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

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, Rodriguez-Suarez Mm, 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 and Linda Sharp
Additional contact information
Alberto Langtry: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Raul Rabadan: Columbia University, Department of Systems Biology
Lola Alonso: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Ioan Filip: Columbia University, Department of Systems Biology
Sergio Sabroso-Lasa: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Ane Moreno-Oya: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Rita Lawlor: Department of Diagnostics and Public Health, ARC-Net Center for Applied Research on Cancer
Alfredo Carrato: CIBERONC
Rafael Alvarez-Gallego: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Mar Iglesias: CIBERONC
Xavier Molero: Hospital Vall Hebron, Department of Gastroenterology
Matthias J. Löhr: Karolinska Institutet and University Hospital, Gastrocentrum
Christoph W. Michalski: Technical University of Munich, Department of Surgery
José Perea: Hospital 12 de Octubre, Department of Surgery
Michael O’Rorke: Queen’s University Belfast, Centre for Public Health, Belfast
Victor M. Barberà: General University Hospital of Elche, Molecular Genetics Laboratory
Adonina Tardón: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Department of Medicine
Antoni Farré: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Luís Muñoz-Bellvís: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
Tatjana Crnogorac-Jurcevic: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Enrique Domínguez-Muñoz: University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology
Thomas M. Gress: University Hospital of Giessen and Marburg, Department of Gastroenterology
William Greenhalf: University of Liverpool, Department of Molecular and Clinical Cancer Medicine
Linda Sharp: University College Cork, National Cancer Registry Ireland and HRB Clinical Research Facility
Joaquim Balsells: Hospital Vall Hebron, Department of Surgery
Eithne Costello: University of Liverpool, Department of Molecular and Clinical Cancer Medicine
Jörg Kleeff: Technical University of Munich, Department of Surgery
Bo Kong: Technical University of Munich, Department of Surgery
Josefina Mora: Hospital de la Santa Creu i Sant Pau, Department of Clinical Biochemistry
Damian O’Driscoll: University College Cork, National Cancer Registry Ireland and HRB Clinical Research Facility
Aldo Scarpa: Department of Diagnostics and Public Health, ARC-Net Center for Applied Research on Cancer
Weimin Ye: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
Francisco X. Real: CIBERONC
Evangelina López de Maturana: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Núria Malats: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Alberto Langtry: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Lola Alonso: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Sergio Sabroso-Lasa: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Ane Moreno-Oya: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Paulina Gómez-Rubio: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Esther Molina-Montes: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Mirari Márquez: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Roger Milne: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Ana Alfaro: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Tania Lobato: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Lidia Estudillo: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Francisco X. Real: CIBERONC
Núria Malats: Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group
Aldo Scarpa: Department of Diagnostics and Public Health, ARC-Net Center for Applied Research on Cancer
Rita Lawlor: Department of Diagnostics and Public Health, ARC-Net Center for Applied Research on Cancer
Stefania Beghelli: Department of Diagnostics and Public Health, ARC-Net Center for Applied Research on Cancer
Rafael Alvarez-Gallego: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Antonio Cubillo: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Manuel Hidalgo: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Paloma Peinado: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Isabel Salas: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Jesús Rodríguez Pascual: HM CIOCC Madrid (Centro Integral Oncológico Clara Campal). Hospital Universitario HM Sanchinarro. Instituto de Investigación Sanitaria HM Hospitales
Alfredo Carrato: CIBERONC
Julie Earl: Ramón y Cajal University Hospital, Department of Oncology
Alejandra Caminoa: Ramón y Cajal University Hospital, Department of Oncology
Carmen Guillén-Ponce: Ramón y Cajal University Hospital, Department of Oncology
Mercedes Rodríguez-Garrote: Ramón y Cajal University Hospital, Department of Oncology
Federico Longo-Muñoz: Ramón y Cajal University Hospital, Department of Oncology
Reyes Ferreiro: Ramón y Cajal University Hospital, Department of Oncology
Vanessa Pachón: Ramón y Cajal University Hospital, Department of Oncology
M. Ángeles Vaz: Ramón y Cajal University Hospital, Department of Oncology
María Muñoz: Ramón y Cajal University Hospital, Department of Oncology
Mar Iglesias: CIBERONC
