Detecting the Presence and Progression of Premalignant Lung Lesions via Airway Gene Expression

Purpose:  Lung cancer (LC) is the leading cause of cancer death in the US. 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 LC.  Here we focus on an earlier stage in the disease process leveraging the airway field of injury to study PMLs and its utility in LC chemoprevention.<br />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 LC-related gene sets differentially expressed between subjects with and without PMLs.  A computational pipeline was developed to build and test a chemoprevention-relevant biomarker.<br />Results:  We identified 280 genes in the airway field associated with the presence of PMLs.  Among the up-regulated genes, oxidative phosphorylation was strongly enriched and immunohistochemistry and bioenergetics studies confirmed pathway findings in PMLs. The relationship to PMLs and squamous cell carcinomas (SCC) was also confirmed using published LC 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 vs. regression of PMLs (AUC=0.75, n=51).<br />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.

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