title: Epigenetic deregulation across chromosome 2q14.2 differentiates normal from prostate cancer and provides a regional panel of novel DNA methylation cancer biomarkers.
abstract: BACKGROUND
  Previously, we showed that gene suppression commonly occurs across chromosome 2q14.2 in colorectal cancer, through a process of long-range epigenetic silencing (LRES), involving a combination of DNA methylation and repressive histone modifications. We now investigate whether LRES also occurs in prostate cancer across this 4-Mb region and whether differential DNA methylation of 2q14.2 genes could provide a regional panel of prostate cancer biomarkers.
  
  
  METHODS
  We used highly sensitive DNA methylation headloop PCR assays that can detect 10 to 25 pg of methylated DNA with a specificity of at least 1:1,000, and chromatin immunoprecipitation assays to investigate regional epigenetic remodeling across 2q14.2 in prostate cancer, in a cohort of 195 primary prostate tumors and 90 matched normal controls.
  
  
  RESULTS
  Prostate cancer cells exhibit concordant deacetylation and methylation of histone H3 Lysine 9 (H3K9Ac and H3K9me2, respectively), and localized DNA hypermethylation of EN1, SCTR, and INHBB and corresponding loss of H3K27me3. EN1 and SCTR were frequently methylated (65% and 53%, respectively), whereas INHBB was less frequently methylated.
  
  
  CONCLUSIONS
  Consistent with LRES in colorectal cancer, we found regional epigenetic remodeling across 2q14.2 in prostate cancer. Concordant methylation of EN1 and SCTR was able to differentiate cancer from normal (P < 0.0001) and improved the diagnostic specificity of GSTP1 methylation for prostate cancer detection by 26%.
  
  
  CONCLUSIONS
  For the first time we show that DNA methylation of EN1 and SCTR promoters provide potential novel biomarkers for prostate cancer detection and in combination with GSTP1 methylation can add increased specificity and sensitivity to improve diagnostic potential.
authors.affiliation: Epigenetics Group, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.forename: Clare
authors.initials: C
authors.lastname: Stirzaker
authors.forename: Wenjia
authors.initials: W
authors.lastname: Qu
authors.forename: Jenny Z
authors.initials: JZ
authors.lastname: Song
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Statham
authors.forename: Kate I
authors.initials: KI
authors.lastname: Patterson
authors.forename: Lisa G
authors.initials: LG
authors.lastname: Horvath
authors.forename: Bruce
authors.initials: B
authors.lastname: Tabor
authors.forename: Marcel W
authors.initials: MW
authors.lastname: Coolen
authors.forename: Toby
authors.initials: T
authors.lastname: Hulf
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Susan M
authors.initials: SM
authors.lastname: Henshall
authors.forename: Ruth
authors.initials: R
authors.lastname: Pe Benito
authors.forename: Anne-Maree
authors.initials: AM
authors.lastname: Haynes
authors.forename: Regina
authors.initials: R
authors.lastname: Mayor
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peinado
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Clark
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002889:Chromosomes, Human, Pair 2; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051549:Glutathione S-Transferase pi / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D014408:Biomarkers, Tumor; C513076:EN1 protein, human; D018398:Homeodomain Proteins; C422402:INHBB protein, human; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D028322:Inhibin-beta Subunits; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi