Skip to main content

Advertisement

SpringerLink
Log in

Landscape of genetic variants in sporadic meningiomas captured with clinical genomics

  • Original Article - Brain Tumors
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Background

Meningiomas are the most common primary central nervous system tumor. Previous studies have characterized recurrent genetic alterations that can predict patient prognosis and potentially provide new avenues for therapeutic intervention. Continued efforts to characterize the genomic changes in meningioma samples can aid in the discovery of therapeutic targets and appropriate patient stratification.

Methods

We performed targeted genomic sequencing on 25 primary and 2 recurrent meningiomas using a 500-gene panel, including canonical meningioma drivers. We further detail the genomic profiles and relevant clinical findings in three cases of angiomatous meningiomas and two recurrent atypical meningiomas.

Results

Our approach uncovers a diverse landscape of genomic variants in meningioma samples including mutations in established meningioma-related genes NF2, AKT1, PIK3CA, and TRAF7. In addition to known meningioma drivers, we uncover variants in genes encoding other PI3K subunits, Notch/hedgehog/Wnt signaling pathway components, and chromatin regulators. We additionally identify 22 genes mutated across multiple samples. Three patients included in the study were diagnosed with angiomatous WHO grade I meningiomas, all three of which contained variants in the PI3K-AKT signaling pathway previously described to regulate tumor angiogenesis. Analysis of patient-matched primary and recurrent atypical meningiomas revealed clonal enrichment for mutations in the SWI/SNF complex subunits ARID1A and SMARCA4.

Conclusions

Targeted genomics implemented in neuro-oncology care can enhance our understanding of the genetic underpinnings of central nervous system tumors, including meningiomas. These molecular signatures may be clinically useful in dictating treatment strategies and patient follow-up.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

CNS:

Central nervous system

WHO:

World Health Organization

AMP:

Association for Molecular Pathology

ASCO:

American Society of Clinical Oncology

CAP:

College of American Pathologists

References

  1. Abedalthagafi M, Bi WL, Aizer AA, Merrill PH, Brewster R, Agarwalla PK, Listewnik ML, Dias-Santagata D, Thorner AR, Van Hummelen P, Brastianos PK, Reardon DA, Wen PY, Al-Mefty O, Ramkissoon SH, Folkerth RD, Ligon KL, Ligon AH, Alexander BM, Dunn IF, Beroukhim R, Santagata S (2016) Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol 18:649–655. https://doi.org/10.1093/neuonc/nov316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abedalthagafi MS, Bi WL, Merrill PH, Gibson WJ, Rose MF, Du Z, Francis JM, Du R, Dunn IF, Ligon AH, Beroukhim R, Santagata S (2015) ARID1A and TERT promoter mutations in dedifferentiated meningioma. Cancer Genet 208:345–350. https://doi.org/10.1016/j.cancergen.2015.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Abedalthagafi MS, Merrill PH, Bi WL, Jones RT, Listewnik ML, Ramkissoon SH, Thorner AR, Dunn IF, Beroukhim R, Alexander BM, Brastianos PK, Francis JM, Folkerth RD, Ligon KL, Van Hummelen P, Ligon AH, Santagata S (2014) Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5. Oncotarget 5:10596–10606. https://doi.org/10.18632/oncotarget.2517

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ananda G, Mockus S, Lundquist M, Spotlow V, Simons A, Mitchell T, Stafford G, Philip V, Stearns T, Srivastava A, Barter M, Rowe L, Malcolm J, Bult C, Karuturi RK, Rasmussen K, Hinerfeld D (2015) Development and validation of the JAX cancer treatment profile for detection of clinically actionable mutations in solid tumors. Exp Mol Pathol 98:106–112. https://doi.org/10.1016/j.yexmp.2014.12.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Beauchamp RL, James MF, DeSouza PA, Wagh V, Zhao WN, Jordan JT, Stemmer-Rachamimov A, Plotkin SR, Gusella JF, Haggarty SJ, Ramesh V (2015) A high-throughput kinome screen reveals serum/glucocorticoid-regulated kinase 1 as a therapeutic target for NF2-deficient meningiomas. Oncotarget 6:16981–16997. https://doi.org/10.18632/oncotarget.4858

