Lung cancer is the leading cause of cancer death in both men and women in the United States. The high mortality in patients with lung cancer results, in part, from the lack of effective tools to diagnose the disease at an early stage before it has spread to regional nodes or has metastasized beyond the lung. Our long-term goal is to develop a relatively noninvasive means of assessing the degree of airway epithelial cell damage and the risk for having or developing lung cancer among smokers. The objective of this application is to develop an intrathoracic (mainstem bronchus) airway gene expression profile capable of serving as an early diagnostic biomarker for lung cancer in smokers with clinical suspicion of disease. This approach is based on the hypothesis that patterns of gene expression in the histologically normal airway epithelium of a smoker reflect the types and degree of damage induced by the tobacco smoke and can predict that smoker's risk for having lung cancer. Using oligonucleotide microarrays, we have identified a gene expression signature in histologically normal large airway epithelial cells obtained at bronchoscopy that can serve as a highly sensitive and specific biomarker for distinguishing smokers with and without lung cancer. In this proposal, we will 1) validate this diagnostic airway biomarker in a large independent cohort of smokers with suspicion for lung cancer;2) evaluate our biomarker's accuracy in predicting the presence of lung cancer in stage 1 disease;3) integrate airway gene expression profiles with established clinical risk factors for disease to produce a clinicogenomic predictive model that can guide patient evaluation and management;4) develop a second gene expression signature in normal airway epithelium capable of distinguishing small cell vs. non-small cell lung cancer using novel reverse engineering algorithms. These studies will produce a relatively noninvasive tool effective in diagnosing lung cancer at an early and potentially curable stage. These gene expression-based biomarkers may eliminate the need for additional and often more invasive diagnostic tests that are costly, incur risk, and prolong the diagnostic evaluation of smokers with suspicion of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA124640-04
Application #
7776874
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Krueger, Karl E
Project Start
2007-05-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$308,750
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Wang, Xuting; Pittman, Gary S; Bandele, Omari J et al. (2014) Linking polymorphic p53 response elements with gene expression in airway epithelial cells of smokers and cancer risk. Hum Genet 133:1467-76
Perdomo, Catalina; Campbell, Joshua D; Gerrein, Joseph et al. (2013) MicroRNA 4423 is a primate-specific regulator of airway epithelial cell differentiation and lung carcinogenesis. Proc Natl Acad Sci U S A 110:18946-51
Beane, Jennifer; Cheng, Luis; Soldi, Raffaella et al. (2012) SIRT1 pathway dysregulation in the smoke-exposed airway epithelium and lung tumor tissue. Cancer Res 72:5702-11
Gower, Adam C; Spira, Avrum; Lenburg, Marc E (2011) Discovering biological connections between experimental conditions based on common patterns of differential gene expression. BMC Bioinformatics 12:381
Beane, Jennifer; Vick, Jessica; Schembri, Frank et al. (2011) Characterizing the impact of smoking and lung cancer on the airway transcriptome using RNA-Seq. Cancer Prev Res (Phila) 4:803-17
Wang, Xuting; Chorley, Brian N; Pittman, Gary S et al. (2010) Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer. PLoS One 5:e11934
Gustafson, Adam M; Soldi, Raffaella; Anderlind, Christina et al. (2010) Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med 2:26ra25
Steiling, Katrina; Kadar, Aran Y; Bergerat, Agnes et al. (2009) Comparison of proteomic and transcriptomic profiles in the bronchial airway epithelium of current and never smokers. PLoS One 4:e5043
Schembri, Frank; Sridhar, Sriram; Perdomo, Catalina et al. (2009) MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium. Proc Natl Acad Sci U S A 106:2319-24
Beane, Jennifer; Spira, Avrum; Lenburg, Marc E (2009) Clinical impact of high-throughput gene expression studies in lung cancer. J Thorac Oncol 4:109-18

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