Ann Surg Treat Res.  2018 Aug;95(2):55-63. 10.4174/astr.2018.95.2.55.

Quantitative analysis of COX-2 promoter methylation in gastric carcinoma

• Kim HG
• Ryu SY
• Lee KH
• Lee JH
• Kim DY

• KMID: 2417770
• DOI: http://doi.org/10.4174/astr.2018.95.2.55

Abstract

PURPOSE
To determine the occurrence of COX-2 methylation in gastric carcinoma (GC), the status and level of CpG methylation in the promoter region of cyclooxygenase-2 (COX-2) were analyzed in early and advanced GCs, as well as in normal gastric tissues.
METHODS
The extent of promoter methylation of the COX-2 gene was assessed quantitatively using pyrosequencing in 60 early and 60 advanced GCs samples harvested upon gastrectomy, and 40 normal gastric mucosa samples from patients with benign gastric diseases as controls.
RESULTS
The methylation frequency for the COX-2 gene was significantly higher in early than in advanced GCs (40.0% vs. 20.0%, P < 0.05). A significant difference was found in COX-2 methylation between GCs and normal gastric tissues (30.0% vs. 10.0%, by PS; P < 0.05). COX-2 gene methylation was significantly associated with the depth of invasion (P = 0.003), lymph node metastasis (P = 0.009), distant metastasis (P = 0.036), and TNM staging (P = 0.007). The overall survival of patients with COX-2 methylation was significantly lower than that of patients without COX-2 methylation (P = 0.005).
CONCLUSION
These results demonstrated that COX-2 promoter methylation was significantly higher in tumor tissues, and was an early event for GC, thus, COX-2 gene methylation may be important in the initial development of gastric carcinogenesis. Thus, GCs with methylation in COX-2 may not be good candidates for treatment with COX-2 inhibitors. Furthermore, COX-2 methylation could be a significant prognostic factor predicting a favorable effect on GC patient outcome when downregulated.

Keyword

Methylation; COX-2; Gastric carcinoma; Pyrosequencing

MeSH Terms

Carcinogenesis
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Gastrectomy
Gastric Mucosa
Humans
Lymph Nodes
Methylation*
Neoplasm Metastasis
Neoplasm Staging
Promoter Regions, Genetic
Stomach Diseases
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors

Figure

• 

  Fig. 1 Representative results from methylation-specific PCR of COX-2 promoter methylation in normal gastric tissues and gastric carcinomas using 2 primer sets (A and B). EGC, early gastric carcinoma; AGC, advanced gastric carcinoma; SM, size marker; M, methylated; U, unmethylated.

• 

  Fig. 2 Survival curve for patients with gastric carcinoma, according to COX-2 expression by immunohistochemistry (P = 0.383).

• 

  Fig. 3 Survival curve for patients with gastric carcinoma, according to methylation of COX-2 as determined by combined methylation-specific PCR and pyrosequencing (P = 0.005). M, methylated; UM, unmethylated case.

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