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Colorectal Cancer Microsatellite Lnstability Colorectal Cancer Microsatellite lnstability by Robert Gryfe A thesis submitted in confomity with the requirements for the degree of Doctor of Philosophy. fnstitute of Medical Science, University of Toronto @Copyrightby Robert Gryfe 2001. Acquisitions and Acquisitions et Bibliographie Services senrices bibkgraphiques The author has granted a non- L'auteur a accordé une licence non exchisive licence dohgthe exchuive permettant à la National Liiof Canada to Bibliothèque nationale du Canada de reproduce, loan, distn'bute or sen reproduire, prêter, distn'buer ou copies of this thesis in microfonn, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/^ de reproduction sur papier ou sur format électronique. The author re& ownership of the L'autem conserve la propri6te du copyright in this thesis. Neither the droit d'auteur q@ protège cette thèse. thesis nor substantial extracts fiom Ït Ni la thèse ni des extraits substantiels may be prhted or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. Colorectal Cancer Microsatellite lnstability by Robert Gryfe A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy, hstitute of Medical Science, University of Toronto, 200 1. Abstract Background: Colorectal cancer is the third most common cancer in both sexes and the second leading cause of cancer-related deaths in Canada. Microsatellite DNA sequences. common throughout the human genome, are subject to high rates of mutation in approximately 15% of colorectal cancers due to deficiency in DNA mismatch repair. Mutations of the Adenornatous Putyposis Coli (APC)gene are thought to initiate colorectal neoplasia The APC 11307K pol ymorphism, common in the Ashkenazi Jewish population, contains an (A)8 microsatellite repeat. The dinical relevance of mismatch repak deficiency and microsatellite instability in colorectai cancer is incompletely understa as is the cancer risk of the APC 11307K polymorphism. Methods: Tumors From a population-based series of 607 young patients with colorectai cancer fiom were screened for microsateLite instability and 476 Ashkenazi Jewish patients with colorectai neoplasms were screened for the APC 113MK polymorphism. Results: High-fkquency microsatellite instability @HI-El)was observed in 17%of the cancm €rom the population-based series. Patients with MSI-H colorectal cancers were found to have significantly better survîvai in multivariate andysis and MSI-H cancers were les likely to metastasue after controlling for the extent of -or invasion. The APC Il3MK poIymorphism was present in more than 10% of Ashkenazï Jewish patients with colorectal neoplasia The (Ah microsatellite sequence of the APC II307K polymorphism was subject to a very high rate of somatic mutation by a mechanism apparendy not related to mismatch repair deficiency. An additional polymorphism, APC EHI 7Q, was identified in this series, but did not appear to be associated with a significant risk for colorectal neoplasia Conclusions: MSI-H is relatively cornmon in colorectal cancers and defines a distinct disease subtype with an improved survivai and a demased risk of metastasis. The APC 11307K polymorphism is a risk factor for colorectal neoplasia due to somatic mutation of the (Ah polymorphic microsateIlite sequence. Acknowledgements 1would iike to acknowledge and thank several people for their guidance, support and contribution to the work presented in this thesis. Many thanks to the members of the Gallinger and Redston laboratories, including Kazy Hay, Geeta Lal, CoUeen Ash, Mol1 y Pind Laura Mirabelü-Rimdahl, Eugene Hsieh and most especiaily Heyja Kim and Nando DiNicola for al1 their help, advice and toierance. Thanks to the numerous technicians, graduate students, post doctoral fellows and investigators of the Samuel Lunenfeld Research Institute who have helped me both directly and indirectly throughout my research training. I am grateful for the efforts of Nelson Chong. Darlene Dale and Eric Holowaty of the Ontario Cancer Registry, Susan Bondy and Marc Thenault of the Institute of Clinical Evaluative Science, and the numerous physicians and hospital staff throughout the province of Ontario who helped me obtain the clinical information and materiais needed for the research contained within this thesis. I am especially indebted to the more than one thousand individuals with colorectal cancer and adenornatous poiyps who served as the subjects for these studies. I wouid iike to thank Steven Nami for his excellent insights, suggestions and participation on my thesis cornmittee and examination. Additionai th& to Joyce Slingerland, Zane Cohen, Serge Jothy and Stan Hamilton for reviewing my thetis manuscript and participating in my examination. 