Gene fusions involving R-spondins occur in 10% of colon cancers.

  • Major finding: Gene fusions involving R-spondins occur in 10% of colon cancers.

  • Concept: R-spondin fusions are mutually exclusive with APC and β-catenin mutations and potentiate WNT signaling.

  • Impact: Patients with R-spondin fusions may respond to antibody-based therapy or WNT pathway inhibitors.

Integrated genomic analyses are identifying an increasing number of recurrent genetic alterations in tumors that provide information on the underlying biology of disease and represent potential therapeutic targets for selected subsets of patients. In an effort to gain insight into the molecular etiology of colon cancer, Seshagiri and colleagues performed whole-exome and transcriptome sequencing and generated single-nucleotide polymorphism arrays for over 70 patient-matched colon tumor–normal tissue pairs. Among the recurrent abnormalities identified were in-frame gene fusions leading to the overexpression of the R-spondin family members, RSPO2 and RSPO3, in 10% of tumors. Notably, EIF3E–RSPO2 and PTPRK–RSPO3 gene fusions did not occur in tumors with β-catenin mutations or mutations or copy loss of APC (with the exception of one tumor that had lost a single APC allele). Because R-spondins are secreted WNT pathway agonists, these observations suggest that RSPO gene fusions may be functionally equivalent to inactivating APC or activating β-catenin mutations in colon cancer. Consistent with this possibility, RSPO fusion-positive tumors showed upregulation of WNT pathway genes, and conditioned media from cells transfected with RSPO fusion genes led to activation of a WNT-responsive luciferase reporter and further potentiated reporter activation in the presence of recombinant WNT ligand. Although further studies are needed to establish whether RSPO gene fusions are driving events in colon cancer, R-spondins may be attractive targets for antibody-based therapies that block binding of these secreted proteins to their receptors.

Seshagiri S, Stawiski EW, Durinck S, Modrusan Z, Storm EE, Conboy CB, et al. Recurrent R-spondin fusions in colon cancer. Nature 2012 Aug 15 [Epub ahead of print].