{
  "abstract": "Background The tumor suppressor RNF43 is frequently mutated in colitis-associated cancer (CAC), yet the functional consequences of these mutations in intestinal inflammation and inflammation-driven tumorigenesis remain unclear. This study aimed to determine the prevalence of RNF43 mutations across stages of ulcerative colitis progression and to define their role in intestinal inflammation and colitis-associated carcinogenesis.Methods RNF43 mutations were analyzed in precancerous lesions and tumor samples from a human cohort spanning multiple stages of ulcerative colitis and CAC development. To investigate functional consequences, mice harboring loss-of-function mutations in Rnf43 were generated and assessed for spontaneous intestinal inflammation and tumor formation. Inflammatory tumorigenesis was further evaluated using Citrobacter rodentium–induced colitis. Intestinal barrier integrity, pathogen control, goblet cell homeostasis, microbiota composition, and mucosal immune responses were analyzed.Results RNF43 mutations were identified in 12.9% of precancerous lesions from patients progressing toward ulcerative colitis and in 24.4% of CAC patients. In mice, loss-of-function mutations in Rnf43 caused spontaneous intestinal inflammation with lesions resembling human ulcerative colitis, progressing to invasive carcinomas. Under Citrobacter rodentium–induced inflammatory conditions, Rnf43 mutant mice developed invasive colorectal carcinomas more rapidly due to exacerbated and persistent inflammation associated with impaired epithelial barrier integrity and defective pathogen control. Rnf43 mutations disrupted goblet cell homeostasis in a cell-intrinsic manner and induced significant alterations in microbiota composition, characterized by increased pro-tumorigenic and pro-inflammatory bacterial species. This dysbiosis promoted epithelial damage and spontaneous mucosal inflammation, accompanied by TGF-β–activating dendritic cells and pro-inflammatory T cell populations producing IL-17, IL-22, and TNF-α.Conclusions RNF43 mutations confer susceptibility to ulcerative colitis-like pathology and drive inflammation-associated tumorigenesis. These findings establish RNF43 as a bona fide driver of colitis-associated cancer and highlight its role in regulating epithelial integrity, microbial homeostasis, and mucosal immune responses.",
  "authors": [
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Markus Gerhard"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Raquel Mejías Luque"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Alisa Dietl"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Anna Ralser"
    },
    {
      "affiliations": [
        "Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Germany"
      ],
      "name": "Theresa Dregelies"
    },
    {
      "affiliations": [
        "Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Germany"
      ],
      "name": "William Sterlacci"
    },
    {
      "affiliations": [
        "Institute of Statistics, Ludwig Maximilian University of Munich, Germany"
      ],
      "name": "Mara Stadler"
    },
    {
      "affiliations": [
        "Institute of Statistics, Ludwig Maximilian University of Munich, Germany"
      ],
      "name": "Roberto Olayo-Alarcon"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Alexandra Bauche"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Martin Skerhut"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Tanja Groll"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Katja Steiger"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Rupert Oellinger"
    },
    {
      "affiliations": [
        "Technical University of Munich, Germany"
      ],
      "name": "Roland Rad"
    },
    {
      "affiliations": [
        "Institute of Statistics, Ludwig Maximilian University of Munich, Germany"
      ],
      "name": "Christian Mueller"
    },
    {
      "affiliations": [
        "Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, Germany"
      ],
      "name": "Michael Vieth"
    }
  ],
  "title": "IDDF2026-ABS-0099 RNF43 mutations drive colitis-associated carcinogenesis",
  "uid": "5b90054f-9a00-5028-81a9-676244bcd566"
}