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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© The Author(s) 2025.Pancreatic ductal adenocarcinoma (PDAC) genetic susceptibility is partially identified. The complement system (CS) influences carcinogenesis and participates in immunological defense and homeostasis; however, its role in PDAC genetic susceptibility and prognosis is underexplored. The association of SNPs within 111 CS-related genes with PDAC risk is assessed in the PanGenEU study and validated in the UKBiobank. We investigate the association between the CS-related gene variation and PDAC risk, followed by an in-depth functional in silico study using TCGA and ICGC data. We assess whether CS-related genes are associated with prognosis at the germline and somatic levels. We investigate the immune infiltration of PDAC tumors according to their transcriptomic profile. Genetic variation in FCN1 and PLAT is significantly associated with PDAC risk. PDAC patients with elevated expression of IGHG3, IGKC, IGHM, F2R, F2RL2, CFI, A2M, or C4A display improved survival and higher infiltration of CD8+, B cells, and Th1 cells. Individuals with high expression levels of either FGA, SERPINE1, FGG, or F3 exhibit poorer survival, higher infiltration of Tregs, and lower infiltration of CD8+ cells. Results from this study suggest that CS-related genes play a role in PDAC genetic susceptibility and survival through specific immune cell infiltration.
Author(s): Langtry A, Rabadan R, Alonso L, Filip I, Lawlor R, Carrato A, Alvarez-Gallego R, Iglesias M, Molero X, Lohr MJ, Michalski CW, Perea J, Barbera VM, Tardon A, Farre A, Munoz-Bellvis L, Crnogorac-Jurcevic T, Dominguez-Munoz E, Gress TM, Greenhalf W, Sharp L, Balsells J, Costello E, Kleeff J, Kong B, Mora J, O'Driscoll D, Scarpa A, Ye W, Real FX, Lopez de Maturana E, Malats N, Alonso L, Sabroso-Lasa S, Sabroso-Lasa S, Moreno-Oya A, Moreno-Oya A, Gomez-Rubio P, Molina-Montes E, Marquez M, Milne R, Alfaro A, Lobato T, Estudillo L, Real FX, Malats N, Scarpa A, Beghelli S, Cubillo A, Hidalgo M, Peinado P, Salas I, Rodriguez Pascual J, Earl J, Caminoa A, Guillen-Ponce C, Rodriguez-Garrote M, Longo-Munoz F, Ferreiro R, Pachon V, Vaz MA, Munoz M, Ilzarbe L, Alvarez-Urturi C, Bessa X, Bory F, Marquez L, Poves I, Burdio F, Grande L, Gimeno J, Guarner L, Balcells J, Salcedo M, Merino X, Esposito I, Kleeff J, Kong B, Mota C, Lohr MJ, Huang J, Verbeke C, Ye W, Yu J, Loinaz C, Perea J, Rodriguez-Peralto JL, Teijo A, Pelaez P, Martin M, Artigas V, Guarner C, Sancho FJ, Concepcion M, Ramon y Cajal T, Szafranska J, O'Rorke M, O'Rorke M, Murray L, Cantwell M, Gallego J, Tardon A, Barneo L, Rodriguez-Suarez MM, Pazos Y, Lozano A, Luaces M, Blanco-Antona F, Sayagues Manzano JM, Gutierrez Troncoso ML, Orfao de Matos A, Munoz-Bellvis L, Gress TM, Buchholz M, Neesse A, Costello E, Kocher HM, Bhattacharya S, Abraham AT, Ennis D, Dowe T, Radon T
Publication type: Article
Publication status: Published
Journal: Nature Communications
Year: 2025
Volume: 16
Issue: 1
Online publication date: 28/11/2025
Acceptance date: 23/10/2025
Date deposited: 16/12/2025
ISSN (electronic): 2041-1723
Publisher: Nature Research
URL: https://doi.org/10.1038/s41467-025-65811-y
DOI: 10.1038/s41467-025-65811-y
Data Access Statement: No custom code or mathematical algorithms were developed for this study. All analyses were performed using publicly available software and packages, as described in the Methods section. Data availability - see paper https://doi.org/10.1038/s41467-025-65811-y
PubMed id: 41315260
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