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

  • Annekathrin Reinhardt
  • Damian Stichel
  • Daniel Schrimpf
  • Felix Sahm
  • Andrey Korshunov
  • David E. Reuss
  • Christian Koelsche
  • Kristin Huang
  • Annika K. Wefers
  • Volker Hovestadt
  • Martin Sill
  • Dorothee Gramatzki
  • Joerg Felsberg
  • Guido Reifenberger
  • Arend Koch
  • Ulrich-W. Thomale
  • Albert Becker
  • Volkmar H. Hans
  • Marco Prinz
  • Ori Staszewski
  • Till Acker
  • Hildegard Dohmen
  • Christian Hartmann
  • Wolf Mueller
  • Muin S. A. Tuffaha
  • Werner Paulus
  • Katharina Heß
  • Benjamin Brokinkel
  • Jens Schittenhelm
  • Camelia-Maria Monoranu
  • Almuth Friederike Kessler
  • Mario Loehr
  • Rolf Buslei
  • Martina Deckert
  • Christian Mawrin
  • Patricia Kohlhof
  • Ekkehard Hewer
  • Adriana Olar
  • Fausto J. Rodriguez
  • Caterina Giannini
  • Amulya A. NageswaraRao
  • Uri Tabori
  • Nuno Miguel Nunes
  • Michael Weller
  • Ute Pohl
  • Zane Jaunmuktane
  • Sebastian Brandner
  • Andreas Unterberg
  • Daniel Hänggi
  • Michael Platten
  • Stefan M. Pfister
  • Wolfgang Wick
  • Christel Herold-Mende
  • David T. W. Jones
  • Andreas von Deimling
  • David Capper
Original Paper

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.

Keywords

Anaplastic pilocytic astrocytoma Pilocytic astrocytoma with anaplasia Methylation profile based classification Panel sequencing ATRX BRAF NF1 FGFR1 MGMT CDKN2A/B Molecular characterization DNA copy number alterations 

