Skip to main content
SpringerLink
Log in

NF2 mutations are associated with resistance to radiation therapy for grade 2 and grade 3 recurrent meningiomas

  • Research
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Purpose

High grade meningiomas have a prognosis characterized by elevated recurrence rates and radiation resistance. Recent work has highlighted the importance of genomics in meningioma prognostication. This study aimed to assess the relationship between the most common meningioma genomic alteration (NF2) and response to postoperative radiation therapy (RT).

Methods

From an institutional tissue bank, grade 2 and 3 recurrent meningiomas with both > 30 days of post-surgical follow-up and linked targeted next-generation sequencing were identified. Time to radiographic recurrence was determined with retrospective review. The adjusted hazard of recurrence was estimated using Cox-regression for patients treated with postoperative RT stratified by NF2 mutational status.

Results

Of 53 atypical and anaplastic meningiomas (29 NF2 wild-type, 24 NF2 mutant), 19 patients underwent postoperative RT. When stratified by NF2 wild-type, postoperative RT in NF2 wild-type patients was associated with a 78% reduction in the risk of recurrence (HR 0.216; 95%CI 0.068–0.682; p = 0.009). When stratified by NF2 mutation, there was a non-significant increase in the risk of recurrence for NF2 mutant patients who received postoperative RT compared to those who did not (HR 2.43; 95%CI 0.88–6.73, p = 0.087).

Conclusion

This study demonstrated a protective effect of postoperative RT in NF2 wild-type patients with recurrent high grade meningiomas. Further, postoperative RT may be associated with no improvement and perhaps an accelerated time to recurrence in NF2 mutant tumors. These differences in recurrence rates provide evidence that NF2 may be a valuable prognostic marker in treatment decisions regarding postoperative RT. Further prospective studies are needed to validate this relationship.

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

Similar content being viewed by others

Data availability

The dataset generated during and analyzed for this study are available from the senior author on reasonable request.

References

  1. Zhu H, Bi WL, Aizer A et al (2019) Efficacy of adjuvant radiotherapy for atypical and anaplastic meningioma. Cancer Med 8(1):13–20. https://doi.org/10.1002/cam4.1531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Vagnoni L, Aburas S, Giraffa M et al (2022) Radiation therapy for atypical and anaplastic meningiomas: an overview of current results and controversial issues. Neurosurg Rev 45(5):3019–3033. https://doi.org/10.1007/s10143-022-01806-3

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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-Oncology 22(Suppl 1):iv1–iv96. https://doi.org/10.1093/neuonc/noaa200

    Article  PubMed  PubMed Central  Google Scholar 

  4. Rogers L, Barani I, Chamberlain M et al (2015) Meningiomas.  J Neurosurg 122(1):4–23. https://doi.org/10.3171/2014.7.JNS131644

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lemée JM, Corniola MV, Meling TR (2020) Benefits of re-do surgery for recurrent intracranial meningiomas. Sci Rep 10(1):303. https://doi.org/10.1038/s41598-019-57254-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Corniola MV, Meling TR (2022) Management of recurrent meningiomas: state of the art and perspectives. Cancers 14(16):3995. https://doi.org/10.3390/cancers14163995

    Article  PubMed  PubMed Central  Google Scholar 

  7. Goldbrunner R, Stavrinou P, Jenkinson MD et al (2021) EANO guideline on the diagnosis and management of meningiomas. Neuro-Oncology 23(11):1821–1834. https://doi.org/10.1093/neuonc/noab150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hemmati SM, Ghadjar P, Grün A et al (2019) Adjuvant radiotherapy improves progression-free survival in intracranial atypical meningioma. Radiat Oncol Lond Engl 14(1):160. https://doi.org/10.1186/s13014-019-1368-z

    Article  Google Scholar 

  9. He L, Zhang B, Zhang J, Guo Z, Shi F, Zeng Q (2020) Effectiveness of postoperative adjuvant radiotherapy in atypical meningioma patients after gross total resection: a meta-analysis study. Front Oncol 10:556575. https://doi.org/10.3389/fonc.2020.556575

    Article  PubMed  Google Scholar 

  10. Song D, Xu D, Han H et al (2021) Postoperative adjuvant radiotherapy in atypical meningioma patients: a meta-analysis study. Front Oncol 11:787962. https://doi.org/10.3389/fonc.2021.787962

