title: Farewell to GBM-O: Genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component reveals distinct molecular subgroups.
abstract: BACKGROUND
  Glioblastoma with oligodendroglioma component (GBM-O) was recognized as a histologic pattern of glioblastoma (GBM) by the World Health Organization (WHO) in 2007 and is distinguished by the presence of oligodendroglioma-like differentiation. To better understand the genetic underpinnings of this morphologic entity, we performed a genome-wide, integrated copy number, mutational and transcriptomic analysis of eight (seven primary, primary secondary) cases.
  
  
  RESULTS
  Three GBM-O samples had IDH1 (p.R132H) mutations; two of these also demonstrated 1p/19q co-deletion and had a proneural transcriptional profile, a molecular signature characteristic of oligodendroglioma. The additional IDH1 mutant tumor lacked 1p/19q co-deletion, harbored a TP53 mutation, and overall, demonstrated features most consistent with IDH mutant (secondary) GBM. Finally, five tumors were IDH wild-type (IDHwt) and had chromosome seven gains, chromosome 10 losses, and homozygous 9p deletions (CDKN2A), alterations typical of IDHwt (primary) GBM. IDHwt GBM-Os also demonstrated EGFR and PDGFRA amplifications, which correlated with classical and proneural expression subtypes, respectively.
  
  
  CONCLUSIONS
  Our findings demonstrate that GBM-O is composed of three discrete molecular subgroups with characteristic mutations, copy number alterations and gene expression patterns. Despite displaying areas that morphologically resemble oligodendroglioma, the current results indicate that morphologically defined GBM-O does not correspond to a particular genetic signature, but rather represents a collection of genetically dissimilar entities. Ancillary testing, especially for IDH and 1p/19q, should be used for determining these molecular subtypes.
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1648 Pierce Dr NE, Atlanta, GA, 30307, USA.
authors.forename: Benjamin H
authors.initials: BH
authors.lastname: Hinrichs
authors.affiliation: Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, 1365 Clifton Rd, Atlanta, GA, 30322, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Newman
authors.affiliation: Department of Pathology, Northwestern University of Feinberg School of Medicine, 303 East Chicago Avenue Ward 3-140W127, Chicago, IL, 60611, USA.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Appin
authors.affiliation: Department of Biomedical Informatics, Emory University, 36 Eagle Row 5th Floor South, Atlanta, GA, 30322, USA.
authors.forename: William
authors.initials: W
authors.lastname: Dunn
authors.affiliation: Department of Biomedical Informatics, Emory University, 36 Eagle Row 5th Floor South, Atlanta, GA, 30322, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Cooper
authors.affiliation: Greenwood Genetics Center, JC Self Research Institute, 106 Gregor Mendel Circle, Greenwood, SC, 29646, USA.
authors.forename: Rini
authors.initials: R
authors.lastname: Pauly
authors.affiliation: Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, 1365 Clifton Rd, Atlanta, GA, 30322, USA.|Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA, 30322, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1648 Pierce Dr NE, Atlanta, GA, 30307, USA.|Department of Radiation Oncology, Emory University School of Medicine, 1648 Pierce Dr NE, Atlanta, GA, 30307, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, 1648 Pierce Dr NE, Atlanta, GA, 30307, USA. dbrat@emory.edu.|Department of Biomedical Informatics, Emory University, 36 Eagle Row 5th Floor South, Atlanta, GA, 30322, USA. dbrat@emory.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics*; D002869:Chromosome Aberrations; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D015870:Gene Expression; D023281:Genomics / Q000379:methods; D005909:Glioblastoma / Q000150:complications* / Q000235:genetics*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009837:Oligodendroglioma / Q000150:complications* / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human