NNK reduction pathway gene polymorphisms and risk of lung cancer

Jennifer L Modesto; Anna Hull; Andrea Y Angstadt; Arthur Berg; Carla J Gallagher; Philip Lazarus; Joshua E Muscat

doi:10.1002/mc.22187

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NNK reduction pathway gene polymorphisms and risk of lung cancer

Journal article

Open access

Peer reviewed

NNK reduction pathway gene polymorphisms and risk of lung cancer

Jennifer L Modesto, Anna Hull, Andrea Y Angstadt, Arthur Berg, Carla J Gallagher, Philip Lazarus and Joshua E Muscat

Molecular carcinogenesis, Vol.54 Suppl 1(S1), pp.E94-E102

06/2015

DOI: https://doi.org/10.1002/mc.22187

Handle:

https://hdl.handle.net/2376/104091

PMCID: PMC6296469

PMID: 24976539

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Abstract

Lung Neoplasms - genetics

Genetic Predisposition to Disease

Humans

Middle Aged

Female

Male

Nitrosamines - pharmacology

Aged

Polymorphism, Single Nucleotide

Case-Control Studies

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.

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Title: NNK reduction pathway gene polymorphisms and risk of lung cancer
Creators: Jennifer L Modesto - Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
Anna Hull - Department of Biology, Lincoln University, Pennsylvania
Andrea Y Angstadt - Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
Arthur Berg - Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
Carla J Gallagher - Departments of Pharmacology, Penn State University College of Medicine, Hershey, Pennsylvania
Philip Lazarus - Department of Pharmaceutical Sciences, Washington State University College of Pharmacy, Spokane, Washington
Joshua E Muscat - Departments of Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
Publication Details: Molecular carcinogenesis, Vol.54 Suppl 1(S1), pp.E94-E102
Academic Unit: Pharmaceutical Sciences, Department of
Publisher: United States
Grant note: R01 DE013158 / NIDCR NIH HHS R01 ES025460 / NIEHS NIH HHS R00-CA131477 / NCI NIH HHS MD003352 / NIMHD NIH HHS P01 CA068384 / NCI NIH HHS R01-DE13158 / NIDCR NIH HHS P01-CA68384 / NCI NIH HHS
Identifiers: 99900546558901842
Language: English
Resource Type: Journal article