Abstract 4721: Airway basal cell signature predicts aggressive phenotype of human lung adenocarcinoma

Abstract

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<0.01 with Benjamini-Hochberg correction; and (3) >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<0.001), lower frequency of prognostically favorable bronchoalveolar carcinoma features (p<0.02), shorter survival (p<0.002) and higher frequency of TP53 mutations (p<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