title: Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024 USA ; Department of Epidemiology, GROW School for Oncology and Developmental biology, Maastricht University, Maastricht, The Netherlands.
authors.forename: Milan S
authors.initials: MS
authors.lastname: Geybels
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024 USA ; Department of Urology, University of Washington School of Medicine, Seattle, WA USA.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Wright
authors.affiliation: Illumina, Inc., San Diego, CA USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Bibikova
authors.affiliation: Illumina, Inc., San Diego, CA USA.
authors.forename: Brandy
authors.initials: B
authors.lastname: Klotzle
authors.affiliation: Illumina, Inc., San Diego, CA USA ; Current address: AnchorDx Corp., Guangzhou, 510300 People's Republic of China.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Fan
authors.affiliation: Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC USA.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Department of Biostatistics, MD Anderson Cancer Center, Houston, TX USA.
authors.forename: Ziding
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD USA.
authors.forename: Elaine A
authors.initials: EA
authors.lastname: Ostrander
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024 USA ; Department of Urology, University of Washington School of Medicine, Seattle, WA USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA USA ; Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA USA ; Department of Medicine, University of Washington School of Medicine, Seattle, WA USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109-1024 USA ; Department of Epidemiology, University of Washington School of Public Health, Seattle, WA USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stanford
mesh_terms: D019540:Area Under Curve; D002453:Cell Cycle; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000601:surgery*
keywords: Clinically localized prostate cancer; DNA methylation; Elastic net regularization; Gene expression; Genome-wide profiling; Risk prediction for prognosis; Tumor tissue