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Advances in meningioma genetics: novel therapeutic opportunities

Nature Reviews Neurology volume 14, pages 106–115 (2018)Cite this article

Subjects

Key Points

  • Meningiomas are the most common primary intracranial tumours found in adults

  • Meningiomas can have an aggressive course characterized by local progression and, infrequently, metastasis to other organs, even when treated with surgery and radiotherapy

  • Key genetic and epigenetic alterations have been identified in meningiomas that strongly associate with clinicopathologic features, such as localization and prognosis, and could represent targets for drug treatment

  • Prospective clinical trials are evaluating novel drugs on the basis of advances in the understanding of the pathobiology of treatment-resistant meningiomas

Abstract

Meningiomas currently are among the most frequent intracranial tumours. Although the majority of meningiomas can be cured by surgical resection, ∼20% of patients have an aggressive clinical course with tumour recurrence or progressive disease, resulting in substantial morbidity and increased mortality of affected patients. During the past 3 years, exciting new data have been published that provide insights into the molecular background of meningiomas and link sites of tumour development with characteristic histopathological and molecular features, opening a new road to novel and promising treatment options for aggressive meningiomas. A growing number of the newly discovered recurrent mutations have been linked to a particular clinicopathological phenotype. Moreover, the updated WHO classification of brain tumours published in 2016 has incorporated some of these molecular findings, setting the stage for the improvement of future therapeutic efforts through the integration of essential molecular findings. Finally, an additional potential classification of meningiomas based on methylation profiling has been launched, which provides clues in the assessment of individual risk of meningioma recurrence. All of these developments are creating new prospects for effective molecularly driven diagnosis and therapy of meningiomas.

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Figure 1: Meningioma localization and genetic aberrations.
Figure 2: Overview of activated signalling pathways and drug targets in meningioma.

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References

  1. Harter, P. N., Braun, Y. & Plate, K. H. Classification of meningiomas-advances and controversies. Chin. Clin. Oncol. 6 (Suppl. 1), S2 (2017).

    Article  PubMed  Google Scholar 

  2. Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 17 (Suppl. 4), iv1–iv62 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Tufan, K. et al. Intracranial meningiomas of childhood and adolescence. Pediatr. Neurosurg. 41, 1–7 (2005).

    Article  PubMed  Google Scholar 

  4. Perry, A. et al. Aggressive phenotypic and genotypic features in pediatric and NF2-associated meningiomas: a clinicopathologic study of 53 cases. J. Neuropathol. Exp. Neurol. 60, 994–1003 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Evans, D. G. R. et al. Cancer and central nervous system tumor surveillance in pediatric neurofibromatosis 2 and related disorders. Clin. Cancer Res. 23, e54–e61 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Ostrom, Q. T. et al. American Brain Tumor Association adolescent and young adult primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 18 (Suppl. 1), i1–i50 (2016).

    Article  PubMed  Google Scholar 

  7. Klaeboe, L. et al. Incidence of intracranial meningiomas in Denmark, Finland, Norway and Sweden, 1968–1997. Int. J. Cancer 117, 996–1001 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Sadetzki, S., Flint-Richter, P. & Ben-Tal, T. Radiation induced meningioma: a descriptive study of 253 cases. J. Neurosurg. 97, 1078–1082 (2002).

    Article  PubMed  Google Scholar 

  9. Schneider, B., Pulhorn, H., Rohrig, B. & Rainov, N. G. Predisposing conditions and risk factors for development of symptomatic meningioma in adults. Cancer Detect. Prevent. 29, 440–447 (2005).

    Article  PubMed  Google Scholar 

  10. Flint-Richter, P., Mandelzweig, L., Oberman, B. & Sadetzki, S. Possible interaction between ionizing radiation, smoking, and gender in the causation of meningioma. Neuro Oncol. 13, 345–352 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Benson, V. S. et al. Mobile phone use and risk of brain neoplasms and other cancers: prospective study. Int. J. Epidemiol. 42, 792–802 (2013).

