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Inherited Predisposition to Pancreatic Cancer in the Era of Next Generation Sequencing

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Inherited Predisposition to Pancreatic Cancer in the Era of Next Generation Sequencing Inherited Predisposition to Pancreatic Cancer in the Era of Next Generation Sequencing Jeremy Humphris A thesis in fulfillment of the requirements for the degree of Doctor of Philosophy St Vincent’s Clinical School Faculty of Medicine August 2015 PLEASE TYPE THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: First name: Other name/s: Abbreviation for degree as given in the University calendar: School: Faculty: Title: Abstract 350 words maximum: (PLEASE TYPE) Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). …………………………………………………………… ……………………………………..……………… ……….……………………...…….… Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: THIS SHEET IS TO BE GLUED TO THE INSIDE FRONT COVER OF THE THESIS ORIGINALITY STATEMENT ‘I hereby declare that this submission is my own work and to the best of my knowledge it contains no materials previously published or written by another person, or substantial proportions of material which have been accepted for the award of any other degree or diploma at UNSW or any other educational institution, except where due acknowledgement is made in the thesis. Any contribution made to the research by others, with whom I have worked at UNSW or elsewhere, is explicitly acknowledged in the thesis. I also declare that the intellectual content of this thesis is the product of my own work, except to the extent that assistance from others in the project's design and conception or in style, presentation and linguistic expression is acknowledged.’ Signed …………………………………………….............. Date …………………………………………….............. COPYRIGHT STATEMENT ‘I hereby grant the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all proprietary rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstract International (this is applicable to doctoral theses only). I have either used no substantial portions of copyright material in my thesis or I have obtained permission to use copyright material; where permission has not been granted I have applied/will apply for a partial restriction of the digital copy of my thesis or dissertation.' Signed ……………………………………………........................... Date ……………………………………………........................... AUTHENTICITY STATEMENT ‘I certify that the Library deposit digital copy is a direct equivalent of the final officially approved version of my thesis. No emendation of content has occurred and if there are any minor variations in formatting, they are the result of the conversion to digital format.’ Signed ……………………………………………........................... Date ……………………………………………........................... Acknowledgements: ..................................................................................... 4 List of Figures: .............................................................................................. 7 List of Tables: ................................................................................................ 9 Chapter 1. Introduction ............................................................................... 14 1.1 Epidemiology of PC............................................................................... 15 1.1.1 Non-genetic risk factors .................................................................... 15 1.1.2 Genetic risk factors ............................................................................ 22 1.1.2.1 Hereditary Tumour Predisposition Syndromes .............................. 23 1.1.2.2 Hereditary Pancreatitis ................................................................... 26 1.1.2.3 Familial Pancreatic Cancer ............................................................ 27 1.1.2.4 Low Penetrance Susceptibility Variants ......................................... 29 1.2 Precursor Lesions and Progression to PC ......................................... 34 1.2.1 Pancreatic Intra-epithelial Neoplasia................................................. 34 1.2.2 Cystic Neoplasms ............................................................................. 36 1.3 Predicting the risk of developing PC ................................................... 38 1.4 Early Detection of PC ............................................................................ 39 1.4.1 Imaging approach .............................................................................. 42 1.4.2 Biomarker approach ........................................................................... 45 Chapter 2: The prognostic and predictive value of serum CA19.9 in pancreatic cancer. ....................................................................................... 54 2.1 Introduction ........................................................................................... 56 2.2 Patients and Methods ........................................................................... 57 2.3 Results ................................................................................................... 61 2.3.1 CA19.9 and disease stage ................................................................ 61 2.3.2 Prognostic Value of CA19.9 .............................................................. 61 2.3.3 Predictive Value of CA19.9 ............................................................... 65 2.4 Discussion ............................................................................................. 68 Chapter 3: Clinico-pathological features of familial PC ........................... 72 3.1 Introduction ........................................................................................... 73 3.2 Patients and methods ........................................................................... 74 3.3 Results ................................................................................................... 76 3.3.1 Clinico-pathologic variables and outcome ......................................... 77 3.3.2 Previous extra-pancreatic malignancy .............................................. 79 3.3.4 Family history of extra-pancreatic malignancy .................................. 80 3.3.5 Other PC risk factors ......................................................................... 80 3.4 Discussion ............................................................................................. 82 Chapter 4: Hypermutation in pancreatic cancer ....................................... 85 4.1 Introduction ........................................................................................... 87 4.2 Patients and Methods ........................................................................... 89 4.3 Results ................................................................................................... 94 4.4 Discussion ........................................................................................... 103 Chapter 5: Comprehensive Assessment of Germline Cancer Predisposition Genes in Pancreatic Cancer ........................................... 107 5.1 Introduction ......................................................................................... 109 5.2 Patients and methods ......................................................................... 110 5.3 Results ................................................................................................. 114 5.3.1 Clinical Cohort ................................................................................ 114 2 5.3.2 Pathogenic mutations in PC predisposition genes .......................... 120 5.3.3 Pathogenic mutations in other cancer predisposition genes ........... 124 5.3.4 Germline copy number variants ...................................................... 134 5.4 Discussion ........................................................................................... 135 Chapter 6: Discussion............................................................................... 138 Appendix .................................................................................................... 148 Chapter 2: Supplementary data ............................................................... 149 Chapter 3: Supplementary data ............................................................... 154
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