    Article  PubMed  PubMed Central  Google Scholar 

  6. Berger MF, Mardis ER (2018) The emerging clinical relevance of genomics in cancer medicine. Nat Rev Clin Oncol 15:353–365. https://doi.org/10.1038/s41571-018-0002-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bi WL, Greenwald NF, Abedalthagafi M, Wala J, Gibson WJ, Agarwalla PK, Horowitz P, Schumacher SE, Esaulova E, Mei Y, Chevalier A, Ducar M, Thorner AR, van Hummelen P, Stemmer-Rachamimov A, Artyomov M, Al-Mefty O, Dunn GP, Santagata S, Dunn IF, Beroukhim R (2017) Genomic landscape of high-grade meningiomas. NPJ Genom Med 2. https://doi.org/10.1038/s41525-017-0014-7

  8. Biczok A, Kraus T, Suchorska B, Terpolilli NA, Thorsteinsdottir J, Giese A, Tonn JC, Schichor C (2018) TERT promoter mutation is associated with worse prognosis in WHO grade II and III meningiomas. J Neurooncol 139:671-678. https://doi.org/10.1007/s11060-018-2912-7

  9. Brastianos PK, Galanis E, Butowski N, Chan JW, Dunn IF, Goldbrunner R, Herold-Mende C, Ippen FM, Mawrin C, McDermott MW, Sloan A, Snyder J, Tabatabai G, Tatagiba M, Tonn JC, Wen PY, Aldape K, Nassiri F, Zadeh G, Jenkinson MD, Raleigh DR, International Consortium on M (2019) Advances in multidisciplinary therapy for meningiomas. Neuro Oncol 21:i18–i31. https://doi.org/10.1093/neuonc/noy136

    Article  CAS  Google Scholar 

  10. Brastianos PK, Horowitz PM, Santagata S, Jones RT, McKenna A, Getz G, Ligon KL, Palescandolo E, Van Hummelen P, Ducar MD, Raza A, Sunkavalli A, Macconaill LE, Stemmer-Rachamimov AO, Louis DN, Hahn WC, Dunn IF, Beroukhim R (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:285–289. https://doi.org/10.1038/ng.2526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bujko M, Machnicki MM, Grecka E, Rusetska N, Matyja E, Kober P, Mandat T, Rydzanicz M, Ploski R, Krajewski R, Bonicki W, Stoklosa T, Siedlecki JA (2017) Mutational analysis of recurrent meningioma progressing from atypical to rhabdoid subtype. World Neurosurg 97(754):e751-754 e756. https://doi.org/10.1016/j.wneu.2016.10.047

    Article  Google Scholar 

  12. Cao X, Hao S, Wu Z, Wang L, Jia G, Zhang L, Zhang J (2015) Survival rates, prognostic factors and treatment of anaplastic meningiomas. J Clin Neurosci 22:828–833. https://doi.org/10.1016/j.jocn.2014.11.022

    Article  PubMed  Google Scholar 

  13. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404. https://doi.org/10.1158/2159-8290.CD-12-0095

    Article  PubMed  Google Scholar 

  14. Choudhury A, Magill ST, Eaton CD, Prager BC, Chen WC, Seo K, Lucas C-HG, Villanueva-Meyer JE, Lam T-C, Pu JK-S, Li L-F, Leung GK-K, Vasudevan HN, Liu SJ, Chan JW, Qiu Z, Zhang MY, Martin MV, Susko MS, Braunstein SE, Oberheim Bush NA, Schulte J, Butowski N, Sneed PK, Berger MS, Perry A, Phillips JJ, Solomon DA, Costello JF, McDermott MW, Rich JN, Raleigh DR (2020) Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities. medRxiv:2020.2011.2023.20237495. https://doi.org/10.1101/2020.11.23.20237495

