title: Urinary DNA Methylation Biomarkers for Noninvasive Prediction of Aggressive Disease in Patients with Prostate Cancer on Active Surveillance.
abstract: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify.
  
  
  
  We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification.
  
  
  
  Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy.
  
  
  
  We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Olkhov-Mitsel
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Theodorus
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Darko
authors.initials: D
authors.lastname: Zdravic
authors.affiliation: Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Vasundara
authors.initials: V
authors.lastname: Venkateswaran
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Urology and Surgical Oncology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Alexandre R
authors.initials: AR
authors.lastname: Zlotta
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Loblaw
authors.affiliation: Department of Urology and Surgical Oncology, University Health Network, Toronto, Ontario, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Division of Urology, Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Laurence
authors.initials: L
authors.lastname: Klotz
authors.affiliation: Department of Radiation Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Danny
authors.initials: D
authors.lastname: Vesprini
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, University Health Network, Toronto, Ontario, Canada. Electronic address: bapat@lunenfeld.ca.
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000652:urine*; D019175:DNA Methylation / Q000235:genetics*; D051517:Digital Rectal Examination; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction / Q000379:methods; D060787:Neoplasm Grading; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011467:Prostate / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000652:urine*; D018570:Risk Assessment / Q000379:methods
chemical_list: D014408:Biomarkers, Tumor
keywords: DNA methylation; biomarkers; disease progression; prostatic neoplasms; watchful waiting