R-spondin fusion

The finding. Sequencing the exomes, transcriptomes and copy number of more than 70 pairs of primary human colon tumours identified recurrent fusion transcripts involving the R-spondin family members RSPO2 and RSPO3, together present in 10 percent of the colon tumours studied. The fusions were mutually exclusive with APC mutations, and the fusion proteins potentiated Wnt signalling in functional assays, which is the evidence that they are an alternative route to the same pathway activation rather than a passenger event (Seshagiri 2012). The same study reported recurrent mutations in TCF7L2, in the chromatin remodellers TET2 and TET3, in ERBB3 and in ATM, and amplification with overexpression of IGF2 in a subset.

Why anyone cares. APC loss is the near-universal first event of the conventional adenoma-carcinoma sequence, and it acts inside the cell, below the level any drug has managed to reach. An R-spondin fusion acts above it, on the receptor, which in principle can be blocked from outside: porcupine and anti-RSPO3 inhibitors are the classes that have been tried. Tumours driven this way may also remain dependent on Wnt ligand, which tumours with APC loss do not.

Where it stands. No approved drug targets it, and the fusions are rare enough that trials have had to screen widely to find carriers. They matter to a reader mainly as evidence that the Wnt pathway is entered by more than one door, and as one of the alterations a comprehensive sequencing panel may report on a bowel cancer.