In [1] it is written that:

Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions

What is a recurrent in-frame activating fusion?

[1] Cancer Genome Atlas Research Network, “Comprehensive molecular characterization of urothelial bladder carcinoma.,” Nature, vol. 507, no. 7492, pp. 315–322, Mar. 2014.


1 Answer 1


This is explained in the linked article.

We found several recurrent translocations of likely pathogenic significance, including an intra-chromosomal translocation on chromosome 4 involving FGFR3 and TACC3 (n=3). The breakpoints were in intron 16 (2 cases) or exon 17 (1 case) of FGFR3 and intron 10 of TACC3 (confirmed by DNA sequencing and RNA-seq). All three lead to fusion mRNA products whose predicted proteins include the N-terminal 758 amino acids of FGFR3 fused with the C-terminal 191 amino acids of TACC3 (Fig. 2a). Based on the structure of the FGFR3-TACC3 fusion protein, we predict that it can auto-dimerize, leading to constitutive activation of the kinase domain of FGFR3. FGFR3-TACC3 fusion, which was recently described in both glioblastoma21 and bladder cancer7,8, represents a promising therapeutic target.

FGFR3 is a member of the fibroblast growth factor receptor family. It is a transmembrane kinase that is normally activated upon ligand binding which triggers dimerisation. TACC3 is a protein that can dimerise through a coiled-coil domain.

The FGFR3-TACC3 gene fusion that is generated by the reported intra-chromosomal translocations thus generates a version of the receptor that is predicted to be constitutively active because it can dimerise in the absence of the growth factor.

Recurrent means occurring frequently.

  • $\begingroup$ Just one little comment: in-frame means inside introns or exons, but not within inter-genic regions? $\endgroup$
    – gc5
    Commented Jul 27, 2017 at 11:55
  • 1
    $\begingroup$ in-frame means anything that generates an open reading frame in the mRNA so that a fusion protein will be produced. Te endpoint in TACC3 was always in an intron, and in two cases the FGFR3 endpoint was also in an intron. This will generate a gene fusion with a hybrid intron. In the other case they say that the FGFR3 endpoint was in the next exon. Since all three fusion proteins have the same structure that means that the exon interrupted by the translocation must have become part of a hybrid intron. If you draw yourself a diagram it will become clear. But yes, not in intergenic regions. $\endgroup$
    – Alan Boyd
    Commented Jul 27, 2017 at 12:52

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