title: DNA methylation signatures for prediction of biochemical recurrence after radical prostatectomy of clinically localized prostate cancer.
abstract: OBJECTIVE
  Diagnostic and prognostic tools for prostate cancer (PC) are suboptimal, causing overtreatment of indolent PC and risk of delayed treatment of aggressive PC. Here, we identify six novel candidate DNA methylation markers for PC with promising diagnostic and prognostic potential.
  
  
  METHODS
  Microarray-based screening and bisulfite sequencing of 20 nonmalignant and 29 PC tissue specimens were used to identify new candidate DNA hypermethylation markers for PC. Diagnostic and prognostic potential was evaluated in 35 nonmalignant prostate tissue samples, 293 radical prostatectomy (RP) samples (cohort 1, training), and 114 malignant RP samples (cohort 2, validation) collected in Denmark, Switzerland, Germany, and Finland. Sensitivity and specificity for PC were evaluated by receiver operating characteristic analyses. Correlations between DNA methylation levels and biochemical recurrence were assessed using log-rank tests and univariate and multivariate Cox regression analyses.
  
  
  RESULTS
  Hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B was highly cancer specific (area under the curve, 0.89 to 0.98). Furthermore, high C1orf114 methylation was significantly (P < .05) associated with biochemical recurrence in multivariate analysis in cohort 1 (hazard ratio [HR], 3.10; 95% CI, 1.89 to 5.09) and was successfully validated in cohort 2 (HR, 3.27; 95% CI, 1.17 to 9.12). Moreover, a significant (P < .05) three-gene prognostic methylation signature (AOX1/C1orf114/HAPLN3), classifying patients into low- and high-methylation subgroups, was trained in cohort 1 (HR, 1.91; 95% CI, 1.26 to 2.90) and validated in cohort 2 (HR, 2.33; 95% CI, 1.31 to 4.13).
  
  
  CONCLUSIONS
  We identified six novel candidate DNA methylation markers for PC. C1orf114 hypermethylation and a three-gene methylation signature were independent predictors of time to biochemical recurrence after RP in two PC patient cohorts.
authors.affiliation: Christa Haldrup, Kamilla Mundbjerg, Else Marie Vestergaard, Philippe Lamy, Michael Borre, Søren Høyer, Torben F. Ørntoft, and Karina D. Sørensen, Aarhus University Hospital, Aarhus, Denmark; Peter Wild, University Hospital Zurich, Zurich, Switzerland; Wolfgang A. Schulz and Christian Arsov, Heinrich Heine University, Düsseldorf, Germany; and Tapio Visakorpi, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Christa
authors.initials: C
authors.lastname: Haldrup
authors.forename: Kamilla
authors.initials: K
authors.lastname: Mundbjerg
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Vestergaard
authors.forename: Philippe
authors.initials: P
authors.lastname: Lamy
authors.forename: Peter
authors.initials: P
authors.lastname: Wild
authors.forename: Wolfgang A
authors.initials: WA
authors.lastname: Schulz
authors.forename: Christian
authors.initials: C
authors.lastname: Arsov
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.forename: Torben F
authors.initials: TF
authors.lastname: Orntoft
authors.forename: Karina D
authors.initials: KD
authors.lastname: Sørensen
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D019175:DNA Methylation; D003718:Denmark; D005387:Finland; D005500:Follow-Up Studies; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality* / Q000601:surgery; D012680:Sensitivity and Specificity; D015996:Survival Rate; D013557:Switzerland; D054928:Validation Studies as Topic
chemical_list: D014408:Biomarkers, Tumor