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Human Genetics

, Volume 133, Issue 12, pp 1467–1476 | Cite as

Linking polymorphic p53 response elements with gene expression in airway epithelial cells of smokers and cancer risk

  • Xuting Wang
  • Gary S. Pittman
  • Omari J. Bandele
  • Jason J. Bischof
  • Gang Liu
  • John F. BrothersII
  • Avrum Spira
  • Douglas A. BellEmail author
Original Investigation

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.

Keywords

Bronchial Epithelial Cell Airway Epithelial Cell Lung Cancer Risk Position Weight Matrix eQTL Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

This work was funded in part by the Intramural Research Program (projects: ZO1-ES100475 and Z01 ES046008) of the National Institute of Environmental Health Sciences, National Institutes of Health and grants to Avrum Spira from the National Institute of Health (U01ES016035, R01CA124640). We are grateful for comments from Drs. Daniel Menendez and Jack Taylor, NIEHS.

Conflict of interest

No potential conflicts of interest were disclosed.

Author contributions

Conceived and designed the experiments: AS DAB. Performed the experiments: XW GSP OJB JB JBII GL. Analyzed the data: XW DAB. Wrote the paper: XW DAB.

Supplementary material

439_2014_1483_MOESM1_ESM.docx (97 kb)
Supplementary material 1 (DOCX 97 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2014

Authors and Affiliations

  • Xuting Wang
    • 1
  • Gary S. Pittman
    • 1
  • Omari J. Bandele
    • 1
  • Jason J. Bischof
    • 1
  • Gang Liu
    • 2
  • John F. BrothersII
    • 2
  • Avrum Spira
    • 2
  • Douglas A. Bell
    • 1
    Email author
  1. 1.Environmental Genomics Section, Laboratory of Molecular GeneticsNational Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUSA
  2. 2.Section of Computational Biomedicine, Department of MedicineBoston UniversityBostonUSA

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