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

• Published in: Clinical cancer research 2003-01, Vol.9 (1), p.223
• Main Authors: Jan Brabender, Henning Usadel, Ralf Metzger, Paul M. Schneider, JiMin Park, Dennis Salonga, Denise D. Tsao-Wei, Susan Groshen, Reginald V. Lord, Naoko Takebe, Sylke Schneider, Arnulf H. Hölscher, Kathleen D. Danenberg, Peter V. Danenberg
• Format: Article
• Language: English
• ISSN: 1078-0432; 1557-3265

Purpose: 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). 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.