© 2008 American Thoracic Society doi: 10.1164/rccm.200710-1604ED
Waiting to Exhale
Columbia University College of Physicians and Surgeons Over 75% of new lung cancer diagnoses are in patients who present with distant or regional metastatic disease (1). Early diagnosis remains an elusive goal. Enthusiasm for imaging by computed tomography (CT) scan and by fluorescent bronchoscopy is lowered by concerns of low specificity and overdiagnosis (2, 3). Enthusiasm for proteomic analysis of blood specimens is tempered by challenges presented by blood proteome complexity (4); and the utility of sputum analysis is diminished by difficulties in specimen acquisition. Compared with other biological specimens, exhaled breath condensate (EBC) is simple to collect and process and is available from all individuals. In a previous study, Carpagnano and colleagues reported that microsatellite alterations representing four loci on chromosome 3p were detected more frequently in the EBC DNA of patients with non–small cell lung cancer compared with EBC acquired from smokers without lung cancer (5). Microsatellites are short, polymorphic, tandem repeat DNA sequences that are dispersed throughout the genome. They are subject to allelic loss (loss of heterozygosity [LOH]) and to changes of microsatellite length (microsatellite instability [MI]) in disease states such as lung cancer (6, 7). LOH and MI are not specific for lung cancer since they are detectable in the airway epithelium of smokers without cancer (8), but taken together these reports and others suggest that the presence of LOH in the lung or blood may be a molecular dosimeter of cigarette carcinogen exposure that correlates with lung cancer risk (8). In this issue of the Journal (pp. 337–341), Carpagnano and colleagues extend their previous findings to now ask if microsatellite alterations in EBC are similar to those in lung tissue from the same individuals (9). Using the same chromosomal 3p microsatellite primers as in the prior study, they examined alterations in EBC, lung tissue, and white blood cell DNA acquired from 41 patients with non–small cell lung cancer and from 18 patients with nonmalignant lung diseases. This analysis presents three important results. First, the study confirms that the prevalence of microsatellite alterations in EBC of patients with cancer is higher than in control subjects. Second, microsatellite alterations appear to be more prevalent in heavy smokers compared with other smokers, although this analysis may be confounded by disease and by classification bias. Third, Table 3 in the article shows the striking finding that, in each instance, microsatellite alterations in EBC matched those detected in lung tissue. What are we to make of this 100% concordance between EBC and the lung? Carpagnano and colleagues suggest that this result indicates the "organ-specificity of 3p microsatellite alterations." This is not necessarily true. Rather, the findings suggest that EBC microsatellite 3p alterations mirror those in the lung and may be a sensitive indicator of pulmonary DNA alterations. We do not know the source of DNA in EBC within the aerodigestive tract and we do not expect it to be specific for lung cancer. However, lung tumor specificity is not required for this assay to be useful or important. For example, Spira and colleagues recently reported gene expression alterations shared by tumor and by nonmalignant lung that were significantly associated with the presence of cancer within an individual smoker (10). Thus, the promise of the EBC assay is that it may provide a simple, noninvasive test that identifies individuals potentially harboring DNA alterations that signify a high risk for lung cancer. Much work lies ahead before the promise of this biomarker can be considered for clinical practice. As suggested by Pepe and colleagues, biomarker development and validation are composed of five conceptual phases (11): (1) preclinical exploratory studies to identify biomarkers unique to cancer, (2) clinical assay development and establishment of assay reproducibility, (3) retrospective longitudinal studies, (4) prospective screening studies, and (5) cancer control studies. Thus far, Carpagnano and colleagues have developed a clinical assay that identifies chromosome 3p microsatellite DNA alterations in EBC and in lung tissue of patients with non–small cell lung cancer. The detection of DNA alterations in EBC is a promising approach for lung cancer risk assessment and early diagnosis. However, until the EBC DNA microsatellite alteration results are reproduced and validated, we need to hold our breath. FOOTNOTES Conflict of Interest Statement: C.A.P. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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