Meningioma (MNG)

Overview

Meningioma (MNG) is the most common primary intracranial tumor, arising from the meninges. On OncoTree it is a child of MNGT (Meningeal Tumors). WHO grades range from 1 (benign) to 3 (anaplastic). Recurrence risk varies substantially by molecular features, and the 2021 WHO classification incorporates genomic criteria.

Cohorts in the corpus

• 121 fresh-frozen meningiomas (discovery) and 80 validation meningiomas from the University Health Network Brain Tumor BioBank (Toronto), enriched for WHO grade 2 and 3 tumors; profiled by WES, EPIC methylation array, mRNA-seq, whole-cell proteomics (6,568 proteins), and single-nuclear RNA-seq (54,393 nuclei). Dataset: mng_utoronto_2021. PMID:34433969

Recurrent alterations

• NF2 — mutations + chromosome 22q loss in 88% of MG1 (immunogenic) vs. 9% of MG2 (benign NF2-wildtype); biallelic inactivation is the dominant driver in aggressive meningiomas. PMID:34433969
• TRAF7 — point mutations exclusive to MG2 (25%). PMID:34433969
• AKT1 — point mutations exclusive to MG2 (13%). PMID:34433969
• KLF4 — point mutations exclusive to MG2 (13%). PMID:34433969
• SMO — point mutations in copy-number-neutral subset of MG2. PMID:34433969
• POLR2A — point mutations exclusive to MG2 (6%). PMID:34433969
• KDM6A, CHD2 — novel recurrent driver mutations in chromatin-remodeling genes enriched in MG3/MG4 (3–5% frequency). PMID:34433969
• PTEN — novel recurrent driver mutations enriched in MG3/MG4. PMID:34433969
• RB1, CREBBP, FBXW7 — subthreshold recurrent inactivating mutations. PMID:34433969

Subtypes

• Four integrative molecular groups (COCA integration of CNA, methylation, mRNA data): PMID:34433969
  • MG1 (immunogenic): NF2-mutant (88%), low CNA burden (median 3.5% genome altered); protein marker S100B.
  • MG2 (benign NF2-wildtype): TRAF7/AKT1/KLF4/SMO/POLR2A mutations (Fisher exact P=1.20e-8); median 9.6% genome altered; protein marker SCGN.
  • MG3 (hypermetabolic): KDM6A/CHD2/PTEN enriched; median 16.9% genome altered; protein marker ACADL.
  • MG4 (proliferative): highest mutational burden (P=1.6e-3); median 19.5% genome altered; protein marker MCM2; FOXM1/MYC enrichment.
• MG classification outperformed WHO grade, methylation-based classification, and individual-datatype clustering for predicting time to recurrence (multivariable Cox, log-rank P=5e-15). PMID:34433969

Therapeutic landscape

• Vorinostat (HDAC inhibitor) selectively reduced viability of MG4 (proliferative) patient-derived cell lines and attenuated tumor growth in MG4 intracranial xenografts, warranting further clinical investigation. PMID:34433969
• MG2 tumors harboring TRAF7/AKT1/KLF4/SMO mutations may be amenable to targeted therapies (PI3K/AKT, Hedgehog pathway). PMID:34433969
• Proteomic IHC markers (S100B, SCGN, ACADL, MCM2) could enable molecular group assignment in conventional neuropathology labs. PMID:34433969

Sources

• PMID:34433969 — A Clinically Applicable Integrative Molecular Classification of Meningiomas (Nature, 2021)

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