Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6‐alkylguanine–DNA alkyltransferase

• Published in: International journal of cancer Vol. 122; no. 4; pp. 791 - 795
• Main Authors: Crosbie, Philip A.J., McGown, Gail, Thorncroft, Mary R., O'Donnell, Paul N.S., Barber, Philip V., Lewis, Sarah J., Harrison, Kathryn L., Agius, Raymond M., Santibáñez‐Koref, Mauro F., Margison, Geoffrey P., Povey, Andrew C.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 15.02.2008; Wiley-Liss
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - etiology; Aged; AGT; Biological and medical sciences; Carcinoma, Small Cell - enzymology; Carcinoma, Small Cell - etiology; Carcinoma, Squamous Cell - enzymology; Carcinoma, Squamous Cell - etiology; Case-Control Studies; Codon - genetics; DNA alkylation; DNA Repair - genetics; Female; Genetic Predisposition to Disease; Genotype; Humans; Introns - genetics; lung cancer; Lung Neoplasms - enzymology; Lung Neoplasms - etiology; Male; Medical sciences; MGMT; Middle Aged; O-Methylguanine-DNA Methyltransferase - genetics; Pneumology; Polymorphism, Single Nucleotide - genetics; polymorphisms; Risk Factors; Smoking - adverse effects; tobacco smoke; Tumors; Tumors of the respiratory system and mediastinum; United Kingdom; Europe; Genetic variability; Lung cancer; Tobacco smoking; Epidemiology; DNA repair; Alkylation; Repair gene; Cancerology; Codon; Genetics; Bronchus disease; Human; Lung disease; tobacco smoke; Enzyme; Respiratory disease; MGMT; Transferases; Genotype; DNA alkylation; Malignant tumor; polymorphisms; AGT; Methylated-DNA-protein-cysteine S-methyltransferase; Tobacco; Methyltransferases; Intron; DNA; Risk factor; Single nucleotide polymorphism; Cancer
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.23059

The association between lung cancer risk and 2 polymorphisms, rs12268840 and rs2308327 (codon K178R), in the DNA repair protein, O6‐alkylguanine–DNA alkyltransferase, which are associated with interindividual differences in activity, have been investigated in 3 hospital‐based case–control studies. Genotyping was carried out on 617 subjects of whom 255 had lung cancer. In 2 of the 3 series, there was a significant inverse association between the 178R allele and case status (p < 0.05). In a meta‐analysis, the odds ratio (95% CI) associated with the 178R allele relative to the 178K allele was 0.64 (0.45–0.92, p = 0.01) and 0.51 (0.24–1.11, p = 0.09) in fixed effects and random effects models, respectively. In a pooled analysis, after adjustment for sex, age, pack years and series, the OR (95% CI) for a heterozygote was 0.67 (0.45–1.01) and for a 178R homozygote was 0.10 (0.01–0.94); the trend for a decreased risk with the number of R alleles was significant (p = 0.008). This trend was particularly pronounced in heavy smokers (trend test p = 0.003), but not significant in light smokers (p = 0.73). There was no evidence of an association between rs12268840 and lung cancer risk. These results suggest that the R allele may protect against lung cancer, specifically in heavy smokers, an effect that may result from this polymorphism affecting the function of the MGMT protein and/or levels in MGMT activity. © 2007 Wiley‐Liss, Inc.