Advertisement

High frequency of H3 K27M mutations in adult midline gliomas

  • Azadeh EbrahimiEmail author
  • Marco Skardelly
  • Martin U. Schuhmann
  • Martin Ebinger
  • David Reuss
  • Manuela Neumann
  • Ghazaleh Tabatabai
  • Patricia Kohlhof-Meinecke
  • Jens SchittenhelmEmail author
Original Article – Cancer Research
  • 129 Downloads

Abstract

Purpose

Diffuse midline gliomas, H3 K27M-mutant were introduced as a new grade IV entity in WHO classification of tumors 2016. These tumors occur often in pediatric patients and show an adverse prognosis with a median survival less than a year. Most of the studies on these tumors, previously known as pediatric diffuse intrinsic pontine glioma, are on pediatric patients and its significance in adult patients is likely underestimated.

Methods

We studied 165 cases of brain tumors of midline localization initially diagnosed as diffuse astrocytomas, oligodendrogliomas, pilocytic astrocytomas, supependymomas, ependymomas and medulloblastomas in patients with an age range of 2–85.

Results

We identified 41 diffuse midline gliomas according WHO 2016, including 12 pediatric and 29 adult cases, among them two cases with histological features of low grade tumors: pilocytic astrocytoma and subependymoma. 49% (20/41) of the patients were above 30 years old by the first tumor manifestation including 29% (11/41) above 54 that signifies a broader age spectrum as previously reported. Our study confirms that H3 K27M mutations are associated with a poorer prognosis in pediatric patients compared to wild-type tumors, while in adult patients these mutations do not influence the survival significantly. The pattern of tumor growth was different in pediatric compared to adult patients; a diffuse growth along the brain axis was more evident in adult compared to pediatric patients (24% vs. 15%).

Conclusion

H3 K27M mutations are frequent in adult midline gliomas and have a prognostic role similar to H3 K27M wild-type high-grade tumors.

Keywords

Diffuse midline glioma H3F3A H3 K27M mutations 

Notes

Funding

JS is supported by a Grant from the Else Uebelmesser Foundation for Applied Cancer Research, Tuebingen, Germany. GT served on Advisory Boards of BMS, Roche Switzerland, MSD Switzerland, received travel grants from Roche Switzerland, MSD Switzerland, Medac; received research support/Grants from Roche Diagnostics and Medac.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

References

  1. Banan R, Christians A, Bartels S, Lehmann U, Hartmann C (2017) Absence of MGMT promoter methylation in diffuse midline glioma, H3 K27M-mutant. Acta Neuropathol Commun 5:98.  https://doi.org/10.1186/s40478-017-0500-2 CrossRefGoogle Scholar
  2. Bechet D et al (2014) Specific detection of methionine 27 mutation in histone 3 variants (H3K27M) in fixed tissue from high-grade astrocytomas. Acta Neuropathol 128:733–741.  https://doi.org/10.1007/s00401-014-1337-4 CrossRefGoogle Scholar
  3. Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C (2014a) Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 128:573–581.  https://doi.org/10.1007/s00401-014-1319-6 CrossRefGoogle Scholar
  4. Buczkowicz P et al (2014b) Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet 46:451–456.  https://doi.org/10.1038/ng.2936 CrossRefGoogle Scholar
  5. Cage TA et al (2013) Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children. Childs Nerv Syst ChNS Off J Int Soc Pediatric Neurosurg 29:1313–1319.  https://doi.org/10.1007/s00381-013-2101-0 CrossRefGoogle Scholar
  6. Capper D et al (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474.  https://doi.org/10.1038/nature26000 CrossRefGoogle Scholar
  7. Castel D et al (2015) Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 130:815–827.  https://doi.org/10.1007/s00401-015-1478-0 CrossRefGoogle Scholar
  8. Chen L et al (2014) Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neurooncology 16:1478–1483.  https://doi.org/10.1093/neuonc/nou097 Google Scholar
  9. Cohen J (1968) Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol Bull 70:213–220CrossRefGoogle Scholar
  10. Daoud EV et al (2018) Adult brainstem gliomas with H3K27M mutation: radiology, pathology, and prognosis. J Neuropathol Exp Neurol 77:302–311.  https://doi.org/10.1093/jnen/nly006 CrossRefGoogle Scholar
  11. Ebrahimi A et al (2016) ATRX immunostaining predicts IDH and H3F3A status in gliomas. Acta Neuropathol Commun 4:60.  https://doi.org/10.1186/s40478-016-0331-6 CrossRefGoogle Scholar
  12. Feng J et al (2015) The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 46:1626–1632.  https://doi.org/10.1016/j.humpath.2015.07.002 CrossRefGoogle Scholar
  13. Fontebasso AM et al (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46:462–466.  https://doi.org/10.1038/ng.2950 CrossRefGoogle Scholar
  14. Foster SA et al (2016) Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell 29:477–493.  https://doi.org/10.1016/j.ccell.2016.02.010 CrossRefGoogle Scholar
  15. Hoffman LM et al (2016) Spatial genomic heterogeneity in diffuse intrinsic pontine and midline high-grade glioma: implications for diagnostic biopsy and targeted therapeutics. Acta Neuropathol Commun 4:1.  https://doi.org/10.1186/s40478-015-0269-0 CrossRefGoogle Scholar
  16. Joyon N et al (2017) K27M mutation in H3F3A in ganglioglioma grade I with spontaneous malignant transformation extends the histopathological spectrum of the histone H3 oncogenic pathway. Neuropathol Appl Neurobiol 43:271–276.  https://doi.org/10.1111/nan.12329 CrossRefGoogle Scholar
  17. Karremann M et al (2018) Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location. Neurooncology 20:123–131.  https://doi.org/10.1093/neuonc/nox149 Google Scholar
  18. Korshunov A et al (2015) Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 129:669–678.  https://doi.org/10.1007/s00401-015-1405-4 CrossRefGoogle Scholar
  19. Korshunov A et al (2016) Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity. Acta Neuropathol 131:137–146.  https://doi.org/10.1007/s00401-015-1493-1 CrossRefGoogle Scholar
  20. Laigle-Donadey F, Doz F, Delattre JY (2008) Brainstem gliomas in children and adults. Curr Opin Oncol 20:662–667.  https://doi.org/10.1097/CCO.0b013e32831186e0 CrossRefGoogle Scholar
  21. Louis D, Ohgaki H, Wiestler O, Cavenee WK (2016) World health organization classification of tumours of the central nervous system. In: Bosman F, Jaffe E, Lakhani S, Ohgaki H (eds) World health organization classification of tumours revised, 4th edn. IARC, LyonGoogle Scholar
  22. Louis DN et al (2018) cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 135:639–642.  https://doi.org/10.1007/s00401-018-1826-y CrossRefGoogle Scholar
  23. Meyronet D et al (2017) Characteristics of H3 K27M-mutant gliomas in adults. Neurooncology 19:1127–1134.  https://doi.org/10.1093/neuonc/now274 Google Scholar
  24. Morita S et al (2018) Brainstem pilocytic astrocytoma with H3 K27M mutation: case report. J Neurosurg 129:593–597.  https://doi.org/10.3171/2017.4.JNS162443 CrossRefGoogle Scholar
  25. Okuda T et al (2018) Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord. Neuropathology.  https://doi.org/10.1111/neup.12471 Google Scholar
  26. Orillac C et al (2016) Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation. Acta Neuropathol Commun 4:84.  https://doi.org/10.1186/s40478-016-0361-0 CrossRefGoogle Scholar
  27. Pages M et al (2016) Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. Brain Pathol.  https://doi.org/10.1111/bpa.12473 Google Scholar
  28. Paugh BS et al (2011) Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol Off J Am Soc Clin Oncol 29:3999–4006.  https://doi.org/10.1200/JCO.2011.35.5677 CrossRefGoogle Scholar
  29. Puget S et al (2012) Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7:e30313.  https://doi.org/10.1371/journal.pone.0030313 CrossRefGoogle Scholar
