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01-08-2018 | Original Paper

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

Authors: 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

Published in: Acta Neuropathologica | Issue 2/2018

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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Title: Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations
Authors: 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
Publication date: 01-08-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 2/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-018-1837-8

At a glance: The STEP trials

Springer Medicine

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

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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