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Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

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Abstract

Tumors with histological features of pilocytic astrocytoma (PA), but with increased mitotic activity and additional high-grade features (particularly microvascular proliferation and palisading necrosis) have often been designated anaplastic pilocytic astrocytomas. The status of these tumors as a separate entity has not yet been conclusively demonstrated and molecular features have only been partially characterized. We performed DNA methylation profiling of 102 histologically defined anaplastic pilocytic astrocytomas. T-distributed stochastic neighbor-embedding (t-SNE) and hierarchical clustering analysis of these 102 cases against 158 reference cases from 12 glioma reference classes revealed that a subset of 83 of these tumors share a common DNA methylation profile that is distinct from the reference classes. These 83 tumors were thus denominated DNA methylation class anaplastic astrocytoma with piloid features (MC AAP). The 19 remaining tumors were distributed amongst the reference classes, with additional testing confirming the molecular diagnosis in most cases. Median age of patients with MC AAP was 41.5 years. The most frequent localization was the posterior fossa (74%). Deletions of CDKN2A/B (66/83, 80%), MAPK pathway gene alterations (49/65, 75%, most frequently affecting NF1, followed by BRAF and FGFR1) and mutations of ATRX or loss of ATRX expression (33/74, 45%) were the most common molecular alterations. All tumors were IDH1/2 wildtype. The MGMT promoter was methylated in 38/83 tumors (45%). Outcome analysis confirmed an unfavorable clinical course in comparison to PA, but better than IDH wildtype glioblastoma. In conclusion, we show that a subset of histologically defined anaplastic pilocytic astrocytomas forms a separate DNA methylation cluster, harbors recurrent alterations in MAPK pathway genes in combination with alterations of CDKN2A/B and ATRX, affects patients who are on average older than those diagnosed with PA and has an intermediate clinical outcome.

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Acknowledgements

We thank the Genomics and Proteomics Core Facility of the German Cancer Research Center (DKFZ) for the performance of methylation analyses and Dr. Stefan Uhrig and Dr. Gnana Prakash Balasubramanian for the help with the detection of gene fusions in the gene panel sequencing raw data. Part of this work was undertaken at UCLH/UCL which received funding from the National Institute of Health Research (NIHR) (Sebastian Brandner). We thank the DKFZ Heidelberg Center for Personalized Oncology (DKFZ-HIPO) for technical support and funding through HIPO_036. In other parts, this work was supported by an Illumina Medical Research Grant and the German Cancer Consortium (DKTK) joint funding project ‘Next Generation Molecular Diagnostics of Malignant Gliomas’.

Author information

Authors and Affiliations

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

    Annekathrin Reinhardt, Damian Stichel, Daniel Schrimpf, Felix Sahm, Andrey Korshunov, David E. Reuss, Christian Koelsche, Kristin Huang, Annika K. Wefers, Andreas von Deimling & David Capper

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

    Annekathrin Reinhardt, Damian Stichel, Daniel Schrimpf, Felix Sahm, Andrey Korshunov, David E. Reuss, Christian Koelsche, Kristin Huang, Annika K. Wefers, Andreas von Deimling & David Capper

  3. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Volker Hovestadt

  4. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany

    Volker Hovestadt, Martin Sill, Stefan M. Pfister, Wolfgang Wick, David T. W. Jones & Andreas von Deimling

  5. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Stefan M. Pfister

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

    Stefan M. Pfister

  7. Department of Neuropathology, Charité Universitaetsmedizin Berlin, Berlin, Germany

    Arend Koch

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

    Albert Becker

  9. Institute for Neuropathology, Heinrich Heine University Duesseldorf, Duesseldorf, Germany

    Joerg Felsberg & Guido Reifenberger

  10. Institute for Neuropathology, University of Essen, Essen, Germany

    Volkmar H. Hans

  11. Institute of Neuropathology, Medical Faculty, University of Freiburg, 79106, Freiburg, Germany

    Marco Prinz & Ori Staszewski

  12. Institute of Neuropathology, University of Giessen, Giessen, Germany

    Till Acker & Hildegard Dohmen

  13. Department of Neuropathology, Hannover Medical School, Hannover, Germany

    Christian Hartmann

  14. Department of Neuropathology, Leipzig University, Liebigstr. 26, 04103, Leipzig, Germany

    Wolf Mueller

  15. Institute of Neuropathology, University Hospital Muenster, Muenster, Germany

    Werner Paulus, Katharina Heß & Benjamin Brokinkel

  16. Institute for Pathology and Neuropathology, University of Tuebingen, Comprehensive Cancer Center Tuebingen, Tuebingen, Germany

