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Molecular Genetic Analysis of Paediatric Low-Grade Astrocytoma

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Molecular Genetic Analysis of Paediatric Low-Grade Astrocytoma Molecular genetic analysis of paediatric low-grade astrocytoma Ruth Grace Tatevossian University College London and Cancer Research UK London Research Institute PhD Supervisor: Professor Denise Sheer A thesis submitted for the degree of Doctor of Philosophy University College London October 2009 1 Declaration I, Ruth Grace Tatevossian, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract The thesis describes the molecular genetic analysis of fifty low-grade paediatric astrocytomas. DNA copy number changes were investigated in paediatric low-grade astrocytomas (WHO grade I and II), using array comparative genomic hybridisation and Affymetrix 250K and 6.0 SNP arrays. A discrete region of DNA copy number gain was identified at chromosome 7q34, primarily although not exclusively in pilocytic astrocytomas of the cerebellum. Further analysis of this region, by PCR and sequencing, demonstrated the presence of gene fusions between KIAA1549 and BRAF. Five KIAA1549- BRAF fusion variants were subsequently identified. A further gene fusion between SRGAP3 and RAF1 was also found in a single tumour with DNA copy number gain at chromosome 3p25. The fusion genes lacked the auto-inhibitory domains of BRAF and RAF1. These were replaced in-frame by N-terminal segments of KIAA1549 and SRGAP3, respectively, conferring constitutive kinase activity. Sequencing confirmed the presence of activating mutations in KRAS and BRAF in three tumours where gene fusions were not identified. Both gene fusions and activating mutations were shown to cause activation of the ERK/MAP kinase pathway by Western blotting. Further sequencing was performed of CDKN2A, PTEN and IDH1/2 to assess the frequency of abnormalities in paediatric low-grade astrocytoma. These genes have previously been found to contain aberrations within adult high-grade astrocytomas. To date, no significant aberrations have been identified in the paediatric astrocytoma samples examined. This confirms previous findings in adult and paediatric astrocytomas, which appear to show distinct molecular changes depending on patient age. Gene fusions or activating mutations were identified in 100% pilocytic astrocytomas studied and were also found in 28% of grade II astrocytomas. These findings highlight the importance of the ERK/MAPK pathway both in the development of paediatric low-grade astrocytomas and as a possible therapeutic target. Gene fusions may provide a means of molecular classification for pilocytic astrocytomas in the future. 3 Acknowledgements I would like to express my warmest thanks and very deepest gratitude to Denise Sheer. She has been a continual source of inspiration, support, guidance and boundless enthusiasm. This work would not have been possible without her dedication to pushing forward the boundaries of knowledge in children’s cancer. I am so pleased to have been given the opportunity to work with her. Many thanks to David Ellison: none of the work presented here would have been possible without him and his team at St Jude. I would like to thank my second supervisor Ian Tomlinson, and my thesis committee member Nic Tapon. I would also like to extend my thanks to Cancer Research UK for supporting me with a clinical research fellowship to enable me to complete my studies. My most heartfelt thanks to my friends and colleagues; Tim Forshew, Andrew Lawson, Tania Jones, Diego Ottaviani, Chiara Mazzanti, and Paul Mulholland for their endless support and advice over the years. I couldn’t have done it without you. Thank you to all the members of the Human Cytogenetics laboratory; William Ogunkolade, Rowena Carter, Guy Hindley, Jarek Szary, Johan Aarum, Rossitza Christova, Petros Takousis, Radost Vacheva, Alistair Newall and Pei Jun Wu. I would also like to thank Gavin Kelly for his helpful advice and patience, all of the staff at Cancer Research London Research Institute’s equipment park for their help and expertise and to Ian Giddings and his staff at the microarray facility at the Institute of Cancer Research in Sutton. Lastly, I would like to thank my family for their love and encouragement. To my parents, Adolph and Cordelia, my sister and brother-in-law Elsa and Adam, to Victor, Philip, Naomi and Luke, and most particularly of all to James and Sophia: this thesis is dedicated to you. 4 Table of Contents Declaration.............................................................................................................................2 Abstract..................................................................................................................................3 Acknowledgements................................................................................................................4 Table of Contents...................................................................................................................5 Table of figures....................................................................................................................10 List of tables.........................................................................................................................14 List of tables.........................................................................................................................14 Abbreviations.......................................................................................................................16 Abbreviations.......................................................................................................................16 Chapter 1. Introduction....................................................................................................18 1.1 Cancer biology – an overview .............................................................................19 1.2 Genetic and epigenetic changes in cancer – a genomic disease ..........................20 1.2.1 Oncogenes......................................................................................................21 1.2.2 Tumour suppressor genes ..............................................................................23 1.3 Epigenetic changes in cancer...............................................................................24 1.3.1 DNA hypermethylation..................................................................................25 1.3.2 DNA hypomethylation in cancer ...................................................................26 1.3.3 Post-translational histone modifications........................................................27 1.4 MicroRNAs..........................................................................................................28 1.5 Chromosomal rearrangements in cancer..............................................................31 1.6 Cancer – an accumulation of genetic aberrations ................................................35 1.7 Cancer in children – a developmental disease? ...................................................37 1.8 Cancer stem cells .................................................................................................38 1.9 An overview of the mitogen-activated protein kinase (MAPK) pathway ...........40 1.10 Paediatric brain tumours ......................................................................................43 1.10.1 Epidemiology .............................................................................................43 1.10.2 Aetiological factors....................................................................................44 1.10.3 Early development of the central nervous system......................................47 1.10.4 Histopathological classification of paediatric astrocytomas ......................47 1.10.5 Clinical presentation and diagnosis............................................................49 1.10.6 Treatment ...................................................................................................50 1.10.7 Molecular biology of low-grade paediatric astrocytomas..........................51 5 1.11 Astrocytomas in children and adults....................................................................53 1.12 Aims of this thesis................................................................................................54 Chapter 2. Materials and methods ...................................................................................55 2.1 Tumour samples...................................................................................................55 2.2 Control DNA samples..........................................................................................55 2.2.1 Control RNA..................................................................................................57 2.2.2 Control protein...............................................................................................57 2.3 Cell lines..............................................................................................................57 2.4 General Methods..................................................................................................57 2.4.1 Cell culture.....................................................................................................57 2.4.2 Metaphase spread preparation........................................................................58 2.4.3 DNA extraction from blood, cell line and tumour samples...........................59 2.4.4 DNA extraction to create pooled
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