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Comprehensive Genomic Characterization of Mantle Cell Lymphoma by Arezoo Mohajeri M.Sc., Lund University, 2012 B.Sc., Shiraz University, 2007 Thesis Submitted in Partial Fulfillment of the Requirements for the Degree of Master of Science in the Department of Molecular Biology and Biochemistry Faculty of Science © Arezoo Mohajeri SIMON FRASER UNIVERSITY Summer 2017 Copyright in this work rests with the author. Please ensure that any reproduction or re-use is done in accordance with the relevant national copyright legislation. Approval Name: Arezoo Mohajeri Degree: Master of Science Title: Comprehensive Genomic Characterization of Mantle Cell Lymphoma Examining Committee: Chair: Dr. Nancy Forde Associate Professor Department of Physics Dr. Mark Paetzel Senior Supervisor Professor Dr. Sharon Gorski Supervisor Professor Dr. Christian Steidl Supervisor Associate Professor Department of Pathology University of British Columbia Dr. Jack Chen Internal Examiner Professor Date Defended/Approved: June 29, 2017 Ethics Statement ii Abstract Mantle cell lymphoma (MCL) is a rare, aggressive and incurable type of cancer with a high incidence of systemic dissemination and poor survival outcomes. Understanding the genetics and biology of MCL is necessary for development of suitable biomarkers and therapies. A limited number of sequencing-based studies were performed on MCL recently, which improved the knowledge on causal mutations and molecular mechanisms of MCL. However, because of the small cohort sizes of these studies and use of outdated computational tools and databases have limited the findings of these studies. The objective of our study was to identify the genetic alterations and molecular pathways that are associated with the development, progression, and dissemination of MCL by using leading-edge bioinformatics tools, up-to-date molecular biology databases, and a large sample size. Presented here is a meta-analysis of whole exome sequencing data from tumor biopsies of 67 MCL patients, which resulted in the identification of several novel candidate driver genes that were targets of recurrent mutations in MCL such as SP140, S1PR1, PTPRD, HNRNPH1, LRP1B, FAT1, MAP3K14, and DST. Our analysis revealed four mutation hotspots in the first exon of MAP3K14 in MCL, five other types of B-cell lymphoma and leukemia, and canine lymphoma. We further proposed that the recurrent mutations of MAP3K14, which have activting effect on the protein, are potentially associated with a higher likelihood of relapse. This finding suggests that the recurrent mutations of MAP3K14 may have application for prediction of disease outcome, response to therapy, and the tanformation of the leukemic variant of MCL to the more aggressive subtype. Finally, we detected a significant accumulation of mutations in signaling pathways with roles in mechanisms of tumor metastasis, such as Rho GTPase mediated signaling, focal adhesion, G-protein coupled receptor signaling, cAMP-PKA signaling, ERK-MAPK signaling, ROBO-Slit signaling, and JAK-STAT signaling. These findings offer new insights into the understanding of the driver genes and molecular mechanisms underlying the aggressive clinical course of MCL and may have implications for the development of therapies. iii Keywords: Mantle cell lymphoma; whole exome sequencing; splicing; tumor microenvironment; migration; signaling pathways iv Dedication To my parents for their love, encouragements, endless support and countless sacrifices. v Preface This thesis is an original and unpublished work by Arezoo Mohajeri. The project was designed by Dr. Ryan Morin, Dr. Steidl, and myself. I wrote the entire thesis, obtained the results, and made the conclusions. The detailed descriptions of the contributions were included at the beginning of chapters 2, 3, and 4. vi Acknowledgements My graduate study in SFU was truly a life changing experience. Working with a fascinating project and having the kind supports of a number of people gave me the encouragements and persistence to finish this study successfully. I owe my deepest gratitude to my supervisors Dr. Mark Paetzel and Dr. Ryan Morin, and to my committee members, Dr. Sharon Gorski, and Dr. Christian Steidl, whom each supported me in various ways over the past two years. I am grateful to Dr. Ryan Morin for giving me the opportunity of working with this project and supervising me through parts of my thesis and research. I am grateful to Dr. Paetzel for his support, patience, guidance, and continuous optimism which made the completion of this work possible for me and to have provided me the opportunity to learn and grow. I am indebted to Dr. Gorski and Dr. Steidl who both generously have gone beyond their duties to guide me in my research. I am grateful to Dr. Gorski who was voluntarily offering her guidance and have supported me in various ways. I am thankful for her detailed proofreading of my thesis, and giving me insightful feedbacks on my thesis. I would like to express my sincere appreciations to Dr. Steidl for sharing his knowledge and intelligent ideas about my project, and for meeting with me and answering my questions during his busiest times. My research would not have had the same outcome without his guidance. I am also grateful for his kind supports and compassions during the difficult times of my study. I would also like to thank my internal examiners, Dr. Jack Chen, for his constructive and detailed comments, and the chair of my defense, Dr. Nancy Forde, for the supportive management of my defense. I am sincerely thankful to Dr. Jeff Derksen and Dr. Mary- Ellen Kelm who both have been tremendously supportive. vii I would like to express my gratitude to Daniel Fornika, our former head lab technician and a supportive friend, for training me in the lab, patiently answering my questions, and sharing his bioinformatics skills with me. I am also thankful to Bruno Grande for his great technical support and for guiding me at the start of my bioinformatics work in the lab. I would also like to thank the past and present lab members, Dr. Sepideh Massoumi Alamouti, Marco Albuquerque, Jordan Davidson, Jasleen Grewal, and Stephen Yu. I am grateful to Dr. Michel Leroux, for giving me the chance to experience teaching assistantship, while giving me confidence and encouragement. I am thankful to, Martin Krzywinski, Dr. Poh Tan, Dr. George Agnes, Persia Sayyari, Christina Batstone, Dr. Nick Harden, and Dr. David Baillie, who all helped me in one way or another through ups and downs of my study. I would like to thank my friends for their friendships, and emotional supports. I extend my appreciation to my parents, Tahere Zafari and Abbas Mohajeri, who have always believed in me, encouraged me, and supported me over the years. I am for ever indebted to my mom for her countless sacrifices and to my dad for his encouragements and supports. There are not enough words to describe how grateful I am to both of you. viii Table of Contents Approval ..............................................................................................................................2 Ethics Statement .................................................................................................................. ii Abstract .............................................................................................................................. iii Dedication ............................................................................................................................v Preface ................................................................................................................................ vi Acknowledgements ........................................................................................................... vii Table of Contents ............................................................................................................... ix List of Tables .................................................................................................................... xii List of Figures .................................................................................................................. xiii List of Abbreviations .........................................................................................................xv Chapter 1. Introduction .................................................................................................1 1.1. Cancer as a disease of the genome ..............................................................................1 1.2. Multistage development of cancer ..............................................................................1 1.3. Genetic variants in cancer ...........................................................................................3 Role of tumor suppressor genes and oncogenes in cancer ............................5 1.4. Hallmarks of cancer ....................................................................................................6 Sustained proliferation ..................................................................................6 Escaping growth inhibitors ............................................................................7 Resistance to cell death .................................................................................7 Immortality ....................................................................................................7 Sustained angiogenesis ..................................................................................8 Invasion and metastasis
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