Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO

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.

Fig. 1

Exome sequencing identifies meningioma subgroups based on mutually exclusive mutation profiles.

Fig. 2

Genomic architecture of meningiomas. (A) NF2, TRAF7, and SMO coding mutations along with recurrent AKT1^E17K and KLF4^K409Q variants reveal meningioma subtypes with mutually exclusive profiles. Analysis for chromosome 22 copy number is also shown. Each bar represents a grade I meningioma sample; 191 samples are depicted. (B) TRAF7 mutations, which are identified in 72 of 300 meningiomas analyzed, are clustered within its WD40 domains. The count of recurrent mutations, which are denoted by diamonds, is indicated. (C) The recurrent KLF4^K409Q mutation is located within the first zinc finger domain, which makes direct DNA contact. (D) Circos plot of large-scale genomic abnormalities identified (blue: deletion, red: amplification). Whereas all NF2/chr22loss meningiomas (outer circles, n = 41, including n = 30 with coding NF2 mutations) show chromosome 22 loss, which is typically associated with further chromosomal abnormalities in grade II tumors (n = 11, including n = 8 with coding NF2 mutations), genomic stability is a hallmark of grade I non-NF2 tumors (inner circles, n = 36). (E) Along the skull base, NF2/chr22loss meningiomas originate from the lateral and posterior regions, whereas the vast majority of anterior and medial meningiomas are non-NF2 mutant. (F) Unsupervised hierarchical clustering of gene expression profiles defines two major benign meningioma subgroups, those with NF2/chr22loss and non-NF2 mutant tumors. Each subgroup reveals differential H3K27ac and gene expression profiles (figs. S10 to S14 and tables S5 to S8).