title: The integrated landscape of driver genomic alterations in glioblastoma.
abstract: Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.
authors.affiliation: 1] Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA. [2].
authors.forename: Veronique
authors.initials: V
authors.lastname: Frattini
authors.forename: Vladimir
authors.initials: V
authors.lastname: Trifonov
authors.forename: Joseph Minhow
authors.initials: JM
authors.lastname: Chan
authors.forename: Angelica
authors.initials: A
authors.lastname: Castano
authors.forename: Marie
authors.initials: M
authors.lastname: Lia
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.forename: Alan X
authors.initials: AX
authors.lastname: Ji
authors.forename: Pietro
authors.initials: P
authors.lastname: Zoppoli
authors.forename: Francesco
authors.initials: F
authors.lastname: Niola
authors.forename: Carla
authors.initials: C
authors.lastname: Danussi
authors.forename: Igor
authors.initials: I
authors.lastname: Dolgalev
authors.forename: Paola
authors.initials: P
authors.lastname: Porrati
authors.forename: Serena
authors.initials: S
authors.lastname: Pellegatta
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Gaurav
authors.initials: G
authors.lastname: Gupta
authors.forename: David J
authors.initials: DJ
authors.lastname: Pisapia
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Ken
authors.initials: K
authors.lastname: Aldape
authors.forename: Gaetano
authors.initials: G
authors.lastname: Finocchiaro
authors.forename: Tom
authors.initials: T
authors.lastname: Mikkelsen
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Privé
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Anna
authors.initials: A
authors.lastname: Lasorella
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.forename: Antonio
authors.initials: A
authors.lastname: Iavarone
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D051177:Catenins / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D005909:Glioblastoma / Q000235:genetics*; D006801:Humans; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics; D000095002:Delta Catenin
chemical_list: D051177:Catenins; C509917:LZTR1 protein, human; D014157:Transcription Factors; D066246:ErbB Receptors; D000095002:Delta Catenin; C000722348:CTNND2 protein, human
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