Reinhardt, Annekathrin, Stichel, Damian, Schrimpf, Daniel, Sahm, Felix ORCID: 0000-0001-5441-1962, Korshunov, Andrey ORCID: 0000-0002-5257-3623, Reuss, David E., Koelsche, Christian, Huang, Kristin, Wefers, Annika K., Hovestadt, Volker, Sill, Martin ORCID: 0000-0001-7616-7665, Gramatzki, Dorothee, Felsberg, Joerg, Reifenberger, Guido, Koch, Arend, Thomale, Ulrich-W., Becker, Albert, Hans, Volkmar H., Prinz, Marco, Staszewski, Ori ORCID: 0000-0002-0579-6701, Acker, Till, Dohmen, Hildegard, Hartmann, Christian, Mueller, Wolf, Tuffaha, Muin S. A., Paulus, Werner, Hess, Katharina ORCID: 0000-0003-3922-6413, Brokinkel, Benjamin, Schittenhelm, Jens, Monoranu, Camelia-Maria, Kessler, Almuth Friederike, Loehr, Mario, Buslei, Rolf, Deckert, Martina, Mawrin, Christian, Kohlhof, Patricia, Hewer, Ekkehard ORCID: 0000-0002-9128-0364, Olar, Adriana, Rodriguez, Fausto J., Giannini, Caterina, NageswaraRao, Amulya A., Tabori, Uri, Nunes, Nuno Miguel, Weller, Michael ORCID: 0000-0002-1748-174X, Pohl, Ute, Jaunmuktane, Zane ORCID: 0000-0001-7738-8881, Brandner, Sebastian, Unterberg, Andreas, Haenggi, Daniel, Platten, Michael ORCID: 0000-0002-4746-887X, Pfister, Stefan M., Wick, Wolfgang ORCID: 0000-0002-6171-634X, Herold-Mende, Christel, Jones, David T. W., von Deimling, Andreas ORCID: 0000-0002-5863-540X and Capper, David ORCID: 0000-0003-1945-497X (2018). Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol., 136 (2). S. 273 - 292. NEW YORK: SPRINGER. ISSN 1432-0533

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Reinhardt, AnnekathrinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stichel, DamianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrimpf, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sahm, FelixUNSPECIFIEDorcid.org/0000-0001-5441-1962UNSPECIFIED
Korshunov, AndreyUNSPECIFIEDorcid.org/0000-0002-5257-3623UNSPECIFIED
Reuss, David E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koelsche, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Huang, KristinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wefers, Annika K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hovestadt, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sill, MartinUNSPECIFIEDorcid.org/0000-0001-7616-7665UNSPECIFIED
Gramatzki, DorotheeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Felsberg, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reifenberger, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koch, ArendUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomale, Ulrich-W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, AlbertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hans, Volkmar H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prinz, MarcoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Staszewski, OriUNSPECIFIEDorcid.org/0000-0002-0579-6701UNSPECIFIED
Acker, TillUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dohmen, HildegardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, WolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuffaha, Muin S. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Paulus, WernerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, KatharinaUNSPECIFIEDorcid.org/0000-0003-3922-6413UNSPECIFIED
Brokinkel, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schittenhelm, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Monoranu, Camelia-MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kessler, Almuth FriederikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loehr, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buslei, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deckert, MartinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mawrin, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kohlhof, PatriciaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hewer, EkkehardUNSPECIFIEDorcid.org/0000-0002-9128-0364UNSPECIFIED
Olar, AdrianaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rodriguez, Fausto J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giannini, CaterinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
NageswaraRao, Amulya A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tabori, UriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nunes, Nuno MiguelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weller, MichaelUNSPECIFIEDorcid.org/0000-0002-1748-174XUNSPECIFIED
Pohl, UteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jaunmuktane, ZaneUNSPECIFIEDorcid.org/0000-0001-7738-8881UNSPECIFIED
Brandner, SebastianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Unterberg, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haenggi, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Platten, MichaelUNSPECIFIEDorcid.org/0000-0002-4746-887XUNSPECIFIED
Pfister, Stefan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wick, WolfgangUNSPECIFIEDorcid.org/0000-0002-6171-634XUNSPECIFIED
Herold-Mende, ChristelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jones, David T. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Deimling, AndreasUNSPECIFIEDorcid.org/0000-0002-5863-540XUNSPECIFIED
Capper, DavidUNSPECIFIEDorcid.org/0000-0003-1945-497XUNSPECIFIED
URN: urn:nbn:de:hbz:38-177022
DOI: 10.1007/s00401-018-1837-8
Journal or Publication Title: Acta Neuropathol.
Volume: 136
Number: 2
Page Range: S. 273 - 292
Date: 2018
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-0533
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
METHYLATION-BASED CLASSIFICATION; MGMT PROMOTER HYPERMETHYLATION; PILOCYTIC ASTROCYTOMA; DNA METHYLATION; BRAIN-TUMORS; GENETIC ALTERATIONS; FREE SURVIVAL; GLIOBLASTOMA; PROGRESSION; FREQUENTMultiple languages
Clinical Neurology; Neurosciences; PathologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/17702

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