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

Journal article

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.

Authors: Palles, C; Freeman-Mills, L; Arbe-Barnes, E; Feeley, N; Chegwidden, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: BMJ Publishing Group
• Journal: Gut
• Pages: gutjnl-2025
• Article number: gutjnl-2025-337030
• Publication date: 2025-12-24
• Acceptance date: 2025-12-02
• DOI: 10.1136/gutjnl-2025-337030
• EISSN: 1468-3288
• ISSN: 0017-5749
• Language: English
• Keywords: COLORECTAL CARCINOMA; COLORECTAL ADENOMAS; COLONIC POLYPS; GENETICS; INHERITED CANCERS