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, and found a high incidence of mutations in the ATRX gene (α 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 determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.forename: Joachim
authors.initials: J
authors.lastname: Silber
authors.forename: Daniel
authors.initials: D
authors.lastname: Gorovets
authors.forename: Jianan
authors.initials: J
authors.lastname: Zhang
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: John H
authors.initials: JH
authors.lastname: Petrini
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000075924:X-linked Nuclear Protein
chemical_list: D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein