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<p>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&#xa0;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 <i>FCN1</i> and <i>PLAT</i> is significantly associated with PDAC risk. PDAC patients with elevated expression of <i>IGHG3</i>, <i>IGKC</i>, <i>IGHM</i>, <i>F2R</i>, <i>F2RL2</i>, <i>CFI</i>, <i>A2M</i>, or <i>C4A</i> display improved survival and higher infiltration of CD8<sup>+</sup>, B cells, and Th1 cells. Individuals with high expression levels of either <i>FGA</i>, <i>SERPINE1</i>, <i>FGG</i>, or <i>F3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • 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,
  • Alberto Langtry,
  • Lola Alonso,
  • Sergio Sabroso-Lasa,
  • Ane Moreno-Oya,
  • Paulina Gómez-Rubio,
  • Esther Molina-Montes,
  • Mirari Márquez,
  • Roger Milne,
  • Ana Alfaro,
  • Tania Lobato,
  • Lidia Estudillo,
  • Francisco X. Real,
  • Núria Malats,
  • Aldo Scarpa,
  • Rita Lawlor,
  • Stefania Beghelli,
  • Rafael Alvarez-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 Burdío,
  • Luis Grande,
  • Javier Gimeno,
  • Xavier Molero,
  • Luisa Guarner,
  • Joaquín Balcells,
  • Mayte Salcedo,
  • Xavier Merino,
  • Christoph W. Michalski,
  • Irene Esposito,
  • Jörg Kleeff,
  • Bo Kong,
  • Carmen Mota,
  • Matthias J. Löhr,
  • Jiaqui Huang,
  • Caroline Verbeke,
  • Weimin Ye,
  • Jingru Yu,
  • Carmelo Loinaz,
  • José Perea,
  • José Luis Rodríguez-Peralto,
  • Ana Teijo,
  • Pablo Peláez,
  • Antoni Farré,
  • Josefina Mora,
  • Marta Martín,
  • Vicenç Artigas,
  • Carlos Guarner,
  • Francesc J. Sancho,
  • Mar Concepción,
  • Teresa Ramón y Cajal,
  • Justyna Szafranska,
  • Michael O’Rorke,
  • Liam Murray,
  • Marie Cantwell,
  • Victor M. Barberà,
  • Javier Gallego,
  • Adonina Tardón,
  • Luis Barneo,
  • MM Rodriguez-Suarez,
  • Enrique Domínguez-Muñoz,
  • Yolanda Pazos,
  • Antonio Lozano,
  • Maria Luaces,
  • Francisco Blanco-Antona,
  • J. M. Sayagués Manzano,
  • M. L. Gutiérrez Troncoso,
  • A. Orfao de Matos,
  • Luís Muñoz-Bellvís,
  • Thomas M. Gress,
  • Malte Buchholz,
  • Albrecht Neesse,
  • William Greenhalf,
  • Eithne Costello,
  • Tatjana Crnogorac-Jurcevic,
  • Hemant M. Kocher,
  • Satyajit Bhattacharya,
  • Ajit T. Abraham,
  • Darren Ennis,
  • Thomas Dowe,
  • Tomasz Radon,
  • Damian O’Driscoll,
  • Linda Sharp

摘要

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.