    Article  PubMed  Google Scholar 

  12. Al-Mefty, O., Topsakal, C., Pravdenkova, S., Sawyer, J. R. & Harrison, M. J. Radiation-induced meningiomas: clinical, pathological, cytokinetic, and cytogenetic characteristics. J. Neurosurg. 100, 1002–1013 (2004).

    Article  PubMed  Google Scholar 

  13. Claus, E. B. et al. Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females. J. Neurosurg. 118, 649–656 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Claus, E. B. et al. Family and personal medical history and risk of meningioma. J. Neurosurg. 115, 1072–1077 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Ji, Y. et al. Double-blind phase III randomized trial of the antiprogestin agent mifepristone in the treatment of unresectable meningioma: SWOG S9005. J. Clin. Oncol. 33, 4093–4098 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Simpson, D. The recurrence of intracranial meningiomas after surgical treatment. J. Neurol. Neurosurg. Psychiatry 20, 22–39 (1957).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gousias, K., Schramm, J. & Simon, M. The Simpson grading revisited: aggressive surgery and its place in modern meningioma management. J. Neurosurg. 125, 551–560 (2016).

    Article  PubMed  Google Scholar 

  18. Kaley, T. et al. Historical benchmarks for medical therapy trials in surgery- and radiation-refractory meningioma: a RANO review. Neuro Oncol. 16, 829–840 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mathiesen, T., Lindquist, C., Kihlstrom, L. & Karlsson, B. Recurrence of cranial base meningiomas. Neurosurgery 39, 2–9 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. ISRCTN Registry. ISRCTN.com http://www.isrctn.com/ISRCTN71502099 (2017).

  21. Dziuk, T. W. et al. Malignant meningioma: an indication for initial aggressive surgery and adjuvant radiotherapy. J. Neurooncol. 37, 177–188 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Goldbrunner, R. et al. EANO guidelines for the diagnosis and treatment of meningiomas. Lancet Oncol. 17, e383–e391 (2016).

    Article  PubMed  Google Scholar 

  23. Norden, A. D. et al. Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma. Neurology 84, 280–286 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  PubMed  Google Scholar 

  25. Perry, A., Scheithauer, B. W., Stafford, S. L., Lohse, C. M. & Wollan, P. C. “Malignancy” in meningiomas: a clinicopathologic study of 116 patients, with grading implications. Cancer 85, 2046–2056 (1999).

    CAS  PubMed  Google Scholar 

  26. Mawrin, C. & Perry, A. Pathological classification and molecular genetics of meningiomas. J. Neurooncol 99, 379–391 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Combs, S. E., Schulz-Ertner, D., Debus, J., von Deimling, A. & Hartmann, C. Improved correlation of the neuropathologic classification according to adapted World Health Organization classification and outcome after radiotherapy in patients with atypical and anaplastic meningiomas. Int. J. Radiat. Oncol. Biol. Phys. 81, 1415–1421 (2011).

    Article  PubMed  Google Scholar 

  28. Pearson, B. E. et al. Hitting a moving target: evolution of a treatment paradigm for atypical meningiomas amid changing diagnostic criteria. Neurosurg. Focus 24, E3 (2008).

    Article  PubMed  Google Scholar 

  29. Rogers, L. et al. Meningiomas: knowledge base, treatment outcomes, and uncertainties. A RANO review. J. Neurosurg. 122, 4–23 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Brastianos, P. K. et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat. Genet. 45, 285–289 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zang, K. Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases. Cytogenet. Cell Genet. 93, 207–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Trofatter, J. A. et al. A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72, 791–800 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Rouleau, G. A. et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363, 515–521 (1993).

    Article  CAS  PubMed  Google Scholar 

  34. Petrilli, A. M. & Fernandez-Valle, C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene 35, 537–548 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Seizinger, B. R., de la Monte, S., Atkins, L., Gusella, J. F. & Martuza, R. L. Molecular genetic approach to human meningioma: loss of genes on chromosome 22. Proc. Natl Acad. Sci. USA 84, 5419–5423 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruttledge, M. H. et al. Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat. Genet. 6, 180–184 (1994).

