CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung

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Abstract
Common polymorphisms in genes encoding phase I and phase II enzymes are considered to modify lung cancer risk due to changes in enzyme activity. Candidates include genetic variants of glutathione S -transferases ( GSTM1 , GSTT1 and GSTP1 ) and myeloperoxidase ( MPO ). We performed a large case–control study of these candidate genes in 1103 patients with non-small cell lung cancer (NSCLC) and 627 controls without NSCLC. Associations between deletion genotypes of GSTM1 and GSTT1 and between single nucleotide polymorphisms (SNPs) of GSTP1 Ile105Val and MPO G-463A were first tested by adjusted logistic regression. Then we analysed gene–gene interactions, also incorporating our published data on the Ile462Val SNP in the phase I enzyme, cytochrome P450 CYP1A1 . The homozygous GSTP1 105Val genotype was significantly under-represented in NSCLC compared with controls (OR = 0.73; 95%CI 0.53–1.00; P = 0.050), especially in females (OR = 0.57; 95%CI 0.34–0.98; P = 0.04). The GSTT1 -null genotype was significantly over-represented in adenocarcinomas (OR = 1.41; 95%CI 1.06–1.90; P = 0.02) but not in squamous cell carcinomas (OR = 1.03; 95%CI 0.76–1.41; P = 0.84). There was weak risk reduction associated with GSTM1 null in heavy smokers (OR = 0.71; 95%CI 0.54–0.94; P = 0.02), but neither GSTM1 nor MPO genotypes affected the overall risk of NSCLC. The MPO and CYP1A1 risk genotypes interacted to increase the overall risk of NSCLC (OR = 2.88; 95%CI 1.70–5.00; P < 0.001). The data are consistent with the concept that multiple genes of modest effect interact to confer genomic-based susceptibility to lung cancer.