title: Airway epithelial gene expression in the diagnostic evaluation of smokers with suspect lung cancer.
abstract: Lung cancer is the leading cause of death from cancer in the US and the world. The high mortality rate (80-85% within 5 years) results, in part, from a lack of effective tools to diagnose the disease at an early stage. Given that cigarette smoke creates a field of injury throughout the airway, we sought to determine if gene expression in histologically normal large-airway epithelial cells obtained at bronchoscopy from smokers with suspicion of lung cancer could be used as a lung cancer biomarker. Using a training set (n = 77) and gene-expression profiles from Affymetrix HG-U133A microarrays, we identified an 80-gene biomarker that distinguishes smokers with and without lung cancer. We tested the biomarker on an independent test set (n = 52), with an accuracy of 83% (80% sensitive, 84% specific), and on an additional validation set independently obtained from five medical centers (n = 35). Our biomarker had approximately 90% sensitivity for stage 1 cancer across all subjects. Combining cytopathology of lower airway cells obtained at bronchoscopy with the biomarker yielded 95% sensitivity and a 95% negative predictive value. These findings indicate that gene expression in cytologically normal large-airway epithelial cells can serve as a lung cancer biomarker, potentially owing to a cancer-specific airway-wide response to cigarette smoke.
authors.affiliation: The Pulmonary Center, Boston University Medical Center, 715 Albany Street, Boston, Massachusetts 02118, USA. aspira@bu.edu
authors.forename: Avrum
authors.initials: A
authors.lastname: Spira
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Beane
authors.forename: Vishal
authors.initials: V
authors.lastname: Shah
authors.forename: Katrina
authors.initials: K
authors.lastname: Steiling
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Frank
authors.initials: F
authors.lastname: Schembri
authors.forename: Sean
authors.initials: S
authors.lastname: Gilman
authors.forename: Yves-Martine
authors.initials: YM
authors.lastname: Dumas
authors.forename: Paul
authors.initials: P
authors.lastname: Calner
authors.forename: Paola
authors.initials: P
authors.lastname: Sebastiani
authors.forename: Sriram
authors.initials: S
authors.lastname: Sridhar
authors.forename: John
authors.initials: J
authors.lastname: Beamis
authors.forename: Carla
authors.initials: C
authors.lastname: Lamb
authors.forename: Timothy
authors.initials: T
authors.lastname: Anderson
authors.forename: Norman
authors.initials: N
authors.lastname: Gerry
authors.forename: Joseph
authors.initials: J
authors.lastname: Keane
authors.forename: Marc E
authors.initials: ME
authors.lastname: Lenburg
authors.forename: Jerome S
authors.initials: JS
authors.lastname: Brody
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D014408:Biomarkers, Tumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D011446:Prospective Studies; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics
chemical_list: D015415:Biomarkers; D014408:Biomarkers, Tumor