  15. Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, Avsar T, Li J, Murray PB, Henegariu O, Yilmaz S, Gunel JM, Carrion-Grant G, Yilmaz B, Grady C, Tanrikulu B, Bakircioglu M, Kaymakcalan H, Caglayan AO, Sencar L, Ceyhun E, Atik AF, Bayri Y, Bai H, Kolb LE, Hebert RM, Omay SB, Mishra-Gorur K, Choi M, Overton JD, Holland EC, Mane S, State MW, Bilguvar K, Baehring JM, Gutin PH, Piepmeier JM, Vortmeyer A, Brennan CW, Pamir MN, Kilic T, Lifton RP, Noonan JP, Yasuno K, Gunel M (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:1077–1080. https://doi.org/10.1126/science.1233009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Clark VE, Harmanci AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, Ercan-Sencicek AG, Abraham BJ, Weintraub AS, Hnisz D, Simon M, Krischek B, Erson-Omay EZ, Henegariu O, Carrion-Grant G, Mishra-Gorur K, Duran D, Goldmann JE, Schramm J, Goldbrunner R, Piepmeier JM, Vortmeyer AO, Gunel JM, Bilguvar K, Yasuno K, Young RA, Gunel M (2016) Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet 48:1253–1259. https://doi.org/10.1038/ng.3651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Collord G, Tarpey P, Kurbatova N, Martincorena I, Moran S, Castro M, Nagy T, Bignell G, Maura F, Young MD, Berna J, Tubio JMC, McMurran CE, Young AMH, Sanders M, Noorani I, Price SJ, Watts C, Leipnitz E, Kirsch M, Schackert G, Pearson D, Devadass A, Ram Z, Collins VP, Allinson K, Jenkinson MD, Zakaria R, Syed K, Hanemann CO, Dunn J, McDermott MW, Kirollos RW, Vassiliou GS, Esteller M, Behjati S, Brazma A, Santarius T, McDermott U (2018) An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures. Sci Rep 8:13537. https://doi.org/10.1038/s41598-018-31659-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Cui Y, Groth S, Troutman S, Carlstedt A, Sperka T, Riecken LB, Kissil JL, Jin H, Morrison H (2019) The NF2 tumor suppressor merlin interacts with Ras and RasGAP, which may modulate Ras signaling. Oncogene 38:6370–6381. https://doi.org/10.1038/s41388-019-0883-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Delaney SK, Hultner ML, Jacob HJ, Ledbetter DH, McCarthy JJ, Ball M, Beckman KB, Belmont JW, Bloss CS, Christman MF, Cosgrove A, Damiani SA, Danis T, Delledonne M, Dougherty MJ, Dudley JT, Faucett WA, Friedman JR, Haase DH, Hays TS, Heilsberg S, Huber J, Kaminsky L, Ledbetter N, Lee WH, Levin E, Libiger O, Linderman M, Love RL, Magnus DC, Martland A, McClure SL, Megill SE, Messier H, Nussbaum RL, Palaniappan L, Patay BA, Popovich BW, Quackenbush J, Savant MJ, Su MM, Terry SF, Tucker S, Wong WT, Green RC (2016) Toward clinical genomics in everyday medicine: perspectives and recommendations. Expert Rev Mol Diagn 16:521–532. https://doi.org/10.1586/14737159.2016.1146593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gao F, Shi L, Russin J, Zeng L, Chang X, He S, Chen TC, Giannotta SL, Weisenberger DJ, Zada G, Mack WJ, Wang K (2013) DNA methylation in the malignant transformation of meningiomas. PLoS One 8:e54114. https://doi.org/10.1371/journal.pone.0054114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Garcia-Rendueles ME, Ricarte-Filho JC, Untch BR, Landa I, Knauf JA, Voza F, Smith VE, Ganly I, Taylor BS, Persaud Y, Oler G, Fang Y, Jhanwar SC, Viale A, Heguy A, Huberman KH, Giancotti F, Ghossein R, Fagin JA (2015) NF2 loss promotes oncogenic RAS-induced thyroid cancers via YAP-dependent transactivation of RAS proteins and sensitizes them to MEK inhibition. Cancer Discov 5:1178–1193. https://doi.org/10.1158/2159-8290.CD-15-0330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Garzon-Muvdi T, Bailey DD, Pernik MN, Pan E (2020) Basis for immunotherapy for treatment of meningiomas. Front Neurol 11:945. https://doi.org/10.3389/fneur.2020.00945

    Article  PubMed  PubMed Central  Google Scholar 

  23. Gill CM, Loewenstern J, Rutland JW, Arib H, Pain M, Umphlett M, Kinoshita Y, McBride RB, Bederson J, Donovan M, Sebra R, Fowkes M, Shrivastava RK (2021) SWI/SNF chromatin remodeling complex alterations in meningioma. J Cancer Res Clin Oncol 147:3431–3440. https://doi.org/10.1007/s00432-021-03586-7

