Artikel
TERT alterations identify a subset of aggressive meningiomas
TERT-Genalteration identifizieren eine Subgruppe aggressiver Meningeome
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Autoren
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Tareq Juratli
- Universitätsklinikum Carl Gustav Carus Dresden, Neurochirurgie, Dresden, Deutschland; Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
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Insa Prilop
- Universitätsklinikum Carl Gustav Carus Dresden, Neurochirurgie, Dresden, Deutschland; Universitätsklinikum Carl Gustav Carus Dresden, Neurochirurgie, Dresden, Deutschland
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Ganesh M. Shankar
- Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
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Shilpa Tummala
- Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
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Gabriele Schackert
- Universitätsklinikum Carl Gustav Carus Dresden, Neurochirurgie, Dresden, Deutschland
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Daniel Cahill
- Massachusetts General Hospital, Department of Neurosurgery, Boston, MA, United States
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Priscilla Brastianos
- Massachusetts General Hospital, Division of Neuro-Oncology, Department of Neurology, Boston, MA, United States
| Veröffentlicht: | 26. Juni 2020 |
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Gliederung
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Objective: Although a significant proportion of aggressive meningiomas acquireTERTpromoter (TERTp) mutations which drive TERT overexpression during progression, alternative mechanisms of telomere maintenance in meningioma are broadly unknown.TERTactivating rearrangements are common in some aggressive cancers and associated with poor outcome. We sought to assessTERTrearrangements in a large cohort of patients with progressive meningiomas.
Methods: We determined the frequency ofTERTmRNA overexpression in 126 temporally- and regionally-distinct specimens from 55 WHO grades II/III meningioma patients using reverse-transcriptase PCR. Subsequently, RNA sequencing was performed in samples withTERToverexpression to detect rearrangements. Additionally, theTERTp region was sequenced in all patients to assess hotspot mutations.
Results: We identified 9 samples from 3 patients (5.4%) with highly amplifiedTERTmRNA expression. RNA sequencing of these samples revealed a novel fusionRETREG1-TERTthat was present in 2 patients, in addition to a previously-reportedLPCAT1-TERTfusion in a third case. One of the 3 patients had received a course of radiotherapy prior to the emergence of detectable mRNA fusion. In all cases theTERTrearrangements began in either exon 2 or 3, upstream of the reverse transcriptase domain that begins in exon 4, consistent with a proposed activating mechanism-of-action. In total, 10 patients (18%) harboredTERTalterations in our cohort: 3TERTrearrangements and 7TERTp mutations. Importantly, patients whose meningiomas harboredTERTalterations had a significantly worse overall survival (5.1 years, 95% CI 3.1 – 7.2) compared toTERTwild-type patients (18.5 years, 95% CI 14.6 – 22.4, p < 0.001).
Conclusion: We discoveredTERTrearrangements in a subset of aggressive meningiomas, including a novelRETREG1-TERTrearrangement. Two distinct mechanisms for TERT activation,TERTrearrangements andTERTp mutations were associated with a particularly poor outcome, suggesting a central role of telomere lengthening in the pathogenesis of aggressive meningioma. Detection ofTERTalterations offers a basis for a more precise identification of patients at-risk for developing early progression of meningioma.
