Gliomatosis cerebri: no evidence for a separate brain tumor entity.
Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification.
Division of Neurooncology, Department of Neurology, University Medical Center Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. ulrich.herrlinger@ukb.uni-bonn.de.
Ulrich
U
Herrlinger
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
David T W
DTW
Jones
Division of Neurooncology, Department of Neurology, University Medical Center Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.|Institute of Reconstructive Neurobiology, Life and Brain Center, University of Bonn, Bonn, Germany.
Martin
M
Glas
Division of Neuroradiology, Department of Radiology, University of Bonn, Bonn, Germany.
Elke
E
Hattingen
Department of Neurology, University of Zurich, Zurich, Switzerland.
Dorothee
D
Gramatzki
Division of Neurooncology, Department of Neurology, University Medical Center Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.
Moritz
M
Stuplich
Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Jörg
J
Felsberg
Dr. Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt, Germany.
Oliver
O
Bähr
Department of Neuropathology, University of Bonn, Bonn, Germany.
Gerrit H
GH
Gielen
Department of Neurosurgery, University of Bonn, Bonn, Germany.
Matthias
M
Simon
Department of Neurosurgery, University of Münster, Münster, Germany.
Dorothee
D
Wiewrodt
Department of Neurology, Klinikum Ludwigsburg, Ludwigsburg, Germany.
Martin
M
Schabet
German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
Volker
V
Hovestadt
German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.
David
D
Capper
Dr. Senckenberg Institute of Neurooncology, University of Frankfurt, Frankfurt, Germany.
Joachim P
JP
Steinbach
German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.
Andreas
A
von Deimling
German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.
Peter
P
Lichter
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.
Stefan M
SM
Pfister
Department of Neurology, University of Zurich, Zurich, Switzerland.
Michael
M
Weller
Department of Neuropathology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.|German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Heidelberg, Partner Site Essen/Düsseldorf, Düsseldorf, Germany.
Guido
G
Reifenberger
D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D018302:Neoplasms, Neuroepithelial / Q000145:classification* / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics; D055815:Young Adult
D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
DNA methylation profiles; Genomic aberrations; Gliomatosis cerebri; IDH1 mutation; MGMT promoter methylation; Molecular classification