Specific peripheral miRNA profiles for distinguishing lung cancer from COPD

Abstract

Recently we reported differential miRNA signatures in blood cells of lung cancer patients and healthy controls. With the present study we wanted to investigate if miRNA blood signatures are also suited to differentiate lung cancer patients from COPD patients. We compared the expression of 863 human miRNAs in blood cells of lung cancer patients, COPD patients, and healthy controls. The miRNA pattern from patients with lung cancer and COPD were more similar to each other than to the healthy controls. However, we were able to discriminate lung cancer patients and COPD patients with 90.4% accuracy, 89.2% specificity, and 91.7% sensitivity. In total, 140 miRNAs were significant for the comparison COPD and controls, 61 miRNAs were significant for the comparison lung cancer and controls, and 14 miRNAs were significant for the comparison lung cancer and COPD. Screening target databases yielded over 400 putative targets for those 14 miRNAs. The predicted mRNA targets of three of the 14 miRNAs were significantly up-regulated in PBMCs of lung cancer patients compared to patients with non-malignant lung diseases. In conclusion, we showed that blood miRNA signatures are suitable to distinguish lung cancer from COPD.

Introduction

Worldwide more than one million people die each year from lung cancer making it the leading cause of cancer related deaths [1]. The five-year survival rate is among the lowest of all cancers. A major challenge is the prevailing lack of specific biomarkers for detection and monitoring of lung cancer. While single markers show a rather low sensitivity and specificity for the identification of lung cancer and other cancers, complex marker signatures often reach a significantly higher degree of accuracy. Most recently, microRNA (miRNA) expression profiles have been proposed as potential biomarkers for cancer diagnosis and treatment monitoring [2]. MicroRNAs are small (17–24 nt) non-coding RNA transcripts, involved in physiological and pathophysiological processes including cancer development through the regulation of gene expression [3], [4].

Based on the differential expression of miRNAs in tumors, miRNA expression signatures allow classification of many cancers, including lung cancer [5]. First attempts were made to differentiate specific subtypes of lung cancer such as primary lung cancer from metastatic lung tumors by miRNA signatures [6]. While the overwhelming majority of published miRNA signatures has been established on tumor cells, recent studies have identified specific miRNA signatures in sera and peripheral blood cells from cancer patients [7], [8], [9], [10], [11]. The remarkable stability of miRNAs makes miRNA signatures in body fluids especially intriguing for future minimally invasive diagnostics [10], [12]. Recently, we identified a microRNA expression signature in blood cells that allows for differentiation between lung cancer patients and healthy individuals [13]. To further evaluate the utility of blood based miRNA signatures for diagnostic purposes, it is important to compare cancer not only to healthy controls but also to other non-cancer diseases of the same organ. Here, we analyzed Chronic Obstructive Pulmonary Disease (COPD), a common pulmonary affliction encompassing chronic obstructive bronchitis and lung emphysema [14]. COPD is a global burden affecting 10–15% of adults older than 40 years [15]. COPD is not only a common co-morbidity but also precedes lung cancer in 50–90% of cases [16]. We compared the expression of 863 miRNAs in blood cells of lung cancer patients, patients suffering from COPD, and healthy individuals to further our knowledge of miRNA signatures in blood cells of lung cancer and COPD patients. In detail, we address the following questions: How similar are miRNA signatures among the aforementioned three groups? Can lung cancer be distinguished from COPD by blood based miRNA signatures? Which miRNAs contribute most to a separation of lung cancer from COPD? What are the predicted target genes of miRNAs differentially expressed in blood cells of patients with lung cancer and COPD. Overall, the study shows that blood miRNA signatures are suitable to distinguish lung cancer from COPD. Furthermore, we identified significant deregulated miRNAs and analyzed their putative target genes by database screening.