  30. Quillien V et al (2016) Validation of the high-performance of pyrosequencing for clinical MGMT testing on a cohort of glioblastoma patients from a prospective dedicated multicentric trial. Oncotarget 7:61916–61929.  https://doi.org/10.18632/oncotarget.11322 CrossRefGoogle Scholar
  31. Reers S, Krug D, Stummer W, Hasselblatt M (2017) Malignant progression of a histone H3.3 K27M-mutated spinal pilocytic astrocytoma in an adult. Clin Neuropathol 36:83–85.  https://doi.org/10.5414/NP300990 CrossRefGoogle Scholar
  32. Reyes-Botero G et al (2014) Molecular analysis of diffuse intrinsic brainstem gliomas in adults. J Neurooncol 116:405–411.  https://doi.org/10.1007/s11060-013-1312-2 CrossRefGoogle Scholar
  33. Robison NJ, Kieran MW (2014) Diffuse intrinsic pontine glioma: a reassessment. J Neurooncol 119:7–15.  https://doi.org/10.1007/s11060-014-1448-8 CrossRefGoogle Scholar
  34. Roujeau T et al (2007) Stereotactic biopsy of diffuse pontine lesions in children. J Neurosurg 107:1–4.  https://doi.org/10.3171/PED-07/07/001 Google Scholar
  35. Ryall S et al (2016) Targeted detection of genetic alterations reveal the prognostic impact of H3K27M and MAPK pathway aberrations in paediatric thalamic glioma. Acta Neuropathol Commun 4:93.  https://doi.org/10.1186/s40478-016-0353-0 CrossRefGoogle Scholar
  36. Sahm F et al (2016) Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 131:903–910.  https://doi.org/10.1007/s00401-015-1519-8 CrossRefGoogle Scholar
  37. Schafer S et al (2018) Low FoxG1 and high Olig-2 labelling indices define a prognostically favourable subset in isocitrate dehydrogenase (IDH)-mutant gliomas. Neuropathol Appl Neurobiol 44:207–223  https://doi.org/10.1111/nan.12447 CrossRefGoogle Scholar
  38. Schittenhelm J, Mittelbronn M, Meyermann R, Melms A, Tatagiba M, Capper D (2011) Confirmation of R132H mutation of isocitrate dehydrogenase 1 as an independent prognostic factor in anaplastic astrocytoma. Acta Neuropathologica 122:651–652.  https://doi.org/10.1007/s00401-011-0885-0 CrossRefGoogle Scholar
  39. Solomon DA, Wood MD, Tihan T, Bollen AW, Gupta N, Phillips JJ, Perry A (2016) Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic. Alter Brain Pathol 26:569–580.  https://doi.org/10.1111/bpa.12336 CrossRefGoogle Scholar
  40. Sturm D et al (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437.  https://doi.org/10.1016/j.ccr.2012.08.024 CrossRefGoogle Scholar
  41. Sufit A et al (2012) Diffuse intrinsic pontine tumors: a study of primitive neuroectodermal tumors versus the more common diffuse intrinsic pontine gliomas. J Neurosurg Pediatr 10:81–88.  https://doi.org/10.3171/2012.3.PEDS11316 CrossRefGoogle Scholar
  42. Taylor KR et al (2014) Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet 46:457–461.  https://doi.org/10.1038/ng.2925 CrossRefGoogle Scholar
  43. Theeler BJ et al (2015) Adult brainstem gliomas: correlation of clinical and molecular features. J Neurol Sci 353:92–97.  https://doi.org/10.1016/j.jns.2015.04.014 CrossRefGoogle Scholar
  44. Venneti S et al (2014) A sensitive and specific histopathologic prognostic marker for H3F3A K27M mutant pediatric glioblastomas. Acta Neuropathol 128:743–753.  https://doi.org/10.1007/s00401-014-1338-3 CrossRefGoogle Scholar
  45. von Bueren AO et al (2018) A suggestion to introduce the diagnosis of “diffuse midline glioma of the pons, H3 K27 wildtype (WHO grade IV)”. Acta Neuropathol.  https://doi.org/10.1007/s00401-018-1863-6 Google Scholar
  46. Walker DA et al (2013) A multi-disciplinary consensus statement concerning surgical approaches to low-grade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neurooncology 15:462–468.  https://doi.org/10.1093/neuonc/nos330 Google Scholar
  47. Wu G et al (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444–450.  https://doi.org/10.1038/ng.2938 CrossRefGoogle Scholar
  48. Zagzag D et al (2000) Primitive neuroectodermal tumors of the brainstem: investigation of seven cases. Pediatrics 106:1045–1053CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of TuebingenEberhard Karls University of TuebingenTuebingenGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Department of Neurosurgery, University Hospital of TuebingenEberhard Karls University of TuebingenTuebingenGermany
  4. 4.Interdisciplinary Division of Neurooncology, Departments of Vascular Neurology and Neurosurgery, University Hospital of TuebingenEberhard Karls University of TuebingenTuebingenGermany
  5. 5.Laboratory for Clinical and Experimental NeurooncologyHertie-Institute for Clinical Brain ResearchTuebingenGermany
  6. 6.Center for Personalized MedicineEberhard Karls University of TuebingenTuebingenGermany
  7. 7.German Consortium for Translational Cancer Research (DKTK), DKFZ Partner Site TuebingenTuebingenGermany
  8. 8.Center for CNS Tumors, Comprehensive Cancer Center Tuebingen-Stuttgart, University Hospital of TuebingenEberhard Karls University of TuebingenTuebingenGermany
  9. 9.Department of General Pediatrics, Hematology/OncologyUniversity Children’s HospitalTuebingenGermany
  10. 10.Department of Neuropathology, Institute of PathologyUniversity Hospital of HeidelbergHeidelbergGermany
  11. 11.Department of PathologyKatharinenhospital StuttgartStuttgartGermany

Personalised recommendations