    Article  CAS  PubMed  Google Scholar 

  24. Harmanci AS, Youngblood MW, Clark VE, Coskun S, Henegariu O, Duran D, Erson-Omay EZ, Kaulen LD, Lee TI, Abraham BJ, Simon M, Krischek B, Timmer M, Goldbrunner R, Omay SB, Baranoski J, Baran B, Carrion-Grant G, Bai H, Mishra-Gorur K, Schramm J, Moliterno J, Vortmeyer AO, Bilguvar K, Yasuno K, Young RA, Gunel M (2018) Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 9:16215. https://doi.org/10.1038/ncomms16215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hortobagyi GN, Chen D, Piccart M, Rugo HS, Burris HA 3rd, Pritchard KI, Campone M, Noguchi S, Perez AT, Deleu I, Shtivelband M, Masuda N, Dakhil S, Anderson I, Robinson DM, He W, Garg A, McDonald ER 3rd, Bitter H, Huang A, Taran T, Bachelot T, Lebrun F, Lebwohl D, Baselga J (2016) Correlative analysis of genetic alterations and everolimus benefit in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: results from BOLERO-2. J Clin Oncol 34:419–426. https://doi.org/10.1200/JCO.2014.60.1971

    Article  CAS  PubMed  Google Scholar 

  26. Huntoon K, Toland AMS, Dahiya S (2020) Meningioma: a review of clinicopathological and molecular aspects. Front Oncol 10:579599. https://doi.org/10.3389/fonc.2020.579599

    Article  PubMed  PubMed Central  Google Scholar 

  27. Jungwirth G, Warta R, Beynon C, Sahm F, von Deimling A, Unterberg A, Herold-Mende C, Jungk C (2019) Intraventricular meningiomas frequently harbor NF2 mutations but lack common genetic alterations in TRAF7, AKT1, SMO, KLF4, PIK3CA, and TERT. Acta Neuropathol Commun 7:140. https://doi.org/10.1186/s40478-019-0793-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Karar J, Maity A (2011) PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci 4:51. https://doi.org/10.3389/fnmol.2011.00051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karsy M, Azab MA, Abou-Al-Shaar H, Guan J, Eli I, Jensen RL, Ormond DR (2018) Clinical potential of meningioma genomic insights: a practical review for neurosurgeons. Neurosurg Focus 44:E10. https://doi.org/10.3171/2018.2.FOCUS1849

    Article  PubMed  Google Scholar 

  30. Kaur G, Sayegh ET, Larson A, Bloch O, Madden M, Sun MZ, Barani IJ, James CD, Parsa AT (2014) Adjuvant radiotherapy for atypical and malignant meningiomas: a systematic review. Neuro Oncol 16:628–636. https://doi.org/10.1093/neuonc/nou025

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, Koplev S, Jenkins SL, Jagodnik KM, Lachmann A, McDermott MG, Monteiro CD, Gundersen GW, Ma’ayan A (2016) Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res 44:W90-97. https://doi.org/10.1093/nar/gkw377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lee Y, Liu J, Patel S, Cloughesy T, Lai A, Farooqi H, Seligson D, Dong J, Liau L, Becker D, Mischel P, Shams S, Nelson S (2010) Genomic landscape of meningiomas. Brain Pathol 20:751–762. https://doi.org/10.1111/j.1750-3639.2009.00356.x

    Article  CAS  PubMed  Google Scholar 

  33. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S, Tsimberidou AM, Vnencak-Jones CL, Wolff DJ, Younes A, Nikiforova MN (2017) Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists. J Mol Diagn 19:4–23. https://doi.org/10.1016/j.jmoldx.2016.10.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li W, Cooper J, Zhou L, Yang C, Erdjument-Bromage H, Zagzag D, Snuderl M, Ladanyi M, Hanemann CO, Zhou P, Karajannis MA, Giancotti FG (2014) Merlin/NF2 loss-driven tumorigenesis linked to CRL4(DCAF1)-mediated inhibition of the hippo pathway kinases Lats1 and 2 in the nucleus. Cancer Cell 26:48–60. https://doi.org/10.1016/j.ccr.2014.05.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Loewenstern J, Rutland J, Gill C, Arib H, Pain M, Umphlett M, Kinoshita Y, McBride R, Donovan M, Sebra R, Bederson J, Fowkes M, Shrivastava R (2019) Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas. Oncotarget 10:3506–3517. https://doi.org/10.18632/oncotarget.26941

    Article  PubMed  PubMed Central  Google Scholar 

  36. Lu VM, Goyal A, Lee A, Jentoft M, Quinones-Hinojosa A, Chaichana KL (2019) The prognostic significance of TERT promoter mutations in meningioma: a systematic review and meta-analysis. J Neurooncol 142:1–10. https://doi.org/10.1007/s11060-018-03067-x

