Dokument: Stellenwert von somatischen Genmutationen auf die Prognose von Patienten mit Myelodysplastischen Syndromen sowie deren Assoziation zu Komorbiditäten
| Titel: | Stellenwert von somatischen Genmutationen auf die Prognose von Patienten mit Myelodysplastischen Syndromen sowie deren Assoziation zu Komorbiditäten | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=58775 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20220323-090750-8 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Seidler, Jenny [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Germing, Ulrich [Gutachter] Prof. Dr. Wieczorek, Dagmar [Gutachter] | |||||||
| Stichwörter: | MDS | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Zusammenfassung
Myelodysplastische Syndrome (MDS) sind sehr heterogene Erkrankungen in Bezug auf ihr molekulares sowie klinisches Erscheinungsbild, was sich in ihrer Prognose und Behandlung widerspiegelt. Die Therapie richtet sich nach der Zugehörigkeit zu einer Risikogruppe und somit nach einem prognostischen Bewertungssystem. Der bislang bestehende Goldstandard IPSS (International Prognostic Scoring System) wurde 2012 überarbeitet (Greenberg et al. 1997). Der aktuelle in Anwendung befindliche IPSS-R verwendet weiterhin Zellzahlen, Knochenmarkblasten sowie Veränderungen des Karyotyps, um Patienten in Risikogruppen zu stratifizieren (Greenberg et al. 2012). Mehr als die Hälfte aller MDS-Patienten weisen einen normalen Karyotyp auf und sogar bei Patienten mit identischen chromosomalen Veränderungen unterscheiden sich die Auswirkungen in Bezug auf Prognose und Therapieerfolg auf die Patienten erheblich. Somatische Mutationen sind bei mehr als 70% aller MDS-Patienten nachweisbar und somit häufiger als zytogenetische Aberrationen (Bejar et al. 2011). Dies eröffnet die Möglichkeit, somatische Mutationen in etablierte Prognosesysteme mitaufzunehmen, um diese zu spezifizieren und um therapeutische Strategien weiter zu personalisieren. Das Interesse dieser Arbeit gilt den molekularen Veränderungen der Patienten ebenso wie den Komorbiditäten in Zusammenhang mit den untersuchten Biomarkern. Für die vorliegende Arbeit wurden 166 Patienten mit verschiedenen MDS-Subtypen analysiert, von denen 74 Personen bis zum Ende des Beobachtungszeitraums verstarben. Das Durchschnittsalter des Patientenkollektivs lag bei 68 Jahren (16-87 Jahre), die mediane Überlebenszeit betrug 5,7 Jahre (95% CI 3,5-7,8). Für die molekulargenetischen Analysen des Gen-Panels (ASXL1, DNMT3A, EZH2, FLT3-ITD, IDH1, IDH2, MLL-PTD, KRAS, NRAS, CBL, RUNX1, SF3B1, SRSF2, TET2, JAK2 und TP53) wurde hauptsächlich Next-Generation Sequencing verwendet. Innerhalb des vorliegenden Patientenkollektivs waren TET2-Mutationen (30,7%) am häufigsten vertreten, gefolgt von SF3B1 (27,5%), ASXL1 (23,5%), RUNX1 (21,1%), SRSF2 (19,5%), DNMT3A (13,9%), EZH2 (8,5%), TP53 (6,7%), MLL-PTD (4,2%), NRAS (3,9%), JAK2 (3,8%), FLT3-ITD (3,7%), IDH1 (3,1%), IDH2 (3,1%), KRAS (2,5%) und CBL (2,2%) -Mutationen. In einer univariaten Analyse konnte ein signifikanter Einfluss auf die Überlebenszeit für folgende Biomarker demonstriert werden: TP53 (p≤0,001), EZH2 (p=0,011), SF3B1 (p=0,014), ASXL1 (p≤0,001), NRAS (p=0,022), IDH2 (p=0,031) und RUNX1 (p=0,006). SF3B1-Mutationen waren bei Patienten mit einem MDS mit einer günstigeren Prognose, Mutationen in den Genen TP53, EZH2, RUNX1, ASXL1, NRAS sowie IDH2 mit einem reduzierten Gesamtüberleben assoziiert. Einen ebenfalls signifikanten Einfluss auf die Überlebenszeit hatte das Alter bei Erstdiagnose (p<0,014), die FAB-Klassifikation (p<0,011), die WHO2016 Klassifikation (p≤0,001), der Hb nach IPSS und IPSS-R (p=0,002/ p=0,015), die Thrombozytenzahl nach IPSS und IPSS-R (p=0,006/ p=0,019), die Anzahl an Knochenmarkblasten nach IPSS (p=0,006) und die Prognoseklassifikation nach IPSS-R (p<0,033). Mit Hilfe der multivariaten Regressionsanalyse konnten ASXL1 und KRAS sowie die Klassifikation der Genetik nach IPSS-R als unabhängige prognostische Variablen mit Einfluss auf die Überlebenszeit definiert werden. Komorbiditäten haben einen signifikanten Einfluss auf die Prognose von Patienten mit MDS. In der vorliegenden Arbeit konnte ein möglicher Zusammenhang zwischen Mutationen und Komorbiditäten konstatiert werden. Ein Beispiel ist ein möglicher Zusammenhang von Autoimmunerkrankungen und SRSF2-Mutationen insbesondere bei männlichen MDS-Patienten. Perspektivisch erscheint es erstrebenswert, patientenindividuelle Parameter (weiterhin und großzügiger) in Prognose-Scores zu integrieren. Die Integration von Mutationsanalysen sowie Komorbiditäten in die klinische Routine könnte somit zur weiteren Spezifizierung der Diagnostik, Prognose und somit Therapiestrategieerstellung im Sinne einer personalisierten Medizin den Patienten zugutekommen.Summary Myelodysplastic syndromes (MDS) are heterogeneous in terms of clinical and molecular characteristics, as well as prognosis and treatment approaches. Therapeutic decision-making relies greatly on prognostic scoring systems. In 2012 the gold-standard IPSS (International prognostic scoring system) has been revised (Greenberg et al. 1997). The new IPSS-R still uses cell counts, marrow blast count and karyotypic abnormalities to stratify patients (pts) into risk groups (Greenberg et al. 2012). However, more than 50% of all MDS pts present with a normal karyotype and even in pts with identical chromosomal abnormalities outcome may vary. Somatic mutations are more common than cytogenetic abnormalities and can be identified in over 70% of pts including pts with normal karyotype (Bejar et al. 2011). Therefore, the addition of such mutations to common prognostic markers might help to refine prognostication in MDS pts and improve therapeutic procedures by individualizing MDS treatment. Due to the highly individual course of MDS, and to individualize therapeutic decisions, somatic mutations and the connection of somatic mutations and comorbidities (present in over 60% of patients) were examined. We analyzed 166 pts with different subtypes of MDS. Most of the data was collected prospectively within the clinical routine diagnostic procedures. During that time the marker panel was adjusted, when new analyses became available. Thus, not all markers are currently available for all pts. To assess the impact of the biomarkers, Kaplan-Meier analyses were estimated starting from the day of diagnosis. Various molecular assays were performed including sensitive next-generation sequencing for mutations in ASXL1, DNMT3A, EZH2, FLT3-ITD, IDH1, IDH2, MLL-PTD, KRAS, NRAS, CBL, RUNX1, SF3B1, SRSF2, TET2, JAK2, and TP53. The most frequent mutation was TET2 (30.7%), followed by SF3B1 (27.5%), ASXL1 (23.5%), RUNX1 (21.1%), SRSF2 (19.5%), DNMT3A (13.9%), EZH2 (8.5%), TP53 (6.7%), MLL-PTD (4.2%), NRAS (3.9%), JAK2 (3.8%), FLT3-ITD (3.7%), IDH1 (3.1%), IDH2 (3.1%), KRAS (2.5%) and CBL (2.2%). A significant influence on survival in univariate analysis could be demonstrated for TP53 (p≤0.001), EZH2 (p=0.011), SF3B1(p= 0.014), ASXL1 (p≤0.001), NRAS (p= 0.022), IDH2 (p=0.031) and RUNX1 (p= 0.006). Other prognostic variables with significant impact regarding survival were age at diagnosis (p<0.014), FAB subgroup (p≤0.011), WHO2016 subgroup (p≤0.001), Hb according to IPSS and IPSS-R (p=0.002/ p=0.015), platelet count according to IPSS and IPSS-R (p=0.006/ p=0.019), marrow blast count according to IPSS (p=0.006) and the IPSS-R classification (p<0.033). We could confirm mutations in TP53, EZH2, RUNX1 and ASXL1 to be predictors of poor overall survival and demonstrate a poor outcome for mutations in NRAS, IDH2, while SF3B1 mutations conferred a favorable prognosis in pts with MDS. To determine the relative contribution of mutation status to overall survival, we generated a multivariable Cox model, using a stepwise variable-selection procedure incorporating cytogenetics according to IPSS-R and mutation status for the 16 most frequently mutated genes in this study. Mutations of ASXL1 and KRAS and cytogenetics according to IPSS-R emerged as independent predictors of survival. Comorbidities also have a significant impact on the prognosis of patients with MDS. The purpose of this study, inter alia, was to determine the association of somatic mutations with comorbidities in MDS. In the present work a possible connection between e.g. autoimmune diseases and SRSF2 in patients with MDS was stated. Additionally, incorporating comorbidities in risk assessment systems may improve the prediction of prognosis and allow for a more individual treatment approach. Integrating mutation assessment and individual comorbidities into the clinical routine might improve diagnostic procedures as well as prognostication, and individualize treatment approaches. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 23.03.2022 | |||||||
| Dateien geändert am: | 23.03.2022 | |||||||
| Promotionsantrag am: | 18.06.2020 | |||||||
| Datum der Promotion: | 11.11.2021 |
