Abstract A21: Global DNA methylation analysis of bronchial epithelia of former smokers with COPD, with and without lung cancer

Abstract

Abstract Introduction: Emerging evidence suggests that aberrant epigenetic regulation is involved in the development and progression of malignant and nonmalignant respiratory diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer. Moreover, patients with COPD have an increased risk of developing lung cancer. Besides similar risk factors such as tobacco smoke exposure, little is known about the shared biology between COPD and lung cancer. Smoking causes aberrations in airway and lung parenchyma at both the genomic and epigenomic levels, resulting in global changes to gene expression. In this study, we hypothesize that alterations at the level of DNA methylation in airway epithelia of former smokers (FS) with COPD with and without non-small cell lung cancer (NSCLC) may be used to identify genes involved in the pathogenesis of these respiratory diseases, independent of the effects of active smoking. Methods: Bronchial epithelial cells were obtained from brushings of small airways (< 2 mm diameter) during bronchoscopy from FS with COPD (n=22), without COPD (n=22) and patients with COPD as well as previous surgical resection of Stage I NSCLC (n=6). Illumina's Infinium Methylation (HM27) assay was used to assess DNA methylation status of 27,578 CpG sites associated with 14,475 genes. Results: COPD patients are distinguished from non-COPD patients based on airway methylation profiles. Genes differentially methylated in airways between COPD and non-COPD patients include several modulators of aryl hydrocarbon receptor and IL6 signaling, as well as genes previously implicated in COPD, including immune chemotaxis regulators (CXCL11, CCR8) and GABA receptor signaling (GABRA5). Airway epithelial DNA from COPD patients with NSCLC compared to those without NSCLC was differentially methylated at sites encoding multiple key regulators of xenobiotic metabolism, regulators of free radical savaging/detoxification and retinol metabolic pathway components including several alcohol dehydrogenase, glutathione S transferase, and UDP glucoronosyltransferase genes. Conclusion: Our preliminary results suggest a role for DNA methylation in the deregulation of previously identified COPD-related genes, and specifically highlight differences in airways of COPD patients with/without NSCLC corresponding to well-known smoking-related metabolomic processes. Knowledge of DNA methylation disruption will further our understanding of the etiological role of COPD in the development of lung cancer, and contribute to the development of chemo-prevention strategies targeting the biology of both COPD and NSCLC. Supported by CIHR. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A21.