Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

• Type of Material: Article
• Authors: Devendra Singh, Columbia University; Joseph Minhow Chan, Columbia University; Pietro Zoppoli, Columbia University; Francesco Niola, Columbia University; Ryan Sullivan, Columbia University; Angelica Castano, Columbia University; Eric Minwei Liu, Columbia University; Jonathan Reichel, Columbia University; Paola Porrati, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta; Serena Pellegatta, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta; Kunlong Qiu, Beijing Genome Institute; Zhibo Gao, Beijing Genome Institute; Michele Ceccarelli, Istituto di Ricerche Genetiche Gaetano Salvatore; Riccardo Riccardi, Catholic University; Daniel J Brat, Emory University; Abhijit Guha, University of Toronto; Ken Aldape, MD Anderson Cancer Center; John G. Golfinos, New York University; David Zagzag, New York University; Tom Mikkelsen, Henry Ford Health System; Gaetano Finocchiaro, Fondazione Istituto Ricovero e Cura a Carattere Scientifico Istituto Neurologico C. Besta; Anna Lasorella, Columbia University; Raul Rabadan, Columbia University; Antonio Iavarone, Columbia University
• Language: English
• Date: 2012-09-07
• Publisher: Volgogradskii Gosudarstvennyi Universitet (Volgograd State University)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Association for the Advancement of Science.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.1220834
• Title of Journal or Parent Work: Вестник Волгоградского государственног... / Science Journal of Volgograd State University. History. Area Studies. International Relations
• ISSN: 1998-9938
• Volume: 337
• Issue: 6099
• Start Page: 1231
• End Page: 1235
• Grant/Funding Information: This work was supported by National Cancer Institute grants R01CA101644 and R01CA131126 (A.L.), R01CA085628 and R01CA127643 (A.I.), U54 CA121852-05 (R.R.), National Library of Medicine grant 1R01LM010140-01 (R.R.), National Institute of Neurological Disorders and Stroke grant R01NS061776 (A.I.), a grant from Partnership for Cure (R.R., 7-78947), and a grant from The Chemotherapy Foundation (A.I.). P.Z. and F.N. are supported by fellowships from the Italian Ministry of Welfare/Provincia di Benevento. G.F. was supported by grants from the Associazione Italiana per la Ricerca sul Cancro and from the Italian Ministry of Health.
• Keywords: DISCOVERY; SELECTIVE INHIBITOR; ANEUPLOIDY; CHROMOSOMAL INSTABILITY; POTENT; RECEPTOR TYROSINE KINASE; Science & Technology - Other Topics; Science & Technology; FAMILY; CANCER; Multidisciplinary Sciences
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology; Health Sciences, Pathology

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.