Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.

Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to populat...

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Autores principales:	Xuting Wang, Brian N Chorley, Gary S Pittman, Steven R Kleeberger, John Brothers, Gang Liu, Avrum Spira, Douglas A Bell
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/920782602b294c528d9f271cb06baab0
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spelling	oai:doaj.org-article:920782602b294c528d9f271cb06baab02021-11-18T06:36:28ZGenetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.1932-620310.1371/journal.pone.0011934https://doaj.org/article/920782602b294c528d9f271cb06baab02010-08-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20689807/?tool=EBIhttps://doaj.org/toc/1932-6203Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n = 20), smokers without lung cancer (SNC, n = 24), and never smokers (NS, n = 8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.Xuting WangBrian N ChorleyGary S PittmanSteven R KleebergerJohn BrothersGang LiuAvrum SpiraDouglas A BellPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 8, p e11934 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Xuting Wang Brian N Chorley Gary S Pittman Steven R Kleeberger John Brothers Gang Liu Avrum Spira Douglas A Bell Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
description	Prior microarray studies of smokers at high risk for lung cancer have demonstrated that heterogeneity in bronchial airway epithelial cell gene expression response to smoking can serve as an early diagnostic biomarker for lung cancer. As a first step in applying functional genomic analysis to population studies, we have examined the relationship between gene expression variation and genetic variation in a central molecular pathway (NRF2-mediated antioxidant response) associated with smoking exposure and lung cancer. We assessed global gene expression in histologically normal airway epithelial cells obtained at bronchoscopy from smokers who developed lung cancer (SC, n = 20), smokers without lung cancer (SNC, n = 24), and never smokers (NS, n = 8). Functional enrichment analysis showed that the NRF2-mediated, antioxidant response element (ARE)-regulated genes, were significantly lower in SC, when compared with expression levels in SNC. Importantly, we found that the expression of MAFG (a binding partner of NRF2) was correlated with the expression of ARE genes, suggesting MAFG levels may limit target gene induction. Bioinformatically we identified single nucleotide polymorphisms (SNPs) in putative ARE genes and to test the impact of genetic variation, we genotyped these putative regulatory SNPs and other tag SNPs in selected NRF2 pathway genes. Sequencing MAFG locus, we identified 30 novel SNPs and two were associated with either gene expression or lung cancer status among smokers. This work demonstrates an analysis approach that integrates bioinformatics pathway and transcription factor binding site analysis with genotype, gene expression and disease status to identify SNPs that may be associated with individual differences in gene expression and/or cancer status in smokers. These polymorphisms might ultimately contribute to lung cancer risk via their effect on the airway gene expression response to tobacco-smoke exposure.
format	article
author	Xuting Wang Brian N Chorley Gary S Pittman Steven R Kleeberger John Brothers Gang Liu Avrum Spira Douglas A Bell
author_facet	Xuting Wang Brian N Chorley Gary S Pittman Steven R Kleeberger John Brothers Gang Liu Avrum Spira Douglas A Bell
author_sort	Xuting Wang
title	Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
title_short	Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
title_full	Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
title_fullStr	Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
title_full_unstemmed	Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
title_sort	genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/920782602b294c528d9f271cb06baab0
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Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer.

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