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
Year: 2025
Type: article
Study design: Observational Study
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 RNF43 mutations 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.
Source: Gut
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, Viktor Hendrik Koelzer, Lai Mun Wang, Roland Arnold, James Edward East, Ian Tomlinson
Institutions: National Institute for Health and Care Research, NIHR Birmingham Biomedical Research Centre, University of Birmingham, Centre for Human Genetics, University of Oxford, University of Edinburgh, Cardiff University, The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, University of Basel, University Hospital of Basel, Changi General Hospital
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Funders: Institute for Research in Biomedicine, Queen Mary University of London, Wellcome Trust, Bowel Cancer UK, Barcelona Institute of Science and Technology, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University College London, University of Oxford, University of Leeds, University of Birmingham, Institució Catalana de Recerca i Estudis Avançats, Oxford University Hospitals NHS Foundation Trust, Centro de Investigación Biomédica en Red de Cáncer, University of California, San Diego, Medical Research Council, NIHR Oxford Biomedical Research Centre, Birmingham Biomedical Research Centre, Institute of Genetics
Awards: G1333614858, Explaining and exploiting the spectrum of isocitrate dehydrogenase driver mutations in different tumour types, G307466776, G3526978472, G439089712, G6352856463, G7864415776, MICA: Stratification in COloRectal cancer: from biology to Treatment prediction: S-CORT, Explaining and exploiting the spectrum of isocitrate dehydrogenase driver mutations in different tumour types
OpenAlex ID: W7117107133