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Characterisation of Genetic and Epigenetic Aberrations in Paediatric High Grade Glioma

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Characterisation of Genetic and Epigenetic Aberrations in Paediatric High Grade Glioma CHARACTERISATION OF GENETIC AND EPIGENETIC ABERRATIONS IN PAEDIATRIC HIGH GRADE GLIOMA PRASANNA CHANNATHODIYIL, MSc A thesis submitted in fulfilment of the requirements of the University of Wolverhampton for the degree of Doctor of Philosophy Brain Tumour Research Centre Research Institute in Healthcare Sciences Faculty of Science and Engineering University of Wolverhampton April 2016 i DECLARATION This work or any part thereof has not previously been presented in any form to the University or to any other body whether for the purposes of assessment, publication or for any other purpose (unless otherwise stated). Save for any express acknowledgments, reference and/or bibliographies cited in the work, I can confirm that the intellectual content of the work is the result of my own efforts and no other person. The right of Prasanna Channathodiyil to be identified as an author of this work is asserted in accordance with ss.77 and 78 of the Copyright, Designs and Patents Act 1988. At this date copyright is owned by the author. Signature Date: 18th April 2016 ii ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my supervisor, Prof. Tracy Warr for offering me this opportunity to pursue my PhD degree. Her tremendous support and guidance has the major role in the successful completion of this project and the writing of this thesis. Working with her has been an amazing experience. I am immensely grateful to my co-supervisor, Dr. Mark Morris for his valuable suggestions and constant encouragement that have always been truly inspiring. Learning with him was so much fun and I wholeheartedly thank him for being so kind and friendly. I have deep appreciation for Prof. John Darling for his vital suggestions and valuable support. My sincere gratitude goes to Prof. Weiguang Wang for providing me an opportunity to work with him during my MSc project that I believe has contributed to a great extent in securing a PhD degree at this University. I owe you a lot, thank you! I am grateful to Dr. Angel Armesilla for his encouragement and friendly conversations. Thanks to Dr. Sarah Brown, Dr.Sarah Jones, Dr.John Howl and Dr.Ian Nicholl for their help and support. I would like to thank the members of my research group, Dr. Katherine Karakoula, Dr. Farzana Rowther, Dr. Hoda Kardooni, Dr. Anushree Singh and Lawrence Eagles, and colleagues at the University, Dr. Rajendra Pangeni, Sheela Pokherel, Dr. Shawna Bolton, Dr. Raji Kilari, Dr. Peng Liu and Dr. Patricia Tawari for their help and encouragement over the last few years. PhD at the University of Wolverhampton has become an unforgettable experience. I am thankful to the lab manager, Dr. Angie Williams, and the laboratory technicians, Keith Holding, Henrik Townsend, Balbir Bains, Andy Brook and Clare Murcott for the technical support. I truly appreciate Ramanjit Kaur for her impeccable efforts in taking care of all the research administration works. I am grateful to The Brain tumour charity and The Ethan Perkins Trust (UK) for funding this project. I also extend my thanks to the collaborators in this project at iii Imperial College, London and at Nottingham University. Special thanks to Dr. Nelofer Syed for providing antibodies and drugs. I am grateful to all my friends outside the University, for their love and encouragement. Special mention goes to Sathishkumar Kurusamy, Karthik Kannappan, Priya Kannappan, Ram Kumar, Saravanan Nagarajan, Kalai Vanan, Neelakandan Bhojan, Manikandan, Jisha, Uma Maheswari, Jithendran Sasidharan, Ranjith Paulson, Jon Yarsley, Julian Hobson, Toye Anifalaje, Bunmi Anifalaje, Dr.Jayan, Dr.Reji, Dr.George Alapatt and my friends from the organisation, Tamil People in UK. On a personal note, I would love to thank my parents, Mrs. Dakshayani Kizhakkekkara and Mr. Vasudevan Channathodiyil who are always ready to go that extra mile to see the smile on my face. I am grateful to my siblings, Pradeep and Priya for being their constant source of love and support. Thanks to Anu chechy and Renju ettan for their encouragement. Most importantly, I thank Vinu for his love and support over the last 12 years. This wouldn‘t have been possible without your help. Thank you! iv DEDICATION To my parents... v “The most beautiful thing we can experience is the mysterious. It is the source of all true art and science.” – Albert Einstein vi ABSTRACT Paediatric high grade glioma (HGG), including diffuse intrinsic pontine glioma (DIPG) are highly aggressive tumours with no effective cures. Lack of understanding of the molecular biology of these tumours, in part due to lack of well-characterised pre-clinical models, is a great challenge in the development of novel