O6-alkylguanine-DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer.
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AuthorsChae, Myung Hwa
Park, Jae Hyung
Park, Jung Min
Lee, Won Kee
Lee, Eung Bae
Park, Jae Yong
MetadataShow full item record
AbstractO6-alkylguanine-DNA alkyltransferase (AGT) plays an important role in the repair of O6-alkylguanine adducts, which are major mutagenic lesions produced by environmental carcinogens. Polymorphisms in the AGT gene may affect the capacity to repair DNA damage and thereby have influence on individual's susceptibility to smoking-related cancer. To test this hypothesis, we investigated the potential association of AGT polymorphisms (485C > A, Leu53Leu (C > T) and Leu84Phe] with the risk of lung cancer in a Korean population. The AGT genotypes were determined in 432 lung cancer patients and in 432 healthy controls who were frequency-matched for age and gender. The 485 AA genotype was associated with a significantly increased risk for overall lung cancer as compared with the 485 CC genotype and the combined 485 CC + CA genotype, respectively (adjusted odds ratio (OR) = 1.83, 95% confidence interval (CI) = 1.12-2.99, P = 0.02, and Bonferroni corrected P-value (Pc) = 0.04; and adjusted OR = 1.67, 95% CI = 1.05-2.66, P = 0.03, respectively). When the lung cancer cases were categorized by the tumor histology, the 485 AA genotype was associated with a significantly increased risk of adenocarcinoma (AC) and small cell carcinoma (SmCC), respectively, as compared with the combined 485 CC + CA genotype (adjusted OR = 2.54, 95% CI = 1.39-4.66, P = 0.003; and adjusted OR = 2.19, 95% CI = 1.06-4.55, P = 0.04, respectively). However, the genotype distributions of the Leu53Leu and Leu84Phe polymorphisms were not significantly different between the lung cancer cases and the controls. On a promoter assay, the 485C > A polymorphism did not have an effect on the promoter activity of the AGT gene. These results suggest that the effect of the AGT 485C > A polymorphism on the risk of lung cancer may be secondary to linkage disequilibrium (LD) with either another AGT variant or with a true susceptibility gene, and that the AGT 485C > A polymorphism could be used as a marker for the genetic susceptibility to lung cancer.
CitationMol. Carcinog. 2006, 45 (4):239-249
DescriptionBiomarkers of individual susceptibility: field studiesBiomarker (including alleles if genetic): AGT polymorphisms (485C>A, Leu53Leu (C>T) and Leu84Phe]Effect studied (phenotype/pathology): lung cancerMethod of analysis: PCR-RFLPStudy design: case-control Study size: 432 lung cancer patients and 432 healthy controlsImpact on outcome (including dose-response):The 485 AA genotype was associated with a significantly increased risk for overall lung cancer as compared with the 485 CC genotype and the combined 485 CCώCA genotype, respectively (adjusted OR=1.83, 95% CI=1.12- 2.99, P=0.02, and Bonferroni corrected P-value, Pc=0.04; and adjusted OR=1.67, 95% CI=1.05- 2.66, P=0.03, respectively).Quality control: performed in triplicates. KEYWORDS CLASSIFICATION: Adenocarcinoma;Adult;biomarkers of individual susceptibility: field studies;cancer epidemiology;Carcinoma,Large Cell;Carcinoma,Small Cell;Carcinoma,Squamous Cell;Case-Control Studies;DNA Damage;DNA Repair;enzymology;Female;genetics;Genetic Predisposition to Disease;Genotype;Humans;Korea;Lung Neoplasms;metabolism;Male;mechanisms of carcinogenesis;O(6)-Methylguanine-DNA Methyltransferase;pathology;Polymorphism,Genetic;Promoter Regions (Genetics);Research;Risk Factors;secondary;field studies;genetic;analysis.