title: Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities.
abstract: IDH wild type (IDHwt) anaplastic astrocytomas WHO grade III (AA III) are associated with poor outcome. To address the possibilities of molecular subsets among astrocytoma or of diagnostic reclassification, we analyzed a series of 160 adult IDHwt tumors comprising 120 AA III and 40 diffuse astrocytomas WHO grade II (A II) for molecular hallmark alterations and established methylation and copy number profiles. Based on molecular profiles and hallmark alterations the tumors could be grouped into four major sets. 124/160 (78 %) tumors were diagnosed as the molecular equivalent of conventional glioblastoma (GBM), and 15/160 (9 %) as GBM-H3F3A mutated (GBM-H3). 13/160 (8 %) exhibited a distinct methylation profile that was most similar to GBM-H3-K27, however, lacked the H3F3A mutation. This group was enriched for tumors of infratentorial and midline localization and showed a trend towards a more favorable prognosis. All but one of the 120 IDHwt AA III could be assigned to these three groups. 7 tumors recruited from the 40 A II, comprised a variety of molecular signatures and all but one were reclassified into distinct WHO entities of lower grades. Interestingly, TERT mutations were exclusively restricted to the molecular GBM (78 %) and associated with poor clinical outcome. However, the GBM-H3 group lacking TERT mutations appeared to fare even worse. Our data demonstrate that most of the tumors diagnosed as IDHwt astrocytomas can be allocated to other tumor entities on a molecular basis. The diagnosis of IDHwt diffuse astrocytoma or anaplastic astrocytoma should be used with caution.
authors.affiliation: Department of Neuropathology, Institute of Pathology, University of Heidelberg, INF 224, 69120, Heidelberg, Germany.
authors.forename: David E
authors.initials: DE
authors.lastname: Reuss
authors.forename: Annekathrin
authors.initials: A
authors.lastname: Kratz
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Daniel
authors.initials: D
authors.lastname: Schrimpf
authors.forename: Christian
authors.initials: C
authors.lastname: Koelsche
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.forename: Melanie
authors.initials: M
authors.lastname: Bewerunge-Hudler
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rushing
authors.forename: Matthias
authors.initials: M
authors.lastname: Simon
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Joerg-Christian
authors.initials: JC
authors.lastname: Tonn
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brandner
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D001254:Astrocytoma / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D019175:DNA Methylation; D005909:Glioblastoma / Q000145:classification / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; C509186:TERT protein, human; D019098:Telomerase