Transforming fusions of FGFR and TACC genes in human glioblastoma

Devendra Singh, Joseph Minhow Chan, Pietro Zoppoli, Francesco Niola, Ryan Sullivan, Angelica Castano, Eric Minwei Liu, Jonathan Reichel, Paola Porrati, Serena Pellegatta, Kunlong Qiu, Zhibo Gao, Michele Ceccarelli, Riccardo Riccardi, Daniel J. Brat, Abhijit Guha, Ken Aldape, John G. Golfinos, David Zagzag, Tom MikkelsenGaetano Finocchiaro, Anna Lasorella, Raul Rabadan, Antonio Iavarone

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1231-1235
Number of pages5
JournalScience
Volume337
Issue number6099
DOIs
Publication statusPublished - Sep 7 2012

    Fingerprint

ASJC Scopus subject areas

  • General

Cite this

Singh, D., Chan, J. M., Zoppoli, P., Niola, F., Sullivan, R., Castano, A., Liu, E. M., Reichel, J., Porrati, P., Pellegatta, S., Qiu, K., Gao, Z., Ceccarelli, M., Riccardi, R., Brat, D. J., Guha, A., Aldape, K., Golfinos, J. G., Zagzag, D., ... Iavarone, A. (2012). Transforming fusions of FGFR and TACC genes in human glioblastoma. Science, 337(6099), 1231-1235. https://doi.org/10.1126/science.1220834