Notes

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’.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Annekathrin Reinhardt
    • 1
    • 2
  • Damian Stichel
    • 1
    • 2
  • Daniel Schrimpf
    • 1
    • 2
  • Felix Sahm
    • 1
    • 2
  • Andrey Korshunov
    • 1
    • 2
  • David E. Reuss
    • 1
    • 2
  • Christian Koelsche
    • 1
    • 2
  • Kristin Huang
    • 1
    • 2
  • Annika K. Wefers
    • 1
    • 2
  • Volker Hovestadt
    • 3
    • 4
  • Martin Sill
    • 4
    • 48
  • Dorothee Gramatzki
    • 29
  • Joerg Felsberg
    • 9
  • Guido Reifenberger
    • 9
    • 30
  • Arend Koch
    • 7
  • Ulrich-W. Thomale
    • 35
  • Albert Becker
    • 8
  • Volkmar H. Hans
    • 10
  • Marco Prinz
    • 11
    • 47
  • Ori Staszewski
    • 11
  • Till Acker
    • 12
  • Hildegard Dohmen
    • 12
  • Christian Hartmann
    • 13
  • Wolf Mueller
    • 14
  • Muin S. A. Tuffaha
    • 36
  • Werner Paulus
    • 15
  • Katharina Heß
    • 15
  • Benjamin Brokinkel
    • 15
  • Jens Schittenhelm
    • 16
  • Camelia-Maria Monoranu
    • 17
  • Almuth Friederike Kessler
    • 37
  • Mario Loehr
    • 37
  • Rolf Buslei
    • 18
    • 19
  • Martina Deckert
    • 20
  • Christian Mawrin
    • 21
  • Patricia Kohlhof
    • 22
  • Ekkehard Hewer
    • 23
  • Adriana Olar
    • 24
    • 25
    • 26
  • Fausto J. Rodriguez
    • 27
  • Caterina Giannini
    • 28
  • Amulya A. NageswaraRao
    • 28
  • Uri Tabori
    • 38
    • 39
    • 40
    • 41
  • Nuno Miguel Nunes
    • 40
    • 41
  • Michael Weller
    • 29
  • Ute Pohl
    • 31
  • Zane Jaunmuktane
    • 32
  • Sebastian Brandner
    • 32
  • Andreas Unterberg
    • 42
  • Daniel Hänggi
    • 43
  • Michael Platten
    • 44
    • 45
  • Stefan M. Pfister
    • 4
    • 5
    • 6
    • 48
  • Wolfgang Wick
    • 33
    • 4
  • Christel Herold-Mende
    • 34
  • David T. W. Jones
    • 4
    • 48
    • 49
  • Andreas von Deimling
    • 1
    • 2
    • 4
  • David Capper
    • 1
    • 2
    • 46
    • 50
  1. 1.Department of NeuropathologyUniversity Hospital HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  3. 3.Division of Molecular GeneticsGerman Cancer Research Center (DKFZ)HeidelbergGermany
  4. 4.German Cancer Consortium (DKTK), Core Center HeidelbergHeidelbergGermany
  5. 5.Division of Pediatric NeurooncologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  6. 6.Department of Pediatric Oncology and HematologyUniversity Hospital HeidelbergHeidelbergGermany
  7. 7.Department of NeuropathologyCharité Universitaetsmedizin BerlinBerlinGermany
  8. 8.Department of NeuropathologyUniversity of BonnBonnGermany
  9. 9.Institute for NeuropathologyHeinrich Heine University DuesseldorfDuesseldorfGermany
  10. 10.Institute for NeuropathologyUniversity of EssenEssenGermany
  11. 11.Institute of Neuropathology, Medical FacultyUniversity of FreiburgFreiburgGermany
  12. 12.Institute of NeuropathologyUniversity of GiessenGiessenGermany
  13. 13.Department of NeuropathologyHannover Medical SchoolHannoverGermany
  14. 14.Department of NeuropathologyLeipzig UniversityLeipzigGermany
  15. 15.Institute of NeuropathologyUniversity Hospital MuensterMuensterGermany
  16. 16.Institute for Pathology and NeuropathologyUniversity of Tuebingen, Comprehensive Cancer Center TuebingenTuebingenGermany
  17. 17.Department of Neuropathology, Institute of PathologyUniversity of Wuerzburg, Comprehensive Cancer Center MainfrankenWuerzburgGermany
  18. 18.Institute for PathologySozialstiftung BambergBambergGermany
  19. 19.Institute for NeuropathologyFriedrich-Alexander University of Erlangen-Nuernberg (FAU)ErlangenGermany
  20. 20.Department of NeuropathologyUniversity Hospital of CologneCologneGermany
  21. 21.Institute for NeuropathologyUniversity of MagdeburgMagdeburgGermany
  22. 22.Institute for PathologyKatharinenhospital StuttgartStuttgartGermany
  23. 23.Institute of PathologyUniversity of BernBernSwitzerland
  24. 24.Department of PathologyMedical University of South Carolina and Hollings Cancer Center CharlestonCharlestonUSA
  25. 25.Department of Laboratory MedicineMedical University of South Carolina and Hollings Cancer Center CharlestonCharlestonUSA
  26. 26.Department of NeurosurgeryMedical University of South Carolina and Hollings Cancer Center CharlestonCharlestonUSA
  27. 27.Division of NeuropathologyJohns Hopkins School of Medicine in BaltimoreBaltimoreUSA
  28. 28.Division of Pediatric Hematology/OncologyMayo ClinicRochesterUSA
  29. 29.Department of NeurologyUniversity Hospital and University of ZurichZurichSwitzerland
  30. 30.German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, German Cancer Research Center (DKFZ)HeidelbergGermany
  31. 31.Department of Cellular PathologyQueen’s HospitalRomfordUK
  32. 32.Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and NeurosurgeryUniversity College London HospitalsLondonUK
  33. 33.Neurology ClinicUniversity of Heidelberg Medical CenterHeidelbergGermany
  34. 34.Division of Experimental Neurosurgery, Department of NeurosurgeryRuprecht-Karls-University HeidelbergHeidelbergGermany
  35. 35.Clinic for Pediatric NeurosurgeryCharité Universitaetsmedizin BerlinBerlinGermany
  36. 36.Institute of PathologyCarl-Thiem-Klinikum CottbusCottbusGermany
  37. 37.Department of NeurosurgeryUniversity Hospital of WuerzburgWuerzburgGermany
  38. 38.Department of PediatricsUniversity of TorontoTorontoCanada
  39. 39.Division of Hematology/OncologyUniversity of TorontoTorontoCanada
  40. 40.Genetics and Genomic Biology ProgramUniversity of TorontoTorontoCanada
  41. 41.The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick ChildrenTorontoCanada
  42. 42.Clinic for NeurosurgeryUniversity Hospital HeidelbergHeidelbergGermany
  43. 43.Clinic for NeurosurgeryUniversity of MannheimMannheimGermany
  44. 44.Department of Neurology, Medical Faculty MannheimHeidelberg UniversityHeidelbergGermany
  45. 45.Clinical Cooperation Unit Neuroimmunology and Brain Tumor ImmunologyGerman Cancer Research Center (DKFZ)HeidelbergGermany
  46. 46.Department of NeuropathologyCharité Universitaetsmedizin Berlin, Corporate Member of Freie Universitaet Berlin, Humboldt-Universitaet zu Berlin, and Berlin Institute of HealthBerlinGermany
  47. 47.BIOSS Centre for Biological Signaling StudiesUniversity of FreiburgFreiburgGermany
  48. 48.Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)HeidelbergGermany
  49. 49.Pediatric Glioma Research GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
  50. 50.German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ)HeidelbergGermany

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