title: Promoter hypermethylation as an independent prognostic factor for relapse in patients with prostate cancer following radical prostatectomy.
abstract: OBJECTIVE
  To analyze the prognostic significance of six epigenetic biomarkers (APC, Cyclin D2, GSTP1, TIG1, Rassf1A, and RARbeta2 promoter hypermethylation) in a homogeneous group of prostate cancer patients, following radical prostatectomy alone.
  
  
  METHODS
  Biomarker analyses were done retrospectively on tumors from 74 prostate cancer patients all with a Gleason score of 3 + 4 = 7 and minimum follow-up period of 7 years. Using quantitative methylation-specific PCR, we analyzed six gene promoters in primary prostate tumor tissues. Time to any progression was the primary end point, and development of metastatic disease and/or death from prostate cancer was a secondary point. The association of clinicopathologic and biomolecular risk factors to recurrence was done using the log-rank test and Cox proportional hazards model for multivariate analysis. To identify independent prognostic factors, a stepwise selection method was used.
  
  
  RESULTS
  At a median follow-up time of 9 years, 37 patients (50%) had evidence of recurrence: biochemical/prostate-specific antigen relapse, metastases, or death from prostate cancer. In the final multivariate analysis for time to progression (TTP), the significant factors were age > 60 [hazard ratio (HR), 0.4; 95% confidence interval (95% CI), 0.2-0.8; P = 0.01], hypermethylation of GSTP1 (HR, 0.23; 95% CI; 0.09-0.64; P = 0.004), and hypermethylation of APC (HR, 3.0; 95% CI, 1.42-6.32; P = 0.004). In another multivariate analysis, a profile of hypermethylation of APC and cyclin D2 hypermethylation was significant as well: if either any one was hypermethylated (HR, 1.84; 95% CI, 0.92-3.72; P = 0.09) or if both were hypermethylated (HR, 4.3; 95% CI, 1.52-12.33; P = 0.01).
  
  
  CONCLUSIONS
  Methylation status of selected genes in the prostate cancer specimen may predict for time to recurrence in Gleason 3 + 4 = 7 patients undergoing prostatectomy. These results should be validated in a larger and unselected cohort.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Head and Neck Cancer Research Division, John Hopkins School of Medicine, Baltimore, MD 21205-2196, USA.
authors.forename: Eli
authors.initials: E
authors.lastname: Rosenbaum
authors.forename: Mohammad Obaidul
authors.initials: MO
authors.lastname: Hoque
authors.forename: Yoram
authors.initials: Y
authors.lastname: Cohen
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: Alan W
authors.initials: AW
authors.lastname: Partin
authors.forename: David
authors.initials: D
authors.lastname: Sidransky
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics; D019175:DNA Methylation; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008297:Male; D056892:Mediator Complex; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017430:Prostate-Specific Antigen; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D014408:Biomarkers, Tumor; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; C416944:MED15 protein, human; D056892:Mediator Complex; D009363:Neoplasm Proteins; C411762:RASSF1 protein, human; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C082925:retinoic acid receptor beta; D051549:Glutathione S-Transferase pi; D017430:Prostate-Specific Antigen