Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis

Palles, Claire, Freeman-Mills, Luke, Arbe-Barnes, Edward, Feeley, Nathalie, Chegwidden, Laura, Curley, Helen, Galavotti, Sara, Woolley, Connor, Cheadle, Jeremy ORCID: https://orcid.org/0000-0001-9453-8458, Mouradov, Dmitri, Sieber, Oliver, Salatino, Silvia, Thorn, Steve, Goel, Anshita, Fernandez-Tajes, Juan, Omwenga, Sulochana, Biswas, Sujata, Maughan, Timothy, Leedham, Simon J, S:CORT Consortium, UK Colorectal Cancer Genomics Consortium, CORGI Consortium, WGS500 Consortium, Koelzer, Viktor Hendrik, Wang, Lai Mun, Arnold, Roland, East, James Edward and Tomlinson, Ian 2025. Comparison between germline and somatic loss-of-function RNF43 mutations reveals different genotype-phenotype associations and provides insights into the genetic mechanisms of colorectal tumourigenesis. Gut 10.1136/gutjnl-2025-337030

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Abstract

Background: Germline RNF43 mutations cause a dominantly inherited syndrome of colorectal cancer (CRC) and serrated polyps. However, these data originate from highly selected families. Objective: We assessed germline RNF43 variants in patients more representative of the general population and compared these with somatic RNF43mutations in CRCs. Design: We studied 49 823 CRC and/or polyp cases from the CORGI study, 100 000 Genomes (100kGP) and UK Biobank (UKB), alongside 165 250 controls. Somatic mutations were analysed in 2722 CRCs. Results: Consistent with the literature, a germline loss-of-function RNF43 variant (p.Thr158ProfsTer6) was found in a multigenerational CORGI family with early-onset CRC and serrated and/or filiform polyps. However, while 23 CRC/polyp cases and 47 controls from 100kGP or UKB had germline RNF43 mutations, cases often lacked multiple polyps or a notable family history. Sometimes, CRCs developed independently of the germline RNF43 mutation. In case-control analyses, germline RNF43 variants were associated with CRC risk (OR=2.696, p=0.010), but penetrance was much greater for germline mutations in the N-terminal half of the gene. Germline C-terminal mutations conferred no increased CRC risk. However, somatic C-terminal mutations were pathogenic, perhaps because their relatively weak effects are supplemented by accompanying mutations in Wnt genes, including ZNRF3 and a new driver, SFRP4. Conclusion: RNF43 is a CRC predisposition gene, but risks are moderate, the reported polyposis phenotype is often absent and molecular phenocopies can occur. N-terminal germline RNF43 variants confer higher risk, although weak effects of C-terminal variants cannot be excluded. Genetic testing and patient management should incorporate these factors.

Item Type:	Article
Date Type:	Published Online
Status:	In Press
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/, Start Date: 2025-12-24, Type: open-access
Publisher:	BMJ Publishing Group
ISSN:	0017-5749
Date of First Compliant Deposit:	8 January 2026
Date of Acceptance:	2 December 2025
Last Modified:	08 Jan 2026 10:45
URI:	https://orca.cardiff.ac.uk/id/eprint/183711

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