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 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<sup>+</sup>, 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<sup>+</sup> cells. Results from this study suggest that CS-related genes play a role in PDAC genetic susceptibility and survival through specific immune cell infiltration.

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Journal
Nature Communications
Published
2025-11-28
DOI
https://doi.org/10.1038/s41467-025-65811-y
Citations
1
Primary Topic
Complement system in diseases
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article
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Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis

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

Federico Longo-Muñoz, Antonio Cubillo, Paulina Gómez-Rubio, Aldo Scarpa, Damian O’Driscoll, Eithne Costello, Paloma Peinado, Evangelina López de Maturana, Xavier Merino, Jiaqi Huang, Albrecht Neeße, Hemant M. Kocher, Marie M. Cantwell, Sergio Sabroso‐Lasa, Antoni Farré, Carmen Mota, Felipe Bory, Alberto Langtry, Javier Gállego, Tania Lobato, Teresa Ramón y Cajal, Francisco Blanco‐Antona, Antonio Lozano, Esther Molina‐Montes, Caroline S. Verbeke, M. Ángeles Vaz, Luisa Guarner, Yolanda Pazos, Alberto Orfao de Matos, Ana Teijo, Justyna Szafranska, Ignasi Poves, Jörg Kleeff, Lola Alonso, María Luaces, Roger Laughlin Milne, Luis Muñoz‐Bellvís, J. Balsells, Vicenç Artigas, Carmelo Loinaz, Isabel Salas, Malte Buchholz, Mercedes Rodríguez-Garrote, Jesús Rodríguez-Pascual, Lucía Márquez, Carmen Guillén‐Ponce, Fernando Burdı́o, Carlos Guarner, Miguel Troncoso, María Muñoz, Tomasz P. Radon, Lidia Estudillo, Xavier Bessa, Thomas Dowe, Raúl Rabadán, Mirari Márquez, Pablo Peláez, Iréne Esposito, Liam Murray, Luis Barneo, Matthias Löhr, W Ye, Stefania Beghelli, Ana Alfaro, Ajit Abraham, Julie Earl, Reyes Ferreiro, Alfredo Carrato, Alejandra Caminoa, Joan Balcells, Vanessa Pachón, Thomas M. Gress, Víctor Manuel Barberá, J. Enrique Domínguez‐Muñoz, Linda A. Sharp, José Luis Rodríguez‐­Peralto, Darren Ennis, Christoph Michalski, Cristina Álvarez–Urturi, Lucas Ilzarbe, Luís Grande, Jingru Yu, Weimin Ye, Bo Kong, Manuel Hidalgo, Francesc J. Sancho, Mar Iglesias, Satyajit Bhattacharya, Mar Concepción, Marta Martín, Javier Gimeno, J.M. Sayagués - Manzano, Ioan Filip, William Greenhalf, Ane Moreno-Oya, MM Rodriguez-Suarez
article en
1 citations

Abstract

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<sup>+</sup>, 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<sup>+</sup> cells. Results from this study suggest that CS-related genes play a role in PDAC genetic susceptibility and survival through specific immune cell infiltration.

Nature CommunicationsVol. 16(1)
University of Verona (IT), Queen's University Belfast (GB), University of Iowa (US), Karolinska University Hospital (SE), University of Liverpool (GB), Queen Mary University of London (GB), Universitat Pompeu Fabra (ES), Universidad de Salamanca (ES), Universidad de Alcalá (ES), Universidade de Santiago de Compostela (ES), Instituto Cajal (ES), Heidelberg University (DE), Universitätsklinikum Gießen und Marburg (DE), University College Cork (IE), Hospital de Sant Pau (ES), Hospital Universitari Arnau de Vilanova (ES), University Hospital Heidelberg (DE), Karolinska Institutet (SE), Research Institute Hospital 12 de Octubre (ES), Spanish National Cancer Research Centre (ES), Complejo Hospitalario de Salamanca (ES), Centro de Investigación Biomédica en Red (ES), Hospital General Universitario de Elche (ES), National Cancer Registry (IE), HM Hospitales (ES), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Vall d'Hebron Hospital Universitari (ES), Parc de Salut (ES), Instituto de Investigación Biomédica de Salamanca (ES), Hospital Universitario HM Sanchinarro (ES), Centro de Investigación del Cáncer (ES), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Camilo José Cela University (ES), Technical University of Munich (DE), Martin Luther University Halle-Wittenberg (DE), Columbia University (US), Newcastle University (GB)
Openalex Percentile: Top 21%
Complement system in diseases
0.80
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