Abstract

Lung cancer is the leading cause of death from cancer in the US and the world¹. 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^{2, 3, 4}. Given that cigarette smoke creates a field of injury throughout the airway^{5, 6, 7, 8, 9, 10, 11}, 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 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.

1. The Pulmonary Center, Boston University Medical Center, 715 Albany Street, Boston, Massachusetts 02118, USA.
2. Bioinformatics Program, Boston University, 44 Cummington Street, Boston, Massachusetts 02215, USA.
3. Pulmonary Division, Department of Medicine, Lahey Clinic, 41 Mall Road, Burlington, Massachusetts 01805, USA.
4. St. James's Hospital and Trinity College, James's Street, Dublin, Ireland.
5. School of Public Health, Boston University, 715 Albany Street, Boston, Massachusetts 02118, USA.
6. Caritas St. Elizabeth's Medical Center and Tufts University School of Medicine, 736 Cambridge Street, Boston, Massachusetts 02135, USA.
7. Department of Genetics and Genomics, Boston University, 715 Albany Street, Boston, Massachusetts 02118, USA.
8. These authors contributed equally to this work.

Correspondence to: Avrum Spira¹ e-mail: aspira@bu.edu

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