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

作者：Alberto Langtry, Raúl Rabadán, Lola Alonso, Ioan Filip, Sergio Sabroso‐Lasa, Ane Moreno-Oya, Rita Lawlor, Alfredo Carrato, Rafael Álvarez-Gallego, Mar Iglesias, Xavier Molero, Matthias J. Löhr, Christoph W. Michalski, José Perea, Michael A. O’Rorke, Víctor Manuel Barberá, Adonina Tardón, Antoni Farré, Luis Muñoz‐Bellvís, Tatjana Crnogorac‐Jurcevic, J. Enrique Domínguez‐Muñoz, Thomas Mathias Gress, William Greenhalf, Linda Sharp, J. Balsells, Eithne Costello, Jorg H. Kleeff, Bo Kong, Josefina Móra, Damian O’Driscoll, Aldo Scarpa, Weimin Ye, Francisco X. Real, Evangelina López de Maturana, Núria Malats, Alberto Langtry, Lola Alonso, Sergio Sabroso-Lasa, Ane Moreno-Oya, Paulina Gómez-Rubio, Esther Molina‐Montes, Mirari Márquez, Roger Laughlin Milne, Ana Alfaro, Tania Lobato, Lidia Estudillo, Francisco X. Real, Núria Malats, Aldo Scarpa, Rita Lawlor, Stefania Beghelli, Rafael Álvarez-Gallego, Antonio Cubillo, Manuel Hidalgo, Paloma Peinado, Isabel Salas, Jesús Rodríguez-Pascual, Alfredo Carrato, Julie Earl, Alejandra Caminoa, Carmen Guillén‐Ponce, Mercedes Rodríguez-Garrote, Federico Longo-Muñoz, Reyes Ferreiro, Vanessa Pachón, M. Ángeles Vaz, María Muñoz, Mar Iglesias, Lucas Ilzarbe, Cristina Álvarez–Urturi, Xavier Bessa, Felipe Bory, Lucía Márquez, Ignasi Poves, Fernando Burdı́o, Luís Grande, Javier Gimeno, Xavier Molero, Luisa Guarner, Joaquín Balcells, Mayte Salcedo, Xavier Merino, Christoph W. Michalski, Iréne Esposito, Jorg H. Kleeff, Bo Kong, Carmen Mota, Matthias J. Löhr, Jiaqui Huang, Caroline Sophie Verbeke, W Ye, Jingru Yu, Carmelo Loinaz, José Perea, José Luis Rodríguez‐­Peralto, Ana Teijo, Pablo Peláez, Antoni Farré, Josefina Móra, Marta Martín, Vicenç Artigas, Carlos Guarner, Francesc Josep Sancho, Mar Concepción, Teresa Ramón y Cajal, Justyna Szafranska, Michael O’Rorke, Liam Murray, Marie M. Cantwell, Víctor Manuel Barberá, Javier Gallego-Plazas, Adonina Tardón, Luis Barneo, MM Rodriguez-Suarez, J. Enrique Domínguez‐Muñoz, Yolanda Pazos, Antonio Lozano, María Luaces, Francisco Blanco Antona, J.M. Sayagués - Manzano, Miguel Troncoso, Alberto Orfao de Matos, Luis Muñoz‐Bellvís, Thomas Mathias Gress, Malte Buchholz, Albrecht Neeße, William Greenhalf, Eithne Costello, Tatjana Crnogorac‐Jurcevic, Hemant Mahendrakumar Kocher, Satyajit Bhattacharya, Ajit Abraham, Darren P. Ennis, Thomas W. Dowe, Tomasz P. Radon, Damian O’Driscoll, Linda A. Sharp · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-65811-y · 被引用次数：4 · 研究领域：Complement system in diseases、Retinal Diseases and Treatments、Glycosylation and Glycoproteins Research

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. The role of the complement system (CS) - part of the immune system - in pancreatic ductal adenocarcinoma (PDAC) remains underexplored. Here, the authors ...