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
- Author(s)
- Palles, C; Freeman-Mills, L; Arbe-Barnes, E; Feeley, N; Chegwidden, L; Curley, H; Galavotti, S; Woolley, C; Cheadle, J; Mouradov, D; Sieber, O; Salatino, S; Thorn, S; Goel, A; Fernandez-Tajes, J; Omwenga, S; Biswas, S; Maughan, T; Leedham, SJ; Koelzer, VH; Wang, LM; Arnold, R; East, JE; Tomlinson, I;
- Journal Title
- Gut
- Publication Type
- Dec 24
- 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.
- Publisher
- BMJ
- Keywords
- Colonic polyps; Colorectal adenomas; Colorectal carcinoma; Genetics; Inherited cancers
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 41443981
- Publisher's Version
- https://doi.org/10.1136/gutjnl-2025-337030
- Open Access at Publisher's Site
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Creation Date: 2026-01-22 10:03:37
Last Modified: 2026-01-22 10:03:53