Meningioma: current updates on genetics, classification, and mouse modeling
Keywords:
Meningioma, Brain tumor, YAP1, Hippo, TRAF7, KLF4, AKT, Mouse modeling, RCAS, Molecular classifications
Abstract
Meningiomas, the most common primary brain tumors in adults, are often benign and curable by surgical resection. However, a subset is of higher grade, shows aggressive growth behavior as well as brain invasion, and often recurs even after several rounds of surgery. Increasing evidence suggests that tumor classification and grading primarily based on histopathology do not always accurately predict tumor aggressiveness and recurrence behavior. The underlying biology of aggressive treatment-resistant meningiomas and the impact of specific genetic aberrations present in these high-grade tumors is still only insufficiently understood. Therefore, an in-depth research into the biology of this tumor type is warranted. More recent studies based on large-scale molecular data such as whole exome/genome sequencing, DNA methylation sequencing, and RNA sequencing have provided new insights into the biology of meningiomas and have revealed new risk factors and prognostic subtypes. The most common genetic aberration in meningiomas is functional loss of NF2 and occurs in both low- and high-grade meningiomas, whereas NF2-wildtype meningiomas are enriched for recurrent mutations in TRAF7, KLF4, AKT1, PI3KCA, and SMO and are more frequently benign. Most meningioma mouse models are based on patient-derived xenografts and only recently have new genetically engineered mouse models of meningioma been developed that will aid in the systematic evaluation of specific mutations found in meningioma and their impact on tumor behavior. In this article, we review recent advances in the understanding of meningioma biology and classification and highlight the most common genetic mutations, as well as discuss new genetically engineered mouse models of meningioma.
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References
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2. Wang JZ, Nassiri F, Saladino A, Zadeh G. Surgical therapy of non-skull base meningiomas. Adv Exp Med Biol. 2023;1416:79–94. doi: 10.1007/978-3-031-29750-2_7
3. Westphal M, Saladino A, Tatagiba M. Skull base meningiomas. Adv Exp Med Biol. 2023;1416:47–68. doi: 10.1007/978-3-031-29750-2_5
4. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 2021;23:1231–51. doi: 10.1093/neuonc/noab106
5. Wang JZ, Nassiri F, Mawrin C, Zadeh G. Genomic landscape of meningiomas. Adv Exp Med Biol. 2023;1416:137–58. doi: 10.1007/978-3-031-29750-2_11
6. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017;18:682–94. doi: 10.1016/S1470-2045(17)30155-9
7. Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339:1077–80. doi: 10.1126/science.1233009
8. Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS, et al. CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol. 2020;140:409–13. doi: 10.1007/s00401-020-02188-w
9. Williams EA, Santagata S, Wakimoto H, Shankar GM, Barker FG, 2nd, Sharaf R, et al. Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic. Acta Neuropathol Commun. 2020;8:171. doi: 10.1186/s40478-020-01040-2
10. Spiegl-Kreinecker S, Lotsch D, Neumayer K, Kastler L, Gojo J, Pirker C, et al. TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. Neuro Oncol. 2018;20:1584–93. doi: 10.1093/neuonc/noy104
11. Goutagny S, Nault JC, Mallet M, Henin D, Rossi JZ, Kalamarides M. High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol. 2014;24:184–9. doi: 10.1111/bpa.12110
12. Kirches E, Sahm F, Korshunov A, Bluecher C, Waldt N, Kropf S, et al. Molecular profiling of pediatric meningiomas shows tumor characteristics distinct from adult meningiomas. Acta Neuropathol. 2021;142:873–86. doi: 10.1007/s00401-021-02351-x
13. Sievers P, Chiang J, Schrimpf D, Stichel D, Paramasivam N, Sill M, et al. YAP1-fusions in pediatric NF2-wildtype meningioma. Acta Neuropathol. 2020;139:215–8. doi: 10.1007/s00401-019-02095-9
14. Szulzewsky F, Arora S, Arakaki AKS, Sievers P, Almiron Bonnin DA, Paddison PJ, et al. Both YAP1-MAML2 and constitutively active YAP1 drive the formation of tumors that resemble NF2 mutant meningiomas in mice. Genes Dev. 2022;36:857–70. doi: 10.1101/gad.349876.122
15. Szulzewsky F, Holland EC, Vasioukhin V. YAP1 and its fusion proteins in cancer initiation, progression and therapeutic resistance. Dev Biol. 2021;475:205–21. doi: 10.1016/j.ydbio.2020.12.018
16. Petrilli AM, Fernandez-Valle C. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2016;35:537–48. doi: 10.1038/onc.2015.125
17. Hamaratoglu F, Willecke M, Kango-Singh M, Nolo R, Hyun E, Tao C, et al. The tumour-suppressor genes NF2/Merlin and expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol. 2006;8:27–36. doi: 10.1038/ncb1339
18. Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D. Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell. 2013;154:1342–55. doi: 10.1016/j.cell.2013.08.025
19. Zhang N, Bai H, David KK, Dong J, Zheng Y, Cai J, et al. The Merlin/NF2 tumor suppressor functions through the YAP oncoprotein to regulate tissue homeostasis in mammals. Dev Cell. 2010;19:27–38. doi: 10.1016/j.devcel.2010.06.015
20. Baia GS, Caballero OL, Orr BA, Lal A, Ho JS, Cowdrey C, et al. Yes-associated protein 1 is activated and functions as an oncogene in meningiomas. Mol Cancer Res. 2012;10:904–13. doi: 10.1158/1541-7786.MCR-12-0116
21. Striedinger K, VandenBerg SR, Baia GS, McDermott MW, Gutmann DH, Lal A. The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. Neoplasia. 2008;10:1204–12. doi: 10.1593/neo.08642
22. Tate G, Kishimoto K, Mitsuya T. A novel mutation of the FAT2 gene in spinal meningioma. Oncol Lett. 2016;12:3393–6. doi: 10.3892/ol.2016.5063
23. Szulzewsky F, Arora S, Hoellerbauer P, King C, Nathan E, Chan M, et al. Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis. Genes Dev. 2020;34:1051–64. doi: 10.1101/gad.338681.120
24. Study to evaluate VT3989 in patients with metastatic solid tumors enriched for tumors with NF2 gene mutations: ClinicalTrials.gov; 2021. Available from: https://clinicaltrials.gov/study/NCT04665206 [cited February 2024].
