This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by de Maat, M. F.G. Articles by Hoon, D. S.B. Search for Related Content PubMed PubMed Citation Articles by de Maat, M. F.G. Articles by Hoon, D. S.B. Related Articles Related Editorial

Epigenetic Silencing of Cyclooxygenase-2 Affects Clinical Outcome in Gastric Cancer

Michiel F.G. de Maat, Cornelis J.H. van de Velde, Naoyuki Umetani, Pieter de Heer, Hein Putter, Anneke Q. van Hoesel, Gerrit A. Meijer, Nicole C. van Grieken, Peter J.K. Kuppen, Anton J. Bilchik, Rob A.E.M. Tollenaar, Dave S.B. Hoon

From the Department of Molecular Oncology and Division of Gastrointestinal Surgery, John Wayne Cancer Institute, Santa Monica, CA; Departments of Surgery and Medical Statistics and Bioinformatics, Leiden University Medical Center; and the Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, the Netherlands

Address reprint requests to Dave S.B. Hoon, Department of Molecular Oncology, John Wayne Cancer Institute, 2200 Santa Monica Blvd, Santa Monica, CA 90404; e-mail: hoon{at}jwci.org

Purpose: 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.

Materials and 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).

Conclusion: 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.

Supported in part by funding from the Martin H. Weil Laboratory (John Wayne Cancer Institute), the Rod Fasone Memorial Fund (John Wayne Cancer Institute) and the Drie Lichten Foundation (Leiden, the Netherlands).

Presented in part on at the Dutch Society for Gastroenterology meeting, Veldhoven, the Netherlands, October 5, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Related Editorial

• Thinking In and Out of the Box When It Comes to Gastric Cancer and Cyclooxygenase-2
  Julie G. Izzo and Jaffer A. Ajani
  JCO 2007 25: 4865-4867 [Full Text]

This article has been cited by other articles:

				J. G. Izzo and J. A. Ajani Thinking In and Out of the Box When It Comes to Gastric Cancer and Cyclooxygenase-2 J. Clin. Oncol., November 1, 2007; 25(31): 4865 - 4867. [Full Text] [PDF]