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, U. W. Thomale, Albert Becker, Volkmar H. Hans, Marco Prinz, Ori StaszewskiTill 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

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-19
Number of pages19
JournalActa Neuropathologica
DOIs
StateAccepted/In press - Mar 21 2018

Fingerprint

Astrocytoma
Glioma
DNA Methylation
Neoplasms
DNA Fingerprinting
Glioblastoma
Methylation
Genes
Cluster Analysis
Necrosis
Mutation

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. / Reinhardt, Annekathrin; Stichel, Damian; Schrimpf, Daniel; Sahm, Felix; Korshunov, Andrey; Reuss, David E.; Koelsche, Christian; Huang, Kristin; Wefers, Annika K.; Hovestadt, Volker; Sill, Martin; Gramatzki, Dorothee; Felsberg, Joerg; Reifenberger, Guido; Koch, Arend; Thomale, U. W.; Becker, Albert; Hans, Volkmar H.; Prinz, Marco; Staszewski, Ori; Acker, Till; Dohmen, Hildegard; Hartmann, Christian; Mueller, Wolf; Tuffaha, Muin S.A.; Paulus, Werner; Heß, Katharina; Brokinkel, Benjamin; Schittenhelm, Jens; Monoranu, Camelia Maria; Kessler, Almuth Friederike; Loehr, Mario; Buslei, Rolf; Deckert, Martina; Mawrin, Christian; Kohlhof, Patricia; Hewer, Ekkehard; Olar, Adriana; Rodriguez, Fausto J.; Giannini, Caterina; NageswaraRao, Amulya A.; Tabori, Uri; Nunes, Nuno Miguel; Weller, Michael; Pohl, Ute; Jaunmuktane, Zane; Brandner, Sebastian; Unterberg, Andreas; Hänggi, Daniel; Platten, Michael; Pfister, Stefan M.; Wick, Wolfgang; Herold-Mende, Christel; Jones, David T.W.; von Deimling, Andreas; Capper, David.

In: Acta Neuropathologica, 21.03.2018, p. 1-19.

Research output: Contribution to journalArticle

Reinhardt, A, Stichel, D, Schrimpf, D, Sahm, F, Korshunov, A, Reuss, DE, Koelsche, C, Huang, K, Wefers, AK, Hovestadt, V, Sill, M, Gramatzki, D, Felsberg, J, Reifenberger, G, Koch, A, Thomale, UW, Becker, A, Hans, VH, Prinz, M, Staszewski, O, Acker, T, Dohmen, H, Hartmann, C, Mueller, W, Tuffaha, MSA, Paulus, W, Heß, K, Brokinkel, B, Schittenhelm, J, Monoranu, CM, Kessler, AF, Loehr, M, Buslei, R, Deckert, M, Mawrin, C, Kohlhof, P, Hewer, E, Olar, A, Rodriguez, FJ, Giannini, C, NageswaraRao, AA, Tabori, U, Nunes, NM, Weller, M, Pohl, U, Jaunmuktane, Z, Brandner, S, Unterberg, A, Hänggi, D, Platten, M, Pfister, SM, Wick, W, Herold-Mende, C, Jones, DTW, von Deimling, A & Capper, D 2018, 'Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations', Acta Neuropathologica, pp. 1-19. https://doi.org/10.1007/s00401-018-1837-8
Reinhardt, Annekathrin ; Stichel, Damian ; Schrimpf, Daniel ; Sahm, Felix ; Korshunov, Andrey ; Reuss, David E. ; Koelsche, Christian ; Huang, Kristin ; Wefers, Annika K. ; Hovestadt, Volker ; Sill, Martin ; Gramatzki, Dorothee ; Felsberg, Joerg ; Reifenberger, Guido ; Koch, Arend ; Thomale, U. W. ; Becker, Albert ; Hans, Volkmar H. ; Prinz, Marco ; Staszewski, Ori ; Acker, Till ; Dohmen, Hildegard ; Hartmann, Christian ; Mueller, Wolf ; Tuffaha, Muin S.A. ; Paulus, Werner ; Heß, Katharina ; Brokinkel, Benjamin ; Schittenhelm, Jens ; Monoranu, Camelia Maria ; Kessler, Almuth Friederike ; Loehr, Mario ; Buslei, Rolf ; Deckert, Martina ; Mawrin, Christian ; Kohlhof, Patricia ; Hewer, Ekkehard ; Olar, Adriana ; Rodriguez, Fausto J. ; Giannini, Caterina ; NageswaraRao, Amulya A. ; Tabori, Uri ; Nunes, Nuno Miguel ; Weller, Michael ; Pohl, Ute ; Jaunmuktane, Zane ; Brandner, Sebastian ; Unterberg, Andreas ; Hänggi, Daniel ; Platten, Michael ; Pfister, Stefan M. ; Wick, Wolfgang ; Herold-Mende, Christel ; Jones, David T.W. ; von Deimling, Andreas ; Capper, David. / Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. In: Acta Neuropathologica. 2018 ; pp. 1-19.
@article{fe2a0e344a594ea7969ac9eff5c3f296,
title = "Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations",
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, ATRX, BRAF, CDKN2A/B, DNA copy number alterations, FGFR1, Methylation profile based classification, MGMT, Molecular characterization, NF1, Panel sequencing, Pilocytic astrocytoma with anaplasia",
author = "Annekathrin Reinhardt and Damian Stichel and Daniel Schrimpf and Felix Sahm and Andrey Korshunov and Reuss, {David E.} and Christian Koelsche and Kristin Huang and Wefers, {Annika K.} and Volker Hovestadt and Martin Sill and Dorothee Gramatzki and Joerg Felsberg and Guido Reifenberger and Arend Koch and Thomale, {U. W.} and Albert Becker and Hans, {Volkmar H.} and Marco Prinz and Ori Staszewski and Till Acker and Hildegard Dohmen and Christian Hartmann and Wolf Mueller and Tuffaha, {Muin S.A.} and Werner Paulus and Katharina He{\ss} and Benjamin Brokinkel and Jens Schittenhelm and Monoranu, {Camelia Maria} and Kessler, {Almuth Friederike} and Mario Loehr and Rolf Buslei and Martina Deckert and Christian Mawrin and Patricia Kohlhof and Ekkehard Hewer and Adriana Olar and Rodriguez, {Fausto J.} and Caterina Giannini and NageswaraRao, {Amulya A.} and Uri Tabori and Nunes, {Nuno Miguel} and Michael Weller and Ute Pohl and Zane Jaunmuktane and Sebastian Brandner and Andreas Unterberg and Daniel H{\"a}nggi and Michael Platten and Pfister, {Stefan M.} and Wolfgang Wick and Christel Herold-Mende and Jones, {David T.W.} and {von Deimling}, Andreas and David Capper",
year = "2018",
month = "3",
day = "21",
doi = "10.1007/s00401-018-1837-8",
language = "English (US)",
pages = "1--19",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",

