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Quantitative O⁶-Methylguanine DNA Methyltransferase Methylation Analysis in Curatively Resected Non-Small Cell Lung Cancer

Associations with Clinical Outcome

Department of Visceral and Vascular Surgery, University of Cologne, Cologne 50931, Germany [J. B., R. M., P. M. S., A. H. H.]; Department of Internal Medicine II, University of Freiburg, Freiburg 79106, Germany [H. U.]; Department of Molecular Biology and Biochemistry and Norris Comprehensive Cancer Center [J. P., S. S., P. V. D.], Department of Biostatistics and Epidemiology [D. D. T-W., S. G.], and Department of Surgery [R. V. L.], Keck School of Medicine, University of Southern California, Los Angeles, California, 90033; Response Genetics Inc., Los Angeles, California 90033 [D. S., K. D. D.]; and University of Maryland Greenebaum Cancer Center, Baltimore, Maryland 21201 [N. T.]

Purpose: Hypermethylation of the O⁶-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).

Experimental Design: 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.

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