    Article  CAS  PubMed  Google Scholar 

  37. Luangdilok S, Box C, Harrington K, Rhys-Evans P, Eccles S (2011) MAPK and PI3K signalling differentially regulate angiogenic and lymphangiogenic cytokine secretion in squamous cell carcinoma of the head and neck. Eur J Cancer 47:520–529. https://doi.org/10.1016/j.ejca.2010.10.009

    Article  CAS  PubMed  Google Scholar 

  38. Ma J, Hong Y, Chen W, Li D, Tian K, Wang K, Yang Y, Zhang Y, Chen Y, Song L, Chen L, Zhang L, Du J, Zhang J, Wu Z, Zhang D, Wang L (2020) High copy-number variation burdens in cranial meningiomas from patients with diverse clinical phenotypes characterized by hot genomic structure changes. Front Oncol 10:1382. https://doi.org/10.3389/fonc.2020.01382

    Article  PubMed  PubMed Central  Google Scholar 

  39. Maggio I, Franceschi E, Tosoni A, Nunno VD, Gatto L, Lodi R, Brandes AA (2021) Meningioma: not always a benign tumor. A review of advances in the treatment of meningiomas. CNS Oncol 10:CNS72. https://doi.org/10.2217/cns-2021-0003

  40. Mawrin C, Perry A (2010) Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:379–391. https://doi.org/10.1007/s11060-010-0342-2

    Article  CAS  PubMed  Google Scholar 

  41. Mirian C, Duun-Henriksen AK, Juratli T, Sahm F, Spiegl-Kreinecker S, Peyre M, Biczok A, Tonn JC, Goutagny S, Bertero L, Maier AD, Moller Pedersen M, Law I, Broholm H, Cahill DP, Brastianos P, Poulsgaard L, Fugleholm K, Ziebell M, Munch T, Mathiesen T (2020) Poor prognosis associated with TERT gene alterations in meningioma is independent of the WHO classification: an individual patient data meta-analysis. J Neurol Neurosurg Psychiatry 91:378–387. https://doi.org/10.1136/jnnp-2019-322257

    Article  PubMed  Google Scholar 

  42. Morrison H, Sperka T, Manent J, Giovannini M, Ponta H, Herrlich P (2007) Merlin/neurofibromatosis type 2 suppresses growth by inhibiting the activation of Ras and Rac. Cancer Res 67:520–527. https://doi.org/10.1158/0008-5472.CAN-06-1608

    Article  CAS  PubMed  Google Scholar 

  43. Murnyak B, Bognar L, Klekner A, Hortobagyi T (2015) Epigenetics Meningiomas Biomed Res Int 2015:532451. https://doi.org/10.1155/2015/532451

    Article  CAS  PubMed  Google Scholar 

  44. Nassiri F, Liu J, Patil V, Mamatjan Y, Wang JZ, Hugh-White R, Macklin AM, Khan S, Singh O, Karimi S, Corona RI, Liu LY, Chen CY, Chakravarthy A, Wei Q, Mehani B, Suppiah S, Gao A, Workewych AM, Tabatabai G, Boutros PC, Bader GD, de Carvalho DD, Kislinger T, Aldape K, Zadeh G (2021) A clinically applicable integrative molecular classification of meningiomas. Nature 597:119–125. https://doi.org/10.1038/s41586-021-03850-3

    Article  CAS  PubMed  Google Scholar 

  45. Nassiri F, Mamatjan Y, Suppiah S, Badhiwala JH, Mansouri S, Karimi S, Saarela O, Poisson L, Gepfner-Tuma I, Schittenhelm J, Ng HK, Noushmehr H, Harter P, Baumgarten P, Weller M, Preusser M, Herold-Mende C, Tatagiba M, Tabatabai G, Sahm F, von Deimling A, International Consortium on M, Zadeh G, Aldape KD (2019) DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management. Neuro Oncol 21:901–910. https://doi.org/10.1093/neuonc/noz061

    Article  CAS  Google Scholar 

  46. Olar A, Wani KM, Wilson CD, Zadeh G, DeMonte F, Jones DT, Pfister SM, Sulman EP, Aldape KD (2017) Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma. Acta Neuropathol 133:431–444. https://doi.org/10.1007/s00401-017-1678-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ostrom QT, Patil N, Cioffi G, Waite K, Kruchko C, Barnholtz-Sloan JS (2020) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2013–2017. Neuro Oncol 22:iv1-iv96. https://doi.org/10.1093/neuonc/noaa200

  48. Park HJ, Kang HC, Kim IH, Park SH, Kim DG, Park CK, Paek SH, Jung HW (2013) The role of adjuvant radiotherapy in atypical meningioma. J Neurooncol 115:241–247. https://doi.org/10.1007/s11060-013-1219-y

