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• W4380185884 abstract "Burkitt lymphoma (BL) is the most common malignancy among pediatric Non-Hodgkin Lymphoma (NHL) patients making up for more than 80% of pediatric B-NHL cases. The primary survival rate of sporadic BL (sBL) today exceeds 90% however in case of relapse or progression during therapy the survival rate drops below 30%. The administered intensive chemotherapy regime results in a high incidence of side effects and potentially in second malignancies. Molecular-based risk stratification of sBL is urgently needed. In a previous study of our group, the genetic material of 191 pediatric patients, of which 30 suffered from relapse, registered within the NHL-BFM study center was analyzed via a targeted resequencing approach. Several recurrently mutated genes including hotspot mutations in TP53, FBXO11/ FOXO1 and PCBP1 were identified. Patients with TP53 wild type status and variants in FBXO11mt and/or FOXO1mt are associated with a lower incidence of relapse (p=0,05). Also TP53mt significantly increased the cumulative incidence of relapse (p=0,0002). Recent studies support the finding that TP53mt correlate with a higher risk for progression, relapse, and a lower event-free survival in sBL. In this study, an in-depth functional analysis of these genes is performed to indicate individual risk potential and to adapt subsequent chemotherapy. To answer these questions clinical data was transferred into an in vitro model. The expression of TP53, FOXO1 and PCBP1 were individually suppressed and the common hotspot mutations were stably integrated in a variety of BL cell lines. Functional analysis revealed that increased expression of FOXO1 regardless of its mutational status results in enhanced cell viability. Whereas alterations of PCBP1 reveal no significant difference in cell growth in vitro. However, TP53 point mutation R248Q results in decreased cellular viability in comparison to the control group. Suppression of TP53 does not have an impact on cytological amendments. Elucidating the discrepancy between the in vitro model and the clinical data on TP53 status requires further investigation. Subsequently the response to commonly employed chemotherapeutic agents in B-NHL treatment of various TP53 mt was examined. TP53mt does not interfere with the tumor cell response towards commonly used drugs like Dexamethasone, Methotrexate and Cytarabine. Whereas a shift in cellular response to Etoposide can be linked to TP53 mt . Overall, the in vitro identification of clinically relevant prognostic markers from previously identified patient material remains challenging. While further research is necessary, our data suggests that especially TP53 modifications are a promising indicator for further risk stratification." @default.
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• W4380185884 date "2023-05-01" @default.
• W4380185884 modified "2023-09-26" @default.
• W4380185884 title "Functional Characterization of potential diagnostic targets in Burkitt-NHL" @default.
• W4380185884 doi "https://doi.org/10.1055/s-0043-1768555" @default.
• W4380185884 hasPublicationYear "2023" @default.
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