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O6-alkylguanine-DNAalkyltransferase (MGMT) is a universal DNA repair protein involved in the DNA direct reversal repair pathway coping with alkylatingcarcinogens. Reduced MGMT expression as well as enzyme activity may result in an increased susceptibility to cancers. To elucidate the role of sequence variation in MGMT in the etiology of lung cancer, we conducted a comprehensive association study focusing on linkage disequilibrium (LD) structure of common variations across MGMT sequence andits modification effect on smoking-related lung cancer risk. We rebuilt the LD block of MGMT by genotyping 39 single-nucleotide polymorphisms (SNPs) and selected a subset of 10 haplotype-tagging SNPs (htSNP) and 3 pre-, inter-block SNPs to capture variation across MGMT. By using a haplotype-based multifactor dimensionality reduction (MDR) analysis,we found that there were significant more-than-multiplicative interaction between diplotypes in block 5 and cumulative smoking and additive interaction between genotypes of pre-block SNP rs1625649:C>A and smoking status in relation on lung caner risk. Diplotypes in block 3 and block 5, genotypes of rs1625649:C>A and trichotomized cumulative smoking are the four factors included in the MDR-defined best model on lung cancer risk. When these variables were combined and dichotomized, we found that subjects carrying the combined risk stratum had a significantly 4.10-fold (odds ratio [OR] = 4.10, 95% confidence interval [CI] = 3.12 - 5.37, P= 2.09 × 10-24) increased risk for lung cancer. These findings suggested that genetic variants in MGMT may modulate the risk of smoking-related lung cancer. This haplotype-based interaction analysis might provide a “proof-of-principle” approach for studying candidate genes in cancer susceptibility.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA