Gene Expression Profiling in Non-Small Cell Lung Cancer

This dissertation, "Gene Expression Profiling in Non-small Cell Lung Cancer" by Chi-leung, David, Lam, 林志良, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Gene Expression Profiling in Non-Small Cell Lung Cancer Submitted by LAM Chi Leung, David for the degree of Doctor of Philosophy at the University of Hong Kong in July 2007 Lung cancer is the worldwide leading cause of cancer morbidity and mortality and Hong Kong is no exception. In some Asian countries/regions including Hong Kong, there is an increasing trend of female, non-smokers and adenocarcinomas among patients with non-small cell lung cancer (NSCLC). Surgical resection for early stage NSCLC remains as the only curative treatment while modern chemoirradiation improves the survival of advanced stage NSCLC patients only marginally. In recent years, molecular targeted therapy has become the focus of clinical trials for advanced stage NSCLC, with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) being one promising therapeutic agent. Clinical characteristics such as female, non-smoker, tumor with activating EGFR gene mutations, adenocarcinoma histology and Asian origin are independent predictors of clinical response to EGFR-TKI. Hong Kong provides an appropriate context for studying the pathogenesis and 1chemotherapeutics in Chinese female non-smokers with lung cancer. The hypotheses being tested were that there is differential gene expression associated with different clinical phenotypes i.e. gender, smoking habits, and EGFR gene mutation status in NSCLC from local Chinese patients. To test these, the gene expression profiles of resected primary lung tumors, normal lung tissues, lung cancer cell lines and normal human bronchial epithelial cells (NHBECs), were analyzed. First, four new lung adenocarcinomas cell lines (HKULC 1 - 4), two from female non-smokers and two from male smokers, were established from local Chinese. They were characterized with morphological and immunohistochemical studies, growth kinetics, and gene expression profiling with microarrays. Differentially expressed genes related to the regulation of cellular proliferation and to EGFR gene exon 18 - 21 mutations were identified. These new cell lines provide tools for future research in lung cancer and for comparisons with research findings from other ethnic groups. Second, gene expression profiling with microarrays was performed for 49 lung adenocarcinomas and 9 normal lung tissues collected from local Chinese. Unsupervised hierarchical clustering revealed stable clusters of lung adenocarcinomas versus normal lung tissues, female non-smokers and tumors bearing EGFR gene mutation at exons 18 - 21. Differential gene expression and molecular classifiers were identified and correlated clinical characteristics. The results were validated with independent test data sets from published microarray data on NSCLC. These gene expression profiling data on lung adenocarcinomas, female non-smokers and EGFR gene mutation status provide 2information for candidate gene selection for further research on lung cancer in Chinese female non-smokers. Third, significant differences were found in the expression levels of nicotinic acetylcholine receptor (nAChR) subunit genes, α6 and β3, between tumors arising from smokers and non-smokers, adjusted for the effects of gender. Gene expression signatures were found associated with high nAChR α6β3 gene expression. Reversible elevations of the expression levels of nAChR α1, α5 and α7 subunit genes were found in