    Article  CAS  PubMed  Google Scholar 

  49. Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN, Kwon J (2006) Mammalian SWI/SNF complexes facilitate DNA double-strand break repair by promoting gamma-H2AX induction. EMBO J 25:3986–3997. https://doi.org/10.1038/sj.emboj.7601291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Patel AJ, Wan YW, Al-Ouran R, Revelli JP, Cardenas MF, Oneissi M, Xi L, Jalali A, Magnotti JF, Muzny DM, Doddapaneni H, Sebastian S, Heck KA, Goodman JC, Gopinath SP, Liu Z, Rao G, Plon SE, Yoshor D, Wheeler DA, Zoghbi HY, Klisch TJ (2019) Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors. Proc Natl Acad Sci U S A 116:21715–21726. https://doi.org/10.1073/pnas.1912858116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Petrilli AM, Fernandez-Valle C (2016) Role of merlin/NF2 inactivation in tumor biology. Oncogene 35:537–548. https://doi.org/10.1038/onc.2015.125

    Article  CAS  PubMed  Google Scholar 

  52. Reddy AK, Ryoo JS, Denyer S, McGuire LS, Mehta AI (2019) Determining the role of adjuvant radiotherapy in the management of meningioma: a surveillance, epidemiology, and end results analysis. Neurosurg Focus 46:E3. https://doi.org/10.3171/2019.3.FOCUS1971

    Article  PubMed  Google Scholar 

  53. Reuss DE, Piro RM, Jones DT, Simon M, Ketter R, Kool M, Becker A, Sahm F, Pusch S, Meyer J, Hagenlocher C, Schweizer L, Capper D, Kickingereder P, Mucha J, Koelsche C, Jager N, Santarius T, Tarpey PS, Stephens PJ, Andrew Futreal P, Wellenreuther R, Kraus J, Lenartz D, Herold-Mende C, Hartmann C, Mawrin C, Giese N, Eils R, Collins VP, Konig R, Wiestler OD, Pfister SM, von Deimling A (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125:351–358. https://doi.org/10.1007/s00401-013-1093-x

    Article  CAS  PubMed  Google Scholar 

  54. Rong R, Tang X, Gutmann DH, Ye K (2004) Neurofibromatosis 2 (NF2) tumor suppressor merlin inhibits phosphatidylinositol 3-kinase through binding to PIKE-L. Proc Natl Acad Sci U S A 101:18200–18205. https://doi.org/10.1073/pnas.0405971102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ruttledge MH, Sarrazin J, Rangaratnam S, Phelan CM, Twist E, Merel P, Delattre O, Thomas G, Nordenskjold M, Collins VP et al (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6:180–184. https://doi.org/10.1038/ng0294-180

    Article  CAS  PubMed  Google Scholar 

  56. Sahm F, Schrimpf D, Olar A, Koelsche C, Reuss D, Bissel J, Kratz A, Capper D, Schefzyk S, Hielscher T, Wang Q, Sulman EP, Adeberg S, Koch A, Okuducu AF, Brehmer S, Schittenhelm J, Becker A, Brokinkel B, Schmidt M, Ull T, Gousias K, Kessler AF, Lamszus K, Debus J, Mawrin C, Kim YJ, Simon M, Ketter R, Paulus W, Aldape KD, Herold-Mende C, von Deimling A (2016) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108. https://doi.org/10.1093/jnci/djv377

  57. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S, Okonechnikov K, Koelsche C, Reuss DE, Capper D, Sturm D, Wirsching HG, Berghoff AS, Baumgarten P, Kratz A, Huang K, Wefers AK, Hovestadt V, Sill M, Ellis HP, Kurian KM, Okuducu AF, Jungk C, Drueschler K, Schick M, Bewerunge-Hudler M, Mawrin C, Seiz-Rosenhagen M, Ketter R, Simon M, Westphal M, Lamszus K, Becker A, Koch A, Schittenhelm J, Rushing EJ, Collins VP, Brehmer S, Chavez L, Platten M, Hanggi D, Unterberg A, Paulus W, Wick W, Pfister SM, Mittelbronn M, Preusser M, Herold-Mende C, Weller M, von Deimling A (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18:682–694. https://doi.org/10.1016/S1470-2045(17)30155-9

