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Molecular Characterisation of Renal Cell Carcinoma and Related Disorders

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Molecular Characterisation of Renal Cell Carcinoma and Related Disorders MOLECULAR CHARACTERISATION OF RENAL CELL CARCINOMA AND RELATED DISORDERS by MARIAM JAFRI A thesis submitted to the University of Birmingham for the degree of DOCTOR OF PHILOSOPHY School of Clinical and Experimental Medicine College of Medical and Dentistry September 2015 University of Birmingham Research Archive e-theses repository This unpublished thesis/dissertation is copyright of the author and/or third parties. The intellectual property rights of the author or third parties in respect of this work are as defined by The Copyright Designs and Patents Act 1988 or as modified by any successor legislation. Any use made of information contained in this thesis/dissertation must be in accordance with that legislation and must be properly acknowledged. Further distribution or reproduction in any format is prohibited without the permission of the copyright holder. ABSTRACT Over the last two decades genetic advances have provided novel insights into the molecular basis of familial and sporadic cancers and provided the basis for the development of novel therapeutic approaches. For example, the identification of the gene for von Hippel Lindau disease provided seminal insights into its role in most clear cell renal carcinomas (RCC) and led to new treatments for RCC. In this thesis I investigated three related genetic aspects of neoplasia. Firstly, I analyzed the results of genetic testing for inherited phaeochromocytoma and investigated how clinical features could be used to stratify patients and improve the cost effectiveness of genetic testing. Secondly, I sought to identify novel causes of inherited neoplasia. Through exome sequencing of familial RCC kindreds, CDKN2B was identified as a novel familial RCC gene. The role of CDKN2B mutations in neoplasia was evaluated in familial and sporadic RCC and phaeochromocytoma. In vitro assays confirmed that germline CDKN2B mutations associated with inherited RCC caused an abrogation of tumour suppressor function. Finally, I explored how a gene-based strategy might be used to identify novel therapeutic strategies, Thus, using a siRNA library screen, in RCC cells with inactivated VHL, potential candidate targets (e.g. PLK1/STK-10) were identified for selectively decreasing the viability of RCC cells with inactivated VHL. ACKNOWLEDGMENTS Firstly I would like to acknowledge God for his many blessings. My mother, Kishwar Jafri has been an immense support to me throughout my life and is a passionate believer in the value of education. During my research, my mother, along with my sister and brother have always stepped in without complaining to look after my two young children, Yusuf and Idris, when I was working late or at weekends or when my experiments ‘over-ran’. Their love and support have not only enabled me to achieve my goals but also is a great comfort to the children who have not missed their mother. I am also thankful to my father who although he passed away many years ago, instilled me with a sense of curiosity and desire for self- improvement. My husband has also had to endure many weekends and bank holidays of me working in the laboratory and not being in the home. His patience has been amazing. I am very grateful to staff in the Department of Medical Genetics, they welcomed me into the department and became my friends. In particular, I’d like to thank, Mr Dean Gentle, Dr Dewi Astuti and Dr Malgosia Zatyka who provided me with friendship and technical support. Lastly, I would like to thank my two supervisors. Professor Eamonn Maher had infectious enthusiasm for science and modesty regarding his many achievements and Professor Farida Latif who was equally modest and taught me a lot about having an inquiring scientific mind. I really enjoyed my training in this rapidly developing field and hope it will hold me in good stead for the rest of my career. Most importantly, I hope it will enable me to help my patients, who suffer with cancer, to have more effective and less toxic treatments. TABLE OF CONTENTS TABLE OF CONTENTS ......................................................................................................... 1 LIST OF FIGURES ................................................................................................................ 10 LIST OF TABLES .................................................................................................................. 12 ABBREVIATIONS ................................................................................................................. 13 CHAPTER 1: INTRODUCTION ......................................................................................... 16 1.1 Current clinical management of cancers ......................................................................... 16 1.1.1 Clinical management of solid organ cancers ............................................................... 17 1.1.2 The development of chemotherapy as a treatment for cancer ..................................... 18 1.2 Genomics and cancer medicine....................................................................................... 21 1.2.1 Overview of the genetics of cancers ............................................................................ 21 1.2.1.1 Hallmarks of cancer: pathways to human cancer .................................................. 21 1.2.2 The step-wise process of cancer development and accumulation of genetic alterations .......................................................................................................................... 21 1.2.2.1 The hallmarks of cancer ........................................................................................ 22 1.2.2.2 Other important enabling characteristics of cancer and stress factors .................. 27 1.2.2.3 The stress phenotype of cancer.............................................................................. 28 1.2.3 Oncogenes and Tumour Suppressor Genes ................................................................ 30 1.2.3.1 Oncogenes ............................................................................................................. 30 1.2.3.2 Tumour Suppressor Genes (TSG). ........................................................................ 31 1.2.3.3 Mechanisms of genetic alteration in proto-oncogenes and TSG ........................... 32 1.2.3.4 Driver and passenger mutations ............................................................................ 33 1.3 Developments in cancer genomics.................................................................................. 34 1.4 The application of cancer genomics to patient care ........................................................ 37 1.4.1 Examples of personalized cancer treatment ............................................................. 37 1.4.2 Application of genomics to diagnosis and prognosis of cancer ............................... 39 1.5 The scope of the research presented in this thesis .......................................................... 40 CHAPTER 2 METHODS ...................................................................................................... 42 2.1 Materials.......................................................................................................................... 42 2.1.1 Companies materials obtained from ......................................................................... 42 2.1.2 General chemicals ........................................................................................................ 42 1 2.2 DNA samples .................................................................................................................. 43 2.2.1 Germline familial RCC samples............................................................................... 43 2.2.2 Sporadic RCC DNA samples ................................................................................... 43 2.2.3 Familial phaeochromocytoma germline samples ..................................................... 43 2.2.4 Sporadic phaeochromocytoma DNA samples .......................................................... 44 2.3 DNA extraction from tissues .......................................................................................... 44 2.4 Whole Exome Sequencing (WES) .................................................................................. 45 2.5 Whole genome amplification .......................................................................................... 47 2.6 Polymerase Chain Reaction ............................................................................................ 48 2.7 Sequencing genes ............................................................................................................ 48 2.7.1 Primer design ............................................................................................................ 48 2.7.2 Polymerase chain reaction (PCR) for sequencing .................................................... 49 2.7.3 Cleaning the PCR product ........................................................................................ 50 2.7.4 Gel extraction ........................................................................................................... 51 2.7.5 The sequencing reaction ........................................................................................... 51 2.7.6 Ethanol precipitation ................................................................................................ 52 2.7.7 Determination of predicted functional significance of genetic alterations
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