| Title: | 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: | Gut |
| Published: | 24 Dec 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41443981/ |
| DOI: | https://doi.org/10.1136/gutjnl-2025-337030 |
Publication 17035
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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.</p>
OBJECTIVE: We assessed germline RNF43 variants in patients more representative of the general population and compared these with somatic RNF43mutations in CRCs.</p>
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.</p>
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.</p>
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.</p>
28 Authors
- Claire Palles
- Luke Freeman-Mills
- Edward Arbe-Barnes
- Nathalie Feeley
- Laura Chegwidden
- Helen Curley
- Sara Galavotti
- Connor Woolley
- Jeremy Cheadle
- Dmitri Mouradov
- Oliver Sieber
- Silvia Salatino
- Steve Thorn
- Anshita Goel
- Juan Fernandez-Tajes
- Sulochana Omwenga
- Sujata Biswas
- Timothy Maughan
- Simon J Leedham
- S:CORT Consortium
- Colorectal Cancer Genomics Consortium
- CORGI Consortium
- WGS500 Consortium
- Viktor Hendrik Koelzer
- Lai Mun Wang
- Roland Arnold
- James Edward East
- Ian Tomlinson
1 Application
| Application ID | Title |
|---|---|
| 86977 | Evaluating germline genetics, environmental exposures and patient characteristics to understand cancer predisposition, cancer survival and response to cancer treatment |
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