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Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course

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Abstract

The “isomorphic subtype of diffuse astrocytoma” was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

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Acknowledgements

We thank K. Böhmer, A. Habel, S. Kocher, U. Lass, K. Lindenberg, R. Quan, S. Sprengart, U. Vogel, M. Werner and V. Zeller for excellent technical assistance. We thank the Genomics and Proteomics Core Facility of the German Cancer Research Center (DKFZ) for the performance of DNA methylation analyses. A.K. Wefers is a fellow of the Physician Scientist-Program of the Medical Faculty of Heidelberg. This study was supported by an International League against Epilepsy (ILAE) Grant to D. Capper. I. Blumcke was supported by the European Union (FP6 DESIRE Grant Agreement #602531). M. Mittelbronn would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). K. Ligon is funded by the Paediatric Low Grade Astrocytoma Foundation and NCI R01CA215489. T. Jacques is funded by The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children’s Charity, Cancer Research UK, the Olivia Hodson Cancer Fund and the National Institute of Health Research. T. Jacques’s work is partly funded by the NIHR GOSH BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the biomedical scientists in the Division of Neuropathology, the National Hospital for Neurology and Neurosurgery (NHNN) for excellent technical assistance. We also thank clinicians and neuropathologists for referring cases for molecular analysis. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical research centre (BRC399/NS/RB/101410). S. Brandner and Z. Jaunmuktane are also supported by the Department of Health’s NIHR Biomedical Research Centre’s funding scheme. Additional funding was provided by the Brain Tumour Charity (UK) for the Everest Centre for Paediatric Low-Grade Brain Tumour Research.

Author information

Authors and Affiliations

  1. Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Annika K. Wefers, Damian Stichel, Daniel Schrimpf, Jochen Meyer, David E. Reuss, Annekathrin Reinhardt, Philipp Sievers, M. Belén Casalini, Azadeh Ebrahimi, Kristin Huang, Christian Koelsche, Andrey Korshunov, Felix Sahm & Andreas von Deimling

  2. Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

    Annika K. Wefers, Damian Stichel, Daniel Schrimpf, Jochen Meyer, David E. Reuss, Annekathrin Reinhardt, Philipp Sievers, M. Belén Casalini, Azadeh Ebrahimi, Kristin Huang, Andrey Korshunov, Felix Sahm & Andreas von Deimling

  3. Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany

    Annika K. Wefers, Stefan M. Pfister, Felix Sahm & David T. W. Jones

  4. Department of Neuropathology, University Hospital Erlangen, Erlangen, Germany

    Roland Coras & Ingmar Blumcke

  5. Department of Neuropathology, Sainte-Anne Hospital, Descartes University, Paris, France

    Mélanie Pages, Arnault Tauziède-Espariat & Pascale Varlet

  6. Department of Neuroradiology, University Hospital Heidelberg, Heidelberg, Germany

    Daniel Schwarz

  7. Department of Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Daniel Schwarz

  8. Department of Pathology, Hacettepe University Faculty of Medicine, Ankara, Turkey

    Figen Söylemezoglu

  9. Department of Cellular Pathology, Queen’s Hospital BHRUT, Romford, UK

    Ute Pohl

  10. Department of Cellular Pathology, Queen Elizabeth Hospital Birmingham/University Hospitals Birmingham, Birmingham, UK

    Ute Pohl

  11. Department of Neurosciences and Mental Health, Laboratory of Neuropathology, Hospital de Santa Maria (CHULN, EPE), Lisbon, Portugal

