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Alkylating agents are among the most potent carcinogens present in tobacco smoke. Their carcinogenicity is believed to be mediated by their ability to produce O6- alkylguanine adducts in DNA. These lesions are repaired by a specific protein O6-alkylguanine DNA alkyltransferase (MGMT). Expression levels of this protein vary considerably between individuals. The causes of this variation are not well understood, but recent results indicate that intragenic polymorphisms correlate with MGMT activity levels. Here we investigate the allele frequencies of the codon 178 polymorphism (K178R) which is in perfect disequilibrium with I143V; a polymorphism that has been shown to affect the activity of the MGMT protein. We genotyped 267 individuals with and 465 individuals without lung cancer visiting the North West Lung Centre at Wythenshawe Hospital (Manchester, UK). The results are consistent with an association between the K178R polymorphism and lung cancer risk (p=0.012). The odds ratios for the K/R and R/R genotypes (with respect to the KK genotype) were 0.77 (95% confidence interval 0.53-1.11) and 0.12 (0.02-0.935) respectively. Our observations indicate that differences in MGMT activity between individuals may affect cancer risk. This research was supported by Cancer Research-UK, the Colt Foundation and the British Lung Foundation.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]