    Article  PubMed  PubMed Central  Google Scholar 

  11. Wang YC, Chuang CC, Wei KC et al (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 

  12. Park HJ, Kang HC, Kim IH et al (2013) The role of adjuvant radiotherapy in atypical meningioma. J Neurooncol 115(2):241–247. https://doi.org/10.1007/s11060-013-1219-y

    Article  CAS  PubMed  Google Scholar 

  13. Rogers CL, Won M, Vogelbaum MA et al (2020) High-risk meningioma: initial outcomes from NRG Oncology/RTOG 0539. Int J Radiat Oncol Biol Phys 106(4):790–799. https://doi.org/10.1016/j.ijrobp.2019.11.028

    Article  PubMed  Google Scholar 

  14. Mair R, Morris K, Scott I, Carroll TA (2011) Radiotherapy for atypical meningiomas. J Neurosurg 115(4):811–819. https://doi.org/10.3171/2011.5.JNS11112

    Article  PubMed  Google Scholar 

  15. Hardesty DA, Wolf AB, Brachman DG et al (2013) The impact of adjuvant stereotactic radiosurgery on atypical meningioma recurrence following aggressive microsurgical resection. J Neurosurg 119(2):475–481. https://doi.org/10.3171/2012.12.JNS12414

    Article  PubMed  Google Scholar 

  16. Champeaux C, Houston D, Dunn L (2017) Atypical meningioma. A study on recurrence and disease-specific survival. Neurochirurgie 63(4):273–281. https://doi.org/10.1016/j.neuchi.2017.03.004

    Article  CAS  PubMed  Google Scholar 

  17. Komotar RJ, Iorgulescu JB, Raper DMS et al (2012) The role of radiotherapy following gross-total resection of atypical meningiomas: clinical article. J Neurosurg 117(4):679–686. https://doi.org/10.3171/2012.7.JNS112113

    Article  PubMed  Google Scholar 

  18. Dziuk TW, Woo S, Butler EB et al (1998) Malignant meningioma: an indication for initial aggressive surgery and adjuvant radiotherapy. J Neurooncol 37(2):177–188. https://doi.org/10.1023/a:1005853720926

    Article  CAS  PubMed  Google Scholar 

  19. Garcia-Segura ME, Erickson AW, Jairath R, Munoz DG, Das S (2020) Necrosis and brain invasion predict radio-resistance and tumor recurrence in atypical meningioma: a retrospective cohort study. Neurosurgery 88(1):E42–E48. https://doi.org/10.1093/neuros/nyaa348

    Article  PubMed  Google Scholar 

  20. Nassiri F, Liu J, Patil V et al (2021) A clinically applicable integrative molecular classification of meningiomas. Nature 597(7874):119–125. https://doi.org/10.1038/s41586-021-03850-3

    Article  CAS  PubMed  Google Scholar 

  21. Leclair NK, Shen E, Wu Q et al (2022) Landscape of genetic variants in sporadic meningiomas captured with clinical genomics. Acta Neurochir (Wien) 164(9):2491–2503. https://doi.org/10.1007/s00701-022-05316-5

    Article  PubMed  Google Scholar 

  22. Yuzawa S, Nishihara H, Tanaka S (2016) Genetic landscape of meningioma. Brain Tumor Pathol 33(4):237–247. https://doi.org/10.1007/s10014-016-0271-7

    Article  CAS  PubMed  Google Scholar 

  23. Gill CM, Loewenstern J, Rutland JW et al (2021) SWI/SNF chromatin remodeling complex alterations in meningioma. J Cancer Res Clin Oncol 147(11):3431–3440. https://doi.org/10.1007/s00432-021-03586-7

    Article  CAS  PubMed  Google Scholar 

  24. Bi WL, Prabhu VC, Dunn IF (2018) High-grade meningiomas: biology and implications. Neurosurg Focus 44(4):E2. https://doi.org/10.3171/2017.12.FOCUS17756

    Article  PubMed  Google Scholar 

  25. Shaikh N, Dixit K, Raizer J (2018) Recent advances in managing/understanding meningioma. F1000Research 7:F1000 Faculty Rev-490. https://doi.org/10.12688/f1000research.13674.1

  26. Youngblood MW, Miyagishima DF, Jin L et al (2020) Associations of meningioma molecular subgroup and tumor recurrence. Neuro-Oncology 23(5):783–794. https://doi.org/10.1093/neuonc/noaa226

    Article  CAS  PubMed Central  Google Scholar 

  27. Patel B, Mahlokozera T, Lu HC, CBIO-24. NF2 loss-of-function cooperates with hypoxia to drive radiation resistance in grade 2 meningiomas et al (2021) Neuro-Oncology 23(Supplement6):vi32–vi32. https://doi.org/10.1093/neuonc/noab196.123

