Molecular Genetics of Meningioma


Meningiomas are the most common primary brain tumours in the adult central nervous system. These tumours are not normally malignant, but can cause brain invasion and lead to various motor and sensory deficits, which are dependent on tumour location. Meningiomas are normally single, sporadic tumours, but can occur as multiple meningiomas. Neurofibromatosis type 2 (NF2) mutations are the most common genetic cause of meningiomas and multiple meningiomas usually occur within the context of NF2 disease. Recent studies have identified a variety of other, less common, germline and somatic mutations in meningioma disease, showing that alternative mechanisms exist for the initiation and progression of meningioma growth. These discoveries will be useful for determining individual risk and prognosis and to develop individualised therapeutic strategies based on specific meningioma subtypes.

Key Concepts

  • Meningiomas are the most common tumours in the adult central nervous system.
  • Most meningiomas are solitary tumours.
  • The neurofibromatosis type 2 gene is the most common cause of meningiomas.
  • Rare non‐NF2 meningioma predisposition genes can cause hereditary meningioma disease.
  • A range of somatic alterations in meningiomas may cause tumour development via differing cellular pathways.

Keywords: meningioma; tumour suppressor; mutation; brain tumour; neurofibromatosis type 2

Figure 1. The layers of the meninges.


Aavikko M, Li SP, Saarinen S, et al. (2012) Loss of SUFU function in familial multiple meningioma. American Journal of Human Genetics 91: 520–526.

Abedalthagafi MS, Bi WL, Merrill PH, et al. (2015) ARID1A and TERT promoter mutations in dedifferentiated meningioma. Cancer Genetics 208: 345–350.

Abedalthagafi M, Bi WL, Aizer AA, et al. (2016) Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro‐oncology 18: 649–655.

Amelot A, Lemaistre G, Cornu P, et al. (2015) Multiple meningiomas in patients with Turner syndrome. Acta Neurochirurgica 157: 621–623.

Basu S, Totty NF, Irwin MS, et al. (2003) Akt phosphorylates the Yes‐associated protein, YAP, to induce interaction with 14‐3‐3 and attenuation of p73‐mediated apoptosis. Molecular Cell 11: 11–23.

Bello MJ, Aminoso C, Lopez‐Marin I, et al. (2004) DNA methylation of multiple promoter‐associated CpG islands in meningiomas: relationship with the allelic status at 1p and 22q. Acta Neuropathologica 108: 413–421.

Biegel JA, Zhou JY, Rorke LB, et al. (1999) Germ‐line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Research 59: 74–79.

Brastianos PK, Horowitz PM, Santagata S, et al. (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nature Genetics 45: 285–289.

CBTRUS (2005) Statistical Report: Primary Brain Tumors in the United States, 1998–2002. Central Brain Tumor Registry of the United States, p 9.

Cea‐Soriano L, Wallander MA and Garcia Rodriguez LA (2012) Epidemiology of meningioma in the United Kingdom. Neuroepidemiology 39: 27–34.

Clark VE, Erson‐Omay EZ, Serin A, et al. (2013) Genomic analysis of non‐NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339: 1077–1080.

Evans DG, Birch JM, Ramsden RT, et al. (2006) Malignant transformation and new primary tumours after therapeutic radiation for benign disease: substantial risks in certain tumour prone syndromes. Journal of Medical Genetics 43: 289–294.

Gonzalez‐Agosti C, Wiederhold T, Herndon ME, et al. (1999) Interdomain interaction of merlin isoforms and its influence on intermolecular binding to NHE‐RF. The Journal of Biological Chemistry 274: 34438–34442.

Goutagny S, Yang HW, Zucman‐Rossi J, et al. (2010) Genomic profiling reveals alternative genetic pathways of meningioma malignant progression dependent on the underlying NF2 status. Clinical Cancer Research 16: 4155–4164.

Goutagny S, Nault JC, Mallet M, et al. (2014) High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathology 24: 184–189.

Hadfield KD, Smith MJ, Trump D, et al. (2010) SMARCB1 mutations are not a common cause of multiple meningiomas. Journal of Medical Genetics 47: 567–568.

Hemminki K and Li X (2003) Familial risks in nervous system tumors. Cancer Epidemiology, Biomarkers & Prevention 12: 1137–1142.

Jagani Z, Mora‐Blanco EL, Sansam CG, et al. (2010) Loss of the tumor suppressor Snf5 leads to aberrant activation of the Hedgehog‐Gli pathway. Nature Medicine 16: 1429–1433.

Jang SW, Yang SJ, Srinivasan S, et al. (2007) Akt phosphorylates MstI and prevents its proteolytic activation, blocking FOXO3 phosphorylation and nuclear translocation. Journal of Biological Chemistry 282: 30836–30844.

Kalamarides M, Niwa‐Kawakita M, Leblois H, et al. (2002) Nf2 gene inactivation in arachnoidal cells is rate‐limiting for meningioma development in the mouse. Genes & Development 16: 1060–1065.

Kluwe L, MacCollin M, Tatagiba M, et al. (1998) Phenotypic variability associated with 14 splice‐site mutations in the NF2 gene. American Journal of Medical Genetics 77: 228–233.

Larson JJ, Tew JM Jr, Simon M, et al. (1995) Evidence for clonal spread in the development of multiple meningiomas. Journal of Neurosurgery 83: 705–709.

Lindhurst MJ, Sapp JC, Teer JK, et al. (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. The New England Journal of Medicine 365: 611–619.

Louis DN, Ohgaki H, Wiestler OD, et al. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica 114: 97–109.

Orloff MS, He X, Peterson C, et al. (2013) Germline PIK3CA and AKT1 mutations in Cowden and Cowden‐like syndromes. American Journal of Human Genetics 92: 76–80.

Ostrom QT, Gittleman H, Liao P, et al. (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro‐oncology 16 (Suppl 4): iv1–iv63.

Pang JC, Chung NY, Chan NH, et al. (2006) Rare mutation of PIK3CA in meningiomas. Acta Neuropathologica 111: 284–285.

Pier DB, Nunes FP, Plotkin SR, et al. (2014) Turner syndrome and meningioma: support for a possible increased risk of neoplasia in Turner syndrome. European Journal of Medical Genetics 57: 269–274.

Peters N, Wellenreuther R, Rollbrocker B, et al. (1998) Analysis of the PTEN gene in human meningiomas. Neuropathology and Applied Neurobiology 24: 3–8.

Rademaker J, Kim YJ, Leibecke T, et al. (2005) Cowden disease: CT findings in three patients. Abdominal Imaging 30: 204–207.

Riobo NA, Lu K, Ai X, et al. (2006) Phosphoinositide 3‐kinase and Akt are essential for Sonic Hedgehog signaling. Proceedings of the National Academy of Sciences of the United States of America 103: 4505–4510.

Romano D, Matallanas D, Weitsman G, et al. (2010) Proapoptotic kinase MST2 coordinates signaling crosstalk between RASSF1A, Raf‐1, and Akt. Cancer Research 70: 1195–1203.

Ruttledge MH, Sarrazin J, Rangaratnam S, et al. (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nature Genetics 6: 180–184.

Schmitz U, Mueller W, Weber M, et al. (2001) INI1 mutations in meningiomas at a potential hotspot in exon 9. British Journal of Cancer 84: 199–201.

Smith MJ, Higgs JE, Bowers NL, et al. (2011) Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. Journal of Medical Genetics 48: 61–65.

Smith MJ, O'Sullivan J, Bhaskar SS, et al. (2013) Loss‐of‐function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nature Genetics 45: 295–298.

Smith MJ, Wallace AJ, Bennett C, et al. (2014a) Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. The Journal of Pathology 234: 436–440.

Smith MJ, Wallace AJ, Bowers NL, et al. (2014b) SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genetics 207: 373–378.

Smith MJ, Isidor B, Beetz C, et al. (2015) Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology 84: 141–147.

Smith MJ, Urquhart JE, Harkness EF, et al. (2016) The contribution of whole gene deletions and large rearrangements to the mutation spectrum in inherited tumor predisposing syndromes. Human Mutation 37: 250–256.

Stangl AP, Wellenreuther R, Lenartz D, et al. (1997) Clonality of multiple meningiomas. Journal of Neurosurgery 86: 853–858.

Striedinger K, VandenBerg SR, Baia GS, et al. (2008) The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. Neoplasia 10: 1204–1212.

Tang X, Jang SW, Wang X, et al. (2007) Akt phosphorylation regulates the tumour‐suppressor merlin through ubiquitination and degradation. Nature Cell Biology 9: 1199–1207.

Taylor MD, Liu L, Raffel C, et al. (2002) Mutations in SUFU predispose to medulloblastoma. Nature Genetics 31: 306–310.

Tsurusaki Y, Okamoto N, Ohashi H, et al. (2012) Mutations affecting components of the SWI/SNF complex cause Coffin‐Siris syndrome. Nature Genetics 44: 376–378.

Turner JT, Cohen MM Jr and Biesecker LG (2004) Reassessment of the Proteus syndrome literature: application of diagnostic criteria to published cases. American Journal of Medical Genetics 130A: 111–122.

Weber RG, Bostrom J, Wolter M, et al. (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proceedings of the National Academy of Sciences of the United States of America 94: 14719–14724.

Wei L and Xu Z (2011) Cross‐signaling among phosphinositide‐3 kinase, mitogen‐activated protein kinase and sonic hedgehog pathways exists in esophageal cancer. International Journal of Cancer 129: 275–284.

Yoo YA, Kang MH, Lee HJ, et al. (2011) Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP‐9 pathway in gastric cancer. Cancer Research 71: 7061–7070.

Further Reading

Domingues P, González‐Tablas M, Otero Á, et al. (2015) Genetic/molecular alterations of meningiomas and the signaling pathways targeted. Oncotarget 6 (13): 10671–10688.

Durand A, Labrousse F, Jouvet A, et al. (2009) WHO grade II and III meningiomas: a study of prognostic factors. Journal of Neurooncology 95 (3): 367–375. DOI: 10.1007/s11060-009-9934-0.

Evans DG, Watson C, King A, et al. (2005) Multiple meningiomas: differential involvement of the NF2 gene in children and adults. Journal of Medical Genetics 42 (1): 45–48.

Evans DG (2015) Neurofibromatosis type 2. Handbook of Clinical Neurology 132: 87–96. DOI: 10.1016/B978-0-444-62702-5.00005-6.

Peyre M and Kalamarides M (2014) Molecular genetics of meningiomas: building the roadmap towards personalized therapy. Neurochirurgie pii: S0028‐3770(14)00113‐1. DOI: 10.1016/j.neuchi.2014.06.007.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Smith, Miriam J(Jul 2016) Molecular Genetics of Meningioma. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026645]