Correlations of PD-1/PD-L1 Gene Polymorphisms with Susceptibility and Prognosis in Non-Hodgkinʼs Lymphoma among Iranian Populatio

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Non-Hodgkinʼs lymphoma (NHL)
Programmed death 1 (PD-1)
Programmed death ligand-1 (PD-L1)
Single-nucleotide polymorphisms (SNPs)

How to Cite

hoseini, hosnie, YaghmaeiP., BahariG., & AminzadehS. (2020). Correlations of PD-1/PD-L1 Gene Polymorphisms with Susceptibility and Prognosis in Non-Hodgkinʼs Lymphoma among Iranian Populatio. Iranian Red Crescent Medical Journal, 22(11).


Background: The activities of programmed cell death 1 (PD-1) and programmed death ligand-1 (PD-L1) have already been identified in various cancers. However, in non-Hodgkinʼs lymphoma (NHL), the prognostic value of PD-1/PD-L1 gene polymorphisms and expression levels remains unclear.

Objectives: The present study aimed to investigate the relationship between the genetic polymorphisms of PD-1/PD-L1 genes and NHL in the Iranian population.

Methods: Four single-nucleotide polymorphisms (SNPs) of PD-1/PD-L1 genes were examined in 134 NHL patients and 134 healthy controls using polymerase chain reaction-restriction fragment length polymorphism. The expression levels of PD-1/PD-L1 genes were analyzed using real-time polymerase chain reaction.

Results: The obtained results of the current study demonstrated that PD-L1 rs2890685 (A>C) SNP (P<0.0001) was significantly associated with the increased risk of NHL. The AA genotype of PD-L1 rs2890685 polymorphism was observed to be more prevalent in the NHL patients, compared to that reported for the healthy controls. There was no significant association between PD-L1 rs4143815, PD-1 rs11568821, and PD-1rs2227981 SNPs with the risk of NHL. Furthermore, the obtained findings showed that the messenger ribonucleic acid transcription levels of both PD-1 and PD-L1 were significantly higher in the NHL patients than those reported for the healthy controls (P<0.001).

Conclusion: According to the results of the current study, there was an association between functional PD-L1 rs2890685 polymorphism and risk of NHL, suggesting that the genetic variant of PD-L1 might be a possible prognostic marker for the prediction of the risk and development of NHL.