}

TY - JOUR

T1 - Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations

AU - Reinhardt, Annekathrin

AU - Stichel, Damian

AU - Schrimpf, Daniel

AU - Sahm, Felix

AU - Korshunov, Andrey

AU - Reuss, David E.

AU - Koelsche, Christian

AU - Huang, Kristin

AU - Wefers, Annika K.

AU - Hovestadt, Volker

AU - Sill, Martin

AU - Gramatzki, Dorothee

AU - Felsberg, Joerg

AU - Reifenberger, Guido

AU - Koch, Arend

AU - Thomale, U. W.

AU - Becker, Albert

AU - Hans, Volkmar H.

AU - Prinz, Marco

AU - Staszewski, Ori

AU - Acker, Till

AU - Dohmen, Hildegard

AU - Hartmann, Christian

AU - Mueller, Wolf

AU - Tuffaha, Muin S.A.

AU - Paulus, Werner

AU - Heß, Katharina

AU - Brokinkel, Benjamin

AU - Schittenhelm, Jens

AU - Monoranu, Camelia Maria

AU - Kessler, Almuth Friederike

AU - Loehr, Mario

AU - Buslei, Rolf

AU - Deckert, Martina

AU - Mawrin, Christian

AU - Kohlhof, Patricia

AU - Hewer, Ekkehard

AU - Olar, Adriana

AU - Rodriguez, Fausto J.

AU - Giannini, Caterina

AU - NageswaraRao, Amulya A.

AU - Tabori, Uri

AU - Nunes, Nuno Miguel

AU - Weller, Michael

AU - Pohl, Ute

AU - Jaunmuktane, Zane

AU - Brandner, Sebastian

AU - Unterberg, Andreas

AU - Hänggi, Daniel

AU - Platten, Michael

AU - Pfister, Stefan M.

AU - Wick, Wolfgang

AU - Herold-Mende, Christel

AU - Jones, David T.W.

AU - von Deimling, Andreas

AU - Capper, David

PY - 2018/3/21

Y1 - 2018/3/21

N2 - 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.

AB - 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.

KW - Anaplastic pilocytic astrocytoma

KW - ATRX

KW - BRAF

KW - CDKN2A/B

KW - DNA copy number alterations

KW - FGFR1

KW - Methylation profile based classification

KW - MGMT

KW - Molecular characterization

KW - NF1

KW - Panel sequencing

KW - Pilocytic astrocytoma with anaplasia

UR - http://www.scopus.com/inward/record.url?scp=85044209632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044209632&partnerID=8YFLogxK

U2 - 10.1007/s00401-018-1837-8

DO - 10.1007/s00401-018-1837-8

M3 - Article

C2 - 29564591

AN - SCOPUS:85044209632

SP - 1

EP - 19

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

ER -