Genomic responses to smoking-induced lung injury: Identifying biomarkers for lung cancer and emphysema

Only 10 to 20% of smokers develop lung cancer or emphysema and an even smaller percentage (∼1-3%) develops both diseases. There are no effective means for identifying smokers at highest risk. To determine whether tobacco smoke causes an airway-wide epithelial cell "field of injury", we examined gene expression profiles in histologically normal bronchial airway epithelial cells obtained via bronchoscopy in order to explore smoking-induced damage and identify a clinically relevant diagnostic biomarker for lung cancer. Gene expression profiling of healthy never, current, and former smokers enabled us to characterize the function of the normal airway transcriptome, define genes differentially expressed in response to tobacco exposure, and identify which changes are reversible upon smoking cessation. Comparisons of smoking-induced gene expression changes to other publicly available bronchial epithelial gene expression datasets provided additional insights into the tobacco response mechanisms of airway epithelial cells. Further, lung cancer specific gene expression changes were detected in normal airway epithelium of smokers with lung cancer. A sensitive and specific biomarker was developed from gene expression patterns of smokers with and without lung cancer, and tested on an independent set and a prospective validation set of samples. The biomarker provided improvement over the diagnostic yield of bronchoscopy alone and bronchoscopy combined with clinical risk factors, and thus would allow for a reduction in the numbers of patients requiring further invasive diagnostic testing. This approach was applied to study another smoking related lung disease, chronic obstructive pulmonary disease (COPD). Initially, gene expression changes between mild/no and severe emphysematous lung tissue were identified and a subset was causally implicated in the disease. Airway epithelial cell gene expression patterns were then examined from current smokers with and without COPD, and pathway analyses suggested that patients with COPD respond differently to the toxic effects of smoke, and that this response bears similarities to lung cancer specific changes identified in the biomarker. These results suggest that gene expression profiles in airway epithelial cells can be used as a relatively non-invasive measure of host response to and damage from smoke and may ultimately serve as early biomarkers for smoking-related lung disease.