Abstract 1063: Examining early events in carcinogenesis by profiling premalignant lesions in the airways of patients with lung squamous cell carcinomas.

Little is known about the mechanisms involved in the initiation and progression of lung cancer, even though lung cancer contributes to the most cancer-related deaths in the world. Lung squamous cell carcinoma (SCC) is the second most common histological subtype, and often arises centrally from a large airway, usually a bronchus. It is believed that squamous lung cancer develops through a series of genetic and epigenetic changes that alter the normal epithelium from squamous metaplasia, to dysplasia, then carcinoma in situ, and finally to invasive SCC. Although there have been studies devoted to discovering the genetic and molecular changes observed in the tumor, few studies have contributed to the investigation of squamous metaplasia or dysplasia. To better understand carcinogenesis in the lung, especially those steps involved in the early and precancerous stages, a precise study of the biology of premalignant lesions is needed. To achieve this, we used laser capture microdissection to specifically isolate normal airway basal cells, premalignant cells, and tumor regions within individual patients with squamous lung cancer. The RNAs obtained were successfully sequenced using Next Generation Sequencing. Using two different statistical models of linear mixed effects and edgeR (empirical analysis of digital gene expression data in R), we identified a list of genes that were differentially expressed in the premalignant lesions and in tumors when compared to the normal basal cells. We were able to validate at RNA and protein levels several of the genes identified to have higher expression in premalignant lesions and tumors than in normal basal cells. We performed a gene network analysis and found that some of these genes are known to be involved in the development of other squamous tumors, cell cycle progression, cell death and survival, and cellular assembly, while some genes are uncharacterized or novel to cancer development. We also discovered that, even though TP53 RNA expression was not significantly different among normal, premalignant, and tumor cells, several proteins that were upregulated in the premalignant lesions were known to target TP53 protein for degradation, cytoplasmic localization, or disruption of its function. This suggests that the disruption of TP53 pathway began at the premalignant stage of carcinogenesis, and persisted through the formation of invasive carcinoma. This is the first comprehensive gene expression profiling of airway premalignant lesions and allows us to study the biology behind these lesions in the setting of carcinogenesis. Citation Format: Aik T. Ooi, Adam Gower, Kelvin Zhang, Jessica Vick, Longsheng Hong, Michael Fishbein, Brian Nagao, W Dean Wallace, David Elashoff, Marc Lenburg, Steven Dubinett, Avrum Spira, Brigitte Gomperts. Examining early events in carcinogenesis by profiling premalignant lesions in the airways of patients with lung squamous cell carcinomas. [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 1063. doi:10.1158/1538-7445.AM2013-1063