Abstract 1721: Gene expression profiling of lung tumors and matched normal airways reveals common and disparate aberrant pathways in squamous cell carcinoma and adenocarcinoma development and potential markers for detection and targets for chemoprevention in early stage lung cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Detection and chemoprevention of non-small cell lung cancer (NSCLC) have been unsuccessful in part due to our limited knowledge of the pathogenesis of the disease. It has been suggested that normal airway epithelia share molecular abnormalities with tumors and may serve as progenitors for lung malignancies. We sought to analyze molecular profiles of lung adenocarcinomas and squamous cell carcinomas (SCCs), two major subtypes of NSCLC, and matched normal airways to elucidate aberrant expression patterns in early phases of lung tumorigenesis. All specimens were obtained from primary early stage NSCLC consented patients who did not receive neoadjuvant therapy (n=20). We profiled RNA isolated from tumors and normal lung as well as from brushings of multiple matched airways that were histologically confirmed to lack neoplastic or preneoplastic cells (n=194). Expression signatures signifying genes significantly and concurrently differentially expressed between both tumors and airways compared to normal lung tissue (tumor-airway-normal/TAN signatures) were then derived independently for SCC and smoker adenocarcinoma cases and were comprised of 1,803 and 1,938 genes, respectively. The TAN signatures effectively clustered tumor and airways from normal lung samples (p<0.001). Further analysis showed that a subset of the genes separated SCC- and adenocarcinoma-adjacent airways. Moreover, pathways and gene-network analysis using Ingenuity pathways software highlighted similarities and differences in pathway modulation between airway epithelial fields of SCCs and adenocarcinomas. Embryonic stem cell and eicosanoid signaling pathways were most significantly modulated among those common to both TAN signatures (p<0.001). Retinoic acid receptor and stem cell signaling pathways mediated by NANOG and lineage oncogene SOX2 were most significantly modulated in the SCC TAN signature, whereas NF-kB and PTEN signaling pathways were most prevalent in the adenocarcinoma TAN airway signature (all p<0.001). Gene networks mediated by lineage oncogene NKX2-1/TITF-1 down-regulation and TP63 up-regulation, and networks mediated by increased expression of the MET and ERBB2 oncogenes were predominantly functionally modulated in the SCC and adenocarcinoma TAN signatures, respectively. Quantitative PCR analysis confirmed up-regulation of MET in adenocarcinomas and normal airways compared to normal lung. These findings highlight expression patterns and pathways that are deregulated differentially in the pathogenesis of lung adenocarcinomas and SCCs and thus offer detection markers as well as therapeutic targets to guide personalized chemoprevention in early stage NSCLC patients. Supported by DoD grant W81XWH-10-1-1007. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1721. doi:1538-7445.AM2012-1721