title: ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma.
abstract: Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the "ISN-Haarlem" consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 oligoastrocytomas and 129 glioblastomas. Following the concepts of the "ISN-Haarlem", we rediagnosed the series to obtain "integrated" diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the "integrated" diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the "integrated" diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.
authors.affiliation: German Cancer Consortium (DKTK), CCU Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David E
authors.initials: DE
authors.lastname: Reuss
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.forename: Daniel
authors.initials: D
authors.lastname: Schrimpf
authors.forename: Benedikt
authors.initials: B
authors.lastname: Wiestler
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.forename: Christian
authors.initials: C
authors.lastname: Koelsche
authors.forename: Leonille
authors.initials: L
authors.lastname: Schweizer
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D001254:Astrocytoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009837:Oligodendroglioma / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D000075924:X-linked Nuclear Protein; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein