Abstract 4721: Airway basal cell signature predicts aggressive phenotype of human lung adenocarcinoma
Authors: Tomoya Fukui, Renat Shaykhiev, Rui Wang, Rachel K. Zwick, Neil R. Hackett, Robert J. Downey, Ronald G. Crystal
Journal: Cancer Research (2011)

Abstract Molecular changes in the airway epithelium are central to the pathogenesis of lung cancer. Human airway epithelium is composed of 4 major cell types including ciliated, columnar, secretory and basal cells (BC), with the BC representing the stem/progenitor population. Although BC have been considered as putative tumor-initiating cells of squamous cell lung carcinoma, there is little evidence with regard to the contribution of BC to human lung adenocarcinoma (ADC). Given that a subset of smokers develop ADC and smoking increases BC proliferation, we hypothesized that BC-associated molecular features are enriched in ADC smokers contributing to a distinct, more aggressive clinical phenotype. BC were purified from the freshly isolated airway epithelium of healthy individuals by a cell culture-based method. Genome-wide gene expression analyses of BC (n=4 nonsmokers; n=4 smokers) compared with the intact large airway epithelium (LAE; n=21 nonsmokers; n=31 smokers) were performed separately for nonsmokers and smokers using HG-U133 Plus 2.0 array to identify the normal and smoking-associated BC signatures, respectively, based on the following criteria: (1) P call of “Present” in ≥50% of BC samples; (2) p&amp;lt;0.01 with Benjamini-Hochberg correction; and (3) &amp;gt;5-fold higher expression level in BC vs complete airway epithelium. ADC samples (n=167) were derived from patients undergoing lung resection. ADC genes related to smoking status were identified by genome-wide comparison of ADC smokers (ADC-S; n=131) and ADC nonsmokers (ADC-NS; n=36). Multivariate survival analysis was performed using Cox proportional hazards model. The BC signature included 1,623 and 2,408 probe sets in healthy nonsmokers and smokers, respectively. Among the ADC-S up-regulated genes, 44% (46 of 105) overlapped with BC signature genes, including 32 smoking-associated BC signature genes compared to 25 BC signature genes among 614 ADC-NS up-regulated genes (4%). ADC patients with high expression of the ADC-S up-regulated BC signature (n=97) exhibited a distinct clinical phenotype with a poorer tumor differentiation grade (p&amp;lt;0.001), lower frequency of prognostically favorable bronchoalveolar carcinoma features (p&amp;lt;0.02), shorter survival (p&amp;lt;0.002) and higher frequency of TP53 mutations (p&amp;lt;0.002) compared to ADC patients with low expression of the BC signature genes (n=70). Human airway BC signature is enriched in ADC in association with smoking status and aggressive clinical phenotype consistent with the hypothesis that airway BC represent a putative cell-of-origin and hence, a therapeutic target for a subset of aggressive lung ADC associated with smoking. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4721. doi:10.1158/1538-7445.AM2011-4721