25. Stamenkovic I, Yu Q. Merlin, a ‘magic’ linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Curr Protein Pept Sci. 2010;11:471–84. doi: 10.2174/138920310791824011
26. Chiasson-MacKenzie C, Morris ZS, Baca Q, Morris B, Coker JK, Mirchev R, et al. NF2/Merlin mediates contact-dependent inhibition of EGFR mobility and internalization via cortical actomyosin. J Cell Biol. 2015;211:391–405. doi: 10.1083/jcb.201503081
27. Fraenzer JT, Pan H, Minimo L, Jr., Smith GM, Knauer D, Hung G. Overexpression of the NF2 gene inhibits schwannoma cell proliferation through promoting PDGFR degradation. Int J Oncol. 2003;23:1493–500. doi: 10.3892/ijo.23.6.1493
28. Cui Y, Groth S, Troutman S, Carlstedt A, Sperka T, Riecken LB, et al. The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling. Oncogene. 2019;38:6370–81. doi: 10.1038/s41388-019-0883-6
29. Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P. Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res. 2007;67:520–7. doi: 10.1158/0008-5472.CAN-06-1608
30. Lim JY, Kim H, Jeun SS, Kang SG, Lee KJ. Merlin inhibits growth hormone-regulated Raf-ERKs pathways by binding to Grb2 protein. Biochem Biophys Res Commun. 2006;340:1151–7. doi: 10.1016/j.bbrc.2005.12.122
31. Rong R, Tang X, Gutmann DH, Ye K. Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proc Natl Acad Sci U S A. 2004;101:18200–5. doi: 10.1073/pnas.0405971102
32. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, 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. 2009;29:4250–61. doi: 10.1128/MCB.01581-08
33. Zotti T, Scudiero I, Vito P, Stilo R. The emerging role of TRAF7 in tumor development. J Cell Physiol. 2017;232:1233–8. doi: 10.1002/jcp.25676
34. Najm P, Zhao P, Steklov M, Sewduth RN, Baietti MF, Pandolfi S, et al. Loss-of-function mutations in TRAF7 and KLF4 cooperatively activate RAS-Like GTPase signaling and promote meningioma development. Cancer Res. 2021;81:4218–29. doi: 10.1158/0008-5472.CAN-20-3669
35. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131:861–72. doi: 10.1016/j.cell.2007.11.019
36. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76. doi: 10.1016/j.cell.2006.07.024
37. Tsytsykova AV, Wiley G, Li C, Pelikan RC, Garman L, Acquah FA, et al. Mutated KLF4(K409Q) in meningioma binds STRs and activates FGF3 gene expression. iScience. 2022;25:104839. doi: 10.1016/j.isci.2022.104839
38. von Spreckelsen N, Waldt N, Poetschke R, Kesseler C, Dohmen H, Jiao HK, et al. KLF4(K409Q)-mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment. Acta Neuropathol Commun. 2020;8:41. doi: 10.1186/s40478-020-00912-x
39. Abedalthagafi M, Bi WL, Aizer AA, Merrill PH, Brewster R, Agarwalla PK, et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol. 2016;18:649–55. doi: 10.1093/neuonc/nov316
40. Clark VE, Harmanci AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48:1253–9. doi: 10.1038/ng.3651
41. Youngblood MW, Duran D, Montejo JD, Li C, Omay SB, Ozduman K, et al. Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas. J Neurosurg. 2019;133(5): 1345–54. doi: 10.3171/2019.8.JNS191266
42. Yang J, Nie J, Ma X, Wei Y, Peng Y, Wei X. Targeting PI3K in cancer: mechanisms and advances in clinical trials. Mol Cancer. 2019;18:26. doi: 10.1186/s12943-019-0954-x
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Published
2024-03-18
How to Cite
Szulzewsky F., Thirimanne H. N., & Holland E. C. (2024). Meningioma: current updates on genetics, classification, and mouse modeling. Upsala Journal of Medical Sciences, 129(S1), e10579. https://doi.org/10.48101/ujms.v129.10579
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Review Articles
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