Abstract
Abstract Purpose: Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential. Methods: Microarray-based screening and bisulfite sequencing of 20 non-malignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 formalin-fixed paraffin-embedded (FFPE) nonmalignant prostate tissue samples, 293 FFPE malignant radical prostatectomy (RP) samples (cohort 1), and 148 fresh-frozen malignant RP samples (cohort 2) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC was evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed by log rank tests as well as uni- and multivariate cox regression analyses. A methylation-based prognostic model was developed in cohort 1 and validated in cohort 2. Results: Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer-specific (AUCs 0.89-0.98). Furthermore, a three-gene methylation signature (AOX1/C1orf114/HAPLN3) was developed in cohort 1 and validated in cohort 2. High AOX1/C1orf114/HAPLN3 methylation was significantly associated with biochemical recurrence in multivariate analysis (P<0.05) with hazard ratios of 1.79 (1.20-2.68) and 1.98 (1.02-3.83), respectively, independently of routine clinicopathological variables in both cohorts. Conclusion: We identified six novel candidate DNA methylation markers for PC and developed a three-gene methylation signature, which was an independent predictor of time to biochemical recurrence after RP in two PC patient cohorts. Citation Format: Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, Philippe Lamy, Peter Wild, Wolfgang A. Schulz, Christian Arsov, Michael Borre Borre, Søren Høyer, Torben F. Ørntoft, Karina D. Sørensen. A three-gene DNA methylation signature for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 649. doi:10.1158/1538-7445.AM2013-649
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