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Und Jugendmedizin Der Universität Zu Köln Klinik Und Poliklinik Für Kinder- Und Jugendmedizin Direktor: Universitätsprofessor Dr

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Und Jugendmedizin Der Universität Zu Köln Klinik Und Poliklinik Für Kinder- Und Jugendmedizin Direktor: Universitätsprofessor Dr Aus dem Zentrum für Kinder- und Jugendmedizin der Universität zu Köln Klinik und Poliklinik für Kinder- und Jugendmedizin Direktor: Universitätsprofessor Dr. med. J. Dötsch Vergleich des Transkriptoms mikrodissezierter Neuroblastome mit fetalen Neuroblasten Inaugural-Dissertation zur Erlangung der Doktorwürde der Hohen Medizinischen Fakultät der Universität zu Köln vorgelegt von Ute Susanne Beutenmüller aus Schopfheim promoviert am 23. Juli 2014 Gedruckt mit der Genehmigung der Medizinischen Fakultät der Universität zu Köln 2014 Dekan: Universitätsprofessor Dr. med. Dr. h.c. Th. Krieg 1. Berichterstatter: Professor Dr. med. M. Fischer 2. Berichterstatter: Privatdozent Dr. med. L. Heukamp Erklärung Ich erkläre hiermit, dass ich die vorliegende Dissertationsschrift ohne unzulässige Hilfe Dritter und ohne Benutzung anderer als der angegebenen Hilfsmittel angefertigt habe; die aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche kenntlich gemacht. Bei der Auswahl und Auswertung des Materials sowie bei der Herstellung des Manuskriptes habe ich Unterstützungsleistungen von folgenden Personen erhalten: Professor Dr. med. Matthias Fischer. Weitere Personen waren an der geistigen Vorstellung der vorliegenden Arbeit nicht beteiligt. Insbesondere habe ich nicht die Hilfe einer Promotionsberaterin/ eines Promotionsberaters in Anspruch genommen. Dritte haben von mir weder unmittelbar noch mittelbar geldwerte Leistungen für Arbeiten erhalten, die im Zusammenhang mit dem Inhalt der vorgelegten Dissertationsschrift stehen. Die Dissertationsschrift wurde von mir bisher weder im Inland noch im Ausland in gleicher oder ähnlicher Form einer anderen Prüfungsbehörde vorgelegt. Köln, 29.04.2013_____________________ (Ute Beutenmüller) Die in dieser Arbeit angegebenen Experimente sind von mir mit Unterstützung meines Betreuers Herrn Professor Dr. med. Matthias Fischer und den medizinisch-technischen Assistentinnen Frau Yvonne Kahlert, Frau Nadine Hemstedt und Frau Anne Engesser durchgeführt worden. Bei bioinformatischen Fragestellungen erfolgte die Unterstützung von Herrn Dr. Frederik Roels, Frau Dr. Ruth Volland und Frau Dr. Barbara Hero. Beratend in Bezug auf technische und organisatorische Fragen standen mir Frau Dr. Hayriye Kocak, Frau Dr. Sandra Ackermann und Frau Heike Düren zur Seite. Die immunhistochemische Färbung, Zellerkennung und Zellgewinnung mittels Lasermikroskopie erfolgte zu großen Teilen in Frankfurt am Main mit Hilfe von Frau Privatdozentin Dr. med. Sylvia Hartmann, Herrn Ralf Lieberz und der technischen Assistentin Frau Yvonne Michel des Dr. Senckenbergischen Instituts für Pathologie des Klinikums der J. W. Goethe-Universität Frankfurt am Main unter Leitung von Herrn Professor Dr. med. Dr. h.c. Martin-Leo Hansmann. Die Zellgewinnung in Köln erfolgte mit Hilfe des Lasermikroskops der Pathologie des Universitätsklinikums zu Köln der Forschungsgruppe unter Frau Privatdozentin Dr. med. Margarete Odenthal unter Leitung von Herrn Professor Dr. med. Reinhard Büttner. Danksagung Ich danke Herrn Professor Dr. med. Frank Berthold für die Möglichkeit, mich dieser Arbeit zu widmen. Ganz besonderer Dank gilt Herrn Professor Dr. med. Matthias Fischer, der viel Zeit in die Betreuung dieser Arbeit investiert hat, für die sehr gute wissenschaftliche Unterstützung und zahlreiche Diskussionen. Des Weiteren danke ich allen Mitarbeitern des Labors für pädiatrische Onkologie des Universitätsklinikums zu Köln, die mir direkt oder indirekt geholfen haben. Ohne die Unterstützung und Hilfe der medizinisch-technischen Assistentinnen Frau Yvonne Kahlert, Frau Nadine Hemstedt und Frau Anne Engesser wäre diese Arbeit nicht möglich gewesen. Des Weiteren möchte ich mich bei Herrn Dr. Frederik Roels, Frau Dr. Ruth Volland und Frau Dr. Barbara Hero für die Unterstützung im Bereich Bioinformatik und Statistik bedanken. Mein Dank gilt auch Frau Dr. Hayriye Kocak, Frau Dr. Sandra Ackermann und Frau Heike Düren für die geduldige Unterstützung und Beantwortung vieler Fragen. Herrn Professor Dr. med. Dr. hc. Martin-Leo Hansmann und der Abteilung für Pathologie des Klinikums der J. W. Goethe-Universität Frankfurt am Main, insbesondere Frau Privatdozentin Dr. Sylvia Hartmann, Herrn Ralf Lieberz und der technischen Assistentin Frau Yvonne Michel gilt mein besonderer Dank für die freundliche Unterstützung bei der immunhistochemischen Färbung, Zellerkennung und Zellgewinnung mittels Lasermikroskopie. Ebenso danke ich Herrn Professor Dr. Reinhard Büttner des Instituts für Pathologie des Universitätsklinikums zu Köln und insbesondere Frau Privatdozentin Dr. med. Margarete Odenthal für die Bereitstellung der technischen Hilfsmittel zur Lasermikroskopie. Zu guter Letzt gilt ganz besonderer Dank meiner Mutter Susanne Beutenmüller und Martin Hellmann für die langjährige Unterstützung und Ermutigung. Für Martin Verzeichnisse I Inhaltsverzeichnis Abkürzungsverzeichnis .................................................................................. IV 1 Einleitung .................................................................................................... 