Autor:innen:
Lea Naomi Eder | Universitätsmedizin Göttingen | Germany
Christina Ganster | Universitätsmedizin Göttingen | Germany
Katayoon Shirneshan | Universitätsmedizin Göttingen | Germany
Katharina Rittscher | Universitätsmedizin Göttingen | Germany
Roxana Schaab | Universitätsmedizin Göttingen | Germany
Roman Martin | Universitätsmedizin Göttingen | Germany
Sascha Dierks | Universitätsmedizin Göttingen | Germany
Detlef Haase | Universitätsmedizin Göttingen | Germany
Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of rare clonal hematopoietic stem cell diseases that lead to different types of cytopenia. The incidence in Germany is 5/100.000 inhabitants per year. Cytogenetics is of high relevance for prognostication, classification and personalized allocation of therapy in MDS. Complex aberrations (≥3 cytogenetic aberrations, cA) to date represent one of the most unfavorable prognostic markers. About 50% of patients (pts) with cA show TP53 mutations that “allow” cell clones with cA to survive and expand. They might further worsen the prognosis of pts with cA. The gene PPM1D located on chromosome 17q23 encodes the protein Wip1. It acts as an inhibitor of p53. About 5% of MDS pts with 5q deletion show mutations in PPM1D (Panagiota et al., ASH 2017) and they are even more common in pts with therapy-related MDS (tMDS, 15%, Lindsley et al., 2017). The aim of our study was to determine the frequency of PPM1D mutations in MDS pts with cA with and without TP53-mutations and their influence on survival.
Methods: Pts were characterized by conventional cytogenetics and fluorescence in situ hybridization (FISH) containing a FISH-probe covering the TP53 locus. By now 78 pts (51x MDS, 24 x sAML 3 x CMML) with known TP53 status have been identified and were subjected to next generation sequencing (NGS) of PPM1D. Our cohort comprised 70 pts with cA (median age: 71 yrs, range 25-95; median number of cytogenetic aberrations: 7, range 3-50; 14 pts with tMDS) and 8 tMDS without cA (median age: 73 yrs, range: 65-79).
Results: A biallelic mutation of TP53 (mutation and deletion) was present in 25 pts (32%), further 19 (24%) had aTP53 mutation without deletion. A deletion without mutation was present in three pts (4%). All pts without cA were TP53 wildtype. We included 22 pts with tMDS, 14 of them with cA.
In five pts we found a sequence variant of PPM1D. All five pts had cA. Two variants have already been described as very rare SNPs. The other three have not been described before. Two of them are at the same position in exon 1, the third very close to the others. All of them are potential missense mutations. One of those three pts shows a TP53 mutation. None of them showed a deletion in 5q. The median number of aberrations in these three pts was 4 (range: 4-8).
Conclusion: As an inhibitor of TP53, and potential pathogenetic alternative to mutations of TP53 itself, we hypothesized that the gene encoding for Wip1, PPM1D, might be mutated in MDS pts with cA but without TP53 mutation, especially in tMDS. We could show that PPM1D is mutated in pts with cA. In our cohort 7% of the pts with cA are affected. One of them had a tMDS. PPM1D mutations might contribute to the pathogenesis of cA as 2/3 potential mutations do not co-occur with a TP53 mutation. To further determine the influence on the prognosis we will test the PPM1D mutation status in a higher number of MDS pts. Respective analyses are on the way.