IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma Journal Article


Authors: Gorovets, D.; Kannan, K.; Shen, R.; Kastenhuber, E. R.; Islamdoust, N.; Campos, C.; Pentsova, E.; Heguy, A.; Jhanwar, S. C.; Mellinghoff, I. K.; Chan, T. A.; Huse, J. T.
Article Title: IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma
Abstract: Purpose: 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. Experimental Design: 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. Conclusion: 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. ©2012 AACR.
Keywords: adolescent; adult; cancer survival; controlled study; human tissue; protein expression; aged; aged, 80 and over; middle aged; survival rate; young adult; gene mutation; human cell; mutation; clinical feature; glioma; brain neoplasms; cancer grading; cell proliferation; gene overexpression; cohort studies; gene amplification; gene expression profiling; tumor markers, biological; genetic transcription; neurons; mutational analysis; wild type; cell lineage; mutator gene; oncogene; tumor suppressor gene; survival time; oligonucleotide array sequence analysis; epigenetics; dna, neoplasm; gene loss; immunophenotyping; nerve cell differentiation; nervous system development; astrocytoma; developmental stage; enzyme modification; astrocytes; isocitrate dehydrogenase; dna copy number variations; spectrometry, mass, matrix-assisted laser desorption-ionization; glia; copy number variation; pten gene; oligodendroglia; isocitrate dehydrogenase 1 gene; isocitrate dehydrogenase 2 gene; epidermal growth factor receptor gene; real-time polymerase chain reaction; neoplasm grading; platelet derived growth factor a gene
Journal Title: Clinical Cancer Research
Volume: 18
Issue: 9
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2012-05-01
Start Page: 2490
End Page: 2501
Language: English
DOI: 10.1158/1078-0432.ccr-11-2977
PROVIDER: scopus
PUBMED: 22415316
DOI/URL:
Notes: --- - "Export Date: 4 June 2012" - "CODEN: CCREF" - "Source: Scopus"
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MSK Authors
  1. Adriana Heguy
    88 Heguy
  2. Timothy Chan
    271 Chan
  3. Ronglai Shen
    147 Shen
  4. Jason T Huse
    132 Huse
  5. Suresh C Jhanwar
    262 Jhanwar
  6. Kasthuri Srinivasan Kannan
    11 Kannan
  7. Carl Campos
    23 Campos