title: Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer.
abstract: OBJECTIVE
  Overexpression of cyclooxygenase-2 (COX-2) in gastric cancer has been shown to enhance tumor progression. We investigated whether silencing by promoter region hypermethylation of the COX-2 gene contributes to disease outcome in gastric cancer.
  
  
  METHODS
  COX-2 methylation status was initially assessed by capillary array electrophoresis methylation-specific polymerase chain reaction (CAE-MSP) and COX-2 protein expression by immunohistochemistry (IHC) in 40 primary gastric cancer tissues in a pilot study. Prognostic end points of correlative studies of COX-2 methylation status were time to recurrence, overall survival, and standard clinicopathologic features. CAE-MSP analysis was then validated in a second independent gastric cancer population (n = 137).
  
  
  RESULTS
  COX-2 methylation was detected in 23% and 28% of the pilot and validation patient groups, respectively. COX-2 expression (IHC) in gastric tumors inversely correlated with COX-2 gene methylation status in the pilot study (P = .02). COX-2 methylation in tumors was significantly associated with lower T, N, and TNM stage in the validation patient group (P = .02, P = .006, and P = .008, respectively). Patients with COX-2 methylated tumors had significantly longer time to recurrence and improved overall survival in a multivariate analysis in the validation patient group (hazard ratio[HR], 0.49; 95% CI, 0.24% to 0.99%; HR, 0.62; 95% CI, 0.38% to 0.99%, respectively).
  
  
  CONCLUSIONS
  Hypermethylation of COX-2 gene promoter was identified as an independent prognostic factor in gastric cancer patients. The results suggest promoter hypermethylation to be an important regulatory mechanism of COX-2 expression in gastric cancer and an important prognostic biomarker.
authors.affiliation: Department of Molecular Oncology and Division of Gastrointestinal Surgery, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
authors.forename: Michiel F G
authors.initials: MF
authors.lastname: de Maat
authors.forename: Cornelis J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Umetani
authors.forename: Pieter
authors.initials: P
authors.lastname: de Heer
authors.forename: Hein
authors.initials: H
authors.lastname: Putter
authors.forename: Anneke Q
authors.initials: AQ
authors.lastname: van Hoesel
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: Meijer
authors.forename: Nicole C
authors.initials: NC
authors.lastname: van Grieken
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Anton J
authors.initials: AJ
authors.lastname: Bilchik
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Dave S B
authors.initials: DS
authors.lastname: Hoon
mesh_terms: D051546:Cyclooxygenase 2 / Q000235:genetics*; D019175:DNA Methylation; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D010865:Pilot Projects; D011379:Prognosis; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy
chemical_list: D051546:Cyclooxygenase 2