Two recent studies identify new gene fusions in solid tumors in humans and provide clues into their role in tumorigenesis (Nature 488, 660–664; Science 337, 1231–1235).

Somasekar Seshagiri et al. identified recurrent gene fusions involving R-spondin family members (RSPO2 and RSPO3) in 10% of colon tumors. They characterized EIF3E–RSPO2 and PTPRK–RSPO3 gene fusions and found that colon tumor samples bearing R-spondin fusions showed increased expression of RSPO2 and RSPO3 compared with colon tumors lacking fusions. R-spondins potentiate canonical Wnt signaling, and consistent with this, the authors found that RSPO fusion constructs led to Wnt pathway activation in a human colon cancer cell line and that tumor samples with RSPO fusions showed upregulation of Wnt signaling. RSPO fusions were mutually exclusive with mutations in the Wnt pathway genes APC or CTNNB1 in colon cancers, suggesting that in the absence of these mutations the RSPO fusions may have a role in activating Wnt signaling and tumorigenesis.

In another study, Devendra Singh et al. identified a small set of glioblastoma multiforme (3.1%) with recurrent, oncogenic gene fusions involving the tyrosine kinase–encoding domain of a fibroblast growth factor gene (FGFR1 or FGFR3) joined to a transforming acidic coiled-coil gene (TACC1 or TACC3, respectively). The fusion proteins have constitutive kinase activity and lead to mitotic delay and aneuploidy. Lentiviruses expressing one of the FGFR–TACC fusion proteins could transform cultured fibroblasts or astrocytes, and injection of FGFR–TACC transduced astrocytes into immunodeficient mice led to the formation of invasive, glioma-like tumors. Treatment of mice bearing FGFR3–TACC3 glioma xenografts with an FGFR inhibitor inhibited tumor growth and prolonged survival compared with untreated mice. Thus, FGFR inhibitors may have potential clinical application in patients with GBM bearing FGFR–TACC fusions.