Quantitative O(6)-methylguanine DNA methyltransferase methylation analysis in curatively resected non-small cell lung cancer: associations with clinical outcome.
OBJECTIVE
Hypermethylation of the O(6)-methylguanine DNA methyltransferase (MGMT) promoter region leads to transcriptional repression of the MGMT gene and is a common event in primary human neoplasia. The purpose of this study was to determine the frequency and clinical relevance of MGMT gene promoter hypermethylation in curatively resected non-small cell lung cancer (NSCLC).


METHODS
MGMT hypermethylation, expressed as the ratio between methylated MGMT to unmethylated MYOD1 in genomic DNA, was analyzed in normal and matching tumor tissue from 90 patients with NSCLC, and a control group of 10 patients without cancer using a methylation-specific fluorogenic Real-Time PCR (Taqman) system.


RESULTS
Hypermethylation of the MGMT promoter was detected in 34 of 90 (38%) tumor specimens and 16 of 90 (18%) matching normal lung tissues of patients with NSCLC, and in 0 (0%) cases of the control group without lung cancer. The mean MGMT methylation level was significantly higher in tumor than in matching normal tissue (P < 0.001). MGMT methylation in normal tissue was always accompanied with MGMT methylation in matching tumor tissue. Patients without MGMT promoter hypermethylation showed a significantly better survival than patients with MGMT promoter hypermethylation (P = 0.017). Multivariate analysis revealed MGMT promoter methylation as an independent unfavorable prognostic factor (P = 0.030).


CONCLUSIONS
MGMT promoter hypermethylation is a common event in patients with primary NSCLC. This epigenetic alteration is associated with inferior survival, suggesting that MGMT promoter hypermethylation might be an important biomarker for a biological aggressive disease in NSCLC.
Brabender
Jan
J
Department of Visceral and Vascular Surgery, University of Cologne, Cologne 50931, Germany. jan.brabender@t-online.de
Usadel
Henning
H
Metzger
Ralf
R
Schneider
Paul M
PM
Park
JiMin
J
Salonga
Dennis
D
Tsao-Wei
Denise D
DD
Groshen
Susan
S
Lord
Reginald V
RV
Takebe
Naoko
N
Schneider
Sylke
S
Hölscher
Arnulf H
AH
Danenberg
Kathleen D
KD
Danenberg
Peter V
PV
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000601:surgery; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000601:surgery; D008297:Male; D008745:Methylation; D008875:Middle Aged; D015999:Multivariate Analysis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013447:Sulfites / Q000494:pharmacology; D013997:Time Factors; D016896:Treatment Outcome
D013447:Sulfites; D019853:O(6)-Methylguanine-DNA Methyltransferase; C009279:sodium bisulfite