Epigenetic silencing of cyclooxygenase-2 affects clinical outcome in gastric cancer.
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.
de Maat
Michiel F G
MF
Department of Molecular Oncology and Division of Gastrointestinal Surgery, John Wayne Cancer Institute, Santa Monica, CA 90404, USA.
van de Velde
Cornelis J H
CJ
Umetani
Naoyuki
N
de Heer
Pieter
P
Putter
Hein
H
van Hoesel
Anneke Q
AQ
Meijer
Gerrit A
GA
van Grieken
Nicole C
NC
Kuppen
Peter J K
PJ
Bilchik
Anton J
AJ
Tollenaar
Rob A E M
RA
Hoon
Dave S B
DS
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
D051546:Cyclooxygenase 2