Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma Journal Article


Authors: Kannan, K.; Inagaki, A.; Silber, J.; Gorovets, D.; Zhang, J.; Kastenhuber, E. R.; Heguy, A.; Petrini, J. H.; Chan, T. A.; Huse, J. T.
Article Title: Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma
Abstract: The molecular foundations of lower-grade gliomas (LGGs)-astrocytoma, oligodendroglioma, and oligoastrocytoma-remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, andfound a high incidence of mutations in the ATRX gene (a thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomere biology. Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability. In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma. Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone. Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability. In summary, our findings both identify ATRX mutation as a defining molecular determinantfor a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs. © Kannan et al.
Keywords: adult; clinical article; human tissue; aged; gene sequence; somatic mutation; glioma; cancer grading; telomere; astrocyte; genetic association; subventricular zone; mutational analysis; gene expression regulation; tumor suppressor gene; transcription regulation; messenger rna; genomic instability; nucleotide sequence; tumor protein; oligodendroglioma; chromosome deletion; tumor gene; nerve cell differentiation; astrocytoma; chromatin assembly and disassembly; chromosome 1p; molecular pathology; idh; chromosome 19q; atrx; exome; high throughput sequencing; whole-exome sequencing; alpha thalassemia mental retardation syndrome x linked gene
Journal Title: Oncotarget
Volume: 3
Issue: 10
ISSN: 1949-2553
Publisher: Impact Journals  
Date Published: 2012-10-01
Start Page: 1194
End Page: 1204
Language: English
PROVIDER: scopus
PUBMED: 23104868
PMCID: PMC3717947
DOI/URL:
Notes: --- - "Export Date: 1 March 2013" - "Molecular Sequence Numbers: GENBANK: NM_000401, NM_000489, NM_000546, NM_000651, NM_000814, NM_002546, NM_004667, NM_005896, NM_012367, NM_018406, NM_020722, NM_032583, NM_033395" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Adriana Heguy
    88 Heguy
  2. Timothy Chan
    317 Chan
  3. John Petrini
    94 Petrini
  4. Jason T Huse
    143 Huse
  5. Joachim Silber
    31 Silber
  6. Kasthuri Srinivasan Kannan
    11 Kannan
  7. Jianan Zhang
    7 Zhang