Table 1.
Recurrent Mutations Associated With Meningiomas
| Gene | Location | Protein | Gene status | Frequency (%) | WHO grade | Modification | Associated meningioma phenotype | Effect of modification | Reference |
|---|---|---|---|---|---|---|---|---|---|
| AKT1 | 14q32.33 | Protein kinase B alpha, beta, and gamma | Oncogene | 10 | 1 | Point mutation | Anterior/middle skull base location, NF2-wild-type meningiomas | Conformational change in protein, altering its localization from the cytoplasm to the plasma membrane, resulting in constitutive activation of the AKT1 kinase and activation of mTOR and ERK1/2 signaling pathways | 38,39,41,383–387 |
| ARID1A | 1p36.11 | AT-rich interaction domain 1A | Tumor suppressor | 5 | 2, 3 | Frameshift mutation | Recurrent and high-grade cases | Destabilizes SWI/SNF complex which normally modulates DNA accessibility for cellular processes involved in chromatin structure including transcription, DNA replication, and repair, resulting in global deregulation of gene transcription | 38,59–61,89 |
| BAP1 | 3p21.1 | BRCA1-associated protein 1 | Tumor suppressor | <1 | 2, 3 | Splice site, nonsense, frameshift mutation | Rhabdoid and papillary histology | Impaired nuclear localization of a ubiquitin carboxy-terminal hydrolase that normally has tumor suppressor activity when bound to BRCA1 or BARD1 | 38,45,53,62,70,71,388 |
| BRAF (V600E) | 7p34 | B-Raf proto-oncogene | Oncogene | <1 | 3 | Point mutation | Rhabdoid histology | Mimics phosphorylation of nearby serine and threonine residues resulting in BRAF activation and subsequent activation of the MAP kinase/ERK-signaling pathway | 43,93,389,390 |
| CDH1 | 16q22 | E-cadherin | Tumor suppressor | 30 | 1–3 | Deletion, nonsense mutation | Unknown | Activation of wnt signaling via dysregulation of β-catenin and the APC protein, resulting in upregulation of cell cycling programs including c-myc and cyclin D1 pathways | 391–393 |
| CDKN2A/B | 9p21.3 | p16, p15INK4b | Tumor suppressor | 1–5 | 3 | Deletion | Anaplastic, biologically aggressive meningiomas | Loss of inhibition of CDK4 and CDK6 mediated phosphorylation of retinoblastoma family of proteins, leading to unchecked cell cycle progression from G1 to S-phase | 3,38,92,93,96,98,101,119,394–398 |
| CDKN2C | 1p32.3 | Cyclin-dependent kinase 4 inhibitor C (p18) | Tumor suppressor | 1 | 2 | Nonsense mutation | Atypical and anaplastic meningiomas | Activation of CDK4 and CDK6 resulting in loss of control of cell growth regulation and subsequent cell cycle G1 progression | 92,96 |
| CHEK2 | 22q12.1 | Checkpoint kinase 2 (Chk2) | Tumor suppressor | 50 | 1–3 | Deletion, frameshift mutation | NF2-altered meningiomas | Defects in DNA homologous recombination or nonhomologous end-joining pathways following DNA damage including double-stranded DNA breaks resulting in increased chromosomal instability | 349,399 |
| Dal-1 | 18p11.3 | Protein 4.1B | Tumor suppressor | 50–80 | 1–3 | Deletion, nonsense mutation | Multiple meningiomas, sporadic meningiomas | Dysregulation of cell-cell contact inhibition growth arrest normally mediated through actin cytoskeletal-associated proteins resulting in similar downstream effects as NF2 inactivation | 354,400–402 |
| EZH2 | 7q36.1 | Enhancer of zeste homolog 2 | Oncogene | 1–5 | 2–3 | Point mutation, amplification | Higher grade meningiomas | Dysregulation of catalytic subgroup of PRC2 complex, upregulation of proliferative genes in the cell cycle-retinoblastoma-E2F pathway | 403–405 |
| FBXW7 | 4q31.3 | F-box and WD repeat domain containing 7 | Tumor suppressor | 1–5 | 1–3 | Frameshift mutation | NF2-altered meningiomas | Deregulation of ubiquitin-mediated proteolysis of oncoproteins such as cyclin E, notch, c-Jun, c-Myc, mTOR resulting in increased tumorigenesis | 406,407 |
| FGFR3 | 4p16.3 | Fibroblast growth factor receptor 3 | Oncogene | 15 | 1–2 | Missense mutation | Skull base location, NF2-wild-type meningiomas | Increased mitogenic signaling from FGF receptors/kinases via activation of the PI3K-Akt-p70S6K pathway and activation of STAT3 | 408,409 |
| KDM6A | Xp11.3 | Lysine demethylase 6A (UTX) | Tumor suppressor | 5 | 2–3 | Deletion | NF2-altered, higher-grade meningiomas | Dysregulation of polycomb repressive complex (PRC2) catalyzed histone methylation including of H3K27 | 38,410 |