Lucas Ilzarbe: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Cristina Álvarez-Urturi: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Xavier Bessa: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Felipe Bory: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Lucía Márquez: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Ignasi Poves: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Fernando Burdío: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Luis Grande: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Javier Gimeno: Hospital del Mar—Parc de Salut Mar, Department of Pathology
Xavier Molero: Hospital Vall Hebron, Department of Gastroenterology
Luisa Guarner: Hospital Vall Hebron, Department of Gastroenterology
Joaquín Balcells: Hospital Vall Hebron, Department of Gastroenterology
Mayte Salcedo: Hospital Vall Hebron, Department of Gastroenterology
Xavier Merino: Hospital Vall Hebron, Department of Gastroenterology
Christoph W. Michalski: Technical University of Munich, Department of Surgery
Irene Esposito: Technical University of Munich, Department of Surgery
Jörg Kleeff: Technical University of Munich, Department of Surgery
Bo Kong: Technical University of Munich, Department of Surgery
Carmen Mota: Technical University of Munich, Department of Surgery
Matthias J. Löhr: Karolinska Institutet and University Hospital, Gastrocentrum
Jiaqui Huang: Karolinska Institutet and University Hospital, Gastrocentrum
Caroline Verbeke: Karolinska Institutet and University Hospital, Gastrocentrum
Weimin Ye: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
Jingru Yu: Karolinska Institutet, Department of Medical Epidemiology and Biostatistics
Carmelo Loinaz: Hospital 12 de Octubre, Department of Surgery
José Perea: Hospital 12 de Octubre, Department of Surgery
José Luis Rodríguez-Peralto: Hospital 12 de Octubre, Department of Surgery
Ana Teijo: Hospital 12 de Octubre, Department of Surgery
Pablo Peláez: Hospital 12 de Octubre, Department of Surgery
Antoni Farré: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Josefina Mora: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Marta Martín: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Vicenç Artigas: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Carlos Guarner: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Francesc J. Sancho: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Mar Concepción: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Teresa Ramón y Cajal: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Justyna Szafranska: Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology
Michael O’Rorke: Queen’s University Belfast, Centre for Public Health, Belfast
Liam Murray: Queen’s University Belfast, Centre for Public Health, Belfast
Marie Cantwell: Queen’s University Belfast, Centre for Public Health, Belfast
Victor M. Barberà: General University Hospital of Elche, Molecular Genetics Laboratory
Javier Gallego: General University Hospital of Elche, Molecular Genetics Laboratory
Adonina Tardón: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Department of Medicine
Luis Barneo: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Department of Medicine
Rodriguez-Suarez Mm: Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Department of Medicine
Enrique Domínguez-Muñoz: University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology
Yolanda Pazos: University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology
Antonio Lozano: University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology
Maria Luaces: University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology
Francisco Blanco-Antona: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
J. M. Sayagués Manzano: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
M. L. Gutiérrez Troncoso: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
A. Orfao de Matos: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
Luís Muñoz-Bellvís: Salamanca; and CIBERONC, Department of Surgery, Hospital Universitario de Salamanca – IBSAL, Universidad de Salamanca
Thomas M. Gress: University Hospital of Giessen and Marburg, Department of Gastroenterology
Malte Buchholz: University Hospital of Giessen and Marburg, Department of Gastroenterology
Albrecht Neesse: University Hospital of Giessen and Marburg, Department of Gastroenterology
William Greenhalf: University of Liverpool, Department of Molecular and Clinical Cancer Medicine
Eithne Costello: University of Liverpool, Department of Molecular and Clinical Cancer Medicine
Tatjana Crnogorac-Jurcevic: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Hemant M. Kocher: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Satyajit Bhattacharya: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Ajit T. Abraham: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Darren Ennis: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Thomas Dowe: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Tomasz Radon: Queen Mary University of London, Barts Cancer Institute, Centre for Cancer Biomarkers and Biotherapeutics
Damian O’Driscoll: University College Cork, National Cancer Registry Ireland and HRB Clinical Research Facility
Linda Sharp: University College Cork, National Cancer Registry Ireland and HRB Clinical Research Facility

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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+, 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.

Date: 2025
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DOI: 10.1038/s41467-025-65811-y

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