Dokument: Hochauflösende Array-CGH-Analysen zum Nachweis submikroskopischer Aberrationen bei Myelodysplastischen Syndromen (MDS)

Titel:	Hochauflösende Array-CGH-Analysen zum Nachweis submikroskopischer Aberrationen bei Myelodysplastischen Syndromen (MDS)
Weiterer Titel:	Detection of submicroscopic aberrations in myelodysplastic syndromes (MDS) using high-resolution array CGH
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=16824
URN (NBN):	urn:nbn:de:hbz:061-20101208-112658-7
Kollektion:	Dissertationen
Sprache:	Deutsch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Dr. rer. nat. Pölitz, Anne [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 9,53 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 02.12.2010 / geändert 02.12.2010
Stichwörter:	MDS, Array-CGH, Aberrationen
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibungen:	Die Myelodysplastischen Syndrome (MDS) sind gekennzeichnet durch eine ineffektive Hämatopoese mit Zytopenien, Zelldysplasien sowie Blasten in Knochenmark und/oder Blut. Sie zählen zu den häufigsten Neoplasien im Alter und gehen zu 25% in die Akute Myeloische Leukämie über. 50% der Patienten weisen zytogenetisch sichtbare, klonale chromosomale Aberrationen (≥ ~5 Mb) auf. Häufigkeit und Loci dieser Veränderungen sind von großer Wichtigkeit und teilweise im Prognose- und Klassifikationssystem (IPSS und FAB/WHO) verankert. In dieser Arbeit wurden MDS-Patienten mit zytogenetisch normalem Karyotyp analysiert. In über 30% dieser Patienten konnten submikroskopische Imbalancen (≥ ~30 kb) mittels hochauflösender Oligonukleotidarray-basierter vergleichender genomischer Hybridisierung (aCGH) nachgewiesen werden. Die wenigen, aber dennoch rekurrent gefundenen kleinen Deletionen betrafen zum einen die bekannten Kandidatenregionen 5q31 und 7q22. Die Detektion zytogenetisch sichtbarer 5q- und 7q-Deletionen hat Konsequenzen für die Prognose und Therapie. Die zum anderen rekurrent auf-getretenen Deletionen von RUNX1 (21q22) und TET2 (4q24) zeigen mögliche neue 'hot spots' für genomische Veränderungen auf. Während Mutationen in RUNX1 häufig bei MDS vorkommen, wurden Deletionen bisher nicht beschrieben. TET2-Deletionen als auch -Mutationen waren zu Beginn dieser Arbeit unbekannt, es konnten jedoch in zwei Patienten genomische Verluste und in vier Patienten Mutationen identifiziert werden. Nicht rekurrent erfasste Aberrationen beinhalteten u. a. wichtige Gene der Zellzyklusregulation (CCNB1, CDKL3) oder des hämatopoetischen Systems (MCFD7, EPB24). Neben Tumor-spezifischen Anomalien könnten einige dieser Aber-rationen auch auf Keimbahnveränderungen zurückzuführen sein und sollten durch Analysen mit DNA aus Normalzellen (z. B. T-Zellen, die nicht in die MDS-Pathogenese involviert sind) überprüft werden. Mit Hilfe von Bruchpunktbestimmungen und analysen konnten häufig Mikrohomologien und seltener auch Baseninsertionen an den Deletionsenden identifiziert werden. Dies weist auf die Entstehungsmechanismen MMEJ und/oder FoSTeS für chromosomale Rearrangements hin. Die beiden verglichenen aCGH-Auswertealgorithmen GLAD und ADM-2 detektierten Imbalancen ähnlich zuverlässig und exakt. Trotzdem sollten Arraydaten mit anderen Methoden wie FISH oder qPCR bestätigt werden. Vergleiche von aCGH-Experimenten mit DNA kultivierter und unkultivierter Zellen erbrachten keine unterschiedlichen Daten. Auf Grund der wenigen rekurrenten Aberrationen konnte keine signifikante Korrelation mit dem Gesamtüberleben oder der Häufung eines MDS-Subtyps gefunden werden. Allgemein wurden weniger submikroskopische Aberrationen detektiert als erwartet und es konnte keine generelle Chromosomeninstabilität festgestellt werden. Zusammenfassend wird die aCGH-Technik, inklusive spezifischer 'custom'-Arrays, in Ergänzung zur Routinediagnostik bei MDS empfohlen, um die Art und Frequenz kryptischer Aberrationen im Hinblick auf die MDS-Pathogenese erforschen zu können. Nur so kann überprüft werden, ob sie in Zukunft als molekulare Marker oder Therapieziele genutzt werden könnten. The myelodysplastic syndromes (MDS) are characterised by an ineffective haematopoiesis with cytopenia, dysplasia and blasts in bone marrow and/or peripheral blood. MDS is a common neoplasia of the elderly and 25% of the patients develop an acute myeloid leukaemia. Half of the patients show cytogenetic visible (≥ ~5 Mb), clonal chromosomal aberrations. Great afford is made to integrate the information on the frequency of anomalies and the involved genomic loci into the prognostic scoring and classification systems. In the present thesis high definition oligonucleotidearray-based comparative genomic hybridisation (aCGH) revealed submicroscopic imbalances (≥ ~30 kb) in over 30% of patients with cytogenetically normal karyotype. Only few recurrent aberrations were found, however, some of them targeted the known candidate regions 5q31 and 7q22. The detection of cytogenetically visible 5q- and 7q-deletions has consequences on prognosis and therapeutic handling. Other recurrent findings showed deletions of RUNX1 (21q22) and TET2 (4q24) making them potential new hot spots for genomic changes. While mutations of RUNX1 are common events in MDS, deletions were not described. Deletions and mutations of TET2 were unknown prior to this thesis. However, loss of TET2 could be revealed in two patients and mutations in this gene were identified in four patients. Non-recurrent aberrations harboured important genes involved in cell cycle regulation (CCNB1, CDKL3) or haematopoietic system (MCFD7, EPB24). Besides of tumour-specific aberrations, some of these imbalances could be germ line defects and should be monitored by using DNA from normal cells (e. g. T-cells are not part of the pathogeneses of MDS). The determination of breakpoints and breakpoint analyses frequently revealed microhomologies and/or nucleotide insertions at the deletion end points, supporting the MMEJ or FoSTeS mechanisms for the formation of chromosomal rearrangements. The used analysis algorithms GLAD and ADM-2 both worked comparably and accurately, nevertheless, FISH and qPCR verifications seemed to be essential. Short culturing of cells prior to aCGH did not affect array results. Because of the small number of recurrent aberrations significant correlations with the overall survival or the MDS subtype could not be observed. In general, fewer submicroscopic aberrations than expected were found and no common chromosome instability was measured. In conclusion, the aCGH-technique with the possible flexibility of using custom-arrays should complement the routine diagnostic of MDS in order to explore the nature and occurrence of cryptic aberrations in the pathogenesis of MDS. This is necessary to evaluate their benefit as molecular markers or therapeutic targets in future.
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Lizenz:	Urheberrechtsschutz
Bezug:	Mai 2006 bis Mai 2010
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät » WE Biologie Medizinische Fakultät » Institute » Institut für Humangenetik und Anthropologie
Dokument erstellt am:	08.12.2010
Dateien geändert am:	02.12.2010
Promotionsantrag am:	12.05.2010
Datum der Promotion:	22.06.2010