title: Multicenter clinical validation of PITX2 methylation as a prostate specific antigen recurrence predictor in patients with post-radical prostatectomy prostate cancer.
abstract: OBJECTIVE
  Radical prostatectomy is potentially curative in patients with clinically localized prostate cancer. However, biochemical recurrence affects 15% to 30% of men who undergo radical prostatectomy. We previously reported the prognostic potential of PITX2 gene promoter methylation using conventional assays. In the current study we validated PITX2 methylation status as a biochemical recurrence predictor after radical prostatectomy using a novel microarray based platform in a multi-institutional setting.
  
  
  METHODS
  PITX2 methylation status was assessed in formalin fixed, paraffin embedded prostatectomy tumor tissue samples from 476 patients from a total of 4 institutions on customized EpiChip PITX2 microarrays. Associations between PITX2 methylation and biochemical recurrence were assessed using the log rank test and Cox regression controlling for prostate cancer features.
  
  
  RESULTS
  On multivariate analysis men with high methylation status were at significantly higher risk for biochemical recurrence than those with low methylation status (HR 3.0, 95% CI 2.0-4.5, p <10(-5)). The biochemical recurrence-free survival rate 5 years after surgery was 85% and 61% in the low and high methylation groups, respectively. In men with pathological Gleason 7 tumors the relative risk of biochemical recurrence was twice as high for high than for low PITX2 methylation (HR 2.0, 95% CI 1.2-3.3, p = 0.005).
  
  
  CONCLUSIONS
  PITX2 methylation status assessed by EpiChip PITX2 identifies patients with prostate cancer who are most likely to have biochemical recurrence. This test independently adds to the prognostic information provided by standard clinicopathological analysis, improving prostatectomy case stratification into those at high and low risk for biochemical recurrence. This new clinical tool would be of particular benefit to assess intermediate risk cases (Gleason 7) in which risk stratification remains a challenge.
authors.affiliation: Division of Urologic Surgery and Duke Prostate Center, and Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Lionel L
authors.initials: LL
authors.lastname: Bañez
authors.forename: Leon
authors.initials: L
authors.lastname: Sun
authors.forename: Geert J
authors.initials: GJ
authors.lastname: van Leenders
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wheeler
authors.forename: Chris H
authors.initials: CH
authors.lastname: Bangma
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Amy L
authors.initials: AL
authors.lastname: Lark
authors.forename: John F
authors.initials: JF
authors.lastname: Madden
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartman
authors.forename: Gunter
authors.initials: G
authors.lastname: Weiss
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Castaños-Vélez
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000601:surgery*; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood; D019175:DNA Methylation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000601:surgery*; D012189:Retrospective Studies; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D017430:Prostate-Specific Antigen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2