Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

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} (A.L.); rabadan{at} (R.R.); ai2102{at} (A.I.)

Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations.
E. Traer, N. Javidi-Sharifi, A. Agarwal, J. Dunlap, I. English, J. Martinez, J. W. Tyner, M. Wong, and B. J. Druker (2014)
Blood 123, 1516-1524
   Abstract »    Full Text »    PDF »
Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors.
R. Dienstmann, J. Rodon, A. Prat, J. Perez-Garcia, B. Adamo, E. Felip, J. Cortes, A. J. Iafrate, P. Nuciforo, and J. Tabernero (2014)
Ann. Onc. 25, 552-563
   Abstract »    Full Text »    PDF »
New Routes to Targeted Therapy of Intrahepatic Cholangiocarcinomas Revealed by Next-Generation Sequencing.
J. S. Ross, K. Wang, L. Gay, R. Al-Rohil, J. V. Rand, D. M. Jones, H. J. Lee, C. E. Sheehan, G. A. Otto, G. Palmer, et al. (2014)
Oncologist 19, 235-242
   Abstract »    Full Text »    PDF »
Integrative and Comparative Genomic Analysis of Lung Squamous Cell Carcinomas in East Asian Patients.
Y. Kim, P. S. Hammerman, J. Kim, J.-a. Yoon, Y. Lee, J.-M. Sun, M. D. Wilkerson, C. S. Pedamallu, K. Cibulskis, Y. K. Yoo, et al. (2014)
J. Clin. Oncol. 32, 121-128
   Abstract »    Full Text »    PDF »
The Centrosomal Adaptor TACC3 and the Microtubule Polymerase chTOG Interact via Defined C-terminal Subdomains in an Aurora-A Kinase-independent Manner.
H. C. Thakur, M. Singh, L. Nagel-Steger, J. Kremer, D. Prumbaum, E. K. Fansa, H. Ezzahoini, K. Nouri, L. Gremer, A. Abts, et al. (2014)
J. Biol. Chem. 289, 74-88
   Abstract »    Full Text »    PDF »
Fibroblast growth factor receptors, developmental corruption and malignant disease.
F. C. Kelleher, H. O'Sullivan, E. Smyth, R. McDermott, and A. Viterbo (2013)
Carcinogenesis 34, 2198-2205
   Abstract »    Full Text »    PDF »
Parallel RNA Interference Screens Identify EGFR Activation as an Escape Mechanism in FGFR3-Mutant Cancer.
M. T. Herrera-Abreu, A. Pearson, J. Campbell, S. D. Shnyder, M. A. Knowles, A. Ashworth, and N. C. Turner (2013)
Cancer Discovery 3, 1058-1071
   Abstract »    Full Text »    PDF »
Coordination of adjacent domains mediates TACC3-ch-TOG-clathrin assembly and mitotic spindle binding.
F. E. Hood, S. J. Williams, S. G. Burgess, M. W. Richards, D. Roth, A. Straube, M. Pfuhl, R. Bayliss, and S. J. Royle (2013)
J. Cell Biol. 202, 463-478
   Abstract »    Full Text »    PDF »
Conserved Chromosome 2q31 Conformations Are Associated with Transcriptional Regulation of GAD1 GABA Synthesis Enzyme and Altered in Prefrontal Cortex of Subjects with Schizophrenia.
R. Bharadwaj, Y. Jiang, W. Mao, M. Jakovcevski, A. Dincer, W. Krueger, K. Garbett, C. Whittle, J. S. Tushir, J. Liu, et al. (2013)
J. Neurosci. 33, 11839-11851
   Abstract »    Full Text »    PDF »
A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.
S. Zheng, J. Fu, R. Vegesna, Y. Mao, L. E. Heathcock, W. Torres-Garcia, R. Ezhilarasan, S. Wang, A. McKenna, L. Chin, et al. (2013)
Genes & Dev. 27, 1462-1472
   Abstract »    Full Text »    PDF »
FGFR Fusions in the Driver's Seat.
A. J. Sabnis and T. G. Bivona (2013)
Cancer Discovery 3, 607-609
   Abstract »    Full Text »    PDF »
Identification of Targetable FGFR Gene Fusions in Diverse Cancers.
Y.-M. Wu, F. Su, S. Kalyana-Sundaram, N. Khazanov, B. Ateeq, X. Cao, R. J. Lonigro, P. Vats, R. Wang, S.-F. Lin, et al. (2013)
Cancer Discovery 3, 636-647
   Abstract »    Full Text »    PDF »
Identification of cancer fusion drivers using network fusion centrality.
C.-C. Wu, K. Kannan, S. Lin, L. Yen, and A. Milosavljevic (2013)
Bioinformatics 29, 1174-1181
   Abstract »    Full Text »    PDF »
Oncogenic FGFR3 gene fusions in bladder cancer.
S. V. Williams, C. D. Hurst, and M. A. Knowles (2013)
Hum. Mol. Genet. 22, 795-803
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882