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Science 337 (6099): 1231-1235

Copyright © 2012 by the American Association for the Advancement of Science

Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

Devendra Singh,1,* Joseph Minhow Chan,2,* Pietro Zoppoli,1,* Francesco Niola,1,*,{dagger} Ryan Sullivan,1 Angelica Castano,1 Eric Minwei Liu,2 Jonathan Reichel,2,3 Paola Porrati,4 Serena Pellegatta,4 Kunlong Qiu,5 Zhibo Gao,5 Michele Ceccarelli,6 Riccardo Riccardi,7 Daniel J. Brat,8 Abhijit Guha,9 Ken Aldape,10 John G. Golfinos,11 David Zagzag,11,12 Tom Mikkelsen,13 Gaetano Finocchiaro,4 Anna Lasorella,1,14,15,{ddagger} Raul Rabadan,2,{ddagger} Antonio Iavarone1,15,16,{ddagger}

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.

1 Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, USA.
2 Department of Biomedical Informatics and Center for Computational Biology and Bioinformatics, Columbia University Medical Center, New York, NY, USA.
3 Tri-Institutional Program in Computational Biology and Medicine, Cornell University and Weill Cornell Medical College, New York, NY, USA.
4 Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta, Milan, Italy.
5 Bioinformatics Center, Beijing Genome Institute, Shenzhen, China.
6 Istituto di Ricerche Genetiche Gaetano Salvatore, Biogem, Ariano Irpino (AV) and Dipartimento di Scienze Biologiche ed Ambientali, Università del Sannio, Benevento, Italy.
7 Department of Pediatric Oncology, Catholic University, Rome, Italy.
8 Departments of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
9 Division of Neurosurgery, Toronto Western Hospital, University Health Network, University of Toronto, Canada.
10 Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA.
11 Department of Neurosurgery, New York University Langone Medical Center, New York, NY, USA.
12 Department of Neuropathology, New York University Langone Medical Center, New York, NY, USA.
13 Departments of Neurology and Neurosurgery, Henry Ford Health System, Detroit, MI, USA.
14 Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
15 Department of Pathology, Columbia University Medical Center, New York, NY, USA.
16 Department of Neurology, Columbia University Medical Center, New York, NY, USA.

* These authors contributed equally to this work.

{dagger} Present address: Neuroscience and Brain Technologies, Italian Institute of Technology, Genoa, Italy.

{ddagger} To whom correspondence should be addressed. E-mail: al2179{at}columbia.edu (A.L.); rabadan{at}dbmi.columbia.edu (R.R.); ai2102{at}columbia.edu (A.I.)


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