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Zusammenhänge zwischen TP53-Mutationsstatus, genetischer Instabilität und Prognose bei MDS und sekundärer AML mit komplex aberrantem Karyotyp

dc.contributor.advisorHaase, Detlef T. Prof. Dr.
dc.contributor.authorSchaab, Roxana Magdalena
dc.titleZusammenhänge zwischen TP53-Mutationsstatus, genetischer Instabilität und Prognose bei MDS und sekundärer AML mit komplex aberrantem Karyotypde
dc.title.translatedInterdependency between TP53 alterations, cytogenetics, genetic instability and prognosis in MDS and secondary AML with complex aberrant karyotypede
dc.contributor.refereePauli, Silke J. Prof. Dr.
dc.description.abstractengINTRODUCTION: In patients with MDS and secondary AML (sAML) complex aberrant karyotypes (≥ 3 clonal cytogenetic aberrations, CK) and mutations of TP53 are known to be prognostically adverse.  There is evidence that TP53 mutational status might work as an independent prognostic factor in patients with complex aberrant MDS/sAML. To examine this correlation, the frequency of TP53 alterations (TP53 mutations, TP53 deletions, CN-LOH in the locus of TP53) in patients with CK-MDS/sAML was evaluated, cytogenetic and clinical data was collected to analyze interdependency between TP53 alterations, genetic instability and prognosis. METHODS: 125 patients with CK-MDS/sAML were comprehensively characterized by chromosome banding analysis, interphase fluorescence in situ hybridization (FISH) of TP53, multicolor FISH (mFISH), Sanger sequencing of TP53 and SNP-array analysis (SNP-A). The extent of genetic instability was objectified by evaluating the number of cytogenetic aberrations (CA) in chromosomal banding analysis, the number of cytogenetic fusions as shown by mFISH and the size of total genomic aberrations (TGA) measured by SNP-A in megabases. Clinical data was analyzed by the method of Kaplan-Meier and multivariate analysis. RESULTS: Any alteration of TP53 was found in 62.4 % of patients. 48.8 % of all patients carried a TP53 mutation and 41.6 % showed a TP53 deletion. Combined TP53 alterations (TP53 mutation and deletion) were found in 28.0 % of patients. The degree of genomic imbalances measured by the median number of CA, median number of fusions and median TGA size was higher in patients with any TP53 alteration (TP53 mutation and/or deletion/CN-LOH) compared to those without. Hb level was significantly lower in all groups with TP53 alterations. Median overall survival for the entire cohort was 14 months. It was shortened for patients showing any type of TP53 alterations compared to those without and also for patients having a higher number of CA compared to patients with a lower number of CA.   Patients with a high number of CA (≥ 5) and TP53 alterations showed a worse median overall survival in comparison to patients without alterations. This was in contrast to the median overall survival of patients with a high number of CA and TP53 mutations, which did not significantly differ from patients without a TP53 mutation.  Median overall survival was longer for patients with any TP53 alteration if they received a therapy with hypomethylating agents. Multivariate analysis considering any type of TP53 alterations, anemia as defined by IPSS, blast percentage in bone marrow > 20 %, high number of CA (≥ 5) and age (≥ 72 years) identified TP53 alterations, anemia and blast percentage > 20 % as significant prognostic factors for overall survival. In contrast TP53 mutation status showed no significant impact on overall survival in multivariate analysis in our cohort.  Based on the three named significant prognostic factors of multivariate analysis a prognostic model was developed to stratify patients with CK-MDS/sAML into distinct prognostic subgroups.  CONCLUSION:  In this cohort of 125 CK-MDS/sAML patients, the majority (62.4 %) showed TP53 alterations. There was a clear association between TP53 mutations/TP53 alterations and a higher degree of genomic imbalances.  TP53 mutation status alone was not able to provide independent prognostic information for patients with CK-MDS/sAML. Combining it with the status of cytogenetic TP53 alterations (TP53 deletions/CN-LOH) a strong and independent effect on overall survival could be seen. Using a score implying as well anemia as defined by IPSS and blast percentage > 20 % the heterogenous group of patients with CK-MDS/sAML could be stratified into distinct prognostic subgroups, which might be relevant for clinical decision making. Taken together, not only molecular TP53 status but also clinical and cytogenetic data play an important role for prognostic classification of patients with CK-MDS/sAML. de
dc.contributor.coRefereeSchön, Margarete Prof. Dr.
dc.subject.gersekundäre AMLde
dc.subject.gerkomplex aberranter Karyotypde
dc.subject.gerzytogenetische Aberrationende
dc.subject.engcomplex aberrant karyotypede
dc.subject.engsecondary AMLde
dc.subject.engTP53 deletionde
dc.subject.engTP53 mutationde
dc.subject.engcytogenetic aberrationsde
dc.affiliation.instituteMedizinische Fakultätde
dc.subject.gokfullMedizin (PPN619874732)de

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