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Whole exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma
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// Kasthuri Kannan 1,4 , Akiko Inagaki 2 , Joachim Silber 1,4 , Daniel Gorovets 1,4 , Jianan Zhang 1,4 , Edward R. Kastenhuber 1,4 , Adriana Heguy 4 , John H. Petrini 2 , Timothy A. Chan 3,4 , and Jason T. Huse 1,4 1 Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 2 Department of Molecular Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 3 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA 4 Department of Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Correspondence: Jason T. Huse, email: // Keywords : glioma, astrocytoma, IDH, ATRX, whole-exome sequencing Received : October 01, 2012, Accepted : October 09, 2012, Published : October 11, 2012 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.
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Citations
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The Somatic Genomic Landscape of Glioblastoma
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“These included spectrin alpha 1 (SPTA1, mutated in 9%), which encodes a cell motility protein that interacts with the ABL oncogene and is related to various hereditary red blood cell disorders; ATRX (6%), a member of the SWI/SNF family of chromatin remodelers recently implicated in pediatric and adult high-grade gliom…”
BackgroundSelf-citationMutational landscape and clonal architecture in grade II and III gliomas
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Metadata
- 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.
- Venue
- Oncotarget
- Publisher
- Impact Journals, LLC
- Published
- 2012-10-11
- Volume
- 3
- Issue
- 10
- Pages
- 1194-1203
- ISSN
- 1949-2553 (ISSN-L)
- OpenAlex
- W2142630775
- Cited by
- 278
- References
- 13
- FWCI
- 14.16
- Type
- journal article
- Language
- en
- Open access
- hybrid
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