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PubMed · 42107534

RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.

Anna Silvia Wenning·Konstantin Bräutigam·Pauline Aeschbacher·Animesh Acharjee·Beat Gloor·Aurel Perren·Eva Karamitopoulou
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Abstract

RNF43 mutations were correlated with microsatellite status in colorectal cancer and with fewer and later recurrences in pancreatic ductal adenocarcinoma (PDAC). Here, we undertake a detailed assessment of RNF43 mutations in PDAC. A total of 313 PDACs (308 microsatellite stable [MSS] and 5 microsatellite-instable [MSI] cases) underwent next-generation sequencing (Oncomine Tumor Mutation Load assay; Thermo Fisher). Spatial analyses (NanoString) classified PDACs according to their transcriptomic and proteomic immune signaling. Fluorescent imaging was used to define spatial compartments (tumor: pancytokeratin+/CD45- and leukocytes: pancytokeratin-/CD45+). Each of 20 PDACs with RNF43 mutations (RNF43mut) and without RNF43 mutations (RNF43wt) underwent multiplex immunofluorescence analysis to determine immune status. A total of 153 PDACs (22 RNF43mut and 131 RNF43wt cases) underwent bulk RNA sequencing to assign into molecular subtypes. Overall, 24 RNF43 mutations were identified (22 MSS PDACs and 2 MSI PDACs). The incidence of RNF43 mutations in MSS PDACs (7.1%) was consistent with The Cancer Genome Atlas (6.7%). However, RNF43 mutations were more frequent among MSI PDACs (40%). Additionally, RNF43mut had differential frequencies of other mutations (including Wnt pathway genes), higher tumor mutational burden values (5.5 mut/mb vs 1.67 mut/mb; P < .01), and significantly longer overall survival (47 vs 18 months; P < .0001) than RNF43wt. Moreover, RNF43mut exhibited significantly higher densities of CD8+ T lymphocytes, dendritic cells, and B lymphocytes (P < .001) and an upregulation of ITGAX, CD11c, CD8, and HLA-DR compared with RNF43wt. Patients with RNF43mut PDACs were more often of the classical molecular subtype (20/22, 90.9%). RNF43mut PDACs showed high tumor mutational burden values, suggesting increased neoantigen load coupled with an abundance of antigen-presenting immune cells and an upregulation of immune determinants promoting antigen presentation. All this contributes to stronger antitumor immune responses and improved clinical outcomes.

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HumansMutationUbiquitin-Protein LigasesPancreatic NeoplasmsMaleFemaleDNA-Binding ProteinsOncogene ProteinsAgedCarcinoma, Pancreatic DuctalMiddle AgedBiomarkers, TumorMicrosatellite InstabilityAged, 80 and overRNF43immune microenvironmentpancreatic cancerproteomicsspatial analysistranscriptomicsJournal ArticleResearch Support, Non-U.S. Gov't

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Anna Silvia Wenning, Konstantin Br&#xe4;utigam, Pauline Aeschbacher, Animesh Acharjee, Beat Gloor, Aurel Perren, Eva Karamitopoulou. 2026-05-08. RNF43 Mutations Are Associated With the Classical Molecular Subtype, Vigorous Antitumor Immune Responses, and Prolonged Survival in Pancreatic Adenocarcinoma.. https://doi.org/10.1016/j.modpat.2026.101010

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