Additionally, RNF43, a gene that negatively regulates Wnt signaling, is often mutated in MSI-H ECs, further enhancing tumor growth; the prevalence of truncating mutations at this locus, combined with the rarity of synonymous mutations, strongly indicates that RNF43 mutations have been positively selected during the evolution of EC and CRC (Figure 4) (111). Here, RNF43 is linked to colorectal carcinoma.