title: O6-alkylguanine-DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer.
abstract: O6-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.
authors.affiliation: Cancer Research Institute, Kyungpook National University Hospital, Samduk, Daegu, Korea.
authors.forename: Myung Hwa
authors.initials: MH
authors.lastname: Chae
authors.forename: Jin-Sung
authors.initials: JS
authors.lastname: Jang
authors.forename: Hyo-Gyoung
authors.initials: HG
authors.lastname: Kang
authors.forename: Jae Hyung
authors.initials: JH
authors.lastname: Park
authors.forename: Jung Min
authors.initials: JM
authors.lastname: Park
authors.forename: Won Kee
authors.initials: WK
authors.lastname: Lee
authors.forename: Sin
authors.initials: S
authors.lastname: Kam
authors.forename: Eung Bae
authors.initials: EB
authors.lastname: Lee
authors.forename: Ji-Woong
authors.initials: JW
authors.lastname: Son
authors.forename: Jae Yong
authors.initials: JY
authors.lastname: Park
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000328:Adult; D018287:Carcinoma, Large Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018288:Carcinoma, Small Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors
chemical_list: D019853:O(6)-Methylguanine-DNA Methyltransferase