    Article  CAS  PubMed  Google Scholar 

  58. Samal S, Patnaik A, Sahu F, Purkait S (2020) Altered expression of epigenetic modifiers EZH2, H3K27me3, and DNA methyltransferases in meningiomas - prognostic biomarkers for routine practice. Folia Neuropathol 58:133–142. https://doi.org/10.5114/fn.2020.96970

    Article  PubMed  Google Scholar 

  59. Shih KC, Chowdhary S, Rosenblatt P, Weir AB 3rd, Shepard GC, Williams JT, Shastry M, Burris HA 3rd, Hainsworth JD (2016) A phase II trial of bevacizumab and everolimus as treatment for patients with refractory, progressive intracranial meningioma. J Neurooncol 129:281–288. https://doi.org/10.1007/s11060-016-2172-3

    Article  CAS  PubMed  Google Scholar 

  60. Sievers P, Sill M, Blume C, Tauziede-Espariat A, Schrimpf D, Stichel D, Reuss DE, Dogan H, Hartmann C, Mawrin C, Hasselblatt M, Stummer W, Schick U, Hench J, Frank S, Ketter R, Schweizer L, Schittenhelm J, Puget S, Brandner S, Jaunmuktane Z, Kusters B, Abdullaev Z, Pekmezci M, Snuderl M, Ratliff M, Herold-Mende C, Unterberg A, Aldape K, Ellison DW, Wesseling P, Reifenberger G, Wick W, Perry A, Varlet P, Pfister SM, Jones DTW, von Deimling A, Sahm F, German Consortium "Aggressive M (2021) Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1. Acta Neuropathol 141:281–290. https://doi.org/10.1007/s00401-020-02247-2

    Article  CAS  PubMed  Google Scholar 

  61. Smith MJ (2015) Germline and somatic mutations in meningiomas. Cancer Genet 208:107–114. https://doi.org/10.1016/j.cancergen.2015.02.003

    Article  CAS  PubMed  Google Scholar 

  62. Spiegl-Kreinecker S, Lotsch D, Neumayer K, Kastler L, Gojo J, Pirker C, Pichler J, Weis S, Kumar R, Webersinke G, Gruber A, Berger W (2018) TERT promoter mutations are associated with poor prognosis and cell immortalization in meningioma. Neuro Oncol 20:1584–1593. https://doi.org/10.1093/neuonc/noy104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Terabe M, Wu J (2021) Rethinking immunotherapy in meningiomas. Neuro Oncol 23:1812–1813. https://doi.org/10.1093/neuonc/noab168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Vasudevan HN, Braunstein SE, Phillips JJ, Pekmezci M, Tomlin BA, Wu A, Reis GF, Magill ST, Zhang J, Feng FY, Nicholaides T, Chang SM, Sneed PK, McDermott MW, Berger MS, Perry A, Raleigh DR (2018) Comprehensive molecular profiling identifies FOXM1 as a key transcription factor for meningioma proliferation. Cell Rep 22:3672–3683. https://doi.org/10.1016/j.celrep.2018.03.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang B, Cui Z, Zhong Z, Sun Y, Yang GY, Sun Q, Bian L (2016) The role and regulatory mechanism of IL-1beta on the methylation of the NF2 gene in benign meningiomas and leptomeninges. Mol Carcinog 55:2268–2277. https://doi.org/10.1002/mc.22467

    Article  CAS  PubMed  Google Scholar 

  66. Wang YC, Chuang CC, Wei KC, Chang CN, Lee ST, Wu CT, Hsu YH, Lin TK, Hsu PW, Huang YC, Tseng CK, Wang CC, Chen YL, Chen PY (2016) Long term surgical outcome and prognostic factors of atypical and malignant meningiomas. Sci Rep 6:35743. https://doi.org/10.1038/srep35743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Williams EA, Santagata S, Wakimoto H, Shankar GM, Barker FG 2nd, Sharaf R, Reddy A, Spear P, Alexander BM, Ross JS, Brastianos PK, Cahill DP, Ramkissoon SH, Juratli TA (2020) Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic. Acta Neuropathol Commun 8:171. https://doi.org/10.1186/s40478-020-01040-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wilson BG, Roberts CW (2011) SWI/SNF nucleosome remodellers and cancer. Nat Rev Cancer 11:481–492. https://doi.org/10.1038/nrc3068

    Article  CAS  PubMed  Google Scholar 

  69. Yin F, Yu J, Zheng Y, Chen Q, Zhang N, Pan D (2013) Spatial organization of Hippo signaling at the plasma membrane mediated by the tumor suppressor Merlin/NF2. Cell 154:1342–1355. https://doi.org/10.1016/j.cell.2013.08.025

