text: Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer | Clinical Cancer Research
  National Institute of Environmental Health Sciences, Biostatistics and Computational Biology Branch, Research Triangle Park, Durham, North Carolina.
  Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington.Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
  MD Anderson Cancer Center, Department of Biostatistics, Houston, Texas.
  Department of Urologic Sciences, University of British Columbia, and the Prostate Center, Vancouver General Hospital, Vancouver, Canada.
  Departments of Pathology, Microbiology, and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, Virginia.
  Department of Urology, Eastern Virginia Medical School, Norfolk, Virginia.
  Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer 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 prostate cancer patients followed prospectively for at least 5 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 nonrecurrent tumors, and which were complementary to Gleason sum.
  Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer 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 prostate cancer 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 nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 1–9. ©2016 AACR.
  S. Zhao and M.S. Geybels are co-first authors of this article.
  J.-B. Fan, Z. Feng, and J.L. Stanford are co-senior authors of this article.
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