Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

Author:

Singh Devendra1,Chan Joseph Minhow2,Zoppoli Pietro1,Niola Francesco1,Sullivan Ryan1,Castano Angelica1,Liu Eric Minwei2,Reichel Jonathan23,Porrati Paola4,Pellegatta Serena4,Qiu Kunlong5,Gao Zhibo5,Ceccarelli Michele6,Riccardi Riccardo7,Brat Daniel J.8,Guha Abhijit9,Aldape Ken10,Golfinos John G.11,Zagzag David1112,Mikkelsen Tom13,Finocchiaro Gaetano4,Lasorella Anna11415,Rabadan Raul2,Iavarone Antonio11516

Affiliation:

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.

Abstract

Oncogenic TACC-tics Human cancers exhibit many types of genomic rearrangements—including some that juxtapose sequences from two unrelated genes—thereby creating fusion proteins with oncogenic activity. Functional analysis of these fusion genes can provide mechanistic insights into tumorigenesis and potentially lead to effective drugs, as famously illustrated by the BCR-ABL gene in chronic myelogenous leukemia. Singh et al. (p. 1231 , published online 26 July) identify and characterize a fusion gene present in 3% of human glioblastomas, a deadly brain cancer. In the resultant fusion protein, the tyrosine kinase region of the fibroblast growth factor receptor (FGFR) is joined to a domain from a transforming acidic coiled-coil (TACC) protein. The TACC-FGFR protein is oncogenic, shows unregulated kinase activity, localizes to the mitotic spindle, and disrupts chromosome segregation. In mice, FGFR inhibitors slowed the growth of tumors driven by the TACC-FGFR gene, suggesting that a subset of glioblastoma patients may benefit from these types of drugs.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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