    Article  CAS  PubMed  Google Scholar 

  70. Yin J, Wan B, Sarkar J, Horvath K, Wu J, Chen Y, Cheng G, Wan K, Chin P, Lei M, Liu Y (2016) Dimerization of SLX4 contributes to functioning of the SLX4-nuclease complex. Nucleic Acids Res 44:4871–4880. https://doi.org/10.1093/nar/gkw354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Youngblood MW, Duran D, Montejo JD, Li C, Omay SB, Ozduman K, Sheth AH, Zhao AY, Tyrtova E, Miyagishima DF, Fomchenko EI, Hong CS, Clark VE, Riche M, Peyre M, Boetto J, Sohrabi S, Koljaka S, Baranoski JF, Knight J, Zhu H, Pamir MN, Avsar T, Kilic T, Schramm J, Timmer M, Goldbrunner R, Gong Y, Bayri Y, Amankulor N, Hamilton RL, Bilguvar K, Tikhonova I, Tomak PR, Huttner A, Simon M, Krischek B, Kalamarides M, Erson-Omay EZ, Moliterno J, Gunel M (2019) Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas. J Neurosurg:1–10. https://doi.org/10.3171/2019.8.JNS191266

  72. Youngblood MW, Miyagishima DF, Jin L, Gupte T, Li C, Duran D, Montejo JD, Zhao A, Sheth A, Tyrtova E, Ozduman K, Iacoangeli F, Peyre M, Boetto J, Pease M, Avsar T, Huttner A, Bilguvar K, Kilic T, Pamir MN, Amankulor N, Kalamarides M, Erson-Omay EZ, Gunel M, Moliterno J (2021) Associations of meningioma molecular subgroup and tumor recurrence. Neuro Oncol 23:783–794. https://doi.org/10.1093/neuonc/noaa226

    Article  CAS  PubMed  Google Scholar 

  73. Yuzawa S, Nishihara H, Tanaka S (2016) Genetic landscape of meningioma. Brain Tumor Pathol 33:237–247. https://doi.org/10.1007/s10014-016-0271-7

    Article  CAS  PubMed  Google Scholar 

  74. Zhou K, Wang G, Wang Y, Jin H, Yang S, Liu C (2010) The potential involvement of E-cadherin and beta-catenins in meningioma. PLoS One 5:e11231. https://doi.org/10.1371/journal.pone.0011231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhu Y, Liu X, Zhao P, Zhao H, Gao W, Wang L (2020) Celastrol suppresses glioma vasculogenic mimicry formation and angiogenesis by blocking the PI3K/Akt/mTOR signaling pathway. Front Pharmacol 11:25. https://doi.org/10.3389/fphar.2020.00025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank members of the clinical genomics laboratory at the Jackson Laboratory for Genomic Medicine for their discussion on variants described here.

Funding

This work was supported by internal funding from the UConn Foundation Tumor Genomics Fund in the Department of Neurosurgery.

Author information

Authors and Affiliations

  1. School of Medicine, University of Connecticut, 263 Farmington Ave, Farmington, CT, 06030, USA

    Nathan K. Leclair

  2. Division of Neurosurgery, Department of Surgery, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Erica Shen & Ketan R. Bulsara

  3. The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06030, USA

    Erica Shen & Lei Li

  4. Department of Pathology and Laboratory Medicine, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Qian Wu

  5. Department of Radiology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Leo Wolansky

  6. Department of Oncology, UConn Health, 263 Farmington Ave, Farmington, CT, 06030, USA

    Kevin Becker

Authors
  1. Nathan K. Leclair
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erica Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Leo Wolansky
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kevin Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ketan R. Bulsara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by NKL, ES, LL, QW, LW, and KRB. Original draft of the manuscript was written by NKL. All authors contributed to editing and revision of the manuscript prior to submission.

Corresponding author

Correspondence to Ketan R. Bulsara.

Ethics declarations

Ethics approval and consent to participate

Ethics approval and waiver for consent was given from the University of Connecticut IRB #21X-251–1.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Brain Tumors

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 22 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leclair, N.K., Shen, E., Wu, Q. et al. Landscape of genetic variants in sporadic meningiomas captured with clinical genomics. Acta Neurochir 164, 2491–2503 (2022). https://doi.org/10.1007/s00701-022-05316-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-022-05316-5

Keywords

Search

Navigation