Genome-Wide Association Study Reveals Novel Genetic Determinants of DNA Repair Capacity in Lung Cancer

Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenoty...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2013-01, Vol.73 (1), p.256-264
Main Authors: WANG, Li-E, GORLOVA, Olga Y, JUN YING, YAWEI QIAO, WENG, Shih-Feng, LEE, Annette T, GREGERSEN, Peter K, SPITZ, Margaret R, AMOS, Christopher I, QINGYI WEI
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic agents
Biological and medical sciences
DNA Repair - genetics
Female
Genetic Predisposition to Disease - genetics
Genome-Wide Association Study
Genotype
Humans
Lung Neoplasms - genetics
Male
Medical sciences
Middle Aged
Pharmacology. Drug treatments
Phenotype
Pneumology
Polymorphism, Single Nucleotide
Risk Factors
Tumors
Tumors of the respiratory system and mediastinum
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Summary:Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with single nucleotide polymorphisms as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables, and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2, and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer, and we defined several genetic loci contributing to DRC phenotype.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-12-1915