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Gene Expression in Pancreatic Ductal Adenocarcinoma Xenografts from BRCA Mutation Carriers Compared to Non-Carriers

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Gene Expression in Pancreatic Ductal Adenocarcinoma Xenografts from BRCA Mutation Carriers Compared to Non-Carriers Gene Expression in Pancreatic Ductal Adenocarcinoma Xenografts From BRCA Mutation Carriers Compared to Non-carriers Nikita H. Desai Department of Biochemistry Goodman Cancer Research Center (GCRC) McGill University, Montreal, QC December 2015 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Masters of Science (MSc.) in the Department of Biochemistry under the Faculty of Medicine © Nikita Desai, 2015 Thesis Abstract The following document contains a manuscript-based Masters of Science (MSc.) thesis submission for Nikita H. Desai. This thesis centers on a manuscript currently being prepared for publication: Gene expression in pancreatic ductal adenocarcinoma xenografts from BRCA mutation carriers compared to non-carriers. Pancreatic cancer has one of the worst prognoses of cancer types due to late diagnosis, rapid metastases, and a lack of effective targeted therapies. An estimated 5-10% of pancreatic cancer cases are familial, and involve germ line mutations in cancer-associated genes. Breast cancer, early onset (BRCA) genes in particular are associated with increased risk of pancreatic cancer and are the most implicated genes in hereditary pancreatic cancer. The following paper studies gene expression of 12 pancreatic ductal adenocarcinoma (PDAC) xenografts, four of which have known BRCA mutations, using RNA sequencing. 26 genes were significantly differentially expressed between the two types of tumors. Two genes and their associated pathways, in particular, were highly differentially expressed between mutation carriers and non-carriers. Cathepsin E (CTSE) and associated mucin-producing pathways were more highly expressed in mutation non-carriers. Protease, serine 1 (PRSS1) and other genes associated with hereditary and chronic pancreatitis were more highly expressed in mutation non-carriers, but all had a much lower expression than normal duct. In addendum to this thesis are included details of three papers to which the author of this thesis has contributed. These papers include: A Drosophila-centric analysis of protein tyrosine phosphatases (Hatzihristidis et al.), TC-PTP regulates the IL-7 transcriptional response during early T cell development (Pike et al.), and Modulation of PTP1b and TC-PTP expression enhances dendritic cell activation and maturation (Penafuerte et al.). ! "! Résumé Le document qui suit contient une maîtrise de la Science (MSc.) thèse pour le Département de biochimie de l'Université McGill par Nikita H. Desai. Cette thèse centres de sur un manuscrit en cours de préparation pour publication: Analyse de l'expression des gènes dans les xénogreffes d'adénocarcinome du pancréas canalaires des transporteurs de mutation BRCA par rapport aux non-porteurs. Le cancer du pancréas est l'un des pires pronostics des les cancer en raison de diagnostic tardifs, métastases rapides, et un manque de thérapies ciblées efficaces. Environ 5- 10% des les cancers du pancréas sont familiaux, et impliquent des mutations dans des gènes associés au cancer. Les BRCA gènes en particulier sont associés à un risque accru de cancer du pancréas, et sont les gènes les plus impliqués dans les cancers du pancréas héréditaire. Le thèse étudie l'expression des gènes en 12 pancréatiques adénocarcinome canalaire (PAC) xénogreffes, dont quatre ont connu des mutations BRCA, utilisant le séquençage de l'ARN. 26 gènes ont été exprimés de façon différentielle entre les deux types de tumeurs. Deux gènes et de leurs voies associées ont été très exprimés de manière différentielle. Cathepsine E (CTSE) et la production de mucine ont été plus fortement exprimés dans la mutation non-porteurs. Protéase, sérine 1 (PRSS1) et d'autres gènes associés à la pancréatite héréditaire et chronique ont été plus fortement exprimé dans la mutation non-porteurs. Dans addendum à cette thèse sont inclus détails de trois documents dont l'auteur de cette thèse a contribué. Ces documents comprennent: Une analyse Drosophile-centrique de protéines tyrosine phosphatases (Hatzihristidis et al.), TC-PTP réglemente l'IL-7 réponse transcription elle pendant le développement précoce des cellules T, et la modulation de PTP1b et TC-PTP (Pike et al) expression augmente l'activation des cellules dendritiques et de la maturation (Penafuerte et al). ! #! Preface This thesis is based on a manuscript to which I contributed as first author. I wrote the entirety of the document, including the bioinformatics analysis, discussions and conclusions herein. The contributions of each of the authors have been outlined below. I am grateful for the collaboration and contribution of many great scientists on the thesis work