Artikel
Distinct genomic subclasses of high-grade/progressive meningiomas – NF2-associated, NF2-exclusive, and NF2-agnostic
Hochgradig progressive Meningeome können in 3 Gruppen unterteilt werden
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Autoren
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Insa Prilop
- Universitätsklinikum Dresden, Neurochirurgie, Dresden, Deutschland
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Tareq Juratli
- Universitätsklinikum Dresden, Neurochirurgie, Dresden, Deutschland
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Erik Williams
- Foundation Medicine Inc Cambridge, Massachusetts General Hospital Cancer Center, Harvard Medical School, Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
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Sandro Santagata
- Brigham and Women’s Hospital, Department of Pathology, Boston, MA, Vereinigte Staaten
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Priscilla Brastianos
- Stephen E. and Catherine Pappas Center for Neuro-Oncology, Division of Hematology/Oncology, Department of Neurology, Boston, MA, Vereinigte Staaten
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Daniel Cahill
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Boston, MA, Vereinigte Staaten
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Shakti Ramkissoon
- Foundation Medicine Inc Cambridge, Massachusetts General Hospital Cancer Center, Harvard Medical School, Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Boston, MA, Vereinigte Staaten; Wake Forest Comprehensive Cancer Center, Department of Pathology, Winston-Salem, NC, Vereinigte Staaten
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Brian Alexander
- Foundation Medicine Inc., Cambridge, MA, Vereinigte Staaten
| Veröffentlicht: | 4. Juni 2021 |
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Gliederung
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Objective: Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date.
Methods: 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed.
Results: Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations.
Conclusion: Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease.
