Journal article
Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis
Nature communications, Vol.16(1), 10769
11/28/2025
DOI: 10.1038/s41467-025-65811-y
PMCID: PMC12663176
PMID: 41315260
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.
Details
- Title: Subtitle
- Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis
- Creators
- Alberto Langtry - Spanish National Cancer Research CentreRaul Rabadan - Columbia UniversityLola Alonso - Spanish National Cancer Research CentreIoan Filip - Columbia UniversitySergio Sabroso-Lasa - Centro de Investigación del CáncerAne Moreno-Oya - Centro de Investigación Biomédica en Red de CáncerRita Lawlor - University of VeronaAlfredo Carrato - Centro de Investigación Biomédica en Red de CáncerRafael Alvarez-Gallego - Camilo José Cela UniversityMar Iglesias - Parc de SalutXavier Molero - Vall d'Hebron Hospital UniversitariMatthias J Löhr - Karolinska University HospitalChristoph W Michalski - Technical University of MunichJosé Perea - Institute of Biomedical Research of Salamanca, Salamanca, SpainMichael O'Rorke - University of IowaVictor M Barberà - Hospital General Universitario de ElcheAdonina Tardón - CIBERESP, Madrid, SpainAntoni Farré - Hospital de Sant PauLuís Muñoz-BellvísTatjana Crnogorac-Jurcevic - Queen Mary University of LondonEnrique Domínguez-Muñoz - Universidade de Santiago de CompostelaThomas M Gress - Universitätsklinikum Gießen und MarburgWilliam Greenhalf - University of LiverpoolLinda Sharp - University College CorkJoaquim Balsells - Vall d'Hebron Hospital UniversitariEithne Costello - University of LiverpoolJörg Kleeff - Technical University of MunichBo Kong - Heidelberg UniversityJosefina Mora - Hospital de Sant PauDamian O'Driscoll - University College CorkAldo Scarpa - University of VeronaWeimin Ye - Karolinska InstitutetFrancisco X Real - Spanish National Cancer Research CentreEvangelina López de Maturana - Centro de Investigación Biomédica en Red de CáncerNúria Malats - Spanish National Cancer Research CentrePaulina Gómez-Rubio - Centro de Investigación del CáncerEsther Molina-Montes - Spanish National Cancer Research CentreMirari Márquez - Spanish National Cancer Research CentreRoger Milne - Spanish National Cancer Research CentreAna Alfaro - Spanish National Cancer Research CentreTania Lobato - Spanish National Cancer Research CentreLidia Estudillo - Spanish National Cancer Research CentreStefania Beghelli - University of VeronaAntonio Cubillo - Camilo José Cela UniversityManuel Hidalgo - Camilo José Cela UniversityPaloma Peinado - Camilo José Cela UniversityIsabel Salas - Camilo José Cela UniversityJesús Rodríguez Pascual - Camilo José Cela UniversityJulie Earl - Centro de Investigación Biomédica en Red de CáncerAlejandra Caminoa - Centro de Investigación Biomédica en Red de CáncerCarmen Guillén-Ponce - Centro de Investigación Biomédica en Red de CáncerMercedes Rodríguez-Garrote - Centro de Investigación Biomédica en Red de CáncerFederico Longo-Muñoz - Instituto Ramón y Cajal de Investigación SanitariaReyes Ferreiro - Instituto Ramón y Cajal de Investigación SanitariaVanessa Pachón - Instituto Ramón y Cajal de Investigación SanitariaM Ángeles Vaz - Instituto Ramón y Cajal de Investigación SanitariaMaría Muñoz - Centro de Investigación Biomédica en Red de CáncerLucas Ilzarbe - Parc de SalutCristina Álvarez-Urturi - Parc de SalutXavier Bessa - Parc de SalutFelipe Bory - Parc de SalutLucía Márquez - Parc de SalutIgnasi Poves - Parc de SalutFernando Burdío - Parc de SalutLuis Grande - Parc de SalutJavier Gimeno - Parc de SalutLuisa Guarner - Vall d'Hebron Hospital UniversitariMayte Salcedo - Vall d'Hebron Hospital