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Abstract

Former heavy tobacco smokers remain at high risk for lung cancer long after they quit smoking. Smoking induces a field of injury in airways, which can be detected as persistent changes in gene expression and epigenetic marks in airway epithelial cells. While most of these changes revert to normal levels after smoking cessation, some changes persist in former smokers for many years. If these changes are shown to contribute to lung cancer tumorigenesis, they could be intercepted before lesions form, used to stratify former smokers by cancer risk for screening programs, or detected in a non-invasive manner. Existing studies have not fully characterized the mechanisms underlying the airway field of injury and how they are linked to lung cancer. We incorporate data from multiple studies to infer genes with persistently altered RNA expression in former smoker airways, mechanisms potentially underlying this persistence, and potential interpretations of the expression changes. We determine which of these expression changes could be linked to lung cancer by performing comparisons with lung cancer ‘omics datasets. We utilize meta-analysis to corroborate the genes’ link to smoking in airways, and exploratory analyses to assess potential mechanisms and biological relevance. To summarize, we have established sets of genes that could link the persistent airway field of injury to lung cancer and explored putative related mechanisms.