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

Reinhardt, AnnekathrinAnnekathrinReinhardtStichel, DamianDamianStichelSchrimpf, DanielDanielSchrimpfSahm, FelixFelixSahmKorshunov, AndreyAndreyKorshunovReuss, David EDavid EReussKoelsche, ChristianChristianKoelscheHuang, KristinKristinHuangWefers, Annika KAnnika KWefersHovestadt, VolkerVolkerHovestadtSill, MartinMartinSillGramatzki, DorotheeDorotheeGramatzkiFelsberg, JoergJoergFelsbergReifenberger, GuidoGuidoReifenbergerKoch, ArendArendKochThomale, Ulrich-WUlrich-WThomaleBecker, AlbertAlbertBeckerHans, Volkmar HVolkmar HHansPrinz, MarcoMarcoPrinzStaszewski, OriOriStaszewskiAcker, TillTillAckerDohmen, HildegardHildegardDohmenHartmann, ChristianChristianHartmannMueller, WolfWolfMuellerTuffaha, Muin S AMuin S ATuffahaPaulus, WernerWernerPaulusHeß, KatharinaKatharinaHeßBrokinkel, BenjaminBenjaminBrokinkelSchittenhelm, JensJensSchittenhelmMonoranu, Camelia-MariaCamelia-MariaMonoranuKessler, Almuth FriederikeAlmuth FriederikeKesslerLoehr, MarioMarioLoehrBuslei, RolfRolfBusleiDeckert, MartinaMartinaDeckertMawrin, ChristianChristianMawrinKohlhof, PatriciaPatriciaKohlhofHewer, Ekkehard WalterEkkehard WalterHewer0000-0002-9128-0364Olar, AdrianaAdrianaOlarRodriguez, Fausto JFausto JRodriguezGiannini, CaterinaCaterinaGianniniNageswaraRao, Amulya AAmulya ANageswaraRaoTabori, UriUriTaboriNunes, Nuno MiguelNuno MiguelNunesWeller, MichaelMichaelWellerPohl, UteUtePohlJaunmuktane, ZaneZaneJaunmuktaneBrandner, SebastianSebastianBrandnerUnterberg, AndreasAndreasUnterbergHänggi, DanielDanielHänggiPlatten, MichaelMichaelPlattenPfister, Stefan MStefan MPfisterWick, WolfgangWolfgangWickHerold-Mende, ChristelChristelHerold-MendeJones, David T WDavid T WJonesvon Deimling, AndreasAndreasvon DeimlingCapper, DavidDavidCapper2024-10-252024-10-252018-08https://boris-portal.unibe.ch/handle/20.500.12422/159988Tumors 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.enATRX Anaplastic pilocytic astrocytoma BRAF CDKN2A/B DNA copy number alterations FGFR1 MGMT Methylation profile based classification Molecular characterization NF1 Panel sequencing Pilocytic astrocytoma with anaplasia500 - Science::570 - Life sciences; biology600 - Technology::610 - Medicine & healthAnaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations.article10.7892/boris.1138392956459110.1007/s00401-018-1837-8