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• W2889759905 abstract "TERT promoter mutations in meningiomas were recently found to be strongly prognostic and associated with malignant progression and risk of recurrence. However, the cellular factors underlying meningioma aggressiveness are comparably unexplored. Due to the limited meningioma cell lines available worldwide, it was aim of our study to analyse an extended cohort of WHO grade I-III meningiomas regarding the impact of TERT promoter mutations, telomerase activity and TERT mRNA expression on cell propagation in vitro. Tumor tissue from 128 meningiomas was analysed for TERT promoter mutations by direct sequencing. Telomerase activity (TA), TERT mRNA expression and telomere lengths were investigated by TRAP assay, RT-PCR, and qPCR, respectively. Correspondingly, tumor-derived primo-cell cultures (121/128) were established. The impact of the ETS-transcription factor inhibitor YK-4–279 on cell viability was analysed in selected primo-cell cultures by MTT assays. To elucidate whether ETS- transcription factor inhibition affects TERT promoter activity, luciferase-based reporter assays were performed. TERT promoter mutations were found in 6 % of all samples analysed and were associated with a significantly upregulated telomerase activity and TERT mRNA expression (p<0.0001 both). Meningioma derived primo-cell cultures were able to be propagated with comparable success rates from TA positive and- negative (55% versus 53%) tumors. In contrast, within the meningioma cohort harbouring TERT promoter mutations, 75% (6/8) viable primo-cell cultures could be established. Out of these, 2 primo-cell cultures (2/6; 33%) developed into stable immortalized cell lines. This strongly indicates that TERT promoter mutations but not telomerase activity or TERT mRNA expression were predicting indefinite cell growth in vitro. TERT promoter mutated meningioma cells were hypersensitive against the ETS transcription factor inhibitor YK-4–279 inducing a significant downregulation of TERT mRNA expression. Accordingly, as shown by the luciferase-reporter assay, the enhanced activity of the mutated TERT promoter was completely blocked by presence of YK-4–279. Patients with TERT promoter mutated meningiomas exhibited a significantly shorter overall survival (p=0.0006; 53.8 vs 115.6 months). Aggressiveness of meningiomas reflected by cell immortalization in vitro is dependent on TERT promoter mutations. This fits well with the data of worse prognosis for meningioma patients harbouring a TERT promoter-mutated tumor. Additionally, TERT promoter mutations might open a promising novel therapeutic opportunity in progressive meningiomas." @default.
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• W2889759905 date "2018-09-01" @default.
• W2889759905 modified "2023-10-03" @default.
• W2889759905 title "P02.10 Aggressiveness of meningiomas is predicted by cell immortalization in vitro and dependent on TERT promoter mutations" @default.
• W2889759905 doi "https://doi.org/10.1093/neuonc/noy139.220" @default.
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