Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy

Milan S. Geybels, Jonathan L. Wright, Marina Bibikova, Brandy Klotzle, Jian-Bing Fan, Shanshan Zhao, Ziding Feng, Elaine A. Ostrander, Daniel W. Lin, Peter S. Nelson, Janet L. Stanford

Identifying the subset of patients with clinically localized prostate cancer (PCa) at the highest risk of recurrence remains challenging, and better prognostic markers are needed. Gleason score is the best predictor of PCa aggressiveness and prognosis. In the present study, we generated an epigenetic signature based on high versus low Gleason score tumors and evaluated its ability to predict recurrence after radical prostatectomy. Genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA; no. of patients = 333) and the elastic net method were used to generate an epigenetic signature by contrasting patients with high (8-10) versus low (≤6) Gleason score tumors. The signature was then tested in a cohort of 523 patients with clinically localized disease who had radical prostatectomy. Samples taken from the primary tumor were used for DNA methylation and mRNA expression profiling. Patients were followed for PCa recurrence on average for 8 years after diagnosis. The epigenetic signature includes 52 differentially methylated CpG sites. In the testing cohort, the signature was associated with poorer recurrence-free survival (hazard ratio per 25 % increase = 1.78; 95 % confidence interval 1.48, 2.16). The signature significantly improved the area under the curve (AUC) for PCa recurrence compared to clinical-pathological parameters alone, particularly among patients diagnosed with Gleason score 7 tumors (0.64 vs. 0.76, P = 1.34E-4). Results were comparable for patients with Gleason 3 + 4 and those with 4 + 3 tumors. Gene Set Enrichment Analysis showed that higher levels of the signature were associated with increased expression of genes related to cell cycle proliferation and decreased expression of androgen-responsive genes. This report shows evidence that DNA methylation patterns measured in prostate tumor cells are predictive of PCa aggressiveness. The epigenetic signature may have clinical utility to improve prognostication particularly in patients with intermediate Gleason score 7 tumors.