Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer

Shanshan Zhao, Milan S. Geybels, Amy Leonardson, Rohina Rubicz, Suzanne Kolb, Qingxiang Yan, Brandy Klotzle, Marina Bibikova, Antonio Hurtado-Coll, Dean Troyer, Raymond Lance, Daniel W. Lin, Jonathan L. Wright, Elaine A. Ostrander, Jian-Bing Fan, Ziding Feng, Janet L. Stanford*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

45 Citations (Web of Science)

Abstract

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 sumalone (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 patientswithmetastatic-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. (C) 2016 AACR.

Original languageEnglish
Pages (from-to)311-319
Number of pages9
JournalClinical Cancer Research
Volume23
Issue number1
DOIs
Publication statusPublished - 1 Jan 2017

Keywords

  • BIOCHEMICAL RECURRENCE
  • RADICAL PROSTATECTOMY
  • PROMOTER HYPERMETHYLATION
  • GLEASON SCORE
  • RISK
  • GENE
  • MORTALITY
  • BIOPSY
  • ASSOCIATION
  • SURVIVAL

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