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Download The MOLECULAR MECHANISMS UNDERLYING TUMORIGENESIS OF NON-SMALL CELL LUNG CANCER SUBTYPES by Larissa A. Pikor BScH., BPHE, Queen's University at Kingston, 2009 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Interdisciplinary Oncology) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) July 2014 © Larissa Pikor, 2014 Abstract Lung cancer is the leading cause of cancer death in Canada and worldwide. A late stage of diagnosis in conjunction with a lack of effective treatment options are largely responsible for the poor survival rates of lung cancer. Histological subtypes of lung cancer are known to respond differently to standard therapies, suggesting they are distinct diseases. A better understanding of the molecular alterations and underlying biology of lung cancer subtypes is therefore necessary for the development of novel detection and treatment strategies in order to improve patient prognosis. We hypothesize that lung adenocarcinoma (AC) and squamous cell carcinoma (SqCC) arise through disparate patterns of molecular alterations and that these differences underlie unique biological mechanisms that contribute to subtype development, phenotypes and response to therapy. In this thesis, I apply multidimensional integrative 'omics approaches to characterize the genomic and epigenomic landscapes of AC and SqCC and elucidate differential patterns of alterations and subtype specific gene disruptions causal to NSCLC and the development of specific subtypes. The integration of DNA copy number, methylation, gene and miRNA expression data on AC and SqCC tumors and patient matched non-malignant tissue identified several subtype specific alterations and revealed unique oncogenic pathways associated with AC and SqCC that can be successfully targeted by existing therapies. By combining genomic analyses with manipulation of candidate genes in vitro and in vivo, we validated the contribution of candidate genes to tumorigenesis and determined the mechanisms through which they contribute to disease pathogenesis. In addition to revealing differentially disrupted genes and pathways we also identified numerous alterations common to both subtypes. Collectively, this work has further characterized the landscape of molecular alterations that define AC and SqCC, and the mechanisms through which these alterations contribute to subtype tumorigenesis. This work has identified novel candidate genes involved in subtype tumorigenesis as well as miRNAs with potential as diagnostic biomarkers for lung cancer. Taken together, these findings underscore the importance of tailoring treatment strategies to the histological subtype based on the underlying biology of that subtype. ii Preface The research in this thesis was conducted with ethics approval from the UBC Research Ethics Board, Certificate Numbers: EDRN H09-00008, CCSRI H09-00934, W81XW-10-1-0634 Portions of Chapter 1 have been published as: 1. [Pikor LA], Ramnarine VR, Lam S, Lam WL (2013). Genetic alterations defining NSCLC subtypes and their therapeutic implications. Lung Cancer 82(2):179-89. 2. Enfield KSS, [Pikor LA], Martinez VD, Lam WL (2012). Mechanistic roles of non-coding RNAs in lung cancer biology and their clinical implications. Genetics Research International 2012:737416 Chapters 2,3 and 4 were co-authored as manuscripts for publication. The following author lists apply for these chapters: A version of Chapter 2 has been published and presented by Will Lockwood in his thesis. Lockwood WW, Wilson IM, Coe BP, Chari R, [Pikor LA], Thu KL, Yee J, English J, Murray N, Tsao MS, Minna J, Gazdar AF, MacAulay CE, Lam S, Lam WL (2012). Divergent genomic and epigenomic landscapes of lung cancer subtypes underscore the selection of different oncogenic pathways during tumor development. PLoS One 2012;7(5). This chapter presents the necessary description of datasets (genomic, epigenomic and expression) used in subsequent chapters to investigate the molecular biology of lung cancer subtypes. As this chapter is quite detailed, it was included as a data chapter rather than integrated into the introduction. I conducted and analyzed dose response experiments, performed SNP6 data analysis and wrote sections of the manuscript pertaining to the experiments I performed. A version of Chapter 3 has been published. Thu KL, [Pikor LA], Chari R, Wilson IM, MacAulay CE, Gazdar AF, Lam S, Lam WL, Lockwood WW (2011) Disruption of KEAP1/CUL3 E3 ubiquitin ligase complex components is a key mechanism for NFkB pathway activation in lung cancer. Journal of Thoracic Oncology 6(9):1521-9. I was co-first author of this manuscript and iii participated in the design of the study, performed experiments, data analysis and interpretation of the results, and wrote and edited the manuscript. R Chari and IM Wilson contributed to project design and data analysis. Patient samples were collected by S. Lam and cell lines provided by AF Gazdar. WL Lam and WW Lockwood oversaw the project. A version of Chapter 4 has been published. [Pikor LA], Lockwood WW, Thu KL, Vucic EA, Chari R, Gazdar AF, Lam S, Lam WL (2013). YEATS4 is a novel oncogene amplified in non- small cell lung cancer that regulates the p53 pathway. Cancer Research 73(24):7301-12. I designed the study, conducted the experiments, performed data analysis and interpretation and wrote the manuscript. Patient samples were collected by S. Lam, cell lines were provided by AF Gazdar and mouse work was performed by WW Lockwood. KL Thu, EA Vucic and R Chari aided in data analysis and interpretation of results. A version of Chapter 5 is being prepared for publication. [Pikor LA], Kennett JY, Thu KL, Vucic EA, Lam S, Lam WL (2014). Characterizing miRNA expression in lung adenocarcinoma and squamous cell carcinoma identifies miR-944 and miR-1287 as subtype specific miRNAs. I conceived the experimental design for this project, performed data analysis and interpretation, in vitro experiments and wrote the manuscript. JY Kennett provided flow cytometry technical assistance and KL Thu and EA Vucic aided in data analysis, project design and edited the manuscript. iv Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iii Table of Contents ...........................................................................................................................v List of Tables ................................................................................................................................ xi List of Figures .............................................................................................................................. xii List of Abbreviations ................................................................................................................. xiii Acknowledgements ......................................................................................................................xv Dedication ................................................................................................................................... xvi Chapter 1: Introduction ................................................................................................................1 1.1 Lung cancer ..................................................................................................................... 1 1.2 Lung cancer subtypes/ histopathology of NSCLC.......................................................... 1 1.3 Molecular pathology of lung cancer ............................................................................... 3 1.3.1 Gene expression .......................................................................................................... 3 1.3.2 Copy number alterations ............................................................................................. 4 1.3.3 DNA methylation ........................................................................................................ 4 1.3.4 DNA mutations ........................................................................................................... 5 1.3.5 Non-coding RNAs ...................................................................................................... 5 1.4 Integrative genomics and a systems biology approach to gene discovery ...................... 6 1.5 Thesis theme and rationale.............................................................................................. 7 1.6 Objectives and hypotheses .............................................................................................. 8 1.7 Specific aims and thesis outline ...................................................................................... 8 Chapter 2: Divergent genomic and epigenomic landscapes underscore the selection of different oncogenic pathways during subtype development ....................................................11 2.1 Introduction ................................................................................................................... 11 2.2 Methods......................................................................................................................... 12 2.2.1 DNA samples ...........................................................................................................
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