title: DNA methylation biomarkers of prostate cancer: confirmation of candidates and evidence urine is the most sensitive body fluid for non-invasive detection.
abstract: BACKGROUND
  A prostate cancer (PCa) biomarker with improved specificity relative to PSA is a public health priority. Hypermethylated DNA can be detected in body fluids from PCa patients and may be a useful biomarker, although clinical performance varies between studies. We investigated the performance of candidate PCa DNA methylation biomarkers identified through a genome-wide search.
  
  
  METHODS
  Real-time PCR was used to measure four DNA methylation biomarkers: GSTP1 and three previously unreported candidates associated with the genes RASSF2, HIST1H4K, and TFAP2E in sodium bisulfite-modified DNA. Matched plasma and urine collected prospectively from 142 patients referred for prostate biopsy and 50 young asymptomatic males were analyzed.
  
  
  RESULTS
  Analysis of all biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers discriminated PCa from biopsy negative patients with AUCs ranging from 0.64 for HIST1H4K (95% CI 0.55-0.72, P < 0.00001) to 0.69 for GSTP1 (95% CI 0.60-0.77, P < 0.00001). All biomarkers showed minimal correlation with PSA. Multivariate analysis did not yield a panel that significantly improved performance over that of single biomarkers. All biomarkers showed greater sensitivity for PCa in urine than in plasma DNA.
  
  
  CONCLUSIONS
  Analysis of the biomarkers in urine DNA significantly discriminated PCa from biopsy negative patients. The biomarkers provided information independent of PSA and may warrant inclusion in nomograms for predicting prostate biopsy outcome. The biomarkers' PCa sensitivity was greater for urine than plasma DNA. The biomarker performances in urine DNA should next be validated in formal training and test studies.
authors.affiliation: Epigenomics, Inc., Seattle, Washington 98101, USA. shannon.payne@epigenomics.com
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Payne
authors.forename: Jurgen
authors.initials: J
authors.lastname: Serth
authors.forename: Martin
authors.initials: M
authors.lastname: Schostak
authors.forename: Jorn
authors.initials: J
authors.lastname: Kamradt
authors.forename: Arne
authors.initials: A
authors.lastname: Strauss
authors.forename: Paul
authors.initials: P
authors.lastname: Thelen
authors.forename: Fabian
authors.initials: F
authors.lastname: Model
authors.forename: J Kevin
authors.initials: JK
authors.lastname: Day
authors.forename: Volker
authors.initials: V
authors.lastname: Liebenberg
authors.forename: Andrew
authors.initials: A
authors.lastname: Morotti
authors.forename: Su
authors.initials: S
authors.lastname: Yamamura
authors.forename: Joe
authors.initials: J
authors.lastname: Lograsso
authors.forename: Andrew
authors.initials: A
authors.lastname: Sledziewski
authors.forename: Axel
authors.initials: A
authors.lastname: Semjonow
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000652:urine*; D003581:Cytodiagnosis; D004247:DNA / Q000378:metabolism; D019175:DNA Methylation; D051549:Glutathione S-Transferase pi / Q000652:urine; D006657:Histones / Q000652:urine; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000652:urine*; D050656:Transcription Factor AP-2 / Q000652:urine; D025521:Tumor Suppressor Proteins / Q000652:urine; D016482:Urinalysis / Q000379:methods*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D006657:Histones; C425300:RASSF2 protein, human; C493680:TFAP2E protein, human; D050656:Transcription Factor AP-2; D025521:Tumor Suppressor Proteins; D004247:DNA; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D017430:Prostate-Specific Antigen