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The Tumorigenic FGFR3-TACC3 Gene Fusion Escapes Mir-99A Regulation in Glioblastoma

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The Tumorigenic FGFR3-TACC3 Gene Fusion Escapes Mir-99A Regulation in Glioblastoma The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma Brittany C. Parker, … , Matti Nykter, Wei Zhang J Clin Invest. 2013;123(2):855-865. https://doi.org/10.1172/JCI67144. Research Article 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. Find the latest version: https://jci.me/67144/pdf Related Commentary, page 548 Research article The tumorigenic FGFR3-TACC3 gene fusion escapes miR-99a regulation in glioblastoma Brittany C. Parker,1,2 Matti J. Annala,1,3 David E. Cogdell,1 Kirsi J. Granberg,1,3 Yan Sun,1,4 Ping Ji,1 Xia Li,1 Joy Gumin,5 Hong Zheng,6 Limei Hu,1 Olli Yli-Harja,3 Hannu Haapasalo,7 Tapio Visakorpi,8 Xiuping Liu,9 Chang-gong Liu,9 Raymond Sawaya,5 Gregory N. Fuller,1 Kexin Chen,6 Frederick F. Lang,2,5 Matti Nykter,3 and Wei Zhang1,2 1Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 2The University of Texas Graduate School of Biomedical Sciences, Houston, Texas, USA. 3Institute of Signal Processing, Tampere University of Technology, Tampere, Finland. 4Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China. 5Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 6Department of Biostatistics and Epidemiology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People’s Republic of China. 7Department of Neuropathology, Tampere University Hospital, Tampere, Finland. 8Institute of Biomedical Technology, Tampere, Finland. 9Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. 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 mutu- ally exclusive with EGFR, PDGFR, or MET amplification. Using cultured glioblastoma cells and a mouse xeno- graft 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 pro- motes tumorigenesis in glioblastoma. Introduction most common type of brain tumor. Gliomas, solid tumors that Fusion genes are hybrid genes that form when a chromosomal arise from glial cells in the brain or spine, are characterized by rearrangement combines parts of 2 genes. Since their original poor patient survival and high resistance to current treatment identification in blood cancers (1), fusion genes have been identi- regimens. The most common form of glioma in humans is glio- fied in many solid tumors, such as Ewing sarcoma (2), synovial blastoma (GBM), an aggressive grade IV tumor associated with a sarcoma (3), prostate cancer (4, 5), lung cancer (6, 7), breast cancer 14.6-month median survival time for patients treated with surgical (8), and ovarian cancer (9). Gene fusions can lead to the produc- resection, radiotherapy, and adjuvant temozolomide (16). GBMs tion of oncogenic fusion proteins, such as the constitutively active frequently harbor alterations in the receptor tyrosine kinases BCR-ABL1 kinase in chronic myelogenous leukemia (10). Alterna- EGFR, PDGFRA, and MET (17, 18). A recurrent KIAA1549-BRAF tively, fusion genes can lead to enhanced expression of oncogenes fusion has been reported in low-grade astrocytoma (19), and 1 iso- via promoter switching, as observed in the case of TMPRSS2-ERG lated case of LEO1-SLC12A1 fusion has been reported in GBM (20). fusions in prostate cancer (4). Recent evidence suggests that some In this study, we identified recurrent FGFR3-TACC3 fusions in fusion genes can bypass microRNA-mediated regulation via 3′– GBM, a finding that was recently and independently reported by untranslated region (3′-UTR) deletion. For example, protein levels another group (21). We also provided evidence that the FGFR3- of the transcription factor MYB are typically low in adenoid cystic TACC3 fusion gene escaped regulation by miR-99a, leading to carcinoma (ACC) due to high expression of the MYB repressors elevated expression levels. miR-15a and miR-16 (11, 12). However, the 3′-UTR of MYB is lost upon formation of the MYB-NFIB fusion gene, leading to elevated Results levels of the MYB protein (13). To search for recurrent fusion genes, we performed whole-transcrip- Molecular therapies targeted at fusion proteins have been suc- tome RNA sequencing (RNA-seq) on 8 pools of human glioma tis- cessfully used in the treatment of chronic myelogenous leuke- sues and 2 pools of normal brain tissues. We searched for RNA-seq mia (14) and non–small-cell lung cancer (15), but fusion genes reads spanning exon-exon junctions connecting 2 distinct genes still remain poorly characterized in cancers such as glioma, the (Supplemental Figure 1; supplemental material available online with this article; doi:10.1172/JCI67144DS1) and obtained a ranked Authorship note: Brittany C. Parker and Matti J. Annala contributed equally to this list of fusion candidates (Supplemental Figure 2). The top fusion work. candidate, FGFR3-TACC3, was discovered based on 16 reads — 4 of Conflict of interest: The authors have declared that no conflict of interest exists. them unique — spanning FGFR3 exon 18 and TACC3 exon 11 in one Citation for this article: J Clin Invest. 2013;123(2):855–865. doi:10.1172/JCI67144. of the GBM pools (Supplemental Figure 3). We validated the fusion The Journal of Clinical Investigation http://www.jci.org Volume 123 Number 2 February 2013 855 research article by performing RT-PCR on a total of 91 glioma tissue samples from The absence of the 3′–untranslated region (3′-UTR) of FGFR3 mixed European descent and Chinese patients. FGFR3-TACC3 was in the FGFR3-TACC3 fusion transcript suggested that the high detected in 4 of 48 (8.3%) GBM samples, but not in any of the 43 levels of fusion proteins in GBM patient samples could be part- low-grade glioma samples. Capillary sequencing of fusion junctions ly explained by loss of microRNA regulation. TargetScan analy- in the positive patient samples (GBM-13, GBM-07, GBM-T01, and sis (27) suggested that FGFR3, but not TACC3, was regulated by GBM-T02) revealed 3 fusion variants at the RNA level (Figure 1A). miR-99a (Figure 3A), a finding that has been supported experi- All fusion variants were predicted to produce in-frame fusion pro- mentally (28). Interestingly, small RNA sequencing results showed teins. Analysis of RNA sequencing data from The Cancer Genome that miR-99a was among the 4 most highly expressed microRNAs Atlas (TCGA) GBM project revealed 2 more positive cases (Supple- in both GBM and normal brain (Figure 3B), and in vitro studies mental Figure 4). Copy number analysis across a cohort of 454 sam- showed it was the only highly expressed microRNA to target FGFR3 ples suggested mutual exclusivity between FGFR3-TACC3 fusions (Supplemental Figure 11). This finding was consistent with the low and high-degree amplification of the receptor tyrosine kinases FGFR3 protein levels observed in samples of GBM compared with EGFR, PDGFRA, and MET (P = 0.004, Fisher exact test; Figure 1B). bladder cancer (Supplemental Figure 12), in which FGFR3 is often FGF receptor 3 (FGFR3) encodes a receptor tyrosine kinase that is overexpressed and miR-99a is downregulated (29). Fusion-positive commonly mutated in bladder and cervical cancers (22). Transform- and -negative patient samples did not show a significant difference ing acidic coiled-coil containing protein 3 (TACC3) encodes a centro- in miR-99a expression (Supplemental Figure 13). To validate the somal protein that is involved in mitosis (23) and is overexpressed regulatory function of miR-99a in GBM, we performed a reporter in lung and colon carcinomas and in multiple myeloma (24). The gene assay in SNB19 cells using a plasmid expressing either the WT predicted fusion protein variants contained the extracellular Ig-like FGFR3 3′-UTR or a mutant with the majority of the miR-99a bind- domains, transmembrane domain, and most of the tyrosine kinase ing site deleted.
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