Ligand-dependent mutations in R-spondin and RNF43 result in disruptions of the RSPO axis.44 RNF43 mutations are frequently truncated frameshift mutations with tandem repeats of microsatellites.45 Thus, these mutations often occur in sporadic MSI colorectal tumours, with MLH1 mismatch repair gene being the most frequently associated mutation, of right colonic distribution, and CMS1 tumour molecular subtype.46–48 Fifty percent of sessile serrated lesions are thought to have RNF43 mutations. The gene discussed is MLH1; the disease is neoplasm.