    Article  PubMed Central  Google Scholar 

  28. Lee G, Lamba N, Niemierko A et al (2021) Adjuvant radiation therapy versus surveillance after surgical resection of atypical meningiomas. Int J Radiat Oncol Biol Phys 109(1):252–266. https://doi.org/10.1016/j.ijrobp.2020.08.015

    Article  PubMed  Google Scholar 

  29. Pain M, Wang H, Lee E et al (2017) Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma. Oncotarget 9(2):2603–2621. https://doi.org/10.18632/oncotarget.23517

    Article  PubMed  PubMed Central  Google Scholar 

  30. Gill CM, Loewenstern J, Rutland JW et al (2020) STK11 mutation status is associated with decreased survival in meningiomas. Neurol Sci 41(9):2585–2589. https://doi.org/10.1007/s10072-020-04372-y

    Article  PubMed  Google Scholar 

  31. Gill CM, Loewenstern J, Rutland JW et al (2020) Recurrent IDH mutations in high-grade meningioma. Neuro-Oncology 22(7):1044–1045. https://doi.org/10.1093/neuonc/noaa065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Loewenstern J, Rutland J, Gill C et al (2019) Comparative genomic analysis of driver mutations in matched primary and recurrent meningiomas. Oncotarget 10(37):3506–3517. https://doi.org/10.18632/oncotarget.26941

    Article  PubMed  PubMed Central  Google Scholar 

  33. Rutland et al (2022) Association of mutations in polymerase epsilon with increased CD8+ cell infiltration and prolonged progression-free survival in patients with meningiomas. Neurosurg Focus. https://doi.org/10.3171/2021.11.FOCUS21592

    Article  PubMed  Google Scholar 

  34. Rutland JW, Gill CM, Loewenstern J et al (2021) NF2 mutation status and tumor mutational burden correlate with immune cell infiltration in meningiomas. Cancer Immunol Immunother CII 70(1):169–176. https://doi.org/10.1007/s00262-020-02671-z

    Article  CAS  PubMed  Google Scholar 

  35. Ammoun S, Hanemann CO (2011) Emerging therapeutic targets in schwannomas and other merlin-deficient tumors. Nat Rev Neurol 7(7):392–399. https://doi.org/10.1038/nrneurol.2011.82

    Article  CAS  PubMed  Google Scholar 

  36. Zhang N, Gao X, Zhao Y, Datta M, Liu P, Xu L (2016) Rationally combining anti-VEGF therapy with radiation in NF2 schwannoma. J Rare Dis Res Treat 1(2):51–55

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chun SW, Kim KM, Kim MS et al (2021) Adjuvant radiotherapy versus observation following gross total resection for atypical meningioma: a systematic review and meta-analysis. Radiat Oncol Lond Engl 16(1):34. https://doi.org/10.1186/s13014-021-01759-9

    Article  Google Scholar 

  38. NRG Oncology (2022) Phase III trial of observation versus irradiation for a gross totally resected Grade II meningioma. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03180268. Accessed 3 Oct 2022

  39. Gao X, Zhao Y, Stemmer-Rachamimov AO et al (2015) Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model. Proc Natl Acad Sci USA 112(47):14676–14681. https://doi.org/10.1073/pnas.1512570112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tamura R, Morimoto Y, Sato M et al (2020) Difference in the hypoxic immunosuppressive microenvironment of patients with neurofibromatosis type 2 schwannomas and sporadic schwannomas. J Neurooncol 146(2):265–273. https://doi.org/10.1007/s11060-019-03388-5

    Article  CAS  PubMed  Google Scholar 

  41. Sievers P, Hielscher T, Schrimpf D et al (2020) CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol (Berl) 140(3):409–413. https://doi.org/10.1007/s00401-020-02188-w

    Article  CAS  PubMed  Google Scholar 

  42. Mirian C, Duun-Henriksen AK, Juratli T et al (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(4):378–387. https://doi.org/10.1136/jnnp-2019-322257

    Article  PubMed  Google Scholar 

  43. Aboukais R, Baroncini M, Zairi F, Reyns N, Lejeune JP (2013) Early postoperative radiotherapy improves progression free survival in patients with grade 2 meningioma. Acta Neurochir (Wien) 155(8):1385–1390. https://doi.org/10.1007/s00701-013-1775-0 (Discussion 1390)