  1. Mahase E. Cancer overtakes CVD to become leading cause of death in high income countries. BMJ. 2019;366:I5368. doi: 10.1136/bmj.l5368. [PubMed: 31481521].
  2. Salmaninejad A, Valilou SF, Shabgah AG, Aslani S, Alimardani M, Pasdar A, et al. PD‐1/PD‐L1 pathway: Basic biology and role in cancer immunotherapy. J Cell Physiol. 2019;234(10):16824-37. doi: 10.1002/jcp.28358. [PubMed: 30784085].
  3. Li Y, Li F, Jiang F, Lv X, Zhang R, Lu A, et al. A mini-review for cancer immunotherapy: molecular understanding of PD-1/PD-L1 pathway & translational blockade of immune checkpoints. Intjmolsci. 2016;17(7):1151. doi: 10.3390/ijms17071151. [PubMed: 27438833].
  4. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl j med. 2016;375(18):1767-78. doi: 10.1056/NEJMra1514296. [PumMed: 27806234].
  5. Davis AA, Patel VG. The role of PD-L1 expression as a predictive biomarker: an analysis of all US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors. J Immunother Cancer. 2019;7(1):278. doi: 10.1186/s40425-019-0768-9. [PubMed: 31655605].
  6. Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA. Structural biology of the immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure. 2017;25(8):1163-74. doi: 10.1016/j.str.2017.06.011. [PubMed: 28768162].
  7. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10. doi: 10.1186/s12943-018-0928-4. [PubMed: 30646912].
  8. Chacon-Cortes D, Griffiths LR. Methods for extracting genomic DNA from whole blood samples: current perspectives. J Bioreposit Sci Appl Med. 2014;2014(2):1-9.
  9. Kong EK, Prokunina‐Olsson L, Wong WH, Lau CS, Chan TM, Alarcón‐Riquelme M, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese. Arthritis Rheum. 2005;52(4):1058-62. doi: 10.1002/art.20966. [PubMed: 15818672].
  10. Lee SH, Lee YA, Woo DH, Song R, Park EK, Ryu MH , et al. Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population. Arthritis Res Ther. 2006;8(6):R163. doi: 10.1186/ar2071. [PubMed: 17064404].
  11. Prokunina L, Castillejo-López C, Öberg F, Gunnarsson I, Berg L, Magnusson V, et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat Genet. 2002;32(4):666-9. doi: 10.1038/ng1020. [PubMed: 12402038].
  12. Zou W, Wolchok JD, Chen L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med. 2016;8(328):328rv4-rv4. doi: 10.1126/scitranslmed.aad7118. [PubMed: 26936508].
  13. Zhou RM, Li Y, Liu JH, Wang N, Huang X, Cao SR, et al. Programmed death-1 ligand-1 gene rs2890658 polymorphism associated with the risk of esophageal squamous cell carcinoma in smokers. Cancer Biomark. 2017;21(1):65-71. doi: 10.3233/CBM-170269. [PubMed: 29060926].
  14. Hashemi M, Karami S, Sarabandi S, Moazeni-Roodi A, Małecki A, Ghavami S, et al. Association between PD-1 and PD-L1 Polymorphisms and the Risk of Cancer: A Meta-Analysis of Case-Control Studies. Cancers (Basel). 2019;11(8):1150. doi: 10.3390/cancers11081150. [PubMed: 31405171].
  15. Salmaninejad A, Khoramshahi V, Azani A, Soltaninejad E, Aslani S, Zamani MR, et al. PD-1 and cancer: molecular mechanisms and polymorphisms. Immunogenetics. 2018;70(2):73-86. doi: 10.1007/s00251-017-1015-5. [PubMed: 28642997].
  16. Yin L, Guo H, Zhao L, Wang J. The programmed death-1 gene polymorphism (PD-1.5 C/T) is associated with non-small cell lung cancer risk in a Chinese Han population. Int J Clin Exp Med. 2014;7(12):5832-6. [PubMed: 25664115].
  17. Dong W, Gong M, Shi Z, Xiao J, Zhang J, Peng J. Programmed cell death-1 polymorphisms decrease the cancer risk: a meta-analysis involving twelve case-control studies. PloS one. 2016;11(3):e0152448. doi: 10.1371/journal.pone.0152448. [PubMed: 27031235].
  18. Wang W, Li F, Mao Y, Zhou H, Sun J, Li R, et al. A miR-570 binding site polymorphism in the B7-H1 gene is associated with the risk of gastric adenocarcinoma. Hum Genet. 2013;132(6):641-8. doi: 10.1007/s00439-013-1275-6. [PubMed: 23430453].
  19. Shi XL, Mancham S, Hansen BE, de Knegt RJ, de Jonge J, van der Laan LJ, et al. Counter-regulation of rejection activity against human liver grafts by donor PD-L1 and recipient PD-1 interaction. J Hepatol. 2016;64(6):1274-82. doi: 10.1016/j.jhep.2016.02.034. [PubMed: 26941095].
  20. Pizarro C, García‐Díaz DF, Codner E, Salas‐Pérez F, Carrasco E, Pérez‐Bravo F. PD‐L1 gene polymorphisms and low serum level of PD‐L1 protein are associated to type 1 diabetes in Chile. DiabetesMetab Res Rev. 2014;30(8):761-6. doi: 10.1002/dmrr.2552. [PubMed: 24816853].
  21. Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-Approved immune checkpoint inhibitors per nccn guidelines with the level of evidence. Cancers (Basel). 2020;12(3):738. doi: 10.3390/cancers12030738. [PubMed: 32245016].
  22. Nomizo T, Ozasa H, Tsuji T, Funazo T, Yasuda Y, Yoshida H, et al. clinical impact of single nucleotide polymorphism in Pd-L1 on response to nivolumab for advanced non-small-cell lung cancer patients. Sci Rep. 2017;7(1):45124. doi: 10.1038/srep45124. [PubMed: 28332580].
  23. Wu X, Gu Z, Chen Y, Chen B, Chen W, Weng L, et al. Application of PD-1 blockade in cancer immunotherapy. Comput Struct Biotechnol J. 2019;17:661-74. doi: 10.1016/j.csbj.2019.03.006. [PubMed: 31205619].
  24. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2007;56(8):1173-82. doi: 10.1007/s00262-006-0266-z. [PubMed: 17186290].
  25. Gevensleben H, Dietrich D, Golletz C, Steiner S, Jung M, Thiesler T, et al. The immune checkpoint regulator pd-l1 is highly expressed in aggressive primary prostate cancer. Clin Cancer Res. 2016;22(8):1969-77. doi: 10.1158/1078-0432.CCR-15-2042. [PubMed: 26573597].
  26. Chen BJ, Dashnamoorthy R, Galera P, Makarenko V, Chang H, Ghosh S, et al. The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma. Oncotarget. 2019;10(21):2030-40. doi: 10.18632/oncotarget.26771. [PubMed: 31007846].
  27. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed death ligand 1 is expressed by non–hodgkin lymphomas and inhibits the activity of tumor-associated T cells. Clin Cancer Res. 2011;17(13):4232-44. doi: 10.1158/1078-0432.CCR-10-2660. [PubMed: 21540239].