1 1.1 Prognosemarker des Neuroblastoms ................................................... 2 1.1.1 Tumorstadium ......................................................................... 3 1.1.2 Alter ........................................................................................ 4 1.1.3 MYCN Amplifikation ................................................................ 5 1.1.4 Tumorzellploidie ...................................................................... 5 1.1.5 Zytogenetische Aberrationen .................................................. 6 1.1.6 Neurotrophinrezeptor TrkA, TrkB, und TrkC ........................... 6 1.1.7 Histologie ................................................................................ 7 1.2 Krankheitsverlauf des Neuroblastoms ................................................. 8 1.3 Neuroblastomentstehung ..................................................................... 9 1.4 Laser Mikrodissektion ........................................................................ 11 1.5 Genexpressionsanalysen ................................................................... 13 1.5.1 Mikroarrays und Hybridisierung ............................................ 13 1.5.2 Genexpressionsanalysen in der onkologischen Forschung .. 14 Fragestellung der Arbeit ................................................................................ 17 2 Material und Methoden ............................................................................ 18 2.1 Systematik der angewandten Methoden ............................................ 18 2.2 Patientenmaterial ............................................................................... 19 2.3 Identifikation der Zellen ...................................................................... 20 2.4 Immunhistochemie ............................................................................. 21 2.4.1 BCL-2 .................................................................................... 22 2.4.2 NCAM ................................................................................... 22 2.5 Schnitte und Hämatoxylin-Eosin Färbung .......................................... 23 2.6 Lasermikrodissektion ......................................................................... 24 2.7 Amplifikation ....................................................................................... 25 2.7.1 Zelllyse, mRNA Markierung und magnetische mRNA Isolation .............................................................................................. 27 2.7.2 cDNA Synthese im Säulchen ................................................ 28 2.7.3 Anhängen einer DNA Sequenz (TAG) an die cDNA ............. 29 2.7.4 Amplifikation der cDNA durch Polymerasekettenreaktion ..... 29 2.7.5 Klenow Markierung der amplifizierten cDNA ......................... 31 2.8 Aufreinigung ....................................................................................... 32 2.8.1 PCR Produkt Aufreinigung .................................................... 32 2.8.2 Illustra CyScribe GFX Aufreinigung ...................................... 32 2.9 Methoden der Qualitäts- und Quantitätskontrolle ............................... 33 2.9.1 Mikroelektrophoretische Kontrolle ......................................... 33 2.9.2 Spectrophotometrische Kontrolle .......................................... 34 2.10 Mikroarray Analyse ............................................................................ 35 II Verzeichnisse 2.10.1 Hybridisierung ....................................................................... 35 2.10.2 Scannen der Mikroarrays ...................................................... 37 2.11 Statistische Methoden ........................................................................ 38 2.11.1 Nicht überwachte Cluster Analysen ...................................... 38 2.11.2 Hauptkomponentenanalyse .................................................. 38 2.11.3 Varianzanalyse ..................................................................... 39 2.12 Gene Ontology Analysen ................................................................... 39 2.13 Chargeneinfluss (Batch Effect) .......................................................... 40 3 Ergebnisse ................................................................................................ 41 3.1 Färbung und Immunhistochemie ........................................................ 41 3.2 RNA
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