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DNA methylation provides diagnostic value for meningioma recurrence in clinical practice

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Abstract

Background

Meningiomas are the most common intracranial tumors. Recent advancements in the genetic profiling of tumors have allowed information including DNA copy number analysis, mutational analysis, and RNA sequencing to be more frequently reported, in turn allowing better characterization of meningiomas. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success.

Method

We report DNA methylation profiling on meningiomas from 17 patients. Formalin-fixed paraffin-embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were processed through the the CNS tumor classifier developed by the Molecular Neuropathology group at the German Cancer Research Center (DKFZ). Corresponding genomics were captured using targeted sequencing panels.

Result

Among the meningioma samples, 13 samples were classified as “benign,” two samples as “intermediate,” and the remaining three samples (from two patients) as “malignant,” based on previously validated classification algorithms. In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (including size and location), surgical approaches, and mutational analysis. The two patients who provided the samples with “malignant” methylation classifications had tumor recurrence, reflecting a more aggressive disease course.

Conclusion

In accordance with prior reports, our case series provides support that tumor DNA methylation profiling adds meaningful classification information and may be beneficial to incorporate in clinical practice. Our report also reveals that DNA methylation combined with WHO histology classification can more accurately predict tumor behavior than WHO classification alone.

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Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Agnihotri S, Suppiah S, Tonge PD, Jalali S, Danesh A, Bruce JP et al (2017) Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas. Nat Commun 8(1):186

    Article  PubMed  PubMed Central  Google Scholar 

  2. Bale TA, Rosenblum MK (2022) The 2021 WHO classification of tumors of the central nervous system: an update on pediatric low-grade gliomas and glioneuronal tumors. Brain Pathol 32(4):e13060

    Article  PubMed  PubMed Central  Google Scholar 

  3. Benjamin C, Shah JK, Kondziolka D (2020) Radiation-induced meningiomas. Handb Clin Neurol 169:273–284

    Article  PubMed  Google Scholar 

  4. Berghoff AS, Hielscher T, Ricken G, Furtner J, Schrimpf D, Widhalm G et al (2022) Prognostic impact of genetic alterations and methylation classes in meningioma. Brain Pathol 32(2):e12970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 2:15. https://doi.org/10.1038/s41525-017-0014-7

  6. Birzu C, Peyre M, Sahm F (2020) Molecular alterations in meningioma: prognostic and therapeutic perspectives. Curr Opin Oncol 32(6):613–622

    Article  CAS  PubMed  Google Scholar 

  7. Brassesco MS, Valera ET, Neder L, Castro-Gamero AM, de Oliveira FM, Santos AC et al (2009) Childhood radiation-associated atypical meningioma with novel complex rearrangements involving chromosomes 1 and 12. Neuropathology 29(5):585–590

    Article  PubMed  Google Scholar 

  8. Brastianos PK, Galanis E, Butowski N, Chan JW, Dunn IF, Goldbrunner R et al (2019) Advances in multidisciplinary therapy for meningiomas. Neuro Oncol 21(Suppl 1):i18–i31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555(7697):469–474

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Choudhury A, Magill ST, Eaton CD, Prager BC, Chen WC, Cady MA et al (2022) Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nat Genet 54(5):649–659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K et al (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339(6123):1077–1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Collord G, Tarpey P, Kurbatova N, Martincorena I, Moran S, Castro M et al (2018) An integrated genomic analysis of anaplastic meningioma identifies prognostic molecular signatures. Sci Rep 8(1):13537

    Article  PubMed  PubMed Central  Google Scholar 

  13. Driver J, Hoffman SE, Tavakol S, Woodward E, Maury EA, Bhave V et al (2022) A molecularly integrated grade for meningioma. Neuro Oncol 24(5):796–808

    Article  CAS  PubMed  Google Scholar 

  14. Gao F, Shi L, Russin J, Zeng L, Chang X, He S et al (2013) DNA methylation in the malignant transformation of meningiomas. PLoS One 8(1):e54114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gauchotte G, Peyre M, Pouget C, Cazals-Hatem D, Polivka M, Rech F et al (2020) Prognostic value of histopathological features and loss of H3K27me3 immunolabeling in anaplastic meningioma: a multicenter retrospective study. J Neuropathol Exp Neurol 79(7):754–762

