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Purpose About 17~40% patients experience biochemical recurrence after radical prostatectomy.Owing to the limitations of existing tools in predicting biochemical recurrence, we sought to investigate the priedictive value of collapsin response mediated protein 4 (CRMP4) promoter methylation in clinically locallized prostate after radical prostatectomy.Methods Bisulfite sequencing of 80 cases with PCa were used to identify CRMP4 methylation as a predictor for biochemical recurrence (defined as two consecutive PSA levels of >0.2 ng/ml after surgery).Prognostic potential was evaluated in 339 radical prostatectomy (RP) samples (cohort 1, training), and 328 malignant RP samples (cohort 2, validation) collected in multicenters of China.Sensitivity and.specificity for PCa were evaluated by receiver operating characteristic(ROC) analyses.Correlations between CRMP4 methylation levels and biochemical recurrence were assessed using log-rank tests and Cox regression analyses.Results The median follow-up was 45 months (interquartile range, 39 to 73) for all these patients.CRMP4 methylation was highly cancer-specific (area under the curve, 0.88 to 0.97).Furthermore, high CRMP4 methylation was significantly (P<0.05) associated with biochemical recurrence in muhivariate analysis in cohort 1 (hazard ratio [HR], 4.20;95% CI, 1.66 to 7.49) and was successfully validated in cohort 2 (HR, 3.97;95% CI, 1.03 to 8.72).In cohort 1, 3-year biochemical recurrence-free survival was 93.6% (95%CI:90.2-97.7) for patients with non-hypermethylated CRMP4 tumors and 62.8% (37.6-76.4) for those with hypermethylated CRMP4 tumors (P<0.05).In cohort 2, 3-year biochemical recurrence-free survival was 91.3% (95%CI: 89.1-98.4) for patients with non-hypermethylated CRMP4 tumors and 58.6% (38.3-79.5) for those with hypermethylated CRMP4 tumors (P<0.001).Conclusion We identified CRMP4 methylation as an independent predictor of time to biochemical recurrence after RP.