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

• Published in: Acta neuropathologica Vol. 136; no. 2; pp. 273 - 291
• Main Authors: 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, Ulrich-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
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-08-2018; Springer; Springer Nature B.V
• Subjects: Analysis; Astrocytoma; Brain tumors; Deoxyribonucleic acid; DNA; DNA fingerprinting; DNA methylation; Embedding; Fibroblast growth factor receptor 1; Glioblastoma; Glioma; Gliomas; Health aspects; Localization; MAP kinase; Medical schools; Medicine; Medicine & Public Health; Methylation; Microvasculature; Mutation; Neurosciences; Original Paper; Pathology; Stochasticity; Methylation profile based classification; Panel sequencing; DNA copy number alterations; Anaplastic pilocytic astrocytoma; Pilocytic astrocytoma with anaplasia; Molecular characterization; CDKN2A/B; MGMT; ATRX; NF1; BRAF; FGFR1
• ISSN: 0001-6322; 1432-0533
• DOI: 10.1007/s00401-018-1837-8

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.