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Oligonucleotide Microarray Analysis of Chromosome-X Gene Expression in Ruman Epithelial Ovarian Cancer Cell Lines

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Oligonucleotide Microarray Analysis of Chromosome-X Gene Expression in Ruman Epithelial Ovarian Cancer Cell Lines By Marie-Helene Benoit Department of Human Genetics McGili University December 2004 A thesis submitted to the Faculty of Graduate Studies and Research in partial fulfillment of the requirements of the degree of Master of Science © Marie-Helene Benoit, 2004 Library and Bibliothèque et 1+1 Archives Canada Archives Canada Published Heritage Direction du Branch 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: 0-494-12400-8 Our file Notre référence ISBN: 0-494-12400-8 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 th es es 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 applied as an approach for identifying cancer­ related genes on chromosome-X (CHR-X) in epithelial ovarian cancer (EOC). The Hu6800 and U133A GeneChips® were used to evaluate the expression of 446 CHR-X genes in an in vitro EOC model system comprising 4 EOC cell lines and 12 primary cultures of normal ovary surface epithelia. Fifty-one new candidate CHR-X genes were identified in addition to 49 genes previously implicated in cancer. Many genes map to regions with frequent genetic aberrations in EOC tumours, or interact with the known EOC tumour suppressors BRCA 1 and BRCA2. Candidate genes described in this study may provide novel markers for histopathological subtypes, or the tumourigenic potential of EOC tumours. The X-inactive-specific-transcript (X/ST) was absent in two highly tumourigenic EOC ceillines, TOV21G and TOV112D. X/ST mRNA is important for the stability of X-chromosome-inactivation (XCI), as its absence destabilizes the silencing of genes on the inactive-X. Aberrant bi-allelic expression of FHL 1, a gene subjected to XCI was detected in the cell line TOV21G but not in the cell line TOV112D. Genotyping assays using polymorphie microsattelite markers suggested that TOV21G has retained heterozygosity of CHR-X. The majority of alleles tested for TOV112D were consistent with loss of heterozygosity of CHR-X. Taken together these findings are consistent with two proposed mechanisms mediating X/ST loss-of-expression in cancer: (1) Duplication of the active-X followed by loss of the inactive-X (TOV112D); or (2) Reactivation of the previously inactive-X (TOV21 G). RESUMÉ Dans le but d'identifier des gènes localisés sur le chromosome-X (CHR-X) associés au cancer de l'ovaire d'origine épithéliale (COE), la technologie des biopuces à ADN (GeneChip® de la compagnie Affymetrix®) a été utilisée comme approche pour étudier l'expression génique de ce chromosome. Les biopuces Hu6800 et U133A ont permis d'évaluer l'expression de 446 gènes, situés sur le CHR-X, dans un système modèle du COE in vitro. Le système modèle comprenait quatre lignées cellulaires COE malignes et douze cultures de cellules normales dérivées d'épithélium de la surface de l'ovaire. Cette étude a identifié 51 nouveau gènes candidats probablement impliqués, soit directement ou indirectement, dans la tumorigènese du COE, en plus d'avoir identifié 49 gènes dont le rôle dans le cancer a déjà été décrit. Plusieurs candidats se situent dans une région chromosomique ou l'on retrouve fréquemment des lésions génétiques dans les tumeurs COE. D'autres candidats codent pour des protéines dont l'interaction avec les gènes suppresseurs de tumeur BRCA 1 et BRCA2 sont bien connus. Les gènes candidats identifiés dans cette étude représentent de plausible bio-indicateurs d'histopathologie et/ou du pouvoir tumorigène des tumeurs COE. L'expression génique du X-inactive-specific-transcript (X/Sn, dont la fonction est clé pour l'inactivation du CHR-X (ICX), étais absente dans deux des lignées cellulaires COE phénotypiquement tumorigènes, soit TOV21 G et TOV112D. Suivant l'établissement de l'ICX, la copie du CHR-X qui a été inactivé demeure pour toujours revêtue d'une fine couche d'ARN X/ST. Ainsi, dans des cellules somatiques la perte du X/ST mène à la déstablilisation de l'état réprimé du CHR-X inactif. Une anomalie, apparemment associée à l'absence du X/ST, a été observée dans l'expression du gène FHL 1 normalement assujetti à l'ICX. L'expression bi-allélique du FHL1 a été détectée dans la lignée TOV21G mais pas dans la lignée TOV112D. L'analyse du génotype, utilisant des indicateurs microsatellites, a établis que TOV21G a retenu l'hétérozygosité du CHR-X. La majorité des allèles dépistés pour TOV112D ont été consistantes avec la perte de l'hétérozygosité. Ces résultats sont dans les normes des deux mécanismes proposés régissant la perte d'expression du gène X/ST dans les cellules tumorales: (1) Dédoublement du CHR-X actif suivi de la perte du CHR-X inactive (TOV112D); ou bien (2) Réactivation du CHR-X inactivé (TOV21 G). 11 ACKNOWLEDGEMENTS This research was funded by the NSERC PGSA scholarship and operating funds from the Canadian Institute for Health Research (CIHR) and Fonds de Recherche en Santé du Québec (Réseau Cancer du Sein et de l'Ovaire). 1 would like to acknowledge Dr Anne-Marie Mes-Masson and the members of her laboratory for ail their work in the collection of clinical materials and the maintenance of tissue cultures. 1 thank Dr Jose Correa for his advice on statistical analyses. 1 am very grateful to the former and current members of my group; Dr Nadège Presneau, Dr Zhen Chen, Dr Emily Manderson, Suzanna Arcand, Kathleen Klein, Neal Cody, and Anna Breznan for their encouragement, helpful suggestions, and numerous thought-provoking discussions. 1 thank my supervisory Committee Dr Mario Chevrette and Dr Tom Hudson for their academic guidance and the many insightful ideas they contributed. 1 am very grateful for the interest they showed in my project. 1would also like to acknowledge the members of my family as weil as my dear friends Henry Cheang, Peter Dutchak, Sandra Laberge, Janna Gowens, Samuel Truyens, Nick Brandon, and Lazlo Benak for their extensive support and encouragement over the last three years. Above ail, 1 sincerely thank my supervisor Dr Patricia Tonin for the intellectual guidance, understanding, encouragement, and support she gave throughout the challenges and successes encountered in the completion of this degree. 1 am incredibly grateful to Patricia for the patience and understanding she showed, in addition to the editorial help, during the preparation of this manuscript. 111 TABLE OF CONTENTS Abstract ........................................................................................................ Resumé ......................................................................................................... 11 Acknowledgements ... ...................... ......... 111 Table of Contents ............................................................................................. IV List of Tables....................................................................... ....... ................... Vll List of Figures... ... ... ... ... ... ... .. ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ............... ........ .... V111 List of Abbreviations............................................................... .................. ....... IX 1. INTRODUCTION 1.1 Research objectives........................................................... ....................... 1 1.2 Ovarian cancer: Clinical characteristics and biology ... ... ... ... ... ... ... ... ... .... ... ... 1 1.3 Why study the x-chromosome? ....................................... .............. .............. 2 1.4 Identification of cancer-related genes: Current strategies and new approaches........ 4 1.5 The biology of Chromosome-X inactivation...... ... ... ...... ...... ...... ............ ......... 5 1.6 Analysis of chromosome-X gene expression in an in vitro OC Model System ............. 6 2. MATERIALS AND METHODS 2.1 Description of clinical materials............................................................................. 8 2.2 Establishment
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