Alterations in bronchial airway microRNA expression for lung cancer detection

We have previously shown that gene-expression alterations in normal-appearing bronchial epithelial cells can serve as a lung cancer detection biomarker in smokers. Given that microRNAs regulate airway gene-expression responses to smoking, we evaluated whether microRNA-expression is also altered in the bronchial epithelium of smokers with lung cancer. Using epithelial brushings from the mainstem bronchus of patients undergoing bronchoscopy for suspected lung cancer (as part of the AEGIS-1/2 clinical trials), we profiled microRNA-expression via small-RNA sequencing from 347 current and former smokers for which gene-expression data was also available. Patients were followed for one year post-bronchoscopy until a final diagnosis of lung cancer (n=194) or benign disease (n=153) was made. Following removal of 6 low-quality samples, we used 138 patients (AEGIS-1) as a discovery set to identify four microRNAs (miR-146a-5p, miR-324-5p, miR-223-3p, miR-223-5p) that were down-regulated in the bronchial airway of lung cancer patients (ANOVA p<0.002, FDR<0.2). The expression of these microRNAs is significantly more negatively-correlated with the expression of their mRNA-targets than with the expression of other non-target genes (K-S p<0.05). Further, these mRNA-targets are enriched among genes whose expression is elevated in cancer patients (GSEA FDR<0.001). Finally, we found that the addition of miR-146a-5p to an existing mRNA-biomarker for lung cancer significantly improves its performance (AUC) in the 203 samples (AEGIS-1/2) serving an independent test set (DeLong p<0.05). Our findings suggest that there are microRNAs whose expression is altered in the cytologically-normal bronchial epithelium of smokers with lung cancer, and that they may regulate cancer-associated gene expression differences.

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