title: The genetic landscape of anaplastic astrocytoma.
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.
authors.affiliation: 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.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Killela
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Pirozzi
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Sian
authors.initials: S
authors.lastname: Jones
authors.forename: B Ahmed
authors.initials: BA
authors.lastname: Rasheed
authors.forename: Eric
authors.initials: E
authors.lastname: Lipp
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D001254:Astrocytoma / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor