Genetische Varianten von PPM1D und TP53 bei Patienten mit myelodysplastischen Syndromen und komplex-aberranten Karyotypen
by Lea Naomi Eder
Date of Examination:2023-03-29
Date of issue:2023-02-07
Advisor:Prof. Dr. Detlef Haase
Referee:Prof. Dr. Detlef Haase
Referee:Prof. Dr. Philipp Ströbel
Persistent Address:
http://dx.doi.org/10.53846/goediss-9713
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Abstract
English
Myelodysplastic syndromes (MDS) are a heterogenous group of clonal bone marrow diseases leading to ineffective hematopoiesis. In over 90% cyto- and molecular genetic aberrations can be detected with complex aberrations (three or more cytogenetic changes, cA) in up to 15%. This subgroup is associated with an unfavorable prognosis and an elevated risk of transformation into an acute myeloid leukemia (AML). In over 60% of those cases, a mutation of the tumor suppressor gene TP53 can be found. TP53 mutations are associated with a higher level of bone marrow blasts, cytogenetic aberrations of increased complexity, and a shortened overall survival. The gene PPM1D encodes for a protein inhibiting p53 and is known to be one of the most frequently mutated genes in clonal hematopoiesis of indeterminate potential (CHIP). In this study we examined the frequency and influence of PPM1D and TP53 mutations in patients with myelodysplastic syndromes and complex aberrant karyotypes. We also aimed to answer the question whether PPM1D mutations could be a possible alternative driver for the occurrence of complex cytogenetic aberrations in patients without TP53 mutations. In this study 115 patients have been analyzed by chromosome banding analyzes (CBA) and fluorescence in situ hybridization (FISH) for cytogenetic aberrations and by Sanger or Next Generation Sequencing (NGS) for molecular genetic changes. 40 patients without cA have been analyzed as a control group. PPM1D mutations were detected in 1.7% only of the patients with MDS and cA. No influence on overall survival or other relevant parameters was observed. However, TP53 mutations were found in 69.5% of the patients with cA. Aberrations of TP53 define the most unfavorable parameter influencing the overall survival with a significant shorter survival than patients with TP53 wildtype. There was no difference in the overall survival of patients with cA with one TP53 mutation (single hit) and with patients having more than one mutation or a mutation and deletion of the TP53 locus (multi hit). Another unfavorable prognostic marker was a deletion of the long arm of chromosome 5 (del5q). This aberration is associated with a low risk MDS if it appears without other aberrations, but with a poor prognosis if it is part of cA. We furthermore observed that complex karyotypes including del5q are strongly associated with TP53 mutations. Summarizing, PPM1D turned out to be no possible alternative driver gene for the formation of complex aberrations. However, mutations in TP53 were confirmed as the strongest predictor for an unfavorable course of disease independent of the type of aberrations. We could demonstrate that del5q is strongly associated with TP53 mutations and confers a shortened overall survival as part of a complex aberrant karyotype.
Keywords: Myelodysplastic Syndromes; TP53 mutations; Complex aberrations; PPM1D mutations