Transforming Fusions of FGFR and TACC Genes in Human Glioblastoma

By D. Singh, Joseph Chan, P. Zoppoli, F. Niola, Ryan Sullivan, Angelica M. Castano, E. Liu, J. Reichel, Paola Porrati, S. Pellegatta and 14 more. Science, 2012

756 citations recorded by the source corpus.

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. A fusion gene detected in a small subset of human brain tumors encodes a potentially druggable target. 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.

Subfields: Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/268b606e55769cdda8dfee772439a9bc5b926c26

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Citations in the corpus

Genetics of adult glioma. (2012, background): “Individuals with glioblastomas with FGFR-TACC may benefit from targeted FGFR kinase inhibition (40).”
Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas (2015, neutral): “Grade II 65 (23) 38 (45) 21 (15) 6 (11)”
Comprehensive genomic characterization of head and neck squamous cell carcinomas (2015, background): “Interestingly, NSD1 functions as an oncogene when fused to nucleoporin-98 (NUP98) t(5;11)(q35;p15.”
The integrated landscape of driver genomic alterations in glioblastoma (2013, result): “Nine GSC samples reported in previous studies were kept in our analysis to evaluate recurrence 9 .”
Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma (2014, neutral): “FGFR3–TACC3 fusion, which was recently described in both glioblastoma 21 and blad-dercancer ,representsapromisingtherapeutictarget.”
The Somatic Genomic Landscape of Glioblastoma (2013, background): “, 2011a), and FGFR1/FGFR2/FGFR3 (Singh et al., 2012), demonstrating the potential clinical impact of this TCGA data set.”
Identification of Targetable FGFR Gene Fusions in Diverse Cancers (2013, neutral): “In the Singh et al GBM study, the mechanism of activation of the FGFR fusions is proposed to be through mis-localization to mitotic spindle poles mediated by the coiled-coil domain of TACC fusion partner (15).”
The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge (2015, background): “confirmed that the survival advantage of the Proneural subgroup is associated with the G-CIMP phenotype, and the methylation status of MGMT promoter may serve as a predictive biomarker for treatment outcome only in the Classical subtype of GBM [47].”
Emergence of FGFR family gene fusions as therapeutic targets in a wide spectrum of solid tumours (2014, background): “One report suggests that the fusion is oncogenic by means of promoting chromosome instability [13].”
The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing (2015, background): “In the case of FGFR3–TACC3, the entire FGFR3 kinase domain is fused with the TACC3 domain that mediates microtubule binding (31, 39).”
Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma (2013, neutral): “Occasional FGFR1 mutations have been observed in adult glioblastoma (GBM) 31,32 , a highly malignant astrocytoma, as have FGFR1 - TACC1 or FGFR3 - TACC3 fusion genes 33 .”