title: Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.
abstract: Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.
authors.affiliation: Ludwig Center for Cancer Genetics and Howard Hughes Medical Institutions, The Johns Hopkins Kimmel Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Jiao
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Killela
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Reitman
authors.forename: Ahmed B
authors.initials: AB
authors.lastname: Rasheed
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Heaphy
authors.forename: Roeland F
authors.initials: RF
authors.lastname: de Wilde
authors.forename: Fausto J
authors.initials: FJ
authors.lastname: Rodriguez
authors.forename: Sergio
authors.initials: S
authors.lastname: Rosemberg
authors.forename: Sueli Mieko
authors.initials: SM
authors.lastname: Oba-Shinjo
authors.forename: Suely Kazue
authors.initials: SK
authors.lastname: Nagahashi Marie
authors.forename: Chetan
authors.initials: C
authors.lastname: Bettegowda
authors.forename: Nishant
authors.initials: N
authors.lastname: Agrawal
authors.forename: Eric
authors.initials: E
authors.lastname: Lipp
authors.forename: Christopher
authors.initials: C
authors.lastname: Pirozzi
authors.forename: Giselle
authors.initials: G
authors.lastname: Lopez
authors.forename: Yiping
authors.initials: Y
authors.lastname: He
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Matthias
authors.initials: M
authors.lastname: Holdhoff
authors.forename: Peter
authors.initials: P
authors.lastname: Burger
authors.forename: Roger
authors.initials: R
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
mesh_terms: D000328:Adult; D001932:Brain Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020868:Gene Silencing; D005910:Glioma / Q000145:classification* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D009154:Mutation; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics*; D016615:Telomere / Q000235:genetics; D000075924:X-linked Nuclear Protein
chemical_list: C498610:CIC protein, human; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein