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Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87108 [L. C. P., K. K. D., D. M. K., S. A. B.]; Keck School of Medicine, Department of Preventative Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California 90089-9021 [F. D. G., T. K.]; Karmanos Cancer Institute and Wayne State University Department of Oncology and Internal Medicine, Detroit, Michigan 48201 [A. G. S.]; and Departments of Family and Community Medicine and Pathology, University of New Mexico, Albuquerque, New Mexico [T. J. B.]
Adenocarcinoma (AC) is the most common type of lung cancer diagnosed in the United States, comprising up to 40% of tumors in smokers and 50–80% of tumors in never-smokers. Exposures to cigarette smoke, direct or second-hand, and radiation in the form of radon progeny are the major risk factors for lung AC in both smokers and never-smokers. The goal of the current study was to determine the prevalence for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in a large sample of central or peripheral ACs from smokers (n = 157), former uranium miners (n = 34), and never-smokers (n = 46). The mutation rate at codon 12 of the K-ras gene was determined to assess whether activation of this oncogene was associated with MGMT methylation. The overall prevalence for MGMT methylation was 51%. Significantly more tumors from never-smokers than smokers exhibited MGMT methylation (66 versus 47%, respectively). In contrast, exposure to radon through uranium mining did not affect the prevalence for methylation. The frequency of MGMT methylation was increased significantly in association with tumor stage. K-ras mutations were detected in 24% of all ACs and 22, 24, and 28% of tumors from never-smokers, smokers, and miners, respectively. Alterations in both the K-ras and MGMT genes were seen in only 11% of ACs. Kaplan-Meier survival estimates did not reveal any difference between patient survival with or without MGMT methylation. In contrast, survival was significantly reduced over the initial 60 months after diagnosis for patients with a transition mutation in the K-ras gene compared with those with a transversion mutation. This investigation demonstrates that MGMT promoter hypermethylation is a common event in the progression of early stage AC of the lung. We have shown that the incidence of MGMT methylation was significantly higher in never-smokers than smokers and have detected a higher frequency of mutations within the K-ras gene than previously reported in never-smokers. This study also suggests that K-ras activation is independent of MGMT methylation.
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