Oncotarget

Research Papers:

The genetic landscape of anaplastic astrocytoma

Patrick J. Killela, Christopher J. Pirozzi, Zachary J. Reitman, Sian Jones, B. Ahmed Rasheed, Eric Lipp, Henry Friedman, Allan H. Friedman, Yiping He, Roger E. McLendon, Darell D. Bigner and Hai Yan _

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Oncotarget. 2014; 5:1452-1457. https://doi.org/10.18632/oncotarget.1505

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Abstract

Patrick J. Killela1,*, Christopher J. Pirozzi1,*, Zachary J. Reitman1,*, Sian Jones2, B. Ahmed Rasheed1, Eric Lipp1, Henry Friedman1, Allan H. Friedman1, Yiping He1, Roger E. McLendon1, Darell D. Bigner1, Hai Yan1

1 Department of Pathology, Duke University Medical Center, The Preston Robert Tisch Brain Tumor Center at Duke, and Pediatric Brain Tumor Foundation Institute at Duke, Durham, NC

2 Personal Genome Diagnostics, Inc. 2809 Boston St, Suite 503, Baltimore, MD

* Denotes equal contribution

Correspondence:

Hai Yan, email:

Keywords: Exome sequencing, Anaplastic Astrocytoma, IDH1, Notch

Received: October 14, 2013 Accepted: October 15, 2013 Published: October 16, 2013

Abstract

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.


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