1wish to thank Mark Redston, an individual of incredible knowledge, insight and expertise. Mark has been a fantastic mentor, advisor. critic and Friend for which 1am eterndiy gratefitl. There is insufficient space here for me to properly thank my supmisor Steve Gailinger. During the course of my training, Steve has not ody served as an outstanding mentor, motivator, advisor, role mode1 and human being, he has become one of my closest fkiends. I am confident that my graduate shdies and surgical nsidency mark only the beginning of our long and rewarding professional and personal friendship. Steve, th& you. Finaily, I would Iike to thank my family who has supported me throughout my Iife and in particular my lengthy pst-secondary school education. My wife and best Fnend Elana, and children Manhew and Marley, are the glue that holcls me together. Their patience, support, encouragement and endless love have made aIl of this possible. 1 acknowledge and th& the Surgical Scientist Program, Department of Surgery and Division of General Surgery, University of Toronto for allowing me the time to pursue my research shidies and thank the National Cancer Institute of Canada and the American Society of Colon and Rectal Surgeons for their generous financial support. Table of Contents Abstract ii Ac knowledgements iv Table of Contents vi List of Tables xi List of Figures xii List of Abbreviations xiii Oissemination of thesis content xvii Chapter One: Introduction 1 Colorectd cancer microsatellite instability 2 Background 2 ne adenorna to carcinoma sequence 2 Clinical aspects of colorectal cancer 7 Colorectal cancer presentation, treatment and prognosis 7 Clinicai screening for colorectai cancer 8 Cancer genes, gatekeepers and caretaicers 10 Gatekeeper genes 10 Caretaker gens 11 Molecular genetic pathways of coiorectal carcinogenesis: chromosomal and microsateIlite instability 11 The chmosomai instability gatekeeper pathway 14 The MCgene and familial adenornatous polyposis 15 Other genetic targets of the gatekeeper pathway 19 The mismatch repair &€icient, microsatellite instability caretaker pathway 21 hstability of micfosateliite DNA 21 Dynamic trinucleotide expansion diseases 23 Hereditary nonpolyposis colorectal cancer 23 Microsatellite instability in colorectal cancer 25 MSI-H and mismatch repair deficiency in hereditary nonpolyposis colorectai cancer 30 MSI-H and mismatch repair deficiency in sporadic colorectal cancer 34 Non-mismatch repair deficient causes of MSI-H colorectal cancer 36 DNA mismatch repair 36 MSI-H and rnismatch repair deficiency in extracolonic cancers 40 Somatic genetic targets of MSI-H and mismatch repair deficiency 41 Transforming growth factor B receptor II 41 APC, PCatenin and TCF-4 43 MCII307K: microsatellite instability in a caretaker gene 44 Other genetic targets of the MSI-H pathway 45 MSI-H,mismatch repair deficiency and colorectal cancer phenotype 47 The Bethesda criteria for hereditary nonpolyposis coIorectai cancer screening 48 MSI-Hcolorectal cancer and patient survival 50 Thesis overview 51 Chapter Two: Tumor microsatellite instability and clinicel outcome in young patients with colorectal cancer 53 s-ary 54 Introduction 55 Methods 57 Study population 57 Clinical database 57 DNA preparation, microsatellite testing, and analysis 59 Statistical anal ysis 60 Results 61 Clinical characteristics associated with MSI-H 61 MSI-H and standard cünical propostic factors for survival 66 Discussion 70 Chapter Three: Somatic instabiltty of the APC 11307Kallele in colorectal ne0plasia 73 s-=Y 74 Introduction 75 Methods 75 Tumor samples 75 Somatic mutation analysis 76 Microsatellite andysis 77 Statistical rnethods 77 Discussion 82 Chapter Four: lnherited colocectal polyposls and cancer risk of the APC Il3Otl( polyrnorphism 88 smar~ 89 Introduction 90 Methods 92 Cohort and phenotypic data 92 MCI1307K germ-line andysis 93 Statisticai methods 93 Resuits 94 Discussion 101 Chapter Fhre: The APC €13110 polymorphism does not preâispose carriers to colorectal adenornatous or hyperplastic polyps 107 introduction 109 Cohort and phenotypic data 1 10 Genetic testing 111 Statistical methods 111 Discussion 116 Chapter Six: Cotorectal cancer microsatellite instabillty, conclusions and future directions 119 Summary 120 The clinical phenotype of MSI-H colorectal cancer 121 APC I1307K and the risk of colorectal neoplasia 123 APC E1317Q does not predispose to colorectai neoplasia 125 List of Tables Table 1-1: Classification of colorectal adenomatous polyps 4 Table 1-2: Classification of colorectal adenocarcinorna 5 Tabie 1-3: Colorectal cancer molecular pathway s 13 Table 14 Microsatellite loci for evaluation of microsatellite instability in colorectal cancer 29 Table
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