title: 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.affiliation: Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Brittany C
authors.initials: BC
authors.lastname: Parker
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Annala
authors.forename: David E
authors.initials: DE
authors.lastname: Cogdell
authors.forename: Kirsi J
authors.initials: KJ
authors.lastname: Granberg
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Ping
authors.initials: P
authors.lastname: Ji
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: Joy
authors.initials: J
authors.lastname: Gumin
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Limei
authors.initials: L
authors.lastname: Hu
authors.forename: Olli
authors.initials: O
authors.lastname: Yli-Harja
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.forename: Tapio
authors.initials: T
authors.lastname: Visakorpi
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Chang-Gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Raymond
authors.initials: R
authors.lastname: Sawaya
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Kexin
authors.initials: K
authors.lastname: Chen
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics* / Q000378:metabolism; D020080:Tandem Repeat Sequences; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D020413:3' Untranslated Regions; C561679:MIRN99 microRNA, human; D035683:MicroRNAs; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D012334:RNA, Neoplasm; C120551:TACC3 protein, human; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3