title: DNA methylation gene-based models indicating independent poor outcome in prostate cancer.
abstract: BACKGROUND
  Prostate cancer has a variable clinical behaviour with frequently unpredictable outcome. DNA methylation plays an important role in determining the biology of cancer but prognostic information is scanty. We assessed the potential of gene-specific DNA methylation changes to predict death from prostate cancer in a cohort of untreated men in the UK.
  
  
  METHODS
  This was a population-based study in which cases were identified from six cancer registries in Great Britain. DNA was extracted from formalin-fixed paraffin wax-embedded transurethral prostate resection tissues collected during 1990-96 from men with clinically-localised cancer who chose not to be treated for at least 6 months following diagnosis. The primary end point was death from prostate cancer. Outcomes were determined through medical records and cancer registry records. Pyrosequencing was used to quantify methylation in 13 candidate genes with established or suggested roles in cancer. Univariate and multivariate Cox models were used to identify possible predictors for prostate cancer-related death.
  
  
  RESULTS
  Of 367 men, 99 died from prostate cancer during a median of 9.5 years follow-up (max = 20). Univariately, 12 genes were significantly associated with prostate cancer mortality, hazard ratios ranged between 1.09 and 1.28 per decile increase in methylation. Stepwise Cox regression modelling suggested that the methylation of genes HSPB1, CCND2 and DPYS contributed objective prognostic information to Gleason score and PSA with respect to cancer-related death during follow-up (p = 0.006).
  
  
  CONCLUSIONS
  Methylation of 13 genes was analysed in 367 men with localised prostate cancer who were conservatively treated and stratified with respect to death from prostate cancer and those who survived or died of other causes. Of the 13 genes analysed, differential methylation of HSPB1, CCND2 and DPYS provided independent prognostic information. Assessment of gene-methylation may provide independent objective information that can be used to segregate prostate cancers at diagnosis into predicted behavioural groups.
authors.forename: Nataša
authors.initials: N
authors.lastname: Vasiljević
authors.forename: Amar S
authors.initials: AS
authors.lastname: Ahmad
authors.forename: Mangesh A
authors.initials: MA
authors.lastname: Thorat
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Fisher
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Berney
authors.forename: Henrik
authors.initials: H
authors.lastname: Møller
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Foster
authors.forename: Jack
authors.initials: J
authors.lastname: Cuzick
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK. a.lorincz@qmul.ac.uk.
authors.forename: Attila T
authors.initials: AT
authors.lastname: Lorincz
mesh_terms: D000368:Aged; D000581:Amidohydrolases / Q000235:genetics*; D056742:Cyclin D2 / Q000235:genetics*; D019175:DNA Methylation; D056726:Genetic Association Studies; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D018832:Molecular Chaperones; D060787:Neoplasm Grading; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D006113:United Kingdom
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D000581:Amidohydrolases; C020047:dihydropyrimidinase