| KLF4 | 9p31 | Krüppel-like factor 4 | Tumor suppressor | 10–15 | 1 | Missense mutation | Skull base location, secretory meningiomas (when combined with TRAF7 mutation) | Deactivation of CDKN1A (cyclin-dependent kinase inhibitor p21) resulting in cell proliferation, and loss of inhibition of CDK1 transcription | 10,39,45,132,411–415 |
| NF2 | 22q12.2 | Merlin | Tumor suppressor | 40–60 | 1–3 | Deletion, nonsense mutation | Non-skull base location | Dysregulation of several essential cell proliferation and survival pathways including loss of cell-to-cell contact inhibition, activation of hippo pathway, mTOR/PI3K/AKT pathway, and receptor tyrosine kinases | 33–35,37,64,91,92,109,175,354,395,402,416–418 |
| PIK3CA | 3q26.32 | Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (p110α protein) | Oncogene | 5 | 1 | Point, missense mutation | Skull base location, benign WHO grade 1, progestin-related meningiomas | Activation of PI3 kinase and PI3K/AKT pathway resulting in downstream signaling cascades mediating cell survival. Apoptosis, transformation, metastasis, and cell migration | 42–44,419,420 |
| POLR2A | 17p13.1 | RNA polymerase II subunit A | Oncogene | 5 | 1 | Missense mutation | Skull base, tuberculum sellae location, benign WHO grade 1 meningiomas, meningothelial histology | Activation of catalytic subunit of RNA polymerase II, hijacking enzyme and driving cell proliferation and neoplastic progression | 40,45,415 |
| PBRM1 | 3p21.1 | Protein polybromo-1 | Tumor suppressor | 1 | 3 | Nonsense mutation, deletion | Papillary histology | Dysregulation of SWI/SNF chromatin remodeling complex, dysfunctional repair of DNA double-stranded breaks via ATM phosphorylation | 38,54 |
| PTEN | 10q23.31 | Phosphatase and tensin homolog | Tumor suppressor | 2–6 | 2, 3 | Frameshift mutation, deletion, rearrangement | Biologically aggressive, proliferative meningiomas | Dysregulation of AKT/PI3K pathway in the cell cytoplasm resulting from loss of feedback inhibition of AKT and subsequent uncontrolled cell cycle progression | 38,62–64 |
| SMARCB1 | 22q11.23 | SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 | Tumor suppressor | <5 | 2, 3 | Missense mutation | NF2-altered, atypical meningiomas | Inactivation of core subunit of SWI/SNF chromatin remodeling complex resulting in aberrant enhancer and promoter regulation and subsequent loss of transcriptional control | 61,421,422 |
| SMARCE1 | 17q21.2 | SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 | Tumor suppressor | <1 | 1 | Splice site, nonsense, frameshift mutation | Clear cell histology | Inactivation of subunit of SWI/SNF chromatin remodeling complex resulting in loss of apoptosis induction via tumor suppressor gene CYLD and other pathways | 47–51,69 |
| SMO | 7p32.1 | Smoothened | Oncogene | 3–5 | 1 | Point mutation | Anterior medial skull base location | Activation of the sonic hedgehog (SHH) signaling pathway resulting in cell proliferation, differentiation, and angiogenesis | 39,41,42,387,423,424 |
| SUFU | 10q24.32 | Suppressor of fused homolog | Tumor suppressor | 1–2 | 2–3 | Frameshift mutation | Familial multiple meningiomas | Abnormal constitutive upregulation of downstream Gli-mediated transcription factors in SHH pathway | 74,75,425,426 |
| TERTp | 5p15.33 | Telomerase reverse transcriptase promoter | Oncogene | 5.5 | 3 | Point mutation | Biologically aggressive, high-grade meningiomas | Activation of telomerase-mediated telomere stabilization resulting in delayed replicative senescence and increased telomere-driven genomic instability | 56–59,427–429 |
| TRAF7 | 16p13.3 | TNF receptor-associated factors 7 | Tumor suppressor | 20–25 | 1 | Missense mutation | Skull base location, brain invasion | Disruption of catalytic activity of E3 ubiquitin ligase interaction with MAPK pathway and RAS GTPases, altering actin dynamics and promoting anchorage-independent growth | 39,132,430 |
While some genes and their alterations have been well investigated by multiple independent groups, others may have been identified in only single or small cohorts of meningiomas. Consequently, the overall frequencies of less studied mutations may be confounded by smaller cohorts biased to include either more benign or clinically aggressive cases from which the data is obtained.