Deciphering the role of complement system genes in pancreatic cancer susceptibility and prognosis.
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Langtry Alberto, Rabadan Raul, Alonso Lola, Filip Ioan, Sabroso-Lasa Sergio, Moreno-Oya Ane, Lawlor Rita, Carrato Alfredo, Alvarez-Gallego Rafael, Iglesias Mar, Molero Xavier, Löhr Matthias J, Michalski Christoph W, Perea José, O'Rorke Michael, Barberà Victor M, Tardón Adonina, Farré Antoni, Muñoz-Bellvís Luís, Crnogorac-Jurcevic Tatjana, Domínguez-Muñoz Enrique, Gress Thomas M, Greenhalf William, Sharp Linda, Balsells Joaquim, Costello Eithne, Kleeff Jörg, Kong Bo, Mora Josefina, O'Driscoll Damian, Scarpa Aldo, Ye Weimin, Real Francisco X, López de Maturana Evangelina, Malats Núria, PanGenEU Consortium Investigators
Аннотация
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.