{
  "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.",
  "authors": [
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Birmingham Biomedical Research Centre, UK, National Institute for Health and Care Research, Birmingham, UK"
      ],
      "name": "Claire Palles"
    },
    {
      "affiliations": [
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Luke Freeman-Mills"
    },
    {
      "affiliations": [
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Edward Arbe-Barnes"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Scotland Cancer Centre, University of Edinburgh, Edinburgh, UK",
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Nathalie Feeley"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Laura Chegwidden"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Helen Curley"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Sara Galavotti"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Connor Woolley"
    },
    {
      "affiliations": [
        "School of Medicine, Cardiff University School of Medicine, Cardiff, UK"
      ],
      "name": "Jeremy Cheadle"
    },
    {
      "affiliations": [
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia",
        "Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia"
      ],
      "name": "Dmitri Mouradov"
    },
    {
      "affiliations": [
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia"
      ],
      "name": "Oliver Sieber"
    },
    {
      "affiliations": [
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Silvia Salatino"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Steve Thorn"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Anshita Goel"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Juan Fernandez-Tajes"
    },
    {
      "affiliations": [
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK"
      ],
      "name": "Sulochana Omwenga"
    },
    {
      "affiliations": [
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK"
      ],
      "name": "Sujata Biswas"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Timothy Maughan"
    },
    {
      "affiliations": [
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK",
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK"
      ],
      "name": "Simon J Leedham"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Birmingham Biomedical Research Centre, UK, National Institute for Health and Care Research, Birmingham, UK",
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Scotland Cancer Centre, University of Edinburgh, Edinburgh, UK",
        "Department of Oncology, University of Oxford, Oxford, UK",
        "School of Medicine, Cardiff University School of Medicine, Cardiff, UK",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia",
        "Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK",
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK",
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland",
        "Computational and Translational Pathology Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland",
        "Department of Laboratory Medicine, Changi General Hospital, Singapore",
        "NIHR Oxford Health Biomedical Research Centre, Oxford, UK"
      ],
      "name": "S:CORT Consortium"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Birmingham Biomedical Research Centre, UK, National Institute for Health and Care Research, Birmingham, UK",
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Scotland Cancer Centre, University of Edinburgh, Edinburgh, UK",
        "Department of Oncology, University of Oxford, Oxford, UK",
        "School of Medicine, Cardiff University School of Medicine, Cardiff, UK",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia",
        "Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK",
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK",
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland",
        "Computational and Translational Pathology Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland",
        "Department of Laboratory Medicine, Changi General Hospital, Singapore",
        "NIHR Oxford Health Biomedical Research Centre, Oxford, UK"
      ],
      "name": "UK Colorectal Cancer Genomics Consortium"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Birmingham Biomedical Research Centre, UK, National Institute for Health and Care Research, Birmingham, UK",
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Scotland Cancer Centre, University of Edinburgh, Edinburgh, UK",
        "Department of Oncology, University of Oxford, Oxford, UK",
        "School of Medicine, Cardiff University School of Medicine, Cardiff, UK",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia",
        "Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK",
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK",
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland",
        "Computational and Translational Pathology Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland",
        "Department of Laboratory Medicine, Changi General Hospital, Singapore",
        "NIHR Oxford Health Biomedical Research Centre, Oxford, UK"
      ],
      "name": "CORGI Consortium"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK",
        "Birmingham Biomedical Research Centre, UK, National Institute for Health and Care Research, Birmingham, UK",
        "Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK",
        "Scotland Cancer Centre, University of Edinburgh, Edinburgh, UK",
        "Department of Oncology, University of Oxford, Oxford, UK",
        "School of Medicine, Cardiff University School of Medicine, Cardiff, UK",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia",
        "Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia",
        "Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia",
        "Nuffield Department of Medicine, University of Oxford, Oxford, UK",
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK",
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland",
        "Computational and Translational Pathology Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland",
        "Department of Laboratory Medicine, Changi General Hospital, Singapore",
        "NIHR Oxford Health Biomedical Research Centre, Oxford, UK"
      ],
      "name": "WGS500 Consortium"
    },
    {
      "affiliations": [
        "Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland",
        "Computational and Translational Pathology Group, Department of Biomedical Engineering, University of Basel, Basel, Switzerland"
      ],
      "name": "Viktor Hendrik Koelzer"
    },
    {
      "affiliations": [
        "Department of Laboratory Medicine, Changi General Hospital, Singapore"
      ],
      "name": "Lai Mun Wang"
    },
    {
      "affiliations": [
        "Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK"
      ],
      "name": "Roland Arnold"
    },
    {
      "affiliations": [
        "Translational Gastroenterology Unit, Univerity of Oxford Nuffield Department of Medicine, Oxford, UK",
        "NIHR Oxford Health Biomedical Research Centre, Oxford, UK"
      ],
      "name": "James Edward East"
    },
    {
      "affiliations": [
        "Department of Oncology, University of Oxford, Oxford, UK"
      ],
      "name": "Ian Tomlinson"
    }
  ],
  "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",
  "uid": "9a06dc63-ca32-5eb8-baeb-9961a94d1f85"
}