therapies. Analysis of paired cell culture/biopsy samples in this study revealed that paediatric HGG short-term cell cultures retain many of the tumour characteristics in vivo. Using a genome-wide approach, copy number, gene and miRNA expression, and methylation changes were characterised in 17 paediatric HGG-derived short-term cell cultures including 3 from DIPG. The majority of the genomic changes were unique from those arising in adult HGG. Approximately 65% (11/17) of paediatric HGG short-term cell cultures had balanced genetic profiles resembling normal karyotypes. The most frequent copy number gain and loss were detected at 14q11.2 (94%) and 8p11.23-p11.22 (59%), respectively. H3F3A (K27M) mutation was present in 2/17 (12%) cases and concurrent loss of CDKN2A and BRAFV600E in 1/17 (6%) case. Genes involved in reelin/PI3K signaling (DAB1), RTK signaling (PTPRE), and arginine biosynthesis (ASS1 and ASL) were frequently deregulated by methylation in these tumours. The anti- growth and anti-migratory properties of DAB1 and PTPRE were demonstrated in vitro. Preliminary investigations validated the therapeutic potential of ADI-PEG20 (arginine depletion), and PI-103 (PI3K/mTOR inhibition) in a subset of paediatric HGG short- term cell cultures. This study has identified novel genetic and epigenetic changes in paediatric HGG that may, following further validation, be translated into potential biomarkers and/or therapeutic targets. vii TABLE OF CONTENTS Declaration................................................................................................................ Dedication................................................................................................................... Abstract....................................................................................................................... Table of contents......................................................................................................... List of Tables............................................................................................................... List of Figures............................................................................................................. Abbreviations.............................................................................................................. Acknowledgements..................................................................................................... Chapter 1 1 Introduction.................................................................................................... 1.1 Cancer....................................................................................................................... 2 1.1.1 Incidence and overview................................................................................ 2 1.1.2 Cancer as a disease of the genome............................................................... 3 1.2 Brain tumours.......................................................................................................... 4 1.3 Paediatric glioma...................................................................................................... 5 1.3.1 Major clinical subgroups of paediatric glioma............................................. 5 1.3.1.1 Low grade glioma (LGG)................................................................. 5 Pilocytic astrocytoma (PA)............................................................... 6 Diffuse astrocytoma.......................................................................... 6 1.3.1.2 High grade glioma (HGG).............................................................. 7 Anaplastic astrocytoma.................................................................... 7 GBM................................................................................................. 7 8 DIPG................................................................................................. viii 1.4 Epidemiology and aetiology of paediatric HGG..................................................... 9 1.5 Current therapy for paediatric HGG........................................................................ 10 1.5.1 Surgery......................................................................................................... 1 0 1.5.2 Radiotherapy................................................................................................ 11 1.5.3 Chemotherapy............................................................................................. 12 1.6 Molecular biology of paediatric high HGG............................................................ 1 3 1.6.1 RTK/Ras/Raf/PI3K pathway alterations...................................................... 1 3 Alterations in receptor tyrosine kinases (RTKs).......................................... 14 v-raf murine sarcoma viral oncogene homologue B1 (BRAF)
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