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ABSTRACT ANGSTADT, ANDREA Y. Evaluation of the Genomic

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ABSTRACT ANGSTADT, ANDREA Y. Evaluation of the Genomic ABSTRACT ANGSTADT, ANDREA Y. Evaluation of the Genomic Aberrations in Canine Osteosarcoma and Their Resemblance to the Human Counterpart. (Under the direction of Dr. Matthew Breen). In the last decade the domestic dog has emerged as an ideal biomedical model of complex genetic diseases such as cancers. Cancer in the dog occurs spontaneously and several studies have concluded that human and canine cancers have similar characteristics such as presentation of disease, rate of metastases, genetic dysregulation, and survival rates. Furthermore, in the genomic era the dog genome was found more homologous in sequence conservation to humans than mice, making it a valuable model organism for genetic study in addition to pathophysiological analysis. Osteosarcoma (OS), the most commonly diagnosed malignant bone tumor in humans and dogs, is one such cancer that would benefit from comparative genomic analysis. In humans, OS is a rare cancer diagnosed in fewer than 1,000 people per year in the USA, while in the domestic dog population the annual number of new cases is estimated to far exceed 10,000. This high rate of disease occurrence in dogs provides a unique opportunity to study the genomic imbalances in canine OS and their translational value to human OS as a means to identify important alterations involved in disease etiology. OS in humans is characterized by extremely complex karyotypes which contain both structural changes (translocations and/or rearrangements) and DNA copy number changes. Metaphase and array comparative genomic hybridization (aCGH) has assisted in uncovering the genetic imbalances that are associated with human OS phenotype. In dog OS, previous low-resolution (10-20Mb) aCGH analysis identified a wide range of recurrent copy number aberrations (CNAs), indicative of a similar level of genomic instability to human OS. To further interpret chaotic OS karyotypes a genome-wide approach was taken to identify, characterize, and directly compare genomic instability in canine and human OS. For identification of genome-wide CNAs 123 cases of canine OS were profiled by 1Mb-resolution aCGH, 23 of the 123 cases were subsequently profiled by ~27kb-resolution aCGH and 15 cases of human OS were profiled by ~100kb-resolution aCGH. Subsequent fluorescence in-situ hybridization (FISH) analysis was used to confirm aCGH data, quantify numerical imbalances, and visualize structural abnormalities in a subset of dog OS cases. Characterization of the affect that CNA has on the expression of select cancer associated genes revealed that imbalance and transcriptional dysregulation in canine OS also paralleled human OS. Specifically, changes in RUNX2, TUSC3, and PTEN expression levels correlated with genomic copy number status in dog OS. This analysis showcased RUNX2 as an ‘OS associated gene’ and TUSC3 as a tumor suppressor gene involved in canine OS. In addition, direct comparison of genomic imbalance in human and dog OS using high resolution oligonucleotide aCGH indicated that the ‘OS associated genes’ RUNX2, CDKN2A/CDKN2B, MYC, RB1, and PTEN resided in orthologous microaberration regions (<500kb) with similar CNA patterns supporting that these genes are key genetic players driving OS progression. Similarities in genome-wide CNA patterns in OS between orthologous regions of the human and dog genome were also found suggesting that characterization of genes in these regions may identify additional alterations important for OS manifestation. Ultimately, this large scale screening of genomic imbalance in canine OS reiterates the value of the dog as a biomedical model of human OS while pinpointing key genes dysregulated in the disease in dogs. Upon further investigation, the genes with parallel CNA frequencies in human and dog OS may serve as possible targets of novel genetic therapeutics that once developed and tried in dogs could be translational to human patients. Evaluation of the Genomic Aberrations in Canine Osteosarcoma and Their Resemblance to the Human Counterpart by Andrea Y. Angstadt A dissertation submitted to the Graduate Faculty of North Carolina State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy Functional Genomics Raleigh, North Carolina 2010 APPROVED BY: _______________________________ ______________________________ Dr. Matthew Breen Dr. Dahlia M. Nielsen Committee Chair _______________________________ ______________________________ Dr. David E. Malarkey Dr. Marlene L. Hauck DEDICATION To my parents, Roy and Ann Young, for your love, guidance, and support To my husband, Nathan, for joining me in this journey ii BIOGRAPHY Andrea developed her love for biology at an early age through hiking trips, raising farm animals, and grade school science fair projects. After graduating high school she went to Penn State University and completed a degree in animal bioscience with a minor in biology. During her time at Penn State she worked in a laboratory studying the genetic affect of external and internal factors on cacao plant growth and response as a means to improve plant productivity. She also completed an undergraduate research project identifying potential mutations in the leptin receptor gene associated with the diabetic and obese phenotype in the Butterball strain of mice. These projects increased her interest in genetics and its’ role in veterinary and human diseases. Therefore, she decided to continue her research training in the Functional Genomics Doctorate program at North Carolina State University. iii ACKNOWLEDGMENTS I would like to thank my committee members, Dr. David Malarkey, Dr. Dahlia Nielsen, and Dr. Marlene Hauck for providing support, discussions, and aid in my research progress. Thanks to Dr. Dahlia Nielsen and Dr. Alison Motsinger-Reif for helping me learn how to manage large datasets and conduct appropriate statistical analyses and to Dr. Eric Stone for your excellent teaching of bioinformatics. Dr. Ted Emigh, it was a pleasure to TA for your genetic class and I appreciate the aid you gave in developing my teaching skills. To the Breen Lab through the years; Tessa Breen, Benoit Hedan, Shannon Becker, Rachael Thomas, Christina Williams, Eric Seiser, Pei-Chen Tsai, Kate Kelley, Katie Kennedy, and Kristen Maloney, thanks for making the work environment so much fun. I cherish all our discussions and will miss you all! To my father, my brother Hugh, and Erin Parker thanks so much for your editing skills and advice. Lastly, a special thanks to Dr. Matthew Breen for your direction and guidance through my graduate years and future endeavors. iv TABLE OF CONTENTS LIST OF TABLES................................................................................................................. viii LIST OF FIGURES ..................................................................................................................x LIST OF ABBREVIATIONS ............................................................................................... xiii Chapter I: Literature Review .................................................................................................1 Overview....................................................................................................................................2 Dog as a suitable model of human disease ................................................................................3 The pathology of osteosarcoma .................................................................................................9 Molecular and genetic dysregulation of osteosarcoma............................................................13 Genomic Studies ......................................................................................................................17 Thesis Outline ..........................................................................................................................31 References................................................................................................................................32 Chapter II: Characterization of canine osteosarcoma by array comparative genomic hybridization and qRT-PCR: Signatures of genomic imbalance in canine osteosarcoma parallels the human counterpart ..........................................................................................49 Abstract....................................................................................................................................50 Introduction..............................................................................................................................51 Materials and Methods.............................................................................................................53 Tissue Specimens...............................................................................................................53 Array Comparative Genomic Hybridization (aCGH)........................................................55 Fluorescence in-situ Hybridization (FISH)........................................................................56 Quantitative RT-PCR.........................................................................................................57 Statistical Analysis.............................................................................................................58 Results......................................................................................................................................59 Clinical Assessment............................................................................................................59
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