Journal Article

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

Jill Everland Larsen, Maree Louise Colosimo, Ian Anthony Yang, Rayleen Bowman, Paul Victor Zimmerman and Kwun Meng Fong

in Carcinogenesis

Volume 27, issue 3, pages 525-532
Published in print March 2006 | ISSN: 0143-3334
Published online September 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi227
CYP1A1 Ile462Val and MPO G-463A interact to increase risk of adenocarcinoma but not squamous cell carcinoma of the lung

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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.

Keywords: GST, glutathione S-transferase; MPO, myeloperoxidase; NSCLC, non-small cell lung cancer; SNPs, single nucleotide polymorphisms

Journal Article.  5843 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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