Abstract 2367: Transcriptomic architecture of the airway field cancerization in early-stage non-small cell lung cancer .

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Earlier work has identified in lung cancer a field cancerization (FC) phenomenon in which tumors and adjacent normal appearing tissues share specific molecular abnormalities (e.g., loss of heterozygosity) that may be highly pertinent to cancer pathogenesis. We sought to characterize the global molecular airway FC adjacent to early-stage non-small cell lung cancer (NSCLC) in an attempt to unravel profiles that may help to explain the development of the disease. We performed whole-transcript expression profiling of a set of resected early-stage NSCLC specimens (n=20 patients) with matched histologically normal airways of varying distance from the tumor and paired uninvolved normal lung tissue (n=194 samples). Using linear mixed-effects models, we derived FC profiles signifying genes concordantly differentially expressed between tumors and airways compared to normal lung tissues. Gene set enrichment analysis demonstrated that a subset of the genes (n=299) was significantly and congruently modulated between large airways of smokers with and without lung cancer. We then questioned whether the airway FC exhibits site from tumor-dependent expression patterns. Ordinal regression analysis identified airway profiles (n=422 genes) that were significantly progressively expressed by distance from tumors and topologically organized into canonical cancer-associated pathways, such as eukaryotic initiation factor, p70S6K kinase, polo-like kinase and mammalian target of rapamycin signaling (all p<0.001). In addition, the site-dependent airway profiles recapitulated NSCLC expression patterns and were concordantly modulated between tumors and uninvolved normal lung tissues pinpointing their probable roles in lung cancer pathogenesis. Quantitative real-time PCR (QRTPCR) analysis confirmed the differential expression of FC markers selected by both pathways analysis and statistical criteria. Notably, lysosome associated protein transmembrane 4 beta (LAPTM4B), a putative oncogene with no known role in lung carcinogenesis, was among the top 5 site-dependent FC markers and was significantly elevated in NSCLC and immortalized bronchial epithelial cell lines compared to normal cells. Furthermore, transient or stable knockdown of LAPTM4B by RNA interference decreased NSCLC cell growth as well as anchorage-dependent and -independent colony formation. In conclusion, our efforts in understanding the adjacent molecular FC in NSCLC unraveled airway profiles that 1) are, in part, relevant to lung cancer detection; 2) are modulated by distance from corresponding tumors; 3) recapitulate NSCLC expression patterns and 4) harbor markers engaged in mediating the lung malignant phenotype. Profiling the adjacent airway FC in conjunction with tumors, may provide additional insights into the molecular pathology of NSCLC. Funded in part by Department of Defense award W81XWH-10-1-1007. Citation Format: Yuho Maki, Junya Fujimoto, Suk-Young Yoo, Adam Gower, Li Shen, Melinda M. Garcia, Mohamed Kabbout, Chi-Wan Chow, Waun Ki Hong, Neda Kalhor, Jing Wang, Cesar Moran, Avrum Spira, Kevin R. Coombes, Ignacio I. Wistuba, Humam Kadara. Transcriptomic architecture of the airway field cancerization in early-stage non-small cell lung cancer . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2367. doi:10.1158/1538-7445.AM2013-2367