    Article  CAS  PubMed  Google Scholar 

  37. Wellenreuther, R. et al. Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma. Am. J. Pathol. 146, 827–832 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Hartmann, C. et al. NF2 mutations in secretory and other rare variants of meningiomas. Brain Pathol. 16, 15–19 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nunes, F. et al. Inactivation patterns of NF2 and DAL-1/4.1B (EPB41L3) in sporadic meningioma. Cancer Genet. Cytogenet. 162, 135–139 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Goutagny, S. et al. Genomic profiling reveals alternative genetic pathways of meningioma malignant progression dependent on the underlying NF2 status. Clin. Cancer Res. 16, 4155–4164 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Curto, M. & McClatchey, A. I. Nf2/Merlin: a coordinator of receptor signalling and intercellular contact. Br. J. Cancer. 98, 256–262 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. James, M. F. et al. NF2/Merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol. Cell. Biol. 29, 4250–4261 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. James, M. F. et al. Regulation of mTOR complex 2 signaling in neurofibromatosis 2-deficient target cell types. Mol. Cancer Res. 10, 649–659 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. Wilisch-Neumann, A. et al. Re-evaluation of cytostatic therapies for meningiomas in vitro. J. Cancer Res. Clin. Oncol. 140, 1343–1352 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Shah, N. R. et al. Analyses of Merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer. Gynecol. Oncol. 134, 104–111 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Shapiro, I. M. et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci. Transl Med. 6, 237ra68 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Schmitz, U. et al. INI1 mutations in meningiomas at a potential hotspot in exon 9. Br. J. Cancer 84, 199–201 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hadfield, K. D. et al. Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J. Med. Genet. 45, 332–339 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Clark, V. E. et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat. Genet. 48, 1253–1259 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448, 439–444 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Keppler-Noreuil, K. M., Baker, E. H., Sapp, J. C., Lindhurst, M. J. & Biesecker, L. G. Somatic AKT1 mutations cause meningiomas colocalizing with a characteristic pattern of cranial hyperostosis. Am. J. Med. Genet. A 170, 2605–2610 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Clark, V. E. et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339, 1077–1080 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Yesiloez, U. K. et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol. 19, 1088–1096 (2017).

    Article  CAS  Google Scholar 

  54. Yuzawa, S. et al. Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system. Modern Pathol. 29, 708–716 (2016).

    Article  CAS  Google Scholar 

  55. Abedalthagafi, M. et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol. 18, 649–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Boetto, J., Bielle, F., Sanson, M., Peyre, M. & Kalamarides, M. SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol. 19, 345–351 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Laurendeau, I. et al. Gene expression profiling of the Hedgehog signaling pathway in human meningiomas. Mol. Med. 16, 262–270 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ng, J. M. Y. & Curran, T. The Hedgehog's tale: developing strategies for targeting cancer. Nat. Rev. Cancer 11, 493–501 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kieran, M. W. Targeted treatment for Sonic Hedgehog-dependent medulloblastoma. Neuro Oncol. 16, 1037–1047 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Smith, M. J. et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J. Clin. Oncol. 32, 4155–4161 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Xu, L. G., Li, L. Y. & Shu, H. B. TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. J. Biol. Chem. 279, 17278–17282 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. McConnell, B. B. & Yang, V. W. Mammalian Kruppel-like factors in health and diseases. Physiol. Rev. 90, 1337–1381 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Schuetz, A. et al. The structure of the Klf4 DNA-binding domain links to self-renewal and macrophage differentiation. Cell. Mol. Life Sci. 68, 3121–3131 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Reuss, D. E. et al. Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol. 125, 351–358 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Mawrin, C. et al. Different activation of mitogen-activated protein kinase and Akt signaling is associated with aggressive phenotype of human meningiomas. Clin. Cancer Res. 11, 4074–4082 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. El-Habr, E. A. et al. Complex interactions between the components of the PI3K/AKT/mTOR pathway, and with components of MAPK, JAK/STAT and Notch-1 pathways, indicate their involvement in meningioma development. Virchows Arch. 465, 473–485 (2014).

