title: Prognostic value of CpG island hypermethylation at PTGS2, RAR-beta, EDNRB, and other gene loci in patients undergoing radical prostatectomy.
abstract: OBJECTIVE
  To evaluate CpG island hypermethylation in a set of candidate genes in prostate cancer (pCA) and its relationship to clinicopathologic parameters and a nomogram predicting prostate-specific antigen (PSA) recurrence after radical prostatectomy.
  
  
  METHODS
  Tissues of 78 prostate carcinomas, 32 benign prostate hyperplasias (BPHs), and prostate cell lines (LNCaP, DU145, PC3, BPH-1) were examined with MethyLight polymerase chain reaction at 13 gene loci (APC, CDC6, CTNNB1, E-Cadherin, EDNRB, FGFR2, GSTP1, NAB2, PKCmu, PTGS2, RAR-beta, RASL11A, WWOX).
  
  
  RESULTS
  APC, RAR-beta, PTGS2, GSTP1, EDNRB, and CTNNB1 (83%, 71%, 65%, 33%, 14%, 9%, respectively) were methylated in pCA but rarely or not methylated in BPH. NAB2 and CDC6 were hypermethylated frequently in pCA (92%, 67%, respectively) and in BPH (91%, 59%, respectively). FGFR2, WWOX, E-Cadherin, PKCmu, and RASLL1A did not display noteworthy methylation in pCA (0-1%) or in BPH. CpG island hypermethylation at APC, retinoic acid receptor beta (RAR-beta), and PTGS2 discriminated with a sensitivity of 65-83% and a specificity of 97-100% between BPH and pCA. The combination of various genes increased the diagnostic expressiveness. PTGS2 hypermethylation correlated with seminal vesicle infiltration (p=0.047), capsular penetration (p=0.004), and pT stage (p=0.014). RAR-beta methylation was accompanied by a higher cumulative Gleason score (p=0.042). The probability of PSA-free-survival calculated with a Kattan nomogram correlated inversely with CpG island hypermethylation at EDNRB, RAR-beta, and PTGS2. All prostate cancer cell lines displayed a varying degree of demethylation after 5-aza-2'deoxycytidine treatment.
  
  
  CONCLUSIONS
  CpG island hypermethylation at various gene loci is frequent in prostate cancer and can distinguish between neoplastic and noncancerous tissue. Furthermore, hypermethylation at PTGS2, RAR-beta, and EDNRB inversely correlated with PSA-free-survival according to a Kattan nomogram and has potential prognostic value.
authors.affiliation: Klinik und Poliklinik für Urologie, Universitätsklinikum Bonn, Rheinische Friedrich-Wilhelms Universität Bonn, Germany. patrick.bastian@ukb.uni-bonn.de
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bastian
authors.forename: Jörg
authors.initials: J
authors.lastname: Ellinger
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Heukamp
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Stefan C
authors.initials: SC
authors.lastname: Müller
authors.forename: Alexander
authors.initials: A
authors.lastname: von Rücker
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000601:surgery*