RSPO translocations and fusions, which occur in 4–18% of gastric, ovarian, and endometrial cancers and in about 9% of CRC cases, are mutually exclusive with APC mutations.294 Unlike APC mutations, which are early events in tumorigenesis, RNF43 mutations are considered late-stage events that drive the progression of adenomas to carcinomas, often associated with lower levels of Wnt pathway activation.131 In the context of adult stem cell niches, the negative feedback from RNF43 and ZNRF3 is partially counterbalanced by RSPO family proteins. This evidence concerns the gene APC and colorectal carcinoma.