Lung cancer mortality is the leading cause of cancer death in the United States in part because diagnosis occurs after regional or distant metastasis of the disease. Identifying effective early detection biomarkers is crucial for improving lung cancer clinical management. Moreover, molecular biomarkers for early disease detection may provide insight into the molecular pathways associated with disease development and progression. Our lab has shown that smoking-induced gene expression alterations are mirrored in the epithelia of the mainstem bronchus, buccal and nasal cavity. We have additionally demonstrated that gene-expression profiles in cytologically normal mainstem bronchial epithelium can serve as an early diagnostic biomarker for lung cancer. Here we expand on our previous work by spatially mapping the molecular field of injury throughout the entire respiratory tract in smokers with lung cancer. Using Affymetrix Gene ST 2.0 arrays, we profiled genome-wide gene-expression in 1) lung lesions and adjacent normal lung obtained from smokers undergoing surgical resection, 2) epithelial brushings obtained at intraoperative bronchoscopy from the nasal epithelium, main carina and ipsilateral and contralateral proximal and distal bronchi (relative to the location of the resected lung lesion), and 3) epithelial brushings obtained at lobectomy from sub-segmental bronchus (adjacent to tumor). Linear modeling approaches comparing the airways and tumors of patients with cancer to those with benign lung disease were used to explore relationships in cancer-specific gene-expression alterations across sites within the respiratory tract. We found that genes upregulated in the small airways leading to the tumor were enriched in genes upregulated in the mainstem bronchus and main carina of smokers with lung cancer. In addition, genes upregulated in the bronchus and main carina of smokers with lung cancer showed enrichment among cancer associated genes elevated in the nose. Furthermore, a linear mixed effects model uncovered genes and pathways which change in expression in a gradient-like manner as distance from the tumor increases. Our findings suggest that the molecular field of injury encompasses airway-wide alterations throughout the entire respiratory tract of smokers with lung cancer as well as gradient profiles that change with respect to proximity of the nearby tumor. These molecular alterations may ultimately serve as early detection biomarkers for lung cancer and provide new insights into early stages of lung carcinogenesis.

Citation Format: Rebecca Kusko, Christina Anderlind, Gerald Wang, Sherry Zhang, W. Dean Wallace, Tonya Wasler, Michael Ebright, Melinda M. Garcia, Rosana Eisenberg, Gina Lee, Gang Liu, David Elashoff, Neda Kalhor, Cesar Moran, Reza Mehran, Junya Fujimoto, Pierre P. Massion, Steven Dubinett, Ignacio Wistuba, Marc Lenburg, Humam Kadara, Avrum Spira. Mapping the airway-wide molecular field of injury in smokers with lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2352. doi:10.1158/1538-7445.AM2014-2352