• Steven A Belinsky, Donna M Klinge, Joseph D Dekker, Mitzi W Smith, Theresa J Bocklage, Frank D Gilliland, Richard E Crowell, Daniel D Karp, Christine A Stidley, and Maria A Picchi.
• Lovelace Respiratory Research Institute, Albuquerque, NM 87108, USA. sbelinsk@LRRI.org
• Clin Cancer Res. 2005 Sep 15; 11 (18): 6505-11.

PurposeLung cancer is the leading cause of cancer mortality in the United States, due in part to the lack of a validated and effective screening approach for early detection. The prevalence for methylation of seven and three genes was examined in DNA from sputum and plasma, respectively, from women at different risk for lung cancer.Experimental DesignLung cancer survivors (n = 56), clinically cancer-free smokers (n = 121), and never smokers (n = 74) comprised the study population. Plasma was collected from all three groups, whereas sputum was collected from lung cancer survivors and smokers.ResultsMethylation was detected in plasma DNA from 10 of 74 women who never smoked. Prevalence for methylation of the p16 gene in plasma was highest in lung cancer survivors. Lung cancer survivors showed a significant increase in the odds of having at least one or more genes methylated in plasma (odds ratio, 3.6; 95% confidence interval, 1.9-9.1) than never smokers. The prevalence for methylation of the O(6)-methylguanine-DNA methyltransferase, ras effector homologue 1, death associated protein kinase, and PAX5alpha genes in sputum was significantly higher in lung cancer survivors compared with smokers. Lung cancer survivors had 6.2-fold greater odds (95% confidence interval, 2.1-18.5) for methylation of three or more genes in sputum compared with smokers. Methylation was more commonly detected in sputum than plasma for O(6)-methylguanine-DNA methyltransferase and ras effector homologue 1, but not p16, in lung cancer survivors.ConclusionConcomitant methylation of multiple gene promoters in sputum is strongly associated with lung cancer risk.

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