title: NNK reduction pathway gene polymorphisms and risk of lung cancer.
abstract: The tobacco-specific nitrosamine NNK is a potent carcinogen found in tobacco smoke and implicated in the development of lung cancer. The major route of NNK metabolism is carbonyl reduction by AKR1C1, AKR1C2, CBR1, and 11β-HSD1 to form NNAL. This study investigated the potential role of variants in this pathway on lung cancer risk by examining 53 tag-SNPs representing the common variations in AKR1C1, AKR1C2, CBR1, and HSD11B1 in 456 lung cancer cases and 807 controls. One SNP in CBR1 (rs2835267) was significantly associated with overall risk of lung cancer, but did not pass multiple testing adjustment (OR: 0.76 95% CI: 0.58-0.99, P = 0.048, FDR P = 0.20). After stratification and multiple testing correction, three SNPs showed significance. One SNP (rs2835267) in CBR1 showed a significant decreased risk for smokers with a high pack-years (OR: 0.3595% CI: 0.17-0.69, P = 0.018) and in SCC (OR: 0.4895% CI: 0.29-0.76, P = 0.018). Another SNP located in CBR1 (rs3787728) also showed a significant decreased risk in SCC (OR: 0.4695% CI: 0.26-0.80, P = 0.024) and small cell carcinoma (only in current smokers) (OR: 0.06895% CI: 0.01-0.42, P = 0.028). The HSD11B1 SNP (rs4844880) showed a significant increased risk for adenocarcinoma within former smokers (OR: 3.9495% CI: 1.68-9.22, P = 0.011). Haplotype analysis found significance with six haplotypes and lung cancer risk. These findings indicate that select variants in genes in the carbonyl reduction pathway of NNK may alter the risk of lung cancer.
authors: Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, Hershey, Pennsylvania.|Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania.
authors: Jennifer L
authors: JL
authors: Modesto
authors: Department of Biology, Lincoln University, Pennsylvania.
authors: Anna
authors: A
authors: Hull
authors: Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, Hershey, Pennsylvania.|Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania.
authors: Andrea Y
authors: AY
authors: Angstadt
authors: Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania.
authors: Arthur
authors: A
authors: Berg
authors: Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, Hershey, Pennsylvania.|Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania.|Departments of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania.
authors: Carla J
authors: CJ
authors: Gallagher
authors: Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington.
authors: Philip
authors: P
authors: Lazarus
authors: Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, Hershey, Pennsylvania.|Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania.
authors: Joshua E
authors: JE
authors: Muscat
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009602:Nitrosamines / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide
chemical_list: D009602:Nitrosamines; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
keywords: AKR; CBR1; HSD11B1; NNAL; NNK; genetic polymorphism; lung cancer