title: Linking polymorphic p53 response elements with gene expression in airway epithelial cells of smokers and cancer risk.
abstract: Chronic cigarette smoking exposes airway epithelial cells to thousands of carcinogens, oxidants and DNA-damaging agents, creating a field of molecular injury in the airway and altering gene expression. Studies of cytologically normal bronchial epithelial cells from smokers have identified transcription-based biomarkers that may prove useful in early diagnosis of lung cancer, including a number of p53-regulated genes. The ability of p53 to regulate transcription is critical for tumor suppression, and this suggests that single-nucleotide polymorphisms (SNPs) in functional p53 binding sites (p53 response elements, or p53REs) that affect gene expression could influence susceptibility to cancer. To connect p53RE SNP genotype with gene expression and cancer risk, we identified a set of 204 SNPs in putative p53REs, and performed cis expression quantitative trait loci (eQTL) analysis, assessing associations between SNP genotypes and mRNA levels of adjacent genes in bronchial epithelial cells obtained from 44 cigarette smokers. To further test and validate these genotype-expression associations, we searched published eQTL studies from independent populations and determined that 53% (39/74) of the bronchial epithelial eQTLs were observed in at least one of other studies. SNPs in p53REs were also evaluated for effects on p53-DNA binding using a quantitative in vitro protein-DNA binding assay. Last, based on linkage disequilibrium, we found 6 p53RE SNPs associated with gene expression were identified as cancer risk SNPs by either genome-wide association studies or candidate gene studies. We provide an approach for identifying and evaluating potentially functional SNPs that may modulate the airway gene expression response to smoking and may influence susceptibility to cancers.
authors.affiliation: Environmental Genomics Section, Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, National Institutes of Health, Mail Drop: C3-03, 111 TW Alexander Drive, PO Box 12233, Research Triangle Park, NC, 27709, USA.
authors.forename: Xuting
authors.initials: X
authors.lastname: Wang
authors.forename: Gary S
authors.initials: GS
authors.lastname: Pittman
authors.forename: Omari J
authors.initials: OJ
authors.lastname: Bandele
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Bischof
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: John F
authors.initials: JF
authors.lastname: Brothers
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bell
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D004847:Epithelial Cells / Q000378:metabolism*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D040641:Quantitative Trait Loci; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D020218:Response Elements; D012306:Risk; D012907:Smoking / Q000009:adverse effects / Q000378:metabolism*; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53