in this document. Contribution of Authors Dr. George Zogopoulos, a clinical oncologist at the McGill University Health Center, resected the pancreatic ductal adenocarcinoma samples analyzed in the paper from 12 of his patients. The resected tumors were xenografted into mice by Anita Hall, a research assistant in the Zogopoulos lab. The RNA was extracted and prepared for RNA sequencing by Anita Hall as well. RNA sequencing of the samples was performed at the Beijing Genomics Institute (BGI) and was paid for by the Tremblay lab. I conducted the bioinformatics analysis in this thesis, with the help and advice of Dr. Diego Miranda-Saavedra, a bioinformatician at Geneix Inc., U.K. Dr. Michel Tremblay supervised the project and revised the manuscript. The computational equipment used for the bioinformatics analysis outlined this paper was provided by the Tremblay lab. Dr. Tremblay also advised on the analysis included in the manuscript. I wrote the manuscript, and conducted the analysis of the RNA data outlined in the paper. My contributions to the three papers in addendum are outlined in detail in the paper descriptions included in addendum. ! $! Table of Contents Thesis Abstract .............................................................................................................................. 2 Résumé ........................................................................................................................................... 3 Preface ............................................................................................................................................ 4 Contribution of Authors ............................................................................................................... 4 Acknowledgements ....................................................................................................................... 8 Literature Review: Gene Expression for BRCA Mutation Carriers in Pancreatic Ductal Adenocarcinoma ........................................................................................................................... 9 Why Study Pancreatic Cancer: Improving Patient Prognosis ................................................. 9 Understanding PDAC Biology: Development and Progression ........................................... 12 Improving Early Detection and Understanding Risk Factors ............................................... 14 Risk Factors: Hereditary PC, Pancreatitis, and Inherited Mutations .................................... 16 PDAC Susceptibility for BRCA1/2 Mutation Carriers ......................................................... 17 Prevalence of BRCA1/2 Mutations ...................................................................................... 20 BRCA1/2 Mutations in Pancreatic Cancer ........................................................................... 22 Studying PDAC Gene Expression for BRCA1/2 mutation carriers ..................................... 23 RNA sequencing for gene expression ................................................................................... 26 Introduction: Gene expression profiles for PDAC xenografts in BRCA mutation carriers compared to non-carriers ....................................................................................................... 29 Abstract .................................................................................................................................... 31 1.0 Background ....................................................................................................................... 34 2. Methodology ........................................................................................................................ 38 2.1 Tumor Resection and Xenografts ................................................................................... 38 2.2 Bioinformatics Analysis .................................................................................................. 38 2.3 Unsupervised Analysis: Hierarchical Clustering ............................................................ 39 2.4 Supervised Clustering: BRCA mutation carriers vs. non-carriers .................................. 40 3. Results .................................................................................................................................. 43 3.1 Unsupervised Analysis: Hierarchical Clustering ............................................................ 43 3.2 Supervised Analysis – Differential Gene Expression: .................................................... 44 ! %! 4. Discussion ............................................................................................................................ 54 4.1 CTSE, MUC6, TFF1 and mucin production in sporadic PDAC cases ........................... 54 4.2 PRSS1 and co-expressed genes have decreased expression in chronic
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