ReviewReview of recent developments in determining volatile organic compounds in exhaled breath as biomarkers for lung cancer diagnosis
Graphical abstract
Introduction
Due to its high, and rising, morbidity and mortality, lung cancer has become the leading cause of cancer deaths globally [1], [2], [3]. Approximately 14.1 million people were diagnosed with cancer in 2012, with 8.2 million deaths worldwide [4], [5]. Of these 14.1 million cases, 1.8 million (13%) were lung cancer. Increases in various environmental risk factors are expected to induce rises in annual numbers of new cancer cases and associated deaths to 24 and 14.6 million, respectively, by 2035 [6]. Therefore, there is a clear need to develop new methods for preventing, detecting, and treating cancer [7].
Cancer screening is important for detecting the disease at early stages, to avoid metastatic spread, thereby increasing the rate of successful treatment. New screening methods that are highly sensitive, specific, and fast are needed for early diagnosis, prognosis, monitoring pathogenesis, and targeted therapy [8], [9], [10], [11], [12]. The search for new diagnostic methods and tools that can meet these needs is increasingly attracting the attention of researchers in interdisciplinary fields, such as biomedicine, biophysics, and analytical chemistry [13].
Lung cancers are usually categorized as one of two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with the latter representing a large majority (85–90%) of cases [14]. Regardless of histopathological subtype, 88% of lung cancer patients die within 5 years of diagnosis, suggesting that delayed diagnosis is a significant problem [15]. Currently, various combinations of multiple techniques, including radiology, endoscopy, and molecular biotechnology, are used to detect lung cancer at early stages [6]. These techniques, and their diagnostic applications, are briefly listed and described in Table 1.
All these methods are useful at various stages of diagnosis and have specific merits. However, in early stages of the disease it remains difficult to distinguish lung cancer from benign nodules based purely on morphological criteria. This results in frequent false positives and unnecessary surgical resection [10], [11], [17], [20], [21]. Detecting volatile organic compounds (VOCs) in the exhaled breath of patients may offer a rapid, noninvasive, inexpensive and more specific alternative [37]. However, the success of VOC-based diagnosis depends on the identification and validation of one or more chemical species that can serve as accurate biomarkers of lung cancer [38], [39].
Recent developments in sampling techniques and detection methods have been discussed extensively in review articles written by Sun et al. and Saalberg et al. [40], [41]. Techniques for determining VOCs, including gas chromatography (GC) or mass spectrometry (MS) based and sensor-based techniques, have been described in detail [40]. In contrast, this review primarily addresses the identification of VOCs, and we aim to highlight research focused on the discovery of biomarkers for early screening and diagnosis of lung cancer. Literature published up to the end of May 2017 is included, and the main compounds considered relevant to lung cancer diagnosis are listed. The reported sensitivity and specificity of these compounds are also summarized.
Section snippets
Determination of VOC as a tool for disease diagnosis
The smell of human breath has been for used for diagnostic purposes since ancient times. The possibility of using it for detecting lung cancer has also been investigated for many years, and greatly boosted by rapid recent developments in metabolomics as a new branch (together with genomics, transcriptomics, and proteomics) of systems biology [38]. Metabolomic analysis of exhaled breath generally focuses on the quantitative determination of metabolites with low molecular weights (less than 1000
Conclusion and perspectives
Lung cancer is one of the most prevalent forms of cancer worldwide, with a high mortality rate. Therefore, screening for lung cancer at an early stage is vital for improving survival rates, as well as improving patients' quality of life. In the past 50 years, breath analysis has developed into an established tool for the clinical detection of early stage lung cancer, based on known molecular pathways contributing to the progression of the disease. The development of new techniques and
Acknowledgements
The authors thank Dr. E. Jane Maxwell for important discussions and editing of this manuscript. This work was supported by the Natural Sciences and Engineering Research Council (NSERC) of Canada, and JZ and ZH acknowledge fellowships from the Canadian MITACS Accelerate Program.
Jiemin Zhou obtained her MD in Clinical Medicine from Nanjing Medical University in 2011, and completed her residency at People's Hospital of Jiangsu Province, Nanjing, China, in 2012. Currently, Dr. Zhou is an MSc student in the Faculty of Pharmaceutical Sciences at the University of British Columbia, Vancouver, BC, Canada.
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Jiemin Zhou obtained her MD in Clinical Medicine from Nanjing Medical University in 2011, and completed her residency at People's Hospital of Jiangsu Province, Nanjing, China, in 2012. Currently, Dr. Zhou is an MSc student in the Faculty of Pharmaceutical Sciences at the University of British Columbia, Vancouver, BC, Canada.
Zi-Ao Huang obtained his BSc and MSc (under the supervision of Prof. Haiping Xia) in Chemistry from Xiamen University in 2013 and 2016, respectively. He is currently a PhD student in the Department of Chemistry of the University of British Columbia.
Ujendra Kumar: received his Ph.D. in Zoology from University of Jodhpur, India. He is presently a Professor in the Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada. His research interests focus on structure, function and regulation of somatostatin receptors in neurodegenerative diseases and cancer biology.
David Da Yong Chen received his BSc from Xiamen University, China, and Ph.D. in Chemistry from University of Alberta. After a short stint as a Postdoctoral Fellow in Chemistry and the Department of Medical Microbiology and Infectious Diseases, University of Alberta, he joined the faculty in the Chemistry Department at the University of British Columbia in July 1994. Dr. Chen is currently a full professor of Chemistry, faculty of Science, as well as an Associate Member of the UBC Department of Anesthesiology, Pharmacology & Therapeutics in the Faculty of Medicine, UBC. He is the recipient of the 2002 Royal Society of Chemistry (RSC) Award in Analytical Separation Methods, and the Charles McDowell Award for Excellence in Research in 2003, a gold medal given to the most outstanding young scientist at UBC. For his contribution in analytical chemistry, Dr. Chen was awarded the W. A. E. McBryde Medal and the Maxxam Award by the Canadian Society for Chemistry in 2008 and 2015, respectively.
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These two authors contributed equally to this paper.