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Phd Thesis All Chapters Final Revisions- Jerry Machado

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Phd Thesis All Chapters Final Revisions- Jerry Machado THE MOLECULAR CHARACTERIZATION OF HEAD AND NECK CANCER IN YOUNG PATIENTS by Jerry Machado A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Laboratory Medicine and Pathobiology University of Toronto © Copyright by Jerry Machado 2010 THE MOLECULAR CHARACTERIZATION OF HEAD AND NECK CANCER IN YOUNG PATIENTS Jerry Machado Doctor of Philosopy Laboratory Medicine and Pathobiology University of Toronto 2010 Abstract Head and neck squamous cell carcinomas (HNSCCs) most commonly develop in older patients (≥60 years of age) with a history of tobacco and alcohol use. However, young individuals (≤45 years of age) can also develop HNSCC, often without common risk factors. Increasing evidence shows that Human Papillomavirus (HPV) infection is associated with particular HNSCC sites (e.g. oropharynx). We assessed the Roche Linear Array HPV Genotyping Test in several lesions and then examined the prevalence of HPV in HNSCCs from young and older patients. HPV infection was most prevalent in oropharyngeal cancers (16/22, 73%), rarely found in oral cavity cancers (2/53, 4%), and other head and neck sites (1/17, 6%). HPV positive tumors were associated with patients that were >40 and <60 years old (p=0.02). The absence or shortened time of carcinogen exposure from common risk factors and the development of oral squamous cell carcinoma (OSCC) at an early age suggest aberrant genetic events that are different than those in OSSCs from older patients. We used Affymetrix SNP 6.0 arrays to genomically profile oral tumors from young and older patients. Tumors from young patients showed different regions/genes of copy number alterations than those from older patient tumors. An increase of regions of loss of ii heterozygosity (LOH) in tumors from older patients was observed, and there was a high prevalence of copy number neutral LOH on chromosome 9 in tumors from young and older patients. These data suggest different genetic mechanisms in these patient groups. We have previously shown that HNSCCs from younger patients exhibited a high incidence of microsatellite instability (MSI), a marker of defective mismatch repair (MMR). Deregulated mRNA levels of hPMS1, hPMS2 and hMLH1 were observed and absent/low expression of hPMS1, hPMS2 and hMLH1 protein levels were observed in >50% of OSCCs. No mutations were observed in hPMS1 and hPMS2 and no significant differences of MSI or LOH were observed across genomic loci between tumors of young and older patients. The role of these genetic mechanisms in oral cancer appears complex; studies such as ours should further improve our knowledge of the molecular mechanisms leading to early-onset oral carcinomas. iii Acknowledgements An old proverb states that it takes a community to raise a child, and I think this proverb can similarly be applied to the many people who have given me support over the years in helping me complete my doctoral studies. I have many people to thank during my time at the Princess Margaret Hospital through the University of Toronto in the department of Laboratory Medicine and Pathobiology. I would like to thank all the students and colleagues I have been able to interact with over the years and share in their experiences. We somehow managed to keep on striving to better ourselves. I would like to acknowledge the people in the laboratory over the years, which have become like family to me. Specifically, I would like to thank Patricia Reis, who has been a mentor to me over the last 5 years; Nilva Cervigne, we had some good times and laughs; Mahadeo Sukhai, a good guy to talk about science, for his revisions, and his constructive criticism; Natalie Naranjo Galloni, for being a good friend and keeping me on track; Rashmi Goswami, for helping me understand pathology and going with me to crazy concerts; and all the other people in our lab that I’m grateful in meeting, including Mariam Thomas, Yali Xuan, Miranda Tomenson, Rikki Bharadwaj, Paula Bohrer, Grace Bradley and the many summer students over the years. I would like to thank my Ph.D. committee members Drs. Jeremy Squire, Jonathan Irish, and Robert Bristow; they always had words of encouragement and helpful suggestions. Lastly I would like to give a big thanks to my Ph.D. supervisor, Dr. Suzanne Kamel‐Reid, for giving me the opportunity to work in her research laboratory, scientific support, and giving me an opportunity to grow as a scientist and as a person. iv The last group of people that I would like to thank is my family, who has given me all the support over the years. I am in debt to my in‐laws, Connie and Philip Buchanan, for all of their support, and for taking me in as a son of their own. I am also extremely lucky to have supporting parents, Maria Deontina “Tina” and Luis Machado, who have always wanted me to grow and strive, and sacrificed a lot for me to get where I am. Also, my brother, Nathan Machado, we have some good times even though we are years apart. To all of my friends, extended family members, including my aunts, uncles, cousins, and those who have passed on I say a big thanks. To the girls of my life: my wife and daughter, Jennifer and Angelina. I am so blessed to have you both, for your love, and for keeping me grounded. We have been through a lot over the years, and our love for each other keeps growing stronger. I look forward to the future together, as we grow as a family. Good things come to those who wait. Lastly I would like to acknowledge God, for all the things he has provided me: family, food, shelter, support, good health and an education. Thanks for giving me the strength to endure the hardships of the Ph.D. I look forward to what is in store for the future. Jerry Machado v Table of Contents Abstract........................................................................................................................... ii Acknowledgements ...................................................................................................... iv Table of Contents.......................................................................................................... vi List of Tables ................................................................................................................. ix List of Figures ............................................................................................................... xi List of Appendices ...................................................................................................... xiii Abbreviations ............................................................................................................... xv CHAPTER 1: HEAD AND NECK CANCER ................................................................... 1 1.1 INTRODUCTION .................................................................................................... 1 1.1.1 Head and Neck Cancer and Risk Factors........................................................ 1 1.1.2 Worldwide Prevalence ..................................................................................... 3 1.1.3 Clinical Presentation and Management ........................................................... 4 1.1.4 Head and Neck Tumor Staging........................................................................ 5 1.1.5 Patient Survival and Tumor Recurrence.......................................................... 8 1.1.6 Cancer Stem Cells and Head and Neck Cancer.............................................. 9 1.1.7 Conventional Therapies................................................................................. 12 1.1.8 Molecular Characterization ............................................................................ 14 1.1.9 Molecular Targeted Therapy in HNSCC ........................................................ 17 1.1.10 Familial Involvement and Genetic Susceptibility.......................................... 19 1.1.11 Young Patients............................................................................................. 22 1.2 PhD THESIS OBJECTIVE.................................................................................... 26 1.2.1 Specific Objectives and Hypotheses.............................................................. 26 CHAPTER 2: HUMAN PAPILLOMAVIRUS AND HEAD AND NECK CANCER......... 29 I. Comparison of Gel-Based PCR and the Digene HPV HC2 DNA Test to the Roche Linear Array HPV Genotyping Test in Cancers and Dysplasias from Different Anatomic Sites. ............................................................................................................ 29 2.1 INTRODUCTION .................................................................................................. 29 2.2 MATERIALS AND METHODS.............................................................................. 31 2.2.1 Patient Consent ............................................................................................. 31 2.2.2 Tumor Samples.............................................................................................. 31 2.2.3 DNA Isolation from Tumor Samples .............................................................. 31 2.2.4 HPV Detection by Gel-Based PCR................................................................ 33 2.2.5 HPV Detection by the Digene HPV HC2 DNA Test....................................... 34 2.2.6 HPV Detection by the Linear Array................................................................ 35 2.3 RESULTS ............................................................................................................
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