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Gene Expression in Ovarian Carcinoma and Correlation with Prognostic Factors and Survival

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Gene Expression in Ovarian Carcinoma and Correlation with Prognostic Factors and Survival Gene expression in ovarian carcinoma and correlation with prognostic factors and survival A study of mRNA and miRNA profiling and differentiality Bente Vilming Elgaaen, MD Department of Gynaecological Oncology, Women and Children's Division, Oslo University Hospital, The Norwegian Radium Hospital Oslo, Norway Department of Medical Biochemistry, Division of Diagnostics and Intervention, Oslo University Hospital, Ullevaal Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway PhD thesis 2013 © Bente Vilming Elgaaen, 2014 Series of dissertations submitted to the Faculty of Medicine, University of Oslo No. 1718 ISBN 978-82-8264-786-1 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Inger Sandved Anfinsen. Printed in Norway: AIT Oslo AS. Produced in co-operation with Akademika Publishing. The thesis is produced by Akademika Publishing merely in connection with the thesis defence. Kindly direct all inquiries regarding the thesis to the copyright holder or the unit which grants the doctorate. TABLE OF CONTENTS 1. ACKNOWLEDGEMENTS .............................................................................................. 5 2. LIST OF PAPERS ............................................................................................................. 7 3. ABBREVIATIONS ........................................................................................................... 9 4. INTRODUCTION ........................................................................................................... 13 4.1 Development of cancer ............................................................................................. 13 4.1.1 Cancer and genetics ................................................................................................. 13 4.1.2 Cancer genes ............................................................................................................ 14 4.1.3 mRNA and miRNA expression ............................................................................... 14 4.1.4 The hallmarks of cancer .......................................................................................... 17 4.2 Ovarian cancer ......................................................................................................... 20 4.2.1 Epidemiology .......................................................................................................... 20 4.2.2 Etiology ................................................................................................................... 20 4.2.3 Origin ....................................................................................................................... 21 4.2.4 Classification ........................................................................................................... 22 4.2.5 mRNA and miRNA expression ............................................................................... 24 4.2.6 Staging and metastasis ............................................................................................. 26 4.2.7 Symptoms and examination .................................................................................... 27 4.2.8 Treatment ................................................................................................................. 28 4.2.9 Prognostic factors and clinical course ..................................................................... 30 5. AIMS OF THE THESIS ................................................................................................. 33 6. MATERIALS AND METHODS .................................................................................... 35 6.1 Patients and tissue material ..................................................................................... 35 6.2 Gene expression quantification ................................................................................ 38 6.2.1 RNA isolation .......................................................................................................... 39 6.2.2 Global gene expression profiling - mRNA and miRNA ......................................... 39 6.2.3 RT-qPCR - mRNA and miRNA .............................................................................. 41 6.3 Ingenuity Pathway Analysis (IPA) ........................................................................... 44 6.4 Statistical analysis .................................................................................................... 45 6.4.1 Global gene expression analysis .............................................................................. 45 6.4.2 RT-qPCR analysis ................................................................................................... 46 6.4.3 Evaluation of associations between gene expression and clinical parameters ........ 46 7. SUMMARY OF RESULTS ........................................................................................... 47 7.1 Paper I...................................................................................................................... 47 7.2 Paper II .................................................................................................................... 48 7.3 Paper III ................................................................................................................... 49 8. GENERAL DISCUSSION ............................................................................................. 51 8.1. Considerations of patients and material ................................................................. 51 8.1.1 Selection of patients and tissue material.................................................................. 51 8.1.2 Evaluation of histological diagnosis and sample quality......................................... 52 8.1.3 Control material ....................................................................................................... 52 8.1.4 Collection of material .............................................................................................. 53 8.1.5 Follow-up data ......................................................................................................... 54 8.2 Methodological considerations ................................................................................ 54 8.2.1 RNA quality ............................................................................................................. 55 8.2.2 Global gene expression analysis .............................................................................. 55 8.2.3 RT-qPCR analysis ................................................................................................... 56 3 8.3 Interpretation of results ........................................................................................... 58 8.3.1 Differential mRNA and miRNA expression and correlation with prognostic factors and survival in HGSC ....................................................................................................... 58 8.3.2 Differential mRNA and miRNA expression and correlation with prognostic factors and survival in CCC ......................................................................................................... 65 8.3.3 General remarks ....................................................................................................... 66 9. CONCLUSIONS .............................................................................................................. 69 10. FUTURE PERSPECTIVES ......................................................................................... 71 11. ERRATUM .................................................................................................................... 73 12. REFERENCE LIST ...................................................................................................... 75 PAPERS I-III 4 1. ACKNOWLEDGEMENTS The work presented in this thesis was carried out at Oslo University Hospital (OUH), the Departments of Medical Biochemistry (Ullevaal), Gynaecology (Ullevaal) and Gynaecological Oncology (The Norwegian Radium Hospital). I am sincerely grateful for the financial support provided by The Women and Children's Division, OUH and The Inger and John Fredriksen Foundation for Ovarian Cancer Research. I also appreciate funding from Organon, providing an annual research award for gynaecology and obstetrics after evaluation by the Norwegian Society for Gynaecology and Obstetrics. I am also grateful for one year of PhD scholarship from the Health Region of South-Eastern Norway, partly applied to studies included in this thesis. I thank my main supervisor Professor emeritus Kaare Gautvik for introducing me to medical molecular genetic research in collaboration with the research group at the Department of Medical Biochemistry, OUH. I appreciate his working capacity and high ambitions, as well as his patience during my two pregnancies and maternity leaves. I am very grateful for good collaboration and invaluable help from Ole Kristoffer Olstad and Kari Bente Foss Haug at the Department of Medical Biochemistry, OUH. I thank them for excellent laboratory work, for always keeping open doors, spending precious time on my work, and for sharing their insight in molecular biology and analytic methods. I am very thankful for all support and help from Professor Anne Cathrine Staff, Departments of Gynecology and Obstetrics, OUH, Ullevaal. I really appreciate the time she has devoted to my work and for her
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