Association of genetic variants of O6-methylguanine-DNA methyltransferase with risk of lung cancer in non-hispanic whites

O-6-methylguanine, a methylated damage lesion in DNA, correlates with spontaneous G:C -> A:T transition mutations and leads to activation of oncogene K-ras or dysfunction of the tumor suppressor gene p53. O-6-methylguanine-DNA methyltransferase (MGMT) is critical for repairing damage to the O-6-position of guanine. Therefore, we tested our hypothesis that genetic variants of MGMT are associated with increased lung cancer risk in a Caucasian population of 1,121 lung cancer patients and 1,163 matched cancer-free controls. We genotyped four potentially functional single nucleotide polymorphisms (SNPs) of MGMT: exon 3 codon 84C -> T (L84F), exon 5 codon 143A -> G (I143V), and two promoter SNPs 135G -> T and 485C -> A. The allele frequency distributions of the SNPs of codon 84C -> T and the promoter 135G -> T in the cases were borderline different from that in the controls. After defining the minor allele (T for codon 84C -> T and G for codon 143A -> G) as the variant allele, we categorized the MGMT genotypes as either 0 variants (84CC-143AA) or 1-4 variants. Compared with 0 variants, those with 1-4 variants showed a statistically significantly increased risk of lung cancer (P=0.040). Further stratification analysis showed that this increased risk was more pronounced in women, current smokers, and non-small cell lung cancer. We did not find any association between the MGMT promoter SNPs and lung cancer risk. Our findings suggest that nonsynonymous SNPs in MGMT are associated with modestly increased risk of lung cancer in Caucasians and need to be further investigated.