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Proquest Dissertations Expression analysis of the 3p25.3-ptelomere genes in epithelial ovarian cancer By Vanessa Delphine Rossiny Department of Human Genetics McGill University, Montreal January 2008 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Master of Science © Vanessa Delphine Rossiny 2008 Library and Bibliothèque et 1+1 Archives Canada Archives Canada Published Heritage Direction du Bran ch Patrimoine de l'édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A ON4 Ottawa ON K1A ON4 Canada Canada Your file Votre référence ISBN: 978-0-494-51333-0 Our file Notre référence ISBN: 978-0-494-51333-0 NOTICE: AVIS: The author has granted a non­ L'auteur a accordé une licence non exclusive exclusive license allowing Library permettant à la Bibliothèque et Archives and Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l'Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans loan, distribute and sell theses le monde, à des fins commerciales ou autres, worldwide, for commercial or non­ sur support microforme, papier, électronique commercial purposes, in microform, et/ou autres formats. paper, electronic and/or any other formats. The author retains copyright L'auteur conserve la propriété du droit d'auteur ownership and moral rights in et des droits moraux qui protège cette thèse. this thesis. Neither the thesis Ni la thèse ni des extraits substantiels de nor substantial extracts from it celle-ci ne doivent être imprimés ou autrement may be printed or otherwise reproduits sans son autorisation. reproduced without the author's permission. ln compliance with the Canadian Conformément à la loi canadienne Privacy Act some supporting sur la protection de la vie privée, forms may have been removed quelques formulaires secondaires from this thesis. ont été enlevés de cette thèse. While these forms may be included Bien que ces formulaires in the document page count, aient inclus dans la pagination, their removal does not represent il n'y aura aucun contenu manquant. any loss of content from the thesis. ••• Canada Abstract Microarray expression analysis was carried out to identify genes with a role in epithelial ovarian cancer (EOC). The U133A Affymetrix GeneChip® was used to determine the expression patterns of the 3p25.3-ptel genes represented on the microarray in 14 primary cultures of normal ovarian surface epithelial (NOSE) samples, 25 frozen malignant ovarian tumor samples and four EOC celllines. Seven genes with differentiai expression patterns in the tumor samples compared to the NOSE samples were identified as candidates for further analysis, starting withARPC4, SRGAP3 andATP2B2. Although none ofthe candidates had been previously studied in ovarian cancer, severa! had either family or pathway members that had. Expression patterns seemed unaffected by either tumor histopathological subtype or the allelic imbalances observed with loss of heterozygosity (LOH) analysis. The absence of association with genomic context suggested that differentiai expression was the result oftranscriptional regulation rather than direct targeting. 11 Résumé La technologie de biopuce à ADN a été utilisée dans le but d'identifier des gènes ayant un rôle dans le cancer de l'ovaire d'origine épithéliale (COE). La Ul33A GeneChip® de la compagnie Affymetrix a permis de déterminer les profils d'expression des gènes situés sur la région 3p25.3-ptel et représentés sur la biopuce dans 14 cultures de cellules normales dérivées de l'épithélium de la surface de l'ovaire, 25 tumeurs malignes de 1' ovaire congelées et quatre lignées cellulaires de COE. Sept gènes ayant une expression différentielle dans les tumeurs comparées avec les cellules normales ont été identifiés comme candidats méritant d'être analysés plus en détail, en commençant par ARPC4, SRGAP3 et ATP2B2. Bien qu'aucun des candidats n'ait été identifié auparavant en relation avec le cancer des ovaires, plusieurs ont des membres de leur famille ou de leur processus cellulaire qui 1' ont été. Les profils d'expression ne semblaient pas être affectés par 1'histopathologie des tumeurs ou la présence de pertes alléliques détectées par une analyse de perte d'hétérozygotie. L'absence d'association avec le contexte génomique suggère que 1' expression différentielle des gènes candidats était due à une régulation au niveau du transcriptome plutôt qu'à un ciblage direct des gènes. 