title: Prospective multicentre evaluation of PCA3 and TMPRSS2-ERG gene fusions as diagnostic and prognostic urinary biomarkers for prostate cancer.
abstract: BACKGROUND
  Prostate cancer antigen 3 (PCA3) and v-ets erythroblastosis virus E26 oncogene homolog (TMPRSS2-ERG) gene fusions are promising prostate cancer (PCa) specific biomarkers that can be measured in urine.
  
  
  OBJECTIVE
  To evaluate the diagnostic and prognostic value of Progensa PCA3 and TMPRSS2-ERG gene fusions (as individual biomarkers and as a panel) for PCa in a prospective multicentre setting.
  
  
  METHODS
  At six centres, post-digital rectal examination first-catch urine specimens prior to prostate biopsies were prospectively collected from 497 men. We assessed the predictive value of Progensa PCA3 and TMPRSS2-ERG (quantitative nucleic acid amplification assay to detect TMPRSS2-ERG messenger RNA [mRNA]) for PCa, Gleason score, clinical tumour stage, and PCa significance (individually and as a marker panel). This was compared with serum prostate-specific antigen and the European Randomised Study of Screening for Prostate Cancer (ERSPC) risk calculator. In a subgroup (n=61) we evaluated biomarker association with prostatectomy outcome.
  
  
  METHODS
  Univariate and multivariate logistic regression analysis and receiver operating curves were used.
  
  
  CONCLUSIONS
  Urine samples of 443 men contained sufficient mRNA for marker analysis. PCa was diagnosed in 196 of 443 men. Both PCA3 and TMPRSS2-ERG had significant additional predictive value to the ERSPC risk calculator parameters in multivariate analysis (p<0.001 and resp. p=0.002). The area under the curve (AUC) increased from 0.799 (ERSPC risk calculator), to 0.833 (ERSPC risk calculator plus PCA3), to 0.842 (ERSPC risk calculator plus PCA3 plus TMPRSS2-ERG) to predict PCa. Sensitivity of PCA3 increased from 68% to 76% when combined with TMPRSS2-ERG. TMPRSS2-ERG added significant predictive value to the ERSPC risk calculator to predict biopsy Gleason score (p<0.001) and clinical tumour stage (p=0.023), whereas PCA3 did not.
  
  
  CONCLUSIONS
  TMPRSS2-ERG had independent additional predictive value to PCA3 and the ERSPC risk calculator parameters for predicting PCa. TMPRSS2-ERG had prognostic value, whereas PCA3 did not. Implementing the novel urinary biomarker panel PCA3 and TMPRSS2-ERG into clinical practice would lead to a considerable reduction of the number of prostate biopsies.
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands.
authors.forename: Gisele H J M
authors.initials: GH
authors.lastname: Leyten
authors.affiliation: Noviogendix, Department of Research and Development, Nijmegen, The Netherlands.
authors.forename: Daphne
authors.initials: D
authors.lastname: Hessels
authors.affiliation: Noviogendix, Department of Research and Development, Nijmegen, The Netherlands.
authors.forename: Sander A
authors.initials: SA
authors.lastname: Jannink
authors.affiliation: Noviogendix, Department of Research and Development, Nijmegen, The Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Smit
authors.affiliation: Noviogendix, Department of Research and Development, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: de Jong
authors.affiliation: ZGT Hospital, Department of Urology, Hengelo, The Netherlands.
authors.forename: Erik B
authors.initials: EB
authors.lastname: Cornel
authors.affiliation: AMC University Medical Centre, Department of Urology, Amsterdam, The Netherlands.
authors.forename: Theo M
authors.initials: TM
authors.lastname: de Reijke
authors.affiliation: CWZ Hospital, Department of Urology, Nijmegen, The Netherlands.
authors.forename: Henk
authors.initials: H
authors.lastname: Vergunst
authors.affiliation: St. Elisabeth Hospital, Department of Urology, Tilburg, The Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Kil
authors.affiliation: Scheper Hospital, Department of Urology, Emmen, The Netherlands.
authors.forename: Ben C
authors.initials: BC
authors.lastname: Knipscheer
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands.
authors.forename: Inge M
authors.initials: IM
authors.lastname: van Oort
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands.
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Pathology, Nijmegen, The Netherlands.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Hulsbergen-van de Kaa
authors.affiliation: Radboud University Nijmegen Medical Centre, Department of Urology, Nijmegen, The Netherlands. Electronic address: j.schalken@uro.umcn.nl.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Schalken
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000652:urine*; D015415:Biomarkers / Q000652:urine; D050939:Gene Fusion; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000652:urine*; D012697:Serine Endopeptidases / Q000235:genetics / Q000652:urine*; D015534:Trans-Activators / Q000235:genetics / Q000652:urine*; D000071230:Transcriptional Regulator ERG
chemical_list: D000951:Antigens, Neoplasm; D015415:Biomarkers; C072312:ERG protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C479341:prostate cancer antigen 3, human; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human