CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung.
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.
Larsen
Jill Everland
JE
Department of Thoracic Medicine, The Prince Charles Hospital, Brisbane, Australia.
Colosimo
Maree Louise
ML
Yang
Ian Anthony
IA
Bowman
Rayleen
R
Zimmerman
Paul Victor
PV
Fong
Kwun Meng
KM
D000230:Adenocarcinoma / Q000235:genetics* / Q000503:physiopathology*; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000503:physiopathology*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000503:physiopathology*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D009195:Peroxidase / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects
D019363:Cytochrome P-450 CYP1A1; D005982:Glutathione Transferase; D009195:Peroxidase; C413545:glutathione S-transferase T1