title: Development and clinical validation of a real-time PCR assay for PITX2 DNA methylation to predict prostate-specific antigen recurrence in prostate cancer patients following radical prostatectomy.
abstract: Prostate cancer is the most common cancer among men. The prospective discrimination of aggressive and clinically insignificant tumors still poses a significant and, as yet, unsolved problem. PITX2 DNA methylation is a strong prognostic biomarker in prostate cancer. Recently, a diagnostic microarray for prostate cancer prognosis based on PITX2 methylation has been developed and validated. Because this microarray requires nonstandard laboratory equipment, its use in a diagnostic setting is limited. This study aimed to develop and validate an alternative quantitative real-time PCR assay for measuring PITX2 methylation that can easily be established in clinical laboratories, thereby facilitating the implementation of this biomarker in clinical practice. A methylation cut-off for patient stratification was established in a training cohort (n = 157) and validated in an independent test set (n = 523) of men treated with radical prostatectomy. In univariate Cox proportional hazards analysis, PITX2 hypermethylation was a significant predictor for biochemical recurrence (P < 0.001, hazard ratio = 2.614). Moreover, PITX2 hypermethylation added significant prognostic information (P = 0.003, hazard ratio = 1.814) to the Gleason score, pathological T stage, prostate-specific antigen, and surgical margins in a multivariate analysis. The clinical performance was particularly high in patients at intermediate risk (Gleason score of 7) and in samples containing high tumor cell content. This assay might aid in risk stratification and support the decision-making process when determining whether a patient might benefit from adjuvant treatment after radical prostatectomy.
authors.affiliation: Institute of Pathology, University Hospital Bonn, Bonn, Germany. dimo.dietrich@gmail.com
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
authors.forename: Oliver
authors.initials: O
authors.lastname: Hasinger
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: Nicolas
authors.initials: N
authors.lastname: Wernert
authors.forename: Sven
authors.initials: S
authors.lastname: Perner
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
authors.forename: John M
authors.initials: JM
authors.lastname: Corman
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: Hartmann
authors.forename: Philipp
authors.initials: P
authors.lastname: Schatz
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
mesh_terms: D000328:Adult; D000368:Aged; D019175:DNA Methylation; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D060888:Real-Time Polymerase Chain Reaction; D012008:Recurrence; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D017430:Prostate-Specific Antigen; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2