    Article  CAS  PubMed  Google Scholar 

  68. Harmanci, A. S. et al. Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat. Commun. 8, 14433 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Sahm, F. et al. TERT promoter mutations and risk of recurrence in meningioma. J. Natl Cancer Inst. 108, djv377 (2016).

    Article  CAS  Google Scholar 

  70. Bi, W. L. et al. Genomic landscape of high-grade meningiomas. NPJ Genom. Med. 2, 15 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Rogers, C. L. et al. Pathology concordance levels for meningioma classification and grading in NRG Oncology RTOG Trial 0539. Neuro Oncol. 18, 565–574 (2016).

    Article  PubMed  Google Scholar 

  72. Vaubel, R. A. et al. Meningiomas with rhabdoid features lacking other histologic features of malignancy: a study of 44 cases and review of the literature. J. Neuropathol. Exp. Neurol. 75, 44–52 (2016).

    Article  PubMed  Google Scholar 

  73. Shankar, G. M. et al. Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol. 19, 535–545 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Carbone, M. et al. BAP1 and cancer. Nat. Rev. Cancer 13, 153–159 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ketter, R. et al. Application of oncogenetic trees mixtures as a biostatistical model of the clonal cytogenetic evolution of meningiomas. Int. J. Cancer 121, 1473–1480 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Catala, M. Embryonic and fetal development of structures associated with the cerebro-spinal fluid in man and other species. Part I: The ventricular system, meninges and choroid plexuses. Arch. d'Anatomie Cytol. Pathol. 46, 153–169 (1998).

    CAS  Google Scholar 

  77. Kros, J. et al. NF2 status of meningiomas is associated with tumour localization and histology. J. Pathol. 194, 367–372 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Lee, J. H., Sade, B., Choi, E., Golubic, M. & Prayson, R. Meningothelioma as the predominant histological subtype of midline skull base and spinal meningioma. J. Neurosurg. 105, 60–64 (2006).

    Article  PubMed  Google Scholar 

  79. Ketter, R. et al. Correspondence of tumor localization with tumor recurrence and cytogenetic progression in meningiomas. Neurosurgery 62, 61–69 (2008).

    Article  PubMed  Google Scholar 

  80. Antinheimo, J. et al. Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas. Neurology 54, 71–76 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Sahm, F. et al. AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. Acta Neuropathol. 126, 757–762 (2013).

    Article  CAS  PubMed  Google Scholar 

  82. Strickland, M. R. et al. Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas. J. Neurosurg. 127, 438–444 (2016).

    Article  PubMed  Google Scholar 

  83. Smith, M. J. et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat. Genet. 45, 295–298 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Smith, M. J. et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J. Pathol. 234, 436–440 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Simon, M. et al. Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res. 55, 4696–4701 (1995).

    CAS  PubMed  Google Scholar 

  86. Ketter, R. et al. Predictive value of progression-associated chromosomal aberrations for the prognosis of meningiomas: a retrospective study of 198 cases. J. Neurosurg. 95, 601–607 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Bello, M. J. et al. Allelic loss at 1p is associated with tumor progression of meningiomas. Genes Chromosomes Cancer 9, 296–298 (1994).

    Article  CAS  PubMed  Google Scholar 

  88. Kalala, J. P., Maes, L., Vandenbroecke, C. & de Ridder, L. The hTERT protein as a marker for malignancy in meningiomas. Oncol. Rep. 13, 273–277 (2005).

    CAS  PubMed  Google Scholar 

  89. Goutagny, S. et al. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 24, 184–189 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sahm, F. et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 18, 682–694 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Kalamarides, M. et al. Nf2 gene inactivation in arachnoidal cells is rate-limiting for meningioma development in the mouse. Genes Dev. 16, 1060–1065 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kawashima, M., Suzuki, S. O., Yamashima, T., Fukui, M. & Iwaki, T. Prostaglandin D synthase (β-trace) in meningeal hemangiopericytoma. Modern Pathol. 14, 197–201 (2001).

