0001) but not in African-Americans and Caucasian PC. Our results suggest thatGSTP1hypermethylation is a sensitive biomarker in African-Americans as compared to that in Caucasians or Asian, and that it strongly influences tumor progression in Asian PC. Ours is the first study investigatingGSTP1methylation differences in PC among African-American, Caucasian and Asian.