RNF43 is suggested to be involved in the serrated pathway towards colorectal cancer and encodes a transmembrane Ring-type E3 ubiquitin ligase that negatively regulates the Wnt pathway. This study aims to elucidate the role of RNF43 gene variants in serrated polyposis syndrome (SPS) and serrated polyps.
Three cohorts were tested. The first cohort included germline DNA of 26 SPS patients tested for pathogenic variants in RNF43 by Sanger sequencing all exons. In the second cohort we tested somatic DNA from sporadic serrated lesions: 25 hyperplastic polyps, 35 sessile serrated lesions and 38 traditional serrated adenomas (TSA) for RNF43 mutations. In the third cohort we investigated RNF43 mutations in 49 serrated polyps and 60 conventional adenomas from 40 patients with Lynch syndrome.
No germline RNF43 pathogenic variants were detected in our SPS cohort. In sporadic colorectal lesions we detected RNF43 deleterious frameshift mutations in 3 TSA and one SSL. The RNF43 mutations in previously described homopolymeric hotspots were detected in microsatellite instable (MSI) polyps, the other RNF43 mutations in microsatellite stable (MSS) serrated polyps. In 7 serrated polyps and 12 conventional adenomas from Lynch patients RNF43 hotspot mutations were discovered.
Truncating germline RNF43 mutations are uncommon in SPS patients. Somatic mutations in RNF43 were found in sporadic TSA and SSL and both serrated polyps and adenomas from Lynch syndrome patients suggesting that they do not develop early in the pathway to CRC and are not specific for serrated polyp subtypes.

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