Deciphering the Role of Complement System Genes in Pancreatic Cancer Susceptibility and Prognosis

  1. A Langtry
  2. R Rabadan
  3. L Alonso
  4. I Filip
  5. S Sabroso
  6. A Moreno-Oya
  7. R Lawlor
  8. A Carrato
  9. R Alvarez-Gallego
  10. M Iglesias
  11. X Molero
  12. MJ Löhr
  13. CW Michalski
  14. J Perea
  15. M O’Rorke
  16. VM BarberĂ 
  17. A TardĂłn
  18. A Farré
  19. L Muñoz-Bellvís
  20. T Crnogorac-Jurcevic
  21. E Domínguez-Muñoz
  22. T Gress
  23. W Greenhalf
  24. L Sharp
  25. J Balsells
  26. E Costello
  27. J Kleeff
  28. B Kong
  29. J Mora
  30. D O’Driscoll
  31. A Scarpa
  32. W Ye
  33. FX Real
  34. E LĂłpez de Maturana
  35. N Malats
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Abstract

Background & Aims

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.

Methods

The association of SNPs within 111 CS-related genes with PDAC risk was assessed in the PanGenEU study and validated in the UKBiobank. We investigated the association between the CS-related gene variation and PDAC risk, followed by an in-depth functionalin-silicostudy using TCGA and ICGC data. We assessed whether CS-related genes were associated with prognosis at germline and somatic levels. We investigated the immune infiltration of PDAC tumors according to their transcriptomic profile.

Results

Genetic variation inFCN1andPLATwas significantly associated with PDAC risk. PDAC patients with elevated expression ofIGHG3,IGKC,IGHM,F2R,F2RL2,CFI,A2M, andC4Adisplayed improved survival and higher infiltration of CD8+, B cells, and Th1 cells. Individuals with high expression levels ofFGA,SERPINE1,FGG, andF3had poorer survival, higher infiltration of Tregs, and lower infiltration of CD8+ cells.

Conclusions

Results from this study suggest that CS-related genes play a role in PDAC genetic susceptibility and survival through specific immune cell infiltration.

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