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Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO
Victoria E Clark1, E Zeynep Erson-Omay, Akdes Serin
1Department of Neurosurgery, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.
Abstract:
We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
Insights
Genomic analysis of 300 meningiomas revealed mutations in TRAF7, KLF4, AKT1, and SMO. These genetic alterations define distinct meningioma subtypes, paving the way for targeted therapies.
Area of Science:
- Neuro-oncology
- Genomics
- Molecular Biology
Background:
- Meningiomas are the most common primary brain tumors.
- Understanding their genomic landscape is crucial for classification and treatment.
Purpose of the Study:
- To perform genomic analysis on a cohort of 300 meningiomas.
- To identify key genetic mutations and their correlation with clinical and pathological features.
- To define distinct meningioma subtypes based on molecular profiles.
Main Methods:
- Whole-exome sequencing or targeted gene sequencing of 300 meningioma samples.
- Analysis of mutation frequencies for genes including TRAF7, KLF4, AKT1, SMO, and NF2.
- Correlation of genetic findings with tumor histology, location, and chromosomal stability.
Main Results:
- Mutations in TRAF7 were found in nearly 25% of meningiomas, often co-occurring with KLF4 or AKT1 mutations.
- SMO mutations were identified in approximately 5% of non-NF2 mutant meningiomas.
- NF2 mutations or chromosome 22 loss were associated with atypical meningiomas, genomic instability, and specific locations.
- Non-NF2 meningiomas exhibited distinct clinical features, including benignancy and chromosomal stability, often originating from the medial skull base.
Conclusions:
- Genomic analysis reveals distinct molecular subtypes of meningioma.
- Specific mutations (TRAF7, KLF4, AKT1, SMO) characterize different meningioma groups.
- Identification of these subtypes suggests potential for targeted therapeutic strategies.
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