The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma
Brittany C. Parker, … , Matti Nykter, Wei Zhang
Brittany C. Parker, … , Matti Nykter, Wei Zhang
Published February 1, 2013; First published January 9, 2013
Citation Information: J Clin Invest. 2013;123(2):855-865. https://doi.org/10.1172/JCI67144.
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Category: Research Article

The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma

Abstract

Fusion genes are chromosomal aberrations that are found in many cancers and can be used as prognostic markers and drug targets in clinical practice. Fusions can lead to production of oncogenic fusion proteins or to enhanced expression of oncogenes. Several recent studies have reported that some fusion genes can escape microRNA regulation via 3′–untranslated region (3′-UTR) deletion. We performed whole transcriptome sequencing to identify fusion genes in glioma and discovered FGFR3-TACC3 fusions in 4 of 48 glioblastoma samples from patients both of mixed European and of Asian descent, but not in any of 43 low-grade glioma samples tested. The fusion, caused by tandem duplication on 4p16.3, led to the loss of the 3′-UTR of FGFR3, blocking gene regulation of miR-99a and enhancing expression of the fusion gene. The fusion gene was mutually exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xenograft model, we found that fusion protein expression promoted cell proliferation and tumor progression, while WT FGFR3 protein was not tumorigenic, even under forced overexpression. These results demonstrated that the FGFR3-TACC3 gene fusion is expressed in human cancer and generates an oncogenic protein that promotes tumorigenesis in glioblastoma.

Authors

Brittany C. Parker, Matti J. Annala, David E. Cogdell, Kirsi J. Granberg, Yan Sun, Ping Ji, Xia Li, Joy Gumin, Hong Zheng, Limei Hu, Olli Yli-Harja, Hannu Haapasalo, Tapio Visakorpi, Xiuping Liu, Chang-gong Liu, Raymond Sawaya, Gregory N. Fuller, Kexin Chen, Frederick F. Lang, Matti Nykter, Wei Zhang

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Figure 1

Detection of FGFR3-TACC3 fusion in GBM at the RNA and protein level.

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Detection of FGFR3-TACC3 fusion in GBM at the RNA and protein level. (...
(A) Fusion transcript structures and electropherograms for the 4 fusion-positive samples. GBM-07 and GBM-13 were patients treated at University of Texas MD Anderson Cancer Center (MDACC); GBM-T01 and GBM-T02 were patients treated at Tianjin Medical University Cancer Institute and Hospital (Tianjin). (B) Plot showing mutual exclusivity between FGFR3-TACC3 fusion and high-degree amplification of EGFR, PDGFRA, and MET. **P < 0.01, Fisher exact test. (C) Schematic of protein domains — Ig, transmembrane (TM), and protein kinase (PTKC) — contained within the FGFR3-TACC3 fusion protein. (D) Immunoblot of patient samples and FGFR3-TACC3 fusion– or WT FGFR3–expressing cells. Asterisk denotes stable cell line. (E) FGFR3 immunostaining of patients GBM-T01 and GBM-T02 and a control fusion-negative tumor. Original magnification, ×200.