    Jens Schittenhelm

  17. Department of Neuropathology, Institute of Pathology, University of Wuerzburg, Comprehensive Cancer Center Mainfranken, Wuerzburg, Germany

    Camelia-Maria Monoranu

  18. Institute for Pathology, Sozialstiftung Bamberg, Bamberg, Germany

    Rolf Buslei

  19. Institute for Neuropathology, Friedrich-Alexander University of Erlangen-Nuernberg (FAU), Erlangen, Germany

    Rolf Buslei

  20. Department of Neuropathology, University Hospital of Cologne, Cologne, Germany

    Martina Deckert

  21. Institute for Neuropathology, University of Magdeburg, Magdeburg, Germany

    Christian Mawrin

  22. Institute for Pathology, Katharinenhospital Stuttgart, Stuttgart, Germany

    Patricia Kohlhof

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

    Ekkehard Hewer

  24. Department of Pathology, Medical University of South Carolina and Hollings Cancer Center Charleston, Charleston, SC, USA

    Adriana Olar

  25. Department of Laboratory Medicine, Medical University of South Carolina and Hollings Cancer Center Charleston, Charleston, SC, USA

    Adriana Olar

  26. Department of Neurosurgery, Medical University of South Carolina and Hollings Cancer Center Charleston, Charleston, SC, USA

    Adriana Olar

  27. Division of Neuropathology, Johns Hopkins School of Medicine in Baltimore, Baltimore, USA

    Fausto J. Rodriguez

  28. Division of Pediatric Hematology/Oncology, Mayo Clinic, Rochester, MN, USA

    Caterina Giannini & Amulya A. NageswaraRao

  29. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Dorothee Gramatzki & Michael Weller

  30. German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Guido Reifenberger

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

    Ute Pohl

  32. Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, WC1N 3BG, UK

    Zane Jaunmuktane & Sebastian Brandner

  33. Neurology Clinic, University of Heidelberg Medical Center, Heidelberg, Germany

    Wolfgang Wick

  34. Division of Experimental Neurosurgery, Department of Neurosurgery, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

    Christel Herold-Mende

  35. Clinic for Pediatric Neurosurgery, Charité Universitaetsmedizin Berlin, Berlin, Germany

    Ulrich-W. Thomale

  36. Institute of Pathology, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany

    Muin S. A. Tuffaha

  37. Department of Neurosurgery, University Hospital of Wuerzburg, Wuerzburg, Germany

    Almuth Friederike Kessler & Mario Loehr

  38. Department of Pediatrics, University of Toronto, Toronto, ON, Canada

    Uri Tabori

  39. Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada

    Uri Tabori

  40. Genetics and Genomic Biology Program, University of Toronto, Toronto, ON, Canada

    Uri Tabori & Nuno Miguel Nunes

  41. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada

    Uri Tabori & Nuno Miguel Nunes

  42. Clinic for Neurosurgery, University Hospital Heidelberg, Heidelberg, Germany

    Andreas Unterberg

  43. Clinic for Neurosurgery, University of Mannheim, Mannheim, Germany

    Daniel Hänggi

  44. Department of Neurology, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany

    Michael Platten

  45. Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Michael Platten

  46. Department of Neuropathology, Charité Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of Health, Berlin, Germany

    David Capper

  47. BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104, Freiburg, Germany

    Marco Prinz

  48. Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), 69120, Heidelberg, Germany

    Martin Sill, Stefan M. Pfister & David T. W. Jones

  49. Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    David T. W. Jones

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

    David Capper

Authors
  1. Annekathrin Reinhardt
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  2. Damian Stichel
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  3. Daniel Schrimpf
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  11. Martin Sill
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  15. Arend Koch
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  16. Ulrich-W. Thomale
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  17. Albert Becker
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  55. Andreas von Deimling
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  56. David Capper
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Corresponding author

Correspondence to David Capper.

Additional information

David T. W. Jones, Andreas von Deimling and David Capper share senior authorship.

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Reinhardt, A., Stichel, D., Schrimpf, D. et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol 136, 273–291 (2018). https://doi.org/10.1007/s00401-018-1837-8

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  • DOI: https://doi.org/10.1007/s00401-018-1837-8

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