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Elucidating the Constitutional Genetic Basis of Multiple Primary Tumours Elucidating the constitutional genetic basis of multiple primary tumours James William Whitworth Gonville and Caius College February 2019 This dissertation is submitted for the degree of Doctor of Philosophy Preface This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text It does not exceed the prescribed word limit for the relevant Degree Committee. Acknowledgments I would like to extend my sincere thanks to the following people. To my supervisor, Eamonn Maher, for his mentorship over a time period longer than the programme of study outlined in this thesis. I am also grateful to Marc Tischkowitz, my second supervisor, for his encouragement and input. To my colleagues past and present in the Academic Department of Medical Genetics for their insights, collaboration, advice, and camaraderie over the past few years. In particular Ruth Casey, Graeme Clark, France Docquier, Ellie Fewings, Benoit Lang-Leung, Ezequiel Martin, Eguzkine Ochoa, Faye Rodger, Phil Smith and Hannah West. To the team at the NIHR BioResource Rare Diseases project, data from which forms the basis of this thesis. I have worked most closely with Sophie Ashford, Chris Penkett and Kathy Stirrups but there are scores of individual contributors. To the recruitment teams at genetics centres across the UK and beyond, who make a large contribution to medical genetic research. To the Gonville and Caius Middle Combination Room for being a great community full of interesting people and enlightening conversations. Most of all, to my wife, Beth, for her loving enthusiasm, support and great times during the years of this PhD programme. List of acronyms used ACC Adrenocortical carcinoma ACMG American College of Medical Genetics AML Acute myeloid leukaemia AUC Area under curve (of receiver operator characteristic) AVL Antoni van Leeuwenhoek (hospital) BHD Birt Hogg Dubé (syndrome) CADD Combined Annotation Dependent Depletion (score) CATGO Cambridge Translational Genomics Laboratory CCDS Consensus Coding Sequence CNS Central nervous system CPG Cancer predisposition gene CRUK Cancer Research United Kingdom CT Computerised tomography ctDNA Circulating tumour deoxyribonucleic acid DSB Double stranded break EA East Anglia (registry) eQTL Expression quantitative trait loci ExAC Exome aggregation consortium FFPE Formalin fixed paraffin embedded GIST Gastrointestinal stromal tumour GO Gene Ontology (term) GTEx Genotype-Tissue Expression (project) GWAS Genome wide association study HGMD Human Gene Mutation Database HGNC HUGO Gene Nomenclature Committee HLRCC Hereditary leiomyomatosis and renal cell carcinoma IARC International Agency for Research on Cancer ICD-O-3 International Classification of Diseases for Oncology (3rd edition) IGV Integrative Genomics Viewer IHC Immunohistochemistry LDL Low density lipoprotein LFS Li Fraumeni syndrome LOH Loss of heterozygosity MEN2 Multiple endocrine neoplasia type 2 MINAS Multilocus inherited neoplasia alleles syndrome MLPA Multiple ligation-dependent probe amplification MMR Mismatch repair Multiple Primary Malignant Tumours (tag as used in NIHR Bioresource - Rare MPMT Diseases project data) MPNT Malignant peripheral nerve sheath tumour MPT Multiple primary tumours MRI Magnetic resonance imaging MSI Microsatellite instability MTS Multiple tumour score NGS Next generation sequencing NMSC Non-melanoma skin cancer P/LP Pathogenic/likely pathogenic (variant) PAF Population attributable fraction PARP Poly ADP-ribose polymerase PCR Plymerase chain reaction RCC Renal cell carcinoma ROC Receiver operator characteristic SIR Standardised incidence ratio SNP Single nucleotide polymorphism SNV Single nucleotide variant SO Sequence Ontology (term) SPEED Specialist Pathology Evaluating Exomes in Diagnostics (study) SV Structural variant TCGA The Cancer Genome Atlas TCP Tru-sight cancer panel (assay) TSG Tumour suppressor gene UCNE Ultraconserved non-coding elements (database) UCSC University of California Santa Cruz (genome browser) UM Uveal melanoma VAF Variant allele fraction VCF Variant call format (file) VEP Variant Effect Predictor VHL Von-Hippel Lindau VUS Variant of uncertain significance WES Whole exome sequencing WGS Whole genome sequencing XP Xeroderma pigmentosum Contents Chapter 1 – Introductory chapter ....................................................................................................... 1 1.1 - Cancer as a genetic disease ............................................................................................................. 2 1.1.1 - Oncogenes, tumour suppressor genes and cancer predisposition ............................................ 2 1.2 - The development of DNA sequencing techniques ......................................................................... 5 1.3 - Identifying cancer predisposition genes ......................................................................................... 9 1.4 - Risks associated with variants in cancer predisposition genes ..................................................... 11 1.5 - Cancer predisposition genes and their contribution to cancer burden .......................................... 12 1.6 - Mendelian conditions due to variants in cancer predisposition genes .......................................... 13 1.6.1 - Tumour spectrum associated with cancer predisposition genes ............................................ 14 1.6.2 - Penetrance of cancer predisposition gene variants ................................................................ 16 1.7 - Impact of next generation sequencing on cancer predisposition gene variant identification in the clinic ...................................................................................................................................................... 17 1.8 - Clinical utility of cancer predisposition variant identification ..................................................... 18 1.8.1 - Information as therapy ........................................................................................................... 19 1.8.2 - Clinical surveillance .............................................................................................................. 20 1.8.3 - Prophylactic surgery .............................................................................................................. 21 1.8.4 - Pharmacological management ............................................................................................... 22 1.9 - Multiple Primary Tumours ........................................................................................................... 22 1.9.1 - Multiple primary tumours in the general population ............................................................. 22 1.9.2 - Aetiology of multiple primary tumours ................................................................................. 23 Chapter 2 – Methods applicable to multiple sections ...................................................................... 28 2.1 - Study participants ......................................................................................................................... 29 2.2 - Tumour labelling and classification .............................................................................................. 29 2.3 - DNA samples ................................................................................................................................ 30 2.4 - Sequencing.................................................................................................................................... 30 2.4.1 - Whole genome sequencing and bioinformatic processing of sequencing output .................. 31 2.4.2 - Gene panel sequencing and bioinformatic processing of sequencing output ........................ 34 Chapter 3 – Multiple primary tumours in referral and registry-based series .............................. 37 3.1 – Introduction .................................................................................................................................. 38 3.2 - Methods ........................................................................................................................................ 38 3.2.1 - Collection and analysis of registry data ................................................................................. 38 3.2.2 - Ascertainment and description of a multiple primary tumour series ..................................... 39 3.2.3 - Comparison of Multiple Primary Tumour series with a population series ............................ 40 3.3 - Results .......................................................................................................................................... 40 3.3.1 - Registry and treatment centre series ...................................................................................... 40 3.3.2 - Multiple Primary Tumour
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