111 Acknowledgments I would like to start by thanking Dr. Patricia Tonin for her continued support and understanding throughout the project, and for the intellectually stimulating and collaborative environment she created. This research was supported by funding from CIHR, Genome Quebec/Canada, and the Banque de tissus et de données of the Réseau de recherche sur le cancer of the FRSQ. I thank the Research Insitute of the McGill University Health Centre for providing me with a scholarship. I am truly grateful for the opportunity I had to work with remarkable lab members, past and present: Suzanna Arcand, Marie-Hélène Benoit, Anna Breznan, Ashley Birch, Luca Cavalloni, Neal Cody, Karen Gambaro, Kathleen Klein, Nadège Presneau, Michael Quinn, Paulina Wojnarowicz and Zhen Shen, and would like to thank them for their help and thought-provoking discussions. I thank Nancy Hamel and Tayma Kahlil of Dr. William Foulkes' laboratory for their support. I thank my Supervisory Committee Members Dr. Mark Trifiro and Dr. Jacques Galipeau for their academie guidance. I acknowledge the work carried out by Dr. Anne-Marie Mes-Masson and her laboratory members in the collection of clinical material, DNA and RNA extraction, and maintenance of tissue cultures, as well as the microarray hybridization. I synthesized the eDNA by reverse transcriptase polymerase chain reaction (RT-PCR) in collaboration with Ashley Birch. I carried out the LOH experiments for the 3p26.3 region and analyzed the microarray and RT-PCR gene expression data and LOH results. Above ali, I would like to express to my family and friends how grateful I am for their support and encouragement, especially Paulina Wojnarowicz and Marie- Hélène Benoit for their insightful help and Ashley Birch for her editorial help during the writing of this the sis. lV Table of Contents ~ 11 Abstract 111 Résumé lV Acknowledgements v Table of Contents vm List of Tables ix List of Figures x Abbreviations ~ Sec. Title 1 1 Introduction 1 1.1 Ovarian cancer biology and Qathology 1 1.1.1 Ovarian cancer overview 2 1.1.2 Potential EOC origins 3 1.1.3 EOC classification 4 1.2 Study models chosen to analyze EOC gene exQression Qattems 6 1.3 Cytogenetic and molecular genetic alterations in EOC 6 1.3.1 Cytogenetic analyses provide information on ovarian . carcmogenes1s 7 1.3.2 Molecular analyses of specifie chromosomal regions and genes 7 1.3.2.1 Cancer genes overview and germline mutations lü 1.3.2.2 Genes, regions and pathways implicated in EOC 12 1.3.2.3 Evidence of a role for chromosome 3p in EOC 14 1.4 Project hyQothesis and study aims 15 2 Materials and Methods 15 2.1 Clinical samQles 15 2.1.1 Ovarian cancer samples 15 2.1.2 Primary cultures ofNOSE samples 17 2.1.3 EOC celllines -~ 17 2.2 Nucleic Acid Extraction v 19 2.3 LOH analysis 20 2.4 Microarray expression data 20 2.4.1 Obtainment of the microarray data 21 2.4.2 Microarray analysis 23 2.5 Reverse-transcriptase PCR (RT-PCR) analysis 25 3 Results 25 3.1 LOH analysis 25 3.2 Expression analysis 25 3.2.1 Microarray gene representation 27 3.2.2 Analysis of the expression data for the primary cultures ofNOSE samples 30 3.2.3 Analysis ofthe EOC cellline gene expression data 34 3.2.4 Analysis of the gene expression data for the TOV samples 34 3.2.4.1 Expression profiles of the TOV expression data 36 3.2.4.2 Two-way comparative analysis between the TOV and NOSE samples 41 3.2.5 RT-PCR analysis 43 3.3 Integration of expression and LOH results 45 4 Discussion 45 4.1 Information on the 3p25.3-ptel chromosomal region 45 4.1.1 Information obtained from the physical and genetic maps 45 4.1.1.1 Physical map information 46 4.1.1.2 Genetic map information 47 4.1.2 End of chromosome information 47 4.1.2.1 Telomeres 50 4.1.2.2 Subtelomeres 50 4.2 LOH analysis supported a role for 3p25.3-ptel genes in EOC 50 4.2.1 AI patterns in the 3p25.3-ptel region may be due to loss or gain ~· 53 4.2.2 Significance ofthe AI patterns observed Vl 53 4.2.3 The TSG candidate genes and their potential role in EOC /""", 54 4.2.3.1 Close homolog ofL1 (CHLJ) 56 4.2.3.2 Contactin 4 and 6 (CNTN4 and CNTN6) 57 4.2.3.3 The LOH candidate genes may play a role in tumor migration 57 4.3 Discussion of the gene exgression data 57 4.3.1 Expression profiles ofthe NOSE, TOV and EOC samples 58 4.3.2 Two-way comparative analyses identify differentiai expression patterns between NOSE and TOV samples which transcend histopathological subtype and genomic content 62 4.3.3 The microarray candidate genes and their potential role in EOC 62 4.3.3.1 The main microarray candidates (ARPC4, SRGAP3, ATP2B2) 64 4.3.3.2 EDEMJ, ITPRJ and OXTR 66 4.3.3.3 Conclusion 66 4.4 Exgerimental and biologicallimitations of this groject 66 4.4.1 Limitations due to the methods used 67 4.4.2 Limitations due to the samples used 68 4.4.3 Limitations due to the analysis carried out 69 4.5 Future directions 71 References 99 Appendices 99 Appendix I - N ormalized microarray gene expression data for the 14 primary cultures ofNOSE samples and the 25 TOV samples 103 Appendix II- Correlation analyses among the NOSE samples (1 ), between the NOSE and TOV samples (2), and among the TOV samples (3) 106 Appendix III - Ethics committee approval 108 Appendix IV - Qualification for radioisotope use vii List of Tables ~· Table Title 16 Table 2.1 Primary culture ofNOSE and TOV sample information 18 Table 2.2 Information regarding the spontaneously transformed EOC celllines 24 Table 2.3 RT-PCRprimers 26 Table 3.1 LOH analysis ofmalignant tumor samples (TOV samples; n=21) 28 Table 3.2 RefSeq Genes and Data- October 2007 UCSC (Mar.
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