DNA methylation biomarkers and prostate cancer prognosis

Purpose: Aside from Gleason sum few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of PCa patients followed prospectively for at least five years. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P-value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from non-recurrent tumors, and which were complementary to Gleason sum. Results: Forty-two biomarkers stratified patients with metastatic-lethal versus non-recurrent PCa in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P <0.05) AUC (range: 0.66-0.75) or pAUC (range: 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal PCa include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range: 0.86-0.89; all P <0.05). Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from non-recurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized PCa and provide new insights on tumor aggressiveness.

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