title: Transforming fusions of FGFR and TACC genes in human glioblastoma.
abstract: The brain tumor glioblastoma multiforme (GBM) is among the most lethal forms of human cancer. Here, we report that a small subset of GBMs (3.1%; 3 of 97 tumors examined) harbors oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. The FGFR-TACC fusion protein displays oncogenic activity when introduced into astrocytes or stereotactically transduced in the mouse brain. The fusion protein, which localizes to mitotic spindle poles, has constitutive kinase activity and induces mitotic and chromosomal segregation defects and triggers aneuploidy. Inhibition of FGFR kinase corrects the aneuploidy, and oral administration of an FGFR inhibitor prolongs survival of mice harboring intracranial FGFR3-TACC3-initiated glioma. FGFR-TACC fusions could potentially identify a subset of GBM patients who would benefit from targeted FGFR kinase inhibition.
authors: Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
authors: Devendra
authors: D
authors: Singh
authors: Joseph Minhow
authors: JM
authors: Chan
authors: Pietro
authors: P
authors: Zoppoli
authors: Francesco
authors: F
authors: Niola
authors: Ryan
authors: R
authors: Sullivan
authors: Angelica
authors: A
authors: Castano
authors: Eric Minwei
authors: EM
authors: Liu
authors: Jonathan
authors: J
authors: Reichel
authors: Paola
authors: P
authors: Porrati
authors: Serena
authors: S
authors: Pellegatta
authors: Kunlong
authors: K
authors: Qiu
authors: Zhibo
authors: Z
authors: Gao
authors: Michele
authors: M
authors: Ceccarelli
authors: Riccardo
authors: R
authors: Riccardi
authors: Daniel J
authors: DJ
authors: Brat
authors: Abhijit
authors: A
authors: Guha
authors: Ken
authors: K
authors: Aldape
authors: John G
authors: JG
authors: Golfinos
authors: David
authors: D
authors: Zagzag
authors: Tom
authors: T
authors: Mikkelsen
authors: Gaetano
authors: G
authors: Finocchiaro
authors: Anna
authors: A
authors: Lasorella
authors: Raul
authors: R
authors: Rabadan
authors: Antonio
authors: A
authors: Iavarone
mesh_terms: D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D043171:Chromosomal Instability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005326:Fetal Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008938:Mitosis; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism; D014178:Translocation, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D005326:Fetal Proteins; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; C115711:PD 173074; D010879:Piperazines; D011720:Pyrazoles; D011743:Pyrimidines; C120584:TACC1 protein, human; C120551:TACC3 protein, human; C496348:FGFR1 protein, human; C496365:FGFR3 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051498:Receptor, Fibroblast Growth Factor, Type 3