    Article  CAS  Google Scholar 

  93. Kalamarides, M. et al. Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. Oncogene 30, 2333–2344 (2011).

    Article  CAS  PubMed  Google Scholar 

  94. Weisman, A. S., Raguet, S. S. & Kelly, P. A. Characterization of the epidermal growth factor receptor in human meningioma. Cancer Res. 47, 2172–2176 (1987).

    CAS  PubMed  Google Scholar 

  95. Maxwell, M., Galanopoulos, T., Hedley-Whyte, E. T., Black, P. M. & Antoniades, H. N. Human meningiomas co-express platelet-derived growth factor (PDGF) and PDGF-receptor genes and their protein products. Int. J. Cancer 46, 16–21 (1990).

    Article  CAS  PubMed  Google Scholar 

  96. Baumgarten, P. et al. Expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2 in primary and recurrent WHO grade III meningiomas. Histol. Histopathol. 28, 1157–1166 (2013).

    PubMed  Google Scholar 

  97. Lichtor, T., Kurpakus, M. A. & Gurney, M. E. Expression of insulin-like growth factors and their receptors in human meningiomas. J. Neurooncol. 17, 183–190 (1993).

    Article  CAS  PubMed  Google Scholar 

  98. Johnson, M. D., Woodard, A., Kim, P. & Frexes-Steed, M. Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells. J. Neurosurg. 94, 293–300 (2001).

    Article  CAS  PubMed  Google Scholar 

  99. Johnson, M. D., Okedli, E., Woodard, A., Toms, S. A. & Allen, G. S. Evidence for phosphatidylinositol 3-kinase-Akt-p7S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in meningioma cells. J. Neurosurg. 97, 668–675 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Pachow, D. et al. mTORC1 inhibitors suppress meningioma growth in mouse models. Clin. Cancer Res. 19, 1180–1189 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Cai, D. X., James, C. D., Scheithauer, B. W., Couch, F. J. & Perry, A. PS6K amplification characterizes a small subset of anaplastic meningiomas. Am. J. Clin. Pathol. 115, 213–218 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Surace, E. I., Lusis, E., Haipek, C. A. & Gutmann, D. H. Functional significance of S6K overexpression in meningioma progression. Ann. Neurol. 56, 295–298 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Lopez-Lago, M. A., Okada, T., Murillo, M. M., Socci, N. & Giancotti, F. G. Loss of the tumor suppressor gene NF2, encoding merlin, constitutively activates integrin-dependent mTORC1 signaling. Mol. Cell. Biol. 29, 4235–4249 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Castelli, M. G. et al. Prostaglandin and thromboxane synthesis by human intracranial tumors. Cancer Res. 49, 1505–1508 (1989).

    CAS  PubMed  Google Scholar 

  105. Kang, H. C., Kim, I. H., Park, C. I. & Park, S. H. Immunohistochemical analysis of cyclooxygenase-2 and brain fatty acid binding protein expression in grades I-II meningiomas: correlation with tumor grade and clinical outcome after radiotherapy. Neuropathology 34, 446–454 (2014).

    Article  CAS  PubMed  Google Scholar 

  106. Johnson, M. D., Horiba, M., Winnier, A. R. & Arteaga, C. L. The epidermal growth factor receptor is associated with phospholipase C-γ1 in meningiomas. Hum. Pathol. 25, 146–153 (1994).

    Article  CAS  PubMed  Google Scholar 

  107. Johnson, M. D., Shaw, A. K., O'Connell, M. J., Sim, F. J. & Moses, H. L. Analysis of transforming growth factor β receptor expression and signaling in higher grade meningiomas. J. Neurooncol. 103, 277–285 (2011).

