title: PITX3promoter methylation is a prognostic biomarker for biochemical recurrence-free survival in prostate cancer patients after radical prostatectomy.
abstract: Molecular biomarkers that might help to distinguish between more aggressive and clinically insignificant prostate cancers (PCa) are still urgently needed. Aberrant DNA methylation as a common molecular alteration in PCa seems to be a promising source for such biomarkers. In this study,PITX3DNA methylation (mPITX3) and its potential role as a prognostic biomarker were investigated. Furthermore, mPITX3was analyzed in combination with the established PCa methylation biomarkerPITX2(mPITX2).
  
  
  
  mPITX3andmPITX2were assessed by a quantitative real-time PCR and by means of the Infinium HumanMethylation450 BeadChip. BeadChip data were obtained from The Cancer Genome Atlas (TCGA) Research Network. DNA methylation differences between normal adjacent, benign hyperplastic, and carcinomatous prostate tissues were examined in the TCGA dataset as well as in prostatectomy specimens from the University Hospital Bonn. Retrospective analyses of biochemical recurrence (BCR) were conducted in a training cohort (n= 498) from the TCGA and an independent validation cohort (n= 300) from the University Hospital Bonn. All patients received radical prostatectomy.
  
  
  
  In PCa tissue,mPITX3was increased significantly compared to normal and benign hyperplastic tissue. In univariate Cox proportional hazards analyses,mPITX3showed a significant prognostic value for BCR (training cohort: hazard ratio (HR) = 1.83 (95 % CI 1.07-3.11),p= 0.027; validation cohort: HR = 2.56 (95 % CI 1.44-4.54),p= 0.001). A combined evaluation withPITX2methylation further revealed that hypermethylation of a singlePITXgene member (eitherPITX2orPITX3) identifies an intermediate risk group.
  
  
  
  PITX3DNA methylation alone and in combination withPITX2is a promising biomarker for the risk stratification of PCa patients and adds relevant prognostic information to common clinically implemented parameters. Further studies are required to determine whether the results are transferable to a biopsy-based patient cohort. Trial registration: Patients for this unregistered study were enrolled retrospectively.
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Emily Eva
authors.initials: EE
authors.lastname: Holmes
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Diane
authors.initials: D
authors.lastname: Goltz
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medicine of Cornell University, New York, NY USA.|Englander Institute for Precision Medicine, Weill Cornell Medicine of Cornell University, New York, NY USA.
authors.forename: Verena
authors.initials: V
authors.lastname: Sailer
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Jung
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Meller
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Uhl
authors.affiliation: Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dietrich
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Magda
authors.initials: M
authors.lastname: Röhler
authors.affiliation: Department of Urology, University Hospital Bonn, Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Ellinger
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Glen
authors.initials: G
authors.lastname: Kristiansen
authors.affiliation: Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.|Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
authors.forename: Dimo
authors.initials: D
authors.lastname: Dietrich
mesh_terms: D019175:DNA Methylation; D018572:Disease-Free Survival; D005819:Genetic Markers / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011468:Prostatectomy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000601:surgery*; D012189:Retrospective Studies; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C433629:homeobox protein PITX3
keywords: DNA methylation; PITX2; PITX3; Prognostic biomarker; Prostate cancer