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Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis

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...

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Main Authors: Langtry, Alberto (Author) , Rabadan, Raul (Author) , Alonso, Lola (Author) , Filip, Ioan (Author) , Sabroso-Lasa, Sergio (Author) , Moreno-Oya, Ane (Author) , Lawlor, Rita (Author) , Carrato, Alfredo (Author) , Alvarez-Gallego, Rafael (Author) , Iglesias, Mar (Author) , Molero, Xavier (Author) , Löhr, Matthias J. (Author) , Michalski, Christoph (Author) , Perea, José (Author) , O’Rorke, Michael (Author) , Barberà, Victor M. (Author) , Tardón, Adonina (Author) , Farré, Antoni (Author) , Muñoz-Bellvís, Luís (Author) , Crnogorac-Jurcevic, Tatjana (Author) , Domínguez-Muñoz, Enrique (Author) , Gress, Thomas M. (Author) , Greenhalf, William (Author) , Sharp, Linda (Author) , Balsells, Joaquim (Author) , Costello, Eithne (Author) , Kleeff, Jörg (Author) , Kong, Bo (Author) , Mora, Josefina (Author) , O’Driscoll, Damian (Author) , Scarpa, Aldo (Author) , Ye, Weimin (Author) , Real, Francisco X. (Author) , López de Maturana, Evangelina (Author) , Malats, Núria (Author)
Format: Article (Journal)
Language:English
Published: 28 November 2025
In: Nature Communications
Year: 2025, Volume: 16, Pages: 1-12
ISSN:2041-1723
DOI:10.1038/s41467-025-65811-y
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-025-65811-y
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-025-65811-y
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Author Notes:Alberto Langtry, Raul Rabadan, Lola Alonso, Ioan Filip, Sergio Sabroso-Lasa, Ane Moreno-Oya, Rita Lawlor, Alfredo Carrato, Rafael Alvarez-Gallego, Mar Iglesias, Xavier Molero, Matthias J. Löhr, Christoph W. Michalski, José Perea, Michael O’Rorke, Victor M. Barberà, Adonina Tardón, Antoni Farré, Luís Muñoz-Bellvís, Tatjana Crnogorac-Jurcevic, Enrique Domínguez-Muñoz, Thomas M. Gress, William Greenhalf, Linda Sharp, Joaquim Balsells, Eithne Costello, Jörg Kleeff, Bo Kong, Josefina Mora, Damian O’Driscoll, Aldo Scarpa, Weimin Ye, Francisco X. Real, Evangelina López de Maturana, Núria Malats, on behalf of the PanGenEU Consortium Investigators
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Summary: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.
Item Description:Online veröffentlicht: 28. November 2025
Gesehen am 04.03.2026
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-025-65811-y

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