P3.01-051 Analysis of Molecular Aberrations Associated with COPD in Patients with Lung Cancer: Topic: Functional Biology in Lung Cancer

Abstract

Chronic obstructive pulmonary disease (COPD) is serious lung disease that is often associated with development of lung cancer. It is well known that both diseases share many common risk factors, most prominently smoking. Much less is known about molecular link between these two pathologies. How to predict which COPD patients will develop lung cancer? Can COPD drugs reduce or increase lung cancer risk? To answer these question we analyzed molecular data from tumor and normal tissue samples obtained from 72 lung cancer patients, comprising methylation, copy number aberrations, gene expression and microRNA expression data acquired from each sample. Various matching spirometric parameters, were used as indicator of severity of the airflow limitation in patients with COPD and were evaluated as potential prognostic indicators with respect to survival. We studied molecular aberrations to identify those that correlate with these parameters or differ between COPD and non-COPD patients. Using data from Broad Institute's Connectivity Map (CMAP), we analyzed gene expression effects of various pharmacological compounds, to identify potential benefits/hazards in administration of various drugs (and their combinations) typically used for treatment of COPD and/or lung cancer, with respect to prognosis of patients with COPD vs. those without COPD. We identified group of 619 genes and 20 microRNAs whose expression is significantly associated with patient's COPD status (and severity of the disease). COPD-associated genes significantly enrich pathways related to G2 M phase of the cell cycle, G-protein coupled receptors signaling, Rho GTPases signaling and several cancer-related pathways. We found that subset of these genes constitute prognostic signature that was subsequently validated using independent publicly available dataset (HR = 2.66, p = 0.01, N = 204, GSE31210). We have also shown that alternative signature with similar prognostic power can also be constituted by COPD-associated micoRNAs (HR = 2.07, p = 0.036, N = 189, TCGA LUAD miRNAseq data). By subsequent CMAP analysis we then identified drugs that significantly (p < 0.01) affect expression of the COPD-associated genes in a manner that may improve the patients prognosis, and those that may cause its worsening. First mentioned include fenspiride — drug for obstructive airways disease and urological anti-infective phenazopyridine. Interestingly, we found calcium folinate — frequently used as a detoxifying agent for antineoplastic treatment, including treatment of lung cancer, as a potentially harmful. Genes and microRNAs associated with COPD are significantly associated with prognosis of the lung cancer patients.