    Article  CAS  PubMed  Google Scholar 

  16. Goldbrunner R, Stavrinou P, Jenkinson MD, Sahm F, Mawrin C, Weber DC et al (2021) EANO guideline on the diagnosis and management of meningiomas. Neuro Oncol 23(11):1821–1834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hancq S, Salmon I, Brotchi J, Gabius HJ, Heizmann CW, Kiss R et al (2004) Detection of S100B, S100A6 and galectin-3 ligands in meningiomas as markers of aggressiveness. Int J Oncol 25(5):1233–1240

    CAS  PubMed  Google Scholar 

  18. Harmancı AS, Youngblood MW, Clark VE, Coşkun S, Henegariu O, Duran D et al (2017) Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 8:14433

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hielscher T, Sill M, Sievers P, Stichel D, Brandner S, Jones DTW, von Deimling A, Sahm F, Maas SLN (2022) Clinical implementation of integrated molecular-morphologic risk prediction for meningioma. Brain Pathol e13132. https://doi.org/10.1111/bpa.13132

  20. Jenkinson MD, Santarius T, Zadeh G, Aldape KD (2017) Atypical meningioma-is it time to standardize surgical sampling techniques? Neuro Oncol 19(3):453–454

    PubMed  Google Scholar 

  21. Juratli TA, Thiede C, Koerner MVA, Tummala SS, Daubner D, Shankar GM et al (2017) Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas. Oncotarget 8(65):109228–109237

    Article  PubMed  PubMed Central  Google Scholar 

  22. Karsy M, Azab MA, Abou-Al-Shaar H, Guan J, Eli I, Jensen RL et al (2018) Clinical potential of meningioma genomic insights: a practical review for neurosurgeons. Neurosurg Focus 44(6):E10

    Article  PubMed  Google Scholar 

  23. Leclair NK, Shen E, Wu Q, Wolansky L, Becker K, Li L et al (2022) Landscape of genetic variants in sporadic meningiomas captured with clinical genomics. Acta Neurochir (Wien) 164(9):2491–2503

    Article  PubMed  Google Scholar 

  24. Li MM, Datto M, Duncavage EJ, Kulkarni S, Lindeman NI, Roy S et al (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(1):4–23

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK et al (2016) The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 131(6):803–820

    Article  PubMed  Google Scholar 

  26. Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D et al (2021) The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol 23(8):1231–1251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Maggio I, Franceschi E, Tosoni A, Nunno VD, Gatto L, Lodi R et al (2021) Meningioma: not always a benign tumor. A review of advances in the treatment of meningiomas. CNS Oncol 10(2):Cns72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nassiri F, Liu J, Patil V, Mamatjan Y, Wang JZ, Hugh-White R et al (2021) A clinically applicable integrative molecular classification of meningiomas. Nature 597(7874):119–125

    Article  CAS  PubMed  Google Scholar 

  29. Nassiri F, Mamatjan Y, Suppiah S, Badhiwala JH, Mansouri S, Karimi S et al (2019) DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management. Neuro Oncol 21(7):901–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Olar A, Wani KM, Wilson CD, Zadeh G, DeMonte F, Jones DT et al (2017) Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma. Acta Neuropathol 133(3):431–444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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(12 Suppl 2):iv1–iv96

    Article  PubMed  PubMed Central  Google Scholar 

  32. Patel AJ, Wan YW, Al-Ouran R, Revelli JP, Cardenas MF, Oneissi M et al (2019) Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors. Proc Natl Acad Sci U S A 116(43):21715–21726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rogers CL, Perry A, Pugh S, Vogelbaum MA, Brachman D, McMillan W et al (2016) Pathology concordance levels for meningioma classification and grading in NRG Oncology RTOG Trial 0539. Neuro Oncol 18(4):565–574

    Article  PubMed  Google Scholar 

  34. 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 (2015) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108(5):djv377. https://doi.org/10.1093/jnci/djv377

