Specific peripheral miRNA profiles for distinguishing 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.
Section snippets
Materials and methods
See Online Data Supplement for additional methologic details.
Results
Using the Geniom Real Time Analyzer Platform, we analyzed the expression of the 863 human miRNAs annotated in miRBase version 12.0. In total, we screened the miRNA expression in blood cells from 71 different individuals, including 28 lung cancer patients, 24 COPD patients, and 19 healthy controls. The group of lung cancer patients included both patients without COPD (n = 15) and with COPD (n = 13).
Intensity values of all analyzed miRNAs and samples were subjected to quantile normalization prior to
Discussion
Here, we compared miRNA expression profiles of peripheral blood cells in patients with lung cancer, patients with COPD, and healthy individuals. As expected, the miRNA signatures of lung cancer patients and COPD patients were more similar to each other than to the signature of healthy controls as revealed by principle components analysis. However, the miRNA signatures of blood cells were still so different between lung cancer patients and COPD patients as to permit separation between these
Conclusion
In conclusion, we showed for the first time that lung cancer patients are distinguishable from COPD patients by their peripheral miRNA expression profile with high accuracy. Therefore, our proof-of-principle study strengthens the hypothesis that blood based miRNA signatures might be potential cancer biomarker. In combination with imaging techniques blood based miRNA signatures might contribute to an earlier lung cancer detection and thus improve the survival rates. Prospective studies will
Conflict of interest
Andreas Keller and Anne Borries are employees of febit biomed GmbH.
Acknowledgements
We acknowledge the technical assistance of Hannah Schroers and Pamela Haeberle. We thank Dr. Jack Leonard for carefully proof-reading and correcting the manuscript.
Funding: This work was supported by funding of the German Ministry of Research Education (BMBF) under contract 01EX0806, the Hedwig-Stalter foundation, Deutsche Forschungsgemeinschaft (DFG, LE2783/1-1), and HOMFOR 2010.
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2017, NeurocomputingCitation Excerpt :Some discarded miRNAs with relatively smaller mean IHT ranks but big standard deviation were also shown in Table 2. Fourteen of the top-15 miRNAs listed in Table 2 were also included in Table 3 that consists of the significant miRNAs for the differentiation between lung cancer and COPD found in [12]. In other words, the findings of [12] are confirmed here independently by a very different method, which may enhance attentions to these findings.
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Both authors equally contributed to this work.