UniversitariXavier Merino - Vall d'Hebron Hospital UniversitariIrene Esposito - Technical University of MunichCarmen Mota - Technical University of MunichJiaqui Huang - Karolinska University HospitalCaroline Verbeke - Karolinska University HospitalCarmelo Loinaz - Research Institute Hospital 12 de OctubreJosé Luis Rodríguez-Peralto - Research Institute Hospital 12 de OctubreAna Teijo - Research Institute Hospital 12 de OctubrePablo Peláez - Research Institute Hospital 12 de OctubreMarta Martín - Hospital de Sant PauPanGenEU Consortium Investigators
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.16(1), 10769
- DOI
- 10.1038/s41467-025-65811-y
- PMID
- 41315260
- PMCID
- PMC12663176
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature; BERLIN
- Grant note
- National Institutes of Health (NIH), USA: R35 CA253126 Stand Up To Cancer (SU2C): SU2C #6179 Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain: PI061614, PI11/01542, PI0902102, PI12/01635, PI12/00815, PI15/01573, PI18/01347, PI21/00495 Ministerio de Ciencia, Innovacion y Universidades, Spain: RTI2018-101071-B-I00, PID2021-128125OB-I00 Red Tematica de Investigacion Cooperativa en Cancer (RTICC), Spain: RD12/0036/0034, RD12/0036/0050, RD12/0036/0073 Fundacion Cientifica de la AECC (Asociacion Espanola Contra el Cancer), SpainCOST (European Cooperation in Science and Technology)EU 6th Framework Programme (EU-6FP): #018771 EU FP7 HEALTH Programme (EU-FP7-HEALTH): #259737, #256974 Associazione Italiana Ricerca sul Cancro (AIRC), Italy: #12182 Cancer Focus Northern Ireland and Department for Employment and LearningALF (Sweden): #SLL20130022 Pancreatic Cancer Collective (PCC) - Lustgarten Foundation & Stand Up To Cancer (USA): #6179 UK Biobank: 47884 TCGA Research Network
The authors are thankful to the patients, coordinators, field and administrative workers, and technicians of the European Study into Digestive Illnesses and Genetics (PanGenEU) study. We also thank Guillermo Pita and Anna Gonzalez-Neira, from CEGEN-CNIO, and Joe Dennis and Laura Fachal, from the University of Cambridge, for genotyping PanGenEU samples, performing variant calling and SNP imputation, and editing data. This research has been conducted using the UK Biobank Resource under Application Number 47884. RR gratefully acknowledge funding from NIH (R35 CA253126.) and SU2C Convergence 3.14. This research has been conducted using the UK Biobank Resource under Application Number 47884. The results here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. The work was partially supported by Fondo de Investigaciones Sanitarias (FIS), Instituto de Salud Carlos III, Spain (#PI061614, #PI11/01542, #PI0902102, #PI12/01635, #PI12/00815, #PI15/01573, #PI18/01347, #PI21/00495); Ministerio de Ciencia, Innovacion y Universidades, Madrid, Spain (#RTI2018-101071-B-I00 and #PID2021-128125OB-I00); Red Tematica de Investigacion Cooperativa en Cancer, Spain (#RD12/0036/0034, #RD12/0036/0050, #RD12/0036/0073); Fundacion Cientifica de la AECC, Spain; European Cooperation in Science and Technology-COST Action #BM1204: EUPancreas. EU-6FP Integrated Project (#018771-MOLDIAG-PACA), EU-FP7-HEALTH (#259737-CANCERALIA, #256974-EPC-TM-Net); Associazione Italiana Ricerca sul Cancro (#12182); Cancer Focus Northern Ireland and Department for Employment and Learning; and ALF (#SLL20130022), Sweden; Pancreatic Cancer Collective (PCC): Lustgarten Foundation & Stand-Up to Cancer, USA (SU2C #6179).
- Language
- English
- Date published
- 11/28/2025
- Academic Unit
- Epidemiology; Pathology
- Record Identifier
- 9985035030602771
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