    José Pimentel

  12. Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    José Pimentel

  13. Institute of Pathology, University of Bern, Bern, Switzerland

    Ekkehard Hewer

  14. Department of Neuropathology, University of Bonn, Bonn, Germany

    Anna Japp & Albert J. Becker

  15. Department of Neuropathology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

    Abhijit Joshi

  16. Department of General Pathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany

    Christian Koelsche

  17. Department of Neurosurgery, Queen’s Hospital BHRUT, Romford, UK

    Hu Liang Low

  18. Neuropathology Unit, Centro Hospitalar de Universidades de Coimbra, Coimbra, Portugal

    Olinda Rebelo & Dina Marnoto

  19. Institute of Neuropathology, University of Freiburg, Freiburg, Germany

    Ori Staszewski

  20. Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt, Germany

    Michel Mittelbronn

  21. Luxembourg Center of Neuropathology (LCNP), Dudelange, Luxembourg

    Michel Mittelbronn

  22. Laboratoire National de Santé (LNS), National Center of Pathology (NCP), Dudelange, Luxembourg

    Michel Mittelbronn

  23. Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg

    Michel Mittelbronn

  24. Department of Oncology (DONC), Luxembourg Institute of Health (LIH), Luxembourg City, Luxembourg

    Michel Mittelbronn

  25. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    Martin Hasselblatt

  26. Department of Neuropathology, Institute of Pathology and Neuropathology, University Hospital of Tübingen, Tübingen, Germany

    Jens Schittenhelm

  27. Center for CNS Tumours, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital of Tübingen, Tübingen, Germany

    Jens Schittenhelm

  28. Department of Paediatric Histopathology, Royal Manchester Children’s Hospital Manchester, Manchester, UK

    Edmund Cheesman

  29. Division of Pediatric Neurosurgery, Department of Surgery and Anatomy, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

    Ricardo Santos de Oliveira

  30. Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil

    Rosane Gomes P. Queiroz & Elvis Terci Valera

  31. Abteilung Neuropathologie, Institut für klinische Pathologie, Dietrich-Bonhoeffer-Klinikum, Neubrandenburg, Germany

    Volkmar H. Hans

  32. Institut für Neuropathologie, Evangelisches Klinikum Bethel gGmbH, Bielefeld, Germany

    Volkmar H. Hans

  33. Departments of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina, Charleston, SC, USA

    Adriana Olar

  34. Hollings Cancer Center, Charleston, SC, USA

    Adriana Olar

  35. Department of Oncologic Pathology, Dana-Farber/Brigham and Women’s Cancer Center, Harvard Medical School, Boston, MA, USA

    Keith L. Ligon

  36. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    Stefan M. Pfister

  37. Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany

    Stefan M. Pfister

  38. Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK

    Zane Jaunmuktane & Maria Thom

  39. Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK

    Zane Jaunmuktane & Sebastian Brandner

  40. Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

    Sebastian Brandner

  41. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ruth G. Tatevossian & David W. Ellison

  42. Developmental Biology and Cancer Section, UCL Great Ormond Street Institute of Child Health, London, UK

    Thomas S. Jacques

  43. Department of Pathology, Hospital Pedro Hispano, Matosinhos, Portugal

    Mrinalini Honavar

  44. Amsterdam UMC, Department of (Neuro)Pathology, University of Amsterdam, Amsterdam and Stichting Epilepsie Instellingen Nederland, Heemstede, The Netherlands

    Eleonora Aronica

  45. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David T. W. Jones

  46. Department of Neuropathology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany

    David Capper

  47. German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany

    David Capper

Authors
  1. Annika K. Wefers
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  2. Damian Stichel
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Corresponding authors

Correspondence to Annika K. Wefers or David Capper.

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Conflict of interest

D. Capper, D. T. W. Jones, A. von Deimling and S. M. Pfister declare that under the No. EP3067432A1 a patent was applied for a “DNA-methylation based method for classifying tumor species”. D. Capper and A. von Deimling are patent holders of “Methods for the diagnosis and the prognosis of a brain tumor”, the IDH1 R132H-specific antibody used in this manuscript (US 8367347 B2). The patent is under the administrative supervision of the DKFZ technology transfer office.

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Wefers, A.K., Stichel, D., Schrimpf, D. et al. Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course. Acta Neuropathol 139, 193–209 (2020). https://doi.org/10.1007/s00401-019-02078-w

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