title: Association between DNA methylation of HSPB1 and death in low Gleason score prostate cancer.
abstract: BACKGROUND
  Heat shock protein 27 (Hsp-27) encoded by gene HSPB1 is a critical regulator of the behavioral phenotype of human prostate cancer (PCa) cells, enhanced expression being associated with highly aggressive disease and poor clinical outcome. In contrast, the protein is not expressed in PCas of low malignant potential. To gain insight into the mechanism regulating its expression, we tested the hypothesis that differential methylation of CpG islands within HSPB1 controls transcription and subsequent translation of the gene.
  
  
  METHODS
  We studied prostate epithelial cell lines and tissue biopsies, including 59 BPH and 415 PCas, of which 367 were a cohort of men with up to 20 years of follow-up. Methylation across the gene (DNA methylation (DNAme)) was assayed by pyrosequencing. Hsp-27 expression was assessed by western blot and immunohistochemistry.
  
  
  RESULTS
  In cancer tissues, methylation increased in a 3' direction (P < 0.0001) whereas in benign hyperplasia methylation was constantly below 5%, a cutoff giving a specificity of 100% and sensitivity of 50%. Although methylation of the promoter region was significantly discriminating between benign and malignant prostatic epithelia, it compared poorly with methylation of the first intron. The prognostic value of HSPB1 DNAme was confirmed by both univariate (hazard ratio 1.77 per 50% increment, P = 0.02) and multivariate models. Interaction between HSPB1 methylation and Gleason score revealed high DNAme to be a reliable prognostic marker of poor outcome in men with low Gleason score (P = 0.014).
  
  
  CONCLUSIONS
  Our data indicate CpG methylation of the first HSPB1 intron to be an important biomarker that identifies aggressive PCas otherwise regarded as low risk by current clinical criteria but that, biologically, require immediate active management.
authors.affiliation: Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
authors.forename: N
authors.initials: N
authors.lastname: Vasiljević
authors.forename: A S
authors.initials: AS
authors.lastname: Ahmad
authors.forename: C
authors.initials: C
authors.lastname: Beesley
authors.forename: M A
authors.initials: MA
authors.lastname: Thorat
authors.forename: G
authors.initials: G
authors.lastname: Fisher
authors.forename: D M
authors.initials: DM
authors.lastname: Berney
authors.forename: H
authors.initials: H
authors.lastname: Møller
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Lu
authors.forename: J
authors.initials: J
authors.lastname: Cuzick
authors.forename: C S
authors.initials: CS
authors.lastname: Foster
authors.forename: A T
authors.initials: AT
authors.lastname: Lorincz
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D055551:HSP27 Heat-Shock Proteins / Q000235:genetics*; D006360:Heat-Shock Proteins; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns / Q000235:genetics; D008297:Male; D018832:Molecular Chaperones; D060787:Neoplasm Grading; D016133:Polymerase Chain Reaction; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones