Purpose:
Lung cancer is the leading cause of
cancer-related death in the United States. The molecular events preceding the onset of disease are poorly understood, and no effective tools exist to identify smokers with premalignant lesions (PMLs) that will progress to invasive
cancer. Prior work identified molecular alterations in the
smoke-exposed airway field of injury associated with
lung cancer. Here, we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in
lung cancer chemoprevention.Experimental Design: Bronchial epithelial cells from normal appearing bronchial mucosa were profiled by
mRNA-Seq from subjects with (n = 50) and without (n = 25) PMLs. Using surrogate variable and gene set enrichment analysis, we identified genes, pathways, and
lung cancer-related gene sets differentially expressed between subjects with and without PMLs. A computational pipeline was developed to build and test a
chemoprevention-relevant
biomarker.Results: We identified 280 genes in the airway field associated with the presence of PMLs. Among the upregulated genes, oxidative phosphorylation was strongly enriched, and IHC and bioenergetics studies confirmed pathway findings in PMLs. The relationship between PMLs and
squamous cell carcinomas (SCC) was also confirmed using published
lung cancer datasets. The
biomarker performed well predicting the presence of PMLs (AUC = 0.92, n = 17), and changes in the
biomarker score associated with progression/stability versus regression of PMLs (AUC = 0.75, n = 51).Conclusions: Transcriptomic alterations in the airway field of smokers with PMLs reflect metabolic and early lung SCC alterations and may be leveraged to stratify smokers at high risk for PML progression and monitor outcome in
chemoprevention trials. Clin
Cancer Res; 23(17); 5091-100. ©2017 AACR.