    Article  PubMed  Google Scholar 

  108. Nagashima, G., Asai, J., Suzuki, R. & Fujimoto, T. Different distribution of c-myc and MIB-1 positive cells in malignant meningiomas with reference to TGFs, PDGF, and PgR expression. Brain Tumor Pathol. 18, 1–5 (2001).

    Article  CAS  PubMed  Google Scholar 

  109. Johnson, M. D., O'Connell, M. J., Vito, F. & Pilcher, W. Bone morphogenetic protein 4 and its receptors are expressed in the leptomeninges and meningiomas and signal via the Smad pathway. J. Neuropathol. Exp. Neurol. 68, 1177–1183 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Ragel, B. T. et al. A comparison of the cell lines used in meningioma research. Surg. Neurol. 70, 295–307 (2008).

    Article  PubMed  Google Scholar 

  111. Puttmann, S. et al. Establishment of a benign meningioma cell line by hTERT-mediated immortalization. Lab. Invest. 85, 1163–1171 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Friedrich, S. et al. Comparative morphological and immunohistochemical study of human meningioma after intracranial transplantation into nude mice. J. Neurosci. Methods 205, 1–9 (2012).

    Article  PubMed  Google Scholar 

  113. Wen, P., Quant, E., Drappatz, J., Beroukhim, R. & Norden, A. Medical therapies for meningiomas. J. Neurooncol 99, 365–378 (2010).

    Article  CAS  PubMed  Google Scholar 

  114. Kaley, T. J. et al. Phase II trial of sunitinib for recurrent and progressive atypical and anaplastic meningioma. Neuro Oncol. 17, 116–121 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Shih, K. C. et al. A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J. Neurooncol. 129, 281–288 (2016).

    Article  CAS  PubMed  Google Scholar 

  116. Mawrin, C., Chung, C. & Preusser, M. Biology and clinical management challenges in meningioma. Am. Soc. Clin. Oncol. Educ. Book https://doi.org/10.14694/EdBook_AM.2015.35.e106 (2015).

    Article  Google Scholar 

  117. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02523014 (2017).

  118. Von Hoff, D. D. et al. Inhibition of the Hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).

    Article  CAS  PubMed  Google Scholar 

  119. Weller, M. et al. Durable control of metastatic AKT1-mutant WHO-grade I meningothelial meningioma by the AKT inhibitor, AZD5363. J. Natl Cancer Inst. 109, djw320 (2016).

    Google Scholar 

  120. Beauchamp, R. L. et al. A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget 6, 16981–16997 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  121. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03071874 (2017).

  122. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02831257 (2017).

  123. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02234050 (2017).

  124. Preusser, M. et al. Trabectedin has promising antineoplastic activity in high-grade meningioma. Cancer. 118, 5038–5049 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Germano, G. et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 11, 249–262 (2013).

    Article  CAS  Google Scholar 

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Acknowledgements

The meningioma research of C.M.'s group is supported by Deutsche Forschungsgemeinschaft (Germany; grant MA2530/6-1 and MA2530/8-1), Wilhelm Sander-Stiftung (Germany; grant 2014.092.1) and Deutsche Krebshilfe (Germany; grant #111853).

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Author notes

  1. Matthias Preusser and Christian Mawrin: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine I and Comprehensive Cancer Center CNS Unit, Medical University of Vienna, Waehringer Guertel 18–20, Vienna, 1090, Austria

    Matthias Preusser

  2. Divisions of Neuro-Oncology and Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Priscilla K. Brastianos

  3. Department of Neuropathology, Otto von Guericke University Magdeburg, Leipziger Strasse, 44, Magdeburg, 39120, Germany

    Christian Mawrin

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  1. Matthias Preusser
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  2. Priscilla K. Brastianos
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  3. Christian Mawrin
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All authors contributed to the research, discussion, writing and review of the manuscript.

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Correspondence to Matthias Preusser or Christian Mawrin.

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Preusser, M., Brastianos, P. & Mawrin, C. Advances in meningioma genetics: novel therapeutic opportunities. Nat Rev Neurol 14, 106–115 (2018). https://doi.org/10.1038/nrneurol.2017.168

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