title: IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma.
abstract: OBJECTIVE
  Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas.
  
  
  METHODS
  We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts.
  
  
  RESULTS
  We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet-derived growth factor receptor (PDGFR)A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors.
  
  
  CONCLUSIONS
  We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gorovets
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Nasrin
authors.initials: N
authors.lastname: Islamdoust
authors.forename: Carl
authors.initials: C
authors.lastname: Campos
authors.forename: Elena
authors.initials: E
authors.lastname: Pentsova
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019070:Cell Lineage; D049109:Cell Proliferation; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000145:classification* / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D015996:Survival Rate; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human