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1 the Identification of Colorectal Cancer Susceptibility Genes Using The Identification of Colorectal Cancer Susceptibility Genes Using a Cross-Species, Systems Genetics Approach DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Madelyn Margaret Gerber Graduate Program in Biomedical Sciences The Ohio State University 2015 Dissertation Committee: Amanda Ewart Toland, PhD, Advisor Joanna Groden, PhD Jeffrey Parvin, MD, PhD Wolfgang Sadee, Dr.rer.nat. 1 Copyright by Madelyn Margaret Gerber 2015 2 Abstract Colorectal cancer (CRC) is the third most commonly diagnosed and third leading cause of cancer-related death in the United States. As much as 35% of risk for developing this disease is due to genetic risk factors. Genome-wide association studies (GWAS) have identified ~40 independent common risk variants that contribute to genetic predisposition. However, these variants fail to explain the majority of the genetic component for risk. Identification of additional susceptibility alleles for CRC is critical for developing genetic screening tools capable of predicting individuals at heightened genetic risk. This dissertation describes three projects aimed at uncovering CRC susceptibility genes using a cross-species systems genetics approach. The first project (Chapter 2) involves assessing single nucleotide polymorphisms (SNPs) at loci that were linked to CRC risk by GWAS for allele-specific somatic copy number gains or losses in human colorectal tumor genomes. We hypothesized that GWAS-identified SNPs exhibit allele-specific copy number changes (termed ‗allele- specific imbalance,‘ or ASI) in the tumor genome of patient specimens in much the same fashion as oncogenes are amplified and tumor suppressors are lost. We tested this hypothesis using quantitative genotyping to detect relative gains or losses of GWAS- identified SNP alleles in a cohort of human paired colorectal tumor/normal DNA samples. Testing of 17 SNPs revealed statistically significant allele-specific copy number ii changes at one SNP, rs6983267 at 8q24, which suggests that ASI occurs at CRC risk loci but perhaps at low frequency. The second project discussed in this document (Chapter 3) describes a large ASI screen of SNPs tagging for candidate genes at the human orthologs of three murine CRC susceptibility quantitative trait loci (QTL). We prioritized genes for inclusion in this study based on RNA-seq data generated from the normal colons of the CRC-resistant and CRC-susceptible mouse parental strains that were used to linkage-map these QTLs. Because no protein-damaging coding SNPs were identified by RNA-seq, we focused largely on genes showing differential expression between the strains and/or genes with a documented role in cancer-relevant pathways or processes. Two SNPs in SNX10 emerged from our screen and warrant further investigation. The third project (Chapter 4) reports our preliminary functional investigations of the hypoxia-inducible factor Epas1, whose gene maps to the Scc4 susceptibility QTL. This gene is differentially expressed in the colons of the CRC-resistant and CRC- susceptible mouse strains used to map Scc4. Furthermore, five tagging SNPs within EPAS1 show suggestive evidence of ASI in human colorectal tumor/normal DNA pairs, but were not statistically significant after correction for multiple comparisons. These data prompted us to investigate EPAS1/Epas1 for functional effects in human and mouse colon cell lines. We tested this gene for effects on β-catenin/TCF-mediated transcriptional activity under conditions of normoxia and hypoxia in SW480 and HCT116 human colon adenocarcinoma cell lines. Under hypoxic culture conditions, we observed activation of our TOPflash β-catenin/TCF reporter construct when Epas1 iii expression was enforced, suggesting a plausible role for EPAS1 in modifying CRC susceptibility. In summary, our data validate our cross-species approach as an innovative strategy for uncovering novel candidate CRC susceptibility genes. iv Dedication This document is dedicated to my parents, John and Rebecca Gerber, for their loving support and guidance. My amazing mom and dad have taught me the value of hard work, optimism, and fearlessness in the face of adversity. They are truly my superheroes without capes. v Acknowledgments I would like to acknowledge my advisor, Dr. Amanda Toland, for the knowledge and training she has imparted over the four years I was fortunate to spend in her laboratory. It was an honor and a pleasure to be mentored by such an outstanding geneticist and role model for women in science. I give sincere thanks to my committee members, Drs. Groden, Parvin, and Sadee, for their wisdom and guidance throughout my graduate education. Each member of my dissertation committee has provided invaluable insights that have been tremendously beneficial to my research and to my development as a scientist. I would like to extend many heartfelt thanks to my friends, classmates, and co-workers for the support and expertise they have provided over the course of my graduate education. Each of the following individuals has contributed their friendship, support, wisdom, and scholarly advice: Jessica Fleming, Jessica Gillespie, Bill Hankey, Andrew Kerns, Morgan Schrock, Mary Severin, Mia Tazi, and Linan Wang. vi My dear friend, Mia ―Precious‖ Tazi, encouraged me on a constant basis and was the best dissertation writing buddy anyone could ask for. I truly could not have written this document were it not for her positive energy and the comic relief she so wonderfully provided. I will forever cherish the memories of working on our dissertations together in the wee hours of the morning and our writing breaks spent laughing together over episodes of Parks and Recreation. Finally, I would like to acknowledge my dear family for giving me the strength and determination to pursue a PhD. My parents, John and Rebecca, and siblings Matthew, Blake, and Eleanor have been a source of tremendous inspiration to me. My aunt, Mary Wiley, has been a role model and second mother to me since an early age. My grandmother, Margaret Wiley, possesses such a curious mind and a keen interest in science. Her curiosity and thirst for knowledge inspire the same in me. Lastly, I wish to acknowledge my late grandfather, Donald Wiley, Jr. Grandpa Wiley was my biggest cheerleader and is the bravest and wisest man I have ever known. All my love and thanks go out to those who have helped me achieve this dream. vii Vita August 6, 1988……………………………...Born, St. Paul, MN 2006…………………………………………Mahtomedi Senior High School 2010 ...............................................................B.A. Biology and Psychology, University of Minnesota, Morris 2010 to present ..............................................Graduate Research Associate, Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University Publications Gerber MM, Hampel H, Schulz NP, Fernandez S, Wei L, Zhou X-P, de la Chapelle A, Toland AE. Evaluation of allele-specific somatic changes in genome-wide association study susceptibility alleles in human colorectal cancers. PLOS ONE 2012; 7(5): e37672. Siekmann TE, Gerber MM, Toland AE. Variants in an Hdac9 intronic enhancer impact Twist1 expression. Submitted to International Journal of Cancer, In Revision, 2015. viii Gerber MM, Hampel H, Zhou XP, Deveci M, Catalyurek U, Schulz NP, Suhy A, de la Chapelle A, Eward Toland A. Allele-specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci. Submitted to International Journal of Cancer, In Revision, 2015. Fields of Study Major Field: Biomedical Sciences (Human Genetics and Cancer Biology Areas of Emphasis) ix Table of Contents Abstract ............................................................................................................................... ii Dedication ........................................................................................................................... v Acknowledgments.............................................................................................................. vi Vita ................................................................................................................................... viii List of Tables ................................................................................................................... xvi List of Figures ................................................................................................................ xviii Chapter 1: Introduction ...................................................................................................... 1 1.1 Biology of the Colon and Rectum ............................................................................. 1 1.2 Colorectal Cancer: Cancer of the Colon or Rectum .................................................. 2 1.3 The Genetics behind Colorectal Cancer .................................................................... 4 1.4 Strategies for Identifying Colorectal Cancer Susceptibility Genes ........................... 6 1.5 Mouse Models for the Study of Colon Carcinogenesis............................................. 9 1.6 A Cross-Species, Systems Genetics Approach to Uncover Candidate Genes ........ 13 Chapter 2: Analysis of Allele-Specific Imbalance at Single Nucleotide Polymorphisms Identified by Genome-Wide Association Studies of Colorectal Cancer .......................... 19 2.1 Introduction ............................................................................................................
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