Clinical significance of aberrant methylation of prostaglandin E receptor 2 (PTGER2) in nonsmall cell lung cancer: association with prognosis, PTGER2 expression, and epidermal growth factor receptor mutation.
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.
Tian
Lei
L
Department of Thoracic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan.
Suzuki
Makoto
M
Nakajima
Takahiro
T
Kubo
Rieko
R
Sekine
Yasuo
Y
Shibuya
Kiyoshi
K
Hiroshima
Kenzo
K
Nakatani
Yukio
Y
Fujisawa
Takehiko
T
Yoshino
Ichiro
I
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D019175:DNA Methylation; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C545644:PTGER2 protein, human; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D066246:ErbB Receptors