Clinical significance of aberrant methylation of prostaglandin E receptor 2 (PTGER2) in nonsmall cell lung cancer

Abstract

BACKGROUND.The expression of prostaglandin E receptor 2 (PTGER2) affects the biologic behavior of various types of malignant tumors. Recently, transactivation of both PTGER2 and epidermal growth factor receptor (EGFR) has been reported in some tumors.METHODS.PTGER2 gene expression and possible aberrant methylation of the PTGER2 gene were investigated in 10 nonsmall cell lung cancer (NSCLC) cell lines, 233 primary tumors, and 168 adjacent nonmalignant lung tissues. They were analyzed with reference to an association with EGFR mutation in 133 clinical lung adenocarcinomas and were correlated with patient survival.RESULTS.Down‐regulation of PTGER2 expression was observed in 8 of 10 NSCLC cell lines. Demethylation of 5 expression‐negative cell lines restored the expression of PTGER2. Aberrant methylation of the PTGER2 gene was reversely concordant with its messenger RNA expression. PTGER2 methylation was detected in 137 of 233 NSCLC specimens (58%) but was detected in only 2 of 168 nonmalignant lung tissues (1%). Both NSCLCs and adenocarcinomas that had PTGER2 methylation predicted a significantly better prognosis than those without PTGER2 methylation (P = .0051 and P = .0171, respectively). PTGER2 methylation was present with greater frequency in tumors with EGFR mutation than in non‐EGFR mutated tumors (P = .0095), and the significance of the correlation was independent after adjusting for sex and smoking status (P = .0144).CONCLUSIONS.Aberrant methylation of the PTGER2 gene was observed frequently in NSCLC tissues and was associated with the presence of EGFR mutation and a better prognosis. Cancer 2008. © 2008 American Cancer Society.

Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers

“…Hypermethylation of the SPARC, PTGER2 and p16 genes has been related to the EGFR mutation (24,25). However, we could not find a correlation between the EGFR mutation and genetic methylation in 30 cases of stage IA adenocarcinoma.…”

“…DNA methylation patterns in the CpG island of 14 tumorrelated genes were determined using methylation-specific PCR (MSP) as described previously (19)(20)(21)(22)(23)(24). These genes were chosen based on reports that their expression is downregulated by hypermethylation in lung cancer (19)(20)(21)(22)(23).…”

Epidermal growth factor receptor reactivation induced by E-prostanoid-3 receptor- and tumor necrosis factor-alpha-converting enzyme-dependent feedback exaggerates interleukin-8 production in airway cancer (NCI-H292) cells

“…The reason for lack of an EP4 effect is uncertain, but could be due to EP4-dependent cAMP accumulation in a cell compartment that is spatially removed from the cAMPdependent processes that regulate the TACE/EGFR cascade [36]. Notably, decreased mRNA levels for the EP2 receptor have been reported in many non-small cell lung cancers [37,38], leading us to speculate that lack of an EP2 receptor "brake" on EP3 receptor activation could exaggerate pro-tumor responses such as IL-8 production in some airway cancers.…”

CpG island methylation of microRNAs is associated with tumor size and recurrence of non‐small‐cell lung cancer

“…(22)(23)(24) A subset of the CpG island methylator phenotype (CIMP), originally established in colorectal carcinoma, (25,26) is characterized by the synchronous hypermethylation of multiple promoter CpG island regions and peculiar clinicopathological findings. Although several reports have indicated that CIMP is also distinguishable in NSCLC and is associated with a poor prognosis, (27,28) we have failed to distinguish the phenotype in the previous study regarding the methylation of the promoter regions of numerous protein-coding genes.…”