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Int J Mol Epidemiol Genet 2012;3(1):1-17

Original Article
Germ line variation in nucleotide excision repair genes and lung cancer risk in

Lori C Sakoda, Melissa M Loomis, Jennifer A Doherty, Liberto Julianto, Matt J Barnett, Marian L Neuhouser, Mark D Thornquist,
Noel S Weiss, Gary E Goodman, Chu Chen

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology,
School of Public Health, University of Washington, Seattle, WA, USA; Department of Otolaryngology: Head and Neck Surgery,
School of Medicine, University of Washington, Seattle, WA, USA

Received November 21, 2011; accepted December 18, 2011; Epub February 5, 2012; Published February 28, 2012

Abstract: Since nucleotide excision repair (NER) is primarily responsible for detecting and removing bulky DNA lesions
induced by tobacco smoke in the respiratory tract, single nucleotide polymorphisms (SNPs) in NER protein-encoding genes
may influence lung cancer risk, particularly in smokers. Studies testing this hypothesis have produced inconsistent results,
with most analyzing a few SNPs in relatively small population samples. In a study nested in the Beta-Carotene and Retinol
Efficacy Trial, we examined 79 tag and previously reported risk-associated SNPs in the ERCC1, ERCC2, ERCC3, ERCC4,
ERCC5, LIG1, POLE, XPA, and XPC genes in 744 lung cancer cases and 1,477 controls, all of whom were non-Hispanic white
smokers. Using logistic regression, odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to estimate lung
cancer risk associated with SNP genotypes and haplotypes, adjusting for case-control matching factors. Lung cancer risk was
modestly associated with LIG1 rs156640 (OR per G allele, 1.23; 95% CI, 1.08-1.40), rs156641 (OR per A allele, 1.23; 95% CI,
1.08-1.40), and rs8100261 (OR per A allele, 0.83; 95% CI, 0.76-0.98); XPA rs3176658 (OR per A allele, 0.83; 95% CI,
0.69-1.00); and ERCC2 rs50871 (OR per C allele, 1.15; 95% CI: 1.01-1.30). Associations with LIG1 and XPA, but not ERCC2,
haplotypes were found. The results of this study and others suggest that inherited variants in LIG1 and possibly other NER
genes may predispose to smoking-related lung cancer. Given that chance likely accounts for one or more of the associations
observed, replication of our findings is needed. (IJMEG1111006).

Key words: Lung cancer, nucleotide excision repair, genetic polymorphism

Address all correspondence to:
Dr. Chu Chen
Division of Public Health Sciences
Fred Hutchinson Cancer Research Center
P.O. Box 19024, Mailstop M5-C800
Seattle, WA 98109-1024, USA.
Tel: 1-206-667-6644; Fax: 1-206-667-2537
E-mail: cchen@fhcrc.org