  35. Sahm F, Schrimpf D, Stichel D, Jones DTW, Hielscher T, Schefzyk S et al (2017) DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol 18(5):682–694

    Article  CAS  PubMed  Google Scholar 

  36. Sayagués JM, Tabernero MD, Maíllo A, Espinosa A, Rasillo A, Díaz P et al (2004) Intratumoral patterns of clonal evolution in meningiomas as defined by multicolor interphase fluorescence in situ hybridization (FISH): is there a relationship between histopathologically benign and atypical/anaplastic lesions? J Mol Diagn 6(4):316–325

    Article  PubMed  PubMed Central  Google Scholar 

  37. Shankar GM, Santagata S (2017) BAP1 mutations in high-grade meningioma: implications for patient care. Neuro Oncol 19(11):1447–1456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shoshan Y, Chernova O, Juen SS, Somerville RP, Israel Z, Barnett GH et al (2000) Radiation-induced meningioma: a distinct molecular genetic pattern? J Neuropathol Exp Neurol 59(7):614–620

    Article  CAS  PubMed  Google Scholar 

  39. Sievers P, Hielscher T, Schrimpf D, Stichel D, Reuss DE, Berghoff AS et al (2020) CDKN2A/B homozygous deletion is associated with early recurrence in meningiomas. Acta Neuropathol 140(3):409–413

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. St Pierre R, Collings CK, Samé Guerra DD, Widmer CJ, Bolonduro O, Mashtalir N et al (2022) SMARCE1 deficiency generates a targetable mSWI/SNF dependency in clear cell meningioma. Nat Genet 54(6):861–873

    Article  CAS  PubMed  Google Scholar 

  41. Umansky F, Shoshan Y, Rosenthal G, Fraifeld S, Spektor S (2008) Radiation-induced meningioma. Neurosurg Focus 24(5):E7

    Article  PubMed  Google Scholar 

  42. Vasudevan HN, Castro MRH, Lee JC, Villanueva-Meyer JE, Bush NAO, McDermott MW et al (2020) DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma. Acta Neuropathol Commun 8(1):82

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vengoechea J, Sloan AE, Chen Y, Guan X, Ostrom QT, Kerstetter A et al (2013) Methylation markers of malignant potential in meningiomas. J Neurosurg 119(4):899–906

    Article  CAS  PubMed  Google Scholar 

  44. Yamanaka R, Hayano A, Kanayama T (2017) Radiation-induced meningiomas: an exhaustive review of the literature. World Neurosurg 97:635–44.e8

    Article  PubMed  Google Scholar 

  45. Youngblood MW, Miyagishima DF, Jin L, Gupte T, Li C, Duran D et al (2021) Associations of meningioma molecular subgroup and tumor recurrence. Neuro Oncol 23(5):783–794

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank members of the clinical genomics laboratory at the Jackson Labs for their discussion on DNA methylation profiling described here.

Funding

This work was supported by internal funding from the UConn Foundation Tumor Genomics Fund.

Author information

Authors and Affiliations

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

    Erica Shen, Hilary Onyiuke, Ian McNeill & Ketan R. Bulsara

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

    Erica Shen, Kristi Herlth, Melissa Soucy, Nick Renzette, Xinming Zhuo, Kevin Kelly, Gregory Omerza & Lei Li

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

    Nathan K. Leclair

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

    Leo Wolansky

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

    Kevin Becker

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

    Qian Wu

Authors
  1. Erica Shen
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  2. Nathan K. Leclair
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  15. Ketan R. Bulsara
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by ES, NKL, KH, MS, NR, XZ, KK, GO, HO, IM, LW, KB, LL, QW, and KRB. Original draft of the manuscript was written by ES. All authors contributed to editing and revision of the manuscript prior to submission.

Corresponding author

Correspondence to Ketan R. Bulsara.

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

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The authors declare no competing interests.

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Shen, E., Leclair, N.K., Herlth, K. et al. DNA methylation provides diagnostic value for meningioma recurrence in clinical practice. Acta Neurochir 165, 1323–1331 (2023). https://doi.org/10.1007/s00701-023-05550-5

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  • DOI: https://doi.org/10.1007/s00701-023-05550-5

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