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, Ulrich 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
N1 - Publisher Copyright:
© 2018, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2018/8/1
Y1 - 2018/8/1
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 - ATRX
KW - Anaplastic pilocytic astrocytoma
KW - BRAF
KW - CDKN2A/B
KW - DNA copy number alterations
KW - FGFR1
KW - MGMT
KW - Methylation profile based classification
KW - Molecular characterization
KW - NF1
KW - Panel sequencing
KW - Pilocytic astrocytoma with anaplasia
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U2 - 10.1007/s00401-018-1837-8
DO - 10.1007/s00401-018-1837-8
M3 - Article
C2 - 29564591
AN - SCOPUS:85044209632
SN - 0001-6322
VL - 136
SP - 273
EP - 291
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 2
ER -