title: DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer.
abstract: BACKGROUND
  Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients.
  
  
  METHODS
  A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation.
  
  
  RESULTS
  Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95% CI, 1.03 to 17.72) as well as in the combined cohort (HR, 2.74; 95% CI, 1.42 to 5.27) in multivariate analysis.
  
  
  CONCLUSIONS
  Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Kirill
authors.initials: K
authors.lastname: Litovkin
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Aleyde
authors.initials: A
authors.lastname: Van Eynde
authors.affiliation: Urology, University Hospitals Leuven & KU Leuven Department of Development and Regeneration, University of Leuven, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Joniau
authors.affiliation: Pathology, University Hospitals Leuven & KU Leuven Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lerut
authors.affiliation: KU Leuven Biostatistics and Statistical Bioinformatics Centre, University of Leuven, Leuven, Belgium.
authors.forename: Annouschka
authors.initials: A
authors.lastname: Laenen
authors.affiliation: Urology, University Hospitals Leuven & KU Leuven Department of Development and Regeneration, University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gevaert
authors.affiliation: Stanford Center for Cancer Systems Biology, Stanford University School of Medicine, Stanford, California, United States of America; Laboratory of Cancer Data Fusion, KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Gevaert
authors.affiliation: Department of Urology, University Hospital Bern, Inselspital, Bern, Switzerland; Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Spahn
authors.affiliation: Department of Urology and Paediatric Urology, University Hospital Würzburg, Würzburg, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kneitz
authors.affiliation: DNAlytics SA, Chemin du Cyclotron 6, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gramme
authors.affiliation: DNAlytics SA, Chemin du Cyclotron 6, 1348 Louvain-la-Neuve, Belgium.
authors.forename: Thibault
authors.initials: T
authors.lastname: Helleputte
authors.affiliation: Radiation Oncology, University Hospitals Leuven & KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Isebaert
authors.affiliation: Radiation Oncology, University Hospitals Leuven & KU Leuven Department of Oncology, University of Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Haustermans
authors.affiliation: Laboratory of Biosignaling & Therapeutics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bollen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism*; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D012306:Risk; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D051549:Glutathione S-Transferase pi