    Article  PubMed  Google Scholar 

  44. Aghi MK, Carter BS, Cosgrove GR et al (2009) Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery 64(1):56–60. https://doi.org/10.1227/01.NEU.0000330399.55586.63 (Discussion 60)

    Article  PubMed  Google Scholar 

  45. Phonwijit L, Khawprapa C, Sitthinamsuwan B (2017) Progression-free survival and factors associated with postoperative recurrence in 126 patients with atypical intracranial meningioma. World Neurosurg 107:698–705. https://doi.org/10.1016/j.wneu.2017.08.057

    Article  PubMed  Google Scholar 

  46. Wang YC, Chuang CC, Wei KC et al (2015) Skull base atypical meningioma: long term surgical outcome and prognostic factors. Clin Neurol Neurosurg 128:112–116. https://doi.org/10.1016/j.clineuro.2014.11.009

    Article  PubMed  Google Scholar 

  47. Fernandez C, Nicholas MK, Engelhard HH, Slavin KV, Koshy M (2016) An analysis of prognostic factors associated with recurrence in the treatment of atypical meningiomas. Adv Radiat Oncol 1(2):89–93. https://doi.org/10.1016/j.adro.2016.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  48. Zhao P, Hu M, Zhao M, Ren X, Jiang Z (2015) Prognostic factors for patients with atypical or malignant meningiomas treated at a single center. Neurosurg Rev 38(1):101–107. https://doi.org/10.1007/s10143-014-0558-2 (Discussion 107)

    Article  PubMed  Google Scholar 

  49. Gill CM, Loewenstern J, Rutland JW et al (2021) Peritumoral edema correlates with mutational burden in meningiomas. Neuroradiology 63(1):73–80. https://doi.org/10.1007/s00234-020-02515-8

    Article  PubMed  Google Scholar 

  50. Bayley JC, Hadley CC, Harmanci AO, Harmanci AS, Klisch TJ, Patel AJ (2022) Multiple approaches converge on three biological subtypes of meningioma and extract new insights from published studies. Sci Adv 8(5):eabm6247. https://doi.org/10.1126/sciadv.abm6247

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was supported by Mount Sinai School of Medicine.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Vikram Vasan, Jonathan T. Dullea, Alex Devarajan, Muhammad Ali, John W. Rutland, Corey M. Gill, Joshua Bederson & Raj K. Shrivastava

  2. Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yayoi Kinoshita, Russell B. McBride, Michael Donovan & Melissa Umphlett

  3. The Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Russell B. McBride

  4. Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Paul Gliedman

  5. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Robert Sebra

  6. Sema4, A Mount Sinai Venture, Stamford, CT, USA

    Robert Sebra

  7. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, Floor 8, New York, NY, 10129, USA

    Vikram Vasan & Corey M. Gill

Authors
  1. Vikram Vasan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan T. Dullea
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alex Devarajan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muhammad Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John W. Rutland
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Corey M. Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yayoi Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Russell B. McBride
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Paul Gliedman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Joshua Bederson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Donovan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert Sebra
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Melissa Umphlett
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Raj K. Shrivastava
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: VV, JTD, AD, RKS. Methodology: VV, JTD. Data curation: VV, JTD, JWR, CMG, YK, RBM, MD, RS, MU. Formal analysis and investigation: VV, JTD, AD, RS, MU. Writing—original draft preparation: VV, JTD, AD. Writing—review and editing: VV, JTD, AD, MA, PG, MU, RKS. Supervision: JB, MU, RKS.

Corresponding author

Correspondence to Vikram Vasan.

Ethics declarations

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

A review of this study by the IRB institutional review board at the senior authors institution verified that it was in compliance with all ethical guidelines outlined in the 1964 Declaration of Helsinki and the later amendments and the Health Insurance Portability and Accountability Act of 1996 (HIPAA) guidelines.

Informed consent

This study was retrospective in nature and thus informed consent was waived.

Additional information

Publisher’s Note

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

This work was previously presented at the American Association for Neurological Surgeons (AANS) 90th Annual Meeting in Philadelphia, PA, from April 29th to May 2nd, 2022.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vasan, V., Dullea, J.T., Devarajan, A. et al. NF2 mutations are associated with resistance to radiation therapy for grade 2 and grade 3 recurrent meningiomas. J Neurooncol 161, 309–316 (2023). https://doi.org/10.1007/s11060-022-04197-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-022-04197-z

Keywords

Search

Navigation